Cardiac Mapping

Cardiac Mapping Second Edition Edited by Mohammad Shenasa, MD Attending Physician Department of Cardiovascular Services O'Connor Hospital; Heart and Rhythm Medical Group San Jose, California

Martin Borggrefe, MD Professor of Medicine (Cardiology) Head, Department of Cardiology, Angiology and Pneumology Klinikum Mannheim GmbH Universitatsklinikum Fakultat fur Klinische Medizin Mannheim der Universitat Heidelberg Mannheim, Germany Gunter Breithardt, MD Professor of Medicine (Cardiology) Head, Department of Cardiology and Angiology and Institute of Arteriosclerosis Research Hospital of the Westfalische Wilhelms-Universitat Munster Munster, Germany

Futura, an imprint of Blackwell Publishing

© 2003 by Futura, an imprint of Blackwell Publishing Blackwell Publishing, Inc./Futura Division, 3 West Main Street, Elmsford, New York 10523, USA Blackwell Publishing, Inc., 350 Main Street, Maiden, Massachusetts 02148-5018, USA Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ Blackwell Science Asia Pty Ltd, 550 Swanston Street, Carlton South, Victoria 3053, Australia Blackwell Verlag GmbH, Kurfurstendamm 57, 10707 Berlin, Germany All rights reserved. No part of this publication may be reproduced in any form or by any electronic or mechanical means, including information storage and retrieval systems, without permission in writing from the publisher, except by a reviewer who may quote brief passages in a review. 03 04 05 06 5 4 3 2 1 ISBN: 0-87993-404-2 Library of Congress Cataloging-in-Publication Data Cardiac mapping / edited by Mohammad Shenasa, Martin Borggrefe, Gunter Breithardt.—2nd ed. p. ; cm. Includes bibliographical references and index. ISBN 0-87993-404-2 (alk. paper) 1. Arrhythmia. 2. Electrocardiography. I. Shenasa, Mohammad. II. Borggrefe, Martin. III. Breithardt, Gunter. [DNLM: 1. Electrocardiography. 2. Electrophysiology. 3. Heart Diseases—physiopathology. WG 140 C267 2003] RC685.A65 C287 2003 616.1'28—dc21 2002014632

A catalogue record for this title is available from the British Library Acquisitions: Steven Korn Production: Joanna Levine Typesetter: International Typesetting and Composition, in New Delhi, India Printed and bound by Walsworth Publishing Company, in Marceline, MO USA For further information on Blackwell Publishing, visit our website: www.futuraco.com

This book is dedicated to those who paved the "roads of cardiac mapping" To all who taught us: our mentors, colleagues, students, and patients We also dedicate this book to our wives, children, and parents for their continuous lifetime support and love

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Acknowledgments

We are grateful to our friends and colleagues for their excellent state-of-theart contribution to the second edition of Cardiac Mapping. We deeply appreciate Ms. Maryam Shenasa for her superb assistance during the preparation of this

work. Our special thanks to Joanna Levine for her tireless efforts in editorial assistance, and to Steve Korn and Jacques Strauss of Blackwell Publishing's Futura Division for their support and advice in completing this project.

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Contributors

Maria Alcaraz, MD Chief, Radiology Service, Hospital Santa Cristina, Madrid, Spain

Jacques Billette, MD, PhD Professor of Physiology, Department de Physiologie, Universite de Montreal, Montreal, Quebec, Canada

Maurits Allessie, MD, PhD Professor of Physiology, Head, Department of Physiology, University of Limburg, Maastricht, The Netherlands

Susan M. Blanchard, PhD Professor of Biological and Agricultural Engineering, North Carolina State University, Raleigh, NC

Thabet Al-Sheikh, MD Consulting Electrophysiologist, Cardiology Consultants, Pensacola, FL

Lucas Boersma, MD Department of Physiology, University of Limburg, Maastricht, The Netherlands

Gregory T. Altemose, MD Consulting Electrophysiologist, Mount Carmel Health System, Columbus, OH

Martin Borggrefe, MD Professor of Medicine (Cardiology), Head, Department of Cardiology, Angiology and Pneumology, Klinikum Mannheim GmbH, Universitatsklinikum, Fakultat fur Klinische Medizin Mannheim der Universitat Heidelberg, Mannheim, Germany

Shlomo A. Ben-Haim, MD, DSc Professor of Medicine, Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel Edward J. Berbari, PhD Professor of Electrical Engineering and Medicine, Director of Biomedical Engineering, Biomedical Engineering Program, Indiana University Purdue University Indianapolis, Indianapolis, IN

Gunter Breithardt, MD, FACC, FESC Professor of Medicine (Cardiology), Head, Department of Cardiology and Angiology and Institute of Arteriosclerosis Research, Hospital of the Westfalische Wilhelms-Universitat Miinster, Munster, Germany

Martin Biermann, MD Josep Brugada, MD, PhD Department of Cardiology and AngiAssociate Professor of Medicine, Arrhythmia Section, Cardiovascular ology, Hospital of the Westfalische Wilhelms-UniversitatTMunster,TER, Institute, Hospital Clinic, University Munster, Germany of Barcelona, Barcelona, Spain vII

viii CARDIAC MAPPING Riccardo Cappato, MD Chief, Center of Clinical Arrhythmia and Electrophysiology, Instituto Policlinico San Donato, San Donato Milanese, Milan, Italy

Andre d'Avila, MD Clinical Arrhythmias and Pacemaker Unit, Heart Institute (InCor)— University of Sao Paulo Medical School, Sao Paulo, Brazil

Corrado Carbucicchio, MD Centro Cardiologico Fondazione Monzino IRCCS, Instituto di Cardiologia dell'Universita, Milan, Italy

Jacques M.T. de Bakker, PhD Professor of Experimental Electrophysiology, Department of Experimental Cardiology, University of Amsterdam, Amsterdam, The Netherlands; Department of Cardiology, University of Utrecht, Utrecht, The Netherlands

Rene Cardinal, PhD Professor of Pharmacology, Department of Pharmacology, Universite de Montreal and Research Center, Hopital du Sacre-Coeur de Montreal, Montreal, Quebec, Canada Edward B. Caref, PhD Research Associate, Cardiology Research Program, NY Harbor VA Health Care Center, Brooklyn Campus, Brooklyn, NY Xu Chen, MD Kardiologisk Laboratorium, Department of Medicine, Rigshospitalet Blegdamsvej, Copenhagen, Denmark Kee-Joon Choi, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France

Paolo Delia Bella, MD Centro Cardiologico Fondazione Monzino IRCCS, Instituto di Cardiologia deH'Universita, Milan, Italy Igor R. Efimov, PhD Elmer L. Lindseth Associate Professor of Biomedical Engineering, Case Western Reserve University, Cleveland, OH Nabil El-Sherif, MD Professor of Medicine and Physiology and Director of Cardiac Electrophysiology Program, State University of New York, Downstate Medical Center; Chief, Cardiology Division, NY Harbor VA Health Care Center, Brooklyn Campus, Brooklyn, NY

Jacques Clementy, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France

Sabine Ernst, MD II Medizinische Abteilung, Allg. Krankenhaus St. Georg, Hamburg, Germany

Francisco G. Cosio, MD, FESC, FACC Chief, Cardiology Service, Hospital Universitario de Getafe, Madrid, Spain

Gaetano Fassini, MD Centro Cardiologico Fondazione Monzino IRCCS, Instituto di Cardiologia dell'Universita, Milan, Italy

D. Wyn Davies, MD Consultant Cardiologist, St. Mary's Hospital and Imperial College School of Medicine, London, UK

Vladimir G. Fast, PhD Assistant Professor, Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL

CONTRIBUTORS ix Peter L. Friedman, MD, PhD Associate Professor of Medicine, Harvard Medical School, Boston, MA; Director, Clinical Cardiac Electrophysiology Laboratory, Cape Cod Hospital, Hyannis, MA; Physician, Brigham and Women's Hospital, Boston, MA Paola Galimberti, MD Centro Cardiologico Fondazione Monzino IRCCS, Instituto di Cardiologia dell'Universita, Milan, Italy Hasan Garan, MD Professor of Medicine, Columbia University College of Physicians and Surgeons; Director of Cardiac Electrophysiology, Columbia Presbyterian Medical Center, New York, NY Stephane Garrigue, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Antonio Goicolea, MD, FESC Cardiac Electrophysiology Laboratory, Clinica Nuestra Senora de America, Madrid, Spain Michel Haissaguerre, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Helena Hanninen, MD Division of Cardiology, Department of Medicine, and BioMag Laboratory, Helsinki University Central Hospital, Helsinki, Finland

Gerhard Hindricks, MD University of Leipzig Heart Center, Co-director, Department of Electrophysiology, Leipzig, Germany Meleze Hocini, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Raymond E. Ideker, MD, PhD Jeanne V. Marks Professor of Medicine, Professor of Physiology, Professor of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL Pierre Jais, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Michiel J. Janse, MD Professor of Experimental Cardiology, Editor-in-Chief, Cardiovascular Research, University of Amsterdam, Amsterdam, The Netherlands Robert Johna, MD Department of Cardiology and Angiology and Institute of Arteriosclerosis Research, Hospital of the Westfalische Wilhelms-Universitat Miinster, Miinster, Germany Eric E. Johnson, MD Cardiology, Stern Cardiovascular Center, Memphis, TN Mark E. Josephson, MD Chief, Cardiovascular Division, Beth Israel Deaconess Medical Center; Professor of Medicine, Harvard Medical School, Boston, MA

Wilhelm Haverkamp, MD Department of Cardiology and Angiology and Institute of Arteriosclerosis Research, Hospital of the Westfalische Wilhelms-Universitat Minister, Minister, Germany

Alan Kadish, MD Professor and Senior Associate Chief, Division of Cardiology, Northwestern University, Chicago, IL

Francois Helie, MSc Graduate Student, Department of Pharmacology, Universite de Montreal, Montreal, Quebec, Canada

Wilhelm Kaltenbrunner, MD The Ludwig Boltzmann Arrhythmia Research Institute, Wilhelminenspital, Vienna, Austria

x CARDIAC MAPPING Karim Khalife, BSc Department de Physiologie, Universite de Montreal, Montreal, Quebec, Canada Andre G. Kleber, MD Professor of Physiology, Department of Physiology, University of Bern, Bern, Switzerland Petri Korhonen, MD Division of Cardiology, Department of Medicine, and BioMag Laboratory, Helsinki University Central Hospital, Helsinki, Finland Hans Kottkamp, MD University of Leipzig Heart Center, Co-director, Department of Electrophysiology, Leipzig, Germany Karl-Heinz Kuck, MD Chief, II Medizinische Abteilung, Allg. Krankenhaus St. Georg, Hamburg, Germany Kenneth R. Laurita, PhD Assistant Professor of Medicine and Biomedical Engineering, Heart and Vascular Research Center, MetroHealth Campus, Case Western University, Cleveland, OH Michael D. Lesh, MD Section of Cardiac Electrophysiology, Department of Medicine, University of California, San Francisco, San Francisco, CA

Laurent Made, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Markku Makijarvi, MD Assistant Professor of Medicine, Division of Cardiology, Department of Medicine, and BioMag Laboratory, Helsinki University Central Hospital, Helsinki, Finland John M. Miller, MD Professor of Medicine, Indiana University School of Medicine, Krannert Institute of Cardiology, Director, Clinical Cardiac Electrophysiology, Indianapolis, IN Maria Antonia Montero, MD Cardiology Service, Complejo Hospitalario de Ciudad Real, Ciudad Real, Spain Juha Montonen, Dr.Tech. BioMag Laboratory, Helsinki University Central Hospital; Laboratory of Biomedical Engineering, Helsinki University of Technology, Helsinki, Finland Reginald Nadeau, MD Centre de Recherche, Hopital du Sacre-Cceur de Montreal; Faculty of Medicine, Universite de Montreal, and Institut de Genie Biomedical, Ecole Polytechnique de Montreal, Montreal, Quebec, Canada

Jukka Nenonen, Dr.Tech. Academy Research Fellow, BioMag Laboratory, Helsinki University Central Hospital; Laboratory of Biomedical Engineering, Helsinki UniPeter Loh, MD versity of Technology, Helsinki, Hospital of the Westfalische WilhelmsFinland Universitat Munster, Department of Cardiology and Angiology and Insti- Ambrosio Nunez, MD Cardiology Service, Hospital Unitute of Arteriosclerosis Research, versitario de Getafe, Madrid, Spain Munster, Germany

Li-Jen Lin, MD Department of Internal Medicine, National Cheng-Kung University Hospital, Tainan, Taiwan

CONTRIBUTORS xi Jeffrey E. Olgin, MD Associate Professor of Medicine, Indiana University School of Medicine, Krannert Institute of Cardiology, Indianapolis, IN

Franz X. Roithinger, MD Electrophysiology Research Group, Department of Cardiology, University Hospital Innsbruck, Innsbruck, Austria

Feifan Ouyang, MD Medizinische Abteilung, Allg. Krankenhaus St. Georg, Hamburg, Germany

David S. Rosenbaum, MD Director, Heart and Vascular Research Center, Associate Professor of Medicine, Biomedical Engineering, and Physiology and Biophysics, MetroHealth Campus, Case Western Reserve University, Cleveland, OH

Pierre L. Page, MD Professor of Surgery, Department of Surgery, Universite de Montreal; Research Center and Staff Surgeon, Division of Cardiac Surgery, Hopital du Sacre-Coeur de Montreal and Institut de Cardiologie de Montreal, Montreal, Quebec, Canada Agustin Pastor, MD Cardiology Service, Hospital Universitario de Getafe, Madrid, Spain Nicholas S. Peters, MD Professor of Cardiac Electrophysiology, Department of Cardiology, St. Mary's Hospital and Imperial College School of Medicine, London, UK Florence Raybaud, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France

Pierre Savard, PhD Centre de Recherche, Hopital du Sacre-Coeur de Montreal; Faculty of Medicine, Universite de Montreal, and Institut de Genie Biomedical, Ecole Polytechnique de Montreal, Montreal, Quebec, Canada Mauricio Scanavacca, MD Unit of Cardiac Arrhythmia, Clinical Arrhythmias and Pacemaker Unit, Heart Institute (InCor) - University of Sao Paulo Medical School, Sao Paulo, Brazil Christophe Scavee, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France

Mark Restivo, PhD Richard Schilling, MD Senior Scientist, Cardiology St. Bartholomew's and Queen Mary's Research Program, NY Harbor VA University, London, UK Health Care Center, Brooklyn Campus; Assistant Professor of Med- Wolfgang Schoels, MD Department of Cardiology, Univericine, State University of New York, sity of Heidelberg, Heidelberg, Downstate Medical Center, Brooklyn, NY Germany Stefania Riva, MD Centro Cardiologico Fondazione Monzino IRCCS, Instituto di Cardiologia dell'Universita, Milan, Italy Pierre Rocque, BSc Research Assistant, Research Center, Hopital du Sacre-Coeur de Montreal, Montreal, Quebec, Canada

Dipen C. Shah, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Hossein Shenasa MD, MSc, FACC Attending Physician, Department of Cardiovascular Services, O'Connor Hospital; Heart and Rhythm Medical Group, San Jose, CA

xii

CARDIAC MAPPING

Jafar Shenasa, MSc Department of Cardiovascular Services, O'Connor Hospital; Heart and Rhythm Medical Group, San Jose, CA Mohammad Shenasa, MD, FESC, FACC Attending Physician, Department of Cardiovascular Services, O'Connor Hospital; Heart and Rhythm Medical Group, San Jose, CA Haris J. Sih, PhD Research Scientist, Guidant Corporation, Cardiac Rhythm Management, St. Paul, MN Edward Simpson, MS Institute for Global Communications, San Francisco, CA Arne SippensGroenewegen, MD, PhD Arrhythmia Service, Thoracic Cardiovascular Institute, Section of Cardiology, College of Human Medicine, Michigan State University, East Lansing, MI Timothy W. Smith, D.Phil., MD Cardiovascular Division, BarnesJewish Hospital; Assistant Professor of Medicine, Washington University School of Medicine, St. Louis, MO William M. Smith, PhD Professor of Medicine, Professor of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL Eduardo A. Sosa, MD Director, Clinical Arrhythmias and Pacemaker Unit, Heart Institute (InCor) - University of Sao Paulo Medical School, Sao Paulo, Brazil Madison Spach, MD James B. Duke Professor of Pediatrics, Emeritus, Department of Pediatrics, Duke University Medical Center, Durham, NC

William Stevenson, MD Associate Professor of Medicine, Harvard Medical School; Director, Clinical Cardiac Electrophysiology Fellowship Program, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA Claudio Tondo, MD Centro Cardiologico Fondazione Monzino IRCCS, Instituto di Cardiologia dell'Universita, Milan, Italy Gioia Turitto, MD Associate Professor of Medicine, Director, Coronary Care Unit and Electrophysiology Laboratory, University Hospital, State University of New York, Downstate Medical Center, Brooklyn, NY Michel Vermeulen, B Pharm, MscA Research Assistant, Research Center, Hopital du Sacre-Coeur de Montreal, Montreal, Quebec, Canada Alain Vinet, PhD Associate Professor, Institute of Biomedical Engineering, Universite de Montreal and Research Center, Hopital du Sacre-Coeur de Montreal, Montreal, Quebec, Canada Jun Wang, MD, PhD Department de Physiologie, Universite de Montreal, Montreal, Quebec, Canada Rukshen Weerasooriya, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Stephan Willems, MD Medizinische Klinik und Poliklinik, Abteilung fur Kardiologie, Universitats-Krankenhaus Eppendorf, Hamburg, Germany Andrew L. Wit, PhD Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY

CONTRIBUTORS xiii Patrick Wolf, PhD Associate Professor of Biomedical Engineering, Duke University, Durham, NC Teiichi Yamane, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France

Douglas Zipes, MD Distinguished Professor of Medicine, Pharmacology, and Toxicology; Director, Division of Cardiology and Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN

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Preface

The first edition of Cardiac Mapping stood out as the only textbook in the field with outstanding contributions from world-renowned authors. The book was well received and indeed sold out. Since the release of the first edition, there have been areas of significant progress and even major breakthroughs in the field of cardiac mapping and catheter ablation of arrhythmias. In particular, the technical advancements in noncontact and nonfluoroscopic mapping improved our understanding of the mechanism and thus the appropriate treatment of many arrhythmias, particularly atrial and ventricular fibrillation. The second edition offers a

xv

unique source for the latest developments in cardiac mapping of arrhythmias. This new edition of Cardiac Mapping provides an important resource for the interventional electrophysiologist, rhythmologist, and those who are interested in understanding the mechanism of cardiac arrhythmias. As the field of interventional electrophysiology continues to evolve, cardiac mapping will remain an integral part of the science and practice of electrophysiology. The Editors San Jose, CA, Mannheim and Munster, Germany

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Preface to the First Edition

Cardiac mapping has always been an integral part of both experimental and clinical electrophysiology. Indeed, Sir Thomas Lewis systematically investigated the activation sequence of the dog ventricle as early as 1915. The detailed activation map from that experiment is shown in Figure 1. Since then, cardiac mapping has evolved from single sequential probe mapping to very sophisticated computerized three-dimensional mapping. By the time cardiac mapping began being used in the surgical management of ventricular as well as supraventricular

tachycardias, a large body of literature had already been collected. Despite this significant progress, a collective textbook that attempted to discuss all aspects of cardiac mapping did not exist. When we first considered working on such a project, we were not sure if our friends and colleagues who had paved the road to this point would think it necessary to join us in this effort, especially in this era of implantable devices. We were surprised and encouraged by their unanimous positive support to go ahead with this text. (Many of the contributors have

Figure 1

XVII

xviii CArDIAC MAPPING already asked about the second revised edition!) The contributors unanimously agreed to prepare manuscripts that discussed their latest work and that would subsequently be published in this, the only comprehensive book to present the state of the art on all aspects of cardiac mapping from computer simulation to online clinical application. Thus, we would like to thank all the contributors for presenting

their best work here. Without them, this book would not have been possible. A unique feature of this book is that chapters are followed by critical editorial comments by the pioneer of that specific area, so that the state of the art is discussed. We hope this book will serve as impetus to stimulate new ideas for cardiac mapping in the future. The Editors

Contents

Dedication Acknowledgments Contributors Preface Preface to the First Edition

iii v vii xv xvii

Part 1. Historical Perspectives Chapter 1. Historical Notes on the Mapping of Arrhythmias: The Contributions of George Ralph Mines Michiel J. Janse, MD 3 Part 2. Methodological and Technical Considerations Chapter 2. The Interpretation of Cardiac Electrograms Martin Biermann, MD, Mohammad Shenasa, MD, Martin Borggrefe, MD, Gerhard Hindricks, MD, Wilhelm Haverkamp, MD, and Gunter Breithardt, MD

15

Chapter 3. Methodology of Cardiac Mapping Haris J. Sih, PhD and Edward J. Berbari, PhD

41

Chapter 4. Noncontact Endocardial Mapping Richard Schilling, MD, Nicholas S. Peters, MD, Alan Kadish, MD, and D. Wyn Davies, MD

59

Chapter 5. Principles of Nonfluoroscopic Mapping: Nonfluoroscopic Electroanatomical and Electromechanical Cardiac Mapping Shlomo A. Ben-Haim, MD, DSc

103

Chapter 6. Principles of Magnetocardiographic Mapping Jukka Nenonen, Dr. Tech., Juha Montonen, Dr. Tech., and Markku Makijarvi, MD

119

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xx CARDIAC MAPPING Chapter 7. Fast Fluorescent Mapping of Electrical Activity in the Heart: Practical Guide to Experimental Design and Applications Igor R. Efimov, PhD, Martin Biermann, MD, and Douglas Zipes, MD 131 Chapter 8. Precision and Reproducibility of Cardiac Mapping Martin Biermann, MD, Martin Borggrefe, MD, Robert Johna, MD, Wilhelm Haverkamp, MD, Mohammad Shenasa, MD, and Gunter Breithardt, MD

157

Chapter 9. The Ideal Cardiac Mapping System Raymond E. Ideker, MD, PhD, Patrick D. Wolf, PhD, Edward Simpson, MS, Eric E. Johnson, MD, Susan M. Blanchard, PhD, and William M. Smith, PhD

187

Part 3. Mapping in Experimental Models of Cardiac Arrhythmias Chapter 10. The Role of Myocardial Architecture and Anisotropy as a Cause of Ventricular Arrhythmias in Pathological States Nicholas S. Peters, MD and Andrew L. Wit, PhD

197

Chapter 11. The Figure-of-Eight Model of Reentrant Ventricular Arrhythmias Nabil El-Sherif, MD, Edward B. Caref, PhD, and Mark Restivo, PhD 237 Chapter 12. Demonstration of Microreentry Hasan Garan, MD

275

Chapter 13. Optical Mapping of the Effects of Defibrillation Shocks in Cell Monolayers Vladimir G. Fast, PhD and Andre G. Kleber, MD

291

Chapter 14. Effects of Pharmacological Interventions on Reentry Around a Ring of Anisotropic Myocardium: A Study with High-Resolution Epicardial Mapping Josep Brugada, MD, PhD, Lucas Boersma, MD, and Maurits Allessie, MD, PhD 311 Chapter 15. Microscopic Discontinuities as a Basis for Reentrant Arrhythmias Madison S. Spach, MD 323 Chapter 16. Mapping in Explanted Hearts Jacques M.T. de Bakker, PhD and Michiel J. Janse, MD

341

Chapter 17. Efferent Autonomic Innervation of the Atrium: Assessment by Isointegral Mapping Pierre L. Page, MD and Rene Cardinal, PhD

363

Chapter 18. Mapping of Atrial Flutter Wolfgang Schoels, MD and Nabil El-Sherif, MD

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CONTENTS xxi Chapter 19. Mapping of Normal and Arrhythmogenic Activation of the Rabbit Atrioventricular Node Jacques Billette, MD, PhD, Jun Wang, MD, PhD, Karim Khalife, BSc, and Li-Jen Lin, MD 383 Chapter 20. Mapping of the AV Node in the Experimental Setting Peter Loh, MD, Jacques M.T. de Bakker, PhD, Meleze Hocini, MD, and Michiel J. Janse, MD

403

Part 4. Noninvasive Methods of Cardiac Mapping Chapter 21. Mapping of Atrial Arrhythmias: Role of P Wave Morphology Arne SippensGroenewegen, MD, PhD, Franz X. Roithinger, MD, and Michael D. Lesh, MD

429

Chapter 22. Surface Electrocardiographic Mapping of Ventricular Tachycardia: Correlation with Electrophysiological Mapping John M. Miller, MD, Jeffrey E. Olgin, MD, Thabet Al-Sheikh, MD, and Gregory T. Altemose, MD 455 Chapter 23. Body Surface Potential Mapping for the Localization of Ventricular Preexcitation Sites and Ventricular Tachycardia Breakthroughs Reginald Nadeau, MD and Pierre Savard, PhD 467 Chapter 24. Clinical Application of Magnetocardiographic Mapping Markku Makijarvi, MD, Helena Hanninen, MD, Petri Korhonen, MD, Juha Montonen, Dr.Tech., and Jukka Nenonen, Dr.Tech

483

Part 5. Mapping of Supraventricular Tachyarrhythmias Chapter 25. Endocardial Catheter Mapping in Patients with Wolff-Parkinson-White Syndrome: Implications for Radiofrequency Ablation Karl-Heinz Kuck, MD and Riccardo Cappato, MD

497

Chapter 26. Endocardial Catheter Mapping in Patients with Mahaim and Other Variants of Preexcitation Hans Kottkamp, MD and Gerhard Hindricks, MD

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Chapter 27. Endocardial Catheter Mapping of Atrial Flutter Francisco G. Cosio, MD, Antonio Goicolea, MD, Agustin Pastor, MD, Ambrosio Nunez, MD, Maria Antonia Montero, MD, and Maria Alcaraz, MD

537

xxii CARDIAC MAPPING Chapter 28. Catheter Ablation of Atrial Fibrillation in Humans: Initiation and Maintenance Michel Haissaguerre, MD, Pierre Jais, MD, Dipen C. Shah, MD, Meleze Hocini, MD, Laurent Made, MD, Rukshen Weerasooriya, MD, Teiichi Yamane, MD, Kee-Joon Choi, MD, Christophe Scavee, MD, Florence Raybaud, MD, Stephane Garrigue, MD, and Jacques Clementy, MD 561 Chapter 29. Mapping of Atrial Fibrillation: Clinical Observations Riccardo Cappato, MD, Sabine Ernst, MD, Feifan Ouyang, MD, and Karl-Heinz Kuck, MD

577

Part 6. Mapping of Ventricular Tachyarrhythmias Chapter 30. Substrate Mapping for Ablation of Ventricular Tachycardia in Coronary Artery Disease Timothy W. Smith, D.Phil., MD and Mark E. Josephson, MD

595

Chapter 31. Intraoperative Mapping of Ventricular Tachycardia in Patients with Myocardial Infarction: New Insights into Mechanisms and Electroanatomical Correlations in Septal Tachycardias Pierre L. Page, MD, Wilhelm Kaltenbrunner, MD, and Rene Cardinal, PhD . . . .605 Chapter 32. Dynamic Analysis of Postinfarction Monomorphic and Polymorphic Ventricular Tachycardias Rene Cardinal, PhD, Alain Vinet, PhD, Francois Helie, MSc, Michel Vermeulen, B Pharm, MScA, Pierre Rocque, BSc, and Pierre L. Page, MD 619 Chapter 33. Mapping of Unstable Ventricular Tachycardia William Stevenson, MD and Peter L. Friedman, MD, PhD

635

Chapter 34. Subthreshold Electrical Stimulation: A Novel Technique in Localization and Identification of Target Sites During Catheter Ablation of Cardiac Arrhythmias Mohammad Shenasa, MD, Stephan Willems, MD, Gerhard Hindricks, MD, Jafar Shenasa, MSc, Xu Chen, MD, Hossein Shenasa, MD, MSc, Martin Borggrefe, MD, and Giinter Breithardt, MD

649

Part 7. New Frontiers Chapter 35. Transcoronary Venous Mapping of Ventricular Tachycardia Paolo Delia Bella, MD, Claudio Tondo, MD, Corrado Carbucicchio, MD, Stefania Riva, MD, Gaetano Fassini, MD, and Paola Galimberti, MD

667

Chapter 36. Transthoracic Epicardial Mapping and Ablation Technique EduardoA. Sosa, MD, Mauricio Scanavacca, MD, and Andre d'Avila, MD . . . .681

CONTENTS xxiii Chapter 37. Nonfluoroscopic Mapping of Supraventricular Tachycardia Gerhard Hindricks, MD and Hans Kottkamp, MD

693

Chapter 38. Optical Mapping of Cellular Repolarization in the Intact Heart Kenneth R. Laurita, PhD and David S. Rosenbaum, MD

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Chapter 39. Techniques for Mapping Ventricular Fibrillation and Defibrillation William M. Smith, PhD and Raymond E. Ideker, MD, PhD 729 Chapter 40. Disorders of Cardiac Repolarization and Arrhythmogenesis in the Long QT Syndrome Nabil El-Sherif, MD and Gioia Turitto, MD

747

Index

775

Color Appendix

Al

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t Historical Perspectives

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Chapter 1

Historical Notes on the Mapping of Arrhythmias: The Contributions of George Ralph Mines Michiel J. Janse, MD

and we started to talk about Mines, who at that time was known to only a few people. We founded the G.R. Mines Club, In the first edition of Cardiac Map- whose other members included Maurits A. ping I provided some historical notes on Allessie, Felix I.M. Bonke, Frans J.L. van the early history of mapping of reentrant Capelle, and Robert H. Anderson, and arrhythmias and on the interpretation of Professor Rytand sent me some very extracellular waveforms.1 Rather than interesting correspondence, parts of which repeating these notes, I would like to I quote in this chapter. He wrote to me on elaborate on the role of George Ralph October 19, 1973: "As Founder and PresMines in our understanding of circus ident of the G.R. Mines Club, you should movement reentry, and to introduce some have copies, at the least, of these letters." Although Professor Rytand has by now, "personal" history as well. In the summer of 1973, David A. in his own words, joined "that Great ReRytand, Bloomfield Professor of Medicine entry in the Sky," I feel that he would at Stanford University, visited our depart- not have objected to my quoting certain ment in the Wilhelmina Gasthuis. Pro- passages. Anyone who ever met Dave fessor Durrer telephoned me, asking to Rytand will understand that he used show Professor Rytand ("you know, the terms such as Founder and President in flutterologist") around. I had read his bril- a very tongue-in-cheek manner. He was a liant review on the early history of delightful person with a great sense of arrhythmia research2 (the title suggests humor and the total opposite of a pompous that it only deals with atrial flutter, professor. In his review he discussed A.G. Mayer's which was the subject of Rytand's own research, but it covers a much wider field) experiments, in which circus movement The Early History of Circus Movement: In Search of a Film

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003.

3

4 CARDIAC MAPPING was described in ring-like preparations from the muscular tissue of the subumbrella of the scyphomedusa Cassiopeia. "In one record specimen the pulsation persisted for 11 days during which it traveled 457 miles."2 In April 1964, Rytand wrote to Sir Henry Dale: "During a recent sabbatical leave as visiting Professor of Physiology with Dr. S.M. Tenney at Dartmouth College, we were able to make some motion pictures of circus movement in Cassiopea Xamachana, repeating A.G. Mayer's classic observations. It occurred to me to try and find the similar films made by George Ralph Mines 50 years ago, and I learned that you had been on their trail ahead of me." In his reply, Sir Henry denies "any knowledge, or interest of mine, in these, or any other films made by Mines"; however, he passes the request to "The one of my friends still living, who was a partial contemporary at least of Mines at Cambridge, E.D. Adrian, now of course Lord Adrian and Master of Trinity College, Cambridge." In June 1964, Sir Henry writes that through Lord Adrian he has "come across what may be a trail; and although my own rather deep immersion in other, and what seemed more urgent, demands, has prevented me from following it as actively as I should have wished, I have not yet given up all hope," and he provides Professor Rytand with the address of Mrs. Dorothy Thacker, "who at that time was Miss Dorothy Dale (not related to me as far as I know, except by name)," and who "worked with Mines at the time when he described the circus movement." "Mrs. Thacker informs me that she thinks that such a film was taken when she was working with Mines at the Marine Biological Station at Plymouth, and that the circus phenomenon was demonstrated on a ring, cut from the auricles of a skate or ray." Sir Henry mentions that he will write to Dr. F.S. Russell, CBE, FRS, the Secretary of the Marine Biological Association and

Director of the Plymouth Laboratory, but in a later letter he writes that Dr. Russell could not find any record of a film taken there by Mines. Meanwhile, Professor Rytand had contacted Mrs. Thacker, and a lengthy correspondence (hand-written on her part) develops. She confirms that she had the "pleasure and privilege of working with him at Cambridge from 1911 onwards, and at the Marine Biological Laboratory, Plymouth. He was full of ideas and enthusiasm, a clever and ingenious experimentator. Apart from music—he was an excellent pianist—physiology was his overwhelming interest." With respect to the film of "circus rhythm" she writes that she "knew nothing of what happened to his records when Mines left Cambridge in the summer of 1914 to become Professor of Physiology at McGill University, Montreal." She gives a list of Mines' publications, of which the last entry is, "1913. IXieme Congres International des Physiologistes a Groningue - le 2-6 sept. 1913. A short communication about circus rhythm 'with demonstration, projection and cinematografic projection.'" She never indicates that she ever saw the film or that she was present when it was made. "I can only think it might have been taken to Montreal. If so, its fate is probably unknown." Thus ends the trail of the film. However, she sent Professor Rytand some very interesting documents: copies of pages 372 and 383 of Mines' 1913 paper in the Journal of Physiology.3 On page 372 Mines described circus movement in a ring-like preparation of a tortoise heart. In the paper, he provides no mechanical or electrographic records of what he saw and described. In his handwriting, he made the following note: "Later I took electrograms of this expt." On page 383 he wrote: "Repeated this experiment about 6 times on auricle rings from Acanthias vulgaris at Roscoff in Sept. 1913. The best test for a circulating excitation is to cut through the ring at one point. Cinematographed the

HISTORICAL NOTES: GEORGE RALPH MINES 5 ring ext. At Toronto, March 1914, before seeing Garrey's paper, I obtain circulating excitations in rings from excised heart of dog (rt. ventricle), [over] In these preparations the contraction wave coursed round rapidly about once a second. It was instantly stopped by section of the ring." (See Figure 1.) Professor Rytand published these pages in his review "by permission of the Editorial Board of the Journal of Physiology (London) from a reprint presented by Lord Adrian to the Library at the Cambridge 372

0. R. MINKS.

To test the hypothesis, I devised another experiment, which I carried out on the heart of a tortoise. The heart was excised and the sinus venosus cut away. A longitudinal incision was then made extending through the anterior and posterior walls of the auricle and ventricle, so that the heart was converted into a ring, as shown in Fig. 23. The auricles were connected with the ventricle in two places, and Fig. 23. across each of these junctions it was found that excitation could pass. The experiment was made at a temperature of 21°C. On stimulating any part of the heart there was, after a slight pause, contraction in each of the other parts. After stimulating several times, the following condition appeared. The four portions of the heart marked V1, V2, A1, A2, contracted in the order given, with distinct pauses between the successive portions. This cycle of events was repeated over and over again without any further external stimulation. When V, became excited the excitation spread to V2 but not back to A, which was still refractory. From V2 it spread to A1, from A, to A2, now recovered from its refractory state, and then again from A2 to V1. While the cycle was being regularly repeated, the application of an external stimulus to either of the chambers, if out of phase with the cycle, stopped the contractions, showing that they were not originated by an automatic rhythm in any part of the preparation, but were due to a wave of excitation passing slowly round and round the ring of tissue. * It seems then that the reciprocating rhythm may reasonably be regarded as due to a circulating excitation. The circumstances under which the phenomenon made its appearance were such as to produce the favourable conditions of slow conduction and short refractory period. By its continuance the circulating rhythm would tend to maintain these conditions. The conditions are easily upset by the occurrence of an extra systole and they may be re-established by other extra systoles. I venture to suggest that a circulating excitation of this type may be responsible for some cases of paroxysmal tachycardia as observed clinically. The to-and-fro character of the movement in the cases of reciprocating rhythm which I have described recalled in a curious way the appearances sometimes seen in fibrillation of the mammalian heart, with the difference that in fibrillation, different portions of the muscle in a single chamber, instead of separate chambers of the heart, appear to exhibit reciprocating rhythm.

Physiological Laboratory. Mrs. Dorothy Thacker and Prof. Sir Bryan Matthews most kindly made this figure available."2 The Garrey paper to which Mines referred was the 1914 paper on the nature of fibrillation,4 in which Garrey used the term circus contractions. As was the case with Mines, no mechanical or electrographic tracings were presented, only the description of what the author had observed with his own eyes. Still, on the basis of Mines' addenda, we may consider him to be the first arrhythmia mapper. CONTRACTION

OF HEART.

383

ADDENDUM. On circulating excitations in the musculature of a tingle chamber. Since the above paper was sent to press I have made further observations on circulating rhythm, which may be briefly noted here. The experiments were carried out at the Plymouth Marine Laboratory on ring preparations cut from the auricles of large rays. In such preparations a single stimulus applied to any point in the ring starts a wave in each direction. The waves meet on the opposite side of the ring and die out Bat by the application of several stimuli in succession it is sometimes possible to start a wave in one direction while the tissue on the other side of the point stimulated is still refractory. Such a wave runs round the ring sufficiently slowly for the refractory phase to have passed off in each part of the ring when the wave approaches it Thus the wave circulates and may continue to do so for fifty revolutions or more. Usually an interpolated extra stimulus stops the wave at once. The preparation may then remain quiescent or it may start beating with a slow spontaneous rhythm. In the latter case the totally different characters of the spontaneous rhythm and the ulating excitation are very striking.

Erratum. In L 3, p. 232 of my paper in vol. XLVI. of the Journal "the muscle u longer, has " should read " the muscle, Do longer has."

Figure 1. Pages 372 and 383 and its reverse of the article on dynamic equilibrium in the heart by Mines3 with footnotes in his handwriting (see text). These figures were given to the author by the late Professor D.A. Rytand and are reprinted with permission from the Annals of Internal Medicine.

6 CARDIAC MAPPING Mrs. Thacker also sent Professor Rytand 2 photographs of Mines, one of which a snapshot probably taken by herself in the summer of 1911 at Plymouth (Figure 2). It is with some trepidation that I publish this snapshot here, because Mrs. Thacker was rather upset when she learned that Professor Rytand was making copies of the photographs. The more official photograph of Mines was published2 and permission to do so was obtained by Professor Rytand from the photographic studio where it was taken. Whom to ask for permission? Anyway, the harm is already done, because the picture was published in Cardiovascular Research in 19925 by Michael R. Rosen,

who got it from me, who got it from Rytand, who got it from Mrs. Thacker.

Mines' Contributions Throughout the years, 2 causes of tachycardia have been considered: enhanced impulse formation and reentrant excitation. In 1887, McWilliam6 suggested for the first time that disturbances in impulse propagation could be responsible for tachyarrhythmias: "Apart from the possibility of rapid spontaneous discharges of energy by the muscular fibres, there seems to be another probable cause for continued and rapid movement. The peristaltic contraction

Figure 2. George Ralph Mines: a photograph probably taken by Mrs. Dorothy Thacker (at that time Dorothy Dale) in the Marine Biological Laboratory, Plymouth, in the summer of 1911. Professor D.A. Rytand made this picture available to the author.

HISTORICAL NOTES: GEORGE RALPH MINES travelling along such a structure as that of the ventricular wall must reach adjacent bundles at different points in time, and since these bundles are connected with one another by anastomosing branches the contraction would naturally be propagated from one contracting fibre to another over which the contraction wave had already passed... Hence the movement would tend to go on until the excitability of the muscular tissue had been lowered, so that it failed to respond with a rapid series of contractions."6 It is clear that Mc William envisaged the possibility that myocardial fibers could be reexcited as soon as their refractory period had ended by an irregularly propagating impulse, and he therefore may be considered a founding father of reentrant excitation. Yet it was the work of Mines and of Garrey some 30 years later that firmly established the role of reentry as a mechanism for arrhythmias. Both investigators, working independently, were inspired by Mayer's work. Garrey's contributions include the demonstration that fibrillation does not result from a single, rapidly firing focus and that a minimal tissue mass is required for fibrillation.4 Here, we shall concentrate on the work of Mines. Apart from a brief biographical sketch by Rytand,2 the most complete biography of Mines can be found in a recent paper by De Silva.7 Briefly, Mines was born in Bath, England, on May 13, 1886. He entered Sidney Sussex College, Cambridge University at the age of 19. In 1911 he was appointed Assistant Demonstrator in the Physiological Laboratory at Cambridge. As already mentioned, he did important work in the Marine Biological Laboratory in Plymouth (summer of 1912, together with Dorothy Dale) and in Roscoff, France, in August and September 1913 (see Figure 1). In 1914, at the age of 28, he was offered the position of Professor and Chair of Physiology at McGill University in Montreal, Canada. On the

7

evening of Saturday, November 7, 1914, the night janitor found Mines lying unconscious in his laboratory. Mines died shortly thereafter, presumably as a result of self-experimentation.7 The accomplishments of such a young man are truly astonishing. In his 1913 and 1914 papers,3,8 Mines formulated the essential characteristics of reentry: 1. For the initiation of reentry, an area of unidirectional block must be present (Garrey4 also emphasized this point, as was acknowledged by Mines.8) In the 1914 paper, he describes an experiment on an isolated auricular preparation from a large dog-fish (Acanthian), slit up in such a way as to form a ring. The ring was spread on a glass plate and serum was poured on. The preparation remained quiescent. "Pricking with a needle point provokes a strong contraction. Wave runs round ring in each direction; the waves meet on the opposite side of the ring and die out. Repeated the stimulus at diminishing intervals and after several attempts started a wave in one direction and not in the other. The wave ran all the way round the ring and then continued to circulate going round about twice a second. After this had continued for two minutes extra stimuli were thrown in. After several attempts the wave was stopped."8 Thus, not only was unidirectional block found to be essential, the principle of antitachycardia pacing was described as well. 2. Mines described the relationship between refractory period duration and conduction velocity, as shown in Figure 3, and can thus be considered the first to formulate the "wavelength" concept. In the 1913 paper he wrote: "With increasing

8 CARDIAC MAPPING

Figure 3. Mines' diagram to explain that reentry will occur if conduction is slowed and the refractory period duration is decreased. A stimulated impulse leaves in its wake absolutely refractory tissue (black area) and relatively refractory tissue (stippled area). In both A and B, the impulse conducts in one direction only. In A, because of fast conduction and a long refractory period, the tissue is still absolutely refractory when the impulse has returned to its site of origin. In B, because of slow conduction and a short refractory period, the tissue has recovered excitability by the time the impulse has reached the site of origin, and the impulse continues to circulate.

frequency of stimulation, each wave of excitation in the heart muscle is propagated more slowly but lasts a shorter time at any point in the muscle. The wave of excitation becomes slower and shorter. Similarly the refractory phase (towards strong induction shocks) is shortened."3 3. Mines realized that establishing the activation sequence during a reentrant rhythm is not sufficient to prove reentry. "Ordinary graphic records either mechanical or electrical are of no value in attesting the occurrence of a true circulating excitation in rings of this kind, since the records show merely a rhythmic series of waves and do not discriminate between a spontaneous series of beats and a wave of excitation which continues to circulate because it always finds excitable tissue ahead of it. The only method of recording the phenomenon which I have found of any use is cinematography."8 If only the film could have been

found! "The chief error to be guarded against is that of mistaking a series of automatic beats originating in one point in the ring and travelling round it in one direction only owing to complete block close to the point of origin of the rhythm on one side of this point... Severance of the ring will obviously prevent the possibility of circulating excitations but will not upset the course of a series of rhythmic spontaneous excitations unless by a rare chance the section should pass through the point actually initiating the spontaneous rhythm."8 Thus, Mines set the stage for catheter ablation of reentrant rhythm. 4. Mines discovered the vulnerable period for fibrillation. It is remarkable that Mines and Garrey almost simultaneously described fibrillation in terms of reentry. "Garrey arrives independently at a closely similar conclusion to that which I expressed in a recent paper, namely, that fibrillation is due to waves

HISTORICAL NOTES: GEORGE RALPH MINES 9 travelling in closed circuits in the syncytium."8 Mines then describes his experiment showing that fibrillation can be induced by a single induction shock: "The point of interest is that the stimulus employed would never cause fibrillation unless it was set in at a certain clinical instant." He shows that a stimulus falling in the refractory period has no effect, "a stimulus coming a little later in the cycle sets up fibrillation" and a stimulus applied "later than the critical instant for the production of fibrillation merely induces an extrasystole..." "In the production of fibrillation just described, the stimulus apparently arrives at some part of the ventricular muscle just at the end of the refractory phase and probably before the refractory phase has ended in some other regions of the muscle. If this is so, we have again a difference in conditions of different regions of the muscle as a basis for the inauguration of the state of fibrillation." "... Suppose that at the time when excitation is set up in A, B is in the refractory state. It cannot then be excited by A. But the excited state set up in A will persist for a considerable time, and the refractory state will disappear from B before the excited state has ceased in A. The question is: Is it ever possible that under these circumstances A will excite B?" It would be 74 years before Chen and colleagues9 answered this question. As described in detail by Acierno,10 around 1920 a considerable number of people were accidentally electrocuted because more and more electrical devices were installed in households. This prompted electric companies such as Con Edison to provide grants to investigate the effects of electrical currents on human beings. This

led to the (re) discovery of the vulnerable period by Wiggers and Wegria in 1940.11 In that paper Mines is not mentioned, but in another paper by Wiggers in 1940, a brief allusion to Mines is made.12 As also noted by De Silva,7 the extensive and otherwise admirable book The History of Cardiology by L.J. Acierno10 makes no note of Mines' contributions. Fortunately, this is not the case in Luderitz' book History of the Disorders of Cardiac Rhythm.13 Some of the most astonishing paragraphs in the 1913 and 1914 papers describe in detail the mechanisms of 2 arrhythmias that at that time were clinically unknown: atrioventricular (AV) reentrant tachycardia in the WolffParkinson-White (WPW) syndrome and AV nodal reentry. As described in detail by Rosen,5 none of the relevant papers on the WPW syndrome from 1930 to 1967 mention Mines. "As for Mines, who predicted and described it all, his name is known only to those who are aficionados of electrophysiological history (e.g., Rytand)."5 In 1913, after describing circulating excitation in a ring-like preparation of a tortoise heart, Mines wrote: "I venture to suggest that a circulating excitation of this type may be responsible for some cases of paroxysmal tachycardia as observed clinically."3 One year later he repeated this suggestion "... in the light of the new histological demonstration by Stanley Kent ... that an extensive muscular connection is to be found at the right-hand margin of the heart at the junction of the right auricle and right ventricle: Supposing that for some reason an impulse from the auricle reached the main A-V bundle but failed to reach this 'right lateral' connexion. It is possible then that the ventricle would excite the ventricular end of this right lateral connexion, not finding it as refractory as it normally would at such a time. The wave spreading then to the auricle might be expected

10 CARDIAC MAPPING to circulate around the path indicated."8 This was written 16 years before Wolff, Parkinson, and White14 described the clinical syndrome that now bears their name, 18 years before Holzmann and Scherf15 ascribed the abnormal ECG in these patients to preexcitation of the ventricles via an accessory AV bundle, and 53 years before the first studies in patients employing intraoperative mapping and programmed stimulation proved Mines' predictions to be correct.16–18 As already mentioned, Mines' name cannot be found in the bibliography of any of these papers. It is ironic that what Kent described is not at all the usual accessory AV connection, found in the WPW syndrome, as discussed in detail by Anderson and Becker.19 They stated that "... there are indeed good scientific reasons for discontinuing the use of 'Kent bundle' ... the most important being that Kent did not describe connections in terms of morphology we know today... If an eponym is really necessary, then let us call them nodes of Kent."19 From Mines' point of view, the important point was of course that a human heart had been described with multiple connections between atria and ventricles. For AV nodal reentry, the story is different. In the 1913 paper Mines describes what he called reciprocating rhythm. This was based on observations in 3 experiments on the "auricle-ventricle preparation of the heart of the electric ray, and in one experiment on the ventricle-bulbus preparation from the frog..." "After the application of rhythmic stimuli at some particular rate, the cessation of the stimuli was followed by a quick reciprocating movement of auricle and ventricle or of ventricle and bulbus. The appearance of the heart gave the impression that the beats of the ventricle were caused by those of the auricle or bulbus, while these in turn were caused by the ventricle." His explanation is as follows: "The connexion between the auricle and ventricle is never

a single muscle fibre but always a number of fibres, and although these are ordinarily in physiological continuity, yet it is quite conceivable that exceptionally, as after too rapid stimulation, different parts of the bundle should lose their intimate connexion... A slight difference in the rate of recovery of the two divisions of the A-V connexion might determine that an extrasystole of the ventricle ... should spread up to the auricle by that part of the A-V connexion having the quicker recovery process and not by the other part. In such a case, when the auricle became excited by this impulse, the other portion of the A-V connexion would be ready to take up the transmission again back to the ventricle. Provided the transmission in each direction was slow, the chamber at either end would be ready to respond (its refractory phase being short) and thus the condition once established would tend to continue, unless upset by the interpolation of a premature systole."3 I can remember my excitement when I gave a talk in the Hopital Lariboisiere in 1970, describing experiments in isolated rabbit hearts employing multiple microelectrode recordings where we induced and terminated AV nodal reentrant tachycardia by extrasystoles, and meeting Philippe Coumel, Alexandre Fabiato, and Robert Slama, who had treated patients with AV nodal reentry by a pacemaker that could be turned on when a tachycardia occurred and would terminate the arrhythmia when the stimuli would be timed just right. I am pleased to say that both our publications gave full credit to Mines,20,21 as did an earlier paper on AV nodal reentry by Moe and Mendez.22 I have no idea why Mines' name is not associated with the preexcitation syndrome, and why he is given proper recognition in papers on AV nodal reentry. It is remarkable that in the wonderful book by Pick and Langendorf, Interpretation of Complex Arrhythmias,23

HISTORICAL NOTES: GEORGE RALPH MINES Mines' 1913 and 1914 papers are quoted in the chapter on "Reentrant Arrhythmias (Reciprocal Beating)," but not in the chapter entitled "The Preexcitation Syndrome." It is as Rosen5 wrote: "Mines is known only to those who are aficionados of electrophysiological history." One may add that anyone who reads Mines' original papers is likely to become an aficionado. References 1. Janse MJ. Some historical notes on the mapping of arrhythmias. In: Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping. Mount Kisco, NY: Futura Publishing Co.; 1993:3-10. 2. Rytand DA. The circus movement (entrapped circuit wave) hypothesis and atrial flutter. Ann Intern Med 1966;65: 125-159. 3. Mines GR. On dynamic equilibrium of the heart. J Physiol (Lond) 1913;46:349–382. 4. Garrey WE. The nature of fibrillar contract of the heart. Its relation to tissue mass and form. Am J Physiol 1914;33: 397-414. 5. Rosen MR. Did Wolff, Parkinson and White mind their Ps and Qs? Cardiovasc Res 1992;26:1164–1169. 6. Mc William JA. Fibrillar contraction of the heart. J Physiol 1887;8:296–310. 7. De Silva RA. George Ralph Mines, ventricular fibrillation and the discovery of the vulnerable period. J Am Coll Cardiol 1997;29:1397-1402. 8. Mines GR. On circulating excitations in heart muscles and their possible relation to tachycardia and fibrillation. Trans R Soc Can 1914;IV:43-52. 9. Chen P-S, Wolf DD, Dixon EG, et al. Mechanism of ventricular vulnerability to single premature stimuli in open-chested dogs. CircRes 1988;62:1191-1209. 10. Acierno LJ. The History of Cardiology. London, Casterton, New York: The Parthenon Publishing Group; 1994. 11. Wiggers CJ, Wegria R. Ventricular fibrillation due to single, localized induction and condenser shocks applied

11

during the vulnerable phase of ventricular systole. Am J Physiol 1940; 128: 500-505. 12. Wiggers CJ. The mechanism and nature of ventricular fibrillation. Am Heart J 1940;20:399–412. 13. Liideritz B. History of the Disorders of Cardiac Rhythm. Second Revised and Updated Printing. Armonk, NY: Futura Publishing Company; 1998. 14. Wolff L, Parkinson J, White PD. Bundlebranch block with short P-R interval in healthy young patients prone to paroxysmal tachycardia. Am Heart J 1930;5: 685-704. 15. Holzmann M, Scherf D. Ueber Elektrokardiogramme mit verkurzter VorhofKammer-Distanz und positiven P-Zacken. Z Klin Med 1932;121:404–423. 16. Durrer D, Roos JR. Epicardial excitation of the ventricles in a patient with a Wolff-Parkinson-White syndrome (type B). Circulation 1967;35:15–21. 17. Burchell HB, Frye RB, Anderson MW, McGoon DC. Atrioventricular and ventriculo-atrial excitation in Wolff-ParkinsonWhite syndrome (type B). Circulation 1967;36:663-672. 18. Durrer D, Schoo L, Schuilenburg RM, Wellens HJJ. The role of premature beats in the initiation and termination of supraventricular tachycardia in the WolffParkinson-White syndrome. Circulation 1967;36:644-662. 19. Anderson RH, Becker AE. Stanley Kent and accessory atrioventricular connections. JThorac Cardiovasc Surg 1981;81: 649–658. 20. Coumel P, Cabrol C, Fabiato A, et al. Tachycardie permanente par rythme reciproque. Arch Mal Coeur 1967;60:1830– 1864. 21. Janse MJ, van Capelle FJL, Freud GE, Durrer D. Circus movement within the AV node as a basis for supraventricular tachycardia as shown by multiple microelectrode recording in the isolated rabbit heart. Circ Res 1971;28:403–414. 22. Moe GK, Mendez C. The physiological basis of reciprocal rhythm. Prog Cardiovasc Dis 1966;8:461–482. 23. Pick A, Langendorf R. Interpretation of Complex Arrhythmias. Philadelphia: Lea & Febiger; 1979.

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Part 2 Methodological and Technical Considerations

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Chapter 2

The Interpretation of Cardiac Electrograms Martin Biermann, MD, Mohammad Shenasa, MD, Martin Borggrefe, MD, Gerhard Hindricks, MD, Wilhelm Haverkamp, MD, and Gunter Breithardt, MD

in relation to anatomical landmarks of the heart and represents the local activation As early as 1915, Lewis and Roth- of myocardium at each recording site by schild, who studied the cardiac activation a single figure, the time of activation.6,7 In sequence in the dog by recording poten- an isochronal map, only a single activatials directly from the heart, wrote: "It tion time can be represented at each site must be evident that it is a matter of first and all other information also contained concern of us, to ensure a correct inter- in the electrograms is discarded.6 In isochronal mapping, the interpretation of pretation of our curves."1 The term electrogram, as opposed to the excitation sequence of the heart rests the term electrocardiogram (ECG), denotes entirely on the individual activation times a recording of cardiac potentials from elec- assigned to each electrogram, which is why trodes directly in contact with the heart, a the correct interpretation of individual elecdefinition introduced by Samojloff in trograms is of crucial importance. Alterna1910.2–4 Electrograms form the raw data tive mapping methods, namely isopotential for cardiac mapping, which has been and isoderivative mapping,7 place emphadefined as "a method by which potentials sis on interpreting a sequence of maps, recorded directly from the surface of the rather than a set of individual electroheart are spatially depicted as a function grams,7 the correct interpretation of which of time in an integrated manner,"5 and is often difficult and at times uncertain. The objective of this chapter is to which is important as both a research tool review the interpretation of individual carand a method for guiding therapy. The most common method of cardiac diac electrograms in 2 parts: (1) in respect mapping is isochronal or activation map- to timing local activation, and (2) in respect ping. A cardiac isochronal map outlines to information contained in the morphothe locations of the various recording sites logies of electrograms. Throughout this Introduction

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003.

15

16 CARDIAC MAPPING chapter it is assumed that negativity of the exploring electrode results in a downward movement in the unipolar electrogram.8,9 The process of creating maps out of electrogram data6,10 is not discussed, and one word of warning by Durrer et al. will have to suffice:"... the presence of time relationships compatible with an excitatory wave progressing in a certain direction does not necessarily prove the existence of such an excitatory wave."11 Activation Detection in Cardiac Electrograms The correct assignment of activation times for electrograms from each recording site is the cornerstone of isochronal mapping. With the transmembrane potential (TMP) as a gold standard, local activation of myocardium at a recording site can be defined as "the time instant when the upslope of the intracellular action potential... is a maximum."6 General Principles Underlying Electrograms

from the recording site, and the reciprocal value of the square of the distance between the dipole layer and the recording site.14,16 Thus, the unipolar electrogram records a combination of local and distant electrical events with the contribution of distant events decreasing in proportion to the square of the distance from the exploring electrode.17 The bipolar electrogram is recorded as the potential difference between 2 closely spaced electrodes in direct contact with the heart; it can be calculated as the difference between the 2 unipolar electrograms at each of the 2 electrode sites.18 These 2 unipolar electrograms differ only in the detail of the local activity at the moment of local excitation, in which case a spike in the bipolar electrogram results,18 the amplitude of which is inversely proportional to the third power of the distance between recording site and dipole.19–21 If the activation front is perpendicular in relation to the electrode pair, the bipolar spike will be of maximum amplitude, while if it is parallel, both electrodes will record the same waveform at the same time and no spike will result.6,22 To compensate the directional sensitivity of bipolar electrodes, investigators have processed bipolar signals from multipolar electrodes in different ways,23,24 or have advocated using bipolar coaxial electrodes,6,25 introduced by Fattorusso et al.26,27 in 1949 for recording precordial ECGs. However, even coaxial bipolar electrodes cannot detect activation fronts parallel to the place of the electrode (Ideker RE, oral communication).

The unipolar electrogram is recorded as the potential difference between a single electrode in direct contact with the extracellular space of the heart, the socalled "exploring electrode," and an "indifferent electrode,"12 which is an electrode placed at a distance from the heart1 or Wilson's central terminal.12 The electrical field produced at the border between resting and excited myocardium can be described as dipole.13–15 During cardiac excitation, the approach of this dipole The History of Activation Detection toward an exploring electrode gives a posAlthough direct cardiac leads had been itive deflection and its passage gives a rapid deflection in the negative direction, recorded2,28–35 (though not by Rothberger with a final return to baseline.5 Depolar- and Winterberg36) and bipolar electrodes ization, too, causes a dipole, albeit of the had been developed22,37,38 before 1914, reverse polarity.14 The amplitude of the Lewis' fame to have performed the first unipolar electrogram is proportional to cardiac mapping in 191439 and 19151 is the area of the dipole layer as "viewed" justified by the scope of his investigations.

INTERPRETATION OF CARDIAC ELECTROGRAMS

17

When Lewis et al.39 examined the spread ventricular outflow tract (RVOT) and the of excitation in the atria of the canine heart, pulmonary artery. The deflection that they used bipolar electrodes, assuming on appeared in all 6 electrograms at practithe ground of various experiments that cally the same time was thought to repre"the prominent spike" in a bipolar lead sig- sent distance cardiac activity and was nified local activation of the myocardium called the extrinsic deflection.1 A second beneath the electrode. When, in their stud- kind of deflection that occurred only in ies on the ventricles, Lewis and Rothschild.1 the 4 leads overlying myocardium and at switched to unipolar leads, they once more progressively later time instants was conhad to solve the question of activation eluded to signal the time of local activation detection. They took a series of electro- and was called the intrinsic deflection.1 grams from 6 equidistant epicardial sites While, according to Lewis' tracings, this arranged in a straight line on the right was the nadir of the S wave1 (Table 1), Table 1 Activation Detection in Unipolar Electrograms Article 1

Lewis T, 1915 Barker PS, 1930102 Wilson FN, 193440 Harris AS, 194146 Wilson FN, 194441 Wilson FN, 194745 Sodi-Pallares D, 195047 Schaefer H, 195154 Veyrat R, 195352 Durrer D, 195455 Durrer D, 195756 Jouve A, I960103 Durrer D, 1961120 Schaefer H, 196214 Durrer D, 196411 Ideker RE, 197980 Smith WM, 1980170 Parson I, 1982171 Cardinal R, 198484 De Bakker JMT, 198478 Parson I, 1984172 Carson DL, 198686 Blanchard SM, 198787 Bonneau G, 198779 Masse s, 198876 Page PL, 198885 Ideker RE, 19896 Paul T, 199090 Pieper CF, 1991168 Pieper CF, 199181 Pieper CF, 199182

Algorithm

Threshold in mV/ms

Evidence

S* S* R* R* R* S* S* FD* FD* FD* FD* FD* FD* FD* FD* MD MD MD* MD MD MD* MD MD MD MD MD MD MD MD MD MD

— — — — — — — — — — — — — — —

E R T E T T E E E E E R E T R R N N E N N E E N E E R R R R R

-2.5 -2.0-5.0 -0.5

-2.5 — —

-0.3 -1.4 -0.5-0.2 -0.5 — — — — —

-2.0

Articles that specified criteria or algorithms for activation detection in unipolar electrograms: fast downstroke (FD), maximum downslope (MD), peak of the R wave (R) or nadir of the S wave (S). Also listed is the type of evidence presented in favor of the criteria: experiment (E), theory (T), references (R), or none (N). It is assumed that negativity of the exploring electrode produces a downward deflection in the unipolar electrogram. An Asterisk (*) marks analog mapping systems.

18 CARDIAC MAPPING Wilson et al.40,41 assumed on the basis of the dipole theory that the time of local activation beneath an epicardial electrode coincided with the peak of the R wave. Later, influenced by the experiments of Cole, Curtis, and Hodgkin,42–44 they identified local activation with the nadir of the S wave.45 Harris46 used a new approach in 1941. Having demonstrated that the closely paired terminals of a bipolar electrode record only local but not distant activity, Harris compared sequential unipolar and bipolar recordings from the same sites and came to the conclusion that the peak of the R wave was "the unipolar manifestation of an action current in the local surface area."46 The investigation by Sodi-Pallares et al.47 in 1950 was based on the same principles. While all these experiments had been performed with the time-honored string galvanometer,9,48,49 Schaefer,50,51 Veyrat,52 Durrer et al.,20 and Scher et al.53 introduced highly accurate cathode tube equipment into their laboratories. The first to make the discovery that the fast downstroke in a unipolar electrogram signifies the moment of local activation were Schaefer54 in 1951, Veyrat52 in 1953, and Durrer and Van der Tweel55 in 1954. Although Schaefer and Trautwein19 had been able to demonstrate that the time of the maximum upstroke of the monophasic action potential precisely coincides with the peak of a bipolar electrogram recorded simultaneously at the same site, Schaefer's experimental evidence concerning unipolar electrograms54 is incomplete. While Veyrat52 essentially applied Lewis' methods of 1915, Durrer and Van der Tweel's approach did not differ markedly from Harris' in 1941: the absence of a fast bipolar complex in leads from thickened epicardium showed "that the fast part of the differential electrocardiogram [=bipolar electrogram] originates from electrical processes directly under the electrode."55 Simultaneous recordings of unipolar and

bipolar electrograms then yielded the following result: "In all cases where a fast part of the intrinsic deflection could be detected, the top of the differential spike [in the bipolar electrogram] was found to coincide with it."55 Thus, the fast downstroke in a unipolar epicardial electrogram was found to represent local activation. Durrer and Van der Tweel56 were able to extend these findings to intramural electrograms by means of a tripolar intramural electrode. Unlike Durrer, Scher et al.16,53 exclusively used bipolar leads for timing local activity, choosing "the positive or negative maxima of the bipolar records"16 as a criterion (Table 2). Intracellular Leads Since the development of suitable microelectrodes,57,58 many investigators have taken intracellular recordings from myocardial fibers to investigate the temporal correlation between extracellular recordings and the TMP (Table 3). The early experiments by Woodbury et al.,59 Sano et al.,60 Hoffman and Cranefield,61 and Dower and Osbourne62 all had serious shortcomings.63 It is, however, interesting to note that the results of the experiments of Sano et al. in 1956, which, due to a methodological error,63 had found no strict temporal correlation between the steep downslope in the unipolar electrogram and the point of the steepest rise of the TMP,60 were addressed by Durrer as late as 1968.64 The first to prove by modern standards "that the steep negative-going downstroke of the local ECG coincides with the upstroke of the transmembrane potential curve of the underlying cell or cells.. ."65 were Dower and Geddes65 in 1960. In their tracings of the in vivo guinea pig heart, the difference between the 2 events is less than 1 ms.65 In 1972, Myerberg et al.66 took simultaneous intracellular and extracellular bipolar recordings from superfused preparations of the right bundle branch of 30 dogs.

INTERPRETATION OF CARDIAC ELECTROGRAMS

19

Table 2 Activation Detection in Bipolar Electrograms Article 22

Clement E, 1912 Erfmann W, 191337 Garten S, 191338 Lewis T, 191439 Harris, AS 1941 46 Schaefer H, 195119 Scher AM, 195353 Durrer D, 1 95455 Durrer D, 195756 Scher AM, 195716 Durrer D, 1961120 Schaefer H, 196214 Durrer D, 196411 Ostermeyer J, 197923 Abendroth RR, 1980108 Rosenfeldt FL, 1984173 Witkowski FX, 1984174 Kaplan DT, 198791 Blanchard SM, 198889 Simpson EV, 198877 Paul T, 199090 Rosenbaum DS, 1990175 Pieper CF, 199181 Pieper CF, 199182

Algorithm

Evid.

onset* onset* onset* peak* peak* peak* peak* peak* peak* MAA* peak* peak peak* MD* 45°* MAA* MAA MAS, morph peak morph MAS, peak, 45° MAS MAS, peak BSS, MAS, morph, peak

N N N E E E E E E N E T R R R N N E E N E N E E

Articles that specified criteria for activation detection in bipolar electrograms in intraoperative or experimental mapping: the baseline crossing with steepest slope (BSS), the maximum absolute amplitude |V|max (MAA), the maximum absolute slope |dV/dt|max (MAS), the major deflection in the rectified bipolar electrogram (MD), morphological algorithms (morph), the onset of the bipolar EG (onset), the maximum amplitude Vmax (peak), the first deflection from baseline steeper than 45° (45°). The type of the main evidence (Evid.) presented in favor of the criteria is also listed: experiment (E), theory (T), references (R), or none (N). An asterisk (*) denotes analog mapping systems.

Bipolar electrograms occurred less than 1 ms before or after the upstroke of the TMP. In case of increasingly premature stimuli, however, disparities up to 10 ms were possible, which the authors explained by the nonuniform arrival time of an impulse across the transverse axis of the Purkinje fiber. Furthermore, the bipolar electrograms usually became unmeasurable some time before conduction finally failed.66 Experiments by Spach et al.67 on dog Purkinje fibers in the same year showed that the maximum downslope of the local unipolar electrogram occurred within less than 0.2 ms from the maximum upslope of the TMP.

Downar et al.68 noted a similar correlation in the acutely ischemic porcine heart. As their and Akiyama's tracings69 from fibrillating hearts show, activity during ventricular fibrillation that is recorded by intracellular electrodes can go undetected in local unipolar electrograms. In 1985, Spach and Kootsey70 published the results of a theoretical model that predicted that "the negative peak of the derivative of the extracellular [unipolar] potential always occurred at the time of dV/dtmax of the transmembrane potential." In experiments on human atrial muscle, Spach and Dolber71 found time differences

20 CAEDIAC MAPPING Table 3 Correlation of Transmembrane Potentials and Local Electrograms Transmembrane Potentials from

Evidence

Article 59

Woodbury LA, 1950 Sano T, 195660 Sano T, 1958176 Dower GE, 195862 Dower GE, 196065 Hoffman BF, 196061 Dower GE, 196263 Myerburg RJ, 197266 Spach MS, 197267 Downar E, 197768 Kleber AG, 1978128 Cinca J, 1980129 Akiyama T, 198169 Spach MS, 1981177 Gardner PI, 1985164 Spach MS, 198570 Spach MS, 198671 Steinhaus BM, 198873 Steinhaus BM, 198974 Haws CW, 199072 Rudy Y, 199175

D, T D, T D, T D, T D, T D, T D, T D, T D, T D, T D D D D D M,T M, D, T M, T M, T M, D,T M, T

Frog Turtle Dog Guinea pig Guinea pig Dog, PM Guinea pig Dog, CS Dog, CS Pig, Al Pig, Al Pig, Al Dog, Al Dog Dog, CMI — Human atrium — — Dog —

Articles that examined the problem of activation detection in extracellular signals by correlating transmembrane potentials and local electrograms, presenting evidence in the form of diagrams with simultaneous recordings (D), theoretical models (M), or remarks in the text (T). Al = acute ischemia; CMI = chronic myocardial infarction; CS = conduction system; PM = papillary muscle.

of less than 50 us between dV/dtmax of the TMP and the maximum downslope of the local unipolar electrogram. The model of Haws and Lux72 made a similar prediction. Steinhaus' computer simulations73,74 in 1988 showed that under conditions of nonuniform coupling resistances and membrane properties, differences in excess of 1.8 ms can occur between the times of maximum negative slope in the unipolar electrogram and the maximum positive slope in the TMP. The criterion of maximum absolute amplitude of electrograms from bipolar electrodes with 0.1-mm interelectrode distance yielded comparable results and performed better during conditions with marked contribution from distant events.73,74 In 1991, Rudy and Quan75 proposed a model that incorporated gap junctions with varying degrees of resistances between cells. They found that in the middle and in the prejunctional area of the cells, the time of the

maximum downslope in the unipolar electrogram and the time of the dV/dtmax in the TMP coincided with a deviation of less than 100 (us. In the postjunctional area of poorly coupled cells, however, deviations of up to 370 (uswere possible.75 Based on this evidence, we may conelude that the time of the maximum downslope in a unipolar electrogram is a valid fiducial point for identifying times of local activation in unipolar electrograms even though error in excess of 1 ms may occur, Computer Algorithms With the advent of computerized multichannel mapping systems, it became necessary to develop computer algorithms for automatic activation detection, manual marking of electrograms being impractical under the severe time constraints imposed on intraoperative mapping studies.76,77

INTERPRETATION OF CARDIAC ELECTROGRAMS 21 Unipolar electrograms

Practically all algorithms for unipolar electrograms are based on the criterion of the "maximum downslope" or "largest negative slope" (Table 1). The typical unipolar activation algorithm is based on the following 2 principles: 1. The algorithm searches each electrogram for time instants in which the negative slope of the electrogram is larger than a threshold slope; these time instants are assumed to represent possible times of local activation. 2. If 2 or more time instants meet criterion 1 within a defined time window, the time instant with the largest negative slope is chosen as the time of local activation. Individual algorithms basically differ in their choice of the threshold value for criterion 1, the width of the time window for criterion 2, for which variable values78 or values of 40 ms76,79 and 50 ms80 have been used, and the way the slope of the electrogram is calculated (e.g., 2-point, 3-point, or 5-point algorithms).81,82 Some unipolar algorithms also provide a refractory period after each time instant for which an activation has been detected using criteria 1 and 2.76,79 A few algorithms use a relative slope threshold in relation to slopes measured in each electrogram analyzed.76 The main controversy concerning unipolar algorithms is the optimum value of the slope threshold, the problem being to reliably distinguish local activity (associated with a steep downslope) from distant activity without local activity (associated with a shallow downslope). Ideker et al.80 used a slope threshold of 5 mV/2 ms, referring to Durrer and Van der Tweel's 1957 mapping study in healthy dogs.56 Roberts et al.83 determined downslopes in unipolar epicardial

electrograms between 11 and 64 mV/2 ms in noninfarcted canine myocardium. In canine chronic myocardial infarction (MI), Cardinal et al.84 were able to observe "organized propagation of wavefronts" at slopes of -0.5 mV/ms. Regardless of slope, a QS complex recorded in epicardial sites overlying transmural infarcts was interpreted as a cavity complex representing no local activity.84,85 Carson et al.86 observed "organized propagation" at slopes of -0.3 mV/ms in acutely ischemic porcine hearts. In a canine model with right ventricular (RV) isolation procedure, Blanchard et al.87,88 were able to simulate various combinations of local and distant activity by sequential or independent pacing of the RV and the left ventricle (LV). A slope threshold of 1.4 mV could reliably distinguish between local plus distant activity and distant without local activity; however, considerable overlap is likely under conditions of ischemia, chronic MI, and ventricular fibrillation.87,88 Checking computer markings against manual markings of electrograms from patients with Wolff-Parkinson-White (WPW) syndrome and ventricular tachycardia (VT), Masse et al.76 found a slope threshold of –0.2 V/s to perform optimally. Thus, recommended slope thresholds for unipolar activation detection algorithms range from -0.2 to –2.5 mV/ms. Bipolar electrograms

There is considerably less agreement on the best computer algorithm for bipolar electrograms. Basically, the following types of algorithms exist for activation detection in bipolar electrograms (Table 2), the respective merits of which are discussed in the succeeding paragraphs: l. the maximum amplitude Vmax of the bipolar electrogram (peak) and the maximum absolute amplitude | V |

max;

22

CARDIAC MAPPING 2. the maximum absolute slope |dV/dt| max of the bipolar electrogram (MAS); 3. the first elevation of more than 45° from the baseline of the bipolar electrogram (45°); 4. the baseline crossing with the steepest slope (BSS); 5. "morphological"82 algorithms.

The peak algorithm: On the conditions that an excitation wave has a constant shape and propagates with a constant velocity—conditions not met on a microscopic level71 and in diseased tissue10—the bipolar electrogram from closely spaced terminals can be considered to approximate the first temporal derivative of the local unipolar electrogram.20,70 In this case, the peak of the bipolar signal would precisely coincide with the maximum downslope of the local unipolar electrogram, which gives the peak criterion some theoretical justification. The maximum absolute amplitude criterion as opposed to the peak criterion has the advantage that it is independent of the polarity of the bipolar electrodes. Recent experimental evidence in favor of the peak criterion came from Blanchard et al.,89 in whose model of the canine RV isolation procedure the peaks of the bipolar electrograms occurred within 5 ms of the maximum downslope of simultaneous unipolar electrograms in 94% of cases regardless of wavefront-to-fiber orientation. Paul et al.,90 who evaluated 3 bipolar algorithms during sinus mapping in dogs, found that bipolar activation times assigned by the peak criterion were closest to those measured in unipolar electrograms from the same sites with the maximum downslope algorithm. Pieper et al.81 found that the peak criterion gave more stable results than the MAS criterion. In another study by Pieper et al.,82 the peak algorithm showed the closest correspondence with manually determined

activation times among all nonmorphological algorithms. The peak criterion has the added advantage that it does not require calculations like MAS.90 The MAS algorithm: Kaplan et al.91 chose the MAS criterion as the nearest equivalent to the criterion of maximum downslope for unipolar electrograms. This is, however, not correct: as each steep slope of the bipolar electrogram coincides with the maximum downslope of either of the 2 component unipolar electrograms,5 the MAS criterion marks the moment of maximum downslope at either of the 2 electrode terminals but not between the terminals. Paul et al.90 found that the MAS criterion corresponded less well than the peak criterion to unipolar activation times based on the maximum downslope criterion. Pieper et al.81 reported similar findings. The 45° algorithm: Scherlag et al.92 used "the first rapid excursion from the isoelectrical line at an angle of 45° or greater" to mark the onset of the A wave in His bundle electrograms. Paul et al.90 found that the 45° criterion led to significantly earlier activation times compared to the unipolar maximum downslope and even to a different localization of the first epicardial breakthrough. The BSS algorithm: Josephson et al.,93 Cassidy et al.,94 and Vassallo et al.95 used the BSS criterion for endocardial catheter mapping with electrode catheters with 10-mm interelectrode distance; these have a wider field of view than bipolar electrodes for intraoperative mapping. In the context of intraoperative mapping, Pieper et al.82 found that the BSS algorithm showed a slightly poorer correspondence with manually determined activation times than the peak algorithm. Morphological algorithms: Kaplan et al.91 compared a morphological algorithm using lead-specific templates with the MAS algorithm and found that the morphological algorithm gave the more

INTERPRETATION OF CARDIAC ELECTROGRAMS consistent results. Simpson et al.77 developed a complex morphological algorithm that marked the point of symmetry in the bipolar waveform. Pieper et al.82 found that their morphological algorithm, which was based on principles similar to those of Simpson's, performed best in every category: of all algorithms tested, it produced the fewest outliers and showed the fewest differences between computer and manual markings. Based on this evidence, we may conclude that the best among the "simple" bipolar activation detection algorithms is the peak criterion, while morphological algorithms perform somewhat better under practical conditions. Still, much remains to be done in the field of activation detection, as Smith et al. stated in 1990: "Much work is required in this area in order to be able to detect and characterize local activations with high sensitivity, specificity, and temporal accuracy, especially in the fast, chaotic milieu of ventricular fibrillation."96

23

"intrinsic deflection" is defined as any fast downstroke in a unipolar electrogram that is interpreted to indicate local activation. Electrograms in the Normal Human Heart The first to map the activation of the in situ human heart were Barker et al.102 in 1930; these investigators upset contemporary views about the ECG patterns of the bundle branch blocks.64 By 1960, Jouve et al.103 were able to list 21 references of mapping studies in humans. Endocardial electrograms

According to the study on 7 Langendorff-perfused preparations of the human heart by Durrer et al.,104 endocardial activation of the ventricles synchronously starts at 3 sites in the LV 0 to 5 ms after the onset of the LV cavity complex (LV-CC): a central area in the interventricular septum, a paraseptal area Morphological Interpretation near the base of the anterior papillary muscle, and a paraseptal area near the of Cardiac Electrograms base of the posterior papillary muscle. The local activation time is but one The endocardial activation becomes conpiece of information contained in an elec- fluent after 30 ms and the posterobasal 104 94 trogram. In the morphology of a unipolar area is activated last. Cassidy et al. electrogram, the activity of the whole largely confirmed these results. Endoheart is encoded, which allows important cardial activation of the RV starts near conclusions under a number of physio- the insertion of the anterior papillary logical and pathological conditions, while muscle between 5 and 10 ms after the 104 the morphology of bipolar complexes may onset of the LV-CC. Unipolar endocardial electrograms contain valuable information about patfrom canine experiments show a QS morterns of local activation. The following phology with a rapid downstroke in the paragraphs concentrate on ventricular first part of the QRS complex.16,53,56,105 electrograms during sinus rhythm in the human heart. We exclude the subjects of Bipolar endocardial electrograms in the mapping of tachycardias, which has normal human LV from catheters with already been amply reviewed,24,97–100 and 10-mm interelectrode distance have of mapping of the atria,17 of the specialized amplitudes of greater than 3 mV and conduction system,17 and of repolariza- durations of less than 70 ms, and no split, 94 tion.72–74,101 For the purpose of this chapter, fractionated electrograms are found.

24 CARDIAC MAPPING Intramural electrograms

The excitation of the thick LV wall proceeds in an almost strictly endocardial to epicardial direction, whereas the activation of the thin RV wall spreads tangentially from the pretrabecular area until, after 60 to 70 ms, the pulmonary conus and posterobasal area are reached. The activation of the interventricular septum proceeds from left to right and in an apical-basal direction.104 Immediately after introduction of a needle electrode, unipolar intramural electrograms show no rapid deflections and an ST segment elevation due to local injury. After 2 to 3 minutes, the ST segment gradually becomes isoelectric and fast downstrokes in the electrogram appear.56 Unipolar intramural electrograms from the normal human heart show a gradual transition from the endocardial QS complex resembling the LVCC to the epicardial complex with a prominent R wave, the greatest increase of which often occurs in the outer layers of the LV wall.106 Bipolar electrograms in the inner layers of the wall are relatively small, sometimes notched, and generally positive, indicating spread of excitation in an epicardial direction. In the middle and outer layers, they are larger, smooth, and always positive.106

The most accurate descriptions of human unipolar epicardial electrograms are those by Jouve et al.103 and Roos et al.106 (Figure 1), other studies109–111 being methodically inferior.103 Unipolar electrograms over the pretrabecular region of the RV surface have an rS morphology.106 As the excitation spreads over the RV, the r wave increases slightly in duration and amplitude106 and rS or RS103 complexes are recorded, which predominantly reflect distant activity of the LV. Electrograms from the RVOT may have an rS (sometimes with notching or r and/or S), rSr', rsr'S', or, rarely, qRS morphology.17 Unipolar complexes over the interventricular septum may have an rS or (v)rS morphology, (v) standing for vibrated initial segment103 and denoting a broad-tipped positive complex with small amplitude (1 to 2 mV) and long duration (20 ms), which begins with the onset of the LV-CC.106

Epicardial electrograms

Epicardial activation of the ventricles begins in the pretrabecular area of the RV about 20 ms after the onset of the LV-CC5,104,107,108 and over the inferior RV.5,107 LV epicardial breakthrough takes place later over the middle portions of the left anterior and left posterior paraseptal regions5,104,107 and occasionally over the left anterior septum near the base.5,104,107 Latest epicardial activation occurs near the base of the posterior LV104,107,108 or of the RV.5,107

Figure 1. Unipolar epicardial electrograms during sinus rhythm in a 61-year-old male patient with normal 12-lead ECG; figures represent the local activation times in milliseconds following the onset of the left ventricular cavity complex. Reproduced from reference 106, with permission.

INTERPRETATION OF CARDIAC ELECTROGRAMS Unipolar complexes from the LV surface may show q waves, the beginning of which coincide with the LV-CC, with amplitudes of up to 3 mV.106 There are no q waves on the anterior RV and on the first 2 cm of the LV lateral to the left anterior descending artery (LAD).112 Q waves with a duration of up to 27 ms can be present or absent over the RVOT and "in a band of 2-4 cm in width located laterally on the left ventricle but parallel to the anterior descending coronary artery and also posteriorly along the course of the posterior descending branch of the right coronary aftery."112 Over the remaining lateral and posterior LV, Q waves with durations between 4 and 32 ms are regularly found.112 Electrograms over the atrioventricular sulcus show long Q waves as the cavity potential is viewed over the rim of the ventricular cavitites.112 At a distance from the anterior attachment of the interventricular septum, R waves increase in size with amplitudes of up to 20 mV over the lateral wall; they can vary very significantly in closely adjacent regions.106 S waves are deep over the anterior aspect of the LV from apex to base and diminish in

25

size in a lateral direction.106 Thus, typical LV epicardial morphologies would be an rS complex on the anterior wall, a qRS complex on the lateral wall, and a qRs complex on the posterior wall. A discussion of epicardial waveforms in RV hypertrophy, RV diastolic overload, and LV hypertrophy is provided by Kupersmith.17 Electrograms in Preexcitation Syndromes The first intraoperative mapping of a patient with WPW syndrome113 was performed by Durrer and Roos114 in 1967, and the first successful mapping-guided ablation by Cobb et al.115 in 1968. In WPW syndrome, the morphology of the earliest recorded unipolar epicardial electrograms may provide information about the location of the accessory pathway (Figure 2).5,100 While a QS morphology indicates epicardial location of the accessory pathway with spread of activation away from the exploring electrode in an epicardial-to-endocardial direction, an rS morphology signifies endocardial location of the accessory bundle.5,116 In case of

Figure 2. Surface ECGs and epicardial unipolar and bipolar electrograms at the earliest site of preexcitation in a patient with Wolff-Parkinson-White syndrome. Reproduced from reference 5, with permission.

26

CARDIAC MAPPING

free wall pathways, the earliest epicardial intrinsic deflection occurs before or simultaneously with the delta wave in the surface ECG.5 Electrogram criteria indicative of septal pathways are earliest ventricular activation over the anterior or posterior septum, an rS morphology, and an intrinsic deflection after the onset of the surface delta wave.5 Electrograms in Acute Myocardial Ischemia and Infarction Since the classic experiments of Johnston et al.117 in 1935, numerous investigators have studied the acute effects of coronary artery occlusion on electrograms in dogs118–126 and pigs.68,127–129 The following paragraphs focus mainly on the porcine

heart, which, in respect to coronary anatomy, resembles the human heart more closely than does the canine heart.130,131 Prinzmetal et al.121 distinguished 2 patterns of ischemia in unipolar epicardial electrograms: "severe acute ischemia," as in acute ligation of the LAD with "elevation of S-T segments, increase in amplitude of R waves (sometimes 'giant' R waves) and decrease in depth or disappearance of S waves," and "mild ischemia,"121 as in hemorrhagic shock, in which epicardial unipolar electrograms showed "numerous islands of S-T depression, often with loss of amplitude of the R wave and increased depth of the S wave." Downar et al.,68 Kleber et al.,128 and Cinca et al.129 gave a precise account of the electrogram changes after acute ligation of the LAD in the porcine heart (Figure 3).

Figure 3. Local transmembrane potentials (upper tracings) and unipolar electrograms (lower tracings) from the ischemic zone (left panel) and from the border zone (right panel) before (control) and 7.5, 14, 30, 42, and 60 minutes after acute left anterior descending coronary artery occlusion in the Langendorff-perfused porcine heart. Note that the monophasic complex at 7.5 minutes is associated with no local activation, while in the other tracings local activation coincides with a shallow intrinsic deflection after the peak of the R wave. Reproduced from reference 128, with permission.

INTERPRETATION OF CARDIAC ELECTROGRAMS

Unipolar electrograms in the ischemic zone show depression of the initially isoelectric TQ segment, caused by a decreased resting TMP of the ischemic myocardium, ST segment elevation due to a decreased amplitude of the action potential, and inversion of the T waves whenever the repolarization of the ischemic cells occurs later than that of the normal cells.128 The main negative deflection in the QRS complex decreases in magnitude and downslope velocity128 while the R wave becomes tall with a delayed intrinsic deflection after the peak of the R (Figure 3, 14),129 the tallness of the R waves being a consequence of the delayed activation because cancellation effects of earlier activated areas of the heart are absent.129 Cells in the ischemic zone then become unresponsive, and unipolar electrograms show monophasic complexes without intrinsic deflection (Figure 3, 7.5).128 When excitability of the ischemic cells transiently returns between 10 and 20 minutes after occlusion in in situ hearts,128 epicardial electrograms show the reappearance of a large intrinsic deflection with diminished TQ depression and ST elevation (electrogram at 42' in Figure 3).129 Unipolar intramural electrograms show essentially the same changes.128 Bipolar epicardial electrograms in canine acute MI show reduced amplitude and increased duration,120,122,124,125 both of which have also been described in human acute MI,122,123 delay or absence of activation,120,124 and, often, ST segment elevation.120,125 Bipolar intramural124 and endocardial126 electrograms show similar changes. Electrograms in Chronic MI Since the classic experiments by Wilson et al.132,133 in 1935, numerous investigators have examined electrogram morphologies in chronic LAD ligation in

27

dogs,11,84,85,112,120,122,134-139 while there are comparatively few studies on chronic MI in humans.112,122,123,137,138 Epicardial electrograms

Durrer et al. made the following generalizations about unipolar epicardial electrograms in canine chronic MI: "(1) The area with abnormal Q waves was always slightly larger than the infarcted area. (...) (2) The beginning of Q and the beginning of the left ventricular cavity potential were synchronous."11 In small canine subendocardial MIs, the only change in the unipolar epicardial QRS complex is deepening and broadening of the Q waves due to loss of depolarizing myocardium.11 In the case of larger subendocardial MIs in which a thin muscle layer overlies a scar devoid of muscle fibers, epicardial electrograms have a qR or QR morphology with a tall R wave and a delayed intrinsic deflection after the peak of the R (Figure 4).11 The tall R waves result from delayed activation of the muscle layer in a tangential direction at a time when the excitatory forces of the remainder of the ventricles are reduced or absent.11 Daniel et al.112 found good correlation between the canine model of subendocardial chronic MI and clinical findings in humans; the concurrence of abnormal Q waves and delayed epicardial activation times permitted the accurate localization of underlying MIs in human hearts.112,137,138 The characteristic unipolar morphology of transmural chronic MI, both in dogs11,20 and in humans,140 is a QS complex which is synchronous with the LV-CC and which may be fractionated.11,120 A smoothlimbed QS complex indicates the absence of local activity11,84,85 regardless of slope.85 Canine septal chronic MI shows a characteristic picture of abnormal Q waves in unipolar electrograms over the RV without delay in epicardial activation.112

28 CARDIAC MAPPING

Figure 4. Cross-section through chronic canine subendocardial infarction (light area) with unipolar epicardial electrograms before (control) and after left anterior descending coronary artery ligation. In the post myocardial infarction electrograms, note the abnormal Q waves, which occur over an area slightly larger than the infarct, the tall R waves, and the delayed intrinsic deflections. The figures indicate activation times in milliseconds. Reproduced from reference 138, with permission.

Page et al.,85 who compared unipolar and bipolar electrograms in canine chronic MI, proposed an interesting classification of unipolar epicardial electrograms in sinus rhythm: "Class A" electrograms were electrograms of rs morphology with an intrinsic deflection within the QRS wave, "Class B" electrograms were electrograms with a wide QS deflection corresponding to a cavity potential, and "Class C" electrograms were electrograms with a QS complex followed by a late intrinsic deflection. Areas of Class C electrograms extending across regions with Class B electrograms were predicative of the inducibility of VT, the Class C areas becoming the common

pathways of figure-of-8 VTs.85 Whether these findings apply to humans remains to be seen.141 Bipolar epicardial electrograms from infarcted areas in both dogs and in humans show reduced amplitude and increased duration and permit accurate localization of infarcts in both dogs122 and humans.122,123 Intramural electrograms

Unipolar complexes from intrainfarction terminals have a QS form.11 In canine subendocardial MI, unipolar electrograms from terminals between the scar and the epicardium have a Qr or Qrs

INTERPRETATION OF CARDIAC ELECTROGRAMS morphology with small r waves (called embryonic r waves), which gradually increase in size toward the epicardium with progressively later intrinsic deflections.11 Bipolar electrograms have a low voltage, are notched, and, by their polarity, indicate predominant outward spread of activation.11 Again, human clinical data and canine experimental data correlate well.112 Intramural unipolar electrograms from all layers of canine transmural MIs show a QS complex synchronous with the LV-CC,11 which results from the unopposed transmission of cavity potential through the ventricular scar.11,132,133 In a scar completely deprived of muscular tissue, the unipolar QS complexes are smooth and the bipolar complexes broad, smooth, and of small amplitude.11 If the scar contains viable muscle fibers, fractionated unipolar and bipolar electrograms can be recorded.11 A classification of canine heart tissue as normal or infarcted based on peak amplitude and maximum slope of intramural unipolar and bipolar electrograms has been proposed.139 Endocardial electrograms

In canine experiments, Purkinje spikes recorded by endocardial electrode terminals have been reported to fall within normal limits.11,112 In human chronic MI, the activation of the endocardial surface over the MI is delayed.95 Fractionated Electrograms Since Durrer et al.120 reported "small, fast deflections" some 75 ms after the beginning of the QRS complex in electrograms over a canine transmural infarct (Figure 5), similar potentials have been recorded in dogs with acute125,142 and chronic11,143,144 MI as well as in patients with chronic MI during intraoperative

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Figure 5. Durrer's original tracings of fractionated electrograms over a transmural canine infarct. Multiple small amplitude deflections occurring 75 ms after the beginning of the QRS complex are recorded in both the local bipolar (top) and unipolar (bottom) electrogram. Reproduced from reference 120, with permission.

mapping112,140,145-150 and endocardial catheter mapping147,151-154 and in patients with arrhythmogenic RV disease.155—157 Electrograms or potentials have been termed late or delayed if they show ventricular activity after the end of the surface QRS complex21,150,152or if they occur "later than normal"158 or are clearly separated from the normal myocardial activation pattern.140 They have been termed fractionated or fragmented if they show several low-amplitude deflections of typically less than 1 mV.158 Late or fractionated potentials can be recorded during sinus rhythm and VT. The term continuous electrical activity denotes a fractionated electrogram that lasts throughout the cycle during VT159 and which is assumed to represent a composite recording of the electrical activity of a reentry circuit.143,160

30 CARDIAC MAPPING The morphology of late potentials is dependent on the recording technique.21 Endocardial bipolar recordings from mapping catheters with 10-mm interelectrode distance show a QRS synchronous potential followed by multiple smaller potentials of amplitudes of less than 1 mV during the ST segment.21,159 Bipolar recordings based on 1-mm interelectrode distance during intraoperative mapping may show one of the following patterns: after QRS synchronous potential, which may be normal,145 small and broad,21 or absent,145 or a delayed sharp potential of high amplitude follows and is often succeeded by another of similar morphology but with different orientation, or the QRS synchronous signal is followed by multiple fragmented potentials.21,145 Unipolar electrograms may show 1 of 3 patterns: a single, rapid biphasic deflection of rs morphology following a wide QS potential, a double rs deflection, or fragmentation with multiple deflections.140 Although fractionated electrograms can be artifacts resulting from distant activation fronts,158 electrode motion,151,161 filter ringing,162 or other sources,18 most instances of late potentials represent true cardiac potentials.158,159,163 According to the experiments in canine chronic MI by Gardner et al.,164 fractionation of electrograms is caused by asynchronous excitation of different poorly interconnected viable muscle fibers separated by fibrosis; the small amplitude of fractionated electrograms is the consequence of the scarcity of myocardium next to the electrode, TMPs in these regions being normal.164 The clinical significance of late fractionated electrograms lies in the fact that they are markers for the electrical and morphological milieu required for VTs.158,165 Among patients with chronic MI, late fractionated electrograms have been recorded more frequently in those with VT than in those without VT.145–147 In patients with VT, however, neither fractionated nor late

electrograms are specific to the site of origin of VT148,149,152 nor are they present at all sites of origin.148,149,152 Artifacts Artifacts in electrograms can be produced at all the different levels of a modern mapping system: electrodes, amplifiers, filters,148,158,162 analog multiplexors,166 analog-to-digital converters,167,168 and the data storage and display system. As a treatise of the technical aspects of multichannel mapping systems169 is beyond the scope of this chapter, our discussion is restricted to artifacts occurring at the level of the electrodes. Local myocardial injury by electrodes results in ST segment elevation in the local unipolar electrogram.56 Polarization of electrodes can cause slow shifts of the baseline of the signals. Electrodes may record pacing artifacts or 50-Hz or 60-Hz noise. Motion artifacts, which are often rhythmic and repeating,158,161 can be sudden shifts of potential,56 which computer algorithms often misinterpret as activations,80 or may mimic fractionated electrograms.158,161 Poor contact between electrode and myocardium leads to wide complexes in bipolar electrograms with heavier weighing of far-field effects and increased 50-Hz or 60-Hz noise.82 Finally, while all noncoaxial bipolar electrodes ignore activation fronts parallel to the line between the electrode terminals,6,22 widely spaced bipolar electrodes may also record a symmetric complex of 2 deflections if a single small activation front passes by.21,82 Conclusion This chapter presents an overview of major aspects of the interpretation of human ventricular electrograms in sinus rhythm. Though most of what is presented is not new, this information is

INTERPRETATION OF CARDIAC ELECTROGRAMS scattered among many articles. With the exception of Kupersmith's review of intraoperative mapping from 1976,17 there seemed to be no single text that could serve as an introduction for newcomers to the method of cardiac mapping, while the historical basis from much of what is now accepted fact appeared to have been largely forgotten. Indeed, we hope that this chapter may be a due tribute to the pioneers of cardiac mapping without whom mapping would not be what it is now: the gold standard in cardiac electrophysiology. Summary Simultaneous recordings of the TMP and of the local electrogram and theoretical models with computer simulations have shown that the time of myocardial activation, defined as the time of the maximum upstroke in the TMP and the time of the maximum downstroke in the local unipolar electrogram, practically coincide with deviations of less than 1 ms in most, though not all, conditions. For activation detection in unipolar leads, there is universal agreement on computer algorithms using the criterion of "maximum downslope." The main controversy is about the optimum slope threshold for distinguishing local from distant activation, recommended thresholds ranging from -0.2 to -2.5 mV/ms. The advantage of bipolar leads lies in the distinction of local versus distant activity, their disadvantage is their directional sensitivity. Among the various algorithms for activation detection, morphological computer algorithms perform the best under practical conditions. Among the simple algorithms, the peak algorithm corresponds the closest with the times of the maximum downslope in simultaneous unipolar leads. During sinus rhythm in the normal heart, the typical unipolar RV epicardial

31

complex has an rS morphology predominantly reflecting activation of the LV. The typical epicardial complexes of the LV are an rS or qrS complex over an anterior wall, a qRS complex over the lateral wall, and a qRs complex over the posterior wall. Q waves of up to 32 ms are typical of the lateral and posterior LV wall. In WPW syndrome, a QS morphology of unipolar epicardial electrograms in the preexcited area indicates epicardial location of the accessory pathway and an rS morphology endocardial location. The characteristic changes of unipolar epicardial complexes during acute ischemia are a reduced amplitude of the initial negative deflection, a tall R wave with or without a shallow intrinsic deflection after the peak of the R, massive ST segment elevation, and TQ segment depression. Unipolar epicardial electrograms overlying subendocardial MI typically show an abnormally deep and long Q wave and a tall R wave with a delayed intrinsic deflection. The typical unipolar complex over a transmural MI is a QS complex, which is synchronous with the LV-CC and which may be smooth or fractionated. Fractionated electrograms consist of several low-amplitude deflections after the QRS complex. They are caused by asynchronous excitation of poorly interconnected muscle fibers and indicate that the electrophysiological milieu for ventricular arrhythmias to occur is present. References 1. Lewis T, Rothschild MA. The excitatory process in the dog's heart. Part II. The ventricles. Philos Trans R Soc Lond [Biol] 1915;206B: 181-226. 2. Samojloff A. Weitere Beiträge zur Elektrophysiologie des Herzens. Pflugers Arch 1910;135:417-468. 3. Lewis T. The Mechanism and Graphic Representation of the Heart Beat. 3rd ed. London: Shaw and Sons; 1925:55.

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4. Wenckebach KF, Winterberg H. Die unregelmäßige Herztätigkeit. Leipzig: Verlag von Wilhelm Engelmann; 1927: 44. 5. Gallagher JJ, Kasell J, Sealy WC, et al. Epicardial mapping in the Wolff-ParkinsonWhite syndrome. Circulation 1978;57: 854-866. 6. Ideker RE, Smith WM, Blanchard SM, et al. The assumptions of isochronal cardiac mapping. Pacing Clin Electrophysiol 1989;12:456–478. 7. Ershler PR, Lux RL. Derivative mapping in the study of activation sequence during ventricular tachyarrhythmias. IEEE Proc Comput Cardiol 1987;623624. 8. Barnes AR, Pardee HEB, White PD, et al. Standardization of precordial leads: Joint recommendations of the American Heart Association and the Cardiac Society of Great Britain and Ireland. Am Heart J 1938;15:107-108. 9. Burch GE, DePasquale NP. A History of Electrocardiography. Chicago: Year Book Medical Publishers; 1964. 10. Berbari EJ, Lander P, Sherlag BJ, et al. Ambiguities of epicardial mapping. J Electrocardiol 1991;24(Suppl): 16-20. 11. Durrer D, Van Lier AAW, Buller J. Epicardial and intramural excitation in chronic myocardial infarction. Am Heart J1964;68:765-776. 12. Wilson FN, Johnston FD, Macleod AG, et al. Electrocardiograms that represent the potential variations of a single electrode. Am Heart J 1934;9:447-458. 13. Wilson FN, Macleod AG, Barker PS. The Distribution of the Currents of Action and of Injury Displayed by Heart Muscle and Other Excitable Tissues. (University of Michigan Studies, Scientific Series. Vol. X.) Ann Arbor: University of Michigan Press; 1933. 14. Schaefer H, Haas HG. Electrocardiography. In: Hamilton WF, Dow P (eds): Handbook of Physiology. Section 2: Circulation. Vol. I. Washington, DC: American Physiological Society; 1962:323–415. 15. Scher AM. The sequence of ventricular excitation. Am J Cardiol 1964;14:287-293. 16. Scher AM, Young AC. Ventricular depolarization and the genesis of the QRS. Ann N YAcad Sci 1957;65:768-778. 17. Kupersmith J. Electrophysiologic mapping during open heart surgery. Prog Cardiovasc Dis 1976;19:167-202.

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of its uses and limitations. Circulation 1972;46:601-613. 93. Josephson ME, Horowitz LN, Spielman SR, et al. Role of catheter mapping in the preoperative evaluation of ventricular tachycardia. Am J Cardiol 1982;49: 207-220. 94. Cassidy DM, Vassallo JA, Marchlinski FE, et al. Endocardial mapping in humans in sinus rhythm with normal left ventricles: Activation patterns and characteristics of electrograms. Circulation 1984;70:37-42. 95. Vassallo JS, Cassidy DM, Marchlinksi FE, et al. Abnormalities of endocardial activation pattern in patients with previous healed myocardial infarction and ventricular tachycardia. Am J Cardiol 1986;58:479-484. 96. Smith WM, Wharton JM, Blanchard SM, et al. Direct cardiac mapping. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: W.B. Saunders Co.; 1990:849-858. 97. Downar E, Harris L, Mickleborough LL. Direct cardiac mapping of ventricular arrhythmias. Prog Cardiol 1987;1:273288. 98. Josephson ME, Miller JM, Hargrove WC III, et al. Intraoperative mapping of ventricular tachycardia associated with coronary artery disease. In: Aliot E, Lazzara R (eds): Ventricular Tachycardia: From Mechanism to Therapy. Boston: Martinus Nijhoff Publishers; 1987:411-436. 99. Tyagii S, Sharma AD, Guiraudon G, et al. Intraoperative cardiac mapping of preexcitation syndromes and ventricular tachycardia. J Electrophysiol 1989;3: 47-64. 100. Shenasa M, Cardinal R, Savard P, et al. Cardiac mapping. Part I. Wolff-ParkinsonWhite syndrome. Pacing Clin Electrophysiol 1990; 12:223-230. 101. Spach MS, Barr RC. Ventricular intramural and potential distributions during ventricular activation and repolarisation in the intact dog. Circ Res 1975;37:243257. 102. Barker PS, Macleod AG, Alexander J. The excitatory process observed in the exposed human heart. Am Heart J 1930; 5:720-742. 103. Jouve A, Corriol J, Torresani J, et al. Epicardial leads in man. Am Heart J 1960;59:856-868.

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137. Daniel TM, Cox JL, Sabiston DC Jr, et al. Epicardial and intramural mapping of activation of the human heart—a technique for localizing infarction and ischemia of the myocardium. Circulation 1969;39(Suppl III):III-66. Abstract. 138. Daniel TM, Boineau JP, Cox JL, et al. Mapping of epicardial and intramural activation of the heart: A technique for localization of chronic infarction during myocardial revascularisation. J Thorac Cardiovasc Surg 1970;60:704-709. 139. Claydon FJ, Pilkington TC, Ideker RE. Classification of heart tissue from bipolar and unipolar intramural potentials. IEEE Trans Biomed Eng 1985;32:513520. 140. Lacroix D, Savard P, Shenasa M, et al. Spatial domain analysis of late ventricular potentials: Intraoperative and thoracic correlations. Circ Res 1990;66:55-68. 141. Ideker RE, Tang ASL, Daubert JP. On the trail of ventricular tachycardia or the adventure of the unspeckled band. Pacing Clin Electrophysiol 1988;11:650-655. Editorial. 142. Boineau JP, Cox JL. Slow ventricular activation in acute myocardial infarction. A source of re-entrant premature ventricular contractions. Circulation 1973;48: 702-713. 143. El-Sherif N, Scherlag BJ, Lazzara R, et al. Re-entrant ventricular arrhythmias in the late myocardial infarction period. 1. Conduction characteristics in the infarction zone. Circulation 1977;55:686702. 144. Berbari EJ, Scherlag BJ, Hope RR, et al. Recording from the body surface of arrhythmogenic ventricular activity during the S-T segment. Am J Cardiol 1978;41:697-702. 145. Klein H, Karp RB, Kouchoukos NT, et al. Intraoperative electrophysiologic mapping of the ventricles during sinus rhythm in patients with a previous myocardial infarction: Identification of the electrophysiologic substrate of ventricular arrhythmias. Circulation 1982;66: 847-853. 146. Wiener I, Mindich B, Pitchon R. Determinants of ventricular tachycardia in patients with ventricular aneurysms: Results of intraoperative epicardial and endocardial mapping. Circulation 1982;65: 856-861.

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147. Simson MB, Untereker WJ, Spielman SR, et al. Relation between late potentials on the body surface and directly recorded fragmented electrograms in patients with ventricular tachycardia. AmJCardiol 1983;51:105-112. 148. Kienzle MG, Miller J, Falcone RA, et al. Intraoperative endocardial mapping during sinus rhythm: Relationship to the site of origin of ventricular tachycardia. Circulation 1984;70:957-965. 149. Vassallo JA, Cassidy DM, Simson MB, et al. Relation of late potentials to site of origin of ventricular tachycardia associated with coronary heart disease. Am J Cardiol 1985;55:985-989. 150. Schwarzmaier H-J, Karbenn U, Borggrefe M, et al. Relation between ventricular late endocardial activity during intraoperative endocardial mapping and lowamplitude signals within the terminal QRS complex on the signal-averaged surface electrocardiogram. Am J Cardiol 1990;66:308-314. 151. Waxman HL, Sung RJ. Significance of fragmented ventricular electrograms observed using intracardiac recording techniques in man. Circulation 1980;6: 1349-1356. 152. Cassidy DM, Vassallo JA, Buxton AE, et al. The value of catheter mapping during sinus rhythm to localize the site of origin of ventricular tachycardia. Circulation 1984;69:1103-1110. 153. Cassidy DM, Vassallo JA, Buxton AE, et al. Catheter mapping during sinus rhythm: Relation of local electrogram duration to ventricular cycle length. Am J Cardiol 1985;55:713-716. 154. Stevenson WG, Weiss JN, Wiener IW, et al. Fractionated endocardial electrograms are associated with slow conduction in humans: Evidence from pace-mapping. J Am Coll Cardiol 1989; 13:369-376. 155. Fontaine G, Frank R, Gallais-Hamonno F, et al. Electrocardiographie des potentiels tardifs du syndrome de post-excitation. Arch Mal Coeur 1978;71:854-864. 156. Marcus FI, Fontaine GH, Guiraudon GM, et al. Right ventricular dysplasia: A report of 24 adult cases. Circulation 1982;65:384-398. 157. Fontaine G, Frank R, Tonet JL, et al. The Mikamo lecture. Arrhythmogenic right ventricular dysplasia: A clinical model for the study of chronic ventricular tachycardia. Jpn Circ J 1984;48: 515-538.

158. Ideker RE, Mirvis DM, Smith WM. Late, fractionated potentials. Am J Cardiol 1985;55:1614-1621. Editorial. 159. Josephson ME, Wit AL. Fractionated electrical activity and continuous electrical activity: Fact or artifact? Circulation 1984;70:529-532. Editorial. 160. Josephson ME, Horowitz LN, Farshidi A. Continuous local electrical activity: A mechanism of recurrent ventricular tachycardia. Circulation 1978;57:659-665. 161. Ideker RE, Lofland GK, Bardy GH, et al. Late fractionated potentials and continuous electrical activity caused by electrode motion. Pacing Clin Electrophysiol 1983;6:908–914. 162. Simson MB. Use of signals in the terminal QRS complex to identify patients with ventricular tachycardia after myocardial infarction. Circulation 1981;64:235— 242. 163. Wit AL, Josephson ME. Fractionated electrograms and continuous activity: Fact or artifact. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology and Arrhythmias. Orlando: Grune & Stratton, Inc.; 1985:343-352. 164. Gardner PI, Ursell P, Fenoglio JJ Jr, et al. Electrophysiologic and anatomic basis for fractionated electrograms recorded from healed myocardial infarcts. Circulation 1985;72:596–611. 165. Breithardt G, Borggrefe M, MartinezRubio A, et al. Pathophysiological mechanisms of ventricular tachyarrhythmias. Eur Heart J 1989;10(Suppl E):9-18. 166. Hoeks APG, Schmitz GML, Allessie MA, et al. Multichannel storage and display system to record the electrical activity of the heart. Med Biol Eng Comput 1988; 26:434–438. 167. Barr RC, Spach MS. Sampling rates required for digital recording of intracellular and extracellular cardiac potentials. Circulation 1977;55:40–48. 168. Pieper CF, Lawrie G, Roberts R, et al. Bandwidth-induced errors in parameters used for automated activation time determination during computerized intraoperative cardiac mapping: Theoretical limits. Pacing Clin Electrophysiol 1991;14:214-226. 169. Ideker RE, Smith WM, Wolff P, et al. Simultaneous multichannel cardiac mapping system. Pacing Clin Electrophysiol 1987;10:281-292. 170. Smith WM, Ideker RE, Kinicki RE, et al. A computer system for the intraoperative

INTERPRETATION OF CARDIAC ELECTROGRAMS mapping of ventricular arrhythmias. Comput Biomed Res 1980;13:61-72. 171. Parson I, Mendler P, Downar E. On-line cardiac mapping: An analog approach using video and multiplexing techniques. Am J Physiol 1982;242:H526–H535. 172. Parson I, Downar E. Clinical instrumentation for the intra-operative mapping of ventricular arrhythmias. Pacing Clin Electrophysiol 1984;7:683-692. 173. Rosenfeldt FL, Harper RW, Wall RE, et al. A digital timing and display unit for intra operative mapping of cardiac arrhythmias.

Pacing Clin Electrophysiol 1984;7:985–992. 174. Witkowski FX, Corr PB. An automated simultaneous transmural cardiac mapping system. Am J Physiol 1984;247: H661-H668.

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175. Rosenbaum DS, Kaplan DT, Wilbur DJ, et al. The precision of electrophysiologi

cal mapping: Localizing depolarization

wave front from digital extracellular electrograms and the role of data sampling rate. J Cardiovasc Electrophysiol 1990;1:2-14. 176. Sano T, Tsuchiahashi H, Shimamoto T. Ventricular fibrillation studied by the microelectrode method. Circ Res 1958: 41-46. 177. Spach MS, Miller WTII, Geselowitz DB, et al. The discontinuous nature of propagation in normal canine cardiac muscle. Evidence for recurrent discontinuities of intracellular resistance that affect the membrane currents. Circ Res 1981;48: 39-54.

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Chapter 3 Methodology of Cardiac Mapping Haris J. Sih, PhD and Edward ]. Berbari, PhD

Cardiac mapping involves making some measurement of the heart in 3-dimensional space and then displaying that measurement on a similar 3-dimensional representation. That measurement could be of its mechanical function, electrical function, structure, or some combination of these. To add further complexity, the measurement itself could be a value (such as activation time) or an array (such as conduction velocity, with a magnitude and direction). In the current literature, cardiac mapping usually refers to measuring the electrical activity of the heart in 2 or 3 dimensions and displaying that activity on 2-dimensional representations. The electrical activity is often activation times or isopotentials that are measured directly from electrodes in contact with the tissue or are calculated from body surface electrodes or other electrodes that are not in contact with the tissue. This chapter provides a brief introduction into the techniques of this category of cardiac mapping, and then illustrates how we have dealt with some typical complications to this type of mapping in infarct regions and during atrial fibrillation.

Overview of Current Techniques Most electrical mapping of the heart is done with either unipolar or bipolar electrodes and with either simultaneous multielectrode arrays or sequential recordings from several electrodes on the distal end of a catheter. A unipolar (or single-ended) measurement is usually made relative to some distant, stable reference on the body, the exact position of which is generally not considered critical to the data acquisition. A bipolar (or differential) measurement is between 2 electrodes that are often closely (<1 cm) spaced. Often, the activation time of the cells beneath the electrode must be determined. Criteria used to derive activation times from the recorded signals are discussed in detail elsewhere in this book. Briefly, the maximum negative derivative is the most widely used criterion for defining activation time in a unipolar electrogram. The most widely used criterion for bipolar electrograms is the peak of the main deflection.1

Supported in part by The Herman C. Krannert Fund and a Specialized Center of Research (SCOR) grant (HL52323) from the National Heart, Lung, and Blood Institute of the National Institutes of Health. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division;©2003. 41

42 CArDIAC MAPPING Using either unipolar or bipolar electrodes, one can map sequentially from a single electrode or simultaneously from multiple electrodes. Aside from the ability to map endocardially without an openchest procedure, mapping using sequential recordings has the advantage of requiring a minimal hardware set-up. Essentially, one only requires a recording catheter, one amplifier, and a display. With such a limited set-up, however, visualization of cardiac activation requires knowledge of the anatomy and a good imagination to mentally reconstruct the sequence of activation. The use of multi-

An epicardial approach avoids these issues, at least to some degree, at the expense of requiring an open-chest procedure. Often, but not always, epicardial electrode arrays are arranged in a regular grid pattern and are of varying construction and dimension. Since epicardial mapping is seldom used in the clinical setting and since each experiment may require unique arrays, most epicardial arrays are made "in-house" with the materials and methods convenient to each researcher. Regardless of the construction, investigators must be aware of the contact quality between the electrodes and the tissue, the necessary interelectrode spacing, whether bipolar or unipolar electrodes are electrode catheters placed under fluoro scopic guidance and the use of multichannel prudent, and the stability and reproelectrophysiology recording systems facil- ducibility of the array placement. Whether itates sequential mapping, but the mental endocardial or epicardial arrays are used, reconstruction of activation is still an inte- the hardware requirements are identical, gral part of this process. While obviously generally consisting of a bank of amplifiers, a useful clinical tool, sequential mapping filters, multiplexers, and analog-to-digital relies on reproducible activation sequences converters, and then some means to write and low spatial variation (i.e., low spatial the data to digital media. As technology develops, the definitions frequency content) of activation, and thus can be insufficient for some research and advantages/disadvantages of multielectrode or sequential mapping become applications. Multielectrode array mapping entails more complex. Two recently developed simultaneously recording the electrical commercial systems are prime examples activity of the heart from a large number of this. The CARTO™ system (Biosense of sites (typically >100). Endocardial map- Webster, Diamond Bar, CA) is essentially ping can be accomplished with basket a sequential mapping system with a catheters, which have electrodes placed sophisticated display.2,3 This system places on thin wire-like splines. When the catheter a catheter tip in an electromagnetic field is inserted into a vein or artery, the and then uses the field to register the splines are contracted to fit into the diam- 3-dimensional location and orientation of eter of the catheter. Once in the chamber the catheter simultaneously with the of interest, the splines are expanded like recorded electrical activity. This allows for the opening of an umbrella, and the elec- a 3-dimensional reconstruction of the endotrodes are exposed and are hopefully in cardial surface and the activation sequence contact with the tissue. While basket across that surface. While this system aids catheters allow for closed-chest, endocar in the visualization of activation, it is still dial recordings, they are limited by sev- limited by its sequential mapping capabileral factors, including the lack of control ities, making it an ineffective tool for mapover which electrodes are in contact with ping nonrepetitive arrhythmias. The EnSite™ system (Endocardial the tissue, unevenly spaced electrodes between splines, and the difficulty in pre- Solutions, Inc., St. Paul, MN) is a multielectrode recording system that records cise anatomical location of the splines.

METHODOLOGY OF CARDIAC MAPPING from 64 sites on a noncontact balloon catheter then reconstructs the endocardial recordings on an ellipsoid-like projection of the endocardium using inverse solution techniques.4 This system changes the definition of spatial resolution for cardiac maps, since "virtual" electrograms can be reconstructed from nearly anywhere on the endocardial projection. The EnSite system can reconstruct activation sequences on the endocardial projection for either repetitive or nonrepetitive arrhythmias. Whether this system can be used to study mechanisms of arrhythmias with high spatial frequency content remains to be determined. As digital hardware speeds have gone up and their prices have come down, the conceivable number of simultaneous channels that can be acquired has increased. However, data management issues, such as electrogram display/review, activation visualization, etc., are more problematic with ever-increasing numbers of channels. These issues are especially troublesome for studying activation in a complex substrate and for studying rapid and irregular rhythms. To illustrate these technical challenges, this chapter focuses on 2 specific areas of cardiac mapping: mapping late potentials and mapping atrial fibrillation. Introduction For studies of late potentials, our original interest in using cardiac mapping was to establish the fundamental bases of the late potentials seen on the body surface ECG.5 The goal was to characterize, in an animal model, the late potential generator, e.g., signal strength, position, and orientation, and to use this information to model and compare with the actual body surface recordings. This prompted a more accurate assessment of the implicit assumptions of cardiac mapping in order to improve the late potential model. Questions concerning the determination of activation time and contour generation became paramount, as

43

did determining which conditions were implicitly and explicitly assumed. While several studies have been performed to correlate activation times to extracellular electrogram features, little has been studied about the mechanics of contour generation for activation maps. Some investigators use a visual approach and manually draw the maps. Others use "canned" contour programs available in scientific subroutine software libraries, and still others use custom-written software. Only a few references exist on the mechanics of contour generation as applied to cardiac activation.6–9 The field of cartography has evolved around, and is usually applied to, geophysical problems,10,11 but a number of newer methods have been used in recent years. It is difficult to determine the extent to which these newer methods have been used in either the published reports or from commercial vendors in cardiac applications. It is our belief that many conclusions about activation sequences have been deduced from poorly constructed contour maps. Some general issues have been discussed by Ideker et al.12 In essence, a fundamental assumption about the underlying structure of activation is implicitly or explicitly made without regard to problems concerning spatial sampling or the assumption of spatial continuity. However, there have been no formal attempts to define the spatial sampling necessary for cardiac activation maps. Spatial continuity is the 2-dimensional property similar to time domain continuity. Most linear mathematical approaches to signal processing require that there be no abrupt changes in the values of the measured quantity; that is, the time derivatives are not infinite. This is also true for the 2dimensional problem where the spatial derivatives are not infinite. In other words, no point in the spatial representation can be multivalued. Unfortunately, mapping in infarct regions almost assures

44 CARDIAC MAPPING discontinuous regions. The inhomogeneity in conduction properties is well known and the presence of dead tissue, i.e., nonconducting regions, must be accounted for in the contour generation process. In geophysical terms, such discontinuities are called faults, and generating contours around a fault region should be considered in cardiac map generation. For atrial fibrillation mapping, the goal has been to use cardiac maps to probe the mechanisms of atrial fibrillation. Some early examples of the successful application of multielectrode mapping to study atrial fibrillation were performed by Allessie et al.13,14 In these studies, the authors were able to verify a long-standing hypothesis on the multiple circulating wavelet behavior of atrial fibrillation.15 One of the greatest complications associated with activation mapping during atrial fibrillation is that the very nature of atrial fibrillation may preclude a succinct presentation of activation. Since a hallmark of atrial fibrillation is its nonrepetitive activation of the atria, categorizing activation can be difficult. Cox et al.16 provided one framework with which to conceptualize possible reentrant patterns during atrial fibrillation by describing the locations of reentrant circuits and how they might activate the atria. More recently, Konings et al.17 categorized activation patterns according to the number of wavelets and the degree of conduction block observed in activation maps. Many other studies resort to a subjective description of the various patterns or the relative complexity of activation with the only quantitative data being cycle length or conduction velocity data. While these observations can be insightful and important, more quantitative measures of activation are needed in order to compare and contrast atrial fibrillation maps. One of our hypotheses is that atrial activation during atrial fibrillation has transient episodes of organization and

that the organization can be quantified. We propose that an organization map may provide new insights into atrial fibrillation mechanisms that could not otherwise be easily discerned with traditional epicardial mapping techniques. Methods

Our mapping system technology has been described previously18,19 and is briefly summarized. The front end consisted of 128 differential amplifiers with programmable gain and bandwidth. Typical settings were a gain of 100 and a bandwidth of 0.1 to 300 Hz. Each signal was sampled at 1000 Hz with a high-speed analog-todigital converter and an interchannel dwell time of 2.0 µs resulting in a maximum time skew of 0.26 ms between channels \ and 128. For late potential mapping, the electrode array was a unipolar 10x10 square grid with a 4-mm spacing between electrode centers. Each side had 6 electrodes, which "rounded out" the edges for a total of 124 epicardial sites within a 6-cm diameter. The remaining 4 channels were for bipolar surface ECG leads. The signal reference was the right leg. The data acquisition computer was an SLS-5450 (Concurrent Computer Corporation, Westford, MA) and was networked to an IBM RS6000 (IBM, Armonk, NY) for data analysis. Experimental data were obtained from the 4-dayold canine infarct model.20 The left anterior descending coronary artery was ligated using the Harris 2-stage tie21 just inferior to the first diagonal branch. All recordings were made during sinus rhythm. For our initial atrial fibrillation studies, we used a commercially available array to epicardially map canine atria during different rhythms. This array had 112 unipolar electrodes in an 8 x 14 grid spanning 2x4 cm. The elements had approximately 1-mm-diameter tips and were constructed of stainless steel. Because of the size of the array, only sections of the

METHODOLOGY OF CARDIAC MAPPING 45 atria could be mapped at any one time. These sequential maps were obtained from the right or left atrial free walls or from the right or left atrial appendages. Two atrial fibrillation models were used: vagal atrial fibrillation induced by atrial burst pacing with superimposed vagal stimulation,22 or self-sustained atrial fibrillation induced by chronic (>4 weeks), continuous rapid atrial pacing.23–25 In our initial experiments on atrial fibrillation organization, we devised a simple algorithm that quantifies the degree of nonlinearity between 2 electrograms on a relatively short time scale (<500 ms). We have shown that this algorithm is more sensitive to changes in atrial fibrillation

organization than 2 previously published algorithms.26 Our initial data are used to compare the relative organization of the vagal model of atrial fibrillation and the chronic pacing model of atrial fibrillation as potential human correlates for nonsustained and chronic atrial fibrillation, respectively. These data demonstrate an alternative method for summarizing mapping data that traditional activation mapping might not as readily quantify. Activation Times in Infarct Regions Figure 1 is an example of a set of recordings overlying the infarct region. Note

Figure 1. A set of 128 electrograms obtained over the infarct in the canine model. The electrode diameter is 6 cm. All recordings are unipolar, with a right leg reference, and were obtained during sinus rhythm.

46 CARDIAC MAPPING the normal biphasic appearance of recordings on the left side. As activation proceeds across the epicardium, the emergence of deep "Q waves" appears and the local late potential appears to migrate after the QRS complex in electrograms on the right side. The top trace in Figure 2 shows the electrograms from channel #71 from the example in Figure 1. The lower traces are the time derivative (dV/dt) and 2 spatial derivatives, dV/dx and dV/dy. The latter are in effect 4-mm spaced bipolar recordings in which the laterally adjacent recording is subtracted to form the horizontally oriented bipole (dV/dx). Similarly, the bottom trace (dV/dy) is formed by subtracting the inferiorly adjacent recording to form the vertically oriented bipole. Note that the x

and y directions only relate to the orientation of the signal plots in Figure 1 and not to any anatomical orientation. In the original electrogram (top trace), the QRS is one of a deep "Q wave" overlying the infarct with a well-defined biphasic late potential well after the QRS complex. The time of local activation of this late potential varies from 109 ms to 104 ms, and 106 ms in dV/dt, dV/dx, and dV/dy, respectively. This slight variation of 5 ms was not considered to be of great significance. Figure 3 is an example of an adjacent electrogram (#84) taken from the same array as the electrogram in Figure 2. The recordings are in the same format. Note now that the activation times differ considerably (=20 ms) between the dV/dt

Figure 2. Electrogram #71, from the same array as in Figure 1, is in the top trace. The second trace is the time derivative, dV/dt. Spatial derivatives, dV/dx and dV/dy were obtained subtracting horizontally and vertically adjacent recordings, respectively.

METHODOLOGY OF CARDIAC MAPPING 47

Figure 3. Electrogram #84 in the same format as in Figure 2.

and the bipolar recordings. The reason for the difference is because the morphology of the late potential has 2 distinct deflections and results in an ambiguous situation. The maximum negative time derivative criterion selected the second deflection, while the maximum of the bipolar recording selected the initial late potential deflection. In our own application for comparing body surface potentials, we selected the end of activation as the parameter of choice and based the selection on different criteria. Another approach is to examine the electrograms in the context of their neighbors. Figure 4 is a column of recordings from Figure 1, showing the time and spatial derivatives adjacent to each. Electrogram #48 shows an ambiguous late potential, i.e., 2 deflections. An arrow

points up from the first late potential deflection to electrogram #37. Note the simultaneous occurrence with the unambiguous late potential. An arrow pointing down from the second deflection of electrogram #48 to the lower electrogram (#59) shows a similar occurrence with a later deflection. The unanswered question is, of course, "Is electrogram #48 recording a local event or just the events occurring at some distance?" In vitro electrograms at an even finer spatial resolution (2 mm) demonstrate that this question may not be easily answered with standard unipolar electrogram analysis. Figure 5 shows an example of 30 unipolar electrograms with a 2-mm interelectrode spacing recording activity over an infarct region. In the top left corner of the map, the unipolar

48 CARDIAC MAPPING

Figure 4. A column of recordings from Figure 1 showing late potentials occurring after the QRS. The arrows imply the possibility that ambiguous recordings (#48 and #84) are recorded from nearby tissue and not directly underneath the electrode.

recordings show fairly typical biphasic electrograms. Recordings in the bottom section of the map, however, are fractionated. Over a distance as small as 2 mm, the character of an electrogram changes dramatically, from unambiguous to highly fractionated. From this example, it is clear that a 2-mm interelectrode spacing is not sufficient to rep-

resent activation through the infarct region. What electrode density is necessary to reveal the nature of the sources of the fractionated electrogram and to identify truly local events has not yet been determined. In vitro correlations with extracellular and intracellular recordings from infarcted regions may be the only way to fully answer this question.

METHODOLOGY OF CARDIAC MAPPING 49 example of how double potentials can occur. In this example, several beats during atrial fibrillation had a repetitive activation sequence. Electrograms in locations A and B are dominated by one repeating wavefront while electrograms in locations D and E are dominated by a different wavefront. Electrograms in location C apparently reflect both wavefronts for approximately 1 second. There is no clear choice between the electrograms to delineate activation times for location C. The choice to delineate activation times for both electrograms, either electrogram, or neither electrogram is arbitrary. One approach to the difficulties associated with activation time delineation Figure 5. A set of 30 electrograms obtained over and the additional problems of concisely the infarct in the canine model. The interelectrode distance is 2 mm. The character of the summarizing multiple activation maps electrograms can change from a simple bipha- is to circumvent the issue by choosing an sic deflection to a multiphasic, fractionated elec- alternative representation of the map. trogram within 2 mm. Such representations could include almost any imaginable signal processing function that might extract some useful Organization Mapping in parameter about activation. Several recently proposed signal processing algoAtrial Fibrillation rithms claim to measure the "organizaActivation maps of atrial fibrillation tion" of atrial fibrillation activation. We can be difficult to interpret because of are currently exploring such a technique the varying patterns and the large that quantifies "disorganization" as the number of activations per second. degree of nonlinearity between 2 elecBecause of these difficulties, alternative trograms. Preliminary results indicate representations of fibrillation mapping that this measure has good sensitivity data have been explored, including maps in discriminating different levels of fibof average cycle length,25 consistency of rillation organization.26 This and simiactivation direction,27 and organization lar methods replace the subjective mapping. 28 Some of these methods delineation of activation times by objecrequire that activation times be detected tively and automatically calculating the from the atrial electrograms. However, relative organization. In one of our first similar to how fractionated electrograms applications of this measure to mapcomplicate activation detection in the ping data, we compared organization betinfarct zone, multiphasic electrograms ween vagal and chronic models of atrial and double potentials complicate atrial fibrillation. Organization as we have defined it fibrillation. During atrial fibrillation, multiphasic electrograms and double can be measured between any pair of elecpotentials often appear, usually because trograms. So, to derive some measure of of the electrode's sensing multiple, the regional organization, we used our nearby wavefronts. Figure 6 shows one technique of quantifying nonlinearity on

50 CARDIAC MAPPING

Figure 6. Double potentials during atrial fibrillation. The activation map with hand-drawn contours is shown in the top and taken during the interval shown by the boxed region on the signals. The double potentials in channel C are a result of recording activity over an arc of block, where 2 wavelets pass on either side of the arc at different times.

multiple pairs. Our 8 x 14 electrode array mapped the left and right atrial free walls and the left and right atrial appendages sequentially. By calculating the nonlinearity between multiple pairs

of electrodes in the 8 x 14 array and then plotting the nonlinearity versus the interelectrode distance, one could derive an exponential-like plot of the regional nonlinearity (Figure 7). Thus in, for

METHODOLOGY OF CARDIAC MAPPING

51

Figure 7. Example of nonlinearity between sites versus interelectrode distance. To summarize regional organization, the nonlinearity is fit to an exponential function, shown in the black line. The exponential decay constant, which has units of distance, can be interpreted as a measure of the spatial extent to which atrial fibrillation is organized. Smaller values of the decay constant indicate less organization, and larger values of the decay constant indicate more organization.

example, the right atrial free wall, one can plot how rapidly over distance the organization decreases between sites during fibrillation. By then determining the exponential decay constant, a measure of the spatial extent of organization (in mm) can be derived, with larger values of the decay constant implying a greater spatial extent of organization and smaller values of the decay constant implying a smaller extent of organization. Over a series of 13 vagal atrial fibrillation dogs and 18 chronically paced atrial fibrillation dogs, we found differences in organization, primarily in the right atrium. The right atria in the vagal atrial fibrillation model were less organized than right atria in the chronic atrial fibrillation model, while left atrial organization was unchanged (Figure 8).

After bilaterally stimulating the vagus in the chronic atrial fibrillation model and remeasuring organization, we found that bilateral vagal stimulation reduced the organization, but only significantly in the right atrium (P < 0.0001). These differences were attributed to the differences in left and right vagal innervation of the atria and to the electrical remodeling that occurs during the longterm pacing in the chronic model. This representation of organization can provide additional insight into atrial fibrillation mechanisms that might not be apparent with traditional activation maps. We are currently pursuing means to quantify the spatial extent of organization over smaller regions to achieve a true map of atrial fibrillation organization.

52 CARDIAC MAPPING

Figure 8. Comparison of organization between vagal atrial fibrillation and chronic atrial fibrillation. Organization was not statistically different between the left atrium (LA) and right atrium (RA) in the vagal atrial fibrillation group. Left atrial activation in the chronic atrial fibrillation group was more disorganized than right atrial. Superimposed vagal stimulation in the chronic group caused organization to decrease, but only in the right atria.

Generating Contours Contour generation can be done manually. This obviously interjects an element of bias, but more importantly it does not allow for a mathematical description of the data. Such descriptions allow the use of transformations such as directional derivatives, smoothing with 2-dimensional filters, and the measurement of error in the contours when compared to the actual underlying data. At this stage, the values chosen from the individual raw data waveforms would be considered

unambiguous. The next assumption in contour generation is that the spatial sampling is adequate. The previous discussion implied that at present there is no known way to assure this since the minimum wavefront length is not known. The next assumption in contour generation is that the data fit some underlying mathematical structure. The simplest structure is the linear model assumed by simple triangulation methods. In essence, this assumes that, if a straight line connects the sample data points, the values under the line vary linearly between the

METHODOLOGY OF CARDIAC MAPPING 2 points. Triangulation has several drawbacks in that there is no physiological basis for the linear assumption, and that depending on how the data points are linked, there is no unique solution. For unevenly spaced recording sites, there are many ways in which the data points can be linked. There are no a priori restrictions on the formation of triangles as the data in the entire region are linked together. Older software algorithms were even susceptible to the order of data entry. Hence, in the early 1970s, triangulation fell into disuse by cartographers because the method is not well defined. More recently, some efforts have been made to regularize the triangulation methods, but other more mathematically based methods are favored. Gridding is a method whereby the data points (usually unevenly spaced) are converted to an underlying, evenly spaced set of points. The grid can be defined to have many more points than the sample points. The value assigned to each grid can be a linear combination, e.g., an average, of nearest data points. The term nearest can be defined in a radial sense, e.g., all data points within 5 mm. Alternatively, using the radial search criterion, the grid value can be weighted with a distance measure. Thus, data points closer to the grid point will have a larger influence in calculating the grid value than data points further away. Much of what has been said can be more succinctly stated in mathematical terms (equation 1).

Here, VG is the value computed at the gridded data point, Vi are the values at the 4 original data points, and DiG are the distances from those original data points to the new grid point. For a more intuitive approach, however, these concepts can be described graphically with a set of simu-

53

lated data points. Figure 9 has 6 panels. Panel A shows a set of irregularly spaced data points with values ranging from 5 to 8. Panel B is a regularly spaced grid, with the open circles at the line intersections representing the new underlying grid points. Panel C demonstrates the variable spacing between the data and grid points by overlapping panels A and B. Panel D is an example of one grid point and its 4 surrounding nearest neighbors. The simplest way to evaluate the value of the grid point is to just average the surrounding data points. This value is 6.5. However, one can also use the weighting approach described by equation 1. Table 1 shows the actual coordinates and data points for this problem. Substituting values into equation 1, VG = (7.69 + 6.0 + 11.67 + 7.0)/4.95 = 6.54. In this example, this is very close to the simple average of 6.5. The rest of the grid points, to one decimal point, are shown in Figure 9F. Now that the data have been converted to a regularized grid, many types of operations can be performed. The method of deriving the contours can be based on one of many different schemes, such as cubic spline fitting or even linear interpolations. Many schemes can be used to form the grid. For example, one could require that there be data points in all 4 quadrants surrounding the grid point, except in the case of boundary grid points. Krige29 proposed a statistically based method that minimizes the variance of data points that coincide to or are very close to the grid points. This minimum Table 1 Coordinates and Data Points Grid Data A Data B Data C Data D

X

Y

2 1.5 3.0 2.0 1.0

3 3.6 3.0 2.4 2.9

D

V

V/D

0.78

6 6 7 7

7.69 6.00 11.67

1.0 0.6 1.0

7.0

54 CARDIAC MAPPING

Figure 9. A simple example of how a grid is formed from a set of unevenly spaced observation points (A). B. The evenly spaced grid points are represented as open circles. C. Superimposition of A and B. D. One grid point and its 4 nearest neighbors. E. Superimposition of C and D. The final grid values (from equation 1 and summarized in Table 1) are shown in F.

variance method, often referred to as kriging, now allows for estimates of error in the map. Detailed discussion of this is beyond the scope of this chapter, but in essence such a statistical approach would allow for the generation of an optimal map and clear delineation of regions with the highest uncertainty. Some examples of gridding to generate activation maps over the infarct are shown in Figure 10. These maps are derived from the electrograms shown in Figure 1. In these maps, we have assumed appropriate spatial sampling, the data are spatially continuous (no dead inac-

tive regions), and each electrogram has a unique activation time. Each isochrone represents 3 ms, with early activation on the left and late activation on the right. The specifics of timing are not considered, and the emphasis is on the actual generation of the contour lines. The dots on each map represent the electrode recording sites. Figure 10A shows a low-resolution map with grid nodes arranged in a 15 x 15 matrix. In generating this grid matrix there is little interpolation since the matrix nodes roughly correspond to the original measurement points. An infarct border zone is encountered approximately

METHODOLOGY OF CARDIAC MAPPING

55

Figure 10. Activation maps from Figure 1, assuming continuous activation. A. A 15 x 15 grid. B and C use a 25 x 25 and 100 x 100 grid, respectively. D. A smoothed version of C.

halfway across the map, and conduction in this region is delayed and nonuniform. Figure 10B is the same map with a 25 x 25 grid matrix. This has twice as many columns and rows as the electrode layout. Artifacts now begin to appear as extreme regions. This is fully appreciated in Figure 10C as the grid matrix is increased to 100 x 100. Figure 10D shows the smoothed version of Figure 9C and appears more like the map in Figure 9A.

However, the high-resolution grid after smoothing contains more spatial temporal information. This is demonstrated by creating a trend map. Figure 11A is the trend map of Figure 10D and is the locus of normal activation extrapolated from the left side of the activation map (the normal region) to the entire epicardial surface under the electrode. It is a first-order polynomial approximation and assumes uniform, constant velocity, conduction. It was derived

56 CARDIAC MAPPING

Figure 11. A. Trend map obtained from the region of Figure 10D showing uniform conduction; roughly the left half of Figure 10D. B. Residual map obtained by subtracting A from Figure 10D. This is a form of high-pass filtering.

from the grid. Figure 11B is a residual map derived by removing the trend map (Figure 11A) from the activation map (Figure 10D). Such mathematical operations are easily performed once the underlying grids are formed. The contours in Figure 11B represent "lateness" or departure from uniform conduction, and it appears that there are 2 regions of localized late activity in the lower right quadrant of the map. The residual map was applied to the late potential problem, but is offered here as an example of map manipulation. The creation of a contour map that takes into consideration a faulted region, e.g., dead nonconducting tissue, is another example of how a gridded structure can be used. It is not enough to just declare that an electrogram site generates no activation time. Without a clear definition of a fault zone, most algorithms will simply interpolate across the dead tissue. The drawing of an isochrone or the inclusion of a data point in the interpolation that is "across" the fault should be considered an invalid approach. It is not known how this has been dealt with in prior studies.

Conclusions The question may be asked, "Why are these details about map generation important?" Most of the theories regarding cardiac activation and arrhythmogenesis are derived from the visual examination of contour maps. However, very little attention has been given to the creation of these maps. Even if the problems of selecting activation times from the electrograms are solved, the validity of the mapping assumptions has not been critically examined. It is quite possible to generate visually different maps, all correct according to their mathematical basis, from the same data sets. Hence, differences in interpretation of a particular activation sequence may in fact be due to different algorithms used in contour generation rather than the underlying pathophysiology. To some degree, organization mapping or similar "parameter extractions" from epicardial mapping data attempt to circumvent these problems by avoiding activation sequence reconstruction entirely.

METHODOLOGY OF CARDIAC MAPPING The methods used to generate a contour map should be examined in greater detail as it applies to cardiac mapping. Investigators must become cognizant of various methods and the strengths and weaknesses of these approaches. Until that time, the conclusions drawn from contour maps should be tempered so that investigators can develop the technical skills to deal with the problems associated with the data presentation. Various mapping approaches will change the interpretation of the data and greater care must be taken in presenting the methods used and the impact these methods have on interpretation. References 1. Sodi-Pallares D, Rodriguez MI, Chair LO, Zuchermann R. Activation of the interventricular septum. Am Heart J 1951;41: 569. 2. Nakagawa H, Jackman WM. Use of a three-dimensional, nonfluoroscopic mapping system for catheter ablation of typical atrial flutter. Pacing Clin Electrophysiol 1998;21:1279-1286. 3. Gepstein L, Evans SJ. Electroanatomical mapping of the heart: Basic concepts and implications for the treatment of cardiac arrhythmias. Pacing Clin Electrophysiol 1998;21:1268-1278. 4. Peters NS, Jackman WM, Schilling RJ, et al. Images in cardiovascular medicine: Human left ventricular endocardial activation mapping using a novel noncontact catheter. Circulation 1997;95:1658-1660. 5. Berbari EJ, Scherlag BJ, Hope RR, Lazzara R. Recording from the body surface of arrhythmogenic ventricular activity during the S-T segment. Am J Cardiol 1978;41:697-702. 6. Barr RC, Gallie TM, Spach MS. Automated production of contour maps for electrophysiology: I. Problem definition, solution strategy, and specification of geometric model. Comput Biomed Res 1980; 13:142-153. 7. Barr RC, Gallie TM, Spach MS. Automated production of contour maps for electrophysiology: III. Construction of contour maps. Comput Biomed Res 1980; 13: 171-191.

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8. Barr RC, Gallie TM, Spach MS. Automated production of contour maps for electrophysiology: II. Triangulation, verification, and organization of the geometric model. Comput Biomed Res 1980;13:154-170. 9. Monro DM. Interpolation methods for surface mapping. Comput Programs Biomed 1980;11:145-157. 10. Robinson JE. Computer Applications in Petroleum Geology. New York: Van Nostrand Reinhold; 1982. 11. Davis JC. Statistics and Data Analysis. New York: John Wiley; 1986. 12. Ideker RE, Smith WM, Blanchard SM, et al. The assumptions of isochronal cardiac mapping. Pacing Clin Electrophysiol 1989;12:456-478. 13. Allessie MA, Bonke FIM, Schopman FJG. Circus movement in rabbit atrial muscle as a mechanism of tachycardia, III: The 'Leading Circle' concept: A new model of circus movement in cardiac tissue without the involvement of an anatomical obstacle. Circ Res 1977;41:9-18. 14. Allessie MA, Lammers WJEP, Bonke FIM, Hollen J. Experimental evaluation of Moe's multiple wavelet hypothesis of atrial fibrillation. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology and Arrhythmias. Orlando: Grune and Straton; 1985:265-275. 15. Moe GK. On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacodyn Ther 1962; 140:183-188. 16. Cox JL, Canavan TE, Schuessler RB, et al. The surgical treatment of atrial fibrillation: II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 1991;101:406-426. 17. Konings KTS, Kirchhof CJHJ, Smeets JRLM, et al. High-density mapping of electrically induced atrial fibrillation in humans. Circulation 1994;89:1665-1680. 18. Berbari EJ, Lander P, Geselowitz DB. A cardiac mapping system for identifying late potentials: Correlation with signal averaged surface recordings. Proceedings of the Computers In Cardiology Conference. Washington, DC: IEEE Computer Society Press; 1988:369-372. 19. Berbari EJ, Lander P, Scherlag BJ, et al. Ambiguities of epicardial mapping. J Electrocardiol 1992;24(Suppl): 16-20. 20. Scherlag BJ, El-Sherif N, Hope R, Lazzara R. Characterization and localization of

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21. 22.

23.

24.

25.

CARDIAC MAPPING ventricular arrhythmias resulting from myocardial ischemia and infarction. Circ Res 1974;35:372-383. Harris AS, Rojas AG. The initiation of ventricular fibrillation due to coronary occlusion. Exp Med Surg 1943; 1:105-122. Lewis T, Drury AN, Bulger HA. Observations upon flutter and fibrillation: VII. The effects of vagal stimulation. Heart 1921;8:141-169. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing: Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation 1995;91:1588-1595. Elvan A, Wylie K, Zipes DP. Pacinginduced chronic atrial fibrillation impairs sinus node function in dogs: Electrophysiological remodeling. Circulation 1996; 94: 2953-2960. Wijffels MCEF, Kirchhof CJHJ, Borland R, Allessie MA. Atrial fibrillation begets

atrial fibrillation: A study in awake chronically instrumented goats. Circulation 1995;92:1954-1968. 26. Sih HJ, Zipes DP, Berbari EJ, Olgin JE. A high-temporal resolution algorithm for quantifying organization during atrial fibrillation. IEEE Trans Biomed Eng 1999;46: 440-450. 27. Damle RS, Kanaan NM, Robinson NS, et al. Spatial and temporal linking of epicardial activation directions during ventricular fibrillation in dogs: Evidence for underlying organization. Circulation 1992; 86:1547-1558. 28. Sih HJ, Sahakian AV, Arentzen CE, Swiryn S. A frequency domain analysis of spatial organization of epicardial maps. IEEE Trans Biomed Eng 1995;42:718727. 29. Krige DG. Two dimensional weighted moving average trend surfaces for ore evaluation. J S Afr Inst Mining Metallurg 1966:13-38.

Chapter 4 Noncontact Endocardial Mapping Richard Schilling, MD, Nicholas S. Peters, MD, Alan Kadish, MD, and D. Wyn Davies, MD

ablation of complex cardiac arrhythmias such as ventricular tachycardia (VT) in structural heart disease, and atrial fibrillation (AF). The importance of accurate mapping is exemplified in ablation of VT in the setting of ischemic heart disease where identification of relevant diastolic activation is critical. Surgical ablation of the diastolic pathway has achieved primary success rates of 63%12 to 76%13 when guided by preoperative and intraoperative mapping, but the mortality associated with this procedure is 9% to 23%.14 Catheter ablation of VT is an attractive alternative approach because it might avoid the risks associated with surgery. Localization of diastolic activation is achieved by sequential acquisition of contact catheter data points from which the operator develops a mental image of the VT circuit. However, only a minority (10%) of patients are considered able to tolerate VT for long enough to allow such conventional mapping to identify the critical diastolic activity that maintains VT.15 The current complication and failure

Introduction Accurate mapping is the cornerstone to successful ablative therapy of cardiac arrhythmias because it provides insight into the arrhythmia mechanism and identifies the location of a suitable target for ablation. Reentry is the mechanism responsible for the majority of sustained arrhythmias in humans.1–9 Ablation of these arrhythmias is critically dependent on locating the abnormal depolarization that completes the diastolic pathway that maintains the reentrant circuit.10–11 Using conventional mapping techniques it has been possible to treat a wide range of arrhythmias with high success and low complication rates. There remain some arrhythmias that are difficult to treat with catheter ablation because of a number of factors, including the small lesion sizes produced by radiofrequency (RF) energy and difficulties with precise localization of the arrhythmia substrate. For this reason, developments in mapping techniques are fundamental to the success of catheter

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003.

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CARDIAC MAPPING

rates therefore largely reflect the lack of rapidity and precision of mapping to guide delivery of sufficient ablative energy to the correct site. Thus, the results of catheter ablation of VT have been disappointing, with immediate success rates of 69% to 90%9,10,15,16 and high recurrence rates. Attempts to improve these results have been directed at increasing the size of ablation lesions and at improving mapping techniques to increase the precision of delivery of lesions by elucidating the full complexity of the substrate underlying VT in ischemic heart disease. A system for 3-dimensional electroanatomical reconstruction of sequentially acquired contact catheter data has recently been described and validated.17 Although this development is a significant advance in mapping technology, like all sequential systems resolution is limited by the time available to acquire data points, and its use remains restricted in cases of nonsustained or hemodynamically unstable arrhythmias. It is therefore apparent that an ideal cardiac mapping system should collect data simultaneously from the entire cardiac chamber, from which high-resolution maps would be produced on which the position of mapping catheters can be shown so that the catheters may be guided to sites of interest on the map. It should be capable of deployment using a percutaneous minimally invasive technique. Simultaneous complete data acquisition will allow mapping of nonsustained and hemodynamically unstable arrhythmias such as VT or arrhythmias that have beat-tobeat changes in activation such as AF. The development of noncontact mapping techniques has been an attempt to produce such a mapping system. Such systems will be commercially available in the near future and this chapter examines their development and describes the validation and initial clinical experience of one such system.

From the Body Surface to the Endocardium: The Development of Noncontact Mapping Body Surface Mapping Body surface mapping is a method for improving the resolution and sensitivity of recordings of surface electrograms. It involves the recording of 2 or more electrograms from the subject's body surface and using these data to interpret the underlying cardiac activation patterns. Recordings made by surface electrodes reflect data from points around the entire cardiac chamber and are a summation of these data which thus varies according to the positions of the electrodes relative to each of these infinite number of cardiac points. The data acquired from each electrode are different from the data of their neighbor data because the degree of influence of each myocardial point on an individual electrode is related to the distance of each point from the electrode and the nature of the tissue interposed between the two.18 If this geometry and the nature of the thoracic tissues are known, it is theoretically possible to determine myocardial potentials from the body surface potentials. This process is known in electrocardiography as solution of the inverse problem. The clinical application of body surface mapping has been limited by the resolution of the data provided. From as early as 1955,19 efforts were made to describe the complex relationships of the cardiothoracic geometry, tissues, and potential fields as mathematical equations so that the nature of unknown epicardial potentials could be inferred from body surface recordings. These solutions were developed by mathematically describing the "forward" relationship between a defined experimental model of cardiac activation and the

NONCONTACT ENDOCARDIAL MAPPING

resulting body surface potentials. Under these in vitro conditions the activation patterns of the source, the resulting potential distribution on the body surface, and the geometric relationship between surface electrodes and each finite point on the source are all known. The forward solution describing the body surface potentials resulting from a known cardiac source can then be "inverted" to calculate cardiac source potentials from the body surface potentials. The models used to simulate cardiac activation were constructed so that they produced body surface maps similar to those seen in clinical practice. However, it must be remembered that body surface potentials are an averaged and simplified version of true activation patterns on the cardiac surface and, as a result, the models used to describe this relationship, although they were of increasing complexity, evolving from single dipoles,19,20 multiple dipoles,21,22 and higher order multipoles,23,24 did not truly describe the cardiac source. This meant that the resulting solutions were not unique, that is, a variety of electrical generators (i.e., myocardial potential fields) could have produced identical body surface maps. For this reason the noninvasive nature of body surface mapping, which is its attraction, is also a limitation, because the development and validation of an accurate inverse solution requires direct measurement of the epicardial potentials while leaving the geometry of the thorax and heart undisturbed, as it would be in the closed-chested living patient. This has been overcome to some extent by directly recording the epicardial potentials of animal hearts suspended in electrolytic tanks.25 With use of this preparation, the complex potential field generated by the heart is equivalent to that in vivo and the geometry between the heart and the body surface (the surface of the electrolytic tank) can be measured

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accurately. However, this model does not account for the nature of structures between the cardiac surface and the body surface. The boundaries between these structures (lung, muscle, bone, and fat) exert complex influences to distort the potential field as it appears on the body surface and must be accounted for in any inverse solution. This may be achieved by using a finite element method (FEM)26 that divides the thorax into a series of small finite elements whose influence on the potential field may be calculated and accounted for by performing a series of highly complex integrations (described in more detail later). This technique is highly complex and thus increases the time taken to construct body surface maps. Endocardial Noncontact Mapping An alternative "noncontact" concept was introduced by Taccardi et al.27 in which intracavity potentials were measured from electrodes on an olive-shaped probe introduced through the left ventricular (LV) apex of animal hearts. Taccardi and colleagues noted that the pattern of endocardial activation was not precisely reflected in the raw cavity potentials recorded by the probe, which exhibit spatially averaged, lower amplitude distributions. This phenomenon closely resembled the noncontact recordings made during body surface maps. It was therefore a logical progression to conceive a mathematical solution to these noncontact endocardial potentials in a manner similar to that applied to body surface maps. Application of inverse-solution methods to raw noncontact endocardial recordings to reconstruct endocardial potentials has been investigated by several groups.28–32 This approach has several advantages over inverse solution of body surface potentials. First, the noncontact

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Figure 1. Multielectrode array (MEA) catheter with 9F shaft (left), deployed 7.5-mL balloon with braided MEA (center), and micrograph of 0.025" long electrode created by removing a spot of insulation with a laser (right).

probe is in closer proximity to the source than is achieved by body surface electrodes, thus reducing distance-related blurring of the endocardial potentials. Second, the space between the intracavitary probe and the endocardium is filled with a medium that may be treated as uniform and electrically inert, i.e., blood. This also means that development and validation of solutions to the inverse problem is easier because in vitro studies may be performed in a tank without having to account for the complexities of extracardiac thoracic tissues. Furthermore, validation of such techniques is feasible both in vitro and in vivo because it is possible to percutaneously access the endocardium to make recordings of contact endocardial electrograms with which to compare the reconstructed electrograms. The first commercially available percutaneous noncontact mapping system uses advanced mathematical methods that provide detailed mapping of the entire endocardial surface of either atrial or ventricular chambers by simultaneously computing electrograms and rapidly displaying

high-resolution color maps of activation33 in the intact beating heart. The system uses a catheter-based noncontact multielectrode array (MEA) to detect far-field endocardial potentials from within a cardiac chamber. From these potentials, the system reconstructs instantaneous endocardial electrograms and isopotential maps on a computer-generated "virtual" endocardium. This noncontact mapping system is also capable of locating and guiding a conventional contact catheter to an area of interest on the isopotential map. Materials The noncontact mapping system consists of a catheter with its MEA (Figure 1) and a custom-designed amplifier system connected to a Silicon Graphics (Mountain View, CA) workstation that is used to run specially designed system software (Figure 2). The MEA catheter consists of a 7.5-mL balloon mounted on a 9F catheter around which is woven a braid of 64 insulated

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Figure 2. Noncontact endocardial mapping system, consisting of the multielectrode array catheter, patient interface unit (rear left), and Silicon Graphics display workstation.

0.003"-diameter wires (Figure 1). During assembly, a laser is used to remove a single spot of insulation on each wire, 0.025" in length, producing 64 noncontact unipolar electrodes. Each electrode is etched at a specified location on each wire in a pattern of 8 rows by 8 columns around the braid, thereby defining the MEA. The raw far-field electrographic data are acquired and applied to a computerized multichannel amplifier (patient interface unit) and digital recording system (display workstation), as shown in Figure 2. The unipolar MEA signals are recorded using a ring electrode, which is located on the proximal shaft of the MEA catheter, as a reference. This reference is at the level of the descending aorta when the MEA is deployed in the LV and in the inferior vena cava (IVC) when the MEA is deployed in the right atrium (RA). Data are sampled at 1.2 kHz and filtered with

a programmable bandwidth between 0.1 and 300 Hz. An electrically based locator signal is also generated by the system and simultaneously sensed by the MEA to track the position of any contact catheter in the same chamber. In addition to electrographic and location data acquired from the MEA, the recording system has 16 channels for contact catheters and 12 channels for the surface ECG. The system is applied in 3 steps: 1. Establish cardiac chamber geometry 2. Identify site(s) critical for maintenance of reentry circuit(s) 3. Navigate ablation catheter to critical site(s) The locator signal is central to steps 1 and 3 while the inverse solution for reconstructing endocardial electrograms is central to step 2.

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Figure 3. The contoured model of the chamber geometry is created by tracing the endocardial surface with a conventional roving catheter while the system tracks its position. The geometry is partially defined midway through the process in the left panel, completed and smoothed as a bicubic spline in the center panel, and rendered in the right panel as an anatomically contoured, wire-frame 3-dimensional model. See color appendix.

Catheter Locator System The system locates any conventional catheter with respect to the MEA by sourcing a 5.68-kHz, low-current "locator" signal from the roving catheter and alternately sinking the current in ring electrodes approximately 1 cm proximal and distal to the MEA on the noncontact catheter shaft. Given the known positions of the array electrodes and the currentsink electrodes, a custom algorithm can determine the position of the roving source by demodulating the 5.68-kHz potentials on the MEA. This locator system serves 2 purposes. First, it can be used to construct a 3-dimensional computer model of the endocardium (virtual endocardium), which is required for the reconstruction of endocardial electrograms and isopotential maps. This model is acquired by moving a conventional catheter around the cardiac chamber, building up a series of coordinates for the endocardium, and gen-

erating a patient-specific, anatomically contoured model of its geometry. To accomplish this, the system automatically stores only the most extreme points visited by the roving catheter in order to ignore those detected when the catheter is not in contact with the endocardial wall. This method is demonstrated midway through the process in the left panel of Figure 3. The green vector provides a graphic representation of the locator signal, which originates at MEA center and indicates the position of roving electrode catheter. As the roving catheter is moved, points accumulate and serve as the vertices of translucent red polygons that are drawn between the points. The set of vertices shown represents the most distant points along each vector, visited by the roving catheter midway through the process, with the chamber geometry partially defined. As the process continues, the number of facets grows and the model evolves to a polygonal representation of the chamber surface at its completion.

NONCONTACT ENDOCARDIAL MAPPING

The sampled coordinates are then automatically fitted to a bicubic spline surface in order to more optimally estimate the actual chamber surface, as shown in the center panel of Figure 3. The total time required to define the contoured geometry is typically between 5 and 10 minutes. The locator signal can then be used to display and log the position of any catheter on the endocardial model. During catheter ablation procedures, the locator system has been used to guide the catheter to sites of interest identified from the isopotential color maps and to log the position of RF energy applications on the virtual endocardium. In Figure 4 the green vector shows the position of the tip of an ablation catheter. Because the geometry of the cardiac chamber is taken with reference to the MEA and is used to produce the inverse solution, it is critical that once geometry is established the MEA should not move. If the MEA is moved, then cardiac geometry must be reestablished. In practice, this is not a problem. The stiffness of the MEA catheter shaft and weight of the balloon means that once sited its position remains stable. A stable position for the MEA catheter pigtail in the LV was the apex, and for the RA either the superior vena cava (SVC) or across the tricuspid annulus (TA). The stability of the MEA is verified during studies by use of a reference quadripolar catheter positioned in the right ventricular apex. The locator signal is passed through the reference catheter immediately after the geometry is established. This locator signal is then used to mark the reference catheter position on the virtual endocardium. The locator signal is then passed through the reference catheter at regular intervals to confirm that the locator signal bisects the previously marked position of the catheter. If the MEA catheter has moved, the reference catheter will have moved relative

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to the MEA, this displacement being shown by the locator signal. Inverse Solution Reconstruction of Endocardial Potentials The electrical activity detected by the electrodes on the surface of the MEA is generated by the potential field on the endocardial surface. Cavity electrograms detected by noncontact electrodes are of lower amplitude and frequency than the source potentials on the endocardium, which limits their clinical utility in raw form.27,28,34 The technique to enhance and resolve the actual endocardial surface potentials has been devised based on an inverse solution to Laplace's equation using a boundary element method (BEM).35 Specialized algorithms have also been developed to further improve the accuracy and stability of the reconstructions. The potential distribution on the MEA created by endocardial activation is described by Laplace's equation. The potential field at any one electrode is influenced to a degree by the potentials from the entire endocardium, with the degree of influence diminishing with the distance between the electrode and each endocardial point. The potential field created on the MEA surface therefore depends on the geometry of both the MEA and the endocardium, and on their relationship in space. The geometry matrix defines the relationship between the location of the 64 electrodes on the MEA and 3360 points on the endocardium where the reconstruction is computed. The locations of the MEA electrodes relative to the center of the balloon are precisely determined at manufacture (Figure 5). The locations of the 3360 endocardial points are obtained during the geometry acquisition described above. With this information, it is possible to compute endocardial electrograms from the MEA potentials by an inverse solution

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Figure 4. Detail from the screen of the noncontact system workstation. Within the geometric contour of the computer-generated "virtual" left ventricular endocardium (top), the position of the multielectrode array (MEA) is represented as a yellow frame. The "virtual" endocardium has been opened and unfolded along the inferior septum (the edges are therefore in continuity) to reveal the endocardial surface. The small yellow letters a, e, and g are an engineering feature of the system, which marks the positions of the columns of MEA electrodes on the virtual endocardium. Some anatomical locations are labeled in yellow having been identified on fluoroscopy and the locations are marked on the map using the catheter locator system. Inf = inferior; Post lat = posterolateral; Ant lat = anterolateral; Ant = anterior; Sept = septal. Superimposed onto the "virtual" left ventricular endocardium is an isopotential map generated from reconstructed electrograms. The color scale for the isopotential map is shown on the line below the "virtual" endocardium and has been set so that white represents endocardial regions where the potential is -1.5 mV or less and purple represents endocardium where the potential is -1.49 mV or more (thus producing an activation map). The green line emerging from the MEA marks the position of a mapping catheter electrode on the endocardium using the locator signal. The isopotential map is set to show the exit site of a ventricular tachycardia as a white dot of activation. Below the "virtual" endocardium is a waveform window showing reconstructed electrograms from the exit site (B and C), the surface ECG, and the contact electrogram from the mapping catheter tip (which is remote from the exit). The white line on the waveform window represents the position in time shown by the isopotential map. See color appendix.

of Laplace's equation. This inverse solution is based on Green's second formula:

where D is a domain (the blood pool), 3D is the boundary of D (the endocardium and the MEA), 3/3n represents the outward normal on D, V2 is the Laplacian, dA is the surface area differential and

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Figure 5. Diagrammatic representation of the balloon showing the positions of electrodes around the balloon. Their exact positions may vary with each balloon. Therefore, the electrode positions on each multielectrode array are determined at manufacture and recorded on a microchip, which is used to calibrate and orientate the computer. See color appendix.

dD is the volume differential, w is the many smaller regions, small enough so potential field created by a unit charge that the behavior of a potential field within in free space, and v is the potential field each element can be accurately approxiin the domain. This equation is dis- mated by an algebraic expression. In addicretized using the BEM, which is a tion, the interactions between each element numerical approach to solving integral are described by other algebraic expresequations such as those governing the sions that equate the properties of electribehavior of electrical fields in volume cal conduction between each element. conductors. This results in a linear system of many In summary, the inverse solution con- equations with many unknowns (one for siders how a signal detected at a remote each element), which can be solved by point will have appeared at source and standard techniques. The BEM works simthe BEM is a method for applying the ilarly, but it only needs to model the 2inverse solution to resolve a matrix of such dimensional surfaces ("boundary") instead signals from a source at a known bound- of the entire 3-dimensional domain. This ary (the blood-endocardial boundary). results in far fewer elements and a much The BEM is related to the more smaller system of equations, small enough widely known FEM. The FEM chops up to be feasibly solved in real time (1200 Hz) the region or space where complex elec- for each instant of voltage potential meatrical phenomena are to be computed into sured by the MEA electrodes.

68 CARDIAC MAPPING Inverse problems are mathematically "ill posed," meaning that small errors (noise) in the measured cavity potentials will be inherently magnified into large errors in the reconstructed endocardial potentials. In order to overcome this problem, stability is provided by applying a mathematical constraint (with a physiological basis) on the solution, using a technique called regularization.36,37 Noise emerges in the recorded data from several sources including electrical interference coupled to the body from the surrounding environment, electrochemical fluctuations at the surface of electrodes, and electrical fluctuations in the amplifier circuitry. Environmental noise comes primarily from power lines and manifests as a common-mode noise across the body. Common-mode noise is largely rejected by connecting the unipolar reference to the biopotential amplifiers in the standard differential configuration. Noise due to electrochemical fluctuations at the surface of electrodes is primarily low frequency in nature and is reduced by coupling the electrodes to the amplifiers through a high-pass filter that attenuates frequencies below 0.1 Hz. The small noise fluctuations in amplifier circuitry are generally broad-band in frequency and are not correlated between channels. Regularization is required to attenuate these random fluctuations plus any residual noise that remains after reduction of the other types of noise described above. Note that the random fluctuations among amplifier channels translate back to an error in the measurement at the recording sites which is also randomly associated between the sites. These errors can be thought of as small and rapid "steps" of potential across the surface of the MEA. Accordingly, regularization attenuates these rapid fluctuations across space at any given instant in time, much as a standard time-domain low-pass filter attenuates

rapid fluctuations across time at any given point in space. In general, accuracy of the system depends on the regularization technique applied, the underlying solution method for Laplace's equation, and the accuracy of the geometry information. In order to improve this accuracy, several modifications have been applied to previously described techniques for inverse solution of endocardial electrograms.34 The regularization scheme used in the noncontact mapping system includes a proprietary enhancement of methods described by Tikhonov and Arsenin.36 The geometry and voltage are modeled using bicubic spline surfaces instead of the standard linear elements. This allows for a physiologically more realistic model of the endocardium in addition to a more accurate application of the boundary element solution method, because it fits the sampled endocardial points with curves rather than lines. Small errors in modeling the geometry may still result from undersampling of endocardial points during geometry acquisition or because of the complexity of the chamber geometry itself. The total system accuracy, including these errors, will be reflected in the results described later. Using these techniques, the system is able to reconstruct and interpolate thousands of unipolar electrograms simultaneously over the entire virtual endocardium (Figure 4). These electrograms may be superimposed on the virtual endocardium to produce isopotential or isochronal maps with a color range representing voltage or timing of onset. In addition, the electrograms may be interactively selected with the mouse pointer as individual points, points along a line, or points within a rectangle from anywhere on the virtual endocardium, and displayed as waveforms. By allowing digital subtraction of adjacent unipolar reconstructed electrograms, bipolar electrograms may

NONCONTACT ENDOCARDIAL MAPPING

69

also be displayed as waveforms by the muscle and endocardium, then theoretisystem. cally the influence of endocardial and Because a BEM is used for the inverse papillary electrical activity on the consolution, the 3-dimensional myocardium, tact electrogram at this point may be with its finite muscle thickness, is treated significantly different from a reconas a 2-dimensional endocardial surface. The structed electrogram which assumes a reconstructed electrograms are analogous 2-dimensional surface. A further theoto those measured by a standard recording retical example may be if the contact catheter in contact with this surface. catheter penetrates through the endoThus, the reconstructed electrograms are cardium into myocardium, which again subject to the same electrical principles as will be indicated to the operator by the contact catheter electrograms insofar as locator signal cross-hair showing the both contain far-field electrical informa- catheter beyond the boundary of the virtion from the surrounding endocardium tual endocardium. as well as the underlying myocardium. The contribution of each such component Mapping Protocols to the electrogram is weighted by the signal vector, amplitude, and distance from the site of measurement. Therefore, Preoperative Investigations anatomical details such as papillary muscles or trabeculae will contribute to The first human clinical studies of both a contact and reconstructed elec- the noncontact system were carried out at trogram recorded at an adjacent site, but St. Mary's Hospital, London, and the meththis contribution is small when compared ods used for these studies are described to that from the larger area of endocar- briefly here. All patients had a full physdial tissue surrounding these structures. ical examination before and after the proThere are several situations in which cedures, with particular attention paid contact and reconstructed elements may to the cardiac and neurological examinatheoretically vary, the first being if a con- tion in order to identify any complications tact catheter rests on a papillary muscle resulting from the procedure. Before and that has extended a significant distance after the studies all patients had a full into the chamber away from the endo- blood count, urea and electrolytes, carcardium. Because the geometry is based diac enzyme assay, and clotting screen. on extreme points collected by moving a Echocardiography was used to determine contact catheter, the papillary muscle LV dimensions and function and to elimanatomy may be ignored in favor of the inate pericardial effusion before and after more distant outlying endocardium. This the study. Chest x-rays were performed may result in some rejection of the pap- before and after the procedure to deterillary muscle electrogram during recon- mine the heart size and identify any pulstruction by the regularization process monary congestion. Oral anticoagulants because of the significant deviation from were stopped, allowing the international established geometry. The locator signal normalized ratio to reach normal values will also alert the operator to the fact that prior to the mapping and ablation procethe catheter is not on the virtual endo- dures, during which time the patients cardium with a cross-hair showing dis- were anticoagulated with heparin. Antitance of the catheter from the MEA and coagulants were recommenced if the risks virtual endocardium. Second, if a contact of thrombosis or embolization were not catheter is wedged between papillary eliminated by the ablation procedure.

70 CARDIAC MAPPING Antiarrhythmics were discontinued after the procedure in patients undergoing successful ablation of atrial flutter (AFL). Antiarrhythmics were also discontinued in those patients with no structural heart disease who had successful ablation of VT. Otherwise, antiarrhythmic therapy was continued as before the mapping or ablation procedure. Mapping Procedure For all studies a conventional mapping system was used to record data in parallel to the noncontact system in order to assist with validation. Before deployment of the MEA, patients were given 10,000 international units heparin and the activated clotting time (ACT) was measured. In order to prevent thrombus formation on the MEA, the MEA was only introduced once the ACT was above 300 seconds. After introduction of the MEA, the ACT was monitored every 30 minutes and further boluses of heparin were given to maintain the ACT between 300 and 400 seconds. At the end of the first 4 studies (all of which were LV), the femoral sheaths were left in situ until the heparin had been eliminated and the sheaths were then removed. Two patients suffered femoral vascular complications so that for subsequent patients protamine was used to reverse the heparin and the sheaths were removed immediately when the ACT was below 120 seconds. LV Mapping Procedures Transesophageal echocardiography was performed prior to LV mapping procedures in the last 20 patients in order to identify any thrombus in the left atrium and LV or significant atheroma in the ascending aorta as potential hazards to catheterization via the transaortic or trans-septal route.

Local anesthetic was used to introduce sheaths in both femoral veins and arteries. Two 7F sheaths in the left femoral vein were used to introduce a standard quadripolar catheter to the right ventricular apex, and a 7F multipurpose catheter was used to monitor pulmonary artery pressure. The right femoral vein was used to introduce a trans-septal sheath, which allowed introduction of a deflectable mapping/ablation 4-mm-tip catheter to the LV. An 8F sheath in the right femoral artery was used to pass an additional 7F mapping/ ablation 4-mm-tip catheter to the LV using the retrograde transaortic route. The same arterial sheath was used to monitor systemic arterial pressure around the mapping catheter. A 9F sheath in the left femoral artery was used to introduce the MEA catheter. The MEA catheter was deployed in the LV of all patients using the retrograde transaortic route. To obtain a stable position and optimal recordings from within the LV, it was necessary to site the pigtail of the MEA at the LV apex and this was done over an exchange length 0.032" J-tipped guidewire previously positioned in the LV apex using a 6F pigtail catheter. With the pigtail of the MEA in the LV apex, the guidewire was withdrawn and the balloon inflated with a contrast-saline mixture (Figure 6). RA Mapping Procedures Sheaths in the left femoral vein were used to introduce a 7F quadripolar catheter (placed in the right ventricular apex) and the MEA catheter. A 7F deflectable mapping/ ablation 4-mm-tip catheter was placed in the RA via a right femoral venous sheath. Systemic arterial blood pressure was continuously monitored via a 6F sheath in the right femoral artery. A further 7F sheath in the right subclavian vein was used to introduce an electrode catheter into the coronary sinus (CS).

NONCONTACT ENDOCARDIAL MAPPING

71

Figure 6. Posteroanterior radiograph showing the noncontact mapping catheter with contrast medium/saline in the balloon, deployed in the left ventricle (LV) (A). Also seen in the LV is a transseptal mapping catheter (B) and a retrograde transaortic mapping catheter (C) in an equatorial position to the multielectrode array. Other catheters are positioned in the high right atrium, middle cardiac vein, and right ventricular outflow tract. This patient also has an implantable defibrillator lead (D).

The MEA catheter was deployed in the RA of all patients over a 0.035" Jtipped guidewire advanced to the SVC (Figure 7) or the pulmonary outflow tract having been positioned using a 7F multipurpose catheter (Figure 8). This technique was developed to cant the balloon toward an area of interest (the atrioventricular junction or IVC-tricuspid isthmus) in patients with a posteroseptal accessory pathway or AFL. This was done to improve the mapping resolution of these areas, because the accuracy of electrogram reconstruction may theoretically improve with decreasing distance between the MEA and to potential field source.

Initial Validation Contact unipolar recordings from a mapping catheter were made in 13 patients during sinus rhythm at up to 6 separate endocardial locations with as varied an anatomical distribution as possible. All locations were marked using the locator signal and these were used to reconstruct electrograms at the same site for comparison with contact electrograms for the following criteria: 1. Timing of activation, indicated by the point of maximum negative dV/dt.

72 CARDIAC MAPPING

Figure 7. Posteroanterior radiograph showing the multielectrode array deployed around the balloon filled with 7.5 mL of contrast (B) in the right atrium, with the pigtail tip positioned near the superior vena cava. Also seen in this image is a mapping catheter positioned on the tricuspid annulus-inferior vena cava isthmus (Map), a coronary sinus catheter (CS), and a halo catheter (H), which were used to map and ablate this patient's atrial flutter.

2. Electrogram morphology, with reference to the polarity and relative amplitude and frequency of electrogram components using a visual morphology score (1 to 5), was used: 5: exact match 4: features exact with phase shift 3: many features match with or without phase shift 2: few features match with or without phase shift 1: no match.

3. In addition to manual analysis, electrogram morphologies were compared using a template comparison algorithm to calculate the crosscorrelation using the formula:

where C(k) is the correlation coefficient and Xj and Yj are a corresponding series of amplitudes,

NONCONTACT ENDOCARDIAL MAPPING

73

Figure 8. Posteroanterior radiograph showing the multielectrode array (B) deployed in the right atrium and canted over toward the tricuspid annulus by a guidewire passed through the central lumen and out through the right ventricular outflow tract, so that the pigtail of the multielectrode array is straightened and sited on the ventricular side of the tricuspid annulus. Also seen in this image are catheters sited at the high right atrium (HRA), right ventricular apex (RVA), His bundle (His), and coronary sinus (CS). A mapping/ablation catheter has been positioned on the tricuspid annulusinferior vena cava isthmus (arrow).

sampled at 1200 Hz, from the contact and reconstructed electrogram waveforms, respectively. X and Y are the mean amplitudes of these series.38,39 4. The cross-correlation computer algorithm was used to produce a measure of difference in timing between reconstructed and contact catheter electrograms that was termed correlation timing.

Results: Data from a total of 76 LV points were collected. The distance of equatorial points from the center of the MEA was 32.12 ± 12.12 mm (mean ± SD). Timing: Reconstructed electrograms differed from the maximum negative dV/dt for the contact electrogram at the same site by -6.44 ± 14.17 ms (95% CI -3.26 to -9.63) (Figure 9). Perfect matches in timing were obtained as far as 52 mm

74 CARDIAC MAPPING

Figure 9. Graph of the difference in timing between maximum negative dV/dt of unipolar reconstructed and mapping catheter tip contact electrograms (ms) versus the distance from the center of the multielectrode array (mm). A negative timing value indicates that the maximum negative dV/dt of the reconstructed electrogram precedes the contact electrogram.

from the MEA center, but differences in timing of maximum negative dV/dt for reconstructed electrograms with respect to corresponding contact electrograms increased gradually with distance but significantly at data points greater than 34 mm from the center of the MEA (Figure 9). For this reason, data were handled in 2 groups of points within and beyond 34 mm from the center of the MEA. Timing differences for electrograms recorded at points less than 34 mm were -1.94 ± 7.12 ms (95% CI -3.96 to 0.07), and at points greater than 34 mm was -14.16 ± 19.29 ms (95% CI -21.08 to -7.01). The difference at distances greater than 34 mm from the balloon appeared to be predominantly negative indicating that the system appears to reconstruct the electrograms earlier than the contact counterparts. Computer timing analysis did not demonstrate this predominantly negative

shift of reconstructed electrograms with respect to contact electrograms. Mean timing shift was -1.93 ± 11.71 ms. Timing differences for reconstructed electrograms compared with contact electrograms at endocardial points less than 34 mm was -1.30 ± 6.34 ms (95% CI -3.20 to 0.59), and for points greater than 34 mm was -3.02 ± 21.03 (95% CI -10.95 to 4.91) suggesting that timing differences do increase at endocardial points greater than 34 mm from the balloon, but the computer algorithm to determine timing difference demonstrates no trend for reconstructed electrograms to be earlier or later than the contact electrogram. Morphology: The mean subjective morphology score for equatorial points was 3.45 ± 0.99 (Figure 10). A general linear model analysis of variance of morphology scores demonstrated a significant (P< 0.001)

NONCONTACT ENDOCARDIAL MAPPING

75

Figure 10. Histogram of mean and standard deviation of subjective morphology scores comparing reconstructed and mapping catheter tip electrograms at equatorial points plotted versus 10-mm ranges of endocardial distance. *P< 0.05, **P< 0.005.

decrease in accuracy of morphology of reconstructed electrograms when compared against contact electrograms with increasing endocardial distance from the MEA (Figure 10). There was no apparent threshold distance beyond which the morphology of reconstructed electrograms worsened. Cross-correlation of reconstructed and contact electrograms was 0.83 ± 0.16 (mean ± SD). Correlation worsened at greater endocardial distances and correlation for points greater than 34 mm from the balloon was 0.76 + 0.18 (95% CI 0.69 to 0.83) compared with correlation at distances less than 34 mm from the balloon 0.87 ± 0.12 (95% CI 0.84 to 0.91) (P < 0.01), but a threshold distance at which this difference occurred was not clear. The noncontact mapping system described here was first validated using

tank tests with accurate catheter location and good correlation between reconstructed and contact potentials using a lower order inverse solution than that used clinically.31 It has also been demonstrated that, using the presently employed inverse solution,35 reconstruction of electrograms and catheter location can be performed with accuracy decreasing only at distances greater than 40 mm from the MEA center. The validation demonstrated that this system is capable of reconstructing electrograms at distances of up to at least 50 mm from the center of the MEA but that accuracy decreases with distance and significantly when the endocardium is greater than 34 mm from the MEA center. There is no significant difference in timing of maximum negative dV/dt between contact catheter and reconstructed

76

CARDIAC MAPPING

electrogram less than 34 mm from the MEA center, but the timing of electrogram maximum -dV/dt becomes earlier than contact electrograms greater than 34 mm from the MEA center. The trend for the reconstructed electrogram to be displayed earlier than the contact electrogram at distances greater than 34 mm from the MEA center is probably a result of a number of combined errors. These may be errors introduced by distance of the endocardium from the MEA, the signal-to-noise ratio, the complexity of anatomy and motion of different regions of the LV, and the presence of scar. These possible sources of error may be further compounded by the need for regularization in which subtle features of the endocardial potentials may be rejected because of rapidly changing geometry or amplitude at various cardiac regions. This means that the complex relationship between errors in reconstruction and MEA-endocardial distance can be demonstrated but not easily defined. If it is eventually possible to define this complex reproducible error in the reconstruction algorithm, it may be possible to modify the mathematical solution to adjust for this. The computerized correlation timing data also demonstrated the phenomenon of differences in electrogram timing increasing with increasing endocardium to MEA distances, but there was not a consistent shift in timing of reconstructed electrograms earlier than contact electrograms, and differences in timing appeared to be less than those measured by maximum -dV/dt. It is possible that a more global measurement of electrogram timing as provided by computerized correlation timing is a better measure of electro-gram timing than maximum -dV/dt, but it is also possible that the computerized correlation timing technique underestimates errors in timing of reconstructed electrograms and requires further validation.

Initial Experience of Noncontact Mapping of Human VT Validation of electrogram reconstruction during VT

A comparison between reconstructed and contact unipolar electrograms recorded at the same site, as identified by the locator system, was made for all patients in all recordings made during VT. Analysis was performed offline by using the previously described computer cross-correlation technique. Isopotential mapping: Voltages are displayed on the isopotential map as colors on the virtual endocardium (Figure 4). The color scale is adjusted so that it covers a narrow range of voltages thus producing a binary display of colors with voltages above a threshold voltage shown as purple and below this threshold shown as white. Adjusting the offset of the display to be just below 0 mV creates a unipolar activation map, with activation shown as white on the virtual endocardium. The sensitivity of the activation map is altered using the color offset adjustment. Identification of diastolic depolarization during VT

Our initial experience indicated that depolarization of the diastolic reentrant pathway could be confused with ventricular repolarization. In order to avoid this problem, we strictly defined diastolic depolarization as activity on an isopotential map that could be clearly and continuously tracked back in time from the exit site of tachycardia (see results). Thus, relevant diastolic depolarization was that which resulted in activation of the ventricle, avoiding confusion with repolarization and bystander activity. Exit sites

NONCONTACT ENDOCARDIAL MAPPING

were seen on the isopotential map synchronous with the onset of the surface ECG QRS and were defined as rapidly spreading white spots from which continuous activation of the entire ventricle occurred. The exit sites were confirmed by selecting reconstructed electrograms from these sites and comparing their timing with that of adjacent reconstructed electrograms and QRS onset on the surface ECG (Figure 4). The sensitivity of the isopotential map was then increased and an attempt was made to progressively trace activity as a discrete "spot" back through diastole until continuity was lost. Diastolic activity seen prior to this earliest point was ignored. Areas of relevant diastolic depolarization and exit sites were then marked on the virtual endocardium and the catheter location system used to guide the mapping catheter to them. If the suitability of these sites for RF ablation of VT was then confirmed by conventional mapping criteria,40–42 the catheter position was recorded using the locator system and RF energy was delivered. Validation of reentry circuits identified Analysis was performed offline that allowed identification of the ablation site within the isopotential map of the reentry circuit of the ablated VT. For the purposes of this analysis, successful ablation was defined as delivery of RF energy resulting in termination of VT with partial success being a change in morphology of VT, after which, in both cases, the original VT morphology was noninducible.

Results

77

was followed by a period of cardiogenic shock. The other patient developed rightsided facial weakness after introduction of the trans-septal mapping catheter and the procedure was abandoned. Validation of reconstructed electrograms during VT: A total of 7593 (range 40–1731 per patient) unipolar electrogram complexes recorded during VT were analyzed using a cross-correlation algorithm. The cross-correlation between contact and reconstructed unipolar electrograms was 0.86 ± 0.16 (mean ± SD) (Figure 11), and the timing shift required to produce the closest electrogram match between these reconstructed and contact unipolar electrograms was -1.67 ± 10.46 ms. VT morphologies induced: 81 of 97 morphologies of VT were mapped using the noncontact system (3.4 per patient) (Table 2). Sixteen morphologies terminated prior to introduction of the MEA. Twenty-four of the mapped tachycardias were clinical morphologies of VT. Fiftyseven morphologies were either previously undocumented or only induced at previous electrophysiological studies. Identification of VT exit: Noncontact mapping identified exit in 80 (99%) of 81 VT morphologies. In 1 patient who had an LV ectopic tachycardia, an exit was identified approximately 1 cm (as assessed by multiple radiographic views) from the final successful ablation site, both being located in the outflow tract of the LV.

Identification of diastolic activity: Despite demonstration of an exit site, diastolic Data were collected from 24 patients activity could not be identified in 27 mor(Table 1). Ablation procedures were com- phologies of tachycardia, including the pleted in 22 patients. Of the 2 patients in fascicular tachycardia and ectopic VT. whom ablation was not performed, ven- Activity in some or all of the diastolic tricular fibrillation was induced in 1 and interval was thus identified in 54 of 81 VT

Table 1 Patient Demographics Patient

1 2 3 4 5 6 7 8 9 10 11 12 13 14* 15 16 17 18 19 20 21 22 23 24*

Mean SD

Age (yrs)

Ml

Follow-up (days)

CABG

Defib

Defib Post

Shock Pre

Shock Post

Aneurysm

EF (%)

LVEDD (cm)

LVESD (cm)

60 65 39 32 60 69 65 61 60 66 64 55 59 64 75 56 65 55 54 48 76 65 55 19

INF ANT — — ANT M M M M ANT ANT ANT M M M M M M — — M LAT M —

746 745 744 743 498 497 496 428 405 400 372 370 365 326 319 258 235 190 176 144 131 130 47 46

N Y N N N N Y Y N N N N Y N Y N Y Y N N Y N N N

Y Y N Y N N N Y N N N Y Y N N N N N Y N N N Y N

n/a n/a N n/a N Y N n/a Y Y N n/a n/a Y N Y Y N n/a Y N Y n/a N

6 unavailable n/a 11 (15 Pace) n/a n/a n/a unavailable n/a n/a n/a 11 2 n/a n/a n/a n/a n/a 3 n/a n/a n/a 23 n/a

none n/a n/a 1 (5 Pace) n/a n/a none n/a n/a none none none none n/a n/a n/a n/a n/a n/a n/a n/a n/a none n/a

INF ANT/AP — — — — LAT ANT/AP — ANT/AP — — — — — — — — — — — — ANT/AP —

33 38 70 40 30 35 45 35 40 35 40 30 29 30 35 38 32 30 35 60 30 40 35 70

6.32

5.14

6.2

4.7

4.47 5.61 7.07 6.49 5.36 6.99 4.73 6.61 6.46

2.98

349

38.91

218.2

1.5

57.79 12.84

LVL

(cm)

6.9 4.8

5.2 6.3 2.7

6.19 6.57 6.83 5.22 7.05 6.89

5.81 5.65 5.96 4.49 6.61 6.06

5.7 6 6.1 6.3 4.1

4.3 5.4 5.7 5.4

3.58

8.56 6.54 7.05 6.89 8.41 9.07 7.48 7.57 6.96 8.08 8.14 9 7 9.87 8.39 8.67 9.63 8.76 8.62 7.8 8 7.8 9.2 7.19

6.04 0.86

5.08 1.06

8.11 0.91

4.1

5.36 5.79 4.78 5.93 3.69 6.19

ANT - anterior; AP = anteroposterior; CABG = previous coronary artery bypass grafting; EF = ejection fraction; LAT = lateral; LVEDD = left ventricular end-diastolic dimension; LVESD = left ventricular end-systolic dimension; LVL = left ventricular length; INF = inferior; M = mid; Ml = myocardial infarction; SD = standard deviation.

NONCONTACT ENDOCARDIAL MAPPING

79

Figure 11. Histogram showing the cross-correlation between contact and reconstructed electrograms recorded during ventricular tachycardia. The majority of compared electrograms had a perfect correlation (1) and almost all comparisons gave a correlation greater than 0.8, which was considered to be an acceptable value. LV = left ventricular.

morphologies (67%). In 17 of these, the noncontact mapping system demonstrated a complete reentrant circuit (Figure 12). Of these 17 VTs, 7 were terminated by application of RF energy, and the position of the successful ablation site was located within the diastolic pathway identified by the noncontact system in all cases. The remaining 10 VT morphologies were not ablated because they were hemodynamically unstable tachycardias (n = 2) or the tachycardia was induced only once during the procedure (n = 8) and the circuits were subsequently identified during analysis offline. In the remaining 37 circuits, diastolic activity was traced over 36 ± 30% (mean ± SD) of the diastolic interval (range 1-95%). Ablation results: 154 RF applications (range 0-34) were used to ablate a total of 38 tachycardias (4 applications per VT ablated). Fifteen clinical VT morphologies and 23 nonclinical VT morphologies were ablated. Four VT were ablated by 2

RF applications on common shared diastolic pathways (Figure 12). Validation of VT circuits identified

The relationship between ablation catheter and the diastolic pathway location to the outcome of RF application is shown in Table 3. A total of 76 RF energy applications were delivered during VT of which 22 were successful, 9 were partially successful, and 45 were unsuccessful. Application of RF to a diastolic pathway identified by the noncontact mapping system resulted in successful ablation in 77% of cases. The success rate of RF delivery at an exit site was significantly lower (P < 0.005) and resulted in failure to eliminate VT in 79% of cases because of a change in morphology or no change to the VT. Delivery of RF at locations remote from the VT diastolic pathway also resulted in a significantly lower incidence of successful ablation (P< 0.0001) resulting in failure of ablation in 91% of RF applications.

Table 2 Procedure and Follow-up Results Ensite Time (min)

VT #

Cycle Length Mean (Range) ms

Clinical VTs

Ablated Clin/Nonclin

426 (250-520) 426 (348-538)

1 1 1 1 1 0 0 1 1 1

1/1 1 /2

345 363 436 370 145 275

4 3 1 2 2 6 6 2 1 3

250 365 73 188 234

3 1 1 1 6

360(316-424) 382 (322-522)

65.4 44.1

231 360 194 20

5 8 2 1

323(170-405) 415(330-446) 328 (308-347)

300 260 140 430 290

55.1 47.9 19.2 44.8 57.4

150 150 90 245 145

5 1 1 6 1

381 (254-352)

400.83 105.47

77.01 65.16

231.45 114.56

81 VTs

399.35 89.76

Screening Time (min)

PT

Procedure Time (min)

1 2 3 4 5 6 7 8 9 10

520 420 435 440 570 495 585 460 315 395

11 12 13 14 15

435 515 390 310 365

363

16 17 18 19

425 460 395 270

102.7

20 21 22 23 24

Mean SD

43 46

48.6 89.6 86.3 105

74.6 72.1 66.3 89.8 61.9 41.2 43.1 73.1 108

PT = patient; VT = ventricular tachycardia.

280

292 (264-320) 365(310-420) 467 (374-600) 426 (338-470) 449 (278-620) 374

512(474-560)

450 370

483 (370-600)

410

458 332

389 (280-528) 448

1/0

1/1 1/1

0/2 0/4 1/0 1/0 1 /2

0 4 0 1 2

0/2

1 1 2 0

?/0 1/1 2/0 0/0

1 1 1 2 1

0/1 ?/0 ?/0 ?/0 1/0

25 VTs

38 VTs 15/23

1

/2

0/0 ?/0 2/4

Recurrent 1 Self terminating None None New fast VT NewVT None None Died at 3 days None New fast VT detected by ICD None None Not ablated Early recurrence Early recurrence of slow nonsustained VT None None None Not ablated, Died at 4 wks None Died at 12 hours None None None

NONCONTACT ENDOCARDIAL MAPPING

81

Figure 12. A series of activation maps recorded during ventricular tachycardia (VT) in a patient with 2 VT morphologies using the same reentry circuit in contrarotation. The virtual endocardium has beenopenedalongtheanteriorseptumsothatthe2edgesare in continuity. Labels have= been placed on sites identified using fluoroscopy as follows: Basal = left ventricular (LV) base; Apex LV apexlat = lateral. Activation is indiCated by White areas. The successful

radiof requency site is shown with

a green dot. A. VT1: frame 1 showS activation in the diastolic component of the reentry circuit just prior to the exit and systolic activation of the LV. Frames 2 through 4 show systolic activation of the

LV; note the sparing of the region of the diastolic pathway. Frames 5 through 8 show activation during diastole Progressing from the apicoseptal end of the diastolic component of the reentry circuit to the exit at the basolateral end. B. VT4: frame 1 shows activation in the diastolic component of the reentry circuit just prior to reaching the exit site and systolic activation; note that the exit site is at the apicoseptal end of the Same diastolic pathway as in A. Frames 2 through 4 show systolic activaion of the LV; note the sparing of the region of the diastolic pathway. Frames 5 through 7 show activation in diastole progressing from base and lateral

(the exit site for the VT morphology shown in A) toward the septum and apex before returning to the exit. See color appendix

82 CARDIAC MAPPING Table 3 Results of Radiofrequency Application During Ventricular Tachycardia On Exit*

Near Diastolic Pathway

Remote from Diastolic Pathway**

Total

5 (21%) 7 (29%) 12 (50%)

4 (80%) 0 (0%) 1 (20%)

3

22

(77%) 2 (15%) 1 (8%)

(9%) 0 (0%) 31 (91%)

13 (100%)

24 (100%)

5 (100%)

34 (100%)

On Diastolic Pathway Success Partial Failure Total

10

9 45 76

Chi-square analysis for all data = P< 0.0001. With respect to the "On diastolic pathway" column: *P< 0.005 and **P< 0.0001.

documented but not targeted for ablation. Two patients had VTs not previously documented, more than 3 months after the procedure. Five patients in the series died of causes unrelated to the use of the nonProcedural Complications contact mapping system. Further details 43 No patient suffered a cardiac com- are given elsewhere. Of 8 patients with defibrillators preplication as a result of deployment of the noncontact mapping system. Procedural sent before the procedure, 6 had therapy complications were arteriovenous fistu- histories available from the device both lae (n = 2), cerebrovascular event (n = 1) before and after the procedure. Over a prior to deployment of the MEA, cardio- follow-up period of 1.19 ± 0.7 years, the genic shock following ventricular fibril- mean shock frequency was reduced from lation (n = 1) and hemothorax (n = 1) after 9.2 (range 2-23) to 0.16 per year (P < 0.05) a difficult trans-septal puncture that was (1 shock for a fast, previously documented but untargeted VT). treated by percutaneous drainage. RF applications made at sites close to an incompletely identified circuit succeeded in ablating VT in 80% of cases.

Patient Follow-up Of 22 patients who underwent ablation, 14 (64%) had no recurrence of VT over a mean follow-up of 1.5 years (range 0.6-2.5 years). Of 38 target VTs, there was sustained recurrence of only 2 (5.3%) (both within 1 week), which were subsequently ablated at repeat procedures without the noncontact system. Two patients had slower nonsustained VT of the same morphology as that ablated, occurring within 1 week in 1 patient and 1 year after the procedure in the other. One patient had recurrence of a fast VT, 6 months after the procedure, which had been previously

Noncontact Mapping of Atrial Arrhythmias Atrial Flutter

A mapping catheter was positioned in the RA using fluoroscopic and electrogram data and the locator signal used to mark anatomical locations on the virtual endocardium. RF applications were then made in sequence from the ventricular aspect of the TA-IVC isthmus to the IVC in order to complete a line of conduction block between the TA and IVC. The location of each RF application was

NONCONTACT ENDOCARDIAL MAPPING

marked on the virtual endocardium using the catheter locator system. If a line of lesions from TA to IVC failed to either terminate AFL or produce conduction block across the isthmus during pacing at the CS os, then the noncontact system was used to identify the point (or points) at which the activation front passed through the isthmus. The mapping/ablation catheter was then moved to these locations and further RF delivered. If AFL terminated prior to completion of this line or was not initiated during the procedure, then ablation was performed during CS pacing, guided using the noncontact system to create bidirectional block. This was then confirmed using a halo catheter at the end of the procedure.3,44 Distance and Conduction Velocity Measurements The coordinates of points on the virtual endocardium may be displayed as a distance from the MEA and used to calculate the straight line distance between 2 points across the endocardium using the formula:

D = ^(Xl -x 2 ) 2 +( yi -y 2 )

-z 2 ) 2 ,

where x1? y1? z1? and x2, y2, z2 are the coordinates of the 2 points (in mm) and D is the straight line distance between the points. This formula was used to calculate a series of short straight-line distances describing the passage of the AFL wavefront and summed to calculate the isthmus length. Wavefront velocity through the isthmus was then calculated by dividing this distance by the time taken for the wavefront to pass through the isthmus. Definitions Anatomical terminology: For the purposes of anatomical orientation, a format of anatomical nomenclature was used

83

that reflected the true orientation and positioning of the human heart in the thorax. With this format, the SVC and right atrial appendage are superior and the IVC and the TA-IVC isthmus are inferior to the TA. TA-IVC isthmus: was defined by locator signal labeling of anatomical landmarks identified using fluoroscopy and electrogram characteristics and was considered to extend from the CS os posteriorly, the TA superiorly, and the IVC inferiorly. The anterior border of the isthmus was considered a line joining the anteroinferior border of the TA with the anterior border of the IVC. It was further defined by the demonstration of a distinct narrowing and expansion of the AFL wavefront on isopotential maps as the wavefront respectively entered and exited the isthmus. Results Patients Eight patients, all males, mean age 49 years (range 33-68 years), were studied. All patients had begun antiarrhythmic therapy prior to the procedure (either flecainide [n = 2], verapamil [n = 1], amiodarone [n = 5], sotalol [n = 2], or digoxin [n = 1]). Three patients were taking multiple antiarrhythmic drugs. After mapping, 7 patients underwent RF ablation of AFL by creation of a line of block along the TA-IVC isthmus. One patient with AF as the predominant arrhythmia did not have an ablation procedure. Six patients were in AFL at the start of the procedure and no attempt was made to initiate AFL in 1 patient who was in sinus rhythm at the onset of the study and in whom RF application was performed during CS pacing. The rotation of the AFL circuit was counterclockwise in 5 patients and clockwise in 1.

84

CARDIAC MAPPING

Characteristics of Isthmus Activation The passage of the flutter wavefront was seen throughout the entire isthmus in 5 patients, with some signal attenuation seen in 2 patients who had had previous ablation procedures. Passage of the flutter wavefront through the isthmus took 78.3 ± 49.5 ms before RF application and 110 ± 57.9 ms (95% CI 63.3 to 156.0) after delivery of the penultimate RF application (P < 0.05). Isthmus activation occupied a mean 32.16 ± 16.0% of the flutter cycle length before delivery of RF and 39.8 ± 16% (95% CI 27% to 52.6%) after the penultimate RF application before flutter terminated (P< 0.05). The velocity of the wavefront in the isthmus was 0.93 ± 0.32 m/s before ablation and slowed to 0.67 ± 0.21 m/s (95% CI 0.5 to 0.84) after the penultimate RF application prior to AFL termination (P < 0.05). In 2 patients the AFL wavefront split into 2 separate wavefronts as it passed the CS os at the region of the eustachian ridge, one wavefront passing inferiorly and one superiorly to the CS os. They then fused into a single wavefront. In 3 patients a single activation wavefront slowed and turned superiorly toward the annulus in the region of the CS os and eustachian ridge, and in an additional 2 patients the wavefront slowed and emerged from the isthmus inferiorly. The pattern of isthmus activation was changed by delivery of RF energy in 5 of the 6 patients in whom RF was applied during AFL. Lateral Wall Activation Patterns During AFL A line of block was seen on the posterolateral RA wall on all isopotential maps recorded during AFL. The presence of this line of block was confirmed by the presence of double potentials in electrograms reconstructed along the

line (Figure 13). In 4 patients the line of block extended from the IVC to the SVC. In 1 patient the line of block extended superiorly from the IVC to the midlateral RA but did not reach the SVC. In another patient the line of block extended from the SVC to the low RA but slow activation was seen progressing over a 70-ms interval between the IVC and the crista terminalis which was further confirmed by long fractionated reconstructed electrograms in this region (Figure 14). Activation Around the TA The pattern of AFL activation wavefront in relation to the portions of the TA not adjacent to the isthmus (nonisthmus TA) was seen in all patients. AFL activation progressed toward the nonisthmus TA from the surrounding RA in 4 patients, suggesting that endocardium around the line of block in the lateral RA activated before the TA and was the critical region of conduction block around which the activation wavefront rotated (Figure 15). In 2 patients activation progressed away from the nonisthmus TA suggesting that, in these patients, one of whom had a massive RA (6 cm x 8 cm), the TA was the critical region of conduction block around which the activation wavefront rotated. AFL Ablation Radiofrequency energy was used to produce a line of block in the isthmus in 7 patients with 13.3 ± 19.5 RF application, and the continuity of the line of block was confirmed using a halo catheter in 6 of these patients; a halo catheter could not be positioned adequately in the patient with the massive RA. The location of a break in the line of block was successfully detected during AFL by the noncontact system during online analysis in 5 patients

Figure 13. The virtual endocardium has been opened and unfolded from superior to inferior along the anterior tricuspid annulus. Anatomical locations have been identified using the fluoroscopic position and electrograms recorded from catheter electrodes and marked on the virtual endocardium using the catheter location system. Locations marked in this manner are as follows: IVC = inferior vena cava; TA = tricuspid annulus; CS - coronary sinus os. Also marked with a blue line are the possible positions of the crista terminalis (CT) and eustachian ridge (ER). A. A series of activation maps recorded from the right atrium (RA) during atrial flutter (AFL) showing counterclockwise flutter. The positions at which reconstructed bipolar electrograms have been displayed in B are labeled a through f, from superior to inferior, along the blue line indicating a line of conduction block and the possible position of the CT. Activation is displayed on the virtual endocardium as a white and colored area. Activation is seen progressing from the anterolateral RA in near the IVC (frame 1) to the superior anterolateral RA (frames 2 and 3) along a line of block. Activation then turns at the superior vena cava and progresses down the opposite side of the line of block from superior to inferior (frames 3 through 5) before it reaches the isthmus. Activation progresses slowly through the isthmus (frames 6 to 1), before activation of the anterolateral RA occurs once more (frame 1). See color appendix. B. Reconstructed bipolar electrograms from positions a through f along a line of block shown in A. Two AFL cycles are shown, and the numbers 1 through 6 indicate the point at which the activation maps (A) have been displayed. The electrograms show double potentials with the isoelectric intervals between potentials increasing from a to f, reflecting the activation pattern shown on the activation maps. Note the long interval between the second potential on electrogram f and the first potential on the subsequent electrogram indicating the time for activation to pass through the isthmus and activate the anterolateral RA.

86

CARDIAC MAPPING

Figure 14. Virtual electrogram as described for Figure 13. A. A series of activation maps recorded during counterclockwise atrial flutter. The positions at which bipolar electrograms have been reconstructed and displayed in B are shown labeled as a through e, from superior to inferior, along the line of block representing the possible position of the CT. Activation passes through the isthmus (frame 1) and turns to toward the TA around a line of block (possibly the ER) (frame 2). The wavefront then begins to split (frame 3), with one front moving superiorly along the line of block while the other moves slowly along the ER. The first wavefront turns at the superior vena cava (frame 4) and then passes inferiorly along the line of block (frames 5 and 6). The second front passes slowly through a break in the line of block (frames 4 to 6). The first and second front then fuse (frame 7) and pass around the IVC to enter (frame 8) and pass through the isthmus (frame 1). See color appendix. B. Waveform window from the noncontact mapping system showing the surface EGG lead II, an electrogram from a catheter at the CS os, and reconstructed bipolar electrograms from points a through e on the activation maps in A. The numbers 1 through 8 represent the points at which the activation maps have been displayed in A. The electrograms from the line of block show double potentials apart for those recorded at the break in the line of block that are long and fractionated representing the slow activation at this point.

Figure 15. A series of activation maps superimposed onto the virtual endocardium with the lateral wall of the right atrium (RA) cut away so that the view is looking toward the tricuspid annulus (TA). Anatomical locations are marked in green as follows: isthmus, ant annulus = anterior TA; ant sup ann = anterior superior annulus; his = His bundle; post sup TA = posterior superior TA; post mid ann = posterior middle TA; mid septal = middle septal TA; post annulus = posterior TA; cs os = coronary sinus os. Also marked as black circles and labeled in yellow are the boundaries of the tricuspid valve (TV) and inferior vena cava (IVC). The possible position of the eustachian ridge is drawn onto the virtual endocardium as a yellow line. Activation is seen as white and colored regions. The atrial flutter wavefront enters and passes through the isthmus (frame 1) and encounters a line of block at the posterior isthmus. The wavefront turns toward the TA (frame 2) and passes up over this line of block and passes back down the posterior aspect of the line of block (frame 3). Activation exits the isthmus and activates the posterior RA (frames 4 to 6), but activation is earliest in the posterolateral RA and progresses toward the TA (frames 6 and 7) and then activates the anterior RA before progressing toward the TA (frame 8). The wavefront then passes into the anterior isthmus (frame 8) and through the isthmus to repeat the circuit (frame 1). See color appendix.

88 CARDIAC MAPPING (Figure 16). The noncontact system was then used to guide a catheter to this break, where energy was then delivered. CS Pacing During Sinus Rhythm At the end of the ablation procedure, CS pacing confirmed a line of block in the isthmus in 5 cases. In 2 patients the size and shape of the RA prevented adequate electrogram recording using a halo catheter, and offline analysis of noncontact data identified the location of a break in the line of block. A line of block in the lateral RA in the same location as seen during AFL was identified during slow pacing at the CS os in 6 patients. In 1 patient CS pacing was performed at a distal CS position, resulting in an RA activation wavefront emerging from the superior RA septum in the region of Bachmann's bundle. The paced RA wavefront thus progressed simultaneously down the RA, anterior and posterior to the line of block identified during AFL.

The AFL wavefront has been seen to turn from the posteroseptal RA to the anterolateral RA at the level of the midlateral RA in 1 patient and in another patient the main wavefront was seen to split, with 1 daughter wavefront turning at the level of the IVC with the slowness of conduction of the wavefront through this region maintaining the reentry circuit. A line of block is also seen during slow CS pacing which suggests that the crista terminalis is a fixed line of block to transverse depolarization. Although this line of block is fixed (i.e., present during slow and fast activation rates) there are differences in the extent of this line of block between patients. Activation in the Region of the CS Os

The anatomy of the triangle of Koch and posterior isthmus is complex and is composed in part by the eustachian ridge extending into the tendon of Todaro, and the CS os. Slow and irregular activation seen in Koch's triangle may be due to fiber Role of the Crista Terminalis arrangement,49 and it has also been noted that circumferential fibers found around The presence of double potentials45,46 the rest of the TA may be absent in this during AFL has suggested the presence of area.50 Noncontact mapping demonstrated barriers to conduction,45,47,48 and intra- that the wavefront slows and turns in the cardiac echocardiography has confirmed posterior region of the triangle of Koch in that these electrical barriers are related the majority of patients, suggesting that it to the anatomical structures of the crista encountered a line of block compatible with terminalis and the eustachian ridge.45 the site of the eustachian ridge. Splitting of Noncontact mapping during AFL has con- the wavefronts in this region was also seen firmed the presence of a line of conduction and may have been a feature of the waveblock in the lateral RA that is compatible front passing around the CS os or it may with the location of the crista terminalis have been that part of the activation front with both double potentials on recon- passed under the eustachian ridge, becomstructed electrograms in this region and ing intramural and thus not visible to the demonstration of block on isopotential noncontact system. While only 1 patient maps. Uniquely, noncontact mapping has with clockwise AFL was included in this demonstrated that this line of conduction series, a similar activation pattern was block does not necessarily extend for the seen indicating that it is not specific to the entire distance between the SVC and IVC. direction of the wavefront.

NONCONTACT ENDOCARDIAL MAPPING

89

Figure 16. Activation maps recorded during atrial flutter (AFL) demonstrating identification of a break in a line of block in the tricuspid annulus-inferior vena cava (TA-IVC) isthmus and the positioning of a catheter on this break with the aid of the noncontact mapping system. The virtual endocardium has been opened along the lateral wall and tilted so that the view is looking from the lateral wall toward the TA with the image focused on the TA-IVC isthmus. The anatomical labels marked during the procedure are shown in green as follows: HRA = high right atrial catheter position; POST ANNULUS = posterior tricuspid annulus; ANT ANNULUS = anterior tricuspid annulus; HIS = his bundle position. The positions at which radiofrequency (RF) applications have been made are marked with green stars. The TA and IVC are marked as black circles and labeled in yellow. Also marked are the positions of a mapping/ablation catheter (RF catheter) and the break in the line of block. Activation is shown as white and colored regions on the purple virtual endocardium. A. The activation map is shown as the wavefront of counterclockwise flutter enters the isthmus and encounters an incomplete line of block produced by the previous RF applications. B. The activation map is now shown with the AFL wavefront seen emerging as a discrete point of activation emerging through the break in the line of block. The catheter location system has been used to position the ablation catheter at this break in the line of block, and delivery of RF at this point resulted in termination of AFL and completion of the line of block in the isthmus. This was confirmed using a halo catheter deployed around the right atrium. See color appendix.

90 CARDIAC MAPPING Conduction Velocity Within the Isthmus It is not possible to conclude from these data that the TA-IVC isthmus is a region of slow conduction because 4 of the patients studied had had previous attempts at AFL ablation and our data suggest that application of RF within the TA-IVC isthmus may result in a significant slowing of conduction velocity in the absence of a complete line of block or termination of the arrhythmia. Catheter Ablation of AFL Ablation of AFL by delivering RF energy to produce a complete line of conduction block between the TA and the IVC is well described.51 Noncontact mapping successfully localized breaks in the line of block in the isthmus during AFL and guided delivery of RF energy at these sites to terminate AFL. The confirmation of a complete line of block was possible in most patients, but in 2 patients further offline analysis identified breaks in the TA-IVC line of block that were associated with subsequent recurrence. The noncontact system proved particularly useful

in 1 patient with a massive RA in whom it was not possible to deploy a halo catheter to confirm the RA activation pattern during CS pacing. Thus, noncontact mapping in the human RA during AFL has confirmed observations made during previous studies. The AFL reentry circuit rotates around anatomical obstacles and is dependent on a fixed line of block created by the TA or, more often, the crista terminalis. The AFL wavefront conduction velocity within the TA-IVC isthmus has been measured for the first time in humans; while it has been confirmed that conduction may be slow in this region, a cause for this has not been identified. Atrial Fibrillation The RA was mapped during AF in 11 patients (8 male, mean age 55 years, range 34-76 years) (Table 4). Three patients had a history of chronic AF and others developed AF during the procedure. A 12-lead ECG was recorded during AF either immediately prior to the mapping procedure in the patients with chronic AF or during AF in the patients with paroxysmal AF. The AF was categorized as "coarse" or "fine"

Table 4 Patient Demographics Patient

1 2 3 4 5 6 7

8 9 10 11

Age 55 40 66 42 34 76 73 75 36 34 74

Underlying Arrhythmia

AF P Septal WPW A Flutter Paroxysmal AF

AF AF A Flutter A Flutter A Flutter AVNRT A Flutter

Drugs

RA lat/TA (cm)

RA AP (cm)

Digoxin, Warfarin Disopyramide Verapamil, Warfarin None Amiodarone, Warfarin Digoxin, Diltiazem, Warfarin Diltiazem, Metoprolol None Amiodarone None Amiodarone

5.5 4.3 4 4 5.6 5.4 5.8 6.2 9.9 7.4 8.4

4.3 3.5 3.2 3.2 4.7 3.7 3.6 2.8 5.1 4.3 5.3

AF = atrial fibrillation; A Flutter = atrial flutter; AVNRT = atrioventricular nodal reentrant tachycardia; P Septal WPW = posteroseptal Wolff-Parkinson-White; RA lat/TA = right atrium lateral/tricuspid annulus; RA AP = right atrial antero-posterior dimension.

NONCONTACT ENDOCARDIAL MAPPING

according to the appearance of the diastolic interval on the surface EGG.52 Entrainment of AF was attempted in 7 patients at multiple sites by bipolar pacing using the mapping/ablation catheter at cycle lengths shorter than the median RA cycle length and at twice the capture threshold determined by pacing at a cycle length 20 ms less than the median RA cycle length. If AF was chronic no attempt was made to terminate it, but persistent AF induced during the procedure was terminated using up to 2 mg/kg intravenous flecainide (to a maximum of 150 mg) infused over 10 minutes. The infusion was stopped as soon as the patient reverted to sinus rhythm. Endocardial activation was recorded throughout the infusion and noncontact mapping data were analyzed offline. Definitions Focal activation: or breakthrough of electrical activity was defined as a wavefront emerging from a point on the endocardium where the surrounding endocardium was electrically silent so that activation was not propagating from a detectable RA wavefront. Entrainment: was defined as activation of an area of endocardium that propagated from a pacing source for at least 2 pacing cycles so that the cycle length of activation of that area equaled the pacing cycle length. Entrainment was confirmed by examination of both the noncontact activation maps, which provided data of the origin of the wavefront and direction of propagation, and examination of individual reconstructed unipolar electrograms, which provided cycle length data. AF pattern: Activation of the RA during AF was divided into 3 categories

91

using a classification similar to that used by Konings et al.53 and was defined as follows: 1. type I AF: only 1 wavefront present in the RA for greater than 50% of the time; 2. type II AF: 2 independent wavefronts present in the RA for greater than 50% of the time; 3. type III AF: 3 or more wavefronts present in the RA for greater than 50% of the time. The definitions used differed from those of Konings et al. in that data were acquired from the entire RA and it was stipulated that a set number of wavefronts were present for greater than 50% of the time period analyzed rather than for the entire time. This was because with noncontact mapping larger areas of the RA were analyzed and for much longer periods than had been possible in the study by Konings et al., so that there was a variation in the number of wavefronts present in most of the cases analyzed. After AF had been established for at least 30 seconds and prior to any drug or pacing intervention, AF was then categorized as type I, II, or III AF according to the number of wavefronts present on activation maps for the majority of the time period analyzed. Results Initiation of AF Initiation of AF in 4 patients without chronic AF was caused by catheter manipulation, and in 4 AF occurred during attempted entrainment of AFL. This occurred before introduction of the MEA in 1 patient. Initiation of AF was recorded by the noncontact mapping system in 1 patient. Noncontact mapping and catheter location demonstrated that the mapping/

92

CARDIAC MAPPING Table 5 Results

AF on ECG

AF type

Focal Activation

1 2*

Coarse Fine

I III

3*

Fine

III

4* 5 6 7 8 9 10 11

Fine Coarse Fine Coarse Fine Coarse Coarse Fine

III II III I II I I III

No No (pace terminated) Sup and CS sept (blocked in isthmus) No Sup sept Sup mid and CS sept Sup and CS sept Sup septum Sup mid and CS sept Sup septum Sup mid and CS sept

PT

Termination by Flecainide

No To A flutter To A flutter Atrial ectopics No No No No No No No

"Indicates patients in whom AF was initiated by catheter manipulation. AF = atrial fibrillation; CS = coronary sinus; PT = patient; sept = septum; Sup = superior.

ablation catheter had provoked 2 atrial ectopic beats. The inferior aspect of the second resulting wavefront encountered a line of block in the IVC-TV isthmus, possibly established by the first wavefront, while the superior portion of the wavefront continued around the superior and anterior TA to form a single macroreentrant wavefront following a path similar to counterclockwise AFL. After 2 complete circuits, lines of conduction block developed causing the wavefront to divide into 3 in the septum that then continued to propagate in a random manner resulting in changing wavefront numbers and vectors as AF established. Mapping of Established AF Atrial fibrillation that had been established for at least 1 minute was recorded in all patients. The results of AF mapping and termination are shown in Table 5. By the criteria described above, 4 patients had predominantly type I AF, 2 patients had predominantly type II AF, and 5 patients had predominantly type III AF in the RA. The patients with type I AF had coarse atrial activity on the surface EGG. Of

patients with type II AF, 1 had coarse and 1 had fine atrial activity on the EGG. All of the patients with type III AF had fine atrial activity on the surface EGG. Periods of electrical silence lasting greater than 50 ms were observed in the RA of 8 patients (3 type I, 2 type II, 3 type III). In all patients the re-initiation of RA activation was from consistent locations on the RA septum probably representing breakthrough from the left atrium. In 3 patients RA reactivation was in the superior septum in the region of Bachmann's bundle; in 2 patients 2 areas were observed in the superior septum (Bachmann's bundle) and near the CS os. In 3 patients 3 sites were observed in the superior septum/ Bachmann's bundle, mid septum, and near the CS os. Example of type I AF

An example of11/2cycles of type I AF is shown in Figure 17. The reentry wavefront rotates around a line of block situated in the posterior septum and postero- lateral wall near the crista terminalis. This line of block did not vary during AF but slight variations in the path of the wave front were seen in other regions of the RA.

Figure 17. A. Unipolar activation maps, shown at 30-ms intervals, of type I atrial fibrillation showing a macroreentry wavefront rotating around a line of block indicated by the blue line. See color appendix. B. Unipolar reconstructed electrograms taken from points on the activation maps a through g showing sequential activation around the right atrium. The larger numbers at top indicate the points at which the corresponding sequential activation map frame has been displayed. Abbreviations as in previous figures.

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Example of type III AF

An example of type III AF is shown in Figure 18. After a period of electrical silence, activation emerges from an area on the septum near the CS. This rapidly splits into 3 activation wavefronts, the central one being of lowest amplitude and velocity possibly representing slowed conduction in the region of the fossa ovalis. This wavefront makes a 180° turn and passes around the inferior TA through the TA-IVC isthmus to collide with a wavefront passing around the anterior RA.

the left atrium or left atrial septum with the wavefront returning to the RA at Bachmann's bundle. Distal CS pacing did not alter activation patterns within the RA but did shorten the cycle lengths of electrograms recorded on the CS catheter. Termination of AF Termination of AF following flecainide infusion was observed and recorded in 3 patients, all with type III AF. Mean flecainide dose was 140 mg. Termination of AF example 1

Entrainment During AF Entrainment was demonstrated during AF in 2 patients. Entrainment was attempted in the 6 other patients, but either the stimulus amplitudes required to achieve local capture of the RA were large enough to saturate the amplifiers of the noncontact system and therefore prevent meaningful analysis of data (n = 4), or it was not possible to demonstrate local or remote entrainment (n = 2). Entrainment example

Pacing at the high RA (in the region of the crista terminalis), IVC-TV isthmus, and CS os resulted in entrainment of the entire RA during type I AF. Pacing in the lateral RA resulted in a wavefront that fused with the advancing spontaneous wavefront at successively earlier stages until the entire RA was entrained. Pacing from the CS os did not locally capture the RA but was followed by remote RA activation from the superior septum in the region of Bachmann's bundle that advanced the entire macroreentry circuit (Figure 19). This phenomenon stopped on cessation of CS pacing and the previously mapped reentry circuit resumed indicating a possibility of entrainment of

Flecainide infusion in a patient with type III AF resulted in progressively fewer wavefronts with longer periods of RA electrical silence which then evolved to a single reentry wavefront, which encountered a line of block in the superior posteroseptal wall. The RA was then reactivated several times from the septum presumably as breakthrough from the left atrium. Following one period of electrical silence, RA tachycardia emerged as a uniform wavefront from a focus on the lateral RA wall in the region of the crista terminalis. A second wavefront emerged from a similarly located focus that was then followed by a longer pause. This was followed by slow regular activity emerging from the same RA point as recorded during sinus rhythm indicating the resumption of sinus rhythm. Termination of AF example 2

Flecainide infusion resulted in progressively fewer wavefronts until a single wavefront remained rotating in a macroreentry circuit around the RA consistent with typical AFL. This terminated several times and random reentry54,55 was reestablished by local reactivation from the septum. After a further 2 rotations,

NONCONTACT ENDOCARDIAL MAPPING

95

Figure 18. A. A series of activation maps, shown at 20-ms intervals, during type III atrial fibrillation (AF). Activity emerges from the coronary sinus (CS) septum and splits into 3 separate lateral, central, and medial wavefronts (frames 1 and 2). The central of these wavefronts is slower and of lower amplitude and splits into 2 further wavefronts traveling superiorly and inferiorly (frame 3). The more inferior wavefront collides in the isthmus with the medial wavefront that has rotated around the tricuspid annulus (TA) (frames 3 and 4) while the more superior wavefront collides with a line of block established by earlier activation by the same medial wavefront (frame 4). The lateral and medial wavefronts fuse in the anterolateral right atrium (RA) (frames 2 and 3) and the resulting wavefront divides in the superior RA with one front rotating around the TA (frames 3 and 4) and the other rotating in the superior septum before fusing with the central superior wavefront (frames 4 and 5). Subsequent activation maps show the continuing complex patterns of activation seen in type III AF. See color appendix. B. Unipolar reconstructed electrograms from points a through e in A demonstrate the complexity of electrograms compared with type I AF (Figure 17B). The point at which each activation map is displayed is shown by the numbers at top.

96

CARDIAC MAPPING

Figure 19. A. Unipolar activation maps at 30-ms intervals during type I atrial fibrillation. Entrainment from a contact catheter sited in the high right atrium lateral wall (indicated by locator signal green line) pacing at a cycle length of 170 ms is shown. See text for detailed descriptions of activation maps. The approximate timing of pacing signals is shown with white arrows and the label "Pace." See color appendix. B. Unipolar reconstructed electrograms from positions a through g on the virtual endocardium in A. Times at which activation maps are shown are indicated by the corresponding frame numbers at the top of the figure.

NONCONTACT ENDOCARDIAL MAPPING

this wavefront then blocked in the region of the TA-IVC isthmus resulting in termination of tachycardia and resumption of sinus rhythm. Termination of AF example 3

In the remaining patient an infusion of flecainide resulted in organization and slowing of the wavefront so that a consistent AFL reentry circuit was formed. Overdrive pacing was required to terminate tachycardia.

97

majority of patients described in the study by Konings et al.53 had a predominantly type I pattern, whereas most of the patients included in this study had predominantly type III patterns. This may be explained by bias resulting from the small numbers included, or by the global nature of the mapping technique used which revealed the presence of other wavefronts that may not have been apparent to Konings' group when mapping a smaller atrial area. Focal atrial activation

Focal atrial activation during AF has been described by several published map53,61,64,68 Of those that used Detailed mapping studies such as ping studies. these are likely to increase our under- high-density mapping, the majority used standing of the mechanisms of AF. epicardial arrays applied during surgery Many mapping studies of human AF and concluded that the focal activation have been published to date,1,2,56–61 but seen was a result of epicardial breakcontain recorded data from limited through of an AF wavefront propagating 53,64,65 endocardial contact sites62,63 or describe in a free-running atrial trabeculum. epicardial electrode arrays used to One study used simultaneous endocardial record high-resolution data over lim- and epicardial mapping in canines to con69 ited areas53,58,64,65 or low-resolution data firm the existence of this phenomenon. The data presented in this chapter over large areas,66,67 often in patients with normal atria who had AF induced demonstrate activity emerging solely from the septum in the region of Bachmann's during a surgical procedure. These are the first experiences of bundle and the septum near the CS where noncontact mapping of human AF and the orientation of atrial fibers might are the first to provide maps of the entire encourage interatrial conduction. One RA endocardium including the septum can surmise from these data that this during AF. Noncontact mapping of AF in activity is the result of breakthrough of the human RA has confirmed the pres- activation from the left atrium. These ence of a variation in AF patterns in dif- conclusions are supported by previous left ferent patients that correspond with the studies that have used simultaneous RA mapping in canines61 and classification of types I, II, and III described atrial and 68 by Konings et al.53 The data have also humans to identify breakthrough of demonstrated entrainment of large areas activation from one atrium to the other, of the RA and recorded the termination of in some cases resulting in reactivation of unstable reentry circuits. AF by intravenous flecainide. Discussion

Atrial reentry

Termination of AF

The range of activation patterns presented here are compatible with previous studies.53,61 It is of interest that the

Previous investigators have used either low-resolution endocardial catheter mapping in humans70 or high-resolution

epicardial mapping of canines57,59,60 and entrained in this study and that seen in humans71 to demonstrate the mechanism previous studies may be because previof termination of a number of different ous high-resolution mapping studies of models of AF and using a variety of drugs. entrainment in AF have been restricted Flecainide has been shown to increase to canines. In addition, the global data the size and reduce the number of reen- provided by the noncontact mapping try circuits.57 In addition, flecainide may system may facilitate the differentiation convert AF to a regular tachycardia before between an entrained wavefront and an terminating the arrhythmia,57,59,71 and arrhythmia wavefront, so that fusion and termination of AF may follow the estab- modification of the native wavefront and lishment of a macroreentry circuit.57 entrainment can be confirmed. NonconMechanisms of termination of AF, similar tact mapping could therefore potentially to the cases described in this study, have demonstrate entrainment that may have been demonstrated previously, showing been overlooked by other techniques. It should be remembered that none of that failure of reexcitation of the RA from the left atrium was important, and that the studies described here examine actitermination may be preceded by wave- vation within the left atrium. It is well fronts emerging from a focus.59 A consid- known that the conduction properties of erable interrelation between AF and AFL the left atrium and the RA are inhomo72,73 and that the fibrillation rates and spontaneous conversion between the geneous 74 60 2 has also been shown previously and may differ between them. fits with the observations of the development of a reentry circuit identical to RA Summary flutter preceding the termination of AF presented in this study. Noncontact mapping has been validated in both sinus rhythm and VT. The Entrainment of AF VT and AFL reentry circuits identified by the noncontact mapping system have In 2 patients with type I AF, it was also been validated by examining the demonstrated that entrainment of large outcome of application of RF energy on areas of the RA was possible from more portions of the circuits critical to maintethan 1 site. Studies using high-resolution nance of the arrhythmias. Electrogram mapping have demonstrated entrainment reconstruction is accurate but this accuof smaller areas of the RA than the pre- racy decreases as the MEA-endocardial sent study, of between 4 cm58 and 6 cm.56 distance increases and this becomes sigLeft atrial activation was not examined in nificant when this distance is greater than our studies, except from the CS electrode, 34 mm. Delivery of RF energy to portions but pacing at the CS os in 1 patient with of the diastolic pathway VT is signifitype I AF resulted in activation of the right cantly more likely to successfully ablate superior septum remote from the pacing VT than energy applications at other site with a coupling interval identical to places. Noncontact mapping has also pacing cycle length suggesting entrain- been able to provide new insights into ment, presumably as a result of capture the mechanisms of AFL and fibrillation. of the left atrium or left atrial septum. Noncontact mapping appears to have 2 Therefore, it may also be possible to entrain major applications, assisting and guiding significant areas of the left atrium. The ablation of arrhythmias, and providing a difference between the proportion of RA better understanding of arrhythmias

NONCONTACT ENDOCARDIAL MAPPING

such as AF that have so far proved difficult and complex to treat using currently available technology.

References 1. Allessie MA, Lammers WJEP, Smeets JRLM, et al. Total mapping of atrial excitation during acetylcholine-induced atrial flutter and fibrillation in the isolated canine heart. In: Kulbertus HE, Olsson SB, Schlepper M (eds): Atrial Fibrillation. Molndal, Sweden: Lindgren and Soner; 1982:44-62. 2. Allessie MA, Lammers WJEP, Bonke FIM, Hollen J. Experimental evaluation of Moe's multiple wavelet hypothesis of atrial fibrillation. In: Zipes DP, Jalife J (eds): Cardiac Arrhythmias. New York: Grune & Stratton; 1985:265-276. 3. Cauchemez B, Haissaguerre M, Fischer B, et al. Electrophysiological effects of catheter ablation of inferior vena cavatricuspid annulus isthmus in common atrial flutter. Circulation 1996;93:284294. 4. Cosio FG, Lopez-Gil M, Arribas F, et al. Mechanisms of entrainment of human common flutter studied with multiple endocardial recordings. Circulation 1994; 89:2117-2125. 5. Josephson ME, Horowitz LN, Farshidi A, Kastor JA. Recurrent sustained ventricular tachycardia. I. Mechanisms. Circulation 1978;57:431-439. 6. Karagueuzian HS, Fenoglio JJ, Weiss MB, Wit AL. Protracted ventricular tachycardia induced by premature stimulation in the canine heart after coronary artery occlusion and reperfusion. Cire Res 1979;44:833-846. 7. deBakker JMT, Coronel R, Tasseron S, et al. Ventricular tachycardia in the infarcted, Langendorff-perfused human heart: Role of the arrangement of surviving cardiac fibers. J Am Coll Cardiol 1990;15:1594-1607. 8. Wellens HJJ, Schuilenberg RM, Durrer D. Electrical stimulation of the heart in patients with ventricular tachycardia. Circulation 1972;46:216-226. 9. Stevenson WG, Friedman PL, Kocovic D, et al. Radiofrequency catheter ablation of ventricular tachycardia after

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myocardial infarction. Circulation 1998; 98:308-314. 10. Stevenson WG, Khan H, Sager P, et al. Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of ventricular tachycardia late after myocardial infarction. Circulation 1993;88:1647-1670. 11. El-Sherif N, Mehra R, Gough WB, Zeiler RH. Reentrant ventricular arrhythmias in the late myocardial infarction period: Interruption of reentrant circuits by cryothermal techniques. Circulation 1983; 68:644-656. 12. Borggrefe M, Podczeck A, Ostermeyer J, Breithardt G. Long term results of electrophysiologically guided antitachycardia surgery in ventricular tachyarrhythmias. A report on 655 patients. In: Breihardt G, Borggrefe M, Zipes DP (eds): Nonpharmacological Therapy of Tachyarrhythmias. Mount Kisco, NY: Futura Publishing Co.;1987:109. 13. Davis LM, Cooper M, Johnson DC, et al. Simultaneous 60-electrode mapping of ventricular tachycardia using percutaneous catheters. J Am Coll Cardiol 1994;24; 709-719. 14. Bockner D, Breithardt G, Block M, Borggrefe M. Management of patients with ventricular tachycardia: Does an optimal therapy exist? Pacing Clin Electrophysiol 1994;17:559-570. 15. Morady F, Harvey M, Kalbfleisch SJ, et al. Radiofrequency ablation of ventricular tachycardia in patients with coronary artery disease. Circulation 1993;87:363-372. 16. Borgreffe M, Chen X, Hindricks G, et al. Catheter ablation of ventricular tachycardia in patients with heart disease. In: Zipes DP (ed): Catheter Ablation of Arrhythmias. Armonk, NY: Futura Publishing Co.;1994:277-308. 17. Gepstein L, Hayam G, Ben-Haim S. A novel method for nonfluoroscopic catheterbased electroanatomical mapping of the heart. Circulation 1997;95:1611-1622. 18. Gulrajani R, Roberge F, Savard P. The inverse problem of electrocardiography. In: Macfarlane P, Veitch Lawrie T (eds): Comprehensive Electrocardiology. New York: Pergamon Press; 1989:237-288. 19. Frank E. Absolute quantitative comparison of instantaneous QRS equipotentials on a normal subject with dipole potentials on a homogenous torso model. Circ Res 1955;3:243-251.

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20. Savard P, Roberge FA, Perry JB, Nadeau RA. Representation of cardiac electrical activity by a moving dipole for normal and ectopic beats in the intact dog. Circ Res 1980;46:415-425. 21. Barnard ACL, Holt JH, Kramer JO. Models and methods in inverse electrocardiology: The UAB choice. In: Nelson CV, Geselowitz DB (eds): Theoretical Basis ofElectrocardiology. Oxford: Clarendon; 1976:305-322. 22. Ideker RE, Brody DA, Cox JW, Keller FW. Examination of a multiple dipole inverse cardiac generator based on accurately determined model data. J Electrocardiol 1973;6:197-209. 23. Arthur RM, Geselowitz DB, Briller SA, Trost RF. Quadrupole components of the human surface electrocardiogram. Am Heart J 1972;83:663-677. 24. Geselowitz DB. Multipole representation for an equivalent cardiac generator. Proc IRE 1960;48:75-79. 25. Oster HS, Taccardi B, Lux RL et al. Noninvasive electrocardiographic imaging. Reconstruction of epicardial potentials, electrograms and isochrones and localization of single and multiple electrocardiac events. Circulation 1997;96:1012-1024. 26. Colli-Franzone P, Taccardi B, Viganotti C. An approach to inverse calculation of epicardial potentials from body surface maps. Adv Cardiol 1978;21:50-54. 27. Taccardi B, Arisi G, Macchi E, et al. A new intracavitary probe for detecting the site of origin of ectopic ventricular beats during one cardiac cycle. Circulation 1987;75:272-281. 28. Khoury DS, Rudy Y. A model study of volume conductor effects on endocardial and intracavitary potentials. Circ Res 1992;71:511-525. 29. Khoury DS, Rudy Y. Reconstruction of endocardial potentials from intracavitary probe potentials: A model study. Proc Comput Cardiol Durham NC: Oct 11-14, 1992:9-12. 30. Macchi E, Arisi G, Colli-Franzone P, et al. Localization of ventricular ectopic beats from intracavitary potential distributions: An inverse model in terms of sources. Proc llth IEEE/EMBS. 1989:191-192. 31. Beatty GE, Remote SC, Hansen R, et al. Noncontact electrical extrapolation technique to reconstruct endocardial potentials. Pacing Clin Electrophysiol 1994; 17:765. Abstract.

32. Derfus DL, Pilkington TC. Assessing the effect of uncertainty in intracavitary electrode position on endocardial potential estimates. IEEE Trans Biomed Eng 1992; 39:676-681. 33. Peters NS, Jackman W, Schilling RJ, et al. Human left ventricular endocardial activation mapping using a novel non-contact catheter. Circulation 1997;95:1658-1660. 34. Khoury DS, Taccardi B, Lux RL, et al. Reconstruction of endocardial potentials and activation sequences from intracavity probe measurements. Localization of pacing sites and effects of myocardial structure. Circulation 1995;91:845-863. 35. Schilling RJ, Peters NS, Davies DW. A non-contact catheter for simultaneous endocardial mapping in the human left ventricle: Comparison of contact and reconstructed electrograms during sinus rhythm. Circulation 1998;98:887-898. 36. Tikhonov AN, Arsenin VY. Solutions of Ill-Posed Problems. Washington, DC: VH Winston & Sons; 1977:27-94. 37. Messinger-Rapport BJ, Rudy Y. Regular ization of the inverse problem in electrocardiography: A model study. Math Biosci 1988;89:79-118. 38. Chiang CM, Jenkins JM, DiCarlo LA. Digital signal processing chip for detection and analysis of intracardiac electrograms. Pacing Clin Electrophysiol 1994;17:13731379. 39. Greenhut SE. Identification of ventricular tachycardia using intracardiac electrograms: A comparison of unipolar versus bipolar waveform analysis. Pacing Clin Electrophysiol 1991;14:427-433. 40. Morady F, Kadish A, Rosenheck S, et al. Concealed entrainment as a guide for catheter ablation of ventricular tachycardia in patients with prior myocardial infarction. J Am Coll Cardiol 1991;17: 678-689. 41. Khan H, Stevenson WG. Activation times in and adjacent to reentry circuits during entrainment: Implications for mapping ventricular tachycardia. Am Heart J 1994; 127:833-842. 42. Josephson ME, Horowitz LN, Spielman SR, et al. Role of catheter mapping in the preoperative evaluation of ventricular tachycardia. Am J Cardiol 1982;49:207221. 43. Schilling RJ, Peters NS, Davies DW. Feasibility of a noncontact catheter for endocardial mapping of human ventricular

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tachycardia. Circulation 1999;99:25432552. 44. Poty H, Saoudi N, Abdel Aziz A, et al. Radio-frequency catheter ablation of type 1 atrial flutter. Prediction of late success by electrophysiological criteria. Circulation 1995;92:1389-1392. 45. Olgin JE, Kalman JM, Fitzpatrick AP, Lesh MD. Role of right atrial endocardial structures as barriers to conduction during human type I atrial flutter. Activation and entrainment mapping guided by intracardiac echocardiography. Circulation 1995; 92:1839-1848. 46. Kalman J, Olgin J, Saxon L, et al. Electrophysiologic characteristics of atypical atrial flutter Circulation 1995;92:I-406. Abstract. 47. Feld GK, Shahandeh RF. Mechanism of double potentials recorded during sustained atrial flutter in the canine right atrial crush-injury model. Circulation 1992;86:628-641. 48. Cosio F, Arribas F, Barbero JM, et al. Validation of double spike electrograms as markers of conduction delay or block in atrial flutter. Am J Cardiol 1988;61:775780. 49. Racker DK. Atrioventricular node and input pathways: A correlated gross anatomical and histological study of the canine atrioventricular junctional region. Anat Rec 1989;224:336-354. 50. Racker DK, Ursell PC, Hoffman BF. Anatomy of the tricuspid annulus: Circumferential myofibers as the structural basis for atrial flutter in a canine model. Circulation 1991;84:841-851. 51. Cosio FG, Lopez-Gil M, Goicolea A, et al. Radiofrequency ablation of the inferior vena cava-tricuspid valve isthmus in common atrial flutter. Am J Cardiol 1993; 71:705-709. 52. Nelson RM, Jenson CB, Davis RW. Differential atrial arrhythmias in cardiac surgical patients. J Thorac Cardiovasc Surg 1969;58:581-587. 53. Konings KTS, Kirchhof CJHJ, Smeets JRLM, et al. High density mapping of electrically induced atrial fibrillation in humans. Circulation 1994;89:16651680. 54. Hoffman BF, Rosen MR. Cellular mechanisms for cardiac arrhythmias. Circ Res 1981;49:1-15. 55. Allessie MA, Kirchhof CJ, Konings KTS. Unravelling the electrical mysteries of

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atrial fibrillation. Eur Heart J 1996;17 (Suppl C):2-9. 56. Allessie MA, Kirchhof CJ, Bonke FIM. The role of the sinus node in supraventricular arrhythmias. In: Mazgalev T, Dreifus LS, Michelson EL (eds): Electrophysiology of the Sinoatrial and Atrioventricular Nodes. New York: Alan R Liss; 1988:53-66. 57. Wang Z, Page P, Nattel S. Mechanism of flecainide's antiarrhythmic action in experimental atrial fibrillation. Circ Res 1992;71:271-287. 58. Kirchhof C, Chorro F, Scheffer GJ, et al. Regional entrainment of atrial fibrillation studied by high-resolution mapping in open chest dogs. Circulation 1993;88:736-749. 59. Wang J, Bourne GW, Wang Z, et al. Comparative mechanisms of antiarrhythmic drug action in experimental atrial fibrillation importance of use-dependent effects on refractoriness. Circulation 1993;88: 1030-1044. 60. Ortiz J, Niwano S, Abe H, et al. Mapping the conversion of atrial flutter to atrial fibrillation and atrial fibrillation to atrial flutter: Insight into mechanisms. Circ Res 1994;74:882-894. 61. Kumagai K, Khrestian C, Waldo AL. Simultaneous multisite mapping studies during induced atrial fibrillation in the sterile pericarditis model: Insights into the mechanism of its maintenance. Circulation 1997;95:511-521. 62. Daoud EG, Pariseau B, Niebauer M, et al. Response of type I atrial fibrillation to atrial pacing in humans. Circulation 1996;94:1036-1040. 63. Jais P, Haissaguerre M, Shah DC, et al. Regional disparities of endocardial atrial activation in paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 1996; 19: 1998-2003. 64. Holm M, Johansson R, Brandt J, et al. Epicardial right atrial free wall mapping in atrial fibrillation: Documentation of repetitive activation with a focal spread— a hitherto unrecognised phenomenon in man. Eur Heart J 1997;18:290-310. 65. Holm M, Johansson R, Olsson SB, et al. A new method for analysis of atrial activation during chronic atrial fibrillation in man. IEEE Trans Biomedical Eng 1996; 43:198-210. 66. Cox JL, Canavan TE, Schuessler RB, et al. The surgical treatment of atrial fibrillation II. Intraoperative electrophysiologic

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67.

68.

69.

70.

CARDIAC MAPPING mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 1991;101:406-426. Chang BC, Schuessler RB, Stone CM, et al. Computerized activation sequence mapping of the human atrial septum. Ann Thorac Surg 1990;49:231-241. Harada A, Sasaki K, Fukushima T, et al. Atrial activation during chronic atrial fibrillation in patients with isolated mitral valve disease. Ann Thorac Surg 1996;61: 104-112. Schuessler RB, Kawamoto T, Hand DE, et al. Simultaneous epicardial and endocardial activation sequence mapping in the isolated canine right atrium. Circulation 1993;88:250-263. Sih HJ, Ropella KM, Swiryn S, et al. Observations from intraatrial recordings

on the termination of electrically induced atrial fibrillation in humans. Pacing Clin Electrophysiol 1994;17:1231-1242. 71. Brugada J, Gursov S, Brugada P, et al. Cibenzoline transforms random reentry into ordered reentry in the atria. Eur Heart J 1993; 14:267-272. 72. Alessi R, Nusynwitz M, Abildskov JA, Moe GK. Non-uniform distribution of vagal effects on the atrial refractory period. Am J Physiol 1958; 194:406-410. 73. Han J, Millet D, Chizzonitti B, Moe GK. Temporal dispersion of recovery of excitability on atrium and ventricle as a function of heart rate. Am Heart J 1966;71: 481487. 74. Allessie MA, Kirchhof CJHJ, Scheffer GJ, et al. Regional control of atrial fibrillation by rapid atrial pacing in conscious dogs. Circulation 1991;84:1689-1697.

Chapter 5 Principles of Nonfluoroscopic Mapping: Nonfluoroscopic Electroanatomical and Electromechanical Cardiac Mapping Shlomo A. Ben-Haim, MD, DSc

Introduction Cardiac mapping is commonly associated with cardiac electrophysiology; it is usually performed by cardiac electrophysiologists, and is used in the diagnosis and treatment of cardiac arrhythmias. Nevertheless, more "cardiac maps" (echocardiograms, ventriculograms, radionuclide imaging, etc.) are performed by nonelectrophysiologists than by cardiac electrophysiologists. Usually, the nonelectrophysiological "cardiac maps" lack electrical information while conventional electrophysiological maps lack mechanical or geometrical information. The recent introduction of modern technologies to the field of cardiac mapping widened the boundaries and scope of conventional cardiac mapping and catalyzed the development of an integrated mapping approach. Conventional cardiac mapping entails recording electrograms from a multiplicity of sites within the heart, the results of which are presented as an activation map.

Advanced cardiac mapping portrays cardiac electromechanical, or the spatial distribution of several different parameters (e.g., metabolism, perfusion, electrical activity). A typical map is usually made up of several data points, each having 2 values: (1) the local information (i.e., activation time in electrophysiological maps, local shortening in mechanical maps, and electromechanical coupling in combined maps), and (2) the location coordinate within the heart. Significant research efforts have been directed toward accurately determining local information. Analysis of electrograms was used for determining local activation time (LAT)1; regional wall motion was evaluated for determining local cardiac mechanics.2 However, only a negligible effort was made to better understand the importance of accurate location determination. In the early days of cardiac electrophysiological tracking, the effects of inaccurate mapping electrode location may have been appropriately disregarded, as the recording electrodes were

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003.

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104 CAEDIAC MAPPING hard fixed to a recording array (e.g., epicardial sock), and the location error was therefore relatively small. However, in modern practice, where catheter ablation is commonly used to treat arrhythmias, determining the location of the mapping electrode in relation to the heart becomes critical. At present, localization of the mapping catheter is based on 2-dimensional fluoroscopic images. These images clearly identify the location coordinates of the electrode within the patient's chest. However, since fluoroscopic images do not reveal endocardial information, they are insufficient to record the electrode coordinates within the patient's heart. Similarly, the nonelectrophysiological "cardiac maps" initially had a poor spatial accuracy, which in turn limited their ability to perform regional therapy. Later on, more precise regional "cardiac maps" became a critical part of guiding regional therapy in patients (e.g., angioplasty). As new local therapies become available to the interventional cardiologist (e.g., laser-induced angiogenesis, growth factor injection, or other forms of local genetic therapies), the need for precise advanced cardiac mapping systems will increase for obtaining the correct diagnosis and for delivering the proper therapy. The nonfluoroscopic mapping system described in this chapter, first described in 1996,3 simultaneously records the location and electrograms of the mapping electrode. This chapter describes the method for cardiac electroanatomical mapping using an intrabody, real-time, high-resolution, nonfluoroscopic location and navigation system. Several applications of technology in electrophysiology as well as in interventional cardiology are presented.

Method Concept The nonfluoroscopic system used for cardiac electrophysiology (CARTO™, Biosense Webster, Diamond Bar, CA) is

an integrated electroanatomical catheterbased cardiac mapping technique that uses a location sensor incorporated into a mapping catheter to allow automatic and simultaneous acquisition of the catheter tip electrogram and its 3-dimensional location coordinates. The mapping system acquires the location of the catheter tip electrode (single location at a fixed time during the cardiac cycle), together with its local electrogram (throughout the cardiac cycle), and reconstructs the 3-dimensional electroanatomical maps of the heart in real time without the use of x-rays. The nonfluoroscopic system used for interventional cardiology (NOGA™, Biosense Webster) is an integrated electromechanical catheter-based cardiac mapping technique that, similarly, uses a location sensor incorporated into a mapping catheter to allow automatic and simultaneous acquisition of the catheter tip electrograms and its continuous 3-dimensional location coordinates. The mapping system acquires the location of the catheter tip electrode (throughout the cardiac cycle) together with its local electrogram (throughout the cardiac cycle) and reconstructs 3-dimensional, dynamic electromechanical maps of the heart in real time, without the use of x-rays or injection of contrast media. System Components The mapping and navigation system comprises a miniature passive magnetic field sensor (location sensor), an external ultralow magnetic field emitter (location pad), and a processing unit (CARTO) (Figure 1). The location sensor is integrated into a regular electrophysiological deflectable tip catheter (Navistar™, Webster, CA). The location pad is located beneath the patient table and generates an ultralow magnetic field (0.05 to 0.5 G). The emitted field possesses well-known temporal and spatial distinguishing characteristics that "code" the mapping space

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coded and incorporated into the endocardial surface reconstruction (red indicating the earliest activation times, purple the latest). To correct for patient movement, a second locatable catheter is used (usually placed externally on the patient's back). The mapping system subtracts the location of the mapping catheter from the simultaneous location of the reference probe, thus compensating for any motion of the patient. It is also possible to use an internal reference probe such as a locatable reference catheter positioned in a secure place within one of the cardiac chambers (e.g., the coronary sinus). In this case, the internal reference probe corrects Figure 1. The CARTO unit (A) connected to the junction box (B), through which the locatable for motion of the patient as well as the catheter is connected. The CARTO unit is also heart (primarily respiratory movements). connected to the ultralow magnetic field generOnce sufficient anatomical data are ator (location pad, C). acquired, the operator may navigate the around the patient's chest. The sensing of catheter without using fluoroscopy. the magnetic field by the location sensor Data may be acquired during the mapenables determination of the location and ping procedure to delineate anatomical orientation of the sensor in 6 degrees of structures, local electrophysiological propfreedom (X, Y, Z and roll, yaw, and pitch). erties, or a combination of both. At each location, before data are added to the map, the stability of the catheter-endocardial Mapping Procedure contact is tested by comparing the distance between consecutive end-diastolic CARTO locations (location stability, mm) and the A locatable mapping catheter is intro- time difference between consecutive duced under fluoroscopic guidance and is LATs (LAT stability, ms). The reconpositioned inside the heart to be mapped. struction is updated in real time with the The mapping system determines the loca- acquisition of each new site. From the data acquired at each site, tion and orientation of the mapping several maps are generated that include: catheter, gated to a fiducial point in the cardiac cycle. The tip electrograms are 1. Activation map: Describes the disrecorded throughout the entire cardiac persion of activation times in the cycle and are automatically associated with mapped region. Red indicates the the catheter tip location. The mapping proearliest activation whereas purple cedure involves sequentially dragging the indicates the latest activation. catheter tip over the endocardium and 2. Propagation map: A dynamic acquiring multiple tip locations, together graphic representation of the actiwith their respective electrograms. The set vation wavefront throughout the of gated catheter tip locations is used to cardiac cycle (active sites are colored red and quiescent sites blue). reconstruct the 3-dimensional endocardial surface. The LAT at each site, determined 3. Voltage maps: Graphic representation of the peak-to-peak voltage from the intracardiac electrograms, is color-

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of the local electrograms is recorded. Low voltages are colored in red. 4. Geometrical maps: These maps present graphic representations of the mapped anatomy (of the corresponding time during the cardiac cycle). Furthermore, the operator can mark an anatomical site with a colored tag; these tags can be used in designing the trajectory of complex ablations or as markers for specific electrophysiological information. NOGA The basic NOGA mapping procedure is identical to that described for the CAKTO system. However, as catheter tip locations are continuously acquired, information regarding each the complete endocardial location trajectory throughout the cardiac cycle is acquired, in addition to the local electrogram. At each location, before data are added to the map, the stability of the catheter-endocardial contact throughout the cardiac cycle is tested by comparing the distance between consecutive location trajectories (loop stability, mm) and the time difference between consecutive LATs (LAT stability, ms). The reconstruction is updated in real time with the acquisition of each new site. From the data acquired at each site several maps are generated that include: 1. Voltage map: Depiction of the peak-to-peak voltage of the local electrograms as recorded. Low voltages are color coded in red. 2. Local shortening maps: The distance between adjacent endocardial sites throughout the cardiac cycle, usually increases during diastole and decreases during systole. The local shortening index calculates the weighted average of endocardial distances around each site. Paradoxical shortening (i.e., increased distance during systole and decreased dis-

tance during diastole) are colored red while highly contractile sites are colored purple. Inherent Limitations Catheter mapping using a roving catheter is a sequential, beat-by-beat mapping approach. This imposes 2 requirements on the mapping process: a stable rhythm and a fixed reference point. Furthermore, as the localization methodology is based on recording low level magnetic fields, large ferromagnetic materials can affect the magnetic field sensed by the sensor in the catheter (usually when large objects are in the range of 1 cm from the tip). Accuracy and Reproducibility The location capabilities of the CARTO system were tested in both in vitro and in vivo studies. In vitro testing

The reproducibility of repeated location in vitro measurements of the tip of the catheter, using different orientations at various sites, was 0.16 ± 0.02 mm) (mean ± SEM) and the maximal range of the standard deviation of the location error was 0.55 ± 0.07 mm.4 Similarly, relative distances measured by the system between alternative sites with known locations were highly accurate (mean error 0.42 ± 0.05 mm).4 In vivo testing

The location error of repeated in vivo location determination of the catheter while in contact with a single site on a porcine left ventricular (LV) endocardium was 0.54 ± 0.05 mm, with a maximal range of 1.26 ± 0.08 mm.4,5 The relative distances measured by the system while sequentially withdrawing the mapping catheter inside

NONFLUOROSCOPIC ELECTROANATOMICAL AND ELECTROMECHANICAL MAPPING a long sheath at 10-mm intervals inside the heart was also determined. The average location error was 0.73 ± 0.03 mm.5 Repeated electroanatomical activation and propagation maps during sinus rhythm and pacing were similar, and enabled accurate identification of the pacing site in all animal studies.6 Accuracy was also tested by repeatedly applying radiofrequency (RF) energy to a site on the endocardium that was tagged on the electroanatomical map.4–6 These studies indicated that the location accuracy could guide delivery of RF energy to create single and multiple lesions.7–9 Furthermore, this navigation and tagging method can be used to direct repetitive applications of RF energy to adjoining sites in order to create a long and continuous lesion. A high correlation between the computer record of the length, location and shape of linear atrial longitudinal lesions, and the actual acute histopathological findings has been demonstrated.9

calculating the end-systolic volume, and 0.29% for calculating the ejection fraction. In vivo testing

The mapping procedure was evaluated in vivo by measuring the interobserver variability in determining the LV volumes, as well as by testing the correlation between the calculated stroke volume to cardiac output measured with thermodilution.5 The interobserver error of determining end-diastolic volume, endsystolic volume, and ejection fraction were 5.9%, 7.5% and 11.3%, respectively. The capability of a NOGA map to measure myocardial viability was tested in animal models with infarcted LVs by comparing the calculated infarct locations and size to the actual pathology.11–13 Results indicated a high correlation between the measured and calculated variables. Results

NOGA

Normal Maps

The capability of the NOGA system to reconstruct chamber morphology and then to calculate its volume was tested in both in vitro and in vivo studies.

CARTO

In vitro testing

The average deviation in calculating the volume of an ellipsoid phantom was 2.23%.5,10 Gepstein et al.5 mapped 6 LV casts and compared their actual volume. The volumetric measurements correlated highly with the actual volumes (r = 0.94). A dynamic jig was used to test the system capability to acquire multiple locations throughout the cardiac cycle. Comparison of the measured data to the calculated data indicated that the system had an average error of 1.43% in calculating the end-diastolic volume, 0.69% when

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Three-dimensional electroanatomical maps of the human heart were recorded by the CARTO nonfluoroscopic mapping system. These maps disclose, for the first time, the complex relationship between cardiac chamber anatomy and electrophysiological properties (Figure 2). noga

The NOGA system enables tracking of the coordinates of endocardial sites throughout the cardiac cycle (Figure 3). With use of this feature, the twist phenomenon is easily demonstrated and quantified (Figure 3). NOGA maps describe the chamber's geometry throughout the cardiac cycle (Figure 4). The end-diastolic image is identical to that generated by the CARTO system.

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Figure 2. Three-dimensional cardiac maps. A. Three-dimensional maps of the right atrium (RA): posteroanterior (PA) view (left map) and right anterior oblique (RAO) view (right map). This map was reconstructed using 65 sampling points (gray dots on map). The right atrial geometry is depicted with the respective positions of the superior and inferior vena cava and the tricuspid annulus (SVC, IVC, and TA, respectively). The earliest site of activation, represented by the red area, is located in the posterosuperior aspect of the RA just below the junction with the superior cava vein. Activation then spreads to the rest of the endocardium with 2 preferential directions, the first on the RA roof toward the left atrium (corresponding to Bachman's bundle) and the second on the posterior RA wall toward the IVC (corresponding to the crista terminalis). B. Left anterior oblique (LAO, left map) and posteroanterior (PA, right map) views of the left atrium (LA) during distal coronary sinus pacing. The maps were reconstructed using 100 sampling points. The LA geometry is depicted with the respective positions of the superior and inferior septal and lateral pulmonary veins and the mitral annulus (SSPV, ISPV, SLPV, ILPV, and MA, respectively). The earliest site of activation, represented by the red area, is located on the anterolateral aspect of the mitral annulus. C. LAO view of 3-dimensional local activation time map of both ventricles (RV, LV) during sinus rhythm. The map was reconstructed using 125 sampling points. Note the distance between the 2 right and left ventricular endocardial surfaces, depicting the interventricular septum, in which the earliest activation sites (colored red) are visualized. Also note that the LV apex protrudes laterally more than the apex of the right ventricle. D. The LV image in C (LAO view) is tilted craniocaudally and clipped (missing the anterolateral wall). The papillary muscles (PM) in both chambers are indenting into the cavity. Note also the relatively smooth endocardial surface in the LV and the trabeculated endocardium in the RV. See color appendix.

NONFLUOROSCOPIC ELECTROANATOMICAL AND ELECTROMECHANICAL MAPPING

The maximal voltage maps (Figure 5A) indicate a rather homogeneous dispersion of endocardial voltages (usually above 1 mV); however, the area of the mitral annulus has a typical low-voltage signature in all maps. Local shortening mechanical maps in normal LVs demonstrate a typical homogenous endocardial shortening (Figure 5B).

Figure 3. Location trajectory of a single site on the left ventricular endocardium. Note the ellipsoid area captured by the closed loop. Its width relates to local twist motion, while its long axis relates to the inward-outward, systolic-diastolic, endocardial movement. Red indicates systole; white indicates diastole. See color appendix.

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Clinical Use of the Nonfluoroscopic Mapping System CARTO In the short time since its introduction to the clinical arena, diverse modes of clinical use have been reported. In the following sections, some of the investigators who have published their clinical results are listed, but other chapters in this book are referred to for specific examples of the clinical use of the CARTO system. The reported clinical applications for the CARTO mapping and navigation system have included: 1. Activation mapping to identify the insertion of an accessory pathway.14–19 2. Activation mapping for detection of focal atrial tachycardia foci.20–23

Figure 4. Left ventricular geometry (right anterior oblique view) at different times throughout the cardiac cycle. Note the correlation with left ventriculography and body surface ECG. See color appendix.

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Figure 5. A normal electrical (A) and mechanical (B) image of a healthy individual (right anterior oblique view). Panel A depicts the dispersion of maximal voltages over the endocardium (red indicating low voltage and purple indicating high voltage). Note the low voltage around the mitral annulus. Panel B depicts the local endocardial shortening of the same ventricle. Note the relatively homogenous shortening properties of the endocardium, excluding the area adjacent to the mitral valve (marked in red). See color appendix.

3. CARTO mapping to identify the location of the slow pathway during the treatment of atrioventricular nodal reentry.24,25 4. Local cardiac anatomy mapping for guiding anatomically based atrial flutter ablation procedures.16,26–30 5. Substrate mapping to identify location of intra- and interscar pathways.31 6. Several recent reports have documented the use of the CARTO system for mapping and treatment of ventricular tachycardia.31–34 7. Atrial fibrillation mapping and ablation.35

2. Use of the electroanatomical/electromechanical maps as the guiding image for navigating the catheter. 3. The ability to tag anatomical and therapy delivery sites (particularly useful for cardiac ablation and local drug therapy). 4. The capacity to re-map cardiac electrical activation relative to the location of a previous intervention. NOGA

NOGA for Hemodynamic Testing: Several investigators have used the NOGA system to map the LV for hemodynamic characteristics. They have mapped subjects with normal LV function as well as pathoThe above-mentioned clinical applicalogical cases (Figure 6). Results showed a tions used the different capabilities of the high correlation between NOGA maps and nonfluoroscopic mapping system. These echocardiographic,fluoroscopic,and radionucapabilities included: clide volumetric measurements.11,36–38 1. Real-time recording of catheter location, enabling accurate navigation of it.

NOGA for Viability Testing: NOGA maps of electromechanical coupling in

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Figure 6. A huge apical aneurysm following anteroapical myocardial infarction (left panel). This 51 year-old male was referred for electrophysiological study because of nonsustained ventricular tachycardia. NOGA accurately depicted the aneurysm, which is clearly nonviable since both local electrical activity and regional contractility are decreased (right panel). The patient later underwent successful surgical aneurysmectomy. See color appendix.

Figure 7. NOGA map of a patient with an anteroapical wall infarct. A. Maximal voltage map (red indicates the low-voltage zone, i.e., scar). B. Local shortening map (red indicates impaired wall contractility). Note the mismatch between electrical activity (preserved) and mechanical property (diminished) in the midanterior wall, indicating viable myocardium. C. Single photon emission computed tomography 201TI perfusion scan at stress and at rest. Note the fixed perfusion defects. D. Positron-emission tomography with 18fluorodeoxyglucose uptake. Note the midanterior zone is indeed viable. See color appendix. (Continued)

patients with ischemic heart disease were compared with the results of a radionuclide study.11,36,38,39 The results showed a high correlation between NOGA maps and radionuclide studies. Specifically, there was a high correlation

between the location and size of areas with reduced electrical and mechanical function (electromechanical match indicating an infarcted tissue) on a NOGA map with areas of fixed defects on the radionuclide images (Figure 7). Furthermore,

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Figure 7. (Continued)

a high correlation was also demonstrated between the location and size of areas with preserved electrical but reduced mechanical activity (electro-

mechanical uncoupling indicating hibernating tissue) on the NOGA map with areas of reversible defects on the radionuclide images.

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Figure 8. NOGA electrical map (maximal voltage, right anterior oblique view) of a patient with an old myocardial infarction and drug refractory angina. One pulse with a Ho:Yag laser was fired at the tagged areas shown on the left ventricular image. See color appendix.

Guidance of Interventional Procedures

studies that the regions close to the lased channel had an angiogenic response.

Direct myocardial revascularization

Direct myocardial injection

Catheter-based direct myocardial revascularization uses laser to create channels connecting the LV lumen to the ischemic myocardium. The combination of a fiber optic carrying Ho:Yag laser radiation into the locatable catheter enabled lasing of endocardial channels (Figure 8). The unique combination of the lasing ability via a navigated catheter enabled precise lasing to ischemic areas only, avoidance of infarct areas, and accurate tagging of the channels. The accuracy and safety of the system was proved in both animal and human studies.40–43 Haudenschild et al.44 demonstrated in animal

New directions in interventional cardiology call for the ability to directly inject drugs, factors, or genes into the myocardium. Several clinical scenarios exist in which such a therapy may be indicated. For example, in the therapy of ischemic heart disease, injection of growth factors was shown to increase angiogenesis; this can also be achieved by injecting viral vectors carrying the growth factor gene. The accuracy of the system was recently tested in animals. This study45 demonstrated that the system can guide the new locatable injection catheter (Figure 9) with the same accuracy as other systems. Furthermore,

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Figure 9. New locatable injection catheter. A. A retractable needle at the catheter tip can inject drugs, factors, viruses, and genes into the myocardium. The catheter tip is locatable with the NOGA system, thus allowing the performance of a NOGA diagnostic study, which creates the baseline map defining the targets for the angiogenic therapy (B: Chronic ischemia model in a porcine heart). C. The injection sites are readily visualized where methylene blue dye was deposited intramyocardially. See color appendix.

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the injection catheter delivered all the injected media into the myocardium. Summary The nonfluoroscopic mapping system enables, for the first time, a new integrated look into cardiac electrophysiology and electromechanics. This new technical capability provides a new dimension for diagnosing different disease states. The diagnostic capabilities of complex cardiac electrophysiological cases were improved significantly with use of electroanatomical maps, which allowed for viewing of the interrelationship between cardiac anatomy and electrical activity. For the interventional cardiologist, the system offers, for the first time, a clinically validated method for determining the electromechanical coupling of the myocardium. A series of locatable therapeutic catheters (RF for cardiac ablation, Ho:Yag laser for direct myocardial revascularization procedures, and injection catheters for the myocardial gene therapy) expand the therapeutic arm of this technology. Furthermore, these minimally invasive procedures are guided using functional electroanatomical and electromechanical maps acquired during the diagnostic part of the study. In addition, the described technology provides a highly accurate, minimally invasive procedure, while minimizing the use of ionizing radiation. The need for accurate location information is becoming more important as minimally invasive therapies evolve. The nonfluoroscopic system described herein is an initial answer to this need. The future development of different locatable catheters and new localization hardware, as well as the development of newer algorithms for analyzing the acquired information, may open new applications for cardiology and expand the scope of cardiac mapping.

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Acknowledgments: The author wishes to thank Dr. Hans Kottkamp for contributing maps from patient procedures for use in this paper. The work of Prof.-Dr. Karl H. Kuck and Dr. Andreas Keck relating to myocardial injection modalities is acknowledged. Thanks also go to Dr. I. Schwartz, Dr. B. Nevo, D. Shapiro, and Y. Kedar for their assistance in preparing the figures. Appreciation is also expressed to Dr. G. Hayam for his support and contributions to this manuscript.

References 1. Ideker RE, Smith WM, Blanchard SM, et al. The assumptions of isochronal mapping. Pacing Clin Electrophysiol 1989; 12: 456-478. 2. Fedele F, Trambaiolo P, Magni G, et al. New modalities of regional and global left ventricular function analysis: State of the art. Am J Cardiol 1998;81:49G-57G. 3. Ben-Haim SA, Osadchy D, Schuster I, et al. Nonfluoroscopic, in vivo navigation and mapping technology. Nat Med 1996;2:1393-1395. 4. Hayam Gepstein L, Ben-Haim SA. Accuracy of the in vivo determination of location using a new nonfluoroscopic electroanatomical mapping system. Pacing Clin Electrophysiol 1996;19:712. 5. Gepstein L, Hayam G, Shpun S, et al. Hemodynamic evaluation of the heart with a nonfluoroscopic electromechanical mapping technique. Circulation 1997;96: 3672-3680. 6. Gepstein L, Hayam G, Josephson ME, et al. Cardiac volumetric measurement based on a novel method for nonfluoroscopic electroanatomical mapping of the heart. Eur Heart J 1996; 17:283. 7. Gepstein L, Hayam G, Ben-Haim SA. A novel method for nonfluoroscopic catheterbased electroanatomical mapping of the heart: In vitro and in vivo accuracy results. Circulation 1997;95:1611-1622. 8. Gepstein L, Shpun S, Hayam G, et al. Accurate linear radiofrequency lesions guided by a nonfluoroscopic mapping method during atrial fibrillation. Eur Heart J 1997;18:207. 9. Shpun S, Gepstein L, Hayam G, et al. Guidance of radiofrequency endocardial ablation with real-time three-dimensional magnetic navigation system. Circulation 1997;96:2016-2021. 10. Ben-Haim SA, Osadchy D, Hayam G, et al. Accuracy of volumetric measurements of a phantom with a new nonfluoroscopic

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cardiac mapping system. J Am Coll Cardiol 1996;27:347A. 11. Kornowski R, Hong MK, Gepstein L, et al. Preliminary animal and clinical experiences using an electromechanical endocardial mapping procedure to distinguish infarcted from healthy myocardium. Circulation 1998;98:1116-1124. 12. Gepstein L, Goldin A, Lessick J, et al. Electromechanical characterization of chronic myocardial infarction in the canine coronary occlusion model. Circulation 1998;98:2055-2064. 13. Gepstein L, Hayam G, Hakim G, et al. Electromechanical mapping of the heart can delineate the presence and extent of chronic myocardial infarction in dogs. Eur Heart J 1998;19(Abstr Suppl):399. 14. Hindricks G, Kottkamp H, Brunn J, et al. A new three dimensional electromagnetic mapping technology for non-fluoroscopic catheter ablation of left-sided accessory pathways. Eur Heart J 1997; 18:205. 15. Hoffmann E, Reithmann C, Nimmermann P, et al. Electroanatomic mapping of atrial tachycardia. Eur Heart J 1997;18:207. 16. Miles WM, Engelstein ED, Krebs ME, et al. Nonfluoroscopic mapping and ablation of human atrial flutter. Circulation 1996;94:SI676. 17. Smeets JLRM, Ben-Haim S, Ben David J, et al. Non-fluoroscopic endocardial catheter mapping: First experience in patients. Pacing Clin Electrophysiol 1996; 19(4 Pt 2): 627. Abstract. 18. Worley SJ. Use of a real-time threedimensional magnetic navigation system for radiofrequency ablation of accessory pathways. Pacing Clin Electrophysiol 1998;21:1636-1645. 19. Smeets JLRM, Ben-Haim SA, Rodriguez L-M, et al. New method for nonfluoroscopic endocardial mapping in humans. Accuracy assessment and first clinical results. Circulation 1998;97:2426-2432. 20. Kottkamp H, Hindricks G, Breithardt G, et al. Three-dimensional electromagnetic catheter technology: Electroanatomical mapping of the right atrium and ablation of ectopic atrial tachycardia. J Cardiouasc Electrophysiol 1997;18:1332-1337. 21. Marchlinski F, Callans D, Gottlieb C, et al. Magnetic electroanatomical mapping for ablation of focal atrial tachycardias. Pacing Clin Electrophysiol 1998;21:1621-1635. 22. Miles WM, Engelstein ED, Krebs ME, et al. Nonfluoroscopic mapping and ablation of

atrial tachycardias. Circulation 1996;94: SI380. 23. Miles WM, Engelstein ED, Krebs ME, et al. Nonfluoroscopic mapping of atrial tachyarrhythmias: Early clinical results. Eur J Cardiac Pacing Electrophysiol 1996;6: 255. 24. Kottkamp H, Hindricks G, Fetsch T, et al. Electromagnetic high-density catheter mapping within the triangle of Koch in AV node reentrant tachycardia: Pathophysiology and implications for catheter ablation. Eur Heart J 1997;18:206. 25. Miles WM, Engelstein ED, Olgin JE, et al. Slow pathway ablation using nonfluoroscopic guidance for the His bundle localization during energy delivery. Circulation 1996;94:452. 26. Shah DC, Jais P, Haissaguerre M, et al. Three-dimensional mapping of the common atrial flutter circuit in the right atrium. Circulation 1997;96:3904-3912. 27. Nakagawa H, Jackman WM. Use of a three-dimensional, nonfluoroscopic mapping system for catheter ablation of typical atrial flutter. Pacing Clin Electrophysiol 1998;21:1279-1286. 28. Shah DC, Jais P, Coste P, et al. Three dimensional right atrial mapping of common atrial flutter: Varying distribution of double spike potential. Eur J Cardiac Pacing Electrophysiol 1996;6:255. 29. Shah DC, Jais P, Coste P, et al. Propagation in the right atrium during common atrial flutter as determined by three-dimensional mapping. Eur Heart J 1996; 17:587. 30. Wilber D, Rubenstein D, Burke M, et al. Tricuspid annular activation during atrial flutter: Insights from electroanatomical mapping. Eur J Cardiac Pacing Electrophysiol 1996;6:257. 31. Dorodtkar PC, Cheng J, Scheinman MM. Electroanatomical mapping and ablation of the substrate supporting intra-atrial reentrant tachycardia after palliation for complex congenital heart disease. Pacing Clin Electrophysiol 1998;21:1810-1819. 32. Miles WM, Engelstein ED, Krebs ME, et al. Nonfluoroscopic mapping and human ventricular tachycardia: Implications of simultaneous earliest ventricular activation at more than one site. Circulation 1996;94:SI22. 33. Nademanee K, Kosar EM. A nonfluoroscopic catheter-based mapping technique to ablate focal ventricular tachycardia. Pacing Clin Electrophysiol 1998; 21:14421447.

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34. Stevenson WG, Delacretaz E, Friedman PL, et al. Identification and ablation of macroreentrant ventricular tachycardia with the CARTO electroanatomical mapping system. Pacing Clin Electrophysiol 1998;21:1448-1456. 35. Pappone C, Oreto G, Furlanello F, et al. Clinical impact of electroanatomically guided catheter compartmentation of human atria in the treatment of paroxysmal atrial fibrillation. Giornale Italiano di Cardiologia 1998;28(Suppl 1):2936. 36. Kornowski R, Hong MK, Leon MB. Comparison between left ventricular electromechanical mapping and radionuclide perfusion imaging for detection of myocardial viability. Circulation 1998;98:18371841. 37. Keck A, Kuchler, Twisselmann T, et al. Validation of a non-fluoroscopic computerbased localization technology by echocardiography. Eur Heart J 1998;19(Abstr Suppl): 156. 38. Reisman M, Wong SC, Bogosian S, et al. The NOGA project: A new method to assess myocardial function and viability. Am Heart Assoc 71st Scientific Session, Dallas, TX; November 8-11, 1998. Circulation 1998;(Suppl 1):I-509. Abstract. 39. Corvaja N, Kornowski R, Wang XD, et al. Correlation between myocardial Biosense NOGA electro-mechanical map and radionuclide perfusion imaging. Eur Heart J 1998;19(Abstr Suppl):277.

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40. Shpun S, Hayam L, Gepstein L, et al. Percutaneous myocardial revascularization with Holmium:Yttrium-aluminum-garnet laser guided by a nonfluoroscopic navigation system in the canine left ventricle. Eur Heart J 1997;18:613. 41. Shpun S, Talpalariu J, Kerner H, et al. Accurate nonfluoroscopic guidance of direct myocardial revascularization with Holmium: Yttrium-Aluminum-Garnet laser in the canine left ventricle. J Am Coll Cardiol 1998;31(2 Suppl A):307A. Abstract. 42. Kornowski R, Hong MK, Ellahham, et al. Safety and feasibility of percutaneous direct myocardial revascularization guided by Biosense™ left ventricular mapping. Eur Heart J 1998;19(Abstr Suppl):589. 43. Kornowski R, Baim DS, Moses JW, et al. Short- and intermediate-term clinical outcomes from direct myocardial laser revascularization guided by Biosense left ventricular electromechanical left ventricular mapping. Circulation 2000; 102:1120-1125. 44. Haudenschild CC, Bastaki M, Boenigk K, et al. Angiogenesis in response to minimal laser injury in porcine myocardium. J Am Coll Cardiol 1998;31(2 Suppl A): 307A. Abstract. 45. Kornowski R, Leon MB, Fuchs S, et al. Electromagnetic-guidance for catheterbased trans-endocardial injection: A platform for intramyocardial angiogenesis therapy: Results in normal and ischemic porcine model. J Am Coll Cardiol 2000;35: 1031-1039.

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Chapter 6 Principles of Magnetocardiographic Mapping Jukka Nenonen, Dr.Tech., Juha Montonen, Dr.Tech., and Markku Mdkijarvi, MD

Introduction Measurements of electrical potential differences arising from the heart (the EGG) have established an important role in clinical diagnosis and research of the cardiac function. The same bioelectrical activity in the body that generates electrical potentials also gives rise to biomagnetic fields, which are extremely low in magnitude (0.1 to 100 pT [1 pT = 10–15 T]). The first successful detection of the magnetocardiogram (MCG) was reported in 1963.1 However, it was only after the development of superconducting quantum interference devices (SQUIDs) in the early 1970s that accurate detection of biomagnetic signals became possible.2 Until the 1990s, most MCG studies were performed with single-channel devices, by moving the system sequentially over the thorax and measuring signals from one location at time. Today, noninvasive MCG mapping recordings are carried out with multichannel systems, acquiring the signals

simultaneously over the whole chest of the patient.3,4 In addition, difficulties with skin-electrode contact, which sometimes cause problems in corresponding ECG mapping studies, are avoided. Although magnetocardiography has not yet been established as a routine clinical tool, successful MCG results have been reported in clinically important problems, such as noninvasive localization of arrhythmia-causing regions in the heart,4–7 assessment of the risk of life-threatening arrhythmias,8–11 and characterization and localization of myocardial ischemia.12,13 This chapter considers the basic principles of cardiomagnetism. We first present briefly the genesis of cardiomagnetic fields. Then, instrumentation and MCG measurements are described. Next, we give an outline of signal processing methods used in evaluating the arrhythmia risk. The basic goal in most MCG studies is to solve the restricted inverse problem, i.e., to estimate the current sources underlying measured extracardiac fields. Some

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003.

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applications of the inverse problem in terms of equivalent sources are described. Finally, the validation of the MCG results is discussed, and future trends are outlined. Clinical applications of the MCG are presented in chapter 24 of this volume. Theory Bioelectrical Current Sources ECGs and MCGs arise primarily from electrical currents in the body associated with flow of charged ions (such as Na+, K+, and Ca2+) in the myocardium. The active source regions are usually characterized with the concept of the primary current density, jp, which leaves cellularlevel details without explicit attention. It comprises the ionic currents inside and in the vicinity of excited cells. The primary current causes an electrical potential ((), which in turn generates ohmic volume currents jv=-aV(|) everywhere in the body with the electrical conductivity of a. The total current density inside the body can be expressed as: j = jp - crV<)). By finding the primary current, we can locate the source of myocardial activity. The electrical field, E, and the magnetic field, B, induced by j can be solved from Maxwell's equations. The time variation of jp is relatively slow (below 1000 Hz), which means that the source currents and external electromagnetic fields can be treated in a quasistatic approximation (the true time-dependent terms in Maxwell's equations vanish).14 Equivalent Sources A very large number of cells must be excited to achieve a measurable signal. Thus, it is convenient to introduce a macroscopic equivalent current dipole (ECD): p = J jpdu, where the integration extends over the excited source volume v. The ECD can

be regarded as the lowest order equivalent source of the ECGs and of the MCGs.15 The role of the ECD model in solving the forward and the inverse problem in magnetocardiography is considered in the following sections. One can also derive higher order equivalent generators, such as quadripoles, by using a multipole expansion.14,15 Instead of a single-current dipole, distributed source currents associated with a propagating cardiac excitation wavefront can be represented by a large number of individual-current dipoles, or more often in terms of a uniform double layer.14 This representation consists of a sheet of dipoles with equivalent strengths, which are oriented perpendicularly to the surface of the propagation wavefront. Electromagnetic Fields It can be shown that the volume currents in an infinite homogeneous volume conductor give no contribution to the electrical potential or to the magnetic field, and the fields are solely a result of the primary currents, jp. In addition, the electrical potential and the magnetic field should be independent of each other.15 If we approximate the torso by a homogeneous semi-infinite space with a plane boundary, it is possible to derive simple analytic expressions for the magnetic field of a current dipole.16 Furthermore, radial currents do not produce any magnetic field outside the semi-infinite volume conductor. MCG is thus to a great extent selectively sensitive to tangential sources, and EGG data are required if we want to recover all components of the primary current. In reality, however, the situation is more complicated because of macroscopic interfaces of electrical conductivity. By assuming that the body is a homogeneous volume conductor, bounded by the surface, S, the surface potential, (o,and the magnetic field, B, in this case can be obtained from integral equations.17

PRINCIPLES OF MAGNETOCAKDIOGRAPHIC MAPPING In the boundary-element method, electrical potential and magnetic field are calculated from discretized linear matrix equations, which can also be extended to torso models with inhomogeneities (i.e., the lungs and intracardiac blood masses).4,17 In most numerical applications to the MCG and EGG inverse problem, the surfaces are tessellated with triangular elements. Realistically shaped geometries of each patient are usually extracted from magnetic resonance imaging data. The regions of interest (e.g., the heart, the lungs, and the thorax) must be segmented from the data first. The surfaces of these volumes are then discretized for numerical calculations. The segmentation and tessellation problems are tedious, but nearly automated computer methods have been reported.18 Instrumentation The detector that offers the best sensitivity for the measurement of the tiny cardiomagnetic fields is the SQUID (see reference 3 for the basic principles). Still, strong environmental magnetic noise, unavoidable at urban hospitals and laboratories, makes the detection of biomagnetic signals impossible without specific techniques to reject the external noise. Shielding against high-frequency electromagnetic noise is relatively easy with conducting materials such as current shields of copper or aluminum. Diminishing low-frequency magnetic noise requires

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the use of magnetically shielded rooms. Besides shielded rooms, differential gradiometric measurements have been performed to reject external magnetic noise. Most instruments use first-order wirewound axial gradiometers with relatively large coils. However, planar gradiometers, realized using integrated magnetometer chips, are more space efficient and are easier to manufacture using thin film techniques. A schematic presentation of the sensor types is presented in Figure 1. A detailed presentation of the shielding and sensor techniques can be found in reference 3. Until the 1990s, most biomagnetic measurements were performed with single-channel instruments; however, reliable localizations require mapping in several locations, and this is time consuming with only one channel. Besides, spatial features of occasional temporal variations in the signals may be lost. Fortunately, the sensitivity of multichannel sensors has been improved and the number of channels increased during the last few years. In shielded rooms, sensitivities of multichannel dc-SQUID magnetometers around 2 x 10~15 TA/Hz have been reported. State-of-the art MCG systems contain more than 60 detectors in an array covering an area of about 30 cm in diameter over the patient's chest or back. The dewar containing the sensors is attached to gantry system, which allows easy positioning of the dewar above the patient's thorax. It is often also possible to move the subject bed horizontally. The position of the dewar with

Figure 1. Sensor types. A. Magnetometer; B. first-order axial gradiometer; C. first-order planar gradiometer. In B and C, the gradiometer baseline length is h.

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respect to the patient's head or torso is typically determined by measuring the magnetic field arising from small marker coils attached to the skin and by calculating their locations with respect to the sensor array. The locations of the marker coils with respect to an anatomical frame of reference can be determined before the measurement by a 3-dimensional digitizer.

The MCG system shown in Figure 2 comprises 99 channels arranged on a slightly curved surface with the diameter of about 30 cm. The magnetic field component perpendicular to the sensor array surface (Bz) is sensed by 33 triple-sensor units, in which a magnetometer is overlaying 2 perpendicular planar gradiometers (Figure 1). Figure 2 also shows an

Figure 2. The 99-channel dc-SQUID (superconducting quantum interference devices) system for cardiomagnetic studies in the HUGH BioMag Laboratory. The sensor array covers the whole anterior chest of the supine patient, who is taken into and out of the magnetically shielded room on a wheeled nonmagnetic bed. The gantry system allows easy movement and adjustment of the position of the measurement dewar. In addition, a nonmagnetic ergometer for exercise magnetocardiography is displayed.

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Figure 3. A. Magnetocardiograms measured with the 99-channel cardiomagnetometer in a patient suffering from ventricular tachycardia. The first QRS complex indicates a normal sinus beat, followed by an abnormal extrasystolic beat after the normal T wave. The signals measured by the 33 magnetometers are shown by the blue curves. Isocontour presentations of the magnetic-field component perpendicular to the sensor array surface can be extrapolated; they are here depicted both at the beginning of B) the normal sinus rhythm beat, and C) the ventricular extrasystolic beat. The circles denote to the magnetometer sensor outlines. See color appendix.

ergometer designed to produce no magnetic noise in supine exercise MCG studies. An example of rest MCG measurements with a multichannel magnetometer is displayed in Figure 3: a sinus beat is followed by a ventricular extrasystolic beat, and morphological MCG signals as well as interpolated distributions of Bz are presented. The field of magnetocardiography may expand during the next few years with the implementation of high-temperature SQUID arrays that can be operated at the temperature of liquid nitrogen.3 The higher noise level of high-temperature SQUIDs is partly compensated by the smaller distance between the sensors and the chest, and the systems are applicable to bedside recordings.19 At present, however, the conventional low-temperature SQUIDs are easier to produce and thus less expensive than the high-temperature ones. In addition, the first commercial lowtemperature SQUID systems designed to operate without external magnetic shielding have become available.19 Such systems can be applied in a catheterization laboratory, allowing to develop new MCG

tools for online electroanatomical imaging studies. Signal Processing Time Domain Analysis In multichannel MCG and EGG studies, signal averaging is often applied to improve the signal-to-noise ratio.20 A template beat is usually selected, and cross-correlation between the template and a triggered beat yields precise timing. In addition, baseline noise and differences in amplitude between beats, calculated from user-selected channels, can be used as rejection criteria. Observation of fragmented low-amplitude MCG signals at the end of the QRS complex, corresponding to the electrical late potentials, was first reported by Erne et al.8 To detect such low-amplitude signals, as well as intra-QRS fragmentation, time domain MCG and ECG analyses use both infinite and finite response filtering. Simson21 first introduced a method based on high-pass filtering for late potential analysis. A recursive Butterworth-type

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CAEDIAC MAPPING possible notching during the averaged QRS complexes.22 In this so-called "Berlin fragmentation analysis," the filtered QRS complex is characterized by finding the number of signal extrema during the QRS (M), and by calculating the product of M and the sum of the amplitude differences between neighboring extrema, called fragmentation index S. For the signal-averaged EGG data, a mean of M and S is calculated over the 3 leads, and in the case of MCG data, a mean is calculated over the sensor locations. A binomial-filtered MCG signal is displayed in Figure 4c. Spectrotemporal Analysis

The spectral turbulence analysis, based on sequential short-time fast Fourier Figure 4. Examples of filtered magnetocardio- transforms, was developed for identifygraphic signals measured from a ventricular ing arrhythmogeneity-related features in tachycardia patient for arrhythmia risk stratifi- the ECG during the QRS complex.23 In cation. A. The signal-averaged magnetocardio- this method, short time Fourier spectra graphic trace; B. the same trace after high-pass filtering; and C. the same trace after binomial fil- are calculated over time intervals of 25 tering. D. A spectrotemporal analysis of the ms through differentiated ventricular depolarization signal at 2-ms steps. A MCG trace in A. See color appendix. resulting spectrocardiogram can be visualized in logarithmic color scale, and it is filter with a cutoff frequency of 40 Hz is described quantitatively by calculating often used. A filtered QRS complex is correlations between the spectra. For the formed as a vector magnitude in the case MCG analysis, the mean value of each of the EGG data, while for the MCG data parameter is formed over the sensor locaa corresponding signal can be obtained tions. An example spectrocardiogram is as an envelope complex in each sensor presented in Figure 4d. location using Hilbert transform. 9 An example of high-pass filtered MCGs is Repolarization Analysis presented in Figure 4B. For each filtered QRS complex, the First attempts to describe vulneraQRS duration, the duration low-amplitude signal below 1 pT or 40 uV from the offset bility for malignant arrhythmias based of the QRS complex, and the root mean on dispersion of the QT time in the mul11,24 square amplitude during the last 40 ms tichannel MCG have been reported. of the QRS complex are calculated. Other For this purpose, an algorithm to facilitate automated determination of the QTthreshold values can also be used. To detect intra-QRS changes, a non- apex and QT-end intervals has been recursive band-pass filter from 37 to 90 Hz developed.24 The analysis begins with with binomial coefficients is used to enhance averaging performed over a 1-second

PRINCIPLES OF MAGNETOCARDIOGRAPHIC MAPPING period covering the PQ segment and the next T-P interval. A baseline is selected from the T-P interval, and beats with T wave amplitude below 0.6 pT from the baseline are excluded. A visual checking of the automatically determined T-apex and T-end intervals is performed to reject possible errors made by the algorithm. The algorithm used in the time domain analysis of late fields is applied to determine the QRS onset and offset times. Finally, in the case of both QT-apex interval and QT-end interval, the QT dispersion over the measured area is calculated as the difference between the longest and shortest QT intervals. Spatial MCG Map Analysis Besides analyses of morphological MCG tracings, extraction of spatial features in MCG mappings can provide valuable information of the arrhythmia vulnerability. In the case of multichannel MCG data, the distributions of the time domain parameters,9,22 as well as the distributions of QT-apex and QT-end times,11,24 can easily be displayed as isovalue colormaps. The spatial heterogeneity in such presentations can be used as a further criterion to assess the arrhythmia risk. In addition, extrema trajectory plots revealing the spatial route of the maxima and the minima in MCG distributions have been used in arrhythmia risk evaluation.10 Stress Magnetocardiography Exercise electrocardiography is a well-standardized and widely used diagnostic and prognostic test for the evaluation of patients with ischemic heart disease. Stress magnetocardiography has also received increasing interest in recent years. Development of multichannel systems has brought MCG mapping during

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interventions technically closer to clinical feasibility. Specially designed nonmagnetic ergometers facilitate the exercise testing during MCG measurements (see Figure 2). In first MCG studies with normal subjects, significant ST segment changes were observed under physical exercise, concomitantly with a normal EGG.25 First results of the method have been published in patients with coronary artery disease, and in studies of myocardial viability. These studies are presented in more detail in chapter 24. In addition to ergometer exercise, pharmacological MCG stress testing has been applied. Brockmeier et al.26 reported that multichannel MCG data showed significantly more distinct repolarization changes than simultaneously recorded 32-lead ECG maps under pharmacological stress in 3 healthy subjects. The consequences of such findings still remain to be confirmed with patient data. Source Localization In the MCG and ECG inverse problems, the objective is to estimate the primary current density underlying the electromagnetic signals measured outside or on the surface of the body. Because the inverse problem does not have a unique solution, one must replace the actual current sources with equivalent generators that are characterized by a few parameters. Thus, in most localization studies the solution to the forward problem is needed first. The simplest physiologically sound model for the myocardial current distribution is to use the best-fitting ECD. In cardiac studies an ECD is applicable for approximating the location and strength of net primary current density confined into a small volume of tissue. Myocardial depolarization initiated at a single site spreads at a velocity of about 0.4 to 0.8 mm/ms, and

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Figure 5. A. An example of a numerical torso model, showing also the triangulated surfaces of the heart. The magnetometer sensor outlines are depicted as circles. B. Magnetocardiographic localization results at 4 successive time instants (blue dots) during the onset of an extrasystolic beat. The magnetocardiographic results are visualized on the transparent 3-dimensional heart surfaces, which can be freely rotated on the computer display. See color appendix.

the ECD can be thought to be moving along the 'center of mass' of the excitation. In practice, localization based on a single ECD is meaningful only during the first 10 to 20 ms of excitation. The ECD is a commonly used source model. It has a long and important history in clinical electrocardiography (e.g., vectorcardiography). Cohen and Hosaka27 were the first to study a single ECD when describing measured MCG maps. In later MCG studies, the ECD model was used to characterize small source regions such as His bundle activation, infarction area, the arrhythmia-causing ventricular preexcitation site in the WolffParkinson-White syndrome, and other arrhythmogenic regions.4–7 Localizations of implanted pacing catheters have also been reported.7,28 In the above-mentioned studies, accuracies of 5 to 25 mm have been reported by comparing the MCG localization results to: (1) cardiac surgery; (2) catheter ablation; (3) the results of invasive electrophysiological studies; (4) ECG localization results; and (5) physio-

logical knowledge (x-ray or magnetic resonance imaging). An example of the MCG localizations is presented in Figure 5. In addition to patient studies, the ability of the MCG to locate artificial current dipoles has been tested with physical thorax phantoms.7,29 A nonmagnetic pacing catheter in a realistically shaped thorax phantom resulted in equal accuracies of 5 to 10 mm between MCG and ECG mapping data.29 On the other hand, the same catheter in 15 patients showed significantly better localization accuracy with MCG data (7 mm) than with simultaneously recorded ECG mapping data (25 mm).28 In practice, the ECG and the MCG arise from distributed current sources. Because the use of even 2 ECDs becomes very complicated in cardiac studies, it is more convenient to solve the inverse problem for a current distribution. The quasistatic bioelectromagnetic forward problem can be written in a general form: bk=J Lj, • jp du, where bk is the MCG signal measured by the kih sensor, and Lfe is the

PRINCIPLES OF MAGNETOCARDIOGRAPHIC MAPPING lead field of that sensor. Most studies dealing with distributed source models are based on the minimum norm estimation,5,12,13 where the estimate of the primary current is constructed as a linear combination of the lead fields, ~Lk. The lead fields are provided by the forward solution in the selected torso and sensor geometry. Because even small contributions of the measurement noise make the solution ill-posed, suitable regularization techniques are needed to stabilize the solution.4,13 Recently, the MCG current density reconstruction was applied for the estimation of ischemic regions induced by ergometer exercise,12,13 and in detection of viable myocardium after chronic ischemia.13 An example of such reconstructions is presented in chapter 24. Besides single-layer sources, such as the equivalent current density above, uniform double-layer sources can be applied. The lead fields from each point on the endocardial and epicardial surfaces to the MCG/body surface potential mapping sensors are used to define the sequence of cardiac excitation during the QRS complex.30 The quality of such solutions has recently been validated with intraoperative epicardial recordings in patients undergoing open-chest surgery.31 Discussion It can be concluded from all MCG studies published so far, that for some applications the diagnostic performance of MCG is superior to the conventional ECG; however, his advantage has not yet driven clinicians to widely accept and use the method, mostly because of its high cost and low availability. Nevertheless, there is a growing interest in clinical applications of MCG to therapy and diagnosis of cardiac diseases. Invasively recorded cardiac signals, such as potentials measured during elec-

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trophysiological studies on epicardial and endocardial surfaces, provide the best gold standard for validation of the MCG inverse solutions. Even though patient populations studied by MCG before or during invasive catheterization are still relatively small, the localization studies of various cardiac arrhythmias have shown encouraging results. Multichannel systems and accurate combination of the results with cardiac anatomy have improved the accuracy to the order of 5 to 10 mm, which is sufficient to aid in planning and delivering curative therapy for arrhythmia patients. Further validation for the MCG localization accuracy has been obtained by locating artificial dipole sources, such as pacing catheters inserted into the heart during electrophysiological studies. For arrhythmia risk evaluation, MCG mapping is an attractive alternative for 2 reasons: first, the ease of measurement makes it well suited for screening purposes, and second, several approaches in the analysis can be applied to a single recording. Time domain analyses of both late fields and intra-QRS fragmentation have performed well in comparison to signal-averaged ECGs. Yet, a clear demonstration of the advantages of spectrotemporal approaches in MCG analysis has yet to be made. The analysis of QT time variability in MCG mappings has yielded promising results, but the methodologies applied are still user dependent. Exploitation of the spatial features in MCG mappings has been reported to result in improved performance when compared to electrical body surface potential mapping. Further improvement may be obtained by combining the analysis of ventricular depolarization, of spatial heterogeneity in MCG repolarization, and of short-term heart rate variability—all possible with one MCG mapping recording. To date, however, no prospective evaluation has

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been done of MCG performance, notwithstanding a few ongoing studies that aim to fill this void. The arrhythmogenic substrate is not manifested in all normal sinus rhythm recordings, and interventions may be needed during MCG to stimulate extrasystolic beats and controlled arrhythmias to locate them. Thus, MCG should be available in a catheterization laboratory, but the demand of magnetic shielding and liquid helium is in practice limiting the use of MCG mapping in guiding invasive arrhythmia localization. Fortunately, compact-size higher order magnetometer arrays operated without external shielding are available and may bring MCG mapping closer to bedside clinical practice.19,32 Despite more than 20 years of MCG research, common standards of measurement techniques, data processing, and presentation are still lacking. Suggestions for such standards are emerging, but there are large differences between sensors and their arrangement in the multichannel magnetometers. Recently, tools have been developed and tested to interpolate signal morphologies and isocontour maps that are directly comparable to studies performed in other centers.33 Finally, effective signal processing and source modeling software is going to be increasingly important to extract and combine all available functional data from the cardiac function. References 1. Baule GM, McFee R. Detection of the magnetic field of the heart. Am Heart J 1963;55:95-98. 2. Cohen D, Edelsack EA, Zimmermann J. Magnetocardiograms taken inside a shielded room with a superconducting point-contact magnetometer. Appl Phys Lett 1970; 16:278-280. 3. Braginski A, Clarke J (eds): SQUID Handbook. Berlin: Wiley VCH; 2002.

4. Hamalainen MS, Nenonen J. Magnetic source imaging. In: Webster J (ed): Encyclopedia of Electrical Engineering. Vol. 12. New York: Wiley & Sons; 1999:133-148. 5. Nenonen J, Purcell C, Horacek BM, et al. Magnetocardiographic functional localization using a current dipole in a realistic torso. IEEE Trans Biomed Eng 1991;38:658-664. 6. Fenici RR, Melillo G. Magnetocardiography: Ventricular arrhythmias. Eur Heart J 1993;14(Suppl E):53-60. 7. Moshage W, Achenbach S, Gobl W, Bachmann K. Evaluation of the non-invasive localization of cardiac arrhythmias by multichannel magnetocardiography (MCG). Int J Card Imaging 1996;12:47-59. 8. Erne SN, Fenici R, Hahlbom HD, et al. High-resolution magnetocardiographic recordings of the ST segment in patients with electric late potentials. Nuovo Cimento 1983;2D:340-345. 9. Montonen J. Magnetocardiography in identification of patients prone to malignant arrhythmias. In: Baumgartner C, Deecke L, Stroink G, Williamson SJ (eds): Biomagnetism: Fundamental Research and Clinical Applications. Amsterdam: Elsevier Science/IOS Press; 1995:606-611. 10. Stroink G, Lant J, Elliot P, et al. Discrimination between myocardial infarct and ventricular tachycardia patients using magnetocardiographic trajectory plots and isointegral maps. J Electrocardiol 1992;25:129-142. 11. van Leeuwen P, Hailer B, Wehr M, et al. Spatial distribution of QT intervals: Alternative approach to QT dispersion. Pacing Clin Electrophysiol 1996; 19:1894-1899. 12. Leder U, Pohl HP, Michaelsen S, et al. Noninvasive biomagnetic imaging in coronary artery disease based on individual current density. Int J Cardiol 1998;64:83-92. 13. Nenonen J, Pesola K, Hanninen H, et al. Current-density estimation of exerciseinduced ischemia in patients with multivessel coronary artery disease. J Electrocardiol 2001;34(Suppl):37-42. 14. Malmivuo J, Plonsey R. Bioelectromagnetism—Principles and Applications of Bioelectric and Biomagnetic Fields. New York: Oxford University Press; 1995. 15. Katila T, Karp PJ. Magnetocardiography: Morphology and multipole presentations. In: Williamson SJ, Romani G-I, Kaufman L, Modena I (eds): Biomagnetism, An Interdisciplinary Approach. New York: Plenum Press; 1983:237-263.

PRINCIPLES OF MAGNETOCARDIOGRAPHIC MAPPING 16. Erne SN. High resolution magnetocardiography: Modeling and source localization. Med Biol Eng Comput 1985;23:14471450. 17. Horacek BM. Digital model for studies in magnetocardiography. IEEE Trans Magn 1973;9:440-444. 18. Lotjonen J, Reissman PJ, Magnin IE, et al. A triangulation method of an arbitrary point set for biomagnetic problems. IEEE Trans Magn 1998;34:2228-2233. 19. Leder U, Schrey F, Haueisen J, et al. Reproducibility of HTS-SQUID magnetocardiography in an unshielded environment. Int J Cardiol 2001;79:237-243. 20. Huck M, Haueisen J, Hoenecker O, et al. QRS amplitude and shape variability in magnetocardiograms. Pacing Clin Electrophysiol 2000;23:234-242. 21. Simson MB. Use of signals in the terminal QRS complex to identify patients with ventricular tachycardia after myocardial infarction. Circulation 1981;64:235-242. 22. Muller HP, Godde P, Czerski K, et al. Magnetocardiographic analysis of the twodimensional distribution of intra-QRS fractionated activation. Phys Med Biol 1999;44:105-120. 23. Kelen GJ, Henkin R, Starr A-M, et al. Spectral turbulence analysis of the signalaveraged electrocardiogram and its predictive accuracy for inducible sustained monomorphic ventricular tachycardia. Am J Cardiol 1991;67:965-975. 24. Oikarinen L, Paavola M, Montonen J, et al. Magnetocardiographic QT-interval dispersion in post myocardial infarction patients with sustained ventricular tachycardia—validation of automated QT measurements. Pacing Clin Electrophysiol 1998;21:1934-1942. 25. Takala P, Hanninen H, Montonen J, et al. Magnetocardiographic and electrocardiographic exercise mapping in healthy

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subjects. Ann Biomed Eng 2001;29:501509. 26. Brockmeier K, Schmitz L, Chavez J, et al. Magnetocardiography and 32-lead potential mapping: Repolarization in normal subjects during pharmacologically induced stress. J Cardiovasc Electrophysiol 1997;8: 615-626. 27. Cohen D, Hosaka H. Magnetic field produced by a current dipole. J Electrocardiol 1976;9:409-417. 28. Pesola K, Nenonen J, Fenici R, et al. Bioelectromagnetic localization of the pacing catheter in the heart. Phys Med Biol 1999;44:2565-2578. 29. Fenici R, Pesola K, Makijarvi M, et al. Non-fluoroscopic localization of an amagnetic catheter in a realistic torso phantom by magnetocardiographic and body surface potential mapping. Pacing Clin Electrophysiol 1998;21:2482-2491. 30. van Oosterom A, Oostendorp TF, Huiskamp GJ, ter Brake M. The magnetocardiogram as derived from electrocardiographic data. Circ Res 1990;67:1503-1509. 31. Oostendorp T, Pesola K. Non-invasive determination of the activation sequence of the heart based on combined ECG and MCG measurements. In: Nenonen J, Ilmoniemi R, Katila T (eds): Biomag 2000, Proc. 12th Int. Conf. on Biomagnetism. Espoo, Finland: Helsinki University of Technology; 2001:813-820. 32. Fenici R, Brisinda D, Nenonen J, et al. First MCG multichannel instrumentation operating in an unshielded hospital laboratory for multimodal cardiac electrophysiology: Preliminary experience. Biomed Tech (Berl) 2001;46(Suppl 2):219-222. 33. Burghoff M, Nenonen J, Trahms L, Katila T. Conversion of magnetocardiographic recordings between two different multichannel SQUID devices. IEEE Trans Biomed Eng 2000;47:869-875.

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Chapter 7 Fast Fluorescent Mapping of Electrical Activity in the Heart: Practical Guide to Experimental Design and Applications Igor R. Efimov, PhD, Martin Biermann, MD, and Douglas Zipes, MD

the effects of electrical stimuli on cellular electrical activity. Optical recordings of transmembrane Optical mapping of electrical activity in the heart with use of imaging tech- potentials can be performed in a wide range niques based on voltage-sensitive dyes of spatial resolutions from the subcellular has become an increasingly common level to the whole heart. The response time research tool in basic cardiac electro- of fast voltage-sensitive dyes lies in the physiology. This was prompted by the microsecond range and the temporal resofailure of conventionally used intra- or lution of the technique can potentially extracellular recordings to provide high- exceed that of conventional microelectrode resolution spatiotemporal maps of elec- recordings. Progress in modern computer trical activity. Despite a century of technology permits simultaneous optical evolution, conventional techniques have recordings from multiple sites, providing failed to work in at least 2 key areas of high-resolution spatiotemporal maps of research: the study of the role of spa- electrical activity. In this chapter we review current tiotemporal organization of repolarization in arrhythmogenesis and the study of technological approaches developed in the Introduction

This project was supported the by American Heart Association Northeastern Ohio affiliate Grant-in-Aid 9806201 and grant E01 HL59464-01A1 from the National Heart, Lung, and Blood Institute of the National Institutes of Health (Dr. Efimov), the Hermann C. Krannert Fund, grant PHS P50 HL52323 from the National Heart, Lung, and Blood Institute of the National Institutes of Health, and the research fellowship grant (Bi 583/1-1) from the Deutsche Forschungsgemeinschaft, Bonn, Germany (Dr. Biermann). From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003.

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area of fluorescence imaging and describe the new cardiac fluorescence imaging systems that have been developed by our research laboratories. History The possibility of recording dynamic changes in the transmembrane potential of excitable cells by optical means was first suggested in 1968 by a group of neuroscientists, Lawrence B. Cohen and co-workers,1 who discovered potential-dependent changes in the intrinsic optical properties of squid giant axons. It took nearly a decade until the first optical action potentials were recorded from giant axons2 and mammalian hearts by means of voltage-sensitive dyes.3 The first cardiac application of this method was the localization of pacemaker activity in embryonic heart preparations in 1981.4 While in the 1980s optical mapping of the heart was mostly restricted to a few noncardiac electrophysiology laboratories, widespread application of these techniques to problems unsolvable by other means began in the 1990s.5-15 Is optical mapping a technique for solving a problem, or do we have to invent problems for the technique? What is its niche in cardiac electrophysiology? One of the pioneers of fluorescent methods in neurophysiology, B.M. Salzberg, predicted that voltagesensitive dyes "could, we believe, provide a powerful new technique for measuring membrane potential in systems where, for reasons of scale, topology, or complexity, the use of electrodes is inconvenient or impossible."16 Based on our current experience in cardiac electrophysiology, Salzberg's list must be extended to recordings of action potentials in the presence of external electrical fields during stimulation and defibrillation, which were impossible with extracellular and intracellular electrodes. After decades of innovations and development, conventional electrode techniques have been brought to the limits of

perfection. The intracellular microelectrode technique still represents the gold standard for recording transmembrane action potentials, and only recently has the optical method approached comparable signal-to-noise ratios (SNRs). The chief disadvantage of the microelectrode technique lies in the impossibility of maintaining stable recordings over longer time periods from more than 2 or 3 sites, especially if the preparation is moving. Similarly, monophasic action potential recordings can be maintained only at a few sites for short periods.17 Thus, spatiotemporal mapping by either method requires the use of a roving probe, limiting the application of either method to the study of periodic activation patterns. While extracellular contact and noncontact multielectrode arrays are excellent for recording activation maps from the heart in vitro, they also remain the only techniques for in vivo mapping. Problems do, however, exist concerning the precise interpretation of the electrogram data,18,19 the determination of repolarization times being particularly unreliable.20 Thus, optical mapping is the only technique capable of recording high-resolution maps of cardiac repolarization.21 Finally, optical mapping is the only method that allows uninterrupted and artifact-free recordings of the transmembrane potentials during pacing stimuli11-13 and defibrillation shocks.7,22,23 Most reviews of the application of voltage-sensitive dyes in electrophysiology24-26 focused almost entirely on neuroscience. The only review on cardiac optical mapping was recently presented in a comprehensive book edited by Rosenbaum and Jalife.27 As highlighted by this book, optical mapping has become one of the major tools in studies of cardiac electrophysiology, significantly contributing to our exploration of various fundamental problems. Widespread application of these techniques was enhanced by the development of new

FAST FLUORESCENT MAPPING OF ELECTRICAL ACTIVITY IN THE HEART technologies during the last several years. Before then, setting up imaging systems for multisite fluorescence mapping of electrical activity in cardiac preparations posed a major technological challenge. Among other problems, it required the custom design of the imaging detector itself, a task which was beyond the capabilities of most research institutions. In this chapter we therefore not only review current technological approaches developed in the area of fluorescence imaging, but also describe the design and implementation of our new cardiac fluorescence imaging systems. These, in our opinion, represent the best current solutions for macroscopic mapping of cardiac electrophysiological activity in terms of image quality, cost and labor of setting up, and ease of operation. Physical Principles of Fluorescent Recordings The general mechanism underlying fluorescence is the absorption of photons of certain energy by a fluorescent compound, which is then excited from the ground state to an unstable energy-rich state. When the compound falls back to an intermediate lower energy level, the compound fluoresces by emitting a photon of a lower energy than the exciting photon. The wavelength of a photon being a function of its energy, the emitted light always has a longer wavelength than the exciting light, the so-called Stoke's shift. Potential-sensitive fluorescence can be the consequence of one of several mechanisms, which are related to voltage gradientdependent intra- and extramolecular rearrangements. Cohen and Salzberg,28 introduced a simple classification of voltage-sensitive dyes into 2 groups, fast and slow dyes, based on their response times and presumed molecular mechanism of voltage sensitivity. Only the fast probes are used in cardiac electrophysiology, due

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to their capability of following electrical responses on a time scale of microseconds.10,29 The precise mechanisms underlying the voltage-dependent spectroscopic properties of fast voltage-sensitive dyes are still not fully understood. According to the electrochromic mechanism, one of the most commonly accepted theories,25 the spectral shift in a chromophore's properties is voltage dependent if 2 conditions are met: (1) the light photon-produced excitation of the chromophore molecule from the ground to an excited state is accompanied by large shift in electronic charge, and (2) the vector of the intramolecular charge movement is oriented in parallel to the electrical field gradient. If the charge movement in the dye molecule occurs perpendicular to the cellular membrane of a cardiomyocyte, a dye's fluorescence will then be sensitive to the transmembrane potential. An alternative theory is the solvatochromic mechanism, which is related to electricalfield-induced reorientation of the dye molecule.30 Dye molecules experience a change in the polarity of the lipid environment during reorientation produced by the voltage gradient. Therefore, energy needed for excitation from the ground state to the first excited state is released during transition in the opposite direction and will be voltage dependent. This dependency causes the spectral voltage dependence of the chromophore. Designers of voltage-sensitive dyes had to solve several problems: 1. finding a chromophore that is capable of producing the largest movements of charges during quantum transition from the ground to the first excited state, and therefore the largest measurable spectral changes with a change in the external electrical field; 2. assuring the possibility of delivering dye molecules to the cellular membrane;

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3. assuring the proper orientation of the dye molecule perpendicular to the membrane; 4. maximizing duration of stay of the dye molecules in the desired position; 5. minimizing photobleaching of the dye; 6. minimizing side effects of the dye on the preparation in the presence and absence of light.

60 seconds, presumably on the basis of the slower translocation of di-8-ANEPPS into the cell. The price for the improved lipophilic properties of di-8-ANEPPS is however a decrease in the water solubility; this necessitates the use of surfactants, such as pluronic (F127, BASF Corporation, Mount Olive, NJ), which may not be free of toxic side effects.34 In a series of Langendorff-perfused and superfused heart preparations, we were able to achieve superior SNRs with di-8In tests of more than 1500 different ANEPPS and pluronic as compared to dicompounds, several useful classes of chro- 4-ANEPPS in only 2 of 8 experiments, mophores have emerged, including mero- while in the other 6 experiments the SNR cyanine, oxonol, and styryl dyes. Styryl was significantly worse. In our opinion, dyes represent the most popular family of di-4-ANEPPS remains the dye of choice dyes, RH-421, di-4-ANEPPS, and di-8- for whole-heart and tissue preparations. The SNR in stained cardiac prepaANEPPS being the most important members of this family. The spectroscopic rations is dependent not only on the dye properties of these dyes have been shown itself, but also on its mode of delivery. to change linearly with membrane poten- Salama32 noted that the SNR in optical tial changes in normal physiological range action potentials in frog hearts stained of transmembrane voltages in axons31 by injection of merocyanine-540 into the and heart.32 The orientation of the mole- aortic root during Langendorff perfusion cules of these dyes in the cell membrane was 10-fold higher than in similar prepais assured by the presence of lipophilic rations stained by superfusion with bath and hydrophilic groups at opposite ends of solution containing the voltage-sensitive the molecule. While the hydrophilic, neg- dye. In the rat papillary muscle, Miiller atively charged sulphonyl group anchors et al.35 were able to demonstrate by fluothe dye molecule in the aqueous extra- rescence microscopy that superfusion cellular space, the highly lipophilic hydro- with 10 to 25 umol/L di-4-ANEPPS stained carbon chains at the other end of the no more than 1 or 2 surface cell layers, molecule hold it within the bilayer lipid whereas preparations stained by arterial perfusion are expected to show a more or membrane. The stability of the position of dye less homogeneous distribution of dye molecule in the membrane can be throughout the wall. The precise depth improved by increasing the length of of optical recordings in preparations the hydrocarbon tails as was done in the stained by perfusion has been the subject ANEPPS family (di-4-ANEPPS, di-8- of debate. Model calculations by Salama32 ANEPPS, di-12-ANEPPS, nomenclature based on the depth of field of the optical described by Loew33). In single-layer cell system predicted a depth of 144 um. culture preparations, Rohr and Salzberg10 Direct measurements by Knisley36 in a demonstrated a significantly retarded tapering wedge of tissue showed that the decay of the amplitude of optical action intensity of optical action potentials potentials in preparations stained with ceased to increase if the thickness of the di-8-ANEPPS as compared with di-4- tissue was larger than 300 (um.Based on ANEPPS on continuous illumination for measurements of the absorption coefficient

FAST FLUORESCENT MAPPING OF ELECTRICAL ACTIVITY IN THE HEART of myocardium for the excitation and emission spectrum, Girouard et al.37 predicted that 95% of the signal energy originates from a tissue depth of 500 (um or less. Our recent observations in the rabbit atrioventricular nodal preparation38 are in agreement with that of Girouard et al.37 Pharmacological Effects of Voltage-Sensitive Dyes The fact that the application of voltagesensitive dyes has been demonstrated to cause side effects on preparations calls for careful control experiments in in vitro studies. So-called photodynamic damage or phototoxic effects have been documented under intense illumination, with alterations of electrical activity in neurons39 and in isolated cardiac myocytes.40 In the isolated cardiac myocytes, 1 minute of illumination with 1 W/cm2 will first cause a gradual depolarization of the membrane resting potential and a decay of the action potential amplitude. This is followed by afterdepolarizations, occasionally triggered activity, and finally cell death. Recently, the voltage-sensitive dye RH421 has been shown to increase the contractility of isolated rat cardiac cells and Langendorffperfused hearts.41 Similar effects were observed during staining with di-4ANEPPS and di-8-ANEPPS. The low level of light used in this study (<1 mW/cm2) suggests that a mechanism different than the formation of free radicals may be involved. Another pharmacological side effect of potential-sensitive styryl dyes is vasoconstriction. This effect was first described for the dye RH-414 by Grinvald et al. in 198442 and has recently been observed for di-4-ANEPPS. Concentrations above 2.5 umol/L led to a reproducible increase in the intravascular resistance of isolated arterially perfused wedge preparations of the canine's left ventricle (LV) in the absence of light (M.B., unpublished observations).

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The exact mechanism of these effects of voltage-sensitive dyes remains unknown. Formation of free radicals, sensitized by the dye molecules in presence of photons, has been implicated in causing the phototoxic effect,43 and the use of radical scavengers (antioxidants) has been shown to reduce the phototoxic effect in isolated cardiac cells.40 The voltage-sensitive dye may directly interact with voltage-gated channels, perhaps L-type Ca2+ or K+ channels, and may alter the conductivity and time-dependent gating of these channels. This hypothesis is supported by data obtained in bilayer preparations, which suggested an interaction of voltage-sensitive dyes with a number of channels. Rokitskaya and coworkers44 showed that RH421 increased the dissociation constant of gramicidin in bilayer preparations, and proposed that this resulted from modification of the dipole potential of the bilayer membrane by RH421. Data from several laboratories have suggested an interaction of RH421 with Na+,K+-ATPase45-47 though there is yet no consensus regarding the mechanism(s) underlying this effect. Frank et al.47 implicated an RH421-induced change in membrane fluidity in the inhibition of the hydrolytic activity of the Na+,K+-ATPase. Fedosova and coworkers,46 on the other hand, proposed an electrostatic mechanism of interaction between potential-sensitive styryl-based dyes (including RH421) and Na+,K+-ATPase. Finally, RH421 has been shown to interact with the water-soluble protein ribulose-1,5bisphosphate carboxylase/oxygenase as well as with polyamino acids (tyrosine, lysine, and arginine residues).47 Mechanical Motion Artifact Faithful optical recordings of cardiac action potentials require immobilization of the preparation, unless the study is limited to the analysis of action potential upstrokes only.9,10 Movement artifacts in

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optical action potentials tend to be most pronounced during the action potential plateau when contraction reaches its peak amplitude, and during the action potential downstroke when relaxation sets in, while action potential upstrokes are generally well preserved. Movement artifacts can occur due to one of several mechanisms. First, physical movement of the tissue from the field of view of one detector element into the field of view of a neighboring element may lead to artifactual recordings of transmembrane potentials from different but neighboring cells in different phases of the action potential. This kind of motion artifact tends to be most pronounced at the edges of the preparation. Second, action potentials can be distorted due to the modulation of light scattering by mechanical contraction, a phenomenon that can be observed in monolayer cell cultures even in the absence of gross movement of cells across the photodetector array.10 There are 3 basic approaches for coping with motion artifacts: (1) mechanical immobilization; (2) use of motion-artifactinsensitive signal analysis algorithms; and (3) pharmacological immobilization. Preparations can be mechanically immobilized by restricting the movement of the muscle between the walls of the tissue chamber and/or pressure pads32,48 or by stretching the tissue.32 While mechanical immobilization is free of pharmacological side effects on the electrical activity of the preparation, this technique has several limitations. This method can only be used in preparations with moderate amplitude of contractions, otherwise the pressure needed to eliminate movements can cause ischemia. This technique has only been successfully applied to guinea pig heart preparations.14,21 In addition to external compression of the heart by pressure pads, Girouard et al14 used endocardial cryoablation,49 which leaves a thin epicardial

rim of viable muscle attached to a noncontracting core of dead myocardium.50 Despite the efforts, mechanical immobilization does not fully eliminate motion artifacts in all channels even in a guinea pig heart. Therefore, special signal processing techniques based on maximum of second derivative of the optical action potential21 are usually employed to measure action potential duration instead of standard criteria such as action potential duration measured at 90% repolarization. The disadvantage of this technique is, however, that it requires very good SNRs in the optical recordings. Pharmacological methods of producing mechanically quiescent preparations may significantly affect electrical activity. Several methods are being used: perfusion with low calcium,3,12 Ca channel blockers,7 2,3-butanedione monoxime (BDM),51 and, most recently cytochalasin D (cyto D).52-54 Low calcium solutions and calcium channel blockers are rarely used in fluorescent recordings of transmembrane voltage because of their effect on crucial calcium-dependent cellular processes.3,37,55 BDM, also known as diacetyl-monoxime (DAM), has effects on a variety of channels13,56-58 and gap junctions.59 The effect of BDM on action potential duration is species dependent. A shortening of action potential duration in rabbits,60 sheep,57 guinea pig,57 and dog hearts is observed, while action potential duration increases in the rat heart.58 This species dependence is the consequence of the reduction of both the calcium current and net potassium outward current, 2 antagonistic currents with opposing influences on action potential plateau development. Thus, even though the above pharmacological methods effectively suppress contractions of the cardiac muscle, they significantly alter the electrical activity of cardiac cells, limiting their usefulness in studies related to repolarization and requiring carefully designed control experiments. Cyto D, an

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Figure 1. Optical recordings of action potentials. An epicardial fluorescence recording from a Langendorff-perfused rabbit heart stained with di-4-ANEPPS (top trace) is juxtaposed with a simultaneous bipolar electrogram from the apex of the same heart. Fluorescence was excited at 520 ± 45 nm, collected above 610 nm, amplified, filtered at 500 Hz, and sampled at 1000 Hz. The light was turned off before the end of the recording to demonstrate the amount of background fluorescence in fluorescence signals without direct current-offset subtraction.

actin filament disrupter, has recently been shown to block contraction without affecting action potential shape or duration in isolated rat myocytes in concentrations between 4 and 40 u.mol/L,52 in isolated canine right ventricular (RV) trabeculae in concentrations of 80 umol/L,53 and in perfused LV wedges at concentrations of 20 to 25 umol/L,54 and may thus be a promising new excitation-contraction uncoupling agent for optical mapping studies of cardiac repolarization. Approaches to Experimental Design Every engineering approach to the design of an optical system must address

one major problem: improving the SNR in the optical recordings at the required spatial and temporal resolution. This is achieved by decreasing system noise and/or improving the amplitude of the signal. An example of a raw optical signal is shown in Figure 1. Cellular depolarization during an action potential causes a reduction in fluorescence of 1% to 10% of the total fluorescence signal. Background fluorescence, which thus accounts for up to 99% of the fluorescence signal, is caused by accumulation of dye in nonexcitable cells, in the inner layer of the lipid membrane, or in the lipid membranes of intracellular organelles across which there is no potential change during excitation.10 To reconstruct the intracellular action potential it

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is therefore necessary to (1) subtract the background fluorescence; (2) invert the signal; and (3) normalize the signals to uniform amplitudes assuming a homogeneity of action potential amplitudes in the imaged area of the preparation. Noise

There are 3 major sources of noise present in optical recordings: shot noise, dark noise, and extraneous noise. Shot noise is the natural fluctuation in the number of photons detected by a photodetector caused by the quantumstatistical nature of photon emission and detection. Thus, shot noise occurs even in the presence of an ideal noise-free light source and ideal noise-free detector and cannot be eliminated. Shot noise is estimated by the root mean square deviation of the number of photons hitting a photodetector per unit time and is equal to the square root of their number. A typical tungsten lamp filament (1800°C) emits 1014 photons/s. Only a small fraction of these, at best about 1010 photons/s,61 will reach the photodetector, because of significant losses in the illumination optics with their narrow-band excitation filter and dichroic mirror and because of losses in the imaging optics with their long-pass emission filter. The number of photons detected by the photodetector will finally be reduced by the quantum efficiency of the photodetector, which is defined as the number of photoelectrons per photon. Of the 2 types of photodetectors used for optical recordings, photodiodes and photocathodes, the former have quantum efficiencies of 0.8 to 1.0 and the latter of only 0.15. Thus, photodiodes have a significant advantage over photocathodes, potentially yielding a nearly 6 times higher SNR. Dark noise is the noise signal emitted by a photodetector in the absence of light. Photodiodes tend to have much higher

dark noise than photocathodes, which despite their much higher quantum efficiency limits their utility at low light intensities such as in single-cell measurements, in which case the dark noise can be comparable to or even higher than the shot noise. Thus, photocathodes may yield higher SNRs than photodiodes at very low light levels, and a direct experimental comparison between the 2 detectors is required in each case. Extraneous noise is caused by noise sources in the laboratory environment. The following measures serve to cut extraneous noise down to acceptable levels: using a dark or direct current (DC)-lightilluminated room to eliminate stray light from noisy sources, using an antivibration table to isolate the set-up from mechanical vibration generated in the building and the rest of the experimental set-up, using a Faraday cage to reduce radiofrequency noise, grounding equipment to a common isolated ground to eliminate 50- or 60-Hz noise picked up by ground loops, using a low-noise light source, and isolating power supplies and amplifiers and from computing equipment. Light source and filters

Three types of excitation light sources are used in optical recordings: tungsten lamps, arc lamps, and lasers. The choice of a light source will depend on the required spatial resolution of the optical recordings. Arc lamps and lasers are typically used in micrometer-scale measurements, while tungsten lamps are most commonly used in macroscopic preparations, in which a resolution of hundreds of microns is sufficient. Lasers can provide intense illumination, which can be easily and rapidly delivered to a small spot. However, lasers have a 1% to 5% variation in the beam intensity, which is comparable to the average signal intensity recorded from most

FAST FLUORESCENT MAPPING OF ELECTRICAL ACTIVITY IN THE HEART voltage-sensitive dyes.62 Ratio-calculation feedback signal processing techniques have been applied during recordings to eliminate signal noise related to laser light intensity variability.62,63 Recent models of sapphire lasers appear to overcome this limitation. They demonstrate remarkable stability and intensity of the light. However, they are available in a limited number of wavelengths, which usually do not correspond to excitation wavelengths of most of the dyes. In addition, these lasers have a very high cost. While the intensities of arc lamps have been reported to exceed 50 to 100 times those of tungsten lamps,39 this large difference in intensity cannot be directly translated into better SNRs, as arc lamps have a significant intensity only at distinct narrow lines of the spectrum. Unfortunately, the excitation frequency of the most efficient dyes which produce the largest fractional change in fluorescence, such as di-4-ANEPPS and RH421, do not overlap with spectral lines of arc lamps. Since the absorption peaks of most of the voltage-sensitive dyes are relatively wide, the lower light output of tungsten lamps at a given spectral line can be compensated by the use of wider band-pass excitation filters. Tungsten lamps remain the most popular light source used for optical recordings. They provide a very stable output of light over a very wide range of the spectrum without the sharp peaks observed in the arc lamps' spectra. The choice of excitation filters with half-width of 90 nm can provide significant improvement in signal quality over narrow-width filters. We recorded action potentials from a Langendorff-perfused rabbit heart (n = 3) stained with di-4-ANEPPS using several narrow- and wide-band excitation filters. There was no significant difference in signal quality observed between the 2 narrow-band filters (520 ± 10 nm and 540 ± 10 nm), while recordings with

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520 ± 45 nm and 545 ± 30 nm yielded 3.1 and 2.4 times better SNR, respectively (I.E., unpublished observations). The increase in excitation bandwidth did not result in a measurable increase in phototoxicity or photobleaching.22 Photodetector design

Three engineering solutions have been used in cardiac electrophysiology for optical multiple-channel recording systems over the last 2 decades: photodiode arrays (PDAs),64 laser scanner systems,65 and charge coupled device (CCD) cameras.51 They differ not only by their way of collecting the fluorescent output of the specimen but also by the way the excitation light is delivered. PDAs have been used for optical mapping studies in neurophysiology and cardiology since 1981.66,67 With quantum efficiency above 0.8,61 photodiodes are the most sensitive sensors for medium to large light intensities, their main drawback being the size of their dark current, which may limit their usefulness at very low light intensities as in neurophysiological applications. Photodiodes are packaged in arrays of 100, 144 or 256, and 464 or more, and each photodiode will record from a large enough surface area of the preparation to receive enough photons per unit time for the accurate representation of an optical action potential. Each recording channel requires independent signal conditioning before analog-to-digital (A/D) conversion by the computer. Subtraction of background fluorescence in optical action potentials is possible on a per-channel basis either before or after A/D conversion, which can be with a resolution of 12 bit or more at sample rates in excess of 1 kHz. CCD cameras were introduced into optical mapping to achieve higher spatial resolutions and avoid the complications of setting up PDA systems. However the

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accuracy of mapping data with CCD cameras is limited by a number of factors: (1) The SNR in signals from CCD cameras is usually very poor, each small pixel being hit by very few photons per sample interval. Only a few CCD cameras allow the so-called binning of pixels, i.e., aggregating several pixels into one, in order to improve SNRs. (2) The time resolution is generally 16.7 ms, which is the National Television Standards Committee standard, 4 ms in the faster cameras and 1 ms only in dedicated high-speed cameras. (3) Many cameras do not allow subtraction of the background fluorescence, and if they do, it is a uniform offset potential subtracted off all channels. (4) Amplitude resolution is usually only 8 bits, so that assuming a fractional fluorescence of the dye of 10% per 100 mV, rarely more than 10 to 20 out of the 256 gray levels will be available for encoding an action potential. Recently, Wikswo and colleagues13 presented details of a new mapping system, in which a cooled CCD camera system was able to achieve a single pixel signal-to-noise rate of 5 to 10 at a spatial resolution of 128 x 127 pixels and 1.2 ms with 12-bit A/D conversion. Several new CCD cameras are very promising. Yet, they still yield significantly to photodiode arrays in signal quality. Laser scanning systems represent an entirely different approach, which has been described in detail elsewhere.68 The output of a single laser is acousto-optically deflected to scan some 100 sites of the whole preparation. The fluorescence emitted by each site at the time of illumination is collected by a single photodiode, which thus sequentially records the optical signals from all sites scanned by the laser beam. The advantages of laser scanning systems over PDAs are that they can cover a wider area and that flatness of the preparation is not an optical requirement. The time resolution, however, is limited to some 1 ms per 100 scanning sites.

The major disadvantage of the laser scanning techniques is the considerable photobleaching at the light intensity levels required for reconstruction of optical action potentials, which will result in a significant decrease of the level of fluorescence on a beat-to-beat time scale, necessitating a recalibration of the signals.69,70 There was no statistically significant decrease in fluorescence on the same time scale through photobleaching in experiments using a tungsten lamp in conjunction with a photodiode array detection system.22 The main drawback of photodiode arrays was that until recently the difficulties in building PDA-based mapping systems were formidable, as there were no ready-made products on the market. This approach could only be used by a few groups with access to advanced engineering resources; however, the situation has changed with the advent of the Hamamatsu C4675 photodetector (Hamamatsu City, Japan), a 256-element photodiode array manufactured in a compact enclosure complete with 256 current-to-voltage converters, with the availability of affordable bioamplifiers (~$30 per channel) originally developed in the laboratory of Dr. Lawrence B. Cohen of Yale University61 and with powerful multichannel A/D conversion boards for personal computers. An improved version of the 64channel bioamplifiers was independently developed by Innovative Technologies (Germantown, MD), in collaboration with Dr. Efimov's laboratory. While previous optical mapping systems had to be custom designed from the ground up, most hardware components can now be bought. In the following text we describe the set-up of our current mapping systems, which were originally developed in the Department of Cardiology at the Cleveland Clinic Foundation and then further improved in close collaboration with the Krannert Institute of Cardiology.

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C4675 PDA detector, which combines a 16 x 16 element photodiode array (chip The core of the optical mapping size 17.45 x 17.45 mm2 with 256 square system (Figure 2) is the Hamamatsu 0.95 x 0.95 mm2 photodiodes spaced 0.15 mm apart) with 256 current-to-voltage converters in a single compact (136 x 136 x 154 mm) enclosure. The optical system is built around a central beamsplitter cube (Oriel Corp., Stratford, CT) bearing the illumination system, a bellows apparatus with the imaging lens, a ground glass screen and reticule for focusing the imaging optics, and the above photodetector. The bellows, beamsplitter cube, and photodetector are all mounted on an optical rail (Nikon, Torrance, CA) born by a ball-bearing boom-stand (Diagnostic Instruments, Sterling Heights, MI), which permits easy readjustments of the detector in all 3 dimensions, including a change in orientation between vertical and horizontal preparations.15,22 The excitation light is produced by a 250-W quartz R tungsten halogen lamp (Oriel Corp.) powFigure 2. Experimental set-up. Fluorescence in ered by a low-noise DC power supply cardiac preparation stained with the potentialsensitive dye di-4-ANEPPS is excited by the (Oriel Corp. or Power-One, Camarillo, CA). light of a 250-W direct-current-powered tung- After cooling by means of a cold mirror, sten lamp. After passing a cold mirror and an which lets the infrared spectrum pass into electrical shutter controlling the light beam, the a finned heat sink (Oriel Corp.), the light beam is made quasimonochromatic by means path is controlled by an electronic shutof an infrared filter and a 520 ± 45 nm interference filter. It is then deflected into the light path ter (Oriel Corp.), which only opens for a of the illumination optics by means of a dichroic few seconds during each scan. The light mirror and finally focused on the preparation by beam is made quasimonochromatic by the imaging lens. Light emitted from the prepa- passing it through an infrared filter (KGl, ration is focused on the light-sensitive area of a Schott Glass, Duryea, PA) and 520 ± 45 nm 16 x 16 element photodiode array (PDA) by the imaging lens after passing the dichroic mirror interference filter (Omega Optical, Batand filtering with a long-pass (>610 nm) colored tleboro, VT). A 585-nm dichroic mirror glass filter. The photocurrents of all 256 photo- (Omega Optical) held in the beamsplitdiodes are converted into voltages by 256 first- ter cube deflects the excitation light into stage amplifiers integrated in the housing of the the imaging lens, which then focuses the PDA. The signals are then amplified and filtered in parallel by a 256-channel second-stage ampli- excitation light onto the preparation. Our fier and finally multiplexed and analog-to-digital original optical design had kept the illuconverted together with 8 additional instrumen- mination optics separate from the imagtation channels by a PC-based data acquisition ing optics, using a liquid light guide and analysis system. To focus the optics on the (Oriel Corp.) to direct the illumination preparation, a front-surfaced mirror replaces the dichroic mirror, deflecting the light from the light onto the preparation. A comparison preparation on a ground-glass reticule bearing of the illumination systems showed that a scale 1:1 outline of the photodiode array. epi-illumination through the imaging PDA System

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optics produced 3 times better SNRs and signal amplitudes as well as improved homogeneity of illumination. Since then, the use of the liquid light guide has been discontinued. The imaging optics consist of a Nikon photographic lens attached to the central beamsplitter cube (Oriel Corp.) by the means of an f-mount adapter ring (Newport, Irvine, CA) and a pair of Nikon bellows. The magnification of the system is set by expanding or shrinking the bellows, while focusing is performed by adjusting the distance between the imaging lens and the preparation. In imaging mode, the fluorescent light emitted from the preparation passes the dichroic mirror without reflection and is then filtered by a long-pass filter (>610 nm, Schott) before hitting the sensing area of the 16 x 16 photodiode array. In focusing mode, the dichroic mirror inside the beamsplitter cube is replaced by a front-surfaced plain mirror that deflects the image of the preparation onto a ground glass reticule, which bears a 1:1 representation of the outline of the photodiode array at precisely the same distance from the center of the beamsplitter cube as the photodetector. We compared several Nikon lenses: 85 mm f/1.4 AF Nikkor; 50 mm f71.2 Nikkor, 50 mm f/1.4 Nikkor, and 28 mm f/2.8 AF Nikkor. Table 1 summarizes range of field of view seen by the detector and by a single photodiode (pixel resolution), as well as the corresponding working distances for different expansion states of the bellows.

The photocurrent produced by each photodiode was first-stage amplified by its own low-noise operational amplifier inside the compact housing of the Hamamatsu C4675 detector (feedback resistors 10 to 100 MQ, resulting in a gain of 107 to 108 V/A). Increasing the first-stage amplification has been reported to improve SNRs in optical signals71; however, increasing the feedback resistors in the C4675 camera reduced its frequency response from 15 kHz to 1.5 kHz, which may be undesirable in some applications. The outputs of the first-stage amplifiers were connected to 256 second-stage amplifiers, four 64-channel cards, developed at and available from Yale University, which offer DC coupling and AC coupling with several time constants (short time constant for DC-offset subtraction, time constant of 30 seconds during data acquisition). A computer-driven transistor-transistor logic pulse is used to reset the second-stage amplifiers immediately before data acquisition in order to remove the DC offset of the optical signals caused by background fluorescence. Signals were filtered by Bessel filters with a cutoff frequency of 500 to 2000 Hz, depending on the sampling rate of the data acquisition system. The signals were fed to a multiplexer and an A/D converter board (DAP 3200/ 415e, Microstar Laboratories, Bellevue, WA). Sampling was performed at a rate of 1000 to 2000 frames/s. The sampling rate S and the cutoff frequency fc of the filters were always kept to satisfy Nyquist criterion (S = 2 fc) in order to avoid aliasing

Table 1 Field of View and Working Distances for Different Nikon Photographic Lenses At 0 To 200 mm Expansion of the Bellows Lens F/1.250mm F/1.4 50 mm F/1.4 85 mm F/2.8 28 mm

Field of View of Photodiode Array (mm) Single Photodiode 4.0-18 3.8-19 6.0-31 5.5-11

250-1120 230-1190 380-1940 340-690

Working Distance (mm)

5-46 13-49 70-200 2-10

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stimulator into the mapping system using a PC-TIO-10 timer board (National Instruments, Austin, TX), which provides 10 programmable 16-bit counters. The front end of our data acquisition system and data analysis package was programmed under Lab VIEW 5.0 for Windows NT, and integrates a fully featured programmable stimulator, control of the Computer-controlled instrumentation interface, mapping system, and an extensive data data acquisition and analysis processing, visualization, and analysis One of the biggest problems in map- package. Supported stimulation protocols include ping system design is the development of user-friendly and efficient software for burst and continuous pacing S1 with up to 3 premature pulses (S2, S3, S4) out of the data acquisition and analysis. While the chief problem in electrical first output channel and a single pulse mapping is optimizing system perfor- triggered on any previous pulse out of a mance to allow continuous data acquisi- second output channel for cross-field stimtion to a high-capacity storage medium ulation or control of another device, such such as a hard disk or a digital tape over as an external stimulator. Any number of long time intervals, in optical mapping, it mapping protocols can be defined and is also essential to provide integrated and stored by the user. For each mapping proeasy-to-use control over the complex instru- tocol, the user can select the name of the mentation. To reduce problems of photo- protocol, the state of the electrical shutter toxicity and/or photobleaching, the exposure during mapping (open or shut), the screen of preparations to intense light must be color during mapping (normal or black to kept to a minimum. Data are typically eliminate stray light from the computer only acquired in short bursts of a few sec- monitor during mapping), the mapping onds, and care must be taken that data script (full array for the entire set of chanacquisitions are not repeated unneces- nels, external for the instrumentation sarily. An optical mapping system control channels only), the matrix that will be unit must (1) precisely synchronize the used to display the data in the analysis initiation of a mapping sequence with the program, the shutter open and close times stimulation of the preparation; (2) pro- relative to the last S1 stimulus of the train, vide pulses for the control of the electri- the width and end of the sample-and-hold cal shutter of the light source, for the DC pulse to the amplifiers, the start of the offset subtraction of the signal amplifiers data acquisition relative to the last S1 and the start of the data acquisition by stimulus, the duration of the data acquithe A/D boards; (3) allow the fast logging sition, the trigger mode, and the sample of data to disk; and (4) give the operator interval in microseconds. Whenever a near-instant feedback on the quality of mapping sequence is initiated, the Labthe logged data so that the mapping VIEW timer program calls an external sequence can be repeated if necessary. 32-bit command-line executable written The purpose of the first requirement under Borland C++ 5.0 using the DAP for is to control stimulation as well as all Windows tool kit (Microstar Laboratories), other components of the mapping system which loads the appropriate data acquiby the same timing device. We therefore sition script into the data acquisition chose to integrate the programmable board's memory, initiates the data logging errors introduced by digitization of the signals. Each frame included 256 optical channels and 8 instrumentation channels including surface electrogram, stimulation and defibrillation triggers, and aortic pressure, which were stored on a hard disk for off-line analysis.

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by the board, and saves the data file to disk. Each data file contains an ANSI header, which not only contains the mapping protocol, time, and date of the recording, but the complete designation of the stimulation protocol as well. Once the data file has been written to disk, the LabVIEW data acquisition program notifies the data analysis program, which then displays the entire mapping data file on the screen for near on-line analysis of the data so that an informed decision can be made on whether the quality of the data is appropriate or the mapping sequence must be repeated. Analysis algorithms include various filtering, calibration, reconstruction of activation, repolarization, and action potential duration maps, subtraction of 2 corresponding responses in order to visualize the differences between them caused by electrical shocks, etc. Experimental preparations

Experiments can be performed in vitro on Langendorff-perfused wholeheart preparations and isolated superfused or coronary-perfused atrial and ventricular preparations in rabbits, dogs, guinea pigs, rats, and humans. The precise details of animal preparation protocols are published elsewhere.15,22 For staining, a stock solution of 5 mg di-4-ANEPPS (Molecular Probes, Inc., Eugene, OR) is prepared in 4 mL dimethyl sulfoxide (DMSO, Fisher Scientific, Pittsburgh, PA), and is stored frozen at +4°C. After gentle rewarming immediately before the experiment, a 100 uL Hamilton glass syringe is filled with the stock solution, which is then gradually injected at a rate of less than 1:1000 into an injection port (Radnoti Glass, Monrovia, CA) above the bubble trap of the perfusion system by means of a custom-built infusion pump. The method of gradual hand injection of dye into the injection port in the bubble trap21 is less cumbersome but less repro-

ducible. Recordings started 5 to 15 minutes following the staining procedure. Levels of optical signals and SNRs decrease over time, presumably because of the translocation of the voltage-sensitive dye molecules into the cell interior, as is illustrated in Figure 3. We monitored the SNR in all 256 channels during a 3-hour mapping experiment in a Langendorff-perfused rabbit heart. The SNR was defined as the ratio between optical action potential amplitude and peak-to-peak noise amplitude as measured during diastolic intervals, while the mean value and standard deviation were as calculated from all 256 recordings. Using a single exponential function approximation (SNR = SNR0 e-t/t) we estimated on half-life of the signal i = 105.2 ± 31.2 minutes. Restaining was done in some preparations, when needed. Areas of Application of the Mapping Technique Two-dimensional submillisecond mapping of transmembrane polarization during defibrillation shocks in intact heart

Optical recording of electrical activity is the only method to resolve questions related to the interaction of strong electrical fields with excitable cells, conventional electrode recordings being distorted by large-amplitude artifacts. With use of fluorescent mapping techniques, we have been able to optically record changes in transmembrane voltage with a high SNR from all 256 channels. This has permitted us to acquire 2-dimensional patterns of shock-induced polarization with submillisecond resolution. Figure 4 shows upstrokes from 2 optical action potentials recorded from the same 650 x 650 (um area of RV epicardium. As can be seen, however, recordings during defibrillation shocks have much faster components22 than normal propagated responses, the frequency content of which

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Figure 3. Decline of signal-to-noise ratios over time. The figure plots mean ± SD of the signal-tonoise ratios in all 256 fluorescence recordings from the epicardial surface of a Langendorff-perfused rabbit heart stained with di-4-ANEPPS versus time. The preparation was kept in a darkened room and was illuminated only during data acquisition for 1 to 2 seconds at a time.

has been reported to be limited to 150 Hz.37 Therefore, faster sampling is required. In our experiments signals were conditioned by a low-pass 1-kHz Bessel filter and sampled at 2 kHz without any additional filtering by software, in order to preserve the frequency content. The reason for a slower rise time of propagated responses is that optical action potentials represent spatially integrated responses of cells confined within the 3-dimensional field of view of each photodiode, which extends some 100 to 500 urn in depth.21,36,37 Thus, optical action potential upstroke rise times are a function of both conduction velocity and the size of the field of view.32 Figure 5 presents several examples of typical cellular responses during biphasic shocks applied in the plateau phase of a propagated action potential. A data

scan included the last normal propagated action potential before the shock (left waveform on trace A) and the action potential altered by the shock (right waveform on trace A). Panels B through E show 2 such action potentials from different regions of the mapping array that are superimposed and aligned by their upstrokes. As can be seen, postshock action potential prolongation is strongly dependent on the polarity of the shock and its timing in respect to the phase of the action potential. Figure 6 shows the entire mapping array with all 256 potential waveforms recorded from an 11 x 11 mm2 area of the LV anterior wall of a rabbit heart during application of a +100/-50 V, 8/8 ms biphasic shock 90 ms after the onset of the action potential in the middle of the array. Recordings such as these cannot be

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node in isolated preparations of the rabbit right atrium.15 The structural complexity of the right atrial preparation, especially in the nodal areas, makes it difficult to apply conventional electrode mapping techniques. While in unipolar electrograms the distinction between local and distant events is often impossible, bipolar electrograms represent complex spatial derivatives of the underlying spatiotemporal substrate of electrical activity.20 Since the precise field of view of both types of electrodes is unknown, interpretation of the electrograms remains challenging and requires verification by means of simultaneous microelectrode recordings.73 Like electrograms, optical recordFigure 4. Optical action potential upstrokes of a ings represent the integrated electrical propagated response during epicardial pacing (circles) and a response induced by an 8-ms 100-V response of cells from a volume of tissue, monophasic electrical shock (squares) indicated the 2-dimensional extent of which is preby the time bar. The data was amplified after direct cisely defined, even though the exact current-offset subtraction, filtered at 1 kHz, sampled depth of the recording is less certain. We at 1.9 kHz (sample interval 528 (us), and reprehave previously suggested that doublesents the summated response of the 500 x 500 um region of subepicardial myocardium within the field component optical action potentials of view of one photodiode. observed in proximal AV node and area of the bundle of His may result from spatial achieved by any other known method. As averaging of electrical activity from sevcan be seen, cellular responses recorded eral layers.15 With use of microelectrode at different locations with respect to the recordings, we were recently able to demonelectrode can differ dramatically in ampli- strate that optical recordings from the tude and polarity of cellular polarization.22 proximal part of the AV nodal area carry Most importantly, these experimental inscriptions of both superficial layers of techniques allowed to link together sev- transitional cells and deeper layer of comeral important parameters, which are pact nodal and nodal-His (NH) regions.38 responsible for arrhythmogenesis during Figure 7 illustrates this finding by juxtafailed defibrillation shocks, such as vir- posing 2 optical traces with conventional tual electrode dispersion of transmem- bipolar surface electrograms recorded brane polarization followed by dispersion from the interatrial septum and the of repolarization, and new wavefront for- bundle of His during 2 basic beats and a mation followed by formation of phase sin- single premature beat. Activation rapidly spread from the stimulation site on the gularities and reentry.72 interatrial septum toward the AV nodal area and finally conducted at the bundle Conduction from the sinoatrial node to and of His. The optical trace recorded from through the atrioventricular node the distal node shows multicomponent We recently demonstrated a nonra- responses. While the first component (T) dial spread of activation from the sinoa- in every beat represents activation of trial (SA) node to the atrioventricular (AV) superficial transitional cells, in which

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Figure 5. Optical recordings during defibrillation-strength shocks. Traces A through E were recorded from the same 650 x 650 um area of the left ventricular epicardium 8 mm from the defibrillation electrode, which was positioned close to the septum of the right ventricular cavity in a Langendorffperfused rabbit heart. This area corresponds to the "virtual electrode" area.22,72 Optical signals were amplified, filtered at 1 kHz, and sampled at 2 kHz. No additional software filtering was applied. During stimulation at 300 ms from the right ventricular apex, shocks were applied during the action potential plateau. Trace A shows a sequential record of a normal action potential followed by the action potential during and after application of the shock, while in traces B through E the 2 action potentials are superimposed, being aligned on their upstrokes. Traces B and C were recorded during shocks applied 100 ms after the upstroke, while traces D and E were recorded during shocks applied 50 ms after the upstroke. Traces B and D were recorded during +150/-100 biphasic shocks applied 100 and 50 ms after the upstroke, while traces C and E were recorded during biphasic shocks of the opposite polarity 100 and 50 ms after the upstroke. As can be seen from the recordings, the action potential prolongation through biphasic defibrillation shocks is strongly dependent on both timing and polarity of the shock.

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Figure 6. Map of 256 optical action potentials recorded from anterior epicardium during application of a +150/-100-V biphasic defibrillation shock applied during the plateau phase of cardiac action potentials in a Langendorff-perfused rabbit heart. The gray rectangular area indicates the position of the distal defibrillation electrode inside the right ventricular cavity. The data show dramatic differences between recordings performed near to and far from the electrode. The bottom traces represent enlarged views of the highlighted recordings.

conduction velocity is fast, the second component (NH) denotes activation of intranodal structures of the NH region. The increased delay between the first and the second components during conduction of the premature beat represents slowing of the intranodal conduction, which is also

indicated by the His electrogram. It should be mentioned that relative amplitudes of the 2 components in the optical trace do not represent differences in action potential amplitudes, but rather the relative contribution of different amounts of tissues from transitional and NH regions

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Figure 7. Three-dimensional (multilayer) imaging of the conduction through the atrioventricular node. The right atrium was opened through the tricuspid valve (TV), right atrial appendage, and superior vena cava (SVC), the atrial preparation containing the sinus node (SN), crista terminalis (CrT), fossa ovalis (FO), inferior vena cava (IVC), coronary sinus (CS), intra-atrial septum (IAS), atrioventricular node (AVN), and the bundle of His (His). The preparation was paced at the site marked with the asterisk at IAS with a basic cycle length S1S1 = 300 ms with a premature stimulus applied with a delay S1S2 = 170 ms. Bipolar electrograms were recorded from I AS (triangle) and bundle of His (black circle). Two optical traces from the septum (black box) and the distal AVN (gray box) are shown. All data were filtered at 50 Hz and sampled at 1 kHz. The optical data were then additionally filtered by a software-implemented 50-Hz low-pass Bessel filter.

and different relative amplitudes of the 2 components can be seen in different areas of the proximal node.38 Transmuml dog heart preparations

While a comparatively large number of optical mapping studies have investi-

gated the time course and spread of endocardial and/or epicardial repolarization, the study of transmural repolarization had previously been thought to be beyond the reach of optical mapping methods.74 We recently applied the Yan and Antzelevitch technique75,76 of isolated arterially perfused wedges of the LV wall to optical

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mapping of transmural repolarization in the canine heart. A diagonal branch of the left anterior descending artery was cannulated with a thin (<1 mm) polyurethane tube and perfused with cardioplegic solution. After unperfused tissue was trimmed off with a razor blade, all the cut vascular branches were ligated and the resulting 20 x 10 x 15 mm (length times width times wall thickness) arterially perfused tissue wedge was transferred into a vertical glass tissue chamber, in which it was gently held against the front window by means of a piston in the rear of the chamber. After an initial equilibration period of 1 hour, preparations were stained with di-4-ANEPPS (Figure 8A) and then immobilized by perfusion with 25 umol/L cyto D for 15 minutes to eliminate motion artifacts (Figure 8B). A repolarization map during endocardial stimulation at a rate of 2000 ms is shown in Figure 8C. Repolarization times were determined by the second derivative criterion,21 which closely agree with the measurements of action potential duration at 90% repolarization determined using floating microelectrodes in control experiments. The mean optical action potential duration in that preparation was 197 ± 15 ms (mean ± SD) with a maximum action potential duration of 215 ms, a finding that may suggest (in agreement with Anyukhovsky's in vivo mapping study77) that the action potential lengthening observed in the midmyocardial layers at long cycle lengths in isolated superfused dermatome slice preparations may not occur to the same extent in well-coupled arterially perfused or in vivo preparations. Application to human heart

We were the first to apply optical mapping to preparations of the human heart.78 Right atrial appendages obtained from patients undergoing bypass surgery at the Cleveland Clinic Foundation were stained

by superfusion with 20 umol/L di-4-ANEPPS for 10 to 15 minutes resulting in peak-topeak SNR of 7.1 x 1.8 (mean ± SD) in all 256 traces from each of the 4 preparations. Preparations were stimulated at a cycle length of 1000 ms at a site a few millimeters above the field of view. Optical action potentials were filtered at 500 Hz and sampled at 1 kHz per channel from 256 recording cites. A typical optical action potential is plotted in the top panel of Figure 9, while the bottom panel shows an isochronal map of endocardial activation. The isochronal map of endocardial activation clearly indicates a nonuniform spread of conduction with maximum propagation velocity along the length of 2 trabeculae, with the 2 activation fronts meeting only at the lower edge of the mapping array. Similar inhomogeneous conduction was observed in the remaining 3 preparations. Conclusions Fluorescent imaging methods developed and refined in a number of laboratories5-15 have proved to be valuable tools extending the frontiers in cardiac electrophysiology. We believe that recent technological advances will make these experimental techniques available for a larger number of research institutions; however, future development of the fast fluorescent mapping will be necessary in order to resolve several limitations and challenges. A major limitation of current techniques of potential imaging is the lack of absolute calibration. Unlike many ratiometric fluorescent probes for calcium imaging, voltage-sensitive dyes can only provide relative information about changes in transmembrane voltage. Although the changes in the absolute amount of fluorescence excited at one wavelength linearly depends on transmembrane voltage of the viewed cells, accurate calibration has so far been impossible because the

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Figure 8. Transmural optical action potentials from an arterially perfused wedge preparation of the anterior wall of the canine left ventricle. Optical action potential maps from the same transmural wedge preparation are shown both before (A) and after (B and C) perfusion with the new electromechanical uncoupling agent cytochalasin D (cyto D) during endocardial stimulation at cycle lengths of 1000 ms (A and B) and 2000 ms (C). Each plot represents the full wall thickness of the left ventricular wall with epicardial traces at the top and endocardial traces at the bottom. Action potentials were sampled at 1000 Hz and low-pass filtered by software at 100 Hz. In A and B, optical potentials are scaled to their full peak-to-peak amplitude. In C, potentials are normalized to an identical action potential amplitude and aligned with their upstrokes in order to facilitate comparison of action potential shapes and durations; the vertical bars indicate the time of repolarization determined by the second derivative criterion and the contour map represents the resulting action potential durations in milliseconds. In the absence of electromechanical uncoupling (A), motion artifacts lead to pronounced distortion of nearly all optical action potentials from the surface of the preparation, precluding the determination of repolarization times. Motion artifacts were almost completely eliminated after application of cyto D (B and C), which unlike 2,3-butanedione-monoxime, has no significant effects on action potential shape or duration in canine myocardium.51-53 Action potential duration during endocardial stimulation at 2000 Hz (C) was 197 ± 15 ms (mean ± SD). See text for further details. Mapping data courtesy of J. Wu, PhD, Krannert Institute of Cardiology.54

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Figure 9. Optical mapping of a superfused preparation of the human right atrial appendage. The top panel shows optical tracing from one of the channels, both unfiltered and after digital filtering with a low-pass frequency of 50 Hz. The bottom panel shows an isochronal map of activation with contours drawn at 2-ms intervals.

number of cells contributing to the signal is unknown. Montana et al79 demonstrated that measurements of fluorescence ratios excited at 2 wavelengths can provide such information. They have shown that the ratio between di-4-ANEPPS fluorescence levels excited at 440 and 505 nm linearly depends on transmembrane potential in a lipid vesicle in the range from -125 mV to +125 mV. Similarly, the ratio of di-8-ANEPPS fluorescence from N1E-115 neuroblastoma

cell excited at 450 and 530 nm linearly depends on transmembrane voltage. Similar efforts are now being made to measure the absolute changes in membrane potentials in the heart. Another interesting area of application is the simultaneous recording of voltage and other intracellular and extracellular characteristics using combined staining with voltage-sensitive dyes and other fluorescent probes. Efimov et al.80

FAST FLUORESCENT MAPPING OF ELECTRICAL ACTIVITY IN THE HEART demonstrated that voltage and cytosolic calcium can be measured from the same Langendorff-perfused guinea pig heart stained with the voltage-sensitive dye RH421 and the [Ca2+]-sensitive dye Rhode2. These 2 dyes have close excitation frequencies, but different emission spectra. Therefore, the only change needed in recording the apparatus was the replacement of the emission filter. A recent report by Fast and Ideker81 presented results of such simultaneous measurements of intracellular calcium and voltage in the cell culture. References 1. Cohen LB, Keynes RD, Hille B. Light scattering and birefringence changes during nerve activity. Nature 1968;218:438-441. 2. Davila HV, Salzberg BM, Cohen LB, Waggoner AS. A large change in axon fluorescence that provides a promising method for measuring membrane potential. Nat New Biol 1973;241:159-160. 3. Salama G, Morad M. Merocyanine 540 as an optical probe of transmembrane electrical activity in the heart. Science 1976; 191:485-487. 4. Kamino K, Hirota A, Fujii S. Localization of pacemaking activity in early embryonic heart monitored using voltage-sensitive dye. Nature 1981;290:595-597. 5. Davidenko JM, Kent PF, Chialvo DR, et al. Sustained vortex-like waves in normal isolated ventricular muscle. Proc Natl Acad Sci USA 1990;87:8785-8789. 6. Rosenbaum DS, Kaplan DT, Kanai A, et al. Repolarization inhomogeneities in ventricular myocardium change dynamically with abrupt cycle length shortening. Circulation 1991;84:1333-1345. 7. Dillon SM. Optical recordings in the rabbit heart show that defibrillation strength shocks prolong the duration of depolarization and the refractory period. Circ Res 1991;69:842-856. 8. Knisley SB, Hill BC. Optical recordings of the effect of electrical stimulation on action potential repolarization and the induction of reentry in two-dimensional perfused rabbit epicardium. Circulation 1993;88(5 Pt 1):2402-2414.

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9. Fast VG, Kleber AG. Microscopic conduction in cultured strands of neonatal rat heart cells measured with voltage-sensitive dyes. Circ Res 1993;73:914-925. 10. Rohr S, Salzberg BM. Multiple site optical recording of transmembrane voltage (MSORTV) in patterned growth heart cell cultures: Assessing electrical behavior, with microsecond resolution, on a cellular and subcellular scale. Biophys J 1994;67: 1301-1315. 11. Windisch H, Ahammer H, Schaffer P, et al. Optical multisite monitoring of cell excitation phenomena in isolated cardiomyocytes. Pflugers Arch-Eur J Physiol 1995;430:508-518. 12. Neunlist M, Tung L. Spatial distribution of cardiac transmembrane potentials around an extracellular electrode: Dependence on fiber orientation. Biophys J 1995;68:2310-2322. 13. Wikswo JP, Lin S-F, Abbas RA. Virtual electrodes in cardiac tissue: A common mechanism for anodal and cathodal stimulation. Biophys J 1995;69:2195-2210. 14. Girouard SD, Pastore JM, Laurita KR, et al. Optical mapping in a new guinea pig model of ventricular tachycardia reveals mechanisms of multiple wavelengths in a single reentrant circuit. Circulation 1996;93:603-613. 15. Efimov IR, Fahy GJ, Cheng YN, et al. High resolution fluorescent imaging of rabbit heart does not reveal a distinct atrioventricular nodal anterior input channel (fast pathway) during sinus rhythm. J Cardiovasc Electrophysioll997;8:295-306. 16. Cohen LB, Lesher S. Optical monitoring of membrane potential: Methods of multisite optical measurement. In De Weer P, Salzberg BM (eds): Optical Methods in Cell Physiology. New York: Wiley InterScience; 1986:71-100. 17. Franz MR. Method and theory of monophasic action potential recording. Prog Cardiovasc Dis 1991;33:347-368. 18. Berbari EJ, Lander P, Geselowitz DB, et al. The methodology of cardiac mapping. In Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping. Mount Kisco, New York: Futura Publishing Co.; 1993:63-77. 19. Biermann M, Shenasa M, Borggrefe M, et al. The interpretation of cardiac electrograms. In Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping. Mount Kisco, New York: Futura Publishing Co.; 1993:11-34.

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Probes. Boca Raton: CRC Press; 1988: 137-199. 33. Loew LM. Voltage-sensitive dyes: Measurement of membrane potentials induced by DC and AC electric fields. [Review]. Bioelectromagnetics 1992;(Suppl 1):179— 189. 34. Cohen LB, Salzberg BM, Davila HV, et al. Changes in axon fluorescence during activity: Molecular probes of membrane potential. J Membr Biol 1974;19:l-36. 35. Muller W, Windisch H, Tritthart HA. Fast optical monitoring of microscopic excitation patterns in cardiac muscle. Biophys J 1989;56:623-629. 36. Knisley SB. Transmembrane voltage changes during unipolar stimulation of rabbit ventricle. Circ Res 1995;77:12291239. 37. Girouard SD, Laurita KR, Rosenbaum DS. Unique properties of cardiac action potentials recorded with voltage-sensitive dyes. J Cardiovasc Electrophysiol 1996;7: 1024-1038. 38. Efimov IR, Mazgalev TN. High-resolution three-dimensional fluorescent imaging reveals multilayer conduction pattern in the atrioventricular node. Circulation 1998; 98:54-57. 39. Grinvald A, Hildesheim R, Farber 1C, Anglister L. Improved fluorescent probes for the measurement of rapid changes in membrane potential. Biophys J 1982;39: 301-308. 40. Schaffer P, Ahammer H, Muller W, et al. Di4-ANEPPS causes photodynamic damage to isolated cardiomyocytes. Pflugers Arch 1994;426:548-551. 41. Cheng Y, Van Wagoner DR, Mazgalev TN, et al. Voltage-sensitive dye RH421 increases contractility of cardiac muscle. Can J Physiol Pharmacol 1998;76:1146-1150. 42. Grinvald A, Anglister L, Freeman JA, et al. Real-time optical imaging of naturally evoked electrical activity in intact frog brain. Nature 1984;308:848-850. 43. Grinvald A, Segal M, Kuhnt U, et al. A. Real-time optical mapping of neuronal activity in vertebrate CNS in vitro and in vivo. In De Weer P, Salzberg BM (eds): Optical Methods in Cell Physiology. New York: John Wiley & Sons; 1986:165198. 44. Rokitskaya TI, Antonenko YN, Kotova EA. Effect of dipole potential of a bilayer lipid membrane on the gramicidin channel

FAST FLUORESCENT MAPPING OF ELECTRICAL ACTIVITY IN THE HEART dissociation kinetics. Biophys J 1997;73: 850-854. 45. Clarke RJ, Schrimpf P, SchoneichM. Spectroscopic investigations of the potentialsensitive membrane probe RH421. Biochim Biophys Acta 1992;1112:142-152. 46. Fedosova NU, Cornelius F, Klodos I. Fluorescent styryl dyes as probes for Na,KATPase reaction mechanism: Significance of the charge of the hydrophilic moiety of RH dyes. Biochemistry 1995;34:1680616814. 47. Frank J, Zouni A, van Hoek A, et al. Interaction of the fluorescent probe RH421 with ribulose-1,5- biphosphate carboxylase/oxygenase and with Na+,K(+)-ATPase membrane fragments. Biochim Biophys Acta 1996;1280:51-64. 48. Efimov IR, Ermentrout B, Huang DT, Salama G. Activation and repolarization patterns are governed by different structural characteristics of ventricular myocardium: Experimental study with voltagesensitive dyes and numerical simulations. J Cardiouasc Electrophysiol 1996;7:512530. 49. Schalij MJ, Lammers WJ, Rensma PL, Allessie MA. Anisotropic conduction and reentry in perfused epicardium of rabbit left ventricle. Am JPhysiol 1992;263(5 Pt 2):H1466-H1478. 50. Allessie MA, Schalij MJ, Kirchhof CJ, et al. Experimental electrophysiology and arrhythmogenicity, anisotropy and ventricular tachycardia. Eur Heart J 1989;10(Suppl E): 2-8. 51. Davidenko JM, Pertsov AV, Salomonsz R, et al. Stationary and drifting spiral waves of excitation in isolated cardiac muscle. Nature 1992;355:349-351. 52. Undrovinas Al, Maltsev VA. Cytoskeleton disruption results in electromechanical dissociation in rat ventricular cardiomyocytes. J Am Coll Cardiol 1997;29:404A405A. 53. Biermann M, Rubart M, Wu J, et al. Effects of cytochalasin D and 2,3-butanedione monoxime on isometric twitch force and transmembrane action potentials in isolated canine right ventricular trabecular fibers. J Cardiovasc Electrophysiol 1998;9: 1348-1357. 54. Wu J, Biermann M, Rubart M, Zipes DP. Cytochalasin D as excitation-contraction uncoupler for optically mapping action potentials in wedges of ventricular myocar-

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cHAPTER 8

Precision and Reproducibility of Cardiac Mapping Martin Biermann, MD, Martin Borggrefe, MD, Robert Johna, MD, Wilhelm Haverkamp, MD, Mohammad Shenasa, MD, and Gunter Breithardt, MD

Introduction A chief objective of cardiac mapping is the analysis of activation wavefronts emerging from structures involved in the genesis of tachyarrhythmias. Accurate localization of such structures is a prerequisite for the understanding of the pathophysiological mechanisms underlying tachyarrhythmias, for the evaluation of antiarrhythmic drugs, and for the development and targeting of nonpharmacological interventions such as catheter ablation or antitachycardia surgery. A limited number of studies have dealt with the precision and reproducibility of cardiac mapping using either a single handheld "roving" electrode guided by visual grid systems or more sophisticated analog or digital multichannel mapping systems. Analysis of electrograms can be based on visual inspection and manual assignment of activation times or on automated analysis.

As computerized multichannel mapping systems are now common in both experimental and clinical settings, an understanding of how digital signal recording and processing influence the observed data and the accuracy of interpretations upon which clinical decisions and research conclusions are based is highly relevant. The purpose of this chapter is to review the currently available information from experimental and clinical studies on the precision, accuracy, and reproducibility of the various approaches for cardiac activation mapping. Definition of Terms If the performance of a given method of measurement is to be evaluated, the terms reproducibility and repeatability, for which there seem to be no uniformly accepted definitions, are frequently used. According to Bland and Altman,1'2 repeatability is

Supported by a Research Grant from the Deutsche Forschungsgemeinschaft, DFG-Projekt Br 759/1-2. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; c2003. 157

158 CAEDIAC MAPPING activation times from all recording sites are displayed in the format of a colorcoded or isochronal activation map, which indicates the spatiotemporal spread of activation across the mapped region(s) of the heart. Other forms of cardiac mapping focus on different aspects of cardiac electrical activity, such as repolarization maps and action potential duration maps to characterize cardiac repolarization (see chapter 7). The traditional mode of open-chest or intraoperative cardiac activation mapping first applied by Lewis and Rothschild4 in 1915, henceforth called roving-probe mapping, employed a single hand-held probe to sequentially record electrograms from different epicardial or endocardial sites during a stable cardiac rhythm such as sinus rhythm, stimulated rhythms, or monomorphic ventricular tachycardia (VT). To identify the various recording sites, most investigators used some kind of visual grid system defined by anatomical landmarks such as the atrioventricular (AV) groove or the course of the Basic Mapping Techniques coronary arteries for epicardial mapping Cardiac mapping can be defined as or the location of the septum, of the base a method by which cardiac potentials of the heart, and of the papillary muscles recorded directly from the heart or from the for endocardial mapping.3'5-12 Signals body surface (body surface mapping) or are displayed on oscilloscope screens or recorded indirectly by other means (optical recorded on paper charts or other media mapping, magnetocardiography, nuclear and activation times are determined visuphase mapping) are spatially depicted as a ally or "manually" by the electrophysiolfunction of time in an integrated manner.3 ogists in relation to a periodically occurring The most common type of cardiac time reference. The main drawbacks of mapping is activation mapping. Extra- this approach are that it is very time concellular electrograms are recorded from suming, that it is impossible to map apethe epicardial or endocardial surface of riodic rhythms such as polymorphic VTs the heart during catheter studies, during and ventricular fibrillation (VF), and that open-heart surgery, or in the experimen- it is difficult to relocate the probe to a tal setting. Each electrogram from each previous recording site with perfect accurecording site is then analyzed for times racy. For intraoperative and experimenof local activation of the myocardium in tal mapping, roving-probe mapping has the vicinity of the recording electrode in therefore been superseded by multichanrelation to a fixed time reference such as nel mapping systems developed since the a surface EGG or the output of the cardiac 1970s. Instead of a single roving probe, stimulator (see chapter 2). Finally, the arrays of recording electrodes—epicardial

inversely related to the variation in independent measurements replicated under identical conditions, i.e., the same subject, the same observer, the same method, and the same experiment. In contrast, reproducibility relates to the variation between 2 test results in the same subjects under differing conditions,2 such as different methods of measurement, different observers, or different times or places of measurement, independent of the agreement of the 2 test results with the true value of the measured parameter. Reproducibility can be quantified by calculating "limits of agreement" representing confidence intervals within which 2 test results will agree with a specified probability.1 Precision can be defined as the degree of exactness to which a measured or estimated parameter is expressed, whereas accuracy relates to the degree of correctness of a measurement or an estimate of a parameter in relation to its true value.

REPRODUCIBILITY OF MAPPING 159 sock or plaque arrays or endocardial balloon arrays inserted through a ventriculotomy or atriotomy—are brought into direct contact with the heart and electrograms from all recording sites are recorded simultaneously. While some early multichannel mapping systems used dedicated analog circuitry for on-line display of the activation sequence,13 all other systems digitize the analog signals and employ computers for the display and analysis of the electrogram data. Closed-chest or catheter mapping was first introduced for the preoperative study of cardiac arrhythmias but has, since the introduction of high-frequency catheter ablation of supra ventricular and ventricular arrhythmias, become the mainstay of the nonpharmacological management of tachyarrhythmias. Conventional catheter-based mapping technology is very much like open-chest roving-probe mapping limited by 2 main shortcomings: first, only a few electrograms from separate endocardial sites can be acquired concomitantly. Second, it is difficult to define and measure the spatial relationship of different endocardial sites with a conventional biplane fluoroscopy unit. Several new technologies have been clinically evaluated in recent years: (1) the basket catheter, (2) electroanatomical mapping, and (3) noncontact mapping. The basket catheter is composed of 8 splines, each bearing 8 equally spaced electrodes and assembled into a cage-like structure, which can be expanded and brought into contact with the endocardium of the heart chamber under study. The catheter allows the synchronous registration of 64 unipolar or 56 bipolar electrograms.14,15 Mapping accuracy with the catheter is limited by the difficulty of achieving satisfactory wall contact of all 64 electrodes and by the large interelectrode spacing, the spatial resolution being insufficient to allow catheter ablation of focal tachycardias

without further conventional mapping. The technique has been successfully applied for mapping ventricular16 and atrial tachyarrhythmias.17,18 For electroanatomical mapping with the CARTO™ system (Biosense Webster, Diamond Bar, CA), 3 magnetic coils attached to the examination table generate magnetic field gradients, which are picked up by a sensor incorporated into the tip of a conventional steerable bipolar mapping catheter. This set-up allows the measurement of the position and orientation of the catheter tip relative to a reference field sensor with a spatial accuracy of <1 mm.19 Sophisticated computer hardware and software relate electrograms with their precise locations in 3-dimensional space and allow the construction of isochronal, isopotential, and voltage maps. Data acquisition is sequential and requires a sustained stable and hemodynamically tolerated heart rhythm19,20; it has been applied for mapping of atrial21 and ventricular tachyarrhythmias.22 For noncontact mapping using the Ensite™ System (Endocardial Solutions, Inc., St. Paul, MN), a 64-electrode balloon array catheter with an inflated size of 1.8 x 4.6 cm is positioned within the heart chamber under study. The catheter emits a 5.6-kHz locator signal that allows tracking of the tip position of a conventional mapping catheter, and the shape of the heart chamber is reconstructed by sweeping this mapping catheter across the endocardium. Based on an inverse solution to Laplace's equation, 3360 'virtual' endocardial electrograms are reconstructed from the 64 far-field signals recorded by the balloon catheter. The accuracy of the algorithm has been validated both in vitro23 and in vivo.24 The reconstruction can be achieved based on data acquired during a single tachycardia cycle and can thus be used to map polymorphic, nonsustained, and hemodynamically unstable arrhythmias.

160 CAEDIAC MAPPING As quantitative data on the performance of these new systems are still lacking, the following discussion focuses on the precision and reproducibility of openchest intraoperative and experimental mapping; further studies will be needed to demonstrate that the advantages provided by the new catheter mapping studies translate into better clinical outcomes.

When evaluating different methods of measurement in biological systems, the challenge is not only to arrive at reliable estimates of the variation between test results under differing conditions but to decide how reproducible and accurate a test must be in order to be experimentally or clinically useful. For targeting surgical interventions, a spatial resolution of 10 mm seems adequate, and based on the assumption of a longitudiBasic Problems of Analysis nal conduction velocity in myocardium of Precision and Reproducibility of 0.5 mm/ms,25 activation time assignof Electrocardiographic Signals ment would have to be accurate within ±10 ms26; however, higher apparent conIndependent of the instrumentation, duction velocities that occur in 2-dimencardiac activation mapping includes many sional measurements when an activation steps between data acquisition (recording) front meets the mapped surface at an and the construction of an isochronal map angle27 may result in more stringent and the final interpretation of an activa- requirements for temporal accuracy. For tion sequence (Table 1). Each step has a targeting of other types of interventions potential bearing on the resulting acti- that have a smaller lesion size, such as vation maps and their interpretation. In high-frequency and laser lesions, it is necthe following discussion, the available map- essary for spatial and temporal accuracy ping techniques are compared in terms to be significantly higher. If the aim was of the reproducibility of the resulting acti- to resolve microreentrant circuits 5 mm vation times and interpretations of the in diameter, electrode locations would have mapped arrhythmias. to be known within 1 mm.27 A different Table 1 Steps Involved in Activation Mapping Step in Activation Mapping Selection of patient or of experimental model Induction of the arrhythmia of interest Recording of electrograms Localization of recording sites Signal conditioning Signal logging Signal analysis Map generation Interpretation of activation sequence

Critical Issues Appropriateness of selection Reproducibility and stability of induced arrhythmia(s) Type of electrode and/or electrode array(s), motion and other artifacts Reproducibility and accuracy of (re)localization Amplification, filtering, digitization Continuous or burst recording, reliability of storage media Interpretation of signals, visual or automated analysis, context (in-)dependent interpretation, verification Manual or automatic, interpolation, adequacy of spatial sampling (density of recording sites, extent of mapped area) Scientific conclusions, targeting of therapeutic intervention (s)

REPRODUCIBILITY OF MAPPING approach for determining the required accuracy in mapping studies was suggested by Pieper et al.,28 who added normally distributed random errors to activation times in an activation map of sustained VT in a human subject recorded with a 119-channel sock electrode array. While maps were still interpretable at a standard deviation (SD) of the artificially induced timing error of 3 ms, epicardial breakthrough and activation sequence were severely distorted at an SD of 6 ms, so that Pieper et al.28 demanded that activation time assignments in multichannel mapping systems be accurate within an SD of 3 ms. Selection of Patient or Experimental Model Any successful mapping study in the clinical field requires appropriate patient selection for the planned therapeutic intervention, e.g., the inducibility of hemodynamically tolerated sustained monomorphic VTs in patients intended for high-frequency catheter ablation of ventricular tachyarrhythmias. In experimental mapping, the chosen animal model and preparation must be relevant for the type of research question under study. For example, the study of ventricular tachyarrhythmias in the chronic phase after myocardial infarction generally requires hearts of a certain size such as the canine heart, while conduction in the AV node region can be studied in smaller hearts. While these issues are pertinent to the eventual success of any cardiac mapping study, they are beyond the scope of this chapter and are not discussed further. Induction of the Arrhythmia of Interest

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intervention or of scientific investigation be reproducible. This is essential if the effect of interventions is to be studied in animal models or during catheter ablation or antitachycardia surgery in humans. Should an arrhythmia not be reproducible, the absence of such an arrhythmia or the appearance of another type of arrhythmia after a therapeutic or investigational intervention may be due to chance rather than to the intervention itself. Reproducibility of the type of induced VT

Multiple morphologies of VT are common in open-chest canine models. Recordings from limb leads may be inadequate to assess whether an induced VT is identical to a previous episode. Bardy et al.29 assessed the reproducibility of induction of specific types of VT in a canine model 3 days after occlusion of the left anterior descending coronary artery followed by reperfusion. A type of VT was considered as reproducible if 2 or more episodes of monomorphic VT were obtained with similar rates, limb lead tracings (leads I, II, III), and epicardial maps based on 27 simultaneously recorded bipolar epicardial electrograms. To provide a method of distinguishing various types of VT without the necessity of a complete epicardial map, 5 of these 27 epicardial electrodes were selected. The same types of VT could be as accurately identified in these 5 electrograms as in the epicardial activation maps of the entire electrode array if activation times and electrogram morphology were analyzed. Thus, a limited number of leads can be used to differentiate between various types of VT in the canine model.29 Beat-to-beat stability

Any successful mapping study further requires that the arrhythmia that is the object of the planned therapeutic

Sequential roving-probe mapping and simultaneous multichannel mapping

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both assume that consecutive beats are identical or that a single beat is representative of ventricular activation during subsequent cycles. It is generally assumed that this is the case in normal myocardium during sinus rhythm; however, in abnormal ventricular myocardium as after myocardial infarction, abnormal activation patterns with regionally slow conduction may demonstrate beat-to-beat irregularities (Wenckebach-like pattern, 2:1 conduction pattern, etc.). Such a variation in the activation pattern may become especially important during VT, either at the onset or prior to termination when a clear-cut variation in cycle length can frequently be observed. In polymorphic VT, changes in local activation times can be expected on a beat-to-beat basis. Our experience from intraoperative mapping in patients with VT suggests that during sinus rhythm or regular paced rhythms electrograms are generally relatively stable.30 In a series of experiments in normal open-chest dogs, we performed epicardial mapping with a 240-pole epicardial plaque electrode (35 x 35.5 mm) during cathodal stimulation from the center of the plaque electrode at twice diastolic threshold. Data were acquired with a computerized multichannel mapping system developed at the University of Maastricht (The Netherlands),31 at 30 minutes after initial placement of the plaque electrode and 8 hours later. Activation times of subsequent beats were reproducible within 0.5 ± 0.9 ms (mean ± SD; range -4 to +5 ms) and within 3.6 ± 4.2 ms (range -13 to 22 ms) between the 2 sets of measurements 8 hours apart.32 To define the periodicity of epicardial and transmural ventricular activation during sustained monomorphic VT, Branyas et al.33 assessed epicardial and transmural ventricular electrograms during 6 consecutive cycles of VT in 10 patients during intraoperative mapping of sus-

tained monomorphic VT. Bipolar electrograms were recorded simultaneously using sock and needle electrodes from up to 96 epicardial and 156 transmural sites. Electrograms were analyzed for local activation time, duration, and morphology. The isochronal activation maps during VT were reproducible in each patient. The mean beat-to-beat variations in local epicardial and transmural activation times were only 1.7 ± 1.7 ms and 2.0 ± 1.9 ms, respectively.33 These and other results suggest that the analysis of a single beat of VT provides reliable information on ventricular activation in patients with sustained monomorphic VT, supporting both the technique of single-cycle activation mapping and of roving-probe mapping of subsequent cycles. Recording of Electrograms Types of recording electrodes

Electrograms can be recorded in multiple ways, by means of a single unipolar "different" electrode against a distant reference electrode (unipolar electrograms), as the difference in potential between 2 closely adjacent electrodes (bipolar electrograms), or by special pressure or suction electrodes (monophasic action potentials).34 Morphology and amplitude of the recorded electrograms depend on (1) the type of normal or abnormal depolarization responsible for the electrical potential and on local myocardial characteristics such as ischemia or infarction; (2) the orientation of the activation wavefront in relation to myocardial fiber direction25; (3) the distance between the source of the potential and the recording electrode(s); (4) the size, configuration, and interpolar distance of the recording electrode(s)35; (5) the orientation of the wavefront in relation to the

REPRODUCIBILITY OF MAPPING poles of a bipolar electrode; (6) the conducting medium in which electrograms are recorded36; and (7) other factors. Unipolar electrograms reflect both local and distant cardiac activity, the contribution of distant events decreasing in proportion to the square of the distance from the recording electrode (see chapter 2). The advantages of unipolar electrodes lie in their capability to record activation fronts from all directions with equal sensitivity, and in the fact that only one lead is required per recording channel, which is an important consideration in the design of multichannel mapping systems. Bipolar electrograms have the advantage of emphasizing local events over distant events, the contribution of which decreases in proportion to the third power of the distance, which aids in the specific detection of local activation for the purpose of activation mapping. Their disadvantage, however, is their directional insensitivity to activation fronts that are parallel to the poles of the electrode. To avoid this, coaxial electrodes or multipolar electrodes have been suggested, which however still cannot detect activation fronts parallel to the plane of the electrodes (see chapter 2). Instead of using coaxial electrodes, it is possible to calculate "virtual" bipolar electrograms as the difference between the potential of a unipolar electrode and the mean potential of the surrounding electrodes in an array of unipolar electrodes, provided these are evenly spaced. Recording artifacts

The correct and timely identification of artifactual electrograms is of crucial importance in any system of cardiac mapping and may have major influence on the final interpretation of an activation sequence, e.g., whether a fractionated electrogram represents a motion artifact or local activation in an assumed zone of

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slow conduction. While roving-probe mapping allows the instant identification and correction of artifactual recordings during on-line analysis of the recorded signals, identification of artifacts in multiple-channel mapping systems tends to be more difficult and is often possible only after completion of the experiment. Typical recording artifacts induced at the myocardium/electrode interface include the following: (1) polarization of electrodes, which can cause slow shifts of the baseline of the signals; (2) local myocardial injury resulting from inappropriate pressure by recording electrodes or after insertion of intramural "plunge" electrodes resulting in ST segment elevation in local unipolar electrograms37; (3) motion artifacts, which are often rhythmic and repeating simulating fractionated electrograms38,39 or which can be sudden shifts of potential that may be misinterpreted as activations by computer algorithms; and (4) poor contact between electrode and myocardium leading to heavier weighing of far-field effects and increased 50- or 60-Hz noise.40 Accurate Localization of Recording Sites As the object of cardiac mapping is the analysis of the spatiotemporal sequence of cardiac events, the accurate localization of the recording sites in relation to anatomical structures is of great concern, for targeting therapeutic interventions and for purposes of investigations correlating cardiac signals and local microanatomy.41 While in roving-probe mapping the chief problem is to relocalize individual recording sites with reasonable accuracy in repeated recordings during or after interventions, the main difficulty in multichannel mapping by means of electrode arrays is to identify the accurate location of an individual recording channel in

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relation to the heart, especially when several electrode arrays are used simultaneously (e.g., an epicardial sock array and an endocardial balloon array) or sequentially (e.g., epicardial sock and plaque electrodes). Unless altering cardiac contraction patterns during different rhythms cause movement of the electrode array across the heart, recording electrodes can be assumed to maintain a constant position in relation to the heart at least within each sequence of recordings. Assuming a high stability of the biological signal, reproducibility is then governed by the performance of the visual or computer-based analysis of the electrograms. The reproducibility of activation time measurements in roving-probe mapping aided by visual grid systems has been examined in a number of studies.30,42 Reproducibility of Activation Times of Visual Grid Systems for Roving-Probe Mapping For epicardial roving-probe mapping in a canine model of chronic myocardial infarction, Spielman et al.12 reported that measurements of activation times by a custom-designed interval counter were reproducible within 2 ms in repeated measurements from the same epicardial or endocardial locations. Abendroth et al.30 assessed the reproducibility of local activation times in epicardial mapping in 10 patients during open-heart surgery before cardiopulmonary bypass. Epicardial electrograms were recorded by means of a tripolar handheld probe (interpolar distance 1.5 mm). To compensate for the directional insensitivity of bipolar electrograms (s.a.), the 3 bipolar signals from each pair of poles of the tripolar electrode were summed after rectification. Activation times were determined by measuring the time of onset of

the complex based on the first elevation from baseline by more than 45°, using the signal from a multipolar electrode on the anterior wall of the right ventricle (RV) as a time reference. During the same paced atrial rhythm, activation times were measured consecutively at 75 epicardial sites defined by the crossing points in a visual grid system that included anatomical landmarks such as the left anterior descending artery. After the first series of 75 electrograms had been recorded, the recording was repeated in an attempt to obtain electrograms from the same 75 points. Mean activation time values at each site were calculated from at least 5 consecutive cycles. A representative example of the absolute differences in local epicardial activation times during repeated measurements is presented in Figure 1. In all 10 patients, the mean difference between the first and second measurements was 8 ms (range 4-12 ms) in the anterior wall, 6 ms (range 3—11 ms) in the left lateral wall, and 7 ms (range 5-15 ms) in the posterior wall.30 Blomstrom et al.42 analyzed the reproducibility and the beat-to-beat variability of local activation time measurements in 20 intraoperative atrial and ventricular mapping studies. Signals were recorded with a single hand-held roving-probe electrode at 53 predefined points in a visual grid system of the ventricular epicardium in 5 patients, at 15 predefined points on the atrial epicardium in 4 patients, and at 10 right atrial endocardial points in a single patient, all patients undergoing antitachycardia surgery. Each intraoperative mapping procedure was performed twice in each patient. The beat-to-beat variability of activation times ranged between 3.9 and 5.2 ms in 95% of the ventricular recordings, but was 11.2 ms in the atrial epicardial and 14.7 ms in the atrial endocardial measurements. The mean differences between

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Figure 1. Representative example of the absolute differences in local epicardial activation times of repeated measurements during intraoperative mapping in a patient with coronary heart disease but without prior myocardial infarction.30

the first and second measurements of activation times were 2.2 ± 5.6 ms (mean ± 2 SD) in the RV anterior wall, 1.2 ± 6.8 ms in the RV posterior wall, -0.8 ± 4.4 ms in the left ventricular (LV) anterior wall, -2.8 + 5.3 ms in the LV wall, and 0.1 ± 5.6 ms in all ventricular wall regions, but -1.5 ± 21.0 ms (!) in the atrial epicardium and 3.9 ± 33.8 ms (!) in the atrial endocardium.42 Cowan et al.43 evaluated the reproducibility of activation and repolarization time measurements in intraoperative monophasic action potential mapping during atrial paced rhythms in 30 patients. Measurements were performed by means of a special hand-held roving probe bearing a central blunt spike electrode surrounded by a concentric ring electrode. To test the reproducibility of activation time and repolarization time measurements, monophasic action potentials from 10 LV and 2 posterior RV sites were

recorded in sequence 4 times with a different starting point on each occasion. The 95% confidence interval for an estimate of epicardial activation time based on a single measurement was ±10 ms but ±21 ms for an estimate of repolarization time, so that Cowan et al. stressed the need for repeated measurements of repolarization times at the same sites if meaningful differences in repolarization times between sites were to be detected.43 These studies indicate that the differences between repeated activation time measurements by means of roving probes can be expected to lie within 5 to 10 ms for ventricular epicardial mapping, which is probably acceptable for most clinical applications during antitachycardia surgery but can be much larger for mapping in the atria. In each study, however, repeated measurements from some sites differed to a remarkable degree, which would not be acceptable for most

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research applications such as the study of drug effects. The main reason for the poor reproducibility of some measurements seems to be difficulty in retrieving the same recording sites, especially in areas that are difficult to reach such as the LV posterior wall.

(r = 0.93) with a rate of 1.1% of activation detection errors per 10% of maximum allowable calibration factor error. Activation detection was more susceptible to calibration-induced errors during VT than during sinus rhythm or epicardial pacing.44

Signal Conditioning

Digitization of electrogram data

Electrograms represent low-amplitude, high-impedance biological signals which must be amplified before they can be displayed on oscilloscope screens, recorded on paper charts or magnetic tape, or digitized for computer processing. It is essential that amplifiers do not lead to distortion of the signals and be calibrated to a uniform gain. In order to reduce the amount of noise picked up by the leads from the recording electrodes, it is desirable to locate preamplifiers and amplifiers as close as possible to the mapped heart. To evaluate the effect of nonuniformity of amplifier gains on the performance of an automatic activation detection algorithm, we repeated automatic activation detection in unipolar epicardial mapping data from chronically infarcted dog hearts after introducing random errors in the calibration factor files used to compensate errors in linear gain between the recording channels. The random errors were normally distributed with an SD of half the maximum allowable calibration factor error. Activations were detected by means of the maximum downslope algorithm with a fixed slope threshold. Detection errors were defined as either false-positive or false-negative activation detections or as differences of more than 5 ms in assigned activation times. Based on the analyses of the same 1440 electrograms with calibration factor files with maximum allowable calibration errors between 1% and 50%, the rate of faulty activation detections increased approximately linearly

In order to eliminate the need for expensive custom-designed analog hardware for the storage, retrieval, display, and analysis of mapping data, nearly all modern multichannel mapping systems digitize the electrogram data before further processing. This raises a number of important issues. Digitization is a form of data reduction. When an analog waveform is digitized, the analog-to-digital (A/D) converter takes a sample of the waveform at a constant rate called the sampling rate. The amplitude of the analog waveform at the time of sampling—which could theoretically be expressed with infinite precision—is translated into a finite discrete number, usually a binary number ranging from -128 to +127 (8-bit A/D conversion), -512 to +511 (10-bit), or -2048 to +2047 (12-bit), representing the full dynamic input range of the A/D converter (typically ±2.5 V or ±10 V). All other information contained in the analog waveform is discarded. If the dynamic range of the A/D converter is exceeded, the A/D converter saturates and potentially important information is irretrievably lost. The sampling theorem states that if a periodic waveform is band limited and sampled at a rate (called the Nyquist rate) that is equal to at least twice its highest component frequency, it can be reconstructed exactly without loss of information through sampling. The following aspects of the sampling theorem deserve special mention:

REPRODUCIBILITY OF MAPPING l.The sampling theorem assumes that sampling is performed with infinite precision, whereas any A/D converter samples with finite precision, introducing so-called digitization noise. 2. It is not possible to identify from measured frequency spectra of cardiac waveforms an upper frequency limit that includes only the physiologically significant waveform and excludes only noise, except by arbitrary choice.45 3. If a signal is sampled below its Nyquist rate, so-called aliasing occurs, in which the upper frequencies are not simply lost but contribute in an unpredictable way to the corruption of important waveform parameters.46 To prevent aliasing, electrogram signals need to undergo low-pass antialias filtering before A/D conversion at a cut-off frequency that is lower than half or even a quarter of the sampling rate. As the amount of data to be handled by a computerized multichannel mapping system increases in direct proportion to any increase in sample rate, the optimum sample rate that still preserves the pertinent features of the electrocardiographic waveforms has long been a subject of intense debate. Even though the cost of computer memory and storage media has been steadily decreasing, system performance is still an issue in systems that are to allow continuous acquisition of mapping data over extended periods. An attractive approach for reducing the amount of data to be retained for processing could be adaptive sampling, in which the sampling interval is not constant but changed according to a specified algorithm that stores samples with a higher rate when the waveform is changing rapidly and otherwise discards nearly redundant samples.47 While adaptive

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sampling has been successfully implemented in some commercially available data acquisition systems for cellular electrophysiology, the computational price for adaptive sampling in the context of multichannel mapping systems is most probably too high, increasing system complexity and potentially even degrading system performance.46 Sample rates for digitization

In a classic paper, Barr and Spach45 examined the optimum sample rates for recording the whole variety of cardiac waveforms, including ventricular electrograms, using both quantitative and qualitative criteria. They defined as the minimum sample rate the lowest rate that allowed the complete analog waveform to be reproduced from the retained digital samples within the prevailing noise level, thus basing their definition on waveform reconstruction rather than on frequency analysis. The minimum sample rates recommended were 500 Hz for ECGs from the body surface, 1000 Hz for unipolar and bipolar ventricular electrograms, and 15,000 Hz for signals from the cardiac conduction system; however, Barr and Spach pointed out that twice or more than these minimum sample rates were desirable to allow for accurate measurement and correct interpretation of unexpectedly complicated waveforms. Purkinje spikes in endocardial unipolar electrograms in particular were invisible at sample rates below 5000 Hz. Interestingly, none of the interpolation algorithms used for the reconstruction of the waveforms (linear, quadratic, and sin x/x) performed significantly better than the others.45 Other studies have investigated the effect of lower sample rates on the performance of activation detection algorithms in ventricular electrograms. Kaplan et al.48 evaluated the performance of computerized

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activation detection algorithms in bipolar epicardial and endocardial electrograms from 4 chronically infarcted dogs at an original sample rate of 1000 Hz and at reduced sample rates of 500,250, and 125 Hz. Using the maximum derivative criterion for activation detection, the criterion performed similarly at sample rates of 1000, 500, 250, and 125 with root mean square errors of the activation times in relation to the "best guesses" of 9.8, 9.0, 8.2, and 8.8 ms, respectively. When using a different morphological template-matching algorithm for the determination of activation times, reducing the sample rate degraded the performance of the algorithm with root mean square errors of 1.1, 2.9, 4.2, and 6.2 ms, respectively.48 Rosenbaum et al.26 sampled bipolar electrograms from 61 epicardial electrodes (interpolar distance 4 mm) during sustained monomorphic VT in 10 chronically infarcted dogs at 1000, 500, 250, and 125 Hz. Activation times were then assigned to the onset of the electrogram's earliest rapid deflection by trained observers aided by a computer algorithm that preselected times of activation based on the maximum absolute slope of the signal. At the full sample rate of 1000 Hz, 95% of activation times were reproducible within 9.5 ms and the mean difference in activation times between repeated assignments at the full sample rate was 2.6 + 0.1 ms (mean ± standard error of the mean). Reductions in sample rate to 500, 250, and 125 Hz increased this difference to 3.2 ± 0.2 ms (n.s.), 3.3 ± 0.2 ms (n.s.), and 6.5 ± 0.3 ms (P< 0.0005). The authors concluded that only digitization at 125 Hz significantly impaired activation time measurements in their animal model.26 Pieper et al.28 recorded unipolar and bipolar (interpolar distance 5 mm) electrograms intraoperatively with an epicardial sock electrode array from 4 patients with VT and 4 patients with Wolff-Parkinson-White (WPW) syndrome

at a sample rate of 1000 Hz. The signals were interpolated to a sample rate of 10,000 Hz and then resampled at lower sample frequencies between 2000 Hz and 200 Hz. Activation times were determined in the resampled signals by means of computer algorithms using the minimum slope criterion in unipolar electrograms and the peak amplitude criterion in bipolar electrograms, and the mean differences between these activation times and the "best guesses" of activation times were calculated. Based on a relatively strict criterion that the mean difference +1 SD be smaller than 4 ms, the minimum sample rates for bipolar signals was 500 Hz and for unipolar signals was 625 Hz.28 These results were in agreement with those of an earlier study of theirs, which had found that a greater bandwidth was necessary for accurate activation detection in unipolar electrograms despite their having lower signal power in the higher frequencies than bipolar electrograms.46 Based on these results it is probably safe to recommend sample rates for electrogram acquisition of 1000 Hz or more. Dynamic range of digitization

Another issue, which has not been examined by systematic studies, is the dynamic range of A/D conversion required for optimum resolution of electrogram signals. While some multiple-channel mapping systems employed A/D conversion at 8 bits31,46 or 10 bits,49 12-bit A/D conversion26,48,50,51 can now be regarded as standard, at least for intraoperative mapping in humans. As is illustrated in Figure 2, saturation of A/D converters by the electrogram signals leads to loss of information in the digitized signal that can result in critical misassignments of activation times. If a uniform amplifier gain is selected so as to avoid saturation in all signal channels, A/D conversion at a resolution of 8 bits

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Figure 2. Influence of amplifier saturation on electrogram analysis. In the upper panel, local activation was identified at 75 ms, whereas at a 3 times higher amplification (lower panel), local activation was identified earlier (55 ms) since part of the relevant signal was cut off because of saturation of the amplifier.

may not be enough to resolve low-amplitude fractionated activity for adequate interpretation of the signals, especially in periinfarction zones and in the human heart, which has a higher amount of epicardial fat.51 Ideker et al.51 therefore suggested that the minimum amplitude resolution in multiple-channel mapping systems should be 12 bit with automatic gain adjustment for each recording channel, or else 16 bit. In this context it is worth noting that 16bit A/D conversion does not increase storage requirements, as it is customary to encode 12-bit signals by 2-byte digits for

ease and speed of handling of information in computer memory. Signal Logging A mapping system with 256 channels sampled at 1000 Hz and 12-bit resolution will generate 29 MB of data per minute. While burst recording of brief episodes of arrhythmias can be an acceptable solution for some applications such as optical mapping, continuous recordings of arrhythmias over longer periods

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continue to pose major challenges in hardware design and optimization. Digital mapping systems may stream data to computer hard disks or to tape drives. While high-end digital tape backup systems allow the storage of redundant information to tape so that data can be fully recovered even if read errors from tape occur, systems that use modified tape drives such as video cassette recorders do not necessarily have this capability. To evaluate the frequency of read errors from video tape in the mapping system developed at the University of Maastricht,31 we repeatedly read mapping data (240 channels sampled at a resolution of 8 bits and 1000 Hz) of the same beat during sinus rhythm after forwarding and rewinding the tape. Read errors occurred randomly but at reproducible locations in the data set with a frequency of 1 error per 64,000 bytes of data or once per 270 ms of electrogram data. For comparison, a typical digital data storage-2 tape drive such as the Hewlett-Packard C1533 A (Palo Alto, CA) is specified to have an uncorrectable bit error rate of less than 1 bit in 4 x 1012 bytes. Even though the video tape logging system was able to identify read errors through the inclusion of a 9th parity bit in the information written to tape returning a uniform amplitude of-128 in case of all read errors, the analysis software misinterpreted this value as a sharp negative spike in the signal that was then falsely detected as a local activation by the activation detection algorithm.44 This example illustrates the importance of testing all aspects of a mapping system's performance before reaching scientific conclusions. Signal Analysis The chief object of signal analysis in activation mapping is the assignment of times of activation to each recorded electrogram, which are to represent instances of

local depolarization of myocardium within the field of view of the recording electrode. Activation times are then calculated as the time intervals between the assigned times of activation and a fixed or recurring time reference such as the output signal of a cardiac stimulator or an electrogram signal from a fixed reference electrode. The problem of activation detection in cardiac mapping is that it is not possible to conclude with absolute certainty from extracellular signals to intracellular events and that the gold standard for detecting activation in myocardium, a recording of the transmembrane potential either by an intracellular impalement or means of a voltage-sensitive dye (see chapter 7), is not available. Theoretical issues, which have already been addressed in chapter 2, include: (1) which morphological features in the extracellular signals best correspond with times of local activation in local transmembrane potentials? Proposed criteria for unipolar electrograms are the criterion of maximum downslope, and for bipolar electrograms the criteria of maximum amplitude, maximum absolute slope, or the point of symmetry in the waveform. (2) Which quantitative and/or qualitative criteria allow the accurate identification of local activation versus distant activation fronts in the extracellular signals? A common practice in activation detection in unipolar electrograms is the use of a slope threshold, which must be exceeded for local activation to be assumed. Confounding issues include the fact that recorded maximum negative slopes are not only highly dependent on the local characteristics of the myocardium35,52 but also on electrode geometry,35 so that results of experimental studies cannot easily be generalized. Manual electrogram analysis

As long as there are no reliable quantitative criteria for activation detection

REPRODUCIBILITY OF MAPPING in extracellular electrograms, mapping studies are forced to accept the activation time assignments by trained observers as best guesses of the underlying activation fronts. The method by which an observer strives to resolve ambiguities in the analysis of the signals is the inclusion of contextual information in the analysis of individual electrogram signals.40 This includes information on myocardial properties such as refractoriness and anisotropy, on the experimental protocol including the placement of the electrodes and the presumed cardiac rhythm (e.g., sinus rhythm versus VT or an AV reentrant tachycardia over an accessory pathway), on the presence or the absence of local pathology such as myocardial infarction, on the electrogram morphology in the same channels during different rhythms, and, most importantly, on time course and morphology of the neighboring electrograms. Electrogram features associated with local excitation generally show a temporal shift between neighboring electrogram channels due to conduction of the impulse across the heart, whereas far events and motion artifacts tend to affect neighboring channels synchronously.53 Considering the importance of these "manual" activation time assignments as de facto gold standard for activation detection in extracellular signals, surprisingly few studies have addressed the problem of the intra- and interobserver reproducibility of these manual interpretations even when these were used as standards for evaluating the performance of automatic activation detection algorithms.40,49,54 It also is of note that while some studies allowed observers to see the entire mapping array and adjust activation time assignments in the context of neighboring electrograms ("contextdependent" analysis), observers in other studies were presented electrograms in random order without access to contex-

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tual information ("context-independent" analysis). In their study on the reproducibility of intraoperative mapping, Abendroth et al.30 found that manual activation time measurements on paper chart recordings of bipolar electrograms based on the 45° criterion (see chapter 2) were reproducible within 3.0 ± 2.0 ms (mean ± SD) by the same observer and 5.0 ± 3.0 ms by different observers. Rosenbaum et al.26 evaluated the reproducibility of context-independent manual activation time assignment in maps of 61 epicardial and endocardial bipolar electrograms recorded from 10 chronically infarcted dogs during VT. Four observers were presented the electrograms in random order on repeated occasions no fewer than 7 days apart. Activation times in the 610 electrograms by the same observers were reproducible within 2.6 ± 3.6 ms (mean ± SD), with approximately 87% of all assignments being reproducible within 5 ms and 95% within 10 ms. Based on these assignments, the location of the epicardial breakthrough site varied by 1.0 ± 1.2 cm between trials. There were no significant differences in intraobserver variability of the results, and activation time assignments by the 4 observers were reported to be very similar although they were not quantified.26 Simpson et al.55 determined the reproducibility of context-independent activation time assignments in 24 mapping data sets of 117 simultaneously recorded bipolar electrograms from mongrel dogs during regular rhythms (sinus rhythm, n = 6; ventricular pacing, n = 6) and VF (n = 12). Activation times were manually assigned through context-independent analysis by 3 observers. In case of regular rhythms, all 3 observers agreed on more than 98% of all detected activations with a detection error rate of approximately 0.05 errors per second of

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electrogram data; however in case of VF, observers agreed only on 90% of all activations with a mean error rate of 0.8 errors per second.55 We evaluated the intraobserver reproducibility of manual activation time assignments of context-dependent interpretations and context-independent interpretations of electrogram data performed 1 week apart. The database included 30 sets of 240 unipolar electrograms recorded by means of a 240-pole sock electrode from 10 chronically infarcted dogs during sinus rhythm, ventricular pacing, and VT (n = 10 each). To perform activation time assignments, the observer was aided by a mouse-driven interactive routine seeking the local minimum of slope in the unipolar waveform. A detection error was defined as a false-positive or false-negative detection in a given electrogram channel or as a difference in activation time of more than 5 ms. The reproducibility of either interpretation method was very similar, with error rates between repeated contextdependent and context-independent analyses by the same observer of 9.1% and 9.0%, respectively. Interestingly, the agreement between the context-dependent and context-independent analyses of each set of interpretations was higher than the reproducibility of either analysis mode, with a mean error rate between both modes of 7.4%. To test interobserver variability, context-dependent analysis of the VT maps was performed by 4 observers on 2 occasions 1 week apart. Mean error rates for repeated analysis of the data by the same observers was 7.9% whereas the overall error rate between the analyses of the 4 observers was 11.6%, the intraobserver reproducibility thus being higher than the interobserver reproducibility. Of the total of 663 contested activation assignments between the observers, 81% concerned the interpretation of deflections as local or distant activations especially in the border zones of myocardial

infarctions, 14% were due to apparent observer errors, 4% were due to differing activation time assignments to signals with multiple deflections, and 1% were due to disagreement on classifying a deflection as artifactual. Despite the substantial differences in the annotation of individual electrogram channels, there was practically no disagreement on the timing of individual responses with root mean square errors between differing activation assignments below 1 ms, and the overall interpretation of the activation sequence was nearly identical in all analyses in the study with locations of first and last epicardial activation never differing by more than a single electrode distance.44 Based on these limited data, activation time assignments tend to be reproducible within some 5 ms in approximately 90% of all electrograms on repeated analyses by the same and by different observers. There seem to be no significant differences in the interpretation of the overall activation sequence, although major differences are to be expected in the detailed analysis of individual electrograms during chaotic rhythms such as VF and of fractionated activity in the border zones of myocardial infarctions. Automated electrogram analysis

Purely manual electrogram analysis is very time consuming.50 As time is very limited both during heart surgery and during experiments, numerous investigators have attempted to automate the process of electrogram analysis by implementing activation detection algorithms either through hardware using dedicated analog circuits or through software using digital technology. As long as there are no reliable quantitative criteria for activation detection in cardiac extracellular signals, a useful activation detection algorithm should at

REPRODUCIBILITY OF MAPPING the very least achieve optimum agreement with manual activation time assignments made by experienced electrophysiologists, which in the absence of more dependable information represent the de facto standard for electrogram analysis. Since the first description of an automatic activation detection algorithm using the criterion of maximum negative slope by Ideker et al.,56 numerous studies have investigated the performance of such algorithms under a variety of conditions. All studies employed databases of electrograms to which standard activation time assignments were made and/or verified by the investigators, either manually or aided by automatic or semiautomatic interactive detection algorithms. Important differences between the studies include (1) the algorithms under evaluation; (2) number and type of electrogram data (e.g., human intraoperative data, data from noninfarcted or infarcted canine models, unipolar or bipolar electrograms, endocardial or epicardial electrograms, regular rhythms or tachycardias); (3) the inclusion44 or exclusion40 of electrograms without detectable local activation; (4) contextdependent40,44,49,54 or context-independent analysis26,55 to build the reference database of activation time assignments; and (5) the use of the same49,54 or of an independent44 database of electrograms for evaluating the results of an optimization process. Automatic activation detection in unipolar electrograms

Nearly all activation detection algorithms for unipolar electrograms proceed according to the following logic: the program will search the electrogram for time instances with a negative slope that is lower than a certain threshold slope (slope criterion). If the slope criterion is met at more than one time instance within a specified time window, the time

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instance with the most negative slope is chosen as the time of local activation (time criterion). Differences between activation detection routines include the algorithm used for slope calculation, the threshold slope, the precise implementation of the time criterion, and the inclusion of other criteria. Slope Calculation: The ability of the available slope calculation algorithms (2-, 3- or 5-point Lagrange algorithms or data fit algorithms) to yield accurate estimates of slope in the analog waveform prior to A/D conversion is a function of many variables, including sample rate and resolution and the prevailing noise levels in the signal.57 Data fit algorithms act as a low-pass filters, which may be a useful property in the presence of excessive digitization or other noise.57 On the other hand, slope algorithms that in effect average slope over several milliseconds will hinder the sensitive detection of the brief minima of slope that occur in the course of an activation front, the width of which has been estimated to be between 0.235 and 2 ms.25 In a series of studies, Pieper et al.28 compared the effect of different slope algorithms on the performance of activation detection algorithms in unipolar electrograms. Three-point and 5-point Lagrange algorithms were the least susceptible to reductions in the sample rate from 2000 to 625 Hz and to random initiation of sampling. In a second study, Pieper et al.40 evaluated the effect of slope calculation algorithms on the temporal accuracy of automatic activation detection. The electrogram database included bipolar and unipolar recordings from a 119-pole epicardial sock electrode from 9 patients (5 with WPW syndrome, 4 with VT) recorded during sinus rhythm and ventricular pacing. Signals without detectable activation were excluded. Using manual reference annotations by 3 observers as a standard,

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detection errors were defined as differences in activation time of 10 ms or more. Activation detection based on the 5-point data fit, the 5-point Lagrange, and the 3point Lagrange algorithms had lower rates of detection errors than based on the 2-point algorithm, with error rates of 4.4%, 5.3%, 5.6% versus 7.0% in the WPW patients and 5.0%, 6.1%, 6.1% versus 7.8% in the VT patients.40 Masse49 compared the performance of activation detection algorithms for unipolar electrograms based on manual context-dependent activation time assignments in a database of 3452 epicardial and endocardial electrograms recorded from 8 patients with WPW syndrome and 13 patients with VT during sinus rhythm, stimulation, and tachycardias. With optimized slope thresholds, slope calculation by means of a 7-point differentiating filter with 60-Hz notch filter characteristics performed better than slope calculation with the 2-point algorithm only in case of signals with prominent 60-Hz noise, so that this approach was not recommended by the investigator.49 We evaluated activation detection algorithms for unipolar electrograms based on manual context-dependent activation time assignments in 6 recordings from a 240-pole sock electrode in 6 chronically infarcted dogs made during sinus rhythm (n = 2), ventricular pacing (n = 2), and VT (n = 2). At optimum parameters for both slope criterion and time criteria, slope calculation by the 3-point Lagrange algorithm yielded a minimum error rate of 6.2% versus 7.2% on slope calculation by the 2point algorithm. Slope calculation across wider time windows than 3 ms increased the activation detection error rate.44 Blanchard et al.58 found that a 17-point second-order data fit algorithm yielded the most stable determination of activation times in unipolar RV epicardial electrograms from dogs after the RV isolation

procedure. As that study excluded the problem of activation detection by means of a slope criterion, the relevance of the finding is, however, doubtful. Slope Thresholds: Most algorithms use a single "fixed" slope threshold that is uniform for all channels to distinguish between local and distant activation in unipolar electrograms. Fixed slope thresholds recommended in the literature range between -0.2 and 2.5 mV/ms, as has already been discussed in chapter 2. An alternative approach, first introduced by Witkowski and Corr59 for activation detection in bipolar electrograms, is the use of "statistical" thresholds that are calculated for each channel based on the distribution of slope values in that channel.49,54 Some activation detection algorithms dispense with slope thresholds altogether and simply search for the maximum absolute slope in the analysis window,60 which will however lead to an unacceptable rate of falsepositive activation time assignments in electrogram leads without discernible activation. While most of the evidence concerning optimal fixed slope thresholds has already been discussed in chapter 2, the following studies that published performance data on their algorithms deserve special mention. Masse et al.49,54 were the first to apply receiver operating characteristics (ROC) analysis to the performance evaluation of an activation detection algorithm. Optimum performance was defined as the point of equal sensitivity and positive predictive accuracy in detecting activation. Automatic signal analysis was rerun with a variety of different fixed and statistical threshold slopes. Optimum performance of the algorithm occurred at a fixed threshold slope of -0.2 mV/ms and a statistical threshold slope of mean -3 SD.54 With the first, the program made

REPRODUCIBILITY OF MAPPING a total of 1609 false detections (895 false negative, 714 false positive) out of 8050 activations, yielding a false detection rate of 20% or 0.45 false detections per second of electrogram data; with the latter, the program yielded very similar results, with 1605 detection errors (829 false negative, 776 false positive). We systematically evaluated the performance of activation detection algorithms for unipolar electrograms based on the aforementioned database of six 240-channel epicardial recordings from chronically infarcted dog hearts during sinus rhythm, ventricular pacing, and VT. A detection error was defined as a false-positive or false-negative detection of activation or a difference in activation times of more than 5 ms in respect to manual context-dependent activation time assignments by the investigators. The first version of the activation detector, which used a complicated statistical threshold slope algorithm, yielded error rates of 27% or higher nearly independent of the choice of threshold parameters, the main problem being false-positive detections of activation. We then modified the algorithm by introducing a fixed slope threshold. Instead of ROC analysis for a single parameter, a numerical optimization program was developed and applied to automatically search for the best combination of threshold and other parameters that resulted in the lowest number of detection errors in respect to the reference database of electrograms. Best performance of the algorithm was achieved using a 3-point Lagrange slope algorithm and at a fixed threshold slope of-1.8 mV/ms, yielding an error rate of 6.2% in respect to the database of 1440 electrograms used for the optimization and 9.6% (9.2% for sinus rhythm, 10.0% for pacing, 9.5% for VT) in respect to an independent database of 7200 electrograms. The latter error rate was of the

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same order of magnitude as the error rates between repeated context-dependent or -independent analyses by the same or by different observers (s.a.).44,61 Time Criteria: While Ideker et al. used the above-described time criterion with a time window width of 50 ms in which to search for the event with the absolute minimum of slope as the time point for the activation time assignment, Masse49 included a refractory period after each activation detection in their algorithm in which signal analysis was skipped. After systematically varying window widths between 40 and 200 ms and refractory periods between 80 and 200 ms, they found a time window of 160 ms and a refractory period of 80 ms optimal, though these settings had very little effect on overall program performance. Using a time criterion similar to Ideker's, we found a time window width of 15 ms optimal for analysis of ventricular pacing data as the program would otherwise ignore activations following stimulator spikes. For sinus rhythm and VT data, time windows between 20 and 60 ms were optimal. The effect of the time criterion was very limited, with an increase in error rate for all 3 rhythms from 6.2% to 8.1% with the least optimal time window setting.44 Additional Criteria: Pieper et al.62 suggested a criterion for the identification of noisy signal channels that calculates the SD of the signal from the mean in each channel, excluding times within ±30 ms of detected activation time and rejects the signal if the SD exceeds certain thresholds. In our above-mentioned study, we evaluated an amplitude threshold algorithm that would require electrograms to have a minimum nadir-to-peak amplitude for activation time assignments to be made.

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The additional amplitude criterion reduced error rates marginally from 6.2% to 5.1%. This was, however, most likely because of observer bias toward assigning activation times to electrograms with larger amplitudes in the electrogram database so that an amplitude criterion cannot be recommended on the basis of these results.44 This finding only applies to unipolar electrograms; an amplitude criterion did prove to be useful for preventing undesired activation time assignments to noisy low-amplitude signals in optical mapping (M. Biermann, unpublished observation). Likewise, filtering of signals did not improve the performance of the activation detection algorithm for unipolar signals,44 although filtering is often indispensable noise reduction in optical mapping signals. An algorithm that may significantly improve activation detection performance is linear interpolation across stimulus artifacts as is illustrated in Figure 3. Automatic activation detection in bipolar electrograms

While there is near universal agreement on using the criterion of maximum

negative slope for activation detection in unipolar electrograms, the criteria for activation detection in bipolar electrograms have been subject to debate. Suggested criteria include: (1) the maximum amplitude and the maximum absolute amplitude of the bipolar electrogram; (2) the maximum absolute slope of the bipolar electrogram; (3) the first elevation of the electrogram of more than 45° from the baseline (45°); (4) the baseline crossing with the steepest slope; and (5) morphological algorithms that search for the point of symmetry in the bipolar waveform. As the results of studies have already been discussed in chapter 2 and in the section on A/D conversion of electrograms in this chapter, it will suffice to cite only the most pertinent results. Paul et al.63 compared the results of activation detection in unipolar and bipolar electrograms recorded from a 41button sock electrode during sinus rhythm in 5 dogs. Activation detection by means of the maximum negative slope criterion in unipolar electrograms and by the peak and maximum absolute slope criteria in bipolar electrograms yielded very similar times of earliest epicardial activation

Figure 3. Improving automatic activation detection by interpolation across stimulus artifacts. Shown is an original epicardial electrogram (gray trace; ampfitude scale in mV, time scale in ms) recorded during unipolar epicardial stimulation from the surface of the canine left ventricle. Without interpolation, the activation detection algorithm fails to recognize the steep downstrokes of the electrogram at 47 and 347 ms as local activation of myocardium because the downstrokes of the preceding stimulus artifacts have a more negative slope. This can be avoided if the mapping program discards all samples in the trace recorded during stimulation and bridges the gap in signal by linear interpolation (solid trace).68

REPRODUCIBILITY OF MAPPING after the onset of the QRS complex of 7.9 ± 2.5 ms, 8.3 ± ms, and 9.5 ± 3.5 ms (differences not significant) and localized the first epicardial breakthrough to the same electrodes. Activation detection using the 45° criterion led to a significantly earlier activation time of-2.4 ± 1.7 ms and to a different apparent location of epicardial breakthrough.63 Using a database of 36 recordings from 119-pole sock electrode from 5 WPW syndrome and 4 VT patients during sinus rhythm and ventricular pacing, Pieper et al.40 compared the peak, baseline crossing with the steepest slope and maximum absolute slope criteria and a morphological algorithm that searched for the point of symmetry in the bipolar waveform in terms of consistency of agreement with manual context-dependent activation time assignments based on a baseline crossing with the steepest slope criterion. Electrograms without discernible activations were excluded. The morphological algorithm and the peak algorithms performed best with error rates (differences in activation times of 10 ms or more) of 1.7% and 3.0% in WPW patients and 6.2% and 6.2% in VT patients, respectively. The mean differences in activation times after the exclusion of detection errors ranged between 1.7 ± 1.6 ms (mean ± SD) and 2.1 ± 1.8 ms and were thus considered negligible. Simpson et al.64 repeatedly evaluated a complex morphological algorithm for activation detection in bipolar electrograms. In respect to a database of 49,717 activations during sinus rhythm and 61,174 activations during VF, the rate of false-positive detections with differences in activation times of 13 ms or more and false-negative detections was reported to be 23.5% for sinus rhythm and 51.6% for VF. In a second study, the authors optimized the threshold parameters of the program by means of ROC analysis aiming at maximum detection sensitivity. Using a database of 2808 electrograms (702 each

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during sinus rhythm and pacing and 1404 during VF; length of recording 200 ms) the program made false-negative detections in 1% in the sinus rhythm data and in 10% in the VF data, with false-positive detections occurring at a rate of 1.0 and 2.4 per second of electrogram data, respectively. Based on the length of the recordings of 200 ms, this would translate in false detection rates of 1 in 5 channels and 1 in 2 channels, respectively. As has been mentioned above, the detection error rates between activation time assignments by 3 different electrophysiologists were 0.05 and 0.8 errors per second for either rhythm, so that the agreement between different observers was significantly higher than between the program and the observers.55 Overall performance of detection algorithms

As can be seen from the above discussion, automatic activation detection in unipolar and bipolar electrograms is fraught with numerous difficulties, the most substantial of which is the lack of reliable quantitative criteria for detecting local activation and the susceptibility of detection programs to artifacts in the electrogram signals. A precise quantitative comparison between the studies that published performance data on the various algorithms is hindered by their use of different performance measures such as errors per activation or errors per data channel. Compared with manual activation time assignments made by electrophysiologists, a well-optimized activation detection program can nevertheless be expected to yield accurate activation detections in some 80% to 90% of all electrograms, depending on the underlying rhythm and the quality of the mapping data. At the present state of technology, automated activation detection algorithms can then serve the following purposes: (1) to help investigators focus their

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attention on the detailed analysis of signals in the region of interest during the near-online analysis of data in the course of a clinical study or an experiment, and (2) to make signal interpretation by observers more consistent and reduce observer mistakes. Unfortunately, due to the imperfections of the available algorithms it must still be considered necessary to review the raw electrogram data in all channels for the purpose of a scientific investigation.26,40,44,51 Map Generation and Interpretation of Activation Sequence The concluding steps in cardiac activation mapping are the generation of activation maps and the interpretation of the spatiotemporal activation sequence. As these steps are closely interrelated, they are discussed in the same section. Activation sequences can be presented in a variety of map formats. The simplest and most flexible format is that of a signal map, which displays sections of the original tracings with or without superimposed activation markers. Colorcoded activation maps represent activation times using a predefined color spectrum. Isochronal activation maps use isochrones connecting points with equal activation times, similar to contour lines connecting geographical points of equal elevation in a topographical map. Vector maps of activation encode activation sequences in the format of arrows, the length and direction of which encode the local apparent conduction velocity at each grid point of the map. Common to these mapping techniques are a number of assumptions that have been discussed in detail by Ideker et al.27 and Berbari et al.65: 1. The location of each recording site can be determined with acceptable accuracy. This assumption includes

both the accuracy of (re)localizing the recordings sites on the heart, which has been discussed above in respect to roving-probe mapping, and the accuracy of the 2-dimensional graphic display to represent the 3-dimensional spatial distribution of recording sites in their proper spatial relationship. If this first assumption is violated, maps may reveal spurious foci of activation.27,44 2. A single discrete activation time must exist at each recording site. This assumption is often violated in activation mapping if 2 activation fronts occur within the field of view of a recording electrode as during fractionated activity in peri-infarction zones or during fibrillatory rhythms, in which it may be conceptually difficult to divide the cardiac activation process into nonoverlapping sequences.27 3. Activation times from each recording site can be determined with acceptable accuracy.27 This assumption has been discussed in depth in the preceding sections, the necessary temporal accuracy being mainly a function of the prevailing conduction velocity and the required spatial accuracy. 4. The locations of the measurement sites must be sufficiently close together. The spatial accuracy required by a mapping study depends on its aim, e.g., to target a therapeutic intervention or to resolve the components of a reentrant circuit in an animal model. Some criteria can help decide whether the density of recording sites in the region of interest is sufficient to support the intended interpretation of the activation sequence. A simple criterion is the comparison of the lesion size of the intended therapeutic intervention such as operative resection,

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Figure 4. Isochronal mapping of one cardiac cycle during normal sinus rhythm using either each electrode (upper panel) or every second electrode (lower panel). See text for details.

cryo-, high-frequency, or laser ablation lesions with the density of recording sites during the mapping procedure. Another criterion is to decide whether the conclusions drawn from an activation map can still be supported after redrawing the map with a reduced number of recording sites.27 Figures 4 and 5 show epi-

cardial maps recorded from a chronically infarcted dog heart with a 240pole sock electrode during sinus rhythm and during figure-of-8 VT. Whereas the information on epicardial breakthrough sites, the infarction zone in the anterior wall, and latest epicardial activation is preserved in the sinus rhythm maps

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Figure 5. Isochronal mapping of one cycle of induced ventricular tachycardia using epicardial mapping data based on all electrodes (upper panel) and a reduced electrode density (every second electrode, lower panel). The presumed reentry pathway in the upper panel seems to represent a figure-of-8 pattern, whereas with a reduced electrode density any speculations about the pattern of reentry are impossible (lower panel).

REPRODUCIBILITY OF MAPPING both at full and at 50% reduced electrode density (Figure 4), suggesting that the density of recording sites was adequate, the figure-of-8 VT appears to have a focal point of origin at 50% reduced electrode density (Figure 5), indicating that electrode density is marginal for the intended interpretation of a reentrant pattern. However, neither criterion suffices to assure the completeness of a map, as is illustrated in a high-density epicardial plaque electrode recording during VT in Figure 6. Despite the nearly identical activation pattern at either recording site density, both maps are incomplete as the cardiac cycle is insufficiently depicted. 5. Isochrone-generation algorithms assume that the surface to be mapped is continuous and locally autocorrelated, i.e., that any value on the surface can be found by interpolation between neighboring measurement points; however, these assumptions are violated if wavefronts break through from below or terminate abruptly in an infarction zone.65 Ambiguities arise especially in case of locally varying conduction velocities and in the distinction between very slow conduction and conduction block. One step toward resolving at least some of these ambiguities would be the application of more advanced contour drawing algorithms that would not interpolate activation times across regions without detectable activation and across regions of conduction block.65 Map formats that obviate the need for at least some of these assumptions include potential maps, which display the spatial distribution of potential either in

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a color-coded format or through isopotential lines, and derivative maps,66 which similarly encode the first derivative of potential. A disadvantage of potential maps and derivative maps is that a sequence of maps is needed to display a single activation sequence, which is the reason why activation maps are still the most popular format for the purpose of printed documentation. If displayed as a movie sequence on a computer screen, they allow a very quick visual assessment of the underlying activation pattern without a need for indepth signal analysis, a technique that was first used by Parson et al.67 in their analog intraoperative mapping system.

Conclusion

Many ambiguities exist in the interpretation of electrogram signals, the limiting factor being the lack of precise quantitative criteria for identifying local activation of myocardium in extracellular signals. Thus, despite major advances in signal processing and computing technology, the effective gold standard for the interpretation of extracellular signals remains their visual analysis by the trained observer, which takes into account clinical or experimental information and the context of the neighboring signals. We believe that in addition to more quantitative pathophysiological information on local and far-field effects in extracellular signals, a major element in the quest to improve reproducibility and reliability of electrogram analysis by human observers will be the development of more intuitive and less restrictive user interfaces, which allow multiple simultaneous user-definable views on the mapping data in conjunction with more flexible options for annotating the data, as is illustrated in Figure 7.

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Figure 6. High-density electrode array recording from the anterior wall of a chronically infarcted canine heart with activation maps based on 100% and 50% electrode density. Despite almost identical activation pattern, both maps are incomplete as the cardiac cycle is insufficiently depicted.

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Figur e 7. Multimoda l signa l analysi s with athird-generatio n mappin g program . Signal analysi s can bemad emor econsisten atn d ma pgenerao ti nca n b esimplifie dthroug h mappni gsoftwar etha a t low s multipl e simultaneou s view s o fth e dat a in avariet yo format f s in a nonmoda l graphi c interface . The screensho t shows "Universa l Mapping, " the f i rts author's mappni g program f o r viewin g and annotatin g unipola r an d bipola r electrogra m and optica l mappn i g data . Simultaneou s windows displa y a ma po fal l signal s (right) , an enlarge dvie wo th f ecurrentl yselecte dtrac e (righ tbottom) , an enlarge d view of th e neighborin g traces ("close-up " window), color-coded map(s ) fo activatio n and/or repolarizatio n times ("color maps") , a movin g dsi pa l y of potentia l rofirs t derivativ e of potentia l ("movie " window) , ad n contour map s of activatio n or repolarizatio n times , action potentia l durations , potential or firs t derivativ e of potentia l ("contour " window ; shown si an isoderivativ e map of th e ventricual r tachycardi a ta the time fo f i r st epicardia l breakthrough) . A mouse click on an y data channe l n i an ywindo wwil l shif th t efocu st oth e n i tende d channel , an d an ychang et oth eannotatio n ofa signa l channel such as a different activation time assignment will instantly be reflected in all other windows.68

Lewi s , T Rothschil d MA. eTh excitator y p r o c ess ni t eh dog's h e a. r tPta rII. Th e ventricles . Philos Trans R Soc LondBBiol 1.B l a JM nd A,l t m aDnG Statistica . ml e t h Sci 191250;168:12-6 . f ods o assessin r a g rge e m ebne ttw e et w n o 5.D u r D r re Roo , JPs Epicardia . excitatio l n m e t h o sd f clinica o l m e a s u r e. m e Lancet nt of the ventricles in a patient with Wolff19863;33:073-10 . P a r k i n s o n - Weh si ty n d r oem( t y pe B) . Cir2. Altman DG. PracticalStatistics for Medical culation 215-35:1967; . Research.London : Chapma nan H dal 1;991 . 6. Fontain G e Guiraudon , G Fran , Rk e, alt . 3. Gallaghe r JJ , Kasell J, Sealy W C, et al. Epicardia lmappin gan dsurgica lt r e a t m e nt Epicardial mapping in the Wolffinis xcase soresistan f ventricula t tachy r Parkinson-White syndrome. Circulation cardi no arelate t t cdoornaro artery easdi y . 1978;57:854-866.

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16. Yoshida Y, Hirai M, Murakami Y, et al. Localization of precise origin of idiopathic ventricular tachycardia from the right ventricular outflow tract by a 12lead ECG:A study of pace mapping using a multielectrode "basket" catheter. Pacing Clin Electrophysiol 1999;22:17601768. 17. Scaglione M, Riccardi R, Calo L, et al. Typical atrial flutter ablation: Conduction across the posterior region of the inferior vena cava orifice may mimic unidirectional isthmus block. J Cardiovasc Electrophysiol 2000;11:387-395. 18. Zrenner B, Ndrepepa G, Schneider MA, et al. Mapping and ablation of atrial arrhythmias after surgical correction of congenital heart disease guided by a 64electrode basket catheter. Am J Cardiol 2001;88:573-578. 19. Gepstein L, Hayam G, Ben Haim SA. A novel method for nonfluoroscopic catheterbased electroanatomical mapping of the heart. In vitro and in vivo accuracy results. Circulation 1997;95:1611-1622. 20. Gepstein L, Evans SJ. Electroanatomical mapping of the heart: Basic concepts and implications for the treatment of cardiac arrhythmias. Pacing Clin Electrophysiol 1998;21:1268-1278. 21. Weiss C, Willems S, Rueppel R, et al. Electroanatomical mapping (CARTO) of ectopic atrial tachycardia: Impact of bipolar and unipolar local electrogram annotation for localization the focal origin. JInterv Card Electrophysiol 2001;5:101-107. 22. Yano K, Keida T, Suzuki K, et al. Catheter ablation of idiopathic left ventricular tachycardia with multiple breakthrough sites guided by an electroanatomical mapping system. JInterv Card Electrophysiol 2001;5:211-214. 23. Gornick CC, Adler SW, Pederson B, et al. Validation of a new noncontact catheter system for electroanatomic mapping of left ventricular endocardium. Circulation 1999; 99:829-835. 24. Schilling RJ, Peters NS, Davies DW. Simultaneous endocardial mapping in the human left ventricle using a noncontact catheter: Comparison of contact and reconstructed electrograms during sinus rhythm. Circulation 1998;98:887898. 25. Roberts DE, Hersh LT, Scher AM. Influence of cardiac fiber orientation on wavefront voltage, conduction velocity, and

REPRODUCIBILITY OF MAPPING 185 tissue resistivity in the dog. Circ Res 1979;44:701-712. 26. Rosenbaum DS, Kaplan DT, Wilber DJ, et al. The precision of electrophysiological mapping: Localizing depolarization wave fronts from digital extracellular electrograms and the role of data sampling rate. J Cardiovasc Electrophysiol 1990;1: 2-14. 27. Ideker RE, Smith WM, Blanchard SM, et al. The assumptions of isochronal cardiac mapping. Pacing Clin Electrophysiol 1989;12:456-478. 28. Pieper CF, Blue R, Pacifico A. Influence of time of sampling onset on parameters used for activation time determination in computerized intraoperative mapping. Pacing Clin Electrophysiol 1991;14:21872192. 29. Bardy GH, Smith WM, Ungerleider RM, et al. Identification of reproducible ventricular tachycardia in a canine model. AmJCardiol 1984;53:619-625. 30. Abendroth RR, Ostermeyer J, Breithardt G, et al. Reproducibility of local activation times during intraoperative epicardial mapping. Circulation 1980;62:75-79. 31. Hoeks APG, Schmitz GML, Allessie MA, et al. Multichannel storage and display system to record the electrical activity of the heart. Med Biol Eng Comput 1988;26: 434-438. 32. Breithardt G, Shenasa M, Biermann M, et al. Precision and reproducibility of isochronal electrical cardiac mapping. In: Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping. Mount Kisco, New York: Futura Publishing Co.; 1993: 35-49. 33. Branyas NA, Cain ME, Cox JL, Cassidy DM. Transmural ventricular activation during consecutive cycles of sustained ventricular tachycardia associated with coronary artery disease. Am J Cardiol 1990;65:861-867. 34. Franz MR. Method and theory of monophasic action potential recording. Prog Cardiovasc Dis 1991;33:347-368. 35. Witkowski FX, Penkoske PA, Kavanagh KM. Mapping of ventricular fibrillation: Technical considerations. In: Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping. Mount Kisco, New York: Futura Publishing Co.; 1993:79-84. 36. Green LS, Taccardi B, Ershler PR, Lux RL. Epicardial potential mapping: Effects of conducting media on isopotential and iso-

chrone distributions. Circulation 1991;84: 2513-2521. 37. Durrer D, Van der Tweel LH. Excitation of the left ventricular wall of the dog and goat. Ann N YAcad Sci 1957;65:779-803. 38. Gallagher JJ, Kasell JH, Cox JL, et al. Techniques of intraoperative electrophysiologic mapping. Am J Cardiol 1982; 49:221-240. 39. Wit AL, Josephson ME. Fractionated electrograms and continuous activity: Fact or artifact. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology and Arrhythmias. Orlando: Grune & Stratton, Inc.; 1985:343352. 40. Pieper CF, Blue R, Pacifico A. Activation time detection algorithms used in computerized intraoperative cardiac mapping: A comparison with manually determined activation times. J Cardiovasc Electrophysiol 1991;2:388-397. 41. De Bakker JMT, Van Capelle FJL, Janse MJ, et al. Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: Electrophysiologic and anatomic correlation. Circulation 1988;77:589-606. 42. Blomstrom P, Blomstrom-Lundqvist C, Berglin-William-Olson E, Olson SB. The variability and reproducibility of atrial and ventricular activation times during cardiac mapping. New Trends Arrhythmias 1989;5:9-18. 43. Cowan JC, Griffiths CJ, Hilton CJ, et al. Epicardial repolarisation mapping in man. Eur Heart J 1987;8:952-964. 44. Biermann M. Die Reproduzierbarkeit des kardialen elektrophysiologischen Mappings. Untersuchungen uber die manuelle und automatische Auswertung unipolarer Elektrogramme. Munster: Westfalische Wilhelms-Universitat Munster; 1994. 45. Barr RC, Spach MS. Sampling rates required for digital recording of intracellular and extracellular cardiac potentials. Circulation 1977;55:40-48. 46. Pieper CF, Lawrie G, Roberts R, Pacifico A. Bandwidth-induced errors in parameters used for automated activation time determination during computerized intraoperative cardiac mapping: Theoretical limits. Pacing Clin Electrophysiol 1991;14: 214-226. 47. Blanchard SM, Barr RC. Comparison of methods for adaptive sampling of cardiac electrograms and electrocardiograms. Med Biol Eng Comput 1985;23:377-386.

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48. Kaplan DT, Smith JM, Rosenbaum D, Cohen RJ. On the precision of automated activation time estimation. Comput Cardiol 1988:101-104. 49. Masse S. Detection optimale des temps d'activation d'electrogrammes epicardiques et endocardiques chez I'homme. Universite de Montreal, 1989. 50. Pieper CF, Parsons D, Lawrie GM, et al. Design and implementation of a new computerized system for intraoperative cardiac mapping: Experience during surgery. JApplPhysiol 1991;71:1529-1539. 51. Ideker RE, Smith WM, Wolf P, et al. Simultaneous multichannel cardiac mapping systems. Pacing Clin Electrophysiol 1987;10:281-292. 52. Page PL, Cardinal R, Savard P. Sinus rhythm mapping in a canine model of ventricular tachycardia. Pacing Clin Electrophysiol 1988;11:632-644. 53. Anderson KP, Walker R, Ershler PR, et al. Determination of local myocardial electrical activation for activation sequence mapping. A statistical approach. Circ Res 1991;69:898. 54. Masse S, Savard P, Shenasa M, et al. Performance of the automatic detection of local activation times on unipolar cardiac electrograms in man. IEEE Eng Med Biol 1988; 10th Ann. Int. Conf.:112. 55. Simpson EV, Ideker RE, Cabo C, et al. Evaluation of an automatic cardiac activation detector for bipolar electrograms. Med Biol Eng Comput 1993;31:118-128. 56. Ideker RE, Smith WM, Wallace AG, et al. A computerized method for the rapid display of ventricular activation during the intraoperative study of arrhythmias. Circulation 1979;59:449-458. 57. Marble AE, Mclntyre CM, HastingsJames R, Hor CW. A comparison of digital algorithms used in computing the derivative of left ventricular pressure. IEEE Trans Biomed Eng 1981;28:24-529. 58. Blanchard SM, Smith WM, Damiano RJ, et al. Four digital algorithms for activa-

tion detection from unipolar epicardial electrograms. IEEE Trans Biomed Eng 1989;36:256-261. 59. Witkowski FX, Corr PB. An automated simultaneous transmural cardiac mapping system. Am J Physiol 1984;247: H661-H668. 60. De Bakker JMT, Janse MJ, Van Capelle FJL, Durrer D. An interactive computer system for guiding the surgical treatment of life-threatening ventricular tachycardias. IEEE Trans Biomed Eng 1984;31: 362-368. 61. Biermann M, Shenasa M, Haverkamp W, et al. Improving automatic activation detection in epicardial electrograms by numerical optimization. Eur Heart J1994; 15(Suppl):212. 62. Pieper CF, Glenn P, Parsons D, Pacifico A. Current source density electrode array improves spatial resolution for intraoperative mapping. Pacing Clin Electrophysiol 1991;14:711. Abstract 63. Paul T, Moak JP, Morris C, Garson A. Epicardial mapping: How to measure local activation? Pacing Clin Electrophysiol 1990;13:285-292. 64. Simpson EV, Ideker R, Smith WM. An automatic activation detector for bipolar cardiac electrograms. IEEE Eng Med Biol 1988; 10th Ann. Int. Conf.: 113-114. 65. Berbari EJ, Lander P, Scherlag BJ, et al. Ambiguities of epicardial mapping. JElectrocardiol 1991;24:16-20. 66. Ershler PR, Lux RL. Derivative mapping in the study of activation sequence during ventricular tachyarrhythmias. Comput Cardiol 1987:623-624. 67. Parson I, Mendler P, Downar E. On-line cardiac mapping: An analog approach using video and multiplexing techniques. Am J Physiol 1982;242:H526-H535. 68. Biermann M, Zipes DP. A new mappingsystem independent analysis program for extracellular electrograms and optical action potentials. Eur Heart J 1997; 18: 38A. Abstract.

Chapter 9

The Ideal Cardiac Mapping System Raymond E. Ideker, MD, PhD, Patrick D. Wolf PhD, Edward Simpson, MS, Eric E. Johnson, MD, Susan M. Blanchard, PhD, and William M. Smith, PhD

This chapter was written for the first edition of this book. It deals almost exclusively with electrical mapping systems. Many techniques that were predicted to improve cardiac mapping systems by the turn of the century have not been implemented. Examples include the ability to record action potentials and ion concentrations from tens of thousands of sites transmurally. While optical mapping techniques can record these variables from numerous sites on the epicardium or endocardium,1 attempts are just beginning to obtain optical recordings transmurally.2,3 Another of our projections that was overly optimistic was the number of electrodes from which simultaneous recordings would be made. We estimated this number to be 3000 by 1995 and 30,000 by 2000. In 2002, the largest operational electrical mapping system of which we are aware can record from approximately 1700 electrodes simultaneously. In this

area also, greater strides have been made in optical than in electrical mapping. Optical mapping systems that utilize charge coupled devices can record from more than 100,000 locations.4 One prediction that has been fulfilled is the automatic detection of activations and the identification and quantification of activation fronts.5 While the ideal cardiac mapping system is not yet available, we remain optimistic that many of the capabilities discussed in this chapter will become available in the foreseeable future. When the editors asked us to discuss the ideal cardiac mapping system, we were delighted because it meant we could have the fun of imagining what such a mapping system should do without having to put forth the effort of actually trying to build it. If technology continues to advance at its present rate, we believe that most of the features of the ideal mapping system we will describe can be

This work is supported in part by the National Institutes of Health research grants HL-28429, HL-33637, HL-42760, HL-44066, and HL-40092; and the National Science Foundation Engineering Research Center grant CDR-8622201 From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; c2003. 187

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implemented by the end of the century. channels feasible around the turn of the Any exceptions will be specifically noted. century, using commercially available comIn the short term, the ideal mapping ponents. Simultaneous recordings from system is easy to describe. It is the same 30,000 electrodes will allow the entire epidescription that we imagine Moe, Harris, cardium to be mapped with electrodes less and Wiggers6 would have given after con- than 2 mm apart or will allow the epistructing their 3-channel string gal- cardium or endocardium bordering an vanometer mapping system in 1941, that infarct to be mapped with a plaque greater we would have given 15 years ago when than 16 cm2 containing electrodes 25 um we built our first 32-channel mapping apart. Such close electrode spacing would system,7 and that we would give now just alleviate much of the uncertainty involved after completing our 528-channel map- with interpolation between more widely ping system.8 The ideal mapping system spaced electrodes; it would provide less is the one that has just a few more elec- ambiguous information about complex actitrodes and that can process the data just vation sequences that occur during fibrillaa little faster than the mapping system tion10,11 and during fractionated activation you now have. Everyone who has ever through regions of patchy infarctions.12 mapped has had the experience of wishThe use of thousands of electrodes ing they had electrodes in some part of will require us to change the way in which the heart where they do not have any or the recordings are processed. It will no wishing they had electrodes more closely longer be possible to inspect all electrospaced in the region where something grams manually to verify that a single particularly interesting looks like it might activation time has been properly selected for each beat of each electrode recording.13 be happening.9 Long-term changes are difficult to If 1 second is necessary to verify a single predict because it is impossible to foresee activation in a single channel, then the what technological breakthroughs will analysis of a single beat will require about occur in the meantime. If we ignore these 1 hour for 3000 electrodes and about 1 day possible breakthroughs and just extrapo- for 30,000 electrodes. Most of the processes late using current rates of improvements of data analysis and display will have to in processor speeds and storage capabili- be automated to make practical the use of ties, the possibilities are still very exciting. a 3000- or 30,000- channel mapping system. In the long term, we think the number of Instead of static pictures of isochronal electrodes will continue to increase. From maps, animations of the recorded poten1940 to 1980 the number of electrodes tials or the temporal or spatial derivatives increased by an order of magnitude from of the potentials will probably be dis3 to approximately 30, while from 1980 played as shown in Figure 1.14,15 These to 1990 they increased another order of two types of displays have the advantage magnitude to approximately 300. We pre- that they show all of the recorded data or dict that within a few years, the number a transform of the data, while isochronal of electrodes will increase another order of maps show only a single time point during magnitude to approximately 3000. Yet each complex.16 For example, during a another order of magnitude larger in the single cycle of an arrhythmia, a tracing number of electrodes, 30,000, would be may contain 2 complexes (Figure 1), while desirable. Processors and buses continue an isochronal map would display only the to get faster and data storage devices con- time of the fastest unipolar downslope. tinue to increase in capacity at a rate of An animation of the spatial derivatives of progress that should make this many the potentials will show both complexes.

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Figure 1. Selected frames of an animated computer display of the temporal derivative of the potentials for 121 simultaneously recorded electrodes during one cycle of ventricular fibrillation in a pig. The electrodes are in an 11 x 11 grid with an interelectrode distance of 280 um. The colors represent the derivative of the potential in units of volts per second as indicated by the scales at the bottom of the figure. One electrode recording was inadequate because the electrode wire was broken; the black square in each frame represents this electrode. The vertical line in the tracing below each frame, recorded from one electrode, indicates the time of each frame. The location of this electrode is indicated by the arrow in frames A and E. The first complex in the electrode recording arises from an activation front that enters the upper left corner of the grid and then blocks about one third of the way across the grid (frames A through D). The second complex arises from activation of the remainder of the grid by 2 fronts that enter the lower left and upper right corners of the grid and then collide (frames E through H). See color appendix.

Sock and plaque electrode arrays containing thousands of electrodes will probably be constructed using microelectronic techniques.17 Connectors containing hundreds or thousands of contacts will be necessary to connect such electrode arrays to the data acquisition system because the use of smaller connectors will be impractical. For example, 1200 DB25 connectors would be required for 30,000 unipolar electrodes. With 30,000 channels, the technology for placing the electrodes, rather than the mapping system, will become the limiting

factor. A 30,000-channel mapping system would provide enough electrodes so that the entire 3-dimensional volume of the ventricle could be mapped with 6000 plunge electrodes either 2 mm or 3 mm apart and with electrodes spaced every 2 mm along each plunge needle. However, insertion of 6000 plunge needles into the heart is probably impractical, even if the electrodes are made very small, light, and flexible using microelectronic techniques and the insertion technique involves inserting many plunge needles as a unit simultaneously. It is likely that some of

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these needles would pierce small arteries, causing ischemia and altering intrinsic cardiac electrical properties. An alternative method for determining the 3-dimensional patterns of cardiac electrical activity is to solve an inverse volume conductor problem similar in some respects to the inverse problem of electrocardiography in which epicardial potentials are estimated numerically from body surface potentials.18 This form of the inverse problem of electrocardiography has a unique solution because all of the electrical sources are contained within the epicardium so that no sources are within the volume bordered by the body surface and the epicardium. For the inverse problem, we are proposing that the potentials recorded from the epicardium and endocardium, as well as from some intramyocardial electrodes on plunge needles, would be used to calculate the potential distribution throughout the heart volume. This inverse problem is much more difficult than the inverse problem of electrocardiography previously mentioned because electrical sources exist and must be identified within the heart volume. This inverse problem does not have a unique solution and we do not know whether a feasible solution is possible. A major problem with acquiring thousands of channels of signals is the analysis and comprehension of a huge amount of data. The ideal mapping system should be capable of displaying the data in a form in which the information can be readily grasped. This will probably entail animated 3-dimensional graphic displays of all or of a part of the heart that can be rotated or sliced through at any desired angle (Figure 2.15 Ideally, such displays should be available almost immediately after the data are recorded. Data acquisition should be continuous through the time the electrodes are in place so that any event of interest will be captured.9 Real time analysis of the data

should be possible so that certain interventions, such as delivering a shock, will be possible when a particular set of predefined criteria occurs. To minimize noise, the initial amplification stage of the ideal mapping system should be as close as possible to the recording site, possibly on the electrode apparatus itself.19 Digitization, data compression, and some analysis may also be performed at this site to decrease storage and computational requirements of the external mapping system. Multiplexing of these data will decrease the number of connectors referred to previously. It should be able to verify that each electrode recording is adequate, for example by monitoring electrode impedance and noise levels. The mapping system should be able to identify the location of each electrode and how it moves throughout the cardiac cycle, possibly by ultrasonic crystals attached to the electrodes or by impedance imaging.20 The ideal mapping system should be able to record the potentials generated by pacemakers and defibrillators and to calculate the potential gradient of the electrical stimuli at each electrode.21 Besides the times of activation, the mapping system should also be able to determine other cardiac electrophysiologic variables,22 such as the action potential duration and the refractory period of the tissue adjacent to each electrode.23 It should also be able to determine the transmembrane potential at each electrode, perhaps by using either optical mapping24 or small monophasic action potential electrodes.25 It should be able to pace or ablate from any recording electrodes. The ideal mapping system should also be able to measure nonelectrophysiological variables such as sodium, potassium, and calcium concentrations, pH, and oxygen levels.26 It should also be able to determine certain anatomical features, such as whether the electrode is in viable

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Figure 2. Potentials generated throughout a canine heart by a defibrillation shock. A representation of a cut volume of the heart is shown in which each cube corresponds to a 2 mm x 2 mm x 2 mm block of myocardial tissue and is colored to indicate potential in that block. The most negative potentials are indicated by violet and the most positive are indicated by orange. Heart geometry was obtained by magnetic resonance imaging. The depth of the cut plane can be varied interactively by the investigator along any of the 3 axes. The cubes containing Xs indicate the locations of those recording electrodes exposed in this cut plane. Values in the other cubes are obtained by interpolation. See color appendix.

myocardium, old infarct scar, or acutely necrotic tissue, thus allowing identification of the location and extent of infarction.27 The ideal mapping system should be small, inexpensive, easy to use, and self calibrating. With a few exceptions,28-30 multichannel computer-assisted mapping studies have been performed by placing electrodes acutely in patients or animals who are under general anesthesia and have their chests open. Electrodes should be developed that can be introduced into a ventricular cavity via a percutaneously

inserted catheter and that can record from many known sites on the endocardium simultaneously.31 Such an electrode array would probably lead to improved ablative therapy for ventricular tachycardia and might allow the development of ablative techniques to treat those patients with recurrent ventricular fibrillation in whom the first cycle of the arrhythmia arises from the same cardiac region during different episodes of fibrillation. Much exciting progress has been made in developing animal models of sudden cardiac death.32-35 Multichannel mapping

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tropically and is guided by fiber orientasystems using chronically implanted election in guinea pig hearts. Circ Res 1995; trodes and telemetry are needed so that 77:784-802. the mechanism of the spontaneous onset 4. Baxter WT, Davidenko JM, Loew LM, of arrhythmias can be investigated in conet al. Technical features of a CCD video scious, unfettered animals. camera system to record cardiac fluorescence data. Ann Biomed Eng 1997;25: Thus, taking a broad view, we think 713-725. the ideal mapping system could (1) record 5. Huang J, Rogers JM, KenKnight BH, cardiac electrical activity, potential graet al. Evolution of the organization of dients created by defibrillation shocks, epicardial activation patterns during transmembrane potentials, action potenventricular fibrillation. J Cardiac Electrophysiol 1998;9:1291-1304. tial durations, refractory periods, ion con6. Moe GK, Harris AS, Wiggers CJ. Analycentrations, and tissue health (i.e., normal sis of the initiation of fibrillation by elecand infarcted), simultaneously and contrographic studies. Am J Physiol 1941; tinuously from 30,000 electrodes; (2) 134:473-492. determine electrode locations and the 7. Ideker RE, Smith WM, Wallace AG, et al. A computerized method for the rapid disadequacy of electrode recordings; and (3) play of ventricular activation during the display the results in an animated 3intraoperative study of arrhythmias. Cirdimensional display almost immediately culation 1979;59:449-458. after the data are acquired. We would be 8. Wolf PD, Rollins DL, Blitchington TF, interested in borrowing such a mapping et al. Design for a 512 channel cardiac mapping system. In: Mikulecky DC, Clarke AM system as soon as someone builds it. (eds): Biomedical Engineering: Opening Taking a more practical view, the New Doors. Proceedings of the Fall 1990 ideal mapping system is the one that Annual Meeting of the Biomedical Engiaccomplishes the job at hand. The ideal neering Society. New York: New York Uniclinical mapping system may be different versity Press; 1990: 5-13. than the ideal experimental mapping 9. Ideker RE, Smith WM, Wolf PD, et al. Simultaneous multichannel cardiac mapsystem. In the final analysis, the ideal ping systems. Pacing Clin Electrophysiol mapping system is the system that effi1987;10:281-292. ciently obtains the diagnosis, identifies 10. Witkowski FX, Penkoske PA. Activation the region, or tests the experimental patterns during ventricular fibrillation. In: Jalife J (ed): Ann. N YAcad Sci, V. 591, hypothesis that one is interested in, even Mathematical Approaches to Cardiac if it only requires recording a single cycle Arrhythmias. New York: The New York from a single electrode. Academy of Sciences; 1990:219-231.

References 1. Girouard SD, Laurita KR, Rosenbaum DS. Unique properties of cardiac action potentials recorded with voltage-sensitive dyes. J Cardiac Electrophysiol 1996;7: 1024-1038. 2. Baxter WT, Pertsov A, Berenfeld 0, et al. Demonstration of three-dimensional reentry in isolated sheep right ventricle. Pacing Clin Electrophysiol 1997;20:1080. Abstract. 3. Kanai A, Salama G. Optical mapping reveals that repolarization spreads aniso-

11. Johnson EE, Idriss SF, Melnick SB, et al. Conduction block during ventricular fibrillation in pigs mapped with closely spaced electrodes. Circulation 1991;84: 11-499. Abstract. 12. Gardner PI, Ursell PC, Fenoglio JJ Jr., et al. Electrophysiologic and anatomic basis for fractionated electrograms recorded from healed myocardial infarcts. Circulation 1985;72:596-611. 13. Smith WM, Ideker RE. Computer techniques for epicardial and endocardial mapping. Prog Cardiovasc Dis 1983;26:15-32. 14. Ershler PR, Lux RL. Derivative mapping in the study of activation sequence during ventricular tachyarrhythmias. In: Ripley KL (ed): Proc. Comput Cardiol. Washington, DC:

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IEEE Computer Society Press; 1986: 26. Richards DA, Cody DV, Denniss AR, et al. Ventricular electrical instability: A pre623-624. dictor of death after myocardial infarc15. Palmer TC, Simpson EV, Kavanagh KM, tion. Am J Cardiol 1982;51:75-80. et al. Visualization of bioelectric phenomena. CRCCrit Rev Biomed Eng 1992; 20:355-372. 27. Cabo C, Wharton JM, Wolf PD, et al. Activation in unipolar cardiac electrograms: 16. Ideker RE, Smith WM, Blanchard SM, A frequency analysis. IEEE Trans Biomed et al. The assumptions of isochronal carEng 1990;37:500-508. diac mapping. Pacing Clin Electrophysiol 28. Spach MS, Barr RC. Ventricular intra1989;12:456-478. mural and epicardial potential distribu17. Mastrototaro JJ, Massoud HZ, Pilkington tions during ventricular activation and TC, et al. Rigid and flexible thin-film mulrepolarization in the intact dog. Circ Res tielectrode arrays for transmural cardiac 197 5;37-.243-257. recording. IEEE Trans Biomed Eng 1992; 29. Spach MS, Barr RC. Analysis of ventric39:271-279. ular activation and repolarization from 18. Rudy Y, Messinger-Rapport BJ. The inverse intramural and epicardial potential disproblem in electrocardiography: Solutions tributions for ectopic beats in the intact in terms of epicardial potentials. CRC Crit dog. Circ Res 1975;37:830-843. Rev Biomed Eng 1988; 16:215-268. 19. Wise KD, Najafi K. Microfabrication tech- 30. Spach MS, Barr RC, Lanning CF, et al. Origin of body surface QRS and T wave niques for integrated sensors and microsystems. Science 1991;254:1335-1342. potentials from epicardial potential distributions in the intact chimpanzee. Cir20. Wolf PD, Smith WM, Pilkington TC. culation 1977;55:268-278. Determination of cardiac geometry from impedance measurements. In: Kim Y, 31. Taccardi B, Arisi G, Macchi E, et al. A new intracavitary probe for detecting the Spelman FA (eds): Proc Annu Int Conf site of origin of ectopic ventricular beats IEEE Eng Med Biol Soc Piscataway, NJ: during one cardiac cycle. Circulation 1987; Institute of Electrical and Electronics Engineers, Inc.; 1989:1239-1240. 75:272-281. 21. Wolf PD, Rollins DL, Smith WM, et al. A 32. Schwartz PJ, Billman GE, Stone HL. Autonomic mechanisms in ventricular cardiac mapping system for the quantifibrillation induced by myocardial tative study of internal defibrillation. In: Harris G, Walker C (eds): Proc Annu ischemia during exercise in dogs with healed myocardial infarction: An experInt Conf IEEE Eng Med Biol Soc Piscataway, NJ: Institute of Electrical and imental preparation for sudden cardiac death. Circulation 1984;69:790-800. Electronics Engineers, Inc.; 1988:217-218. 22. Simpson EV, Ideker RE, Cabo C, et al. 33. Parker GW, Michael LH, Entman ML. An Evaluation of an automatic cardiac actianimal model to examine the response to vation detector for bipolar electrograms. environmental stress as a factor in Med Biol Eng Comput 1993;31:118-128. sudden cardiac death. Am J Cardiol 1987;60:9J-14J. 23. Haws CW, Lux RL. Correlation between in vivo transmembrane action potential 34. Patterson E, Holland K, Eller BT, et al. durations and activation-recovery interVentricular fibrillation resulting from vals from electrograms: Effects of interischemia at a site remote from previous ventions that alter repolarization time. myocardial infarction. A conscious canine Circulation 1990;81:281-288. model of sudden coronary death. Am J 24. Dillon S, Morad M. A new laser scanning Cardiol 1982;50:1414-1423. system for measuring action potential 35. Li HG, Jones DL, Yee R, et al. Electropropagation in the heart. Science 1981; physiologic substrates associated with 214:453-456. pacing-induced heart failure in dogs: 25. Franz MR. Method and theory of monoPotential value of programmed stimulaphasic action potential recording. Prog tion in predicting sudden death. J Am Coll Cardiouasc Dis 1991;33:347-368. Cardiol 1992; 19:444-449.

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Part 3 Mapping in Experimental Models of Cardiac Arrhythmias

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Chapter 10 The Role of Myocardial Architecture and Anisotropy as a Cause of Ventricular Arrhythmias in Pathological States Nicholas S. Peters, MD and Andrew L. Wit, PhD

It has been recognized that abnormalities in conduction of the cardiac impulse are an important cause of arrhythmias since Mayer1 and Mines2 performed their classic experiments on circulating excitation in rings of excitable tissue. These investigators showed the important relationships between the conduction velocity, path length, and recovery of excitability that are the prerequisites for reentrant excitation. The reentrant impulse must continuously encounter excitable tissue as it propagates through the reentrant pathway. Regions of this pathway that have already been excited must have adequate time to recover before they can be excited again. This adequate time is often provided by slower than normal conduction of the reentrant impulse in part or all of the pathway.3 Conduction of the cardiac impulse is dependent on both the active membrane properties of cardiac cells (depolarization phase of the action potential) and the

passive properties determined by resistive discontinuities to cytoplasmic current flow determined in part by the distribution of intracellular (gap) junctions.4 Most investigations on reentry until the mid 1970s focused on abnormalities in the depolarization phase of the action potential as the primary cause of the altered conduction needed for reentry. This culminated in the concept of the slow response action potential, which Cranefield5 proposed was the major cause of reentrant arrhythmias. Although gap junctions were, at this time, known to be the low-resistance pathways between the cytoplasmic compartments of the cardiac myocytes, receiving a lot of attention from experimental electrophysiologists for their central role in myocardial conduction,6 gap-junctional coupling did not play a prominent role in the development of concepts on the mechanisms of reentrant arrhythmias up to this time.

Supported by Program Project Grant HL 30557 and by Grant R-37 HL 31393 from the National Heart Lung and Blood Institute, National Institutes of Health. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; c2003. 197

198 CARDIAC MAPPING In 1959, Sano et al.7 reported that conduction properties in myocardium were different in different directions, the definition of anisotropic conduction. In 1976, Clerc8 extended these observations, showing that the more rapid conduction in the direction of the long axis of myocardial fiber bundles that is characteristic of heart muscle was associated with a lower intracellular resistivity in this direction and that the slower conduction transverse to the long axis of the myocardial fiber bundles could be attributed to a greater intracellular resistance in this direction. However, it was not until Spach and his colleagues published a series of papers between 1979 and 1989 9-16 that the anisotropic properties of cardiac muscle and the myocardial structure, i.e., architecture, that determines these properties were considered to be an important cause of slow activation that is instrumental in the occurrence of reentrant arrhythmias. In broad terms, the influence of tissue architecture on conduction is determined by the size and shape of individual myocytes, and by the quantity, 3dimensional distribution, and physiological behavior of the gap junctions. There is also some influence of the properties of the extracellular space in which current flows during action potential propagation. The role of gap junctions in influencing myocardial conduction properties in health and disease has developed from simple concepts to a more complex subject as research has demonstrated progressively increasing complexity of gap-junctional form and function. Understanding in this area has been greatly advanced in recent years by elucidation of the morphological, physiological, and molecular aspects of these junctional resistances. In this chapter we discuss the role of the anisotropy of ventricular muscle as a cause of ventricular arrhythmias in pathological conditions, and the evidence indicating how alterations in

myocardial architecture, particularly involving the gap junctions, that occur in these conditions may underlie the arrhythmogenesis. Anisotropic Conduction in Normal Ventricular Myocardium Conduction in normal ventricular myocardium is anisotropic, meaning that conduction properties vary depending on the direction in which they are measured relative to the structure of the myocardium. In normal ventricular myocardium, conduction in the direction parallel to the long axis of the myocardial fiber bundles is about 3 times more rapid than that transverse to the long axis. The anisotropy is considered to be uniform because it is characterized by "an advancing wavefront that is smooth in all directions relative to the orientation of the long axis of the myocardial fiber bundles."11 Uniform anisotropy is exemplified by the conduction properties of normal septal ventricular muscle shown in Figure 1A. The muscle in the diagram was stimulated in the center (pulse symbol) and activation spread away from this site in all directions. In the direction of the longitudinal axis of the fibers (from top to bottom) the isochrones are widely spaced indicating rapid conduction, in this case conduction velocity is 0.51 m/s. There is a relatively broad area of fast conduction with an elliptic shape of the isochrones that is characteristic of uniform anisotropy.12 In the direction transverse to the long axis (to the right and to the left), the isochrones are spaced close together indicating slower conduction; conduction velocity is 0.17 m/s in this example. As the direction of propagation changes between these 2 axes, the apparent conduction velocity changes monotonically from fast to slow, another characteristic of uniform anisotropy.10

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Figure 1. Characteristics of uniform anisotropic conduction in ventricular muscle. The excitation sequence in A was constructed from extracellular electrograms recorded at 100 sites on the endocardial surface of the right ventricular septum. The isochrones showing the activation pattern are characteristic of uniform anisotropy. The extracellular waveforms in B were recorded at the sites indicated by the dots on the activation map. The electrogram with the solid trace was recorded from a region of transverse propagation while the electrogram indicated by the dashed trance was recorded from a region of longitudinal propagation. The effects of different directions of propagation on the upstroke of the action potential are shown in C. The direction of propagation at the single transmembrane recording site was altered from longitudinal (dashed upstroke) to transverse (solid upstroke). Reproduced from reference 12, with permission.

The slow conduction in the direction transverse to the longitudinal fiber axis occurs despite action potentials with normal resting potentials and upstroke velocities. Spach et al.10 have described that the differences in conduction velocity based on direction of propagation are accompanied by changes in the action potentials. Their experiments have shown that when going from fast longitudinal conduction to slow transverse conduction, the rate of depolarization during the upstroke of the action potential (Vmax) increases and the time constant of the foot of the upstroke decreases without any change in the resting potential as illustrated in Figure 1C; the upstroke that is dashed was recorded from a cell during longitudinal propagation while

the upstroke indicated by the solid line was recorded from the same cell during transverse propagation. These characteristics are opposite to the changes in the action potentials associated with slowing of conduction when the membrane currents are altered (such as by resting membrane depolarization) where slow activation is associated with slowing of the rate of depolarization during the upstroke of the action potential17,18; however, results of other studies do not agree with these observations. Studies on anisotropic propagation in tissue cultures of rat neonatal myocytes have not shown a difference in upstroke velocity dependent on direction of impulse propagation relative to the long axis of the cells, although the cultures demonstrated prominent

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anisotropic conduction patterns.19,20 This controversy must be solved by further investigation. Slow conduction in the transverse direction is also associated with a decrease in the amplitude of the extracellular electrogram showing that there is a decrease in the extracellular current flow as a result of the increased axial resistivity. In uniform anisotropic tissue, the extracellular unipolar waveform has a large-amplitude, smooth biphasic positive-negative morphology during propagation in the fast longitudinal direction, which is shown in Figure 1B by the dashed lines, and a low-amplitude smooth triphasic (negative-positive-negative) morphology in the transverse direction, which is shown by the solid line. The initial negativity of the electrogram in the transverse direction is a reflection of distant activity rapidly propagating along the longitudinal axis.9 Myocardial Architecture Underlying Uniform Anisotropic Conduction in Ventricular Muscle The mechanism for anisotropic propagation in normal ventricular myocardium with rapid conduction in the longitudinal direction and slow conduction in the transverse direction is related to the myocardial architecture, that is, the size and shape of the myocardial cells and bundles and the distribution of their interconnections. Ventricular muscle cells are elongated, about 120 um long and 20 um in diameter, but are irregular in shape with multiple step-like, transversely oriented sites of interconnection between adjacent cells called intercalated DISKS.21,22 The intercalated disk The intercalated disks incorporate the closely opposed plasma membranes

of 2 adjacent cardiac myocytes to form the specialized intercellular junctions that facilitate the coordinated interaction of the cardiac myocytes to form whole muscle fibers and to integrate myocardial function.23 They maintain mechanical, metabolic, and electrical coupling of the abutting myocytes.21,22,24 Thin section electron microscopy reveals the ultrastructural arrangement of the intercalated disk, and how the cells abutting at the disk interdigitate such that their paired plasma membranes follow the contour of the myofibril ends21 (Figure 2). The disk steps back and forth across the cell terminal, alternating between longitudinal and transverse orientations with respect to the long axis of the myocytes.21 The size of intercalated disks varies, spanning up to 20 or more myofibrils transversely and the length of several sarcomeres longitudinally. In ventricular myocardium, large intercalated disks exist at the ends of the myocytes, with smaller disks, each orientated transversely, along the length of the cell. Each myocyte in human ventricular myocardium has a mean of 11.6 intercalated disks.25 Specialized intercellular junctions comprise the intercalated disk. Two of these junctions, the fascia adherens and the desmosome, are referred to as anchoring junctions and are concerned with intercellular adhesion.21 The other specialized intercellular junction in the intercalated disk is the gap junction, which is responsible for intercellular communication, forming low-resistance pathways for passive flow of ions, and small molecules between cells.6 These junctions are the focus in this chapter of the discussion on myocardial architecture and arrhythmogenesis, since the distribution of gap junctions and their physiological properties have important influences on conduction and anisotropy. The arrangement of the 3 specialized junction types in the intercalated disk

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Figure 2. Micrographs illustrating the characteristic architecture of myocardial cellular interconnections. A. Light micrograph of longitudinally sectioned ventricular myocardium (stained with toluidine blue), showing the darkly stained transversely orientated intercalated disks (arrows) traversing at sites of intercellular abutment. B. Low-power thin section electron micrograph of a single intercalated disk, illustrating the step-like structure of convoluted (plicate) regions interspersed by the less conspicuous and less convoluted, more longitudinally orientated interplicate regions containing some of the larger gap junctions (arrows, see text) which appear as fine, electron-dense membranes. C. Higher power electron micrograph of a small intercalated disk illustrating the long stretch of gap-junctional membrane at the edges (periphery) of the disk (arrows). D. High-power electron micrograph of part of a gap junction, showing the pentalaminar structure of the closely apposed cell membrane lipid bilayers. A x450, B x10,000, C x25,000, D x100,000. B and D reproduced from reference 107, with permission. C reproduced from reference 25, with permission.

differs between the regions of transverse and longitudinal orientation.21 Fasciae adherents are confined predominantly to the transverse regions, which are highly convoluted, or plicate. Gap junctions are located predominantly in the longitudinal nonplicate (interplicate) regions, although small gap junctions are also present among the adhering junctions of the plicate regions (Figure 3). Desmosomes may exist in both regions. Although typically found in the intercalated disk of ordinary working ventricular myocardium as described, gap junctions are not necessarily confined to disks in all parts of the heart; the specialized myocytes of the atrioventricular node, for example, have

no identifiable intercalated disks even though gap junctions are present.21,26,27 The gap junctions Structure of Gap Junctions: Gap junctions are specialized regions of close interaction between the sarcolemmata of neighboring myocytes in which clusters of transmembrane channels bridge the paired plasma membranes (for reviews see references 6 and 28 through 33). Figure 4A is a 3-dimensional diagrammatic representation of the structure of a gap junction, spanning the 2-component cell membranes as defined by the model of Makowski et al.34'35 Gap junctions are relatively

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Figure 3. Diagrammatic representation of the intercalated disk region of a cardiac myocyte, at which an abutting myocyte would interact with complementary disk features (compare with Figure 2). Note the step-like structure of the disk, with longitudinal (interplicate) and transverse (plicate) regions. The specialized intercellular junctions of the disk have a specific pattern of distribution (see Figure 2). Fasciae adherents (not shown) are located in the plicate regions. Gap junctions (indicated by solid ovals) occur predominantly in the interplicate regions (larger junctions) with smaller junctions in the plicate regions. Desmosomes (not shown) exist in both regions.

inconspicuous at thin section electron microscopy because there is little electron-dense material on the cytoplasmic side of the membranes, which are separated by a gap of only 2 to 3 nm (Figure 2D).36 The technique of freeze-fracture enables electron microscopic examination of detail of gap junctions viewed face on in the plane of the membrane,37,38 with visualization of the densely packed protein particles responsible for the physiological properties of these membrane specializations (Figure 5). The integral proteins of the gap junction, called connexins, exist in hexameric units called connexons, each of which possesses a 1.5- to 2-nm central pore and makes contact with another connexon in the opposing membrane (Figure 4). The

Figure 4. Model of the connexin43 gap junction. Gap junctions consist of clusters of channels (a). Each channel consists of a pair of connexons, one contributed from each plasma membrane. The connexon consists of 6 connexin molecules (connexins 43, 40, and 45 in mammalian myocardium, singly or in combination). Each connexin molecule has 4 transmembrane regions, with the amino and carboxy termini situated on the cytoplasmic side of the membrane (b).

pair forms a complete channel linking the cytoplasmic compartments of the abutting cells, providing a low-resistance pathway for the passage of ions and small molecules (up to 1 kd) 39-41 and for electrical propagation.42 Using ultrarapid freezing techniques to capture gap-junctional organization as it is in the myocardium of the living animal, freeze-fracture electron microscopy shows the clusters of connexons comprising a gap junction containing ordered hexagonal arrays with connexonfree aisles of membrane separating each array (Figure 5). The results of gap junction modeling suggest that this channel arrangement lowers the access resistance, and thus increases the conductance, of a

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Figure 5. Electron micrograph of freeze-fracture replica showing the densely packed connexon particles (arrow) of an entire junctional plaque. x100,000. Reproduced from reference 25, with permission.

gap junction compared with a denser junctional channels on electrical propagamass of an equal number of channels.43 tion are likely to be of biological relevance, Furthermore, these same authors sug- they remain unproven. It is likely, howgest that the peripheral ring of large gap ever, that both the physiological properjunctions characteristic of intercalated ties of the channels and their distribution disks in ventricular myocardium lies influence conduction. directly in the path of the depolarizing The connexins are a multigene family membrane potential as it passes along the of conserved proteins, different members lateral sarcolemma of abutting myocytes, of which are expressed in different cell enhancing longitudinal conduction veloc- types, tissues, and species.30,32,33,44,45 Gap ity and the degree of anisotropy of prop- junctions and connexins occur in all mulagation.43 Although the influences of these ticellular tissues in the body, and throughultrastructural arrangements of gap- out the animal kingdom from the sponges

204 CARDIAC MAPPING to humans.44 Transcripts for 14 different connexin molecules have now been identified in mammals.30,32,33,45-47 This family of connexin isoforms possesses varying degrees of molecular homology and similarity of topology within the cell membrane (Figure 4B), 44 but the domains of the connexin molecule that lie on the cytoplasmic side of the membrane are the regions of greatest difference in sequence and length between the connexin species and appear to be the main determinants of the differences in biophysical properties between gap junctions composed of the specific connexins.44 The conventional nomenclature for a connexin (Cx) is with a suffix referring to its molecular weight, ranging from 26 kd (Cx26) to 50 kd (Cx50). Qualitative data on the differential expression of the different principal connexin isoforms (connexins 43, 40, 45) in the mammalian heart including humans have confirmed that connexin43 is the most abundant connexin in ordinary atrial and ventricular myocardium. Moderate amounts of connexin45 are also found in both tissue types. Connexin40 is present in large amounts in the atria but not in the ventricles.48-51 It has been reported that working subendocardial ventricular myocardium expresses connexin40 (although less than in atrial tissue) and that this expression can be upregulated by hypertensive hypertrophy.52 Although there remains some debate about connexin expression in the His bundle and bundle branches, with interspecies differences complicated by conflicting data likely to be attributable to difficulty locating these tissues with certainty, there is general consensus that in the conducting tissue of the human heart, connexin40 is present only in the His bundle, and not in the bundle branches. This finding is consistent with the emergence of connexin40 as a potential candidate gene for mutations responsible for a hereditary conduction tissue disease.53 In other mammalian

species, connexin40 may be expressed in the proximal bundle branches in addition to the His bundle. Sinus and atrioventricular nodal gap junctions are small and sparse,27,54,55 making connexin detection difficult and variable using the different immunohistochemical techniques employed (described below). Although it is therefore difficult to reach a general conclusion, these nodal tissues are reported to contain mainly connexin45, with lower levels of connexin40 and, in the atrioventricular node but not the sinus node of human hearts, connexin43.49 Other connexins including connexin37,56 connexin46,57 and a connexin-related protein, MP70,58 are not thought to be expressed to any significant level in cardiac myocytes, and are not considered further in this chapter. Physiological Properties of Gap Junctions: In general, gap-junctional membrane is several orders of magnitude more permeable than nonfunctional plasma membrane, as indicated by a relative high junctional conductance, and therefore provides lowresistance pathways for current flow between myocardial cells.6 Early studies using molecular probes to investigate the nature of gap-junctional coupling demonstrated that the aqueous pore in the gapjunctional channel, which is the cause of the low resistance, is 1.5 to 2 nm in diameter.59 There is also evidence that gapjunctional channels show selectivity to diffusion of molecules, depending on their size and, possibly, their charge.60 The cation/anion selectivity ratio for rat connexin43 gap-junctional channels has been estimated as close to 1.0, indicating that these channels are nonselective aqueous pores.60 Connexin45, however, has marked cation selectivity.61 There also appears to be connexin-specific, size-dependent permeability of molecules,62 although there is no apparent relationship between molecular size permeability and ion selectivity.63 The physiological impact of these

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observations is likely to be significant, and tary conductance of connexin40 is 150 to they clearly demonstrate that gap-junc- 200 pS,73 a value higher than that of contional channels cannot be considered to nexin43 that possibly contributes to the be simple passive conduits between cyto- high conduction velocity of the His-Purkinje plasmic compartments of adjacent cells. tissue, in which there is abundant conThe permeability of a gap junction (or nexin40. Connexin45 shows low values for junctional conductance) is determined by unitary conductance (36 pS, 22 pS).33 To the number of junctional channels, the pro- add to this complexity, it has become apparportion of these channels that are in the ent that connexons, at least in vitro, may open state, and the permeability (conduc- be composed of a single connexin species tance) of the open channel. Other factors (homomeric) or several connexin species that affect gap-junctional conductance, in (heteromeric), and a gap-junctional chanaddition to the permeability of the open nel may be made up of 2 connexons that channels (single-channel conductance) and are identical (homotypic) or not (hetthe proportion of channels that are open, erotypic). Although little is known of the are the total surface area of the gap junc- occurrence of heterotypic and heteromeric tion and the number of junctional channels channels in naturally occurring gap juncper unit area of junction. These factors can tions, there is evidence for the potential vary among tissue types and are affected physiological properties of such channels in vitro.74"76 Of importance, is the inabilby disease, as is discussed later. The gap-junctional channels are gated ity of connexin40 connexons to interact and can exist in an open or closed state. with connexin43 connexons to make funcThe proportion of channels that are in an tional heterotypic channels.76"78 This is open state and the permeability (conduc- the only example of incompatibility among tance) of each channel have an important the cardiac connexins. Thus, the myocytes influence on the gap-junctional perme- of the connexin40-bearing regions of the ability or gap-junctional conductance. The conducting system are electrically isopermeability of the gap junction channel lated from the surrounding ordinary in the open state, or unitary conductance, myocardium expressing connexin43, preis determined by the connexin protein that cluding dissipation of electrical current forms the channel. The different connexin and possibly increasing the efficiency of conisoforms have different unitary conduc- duction and the coordination of ventricular tances. The conductance of a single con- activation. The transjunctional voltage may also nexin43 channel in its main conductance state is of the order of 40 to 60 PS.51, 63-65 influence gap-junctional conductance by Although it was originally believed that its effect on the number of channels in the unitary conductance of a single chan- the open state. In large gap junctions connel does not vary and that the channel taining many cell-to-cell channels, both functions in an all-or-nothing manner, the instantaneous (immediately after either open or closed,4,6 it is now recog- applying an intercellular potential difnized that channels may also have one or ference) and steady-state current-voltage several subconductance states.66-69 Two relationships tend to be linear.79-81 When minor conductance states of 20 to 30 pS only a few open channels are present, and 70 to 100 pS have been reported under although the instantaneous relationship various experimental conditions.70-72 The may be linear, the steady-state currentphysiological, and potential pathophysi- voltage relationship progressively falls to ological, significance of this, however, near zero with increasing voltage.82'84 remains to be elucidated. The main uni- This observation reflects so-called voltage

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dependence of channel gating causing a progressive closure of channels, a phenomenon that is not apparent when measuring the net conductance of larger junctions,80 and is of unknown physiological significance. In the case of connexin43, conductance starts to decrease when the transjunctional voltage exceeds -40 mV.82 This value is similar to that of connexin40,73 and indicates that these connexins are only weakly voltage sensitive. By contrast, connexin45 is highly voltage dependent, with an opening probability of only -10% at -40 mV. It has been suggested that, although the physiological role of connexin45, which has low conductance and is present at low levels, is uncertain, its strong voltage dependence may serve to electrically isolate diseased myocytes in which there are persistent disturbances of resting and/or action potential with respect to healthier neighboring cells.32 Prolonged depolarization, for example, as may occur in ischemic regions, may result in a degree of electrical isolation of tissue containing connexin45 junctions. The conductance of gap-junctional channels may change under different physiological or pathophysiological conditions and these changes may have a profound influence on conduction. Two possible mechanisms for changes in conductance of gap junctions are changes in the proportion of channels in the open state and alterations in expression of channels, either numbers or their constituent proteins (connexins). There are a number of changes to the chemical and electrical environment that can alter the number of channels in the open state and that might influence conduction. We only mention a few of these influences. Gapjunctional conductance is reduced by elevated intracellular [Ca2+]85,86 and by low intracellular pH (below 6.5).87,88 Singlechannel studies have shown the effects of Ca2+ and pH to result from a change in opening probability, the single-channel

conductance remaining unchanged.64,89,90 There is also an interrelationship between intracellular calcium and pH. Although changes of pH within the physiological range (7.4 to 6.5) may not directly affect junctional coupling, they may modulate the response to changes in [Ca2+],80 the lower the pH, the greater the Ca required to reduce junctional conductance to its half maximum value. pH may become an important direct influence at the low pH associated with hypoxia and ischemia in diseased myocardium.91 Connexin45 is considerably more sensitive to pH than connexin43, showing near complete closure of connexin45 connexons (due to an opening probability of ~0) at pH 6.3. Internal longitudinal resistance through the intracellular pathway in myocardium increases substantially in myocardium deprived of oxygen.92,93 Although this phenomenon may be mediated predominantly by changes (decrease) in intracellular pH and calcium concentrations (increase) that accompany hypoxia, there is evidence that there may also be early ischemic and hypoxic changes in connexon configuration in gap junctions.94-96 These changes may represent a stage of altered gap junction function before the irreversible changes heralding the onset of irreversible cell damage (recently reviewed by Peters97 and discussed later in this chapter). Arachidonic acid, as well as nonesterified fatty acids and long-chain acyl carnitines that may accumulate during myocardial ischemia, are capable of closing intercellular gap-junctional channels in cardiac myocytes.98-101 Doxyl stearic acids (with a fatty acyl chain), but not stearic acids, rapidly and reversibly reduce junctional conductance to very low levels without affecting the unitary conductance.98-102 In addition to the rapid changes in gap-junctional conductance that occur through gap-junctional gating discussed above, the turnover of connexins is a highly dynamic and presumably flexible

MYOCARDIAL ARCHITECTURE AND ANISOTROPY AND VENTRICULAR ARRHYTHMIAS process that might influence gap-junctional physiology. Gap-junctional plaques as a whole appear to remain relatively constant and stable, but observed halflives of the order of 3 hours50,103 for connexin43 and connexin45 indicate that although relatively slow when compared with changes brought about by changes in gap-junctional gating, turnover of connexins might be altered in certain pathophysiological states. Therefore, disease processes acting at one or more sites of the genetic control and expression of junc tional proteins may influence the conductance properties of gap junctions by affecting connexin turnover, influencing gap-junctional size, distribution, and composition. In addition, post-translational modification of gap-junctional proteins may affect gap-junctional conductance. In cardiac myocytes, connexin43 is present in at least 2 phosphorylated forms and in one unphosphorylated form. The native protein is post-translationally modified by the addition of phosphate groups onto serine residues.32 Phosphorylation appears to reduce unitary conductance of connexin43 gap junctions by increasing the proportion of channels from the main conductance state of about 50 pS, to the lower conductance of 20 pS. Dephosphorylation induces a third conductance state of 70 pS.71,72,104 Connexin45 is a phosphoprotein,78'105 and, like connexin43, has multiple conductance states depending on the degree of phosphorylation. Pathophysiological processes that can influence phosphorylation are therefore predicted to alter current flow through gap junctions and to affect cardiac conduction. Gap-junctional Organization in Ventricular Myocardium and its Relationship to Anisotropic Conduction: With the advent of the molecular biological techniques used to determine the amino acid sequence of what was, at that time, the only identified mammalian myocardial connexin, connexin43,46

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antibodies were generated in the early 1990s to selected sequences from the connexin43 molecule. One such antipeptide antibody raised in rabbits against residues 131 to 142 of the connexin43 molecule58,106,107 (part of the cytoplasmic loop Figure 4) has been used to characterize mammalian ventricular myocardial gap junction organization by incubating tissue sections with this antibody, followed by a second incubation with a fluorosceinlabeled swine antirabbit antibody. The result is fluoroscein label localized to the sites of connexin43 concentration, which, in combination with the technique of confocal laser scanning microscopy, has permitted highly sensitive immunofluorescent imaging of gap junctions in isolated cardiac myocytes (Figure 6C), and through thick slices of intact cardiac tissue (Figure 6A). By this approach, mapping of spatial patterns of gap junction distribution and quantification of connexin expression levels from the digital images so acquired has been accomplished27,106-110 through volumes of myocardium that are sufficiently large to make them relevant to overall electromechanical function of the tissue and the heart as a whole. Furthermore, by comparative measurement of connexin content in health and disease,25,111,112 and by applying similar immunohistochemical approaches to localizing the other cardiac connexins, the relative abundance of each of the myocardial connexins has been determined.27,48,113 The novel insights so derived have been highly complementary to the ultrastructural data generated by electron microscopic techniques. As discussed above, ultrastructural studies have revealed that in ordinary mammalian ventricular myocardium, gap junctions are confined almost exclusively to the well-developed intercalated disks and exist therein as ovoid or irregular plaques, measuring up to 2 (im or greater in diameter25,38,107 and containing up to

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Figure 6. Confocal immunolocalization of connexin43 gap junctions in human left ventricular myocardium. A. A single optical section of longitudinally sectioned myocardium revealing each individual gap junction domain as a separate spot grouped within intercalated disks. B. An optical projection series from transversely sectioned myocardium showing a number of intercalated disks viewed enface, showing the labeled gap-junctional population within each. C. Higherpower transverse section showing 2 intercalated disks in which there is the characteristic arrangement of a peripheral ring of large gap junctions and smaller central domains (see Figure 2C). D. Optical projection series through a single isolated ventricular myocyte labeled for connexin43, showing the positions of the intercalated disks, as clusters of transversely oriented labeled gap junctions. A x700, B x850, C x3500, D x1000.Reproduced from reference 25, with permission.

several thousand connexons. The inter- ters of fluorescent label confined to the locaplicate (longitudinally orientated) regions tions of the intercalated disks (Figure 6), of the intercalated disk in canine ventri- and show a similar distribution to that cle contain large gap junctions,25,109 with observed in the working ventricular smaller gap junctions interspersed among myocytes of other mammalian species.115,116 the anchoring junctions in the plicate Gap junctions within the disk in the regions (Figure 3). Particularly large gap human heart are typically organized as a junctions have been observed at the peripheral ring of larger junctions (mean periphery of the disk25,109 (Figures 3 and long axis length 0.67 |im), with smaller 6C). Consistent with these observations, junctions centrally (0.36 u,m), and occupy confocal images of immunolabeled human a mean surface area of 0.005 )j,m2/u,m3 ventricular myocardium reveal that from myocyte volume (Figure 6).25 6 years of age,114 connexin43-containing The pattern of gap junction distribugap junctions are organized in a well- tion in normal myocardium is believed to ordered pattern visible as multiple clus- be one major determinant of the normal

MYOCARDIAL ARCHITECTURE AND ANISOTROPY AND VENTRICULAR ARRHYTHMIAS uniformly anisotropic pattern of electrical propagation, by which conduction parallel to the fiber orientation is up to 3 times more rapid than transverse to it.115'116 Furthermore, the pattern of coupling of myocytes and, in particular, the adequacy of the side-to-side connections, is important in determining that a wavefront shows homogeneous propagation,19 loss of which promotes the formation of reentrant circuits causing arrhythmias (described later). Normal gap-junctional organization may therefore require precise control, with the possibility that arrhythmias may arise if the normal gap junction distribution is disrupted. In mature human ventricular myocardium, the cells have an average of 11.6 intercalated disks.25 In canine ventricular (subendocardial) myocardium, each ventricular muscle cell is connected to approximately 11 to 12 other muscle cells.114"122 As a result of the intercalated disks that exist at sites along the length of cardiac myocytes, gap-junctional connections between the cells occur between both the ends of cells and the sides of cells; in canine ventricular myocardium, 29% of cells are connected to each other only side to side, while 34% are connected only end to end. The remaining cells are connected in both the end-to-end and side-to-side direction, such that approximately half of all connections are side to side and half are end to end.117'122'123 Therefore, with respect to gap-junctional coupling in ventricular myocardium, activation wavefronts can conduct equally well between individual cells in both the longitudinal and transverse directions because there are approximately equal numbers of connections. However, in the transverse direction a wavefront will encounter more gap junctions than over an equivalent distance in the longitudinal direction because cell diameter is much less than cell length (23 p,m versus 122 |um in the study of Saffitz et al.123)

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and, therefore, the wavefront must traverse more cells transversely per unit distance. The resistivity of gap-junctional membrane, although several orders of magnitude lower than non-gap-junctional plasma membrane, is several orders of magnitude higher than the cytoplasmic intracellular resistivity. In the longitudinal direction, the cytoplasmic and gapjunctional components to the total impedance are about equal124; however, there is a greater resistance transversely than longitudinally because of the increased number of gap junctions and, therefore, slower transverse conduction. Myocytes in different cardiac tissues are interconnected with tissue-specific 3dimensional patterns that appear to determine their conduction properties. In the studies on canine ventricular myocardium referred to in the preceding paragraph,117'122 although the ratio of cell length to width measured in isolated canine ventricular myocytes is approximately 6.1:1, the side-to-side and end-toend distribution of connections between the irregularly shaped myocytes means that in whole tissue, the length-to-width ratio of cell profiles traversed by the lines on a grid orientated parallel and perpendicular to the long cell axis is only 3.4:1.117'122 This ratio, derived from the packing geometry, is consistent with the degree of anisotropy of conduction as measured in ventricular myocardium, and illustrates the importance of considering both the distribution of gap-junctional connections and the packing geometry in correlating architecture with conduction properties. In contrast to these data from ventricular myocardium, the crista terminalis of the right atrium has most connections in the end-to-end direction, with few side-to-side connections, and has anisotropic conduction properties that are distinctly different from those of the left ventricle (LV). Longitudinal conduction is considerably more

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rapid in the crista terminalis than in the to extracellular space and cellular couventricle, but transverse conduction in pling that cardiac myocytes, as discussed the crista terminalis is very slow, with a previously, are coupled almost exclusively longitudinal-to-transverse velocity ratio at only a few intercalated disks, which of approximately 10:1 compared with 3:1 may exist on parallel side branches of the main cell long axis. Although at other in ventricular myocardium.11 A further level of complexity in the points along their length and circumferrelationship between tissue structure and ence, adjacent myocytes may be partially propagation involves the properties of the separated from the adjacent cells by extracellular space. In some regions of extracellular space or tissue, there may the ventricles, particularly the papillary still be sites of approximation and juncmuscles, connective tissue septa subdi- tional interaction between them. It is vide the myocardium into unit bundles, a therefore not possible to determine structural feature that also contributes whether adjacent cells are coupled to each to the anisotropic conduction properties of other from histological examination of ventricular muscle. Such bundles are only a single, or even several, tissue seccomposed of 2 to 30 cells surrounded by tion^)—complete sectioning through the a connective tissue sheath. Within a unit entire cell concerned, in the manner of bundle, cells are tightly connected or cou- Hoyt et al.,117 is necessary. Fine connecpled to each other through the gap junc- tive tissue septae, per se, may not signiftions in the intercalated disks, as icantly alter intercellular coupling or described above. All the cells of a unit conduction velocity through the tissue bundle are connected to each other within unless they divide points of potential gapthe space of 30 to 50 [im down the length junctional intercellular contact. Gap juncof a strand.125 As a consequence of the tions occupy only a small proportion of the many intercellular connections, the myo- cell surface, so even a substantial increase cytes in a unit bundle are activated uni- in connective tissue septation may have formly and synchronously as an impulse little effect on electrical coupling. Although the definition of uniform propagates along the bundle. The unit bundles are also connected to each other. anisotropy is an advancing wavefront Unit bundles lying parallel to each other that is smooth in all directions relative to are connected in a lateral direction at the long axis of the myocardial fiber bunintervals in the range of 100 to 150 |im.125 dles, this is based on the characteristics As a consequence of this structure, the of activation at a macroscopic level where myocardium is better coupled in the the spatial resolution encompasses numerdirection of the long axis of its cells and ous myocardial cells and bundles. Because bundles (because of the high frequency of of the irregularities in cell geometry and the gap junctions within a unit bundle) irregular distribution of the gap junctions than the direction transverse to the long of normal ventricle as described in the axis (because of the low frequency of previous paragraphs, activation at a interconnections between the unit bun- microscopic level with a spatial resolution dles). This is reflected in a lower axial comparable to individual cells is, in fact, resistivity in the longitudinal direction quite irregular. This irregularity has been than in the transverse direction in car- shown in the computer model of Spach and diac tissues that are composed of many Heidlage127 that approximates the architecture of LV epicardium (Figure 7) with plibundles.8,126 It is necessary to bear in mind when cate junctions connecting the cells in the interpreting any of the studies relating longitudinal direction, and interplicate

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Figure 7. Diagram showing the electrical equivalent circuit of 3 interconnected myocytes in a 2dimensional computer model. Each membrane patch corresponds to a 10 [o,m x 10 jam intracellular segment. In each patch, during depolarization, there is an outward capacitive current (lc) in parallel with an inward ionic current (llon). Intracellularly, the patches are interconnected with low resistances (r,) to produce an isotropic sheet. The boundaries between cells (diagonal lines) are represented by the absence of cytoplasmic interconnections. Electrical coupling between myocytes is achieved through 3 resistors that represent 3 types of gap junctions: plicate, interplicate, and combined plicate. Reproduced from reference 127, with permission.

and combined plicate junctions connecting the cells in the lateral direction (70% of gap-junctional conductance in the interplicate areas and 30% in the plicate areas). In this model, during both longitudinal and transverse conduction, plane waves did not occur at a microscopic level because of the disruption of the excitation wave by the irregularly located cell boundaries and the associated irregular distribution of the gap junctions. Steplike increases in activation time in the longitudinal direction occurred in the regions of end-to-end connections between cells, corresponding to the irregular distribution of the plicate junctions and large lateral jumps in activation times occurred between cells in the transverse direction at the lateral borders of the cells. Nonuniformities at a microscopic scale have also been shown by Fast and Kleber and colleagues19,20 in a tissue culture preparation of neonatal myocytes, in which optical dyes permitted the con-

struction of high-resolution excitation maps. Nonuniformity was most evident in the transverse direction. Discontinuous transverse propagation was amplified by the presence of intercellular clefts between cells and in regions where nonmyocyte cells (fibroblasts) were coupled to myocytes and acted as a current sink.20 Such clefts and nonmyocyte cells are present in normal myocardium, and therefore influence conduction but may become more of a factor in diseased myocardium, leading to nonuniform anisotropy (see next section). Normal Myocardial Architecture, Uniform Anisotropy, and Arrhythmogenesis In general, the normal ventricles are not prone to the occurrence of reentrant arrhythmias except for ventricular fibrillation. The spiral wave reentrant mechanism that has been suggested to be an

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important cause of fibrillation can occur in a homogeneous medium and is not dependent on anisotropy. However, myocardial fiber orientation (anisotropy) has been shown to be an important factor in determining the patterns of activation during the electrical induction of ventricular fibrillation.128 The Effects of Cardiac Disease on Anisotropy and Arrhythmogenesis

tions, in addition to the more gross associated structural disruption caused by fibrosis and the formation of connective tissue septa. It has been shown in myocardial cultures that sites of inhomogeneity of gap-junctional distribution represent sites for nonuniform propagation and block of conduction in the direction transverse to the myocardial fiber axis.20 Myocardial ischemia and hypertrophy cause alterations in gap-junctional organization25,111,129 and connexin expression25,52,129 that might have similar effects.

Changes in the characteristics of anisotropic propagation from uniform Ischemic Heart Disease: Effects anisotropy to nonuniform anisotropy can lead to the occurrence of arrhythmias. on Ventricular Gap Junctions, This association was first described in the Anisotropy, and Arrhythmogenesis atrium by Spach et al.11,13 Nonuniform The principal cause of the mortality anisotropy is defined as the maintenance and morbidity in ischemic heart disease of tight electrical coupling between cells is myocardial contractile dysfunction and in the longitudinal direction but disruparrhythmias. A mechanism that may be tion of the smooth transverse pattern common to dysfunction of both the coorcharacteristic of uniform anisotropy dination of contraction and the cardiac described above. Propagation transverse rhythm is the reduced velocity and the to the long axis in nonuniformly anisotropic altered patterns of conduction known to myocardium occurs in a markedly irreg11,13 occur in myocardial ischemia. In ischemic ular sequence or "zigzag conduction." A marker for nonuniform anisotropic con- heart disease, changes in the electroduction is fractionation of the waveforms physiological properties of the myocardium of the extracellular electrograms caused associated with arrhythmogenesis are by the zigzag transverse propagation. The dependent on such variables as the duranonuniformity of anisotropic conduction tion of ischemia, the degree of ischemia, in atrial myocardium described by Spach and the presence or absence of infarction and Dolber13 resulted from disruption of and cell death. Throughout this range the lateral gap-junctional connections by of pathophysiological settings, there is evithe formation of connective tissue septae dence to implicate gap-junctional derangeduring aging, while longitudinal coupling ment and anisotropy of conduction in the by gap junctions was maintained. Trans- mechanism of the ensuing electromechanformation of the anisotropic conduction ical dysfunction. properties from uniform to nonuniform is also associated with the occurrence of Effects of acute ischemia ventricular arrhythmias associated with The arrhythmias that occur within the some pathological conditions. The structural basis for nonuniform anisotropic first hour after the onset of severe ischemia conduction in the ventricles in arrhythmo- caused by an acute coronary artery occlugenic disease states may relate directly to sion are associated with depolarization alterations in the organization of gap junc- of the membrane resting potential and

MYOCARDIAL ARCHITECTURE AND ANISOTROPY AND VENTRICULAR ARRHYTHMIAS partial inactivation of sodium channels resulting from the membrane depolarization.130 The changes in Na+ channel function contribute to slowing of conduction and the occurrence of reentrant excitation. Much of the depolarization can be attributed to an increase in extracellular potassium accumulation. In addition, there are important changes in the functional properties of the gap-junctional connections that are likely to contribute to the very slow conduction characteristic of acutely ischemic myocardium. In a computer model, Quan and Rudy131 have shown that by decreasing membrane conductance for Na+, conduction velocity can only be reduced to about one third of its normal value, whereas by increasing the degree of cellular uncoupling it can be reduced by a factor of 20 before block occurs. Internal longitudinal resistance and resistivity of the cell-to-cell conduction pathway (gap-junctional resistance) increase substantially in myocardium deprived of oxygen by 10 to 15 minutes.92,93,132-134 Since gap-junctional conductance is impaired by such factors as an increase in intracellular Ca2+ and H+ concentration (see previous section), one might expect a priori that myocardial hypoxia, by inducing these cytoplasmic changes, would reduce cellular coupling and therefore slow conduction. Furthermore, long-chain acyl carnitines, lipid metabolites that accumulate within minutes of the onset of ischemia and which are highly arrhythmogenic, markedly reduce gap-junctional conductance.101 On the other hand, in that ATP depletion may result in dephosphorylation of connexin43 and may increase coupling,70,73,104 at least partial compensation for these uncoupling ionic changes may be expected. When hypoxia is caused by occlusion of a coronary vessel, extracellular resistance (comprising both intravascular and interstitial resistance) immediately increases by

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approximately 30%.92 This increase is related to collapse of the vascular bed. Thereafter, there is a slow further increase in extracellular resistance most likely caused by osmotic cell swelling135 and the consequent reduction of the extracellular space. The intracellular resistance remains unchanged during the initial phase of ischemia; this phase may vary from 12 to 23 minutes. Afterward, rapid cellular uncoupling occurs to cause an increase in intracellular resistance.92 During the initial phase, when intracellular coupling resistance remains unaltered, a small decrease in conduction velocity of about 15% can be expected as a consequence of the increase in extracellular resistance, assuming that action potential upstroke remains unchanged (which it does not). The rapid cellular uncoupling that occurs later causes conduction to become slow and discontinuous and eventually leads to complete conduction block. Actual conduction velocity measured in acutely ischemic papillary muscles is lower than predicted by cable theory and this is due to the changes in action potential upstroke characteristics and excitability. So far, no precise quantitative assessment has been made of the relative contributions of the changes in both passive and "active" electrical properties to conduction velocity, but a recent report suggests that an alteration in coupling is an important factor.124 The changes in coupling resistance are expected to alter the anisotropic properties of the ventricular myocardium. Since transverse propagation occurs over many more gapjunctional connections than longitudinal conduction, slowing of conduction transversely would be expected to be more severe than longitudinally and to become much more irregular.136 This sudden increase in intracellular resistance after about 20 minutes of ischemia in physiological studies92 can be correlated with the results of early ultrastructural studies that showed alterations

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of gap junction membranes after 20 to 30 minutes of ischemia,94,136 and suggested that morphological changes of gap junctions, particularly with respect to the packing of the junctional channels, may contribute to the uncoupling process. The quantity of gap-junctional membrane does not seem to change.96 This led to the widely held view that uncoupling agents such as hypoxia and ischemia may act via conformational change of the connexons within the cell membrane lipid bilayers, thereby closing the junctional channels.137 There have been many attempts to correlate gap-junctional morphology with functional state.41,94,138-141 Despite a lack of consensus, considerable knowledge of gap junction organization has arisen from these freeze-fracture studies, which might be summarized by the predominant (but not unanimous139) view that the connexons in the functioning gap junctions of living ventricular myocytes typically exist in multiple small hexagonal arrays, becoming randomly distributed and then compacted (with a higher overall density in a homogeneous hexagonal pattern) in conditions under which uncoupling may occur. More extensive uncoupling after 60 minutes of hypoxia is accompanied by a 45% reduction in gap-junctional membrane and reduction in the total number of intercellular gap-junctional channels. Thus, cellular uncoupling heralds the onset of irreversible damage and coincides with the second phase of extracellular K+ accumulation.142,143 Chronic Myocardial Ischemia: Chronic myocardial ischemia is also associated with arrhythmogenesis that may involve alterations in intercellular coupling and anisotropy. There is a substantially reduced connexin43 gap-junctional surface area in recurrently ischemic, but not infarcted, human ventricular myocardium.25 Structurally well-preserved LV biopsies of

recurrently ischemic myocardium have been obtained from patients with triplevessel coronary artery disease and demonstrable regional ischemia at preoperative assessment who were undergoing bypass operations.25 Despite a normal pattern of gap-junctional distribution in a normal number of intercalated disks per myocyte, and a normal mean density of packing of the constituent connexons, a 47% reduction in connexin43—gap junction surface area was detected in the ischemic samples, translating to a significant reduction in connexin43 expression per myocyte.25 The intercalated disk counts in ventricular myocardium from the human ischemic hearts were normal, and the distribution of long-axis lengths of labeled gap junctions also showed no difference from the normal, suggesting that the reduction in gap-junctional content in the ischemic myocardium occurs as a result of reduction in the numbers of all sizes of junctions within each intercalated disk. Therefore, the basic architecture of intercellular abutments is not altered significantly. Thus, although ultrastructural studies have suggested that gap-junctional surface area is reduced in the setting of ischemia persisting to the point of irreversible damage and destruction of the cells (infarction),96 this stage is, by definition, not reached in patients with recurrent or persistent ischemia without infarction. A reduced gap-junctional connexin43 content is a possible anatomical factor in the pathogenesis of electromechanical dysfunction and arrhythmias in the chronically ischemic heart providing the potential for slowing and nonuniformity of conduction, without invoking the gross alterations consequent on infarction and ensuing fibrosis as the explanation. Gap Junction Organization in InfantRelated Myocardium: The Infant Border Zones: Reentry is the primary mechanism of ventricular tachycardias (VTs) late after

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myocardial infarction (>72 hours).130 The region in which reentry occurs in infarcted ventricles has been localized to the surviving borders of healing or healed myocardial infarcts.116,130,144,145 The site of origin of arrhythmias at these later periods depends on the location of the surviving myocardial cells in and around the infarcted region that form the infarct border zone. The electrophysiological mechanisms causing these arrhythmias (functional or anatomical reentry) depend on the anatomical arrangement of the surviving myocardium and the alterations in their membrane function. In that reentry requires an electrophysiological substrate that includes regions of slow conduction and block, the demonstration of abnormal conduction in infarct border zone myocardium with normal, or near normal, action potential depolarization phases130,146,147 indicates that structural remodeling of the constituent myocytes, and in particular the changing balance of longitudinal and transverse connections between them that influence the anisotropic properties, may be an important determinant of arrhythmogenesis.148 Patients with sustained VT often have a large area of solid, homogeneous infarct, which may include the septum and which extends around much of the circumference of the ventricular cavity, from the anterior to the lateral wall.149 The solid infarct may be transmural in that it extends from the subendocardium into the subepicardium. On the subepicardial surface over solid infarct, there is patchy infarct and surviving subepicardial muscle, the epicardial border zone in which reentrant circuits sometimes occur. Older infarcts are composed of larger areas of patchy infarct and thinner epicardial border zones. Surviving subepicardial muscle cells can be found even in ventricular aneurysms. Similarly, in canine models of myocardial infarction caused by com-

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plete occlusion of a main coronary artery such as the left anterior descending (LAD), a narrow layer of epicardial muscle (epicardial border zone) survives over the region of solid transmural infarction.116,150,151 Muscle fibers on the epicardial surface of transmural anteroseptal canine infarcts caused by permanent occlusion of the LAD near its origin survive because they still receive blood flow from epicardial branches of the circumflex artery or from collaterals of the LAD that anastomose with the patent circumflex. A redistribution of coronary blood flow from necrotic endocardial layers to surviving epicardial ones may also maintain their viability.152 A narrow "ribbon" consisting of Purkinje fibers, and sometimes ventricular muscle, survives between the subendocardial surface of the solid infarct and the ventricular cavity in both human and experimental infarcts—the subendocardial border zone.149,153,154 Subendocardial scarring and trapping of myocardial fibers in a subendocardial scar may also extend into areas around the periphery of infarcts. This is most often the site of origin of VT in human infarcts.155 In some hearts, bundles of myocardial fibers extend from the subendocardial border zone or lateral border zone, deeper into the subendocardium, and also into midmyocardial regions of the solid infarct, forming subendocardial or intramural conducting pathways.130,145 Tracts of subendocardial and intramural muscle bundles may sometimes form reentrant circuits. The epicardial border zone is an important site of arrhythmia origin in healing experimental (canine) infarcts.116,151,156 Although there is some evidence that clinical arrhythmias sometimes arise in this region,157 it is probably not the primary site of origin of most clinical VTs. The microscopic anatomy (architecture) of the border zone of surviving epicardial muscle in canine infarcts has important influences

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on impulse conduction in this region that cause arrhythmias in the experimental model. The microscopic anatomy also changes with time as the infarct heals, causing time-dependent changes in conduction properties. The influences of architecture on conduction as determined in this model can be applied to border zones in human infarcts and provide information relevant to the origin of clinical tachycardias. The surviving muscle fibers in the epicardial border zone are arranged parallel to one another during the healing phase of myocardial infarction (first week after coronary occlusion). The long axis of the muscle fiber bundles is perpendicular to the LAD and extends from the coronary artery toward the lateral LV and apex,116,158 the same orientation as epicardial muscle fibers in the noninfarcted anterior LV.126 The muscle fibers may be either tightly packed together, as they are in the normal subepicardium, or they may be separated by edema that is commonly seen in a healing infarct (Figure 8). The parallel orientation forms an anisotropic structure that has important influences on conduction properties that may cause reentry. The intracellular ultrastructure of the surviving muscle fibers is mostly normal except for the accumulation of large amounts of lipid droplets that may be a reflection of changes in metabolism of the cells. However, a striking change in structure of this region is an abnormal distribution of gap-junctional interconnections among cells that occurs by 4 days after coronary occlusion.159 Although the surviving myocytes in the border zone adjacent to necrotic cells have normal histological features, they have varying degrees of disruption of gap junction distribution, as shown by immunolabeling of connexin43 (Figure 9), similar to that which has also been described in healed human infarcts (described in the next section). Connexin43 is distributed

around the entire cell surface, with a large amount located along the lateral membrane (Figure 9). This disturbance occurs early after infarction as a primary pathophysiological response of these cells, prior to the physical disruption of intercellular connections by extrinsic fibrotic scarring and distortion that occurs later in the healing and healed phases (see next section). The disturbed gap-junctional pattern is most prominent immediately abutting the necrotic tissue, and extends through the border zone toward the epicardial surface to a distance of up to 840 (im from the interface with the necrotic myocardium. In most regions disturbed gap-junctional distribution does not extend throughout the full thickness of the epicardial border zone, the distribution of connexin43 in myocytes closest to the epicardial surface and most distant from necrotic tissue being in the normal transversely oriented pattern describing the locations of the normal intercalated disks (partial-thickness gap-junctional disarray) (Figure 10). In thinner regions of the epicardial border zone, however, the layer of disturbed gap-junctional distribution extends throughout the entire thickness of the surviving epicardial border zone, all the way to the epicardial surface (Figure 10). The arrangement of the muscle fiber bundles and the alterations in intercellular connections as indicated by the altered connexin43 distribution are both associated with nonuniform anisotropic properties of conduction in the canine epicardial border zone and related to the mechanisms of arrhythmogenesis.116'148 The nonuniform anisotropic properties are illustrated in Figure 11 (left panel), which shows a map of impulse propagation in the epicardial border zone of a 4day-old canine infarct when the border zone was stimulated in the center of the anterior wall of the LV. Rapid activation toward the margin of the anterior LV

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Figure 8. Photomicrographs of the parallel oriented surviving muscle fibers in the epicardial border zone of a healing canine infarct (4 days old). In some regions fibers are widely separated (A), while in others (B), they are more closely packed together. Reproduced from reference 116, with permission.

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Figure 9. Confocal micrographs of connexin43-labeled canine infarct epicardial border zone myocardium, 4 days after left anterior descending artery ligation. A. The necrotic infarct (inf) is free of label, but the surviving myocytes abutting the infarct show grossly abnormal connexin43 gap junction distribution with label distributed all around the cell borders. B. A transmural section showing orderly, predominantly transversely orientated arrays of label abutting the epicardium at the top of the micrograph, contrasting with the abnormal longitudinal arrays in the myocytes abutting the label-free infarct beneath. Note the frequently observed absence of label along the border of the myocytes immediately abutting the infarct. A x700, B x300. Reproduced from reference 159, with permission.

Figure 10. Schematic representation of connexin43-immunolabeled epicardial border zone of 4day-old canine infarct showing the distinction between partial-thickness (to left of diagram) and fullthickness (to right of diagram) disturbance of connexin43 gap-junctional distribution (gj disarray). Reproduced from reference 159, with permission.

bounded by the LAD and toward the apex of the lateral left ventricle (LL) is indicated by the widely spaced isochrones. This is the direction of the long axis of the myocardial fiber bundles. Transverse to the long axis, activation is very slow and irregular as indicated by the closely bunched isochrones. Electrogram fractionation is also associated with the transverse activation.

The mechanism of the nonuniform anisotropy is uncertain. During the first 4 days after coronary occlusion, it is not a result of increased connective tissue associated with infarction,159 which is only evident at later times (see below). It is possible that the edema formation "pulls apart" muscle bundles, disrupting some of the gap-junctional connections and preferentially influencing transverse conduction.

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Figure 11. Left: Activation map of the epicardial border zone of a 4-day-old canine infarct during pacing. Each small number is the activation time at a site where an extracellular electrogram was recorded. Isochrones are drawn at 10-ms intervals and labeled with larger numbers. Margins of the recording electrode array at the left anterior descending coronary artery (LAD), base, apex, and lateral left ventricle (LL) are labeled. The border zone was stimulated in the center (pulse symbol) and activation spread toward all margins of the electrode array (arrows). Rapid activation occurred in the direction of the long axis of the myocardial fiber bundles (toward the LL and LAD margins) while very slow, nonuniform propagation occurred transverse to the long axis (toward the base and apex). Right: The activation pattern in the epicardial border zone of the same heart during sustained ventricular tachycardia induced by programmed stimulation. Two reentrant wavefronts rotate around parallel lines of functional block (thick black lines) that formed in regions of nonuniform transverse propagation (see left panel). This figure-of-8 reentrant pattern is indicated by the arrows.

The role of increased connexin43 location along lateral aspects of the cells would seem to contradict the electrophysiological findings of decreased transverse conduction; however, the functional properties of the lateral connexins have not yet been determined (discussed later). There is a relationship between regions of nonuniform anisotropic conduction and the occurrence of reentrant circuits that cause sustained VT in the canine model of infarction.116 Reentrant circuits in the epicardial border zone that cause arrhythmias are functional; they can be induced to form by programmed stimulation which initiates tachyarrhythmias. The circuits form when an appropriately timed stimulated premature impulse blocks in the epicardial border zone.116,151,156 The mechanism for block may involve anisotropic properties of this region: preferential conduction block of premature impulses in

the longitudinal direction in nonuniformly anisotropic myocardium,14 although there is also evidence for an increased refractory period at the site of block.156 There is also a relationship between regions of nonuniform anisotropic conduction and the location of the functional lines of block of stable reentrant circuits that cause sustained VT. These are not the same lines of block that occur during premature stimulation. The right panel of Figure 11 is an activation map of the reentrant circuit that formed to cause a sustained VT initiated by programmed ventricular stimulation in the same heart in which the nonuniform anisotropic activation pattern was described in the left panel of Figure 11. The map illustrates activation occurring in a figure-of-8 reentrant pattern.156 The reentrant wavefront propagates around 2 lines of functional conduction block indicated by the thick

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black lines. These lines of block formed in the regions of very slow transverse propagation resulting from the nonuniform anisotropic conduction characteristics of this area. The exact mechanism for block has not been determined but there appears to be failure of transverse propagation during the tachycardia. Sometimes very slow conduction also occurs across parts of the lines of block (pseudoblock) transverse to the long axis of the myocardial fibers.116 The formation of long lines of stable functional block and the slow activation around the ends of the lines of block that occurs transverse to the long axis of the fiber bundles are necessary for the occurrence of sustained tachycardia. When these block lines do not form, perhaps because of insufficient nonuniform anisotropy, unsustained VT or ventricular fibrillation, but not sustained tachycardia, occur. Functional reentrant circuits in which lines of block form in regions of nonuniform anisotropy and in which much of the slow activation necessary for reentry to occur is caused by slow nonuniform anisotropic conduction around the ends of the lines of block, is called anisotropic reentry.148 Although the mechanisms for the formation of the functional lines of block in anisotropic reentrant circuits has not yet been completely elucidated, the relationship between the regions in which they form and the microscopic anatomy of those regions may be relevant.159 Stable reentrant circuits associated with sustained, monomorphic VT in the canine model of infarction occur in the very thin areas of the epicardial border zone where the altered distribution of connexin43 extends throughout its full thickness. Boundaries between these regions with full-thickness abnormalities and adjacent regions that have more layers of surviving cells, and abnormal connexin43 distribution extending only part way through the epicardial border zone, are the locations

of the functional lines of block in the reentrant circuits.159 This relationship is shown in Figure 12. The top panel is an activation map of a figure-of-8 reentrant circuit in the epicardial border zone of a 4-day-old canine infarct. The bottom panel shows the location of full-thickness gap-junctional disturbances (circles) and partial-thickness gap-junctional disturbances (X's) determined by fluorescent antibody techniques. The junction of the full-thickness and partial-thickness disturbance correlates with the location of the functional lines of block of the reentrant circuit. Therefore, transverse conduction is decreased in these regions, leading to the occurrence of the lines of block. Although much has been written on the role of fibrosis and increased connective tissue septation in promoting nonuniformity of propagation,11,13,122,160 an abnormal pattern of gap junction distribution in the absence of fibrotic scarring may be an important factor in the substrate for reentry after infarction. The mechanism by which the change in gapjunctional distribution causes nonuniform anisotropy and influences the location and characteristics of the reentrant circuit in this experimental model, possibly by defining the location of the lines of functional block, has yet to be determined. The abnormal redistribution of gap junctions to the lateral interfaces between myocytes might be expected to enhance (rather than impair) side-to-side coupling, thereby improving transverse conduction and reducing anisotropy. However, the presence of connexin labeling in immunohistochemical studies, the observation of morphologically recognizable gap junctions using electron microscopic techniques, or the detection of mRNA for a particular connexin must be interpreted with some caution, as these findings do not necessarily signify the presence of intact or functional gap

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Figure 12. Top: Map of activation times of a stable reentrant circuit during sustained ventricular tachycardia in the epicardial border zone of a 4day-old canine infarct. The activation times (in ms, small numbers) are shown, as are lines of isochronal activation, at 10-ms intervals (larger numbers). The lines of functional block are shown by the thick black lines. Arrows point out the activation pattern. Bottom: Map of the distribution of fullthickness disturbance of gap junction organization (o = fullthickness disturbance, x = partial-thickness disturbance) in the same 6 x 6 cm square of the epicardial border zone. The area of full-thickness gap junction disarray coincides approximately with the common central pathway of the reentrant circuit, and the borders between full-thickness and partial-thickness gap junctional array locates the line of functional block. Reproduced from reference 159, with permission.

junctions nor do they indicate the func- dosis, increased intracellular calcium) tional status of the gap junctions. Growing that may act to uncouple the border zone knowledge of the multiplicity of connexin myocytes. Furthermore, there is a conisoforms that exist in normal mammalian centration-dependent stimulation of conmyocardium 54,113 raises the additional nexin43 mRNA and protein expression, question of alterations of the relative albeit in cultured fibroblasts,161 which expression of these connexins in disease could also have an important pathophysstates.52,129 Presently, it is unknown iological role in the early healing phase whether such changes take place in the following infarction. At present, the funcsetting of myocardial ischemia or infarc- tional status of the gap junctions in these tion; but if they do, alterations in cou- border zone cells is unknown, but one pospling characteristics would be expected sibility is that the redistribution of gap to accompany them. The redistribution junctions may be a compensatory response of connexin43 in the epicardial border to substantial metabolic uncoupling in zone should, however, be considered in this tissue. Metabolic uncoupling may the context of the likely metabolic dis- reduce conductance more in the transturbances of ischemic tissue (hypoxia, aci- verse direction than longitudinal,115, 162

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and the redistribution of gap junctions to the lateral cell borders may incompletely counteract the consequent tendency to enhanced anisotropy of conduction. A similar concept of compensatory alterations of gap junctions in pathological tissue has previously been hypothesized as a possible explanation for the alterations of connexin isoform expression in myocardial hypertrophy.52 It would therefore seem possible that, under pathological conditions, myocytes may be capable of modulating the nature of their coupling to neighboring cells by varying the organization and composition of gap junctions. If the zone of full-thickness gap-junctional disturbance was characterized by selective impairment of transverse coupling, myocardial conduction between the lines of functional block (the common central pathway) would show enhanced anisotropy, with an even greater tendency than normal for this myocardium to support longitudinal conduction more than transverse (Figure 12). However, as a propagating wavefront through the common central pathway reaches the end of the region of full-thickness disturbance, its outer edges would tend to encounter myocardium with only a partial-thickness disturbance of junction distribution and with better transverse coupling particularly in the more superficial cell layers. Propagation would therefore be improved transversely, and start turning laterally. Once transverse conduction in this direction extended beyond the line of full-thickness disturbance, propagation would then occur longitudinally (in the opposite direction) through the excitable tissue lateral to, and previously protected from depolarization by, the enhanced anisotropy defining the lines of functional block. With the curvature of the limit of full-thickness gapjunctional disturbance at the other end of the lines of functional block, the parallel wavefronts in the outer pathways will, by the same mechanism, start to propagate

transversely and turn medially to coalesce, thus defining the other end of the line of functional block (Figure 12). Remodeling of experimental and human infarct structure continues as the infarcts heal, leading to further changes with time. In particular, the deposition of connective tissue and the formation of the scar can distort the normal relationship of the surviving myocardial fiber bundles.158 This in turn influences conduction characteristics. Figure 13 illustrates these changes in the epicardial border zone of canine infarcts; however similar changes occur in the subendocardial border zone or in regions where fiber bundles penetrate into the solid core of the infarct in both experimental and human infarcts. The muscle cells become trapped in the dense scar tissue formed from the adjacent infarct. In some regions myocardial fibers can become markedly separated from each other along their length.122, 146, 158 In a quantitative study on healed canine infarcts, it was found that there is a concomitant reduction in the number of cells to which each myocyte is connected, from 11.2 in normal tissue to 6.5 in the fibrotic infarct border zone, associated with a greater reduction of predominantly side-to-side cell interconnections than end-to-end.122 Connections of cells in primarily side-to-side apposition were found to be reduced by 75% whereas primarily end-to-end connections was reduced by 22%.122 Overall, these results are consistent with the hypothesis that there is reduced cellular coupling with a disproportionate increase of resistivity in the transverse direction, thus enhancing anisotropy. In canine LVs up to 10 weeks after infarction, the surviving myocardium adjacent to the healed infarct has smaller and fewer gap junctions per unit length of intercalated disk and per unit myocyte sectional area.122 A selective reduction of the larger junctions results in a decrease in the proportion of total gap junction in the interplicate segments of the intercalated disk.122

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Figure 13. Surviving epicardial border zone muscle fibers in a 2-week-old canine infarct (A and B) and in a 2-month-old canine infarct (C and D). In A, the thin surviving rim (arrows) consists of several layers of ventricular muscle cells between the epicardium and the granulation tissue of the healing infarct. These surviving cells are separated by fibrous tissue, especially adjacent to the infarct. The parallel orientation of the myocardial fibers is maintained. At high magnification (B), these myocardial cells are shown to be intact with distinct cross striations. In C, the disorganization of the surviving myocardial cells in the thin rim at 2 months is evident. The cells are widely separated and disoriented because of ingrowth of fibrous tissue from the adjacent infarct. At high magnification (D), the myocardial cells have distinct cross striations and central nuclei. The bars represent 50 jam. Reproduced from reference 158, with permission.

Immunohistochemical examination of connexin43 gap-junctional membrane in the border zone of healed human infarcts has demonstrated the occurrence of gap-junctional reorganization in addition to the reduced transverse connections described above; altered gap junction distribution occurs in surviving myocytes up to 700 [im from the interface with the fibrotic infarcted tissue (Figure 14).111 Within this border zone region, compar-

atively few labeled gap junctions are organized into discrete, transversely orientated intercalated disks, and many are spread longitudinally over the cell surface. The dispersed connexin43 is still located at cell-to-cell appositions in regions where they are not disrupted by the encroaching scar tissue (Figure 14A). Individual junctions and groups of junctions, though often maintaining intercellular gap-junctional contact, are displaced so that discrete

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Figure 14. Confocal micrographs of longitudinally sectioned connexin43-immunolabeled human ventricular myocardium from the border of a healed infarct. A. At lower power, showing the infarct scar (s) with no labeling, the highly disrupted gap-junctional distribution within about 700 jim of the scar and the normal appearances more distant from the scar (top left corner). x210. B. At high power, showing myocytes traversing densely fibrotic scar (no labeling). There is profuse label along the length of these attenuated and degenerated but viable cells. x810. Reproduced from reference 108, with permission.

intercalated disk zones are less clearly defined (Figures 14 through 16). This latter feature is most evident in healed partial-thickness myocardial infarction, in which the demarcation between scar and myocardium is least discrete, with greater interdigitation of these tissues. The disruption of the gap junction distribution in the infarct-related tissue is possibly due to a redistribution of the preexisting population of junctions rather than the cells producing an entirely new, modified population.111 In addition, some junctional contacts are entirely disrupted, and

intracytoplasmic junctions, previously reported as a feature of degenerating myocytes in a variety of cardiac pathological conditions,163 are seen and are likely to contribute to the dispersed immunolabeling pattern observed by confocal microscopy.111 The electrophysiological effects of the anatomical structure of healed infarct border zones are striking. The reduced connections among fiber bundles described above lead to slow activation. Detailed measurements of activation patterns and transmembrane potentials in isolated,

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Figure 15. Localization of the abnormally distributed connexin43 illustrated by a confocal optical section series of images taken at 1-jim steps through a human infarct border zone myocyte, showing connexin43 label along the edge of the cell in (i) (arrow), with a progressive change in successive slices to show the upper surface of the cell in (v) and the other edge of the cell in (vi), thus describing the surface of the myocyte. Images such as these suggest that this abnormally distributed label is at or near the cell surface. x1100. Reproduced from reference 97, with permission.

superfused preparations of the epicardial border zone from healed canine infarcts

plified in the left panel, in which conduction velocity in the direction of the arrows have illustrated these conduction prop(in the direction of the long axis of the erties, which are also expected to occur in muscle fibers) is 20 to 40 cm/s. (The other regions of healed infarcts with a isochrones are much more widely spaced, similar anatomy.146 Figure 17 compares reflecting the faster conduction velocity.) activation of the epicardial border zone The very slow conduction velocity occurs in a healed infarct (2 months, right panel) in the border zone of healed infarcts (right with activation in a healing infarct (5 panel) despite the normal transmembrane days, left panel). In the 2-month infarct, potentials recorded at most sites as exemactivation moving in the directions indi- plified by the record of the action potencated by the arrows is very slow, as shown tial above the map. The slow activation is by the close bunching of the isochrones. In therefore dependent on the structural altersome regions it takes the activation wave ations that occur as the infarct heals rather 10 ms to move a distance of 0.5 mm, a con- than on abnormalities in transmembrane duction velocity of 0.05 cm/s. This is much potentials.146 In regions in which there is slower than in healing infarcts as exem- no longer parallel orientation of muscle

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Figure 16. Thin section electron micrograph showing intact gap-junctional membrane (arrows) between cell processes of 2 highly degenerated myocytes in a human infarct border zone, showing amorphous cytoplasm and an absence of contractile apparatus. x40,000. Reproduced from reference 111, with permission.

bundles, there no longer exist the welldefined anisotropic properties seen in healing infarcts, that is, conduction is slow in all directions rather than just transverse to the long axis of parallel organized muscle bundles. These same structural features found in the epicardial border zone of canine infarcts, regions of sparse, poorly connected myocardial fibers in disarray, and regions of parallel oriented bundles of fibers disconnected in the transverse direction, also occur in the epicardial and endocardial border zone of human infarcts and are expected to affect conduction properties in the same way that they do in the experimental infarcts. In studies on infarcted human papillary muscle, de Bakker et al.164 mapped impulse propaga-

tion in the thin bundles of muscle fibers that coursed through the infarct scar on the subendocardial surface. They found that the parallel oriented fiber bundles formed conduction pathways insulated from each other by the connective tissue septa except at occasional sites along the length where they were interconnected. Conduction velocity along each of the tracts, parallel to the long axis of the fiber bundles, was rapid, 0.79 m/s (probably because action potentials may be normal and longitudinal connections are not disrupted), but transverse activation was very slow because of the sparse interconnections among the bundles. These conduction pathways can form reentrant circuits.

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Figure 17. Activation maps of small regions of epicardial border zones from a 5-day-old canine infarct (left) and a 2-month-old infarct (right). Action potentials were recorded at each of the sites shown by the dots to construct the map. An electrogram was recorded at the site indicated by the larger stippled circle. Representative action potentials and electrograms are shown above each map. The arrows and isochrones show the direction of propagation. The distance scale for each panel is shown below; note that the scale is twice as large for the 5-day-old infarct than the 2-month-old infarct. Reproduced from reference 146, with permission.

Altered Expression of Connexin43— A General Occurrence in Chronic Myocardial Disease? An alteration in connexin43 gap junctions is not confined to the ischemic heart. Ischemic hearts can have associated hypertrophy,165 and the effects of hypertrophy alone have been assessed by examination of nonischemic hypertrophied myocardium obtained from patients undergoing surgical replacement of a stenosed aortic valve. Quantitative confocal microscopy revealed a 40% reduction per unit volume of connexin43 compared to control heart tissue.25 The reduction appears to occur by cells

maintaining an approximately constant gap junction complement per cell while undergoing considerable increase in size. Decreased connexin43 levels have also been reported by quantitative immunoblotting of myocytes isolated from transgenic hypertensive rats.52 A marked (54%) downregulation of connexin43 mRNA and protein expression occurs in the LVs of patients with idiopathic dilated cardiomyopathy and severely impaired LV function, which, unlike the ischemic heart, in which there is a concomitant upregulation of connexin40 mRNA, shows no change in connexin40 mRNA or protein levels.166 Infection of cultured myocytes with Trypanosoma cruzi,

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the unicellular parasite responsible for Chagas' disease (the most common cause of heart disease in South America), is reported to lead to reduced levels of immunocytochemical staining of connexin43 gap junctions.167 Altered expression of connexin43 in the heart may therefore prove to be a general feature of diverse chronic myocardial diseases. Further, that this feature is common to ischemic heart disease, hypertrophy, and Chagas' disease, all of which have an arrhythmic tendency, supports the possibility of an association between connexin43 levels and conduction disturbances. If this is the case, possible alterations in the quantity and spatial distribution of myocardial connexins and gap junctions along with changing connexin phenotypes and post-translational modification (e.g., phosphorylation states) may modulate the effects of altered connexin43 expression. The development of models for investigating the effects of overexpression and underexpression (or complete ablation) of connexin expression168 in genetically altered animals will provide a useful tool with which such fundamental questions can be investigated.

Summary and Conclusions

In the complex world of arrhythmogenesis and the electrical myocyte networks that underlie both normal and abnormal conduction, there has been progress in understanding the relevance of tissue architecture and the hardware for communication in the form of the gapjunctional channels. Myocardium has the potential for substantial remodeling of its gap-junctional network to become a fundamental component of the anatomical substrate for arrhythmogenesis. Little is yet known, however, of the language of communication via these networks and

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structure on reentrant circuits in the epicardial border zone of subacute canine infarcts. Circ Res 1988;63:182–206. Hoyt RH, Cohen ML, Saffitz JE. Distribution and three-dimensional structure of intercellular junctions in canine myocardium. Circ Res 1989;64:563-574. Dolber PC, Beyer EC, Junker JL, Spach MS. Distribution of gap junctions in dog and rat ventricle studied with a doublelabel technique. J Mol Cell Cardiol 1992;24:1443-1457. Beyer EC, Kistler J, Paul DL, Goodenough DA. Antisera directed against connexin43 peptides react with a 43-kd protein localized to gap junctions in myocardium and other tissues. J Cell Biol 1989;108:595–605. Yancey SB, Biswal S, Revel J-P. Spatial and temporal patterns of distribution of the gap junction protein connexin43 during mouse gastrulation and organogenesis. Development 1992; 114:203–212. Fromaget C, El Aoumari A, Gros D. Distribution pattern of connexin43, a gap-junctional protein, during the differentiation of mouse heart myocytes. Differentiation 1992;51:9-20. Luke RA, Saffitz JE. Remodeling of ventricular conduction pathways in healed canine infarct border zones. J Clin Invest 1991;87:1594-1602. Saffitz JE, Davis LM, Darrow BJ, et al. The molecular basis of anisotropy: Role of gap junctions. J Cardiovasc Electrophysiol 1995;6:498–510. Cooklin M, Sheridan DJ, Fry CH. Investigation of conduction velocity changes in myocardial hypertrophy: Role of altered junctional impedance. Circulation 1995;92:I503. Sommer JR, Dolber PC. Cardiac muscle: Ultrastructure of its cells and bundles. In: Paes de Carvalho A, Hoffman BF, Lieberman M (eds): Normal and Abnormal Conduction in the Heart. Mt. Kisco, New York: Futura Publishing Co.; 1982:127. Roberts DE, Hersh LT, Scher AM. Influence of cardiac fiber orientation on wavefront voltage, conduction velocity and tissue resistivity in the dog. Circ Res 1979;44:701-712. Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at a microscopic level. Electrical description of myocardial architecture and its

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application to conduction. Circ Res 1995; 76:366-380. 128. Chen PS, Cha YM, Peters BB, Chen LS. Effects of myocardial fiber orientation on the electrical induction of ventricular fibrillation. Am J Physiol 1993;264: H1760-H1773. 129. Peters NS, del Monte F, MacLeod KT, et al. Increased cardiac myocyte gapjunctional membrane early in renovascular hypertension. J Am Coll Cardiol 1993;21:59A. 130. Wit AL, Janse MJJ. The Ventricular Arrhythmias of Ischemia and Infarction. Electrophysiological Mechanisms. Mt Kisco, New York: Futura Publishing Co.; 1993. 131. Quan W, Rudy Y. Unidirectional block and reentry of cardiac excitation: A model study. Circ Res 1990;66:367-382. 132. Hiramatsu Y, Buchanan JW, Knisley SB, Gettes LS. Rate-dependent effects of hypoxia on internal longitudinal resistance in guinea pig papillary muscles. Circ Res 1988;63:923–939. 133. Ikeda K, Hiraoka M. Effects of hypoxia on passive electrical properties of canine ventricular muscle. Pflugers Arch 1982; 393:45-50. 134. Streit J. Effects of hypoxia and glycolytic inhibition on electrical properties of sheep cardiac Purkinje fibres. J Mol Cell Cardiol 1987; 19:875–885. 135. Tranum-Jensen J, Janse MJ, Fiolet JWT, et al. Tissue osmolality, cell swelling and reperfusion in acute regional myocardial ischemia in the isolated porcine heart. Circ Res 1981;49:364–381. 136. McCallister LP, Trapukdis S, Neely JR. Morphometric observations on the effects of ischemia in the isolated perfused rat heart. JMol Cell Cardiol 1979;11:619–630. 137. Unwin PNT, Zampighi G. Structure of the junction between communicating cells. Nature 1980;283:545-549. 138. Dahl G, Isenberg G. Decoupling of heart muscle cells: Correlation with increased cytoplasmic calcium activity and with changes in nexal ultrastructure. J Membr Biol 1980;53:63–75. 139. Deleze J, Herve JC. Effect of several uncouplers of cell-to-cell communication on gap junction morphology in mammalian heart. J Membr Biol 1983;74: 203-215. 140. Green CR, Severs NJ. Gap junction connexon configuration in rapidly frozen myocardium and isolated intercalated disks. J Cell Biol 1984;99:453-463.

141. Shibata Y, Page E. Gap junctional structure in intact and cut sheep cardiac Purkinje fibers: A freeze-fracture study of Ca2+-induced resealing. J Ultrastruc Res 1981;75:195-204. 142. Kleber AG, Cascio WE. Ischemia and Na+/K+ pump function. In: Rosen MR, Palti Y (eds): Lethal Arrhythmias Resulting from Myocardial Ischemia and Infarction. Boston: Kluwer Academic Publishers; 1989:77-90. 143. Cascio WE, Yan GX, Kleber AG. Passive electrical properties, mechanical activity, and extracellular potassium in arterially perfused and ischemic rabbit ventricular muscle. Effects of calcium entry blockade or hypocalcemia. Circ Res 1990;66:1461-1473. 144. Josephson ME, Horowitz LN, Farshidi A, Kastor JA. Recurrent sustained ventricular tachycardia. 1. Mechanisms. Circulation 1978;57:431-440. 145. DeBakker JMT, Coronel R, Tasseron S, et al. Ventricular tachycardia in the infarcted, Langendorff-perfused human heart: Role of the arrangement of surviving cardiac fibers. J Am Coll Cardiol 1990;15:1594-1607. 146. Gardner PI, Ursell PC, Fenoglio JJ Jr, Wit AL. Electrophysiologic and anatomic basis for fractionated electrograms recorded from healed myocardial infarcts. Circulation 1985;72:596–611. 147. Myerburg RJ, Gelband H, Nilsson K, et al. Long-term electrophysiological abnormalities resulting from experimental myocardial infarction in cats. Circ Res 1977;41:73–84. 148. Wit AL, Dillon SM, Coromilas J, et al. Anisotropic reentry in the epicardial border zone of myocardial infarcts. Ann NYAcad Sci 1990;591:86–108. 149. Bolick DR, Hackel DB, Reimer KA, Ideker RE. Quantitative analysis of myocardial infarct structure in patients with ventricular tachycardia. Circulation 1986;74:1266–1279. 150. Wit AL, Allessie MA, Bonke FIM, et al. Electrophysiologic mapping to determine the mechanism of experimental ventricular tachycardia initiated by premature impulses. Experimental approach and initial results demonstrating reentrant excitation. Am J Cardiol 1982;49:166185. 151. Mehra R, Zeiler RH, Gough WB, ElSherif N. Reentrant ventricular arrhythmias in the late myocardial infarction

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period. 9. Electrophysiologic-anatomic correlation of reentrant circuits. Circulation 1983;67:11–24. Hirzel HO, Nelson GR, Sonnenblick EH, Kirk ES. Redistribution of collateral blood flow from necrotic to surviving myocardium following coronary occlusion in the dog. Circ Res 1976;39:214–222. Friedman PL, Fenoglio JJ Jr, Wit AL. Time course for reversal of electrophysiological and ultrastructural abnormalities in subendocardial Purkinje fibers surviving extensive myocardial infarction in dogs. Circ Res 1975;36:127–144. Fenoglio JJ Jr, Pham TD, Harken AH, et al. Recurrent sustained ventricular tachycardia: Structure and ultrastructure of subendocardial regions in which tachycardia originates. Circulation 1983; 68:518–533. Josephson ME. Clinical Cardiac Electrophysiology. Techniques and Interpretations. Philadelphia: Lea and Febiger; 1993. El-Sherif N. The figure 8 model of reentrant excitation in the canine postinfarction heart. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology and Arrhythmias. New York: Grune & Stratton; 1985:363-378. Littmann L, Svenson RH, Gallagher JJ, et al. Functional role of the epicardium in postinfarction ventricular tachycardia. Observations derived from computerized epicardial activation mapping, entrainment, and epicardial laser photoablation. Circulation 1991;83:1577– 1591. Ursell PC, Gardner PI, Albala A, et al. Structural and electrophysiological changes in the epicardial border zone of canine myocardial infarcts during infarct healing. Circ Res 1985;56:436–451. Peters NS, Coromilas J, Severs NJ, Wit AL. Disturbed connexin43 gap junction

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distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation 1997;95:988–996. Saffitz JE, Hoyt RH, Luke RA, et al. Cardiac myocyte interconnections at gap junctions-role in normal and abnormal electrical conduction. Trends Cardiovasc Med 1992;2:56–60. Doble BW, Kardami E. Basic fibroblast growth factor stimulates connexin-43 expression and intercellular communication of cardiac fibroblasts. Mol Cell Biochem 1995;143:81–87. Balke CW, Lesh MD, Spear JF, et al. Effects of cellular uncoupling on conduction in anisotropic canine ventricular myocardium. Circ Res 1988;63:879-892. Buja LM, Ferrans VJ, Maron BJ. Intracytoplasmic junctions in cardiac muscle cells. Am JPathol 1974;74:613-648. de Bakker JMT, van Capelle FJL, Janse MJJ, et al. Slow conduction in the infarcted human heart. "Zigzag" course of activation. Circulation 1993;88:915–926. Anversa P, Beghi C, Kikkawa Y, Olivetti G. Myocardial response to infarction in the rat. Morphometric measurement of infarct size and myocyte cellular hypertrophy. Am J Pathol 1985;484:492. Dupont E, Kaprielian R, Yeh H-I, et al. Connexin messenger ribonucleic acid expression in the healthy and diseased human heart. Eur Heart J 1996; 17(Abstract):600. Campos De Carvalho AC, Tanowitz HB, Wittner M, et al. Gap junction distribution is altered between cardiac myocytes infected with Trypanosoma cruzi. Circ Res 1992;70:733-742. Reaume AG, De Sousa PA, Kulkarni S, et al. Cardiac malformation in neonatal mice lacking connexin43. Science 1995; 267:1831-1834.

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Chapter 11 The Figure-of-Eight Model of Reentrant Ventricular Arrhythmias Nabil El-Sherif, MD, Edward B. Caref PhD, and Mark Restivo, PhD

Reentrant excitation is an important mechanism for ventricular tachyarrhythmias. A better understanding of this mechanism can provide a basis for improved management. Reentrant excitation occurs when the propagating impulse does not die out after complete activation of the heart, as is normally the case, but persists to reexcite the atria or ventricles after the end of the refractory period. Reentrant excitation can be subdivided into circus movement excitation and reflection. In circus movement reentry, the activation wavefront encounters a site of unidirectional conduction block and propagates in a circuitous pathway before reexciting the tissue proximal to the site of block after expiration of its refractory period. In this chapter, circus movement reentry is discussed with special reference to the figure-of-8 model of reentry first described in the canine postinfarction model.1 Classification of Circus Movement Reentry Circus movement reentry can be classified into anatomical and functional

types. This classification is based primarily on the nature of the central obstacle around which the circulating wavefront propagates. A combination of functional and anatomical obstacles is sometimes necessary for the initiation of circus movement reentry. Anatomical or Ring Models of Reentry In the anatomical model of reentry, the reentrant pathway is fixed and anatomically determined. The earlier models of circus movement consisted of rings of cardiac and other tissue obtained from various animals including mammals (Figure 1).2–5 In the intact heart, excitable bundles isolated from surrounding myocardium can form anatomical rings for potential circus movement. Examples include circus movement involving normal atrioventricular (AV) conducting bundles and AV accessory pathways,6 circus movement involving the His bundle branches or Purkinje network,7 and circus movement

Supported in part by Veterans Administration Medical Research Funds to NES and MR. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003. 237

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Figure 1. Anatomical (ring) models of reentry. A. Mines' diagram of a ring preparation composed of the auricle and ventricle of the tortoise, in which he observed reciprocating rhythm. Both connections between auricle and ventricle could transmit an excitation wave. During reciprocating rhythm, the 4 portions of the preparation marked V1, V2, A1, A2 contracted in that order. From Mines GR. J Physiol 1913;46:349–382. B. A proposed mechanism for reentry in a Purkinje-muscle loop. The diagram shows a Purkinje fiber bundle (D), which divides into 2 branches, both connected distally by ventricular muscle. Circus movement will develop if the stippled segment (A-B) is an area of unidirectional conduction. An impulse advancing from D would be blocked at A but would reach and stimulate the ventricular muscle at C by way of the other terminal branch. The excitation from the ventricular fiber would then reenter the Purkinje system at B and traverse the depressed region at a slow rate so that by the time it arrived at A, the site would have recovered from refractoriness and would again be excited. From Schmitt FO, Erlanger J. Am J Physiol 1928/1929;87:326. C. Diagram of a possible reentrant pathway, partly through bundles of surviving myocardial fibers embedded in the fibrous tissue of an old myocardial infarct. The main bundle bifurcates and gives rise to 2 possible exits toward the larger subendocardial muscle mass. Reproduced with permission from deBakker JMT, Van Capelle FJL, Janse MJ, et al. Circulation 1988;77:589–606. Copyright 1988, American Heart Association. D. Diagram of the initiation of circus movement in a ring model, emphasizing the importance of unidirectional block. A properly timed stimulus (*) will block in one direction because of nonhomogeneous refractoriness (stippled zone) but will continue to conduct in the ring in the other direction. A circus movement will be established if the returning wavefront finds that the site of unidirectional block has recovered excitability, thus permitting conduction to proceed uninterrupted.

using surviving myocardial bundles in a postinfarction scar.8 It is important to remember, however, that an anatomically determined pathway that can potentially support reentry does not automatically create circus movement. A critical functional perturbation of part of

the pathway must take place before a circus movement is initiated. Central to the initiation of a circus movement in an anatomical ring is the development of unidirectional block. Here, a stimulus blocks in one direction because of nonhomogeneous electrophysiological properties, but

FIGURE-OF-8 MODEL OF REENTRANT VENTRICULAR ARRHYTHMIAS it continues to conduct in the other direction. A circus movement is established if the returning wavefront finds that the site of unidirectional block has recovered excitability, permitting conduction to proceed uninterrupted. Thus, it is clear that in an anatomically predetermined circuit, a significant functional component exists and can be modulated, for example, by pharmacological agents. Surgical interruption of an anatomical ring-like circuit can be accomplished by cutting (or ablating) at any point along the ring. For example, in the ring circuit that uses an AV accessory pathway, the anatomical substrate consists in large part of pathways of excitable bundles that are not connected to adjacent atrial and ventricular myocardium. The circuit can be interrupted with ease by interrupting conduction of either the normal AV pathway or, as is currently the practice, the accessory AV pathways.

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model,1 the anisotropic model,16 and the spiral wave model17,18 (Figure 2). Nature and Characteristics of the Functional Obstacle of the Reentrant Circuit

The nature of the functional arc of block during the initiation of a reentrant circuit has been investigated by several groups. Allessie et al.11 were the first to show that differences in refractory periods of atrial fibers at adjacent sites can result in functional block if premature stimulation is applied to the site of shorter refractoriness. Later, Gough et al.12 showed that circus movement developed around arcs of functional conduction block in the surviving epicardial layer overlying canine ventricular infarction owing to spatial inhomogeneity of refractoriness. The latter could be due to differences in active membrane properties of adjacent fibers that affect their depolarization or repolarization characteristics, or due Functional Models of Reentry to discrete differences in intercellular Functional reentrant circuits can connections. Depression of active membrane propdevelop in the interconnected syncytium of myocardial bundles in the atria or ven- erties of myocardial fibers is a major tricles. Central to the development of a determinant of functional conduction functional circus movement is the cre- block and slowed conduction, leading to ation of a functional barrier of conduc- circus movement reentry in the acute tion block. The nature of this functional phase of myocardial ischemia.19,20 Within barrier has been investigated in some minutes of coronary artery occlusion, the detail during the initiation of circus move- cells in the center of the ischemic zone ment. Functional conduction block initi- show progressive decrease in resting ating a circus movement can be caused by membrane potential, action potential (1) abrupt changes in cardiac geometry9; amplitude, duration, and upstroke veloc(2) decremental conduction leading to ity.19 After a brief initial shortening, the propagation failure10; (3) regional differ- refractory period begins to lengthen even ences in refractory periods11–13; or (4) dif- though action potential duration continferences in conduction properties relative ues to shorten.19 El-Sherif et al.21 and to fiber orientation.14 The last 2 mecha- Lazzara et al.22 used the term postreponisms have received wider attention. The larization refractoriness to indicate that models of functional reentrant circuits at certain stages of ischemia, the memthat have been widely investigated are brane may remain inexcitable even when the leading circle model,15 the figure-of-8 it has been completely repolarized. Such

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Figure 2. Functional models of reentry. Leading Circle Model: diagrammatic representation of this model in isolated left atrium of the rabbit. The central area is activated by converging centripetal wavelets. Reproduced with permission from Allessie MA, Bonke FIM, Schopman FJG. Circ Res 1977;41:9–18. Copyright 1977, American Heart Association. Figure-of-8 Model: activation map (in 20-ms isochrones) of a figure-of-8 circuit in the surviving epicardial layer of a dog 4 days after ligation of the left anterior descending artery (LAD). The circuit consists of clockwise and counterclockwise wavefronts around 2 functional arcs of conduction block that coalesce into a central common front that usually represents the slow zone of the circuit. From El-Sherif N. In: Zipes D, Jalife J (eds): Cardiac Electrophysiology and Arrhythmias. New York: Gruneand Stratton; 1985:363-378. Anisotropic Model: activation map and schematic representation of the reentrant circuit during sustained monomorphic ventricular tachycardia in a thin epicardial layer frame obtained by an endocardial cryotechnique in a Langendorff-perfused rabbit heart. A single-loop reentry forms around a functional arc of conduction block. From Brugada J, et al. Pacing Clin Electrophysiol 1991 ;14:1943–1946. Spiral Wave Model: activation map of spiral wave activity in a thin slice of isolated ventricular muscle from a sheep heart (right panel). Isochrone lines were drawn from raw data by overlaying transparent paper on snapshots of video images during spiral wave activity (left panel not from same experiment). Each line represents consecutive positions of the activation front recorded every 16.6 ms. From Krinsky VL, et al. Proc R Soc Lond 1992;437:645–655.

increases in refractory period can exceed the basic cycle length, at which point 2:1 responses occur.19 The marked dependence of recovery of excitability on the resting potential in partially depolarized ischemic myocardial cells is probably the most

important determinant for the occurrence of slow conduction and conduction block in the acute phase of myocardial ischemia.20 The depressed upstroke of ischemic action potentials is the result of a depressed fast Na+ current.23 The postrepolarization

FIGURE-OF-8 MODEL OF REENTRANT VENTRICULAR ARRHYTHMIAS refractoriness in depolarized cells has been attributed to delayed recovery from inactivation of the fast Na+ current.24 In the subacute (healing) phase of myocardial ischemia (1 to 7 days after infarction), depressed membrane properties of surviving myocardial fibers bordering the infarction continue to be a major determinant of conduction abnormalities underlying circus movement reentry. Intracellular recordings from the surviving "ischemic" epicardial layer of 3 to 5 days postinfarction canine heart show cells with various degrees of partial depolarization, reduced action potential amplitude, and decreased upstroke velocity.25–27 Full recovery of responsiveness frequently outlasts the action potential duration reflecting the presence of postrepolarization refractoriness. In these cells, premature stimuli could elicit graded

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responses over a range of coupling intervals. Slowed conduction, Wenckebach periodicity, and 2:1 or higher degrees of conduction block could easily be induced by fast pacing or premature stimulation (Figure 3). Isochronal mapping studies have shown that both the arcs of functional conduction block and the slow activation wavefronts of the reentrant circuit develop in the surviving electrophysiological abnormal epicardial layer overlying the infarction.28–30 Studies from the same laboratory using high-resolution mapping of activation and refractory patterns have shown that functional block is necessary for both the initiation and sustenance of reentrant excitation and that the functional block necessary for initiation of reentry is due to abrupt changes in refractoriness occurring over distances of 1 mm or less (Figures 4 and 5).13 The abrupt

Figure 3. Recordings from a dog with a 3-day-old infarction, illustrating action potential characteristics in ischemic epicardium. The sketch of the preparation shows 2 intracellular recordings (X and Y) and a close bipolar recording (1) from the infarction zone (stippled area). Ischemic cells had decreased upstroke velocity, reduced action potential amplitude, and a variable degree of partial depolarization. The 2 cells were recorded 5 mm apart in the infarction zone but showed significant difference in their resting potential. The resting potential of the Y cell was only slightly reduced (-80 mV), but it still had a poor action potential. The preparation was stimulated at a cycle length of 290 ms, which resulted in a Wenckebach-like conduction pattern. Note that the pacing cycle length exceeded the action potential duration of the cells, suggesting that refractoriness extended beyond the completion of the action potential (i.e., postrepolarization refractoriness). Reproduced with permission from El-Sherif N, Lazzara R. Circulation 1979;60:605–615. Copyright 1979, American Heart Association.

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Figure 4. High-resolution determination of spatial refractory gradients and their relationship to the arc of functional conduction block from a 4-day-old canine infarction. A high-density bipolar electrode plaque with 1 -mm interelectrode spacing was positioned on the epicardial surface at the site of the arc of block induced by premature stimulation (S2) as determined from an earlier low-resolution sock electrode array. The plaque was oriented with the electrode rows perpendicular to the arc. The figure illustrates 5 bipolar electrograms recorded successively at 1-mm distance (a to e). The values of the effective refractory period in milliseconds at each site are shown. The arrows indicate the end of the effective refractory period relative to S1 activation at each site. The S1,and S2 activation maps are shown on the right. The asterisk on the S1, map denotes the site of stimulation. During S1, sites a to e were activated sequentially within a 12-ms interval (conduction velocity of 42 cm/s). During S2, conduction between sites a and c was relatively slow compared with S1,. Conduction block developed abruptly between sites c and d. Sites d and e were activated 65 ms later by the wavefront that circulated in a clockwise direction around one end of the arc of block. The site of conduction block coincided with a 35-ms abrupt increase in the effective refractory period between sites c and d. Note that the arc of block was parallel to the left anterior descending artery (LAD), represented by the broken line. Reproduced with permission from Restivo M, Gough WB, El-Sherif N. Circ Res 1990;66:1310–1327. Copyright 1990, American Heart Association.

changes in refractoriness did not seem to be related to specific geometric characteristics or anisotropic conduction properties of the ischemic myocardium. Action potential recordings from surviving myocardial bundles from hearts with chronic (healed) myocardial infarction (MI) have shown a wide spectrum of configurations. Some studies have shown normal action potential characteristics of surviving myocardial bundles from hearts in which circus movement reentry could

be initiated,8,31 whereas other studies have shown various degrees of depressed action potentials.32 In the former situation, reentrant excitation is explained primarily on the basis of the nonuniform anisotropic properties of the surviving myocardial bundles in a healed infarction scar. However, a combination of functional and anatomically determined reentrant circuits in those hearts, similar to original examples of ring model reentry, cannot be ruled out.

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Figure 5. Five successive bipolar electrograms (A-E) recorded at 1 -mm distance across an arc of functional conduction block induced by S2 stimulation (right panel). The layout of the high-density plaque was similar to that shown in Figure 4, but the recordings were obtained from a different experiment. The effective refractory period (ERP) at each site is shown, and the arrows indicate the end of the ERP relative to ST activation. Abrupt conduction block occurred during S2 stimulation between sites B and C and coincided with an abrupt increase in ERP of 25 ms. The asterisks indicate the electrotonic deflection recorded in electrograms C and D distal to block. The amplitude of the electrotonic deflection diminished with the distance from the site of block. A graphic illustration of the distribution of ERP across an 8-mm distance is shown on the left. Reproduced with permission from Restivo M, Gough WB, El-Sherif N. CircRes 1990;66:1310–1327. Copyright 1990, American Heart Association.

Primarily through the work of Spach et al.,14 anisotropic discontinuous propagation was shown to produce all of the conduction disturbances necessary for circus movement reentry without the presence of spatial differences in refractoriness. The safety factor of propagation of early premature impulses was shown to be dependent on fiber orientation, with unidirectional block occurring during propagation along the long axis of the fibers and slowed conduction persisting across the fibers, thus setting the stage

for reentrant excitation. The slower conduction in the transverse direction is due higher axial resistivity, which may be partly explained by fewer shorter gapjunctional contacts in a side-to-side direction.33 The normal uniform anisotropic conduction properties of the myocardium may be altered further after ischemia and can be markedly exaggerated in healed infarcts. Electrical uncoupling and increase of extracellular resistance resulting in reduced space constant have been shown in slowly conducting regions of chronically

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infarcted canine myocardium.34 Spach et al.35 suggested that both spatial inhomogeneity of refractoriness and anisotropic conduction properties may contribute to one model of reentrant excitation in the canine atria. The combination of spatial inhomogeneity of refractoriness and anisotropic conduction properties may be applicable to other models of reentry. A possible example is the experimental model of functional "anisotropic" reentry in which circus movement could be induced in a thin layer of normal myocardium obtained by endocardial cryotechnique in a Langendorffperfused rabbit heart.16 The nature of the central arc of functional block during sustained reentry has been more difficult to investigate. In a report by Dillon et al.,36 it was suggested that most of the central barrier around which circus movement orients in the surviving epicardial layer of the postinfarction canine heart was in fact a line of pseudoconduction block resulting from very slow conduction along the longitudinal fiber axis. However, high-resolution recordings of the central arc of block in this model13 as well as in other atrial models of functional reentry 37,38 clearly showed the presence of a discrete finite zone of functional conduction block explained by the bidirectional invasion of this zone by the opposing activation wavefronts on either side of the central barrier (Figure 6). Electrotonic conduction in this zone could create a constant functional block around which circus movement is oriented. The factors that determine the location and orientation of the central functional barrier during sustained reentry are not well defined and may be related to refractoriness or anisotropic differences. The length of the central functional barrier is also of interest. A circuit with a very small central barrier (i.e., a central core of functional refractory tissue) is typical of the leading circle model of reentry15

and resembles the vortex-like waves or spirals that have been demonstrated in a number of excitable media39 and in normal isolated ventricular muscle.17,18 However, in most of the functional circuits that have been mapped in vitro or in vivo, including the original leading circle model15 and the model of reentry in the Langendorff-perfused rabbit heart,16 the central obstacle was shown to consist of an arc of block of some finite length rather than a confluent central vortex. Topology of Functional Circus Movement The topology of functional circus movement is of both theoretical and practical importance. The typical functional circus movement in a syncytium has a figure-of-8 configuration consisting of clockwise and counterclockwise wavefronts around 2 functional arcs of block that coalesce into a central common front that commonly represents the slow zone of the circuit.1 This zone is the most vulnerable part of the circuit and the site at which pharmacological agents or ablative procedures can selectively modulate the circus movement. On the other hand, a single reentrant functional loop can also develop in a syncytium. However, it usually develops contiguous to an anatomical barrier. The most typical example of the development of a single functional reentrant loop has been shown by Schoels et al.38 in a study of circus movement atrial flutter in the canine postpericarditis model (Figure 7D). In this model, the majority of atrial flutter is due to a single-loop circus movement. During the initiation of a single reentrant loop, an arc of functional conduction block extends to the AV ring, forcing activation to proceed only as a single wavefront around the free end of the arc before breaking through the arc at a site close to the AV ring. Activation continues as

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Figure 6. Recordings of high-density bipolar electrode array at multiple locations (I to IV) along a continuous arc of functional conduction block during a figure-of-8 sustained monomorphic ventricular tachycardia (top panel). In this and subsequent maps, epicardial activation is displayed as if the heart was viewed from the apex located at the center of the circular map. The perimeter of the circle represents the atrioventricular junction. Activation isochrones are drawn at 20-ms intervals. Arcs of functional conduction block are represented by heavy solid lines. Arrows indicate wavefront direction during sustained ventricular tachycardia. Both arcs are oriented approximately parallel to the longitudinal axis of the epicardial muscle fibers. A portion of this activation map is shown in the lower right panel. The shaded rectangles represent the column for each array location. Electrograms recorded in proximity to the arc of block show split electrograms composed of 2 discrete potentials separated by a variable isoelectrical interval: one deflection represents local activation, the other deflection is an electrotonic potential reflecting activation recorded 1 mm away. The interval between the 2 deflections is greatest at the center of the arc (locations II and III), where the difference in isochronal activation, by whole ventricle mapping, is greatest. The interval between the 2 deflections is less as the reentrant impulse circulates around the end of the arc (location I). The electrographic characteristics of functional conduction block are the same at location IV, which indicates that the arc of functional conduction block was longer than that predicted by the whole ventricle mapping technique. The 2 deflections in electrogram d at location III may both represent electrotonic potentials. Reproduced with permission from Restivo M, Gough WB, El-Sherif N. Circ Res 1990;66:1310–1327. Copyright 1990, American Heart Association.

a single circulating wavefront around an arc of block in proximity to the AV ring or around a combined functional/anatomical obstacle with the arc usually contiguous with the inferior vena cava. Spontaneous38 or pharmacologically induced40 termination

of single-loop reentrant circuit occurs when conduction fails in a slow zone and the arc of block rejoins the AV ring. A critical analysis of the leading circle or anisotropic models of reentry15,16 shows that they may be a special modification of

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Figure 7. The leading circle model of reentry. A. and B. Isochronal maps of activation of a premature beat (S2) and the first reentrant beat (A1) from an in vitro preparation of atrial myocardium of the rabbit. The arcs of functional conduction block are represented by heavy solid lines. Isochrones are drawn at 5-ms intervals. Note that the properly timed premature stimulus resulted in a continuous arc of functional conduction block; the activation front circulated around both ends of the arc, coalesced, and then broke through the arc to reexcite myocardial zones on the proximal side of the arc. This resulted in splitting of the original arc into 2 separate arcs. Modified with permission from Allessie MA, Bonke Fl, Schopman FJG. Circ Res 1976;39:168–177. Copyright 1976, American Heart Association. B. A circulating wavefront continued around one of the arcs. However, the second arc of block shifted its site and joined the edge of the preparation so that the second circulating wavefront was aborted. If the preparation in B was inserted into the in situ heart, the second aborted circulating wavefront would be activated, thus resulting in a figure-of-8 reentrant pattern. C. Diagram of the leading circle model. Reproduced with permission from Allessie MA, Bonke FIM, Schopman FJG. Circ Res 1977;41:9–18. Copyright 1977, American Heart Association. D. Isochronal map of atrial epicardial activation during circus movement atrial flutter in the canine sterile pericarditis model. The atria are displayed in a planar projection as though separated from the ventricles along the atrioventricular ring and incised on the inferior bodies of both atrial appendages from the atrioventricular ring to their tips. The shaded area represents the orifices of the atrial vessels. The figure shows a single-loop reentrant circuit around a central obstacle composed of a functional arc of block (heavy solid line) and an anatomical obstacle (the orifice of the inferior vena cava). Reproduced with permission from Schoels W, Gough W, Restivo M, El-Sherif N. Circ Res 1990;67:35–50. Copyright 1990, American Heart Association.

the figure-of-8 model (Figure 7A-C). Thus, a figure-of-8 pattern may be the basic topology of a functional reentrant circuit in the interconnected syncytial structure of the atria and ventricles.1 The long arcs

of functional conduction block that sustain large reentrant circuits in the canine postinfarction ventricle and the small arcs of functional block that sustain small reentrant circuits in the leading circle or

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anisotropic models may represent 2 ends of a spectrum of the same electrophysiological phenomenon. Induced Versus Spontaneous Circus Movement Reentry Figure-of-8 reentrant excitation in the canine postinfarction heart may occur "spontaneously" during a regular cardiac rhythm41 but is commonly induced by premature stimulation. Induction of reentry by premature stimulation depends on the length of the arc of functional conduction block and the degree of slowed conduction distal to the arc induced by premature stimulation.28,29 A premature beat that successfully initiates reentry results in a longer arc of conduction block or slower conduction compared with one that fails to induce reentry (Figure 8). When a single premature stimulus (S2) fails to initiate reentry, the introduction of a second premature stimulus (S3) may be necessary. S3 usually results in a longer arc of conduction block or slower conduction around the arc. The slower activation wavefront travels around a longer, more circuitous route, thus providing more time for refractoriness to expire along the proximal side of the arc of unidirectional block. Reexcitation of this site initiates reentry. The beat that initiates the first reentrant cycle, whether it is an S2 or an S3, results in a continuous arc of conduction block. The activation front circulates around both ends of the arc of block and rejoins on the distal side of the arc of block before breaking through the arc to reactivate an area proximal to the block. This results in splitting of the initial single arc of block into 2 separate arcs. Subsequent reentrant activation continues with afigure-of-8activation pattern, in which 2 circulating wavefronts advance in clockwise and counterclockwise directions, respectively,

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around 2 arcs of conduction block. During a monomorphic reentrant tachycardia, the 2 arcs of block and the 2 circulating wavefronts remain fairly stable. On the other hand, during a pleomorphic reentrant rhythm, both arcs of block and the circulating wavefronts can change their geometric configurations while maintaining their synchrony. The development of multiple asynchronous reentrant circuits usually ushers the onset of ventricular fibrillation.29,42 Reentrant activation spontaneously terminates when the leading edge of both reentrant wavefronts encounters refractory tissue and fails to conduct. This results in coalescence of the 2 arcs of block into a single arc and termination of reentrant activation. For reentry to occur during regular cardiac rhythm, on the other hand, the heart rate should be within the relatively narrow critical range of rates during which conduction in a potentially reentrant pathway shows a Wenckebach-like pattern.41 During a Wenckebach-like conduction cycle, a beat-to-beat increment in the length of the arc of conduction block or the degree of conduction delay occurs until the activation wavefront is sufficiently delayed for certain parts of the myocardium proximal to the arc of block to recover excitability and become reexcited by the delayed activation front. A Wenckebach-like conduction sequence may be the initiating mechanism for repetitive reentrant excitation (e.g., a reentrant tachycardia) or may result in a single reentrant cycle in a repetitive pattern, giving rise to a reentrant extrasystolic rhythm (Figure 9). The majority of reentrant circuits in the canine postinfarction model develop in the surviving epicardial layer and can be viewed as having an essentially 2dimensional configuration. However, reentrant circuits can also be identified in intramyocardial41,43 or subendocardial locations.29 The latter location is of special

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Figure 8. Epicardial isochronal activation maps during a basic ventricular stimulated beat (S-,), initiation of reentry by a single premature stimulus (S2), and sustained monomorphic reentrant ventricular tachycardia (VT). A representative ECG is shown in the lower right panel. The recordings were obtained from a dog 4 days after ligation of the left anterior descending artery (LAD). Site of ligation is represented by a double bar. The outline of the epicardial ischemic zone is represented by the dotted line. During S1, the epicardial surface was activated within 80 ms, with the latest isochrone located in the center of the ischemic zone. S2 resulted in a long, continuous arc of conduction block within the border of the ischemic zone. The activation wavefront circulated around both ends of the arc of block and coalesced at the 100-ms isochrone. The common wavefront advanced within the arc of block before reactivating an area on the other side of the arc at the 180-ms isochrone to initiate the first reentrant cycle. During sustained VT, the reentrant circuit had a figure-of-8 activation pattern in the form of a clockwise and counterclockwise wavefront around 2 separate arcs of functional conduction block. The 2 wavefronts joined into a common wavefront that conducted between the 2 arcs of block. The sites of the 2 arcs of block during sustained VT were different to various degrees from the site of the arc of block during the initiation of reentry by S2 stimulation. The lower right panel illustrates the orientation of myocardial fibers in the surviving ischemic epicardial layer perpendicular to the direction of the LAD. The arrow represents the longitudinal axis of propagation of the slow common reentrant wavefront during a sustained figure-of-8 activation pattern, which is oriented parallel to fiber orientation and perpendicular to the nearby LAD segment. Modified from Assadi M, et al. Am Heart J 1990; 119:1014–1024.

interest because it may be comparable to reentrant circuits described in the surviving subendocardial muscle layer in the heart of patients with chronic ML44 This underscores the fact that, depending on

the particular anatomical features of the infarction and the geometric configuration of ischemic surviving myocardium, reentrant circuits can be located in epicardial, subendocardial, or intramyocardial zones.1

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Figure 9. Isochronal maps of a reentrant trigeminal rhythm. Epicardial activation maps as well as selected electrographic recordings from a dog 4 days after infarction in which a reentrant trigeminal rhythm developed during sinus tachycardia are shown. During sinus rhythm at a cycle length of 325 ms there was a consistent small arc of functional conduction block near the apical region of the infarct and relatively slow activation of nearby myocardial zones (map 1). The activation pattern, however, was constant in successive beats reflecting a 1:1 conduction pattern. Spontaneous shortening of the sinus cycle length to 305 ms resulted in the development of a single reentrant beat after every second sinus beat. During the reentrant trigeminal rhythm, the epicardial activation map of the first sinus beat showed the development of a longer arc of functional conduction block compared with the one during sinus rhythm at a cycle length of 325 ms (map 2). The activation front circulated around both ends of the arc of block but was not sufficiently delayed on the distal side of the arc of block. On the other hand, the activation map of the second sinus beat showed more lengthening of the arc of block at one end but more characteristically a much slower conduction of the 2 activation fronts circulating around both ends of the arc of block (map 3). The degree of conduction delay was sufficient for refractoriness to expire at 2 separate sites on the proximal side of the arc, resulting in 2 simultaneous breakthroughs close to the ends of the arc, thus initiating reentrant excitation. The leading edge of the 2 reentrant wavef ronts coalesced but failed to conduct to the central part of the epicardial surface of the infarct—that is, to areas that were showing slow conduction during the preceding cycle. This limited the reentrant process to a single cycle (map 4). It also resulted in recovery of those myocardial zones in the central part of the infarct, allowing the next sinus beat to conduct with a lesser degree of conduction delay, thus perpetuating the reentrant trigeminal rhythm. Analysis of the 2 electrograms recorded from each of the 2 reentrant pathways (B and C, and D and E, respectively) shows a characteristic 3:2 Wenckebach-like conduction pattern. The figure illustrates the complexity of conduction patterns in ischemic myocardium and the presence of a zone of dissociated conduction. This is represented by site F, which was showing a 2:1 conduction pattern during the 3:2 Wenckebach cycle and reentrant trigeminal rhythm described earlier. From El-Sherif N, et al. J Am Coll Cardiol 1985;6:124–132. Reprinted with permission from the American College of Cardiology.

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lating excitation and to identify the critical site along the reentrant circuit at which interruption of reentrant excitation could be successfully accomplished.45 Spontaneous termination of figure- These studies have demonstrated that of-8 sustained monomorphic reentrant reentrant activation could be successfully ventricular tachycardia (SMVT) always interrupted when cooling or cryoablation occurs when the 2 circulating wavefronts was applied to the part of the slow block in the central common pathway common reentrant wavefront immedi(CCP). Distinct electrophysiological chan- ately proximal to the zone of earliest reacges consistently precede spontaneous tivation (Figure 12). At this site, the termination of stable SMVT. Two basic common reentrant wavefront is usually mechanisms of spontaneous termination narrow and is surrounded on each side have been observed: (1) acceleration of by an arc of functional conduction block. conduction occurs in parts of the reen- On the other hand, localized cooling of trant circuit and is associated with slow- the site of earliest reactivation commonly ing of the conduction and finally conduction failed to interrupt reentry. The common block in the CCP. Acceleration of conduction reentrant wavefront usually broke through occurs in the last few cycles of VT both at the arc of functional conduction block to the outer border of the arcs of functional reactivate other sites close to the origiconduction block in the "normal" myocar- nal reactivation site without necessarily dial zone and at the pivot points to the changing the overall reentrant activation entrance to the CCP (Figures 10 and 11). pattern. Intraoperative detailed endocardial When acceleration of conduction was and epicardial mapping during VT in compensated on a beat-to-beat basis by an patients with previous myocardial infarct equal degree of slowing in the CCP, there and ventricular aneurysm has demowas no discernible change in the cycle nstrated the presence of a figure-of-8 length of the VT in the ECG. In some reentrant circuit in the endocardial episodes, the termination of the original region. A figure-of-8 reentrant circuit reentrant circuit was followed by the could be interrupted by electrical fulgudevelopment of a different, slower reenration of the region encompassing the trant pathway that lasted for one or a few 46 common reentrant wavefront. Recently, cycles prior to termination. (2) The activation wavefront in the CCP abruptly 3-dimensional electromagnetic mapping broke across a stable arc of functional has been used to localize the optimal site conduction block, resulting in premature for radiofrequency ablation of postinactivation of the CCP and conduction farction sustained VT. Macroreentrant circuits with 1 or 2 loops rotated around block. a protected isthmus bound by 2 approximately parallel conduction barriers of Interruption of a Figure-of-8 either a functional line of block, a scar area, or the mitral annulus. The same Reentrant Circuit critical isthmus could be shared by more Reversible cooling or cryoablation of than one VT morphology. Radiofrequency localized areas of the figure-of-8 reentrant ablation performed across the critical circuit in the canine postinfarction heart isthmus prevented the recurrence of VT was used to prove the presence of circu- in 90% of cases.47 Electrophysiological Mechanisms of Spontaneous Termination of Figure-of-8 Reentry

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Figure 10. Epicardial isochronal activation maps of the last 4 cycles of the ventricular tachycardia (VT) shown in Figure 11. Isochrones are represented by closed contours at 10-ms intervals; arcs of functional block are represented by heavy solid lines. The position of the left anterior descending coronary artery is represented by the dashed lines. The electrode sites of the electrograms shown in Figure 11 are represented by solid circles. The tachycardia was maintained by a stable clockwise wavefront at the anterolateral border of the ischemic zone, while the location and configuration of the counterclockwise wavefront at the apex varied from beat to beat. However, both wavefronts joined into a central common pathway (CCP), where conduction was significantly slowed. The maps illustrate gradual acceleration of conduction at the outer border of the arcs of block and the pivot points to the entrance to the CCP. During the last VT cycle (V_T), conduction block developed in the CCP with termination of reentry.

Entrainment, Termination, or Acceleration of Figure-of-8 Reentrant Tachycardia by Programmed Stimulation In thefigure-of-8reentrant circuit, the 2 arcs of conduction block and the slow

common reentrant wavefront are functionally determined and cycle length dependent. A tight fit exists at certain locations during the reentrant tachycardia, with the circulating wavefront closely following the refractory tail of the previous revolution. This is particularly significant in the zone of the slow common reentrant wavefront.

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ulated termination of reentrant tachycardia, the stimulated wavefront must arrive at the area with the longest refractoriness in the zone of the slow common reentrant wavefront before refractoriness expires, thus resulting in conduction block. If this area is strategically located between the 2 arcs of functional conduction block, reentrant excitation is terminated. The 3 factors that determine whether the stimulated wavefront can reach this zone in time for conduction block are (1) the cycle length of stimulation; (2) the number of stimulated beats; and (3) the site of stimulation (Figures 13 and 14).48 The optimal method for stimulated termination of reentry is to apply a critically coupled single stimulus to the proximal side of the slow common reentrant wavefront that conducts prematurely to the strategic zone for conduction block. The stimulus can only result in local capture and does not have to conduct to the rest of the ventricles (i.e., concealed conduction). When a single stimulated waveFigure 11. Surface ECG lead and selected elecfront fails to terminate reentry, one or trograms along the clockwise wavefront shown in Figure 10. Spontaneous termination of sus- more subsequent wavefronts may suctained monomorphic ventricular tachycardia (VT) ceed. However, the stimulated train must is illustrated. Numbers are in milliseconds and be terminated after the beat that interillustrate the shortening of the VT cycle length rupts reentry. Otherwise, a subsequent prior to termination at different electrode sites as shown in Figure 10. The vertical bars at the top stimulated beat could reinitiate the of the figure delineate the time intervals of the 4 same reentrant circuit or induce a difactivation maps shown in Figure 10. ferent circuit. The new circuit could have a shorter revolution time, resulting in The reentrant circuit conduction time is tachycardia acceleration and occasiondetermined by the area with the longest ally degeneration into ventricular fibrilrefractoriness in the zone of the slow lation. Overdrive termination of reentry common reentrant wavefront. It is safe requires both a critical cycle length of to assume that during reentrant tachy- stimulation and a critical number of cardia, the duration of refractoriness in beats in a stimulated train. Otherwise, the zone with the longest refractoriness the stimulated train could establish a probably cannot shorten any further. This new balance of refractoriness and conis not the case, however, with the rest of duction velocity in the reentrant paththe reentrant pathway. A stimulated way. This could perpetuate the reentrant wavefront at a cycle length shorter than process at the shorter cycle length of the the tachycardia cycle length can still con- stimulated train, resulting in entrainment, duct in these zones. In other words, these and spontaneous reentry would resume zones have a gap of excitability. For stim- on termination of the train. Studies of

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Figure 12. Interruption of a figure-of-8 reentrant tachycardia in the epicardial layer overlying 4-dayold canine infarction by cryothermal techniques. The control activation map is shown on the left (VT), and the map of the last reentrant beat before termination on the right (VT-CRYO). Selected epicardial electrograms are at the bottom. The position of the cryoprobe is represented by the shaded circle. The reentrant circuit was interrupted by reversible cooling of the distal part of the common reentrant wavefront (site H). During control, the conduction time between the proximal electrode site G and the more distal site H was 33 ms. Before termination of the tachycardia, an incremental beat-to-beat increase of the conduction time between sites G and H occurred, associated with equal increases in the tachycardia cycle length. When conduction block developed between the 2 sites, the reentrant circuit was terminated and electrogram H recorded an electrotonic potential but no local activation potential. This was represented on the isochronal map by an arc of conduction block (heavy solid line) that joined the 2 separate arcs of conduction block into one. Modified from Assadi M. Am Heart J 1990; 119:1014–1024.

the effects of programmed stimulation on figure-of-8 reentrant tachycardia illustrate the significance of the site of stimulation and emphasize the need for more precise localization of the slow zone of reentry and the direction of the activation front in this zone in the clinical setting.

Effects of Modulation of Spatially Nonhomogeneous Refractory Patterns on the Initiation of Reentry Evidence of the role of spatially nonhomogeneous distribution of refractoriness

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Figure 13. Electrocardiographic recording showing that a train of 4 stimulated beats (marked by vertical bars) resulted in entrainment, termination, or acceleration of a monomorphic reentrant tachycardia, depending on the cycle length of stimulation. Recordings were obtained from 4-dayold canine infarction. The numbers are in milliseconds. The time lines represent 100 ms. From El-Sherif N, et al. Pacing Clin Electrophysiol 1987; 10:341–371.

in the formation of the arc of functional conduction block in the figure-of-8 model of reentry in the canine subacute infarction heart can be obtained from at least 4 types of experiments: (1) experiments in which a short-long-short stimulated cardiac sequence is required for successful initiation of reentry49; (2) experiments in which the initiation of reentry can be prevented by changing the activation pattern of the basic stimulated beat50; (3) experiments showing the effects of adrenergic stimuli on the initiation of reentrant excitation51; and (4) data on the modulation of refractoriness by antiarrhythmic agents. Short-Long-Short Cardiac Sequence Facilitating Induction of Reentry A short-long-short cardiac sequence frequently precedes episodes of ventricular

tachyarrhythmias. Programmed electrical stimulation techniques that use such a sequence have been shown to facilitate the induction of VT52 and macroreentry within the His-Purkinje system.53 For the His-Purkinje system, a short-long-short cardiac sequence has been shown to result in differential changes in refractoriness of Purkinje and muscle fibers that could facilitate the initiation of reentry.54 For the canine postinfarction model, it was also shown that a critically coupled premature stimulus applied after a conditioning train consisting of a series of short cardiac cycles with abrupt lengthening of the last cycle of the train was more successful in inducing a reentrant ventricular tachyarrhythmia than were fixed conditioning trains of short or long cycles (Figure 15).49 The abrupt lengthening of the cardiac cycle before the introduction of a premature stimulation resulted in differential

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Figure 14. Diagram of the mechanisms of entrainment, termination, and acceleration of reentrant ventricular tachycardia by overdrive stimulation as shown in Figure 13. In each of the 3 panels, the control reentrant circuit is labeled 1 and the 4 beats of the stimulated train are labeled 2 to 5. The control circuit has a figure-of-8 configuration, and conduction in the slow zone of reentry proceeds from left to right. The heavy solid lines represent arcs of functional conduction block. Stimulation was applied at the distal side of the slow zone, as shown by the asterisks. During entrainment (left panel), the stimulated wavefront collides with the emerging slow reentrant wavefront. It then circulates and arrives earlier to the proximal part of the slow zone of reentry. This is consistently associated with a change in the conduction pattern in the slow zone, with the development of new functional arcs of block and much slower conduction in parts of this zone. However, a new equilibrium quickly develops in which successive stimulated beats, represented by cycles 3, 4, and 5, maintain the same new conduction pattern at the shorter cycle length of stimulation, thus entraining the tachycardia. On cessation of stimulation, reentry will resume as shown in cycle 6. For termination of reentry, on the other hand (middle panel), successive stimulated beats, now applied at a relatively shorter cycle compared with the entraining train, will result in gradually more conduction delay. Conduction block eventually develops at the proximal part of the slow zone of reentry, as shown in cycle 5. Right panel: The same 4-beat stimulated train is applied at a still shorter cycle length. In this case and because of the short cycle length of stimulation, the second stimulated beat represented by cycle 3 has already blocked in the proximal part of the slow zone of reentry. If stimulation is stopped at this point, the reentrant tachycardia terminates. However, if stimulation is continued, the third and fourth stimulated beats represented by cycles 4 and 5 initiate new arcs of block and different reentrant pathways so that on termination of the stimulated train, a new and possibly faster reentrant circuit will occur. From El-Sherif N, et al. Pacing Clin Electrophysiol 1987;10:341–371.

lengthening of effective refractory periods (ERPs) at adjacent sites within the border of the epicardial ischemic zone. On the other hand, those same sites showed comparable shortening of refractory periods after a train of regular short cycles and comparable lengthening of ERPs after a train of regular long cycles (Figure 16).

Epicardial sites closer to the center of the ischemic zone that showed more electrophysiological abnormality, as suggested by their longer refractory periods, showed greater dependence on the immediately preceding cycle compared with more normal sites located close to the border of the ischemic zone. This suggested that

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Figure 15. Epicardial activation maps of the premature stimulus following 3 different conditioning stimulated trains from a dog with 4-day-old myocardial infarction. Protocol A consisted of a train of 8 beats at a cycle length of 300 ms. Protocol B consisted of a train of 8 beats at a cycle length of 300 ms, with the exception of the last cycle before the premature stimulus, which was abruptly increased to 600 ms. Protocol C consisted of a train of 8 beats at a cycle length of 600 ms. The coupling interval of the premature stimulus was the same during the 3 stimulation protocols at 170 ms. During protocol A, the premature stimulus resulted in an arc of functional conduction block (heavy solid line) within the border of the ischemic zone. The activation wavefront circulated around both ends of the arc, coalesced, and reached the distal side of the arc at the 100-ms isochrone. The relatively short circulation time around the arc did not allow for refractoriness to expire proximal to the arc and for reexcitation to take place. The epicardial activation pattern of the premature stimulus during protocol C was largely similar to that during protocol A. On the other hand, during protocol B, the premature stimulus resulted in a significantly longer arc of functional conduction block by extending the arc during protocols A and C on both the septal and lateral borders of the ischemic zone. The activation wavefront circulated around both ends of the arc, coalesced, and advanced slowly to reach the distal side of the arc at the 160-ms isochrone. The longer circulation time allowed for refractoriness to expire on the proximal side of the arc and for reexcitation to take place. Reproduced with permission from El-Sherif N, Gough WB, Restivo M. Circulation 1991;83:268–278. Copyright 1991, American Heart Association.

ischemic myocardium may have less memory of the cumulative effect of preceding cycle lengths than does normal myocardium. The differential lengthening of refractory periods at adjacent sites after abrupt lengthening of the cardiac cycle resulted

in sufficiently increased dispersion of refractoriness during which a premature stimulus resulted in the development of functional conduction block between those sites. The development of longer arcs of functional conduction block with the short-long-short cardiac sequence resulted

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Figure 16. Recordings obtained from the same experiment shown in Figure 15, illustrating effective refractory measurements at selected adjacent sites proximal and distal to the arc of block during stimulation protocols A to C. During the 3 stimulation protocols, the difference in refractory periods between adjacent paired sites that spanned the arc of block was 20 ms or longer, whereas adjacent sites on the same side of the arc of block differed by less than 20 ms. The refractory periods at all sites were shortest during protocol A, showing an increment during protocol B, and generally increased further during protocol C. However, the percentage of increment in the refractory periods between protocols A, B, and C differed at sites proximal and distal to the arc. At sites proximal to the arc, the step increment in refractory period was approximately equal between protocols A and B and between protocols B and C. On the other hand, at sites distal to the arc, most of the increment in refractory period occurred between protocols A and B. This differential behavior of refractory period in response to protocol B resulted in an increased dispersion of refractoriness between adjacent sites within the border of the ischemic zone and in the development of functional conduction block between these sites. Reproduced with permission from El-Sherif N, Gough WB, Restivo M. Circulation 1991 ;83:268-278. Copyright 1991, American Heart Association.

in a longer reentrant pathway and, hence, an increased reentrant circuit conduction time. Another factor that contributed to increased reentrant circuit conduction time was further slowing of conduction

around the arc of block. The combination of these factors allowed more time for refractoriness to expire proximal to the arc of block and for the circulating wavefront to reexcite those sites to initiate reentry.

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Prevention of Reentrant Excitation by Dual Stimulation During Basic Rhythm Initiation of reentrant excitation can be prevented by changing the activation pattern of the basic stimulated beat. The spatial patterning of recovery time depends on the activation pattern of the basic beat, in addition to the spatially nonhomogeneous refractory distribution induced by ischemia. The dispersion of recovery time can be modified by stimulation at 2 ventricular sites during the basic beat. The arc of conduction block can be modified or abolished entirely by appropriate selection of the secondary stimulation site in the ischemic zone and the temporal sequencing of the paired

stimuli (Figure 17). Asynchronous dual stimulation, with preexcitation of an appropriate site in the ischemic zone, was frequently successful in preventing the initiation of reentry by a fixed coupled premature stimulus. In all instances that resulted in the prevention of reentry, the secondary site was distal to the arc of block that formed after the control S2 stimulation. The secondary site should be in an area of long refractoriness that activated late during the basic beat. Properly applied dual stimulation differentially peels back recovery time in the ischemic zone. Successful dual stimulation depended on the reduction of 2 factors: the spatial gradient of recovery time and the dispersion of recovery time across the arc. The former determines

Figure 17. Abolition of the arc of functional conduction block by dual S1 stimulation. Top (control): S1 activation occurred within 60 ms. A gradient of recovery time between the 190and 230-ms isochrones supported the formation of an arc of block during S2. Bottom (dual asynchronous stimulation): The 2 sites of stimulation, one from the right ventricle (as in control) and one from the ischemic zone distal to the arc of block, are represented by asterisks. When the dual ischemic site was preexcited by 40 ms, no 2 adjacent sites differed in recovery time by more than 20 ms. A zone of graded recovery time that could support functional conduction block was not present. An arc of conduction block did not form. In this experiment, the recovery time was computed by the sum of the activation time (stimulus artifact to response during S1,) plus the effective refractory period at each site. Reproduced with permission from Restivo M, Gough WB, El-Sherif N. Circulation 1988;77:429-444. Copyright 1988, American Heart Association.

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the extent and location of the continuous arc of conduction block and the latter determines whether areas distal to block have recovered during the premature stimulation. Reducing the difference in activation time across the arc of block to a value less than the ERP of the premature stimulus proximal to the arc is the mechanism by which dual S1 stimulation can prevent the initiation of reentry.50 Recently, the technique of biventricular pacing that involves simultaneous pacing of the right and left ventricles has gained wide acceptance. The technique is indicated in patients with depressed left ventricular function and a wide QRS complex and is primarily intended to improve the ventricular function. However, it is also expected to be antiarrhythmic by decreasing the spatial dispersion of repolarization. Effects of Adrenergic Stimuli on the Initiation of Reentrant Excitation It is well known that adrenergic autonomic activity has a role in the generation and perpetuation of cardiac arrhythmias.55,56 However, ischemia can directly affect the sympathetic innervation of the ventricles and thereby alter the effects of sympathetic tone on the ventricle.57 Transmural myocardial ischemia has been shown to disrupt sympathetic innervation of the ventricles and to cause denervation hypersensitivity.58,59 In this case, sympathetic stimulation would increase the dispersion or gradient of refractoriness between innervated and denervated regions.57 The adrenergic effects on reentrant excitation in the canine postinfarction model were investigated by Butrous et al.51 Bilateral stimulation of the ansae subclaviae preferentially improved conduction of premature beats in the normal zones. This corresponded to an improvement in excitability, as measured by a

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decrease in stimulus strength at the same premature coupling interval as control. Consequently, the ERP was preferentially shortened at normal sites but not at ischemic sites. Both of these changes contributed to a shift of the arc of functional conduction block toward more normal tissue. As a result, sites proximal to the arc of functional conduction block had more time to recover excitability and thereby were available to be reexcited by the distal activation wavefront (Figure 18). These observations are consistent with the tenet that sympathetic denervation occurred in the ischemic area, where a thin epicardial layer of myocardium survived the infarction. Another effect of preferential shortening of the refractory period in the normal zone was the extension of the arc of functional conduction block. The lengthening of the arc of functional conduction block or the de novo creation of an arc of functional conduction block in the ischemic zone can potentially facilitate the occurrence of reentrant excitation. In contrast to sympathetic stimulation, intravenous infusion of norepinephrine preferentially shortened the ERP of sites in the ischemic zone, thereby indicating that denervation hypersensitivity had occurred at those sites. The spatial dispersion of refractoriness and the arc of functional conduction block were significantly reduced in size. As a consequence, previously inducible reentrant rhythms were no longer inducible (Figure 19). Thus, sympathetic stimulation can be considered an arrhythmogenic intervention, whereas norepinephrine infusion may be considered antiarrhythmic in this model. Effects of Antiarrhythmic Agents on Figure-of-8 Reentry The pharmacological basis of antiarrhythmic drug therapy in the treatment of reentrant tachyarrhythmias has been

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Figure 18. Epicardial activation patterns and representative electrograms from a dog with 4-dayold myocardial infarction showing the effects of sympathetic stimulation (SS) on the initiation of reentrant excitation. The heart was stimulated at a basic cycle length of 400 ms (S^, and a premature beat (S2) was introduced at a cycle length of 160 ms. During control, S2 resulted in an arc of functional conduction block. Activation arrived on the distal side of the arc of block but did not reexcite areas proximal to the arc (i.e., no reentrant beat occurred). During subsequent bilateral ansae subclaviae stimulation, an S2 at 160 ms produced an arc of functional block and a reentrant beat. The upward arrows on the electrograms represent the effective refractory periods (values indicated) relative to the time of activation at 3 sites across the arc of block. During the control S2, the arc of block was located between sites b and c. During bilateral ansae subclaviae stimulation, the arc of block shifted toward the more normal myocardium (to between sites a and b). Conduction was improved proximal to the arc, as evidenced by the reduction in response interval (R^)- The R1R2 interval at site a shortened during sympathetic stimulation, but the effective refractory periods at sites a, b, and c were not changed. Therefore, S2 arrived earlier at site a, and R2 was unable to propagate directly to site b because it was still refractory (see electrograms). Consequently, the wavefront conducted around the arc of block and then excited site b. The conduction time from site a to site b provided sufficient time for site a to recover its excitability, and the wavefront was then able to reexcite site a. Thus, a reentrant beat was initiated. Reproduced with permission from Butrous GS, Gough WB, Restivo M, et al. Circulation 1992;86:247-254. Copyright 1992, American Heart Association.

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Figure 19. Epicardial activation maps of a premature stimulus (S2) during control (left) and during norepinephrine infusion (right) from a dog with 4-day-old myocardial infarction. During control S2, a long continuous arc of functional conduction block developed. The activation wavefront circulated around the arc then reexcited a site proximal to the arc to initiate a reentrant beat. The dotted line in the control map represents the area of earliest reentrant excitation. The enlarged section (bottom) is from the area of the arc of functional conduction block, with the refractory period of each respective site noted. During norepinephrine infusion, the arc divided into 2 smaller arcs. The dotted line in the norepinephrine maps represents the previous position of the arc of functional conduction block during control. The total activation time shortened during norepinephrine infusion, and there was preferential shortening of the effective refractory period at sites previously distal to the arc of functional conduction block. In this example, the average refractory period for all sites proximal to the arc of functional conduction block during control was 179 ± 12 ms. It was shortened to 161 ± 10 ms (an average shortening by 18 ms) during norepinephrine infusion. The average refractory period for all sites distal to the arc of functional conduction block during control was 249 ±15 ms. It was shortened to 195 ± 18 ms (an average shortening by 54 ms) during norepinephrine infusion. Therefore, norepinephrine decreased the gradient of refractoriness between the normal and ischemic sites. Consequently, the length of the arc of functional conduction block was reduced and shifted toward more ischemic tissue, resulting in prevention of the initiation of reentrant excitation. Reproduced with permission from Butrous GS, Gough WB, Restive M, et al. Circulation 1992;86:247-254. Copyright 1992, American Heart Association.

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guided mostly by the original observations of Mines.5 For any model of reentrant activity, the key ingredients are unidirectional block and conduction around an alternate pathway that is impaired to a degree to permit reexcitation. Drug action is usually defined by its effect on action potential characteristics (upstroke velocity and action potential duration). In the not too distant past, if one were to pick up Goodman & Gilmaris The Pharmaceutical Basis of Therapeutics,60 one would find that antiarrhythmic efficacy was based on drug action on reentry within an anatomically predetermined pathway. In the simplest sense, Class I agents were believed to cause conduction failure in the slow conduction portion of the circuit and Class III agents were believed to cause block within the circuit due to prolonged refractoriness. Besides the simplicity of the reentrant circuit topology, the primary flaw in this reasoning was that drug action was evaluated in normal tissue. Even the sophistication of the more recent Sicilian Gambit61 classification system is limited because of insufficient allowance for evaluation of drug action in diseased myocardium. The results of the Cardiac Arrhythmia Suppression Trial (CAST)62 brought attention to drug-induced proarrhythmia and, in particular, to the problems associated with the means by which the efficacy of potential antiarrhythmic drugs are determined. While there is a heightened awareness of the problems associated with antiarrhythmic drugs (especially in the treatment of ventricular tachyarrhythmias), drug development is hampered by the fact that the mechanisms of drug-induced antiarrhythmic or proarrhythmic effects still remain unclear. The induction or suppression of reentrant activation in the figure-of-8 model

involves a complex interplay of functional activation properties and changes in these properties that are associated with the pathological state of the heart. The antiarrhythmic or proarrhythmic effect of a drug can be best studied by measuring the rate-dependent effects of the agent on conduction and refractory properties of normal and ischemic zones in the heart.63-65 The proceeding section reviews the electrophysiological actions of 3 antiarrhythmic agents, flecainide, lidocaine and azimilide, in the figure-of-8 model of circus movement reentry in the subacute MI period in the dog. The working model is based on the facts that functional conduction block occurs because of differentially prolonged refractoriness between normal and ischemic zones and that tachycardiadependent slow conduction occurs in the hypoperfused ischemic layer. The hypothesis tested is that agents that promote slower conduction in the ischemic zone or extend the line of block by differential prolongation of refractoriness in the ischemic zone favor reentry. Figure 20 is a bubble diagram illustrating the antiarrhythmic (or proarrhythmic) effects of all 3 drugs. Results are from 3 different studies and no statistical comparisons were made to compare antiarrhythmic efficacy between the 3 drugs. Flecainide is a Class Ic agent whose effects are believed to be highly selective for use-dependent blockade of sodium channels. Some of the proarrhythmic effects of flecainide were known prior to CAST. Ranger et al.66 made the interesting observation that VT could be aggravated in patients by exercise, i.e., fast heart rates. We studied the rate-dependent effect of flecainide in the canine subacute infarction model. The ECGs in Figure 21 illustrate the rate-dependent aggravation of arrhythmia due to flecainide. Insight into

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Figure 20. Bubble diagrams illustrating the effects of flecainide, azimilide, and lidocaine for induction of reentry with only a single premature beat (S2). Responses were classified as follows: VT = sustained monomorphic ventricular tachycardia; NS-RA = nonsustained reentrant activity; NR = no response (less than 3 unstimulated responses). Proarrhythmic effects (upward sloping lines) are defined as the drug-induced transformation of: (1) NR to either NS-RA or VT, or (2) NS-RA to VT. Antiarrhythmic affects are the converse of above and are indicated by downward sloping lines. Horizontal movement indicates no effect of the drug on arrhythmia induction. A. Flecainide was administered as a bolus dose of 1 mg/kg given over 8 minutes, followed by a maintenance infusion of 1 mg/kg/h. For flecainide, there were 4 proarrhythmic events in 16 dogs (25%) at a basic cycle length (BCL) of 500 ms, and 10 proarrhythmic events at a BCL of 300 ms (62.5%). The proarrhythmic effect of flecainide was more prominent at a BCL of 300 ms (P < 0.005, Pearson chi-square). B. Azimilide was tested at 3 doses. It had essentially no effect at 3 mg/kg. The drug was effective in suppressing reentrant ventricular arrhythmias in 6 dogs at a dose of 10 mg/kg and 2 additional dogs at 30 mg/kg. In 2 dogs, there was a drug-induced aggravation of inducible reentrant VT at a dose of 10 mg/kg and at 30 mg/kg there was one case of drug-induced conversion of NR to NS-RA. C. Lidocaine was administered as a bolus dose of 6 mg/kg, i.v., delivered over 10 minutes, followed by a maintenance infusion of 75 jig/kg/min. For lidocaine, there were 3 proarrhythmic events in 18 dogs (16.7%) at a BCL of 500 ms, and 8 proarrhythmic events at a BCL of 300 ms (44.4%). The overall proarrhythmic effect of lidocaine showed increased tendency at a BCL of 300 ms, but the difference was not statistically significant. On the other hand, the proarrhythmic effect of lidocaine through transformation to VT was more prominent at a BCL of 300 ms compared to 500 ms and was statistically significant (P < 0.05). There were no cases of drug-induced transformation of VT to NS-RA or NR.

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Figure 21. A. Lead II ECG from an experiment during which, in the control pre-drug state, S1,S2 of 170 ms did not induce any response at basic cycle lengths (BCLs) of 300 ms or 500 ms. After flecainide infusion, no response was elicited at a cycle length of 500 ms. However, at a cycle length of 300 ms, a single extrastimuli induced a sustained monomorphic ventricular tachycardia. B. and C. Isochronal activation maps during regular pacing and premature stimulation. The maps show the epicardial ventricular surface with the perimeter representing the atrioventricular ring and the center the apex; the left anterior descending coronary artery is shown by the dotted line. In these maps each isochronal contour represents a portion of the heart that was activated within a 20-ms time frame. Panel B shows S1, activation patterns during BCLs of 500 ms and 300 ms. In control, the ventricles were activated within 80 ms. There was no evidence of conduction block in any of the maps. After flecainide, the heart activated within 80 ms at a BCL of 500 ms and increased slightly to 100 ms at a BCL of 300 ms. The S2 activation maps for an S^ coupling of 170 ms are shown in C. The upper left map shows the control pre-drug activation pattern at BCL of 500 ms. An arc of functional conduction block formed during the 40-ms isochrone. Activation reached the distal border of the arc during the 160-ms isochrone. Because the maximum activation time difference across the arc of block was only 120 ms, the impulse was unable to reenter. Following flecainide, reentry could not be induced by premature stimulation at that cycle length. The activation map was essentially the same as control. At a BCL of 300 ms, reentry was not induced during control, but following flecainide, more dramatic changes in S2 activation are apparent. Again, the premature wavefront blocked within 40 ms. Flecainide depressed conduction in the slow zone and delayed activation at the distal border of the arc of block to the 200-ms isochrone, increasing the activation time difference across the line of block to 160 ms, and the impulse was able reenter near the site of initial conduction block.

the mechanism is revealed by analysis of the isochronal activation maps in panels B and C, which show that conduction in the ischemic zone is differentially depressed (without conduction failure) relative to

the normal zone. In the S2 maps, there is little difference in the size of the line of block before or after flecainide. Because we have shown that block results from differences in ERPs between normal and

FiGURE-OF-8 MODEL OF REENTRANT VENTRICULAR ARRHYTHMIAS ischemic zones, we measured ERPs before and after flecainide. Consistent with its Class Ic action and lack of change in the lines of block, we found no statistically significant difference in ERP.63 We then

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measured the rate dependence of conduction velocity in normal and ischemic tissue using a specially designed highresolution cross electrode. The results, shown in Figure 22, show a rate-dependent

Figure 22. Rate dependence of conduction velocity in control and in the presence of flecainide. Results shown are from 6 dogs. In these graphs, conduction velocities were normalized to the longest basic cycle length (BCL) (600 ms). The effect of the drug was more pronounced for propagation in the ischemic zone relative to the normal zone and was statistically significant at the shorter BCLs in all 4 groups. Flecainide caused a rate-dependent reduction of conduction velocity of 14% (longitudinal) and 8% (transverse) for a change in basic drive from 600 ms to 250 ms in normal tissue, and a reduction of 27% (longitudinal) and 25% (transverse) for a change in basic drive from 600 ms to 250 ms in ischemic tissue.

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preferential depression of conduction in the ischemic zone. Azimilide is a Class III agent that acts by prolonging refractoriness and has little effect on conduction velocity. Figure 23 shows maps from a representative experiment in which a sustained monomorphic VT was induced by a single premature beat. A dose of 10-mg/kg azimilide slowed the VT with termination coinciding with block of the reentrant impulse within the slow common reentrant pathway. To understand the mechanism of azimilide action, we measured ERPs in this vicinity at cycle lengths of 350 ms and 600 ms, before and after drug infusion. Data shown in panel A of Figure 24 indicate that block occurred because of a prolongation of ERP at the

critical sites. The preferential prolongation of ERP in the ischemic zone by azimilide is illustrated in panel B. Recently we have shown that in the canine right atrial enlargement model of circus movement atrial flutter, both azimilide and dofetilide were 100% effective in terminating flutter and preventing reinduction. Efficacy relied on a similar mechanism of differentially prolonged refractoriness in the slow conduction component of the reentrant circuit where drug-induced termination occurred.67 Lidocaine is a familiar and widely used antiarrhythmic agent, with occasional proarrhythmic effects having been noted for years.68,69 Lidocaine is more of a mixed bag compared to the previous drugs described above. Lidocaine has

Figure 23. Isochronal activation maps of control ventricular tachycardia (VT) induction and termination of VT by azimilide. The left panel shows the map of the control VT induced by a single premature beat. The cycle length of the VT in this example was 285 ms. In this experiment, the reentrant circuit had a figure-of-8 morphology in which 2 wavefronts circulated around 2 lines of functional conduction block. Each isochronal contour line represents the boundary of a region activated by the reentrant wavefronts in successive 10-ms intervals. In this particular experiment, there was a region of necrosis extending through to the epicardial surface and is indicated in the maps by shaded region. The 2 wavefronts joined once every cycle and conducted slowly through the ischemic epicardial layer in the area bounded between the 2 lines of block (isochrones 120 through 250). The maps in the middle panel show that following a 10 mg/kg infusion of azimilide, the cycle length of the VT progressively slowed to 320 ms before druginduced termination of the rhythm. Azimilide caused a marked increase in overall conduction time within the slow conducting pathway. In the last beat (right panel; VTerm), the reentrant impulse failed to penetrate through the ischemic zone and blocked during the 470-ms isochrone between sites L and M.

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Figure 24. A. Effective refractory period (ERP) values near the site of block during termination for the example shown in Figure 23. The lines of block from the activation maps are shown with ERP values, and clearly show that conduction block occurred near sites with the greatest refractory period values in control (sites M and N). These sites also had the longest refractory period values after 10 mg/kg azimilide. B. A grouped analysis on the effect of azimilide on increasing ERP in normal and ischemic zones using 2 basic cycle lengths (BCLs). Data presented in this figure are for those sites in which ERP data was obtained in control, 10 mg/kg azimilide, and 30 mg/kg azimilide. One way analysis of variance was performed to test for significant differences between the groups. Student's paired Mest for paired data was then performed to test for differences between control ERP and ERP at both drug doses. There was a statistically significant increase in ERP by azimilide in normal and ischemic tissues at both BCLs. The drug-induced increase in ERP was statistically greater in ischemic tissue compared to normal tissue for both drug doses and at both BCLs.

been shown to completely abolish membrane responsiveness in severely ischemic cells in the epicardial border zone during the subacute phase of MI.69 Not only does lidocaine depress conduction, but it also has a prolonging effect on ERP. Similar to flecainide, lidocaine has been shown to cause a selective ratedependent decrease in conduction velocity in the ischemic zone. This is keeping with its possible proarrhythmic action.

We examined the effect of lidocaine on normal and ischemic tissue.63 The proarrhythmic effects of lidocaine, shown in Figure 25, are due not only to depressed conduction in the ischemic zone but an increased path length resulting from differential prolongation of ERP. Figure 26 shows that lidocaine could be antiarrhythmic only if ERPs in the ischemic zone were prolonged to such a degree that the reentrant impulse blocked in

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Figure 25. Proarrhythmic effect of lidocaine. Activation maps from a representative experiment illustrating the effects of lidocaine at different basic cycle lengths (BCLs). The upper left panel shows a control isochronal map of a premature beat following a drive of 29 basic beats at a BCL of 300 ms. After an S1,S2 of 180 ms, the premature activation wavefront encountered a continuous line of block within 40 ms. Conduction then proceeded retrogradely through the slow zone and blocked at 140 ms distal to the block. After lidocaine, premature stimulation at the sameS1S2coupling interval had a proarrhythmic effect. The line of block was longer compared to the control pre-drug map, and conduction within the slow zone proceeded much slower. Because of the additional delays incurred, the impulse reached the distal border of the block later than in control and reactivation occurred within 240 ms. In this experiment, a sustained monomorphic ventricular tachycardia (VT) (upper right panel) was induced. The VT cycle length was 184 ms. In the same experiment, lidocaine also had a proarrhythmic effect (nonsustained VT) at a BCL of 500 ms but no sustained VT was induced.

the common reentrant pathway. The effects of lidocaine on ERP in normal and ischemia tissue are summarized in Figure 27. In summary, in the subacute MI model, pure Class I drug action appears to be proarrhythmic with regard to reentrant substrates. This is due to a preferential depression of conduction in the

ischemic zone, a factor that favors reentry. The role of Class III or Class Ib agents is more complex. In this functional model of reentry, the obstacle around which the reentrant impulse circulates is most probably due to differential prolongation of refractoriness between normal and ischemic zones. Therefore, any agent that preferentially prolongs refractoriness

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Figure 26. Antiarrhythmic effect of lidocaine. Lidocaine exhibited antiarrhythmic behavior if there was a marked increase in effective refractory period (ERP) after drug, as illustrated in the following maps. In this example at a basic cycle length of 500 ms, a single premature beat at 200 ms (left panel) caused block and reentry within 200 ms. After lidocaine (right panel), reentry did not occur with the same premature coupling interval. The impulse coalesced at the entrance of common reentrant pathway within 120 ms, and blocked within the common reentrant pathway within 180 ms. ERPs were measured at critical sites within the common pathway. Though conduction in the vicinity of sites C and D was slowed after lidocaine, there was a marked prolongation of refractoriness at sites within the ischemic zone (C and D) relative to border sites (B) and normal sites (A). Site D could not activate because it was still refractory; block occurred between sites C and D.

may increase the length of the functional obstacle, again a factor that favors reentry. In the examples presented here, antiarrhythmic action occurs only when refractoriness is prolonged to such a degree that conduction block within the slow pathway of the circuit is possible. Because it

is impossible to predict the wide range of electrophysiological consequences of MI in all cases, antiarrhythmic drug therapy must be carefully tailored to individual situations. What may be good in one situation may result in opposite results in another.

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CAEDIAC MAPPING Figure 27. Effect of lidocaine on effective refractory period (ERP) in normal and ischemic tissue. Lidocaine increased refractoriness to a greater extent in the ischemic zone compared with the normal zone, but tne effect was rate independent. The drug-induced ERP increase (ERPlidocaine-ERPcontrol) was more pro-

nounced in the ischemic zone compared to normal. The difference was statistically significant at 300 ms (16.3 ±19.1 versus 9.8 ± 10.7; P < 0.05). Pacing threshold increased significantly after lidocaine in both normal (0.9 ± 0.7 mA versus 1 .4 ± 1.3mA; P< 0.01) and ischemic (0.8 ± 0.5 versus 1.2 ± 0.9; P < 0.01) zones, but there was no statistically significant difference in excitability between normal and ischemic zones before or after drug. Our previously published reports established that arcs of functional conduction block result from regional disparities in refractoriness along a continuous region of the ischemic border zone. Arcs of block were measured before and after lidocaine by planimetry on a 3-dimensional heart model. The lengths of the arcs of functional conduction block for all experiments were 11 .8 ± 3.9% longer after lidocaine; the effect was statistically significant (P < 0.01). The lengths of arcs of block were computed in the proarrhythmic and antiarrhythmic groups for those beats in which the activation wavefront reached the distal side of the arc. The lengthening by lidocaine was greater (14.3 ± 5.2%; P< 0.05) in the proarrhythmic group compared to the antiarrhythmic group (10.2 ± 1.7%).

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FiGURE-op-8 MODEL OF REENTRANT VENTRICULAR ARRHYTHMIAS 50. Restivo M, Gough WB, El-Sherif N. Reentrant ventricular rhythms in the late myocardial infarction period: Prevention of reentry by dual stimulation during basic rhythm. Circulation 1988;77:429-444. 51. Butrous GS, Gough WB, Restivo M, et al. Adrenergic effects on reentrant ventricular rhythms in subacute myocardial infarction. Circulation 1992;86:247-254. 52. Denker S, Lehman MH, Mahmud R, et al. Facilitation of ventricular tachycardia induction with abrupt changes in ventricular cycle length. Am J Cardiol 1984; 53:508-515. 53. Denker S, Lehman MH, Mahmud R, et al. Facilitation of macroreentry within the His-Purkinje system with abrupt changes in cycle length. Circulation 1984;69:26— 32. 54. Denker S, Lehman MH, Mahmud R, et al. Divergence between refractoriness of HisPurkinje system and ventricular muscle with abrupt changes in cycle length. Circulation 1983;68:1212-1221. 55. Zaza A, Schwartz PJ. Role of the autonomic nervous system in the genesis of early ischemic arrhythmias. J Cardiovasc Pharmacol 1985;7:8-12. 56. Szekeres L, Boros E, Pataricza J, Udvary E. Sympathetic neural mechanisms in cardiac arrhythmias. J Mol Cell Cardiol 1986; 18:369-373. 57. Inoue H, Skale BT, Zipes DP. Effects of myocardial ischemia and infarction on cardiac afferent sympathetic and vagal reflexes in the dog. Am J Physiol 1988; 255:H26-H35. 58. Kammerling JJ, Green FJ, Watanabe AM, et al. Denervation supersensitivity of refractoriness in noninfarcted areas apical to transmural myocardial infarction. Circulation 1983;67:787-796. 59. Inoue H, Zipes DP. Results of sympathetic denervation in the canine heart: Supersensitivity that may be arrhythmogenic. Circulation 1987;75:877-887. 60. Goodman AG, Goodman LS, Gilman A (eds): Goodman & Oilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan; 1980.

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61. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology: The Sicilian Gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Circulation 1991;84:1831-1851. 62. Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: Effect of encainide and flecainide on mortality in randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321:406-412. 63. Restivo M, Yin H, Caref EB, et al. Reentrant arrhythmias in the subacute infarction period. The proarrhythmic effect of flecainide acetate on functional reentrant circuits. Circulation 1995;91:1236-1246. 64. Yin H, El-Sherif N, Caref EB, et al. Actions of lidocaine on reentrant ventricular rhythms in the subacute myocardial infarction period in dogs. Am J Physiol 1997;272:H299-H309. 65. Restivo M, Yin H, Caref EB, et al. Selective effect of class III antiarrhythmic agents on refractoriness determines efficacy in post infarction reentrant ventricular tachyarrhythmias (VT). Circulation 1996;94(Suppl):I-161. 66. Ranger S, Talajic M, Lemery R, et al. Amplification of flecainide-induced ventricular conduction slowing by exercise. A potentially significant clinical consequence of use-dependent sodium channel blockade. Circulation 1989;79:1000-1006. 67. Restivo M, Hegazy M, El-Hamami M, et al. Efficacy of azimilide and dofetilide in the dog right atrial enlargement model of atrial flutter. J Cardiovasc Electrophysiol 2001;12:1018-1024. 68. Krejcy K, Krumpl G, Todt H, Raberger G. Lidocaine has a narrow antiarrhythmic dose range against ventricular arrhythmias induced by programmed electrical stimulation in conscious dogs. Pflugers Arch 1992;346:213-218. 69. Lazzara R, Hope RR, El Sherif N, Scherlag BJ. Effects of lidocaine on hypoxic and ischemic cardiac cells. Am J Cardiol 1978; 41:872-879.

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Chapter 12 Demonstration of Microreentry Hasan Garan, MD

The accepted criteria for demonstrating that the mechanism of an arrhythmia is reentry include the presence of a region of unidirectional conduction block with return of an impulse to its site of origin via retrograde conduction in the previously blocked, but now recovered, pathway before the onset of the next cardiac cycle, and perpetuation of this geometry during the subsequent cardiac cycles.1 Reentry as the underlying mechanism becomes more convincing if the impulses expected to arise from reentry are eliminated by reversible or irreversible interruption of this pathway. When a wavefront satisfying these criteria travels along pathways several centimeters long, reentrant excitation in the form of a closed loop can, at least in theory, be detected directly by examining the local electrograms recorded by electrodes positioned along the pathways provided that the mapping system allows recordings dense enough to define the entire circuit.2 This finding has been termed macroreentry. Demonstration of the classic criteria for entrainment,3 such as progressive fusion during pacing at decreasing cycle

lengths from a site outside the circuit, is used to further support macroreentry as mechanism. However, if reentry is present but confined to a smaller area, e.g., 1 cm in diameter, direct demonstration of reentrant excitation underlying a clinical arrhythmia may not be possible within the resolution of the recording system. Reentry confined to such a small volume of myocardium has been termed microreentry to distinguish it from macroreentry. Definition of Microreentry It is difficult to formulate a canonical definition of microreentry based on circuit size alone since it may not be possible to determine pathway size with precision in clinical tachycardias using intracardiac recording techniques. This task, difficult enough sometimes for even obviously reentrant rhythms such as atrioventricular nodal reentrant tachycardia, may be more difficult for intra-atrial reentry and even more so for the majority of clinical reentrant ventricular tachycardias (VTs). Circuit size and geometry

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003. 275

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are likely to be complex and determined by the underlying individual pathology. Furthermore, only certain special components of the circuit may be fixed while other components may be dynamically coupled or uncoupled to the former resulting in changes in cycle length or surface QRS morphology.4 Therefore, rather than being categorical, the distinction between "microreentry" and "macroreentry" becomes a question of degree, and the circuit size may display a continuum from small to large. A more practical and clinically relevant definition of microreentry may be based on operational criteria. The tachycardia in question should manifest the accepted general characteristics of reentry rather than triggered activity or automaticity.5 Other supporting observations for reentry such as classic criteria for entrainment should be sought, although inability to demonstrate entrainment does not rule out microreentry since the excitable gap may be narrow and attempts to entrain may result in entry block. Furthermore, in microreentry, activation sequence mapping during tachycardia usually identifies an early site of origin, but in contrast to macroreentry where a circular loop of electrical activity can be demonstrated during each cardiac cycle, e.g., atrial flutter,6 the global activation pattern during a tachycardia with underlying microreentry manifests a radial, centrifugal spread away from this site of earliest activation or the "source." The practical question then becomes whether any component of microreentry, located close to the site of breakthrough, can be identified during endocardial catheter mapping. A Protected Zone with Altered Conduction Most models of reentry incorporate a zone of slow, often decremental, conduction taking place in a region that is "protected," or surrounded by nonconducting

tissue that prevents the wavefront, which is progressing unidirectionally in the area of slow conduction, from breaking through into the surrounding tissue at random sites. The absence of conduction in the surrounding tissue may be due to an anatomical barrier or, more commonly, to functionally refractory tissue.7 It is no longer generally accepted that these areas have well-defined and fixed entry and exit sites and also well-defined orthodromic and antidromic directions of conduction during arrhythmia. Such regions of slow conduction have been clearly demonstrated in animal models of experimental infarction.7-9 They may be epicardial,7 endocardial,8 or intramural (midmyocardial)8'9 in location, depending on the specific model and the technique used to create the experimental myocardial infarction. Extracellular recordings from such regions often display fractionated, low-amplitude electrograms with long duration.8,10 The electrophysiological and anatomical bases for the fractionated electrograms have been carefully investigated in a canine model.11 The fractionated electrograms correspond to regions where fibrosis during infarct healing has caused wide separation of individual myocardial fibers and has distorted their orientation.11 This distortion results in a matrix of inhomogeneous anisotropy, and even if transmembrane action potentials recorded from individual myocytes may be normal, the overall conduction in the area is abnormally slow due to its fiber geometry, and the extracellular electrograms recorded from within such a region look fractionated and prolonged.11 For the clinical cardiac electrophysiologist, the demonstration of microreentry during mapping requires (1) identification of a zone of slow conduction manifesting either fractionated and prolonged local electrograms spanning diastole and recorded from closely spaced sites or, rarely, continuouelPANDIASTOLIC ectrical

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this would be reentry in a small confined area. It has been demonstrated in an experimental canine model that in cases of midmyocardial reentry, the zone of slow conduction may remain "hidden" from the electrodes confined to the endocardial and the epicardial surfaces.8 Thus, specific location as well as the orientation of the slowly conducting pathways will determine whether they can be detected by endocardial catheters, and not all such regions can be adequately investigated by endocardial catheters. Intimately tied in with these issues is the question of Location of Microreentry whether there is a critical myocardial The electrode catheters are confined thickness necessary for observation comto the endocardial surface of the heart. patible with microreentry as defined above. Since the site of origin for clinical ischemic For example, in contrast to macroreentry, sustained VT frequently resides in a suben- microreentry is rarely, if ever, observed as docardial region,12 it is usually possible to a mechanism of clinical arrhythmia in record electrograms from such a subendo- the human atrial myocardium, and focal cardial region of abnormal conduction with atrial tachycardias almost always result the use of endocardial catheters. However, from automaticity or triggered activity.16 not all regions of slow conduction are Furthermore, it is not entirely clear subendocardial, and in a small number of whether microreentry is an arrhythmia cases of clinical VT, intraoperative record- mechanism that can occur solely in disings have convincingly demonstrated the eased myocardium, which provides the presence of epicardial reentry incorporat- substrate for nonuniform anisotropy. ing a zone of slow conduction with com- Spach at al.17 have demonstrated in superplete diastolic bridging in electrodes limited fused human atrial pectinate muscle fibers age-related obliteration of side-to-side to the epicardial surface.13,14 The orientation of the zone of slow electrical coupling between fibers resultconduction is also critical. Slow conduc- ing in reentry, even if not sustained reention taking place in a midmyocardial trant activation, arising within very small region may be difficult if not impossible areas. This mechanism results from the to detect by endocardial electrodes. Con- age-related exaggeration of the homogesider for example the mechanism of non- nous or uniform anisotropy and may be homogeneous anisotropic reentry.15 A scar categorized as microreentry due to the or a functional arc of conduction block small dimensions of the interdigitating may be located in the midmyocardium fibers involved (Figure 1).17 It is not clear if with slow transverse conduction moving such a mechanism in aging but undiseased around a fulcrum point resulting from human atrium can result in "idiopathic" the geometry of the edges,15 alternating clinical atrial tachycardia. Atrioventricuwith faster longitudinal conduction which lar nodal reentry may be the best undermay result in a discrete focus of endocar- stood clinical microreentry in the atrium. dial breakthrough and a "monoregional It had been believed that the circuit underspread" of activation from this source on lying this arrhythmia was confined to the the endocardial surface, whereas, in fact, compact atrioventricular node, but recent activity recorded from a single site, and (2) proof that these electrograms represent electrical activity in an essential component of the circuit, rather than representing activity in pathways outside the circuit, bearing no relationship to the reentry process. In other words, demonstration of microreentry requires finding a zone manifesting early, mid, and late diastolic potentials all recorded within a "reasonably small" site, and demonstrating their specificity as part of the arrhythmia mechanism.

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Figure 1. Microreentry in response to premature stimulation in superfused nonuniform anisotropic atrial bundle. Results were obtained at basic stimulus rate of 171/min; a premature stimulus was introduced every 10th beat at interval shown in box above each group of waveforms. Drawing at upper left shows locations where each waveform was recorded. Drawing at lower right shows perimeter of reentrant circuit, indicated by solid lines with arrows. Shaded region denotes surrounding areas in which 0 waveforms were measured at 16 sites; at each of these peripheral sites, local excitation occurred after that of sites confined to perimeter of reentrant circuit for the corresponding areas. From Spach et at. Circ Res 1988;62:828.

data from several electrophysiology laboratories suggest a substantially larger circuit incorporating atrial tissue with slow conduction due to anisotropy.18 Intrafascicular microreentry, as opposed to interfascicular macroreentry, has been proposed as a plausible mechanism for idiopathic left ventricular VT in the absence of myocardial pathology.19 Detection of the Region of Slow Conduction No matter where it is, microreentry has to "solve" the problem of slow conduction taking place in a small region.

In order to have "hidden" diastolic activation for a long time, sometimes few hundreds of milliseconds, taking place in such a small region, the average local velocity must be exceedingly low. There are several possible mechanisms, including nonhomogeneous anisotropy, of such a slow average conduction. It is not known whether directional differences in velocity in nonuniformly anisotropic tissue of the diseased myocardium alone may account for a very low average velocity necessary for clinical microreentry. Alternatively, a very special redundant pathway geometry may be needed. As a third mechanism, one may think of isolated but closely spaced myocardial fibers, able

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to communicate with each other by elec- from this site displays potentials throughtrotonus not altogether interrupting but out the entire cardiac cycle without any slowing continuous conduction by pro- appreciable isoelectric diastolic interval, ceeding in "jumps." Clinically used endo- thereby bridging the discrete local eleccardial electrode catheters are incapable trograms that do have such isoelectric of making a distinction among these interectopic intervals recorded from neighboring sites.22-24 Initiation of VT preceded mechanisms. Fractionated, prolonged local elec- by critical delay and fractionation in local trograms may be recorded from several electrograms bridging the interectopic disparate sites in the myocardium if the interval between the last extrastimulus underlying pathological process is wide- and the first VT complex was first demonspread. The zone of slow conduction of the strated in a canine model25 and subsegreatest interest is the one linked to the quently recorded during endocavitary earliest "presystolic" local electrogram left ventricular mapping with the use that precedes the onset of the QRS deflec- of electrode catheters during clinical tion in any surface ECG lead. Electrical VT.22 In a larger series, some form of activity in the small pathways with abnor- CEA bridging 2 consecutive QRS commal conduction participating in microreen- plexes during monomorphic VT was try is thought to contribute little, if any, demonstrated in 36% of the 56 patients to the surface ECG signal whose onset studied.23 According to the microreentry model, comes after the electrical activity exits the slow pathway and begins to rapidly electrical activity is present in some comdepolarize the bulk of the surrounding ponent of a small circuit at any moment myocardium. Thus, the distal segment or throughout the entire cardiac cycle. CEA, the site of exit of such a pathway is likely recorded by closely spaced bipolar electo be at or near the site that displays the trodes,24 rather than composite electrodes earliest discrete local electrogram in the covering a large area of the ventricular tachycardia cycle, preceding the onset of wall,25 is more likely to represent microreenthe QRS complex. The surface ECG algo- try. Furthermore, CEA should demonrithms applied to the surface QRS com- strate an organized pattern that displays plexes recorded during sustained VT and repeating and reproducibly identifiable pace mapping techniques20,21 may be used components bearing the same temporal to facilitate the detection of the approximate relation to each other during every carlocation of the earliest local electrogram, diac cycle (Figure 2).24 However, CEA, and therefore, by proximity, the approxi- even if it manifests an organized pattern mate location of the zone of microreentry. with regularly recurring, reproducible comBeyond this approximate localization, ponents, and recorded by closely spaced defining the exact site and various com- bipolar electrodes, should not be equated ponents of microreentry requires detailed with microreentry unless other confirmapping in a relatively small area of the matory electrophysiological phenomena ventricle. are shown to be present. Marked fractionation of a bipolar electrogram into multiple asynchronous high-frequency signals during pacing has been observed Continuous Electrical Activity before and interpreted as exaggerated Continuous electrical activity (CEA) is desynchronization of activation within a said to be present at a recording site when region comprising distorted heterogeneous the local bipolar electrogram recorded fibers.26

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Figure 2. The reproducible components of continuous electrical activity (CEA) during sustained monomorphic ventricular tachycardia (VT) in a canine model of experimental myocardial infarction recorded by endocardial left ventricular electrodes. The components display the same temporal relationship during each cardiac cycle.

In order to prove its close relationship to reentry in a small region, one must show that CEA is coextensive and coterminal with the tachycardia. This means, among other things, that at the recording site manifesting CEA during the tachycardia, CEA should not be present during pacing (with sinus rhythm background) at the same cycle length as the tachycardia. This however, is a necessary but not a sufficient criterion. During the arrhythmia, CEA should not only be present at the critical site of reentry, but during a train of stimuli that entrain the tachycardia

without interrupting it, its reproducible components should manifest simultaneous entrainment. Conversely, stimuli that terminate the tachycardia should interrupt the CEA first and transform it into more discrete electrograms after which no tachycardia complexes should be observed (Figure 3).24 Pacing during the tachycardia at cycle lengths shorter than the tachycardia cycle length, which captures the ventricle but encounters entry block at the site of origin of the tachycardia and therefore fails to either entrain or terminate the tachycardia,

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Figure 3. Ventricular pacing during sustained monomorphic ventricular tachycardia (VT) in the same canine model as in Figure 2. The arrowheads depict the reproducibly recurrent components of continuous electrical activity (CEA). Despite capture, the first train of stimuli neither terminates nor entrains VT (entry block) and at the same time leaves the components of CEA unaffected. The second train of stimuli transforms CEA into fractionated but discrete local electrograms (penetration of the circuit), and at the same time interrupts VT.

should not reset or alter in any way the pattern of organized CEA since there is no penetration into the area where CEA is taking place (Figure 3). After cessation of pacing, the tachycardia and the components of CEA should both continue unaffected, bearing the same temporal relationships and phase delays (Figure 3).

By contrast, extrastimuli that reset the tachycardia should also reset the components of CEA and should leave them unaffected. One of the most convincing ways to demonstrate the basic relationship between organized reproducible CEA and the tachycardia circuit is to terminate the

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Figure 4. Interruption of continuous electrical activity (CEA) with termination of ventricular tachycardia (VT) by a single subthreshold stimulus delivered at a site immediately adjacent to the site of CEA, during the refractory period of the ventricular myocardium, 85 ms after the onset of the surface ECG QRS complex.

tachycardia using a subthreshold stimulus scanning the diastolic CEA and delivered to the site of CEA. If such a stimulus is delivered during the refractory period of the tissue surrounding the protected zone, e.g., within or immediately after the QRS complex, it may still penetrate the circuit locally and terminate microreentry. If such a subthreshold stimulus terminates CEA and at the same time interrupts the tachycardia (Figure 4), the cause-effect relationship will be established. Isolated Mid-diastolic Potentials Pandiastolic CEA with reproducible components manifesting all the criteria mentioned above is a rare finding in the clinical cardiac electrophysiology labora-

tory. It is much more common during mapping to record isolated, low-amplitude, middiastolic electrograms corresponding to electrical activity in a protected zone of abnormally slow conduction, especially when mapping VT or ischemic disease (Figure 5).27-30 It is not possible to define local geometry with precision using a single mapping catheter in the left ventricle. However, fractionated, prolonged, mid-diastolic potentials may result from activity in different nonlinear components of the microreentry circuit.29,30 These potentials may thus represent specific segments of CEA associated with microreentry, all of which may not be recorded with a single bipolar electrode. As with CEA, demonstrating the specificity of these mid-diastolic signals is of greatest importance, and electrophysiological phenomena confirming

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Figure 5. Fractionated low-amplitude local electrograms identified with arrows recorded in middiastole (160 ms prior to surface EGG fiducial point) recorded during clinical sustained monomorphic ventricular tachycardia, with the use of a quadripolar exploring (Expl.) electrode. RVA = right ventricular apex.

that these potentials are recorded from pathways within the VT circuit must be sought. First, it should be demonstrated that the low-amplitude, mid-diastolic electrogram results from conduction in a pathway which gives rise to the subsequent VT wavefront, rather than resulting from secondary, late activation of a site outside the circuit from the previous VT beat. Careful examination of resetting and entrainment patterns may help to make this distinction. An extrastimulus applied during VT to a site spatially remote from the catheter recording the mid-diastolic potential, and synchronized to this middiastolic signal, that resets the VT should also reset the mid-diastolic potential with little or no change in the temporal relationship and phase delay between the mid-diastolic potential, the surface QRS complex, and the rest of the local electro-

grams (Figure 6).29 Similarly, trains of extrastimuli applied at a site far from the electrode recording the mid-diastolic potential that entrain the VT must entrain the mid-diastolic potential as well,27,30 again with no variation in the temporal relationship of this mid-diastolic component and the QRS complex of the VT which follows (Figure 7). With the geometry shown in Figure 8A, microreentry appears as a modified version of figure-of-8 mechanism.31 Prototypical figure-of-8 reentry incorporates one central pathway of slow conduction with larger, faster conducting pathways coupled to it.31 Similarly, microreentry may be considered a mechanism incorporating multiple small pathways coupled to each other, making up a small circuit with narrow exit points simulating focal mechanism with monoregional spread.

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Figure 6. Resetting of ventricular tachycardia (VT) and the mid-diastolic potential recorded from an exploring electrode (Expl.) during diastole from the right ventricular apex, remote from the site of earliest recorded electrogram. The resetting stimulus is delivered at a ventricular site outside the VT circuit.

An extrastimulus during VT delivered at a site within the microreentry circuit produces results different from the findings described above. First of all, one would expect a narrow excitable gap in a small area manifesting nearly CEA. If the paced wavefront propagates only in antidromic direction, VT is likely to terminate, possibly after a fusion beat. If the stimulus propagates in the orthodromic direction, the VT will be reset, but with no change in QRS morphology. Such a finding should be spatially (site of stimulation) and temporally (coupling interval) reproducible. Similarly, as with macroreentry, entrainment from a site within the protected zone of slow conduction should cause no fusion activation, and therefore no change in the surface QRS morphology of the entrained complexes27 (Figure 9).

This brings up another mapping-related question, namely whether entrainment with concealed fusion can be used to assess the approximate size of the reentrant circuit. The size of the area over which entrainment with concealed fusion is demonstrable, possibly with different degrees of latency, may be assessed with reasonable accuracy. This observation alone is not able to determine the actual geometry or the orientation of the pathways but may provide a rough estimate of the relative size of the tissue in which microreentry is confined. Figures 8C and 8D show schematically how pacing attempts from closely spaced sites may be used to probe the geometry of the underlying circuit. Newly available techniques of electroanatomical mapping may be superior to conventional fluoroscopy for this purpose.32

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Figure 7. "Entrainment" of the diastolic potentials recorded during the same ventricular tachycardia (VT), as shown in Figure 6. The low-amplitude, fractionated potentials recorded by the exploring electrode (Expl.) are accelerated to the pacing cycle length (300 ms) with long stimulus-to-potential interval, but without disturbing the potential-to-VT temporal relationship in the first VT return beat.

Another rare finding that may increase the specificity of mid-diastolic potentials as electrical activity recorded from within a protected zone of microreentry is the demonstration that isolated diastolic potentials march through the entire diastole in a continuous fashion, during small displacements of the recording electrode. This finding is almost as specific as pandiastolic CEA with all components recorded from a single recording site. It also identifies the proximal and the distal segments of the circuit for purposes of ablation. As the diastolic potential marches temporally from early to mid to late portions of diastole, it is assumed that the recording electrode catheter is marching spatially from proximal to middle to distal segments of the circuit, relative to the site of exit. It should be

realized, however, that this temporal-spatial correlation may be the consequence of our perception of a 3-dimensional mechanism as 2-dimensional, confined to the endocardial surface. Resetting and entrainment maneuvers may be tried at successive catheter sites for acquiring corroborating data. It is important to emphasize that local geometry cannot be defined with precision with the use of endocardial electrode catheters, even with ones incorporating multiple recording bipoles. Furthermore, the novel techniques of noncontact mapping are not likely to elucidate the components of microreentry, as it is likely to be identified with this technique as any other focal mechanism with centrifugal spread.

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Figure 8. A. Schematic diagram representing a microreentry circuit with the slowly conducting pathway depicted by a wavy line (p) and surrounded by functionally (broken line) and anatomically (hatched rectangle) refractory zones. The site of exit is marked by the letter E. B. Resetting of ventricular tachycardia (VT) and the microreentry circuit by a stimulus delivered at a site remote from the site of exit (E) from the circuit. The VT cycle number is indicated by n. C. Resetting of VT and microreentrant activation by a stimulus delivered at a site within the slow component of reentry, resulting in antidromic conduction block and orthodromic propagation. D. Termination of VT with a stimulus delivered slightly more distally in the pathway blocking both in antidromic and in orthodromic directions.

Termination of the Tachycardia -with Interruption of Conduction Within Microreentry Another method of confirming the specificity of the mid-diastolic potentials as basic to VT mechanism involves interruption of VT by interventions that

reversibly inhibit conduction in the circuit located within the protected region where these mid-diastolic fractionated potentials are recorded.33 Unlike the operating room, the electrophysiology laboratory is not a setting where reversible cooling of a recording site can readily be carried out, at least with currently available electrode catheters. Subselective cold saline

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Figure 9. Entrainment with concealed fusion during ventricular tachycardia with a cycle length of 500 ms. Pacing at a cycle length of 460 ms accelerates the tachycardia rate with no change in surface QRS morphology in surface ECG leads I, aVF, and V^ . Latency during pacing is similar to the diastolic potential-to-QRS interval during the ventricular tachycardia.

injections into coronary artery branches can be used to terminate VT, but this technique is not specific enough to serve as a probe for a microreentry circuit. Subthreshold stimuli delivered within the refractory period to the zone of slow conduction and timed appropriately to prolong the refractoriness in the slow pathway, but without resulting in a propagated beat, may be used to attempt termination of the VT. When such a subthreshold stimulus captures the local tissue that does not generate a surface vector, and fails to propagate in both the orthodromic and the antidromic directions and eliminates the mid-diastolic potential, one would expect VT to terminate if the site of stimulation is instrumental for giving rise to the following VT wavefront (Figures 8D and 10). Although a rare finding, if present and reproducible, this observation lends powerful support to the idea that a small protected zone, the site of the mid-diastolic potential recording, is within the VT circuit. It is less likely for a macroreentry or a large figure-of-8 mechanism to be affected by a subthreshold stimulus since there would be a greater chance for the participation

of alternate pathways or alternate exit sites necessary for the continuation of the tachycardia. Conclusion

Microreentry is an arrhythmia mechanism that may be difficult to define with precision in the cardiac electrophysiology laboratory. For the practical purposes of endocardial mapping, it may be reduced to the simplified concept of slow conduction in pathways confined to a small volume of myocardium protected by surrounding refractory tissue. Demonstration of microreentry then requires a search for bridging diastolic CEA or isolated, mid-diastolic, fractionated electrograms scanning diastole, whose specificity must be properly tested before their putative link to the reentry process can be established. Several questions remain. First, whether microreentry, based on unusual geometry or physiological aging, can exist in cardiac tissue without injury or disease, is an interesting question that warrants further investigation. Second, it is not clear whether microreentry can be the basis of

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Figure 10. Termination of clinical ventricular tachycardia (VT) by a subthreshold stimulus delivered to a recording site manifesting prolonged fractionated electrograms. A bipolar stimulus is delivered by the distal pair of electrodes and the local electrogram is recorded by the proximal pair on a quadripolar electrode catheter.

clinical atrial arrhythmias or can be confined to the endocardial or the epicardial layers of the ventricular myocardium rather as a 2-dimensional mechanism. If, alternatively, microreentry can occur only as a 3-dimensional mechanism in the ventricular myocardium, it may represent, as described above, the special case of a small figure-of-8 circuit, which, because of its orientation and special geometry, mimics a focal mechanism. Clarification of these issues influences the success of ablative therapies for clinical tachycardias.

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DEMONSTRATION OF MICROREENTRY 7. Mehra R, Zeiler R, Gough WB, El-Sherif N. Reentrant ventricular arrhythmias in the late myocardial infarction period. 9. Electrophysiologic-anatomic correlation of reentrant circuits. Circulation 1983;67: 11-24. 8. Garan H, Fallon JT, Rosenthal S, Ruskin JN. Endocardial, intramural, epicardial activation patterns during sustained monomorphic ventricular tachycardia in late canine myocardial infarction. Circ Res 1985;56:736-754. 9. Kramer JB, Saffitz JE, Witkowski FX, Corr PB. Intramural reentry as a mechanism of ventricular tachycardia during evolving canine myocardial infarction. Circ Res 1985;56:736-754. 10. Okumura K, Olshansky B, Henthom RW, et al. Demonstration of the presence of slow conduction during sustained ventricular tachycardia in man. Circulation 1987;75:369-378. 11. Gardner PI, Ursell PC, Fenoglio JJ Jr., et al. Electrophysiologic and anatomic basis for fragmented electrograms recorded from healed myocardial infarcts. Circulation 1985;72:596-611. 12. Josephson ME, Harken AH, Horowitz LN. Endocardial excision. A new technique for the treatment of recurrent ventricular tachycardia. Circulation 1979;60:14301439. 13. Littman L, Svenson RM, Gallagher JJ, et al. Functional role of the epicardium in postinfarction ventricular tachycardia. Circulation 1991;13:1577-1591. 14. Harris L, Downar E, Mickleborough L, et al. Activation sequence of ventricular tachycardia: Endocardial and epicardial mapping studies in the human ventricle. JAm Coll Cardiol 1987;10:1040-1047. 15. Wit AL, Dillon SM. Anisotropic reentry. In: Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping. Mount Kisco, NY: Futura Publishing Co.; 1993:127-154. 16. Wellens HJJ, Brugada P. Mechanisms of supraventricular tachycardia. Am J Cardiol 1988;62:10D-15D. 17. Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. Circ Res 1988;62:811-832. 18. Janse MJ, Anderson RH, McGuire MA. AV nodal reentry: Part I: AV nodal reen-

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try revisited. J Cardiovasc Electrophysiol 1993;4:573-586. 19. Tai Y, Lee KL. Interfascicular macroreentry versus intrafascicular microreentry. J Cardiovasc Electrophysiol 1996;7:275. Letter. 20. Josephson ME, Waxman HL, Cain ME, et al. Ventricular activation during ventricular endocardial pacing. II. Role of pacemapping to localize origin of ventricular tachycardia. Am J Cardiol 1982;50:11-22. 21. Kuchar DL, Ruskin JN, Garan H. Electrocardiographic localization of the site of origin of ventricular tachycardia in patients with prior myocardial infarction. JAm Coll Cardiol 1989;13:843. 22. Josephson ME, Horowitz LN, Farshidi A. Continuous local electrical activity. A mechanism of recurrent ventricular tachycardia. Circulation 1978;57:659-665. 23. Brugada P, Abdollah H, Wellens HJJ. Continuous electrical activity during sustained monomorphic ventricular tachycardia. Am J Cardiol 1985;55:402-411. 24. Garan H, Ruskin JN. Localized reentry: Mechanisms of induced sustained ventricular tachycardia in canine model of myocardial infarction. J Clin Invest 1984; 74:377. 25. El-Sherif N, Hope RR, Scherlag BJ, Lazzara R. Reentrant arrhythmias in the late myocardial infarction period. 2. Patterns of initiation and termination. Circulation 1977;55:702-719. 26. Elharrar V, Foster PR, Jirak TL, et al. Alterations in canine myocardial excitability during ischemia. Circ Res 1977;40: 98-105. 27. Morady F, Fran R, Kou WH, et al. Identification and catheter ablation of a zone of slow conduction in the reentrant circuit of ventricular tachycardia in humans. J Am Coll Cardiol 1988;ll:775-782. 28. Fitzgerald DM, Friday KJ, Yeung JA, et al. Electrogram patterns predicting successful catheter ablation of ventricular tachycardia. Circulation 1988;4:806-814. 29. Garan H, Ruskin JN. Reproducible termination of ventricular tachycardia by a single extrastimulus within the reentry circuit during the ventricular effect refractory period. Am Heart J 1988; 11:546-550. 30. Kay GN, Epstein AE, Plumb VJ. Region of slow conduction in sustained ventricular tachycardia: Direct endocardial recordings and functional characterization in

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humans. J Am Coll Cardiol 1988; 11:109116. 31. El-Sherif N, Smith A, Evans K. Canine ventricular arrhythmias in the late myocardial infarction period: Epicardial mapping of reentrant circuits. Circ Res 1981;49:255-265. 32. Shpun S, Gepstein L, Hayam G, BenHaim SA. Guidance of radiofrequency

endocardial ablation with real-time threedimensional magnetic navigation system. Circulation 1997;96:2016-2021. 33. El-Sherif N, Mehra G, Gough WB, Zeiler RH. Reentrant ventricular arrhythmias in the late myocardial infarction period: Interruption of reentrant circuits by cryothermal techniques. Circulation 1983; 68:644-656.

Chapter 13 Optical Mapping of the Effects of Defibrillation Shocks in Cell Monolayers Vladimir G. Fast, PhD and Andre G. Kleber, MD

Introduction Strong electrical shocks are applied to terminate life-threatening cardiac arrhythmias such as ventricular fibrillation. Although this procedure is used in patients on a routine basis, the mechanism by which the extracellular electrical field affects the transmembrane potential (Vm) of cardiac cells and terminates fibrillation is not fully understood. From theoretical studies it has been proposed that the microscopic structure of cardiac tissue might cause Vm changes (AVm) necessary for defibrillation. Until recently, the experimental verification of this hypothesis was not possible because of the complex 3-dimensional structure of cardiac tissue and the lack of methods to measure distribution of Vm at the microscopic level. These problems were overcome with the development of a new experimental approach that combines high-resolution optical mapping of Vm and techniques for growing cardiac tissue

with defined architecture in cell culture. This chapter discusses the application of this approach to studying effects of extracellular shocks on Vm and presents a short overview of recent experimental results. Mechanisms for Vm Changes During Defibrillation Analysis of the classic cable model indicates that in a structurally continuous tissue, the Vm changes induced by a uniform extracellular field should be limited to a very small tissue area near the shock electrodes.1,2 With increasing distance from the electrodes, changes in Vm will decay exponentially and approach zero beyond 1 to 2 mm from the shock electrodes. To induce Vm changes in tissue far from the shock electrodes, a redistribution of axial current between intracellular and extracellular spaces must take place. In general, this can occur either because of the nonuniform distribution of the extracellular shock field or because of the

This work was supported by the Swiss National Science Foundation and the Swiss Heart Foundation. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003.

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spatial variation in the tissue structure. The first mechanism relates AVm, or "virtual electrodes," to the spatial derivative of the extracellular field called activating function. 3-6 Several mechanisms of the second kind have been proposed. One of them, known as the mechanism of secondary sources, suggests that changes in Vm are produced by the microscopic resistive barriers associated with cell boundaries7-10 or by larger resistive barriers associated with the vasculature, intercellular clefts, or connective tissue sheets separating cell bundles and cell layers.11-12 Another structure-dependent mechanism relates Vm changes to rotation of anisotropy axes in space.13 Combination of both structural factors (tissue anisotropy) and the nonuniform shock field can produce Vm changes via the "dog-bone" effect.14-15 Cell Culture as a Model for Studying Defibrillation Mechanisms Until recently, the effects of tissue structure on defibrillation were investigated almost exclusively in computer models.7-10,16,17 Experimental studies of the structural effects in the heart are hampered by the 3-dimensional anatomy of cardiac muscle that prevents precise correlation of Vm changes with the tissue structure, especially at the microscopic level. Also, because cardiac muscle contains structural discontinuities of multiple types, separating the effects of one individual structure from another as well as from effects of other, structureindependent, factors is extremely difficult. These obstacles can be overcome using cultures of cardiac cells. The advantage of cell cultures is that they grow as 2-dimensional monolayers and their microscopic structure can be precisely determined and correlated with electrophysiological measurements. In addition, the monolayer structure can be modified in

a desirable way using techniques for directed cell growth, which greatly facilitates structure-function studies. A number of such techniques were developed at the Department of Physiology of the University of Bern (Switzerland) that allow the growth of cell cultures in predetermined geometric patterns such as cell strands and geometric expansions,18,19 or in anisotropic patterns.20,21 Electrophysiological parameters of cell cultures such as the maximal upstroke rate of rise and the conduction velocity are quite similar to those measured in adult ventricular tissue.18,22 The differences include smaller cell size and more uniform distribution of gap junctions along the cell perimeter in cell cultures as compared to the adult tissue.20,21 Microscopic Optical Mapping of Vm in Cell Cultures The optical mapping technique was used to measure Vm changes with microscopic resolution. This technique, which involves staining of excitable tissue with a voltage-sensitive dye and measurement of the dye fluorescence with an array of photodetectors, has been widely used for multisite recordings of Vm from brain and cardiac tissue.23 We have adapted this method for microscopic measurements of Vm in myocyte cultures.20-"22,24 The key elements of this technique, a voltagesensitive dye, a light source, optical filters, objectives, and amplifiers, were selected to achieve high signal-to-noise ratio when measuring weak optical signals from a small cell membrane area. The experimental set-up for optical recordings, shown schematically in Figure 1, was built around an inverted epifluorescent microscope (Axiovert 35M, Zeiss, Germany). To optically record Vm, the voltage-sensitive dye RH-237 (Molecular Probes, Eugene, OR) was used. The excitation light was provided by a 100-W arc

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Figure 1. Schematic diagram of the optical mapping set-up. See text for detailed description.

mercury lamp, which delivers a strong light in the green range, where the RH237 dye has its absorption maximum. The light was passed through a heat filter and a band-pass exciting filter with a transmittance range of 530 to 585 nm. The light was deflected by a dichroic mirror with transmittance at greater than 600 nm, and focused on the preparation by the objective lens. The emitted fluorescent light was collected by the same objective, passed through the dichroic mirror, filtered with a low-pass filter at greater than 615 nm, and measured using a 10 x 10 photodiode array (Centronic Ltd., Surrey, England) attached to the photographic port of the microscope. Individual diodes in this array have dimensions of 1.4 x 1.4 mm2 with an interdiode distance of 0.1 mm. Microscopic objectives with magnification lOx, 20x, 40x, 63x, and lOOx (Zeiss) and numerical apertures of 0.5, 0.75, 1.3, 1.25, and 1.3, respectively, were used. Objectives with lower magnifications are also available but, because of

their small numerical apertures and poor light collecting efficiency, they did not provide enough light for the voltagesensitive measurements in cell cultures. Taking into account the additional magnification of the photographic port of 2.5x, the total optical magnification was in the range between 25x and 250x that resulted in an imaged area of 56 x 56 (im2 (lOx magnification) to 5.6 x 5.6 Jim2 (lOOx magnification) per diode. The photocurrents from the 96 diodes were converted to voltages by custom-built current-to-voltage converters. The 2 most important parameters of the converters are the gain and the bandwidth. The gain depends on the value of the feedback resistors, Rf. The bandwidth depends on the speed of operational amplifiers and, because of the presence of a stray capacitance parallel to the feedback resistors, on the Rf value as well. To faithfully reproduce a normal cardiac action potential upstroke, the system bandwidth should be greater than 1 kHz. We achieved a

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Figure 2. A. Schematic diagram of the experimental chamber showing an area of cell growth (black) on a glass cover slip (white) and shock electrodes (+ = anode; - = cathode). B. Optical recording of background fluorescence and an action potential upstroke. The fractional change of fluorescence associated with the action potential was 12% of the background level. C. Determination of shock-induced change in transmembrane potential (AVm). A stimulus was applied to induce an action potential. Action potential amplitude (APA) was measured as the difference between the fluorescence levels immediately before and after the upstroke. The Vm was measured twice: without a shock (gray line) and with a 10-ms shock applied during action potential plateau (black line). The shock-induced AVm was measured as the difference in fluorescence intensity between a linear fit of the plateau phase depicted by a thin line and the signal magnitude 5 ms after the shock onset and expressed as a percentage of APA. This linear fit corresponded to the time course of Vm without a shock.

bandwidth of ~1.6 kHz and a low noise level by using feedback resistors with a value of 100 MO and operational amplifiers OPA121 from Burr-Brown (Tucson, AZ). A typical signal at the output of a current-to-voltage converter is shown in Figure 2B. It consists of a large negative deflection associated with the beginning of light exposure and corresponding to background fluorescence. The smaller positive deflection corresponds to the upstroke of an action potential initiated by a stimulation pulse. The fractional change of fluorescence given by the ratio of the action potential amplitude (APA) and the value of the background fluorescence can vary throughout the preparation and it also changes during the course of the experiment. Immediately

after the dye staining, the fractional change can be as high as 15%. As a result of dye internalization, the fractional fluorescence change decreases down to 5% within the first hour after staining. The useful portions of optical signals typically do not exceed a few dozen millivolts, which is too small to be measured without amplification by standard 12-bit analog-to-digital (A/D) converters. However, amplifying the useful signals also amplifies the portions corresponding to the background fluorescence, which may saturate the A/D converters. To avoid this limitation, the background fluorescence was subtracted before amplification. Both background subtraction and subsequent amplification were performed using second-stage

OPTICAL MAPPING OF EFFECTS OF DEFIBRILLATION SHOCKS amplifiers with a sample-and-hold circuitry (Figure 1). Subsequently, signals were multiplexed and digitized at 12-bit resolution and sampling rate of 10 to 25 kHz for each of the 96 channels. One of the major limitations of optical mapping is the phototoxic effect of voltage-sensitive dyes. This effect is especially important in cell cultures in which a relatively small amount of light is emitted by a cell monolayer and achievement of a high signal-to-noise ratio demands loading cells with a dye at a high concentration and a strong light excitation. To limit the phototoxic effect, cells were illuminated by excitation light for only a short period, typically 80 ms. Depending on optical magnification and intensity of illumination, up to 6 measurements can be performed in these conditions without significant cell deterioration. Measurements of the Shock-Induced Vm Changes An important advantage of optical mapping over conventional recordings using electrodes is that optical signals are devoid of stimulation artifacts. This is especially important for defibrillation studies where strong artifacts created by the defibrillation shocks interfere with conventional measurements of Vm during shocks and during at least the first 20 to 50 ms after the shocks. The disadvantage of optical recordings is that the optical signals reflect only relative changes of Vm. The absolute value of optical signals depends, in addition to Vm, on density of dye staining, degree of dye internalization, and uniformity of light intensity. Combination of these factors results in a significant variability of fluorescence intensity throughout the preparation, independently of the underlying variation of Vm. The V m -independent variability of

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optical signals can be reduced somewhat by measuring the fractional changes in fluorescence. This does not, however, eliminate the signal variability completely, because the fractional change of fluorescence itself varies throughout the preparation (mainly because of nonuniform dye internalization). To eliminate the V m -independent variability, optical signals were normalized relative to the portion of optical signals, which represents the APA. To accomplish that, an action potential was initiated before each shock, the optical APA was measured, and the shockinduced changes in Vm were normalized by the APA (Figure 2C). In doing so, an assumption was made that APA does not vary throughout the imaged area. This assumption is likely to be true in the microscopic measurements when the size of an imaged area is comparable to the length of the electrotonic constant, which in cell monolayers is about 360 urn.25 This assumption might not hold true on a larger spatial scale in pathological conditions, such as ischemia, favqring nonuniform distribution of APA. To create a uniform extracellular field, electrical shocks were applied via 2 large platinum plate electrodes positioned at opposite ends of the perfusion bath (Figure 2A). The bath measured 2.2 x 2.2 cm2 and the electrode dimensions were 2 x 0.2 cm2. Monophasic truncated exponential shocks with a duration of 10 to 12 ms were delivered using custom-built shock generators. The generators were triggered by the stimulus pulse and could produce shocks at specified times during the cardiac cycle. In most of the measurements, the extracellular voltage gradient produced by the shock in the bath was measured simultaneously with the optical recordings of Vm by 2 silver electrodes with a diameter of 0.2 mm and an interelectrode distance of 3.5 mm.

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The electrodes were positioned near the mapping area and aligned with the direction of the electrical field. Effects of Cell Boundaries on AVm One of the intriguing possibilities is that changes in Vm can be created by boundaries of the individual cell. This idea was proposed in 1986 by Plonsey and Barr,7 based on theoretical studies of a 1-dimensional cable model with periodic resistive barriers. In this model, changes in Vm appear as periodic ("sawtooth") oscillations with hyperpolarization on one side of a resistive barrier and depolarization on the other side. The idea that cell boundaries account for defibrillation was attractive because this type of structural discontinuity is the most universal feature of cardiac tissue. However, the hypothesis that cell boundaries induce major changes in Vm was not confirmed experimentally.

The effect of cell boundaries on shock-induced Vm changes was investigated in narrow cultured cell strands with a width of 30 to 60 (im.26 In such strands, because of the aligning influence of the strand edges, cells were oriented along the strand axis. A uniform extracellular shock field was applied along the strand axis and changes in Vm were measured with subcellular resolution. Figure 3 shows an example of AVm/ APA measured with resolution of 6 um during application of a shock with strength of 11 V/cm. Panel A shows the phase-contrast image of cells with superimposed grid of photodiodes, and panel B illustrates selected action potentials. At all measuring sites, the cell membrane was hyperpolarized during the shock. There was no abrupt transition from hyperpolarization to depolarization as expected from secondary sources, and no significant changes in AV m / APA were found between measuring sites localized in neighboring cells.

Figure 3. Effect of cell boundaries on transmembrane potential (VJ. A. Image of cells at xlOO magnification with overlaid photodiode array grid. B. Drawing of the cell strand with outlined boundaries of individual cells and selected optical recordings of change in Vm during application of shock. Reproduced from reference 26, with permission.

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Similar results were obtained in 12 cell in Vm, the search for secondary sources preparations. shifted to larger anatomical discontinuA likely explanation for the discrepancy ities. One type of such a discontinuity in between the theory and the experiments cardiac muscle is related to the incluregarding secondary source formation is the sions of connective tissue into the effect of "lateral averaging" described for myocardial structure that interrupt the microscopic conduction.22 The mechanism continuity of the intracellular space on a of secondary source formation was origi- scale of several cell lengths or more, i.e., nally proposed from 1-dimensional models several hundred micrometers. To invesof cardiac tissue where axial current is tigate the effect of such discontinuities on forced to flow through each resistive bar- Vm, we have produced cell monolayers rier represented by an intercellular junc- with intercellular clefts of variable tion, which resulted in a large voltage dimensions.29 Uniform-field shocks were drop across this junction. In a 2-dimen- applied across clefts and the Vm changes sional tissue, however, a portion of local were measured as a function of the cleft axial current can bypass an individual length. resistive barrier and flow through cell juncFigure 4 demonstrates the effect of an tions offered by lateral cell connections. In electrical shock on Vm near an intercellucell cultures, this averaging effect might lar cleft. Panel A shows an image of the cell be especially prominent because of the monolayer and the grid indicating the posirelatively uniform distribution of gap tion of the photodiodes. The intercellular junctions along the cell perimeter.21 cleft is delineated with a dashed line. The Whether cell junctions can change Vm sub- length and the width of the cleft were stantially in adult cardiac tissue in vivo is approximately 240 |nm and 60 |im, respecnot known. On one hand, adult myocytes tively. The stimulation electrode was are longer than the neonatal cells in cul- located above the mapping area and the ture and gap junctions in the ventricular shock electrodes were located on the left myocardium tend to be more concentrated and the right sides. Panel B shows the at cell ends27 thus favoring the formation isochronal map of activation spread initiof secondary sources. On the other hand, ated by the stimulus. Panels C and D cells in the intact tissue are arranged in depict isopotential maps of the relative a 3-dimensional structure, which increases changes in Vm, AVm/APA, caused by electhe degree of intercellular connectivity trical shocks of opposite polarities. The and is predicted to reduce effects of indi- pattern of AVm/ APA distribution was convidual resistive discontinuities on Vm. sistent with the mechanism of secondary How these opposing influences interplay sources. In panel C, cells were depolarized is not presently known. Measurements of on the right side and hyperpolarized on the effects of shocks carried out recently in the left side of the cleft. The isopotential rabbit papillary muscle using a roving map contained 2 localized regions of microelectrode did not reveal secondary maximal depolarization and maximal sources at the cell boundaries,28 adding hyperpolarization adjacent to the obstasupport to the conclusions drawn from the cle, corresponding to current sources and current sinks, respectively. With the cell culture studies. reversed shock polarity (panel D), the Effects of Intercellular Clefts on AVm regions of depolarization and hyperpolarization were interchanged. After it was found that cell boundIndividual recordings illustrating aries do not produce significant changes changes in Vm across the obstacle from the

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Figure 4. Effect of an intercellular cleft on transmembrane potential (Vm). A. Image of a cell monolayer (x20 magnification) with the grid illustrating the position of the photodiodes and the dashed line outlining the position of the intercellular cleft (length = 240 (im). B. Isochronal map of activation spread initiated by stimulation from above the mapping area. Activation times are determined from the time of earliest activation within the mapping region. Isochrones are drawn at intervals of 100 us. C and D. Isopotential maps of change of Vm/action potential amplitude (AVm/APA; in %) induced by shocks of opposite polarities. Shock strength was 7.5 V/cm (A) and 8.5 V/cm (B). Gray areas depict the intercellular cleft. The outline corresponds to the boundary of the photodiode array. See color appendix. Reproduced from reference 29, with permission.

OPTICAL MAPPING OF EFFECTS OF DEFIBRILLATION SHOCKS same experiment are shown in Figure 5 (panels A and B) for opposite shock polarities. The shape of AVm traces in most cases corresponded to the truncated exponential field pulse in both depolarized and hyperpolarized areas. Panels C and D illustrate profiles of AVm/APA along the horizontal axis for the 2 shock polarities. In the first case (panel C), the profile was symmetrical with depolarization and hyperpolarization decaying within a short distance from the

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obstacle. A slightly asymmetrical voltage profile was observed when shock polarity was reversed (panels B and D). The strength of secondary sources depended on both field strength and cleft length. We defined the magnitude of secondary sources as the difference of AVm/APA measured across the middle of an obstacle, (AVm/APA)diff. For a given obstacle, the average of 2 (AVm/APA)diff values was taken that were measured in

Figure 5. Action potentials near intercellular cleft during shock application. A and B. Selected optical traces recorded across the cleft at 2 shock polarities. The numbers correspond to the photodiode locations in Figure 4C and D. C and D. Dependence of change of transmembrane potential/action potential amplitude (AVm/APA; in %) on distance. Distance 0 corresponds to the center of the photodiode 1 in Figure 4C. Reproduced from reference 29, with permission.

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response to shocks of opposite polarities. Figure 6 demonstrates the dependence of the (AVm/APA)diff on the obstacle length for 2 shock strengths. In the first group, the average shock strength was 8.5 ± 0.6 V/cm (range of 7.5-9.4 V/cm, n=14). In the second group, the average shock strength was 18.0 ± 1.0 V/cm (range of 16.1-19.3 V/cm, n=16). The (AVm/APA)diff values measured across 20 clefts are plotted in Figure 6B. The cleft lengths were in the range of 45 to 270 jam. Within this range of cleft lengths, the relation between the obstacle length and the magnitude of the secondary sources could be closely approximated by a linear fit. From these data, an estimate of the critical obstacle length necessary for direct activation of cells can be predicted. Assuming that a shock produces symmetrical changes in Vm and that cells are excited in the area of maximal depolarization (if Vm is depolarized by 25% APA above the resting level, corresponding to a depolarization of 25 mV30), cells will be directly activated when the (AVm/APA)diff value is larger than 50%. From the linear functions in Figure 6B, this estimated critical obstacle length is approximately 85 ± 8 urn for a shock strength of 18.0 V/cm and 171 ± 7 |um for a shock strength of 8.5 V/cm. Direct Stimulation by Secondary Sources To test the prediction that resistive discontinuities cause direct excitation of cardiac tissue during application of extracellular shocks, shocks were delivered during diastole and the isochronal maps of activation spread initiated by shocks were analyzed. Figure 7 illustrates direct activation of myocytes by a secondary source created by an inexcitable obstacle. Panels A and C show isochronal maps of activation spread initiated by shocks of opposite polarities, and panels B and D

show the corresponding recordings of Vm from the sites surrounding the obstacle. With one shock polarity (panel A), a small cell region adjacent to the obstacle on the left side was directly activated by the shock. This was evident from the fact that the cells in this region had the earliest activation times, and action potential upstrokes (panel B, traces 1 and 2) exhibited biphasic shapes: the shock caused initial rapid membrane depolarization (shown by arrows), which was followed by excitation. This area of earliest activation was superimposed on the region of maximal depolarization produced by the shock during the plateau phase of the action potential (Figure 4D). Away from this area the amplitude of initial depolarization decreased (traces 3 through 6). The cells on the right side of the obstacle were transiently hyperpolarized by the shock, with hyperpolarization gradually increasing toward the center (traces 7 through 10). The initial membrane hyperpolarization was followed by depolarization, which resulted from the propagating wave initiated on the left side of the obstacle. An almost symmetrically reversed activation pattern was observed when the shock polarity was reversed (panels C and D). The site of the earliest activation in this case was located on the right side, superimposed on the area of maximal depolarization during application of shock in the plateau phase (Figure 4C). The stimulating efficacy of secondary sources depended on both shock strength and obstacle length. With an average strength of 8.2 V/cm (number of obstacles, n=28), shocks of both polarities directly excited cells when the obstacle length was 196 ± 53 [im (n = 14). Shocks of only one polarity resulted in direct activation when the obstacle length was 134 ± 49 fim (n=5, P<0.05). No activation by shocks of both polarities was observed at obstacles with length of 84 ± 23 \im (n = 9, P < 0.001). Thus, the critical obstacle length necessary

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Figure 6. Strength of secondary sources as a function of obstacle length. A. Scheme illustrating the definition of the strength of secondary source, (AVm/APA)diff. B. Plot of the dependence of the difference of change of transmembrane potential/action potential amplitude (AVm/APA)diff on the obstacle length at 2 shock gradients: 8.5 V/cm (open circles) and 18 V/cm (closed triangles); R indicates the correlation coefficient of the linear regression. Reproduced from reference 29, with permission.

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Figure 7. Direct activation of cells by secondary sources. A. Isochronal map of activation spread (interval = 150 (is) initiated from a secondary source on the left side of the obstacle during the application of a shock in diastole. The location of the secondary source coincides with the location of the area of maximal depolarization observed during shock application in the plateau phase of the action potential (Figure 4D). The obstacle is shown in white. Arrows indicate the direction of activation spread. Circles with numbers represent the centers of photodiodes selected for display of optical signals (B). Activation times are determined from the time of earliest activation within the mapping region. B. Optical recordings from locations indicated in A. Arrows indicate the direct membrane depolarization produced by a shock in the area of earliest activation. C and D. Isochronal map of activation (C) and selected optical signals (D) during the application of a shock of opposite polarity. The format is the same as in A and B. Reproduced from reference 29, with permission.

OPTICAL MAPPING OF EFFECTS OF DEFIBRILLATION SHOCKS for the direct cell activation with shocks of 8.2 V/cm was between 84 and 196 |um. The estimate of critical length of 171 ± 7 ^m obtained from shock-induced changes of Vm during the plateau phase of action potential (Figure 5) falls within this range. Discontinuities with dimensions of several hundred micrometers and larger are common in ventricular myocardium. In human pectinate muscle, connective tissue septa with such dimensions were found in ventricular tissue from young individuals and much larger (up to I mm) septa were found in the aging myocardium.31 Experiments in cell cultures suggest that such inexcitable obstacles may contribute to tissue excitation and defibrillation during the application of extracellular electrical shocks in the whole heart. The importance of tissue discontinuities for stimulation and defibrillation is also supported by the results of recent experiments in canine heart where it has been shown that artificial transmural incisions in ventricular wall give rise to activation fronts during stimulation and reduce the threshold of stimulation.32 Shock-Induced AVm in Cell Strands The boundaries of cell bundles and cell layers form a different type of structural discontinuity, which might be responsible for formation of secondary sources in cardiac muscle. The layer structure might be especially important because it is present throughout the bulk of ventricular myocardium, where cardiac cells are organized into lamina of variable thickness running across ventricular walls.12 To evaluate the role of this type of structures in defibrillation, we have carried out several studies in which Vm changes were measured in linear cell strands during application of uniform-field shocks. In the first study performed on strands averaging 0.2 mm in width, it

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was shown that, in accordance with the cable theory, shocks induced a hyperpolarization in cells facing the anode and a depolarization in the cells facing the cathode.26 Contrary to the linear cable theory, however, the effects of shocks on Vm were asymmetrical. When shocks were applied during action potential plateau, the magnitude of maximal hyperpolarization measured at one boundary of a strand was much larger than the magnitude of maximal depolarization measured at the opposite strand boundary. The effect of AVm asymmetry was voltage dependent. When shocks were applied in the repolarization phase, the Vm changes were symmetrical. The asymmetry of AVm indicates a strong nonlinearity in the Vm response to a defibrillation shock. A similar nonlinear response of Vm to electrical shocks was also observed in experiments on intact cardiac muscle.33,34 Two other studies were performed to investigate the mechanism of AVm asymmetry.35,36 In the first, the Vm responses to shocks were investigated as a function of strand width and shock strength.35 It was found that depending on these parameters, 3 different types of Vm responses could be produced. Relatively weak shocks applied to narrow strands induced the simplest symmetrical type of Vm changes. Figure 8 shows an example in which a 1.9-V/cm shock was delivered across a 0.15-mm-wide strand during the action potential plateau. The shock induced a depolarization in cells facing the cathode and a hyperpolarization in the cells facing the anode. The shape of the shock-induced AVm (panel C) was very similar to the rectangular shape of the shock waveform. The map of AVm distribution (panel B) was uniform and the transition from hyperpolarization to depolarization was gradual and linear (panel D). Overall, the AVm of this type reflects the redistribution of current supplied by the shock electrodes

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Figure 8. Symmetrical shock-induced change in transmembrane potential (AVm) in cell strands. A. Image of a cell strand with mask outlining the photodiode array. B. Isopotential map of AVm (%action potential amplitude [APA]) induced by 1.9-V/cm shock. Isopotential lines are drawn at an interval of 5%APA. C. Optical recordings of Vm during action potential upstroke and shock application. The numbers correspond to the photodiodes in A. E = recording of shock field in the bath. D. Spatial distribution of AVm measured 2 ms after the shock onset. Distance 0 corresponds to the center of photodiode 1 in A. Reproduced from reference 35, with permission.

according to the predictions of the linear cable model. Two other types of Vm responses were observed as shock strength or strand width were increased. Figure 9 illustrates AVm induced by shocks with a strength of 27 V/cm (panel B, thin traces) and 39 V/cm (panel B, thick traces) in a 0.15-mm strand. In the case of the 27-V/cm shock, the AVm

distribution across the strand was time dependent. During the early phase of the shock, the AVm distribution was symmetrical, as illustrated by the AVm profile measured 0.3 ms after the shock onset (panel C, dashed line). This indicates that, similar to effect of weak shocks (Figure 8), the initial response of Vm to the stronger shock was passive and linear.

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Figure 9. Asymmetrical shock-induced change in transmembrane potential (AVm). A. Image of a cell strand with grid of photodiodes. B. Recordings of AVm during application of 27-V/cm shock (thin traces) and 39-V/cm shock (thick traces). Signals are normalized by action potential amplitude (not shown). The numbers correspond to the photodiodes in A. C and D. Profiles of spatial distribution of AVm at different times during shocks. Distance 0 corresponds to the center of the photodiode 1 in A. Reproduced from reference 35, with permission.

Soon after the shock onset, however, Vm at all points shifted toward more negative levels. As a result, the AVm distribution became asymmetrical with hyperpolarization much greater than depolarization, which is exemplified by the AVm profile at t = 3 ms. Such shifts of Vm to

more negative levels indicate a net increase of current in the outward direction, which can be caused by generation of an outward current within the strand or by a decrease of an inward current. When the shock strength was increased to 39 V/cm, a third type of AVm

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was observed (panel B, thick traces). Similar to the case with the 27-V/cm shock, very early changes in Vm were nearly symmetrical; this is illustrated by the AVm profile measured at t = 0.3 ms (panel D). At t = 3 ms, the AVm distribution became strongly asymmetrical. Later during the shock, however, the membrane potential shifted to more positive levels approaching the level measured with the weaker, 27V/cm shock. As a result of this shift, the degree of AVm asymmetry was reduced. This later shift of Vm to more positive levels indicates increased current flow in the inward direction. To determine more precisely the voltage dependence for different types of AVm, the absolute values of maximal positive and negative changes in Vm at opposite strand borders were measured 2 ms after the shock onset as a function of shock strength in the 0.15-mm strands (n = 14). These data are shown in Figure 10. The linear and symmetrical AVm (Type I) were observed when shock strength was less than ~9 V/cm and the maximal magnitudes of AV^ and AV^ were less than ~40%APA. The thin straight line extrapolates this linear dependence into areas of larger voltages. The asymmetrical AVm (Type II), that deviated from the passive linear dependence, were observed when AVm exceeded ~40%APA. The transition to AVm with hyperpolarization-induced positive shift of Vm (Type III) occurred when shock strength was increased above -27 V/cm and the maximal negative AVm exceeded ~200%APA. Mechanism of Nonlinear AVm The ionic mechanisms of nonlinear Vm responses to electrical shocks are not yet known. The AVm asymmetry with larger AV-m thanAV+mreflects an increase in the net outward current. Therefore, it was expected that AVm asymmetry was related to the flow of an outward potas-

sium current and that application of potassium channel blockers should reduce the degree of the AVm asymmetry. Contrary to this expectation, however, application of potassium channel inhibitors barium chloride (inward rectifier), dofetilide (delayed rectifier), and 4-AP (transient outward current) did not reduce the AVm asymmetry,35,36 indicating that none of these outward currents was responsible for the AVm asymmetry. Unexpectedly, it was found that the asymmetrical behavior of AVm was reversed by application of the calcium channel blocker nifedipine. Figure 11 shows the effect of nifedipine on AVm caused by a 10.8-V/cm shock (control) and by a 10.6-V/cm shock (nifedipine) in a strand 0.8 mm in width. The spatial distribution of AVm in both cases was uniform (panel B) and nonlinear (panel C) as expected from AVm in strands with width larger than electrotonic space constant (about 350 jum25). In the control, the maximal amplitudes of AV+ and AV-m were 57 and -200%APA (panel C), respectively, resulting in the asymmetry ratio of 3.5. Application of nifedipine caused a strong increase of the AV+ (to 100%APA), whereas the maximal AV^ only slightly increased (to -207%APA). The increase of AV+ by nifedipine reduced the asymmetry ratio from 3.5 to 2.1. Similar results were obtained in a total of 8 strands measuring 0.8 mm in width. Panel D presents statistical data from these measurements. Nifedipine caused a large and reversible increase of AV^ by 70% (P < 0.001), a small increase if AV~, and, therefore, a decrease of the AVm asymmetry from 2.52 ± 0.5 to 1.62 ± 0.2 (P < 0.001). The effect of nifedipine on AV^ and AVjn indicates that the AVm asymmetry was caused by the outward flow of ICa in the depolarized portions of strands. Normally, ICa is inward but it changes direction when Vm exceeds the ICa reversal potential. According to patch clamp

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307

Figure 10. Voltage dependence of transmembrane voltage (Vm) response to shocks. The graph shows the dependence of maximal positive and maximal negative changes in Vm (AVm) on shock strength in 0.15-mm strands (n = 14). The AVm were measured at the opposite strand borders 2 ms after shock onset. Thick solid lines depict 3-order polynomial fits of data. The thin solid line corresponds to the linear dependence of AVm observed at weak shocks. Vertical dashed lines separate ranges of linear and symmetrical Vm response (Type I), asymmetrical Vm response (Type II), and nonmonotonic Vm response with hyperpolarization-induced positive shift of Vm (Type III). Reproduced from reference 35, with permission.

studies, the ICa reversal potential in rat and rabbit myocytes is 45 to 50 mV.37'38 Therefore, positive AVm with magnitudes larger than 45 to 50 mV, such as shown in Figure 11, should be reduced by the outward flow of ICa, which explains how blocking of ICa with nifedipine increases AV^. The effect of AVm asymmetry might have important implications for defibril-

lation in the whole heart. During fibrillation, most of the myocardium is in the depolarized state. Therefore, the effects of defibrillation shocks on Vm are predicted to be asymmetrical, with a larger portion of myocardium undergoing negative Vm (hyperpolarization) changes than positive Vm changes (depolarization). It has been shown that an interaction between areas

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Figure 11. Effect of nifedipine on shock-induced change in transmembrane potential (AVm). A. Optical recordings of Vm from selected diodes and shock waveform taken in control and during nifedipine application in strand with width of 0.8 mm. The corresponding shock strengths were 10.8 V/cm and 10.6 V/cm. B. Isopotential maps of AVm distribution 5 ms after the shock onset. Thick lines depict the zero isoline, which separates areas of depolarization and hyperpolarization. C. Spatial profiles of AVm across the strand. D. Effect of nifedipine on optical AV+, AV~, and the asymmetry ratio AV^/AV+ in 8 strands. Shock strength was 9.3 ± 0.8 V/cm. Reproduced from reference 36, with permission.

OPTICAL MAPPING OF EFFECTS OF DEFIBRILLATION SHOCKS of hyperpolarization and depolarization might determine the success or the failure of defibrillation.39 Because the asymmetry in AVm affects the size and the shape of the areas of hyperpolarization and depolarization, it might affect the outcome of a defibrillation shock. Knowledge of ionic mechanisms involved in shock-induced AVm might provide an opportunity for pharmacological modulation of AVm and, therefore, of defibrillation efficacy.

Conclusions These studies demonstrate the feasibility of the approach that uses voltage-sensitive dyes and the optical mapping technique to study the mechanisms of shock-induced changes of Vm. Experiments carried out in cell cultures indicate that smallest resistive discontinuities related to individual cell boundaries are unlikely to play a significant role in defibrillation. Larger discontinuities in tissue structure such as intercellular clefts and strand boundaries produce substantial changes in Vm and might contribute to tissue excitation and defibrillation. Shock-induced changes in Vm are strongly nonlinear and are a result of dynamic interaction between several factors, including active and passive properties of cell membrane, myocardial structure, as well as applied electrical field.

References 1. Weidmann S. Electrical constants of trabecular muscle from mammalian heart. J Physiol (Lond) 1970;210:1041-1054. 2. Kleber AG, Riegger CB. Electrical constants of arterially perfused rabbit papillary muscle. J Physiol (Lond) 1987;385: 307-324. 3. Rattay F. Analysis of models for external stimulation of axons. IEEE Trans Biomed Eng 1986;33:974-977. 4. Rattay F. Analysis of models for extracellular fiber stimulation. IEEE Trans Biomed Eng 1989;36:676-682.

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5. Sobie E, Susil R, Tung L. A generalized activating function for predicting virtual electrodes in cardiac tissue. Biophys J 1997;73:1410-1423. 6. Muzikant A, Henriquez C. Bipolar stimulation of a three-dimensional bidomain incorporating rotational anisotropy. IEEE Trans Biomed Eng 1998;45:449462. 7. Plonsey R, Barr R. Inclusion of junction elements in a linear cardiac model through secondary sources: Application to defibrillation. Med Biol Eng Comput 1986; 24:137-144. 8. Plonsey R, Barr R. Effect of microscopic and macroscopic discontinuities on the response of cardiac tissue to defibrillating (stimulating) currents. Med Biol Eng Comput 1986;24:130-136. 9. Krassowska W, Pilkington T, Ideker R. Periodic conductivity as a mechanism for cardiac stimulation and defibrillation. IEEE Trans Biomed Eng 1987;34:555560. 10. Plonsey R, Barr RC, Witkowski FX. Onedimensional model of cardiac defibrillation. Med Biol Eng Comput 1991;29:465469. 11. Sommer JR, Scherer B. Geometry of cell and bundle appositions in cardiac muscle: Light microscopy. Am J Physiol 1985;17: H792-H803. 12. Le Grice IJ, Smaill BH, Chai LZ, et al. Laminar structure of the heart: Ventricular myocyte arrangement and connective tissue architecture in the dog. Am J Physiol 1995;38:H571-H582. 13. Trayanova N, Skouibine K, Aguel F. The role of cardiac tissue structure in defibrillation. Chaos 1998;8:221-233. 14. Wikswo J. Tissue anisotropy, the cardiac bidomain, and the virtual electrode effect. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: W.B. Saunders Co.; 1995: 348-361. 15. Roth B. Mechanisms for electrical stimulation of excitable tissue. Crit Rev Biomed Eng 1994;22:253-305. 16. Keener JP. Direct activation and defibrillation of cardiac tissue. J Theor Biol 1996;178:313-324. 17. Pumir A, Krinsky VI. How does an electric field defibrillate cardiac muscle? Physica D 1996;91:205-219. 18. Rohr S, Scholly DM, Kleber AG. Patterned growth of neonatal rat heart cells in culture.

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Morphological and electrophysiological characterization. Circ Res 1991;68:114-130. 19. Rohr S, Kucera JP, Fast VG, Kleber AG. Paradoxical improvement of impulse conduction in cardiac tissue by partial cellular uncoupling. Science 1997;275:841-844. 20. Fast VG, Kleber AG. Anisotropic conduction in monolayers of neonatal rat heart cells cultured on collagen substrate. Circ Res 1994;75:591-595. 21. Fast VG, Darrow BJ, Saffitz JE, Kleber AG. Anisotropic activation spread in heart cell monolayers assessed by high-resolution optical mapping: Role of tissue discontinuities. Circ Res 1996;79:115-127. 22. Fast VG, Kleber AG. Microscopic conduction in cultured strands of neonatal rat heart cells measured with voltage-sensitive dyes. Circ Res 1993;73:914-925. 23. Grinvald A, Frostig RD, Lieke E, Hildesheim R. Optical imaging of neuronal activity. PhysiolRev 1988;68:12851367. 24. Fast VG, Kleber AG. Cardiac tissue geometry as a determinant of unidirectional conduction block: Assessment of microscopic excitation spread by optical mapping in patterned cell cultures and in a computer model. Cardiovasc Res 1995;29: 697-707. 25. Jongsma HJ, van Rijn HE. Electrotonic spread of current in monolayer cultures of neonatal rat heart cells. J Membr Biol 1972;9:341-360. 26. Gillis AM, Fast VG, Rohr S, Kleber AG. Effects of defibrillation shocks on the spatial distribution of the transmembrane potential in strands and monolayers of cultured neonatal rat ventricular myocytes. CircRes 1996;79:676-690. 27. Hoyt RH, Cihen ML, Saffitz JE. Distribution and three-dimensional structure of intercellular junctions in canine myocardium. CircRes 1989;64:563-574. 28. Zhou X, Knisley SB, Smith WM, et al. Spatial changes in the transmembrane potential during extracellular electric stimulation. CircRes 1998;83:1003-1014. 29. Fast VG, Rohr S, Gillis AM, Kleber AG. Activation of cardiac tissue by extracellular electrical shocks: Formation of "secondary

sources" at intercellular clefts in monolayers of cultured myocytes. CircRes 1998; 82:375-385. 30. Luo CH, Rudy Y. A model of the ventricular cardiac action potential. Depolarization, repolarization, and their interaction. CircRes 1991;68:1501-1526. 31. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle. Evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res 1986;58:356-371. 32. White J, Walcott G, Pollard A, Ideker R. Myocardial discontinuities: A substrate for producing virtual electrodes to increase directly excited areas of the myocardium by shocks. Circulation 1998;97:17381745. 33. Zhou XH, Rollins DL, Smith WM, Ideker RE. Responses of the transmembrane potential of myocardial cells during a shock. J Cardiovasc Electrophysiol 1995;6: 252-263. 34. Zhou X, Smith W, Rollins D, Ideker R. Transmembrane potential changes caused by shocks in guinea pig papillary muscle. Am JPhysiol 1996;271:H2536-H2546. 35. Fast VG, Rohr S, Ideker RE. Non-linear changes of transmembrane potential caused by defibrillation shocks in strands of cultured myocytes. Am JPhysiol 2000; 278:H688-H697. 36. Cheek E, Ideker R, Fast V. Non-linear changes of transmembrane potential during defibrillation shocks: Role of Ca2+ current. Circ Res 2000;87:453-459. 37. Yuan W, Ginsburg KS, Bers DM. Comparison of sarcolemmal calcium channel current in rabbit and rat ventricular myocytes. JPhysiol 1996;493:733-746. 38. Gomez JP, Potreau D, Branka JE, Raymond G. Developmental changes in Ca2+ currents from newborn rat cardiomyocytes in primary culture. Pflugers Arch 1994;428:241-249. 39. Efimov I, Cheng Y, Van Wagoner D, et al. Virtual electrode-induced phase singularity. A basic mechanism of defibrillation failure. CircRes 1998;82:918-925.

Chapter 14 Effects of Pharmacological Interventions on Reentry Around a Ring of Anisotropic Myocardium: A Study with High-Resolution Epicardial Mapping Josep Brugada, MD, PhD, Lucas Boersma, MD, and Maurits Allessie, MD, PhD

Introduction Reentry has been recognized as the mechanism of most clinically relevant arrhythmias. It is not surprising though that increasing efforts have been directed toward understanding the mechanisms by which different therapeutic options might modify a reentrant pathway. In this chapter we review the different mapping studies that we have performed concerning the effects of several pharmacological interventions on a simplified model of reentry around a ring of anisotropic myocardium in Langendorff-perfused rabbit hearts. Description of the Experimental Model Our experimental model consists of a ring of healthy epicardium in the left

ventricle (LV) of Langendorff-perfused rabbit hearts. Briefly, once the heart has been removed from the animal and connected to a Langendorff perfusion system, the right ventricle (RV), the interventricular septum, and the endocardial and intramural layers of the LV are destroyed by an endocardial cryoprocedure described extensively elsewhere. As a result, only a thin layer of approximately 1 mm thick of LV epicardium survives. The rest of the myocardium is completely destroyed. A cryoprobe is then applied through the epicardium and an area of approximately 20 x 10 mm is destroyed in the surviving layer. The result is a perfused ring of epicardium in the LV. We have previously shown that application of programmed electrical stimulation induces a sustained and stable reentrant rhythm around the ring.1

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003.

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Mapping Technique

and analog-to-digital converted into a single digital signal. A computerized system was then used to store, analyze, and generate color-coded activation maps.

For high-resolution mapping of epicardial excitation, a mapping system developed in the Department of Physiology at the University of Limburg in Maastricht, The Netherlands was used.2 A spoon- Characteristics of the Reentrant shaped electrode containing 248 individual Ventricular Tachycardia electrodes at regular distances of 2.25 mm allowed continuous and simultaneous Epicardial mapping showed that recording of 248 unipolar electrograms tachycardias induced during programmed covering the whole LV epicardium. The electrical stimulation were based on conindividual leads converged into a main tinuous reentry of the electrical impulse cable and were connected to an amplifica- around the ring.1 In Figure 1, an example tion unit containing 248 different amplifiers. of initiation of ventricular tachycardia (VT) After amplification and filtering (bandwidth by 2 premature beats is given. Ten selected 1 to 400 Hz), the analog signals were sam- electrograms around the obstacle and 4 actipled by multiplexors (1-kHz sampling rate) vation maps during induction of VT are

Figure 1. Ten electrograms around the ring and 4 activation maps are shown during initiation of reentrant ventricular tachycardia. The 4 consecutive activation maps are obtained during application of the last of a series of 10 stimuli given at a regular cycle of 250 ms (S1), the first premature beat (S2), the second premature beat (S3), and the first reentrant beat. Numbers indicate local activation time in milliseconds. Isochrones are drawn at 10-ms intervals. Arrows indicate direction of propagation. Double bars during S1 and S2 indicate collision of opposite wavefronts, and during S2 the double bars indicate unidirectional block. LAD = left anterior descending coronary artery. Empty area at the center of the map indicates the central anatomical obstacle.

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Figure 2. Activation maps and a single electrogram during 2 different reentrant tachycardias with cycle lengths of 136 and 195 ms, respectively. Encircled numbers indicate the position of the electrograms in the circuit. Abbreviations and symbols as in Figure 1.

shown. During S: (basic pacing at 250-ms intervals) and S2 (first premature beat given 154 ms after S^, the impulse propagated from the site of stimulation around both sides of the ring to collide in the corridor between the left anterior descending coronary artery and the obstacle. During S3 (second premature beat given 116 ms after S2), the impulse propagating counterclockwise blocked in the base of the LV. The clockwise wavefront continued to propagate and arrived at the site of unidirectional block 150 ms after block occurred. The cells proximal to the line of block already recovered their excitability and the impulse continued to propagate in a clockwise reentrant pathway. The resulting sustained VT had a regular cycle length (CL) of 128 ms. In different hearts, the CL of VT ranged between 121 and 224 ms (mean 165 ± 17 ms) and strongly depended on the size of the

obstacle. During each experiment, the tachycardia CL was very regular with a maximal variation in time of ±3 ms. In Figure 2,2 reentrant VTs with a regular CL of 136 and 195 ms are shown. Due to the anisotropic characteristics of the ventricular myocardium, conduction velocity was different in different segments of the ring depending on the angle between the fiber orientation and the direction of propagation of the impulse. In segments of the ring where the excitation wave propagated parallel to the epicardial fiber direction (base and lateral wall of the LV), longitudinal conduction velocity was approximately 60 cm/s. In segments of the ring where the excitation wave propagated perpendicular to the epicardial direction (corridor between the left anterior descending coronary artery and the obstacle), transverse direction velocity was 3 times slower (20 cm/s).

314 CAKDIAC MAPPING As is shown later in this chapter, this anisotropic distribution in conduction velocity during tachycardia plays an important role in modulating the effects of different pharmacological interventions.3-11 Effects of Pharmacological Interventions on Reentry We tested the effects of several pharmacological interventions administered during VT in this simplified model of reentry, including increasing doses of some well-known Class I antiarrhythmic drugs (propafenone and flecainide), a local anesthetic with Class I properties (bupivacaine), a new Class I drug (barucainide), a pure sodium channel blocker (tetrodotoxin), a new Class III antiarrhythmic drug (RP62719), extracellular potassium, an electrical uncoupler (heptanol), and a potassium channel opener. Table 1 shows the effects of the different interventions on the VT CL. All drugs with Class I effects (flecainide, propafenone, barucainide, and bupivacaine), the cellular uncoupler heptanol, and high concentrations of extracellular potassium significantly prolonged the VT CL and, at a given dosage, terminated

reentry in all hearts. The Class III drug RP62719 did not significantly prolong the VT CL, and reentry terminated in only 4 of 8 hearts tested. Administration of the potassium channel opener shortened the VT CL in 2 of 4 hearts, did not modify it in the remaining 2 hearts, and no VT termination was observed. Drugs or Pharmacological Interventions that Decrease the Number of Sodium Channels Available During the Phase 0 of the Action Potential: Class I Drugs, Tetrodotoxin, and Extracellular Potassium These pharmacological interventions can be discussed together since they all had similar electrophysiological effects on VT. The administration of these drugs resulted in a dose-dependent increase in CL of VT until reentry terminated. Figure 3 shows 18 electrograms around the ring and 2 activation maps during control and at the moment of tachycardia termination during the administration of 7 mg/L of flecainide. The tachycardia CL, which was 199 ms during control, prolonged to 575 ms just prior to termination. The increase in

Table 1 Effects of Pharmacological Interventions in Ventricular Tachycardia Drug

n

CL Control

Propafenone Flecainide Barucainide Bupivacaine Tetrodotoxin Potassium Heptanol RP62719 K-opener

5 5 5 8 6 10 10 8 4

142 ±12 1481115 153±11 152 ±16 167117 142 + 13 144 ±13 165117 128 ±7

CL Drug 1134198 873 1 75 433 + 46 684 + 78 7931122 774 + 378 4881118 182 ±24 11915

Termination 5/5 5/5 5/5 8/8 6/6 10/10 10/10 4/8 0/4

Ventricular tachycardia cycle length is compared during control (CL control) and after administration of the maximal dose of the drug or prior to termination of tachycardia (CL drug). All numbers are represented in milliseconds as mean ± SD. Termination means the number of tachycardias that did terminate during administration of the drug.

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Figure 3. Eighteen electrograms around the ring during control (tachycardia cycle length 199 ms) and administration of 7 mg/L of flecainide. Prior to termination, tachycardia cycle length prolonged to 575 ms. Termination of tachycardia occurred because of complete conduction block of the circulating impulse between electrograms 13 and 14.

CL was the result of a dose-dependent depression in conduction velocity around the ring. However, this depressing effect on conduction velocity was not homogenous in all segments of the ring. A predominant effect was observed in those segments in which conduction velocity was faster during control, that is, where conduction was parallel to the epicardial fiber direction. This is illustrated in Figure 4. During control (potassium 4 mmol/L), the tachycardia CL was 134 ms. Longitudinal

conduction velocity was 66 cm/s. During administration of 6, 10, and 12 mmol/L of potassium, the CL prolonged to 142, 215, and 467 ms, respectively. Longitudinal conduction velocity was depressed by approximately 5 times more than transverse conduction velocity. Thus, the first conclusion of these results is that drugs with Class I properties prolong the VT CL in a dose-dependent manner. At a given dose, reentry can no longer proceed and tachycardia terminates. This effect was

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Figure 4. Activation map during control tachycardia (potassium 4 mmol/L) and administration of 6, 10, and 12 mmol/L potassium. Cycle length increased from 134 to 467 ms. Abbreviations and symbols as in Figure 1.

common to all drugs with Class I proper- resulted in a marked prolongation in tachyties and was related to a predominant cardia CL and, at a given dose, reentry could action on longitudinal conduction velocity. no longer proceed and tachycardia terminated. However, as for drugs with Class I Cellular Uncouplers: Heptanol effects, this prolongation in tachycardia CL was the result of a predominant depression The administration of heptanol pro- on transverse conduction velocity. This is duced a dose-dependent prolonging effect illustrated in Figure 5. During control, the on tachycardia CL. As for drugs with Class tachycardia CL was 147 ms. Longitudinal I properties, increasing doses of heptanol conduction velocity was 69 cm/s and

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Figure 5. Activation map during control and administration of 1, 2, and 3 mmol/L of heptanol. Cycle length prolonged from 147 to 345 ms. Crowding of isochrones indicates a preferential effect on transverse conduction. Abbreviations and symbols as in Figure 1.

transverse conduction velocity was 21 ms. During administration of 1,2, and 3 mmol/L of heptanol, the CL prolonged to 185, 292, and 345 ms, respectively. Longitudinal conduction velocity was similar, whereas transverse conduction velocity had been drastically reduced to less than 10 cm/s. It can thus be concluded that the administration of heptanol produces a dose-dependent prolongation in tachycardia CL. This effect

is related to a predominant depression in transverse conduction velocity. Drugs that Prolong the Refractory Period of the Cells Involved in the Circuit: Class III Drugs These drugs had a completely different effect on reentry than sodium channel

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blockers or electrical uncouplers. They did not modify conduction velocity; however, by increasing the refractory period, they shortened the excitable gap. If the excitable gap became short enough to allow collision of the head of the propagating impulse with its own tail of refractoriness, termination of tachycardia occurred. Conversely, if the increase in refractoriness was not enough to close the excitable gap, tachycardia persisted. Drugs that Shorten the Refractory Period of the Cells Involved in the Circuit: Potassium Channel Openers The administration of drugs with potassium channel opener properties results in a shortening in the duration of the action potential and, thus, a decrease in the effective refractory period of the cells. In 2 of the 4 tachycardias tested (those with the shorter CL during control), administration of the drug resulted in a slight but significant shortening of the CL. This suggests that due to the short CL during control, the head of the circulating impulse propagated into partially refractory tissue. Thus, these tachycardias had no fully excitable gap. Shortening of the refractory period by the drug resulted in the creation of a fully excitable gap, allowing the circulating impulse to propagate through completely recovered tissue and thus speeding up conduction velocity. In the remaining 2 tachycardias, a fully excitable gap was already present during control and a decrease in the refractory period did not modify conduction velocity because the impulse was already propagating through totally recovered tissue. Mechanisms of Termination of Reentrant VT by Various Pharmacological Interventions In all cases, drugs with Class I properties and cellular uncouplers terminated

VT when a given dose was reached. This suggests that when the depressing effect in conduction velocity produced by these drugs reaches a certain level, the impulse can no longer propagate, and block in conduction occurs resulting in tachycardia termination. This mechanism of termination was true in the majority of cases.5 In Figure 6, an example is shown during administration of potassium and heptanol in the same heart. After administration of 4 mmol/L of heptanol, the CL prolonged to 390 ms and depression in conduction velocity was so important in the corridor between the left anterior descending coronary artery and the obstacle that the impulse could no longer proceed and tachycardia terminated. Block in conduction was observed in an area of the circuit where during control conduction velocity was slower (transverse conduction). However, in the same heart, after administration of 23 mmol/L of potassium the CL prolonged to 386 ms and depression in conduction velocity was then so important in the free wall of the LV that tachycardia terminated. Termination now occurred in an area of fast conduction (longitudinal conduction). Modification in conduction properties by these drugs was not homogeneous. In some cases we observed that the depression in conduction velocity resulted in the creation of arcs of functional conduction block not extending along the whole width of the ring. The occurrence of these arcs of functional block had some important consequences in determining the mechanism of termination of tachycardia. If conduction around one of these arcs of functional conduction block was slow enough to allow recovery of the cells situated proximal to the line of block, reentry of this area could occur and initiate an antidromic wavefront. Collision of this antidromic wavefront with the ongoing orthodromic wave might then result in termination of tachycardia. This is shown in Figures 7 and 8. During control, tachycardia had

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Figure 6. Activation maps during termination of tachycardia during administration of 4 mmol/L of heptanol and during administration of 12 mmol/L of potassium in the same heart. Control tachycardia had a cycle length of 147 ms. During administration of 4 mmol/L of heptanol, the cycle length was prolonged to 390 ms just prior to termination. Termination of reentry occurred because of complete conduction block of the impulse at the area of slow transverse conduction. During administration of 12 mmol/L of potassium the cycle length was prolonged to 386 ms just prior to termination. Termination now occurred because of complete conduction block of the impulse at the area of fast longitudinal conduction. Abbreviations and symbols as in Figure 2.

a CL of 130 ms; after administration of 30 umol/L of tetrodotoxin, CL was prolonged to 672 ms. A long arc of functional block occurred in the base and free wall of the LV. The impulse propagated around the bottom end of this arc of block and initiated propagation in the opposite direction in the circuit. However, the time difference between the orthodromic and antidromic wavefronts was not long enough to allow recovery of cells situated proximal to the block line and bidirectional

block occurred in this area. During the next cycle, the impulse again initiates an antidromic wavefront that propagates slower than in the previous cycle, and thus the time difference at the line of block is long enough to allow recovery of the cells proximal to the block. Reentry of this area occurs and the antidromic wavefront propagates around the circuit. Because the ongoing orthodromic wavefront still propagates, collision of both the antidromic and the orthodromic wavefronts results in

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Figure 7. Activation maps during control and administration of 30 mmol/L of tetrodotoxin. During control, tachycardia had a cycle length of 130 ms. During administration of 30 mmol/L of tetrodotoxin, the cycle length was prolonged to 672 ms 2 cycles prior to termination. Multiple arcs of functional conduction block are now apparent, especially a long line of block at the atrial free wall. The clockwise wavefront proceeds around this line of block and reactivates the area distal to the block in a counterclockwise direction. During the next cycle, this line of block extends toward the apex and conduction around the line results in a delay sufficient to allow recovery of cells proximal to the block. The clockwise wavefront continues to propagate and collides with the counterclockwise wavefront that results from microreentry within the macroreentrant circuit.

termination of the tachycardia. We call this phenomenon echo-wave termination.5 Echo-wave termination occurred during administration of all drugs with Class I effects, heptanol, and Class III drugs.

Implications of These Results Pharmacological interventions modify conduction properties in a reentrant pathway depending on their electrophysiological

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Figure 8. Same example as in Figure 7, now showing the 21 electrograms around the ring shown in control panel of Figure 7 by encircled numbers.

effects. Drugs that decrease the number of sodium channels available during phase 0 of the action potential and thus depress the Vmax, produce a marked slowing in conduction velocity. This results in an increase in the tachycardia CL and termination of reentry. The same effect was observed with drugs that predominantly modify the passive membrane properties, like heptanol, by increasing intercellular resistance. As has been demonstrated, however, sodium channel blockers and heptanol modify a different segment in the reentrant circuit depending on the anisotropic properties of the tissue.12 Thus, depending on the drug used, we can target our effect to a specific segment of the circuit. Heptanol cannot be used as an antiarrhythmic because of its toxic effects when administered in vivo. It is not unlikely that the development of new drugs with a similar electrophysiological effect but without toxic side effects may introduce a new generation of antiarrhythmic drugs that could be used to specifically modify the zone of slow conduction in the reentrant circuit. In our model, Class III drugs terminated only those tachycardias with a rather short excitable gap. This suggests that Class III drugs might only be effective in

terminating fast VTs based on functional rather than anatomical reentry. These results do not preclude a preventing effect on tachycardia inducibility. We have previously demonstrated that the initiation of tachycardia in this model occurred when very short coupled premature beats were applied to areas of the circuit with a short refractory period. It can be speculated that prolongation in refractoriness of the myocardium avoids the occurrence of these very short coupled premature beats, which might be the ones initiating reentry. Administration of potassium channel openers has some interesting physiological implications. It is difficult during fast tachycardias to measure the excitable gap. It is even more difficult to measure the fully and the nonfully excitable gap. In the 4 experiments we performed, shortening of the refractory period resulted in acceleration of the faster tachycardias, suggesting that a fully excitable gap was not present. On the contrary, in the 2 slower tachycardias, in which an excitable gap could be demonstrated by the resetting response, the lack of acceleration during administration of the drug suggested that the gap was fully excitable. In the future, it will be interesting to study the effects of these drugs in the so-called functional

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reentrant tachycardias in order to characterize the electrophysiological properties of these circuits. In this model, using high-resolution epicardial mapping, it could be demonstrated that areas of very slow conduction could be the result of what has been called zigzag conduction. Clinical mapping of tachycardias with a transvenous approach is far less accurate. Areas in which large conduction delays are demonstrated are usually taken as areas of conduction block. It is possible that some of them are in fact areas of zigzag conduction, absolutely necessary to the circuit, and probably the ones to be targeted during nonpharmacological treatments, especially catheter ablation. In summary, high-resolution epicardial mapping is a useful tool in the study of conduction properties of the electrical impulse. The use of more complex and sophisticated mapping systems both experimentally and clinically will probably allow recognition of new and unsuspected features during reentry. References 1. Brugada J, Boersma L, Kirchhof C, et al. Reentrant excitation around a fixed obstacle in uniform anisotropic ventricular myocardium. Circulation 1991;84:1296— 1306. 2. Brugada J, Mont LL, Boersma L, et al. Differential effects of heptanol, potassium and tetrodotoxin on reentrant ventricular tachycardia around a fixed obstacle in anisotropic myocardium. Circulation 1991; 84:1307-1318. 3. Brugada J, Boersma L, Kirchhof C, et al. Double-wave reentry as a mechanism of

ventricular tachycardia acceleration. Circulation 1991;84:1633-1643. 4. Brugada J, Brugada P, Boersma L, et al. On the mechanisms of ventricular tachycardia acceleration during programmed electrical stimulation. Circulation 1991;82: 1621-1629. 5. Brugada J, Boersma L, Abdollah H, et al. Echo-wave termination of ventricular tachycardia. A common mechanism of termination of reentrant arrhythmias by various pharmacological interventions. Circulation 1992;85:1879-1887. 6. Brugada J, Boersma L, Kirchhof C, et al. Proarrhythmic effects of flecainide. Experimental evidence for increased susceptibility to reentrant arrhythmias. Circulation 1991;84:1808-1818. 7. Brugada J, Brugada P, Boersma L, et al. Value of an anisotropic model of ventricular tachycardia in the screening of antiarrhythmic drugs. Pacing Clin Electrophysiol 1989;12:102. 8. Brugada J, Boersma L, Kirchhof C, et al. Induction of reentry is related to the refractory period at the site of stimulation. Pacing Clin Electrophysiol 1990; 13: 512. 9. Brugada J, Boersma L, Escande D, et al. Mechanism of action of Class III antiarrhythmic drugs. J Am Coll Cardiol 1991; 17: 42A. 10. Boersma L, Brugada J, Kirchhof C, et al. Drug-induced acceleration of reentrant ventricular tachycardia by double-wave reentry. Importance of the wavelength. Eur Heart J 1991;12:146. 11. Allessie M, Hoeks APG, Schmitz GML, et al. On-line mapping system for the visualization of the electrical activation of the heart. Int J Card Imaging 1987;2:59. 12. Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. Circ Res 1988:62:811.

Chapter 15

Microscopic Discontinuities as a Basis for Reentrant Arrhythmias Madison S. Spach, MD

level allows excitation wavefronts to be represented by isochrones and to be ana5 During the past 2 decades the con- lyzed for wavefront curvatures and for 6 7 cept of discontinuous conduction has spiral waves. - Second, normal uniform gained acceptance as a paradigm for anisotropic cardiac bundles have extenstructural biophysical mechanisms of sive electrical coupling between cells and normal and abnormal propagation events groups of cells, which provides a protecthat lead to cardiac reentrant arrhyth- tive effect against the initiation of reen4 mias.1'2 It has also become clear that dis- trant arrhythmias. On the other hand, continuous anisotropic propagation has side-to-side electrical connections between a dual nature dependent upon the size cells are lost when there is deposition of scale at which the propagating events are collagenous septa in interstitial space, evaluated.3 Examples of this dual char- which occurs following myocardial infarc8 9 acter of discontinuous anisotropic con- tion and with aging. At that point the duction include the following: First, at a electrical loading effects become distribmicroscopic level the events of conduc- uted over many cells and the structure 10 tion appear stochastic (nonuniform and becomes proarrhythmic. Based on the foregoing, it now appears irregular) due to electrical loading effects produced by the complex microscopic that an integral part of a complete theory structure of cardiac muscle.4 However, of normal and abnormal cardiac conducthese effects at a microscopic level become tion will have to include electrical loading averaged at the larger macroscopic size mechanisms produced by the complex scale where conduction appears to be uni- architecture of cardiac muscle. These bioform and regular as occurs in a continu- physical mechanisms involve several comous medium. This feature at a macroscopic ponents of cardiac microstructure that Introduction

This work was supported by U.S. Public Health Service Grant HL 50537 and The North Carolina Supercomputing Center. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003.

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produce variable loading of the sarcolemmal membrane within individual cells and groups of cells.4,11 Consequently, an important goal for the future is to develop yet to be achieved high-resolution mapping of propagation events in naturally occurring cardiac bundles to demonstrate the manner by which the stochastic phenomena of discontinuous propagation at a microscopic level are translated into the smooth appearing macroscopic excitation waves like those that occur in a continuous medium. The purpose of this chapter, therefore, is to identify several features of the dual nature of discontinuous anisotropic conduction and to describe how propagating action potentials are affected by naturally occurring electrical remodeling of cardiac muscle secondary to changes in

the distribution of the gap junctions and by variations in the composition of interstitial space. Interpretation of Excitation Spread from Isochrones and Extracellular Waveforms in Uniform Anisotropic Normal Bundles The multidimensional spread of excitation at a macroscopic level in normal anisotropic ventricular muscle is depicted by isochrones in Figure 1A for propagation initiated at a single site.12 The pattern and shapes of the isochrones indicate fast propagation along the longitudinal axis of the fibers (LP) and slower propagation along an axis transverse to the orientation

Figure 1. A. Multidimensional excitation spread at a macroscopic level as represented by an isochrone map when propagation was initiated at a point stimulus (*) in a uniform anisotropic left ventricular preparation from an adult dog. The isochrones were drawn at 1-ms intervals. The first isochrone begins 2 ms from the onset of the stimulus. At the bottom of the isochrone map, the solid circles indicate the location of a microarray containing 11 unipolar extracellular electrodes with 100-(im center-to-center spacing. B. Original unipolar extracellular waveforms (Oe) and the first and second derivative extracellular waveforms (dOe/dt and d2Oe/dt2, respectively) recorded with the microarray. Reproduced from Spach MS, Heidlage JF, Darken ER, et al. Cellular Vmax reflects both membrane properties and the load presented by adjoining cells. Am J Physiol 1992;263:H1855-H1863, with permission of the American Physiological Society.

MICROSCOPIC DISCONTINUITIES AS A BASIS FOR REENTRANT ARRHYTHMIAS of the fibers (TP). The effective velocity along the longitudinal axis of the fibers was 0.51 m/s and in the transverse direction it was 0.17 m/s. These directionally different velocities produced an LP-to-TP velocity ratio of 3. The isochrones produced a picture at the macroscopic level that is consistent with the spread of excitation in a continuous anisotropic medium. A microarray of unipolar electrodes was located as shown at the bottom of Figure 1A to record the extracellular waveforms (<E>e) during LP and during the change from LP to TP at varying angles to the long axis of the fibers. The original Oe waveforms during LP (waveform #1) and TP (waveform #11) appear smooth in contour (Figure IB), which also is expected in a continuous anisotropic medium.13 Although the original Oe waveforms appeared smooth in contour, the first and second derivatives of the original Oe waveforms revealed small notches (dOe/dt and d2Oe/dt2, respectively, in Figure IB).12 Also, the notches increased in number as the amplitude of Oe decreased when propagation changed from along the longitudinal axis of the fibers to a direction across the fibers. Notches in the derivative waveforms indicate asynchronous excitation of small groups of cells at a microscopic level.3,9 Thus, the irregular shapes of the first and second derivatives of the original extracellular waveforms indicate that propagation was discontinuous in nature at a small size scale in this normal uniform anisotropic ventricular preparation. Electrical Loading in Normal Mature Myocardium at a Microscopic Level When one attempts to study the mechanisms of discontinuous conduction at a microscopic level in naturally occurring normal or diseased cardiac muscle, significant difficulties become evident.

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A major problem is that electrical loading, which greatly affects the safety factor of conduction,1,14 is strongly dependent on the nonuniform and irregular distribution of the electrical connections between cells. Consequently, electrical loading in a multicellular network is like the effective coupling coefficient between cells15 in that it cannot be measured directly. Further, this problem cannot be resolved by measurements in isolated cell pairs because their isolation removes the nonuniform loading produced by the stochastic distribution of their interconnections to other contiguous cells present in the intact cellular network. These difficulties likely account for the paucity of experimental information about the most fundamental features of cardiac excitation waves—the events associated with excitation spread within individual cells and the transfer of the excitatory impulse to neighboring cells in normal and abnormal cardiac muscle. The high-resolution optical mapping techniques used by Fast and Kleber16,17 and by Rohr18 provide an important recent experimental advance for the measurement of excitation spread at a microscopic level in synthetic neonatal cellular monolayers. However, at present it is not clear how to achieve the increased spatial resolution needed to evaluate electrical loading within individual myocytes, as well as the transfer of the excitation impulse from cell to cell, in naturally occurring cardiac muscle. Possibly combined optical and microelectrode measurements, along with high-resolution extracellular potential measurements like those in Figure 1, or the greater spatial resolution of Oe measurements achieved by Hofer et al.19 with thin-film sensors, will be a next experimental step. Increases in electrical load produce a decrease inV max , and decreases in electrical load are associated with increases in Vmax.4,20 Therefore, one experimental approach to evaluate spatial differences

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in electrical loading, as well as differences in load at a given site for different directions of conduction, is to measure Vmax at multiple sites and at each site change the direction of conduction from along the longitudinal axis of the fibers to a direction across the fibers. This method changes the complex geometric relationships between the impalement site, the

boundaries of the impaled and juxtaposed cells, and the associated contiguous gap junctions.12 Figure 2A shows the arrangement of 2 pairs of electrodes used to produce bidirectional longitudinal propagation (LP1 and LP2) and bidirectional transverse propagation (TP1 and TP2) at each of 17 centrally located microelectrode impalement sites in an uniform

Figure 2. A. Arrangement of 4 pairs of unipolar stimulus electrodes to produce 4-way plane wave conduction along the longitudinal and transverse axis of the fibers. The solid circles represent 17 microelectrode impalement sites at which 4-way conduction was produced. B. Histograms illustrate values of the maximum rate of rise of the transmembrane potential (Vmax) for one direction of longitudinal propagation (LP) and one direction of transverse propagation (TP) at each impalement site. C. Bar graph shows values of Vmax during one direction of LP and TP at each of the 17 microelectrode impalement sites. Reproduced from reference 12, with permission of the American Physiological Society.

MICROSCOPIC DISCONTINUITIES AS A BASIS FOR REENTRANT ARRHYTHMIAS anisotropic adult canine ventricular preparation. Figure 2B shows the histograms of the Vmax values obtained at each site for one direction of LP and for one direction of TP. The mean value of TP Vmax was greater than the mean value of LP Vmax (P < 0.001), as expected1; however, there was considerable variation in the values of Vmax in both directions. The histograms for each group (Figure 2B) show that a few of the lowest values of TP Vmax were in the same range of some of the LP Vmax values. The paired values of LP and TP Vmax for each of the 17 impalement sites are shown in the bar graph of Figure 2C. Note that at 2 sites LP Vmax exceeded TP Vmax (arrows), and some of the lowest values of LP Vmax occurred at the same sites that had the highest TP Vmax values. The major point illustrated by Figure 2 is that in mature uniform anisotropic bundles the distribution of electrical load on the sarcolemmal membrane is quite nonhomogeneous. Also, changes in electrical load are quite sensitive to the direction of propagation relative to the impalement site, as reflected in the differences of Vmax at the same site for different directions of conduction and at different sites for the same direction of conduction. It is interesting that these variations in electrical load produce undulating values of Vmax in any given direction of propagation, and it is the average Vmax value that is larger during TP than LP.12 Electrical Description of Myocardial Architecture and Its Application to Conduction Only recently have analyses of cardiac conduction begun to include the details of the arrangement of cardiac myocytes, their irregular shapes, and the associated nonuniform distribution of

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their gap junctions. Also, to this point, experimental mapping has not provided sufficient detailed data to produce a clear picture of the cellular events that occur with anisotropic conduction in naturally occurring preparations. Thus, electrical representation (models) of the microarchitecture of normal and abnormal cardiac muscle should become an integral part of the task to gain insight to propagation events at a cellular level. As an example, the effects of normal cellular structure on conduction have been shown in a recent 2-dimensional cellular model based on the nonuniform shapes of disaggregated adult ventricular canine myocytes. Details of the model are presented in prior papers.4'21 Variations in cell shape and in the topology of the gap junctions of any one model, however, represent only one of an infinite number of possible configurations. Thus, rather than emphasize a specific cardiac structure, the following results illustrate how the variable sizes and shapes of cardiac myocytes, along with the nonuniform arrangement of the gap junctions, have a major effect on propagation events at a microscopic level. Figure 3 shows diagrams of the formation of a 33-cell basic unit of the 2-dimensional cellular model.4 Intracellular space is represented by the cytoplasm of each myocyte surrounded by discrete cellular boundaries, and the myocytes are coupled together by gap junctions located in the intercalated disks and in areas juxtaposed to the disks as described by Hoyt et al.,22 i.e., plicate and interplicate gap junctions, respectively. This model, like several well-known 1-dimensional23,24 and 2-dimensional16,25 models, is a "monodomain" model in which the active membrane (sarcolemma) separates intracellular space from a large volume conductor of low resistance. Thus, the cellular model of Figure 3 does not include an electrical representation of the

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Figure 3. Diagrams showing the formation of a 33-myocyte basic unit to produce a 2-dimensional cellular model. A. Outlines of 5 myocytes and the manner they were fitted together to form a multicellular network. The stippled areas next to the intercalated disks represent interplicate gap junctions.22 The grids show 10-^im x 10-fim segments that represent the sarcolemmal membrane patches and the interior of each cell. B. Arrangement of 3 types of gap junctions (symbols) that electrically interconnect the 5 myocytes (a through e). C. Arrangement of 33 myocytes and the distribution of their intercellular connections (symbols). The 33-cell unit could be replicated longitudinally and vertically by fitting the ends and sides together to form cellular arrays of different sizes and shapes. The group of 5 myocytes (a through e) is highlighted within the 33-cell unit by marking each segment within these myocytes. Reproduced from Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at a microscopic level. An electrical description of myocardial architecture and its application to conduction. Circ Res 1995;76:366-380, with permission.

interstitium that separates myocytes cellular boundaries was best depicted by beneath the surface of a cardiac bundle.11 perspective plots, which provided a view of the multidimensional spatial distribution of the activation times. A represenThe Nature of Excitation Spread tative result is presented in Figure 4 for Between Myocytes in the the 5 myocytes highlighted within the Multicellular Network 33-cell unit shown in Figure 3C. To examine cell-to-cell excitation spread during LP and TP, the times of Vmax were identified in each of the segments of 16 interconnected myocytes at the center of an array of 700 cells.4 The sensitivity of excitation spread to the

Longitudinal Propagation During LP, step increases in activation time (discontinuities) occurred at the end-to-end connections between myocytes

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Figure 4. Perspective plots of activation spread through a network of 5 myocytes within the 2-dimensional cellular model. The activation sequence was determined from the time of Vmax at each of the segments (8 rows of longitudinal marks) with the 5 myocytes that formed a group 80 urn wide and 300 |im long as shown at the top of the figure. A. Longitudinal propagation in a left-to-right direction. B. Transverse propagation in a bottom-to-top direction. In each perspective plot, the activation times along each of the 8 rows of segments are plotted as a function of distance along the long axis of the cells. The hatched steps denoted delays across the plicate gap junctions at the intercalated disks. In both panels the letters a through e are included to identify each myocyte with the activation times along the corresponding rows. Reproduced from Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at a microscopic level. An electrical description of myocardial architecture and its application to conduction. Circ Res 1995;76:366-380, with permission.

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(Figure 4A). The major increases in activation time, however, occurred along the sarcolemmal membrane of each cell. The overall process resulted in a predominantly smooth pattern of activation spread. A major feature of LP was that the locations of the discontinuities of propagation along the longitudinal axis corresponded to the irregular distribution of the plicate gap junctions at the intercalated disks. These irregular delays at the end-to-end connections of the cells produced asynchrony of excitation in different portions of myocytes located side by side. Consequently, superimposed on the overall smooth process of LP, the nonuniformly distributed discontinuities of activation spread reflected the irregular shapes of the cells (Figure 4A).

Excitation Spread Within Individual Myocytes Longitudinal Propagation

Representative intracellular excitation sequences during LP are shown in Figure 5A for the 5 interconnected myocytes shown in Figure 4. The isochrones maintained a vertical orientation throughout each myocyte, except there was slight bending near the intercalated disks at the ends of the irregularly shaped cells. Within each cell, however, the isochrones shifted further apart as excitation moved from the subcellular area where the action potential entered the myocyte to the area where the action potential exited the myocyte. As a result, the major subcellular feature of LP was that conduction was slower in the proximal part and Transverse Propagation faster in the distal part of each cell.4 These events produced an alternating During TP, there were large lateral sequence of slower and faster conduction '^jumps'' of activation time between myocytes, along the pathway of longitudinal conwhile within each myocyte the entire sar- duction. Reversing the direction of longicolemma activated very rapidly (Figure 4B). tudinal conduction showed that the Further, there were a few prominent step subcellular differences in the speed of increases in activation time in the region conduction were not created by variations of the end-to-end plicate gap junctions in the cross-sectional area within each (Figure 4B, steps connecting cells c and e). myocyte. As shown in Figure 5A, when Therefore, the cell-to-cell pattern of trans- the direction of longitudinal conduction verse activation spread was quite differ- was reversed, the proximal part of each ent from that which occurred during LP. myocyte with respect to the direction of LP TP occurred as large jumps in activation remained the region of slowest conduction time between the lateral borders of jux- and the distal part of each cell remained taposed cells, while within each myocyte the region of fastest conduction. there was almost simultaneous activation of the entire sarcolemmal membrane. A general conclusion to be drawn Transverse Propagation from the results of Figure 4 is that for The major subcellular feature of actiany given direction of conduction, plane waves of excitation do not occur at a vation spread during TP was the rapidity microscopic level because of the disrup- with which excitation of each myocyte tion of the excitation wave by the irregu- occurred (Figure 5B). Unlike LP, during larly distributed cell boundaries and the TP the pattern of excitation spread was associated irregular locations of the gap different in each myocyte. Within the same cell, the isochrones were oriented junctions.4

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Figure 5. Intracellular activation sequences during 4-way propagation along the longitudinal and transverse axes of the myocytes. A. Isochrones within each of the myocytes (a through e) during propagation in both directions (arrows) along the longitudinal axis of the myocytes. The isochrones are separated by 4 (is. B. Intracellular isochrones during propagation in both directions (arrows) along the transverse axis of the cells. The isochrones are separated by 3 jus. Cells a through e are the same 5 myocytes shown in Figure 4. Reproduced from Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at a microscopic level. An electrical description of myocardial architecture and its application to conduction. Circ Res 1995;76:366-380, with permission.

in different directions, and there were collisions (asterisks) inside a few cells when TP occurred in a top-to-bottom direction (cells a and c in Figure 5B, top). The pattern of excitation spread within

each cell changed markedly when the direction of conduction was reversed along the transverse axis of the myocytes (Figure 5B), and the collisions shifted to other cells; e.g., a collision occurred only

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in cell b when TP occurred in a bottom-to- (Figure 6, LP). When comparing the 2top direction. dimensional cellular model results to the experimentally observed variation in Vmax at differnt locations along the axis of conVmax Variations Within Adult duction (Figure 2C), it is reasonable to Ventricular Myocytes presume that in the experimental measurements the tip of the microelectrode Longitudinal Propagation varied randomly in its intracellular location relative to the ends of the impaled cell. During LP, Vmax was lowest in the prox- The cellular model results show that at difimal area of each cell (Figure 6, LP), where ferent locations within each cell the values intracellular conduction was slowest. Vmax of Vmax would be different due to the flucincreased to a maximum value between the tuation of Vmax within the individual cells. middle and distal fourth of each myocyte. Consequently, the cellular model results In the distal part of each myocyte, Vmax indicate that variations in electrical load decreased although subcellular conduction within individual cells can account for the was fastest in this area. During longitu- experimental variety of Vmax values observed dinal conduction, the Vmax minimum in at different impalements sites during LP. the output area of each cell had a higher That is, the variable values of Vmax within value than did the minimum at input area each myocyte resulted in an undulating

Figure 6. Subcellular distribution of Vmax within 3 myocytes during longitudinal and transverse propagation. In each panel the values of Vmax are plotted as a function of distance (|o.m) along a line of consecutive segments extending between the ends of the each cell. The outline of each myocyte with the accompanying intracellular activation sequences for transverse conduction (isochrones separated by 3 |is) is presented above each panel. A similar outline of the myocyte with the accompanying intracellular activation sequence for longitudinal conduction (isochrones separated by 4 |is) is presented below each panel. Myocytes a, c, and e are those of the previous 2 figures. Reproduced from Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at a microscopic level. An electrical description of myocardial architecture and its application to conduction. Circ Res 1995;76:366-380, with permission.

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region of the highest value of Vmax. Consequently, in normal adult myocardium the greatest electrical load within each cell is concentrated at the intercalated disks near the ends of the cells where curTransverse Propagation rents are received and transferred to The same general subcellular pat- adjoining cells via the associated gap tern of Vmax variability occurred during junctions. TP as during LP; i.e., in each cell the maximum Vmax value occurred near the center Microfibrosis with Loss of of the myocyte and lower Vmax values Side-to-Side Cellular occurred at the ends of each cell. The Interconnections Alters the mean Vmax value within almost every cell was greater during TP than during LP. Curvature of Wavefronts However, the TP Vmax minima near the ends of each cell were often lower in value In the foregoing sections, adult carthan the LP Vmax maximum located near diac myocytes have been considered to form the center of each cell (cells c and e of networks in which each myocyte is conFigure 6). This feature resulted in con- nected to multiple surrounding cells.22'26'27 siderable overlap of TP and LP Vmax val- This normal arrangement produces tight ues when comparing Vmax values from electrical coupling in all directions relative different subcellular areas of the same or to the orientation of the fibers. However, different cells. The different TP Vmax values aging is associated with the deposition within each myocyte thereby were consis- of fine, longitudinally oriented collagetent with the experimental results, which nous septa (microfibrosis) that surround demonstrated considerable variation in the small groups of cells in atrial bundles TP Vmax values, and some of the TP Vmax (Figure 7), and coarse collagenous septa values overlapped those that occurred develop in healed myocardial infarcts.8 during longitudinal conduction. When the Because sarcolemmal membrane appopaired values of Vmax were compared for sition does not occur between cells sepeach membrane segment (Figure 6), TP arated by collagen, the deposition of Vmax was greater than LP Vmax through- collagenous septa in interstitial space out most myocytes. However, near the marks areas where there has been loss of ends of a few cells there was a reversal of side-to-side electrical connections over the usual TP > LP Vmax relationship, e.g., variable distances. The "normal" deposicell e in Figure 6. These areas near the ends tion of collagenous septa occurs in atrial of myocytes likely provide a subcellular bundles at 2 widely separated time peribasis for the experimental result that at ods—during the first months of life 28 and a few microelectrode impalement sites, during the aging process.9 This structural TP Vmax was found to be less than LP Vmax. arrangement produces nonuniform A major conclusion to be drawn from anisotropic electrical properties of carFigure 6 is that for all directions of prop- diac bundles. agation the greatest load within each cell The deposition of collagen also reoccurs in the sarcolemmal membrane sults in the loss of tight packing of the located adjacent to the intercalated disks myocytes; i.e., there is a relative widenat the ends of cells in the regions of the ing of interstitial space, which should Vmax minima, and the least load occurs reduce the interstitial resistance to curtoward the center of each cell in the rent flow.11 A reduction in interstitial sequence of lower and higher Vmax values along the longitudinal axis of the network of cells.

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Figure 7. Collagenous septa in an atrial bundle with nonuniform anisotropic electrical properties from a 64-year-old patient. The collagenous septa (gray to black) are thick and long and result in isolation of adjacent cells and groups of cells (white). Bar = 50 |im. Reproduced from Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic discontinuous propagation. Circ Res 1988;62:811-832, with permission.

resistance secondary to an increase in interstitial volume at sites of collagen deposition is consistent with the demonstration by Fallert et al.29 that the impedance of the dense scar of healed infarcts is 50% lower than the impedance of normal myocardium. Further, recent evidence indicates that there are unexpected (and unexplored) mechanisms of extracellular loading of the sarcolemmal membrane due to resistive discontinuities produced by the spatial variations in the volume of interstitial space associated with collagenous septa.11 When analyzing the curvature of wavefronts, puzzling questions arise as to whether the conduction events are due to 1 of the 2 following phenomena: (1) At the larger macroscopic size scale (>1 to 2 mm), variations in conduction velocity are considered to occur in relation to the degree of

curvature of wavefronts that form spiral waves in a continuous medium,5-7 i.e., a greater curvature is associated with a greater electrical load, which generates a decrease in conduction velocity. (2) Conduction events are related to variations in loading produced by differences in cellular connectivity that occur in anisotropic cardiac bundles.2,3 To illustrate that differences in the curvature of cardiac wavefronts are highly determined by the anisotropic distribution of the cellular interconnections, Figure 8 shows activation sequences in 2 types of anisotropic cardiac muscle. In the well-coupled uniform anisotropic preparation (Figure 8, left), the effective longitudinal conduction velocity was 0.51 m/s and the effective transverse velocity was 0.17 m/s, which resulted in an LP/TP velocity ratio of 3.0. In the nonuniform anisotropic preparation with

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Figure 8. Effect of uniform versus nonuniform anisotropy on the spread of activation. The sequence for a uniform anisotropic preparation of canine ventricular epimyocardium is shown on the left, along with unipolar extracellular waveforms (bottom) recorded at the sites noted on the isochrone map. The sequence for a nonuniform anisotropic canine atrial preparation (crista terminalis) is shown on the right. Each activation sequence was associated with normal action potentials. The isochrones represent 1-ms intervals. Reproduced from Spach MS. The stochastic nature of cardiac propagation due to the discrete cellular structure of the myocardium. Int J Bifurcation Chaos 1996;6:16371656, with permission.

decreased side-to-side coupling between fibers (Figure 8, right), the effective LP conduction velocity was 1.0 m/s and the effective TP conduction velocity was 0.1 m/s, which produced an LP/TP velocity ratio of 10. Myocardial bundles with uniform anisotropic properties usually have an LP/TP ratio between 2 and 4, and bundles with nonuniform anisotropic properties produce a much higher LP/TP velocity ratio ranging from 7 to 15.2 As can be seen in Figure 8, in the shift from LP to TP the curvature of the wavefronts was much greater in the preparation with -I side-toside coupling between the fibers than in the well-coupled anisotropic preparation.30 Figure 8 also shows that a major effect of the loss of side-to-side electrical

coupling between fibers is a prominent decrease in the effective conduction velocity in the transverse direction. The decrease in the effective transverse conduction velocity largely accounts for the high LP/TP velocity ratio exhibited by nonuniform anisotropic bundles with microfibrosis. Further, in nonuniform anisotropic atrial bundles from humans older than 60 years of age, the effective transverse conduction velocities are as low as 0.04 m/s in the presence of rapid upstroke action potentials.10 This type of very slow anisotropic conduction should be of increasing importance in the analysis of the low conduction velocities that enhance the initiation of atrial fibrillation in the geriatric age group, as well as in the initiation of

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have different effective refractory periods in the absence of repolarization inhomogeneities.10 A representative wellcoupled uniform anisotropic atrial bundle Proarrhythmic Effects of from a child is illustrated in Figure 9A. Microfibrosis with Loss of This shows the pattern of activation spread and associated extracellular waveSide-to-Side Gap Junctions forms of TP (waveform 1) and LP (waveA widely used electrophysiological forms 2 and 3) of a normal beat at an parameter is the effective refractory period, interstimulus interval of 800 ms (left which is measured as the shortest pre- side) and the earliest propagated premamature interval at which a propagated ture beat that occurred at an interval of action potential occurs. Moe et al.31 initially 345 ms (right side). As the premature demonstrated that an abrupt increase (dis- interval was reduced to the earliest stimcontinuity) in a conduction time curve, ulus that would produce a propagated which is produced by initiating progres- response, all of the extracellular wavesively earlier premature stimuli, indi- forms remained smooth in contour and cates that there are 2 or more functionally maintained the same general shape as different pathways in the total conduc- they decreased in amplitude. Earlier pretion circuit. Such discontinuities in a con- mature stimuli failed to produce conducduction time curve occur when the tion in any direction. Figure 9B shows the corollary results effective refractory period of one pathway is longer than that of another. In this sit- in a nonuniform anisotropic atrial bundle uation, when a premature beat occurs at from a 64-year-old patient. Normal beats an interval that is shorter than that of the produced TP extracellular waveforms that longer refractory period of one pathway, the had irregular deflections superimposed on propagation of premature impulses can the overall waveforms (waveforms 1 and 2); continue in another pathway that has a these multiphasic or fractionated waveforms shorter effective refractory period. This were associated with the underlying microphenomenon produces unidirectional fibrosis shown in this patient's atrial bundle block, which is a requirement for the in Figure 7. When the premature interval initiation of a reentrant arrhythmia. was decreased to 327 ms (Figure 9B, right), Mechanistically, the importance of uni- stable but very slow TP continued in assodirectional block is that it must occur in ciation with a considerable increase in the order for the remaining activation wave time intervals between the multiple small to circulate back and reexcite the initial deflections in the multiphasic TP wavestimulus area. Spatial differences in forms. In the longitudinal direction of the action potential duration (inhomogeneities fibers, however, decremental conduction to of repolarization) are usually consid- block occurred. The same events occurred ered the underlying cause of spatial dif- when the stimulus site was moved to differences in the effective refractory period ferent locations throughout the bundle, and unidirectional block. Figure 9, how- which again demonstrated that the direcever, demonstrates that changes in cel- tion of unidirectional block of the premature lular connectivity associated with the impulses was related to the orientation of microstructural remodeling of uniform the fibers. Although not shown, further anisotropic properties to nonuniform aniso- slight shortening of the premature interval tropic properties create the general property resulted in anisotropic reentry within the of functionally different pathways that muscle bundle.10 ventricular tachycardia in patients with healed infarcts.8

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Figure 9. Propagation responses to premature action potentials in atrial bundles with (A) uniform and (B) nonuniform anisotropic properties. Each panel shows the normal activation sequence and a few of the extracellular waveforms on the left, and those of an early premature beat are shown on the right. The interstimulus intervals (ms) are listed in the boxes above each set of extracellular waveforms. A. Isochrones are separated by 1 ms. The atrial bundle is from a 12-year-old patient. B. Activation sequences in the transverse direction were so complex that it was not possible to construct isochrone maps. In the drawing of the normal activation sequence (B, left), the elongated open arrow represents the narrow region of fast longitudinal conduction. On the right side, the elongated triangle represents decremental conduction to block along the longitudinal axis of the fibers. Reproduced from Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic discontinuous propagation. Circ Res 1988;62:811-832, with permission.

activation waves at a macroscopic level, the events of propagating excitation at the The results presented in this chapter microscopic level are constantly changing show that the microstructure of the and disorderly due to intracellular loading myocardium creates inhomogeneities of effects and conduction delays between electrical load that cause cardiac propaga- cells.4 An important feature of the stotion to be discontinuous and stochastic in chastic nature of discontinuous propaganature at a microscopic level. Thus, under- tion at a microscopic level is that small lying the movement of smooth appearing input changes produce major changes in Significance

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the events of propagation. For example, a simple change in the direction of conduction of the excitation wave produces considerable change in the excitatory events during the upstroke of the action potential and in the delays between cells. Although the events of discontinuous conduction are stochastic in nature at a microscopic level, these stochastic events become averaged and appear consistent with a continuous medium at the larger macroscopic size scale, as depicted experimentally.32 It may seem bewildering that excitation spread in normal anisotropic muscle can be viewed as continuous and discontinuous. Although these phenomena may appear contrasting at first sight, they present a biological analogy to the theory of Bohr and Heisenberg in quantum physics in the context that there are 2 truths rather than 1. At a large size scale in normal ventricular muscle, curved wavefronts appear continuous, but when analyzed at a microscopic size scale they are discontinuous and stochastic in nature.4 This is only one example of a general principle that when biological phenomena (e.g., bursting of pancreatic (3-cells,33 ion channel events, etc.) are examined at a small enough size scale, they are found to occur in steps with abrupt changes (discontinuous), and normally their stochastic properties become averaged to produce order at a larger spatial or time scale. This relationship is a feature of the central limit theorem,34 which provides a course from discontinuous events at a microscopic level to smoothed (averaged) events at a macroscopic level. A fundamental property of the stochastic nature of normal propagation is that it provides a major protective effect against arrhythmias by reestablishing the general direction of wavefront movement when small variations in excitation events occur. However, a loss of side-toside electrical connections between small groups of fibers results in a decrease in

the diversity of conduction events at a very small size scale. This produces relatively isolated groups of cells throughout cardiac bundles in which larger fluctuations of electrical load can develop and be distributed over more cells than occurs normally. Now, due to the relative isolation of small groups of cells, the discontinuous events at a microscopic size scale no longer can be averaged to produce the smooth curved wavefronts that occur at a macroscopic level in normal cardiac muscle. As illustrated in Figure 9B, at this point premature impulses can induce abnormal conduction events that produce breaks in the overall wavefront,35 resulting in the initiation of a reentrant circuit. This view implies an important synthesis for future combined structuralelectrical mapping studies to establish a new relationship between discontinuous propagation at a microscopic level and spiral waves at a macroscopic size scale.3 Such a synthesis will be necessary to understand how the occurrence of wavefront breaks35 and spiral waves5-7 (reentry) are enhanced by the loss of side-to-side cellular interconnections in association with collagen accumulation in interstitial space. Thus, a variety of improved mapping techniques will be needed to obtain needed information about microscopic conduction events in normal and diseased cardiac structures. Such highresolution mapping studies should be analogous to the fact that quantum physics takes advantage of the "microscopic" variations of particles to predict new phenomena not possible from the measurements of classic physics at a larger size scale. There are some events related to discontinuous anisotropic propagation at a microscopic level that are not accounted for by the theory of the curvature of wavefronts at a macroscopic level. One example is the relationship between conduction velocity and Vmax. According to the theory of spiral

MICROSCOPIC DISCONTINUITIES AS A BASIS FOR REENTRANT ARRHYTHMIAS waves in a continuous medium, when the local curvature of a wavefront becomes sufficiently great, there is a reduction in the local conduction velocity.36 These decreases in velocity related to wavefront curvature should be associated with a reduction in the rate of rise of the action potential37; i.e., changes in wavefront curvature produce a monotonic relationship between the local conduction velocity and Vmax. However, in anisotropic cardiac bundles, there is a general reciprocal relationship between the local conduction velocity and Vmax. Fast longitudinal conduction is associated with a relatively low Vmax compared to the increase in Vmax that occurs when the local conduction velocity decreases as the wavefront propagates at progressively greater angles with respect to the longitudinal axis of the fibers. Here, the highest values of Vmax are associated with the lowest conduction velocities of the macroscopic activation wavefront (see Figures 4 and 5 in reference 1). Of considerable long-term interest is the elucidation of the specific proarrhythmic mechanisms associated with the accumulation of collagen in interstitial space. The results presented here indicate there is a close relationship between the deposition of collagen and the loss of lateral interconnections between small groups of fibers. This relationship provides a major challenge to develop interventions that alter collagen deposition as an antiarrhythmic therapeutic measure. References 1. Spach MS, Miller WT III, Geselowitz DB, et al. The discontinuous nature of propagation in normal canine cardiac muscle: Evidence for recurrent discontinuities of intracellular resistance that affect the membrane currents. CircRes 1981;48:39-45. 2. Spach MS. Discontinuous cardiac conduction: Its origin in cellular connectivity with long-term adaptive changes that

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cause arrhythmias. In Spooner P, Joyner RW, Jalife J (eds): Discontinuous Conduction in the Heart. Armonk, NY: Futura Publishing Co.; 1997:5-51. 3. Spach MS, Heidlage JF, Dolber PC. The dual nature of anisotropic discontinuous conduction in the heart. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. 3rd ed. Philadelphia: W.B. Saunders; 2000:213-222. 4. Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at a microscopic level. An electrical description of myocardial architecture and its application to conduction. CircRes 1995;76:366380. 5. Cabo C, Pertsov AM, Baxter WT, et al. Wave-front curvature as a cause of slow conduction and block in isolated cardiac muscle. CircRes 1994;75:1014-1028. 6. Davidenko JM, Kent PF, Chialvo DR, et al. Sustained vortex-like waves in normal isolated ventricular muscle. Proc NatlAcad Sci USA 1990;87:8785-8789. 7. Pertsov AM, Jalife J. Three-dimensional vortex-like reentry. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia: W.B. Saunders; 1995:403-410. 8. Dillon SM, Allessie MA, Ursell PC, et al. Influences of anisotropic tissue structure on reentrant circuits in the EBZ of subacute canine infarcts. CircRes 1988;63:182-206. 9. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle: Evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res 1986;58:356-371. 10. Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic discontinuous propagation. CircRes 1988;62:811-832. 11. Spach MS, Heidlage JF, Dolber PC, et al. Extracellular discontinuities in cardiac muscle: Evidence for capillary effects on the action potential foot. Circ Res 1998;83: 1144-1164. 12. Spach MS,.Heidlage JF, Darken ER, et al. Cellular Vmax reflects both membrane properties and the load presented by adjoining cells. Am J Physiol 1992;263: H1855-H1863.

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13. Spach MS, Miller WT III, Miller-Jones E, et al. Extracellular potentials related to intracellular action potentials during impulse conduction in anisotropic canine cardiac muscle. Circ Res 1979;45:188— 204. 14. Rushton WA. Initiation of the propagated disturbance. Proc R Soc Lond (Biol) 1937; 124:124-210. 15. Socolar SJ. The coupling coefficient as an index of junctional conductance. J Membr Biol 1977;34:29-37. 16. Fast VG, Kleber AG. Microscopic conduction in cultured strands of neonatal rat heart cells measured with voltage-sensitive dyes. Circ Res 1993;73:591-595. 17. Fast VG, Kleber AG. Anisotropic conduction in monolayers of neonatal rat heart cells cultured on collagen substrate. Circ Res 1994;75:591-595. 18. Rohr S. Determination of impulse conduction characteristics at a microscopic scale in patterned growth heart cell cultures using multiple site optical recording of transmembrane voltage. J Cardiovasc Electrophysiol 1995;6:551-568. 19. Hofer E, Urban G, Spach MS, et al. Measuring activation patterns of the heart at a microscopic size scale with thin-film sensors. Am JPhysiol 1994;35:H2136-H2145. 20. Joyner RW, Westerfield M, Moore JW. Effect of cellular geometry on current flow during a propagated action potential. Biophys J I980;3l:183-194. 21. Spach MS, Heidlage JF. A multidimensional model of cellular effects on the spread of electrotonic currents and on propagating action potentials. Crit Rev Biomed Eng 1992;20:141-169. 22. Hoyt RH, Cohen MI, Saffitz JE. Distribution and three-dimensional structure of intercellular junctions in canine myocardium. Circ Res 1989;64:563-574. 23. Joyner RW. Effects of the discrete pattern of electrical coupling on propagation through an electrical syncytium. Circ Res 1982;50:192-200. 24. Rudy Y, Quan W. A model study of the effects of the discrete cellular structure on electrical propagation in cardiac tissue. Circ Res 1987;61:815-823.

25. Leon LJ, Roberge FA. Directional characteristics of action potential propagation in cardiac muscle. A model study. Circ Res 1991;69:378-395. 26. Gourdie RG, Green CR, Severs NJ. Gap junction distribution in adult mammalian myocardium revealed by anti-peptide antibody and laser scanning confocal microscopy. J Cell Sci 1991;99:41-55. 27. Dolber PC, Beyer EC, Junker JL, et al. Distribution of gap junctions in dog and rat ventricle studied with a double-label technique. JMol Cell Cardiol 1992;24:1443-1457. 28. Spach MS, Miller WT III, Dolber PC, et al. The functional role of structural complexities in the propagation of depolarization in the atrium of the dog. Cardiac conduction disturbances due to discontinuities of effective axial resistivity. Circ Res 1982;50:175-192. 29. Fallert MA, Mirotznik MS, Downing EB, et al. Myocardial electrical impedance mapping of ischemic sheep hearts and healing aneurysms. Circulation 1993;87:199-207. 30. Spach MS. The stochastic nature of cardiac propagation due to the discrete cellular structure of the myocardium. Int J Bifurcation Chaos 1996;6:1637-1656. 31. Moe GK, Preston JM, Burlington H. Physiologic evidence for a dual A-V transmission system. Circ Res 1956;4:357-375. 32. Clerc L. Directional differences of impulse spread in trabecular muscle from mammalian heart. J Physiol (Lond) 1976;255: 335-346. 33. Sherman A, Rinzel J. Model for synchronization of pancreatic (3-cells by gap junction coupling. Biophys J 1991;59:547-559. 34. Kleinbaum DG, Kupper LL, Muller KE. Applied Regression Analysis and Other Multiuariable Methods. Boston: PWSKent Publishing Co.; 1988:17. 35. Agladze K, Keener JP, Muller SC, et al. Rotating spiral waves created by geometry. Science 1994;264:1746-1748. 36. Tyson JJ, Keener JP. Singular perturbation theory of traveling waves in excitable media. Physica D 1988;32:327-361. 37. Zykov VS. Spiral waves in two-dimensional excitable media. Ann NY Acad Sci 1990;591:75-88.

Chapter 16

Mapping in Explanted Hearts Jacques M. T. de Bakker, PhD and MichielJ. Janse, MD

Introduction

Electrophysiological changes in cardiac muscle and mechanisms of arrhythmias caused by heart diseases cannot easily be studied in patients, and therefore experimental models are frequently used. Animal models are usually the first choice for investigations on electrophysiological mechanisms of arrhythmias. In the development of animal models, attempts must be made to fulfill the criteria that would make the model a realistic representation of the clinical events. A large number of laboratory models that use experimental animals have been developed in an attempt to achieve this goal. In these models, different approaches are applied. Different procedures of occlusion have been used to create infarction, resulting in different anatomical characteristics of the infarcts, which makes comparison between the models and the clinical setting difficult. x~5 In addition, various species are being used, which introduces differences in electrophysiological properties of the heart and differences in cardiac and coronary anatomy. In an effort to introduce some sort

of standardization, a set of guidelines for the study of arrhythmias caused by ischemia, infarction, and reperfusion, known as the Lambeth Convention, was published by Walker et al.6 in 1988. This convention addresses statistical problems, uniformity of animals, classification and detection of arrhythmias, and definition and detection of ischemia and infarction. To delineate the electrophysiological abnormalities in dilated cardiomyopathy, various experimental models have been developed as well.7"10 While arrhythmias frequently occur in patients with dilated cardiomyopathy, monomorphic, sustained ventricular tachycardias (VTs) are rare,11'12 hampering their mechanistic delineation. The animal models have also mainly been used to study cellular electrophysiological abnormalities. Although animal models have all fallen short in one respect or another, each has provided important information that has improved our understanding of the pathophysiology of arrhythmias in the diseased human heart. The use of Langendorff-perfused human hearts from patients who underwent

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003.

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heart transplantation because of extensive infarction or cardiomyopathy presents an alternative method to study electrophysiology and arrhythmias caused by these diseases. Although the pathology is a realistic representation of the clinical events, this model also lacks some clinical characteristics. Explantation results in denervation of the heart, which may affect arrhythmogenicity. It has been shown in animal models that transmural infarcts that extend to the epicardial surface may damage efferent sympathetic fibers in the subepicardium and produce heterogeneous sympathetic denervation of normal myocardium apical to the infarct.13'14 In addition, only studies in the healed phase of myocardial infarction are possible, because infarctions in these patients already exist long before transplantation. Although sustained VTs are usually not present spontaneously in the explanted infarcted hearts, they often can be induced by programmed stimulation. This is compatible with clinical observations that sustained VTs can be induced in approximately 50% of patients with healed myocardial infarction but without documented arrhythmias.15^17 This suggests that in at least half of the patients who survive myocardial infarction, the substrate for sustained VT is present but, in most cases, the trigger for starting the tachycardia never occurs because only a small percent of patients who survive myocardial infarction develop sustained VT late after the onset of infarction. In contrast to infarcted hearts, we were unable to induce sustained monomorphic VTs in explanted hearts from patients with dilated cardiomyopathy. Although innervation in explanted hearts is corrupted by the resection procedure, study of these hearts is particularly helpful to correlate electrophysiology with anatomy of the arrhythmogenic area.

LangendorfF Perfusion of the Isolated Human Heart Langendorff perfusion of explanted human hearts does not differ essentially from that procedure applied in animal hearts except for the cannulation procedure. In animal hearts, a cannula is inserted into the aorta and fixed with a suture around the aortic root. In the explanted human heart, the aorta is often too short for the cannula and the left main artery and right coronary artery must be cannulated separately. To avoid blood clotting in the arteries and to protect the heart directly after explantation, hearts were perfused with cardioplegia just before explantation. After removal, hearts were submerged in Tyrode's solution containing (in mmol/L): sodium (Na+) 156.5; potassium (K+) 4.7; calcium (Ca2+) 1.5; phosphate (HaPO^) 0.5; chlorine (Clr) 137; bicarbonate (HCOg) 28; and glucose 20. The left and right coronary arteries were cannulated via the ostia with the heart submerged in the cold Tyrode's solution. Thereafter, the heart was attached to the Langendorff perfusion system. Details of this system are given elsewhere.18 The perfusion fluid consisted of a mixture of 50% human blood and 50% of the Tyrode's solution (total volume 2 L). After the heart was connected, coronary flow was stabilized to approximately 200 mL/min. The ventricles were drained by rubber tubes in the apex, one into the left and the other into the right cavity. Hearts started to beat spontaneously or to fibrillate within minutes of perfusion. If fibrillation occurred, the heart was defibrillated after approximately 5 minutes. Perfusion was maintained at a temperature of 37±0.5°C until either the measurements were completed or contraction noticeably decreased (after 4 to 5 hours).

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Recording Electrical Activity

Histology of the Hearts

Electrograms recorded with bipolar hook electrodes attached to the base of the left and right ventricles served as a time reference and were used to distinguish the configuration of induced tachycardias. Epicardial as well as endocardial mapping of the electrical activity was performed during tachycardia. Tachycardia was induced by premature stimulation via a bipolar hook electrode attached to the left ventricular wall. Endocardial electrical activity of the left ventricle (and of the right ventricle in a number of cases) was recorded with a balloon electrode covered with 64 electrode terminals. The interelectrode distance was approximately 1.2 cm. The balloon was introduced into the left ventricular cavity through the mitral (or tricuspid) valve orifice. For recording of epicardial signals, flexible grid electrodes with 64 electrode terminals were used. High-resolution mapping of electrical activity using plaque electrodes (105 to 208 electrode terminals; interelectrode distance 0.8 and 0.5 mm, respectively) was carried out to determine the role of the architecture of interstitial fibrosis for activation delay.

Figure 1 shows typical examples of the histology of the explanted hearts. Panel A, a section of the posteroseptal wall of one of the hearts, illustrates that the endocardium (endo) is thickened by fibroelastosis (dark rim). This is a frequent finding in these hearts, where the endocardium can be as thick as 1 mm.19 A major part of the posterior wall is fibrotic (F), but a thin rim of surviving myocardial tissue is found subendocardially along the entire posterior wall (arrow) and contacts remaining healthy myocardium (M) of the septal wall. A surviving subendocardial rim is a common finding in infarcted myocardium and is supposed to be caused by the presence of a subendocardial plexus.20'21 White areas along the epicardium (epi) point to fatty tissue. Panel B, a section from the septal wall of another heart, shows that myocardial bundles (dark areas) may also survive deep in the infarcted zone. Note that these surviving myocardial bundles are often divided into smaller bundles by strands of fibrous tissue, yielding a complex structure of isolating and conducting tissue. Such areas of intermingled muscle bundles and fibrous septae may cause profound conduction delay (discussed later in this chapter). A similar architecture has been found in the infarcted canine heart.22 Panel C is a section from the apical part of the septum in the same heart. The left wall (top) of the septum is entirely fibrotic (light area marked F) in contrast to the right wall (bottom). A myocardial bundle, entirely encaged by fibrosis, seems to have survived in the left septal wall (arrow). It is conceivable that such bundles, when they traverse the infarcted zone, may constitute the return path of a reentry circuit.

Characteristics of the Infarcted Human Heart Studies were carried out at 9 hearts from patients who underwent heart transplantation because of congestive heart failure caused by myocardial infarction. The location of the infarct was in the anterior wall including the septum in 6 patients, inferoposterior in 2, and diffuse in 1. Ejection fraction before transplantation ranged from 13% to 27%. A history of sustained VT was documented in one patient only.

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Figure 1. A. Histologic section of the infarcted area in the posteroseptal region of an explanted human heart. The posterior wall consists mainly of fibrous tissue (F); in contrast, the septal region is not affected and consists of healthy myocardial tissue (M). The endocardium is thickened by fibroelastosis, which is present along the entire posterior wall (dark rim). A small rim of surviving myocardium is present between the endocardium and the infarcted area (arrow). The white zone along the epicardium indicates the presence of fatty tissue. B. Histologic section from the infarcted mid septal region of another explanted heart. In contrast to A, this region consists of numerous surviving myocardial bundles (dark areas) that survive within the fibrotic regions (F). Note that the myocardial bundles are often divided into smaller bundles by fibrotic strands. Areas in which numerous myocardial bundles are embedded in fibrous tissue are a common finding in infarcted myocardium.C. Histologic section from the same heart as in B. This section is taken from the septal wall as well, but at a more apical position. The infarction is almost transmural at this level, but a large strand of myocardium was able to survive in the middle of the septum (arrow). F = fibrous tissue.

MAPPING IN EXPLANTED HEARTS Spread of Activation During Tachycardia In the 9 isolated hearts, 15 monomorphic sustained VTs were induced. The cycle length (CL) ranged from 260 to 560 ms. In 7 of 10 tachycardias, earliest epicardial activation appeared more than 20 ms after earliest endocardial activation, whereas in 3 tachycardias, earliest epicardial and endocardial activation was almost simultaneous. In all cases, the endocardial activation pattern showed a focal area of earliest activity from which activation spread more or less centrifugally with activation block toward the infarcted zone. The site of earliest activation was always located within 2 cm of the border of the infarct. These characteristics were similar to those of the tachycardias recorded in patients during arrhythmic surgery.23"27 Although the tachycardias induced in healed myocardial infarction usually reveal a focal activation pattern, there was convincing evidence from clinical and experimental studies28"33 that reentry is the underlying mechanism of these arrhythmias. It was supposed that activation returned from the latest activated site of one cycle to the earliest activated site of the next cycle via surviving myocardial fibers in the infarcted zone. Remaining healthy myocardium constituted the other part of the circuit. The exact path within the infarcted area was, however, unknown. Because electrophysiology and histology can be well correlated in explanted hearts, detection of the reentry circuit within the compromised area was expected to be possible. In 2 tachycardias recorded in 2 different hearts, activation delay between earliest and latest endocardial activation was approximately 30 ms. The distance between earliest and latest activated sites was approximately 1.2 cm. Assuming that activation returns from the latest activated

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site to the earliest activated site via surviving myocardial bundles yields a mean conduction velocity of 0.4 m/s in the return path. Thus, in these cases, which are rather exceptional, the conduction velocity in the return tract was close to normal. In contrast, the majority of activation maps showed delays of more than 120 ms between latest and earliest activation over a similar distance, resulting in conduction velocities of less than 0.1 m/s. Endocardial activation patterns of 2 tachycardias induced in the same heart are shown in Figure 2. VT1 shows a tachycardia where conduction in the return path was close to normal; in contrast, the activation map of VT2 shows that the conduction velocity in the presumed return path is low. Hatching indicates that an area of damaged tissue extended from base to apex in the posterior wall. Activation of VT1 started at the right border of the infarct, and main activation (arrows) spread out toward the base and the lateral wall. Activation toward the septum was blocked after 120 ms; 240 ms after the onset of endocardial activation, activity reached the septal side of the infarct (site e). Delay between activation at this site and the onset of the next cycle (at site a) was only 30 ms, suggesting reexcitation at the "origin" by means of activation through surviving myocardial tissue between sites e and a. The electrogram recorded at site f, located between a and e, had 3 deflections; the first and third deflection were remote and caused by activation removing from the right side of infarcted zone and the wavefront approaching the left side of the infarcted zone, respectively. The second deflection did not coincide with documented activity anywhere else in the tissue, which indicated that it was generated by viable tissue underneath the recording site. The time delay of 30 ms between activation at the sites e and a (distance approximately 1.2 cm) suggested that activation was carried back toward

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Figure 2. Endocardial activation patterns of 2 monomorphic sustained ventricular tachycardias that were induced in a Langendorff-perfused human heart with extensive posterior infarction. Isochrones are in ms and timed with respect to the onset of endocardial activation. Arrows indicate main spread of activation. The activation map of VT1 shows that there is a time gap of 30 ms between latest activation of one cycle (recorded at site e) and earliest activation of the next cycle (recorded at site a). Reentry probably occurred through surviving pathways in the infarct zone between sites e and a (distance, 1.2 cm). The conduction velocity in the return tract, is approximately 0.4 m/s, which is close to normal. In contrast, delay in the return tract of VT2 is 140 ms, while the distance between the earliest and latest activated sites is 1.2 cm as well. This implies that the conduction velocity in the return tract of VT2 is low, approximately 0.07 m/s.

MAPPING IN EXPLANTED HEARTS the "origin" with close to normal conduction velocity (0.4 m/s). VT2 shows the activation pattern of another tachycardia induced in the same heart. Earliest endocardial activation arose at the septal side of the infarct zone. At the base of the septum, spread of activation toward the posterior wall was blocked. However, the wavefront reached the posterior wall by way of the anterolateral wall and apex. The wavefronts merged at a mid posterior level (160 ms isochrone) to arrive 240 ms after the onset at the base of the posterior septal border (site a). Because the CL of the tachycardia is 400 ms, a time gap of 160 ms had to be bridged to close the reentrant circuit that reactivated the "origin." The distance between latest and earliest activated sites was about 1.2 cm, yielding a mean conduction velocity in the presumed return tract of approximately 0.07 m/s.

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Characteristics of the Return Path For both tachycardias shown in Figure 2 the location of the return path of the presumed reentry circuit could be determined from the activation maps; however, only for the tachycardia of VT1 were we able to trace the exact route. After fixation in formalin, the area comprising the earliest and latest activated site was removed and sectioned. Sections of 10-u,m thickness were produced. A total of 500 sections were analyzed. Figure 3 shows a stacking of transparencies made of 10 sections 100 |im apart. In the upper and lower sections, the infarction was transmural. The stacking, however, suggests that a continuous tract (arrow) was present traversing the infarcted area, connecting the septum with the posterior wall. Thus, it could

Figure 3. Schematic drawings of sections of the area harboring the return tract for reentry of VT1 in Figure 2. Black areas are myocardial tissue; white areas are fibrotic. Transparencies of 10 sections have been stacked. The infarction is transmural at the level of sections 1 and 10. The stacking, however, suggests that there is a bridge of surviving myocardial tissue (white arrow) connecting surviving myocardial tissue at either side of the infarcted zone. Note that this tract is located endocardially, almost intramurally. In the same area an epicardially located tract could be traced in the area indicated by the open arrow.

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Figure 4. Three-dimensional reconstruction of a tract of surviving myocardial tissue traversing the infarcted zone as suggested by Figure 3. Surviving myocardium of the sections is indicated in black and that of the tract in gray. Eleven consecutive sections, 100 jim apart, were used for the reconstruction. The tract is connected with remaining healthy tissue of the posterior wall at level d and with the septal wall at level a. The length of the tract is approximately 13 mm. The width varies along the tract, with bottlenecks appearing in both the descending and the ascending parts of the tract. Reproduced from reference 33, with permission.

well be that a surviving bundle of myocardial tissue was present, connecting viable tissue at either side of the infarct zone and possibly forming a return path for reentry.

To prove that the supposed tract was indeed continuous, a 3-dimensional reconstruction of the tract had to be made (Figure 4). The schematic drawings of 10 successive sections (a to k), each 100 um

MAPPING IN EXPLANTED HEARTS apart, show that the tract (gray area) fuses with remaining healthy tissue of the posterior wall at level d. From here, the tract runs down toward level k, and remains horizontal over a distance of about 6 mm in level j before it ascends and finally merges with remaining healthy tissue of the septal wall at level a. Although the tract appears to be continuous, there are a number of narrow passages, especially in the descending and ascending parts of the tract. The smallest width of these bottlenecks was approximately 250 um. One might speculate that unidirectional activation block, necessary for initiating the tachycardia, could preferentially occur at such sites.34-36 The length of the endocardial tract within the infarct zone was approximately 13 mm. The short length of the tract may account for the small delay of activation in this area. It occurred to us that the subendocardial tract did not constitute the only possibility for reentry. The epicardial activation map suggested the presence of a surviving tract in the subepicardial part of the infarct, and an anatomical substantiation for such a tract could be demonstrated by applying the same procedure as described before.37 There was only one other heart in which delay between latest activation of one cycle and earliest activation of the next cycle was less than 30 ms, whereas the distance between the sites was only 1.2 cm. A tract of surviving myocardium, located 1.5 mm from the epicardial surface of the anterior wall, was traced. Its smallest width was approximately 350 |im. Two morphologically different tachycardias could be induced in this heart. In both tachycardias, the return path of the reentry circuit was the same. Because we could trace only one surviving tract in this area, it was likely that this return path was used for activation in both

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tachycardias. The tachycardias revolved in opposite directions, indicating that unidirectional block in this area could occur in either direction. These observations show that surviving tracts may be present throughout the entire infarcted ventricular wall and that return tracts may be used in either direction. The latter gives rise to VTs with different configuration. Direction of Surviving Fibers The area of the return path in VT2 in Figure 2, and in 3 other hearts where the apparent conduction velocity between the site of latest activation of one cycle and earliest activation of the next was low, consisted of a collection of surviving bundles with various diameters, separated from each other by fibrous or fatty tissue. Surviving bundles coursed separately over a few hundred micrometers and then merged into a single bundle (Figure 5). The fiber direction of the bundles was perpendicular to the line connecting the sites of earliest and latest activation, indicating that it was necessary for activation to proceed perpendicular to the fibers. The clusters of surviving muscle bundles separated by fibrous tissue and the repeated fusion and bifurcation of these bundles resembles inhomogeneous anisotropy, which could well account for the delayed conduction.38,39 Because of the complicated architecture of the branching bundles in the infarct, it was impossible to reconstruct a possible return path in either of these hearts. In the remaining hearts, the surviving fibers had no fixed direction, but varied throughout the area of the presumed return path. In the infarcted dog heart too, disorganization of surviving myocardial cells due to the ingrowth of fibrous tissue is a common finding.40

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Figure 5. Photomicrographs of an area revealing slow conduction during tachycardia. The left panel shows that the area consists of a number of surviving myocardial bundles (bright areas), separated from each other by fibrous tissue (dark areas). The photomicrograph at the right shows histological features in a section 100 jj,m beneath the one at the left. Here, the separated bundles have merged into a single bundle. Fiber direction in the area shown was perpendicular to the line connecting earliest and latest activated sites, indicating that activation had to proceed perpendicular to the fiber direction. Modified from reference 37.

slow conduction in healed infarcts. Impaired coupling between cells presents Unraveling the mechanism of con- another option for impaired conduction. duction delays of greater than 100 ms over Several investigators have shown that in distances less than 1 cm, which were compromised myocardium the connecfound in the majority of the tachycardias, tions of cells in side-to-side apposition are presented a challenge. Microelectrode reduced, whereas end-to-end connections recordings of myocardial tissue surviving are virtually unaffected.43,44 This is comin the infarcted zone have shown that patible with our finding that conduction action potentials were close to normal in delay preferentially occurred perpendichealed myocardial infarction.33,40-42 There- ular to the fiber direction. fore, abnormal membrane characteristics Disruption of side-to-side connection were unlikely candidates as the cause of may increase path length. Histology showed Superfused Preparations

MAPPING IN EXPLANTED HEARTS proliferation of fibrous tissue resulting in longitudinally oriented shells of connective tissue, insulating adjacent groups of myocardial fibers. Side-to-side electrical coupling among these fibers could be absent over distances of several millimeters, but interconnections farther away transferred activation to neighboring bundles. Diameter of the surviving bundles ranged from a few millimeters to the diameter of single cells. The small diameter of the isolated bundles together with the large delays over short distances suggested that very high resolution measurements were required to unravel the mechanism of activation delay. Measurements in the isolated hearts were not very suitable for such high-resolution mapping and therefore we studied conduction in and histology of papillary muscles resected from the explanted hearts.45 Muscles were superfused in a tissue bath; this has the advantage that only a rim of subendocardial myocardium 300 to 600 um thick survives. Thus, these preparations were more or less 2 dimensional. Papillary muscles were chosen because bundles of viable myocardial cells that survive in the subendocardial rim remain parallel in orientation.31 In infarcted myocardium, the parallel orientation of the surviving fibers often is not preserved and the surviving fibers appear to course in different directions.38,40 During basic stimulation, spread of activation was determined from recordings made at distances of 200 um from up to 416 sites. Electrograms showed multiple deflection in virtually all preparations (fractionated electrograms). Such electrograms are a common finding in diseased myocardium and point to asynchronous conduction. Electrical separation of myocardial fibers by anatomical barriers such as fibrous or fatty tissue give rise to separated conducting paths, which may result in asynchronous conduction. Separation of

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conducting paths is not exclusively the result of anatomic barriers. Reduced coupling between cells caused by a decrease in the number of gap junctions or reduction of the conduction properties may result in fractionation of electrograms as well. Analysis of activation times revealed that activation in the infarcted papillary muscle spread in myocardial tracts parallel to the fiber direction. Conduction velocity in the tracts was high (0.79 m/s). Tracts were separated by collagenous septa over distances up to 3 mm, but often connected with each other at one or more sites, forming a complex network of merging and diverging tracts. For propagation perpendicular to the fiber direction, delays of up to 36.5 ms over a distance of 1.2 mm were observed. Conduction delay in the direction perpendicular to the fibers was caused mainly by the increase of the route activation had to travel through the branching and merging bundles. Figure 6 shows an example of the complex architecture of merging and diverging bundles in one of the papillary muscles. The preparation was stimulated in the lower left corner (near site A); numbers within the tracts indicate activation times with respect to the stimulus. To reach site B, at a distance of 1.2 mm from site A, activation had to follow the indicated zigzag route. At site B, activation arrived after a delay of 36.5 ms, indicating that the apparent conduction velocity perpendicular to the fiber direction was 0.04 m/s. Note that in a number of tracts activation proceeded from the right to the left, that is toward the site of stimulation. The tracings in Figure 7 are 8 electrograms recorded along a line perpendicular to the fiber direction. The interelectrode distance of the recording electrode was 0.2 mm. All electrograms are highly fractionated because of the asynchronous conduction within the different bundles. The architecture

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Figure 6. Tracts along which activation proceeded in an infarcted papillary muscle from an explanted human heart. The tracts, which were reconstructed using electrograms recorded with a resolution of 200 jim, run parallel to the fiber direction and are separated over distances of several millimeters before they connect to neighboring tracts. The preparation was stimulated at the lower left corner (close to site A). Numbers in the tracts indicate activation times measured with respect to the stimulus. Activation delay between sites A and B along a line perpendicular to the fiber direction is 36.5 ms. Sites A and B are 1.2 mm apart, resulting in an apparent conduction velocity between A and B of 0.04 m/s. The continuous line indicates the tortuous route activation had to travel from A to reach B. Activation delay between A and B is caused mainly by the increase of the route activation must travel. Conduction velocity in the tracts is close to normal (0.78 m/s).

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Figure 7. Eight of 240 unipolar recordings made to determine the tracts in Figure 6. Electrograms are highly fractionated indicating asynchronous activation in the various tracts. Modified from reference 45.

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Figure 8. Photomicrograph of a section of the papillary muscle in Figure 6. A surviving subendocardial rim (bright area) surrounds a core of dense connective tissue (dark area). The surviving subendocardial rim is divided into several bundles of myocytes that are sheathed by septae of fibrous tissue. Reproduced from reference 45, with permission.

of isolated myocardial bundles in the surviving subendocardial rim is shown in Figure 8. A narrow surviving subendocardial rim (bright area) surrounds a core of dense connective tissue (dark area). The surviving subendocardial rim is divided into several bundles of myocytes that are sheathed by septae of fibrous tissue. The infarcted papillary muscle presents the simplest model for studying conduction abnormalities imposed by healed myocardial infarction. As illustrated, very high resolution mapping is required to gain insight into the mechanism of slow conduction. Such recordings are difficult to perform in the isolated Langendorffperfused heart. In addition, superfusion

virtually reduces the 3-dimensional structure to 2 dimensions and fiber direction in the papillary muscles remains almost parallel.

Conduction in Dilated Cardiomyopathy Electrophysiological abnormalities have been observed in various experimental models of dilated cardiomyopathy.7"10 Anderson et al.46 have shown that the severity of abnormal propagation correlates with the amount of myocardial fibrosis in patients with dilated cardiomyopathy who underwent heart transplantation.

MAPPING IN EXPLANTED HEARTS To unravel the mechanism of abnormal conduction in dilated cardiomyopathy, we carried out similar measurements as described before in papillary muscles derived from explanted hearts of patients who underwent heart transplantation while in the end stage of heart failure due to dilated cardiomyopathy.47 Although preparations revealed fractionated electrograms and conduction delay as observed in the infarcted preparations, architecture of the cardiomyopathic papillary muscles differed from that of the infarcted ones. Impaired conduction in dilated cardiomyopathy was indeed associated with collagen infiltration, but the matrix of intermingling myocardial bundles and fibrosis differed. Discernible lines of block consisting of broad strands of fibrosis were present but most often electrical barriers consisted of short stretches of fibrous tissue. Delayed conduction was caused by curvature of activation around the distinct lines of block and by a wavy course of activation between the short barriers. The latter reflects extreme nonuniform anisotropy. Architecture of Interstitial Fibrosis and Conduction Delay The previous observations suggest that the architecture of interstitial fibrosis is an important parameter in determining the amount of conduction delay. To investigate the role of the architecture of fibrosis on conduction, we performed high-resolution mapping in another 8 Langendorff-perfused human hearts.48 Three patients had coronary artery disease (with myocardial infarction), 1 suffered from hypertrophic cardiomyopathy, and 4 had dilated cardiomyopathy. Multiterminal plaque electrodes harbored 105 or 208 terminals consisting of 70-jimdiameter silver wires, isolated except at

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the tip. Terminals were arranged in a 9 x 12 or 16 x 13 matrix at interelectrode distances of 0.8 and 0.5 mm, respectively. Plaque electrodes were positioned over nonfatty epicardial areas. Electrical stimulation was applied with bipolar hook electrodes positioned adjacent to any one of the 4 sides of the multielectrode. Pacing was at twice diastolic current threshold with an 8-pulse drive train (CL 600 ms) and one premature stimulus. Coupling intervals of premature stimuli were from 500 ms down to the refractory period in steps of 10 ms. Tissue at 16 of the 26 positions of the multielectrode was subjected to histological investigation. Mean density of fibrosis in the recording areas ranged from 7% to 43% (mean 18 ± 10%). Three types of fibrosis with regard to architecture were distinguished: • Patchy: patchy fibrosis with long, compact groups of strands • Diffuse: more or less diffusely distributed fibrosis with short strands • Stringy: homogeneously distributed fibrosis with long "single" strands; sometimes local, compact areas of fibrosis were present in this type. Density of fibrosis did not correlate with conduction delay, but the architecture of fibrosis played a major role. Figure 9 shows 2 types of fibrosis, patchy (left panel) and diffuse (right panel) with similar mean density of fibrosis (22% and 33%, respectively). Conduction velocity during basic CL was similar for both types of fibrosis when propagation was parallel to the fiber direction. However, for propagation perpendicular to the fiber direction, conduction velocity, which was 0.24 ± 0.04 m/s during basic CL, reduced to 0.17 ± 0.06 m/s after premature stimulation with a coupling interval 10 ms longer than the refractory period. In contrast, conduction velocity reduced from

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Figure 9. Histological sections showing patchy fibrosis with long strands (left panel) and diffuse fibrosis (right panel). See text for discussion. See color appendix. Adapted from reference 48.

0.28 ± 0.07 m/s to 0.05 ± 0.01 m/s for patchy fibrosis. This is illustrated in Figure 10. Stimulation at site A (panel A) resulted in propagation of activation nearly perpendicular to the fiber direction. Tracings at the left in panel b show a progressive increase in conduction delay during premature stimulation at site A. Activation maps (panel C) during baseline stimulation at site A revealed widely separated isochronal lines, compatible with continuous conduction. Following premature stimulation, however, conduction became irregular with functional lines of conduction block at decreasing coupling intervals. Delay of activation within the recording area increased from 11 ms to 68 ms. Activation patterns resulting from stimulation at site B (lower maps) showed no irregularities after premature stimuli, and only a marginal increase of conduction delay was observed (from 7 to 17 ms). Thus, this study showed that, in chronically diseased human myocardium,

progressive increase of conduction delay during premature stimulation arises in areas with patchy fibrosis having long, compact, groups of strands. Delay strongly depends on the direction of wavefront propagation with respect to fiber direction, the effect during propagation perpendicular to the fiber direction being large as compared to that found upon parallel propagation. Diffusely distributed fibrosis with short strands only marginally affected conduction delay, even at high densities of fibrosis. In summary, mapping of the electrical activity in Langendorff-perfused human hearts allowed detection of the reentry circuit by correlating electrophysiology with anatomy in only a minority of the cases. In these cases, surviving myocardial bundles within the infarct zone constituted a continuous tract that traversed the infarct; activation delay in these tracts was close to normal. In the majority of the cases, activation delay in the area supposed to harbor the return

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Figure 10. a. Histological section of the recording area (rectangle) in a heart showing patchy fibrosis with long strands (red areas). Yellow areas show myocardial tissue. A and B are pacing sites. b. Extracellular electrograms recorded at the center of the recording electrode (asterisks). Numbers are coupling intervals of the premature stimuli, c. Activation maps during stimulation at site A (upper maps) and site B (lower maps) during basic cycle length of 600 ms and premature stimuli at coupling intervals from 500 to 320 ms. Numbers beneath the maps indicate the time in which the recording area was activated. See color appendix. Adapted from reference 48.

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Figure 11. Schematics of delayed conduction in infarcted myocardium. Fibrous tissue separates surviving myocardial bundles within the infarcted zone, although bundles may merge at a number of sites to connect with neighboring tracts. Activation starting at site A must follow the tortuous route indicated by the black line to reach site B. Activation delay between sites A and B is caused mainly by the increase of the route activation must travel.

tract was, however, large and the architecture of the area was too complex to correlate electrophysiology with histology. To reveal the mechanism of conduction delay in the return tract in these cases, refined measurements in papillary muscles superfused in a tissue bath were more appropriate. These measurements showed that slow conduction perpendicular to the fiber direction in infarcted myocardial tissue is caused by zigzag conduction at normal speed due to lengthening of the pathway by branching and merging of surviving myocardial bundles ensheathed by collagenous septae (Figure 11). Impaired conduction in dilated cardiomyopathy is caused, at least in part,

by the development of fibrous tissue as well. In these hearts, delayed conduction was caused by curvature of activation around distinct barriers (Figure 12A) and by the wavy course of activation between short barriers of fibrous tissue (Figure 12B). Finally, architecture of fibrosis plays a major role in determining progressive increase of conduction delay at incremental shortening of the coupling interval of premature stimuli. The effect of long fibrotic strands on conduction was much greater than that of diffuse fibrosis with short strands. The architecture of fibrosis is more important than its density for generating conduction disturbances.

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Figure 12. Schematic representations of activation in myocardium impaired by cardiomyopathy. Conduction delay arises because of curvature of activation around distinct barriers (A) or by the wavy course of activation between short barriers (B). Numbers indicate activation times.

References 1. Harris AS. Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation 1950;1:1318-1328. 2. Uemura N, Knight DR, Shen J, et al. Increased myocardial infarct size because of reduced coronary collateral blood flow in beagles. Am JPhysiol 1989;257(6 Pt 2): H1798-H1803. 3. El-Sherif N, Scherlag BJ, Lazarra R, et al. Reentrant ventricular arrhythmias in the late myocardial infarction period. 1. Conduction characteristics in the infarcted zone. Circulation 1977;55:686-702. 4. Wit AL, Allessie MA, Bonke FIM, et al. Electrophysiologic mapping to determine the mechanism of experimental ventricular tachycardia initiated by premature impulses. Experimental approach and initial results demonstrating reentrant excitation. Am J Cardiol 1982;49:166-185.

5. Kramer JB, Saffitz JE, Witkowski FX, et al. Intramural reentry as a mechanism of ventricular tachycardia during evolving canine myocardial infarction. Circ Res 1985; 56:736-754. 6. Walker MJA, Cirtis MJ, Hearse DJ, et al. The Lambeth Conventions: Guidelines for the study of arrhythmias in ischemia, infarction and reperfusion. Cardiouasc Res 1988;22:447-455. 7. Hano O, Mitsuoka T, Matsumoto Y, et al. Arrhythmogenic properties of the ventricular myocardium in cardiomyopathic Syrian hamster, BIO 14.6 strain. Cardiovasc Res 1991;25:49-57. 8. Weber KT, Pick R, Silver MA, et al. Fibrillar collagen and remodeling of dilated canine left ventricle. Circulation 1990;82: 1387-1401. 9. Einzig S, Detloff BLS, Borgwardt BK, et al. Cellular electrophysiological changes in "round heart disease" of turkeys: A potential basis for dysrhythmias in myopathic

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ventricles. Cardiouasc Res 1981;15:643— 21. Estes HE Jr, Entman ML, Dixon HB, 651. et al. The vascular supply of the left ven10. Fein FS, Capasso JM, Aronson RS, et al. tricular wall: Anatomic observations, plus a hypothesis regarding acute events in Combined renovascular hypertension in diabetes in rats: A new preparation for coronary artery disease. Am Heart J 1966;71:58-67. congestive cardiomyopathy. Circulation 1984;70:318-330. 22. Gardner PI, Ursell PC, Due Pham T, 11. Poll DS, Marchlinski FE, Buxton AE, et al. Experimental chronic ventricular et al. Sustained ventricular tachycardia in tachycardia: Anatomic and electrophysiopatients with idiopathic dilated cardiomylogic substrates. In Josephson ME, Wellens HJJ (eds): Tachycardias: Mechaopathy: Electrophysiologic testing and lack of response to antiarrhythmic drug therapy. nisms, Diagnosis, Treatment. PhiladelCirculation 1984;70:451-456. phia: Lea and Febiger; 1984:29. 12. Milner PG, DiMarco JP, Lerman BB. Elec- 23. de Bakker JMT, van Capelle FJL, Janse trophysiologic evaluation of sustained MJ, et al. Macroreentry in the infarcted human heart: The mechanism of ventricventricular tachyarrhythmias in idiopathic dilated cardiomyopathy. Pacing ular tachycardias with a "focal" activation pattern. J Am Coll Cardiol 1991; 128: Clin Electrophysiol 1988;ll:562-568. 1005-1015. 13. Barber MJ, Mueller TM, Henry DP, et al. Transmural myocardial infarction in the 24. Josephson ME, Horowitz LN, Farshidi A, dog produces sympathectomy in noninet al. Recurrent sustained ventricular farcted myocardium. Circulation 1983; tachycardia. I. Mechanisms. Circulation 1978;57:431-439. 67:787-796. 14. Zipes DP. Influence of myocardial 25. Horowitz LN, Josephson ME, Harken AM. ischemia and infarction on autonomic Epicardial and endocardial activation innervation of heart. Circulation 1990; during sustained ventricular tachycardia 82:1095-1105. in man. Circulation 1980;61:1227-1238. 15. Brugada P, Waldecker B, Kersschot Y, 26. Mickleborough LL, Harris L, Downar E, et et al. Ventricular arrhythmias initiated al. A new intraoperative approach for by programmed stimulation in four groups endocardial mapping of ventricular tachyof patients with healed myocardial infarccardia. JThorac Cardiouasc Surg 1988;95: 271-280. tion. JAm Coll Cardiol 1986;8:1035-1040. 16. Roy DE, Marchand E, Theroux P, et al. 27. Mason JW, Stinson EB, Oter PE, et al. The mechanism of ventricular tachycardia Programmed ventricular stimulation in survivors of an acute myocardial infarcin humans determined by intraoperative recording of the electrical activation tion. Circulation 1985;72:487-494. 17. Kuck KH, Costard A, Schlulter M, et al. sequence. Int J Cardiol 1985;8:163-172. Significance of timing programmed elec- 28. Josephson ME, Buxton AE, Marchlinski FE, et al. Sustained ventricular tachytrical stimulation after acute myocardial cardia in coronary artery disease— infarction. J Am Coll Cardiol 1986;8: evidence for reentrant mechanism. In: 1279-1288. 18. Downar E, Janse MJ, Durrer D. The effect Zipes DP, Jalife J (eds): Cardiac Electroof acute coronary artery occlusion on physiology and Arrhythmias. Orlando: subepicardial transmembrane potentials Grune & Stratton; 1985:409-418. in the intact porcine heart. Circulation 29. El Sherif N, Smith RA, Evans K. Canine 1977;56:217-224. ventricular arrhythmias in the late 19. Fenoglio JJ, Due Pham T, Harken AM, et myocardial infarction period: Epicardial mapping of reentrant circuits. Circ Res al. Recurrent sustained ventricular tachy1981;49:255-271. cardia: Structure and ultrastructure of subendocardial regions in which tachy- 30. Karagueuzian HS, Fenoglio JJ, Weiss MB, et al. Protracted ventricular tachycardia originates. Circulation 1983; cardia induced by premature stimulation 68:518-533. in the canine heart after coronary artery 20. Fulton WFM. The dynamic factor in occlusion and reperfusion. Circ Res 1979; enlargement of coronary arterial anasto44:833-846. moses, and paradoxical change in the subendocardial plexus. Br Heart J 1964; 31. Mehra R, Zeiler R, Cough WB, et al. Reentrant ventricular arrhythmias in the 26:39-50.

MAPPING IN EXPLANTED HEARTS late myocardial infarction period. 9. Electrophysiologic-anatomic correlation of reentrant circuits. Circulation 1983;67: 11-24. 32. Gessman LJ, Agarwal JB, Endo T, et al. Localization and mechanism of ventricular tachycardia by ice mapping 1 week after the onset of myocardial infarction in dogs. Circulation 1983;68:657-666. 33. de Bakker JMT, van Capelle FJL, Janse MJ, et al. Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: Electrophysiologic and anatomic correlation. Circulation 1988;77:589-606. 34. De la Fuente D, Sasyniuk B, Moe GK. Conduction through a narrow isthmus in isolated canine atrial tissue: A model of the WPW syndrome. Circulation 1971; 44:803-809. 35. Fast VG, Kleber AG. Cardiac tissue geometry as a determinant of unidirectional conduction block: Assessment of microscopic excitation spread by optical mapping in patterned cell cultures and in a computer model. Cardiovasc Res 1995; 29:697-707. 36. Maglaveras N, de Bakker JMT, van Capelle FJL, et al. Activation delay in healed myocardial infarction: A comparison between model and experiment. Am J Physiol 1995;269(4 Pt 2):H1441-H1449. 37. de Bakker JMT, Coronel R, Tasseron S, et al. Ventricular tachycardia in the infarcted Langendorff-perfused human heart: Role of the arrangement of surviving cardiac fibers. J Am Coll Cardiol 1990;15:1594-1607. 38. Dillon S, Allessie MC, Ursell PC, Wit AL. Influence of anisotropic tissue structure on reentrant circuits in the epicardial border zone of subacute canine infarcts. CircRes 1988;63:182-206. 39. Spach MS, Miller WT, Dolber PC, et al. The functional role of structural complexities in the propagation of depolar-

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ization in the atrium of the dog. Cardiac conduction disturbances due to discontinuities of effective axial resistivity. Circ Res 1982;50:175-191. 40. Ursell PC, Gardner PI, Albala A, et al. Structural and electrophysiological changes in the epicardial border zone of canine myocardial infarcts during infarct healing. CircRes 1985;56:436-451. 41. Meyerburg RJ, Gelband H, Nilsson K, et al. Long-term electrophysiologic abnormalities resulting from experimental myocardial infarction in cats. Circ Res 1977;41: 73-84. 42. Spear JF, Horowitz LN, Hodess AB, et al. Cellular electrophysiology of human myocardial infarction, I: Abnormalities of cellular activation. Circulation 1979;59: 247-256. 43. Luke RA, Saffitz JE. Remodeling of ventricular conduction pathways in healed canine infarct border zones. J Clin Invest 1990;87:1594-1602. 44. Hoyt RH, Cohen ML, Saffitz JE. Distribution and three-dimensional structure of intercellular junctions in canine myocardium. Circ Res 1988;64:563-574. 45. de Bakker JMT, van Capelle FJL, Janse MJ, et al. Slow conduction in the infarcted human heart. 'Zigzag' course of activation. Circulation 1993;88:915-926. 46. Anderson KP, Walker R, Urie P, et al. Myocardial electrical propagation in patients with idiopathic dilated cardiomyopathy. J Clin Invest 1993;92:122-140. 47. de Bakker JMT, van Capelle FJL, Janse MJ, et al. Fractionated electrograms in dilated cardiomyopathy: Origin and relation to abnormal conduction. J Am Coll Cardiol 1996;27:1071-1078. 48. Kawara T, Derksen R, de Groot JR, et al. Activation delay after premature stimulation in chronically diseased myocardium relates to the architecture of interstitial fibrosis. Circulation 2001;104: 3069-3075.

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Chapter 17 Efferent Autonomic Innervation of the Atrium: Assessment by Isointegral Mapping Pierre L. Page, MD and Rene Cardinal PhD

Introduction Autonomic nerves affect heart rate, atrioventricular (AV) conduction, and contractile force through their efferent projections to the sinus node, AV node, and atrial musculature. These parameters have therefore been used as markers for the study of atrial innervation in the canine heart.1"3 From these previous reports, we have learned that parasympathetic postganglionic efferent neurons were localized in the right atrial (RA) ganglionated plexus, a collection of neural elements contained in a triangular fat pad on the ventral aspect of the RA free wall (pulmonary vein fat pad), as well as in a ganglionated plexus located in fatty tissues overlying the junction of the inferior vena cava and inferior left atrium (LA).4"7 Selective stimulation4'8 or surgical removal9"12 of these structures were used to demonstrate the specificity of parasympathetic efferent innervation of the sinus node and AV node that may

occur through the RA and inferior LA ganglionated plexi, respectively. However, little information was available on functional pathways to regions of the atria other than the sinus and AV nodes. In addition, a precise knowledge of the anatomical distribution of autonomic neural elements may have important implications for clinical procedures such as those used in cardiac surgery or during invasive electrophysiological ablation sessions. In this chapter, new information on the autonomic innervation of the atrium resulting from experimental and clinical work based on repolarization mapping is discussed. Atrial Integral Distribution Mapping The repolarization phase of the cardiac action potential is very sensitive to parasympathetic and sympathetic nerve stimulation.13'14 Therefore, refractory

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003. 363

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period determinations have been used to study regional atrial effects in response to stimulation of intrathoracic autonomic nerves. However, the extrastimulus technique commonly used for refractory period measurements is limited by the fact that only one site can be sampled at a time and that each determination requires several seconds to complete. Other parameters—QRST area, activationrecovery interval, QT interval, and T wave amplitude—have been used to determine ventricular recovery properties.15'16 In conjunction with a multichannel recording system and multiple electrode arrays, the QRST area calculated from unipolar electrograms was used to assess ventricular patterns of sympathetic innervation.17 This concept was then applied to atrial unipolar electrograms to assess repolarization properties on a beatto-beat basis, thereby analyzing the spatial distribution of electrical responses induced by stimulation of specific efferent autonomic neural elements with a high degree of spatial and temporal resolution.18 In the studies summarized herein, the integral of the atrial unipolar electrogram waveform was calculated with reference to the isoelectric diastolic baseline. The distribution of integral values measured from multiple simultaneous recordings (Figure 1) was used to detect regional changes in atrial electrical events induced by stimulation of individual intrathoracic and intracardiac neural elements. To allow the analysis of atrial unipolar electrograms without interference made by ventricular QRS complexes usually occurring before the end of the atrial T wave, a complete AV block was induced by the injection of formaldehyde into the His bundle region in all of our canine studies. Unipolar electrograms were simultaneously recorded from 192 sites by means of flexible electrode tern-

Figure 1. A. Unipolar atrial electrogram recorded during control conditions (sinus rhythm, atrioventricular block, no ventricular pacing, no nerve stimulation). B. Atrial unipolar electrogram recorded during stimulation of the right vagosympathetic complex. C. Superimposition of electrograms shown in A and B. Neural stimulation affected primarily the T wave (arrows) of unipolar electrograms. The hatched area represents the integral of changes in the T wave morphology. This value was plotted on the atrial grid for each recording site and used to generate an integral distribution map.

plates sutured to the epicardial surfaces of both atria. The signals were recorded with reference to the Wilson central terminal, and amplified, filtered (0.05 to 200 Hz), multiplexed, digitized at I kHz, and stored on hard disk using a data acquisition system (Institut de Genie Biomedical, Universite de Montreal).18 Data obtained

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Figure 2. Integral distribution maps showing effects of neural stimulation in selected preparations (A through C). The grids represent a posterior view of the atria. The left atrium is displayed on the left-hand side of the map. The two upper corners of the maps correspond to the atrial appendages. Isoarea lines delimit color-coded zones including points where integral measurements were within a given 60 mV/ms range of values. Increases in T wave amplitude are shown as positive values (green to blue), whereas reductions of T wave amplitude or inversion are represented as negative values (orange to red). The major effects common to the right (A) and left (B) vagosympathetic stimulation and right atrial ganglionated plexus (C) consisted of a blue shift in the right atrial free wall. The map in panel D was obtained during nerve stimulation after an inverted Y-shaped incision was performed in the right atrium. Compared to map A, the effect of RVSC stimulation was suppressed. RVSC = right vagosympathetic complex; LVCS = left vagosympathetic complex; RAGP =right atrial ganglionated plexus (fat pad). RVSC-Y = RVSC stimulation after a Y-shaped incision in the right atrium. See color appendix.

during each period of neural stimulation were compared to control data obtained prior to stimulation. The net area (integral) under the intrinsic deflection and T wave of each atrial electrogram was computed by an integration process using a modified Simpson's technique and custom software that added the values of sample sectors multiplied by the duration of each sampling period (Institut de Genie Biomedical, Universite de Montreal).17'18 The difference between prestimulation integral and that measured

during stimulation was calculated for each recording site (Figure 1C). This value was plotted on an atrial grid using color-coded zones including points displaying values within a given range (Figure 2). The incidences, among preparations, of specific regional effects were assessed by counting the number of preparations that displayed integral changes beyond a threshold of ±60 mV/ms corresponding to 2 standard deviations of changes obtained when measurements were repeated under basal conditions.

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14

Figure 3. Histogram representing the incidence, in 12 preparations, of electrogram integral changes beyond ±60 mV/ms in each atrial region in response to nerve stimulation. Nerves: LVSC = left vagosympathetic complex; RAGP = right atrial ganglionated plexus; RVSC = right vagosympathetic complex. IAB = interatrial band; LAFW = left atrial free wall; LatRA = lateral right atrial free wall, adjacent to the AV groove; LowRA = lower half of right atrial free wall; SAN = sinus node area.

Stimulation of Autonomic Neural Elements Figure 3 shows the incidence of significant changes (>60 mV/ms) in each region of the RA and LA in a series of 12 preparations. Stimulation of the right vagosympathetic complex induced positive integral changes in the RA free wall in all preparations (Figure 2A). Interanimal variability of responses occurred, as illustrated by the fact that right vagosympathetic complex stimulation induced similar global patterns of effects, albeit with a variable distribution in the RA. The interatrial band and the LA free wall were both affected in half of the preparations. On the other hand, negative integral changes were induced in the LA in approximately half of the animals (Figure 3).

Stimulation of the left vagosympathetic complex also induced positive integral changes in the sinus node area in most preparations (Figure 2B). However, positive changes were also induced in the LA free wall in all animals. Stimulation of loci in the RA ganglionated plexus produced positive changes in the sinus node area and the RA free wall (Figure 2C). These effects were more restricted than those of the right vagosympathetic complex, encompassing smaller regions of the RA (31 ± 13 cm2 and 43 ± 10 cm2, respectively, P< 0.01). Negative integral changes of a lesser amplitude were induced in small regions of the LA free wall in less than 25% of the preparations. Efferent sympathetic neural elements in the RA ganglionated plexus were also identified following atropine administration

EFFERENT AUTONOMIC INNERVATION OF THE ATRIUM in 11 preparations, since the induction of positive integral changes in the RA was inhibited, whereas changes similar to those generated in response to right or left stellate ganglion stimulation were induced. These data indicate that the RA ganglionated plexus may contain neural elements originating from neural structures other than the right vagosympathetic complex, possibly from the right stellate ganglion.

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Effects of the Maze Procedure

Surgical procedures designed to prevent or cure atrial fibrillation must comply with a wide range of electrophysiological conditions. Therefore, the major rationale of the development of the Maze operation led to a global, biatrial approach.22 This operation consists of an arrangement of numerous incisions performed in both the RA and the LA that are meant, first, to eliminate most opportunities for reentrant circuits, and second, to reduce the likeliEffects of Atrial Incisions hood of fibrillation in any remaining single fragment of tissue because of the Incisions in the RA free wall are myocardial mass reduction. As shown in often used in experimental models of the previous section, all parts of the reentry19'20 or during human open-heart atrium are richly innervated by efferent surgery aimed at the correction of intra- parasympathetic elements. Experiments atrial abnormalities. The effect of a Y-- were conducted in canines to determine shaped incision in the RA free wall was whether extensive surgical modification investigated through integral mapping of atrial anatomy lead to parasympathetic during vagal stimulation in 7 anes- denervation.23"26 thetized dogs. Right and left vagal stimIn the experiments with the Maze III ulation and that of the RA ganglionated procedure, the sinus bradycardia induced plexus decreased heart rate by 87 ± 25, by vagal stimulation was suppressed in all 76 ± 17, and 42 ± 15 beats per minute 9 preparations. Isointegral maps (Figure 4) (bpm), respectively, before the incision, indicated that neurally induced repolarand by 25 ± 21, 14 ± 9, and 8 ± 9 bpm, ization changes were suppressed by the respectively, after the incision (P< 0.01).21 Maze procedure in most atrial regions in Figure 2D shows an example of suppres- 7 of 9 preparations. Neural effects induced sion of integral changes induced by right by left vagal stimulation persisted in the vagal stimulation. The incidence of sup- Bachmann's bundle region (4 of 9) and in pression of significant neural effects after the superior RA (3 of 9), and in the supethe incision suggested the following con- rior RA (3 of 9) during right vagal stimuclusions: (1) The denervated area included lation. We concluded that the Maze III the rostral RA encompassing the anterior procedure induces parasympathetic denpart of the tricuspid ring. (2) The supe- ervation of the sinus node in canine rior LA and, to a lesser extent, the infe- preparations. The procedure also interrior LA are innervated directly by the feres with parasympathetic innervation right and/or the left vagal nerve. (3) Post- of atrial regions remote from the sinus ganglionic axons of the RA ganglionated node, mainly the inferior RA and LA. The plexus may innervate the LA by coursing extent to which this effect contributes to through the RA free wall. Thus, incision the antiarrhythmic mechanism of the in the RA induces parasympathetic procedure and whether this effect will denervation of a significant portion of persist over the long term is not yet the RA. established.

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Figure 4. Integral maps during stimulation of the right vagosympathetic complex in a dog experiment before and 90 minutes after a Maze procedure. In this example, neurally induced repolarization changes persisted in the interatrial band but were completely suppressed on the right atrial free wall. See color appendix.

Stimulation of Intrinsic Cardiac Ganglia in Humans The implication of the autonomic nervous system in the occurrence and maintenance of postoperative atrial arrhythmias motivated us to investigate the regional distribution of neural terminations throughout the atrium in human subjects during routine open-heart surgery. In 7 patients scheduled for elective coronary bypass procedures, atrial mapping was performed during normothermic cardiopulmonary bypass.27 Multielectrode templates containing 128 unipolar contacts were sutured onto the epicardial surface of the RA and the LA. In order to allow the analysis of whole atrial activation, a programmed stimulation protocol independently applied to the RA was used to increase the PR interval. This protocol was performed during the control acquisition and during the stimulation of the RA ganglionated plexus (i.e., the pulmonary vein fat pad). The stimulation of the fat pad

decreased the sinus rate from a mean of 73 ± 12 bpm to 52 ± 9 bpm, indicating the recruitment of parasympathetic neural elements within the RA ganglionated plexus. The map shown in Figure 5 shows cumulative data obtained in all 7 patients. The results show that the changes occurred only in the RA and in the RA appendage. The area encompassed by significant changes has been calculated with planimetry of the maps. Neural stimulation induced changes in 32% of the surface of the RA and in 8.5% of the surface of the LA; however, although mathematically significant, changes noted on the LA were always measured on a single, isolated electrode, thus not reflecting an actual local neural effect. These data suggest that the electrophysiological effects of stimulation of the RA ganglionated plexus in humans are parasympathetic, as also demonstrated by others,28 and appear to be more specific to the sinus node region than in the dog. The reasons for these observations are not yet well understood.

EFFERENT AUTONOMIC INNERVATION OF THE ATRIUM

369

Figure 5. Cumulative integral mapping data obtained in 7 patients during electrical stimulation of the right atrial ganglionated plexus. Effects are restricted in the right atrial free wall and the sinus node area. See color appendix.

Summary and Conclusion

The spatial distribution of repolarization changes induced by neural stimulation can be determined using integral distribution maps obtained from multiple atrial recordings.18 The data so obtained indicate that the autonomic nervous system displays a heterogeneity of atrial electrical responses when its various extrinsic and intrinsic neural elements are stimulated electrically. In our experiments, consistent atrial electrogram integral changes were induced in the RA free wall during stimulation of the right and left vagosympathetic com-

plexes as well as the RA ganglionated plexus. Such integral changes were also induced by vagal stimulation in other atrial regions (Figures 2 and 3). Our data also indicate that stimulation of loci in the RA ganglionated plexus induced changes in regions of the RA remote from the sinus node region and, in about a third of the animal preparations, also in the LA, indicating that neural elements in the RA ganglionated plexus project to many more atrial sites than suggested previously.6'9"12'29'30 Other work performed in laboratory used intrapericardial dissections to delineate the contribution of specific neural structure to atrial innervation.31 Interestingly,

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the data from these studies have sugReferences gested that (1) parasympathetic dener1. Randall WC, Priola DV, Ulmer RHG. A vation induced by the ablation of the RA functional study of the distribution of fat pad largely exceeds the region of the cardiac sympathetic nerves. Am JPhysiol sinus node, and (2) the RA fat pad con1963'205' 1227—1231 tains parasympathetic axons from the 2. GeisWP, Kaye MP, Randall WC. Major right vagal nerve that terminate in both autonomic pathways to the atria and S-A and A-V nodes of the canine heart. Am J atria and also contains elements from the Physiol 1973;224:202-208. left vagal nerve that distribute only to 3. Stuesse SL, Wallick DW, Levy MN. Autothe RA, as the LA receives parasympanomic control of right atrial contractile thetic axons directly from the left vagus. strength in the dog. Am JPhysiol 1979;236: In another group of studies, the interaH860-H865. 4. Lazzara R, Scherlag BJ, Robinson MJ, trial septum was mapped using an inflatSamet P. Selective in situ parasympaable balloon electrode array.32'33 These thetic control of the canine sinoatrial and studies demonstrated that the atrial atrioventricular nodes. Circ Res 1973;32: septum is richly innervated by parasym393-401. pathetic efferent pathways coursing near 5. Randall WC, Ardell JL, Calderwood D, et al. Parasympathetic ganglia innervating the the superior vena cava and via the RA canine atrioventricular nodal region. J ganglionated plexus. Tissues near the Autonom Nerv Syst 1986;16:311-323. pulmonary artery or inferior vena cava 6. Randall WC, Ardell JL, Wurster RD, do not appear to play a significant role in Miloslavljevic M. Vagal postganglionic septal innervation. innervation of the canine sinoatrial node. JAuton Nerv Syst 1987;20:13-23. Integral changes identified in the pre7. Gagliardi M, Randall WC, Bieger D, et al. sent study are consistent with heterogeActivity of in vivo canine cardiac plexus neous modifications of repolarization. The neurons. Am JPhysiol 1988;255(4 Pt 2): nonuniform distribution of atrial refracH789-H800. tory period shortening is a well-known 8. Butler CK, Smith FM, Cardinal R, et al. Cardiac responses to electrical stimulaeffect of vagal stimulation.13'14 Using tion of discrete loci in canine atrial and refractory period determinations by the ventricular ganglionated plexi. Am J extrastimulus technique, Zipes et al.14 Physiol 1990;259(5 Pt 2):H1365-H1373. have shown that right vagal stimulation 9. Ardell JL, Randall WC. Selective vagal elicits greater effects in the RA than the innervation of sinoatrial and atrioventricular nodes in canine hearts. Am J LA and that shortening of atrial refracPhysiol 1986;251(4 Pt 2):H764-H773. tory periods is more pronounced during 10. Randall WC, Ardell JL. Selective parasymright than left vagal stimulation. The prepathectomy of automatic and conductile sent study not only supported these findtissues of the canine heart. Am J Physiol ings but also provided information depict1985;248(2 Pt 2):H61-H68. ing the complexity of atrial parasympa- 11. Randall WC, Wurster RD, Duff M, et al. Surgical interruption of postganglionic thetic innervation. Furthermore, the coninnervation of the sinoatrial nodal region. cept of integral distribution mapping JThorac Cardiovasc Surg 1991;101:66-74. based on multiple-site simultaneous record- 12. Mick JD, Wurster RD, Duff M, et al. ings appears to be feasible in humans Epicardial sites for vagal mediation of sinoatrial function. Am JPhysiol 1992;262 during cardiac surgical procedures. This (5 Pt 2):H1401-H1406. new concept opens the way to further 13. Alessi R, Nusynowitz M, Abildskov JA, investigate the functional anatomy of the Moe GK. Nonuniform distribution of vagal cardiac autonomic nervous system in effects on the atrial refractory period. Am humans. JPhysiol 1958;194:406-410.

EFFERENT AUTONOMIC INNERVATION OF THE ATRIUM 14. Zipes DP, Mihalik MJ, Robbins GT. Effects of selective vagal and stellate ganglion stimulation on atrial refractoriness. Cardiovasc Res 1974;8:647-655. 15. Abildskov JA, Evans AK, Lux RL, Burgess MJ. Ventricular recovery properties and the QRST deflection area in cardiac electrograms. Am JPhysiol 1980;239:H227-H231. 16. Millar CK, Kralios FA, Lux RL. Correlation between refractory periods and activationrecovery intervals from electrograms: Effects of rate and adrenergic interventions. Circulation 1985;72:1372-1379. 17. Savard P, Cardinal R, Nadeau RA, Armour JA. Epicardial distribution of ST segment and T wave changes produced by stimulation of intrathoracic ganglia or cardiopulmonary nerves in dogs. JAuton Nerv Syst 1991;34:47-58. 18. Page PL, Dandan N, Savard P, et al. Regional distribution of atrial electrical changes induced by stimulation of extracardiac and intracardiac neural elements. J Thorac Cardiovasc Surg 1995;109:377-388. 19. Frame LH, Page RL, Hoffman BF. Atrial reentry around an anatomic barrier with a partially refractory excitable gap. Circ Res 1986;58:495-511. 20. Derakhchan K, Page P, Lambert C, Kus T. Effects of procainamide and propafenone on the composition of the excitable gap in canine atrial reentry tachycardia. J Pharmacol Exp Ther 1994;270:47-54. 21. Dandan N, Do Q-B, Page P, Cardinal R. The right atrial Y-shaped incision model of atrial flutter affects parasympathetic innervation of the reentry pathway: Assessment by integral distribution mapping. Pacing Clin Electrophysiol 1996; 19 (Pt II): 705. 22. Cox JL, Schuessler RB, DAgostino HJ Jr, et al. The surgical treatment of atrial fibrillation. III. Development of a definitive surgical procedure. J Thorac Cardiovasc Surg 1991;101:569-583. 23. Do Q-B, Page P, Dandan N, Cardinal R. Maze procedure against atrial fibrillation abolishes atrial parasympathetic efferents. Cardiostim '96. Nice, France: June

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19-22, 1996. Eur J Card Pacing Electrophysiol 1996;6(Suppl 5):21. 24. Do Q-B, Page P, Dandan N, Cardinal R. The Maze III procedure for surgical treatment of atrial fibrillation abolishes parasympathetic influences on the atrium. Pacing Clin Electrophysiol 1996;9(Pt II): 628. 25. Do QB, Page P, Dandan N, Cardinal R. Effects of Maze III procedure on atrial parasympathetic innervation. Can J Cardiol 1996;12(Suppl E):145E. 26. Do QB, Page PL, Dandan N, Cardinal R. Influence of the Maze III procedure on atrial autonomic innervation: Assessment by repolarization mapping. Circulation 1996;94(Suppl I):I493-I494. 27. Page P, Corriveau MM, Cardinal R. Atrial parasympathetic innervation in the human: Assessment by intraoperative epicardial isointegral mapping. Can J Cardiol 1998;14(Suppl F):101F. 28. Carlson MD, Geha A, Hsu J, et al. Selective stimulation of parasympathetic nerve fibers to the human sinoatrial node. Circulation 1992;85:1311-1317. 29. Furakawa Y, Narita M, Takei M, et al. Differential intracardiac sympathetic and parasympathetic innervation to the SA and AV nodes in anesthetized dog hearts. Jpn JPharmacol 1991;55:381-390. 30. Wallick DW, Martin PJ. Separate parasympathetic control of the heart rate and atrioventricular conduction of dogs. Am J Physiol 1990;259:H536-H542. 31. Do QB, Page P, Dandan N, Cardinal R. Effect of intrapericardial dissections on atrial innervation: Assessment by integral distribution mapping. Can J Cardiol 1995;ll(Suppl E):95E. 32. Do QB, Page P, Dandan N, Cardinal R. Autonomic innervation of the atrial septum: Assessment by integral mapping. Can J Cardiol 1996;12(Suppl E):112E. 33. Do QB, Dandan N, Cardinal R, Page P. Etude de 1'innervation autonomique du septum interauriculaire par cartographic isointegrale chez le chien. Ann Chir 1996; 50:659-666.

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Chapter 18

Mapping of Atrial Flutter Wolfgang Schoels, MD and Nabil El-Sherif, MD

It is now very well accepted that typical atrial flutter results from single-loop reentry around a large combined functional-anatomical obstacle consisting of the circumference of both caval veins and an arc of functional conduction block in between.1'2 The rim of atrial tissue bounded by the inferior vena cava and the adjacent atrioventricular (AV) ring constitutes a crucial part of the reentrant circuit, since any obstacle within this isthmus linking both boundaries will inevitably stop the circulating wavefront. Accordingly, "isthmus ablation" has now become the treatment of choice for recurrent typical atrial flutter.3"5 It might therefore appear that there is no need for further mapping studies of this particular arrhythmia. There are still, however, several unsettled issues regarding the pathophysiology of typical and atypical atrial flutter that are of relevance for the development of future preventive therapeutic strategies and the selection of current treatment options. This relates, for example, to the nature of functional conduction block in general, to the electrophysiological properties of the intercaval region as a preferential site for extensive

conduction block, to the question on hemodynamic-electrophysiological interactions, and to the value of surface EGG characteristics for the prediction of epicardial activation patterns during atrial flutter. Standard electrophysiological mapping techniques were used to analyze activation and refractory patterns in dogs with right atrial (RA) enlargement,6 to specifically determine conduction properties and gradients of refractoriness within the intercaval region in normal canine hearts, to assess the effects of acute RA pressure load on atrial repolarization, and to correlate surface EGG characteristics and epicardial activation maps in dogs with sterile pericarditis and inducible sustained atrial flutter.7 We used a custom-designed electrode array for simultaneous recording of 127 bipolar epicardial electrograms (interpolar distance 1 to 2 mm, interelectrode distance 3 to 8 mm) from the in situ canine heart. A high-density patch-electrode (10 x 10 bipoles, interelectrode distance 1.5 mm) allowed for more detailed analysis of activation and refractory patterns in the intercaval region. Data were stored and

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003. 373

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analyzed on a 256-channel computerized multiplexer mapping system. Details of the model preparation, the recording techniques, and the methods for constructing isochronal maps have been described elsewhere.1 Activation and Refractory Patterns in the RA Enlargement Model As in the sterile pericarditis model, atrial flutter in the RA enlargement model generally results from single-loop reentry around combined functional-anatomical obstacles.8 In response to a premature stimulus, an arc of functional conduction block occurs. With an isolated short arc of block, the stimulated wavefront proceeds around both of its ends. The 2 wavelets then collide on the distal side of the arc. For either wavelet, the pathway includes the distance from the site of stimulation to the respective end of the arc and then half of its length distally. Based on the length of this pathway and the conduction velocity within atrial tissue, one might calculate the conduction time required to reach the site of collision. For reentry to occur, this conduction time must exceed the refractory period of the tissue on the proximal side of the arc. Obviously, conduction and repolarization characteristics of the atria imply rather long pathways and, thus, rather long arcs of functional conduction block. Two aspects of the normal atrial anatomy seem to facilitate reentry. The atrial vessels and, especially, the caval veins introduce large discontinuities, which might combine with arcs of block to form large functionalanatomical obstacles. Furthermore, the atrial surface area is relatively small, being electrically isolated from the ventricles by the AV ring. If one end of an arc of block occurring in response to a premature stimulus reaches the AV ring,

bidirectional activation of the tissue on the distal side of this arc is no longer possible. Instead, only one stimulated wavefront might proceed around the free end of the arc, reaching the distal AV ring connection as the last site to be activated. This sudden increase in the length of the effective pathway seems to facilitate reentry, possibly explaining why most reentrant circuits underlying typical and atypical atrial flutter reveal some spatial relationship to the AV ring. Although there is some temporal dispersion of refractoriness even in normal hearts, the transition of areas with relatively long refractory periods, typically located below the superior vena cava and in the lateral RA wall, and areas with shorter refractoriness, predominantly found in the left atrium (LA), is gradual for most of the epicardial surface. Only a few small areas exhibit local gradients of refractoriness reaching 20 ms or more. In response to premature atrial stimulation, short arcs of functional conduction block tend to coincide with respective areas (Figure 1). In enlarged atria, the temporal dispersion of refractoriness is not much different. However, the refractory pattern appears to be much more inhomogeneous, with areas of short and long refractoriness being commonly located next to each other. This spatiotemporal dispersion of refractoriness seems to underlie the occurrence of regional conduction block, since there is generally a compelling correlation between the location of these arcs of block and the isochrones of refractoriness (Figure 2). At individual sites, a lack of correlation might indicate that anisotropic conduction properties are also of some relevance. Thus, our interpretation would be that the long arcs of functional conduction block seen during atrial flutter are primarily based on local inhomogeneities in repolarization with anisotropic conduction properties serving as a modifying factor.

MAPPING OF ATRIAL FLUTTER

375

Figure 1. Epicardial refractory map (left panel) and endocardia! activation map during premature atrial stimulation (right panel) in a normal dog. The site of stimulation is indicated by E. Here and in all subsequent figures in this chapter, the epicardial atrial surface is displayed as a planar projection of a posterior view. The atria are separated from the ventricles along the atrioventricular ring, the atrial appendages are incised inferiorly and unfolded. The refractory map shows a gradual transition from areas of short refractoriness to areas with longer refractoriness. Only at a few sites, local gradients in refractoriness of 20 ms occur. During S2 stimulation, short arcs of functional conduction block (the heavy solid lines) occur at those very sites.

Figure 2. Epicardial refractory map (left panel) and endocardial activation map during premature atrial stimulation (right panel) in a dog with right atrial enlargement. The refractory pattern appears to be much more complex, with local gradients in refractoriness occurring at several sites and over a considerable distance. With S2 stimulation, long arcs of functional conduction block in the activation map coincide with respective isorefractory lines in the refractory map.

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sists mainly of the pectinate muscles and a thin overlying epicardial muscle layer. The pectinates run more or less perpenThe fact that typical atrial flutter is dicular to the intercaval axis before they so uniform in cycle length and ECG mor- reach the crista terminalis. Within the phology from patient to patient and from free RA wall, apparent conduction velocepisode to episode already suggests some ities reach 1.5 ± 0.5 m/s in the direction involvement of well-defined anatomical perpendicular and 0.5 ± 0.2 m/s in the structures. The finding of a common cen- direction parallel to the intercaval axis. tral obstacle consisting of the circumfer- While this could explain anisotropic conence of both caval veins and a long arc of duction block perpendicular to the interfunctional conduction block in between caval axis, one would then have to expect fits very well with this expectation. Still, this type of block anywhere within the one might wonder why the intercaval free RA wall. It seems, however, tempting region is so obviously prone to functional to speculate that the directional changes conduction block. Theoretically, the local in fiber orientation supposedly occurring tissue could be particularly sensitive to any at the junction of the pectinate muscles type of pathology associated with atrial with the crista terminalis increase the likeflutter. It would, however, seem more likely lihood for anisotropic conduction block. that the normal anatomy provides a phys- Obviously, this hypothesis must be subiological basis for the occurrence of con- stantiated by future studies. duction block. The intercaval region, as RA Pressure and Local described by epicardial activation maps, Refractory Patterns roughly coincides with the location of the crista terminalis seen endocardially. This Clinically, an increase in LA or RA compact strand of atrial muscle fibers runs parallel to the intercaval axis. pressure, as seen, for example, with mitral Accordingly, the crista terminalis exhibits valve stenosis, pulmonary embolism, or marked anisotropic conduction proper- hypertension, is frequently associated ties, with fast, longitudinal conduction with atrial tachyarrhythmias.10 Once iniparallel and slow, transverse conduction tiated, atrial tachyarrhythmias also cause perpendicular to the intercaval axis. an increase in atrial pressure, and this Thus, conduction block across the crista might in turn facilitate their perpetuaterminalis could not be easily explained tion, provided there is some sort of hemoon the basis of current concepts on dynamic/electrophy siological interaction. In normal dogs, hemodynamically tolanisotropy, claiming faster conduction but a reduced safety factor for impulse erated acute banding of the pulmonary propagation along the long axis, and artery results in a slight but significant slower conduction but a higher safety increase in mean RA pressure in the range factor for impulse propagation along the of 2 to 4 mm Hg. At the same time, atrial short axis of myocardial muscle fibers.9 flutter and particularly atrial fibrillaHigh-density refractory patterns in tion might easily be induced. The overall normal dogs, on the other hand, also do activation pattern remains unchanged. not reveal any systemic decrease or Accordingly, total RA or LA activation increase in local refractoriness within the time is also unaffected. There is, however, intercaval region (Figure 3). This also a significant decrease in mean RA refracrelates to the free RA wall, which con- toriness (from 129 ± 17 ms to 119 ± 16 ms), Electrophysiological Properties of the Intercaval Region

MAPPING OF ATRIAL FLUTTER

377

Figure 3. Local refractory periods across the intercaval axis in normal dogs. A systemic decrease or increase in local refractoriness is not evident; the maximum gradient in refractoriness is 30 ms.

which is not evident in the LA (110 ± 18 versus 114 ± 21 ms). Even within the RA, the changes in local refractoriness reveal regional inhomogeneities, so that the refractory pattern appears to be more irregular and discontinuous with elevated pressure. Unhanding and consecutive restitution of baseline hemodynamic conditions also results in restitution of baseline refractory patterns. Thus, hemodynamic changes seem to be of relevance for local electrophysiological properties, potentially leading to an increase in the dispersion of refractoriness. It is not clear at the moment whether this reflects direct hemodynamic-electrophysiological coupling or an indirect effect based on autonomic counter-regulation. The fact

that increased RA pressure affects RA but not LA refractory patterns would favor a direct interaction. Characteristics of the Surface EGG and Epicardial Activation Patterns Comparable to the clinical situation, the electrocardiographic manifestation of experimental atrial flutter in both the canine sterile pericarditis model and the RA enlargement model is characterized by either undulating F waves without isoelectric intervals ("typical" atrial flutter) or by discrete P waves separated by

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isoelectric intervals (" atypical" atrial flut- circuits in P wave atrial flutter, the ter).11 Undulating F waves suggesting requirement of a revolution time exceedcontinuous atrial activation are very well ing the longest refractory period within compatible with a reentrant activation the circuit might only be fulfilled by a pattern. Discrete P waves with interven- reduction in conduction velocity. Typiing, seemingly isoelectric, intervals, on cally, this is achieved through a marked the other hand, would rather suggest a area of very slow conduction, with normal focal mechanism. When comparing epi- conduction in the remainder of the reencardial activation maps and surface ECG trant pathway. Propagation of the reencharacteristics during sustained atrial trant wavefront within the area of slow flutter, it becomes quite evident that F conduction results in activation of very wave atrial flutter is almost invariably little tissue per 10-ms interval, and thus associated with single-loop reentrant acti- the electromotive force is not sufficient to vation around the combined functional- be depicted by the surface ECG. Accordanatomical obstacle mentioned above. The ingly, conduction time within the area of polarity of the F waves in the inferior slow conduction corresponds to the isoleads (II, III, and aVF) is determined by electric interval between subsequent P the direction of rotation, with a cranio- waves, whereas the P wave duration caudal activation of the LA resulting in reflects the activation time of atrial tissue positive F waves and a caudocranial acti- outside the slow zone. vation in negative F waves (Figure 4). P wave atrial flutter might actually reflect Clinical Implications a focal activation pattern with rapid activation of the epicardial atrial surface and The uniform activation pattern of an interval of electrical silence preceding subsequent activations. However, P wave typical atrial flutter has already led to atrial flutter might also be associated with the development of ablative strategies reentrant activation, the underlying reen- that can be easily applied without extentrant circuits being variable in size and sive mapping procedures. The relevance location from dog to dog (Figure 5). P wave of refractory patterns for the occurrence reentrant circuits are typically relatively of functional conduction block not only small. A possible explanation for the strik- forms the basis for pharmacological intering difference in the electrocardiographic ventions, but should also encourage preappearance of reentrant P wave atrial ventive pacing strategies that modify the flutter and F wave atrial flutter emerges sequence of activation and repolarization. when comparing the amount of atrial Even though anisotropy rather than distissue being activated during each 10-ms persion of refractoriness seems to conisochronal interval of respective circus tribute to the preferential occurrence of movements. With the large reentrant cir- conduction block along the intercaval cuits in F wave atrial flutter, the circu- axis, premature activation of the tissue on lating impulse spreads at a relatively fast, either side of this arc, potentially through more or less uniform conduction velocity. septal stimulation, might prevent reenA marked area of slow conduction is not try. Since hemodynamic-physiological evident. Thus, at any given time during interactions seem to be of relevance for each cycle, a relatively large amount of the initiation and perpetuation of atrial atrial tissue is being activated, accounting tachyarrhythmias, interventions aiming for some undulation of the baseline on the at a reduction in atrial pressure should be insurface ECG. For the smaller reentrant corporated more vigorously into therapeutic

MAPPING OF ATRIAL FLUTTER

379

Isochronal Intervals (10 msec)

Figure 4. A. Electrocardiographic leads II, III, and aVF together with an atrial electrogram during sustained atrial flutter in a dog with typical F waves. The epicardial activation map illustrates the activation sequence for one tachycardia cycle. B. Number of electrode sites activated during each 10-ms isochronal interval of 4 consecutive tachycardia cycles. Note that for most 10-ms intervals of each cycle, at least 5 electrode sites are being activated. This accounts for the continuous undulations of the baseline on the surface EGG.

and preventive strategies. The surface EGG characteristics of typical and atypical atrial flutter are already used as a guide to anatomically guided or mappingguided ablative interventions. A more

detailed analysis of the P wave morphology in atypical atrial flutter may help to direct therapeutic approaches for this particular arrhythmia prior to any invasive evaluation.

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Figure 5. A. Electrocardiograph^ leads II, III, and aVF together with an atrial electrogram during sustained atrial flutter in a dog with typical P waves. The epicardial activation map illustrates the activation sequence for one tachycardia cycle. B. Number of electrode sites activated during each 10-ms isochronal interval of 4 consecutive tachycardia cycles. For more than 50% of each cycle, less than 5 electrode sites are being activated per 10-ms isochronal interval, due to propagation of the circulating wavefront within the area of slow conduction. This corresponds to the seemingly isoelectric interval between P waves on the surface ECG.

MAPPING OF ATRIAL FLUTTER

References 1. Cosio FG, Arribas F, Palacios J, et al. Fragmented electrograms and continuous electrical activity in atrial flutter. Am J Cardiol 1986;57:1309-1314. 2. Scheols W, Gough WB, Restivo M, et al. Circus movement atrial flutter in the canine sterile pericarditis model. Activation patterns during initiation, termination, and sustained reentry in vivo. Circ Res 1990;67:35-50. 3. Saoudi N, Atallah G, Kirkorian G, et al. Catheter ablation of the atrial myocardium in human type I atrial flutter. Circulation 1990;81:762-771. 4. Cosio FG, Lopez-Gil M, Goicolea A, et al. Radiofrequency modification of the critical isthmus in atrial flutter. Eur Heart J1991;21:369. 5. Feld FK, Fleck P, Chen PS, et al. Radiofrequency catheter ablation for the treatment of human type 1 atrial flutter. Identification of a critical zone in the reentrant circuit by endocardial mapping techniques. Circulation 1992;86:12331240. 6. Boyden PA, Hoffman BF. The effects on atrial electrophysiology and structure of surgically induced right atrial enlarge-

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ment in dogs. Circ Res 1981;49:13191331. 7. Page PL, Plumb VJ, Okumura K, et al. A new animal model of atrial flutter. J Am Coll Cardiol 1986;8:872-879. 8. Schoels W, Kiibler W, Yang H, et al. A unified functional/anatomic substrate for circus movement atrial flutter: Activation and refractory patterns in the right atrial enlargement model. J Am Coll Cardiol 1993;21:73-84. 9. Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle: A model of reentry based on anisotropic discontinuous propagation. Circ Res 1988;62:811-832. 10. Henry WL, Morganroth J, Pearlman AS, et al. Relation between echocardiographically determined left atrial size and atrial fibrillation. Circulation 1976; 53:273-279. 11. Schoels W, Offner B, Brachmann J, et al. Circus movement atrial flutter in the canine sterile pericarditis model. Relation of characteristics of the surface electrocardiogram and conduction properties of the reentrant pathway. J Am Coll Cardiol 1994;23:799-808.

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Chapter 19

Mapping of Normal and Arrhythmogenic Activation of the Rabbit Atrioventricular Node Jacques Billette, MD, PhD, Jun Wang, MD, PhD, Karim Khalife, BSc, and Li-Jen Lin, MD

Introduction

may help understand its circuitry.7"12 This chapter briefly summarizes current knowledge of nodal function and the contribution of different mapping techniques to its understanding.

The slow conduction and filtering properties of the atrioventricular (AV) node largely control the ventricular response during supraventricular tachyarrhythmias. Despite this strategic role and Rate-Dependent Nodal abundant study, underlying mechanisms Functional Properties remain debated. Among the questions are the exact intranodal origin of nodal delay The activation of the AV node varies and its rate-dependent variations, the nature of compact node conduction, sub- widely with the underlying functional strate of nodal dual pathway physiology conditions, and the understanding of its and reentry, and the role of nodal inputs physiology is essential for an accurate in nodal function. New optical technology interpretation of mapping results. The may help resolve these issues, but further following is a summary of its basic and development will be needed to achieve rate-dependent function. The AV node cell-level resolution in AV nodal mapping conduction time (AH interval = atrial-His such as achieved in cultured cells.1"6 interval) accounts for nearly 50% of the Other recent developments in surface PR interval and provides time for the potential recording have also improved atrial contraction to contribute to venaccess to critical intranodal events that tricular filling. The AV node also filters Supported by the Medical Research Council of Canada, the Heart and Stroke Foundation of Quebec, and the Fonds de la recherche en sante du Quebec. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003. 383

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impulses during supraventricular tachyarrhythmias to achieve a ventricular rate compatible with effective pumping. Resulting AH intervals vary widely and form different patterns of response. A typical example is the response to a constant fast atrial rate. At the beginning of the fast rate the AH interval is prolonged, but each atrial beat is conducted to His bundle (1:1 nodal conduction). However, the AH interval increases further with fast rate duration until Wenckebach cycles develop. During these cycles, the AH interval increases from beat to beat until an atrial beat is blocked and resets the process. Different A:H ratios may then be observed. The most intricate case of nodal filtering occurs during atrial fibrillation that results in a highly irregular ventricular response characterized by a nearly random distribution of RR intervals (ventricular cycle lengths [CLs]). The main factors involved in these rateinduced AV nodal responses and blocks were recognized early.13 They are now described as 3 functional rules, known as recovery, facilitation, and fatigue, which can be independently characterized with specifically designed premature protocols (Figure 1A) and represented with recovery curves (Figure 1B).14~17 As the transitional, compact node, posterior extension, and lower bundle tissues are important determinants of the AH interval, they are all considered parts of the AV node.8"10'18"20 This functional definition of the AV node is also best suited for correlation between clinical and experimental data. The recovery property reflects the nonlinear increase in AH interval with increasing prematurity (Figure IB). It can be independently characterized with a premature protocol performed at a slow basic rate (Figure 1A). Its contribution to AH interval, however, is the same at any basic rate.21 This contribution is similar during nodal slow and fast pathway conduction.22 The facilitation property can

be selectively characterized by the introduction of a short cycle before the premature test cycle during a slow basic rate (Figure 1A). The resulting curve is tilted down and left with respect to the control curve in the short coupling interval range (Figure IB); premature AH intervals are shorter and nodal block occurs at a shorter recovery time under facilitation. Facilitation develops after one beat of a fast rate, remains unchanged during a constant fast rate, and dissipates after one long cycle.23 For a given recovery time and level of facilitation, the AH interval increases progressively with the duration of a fast rate, a change that is attributed to fatigue.13'21-24'25 Fatigue can be selectively characterized by overdriving the atrium for 5 minutes to reach a steady state, and then introducing a facilitationdissipating long cycle (L) and a premature cycle (Figure 1A).25 The resulting curve is bodily shifted upward with respect to the control curve (Figure IB). The fatigue induction and dissipation can also be selectively characterized from changes in AH interval observed during a fast rate imposed with a constant Hisstimulus interval and ensuing return to the control rate. The combined facilitation and fatigue effects present during a fast rate can also be determined by simply omitting the facilitation-dissipating long cycle from the fatigue protocol (Figure 1A). While identical to the fatigue curve in long coupling interval range, the combined effect curve is tilted to the left in short coupling interval range (Figure IB). This tilting may result in a crossing with the control curve; beyond the crossing point, AH intervals are shorter (faster conduction) during the fast rate than at control (Figure IB). This occurs because the nevertheless present fatigue is then overcome by greater facilitation. The 3 nodal properties persist after autonomic blockade26 and can also be demonstrated while controlling the interstimulus interval

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Figure 1. Characterization of nodal functional properties with premature stimulation protocols (A) and resulting recovery curves (B) in a rabbit heart preparation. The control recovery protocol shows the last of a series of 20 long cycles (L, slightly shorter than spontaneous cycle length) followed by a premature cycle (P). The selective facilitation protocol differs from the control one only by a facilitationinducing short cycle (SC) introduced between the long and premature cycle. The steady-state selective fatigue protocol shows the last of a series of 20 short cycles followed by one facilitation-dissipating long cycle and a premature cycle. Testing of premature cycles is started after 5 minutes of short cycles. The combined effects of facilitation and fatigue produced by a fast rate are obtained by repeating the fatigue protocol while omitting the facilitation-dissipating long cycle. All stimuli are imposed with controlled HS intervals. S2 identifies the test premature beat. For simplicity, all other beats are marked Si regardless of protocol and cycle length. B. The 4 recovery curves obtained when plotting the premature nodal conduction time (A2H2 interval) against the corresponding recovery time (H^ interval).

in a standard fashion.27'28 The beat-tobeat variations in the contribution of recovery, facilitation, and fatigue to the AH interval have been shown to account for Wenckebach cycles, response to incremental pacing, hysteresis, alternans, and retrograde conduction.29"35 Autonomic

modulations and drug effects can also be explained in this context.36"38 A much debated issue is whether the PP or RP (AA or HA in our context) should be used to assess the nodal recovery time.13-39"44 For a given protocol, the shape of the recovery curve, i.e., nodal recovery

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pattern, is identical when the AH intervals are plotted against the preceding atrial or His-atrial interval.41 However, the difference between recovery curves obtained in different conditions varies markedly with the chosen recovery parameter, which, by definition, does not affect nodal function (same nodal responses in the 2 formats). Our data indeed suggest that the 2 formats similarly reflect nodal function. Their difference arises entirely from changes in the AH interval of the last beat that affects the nodal recovery time preceding a premature beat and invalidates the assumption that similar AA reflects similar nodal recovery time. One particular data point of the recovery curve corresponds to the nodal functional refractory period or minimum interval reached between 2 consecutive His bundle activations. This parameter is important because it reflects the capacity of the node to impose a minimum ventricular CL during supraventricular tachyarrhythmias. The functional refractory period was found to vary predictably under the influence of facilitation and fatigue.45 The interaction between these properties during a fast rate can result in shortening, prolongation, or no change in the functional refractory period depending upon the duration of the fast rate. The functional refractory period also controls the minimum RR interval during atrial fibrillation.46'47 However, the beat-to-beat variations in the contribution of nodal properties to the gross irregularity of the ventricular response observed during atrial fibrillation remain to be established. In summary, the nodal properties of recovery, facilitation, and fatigue can be individually characterized and their contribution to rate-induced responses can be established with specifically designed stimulation protocols. Consistent characterization of nodal function can be obtained with different recovery measures.

Nodal Inputs, Dual Pathway Physiology, and Reentry The AV node frequently generates echo beats and reentrant rhythms. These phenomena are unanimously attributed to the presence of a slow and a fast AV nodal pathway the substrate of which remains debated. The authors of 5 chapters addressing this question in a recent book proposed a number of mechanisms. The functional asymmetry underlying dual pathways was postulated to arise from (1) different properties of crista terminalis and interatrial septum input48; (2) different properties of the inputs with their compact node prolongation49; (3) 2 posterior input limbs connecting through the proximal compact node and a fast conducting anterior input11; 4) a slow posterior input and anterior shortcut track bypassing or only traveling through a portion of the compact node49; 5) a slow and fast portion in dissociated compact node and perhaps some nearby transitional cells50; and 6) different properties of compact node and its posterior extension.17 Further investigation will likely be required in order to sort out these hypotheses. The current thoughts are strongly influenced by the fact that the slow or fast pathway can be altered by crista terminalis or interatrial septum input ablation, respectively.51"55 Because such lesions leave the compact node intact, the asymmetry seems to arise within inputs. However, no differences in local input conduction and refractory properties have been found that could account for dual pathways.7'56"62 Optical dye mapping has not revealed the existence of an independent input-based fast pathway either.1 Diverging results have also been reported.63'64 No specific anatomical input features have been identified in patients suffering from AV nodal reentrant tachycardia.65 The possibility of multiple nodal inputs has also been reported.11'66'67 There is

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Figure 2. Atrioventricular node landmarks and structures of the recently proposed reentrant circuit.8"10 For practical purposes, orientation is relative to a horizontal septal baseline rather than to the real intrathoracic position. S = superior; I = inferior; P = posterior; A = anterior; DA = upper atrium; CT = crista terminalis; IAS = interatrial septum; HIS = His bundle; TT = tendon of Todaro; TV = tricuspid valve; CS = coronary sinus; TC = transitional cell zone; CN = compact node; LNC = lower nodal cell bundle; PNE = posterior extension of AVN.

equally convincing evidence that the compact node plays a determinant role in the reentrant circuit.50'68"70 In our recently proposed model (Figure 2), slow pathway and fast pathway correspond to the posterior extension and compact node, respectively.8"10'71 Perinodal and lower nodal tissues provide a common proximal and distal pathway, respectively. During very early premature beats, the impulse is blocked at the perinodal compact node junction but can nevertheless reach the His bundle by means of posterior extension propagation. The resulting long delay allows for recovery of transitional tissues, which may then support reentry. The reentrant retrograde perinodal activation may break at different positions of the junction between compact node and transitional tissues and, whatever its breakthrough point, always forms a broad perinodal wavefront.9 These studies also show that the conventional

nodal structures impose the functional refractory period while the posterior extension accounts for the nodal effective refractory period.9'10 The slow pathway and the fast pathway can be selectively interrupted with discrete lesions of the posterior extension and transitional compact node junction, respectively.10'71 Despite their neighborhood, connection, and overlap near the tricuspid annulus, anatomical and functional properties of the posterior extension and input differ markedly. The posterior input is made of rapid transitional cells that cover the region from tricuspid annulus to tendon of Todaro and establish a broad contact with working atrial myocardium.19'72 Its activation time covers 25% of the AH interval and is largely independent of CL.7~10 The posterior extension is a small bundle of compact-node-like tissues.8'73 Along the AV axis at a position just posterior to the compact node, the posterior

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extension measures approximately 600 um. It progressively decreases to about 100 um along its 2.5-mm length.8 This thin structure (<120 um) lies just above, and is confined near, the tricuspid annulus. It does not establish contact with working myocardium. Typical slow cycle-length-dependent transmembrane and surface potentials can be recorded from it.8 Its activation covers a large fraction of the AH interval. The extension is consistently present in the human heart and varies with age.73'74 It remains unknown, however, whether the extension has a similar functional role in humans and rabbits. Further studies will obviously be needed to assess quantitatively the functional properties and roles of the 2 pathways, their pharmacological modulation, and their involvement in AV nodal reentrant tachycardia.

Microelectrode and Surface Mapping of AV Node Activation Early studies based on recordings of extracellular potentials from the AV node yielded signals of highly variable amplitude, shape, timing, and frequencyresponse.75"82 Although dissimilarities in techniques, preparations, and species probably contributed to these differences, the anatomical complexity and overlapping structures of the AV node have further complicated the sorting out of these potentials. Moreover, the small number of recordings did not support a rigorous mapping of the activation. Despite these limitations, early studies recognized the presence of a zone of nodal delay during which no potential can be recorded. The question of whether this gap represents absence of activity or very low amplitude activity could not be resolved. Another consistent finding was the decrease in the amplitude of the nodal potential with increasing rate. The first exhaustive extracellular mapping study of AV nodal antegrade

and retrograde conduction was performed in dog and rabbit hearts (Figure 3).81 An important observation was that the atrial pacing site affects the progression of activation at the nodal entrance. Another was that input wavefronts corresponding anatomically to the low crista terminalis and interatrial septum merge into one wavefront to activate the compact node. The study also showed that there is a smooth transition between atrial and AV node activity, and that the position of this boundary between the atrium and AV node changes between antegrade and retrograde conduction. In the retrograde direction, the impulse activates the low interatrial septum before the crista terminalis, while these 2 inputs are activated together during antegrade conduction (Figure 3). During sinus rhythm in humans, the activation of anterior septal input occurred first83; however, the activation pattern of the 2 inputs did not differ between the slow and the fast pathway. The retrograde fast pathway exit occurred through a broad wavefront preferentially located in the anterior portion of Koch's triangle, but occasionally involved the posterior input or entire triangle. The slow pathway exit was found to be posterior near the coronary sinus ostium 15 mm from the His bundle. Janse's group has studied extensively the spread of activation through AV nodal cells with a multiple microelectrode probe in rabbit heart preparations.18'19'68'84-86 Figure 4A illustrates cell activation times (expressed as a percentage of total nodal activation time) obtained during antegrade conduction.19 The activation times show that the node receives an input wavefront from the interatrial septum and another from the low crista terminalis beneath the coronary sinus. These inputs, which correspond to transitional cells, merge into a single wavefront impinging on the central node. The progression of activation in and around

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Figure 3. Functional 3-dimensional model of antegrade and retrograde excitation of the atrioventricular (AV) node region. The direction of excitation through atrium, AV node, and His bundle from puppy data is indicated with arrows. The width of atrial arrows is roughly proportional to conduction velocity. Atrial arrows overlap the AV node and His bundle. Reproduced from reference 81, with permission.

the compact node, where conduction is slowest, remains only partly understood. Although the 3 classic functional types of nodal cells (atrionodal [AN], nodal [N], and nodo-His [NH]) are all found in the compact node area, the complex interweaving and overlapping of tissues have so far prevented a rigorous correlation between cell type, position, and function.1^20'24'84'87-91 For instance, although N action potentials clearly originate in the central part of the node, it is uncertain whether this is from midnodal cells per se, from circumferential transitional cells, or from both. As stated by Meijler

and Janse,85 most "typical" nodal action potentials have not yet been linked to most "typical" nodal cells. Isochrone-based mapping of compact node activation may in fact be impossible. Records of premature transmembrane action potentials indeed show that conduction across this part of the node is electrotonic and results in a gap of upstrokes between latest N cells and earliest NH cells (Figure 5).20'91 The electrotonic current, though small and decreasing in amplitude with increasing prematurity, slowly depolarizes NH cells toward their threshold. The time to reach threshold increases with prematurity

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Figure 4. Maps of the atrioventricular (AV) nodal area indicating the spread of activation during antegrade (A) and retrograde (B) conduction. The moments of activation are expressed as a percent of total conduction time from the atrium to His bundle (A) and His bundle to atrium (B). For moments of activation of the atrium, the spike of the surface electrogram recorded from an electrode high on the crista terminalis not shown on this figure was taken. The insets are diagrams showing the disposition of the morphologically distinct cell types derived from the spatial reconstruction of the specimen. CS = coronary sinus; CT = crista terminalis; IAS = interatrial septum; His - position of electrode on His bundle; TC = transitional cells; MNC = midnodal cells; LNC = lower nodal cells. Reproduced from reference 19, with permission.

and largely accounts for the cycle-lengthdependent increase in the AH interval. Resulting action potentials from NH cells propagate toward the His bundle and are reflected back as a second passive component of action potentials recorded from the compact node. The occurrence of a nodal block markedly reduces the second component without affecting the first.91

During this electrotonic activation, subthreshold depolarization is initiated simultaneously in all cells, no upstroke can be recorded, and, thus, a silent zone appears on isochrone maps (Figure 6). Another characteristic of overall nodal activation is the absence of substantial changes in activation pattern with increasing delay.91 The isochrones reflecting the progression

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Figure 5. Progressive prematurity-dependent dissociation of action potentials in N cells. Superimposed recordings were obtained from 9 different cells, one at a time within a 30-minute period in one rabbit heart preparation while the same premature protocol was continuously repeated. Illustrated responses correspond 4 S-,S2 intervals (360,200,160, and 130 ms). Potentials are presented in reference to premature interatrial septum activation (A2, vertical dotted line). Note the increasing dissociation of action potentials into 2 components with increasing prematurity. The timing of the onset of the first component coincides in different N cells while its amplitude decreases monotonically from cells ^ to N5. This is best seen at S1S2 160 and 130 ms. The decreasing amplitude and rate of rise of first component result in a progressive increase in NH cell activation time. The second component also coincides closely in time in different N cells but, in contrast to first component, its amplitude decreases monotonically from N5 to N1 Note the time relationship between the upstroke in NH cells and beginning of second component. Reproduced from reference 16, with permission.

of the impulse within AN and NH cells remain largely unchanged in a basic beat compared with a premature beat (Figure 6). Only the time at which any given section of the node is activated increases with increasing AH interval. Thus, changes in nodal delay alone do not change the nodal activation pattern. A recent report based on dye mapping data obtained during different fast rates also indicates that the rate does not affect the nodal activation pattern. 2 Conversely, another recent study reports substantial changes in perinodal activation pattern with a prematurity-dependent shift from fast to slow pathway conduction.5 Conversely to that observed in the compact node area,

microelectrode and surface recordings from the posterior extension yielded upstrokes and, thus, activation times that increased progressively with distance and prematurity.8 No silent zone was observed in the posterior extension. The above considerations suggest that the control-recovery curve is a complex composite. The transitional and lower nodal cells contribute in a largely cycle-length-independent manner to all AH intervals. At intermediate and long coupling intervals, the impulse travels through the compact node in a cyclelength-dependent manner.8,10 At short coupling intervals, the posterior extension takes over the conduction also in a

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Figure 6. Activation pattern of atrioventricular node during basic beat (upper map) and fourth beat (lower map) of an accelerating train in a rabbit heart preparation. Each chopped line corresponds to an isochrone. The central surrounded dark area corresponds to a zone from which N cells were recorded. Activation pattern is grossly similar in the 2 beats despite a difference in nodal delay (70 ms versus 100 ms). Reproduced from reference 91, with permission.

cycle-length-dependent manner. When using criteria based on action potential morphology and activation times obtained during a complete cycle of premature stimulation, the mean activation time of the proximal node including N cells accounts for 11 ms of a 48-ms mean basic AH interval.20 The NH-H conduction also accounts for 11 ms of this delay. Mean NH activation occurred at 37 ms and thus 26 ms after N cell activation; however, this difference between mean values overestimates the N-NH unexcitable gap. When approximated from latest N and earliest NH recorded in any given experiment, the mean N-NH delay was smaller (18 ms) at basic CL.

The contribution of the central node to the delay increases with prematurity.20'91 The intranodal origin of facilitation and fatigue remains to be precisely defined. Facilitation is compatible with action potential shortening observed in the distal node20 but has also been attributed to prolonged CL in proximal node following a facilitating beat.43,44 Fatigue has been attributed to a depressed recovery of excitability of N cells24 but the exact contribution of the different cell groups to fatigue remains unclear. Further studies are needed to improve our understanding of the intranodal origin of these properties.

ELECTRICAL ACTIVATION OF AV NODE Recent developments in nodal surface recordings from known structures may help to elicit the intranodal origin of nodal responses.7-12 With surface recordings taken from distal transitional tissues, we showed that pacing site, input interaction, and summation affect the activation pattern of transitional tissues but do not alter nodal recovery, facilitation, and fatigue properties.7 As mentioned above, surface recording from the posterior extension of the compact node also provides evidence that this structure plays a key role in slow pathway physiology and reentry. Figure 7 shows typical local activation curves constructed from simultaneously obtained surface recordings during a premature protocol. They are superimposed

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together with control curve (His). The local transitional curve (T) is typically flat and thus CL independent. The 2 curves from the posterior extension (PNE1 and PNE2) show different degrees of CL dependence. The one obtained from most anterior position (PNE2) shows a biphasic relationship to His bundle curve, first diverging and then converging with His curve at progressively shorter coupling intervals. Note that block occurs at the same coupling interval in PNE and His bundle. The local activation of the lower node (LN) precedes the His bundle activation by a nearly constant interval. Thus, surface recordings allow for stable simultaneous sensing of different critical events controlling intranodal activation. Stable sensing of

Figure 7. Prematurity-dependent changes in local intranodal activation time as measured from surface recordings in a rabbit heart preparation. All activation times were measured from crista terminalis. T = transitional; PNE = posterior nodal extension; 1 and 2 = 2 recording positions along the extension; LN = lower nodal cell curve; HIS = conventional nodal recovery curve constructed from His bundle activation times.

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compact node events will require further development. During retrograde propagation (Figure 4B), activation of the central part of the node is largely the inverse of antegrade conduction; however, the activation of the low interatrial septum occurs systematically earlier than that of the crista terminalis during retrograde conduction. Comparison of antegrade and retrograde conduction also allows for the identification of the so-called dead-end pathway.18 Some of these pathways were later reported to be part of the posterior extension of the lower nodal cell tract, which is in continuity with the His bundle.19 In our opinion, the posterior extension could act as a deadend pathway and/or a slow pathway. 8 Dead-end pathways were also observed in the anterior overlay transitional cells. Optical Mapping of the AV Node Several studies1-5 have now applied dye mapping technology to characterize AV nodal activation in the rabbit and dog heart. Efimov et al.1 first reported optical signals from the AV nodal region. Their records indicated that during sinus rhythm the impulse preferentially enters the AV node through the posterior input and activates the septal input in a retrograde fashion (Figure 8). These investigators proposed that this posterior dominance would not prevent fast pathway activation through circumferential transitional cells. A well-defined slow signal, presumably from the compact node, was illustrated. Further study of AV nodal activation by the same group led to the confirmation that nodal activation occurs through a multilayer conduction pattern.3 This report provides a number of examples of double hump potentials; the first component was attributed to transitional cell activation and the second component to distal nodal activation, as assessed from microelectrode recordings.

Some optical signals were obtained over the compact node area. However, the exact anatomical origin of the action potentials and optical signals was not factually established. Another paper published slightly earlier also provides evidence for multiple peak potentials and multilayer activation from the AV node area.2 The optical signal recorded from the AV node area had 3 components. The first component and last component were attributed to atrial and ventricular activation, respectively. The second component was small, located between the other 2, and attributed to compact node activation. A delay of 30 to 40 ms was observed between latest AN and earliest activation of midnodal activation signal. This gap was attributed to a conduction barrier between the atrium and compact node. However, no definition of AN and N cells was provided, nor was their exact location factually established. This gap cannot be easily reconciled with evidence from microelectrode recordings documenting a continuum of AN cell activation times from the nodal entrance to the detection of the N cell potentials.18'20-91 The optical activation gap could therefore represent a detection failure or be the result of functional interference. Another possibility is that after cell definition adjustments, the optical gap would in fact correspond to the N-NH cell gap observed in the compact node area in microelectrode studies.20'91 If this was the case, the largely electrotonic nature of the propagation during this gap would not support the construction of isochronal maps. The isochrone maps of compact node activation reported by Choi and Salama2 are thus at variance with the possibility of an electrotonic gap in compact node activation. The reason for this discrepancy remains unclear. Recent developments have allowed the detailed dye mapping of the AV nodal reentrant circuit during echo beats in the rabbit and dog heart.4'5

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Figure 8. Optical action potentials recorded from the atrioventricular nodal area of a rabbit heart. The 256 action potentials were recorded simultaneously at a sampling rate of 2 kHz per channel. Each signal represents the integral optical activity of an area of 430 x 430 (im. The "dead" space between neighboring diodes was 66 |im. Signals were normalized to the same amplitude. SAN = sinoatrial node; CrT = crista terminalis; CS = coronary sinus; TT = tendon of Todaro; AVN = atrioventricular nodal region; His = bundle of His. Modified from reference 1, with permission.

In agreement with observations made from surface recordings,8 isochrone maps by Wu et al.5 showed that the transition from fast to slow pathway conduction during a premature protocol occurs when a block develops at the entrance of the compact node while slow pathway conduction remains possible through posterior extension. During echo beats, the activation retrogradely reentered through

the compact node and fast pathway to exit at the anterior portion of the node. During His bundle pacing, the activation could exit either anteriorly or posteriorly from the node.4 Posterior activation pattern was compatible with a posterior extension exit. These fascinating studies begin a new era of investigations that will greatly help understand AV nodal activation and function. Further technological

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some of the microelectrode-based mapping limitations. First, the number of cells that can be recorded from with microelectrodes in any given stable functional condition is limited. These records rarely constitute a representative cell sample, a problem aggravated by cell diversity and complex 3-dimensional topography. Spontaneous drifts or manipulation-induced Limitations of AV Nodal Mapping modulations in nodal function may further complicate this problem. These difThe mapping of a complex 3-dimen- ficulties can be minimized by increasing sional structure such as the ventricles has the number of electrodes, multiplying required elaborate transmural record- the number of recording sites, and repings.92 This problem is aggravated in the resenting cell activation time as a perAV node by an even greater anatomical centage of total activation time.18 This complexity at a microscopic scale and by approach has a reduced discriminating the presence of different interweaving and capacity as compared to records simuloverlapping cell types. Only the endocar- taneously obtained from multiple sites, dial surface of the node is accessible for which can be more easily achieved with extracellular recording; its septal side is extracellular electrodes as compared to covered with dense fibrous tissue, and microelectrodes. Furthermore, because intranodal implantation of extracellular the depth of the microelectrode tip electrodes perturbs nodal function. These within nodal tissues cannot be rigorously difficulties limit the significance of data controlled, the third dimension is unknown obtained from extracellular 2-dimensional or at best qualitatively estimated, so nodal mapping. Other intrinsic limitations that only 2-dimensional maps can be of isochronal cardiac mapping techniques reliably constructed. For this reason, van are also present, if not accentuated, in Capelle et al.18 did not use isochrones to nodal mapping.93 Moreover, it is difficult to represent wavefront progression in the identify in the typically small potentials node. Another difficulty concerns viabilrecorded from the node the implications ity of the superfused, isolated rabbit of factors such as the small dimension of heart preparation, which has become the the slow source, distance from the source, standard for microelectrode mapping. and complex overlapping and interaction There is histological evidence that this of minute sources. Atrial repolarization preparation may suffer from hypoxia.94 waves can also overlap these slow nodal In our recent studies, the average basal AH interval has consistently varied depolarization potentials. While it is quite clear that there is around 50 ms, a substantially shorter an upstroke gap between N and NH cell value than those reported by various activation,20'91 it remains unclear whether investigators. Moreover, control experithis gap corresponds, and if so to what ments performed in rabbit preparations degree, to the silent zone observed with have yielded basal AH intervals that surface recordings.75"81 If this turns out varied by less than 1 or 2 ms over 4 hours to be the case, surface recordings will (unpublished observations). We have not provide a unique tool to reliably sense yet verified whether this improved elecmidnodal activation during dynamic trophysiological performance and stability nodal responses. This may help overcome is paralleled by an improved histological developments will, however, be necessary before it becomes possible to establish 3dimensional maps of AV nodal activation, particularly in the compact node zone in the different typical conditions used to establish rate-dependent and dual-pathway properties.

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slowly activated structures. The formal demonstration of a relationship between extracellular potentials and activation times of N and NH cells would greatly facilitate the interpretation of extracellular recordings and validate their use on a larger scale. This would then constitute an alternative to the difficult microelectrode studies in the determination of the AV nodal activation pattern. Future of AV Nodal Mapping Practical tools such as subthreshold A number of questions deserve a mapping99"101 and ice mapping102'103 used particular attention. The complete map- to target some specific nodal structures ping of the reentrant circuit during will have to be further developed and single echo beats and reentrant tachy- understood. The small dimension of cardia will be necessary to establish microwave ablation lesions may help in their substrate. Another area in which this respect.104 Finally and hopefully, information is greatly needed concerns molecular probes that will enable the the activation of the compact node; selective modulation of nodal substructures "what is the exact activation pattern and and "subfunctions" must be developed. In mechanism of the compact node?" is a fun- conclusion, despite their important limidamental question that must answered tations, mapping approaches have greatly with refined precise combined anatomi- contributed to current understanding of cal and functional studies. This applies AV nodal function, but giant steps still to basic activation time but also to the stand ahead in the sorting out of this numerous rate-dependent modulations puzzle. of the conduction such as those observed during Wenckebach cycles and atrial fibrillation. The changes in nodal activation References associated with changes in functional state, such as those resulting from facil1. Efimov IR, Fahy GJ, Cheng Y, et al. itation, fatigue, autonomic tone, drug High-resolution fluorescent imaging does not reveal a distinct atrioventricular effects, and arrhythmias, also largely nodal anterior input channel (fast pathremain to be determined. The functional way) in the rabbit heart during sinus origin of species-related variations of the rhythm. J Cardiovasc Electrophysiol 1997; mammalian PR interval is also far from 8:295-306. being determined.95'96 A better under2. Choi BR, Salama G. Optical mapping of atrioventricular node reveals a conducstanding of AV nodal activation would tion barrier between atrial and nodal require a detailed sensing of individual cells. Am J Physiol 1998;274(3 Pt 2):H829cell activation similar to that achieved in H845. cultured strands of myocardium in 3. Efimov IR, Mazgalev TN. High-resolution, recent breakthrough studies on myocarthree-dimensional fluorescent imaging dial activation mechanisms.97'98 Unforreveals multilayer conduction pattern in the atrioventricular node. Circulation tunately, current technology does not 1998;98:54-57. support such an application to the AV 4. Nikolski V, Efimov IR. Fluorescent imagnode. Meanwhile, one can improve probing of a dual-pathway atrioventricularing tools to better sense extracellular nodal conduction system. Circ Res 2001;88: weak fields generated by these small, E23-E30. integrity. The reasons why previous studies measured longer basal AH intervals are not certain. Some of these differences can probably be explained by perfusion rate, pH values, PO2, bath design, speed of dissection, tissue stretch, and electrode location.

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5. Wu J, Olgin J, Miller JM, et al. Mechanisms underlying the reentrant circuit of atrioventricular nodal reentrant tachycardia in isolated canine atrioventricular nodal preparation using optical mapping. Circ Res 2001;88:1189-1195. 6. Kleber AG, Janse MJ, Fast VG. Normal and abnormal conduction in the heart. In: Page E, Fozzard HA, Solaro J (eds): Handbook of Physiology; Section 2 The Cardiovascular System, Volume 1: The Heart. New York: Oxford University Press; 2001:455-530. 7. Amellal F, Billette J. Selective functional properties of dual atrioventricular nodal inputs. Role in nodal conduction, refractoriness, summation, and rate-dependent function in rabbit heart. Circulation 1996; 94:824-832. 8. Medkour D, Becker AE, Khalife K, et al. Anatomic and functional characteristics of a slow posterior AV nodal pathway: Role in dual-pathway physiology and reentry. Circulation 1998;98:164-174. 9. Lin LJ, Billette J, Khalife K, et al. Characteristics, circuit, mechanism and ablation of reentry in the rabbit atrioventricular node. J Cardiovasc Electrophysiol 1999; 10:954— 964. 10. Khalife K, Billette J, Medkour D, et al. Role of the compact node and its posterior extension in normal atrioventricular nodal conduction, refractory, and dual pathway properties. J Cardiovasc Electrophysiol 1999;10:1439-1451. 11. Patterson E, Scherlag BJ. Longitudinal dissociation within the posterior AV nodal input of the rabbit: A substrate for AV nodal reentry. Circulation 1999;99: 143-155. 12. Mazgalev TN, Tchou P. Surface potentials from the region of the atrioventricular node and their relation to dual pathway electrophysiology. Circulation 2000;101:2110-2117. 13. Lewis T, Master AM. Observations upon conduction in the mammalian heart. AV conduction. Heart 1925; 12:209-269. 14. Billette J, Giles WR. Electrophysiology of the atrioventricular node: Conduction, refractoriness, and ionic current. In: Dangman KH, Miura DS (eds): Electrophysiology and Pharmacology of the Heart: A Clinical Guide. New York: Marcel Dekker, Inc.; 1991:141-160. 15. Billette J, Nattel S. Dynamic behavior of the atrioventricular node: A functional

model of interaction between recovery, facilitation, and fatigue. J Cardiovasc Electrophysiol 1994;5:90-102. 16. Billette J, Shrier A. Atrioventricular nodal activation and functional properties. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: W.B. Saunders; 1995:216228. 17. Billette J, Amellal F. Functional properties of the AV node: Characterization and role in cardiac rhythms. In: Mazgalev TN, Tchou PJ (eds): Atrial-AV Nodal Electrophysiology: A View from the Millennium. Armonk, NY: Futura Publishing Co.; 2000:155-173. 18. van Capelle FJL, Janse MJ, Varghese PJ, et al. Spread of excitation in the atrioventricular node of isolated rabbit hearts studied by multiple microelectrode recording. Circ Res 1972;31:602-616. 19. Anderson RH, Janse MJ, van Capelle FJL, et al. A combined morphological and electrophysiological study of the atrioventricular node of the rabbit heart. Circ Res 1974;35:909-922. 20. Billette J. Atrioventricular nodal activation during periodic premature stimulation of the atrium. Am J Physiol 1987;252:H163-H177. 21. Ferrier GR, Dresel PE. Relationship of the functional refractory period to conduction in the atrioventricular node. Circ Res 1974;35:204-214. 22. Young ML, Kuo CT, Kohli V, et al. Similar time-dependent recovery property of fast and slow atrioventricular nodal pathways. Am J Cardiol 1997;79:424430. 23. Billette J. Short time constant for ratedependent changes of atrioventricular conduction in dogs. Am J Physiol 1981; 241:H26-H33. 24. Merideth J, Mendez C, Mueller WJ, et al. Electrical excitability of atrioventricular nodal cells. Circ Res 1968;23:69-85. 25. Billette J, Metayer R, St-Vincent M. Selective functional characteristics of rate-induced fatigue in rabbit atrioventricular node. Circ Res 1988;62:790-799. 26. Gendreau R, Billette J, Zhao J, et al. Intrinsic origin of atrioventricular nodal functional properties in rabbits. Can J Physiol Pharmacol 1989;67:722-727. 27. Shrier A, Dubarsky H, Rosengarten M, et al. Prediction of complex atrioventricular conduction rhythms in humans

ELECTRICAL ACTIVATION OF AV NODE with use of the atrioventricular nodal recovery curve. Circulation 1987;76:11961205. 28. Talajic M, Papadatos D, Villemaire C, et al. A unified model of atrioventricular nodal conduction predicts dynamic changes in Wenckebach periodicity. Circ Res 1991;68:1280-1293. 29. Zhao J, Billette J. Beat-to-beat changes in AV nodal refractory and recovery properties during Wenckebach cycles. Am J Physiol 1992;262:H1899-H1907. 30. O'Hara G, Gendreau R, Billette J, et al. Rate-dependent functional properties of retrograde atrioventricular nodal conduction in experimental animals. Am J Physiol 1993;265:H1257-H1264. 31. Billette J, Zhao J, Shrier A. Mechanisms of conduction time hysteresis in rabbit atrioventricular node. Am J Physiol 1995;269:H1258-H1267. 32. Zhao J, Billette J. Characteristics and mechanisms of the effects of heart rate history on transient AV nodal responses. Am J Physiol 1996;270:H2070-H2080. 33. Amellal F, Hall K, Glass L, et al. Alternation of atrioventricular nodal conduction time during atrioventricular reentrant tachycardia: Are dual pathways necessary? J Cardiouasc Electrophysiol 1996; 7:943-951. 34. Hall K, Christini DJ, Tremblay M, et al. Dynamic control of cardiac alternans. Phys Rev Let 1997;78:4518-4521. 35. Christini DJ, Stein KM, Markowitz SM, et al. Complex AV nodal dynamics during ventricular-triggered atrial pacing in humans. Am J Physiol 2001;281:H865H872. 36. Nayebpour M, Talajic M, Villemaire C, et al. Vagal modulation of the rate-dependent properties of the atrioventricular node. Circ Res 1990;67:1152-1166. 37. Nayebpour M, Talajic M, Nattel S. Effects of beta-adrenergic receptor stimulation and blockade on rate-dependent atrioventricular nodal properties. Circ Res 1992;70:902-911. 38. Nayebpour M, Billette J, Amellal F, et al. Effects of adenosine on rate-dependent atrioventricular nodal function. Potential roles in tachycardia termination and physiological regulation. Circulation 1993;88:2632-2645. 39. Billette J. Preceding His-atrial interval as a determinant of atrioventricular nodal conduction time in the human and

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rabbit heart. Am J Cardiol 1976;38:889896. 40. Lehmann MH, Steinman RT, Meissner MD, et al. Quantitating AV nodal function: Has A1A2 outlived its usefulness? Pacing Clin Electrophysiol 1990; 13:16741677. 41. Billette J, Amellal F, Zhao J, et al. Relationship between different recovery curves representing rate-dependent AV nodal function in rabbit heart. J Cardiovasc Electrophysiol 1994;5:63-75. 42. Moe GK, Childers RW, Merideth J. An appraisal of "supernormal" A-V conduction. Circulation 1968;38:5-28. 43. Fahy GJ, Efimov I, Cheng Y, et al. Mechanism of atrioventricular nodal facilitation in the rabbit heart: Role of the distal AV node. Am J Physiol 1997;272:H2815H2825. 44. Mazgalev T, Mowrey K, Efimov I, et al. Mechanism of atrioventricular nodal facilitation in rabbit heart: Role of proximal AV node. Am J Physiol 1997;273: H1658-H1668. 45. Billette J, Metayer R. Origin, domain, and dynamics of rate-induced variations of functional refractory period in rabbit atrioventricular node. Circ Res 1989;65: 164-175. 46. Billette J, Nadeau RA, Roberge F. Relation between the minimum RR interval during atrial fibrillation and the functional refractory period of the AV junction. Cardiouasc Res 1974;8:347— 351. 47. Asano Y, Saito J, Yamamoto T, et al. Electrophysiologic determinants of ventricular rate in human atrial fibrillation. J Cardiovasc Electrophysiol 1995;6:343349. 48. McGuire MA. What is the slow AV nodal pathway? In: Mazgalev TN, Tchou PJ (eds): Atrial-AV Nodal Electrophysiology: A View from the Millennium. Armonk, NY: Futura Publishing Co.; 2000:183197. 49. Mazgalev TN, Tchou PJ. The AV nodal dual pathway electrophysiology: Still a controversial concept. In: Mazgalev TN, Tchou PJ (eds): Atrial-AV Nodal Electrophysiology: A View from the Millennium. Armonk, NY: Futura Publishing Co.; 2000:217-236. 50. Janse MJ, Loh P, de Bakker JMT. Is the atrium involved in AV nodal reentry? In: Mazgalev TN, Tchou PJ (eds): Atrial-AV

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Nodal Electrophysiology: A View from the Millennium. Armonk, NY: Futura Publishing Co.; 2000:175-182. 51. Haissaguerre M, Gaita F, Fischer B, et al. Elimination of atrioventricular nodal reentrant tachycardia using discrete slow potentials to guide application of radiofrequency energy. Circulation 1992; 85:2162-2175. 52. Haissaguerre M, Warin JF, Lemetayer P, et al. Closed-chest ablation of retrograde conduction in patients with atrioventricular nodal reentrant tachycardia. NEngl JMed 1989;320:426-433. 53. Jackman WM, Beckman KJ, McClelland JH, et al. Treatment of supraventricular tachycardia due to atrioventricular nodal reentry, by radiofrequency catheter ablation of slow-pathway conduction. N EnglJMed 1992;327:313-318. 54. Jazayeri MR, Hempe SL, Sra JS, et al. Selective transcatheter ablation of the fast and slow pathways using radiofrequency energy in patients with atrioventricular nodal reentrant tachycardia. Circulation 1992;85:1318-1328. 55. Mitrani RD, Klein LS, Hackett FK, et al. Radiofrequency ablation for atrioventricular node reentrant tachycardia: Comparison between fast (anterior) and slow (posterior) pathway ablation. JAm Coll Cardiol 1993;21:432-441. 56. Amat y leon F, Denes P, Wu D, et al. Effects of atrial pacing site on atrial and atrioventricular nodal function. Br Heart Jl975;37:576-582. 57. Aranda J, Castellanos A, Moleiro F, et al. Effects of the pacing site on A-H conduction and refractoriness in patients with short P-R intervals. Circulation 1976;53:33-39. 58. Batsford WP, Akhtar M, Caracta AR, et al. Effect of atrial stimulation site on the electrophysiological properties of the atrioventricular node in man. Circulation 1974;50:283-292. 59. Ross DL, Brugada P, Bar FW, et al. Comparison of right and left atrial stimulation in demonstration of dual atrioventricular nodal pathways and induction of intranodal reentry. Circulation 1981;64: 1051-1058. 60. Yamada S, Watanabe Y. Does A-H interval accurately represent intranodal conduction time during ectopic rhythms? J Electrocardiol 1985;18:331-339.

61. Sanchis J, Chorro FJ, Such L, et al. Effect of site, summation and asynchronism of inputs on atrioventricular nodal conduction and refractoriness. Ear Heart J1993;14:1421-1426. 62. Amellal F, Billette J. Effects of atrial pacing site on rate-dependent AV nodal function in rabbit hearts. Am J Physiol 1995;269:H934-H942. 63. Tchou PJ, Cheng YN, Mowrey K, et al. Relation of the atrial input sites to the dual atrioventricular nodal pathways: Crossing of conduction curves generated with posterior and anterior pacing. J Cardiovasc Electrophysiol 1997;8:1133-1144. 64. Stein KM, Lerman BB. Evidence for functionally distinct dual atrial inputs to the human AV node. Am J Physiol 1994;267:H2333-H2341. 65. Ho SY, McComb JM, Scott CD, et al. Morphology of the cardiac conduction system in patients with electrophysiologically proven dual atrioventricular nodal pathways. J Cardiovasc Electrophysiol 1993;4:504-512. 66. Hirao K, Scherlag BJ, Poty H, et al. Electrophysiology of the atrio-AV nodal inputs and exits in the normal dog heart: Radiofrequency ablation using an epicardial approach. J Cardiovasc Electrophysiol 1997;8:904-915. 67. Antz M, Scherlag BJ, Otomo K, et al. Evidence for multiple atrio-AV nodal inputs in the normal dog heart. J Cardiovasc Electrophysiol 1998;9:395-408. 68. Janse MJ, Capelle FJ, Freud GE, et al. Circus movement within the AV node as a basis for supraventricular tachycardia as shown by multiple microelectrode recording in the isolated rabbit heart. CircRes 1971;28:403-414. 69. Loh P, deBakker JMT, Hocini M, et al. Reentrant pathway during ventricular echoes is confined to the atrioventricular node: High-resolution mapping and dissection of the triangle of Koch in isolated, perfused canine hearts. Circulation 1999;100:1346-1353. 70. Josephson ME, Miller JM. Atrioventricular nodal reentry: Evidence supporting an intranodal location. Pacing Clin Electrophysiol 1993; 16:599-614. 71. Lin LJ, Billette J, Medkour D, et al. Properties and substrate of slow pathway exposed with a compact node targeted fast pathway ablation in rabbit

ELECTRICAL ACTIVATION OF AV NODE atrioventricular node. J Cardiovasc Electrophysiol 2001;12:479-486. 72. Racker DK, Kadish AH. Proximal atrioventricular bundle, atrioventricular node, and distal atrioventricular bundle are distinct anatomic structures with unique histological characteristics and innervation. Circulation 2000;101:10491059. 73. Inoue S, Becker AE. Posterior extensions of the human compact atrioventricular node: A neglected anatomic feature of potential clinical significance. Circulation 1998;97:188-193. 74. Waki K, Kim JS, Becker AE. Morphology of the human atrioventricular node is age dependent: A feature of potential clinical significance. J Cardiovasc Electrophysiol 2000;11:1144-1151. 75. van der Kooi MW, Durrer D, van Dam RT, et al. Electrical activity in sinus node and atrioventricular node. Am Heart J 1956;51:684-700. 76. Alanis J, Mandoki JJ, Pilar G. The functional discontinuities of the atrioventricular node. Acta Physiol Lat Am 1960; 10:96-103. 77. Scher AM, Rodriguez MI, Liikane J, et al. The mechanism of atrioventricular conduction. Circ Res 1959;7:54-61. 78. Pruitt RD, Essex HE. Potential changes attending the excitation process in the atrioventricular conduction system of bovine and canine hearts. Circ Res 1960;8:149-174. 79. Giraud G, Puech P, Latour H. L'activite electrique physiologique du noeud de Tawara et du faisceau de His chez rhomme. Acad Nat Med 1960;17:363366. 80. Damato AN, Lau SH, Berkowitz WD, et al. Recording of specialized conducting fibers (A-V nodal, His bundle, and right bundle branch) in man using an electrode catheter technique. Circulation 1969;39:435-447. 81. Spach MS, Lieberman M, Scott JG, et al. Excitation sequences of the atrial septum and the AV node in isolated hearts of the dog and rabbit. Circ Res 1971;29:156-172. 82. Scherlag BJ, Berbari EJ, Lazarra R. In vivo recordings of A-V nodal potentials: A review. In: Hombach V, Hilger HH (eds): Signal Averaging Technique in Clinical Cardiology. Stuttgart-New York: Schattauer Verlag; 1981:109-119.

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83. McGuire MA, Bourke JP, Robotin MC, et al. High resolution mapping of Koch's triangle using sixty electrodes in humans with atrioventricular junctional (AV nodal) reentrant tachycardia. Circulation 1993;88:2315-2328. 84. Janse MJ, van Capelle FJL, Anderson RH, et al. Electrophysiology and structure of the atrioventricular node of the isolated rabbit heart. In: Wellens HJJ, Lie KI, Janse MJ (eds): The Conduction System of the Heart. Leiden, The Netherlands: Stenfert Kroese; 1976:296-315. 85. Meijler FL, Janse MJ. Morphology and electrophysiology of the mammalian atrioventricular node. Physiol Rev 1988;68: 608-647. 86. Janse MJ. Influence of the direction of the atrial wave front on A-V nodal transmission in isolated hearts of rabbits. Circ Res 1969;25:439-449. 87. Paes de Carvalho A, de Almeida DF. Spread of activity through the atrioventricular node. Circ Res 1960;8:801-809. 88. Hoffman BF, Cranefield PF. Electrophysiology of the Heart. New York: McGraw-Hill Book Co.; 1960:132-174. 89. Sherf L, James TN, Woods WT. Function of the atrioventricular node considered on the basis of observed histology and fine structure. J Am Coll Cardiol 1985;5:770-780. 90. Mendez C, Moe GK. Some characteristics of transmembrane potentials of AV nodal cells during propagation of premature beats. Circ Res 1966;19:933-1010. 91. Billette J, Janse MJ, van Capelle FJ, et al. Cycle-length-dependent properties of AV nodal activation in rabbit hearts. Am J Physiol 1976;231:1129-1139. 92. Durrer D, van Dam RT, Freud GE, et al. Total excitation of the isolated human heart. Circulation 1970;41:899-912. 93. Ideker RE, Smith WM, Blanchard SM, et al. The assumptions of isochronal cardiac mapping. Pacing Clin Electrophysiol 1989; 12:456-478. 94. Janse MJ, Tranum-Jensen J, Kleber AG, et al. Techniques and problems in correlating cellular electrophysiology and morphology in cardiac nodal tissues. In: Bonke FIM (ed): The Sinus Node, Structure, Function and Clinical Relevance. The Hague: Martinus Nijhoff; 1978:183-194. 95. van der Tweel LH, Strackee J, Stokhof AA, et al. EGG of the "newborn" mouse

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(Mus domesticus) with specific reference to comparative AV transmission. J Cardiovasc Electrophysiol 1999;10:168— 173. 96. Billette J. Functional origin of mammalian PR interval variations, a challenge for the 21st century. J Cardiovasc Electrophysiol 1999;10:174-177. 97. Rohr S, Kucera JP, Kleber AG. Slow conduction in cardiac tissue, I: Effects of a reduction of excitability versus a reduction of electrical coupling on microconduction. CircRes 1998;83:781-794. 98. Kucera JP, Kleber AG, Rohr S. Slow conduction in cardiac tissue, II: Effects of branching tissue geometry. Circ Res 1998;83:795-805. 99. Fromer M, Shenasa M. Ultrarapid subthreshold stimulation for termination of atrioventricular node reentrant tachycardia. J Am Coll Cardiol 1992;20:879883. 100. Shenasa M, Fromer M, Borggrefe M, et al. Subthreshold electrical stimulation for termination and prevention of reen-

trant tachycardias. JElectrocardiol 1992; 24:25-31. 101. Willems S, Weiss C, Shenasa M, et al. Optimized mapping of slow pathway ablation guided by subthreshold stimulation: a randomized prospective study in patients with recurrent atrioventricular nodal re-entrant tachycardia. J Am Coll Cardiol 2001;37:1645-1650. 102. Keim S, Werner P, Jazayeri M, et al. Localization of the fast and slow pathways in atrioventricular nodal reentrant tachycardia by intraoperative ice mapping. Circulation 1992;86:919-925. 103. Dubuc M, Khairy P, Rodriguez-Santiago A, et al. Catheter cryoablation of the atrioventricular node in patients with atrial fibrillation: A novel technology for ablation of cardiac arrhythmias. J Cardiovasc Electrophysiol 2001;12:439-444. 104. Liem LB, Mead RH, Shenasa M, et al. Microwave catheter ablation using a clinical prototype system with a lateral firing antenna design. Pacing Clin Electrophysiol 1998;21:714-721.

Chapter 20

Mapping of the AV Node in the Experimental Setting Peter Loh, MD, Jacques M. T. de Bakker, PhD, Meleze Hocini, MD, and MichielJ. Janse, MD

ior of the AV node is mainly limited to an indirect approach by evaluating the interIn normal hearts, the atrioventricular vals between atrial and His bundle acti(AV) node is the only electrical connection vation. Transmembrane action potentials between the atria and the specialized con- measured with microelectrode impalements duction system of the ventricles. The allowed access to the cellular electrophysirecent success of surgical and catheter ology of the specialized AV junction and 1 3 ablation techniques in the treatment of correlation with histology. " The limited AV nodal reentrant tachycardia (AVNRT) number of simultaneous impalements and has rekindled interest in AV nodal elec- the transient nature of impalements of trophysiology. Although the AV node has nodal cells, however, make it difficult to challenged clinical and experimental study the complex activation patterns in investigators since the beginning of the the AV junction. This chapter describes 3 experimen20th century, many of its functional and morphological aspects remain unclear. AV tal approaches to the electrophysiology of nodal activation is, by nature, slow and the AV nodal area: (1) Endocardial mapinvolves a relatively small number of his- ping of the AV node was performed during tologically specialized cells, concealed atrial stimulation to study anisotropic 4 deep within the atrial walls and covered conduction in the triangle of Koch. by fast-conducting atrial tissue. There- Nonuniform anisotropy has been sugfore, the low-amplitude, low-frequency AV gested as a mechanism for AV nodal nodal potentials cannot be easily depicted. reentry. (2) The retrograde atrial activaThe assessment of the functional behav- tion sequence in the triangle of Koch was Introduction

Part of the work referred to in this chapter was done during a Research Fellowship of the Deutsche Forschungsgemeinschaft (DFG; Bonn-Bad Godesberg, Germany, Grant No. 572/1-1) granted to Dr. Peter Loh. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003. 403

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mapped during ventricular echoes to study the reentrant circuit and to assess the role of the atrial tissue in AV nodal reentry.5 (3) Transmembrane action potentials exhibiting double components were studied with microelectrodes.6 Doublecomponent action potentials are often associated with activation delay and may reflect slow pathway conduction. Anatomical and Electrophysiological Characteristics of the AV Nodal Area The AV nodal area lies within the boundaries of the triangle of Koch, which is delineated superiorly by the tendon of Todaro, inferiorly by the tricuspid valve annulus, and at the base by the ostium of the coronary sinus. Tawara7 described the "atrioventricular connecting system" as a "relatively large, complicated network of muscular tissues immediately above the atrioventricular fibrocartilaginous septum. ...short bundles of muscle fibers, arranged more or less parallel to each other, posteriorly extend approximately to the front end of the coronary sinus, where they connect with the ordinary atrial muscle fibers.'" This area comprises basically 3 cell types that are arranged in a 3-dimensional lattice. Based on activation times and transmembrane action potential characteristics, these cells have been classified into atrionodal (AN), nodal (N) and nodoHis (NH).1 Correlation between cellular electrophysiology and histology showed that AN action potentials were generated by the transitional cells, separated from each other by connective tissue septa. The histological compact node is a half-oval structure of more solidly packed midnodal cells closely adherent to the central fibrous body.8 It seems important to note that Ntype action potentials were recorded not only from the midnodal cells, but also from transitional cells located more inferiorly, suggesting an overlap between histological and electrophysiological char-

acteristics of the cells.2 NH potentials were recorded from the distal part of the AV bundle. More recently, AN and N-type action potentials were also found around the mitral and tricuspid valve annuli.9 Lately, combined anatomical and electrophysiological studies focused on the inferior extension of the compact AV node and emphasized its possible role in slow pathway conduction.10"12 These complex anatomical and electrophysiological characteristics lead to semantic difficulties in delineating the AV node. Some authors only consider the compact AV node, described by Tawara as the 'Knotenpunkt' area,13 even though anatomical and electrophysiological studies suggest that the AV node comprises all the different cell types that determine its functional properties.14"16 Functional Aspects of the AV Node Normal functional behavior of the AV node includes conduction delay between atria and ventricles and block of impulses. The exact course of AV nodal excitation has not yet been clarified. It is, however, conceivable that AV nodal architecture as well as cellular morphology and electrophysiology contribute to the functional properties. Transitional cells form small, frequently branching strands separated by connective tissue septa. This network forms an ideal substrate for activation delay, summation, and longitudinal dissociation, which may all affect action potential configuration and, consequently, conduction through the AV node.16'17 On the cellular level, differences in cell electrophysiology such as Ca2+ dependency of the action potential upstroke in the N cells and probable Na+ dependency in the AN and NH cells, and cell coupling, influence conduction.18 Connexin43, a gap-junctional protein, is abundantly present in the atrial

MAPPING OF AV NODE IN THE EXPERIMENTAL SETTING and ventricular myocardium but is lacking in the AV node,9'19 suggesting weak cell coupling in this area. Tissue and cell electrophysiology find their expression in the morphology of the transmembrane action potential. Double-component action potentials are defined as action potentials that reveal a distinct change in the upstroke velocity, indicating electrotonic interaction between 2 cells. They point to asynchronous depolarization and reflect activation delay between adjacent sites. Double-component action potentials are also associated with discontinuities in cardiac structures and have been recorded at sites where mismatch exists between current demand and supply, that is isthmus sites20'21 or regions where activation fronts curve.22 Weak cell coupling or asynchronous arrival of activation fronts also give rise to double-component action potentials.23'24

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Spach and Josephson35 suggested that the transitional zone of the AV junctional area has marked nonuniform anisotropic conduction properties that could provide a mechanism for AV nodal reentry. Anisotropic conduction refers to differences in conduction velocity related to the direction of propagation relative to fiber orientation. Conduction velocity perpendicular to fiber direction is slow compared to the conduction velocity in the longitudinal direction. This difference in conduction velocity is adequately explained by differences in the electrical coupling between groups of fibers which are tighter in the longitudinal than in the transverse direction.36"39 Anisotropic conduction properties of cardiac muscle may be responsible for slow conduction and unidirectional conduction block that may allow reentry to occur.35'40 Methodology

Dual AV Nodal Physiology The prerequisites for AV nodal reentry are functional dissociation, unidirectional block, and slow conduction. The prevailing theory suggests that reentrant excitation involves 2 functionally distinct pathways in the AV nodal area: a superior "fast" pathway with a long refractory period, and an inferior "slow" pathway with a short refractory period. This concept of dual AV nodal physiology provides a basis for AV nodal reentry manifesting as atrial or ventricular echoes, as well as for sustained AVNRT. The precise location of the reentrant circuit and the participation of atrial tissue in the circuit are still debated.25"35 Histological and electrophysiological studies have never identified discrete or insulated tracts in the AV nodal area. This suggests that the so-called slow and fast pathways are not anatomically delineated but must be understood as functional properties of the AV node.

Measurements were performed in isolated, Langendorff-blood-perfused dog and pig hearts in accordance with the guiding principles of the American Physiological Society. The methods of preparation and perfusion of isolated hearts have been described in detail elsewhere.41 Briefly, following deep anesthesia, each heart was excised and the aortic root was cannulated to permit Langendorff perfusion with a 1:1 mixture of heparinized blood and modified Tyrode's solution. The right atrium was excised to allow exposure of the triangle of Koch. Interference from sinus rhythm during pacing was avoided by resection of the sinus node. Extracellular recordings were made simultaneously using multiterminal electrodes: (1) 84 unipolar terminals, arranged in a 12 x 7 matrix at interelectrode distances of 2.5 mm, and (2) 96 quasiunipolar terminals,42 arranged in a 12 x 8 matrix at interelectrode distances of 1 mm. Intracellular

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recordings were made with flexibly mounted microelectrodes. Diacetyl monoxime (10 to 15 mmol/L) was added to the perfusate to dampen contraction.41 To investigate the significance of the endocardial and subendocardial layers during ventricular echoes, these layers were chemically destroyed in 3 hearts using phenol (75%). Phenol, in this concentration, is reported to cause necrosis to a depth of approximately 300 urn.43 After the study, the hearts were preserved in 10% formaldehyde for histological analysis. Signal Processing and Analysis A customized data acquisition system allowed simultaneous recording at a sample frequency of 1 kHz/channel. Signals were amplified 256-fold and band-pass filtered with lower and upper cutoff frequencies of 0.1 Hz and 500 Hz, respectively. The dV/dt was calculated for each electrogram using a computer algorithm. The point of maximum negative dV/dt was selected as the time of local activation. The latter could be manipulated by the operator. In case of doubt, recordings from contiguous sites were taken into consideration to determine the activation times. Isochronal maps were constructed manually by connecting points with the same time of local activation. Anisotropic Conduction in the Triangle of Koch Does Not Reflect "Slow Pathway" Conduction Anatomical Examination After electrophysiological study, the endocardium was peeled off using watchmaker forceps to expose the fiber orientation in Koch's triangle. Serial histological

sections confirmed that these superficial fibers did not show histologically specialized characteristics and resembled ordinary atrial fibers. In the nodal region, they represented the atrial overlay fibers and varied from 10 to 30 cells deep. Figure 1A illustrates the fiber orientation in one of the pig hearts. Figure IB is a schematic drawing of the photograph of panel A, highlighting the main pattern of the fibers. The 4 dots and the dashed rectangle mark the position of the recording electrode. As illustrated in Figure IB, fibers in the posterior region (a) between the coronary sinus ostium and the tricuspid valve annulus ran parallel to the annulus. Toward the anterior region (b), the fibers turned off in the direction of the interatrial septum to proceed finally almost perpendicular to the annulus. Fibers in the far anterior region (c) were again more or less parallel to the tricuspid valve annulus and contacted the fibers arriving from the annulus under a sharp angle. In fact, the fibers from the anterior region subducted the fibers running perpendicular to the annulus.

Extracellular Electrograms and Isochronal Maps Figure 2 shows activation patterns and extracellular electrograms after stimulation from different sites. Activation maps were recorded with the electrode containing 96 quasiunipolar terminals. This electrode was designed to unveil low-frequency, low-amplitude signals in the AV nodal area. In panel A, after stimulation from the left margin of the recording area, isochronal lines were nearly perpendicular to the tricuspid valve annulus, compatible with activation parallel to the fiber direction. In the anterior part of the recording area, isochronal lines were slightly crowded, suggesting

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Figure 1. Top: Photograph of the junctional area of a porcine heart, showing the geometrical pattern of the myocardial fibers in and near the triangle of Koch. Bottom: Schematic drawing of the photograph, highlighting the main pattern of the fiber direction. CS = coronary sinus; OF = oval fossa; TVA = tricuspid valve annulus.

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Figure 2. Isochronal maps and electrogram morphology during stimulation from different sites along the margins of the recording electrode. A. Stimulation from the left margin of the recording area. B. Stimulation from the upper margin of the recording area. Numbers are activation times in ms, measured with regard to the stimulus. Isochronal lines are drawn every 2 ms. The position of the stimulation electrode is indicated by markers next to the maps. See text for discussion. CS = coronary sinus; TT = tendon of Todaro; TVA = tricuspid valve annulus.

reduced speed of conduction (0.25 m/s versus 0.5 m/s in the posterior area). The reason for the crowding may be the change of alignment of the fibers in the anterior part of the Koch's triangle. Electrograms recorded during activation parallel to the fiber direction show a biphasic deflection. The activation pattern changed dramatically when the site of stimulation was moved to locations along the upper margin of the recording electrode

(Figure 2B). A narrow and short zone of crowded isochrones appeared near the upper margin of the recording area. This zone was almost parallel to the annulus. Crowding of isochrones, suggesting a reduced conduction velocity, occurred because activation had to propagate perpendicular to the direction of the fibers in this area. The apparent speed of conduction in the area of crowded isochrones was as low as 0.08 m/s. In contrast to

MAPPING OF AV NODE IN THE EXPERIMENTAL SETTING conventional patterns of activation in areas where propagation proceeds perpendicular to the alignment of fibers, this zone of crowded isochrones was narrow. Close to the upper margin, activation ran rightward at an apparent speed of approximately 0.5 m/s. Near the right margin, activation followed the fiber direction, resulting in activation running toward the annulus. Before this activation front could move posteriorly, however, it collided with another front arriving from the posterior region. The latter front proceeded parallel to the annulus at a speed of approximately 0.5 m/s. As illustrated, electrograms recorded from the zone of slow conduction are highly fractionated.

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Atrial-His Interval During Baseline and After Premature Stimulation During baseline stimulation, the delay between earliest and latest activation within the recording area ranged from 21 to 33 ms, depending on the site of stimulation. Differences in the atrial-His (AH) interval ranged from 3 to 10 ms when the site of stimulation was changed. After premature stimulation at coupling intervals that just caused conduction toward His, delay between earliest and latest activation within the recording area increased by only 4 to 21 ms. In contrast, the AH interval increased by up to 210 ms in the dog and 80 ms in the pig hearts. As illustrated in Figure 3A, premature stimulation at a

Figure 3. A. His bundle recording during basic stimulation at a cycle length of 600 ms and after premature stimulation with a coupling interval of 220 ms. B and C. Spread of endocardia! activation in the triangle of Koch during baseline (B) and premature stimulation (C). Numbers in the maps are activation times in ms measured with respect to the stimulus. Isochronal lines are drawn every 2 ms. The premature stimulus is masked by the ventricular electrogram (V^). S^ - basic stimulus; AL H1( and V1 = atrial, His bundle, and ventricular deflections, respectively, during basic stimulation; A2, H2, and V2 = atrial, His bundle, and ventricular deflections, respectively, following premature stimulation; CS = coronary sinus; TT = tendon of Todaro; TVA = tricuspid valve annulus.

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coupling interval that just caused conduction toward His resulted in an increase in the AH interval of 105 ms. The main spread of activation was equal to that following baseline stimulation (Figure 3B). Despite the large increase in the AH interval, delay between earliest and latest endocardial activation within the recording area increased by only 4 ms (Figure 3C).

plain atrial myocardium.45 It is these fibers that were revealed by our dissection. Relation with Slow Pathway Conduction

Our data show that conduction depends markedly on the site of stimulation. Although we found large differences in the speed of conduction during basic stimulaNonuniform Anisotropy tion from different sites, these differences were not reflected in the duration of the Spach et al.36>38 have classified the AH interval. Furthermore, during premaanisotropic properties of cardiac muscle ture stimulation, the increase of conducas uniform and nonuniform. Anisotropy is tion delay in the AV junctional area was said to be nonuniform when side-to-side only 10% of the increase of the AH interelectrical coupling of adjacent groups of val. Thus, the increase in the AH interval parallel fibers is absent because of the can only be partly due to the increase in interposition of strands of connective the conduction delay in the superficial tissue.44 This connective tissue may be a layers of the AV junction. It is therefore normal component of the heart in regions unlikely that anisotropic conduction in the such as the crista terminalis, or can result subendocardial layers of the AV junction from aging or pathological changes. Prop- plays an important role in slow AV conducagation of activation transverse to the tion. However, activation of the AV nodal long axis is interrupted, such that adja- area is by nature a complex 3-dimensional cent bundles are excited in an irregular event, and is certainly not confined to sequence that results in slow conduction. superficial layers alone. Conduction delay The irregular activation is evident in the must have occurred in deeper layers and extracellular electrograms, which are highly escaped our attention. Thus, we cannot fractionated. Propagation parallel to the rule out the possibility that anisotropic fibers is still fast, and electrograms are conduction in deeper layers plays a role in smooth with single deflections. Our anatom- the increase in the AH interval after preical as well as electrophysiological data mature stimulation. are compatible with such nonuniform anisotropic characteristics. An additional The Reentrant Pathway During complicating factor for the spread of actiVentricular Echoes is Confined vation arises, nonetheless, because of the changing direction of fibers in the anteto the AV Node rior aspect of the triangle of Koch. Atrial Activation Sequence During Relation with the Transitional Ventricular Stimulation Cell Zone Sixteen canine hearts were studied. In the rabbit, transitional cells con- All hearts revealed 2 distinct atrial exit stitute the most superficially located group sites. One was located in the anterior of fibers.8 In the pig and dog, however, as area of the AV junction, the other was in the human, the superficial fibers are located posteriorly between the tricusmade up of cells that, histologically, are pid valve annulus and the orifice of the

MAPPING OF AV NODE IN THE EXPERIMENTAL SETTING coronary sinus. In 5 of the 16 hearts, earliest atrial activation was found at the anterior site during pacing at long cycle lengths (CLs) (>600 ms). During incremental pacing, the sequence of atrial activation changed gradually until earliest atrial activation was recorded at the posterior site during pacing at shorter CLs.

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Figure 4 shows the change of the atrial activation pattern during incremental ventricular pacing in 1 of these 5 hearts. Although the change in the activation pattern suggests a shift from retrograde fast (panel A) to retrograde slow pathway conduction, earliest atrial activation was delayed by only 4 ms (panel C). Likewise,

Figure 4. Activation maps during incremental ventricular pacing. The dashed lines indicate the anatomical landmarks of the mapped area. Isochrones are drawn at 4-ms intervals (A and C) and 2-ms intervals (B), respectively, with the ventricular stimulus as time zero. For maps A and C, 24 of 94 recorded atrial electrograms are shown in the approximate position of recording. A. Cycle length (CL) = 600 ms; earliest atrial activation is at the anterior site with initial negativity of the corresponding unipolar atrial electrogram (marked with an asterisk*). B. CL = 460 ms; conduction to the anterior exit delays by 6 ms. A second endocardial breakthrough manifests at a posterior site with an SA interval of 114 ms. C. CL = 360 ms; earliest atrial activation is now at the posterior site with an initially negative unipolar atrial electrogram (marked with an asterisk*). Note that the electrogram at the site of the anterior exit reveals a positive deflection (marked with #). CS = coronary sinus orifice; TVA = tricuspid valve annulus; TT = tendon of Todaro.

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Figure 5. Activation map in a heart with 2 atrial exit sites after ventricular pacing at a cycle length of 1000 ms. The dashed lines indicate the anatomical landmarks of the mapped area. Isochrones are drawn at 4-ms intervals with the ventricular stimulus as time zero. Sixty-four of 94 recorded atrial electrograms are shown in the approximate position of recording. The tracing in the lower right part shows a His bundle recording with the stimulus artifact (S), a retrograde His deflection (H), the ventricular (V) depolarization, and the atrial depolarization (A). See text for discussion. CS = coronary sinus orifice; TVA = tricuspid valve annulus; TT = tendon of Todaro.

sudden changes in the ventriculoatrial (VA) conduction time consequent upon the alteration of the retrograde atrial activation sequence were not observed in the remaining 4 hearts. In 1 of the 16 hearts, a spontaneous switch from the anterior to the posterior exit site was recorded during baseline stimulation at a CL of 600 ms. In contrast to the other 5 hearts, this change in the retrograde atrial activation sequence was associated with an increase of the Hisatrial conduction time from 168 ms to 260 ms, suggesting a VA "jump." In 10 hearts, the retrograde impulse activated the atrium using both exit sites concurrently over a wide range of paced CLs. The activation maps revealed 2 early

sites with intrinsic negative deflections (indicative of areas where activation arises) separated by recording sites with later local activation times. An example is shown in Figure 5. The site of earliest atrial activation (signal marked with *) was recorded in the posterior area close to the tricuspid valve annulus. A second exit site, activated 12 ms after the posterior exit site, was in the anterior area near the apex of the triangle of Koch (signals marked with #). Atrial Activation Sequence During Ventricular Echoes Although single ventricular echoes were consistently induced in all hearts,

MAPPING OF AV NODE IN THE EXPERIMENTAL SETTING sustained AVNRT was never observed. None of the hearts investigated showed discontinuous AV nodal function curves during baseline study. A critical delay in VA conduction achieved by means of programmed ventricular extrastimulation was mandatory for the appearance of ventricular echoes. Surprisingly, the sequence of atrial activation and the signal morphology did not differ between baseline ventricular stimulation and retrograde atrial activation followed by ventricular echoes. Figure 6 shows the atrial activation pattern and the morphology of the unipolar atrial

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electrograms preceding a ventricular echo in the same heart as in Figure 5. VA conduction delay compared to Figure 5 is 25 ms. Note that the activation pattern and the signal morphology match those in Figure 5. The tracings in the lower right part show His bundle electrograms of the ventricular echo (a), and baseline atrial stimulation (b). The retrograde His deflection in a appeared before the ventricular electrogram. The He-Ve interval and the morphology of the ventricular electrogram of the echo (Ve) match those during normal antegrade conduction, indicating that the

Figure 6. Activation map in the heart of Figure 5 after a premature ventricular extrastimulus (S1S2 = 520 ms) at a basic cycle length of 800 ms, followed by a ventricular echo (Ve). Isochrones are drawn at 4-ms intervals with the premature ventricular extrastimulus (S2) as time zero. Sixty-four of 94 recorded atrial electrograms are shown in the approximate position of recording. The anterior exit was close to the site where antegrade His deflections were recorded during reciprocation (marked with H). See text for discussion. S = stimulus artifact; V = ventricular electrogram; A = atrial electrogram; He and H = His bundle electrogram during echo and during baseline atrial stimulation, respectively. Other abbreviations as in Figure 5.

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closely coupled ventricular extrastimuli, the preferential route of atrial activation was via the posterior exit site, suggesting functional differences between the 2 areas. The exit sites observed in our study correspond to the sites of earliest atrial activation described in both animal studies and clinical settings. The studies of Sung et al.26 and of McGuire et al.46'47 suggest that during VA conduction, strands of Histology of the Exit Sites atrial cells that connect the compact node with the endocardial exit sites are the The anterior and the posterior exit site underlying substrate of fast and slow were found to be lying in atrial myocardium, pathway conduction. The observations of well away from the compact AV node and our study, however, clearly show that: (1) the transitional cell zone. The myocardium ventricular echoes occurred irrespective between the sites of endocardial breakof the atrial activation pattern; (2) synthrough and the compact AV node or the chronous retrograde activation of both transitional cells was not specialized in exit sites often preceded ventricular echoes; terms of histological characteristics, nor and (3) ventricular echoes occurred after were histologically discrete or insulated chemical destruction of the endocardial tracts identified. and subendocardial tissue. These findings limit the reentrant circuit to the AV Phenol Application node. In an attempt to further restrict the reentrant circuit, surgical dissection Ventricular echoes were still inducible of the AV nodal area was performed.5 In after application of phenol on the endo- these experiments, the perinodal atrial cardium within the triangle of Koch, on tissue, including both endocardial exit the perinodal area, and on the floor of the sites, could be disconnected from the AV coronary sinus. Retrograde and ante- node without abolishing dual-pathway grade AV nodal conduction parameters physiology. did not differ before and after phenol application. Light microscopy of histological sections cut from the anterior and Canine Dual AV Nodal Physiology the posterior AV junction revealed a mean zone of necrosis to a depth of 475 |im Although dual AV nodal pathways (range 350-600 jim). manifested as ventricular echoes in all

antegrade limb of the circuit used the AV node-His-Purkinje system. Mapping was also performed with the high-resolution, quasiunipolar electrode. Although this electrode was specifically designed to unveil low-frequency signals, no distinct potentials were discerned that could be attributed to activation of the compact node or the transitional cell zone.

Dual Atrial Exit Sites Versus Dual Pathways In the canine hearts, activation of the right atrium following ventricular stimulation occurred via 2 distinct endocardial exit sites in the anterior and posterior right AV junction. During ventricular pacing with short CLs or after

hearts, none of the hearts showed discontinuous AV nodal function curves during baseline electrophysiological study. Since discontinuous AV nodal conduction can be observed in the majority of patients undergoing electrophysiological study,48 this might indicate a substantial difference between human and canine AV nodal physiology. The explanation for this apparent discrepancy might be simple: if

MAPPING OF AV NODE IN THE EXPERIMENTAL SETTING

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in humans with AVNRT suggest that damage to the AV node is not a prerequisite for cure.27'54"56 There are several possible explanations for this discrepancy: (1) The persistence of single echo beats after selective slow pathway ablation in patients with AVNRT is a common finding. If successful ablation for AVNRT could only be achieved by complete destruction of the circuit, this should equate with eradication of the echo beat. Radiofrequency or surgical lesions, even if placed well away from the compact AV node, certainly modify the complex architecture of the AV junction. Modulation of the atrial input to the AV node might disturb the delicate balance that seems to be necessary to sustain circus movement, Where is the Site of AV while the circuit is still intact and allows single echoes. (2) The success of radiofreNodal Reentry? quency ablation in abolishing AVNRT The observations made in our study at sites well away from the compact AV excluded the atrial tissue outside the AV node can be attributed to remote effects nodal area from the reentrant circuit on the transitional cells or the compact during ventricular echoes. Early studies node itself. It has been shown that already demonstrated that the anatomi- sequences of 60-second, 25-W radiofrecal and functional potentials for a dual quency pulses rise myocardial temperatransmission system within the AV node ture to greater than 50°C at distances as do certainly exist. In their original study, large as 10 mm.57 (3) Recent concepts Mendez and Moe suggested that "...the suggest intranodal "microreentry" as the upper region of the node was functionally basis for single AV nodal echoes, whereas and spatially split into two effective some forms of AVNRT are ascribed to pathways..."53 This early observation is "macroreentry" with the participation of strongly supported by a recent report by atrial tissue well outside the AV nodal Patterson and Scherlag,31 who studied area.58 (4) The mechanism of the ventricAVNRT in the superfused rabbit heart ular echoes induced in the dog hearts is preparation. They suggested longitudi- different from the mechanism of AVNRT nal dissociation within the posterior AV in humans. Despite the fact that dual AV nodal nodal area as a substrate for AV nodal reentry. physiology seems to be a normal propOur findings limit the reentrant cir- erty of the dog heart, sustained AVNRT cuit during ventricular echoes to the AV could not be induced. Although it has node. Since it is generally thought that been shown that the conduction system atrial and ventricular echoes represent a in dogs and in humans is basically simi"single-beat expression" of AVNRT, they lar,14 extrapolation of our observations might be in contradiction to findings in to the pathophysiology of human hearts humans with AVNRT: recent results of with AVNRT should be considered with surgical and catheter ablation techniques care. the differences in conduction velocities between the retrograde dual pathways are not sufficiently distinct, block in the pathway with the longer effective refractory period will not yield discontinuous conduction. The occurrence of ventricular echoes with smooth AV nodal function curves is a common finding in experimental and clinical settings,49'50 and patients presenting with AVNRT do not necessarily demonstrate discontinuous AV conduction.51'52 Thus, conduction delay due to decremental conduction properties, rather than differences in conduction velocities, is essential for AV nodal reentry to occur.

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CARDIAC MAPPING Double Component Action Potentials in the Posterior Approach to the AV Node

Action potentials with double components were preferentially recorded in the area between the coronary sinus orifice and the tricuspid valve annulus almost up to the middle of the triangle of Koch (posterior approach to the AV node). During basic stimulation, delay between the 2 components could be as large as 60 ms, but it could increase to 150 ms after premature stimulation. As illustrated in Figure 7, progressive shortening of the 8^2 interval yielded action potentials with increasing delay between the 2 components (lower tracings). The tracings in the middle panel show action potentials during basic stimulation (Si) and after an early coupled extrastimulus (S2). The amplitude of the action potentials decreased with increasing prematurity of the extrastimulus. Double-component action potentials could be recorded in cells located superficially directly beneath the endocardium, as well as in cells from deeper layers. In those cases, the earliest component was recorded from cells directly beneath the endocardium, whereas late components were always generated by depolarization of cells in deeper layers (Figure 8). Histological investigation at these sites revealed a subendocardial zone of mainly transitional cells, arranged in clusters and single strands interspersed with connective tissue. Changes in the site of stimulation from posterior to anterior only marginally affected the configuration of the doublecomponent action potentials. The delay between the 2 components was always less during stimulation from a posterior site. The effectiveness of posterior stimulation was always greater than that of anterior stimulation, as evidenced by conduction block toward His occurring at

shorter coupling intervals of the premature stimulus. The first upstroke of the doublecomponent action potential always occurred before the His deflection. The upstroke of the second deflection, however, often ensued after the His deflection during basic stimulation (26% of registrations) and after premature stimulation (50% of registrations). This suggests that the activation generating that second component did not participate in AV conduction in these cases. Cooling of the Anterior Exit Site To study the nature of doublecomponent action potentials, the anterior region was cooled at the site where the atrial exit site was located during retrograde conduction in 3 hearts. The cooling probe consisted of a stainless steel tube with a diameter of 3 mm and a length of 10 cm, and could be cooled to a temperature of 4°C. Cooling of the anterior exit site resulted in an increase of the delay between the stimulus artifact and the second component of the double-component action potential (Figure 9). The interval between the stimulus and the first component did not change. The delay increased with decreasing temperature. During cooling, incremental pacing often resulted in Wenckebach periodicity of the AV conduction, whereas 1:1 conduction was still present in both components of the action potential of the cell impaled in the posterior approach to the compact AV node. Double-Component Action Potentials Our observation that the delay between the 2 components increases after premature stimulation suggests that doublecomponent action potentials are caused

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Figure 7. Top tracing: Extracellular recording from the His bundle region. Middle tracing: Action potentials with a double upstroke recorded in the posterior aspect of the atrioventricular node during basic stimulation (S1) with a cycle length of 500 ms followed by an early coupled stimulus (S2). The heart was stimulated from a posterior site. Bottom tracing: Action potentials recorded after a premature stimulus with a coupling interval of (1) 310, (2) 290, and (3) 280 ms. Delay between the first and the second components of the action potential increased and the amplitude of the second component decreased with increasing prematurity. Delay between the stimulus and the first upstroke remained virtually the same. Activation evoked after the extrastimulus of 280 ms was blocked toward His. Inset: Schematic drawing of the atrioventricular junctional area, showing the recording site. A = atrial deflection; H = His deflection; V = ventricular deflection; TVA = tricuspid valve annulus; CS = coronary sinus orifice; TT = tendon of Todaro; ME = microelectrode; CFB = central fibrous body.

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Figure 8. Top tracing: Extracellular electrogram from the His bundle region. Lower tracings: Action potentials recorded from the same endocardial site after the last basic stimulus (S1) and an early coupled extrastimulus (S2). The tracing marked "superficial" shows the action potential from a cell located in a superficial layer (directly beneath the endocardium). The tracing marked "deep" shows the action potential from a cell located at a deeper level. Both tracings show double components during basic stimulation (S1), but the notch in the superficial tracing (bold arrow) becomes more distinct after the premature stimulus (S2). The main (first) component of the action potential of the superficial tracing has a low upstroke velocity. The timing corresponds to the first, low-amplitude deflection of the action potentials from the deeper tracing. The main (second) component of the deeper tracing has a high amplitude and fast upstroke velocity. The timing corresponds to the notches marked by the bold arrow in the superficial tracing. The inset shows the endocardial location of the microelectrode. The dips following the bold arrows are artifacts caused by the reference of the microelectrode. Abbreviations as in Figure 7.

by activation arriving at discontinuities, e.g., electrotonic impulse transmission over an inexcitable or high resistance gap (Figure 10, panel a) or transmission of activation at isthmus sites, where a small bundle inserts into a large bundle

(panel b). The large bundle represents a high load for the relatively weak wavefront generated by the small bundle that results in activation delay.20 If propagation occurs at the discontinuity, at least one of the deflections in the action potential

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Figure 9. Tracings are intracellular recordings made during cooling of the anterior area of the atrioventricular junction. This area was the atrial exit site during retrograde conduction. Recordings were made during posterior stimulation at 3 instants during the cooling procedure: (1) baseline, no cooling; (2) 30 seconds of cooling; (3) 60 seconds of cooling. A double component is present during baseline (tracing 1). Delay between the first and second components of the action potential increases with cooling. Delay between the stimulus and the first component remains unchanged. The inset shows the location of the cooling probe and the recording microelectrode. The distance between the center of the cooling probe and the endocardial site where the microelectrode was impaled was 5 mm. Abbreviations as in Figure 7.

will reach threshold (panel c). In case of activation block, only single deflections remain (panel d). The observation that in virtually all cases the amplitude of both components becomes less than 20 mV with increasing prematurity, however, does not fit with the discontinuity concept and favors the concept of asynchronous arrival of activation due to discontinuous propagation between poorly coupled sheets of transitional cells (Figure 10, panel e), or the asynchronous arrival of converging wavefronts (panel f). In these instances, both components may become subthreshold (panel h). Relation with Slow Pathway Conduction Arguments in favor of the hypothesis that double-component action potentials in the posterior approach to the compact

AV node reflect activation delay are as follows: (1) in 74% of the recordings, the second component preceded the His bundle deflection during basic stimulation and in 50% during premature stimulation. (2) With premature stimulation, delay of the second component and delay of the His bundle potential increased more or less equally; however, in 26% of the recordings during basic stimulation and in 50% during premature stimulation, the second component occurred after activation of the His. In these cases, the second component did not participate in AV conduction and was most likely recorded from a dead-end pathway. In our view, this argues against the notion that these potentials arise in the slow pathway, which is supposed to ensure atrium-His conduction of premature impulses that are blocked in the fast pathway. However, since we were unable to find an animal with demonstrable dual

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Figure 10. Schematic drawings illustrating how double-component action potentials may arise. An activation front (arrows) that passes a discontinuity, being a high-resistance gap (a) or a site with impedance mismatch (b), generates double-component action potentials at sites before (1) and after (2) the discontinuity (c). Because this process is active, at least one of the components has a large (suprathreshold) amplitude. When activation blocks at the discontinuity, only one deflection remains (d). A weak coupling between bundles (e) or summation of activation in branching structures (f) also gives rise to double-component action potentials. When the wavefronts (arrows) are propagating in these structures (g), the configuration of the generated action potentials is similar to those that arise at high-resistance gaps or sites with a load mismatch. When, however, wavefronts are dying, double-component action potentials with subthreshold amplitudes may arise (h). 1 and 2 indicate recording sites.

MAPPING OF AV NODE IN THE EXPERIMENTAL SETTING antegrade AV nodal pathways, we could not link activation in the posterior approach to the compact AV node to slow pathway conduction. Whereas cooling of the posterior area hardly affected the timing of the 2 components, cooling of the anterior area delayed the second component that was recorded in the deeper layers. These observations suggest asynchronous arrival of a second wavefront from the anterior area through deeper layers. Summary and Prospects In this chapter, the anatomical, electrophysiological, and functional aspects of the AV node in normal conduction and in arrhythmogenesis have been briefly discussed. Prerequisites for the initiation of reentry in the AV nodal area are 2 pathways or areas with different functional properties, allowing unidirectional block, slow conduction, and early restoration of excitability in the area of unidirectional block. The substrate and the precise location of this reentrant circuit, however, have not been identified. Functional dissociation resulting from dual pathways or nonuniform anisotropic conduction because of morphological aspects of the AV nodal area could provide the functional basis for AV nodal reentry. Experiments were performed in isolated, Langendorff-bloodperfused dog and pig hearts: 1. To characterize anisotropic conduction in the triangle of Koch, the endocardial activation sequence was determined by multichannel mapping and was related with fiber orientation: fibers were parallel to the tricuspid valve annulus in the posterior part of the triangle of Koch, and changed to a perpendicular direction in the anterior area. Activation patterns correlated well with the arrangement

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of the superficial atrial fibers, supporting the concept of anisotropic conduction. However, the increase in AH delay after premature stimulation was only partly caused by activation delay in the superficial layers within the AV junction. This disproves that anisotropy in these layers plays an important role in the initiation of reentry. 2. Multiterminal electrodes were used to map electrical activity in the Koch's triangle after ventricular stimulation and during ventricular echoes. In some hearts the subendocardial cell layers were chemically destroyed with phenol. Retrograde atrial activation occurred via 2 distinct endocardial exit sites. Ventricular echoes were induced in all hearts, irrespective of the atrial activation pattern. Simultaneous retrograde activation of both exit sites often preceded reciprocation. Ventricular echoes could be induced after chemical destruction of the endocardial and subendocardial tissue as well as after surgical dissociation of the atrial exit sites of the putative dual pathways from the AV node, indicating that the reentrant pathway is confined to the AV node. 3. Double-component action potentials in the posterior approach to the compact AV node are often associated with activation delay and might reflect slow pathway conduction. Microelectrode recordings showed that the double-component action potentials in the posterior approach to the compact node are the result of the asynchronous arrival of activation fronts in superficial and deeper layers. Indications for and against an association with slow pathway conduction were found.

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The observations in our studies sug- cells might play an important role in the gest that the reentrant circuit during 'AV origin of reentry. nodal' reentry is indeed confined to the AV node. It cannot be excluded that a rim of perinodal atrial cells might participate in References the reentrant circuit, but the atrial exit sites of the putative dual pathways could 1. Paes de Carvalho A, Almeida DF. Spread be disconnected from the AV node without of activity through the atrioventricular node. Circ Res 1960;8:801-809. any effect on ventricular echoes. Atrial 2. Anderson RH, Janse MJ, van Capelle echoes and sustained AVNRT could not FJL, et al. A combined morphological and be induced in the isolated hearts. Obvielectrophysiological study of the atrioously, the question of whether single echoes ventricular node of the rabbit heart. Circ Res 1974;35:909-922. and sustained AV nodal reentry employ 3. Janse MJ, van Capelle FJL, Freud GE, the same substrate remains to be eluciDurrer D. Circus movement within the dated. Comprehensive understanding of AV node as a basis for supraventricular the arrhythmogenesis in the AV junction tachycardia as shown by multiple microis still hampered by the lack of an accurate electrode recording in the isolated rabbit heart. Circ Res 1971;28:403-414. model of AVNRT in an experimental set4. Hocini M, Loh P, Ho SY, et al. Anisotropic ting and by the lack of appropriate techconduction in the triangle of Koch of mamniques to study AV nodal activation. malian hearts: Electrophysiology and Recently, techniques such as optical anatomic correlations. J Am Coll Cardiol imaging using a voltage-sensitive dye 1998;31:629-636. 5. Loh P, De Bakker JMT, Hocini M, et al. have established their role in AV nodal Reentrant pathway during ventricular mapping.32'34 Considering its limitations, echoes is confined to the atrioventricular optical mapping was largely restricted to node: High-resolution mapping and disthe study of electrical activation in thin, section of the triangle of Koch in isolated, 2-dimensional cell layers. Wu et al.32 perperfused canine hearts. Circulation 1999; 100:1346-1353. formed optical mapping of AV nodal con6. De Bakker JMT, Loh P, Hocini M, et al. duction and reentry in a perfused canine Double potentials in the posterior approach heart preparation, and suggested that the to the AV node: Do they reflect activation inferior AV nodal extension might be the in the slow pathway? J Am Coll Cardiol anatomical substrate of the slow path1999;34:570-577. 7. Tawara S. The Conduction System in way and that unidirectional block occurs the Mammalian Heart—AnAnatomicoat the interface between the AV node and Histological Study of the Atrioventricular the connecting atrial tissue. Bundle and the Purkinje Fibers (transIn our laboratory, we succeeded in lated by K. Suma and M. Shimada). mapping AV nodal potentials after careful London: Imperial College Press; 2000. 8. Anderson RH, Becker AE, Brechenmacher resection of the overlying atrial endoC, et al. The human atrioventricular junccardium.59 Programmed electrical stimutional area: A morphological study of the lation before and after endocardial resection A-V node and bundle. Eur J Cardiol showed that the resection did not change 1975;3:ll-25. the functional characteristics of the AV 9. McGuire MA, De Bakker JMT, Vermeulen JT, et al. Atrioventricular junctional node. First results after high-resolution tissue: Discrepancy between histological mapping of AV nodal activation during and electrophysiological characteristics. ventricular and atrial echoes and histoCirculation 1996;94: 571-577. logical correlation suggested that tissue 10. Inoue S, Becker AE. Posterior extensions architecture and the contact zones between of the human compact atrioventricular node: A neglected anatomic feature of atrial, transitional, and compact nodal

MAPPING OF AV NODE IN THE EXPERIMENTAL SETTING potential clinical significance. Circulation 1998;97:188-193. 11. Mazgalev TN, Ho SY, Anderson RH. Anatomic-electrophysiological correlations concerning the pathways for atrioventricular conduction. Circulation 2001;103: 2660-2667. 12. Medkour D, Becker AE, Khalife K, Billette J. Anatomic and functional characteristics of a slow posterior AV nodal pathway: Role in dual-pathway physiology and reentry. Circulation 1998;98:164-174. 13. Tawara S. Das Reizleitungssystem des Herzens. Jena: Gustav Fischer; 1906. 14. Ho SY, Kilpatrick L, Kanai T, et al. The architecture of the atrioventricular conduction axis in dog compared to man: Its significance to ablation of the atrioventricular nodal approaches. J Cardiovasc Electrophysiol 1995;6:26-39. 15. Becker AE, Anderson RH. Morphology of the human atrioventricular junctional area. In: Wellens HJJ, Lie KI, Janse MJ (eds): The Conduction System of the HeartStructure, Function and Clinical Implications. Philadelphia: Lea and Febiger; 1976:263-286. 16. Janse MJ, van Capelle FJL, Anderson RH, et al. Electrophysiology and structure of the atrioventricular node of the isolated rabbit heart. In: Wellens HJJ, Lie KI, Janse MJ (eds): The Conduction System of the Heart: Structure, Function and Clinical Implications. Philadelphia: Lea and Febiger; 1976:296-315. 17. Zipes DP, Mendez C, Moe GK. Evidence for summation and voltage dependency in rabbit atrioventricular nodal fibers. Circ Res 1973;32:170-177. 18. Kleber A, Kucera JP, Rohr S. Principles of slow and discontinuous conduction: Experimental observations. In: Mazgalev TN, Tchou PJ (eds): Atrial-AVNodal Electrophysiology: A View from the Millennium. Armonk, NY: Futura Publishing Co.; 2000:73-88 19. van Kempen MJA, Fromaget C, Gros D, et al. Spatial distribution of connexin-43, the major gap-junction protein, in the developing and adult rat heart. Circ Res 1991;68:1638-1651. 20. Rohr S. Determination of impulse conduction characteristics at a microscopic scale in patterned growth heart cell cultures using multiple site optical recording of transmembrane voltage. J Cardiovasc Electrophysiol 1995;6:551-568.

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21. Maglaveras N, De Bakker JMT, van Capelle FJL, et al. Activation delay in healed myocardial infarction: A comparison between model and experiment. Am J Physiol 1995;38(4 Pt 2):H1441-H1449. 22. Cabo C, Pertsov AM, Baxter WT, et al. Wave-front curvature as a cause of slow conduction and block in isolated cardiac muscle. Circ Res 1994;75:1014-1028. 23. Jalife J. The sucrose gap preparation as a model of AV nodal transmission: Are dual pathways necessary for reciprocation and AV nodal "echoes"? Pacing Clin Electrophysiol 1983;6:1106-1122. 24. van Capelle FJL, Janse MJ. Influence of geometry on the shape of the propagated action potential. In: Wellens HJJ, Lie KI, Janse MJ (eds): The Conduction System of the Heart: Structure, Function and Clinical Implications. The Hague: Martinus Nijhoff Medical Division; 1978:316-335. 25. linuma H, Dreifus LS, Mazgalev T, et al. Role of the perinodal region in atrioventricular nodal reentry: Evidence in an isolated rabbit heart preparation. J Am Coll Cardiol 1983;2:465-473. 26. Sung RJ, Waxman HL, Saksena S, Juma Z. Sequence of retrograde atrial activation in patients with dual atrioventricular nodal pathways. Circulation 1981;64: 1059-1067. 27. Jackman WM, Beckman KJ, McClelland JH, et al. Treatment of supraventricular tachycardia due to atrioventricular nodal reentry by radiofrequency catheter ablation of slow-pathway conduction. N Engl JMed 1992;327:313-318. 28. Josephson ME, Miller JM. Atrioventricular nodal reentry: Evidence supporting an intranodal location. Pacing Clin Electrophysiol 1993;16:599-614. 29. Janse MJ, Anderson RH, McGuire MA, Ho SY. AV nodal' reentry: Part I: AV nodal' reentry revisited. J Cardiovasc Electrophysiol 1993;4:561-572. 30. McGuire MA, Janse MJ, Ross DL. AV nodal' reentry: Part II: AV nodal, AV junctional, or atrionodal reentry? J Cardiovasc Electrophysiol 1993;4:573-586. 31. Patterson E, Scherlag BJ. Longitudinal dissociation within the posterior AV nodal input of the rabbit: A substrate for AV nodal reentry. Circulation 1999;99:143155. 32. Wu J, Wu J, Olgin J, et al. Mechanisms underlying the re-entrant circuit of atrioventricular nodal re-entrant tachycardia

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in isolated canine atrioventricular nodal preparation using optical mapping. Circ Res 2001;88:1189-1195. 33. Yamabe H, Shimasaki Y, Honda 0, et al. Demonstration of the exact anatomic tachycardia circuit in the fast-slow form of atrioventricular nodal reentry tachycardia. Circulation 2001; 104:1268-1273. 34. Nikolski V, Efimov IR. Fluorescent imaging of a dual-pathway atrioventricularnodal conduction system. Circ Res 2001; 88:e23-e30. 35. Spach MS, Josephson ME. Initiating reentry: The role of nonuniform anisotropy in small circuits. J Cardiovasc Electrophysiol 1994;5:182-209. 36. Spach MS, Miller WT III, Geselowitz DB, et al. The discontinuous nature of propagation in normal canine cardiac muscle: Evidence for recurrent discontinuities of intracellular resistance that affect the membrane currents. Circ Res 1981;48: 39-54. 37. Spach MS, Dolber PC, Heidlage JF, et al. Propagating depolarization in anisotropic human and canine cardiac muscle: Apparent directional differences in membrane capacitance. Circ Res 1987;60:206-219. 38. Spach MS, Miller WT III, Dolber PC, et al. The functional role of structural complexities in the propagation of depolarization in the atrium of the dog: Cardiac conduction disturbances due to discontinuities of effective axial resistivity. Circ Res 1982;50:175-191. 39. Roberts DE, Hersh LT, Scher AM. Influence of cardiac fiber orientation on wavefront voltage, conduction velocity and tissue resistivity in the dog. Circ Res 1979;44:701-712. 40. Wit AL, Dillon S, Ursell PC. Influences of anisotropic tissue structure on reentrant ventricular tachycardia. In: Brugada P, Wellens HJJ (eds): Cardiac Arrhythmias: Where To Go From Here? Mount Kisco, NY: Futura Publishing Co.; 1987:27-50. 41. McGuire MA, De Bakker JMT, Vermeulen JT, et al. Origin and significance of double potentials near the atrioventricular node: Correlation of extracellular potentials, intracellular potentials, and histology. Circulation 1994;89:2351-2360. 42. Veenstra RD, Joyner RW, Rawling DA. Purkinje and ventricular activation sequences of canine papillary muscle. Effects of quinidine and calcium on the

Purkinje-ventricular conduction delay. Circ Res 1984;54:500-515. 43. Lack W, Lang S, Brand G. Necrotizing effect of phenol on normal tissues and on tumors. A study on postoperative and cadaver specimens. Acta Orthop Scand 1994;65:351-354. 44. Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle: A model of reentry based on anisotropic discontinuous propagation. Circ Res 1986;62:811-832. 45. Truex RC, Smythe MQ. Comparative morphology of the cardiac conduction tissue in mammals. Ann NY Acad Sci 1965;127: 19-33. 46. McGuire MA, Robotin M, Yip ASB, et al. Electrophysiologic and histologic effects of dissection of the connections between the atrium and posterior part of the atrioventricular node. J Am Coll Cardiol 1994;23:693-701. 47. McGuire MA, Bourke JP, Robotin MC, et al. High resolution mapping of Koch's triangle using sixty electrodes in humans with atrioventricular junctional (AV nodal) reentrant tachycardia. Circulation 1993;88:2315-2328. 48. Denes P, Wu D, Dhingra R, et al. Dual atrioventricular nodal pathways: A common electrophysiological response. Br Heart J 1975;37:1069-1076. 49. Moe GK, Preston JB, Burlington H. Physiological evidence for a dual A-V transmission system. Circ Res 1956;4:357— 375. 50. Schuilenburg RM, Durrer D. Further observations on the ventricular echo phenomenon elicited in the human heart: Is the atrium part of the echo pathway? Circulation 1972;45:629-638. 51. Sheahan RG, Klein GJ, Yee R, et al. Atrioventricular node reentry with 'smooth' AV node function curves: A different arrhythmia substrate? Circulation 1996;93:969-972. 52. Goldreyer BN, Damato AN. The essential role of atrioventricular conduction delay in the initiation of paroxysmal supraventricular tachycardia. Circulation 1971;43: 679-687. 53. Mendez C, Moe GK. Demonstration of a dual A-V nodal conduction system in the isolated rabbit heart. Circ Res 1966;19:378-393. 54. Haissaguerre M, Gaita F, Fischer B, et al. Elimination of atrioventricular nodal reentrant

MAPPING OF AV NODE IN THE EXPERIMENTAL SETTING tachycardia using discrete slow potentials to guide application of radiofrequency energy. Circulation 1992;85:2162-2175. 55. Keim S, Werner P, Jazayeri M, et al. Localization of the fast and slow pathways in atrioventricular nodal reentrant tachycardia by intraoperative ice mapping. Circulation 1992;86:919-925. 56. Sanchez-Quintana D, Davies W, Ho SY, et al. Architecture of the atrial musculature in and around the triangle of Koch: Its potential relevance to atrioventricular nodal reentry. J Cardiovasc Electrophysiol 1997;8:1396-1407.

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57. Wittkampf FHM, Simmers TA, Hauer RNW, et al. Myocardial temperature response during radiofrequency catheter ablation. Pacing Clin Electrophysiol 1995; 18: 307-317. 58. Scherlag BJ, Patterson E, Nakagawa H, et al. Changing concepts of A-V nodal conduction: Basic and clinical correlates. Primary Cardiol 1995;21:13-21. 59. Loh P, de Bakker JM, Borggrefe M, Janse MJ. High resolution mapping of reentrant activation in the AV node during ventricular echoes. Circulation 1999;100(Suppl): 4412. Abstract.

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Part 4 nONINVASIVE Methods

of Cardiac Mapping

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Chapter 21 Mapping of Atrial Arrhythmias: Role of P Wave Morphology Arne SippensGroenewegen, MD, PhD, Franz X. Roithinger, MD, and Michael D. Lesh, MD

Introduction The pioneering experimental work by Lewis in the early days of clinical electrocardiography provided the fundamental basis for the paradigm that the morphology of the P wave on the surface ECG is uniquely related to the location of the underlying focal origin.1 Observations during canine and human atrial flutter by the same author and his co-workers have initiated our understanding of the mechanism of this arrhythmia and the genesis of the flutter wave on the torso surface.2,3 Many scientists have subsequently studied the value of the surface ECG to localize ectopic atrial rhythms or to characterize reentrant atrial activity, particularly after the introduction of programmed stimulation, direct intracardiac mapping, and radiofrequency catheter ablation. Fueled by the ongoing evolution in the electrophysiological study and ablation of atrial arrhythmias, it seems timely to reassess

the clinical role of the surface ECG and to consider the development of novel methods to improve its noninvasive diagnostic performance. This chapter features a historic overview of the clinical electrocardiography in this field and presents newly developed ECG applications that are aimed at providing a higher spatial resolution to localize focal atrial activity, obtaining more reliable classification of atrial flutter, and improving characterization of atrial fibrillation. The Surface ECG of Ectopic Focal Atrial Activity Early investigations using atrial pacing in humans to study the variations in scalar morphology and vector loop of the P wave with varying sites of focal origin were primarily geared toward the differentiation of left-sided rhythms from right-sided rhythms.4–6 Despite several

This study was supported in part by the Royal Netherlands Academy of Arts and Sciences, the National Institutes of Health (HL09602-01), and the Fonds zur Foerderung der Wissenschaftlichen Forschung, Vienna, Austria. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003.

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attempts to develop a set of morphological ECG criteria specific to a left-sided origin of an ectopic atrial rhythm, different algorithms were proposed and consensus appeared difficult to attain. Mirowski7 initially suggested that a negative P wave polarity in lead I and a "dart and dome" configuration in V1 was related to a leftsided origin, and later added that a negative P wave in V6 was more specific particularly when the aforementioned features were absent. Although these findings were partly underlined by others,6 Harris et al.5 contested the importance of P wave inversion in leads I and V6 for a left-sided rhythm and alternatively proposed that a terminally positive P wave in V1 was a more specific finding for a left atrial origin. Conversely, Massumi and Tawakkol4 noted a profound variability in P wave morphology when stimulating from similar left atrial sites in different patients, and did not believe that distinct ECG criteria specific to areas of ectopic impulse formation could be developed. Using temporarily implanted pacing wires following cardiac surgery, Maclean et al.8 subsequently performed a comprehensive study in 69 patients by stimulating both atria at a total of 12 epicardial regions. Overall, the results of this study were disappointing in that only a few specific correlations between P wave morphology and site of origin could be made: (1) a negative P wave in the inferior leads with pacing of the inferior regions in either atrium; (2) a negative P wave in lead I with left atrial pacing near the left pulmonary veins; and (3) a positive bifid P wave in V1 with pacing near the lower pulmonary veins and coronary sinus. Therefore, these investigators, and more recently others using contemporary multisite endocardial catheter pace mapping techniques,9 underlined the complexity of visual analysis of the lowvoltage P wave and concluded that the 12-lead ECG was of limited clinical value in localizing ectopic atrial foci.

The successful treatment of focal atrial tachycardia using catheter ablation has resulted in a renewed interest in the design of ECG algorithms capable of regionalizing the arrhythmia origin prior to invasive catheter mapping.10,11 Tang et al.10 showed that the P wave morphology in aVL and V1 allows separation of left from right atrial tachycardia foci while the P wave polarity in the inferior leads enables discrimination of tachycardias with an inferior or superior origin. Using the polarity of the P wave in aVR, Tada and collegues11 were able to distinguish atrial tachycardias arising from the terminal crest from those originating from the tricuspid annulus. In accordance to the findings of Tang et al.,10 they found that right atrial tachycardias with an inferior or superior origin could be discriminated by the P wave polarity in the inferior leads. They additionally found that inferior right-sided tachycardias could be further separated into a medial or lateral origin based on the P wave polarity in V5 and V6. There have also been attempts to localize the atrial insertion site of an accessory pathway during orthodromic atrioventricular (AV) reentrant tachycardia.12–14 Farshidi et al.12 initially demonstrated that a negative retrograde P wave in lead I was associated with a left-sided atrial insertion of the accessory pathway. Garcia Civera et al.13 were able to separate free wall accessory pathway locations in the left atrium and right atrium using the retrograde P wave polarity in leads I and V1. Other investigators later studied the localization resolution of the 12-lead ECG for this particular application by confining pace mapping to the annular regions of the left atrium and right atrium.15,16 However, despite a more directed pace mapping approach, the paced P wave morphology only allowed a gross separation of pacing sites in terms of a left- versus right-sided

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origin, an inferior origin in either atrium, performing ECG signal analysis.26–28 In or an origin in the right free wall. In con- our opinion, these features of the surface trast, Tai et al.14 recently reported that mapping technique are of paramount the polarity of the retrograde P wave in importance to increase the resolving power leads I, II, III, aVF, and V1 obtained of the surface ECG in localizing ectopic during AV reentrant tachycardia allows atrial activation. accessory pathway localization to 9 possiTo assess the localization perforble annular regions with an overall accu- mance of ECG mapping in discriminatracy of 88% provided a clearly visible P ing various sites of right atrial ectopic wave could be discriminated. It must be impulse formation, we performed endocarrealized with this application of the sur- dial pace mapping in 9 patients with echoface ECG that visual analysis of the low- cardiographically demonstrated normal voltage retrograde P wave is frequently biatrial anatomy.20 Body surface maphampered by the simultaneous occur- ping was carried out using a 62-lead rence of the preceding cardiac cycle's high- radiotransparent electrode array during voltage T-U wave. bipolar pacing with a roving catheter at Triggered by the limited clinical util- a total of 86 widely distributed endocarity of the 12-lead ECG in localizing dial sites. Pacing was executed at a slow ectopic atrial rhythms, there have been a rate to ensure adequate separation of few experimental17,18 and some more the P wave and the preceding T-U wave. recent clinical reports19–22 on the use of Integral maps of the excitation component multiple surface ECG lead mapping to of the P wave were computed for each obtain improved spatial resolution in dis- paced sequence (Figure 1). The pacing site criminating focal atrial activity. These location was carefully documented using studies were carried out based on the biplane fluoroscopic imaging and right notion that ECG sampling over the entire atrial angiography. This information was torso surface provides a more compre- used to compute the 3-dimensional locahensive electrocardiographic blueprint tion of each pacing site relative to anaof the cardiac electrical activity and its tomical fiducial points, and to extrapolate distribution on the chest.23–25 An instan- the location of each pacing site to an endotaneous or time-interval—related presen- cardial diagram of the right atrium. 29 tation of the entire set of electrical All 86 paced P wave integral maps information on the body surface offers showed a dipolar voltage distribution and the unique advantage over lead-by-lead were visually grouped into 17 subsets scalar ECG interpretation that informa- with nearly identical map patterns. tion obtained at all electrode sites can be Spatial map pattern analysis used prejudged simultaneously. This presentation viously reported concepts, which include approach not only enables one to appre- an assessment of the position and ciate the intricate spatial voltage rela- mutual orientation of the extremes and tionships between the various electrode the zero line contour.30,31 Subset selecsites but also allows a more intuitive and tion was statistically supported by condirect interpretation of the signals in firming an adequate level of intragroup terms of the underlying cardiac source. pattern correspondence and intergroup Furthermore, the use of surface mapping pattern variability. After a mean P wave techniques allows application of inverse integral map was computed for every modeling to compute the location of subset of paced P wave integral maps, ectopic activation and, thus, provide a the stimulus sites corresponding to each more accurate mathematical means of subset were indicated as segments in

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CARDIAC MAPPING Figure 1. A. Torso anatomy with superimposed location of the 62 lead sites, which include standard precordial leads V1 to V6. Electrodes are applied as 14 vertical straps on the chest surface and secured in place using double adhesive tape. B. P wave integral map obtained in a 54year-old male patient during pacing at the middle lateral wall of the right atrium using a stimulation cycle length of 700 ms. The integral map was computed over the excitation component of the P wave (duration of 106 ms), which is depicted by the shaded gray area between the 2 vertical bars in the scalar V1 tracing below the map. Note the discrete stimulus artifact prior to the P wave onset in the ECG tracing. The 2-dimensional map format relates to a 3-dimensional representation of the chest as a cylinder that is cut open at the level of the right posterior axillary line. The schematic locations of the sternum (left) and spine (right) are shown at the top of the map. Positive, negative, and zero isointegral lines are indicated by solid (shaded gray area), dashed, and dotted lines, respectively. The scaling between isointegral lines varies linearly according to the absolute magnitude of each positive or negative voltage distribution. The spatial position and amplitude of the maximum and minimum are shown within (plus and minus sign) and below the map, respectively. Notice that this particular paced P wave integral map displays leftward directed electromotive forces consequent to the right atrial origin of activation onset.

the anatomical diagram of the right atrium. Figure 2 demonstrates the complete atlas of 17 mean paced P wave integral maps (panel A) together with the location of the right atrial endocardial segments at which pacing was performed (panel B). It may be noted that quite apparent as well as more subtle spatial differences exist between the various mean P wave integral map patterns. For instance, pacing at superior (segments 2 to 5) versus distant inferior (segments 13 to 15) locations in the right atrium results in maps with diametrically opposed voltage patterns. Also, stimulation at adjacent segments in the lower regions of the posterior (segment 10), lateral (segment 11), and inferior (segment 12) right atrium produces clear pattern differences that feature a major

spatial shift in P wave forces. Conversely, subtle differences in zero line contour and extreme orientation with fairly comparable extreme locations may be observed with pacing at segments in the superior vena cava (segments 2 and 3) and sinus node region (segment 4). Using the quantitative fluoroscopic technique to assess the 3-dimensional stimulus site location, we approximated the spatial resolution of body surface mapping to discriminate right atrial ectopic impulse formation. This resulted in a mean right atrial segment size of 3.5 ± 2.9 cm2. In a preliminary clinical study, Kawano and Hiraoka19 showed that endocardial pacing at 1 right (low) and 3 left (low, middle, and high) atrial locations produced characteristic P wave body surface potential map patterns. The map pattern that they obtained

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Image Not Available

Figure 2. Atlas of 17 different mean paced P wave integral maps (A) shown in combination with the endocardial locations of the associated segments of ectopic impulse formation indicated in a schematic diagram of the right atrium (B). Maps are depicted without isointegral lines to delineate the discriminating spatial map parameters, i.e., location of maximum (plus sign) and minimum (minus sign), mutual orientation of maximum and minimum, and zero line contour (solid lines).30,31 The encircled numbers relate each map to its corresponding endocardial segment. The endocardial diagram features an anteroposterior (AP) and posteroanterior (PA) view of the right atrial endocardium and includes the major anatomical structures: superior (SVC) and inferior (IVC) vena cava; right atrial appendage (RAA); smooth (SRA) and trabeculated (TRA) right atrium; crista terminalis (CT); fossa ovalis (FO); eustachian valve (EV); coronary sinus os (CSO); tricuspid valve (TV); left atrium (LA); aorta; and right (RPA) and left (LPA) pulmonary arteries. See to text for discussion. Reproduced from reference 20, with permission.

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during low right atrial stimulation compares favorably with the mean P wave integral map pattern that we noted during pacing at the inferior wall of the right atrium in the subeustachian isthmus (segment 12) (Figure 2). Initial results of the clinical application of the atlas of 17 mean paced P wave integral maps to localize right atrial tachycardia were obtained in 8 patients who underwent catheter activation sequence mapping and subsequent radiofrequency ablation of their ectopic focus.22 Compared to activation mapping, body surface mapping was able to predict the correct or an adjacent segment of origin in 5 of 8 and 3 of 8 tachycardias, respectively. Figure 3 includes an example of a right atrial tachycardia that was correctly localized to the medial part of the subeustachian isthmus close to the coronary sinus os (segment 13) using the atlas of 17 mean paced P wave integral maps. These preliminary data demonstrate that a spatial presentation of the P wave morphology using ECG mapping techniques allows discrete localization of right atrial tachycardia foci and may be useful in targeting invasive mapping prior to ablative interventions. At present, however, we are not able to report on the ability of body surface mapping to discriminate right-sided ectopic atrial rhythms from left-sided ectopic atrial rhythms. The limited role of the standard 12lead ECG in distinguishing right atrial from left atrial focal activity has already been reported using pace mapping techniques8,9 and also, more recently, during ablation of atrial tachycardia guided by intracardiac echocardiography.32 Kalman et al.32 reported that the P wave morphology on the 12-lead ECG of tachycardias arising from the upper part of the crista terminalis in the right atrium or from the right upper pulmonary vein in

the left atrium demonstrate considerable overlap because of the anatomical proximity of both structures. However, Tang et al.10 suggested previously that a change in P wave morphology in lead V1 from biphasic during sinus rhythm to completely positive during tachycardia would be helpful in discriminating foci arising from the superior portion of the crista terminalis and the right upper pulmonary vein. The latter finding was found to be predictive for right upper pulmonary vein tachycardia foci even when lead aVL would demonstrate a positive instead of a negative P wave. Figure 4 displays 12lead ECG recordings obtained during sinus rhythm (panel A) and atrial tachycardia with a focal origin at the right upper pulmonary vein (panel B). Although lead aVL displays a negative P wave during atrial tachycardia indicative of a left-sided origin, one may note that the morphology of the P wave in lead V1 remains biphasic during both sinus rhythm and atrial tachycardia and, thus, is not helpful in providing additional evidence to support a focal origin in the right upper pulmonary vein. Nevertheless, it should also be stated that analysis of the P wave morphology on the 12-lead ECG does not always lead to a disputable result and can indeed be clinically helpful in providing a global impression of the origin of ectopic atrial activity. For instance, panel A of Figure 5 is a 12-lead ECG recording of an atrial premature beat with an endocardial origin at the middle section of the crista terminalis. The positive P wave in lead aVL and negative P wave in lead Vl that are noted in this recording are features compatible with a right-sided focal origin.10 Also, the negative P wave in aVR is found to be consistent with an origin at the crista terminalis.11 Panel B of Figure 5 displays the 12-lead ECG of an atrial premature beat where the focal activity was found to arise from the left upper

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Figure 3. P wave integral map (A) and 12-lead ECG (B) obtained during atrial tachycardia (cycle length 590 ms) in a 43-year-old male patient who did not have any concomitant structural cardiac disease. The schematic diagram of the right atrial endocardium (C) features the focal tachycardia origin, which was determined by catheter activation sequence mapping (CM) and was found to be situated just inferior to the coronary sinus os in the medial part of the subeustachian isthmus. See legend of Figure 2 for explanation of abbreviations. Correlation of the atrial tachycardia P wave integral map (see legend of Figure 1 for further explanation) with the atlas of 17 mean paced P wave integral maps (Figure 2) revealed that the paced map pattern obtained at segment 13, also located at the inferior border of the coronary sinus os, demonstrated the best morphological match. Note the negative P wave polarity in the inferior leads of the 12-lead ECG corresponding with an inferior atrial origin of the tachycardia focus. See text for further discussion.

pulmonary vein. In this example, the P wave appears negative in aVL and positive in V1—criteria indicative of a left-sided origin.10 It may also be appreciated that the positive P wave in V1 contains a distinct

M-shaped pattern; we have found this morphological feature to be specific for a focal origin at the left upper pulmonary vein provided the polarity of the P waves in the inferior leads is also positive.

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Figure 4. Twelve-lead ECG recordings acquired during sinus rhythm (A) and atrial tachycardia (cycle length 410 ms) (B) in a 42-year-old female patient with no structural heart disease. The tachycardia was localized using catheter activation sequence mapping and was found to arise from the right upper pulmonary vein. Note that the atrial tachycardia is associated with 2:1 atrioventricular conduction resulting in both an obscured and unobscured P wave. See text for further discussion.

In a preliminary attempt to study the resolving power of ECG mapping in localizing left atrial ectopic activity, we performed trans-septal pace mapping of the left atrium and observed a mean of

5.0 ± 1.4 P wave integral map patterns per patient after pacing at up to 7 different endocardial locations.21 Figure 6 comprises 3 P wave integral maps that were produced during pacing at the left atrial

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Figure 5. Standard 12-lead ECG tracings of 2 different spontaneous atrial premature beats where activation mapping by catheter identified a focal origin at the middle part of the crista terminalis in a 29-year-old male patient (A) and at the os of the left upper pulmonary vein in a 33-year-old female patient (B). Both patients did not have any associated organic heart disease. See text for further discussion.

appendage (panel A), the lateral mitral annulus (panel B), and the posterior mitral annulus close to the septum (panel C). It may be appreciated that the first 2 map patterns (panels A and B) are clearly

different from any of the 17 right-sided mean paced P wave integral maps shown in Figure 2. The map pattern displayed in panel C, however, does demonstrate features comparable to the mean P wave

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Figure 6. Three distinct P wave integral maps obtained during trans-septal left atrial pacing in a 39-year-old female patient who underwent ablation of a left anterolateral accessory pathway. See legend of Figure 1 for further explanation. Bipolar pacing (cycle length 650 ms) was performed with a roving catheter positioned in a stable location at the left atrial appendage (A), the lateral mitral annulus (B), and the posterior mitral annulus close to the septum (C). One may notice the profound morphological differences between these 3 map patterns. See text for further discussion.

integral map produced at an opposing atrial rhythms as well as its spatial reslocation in the right atrium (i.e., segment olution in the left atrium will have to 15 situated at the low right atrial septum) await the results of ongoing and future (Figure 2). Similar findings with regard investigations. to the spatial correspondence of QRS integral maps were previously noted during The Surface ECG of Typical pace mapping at spatially opposed locations in the left and right ventricular Atrial Flutter septum.30 Although the aforementioned results clearly underscore the potential The first ECG recording of human utility of body surface P wave integral atrial flutter was reported more than 90 mapping in providing detailed nonin- years ago by Jolly and Ritchie,33 who used vasive localization of ectopic right atrial the Cambridge model of Einthoven's foci, its clinical performance in separat- string galvanometer. This was followed ing left-sided from right-sided ectopic by a series of clinical and experimental

MAPPING OF ATRIAL ARRHYTHMIAS 439 publications by Lewis et al.,2,3,34 who described the uniform configuration and continuous nature of the classic counterclockwise "sawtooth" flutter wave pattern in leads II and III at rate of 260 to 335 beat per minute. Based on experimental extrapolations, these authors attributed the electrocardiographic flutter wave pattern to a wavefront rotating around the superior and inferior caval veins. Furthermore, they suggested that the main upstroke or positive deflection in lead II was caused by craniocaudal propagation of the impulse along the right atrial free wall. Kato et al.35 performed a similar comparison of the human lead II recording of counterclockwise atrial flutter with canine endocardial and esophageal mapping data obtained during experimental atrial flutter, and showed that the negative deflection of the flutter wave in lead II coincided with caudocranial activation of the left atrium. Subsequently, in 1970, Puech et al.36 reported the clinical results of endocardial and esophageal recordings by catheter combined with complete 12lead ECG tracings that were obtained during common or counterclockwise typical atrial flutter. These authors demonstrated the distinct surface morphology of counterclockwise typical flutter with predominantly negative flutter waves in the inferior leads and V6 in conjunction with a predominantly positive flutter wave in V1.They showed that the positive part of the flutter wave in the inferior leads was indeed associated with craniocaudal impulse propagation along the right atrial free wall, while the negative part of the flutter wave was found to relate to caudocranial impulse conduction along the right atrial septum and left atrium. More recent multisite catheter mapping and entrainment studies have shown that the aforementioned characteristic 12-lead ECG pattern is caused by macroreentrant counterclockwise wavefront propagation around the tricuspid annulus of

the right atrium in a circuit that is confined by natural anatomical barriers.37–46 This right atrial reentrant circuit has also been demonstrated to be capable of impulse propagation in a reverse clockwise direction giving rise to a 12-lead ECG pattern that has led to more ambiguous opinions with regard to its particular appearance. Cosio et al.37,40 reported that clockwise typical atrial flutter was characterized by positive deflections in the inferior leads. Kalman et al.46 also noted the presence of predominantly positive deflections in the inferior leads, but additionally demonstrated that these positive deflections were preceded by a negative deflection of variable magnitude. Additionally, they mentioned that a positive deflection in V6 was a highly specific marker to distinguish clockwise from counterclockwise flutter. Conversely, Saoudi et al.42 noted a high incidence of the sawtooth pattern in the inferior leads during clockwise flutter albeit that the negative deflection was lower in magnitude than during counterclockwise flutter. Thus, these authors concluded that a short plateau phase and a wide negative component in the inferior leads, as well as a negative flutter wave in V1, were more specific in characterizing clockwise flutter wave rotation. Figure 7 features the 12-lead ECG, leads II and aVF with a set of right atrial endocardial electrograms, and the presumed anatomical location of the reentrant circuit of counterclockwise, clockwise, and atypical atrial flutter obtained in the same patient.41 Correlation of the deflections in the inferior leads of the surface ECG and the intracardiac activation sequence during counterclockwise flutter (panel A) confirms the aforementioned findings described in the original report by Puech et al.36 With clockwise flutter, it may be observed that the predominantly positive flutter wave component is caused by craniocaudal activation of the right atrial septum, while the negative flutter

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Figure 7. Recordings of the 12-lead ECG, leads II and aVF (at higher gain and paper speed) with bipolar endocardial electrograms obtained around the atrial circumference of the tricuspid annulus (TA) and coronary sinus (CS) os of counterclockwise (A) and clockwise (B) typical atrial flutter as well as atypical atrial flutter (C) obtained in a 65-year-old male patient. Each panel also features the anatomical location of the macroreentrant circuit shown in a schematic diagram of the exposed right atrial endocardium previously reported by Anderson and Becker.47 See legend of Figure 2 for explanation of abbreviations. The endocardial electrograms are ordered according to their locations respective to the left anterior oblique fluoroscopic view (2:00 and 7:00 refer to a position at the high right atrial septum and inferior right posterolateral atrium, respectively). See text for discussion. Reproduced from reference 41, with permission.

wave component is the result of caudocranial activation of the right atrial free wall (panel B). The atypical flutter shown in panel C, on the other hand, demonstrates an intracardiac right atrial free wall activation sequence compatible with counterclockwise wavefront rotation around the tricuspid annulus in combination with a "clockwise appearance" of the surface ECG featuring predominantly positive flutter waves in the inferior leads.

One may also appreciate from Figure 7 that visual assessment of the low-voltage flutter waves on the scalar 12-lead ECG is not a trivial matter, particularly when standard gain settings and paper speeds are used. The lack of a clear isoelectric interval in a continuously undulating signal impedes evaluation of the polarity of the individual flutter wave components.37,44 Also, the flutter waves may be partly or completely obscured by the QRST segment when a low degree of AV

MAPPING OF ATRIAL ARRHYTHMIAS block is present (Figure 7, panels A and B)42 or when there is significant QRST prolongation because of antiarrhythmic drug use with or without associated abnormalities in ventricular conduction. Saoudi et al.42 also noted that clockwise atrial flutter may not be recognized and considered for ablative therapy due to a 12-lead ECG pattern that is not "close to classic." In addition, Kalman et al.46 mentioned that the surface ECG morphology of atypical or non-isthmusdependent flutter may resemble the morphology of counterclockwise or clockwise typical atrial flutter, particularly when visual ECG analysis is restricted to the inferior leads only. These authors emphasized the importance of including both activation and entrainment mapping data to obtain a reliable distinction between these 2 forms of flutter. These factors clearly limit the role of the 12lead ECG to classify the various types of clinical atrial flutter, and should be taken into consideration when corroborative invasive mapping procedures are not available. In a recent study, we used 62-lead ECG mapping to study the temporal changes in the spatial surface map pattern of typical atrial flutter and develop improved electrocardiographic criteria to classify the 2 directions of flutter wave rotation.48 Body surface mapping and simultaneous multisite endocardial catheter mapping were performed during 17 counterclockwise and 7 clockwise flutter wave episodes in 20 patients with or without associated structural cardiac abnormalities. Adenosine was delivered intravenously when a low degree of AV block (<2:1) occurred so that adequate isolation of the flutter waves from the QRST segment was attained. Potential maps were then computed at 2-ms intervals and compared with the sequence of endocardial activation.

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Figure 8 includes a representative example of simultaneous intracardiac and surface ECG recordings obtained during a counterclockwise typical flutter wave episode. A stable surface map pattern featuring right superiorly directed electromotive forces occurs during caudocranial activation of the lower two thirds of the septum (sites 1 and 2) and concurrent eccentric activation of the coronary sinus. When the activation wavefront progresses to the level of the upper septum (site 3) and the junction with the anterior right atrial wall (site 4), a change in the voltage distribution takes place. This results in complete reversal of the flutter wave pattern that then stabilizes and proceeds to display inferiorly directed forces upon craniocaudal activation of the free wall of the right atrium (sites 5 to 9). It may be noted that the electrically silent zone (surface voltage level <30 uV) occurs during activation of the subeustachian isthmus. Figure 9 features a representative example of a similar set of invasive and noninvasive recordings obtained during an episode of clockwise typical atrial flutter. The surface map pattern shows a stable pattern reflecting inferiorly oriented forces during craniocaudal activation of the medial part of the right anterior free wall (site 1), the septum (sites 2 and 3), and the coronary sinus os (site 4). This pattern continues to exist when the medial half of the subeustachian isthmus is being activated (site 5), although the negative voltages on the posterior torso show a more downward expansion. The latter phenomenon is the result of eccentric activation of the coronary sinus (not shown in this figure) and terminal activation of the left atrium occurring concurrent with activation of the medial isthmus. Analogous to counterclockwise flutter, complete reversal of the map pattern can then be observed when the right

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Figure 8. Episode of counterclockwise atrial flutter (cycle length 210 ms) obtained in a 70-year-old male patient with structural heart disease (i.e., dilated left atrium). A. Recordings of lead II and 10 bipolar right atrial electrograms ranked according to their temporal sequence of activation (CS dis = distal coronary sinus). B. Photograph showing 9 of the 10 corresponding recording positions indicated in a previously published schematic display of the right atrial endocardium.47 See legend of Figure 2 for explanation of abbreviations. C. Body surface potential maps of 9 different time instants in the flutter wave cycle that are identical to the times of local endocardial activation shown in B; the encircled numbers relate each potential map with the site of local endocardial activation. The successive 9 time instants are shown below the maps and depicted by the vertical bars in the unipolar ECGs that were all obtained at the same lead site located at the left lower anterior chest. Positive (solid lines in shaded gray area), negative (dashed lines), and zero (dotted lines) isopotential contour lines are indicated. The incremental step between positive and negative isopotential lines is linear and shown in uV below the actual extreme amplitudes. See legend of Figure 1 for further explanation; see text for discussion.

free wall (sites 6 to 9) is being activated in a caudocranial direction. The electrically silent zone of this clockwise flutter wave cycle subsequently occurs during activation of the anterior free wall of the

right atrium (i.e., the area between sites 9 and 1). A division of each counterclockwise and clockwise flutter wave cycle in successive intervals was carried out by

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Figure 9. Clockwise atrial flutter (cycle length 230 ms) obtained in a 69-yearold female patient with organic cardiac disease (i.e., dilated right atrium). A. and B. Tracings of lead aVF with 9 bipolar right atrial electrograms and their respective endocardial recording sites. C. The 9 corresponding body surface potential maps. The unipolar tracing below each map was acquired using an electrode situated at the right upper anterior torso. See legends of Figures 1, 2, and 8 for abbreviations and further explanation; see text for discussion.

identifying time periods that demonstrated stable voltage distributions. With counterclockwise and clockwise rotation, 2 (41% and 29%) or 3 (59% and 71%) intervals showing a stable voltage distribution could be distinguished. After

integral maps for each of these intervals were computed in individual patients, mean integral maps of these intervals were obtained for the entire set of counterclockwise or clockwise flutter wave episodes to generate a reference set that featured

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the characteristic surface map pattern of counterclockwise and clockwise typical atrial flutter (Figure 10). The mean integral map of the (1) initial; (2) intermediate; and (3) terminal counterclockwise flutter wave corresponded with (1) caudocranial activation of the right atrial septum together with eccentric activation of the coronary sinus; (2) craniocaudal activation of the right atrial free wall; and (3) activation of the lateral part of the subeustachian isthmus (panel A in Figure 10). With clockwise atrial flutter, the mean integral map of the (1) initial; (2) intermediate; and (3) terminal flutter wave was associated with (1) craniocaudal activation of the right atrial septum; (2) activation of the subeustachian isthmus concurrently with eccentric activation of the coronary sinus; and (3) caudocranial activation of the right atrial free wall (panel B in Figure 10). During quantitative validation of the mean counterclockwise and clockwise flutter wave integral maps, it was remarkable to find a high degree of pattern homogeneity among patients for each direction of flutter wave rotation irrespective of differences in flutter wave cycle length (CL) and the presence or absence of structural heart disease. These results contrast with earlier statements regarding the potential inaccuracy of the 12-lead ECG in providing information on the origin of ectopic atrial rhythms based on P wave polarity when structural atrial disease is present.10,49 Although our findings concern macroreentrant rather than focal atrial activity, it seems appropriate to state that a spatially directed representation of flutter waves using 62-lead ECG maps provides a more accurate marker for direction of activation that appears less susceptible to abnormalities in intra-atrial and interatrial conduction. When considering the genesis of the electrocardiographic flutter wave and the role of the left atrium, our results are in agreement with previous

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Figure 10. Reference set of 3 counterclockwise (A) and clockwise (B) typical mean integral maps featuring the characteristic dipolar map patterns during the initial (T1-T2), intermediate (T2-T3), and terminal (T3-T4) time periods in the flutter wave cycle. The isointegral contour line scaling is linear and the increment is indicated in mV/ms below the amplitudes of the maximum and minimum. See legend of Figure 1 for further explanation; see text for discussion. Reproduced from reference 48, with permission.

experimental50,51 and clinical studies42,46 using combined standard lead ECG analysis and intracardiac mapping. We found that the synchronized activation of the right atrial septum and the "bystander" left atrium in either an inferior-to-superior or a superior-to-inferior direction is the principal determinant for the dominant scalar flutter wave polarity on the surface ECG in counterclockwise or clockwise atrial flutter, respectively.

MAPPING OF ATRIAL ARRHYTHMIAS 445 It is interesting to note that the mean integral map of the initial part of the counterclockwise flutter wave (Figure 10) is highly comparable with the mean P wave integral map obtained during pacing at the inferior border of the coronary sinus os (Figure 2). Although this finding suggests that similar routes of right septal, trans-septal, and left-sided wavefront propagation are engaged with counterclockwise typical flutter as with focal activation arising from the low right atrial septum, it should be noted that a low ectopic focus in the septum will not only cause synchronous and similarly directed caudocranial impulse propagation in the right atrial septum and left atrium but also concurrent caudocranial impulse propagation in the free wall of the right atrium. However, the addition of caudocranial free wall activation does not appear to influence the overall morphology of the paced P wave integral map, since isolated activation of the right atrial free wall in a caudocranial direction (i.e., during the terminal part of the clockwise flutter wave) is associated with a mean integral map pattern that is very compatible with the mean integral map pattern of the initial counterclockwise flutter wave (Figure 10). A similar explanation may also be adopted for the resemblance between the initial integral map of the clockwise flutter wave (Figure 10) and the mean P wave integral map obtained during pacing at the high right atrial septum (Figure 2). The use of body surface mapping enables a unique spatial display of the counterclockwise and clockwise flutter wave distribution on the torso surface that can be related on an instant-byinstant basis to the endocardial activation sequence. A representation of the flutter waves in terms of integral maps offers an alternative and potentially more reliable noninvasive means of classifying typical atrial flutter. Moreover, in

contrast to the limited specificity of the 12-lead ECG in recognizing clockwise flutter, the body surface map patterns appear specific for both directions of flutter wave rotation. It should be realized, however, that this is the first comprehensive series of patients in whom this technique is applied to electrocardiographically characterize typical atrial flutter. To date, there exists only an isolated 2-case report featuring body surface potential maps of atrial flutter expressing predominantly negative flutter waves in the inferior leads.52 Although confirmation of the actual location of the macroreentrant circuit was not carried out, it appears that 1 of these 2 flutter episodes showed a potential map pattern that was comparable to the counterclockwise flutter wave maps shown in Figure 8, while the other one displayed a clearly different pattern not compatible with our findings and probably reflected underlying activation of a non-isthmusdependent flutter. Nevertheless, comparative studies will have to be carried out in the future in order to clinically validate the specificity of the reference set of mean integral maps of counterclockwise and clockwise typical atrial flutter. Future investigations will also have to address the potential clinical utility of surface mapping techniques in separating typical atrial flutter from atypical or non-isthmus—dependent atrial flutter. Ultimately, the latter studies may lead to the recognition and classification of surface map patterns that are specific for alternative reentrant circuits in either the right atrium or the left atrium. The Surface ECG of Atrial Fibrillation The electrocardiography of atrial fibrillation focused mainly on a descriptive analysis of the variations in fibrillation wave amplitude.53-58 Subdivisions into

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"very coarse," "coarse," "fine," and "straightline" atrial fibrillation were proposed based on a progressive decrease in the amplitude of the fibrillation wave in V1.54-58 There have been several reports in which these electrocardiographic patterns could be related to the type of underlying heart disease and left atrial size.54,55,57 Atrial fibrillation with a "coarse" pattern on the surface ECG was observed more frequently in patients with rheumatic heart disease and a dilated left atrium, as opposed to the "fine" pattern that seemed to occur more often in patients with nonrheumatic heart disease and normal left atrial size. These findings were, however, contested by other reports in which the atrial fibrillation pattern on the surface ECG could not be associated with cardiac etiology or left atrial size.56,58 Although atrial fibrillation was originally perceived as a disorganized and random activation process,59 more recent animal60-62 and human data60,63,64 support a mechanistic concept that favors spatiotemporal organization of the activation sequence. Zipes and DeJoseph 60 obtained combined ECG, endocardial, and esophageal recordings in both canines and humans and noted that dissimilar atrial rhythms were responsible for "coarse" atrial fibrillation and "flutter-fibrillation." They concluded that both electrocardiographic patterns of atrial fibrillation were the result of a more uniform and slower activation sequence in the entire or major part of one atrium while disorganized atrial fibrillation persisted in the other atrium. In order to obtain more detailed information on the differences in the patterns of endocardial activation that are responsible for the variations in the morphological appearance of the surface ECG, we recently acquired simultaneous standard surface ECG recordings and endocardial electrograms from multiple sites in the right atrium and coronary sinus during chronic

atrial fibrillation in humans.65 This study was based on the hypothesis that (1) structural barriers such as the crista terminalis create a higher degree of spatiotemporal organization along the trabeculated right atrium than on the septum,66,67 and (2) the presence of organization during atrial fibrillation can be detected on the surface ECG. Right endocardial mapping during atrial fibrillation was performed in 16 patients with spontaneous atrial fibrillation. Multipolar catheters were positioned along the lateral trabeculated part of the right atrium, the posteroseptal "smooth" right atrium, and the coronary sinus. During 50 minutes of atrial fibrillation, organized activation was present in 72 ± 30% of the analyzed time on the trabeculated right atrium, in 19 ± 15% on the smooth right atrium, and in 51 ± 33% along the coronary sinus (Figure 11). Furthermore, we found that when atrial fibrillation was organized along the trabeculated right atrium, the direction of activation was predominantly craniocaudal (72 ± 16%) (panel A in Figure 11), as compared to caudocranial (10 ± 9%) (panel B in Figure 11) or indeterminable (18 ± 11%) (panel C in Figure 11). The finding of a significantly more organized endocardial activation pattern on the right atrial free wall is in accordance with previously reported data obtained during catheter68 and intraoperative69 mapping. The average amplitude of the atrial fibrillation waves in 8 standard surface ECG leads was calculated in consecutive segments of atrial fibrillation unobscured by the QRST segment. In lead V1, the mean amplitude was 0.128 ± 0.061 mV during organized endocardial activation on the trabeculated right atrium (panel A in Figures 11 and 12) and 0.065 ± 0.024 mV during disorganized activation (panels D and C in Figures 11 and 12, respectively). Likewise, the mean fibrillation wave amplitude for leads I and aVF was significantly

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Figure 11. Three surface ECG lead tracings and 16 bipolar endocardial electrograms obtained simultaneously from the lateral right atrial free wall (LRA), the smooth posteroseptal right atrium (SEPT), and the coronary sinus (CS) during 4 different forms of regional endocardial organization during chronic atrial fibrillation in a 39-year-old male patient with dilated cardiomyopathy and left atrial dilatation. A. Atrial fibrillation featuring organized activation along the trabeculated right atrium with a craniocaudal direction of activation; positive fibrillation waves in leads aVF and V, demonstrate a 1:1 relation with right atrial free wall activation. B. Atrial fibrillation showing caudocranial organized activation along the right atrial free wall; negative fibrillation waves are present in surface leads aVF and V1. C. Atrial fibrillation displaying organized activation along the right atrial free wall but the predominant direction of activation is considered indeterminable; no distinct fibrillation waves are present in leads I and aVF but distinct fibrillation waves without a predominant polarity can be noted in lead V1. D. Atrial fibrillation with a disorganized activation pattern along the right atrial free wall; leads I, aVF, and V1 show low-amplitude atrial fibrillation without distinct fibrillation waves. Activation along the smooth posteroseptal right atrium is disorganized while the coronary sinus demonstrates organized activation featuring a predominantly concentric activation sequence. LRA 1-2 = recording at low lateral right atrium; LRA 15-16 = recording at high lateral right atrium; SEPT 1-2 = recording at high right atrial septum; SEPT 7-8 = recording at low right atrial septum; CS 1-2 = recording at distal coronary sinus; CS 7-8 = recording at coronary sinus os. Reproduced from reference 65, with permission.

higher during organized as compared to disorganized endocardial activation. A mean atrial fibrillation wave amplitude in lead V1 of more than 0.11 mV appeared 79% sensitive and 100% specific in predicting organized activation along the lateral part of the right atrium. In addition, when comparing the mean CL of fibrillation waves on the surface ECG (190 ± 27 ms) with the mean CL of the

simultaneously measured endocardial activation on the right atrial free wall (191 ± 27 ms), both values appeared highly comparable. Visual analysis of fibrillation wave polarity by 2 independent observers demonstrated a high incidence of positive fibrillation waves in lead V1 (12 of 14 episodes) during craniocaudal organized activation along the lateral right atrium

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Figure 12. Simultaneous recordings of 8 surface leads and 5 bipolar endocardial electrograms acquired from the lateral right atrial free wall during regionally organized (A and B) and disorganized (C) chronic atrial fibrillation in a 51-year-old-male patient with structural heart disease (i.e., left atrial dilatation). See legend of Figure 11 for abbreviations. Leads II, III, aVF, and \/1 feature positive high-amplitude fibrillation waves that demonstrate a 1:1 relation to the craniocaudal activation pattern on the trabeculated right atrium (A). Leads II, III, aVF, and V., show negative highamplitude fibrillation waves with a 1:1 relation to the caudocranial activation sequence on the trabeculated right atrium (B). All ECG signals demonstrate low-amplitude atrial fibrillation without distinct fibrillation waves during disorganized activation on the trabeculated right atrium (C). Reproduced from reference 65, with permission.

and negative fibrillation waves in lead V1 during caudocranial organized activation (11 of 14 episodes) (panels A and B in Figures 11 and 12). This resulted in an 82% specificity of the fibrillation wave polarity in lead V1 to predict the direction of activation along the lateral free wall. A subset of 4 patients demonstrated comparable results in the inferior leads, i.e., positive versus negative fibrillation waves with craniocaudal as opposed to caudocranial organized activation along the lateral right atrium (Figures 11 and 12). Our results demonstrate that a low surface amplitude in lead V1 during "fine" atrial fibrillation is associated with a disorganized activation pattern along the trabeculated right atrium. Conversely, a

high surface amplitude in lead V1 during "coarse" atrial fibrillation corresponds with organized activation in that same region. Thus, the surface ECG is capable of detecting differences in the degree of endocardial organization during atrial fibrillation. A consistent 1:1 relation was found between the fibrillation waves on the surface ECG and the organized sequence of right free wall activation. In contrast, no relation could be established between the surface fibrillation waves or right free wall activation and activation along the septum or the coronary sinus (Figures 11 and 12). This means that an approximation of the rate of activation in the trabeculated right atrium during atrial fibrillation is feasible with the

MAPPING OF ATRIAL ARRHYTHMIAS 449 standard surface ECG. Similar findings were recently obtained by Holm et al.,70 who demonstrated that the dominant atrial fibrillation CL obtained using spectral analysis of the "residual" lead V1 signal after prior QRST segment extraction ranged from 130 to 185 ms and correlated well with a spatial average of the manually determined CLs obtained from 4 right atrial endocardial recordings. It was also interesting to note that visual analysis of the fibrillation wave polarity on the surface ECG allows prediction of the direction of activation in the trabeculated right atrium. A positive and negative fibrillation wave polarity in lead V1 occurred during craniocaudal and caudocranial activation of the trabeculated right atrial free wall, respectively (panels A and B in Figure 11). These findings are in agreement with the polarity of the dominant flutter wave component in lead V1 during counterclockwise and clockwise typical atrial flutter.42,46 However, consistency in surface ECG polarity is not present when fibrillation and flutter waves in the inferior leads are compared; craniocaudal right free wall activation during atrial fibrillation is associated with positive fibrillation waves, while counterclockwise flutter results in predominantly negative flutter waves; conversely, negative fibrillation waves occur during caudocranial right free wall activation as opposed to predominantly positive flutter waves during clockwise atrial flutter. These differences may be understood when considering that the predominant flutter wave polarity in the inferior leads during both forms of typical atrial flutter is dominated by activation of the septum and left atrium.42,46,48,50,51 During atrial fibrillation, however, septal and left atrial activation is largely disorganized67 and consequently does not generate a sufficient amount of electromotive forces on

the surface ECG due to local and global cancellation effects. This leaves the trabeculated right atrium as the major electromotive force in determining the presence and polarity of fibrillation waves on the surface ECG. These assumptions are also supported by the findings of Zipes and DeJoseph,60 who demonstrated that regular right atrial activation during atrial fibrillation corresponded temporally with the fibrillation waves observed in the lead V1 recording while clearly apparent fibrillatory activity was present in the left atrium. Although only a limited number of chest leads were analyzed, we feel that the close proximity of lead Vl to the right atrium explains its sensitivity of capturing surface effects created by the activation of the trabeculated right atrial free wall during atrial fibrillation. However, more extensive ECG sampling using surface mapping techniques may provide more accurate estimates of regional differences in endocardial organization during atrial fibrillation. Some of the ongoing efforts to develop a catheter-based cure for atrial fibrillation71,72 have created a need for noninvasive techniques that enable differentiation of patients with atrial fibrillation so that their response to various treatment options can be predicted. Indeed, the ability of the surface ECG to detect organized endocardial activation makes it a potentially powerful tool with which noninvasive subsetting of patients with atrial fibrillation can be accomplished. In this respect, it is noteworthy to report on some developments in the use of ECG spectral analysis techniques to measure organization in experimental62 and clinical atrial fibrillation. 70,73-76 In the Langendorffperfused sheep heart, Skanes et al.62 demonstrated spatiotemporal periodic activity, with a high correlation to the frequency content of a pseudosurface ECG. In humans, we have shown that a

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distinction between organized and pharmacologically disorganized atrial fibrillation can be estimated from spectral variance analysis of the 62-lead body surface ECG.74 Slocum et al.73 performed power spectral analysis on a "remainder" ECG containing only fibrillation waves after developing a technique that allowed subtraction of the QRST segment from the surface signal in leads II and V1. Although this method was originally construed to automatically differentiate atrial fibrillation from a variety of other atrial rhythms, these authors also stated that the power spectra of intra-atrial and surface lead recordings were remarkably similar and were both found to occur in the 5- to 9-Hz range. A comparable approach using the V1 lead recording was adopted by Holm and co-workers70 and initially applied to document the effects of changes in vagal and sympathetic tone on the dominant atrial fibrillation CL.76 Furthermore, it has been found by Bollmann et al.75 that frequency analysis of atrial fibrillation using leads aVF, V1, and V5 of the surface ECG after QRST removal can be useful to predict spontaneous termination of atrial fibrillation and the response to antiarrhythmic agents. These investigators found that a low peak frequency in the ECG signal was associated with a higher spontaneous and ibutilide-induced conversion rate. Although the methods to characterize atrial fibrillation using the surface ECG require further investigation and development, it is evident that they may be of critical importance in providing a noninvasive clinical tool to subset patients with atrial fibrillation. Conclusions and Future Directions In this chapter, we have attempted to provide new insight in the role of the surface ECG in the diagnosis and man-

agement of atrial arrhythmias. Several novel clinical ECG applications were introduced that are aimed at improving the noninvasive diagnostic performance of the surface ECG. These applications are based on either the classic 12-lead scalar ECG format using conventional visual or advanced spectral analysis techniques or a spatial approach featuring sophisticated multiple-lead ECG mapping. All of these developments clearly must be considered in the light of the advances achieved in the invasive electrophysiological study and catheter ablative treatment of atrial arrhythmias. The vastly improved understanding of the complex atrial arrhythmia substrate, provided by a wealth of experimental and invasive clinical data, has led to this renaissance of the role of the surface ECG mainly because of the selection of more appropriate ECG techniques and improved gold standard correlations of the surface ECG with the actual underlying intracardiac activation sequence. The currently proposed ECG indications to localize atrial tachycardia, classify atrial flutter, and characterize atrial fibrillation do require further development and prospective validation before widespread clinical application can be considered. Also, the aforementioned indications are by no means conclusive and we are convinced that other applications will be introduced in the near future. In this respect, it is particularly interesting to consider the recent advances achieved with the use of catheter ablation to cure focally mediated atrial fibrillation.72,77-79 Rapid noninvasive identification of the focal origin of this type of atrial fibrillation using an ECG localization algorithm based on surface mapping techniques may be of great clinical significance to select patients and target catheter mapping prior to the ablative intervention.

MAPPING OF ATRIAL ARRHYTHMIAS References 1. Lewis T. Galvanometric curves yielded by cardiac beats generated in various areas of the auricular musculature. The pacemaker of the heart. Heart 1910-1911;2: 23-46. 2. Lewis T, Feil HS, Stroud WD. Observations upon flutter and fibrillation: Part II. The nature of auricular flutter. Heart 1918-1920;7:191–245. 3. Lewis T, Drury AN, Iliescu CC. A demonstration of circus movement in clinical flutter of the auricles. Heart 1921;8:341359. 4. Massumi R, Tawakkol AA. Direct study of left atrial P waves. Am J Cardiol 1967:20: 331-340. 5. Harris BC, Shaver JA, Gray S, et al. Left atrial rhythm. Experimental production in man. Circulation 1968;37:1000-1014. 6. Leon DF, Lancaster JF, Shaver JA, et al. Right atrial ectopic rhythms. Experimental production in man. Am J Cardiol 1970; 25:6-10. 7. Mirowski M. Ectopic rhythms originating anteriorly in the left atrium. Analysis of 12 cases with P-wave inversion in all precordial leads. Am Heart J 1967; 74:299308. 8. Maclean WAH, Karp RB, Kouchoukos NT, et al. P waves during ectopic atrial rhythms in man. A study utilizing atrial pacing with fixed electrodes. Circulation 1975;52:426-434. 9. Man KG, Chan KK, Kovacek P, et al. Spatial resolution of atrial pace mapping as determined by unipolar atrial pacing at adjacent sites. Circulation 1996;94:13571363. 10. Tang CW, Scheinman MM, Van Hare GF, et al. Use of P wave configuration during atrial tachycardia to predict site of origin. J Am Coll Cardiol 1995;26: 1315-1324. 11. Tada H, Nogami A, Naito S, et al. Simple electrocardiographic criteria for identifying the site of origin of focal right atrial tachycardia. Pacing Clin Electrophysiol 1998;21(Pt II):2431-2439. 12. Farshidi A, Josephson ME, Horowitz LN. Electrophysiologic characteristics of concealed bypass tracts: Clinical and electrocardiographic correlates. Am J Cardiol 1978;41:1052-1060. 13. Garcia Civera R, Ferrero JA, Sanjuan, R, et al. Retrograde P wave polarity in reci-

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procating tachycardia utilizing lateral bypass tracts. Eur Heart J 1980; 1:137145. 14. Tai CT, Chen SA, Chiang CE, et al. A new electrocardiographic algorithm using retrograde P waves for differentiating atrioventricular node reentrant tachycardia from atrioventricular reciprocating tachycardia mediated by concealed accessory pathway. J Am Coll Cardiol 1997;29:394402. 15. Kuchar DL, Thorburn CW, Sammel NL, et al. Surface electrocardiographic manifestations of tachyarrhythmias: Clues to diagnosis and mechanism. Pacing Clin Electrophysiol 1988;ll:61-82. 16. Fitzgerald DM, Hawthorne HR, Crossley GH, et al. P wave morphology during atrial pacing along the atrioventricular ring. ECG localization of the site of origin of retrograde atrial activation. J Electrocardiol 1996;29:1-10. 17. King TD, Barr RC, Herman-Giddens S, et al. Isopotential body surface maps and their relationship to atrial potentials in the dog. Circ Res 1972;30:393-405. 18. Kawano S, Hiraoka M, Yamamoto M, et al. Body surface maps of ectopic P waves originating in the left atrium in the dog. J Electrocardiol 1989;22:27-43. 19. Kawano S, Hiraoka M. P wave mapping in ectopic atrial rhythm. In: Yasui S, Abildskov JA, Yamada K, Harumi K (eds): Advances in Body Surface Mapping and High Resolution ECG. Nagoya, Japan: Life Medicom; 1995:47-56. 20. SippensGroenewegen A, Peeters HAP, Jessurun ER, et al. Body surface mapping during pacing at multiple sites in the human atrium. P wave morphology of ectopic right atrial activation. Circulation 1998;97:369-380. 21. SippensGroenewegen A, Roithinger FX, Scholtz DB, et al. Body surface mapping during left atrial pace mapping: Evaluation of spatial differences in P wave configuration. J Am Coll Cardiol 1998;31: 46A. Abstract. 22. SippensGroenewegen A, Roithinger FX, Scholtz DB, et al. Noninvasive localization of right atrial tachycardia using an atlas of paced P wave body surface integral map patterns. Pacing Clin Electrophysiol 1998;21:858. Abstract. 23. Mirvis DM. Rationale for body surface electrocardiographic mapping. In: Mirvis DM (ed): Body Surface Electrocardiographic

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Mapping. Norwell, MA: Kluwer Academic Publishers; 1988:31-41. 24. Flowers NC, Horan LG. Body surface potential mapping. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology. From Cell to Bedside. Philadelphia: W.B. Saunders Co.; 1995:1049-1067. 25. Taccardi B, Punske BB, Lux RL, et al. Useful lessons from body surface mapping. J Cardiovasc Electrophysiol 1998;9: 773-786. 26. Rudy Y. The electrocardiogram and its relationship to excitation of the heart. In: Sperelakis N (ed): Physiology and Pathophysiology of the Heart. Norwell, MA: Kluwer Academic Publishers; 1995:201239. 27. Oster HS, Taccardi B, Lux RL, et al. Noninvasive electrocardiographic imaging: Reconstruction of epicardial potentials, electrograms, and isochrones and localization of single and multiple electrocardiac events. Circulation 1997;96:10121024. 28. Huiskamp G, Greensite F. A new method for myocardial activation imaging. IEEE Trans Biomed Eng 1997;44: 433-446. 29. McAlpine WA. An attitudinal review of the heart. An introduction to spatial clinical investigations. In: McAlpine WA (ed): Heart and Coronary Arteries. New York: Springer-Verlag; 1975:101-122. 30. SippensGroenewegen A, Spekhorst H, van Hemel NM, et al. Body surface mapping of ectopic left and right ventricular activation. QRS spectrum in patients without structural heart disease. Circulation 1990;82:879-896. 31. SippensGroenewegen A, Spekhorst H, van Hemel NM, et al. Body surface mapping of ectopic left ventricular activation. QRS spectrum in patients with prior myocardial infarction. CircRes 1992;71:1361-1378. 32. Kalman JM, Olgin JE, Karch MR, et al. "Cristal tachycardias": Origin of right atrial tachycardias from the crista terminalis identified by intracardiac echocardiography. J Am Coll Cardiol 1998;31:451459. 33. Jolly WA, Ritchie WT. Auricular flutter and fibrillation. Heart 1910-1911;2:177221. 34. Lewis T. Observations upon a curious and not uncommon form of extreme acceleration of the auricle. "Auricular flutter." Heart 1912-1913;4:171-219. 35. Kato S, Sato M, Harumi K, et al. Observations upon F wave. Resp Circ 1957;5:837.

36. Puech P, Latour H, Grolleau R. La flutter et ses limites. Arch Mai Coeur 1970;61: 115-144. 37. Cosio FG, Goicolea A, Lopez-Gil M, et al. Atrial endocardial mapping in the rare form of atrial flutter. Am J Cardiol 1990;66:715-720. 38. Olshansky B, Okumura K, Hess PG, et al. Demonstration of an area of slow conduction in human atrial flutter. J Am Coll Cardiol 1990; 16:1639-1648. 39. Feld GK, Fleck PR, Chen PS, et al. Radiofrequency catheter ablation for the treatment of human type I atrial flutter. Identification of a critical zone in the reentrant circuit by endocardial mapping techniques. Circulation 1992;86:12331240. 40. Cosio FG, Arribas F, Lopez-Gil M, et al. Radiofrequency ablation of atrial flutter. J Cardiovasc Electrophysiol 1996;7:60-70. 41. Lesh MD, Kalman JM. To fumble flutter or tackle "tach" ? Toward updated classifiers for atrial tachyarrhythmias. J Cardiovasc Electrophysiol 1996;7:460-466. 42. Saoudi N, Nair M, Abdelazziz A, et al. Electrocardiographic patterns and results of radiofrequency catheter ablation of clockwise type I atrial flutter. J Cardiovasc Electrophysiol 1996;7:931-942. 43. Olgin JE, Kalman JM, Lesh MD. Conduction barriers in human atrial flutter: Correlation of electrophysiology and anatomy. J Cardiovasc Electrophysiol 1996; 7:1112-1126. 44. Cosio FG, Arribas F, Lopez-Gil M, et al. Catheter mapping studies in atrial flutter. In: Waldo AL, Touboul P (eds): Atrial Flutter: Advances in Mechanisms and Management. Armonk, NY: Futura Publishing Co.; 1996:269-283. 45. Shah DC, Jais P, Haissaguerre M, et al. Three-dimensional mapping of the common atrial flutter circuit in the right atrium. Circulation 1997;96:3904-3912. 46. Kalman JM, Olgin JE, Saxon LA, et al. Electrocardiographic and electrophysiologic characterization of atypical atrial flutter in man. Use of activation and entrainment mapping and implications for catheter ablation. J Cardiovasc Electrophysiol 1997;8:121-144. 47. Anderson RH, Becker AE (eds): Cardiac Anatomy. An Integrated Text and Color Atlas. London: Gower Medical Publishing; 1980. 48. SippensGroenewegen A, Lesh, MD, Roithinger FX, et al. Body surface mapping

MAPPING OF ATRIAL ARRHYTHMIAS of counterclockwise and clockwise typical atrial flutter: A comparative analysis with endocardial activation sequence mapping. JAm Coll Cardiol 2000;35:1276-1287. 49. Josephson ME. Ectopic rhythms and premature depolarizations. In: Josephson ME (ed): Clinical Cardiac Electrophysiology. Techniques and Interpretations. Malvern, PA: Lea and Febiger; 1993:167-180. 50. Okumura K, Plumb VJ, Page PL, et al. Atrial activation sequence during atrial flutter in the canine pericarditis model and its effects on the polarity of the flutter wave in the electrocardiogram. J Am Coll Cardiol 1991;17:509-518. 51. Schoels W, Offner B, Brachmann J, et al. Circus movement atrial flutter in the canine sterile pericarditis model. Relation of characteristics of the surface electrocardiogram and conduction properties of the reentrant pathway. J Am Coll Cardiol 1994;23:799-808. 52. Kawano S, Sawanobori T, Hiraoka M. Body surface maps in 2 cases of atrial flutter. Jpn Heart J 1984;25:283-292. 53. Hewlett AW, Wilson FN. Coarse auricular fibrillation in man. Arch Intern Med 1915; 15:786-792. 54. Thurmann M, Janney JG. The diagnosis and importance of fibrillatory wave size. Circulation 1962;2:991-994. 55. Culler MR, Boone JA, Gazes PC. Fibrillatory wave size as a clue to etiological diagnosis. Am Heart J 1963;66:435-436. 56. Morganroth J, Horowitz LN, Josephson ME, et al. Relationship of atrial fibrillatory wave amplitude to left atrial size and etiology of heart disease. An old generalization re-examined. Am Heart J 1979;97: 184-186. 57. Aysha MH, Hassan AS. Diagnostic importance of fibrillatory wave amplitude: A clue to echocardiographic left atrial size and etiology of atrial fibrillation. J Electrocardiol 1988;21:247-251. 58. Li YH, Hwang JJ, Tseng YZ, et al. Clinical significance of fibrillatory wave amplitude. A clue to left atrial appendage function in nonrheumatic atrial fibrillation. Chest 1995; 108:359-363. 59. Moe GK. On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacodyn Ther 1962; 140:183-188. 60. Zipes DP, DeJoseph RL. Dissimilar atrial rhythms in man and dog. Am J Cardiol 1973;32:618-628. 61. Kirchhof C, Chorro F, Scheffer GJ, et al. Regional entrainment of atrial fibrilla-

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tion studied by high-resolution mapping in open-chest dogs. Circulation 1993;88:736749. 62. Skanes AC, Mandapati R, Berenfeld 0, et al. Spatiotemporal periodicity during atrial fibrillation in the isolated sheep heart. Circulation 1998;98:1236-1248. 63. Gerstenfeld EP, Sahakian AV, Swiryn S. Evidence for transient linking of atrial excitation during atrial fibrillation in humans. Circulation 1992;86:375-382. 64. Botteron GW, Smith JM. Quantitative assessment of the spatial organization of atrial fibrillation in the intact human heart. Circulation 1996;93:513-518. 65. Roithinger FX, SippensGroenewegen A, Karch MR, et al. Organized activation during atrial fibrillation in man: Endocardial and electrocardiographic manifestations. J Cardiovasc Electrophysiol 1998;9:451-461. 66. Roithinger FX, Karch MR, Steiner PR, et al. The relationship between atrial fibrillation and typical atrial flutter in man: Activation sequence changes during spontaneous conversion. Circulation 1997;96: 3484-3491. 67. Lesh MD, Kalman JM, Olgin JE, et al. The role of atrial anatomy in clinical atrial arrhythmias. J Electrocardiol 1996; 29(Suppl): 101-113. 68. Jais P, Haissaguerre M, Shah DC, et al. Regional disparities of endocardial atrial activation in paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 1996;19: 1998-2003. 69. Konings KTS, Kirchhof CJHJ, Smeets JRLM, et al. High-density mapping of electrically induced atrial fibrillation in humans. Circulation 1994;89:1665-1680. 70. Holm M, Pehrson S, Ingemansson M, et al. Non-invasive assessment of the atrial cycle length during atrial fibrillation in man: Introducing, validating and illustrating a new ECG method. Cardiovasc Res 1998:38:69-81. 71. Haissaguerre M, Jais P, Shah DC, et al. Right and left atrial radiofrequency catheter therapy of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 1996; 7:1132-1144. 72. Haissaguerre M, Jais P, Shah DC, et al. Radiofrequency catheter ablation for paroxysmal atrial fibrillation in humans: Elaboration of a procedure based on electrophysiological data. In: Murgatroyd FD, Camm AJ (eds): Nonpharmacological Management of Atrial Fibrillation.

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Armonk, NY: Futura Publishing Co.;1997: 257-279. 73. Slocum J, Sahakian A, Swiryn S. Diagnosis of atrial fibrillation from surface electrocardiograms based on computer-detected atrial activity. JElectrocardiol 1992;25:l-8. 74. Roithinger FX, SippensGroenewegen A, Ellis WS, et al. Analysis of spectral variance from the total body surface ECG: A new quantitative noninvasive tool for measuring organization in atrial fibrillation. Circulation 1997;96:I-459. Abstract. 75. Bollmann A, Kanuru NK, McTeague KK, et al. Frequency analysis of human atrial fibrillation using the surface electrocardiogram and its response to ibutilide. Am JCardiol 1998;81:1439-1445.

76. Ingemansson MP, Holm M, Olsson SB. Autonomic modulation of the atrial cycle length by the head up tilt test: Non-invasive evaluation in patients with chronic atrial fibrillation. Heart 1998;80:71-76. 77. Jais P, Haissaguerre M, Shah DC, et al. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation 1997;95:572-576. 78. Haissaguerre M, Jais P, Shah D, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. NEngl JMed 1998; 339:659-666. 79. Chen SA, Tai CT, Yu WC, et al. Right atrial focal atrial fibrillation: Electrophysiologic characteristics. J Cardiovasc Electrophysiol 1999; 10:328-335.

Chapter 22

Surface Electrocardiographic Mapping of Ventricular Tachycardia: Correlation with Electrophysiological Mapping John M. Miller, MD, Jeffrey E. Olgin, MD, Thabet Al-Sheikh, MD, and Gregory T. Altemose, MD

Introduction

that had occurred spontaneously cannot be readily initiated at electrophysiology study, or only nonsustained episodes can be induced, precluding detailed activation mapping. Thus, other ways of obtaining mapping data that can guide ablation efforts have been sought. In this chapter we discuss techniques of obtaining information from the surface ECG during VT that can be used to guide the electrophysiologist to place catheters in regions likely to contain sites at which ablation will be successful. Current techniques allow consideration of only uniform morphology VT, and not of polymorphic VT or ventricular fibrillation.

Radiofrequency catheter ablation of ventricular tachycardia (VT) remains one of the most demanding procedures in clinical electrophysiology. Successful ablation requires energy delivery at highly specific target sites. This is necessitated by the limited amount of damage that can be effected with currently available ablation technologies at the often-scarred arrhythmogenic areas in patients with structural heart disease, as well as by the desire to limit the amount of damage to normal, nonarrhythmogenic myocardium in all patients. Several techniques have been devised and validated to locate these target sites, most of which are based on Background activation mapping during prolonged episodes of VT; however, many patients Efforts at correlating surface ECG with VT have poor hemodynamic toler- morphology with site of impulse formation ance of even a few minutes of VT. In addi- or propagation began with the attempt tion, in many patients, morphologies of VT to predict the location of the ventricular From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003.

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insertion of an accessory pathway in patients with Wolff-Parkinson-White syndrome. Several algorithms have been proposed for this purpose, with good accuracy.1-4 In the setting of VT, similar efforts to correlate ECGs with sites of earliest diastolic activation during VT ("site of origin") were an outgrowth of early pace mapping studies. In these studies, endocardial pacing was performed at putative VT "sites of origin" in an attempt to replicate the 12-lead ECG of VT.5,6 These studies showed a remarkable interpatient consistency of ECGs when pacing in certain regions. Based on these findings, these investigators began looking at the ECG during VT to determine if it contained any information that would be helpful in localizing sites for possible ablation.7 Techniques and Results Several techniques have been used to correlate VT configurations on the surface ECG with sites of earliest diastolic activity during VT. These may be divided into those using morphological features (QRS contours on standard ECG), those based on body surface minima, and those based on isointegral mapping. These techniques are discussed in other chapters and are therefore not discussed further here. The remainder of this chapter deals with standard surface ECGendocardial mapping correlates. Most of the available information in this area was obtained in patients with postinfarct VT; fewer data exist for other VT substrates. Postinfarct VT Miller et al.8 published the most extensive study correlating surface ECG features during VT with data from endocardial mapping. These authors retrospectively analyzed 182 VT s in 108 patients with postinfarct VT. Parameters analyzed included (1) area of infarction (anterior or

inferior wall); (2) bundle branch block (BBB) type configuration (right [R] or left [L]); (3) quadrant of frontal plane axis (R or L superior [S] or inferior [I]); and (4) one of 8 distinct precordial R wave progression patterns. All VTs in this series could be characterized using these features. VT sites of origin (site of earliest diastolic activity during VT) were determined by catheter or intraoperative mapping. These authors found that 48% of VTs were mapped to a particular region (comprising about 5 to 7 cm2) with greater than 70% positive predictive accuracy; the analysis required at least 5 instances of the same morphology of VT in order to infer a relationship with an endocardial region. This was more often true of VTs in the setting of inferior infarction (in which 74% of VTs had good correlations between surface ECG and endocardial mapping data) than anterior infarction (37% of VTs correlated), and with LBBBtype VTs (73% of VTs correlated) than with RBBB-type VTs (31% of VTs correlated). The authors derived an algorithm based on these retrospective data, and then applied it in a prospective, blinded fashion to a group of 110 VTs from 63 other patients. They found that the algorithm correctly indicated the mapped endocardial origin in 93% of the VTs to which the algorithm could be applied; however, the algorithm could only be applied to 65 (59%) of VTs. This applicability rate was not due to an inability to characterize the VTs according to the 4 types of features used, rather that 41% of all VTs did not originate in a specific area in at least 70% of cases. Figures 1 through 3 contain a synopsis of the results of this analysis. Kuchar et al.9 performed a similar correlation of surface ECG features during VT with endocardial mapping. These authors approached the problem somewhat differently: they developed an algorithm for predicting the endocardial site of origin of VT based on a set of consistent

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Figure 1. Standard endocardial catheter mapping scheme. Top: The heart is depicted with the lateral wall opened and anterior and inferior walls reflected to reveal the entire endocardial surface. Numbered sites constitute the mapping scheme. Bottom: Right (RAO) and left (LAO) anterior oblique projections of the left ventricle (shaded) with catheter mapping sites as they appear fluoroscopically. Axial diagrams at bottom show orientation of the heart within the body.

ECG characteristics derived from detailed pace mapping in the setting of sinus rhythm in a group of 22 patients with prior infarction. For localizing sites of pace mapping, they divided the left ventricle (LV) into apical, middle, and basal zones and anterior, middle, and inferior zones in the right anterior oblique (RAO) view, and septal, central, and lateral zones in the left anterior oblique (LAO) view. With this system, any LV site could be characterized in all 3 spatial axes. They found that (1) a net positive deflection in lead I indicated

septal or central pacing sites (LAO view); (2) a net positive deflection in lead II indicated anterior or midventricular pacing sites (RAO view); (3) a net negative deflection in lead Vl suggested septal or central sites (LAO view); and (4) a net negative deflection in lead V4 was seen when pacing at apical or mid zones (RAO view). The resultant algorithm is complex (Figure 4) but relatively easy to use. The authors applied the algorithm in another group of 42 postinfarct patients with 44 VTs. In 17 (39%) of these VTs, the algorithm correctly

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Figure 2. Results of correlation of ventricular tachycardia (VT) morphology with endocardial activation mapping in patients following anterior infarction, adapted from reference 8. A condensed algorithm is shown at top for determining where in the left ventricle a particular VT morphology typically arises. Below are the right (RAO) and left (LAO) anterior oblique projections shown in Figure 1; shaded areas indicate regions at which the indicated VT morphologies are typically mapped. Note that only septal sites are represented; however, the number of VTs included within these regions comprise approximately 40% of all VTs encountered in anterior infarction patients. BBB = bundle branch block; Inf = inferior; Ant = anterior; R = right; L = left; Sup = superior.

predicted the site of earliest endocardial activation during VT in all 3 axes (apicalbasal, inferior-anterior, septal-lateral), and in 2 of 3 axes in another 16 (36%) VTs. No distinction in predictive capacity was found between anterior and inferior infarction locations, although the number of cases studied may have been insufficient to detect a difference. This study correlated

sinus rhythm pace mapping with endocardial activation mapping during VT surprisingly well, considering the sensitivity and specificity limitations inherent with pace mapping.6 The low specificity of pace mapping (very similar QRS complexes resulting from pacing over a wide area) may be related to the presence of anatomical barriers around slowly conducting tissue,

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Figure 3. Results of correlation of ventricular tachycardia (VT) morphology with endocardial activation mapping in patients following inferior infarction, following the same format as in Figure 2; adapted from reference 8. A larger variety of VT morphologies is shown than in the case of anterior infarction-related VT; the number of VTs included within these regions comprises approximately 80% of all VTs encountered in inferior infarction patients. BBB = bundle branch block; Inf = inferior; R = right; L = left; Sup = superior; Lat = lateral; Sept = septum; Rev = reverse.

while poor sensitivity of pace mapping (pacing at an appropriate site but yielding a QRS configuration distinctly different from that of VT) may be due to the presence of functional rather than anatomically based block protecting diastolic elements. Davis et al.10 attempted a similar correlation of the ECG contours during VT and endocardial activation mapping during 68 distinct VTs in 20 postinfarct

patients. They compared the results of activation mapping during VT obtained with 60 simultaneous recordings from intracardiac catheters with the calculated integrals of the initial 60 ms of the surface ECG of VT. This analysis showed that VTs with initial vectors pointing either inferoposteriorly or anterosuperiorly typically had septal origins, while VTs with rightward superior vectors were mapped to

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Figure 4. Results of correlation of ventricular tachycardia (VT) morphology with endocardial activation and pace mapping in postinfarct patients, adapted from reference 9. Top: Left ventricular topographical designation used by these authors, dividing the chamber into 3 zones in each spatial axis. Bottom: Process for analyzing the VT ECG; each step attempts to place the VT in one zone of within its axis. (+) = net positive deflection; (-) = net negative deflection; iso = isoelectric; Mid = middle; Cent = central.

the inferior wall or apex. The initial vector did not define the arrhythmogenic region more precisely than the entire QRS complex. The authors found that similar morphologies could have origins in widely different regions and that a given region could give rise to many different QRS configurations, and thus they felt that the surface ECG was of limited value in guiding mapping procedures.

Outflow Tract VT Ventricular tachycardia with an LBBB configuration and inferior axis occurring in the absence of structural heart disease has long been recognized as having its origin in the right ventricular outflow tract (RVOT). Based on clinical presentation alone, detailed mapping could be carried out in a relatively small anatomical

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area (the right RVOT). Some additional RVOT region in 29; but no adequate ablamethods of further refining where within tion sites (activation or pace mapping crithe RVOT the catheter should be placed teria) were found in the RVOT for 4 for optimal mapping would be helpful in patients. Each of these had precordial R cases in which only nonsustained VT or wave transitions at or before V2 during even isolated ectopic beats can be initi- VT and each was mapped to the LV outated. Jadonath et al.11 reported results of flow tract (LVOT).15 These investigators pace mapping in the RVOT in 11 patients thus suggested that an early precordial R in an attempt to correlate site of impulse wave transition from negative to positive formation within the RVOT with ECG (i.e., dominant R wave appearing in Vl or V?) features. They divided the septal portion during VT indicated an LVOT origin rather of the RVOT into 9 equal regions and per- than an RVOT origin. Similar observations formed an analysis very similar to that have been made by others. used by Kuchar et al.9 in postinfarct VT by pacing at each predetermined region and correlating location of the paced site LV Septal VT with ECG characteristics. The authors This unusual form of VT, often sensifound that the QRS in lead I became more positive as the site of pacing moved more tive to verapamil, has a typical ECG morposteriorly along the septum; when lead phology (RBBB, leftward superior axis, I had any R wave, the presence or absence reverse R wave progression with relatively of an R in lead aVL helped further refine narrow QRS complexes) and relatively the site of impulse origin in the apical- consistent sites of earliest endocardial actibasal plane, and if the precordial R wave vation during VT (midinferior LV septum 16 20 transition occurred by lead V3, more basal or just onto the inferior wall), " although and superior sites (closer to the pulmonic some variation has been observed (Figure 5). valve) were suggested (Figure 5). The Purkinje potentials during VT and sinus results of testing this algorithm in 18 rhythm are almost uniformly present at patients with outflow tract tachycardia sites of successful ablation. Why this parwere subsequently reported by this ticular area is arrhythmogenic while others group.12 They found that it correctly indi- within the Purkinje network are not is cated sites from which pace mapping entirely unclear. replicated the patient's VT in 16 of the 18 cases. Gumbrielle et al.13 observed a mean 35° rightward shift in axis from Other VTs in the Absence sinus rhythm to RVOT VT in each of 10 of Structural Heart Disease patients studied, but all tachycardias in Although no large series of these VTs this series had a septal origin; no information was available on nonseptal VTs. have been reported in the literature, the Rodriguez et al.14 suggested that a nega- general experience has been that the ECG tive QRS in lead I and precordial transi- morphology during VT correlates relatively tion prior to lead V4 suggested septal sites well with anticipated regions of impulse of origin for RVOT VT, whereas a positive origin when there is no myocardial damage QRS in lead I and precordial transition at to alter impulse propagation. Thus, a VT V2 suggested a free wall site of origin. with an RBBB, rightward inferior axis, and Callans et al.15 studied 33 patients who positive concordance can be expected to had a clinical presentation consistent arise in the posterobasal lateral LV, while with RVOT VT, and mapped VT to the VT with an LBBB, leftward superior axis,

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Figure 5. Results of correlation of ventricular tachycardia (VT) morphology with endocardial activation and pace mapping in patients without structural heart disease, following the same format as previous figures. The right ventricular outflow tract (RVOT) septal and free walls are shaded, as are portions of the left ventricle at which the indicated VTs are mapped. The triaxial diagrams in the center differ from those in prior figures because the directions are shown relative to the right ventricle (septal and lateral reversed). At bottom is an algorithm adapted from reference 11 for localizing RVOT VTs.

and poor R wave progression would be expected to arise near the RV apex. Other VT Substrates (Structural Heart Disease Present) No significant body of data exists regarding correlation of ECG morphology during VT with endocardial activation mapping in idiopathic cardiomyopathy, RV dysplasia,

Chagasic cardiomyopathy, or other less common substrates for VT. Anecdotally, VT in the setting of Chagas' disease has characteristics very similar to those of postinfarct VT (ability to record mid-diastolic activation during VT, presence of LV aneurysms)21,22 and it is thus possible that algorithms correlating VT morphology with mapping data in postinfarct VT may be similarly applicable. On the other hand, it

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FigureS. Cardiomyopathic ventricular tachycardia (VT) in which ECG morphology-derived predicted endocardial mapping sites are discordant with actual mapping data. The ECG (top) shows a right bundle branch block, left superior axis VT with reverse R wave progression. This would ordinarily indicate an ablation target site in the basal inferomedial left ventricle, perhaps on the septum (Figure 3); however, catheter mapping (bottom) showed a site in the high lateral basal left ventricular free wall (near site 10 on Figure 1) having a mid-diastolic electrogram (arrow) preceding the QRS onset (dashed line) by 190 ms. Radiofrequency energy delivered here terminated this VT and rendered it noninducible. Abl = ablation; 1-2 = tip electrode; HRA = high right atrium; RVA = right ventricular apex.

seems clear that the ECG during VT related Limitations to idiopathic dilated cardiomyopathy is very difficult to correlate with any consis- Validity of the Previous Studies tent or logical anatomical site (i.e., a case of RBBB leftward superior axis VT ablated Most of the data from prior studies successfully from the high basal lateral LV were gathered using relatively old mapfree wall [Figure 6]). ping techniques (diastolic activation times

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during VT > 40 ms prior to QRS onset as the sole criterion). This may have resulted in false associations in some cases, and an inability to find an association that actually did exist in others. In recent years, mapping techniques have been refined beyond those used in these prior studies, and future studies using these newer techniques should have greater validity (actually measuring what is intended). Scope of Available Predictive Models It is important to note that the algorithms discussed were derived from a somewhat select group of patients who generally had single regions of infarction (anterior or inferior walls). Most of these patients had large infarctions in the prethrombolytic era. The findings from these studies may not be as readily applied to patients who have smaller infarct zones resulting from incomplete reperfusion following attempted thrombolytic therapy. In addition, as good as the algorithms appear, they are not universally applicable. Indeed, the complex analysis by Miller and colleagues8 could be applied to only 59% of VTs in the prospective portion of their analysis. To What Do These Techniques Actually Point? Most of the techniques discussed above attempt to correlate the contours of the surface ECG during VT with the site at which global ventricular activation begins. They succeed reasonably well; however, it should be recalled that in cases of reentrant VT (particularly in the postinfarct patient), the site of electrical activation coincident with the onset of the QRS complex in VT (the "zero isochrone") is not itself the optimal target site for ablation, but is instead the exit site from a circuit or relatively protected slow conduction zone.23,24 This dissociation between optimal ablation

site and site at which endocardial activation occurs simultaneously with QRS onset is a function of slow impulse propagation through a relatively small amount of myocardium such that during the time it is activated no surface QRS activity is registered. The distance between the site activated at the time of QRS onset and sites at which ablation attempts are most likely to succeed may be several centimeters.25-28 In contrast, in most cases of VT occurring in the absence of structural heart disease, a focal mechanism (automaticity, triggered activity, or microreentry) is most likely responsible and the site of impulse formation is at or very near where global activation begins, coincident with the onset of the surface QRS complex. This close correlation between optimal ablation site and the site activated at the time of QRS onset is due to the lack of slow impulse propagation in or away from the arrhythmogenic tissue in these cases. Spatial Resolution Limitations The spatial resolution of these techniques is not adequate as a single technique to guide catheter placement for VT ablation. When the existing correlations between VT morphology and mapping data were corroborated by cure of VT, the curative procedure was surgical, not catheter based. The amount of tissue removed or damaged at surgery is clearly more than can be affected by current catheter ablation techniques. Despite this shortcoming, features of the ECG during VT can still serve as a guide to regionalize where efforts at activation mapping during VT should be concentrated. Substrate Limitations The vast majority of the extant data correlating surface ECG features of VT with the region of "origin" were derived from cases of postinfarct VT (usually with

SURFACE ECG MAPPING OF VENTRICULAR TACHYCARDIA single large infarctions, anterior or inferior). The results of these studies may not be applicable in cases of multiple regions of infarction or VT substrates other than prior infarction (such as cardiomyopathy, sarcoid, ventricular dysplasia, Chagas' disease, etc.). The principles do appear to apply to cases of VT occurring in the absence of overt structural heart disease. Given all of the problems inherent in using the ECG morphology as a guide to mapping, what is the present role of these tools in catheter mapping and ablation of VT? Acknowledging the limitations of the currently available techniques, the ECG during VT should still be analyzed and existing algorithms employed where applicable to direct attention and mapping efforts to endocardial regions likely to contain reasonable target sites for ablation. This can expedite the mapping process considerably by allowing the operator to spend time mapping in high-yield regions (some of which may not be readily accessed by the catheter) rather than randomly surveying the majority of the ventricular endocardium that is passively activated during VT. If no suitable electrograms are found after extensive mapping in the region indicated by the algorithm, mapping efforts can be broadened to other areas. Surface ECG Mapping of VT: What Is Next? Catheter ablation of VT is being attempted more frequently now than in previous years. Additional tools to facilitate successful ablation by directing the electrophysiologist's attention to specific target regions are certainly welcome. Paradoxically, however, use of the surface ECG morphology during VT for this purpose has become less useful than in the era of surgical therapy because the spatial resolution of this technique—more than adequate for surgical resection—is not of

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sufficient precision as a single tool to guide catheter ablation. As experience with mapping and ablation of VT continues to grow, it is anticipated that additional refinements will be made in the above techniques for correlating ECG morphology with mapping data. At the same time, the availability of sophisticated simultaneous multielectrode mapping systems may make localizing information derived from the surface ECG less important. We are currently in the process of revising our original algorithm correlating surface ECG features of VT with endocardial mapping by analyzing a more contemporary series of VTs that have been studied using improved mapping techniques. Hopefully, this will yield refinements in the algorithm that can make the surface ECG during VT a more accurate indicator of where the ablationist should concentrate his or her mapping efforts, or can potentially even obviate the need for activation mapping during VT in some cases. References 1. Gallagher JJ, Pritchett EL, Sealy WC, et al. The preexcitation syndromes. Prog Cardiovasc Dis 1978;20:285-327. 2. Reddy GV, Schamroth L. The localization of bypass tracts in the Wolff-Parkinson-White syndrome from the surface electrocardiogram. Am Heart J1987;113:984-993. 3. Milstein S, Sharma AD, Guiraudon GM, et al. An algorithm for the electrocardiographic localization of accessory pathways in the Wolff-Parkinson-White syndrome. Pacing Clin Electrophysiol 1987;10:555-563. 4. Lindsay BD, Crossen KJ, Cain ME. Concordance of distinguishing electrocardiographic features during sinus rhythm with the location of accessory pathways in the Wolff-Parkinson-White syndrome. AmJCardiol 1987;59:1093-1102. 5. Waxman HL, Josephson ME. Ventricular activation during ventricular endocardial pacing. I. Electrocardiographic patterns related to the site of pacing. Am J Cardiol 1982;50:1-10. 6. Josephson ME, Waxman HL, Cain ME, et al. Ventricular activation during ventricular

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endocardial pacing. II. Role of pace-mapping to localize origin of ventricular tachycardia. Am J Cardiol 1982;50:11-22. 7. Josephson ME, Horowitz LN, Waxman HL, et al. Sustained ventricular tachycardia: Role of the 12-lead electrocardiogram in localizing site of origin. Circulation 1981;64:257-272. 8. Miller JM, Marchlinski FE, Buxton AE, et al. Relationship between the 12-lead electrocardiogram during ventricular tachycardia and endocardial site of origin in patients with coronary artery disease. Circulation 1988;77:759-766. 9. Kuchar DL, Ruskin JN, Garan H. Electrocardiographic localization of the site of origin of ventricular tachycardia in patients with prior myocardial infarction. J Am Coll Cardiol 1989;13:893-903. 10. Davis LM, Byth K, Uther JB, et al. Localisation of ventricular tachycardia substrates by analysis of the surface QRS recorded during ventricular tachycardia. Int J Cardiol 1995;50:131-142. 11. Jadonath RL, Schwartzman DS, Preminger MW, et al. Utility of the 12-lead electrocardiogram in localizing the origin of right ventricular outflow tract tachycardia. Am Heart J 1995;130:1107-1113. 12. Movsowitz C, Schwartzman D, Callans DJ, et al. Idiopathic right ventricular outflow tract tachycardia: Narrowing the anatomic location for successful ablation. Am Heart J 1996;131:930-936. 13. Gumbrielle TP, Bourke JP, Doig JC, et al. Electrocardiographic features of septal location of right ventricular outflow tract tachycardia. Am J Cardiol 1997;79:213-216. 14. Rodriguez LM, Smeets JLRM, Weide A, et al. The 12 lead ECG for localizing origin of idiopathic ventricular tachycardia. Circulation 1993;88:643. 15. Callans DJ, Menz V, Schwartzman D, et al. Repetitive monomorphic tachycardia from the left ventricular outflow tract: Electrocardiographic patterns consistent with a left ventricular site of origin. J Am Coll Cardiol 1997;29:1023-1027. 16. Nakagawa H, Beckman KJ, McClelland JH, et al. Radiofrequency catheter ablation of idiopathic left ventricular tachycardia guided by a Purkinje potential. Circulation 1993;88:2607-2617. 17. Lau CP. Radiofrequency ablation of fascicular tachycardia: Efficacy of pace-mapping and implications on tachycardia origin. Int J Cardiol 1994;46:255-265. 18. Kottkamp H, Chen X, Hindricks G, et al. Idiopathic left ventricular tachycardia: New

insights into electrophysiological characteristics and radiofrequency catheter ablation. Pacing Clin Electrophysiol 1995;18: 1285-1297. 19. Katritsis D, Heald S, Ahsan A, et al. Catheter ablation for successful management of left posterior fascicular tachycardia: An approach guided by recording of fascicular potentials. Heart 1996;75:384388. 20. Thakur RK, Klein GJ, Sivaram CA, et al. Anatomic substrate for idiopathic left ventricular tachycardia. Circulation 1996;93: 497-501. 21. de Paola AA, Gomes JA, Miyamoto MH, et al. Transcoronary chemical ablation of ventricular tachycardia in chronic Chagasic myocarditis. J Am Coll Cardiol 1992; 20:480-482. 22. Sosa E, Scanavacca M, D'Avila A, et al. Endocardial and epicardial ablation guided by nonsurgical transthoracic epicardial mapping to treat recurrent ventricular tachycardia. J Cardiovasc Electrophysiol 1998;9:229-239. 23. Stevenson WG, Weiss J, Wiener I, et al. Localization of slow conduction in a ventricular tachycardia circuit: Implications for catheter ablation. Am Heart J1987;114: 1253-1258. 24. Stevenson WG, Khan H, Sager P, et al. Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of ventricular tachycardia late after myocardial infarction. Circulation 1993;88:1647-1670. 25. Miller JM, Harken AH, Hargrove WC, et al. Pattern of endocardial activation during sustained ventricular tachycardia. J Am Coll Cardiol 1985;6:1280-1287. 26. de Bakker JMT, Van Capelle FJL, Janse MJ, et al. Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: Electrophysiology and anatomic correlation. Circulation 1988;77:589-606. 27. Downar E, Harris L, Mickleborough LL, et al. Endocardial mapping of ventricular tachycardia in the intact human ventricle: Evidence for reentrant mechanisms. J Am Coll Cardiol 1988;11:783-791. 28. Downar E, Saito J, Doig JC, et al. Endocardial mapping of ventricular tachycardia in the intact human ventricle. III. Evidence of multiuse reentry with spontaneous and induced block in portions of reentrant path complex. J Am Coll Cardiol 1995;25:1591-1600.

Chapter 23

Body Surface Potential Mapping for the Localization of Ventricular Preexcitation Sites and Ventricular Tachycardia Breakthroughs Reginald Nadeau, MD and Pierre Savard, PhD

ers, following the pioneering work of Taccardi,2 who used this method to investigate This chapter describes clinical appli- the nature of the cardiac electrical field. With the current state of development cations of body surface potential mapping of computer technology, BSPM is no longer (BSPM) for the localization of early actia painstaking, time-consuming endeavor vation sites in patients with the Wolffand has become a feasible noninvasive tool Parkinson-White (WPW) syndrome or for clinical use. In contrast to time-based ventricular tachycardia (VT). In a first electrocardiography, BSPM collects inforgroup of patients subjected to arrhythmation in the spatial domain. It is thus mia surgery, it was possible to obtain an appropriate technique for investigatboth intraoperative epicardial activation ing electrocardiographic problems related and isopotential maps. This allowed direct to the position of cardiac electrical activity comparison of epicardial and thoracic potential maps. In a second group of and, more specifically, to the position of a patients, body surface recordings were site of initial activation. For example, the used for pace mapping during endocardial analysis of BSPM recorded during vencatheter ablation procedures both WPW tricular pacing at known sites has shown that typical patterns of body surface potenand VT patients. Body surface potential mapping is a tial distributions during the QRS complex concept as old as electrocardiography itself, could be associated with specific pacing 3 having been proposed by Waller1 in 1888. Its sites. Similarly, SippensGroenewegen 4 practical realization, however, only became et al., showed in patients without strucpossible with the advent of digital comput- tural heart disease that maps depicting Introduction

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003. 467

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the distribution of QRS time integral values over the torso surface allowed discrimination among nearly 40 different pacing sites whose locations were determined by biplane fluoroscopy.

The relationship between the position of epicardial sources and body surface potential distributions has been investigated theoretically with a realistic computer torso model.5 This relationship can be

Figure 1. A. The 63 thoracic electrodes and the rectangular format of the body surface potential maps. B. Electrical projection of the epicardial surface unto the thoracic surface. This projection was made using a computer model of the thorax in which the epicardial and thoracic potential distributions were each represented by 63 values corresponding to our epicardial and thoracic recording sites. To each epicardial site, we assigned a positive unit potential while assigning a zero value to the other epicardial sites, and computed the thoracic potential distribution. On each of these 63 thoracic distributions, we measured the position of the maximum potential, and these maximum sites were then joined by the grid lines shown in B. RV = right ventricle; LAD = left anterior descending coronary artery; LV = left ventricle; BASE = row of electrodes over the base of the ventriclesAPEX = apex of the ventricles.

BODY SURFACE POTENTIAL MAPPING simply expressed as an electrical projection of the epicardial surface unto the thoracic surface (Figure 1A) where grid lines join sites of maximum thoracic potential when a single epicardial site is activated in the model. This electrical projection clearly shows that the anterior portion of both ventricles is mapped without much distortion to a small part of the anterior chest, whereas the lateral, posterior, and inferior portions of both ventricles are projected over the rest of the torso with significant distortion. Thus, 2 close anterior sites produce thoracic potential maxima that are close on the anterior chest, whereas 2 close inferior sites produce thoracic potential maxima that are widely separated on the right anterior and left posterior torso. This electrical projection establishes a theoretical framework for the interpretation of BSPMs and constitutes a valid tool for the localization of a single potential extremum on the epicardial surface, such as a small breakthrough site. In this chapter, we report on a more experimental approach to the problem of source localization that is based on the comparison between BSPM and epicardial maps recorded during surgery. The sources that are investigated are ventricular preexcitation sites in patients with the WPW syndrome and epicardial breakthrough sites in patients with VT. Methods Patient Population The observations reported here were carried out in 101 patients who all underwent standard electrophysiological study. BSPMs were obtained with the patient in the supine position in normal sinus rhythm, during right atrial and right ventricular (RV) pacing, and during induced supraventricular or ventricular arrhythmias. Epicardial maps were obtained in 25 WPW patients during open-chest acces-

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sory pathway cryoablation, and compared to the BSPM obtained just prior to surgery. In 35 other patients with the WPW syndrome, endocatheter radiofrequency ablation was carried out using BSPM pace mapping. BSPM was recorded during induced VT in 29 patients with prior myocardial infarction. The location of the myocardial infarction was anteroseptal in 14 patients, inferior in 11, and both anterior and inferior in 4. VT was induced in all patients by a programmed stimulation protocol that consisted of 1 to 3 extrastimuli delivered after a train of 10 paced beats. Eight of the 29 patients underwent cryoablation surgery guided by computerized epicardial and endocardial mapping. BSPM-guided pace mapping was also carried out during radiofrequency endocardial catheter ablation in 12 patients with monomorphic VT without evidence of heart disease. BSPM Methodology Body surface maps were obtained during electrophysiology studies with the patients lying in the supine position.6 Unipolar electrographic recordings were obtained from 63 electrodes referenced to the Wilson central terminal (Figure 1B). Forty-three electrodes were distributed on the front and sides of the thorax and 20 on the back. The electrodes consisted of plastic disks containing Ag/Ag Cl particles mounted on plastic strips. These leads were radiotranslucent to prevent interference with the fluoroscopic image. The interelectrode distance was 6 cm. Twelve vertical strips were applied. The first over the sternum with the top electrode over the suprasternal notch. The first electrode of each of the 11 other strips was applied at the same level. Three standard leads (I, aVF, and V2) were also recorded on paper throughout the whole electrophysiological study. The 63 ECGs were amplified, filtered with a bandwidth of 0.5 to 200 Hz, sampled

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at 500 Hz, digitized, and stored on a hard disk. Maps were drawn on a rectangular format as shown in Figure IB. The 63 ECGs of a single beat were displayed so as to identify faulty leads; these signals were eventually replaced by interpolating from

the neighboring leads. Isopotential maps were drawn at each 2 ms and displayed on a computer terminal. Isopotential lines that join points with equal potential values were obtained by cubic spline interpolation. The zero potential line is identified

Figure 2. Epicardial and thoracic potentials during induced ventricular tachycardia. A. Alignment of the normalized root mean square signals for the 63 thoracic and the 63 epicardial leads. The arrow indicates the onset of the QRS complex. B. Epicardial isochronal map. In this polar format, the apex is at the center, the base at the circumference, the left ventricle (LV) on the right, the right ventricle (RV) on the left, and the anterior part of both ventricles on the top. Isochronal lines join points having the same activation time with an interval of 10 ms. The area on the left ventricle with no isochronal lines corresponds to a region of conduction block where no activation was detected. C. Thoracic (left) and epicardial (right) isopotential maps. Thoracic maps are presented in a rectangular format; the left part of the map corresponds to the anterior torso and the right part to the posterior torso. The epicardial map format is the same as in B. The intervals between isopotential lines are 0.2 mV for the 2 body surface potential maps, and 1 mV and 2 mV for the epicardial maps at 20 ms and 40 ms after QRS onset, respectively. The zero potential line is identified by a heavier line and the plus and minus signs identify the locations of the maximum and minimum.

BODY SURFACE POTENTIAL MAPPING by a heavier line (Figure 2). The plus and minus signs identify the locations of the maximum and minimum potential values.

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Results Localizing Preexcitation Sites

In the WPW syndrome, preexcitation is focal in nature, and can be reasonably Epicardial activation mapping was represented by a single dipole that genperformed under normothermic cardiopul- erates the delta wave on the ECG.8 The monary bypass.7 A 63 unipolar electrode BSPM of the delta wave can be easily sock array was used to obtain epicardial interpreted to localize the area of the venpotential distributions over both ventricles. tricle that is preexcited. Thus, at the The interelectrode distance depended on onset, the activation wavefront can be repheart size. A specific electrode row was resented as a single dipole oriented from aligned over the left anterior descending the base of the ventricles toward the apex. coronary artery to serve as an anatomical Wherever the preexcitation site, a maxireference. Data acquisition was carried mum is always found in the precordial out with a sampling rate of 500 Hz. The region. It is the location of the negative epicardial maps are presented in a polar region and of the minimum that varies format with the apex at the center and significantly and can be used to identify the atrioventricular (AV) groove along the area of earliest depolarization. Negathe circumference. Epicardial activation tive potentials covering the right site of sequences were first determined using the thorax are associated with RV preexisochrone maps. Local activation times citation; negative potentials over the back were automatically detected for each unipo- reflect left ventricular (LV) preexcitation. lar electrogram as the part of most nega- Negative potentials over the inferior tive slope exceeding -0.5 V/s. Epicardial thorax correspond to posterior and posisopotential maps were plotted in simi- teroseptal preexcitation and negative lar format for each sampling instant potentials over the upper thorax to anteduring the QRS complex after faulty sig- rior preexcitation. Lateral wall preexcitanals were interpolated and the baseline tions are associated with a nearly critical corrected (Figure 2B). separation between the positive and negSince the thoracic and epicardial ative regions. For example, Figure 3 prepotential distributions were not recorded sents maps recorded during the delta simultaneously, the following alignment wave in 6 different patients whose sites of procedure was applied. The QRS complex earliest ventricular activation were deterobserved on the normalized root means mined at surgery. These patterns are typsquare (RMS) signal computed from the 63 ical for the areas identified, but they are thoracic leads was visually aligned on the unlikely to be more specific than the genQRS complex of the epicardial RMS signal eral orientation of the cardiac dipole and so that the upslope of both QRS complexes cannot be related to specific anatomical coincided (Figure 2A). A common QRS onset substrates, since many factors, such as was then determined on the superimposed heart orientation, may cause differences RMS signals. The patterns of spatial dis- in the projection of the dipole onto the tribution of potentials on the epicardial sur- body surface. BSPM has been found useful in face were compared to those on the surface of the torso; the temporal sequence of ven- identifying multiple pathways in the tricular activation and the changes in same patient.9 Detection of multiple conpotential amplitudes were also compared. nections that occur in approximately Intraoperative Epicardial Mapping

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Figure 3. Body surface potential mapping (BSPM) recorded during the delta wave in 6 WolffParkinson-White patients, with their corresponding preexcitation site determined during surgery. From Shenasa et al. Cardiol Clin 1990;8:443-464.

15% to 20% of symptomatic patients with the WPW syndrome is presently not possible using the standard ECG. Varying degrees of preexcitation in the different areas of the ventricle usually cause a dominant pattern that masks the others. Atrial pacing during BSPM at increasing frequencies has been found to be helpful, as shown in Figure 4. During sinus rhythm (panel A), the pattern is typical of an anterior RV preexcitation. Increasing the atrial rate by pacing at a cycle length of 400 ms causes the former pattern to disappear, as the refractory period of the accessory connection is reached, and a pattern representative of a right posterior pathway appears (panel B). These 2 sites of preexcitation were confirmed at surgery. Epicardial isopotential maps provide a more accurate representation of cardiac activation than do the isochronal

maps currently used to map activation sequences. The epicardial isopotential maps not only identify the location of the wavefronts, but also give information concerning their electromotive strength and orientation that is essential for the interpretation of the corresponding thoracic potential distribution. In Figure 5, the polar epicardial maps show successively left lateral preexcitation (10 ms), the normally conducted RV breakthrough (50 ms), and terminal QRS activity (90 ms) in a WPW patient. It is interesting to note that the distribution of potentials in the preexcited area is oriented along the long axis of epicardial muscle fibers in this region. Although the maps are not simultaneous, there is sufficient concordance between the two to validate the interpretation of the thoracic potential distribution maps, as projections from the epicardial surface. Thus, at 10 ms

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Figure 4. Body surface potential mapping from a patient with Wolff-Parkinson-White syndrome with 2 accessory pathways recorded during normal sinus rhythm (left) and atrial pacing (right).

the typical pattern of left anterior to lateral preexcitation appears, and at 50 ms a second minimum emerges corresponding to the normal breakthrough on the anterior RV.

epicardial data for a particular morphology had to be matched with the corresponding thoracic data for the same morphology. The 2 standard ECG leads that were recorded during the electrophysiological study and the surgery were used to match beats with a similar QRS Ventricular Tachycardia axis in the frontal plane, similar QRS duration and morphology, and similar For the 29 patients who underwent heart rate. The analysis of the sequence an electrophysiological study, BSPM was of thoracic and epicardial potential disrecorded during 39 episodes of sustained tributions provided additional informamonomorphic VT with different ECG mor- tion, such as the simultaneous occurrence phologies. Nineteen patients had a single of distinctive changes in the potential disECG morphology whereas 10 patients tributions on both surfaces as well as the had 2 distinct morphologies. For the 8 orientation of the potential extrema on patients who underwent surgery, iso- both surfaces, so as to confirm the match. chronal maps were recorded during 17 For example, the isopotential maps from episodes of induced VT with different acti- Figure 2C show positive potentials at 20 ms vation patterns. Seven of these 8 patients after QRS onset over both the precordial had 2 distinct activation patterns whereas area on the torso, and the anteroseptal 1 patient had 3 different patterns. For area on the epicardium. As seen on the these 8 patients, BSPM was recorded isochronal map (Figure 2B), the earliest during 14 episodes of VT with different epicardial activation, or epicardial breakECG morphologies. through, occurs at 30 ms in the anterosepSince some patients had multiple tal area. Later, this epicardial breakmorphologies of VT and since the thoracic through extends and produces a steep and epicardial potential distributions potential depression on the epicardial isopocannot be recorded simultaneously, the tential map at 40 ms. The displacement of

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Figure 5. Epicardial (left) and thoracic (right) isopotential maps at 3 different time instants during the QRS complex in a patient with Wolff-Parkinson-White syndrome. The map formats are the same as in Figures 1 and 2.

the epicardial minimum from a lateral to a more anterior site is concomitant with the displacement of the thoracic minimum from the lower back to the left midaxillary line (arrow). The epicardial and thoracic potential distributions thus reflect an activation wavefront oriented in an anterior direction, moving from the endocardium to the epicardium.

For endocardial sites of origin where activation moves from the endocardium to the epicardium, the detection of the occurrence of an epicardial breakthrough on the BSPM was observed more frequently for breakthrough sites located anteriorly over either ventricle, laterally over the LV, or near the apex. This was characterized on the BSPM, as in Figure 2,

BODY SURFACE POTENTIAL MAPPING by the occurrence of a new minimum or a shift of the position of the minimum over the torso surface. Also, the presence of a large anterior myocardial infarction reflected on the torso surface by large negative potentials covering the precordial region tended to mask the negative thoracic potentials that accompanied the epicardial breakthroughs. The analysis of the epicardial isopotential maps showed that epicardial breakthroughs occurred between 4 and 60 ms after the QRS onset, with most breakthroughs occurring before 40 ms. Figure 6 shows the body surface potential maps

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recorded during different episodes of VT in different patients at 40 ms or later, just after the epicardial breakthrough. The different body surface maps are located on a polar representation of the epicardium, at the site of epicardial breakthrough observed on the corresponding epicardial isopotential maps. A general pattern emerges from all these maps. Epicardial breakthrough sites located over the RV were associated with a potential minimum on the right chest. Conversely, breakthrough sites located over the LV were related to a potential minimum on the back or the near the left midaxillary line. Anteroseptal

Figure 6. Body surface potential maps for different epicardial breakthrough sites. These 14 maps were recorded 40 to 60 ms after QRS onset during 14 different episodes of ventricular tachycardia recorded in 8 patients. The large circle is a polar representation of the epicardial surface over which each body surface potential map is located at the site of epicardial breakthrough observed on the corresponding epicardial isopotential maps. For clarity, only the zero isopotential line is shown on the maps, along with the plus and minus signs indicating the location of the maximum and minimum. The size of the plus and minus signs indicates the relative amplitude of the potential extremum. The shaded regions indicate the negative areas. The 2 superimposed maps near the base of the lateral wall of the right ventricle were identical.

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breakthrough sites were associated with a minimum in the precordial region, near the sternum. Inferior breakthrough sites and some of the lateral sites were associated with negative potentials covering the lower torso. Conversely, breakthrough sites located anteriorly near the base of both ventricles were related to negative potential covering all of the upper torso and the shoulders. Thus, the location of the minimum and of negative potentials on the torso surface appears to be a projection of the epicardial breakthrough site. In Figure 6, two maps near the base of the lateral wall of the RV are superimposed because they were identical. These maps were associated with similar breakthrough sites in 2 different patients. However, another patient with a similar breakthrough location had a different body surface potential map. As illustrated in Figure 7, this difference is due to differences in the location of the myocardial infarction. Panels A and B show maps

from a patient with an inferior myocardial infarction, whereas panels C and D show maps from a patient with an inferoanterior myocardial infarction. For the first patient, a single wavefront moves away from the breakthrough site, first activating the RV from the base toward the apex, then the anterior LV, and, finally, the base of the lateral wall of the LV (panel A). At 40 ms, the epicardial potential distribution shows a minimum at the breakthrough site and a dipolar potential distribution that is oriented anteriorly (probably because of the orientation of the epicardial fibers); this is well reflected on the torso surface by a precordial maximum and a minimum over the right anterior chest with negative potentials covering the lower torso (panel B). At 120 ms, the epicardial potential distribution shows a leftward dipolar pattern with an anterior minimum and a left lateral maximum; again, this is well reflected of the torso surface by a sternal minimum and a maximum

Figure 7. Maps recorded for 2 patients with similar epicardial breakthrough sites near the base of the lateral wall of the right ventricle, but with 2 different locations of myocardial infarction. A. Epicardial isochronal map for a patient with inferior myocardial infarction (the area with no isochronal lines corresponds to a region of conduction block where no activation was detected). The arrows indicate the direction of the propagation. B. The thoracic and epicardial isopotential maps at 40 and 120 ms after QRS onset for the activation sequence shown in A. C. Epicardial isochronal map for a patient with an anteroposterior myocardial infarction (the central area with no isochronal lines). D. The corresponding thoracic and epicardial isopotential maps at 40 ms and 120 ms. The intervals between isopotential lines are 0.2 mV for the body surface potential maps and 1 mV for the epicardial maps. The map format is the same as in Figure 1.

BODY SURFACE POTENTIAL MAPPING over the left midaxillary line. For the second patient, the activation sequence is very different because the initial wavefront breaks down into 2 distinct segments, one that moves anteriorly around the myocardial infarction and another that moves inferiorly (panel C). At 40 ms, the epicardial isopotential map shows 2 dipolar potential distributions that are oriented anteriorly and inferiorly, respectively; on the torso surface, the anterior and inferior components seem to cancel each other and only a leftward orientation remains that is reflected by negative potentials over the right chest and positive potentials over the left chest (panel D). At 120 ms, the epicardial isopotential map shows 2 distinct dipolar potential distributions, the most anterior is oriented leftward and inferiorly, and the most inferior is oriented leftward and anteriorly; on the torso surface, again, the anterior and inferior components seem to cancel each other and a leftward orientation dominates with negative potentials over the right chest and positive potentials over the left chest.

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aligning the paced BSPM with the preexcited BSPM using the RMS signal from all the 63 electrodes. As shown in Figure 8, the tip is displaced until the patterns of the paced and preexcited body surface potential maps become similar, and radiofrequency energy is applied. Pacing along the AV ring showed a discrimination of 5 mm with a high degree of sensitivity and specificity. Despite this high spatial resolution of pace mapping, its application to endocardial ablation showed a low positive degree of accuracy, no doubt related to anatomical features of accessory pathway insertion.11 Pace mapping was also successfully applied to radiofrequency ablation of idiopathic VT in both the RV and the LV.12 The absence of associated myocardial infarction made the procedure quite simple to carry out. BSPM showed more accurate spatial resolution than 12-lead ECG pace mapping. Discussion Localizing Preexcitation Sites from BSPM

Pace Mapping and Radiofrequency Ablation

The application of BSPM to the study of patients with WPW syndrome was iniRadiofrequency ablation has now tiated by Yamada et al.13 in 1975. Shortly replaced surgery as the preferred mode of after that, De Ambroggi et al.14 demontreatment of symptomatic WPW patients. strated the importance of the location of The precise localization of the accessory the maximum and of the minimum, and pathway is essential to a successful pro- were able to relate the projection of negcedure because of the small size of lesions ative potentials during the delta wave to produced by the application of radiofre- the area of ventricular preexcitation. The quency current. We have found that BSPM focal nature of ventricular depolarization recorded during sinus rhythm or right during the delta wave was the basis for atrial pacing can be used to guide the ini- the investigations of Spach et al.,15 who tial position of the catheter.10 When BSPM simulated preexcitation by stimulating pace mapping is carried out by stimulat- the basal ventricle in the chimpanzee. ing the endocardium with the tip of the They demonstrated that the maximum ablation electrode, a precise localization of is relatively stationary over the left antethe site of insertion of the accessory path- rior chest while the minimum is clearly way can be achieved. This is done by distinctive for the site of stimulation.

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Figure 8. An example of the body surface potential mapping pace mapping procedure for the localization of a left posterior accessory pathway (arrow) in patient with Wolff-Parkinson-White syndrome. The maps were recorded during the delta wave (left), at the beginning of the QRS complex during pacing at a first ventricular pacing site (center), and at a second pacing site that was closer to the preexcitation area (right). The left part of each map corresponds to the anterior torso, the right part to the posterior torso, isopotential lines join points with the same potential value, and the plus and minus signs identify the potential maximum and minimum, respectively. The proximity of the catheter to the ventricular preexcitation area is reflected by the similarity of the maps (left and right), whereas differences in the location of the potential minimum and isoelectric line indicate the direction for the repositioning of the catheter (left and center; see text). From Molin F, et al. Pacing Clin E/ecfrophys/b/ 1997;20(Pt l):683.

Corresponding opposite polarities observed during repolarization could also distinguish one ectopic site from the other. In a subsequent clinical paper, Benson et al.16 correlated the body surface patterns to the earliest areas of epicardial activation determined at time of surgery, and essentially corroborated the principles of interpretation proposed by Spach et al.15 The accuracy of BSPM in predicting the site of preexcitation verified at surgery was reported by Iwa and Magara,17 Nadeau et al.,18 Kamakura et al.,19 Liebman et al.,20 and Giorgi et al.9 Moreover, careful analysis of potential distribution during delta wave inscription allows the differentiation of negative potential related to preexcitation from negative potentials

related to coexisting cardiac pathology, which is not possible on standard ECG.21 Accessory AV connections may potentially exist at any point along the AV junction. Based on surgical anatomy, these can be subdivided into left free wall, anteroseptal, right free wall, and posteroseptal.22 Electrocardiographically, the possible preexcited regions are distributed around the AV groove in a rather continuous manner with the exception of the fibrous trigon. The use of a finite number of electrocardiographic categories does not reflect this continuum and an infinite variety of electrocardiographic patterns can be interpolated between neighboring categories, a feature that cannot be easily performed by the 12-lead ECG. Thus, with

BODY SURFACE POTENTIAL MAPPING BSPM, we were able to demonstrate significant differences by displacing the stimulating electrode by only 5 mm.11 Ventricular Tachycardia The qualitative analysis of the sequence of epicardial and thoracic isopotential maps can be used to identify electrocardiographic features that reflect specific cardiac events occurring at specific sites. Epicardial and thoracic potential distributions have been recorded to determine precisely the origin of the P wave in canines,23,24 of the QRS complex and T wave in chimpanzees,15 and of ventricular late potentials in patients with prior myocardial infarction.25 The origin of VT, with possible subendocardial or subepicardial reentry circuits,26 is more complex and renders the analysis of the ECG more difficult since activation can be continuous and repolarization can overlap depolarization. Thus, the onset of the QRS does not exactly reflect the "site of origin" of the VT, but rather the exit of activation from the arrhythmogenic substrate where the slow and abnormal propagation hardly generates any ECG signal, into the bulk of the normal myocardium that generates larger ECG signals. Body surface potential maps can then detect the onset of this activation even before the activation reaches the epicardial surface. The maps shown in Figure 6 simply summarize the results obtained for our small population of patients and do not constitute a set of criteria for predicting the site of epicardial breakthrough. It is interesting to note that the morphologies of those maps with breakthrough sites located near the base of the ventricles are similar to those observed in patients with the WPW syndrome. For VT, a map recorded at single time instant conveys less information than the sequence of maps during the entire QRS complex that reflect not only where activa-

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tion begins, but also how it propagates and where it terminates. For example, the detection of the occurrence of an epicardial breakthrough (Figure 2) provides information about the subendocardial or trans mural origin of the activation. The importance of the position and extent of myocardial infarction on the QRS morphology during VT, which is illustrated in Figure 7, has also been suggested by Josephson et al.,27 who noted the interindividual variability of QRS morphology for VTs arising from the same region. Thus, the interpretation of BSPM during VT relies on information about the exact delineation of the infarcted area. For example, the presence of a small strip of surviving tissue between the infarct and the base could completely alter the activation sequence in comparison with an infarct that extends completely to the base. Finally, the conclusions of this study should be tempered by (1) the small population of patients, which prevents us to extensively evaluate the interindividual variability in BSPM patterns; (2) the nonsimultaneous recording of the epicardial and thoracic potentials that can be responsible for mismatch between the epicardial and thoracic data; (3) the difficulties in the manual selection of an EGG baseline and the repolarization overlap with the QRS complex during VTs with a rapid rate; and (4) the intraoperative recording technique that can alter the magnitude of the epicardial potentials in areas that are exposed to air, but without altering the activation sequence. References 1. Waller AD. The electromotive properties of the human heart. SrAfede/1888;2:751. 2. Taccardi B. Distribution of heart potentials on the thoracic surface of normal human subjects. Circ Res 1963;12:341. 3. Hayashi H, Watabe S, Takami K, et al. Sites of origin of ventricular premature

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beats in patients with and without cardiovascular disease evaluated by body surface potential mapping. J Electrocardiol 1988;21:137-146. 4. SippensGroenewegen A, Spekhorst H, van Hemel NM, et al. Body surface mapping of ectopic left and right ventricular activation. QRS spectrum in patients without structural heart disease. Circulation 1990;82:879-896. 5. Vahid-Shahidi A., Savard P. Finite element modeling of the human torso. Med Biol Eng Comput 1994;32:S25-S33. 6. Bonneau G, Tremblay G, Savard P, et al. A real-time cardiac mapping system. IEEE Trans Biomed Eng 1987;34:415. 7. Page P, Cardinal R, Shenasa M, et al. Surgical treatment of ventricular tachycardia: Regional cryoablation guided by computerized epicardial and endocardial mapping. Circulation 1989;80(Suppl I):I124-I134. 8. Nadeau RA, Savard P, Faugere G, et al. Localization of pre-excitation sites in the Wolff-Parkinson-White syndrome by body surface potential mapping and a single moving dipole representation. In: van Dam RTh, van Oosterom A (eds): Electrocardiographic Body Surface Mapping. Dordrecht: Martinus Nijhoff; 1986:95. 9. Giorgi C, Nadeau R, Savard P, et al. Body surface isopotential mapping of the entire QRST complex in the Wolff-ParkinsonWhite syndrome. Correlation with the location of the accessory pathway. Am Heart J 1991;121:1445-1453. 10. Dubuc M, Nadeau R, Tremblay G, et al. Pace-mapping using body surface potential maps to guide catheter ablation of accessory pathways in patients with the Wolff-Parkinson-White syndrome. Circulation 1993;87:135-143. 11. Molin F, Savard P, Dubuc M, et al. Spatial resolution and role of pace-mapping during catheter ablation of accessory pathways. Pacing Clin Electrophysiol 1997;20(3 Pt l):683-694. 12. Klug D, Ferracci A, Dubuc M, et al. Body surface potential and QRS isoarea maps of idiopathic ventricular tachycardia. Circulation 1995;91:2002-2009. 13. Yamada K, Toyama J, Wada M, et al. Body surface isopotential mapping in Wolff-Parkinson-White syndrome: Noninvasive method to determine the localization of the accessory atrioventricular pathway. Am Heart J 1975;90:721-734.

14. De Ambroggi L, Taccardi G, Macchi E. Body surface maps of heart potentials. Tentative localization of pre-excited areas in forty-two Wolff-Parkinson-White patients. Circulation 1976;54:251-263. 15. Spach MS, Barr RC, Lanning CF. Experimental basis for QRS and T wave potentials in the WPW syndrome. The relation of epicardial to body surface potential distributions in the intact chimpanzee. Circ Res 1978;42:103-118. 16. Benson DW Jr, Sterba R, Gallagher JJ, et al. Localization of the site of ventricular preexcitation with body surface maps in patients with Wolff-Parkinson-White syndrome. Circulation 1982;65:1259-1268. 17. Iwa T, Magara T. Correlation between localization of accessory conduction pathway and body surface maps in the WolffParkinson-White syndrome. Jpn Circ J 1981;45:1192-1198. 18. Nadeau R, Ackaoui A, Giorgi C, et al. PQRST isoarea maps in the Wolff-Parkinson-White syndrome. An index for global alterations of ventricular repolarization. Circulation 1988;77:499-503. 19. Kamakura S, Shimomura K, Ohe T, et al. The role of initial minimum potentials on body surface maps in predicting the site of accessory pathways in patients with Wolff-Parkinson-White syndrome. Circulation 1986;74:89-96. 20. Liebman J, Zeno JA, Olshansky B, et al. Electrocardiographic body surface potential mapping in the Wolff-Parkinson-White syndrome. Noninvasive determination of the ventricular insertion sites of accessory atrioventricular connections. Circulation 1991;83:886-901. 21. Giorgi C, Nadeau R, Savard P, et al. Body surface potential mapping in the evaluation of coexisting old myocardial infarction and ventricular preexcitation. Am Heart J 1991;121:1240-1243. 22. Anderson RH, Becker AE. Anatomy of the conduction tissues and accessory atrioventricular connections. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: W.B. Saunders Co.; 1990:240. 23. King TD, Barr RC, Herman-Giddens GS, et al. Isopotential body surface maps and their relationship to atrial potentials in the dog. Circ Res 1972;30:393-405. 24. Pinter A, Molin F, Savard P, et al. Body surface mapping of retrograde P waves in the intact dog by simulation of accessory

BODY SURFACE POTENTIAL MAPPING pathway re-entry. Can J Cardiol 2000;16: 175-182. 25. Lacroix D, Savard P, Shenasa M, et al. Spatial domain analysis of late ventricular potentials. Intraoperative and thoracic correlations. Circ Res 1990;66:55-68. 26. Kaltenbrunner W, Cardinal R, Dubuc M, et al. Epicardial and endocardial mapping

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of ventricular tachycardia in patients with myocardial infarction. Is the origin of the tachycardia always subendocardially localized? Circulation 1991;84:1058-1071. 27. Josephson ME, Horowitz LN, Waxman HL. Sustained ventricular tachycardia: Role of the 12-lead electrocardiogram in localizing site of origin. Circulation 1981;64:257-272.

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Chapter 24 Clinical Application of Magnetocardiographic Mapping Markku Mdkijdrvi, MD, Helena Hdnninen, MD, Petri Korhonen, MD, Juha Montonen, Dr.Tech., and Jukka Nenonen, Dr.Tech.

Magnetocardiography has already provided clinically useful results in several Magnetocardiography (MCG) was initiated applications. For example, MCG can in the early 1960s but remained a primar- diagnose and localize acute myocardial ily experimental method practiced by engi- infarctions (Mis), separate postinfarction neers in research laboratories until the patients with and without susceptibility of 1990s.1 Today, it has developed into one of malignant ventricular arrhythmias, detect the emerging new technologies in cardiol- ventricular hypertrophy and rejection after ogy, used by medical doctors in several lab- heart transplant, localize the site of venoratories in a clinical environment. Although tricular preexcitation and many types of MCG still poses technical demands such as cardiac arrhythmias, and reveal fetal 2 instrumentation based on the use of liquid arrhythmias and conduction disturbances. Several other clinical applications of helium and the need for magnetically shielded rooms, the clinical application of MCG have also recently been studied, the method has greatly benefited from including detection and risk stratificamodern multichannel instrumentation at tion of cardiomyopathies (dilated, hyperhospitals. In addition, the signal-to-noise trophic, arrhythmogenic, diabetic), risk ratio in routine MCG recordings is compa- stratification after idiopathic ventricular rable to that in the best electrical potential fibrillation (VF), detection and localizameasurements, MCG studies provide on- tion of myocardial viability, and follow-up line results, and many groups are collect- of fetal growth and neural integrity. Some ing libraries of reference data with studies have clearly indicated that MCG increasing speed. Profound efforts in direc- is very sensitive to the changes of repotion of standardization and data compara- larization, e.g., after MI or in a hereditary long QT syndrome.3 bility have also been taken. Introduction

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003. 483

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In this chapter, we present a brief overview of the developments in clinical MCG during the last few years and present some perspective for the near future. The basics of MCG are presented in chapter 6. Localization of Preexcitation and Cardiac Arrhythmias by MCG Mapping

results in localizing a pacing catheter and the preexcitation confirm the good localization capability of the MCG method. The lower localization accuracy of extrasystoles and tachycardias is partly explained by inherent problems concerning the clinical and imaging reference data. An example of MCG localization in a patient suffering from continuous atrial tachycardia is presented in Figure 1. A more detailed discussion of the validation of MCG results, e.g., with phantom experiments, can be found in chapter 6.

The clinical localization accuracy of the MCG method has been tested by localizing the site of earliest ventricular activation during the preexcitation in WolffRisk Stratification After MI Parkinson-White syndrome patients.4-10 by MCG The clinical reference was obtained during endocardial catheter mapping or from A substantial proportion (5% to 15%) successful catheter or surgical ablation of the accessory pathway. The results of patients after the first years of MI carry show that the MCG method is accurate a high risk of sudden death. Several enough for localization of cardiac electri- methods, such as left ventricular (LV) cal sources for clinical purposes. The ejection fraction, signal-averaged and results of published patient series are high-resolution electrocardiography, and heart rate variability, have been applied summarized in Table 1. Magnetocardiography has also been to assess the prognosis of such patients. used for localization of other sources of MCG seems to be one of the most promising cardiac arrhythmias, such as origin sites methods.13-17 Korhonen et al.17 studied of tachycardias and extrasystoles, as well 100 patients after remote MI; 38 of them as for localization of a cardiac pacing had experienced documented episodes of catheter.10-12 The localization accuracies sustained ventricular tachycardia (VT). for a pacing catheter are reportedly excel- MCG recordings were performed for 5 lent (<1.0 cm), for extrasystoles 0.5 to minutes over the anterior chest, and time 2.0 cm, and for tachycardias more vari- domain parameters describing delayed able (1.6 to 4.0 cm).10-12 In particular, the ventricular conduction were computed. Table 1 Magnetocardiographic Localization Accuracy of Ventricular Preexcitation Author

Year

Patients

Channels

Reference

Accuracy

4

1989 1991 1992 1995 1993 1994 1996

18 13 9 25 12 14 23

1 1 37 37 1 7 37

X-ray MRI MRI MRI MRI MRI MRI

2.0cm 2.9cm 1.8cm 0.5-2.0 cm 2.1 cm Good <2.0 cm

Fenici Schirdewan5 Weissmuller6 Oeff7 Nenonen8 Nomura9 Moshage10

MRI = magnetic resonance imaging.

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485

Table 2 Magnetocardiographic Studies in Identifying the Risk of Ventricular Tachycardia After Myocardial Infarction Author 13

Stroink Makijarvi14 Achenbach15 Oeff16 Korhonen17

Year

Patients

Sensitivity

1989 1993 2000 1998 2000

27 20 38 56 100

67% 70%

67% 80%

80% 92%

93% 61%

Specificity

MRI = magnetic resonance imaging.

Figure 1. An example of magnetocardiographic (MCG) localization of an atrial tachycardia. The patient was a 24-year-old male suffering from continuous atrial tachycardia. A. Spatial MCG distribution during the abnormal small-amplitude P wave. B. MCG localization of the P wave, superimposed on a transaxial magnetic resonance image of the heart. The result was in excellent agreement with the invasive localization obtained during catheter ablation. See color appendix.

Using the combination of QRS duration >115 ms or low-amplitude signal duration >30 ms as the criterion for abnormality yielded sensitivity and specificity of 92% and 61%, respectively, in the identification of VT patients. In postinfarction arrhythmia risk assessment, MCG parameters yield information that is independent of several clinical variables including LV function.18

Several other research groups have reported comparable results. The summary of the results of these studies is presented in Table 2. As an example, spatial distribution of defined QRS durations in patients with and without VT are displayed in Figure 2. The localization of the arrhythmogenic activity has also been attempted by MCG techniques.19,20 Initial results

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Figure 2. Identification of propensity to ventricular tachycardia (VT) using magnetocardiographic mapping. Local high-pass filtered (40 Hz) QRS durations are displayed. Upper panel presents a recording of a myocardial infarction (Ml) patient without ventricular arrhythmias in the follow-up. Local QRS durations are short and colored green. Lower panel presents an MCG recording of an Ml patient with documented sustained VT. Local QRS durations are clearly longer toward red color. Note the longest QRS durations localize to the left lower quadrant of the measurement area corresponding the infarction scar in the left ventricle. See color appendix.

are promising, but the data reported so far are too limited to draw any firm conclusions. Ventricular Hypertrophy in MCG Right ventricular and LV hypertrophy related to valve diseases, hypertension, and cardiomyopathies have been detected successfully using MCG mapping.1-3 Recently, Karvonen et al.21 reported a study of 47 hypertensive patients in whom the degree of LV hypertrophy was measured using MCG mapping and compared with echocardiographic studies. The performance of MCG was compared to the standard 12-lead ECG. The MCG analyzing method was the measure of the area under the QRS and T wave, and the socalled MCG strain (Figure 3).When the specificity was fixed to 81%, the MCG method resulted in a sensitivity of 69% when using the strain, and 81% when using the QRS-T area. The conventional Sokolow-Lyon parameters defined from the ECG resulted in lower values (sensi-

tivity 57%, specificity 64%). According to the results of this pilot study, MCG mapping may become a practical screening method for detection of pathological LV hypertrophy in hypertensive patients. Ventricular Repolarization and MCG The general interest in noninvasive methods capable of characterizing ventricular repolarization has been growing rapidly.22-25 The disparity and variability of repolarization is considered a good measure of vulnerability to ventricular arrhythmias and sudden cardiac death, especially in patients with coronary heart disease or inherited long QT syndrome. In 1995, Rovamo et al.23 published a study of 13 children suffering from the long QT syndrome. MCG maps during the T wave were analyzed using the eigenvector decomposition. The eigenvector maps during the repolarization phase were multipolar in patients who had experienced a syncopal attack. These results are in concordance

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487

Figure 3. Left ventricular hypertrophy in magnetocardiogram (MCG). The MCG strain is defined as the angle between the magnetic field map angles of the QRS and T wave isointegral distributions. In patients with left ventricular hypertrophy the strain is typically greater than 90°, while in normal subjects the value is close to 0°. In this case, the strain is 170°. See color appendix.

with a previous study reported by Brock- Myocardial Ischemia and Viability meier et al.22 Detected by MCG Recently, Hailer et al.24 developed an index for the variability of the QT interOne of the newest developments in val dispersion. With this "smoothness clinical MCG is the detection and charindex" they could reliably separate MI acterization of myocardial ischemia and patients from normals. Oikarinen et al.25 viability. An increasing number of studdeveloped a method for automated mea- ies are reported in this field, with encoursurements of QT intervals in MCG data. aging results.30-42 A new and accurate Using this method they found that the noninvasive method for recognition of interval from T wave apex to T wave end acute and chronic ischemia could have in MCG was prolonged in postinfarction important clinical applications, especially patients with sustained ventricular because novel therapeutic interventions arrhythmias in comparison to nonar- for revascularization, such as coronary rhythmia patients.26 This suggests that angioplasty, rotablation, and transmyMCG might be of value in the assessment ocardial laser, have recently emerged. of increased transmural dispersion, which Brockmeier et al.30 reported prelimis known to be associated with ven- inary results in a study of MCG mapping tricular arrhythmia propensity. Patients before and during exercise testing of 20 with nonischemic dilated cardiomyopathy normal subjects. The field magnitudes and sustained ventricular arrhythmias of the early repolarization period were also show prolongation in the T wave apex seen to increase by 100% under conto T wave end interval in MCG.27 trolled step wise exercise conditions. Such An interesting method to assess the changes of the ST segment in normals vulnerability to ventricular arrhythmias could be explained by the ability of MCG is MCG QRST integral mapping. Accord- to detect direct current (DC) currents, ing to the results of 2 preliminary stud- thus being sensitive to their changes. In ies,28,29 MCG QRST integral mapping the second study of pharmacologically seems to adequately discriminate VT/VF induced stress in healthy volunteers, they patients from normal controls.29 The could demonstrate repolarization changes method was less successful in the identi- presumably caused by so-called vortex fication of VT/VF patients from MI currents visible in MCG but not in ECG 31 • 31 patients without documented VT/VF.28 mapping.

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The analysis of myocardial injury ties were calculated in discrete myocarcurrents has been used by Seese et al.32 dial points. The results, overlaid with the for identification and localization of acute MR images, showed that the current denischemia in 16 patients with coronary sity increases from the QRS onset to the artery disease. Eleven of the patients had QRS maximum. The majority of healthy positive exercise ECG, and they were myocardial regions had a high current studied by use of a nonmagnetic bicycle magnitude during the QRS. Correspondergometer in a magnetically shielded ing to the absence of electrical active room. Multichannel MCG was recorded myocardial tissue, reduced current magbefore and immediately after exercise nitudes were observed for regions of when signs of ischemia were still present infarcted myocardium (<1 uA/mm2). In in the ECG. In addition, 5 patients were general, the current density distributions examined in the acute phase of MI. In all correlated well with other cardiological cases, an equivalent current density dis- investigations (e.g., left ventricle cathetertribution was computed during the ST ization, scintigraphy, echocardiography). segment. The reconstructed estimates Lant et al.34 have demonstrated the were combined with x-ray and magnetic complementary nature of ECG and MCG resonance (MR) images. The results were data. The differences between postinfarcthen compared with coronary angiogra- tion patients and normals were larger in phy and myocardial scintigraphy. In all patients, both MCG and ECG showed a MCG mapping showed larger differences significant elevation or depression of the during repolarization. In particular, MCG ST segment during ischemia. The injury mapping showed complex nondipolar field currents were, in most cases, directed patterns of repolarization in patients with from the ischemic area to the nonischemic non-Q-wave infarction. Such fragmented area. For example, anterior ischemia patterns may be caused by prolonged caused an injury current directed from ischemic injury increasing tangential curthe apex to the base of the heart. The rent flow through the spared subendoinjury currents induced by transient cardial tissue. The equivalent current ischemia and infarction of the same dipole calculation during depolarization anatomical region were found to flow in and repolarization has also allowed a septhe opposite direction. This change of aration of patients with coronary artery direction is reflected to either ST depres- disease, with or without remote MI, from sion or ST elevation in morphological healthy controls.35 signals. The anatomical location of the Van Leeuwen and co-authors36 found injury currents was in topographical that the magnetic field orientation at rest agreement with the results of the refer- separates coronary artery disease patients ence methods. from healthy controls, with more promiLeder et al.33 investigated a total of 40 nent changes in the field orientation in subjects, including normals and patients severe disease. They defined the magnetic with a history of MI. All patients under- field orientation as the angle between the went the 12-lead ECG, stress test, echo- line joining the field extrema and the rightcardiography, coronary angiography, and left line of the torso. Our group has also Trsingle photon emitted computed tomog- developed a semiautomatic method to raphy. Individual torso and heart geome- define the magnetic field orientation.37 tries for current generator reconstructions This surface gradient method defines the were extracted from T1-weighted MR magnetic field orientation as the orientaimaging data. Equivalent current densi- tion of the maximum spatial field gradient,

ECG

CLINICAL APPLICATION OF MAGNETOCARDIOGRAPHIC MAPPING thereby closely resembling the method by Van Leeuwen et al.36 In our study, during exercise-induced ischemia the magnetic field orientation separated patients with both single-vessel and triple-vessel coronary artery disease from healthy controls.37,38 In accordance with the findings of Lant et al.,34 the most prominent T wave changes were found in patients with inferior ischemia and in patients with a history of ML37,38 Takala et al.39 developed a method for heart rate adjustment of the magnetic field orientation during the recovery phase of exercise stress testing that further improved the ischemia detection. An example of the magnetic field orientation changes is presented in Figure 4. ST segment depression and ST segment slope, used in 12-lead ECG as ischemia parameters, also detect ischemia in MCG.38 The ischemia-induced ST depression takes place over the lower middle

489

anterior thorax, and the reciprocal ST elevation over the left anterior shoulder, locations orthogonal to those found in body surface potential mapping.38,40 Tsukada and co-workers41 have investigated the ratio of the maximum repolarization and depolarization values in MCG by comparing the ST-T and QRS isointegral maxima. The ratio of the ST-T and QRS isointegral maxima has been reduced in coronary artery disease patients compared to healthy controls. Several ongoing studies have been designed to test the diagnostic performance of MCG mapping to detect and localize areas of hibernating myocardium. The viability of the myocardium is confirmed by a full set of other diagnostic tests: exercise ECG, thallium stress test, dobutamine MR imaging, and positron emission tomography. Preliminary results look promising, but there are still some

Figure 4. Examples of magnetocardiographic distributions and magnetic field map (MFM) angle data of a patient with the left circumflex coronary artery disease. Left: The data at the ST segment. Right: The data at the T wave maximum. Top: The MFM angles at rest and during the recovery from exercise are plotted against time. The exercise data have been omitted. Bottom: The MFM angles are plotted against the heart rate. Whole recovery data of the ST segment, and T wave data from 1 to 10 minutes postexercise are shown. Regression lines through the data sets were used for quantifying the change in MFM angles. See color appendix.

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Figure 5. An example of magnetocardiographic current density reconstructions (right) in a patient suffering from chronic ischemia after supine ergometer exercise. In this patient the chronic ischemia (dark red areas) is localized into the posteroseptal region of the heart. This finding is confirmed by the thallium single photon emitted computed tomography image (light areas) shown on the left. See color appendix.

in general it was more difficult below 28 weeks. The QRS duration was found to increase significantly with increasing gestation. They concluded that fetal MCG provides a significant advantage in the technology available for recording the antenatal fetal heart. Fetal MCG Recently, Menendez et al.44 reported 42 Achenbach et al. investigated 33 69 fetal MCG recordings in 40 consecutive women in 45 recordings during the 16th women (24th to 41st gestational week), and 40th week of pregnancy. They found all evaluated because of fetal arrhythfetal QRS complexes detectable in 25% mias in Doppler sonography. While single to 100%, P waves in 0% to 85%, and T supraventricular ectopic beats were the wave only in 7% of the recordings. They most common individual class of arrhythconcluded that the diagnosis of fetal mia diagnosed, supraventricular tachycararrhythmias is possible but very variable dia, atrial flutter, VT (torsades de pointes), and second-degree and complete atrioin this patient population. Quinn et al.43 studied 102 low-risk ventricular block were also detected. The pregnant women at the 20th to the 42nd authors concluded that various paramegestational week. In the unaveraged re- ters concerning the electrical excitation of cordings, a QRS complex was successfully the heart, such as atrioventricular condetected in 68 cases (67%). Of those 68 duction, repolarization period, and mortraces, a P wave was detected in 51 (77%) phology of the QRS complex, could be and a T wave in 49 (72%) of the traces, determined, leading to a more profound using off-line signal averaging techniques. analysis of fetal arrhythmias. Wakai et al.45 found the fetal MCG Although good quality traces were obtained throughout the range of gestational ages, useful in the evaluation of fetal rhythm in problems concerning the modeling of chronic ischemia. An example of a reconstructed current density on the LV surface is presented in Figure 5.

CLINICAL APPLICATION OF MAGNETOCARDIOGRAPHIC MAPPING a fetus suffering a complete congenital heart block, where the fetal MCG revealed a strong tendency for atria and ventricles to synchronize. Menendez et al.46 diagnosed 2 prenatal cases of QT prolongation with fetal MCG, evaluated because of sustained fetal bradycardia at the 29th and the 35th gestational week. In both newborns the QT prolongation was confirmed by the postpartal ECG. Van Leeuwen et al.47 recorded a total of 189 fetal MCGs in 63 pregnant women between the 13th and 42nd week of pregnancy. In 16 recordings before the 20th gestational week, the signal strength was too weak to permit evaluation. Brief episodes of bradycardia, isolated supraventricular and ventricular premature beats, bigeminy and trigeminy, sinoatrial block, and atrioventricular conduction delays were found. In general, there was good agreement of the MCGs and the cardiac findings in the newborns. Horigome et al.48 studied 95 fetuses with gestational ages of 20 to 40 weeks. Of the 95 fetuses, 88 had normal ultrasonography, whereas 7 had fetal cardiomegaly in echocardiography. In uncomplicated pregnancies, the magnitude of the MCG current dipole correlated with the gestational age, whereas in fetuses with cardiomegaly, the magnitude of the current dipole was higher, reflecting the increased myocardial mass. The authors suggested that MCG could be used for noninvasive evaluation of hypertrophy of the fetal heart. Discussion A clinical application of any method means that it must contribute to at least one of the following fields of clinical medicine: diagnosis, therapy, or prognosis. In particular, noninvasive methods improving the accuracy of diagnosis of a cardiac disease are valuable. Most important new methods, however, enable palliative or curative therapy, either by improving the

491

results of existing therapies or by providing new modes of therapy. Methods that help to better assess the prognosis of certain heart diseases in individual patients are also desired. Magnetocardiography has many advantages enabling it to become a clinically accepted method. First, it is totally noninvasive: it is not necessary to attach electrodes or other sensors that require direct contact with the patient. Currently, use of operating multichannel magnetometers is feasible and enables fast recordings; a full measurement can be carried out in few minutes. Such advantages of MCG recordings also mean high patient comfort. In addition, multiple temporal and spatial parameters can be extracted from a single heartbeat for complete electromagnetic characterization of the function of the patient's heart. The spatiotemporal resolution of MCG mapping is much higher than that of conventional ECG methods. Moreover, the MCG methods still have unexplored potential for extracting new physiological and pathophysiological information of the electrical activation in the myocardium. Magnetocardiography does, however, have some disadvantages. The equipment is currently expensive and requires the use of liquid helium and a magnetically shielded room. Such technical demands so far exclude wider applicability of MCG as a quick bedside test and during catheter interventions. The development of new superconducting materials, operating in higher temperatures achieved using liquid nitrogen, might solve this problem. In addition, MCG systems are generally sensitive to moving magnetic objects, which excludes some patients from the studies. Conclusions From all MCG studies published to date, it can be concluded that the diagnostic

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performance of MCG is superior to the conventional ECG in several applications. This advantage, however, has not yet driven clinicians to widely accept and use the method, mostly because of the high cost and low availability. Nevertheless, clinical applications of MCG in the fields of therapy and prognosis are currently attracting growing interest. The localization of arrhythmias and the detection of arrhythmia risk are already established therapy-related applications. Antiarrhythmic and antirejection medical therapies guided by MCG have been proposed, but such suggestions need more comprehensive studies. Detection and localization of ischemia and viability would concern a large number of cardiac patients if the MCG method proves to be successful in larger patient series. Ongoing studies on the prognostic value of MCG after MI, long QT syndrome, congenital heart disease, and cardiomyopathy may open new applications, taking into account the promising results of recent studies on the prophylactic use of implantable defibrillators in high-risk patient groups. The increasing availability of high-performance multichannel MCG systems in clinical environment will contribute greatly to these efforts. References 1. Siltanen P. Magnetocardiography. In: MacFarlane PW, Lawrie TDV (eds): Comprehensive Electrocardiology, Vol. II. Oxford: Pergamon Press; 1989:1405-1438. 2. Stroink G, Moshage W, Achenbach S. Cardiomagnetism. In: Andra W, Nowak H (eds): Magnetism in Medicine. Berlin: Wiley VCH; 1998:136-189. 3. Makijarvi M, Brockmeier K, Leder U, et al. New trends in clinical magnetocardiography. In: Aine C, Okada Y, Stroink G, et al (eds): Biomag96: Proc Tenth Int Conf on Biomagnetism. New York: Springer; 2000:410-417. 4. Fenici RR, Melillo G. Biomagnetic imaging in the cardiac catheterization laboratory.

In: Williamson SJ, Hoke M, Stroink G, Kotani M (eds): Advances in Biomagnetism. New York: Plenum Press; 1989:409-415. 5. Schirdewan A, Haberkorn W, Sandring KH, et al. Preoperative magnetocardiographic mapping in patients with WolffParkinson-White syndrome. In: Abstr 8th Int Conf on Biomagnetism. Minister: 1991: 479-480. 6. Weissmuller P, Abraham-Fuchs K, Schneider S, et al. Magnetocardiographic non-invasive localization of accessory pathways in the Wolff-Parkinson-White syndrome by a multichannel system. Eur Heart J 1992;13:616-622. 7. Oeff M, Burghoff M, Henning L, et al. Magnetocardiographic guiding for catheter ablation of accessory pathways. In: Baumgartner C, Deecke L, Stroink G, Williamson SJ (eds): Biomagnetism: Fundamental Research and Clinical Applications. Amsterdam: Elsevier; 1995:615-618. 8. Nenonen J, Makijarvi M, Toivonen L, et al. Noninvasive magnetocardiographic localization of ventricular preexcitation in Wolff-Parkinson-White syndrome using a realistic torso model. Eur Heart J1993; 14: 168-174. 9. Nomura M, Nakaya Y, Saito K, et al. Noninvasive localization of accessory pathways by magnetocardiographic imaging. Clin Cardiol 1994; 17:239-244. 10. Moshage W, Achenbach S, Gohl K, et al. Evaluation of the noninvasive localization accuracy of the cardiac arrhythmias attainable by multichannel magnetocardiography (MCG). Int J Card Imaging 1996;12:47-59. 11. Fenici R, Pesola K, Korhonen P, et al. Magnetocardiographic pacemapping for non-fluoroscopic localization of intracardiac electrophysiology catheters. Pacing Clin Electrophysiol 1998;21:2492-2498. 12. Oeff M, Burghoff M. Magnetocardiographic localization of the origin of ventricular ectopic beats. Pacing Clin Electrophysiol 1994;17:517-522. 13. Stroink G, Vardy D, Lamothe R, et al. Magnetocardiographic and electrocardiographic recordings of patients with ventricular tachycardia. In: Williamson SJ, Hoke M, Stroink G, Kotani M (eds): Advances in Biomagnetism. New York: Plenum Press; 1989:437-440. 14. Makijarvi M, Montonen J, Toivonen L, et al. Identification of patients with ventricular tachycardia after myocardial infarction

CLINICAL APPLICATION OF MAGNETOCARDIOGRAPHIC MAPPING by high-resolution magnetocardiography and electrocardiography. J Electrocardiol 1993;26:117-124. 15. Achenbach S, Moshage W, Fliig M, et al. Comparison of the QRS duration and RMS40 in signal-averaged recordings of the multichannel MCG to the signal-averaged ECG. In: Aine C, Okada Y, Stroink G, et al (eds): Biomag96: Proc Tenth Int ConfonBiomagnetism. New York: Springer; 2000:433-436. 16. Oeff M, Trahms L, Endt P, et al. Noninvasive recording of the arrhythmogenic substrate within the QRS complex using magnetocardiography. J Am Coll Cardiol 1998;27(SupplA):1018. 17. Korhonen P, Montonen J, Makijarvi M, et al. Late fields of the magnetocardiographic QRS complex as indicators of propensity to sustained ventricular tachycardia after myocardial infarction. J Cardiovasc Electrophysiol 2000; 11:413-420. 18. Korhonen P, Montonen J, Endt P, et al. Magnetocardiographic intra-QRS fragmentation analysis in the identification of patients with sustained ventricular tachycardia after myocardial infarction. Pacing Clin Electrophysiol 2001;24:1179-1186. 19. Weissmiiller P, Abraham-Fuchs K, Killmann R, et al. Magnetocardiography: Three-dimensional localization of the origin of ventricular late fields in the signal-averaged magnetocardiogram in patients with ventricular late potentials. Eur Heart J 1993;14:E61-E68. 20. Leder U, Haueisen J, Huck M, et al. Noninvasive imaging of arrhythmogenic left ventricular myocardium after infarction. Lancet 1998;352:1825. 21. Karvonen M, Takala P, Kaartinen M, et al. Detection of left ventricular hypertrophy by multichannel magnetocardiography. In: Nenonen J, Ilmoniemi RJ, Katila T (eds): Biomag2000: Proc Twelfth Int Conf on Biomagnetism. Espoo, Finland: Helsinki University of Technology; 2001: 579-582. 22. Brockmeier K, Schmitz L, Trahms L, et al. Magnetocardiography in patients with the long QT syndrome. In: Williamson SJ, Hoke M, Stroink G, Kotani M (eds): Advances in Biomagnetism. New York: Plenum Press; 1989:421-424. 23. Rovamo L, Paavola M, Montonen J, et al. Magnetocardiographic repolarisation maps in children with long QT syndrome. In: Baumgartner C, Deecke L, Stroink G,

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Williamson SJ (eds): Biomagnetism: Fundamental Research and Clinical Applications. Amsterdam: Elsevier; 1995:615-618. 24. Hailer B, van Leeuwen P, Lange S, et al. Spatial distribution of QT dispersion measured by magnetocardiography under stress in coronary artery disease. J Electrocardiol 1999;32:207-216. 25. Oikarinen L, Paavola M, Montonen J, et al. Magnetocardiographic QT-interval dispersion in post myocardial infarction patients with sustained ventricular tachycardia—validation of automated QT measurements. Pacing Clin Electrophysiol 1998;21:1934-1942. 26. Oikarinen L, Viitasalo M, Korhonen P, et al. Postmyocardial infarction patients susceptible to ventricular tachycardia show increased T wave dispersion independent of delayed ventricular conduction. J Cardiovasc Electrophysiol 2001;12:1115-1120. 27. Korhonen P, Vaananen H, Makijarvi M, et al. Repolarization abnormalities detected by magnetocardiography in patients with dilated cardiomyopathy and ventricular arrhythmias. J Cardiovasc Electrophysiol 2001;12:772-777. 28. Stroink G, Meeder RJ, Elliott P, et al. Arrhythmia vulnerability assessment using magnetic field maps and body surface potential maps. Pacing Clin Electrophysiol 1999;22:1718-1728. 29. Hren R, Steinhoff U, Gessner C, et al. Value of magnetocardiographic QRST integral maps in the identification of patients at risk of ventricular arrhythmias. Pacing Clin Electrophysiol 2000-22:1292-1304. 30. Brockmeier K, Comani S, Erne S, et al. Magnetocardiography and exercise testing. J Electrocardiol 1994;27:137-142. 31. Brockmeier K, Schmitz L, Bobadilla Chavez JD, et al. Magnetocardiography and 32-lead potential mapping: Repolarization in normal subjects during pharmacologically induced stress. J Cardiovasc Electrophysiol 1997;8:615-626. 32. Seese B, Moshage W, Achenbach S, et al. Magnetocardiographic (MCG) analysis of myocardial injury currents. In: Baumgartner C, Deecke L, Stroink G, Williamson SJ (eds): Biomagnetism: Fundamental Research and Clinical Applications. Amsterdam: Elsevier; 1995:628-632. 33. Leder U, Pohl HP, Michaelsen S, et al. Noninvasive biomagnetic imaging in coronary artery disease based on individual current density. Int J Cardiol 1998;64:83-92.

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34. Lant J, Stroink G, ten Voorde B, et al. Complementary nature of electrocardiographic and magnetocardiographic data in patients with ischemic heart disease. J Electrocardiol 1990;23:315-322. 35. Van Leeuwen P, Hailer B, Wehr M. Changes in current dipole parameters in patients with coronary artery disease with and without myocardial infarction. Biomed Tech (Berl) 1997;42:132-136. 36. Van Leeuwen P, Hailer B, Lange S, et al. Spatial and temporal changes during the QT-interval in the magnetic field of patients with coronary artery disease. Biomed Tech (Berl) 1999;44:139-142. 37. Hanninen H, Takala P, Makijarvi M, et al. Detection of exercise induced myocardial ischemia by multichannel magnetocardiography in single vessel coronary artery disease. Ann Noninvasive Electrocardiol 2000;5:147-157. 38. Hanninen H, Takala P, Korhonen P, et al. Features of ST segment and T-wave in exercise-induced myocardial ischemia evaluated with multichannel magnetocardiography. Ann Med 2002;34:1-10. 39. Takala P, Hanninen H, Montonen J, et al. Heart rate adjustment of magnetic field map rotation in detection of myocardial ischemia in exercise magnetocardiography. Basic Res Cardiol 2002;97:88-96. 40. Hanninen H, Takala P, Makijarvi M, et al. Recording locations in multichannel magnetocardiography and body surface potential mapping sensitive for regional exercise-induced myocardial ischemia. Basic Res Cardiol 2001;96:405-414.

41. Tsukada K, Miyashita T, Kandori A, et al. An iso-integral mapping technique using magnetocardiogram, and its possible use for diagnosis of ischemic heart disease. Int J Card Imaging 2000;16:55-66. 42. Achenbach S, Menendez T, Moshage W, et al. The fetal magnetocardiogram during different stages of pregnancy. In: Aine C, Okada Y, Stroink G, et al (eds): Biomag96: Proc Tenth Int Conf on Biomagnetism. New York: Springer; 2000:422-424. 43. Quinn A, Weir A, Shahani U, et al. Antenatal fetal magnetocardiography: A new method for fetal surveillance? Br J Obstet Gynaecol 1994;101:866-870. 44. Menendez T, Achenbach S, Beinder E, et al. Usefulness of magnetocardiography for the investigation of fetal arrhythmias. Am J Cardiol 2001;88:334-336. 45. Wakai RT, Leuthold AC, Cripe L, et al. Assessment of fetal rhythm in complete congenital heart block by magnetocardiography. Pacing Clin Electrophysiol 2000; 23:1047-1050. 46. Menendez T, Achenbach S, Beinder E, et al. Prenatal diagnosis of QT prolongation by magnetocardiography. Pacing Clin Electrophysiol 2000;23:1305-1307. 47. Van Leeuwen P, Hailer B, Bader W, et al. Magnetocardiography in the diagnosis of fetal arrhythmia. Br J Obstet Gynaecol 1999;106:1200-1208. 48. Horigome H, Shiono J, Shigemitsu S, et al. Detection of cardiac hypertrophy in the fetus by approximation of the current dipole using magnetocardiography. Pediatr Res 2001;50:242-245.

Part 5 Mapping of Supraventricular Tachyarrhythmias

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Chapter 25

Endocardial Catheter Mapping in Patients with Wolff-Parkinson-White Syndrome: Implications for Radiofrequency Ablation Karl-Heinz Kuck, MD and Riccardo Cappato, MD

When using radiofrequency (RF) catheter ablation techniques1-8 to abolish accessory atrioventricular (AV) pathways, several factors are important to optimize the probability of a successful pulse, including expertise in radiological anatomy, clinical electrophysiology, and catheter manipulation. The latter is most important, not only to minimize the complications related with catheter procedures, but also to select the proper approach to the targeted fiber. The investigator should also take time to familiarize himself or herself with the local electrograms recorded at several annular sites; in the region of interest, which may have different characteristics with regard to anatomical location, the annular site selected for ablation, and the accessory pathway (AP) geometry, all attempts should be made to reach the optimal site and to obtain firm catheter-tissue contact before and during RF current delivery.

RF Ablation of Right-Sided APs Common APs To access APs located on the right side of the heart, the mapping/ablation catheter is commonly introduced into the right atrium and advanced toward the atrial aspect of the tricuspid annulus (TA) using a femoral transvenous approach. For APs located anterosuperiorly, a jugular transvenous route may be used. Catheter stability at the atrial aspect of the TA is considerably less than at the ventricular aspect of the mitral annulus. Nevertheless, ablation of right-sided APs is usually achieved at annular right atrial sites. The use of a long vascular sheath embedding the ablation catheter up to the orifice of the inferior vena cava may improve catheter stability in this setting, and longer current application times may be required than on the left side of the heart,

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003. 497

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to achieve adequate heating of tissue.9 Temperature profiles during RF current delivery at the right AV annulus reflect the cooling effect produced by the large electrode surface not in contact with the target area and are therefore different from those observed at the left subannular level. Higher preset levels of power will partly compensate for the dispersed energy at the right annulus site; however, one should take into account that the actual temperature at the target site is underestimated by the monitored temperature profiles. Catheter stability at the AV groove plays a key role in the efficacy of catheter techniques for ablation of APs. Although there are no definitive criteria to assess stability at target ablation sites, monitoring of catheter movements on fluoroscopy and potential amplitude changes between consecutive beats on the local electrogram are useful indicators to judge the contact of the ablation tool with the target substrate. During RF delivery, power should be titrated such that an initial decrease of 5 to 10 Q in impedance is achieved and maintained thereafter throughout the duration of current delivery.10 Power and temperature profiles during RF pulse delivery are also used to assess cathetertissue contact at target sites (Figure 1). The following electrophysiological parameters are commonly used to identify the anatomical location of an AP: (1) the direct recording of an AP activation potential; (2) the earliest timing of preexcited local ventricular and/or atria/activation; and (3) the shortest length of the local atrioventricular (A-V) and/or ventriculoatrial (V-A) interval. APs Associated with Ebstein's Anomaly A special substrate for right-sided APs is represented by Ebstein's anomaly. This condition is characterized by an

apical displacement of the attachment of the septal and posterior tricuspid valve leaflets from the right AV annulus resulting in a variable extent of "atrialized" right ventricle.11 An apical displacement of the attachment of the septal tricuspid valve leaflet exceeding 1.2 cm in length on echocardiography is commonly used as a diagnostic criterion.12 Paroxysmal AV reentrant tachycardia has been reported in 25% to 30% of patients with Ebstein's anomaly, with ventricular preexcitation being present in 5% to 25% of surface ECGs.13-16 Accessory AV connections are usually located on the same side as the malformed valve; in addition, the presence of multiple APs in up to 50% of these patients14,16 likely reflects an incomplete annular development with discontinuities of the fibrous skeleton associated with the embryological malformation. The incidence of APs associated with this disease among all clinically relevant accessory AV connections is about 2% and 9% among rightsided APs.17 In patients with Ebstein's anomaly, precise AP localization may be impaired by the presence of multiple pathways and by their usual location along the dysplastic TA, a region where fractionated endocardial electrograms (multiple spikes lasting for >50 ms) are observed in about 50% of cases.17 Fractionated potentials reflect local conduction delay and are generally responsible for the right bundle branch block configuration typically observed on the 12-lead ECG. The presence of fragmented local electrograms cannot be predicted based on the extent of septal tricuspid leaflet displacement as determined in the echocardiographic 4-chamber projection (Figure 2). With regard to a potential target site for RF current delivery, fractionated activation potentials impair (1) the definite recording of an AP activation potential; (2) the determination of the site of earliest antegrade ventricular activation;

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Figure 1. Power (dotted line) and temperature (continuous line) profiles of radiofrequency (RF) pulses delivered at an unsuccessful (A) and successful right atrial supra-annular site (B), and at a successful left ventricular subannular site (C). In all cases, a preset temperature value of 70°C was used. A. The inability by the thermistor located at the catheter tip to record temperatures higher than 50°C throughout the whole pulse duration (60 s) despite maximal power (50 W) and high cumulative energy delivery (1409 J) reflects a poor catheter-tissue contact at the target ablation site. B. In the presence of a good catheter-tissue contact, the preset value of 70°C T is reached after 15 s with low P (10 to 15 W) and cumulative energy delivery (812 J). C. In the presence of a good cathetertissue contact, the preset value of 70°C T is reached after 20 s with low P (10 W) and cumulative energy delivery (283 J). Compared to the situation described in B, smoother profiles of T and P curves in the initial phase of RF pulse delivery and lower cumulative energy are observed, indicative of a better catheter-tissue contact at the left ventricular subannular than at a right atrial supraannular site. J = joules; P = power; T = temperature; t = time.

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annulus along the atrialized ventricle. If the anatomical course of the artery is confined to the AV groove, as observed in about 80% of these patients,17 mapping for AP potentials and for sites of earliest antegrade ventricular activation or earliest retrograde atrial activation can be performed by slowly withdrawing a miniaturized (2F) multipolar catheter from the crux of the heart to the ostium of the coronary artery. Using this technique, ablation can be attempted at the endocardial Figure 2. Relationship between the extent of site that best matches the anatomical septal tricuspid leaflet displacement normalized location of, and the electrogram configuby body surface area (mm/m2) and the pres- ration recorded from, the epicardial elecence of abnormal fragmented electrograms trode pair identifying AP location (Figures recorded at the endocardial aspect of the atrialized right ventricle in 20 patients with Ebstein's 3 and 4). The electrograms recorded by anomaly undergoing radiofrequency ablation of means of right coronary artery mapping accessory pathway at our institution. No differ- have proven relevant to localize and ablate ences are observed in the distribution of normal one or more APs in about 70% of patients versus abnormal electrograms depending on in whom the endocardial approach alone the extent of valve displacement. fails.17 Although the success rate of AP ablation in patients with Ebstein's anomaly and (3) the identification of the site of earis at 76% lower than the 95% usually liest retrograde atrial activation during achieved in patients with regular rightorthodromic tachycardia. In addition, frac17 sided APs, it is likely that the use of long tionated ventricular potentials may occasheaths to improve catheter stability,9 sionally exhibit late components of high amplitude that mimic retrograde atrial together with a better understanding of the complex electrograms generated in activation during tachycardia. To distinguish between atrial and the atrialized right atrium, will result in ventricular activation, timed extrastimuli higher success rates. are delivered from the high right atrium to dissociate the atrial from the ventricular component. During sinus rhythm, the Epicardial APs atrial extrastimuli are timed early in an In 0.5% of patients referred for RF attempt to find the AP refractory and thus discriminate the earliest ventricular acti- ablation of APs, an epicardial location can vation component during preexcitation. be identified along the right AV annulus.18 During tachycardia with preexcited retro- Usually, at sites of earliest ventricular grade atrial activation, atrial extrastim- activation during antegrade conduction uli are timed late to dissociate the local and of earliest atrial activation during atrial electrogram and identify its earli- retrograde conduction, small or no AP potentials are recorded. In such cases, est activation along the AV annulus. If pacing techniques fail to guide AP catheter electrodes advanced into the location, right coronary artery mapping coronary artery may reveal large AP may be used to improve the resolution of potentials. Stimulation techniques allow electrical activation recorded at the AV for dissociation of these potentials from

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Figure 3. Right anterior oblique (RAO) fluoroscopic projection in a patient with Ebstein's anomaly and incessant orthodromic tachycardia secondary to 2 right posteroseptal accessory pathways. A 2F quadripolar catheter is advanced into the right coronary artery (RCA) up to the posteroseptal region to guide intracardiac mapping during orthodromic tachycardia. The course of the RCA is outlined by means of contrast medium injected through a 7F right Judkins catheter. Also shown are catheters positioned in the right atrial free wall (HRA), at the His bundle region (His), and inside the coronary sinus (CS). A. The ablation catheter (MAP) is positioned at the endocardial site matching the distal pair of epicardial electrodes, where the earliest retrograde atrial activation during tachycardia is recorded (see left panel of Figure 4). B. After ablation of the first accessory pathway, the tachycardia is still present and the earliest retrograde atrial activation is now recorded opposite the epicardial proximal electrode pair (see center panel of Figure 4). Ablation at this site results in tachycardia termination (see right panel of Figure 4).

local atrial and ventricular activation potentials. RF current delivery at the annular level frequently fails or only transiently interrupts AP conduction.18 Ablation of these APs occasionally can be achieved at sites away from the annulus by insulation of the AP insertion site from the surrounding atrial or ventricular tissue (Figure 5) APs with Mahaim-Type Preexcitation The incidence of decrementally conducting antegrade APs among all clinically relevant accessory AV connections is about 2%.19 Due to the electrophysiological properties of these APs, the baseline ECG commonly displays poor or no preexcitation. Clinical arrhythmias are typically characterized by a regular

wide-QRS tachycardia exhibiting a left bundle branch block pattern. Based on their upper and lower insertion sites, APs are classified into AV, atriofascicular (if the lower insertion site is very proximal to the Purkinje extension of the right bundle), nodoventricular, and nodofascicular APs. In the usual case, the lower AP insertion site is located deep inside the ventricle, although it may occasionally be at the ventricular aspect of the TA.19 An atrial origin can be distinguished from a nodal (or fascicular) origin of the AP whenever one or more of the following criteria is met: (1) late right atrial extrastimuli (delivered as late as 40 ms after onset of the low right atrial septal electrogram)20 advanced ventricular activation of the next beat during preexcited tachycardia without affecting atrial activation at the low right atrium; (2) the presence

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Figure 4. Surface ECG lead III with 3 intracardiac electrograms (1 endocardial, R postsept; 2 epicardial, RCA 1/2 and 3/4) recorded from the patient in Figure 3. Left: One beat during tachycardia is shown; note the fragmented activation of electrograms at the endocardial site opposite to the epicardial site (RCA 1/2) recording the earliest retrograde atrial activation. Middle: Ablation at the endocardial site shown in left panel results in a change of tachycardia cycle length secondary to prolongation of ventriculoatrial (VA) activation time and in the intra-atrial activation sequence, suggestive of a second accessory pathway. Note that a corresponding change in the P wave morphology during tachycardia is also observed on surface ECG lead II. Separation of V from A activation potentials allows an accurate mapping from the endocardial site; the earliest endocardial activation is now recorded at a site opposite to the proximal epicardial electrode pair (see Figure 3B) and ablation at this site results in tachycardia termination. Right: Recording during sinus rhythm, after ablation of the 2 accessory pathways.

of tachycardia entrainment with atrial fusion during right atrial pacing20; and (3) ventricular preexcitation is more readily exposed by pacing from the right atrium than from the coronary sinus.21

A V/atriofascicular fibers

Three mapping techniques are commonly used to identify the atrial insertion site of accessory fibers exhibiting Mahaim-like preexcitation: the recording of a local AP activation potential along the right AV junction22,23; the induction by catheter manipulation at the TA of mechanical conduction block in the AP; and the shortest stimulus-to-QRS interval of maximally preexcited beats during

pacing at a fixed rate from the TA.24 The recording of a local AP potential is the most commonly used technique as its recording site along the TA coincides with the atrial insertion of the AP. Because of the AP slow antegrade conduction and its lower insertion deep in the ventricle, the local atrial and ventricular potentials are clearly separated all along the annulus during both sinus rhythm and maximal preexcitation; when recorded, the AP potential is inscribed onto the isoelectric baseline between the 2 potentials. The decremental pattern of the AP is usually reflected by a prolongation of the A-AP interval which becomes maximal during AP-dependent tachycardia. Transient block of antegrade conduction induced by catheter manipulation,

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Figure 5. A. Surface ECG leads II, II, and aVL with 2 intracardiac electrograms recorded during atrial pacing in a patient with a right posterior manifest epicardial accessory pathway. After multiple failed attempts at the annular region, the ablation catheter is advanced to the ventricular posterior wall (RV post), 1.5 cm away from the annulus. Note that no atrial potential is recorded at this site. RA = endocardial electrogram recorded along the right free wall; S = stimulus artifact. B. Radiofrequency delivery at this site results in loss of preexcitation after 3.5 s.

504 CAEDIAC MAPPING which is specific to APs with Mahaim-like preexcitation, likely reflects a subendocardial course of these fibers. Catheter maneuvering techniques to systematically achieve mechanical block of AP conduction during maximal preexcitation have been proposed.19 At sites of conduction block, an AP potential in the absence of preexcitation may occasionally be observed, suggestive of residual impulse penetration into the AP segment proximal to the site of block. After resumption, definitive abolition of AP conduction can be accomplished by delivering RF current to the site of transient mechanical block.19 This technique is particularly useful if no AP potentials are recorded despite careful mapping around the AV annulus as well as in case of atrial fibrillation. Criteria to guide ablation of the lower AP insertion include identification of the earliest ventricular activation site of maximally preexcited beats, possibly in the presence of a local AP activation potential and/or a paced QRS matching the tachycardia QRS in the 12-lead ECG.25 Although the lower insertion site of these fibers is usually found up to 2 to 3 cm away from the annulus, a subannular location has been occasionally reported.19,24 Nodoventriculur/nodofascicular fibers

Ablation of APs with Mahaim-like preexcitation at the ventricular aspect of the right midseptal annulus26 suggests a possible nodoventricular/nodofascicular course of the accessory fibers. In the few cases reported, the earliest ventricular activation of preexcited beats is recorded at the ventricular annular aspect or close to it, suggestive of a ventricular rather than fascicular lower insertion site. In these patients, AV nodal reentrant tachycardia is also commonly observed and AP ablation may or may not result in concomitant ablation of the AV nodal slow

pathway. Given their location, it is not clear whether these fibers originate from the AV node, as initially described by Mahaim and Benatt,27 or course the AV annulus in close proximity to the AV node. In the latter case, antegrade decremental conduction may be inherent to the fiber or depend on conduction properties of the area of transitional cells surrounding the AP upper insertion; in this case, absence of retrograde AP conduction may be secondary to a conduction mismatch at the AP-atrial interface. Ablation of these APs is achieved by RF delivery at the site of earliest ventricular activation during maximal preexcitation. RF Ablation of Septal APs Any attempt to correlate a true anatomical classification of "septa!" pathways with an electrophysiologically and radiographically applicable classification is limited. A classification of septal pathways useful for catheter ablation should take into account the spatial relationship between an AP and the AV-node/Hisbundle axis and should be based on radiographic landmarks obtained in the right anterior oblique and left anterior oblique (LAO) projections. "Septal" APs are classified as anteroseptal, midseptal, and posteroseptal. According to the anatomy of the septum, APs classified as "midseptal" are the only pathways that can be related to both the atrial and the ventricular septum. They are in part the only truly septal pathways. Pathways classified as "anteroseptal" generally have no septal connection at all; they skirt anteriorly along the central fibrous body or the right fibrous trigone, i.e., along the right anterior free wall. Pathways classified as "posteroseptal" are located posterior to the central fibrous body. As described earlier, this region is definitely not part of the septum.

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Pathways are classified as anteroseptal if an AP activation potential as well as a His bundle potential is simultaneously recorded from a catheter placed at the His bundle region.28 With the His bundle catheter left in place, the precise location of the AP is verified by mapping this space in the 30° LAO projection using the ablation catheter. The optimal site chosen for RF current application is one from which atrial and ventricular potentials are recorded in conjunction with an AP activation potential, but with no or only a tiny His bundle potential. Several techniques to position this catheter have been introduced. In one, the catheter is introduced from the right jugular vein and positioned at the atrial aspect of the TA or advanced into the right ventricle and then curved back to ablate the pathway from the ventricular aspect of the TA.29 Another approach involves introducing the ablation catheter from the right femoral vein and positioning it at the ventricular aspect of the TA.

are recorded simultaneously with an AP potential in between. Since the AV node may be in close proximity to such a site, a catheter positioning more to the ventricular aspect of the AV ring should be attempted. Such a position is indicated by a local ventricular potential exceeding the amplitude of the local atrial potential. The catheter is generally introduced by way of the right femoral vein and positioned in the 30° LAO projection. The complexity of the AP geometry in this region may be reflected in the possibility to record AP potentials away from the ablation site (Figures 6 and 7); however, earliest ventricular (during antegrade conduction, Figure 6) and atrial activation potentials (during retrograde conduction, Figure 7) are recorded at ablation sites. In a subgroup of pathways localized on the left annulus, the ablation catheter is positioned at the mitral annulus within the area between the His and the coronary sinus catheters. The ablation catheter may be introduced either using the retrograde arterial approach2 or by transseptal puncture.31,32

Midseptal APs

Posteroseptal APs

Pathways are classified as right midseptal if an AP potential is recorded through a catheter located in an area bounded anteriorly by the tip electrode of the His bundle catheter and posteriorly by the coronary sinus ostium as marked by the vortex of curvature in the coronary sinus catheter.30 In left midseptal pathways, the AP potential recording catheter is placed at the left side of the septum within a region also bounded by the His bundle and coronary sinus catheters. With the His bundle catheter and the coronary sinus catheter in place, the area along the TA between these catheters represents the midseptal space. The optimal site for RF current applications is one from which atrial and ventricular potentials

Accessory Pathways traversing the pyramidal space posterior to the septum may be subclassified as right posteroseptal and left posteroseptal. The former insert along the tricuspid ring in the immediate vicinity of the coronary sinus ostium; the latter have an anatomical course close to the terminal portion of the coronary sinus and may be located either at a subepicardial site around the proximal coronary sinus or the middle cardiac vein or at a subendocardial site along the posteromedial ventricular aspect of the mitral annulus. The area between the coronary sinus ostium and the TA represents the space right posteriorly to the septum. APs at this location are characterized by the recording of a distinct AP

Anteroseptal APs

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Figure 6. Surface ECG lead II with 4 intracardiac electrograms recorded in a patient with a left midseptal manifest accessory pathway. Intracardiac recordings are obtained from the left midseptal subannular (LV midsept), left posteroseptal subannular (LV postsept), left epicardial (CS postsept), and right posteroseptal supra-annular regions (RA midsept). Note that at the ablation site, earliest ventricular (V) activation (A - V = -20 ms) associated with accessory pathway potential (AP) recording is observed during preexcited sinus beats. At the RA midseptal location, opposite the ablation site, a high-frequency, low-amplitude potential suggestive of an AP potential is recorded following the atrial (A) and preceding the V deflection. A = onset of delta wave.

activation potential clearly separated from the atrial and ventricular potential. Left posteroseptal APs should be classified into 2 subgroups: subepicardial and subendocardial. APs located left posteriorly to the septum at a subepicardial site are related to either the proximal portion

of the coronary sinus, the middle cardiac vein, or a diverticulum connected either to the coronary sinus or the middle cardiac vein. Patients with APs related to the middle cardiac vein present with a preexcitation pattern characterized by wide and deep Q waves in leads II, III, and aVF

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Figure 7. Surface ECG lead II with 4 intracardiac electrograms recorded in a patient with a left midseptal concealed accessory pathway. At the ablation site, earliest atrial (A) activation (Q - A = 130 ms) is observed during orthodromic tachycardia. Note that at the right supra-annular midseptal (RA midsept) location, opposite the ablation site, a high-frequency, low-amplitude potential suggestive of an accessory pathway (AP) potential is recorded preceding the A deflection. The vertical line identifies the onset of the QRS complex on the surface ECG. Abbreviations as in Figure 6.

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Figure 8. Surface ECG leads in a patient with an accessory pathway ablated from inside the middle cardiac vein. Note the wide and deep Q wave configuration of the preexcited QRS complexes in leads II, II, and aVF characteristic of this accessory pathway location.

(Figure 8). With a mapping coronary sinus catheter in place, the ablation catheter is introduced via the right femoral vein and advanced 2 to 3 cm into the coronary sinus in the 30° LAO projection. The catheter is then slowly withdrawn along the floor of the coronary sinus until a large AP potential is recorded, either from the proximal part of the coronary sinus, from the middle cardiac vein, or from the neck of a diverticulum. In the latter 2 situations, the coronary sinus catheter will drop into

one of the venous structures during withdrawal from a posterior to a posteroseptal position. If the catheter drops into such a structure, injection of contrast agent into the coronary sinus or directly into the venous structure is mandatory. After RF current has been applied at such a site, angiography must be repeated to demonstrate integrity of the veins. The angiography catheter is introduced from the femoral veins with the ablating catheter left in place.33,34 APs located subendocardially

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AP conduction time, the P wave morphology is of help to tentatively identify AP location. During electrophysiological study, the following criteria are helpful, but not conclusive, to distinguish PJRT from the atypical form (fast/slow) of AV nodal reentrant tachycardia: during tachycardia, a timed ventricular premature beat introduced when the His bundle is refractory (1) produces advancement of retrograde Permanent junctional reciprocating atrial potentials (with unchanged activatachycardia tion sequence); (2) terminates tachycardia The permanent form of junctional without retrograde atrial activation; and reciprocating tachycardia (PJRT) is char- (3) results in a significant (>50 ms) proacterized by a narrow QRS complex, an longation of the local V-A interval. In the initiation mode that is not preceded by a presence of 1 or more of the above criteprolongation of the PR interval, a 1:1 AV ria, an AP location away from the septum relationship, an RP interval longer than is conclusive for PJRT. Target sites for ablation are those in the PR interval, and a negative polarity of the retrograde P wave in surface leads which the earliest retrograde atrial actiII, III, and aVF in most cases.35"38 Typi- vation (during tachycardia, echo beats, or cally, widely varying rates are observed. ventricular pacing) is recorded. Bipolar This tachycardia commonly presents in atrial deflections exhibit a fragmented infants and children and may persist into configuration in most cases.54 At these adulthood; it is usually refractory to drug sites, an AP potential is mostly absent, therapy.37-41 Although PJRT is usually although high-frequency, low-amplitude associated with no or only mild clinical potentials with variable location along the symptoms, it may precipitate tachycardia- isoelectric baseline between the ventricular and the atrial deflection that disapinduced cardiomyopathy.42,43 Contrary to the previous under- pear after ablation have been reported.54 standing of PJRT as an atypical variant Ablation of APs in the septal area is of AV nodal reentrant tachycardia,43-47 mostly accomplished using a right-sided several recent studies48-53 have provided catheter approach; in about 70% of cases, evidence for an extranodal AP with slow, successful pulses are delivered within the decremental, and predominantly retro- proximal coronary sinus with no need to grade conduction properties to be the introduce a catheter into the left heart.54 anatomical substrate of orthodromic reen- An additional left-sided endocardial catheter trant tachycardia. Occasionally, ante- approach is recommended whenever the grade decremental conduction can be earliest atrial activation is recorded more observed resulting in variable degrees of than 1 cm away from the coronary sinus preexcitation.38 AP location is close to or orifice. Residual antegrade and retrograde just inside the coronary sinus orifice in more penetration of the electrical impulse into than 80% of patients54 and along the right the AP without chamber activation can or left annular free wall in the remain- occasionally be observed after ablation ing patients. Given the long retrograde (Figure 9). along the mitral annulus posterior to the septum are approached with a catheter positioned either at the ventricular or atrial aspect of the annulus. The ablation catheter is introduced via the right femoral artery using the retrograde aortic approach or from the right femoral vein using the trans-septal approach.

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Figure 9. Surface ECG leads II, III, and V6 with 9 endocardial leads recorded after ablation in a patient with a permanent junctional reciprocating tachycardia secondary to a posteroseptal accessory pathway. During the first 2 paced beats (cycle length 600 ms), the distal electrode pair of the mapping catheter (Mp Dis) located at the successful site records an atrial potential (A) followed by an accessory pathway potential (AP) and a ventricular potential (V) suggestive of concealed antegrade conduction through the AP. Following the second beat, retrograde activation of the AP is recorded without A activation. The subsequent sinus beat shows A but not AP activation, likely due to antegrade AP refractoriness secondary to the previous retrograde impulse penetration. CS = distal (1-2), middle (5-6), and proximal (9-10) electrode pairs of a 12-polar catheter advanced into the coronary sinus; HBE = distal (1-2), middle (3-4), and proximal (5-6) electrode pairs of a 6-polar catheter located at the His-bundle region; Mp Prox = proximal electrode pair of the mapping catheter (Mp Dis); STIM = stimulation channel; Swartz = unipolar recording from the mapping catheter.

RF Ablation of Left-Sided APs Common APs Localization and ablation of endocardial left free wall APs can be achieved according to the general concepts discussed in the section entitled "RF Ablation of Right-Sided APs."

large AP potential recorded from the coronary sinus or its tributaries, has been reported in a small group of patients (about 4%) in whom ablation can be successfully and safely achieved using RF current delivered from within the coronary sinus or its tributaries.55,56 These APs may or may not be associated with anatomical anomalies of the coronary venous system.

Left-sided epicardial APs

Left anterior APs

Epicardial location of APs along the left AV annulus, as characterized by a

In about 0.5% of cases, manifest APs exhibiting a 12-lead ECG pattern

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suggestive of an anteroseptal location and Efficacy of RF Current Ablation a local AP activation potential recorded in Patients with APs from the His bundle region present with a local ventricular potential that does not Currently, success rates well exceedprecede the onset of the delta wave; in ing 90% are reported from experienced such cases, ablation from the right side centers for RF current ablation of AV cannot be achieved and the risk of AV tachycardias secondary to an accessory nodal block is increased by repeated AV pathway. unsuccessful attempts at RF current delivery. Mapping of the most anterior Recurrences extension of the great cardiac vein reveals an AP potential and a local ventricular The incidence of patients developing potential which may precede the onset of the delta wave by 20 to 30 ms. Ablation clinical symptoms post ablation and necessiat this site may be achieved by RF cur- tating a repeat ablation60-65session ranges It has been rent application either from within the between 5% and 10%. vein or using a transaortic retrograde reported that in a minority of these patients the manifestation of a previously approach.57 unnoticed ("dormant") AP had caused symptom recurrence.66 Late manifesting APs are ablated at a site clearly different Atrial Appendage-Ventricular from that of the initially targeted AP; in Connections addition, the manifestation of conduction over a previously "dormant" AP, which in The atrial insertion of an AP may most cases is concealed, occurs signifioccasionally (0.4%) be located within the cantly later (median of 201 days) than right or left atrial appendage.58 These the recovery of a presumably ablated AP fibers usually conduct bidirectionally; (median 77 days). in left-sided locations, the earliest antegrade and retrograde conduction are likely Complications of RF Current recorded from a ventricular tributary of the coronary sinus, whereas in right-sided Ablation Techniques locations the earliest ventricular activation is either low in amplitude or can be The complication rate of RF catheter recorded up to 10 mm away from the ablation procedures is about 5%; it includes annulus. complications related to catheter manipRF current application at sites of ear- ulation and to RF current delivery. Among liest activation at the AV annulus fre- complications are inadvertent complete quently fails or only transiently interrupts AV nodal block, pericardial effusion, carAP conduction. In the only series reported, diac tamponade, coronary artery spasm ablation of AP conduction was ultimately or thrombosis, intracavitary thrombus forobtained by RF current delivery at the tip mation, thromboembolism, pneumothorax, of the right appendage in 1 patient; in aortic wall dissection, local hematoma, another 2 patients, AP conduction was arteriovenous fistulae, and death. In coopeliminated during surgery by separating erative reports, the incidence of complithe right appendage in 1 and the left atrial cations was 3.8% in a large American appendage in the other from the ventricle, collective67 and 4.4% in the Multicentre distant from the annulus.59 European Radiofrequency Survey.68 In the

512 CARDIAC MAPPING latter study, life-threatening complications such as tamponade and embolism were reported in 0.7% and 0.6% of cases, respectively. A procedure-related death has been occasionally reported in patients undergoing RF current ablation. Complications related to the location oftheAP

Inadvertent complete AV nodal block has been reported in patients undergoing ablation of APs located in the septal space. Some precautions may minimize this risk whenever RF current must be delivered to the midseptal or anteroseptal region; they include (1) selection of the venous access associated with the greatest catheter stability at these sites; (2) use of a temperature-controlled current delivery with initial preset values not exceeding 55°C to 60°C; (3) careful monitoring of atrial retrograde conduction if junctional ectopic rhythm ensues during RF current applications, with immediate discontinuation of pulse delivery in case of a retrograde (ventriculoatrial) block; and (4) early discontinuation of energy delivery for pulses that fail to produce an early AP conduction block. As a side effect during catheter ablation of an AP anterior to the septum, a right bundle branch block may occur in approximately 5% of patients, likely because of a catheter displacement to the ventricular aspect of the TA. Epicardial APs ablated from within the coronary sinus or its tributary veins account for about 5% of all left-sided APs. RF current pulses delivered inside the cardiac venous system should be titrated at low power (not exceeding 15 W) or low preset temperature (not exceeding 55°C to 60°C). In case of a sudden impedance rise during pulse delivery, which may frequently occur because of the less pronounced convective cooling in this region,

immediate pulse discontinuation is mandatory to minimize the risk of thrombus formation and catheter adhesion to the venous wall. Despite these safety measures, thrombosis may nevertheless develop, occasionally leading to occlusion of the coronary sinus; in our experience, this event was never associated with clinical complications and complete recanalization could be documented within a few days of the procedure. Thus far, there are no reports of a perforation induced by RF current delivered within the cardiac veins. Potential Hazards of RF Current Catheter Ablation A potential source of risk to the patient and the investigators performing RF current catheter ablation procedures is the radiation exposure from fluoroscopic imaging required to guide catheter manipulation. The estimated absorbed dose per RF ablation procedure in a high-volume American center was 2.5 rem in the breast, 2.0 rem in the active bone marrow, and 7.5 rem in the lungs.69 These figures would lead to a lifetime risk of excess malignancies per 1 million patients undergoing 60 minutes fluoroscopy of 150 (only females), 120, and 710, respectively (a 0.07% lifetime risk of developing a fatal malignancy due to radiation exposure). In addition, the risk estimation for autosomal dominant abnormalities in the first generation is 5 to 35 cases per 1 million liveborn per absorbed rem, and the risk for all genetic disorders less than 50 cases per million liveborn per absorbed rem. Although difficult to translate into clinical practice, these estimates outline the necessity to minimize fluoroscopy time during RF current catheter ablation procedures without reducing efficacy and safety; also, the volume of exposed body weight and the lifetime expectancy with

ENDOCARDIAL CATHETER MAPPING IN WPW respect to the effective clinical benefit should be taken into account at the time of patient selection. In patients in whom RF current delivery in the proximity of the AV node is performed to ablate an AP, long-term follow-up is recommended to evaluate the potential impact of fibrotic lesions on AV conduction. Conclusions Radiofrequency current catheter ablation is currently widely used for the treatment of many cardiac tachyarrhythmias. Further development is presently under way to improve recording power, as provided by the electrode miniaturization in the split-tip catheter design,26 and produce deeper thermocoagulative lesions, as provided by the irrigated tip catheter design. Application of these technologies will likely allow ablation of "deep" APs and optimize the therapeutic approach to a variety of other arrhythmias, such as ventricular tachycardia, in which RF ablation is presently associated with unsatisfying success rates. In addition, use of temperatureand impedance-guided devices will improve the safety of this technique. Finally, followup surveillance of patients undergoing RF catheter ablation is demanded to assess long-term safety. References 1. Borggrefe M, Budde T, Podzeck A, Breithardt G. High frequency alternating current ablation of an accessory pathway in humans. J Am Coll Cardiol 1987; 10:576-582. 2. Kuck KH, Kunze KP, Schliiter M, et al. Modification of a left-sided accessory atrioventricular pathway by radiofrequency current using a bipolar epicardial-endocardial electrode configuration. Eur Heart J 1988;9:927-932. 3. Jackman WM, Wang X, Friday KJ, et al. Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White

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syndrome) by radiofrequency current. N EnglJMed 1991;324:1605-1611. 4. Kuck KH, Schluter M, Geiger M, et al. Radiofrequency current catheter ablation of accessory atrioventricular pathways. Lancet 1991;337:1557-1561. 5. Calkins H, Sousa J, Rosenheck S, et al. Diagnosis and cure of the WolffParkinson-White syndrome or paroxysmal supraventricular tachycardias during a single electrophysiologic test. N Engl J Med 1991;324:1612-1618. 6. Schluter M, Geiger M, Siebels J, et al. Catheter ablation using radiofrequency current to cure symptomatic patients with tachyarrhythmias related to an accessory atrioventricular pathway. Circulation 1991;84:1644-1661. 7. Leather RA, Leitch JW, Klein GJ, et al. Radiofrequency catheter ablation of accessory pathways: A learning experience. Am J Cardiol 1991;68:1651-1655. 8. Lesh MD, Van Hare GF, Schamp DJ, et al. Curative percutaneous catheter ablation using radiofrequency energy for accessory pathways in all locations: Results in 100 consecutive patients. J Am Coll Cardiol 1992;19:1303-1309. 9. Cappato R, Curnis A, Schluter M, et al. Catheter ablation of accessory pathways in Ebstein's anomaly: Improved efficacy using a long sheath. Eur Heart J1997; 18 (Abstr Suppl):313. Abstract. 10. Hoffmann E, Remp T, Gerth A, et al. Does impedance monitoring during radiofrequency catheter ablation reduce the risk of impedance rise? Circulation 1993;88: 1-165. Abstract. 11. Anderson KR, Zuberbuhler JR, Anderson RH, et al. Morphologic spectrum of Ebstein's anomaly of the heart: A review. Mayo ClinProc 1979;54:174-180. 12. Feigenbaum H. Echocardiography. 4th ed. Philadelphia; Lea and Febiger; 1986: 622. 13. Kastor JA, Goldreyer BN, Josephson ME, et al. Electrophysiologic characteristics of Ebstein's anomaly of the tricuspid valve. Circulation 1975;52:987-995. 14. Smith WM, Gallagher JJ, Kerr CR, et al. The electrophysiologic basis and management of symptomatic recurrent tachycardia in patients with Ebstein's anomaly of the tricuspid valve. Am J Cardiol 1982;49: 1223-1234. 15. Kumar AE, Fyler DC, Mietinen OS, Nadas AS. Ebstein's anomaly: Clinical

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profile and natural history. Am J Cardiol 1971;28:84-95. 16. Colavita PG, Packer DL, Pressley JC, et al. Frequency, diagnosis and clinical characteristics of patients with multiple accessory atrioventricular pathways. Am J Cardiol 1987;59:601-606. 17. Cappato R, Schluter M, WeiB C, et al. Radiofrequency current catheter ablation of accessory atrioventricular pathways in Ebstein's anomaly. Circulation 1996;94: 376-383. 18. Kuck KH, Schluter M, Siebels J, Hebe J. Right-sided epicardial accessory pathways: Rare but there. Circulation 1994; 90:1-127. Abstract. 19. Cappato R, Schluter M, WeiB C, et al. Catheter-induced mechanical conduction block of right-sided accessory fibers with Mahaim-type preexcitation to guide radiofrequency ablation. Circulation 1994;90: 282-290. 20. Tchou P, Lehman MH, Jazayeri M, Akhtar M. Atriofascicular connection or a nodofascicular Mahaim fiber? Electrophysiologic elucidation of the pathway and associated reentrant circuit. Circulation 1988;77:837-848. 21. Gallagher JJ, Selle JG, Sealy WC, et al. Variants of pre-excitation: Update 1989. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology. From Cell to Bedside. Philadelphia: W.B. Saunders; 1990:480-490. 22. McClelland J, Jackman W, Beckman K, et al. Direct recording of right atriofascicular accessory pathway (Mahaim) potentials at the tricuspid annulus. Pacing Clin Electrophysiol 1992;15:548. Abstract. 23. Tchou P, Keim SG, Kion RM, et al. Electrophysiological evidence for an ectopic node-His like atrioventricular conduction system. Pacing Clin Electrophysiol 1992;15: 51. Abstract. 24. Klein LS, Hackett FK, Zipes DP, Miles WM. Radiofrequency catheter ablation of Mahaim fibers at the tricuspid annulus. Circulation 1993;87:738-747. 25. Haissaguerre M, Fischer B, Le Metayer P, et al. Nature of the distal insertion of Mahaim fibers as defined by catheter ablation. Eur Heart J 1993;14:33. Abstract. 26. Grogin HR, Randall JL, Kwasman M, et al. Radiofrequency catheter ablation of atriofascicular and nodofascicular Mahaim tracts. Circulation 1994;90:272-281. 27. Mahaim I, Benatt A. Nouvelle recherches sur les connexions superieures de la branche

28.

29.

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31.

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35. 36.

37.

38.

39.

gauche du faisceau de His-Tawara avec cloison interventriculaire. Cardiologia 1938; 1:61-68. Schluter M, Kuck KH. Catheter ablation from right atrium of anteroseptal accessory pathways using radiofrequency current. J Am Coll Cardiol 1992;19:663670. Twidale N, Wang X, Moulton K, et al. Catheter placement for radiofrequency ablation of anteroseptal accessory pathways. J Am Coll Cardiol 1991;17:231A. Abstract. Kuck KH, Schluter M, Giirsoy S. Preservation of atrioventricular nodal conduction during radiofrequency current catheter ablation of midseptal accessory pathways. Circulation 1992;86:1743-1752. Natale A, Klein GJ, Yee R, et al. Radiofrequency ablation of left lateral accessory pathways: Transseptal vs. retrograde aortic approach. Pacing Clin Electrophysiol 1992;15:518. Abstract. Lesh MD, Van Hare GF, Scheinman MM, Ports TA. What is the best approach to radiofrequency ablation of left-sided accessory pathways: Retrograde or transseptal? Pacing Clin Electrophysiol 1992; 15: 535. Abstract. Oren J, McClelland J, Beckman K, et al. Epicardial posteroseptal accessory pathways requiring ablation from the middle cardiac vein. Pacing Clin Electrophysiol 1992;15:535. Abstract. Kuck KH, Schluter M, Chiladakis I. Accessory pathways anatomically related to the coronary sinus. Circulation 1992; 86:1-782. Abstract. Gallavardin L, Veil P. Tachycardies auric ulaires en salves. Arch Mal Coeur 1927; 20:1. Coumel P, Cabrol C, Fabiato A, et al. Tachycardie permanente par rythme reciproque. I—Preuves du diagnostic par stimulation auriculaire et ventriculaire. Arch Mai Coeur 1967;60:1830-1864. Gallagher JJ, Sealy WC. The permanent form of junctional reciprocating tachycardia: Further elucidation of the underlying mechanism. Eur J Cardiol 1978; 8:413-430. Critelli G, Gallagher JJ, Monda V, et al. Anatomic and electrophysiologic substrate of the permanent form of junctional reciprocating tachycardia. J Am Coll Cardiol 1984;4:601-610. Guarnieri T, Sealy WC, Kasell JH, et al. The nonpharmacological management of

ENDOCAEDIAL CATHETER MAPPING IN WPW permanent junctional reciprocating tachycardia. Circulation 1984;69:269-277. 40. Okumura K, Henthorn RW, Epstein AE, et al. "Incessant" atrioventricular (AV) reciprocating tachycardia utilizing a left lateral AV by-pass pathway with a retrograde long conduction time. Pacing Clin Electrophysiol 1986;9:332-342. 41. O'Neill BJ, Klein GJ, Guiraudon GM, et al. Results of operative therapy in the permanent form of junctional reciprocating tachycardia. Am J Cardiol 1989;63: 1074-1079. 42. Cruz FE, Cheriex EC, Smeets JL, et al. Reversibility of tachycardia-induced cardiomyopathy after cure of incessant supraventricular tachycardia. J Am Coll Cardiol 1990;16:739-744. 43. Packer DL, Bardy GH, Worley SJ, et al. Tachycardia-induced cardiomyopathy: A reversible form of left ventricular dysfunction. Am J Cardiol 1986;57:563-570. 44. Colvin EV, Gillette PC, Garson A Jr., Porter CJ. Electrophysical-clinical correlation of AV node reentry tachycardia. Circulation 1983;68:III-269. Abstract. 45. Coumel P. Junctional reciprocating tachycardias: The permanent and paroxysmal forms of AV nodal reciprocating tachycardias. J Electrocardiol 1975;8:79-90. 46. Wu D, Denes P, Amat-y-Leon F, et al. An unusual variety of atrioventricular nodal reentry due to retrograde dual atrioventricular nodal pathways. Circulation 1977;56:50-59. 47. Sung RJ, Waxman HL, Saksena S, Juma Z. Sequence of retrograde atrial activation in patients with dual atrioventricular nodal pathways. Circulation 1981;64:1059— 1067. 48. Gallagher JJ, Sealy WC. The permanent form of junctional reciprocating tachycardia: Further elucidation of the underlying mechanism. Eur J Cardiol 1978;8: 413-430. 49. Critelli G, Gallagher JJ, Monda V, et al. Anatomic and electrophysiologic substrate of the permanent form of junctional reciprocating tachycardia. J Am Coll Cardiol 1984;4:601-610. 50. Brugada P, Bar FW, Vanagt EJ, et al. Observations in patients showing AV junctional echoes with a shorter P-R than R-P interval: Distinction between intranodal reentry or reentry using an accessory pathway with a long conduction time. Am J Cardiol 1981;48:611-622.

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51. Brugada P, Farre J, Green M, et al. Observations in patients with supraventricular tachycardia having a P-R interval shorter than the R-P interval: Differentiation between atrial tachycardia and reciprocating atrioventricular tachycardia using an accessory pathway with long conduction times. Am Heart J 1984;107:566-570. 52. Farre J, Ross D, Wiener I, et al. Reciprocal tachycardias using accessory pathways with long conduction times. J Am Coll Cardiol 1979;4:1099-1109. 53. Klein GJ, Kostuk WJ, Ko P, Gulamhusein S. Permanent junctional reciprocating tachycardia in an asymptomatic adult. Further evidence for an accessory ventriculoatrial nodal structure. Am Heart J 1981;102:282-286. 54. Gaita F, Haissaguerre M, Giustetto C, et al. Catheter ablation of permanent reciprocating tachycardia with radiofrequency current. J Am Coll Cardiol 1995;25:655-664. 55. Arruda MS, Beckman KJ, McCelland JH, et al. Coronary sinus anatomy and anomalies in patients with posteroseptal accessory pathway requiring ablation within a venous branch of the coronary sinus. J Am Coll Cardiol 1994;23:224A. Abstract. 56. Haissaguerre M, Gaita F, Fischer B, et al. Radiofrequency catheter ablation of left lateral accessory pathways via the coronary sinus. Circulation 1992;86:14641468. 57. Kuck KH, Schluter M, Cappato R, et al. Left anterior accessory pathways mimicking a right anteroseptal location. Implications for catheter ablation. Circulation 1995;92:I-212. Abstract. 58. Arruda M, McClelland J, Beckman K, et al. Atrial appendage-ventricular connections: A new variant of preexcitation. Circulation 1994;90:I-126. Abstract. 59. Gallagher JJ, Sealy WC, Kasell J, Wallace AG. Multiple accessory pathways in patients with the pre-excitation syndrome. Circulation 1976;54:571-591. 60. Kay GN, Epstein AE, Dailey SM, et al. Role of radiofrequency ablation in the management of supraventricular arrhythmias: Experience in 760 consecutive patients. J Cardiovasc Electrophysiol 1993;4:371-389. 61. Twidale N, Wang XZ, Beckman KJ, et al. Factors associated with recurrence of accessory pathway conduction after radiofrequency catheter ablation. Pacing Clin Electrophysiol 1991;14:2042-2048.

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62. Langberg JJ, Calkins H, Kim YN, et al. Recurrence of conduction in accessory atrioventricular connections after initially successful radiofrequency catheter ablation. J Am Coll Cardiol 1992; 19:15881592. 63. Chen SA, Chiang CE, Tsang WP, et al. Recurrent conduction in accessory pathway and possible new arrhythmias after radiofrequency catheter ablation. Am Heart J 1993;125:381-387. 64. Chen X, Kottkamp H, Hindricks G, et al. Recurrence and late block of accessory pathway conduction following radiofrequency catheter ablation. J Cardiovasc Electrophysiol 1994;5:650-658. 65. Calkins H, Prystowsky E, Berger RD et al. Recurrence of conduction following radiofrequency catheter ablation procedures: Relationship to ablation target and

66.

67. 68.

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electrode temperature. J Cardiovasc Electrophysiol 1996;7:704-712. Schliiter M, Cappato R, Ouyang F, et al. Clinical recurrences after successful accessory pathway ablation: the role of "dormant" accessory pathways. J Cardiovasc Electrophysiol 1997;8:1366-1372. Scheinman MM. Catheter ablation for cardiac arrhythmias, personnel and facilities. Pacing Clin Electrophysiol 1992;15:715-721. Hindricks G. The Multicentre European Radiofrequency Survey (MERFS): Complications of radiofrequency catheter ablation of arrhythmias. Eur Heart J1993; 14: 1644-1653. Calkins H, Niklason L, Sousa J, et al. Radiation exposure during radiofrequency catheter ablation of accessory atrioventricular connections. Circulation 1991;84: 2376-2382.

Chapter 26

Endocardial Catheter Mapping in Patients with Mahaim and Other Variants of Preexcitation Hans Kottkamp, MD and Gerhard Hindricks, MD

Introduction At the end of the 19th century, Kent1 and His2 sought to discover a muscular bridge that forms an atrioventricular (AV) connection across the AV fibrous ring. They independently published their findings in 1893. Both of these investigators sought to find the normal conduction system between the atria and the ventricles. His discovered the penetrating AV bundle, and later, in his monograph, Tawara3 comprehensively described the human specialized junctional area in continuity including the AV node, the penetrating AV bundle, and the bundle branches and their terminal ramifications. On the other hand, in his original paper, Kent1 reported on muscular connections in the left and right lateral walls of mammalian but not human hearts and gave no specific description about the localization and the morphology of the AV connections. In 1913 and 1914, Kent4-8 illustrated a case of a human heart in which he had found

a specialized node-like structure in the lateral atrial aspect of the right AV sulcus. In 1930, Wolff, Parkinson, and White9 described a syndrome of short PR interval, abnormal QRS complex with bundle branch block (BBB) pattern, and paroxysmal tachycardia. An accessory AV muscular connection was considered to constitute the morphological basis for this syndrome by Holzmann and Scherf in 193210 and by Wolferth and Wood in 1933.11 These authors tried to correlate the clinical and electrocardiographic data of patients with the so-called Wolff-Parkinson-White (WPW) syndrome to anatomical findings that could support their theory. In this light, the AV connections described by Kent4-8 were presumed to constitute the clinicoanatomical correlate that was sought.11 Wood, Wolferth, and Geckeler12 later were the first to demonstrate histologically an accessory AV connection in a patient with WPW syndrome. These findings were confirmed and extended by the report from Ohnell.13 Ohnell also proposed the teicmpreexcitation,

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003. 517

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which has, since then, been used to describe the premature ventricular activation apart from the conduction through the AV (His) bundle. The small muscular connections identified histologically in patients with WPW syndrome did not, however, resemble the node-like structure reported by Kent. In contrast, the AV ring specialized tissue described by Anderson and co-workers14,15 strongly resembled this node-like structure. In contrast to the well-delineated clinicopathological correlation of accessory AV connections in patients with WPW syndrome, corresponding functional-morphological correlations do not exist to the same extent for the variants of the preexcitation syndromes, i.e., for atriofascicular, nodofascicular, and fasciculoventricular connections. In a series of papers between 1932 and 1947, Mahaim and his co-workers16-19 originally described anatomical connections of the AV node to the myocardial septum as well as connections of the origin of the left bundle branch to the upper part of the interventricular septum. Since then, the role of so-called "Mahaim pathways" for the initiation and perpetuation of tachycardias with the typical left BBB morphology as well as their electrophysiological and anatomical characteristics have been controversial. Originally, accessory pathways were designated by electrophysiologists as "Mahaim pathways" when they were thought to originate within the AV node and to insert into the distal right bundle branch ("nodofascicular" pathways) or into the right ventricular myocardium ("nodoventricular" pathways).20-26 The anatomical description of an accessory pathway connecting the AV node and the ventricular myocardium seemed to be compatible with electrophysiological characteristics of the "Mahaim pathways" that resembled the properties of the normal AV node. This original concept was challenged by a report from Gillette and co-workers,27

who surgically interrupted accessory pathways at the right parietal tricuspid annulus that had been believed to be ftodoventricular pathways because of their electrophysiological properties. These results have been confirmed by electrophysiological and cardiosurgical studies identifying the atrial insertion of these accessory pathways at a distance from the AV node at the lateral free wall of the tricuspid annulus.28-30 Overall, the concept of nodofascicular and nodoventricular pathways as the morphological correlates of this distinct, electrophysiologically defined subset of the preexcitation syndromes has been replaced by the concept of atriofascicular pathways, and the pure existence of nodoventricular and fasciculoventricular pathways, or at least their functional role in participation in preexcited tachycardias, is still controversial. The nonpharmacological therapy for patients with atriofascicular pathways originally comprised surgical interruption of the accessory pathways and catheter ablation of the His bundle.27-29,31,32 Thereafter, catheter ablation of the ventricular insertion of the atriofascicular pathways using direct current33 and of the atrial insertion using radiofrequency current34 has been introduced as a direct curative treatment modality. Recently, different mapping techniques and electrophysiological criteria for successful radiofrequency current catheter ablation of atrio-fascicular accessory pathways have been described.35-42 In this chapter, the existing concepts of the anatomical-electrophysiological correlations for the variants of preexcitation are discussed. The electrophysiological findings in patients with different types of variants of preexcitation, i.e., atriofascicular, nodofascicular, and fasciculoventricular fibers, and the results of radiofrequency catheter ablation using different target sites are described.

VARIANTS OF PREEXCITATION

Specialized Atriofascicular and AV Pathways In 1981, before the era of surgical or catheter ablation therapy of atriofascicular pathways, Gallagher et al.25 suggested that an alternative explanation to the old concept of so-called nodoventricular pathways would be an accessory AV node. These investigators had observed that right atrial pacing resulted in greater degrees of preexcitation compared with coronary sinus pacing at comparable pacing cycle lengths, and suggested that the atrial insertion of these accessory pathways was functionally related to the right atrium. Gillette and co-workers27 then performed their abovementioned surgical interruption of acces-

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sory pathways at the right parietal tricuspid annulus that had been believed to be Mocfoventricular pathways because of their electrophysiological properties. Electrophysiological evidence leading to the reassessment of these pathways came from Tchou et al.,30 who demonstrated that late atrial extrastimuli delivered during antidromic AV reentrant tachycardia (AVRT) could advance the ventricular activation despite their inability to enter the AV node (Figure 1). Thus, the atrial insertion of the accessory pathways was suggested to originate directly from the right atrium remote from the normal AV node. McClelland et al.36 further characterized the properties of atriofascicular pathways and observed conduction time

Figure 1. Surface ECG leads and intracardiac recordings during antidromic atrioventricular reentrant tachycardia (AVRT) involving an atriofascicular pathway as the antegrade limb and the AV node as the retrograde limb of the circuit. The AVRT is reset with a late atrial extrastimulus (S2) delivered from the high right atrium (HRA) without anterograde penetration into the normal AV node and without a change in the QRS morphology and the ventricular activation sequence indicating the "extranodal" origin of the atriofascicular pathway. His = His bundle; RBB = right bundle branch; RVA = right ventricular apex; CS = coronary sinus.

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prolongation of the accessory pathways during atrial extrastimulation and adenosine, a Wenckebach periodicity proximal to the recording of the accessory pathway activation potential, and an intrinsic automaticity of the accessory pathways (Figures 2, 3, and 4). The earliest ventricular activation during maximal preexcitation was usually found remote from the tricuspid annulus at the apical third of the right ventricular free wall.36-38 In addition, the relative late ventricular activation at sites close to the tricuspid annulus and the relative early ventricular activation at sites close to the right ventricular apex during preexcited QRS complexes suggested an insulated course of the atriofascicular pathways. At the ventricular insertion, a high-frequency potential could be recorded in many cases during antidromic AVRT as well as during sinus rhythm, indicating the insertion of the accessory pathway in the distal segments of the right bundle branch. Further indirect evidence for the insulated connection of atriofascicular pathways to the right bundle branch system came from mapping studies during arrhythmia surgery.43-44 Epicardial mapping during maximal preexcitation identified the earliest site of ventricular activation in most cases at the midanterior right ventricle at the same site of the early breakthrough in the normal heart. However, in the series of McClelland et al.36 and Murdock et al.,43 in some patients the distal insertion of the accessory pathways was found close to the tricuspid annulus indicating atrioventricular pathways. An endocardial course of atriofascicular fibers is suggested by the loss of accessory pathway conduction resulting from light pressure exerted with the mapping catheter.36-38 Cappato et al.38 further showed that accessory pathway activation potentials could be more easily recorded with endocardial mapping compared with epicardial mapping via the right coronary artery.

Recently, Guiraudon and co-workers45 reported on the results of surgical therapy and pathology in patients with atriofascicular pathways. In 5 of their patients, pathological examination of the right atrial attachment of the atriofascicular pathway showed AV nodal cells within AV nodal tissue organization. These findings confirm the electrophysiological hypothesis that atriofascicular pathways represent an accessory AV node and connecting AV conduction system. Thus, the morphological correlate for the electrophysiologically and surgically defined atriofascicular pathways has nothing to do with the anatomical descriptions by Mahaim et al.16-19 On the other hand, Kent4-8 found a specialized node-like structure at the right lateral AV sulcus, although he did not document the connection of this node-like structure with the ventricular myocardium in an illustration. Specialized ring tissue around the embryonic AV canal had been described even earlier by Keith and Flack.46 Later, Anderson and co-workers14-15 analyzed the AV ring specialized tissue in fetal, infant, and adult human hearts. In fetal specimens of 10 to 12 weeks, a complete ring of specialized tissue was found around the tricuspid orifice and also in the posterior margin of the mitral orifice.15 In a later series from the same group,47 the specialized ring tissue was confined to the right AV junction. Contiguities of the specialized tissue with ventricular myocardium were often observed during the early stage of ontogenesis through gaps of the developing fibrous skeleton.15 In infant hearts, specialized tissue was found by these investigators at various points around the tricuspid valve attachment. In this stage, the specialized tissue was separated from the ventricular myocardium by the developed annulus fibrosus.15 Interestingly, Anderson et al.15 described the arrangement of the atrial fibers around the specialized tissue areas as reminiscent of the transitional

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Figure 2. Twelve-lead ECG in a patient with an atriofascicular pathway. Top: During sinus rhythm, slight preexcitation is visible. Middle: During stimulation from the high right atrium (HRA) with a cycle length of 400 ms, maximal preexcitation is revealed. The stimulus-QRS interval measured 130 ms. Bottom: During faster stimulation at a cycle length of 380 ms, the preexcitation pattern remains the same and the stimulus-QRS interval further increased to 190 ms (so-called long conduction times and decremental conduction properties).

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Figure 3. Surface ECG leads I, II, and V1 and intracardiac recordings in a patient with an atriofascicular pathway during sinus rhythm (SR) and high right atrium pacing (HRA) at cycle lengths (CLs) of 550, 500, and 450 ms, respectively. During sinus rhythm, the interval from the atrial potential to the atriofascicular potential measured 90 ms. During HRA stimulation, this interval increased to 120, 140, and 160 ms, respectively. Note that the interval between the atriofascicular potential and the onset of the QRS complex remained constant at 50 ms. On the other hand, the atrium-His interval at the His bundle catheter (HBE) increased from 120 ms to 170, 230, and 280 ms, respectively. Note, that during stimulation at a cycle length of 450 ms, the His bundle is activated retrogradely (distal HBE 1/2 before proximal HBE 3/4). Abl uni = unipolar electrogram of the ablation catheter placed at the parietal tricuspid annulus; Abl bi = bipolar electrogram of the ablation catheter; RBB = right bundle branch; CS = coronary sinus; RVA = right ventricular apex.

cells of the AV node. The specialized ring tissue is also a remnant of the inlet-outlet ring, which, at the inner curve, has an AV location and, according to recent analysis, is true nodal tissue.48 In adult hearts, remnants of AV ring specialized tissue were found in 15% of the cases.15 These remnants were most frequently observed in the anterolateral area but also in the lateral to posterolateral region and, in a single case, on the left side of the heart posterior to the mitral orifice.15 In all their cases, the AV ring specialized tissue was confined to the atrial myocardium and separated from the ventricular myocardium

by the fibrous skeleton. Anderson and coworkers15 suggested that in abnormal situations, the AV ring specialized tissue might form a specialized substrate for ventricular preexcitation besides the more often observed AV accessory connections in WPW syndrome composed of ordinary myocardium. Thus, atriofascicular pathways seem to originate from remnants of the specialized ring tissue from which a connecting AV conduction system might arise.15 The predilection of the atrial insertion of electrophysiologically defined atriofascicular fibers for the antero- to posterolateral aspect of the tricuspid

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Figure 4. Surface ECG leads and intracardiac recordings during antidromic atrioventricular reentrant tachycardia (AVRT) with a cycle length of 405 ms involving an atriofascicular pathway as the antegrade limb. An accessory pathway activation potential was recorded at the parietal tricuspid annulus. The interval from the atrium (A) to atriofascicular pathway (arrow) measured 225 ms; the interval from the atriofascicular pathway to the onset of the QRS complex measured 50 ms. Note the retrograde activation of the His bundle inscribed after the onset of the QRS complex. For abbreviations, see the legend for Figure 3.

annulus represents further evidence for this hypothesis. The concept that the embryonic AV ring specialized tissue is able to effect AV conduction in situations of congenital heart disease when the formation of the normal AV node and conduction system is prevented had been described in 1913 by Monckeberg49 and was later described by Anderson et al.50 Becker et al.51 reported on the clinicopathological correlation of a series of patients with WPW syndrome. One of their patients had, in addition to an accessory AV pathway composed of working myocardium, a second connection in a right anterolateral position arising from a node-like structure. A bundle was described that originated from this node-like structure and

coursed caudally to become contiguous with the ventricular myocardium in a patient who also presented with Ebstein's malformation.51 It seems very likely that this accessory AV pathway represented a specialized atriofascicular or AV pathway. Definitive pathological assessment of a complete atriofascicular pathway including the ventricular course of the connecting conduction system to the distal ramifications of the normal right bundle branch, however, is still missing. In an attempt to add to the commonly used nomenclature for the substrates of ventricular preexcitation,48,52 a descriptive name for these accessory AV nodes and AV bundles therefore could be specialized atriofascicular and specialized AV

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pathways. The term specialized would clearly differentiate these pathways from the accessory AV connections composed of working myocardium in the WPW syndrome. An atriofascicular pathway is now suggested if preexcitation is minimal or absent and the PR interval is within normal limits during sinus rhythm, and if incremental atrial stimulation or atrial extrastimuli reveal preexcitation with a left-BBB-like morphology that is identical to the configuration during tachycardia. Atriofascicular fibers exhibit long conduction times, decremental conduction properties by atrial extrastimuli or incremental atrial pacing, and conduction only in the anterograde direction. The earliest retrograde conduction during ventricular pacing or tachycardia is found at the fast or slow pathway of the AV node or via an accessory AV pathway remote from the atriofascicular pathway. Late extrastimuli that are delivered at the high or lateral right atrium reveal advancement of the tachycardia ("reset") without changing the QRS configuration and without anterograde penetration into the AV node indicating the extranodal atrial origin of the atriofascicular pathway and participation of the right atrium in the reentrant circuit. Ablation of Specialized Atriofascicular and AV Pathways Stimulus to delta wave mapping was performed in the initial ablation studies during constant rate atrial pacing.34,35,38 Among the reasons for its moderate utility is the variability of the conduction time through the AV-node—like proximal portion of the specialized atriofascicular fibers. This shortcoming, however, might be avoided by applying atrial extrastimuli during antidromic AVRT when constant AV intervals usually are present.

Ablation of the retrograde route during antidromic AVRT, i.e., ablation of the so-called fast pathway of the AV node, has been described when ablation attempts targeted at the atriofascicular pathway had failed.39 However, several pitfalls accompany this technique in patients with atriofascicular pathways, and therefore it cannot be recommended in these patients. First, application of radiofrequency energy must be stopped immediately when maximal preexcitation occurs since successful selective fast pathway ablation might not be distinguished from complete anterograde block in the normal AV node. Thus, the inherent risk of complete AV block during modification of the AV node is increased in patients with atriofascicular pathways. Second, the retrograde route during antidromic AVRT must be carefully investigated because the slow pathway of the AV node as well as additional AV accessory pathways with retrograde conduction capabilities might serve as the retrograde limb. Third, even when the fast pathway is identified during catheter mapping as the retrograde limb, the slow pathway might also be capable of conducting retrogradely. In contrast, catheter ablation guided by the recording of atriofascicular pathway activation potentials as target sites has demonstrated high success rates in several studies36-42 (Figure 4). Radiofrequency energy may be applied at the proximal-node-like structure close to the tricuspid annulus. In these cases, accelerated "junctional" rhythms originating in the node-like structure of specialized atriofascicular pathways may be recorded (Figure 5) that closely resemble the junctional rhythms commonly seen during modification of the normal AV node in patients with AV node reentrant tachycardia. Catheter ablation is also effective when energy is applied to the subannular

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Figure 5. Twelve-lead ECG during ablation of an accessory atriofascicular pathway. At the onset of radiofrequency energy application, accelerated beats of the atriofascicular pathway with maximal preexcitation were recorded that resembled the junctional rhythms observed during modification of the normal atrioventricular node in patients with atrioventricular node reentrant tachycardia.

level of the tricuspid annulus and/or along the ventricular course of the pathways proximal to the merging point with the distal branching system of the normal right bundle branch. Sustained atrial fibrillation may occur during the mapping procedure and may complicate the recording of accessory pathway activation potentials at the subannular level. In these cases, successful ablation can be performed close to the ventricular insertion, where a high-frequency potential can be recorded that is separated from the local ventricular electrogram by a short isoelectric interval (Figure 6). Cappato et al.38 recently also described successful ablation of atriofascicular fibers during atrial fibrillation in 2 patients.

Nodofascicular and Nodoventricular Pathways Functional-morphological correlations for the rare variants of the preexcitation syndromes, i.e., for nodofascicular/ventricular pathways and fasciculoventricular connections, are even less well elucidated compared with specialized atriofascicular or AV pathways. Mahaim and his co-workers16-19 originally described anatomical connections of the AV node to the myocardial septum as well as connections of the origin of the left bundle branch to the upper part of the interventricular septum. Mahaim himself, however, stated that these connections were rather delicate and questioned their functional role.17 The concept of nodofascicular and nodoventricular

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Figure 6. Surface ECG leads I, II, V2, and V6 and intracardiac electrograms from the mapping and ablation catheter (Map), high right atrium (HRA), and right ventricular apex (RVA) (patient with Ebstein's anomaly). Top: During antidromic atrioventricular reentrant tachycardia (cycle length 400 ms), mapping at the subannular level of the tricuspid annulus revealed a relatively large atrial potential (A), a ventricular potential (V), and an activation potential of the atriofascicular pathway (arrow). The atrial-atriofascicular pathway potential interval measured 150 ms; the interval from the atriofascicular pathway potential to the onset of the QRS complex measured 50 ms. Note the basal ventricle close to the tricuspid annulus is activated late (45 ms after the onset of the QRS complex), whereas the right ventricular apical region is activated relatively early (10 ms after the onset of the QRS complex). Bottom: During the electrophysiological study, the antidromic atrioventricular reentrant tachycardia degenerated into atrial fibrillation with predominant conduction over the atriofascicular pathway (mean ventricular rate 125 beats per minute). The recording of irregular atrial potentials during atrial fibrillation did not allow the reliable recording of an atriofascicular activation potential at the subannular level of the tricuspid annulus. Mapping of the atriofascicular pathway was therefore performed close to the ventricular insertion at the apical part of the right lateral free wall. An atriofascicular pathway activation potential could be recorded (arrows) that was separated by the ventricular potential by a short isoelectric line and that preceded the onset of the QRS complex by 20 ms (successful ablation site). Reproduced from reference 39, with permission.

VARIANTS OF PREEXCITATION pathways has been replaced by the concept of specialized atriofascicular pathways, and presently the pure existence of nodofascicular or nodoventricular pathways, or at least their functional role in participation in preexcited tachycardias with left BBB morphology, is doubted. A combined morphological and electrophysiological study of the AV conduction system of the human fetal heart with gestational ages between 12 and 16 weeks was performed by Janse and co-workers.53 Their results indicated that the fetal AV conduction system worked comparably to that of the adult human heart. However, this mature function without evidence for ventricular preexcitation was in contrast to the morphological immaturity because the fibrous annulus was incompletely developed and the AV node as well as the AV bundle and right bundle branch were in histological contiguity with the ventricular myocardium.53 Nodoventricular connections had also been described in addition to accessory AV pathways in cases of WPW syndrome without evidence of a clinical significance of the former connections.54,55 A clinicopathological correlation in a case with a presumed nodoventricular bypass tract was described by Gmeiner et al.56 During the electrophysiological study, the preexcited tachycardia showed a left BBB morphology indicating an apical insertion of the accessory pathway at or near the distal right bundle branch. However, the pathological examination revealed a nodoventricular tract, which originated from the posterior extension of the compact AV node and inserted in the crest of the ventricular septum. Electrophysiological Findings in Nodofascicular/Ventricular Pathways and Radiofrequency Catheter Ablation The differential diagnosis for a nodofascicular or nodoventricular pathway

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includes a midseptal accessory pathway with decremental properties. However, the preexcitation pattern of nodofascicular pathways with left BBB morphology elicited by atrial pacing with progressive shorter cycle length cannot be distinguished from the typical preexcitation pattern of atriofascicular fibers and thereby indicates an apical insertion of the nodofascicular pathway at or close to the distal right bundle branch similar to specialized atriofascicular pathways. However, no obvious anatomical route exists for a nodofascicular fiber from the under surface of the AV node to the right bundle branch, and this type of accessory pathway therefore might also insert into ventricular myocardium with subsequent early activation of the right bundle branch. Further strong evidence for the potential participation of nodoventricular pathways in reentrant tachycardias came from Gallagher et al.25 These authors described ventriculoatrial dissociation during tachycardia with 2:1 retrograde conduction. In a report by Grogin et al.,37 one patient with a nodoventricular pathway and dual AV node physiology presented with both AV node reentrant tachycardia and antidromic AVRT with the nodoventricular pathway as the anterograde limb of the reentrant circuit. Application of radiofrequency energy to the midseptal region successfully ablated the nodoventricular pathway and the slow AV node pathway.37 In a different series, a nodofascicular pathway served as a bystander in AV node reentrant tachycardia39 (Figure 7). The surface ECG lead preexcitation pattern during tachycardia resembled that seen in atriofascicular pathways. Fast pathway ablation was performed to eliminate the retrograde pathway during AV node reentrant tachycardia and the retrograde route of potential AVRTs incorporating the nodofascicular pathway. Fast pathway ablation resulted in an increment of the PR interval from 150 ms to 270 ms

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Figure 7. Surface ECG leads I, II, V2, and V6 and intracardiac electrograms from the right ventricular apex (RVA), His bundle area (HBE), and high right atrium (HRA) in a patient with atrioventricular (AV) node reentrant tachycardia and a variant of the preexcitation syndromes, i.e., an accessory nodofascicular pathway serving as a bystander. A. During atrial stimulation, a tachycardia with a left bundle branch block morphology and cycle lengths between 320 and 330 ms was reproducibly inducible. The VA interval was very short and there was a nearly simultaneous activation at the HRA and the RVA. The interval between the activation of the His bundle and the onset of the QRS complex varied slightly between 20 and 0 ms, i.e., no retrograde activation of the His bundle suggesting a typical antidromic AV reentrant tachycardia was present. In addition, the right ventricular basal septum and the right ventricular apical region were activated nearly simultaneously during the tachycardia, which also argued against a typical antidromic AV reentrant tachycardia where the apical region is activated before the basal ventricular septum. Atrial extrastimuli failed to reset the tachycardia without anterograde penetration into the AV node. Programmed stimulation with double ventricular extrastimuli resulted in fusion of the next QRS complex (asterisk), indicating a simultaneous anterograde ventricular activation over the normal AV node and the nodofascicular pathway. B. Programmed ventricular stimulation dissociated the ventricle from the tachycardia (arrow), indicating that the tachycardia was a supraventricular tachycardia (AV node reentrant tachycardia with a nodofascicular pathway serving as an innocent bystander). Reproduced from reference 39, with permission.

and in complete ventriculoatrial block. Interestingly, no preexcitation was visible during sinus rhythm after ablation despite the long PR interval. Instead, preexcitation occurred during incremental atrial pacing at cycle lengths of less than 400 ms that was identical to the preexcitation pattern before ablation, indicating that the proximal portion of the nodofascicular pathway was located distal to the delayproducing area of the normal AV node.

After ablation, no AV node reentrant tachycardia or AVRT incorporating the nodofascicular pathway could be induced.39 Okishige and Friedman57 described electrophysiological findings and radiofrequency catheter ablation in a patient with an atypical nodofascicular pathway. Using atrial-delta wave interval mapping, these authors identified the atrial insertion of the accessory pathway at the midseptal region. Interestingly, maximal preexcitation over

VARIANTS OF PREEXCITATION this pathway revealed a right BBB pattern and left axis deviation suggestive of an insertion at or near the left posterior fascicle.57 A single radiofrequency energy application targeted at the low midseptal right atrium resulted in disappearance of preexcitation but also induced complete block in the AV node.57 Overall, in cases with nodofascicular pathways, no activation potential of the specialized pathway can be recorded at the parietal tricuspid annulus. Instead, transient mechanically induced conduction block of the accessory pathway may be observed during catheter mapping at the septal area. A nodoventricular or nodofascicular fiber is suggested if ventriculoatrial dissociation occurs during tachycardia or if atrial extrastimuli fail to reset the tachycardia without anterograde penetration into the AV node.25,30 An atriofascicular or nodoventricular pathway is considered a bystander in AV node reentrant tachycardia if fusion of the QRS complex is observed during tachycardia spontaneously or in response to programmed atrial or ventricular stimulation.39 Fasciculoventricular Fibers Fasciculoventricular connections are suggested if the proximal insertion of the accessory pathway is found to arise from the His bundle or bundle branches. The PR interval is expected within normal limits during sinus rhythm unless associated anomalies including enhanced conduction within the AV node or an additional accessory AV pathway were present. The QRS complex is expected to be slightly prolonged with a discrete slurring of the R wave suggesting a small delta wave (Figure 8).25 In cases with a fasciculoventricular connection, no isolated His bundle activation potential can be recorded in the typical His bundle area. Instead, a potential may be recorded that cannot be distinguished between a

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His bundle potential or an accessory pathway potential and that follows the local atrial potential after an isoelectric line (Figures 9 and 10). This potential is directly followed by a local ventricular potential, i.e., the His bundle-ventricle interval is zero. Programmed atrial stimulation with extrastimuli and constant rate pacing with different cycle lengths reveals progressively increasing AV intervals and a constant degree of preexcitation which was identical to that during normal sinus rhythm. Therefore, the proximal insertion is suggested to arise distal to the AV node at the site of the penetrating AV bundle. The earliest ventricular activation at the His bundle recording site that is earlier than the ventricular activation at the right or left bundle branch indicates the ventricular insertion of this accessory connection in the ventricular summit. These fasciculoventricular connections may give rise to ventricular preexcitation but usually serve as innocent bystanders during orthodromic AVRT incorporating a muscular accessory AV pathway or AV node reentrant tachycardia39 (Figures 8, 9, and 10). Gallagher58 reported on the electrophysiological findings in 11 patients with fasciculoventricular connections. In this study, the PR interval was abbreviated in the majority of the patients because of enhanced AV node conduction. The QRS complex was slightly prolonged because of discrete preexcitation during sinus rhythm and the PR interval was prolonged during programmed atrial stimulation in association with a constant degree of preexcitation. Gallagher58 observed no arrhythmias that were causally related to the presence of the fasciculoventricular connections in his patient cohort. Grogin et al.37 recently described a patient with fixed preexcitation in which the accessory pathway served as a bystander during AV node reentrant tachycardia. Transiently effective fast AV

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Figure 8. Twelve-lead ECGs in a patient with a left lateral accessory atrioventricular pathway and a fasciculoventricular pathway. Top: Prior to ablation, the QRS complexes during normal sinus rhythm (cycle length 710 ms) showed preexcitation with positive delta waves in leads I, II, and III and in V2 through V6. Middle: A tachycardia with a cycle length of 250 ms and a discrete slurring of the R wave in the precordial leads V4 to V5 and in lead I suggesting small delta waves had been documented clinically and was reproducibly inducible with programmed electrical stimulation. The morphology of the QRS complexes during tachycardia matched the QRS complexes during sinus rhythm after ablation of the accessory atrioventricular pathway, i.e., the tachycardia was a preexcited orthodromic atrioventricular reentrant tachycardia with the fasciculoventricular accessory pathway serving as a bystander. Bottom: After ablation of the left lateral accessory atrioventricular pathway, the QRS complexes during normal sinus rhythm (cycle length 690 ms) still showed a slurring of the R waves with positive delta waves in leads I and V4 to V5, indicating preexcitation over the fasciculoventricular pathway that connected the penetrating atrioventricular bundle (bundle of His) with the adjacent ventricular septal myocardium. Reproduced from reference 39, with permission.

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Figure 9. Surface ECG lead II and intracardiac electrograms from the right ventricular apex (RVA), the right bundle branch (RBB), the right atrial mapping catheter in the His bundle recording area (Map-RA [HBE]), the high right atrium (HRA), and the distal (1/2), middle (3/4), and proximal (5/6) pair of electrodes of the coronary sinus catheter (CS) during sinus rhythm (same patient as in Figure 8). Coronary sinus mapping localized the accessory atrioventricular pathway in the left lateral region (CS 1/2) where the shortest AV interval was obtained. In addition, right atrial mapping during sinus rhythm showed ventricular activation preceding the onset of the delta wave in the anteroseptal region. In the typical His bundle area, no isolated His bundle activation potential could be recorded. Instead, a potential was recorded which could not be distinguished between a His bundle potential and an accessory pathway potential and which followed the local atrial potential with an atrialHis bundle potential interval or an atrial-accessory pathway potential interval of 65 ms. This potential was directly followed by a local ventricular potential, i.e., the His bundle-ventricle interval was zero. The ventricular activation in the right bundle branch recording region was recorded slightly after the ventricular activation in the His bundle recording area. The vertical line marks the activation time of the His bundle and the fasciculoventricular pathway. Reproduced from reference 39, with permission.

node pathway ablation led to PR prolongation without change in the preexcitation pattern. Radiofrequency energy application in the midseptal area finally abolished the slow AV node pathway and resulted in loss of preexcitation. Grogin et al.37 thus interpreted this accessory pathway as a nodofascicular pathway that originated from the final common pathway of the AV node reentrant circuit or the His bundle. Overall, 2 different kinds of nodofascicular/ventricular and fasciculoventricu-

lar connections seem to exist: first, as initially described by Mahaim, the AV node and the AV bundle and/or bundle branches may be in direct histological contiguity with the ventricular septal myocardium, i.e., connections as a result of insulation defects of poorly developed fibrous skeletons or fibrous tissue sheaths. These nodoventricular or fasciculoventricular connections therefore might be better called paraspecific connections than accessory pathways in the sense of accessory bundles of muscle fibers. In many cases,

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Figure 10. Surface ECG lead II and intracardiac electrograms from the right ventricular apex (RVA), the right bundle branch (RBB), the right atrial mapping catheter in the His bundle recording area (MapRA [HBE]), the high right atrium (HRA), the distal (1/2) and middle (3/4) pair of electrodes of the coronary sinus catheter (CS), and the left atrial mapping catheter during preexcited orthodromic atrioventricular (AV) reentrant tachycardia (same patient as in Figures 8 and 9). Right atrial mapping during AV reentrant tachycardia revealed ventricular activation preceding the onset of the QRS complex in the His bundle recording area. The tachycardia cycle length varied between 260 and 290 ms because of changes in the atrial-fasciculoventricular pathway potential interval that varied between 70 and 100 ms, whereas the retrograde conduction time over the accessory AV pathway remained constant. Left atrial mapping during orthodromic AV reentrant tachycardia identified the atrial insertion of the left lateral accessory AV pathway. At this site, continuous ventriculoatrial activation and a presumed activation potential of the accessory pathway were recorded. Application of radiofrequency energy at this site successfully abolished conduction over the accessory AV pathway. The vertical line marks the activation time of the His bundle and the fasciculoventricular pathway. V = ventricle; A = atrium; AP = accessory pathway activation potential. Reproduced from reference 39, with permission.

these anatomically incompletely differentiated AV conduction systems seem to be functionally mature not giving rise to any kind of preexcitation.53 Second, there is rare but conclusive evidence that accessory nodofascicular/ventricular pathways indeed exist as a very rare variant of true accessory pathways with their ventricular insertion close to or at the distal right bundle branch. These accessory pathways may give rise to ventricular preexcitation during AV node reentrant tachycardia or

may even serve as the anterograde limb in antidromic AVRT.37 In addition, connections from atrial myocardium to the bundle of His had been described59 and termed atriofascicular by the European Study Group for Preexcitation.52 These accessory pathways may result in a clinical entity with a short PR interval and normal QRS complex. However, these pathways seem to be extremely rare and their role in the initiation or perpetuation of atrial or AVRTs is unknown.

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ventricular conduction (bundle of Kent). Am Heart J 1933;8:297-311. 12. Wood FC, Wolferth CC, Geckeler GD. Histologic demonstration of accessory muscular connections between auricle and ventricle in a case of short P-R interval and prolonged QRS complex. Am Heart J 1943;25:454-462. 13. Ohnell RF. Preexcitation, a cardiac abnormality. Acta Med Scand 1944;152(Suppl CLII):1-167. 14. Anderson RH, Taylor IM. Development of atrioventricular specialized tissue in human heart. Br Heart J 1972;34:1205References 1214. 15. Anderson RH, Davies MJ, Becker AE. 1. Kent AFS. Researches on the structure Atrioventricular ring specialized tissue in the normal heart. Eur J Cardiol 1974;2: and function of the mammalian heart. J 219-230. Physiol 1893;14:233-254. 2. His W Jr. Die Tatigkeit des embryonalen 16. Mahaim I. Le bloc bilateral manque, nouHerzens und deren Bedeutung fur die velle forme anatomique de bloc du cer, a Lehre von Herzbewegungen beim Erwachsubstituer au bloc dit "d'arborisations." senen. Arbeiten aus der Medizinischen Ann de Med 1932;32:347. Klinik zu Leipzig 1893;l:14-49. 17. Mahaim I, Benatt A. Nouvelle recherches 3. Tawara S. Das Reizleitungssystem des sur les connexions superieures de la branche gauche du faisceau de His-Tawara Sdugetierherzens. Jena: Gustav Fischer; 1906:135-149. avec cloison interventriculaire. Cardiolo4. Kent AFS. Observations on the auriculogia 1938;l:61-68. ventricular junction of the mammalian 18. Mahaim I, Winston MR. Recherches heart. Q J Exp Physiol 1913;7:193-195. d'anatomie comparee et de pathologie 5. Kent AFS. The structure of the cardiac tisexperimentale sur les connexions hautes sues at the auriculo-ventricular junction. de faisceau de His-Tawara. Cardiologia J Physiol 1913;47:xvii-xviii. 1941;5:189-260. 6. Kent AFS. The right lateral auriculo- 19. Mahaim I. Kent's fibers and the A-V ventricular junction of the heart. J Physparaspecific conduction through the upper iol 1914;48:xxii—xxiv. connections of the bundle of His-Tawara. Am Heart J 1947;33:651-653. 7. Kent AFS. A conducting path between the right atrium and the external wall of the 20. Wellens HJJ. Tachycardias related to the right ventricle in the heart of the mammal. pre-excitation syndrome. In: Wellens HJJ (ed): Electrical Stimulation of the Heart in J Physiol 1914;48:lvii. 8. Kent AFS. Illustrations of the right latthe Study and Treatment of Tachycardias. eral auriculo-ventricular junction in the Baltimore: University Park Press; 1971: heart. J Physiol 1914:48:lxiii-lxiv. 97-109. 9. Wolff L, Parkinson J, White PD. Bundle- 21. Lev M, Fox SM, Bharati S, et al. Mahaim branch block with short P-R interval in and James fibers as a basis for a unique healthy young people prone to paroxysmal variety of ventricular preexcitation. Am J Cardiol 1975;36:880-887. tachycardia. Am Heart J 1930;5:685-704. 10. Holzmann M, Scherf D. Uber Elektro- 22. Tonkin AM, Dugan FA, Svenson RH, kardiogramme mit verkurzter Vorhofet al. Coexistence of functional Kent and Kammer-Distanz und positiven P-Zacken. Mahaim-type tracts in the pre-excitation syndrome: Demonstration by catheter Z Klin Med 1932;121:404-423. 11. Wolferth CC, Wood FC. The mechanism techniques and epicardial mapping. Circulation 1975;52:193-202. of production of short P-R intervals and prolonged QRS complexes in patients with 23. Touboul P, Vexler AM, Chatelain MT. Reentry via Mahaim fibers as a possible basis presumably undamaged hearts: Hypothesis of an accessory pathway of auriculofor tachycardia. Br Heart J 1978;40:806-811.

In addition, the electrophysiological distinction from accelerated AV node conduction might be impossible. In the light of the current concepts, this type of connections might now be termed atrio-Hisian.48 Together with enhanced AV node conduction, atrio-Hisian tracts might thus form the anatomical substrate for the LownGanong-Levine syndrome.60

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24. Ward DE, Camm AJ, Spurell RAJ. Ventricular preexcitation due to anomalous nodo-ventricular pathways: Report on 3 patients. Eur J Cardiol 1979;9:111-127. 25. Gallagher JJ, Smith WM, Kasell JH, et al. Role of Mahaim fibers in cardiac arrhythmias in man. Circulation 1981;64:176-189. 26. Bardy GH, German LD, Packer DL, et al. Mechanism of tachycardia using a nodofascicular Mahaim fiber. Am J Cardiol 1984;54:1140-1141. 27. Gillette PC, Garsoh A Jr, Cooley DA, McNamara DG. Prolonged and decremental antegrade conduction properties in right anterior accessory connections: Wide QRS antidromic tachycardia of left bundle branch block pattern without WolffParkinson-White configuration during sinus rhythm. Am Heart J 1982;103:6674. 28. Klein GJ, Guiraudon GM, Kerr CR, et al. "Nodo-ventricular" accessory pathway: Evidence for a distinct accessory atrioventricular pathway with atrioventricular node-like properties. J Am Coll Cardiol 1988;11:1035-1040. 29. Ross DL, Johnson DC, Koo CC, et al. Surgical treatment of supraventricular tachycardia without the WPW syndrome: Current indications, techniques and results. In: Brugada P, Wellens HJJ (eds): Cardiac Arrhythmias: Where to Go From Here? Mount Kisco, NY: Futura Publishing Co.; 1987:591-603. 30. Tchou P, Lehmann MH, Jazayeri M, Akhtar M. Atriofascicular connection or a nodoventricular Mahaim fiber? Electrophysiologic elucidation of the pathway and associated reentrant circuit. Circulation 1988;77:837-848. 31. Bhandari A, Morady F, Shen EN, et al. Catheter-induced His bundle ablation in a patient with reentrant tachycardia associated with a nodoventricular tract. J Am Coll Cardiol 1984;4:611-616. 32. Ellenbogen KA, O'Callaghan WG, Colavita PG, et al. Catheter atrioventricular junction ablation for recurrent supraventricular tachycardia with nodoventricular fibers. Am J Cardiol 1985;55:1227-1229. 33. Haissaguerre M, Warin JF, Metayer P, et al. Catheter ablation of Mahaim fibers with preservation of atrioventricular nodal conduction. Circulation 1990;82:418-427. 34. Okishige K, Strickberger SA, Walsh EP, et al. Catheter ablation of the atrial origin of a detrimentally conducting atriofascic-

ular accessory pathway by radiofrequency current. J Cardiovasc Electrophysiol 1991; 2:465-475. 35. Klein LS, Hackett FK, Zipes DP, Miles WM. Radiofrequency catheter ablation of Mahaim fibers at the tricuspid annulus. Circulation 1993;87:738-747. 36. McClelland JH, Wang X, Beckman KJ, et al. Radiofrequency catheter ablation of right atriofascicular (Mahaim) accessory pathways guided by accessory pathway activation potentials. Circulation 1994;89: 2655-2666. 37. Grogin HR, Lee RJ, Kwasman M, et al. Radiofrequency catheter ablation of atriofascicular and nodoventricular Mahaim tracts. Circulation 1994;90:272-281. 38. Cappato R, Schluter M, Weiss C, et al. Catheter-induced mechanical conduction block of right-sided accessory fibers with Mahaim-type preexcitation to guide radiofrequency ablation. Circulation 1994;90: 282-290. 39. Kottkamp H, Hindricks G, Shenasa M, et al. Variants of preexcitation: Specialized atriofascicular pathways, nodofascicular pathways, and fasciculoventricular pathways. J Cardiovasc Electrophysiol 1996;7:916-930. 40. Hluchy J, Schlegelmilch P, Schickel S, et al. Radiofrequency ablation of a concealed nodoventricular Mahaim fiber guided by a discrete potential. J Cardiovasc Electrophysiol 1999;10:603-610. 41. Hluchy J, Schickel S, Jorger U, et al. Electrophysiologic characteristics and radiofrequency ablation of concealed nodofascicular and left anterograde atriofascicular pathways. J Cardiovasc Electrophysiol 2000;11: 211-217. 42. Peinado R, Merino JL, Ramirez L, Echeverria I. Decremental atriofascicular accessory pathway with bidirectional conduction: Delineation of atrial and ventricular insertion by radiofrequency current application. J Cardiovasc Electrophysiol 2001;12:489492. 43. Murdock CJ, Leitch JW, Klein GJ, et al. Epicardial mapping in patients with "nodoventricular" accessory pathways. Am J Cardiol 1991;68:208-214. 44. Sealy WC, Kopelman HE, Murphy DA. Accessory atrioventricular node and bundle: A cause of antidromic reentry tachycardia. Ann Thorac Surg 1992;54:306-310. 45. Guiraudon GM, Guiraudon CM, Klein GJ, et al. Atrio-fascicular (Mahaim)

VARIANTS OF PREEXCITATION fibers—surgical anatomy and pathology— experience with 13 patients. Eur Heart J 1994;15(Suppl):431. Abstract. 46. Keith A, Flack A. The form and nature of the muscular connections between the primary divisions of the vertebrate heart. J Anat Physiol 1907;41:172-189. 47. Lamers WH, Wessels A, Verbeek FJ, et al. New findings concerning ventricular septation in the human heart. Implications for maldevelopment. Circulation 1992;86: 1194-1205. 48. Anderson RH, Ho SY, Gillette PC, Becker AE. Mahaim, Kent and abnormal atrioventricular conduction. J Cardiovasc Res 1996,31:480-491. 49. Monckeberg JG. Zur Entwicklungsgeschichte des Atrioventrikularsystems. Verhandlung Dtsch Path Ges 1913;16: 228. 50. Anderson RH, Arnold R, Wilkinson JL. The conducting tissue in congenitally corrected transposition. Lancet 1973;1:1286— 1288. 51. Becker AE, Anderson RH, Durrer D, Wellens HJJ. The anatomical substrates of Wolff-Parkinson-White syndrome: A clinicopathologic correlation in seven patients. Circulation 1978;57:870-879. 52. Anderson RH, Becker AE, Brechenmacher C, et al. Ventricular preexcitation: A proposed nomenclature for its substrates. Eur J Cardiol 1975;3:27-36.

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53. Janse MJ, Anderson RH, van Capelle FJL, Durrer D. A combined electrophysiological and anatomical study of the human fetal heart. Am Heart J 1976;91: 556-562. 54. Lev M, Gibson S, Miller RA. Ebstein's disease with Wolff-Parkinson-White syndrome. Am Heart J 1955;49:724-741. 55. Lev M, Fox SM, Bharati S, et al. Mahaim and James fibers as a basis for a unique variety of ventricular preexcitation. Am J Cardiol 1975;36:880-888. 56. Gmeiner R, Ng CK, Hammer I, Becker AE. Tachycardia caused by an accessory nodoventricular tract: A clinico-pathologic correlation. Eur Heart J 1984;5:233-242. 57. Okishige K, Friedman PL. New observations on decremental atriofascicular and nodofascicular fibers: Implications for catheter ablation. Pacing Clin Electrophysiol 1995;18:986-998. 58. Gallagher JJ. Role of nodoventricular and fasciculoventricular connections in tachyarrhythmias. In: Benditt DG, Benson DW (eds): Cardiac Preexcitation Syndromes. Boston: Martin Nijhoff Publishing; 1986: 201-232. 59. Brechenmacher C. Atrio-His bundle tracts. Br Heart J 1975;37:853-855. 60. Lown B, Ganong WF, Levine SA. The syndrome of short P-R interval, normal QRS complex and paroxysmal rapid heart action. Circulation 1952;5:693-706.

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Chapter 27

Endocardial Catheter Mapping of Atrial Flutter Francisco G. Cosio, MD, Antonio Goicolea, MD, Agustin Pastor, MD, Ambrosio Nunez, MD, Maria Antonia Montero, MD, and Maria Alcaraz, MD

Introduction Since the first edition of this book,1 new developments have changed the field of clinical cardiac electrophysiology at an exponentially accelerating rate. In 1992, when the Cardiac Mapping Workshop took place in northern Spain, radiofrequency ablation was a beginning promise; today it has become one of the most successful therapeutic techniques in modern medicine, and this has made electrophysiology a focus of interest for growing numbers of researchers and clinically oriented cardiologists. In 1992 Wolff-ParkinsonWhite syndrome was still the main area of interest and most laboratories were dealing with accessory pathway and atrioventricular (AV) nodal tachycardia ablation. However, as existing populations of patients with accessory pathways and nodal tachycardia were cured by radiofrequency ablation, the prevalence of these diseases has decreased markedly, and

most electrophysiology laboratories now focus more on atrial arrhythmias. Atrial flutter (AFL) mapping was, in 1992, a developing technique, and radiofrequency AFL ablation was referred to as a promising technique. Today it is clearly established and comprises 20% or more of the workload of many laboratories. Many of the initial findings then described have been confirmed, and new information has been added. Electrophysiologists now face the frontier of atrial fibrillation; and in the way of these developments the need for some changes has become evident. Anatomy has become a crucial element in our understanding of atrial arrhythmias. Most atrial tachycardias result from macroreentry, and spatial organization of activation is a basic aspect of the mechanism. While a crude schematic representation was once sufficient to offer a theoretical explanation for electrogram morphologies, we now feel the need to match electrogram sequence to anatomy,

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; C 2003. 537

538 CARDIAC MAPPING because ablation approaches are based on drawing lines between anatomical boundaries of the reentry path. The classification of atrial tachycardias is another emerging difficulty. A better understanding of mechanisms has shown that ECG patterns currently recognized as atrial tachycardia and AFL do not reflect the underlying mechanisms. A new classification that reflects mechanisms has become necessary to facilitate orientation of clinicians toward available therapy and to facilitate comparisons between experiences reported from different laboratories. The Anatomical Bases of Atrial Arrhythmias The definition of AFL circuits led to our understanding of the crucial role of anatomical boundaries in reentrant activation. The concepts generally applied to postinfarction ventricular tachycardia rarely apply to atrial arrhythmias. In ventricular tachycardia the central (isthmic) portion of the circuits is made of strands of viable fibers interspersed in a scarred area without clear-cut anatomical boundaries.2 In this setting, validation of local electrograms by entrainment techniques has been most successful in localizing the obligatory path of activation.3 In AFL the set-up is very different. All parts of the circuit are relatively large and anatomically defined by fixed or functional boundaries. Valve and vein orifices are important as fixed obstacles, and a muscle bundle, the terminal crest, forms a functional barrier at the center of the circuit.4 Typical AFL, however, was only the beginning. Reentry around "artificial" obstacles such as right atrial (RA) surgical scars has been characterized, and an accurate anatomical localization of the diseased areas, and their relation to other structures, has allowed also an effective ablative approach.

Three-Dimensional Atrial Anatomy Most electrophysiologists and surgeons use terminology for the AV rings and Koch's triangle that does not reflect true anatomical position. This is based on a "surgical" perspective placing these structures in a horizontal plane5 where aorta and His bundle are anterior, and coronary sinus posterior, AV nodal approaches are anterior and posterior, and paraseptal accessory pathways are anteroseptal andposteroseptal. This description is completely at odds with the actual anatomical position of the heart in the body as shown in the fluoroscopic screen, where the aorta is superior and the coronary sinus inferior. While this discrepancy has not prevented location and ablation of accessory pathways and AV nodal approaches, it has become a significant obstacle in our path to understanding atrial arrhythmias. Threedimensional atrial anatomy is impossible to describe using these coordinates, and an anatomically correct nomenclature has been proposed as a better approach.6 Nuclear magnetic resonance imaging shows the real position of cardiac structures in the body, with the added advantage of reproducing body position as seen in the fluoroscopic screen (Figure 1). The importance of defining a true antero-posterior direction is demonstrated by the relative positions of RA and left atrium (LA). The LA is the most posterior portion of the heart, in the midline, directly anterior to spine and esophagus. The pulmonary veins drain on the lateral sides of the superiorposterior LA wall. The superior/anterior LA wall, which contains the Bachmann's bundle, extends from the superior RA to the superior-posterior mitral ring, behind the aortic root. Around the posterior and inferior LA, the coronary sinus runs from posterior-superior to inferior-anterior, to its drainage in the low paraseptal RA. The RA is located to the right of the spine, anterior to the LA. The smooth

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Figure 1. A. Serial magnetic resonance transverse (horizontal) cuts of a normal heart displaying anatomical relations of right atrium (RA) and left atrium (LA) in a posterior-anterior axis. The spine marks the posterior direction. The left side of the figures shows the right side of the body. The cut on the left shows the posterior position of the superior LA in relation to the superior vena cava (SVC) and aortic valve (AO). The more inferior cut on the right shows the RA in an anterior position in relation to the LA, so that the interatrial wall is the posterior wall of the RA. LV = left ventricle; RV = right ventricle. B. Serial coronal (frontal plane) magnetic resonance cuts of a normal heart displaying anatomical relations of RA and LA (different patient than in A). From left to right the cut plane becomes more anterior. The most posterior cut (left) shows LA and left superior pulmonary vein (PV). The right pulmonary artery (RPA) runs parallel to the LA roof. A more anterior cut (center) shows the SVC, right superior pulmonary vein (PV), and pulmonary artery bifurcation (PA). The inferior vena cava (IVC) enters the RA, facing the interatrial septum (the thin segment is the oval fossa) and the coronary sinus (unmarked) can be seen immediately below (inferior) the LA. A more anterior cut (right) shows the RA and pulmonary artery trunk (unmarked), but not the LA.

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venous portion, extending from superior vena cava to inferior vena cava, makes the posterior wall of the RA. The interatrial wall forms part of the posterior RA wall because of the posterior position of the LA. The terminal crest, running superiorinferiorly between the posterior and lateral RA walls, separates the smooth venous portion from the heavily trabeculated (pectinate muscles) lateral and anterior RA walls. The anterior RA wall reaches the anterior side of the tricuspid valve. The septal RA has a main superiorinferior dimension. The apex of Koch's triangle is superior and the base inferior. The oval fossa, the only true interatrial septal structure, is located posterior to Koch's triangle. The inferior vena cavatricuspid valve isthmus is immediately anterior to the inferior vena cava orifice. The terms used in the following pages are adjusted to this anatomical description.

Classification of Atrial Tachycardias As often happens with expanding knowledge, present concepts of atrial tachycardia mechanisms do not fit easily into the classic ECG classifications of atrial arrhythmias.7,8 Continuous undulation of the atrial ECG wave relates well with continuous circular activation in typical AFL, in both the common (counterclockwise) and in the reverse (clockwise) forms. The "sawtooth" AFL pattern of continuous undulation with predominantly negative deflections in the inferior ECG leads is very specific for typical counterclockwise AFL. Another pattern of continuous undulation with predominantly positive, notched atrial deflections in the inferior leads and wide negative deflections in lead V1 appears quite specific for reverse typical AFL. However, some tachycardias that are not due to reentry in the typical AFL circuit can mimic these ECG patterns.8,9

Atrial tachycardia is classically defined as a pattern of discrete P waves separated by isoelectric baselines; it had been thought to represent the sequence of activation and rest periods typical of focal automatic discharge. It is known, however, that some focal atrial tachycardias with a radial spread of activation result from a reentrant mechanism.10 Furthermore, macroreentrant atrial tachycardias can produce a pattern of discrete P waves with isoelectric baseline when areas of slow conduction are extensive in the circuit.11 Another problem has arisen with the use of the terms type I and type II AFL proposed by Wells et al.12 in 1979. Some authors identify type I AFL with the common typical AFL pattern of negative waves, or "sawtooth" pattern in the inferior leads. However, the term type I defined AFL that could be entrained and interrupted by pacing, without any reference to ECG morphology, and therefore includes atypical AFL that can be entrained. On the other hand, there is very little information on the nature of type II AFL, defined then as a faster tachycardia that could not be entrained. Definition of Terms In this chapter we use a mechanistic classification of atrial tachycardias8 (Figure 2). The term flutter is used to reflect an ECG pattern with continuous activity (no stable atrial baseline), and it has been considered indicative of reentry but can also be caused by rapid focal tachycardias. Focal atrial tachycardia is a regular tachycardia with a radial spread from a point of origin, determined by mapping. Entrainment with evidence of fusion or collision of activation fronts is not possible. A macroreentrant tachycardia (MRT) is a regular tachycardia that can be entrained and shows: (1) fusion or collision of activation fronts during entrainment, or (2) a circular activation pattern with activation

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Image Not Available

Figure 2. Mechanistic classification of regular atrial tachycardias. Mechanisms are listed on the left and the usual ECG patterns (classic definition) are represented on the right. Note that macroreentrant atrial tachycardias (AT) can produce ECG patterns of flutter (FL) of AT. Reproduced from reference 9, with permission.

recorded during the whole cycle. This definition includes typical AFL. Typical AFL is an MRT based in the RA, activation rotating around a central obstacle formed by superior vena cava, inferior vena cava, and terminal crest. Activation of the anterolateral RA is superior-inferior, and of the septal RA inferior-superior. The inferior vena cavatricuspid valve isthmus is an obligatory passage for activation. The LA is a passive bystander. Reverse typical AFL is basically the same MRT as typical AFL but with an opposite direction of rotation (inferiorsuperior in the anterolateral RA and superior-inferior in the septal RA). Atypical AFL is a tachycardia with continuous atrial activity on the ECG and/or cycle length (CL) less than 250 ms,

that: (1) cannot be entrained, or (2) does not have the inferior vena cava-tricuspid valve isthmus as an obligatory passage. Catheter-Based Atrial Mapping Some progress has been made in multipoint instantaneous mapping of atrial activation by use of basket-shaped devices,13-15 and in noncontact methods allowing simultaneous recording of up to 3000 points.16-18 Complex electrogram recognition and computing algorithms and graphic animation programs are necessary to handle all the information "on line." Meanwhile, catheter-based, sequential endocardial mapping is still the main tool for the study of atrial arrhythmias,19 including methods that allow precise

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electromagnetic catheter location in space.20-22 This poses important limitations to the study of atrial fibrillation and nonsustained arrhythmias. Endocardial References Unlike the QRS complex, the P wave is not generally useful as a timing reference because its low voltage and overlap of QRS and T waves limits the reproducibility of its deflections. Multiple, stable endocardial reference recordings should support sequential endocardial mapping in order to check activation stability through the mapping procedure. Local activation timing at each recording site should be related to a chosen stable endocardial reference. Available multipolar catheters with up to 24 electrodes allow recording of multiple endocardial references (Figure 3). An important clue is proper placement of these multiple electrodes along significant activation lines, so that clearly recognized activation patterns can be detected at a glance. Superior-inferior alignment on the septal and anterolateral RA serve this purpose well, because it shows counterclockwise and clockwise circular RA activation. LA references are usually obtained from the coronary sinus, but in the presence of a patent foramen ovale a multipolar reference catheter can be placed covering the superior, posterior, and inferior LA (Figure 3). Another interesting alternative is the right pulmonary artery, because its course is closely parallel to the superior LA wall, allowing mapping of Bachmann's-bundledependent activation23,24 (Figure 1). A popular mapping set-up is the 20pole "halo" catheter, which has an active curve that helps stabilize in an anterior position, close to the tricuspid valve; however, the electrode span is such that no recordings from the septal RA can be obtained with this catheter alone, and

His bundle and coronary sinus catheters are needed to record the septal activation sequence.25 We prefer to use a single 24pole catheter covering septal and anterolateral walls with multiple electrode pairs19,26 (Figure 3). This type of catheter allows fairly complete recording from areas of the RA inside or close to the typical AFL circuit, and it is also a good guide for scar-related RA tachycardias. Only if a LA mechanism is suspected is it necessary to use a coronary sinus or LA catheter. The areas of the RA and LA not covered by the reference catheter or catheters are mapped sequentially by a deflector tip catheter. To avoid overlooking any areas, use of a standard mapping order is important, and we find it quite useful to have a schematic representation of the mapped chamber in sight during mapping to maintain this order.1 Circular and Focal Patterns Displaying the recordings in a logical order allows rapid, intuitive analysis of activation sequences (Figure 4). Many simultaneous recordings are often used, and these should be placed in the same position from case to case to facilitate rapid interpretation at the time of the study. A particular order is not as helpful for every arrhythmia, but the electrophysiologist should seek a balance between using multiple recording and electrode set-ups, which require difficult mental adjustments for each case, and using small variations of one basic set-up, even if it becomes suboptimal for the less frequent cases. One of the main clues for the diagnosis of reentry is recording electrical activity throughout the atrial cycle (Figure 4). If the recordings are displayed in the order in which activation occurs, the electrogram draws a continuous ascending or descending ladder-like image with each cycle that is very typical of circular activation. In this type of activation, the point

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Figure 3. Posterior-anterior (A) and left anterior oblique (B) fluoroscopic views of 24 electrode catheters (2-mm interelectrode, 8-mm interpair separation; Bard Electrophysiology, Ballerica, MA) placed as multisite stable references in right atrium (RA) and left atrium (LA) through a patent foramen ovale. The spine marks posterior direction and metallic sternal sutures anterior direction. The figures are mounted from 2 different frames to show a wider field. The posterior-anterior view is composed so that it also shows the position of a catheter in the junction of the right upper pulmonary vein with the LA, marking the position of part of the LA behind (posterior) the RA. Note that with this catheter-electrode position, simultaneous recordings can be obtained from septal, superior, and anterolateral RA and superior, posterior, and inferior LA.

of origin (zero time) is arbitrary and the concept of early or late activation is not applicable, because in a circular sequence an earlier electrogram can always be found. The goal of mapping in MRT (including AFL) is to define the precise location and anatomical boundaries of the circuit, lead-

ing to the localization of narrow areas that can be therapeutic targets. On the other hand, focal activation (or tachycardia) shows radial spread of activation, with simultaneous activation times in points around a well-localized point of earliest (zero time) activation (Figure 4).

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Figure 4. Schematic representation of the use of multiple simultaneous recordings in macroreentry. The bottom drawings represent direction of activation during focal activation, in this case a paced rhythm (S1). The schema could represent high right atrial pacing with descending right atrial activation of the anterior (light arrow) and septal (dark arrow) walls. The way the electrograms are displayed, descending activation converges in the center of the recording. Note a period of electrical silence between paced activations. An extrastimulus (S2) results in unidirectional block on the septal side and slower conduction on the anterior side followed by reentry. Circular activation with a time dimension develops into a spring-shaped helical curve. Note ascending septal activation during reentry and continuous presence of electrical activity in the multisite recordings throughout the reentry cycle.

No earlier activation can be found around this point, despite detailed mapping.27-29 Total atrial activation time is relatively short, so that large portions of the cycle are devoid of electrical activity, even when recording from both atria (Figure 4). When early RA activation is recorded in the lateral or anterior walls, the lack of LA data does not change the diagnosis of focal tachycardia. On the other hand, an apparent origin of activation in the septal RA could hide a LA mechanism requiring LA recordings, and/or entrainment mapping, to rule out this possibility19,30 (see below). Electrogram Interpretation Despite the fact that unfiltered unipolar recordings can be more accurate, and

also afford vectorial information, most laboratories still use bipolar recordings. The technical difficulties added by unipolar recordings, such as far-field interference and moving baselines, can be very time consuming and make interpretation difficult. Bipolar recordings have proven to be sufficient for clinical atrial mapping, and they are easier to obtain in most laboratories. Bipolar electrograms recorded from the atrial endocardium are generally discrete, biphasic or triphasic, 50 ms or less in duration, and have a sharp main deflection (Figure 5). The peak of the main deflection best defines local timing.31 However, wide or fragmented electrograms can be recorded in certain areas that can be the clue to the localization of areas of slow conduction or block.

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Figure 5. Multiple simultaneous electrograms during typical counterclockwise atrial flutter (AFL) (left) and reversed-clockwise (right) AFL in the same patient. From top to bottom: lead II and endocardial right atrial electrograms from high (HAL), mid (MAL), and low (LAL) anterolateral right atrium; inferior vena cava-tricuspid valve isthmus (CT); low (LPS), mid (MRS), and high (posterior-septal right atrium; HPS) and superior right atrium (ROOF). Recording sites are marked on the schema that represents the right atrium in a left anterior oblique view. On the endocardial side (shaded) the orifices of the superior vena cava, inferior vena cava, and coronary sinus and the terminal crest are shown. Note the typical sawtooth ECG of typical AFL and the broad positive deflections of reverse AFL. The recordings show circular activation, descending anterolateral right atrium, and ascending septal right atrium in typical AFL and in the opposite direction in reverse AFL. Most electrograms are sharp and narrow with one main deflection, but the LPS electrogram shows 2 well-defined deflections per cycle. There is widening and fragmentation of the CT electrogram during reverse AFL.

Fragmented electrograms

Poliphasic (fragmented) electrograms of long duration can be recorded in experimental atrial arrhythmias in association with slow conduction, particularly at turning points around lines of functional block.32-34 Electrogram fragmentation related to slow conduction can be produced also by early extrastimuli, especially in patients with a history of atrial fibrillation.35,36 During atrial arrhyth-

mias, fragmentation can be widespread if intra-atrial conduction is severely depressed or if CL is very short.37,38 This conduction delay can occur outside the arrhythmia core, unrelated to the mechanism of reentry. A fragmented electrogram should not be considered to belong to an essential part of the circuit unless it is validated by the general activation sequence and/or by pacing studies.26,39 Fragmentation can be found in some cases at critical isthmuses of the circuit

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Figure 6. Sequential mapping of the terminal crest area in typical atrial flutter. Lead II (D II) and fixed endocardial reference right atrial recordings from the high (A 1), mid (A 2-3), and low (A 4) anterior wall; low (PS 4), mid (PS 2-3), and high (PS 1) posterior septum. The electrogram in the center shows sequential recordings from the posterolateral right atrium from superior (PL 1) to inferior (PL 4), at intervals of approximately 1 cm. Note double deflections in the PL recordings. Also note fragmentation in the PS 4 electrogram.

(Figures 5 and 6); however, it is not a good marker of isthmic areas, especially in typical AFL,40 in which the isthmus is made of apparently normal tissue and isthmic electrograms are usually sharp. Double electrograms

Electrograms with 2 deflections for each cycle, separated by an isoelectric line (Figures 5 and 6), have become recognized as a manifestation of block at the core of a reentry circuit.32-34 Double electrograms were already described in AFL by the groups of Gravilescu and Luca41 and Puech et al.,42 but were only later recognized as a marker of a line of functional block at the level of the terminal crest, forming the center of reentrant activation in association with the caval vein orifices.43-46 Block along the terminal crest in AFL has become a classic example of the role of anisotropic conduction in reentry. The terminal crest is a tightly packed muscle bundle running superior to inferior from the lateral side of the superior

vena cava orifice to the lateral side of the inferior vena cava then spreading to insert on the inferior tricuspid valve along the inferior vena cava-tricuspid valve isthmus.47 An end-to-end disposition of the gap junctions48 and a special ionic channel composition49 make anisotropic conduction very prominent, to the point that conduction velocity along the crest can be 10 times faster than across its main axis. At rapid rates the terminal crest becomes an obstacle to transverse conduction,50,51 making possible circular activation along the superior-inferior axis of the RA. Recording double electrograms along a superior-inferior line in the posterolateral RA has become one of the hallmarks of typical AFL (Figure 6). The separation of the deflections is quite variable, and sometimes multiphasic electrograms are recorded.37 With clinical methods it is impossible to determine whether there is actual block or very slow conduction with collision of the posterior and anterolateral activation fronts along the crest. Nevertheless, pacing studies have clearly shown

ENDOCARDIAL MAPPING OF ATRIAL FLUTTER that each deflection of the double electrogram represents activation in opposite directions on both sides of the crest.43,45,46 When flutter is interrupted and whole RA activation becomes superior-inferior, the terminal crest ceases to be a line of block, and double electrograms disappear.37,50 Another circumstance in which double electrograms reflect a line of block at the center of reentry is MRT around surgical scars.19,25 Separation of the 2 components can be very wide (>100 ms), and voltage tends to be lower than in surrounding tissue (see below). Furthermore, double or fragmented electrograms, generally of low voltage, are recorded also in sinus rhythm along these areas. The eustachian ridge is another area where a line of block is part of the circuit in the majority of cases of typical AFL46,52 (Figure 5). The ridge extends the obstacle formed by the inferior vena cava posteriorly, reaching the coronary sinus in about 80% of the cases. In these cases double electrograms are recorded, and pacing studies have also shown separation of activation on both sides of this line; however, the eustachian ridge can contain muscle fibers47 and variations from case to case are to be expected in its role in the AFL circuit. Interpretation of double electrograms must be done cautiously, in the context of the general activation sequence. The presence of local block does not mean participation in the circuit.38,39 Double electrograms can be recorded at the terminal crest area during rapid rhythms arising in the LA, including coronary sinus pacing,50,51 when the crest is far from the origin of activation. In other cases, block between the 2 components of a double electrogram occurs spontaneously without affecting tachycardia CL and in others it can be produced by transient entrainment.26,39 In neither situation does the double electrogram represent an essential part of the circuit. Furthermore, split or double electrograms can also be produced by slow conduction, as in

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intra-Hisian block,53 or in ventricular tachycardia circuits.54 Therefore the presence of a double electrogram always requires validation by mapping and/or pacing.

Entrainment Mapping Sequential mapping should lead to a first hypothesis of circuit configuration, but an apparent circular sequence should not be considered proof of reentry. Complex conduction block lines can be present, especially in patients who have undergone surgery or previous ablation, and these could produce a false appearance of circular activation. This is where the study of return cycles after transient entrainment becomes important. During transient entrainment, all electrograms show the same paced CL, and when pacing stops the undisturbed circuit recovers its spontaneous CL.26,55 However, if pacing is done at a distance from the circuit, the postentrainment cycle is longer at the pacing site, because it includes conduction time to and from the circuit3,56,57 (Figure 7). Repeated pacing could lead to modification or interruption of the reentry circuit, especially in atypical AFL or MRT, and it should be used judiciously. Selection of pacing sites should be guided by the circuit configuration hypothesis to avoid repeated pacing runs, leading to circuit disruption. Furthermore, entrainment CL should be as close as possible to basic CL to prevent rate-dependent conduction delay that could result in long return pauses within the circuit.19,26,56 During pacing, the use of multiple endocardial recordings makes entrainment easily recognizable. In typical AFL when pacing the RA (inside the circuit) little antidromic capture is observed, even in the presence of fusion on the ECG. Return pauses are equal to basic AFL CL, unless short pacing CLs produce conduction slowing in the circuit.19,26,46 On the other hand,

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Figure 7. Schematic representation of activation and recordings during transient entrainment. Circular activation with a time dimension develops into a spring-shaped helical curve, as in Figure 4. Recording sites 1 through 6 are inside the circuit. Sites 7 and 8 are outside the circuit in the path from the pacing site (S) outside the circuit to the circuit. Note that during entrainment (first 3 cycles) activation sequence is reversed at sites 7 and 8. Site 1 is captured antidromically, changing in shape and in sequence in relation to 2. Collision between orthodromic and antidromic paced fronts occurs in the circuit between sites 1 and 2. When pacing stops, activation sequences return to baseline with a return cycle equal to reentry cycle length within the circuit but longer in the sites outside the circuit. Return cycle in site 1, captured antidromically, is shorter than reentry cycle length.

when pacing is far from the circuit, collision of activation fronts can be readily identified by partial electrogram sequence changes (Figure 7). This is considered equivalent to ECG fusion for the diagnosis of transient entrainment, and it is generally easier to detect than fusion in atypical AFL or MRT.

Typical Flutter Typical AFL has a characteristic appearance in the inferior ECG leads with a continuously waving line with sharp negative deflections, preceded by a gently sloping segment. This pattern reflects very

specifically RA macroreentry with superiorinferior activation of the anterolateral wall and inferior-superior activation of the septal RA, often called counterclockwise reentry (Figures 5 and 8). In the inferior RA, the turning point is the inferior vena cava-tricuspid valve isthmus, most probably because the terminal crest blocks conduction from the lateral to the posterior wall,46,50,51 although a recent report locates the zone of block on the posterior RA wall, medial to the crest.58 In the high RA, the turning point was thought to be superior and anterior to the superior vena cava59-61; however, recent evidence suggests that in some cases activation can cross the upper

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Figure 8. Schematic representation of atrial activation in typical and reverse typical atrial flutter. The atria are shown in a left anterior oblique view and the size of the tricuspid ring is magnified to show right atrial endocardium. Superior vena cava (SVC), inferior vena cava (IVC), coronary sinus (CS), pulmonary veins (PV), and terminal crest (TC) are shown for orientation. Arrows mark direction of activation. See text for explanation.

end of the terminal crest, below the superior vena cava,20 and an infrequent form of lower loop reentry turns around the inferior vena cava, across the lower part of the terminal crest.62 The LA is a passive bystander and coronary sinus activation occurs from the ostium to the distal coronary sinus with approximately the same timing as in the septal RA. Descending anterolateral wall activation proceeds quite rapidly, generally in 50 ms or less, inscribing sharp, highvoltage electrograms. A similar sequence can be observed in recordings obtained close to the septal rim of the tricuspid valve, where there is ascending activation toward the superior RA (roof). Recordings from the posterior wall often show less clear-cut sequences, perhaps suggesting transverse activation from the septal tricuspid valve toward the terminal crest. A most characteristic finding, as mentioned above, is a superior-inferior line of double electrogram in the posterolateral RA, corresponding to the location of the terminal crest (Figure 6). When placed in the context of general activation sequence, one of

the electrogram components is seen to reflect lateral wall activation and the other posterior wall activation.38,40,44 A logically organized recording array shows very nicely a classic pattern of reentrant activation, covering 100% of the cycle in orderly sequence (Figure 5). Three or 4 recordings from the septal wall are enough to show ascending activation on this side, and the same number will show descending activation on the anterolateral RA. An electrogram from the RA roof, anterior to the superior vena cava, fills the interval between the high septal and high anterior walls. Electrograms from anterolateral and septal RA can make a convenient reference to localize the inferior turning point in the circuit. If the anterior wall electrograms are displayed in a superior-inferior sequence and the septal wall electrogram immediately below and in an inferior-superior sequence, a 50- to 100-ms gap between low anterior and low septal recordings becomes clearly apparent. If the sequential mapping electrograms are displayed between low anterior and low septal electrogram,

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the inferior vena cava-tricuspid valve isthmus electrogram will be the only one bridging this gap in typical AFL63 (Figures 5 and 6). Electrograms from the inferior vena cava-tricuspid valve isthmus are generally sharp, but fragmented and/or double electrograms can be recorded toward the septal end, reflecting block at the eustachian ridge and/or slow conduction in the isthmus (Figure 5). Conduction across the isthmus appears to be slower than in the anterior wall, and rate-dependent slowing and block have been observed in some studies,64 although there is still room for controversy.65 The inferior end of the terminal crest fans out to insert on the tricuspid valve in the anterior and mid isthmus with a direction of muscle fibers mostly perpendicular to the isthmus, and fiber arrangement on the septal end is also perpendicular to the direction of conduction during AFL.47,66 Anisotropy might be the explanation for slow conduction and block in the inferior vena cava-tricuspid valve isthmus in typical AFL.

counterclockwise reentry. It has been observed that reverse AFL is more commonly induced by pacing the anterolateral RA, while typical counterclockwise AFL is induced by pacing the coronary sinus.64,69 We have observed that reverse AFL is easier to induce after radiofrequency application in the mid inferior vena cava-tricuspid valve isthmus. The spontaneous preference for counterclockwise AFL could be related to a low conduction safety factor in the posterior (septal) side of the inferior vena cava-tricuspid valve isthmus, favoring unidirectional block in the clockwise direction.70 Another strong argument for the anatomical dependence of typical and reverse typical AFL is the observation that radiofrequency application to the inferior vena cava-tricuspid valve isthmus interrupts reentry and complete isthmus block prevents recurrence.71 Interestingly, once the typical AFL circuit is interrupted by ablation, atrial fibrillation is not uncommon but other forms of atypical AFL are rare.72,73

Reverse Typical Flutter Scar-Related Macroreentry The reproducible configuration of common flutter circuits in patients without and with different types of cardiac disease suggests a strong anatomical dependence. This concept is further supported by the induction of reverse reentry in the same circuit in many patients with typical AFL.44,67,68 Activation of the septal wall is now descending and activation of the anterior wall ascending (Figures 5 and 8) but the inferior vena cava-tricuspid valve isthmus is also the inferior turning point, and double electrograms are recorded in the area of the terminal crest and eustachian ridge. Even though reverse reentry is relatively easy to induce in patients with typical AFL, the clinical incidence is about one tenth of that of

Macroreentrant tachycardia based on surgical scars is now well characterized.19,25,74-77 The circuits can be very complex when the patient has undergone the Mustard, Senning, or Fontan procedure74 because large parts of the circuit can be difficult to reach, and entrainment mapping becomes very important to localize isthmic areas.75,76 In patients with atrial septal defect patch repair, reentry can occur around the patch.25 The ECG can show P waves with isoelectric baselines, or AFL-like patterns. A relatively simple form of scar MRT is found after surgery for atrial or ventricular septal defects or myxoma, with a large scar in the lateral RA77,78 (Figure 9).

ENDOCARDIAL MAPPING OF ATRIAL FLUTTER

Figure 9. Schematic representation of macroreentrant atrial tachycardia around a lateral right atrial wall surgical scar (right anterior oblique view). TV = tricuspid valve; IVC = inferior vena cava; SVC = superior vena cava.

The RA anterior to the scar is part of the circuit, but the septal RA and the inferior vena cava-tricuspid valve isthmus are not, as shown by entrainment mapping (Figure 10). At the scarred area, in the center of the reentry circuit, low-voltage double electrograms are recorded. Contrary to typical AFL, fragmented or double low-voltage electrograms can often be recorded from the same area during sinus rhythm. The inferior turning point of activation is located between the inferior end of the scar and the inferior vena cava. Wide, fragmented electrograms, suggesting conduction slowing, are often recorded at the inferior turning point, and it is not uncommon to interrupt reentry by catheter pressure in this area. Most, if not all, patients with scar macroreentry also have typical AFL reen-

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try,79 and this can make diagnosis difficult because of switching from one to the other during mapping, and especially, entrainment. Scar-related MRT can be very unstable and multiple pacing runs are likely to modify or interrupt the rhythm. Multiple endocardial references are particularly useful in these cases, as minor changes in septal activation sequence can suggest the switch in tachycardia mechanism.19 An interesting new development has been the recognition of MRT, not using the inferior vena cava-tricuspid isthmus, centered in the lateral RA wall, the same as scar MRT, in patients without a history of previous surgery.21 Similarly to LA MRT (see below) the nature of the central obstacle in these cases is uncertain, and the clinical significance of these MRT requires further study. LA Macroreentry or Flutter In our experience, approximately 10% to 15% of MRTs result from LA circuits, according to mapping and entrainment data.80 Patients with LA MRT have a high prevalence of organic heart disease, including valvular surgery. Direct LA mapping shows the presence of large low-voltage areas, similar to those found in scar-related and non-scar-related MRT of the RA free wall. As in those cases, the nature of the obstacles is uncertain,22 but the association of severe intra-atrial conduction disturbances and a high prevalence of organic heart disease81 suggests severe atrial myocardial damage. However, most information is presently indirect, derived from coronary sinus recordings and postentrainment return cycles that are long in the RA and short in the LA.19 The ECG can show continuous undulation, as in AFL, but low-voltage discrete P waves can be recorded in other cases.

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Image Not Available

Figure 10. A. Sequential recordings along a surgical scar in a patient with previous surgery for atrial septal defect. From left to right 5 panels are shown with lead II and fixed reference recordings from high (HA), mid (MA), and low (LA) anterior, and low (LPS), mid (MRS), and high (HPS) posteroseptal right atrium (see schema). Anterior right atrial activation is descending, but septal right atrial activation starts in MRA. The electrogram in the center shows sequential recordings along the lateral wall from high (L1) to low (L5). Note widely separated, low-voltage double deflections in L1 through L4 and a wide, fragmented electrogram in L5. See text for further explanation. B. Postentrainment returns from LA, MA, and right atrial roof (R). Recordings are displayed as in Figure 1 A. Note return cycles equal to basic cycle length in MA and R, but longer in LA, indicating that LA is at some distance from the reentry circuit. C. Postentrainment returns from inferior cava-tricuspid isthmus (IVC-T) and low septum (LS). Recordings are displayed as in Figure 1A. Note return cycles longer than baseline at both sites, ruling out their participation in the circuit. Reproduced from references 17 and 69, with permission.

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553

The coronary sinus is activated most CLs 180 to 160 ms, but fragmentation commonly from distal (posterior) to prox- and continuous electrical activity can be imal (anterior), or in both distal and prox- recorded in others.32 Pacing can modify imal directions from a middle "earlier" electrogram sequence and CL, and "move" point. A large gap without electrogram continuous activity to another area. It can remain in the tachycardia cycle is tempting to speculate that type II when no direct endocardial LA mapping flutter may be caused by functional is performed, but LA activity within this reentry circuits, similar to those induced gap can be recorded from the pulmonary by Allessie et al.84 in dogs under vagal arteries and/or esophagus. The septal stimulation. RA can be activated from inferior to superior, but there is no clear circular RA activation. The reentrant mechaFibrillatory Conduction nism can be confirmed by entrainment with the help of coronary sinus or LA The electrophysiological diagnosis of recordings (Figure 11) that can show atrial fibrillation is becoming a challenge collision when fusion is not evident on because of the definition of relatively regthe ECG. ular activation sequences and focal origin of activation locally85-88; however, irregular interelectrogram intervals are recorded in these cases. Schuessler et Atypical Flutter al.,89 on the other hand, have shown irregIn certain patients, multiple AFL ular conduction through the atria of a regmorphologies can be induced by pro- ular rapid tachycardia originated at a grammed stimulation that either are too stable site in animals under vagal stimunstable to be entrained or cannot be ulation, and recent work by Mandapati et entrained.82 In some of these RA activa- al.90 has revealed underlying stable reention sequence can rule out typical AFL trant activation in experimental atrial (Figure 1), but in others activation fibrillation in sheep. This possibility was sequences recorded with multiple refer- already suggested by the endocardial ences can be similar to typical AFL. It is mapping data in humans reported by possible that some of these unstable Puech et al.42 In the presence of ECG patrhythms can be due to reentry around terns of atrial fibrillation, multiple obstacles too small to allow an excitable recordings can clearly show patterns congap in the circuit. Unstable double-wave sistent with AFL or focal tachycardia, reentry has been described in the typical originating in the LA, conducted irreguAFL circuit after pacing typical AFL.83 larly to the RA (Figure 12). Only higher ECG morphologies are generally low- density mapping could elucidate the voltage continuous deflections, but some- ultimate local atrial tachycardia mechatimes they can mimic typical or reverse nism, and this may be beyond the methodology used in the clinical electroflutter morphologies.82 Wells et al.12 described type II AFL as physiology laboratory. Nevertheless, a rapid AFL with rates of 340 to 430 per these observations underline the need for minute, commonly appearing after pacing multisite simultaneous recordings from type I AFL. Multiple simultaneous elec- both RA and LA to separate atrial fibriltrogram recording during these rapid AFL lation from other tachycardia mechawill appear regular in most sites, with nisms of local origin.

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Figure 11. Left atrial macroreentrant tachycardia induced after typical flutter isthmus ablation. Lead III shows low-voltage continuous undulation. Spontaneous activation sequence is shown on the right of panels A and B, after pacing. High anterior (HA) precedes low anterior (LA) right atrium, and low posterior septum (LPS) precedes high posterior septal right atrium (HPS), as in typical flutter. However, distal coronary sinus (DCS) precedes mid (MCS) and proximal (PCS) coronary sinuses. During pacing from mid anterior right atrium at cycle length of 200 ms (A), there is a change in activation sequence of the septal and anterior walls, but not the coronary sinus. Collision is shown by change in relative sequence between PCS and MCS. Postpacing pauses are long in the right atrial recordings, but very close to basic cycle length in DCS and MCS. Pacing at a cycle length of 180 ms (B) shows further antidromic penetration of the coronary sinus, with change in relative sequence now between DCS and MCS. Note a slight prolongation of return cycles, suggesting pacing-induced conduction delay in the circuit.

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Image Not Available

Figure 12. Irregular conduction in the right atrium of a rapid regular tachycardia originating in the left atrium. From top: lead II and electrograms from high (HA), mid (MA), and low (LA) anterior right atrium; low (LPS), mid (MPS), and high (HPS) posterior septum; and proximal (PCS) and distal (DCS) coronary sinus. Note fragmentation and irregular sequences in anterior and septal right atrium and a perfectly regular cycle length and sequence in the coronary sinus. From Cosio FG et al. Electrophysiologic findings in atrial fibrillation. In: RH Falk y PJ Podrid (eds): Atrial Fibrillation. Mechanisms and Management. Philadelphia: Lippincott-Raven; 1997:397-410, with permission. Acknowledgments: This work was made possible by the cooperation of Pilar Adoue, D.U.E., Isabel de las Fuentes, D.U.E., and Pilar Gomez, D.U.E. We thank Ms. Jessica Cabello for her secretarial assistance.

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56. Almendral JM, Gottlieb CD, Rosenthal ME, et al. Entrainment of ventricular tachycardia: Explanation for surface electrocardiographic phenomena by analysis of electrograms recorded within the tachycardia circuit. Circulation 1988;77:569-580. 57. Arenal A, Almendral J, San Roman D, et al. Frequency and implications of resetting and entrainment with right atrial stimulation in atrial flutter. Am J Cardiol 1992; 70:1292-1298. 58. Friedman PA, Luria D, Fenton AM, et al. Global right atrial mapping of human atrial flutter: The presence of posteromedial (sinus venosa region) functional block and double potentials. A study in biplane fluoroscopy and intracardiac echocardiography. Circulation 2000;101:1568-1577 59. Kalman J, Olgin J, Saxon L, et al. Activation and entrainment mapping defines the tricuspid annulus as the anterior barrier in typical atrial flutter. Circulation 1996;94:398-406. 60. Tsuchiya T, Okumura K, Tabuchi T, et al. The upper turnover site in the reentry circuit of common atrial flutter. Am J Cardiol 1996;78:1439-1442. 61. Arribas F, Lopez-Gil M, Nunez A, et al. The upper link of the common atrial flutter circuit. Pacing Clin Electrophysiol 1997; 20:2924-2929. 62. Cheng J, Cabeen WR, Scheinmann MM. Right atrial flutter due to lower loop reentry. Mechanism and anatomic substrate. Circulation 1999;99:1700-1705. 63. Cosio FG, Arribas F, Lopez-Gil M, et al. Radiofrequency ablation of atrial flutter. J Cardiovasc Electrophysiol 1996;7:60-70. 64. Tai C-T, Chen S-A, Chiang C-E, et al. Characterization of low right atrial isthmus as the slow conduction zone and pharmacological target in typical atrial flutter. Circulation 1997;96:2601-2611. 65. Kinder C, Kall J, Kopp D, Robenstein D, et al. Conduction properties of the inferior vena cava-tricuspid annular isthmus in patients with typical atrial flutter. J Cardiovasc Electrophysiol 1997;8:727-737. 66. Racker DK, Ursell PC, Hoffman BF. Anatomy of the tricuspid annulus: Circumferential myofibers as the structural basis for atrial flutter in a canine model. Circulation 1991;84:841-851. 67. Tai C-T, Chen S-A, Chiang C-E, et al. Electrophysiologic characteristics and radiofrequency catheter ablation in patients

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with clockwise atrial flutter. J Cardiovasc Electrophysiol 1996;8:24-34. Saoudi N, Nair M, Abdelazziz A, et al. Electrocardiographic patterns and results of radiofrequency catheter ablation of clockwise type I atrial flutter. J Cardiovasc Electrophysiol 1996;7:931-942. Olgin JE, Kalman JM, Saxon L, et al. Mechanism of initiation of atrial flutter in humans: Site of unidirectional block and direction of rotation. J Am Coll Cardiol 1997;29:376-384. Cosio FG, Lopez-Gil M, Arribas F, Gonzalez HD. Mechanisms of induction of typical and reversed atrial flutter. J Cardiovasc Electrophysiol 1998;9:281-191. Cosio FG, Arribas F, Lopez-Gil M, et al. Atrial flutter mapping and ablation II. Radiofrequency ablation of atrial flutter circuits. Pacing Clin Electrophysiol 1996; 19:965-975. Cosio FG, Lopez-Gil M, Arribas F, et al. Ablacion de flutter auricular. Resultados a largo plazo tras 8 anos de experiencia. Rev Esp Cardiol 1998;51:832-839. Anselme F, Saoudi N, Poty H, et al. Radiofrequency catheter ablation of common atrial flutter: Significance of palpitations and quality-of-life evaluation in patients with proven isthmus block. Circulation 1998;99:534-540. Cronin CS, Nitta T, Mitsuno M, et al. Characterization and surgical ablation of acute atrial flutter following the Mustard procedure. A canine model. Circulation 1993;88(Suppl 2):461-471. Triedman JK, Saul JP, Weindling SN, et al. Radiofrequency ablation of intraatrial reentrant tachycardia after surgical palliation of congenital heart disease. Circulation 1995;91:707-714. Van Hare GF, Lesh MD, Ross BA, et al. Mapping and radiofrequency ablation of intraatrial reentrant tachycardia after the Senning or Mustard procedure for transposition of the great arteries. Am J Cardiol 1996;77:985-991. Kalman JM, Van Hare GF, Olgin JE, et al. Ablation of 'incisional' reentrant atrial tachycardia complicating surgery or congenital heart disease. Circulation 1996;93: 502-512. Cosio FG, Arribas F, Lopez Gil M. Mapping and ablation of atrial flutter. In: Luderitz B, Saksena R (eds): Interventional Electrophysiology: A Textbook.

ENDOCARDIAL MAPPING OF ATRIAL FLUTTER Armonk, New York: Futura Publishing Co.; 1996:493-507. 79. Shah D, Jais P, Takahashi A, et al. Dualloop intra-atrial reentry in humans. Circulation 2000;101:631-639. 80. Nunez A, Arribas F, Lopez-Gil M, et al. A study of the mechanism of atrial flutter and atrial tachycardia in adults by mapping and pacing. Pacing Clin Electrophysiol 1995;18:803. Abstract. 81. Cosio FG, Cantale C, Nunez A, et al. Electrophysiologic and clinical characterization of left atrial macroreentrant tachycardia. Pacing Clin Electrophysiol 2000;23:573. Abstract. 82. Kalman JM, Olgin JE, Saxon LA, et al. Electrocardiographic and electrophysiologic characterization of atypical atrial flutter in man: Use of activation and entrainment mapping and implications for catheter ablation. J Cardiovasc Electrophysiol 1996;8:121-144. 83. Cheng J, Scheinman MM. Acceleration of typical atrial flutter due to double-wave reentry induced by programmed electrical stimulation. Circulation 1998;97:15891596. 84. Allessie MA, Lammers WJEP, Bonke FIM, et al. Intra-atrial reentry as a mechanism for atrial flutter induced by acetyl-

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choline and rapid pacing in the dog. Circulation 1984;70:123-135. 85. Wells JL, Karp RB, Kouchoukos NT, et al. Characterization of atrial fibrillation in man: Studies following open heart surgery. Pacing Clin Electrophysiol 1978;l:426-438. 86. Konings KTS, Kirchhof CJHJ, Smeets JRLM, et al. High-density mapping of electrically induced atrial fibrillation in humans. Circulation 1994;89:1665-1680. 87. Holm M, Johansson R, Brandt J, et al. Epicardial right atrial free wall mapping in chronic atrial fibrillation. Documentation of repetitive activation with a focal spread—a hitherto unrecognised phenomenon in man. Eur Heart J 1997;18:290-310. 88. Roithinger FX, Lesh MD, Power JM, et al. Organized activation during atrial fibrillation in man: Endocardial and electrocardiographic manifestations. J Cardiovasc Electrophysiol 1998;9:451-461. 89. Schuessler RB, Grayson TM, Bromberg BI, et al. Cholinergically mediated tachyarrhythmias induced by a single extrastimulus in the isolated canine right atrium. Circ Res 1992;71:1254-1267. 90. Mandapati R, Skanes A, Chen J, et al. Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart. Circulation 2000;101:194-199.

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Chapter 28 Catheter Ablation of Atrial Fibrillation in Humans: Initiation and Maintenance Michel Haissaguerre, MD, Pierre Jais, MD, Dipen C. Shah, MD, Meleze Hocini, MD, Laurent Made, MD, Rukshen Weerasooriya, MD, Teiichi Yamane, MD, Kee-Joon Choi, MD, Christophe Scavee, MD, Florence Raybaud, MD, Stephane Ganigue, MD, and Jacques Clementy, MD

Introduction Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance. It is associated with manifestations ranging from palpitations to cardiac failure, and its prevalence increases rapidly with age, affecting 5.9% of people over the age of 65.1,2 The most dreaded complication is stroke, with 30% of strokes occurring in people over the age of 65 resulting from AF. Catheter techniques for ventricular rate control (atrioventricular junction ablation, atrioventricular nodal modification)3-6 have been shown to be effective, but the persistence of AF and the frequent requirement for a permanent pacemaker are significant disadvantages of these techniques. Curative therapies based on either eliminating the initiating trigger or modifying the maintaining substrate of AF are currently being

developed both by surgeons7-14 and cardiologists. Multiple reentrant wavelets are necessary for perpetuating AF,15-20 and therefore linear ablative lesions created by applications of radiofrequency (RF) energy21-37 or by the surgeon's knife (atriotomies) have been shown to prevent paroxysmal or chronic AF by depriving the wandering of wavelets of the spatial extent necessary for their persistence. The initial beats triggering AF originate mainly from the pulmonary veins (PVs), which can be focally targeted for a curative therapy by percutaneous transcatheter techniques as well as isolating surgical atriotomies.

Mapping of the Atrial Tissue Substrate

From experimental and simulation studies, AF is considered to be maintained

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; C2003. 561

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by the simultaneous existence of several reentrant wavelets in a critical mass of atrial tissue (the substrate). Accepting this hypothesis, one would expect that in the clinical setting, the right atrium (RA) and the left atrium (LA) would contribute in proportion to their respective masses. Clinical studies have shown, however, that AF exhibits spatially demarcated activation patterns and a more prominent role of the LA, and that it can also result from a discrete arrhythmogenic area or single regular (fixed) reentry with either fibrillatory conduction or wavefronts from the native and previous cycles coexisting simultaneously.15-20,38-43 Disparities of the Atrial Tissue Substrate During AF Mapping Epicardial mapping during surgery

In patients undergoing surgery for Wolff-Parkinson-White syndrome, Cox et al.18 found activation patterns in the RA either suggestive of reentry (cycle length [CL] 180 to 210 ms) or compatible with a large circuit involving the interatrial septum. The LA was activated "nonuniformly," and documentation of complete LA reentry was rare. The circuits were so variable that it was "impossible to use on-line maps to guide surgical therapy." In 25 patients, Konings et al.19 described 3 types of AF based on the complexity and number of wavefronts without detecting any differences between the RA and LA free walls. Single electrograms were present most of the time, indicating rapid uniform conduction. Techniques to assess spatial organization during AF were applied in the RA (the lateral wall) and evidence for transient linking of atrial excitation were obtained during paroxysmal AF42; in patients with chronic AF, Holm et al.44 reported uniform activation consistent with either the

presence of large reentrant circuits in the RA or repetitive focal activation. Endocardial recording of atrial myocardial activity

Using multipolar electrode catheters, Jais et al.45 studied 27 patients suffering from paroxysmal AF. Continuous electrical activity or electrograms with FF intervals less than 100 ms were designated as complex electrical activity which can be viewed as the ultimate degree of temporal asynchrony, morphologically termed disorganization, during AF. A variable and characteristically heterogeneous distribution of complex electrograms illustrating the respective regional complex activity times in both atria is shown in Figure 1. In the RA, the intercaval (posterior) and adjacent septal regions exhibit complex electrical activity for longer periods in contrast to lateral and anterior regions, which are predominantly trabeculated areas. The border between these 2 very different regions appears to be the crista terminalis region, as shown by using intracardiac echocardiography or CARTO™ system (Biosense Webster, Diamond Bar, CA).46 Gaita et al.27 reported similar data, with more irregularity of the electrical activity and greater beat-to-beat variations in the local activity of the septum. In the LA, most regions showed disorganized complex electrical activity, with the maximal duration of complex activity being in the septum, the roof, and the posterior (87%) regions between the PVs; these data are in keeping with animal results. In the anterior trabeculated LA, the appendage frequently exhibited organized electrical activity. In some patients, there was clear dissociation between the organized distal coronary sinus and corresponding disorganized

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Image Not Available

Figure 1. Schematic diagram of both atria in the posteroanterior view. Complex electrical activity during atrial fibrillation is expressed in percentage of time. The septum has been assessed from both right and left sides. Reproduced from reference 45, with permission.

adjacent LA endocardial activity (while the proximal coronary sinus exhibited activity similar to the septal region), indicating a limitation to the use of the coronary sinus activity as a reflection of LA activity during AF. Roithinger et al.47 investigated spatiotemporal RA organization and its surface ECG manifestations in humans. During AF, organized activation was present 72 ± 32% of the analyzed time on the trabeculated versus 19 ± 15% on the smooth RA, with the direction of organized activation craniocaudal in most cases. The mean surface F wave amplitude in lead V1 was 0.128 ± 0.06 mV during AF with a craniocaudal direction of activation and 0.065 ± 0.02 mV during disorganized activation. A stable relation between surface F waves and organized trabeculated RA activation was observed, and the mean F wave CL (190 ± 27 ms)

was highly comparable to the simultaneously measured endocardial CL (191 ± 27 ms): F wave polarity in V1 was positive in 12 of 14 patients during craniocaudal and negative in 11 of 14 patients during caudocranial RA free wall activation. Therefore, during AF organized activation with a predominant craniocaudal direction on the trabeculated RA is frequently present and influences the appearance of "coarse" or "fine" AF as well as F wave polarity on the surface ECG. Great vein electrical activity during AF

Bands of cardiac muscle extend from the atrium into the great veins and provide an extension of atrial electrical activity. However, their coupling with the adjacent atrial input contrasts strikingly in the RA and LA.

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Electrical Activity in the Great Veins of the RA: While performing mapping during paroxysmal AF, spike-like activity ranging from 0.4 to 1.2 mV in bipolar amplitude in the superior vena cava (SVC) can be found in most patients either dissociated or with a lesser frequency. The SVC activity followed the dominant RA activity only in few patients. During sinus rhythm, this spike formed part of a multicomponent potential, which could be separated and the sequence altered by atrial pacing. The spike activity could be traced superiorly for about 3.5 cm into the SVC.24 Unlike in the SVC, no local electrical activity was recorded in the inferior vena cava (IVC). During ascent from the IVC into the RA, an abrupt appearance of electrical activity was consistently noted upon entrance into the RA (unpublished data).24 Electrical Activity in the PVs: Local electrical activity can be recorded for up to 4 cm into the superior veins and for a lesser extent into the inferior veins. In contrast to SVC activity, the PV electrograms followed the intrinsic deflections of the nearby atrium at a high rate in one-toone fashion in most patients, indicating strong electrical coupling, and was rarely dissociated. Rapid pacing from inside the vein was able to induce AF in some patients. Perhaps because this area represents an electrical "cul-de-sac" receiving impulses from a restricted input, the resulting local electrograms during AF reflect a rapid and relatively regular organized activity unlike the disorganized activity in the adjoining posterior LA. In patients with AF, the refractory period in the PVs is extremely short (as short as 60 ms)—shorter than that of the LA in most cases—whereas in patients without AF, it is generally longer than that in the LA. We do not know if this

phenomenon is a cause or a consequence of AF.

Electrophysiological Effects of Catheter Ablation of the Atrial Substrate Linear Ablation in the RA The efficacy of linear ablation limited to the RA was evaluated in 45 patients with daily paroxysmal AF (mean duration = 379 min/day) by use of a multipolar catheter.23 Three groups of 15 patients each underwent increasingly complex lesion patterns in the RA. Ablation led to stable sinus rhythm during the procedure in 18 patients (40%), but noninducibility of AF using burst pacing was achieved in only 5 patients (11%). Final success rates with all 3 types of lesion patterns were similar: globally, only 6 patients (13%) were cured without drug. Another series of catheter ablation in the RA has been reported by Gaita et al.27 with concordant limited results. Ernst et al.28 created linear lesions achieving complete conduction block (to the extent of producing intra-atrial dissociation) in the RA; however, most patients in this study continued to have fibrillation pointing to the dominant role of the LA. The subset of patients who could benefit on a long-term basis from a RA only approach with or without additional drug therapy is not presently defined. Linear Ablation in the LA Linear lesions in the LA were attempted, to create a rectangle with the mitral annulus (as its base) on the posterior wall (which exhibits the most disorganized activity). Anatomical structural blocks (the PVs, mitral annulus) were connected to minimize the length of lines

CATHETER ABLATION OF ATRIAL FIBRILLATION IN HUMANS and avoid peri-incisional reentry. The procedures were performed under full heparinization (partial thromboplastin time 60 to 90 seconds) and after transesophageal echocardiography confirmed the absence of thrombi. A drag technique with a catheter equipped with a thermocouple and a maximal target temperature of 57°C was used to perform the lines and repeated in an attempt to produce linear conduction block. The procedures were prolonged, lasting 280 ± 101 minutes with 78 ± 37 minutes of fluoroscopy time and a total RF delivery duration of 85 ± 49 minutes despite the use of an irrigated tip ablation catheter to increase RF power.48 Stable sinus rhythm was obtained in 85% of cases, whereas AF or LA flutters persisted in others at the end of the session, requiring electrical cardioversion. Inducibility was tested using high-rate biatrial pacing, and the most impressive finding was that sustained AF (>3 minutes) was rendered noninducible in 70% of patients. However, LA flutters appeared secondarily in most patients despite their noninducibility in most cases, at the end of the session,49 indicating that 'remodeling' of linear lesions leaves gaps. These secondary LA flutters represented a major problem because they required extensive mapping to reconstruct the circuit, had multiple morphologies, and required repeated sessions to be eliminated. Segments of complete linear block produced local double potentials (indicating detour of activation), whereas gaps were indicated by continuous electrograms spanning the double potential interval.49,50 The completeness or incompleteness of lines connected to the mitral annulus could be evaluated simply by mapping the coronary sinus electrograms during sinus rhythm or pacing.49,51 Gaps were encountered in each of the 4 LA lines at any point along the line but most frequently close to their insertion on the

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mitral annulus, which is the thickest part of the LA. Extremely discrete gaps were sufficient to maintain LA flutters, which could be interrupted within a few seconds by a single punctiform pulse, while prolonged and multiple RF pulses were necessary in the majority of cases. The achievement of at least one complete line of block was the strongest variable predictive of successful ablation (78% cure). Other groups have reported similar experience. Packer et al.30 performed 5 linear lesions in the LA and 2 in the RA. Acute conversion in sinus rhythm was obtained in 15 of 18 patients following a mean procedure of 11.6 hours and maintained in 4 and 10 with and without an antiarrhythmic drug. Maloney et al.52 achieved long-term success without drug in 9 of 15 patients. The predictive value of linear block and the high incidence of LA flutters caused by recovery/remodeling of ablated tissue indicate that significant improvements in catheter design are crucial to optimize lesion characteristics at the index procedure and, thus, prevent the need for further ablation sessions; this is certainly the most important challenge facing the development of RF catheter ablation of AF. Mapping and Ablation of Triggers of AF There is no currently available in vivo experimental model with spontaneous initiation of AF to allow the study of triggering events, though a focal mechanism had been considered to be very unlikely on the basis of experimental studies and surgical human mapping data.17-19,53 Recent studies have demonstrated that focal sources of activity are critical for patients with paroxysmal AF.54-63 They may represent the sole abnormality in some patients in whom the focus discharges for long periods

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(focal AF) or one or few sources act as the from the focus occur only in trains, with dominant trigger to induce episodes of AF every discharge or train inducing AF. In that subsequently continue independently patients with AF, initiation of common of the initiating event (focally initiated atrial flutter, its degeneration into AF, AF). These foci have a characteristically or its interruption are also frequently the predominant anatomical location: in the result of PV discharges. The first ectopic thoracic veins, particularly in all 4 PVs; P wave—whether isolated or initiating they have unusual properties including AF—characteristically has a coupling interlong conduction time to the LA, unpre- val that results in superimposition on the dictable firing, and frequent occurrence of T wave of the previous QRS complex, profocal discharges confined within the atrio- ducing a P-on-T pattern recognizable at first sight. venous cul-de-sac. A single arrhythmogenic PV (proven Paroxysms of AF are consistently initiated by trains of spontaneous activity, by long-term cure of AF after single PV which, much like programmed stimula- ablation) is significantly associated with tion, are responsible for the transforma- younger age, lesser number of AFs, and tion of sinus rhythm into the temporally smaller atrial dimensions, whereas muland spatially varying pattern of rapid and tiple arrhythmogenic PVs are associated irregular activity considered to be char- with older patients having a longer hisacteristic of typical AF. However, spon- tory of AF, more frequent episodes, and taneous activity arising from the PVs can larger atrial dimensions.64 produce a range of different types of atrial The patients investigated in our arrhythmias. Single discharges manifest center present a male/female sex ratio as isolated extrasystoles, repetitive dis- of 5:1, a mean daily duration of AF of charges with long CLs manifest as an 447±449 minutes (0 to 1440), a broad automatic rhythm (sometimes mimicking range of age (16 to 82 years), AF clinical sinus rhythm but with a different P wave) profiles, and right or left heart disease. while shorter cycles result in organized Mapping of the PVs and the LA is facilimonomorphic tachycardia or a pattern of tated by performing selective angiografocal 'flutter.' At short CLs an ECG pattern phy of each of the veins. Coronary sinus of focal AF, i.e., a rapid and irregular tachy- angiography is performed in the few cases cardia without discrete P waves, is pro- when ectopic activity with a negative P duced. Sudden variations (up to 350 ms wave and possibly arising from the vein of beat to beat) in the CL are the most char- Marshall is suspected.59 Two roving steeracteristic pattern for a focal mechanism. able catheters with different curve sizes True intracardiac AF is initiated when are typically introduced into the LA: a cirthe focus abruptly discharges in a rapid cumferential multielectrode PV catheter train of impulses with a CL of 182 ± 57 ms (Lasso, Biosense Webster) allowing con(330 beats per minute) leading to chaotic tinuous assessment of activation around and practically unmappable atrial activity the full circumference of the vein in addithat therefore cannot be linked to the PVs. tion to providing a fluoroscopic marker, These foci have a predominant anatomical and an ablation quadripolar catheter. location in the PVs, but triggers may also originate from other veins (SVC, ligament of Marshall, coronary sinus) or atrial Definition of an Arrhythmogenic PV tissue, notably the posterior LA. In patients without apparent isolated An arrhythmogenic PV is defined as ectopy, AF is initiated because discharges a PV (extending from the ostium to its

CATHETER ABLATION OF ATRIAL FIBRILLATION IN HUMANS tributaries) that gives rise to spontaneous discharges, single or multiple and with or without conduction to the LA.56 During sinus rhythm, double or multiple potentials are recorded in sequence from the proximal to the distal PV, synchronous with the first (right PVs) or second (left PVs) half of the P wave. The first potential is low in frequency (far-field) reflecting activation of the adjacent LA; an additional early (synchronous with the P wave onset) potential emanating from the adjacent RA is recorded from the right superior PV anterior wall. The latest potentials are high-frequency spikes indicating local activation of muscular bands65-67 extending into the PV from the LA (PV potential [PVP]). The PVPs are usually concealed in the left PVs (Figure 2), in contrast to the right PVs, because of the superimposed (fusing) LA potential during sinus rhythm requiring pacing of the distal coronary sinus or LA appendage (when distal coro-

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nary sinus cannot be reached) for their separation. During ectopy from within an arrhythmogenic PV, there is a reversal of the activation sequence, proceeding from the distal to the proximal bipole with the PVP preceding the LA potential. Rarely, ectopy originates from the ostium, thus producing early local activation and an unchanged sequence (proximal to distal) within the vein. The source of ectopy marked by the earliest PVP is often discrete in contrast to the intravenous course and atrial exit, where a synchronous PVP with a later timing (up to 160 ms) can be recorded in wide sectors (Figure 3). A lower amplitude far-field PVP (<0.1 mV) can also be recorded from a neighboring PV trunk: for instance, a far-field left inferior PVP reflecting a sharp PVP originating actually from the left superior PV bottom. During ectopy, orthodromic and antidromic conduction can also be recorded in different parts of the

Figure 2. Coronary sinus pacing (first 2 beats) separates left superior pulmonary vein electrogram into 2 components: the far-field first potential representing left atrial appendage and the second representing local pulmonary venous muscle.

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Figure 3. Extrasystoles originating from right superior pulmonary vein with the earliest activity confined to bipoles 9-10 and 10-1 (*) and significant conduction delay to other bipoles.

same vein (indicating 2 independent atriovenous fascicles) so that recording late activity (with an orthodromic LA-PVP sequence) in one sector of the PV during ectopy does not exclude an origin in another part of the same vein particularly after an initial ablation. Simultaneous mapping of the complete venous perimeter is also capable of documenting multiple foci from the same vein. Changes in the site of earliest activation (source) and intra-PV activation are observed in 24% of cases during isolated ectopy. During repetitive ectopy and/or AF, initiation from varying sources, and/or with distinct activation patterns, is noted in 55% of cases. The conduction time to the LA is typically long and exhibits decremental conduction with increasing prematurity. Ectopics closely coupled to the previous sinus beat are not conducted to the LA (i.e., confined within the vein) and are documented in 42% to 70% of arrhythmogenic PVs (Figure 4). Such ectopic PVPs are

usually synchronous to the local ventricular electrogram and distinguished from it by intermittent occurrence or disappearance with atrial pacing. A slightly longer coupling interval—5 to 10 ms—is sufficient to allow conduction to the LA. RF ablation of PVs

During an ablation procedure, all PVs are targeted for ablation even without documentation of their role in AF initiation, because when these foci are spared, the great majority of patients develop recurrences of AF originating from the unablated PV and require a new ablation session. The circumferential PV catheter allows an instantaneous assessment of the extent of muscle coverage by the number of bipoles showing sharp PVPs during sinus rhythm. At the atrial margin of the ostia, PVPs are usually present circumferentially (all bipoles display PVP),

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Figure 4. Concealed trigeminy (*) from a right pulmonary vein focus.

whereas inside the PV, potentials cover only varying parts of the perimeter with a different circumferential distribution for each PV, and a gradual reduction in their width from proximal to distal. In the proximal part of the vein (where ablation is performed), synchronous PVP activation in a sector indicates wide fascicles which will require multiple contiguous RF applications for a progressive elimination of all PV muscle. In contrast, limited PVP sites (1 or 3 bipoles) or sequential PVP activation (cascade pattern) indicate limited breakthroughs (Figure 5). Electrophysiological Endpoint of Ablation: Radiofrequency ablation can be performed distally at the site of earliest spike activity (source), along its intravenous course, or at its ostial exit into the LA. While the substrate toward the ostium is wider, proximal ablation has a lower risk of inducing significant stenosis and the advantage of isolating all potential foci into the vein. Electrophysiologically definable sites of preferential inputs to the veins enable disconnection to be achieved at the ostia with-

out circumferential ablation in half of the cases. The procedural endpoint is purely electrophysiological, defined by abolition or dissociation of PVPs.64 The PV producing the most repetitive ectopy and/or inducing AF is first targeted; RF energy is then delivered in other PVs if possible during sinus rhythm. Ablation During Sinus Rhythm: Sequential RF applications are delivered, targeting the earliest PVP during sinus rhythm or LA pacing (for left PVs). Distal coronary sinus pacing (if not distal enough, left appendage pacing) is required to separate PVP from LA appendage activation. An additional means to localize the LA-PV breakthrough is to use the site of electrogram polarity reversal recorded from circumferentially placed bipoles (orthogonal to the PV axis). Polarity reversal, defined by opposite major (filtered) deflections, indicates diverging wavefronts) similar to the paradigm described by Fisher et al. for accessory pathways. This criterion is useful when a wide front of synchronous activation is recorded on the

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Figure 5. A multielectrode circular catheter placed inside the left superior pulmonary vein exhibits progressively delayed potentials in a cascade pattern during pacing from the coronary sinus. Proximal radiofrequency ablation at the level of the vein ostium facing the Lasso bipole 15-16 ('gap'like electrogram continuum on the top trace) eliminates all pulmonary vein potentials.

Lasso because it allows a more restricted definition of the breakthrough (Figure 6). Usually RF ablation progressively delays PVPs before their abrupt abolition, while in 15% of cases PVP is still seen as an automatic dissociated rhythm with an incidence higher in the superior (22%) than in the inferior (8%) PV. Dissociated PVPs in one part of the vein while conduction is present in another part is possible (Figure 7). Dissociated repetitive discharges can be also observed in few patients (Figure 8). When the PVs are disconnected, persistent ectopics may sometimes result from discharges from the atrial edge of the ostia (proximal to the ablation lesion) or foci from other PVs or atrial tissue. Ablation During Sustained AF: When several cardioversions are required to interrupt AF but with prompt recurrence, ablation can be performed during AF

while still monitoring the distal PVP. The activity inside the vein typically varies but sometimes may be organized with a consistent (but irregular) PV activation sequence recorded from the Lasso. In the latter case, ostial ablation can be performed by targeting the earliest activity (polarity reversal is under evaluation). When PV activation is chaotic, ablation is performed anatomically around the PV perimeter, always resulting in a progressive or abrupt PV organization that allows secondarily a more localized targeting. PVP changes may be difficult to recognize in the left PV (because of superimposed left appendage potentials), whereas in the right PV complete or near complete abolition is usually observed after successful ablation. Ablation is started anatomically around the PV perimeter, and after return in sinus rhythm (spontaneous or after a new cardioversion) additional ablation is

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Figure 6. An example of changing breakthrough during radiofrequency delivery. The radiofrequency probe is facing the Lasso bipole 7-8 and 8-9 showing earliest activity and electrogram polarity reversal. The same criteria localized the second breakthrough to bipole 2/3 in the last 2 beats.

Figure 7. Multielectrode mapping in the ostial right inferior pulmonary vein after radiofrequency ablation demonstrates dissociated activity conduction to a discrete part of the vein circumference (poles 9-10 *) while there is a different dissociated rhythm (arrow) in the remaining part of the circumference.

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Figure 8. Persistent focal discharges in sinus rhythm during radiofrequency delivery in left superior pulmonary vein.

performed, targeting the remaining PVP if necessary. When no changes are observed in the activation sequence recorded within a PV despite multiple RF applications, far-field non-PV sources of potentials must be excluded. LA appendage potentials in the left superior PV and less commonly in the left inferior PV, and SVC/high RA potentials in the right superior PV, may be frequent culprits. The absence of proximalto-distal activation, relative far-field character, and timing in response to pacing maneuvers from outside the PV can be used to distinguish these non-PVPs. Total PV disconnection may be corroborated by the inability to capture the LA by pacing from the PV. However, since a limited PV fascicle may be not captured by venous pacing, circumferential PV mapping is a more reliable technique. Following disconnection, provocative maneuvers in the form of isoprenaline infusion and rapid atrial pacing are performed to unmask non-PV foci. Unlike the PVs, with their relatively constant location and

arborizing structure, these focal sources present specific problems. Sporadic discharges and initiation of sustained AF coupled with a limited electrode coverage make their localization difficult; and they usually require a longer procedural time compared to disconnection of all PVs. Multielectrode systems (basket catheters or the EnSite™ System [Endocardial Solutions, Inc., St. Paul, MN]) are being evaluated to map these elusive foci. When successfully mapped (and ablated), these non-PV foci originate mainly from the PV ostia within 1 cm proximal to the level of previous ablation (indicating 'wandering' foci) or from posterior LA. Their location is then, in order of decreasing frequency, in other parts of the LA, septum, coronary sinus, SVC, or RA. Non-PV foci cannot be localized in 20% to 30% of patients. Efficacy: Complete elimination of AF without drug, allowing interruption of anticoagulant treatment, is observed in 70% of patients. The success rate is mainly

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dependent on the presence of non-PV foci. require precise analysis of intracardiac Most of the unsuccessfully treated patients electrograms. are significantly improved or free of AF with a previously unsuccessful drug. In References centers where only a single session of AF ablation is performed, a 30% to 60% suc1. Prystowsky EN, Benson DW, Fuster V. cess rate is reported with patients off Management of patients with atrial fib61 drug. Chen et al. reported an 86% sucrillation: A statement for Healthcare Professionals from the subcommittee on cess rate in 79 patients who did, however, electrocardiography and electrophysiolhave short episodes of AF (daily duration ogy, American Heart Association. Circu28±30 minutes). Their procedural endlation 1996;93:1262-1277. point was acute ectopy suppression with2. Levy S, Breithardt G, Campbell RWF, et al. out relying on PVP mapping. Atrial fibrillation: Current knowledge and recommendations for management. Eur Ernst et al.28 and Pappone et al.63 Heart J 1998;19:1294-1320. performed catheter-mediated linear lesions MM, Morady F, Hess DS, et al. mimicking the surgical procedures of PV 3. Scheinman Catheter-induced ablation of atrioventricisolation by a line encircling 2 or all 4 ular junction to control refractory supravenPVs, as described by Sueda et al.13 and tricular arrhythmias. JAMA 1982;248: Melo et al.,14 but with varying results in 855-861. 4. Gallagher JJ, Svenson RH, Kasell JH, terms of achievement of conduction block et al. Catheter technique for closed chest and clinical success rate. Different ablaablation of the atrioventricular conduction catheters are now being developed tion system: A therapeutic alternative for to cauterize a wider substrate with each the treatment of refractory supraventricapplication. These include supple elecular tachycardia. N Engl J Med 1982;306: 194-200. trodes conforming to part of the venous 5. Huang SK, Bharati S, Graham AR, et al. perimeter (selected by prior mapping) or Closed chest catheter desiccation of the devices expanded into the vein orifices to atrioventricular junction using radiofre'anatomically' perform circumferential quency energy: A new method of catheter ablation. J Am Coll Cardiol 1987;9:349-358. lesions with promising results, as re6. Williamson BD, Man KC, Daoud E, et al. ported by Natale et al.68

Radiofrequency catheter modification of atrioventricular conduction to control the Conclusions ventricular rate during atrial fibrillation. N Engl J Med 1994;331:910-917. 7. Williams JM, Ungerleider RM, Lofland Catheter ablation of triggers presently GK, et al. Left atrial isolation. A new techeliminates paroxysmal AF in about 70% of nique for the treatment of supraventricular patients, the efficacy being limited by the arrhythmias. J Thorac Cardiovasc Surg presence of foci scattered outside the PV. 1980;80:373-380. Modification of the atrial substrate also 8. Cox JL, Canavan TE, Schuessler RB, et al. The surgical treatment of atrial fibrilladominantly in the LA can be used alone or tion II: Intraoperative electrophysiologic in combination with PV isolation but is limmapping and description of the electroited by the difficulty of achieving complete physiologic basis of atrial flutter and fiblinear block with the inherent risk of crerillation. J Thorac Cardiovasc Surg 1991; ating proarrhythmic discontinuity. Con101:406-426. 9. Cox JL, Boineau JP, Schuessler RB, et al. tinued technological developments will Five year experience with the Maze prooptimize and facilitate these techniques,69 cedure for atrial fibrillation. Ann Thorac but it is likely that electrical disconnection Surg 1993;56:814-824. of PVs, ablation of non-PV foci, and cre- 10. Van Hemel NM, Defauw JJAM, Guiraudon ation of linear lesions will continue to GM, et al. Long-term follow-up of corridor

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operation for lone atrial fibrillation: Evidence for progression of disease? J Cardiovasc Electrophysiol 1997;8:967-973. 11. Shyu KG, Cheng JJ, Chen JJ, et al. Recovery of atrial function after atrial compartment operation for chronic atrial fibrillation in mitral valve disease. J Am Coll Cardiol 1994;24:392-398. 12. Kosakai Y, Kawaguchi AT, Isobe F, et al. Modified Maze procedure for patients with atrial fibrillation undergoing simultaneous open heart surgery. Circulation 1995; 92(II):359-364. 13. Sueda T, Nagata H, Khirkata H. Simple left atrial procedure for chronic atrial fibrillation associated with mitral valve disease. Ann Thorac Surg 1996;62:17961800. 14. Melo JQ, Neves J, Adragao P. When and how to report results of surgery on atrial fibrillation. Eur J Cardiothorac Surg 1997; 12:739-745. 15. Garrey WE. The nature of fibrillatory contraction of the heart: Its relation to tissue mass and form. Am J Physiol 1914;33: 397-414. 16. Moe GK, Rheinboldt WC, Abildskov JA. A computer model of atrial fibrillation. Am Heart J 1964:200-220. 17. Allessie MA, Lammers WJEP, Bonke FIM, et al. Experimental evaluation of Moes' multiple wavelet hypothesis of atrial fibrillation. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology and Arrhythmias. Orlando: Grune & Stratton; 1985:265-276. 18. Cox JL, Canavan TE, Scheussler RB, et al. The surgical treatment of atrial fibrillation. II. Intraoperative mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 1991;101:402-426. 19. Konings KTS, Kirchhof CJHJ, Smeets JRLM, et al. High density mapping of electrically induced atrial fibrillation in humans. Circulation 1994;89:1665-1680. 20. Misier ARR, Opthof T, Van Hemel NM, et al. Increased dispersion of refractoriness in patients with idiopathic paroxysmal atrial fibrillation. J Am Coll Cardiol 1992;19:1531-1535. 21. Haissaguerre M, Gencel L, Fischer B, et al. Successful catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 1994;5:1045-1052. 22. Swartz JF, Pellersels G, Silvers J, et al. A catheter-based curative approach to atrial

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fibrillation in humans. Circulation 1994; 90(4 Pt 2):I-335. Haissaguerre M, Jais P, Shah DC, et al. Right and left atrial radiofrequency catheter therapy of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 1996;12:11321144. Li H, Hare J, Mughal K, et al. Distribution of atrial electrogram types during atrial fibrillation: Effect of rapid atrial pacing and intercaval junction ablation. J Am Coll Cardiol 1996;27:1713-1721. Cosio FG, Lopez-Gil M, Goicolea A, et al. Radiofrequency ablation of the inferior vena cava-tricuspid valve isthmus in common atrial flutter. Am J Cardiol 1993; 71:705-709. Morillo CA, Klein GJ, Jones DL, et al. Chronic rapid atrial pacing: Structural, functional and electrophysiologic characteristics of a new model of sustained atrial fibrillation. Circulation 1995;91:1588-1595. Gaita F, Riccardi R, Lamberti F, et al. Right atrium radiofrequency catheter ablation in idiopathic vagal atrial fibrillation. Circulation 1998;97:2136-2145. Ernst S, Schluter M, Ouyang F, et al. Modification of the substrate for maintenance of idiopathic human atrial fibrillation. Circulation 1999;100:2085-2092. Calkins H, Hall J, Ellenbogen K, et al. A new system for catheter ablation of atrial fibrillation. Am J Cardiol 1999;83:227D236D Packer DL, Johnson SB, Pederson B, Hauck J. The utility of non-contact mapping in identifying and rectifying discontinuity-mediated atrial proarrhythmia accompanying linear lesion creation. Pacing Clin Electrophysiol 1998;21(II):867. Elvan A, Pride HP, Eble JN, et al. Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs. Circulation 1995;91: 2235-2244. Haines DE, McRury IA. Primary atrial fibrillation ablation (PAFA) in a chronic atrial fibrillation model. Circulation 1995; 92:I-265. Nakagawa H, Kumagai K, Imai S, et al. Catheter ablation of Bachmann's bundle from the right atrium eliminates atrial fibrillation in a canine sterile pericarditis model. Pacing Clin Electrophysiol 1996; 19:581. Kalman J, Olgin J, Karch M, et al. Are linear lesions needed in both atria to prevent

CATHETER ABLATION OF ATRIAL FIBRILLATION IN HUMANS atrial fibrillation in a canine model? Circulation 1996;94:I-555. 35. Olgin J, Kalman JM, Maguire M, et al. Electrophysiologic effects of long linear atrial lesions placed under intracardiac echo guidance. Circulation 1997;96:2715-2721. 36. Tondo C, Scherlag BJ, Otomo K, et al. Critical atrial site for ablation of pacinginduced atrial fibrillation in the normal dog heart. J Cardiovasc Electrophysiol 1997;8:1255-1265. 37. Elvan A, Huang W, Pressler M, et al. Radiofrequency catheter ablation of the atria eliminates pacing-induced sustained atrial fibrillation and reduces connexin 43 in dogs. Circulation 1997;96:1675-1685. 38. Ortiz J, Niwano S, Abe H, et al. Mapping the conversion of atrial flutter to atrial fibrillation and atrial fibrillation to atrial flutter: Insights into mechanism. Circ Res 1994;74:882-894. 39. Wang Z, Feng J, Nattel S. Idiopathic atrial fibrillation in dogs: Electrophysiologic determinants and mechanisms of antiarrhythmic action of flecainide. J Am Coll Cardiol 1995;26:277-286. 40. Schuessler RB, Boineau JP, Bromberg BI, et al. Normal and abnormal activation of the atrium. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia: W.B. Saunders Co.; 1995:543-562. 41. Ikeda T, Yashima M, Uchida T, et al. Attachment of meandering reentrant wave fronts to anatomic obstacles in the atrium. Role of the obstacle size. Circ Res 1997;81:753-764. 42. Botteron GW, Cain ME. Lesions from mapping atrial fibrillation in humans: Implications for ablation. In: Murgatroyd FD, Camm AJ (eds): Nonpharmacological Management of Atrial Fibrillation. Armonk, NY: Futura Publishing Co.; 1997:185-200. 43. Jalife J, Gray RA. Insights into the mechanism of AF: Role of the multidimensional atrial structure. In: Murgatroyd FD, Camm AJ (eds): Nonpharmacological Management of Atrial Fibrillation. Armonk, NY: Futura Publishing Co.; 1997:357-376. 44. Holm M, Johansson R, Brandt J, et al. Epicardial right atrial free wall mapping in chronic atrial fibrillation. Documentation of repetitive activation with a focal spread a hitherto unrecognized phenomenon in man. Eur Heart J 1997;18:290-310. 45. Jais P, Haissaguerre M, Shah DC, et al. Regional disparities of endocardial atrial

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activation in paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 1996;19 (Pt II):1998-2003. 46. Gepstein L, Hayam G, Shpun S, Benhaim SA. 3D spatial dispersion of cycle length histograms during atrial fibrillation in the chronic goat model. Circulation 1997;96: 236. 47. Roithinger FX, SippensGroenewegen A, Karch MR, et al. Organized activation during atrial fibrillation in man: Endocardial and electrocardiographic manifestations. J Cardiovasc Electrophysiol 1998;9:451-461. 48. Nakagawa H, Yamanashi WS, Pitha JV, et al. Comparison of in vivo tissue temperature profile and lesion geometry for radiofrequency ablation with a salineirrigated electrode versus temperature control in a canine thigh muscle preparation. Circulation 1995;91:2264-2273. 49. Jais P, Shah DC, Haissaguerre M, et al. Efficacy and safety of septal and left atrial linear ablation for atrial fibrillation. Am J Cardiol 1999;84:139R-146R. 50. Sih HJ, Berbari EJ, Zipes DP. Epicardial maps of atrial fibrillation after linear ablation lesions. J Cardiovasc Electrophysiol 1997;8:1046-1054. 51. Haissaguerre M, Jais P, Shah DC, Clementy J. Electrophysiology of linear lesions. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. 3rd ed. Philadelphia: WB Saunders Co.; 1999:994-1008. 52. Maloney JD, Milner L, Barold SS, et al. Two-staged biatrial linear and focal ablation to restore sinus rhythm in patients with refractory chronic atrial fibrillation: Procedure experience and follow-up beyond one year. Pacing Clin Electrophysiol 1998; 21(II):2527-2532. 53. Kumagai K, Krestian C, Waldo AL. Simultaneous multisite mapping studies during induced atrial fibrillation in the sterile pericarditis model. Insights into the mechanism of its maintenance. Circulation 1997;95:511-521. 54. Haissaguerre M, Marcus FI, Fischer B, et al. Radiofrequency catheter ablation in unusual mechanisms of atrial fibrillation: Report of three cases. J Cardiovasc Electrophysiol 1994;5:743-751. 55. Jais P, Haissaguerre M, Shah DC, et al. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation 1997;95:572-576.

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56. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. NEngl J Med 1998;339: 659-666. 57. Robbins IM, Colvin EV, Doyle TP, et al. Pulmonary vein stenosis after catheter ablation of atrial fibrillation. Circulation 1998;98:1769-1775. 58. Chen SA, Tai CT, Yu WC. Right atrial focal atrial fibrillation: Electrophysiologic characteristics and radiofrequency catheter ablation. J Cardiovasc Electrophysiol 1999; 10:328-335. 59. Hwang C, Karagueuzian HS, Chen PS. Idiopathic paroxysmal atrial fibrillation induced by a focal discharge mechanism in the left superior pulmonary vein: Possible roles of the ligament of Marshall. J Cardiovasc Electrophysiol 1999;10:636-648. 60. Lau CP, Tse HF, Ayers GM. Defibrillationguided radiofrequency ablation of atrial fibrillation secondary to an atrial focus. J Am Coll Cardiol 1999;33:1217-1226. 61. Chen SA, Tai CT, Tsai CF, et al. Radiofrequency catheter ablation of atrial fibrillation initiated by pulmonary vein ectopic beats. J Cardiovasc Electrophysiol 2000;11: 218-227. 62. Tsai CF, Tai CT, Hsieh MH, et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava:

Electrophysiological characteristics and results of radiofrequency ablation. Circulation 2000;102:67-74. 63. Pappone C, Oreto G, Lamberti F, et al. Catheter ablation of paroxysmal atrial fibrillation using a 3D mapping system. Circulation 1999;100:1203-1208. 64. Haissaguerre M, Jais P, Shah DC, et al. Electrophysiological end point for catheter ablation of atrial fibrillation initiated from multiple pulmonary venous foci. Circulation 2000;101:1409-1417. 65. Zipes DP, Knope RF. Electrical properties of the thoracic veins. Am J Cardiol 1972; 29:372-376. 66. Spach MS, Barr RC, Jewett PH. Spread of excitation from the atrium into thoracic veins in human beings and dogs. Am J Cardiol 1972;30:844-854. 67. Nathan H, Eliakim M. The junction between the left atrium and the pulmonary veins. An anatomic study of human hearts. Circulation 1966;34:412-422. 68. Natale A, Pisano E, Shewchik J, et al. First human experience with pulmonary vein isolation using a through-the-balloon circumferential ultrasound ablation system for recurrent atrial fibrillation. Circulation 2000;102:1879-1882. 69. Scheinman MM, Morady F. Nonpharmacological approaches to atrial fibrillation. Circulation 2001;103:2120-2125.

Chapter 29 Mapping of Atrial Fibrillation: Clinical Observations Riccardo Cappato, MD, Sabine Ernst, MD, Feifan Ouyang, MD, and Karl-Heinz Kuck, MD

Introduction Atrial fibrillation (AF) is the most common arrhythmia in humans and is associated with a considerable morbidity rate.1-4 Increased overall mortality rate is also reported in patients with AF; however, there is disagreement as to whether this arrhythmia is an independent risk factor in terms of prognosis.5-8 Elderly, sedentary patients are often unaware that they have AF and are unlikely to show any functional benefit from restoration of sinus rhythm. Conversely, young, active individuals who have no identifiable structural disease may complain of reduced exercise capacity and decreased quality of life during AF. Restoration of sinus rhythm has proven efficacious in increasing physical performance in a limited series of patients with lone AF, and has been associated with a marked increase of left ventricular ejection fraction in patients with significantly impaired left ventricular function secondary to idiopathic dilated cardiomyopathy.9

Severe cardiomyopathy may also develop because of permanent rapid AF10; in such cases, complete recovery after reversion to sinus rhythm has been reported.11 Clinical Observations Although systematic comparisons are lacking, empirical observations suggest that paroxysmal AF may be the variant of this arrhythmia that is most often debilitating. The abrupt changes in heart rhythm and rate surrounding the onset and offset of paroxysmal AF represent an unusually stressful burden on the circulatory system and cause a spectrum of symptoms ranging from severe dyspnea during AF to syncope in the immediate period that follows return to sinus rhythm. At present, there are no clearly established definitions of paroxysmal AF, nor is the history of paroxysmal AF well defined. The duration of paroxysms may vary from a few minutes to longer than 15 days, and

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; C2003.

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evolution to permanent forms likely Similar conversion rates have been reaccounts for about 20% of cases.12 AF ported following intravenous flecainide,24 occurring in the absence of identifiable propafenone,25 sotalol,26 and amiodarone.27 heart disease, or "lone AF," carries an In these patients, sinus rhythm is maintained excellent prognosis; in patients younger in more than 50% of cases.25,28,29 In case of than 60 years at time of diagnosis, the failure to maintain sinus rhythm, a number survival is excellent and the cumulative of drugs can be used to control ventricular rate, including digitalis,B-adrenergicblockers, rate of stroke is 1.3%.13 and calcium channel blockers. Restoration and Maintenance Invasive Therapy for AF of Sinus Rhythm The 2 most important reasons to eliminate AF and restore sinus rhythm are: (1) restitution of mechanical atrial activity, and (2) reduction of risk of thromboembolism. Approximately 50% of patients with new-onset AF will convert spontaneously to sinus rhythm within 48 hours of presentation.14 When accomplished pharmacologically or electrically, cardioversion to sinus rhythm should be preceded by a 4-week period of full anticoagulation.15 To minimize the incidence of thromboembolism, conservative guidelines suggest proceeding with postcardioversion anticoagulation for 2 to 3 weeks after return of sinus rhythm; this approach appears justified due to the delay in restitution of left atrial function to a normal status observed in some patients.16,17 The success rate of cardioversion attempts is quite dependent on patient selection. Firmly established determinants of successful return to sinus rhythm on a short- and long-term basis are limited enlargement of left atrium, shorter duration of AF, a conversion with medication alone, and continuation of antiarrhythmic drug therapy.18-22 Several antiarrhythmic drugs that affect atrial electrophysiology can terminate or prevent AF. These include quinidine, procainamide, disopyramide, propafenone, sotalol, flecainide, and amiodarone. Oral quinidine up to 1200 mg in 6 hours is associated with a 70% acute success rate.23

Alternative treatments to drug therapy have been introduced for control of rapid ventricular response to AF; they include surgical procedures to prevent recurrence of AF,30-32 and atrioventricular (AV) nodal ablation followed by pacemaker implantation33,34 to relieve symptoms associated with rapid ventricular response. The clinical efficacy of these techniques appears satisfactory; however, both of these nonpharmacological approaches have drawbacks, including the risk and morbidity associated with open-heart surgery and the development of pacemaker dependency associated with AV nodal ablation. Radiofrequency (RF) current catheter "modification" of AV nodal conduction has been proposed as an alternative strategy for the control of rapid ventricular response to AF35,36; this technique, which essentially consists of impairment of AV nodal conduction produced by thermocoagulative lesions brought onto the right posteroseptal to midseptal AV region, proved efficacious in 70% to 80% of cases during intermediate follow-up. An inherent limitation of AV nodal modification is its inability to alleviate symptoms related to rate irregularity or reduced exercise tolerance due to loss of atrial contribution to cardiac output. In addition, the clinical data reported at present concentrate on relatively small series and are in need of confirmation by means of large-scale trials.

MAPPING OF ATRIAL FIBRILLATION Electrophysiological Substrate of AF The mechanisms underlying AF in humans are not yet fully understood. The prevalent hypothesis, based on a large bulk of experimental data, suggests that AF is based on multiple wavelets wandering around natural anatomical obstacles and functional arcs of block.37-39 Studies in humans have confirmed the reentrant nature of AF with possible macroreentrant and microreentrant circuits sustaining different episodes or different phases within a single episode.40 It has long been recognized that for perpetuation of true AF, a critical mass of myocardial tissue is required.41,42 This explains why hearts of small animals such as the rat, rabbit, and cat exhibit a high tendency to recover spontaneously from atrial and even ventricular fibrillation.43 Based on these assumptions, surgical techniques were developed to produce multiple incisions in the atrial tissue.30-32 Surgical interventions have proven that AF can be prevented if multiple incisions are made within both the right and left atria. The aim of these interventions is to either electrically isolate segments of the atrium or reduce the muscular mass to such an extent that the atria become too small to sustain fibrillation. The Maze design for surgical atrial compartmentalization proved efficacious in 98% of 75 patients with paroxysmal or permanent AF.44 The operative death rate was 1.3% and the incidence of postoperative complications was similar to that for other types of open-heart surgery. During follow-up, all patients had restoration of AV synchrony, and 60% had acceptable sinus node chronotropic function; importantly, restoration of atrial transport function could be demonstrated in all patients. Despite these encouraging figures, cardiac surgery for the cure of AF remains

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indicated in very selected patients and should be performed in highly qualified centers. Use of RF Catheter Ablation to Produce Linear Atrial Lesions The advent of catheter ablation using RF current has provided electrophysiologists with the means to cure patients suffering from several forms of cardiac arrhythmias.45-53 The presumed mechanism of myocardial injury in response to RF current delivery is thermal. In addition, it has been suggested that the oscillating electromotive force may exert a direct effect on the myocyte sarcolemmal membrane. Thermal coagulation of about 100 mm3 of the target tissue occurs in response to electrode-tissue interface temperatures of approximately 50°C or more during a single pulse. The uniform nature and the small volume of the lesion likely account for the low rate of reported acute and late arrhythmic and nonarrhythmic complications from RF current catheter ablation. Because of the discrete nature of the lesions it brings on, RF current provides optimal results in the therapy of arrhythmias associated with a small arrhythmogenic substrate. The feasibility of producing linear lesions from the endocardial aspect of the atria would offer the possibility to replicate a Maze procedure or any equivalent strategy without the need for thoracotomy. The efficacy of this strategy in atrial flutter has been demonstrated, as linear lesions crossing the isthmus between the tricuspid annulus and the orifice of the inferior vena cava (TA-IVC isthmus) cannot only terminate atrial flutter, but are also associated with an event-free follow-up.52 Lesions in the TA-IVC isthmus are aimed to provide a continuous anatomical obstacle in a portion of the

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atrial circuit crucial to the propagation Preliminary experience in humans of the electrical wavefront sustaining has shown that replication of the Maze macroreentry. Given the presently avail- procedure from the endocardium may terable catheter techniques, linear lesions minate acutely permanent AF.56 In their in the TA-IVC isthmus are achieved pivotal report, Swartz and co-workers56 either by stepwise movements of the abla- used 8 long intravascular introducers, tion catheter preceding a new pulse appli- which conformed a conventional 7F ablacation, or by continuous movement of the tion catheter to be guided along 4 precatheter during RF current delivery. Elec- designed linear lesions in the right trical insulation at either side of the atrium, 3 in the left atrium, and 1 in the linear lesion produced by RF current can interatrial septum. Progressive change of be assessed by analyzing the activation AF to regular intra-atrial tachycardia of sequence of closely spaced bipolar elec- increasing cycle length was observed as trograms recorded at 1 of the 2 atrial the number of linear lesion was increased. regions adjacent to the TA-IVC isthmus Restoration of sinus rhythm required (i.e., the midlateral right atrium and completion of all 8 ablation lines. Intra-atrial mapping has allowed proximal coronary sinus) in response to pacing from the other region during sinus identification of focal mechanisms initirhythm. Compared to preablation, pacing ating and perpetuating AF.57 Although from one site after electrical insulation usually guided by intracardiac mapping in the TA-IVC isthmus will result in a during atrial extra beats originating from change of the activation sequence, delay, the target focus, RF ablation may occaand/or morphology of sequential electro- sionally be attempted during AF. The grams recorded at the other. Due to the prevalence of a focal mechanism as a trigpresence of a line of block along the short- ger of paroxysmal AF remains to be deterest anatomical route, the propagation mined. However, it is reasonable to expect wavefront will now invade the area that the majority of patients with this immediately distal to the block through a arrhythmia (particularly in the presence different and longer route. of an underlying heart disease) as well as those with permanent AF would require a compartmentalization technique for curative purposes. RF Catheter Ablation in AF Animal models of AF have served as a gold standard to assess the influence of Catheter Techniques to Replicate linear lesions produced in the atria on Atrial Compartmentalization the arrhythmia characteristics. In one canine model, the continuity of atrial The experience developed with the lesions produced from the superior vena cure of atrial flutter shows that RF curcava to the IVC and from the superior rent is efficacious and safe to produce vena cava to the tricuspid ring proved linear lesions in the human atrium.52 crucial to reproducibly reduce the length Still, the TA-IVC isthmus represents a of induced AF from longer than 3 minutes 2-dimensional substrate, as its short course to a few seconds.54 In the presence of good and smooth surface may be approximated catheter-tissue contact, power require- to a straight layer; this limits the possiments to produce transmural lesion in the bility of simply extrapolating the experiatrial tissue appear to require no more ence developed with RF lesions produced than 15 W of RF power.55 in the TA-IVC isthmus to other regions in

MAPPING or ATRIAL FIBRILLATION 581 the atria, where a more convex configuration and an irregular course and anatomy of the target wall can be found. The use of catheter techniques for replication of the Maze procedure from the endocardium has several advantages: if efficacy and safety were proven, it provides a curative tool for a potentially large number of patients. Compared to surgery, it allows more time for completion of the technical procedure, including mapping of the electrophysiological substrate and ablation. At present, replication of the Maze technique from the endocardial side does not allow us to fully interpret the nature of changes produced on the electrophysiological substrate. Production of linear RF ablation designs using fluoroscopy is inherently limited by the poor reproducibility of catheter positioning at preselected sites and the inadequacy of the presently used point-to-point RF pulse delivery modality. In the latter case, conduction gaps along the intended severing line may persist; identification and ablation of such sites is mandatory to maximize acute success and minimize recurrence in the therapy of macroreentrant atrial tachycardia. Given the present limitations in mapping and ablation of AF, new mapping and catheter techniques are demanded. Nonfluoroscopic Catheter-Based Mapping to Guide RF Atrial Compartmentalization The technical characteristics pertaining to nonfluoroscopic catheter-based mapping (CARTO, Biosense Webster, Diamond Bar, CA) are described in chapter 5 of this book. In brief, this is an electrophysiological navigation system consisting of a location pad, a CARTO processor, a monitor, a workstation (Silicon Graphics Inc., Mountain View, CA) and a 7F mapping/ ablation catheter equipped with a location

sensor encased close to the tip (Navistar CARTO, Biosense Webster). Weak electromagnetic energy is constantly radiated from 3 pods mounted on a triangular frame located beneath the patient's table. The real time, high-resolution, miniature location sensor incorporated into the catheter reports in 6 degrees of freedom its location and orientation, thus enabling tracking of the catheter tip while it is deployed in the targeted chamber. While sampling a multitude of points (sequential mapping), a dedicated algorithm is able to generate and display in real time on a monitor the 3-dimensional structure reproducing the endocardial contour of the targeted chamber relative to an anatomical (fixed) fiducial point. The reconstructed chamber contour is depicted in color code (rainbow spectrum) reflecting the correspondent electrophysiological information recorded at any point during mapping.58 The use of nonfluoroscopic catheterbased mapping in patients with AF allows clinical applicability in 2 separate directions: (1) definition of cycle length distribution in several regions within the mapped chamber during AF, and (2) identification of the anatomical contour of the chamber to be compartmentalized during sinus or paced regular rhythm. Mapping of Cycle Length Distribution During AF Using a dedicated algorithm, the system59 allows reconstruction of the fibrillating chamber by annotating pertinent cycle lengths of local activation potentials recorded at different sites. To this aim, the Navistar catheter is positioned at a given site and local recording is performed for 45 s, after which the catheter is moved to a new position within the targeted chamber. By collecting the electrical information at any point, the algorithm is able to reconstruct the endocardial contour of

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the mapped chamber, superimposed with a color-coded map (rainbow spectrum, with red representing the shortest and purple the longest local cycle length) of pertinent mean cycle lengths. Following acquisition of all intra-atrial points, annotated electrograms are screened for postprocessing by the operator, and corrections are applied when deemed appropriate. Preset values of minimal sampled cycle length and potential amplitude threshold can be manually selected to possibly eliminate the influence produced by signal originating away from the recording site. Distributions of

cycle lengths over the 45-s sampling time are displayed for each recorded site. Using the CARTO mapping system during the ongoing arrhythmia, we investigated the distribution of cycle lengths within 20 predefined anatomical segments of the left atrium (Figure 1) in 6 patients with drug-refractory paroxysmal lone AF.58 Automatic values of 77-ms minimal cycle length and a bipolar potential amplitude threshold of 25% the maximal amplitude recorded at that same site during the 45-s sampling time were preset. Based on their morphological characteristics, local

Figure 1. Schematic representations of the anterior (A) and posterior (B) view of the left atrium. The chamber is arbitrarily divided into 20 anatomical segments and cycle length distribution of sampled atrial fibrillation phases are taken from every segment.

MAPPING OF ATRIAL FIBRILLATION electrograms were classified as follows: type A = regular local activation potentials separated by a clear isoelectric baseline; type B = irregular local activation potentials with perturbations of the isoelectric baseline and/or highly fragmented electrograms with no identification of isoelectric baseline; type C = alternation of type A and B electrograms throughout the allotted sampling time. An example of the 3 different electrogram patterns with the correspondent cycle length histograms is given in Figure 2. Out of 217 sites sampled, 27.3% presented type A, 9.7% type B, and 63.1% type C electrogram patterns; of note, clusters of type A patterns were found significantly more often (22%) in the region surrounding the upper lateral pulmonary vein (cycle length 191 ± 34 ms) than in any other atrial region, whereas the remaining 2 patterns resulted homogeneously distributed throughout all investigated atrial regions. Predominance of type C electrograms in patients with paroxysmal lone AF is suggestive of dynamic patterns of local activation including either wandering leading wavelets or passive bystander activation. Given the absence of pacing maneuvers at recording sites and the characteristics of mapping (multisite sequential and not simultaneous) by means of the CARTO system, it is not possible to assess the true nature of the recorded electrograms. However, identification of specific areas using this catheter technique may help to target selective ablation for curative purposes. Mapping of Cardiac Chamber During Regular Rhythm to Guide Atrial Compartmentalization Using a dedicated algorithm, the CARTO system allows reconstruction of the target chamber by annotating pertinent local activation potentials recorded

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at different sites during sinus or paced (regular) rhythm. To this aim, the Navistar catheter is positioned at a given site and local recording is performed for 2 to 3 regular cycles reflecting stable cathetertissue contact. After collection of the local activation potential at several points, the reconstructed chamber contour is depicted in color code (rainbow spectrum, with red representing earliest and purple latest local activation) reflecting the correspondent electrical information recorded at any point relative to a fixed time reference. An example of color-coded maps or the right and left atrium obtained during coronary sinus pacing in a patient with paroxysmal lone AF is shown in Figure 3. Dedicated software allows depiction of the intended lines for Compartmentalization superimposed onto the chamber anatomy (Figure 4). Guided by the line design, the Navistar catheter is then navigated to the target region and point-by-point RF current is delivered until ablation along the whole line has been achieved. Criteria deemed sufficient for RF discontinuation at any point include abatement of local potential amplitude by 60% to 70% of the baseline value. Upon completion of the Compartmentalization model, a new mapping of the target chamber is performed to assess the electrophysiological changes provided in electrical activation and to possibly validate the continuity and the transmurality of the lesions produced. Right Atrial Compartmentalization A possible design to obtain effective Compartmentalization of the right atrium is illustrated in Figure 4A. It consists of 3 ablation lines: 1 bridging the isthmus between the orifice of the IVC and the TA (isthmic line); 1 in between the orifices of the 2 caval veins (intercaval line) leaving a 2- to 3-cm conduction gap in its superior segment for physiological propagation of

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Figure 2. Electrogram patterns (left) and corresponding cycle length histograms (right) representative of type A, type B, and type C atrial fibrillation as classified based on morphological characteristics. For each type, unipolar and bipolar electrograms are shown in the upper and lower row, respectively. Note the different mean cycle lengths (CLs) and peak distribution associated with the 3 different types of atrial fibrillation.

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Figure 3. Color-coded electroanatomical reconstruction of the right (A) and left (B) atrium in 2 patients with paroxysmal atrial fibrillation, obtained during constant pacing from the distal coronary sinus as viewed from a left anterior oblique projection. A. SCV and I VC delineate the orifice of the superior and inferior vena cava, respectively. The brown circle identifies the tricuspid annulus (TA), and the yellow tube the proximal coronary sinus (CS). A pink dot outlines the site of His bundle recording (His). Mapping is performed after production of the cavotricuspid ablation line. Note that the earliest activation (in red) occurs in the inferoseptal right atrium 25 ms after the CS stimulus and propagates around the TA in a counterclockwise direction. The latest activation (in purple) recorded 244 ms after the CS stimulus in the cavotricuspid isthmus, adjacent to the site of earliest activation, denotes the presence of a radiofrequency-produced conduction block within the isthmus. B. The 4 pulmonary veins (PV) are outlined by means of tubular-shaped structures, whereas the brown circle delineates the mitral annulus (MA). Electrical activation originates in the inferolateral wall, adjacent to the stimulation site within the CS and propagated homogeneously within the left atrium. Note that the latest activation is recorded at the orifice of the superoseptal (sup. sept) PV. inf. = inferior; lat. = lateral. See color appendix.

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Figure 4. Superimposition of ablation lines onto the anatomical profiles of the right (A) and left (B) atrium in 2 patients with paroxysmal atrial fibrillation. A. Outlined with pink dots are the anterior line (between the tricuspid annulus [TA] and the superior vena cava [SVC]), the isthmus line (between the TA and the IVC), and the intercaval line (between the SVC and the inferior vena cava [IVC]). Note that a conduction gap is intentionally left in the superior segment of the intercaval line in order to allow physiological propagation of sinus impulses to the atrioventricular node. B. Outlined in pink are the "pulmonary" lines encircling the 4 pulmonary veins (PV) and the linear line connecting the mitral annulus (MA) to the closest segment of the "pulmonary" line (PVMA). Other abbreviations as in Figure 3. See color appendix.

MAPPING OF ATRIAL FIBRILLATION sinus impulses to the AV node; and 1 between the orifice of the superior caval vein and the superior aspect of the TA, at least 1 cm away from the location of the compact AV node (anterior line). From our experience, a number of RF pulses (preset duration 180 s) ranging between 20 and 55 may be required to obtain the intended compartmentalization. Procedure duration may range between 6 and 9 hours, whereas the fluoroscopy time may be as short as 6 minutes. Although it may be substituted with any alternative design, the proposed one has several advantages: a clinical familiarity with the creation of the isthmic line, as required for the cure of atrial flutter; the possibility to validate the continuity and transmurality of the ablation line by means of conventional recording techniques (multisite recording along the right atrial free wall), and the ease of manipulation by means of catheter dragging along the intended line (using a right femoral approach for the isthmic and intercaval line and a right jugular approach for the anterior line). Given the investigational nature of the technique and the design, we found that these requisites facilitate achievement and validation of the intended compartmentalization model; this is mandatory to interpret the clinical efficacy of the proposed therapy and to secure its reproducibility. Parallel use of conventional recording techniques at this investigational stage may help to define the criteria validating achievement of the compartmentalization model, as observed with the nonfluoroscopic mapping system. In addition, based on the assumption that assessment of the clinical impact produced by the ablation design requires an unaltered electrophysiological and bioumoral substrate, patients are discharged from the hospital undergoing the same antiarrhythmic regimen as at the time indication to RF ablation was set.

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Fulfillment of the electrophysiological criteria for right atrial compartmentalization according to the model presented above can be achieved in about 60% of patients with drug-refractory paroxysmal lone AF who are undergoing atrial compartmentalization by nonfluoroscopic mapping, whereas in the remaining patients, either unintended conduction gaps can be observed or postablation "remap" cannot be performed because of ensuing AF. In the 6 months following right atrial compartmentalization, symptomatic improvement can be observed in about 30% of patients, although maintenance of stable sinus rhythm is rarely recorded (<10% in our experience). Underlying rhythms in patients reporting symptomatic improvement include occasional atrial ectopy, junctional escape, or a decreased frequency and/or duration of AF episodes. Worsening of symptoms has, in our experience, been observed in less than 10%. Of interest, in subgroups of patients developing either permanent or transient complete isolation of the sinus node from the AV node, AF can be documented during follow-up; during the clinical arrhythmia, the right atrium exhibits ECG findings suggestive of sinus node activation (Figure 5). Left Atrial Compartmentalization A possible design to obtain effective compartmentalization of the left atrium is illustrated in Figure 4B. It consists of 2 lines; 1 encircling the orifices of the 4 pulmonary veins (pulmonary line), and 1 connecting the mitral annulus to the closest segment of the encircling line (linear line). Access to the left atrium is acquired by way of a patent foramen ovale or a transseptal puncture using the Brockenbrough technique. Compared to the right atrium, careful mapping of left atrial activation is limited using conventional recording

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Figure 5. Surface ECG leads II and V1 and 2 endocardial leads in a patient during an episode of paroxysmal atrial fibrillation after radiofrequency isolation of the right atrium. Left atrial fibrillatory activity is recorded by the distal bipole of the electrode catheter advanced in the coronary sinus (CS) while sinus rhythm is observed from the electrode bipole located in the high right atrium (RA). Note that distinct P waves (arrows) can be recorded on the surface ECG simultaneous with the endocardial RA deflection.

techniques, as only 1 catheter can be advanced to the endocardial wall; to partially overcome this limitation, mapping of the apicardial AV annulus is systematically performed using a multipolar catheter advanced to the distal great cardiac vein via a left subclavian approach. In addition, achievement of firm and stable catheter-tissue contact for effective RF pulse delivery may be especially difficult along the septum, the lower septal pulmonary vein, and the anterior left atrial wall. Also, the atrial wall in the left atrium is thicker than in the right atrium; this may account for a higher rate of discontinuity in the intended transmural linear compartmentalization model. A number of RF pulses ranging between 38 and 60 may be required to obtain the intended compartmentalization according to our experience. Procedure duration may range between 6.6 and 9.2 hours. In patients receiving a left atrial compartmentalization, postablation electro-

physiological evidence of substantial changes in the intra-atrial activation can be observed in about 30% of cases. This finding is associated with a reduced incidence of clinical events during the first month of follow-up; the underlying rhythm in such cases is either regular atrial tachycardia or AF. In those patients whose postablation electrophysiological activation is unchanged, no changes in symptoms and AF frequency and/or duration are commonly noted during follow-up. Right and Left Atrial Compartmentalization In patients presenting an unsatisfactory outcome following a single-chamber compartmentalization, combined right and left atrial compartmentalization can be attempted. Using this approach, improvement in symptoms and AF frequency and/or duration can be noted during an 11-month follow-up in about 75% of patients, with

MAPPING OF ATRIAL FIBRILLATION complete restitution to sinus rhythm in about 20%, atrial ectopy in about 10%, recurrent regular atrial tachycardia in about 10%, and reduced AF frequency and/ or duration in about 35%. In patients who require pacemaker implantation because of late development of sinus node isolation, clinical improvement has been reported with the artificial rhythm. Unchanged or worsened symptoms can be observed in approximately 25% of patients following a biatrial compartmentalization. Hazards and Complication Associated with RF Atrial Compartmentalization The long procedure time and the large number of RF pulses required to achieve compartmentalization demand careful assessment of safety. Thromboembolic risk can be minimized by a careful screening of the candidates using transesophageal echocardiography; intra-atrial thrombi or iperechogeneity should represent contraindications to the therapeutic procedure. Full (oral) anticoagulation should precede, accompany (intravenous), and follow (oral) the scheduled procedure. Also, to minimize the risk of coagulum formation during RF pulse delivery, power should be titrated such that an initial decrease of 5 to 10 O in impedance is achieved and maintained throughout the duration of current delivery. In our experience, a total of 9 pulses delivered in the left atrium were associated with sudden impedance rise of no clinical consequence. Some complications are related to the complexity of the procedure. RF ablation pulses should be delivered well away from the sinus and the AV nodes to avoid permanent damage. Also, complete isolation of the sinus node from the AV conduction system may be observed some days after right atrial compartmentalization; given the presence of conduction gaps along 1 of

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the 3 intended (most commonly the intercaval) lines and the possibly transient nature of isolation, one may speculate that anisotropic conduction along the superior intercaval atrial region, together with late extension of RF-related damage, plays a role to produce this effect. Other complications, such as uneventful pericardial effusion, tamponade, retroperitoneal hematoma, pneumothorax, and false aneurysm of a femoral artery are rather related to the invasive nature of the therapeutic procedure.

Summary

Use of nonfluoroscopic mapping provides a meaningful tool to identify the anatomical substrate to be selected for complex ablation designs. Complimentary conventional recording techniques add important reference to provide validation standards for nonfluoroscopic mapping. In this investigational phase, selection of patients with the simplest substrate (paroxysmal lone AF) and the heaviest clinical impact (frequent episodes, drug refractory) is of utmost importance to justify the procedure-related risks and evaluate clinical impact. Preliminary results show that right atrial compartmentalization (whether alone or in combination with left atrial compartmentalization) using an arbitrarily selected design is safe, effectively changes intra-atrial activation patterns, and provides meaningful, although not sufficient, clinical benefit in a significant proportion of patients. Inefficacy of left atrial compartmentalization is likely related to the limitations of the present technology concerning catheter manipulation within the left atrium and, consequently, energy delivery. New catheter techniques as well as improved energy sources and delivery modalities may consistently improve the clinical impact of this strategy to provide a curative treatment for AF.

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References 1. Petersen P, Godtfredsen J. Atrial fibrillation: A review of course and prognosis. Ada Med Scand 1984;216:5-9. 2. Alpert JS, Petersen P, Godtfredsen J. Atrial fibrillation: Natural history, complications and management. Annu Rev Med 1988;39:41-45. 3. Kannel WB, Abbott RD, Savage DD, et al. Epidemiologic features of chronic atrial fibrillation. The Framingham study. N EnglJMed 1982;307:1018-1022. 4. Brand FN, Abbott RD, Kannel WB, et al. Characteristics and prognosis of lone atrial fibrillation. Thirty-year follow-up in the Framingham study. JAMA 1985; 254:3449-3453. 5. Unverferth DV, Magorien RD, Moeschberger ML, et al. Factors influencing the oneyear mortality of dilated cardiomyopathy. Am J Cardiol 1984;54:147-152. 6. Romeo F, Pelliccia F, Cianfrocca C, et al. Predictors of sudden death in dilated cardiomyopathy. Am J Cardiol 1989;63: 138-140. 7. Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in advanced heart failure. Circulation 1991;84:40-48. 8. Carson PE, Johnson GR, Dunkman WB, and the V-HeFT VA Cooperative Studies Group. The influence of atrial fibrillation on prognosis in mild to moderate heart failure. Circulation 1993;87:VI102-VI110. 9. Kieny JR, Sacrez A, Facello A, et al. Increase in radionuclide left ventricular ejection fraction after cardioversion of chronic atrial fibrillation in idiopathic dilated cardiomyopathy. Eur Heart J 1992; 13:1290-1295. 10. Grogan M, Smith HG, Gersh BJ, et al. Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy. Am J Cardiol 1992;69:1570-1573. 11. Peters KG, Kienzle MG. Severe cardiomyopathy due to chronic rapid atrial fibrillation: Complete recovery after reversion to sinus rhythm. Am J Med 1988;85: 242-244. 12. Takahashi N, Seki A, Imataka K, et al. Clinical features of paroxysmal atrial fibrillation. An observation of 94 patients. Jpn Heart J 1981;22:143-149. 13. Kopecky SL, Gersh BJ, McGoon MD, et al. The natural history of lone atrial

fibrillation. A population-based study over 3 decades. NEngl JMed 1987;317:669-674. 14. Falk RH, Knowlton AA, Bernard SA, et al. Digoxin for converting recent-onset atrial fibrillation to sinus rhythm: A randomized, double blinded trial. Ann Intern Med 1987;106:503-506. 15. Bjerkelund CJ, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation. Am J Cardiol 1969;23:208-216. 16. Ikram H, Nixon PGF, Arcan T. Left atrial function after electrical cardioversion to sinus rhythm. Br Heart J 1968;30:80-83. 17. Jordaens L, Missault L, Germonpre E, et al. Delayed restoration of atrial function after conversion of atrial flutter by pacing or electrical cardioversion. Am J Cardiol 1993; 71:63-67. 18. Henry WL, Morganroth J, Pearlman AS, et al. Relation between echocardiographically determined left atrial size and atrial fibrillation. Circulation 1976;53:273-279. 19. Byrne-Quinn E, Wing AJ. Maintenance of sinus rhythm after DC reversion of atrial fibrillation. Br Heart J 1970;32:370376. 20. Sodemark T, Yansson B, Olson A, et al. Effect of quinidine on maintaining sinus rhythm after conversion of atrial fibrillation or flutter. A multicenter study from Stockholm. Br Heart J 1975;37:486-492. 21. Hartel G, Louhija A, Konttinern A, et al. Value of quinidine in maintenance of sinus rhythm after electric cardioversion of atrial fibrillation. Br Heart J 1970;32:57-60. 22. Hollested L, Bjelkelund C, Dole J, et al. Disopyramide in the maintenance of sinus rhythm after electroversion of atrial fibrillation. A placebo-controlled one-year follow-up study. Eur Heart J1988;9:284290. 23. Holzman D, Brown MG. The use of quinidine in established auricular fibrillation and flutter. Am JMed Sci 1951;222:664671. 24. Goy JJ, Grbic M, Hurni M, et al. Conversion of supraventricular arrhythmias to sinus rhythm using flecainide. Eur Heart J l985;6:518-523. 25. Connolly SJ, Hoffert DL. Usefulness of propafenone for recurrent paroxysmal atrial fibrillation. Am J Cardiol 1989;63: 817-819. 26. Juul-Moller S, Edvardsson N, RehngvistAhlberg N. Sotalol versus quinidine for

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the maintenance of sinus rhythm after 37. Allessie MA, Lammers WJEP, Smeets JRLM, et al. Experimental evaluation of direct current conversion of atrial fibrilMoe's multiple wavelet hypothesis of lation. Circulation 1990;82:1932-1939. atrial fibrillation. In: Zipes DP, Jalife J 27. Gronda M, Occhetta E, Magnani A, (eds): Cardiac Arrhythmias. New York: et al. Cardioversione del flutter e delta Grune & Stratton; 1985:265-276. fibtillazione atriale. G Ital Cardiol 1982; 38. Allessie MA, Rensma PL, Lammers 12:628-633. WJEP, et al. The role of refractoriness, 28. Pritchett ELC, Da Torre SD, Platt ML, conduction velocity, and wavelength in et al. Flecainide acetate treatment of initiation of atrial fibrillation in normal paroxysmal supraventricular tachycardia conscious dogs. In: Attuel P, Coumel P, and paroxysmal atrial fibrillation: DoseJanse MJ (eds): The Atrium in Health and response studies. The Flecainide SupravenDisease. Mt. Kisco, NY: Futura Publishing tricular Tachycardia Study Group. J Am Coll Co.; 1989:27-41. Cardiol 1991;17:297-303. 29. Antman EM, Beamer AD, Cantillon CO, 39. Kirchhof CJHJ, Chorro F, Scheffer GJ, et al. Regional entrainment of atrial fibrillation et al. Long-term oral propafenone therstudied by high-resolution mapping in apy for suppression of refractory symptoopen-chest dogs. Circulation 1993;88:736matic atrial fibrillation and atrial flutter. 749. J Am Coll Cardiol 1988;12:1005-1011. 30. Guiraudon GM, Campbell CS, Jones DL, 40. Konings KTS, Kirchhof CJHJ, Smeets JRLM, et al. High-density mapping of et al. Combined sino-atrial node atrielectrically induced atrial fibrillation in oventricular isolation: A surgical alternahumans. Circulation 1994;89:1665-1680. tive to His bundle ablation in patients with atrial fibrillation. Circulation 1985; 41. Mines GR. On dynamic excitation in the heart. J Physiol 1913;46:349-382. 72(3):220. 31. Defauw JJAMT, Guiraudon GM, van 42. Garrey WE. The nature of fibrillary contraction of the heart. Its relation to tissue Hemel NM, et al. Surgical therapy of mass and form. Am J Physiol 1914;33: paroxysmal atrial fibrillation with the 497-508. "corridor" operation. Ann Thorac Surg 1992; 43. On circulating excitation in heart muscle 53:564-571. and their possible relation to tachycardia 32. Cox JL, Boineau JP, SchuBler RB, et al. and fibrillation. Trans R Soc Can 1914;8: Five-year experience with the Maze pro43-52. cedure for atrial fibrillation. Ann Thorac 44. Ferguson TB Jr., Cox JL. Surgery for Surg 1993;56:814-824. atrial fibrillation. In: Zipes DP, Jalife J 33. Kay GN, Bubien RS, Epstein AE, Plumb (eds): Cardiac Electrophysiology: From Cell VJ. Effect of catheter ablation of the atrito Bedside. Philadelphia: W.B. Saunders; oventricular junction on quality of life and 1995:1563-1576. exercise tolerance in paroxysmal atrial fibrillation. Am J Cardiol 1988;62:741- 45. Jackman WM, Wang X, Friday KJ, et al. Catheter ablation of accessory atrioven744. tricular pathways (Wolff-Parkinson-White 34. Rodriguez LM, Smeets JLRM, Xie B, et al. syndrome) by radiofrequency current. N Improvement in left ventricular function EnglJMed 1991;324:1605-1611. by ablation of atrioventricular nodal conduction in selected patients with lone 46. Kuck KH, Schluter M, Geiger M, et al. Radiofrequency current catheter ablation atrial fibrillation. Am J Cardiol 1993;72: of accessory atrioventricular pathways. 1137-1141. Lancet 1991;337:1557-1561. 35. Williamson BD, Man KC, Daoud E, et al. Radiofrequency catheter modification of 47. Jackman WM, Beckman KJ, McClelland JH, et al. Treatment of supraventricular atrioventricular conduction to control the tachycardia due to atrioventricular nodal ventricular rate during atrial fibrillation. reentry by radiofrequency catheter ablaNEnglJMed 1994;331:910-917. tion of slow pathway conduction. N Engl 36. Chen SA, Lee SH, Chiang CE, et al. ElecJMed 1992;327:313-318. trophysiological mechanisms in successful radiofrequency catheter modification of 48. Walsh E, Saul JP, Hulse JE, et al. Transcatheter ablation of ectopic atrial tachyatrioventricular junction for patients with cardia by ablation procedure. Circulation medically refractory paroxysmal atrial fib1992;86:1138-1146. rillation. Circulation 1996;93:1690-1701.

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49. Coggings DL, Lee RJ, Sweeney J, et al. Radiofrequency catheter ablation as a cure for idiopathic tachycardia of both left and right ventricular origin. J Am Coll Cardiol 1994;23:1333-1341. 50. Kalman JM, Van Hare GF, Olgin JE, et al. Ablation of 'incisional' reentrant atrial tachycardia complicating surgery for congenital heart disease: Use of entrainment to define a critical isthmus of conduction. Circulation 1996;93:502-512. 51. Cosio FG, Lopez-Gil M, Giocolea A, et al. Radiofrequency ablation of the inferior vena cavatricuspid valve isthmus in common atrial flutter. Am J Cardiol 1993; 71:705-709. 52. Poty H, Saoudi N, Aziz AA, et al. Radiofrequency catheter ablation of type I atrial flutter: Prediction of late success by electrophysiological criteria. Circulation 1995; 92:1389-1392. 53. Kaltenbrunner W, Cardinal R, Dubuc M, et al. Epicardial and endocardial mapping of ventricular tachycardia in patients with myocardial infarction: Is the origin of the

tachycardia always sub-endocardially localized? Circulation 1991;84:1058-1071. 54. Avitall B, Hare J, Mughal K, et al. Ablation of atrial fibrillation in a dog model. J Am Coll Cardiol 1994;23:276A. 55. Avitall B, Hare J, Krum et al. Radiofrequency ablation of atrial tissues: Power requirements. J Am Coll Cardiol 1994;23: 276A. 56. Swartz JF, Pellersels G, Silvers J, et al. A catheter-based approach to atrial fibrillation in humans. Circulation 1994;90: I-335. 57. Haissaguerre M, Gencel L, Fischer B, et al. Successful catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 1994; 5:1045-1052. 58. Kuck KH, Ernst S, Cappato R, et al. Nonfluoroscopic endocardial catheter mapping of atrial fibrillation. J Cardiovasc Electrophysiol 1998;9:S57-S62. 59. Ben-Haim SA, Osadky D, Schuster I, et al. Nonfluoroscopic, in vivo navigation and mapping technology. Nat Med 1996;2:13931395.

Part 6 Mapping of Ventricular Tachyarrhythmias

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Chapter 30

Substrate Mapping for Ablation of Ventricular Tachycardia in Coronary Artery Disease Timothy W. Smith, D.Phil., MD and Mark E. Josephson, MD

saving but can only treat arrhythmias after they occur. Moreover, ICD implantation Ventricular tachycardia (VT) degen- and therapy is not free of morbidity.4 In erating to ventricular fibrillation is a addition to the risks of implantation, ICD major cause of mortality in patients with shocks are painful and may not prevent coronary artery disease (CAD) and pre- syncope and injury associated with venvious myocardial infarction (MI).1-3 Scar tricular arrhythmias. Many patients require at the site of the healed infarction is additional therapy after ICD implantation, widely believed to provide the substrate to prevent multiple ICD shocks. Surgical or catheter ablation may be for reentry, the most common mechanism of VT in the setting of coronary disease. curative. Ablation therapy requires accurate Typical treatment approaches to location of the origin of the VT. Endocardial patients with coronary disease thought catheter mapping is now well established as to be at high risk for ventricular arrhyth- the primary means of guiding ablation.5,6 mia and sudden cardiac death include the Conventional methods require mapping and use of pharmacological antiarrhythmic pacing during relatively extended periods agents and of implantable cardioverter- (minutes) of VT. This requirement excludes defibrillators (ICDs). Neither of these those patients who have VTs that cause approaches is curative. Antiarrhythmic hemodynamic collapse too rapidly to permit agents may prevent or slow VT, making detailed mapping. This, in part, explains the it more tolerable; however, an efficacy less relatively low success rate of VT ablation.7 than 100% can be lethal. Side effects, Indeed, the vast majority of patients at risk including proarrhythmia, and toxicity also for life-threatening ventricular arrhythmias decrease the utility of currently available cannot undergo conventional mapping and antiarrhythmic agents. ICDs can be life ablation.8 Introduction

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003.

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Since the anatomical substrate (healed MI) is known to correspond to a specific electrophysiological substrate, which can be detected, and in sinus rhythm ablation guided by a substrate map, obtained entirely in sinus rhythm, can prevent VT. New technologies for mapping and ablation have already been major contributors to guidance of catheter ablation therapy. These technologies also have applications in substrate mapping as well as conventional arrhythmia mapping. Application of substrate mapping and ablation during sinus rhythm may ultimately allow curative therapy for many of the large proportion of VT patients who cannot undergo conventional VT mapping and ablation.

Methods of Mapping for VT Mechanism of VT in CAD Reentry is the most common mechanism of VT in the setting of coronary heart disease and healed MI.9 Reentry requires a functional and/or anatomical circuit with a region of unidirectional block and a path of slow conduction through which the excitatory wavefront propagates, allowing the rest of the circuit to recover excitability and perpetuate reentry. Scar tissue in the region of a healed MI has been shown to contain normal myocytes interspersed with connective tissue.10 The heterogeneity of the tissue creates nonuniform anisotropy and slow conduction through the region of scar.11,12 The connective tissue itself and/or its production of functional block due to nonuniform anisotropy is thought to isolate an isthmus through which the wavefront passes. Most of these regions are in the subendocardium of the scar.13 During VT, local electrical activity in this protected isthmus can be detected during diastole using a bipolar recording catheter; occasionally, electrical activity spanning all of diastole can be recorded. Curative surgi-

cal resection has been found to abolish these abnormal electrograms, strengthening the hypothesis that they are closely associated with substrate for VT.14 Conventional Mapping and Ablation Strategies The standard technique for mapping and ablating VT is based on the localizing the protected isthmus and breaking the reentrant circuit by placing an ablation lesion to interrupt the isthmus. Several groups have been instrumental in developing the methods for localizing the critical site for maintenance of reentry, entrainment mapping. 8,15-17 To be a candidate for ablation therapy, the VT should be induced by programmed electrical stimulation, and the VT must be hemodynamically tolerated well enough to complete mapping of the ventricle and to examine the interaction of the VT circuit with further programmed stimulation. Candidate sites are selected on the basis of the ventricular anatomy, the VT morphology, and the presence of diastolic electrical activity. If the response to overdrive pacing at the candidate site is appropriate, the site likely represents a protected isthmus that is a necessary part of the reentrant circuit.17,18 Creation of an ablation lesion that spans the isthmus and therefore causes conduction block in the reentrant circuit will terminate the tachycardia and render it uninducible. Limitations of Entrainment Mapping The primary limitation of entrainment mapping is obvious. If the tachycardia rapidly leads to hemodynamic collapse and the need for immediate termination, entrainment mapping cannot be carried out. Unfortunately, because of the hemodynamic instability of VT, the majority of patients at high risk for VT in CAD cannot readily undergo this method

SUBSTRATE MAPPING FOR ABLATION OF VT IN CAD of mapping and ablation. Alternatives have been suggested, but they all have drawbacks. Administration of an antiarrhythmic agent (e.g., procainamide) can transform polymorphic VT to monomorphic VT so that it may be tolerated for extended periods.19 Similarly, antiarrhythmic agents may slow hemodynamically unstable monomorphic VT to a rate that is tolerable. Unfortunately, the drug may allow inducibility of a VT that is not inducible in the drug-free state. Another method might utilize multiple inductions with short periods of mapping until the tachycardia must be terminated. This technique is highly time consuming and exposes the patient to multiple episodes of hemodynamically unstable VT and multiple cardioversion shocks. Another alternative might be to provide cardiopulmonary support during extended periods of VT. Such a procedure would be expensive and would introduce additional risks and morbidity.

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terms of the QRS morphology at a site of successful ablation in the isthmus.23,24 Substrate Mapping

Substrate mapping is another strategy that may potentially be used to guide ablation therapy for VT. In patients with VT, Cassidy et al.25 found that electrograms in areas of healed MI had recognizable abnormalities that can be seen during sinus rhythm. These abnormalities were not seen in patients with normal left ventricles.26 They examined the abnormalities and categorized the abnormal electrograms as fractionated, late, and abnormally long. Normal left ventricular bipolar electrograms have amplitude greater than 3 mV, duration less than 70 ms, and amplitude/duration ratio greater than 0.045 (Figure 1). Abnormalities have been shown to be present in all patients with previous MI and VT. Further experience with conventional mapping has shown that the site of origin of VT is nearly Pace Mapping always associated with an abnormal elecPace mapping is the technique of trogram.27 Additional work showed that, pacing at potential ablation sites and com- though all patients with coronary disease paring the 12-lead ECG to the ECG of the have abnormal electrophysiological subpatient's clinical and/or induced VT.20 Pace strate, those with VT have more marked mapping should not be confused with abnormalities.28 Furthermore, cardiac entrainment, in which pacing occurs arrest patients with marked substrate during the tachycardia; pace mapping is abnormalities but not inducible VT were performed entirely in sinus rhythm. The found to be at higher risk for clinical recurtechnique has been effective in normal rence of ventricular arrhythmia than those hearts for guiding ablation of idiopathic who did not have abnormal substrate.29 VTs.21,22 However, pace mapping has Finally, endocardial recordings made prior proven disappointing in the setting of CAD to and after subendocardial resection for and MI. Since the scar surrounds the site the treatment of VT revealed diminution of the protected isthmus that may have of the abnormality of the electrograms in several dead-end pathways, pacing from the region of resection.14 The authors of many sites within the scar may produce an this study concluded that fractionated identical QRS morphology to the tachy- electrograms were generated by heterocardia if the wavefront's exit from the scar geneous myocardium and connective tissue is the same as the tachycardia. Moreover, in the resected subendocardium. Recent experience has shown that in VT associ- work in animal models of MI has confirmed ated with CAD, it is rare to find a pacing that the margin of an infarct-related scar site that matches the VT identically in can be identified by qualitative differences

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Image Not Available

Figure 1. Normal and abnormal electrograms recorded in sinus rhythm. Three surface electrocardiographic recordings (leads I, aVF, and V1) and 3 local electrograms (normal, abnormal, and fractionated and late) recorded from different left ventricular endocardial sites. The dotted vertical line denotes the end of the surface QRS activity. The arrows show the onset and offset of local electrical activity. 1-mV calibration bars are shown for each electrogram. Reproduced from reference 25, with permission.

in electrograms recorded from the scar and from surrounding normal myocardium.30,31 These data suggest the potential utility of a substrate mapping strategy to guide ablation therapy for VT in coronary disease. Electrograms can be recorded at multiple sites during sinus rhythm, and areas defined by abnormal electrograms might be resected or ablated to remove the substrate for the tachycardia. Such a procedure would eliminate the need for prolonged periods of VT for mapping. Unfortunately, the specificity of substrate mapping is poor. Cassidy et al.25 concluded in the original work that resection based on substrate mapping was highly likely to result in an excessive amount of myocar-

dial resection. This low specificity almost certainly results from the fact that not all parts of healed infarction are capable of sustaining reentry, though abnormal electrograms can be found throughout the healed infarct. Since conventional catheter ablation is directed at a relatively small single site, substrate mapping is unlikely to be specific enough to direct successful ablation of using standard catheter ablation techniques. However, the sensitivity of abnormal electrogram was found to be 86%.25 This high sensitivity raises the possibility that catheter ablation techniques designed to isolate potential sites of origin of VT can be successful. Such an ablation procedure would have less specific targets

SUBSTRATE MAPPING FOR ABLATION OF VT IN CAD than conventional mapping and ablation. Several ablation lesions, intended to span the infarct border zones, would be made with the intention of interrupting any isthmuses of myocardium that could support VT. Substrate Mapping in Conjunction with New Mapping and Ablation Technologies Substrate mapping with the conventional electrophysiology laboratory tools of fluoroscopy and continuous monitoring of intracardiac electrograms is feasible. When using fluoroscopy alone, however, the substrate map must be assembled as a mental image by the operator. Its accuracy and reproducibility are limited. Long fluoroscopy procedures are potential radiation hazards to the patients and the operators. Several new mapping and catheter navigation systems have the potential to assist in substrate mapping. Magnetic Electroanatomical Mapping One new technology, the CARTO™ electroanatomical mapping system (Biosense Webster, Diamond Bar, CA) uses ultralow magnetic fields to continuously localize the mapping catheter tip in 3-dimensional space. In combination with electrograms recorded by the catheter at multiple sites throughout, the system can develop a map of the ventricle (or any other chamber) based on the timing and location of the electrogram.32-34 The resulting map is displayed on a computer monitor, and since 3-dimensional information is obtained, the map can be viewed from any orientation. The catheter position is also visible on the monitor in real time, superimposed on the map, and the system can be used to guide catheter manipulation. The ability to mark specific points of interest on the map allows for return to a precisely located area of interest to gather more data from nearby sites or for ablation.35 The activa-

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tion map is color coded to display the local activation time of the electrogram at each recorded site. Activation mapping using this system has been very successful for a variety of tachyarrhythmias. An electrogram amplitude map can also be created, with a color-coded display of the electrogram amplitude at each site recorded throughout the chamber. Such a map is shown in Figure 2A for a patient with a previous inferior ML The electrograms of lowest amplitude (red) identify the site of infarction. The border zone of the infarction and the surrounding normal myocardium can be seen. The CARTO system is highly versatile. As described above, after the map is created, it can be displayed as an activation map, an amplitude map, or a purely anatomical map. Figure 2B is an unusual map created from the same data as the map shown in Figure 1A. The map shows duration of the recorded electrograms, calculated from the local activation times of the beginning and end of the electrograms. The longer duration of the electrograms (blue and purple) correlate well to the known area of the infarct and to the low-amplitude electrograms seen in Figure 2A. Original descriptions of abnormal substrate included electrogram amplitude and duration, as well as ratio of duration to amplitude.25 Though versatile, the CARTO system has limitations. The mapping and ablation catheter must be specifically compatible with the system. The map is built one point at a time, which is time consuming. Other Mapping and Navigation Systems In the last few years, other mapping and navigation systems have been developed that have potential utility for substrate mapping. One of these uses a 64-pole noncontact multielectrode array mounted on a balloon catheter and placed in the left ventricle.

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Figure 2. CARTO recorded in sinus rhythm from a patient with previous inferior myocardial infarction. The map is seen from the inferoposterior viewpoint. A. Local electrogram amplitude map. Red regions represent the lowest amplitude electrograms (<3 mV) and correspond to the inferior myocardial infarction. B. Map of duration of local electrograms in the same patient, also from the inferoposterior viewpoint. The longest electrograms were recorded in the blue and purple regions, which correspond to the area of infarction. See color appendix.

SUBSTRATE MAPPING FOR ABLATION OF VT IN CAD The multielectrode array allows reconstruction of 3360 electrograms superimposed on a computer model of the ventricle.36 With this system, the entire endocardial activation can be mapped in a single cardiac cycle. This system was intended for activation mapping during the arrhythmia (and requires one or a very few cycles of the arrhythmia). However, the system could also be used to quickly create a substrate map in sinus rhythm. Other systems use "basket catheters," also with multiple electrodes, allowing rapid construction of maps.37 Another technology that could serve as an adjunct to fluoroscopy is echocardiography. Intracardiac echocardiography catheters that can allow real-time examination of ventricular function and wall motion abnormalities associated with scar are available. The intracardiac echocardiography-guided delineation of infarction related scar correlated well with lowamplitude electrograms and pathological examination in one animal study.31 Some newer systems are directed more toward reproducible catheter navigation than mapping. They use a triangulation system to continuously track electrode location(s) in space, and render a computerized map on a monitor. As with the CARTO system, points of interest, such as those with low-amplitude electrograms, can be marked on the map. The mapping or ablation catheter can then be returned to the marked point. Points of ablation can also be marked, facilitating creation of linear ablation lesions. One of these systems uses ultrasound for localization, and one uses an electrical potential gradient.38,39 Potential Utility of Substrate Mapping for Ablation Therapy for VT The information in a substrate map cannot provide the precise location of the site of origin of VT sought in conventional

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mapping, but rather indicates a region or regions of potential origins. Therefore, a less specific ablation strategy is required. Lesions that prevent propagation of the reentrant wavefront can be produced by encirclement of the area of abnormal substrate or superimposition of a number of linear lesions of the area. In this manner, potential avenues of reentry can be eliminated even if the precise location of a protected isthmus is not known. This approach, creating lines of block in an anatomical region in order to render it incapable of supporting reentry, is analogous to other anatomically guided ablation procedures for different arrhythmias such as typical atrial flutter and the mazelike ablations proposed for atrial fibrillation.40,41 A good substrate map can delineate the region in which such lesions are required to prevent VT. Preliminary work has suggested the feasibility of such an approach using the CARTO system. In one study, the sites of all VTs in 5 patients were within regions of abnormal electrograms and were most closely associated with electrograms of long duration.42 There are also early data indicating that substrate mapping (though it may not be identified as such) can be effectively used for ablation of VTs that are not hemodynamically tolerated.43-45 Many questions remain. For example: 1. How many ablation lesions will be required to prevent VT? 2. Should the lesion pass all the way through a scar, or only through a border zone? 3. Should the lesions connect the scar to normal myocardium or should they be extended to an anatomical barrier? 4. Can gaps in linear lesions allow reentry and be proarrhythmic, as has been seen with atrial linear lesions?46 5. Is better technology for the creation of linear lesions forthcoming?

602 CARDIAC MAPPING Conclusion Substrate mapping has the potential to guide ablation therapy for VT in coronary disease without prolonged periods of VT in the electrophysiology laboratory. This may provide means of curative therapy for patients who cannot undergo conventional mapping procedures. With the current level of experience, substrate mapping and ablation are unlikely to guarantee prevention of arrhythmia, and we acknowledge the utility of ICDs. However, it is clear that ICDs neither cure nor prevent VT. ICD implantation can provide a therapy of last resort that may be life saving, but ideally it should be an adjunct to attempted cure. The majority of VT patients, however, are excluded from conventional mapping and ablation techniques. Substrate mapping may afford these patients the opportunity for curative therapy. Further development of substrate mapping and ablation in sinus rhythm (in conjunction with ICD implantation) is necessary. The alternative is to implant ICDs without attempting to learn better ways to approach prevention and cure of these arrhythmias—a very unsatisfying prospect. References 1. Callans DJ, Josephson ME. Ventricular tachycardias in the setting of coronary artery disease. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia: W.B. Saunders Co.; 1995:732-743. 2. Josephson ME. Recurrent ventricular tachycardia. In: Josephson ME (ed): Clinical Cardiac Electrophysiology: Techniques and Interpretations. 2nd ed. Philadelphia: Lea & Febiger; 1993:417-615. 3. Kempf FC, Josephson ME. Cardiac arrest recorded on ambulatory electrocardiograms. Am J Cardiol 1984;53:1577. 4. Rosenqvist M, Beyer T, Block M, et al. Adverse events with transvenous implan-

table cardioverter-defibrillators: A prospective multicenter study. Circulation 1998;98: 663-670. 5. Josephson ME, Horowitz LN, Spielman SR, et al. Comparison of endocardial catheter mapping with intraoperative mapping of ventricular tachycardia. Circulation 1980; 61:395-404. 6. Josephson ME, Horowitz LN, Waxman HL, et al. Role of catheter mapping in evaluation of ventricular tachycardia. In: Josephson ME (ed): Ventricular Tachycardia: Mechanisms and Management. Mt. Kisco, NY: Futura Publishing Co.; 1982:309-330. 7. Callans DJ, Zado E, Sarter BH, et al. Efficacy of radiofrequency catheter ablation for ventricular tachycardia in healed myocardial infarction. Am J Cardiol 1998; 82:429-432. 8. Morady F, Harvey M, Kalbfleisch SJ, et al. Radiofrequency catheter ablation of ventricular tachycardia in patients with coronary artery disease. Circulation 1993; 87:363-372. 9. Josephson ME, Horowitz LN, Farshidi A, et al. Recurrent sustained ventricular tachycardia: 2. Endocardial mapping. Circulation 1978;57:440-447. 10. Fenoglio JJ, Pham TD, Harken AH, et al. Recurrent sustained ventricular tachycardia: Structure and ultrastructure of subendocardial regions in which tachycardia originates. Circulation 1983;68:518-533. 11. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle: Evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res 1986;58:356-371. 12. de Bakker JMT, Van Capelle FJL, Janse MJ, et al. Reentry as a cause of ventricular tachycardia in patients with ischemic heart disease: Electrophysiology and anatomic correlation. Circulation 1988;77:589-606. 13. Josephson ME, Zimetbaum P, Huang D, et al. Pathophysiologic substrate for sustained ventricular tachycardia in coronary artery disease. Jpn Circ J 1997;61:459-466. 14. Miller JA, Tyson GS, Hargrove III WC, et al. Effect of subendocardial resection on sinus rhythm endocardial electrogram abnormalities. Circulation 1995;91:23862391. 15. Josephson ME, Horowitz LN, Farshidi A. Sustained ventricular tachycardia:

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sinus rhythm with normal left ventricles: Evidence for protected localized reentry. Activation patterns and characteristics Am J Cardiol 1978;42:416. of electrograms. Circulation 1984;70:37— 16. Morady F, Frank R, Kou WH, et al. Iden42. tification and catheter ablation of a zone of slow conduction in the reentrant circuit 27. Josephson ME. Surgical and nonsurgical ablation in the therapy of arrhythmias. of ventricular tachycardia in humans. J In: Josephson ME (ed): Clinical Cardiac Am Coll Cardiol 1988;ll:775-782. Electrophysiology: Techniques and Inter17. Stevenson WG, Khan H, Sager P, et al. pretations. 2nd ed. Philadelphia: Lea & Identification of reentry circuit sites Febiger; 1993:726-821. during catheter mapping and radiofrequency ablation of ventricular tachycardia 28. Cassidy DM, Vassallo JA, Miller JM, et al. Endocardial catheter mapping in patients late after myocardial infarction. Circulation in sinus rhythm: Relationship to underly1993;88:1647-1670. ing heart disease and ventricular arrhyth18. El-Shalakany A, Hadjis T, Papgeorgiou P, mias. Circulation 1986;73:645-652. et al. Entrainment/mapping criteria for the prediction of termination of ventricular 29. Kadish AH, Rosenthal ME, Vassallo JA, et al. Sinus mapping in patients with cartachycardia by single radiofrequency diac arrest and coronary disease—results lesion in patients with coronary disease. and correlation with outcome. Pacing Clin Circulation 1999;99:2283-2289. Electrophysiol 1989;12:301-310. 19. Buxton AE, Josephson ME, Marchlinski FE, Miller JM. Polymorphic ventricular 30. Otomo K, Bussey J, Patterson E, et al. Electrogram identification of the margin tachycardia induced by programmed stimof a canine myocardial infarction scar. ulation: Response to procainamide. J Am Pacing Clin Electrophysiol 1998;21:903. Coll Cardiol 1993;21:90-98. 20. Josephson ME, Simson MB, Harken AH, 31. Callans DJ, Ren J-F, Michele J, et al. Electroanatomic left ventricular mapping in et al. The incidence and clinical significance the porcine model of healed anterior of epicardial late potential in patients with myocardial infarction: Correlation with recurrent sustained ventricular tachycarintracardiac echocardiography and pathodia and coronary artery disease. Circulation 1982;66:1199-1204. logical analysis. Circulation 1999;100:174421. Morady F, Kadish AH, DiCarlo L, et al. 1750. Long-term results of catheter ablation of 32. Ben-Haim S, Osadchy D, Schuster I, et al. Nonfluoroscopic, in vivo navigation and idiopathic right ventricular tachycardia. mapping technology. Nat Med 1996;2:1393Circulation 1990;82:2093-2099. 22. Klein LS, Shih HT, Hackett K, et al. 1395. Radiofrequency catheter ablation of ven- 33. Gepstein L, Hayam G, Ben-Haim SA. A novel method for nonfluoroscopic cathetertricular tachycardia in patients without based electroanatomical mapping of the structural heart disease. Circulation 1992;85:1666-1674. heart: In vitro and in vivo accuracy results. Circulation 1997;95:1611-1622. 23. Josephson ME, Waxman HL, Cain ME, et al. Ventricular activation during endo- 34. Gepstein L, Evans SJ. Electroanatomical mapping of the heart: Basic concepts and cardial pacing. II. Role of pace-mapping to implications for the treatment of cardiac localize origin of ventricular tachycardia. arrhythmias. Pacing Clin Electrophysiol Am J Physiol 1982;50:11-22. 24. Waxman HL, Josephson ME. Ventricular 1998;21:1268-1278. activation during ventricular endocardial 35. Shpun S, Gepstein L, Ben-Haim SA. Guidpacing: I. Electrocardiographic patterns ance of radiofrequency endocardial ablarelated to the site of pacing. Am J Cardiol tion with real-time three-dimensional 1982;50:1-10. magnetic navigation system. Circulation 25. Cassidy DM, Vassallo JA, Buxton AE, et al. 1997;96:2016-2021. The value of catheter mapping during sinus 36. Schilling RJ, Peters NS, Davies W. Simulrhythm to localize the site of origin of ventaneous endocardial mapping in the human tricular tachycardia. Circulation 1984;69: left ventricle using a noncontact catheter: 1103-1110. Comparison of contact and reconstructed 26. Cassidy DM, Vassallo JA, Marchlinski FE, electrograms during sinus rhythm. Circuet al. Endocardial mapping in humans in lation 1998;98:887-898.

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37. Greenspan AJ, Borge RP, Panescu D, et al. Validation of a new nonfluoroscopic system for simultaneous multisite mapping and discrete three dimensional localization. Pacing Clin Electrophysiol 1998;21: 965. 38. De Groot NMS, Bootsma M, Van Der Velde ET, Schalij MJ. Three-dimensional catheter positioning during radiofrequency ablation. J Cardiovasc Electrophysiol 2000;11:11831192. 39. Wittkampf FHM, Wever EFD, Derkson R, et al. LocaLisa: New technique for realtime 3-dimensional localization of regular intracardiac electrodes. Circulation 1999;99:1312-1317. 40. Cosio FG, Lopez-Gil M, Goicolea A, et al. Radiofrequency ablation of the inferior vena cava-tricuspid valve isthmus in common atrial flutter. Am J Cardiol 1993; 71:705-709. 41. Haissaguerre M, Gencel L, Fischer B, et al. Successful catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 1994;5:1045-1052.

42. Josephson ME, Monahan KM. Three dimensional localization of the substrate of ventricular tachycardia in coronary artery disease. Circulation 1997;96:I-587. 43. Marchlinski F, Callans D, Zado E, et al. Multiple linear ablation lesions to control unstable ventricular tachycardia: Facilitation by nonfluoroscopic electroanatomic mapping. Pacing Clin Electrophysiol 1998;21: 843. 44. Ellison KE, Stevenson WG, Sweeney MO, et al. Catheter ablation for hemodynamically unstable monomorphic ventricular tachycardia. J Cardiovasc Electrophysiol 2000;ll:41-44. 45. Sra J, Bhatia A, Dhala A, et al. Electroanatomically guided catheter ablation of ventricular tachycardias causing multiple defibrillator shocks. Pacing Clin Electrophysiol 200l;24:l645-1652. 46. Avitall B, Helms RW, Chiang W, Periman BA. Nonlinear atrial radiofrequency lesions are arrhythmogenic: A study of skipped lesion in the normal atria. Circulation 1995;92:I-265.

Chapter 31

Intraoperative Mapping of Ventricular Tachycardia in Patients with Myocardial Infarction: New Insights Into Mechanisms and Electroanatomical Correlations in Septal Tachycardias Pierre L. Page, MD, Wilhelm Kaltenbrunner, MD, and Rene Cardinal, PhD

or subepicardial layers in initiating and perpetuating reentrant VT.13-16 The mapping technique in use in our The development of intraoperative institution consists of computerized mapmapping techniques has enabled us to ping of the LV endocardial surface simulrelate ventricular tachycardias (VTs) assotaneously with the entire epicardial ciated with coronary artery disease and 11,13,17 surface of the ventricles. In a study prior myocardial infarction (MI) to their published in 1991, we retrospectively actual anatomical substrate and to achieve an effective surgical treatment.1-4 analyzed mapping data obtained intraSites of VT origin have been most fre- operatively in 28 patients with postinquently localized in left ventricular (LV) farction VT, leading us to group the VT subendocardial layers1-7 and procedures activation patterns into 5 types according aimed at ablating this type of substrate to the following criteria: (1) the relative (subendocardial resection, cryosurgery, timing of the earliest activations on the catheter ablation) have been widely used endocardial and epicardial surfaces; (2) to treat patients with recurrent sustained detection of a complete reentry pattern monomorphic VT.1,3,6-12 Several experi- in which 90% or more of the tachycardia mental and clinical studies, however, cycle length (CL) was accounted for by point to an important role of intramural actual recordings and the site of earliest Introduction

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; C2003.

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activation was localized next to the site of taneously from the epicardium and the latest activation; and (3) localization of the endocardium with reference to Wilson's epicardial breakthrough on either the left central terminal. Using a PC-based data or the right ventricle (RV). This analysis acquisition system, the signals are amplisuggested that LV endocardial mapping fied by programmable-gain analog amplialone may underestimate the significance fiers with a 0.05- to 200-Hz bandwidth, of concomitant epicardial mapping.13 It multiplexed, sampled at 1 kHz, and conalso suggested that a 3-dimensional view verted to a 10-bit digital format. All electroof the substratum of a given VT can be grams are then processed and analyzed derived from simultaneous epicardial and using a Silicon Graphics Workstation and LV endocardial mapping and that the a custom-made software, Cardiomap III information regarding the epicardial/LV (Institut de genie biomedical, Ecole Polyendocardial relationship is useful to esti- technique de Montreal, Universite de mate the depth of VT origin for any given Montreal). Activation times are deterLV segment. mined by a maximum negative slope in After a brief summary of our mapping excess of-0.5 mV/ms as described previtechnique, the following sections address ously.11,13,17,19 Sites at which unipolar previously described VT activation pat- electrograms do not fulfill these criteria terns, modification of their definition, their are considered unexcitable. Each activarelevance to the surgical ablation tech- tion map was generated for a single beat nique, and the need for further investiga- over a time interval corresponding to the tion of the putative mechanisms of duration of one tachycardia cycle. Activapostinfarction VT. Then, a section specif- tion times are plotted on their correspondically devoted to VTs originating in the ing grid (Figure 1) to allow construction interventricular septum allows us to of isochronal maps. emphasize how simultaneous epicardialendocardial mapping can be used to estiActivation Patterns mate the depth of septal arrhythmogenic substrates. Epicardial and LV endocardial mapping data obtained in patients operated for recurrent VT between 1985 and 1989 (the Mapping Methodology "1991" series)13 and between 1996 and 1998 After initiation of normothermic car- (the "1999" series) were reviewed. In the diopulmonary bypass, the entire epicar- 1991 series, 47 VTs were analyzed from dial surface of the heart is covered with the mapping files of 28 patients (24 VTs in a sock array of 128 unipolar electrodes. 14 patients with anterior MI and 23 VTs The electrode identification numbers are in 14 patients with inferior infarction). In verified in order to confirm the anatomi- the 1999 series, 37 VTs were studied from cal orientation of the sock array over the the mapping files of 18 patients (37 VTs in epicardium. An inflatable balloon (Institut 15 patients with anterior infarction and 12 de genie biomedical, Ecole Polytechnique VTs in 3 patients with inferior infarction). The classification of VT activation de Montreal, Universite de Montreal, Montreal, Quebec, Canada) introduced patterns proposed in 1991 was as follows: into the intact LV from the left atrium is type 1 and type 2 patterns consisted of used to obtain 64 unipolar recordings complete (>90% of VT CL) subendocarfrom the LV endocardial surface.11,13,17,18 dial or subepicardial reentry circuits, Unipolar electrograms are recorded simul- respectively (Figure 2); type 3 (Figure 3)

INTRAOPERATIVE MAPPING OF VT IN MI PATIENTS

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Image Not Available

Figure 1. Epicardial, right ventricular (RV) endocardial, and left ventricular (LV) endocardial mapping grids representing a polar view of the heart in which the base is at the periphery of the circle and the apex is at the center. The epicardial surface is classified into 5 areas: RV free wall area (RVFW), LV free wall area (LVFW), anterior interventricular groove area (AIVG), posterior interventricular groove area (PIVG), and apical area (APEX). The endocardial grids display their corresponding septal and free wall aspects. Semicircular upward extensions on the RV endocardial grid indicate the balloon prolongation into the right ventricular outflow tract (RVOT). Reproduced from reference 17, with permission.

Figure 2. Epicardial (epi) and endocardial (endo) activation sequence maps of complete reentry. Isochrone lines are drawn at 20-ms intervals and activation times are displayed with a color code explained at the bottom. A. Complete subendocardial reentry complying with the definition of type 1 activation pattern. At the right, the endocardial map shows that from the site of zero (0 ms) activation time, the wavefront spread in a single counterclockwise circular movement. The latest (212 ms) activation time was adjacent to the earliest activation in completing the reentry circuit between the anterior septum and the anterior left ventricular free wall. The epicardial map (left) showed passive activation from the anterior left ventricular free wall to the posterior right ventricle. B. Complete subepicardial reentry with a figure-of-8 pattern. The earliest activation (zero time) occurred at the apex of the heart. From this area, activation spread out in 2 circular wavefrents (arrows): in a counterclockwise direction inferiorly and clockwise anteriorly. These wavefronts circulated around areas of inexcitability (black) and merged into a common wavefront (activation time of 200 ms). The common wavefront traversed the region of infarction (200 to 244 ms) and propagated back to the site of onset of endocardial activation (zero time). See color appendix.

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Figure 3. Diagrams showing epicardial and endocardial mapping of ventricular tachycardia (VT) originating in the left subendocardial layers of the septum in a patient with an anteroseptal infarct (cross hatch). The earliest activation occurred in the anterior septum (right, 0 ms) and preceded the epicardial breakthrough (left, 40 ms). The center diagram shows that onset of right ventricular (RV) activation was later than the onset of the left ventricular (LV) endocardial activation by 28 ms, demonstrating a left-sided septal VT substrate. Reproduced from reference 17, with permission.

Figure 4. Epicardial (EPI) and endocardial (ENDO) maps of a type 4 ventricular tachycardia (VT). The posterior epicardial breakthrough preceded the left ventricular (LV) endocardial breakthrough by 32 ms. The VT site of origin in this example is likely the right side of the posterior septum. Such a pattern can also be seen on the LV free wall, where it would suggest an epicardial arrhythmogenic substrate. LAD = left anterior descending coronary artery; PDA = posterior descending coronary artery; RV = right ventricle.

and type 4 (Figure 4) patterns referred to incompletely mapped circuits with an LV endocardial breakthrough respectively preceding or following the epicardial breakthrough; the type 5 pattern (Figure 5) consisted of an RV epicardial

breakthrough preceding the LV endocardial breakthrough.13 Table 1 shows the relative incidence of each VT type in the 2 series. LV endocardial reentry substrates (types 1 and 3) accounted for 68% and 47% of VTs in the

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Table 1 Respective Incidence of VT Mapping Types in the 1991 and 1999 Series

1991 VT Mapping Type (n = VTs) 1. 2. 3. 4. 5.

Subendocardial reentry Subepicardial reentry Endocardial breakthrough Epicardial breakthrough Deep septal substrate

1999

AMI/IMI

%

AMI/MI

%

5/2 2/2 15/10 0/3 2/6

15 9 53 6 17

6/0 5/3 15/2 3/5 7/2

12 17 35 17 18

47

100

48

100

VT = ventricular tachycardia; AMI = anterior myocardial infarction (1991, 14 patients, 1999, 15 patients); IMI = inferior myocardial infarction (1991, 14 patients; 1999, 3 patients).

Image Not Available

Figure 5. Diagrams showing epicardial and endocardial mapping of type 5 ventricular tachycardia originating in the right subendocardial layers of the septum in a patient with an anteroseptal infarct (cross hatch). See text for details. Reproduced from reference 17, with permission.

1991 and 1999 series, respectively, whereas substrates involving subepicardial or deep septal layers (types 2, 4, and 5) accounted for 32% and 52% of VTs in the 2 series, respectively. Under the assumption that the difference in the incidences of the VT types between the 2 series are not due to chance, possible explanations include (1) modification of definitions, including demonstration of reentry by cryothermal applications; (2) a change in infarct morphology in the patient population; and (3) the evolution of criteria to select patients for surgical therapy. The first possibility is discussed in the following section on

mechanisms. The second receives some support from the more frequent occurrence of subepicardial reentry, mostly in patients with anterior MI, considering that it is unlikely that a large, transmural anterior aneurysm can provide the viable subepicardial myocardial cell layers necessary to sustain reentry. The 2 clinical series are similar in terms of the age, clinical VT presentation, functional class, and number of diseased vessels. However, the 1991 and 1999 series differ (P< 0.05) with respect to ejection fraction (0.28 versus 0.32, respectively), the incidence of aneurysm (64% versus 77%), the infarction to surgery interval (51 versus 114 months),

610 CARDIAC MAPPING and the number of VT morphologies mapped in the operating room (1.6 versus 2.05). These differences alone could hardly explain the differences in the relative incidence of VT mapping types. The higher ejection fraction of the recent cases may suggest that the aneurysms, although more frequent, might be smaller in size. Therefore, there might be a smaller area of complete, transmural scar and a larger border- zone exhibiting heterogeneous, viable tissue capable of sustaining subepicardial reentry.

In the classification proposed in 1991, the assumption (or evidence) for reentry was based on the criterion of continuous activity (at least 90% of the VT CL and proximity of the sites of latest activity and earliest activity of the next cycle). Since then, we have introduced into our intraoperative procedure the use of a cool (-20°C) cryoprobe application to establish a given subepicardial area as a putative reentrant substrate even when the actual recordings span less than 90% of the VT CL. In Figure 6A, an easily

Figure 6. A. Epicardial and endocardial maps (same format as in Figure 2) of a patient with subepicardial reentry proven by application of a cryoprobe at the site of 198 ms activation time. At right are selected unipolar electrograms recorded at the onset of epicardial activation (0 ms) and in the common pathway (90 to 198 ms). Both the amplitude and the slope (numbers at the right of the electrograms, in mV/ms) of the late deflection were depressed compared to those seen in panel B electrograms. B. Epicardial map of a ventricular tachycardia (VT) in which onset of epicardial activation preceded the onset of endocardial activation. However, cryothermal application at site marked by the 114 ms activation time failed to terminate the tachycardia, suggesting an intramural VT substrate. Epicardial electrograms shown at right exhibited higher amplitude and slope. See color appendix.

INTRAOPERATIVE MAPPING OF VT IN MI PATIENTS reinducible VT was interrupted 3 times by a brief cryothermal application at the epicardial site at which relatively late activity (198 ms of a 280-ms CL) was detected, whereas in a different patient (Figure 6B), cryothermal application at an epicardial site of delayed activity bordering the scar (114 ms) did not affect the arrhythmia (discussed further in the section on Mechanisms). Identification of the type of the VT activation pattern helps the surgeon to design an appropriate ablation procedure. Detection of mid-diastolic or later potentials with a depressed amplitude and slope is a critical complement to the socalled "site of origin" determined by the earliest activation at the beginning of VT cycle, guiding the operator's hand toward tissue with a possible arrhythmogenic power, be it endocardial or epicardial. When this critically delayed, depressed activity has evaded detection, its localization is inferred from the site of latest electrical activation available and the site of earliest activation of the next VT cycle. This tissue is invariably involved in the VT mechanism and should be ablated. This approach usually leads to resection or cryoablation of large portions of diseased myocardium. Ablation of VTs with a septal origin is discussed in the last section. Mechanisms of VT The electrical abnormalities underlying slow conduction can, in principle, be related to the muscle fibers' depressed generator properties (Na channel) and/or to alterations in cellular coupling. It is a widely held view that, in patients with remote MI, the arrhythmogenic substrate is composed of cells generating action potentials with completely normal configuration but arranged in bundles separated by strands of fibrous tissue.15,20-22 However, some of our intraoperative data

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would point to a role for depressed generator properties in addition to fiber bundle separation. These include (1) the fact that many of these monomorphic VTs display an initial phase of CL prolongation after their induction by programmed stimulation (see Figure 1 of chapter 32), and (2) the fact that delayed activation is seen, in a unipolar electrogram recorded from a given site, in the form of a single, discrete deflection with a low amplitude and depressed slope (see right panel of Figure 6A in contrast to that of Figure 6B). The conversion of nonsustained and polymorphic VTs into sustained monomorphic ones can also be interpreted in the context of depressed Na channels since this drug has a high affinity for the channel in its inactivated state as well as in the open state,23 and it is selective for depressed Na-dependent activity (the difference with lidocaine residing in the kinetics of interaction with the channel24). Figure 7 shows intraoperative data from a patient with an anteroapical LV infarction in whom only nonsustained VTs could be induced in the basal state (BSL: panel A) whereas sustained monomorphic VTs could be induced after administration of 500 mg of procainamide (PA: panel B). The isochronal epicardial maps of the arrhythmias show an early breakthrough in the basal LV region (red) followed by spread of the activity, with marked delay development in the region of infarction (blue). The difference map comparing activation times between the basal state and procainamide (PA-BSL: panel C) shows that, while the drug caused a prolongation of conduction times in all regions, there was a relatively greater prolongation in the anteroapical areas, in agreement with the notion of a selective action in damaged muscle. Figure 2A shows that the arrhythmias illustrated in Figure 7 were in fact caused by a subendocardial reentrant mechanism. However, in another sustained tachycardia induced in this

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Figure 7. Surface ECG lead II (upper tracings) of the induction of a nonsustained ventricular tachycardia (VT) (A) induced under basal conditions (BSL) (see termination at the end of the tracing) and a sustained VT (B) obtained after administration of 500 mg of procainamide (PA). Lower panels display epicardial activation maps of these VTs. C. A theoretical epicardial map obtained by calculating, at each recording site, the difference (in ms) between the activation times shown of the maps of panels A and B. The data indicate the localization of the maximum effect the procainamide (blue). See color appendix.

INTRAOPERATIVE MAPPING OF VT IN MI PATIENTS patient after procainamide administration (Figure 7B), the anteroapical areas (where the drug exerted maximal effects on conduction) generated delayed activation sustaining reentry. Conclusion Based on the results of dynamic analysis of VT patterns and on the results of pharmacological manipulations, we propose that the cellular mechanisms involved in slow conduction and reentrant activity in remote MI may be heterogeneous among patients, depending on abnormal generator properties of the surviving muscle (micro hibernating myocardium) in addition to the anatomical abnormalities altering cellular coupling and connections between muscle fiber bundles. It will therefore be a challenge for future investigations to confirm, or refute, this long-standing concept of VT mechanism. Septal VTs The epicardial and LV endocardial relationship is more complex in the case of septal VTs, which occur in 46% to 94% (mean 68%) of patients who undergo mapguided surgery.2-7,22,25-30 This incidence was 76% in our total series of 145 patients operated on since 1983. In 50% of our patients, at least one septal VT was associated with remote epicardial breakthrough sites designated previously as type 5 VTs.13,17 Based on our clinical results, these tachycardias were associated with a higher risk of surgical failure, presumably because surgical ablation was performed solely on the LV septal surface either by endocardial resection or by cryosurgery.11,13,31 Until 1989, the technique used in our institution to ablate VT substrates consisted of cryosurgery alone applied regionally to the endocardial half

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of the LV encompassing the site of earliest activation.11 Our concerns regarding the significance of type 5 VT31 prompted us to modify the surgical technique used for septal VT ablation. This modification consisted of producing transmural freezing injury of the septum by resecting all visible scar from the LV septal surface prior to the application of cryosurgery inside the margins of this resection. This modification is performed whenever a type 5 VT is identified at mapping. The following experience indicated a significant improvement in the success rate of surgery using this approach.32,33 To clarify the significance of the type 5 VT activation pattern, the relative timing of epicardial and RV endocardial as well as LV endocardial activations were investigated through the use of both RV and LV balloon arrays in patients with septal VT.17 These mapping data were compared to those obtained in the animal laboratory during VT caused by reentry in a canine model of septal infarction and relative timing relationships were investigated in the canine hearts during pacing from left, right, and intermediate septal sites in the presence or absence of a septal infarct. In that study, published in 1996, we reported mapping data of 18 consecutive patients selected on the basis of the occurrence of at least one VT displaying an LV endocardial breakthrough on the interventricular septum. In these patients, aged 55 ± 10 years (16 males, 2 females), a prior MI was anteroseptal in 12 and inferiorly located in 6 patients.17 Among 31 VTs analyzed in that study, 2 situations were encountered. In 20 VTs, the earliest activation was detected on the LV aspect of the septum and it preceded the epicardial breakthrough (Figure 3). Conversely, the earliest epicardial breakthrough (localized in the RV free wall) preceded the LV endocardial activation in 11 VTs (Figure 5).

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Figure 3 shows an example of the first situation (fulfilling a type 3 characterization) in a patient in whom RV endocardial activation was mapped concomitantly with epicardial and LV endocardial activation with a specially designed balloon array introduced in the RV through the right atrium. In the 20 tachycardias of this type, the epicardial breakthrough occurred in either the anterior (8) or posterior (10) interventricular groove and in the RV free wall in only 2 tachycardias. In Figure 5, illustrating the second situation (a type 5 pattern), the RV endocardial activation (0) preceded both the epicardial breakthrough (6 ms) and the LV endocardial activation (10 ms). In 13 VTs for which an RV endocardial map was obtained, the right-sided septal activation preceded the left-sided septal activation in all (5/5) tachycardias with an RV free wall epicardial breakthrough, whereas only 3 of the 8 tachycardias with an epicardial breakthrough

in the interventricular groove area had an earlier RV septal breakthrough. Thus, the origin of septal tachycardias could occur closer to the RV or LV aspect of the septum, yielding in each case a set of distinct mapping characteristics which includes the relative timing of the RV endocardial, LV endocardial, and epicardial breakthrough as well as the localization of the epicardial breakthrough in either the RV free wall or the interventricular groove area. This concept was corroborated experimentally in canine preparations with either normal myocardium or an intraseptal infarction produced by the ligation of the first septal artery. During intraseptal pacing near the RV endocardium in a healthy preparation (Figure 8A, left image), the earliest activation was detected in the corresponding septal region and preceded LV endocardial activation, and the epicardial breakthrough occurred in the RV

Image Not Available

Figure 8. Maps obtained by pacing the right-anterior-central and the left-anterior-central septal sites in healthy and infarcted heart preparations. A. Healthy heart preparation: pacing from the right (RV; left maps) and the left (LV; right maps) ventricular thirds of the septum. B. Infarcted heart preparation. See text for details. Reproduced from reference 17, with permission.

INTRAOPERATIVE MAPPING OF VT IN MI PATIENTS

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free wall concomitantly with LV endocar- circuit involving the interventricular dial activation. The region over which the septum, obviating the need for RV endoRV epicardial breakthrough occurred was cardial mapping: (1) an RV anterior free similar to that in sinus rhythm (not shown). wall breakthrough preceding the LV endoDuring intraseptal pacing near the LV cardial breakthrough predicts a site of endocardium (Figure 8A, right image), the origin located in the right subendocardial earliest LV endocardial activation pre- layers of the septum, and (2) an epicardial ceded RV endocardial activation and the breakthrough occurring in the intervenepicardial breakthrough occurred in the tricular groove area suggests that the VT RV free wall in a more anterior location originates in left half of the septum, being that was distinct from the breakthrough closer to the subendocardial layers of the area in sinus rhythm. When intraseptal left side if it is preceded by the onset of the pacing was performed in infarcted heart LV endocardial activation.17,25 This was preparations (Figure 8B), conduction time confirmed by transseptal pacing as well from the RV to LV endocardial aspects of as by the creation of a septal reentry the septum was significantly increased substrate in canine preparations and by (from 20 ± 10 ms in healthy hearts to 28 ± the simultaneous acquisition of RV endo9 ms; P < 0.005) and the RV epicardial cardial data in patients with septal VT.17 breakthrough preceded the earliest LV The incidence and surgical approaches endocardial activation (by 6 ± 16 ms) to septal VTs have been anecdotally 2,6, (Figure 8B, left image). This was similar addressed in the surgical 7,26-30 or exper14,34,35 literature. However, these as seen in human and animal VTs origi- imental nating from the RV septal region.17 During concepts become increasingly important pacing near the LV endocardial aspect, the now, in the era of evolving application of epicardial breakthrough occurred more percutaneous catheter ablation techanteriorly in the RV free wall (Figure 8B, niques, often supplanting the use of direct right image) or in the interventricular open-heart surgery in the treatment of groove, a situation that was also encoun- recurrent VT.12,36 tered in humans (see above, Figure 3). Implication Discussion Early in the development of mapThe data presented in this chapter guided VT surgery, attention was focused and those detailed in the previous edition on the LV endocardium. This was based of this book25 support the notion that there on the observation that the sites of epiis a conceptual continuity between septal cardial and endocardial onset of activaVTs in which reentry may either (1) occur tion could be widely separate and that completely in subendocardial layers on the onset of endocardial activation the LV aspect of the septum; (2) involve always preceded the onset of epicardial intraseptal layers; or (3) occur completely activation.1,2,22 Consequently, the pertiin subendocardial layers on the RV aspect nence of epicardial mapping was deof the septum. Although a complete reen- emphasized and sophisticated techniques trant circuit could not always be mapped of endocardial mapping have been develon the LV endocardial surface, the relative oped.11,18,30 Our mapping experience, on timing between RV epicardial and LV the other hand, brought the suggestion endocardial breakthroughs may be used that simultaneous epicardial and endoto estimate the depth of a VT reentrant cardial multiple site data acquisition and

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interpretation improve the critical understanding of the arrhythmogenic substrate in its 3-dimensional arrangement. The information so gathered may be interpreted such that epicardial mapping, easier to perform than endocardial mapping, may provide enough information to guide successful surgical ablation. Moreover, most subepicardial reentry circuits, or at least subepicardial arrhythmogenic tissue, may be detected without endocardial mapping, by combining information from epicardial activation during VT, sinus rhythm mapping, visual inspection (e.g., heterogeneous scars), and functional manipulation of suspect tissue such as cryothermal applications. In the context of nonsurgical ablation approaches, the same evolution of thoughts appears to be in effect. Noncontact endocardial mapping with multielectrode devices has been introduced clinically.37 This newer approach is still limited by the possibility of VT substrates in remote regions from the classic endocardial muscle layers, a situation that was seen in 52% of the VTs and 31% of our surgical patients (types 2, 4, and 5 combined). These include epicardial VTs as described above as well as by others,16 and VTs with deep septal substrates also addressed in this chapter and in our previous work.13,17,31,38,39 Thus, new methods to assess the epicardial-endocardial relationship will have to be developed in the future, in order to increase the span of endovascular ablative approaches. The only noninvasive method currently in use to assess epicardial electrical events during VT is body surface potential mapping.40 Combining or articulating this with noncontact endocardial mapping to assess the role of septal and free wall intramural muscle layers will be the next challenge of cardiac mapping. Acknowledgments: The authors wish to thank Mr. Gaetan Tremblay for computer software design

and upgrade, Mr. Michel Vermeulen and Mr. Denis Guerette for their technical assistance, and Mrs. Suzan Senechal for her assistance in the preparation of this manuscript.

References 1. Wittig JH, Boineau JP. Surgical treatment of ventricular tachycardia using epicardial, transmural and endocardial mapping. Ann Thorac Surg 1975;20:117-126. 2. Horowitz LN, Josephson ME, Harken AH. Epicardial and endocardial activation during sustained ventricular tachycardia in man. Circulation 1980;61:1227— 1238. 3. Josephson ME, Harken AH, Horowitz LN. Endocardial excision: A new surgical technique for the treatment of recurrent ventricular tachycardia. Circulation 1979; 41:1035-1044. 4. Miller JM, Harken AH, Hargrove WC, Josephson ME. Pattern of endocardial activation during sustained ventricular tachycardia. J Am Coll Cardiol 1985;6:1280-1287. 5. Josephson ME, Miller JM, Hargrove III WC. Intraoperative mapping of ventricular tachycardia associated with coronary artery disease. In: Aliot E, Lazzara R (eds): Ventricular Tachycardia, From Mechanism to Therapy. Boston: Martinus Nijhoff Publishers; 1987:411-436. 6. Krafchek J, Lawrie GM, Roberts R, et al. Surgical ablation of ventricular tachycardia: Improved results with a map directed regional approach. Circulation 1986;6: 1239-1247. 7. Ostermeyer J, Borgreffe M, Breithardt G, et al. Direct operation for the management of life threatening ischemic ventricular tachycardia. J Thorac Cardiouasc Surg 1987;94:848-865. 8. Josephson ME, Harken AH, Horrowitz LN. Long-term results of endocardial resection for sustained ventricular tachycardia in coronary disease patients. Am Heart J 1982;104:51-57. 9. Swerdlow CD, Mason JW, Stinson EB, et al. Results of operations for ventricular tachycardia in 105 patients. J Thorac Cardiovasc Surg 1986;92:105-113. 10. Cox JL. Patient selection criteria and results of surgery for refractory ischemic ventricular tachycardia. Circulation 1989; 79(Suppl I):I-163-1-177.

INTRAOPERATIVE MAPPING OF VT IN MI PATIENTS 11. Page PL, Cardinal R, Shenasa M, et al. Surgical treatment of ventricular tachycardia. Regional cryoablation guided by computerized epicardial and endocardial mapping. Circulation 1989;80(Suppl I): I-124-I-134. 12. Breithardt G, Borggrefe M, Wietholt D, et al. Role of ventricular tachycardia surgery and catheter ablation as complements or alternatives to the implantable cardioverter defibrillator in the 1990s. Pacing Clin Electrophysiol 1992;15:681689. 13. Kaltenbrunner W, Cardinal R, Dubuc M, et al. Epicardial and endocardial mapping of ventricular tachycardia in patients with myocardial infarction. Is the origin of the tachycardia always subendocardially localized? Circulation 1991;84:10581071. 14. Pogwizd SM, Hoyt RH, Saffitz JE, et al. Reentrant and focal mechanisms underlying ventricular tachycardia in the human heart. Circulation 1992;86:18721887. 15. de Bakker JMT, van Capelle FJL, Janse MJ, et al. Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: Electrophysiologic and anatomic correlation. Circulation 1988;77:589-606. 16. Littmann L, Svenson RH, Gallagher JJ, et al. Functional role of the epicardium in postinfarction ventricular tachycardia. Observations derived from computerized epicardial activation mapping, entrainment and epicardial laser photoablation. Circulation 1991;83:1577-1591. 17. Kawamura Y, Page PL, Cardinal R, et al. Mapping of septal ventricular tachycardia: Clinical and experimental correlations. J Thorac Cardiouasc Surg 1996;112: 914-925. 18. Mickelborough L, Harris L, Downar E, et al. A new intraoperative approach for mapping of ventricular tachycardia. J Thorac Cardiovasc Surg 1988;95:271-280. 19. Durrer D, Van Lier AAW, Buller J. Epicardial and intramural excitation in chronic myocardial infarction. Am Heart J 1964;68:765-776. 20. Kirchhof CJHJ, Josephson ME. Role of discontinuous conduction/nonuniform anisotropy in clinical arrhythmias. In: Spooner PM, Joyner RW, Jalife J (eds): Discontinuous Conduction in the Heart.

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Armonk, NY: Futura Publishing Co.; 1997:135-157. 21. Gardner PI, Ursell PC, Fenoglio JJ, et al. Electrophysiologic and anatomic basis for fractionated electrograms recorded from healed myocardial infarcts. Circulation 1985;72:596. 22. Josephson ME. Recurrent ventricular tachycardia. In: Josephson ME (ed): Clinical Cardiac Electrophysiology: Techniques and Interpretations. Philadelphia/ London: Lea and Febiger; 1993:417-615. 23. Ehring GR, Moyer JW, Hondeghem LM. Quantitative structure activity studies of antiarrhythmic properties in a series of lidocaine and procainamide derivatives. J Pharmacol Exp Ther 1988;244:479492. 24. Campbell TJ. Kinetics of onset of ratedependent effects of Class I antiarrhythmic drugs are important in determining their effects on refractoriness in guineapig ventricle, and provide a theoretical basis for their subclassification. Circ Res 1983;17:344-352. 25. Kaltenbrunner W, Veit F, Winter S, et al. Epicardial and left ventricular endocardial activation mapping of septal tachycardia in patients after myocardial infarction. Is estimation of the depth of origin feasible? In: Breithardt G, Borggrefe M, Shenasa M (eds): Cardiac Mapping. Mount Kisco, NY: Futura Publishing Co.; 1993:467-494. 26. Kron IK, Lerman BB, DiMarco JP. Extended subendocardial resection. A surgical approach to ventricular tachyarrhythmias that cannot be mapped intraoperatively. J Thorac Cardiovasc Surg 1985;90:536-591. 27. Haines DE, Lerman BB, Kron IL, DiMarco JP. Surgical ablation of ventricular tachycardia with sequential map-guided subendocardial resection: Electrophysiologic assessment and long-term follow-up. Circulation 1988;77:131-141. 28. Waspe LE, Brodman R, Kim SG, et al. Activation mapping in patients with coronary artery disease with multiple ventricular tachycardia configurations: Occurrence and therapeutic implications of widely separate apparent site of origin. J Am Coll Cardiol 1985;5:1075-1086. 29. Svenson RH, Gallagher JJ, Selle JG, et al. Neodymium:YAG laser photocoagulation: A successful new map-guided technique

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for the intraoperative ablation of ventricular tachycardia. Circulation 1987;76: 1319-1328. 30. Branyas NA, Cain ME, Cox JL, Cassidy DM. Transmural ventricular activation during consecutive cycles of sustained ventricular tachycardia associated with coronary artery disease. Am J Cardiol 1990;65:861-867. 31. Page PL, Cardinal R, Kaltenbrunner W, et al. Epicardial/endocardial patterns associated with failure of surgery for ventricular tachycardia. Circulation 1989; 80(Suppl II):II-221. 32. Page PL, Cardinal R, Dubuc M, et al. Surgical approach of ventricular tachycardia with deep septal substratum. Circulation 1991;84(Suppl II):II-195. 33. Page P, Cardinal R, Molin F, et al. Map guided surgery for ventricular tachycardia: A 13-year experience. Can J Cardiol 1996;12(Suppl E):111E. 34. Tweddell JS, Rokkas CK, Harada A, et al. Anterior septal coronary artery infarction in the canine: A model of ventricular tachycardia with a subendocardial origin. Ablation and activation sequence mapping. Circulation 1994;90:2982-2992.

35. Smith WM, Ideker RE, Smith WM, et al. Localization of septal sites in the dog heart by epicardial mapping. J Am Coll Cardiol 1983;1:1423-1434. 36. Stevenson WG, Ellison KE, Lefroy DC, Friedman PL. Ablation therapy for cardiac arrhythmias. Am J Cardiol 1997;80: 56G-66G. 37. Schilling RJ, Peters NS, Davies DW. Simultaneous endocardial mapping in the human left ventricle using a noncontact catheter: Comparison of contact and reconstructed electrograms during sinus rhythm. Circulation 1998;98:887-898. 38. Page PL. Surgical treatment of ventricular tachycardia. Indications and results. Arch Mal Coeur 1996;89:115-121. 39. Page PL. Surgical treatment of ventricular tachycardia: Indications and results. In: ElSherif N, Lekieffre J (eds): Practical Management of Cardiac Arrhythmias. Armonk, NY: Futura Publishing Co.; 1997:233-246. 40. SippensGroenewegen A, Spekhorst H, van Hemel NM, et al. Value of body surface mapping in localizing the site of origin of ventricular tachycardia in patients with previous myocardial infarction. J Am Coll Cardiol 1994;24:1708-1724.

Chapter 32 Dynamic Analysis of Postinfarction Monomorphic and Polymorphic Ventricular Tachycardias Rene Cardinal, PhD, Alain Vinet, PhD, Francois Helie, MSc, Michel Vermeulen, B Pharm, MScA, Pierre Rocque, BSc, and Pierre L. Page, MD

Activation sequences consistent with reentry have been demonstrated in several intraoperative studies of monomorphic ventricular tachycardias (VTs) induced in patients with coronary artery disease and prior myocardial infarction (MI).1-3 By definition, all beats of a monomorphic tachycardia display a uniform ECG morphology reflecting the fact that the circuit remains at a fixed location and that the centrifugal waves propagate to the rest of the ventricles from constant exit points and according to a constant pattern. Traditionally, a monomorphic VT has been represented by the isochronal map of a single beat, under the assumption that all beats display a highly repetitive activation pattern. Intraoperative mapping data have been reported that support that this assumption may be valid, at least in the stabilized phase of sustained VTs.4 Likewise, it has been assumed that the

tachycardia cycle length (CL) is stable from the very onset. Oscillations in tachycardia CL do, however, occur in nonsustained tachycardias and in the final beats of spontaneously terminating protracted episodes induced in patients with prior MI.5-7 Such temporal oscillations often, but not always, occur in association with spatial instability in the form of shifting sites of beat initiation.6 It has been suggested that CL oscillations occurring in clinical tachycardias are the reflection of a dynamic interplay between the interval-dependent properties of myocardial conduction (estimated from QRS duration or total activation interval) and repolarization (QT interval).5 This view is consistent with observations made in the canine atrial tricuspid ring model of reentry occurring around a fixed anatomical barrier with a partially excitable gap.8 Interestingly, CL

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003.

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oscillations have been shown to occur less frequently in the functional circuits of canine subacute infarct preparations.9 Less attention has been paid to the temporal patterns of CL variations that occur in the initial beats of sustained monomorphic VTs.10-12 (In the following, variations in sinus rate that precede the onset of sustained VTs are not considered.)13-15 Tachycardia induction by the application of 1 to 3 premature stimuli (S2, S3, S4) may be regarded as a transition from a relatively slow rate (sinus rhythm and basic train of S1 pulses) to a faster one (tachycardia), calling into play the rate-dependent conduction and repolarization properties of fibers involved in the reentrant circuit. Therefore, it should be expected that beat-to-beat CL variations occur before stabilizing. This issue was addressed through retrospective analysis of computer files comprising 127 to 192 unipolar electrograms recorded intraoperatively from the epicardium and ventricular cavities, to guide cryoablation of regions involved in

tachycardia generation in patients with prior ML3,16 The CL dynamics and spatial stability in the initial beats of VTs were analyzed to investigate the hypothesis that information might thus be generated regarding the properties of the underlying reentrant substrate. CL Dynamics at the Onset of Monomorphic VTs The time course of CL was analyzed in 59 monomorphic VTs induced in 40 patients and 12 tachycardias induced in 3-day-old infarct canine preparations.17 Activation times were determined at all recording sites over the entire beat series beginning with tachycardia induction, and the mean activation times were calculated, from which CLs were derived. We found that CL variations occurred according to distinctive trends which were, in most cases, either decelerating (Figure 1A,

Figure 1. Decelerating trend in instantaneous rate at the onset of a ventricular tachycardia induced by programmed stimulation (S2) in a patient with prior myocardial infarction. A. Top: ECG. Bottom: Time course of the tachycardia cycle length showing an increase as a function of beat number (modified from reference 17). B. Action potential drawing illustrating the hypothesis that a decelerating trend in rate might be associated with rate-dependent depression of action potential upstroke characteristics during transition from a relatively slow rate (sinus rhythm or basic programmed stimuli) to a fast rate (onset of tachycardia). By exaggerating the rate-dependent depression of excitability, Class I antiarrhythmic drugs can convert slow conduction to complete block.

POSTINFARCTION MONOMORPHIC AND POLYMORPHIC VTs

increasing CL) or accelerating (Figure 2A, decreasing CL), deceleration and acceleration being expressed with reference to the instantaneous rate. The time course of CLs was fitted to an exponential function: CL(t) = CLS + A exp(-t/t, where CLS is the CL after stabilization, A is the magnitude of the initial CL variation, t is time in beat numbers (i.e., first beat after programmed stimulation, second, third, etc.), and t is the time constant (in number of beats). (Note that in Figures 1 and 2, the dark lines indicate the fitted exponentials, and the data points indicate mean ± SD of CLs measured at all electrode sites for each beat.) The accelerating trends were faster (T = ~6 beats) than the decelerating ones (T = ~15 beats). Mixed trends occurred in which there was an ini-

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tial accelerationfollowedby deceleration. In a minority of cases, CL fluctuated about a constant CL. In addition to the protracted trends, faster fluctuations consisting of alternans or higher order periodicity (3 to 6 periods) were superimposed onto the accelerating, decelerating, or constant trends and accounted for a significant portion of the CL variance that was not explained by the exponential model. Fast fluctuations may depend on the interval-dependent properties of ionic mechanisms involved in myocardial conduction and repolarization, as demonstrated in experimental8 and mathematical models of anatomically determined reentrant ring structures.18 In the functional substrate of subacute infarct canine preparations, alternans and small,

Figure 2. Accelerating trend in instantaneous rate at the onset of a ventricular tachycardia induced by programmed stimulation (S1,S2, S3) in another patient with remote myocardial infarction. A. Top: ECG. Bottom: Time course of the tachycardia cycle length showing a decrease as a function of beat number. Modified from reference 17. B. Action potential drawing illustrating the hypothesis that an accelerating trend in rate might be associated with rate-dependent shortening of the action potential duration during transition from a relatively slow rate (sinus rhythm or basic programmed stimuli) to a fast rate (onset of tachycardia). Class III antiarrhythmic drugs can abort the induction of reentry by prolonging the action potential duration.

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127 epicardial and 64 endocardial electrodes). Figure 3 shows that any series of n beats can be represented by a matrix formed by collecting all beat vectors side by side. It is then possible to extract from the matrix a number of basic activation Spatial Stability of Activation patterns, the principal components (Vl, Patterns V2, V3,...) presenting features that are common to several beats. It is also possiTo investigate whether CL dynamble to represent each beat Ti as a ics at tachycardia onset occurred while weighted sum of several principal comthe activation sequence remained constant ponents and also to estimate the concoror in association with sequence modificadance between the activation sequence of tion, we used a method of multivariate an individual beat and a principal comanalysis—principal component analysis— ponent expressed as a correlation coeffiwhereby series of several beats, each cient r. (Principal component analysis being characterized by a set of 127 actiis a method of multivariate analysis vation times (the multiple variables), are involving the resolution of an eigenvalue analyzed to extract a single set of values problem—the principal components are (the first principal component) repreeigenvectors—as described in reference senting a typical activation pattern 23 and in Appendix 2 of reference 17). common to all beats. If the tachycardia is rigorously monomorphic, a single principal component is needed to represent a Spatiotemporal Stability series of several beats. If, however, modCycle length variations may reflect ifications of the activation sequence occur in some beats, a second and perhaps addi- either (1) remodeling of the reentrant tional principal components will be needed pathways (i.e., a change in circuit configto account for the entire beat series, and the uration); (2) inhomogeneous fluctuations activation sequence of each beat will be of propagation with a constant circuit conequal to a weighed sum of the principal figuration; or (3) beat-to-beat acceleracomponents. This approach has been used tion or deceleration uniformly distributed previously for various purposes in the throughout the reentry circuit. In the first medical sciences, and particularly in elec- case, multiple distinct activation sequences trocardiology, to analyze multielectrode would be found during each episode and body surface potential maps in groups of therefore it should be possible to extract patients,20,21 time series of sinus CL,15 fluc- from the analysis of the beat series 2 printuations in epicardial activation sequences, cipal components or more, each correpatterns of repolarization intervals in suc- sponding to a distinct pattern. In the second case, there would be a basic activation patcessive cardiac cycles,22 etc. tern (corresponding to the first principal component V1) onto which would be superimposed inhomogeneous beat-toVectors and Matrices beat fluctuations (i.e., one or several other Each beat i of a tachycardia may thus principal components, each being a conbe represented as a vector Ti = (Ti1, Ti2... trast correcting V1 to produce relatively Ti127), where Tij represents the activation earlier activation in some areas and delay time at each recording site j (typically, in others, rather than representing, per se, quasiperiodic oscillations in CL were shown (when they occurred) to be related to modifications of the reentrant circuit path length.19

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Figure 3. Analysis of the spatial stability of ventricular tachycardias. The activation sequence in each beat of a tachycardia is represented by a column vector displaying the activation times at all recording sites (here, 127 sites). A run of n beats is represented by a matrix constructed by collecting all n vectors side by side. Principal component analysis allows one to extract the smallest number of typical maps (principal components: V1, V2, V3,...) needed to reconstruct the sequence of any individual beat by weighted summation of the principal components. The correlation between a principal component and any individual beat may be estimated by calculating the usual coefficient r.

an activation pattern). In the third case, all maps should appear as uniformly scaled copies of one another (weighing factor acting on V1). Applied to monomorphic VTs, the analysis showed that a single principal

component accounted for most of the information content (designated as the activation variance) in series of many beats. The correlation coefficients between the individual beats and V1 were close to 1, thereby confirming that CL variations

624 CARDIAC MAPPING (e.g., decelerating trend in rate) could negative slope of the activation complex occur while the basic activation pattern in unipolar electrograms recorded in the remained constant, and corresponded to reentry circuit (lower map, dV/dtmax). In a uniform change in activation times fact, we showed that a decrease in the (delay) at all sites. -dV/dtmax of unipolar electrogram activation complexes occurred in association with prolongation of conduction times during the course of CL prolongation.27 Potential Significance of CL In theory, the unipolar electrogram ampliDynamics at Tachycardia Onset tude and the -dV/dtmax of its activation We therefore proposed that the expo- complex are determined by the current nential trends in CL occurring at tachy- strength and speed of the wavefront, which cardia onset may provide signatures related in turn depend on+ (1) the active generato the properties of tissue involved in the tor properties (Na current) of individual reentry circuit (rather than to changes in fibers; (2) the size of the fiber population circuit configuration), a proposition that sampled by the electrode; (3) synchrony of could be investigated further in canine their activation; and (4) intercellular infarct preparations. Morphological exam- resistivity. In the context of 3-day-old ination of canine hearts several days after infarct canine preparations, low -dV/dtmax occlusion of their left anterior descending values are consistent with depression of potential upstroke coronary artery shows anteroseptal infarc- intracellular action 28 29,30 tion and survival of a subepicardial muscle characteristics and reduction in INa. layer (1 to 3 mm in thickness) overlying Progressive increase in conduction time necrotic tissue in the anterior wall of the associated with further depression of left ventricle (LV). VTs are generated by action potential upstrokes occurs in surreentrant activity induced in the surviving viving muscle of canine infarct preparamuscle.24-26 The subepicardial location of the tions after abrupt transition to a faster 31,32 reentry substrate allows high-resolution pacing rate or programmed stimulation, mapping with a plaque electrode carrying whereas in healthy canine ventricular up to 256 recording contacts (2.5-mm muscle subjected to a similar pacing prospacing) applied onto the anterior LV tocol in situ, conduction velocity is unaffected in the longitudinal fiber direction wall. and only slightly reduced in the transverse direction.33,34 We found that abrupt Decelerating Trend transition to rapid pacing in normal canine muscle superfused in vitro The dynamic trend most frequently induced prolongation of conduction times observed in patients (42% of 59 tachycar- that could be fitted to an exponential dias) and in canine preparations (75% of mathematical model, and that verapamil 12 tachycardias)17 was one in which CL induced an increase in the time constant increases (i.e., instantaneous rate decel- to stabilization; this suggests that Ca2+ erates). In the canine preparation illus- modulation of cellular coupling may also trated in Figure 4, the activation sequence be involved in the prolongation of conduc(V1) shows a figure-of-8 pattern24 (upper tion times.35 We surmise that in canine subacute map, activation) and is consistent with functionally determined reentry (of the MI, a decelerating rate trend at tachycaranisotropic type).25,26 Low -dV/dtmax values dia onset indicates the involvement of were measured at the point of maximum depressed Na+-dependent action potentials

POSTINFARCTION MONOMORPHIC AND POLYMORPHIC VTS

625

Figure 4. Decelerating dynamic behavior during reentry occurring in functionally depressed subepicardial muscle surviving in a 3-day-old infarct canine preparation. Upper trace: Induction by programmed stimulation (S2) of a sustained monomorphic ventricular tachycardia. Graph: Cycle length increased as a function of beat number. Upper map: Activation sequence suggesting that functional reentry occurred according to a figure-of-8 activation pattern (arrows) in which the tachycardia cycle was initiated in the center of the ischemically damaged region (time 0), and the impulse then divided at the 40 ms isochronal line into 2 wavefronts (downward arrows) which were conducted in the apical (left) and basal (right) parts of the ischemically damaged region, respectively, around arcs of functional dissociation (thick lines). At the 170 ms point, the wavefronts merged again into a single wavefront, which was conducted back along a common reentrant pathway (from 170 to 244 ms) and initiated the next tachycardia cycle (time 0). Lower map: Conduction occurred in muscle generating unipolar electrograms displaying depressed -dV/dtmax values (<1.0 V/s). The inset shows a representation of the anterior face of the right (RV) and left (LV) ventricles and the position of the plaque electrode carrying 127 recording contacts on the anterolateral wall of the LV. By convention, one edge of the plaque electrode (thick edge) was aligned along the nearby segment of the left anterior descending (LAD) coronary artery. Modified from reference 17.

in the reentry circuit, as illustrated with a drawing shown in Figure 1B. However, there is no consensus regarding the role of depressed Na+-dependent action potentials in human long-term MI. Several authors have expressed the view that "the tissues responsible for arrhythmogenesis are, in fact, comprised of normal myocardial cells, and that the slowing in conduction reflects cellular uncoupling by intervening fibrosis"36 on the basis that (1) drugs acting

selectively on depressed action potentials (lidocaine) show poor efficacy in patients with late postinfarction VTs, and (2) action potentials with apparently normal configuration have occasionally been recorded from tissue putatively involved in tachycardia generation excised at surgery.37 On the other hand, it is possible to record action potentials displaying depressed upstrokes from human arrhythmogenic ventricular tissues.38

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CARDIAC MAPPING

Lidocaine failed to suppress reentry in canine subacute infarct preparations.39 We found that the drug produced electrical inactivation over a wider area of the ischemically damaged region as the dose was increased, but some areas were spared from block and activity persisted along a continuous path in the circuit (Figure 4 in reference 39); therefore, the monomorphic VTs could still be induced even with lidocaine concentrations in the high therapeutic range. Thus, the selective inhibition by lidocaine of Na+ channel activity in the inactivated state did not translate into tachycardia suppression because the drug failed to produce complete block in the ischemically damaged region. Our recent experiments in canine preparations show that it is also important to consider the individual Class I drugs' kinetics of interaction with Na+ channels and blocking action on K+ currents since procainamide (displaying slower kinetics of interaction with Na+ channels40 as well as prolonging repolarization intervals) can induce cumulative depression of excitability in successive beats, leading to complete block in the reentry circuit and termination of the tachycardias, an effect that is consistent with its relatively greater clinical efficacy.41-43 Accelerating Trend This type of trend occurred in a smaller number of VTs induced in patients and in canines.17 In a different canine preparation than the one illustrated in Figure 4, the plot of CL as a function of beat number shows that there was a rapid decrease in CL (rate acceleration) before stabilization occurred (Figure 5). The activation map (V1) shows that single-loop reentry occurred around a region of inexcitability playing the role of a central obstacle. Also, the dV/dtmax values of the unipolar electrogram activation complex (lower map) measured in muscle

sustaining reentry were higher than in the VT showing a decelerating trend. We suggest that the accelerating trend may be related to adaptation of the duration of action potentials to the change in rate. It is known that after a sudden change in rate to a shorter CL, the time course of the action potential duration shows an initial shortening over the first few beats (followed by decremental shortening over the next few minutes).44-46 We postulate that in the early beats of some tachycardias, the action potential upstroke might encroach on the repolarization phase of the preceding action potential and that the initial phase of CL acceleration might occur as the head of the reentrant impulse withdraws from the refractory tail of the preceding action potential with shortening of the action potential duration (illustrated with a drawing in Figure 2B). It is reasonable to expect that such a mechanism would be operative in fast tachycardias only. Accordingly, the clinical tachycardias displaying accelerating onset dynamics had shorter CL (mean of 224 ms) than those displaying decelerating trends (mean of 319 ms).17 In principle, such tachycardias could be inhibited at their onset by Class III antiarrhythmic drugs. Interestingly, several investigators47-49 reported that sotalol's efficacy in preventing arrhythmia induction was relatively greater against ventricular fibrillation versus VTs, and especially against tachycardias with relatively shorter CL at baseline study. Constant CL (Flat Trend) In approximately 20% of the clinical VTs investigated in the operating room, CL fluctuations occur about a constant CL. This might imply that (1) the circuit length is long enough and the tachycardia rate is slow enough for rate-dependent properties to remain latent, or (2) the circuit consists of

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627

Figure 5. Accelerating dynamic behavior during circus movement reentry induced in another 3-dayold infarct canine preparation. Upper trace: Induction, by programmed stimuli (3 x S1, S2, S3, S4, S5), of a rapid sustained monomorphic ventricular tachycardia. Graph: Cycle length was a decreasing function of beat number. Upper map: Circus movement reentry occurred around an obstacle created by inexcitable tissue (gray). The beginning of the cycle (0 time) was arbitrarily taken to occur in the lateral part of the ischemically damaged region (lower portion of map). The impulse propagated in a clockwise direction along the apical portion (0 to 30 ms), the right ventricular margin (30 to 100 ms), the basal (100 to 130 ms), and the lateral portions (130 to 192 ms) of the ischemically damaged region, back to the site where the next cycle began. This tachycardia was induced during infusion of d-sotalol (4 mg/kg/h). Although a similar reentrant tachycardia was induced under basal conditions, the circuit was clearer during the tachycardia induced under Class III drug. Lower map: The muscle sustaining reentry displayed fairly good action potential upstroke properties as indicated by -dV/dtmax values >1.0 V/s along most of the reentrant pathway. The inset shows the position of the plaque electrode on the anterolateral left ventricular wall. Modified from reference 17.

tissue displaying no rate-dependent conduction properties. We have not encountered this type of trend in 3-day-old infarct canine preparations. In the context of the Sicilian Gambit group's proposition that antiarrhythmic drug therapy should be targeted on the basis of pathophysiological mechanisms involved in specific arrhythmias,50 consideration of the dynamic properties of

reentrant arrhythmias could be useful in the identification of critical components of the reentrant substrate and vulnerable parameters. Polymorphic VTs Polymorphic VTs show beat-tobeat changes in EGG morphology that

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correspond to yet undefined modifications of the ventricular activation sequence. One reason for the fact that much less is known about the substrates underlying polymorphic tachycardias in patients with prior MI (in the presence of normal QT interval) is methodological, since the EGG can yield little information other than to indicate their polymorphic character. The lack of a repetitive activation sequence precludes the pooling of data collected in different beats during sequential mapping with a transvenous electrode catheter or a hand-held probe. A more fundamental reason, however, is that their significance remains unclear since polymorphic VTs can be induced by aggressive programmed stimulation protocols in patients without documented or suspected ventricular arrhythmia.51 Sustained polymorphic VTs can be induced in many patients with prior MI, characteristically in those who suffered a cardiac arrest rather than presenting with a history of sustained monomorphic yp 52,53 The hypothesis that polymorphic tachycardias induced in the setting of chronic infarction share the same reentrant substrate as the sustained monomorphic ones53 is supported by indirect evidence including the fact that they are associated with typical conduction abnormalities (e.g., fractionated electrograms recorded during sinus rhythm) and that they can be converted to typical sustained monomorphic VTs by Class I antiarrhythmic agents (e.g., procainamide). It is also consistent with the fact that a VT may become monomorphic after an initial polymorphic phase. During intraoperative study for antiarrhythmic surgery, a rapid VT (CL = 180 to 210 ms) induced in a patient with prior anteroseptal infarction (Figures 6 and 7) displayed polymorphic complexes during the initial 20 beats, a tendency to stabilize between beats 21 and 105, and then, again, polymorphic beats before spontaneous termination of the tachycardia.

Beats 1 to 6 as well as beats 21 to 105 correlated highly with the primary principal component (V1), whereas significant contributions from a second principal component (V2) occurred in beats 9 to 11 and 119 to 123 (Figure 6). In beats correlating highly with V1 (Figure 7A), the area of earliest activation (zero time, defined as the beginning of bulk ventricular activation, i.e., QRS onset) was located in the lateral LV wall, probably being the exit point of reentrant activity occurring at the anterolateral margin of the scar (where low-amplitude delayed activity was detected on the endocardial surface), as indicated by a thick arrow directed from the endocardial to the epicardial surface. The epicardial activation pattern occurred from the anterolateral LV wall toward the lateral wall of the right ventricle (RV) (thin arrows). In the isochronal map of beat 11 (Figure 7B, representing the contribution of V2), the area of earliest activation (0) was detected on the endocardial surface in the posterior LV wall, next to a site of delay (130 ms), from which reentrant activity may have propagated from one beat to the next (thick arrow: 180 ms in the illustrated beat marks the beginning of the next beat). The earliest epicardial activation (at 5 ms) was localized at a posterior location (overlying the site of earliest endocardial activation) and the epicardial activation sequence occurred in the posterior to anterior direction (thin arrows). Thus, the correlation coefficient between the primary principal component and the activation vectors was high in the early beats (1 to 6), but it then decreased as the earliest epicardial breakthrough site shifted from the LV anterolateral region toward the LV posterior region (beat 11) and correlation with V2 increased (Figure 6). In beat 17 (Figure 7C), which showed a high degree of negative correlation with Vl5 the earliest epicardial breakthrough shifted to the RV lateral wall, thereby imposing a reverse epicardial activation

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629

Figure 6. Principal component analysis of a rapid ventricular tachycardia induced in a patient with long-term myocardial infarction subjected to intraoperative mapping (127 epicardial and 64 endocardial recordings). Upper trace: Lead II ECG showing the induction of ventricular tachycardia by programmed stimulation (S2, S3). Graphs: Concordance (expressed as the correlation coefficient A) between the activation vector of individual beats (activation times) and the primary (V1: upper graph) and second principal component (V2: lower graph).

sequence (i.e., from lateral RV to lateral LV: thin arrows) with reference to that in V1. The RV epicardial breakthrough may have been generated by reentry of the delayed activity detected on the LV endocardial aspect of the posterior septum (here expressed as presystolic activity: -51 ms). The epicardial breakthrough shifted back to the LV anterolateral area in beats 21 to 105.

Thus, principal component analysis is a useful means to extract common features between the activation sequences of individual beats in series of many polymorphic beats. When a single principal component is sufficient to reconstruct all beats of a tachycardia (a monomorphic one), it corresponds to an isochronal map that is practically identical to the activation sequences of each individual beat

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Figure 7. Varying activation sequences during a rapid ventricular tachycardia induced in a patient with remote anteroapical infarction (same as in Figure 6). Upper trace: Lead II ECG showing the same tachycardia as in Figure 6. Upper isochronal maps: Polar representation of the epicardial surface in which the base of the ventricles is at the circumference and the apex at the center (sock electrode array). The inset indicates the course of the left anterior descending (LAD) and posterior descending (PDA) coronary arteries, which mark the anterior and posterior boundaries, respectively, between the right (RV) and the left ventricle (LV). Lower isochronal maps: Activation times (ms) at the LV endocardial surface (endocardial balloon array; sep. = septum; ant., post., lat. = anterior, posterior, and lateral walls, respectively). The epicardial and endocardial locations of the areas of inexcitability are indicated by shading. A. Isochronal map representative of beats 1 to 6 and 21 to 105. B. and C. Isochronal maps for beats 11 and 17, respectively. In A and B, also indicated, at the site of the earliest activation (0) of the illustrated activation cycle, are the activation time marking the beginning of the next tachycardia cycle (206 and 180 ms, respectively).

(r is close to 1). In polymorphic tachycardias, only a few principal components are needed to represent episodes of several dozen beats.54,55 In preliminary analyses of 8 polymorphic VT induced in 5 patients, all beats were generated in association with the region of infarction, as indicated by the localization of the sites of earliest activation and areas of maximum recorded delay in peri-infarction tissue. Beat-tobeat changes in QRS morphology occurred in 3 different situations. In the first, the

locations of both the sites of earliest activation and the sites of delayed activity shifted between distinct parts of the region of infarction (as between Figure 7A and Figure 7B), suggesting that different parts of the region of infarction acted as distinct substrates. In a second situation, the sites of earliest activation shifted along the epicardial and endocardial margins of the region of infarction while the area of maximum delay occurred at a constant location

POSTINFARCTION MONOMORPHIC AND POLYMORPHIC VTs in the region of infarction (e.g., the posterior septum in Figures 7B and 7C). This suggests that changes in ECG morphology may occur as a result of variable exit points from a constant regional substrate of slow conduction.56,57 Third, the occurrence of a typical RV epicardial breakthrough pattern similar to that occurring in sinus rhythm (not illustrated herein), suggested that the left bundle branch may have been retrogradely invaded by impulses generated in the region of infarction and anterogradely conducted in the right bundle branch. Changes in morphology may then have been caused by intermittent involvement of the conduction system and its variable timing. A similar mechanism for spontaneous change in ECG morphology during VT has been demonstrated in canine preparations of MI.58 The cause of such instability of activation patterns may be related to the fact that beat-to-beat CL variations call into play the frequency-dependent conduction properties within the reentry circuit(s) or along their exit paths, thereby causing changes in circuit configuration or ventricular activation pattern, or alternating expression of one or the other circuit. Polymorphic VTs, which, unlike the ones discussed above, are not associated with fixed pathological substrates, may occur under conditions inducing extreme prolongation and heterogeneity of repolarization intervals, as with the combination of a slow heart rate and Class III antiarrhythmic drug. This type of arrhythmia, which displays characteristics similar to those expected from torsades de pointes, is discussed in detail elsewhere in this book. Briefly, arrhythmias occurring in the presence of d-sotalol appeared, in our analyses, to involve abnormal impulse formation in shifting portions of the ventricular conduction system as well as changing reentry circuits around the refractory barriers created by inhomo-

631

geneous prolongation of repolarization intervals.59,60 Conclusion Analysis of the CL dynamics of monomorphic VTs at their onset can be used to gain further information on the functional properties of the underlying reentry circuit. Since the temporal analysis can be made from a single ECG lead, this may be an interesting noninvasive method to acquire such information. Further studies are needed to explore its usefulness for the selection of antiarrhythmic drug and device therapeutic modalities. The electrophysiological substrates of tachycardias, especially fast ones, also display spatial dynamic properties marked by changes in the global ventricular activation sequence in relation to shifts in the tachycardia origin, varying exit from a constant site of origin, or intermittent involvement of the conduction system. References 1. Downar E, Kimber S, Harris L, et al. Endocardial mapping of ventricular tachycardia in the intact human heart. II. Evidence for multiuse reentry in a functional sheet of surviving myocardium. J Am Coll Cardiol 1992;20:869-878. 2. De Bakker JMT, van Capelle FJL, Janse MJ, et al. Macroreentry in the infarcted human heart: The mechanism of ventricular tachycardias with a "focal" activation pattern. JAm Coll Cardiol 1991;18:1005-1014. 3. Kaltenbrunner W, Cardinal R, Dubuc M, et al. Epicardial and endocardial mapping of ventricular tachycardia in patients with myocardial infarction: Is the origin of the tachycardia always subendocardially localized? Circulation 1991;84:1058-1071. 4. Branyas NA, Cain ME, Cox JL, Cassidy DM. Transmural ventricular activation during consecutive cycles of sustained ventricular tachycardia associated with coronary artery disease. Am J Cardiol 1990;65:861867.

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as a precursor of sustained ventricular 5. Duff HJ, Mitchell LB, Gillis AM, et al. Electrocardiographic correlates of spontachyarrhythmias. Circ Res 2001;88:705712. taneous termination of ventricular tachycardia in patients with coronary artery 16. Page PL, Cardinal R, Shenasa M, et al. Regional cryoablation guided by computdisease. Circulation 1993;88:1054-1062. 6. Pogwizd SM, Chung MK, Cain ME. Termierized epicardial and endocardial mapping. nation of ventricular tachycardia in the Circulation 1989;80(Suppl I):I124-I134. human heart. Insights from three-dimen- 17. Vinet A, Cardinal R, Le Franc P, et al. sional mapping of nonsustained and susCycle length dynamics and spatial stability at the onset of post-infarction monomortained ventricular tachycardias. Circulation 1997;95:2528-2540. phic ventricular tachycardias induced in 7. Sigman E, Cardinal R, Vinet A, et al. patients and canine preparations. CircuDecelerating dynamic behavior of nonsuslation 1996;93:1845-1859. tained reentrant monomorphic ventricu- 18. Hund TJ, Otani NF, Rudy Y. Dynamics of lar tachycardias in human myocardial action potential head-tail interaction during infarction. Circulation 1997;96(Suppl I): reentry in cardiac tissue: Ionic mechanisms. 1-747. Am JPhysiol 2000;279:H1869-H1879. 8. Frame LH, Simson MB. Oscillations of 19. Ciaccio EJ. Dynamic relationship of cycle conduction, action potential duration and length to reentrant circuit geometry and to refractoriness: A mechanism for spontathe slow conduction zone during ventricuneous termination of reentrant tachycarlar tachycardia. Circulation 2001;103:10171024. dias. Circulation 1988;78:1277-1287. 9. Schmitt H, Wit AL, Coromilas J, Waldecker 20. Lux RL, Evans AK, Burgess MJ, et al. B. Mechanisms for spontaneous terminaRedundancy reduction for improved display and analysis of body surface potential tion of monomorphic, sustained ventricular tachycardia: Results of activation mapping maps. I. Spatial compression. Circ Res of reentrant circuits in the epicardial border 1981;49:186-196. zone of subacute canine infarcts. J Am Coll 21. Hubley-Kozey CL, Mitchell LB, Gardner Cardiol 1998;31:460-472. MJ, et al. Spatial features in body-surface potential maps can identify patients with 10. Geibel A, Zehender M, Brugada P. Changes in cycle length at the onset of sustained a history of sustained ventricular tachytachycardia—importance for antitachycarcardia. Circulation 1995;92:1825-1838. dia pacing. Am Heart J1998; 115:588-592. 22. Watanabe T, Yamaki M, Kubota I, et al. 11. Volosin KJ, Beauregard LAM, Fabiszewski Relation between activation sequence flucR, et al. Spontaneous changes in ventricutuation and arrhythmogenicity in sodiumlar tachycardia cycle length. J Am Coll channel blockades. Am JPhysiol 1999;277: H971-H977. Cardiol 1991;17:409-414. 12. Fromer M, Cardinal R, Page P, et al. Vari- 23. Morrison DF. Multivariate Statistical Methation in cycle length of induced ventricuods. New York: McGraw-Hill; 1990:312-351. lar tachycardia episodes in humans. In: 24. Mehra R, Zeiler RH, Gough WB, El-Sherif N. Shenasa M, Borggrefe M, Breithardt G Reentrant ventricular arrhythmias in the (eds): Cardiac Mapping. Mount Kisco, NY: late myocardial infarction period. 9. Electrophysiologic-anatomic correlation of reenFutura Publishing Co.; 1993:507-514. 13. Anderson KP, Shusterman V, Aysin B, et al. trant circuits. Circulation 1983;67:11-24. Distinctive RR dynamics preceding two 25. Cardinal R, Vermeulen M, Shenasa M, et al. Anisotropic conduction and functional dismodes of onset of spontaneous sustained ventricular tachycardia. (ESVEM) Invessociation of ischemic tissue during reentrant ventricular tachycardia in canine tigators. Electrophysiologic study versus myocardial infarction. Circulation 1988;77: electrocardiographic monitoring. J Car1162-1176. diovasc Electrophysiol 1999;10:897-904. 14. Pruvot E, Thonet G, Vesin JM, et al. 26. Dillon SM, Allessie MA, Ursell PC, Wit Heart rate dynamics at the onset of venAL. Influences of anisotropic tissue structricular tachyarrhythmias as retrieved ture on reentrant circuits in the epicardial border zone of subacute canine from implantable cardioverter-defibrillators in patients with coronary artery disinfarcts. Circ Res 1988;63:182-206. ease. Circulation 2000;101:2398-2404. 27. Helie F, Vinet A, Cardinal R. Cycle length dynamics at the onset of postinfarction 15. Shusterman V, Aysin B, Anderson KP, Beigel ventricular tachycardias induced in canines: A. Multidimensional rhythm disturbances

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Dependence on interval-dependent excitation properties of the reentrant substrate. J Cardiovasc Electrophysiol 2000; 11:531-544. 28. Ursell PC, Gardner PI, Albala A, et al. Structural and electrophysiological changes in the epicardial border zone of canine myocardial infarcts during infarct healing. CircRes 1985;56:436-451. 29. Patterson E, Scherlag BJ, Lazzara R. Rapid inward current in ischemicallyinjured subepicardial myocytes bordering myocardial infarction. J Cardiovasc Electrophysiol 1993;4:9-22. 30. Pu JP, Boyden PA. Alterations of Na+ currents in myocytes from epicardial border zone of the infarcted heart. A possible mechanism for reduced excitability and postrepolarization refractoriness. Circ Res 1997;81:110-119. 31. Hope RR, Scherlag BJ, Lazzara R. Excitation of ischemic myocardium: Altered properties of conduction, refractoriness and excitability. Am Heart J 1980;99:753-765. 32. El-Sherif N, Mehra R, Gough WB, Zeiler RH. Reentrant ventricular arrhythmias in the late myocardial infarction period. 11. Burst pacing versus multiple premature stimulation in the induction of reentry. J Am Coll Cardiol 1984;4:295-304. 33. Spach MS, Kootsey JM, Sloan JD. Active modulation of electrical coupling between cardiac cells of the dog. A mechanism for transient and steady state variations in conduction velocity. CircRes 1982;51:347-362. 34. Tsuboi N, Kodama I, Toyama J, Yamada K. Anisotropic conduction properties of canine ventricular+ muscles. Influence of high extracellular K concentration and stimulation frequency. Jpn Circ J 1985;49:487-497. 35. Lemarbre F, Vinet A, Vermeulen M, Cardinal R. Onset dynamics of reentrant tachycardia and rate-dependent conduction changes in canine ventricular muscle: Effects of Na+ and Ca2+ channel blockade. J Electrocardiol 2000;33:349-360. 36. Hook BG, Josephson ME. Effects of drugs on arrhythmia substrate in vivo: Update. In: Fisch C, Surawicz B (eds): Cardiac Electrophysiology and Arrhythmias. New York: Elsevier Science Publishing Co.; 1991:297313. 37. De Bakker JMT, van Capelle FJL, Janse MJ, et al. Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: Electrophysiologic and anatomic correlation. Circulation 1988;77:589-606.

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38. Moore EN, Spear JF, Horowitz LN, Josephson ME. Electrophysiological mechanisms causing ventricular tachyarrhythmias. In: Sandoe E, Julian DG, Bell JW (eds): Management of Ventricular Tachycardia— Role of Mexiletine. Amsterdam, The Netherlands: Excerpta Medica; 1978:3-15. 39. Helie F, Cossette J, Vermeulen M, Cardinal R. Differential effects of lignocaine and hypercalcaemia on anisotropic conduction and reentry in the ischaemically damaged canine ventricle. Cardiovasc Res 1995;29:359-372. 40. Campbell TJ. Kinetics of onset of ratedependent effects of Class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification. Cardiovasc Res 1983; 17: 344-352. 41. Horowitz LN, Josephson ME, Farshidi A, et al. Recurrent sustained ventricular tachycardia 3. Role of the electrophysiologic study in selection of antiarrhythmic regimens. Circulation 1978;58:986-997. 42. Iesaka Y, Aonuma K, Nitta J, et al. Effects of procainamide and lidocaine on electrically inducible ventricular tachycardia studied with programmed ventricular stimulation in post myocardial infarction. Jpn Circ J 1988;52:262-271. 43. Gorgels AP, van den Dool A, Hofs A, et al. Comparison of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Am J Cardiol 1996;78:43-46. 44. Elharrar V, Surawicz B. Cycle length effect on restitution of action potential duration in dog cardiac fibers. Am JPhysiol 1983;244: H782-H792. 45. Kanaan N, Jenkins J, Childs K, et al. Monophasic action potential duration during programmed electrical stimulation. Pacing Clin Electrophysiol 1991;14:1049a-1059. 46. Franz MR, Swerdlow CD, Liem LB, Schaefer J. Cycle length dependence of human action potential duration in vivo. Effects of single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies. J Clin Invest 1988;82:972-979. 47. Kuchar DL, Garan H, Venditti FJ, et al. Usefulness of sotalol in suppressing ventricular tachycardia or ventricular fibrillation in patients with healed myocardial infarcts. Am J Cardiol 1989;64:33-36. 48. Young GD, Kerr CR, Mohama R, et al. Efficacy of sotalol guided by programmed

634 CARDIAC MAPPING electrical stimulation for sustained ventricular arrhythmias secondary to coronary artery disease. Am J Cardiol 1994; 73:677-682. 49. Haverkamp W, Martinez-Rubio A, Hief C, et al. Efficacy and safety of d,l-sotalol in patients with ventricular tachycardia and in survivors of cardiac arrest. J Am Coll Cardiol 1997;30:487-495. 50. Breithardt G, Camm AJ, Campbell RWF, et al. Antiarrhythmic Therapy: A Pathophysiologic Approach. Armonk, NY: Futura Publishing Co.; 1994. 51. Buxton AE, Waxman HL, Marchlinski FE, et al. Role of triple extrastimuli during electrophysiologic study of patients with documented sustained ventricular tachyarrhythmias. Circulation 1984;69: 532-540. 52. Adhar GC, Larson LW, Bardy GH, et al. Sustained ventricular arrhythmias: Differences between survivors of cardiac arrest and patients with recurrent sustained ventricular tachycardia. J Am Coll Cardiol 1988; 12:159-165. 53. Josephson ME. Clinical Cardiac Electrophysiology. Philadelphia, London: Lea & Febiger; 1993:446, 477. 54. Cardinal R, Vinet A, Le Franc P, et al. Beat-to-beat stability of spatial activation patterns during monomorphic and polymorphic ventricular tachycardias induced in human myocardial infarction. Circulation 1995;92(Suppl I):I-335.

55. Cardinal R, Vinet A, Vermeulen M, et al. Do monomorphic and protracted polymorphic ventricular tachycardias induced in human myocardial infarction share common electrophysiologic substrates? Circulation 1997;96(Suppl I):I-334. 56. Kimber SK, Downar E, Harris L, et al. Mechanisms of spontaneous shift of surface electrocardiographic configuration during ventricular tachycardia. J Am Coll Cardiol 1992;20:1397-1404. 57. Downar E, Saito J, Doig JC, et al. Endocardial mapping of ventricular tachycardia in the intact human heart. III. Evidence of multiuse reentry with spontaneous and induced block in portions of reentrant path complex. JAm Coll Cardiol 1995;25:1591-1600. 58. Cardinal R, Savard P, Carson DL, et al. Mapping of ventricular tachycardia induced by programmed stimulation in canine preparations of myocardial infarction. Circulation 1984;70:136-148. 59. Derakhchan K, Cardinal R, Brunet S, et al. Polymorphic ventricular tachycardias induced by d-sotalol and phenylephrine in canine preparations of atrioventricular block: Initiation in the conduction system followed by spatially unstable reentry. Cardiovasc Res 1998;38:617-630. 60. Gray RA, Jalife J, Panfilov A, et al. Nonstationary vortexlike reentrant activity as a mechanism of polymorphic ventricular tachycardia in the isolated rabbit heart. Circulation 1995;91:2454-2469.

Chapter 33

Mapping of Unstable Unstable Ventricular Ventricular Tachycardia William G. Stevenson, MD and Peter L. Friedman, MD, PhD

Scar-related ventricular tachycardias (VTs), such as those resulting from prior myocardial infarction, can be due to large, complex reentry circuits.1-8 Many reentry circuits use a relatively narrow channel or isthmus in the abnormal area. Depolarization of the isthmus is not detected from the surface ECG. The QRS complex is inscribed when the circulating reentry wavefront emerges from the exit and propagates across the ventricles. The circuit can often be interrupted by radiofrequency (RF) ablation in the isthmus, but the isthmus can be difficult to identify, sometimes requiring extensive mapping,6,9,10 which is possible is VT if inducible, well tolerated, and stable. The patient remains in VT for a period of time, while a simple roving catheter is moved from point to point to find the appropriate target. Initial catheter ablation approaches were therefore largely limited to monomorphic VTs that are sufficiently stable to allow catheter mapping. Many patients have unstable tachycardias that do not allow extensive catheter

mapping. VT can be unstable, preventing extensive mapping for any of several reasons. The tachycardia can cause hemodynamic collapse. Multiple tachycardias can be present in an individual patient with repeated transformation from one tachycardia to another during attempted mapping. In some cases, a tachycardia that has occurred repeatedly, spontaneously is not inducible in the electrophysiology laboratory. Burke and co-workers11 found that inducible VT was not sufficiently hemodynamically stable to allow catheter mapping in 52 (44%) of 117 consecutive patients with sustained monomorphic VT resulting from prior myocardial infarction. Even when spontaneous VT is well tolerated, initiation of the arrhythmia in the electrophysiology laboratory may cause hypotension, possibly related to impaired reflex responses resulting from sedation and diminished intravascular volume due to fasting. Of 40 consecutive patients with recurrent VT due to prior myocardial infarction who were referred for catheter ablation, 50% had both stable and unstable VTs

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003.

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promptly restored. If induced tachycardias are poorly tolerated, intracardiac filling pressures should be assessed with a pulmonary artery catheter. Even patients I. Optimize hemodynamic support who have poor ventricular function can be A. Adjust filling pressures B. Inotropic support volume depleted with relatively low pulC. Intra-aortic balloon counterpulsation monary capillary wedge pressure after D. Cardiopulmonary support diuresis and periods of fasting prior to the II. Antiarrhythmic drug administration to study. Careful volume expansion may be slow VT required even in patients with chronic heart III. Mapping the arrhythmia substrate during sinus rhythm failure. If filling pressures are adequate, A. Abnormal electrograms administration of intravenous dopamine, 1. Low-amplitude areas starting at a low dose of 2 to 3 jug/kg/min 2. Late potentials may aid in maintaining hemodynamic sta3. Fractionated electrograms bility. Often these measures allow tolerB. Pace mapping 1. QRS morphology suggests reentry ance of brief periods of VT. In some cases, circuit exit VT can then be repeatedly induced and 2. S-QRS >40 ms indicates abnormal terminated by pacing with sufficient reliconduction ability to allow mapping. This approach IV. Mapping systems for simultaneous combined with targeting regions of abnorsampling of multiple sites A. Basket catheters mal conduction identified during sinus 1. Mathematical reconstruction of virtual rhythm (see below) may allow successful electrograms—"noncontact" mapping ablation in some cases. systems If VT is not sufficiently tolerated with the measures discussed above but tachyinducible, 33% had only unstable VTs, and cardia is relatively slow, it may be possible only 7 (17%) had solely stable VTs that 9 to use intra-aortic balloon counterpulsaallowed extensive mapping. tion to provide hemodynamic support. It is Several potential approaches to ablaimportant to recognize that inflation of the tion of unstable VTs have been considered balloon against a mapping catheter in the (Table 1). These approaches attempt to aorta produces an artifact that can be misimprove stability to allow extensive mapping, to acquire relevant mapping data from taken for diastolic electrograms. The use of cardiopulmonary support to a very short period during tachycardia, or maintain hemodynamic stability during to use assessment of electrophysiological VT in the electrophysiology laboratory has characteristics during stable sinus rhythm 12 been suggested. This system requires to guide placement of ablation lesions. arterial and venous access with large cannulae and a perfusionist to operate the Optimizing Hemodynamic system. The risks and potential benefits Support have not been defined for patients with VT. Careful hemodynamic monitoring is mandatory during catheter mapping and Antiarrhythmic Drugs for Slowing VT ablation of VT. Frequently, initiation of VT Administration of an antiarrhythis followed by transient hypotension with gradual recovery of arterial pressure over mic drug may slow inducible VT and 30 to 60 seconds. If recovery does not occur improve hemodynamic tolerance. Intrapromptly, or if hypotension is associated venous administration of procainamide with syncope, sinus rhythm should be has been commonly used for this purpose, Table 1 Mapping Poorly Tolerated Ventricular Tachycardia (VT)

MAPPING OF UNSTABLE VENTRICULAR TACHYCARDIA but this practice has not been well studied.13 After a loading bolus, a continuous infusion should be considered, particularly during long procedures. Antiarrhythmic drug administration introduces several potential problems. Fluctuating drug levels introduce another variable that influences arrhythmia induction, potentially complicating the interpretation of ablation effects. If a VT is no longer inducible, it may be difficult to know whether the drug is responsible for the change, as opposed to successful ablation. In some cases, the VT is slowed but hemodynamic tolerance is not improved. Procainamide is a potent vasodilator and it also has negative inotropic effects. Marked slowing of conduction through the myocardium may lengthen the QRS duration, which sometimes seems to impair cardiac performance. Drug administration may have a proarrhythmic effect with incessant but slowed VT. Some of these concerns may be less of a problem during chronic, oral drug administration. Chronic oral drug administration also allows use of amiodarone or sotalol which, despite less depression of conduction than the Class I sodium channel blocking agents, nonetheless often slow the VT rate. A major and unresolved concern regarding the use of antiarrhythmic drugs to facilitate mapping is the possibility that the drug will modify the arrhythmic substrate, leading ablation attempts to target a region that does not cause spontaneous VT in the absence of the drug.14 These potential problems have not been adequately denned. If antiarrhythmic drugs are used during ablation and then subsequently withdrawn, repeat electrophysiological testing should be considered to assess the effects of the ablation procedure.

Mapping the Arrhythmia Substrate During Sinus Rhythm Identifying likely target regions during sinus rhythm allows limited mapping to be

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performed during induced VT or ablation to be performed entirely during stable sinus rhythm. Sinus Rhythm Electrograms The amplitude of electrograms recorded by mapping catheters is lower in areas of infarction or scar than in areas of normal myocardium.15-17 Areas of scar or infarct that give rise to ventricular reentry circuits can thereby be identified from 3dimensional reconstructions of the ventricles that plot electrogram amplitude (Figure 1). The recording methods are important in assessing these maps. Electrogram amplitude is influenced by interelectrode distance, contact of the electrode with the underlying tissue, and filter settings. In general, bipolar electrograms recorded from regions of infarction have an amplitude less than 1.5 mV, and often substantially less.15-17 Kornowski and co-workers16 observed a mean bipolar electrogram amplitude of 1.4 ± 0.7 mV in the infarct region compared to 4.5 ± 1.1 outside the infarct region. Marchlinski and co-workers,18 using bipolar recordings with a 1-mm spacing and filtering at 10 to 400 Hz, found that 95% of all left ventricular (LV) electrograms in 4 normal patients had an amplitude greater than 1.5 mV. An electrogram amplitude cutoff of 1.5 mV (peak to peak) appears to provide a reasonable guide for delineation of infarct regions in patients with VT.9 Although electrogram amplitude is a good marker of an infarct area of scar, these regions of low amplitude are often quite large in patients with VT. In 40 patients with VT due to prior infarction, the average area of low-amplitude (<1.5 mV) electrograms was 38.6 ± 34.6 cm2 (range 6.4-205.4 cm2) with an average circumference of 21.4 ± 6.0 cm (range 9.4-51.0 cm).9 Additional markers are desirable for determining the location of reentry circuits within these lowamplitude regions to either focus mapping on that region during induced VT or

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Figure 1. Left ventricular maps from a patient with an old anterior wall infarction and recurrent ventricular tachycardia. Electroanatomical maps are constructed using the CARTO system. A. Map created by sampling sinus rhythm signals and displaying the maximal amplitude of each signal. The red zone indicates low-amplitude signals, purple maximal-amplitude signals. The infarct region is located over the anterior wall. Radiofrequency ablation at the superior margin of the infarct extending inferiorly and laterally abolished inducible ventricular tachycardia. B. Map of sinus rhythm activation from the same patient. Delayed activation (purple region) is present at the mid anterior wall. C. Map of SQRS intervals during pace mapping; the longest S-QRS internals are observed at the anterior wall. See color appendix.

MAPPING OF UNSTABLE VENTRICULAR TACHYCARDIA reduce the amount of ablation required for an anatomical ablation approach. Identification of regions of dense fibrosis that create conduction block is potentially useful because these regions create the border of some portions of the reentry circuit. Transection of the circuit from an area of fibrosis to another border of the circuit should interrupt the circuit. Some investigators have designated very low amplitude regions (e.g., <0.1 mV) as dense scar for the purposes of guiding ablation. The maximal peak-to-peak electrogram amplitude is not, however, a reliable indication of whether unexcitable scar is present. Unipolar pacing in these regions often captures, indicating the presence of functioning myocardium.19,20 At some sites where dense scar is present and pacing does not capture, a far-field electrogram is recorded, that is generated by depolarization of adjacent electrically active myocardium. Sinus rhythm electrograms can potentially provide further information as to the location of reentry circuit paths in low-voltage regions. Slow, asynchronous activation of muscle bundles gives rise to multiple components of the local electrogram creating a fractionated appearance (Figure 2).7,21-23 Fractionated electrograms are recorded from some areas of abnormal conduction that form isthmuses in reentry circuits. Late potentials, defined as signals that are recorded after the end of the sinus rhythm QRS complex (Figure 2), also indicate abnormal activation and are recorded from some reentry circuit isthmuses.21-25 Surgical resection of all areas that have abnormal electrograms usually abolishes VT.23'26'27 Such an extensive approach may not be feasible with catheter ablation. Abnormal sinus rhythm electrograms are virtually always recorded at sites of successful ablation where RF ablation terminates VT, suggesting that this is a sensitive finding for identifying target regions for ablation.19,24,28,29 In patients

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with prior infarction, abnormal electrograms are often recorded from several regions and do not appear to be a specific finding for locating an individual reentry circuit, but are a potential guide to general regions of interest (see below). The QRS Morphology and Pace Mapping The 12-lead ECG of spontaneous VT, if available, can be useful for identifying the quadrant of the scar that is likely to contain the exit from a critical isthmus.19,30-32 VT that has a superiorly directed frontal plane axis usually has an exit in or near the inferior wall. VT with an inferiorly directed frontal plane axis has an exit on the superior (cranial) aspect of the heart. VT with a left bundle branch block configuration has an exit in the interventricular septum or right ventricle. VT with dominant R waves across the precordial leads (V2-V5) has an exit near the base (e.g., mitral annulus). However, when the ventricle is scarred and abnormal the QRS morphology of VT can be very misleading as a guide to the reentry circuit location.19,25 Pace mapping can help to clarify the relation of the QRS morphology to the reentry circuit exit.19,31,32 Pacing at sites near the reentry circuit exit usually produces a QRS morphology similar to that of the VT. Occasionally, pace mapping at some sites yields a QRS morphology that is substantially different than expected based on the anatomical location of the pacing site. For example, in some patients with posterobasal LV aneurysms, pace mapping at the inferobasal LV produces a QRS with a left bundle branch block configuration rather than a right bundle branch block configuration, as would be expected from pacing in this portion of the LV. In addition to suggesting the reentry circuit exit location, pace mapping also detects some regions of abnormal

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Image Not Available

Figure 2. Bipolar electrograms recorded from a left ventricular infarct region during sinus rhythm before (left) and after (right) radiofrequency catheter ablation. From the top of each panel are surface ECG leads I, AVF, V1, and V5, and the bipolar electrogram recorded from the basal lateral left ventricle (LV7_10). Prior to ablation, the bipolar electrogram has a low-amplitude fractionated tail (late potential) extending beyond the end of the QRS complex (vertical arrow). After ablation, the fractionated signal is largely gone. The larger amplitude signal inscribed during the QRS complex is not significantly altered by ablation, indicating that this signal is probably due to depolarization of the larger mass of myocardium adjacent to the infarct region (far-field signal). See color appendix. From reference 21, with permission.

conduction.19 During pacing at normal sites, the shortest S-QRS interval in all 12 leads of the surface ECG is less than 40 ms. At some sites with abnormal conduction there is a discrete interval greater than 40 ms between the stimulus and the QRS onset (Figure 3).This conduction delay is consistent with slow conduction away from the pacing site and is associated with reentry circuit isthmuses (Figure 1C).19,33 This evidence of slow conduction is present at many reentry circuit sites but can also occur at bystander sites. Mapping During Sinus Rhythm to Guide Linear Ablation Approaches Several groups have shown that RF catheter ablation guided by sinus rhythm mapping and pace mapping is feasible in patients with unstable VTs.9,18,30,34 Our approach is to first induce VT and determine its morphology. If the VT is unstable, sinus rhythm is restored and mapping begun during sinus rhythm to define the

low-amplitude area of infarct. Sinus rhythm mapping is facilitated with the use of a system to create 3-dimensional ventricular plots of the ventricle (Figure 1) (e.g., CARTO, Biosense Webster, Diamond Bar, CA). At each site the presence of fractionated electrograms and late potentials is noted. Pace mapping is performed and sites with slow conduction (S-QRS > 40 ms) and where the paced QRS resembles that of the induced VT are tagged. After the abnormal area is defined, the roving mapping catheter is placed at a site in the abnormal region where pace mapping indicated abnormal conduction or a QRS similar to that of VT indicating close proximity to the reentry circuit exit. VT is then induced and entrainment quickly performed to assess whether the site is in the circuit. If the site is in the circuit and tachycardia is stable, RF current is applied to attempt to terminate the VT. If induced VT is not stable, sinus rhythm is restored and a line of RF lesions is applied through the region over a length averaging 3 cm, until pacing along the

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Figure 3. Pace mapping at an abnormal site in a left ventricular infarct region. From the top are surface ECG leads. The underlying rhythm is complete heart block with backup ventricular pacing from an implanted pacemaker (last beat at the left). Unipolar pacing at a cycle length of 400 ms is shown. Each pacing stimulus (S) is followed by a QRS complex with an S-QRS delay of 230 ms (arrow), indicating slow conduction away from the pacing site. Reproduced with permission from Stevenson WG, Kocovic D, Friedman PL. Ablation of ventricular tachycardia late after myocardial infarction: Techniques for localizing target sites. In: Huang SKS, Wilber DJ (eds): Radiofrequency Catheter Ablation of Cardiac Arrhythmias. Basic Concepts and Clinical Application. 2nd ed. Armonk, NY: Futura Publishing Co.© 2000

line fails to capture, indicating creation of a significant lesion. Lines are placed only in areas with abnormal electrograms to prevent damage to adjacent normal myocardium. When an abnormal area extends to the mitral annulus, as in an inferior or posterior wall infarction, the RF line usually extends to the mitral annulus because the submitral region of the ventricle is a common location for reentry circuit

isthmuses.35,36 After application of the initial line, programmed stimulation is repeated to assess the effect. If VT remains invducible, or if other VTs are inducible, the initial line is extended. If new morphologies of VT suggest origins remote from the initial region, a second line is started. Figure 1 shows LV maps from a patient with an old anterior wall myocardial infarction. Figure 1A shows the amplitude

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of the bipolar electrograms over the LV constructed using point-by-point acquisition with an electroanatomical mapping system.28 Low-voltage electrograms are recorded over the anterior wall consistent with prior anterior wall infarction. Some areas are not excitable, probably dense scar (gray areas), where pacing stimuli do not capture. Figure 1B shows activation during sinus rhythm. The latest activation occurs between two scarred regions in the anterior wall. Figure 1C shows the stimulus-QRS delays during pace mapping. The longest S-QRS is observed in the anterior wall region of latest activation during sinus rhythm. Programmed stimulation induced 5 different morphologies of sustained monomorphic VT. The QRS morphology of pace mapping at this region was similar to that of one of the VTs. RF ablation at this region terminated VT. A line of RF lesions was created across this region. Following ablation this VT was no longer inducible. This approach was applied in 40 patients with an average of 3.6 different inducible VTs resulting from prior myocardial infarction, 33 of whom had at least one unstable VT.9 At least one reentry circuit isthmus was identified in 25 (63%) patients. Patients in whom a VT isthmus was identified received fewer RF lesions (18 ± 10 compared to 23 ± 11), a shorter total RF line length (4.9 ± 2.4 versus 7.4 ± 4.3 cm), and were more likely to have no VT of any type inducible at the end of the procedure (72% versus 33%). Following ablation, monthly episodes of sustained VT, detected by an implantable cardioverterdefibrillator, decreased from 11 to 0.4. No episodes of VT were detected in 72% of patients with an identified isthmus, compared to 47% of patients with no isthmus identified during an average follow-up of 11.5 months. Two complications from peripheral arterial access were observed. A 4- to 5-cm RF ablation line was effective

in more than 50% of patients with this approach. The average procedure time (from entry into the laboratory to transport out of the laboratory) was 7 to 8 hours, and fluoroscopy times were approximately 30 minutes. Marchlinski and co-workers18 reported a more extensive ablation approach in 16 patients with recurrent, scar-related VTs (9 with prior myocardial infarction and 7 with nonischemic cardiomyopathies). Lines of RF lesions were placed through areas of the lowest amplitude sinus rhythm electrograms to the atrioventricular annulus or regions of normal electrogram voltage and through areas where pace mapping suggested an exit. A median of 4 (range 1-9) ablation lines, each averaging 3.9 cm in length, were created with a median of 55 RF applications. All inducible VTs were abolished in 3 of the 9 patients with prior infarction, and VTs were modified in 4 patients. In 7 patients with cardiomyopathy, inducible VT was abolished in 4, and modified in 1. During a median followup of 8 months 75% of patients were free of VT; only 1 of the remaining patients continued to have frequent episodes of VT. One procedure-related stroke occurred. Average procedure duration was 8.8 hours, with average fluoroscopy time of 2 hours. Although this approach is feasible with present catheter techniques, the procedures are long and repeated RF applications are required. As methods become available to ablate large regions, avoiding damage to adjacent functioning myocardium will become an important concern. Echocardiographic assessment of LV function in 60 patients undergoing RF catheter ablation for VT due to prior myocardial infarction did not detect an adverse impact on ventricular function for the group as a whole.37 Ablation lesions were restricted to abnormal areas. Caution to avoid damage to contracting myocardium remains an important consideration.

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into a long sheath for introduction into the ventricles. Feasibility of sampling from multiple sites during VT has been Identification of the arrhythmia cir- demonstrated (Figure 6). Much of the vencuit or focus from analysis of a few beats of tricle is not sampled, however (e.g., the tachycardia could potentially allow abla- regions between the splines and regions tion to specifically target VTs that are not where tissue contact is poor due to the mappable by point-by-point sampling. The irregularity of the endocardial contour). feasibility of placing 4 separate multielec- Chordae and valve apparatus can restrain trode catheters into the LV by combining some splines of the basket. In contrast to trans-septal and retrograde aortic appro- the noncontact electrode (chapter 4), aches has been demonstrated by Davis and pacing from electrodes along the splines co-workers,38 but has not been studied as is possible for pace mapping during sinus an approach to mapping hemodynamically rhythm and potentially for entrainment unstable tachycardia. Two types of investi- mapping during VT. The value of basket gational mapping systems have been devel- catheters for guiding ablation of poorly oped for multipoint activation sequence tolerated VTs is not yet known. Potential mapping. Both attempt to reconstruct the complications of these catheters include ventricular activation sequence from peripheral vascular injury, damage to caranalysis of potentials recorded during diac valves or chordae, and formation of tachycardia. Thus, they are subject to the thrombi on the catheter or introducer limitations inherent in attempts to infer sheath. Further studies are required. the timing of local depolarization from endocardial potentials.6,39,40 Noncontact Electrogram Recording Multipoint Activation Sequence Mapping

Systems

Basket Catheters Multielectrode basket catheters (Figures 4 and 5) are composed of several splines, each containing a series of electrodes.41,42 The "basket" catheter collapses

A noncontact electrode system (chapter 4) reconstructs the ventricular activation sequence based on mathematical reconstruction of "virtual electrograms" computed from the potentials sampled by a balloon electrode array in

Figure 4. Two multielectrode basket catheters that have been evaluated in humans. Left: Catheter manufactured by Cardiac Pathways Corp., Sunnyvale, CA. Right: Catheter manufactured by Boston Scientific, Billerica, MA. Pictures kindly provided by the manufacturers.

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Figure 5. Right anterior oblique fluoroscopic view of a basket catheter deployed through the aortic valve into the left ventricle in a patient with recurrent ventricular tachycardia. The apex of the ventricle is at the right. In the right ventricle, an implantable cardioverter-defibrillator lead and right ventricular septal pacing lead are also shown.

the ventricular cavity (Endocardial Solutions, St. Paul, MN).43,44 Compared to basket catheters, much greater spatial sampling is theoretically possible with this system, and the ventricular activation from a single beat of tachycardia can be assessed. Pacing from the catheter for pace mapping and entrainment is not possible, but the location of a roving catheter used for pacing and ablation can be tracked. Strickberger and co-workers44 used this system to target 19 different VTs, 9 which were unstable, in 15 patients who had a mean of 19 episodes of VT per month. Ablation was acutely successful for 15 (78%) of the VTs targeted, including 5 (56%) of the unstable VTs. During a short follow-up period of only 1 month 10 of 14 patients were free of VT. This system has the potential to allow more precise targeting of unstable VTs. It is hoped that future development of means to identify areas of low-amplitude

scar, similar to voltage maps, will be developed for this system. Among 35 patients from 2 reported series using this system 2 strokes and 2 cardiac perforations requiring treatment were observed.43,44Although these complications were not attributed directly to the mapping system, further assessment of safety is warranted. Conclusions

Ablation of VT that is hemodynamically poorly tolerated is feasible in some patients. Optimization of intracardiac filling pressures, administration of intravenous inotropic agents, and administration of antiarrhythmic medications to slow tachycardia may allow for limited mapping to be performed during VT. Sinus rhythm mapping approaches guiding more extensive ablation in low-voltage areas of infarct or scar are promising. It is hoped

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Figure 6. Mapping data acquired from the basket catheter shown in Figure 4A and Figure 5. Selected ECG leads are shown at left. The yellow region indicates the window corresponding to the activation sequence shown. Ventricular tachycardia with a cycle length of 200 ms is present. The activation sequence is displayed in a polar projection, with the apex of the ventricle at the center and the septum at the left, superior portion of the figure. The location of each electrode spline is indicated with a letter. A number indicates the location of each electrode pair on a spline. Earliest activation (red) begins at the lateral apical ventricle and spreads superiorly and inferiorly toward the septum, with latest activation at the apical, inferoseptal region (purple). See color appendix.

that technologies that can determine activation sequence across the ventricles from a few beats, such as basket catheters and noncontact electrodes, will facilitate targeting of rapid tachycardia circuits within abnormal areas. Ablation methods that allow rapid creation of lines of block may facilitate anatomically guided ablation approaches. The efficacy and safety of such approaches will need to be carefully tested in clinical trials. References 1. de Bakker JM, van Capelle FJ, Janse MJ, et al. Macroreentry in the infarcted human heart: The mechanism of ventricular

tachycardias with a "focal" activation pattern. J Am Coll Cardiol 1991;18:1005-1014. 2. de Bakker JM, van Capelle FJ, Janse MJ, et al. Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: Electrophysiologic and anatomic correlation. Circulation 1988;77: 589-606. 3. Downar E, Kimber S, Harris L, et al. Endocardial mapping of ventricular tachycardia in the intact human heart. II. Evidence for multiuse reentry in a functional sheet of surviving myocardium. J Am Coll Cardiol 1992;20:869-878. 4. Kaltenbrunner W, Cardinal R, Dubuc M, et al. Epicardial and endocardial mapping of ventricular tachycardia in patients with myocardial infarction. Is the origin of the tachycardia always subendocardially localized? Circulation 1991;84:1058-1071.

646 CARDIAC MAPPING 5. Pogwizd SM, Hoyt RH, Saffitz JE, et al. Reentrant and focal mechanisms underlying ventricular tachycardia in the human heart. Circulation 1992;86:1872-1887. 6. Stevenson WG, Khan H, Sager P, et al. Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of ventricular tachycardia late after myocardial infarction. Circulation 1993;88:1647-1670. 7. de Bakker JM, van Capelle FJ, Janse MJ, et al. Slow conduction in the infarcted human heart. 'Zigzag' course of activation. Circulation 1993;88:915-926. 8. Littmann L, Svenson RH, Gallagher JJ, et al. Functional role of the epicardium in post-infarction ventricular tachycardia. Observations derived from computerized epicardial activation mapping, entrainment, and epicardial laser photoablation. Circulation 1991;83:1577-1591. 9. Soejima K, Suzuki M, Maisel WH, et al. Catheter ablation in patients with multiple and unstable ventricular tachycardias after myocardial infarction: Short ablation lines guided by reentry circuit isthmuses and sinus rhythm mapping. Circulation 2001; 104:664-669. 10. Bartlett TG, Mitchell R, Friedman PL, et al. Histologic evolution of radiofrequency lesions in an old human myocardial infarct causing ventricular tachycardia. J Cardiovasc Electrophysiol 1995;6:625-629. 11. Burke MC, Alberts M, Cooke PA, et al. Eligibility for catheter ablation of sustained ventricular tachycardia associated with prior myocardial infarction. Pacing Clin Electrophysiol 1998;21:870A. 12. Teirstein PS, Vogel RA, Dorros G, et al. Prophylactic versus standby cardiopulmonary support for high risk percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1993;21:590-596. 13. Marchlinski FE, Buxton AE, Kindwall KE, et al. Comparison of individual and combined effects of procainamide and amiodarone in patients with sustained ventricular tachyarrhythmias. Circulation 1988;78:583— 591. 14. Buxton AE, Josephson ME, Marchlinski FE, et al. Polymorphic ventricular tachycardia induced by programmed stimulation: Response to procainamide [see comments]. J Am Coll Cardiol 1993;21:90-98. 15. Gepstein L, Goldin A, Lessick J, et al. Electromechanical characterization of

chronic myocardial infarction in the canine coronary occlusion model. Circulation 1998; 98:2055-2064. 16. Kornowski R, Hong MK, Gepstein L, et al. Preliminary animal and clinical experiences using an electromechanical endocardial mapping procedure to distinguish infarcted from healthy myocardium. Circulation 1998;98:1116-1124. 17. Callans DJ, Ren JF, Michele J, et al. Electroanatomic left ventricular mapping in the porcine model of healed anterior myocardial infarction: Correlation with intracardiac echocardiography and pathological analysis [In Process Citation]. Circulation 1999; 100:1744-1750. 18. Marchlinski FE, Callans DJ, Gottlieb CD, et al. Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy. Circulation 2000;101:12881296. 19. Stevenson WG, Sager PT, Natterson PD, et al. Relation of pace mapping QRS configuration and conduction delay to ventricular tachycardia reentry circuits in human infarct scars. J Am Coll Cardiol 1995;26:481-488. 20. Brunckhorst CB, Stevenson WG, Delacretaz E, et al. Electroanatomic voltage mapping of left ventricular infarcts causing ventricular tachycardia. Circulation 2000;102:3006. Abstract. 21. Cassidy DM, Vassallo JA, Buxton AE, et al. The value of catheter mapping during sinus rhythm to localize site of origin of ventricular tachycardia. Circulation 1984;69:1103— 1110. 22. Miller JM, Tyson GS, Hargrove WC 3rd, et al. Effect of subendocardial resection on sinus rhythm endocardial electrogram abnormalities. Circulation 1995;91:2385— 2391. 23. Wiener I, Mindich B, Pitchon R. Fragmented endocardial electrical activity in patients with ventricular tachycardia: A new guide to surgical therapy. Am Heart J 1984:107:86-90. 24. Harada T, Stevenson WG, Kocovic DZ, et al. Catheter ablation of ventricular tachycardia after myocardial infarction: Relation of endocardial sinus rhythm late potentials to the reentry circuit. J Am Coll Cardiol 1997;30:1015-1023. 25. Bogun F, Bahu M, Knight BP, et al. Response to pacing at sites of isolated diastolic

MAPPING OF UNSTABLE VENTRICULAR TACHYCARDIA potentials during ventricular tachycardia in patients with previous myocardial infarction. J Am Coll Cardiol 1997;30: 505-513. 26. Bourke JP, Campbell RW, Renzulli A, et al. Surgery for ventricular tachyarrhythmias based on fragmentation mapping in sinus rhythm alone. Eur J Cardiothorac Surg 1989;3:401-406. 27. Zee-Cheng CS, Kouchoukos NT, Connors JP, et al. Treatment of life-threatening ventricular arrhythmias with nonguided surgery supported by electrophysiologic testing and drug therapy. J Am Coll Cardiol 1989;13:153-162. 28. Stevenson WG, Weiss JN, Wiener I, et al. Fractionated endocardial electrograms are associated with slow conduction in humans: Evidence from pace-mapping. J Am Coll Cardiol 1989;13:369-376. 29. Brunckhorst CB, Stevenson WG, Jackman WM, et al. Ventricular mapping during atrial and ventricular pacing: Relation of multipotential electrograms to ventricular tachycardia reentry circuits after myocardial infarction. Eur Heart J 2002. In press. 30. Ellison KE, Stevenson WG, Sweeney MO, et al. Catheter ablation for hemodynamically unstable monomorphic ventricular tachycardia. J Cardiovasc Electrophysiol 2000;ll:41-44. 31. Miller JM, Marchlinski FE, Buxton AE, et al. Relationship between the 12-lead electrocardiogram during ventricular tachycardia and endocardial site of origin in patients with coronary artery disease. Circulation 1988;77:759-766. 32. Kuchar DL, Ruskin JN, Garan H. Electrocardiographic localization of the site of origin of ventricular tachycardia in patients with prior myocardial infarction. J Am Coll Cardiol 1989; 13:893-903. 33. Brunckhorst CB, Delacretaz E, Soejima K, et al. Identification of the ventricular tachycardia isthmus after infarction by pace mapping. Pacing Clin Electrophysiol 2001;24(II):637A. 34. Furniss S, Anil-Kumar R, Bourke JP, et al. Radiofrequency ablation of haemodynamically unstable ventricular tachycardia after myocardial infarction. Heart 2000; 84:648-652.

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35. Wilber DJ, Kopp DE, Glascock DN, et al. Catheter ablation of the mitral isthmus for ventricular tachycardia associated with inferior infarction. Circulation 1995; 92:3481-3489. 36. Hadjis TA, Stevenson WG, Harada T, et al. Preferential locations for critical reentry circuit sites causing ventricular tachycardia after inferior wall myocardial infarction. J Cardiovasc Electrophysiol 1997; 8:363-370. 37. Khan HH, Ho C, Maisel WH, et al. Effect of radiofrequency ablation for ischemic ventricular tachycardia on left ventricular function. Pacing Clin Electrophysiol 2001; 24(II):545. 38. Davis LM, Cooper M, Johnson DC, et al. Simultaneous 60-electrode mapping of ventricular tachycardia using percutaneous catheters. J Am Coll Cardiol 1994; 24:709-719. 39. Ideker RE, Smith WM, Blanchard SM, et al. The assumptions of isochronal cardiac mapping. Pacing Clin Electrophysiol 1989; 12:456-478. 40. Waxman HL, Sung RJ. Significance of fragmented ventricular electrograms observed using intracardiac recording techniques in man. Circulation 1980;62: 1349-1356. 41. Greenspon AJ, Hsu SS, Datorre S. Successful radiofrequency catheter ablation of sustained ventricular tachycardia postmyocardial infarction in man guided by a multielectrode "basket" catheter. J Cardiovasc Electrophysiol 1997;8:565-570. 42. Schalij MJ, van Rugge FP, Siezenga M, et al. Endocardial activation mapping of ventricular tachycardia in patients: First application of a 32-site bipolar mapping electrode catheter. Circulation 1998;98: 2168-2179. 43. Schilling RJ, Peters NS, Davies DW. Feasibility of a noncontact catheter for endocardial mapping of human ventricular tachycardia. Circulation 1999;99:25432552. 44. Strickberger SA, Knight BP, Michaud GF, et al. Mapping and ablation of ventricular tachycardia guided by virtual electrograms using a noncontact, computerized mapping system. J Am Coll Cardiol 2000; 35:414-421.

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Chapter 34 Subthreshold Electrical Stimulation: A Novel Technique in Localization and Identification of Target Sites During Catheter Ablation of Cardiac Arrhythmias Mohammad Shenasa, MD, Stephan Willems, MD, Gerhard Hindricks, MD, Jafar Shenasa, MSc, Xu Chen, MD, Hossein Shenasa, MD, MSc, Martin Borggrefe, MD, and Gtinter Breithardt, MD

Introduction Historically, the notion of subthreshold stimulation dates back to Lewis, Drury, and Love,1,2 who investigated the effect of lowlevel currents on refractoriness and circus movement tachycardias. They showed that low-level currents produce changes in refractoriness. Similar observations were also made by Wedensky3 and Hodgkin4 in nerves where an impulse crosses an area of block electrotonically and affects the excitability so that it becomes more susceptible to activation. Weidmann5 later investigated the effect of subthreshold stimulation in cardiac muscle and Purkinje fibers, and demonstrated that low-level currents alter membrane potential and reset

the spontaneous activity. Antzelevitch and Moe6 further investigated the low-level current effect in Purkinje fibers. In humans, the effect of subthreshold stimuli on ventricular effective refractory period was investigated by Prystowsky and Zipes,7 where a single subthreshold pulse delivered within the effective refractory period of the ventricular myocardium inhibited the response of extrastimuli that otherwise would have produced a response. In this chapter we present our clinical observations on the use of subthreshold stimulation in patients with ventricular tachycardia (VT) as well as those with supraventricular tachycardias (SVTs). We also discuss the possible electrophysiological

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; C2003.

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mechanisms and the potential applications of subthreshold stimuli. Methods of Subthreshold Stimulation Two modes of subthreshold stimuli have been used: 1. Trains of subthreshold stimuli were delivered during diastole with cycle lengths beginning at 100 ms with stepwise decrements of 10 ms until cycle length of 10 ms. The number of pulses varied between 3 and 16 and stimulation duration was 2.0 ms. Stimulation intensity ranged from 10% to 80% of captured threshold. 2. Single long constant current pulse: a direct-current low-level stimulation of adjustable intensity, was used. Stimulation intensity began with 0.4 mA, with stepwise increase of 0.4 mA until capture occurred. With both protocols, any captured beats were disregarded. A given step that terminated the tachycardia was also applied during sinus rhythm to demonstrate lack of capture. Stimulation with both protocols was done in a bipolar mode, with distal being positive. Definitions Stimulation was considered subthreshold when there was no change in surface ECG or in local electrograms. Termination of tachycardias by subthreshold stimuli was considered to occur only if the tachycardias were terminated at least twice without apparent capture as evident from surface ECG and intracardiac recordings. Subthreshold Stimulations in Patients with Sustained Monomorphic VT Since investigations on the effect of subthreshold stimulation on ventricular

refractory period indicated that proximity to the pacing electrode is critical for refractory period prolongation,7,8 we hypothesized that subthreshold currents, if applied adjacent to the areas that are critical for initiation and sustenance of VT may prevent and terminate VT. To test this hypothesis we applied either trains of subthreshold stimuli or single long subthreshold constant current in 23 patients at the site of early activity during VT as determined by endocardial catheter mapping. The cycle length of VT ranged from 440 ms to 290 ms. Details of this procedure are explained elsewhere.9,10 Effect of Subthreshold Stimulation on Termination of VT Trains of subthreshold stimulation were applied at the site of origin of VT in 19 patients with coronary artery disease. Twelve patients had VT with right bundle branch block and 7 patients had left bundle branch block morphology. VT was terminated at least twice in 10 of 19 patients (53%) and in the remaining 9 patients it was not (Figure 1). There was no statistically significant difference between VT cycle length of tachycardias that terminated by subthreshold train versus those that did not. The number of subthreshold pulses and the intensity and cycle length that effectively terminated the tachycardias ranged between 5 and 11, 0.8 to 2.4 mA, and 40 to 80 ms, respectively. Effect of Long Subthreshold Constant Current on Termination of VT This mode of stimulation was tested in 14 patients with sustained VT, and terminated the tachycardia in 9 of these 14 patients (64%). VT cycle length ranged from 495 ms to 290 ms. The stimulation intensity

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Figure 1. Termination of sustained monomorphic ventricular tachycardia (VT) by a train of 8 pulses of subthreshold stimuli with cycle lengths of 50 ms and intensity of 3.0 mA. Subthreshold stimulation was delivered at the anterior left ventricular (LV) septum where the tachycardia originated. Note that during VT, the LV endocardial electrogram precedes the right ventricular (RV) electrogram.

and duration that effectively terminated VT ranged from 0.8 to 2.8 mA (mean ± SD 1.2 ± 0.6) and 900 to 3500 ms (mean ± SD 2100 ± 600), respectively. Figure 2 illustrates an example where subthreshold current of 0.8mA intensity was applied at the site of early activity during VT with cycle length of 480 ms and failed to terminate, but application of higher current (still threshold) of 1.2 mA with duration of 3000 ms terminated the tachycardia without apparent capture. Note the presence of presystolic potentials (arrow) during tachycardia at the site of origin of VT that are also present during sinus rhythm after the local ventricular electrogram (delayed potentials). Effect of Subthreshold Stimulation on Prevention of VT In order to examine whether subthreshold stimulation can prevent initiation

of the tachycardia when applied at the site of origin of VT, we first identified the site of early activity during VT in 13 patients. The range of coupling intervals that initiated VT was also determined. Trains of subthreshold current were then applied to the site of origin of tachycardia during simultaneous induction of VT from the right ventricular apex. Overall, subthreshold stimulation prevented initiation of VT in 7 of 12 patients (58%) in whom it was tested. Figure 3 shows induction of sustained VT from the right ventricular apex at a drive cycle length of 600 ms (upper panel). The same induction protocol was simultaneously applied with trains of 8 pulses of subthreshold stimuli with a cycle length of 40 ms to the site of origin of VT in the left ventricle and prevented induction of VT (lower panel). Note that during sustained VT, the left ventricular electrogram recorded at the site of

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Figure 2. Tracing from a patient with sustained monomorphic ventricular tachycardia (VT). The tachycardia cycle length is 480 ms. Application of a subthreshold constant current of 3000-ms duration and 0.8-mA intensity at the site of origin did not terminate the tachycardia (A). The stimulation intensity was increased to 1.2 mA, and at the same site (B), the tachycardia was terminated by subthreshold current. See text for detailed explanation. Onset and offset of the subthreshold current is indicated by the arrows. MAPE/dis and MAPE/pr = electrograms from distal and proximal parts of the mapping electrode; RV = right ventricle.

(10 patients) was tested in 18 patients with the common type (slow anterograde— fast retrograde) atrioventricular (AV) node reentry tachycardia. The tachycardia Effect of Subthreshold cycle length ranged from 450 ms to 285 ms Stimulation in Patients with SVTs (mean ± SD 345 ± 60). Trains of subthreshold stimulation terminated the tachycarPatients with Atrioventricular Node dias in 6 of 8 patients (75%). The number, Reentry Tachycardias cycle length, and intensity ranged from 4 to The effect of either subthreshold pulse 12, 30 to 40 ms, and 0.8 to 2.4 mA, respectrains (8 patients) or single constant current tively. Subthreshold stimuli terminated origin of VT precedes the electrogram from the right ventricular apex.

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Figure 3. Prevention of induction of ventricular tachycardia (VT) by subthreshold stimulation at the site of origin of tachycardia. VT was induced by two extrastimuli (A). Note that during VT, left ventricular activation precedes right ventricular activation. During attempt of VT induction from the right ventricular apex, trains of subthreshold pulses simultaneously delivered to the site of origin of VT prevented initiation of the tachycardia.

the tachycardia in the anterograde direction (slow pathway block) in 4 patients, and the retrograde direction (fast pathway block) in the other 2 patients. Figure 4 demonstrates an example of termination of AV node reentry tachycardia by 8 pulses of subthreshold current with a cycle length of 40 ms and intensity of 0.1 mA. The pulses were delivered to the AV nodal region either at the most proximal coro-

nary sinus area (CS ostium) or the low septal atrium where the most proximal His bundle electrogram was recorded. Single long subthreshold constant current effectively terminated AV node reentry tachycardia in 8 of 10 patients (80%). The duration and intensity of the subthreshold current that effectively terminated the tachycardia ranged from 1600 to 3000 ms and 1.2 to 3.8 mA, respectively (Figure 5). Application of the same

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Figure 4. Termination of sustained atrioventricular node reentry tachycardia by a train of 8 stimuli with a cycle length of 40 ms. Stimulation intensity and duration were 0.7 and 2 ms, respectively. Note that the tachycardia terminated in the retrograde fast pathway. HRA = high right atrium; HBE = His bundle electrogram; AE = atrial echo. Reproduced from reference 10, with permission.

Figure 5. Termination of atrioventricular node reentry tachycardia by a single long constant current pulse. The pulse duration and intensity are 1740 ms and 3.5 mA, respectively. The tachycardia terminated in the fast retrograde pathway. Onset and offset of the subthreshold pulse are shown by arrows.

ROLE OF SUBTHRESHOLD ELECTRICAL STIMULATION subthreshold current during sinus rhythm did not produce capture. A recent report from our laboratory using subthreshold stimulation in a randomized fashion suggests that this technique can be used to avoid unnecessary radiofrequency applications, (see discussion) Effect of Subthreshold Stimulation in Patients with Orthodromic Tachycardias Subthreshold constant currents were applied to the ventricular or atrial site of insertion of accessory pathways in a total of 28 patients with either manifest (20 patients) or concealed (8 patients) accessory pathways who underwent transcatheter radiofrequency current ablation of accessory pathways. Details of endocardial electrode catheter mapping for localization of

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accessory pathways have been previously reported from our laboratory.11 Subthreshold current of long constant pulses was applied to the presumed site of accessory pathways during orthodromic tachycardia using the same protocol that was described earlier. The cycle length of orthodromic tachycardia ranged from 350 ms to 270 ms (mean ± SD 318 ± 58). Accessory pathways were localized to left lateral in 11 patients, left posterior in 5 patients, left posteroseptal in 6 patients, right posteroseptal in 2 patients, right lateral in 3 patients, and right anterior in 1 patient. When applied adjacent to the accessory pathway, subthreshold current terminated orthodromic tachycardias in 25 of 28 patients (89%) without apparent capture. The tachycardia was terminated in the retrograde direction (accessory pathway block) in all patients. Figure 6 shows termination of orthodromic tachycardia

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Figure 6. Termination of orthodromic tachycardia with subthreshold current applied at ventricular site of insertion of accessory pathway. The pulse duration and intensity are 2000 ms and 2.0 mA, respectively. The tachycardia cycle length is 340 ms, which does not change the tachycardia cycle length during application of the subthreshold current until it terminates in the retrograde direction. Onset and offset of the subthreshold current are indicated by arrows. Reproduced from Shenasa et al. J Cardiovasc Electrophysiol, with permission.

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by subthreshold stimulation with duration of 2000 ms and intensity of 1.8 mA. The subthreshold duration and intensity that effectively terminated the orthodromic tachycardias ranged between 900 and 1500 ms (mean ± SD 2870 ± 750) and 0.8 to 4.2 mA (mean ± SD 2.4 ± 0.9), respectively. In the 3 patients in whom subthreshold currents failed to terminate, the tachycardia intensity of up to capture threshold was tested at several sites. Termination of orthodromic tachycardia by subthreshold stimulation was assumed to be in the proximity of accessory pathway location. To verify this assumption, we further analyzed the correlation between effectiveness of radiofrequency current ablation of accessory pathways and termination of orthodromic tachycardias by subthreshold stimulation. A close correlation between these 2 effects was found.12 Discussion The results presented here and in our previous reports suggest that subthreshold stimulation, when applied at or to the proximity of the arrhythmogenic substrate, may terminate reentry tachycardias in the majority of instances. Electrophysiological Effects of Subthreshold Currents Studies performed on isolated tissues suggest that subthreshold current changes cellular excitability and refractoriness.5,6,13 Single subthreshold stimuli are reported to prolong atrial and ventricular refractoriness when applied close to the pacing site.8,13,14 In some cases, shortening of refractoriness has also been observed.15,16 Studies by Spear and Moore17 suggest that a subthreshold pulse can improve excitability and bring the cells into their

so-called "supernormal phase." Using dyesensitive optical mapping, enhancement of ventricular conduction velocity in the guinea pig by trains of subthreshold trains were investigated in patients who underwent simultaneous epicardial computerized mapping.18 Interestingly, trains of subthreshold stimuli enhanced ventricular conduction time. This is clearly evident from. the maps of VT beats with (maps 4 and 6) and without (maps 3 and 5) subthreshold pulses shown in Figure 7.9 Similarly, Rothschild et al.19 observed enhancement of conduction in an accessory pathway by local noncaptured stimuli. Subthreshold stimuli may terminate reentrant tachycardias by producing areas of block in the reentry circuit as also demonstrated by Scherlag et al.20 or by enhancing the conduction in some parts of the reentry circuit. The latter can further be speculated on as due to changing the excitable gap of the reentry circuit. Trains of subthreshold stimuli may have summation of the local electrotonic effects, whereas single long constant currents may exert an effect by decreasing the membrane threshold potential to the threshold potential. During application of long subthreshold constant current during sinus rhythm to demonstrate lack of capture, successive ventricular extrasystoles of relatively long cycle length compatible with enhanced automaticityhaveabeen observed (Figure 8). This phenomenon should not be mistaken as capture by the subthreshold current. One might argue that the effect of subthreshold stimulation is mediated via the stimulation of nerve ending at the endocardial surface. This mechanism is unlikely since data obtained from isolated heart and tissues support the direct effect. Furthermore, although systematically not investigated, administration of p-blockers and/or vagal blockers (atropine) did not prevent termination of tachycardias by subthreshold stimulation.

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Figure 7. Tracing and isochronal maps showing effect of subthreshold stimulation on endocardial activation during ventricular tachycardia (VT). ECG shows induction of sustained VT by programmed stimulation (S1,82, S3, and S4) and its termination by subthreshold stimulation. Artifacts during 3 periods of stimulation are shown (retouched) on the left ventricular bipolar electrogram (LVeg). Atrial electrogram (Aeg) was dissociated from ventricular activation. Isochronal map (traced 15-ms intervals) during normal sinus rhythm (NSR) shows the earliest endocardial activation on the septum, and that of a response to programmed stimulation (S3) shows earliest endocardial activity on the lateral wall. Maps 1, 3, and 5 show tachycardia beats just before subthreshold stimulation, and maps 2, 4, and 6 show tachycardia beats during subthreshold stimulation. Note that the first train of subthreshold stimuli affected neither the tachycardia nor the Endocardial activation patterns (1 and 2). The second and third trains produced an acceleration of subendocardial conduction. The third train was followed by 2 beats with accelerated conduction (7) and VT termination. Reproduced with permission from the American Heart Association.

Evidence of Lack of Capture During Subthreshold Stimulation Since the criteria set for subthreshold termination of tachycardia is lack of capture, the relationship of subthreshold pulses to tachycardia terminated must be proved indirectly. Consequently, the question remains whether subthreshold pulses and tachycardia termination is a fortuitous phenomenon. The following argues for termination of tachycardias by subthreshold stimulation: 1. Patients included here and in our earlier reports met the criteria of having sustained tachycardias

that were induced by programmed electrical stimulation. All patients with spontaneous termination of their tachycardias were excluded. 2. Termination of tachycardias by subthreshold stimulation has been a reproducible phenomenon. At each site, subthreshold stimulation was applied at least twice; therefore it is a fairly reproducible phenomenon. 3. Application of subthreshold currents at sites remote from the site of origin of tachycardia failed to terminate the tachycardia. 4. Careful examination of surface ECGs and local electrograms was done to exclude any capture. Figure 9

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Figure 8. Tracing showing emergence of successive ventricular ectopic beats during application of subthreshold current with intensity of 1 mA and duration of 2000 ms at the left lateral of the ventricular wall in a patient with left lateral accessory pathway. The cycle length of ventricular ectopic beats is 440 ms. Note that the atria are activated retrogradely (Ar) during ventricular ectopies.

(same patient as in Figure 7) shows selected electrograms of beats with and without subthreshold pulses and indicates absence of local capture. Although local capture or electrotonic effect cannot be ruled out. New observation

Concealed capture: We, for the first time, observed a fascinating phenomenon of concealed capture. Figure 10 clearly shows atrial capture during ventricular subthreshold stimulation. Another interesting phenomenon is manifestation of preexcitation in patients with exclusively concealed accessory pathways, i.e., no preexcitation in sinus rhythm or atrial fibrillation at baseline or during isoproterenol infusion. Figure 11 illustrates emergence of preexcitation during application of subthreshold stimulation to the ventricular site of insertion of the accessory pathway.

Low Level on Subthreshold Current? An interesting question is, "What is considered subthreshold?" By definition, subthreshold pulses are those that do not produce surface electrocardiographic changes or local electrogram capture. Since constant long direct current pulses or trains of pulses below diastolic threshold still exert some electrophysiological changes and produce alteration in refractoriness or excitability, one may argue that this is no longer subthreshold, and lower level current may be a better nomenclature. Implication There are several implications for the use of subthreshold currents during investigation of cardiac arrhythmias: 1. Subthreshold stimulation may be used to investigate the mechanism

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Figure 9. Tracings and isochronal map show effect of subthreshold stimulation on unipolar electrograms. Selected electrograms (A, B, C, and D) recorded at the sites indicated on the endocardial map of a ventricular tachycardia (VT) beat are shown during S3 and beats 1 to 7 of VT described in Figure 7. Activation times are indicated by numbers next to the intrinsic deflections. Subthreshold stimulation (2, 4, 6) did not affect the localization of the earliest activity or the unipolar waveforms but reduced the activation times (by comparison with beats 1, 3, and 5). Reproduced with permission from the American Heart Association.

of tachycardias. Termination of tachycardias during a wider range of the tachycardia interval may favor reentry mechanism. Although not adequately investigated in the present and in our former patients population, tachycardias with other mechanisms such as abnormal automaticity, or triggered activity may exhibit a different response. 2. Subthreshold stimulation may be used as a mapping guide to identify

target sites during catheter or surgical ablative procedures. Both termination of tachycardias by subthreshold stimulation and ablation of the arrhythmogenic substrate by radiofrequency current ablation depend critically on its proximity to the sites critical for initiation and sustenance of tachycardias. Thus, it is conceivable that a close concordance between subthreshold effect and radiofrequency effect exists. Observations

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Figure 10. Concealed capture. Tracings are surface ECG leads I and II and electrograms from mapping electrode (MAP-E) and high right atrium (HRA). Note application of long count and current into the right ventricular apex produced atrial activation in the retrograde direction and termination of orthodromic tachycardia. There is no evidence of apparent capture in the surface ECG lead.

on use of subthreshold stimulation in identification of target sites in patients with accessory pathways and in AV node reentrant tachycardias confirms this hypothesis.21,22 We found that termination of AV node reentrant tachycardia and orthodromic tachycardia by subthreshold stimulation highly correlated with the results of radiofrequency current ablation. 3. Willems et al.22 reported on the role of subthreshold stimulation mapping and radiofrequency ablation of slow pathway in patients with AV node reentrant tachycardia. Termination of AV nodal reentry by subthreshold stimulation correlated well with effective target sites for radiofrequency ablation (Figure 12). Subthreshold stimulation may be used alone or in combination with other antitachy-

cardia pacing modalities for termination and/or prevention of tachycardia. Figure 13 is from a patient with recurrent sustained AV nodal reentry tachycardia. In an attempt to investigate the feasibility of antitachycardia pacing, the devices were temporarily programmed to deliver 5 subthreshold pulses with cycle lengths of 60 ms at the low septal right atrium. Several episodes of tachycardia were properly detected by the device and were subsequently terminated. Prystowsky et al.23 proposed that it is feasible that in the future devices may able to incorporate subthreshold pulses that are constantly delivered within the relative refractory period of the ventricle and to prolong ventricular refractoriness that may potentially prevent initiation of tachycardias. Termination of

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Figure 11. Emergence of preexcitation during subthreshold application suggesting concealed capture at the ventricular insertion site in a patient with concealed accessory pathway. Tracings are surface ECG leads I and II and intracardiac electrograms from the distal and proximal mapping electrode (MAPEd and MAPEp, respectively) and distal and proximal coronary sinus (CSd and CSP, respectively). Note during application of long constant current subthreshold (duration of 4940 ms) preexcitation emerged. There is no change in sinus cycle length.

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Figure 12. Distribution of successful ablation sites. This figure depicts all target sites with subsequent ablation of atrioventricular nodal reentrant tachycardia (AVNRT) in patients undergoing the conventional approach (group A, open circles [n = 50]) and subthreshold stimulation (STS)-guided ablation strategy (group B, solid circles [n = 50]). There is a well-balanced distribution of target sites from the posteroseptal aspect around the coronary sinus ostium up to the lower midseptal region in both groups. RFC = radiofrequency catheter. Reproduced from reference 22, with permission.

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Figure 13. Tracing illustrating termination of atrioventricular nodal reentry tachycardia with a train (5 pulses) of subthreshold stimulation delivered by an antitachycardia pacer. The pacer is programmed to deliver the pulses after 8 beats of sudden onset of the tachycardia. Note that the tachycardia is initiated after a spontaneous atrial extrasystole. This unit was temporarily programmed to deliver the subthreshold pulses.

sustained VT by subthreshold stimuli via epicardial patch electrodes was effectively done in selected patients during implantation of an automatic implantable cardioverterdefibrillator.24 Needless to say, further investigation of this mode of stimulation is required.

References 1. Lewis T, Drury AN. Revised views of the refractory period in relation to drugs reputed to prolong it and in relation to circuit movement. Heart 1926;13:95. 2. Drury AN, Love WS. The supposed lengthening of the absolute refractory period of dogs' ventricular muscle by veratrine. Heart 1926;13:77. 3. Fisch C, Greenspan K. Wedensy's observations. Circulation 1966;28:1276-1283. 4. Hodgkin AL. Evidence for electrical transmission in nerve. Part 1. JPhysiol (Lond) 1937;90:1983-2210. 5. Weidmann S. Effect of current flow on the membrane potential of cardiac muscle. J Physiol 1951;115:227.

6. Antzelevitch C, Moe GK. Electrotonic inhibition and summation of impulse conduction in mammalian Purkinje fibers. Am J Physiol 1983;245:H42. 7. Prystowsky EN, Zipes DP. Inhibition in the human heart. Circulation 1983;68:707. 8. Windle JR, Miles WM, Zipes DP, Prystowsky EN. Subthreshold conditioning stimuli prolong human ventricular refractoriness. Am J Cardiol 1986;57:381. 9. Shenasa M, Cardinal R, Kus T, et al. Termination of sustained ventricular tachycardia by ultrarapid subthreshold stimulation in humans. Circulation 1986;78: 1135-1143. 10. Fromer M, Shenasa M. Ultrarapid subthreshold stimulation for termination of atrioventricular node reentrant tachycardia. J Am Coll Cardiol 1992;20:879-883. 11. Chen X, Borggrefe M, Shenasa M, et al. Characteristics of local electrogram predicting successful transcatheter radiofrequency ablation of left sided accessory pathways. J Am Coll Cardiol 1992;20:656-665. 12. Shenasa M, Hindricks G, Haverkamp W, et al. Value of subthreshold stimulation for identification of target sites during radiofrequency catheter ablation of accessory pathway. Circulation 1992;86(Suppl 1):722.

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13. Skale BT, Kaltok MJ, Prystowsky EN, et al. Inhibition of premature ventricular extrastimuli by subthreshold conditioning stimuli. J Am Coll Cardiol 1985;6:133. 14. Connelly DT, Cunningham D, Spicer M, et al. Inhibition in the human heart using long duration subthreshold conditioning pulses. Pacing Clin Electrophysiol 1991;14:625. 15. Paya R, Chorro FJ, Sanchis J, et al. Changes in canine ventricular refractoriness induced by trains of subthreshold high-frequency stimuli. Elecktrocardiol 1991;24:63-69. 16. Saihara S, Inoue H, Toda I, et al. Reappraisal of inhibition and summation with a single conditioning stimulus in man. Pacing Clin Electrophysiol 1990;13:151-157. 17. Spear JF, Moore EN. Supernormal excitability and conduction. In: Wellens HJJ, Lie KL, Janse MJ (eds): The Conduction System of the Heart: Structure, Function, and Clinical Implications. The Hague: Martinus Nijhoff Medical Division; 1978:111. 18. Kanai A, Shenasa M, Salama G. Subthreshold stimulation increases normal conduction velocity and interrupts ventricular tachycardia measured using voltage sensitive dyes and imaging techniques. Circulation 1990;82(Suppl III):III-98. 19. Rothschild R, Stevenson WG, Klitzner T, Weiss J. Enhancement of conduction in an accessory pathway by local noncaptured stimuli. JAm Coll Cardiol 1987;9:455-458.

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20. Scherlag BJ, Shenasa M, Page P, et al. Mechanisms of action of subthreshold stimulation in terminating sustained ventricular tachycardia. In: Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping. Mount Kisco, NY: Futura Publishing Co.; 1993:537-548. 21. Willems S, Hoffmann MW, Shenasa M, et al. Role of subthreshold stimulation as a guide for slow pathway ablation of AV nodal reentrant tachycardia: A randomized prospective study. Circulation 1998; 98(Suppl P):I-72. 22. Willems S, Weiss C, Shenasa M, et al. Optimized mapping of slow pathway ablation guided by subthreshold stimulation: A randomized prospective study in patients with slow recurrent atrioventricular nodal reentrant tachycardia. J Am Coll Cardiol 2001;37:1645-1650. 23. Prystowsky EN, Miles WM, Windle JR, et al. Electrical inhibition of myocardium: A mode to prevent the occurrence of tachyarrhythmias? In: Breithardt G, Borggrefe M, Zipes DP (eds): Nonpharmacological Therapy of Tachyarrhythmias. Mount Kisco, NY: Futura Publishing Co.; 1987:359-372. 24. Shenasa M, Fromer M. Termination of sustained ventricular tachycardia by subthreshold electrical stimulation via epicardial patch electrodes. Circulation 1991;84(SupplII): 11-427.

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Part 7 New Frontiers

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Chapter 35 Transcoronary Venous Mapping of Ventricular Tachycardia Paolo Delia Bella, MD, Claudia Tondo, MD, Corrado Carbucicchio, MD, Stefania Riva, MD, Gaetano Fassini, MD, and Paola Galimberti, MD

Introduction A deep intramyocardial or a subepicardial location of the critical area of the reentry circuit was a recognized cause of failure at surgery when endocardial resection techniques were used for the treatment of post myocardial infarction (MI) ventricular tachycardia (VT).1-3 In the open-chest surgical setting, epicardial mapping with a multielectrode socket was used to locate the critical isthmus responsible for the VT, and to guide successful epicardial ablation.4 This experience led to the recognition that in about 20% of VTs related to a previous posterior or posterior-inferior wall infarction, the location of the substrate is epicardial. Furthermore, the elegant mapping studies by Downar and colleagues56 have provided evidence that a surviving epicardial layer of myocardium is used as part of the reentry pathway in patients with VT following anterior wall MI. In these studies, the criteria to establish the epicardial origin

of the VT were based on the presence of earliest diastolic activity or earliest isolated diastolic potentials in epicardial recordings. 7~Q The 1990s saw an increased number of radiofrequency catheter ablation procedures performed in patients with VT, both in the absence of structural heart disease10 and in the setting of chronic coronary artery disease.11"13 The improvement of the techniques of intracardiac mapping to identify with precision the target for ablation, and the growing experience in VT mapping, led to the recognition of 2 situations of VT in which epicardial mapping can achieve additional information relevant to catheter ablation: VT following an MI, and idiopathic VT originating from the outflow tract of the right or left ventricle. The technical details pertinent to the performance of epicardial mapping in these VTs and the type of information that can be derived from this approach are analyzed in this chapter.

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003.

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The Coronary Venous System

The use of the coronary venous system to achieve recordings from epicardial layers16 is safer compared to the use of the coronary arterial system, since it does not carry the risk of thrombotic occlusion of the vessel; in patients with coronary artery disease, mapping of infarcted areas distal to an occlusion site may be impractical or even impossible.

The coronary veins constitute a diffuse system of vessels running over the epicardial surface of the left ventricle, with major branches parallel to the coronary arteries and a single major drainage into the right atrium represented by the coronary sinus. This is a structure very well known to any experienced electrophysiologist, since catheterization of these Access to the Coronary Venous vessels is frequently required as a guide System (Figure 1) to the ablation of left-sided accessory pathways. Due to their small size and to the soft The techniques to perform coronary sinus and coronary venous angiograms fabric of the catheters commonly used in were first described in the 1960s.14 Even our laboratory (PATHFINDER™ 1.5F to in the normal human heart, the venous 2.5F; Cardima, Fremont, CA), access to the system is characterized by a greater main body of the coronary sinus is achieved degree of variability as compared to the by standard angiographic 8F catheters coronary arterial system15; in spite of introduced from the femoral vein.17 Amplatz AL 2 or 3 catheters (Cordis this, the following tributaries are normally present and can be visualized by Endovascular, a Johnson & Johnson Comretrograde constant injection, particu- pany, Miami Lakes, FL) can be easily larly if the "occlusive" technique is used: introduced into the coronary sinus followthe middle cardiac vein, usually running ing the deployment in the right atrium, parallel to the posterior interventricular across the tricuspid valve, followed by a artery; 1 or 2 posterior or posterolateral gentle withdrawal performed keeping a branches; the marginal vein(s); and the clockwise torque. Due to its long reach, the great cardiac vein, running anteriorly catheter retains a very stable position in over the left atrioventricular sulcus—this the coronary sinus and acts as a support vein proceeds toward the apex with a in enhancing the delivery of 1 or 2 multicourse parallel to that of the left ante- electrode catheters to the lateral or marrior descending coronary artery, giving ginal veins or the cardiac vein. Subselective rise to multiple septal and marginal catheterization of smaller branches can be achieved by advancing subsequently smaller branches. One characteristic feature of the (1.5F) or more flexible catheters (the lesser venous system is the presence of an exten- number of electrodes, the easier the manipsive net of anastomoses connecting veins ulation of the catheter to gain access to a given vessel). The anterior and lateral surdraining from different territories. The development in the recent years face of the left ventricle can be mapped of flexible, small-diameter (1.5F to 2.5F) extensively, not withstanding with the multielectrode catheters has provided the inherent limitations related to the distritechnical possibility of investigating exten- bution of the veins, from the atrioventricsively the electrophysiological properties of ular sulcus to the apex. Most frequently, the take-off of the the left ventricle with particular reference middle cardiac vein is located in the most to the above-mentioned types of VT.

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Figure 1. A. Left anterior oblique view of a patient in whom a coronary sinus angiogram reveals a proximal origin of a marginal vein, where (arrows) a 16-electrode catheter is advanced through an 8F Judkins catheter. B. In the same patient, 2 additional catheters are advanced through an 8F Amplatz AL 3 catheter to the great cardiac vein and to an anterolateral branch. C. In the same patient, a 30° right anterior oblique view of the position of the catheters.

proximal part of the coronary sinus, and often the tip of the Amplatz introducer is more distal, thereby preventing the catheterization of this vein. In this setting, we have frequently found very practical the use of the Judkins left (4 or 5) catheter (Cordis Endovascular, a Johnson & Johnson Company, Miami Lakes, FL), which frequently allows a selective and stable catheterization of the middle cardiac vein and its tributaries; this can be easily accessed in the left anterior oblique projection, and the right position of the introducing catheter can be felt as a "jump" of the catheter, reaching a level below that of the floor of the coronary sinus. A coronary sinus proximal angiogram is always required to check this position. Once the Judkins catheter is in place, 1 or 2 multielectrode catheters can be advanced

throughout the middle cardiac vein toward the apex. A more complete mapping of the inferior wall can be obtained by additional catheters advanced to the small venous branches feeding the middle cardiac vein. Once the catheters have been positioned, they remain very stable for hours; systemic anticoagulation with heparin, to achieve activated coagulation time values of 200 seconds, is used to avoid clotting around the catheters.

Epicardial Mapping in Patients with VT Following MI Following coronary arterial and venous angiography, the most useful information is usually achieved by placing the

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mapping catheter in veins running close or parallel to coronary arteries or branches related to the infarcted area. As shown in Figure 2, the recording of abnormal (fragmented, with low amplitude and long duration) electrograms during sinus rhythm is related to an even greater degree of prematurity of the local electrogram during VT; these aspects can be taken as evidence of epicardial involvement on the reentry circuit during a ventricular arrhythmia. On the other hand, epicardial electrograms that are normal during sinus rhythm tend to remain so during VT, and this behavior indicates that the epicardial layers of the area undergoing mapping are not related to the tachycardia mechanism. As previously demonstrated at surgery, an epicardial location of the critical area of the reentry circuit occurs in about 20% of VT related to posterior or posteriorinferior wall ML In line with these data, earliest diastolic activity or earliest isolated diastolic potentials (as compared with any endocardial activity) can be recorded in the epicardial surface of the posterior or inferior wall of the left ventricle by mapping with the catheters from the middle cardiac vein, the coronary sinus, and the posterior or the posterolateral branches. This type of pattern can be recorded, during simultaneous endocardial and epicardial mapping, in about 35% of patients with VT related to posterior or inferior wall infarction.18 In patients with anterior MI, epicardial mapping over the infarcted area can be performed extensively through the great cardiac vein, the anterior interventricular vein, and its many septal or diagonal branches (Figure 3). The recording of abnormal potential over a wide area of the anterior wall is common in patients with extensive anterior infarction and multiple VT morphologies, and in most of these cases the arrhythmias are not

tolerated and not amenable to catheter ablation (Figure 4). The demonstration at preliminary mapping that an arrhythmia substrate has a deep intramyocardial or an epicardial location may have important implications when a transcatheter ablation procedure is considered, because it supports the use of a variety of new interventions. Cooling of the catheter tip, either by an internal circuit or by irrigating the tip with saline, has been shown to create deeper and larger lesions in experimental models; the effectiveness of this technique has been investigated in a large multicenter trial.19 In our experience, the use of irrigatedtip catheters has proved effective in patients undergoing a repeat attempt at radiofrequency because of previous failures (Figure 5). It appears therefore justified that following a failure of conventional radiofrequency ablation approach, the demonstration of an epicardial substrate may guide the choice for a cooled-tip radiofrequency delivering system. A method of transthoracic puncture to introduce a mapping catheter into the pericardial space has been described by Sosa et al.20 The technique was originally introduced to demonstrate the epicardial location of the slow conduction area in patients with Chagasic VT21 and to perform ablation from the epicardial catheter of that peculiar substrate. In a more recent selected series of patients with VT related to inferior wall MI, successful epicardial ablation was reported in patients with mid-diastolic potentials recorded on the epicardial surface.22 Although this important technique probably cannot be recommended as a first-line approach, the demonstration of an epicardial origin of the arrhythmia at electrophysiological study may constitute one factor supporting the choice of this approach.

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Figure 2. A. Simultaneous recording of multiple surface EGG and bipolar intracavitary recording from the middle cardiac vein (MCV) (Epipos 1-16) and the great cardiac vein (GCV) (Epiant 1-8) in a patient with a previous inferior-posterior infarction. Normal epicardial electrogram (short duration, high amplitude) can be recorded from the anterior wall (GCV) and from the apical inferior wall (MCV recording 1-2 through 7-8). Starting from electrodes 9-10, a progressive decrease of the local electrogram amplitude can be appreciated; at sites 13-14 and 15-16 the fragmentation is so pronounced that distinct late electrograms (arrows) occur after the surface QRS onset. B. In the same patient, during an episode of induced ventricular tachycardia, the fragmentation of the epicardial electrograms becomes even more evident at the aforementioned recording sites, while a normal morphology is retained at the remaining epicardial electrograms. In this patient, however, local delay at the endocardial recording site (LVd) becomes more marked and an isolated diastolic potential preceding by 145 ms the onset of the surface QRS is marked by arrows.

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B Figure 3. A. Right anterior oblique (30°) view of 3 multielectrode catheters advanced from the coronary sinus to the anterior interventricular vein until the apex and to other branches B. Left anterior oblique view of the same patient, showing the catheters in the anterior interventricular vein (left) in one diagonal branch (middle), and in a lateral branch (right).

Epicardial Mapping in Idiopathic Right (or Left) Ventricular Outflow Tract Tachycardia A focal origin in the septal or anterior aspect of the right ventricular infundible

(or outflow tract) is most frequently found while mapping a distinct type of VT with a left bundle branch block pattern and inferior axis. Whether this type of VT is entirely idiopathic or it must be considered a

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Figure 4. Surface ECG and intracavitary recordings from the same patient as in Figure 3 during simultaneous endocardia! and epicardial mapping of multiple postinfarction ventricular tachycardia (VT) morphologies. A. During VT 1 earliest activity is recorded from the right ventricular apex (RVAp); prolonged and fractionated electrograms are recorded along the anterior interventricular vein (AIV), particularly at pairs 5-6 to 9-10. Atrial activity, with clear signs of atrioventricular dissociation, can be seen before the first and after the third beat in recordings AIV 5-6 to 11-12. B. During VT earliest activity is now recorded at EPI2 1-2; extreme electrogram fractionation can be seen over the anterior wall, from recordings AIV 3-4 to AIV 9-10. Continues.

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Figure 4. Continued. C. During the slower form (VT 3, cycle 388 ms) the degree of epicardial fractionation is markedly reduced at Epi2 and AIV recording sites. Note that during all 3 VTs the epicardial electrograms of the anterolateral vein remained normal. Epi2 = diagonal branch vein; LVd = left ventricular mapping catheter; AL = anterolateral vein.

mild and localized form of arrhythmogenic right ventricular dysplasia is still a matter of debate23,24; however, there is a general consensus that catheter ablation is highly effective in this form of arrhythmia and that it can be successfully performed in 90% of cases from a localized area of the right ventricular outflow tract. More recently, attention has been focused on the relation between the surface EGG pattern and the site of origin of the VT; the higher failure rate among patients presenting with a prominent R wave in leads V\ to V2 during VT suggests a leftsided origin in these cases.25 In this setting, the placement of a multielectrode catheter in the great cardiac vein and in the proximal anterior interventricular vein allows the recording from a wide area of the basal left ventricle26 (Figure 6).

The simultaneous analysis, during VT, of the activation sequence from the right and left outflow tract and from the epicardial layers overlying the left outflow tract provides information to guide an endocardial, right- or left-sided approach (Figure 7). On the other hand, earliest activity recorded epicardially is a strong indication of an epicardial or intramural location of the arrhythmogenic focus; in this latter instance, the ablation performed through a standard endocardial approach is less likely to be successful and alternative treatment modalities (surgery, direct endocardial approach) should be considered, although a case report has demonstrated the possibility of a successful ablation from the coronary sinus in a patient with idiopathic VT.27

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Figure 5. A. Simultaneous endocardial and epicardial mapping in a patient with ventricular tachycardia (VT) after a posterior wall myocardial infarction. Epi2 and Epi = recordings from multielectrode catheters advanced to 2 posterolateral venous branches. During VT, earliest (-70 ms to the onset of the surface QRS) activity is recorded epicardially at Epi 15-16 (bottom tracing, marked by an arrow); a lesser degree of prematurity is present at the corresponding endocardial target site for ablation. B. Termination of VT within 7 seconds of radiofrequency delivery by an irrigated-tip electrode catheter, allowing the delivery of an energy of 35 W with a tip temperature of 40°C.

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Figure 6. Right and left anterior oblique views of a patient with idiopathic left ventricular outflow tract ventricular tachycardia. A multielectrode catheter is advanced through the coronary sinus to the anterior interventricular vein; a quadripolar mapping/ablation catheter is positioned across the aortic valve, in the left ventricular outflow tract; a quadripolar electrode is visible in the right atrium.

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Figure 7. A. Simultaneous endocardial and epicardial mapping in the same patient as in Figure 6 during an episode of ventricular tachycardia (VT). Note the prominent R wave in lead V1 The degree of prematurity is higher on the left ventricular epicardial wall (great cardiac vein [GVC] recording 13-14) as compared to that recorded in the right ventricular outflow tract (RVAd). Note the distinct electrogram recorded with the left ventricular catheter in the position shown in Figure 6. B. Prompt termination of the VT during radiofrequency energy delivery at the left ventricular ablation site.

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10. Lerman BB, Stein KM, Markowitz SM. Idiopathic right ventricular outflow tract tachycardia: A clinical approach. Pacing Clin Electrophysiol 1996;19:2120-2137. 11. Morady F, Harvey M, Kalbfleish S, et al. Radiofrequency catheter ablation of venReferences tricular tachycardia in patients with coro1. Miller JM, Kienzle MG, Harken AH, nary artery disease. Circulation 1993;87: 363-372. Josephson ME. Subendocardial resection for ventricular tachycardia: Predictors of 12. Rothman SA, Hsia HH, Cossu SF, et al. Radiofrequency catheter ablation of postinsurgical success. Circulation 1984;70: farction ventricular tachycardia. Long624-631. term success and the significance of 2. Krafcheck J, Lawrie GM, Wyndham CRC. inducible nonclinical arrhythmias. CircuCryoablation of arrhythmias from the interventricular septum: Initial experience with lation 1997;96:3499-3508. a new biventricular approach. J Thorac Car- 13. Stevenson WG, Friedman PL, Kocovic D, et al. Radiofrequency catheter ablation of diovasc Surg 1986;91:419-427. ventricular tachycardia after myocardial 3. Caceres J, Werner P, Jazayeri M, et al. infarction. Circulation 1998;98:308-314. Efficacy of cryosurgery alone for refractory monomorphic sustained ventricular 14. Gensini G, Di Giorgi S, Coskun O, et al. Anatomy of the coronary circulation in tachycardia due to inferior wall infarction. living man. Coronary venography. CircuJAm Coll Cardiol 1988;11:1254-1259. lation 1965;31:778-784. 4. Littmann L, Svenson RH, Gallagher JJ, et al. Functional role of the epicardium in 15. Von Ludinghausen M. Clinical anatomy of cardiac veins. Vv. Cardiacae. SurgRadiol postinfarction ventricular tachycardia. Anat 1987;9:159-168. Circulation 1991;83:1557-1591. 5. Downar E, Kimber S, Harris L, et al. 16. De Paola AAV, Melo WDS, Tavora MZP, Martines EE. Angiographic and electroEndocardial mapping of ventricular tachyphysiological substrates for ventricular cardia in the intact human heart. II. Evitachycardia mapping through the corodence of multiuse reentry in a functional nary veins. Heart 1998;79:59-63. sheet of surviving myocardium. JAm Coll 17. Cappato R, Schluter M, Weiss C, et al. Cardiol 1992;20:869-878. Mapping of the coronary sinus and great 6. Downar E, Saito J, Doig C, et al. Endocardiac veins using a 2-French electrode cardial mapping of ventricular tachycarcatheter and a right femoral approach. J dia in the intact human ventricle. III. Cardiovasc Electrophysiol 1997;8:371-376. Evidence of multiuse reentry with spontaneous and induced block in portions of 18. Delia Bella P, Tondo C, Carbucicchio C, et al. Role of the epicardial mapping in reentrant path complex. J Am Coll Caridentifying patients with postmyocardial diol 1995;25:1591-1600. infarction ventricular tachycardia suit7. Harris L, Downar E, Mickleborough L, et able for radiofrequency catheter ablation. al. Activation sequence of ventricular Eur Heart J1998; 19:84. Abstract. tachycardia: Endocardial and epicardial mapping studies in the human ventricle. 19. Calkins H, Wharton M, Epstein A, et al. Safety and efficacy of catheter ablation of JAm Coll Cardiol 1987; 10:1040-1047. ventricular tachycardia using the cooled 8. Kaltenbrunner W, Cardinal R, Duboc M, ablation system: Final report. Pacing Clin et al. Epicardial and endocardial mapping Electrophysiol 1998;4:842. Abstract. of ventricular tachycardia in patients with myocardial infarction. Is the origin of the 20. Sosa E, Scanavacca M, d'Avila A, Pilleggi F. A new technique to perform epicardial maptachycardia always subendocardially ping in the electrophysiology laboratory. J localized? Circulation 1991;84:1058-1071. Cardiovasc Electrophysiol 1996;7:531-536. 9. Svenson R, Littmann L, Colavita PG, et al. Laser photoablation of ventricular tachy- 21. Sosa E, Scanavacca M, d'Avila A, et al. Endocardial and epicardial ablation guided cardia: Correlation of diastolic activation by nonsurgical transthoracic epicardial time and photoablation effect on cycle mapping to treat recurrent ventricular length and termination—observations tachycardia. J Cardiovasc Electrophysiol supporting a macroreentrant mechanism. 1998;9:229-239. JAm Coll Cardiol 1992;19:607-613.

Acknowledgments: We would like to thank Mrs. Miriam Bottani, Mr. Pascquale De lulis, and Mr. Marco Piras for their excellent technical assistance during the epicardial mapping studies.

TRANSCORONARY VENOUS MAPPING OF VT 22. Sosa E, Scanavacca M, d'Avila A, Sanchez 0. Transthoracic epicardial radiofrequency catheter ablation related to an old inferior wall myocardial infarction. Pacing Clin Electrophysiol 1998;21:843. 23. Carlson MD, White RD, Trohman RG, et al. Right ventricular outflow tract ventricular tachycardia: Detection of previously unrecognized anatomic abnormalities using cine-magnetic imaging. J Am Coll Cardiol 1994;24:720-727. 24. Markowitz SM, Livtack BL, Ramirez de Arrellano EA, et al. Adenosine sensitive ventricular tachycardia. Right ventricular abnormalities delineated by magnetic resonance imaging. Circulation 1997;96: 1192-1200.

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25. Callans DJ, Menz V, Schwartzman D, et al. Repetitive monomorphic tachycardia from the left ventricular outflow tract: Electrocardiographic patterns consistent with a left ventricular site of origin. J Am Coll Cardiol 1997;29:1923-1927. 26. Arruda M, Chandrasekaran K, Reynolds D, et al. Idiopathic epicardial outflow tract ventricular tachycardia: Implications for radiofrequency catheter ablation. Pacing Clin Electrophysiol 1996; 19: 611. Abstract. 27. Stellbrink C, Diem B, Schauerte P, et al. Transcoronary venous radiofrequency catheter ablation of ventricular tachycardia. J Cardiovasc Electrophysiol 1997; 8:916-921.

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Chapter 36

Transthoracic Epicardial Mapping and Ablation Technique Eduardo Sosa, MD, Maurido Scanavacca, MD, and Andre d'Avila, MD

Introduction Radiofrequency (RF) catheter ablation has been proved to be a safe and efficient procedure to treat a significant number of cardiac arrhythmias. Success can often be as high as 95% in patients with supraventricular tachycardia involving accessory pathways or atrioventricular nodal tachycardia, and, accordingly, catheter ablation is considered the treatment of choice for these pathologies.1^3 However, results are not satisfactory when this procedure is used to treat ventricular tachycardia (VT), especially when associated with structural heart disease.4"8 Although successful endocardial ablation of VT associated with myocardial infarction (MI) can be achieved in 60% to 80% of selected cases, this is not true for VT associated with chronic Chagasic cardiomyopathy, which is a very common type of VT in Brazil; while in some regions it is even more frequent than post-Mi VT, the results of endocardial ablation for this

type of tachycardia have been disappointing in our institution, with success rates below 20%.9-11 Interestingly, this VT originates in the left ventricular inferior wall in the vast majority of these patients. Taking into account data obtained from intraoperative mapping in post-Mi VT patients that suggests that epicardial circuits are common in VT related to an old inferior MI,12~17 one could speculate that one of the reasons for our failure in ablating Chagasic VT might be the fact that the reentrant circuit or part of it could be epicardial and/or intramyocardial. Not long ago, epicardial mapping could only be undertaken during cardiac surgery and was thus restricted to the surgical theater. Attempts to map epicardial surface with a less invasive approach, through thoracoscopy, were soon abandoned, not only because it must be performed in the surgical room, but also because of the difficulty in keeping the catheter stable. Another limitation was the fact that the accessible area for

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003. 681

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mapping was restricted to the anterior wall of the ventricles. Alternatively, insertion of a multipolar catheter into the epicardial veins may be used to obtain epicardial signals as previously described18; however, mapping is limited by the cardiac anatomy and the technique is not helpful when the site of origin is not close enough to the epicardial vessels to be mapped. Transthoracic epicardial mapping, on the other hand, became a feasible procedure owing to the substantial experience gained from draining pericardium effusion occurring during the learning curve of endocardial ablation. Moreover, the availability of the adequate material necessary to puncture a virtual space without damaging the structures inside it was important. This technique, as we show, permitted a great deal of epicardial exploration in the electrophysiology laboratory. Its feasibility and safety for mapping and ablation of sustained VT have been previously described.19"22

catheter is introduced in the pericardial sac to map and ablate. The first 2 catheters are inserted percutaneously into the femoral vein, while the third is introduced through transthoracic puncture. After the catheters are positioned, epicardial mapping is undertaken, followed by ablation when an adequate target is identified. If VT is still induced after epicardial ablation, routine endocardial ablation is performed. The entire invasive procedure is undertaken in the electrophysiology laboratory after deep sedation with midazolam and fentanyl and/or a continuous drip of propofol. Transthoracic Puncture

Transthoracic puncture is the most important step in the whole procedure and it can be safely and efficiently undertaken in the electrophysiology laboratory.19"22 After proper asepsis of the subxiphoid area, pericardial puncture is undertaken according to the technique previously described by Krikornian and Hancock.23 A regular needle used for Mapping Technique epidural anesthesia (Tuohy-17-gr., effecSelection of the ablation site for VT tive length 79.4 mm, overall 101.6 mm, ablation follows a routine procedure, sim- O. D. 1.5 mm, Abbot I/ N# E622, Abbot ilar to that used in most electrophysiology Ireland Ltd., Sligo, Republic of Ireland) is laboratories. The ablation site is initially used for this procedure. The needle is noninvasively selected through analysis introduced at a 45° angle and then gently of QRS complex morphology (12-lead advanced under fluoroscopy until close to ECG) during VT. Unfortunately, no elec- the cardiac silhouette, where a light negtrocardiographic criteria have been found ative pressure is felt (Figure 1). Needle angle is adjusted according to useful in distinguishing endocardial from the region that the operator wishes to epicardial VT. Invasive analysis begins by inducing access. This region is most frequently the VT with programmed electrical stimulation medial third of the right ventricle, where, from the apex of the right ventricle or the based on the coronary angiography, no right ventricular outflow tract with up to 3 major coronary vessels can be found. This extrastimuli during sinus rhythm and area is monitored by fluoroscopy in several pacing from at least 2 different cycles projections (anteroposterior, left anterior lengths (600 and 400 ms). If induced, VT is oblique, right anterior oblique). Operator hemodynamically tolerable, mapping is experience is crucial to visualize the heart assumed to be feasible, and, accordingly, a as a 3-dimensional structure while looking second multipolar catheter is introduced in at a 2-dimensional image. The presence of the coronary sinus, while a deflectable tip a catheter at the right ventricular apex and

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Figure 1. A regular needle used for epidural anesthesia (shown in details in the left superior corner) is used during transthoracic puncture according to the technique described by Krikornian and Hancock23 to drain epicardial effusions.

in the coronary sinus is a useful reference to guide the needle tip. In order to demonstrate the precise site of the needle tip, 2 mL of contrast media are injected (loxitalamato de meglumina e sodio, Telebrix Coronar, Gulbert Produgoes Ltda, Rio de Janeiro, Brazil). When the needle tip is inside the pericardial space, contrast medium can be seen surrounding the cardiac silhouette (Figure 2). Visualization of a thin layer of contrast in the pericardial space is crucial, as this confirms that the needle is correctly placed in the pericardial space. The needle tip can occasionally perforate the right ventricle, something that can be easily recognized after a new injection of contrast medium. If this happens, the needle is slightly retrieved and a little more contrast medium is injected until the pericardial space is reached. Although it normally does not offer much resistance, sometimes firmer pressure may be necessary, thus the importance of the visualization of contrast

medium in the pericardial space. Finally, a soft floppy-tip guidewire is introduced in the pericardial space through the puncture needle. As a rule, the guidewire easily slips into the pericardial space (Figure 2). Guidewire position is also monitored through fluoroscopy. Perforation of the right ventricle related to the guidewire can also happen, but because of its small width, these perforations are "dry," that is, no hemopericardium occurs. In the majority of cases, both pericardial puncture and guidewire introduction occur without right ventricular perforation. An 8F introducer is then placed in the pericardial space and the guidewire removed. Finally, under fluoroscopy, a quadripolar deflectable catheter with a 4-mm tip is inserted into the pericardial space for mapping and ablation (Figure 2). As soon as the catheter is in the pericardial space, the pericardial fluid is aspirated to check for blood. Normally only a trivial amount of translucent pericardial fluid is expected.

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Figure 2. Technique used to insert the mapping catheter in the pericardial space. RV = right ventricle. See text for details.

Once the ablation catheter is introduced in the epicardial space, extensive mapping may be performed without increasing the procedure risk, because there are no papillary muscle or thrombi in the pericardial sac to restrict catheter movement. Epicardial Mapping As the catheter is in the pericardial space, the operator can easily manipulate it, covering the entire surface of the right and left ventricles as well as the atria. The limits of this surface are marked by pericardial reflection. The lateral and posterior left ventricular wall of both ventricles and atria are easier to map than the anterior wall.

Another noteworthy peculiarity found in this approach is catheter stability. When the catheter is not being manipulated, it rests stable in a selected site, following ventricular wall motion. This stable catheter position is obtained by apposition of the 2 layers of pericardium and the weight of both lungs lying against it. Moreover, the negative pressure found in the pericardial space may also contribute to that. In this sense, the epicardial catheter is more easily manipulated and shows more stability than the endocardial catheter, which tends to be expelled every systole, especially when inside the left ventricular cavity. Epicardial electrograms are as clear as endocardial electrograms and their interpretation follows the same pattern

TRANSTHORACIC EPICARDIAL MAPPING AND ABLATION as for standard endocardial signs. The possibility of mapping an extensive epicardial surface permits the assessment of electrical activity at very close sites thus displaying more data about electrical activity of the heart. This is not usually possible with endocardial mapping, since the presence of papillary muscles and chordae as well as repetitive ventricular systoles are obstacles for the free manipulation of the endocardial catheter. Finding the adequate epicardial target site for sustaining the VT, just as in endocardial mapping, depends on diastolic activity analysis and, when feasible, response to programmed ventricular stimulation (Figure 3). However, we have observed that the epicardial bipolar stimulation

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thresholds are extremely high. Thus, in order to obtain regular capture, stimuli higher than 10 mA are often necessary. Because unipolar stimulation causes a great deal of interference thus limiting analysis of recordings, this technique has not been used in our laboratory. Apart from that, because Chagas' VT is usually associated with multiple morphologies, pacing techniques frequently can interrupt clinical VT or induce unstable VT. The presence of diastolic activity during induced VT, as well as the use of entrainment mapping techniques, has shown that the epicardial circuits could be safely and effectively identified by transthoracic epicardial mapping.

Figure 3. Bipolar pacing from the distal par of epicardial electrodes demonstrates concealed entrainment with a returning cycle identical to the tachycardia cycle length (bottom channel). The stimuli delivered from the distal par (not seen in the picture) is being blocked antidromically but captures the epicardial mid-diastolic potential orthodromically (LV epic channel): the spike-ventricle delay is shorter than the time delay between the mid-diastolic potential and the ventricular electrogram but its cycle length equals the mid-diastolic potential cycle length. Shown are ECG leads I, II, V^ and V6. PCS = proximal coronary sinus; DCS = distal coronary sinus; RVA = right ventricular apex; LV endo = left ventricular endocardial catheter; LV epic = left ventricular epicardial catheter.

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Transthoracic Epicardial Ablation: Is it Safe? Two different investigational approaches were developed after our initial clinical experience with epicardial mapping, in order to determine the usefulness and safety of this technique for RF ablation procedures. Initially, clinical investigation consisted of the use of epicardial mapping to guide standard endocardial ablation of VT associated with chronic Chagasic cardiomyopathy. This attempt showed that VT could be satisfactorily mapped from the epicardium and interrupted through an endocardial approach. However, VT interruption only occurred after long applications of more than 30 seconds. Besides, all VT could eventually be re-induced at short- or long-term follow-up.22 At the same time, experimental studies on canine hearts were designed to analyze the effects of linear and punctiform lesions caused by RF ablation on the ventricular myocardium, coronary vessels, and aorta because vascular damage has been pointed out as a limitation for transthoracic epicardial RF catheter ablation. Nine mongrel dogs (24 ± 6 kg) underwent lateral thoracotomy to allow positioning and suture of the ablation catheters against the left ventricular epicardial surface. Temperature-controlled applications were delivered through a multielectrode catheter (Amazr®, Medtronic, Inc., Minneapolis, MN) placed perpendicularly to the proximal and distal portion of the interventricular coronary artery and a regular 4-mm-tip catheter placed beside the vessel. The multielectrode catheter was also placed around the descending aorta where linear lesions were created. All animals were sacrificed 14 days after the last application. One hundred seventeen pulses were delivered through the multipolar catheter to create 24 linear lesions in the epicardial

left ventricular surface (1007 mm). These applications produced lesions 8.5 ± 1 mm long per electrode, 7 ± 2 mm wide, and 3.8 ± 1 mm deep. Mean temperature, impedance, and power were 70 ± 12° C, 10 ± 6 W, and 161 ± 29 Q, respectively. Twenty-six vessels were found along 606 mm of linear lesions: in all of them RF applications induced extracellular matrix accumulation in the media without neointima formation. Severe medial hyperplasia was noted in one artery and intravascular thrombosis in another 6 arteries. Veins related to the arteries were always patent. Multivariable regression analysis identified the internal perimeter of the vessel (0.78 ± 0.49 mm versus 1.79 ± 0.83 mm [P < 0.05]) as the only variable associated with artery damage. Applications with the 4-mm catheter never caused neointima formation or thrombosis. In the aorta, lesions ranged from minimal to transmural and a clear destruction of the elastic lamina at different degrees was consistently found in 3 of 4 animals. Therefore, during epicardial application of RF energy, the larger the coronary artery the safer the application will be because medial hyperplasia and intravascular thrombosis were only found in the smallest vessels. In the aorta, RF applications caused moderate destruction of the elastic lamina, and lesions can be transmural. The effects of epicardial RF applications on the adjacent structures (pericardium and lungs) was also evaluated in swine hearts. As far as the lungs are concerned, injury is also restricted, allowing us to assume that no functional hazards could emerge. In these animals no pericardial perforation was observed. Criteria for the Diagnosis of an Epicardial VT Due to the high stimulation threshold, entrainment techniques have rarely

TRANSTHORACIC EPICARDIAL MAPPING AND ABLATION been used as an indication to select target sites for ablation. More often, selection has been accomplished by heating the tip of the electrode (thermo mapping) and examining its effect on the VT. This empirical thermo mapping technique consists of RF pulses of 60°C for 10 seconds. If VT is interrupted within 10 seconds, application is maintained for 30 seconds. If VT is not modified within the first 10 seconds, the catheter is manipulated until better electrograms are obtained, and new thermo mapping pulses are applied. The limitations for the use of entrainment and the small lesions produced by empirical use of thermo pulses of 60°C during 10 seconds can be a limitation to distinguish between a bystander site and a common pathway. Therefore, potential adequate sites for ablation might not be identified. The use of higher temperature pulses during a longer period might identify a larger number of epicardial circuits.

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patterns predictive of ablation success and whether thermo mapping could be safely and effectively used to guide RF epicardial ablation. A regular ablation catheter was introduced into the pericardial space by transthoracic puncture during 21 procedures in 19 consecutive patients with Chagasic VT. Two hundred thirty-nine sites were analyzed and the electrograms defined as mid-diastolic potentials, continuous activity, and early signal. A 60°C pulse was delivered for 10 seconds at each site. Electrogram duration and precocity were determined for each application and a 12-lead ECG for ST segment analysis was obtained after VT interruption. VT was interrupted at 47 of 239 sites (19%). At 57 sites, electrograms were defined as mid-diastolic signals (24%). VT interruption occurred in 5 sites (9%) whereas 52 applications did not interrupt VT. Duration and precocity did not differ between successful and unsuccessful applications. Electrograms were defined as continuous electrical activity at 27 sites (11%) Is There an Electrogram Pattern and interruption occurred in 8 of them Predictive of Successful (30%). In 19 sites where continuous elecApplication During Transthoracic trical activity was found, RF application RF Epicardial Catheter Ablation did not change VT. An early electrogram was found in 155 sites (65%). RF interto Treat VT? rupted VT in 34 sites (22%) but electroWhen patients with chronic Chagasic gram duration (181 ± 72 ms versus 177 ± cardiomyopathy are subjected to RF 68 ms) and precocity (107 ± 47 ms versus pulses for VT interruption, results of epi- 94 ± 44 ms) did not differ among these cardial mapping shows a variety of elec- sites. No early or late complications trograms. These electrograms have occurred during follow-up. Electrogram pattern was therefore multiple characteristics, certainly because of the heterogeneous ventricular involve- not helpful in defining a site for a successment in this cardiopathy. Unfortunately, ful epicardial RF application. Although the epicardial stimulation threshold in safe, epicardial catheter ablation based the area of slow conduction is high enough on empirical thermo mapping is not ideal. to prevent ventricular capture in most VT interruption based on this technique patients. Thus, entrainment maneuvers was achieved in 20% of the attempted cannot be performed to define whether a sites, making necessary a large number of site is part of the circuit. A study was applications to successfully treat these therefore carried out in order to define patients. These results mimic those found whether there are epicardial electrogram for endocardial ablation.24

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mapping were subjected to epicardial mapping and ablation. Eighteen VTs could be mapped epicardially (1 to 4 VTs Based on the former observations, per patient); 14 of these had an epicardial the next step was to investigate the safety circuit. Four were interrupted by RF and efficacy of epicardial applications of application of pulses in the endocardium RF pulses guided by epicardial mapping guided by epicardial mapping (mean in patients with VT associated with interruption time 20.1 ± 14 seconds), but chronic Chagasic cardiomyopathy. Pre- all of them were re-induced. Ten of 14 liminary results of this study have been were interrupted with RF pulses in the previously published.22 In this study, 10 epicardium (mean interruption time of consecutive patients with chronic Cha- 4.8 ± seconds) and were not re-induced gasic cardiomyopathy and VT suitable for (Figure 4). One of the patients had a Transthoracic Epicardial Ablation of Chagasic VT

Figure 4. Activation mapping during ventricular tachycardia (VT) obtained during transthoracic epicardial mapping in 2 distinct patients with Chagas' disease. In the upper panel, epicardial electrograms found in EPi preceed the onset of the QRS complex by 90 ms (A). Due to a high stimulation threshold, ventricular capture was not obtained during pacing from the epicardial catheter. At this site, an epicardial application of radiofrequency (RF) interrupted VT within 1.4 seconds and rendered it noninducible. In the bottom panel, epicardial electrograms found in Epi-d precedes the onset of the QRS complex by 195 ms and presents 2 main components. The first fractionated portion of the electrogram coincides with the end of the preceding QRS complex and spans through the entire electrical diastole. At this site, an epicardial application of RF interrupted VT after 0.8 seconds and rendered it noninducible. VTCL = ventricular tachycardia cycle length; V = ventricular electrogram; CS^ to CS5 and SCP, 2, 3, 4, and SCO = sequence of electrograms obtained from decapolar catheter in the coronary sinus; VDP = proximal bipolar signal from the right ventricular endocardial catheter.

TRANSTHORACIC EPICARDIAL MAPPING AND ABLATION small hemopericardium (about 50 mL) drained at the electrophysiology laboratory, and 3 patients complained of brief precordial discomfort. Transthoracic Epicardial Ablation of Post-Mi VT Transthoracic epicardial ablation of potential epicardial VT circuits associated with chronic MI had not been attempted initially, because the possibility of pericardial adherence occurring after a transmural MI could be an important limitation for the procedure. In order

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to investigate this hypothesis, we performed transthoracic epicardial mapping and ablation in a series of 5 consecutive patients with VT associated with an old inferior infarction.25 The reason to favor an inferior infarction was that epicardial circuits are most frequently found at that localization. Transthoracic epicardial mapping could be performed in all patients, and adherence did not constitute a limitation for the catheter manipulation. In this group, 10 tachycardias were induced (5 clinical, 5 nonclinical). Four of 5 clinical tachycardias had an epicardial circuit, and all of them were successfully ablated with epicardial pulses of RF (Figure 5).

Figure 5. Activation mapping during ventricular tachycardia (VT) obtained by transthoracic epicardial mapping in 2 patients with VT related to an old inferior myocardial infarction. In the upper panel, all epicardial electrograms precede the onset of the QRS complex but the electrogram found in EPi is the earliest one. At these sites, an epicardial application of radiofrequency (RF) interrupted VT after 4 seconds and rendered it noninducible. In the bottom panel, a mid-diastolic potential preceding the onset of the QRS complex by 100 ms (Epi-d) was used to guide an RF application that interrupted VT after 4 seconds. CS = coronary sinus; P = proximal; D = distal; RV = right ventricle; Epi = epicardial bipolar electrogram; HR = heart rate.

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Results obtained with these 2 selected groups of patients support the concept that transthoracic epicardial mapping is a safe and efficient procedure to control recurrences of epicardial VT. How to Avoid Damage to the Coronary Arteries

them. Serial analysis of MB fraction of creatine phosphokinase was determined every 4 hours during the first 24 hours; in none of the patients was it superior to 6IU. Complications

The transthoracic epicardial mapping and ablation technique is a safe procedure; There are 3 theoretical ways to however, some complications can occur. damage the coronary arteries during The hemopericardium, which is the most transthoracic epicardial mapping and/or common, was observed in 10% of both ablation. First, it has been postulated Chagasic and post-Mi VTs. Pericardial that the needle can perforate a coronary adherence after MI was never so intense artery, but this is exceedingly unlikely to as to preclude epicardial mapping and occur during transthoracic puncture since ablation in patients with postinfarction there are no major epicardial vessels close or Chagasic VT related to an epicardial to right apical ventricular wall (the area circuit. The amount of blood drained from where the needle tip is inserted). It has the pericardial space ranged from 20 to also been suggested that once in the peri- 300 mL, with an average of 154 ± 32 mL. cardial space, the ablation catheter could The bleeding did not preclude the contintear an epicardial vessel. However, con- uation of the procedure and blood transtrary to most people's beliefs, these ves- fusion was never required in this situation, sels are not so superficially located; they as the blood drained was immediately reare covered by the visceral pericardium injected through the sheath inserted in and lay in a deep groove of adipose tissue the femoral vein. "Dry" puncture of right in the epicardial ventricular muscle. ventricle was observed in 8% of Chagas' Finally, a major concern involves the patients and in 5% of the post-Mi populaeffect of RF pulse application on the coro- tion. Transient precordial distress was nary arteries. Taking into account exper- observed in 10% of the whole population imental data suggesting that coronary and was easily controlled with nonsteroidal artery occlusion depends more on the anti-inflammatory medications. vessel caliber than on the type of applicaTwo Chagasic patients experienced a tion, we established that the minimal dis- major, nonfatal complication. One patient tance between catheter tip and the artery had hemoperitoneum from an injured was 12 mm (3 times the catheter tip). So, diaphragmatic vessel requiring laparoin some patients in whom the site of tomy and blood transfusion. In another application is located close to the coro- patient with incessant VT, RF pulse was nary sinus (where a major coronary artery applied very close to a marginal branch of may be found), a coronary angiogram is the circumflex artery resulting on its occluobtained before applying RF pulses to sion and non-Q-wave infarction with a determine the distance between the peak creatine kinase-MB of 35 U/dL. The catheter tip and the coronary artery. patient was discharged in sinus rhythm. Continuous electrocardiographic monitoring of ST segment was undertaken in Conclusion the first 10 patients during the entire procedure and in the first 24 hours after it, but Nonsurgical epicardial catheter ablano ST changes were detected in any of tion is a minimally invasive procedure

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5. Kottkamp H, Hindricks G, Chen X, et al. that has proven to be efficacious for the Radiofrequency catheter ablation of sustreatment of VT and can be safely pertained ventricular tachycardia in idiopathic formed in the electrophysiology laboradilated cardiomyopathy. Circulation 1995;92: tory. This technique allows identification 1159-1168. of epicardial circuits, the prevalence of 6. Kim YH, Sosa-Suarez G, Trouton TG, et al. Treatment of ventricular tachycardia by which seems to depend on the underlying transcatheter radiofrequency ablation in heart disease being more frequent in Chapatients with ischemic heart disease. gasic than in post-Mi VT. Therefore, the Circulation 1994;89:1094-1102. usefulness of this technique will depend 7. Gonska BD, Cao K, Schaumann A, et al. on the prevalence of epicardial circuits in Catheter ablation of ventricular tachycardia in 136 patients with coronary a given population. This approach is limartery disease: Results and long-term ited by concern regarding the potential follow-up. J Am Coll Cardiol 1994;24: adverse effects of RF ablation on the epi1506-1514. cardial coronary arteries. Hemoperi8. Rodriguez LM, Smeets JL, Timmermans cardium, a predictable complication that C, et al. Radiofrequency catheter ablation of sustained monomorphic ventricular can be easily controlled in the electrotachycardia in hypertrophic cardiomyopaphysiology laboratory, occurs in 10% of thy. J Cardiouasc Electrophysiol 1997; patients undergoing this procedure, but 8:803-806. coronary artery injury, possibly pre9. Scanavacca M, Sosa E. Electrophysiologic ventable by a coronary angiogram prior to study in chronic Chagas' heart disease. Sao Paulo Med J 1995;113:841-850. ablation, is uncommon (<1%). Thus, it is our thought that it should be incorporated 10. Sosa E, Scalabrini A, Rati M, et al. Successful catheter ablation of the origin of to the electrophysiological routine of maprecurrent ventricular tachycardia in ping and ablation of VT associated with chronic Chagasic heart disease. J Elecstructural heart disease. trophysiol 1987; 1:58-61.

References 1. Haissaguerre M, Gaita F, Fischer B, et al. Elimination of atrioventricular nodal reentrant tachycardia using discrete slow potentials to guide application of radiofrequency energy. Circulation 1992;85:21622175. 2. Jackman WM, Beckman KJ, McClelland JH, et al. Treatment of supra ventricular tachycardia due to atrioventricular nodal reentry, by radiofrequency catheter ablation of slow-pathway conduction. N Engl JMed 1992;327:313-318. 3. Calkins H, Sousa J, el-Atassi R, et al. Diagnosis and cure of the Wolff-ParkinsonWhite syndrome or paroxysmal supraventricular tachycardias during a single electrophysiologic test. N Engl J Med 1991; 324:1612-1618. 4. Trappe HJ, Klein H, Auricchio A, et al. Catheter ablation of ventricular tachycardia: Role of the underlying etiology and the site of energy delivery. Pacing Clin Electrophysiol 1992; 15:411-424.

11. Sosa E, Scanavacca M, Barbero Marciel M, et al. Surgical treatment of cardiac arrhythmias. In: Cruz Filho FES, Maia IG (eds): Eletrofisiologia Clinica e Intervencionista das Arritmias Cardiacas. Rio de Janeiro: EditoraRevinterLtda.; 1997:443-455. 12. Kaltenbrunner W, Cardinal R, Dubuc M, et al. Epicardial and endocardial mapping of ventricular tachycardia in patients with myocardial infarction. Is the origin of the tachycardia always subendocardially localized? Circulation 1991;84:1058-1071. 13. Hadjis T, Stevenson WG, Friedman PL, et al. Ventricular tachycardia after inferior wall myocardial infarction: Predominance of locations for critical slow conduction zones. J Am Coll Cardiol 1995;25:108A. Abstract. 14. Svenson RH, Littmann L, Gallagher JJ, et al. Termination sequence of ventricular tachycardia with epicardial laser photocoagulation: A clinical comparison with patients undergoing successful endocardial photocoagulation alone. J Am Coll Cardiol 1990; 15:163-170. 15. Svenson RH, Littmann L, Colavita PG, et al. Laser photoablation of ventricular

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tachycardia: Correlation of diastolic activation times and photoablation effects on cycle length and termination: Observations supporting a macroreentrant mechanism. JAm Coll Cardiol 1992;19:607-613. 16. Littman L, Svenson RH, Gallagher JJ, et al. Functional role of ventricular tachycardia. Observations derived from computerized epicardial activation mapping, entrainment, and epicardial laser photoablation. Circulation 1991;83:1577-1591. 17. Pfeiffer D, Moosdorf R, Svenson RH. YAG laser photocoagulation of ventricular tachycardia without ventriculotomy in patients after myocardial infarction. Circulation 1996;94:3221-3225. 18. Arruda M, Chandrasekaran K, Reynolds D, et al. Idiopathic epicardial outflow tract ventricular tachycardia: Implications for RF catheter ablation. Pacing Clin Electrophysiol 1996;19:611. Abstract. 19. de Paola AAV, Melo WDS, Tavora MZ, Martinez EE. Coronary venous mapping in patients with sustained ventricular tachycardia. J Am Coll Cardiol 1997;29: 202A. Abstract. 20. Sosa E, Scanavacca M, d'Avila A, Pileggi F. A new technique to perform epicardial

21.

22.

23. 24.

25.

mapping in the electrophysiology laboratory. J Cardiovasc Electrophysiol 1996;7: 531-536. Sosa E, Scanavacca M, d'Avila A, et al. Radiofrequency catheter ablation of ventricular tachycardia guided by non-surgical epicardial mapping in chronic Chagasic heart disease. Pacing Clin Electrophysiol 1999;22:128-130. Sosa E, Scanavacca M, d'Avila A, et al. Endocardial and epicardial ablation guided by nonsurgical transthoracic epicardial mapping to treat recurrent ventricular tachycardia. J Cardiovasc Electrophysiol 1998;9:229-239. Krikornian JG, Hancock EW. Pericardiocentesis. Am JMed 1978;65:808-816. Stevenson WG, Khan H, Sager P, et al. Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of VT late after myocardial infarction. Circulation 1993;88: 1647-1670. Sosa E, Scanavacca M, d'Avila A, Sanchez O. Transthoracic epicardial RF catheter ablation related to an old inferior wall myocardial infarction. Pacing Clin Electrophysiol 1998;21:843. Abstract.

Chapter 37

Nonfluoroscopic Mapping of Supraventricular Tachycardia Gerhard Hindricks, MD and Hans Kottkamp, MD

Introduction The major objective of cardiac mapping is to evaluate the mechanisms of excitation of the heart during normal rhythms as well as to analyze the activation wavefronts emerging from those structures that are involved in the genesis of cardiac arrhythmias. The exact localization of such structures is a prerequisite for understanding the pathophysiological mechanisms that underlie the different types of cardiac arrhythmias. In the era of curative nonpharmacological treatment of cardiac arrhythmias with percutaneous catheter ablation techniques, cardiac mapping has evolved as an important technique to localize arrhythmogenic structures and subsequently destroy these structures by the application of radiofrequency (RF) current. Percutaneous endocardial catheter mapping is conventionally performed using monoplane or biplane fluoroscopy to manipulate the mapping catheter sequentially to different sites in the heart chamber of interest

in order to understand the activation sequence and mechanism of an arrhythmia and, finally, to define appropriate target sites for catheter ablation. Conventional mapping and catheter ablation has been shown to be effective to localize precisely the arrhythmogenic substrate in a variety of supraventricular and atrioventricular (AV) arrhythmias. Especially when the target area for catheter ablation is well known, e.g., in AV nodal reentrant tachycardia or Wolff-Parkinson-White syndrome, conventional fluoroscopy-guided endocardial catheter mapping is very feasible for the successful definition of target sites for catheter ablation. However, in patients with more complex arrhythmias, fluoroscopy-guided catheter mapping can be inaccurate and cumbersome. In addition, in patients with complex cardiac arrhythmias, long fluoroscopy times may be necessary, causing significant risk for the patient. With the CAETO system (Biosense Webster, Diamond Bar, CA), a technology was introduced that offered the option of nonfluoroscopic catheter-based endocardial

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003.

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mapping.1"3 The system is capable of reconstructing a 3-dimensional electroanatomical map of the heart in a real time mode from the multitude of endocardial sites that have been sequentially mapped; it then color codes the individual activation times with respect to a predetermined reference time. Experimental in vitro and in vivo studies as well as clinical investigations have indicated that the results obtained with the system are highly accurate and reproducible.1"7 The technical aspects of nonfluoroscopic 3dimensional endocardial mapping are described in detail chapter 5 of this book. This chapter focuses on the use of the technology for endocardial catheter mapping in patients with supraventricular or AV arrhythmias.

Usually the whole TA can be reconstructed by acquiring 8 to 10 mapping points. This should be followed by visiting the ostium of the coronary sinus and the superior and inferior caval veins. Now the operator who is experienced in the use of nonfluoroscopic mapping has all anatomical information necessary to complete the map with only minimal use of fluoroscopy. For the experienced operator, less than 1 minute of fluoroscopy time may be necessary for a complete RA map. For nonfluoroscopic mapping of the left atrium (LA), we usually proceed in a comparable fashion (Figure 2). The first mapping points are taken along the mitral annulus, followed by mapping of the ostia of 2 or all pulmonary veins. In parallel to the anatomical information provided by the reconstruction, local electrograms obtained at each mapping site are annotated and provide the first information on the actiElectroanatomical Mapping vation sequence of the heart chamber. of Supraventricular or AV When the rough geometry of the chamber Tachycardia: Methodological has been reconstructed, mapping is focused on the area of interest. In patients with and Practical Considerations focal arrhythmias, it is generally easy to The 3-dimensional electroanatomical define the area of interest within the mapping technology allows the complete heart chamber rather quickly. However, reconstruction of a single or even multi- in patients with macroreentrant arrhythple heart chambers. In the vast majority mias, e.g., atypical AFL, it is often necof patients, the complete reconstruction of essary to reconstruct most of or even the a whole heart chamber is not necessary whole heart chamber to get all the inforand the mapping procedure is focused on mation needed to completely understand an area of interest, e.g., the site of origin the arrhythmia mechanisms and develop of an ectopic atrial tachycardia or the a treatment strategy for catheter ablaright atrial (RA) isthmus in patients with tion. The option of the CARTO technology atrial flutter (AFL). However, in order to to accurately navigate the mapping appropriately use the nonfluoroscopic catheter to areas of interest and to option of the technology, it is crucial to renavigate the catheter to previously visstart the reconstruction by visiting cer- ited sites enables the investigator to tain anatomically defined landmarks to complete the map with a high degree of allow proper orientation. When the RA is accuracy and spatial resolution. Electroanatomical mapping is perthe chamber of interest, we recommend acquiring the first mapping point at the formed as a sequential "point-by-point" His bundle area. From this site it is easy mapping procedure. The stability of the to reconstruct the tricuspid annulus (TA) arrhythmia during the reconstruction is either completely or partially (Figure 1). a crucial precondition to guarantee valid

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Figure 1. Electroanatomical reconstruction of the right atrium obtained during reversed common atrial flutter. The projection shown is equivalent to left anterior oblique 30° as indicated by the headand-eyes icon. The first mapping point was taken with the help of fluoroscopy from the His bundle (His) area (A). This was followed by the electroanatomical reconstruction of the septal and inferior tricuspid annulus (TA) (B). Mapping points obtained at the superior and anterior aspect of the annulus complete the reconstruction of the TA (C). In experienced hands, the completion of the electroanatomical reconstruction of the right atrium can now be performed nearly without fluoroscopy (<30 seconds in this particular case). The orifice of the superior caval vein demarks the most superior aspect of the right atrium (D). Acquisition of mapping points from the ostium of the coronary sinus and the orifice of the inferior caval vein demark further anatomical landmarks (E). A total of 129 mapping points were acquired to complete the right atrial electroanatomical reconstruction. Note the homogeneous distribution of mapping points at all sites of the right atrial free wall. E. The "open" geometry (grid map) of the right atrium. F. Complete electroanatomical map during reversed common atrial flutter with the activation sequence color coded superimposed to the chamber geometry. The inferior-anterior aspect of the right atrium is activated first as indicated in red and yellow. The clockwise activation around the annulus is indicated by the color shift from green to blue and finally to purple at the septal aspect of the inferior isthmus representing the area of latest activation. See color appendix.

information on the activation sequence. Thus, before a certain mapping site is accepted and incorporated in the map, it is important to carefully check the cycle length at each recording site. A single signal that has been acquired and incorporated into the reconstruction but incorrectly annotated may confuse the whole map. Although the CARTO data acquisition software has some features to avoid

this problem, i.e., stability criteria for catheter location and activation time, it is important to critically evaluate the data taken from each mapping site before incorporating them into the map. If the investigator is not sure whether data obtained at a certain mapping site are valid, we highly recommend to reject the data and validate the catheter location and local activation by taking new data.

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Figure 2. Electroanatomical map of an ectopic atrial tachycardia with a left septal origin. Upper panels: After acquisition of the initial 4-5 tricuspid annulus (TA) mapping points, the map was continued toward the complete triangle of Koch where relatively early activation was recorded in a midseptal position (upper left, open asterisk). However, the morphology of the unipolar and bipolar electrograms indicated a left atrial origin of the tachycardia and the map was continued in the left atrium (upper right panel). Directly opposite the relatively early right side septal activation, the earliest detectable activation with a pure QS complex in the unipolar electrogram (arrow) and an early activation time in the bipolar electrogram was recorded. The left lower panel shows the renavigated ablation catheter positioned at the earliest activation site and subsequent application of radiofrequency energy terminated the ectopic atrial tachycardia. The lower right panel shows the corresponding catheter positions in a left anterior oblique 60° oblique position. HRA = high right atrium; His = His bundle; RVA = right ventricular apex; CS = coronary sinus; Abl = ablation catheter. See color appendix.

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Electroanatomical Mapping of the RA During Sinus Rhythm

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taken to create a rough picture of the atrial geometry, whereas acquisition of mapping points was concentrated in the area of interIn a previous study,4 we performed est. Whenever an early activation site was mapping of the entire RA in 12 patients. In identified during the mapping procedure, these patients, 50 to 150 points were nec- the catheter was manipulated to adjacent essary to complete an RA map. The anatom- sites using the navigation features of the ical landmarks of the RA, i.e., the TA, RA CARTO system. In order to achieve a high appendage, mouth of the coronary sinus, degree of spatial resolution within the area and ostia of the superior and inferior caval of interest, all adjacent sites were visited in veins, could be delineated in all cases. a cross-shaped manner leaving only a few The region of earliest endocardial activa- millimeters of unmapped space between tion during normal sinus rhythm, i.e., the each recording site (Figure 3). After complesinus node area, was found at the lateral tion of the map, the ablation catheter was free wall close to the junction with the supe- renavigated to the earliest activation site rior caval vein. The preferential fast con- and RF energy was delivered. One to 6 duction along the crista terminalis down energy applications resulted in termination the lateral free wall of the RA could be and noninducibility of the ectopic atrial depicted, whereas conduction was consid- tachycardias. Figure 4 presents an interesting case erably slower in the direction perpendicular to the crista terminalis. In addition, the of ectopic atrial tachycardia. Data were relatively fast conduction also extended obtained in a patient who had undergone anteriorly toward the septal area; this could surgical closure of an atrial septal defect 10 be attributed to the anterior extension of years ago and thus intra-atrial reentrant the crista terminalis. This route was found tachycardia ("incisional reentry") was susto be the fastest toward the triangle of Koch. pected. However, the mode of induction of The total activation time of the RA during the tachycardia with constant rate pacing normal sinus rhythm varied between 68 as well as the resetting response pattern suggested an ectopic tachycardia mechaand 92 ms. nism and argued against reentrant tachycardia. The earliest atrial activation during Electroanatomical Mapping the tachycardia was found at the posof Ectopic Atrial Tachycardia teroseptal free wall of the RA in the area of the crista terminalis. From this point, After our initial report on the use of the activation spread radially in 3 direcelectroanatomical mapping in a limited tions, thereby supporting the focal origin of number of patients with ectopic atrial the tachycardia. However, the radial excitachycardia,4 we have extended our expe- tation pattern was interrupted by the black rience to more than 25 patients. All but line where a sharp transition from yellow 4 patients had ectopic RA tachycardia. In to blue was found. Neighboring points these patients, the electroanatomical re- along this line that were only 7 to 11 mm construction was performed as described apart revealed activation time differences above: after data acquisition at anatomical of more than 100 ms, indicating complete landmark sites (the His-bundle area and conduction block. Therefore, construction of the TA) with fluoroscopic guidance, map- the map helped not only to identify the ping was focused on the area of interest, origin of this ectopic tachycardia but also i.e., the region of earliest endocardial acti- to reconstruct the old atriotomy scar that vation. Therefore, only a few points were led to conduction block.

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Figure 3. Ectopic atrial tachycardia arising from the triangle of Koch. The projections are equivalent to left anterior oblique 60° and 75°. The tricuspid annulus is demarked by the green dots. The His bundle area is tagged pink and labeled His. Note the cross-shaped acquisition of mapping points adjacent to the site of earliest activation clearly validating the site of earliest activation during the tachycardia. The ablation catheter was renavigated to the site of earliest activation (as indicated by the catheter icon) and radiofrequency current delivery resulted in termination of the tachycardia. In order to enhance the accuracy of catheter positioning to the target site, the reconstruction shown on the right side (B) was enlarged. In both cases ablation was successful with a single radiofrequency application without affecting conduction properties of the atrioventricular node. See color appendix.

The high degree of anatomical accuracy of electroanatomical mapping proved also to be very helpful in patients with ectopic atrial tachycardia originating in the triangle of Koch. In these patients, curative treatment with RF ablation may carry an enhanced risk of complete AV block because of the close anatomical relation to the specific conduction system. Figure 3 depicts 2 representative examples. In both cases, ectopic atrial tachycardia originated from a high midseptal site anatomically close to the bundle of His. The advantages of electroanatomical mapping in this special situation are 2fold: first, the catheter can be renavigated to the site of earliest activation with a high degree of accuracy, and second, catheter stability can be easily controlled during RF energy application. Needless to say, conventionally recorded electrograms must also be recorded and analyzed during energy

application in order to observe conduction impairment of the AV node and to prevent the occurrence of AV block.

Electroanatomical Mapping of the RA Isthmus in AFL Common AFL is a macroreentrant arrhythmia with an anatomically welldefined reentrant circuit.8 Both counterclockwise and clockwise common ("reverse common") AFLs are confined to the RA and can be cured by linear RF lesions placed in the so-called RA isthmus, i.e., the area between the inferior aspect of the tricuspid valve and the ostium of the inferior caval vein. Using conventional mapping and ablation technology, the ablation catheter is placed at the boundary of the inferior TA to the RA under fluoroscopic guidance and RF energy is applied. The ablation catheter is

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Figure 4. Activation map obtained during a focal atrial tachycardia presented in a right posterior oblique projection. This patient had had a right atrial atriotomy 10 years before, for closure of an atrial septal defect. The earliest activation during tachycardia was found at the posterolateral free wall of the right atrium. From this point, the activation spread radially in 3 directions. However, along the black line there was a sharp transition from yellow to blue. Activation time differences between adjacent sites that were only 5 to 10 mm apart measured more than 100 ms, indicating complete conduction block and thereby reconstructing the old atriotomy scar. See color appendix. From reference 4, with permission.

then withdrawn in a stepwise manner toward the inferior caval vein and RF energy is sequentially applied until a complete linear lesion has been induced resulting in complete conduction block over the isthmus. Although it has been shown that conventional ablation of AFL can be performed with high success rates, these procedures are sometimes long lasting and a significant amount of fluoroscopy time may be necessary to induce complete block. In view of the fact that the curative treatment strategy for common AFL is mainly based on the anatomically correct and complete induction of the linear lesion, catheter ablation

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of this arrhythmia may constitute an ideal indication for electroanatomical mapping. We therefore developed a new and simplified treatment strategy using electroanatomical mapping technology: In patients with isthmus-dependent AFL, the individual isthmus anatomy is reconstructed by tagging 3 points at the TA, I central point at the most inferior part of the annulus and 2 points at adjacent lateral and septal sites, each approximately 15 mm apart from the central point (Figure 4). The mapping catheter is then withdrawn to the ostium of the inferior caval vein and 3 mapping points corresponding to the 3 points at the TA are acquired (Figure 5). This "6-point" reconstruction results in a rectangular-shaped figure that clearly defines the target area for catheter ablation, i.e., the isthmus area. After completion of the 6-point mapping grid, RF energy is applied in a linear fashion from the TA to the inferior caval vein. The advantages of this approach compared with conventional ablation are multiple: First, the individual isthmus anatomy can be well delineated, and second, the RF application sites can be reliably selected to form a contiguous lesion line because the ablation catheter can be navigated more precisely using magnetic field navigation when compared tofluoroscopicguidance. Thus, precise renavigation to predetermined sites can be reliably achieved even after catheter dislocation or after withdrawal of the ablation catheter that may be necessary due to coagulum formation at the tip. In addition, in experienced hands the complete ablation procedure can be performed with less than 10 minutes of fluoroscopy time needed. Kottkamp and co-workers9 recently reported on 50 consecutive patients with common AFL randomly assigned to conventional mapping and ablation or electroanatomical mapping. The success rates were similar in both groups. The fluoroscopy time, however, was significantly shorter (3.9 ± 15 min. versus 22 ± 6.3 min.) in patients treated with electroanatomical mapping.

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Figure 5. The "6-point-approach" for induction of complete isthmus block to cure common atrial flutter. The electroanatomical reconstruction of the isthmus is presented in 30° right anterior oblique view (RAO, left), 45° left anterior oblique view (LAO, middle), and bottom view (bottom, right). The first and most inferior point at the tricuspid annulus (TA) is taken with the help of fluoroscopy (A, B, and C). In experienced hands, the whole procedure can then be completed without fluoroscopy using the electromagnetic tools of the system: the catheter turned clockwise to reach the inferior septal aspect of the TA and turned counterclockwise to reach the inferolateral aspect of the TA. These 3 points demark the "distal" boundaries of the isthmus. The catheter is then withdrawn to the inferior caval vein and 3 points corresponding to the TA points are taken (D, E, and F). These 6 points demark the isthmus and define the target site for catheter ablation. Radiofrequency (RF) energy is sequentially applied from the TA to the orifice of the inferior vena cava (VCI). The continuity of the lesion line can be easily controlled by electromagnetic navigation of the ablation catheter. With this approach, complete isthmus block can be achieved in the majority of cases after induction of a single ablation line requiring 5 to 8 energy applications. Due to natural block at the isthmus site close to the inferior caval vein, only 3 applications were necessary to achieve complete isthmus block in this particular case (G, H, and I). See color appendix.

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In 14 of 25 patients, the whole isthmus ablation and the validation of completeness of the lesion line was done completely nonfluoroscopically. In another study, Kottkamp and co-workers10'11 evaluated the use of high-resolution electromagnetic mapping of gaps within the inferior isthmus in patients with recurrences of AFL following an ablation attempt. In this patient cohort, high-density electroanatomical mapping during coronary sinus stimulation allowed the precise identification of discrete gaps within noncontiguous lesion lines. In 9 of 16 patients, an incompletely damaged isthmus could be identified although complete reversal of conduction around the TA simulated complete block. In 8 patients, the gap was found close to the TA, in 5 patients close to the inferior caval vein, and in 3 patients in the middle part of the isthmus. The electromagnetic navigation system allowed precise renavigation to the predetermined sites of conduction breakthrough (Figure 6). In all patients, specific gap ablation was successfully performed with 3.2 ± 3.3 RF applications for induction of complete isthmus

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block. Shah and co-workers6 also demonstrated the usefulness of high-density electromagnetic mapping of the isthmus in patients with common AFL. Nakagawa and Jackman5 reported on the feasibility of electromagnetic mapping for the induction of a contiguous lesion line across the subeustachian isthmus between the TA and the eustachian ridge to eliminate common AFL. Their investigations showed that electroanatomical mapping allowed precise 3dimensional localization of the anatomical boundaries of AFL reentrant circuits, and facilitated catheter ablation by accurately locating defects in the ablation line. Electromagnetic mapping to guide RF catheter ablation for ablation of common AFL has several important advantages when compared with conventional treatment. The most striking advantage is the significant reduction of radiation exposure time, which represents a substantial benefit for both patients and physicians. In addition, the technology is particularly helpful for highdensity isthmus mapping to localize gaps in patients with arrhythmia recurrences

Figure 6. Activation maps of the right atrial isthmus obtained during coronary sinus pacing presented in bottom views. The green dots represent the tricuspid annulus (TA) and the pink dots the orifice of the inferior caval vein (ICV). The map on the left shows activation of the isthmus before ablation. Conduction time from the septal site (red) to the lateral site of the isthmus (purple) was 51 ms. Following induction of the first ablation line along the isthmus, partial block was observed (middle). Conduction time was 81 ms. There is block along two thirds of the isthmus close to the TA as indicated by the abrupt change in colors. However, conduction through the isthmus is present close to the inferior caval vein (white arrow). One additional radiofrequency application to the gap site resulted in complete isthmus block (right). After induction of complete block, conduction time was 154 ms. See color appendix.

702 CARDIAC MAPPING following ablation. Because of the ability to precisely renavigate the catheter to previously visited mapping and ablation sites, electromagnetic mapping allows the fast and reliable identification of double potentials along the ablation line in order to validate complete isthmus block. For this validation it is necessary to prove the presence of double potentials all along the lesion line. The presence of double potentials at a single site, e.g., close to the TA, as well as reversal of conduction recorded with multipolar electrode catheters along the TA does not exclude gaps at distant sites, e.g., at the ostium of the inferior caval vein. Thus, at least 3 sites along the isthmus lesion line (at the TA, at the middle part of the isthmus, and at the inferior caval vein) showing widely split double potentials must be visited to ensure complete isthmus block. This validation procedure can be performed using electromagnetic mapping quite quickly and precisely. Electroanatomical Mapping of Accessory AV Connections Endocardial mapping and catheter ablation using conventional technology has been shown to be highly effective and safe in patients with accessory AV pathways.12 Thus, for routine ablation of accessory AV pathways there is no need for advanced mapping technology. However, in order to gain experience with electroanatomical mapping, we performed our initial clinical studies in patients with an accessory AV pathway. In addition, electroanatomical mapping offers the unique opportunity to analyze local endocardial electrogram characteristics with respect to the spatial location of each individual recording site to the insertion of the accessory pathway. Thus, the distance between each recording site and the insertion of the accessory pathway as evident from successful RF ablation was

measured and timing as well as morphological criteria from unipolar and bipolar electrograms recorded at all mapping sites were analyzed to gain further insights into the changes of local electrogram characteristics as a function of distance from the insertion of the accessory pathway. Electroanatomical reconstruction of the mitral annulus was performed in 16 patients with 17 anterogradely conducting accessory pathways. A mean of 20 ± 11 mapping points (range 11-58) were sequentially taken during preexcited sinus rhythm (Figure 7). Activation times along the mitral annulus were obtained from unipolar electrograms recorded from the tip of the ablation catheter positioned at the mitral annulus using the retrograde approach. The annotation of the maximal downslope of the unipolar electrograms was done with the assistance of the computer using the CARTO software algorithm. After completion of the electroanatomical maps, exact renavigation of the ablation catheter for RF application was achieved in all cases. All ablation procedures were completed successfully. A single RF application resulted in permanent conduction block in 13 of 17 accessory pathways (76%). The spatial resolution of the electroanatomical maps at the site of earliest ventricular activation was high: the distance from the ventricular insertion of the pathways to adjacent mapping sites measured 5.1 ± 3.0 mm (range 1.9— 8.1 mm). At successful ablation sites as well as at adjacent sites up to a distance of 9 mm from the successful ablation sites, 76% of the unipolar electrograms showed a PQS-morphology and 24% a P-QS or a PrS morphology. At sites >10 mm away from the insertion of the accessory pathway, an r wave was consistently present in the unipolar electrogram. Activation times along the annulus increased by 8 to 12 ms per 10 mm. Sharp deflections preceding the onset of local ventricular

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Figure 7. Electroanatomical reconstruction of the mitral annulus obtained in a patient with an overt left lateral accessory atrioventricular pathway in left anterior oblique (LAO) 30° projection (A), right anterior oblique (RAO) 30° projection (B), and a posteroanterior (PA) projection (C and D). The ventricular insertion of the accessory pathway is clearly indicated by the red "hot spot." Radiofrequency application following renavigation of the ablation catheter (D) resulted in complete accessory pathway conduction block. See color appendix.

activation in the bipolar electrogram representing presumably accessory pathway activation were present at 46% of successful ablation sites but were never recorded at distances of more than 5 mm away from the successful ablation sites. Within the area of interest around the insertion of the accessory pathway, i.e., 10 mm along the mitral annulus in both

directions, the onset of activation of ventricular activation measured from the local bipolar electrogram was not significantly different when compared to the successful ablation site. However, ventricular activation time, measured as the maximal electrogram deflection, consistently increased with distance from the accessory pathway insertion site.

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Two interesting cases of variants of accessory AV connection were also investigated using electroanatomical mapping technology. In 1 patient with an atriofascicular accessory pathway, the whole course of the accessory pathway from the lateral TA all along the free right ventricular wall to the ventricular insertion was electroanatomically mapped (Figure 8). Ablation was successfully performed at the subannular level. In another patient with a decremental retrogradely conducting accessory pathway and the permanent form of junctional reciprocating tachycardia, the atrial insertion of the accessory pathway was mapped. In this patient, however, we were unable to ablate the atrial insertion of the accessory pathway

guided by the electroanatomical map. Instead, the pathway was ablated at the TA guided by a conventionally recorded accessory pathway potential approximately 10 mm away from the site of earliest atrial activation.

Electroanatomical Mapping in Patients with Atrial Fibrillation The development of treatment strategies to cure atrial fibrillation (AF) is one of the main challenges of electrophysiology today. The ideal treatment strategy should be effective, safe, and easy to apply to allow a widespread use. In addition,

Figure 8. Electroanatomical reconstruction of the right ventricle obtained in a patient with an atriofascicular accessory pathway during antidromic tachycardia (right anterior oblique 30°). The tricuspid annulus (TA) is also depicted (black line). Earliest ventricular activation was observed 4.5 cm away from the TA at the right ventricular free wall. Potentials of the atriofascicular pathway were recorded at the subannular level (successful ablation site) as well as along the right ventricular free wall from the annulus to the earliest ventricular activation site. See color appendix.

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curative treatment should aim to not only restore sinus rhythm but also to restore mechanical atrial function to improve hemodynamics thereby avoiding anticoagulation. The only treatment concept to cure chronic permanent AF with proven efficiency available today is the surgical Maze procedure introduced by Cox and colleagues13 in 1991. In 1994, however, Haissaguerre and co-workers14 were able to define a subset of patients with chronic paroxysmal AF in whom the arrhythmia originated from a focal source located in the pulmonary veins. These foci exhibited spontaneous ectopic activity and induced runs of fast atrial tachycardia that may degenerate into AF. In this patient cohort, curative treatment could be achieved with percutaneous RF catheter ablation.14 However, high recurrence rates have been reported following focal ablation within the pulmonary veins. In addition, severe complications such as high-grade pulmonary vein stenosis have been reported following focal pulmonary vein ablation. Recently the treatment strategy of focal ablation has been replaced by so-called pulmonary vein disconnection procedures. A different treatment strategy based mainly on the concept of the surgical Maze procedure aims to modify the maintaining substrate of AF. Multiple reentrant wavelets are necessary to perpetuate AF and linear ablative lesions have been shown to prevent paroxysmal or permanent AF by depriving the wavelets of the space necessary for their persistence. Swartz and coworkers15 were the first to describe the successful application of a biatrial Maze-like procedure in a patient with chronic AF. Unfortunately, the results of this study have not been published as a peer-reviewed paper. Based on the oral presentations of that investigation, it seems that successful ablation of AF can be achieved with percutaneous catheter-guided induction of contiguous RA and LA lesion lines. However, with conventional mapping and

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ablation technology, the procedures were long lasting and were associated with a significant complication rate. In the same year, Haissaguerre et al.15 reported on the successful catheter ablation in a patient with paroxysmal AF with linear lesions restricted to the RA. The same group reported in 1996 on a series of patients with chronic paroxysmal AF that were treated with different RA and LA lesion lines.16 In patients treated with an approach restricted to the RA, only a 15% success rate was reported, while in patients treated with RA and LA lesion lines, a success rate of 40% was observed.17 Recently, Schwartzman and Kuck18 reported on the use of electroanatomical mapping technology to induce contiguous LA and RA lesion lines in experimental animals. Their studies showed that contiguous lesions can be induced in both the RA and the LA with use of electroanatomical mapping. In addition, validation of completeness of lesion lines could also be confirmed. Ernst and co-workers19 reported on 14 patients with idiopathic AF who underwent percutaneous catheter ablation with use of electroanatomical mapping technology. In all patients, contiguous RA lesion lines were induced during the first ablation session and AF recurred in all. After failure of the RA approach, 3 LA lesion lines were induced during a second ablation session. One line extended from the ostium of the upper left to the upper right pulmonary vein all along the roof of the LA. A second line was induced from the anterior roof of the mitral annulus toward the line induced along the roof, and a third line from the center of the roof to the posterior mitral annulus. This procedure required 47 ± 18 RF applications and a duration of 8.7 ± 1.9 hours. During a follow-up period of 112 days and continued antiarrhythmic medication, 7 of 14 patients were predominately in sinus rhythm. All but one of these patients developed LA reentrant

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tachycardia presumably because of gaps in the lesion lines. Pappone and co-workers21 reported 27 patients with chronic paroxysmal AF who were also treated with electromagnetic mapping technology. In 8 patients treatment was restricted to the RA and in 5 patients to the LA, while in 14 patients linear lesion lines were induced in both atria. The authors reported an overall success rate of 44% following ablation, which increased to 59% with additional antiarrhythmic medications. The success rate was lower in patients who were treated in 1 atrium only (50% for RA and 60% for LA), while treatment of both atria resulted in a success rate of 85%. Session duration was 312 ± 103 minutes and fluoroscopy time was 107 ± 68 minutes. However, several results of this study are not supported by the results from other groups17'19 and must be reproduced in larger patient cohorts. Based on the currently published data, it seems that electroanatomical mapping represents a relatively new technology

that is helpful to induce contiguous RA and/or LA lesion lines for the curative treatment of AF (Figure 9). Its main advantages compared to conventional mapping and ablation include limitation of fluoroscopy, reliable renavigation to previous visited sites, and applicable concepts for validation of lesion line completeness. At this point, however, it seems unclear whether point-by-point ablation to induce long contiguous atrial lesion lines will be the method of choice to cure AF. Overall, the percutaneous approach of RF catheter ablation of AF is still a highly investigational technique with several problems. The optimal composition of RA and/or LA lesion lines is unknown. Failure of percutaneously induced lesion lines may be the consequence of insufficient lesion extent and/or geometry, or ablation failure may result from the insufficient realization of the proposed lesion lines, i.e., incomplete or inconsistent lesion deployment. Curative treatment of AF with catheter technologies will become a reality in the

Figure 9. Electroanatomical reconstruction of the left atrium in a patient with atrial fibrillation in an anterior (left) and posterior (right) projection. The mitral annulus (MA) and the pulmonary veins (PV) are shown. Substrate modification was performed by placement of lesions (red dots) around the orifices of the left and right pulmonary veins. In addition, lesion lines were placed between the mitral annulus and the left-sided pulmonary veins and a lesion line along the roof of the left atrium between the left-sided and right-sided pulmonary veins. See color appendix.

NONFLUOROSCOPIC MAPPING OF SVT future; however, the treatment concept and the mapping and ablation technology that will represent the method of choice must be elucidated by future studies. References 1. Ben-Haim S, Osadchy D, Schuster I, et al. Nonfluoroscopic in vivo navigation and mapping technology. NatMed 1996;2:13931395. 2. Gepstein L, Hayam G, Ben-Haim S. A novel method for nonfluoroscopic catheter-based electroanatomical mapping of the heart. Circulation 1997;95:1611-1622. 3. Gepstein L, Evans SJ. Electroanatomical mapping of the heart: Basic concepts and implications for the treatment of cardiac arrhythmias. Pacing Clin Electrophysiol 1998;21:1268-1278. 4. Kottkamp H, Hindricks G, Borggrefe M, Breithardt G: Three-dimensional electromagnetic catheter technology: Electroanatomical mapping of the right atrium and ablation of ectopic atrial tachycardia. J Cardiovasc Electrophysiol 1997;8:13321337. 5. Nakagawa H, Jackman WM. Use of a threedimensional, nonfluoroscopic mapping system for catheter ablation of typical atrial flutter. Pacing Clin Electrophysiol 1998;21:12791286. 6. Shah D, Haissaguerre M, Jais P, et al. High-density mapping of activation through incomplete isthmus ablation. Circulation 1999;99:211-215. 7. Smeets JRLM, Ben-Haim S, Rodriguez LM, et al. New method for nonfluoroscopic endocardial mapping in humans. Accuracy assessment and first clinical results. Circulation 1998;97:2426-2432. 8. Cosio FG, Lopez-Gil M, Goicolea A, et al. Radiofrequency ablation of the inferior vena cava-tricuspid valve isthmus in common atrial flutter. Am J Cardiol 1993;71:705-709. 9. Kottkamp H, Wasmer C, Hiigl B, et al. Electromagnetic versus conventional fluoroscopic isthmus ablation in patients with atrial flutter: A prospective randomized study. Circulation 2000; 102:2082-2086.

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10. Kottkamp H, KrauB B, Wasmer K, Hindricks G. Specific re-ablation in recurrences of atrial flutter: High-resolution electromagnetic catheter mapping of gaps within the tricuspid annulus-inferior caval vein-isthmus. Eur Heart J 1999;20(Suppl.):344. Abstract. 11. Kottkamp H, Hindricks G, Breithardt G, Borggrefe M. High-density electroanatomical non-fluoroscopic mapping of the isthmus in atrial flutter: Complete de-novo ablation and specific gap ablation in recurrences. Eur Heart J 1998;19(Suppl):535. Abstract. 12. Kuck KH, Schluter M, Geiger M. Radiofrequency current catheter ablation of accessory atrioventricular pathways. Lancet 1991;337: 1557-1561. 13. Cox JL, Schuessler RB, D'Agostino HJ Jr., et al. The surgical treatment of atrial fibrillation: III. Development of a definitive surgical procedure. J Thorac Cardiovasc Surg 1991;101:569-583. 14. Haissaguerre M, Gencel L, Fischer B, et al. Successful catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 1994; 5:1045-1052. 15. Swartz JF, Pellersels G, Silvers J, et al. A catheter-based curative approach to atrial fibrillation in humans. Circulation 1994; 90:1-335. Abstract. 16. Haissaguerre M, Jais P, Shah DC, et al. Right and left atrial radiofrequency catheter therapy of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 1996;7:1132-1144. 17. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339: 659-666. 18. Schwartzman D, Kuck KH. Anatomyguided linear atrial lesions for radiofrequency catheter ablation of atrial fibrillation. Pacing Clin Electrophysiol 1998; 21:1959-1978. 19. Ernst S, Ouyang F, Schluter M, et al. Clinical follow-up after linear left atrial radiofrequency lesions to treat atrial fibrillation. Eur Heart J 1999;20:235. Abstract. 20. Pappone C, Oreto G, Lamberti F, et al. Catheter ablation of paroxysmal atrial fibrillation using a 3D mapping system. Circulation 1999; 100:1203-1208.

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Chapter 38 Optical Mapping of Cellular Repolarization in the Intact Heart Kenneth R. Laurita, PhD and David S. Rosenbaum, MD

A critical step in the initiation of reentrant excitation is the formation of unidirectional impulse block. Once unidirectional block forms, the maintenance of reentry is governed, in part, by the complex interplay between the spatial extent of inexcitable tissue (i.e., cardiac wavelength) and the path length of the reentrant circuit. Repolarization plays a central role in both of these processes and is therefore thought to play an important role in both the initiation and maintenance of reentrant cardiac arrhythmias.1"4 The close relationship between repolarization and reentrant arrhythmias has been underscored by a growing interest in the spatial diversity of ion currents known to govern cellular repolarization. Recent studies have focused on ion channel diversity present across ventricular muscle layers,5"11 giving rise to functionally distinct regions within the ventricle. Furthermore, there is growing appreciation of the molecular determinants of abnormal repolarization in human diseases such as long QT syndrome.12'13 Finally, clinical

manifestations of abnormal repolarization such as T wave alternans have recently attracted considerable attention because of their potential prognostic significance. Although these findings emphasized the potential importance of repolarization, we still do not completely understand the precise role played by repolarization in the mechanism of reentry. Traditionally, components of the electrophysiological substrate such as tissue anisotropy14-15 and dispersion of repolarization1'3'16 are thought of as static properties of the tissue that do not vary over time or space. However, this view is limited because it does not take into account spatial heterogeneities of cellular repolarization and tissue structure. For example, one would predict that regional diversity of timedependent outward repolarization currents would significantly influence the pattern and spatial synchronization of ventricular repolarization on a beat-by-beat basis. Therefore, a suitable electrophysiological substrate for reentry (e.g., dispersion of repolarization) may not initially exist but

Supported by National Institutes of Health grant Hl-54807, the Medical Research Service of the Department of Veterans Affairs, The Whitaker Foundation, and the American Heart Association. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003.

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may dynamically form, disappear, and reform in response to provocative premature stimuli. Likewise, the wavelength of a reentrant impulse may expand or contract over a single reentrant beat because of heterogeneities of depolarization and/or repolarization. Using optical mapping techniques, we have demonstrated that the electrophysiological substrate is not static but can vary significantly over a single beat and critically influence the initiation and maintenance of reentry. There is some evidence that supports this concept. Following an abrupt increase in heart rate, heterogeneity of action potential duration (APD) across the guinea pig epicardium decreases significantly,17 indicating that repolarization gradients can recede dynamically over several beats thereby influencing synchronization of ventricular repolarization. Using conventional recording techniques it is difficult to monitor beat-to-beat changes in repolarization and their effect on the initiation and maintenance of reentry. On one hand, microelectrode and monophasic action potential recordings faithfully reproduce beat-to-beat changes in cellular repolarization; however, measuring dynamic changes in the spatial gradients of cellular repolarization is nearly impossible. On the other hand, direct cardiac mapping is capable of recording extracellular potentials from hundreds of sites simultaneously but does not provide direct information regarding repolarization. In contrast to these techniques, optical action potential mapping with voltage-sensitive dye has made it possible to simultaneously measure high-fidelity action potentials from hundreds of sites with high temporal and spatial resolution. In this chapter, we review how we have used optical mapping of ventricular repolarization to develop new insights to the mechanism of initiation and maintenance of reentry.

Optical Action Potential Mapping Voltage-sensitive dyes have been used for several decades to measure trans-

membrane potential in excitable cells.18 These dyes bind to the cell membrane with high affinity, exhibit changes in fluorescence that vary linearly with transmembrane potential, and closely reproduce the time course of the cardiac action potential.19-20 When the dye is excited at a specific wavelength, it emits light at a longer wavelength,21 which allows fluoresced light to be distinguished from reflected light using appropriately selected optical filters and a photodetector. In addition to measuring transmembrane potential, optical mapping techniques can be used with other fluorescent indicators of important cellular parameters such as intracellular calcium.22'23 Voltage-sensitive dyes can be divided into 2 classes, distributive and electrochromic, according to their response to membrane potential.21 Electrochromic dyes have a response time on the nanosecond time scale, respond directly to the membrane's electrical field, and are therefore suitable for measuring the action potential. One of the most widely used electrochromic dyes is di-4ANEPPS, a styryl dye whose fluorescence response varies linearly with membrane potential.24 Although the change in fluorescence is fairly small (8% to 10% per 100 mV), it is almost instantaneous, making it ideal for detecting the rapid changes within the action potential. As with most styryl dyes, di-4ANEPPS exhibits good photostability and no apparent toxicity in intact heart preparations.21 Using a scanning laser, video camera, or an array of photodetectors, it is possible to record action potentials from hundreds to thousands of cardiac sites simultaneously.17'25"27 Therefore, in many respects, optical mapping combines the advantages of microelectrode recording techniques and multisite simultaneous extracellular mapping. We have developed an optical system to map cardiac action potentials with high resolution from the intact beating heart.28"31 After staining with the voltage-sensitive dye, the preparation is illuminated with a 250-W tungsten-halogen lamp at the

OPTICAL MAPPING OF REPOLARIZATION excitation wavelength (540 ± 5 nm). Fluoresced light from the preparation is focused onto a photodetector array using an arrangement of photographic lenses.32 Each photodetector element is a silicon photodiode, which features a fast response time and high sensitivity in the visible to near-infrared range. The output of the photodiode is coupled to several amplifier stages, which are used to amplify and filter the optical action potential. Depolarization is defined as the time of maximum first derivative of the action potential, and repolarization is defined as the time of maximum second derivative during the downstroke of the action potential. APD is the difference between the time of cellular depolarization and repolarization.

Modulation of Ventricular Repolarization and Arrhythmia Vulnerability During Premature Stimulation of the Heart Influence of Restitution Heterogeneity on Ventricular Repolarization Gradients The cellular kinetics of repolarization can be characterized by the response

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of APD to a premature stimulus. This is referred to as APD restitution.33'34 Using optical mapping with voltage-sensitive dye, we have been able to simultaneously measure APD restitution from hundreds of recording sites on the epicardial surface of the guinea pig. Optical mapping is well suited for measuring cellular (i.e., intrinsic) properties such as APD restitution because it is insensitive to far-field influences and because each action potential represents an average of local transmembrane potential that is far less sensitive to biological variability between individual myocytes.35 We have previously shown that the kinetics of restitution as measured with a restitution rate constant, RK, varies significantly across the epicardial surface of the guinea pig (Figure I).11 Moreover, spatial heterogeneity of restitution is not random; rather, there is an organized pattern across the epicardial surface. Since RK indicates the response of APD to a premature stimulus, spatial heterogeneity of RK is expected to alter significantly the sequence and pattern of repolarization during a premature beat. Figure 2 shows the ECG (top), depolarization (middle), and repolarization

Figure 1. Diagram of the mapping field (1 -cm2 grid) and its position relative to the intact heart preparation (left). Spatial dispersion of restitution kinetics (RK, right). Larger values of RK correspond to regions where action potential duration decreases more rapidly in response to a premature stimulus. Shown to the right of the contour map is a gray scale with corresponding numerical values in normalized units (RK). RA = right atrium; LA = left atrium; RV = right ventricle; LV = left ventricle; LAD = left anterior descending coronary artery.

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Figure 2. The dependence of depolarization and repolarization on premature coupling interval from a representative experiment (Exp. #8). Depolarization and repolarization ECG (top) and contour maps of depolarization (middle) and repolarization (bottom) during a premature stimulus delivered at a coupling interval near the baseline pacing cycle length (A), at an intermediate coupling interval (B), and at a short coupling interval near the effective refractory period (C). All values shown are in milliseconds unless otherwise indicated. The site of baseline pacing and premature stimulation (stimulus symbol) were identical for each coupling interval. Dispersion of repolarization (S2DISP) was calculated for eachS1S2coupling interval shown. Reprinted from Laurita et al. Circulation 1998;98:2774-2780.

(bottom) contour plots during baseline pacing (panel A), premature stimulation at an intermediate coupling interval (panel B), and at a coupling interval just beyond (<2 ms) the effective refractory period of the baseline beat (panel C). During baseline pacing (panel A), the impulse propagated uniformly from the site of stimulation and a significant gradient of repolarization was present, with latest repolarization occurring near the base of the heart and earliest repolarization occurring near the apex. In general, the repolarization gradient (solid arrow) during baseline pacing was oriented in an apex-

to-base direction, which produced a spatial dispersion of repolarization times (as measured by the variance of repolarization times, equal to 46 ms2). A premature stimulus introduced at an intermediate coupling interval (panel B) produced no significant change in the pattern of depolarization; however, the repolarization gradient that was evident during baseline pacing was essentially eliminated, minimizing dispersion of repolarization to 10 ms2. When a premature stimulus was introduced at a very short coupling interval (panel C), conduction slowed somewhat, as evidenced by slight crowding of

OPTICAL MAPPING OF REPOLARIZATION isochrone lines, but the overall pattern of depolarization remained unchanged. In contrast, repolarization changed substantially as the gradient of repolarization reappeared, increasing dispersion to levels (38 ms2) comparable to that during baseline pacing. However, the orientation of the repolarization gradient reversed and was completely opposite to repolarization at baseline. Also note that the eradication and subsequent reversal of the repolarization gradient by intermediate and short premature coupling intervals were closely paralleled by flattening and inversion of the ECG T wave (top). Since the ECG T wave amplitude and polarity reflect ventricular repolarization of the entire heart, similar coupling-interval—dependent changes in repolarization were most likely occurring throughout the heart and not just within the region of myocardium being mapped. The initial decrease and subsequent increase (i.e., modulated dispersion) of repolarization gradients with shortening of premature stimulus cycle length can be explained by heterogeneity of cellular restitution kinetics across the epicardial surface.11'36 Since the timing of repolarization is dependent on conduction time plus APD, spatial heterogeneity of repolarization is determined by the combined effect of conduction gradients and spatial gradients of APD. We observed a much greater change in repolarization gradients compared to conduction gradients as S1S2 coupling interval was shortened, indicating that the magnitude and orientation of repolarization gradients are determined primarily by changes in APD. Similar observations were made by Kanai and Salama,37 who reported that the pattern of repolarization in guinea pig epicardium was dominated by APD and was essentially independent of the sequence of propagation. There is also evidence suggesting that this may be the case under conditions of abnormal repolarization. In experimental models of the

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congenital long QT syndrome, dispersion of repolarization is predominantly due to regional heterogeneity of APD.38"40 Spatial heterogeneities of APD may also be enhanced in patients with sustained monomorphic ventricular tachycardia (VT).41 On the other hand, in the presence of marked conduction slowing caused by chronic myocardial infarction, propagation delays may also contribute to heterogeneity of ventricular repolarization.42 Clearly, the factors that determine dispersion of repolarization in the heart are dependent on the specific pathophysiological substrate involved. Modulation of the Substrate for Ventricular Fibrillation by a Premature Stimulus A premature impulse is traditionally viewed as a "trigger" for reentrant arrhythmias, which, in the presence of a suitable arrhythmogenic "substrate,"43 can provoke reentry. However, our data demonstrate that the trigger and the substrate are not necessarily independent, since a premature stimulus actively modulates the electrophysiological properties of the heart. Such modulation has several important consequences. First, premature stimuli delivered at progressively shorter coupling intervals shorten refractoriness at the stimulus site, allowing capture of subsequent stimuli at increasing degrees of prematurity, shortening cardiac wavelength, and thus increasing the likelihood of inducing reentry (i.e., a concept similar to "peeling back" refractoriness44). However, an alternative hypothesis, referred to here as the modulated dispersion hypothesis, is that a premature beat, in addition to shortening refractoriness, also changes the underlying arrhythmogenic substrate by modulating spatial dispersion of repolarization in a coupling-interval-dependent manner. Such coupling-interval-dependent changes are an expected consequence of

714 CARDIAC MAPPING heterogeneity of restitution properties between cells. We tested this hypothesis using high-resolution action potential mapping with voltage-sensitive dye as a tool for measuring dispersion of repolarization that forms in the wake of a premature stimulus.45 Vulnerability to ventricular fibrillation (VF) following a premature beat was measured using a modified VF threshold (VFT) protocol,45 where a train (100 Hz) of S3 pulses were applied during the T wave of the premature beat (S2). The minimum current strength that initiated VF defined the VFT (S3-VFT). The S3-VFT was measured as repolarization was modulated over a broad range of SiS2 coupling intervals. To quantitatively determine the relationship between S^ coupling interval and repolarization properties of the ventricle, mean repolarization time (S2-RT) and dispersion of repolarization time (S2-DISP) were calculated for each S1S2 coupling interval. Shown in Figure 3 (panel A) are the S2-RT (open circles) and S2-DISP (closed circles) generated during each prematurely stimulated beat in a representative experiment. Mean repolarization decreased monotonically from 221 ms to 145 ms as S1S2 coupling interval was shortened from 300 ms to 230 ms. These changes were attributed to coupling-interval-dependent changes in APD, which were most marked at short S1S2 coupling intervals, as predicted from restitution properties of cardiac myocytes.46 In contrast, dispersion of repolarization was modulated in a biphasic fashion as coupling interval was shortened. For SiS2 coupling intervals near the baseline pacing rate, dispersion of repolarization was relatively high; however, as SXS2 coupling interval was shortened, dispersion of repolarization decreased until a critical coupling interval was reached (255 ms; Figure 3, dashed arrow). With further shortening of SiS2 coupling interval, dispersion of repolarization rose sharply to a level slightly higher than that measured during baseline pacing.

Figure 3. A. Mean repolarization (S2-RT, open circles) and dispersion of repolarization (S2DISP, filled circles) of an S2 premature beat as a function of S^ coupling interval. These values were calculated from 128 optical action potentials recorded from the epicardial surface of guinea pig ventricle. Dispersion of repolarization was calculated by the variance of repolarization times measured over the entire mapping field. B. The changes in vulnerability to ventricular fibrillation induced by an S3 pulse train (S3-VFT) in the wake of repolarization patterns induced by various S^ coupling intervals. Dispersion of repolarization (A, filled circles) and vulnerability to fibrillation (B) were modulated in a similar biphasic fashion, with minimum vulnerability (maximum S3-VFT) and minimum dispersion occurring at the same S-,S2 coupling interval (255 ms, dashed arrow). Reprinted from Laurita et al. Circulation 1998;98:2774-2780.

The effect of cycle-length-dependent modulation of repolarization on susceptibility to VF is illustrated in panel B of Figure 3. It is evident that vulnerability to VF, as measured by S3-VFT, was modulated in a biphasic fashion in parallel with dispersion of repolarization (filled circles, panel A). As SiS2 coupling interval was shortened to a critical value (Figure 3, dashed arrow), S3-VFT increased (i.e., vulnerability decreased). With further

OPTICAL MAPPING OF REPOLARIZATION shortening of S^, S3-VFT decreased (i.e., vulnerability increased) to levels below those present at baseline pacing. These data indicate that the electrophysiological substrate for VF is not constant, but can potentially form, disappear, and reform in a predictable fashion just by changing stimulus timing. It is generally assumed that the effect of shortening premature stimulus coupling interval is to increase the likelihood of inducing reentry. However, Figure 3 illustrates a paradoxical decrease in arrhythmia vulnerability as premature stimulus coupling interval was initially shortened over a broad range of coupling intervals. The attenuation of repolarization gradients by a premature stimulus may serve as a protective mechanism in electrophysiologically normal myocardium. On the other hand, the rapid increase in vulnerability at very short coupling intervals may explain why multiple, closely coupled, premature stimuli are typically required to initiate VF in normal hearts. These findings also highlight the importance of accounting for changes in dispersion of repolarization throughout the heart, and

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not just refractory period at one site, to develop a more comprehensive understanding of the underlying electrophysiological substrate for reentry. Inferences from these studies must be cautiously extrapolated to VF in patients since the mechanism of VF initiation during VFT testing is not completely understood. Because of these limitations, we also investigated the role of modulated dispersion in the formation of unidirectional block, a specific and necessary condition for reentry. Modulation of the Electrophysiological Substrate for Unidirectional Block by a Premature Stimulus To determine if modulation of repolarization gradients can directly influence the electrophysiological requirements of unidirectional block, we examined the characteristics of propagation of an S3 stimulus in the wake of repolarization gradients established by a premature (i.e., S2) beat (Figure 4).29 To confine

Figure 4. Dependence of unidirectional block of an S3 impulse (asterisk) delivered from the center of an isthmus within a linear lesion (hatched bar) on repolarization gradients formed by a single, S2, premature stimulus (stimulus symbol). Three different S.,S2 premature coupling intervals were tested: baseline pacing (A, S1S2 = S^ = 600 ms), an intermediate coupling interval (B, S.,S2 = 300 ms), and a short coupling interval (C, S.,S2 = 225 ms). Contour maps show propagation of the S3 beat in the wake of repolarization gradients (open arrow) established by the S2 beat. The S3 stimulus was always introduced just beyond the effective refractory period of an S2 beat. A gradient of repolarization with sufficient magnitude to produce unidirectional block across the isthmus was present during baseline pacing (A) and the shortest coupling interval (C). However, repolarization gradients were eradicated and unidirectional block did not occur following an intermediate S1S2 coupling interval (B).

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propagation to the epicardial surface and avoid the confounding influence of subepicardial breakthrough from the His-Purkinje system, the endocardial muscle layers were eliminated using a cryoablation procedure described previously.47 To control the trajectory of propagation, a linear lesion containing a 1-mm isthmus (Figure 4, hatched bar) was "etched" precisely (±1 micron) onto the epicardial surface using a computerdriven 5-W argon ion laser. The lesion created a line of anatomical block that was parallel to the left anterior descending coronary artery and perpendicular to the orientation of repolarization gradients typically found in guinea pig.11 Baseline pacing (S1Sl = 600 ms) and a single premature stimulus (S2) were delivered from the same site near the basal end of the laser lesion (black stimulus symbol). For each SiS2 coupling interval tested, a second premature stimulus (S3) was delivered just beyond (<2 ms) the effective refractory period of the S2 beat at 2 x diastolic threshold from the center of the isthmus (white stimulus symbol). Thus, propagation out of the isthmus encountered an abrupt tissue expansion that was equal on both sides of the isthmus. Figure 4 shows data from a representative experiment where S^ coupling interval was sequentially shortened from 600 ms (baseline cycle length) to 225 ms to modulate dispersion of repolarization. The magnitude of the S2 repolarization gradient (open arrow) initially decreased over a broad range of coupling intervals from 18 ms/mm (panel A) to a minimum of 8 ms/mm (panel B), then rapidly increased (28 ms/mm, panel C) and reversed direction compared to baseline. Shown is propagation (contour map) of a second premature stimulus (S3) introduced at the isthmus (asterisk) in the wake of repolarization of each S2 beat. At a long SiS2 coupling interval (panel A), unidirectional block of the S3 beat occurred in the direction of

the repolarization gradient in a pattern like figure-of-8 reentry; however, at a shorter S^ coupling interval (300 ms, panel B), unidirectional block of S3 failed to occur. At the shortest S1S2 coupling interval, unidirectional block reappeared and its direction inverted in parallel with the repolarization gradient (panel C). Therefore, at a short S^ coupling interval the electrophysiological requirements for unidirectional block were restored. We know that the isthmus was important since unidirectional block was not observed in the absence of an isthmus, even when repolarization gradients of similar magnitude were present. Likewise, repolarization gradients are also an essential condition for unidirectional block, because when these gradients were eradicated by a premature stimulus delivered at an intermediate coupling interval (8^2 = 300 ms), unidirectional block could not be produced. Therefore, these data demonstrate how the underlying substrate for unidirectional block and reentry are critically influenced by the trigger used to initiate it. Such dynamic beat-to-beat alternations of repolarization may explain how the substrate for reentry forms or disappears in a manner that ultimately determines the initiation and stability of reentry. Role of Repolarization Alternans in the Formation of Arrhythmogenie Substrates There are other mechanisms by which regional heterogeneities of membrane repolarization properties can influence the electrophysiological substrate for reentry. From the aforementioned discussion, it is clear that the time course of repolarization is highly sensitive to perturbations in heart rate (i.e., premature stimulation) and can be explained by regional heterogeneities of repolarization kinetics. Such heterogeneities may also

OPTICAL MAPPING OF REPOLARIZATION alter the time course of repolarization from beat to beat even as heart rate is maintained constant. One common pattern is repolarization alternans, which is manifest as a periodic change in the time course of repolarization (i.e., either the action potential or ECG T wave) that repeats once every other beat. Repolarization alternans is of particular interest because T wave alternans is a marker of vulnerability to ventricular arrhythmias in humans,48 and often immediately precedes ventricular arrhythmias in many pathological conditions.49-53 It is now evident that microvolt-level T wave alternans, which is generally unrecognized on clinical ECG tracings, is quite common in patients at risk for sudden cardiac death.48,54 There is considerable evidence from single-site action potential recordings to suggest that T wave alternans of the surface ECG arises from alternans of repolarization occurring at the level of the single cell.55-62 Theoretically, spatial heterogeneity of repolarization, the primary source of the ECG T wave, is a likely target for investigation. Optical mapping is extremely well suited for tracking beatto-beat changes in repolarization heterogeneity, making it ideal for investigating the cellular mechanisms of T wave alternans. Recently, we have found that repolarization alternans occurring between cells with different restitution properties is a novel mechanism by which arrhythmogenic substrates form.63 Spatial Heterogeneity of Action Potential Alternans Parallels Heterogeneity of Restitution We applied the technique of highresolution optical mapping to the endocardial cryoablated Langendorff-perfused guinea pig model to investigate repolarization alternans.63 At a time when T wave alternans was induced by steady-state

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pacing, action potentials were recorded simultaneously from 128 epicardial sites encompassing the majority of the anterior left ventricular surface. We found that an alternans threshold heart rate is present in action potentials recorded from cells in the intact heart. This is not surprising since EGG T wave alternans64 and APD alternans from single ventricular myocytes55 have been shown to occur above a critical threshold heart rate. We also found that the heart rate threshold for repolarization alternans varied between cells across the epicardial surface of the heart.63 In addition, the magnitude and phase of repolarization alternans were also heterogeneously distributed across the surface of the heart in a systematic pattern. The distribution of local repolarization time alternans is plotted in Figure 5 (panel A). Interestingly, the pattern of repolarization alternans closely followed the typical distribution of cellular restitution properties (panel B). Local repolarization time alternans was calculated from the difference in cellular repolarization time measured during sequential beats. Therefore, positive and negative values indicate relative prolongation and abbreviation of local repolarization on a particular beat, respectively. Note that during the same beat, repolarization is prolonging near the base of the heart while shortening near the apex, indicating regional differences in the phase of alternation between epicardial cells. Such disruption of the phase relationship between cells has been referred to as discordant alternans.60'65'66 Discordant alternans occurred despite the presence of normal intercellular coupling, and was explained by regional heterogeneities in membrane restitution kinetics. Discordant alternans was consistently observed above a critical threshold heart rate, was always preceded by concordant alternans (action potential alternations having the same phase), and,

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CARDIAC MAPPING ization time occurring between neighboring regions of cells suggest that the ionic currents that determine repolarization differ substantially between these regions so as to overcome electrotonic forces that ordinarily act to synchronize repolarization. Role of Discordant Alternans in the Initiation of Reentry

Figure 5. Distribution of action potential alternans in the intact ventricle. Shown is a plot of local repolarization alternans measured as the difference in repolarization time between consecutive beats at each ventricular recording site. Local repolarization alternans varies from apex to base according to known distribution of cellular restitution properties across the epicardial surface of guinea pig (B). Notice the change in phase of repolarization alternans denoted by the thick black line and demonstrated by action potential recordings shown for selected sites (A). These action potentials were recorded from 2 sequential beats (depicted by bold and thin traces) to illustrate the relative phase of repolarization alternans between cells. The alternation of action potentials with opposite phase is termed discordant alternans. Reprinted from Laurita K, et al. Mapping arrhythmia substrates related to repolarization: 1 Dispersion of repolarization. In: Rosenbaum D, Jalife J (eds): Optical Mapping of Cardiac Excitation and Arrhythmias. Armonk, NY: Futura Publishing Co.; 2001:205-225.

in contrast to concordant alternans, produced marked changes in the pattern and sequence of ventricular depolarization and repolarization (next section). Such inhomogeneous alternations of repolar-

The initiation of repolarization alternans during constant cycle length pacing caused a reproducible cascade of events leading to reentrant VF.63 First, alternation of repolarization with the same phase between all cells (i.e., concordant alternans) was easily induced and typically manifested as microvolt-level T wave alternans on the surface ECG (not shown). Concordant alternans was associated with only subtle beat-to-beat alternation in the magnitude of repolarization with no change in the orientation of repolarization gradients. In addition, essentially no changes in beat-to-beat propagation occurred. As pacing rate was increased, a critical heart rate was achieved at which cells within neighboring regions of myocardium alternated with opposite phase (i.e., discordant alternans). As shown in Figure 6, discordant alternans produced several key changes in the pattern and sequence of propagation and repolarization of the heart. First, steep gradients of repolarization formed, as evidenced by marked crowding of repolarization isochrone lines (Figure 6, bottom). Differences in the phase of action potential alternations across the epicardium directly accounted for the magnitude of these gradients. Second, the orientation of repolarization gradients underwent nearly a complete reversal in direction from beat to beat. Although repolarization patterns are complex, they are highly reproducible on alternate beats (Figure 6, compare repolarization maps on beat 1 versus beat 3). Finally, conduction begins to alternate as impulses slow

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Figure 6. Representative example demonstrating mechanism linking repolarization alternans to the genesis of reentrant ventricular fibrillation (VF). Contour maps indicate pattern of depolarization and repolarization across the epicardial surface of guinea pig ventricle (times shown in ms). As pacing rate is increased, discordant alternans develops producing complete reversal in the direction of repolarization gradients from beat to beat and, most importantly, steep gradients of repolarization that were not present during concordant alternans (not shown). These gradients formed a suitable substrate for reentry, as slight shorting of stimulus cycle length (beat 4) causes local propagation failure against a repolarization gradient established during the previous beat (upper right corner of beat 3 repolarization map). Discordant alternans produces conditions necessary for unidirectional block after which reentrant VF immediately ensues. The ECG across the top is shown for reference. Reprinted from Laurita K, et al. Mapping arrhythmia substrates related to repolarization: 1 Dispersion of repolarization. In: Rosenbaum D, Jalife J (eds): Optical Mapping of Cardiac Excitation and Arrhythmias. Armonk, NY: Futura Publishing Co.; 2001:205-225.

when propagating against steep gradients of repolarization created by the previous beat. Under these conditions, a small reduction of stimulus cycle length (10 ms in Figure 6, beat 4) resulted in conduction block into a region having most delayed repolarization from the previous beat (Figure 6, beat 3 repolarization map). The impulse then propagated around either side of the line of block (hatched area), and 90 ms later the zone of block regained excitability allowing the impulse to reenter from outside the mapping field, forming the first spontaneous beat of reentrant VF. Importantly, in

these experiments the initiation of VF was always preceded by discordant alternans, closely linking it to the mechanism of reentry. Therefore, in the presence of regional heterogeneities of cellular restitution, discordant repolarization alternans could transform relatively minor gradients of repolarization into critical gradients, which were directly responsible for the development of unidirectional block and reentrant VF. This concept was supported by elegant studies in isolated myocytes that showed that the timing of membrane depolarization relative to the kinetics of

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membrane repolarization determined the phase of alternation.55 One would predict, therefore, that pathological conditions which either increase spatial heterogeneity of repolarization or that impair coupling between cells may facilitate the development of discordant alternans. Therefore, it is not surprising that discordant alternans has been observed in clinical conditions associated with marked spatial dispersion of repolarization properties such as the congenital long QT syndrome.62 Similarly, discordant alternans was also observed during interventions that reduce cell-to-cell coupling such as ischemia65 and hypoxia.66 Clearly, a large number of questions regarding the role of repolarization alternans in the mechanism of sudden cardiac death remain unanswered. Based on currently available data, we propose one possible mechanism. First, it is apparent that patients with structural heart disease who are at risk for life-threatening ventricular arrhythmias develop microvoltlevel T wave alternans at significantly lower heart rates (typically 90 to 100 beats per minute) compared to patients in lower risk groups.48'54'64 Microvolt-level T wave alternans is most likely associated with concordant patterns of repolarization alternans (i.e., alternations that occur with the same phase) of cells within the heart. A critical trigger is required for the transformation from concordant to discordant alternans, forming a suitable substrate for reentry. Although we cannot determine from our data the exact mechanisms responsible for triggering discordant alternans in patients, physiological perturbations such as transient ischemia, premature ventricular beats, or sympathetic stimulation are known to affect the phase and magnitude of repolarization alternans. Further studies aimed at delineating these mechanisms are expected to improve our ability to understand and potentially prevent the complex sequence

of events that precipitate sudden cardiac death episodes in patients. Heterogeneity of Wavelength During Reentrant Excitation In the previous 2 sections, we described how optical mapping was extremely useful for tracking dynamic changes in the electrophysiological substrate (i.e., repolarization heterogeneities) and how such changes directly influenced the initiation of arrhythmias. Equally important are changes in the electrophysiological substrate that occur during the first few beats of reentry, which determine the ultimate stability of the arrhythmia. In the following section, we describe how optical mapping was used to investigate dynamic changes in cardiac wavelength during reentrant excitation. Since its introduction in 1913, the concept of wavelength has been widely applied to the analysis of theoretical, experimental, and clinical reentrant arrhythmias. One of the fundamental requirements for reentrant excitation is that wavelength of the reentrant impulse is shorter than the reentrant path length. Wavelength can be calculated from the product conduction velocity and APD, at one particular site. However, this characterization is limited because it fails to account for electrophysiological heterogeneities that may exist within a reentrant circuit. A more precise implementation of wavelength should account for heterogeneities of conduction and refractoriness throughout an entire reentrant circuit. However, such heterogeneities are difficult to characterize using conventional electrophysiological recording techniques. We have used optical mapping with voltage-sensitive dyes to overcome the limitations of conventional electrophysiological recording techniques. Optical mapping can be used to measure wavelength

OPTICAL MAPPING OF REPOLARIZATION directly by mapping the spatial extent of depolarized tissue. Action potentials were recorded from a Langendorff-perfused guinea pig heart in which propagation was confined to the epicardial surface by use of the cryoablation procedure described above.47 To create an anatomical obstacle that reentrant impulses could propagate around, a linear lesion (2 x 10 mm) was "etched" precisely (±1 micron) onto the epicardial surface using a computer driven 5W argon ion laser.47 The lesion created a line of anatomical block that was parallel to the left anterior descending coronary artery and perpendicular to the orientation of repolarization gradients typically found in guinea pig.11 This model shares many of the characteristics of VT in patients in that sustained monomorphic VT is reproducibly induced by extrastimuli and exhibits characteristic responses to stimulation such as termination and acceleration using programmed ventricular stimulation (5 x diastolic threshold) from the epicardial surface. Cardiac Wavelength During Reentry Using optical mapping it was possible to directly measure dynamic changes in wavelength by plotting the spatial extent of depolarized tissue within the reentrant circuit at any point in time. Shown in Figure 7 are 2 contour plots demonstrating the extent of depolarized tissue (red) and resting tissue (black) at 2 points in time (A and B) separated by 27 ms. The white arrow extends from the head of activation to the tail of recovery and therefore corresponds to wavelength. In this example, impulse conduction was counterclockwise around the lesion. We found that APD did not vary during reentry. In contrast, conduction did vary and was most rapid parallel to the lesion and slowest while pivoting around each end of the lesion (i.e., pivot points). At time A,

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the head of the impulse, having just passed through the region of slow conduction, allows the tail of recovery to draw near. As a result, wavelength contracts. In contrast, at time B, the head of the impulse rapidly conducts parallel to the lesions, distancing itself from the tail of recovery and, thus, the wavelength expands. Over one entire VT cycle wavelength varied considerably, expanding and contracting several times (Figure 7, graph). Over all experiments, wavelength varied by as much as 20% to 50% within a single reentrant circuit. Such variations were primarily due to spatial heterogeneities of conduction velocity rather than to refractoriness. These data do not argue against the concept of wavelength; rather, they demonstrate the complexity of reentry and that wavelength theory must be implemented with caution. Optical mapping was essential in determining the underlying cellular mechanism of conduction slowing at the pivot points. Optical maps were obtained with high magnification (400-micron interpixel resolution) at each pivot point. Figure 8 shows an example of an activation map and action potential upstrokes recorded from 5 evenly spaced sites around the pivot point. Prior to the impulse entering the pivot point, conduction is normal as indicated by the rapid upstroke of the action potentials recorded from sites A and B. In contrast, while the impulse rotates around the pivot point, conduction is slowed as indicated by the crowding of isochrone lines in the contour map and by the slow rise time of the upstrokes at sites C and D. Finally, after the impulse exits the pivot point, conduction returns to normal. Slowing of conduction at the pivot points could not be explained by depressed excitability because conduction at the pivot point was normal during pacing at the VT cycle length (i.e., in the absence of reentry). In addition, because APD did not vary significantly over the

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Figure 7. Isopotential maps derived from high-resolution optical action potential recordings demonstrating the heterogeneity of A, and excitable gap during a single reentrant ventricular tachycardia cycle. Transmembrane potential was normalized at each recording site (-80 mV resting potential; +20 mV maximum amplitude) and the distribution of potentials measured in the reentrant circuit are plotted for 2 timepoints A and B. Reentry proceeds counterclockwise around an epicardial obstacle (hatched area). A. is indicated by the white arrow that extends from the head to the tail of the wavefront and corresponds to the extent of depolarized (inexcitable) tissue. Conversely, the excitable gap is depicted by the area of repolarized (excitable) tissue shown in black. At time A, A comprised 48% of the circuit, whereas at time B, A, comprised 88% of the circuit. Inset demonstrates variations of A during the entire reentrant VT cycle. See color appendix. Reprinted from Girouard et al. Circulation 1996;93:603-613.

entire reentrant circuit, prolonged refractoriness at the pivot point could not account for conduction slowing. Conduction slowing could also not be explained by tissue anisotropy. While pivoting, propagation wavefront turned parallel to fiber direction yet conduction was slower compared to conduction along the lesion where impulse propagation was perpendicular to fiber direction.47 Therefore, conduction

slowing at the pivot points could not be explained by tissue structure or membrane excitability. Our results suggest that slow conduction at the pivot points was due to the geometry (curvature) of the rotating wavefront. While pivoting, the wavefront curves, producing a source sink mismatch where available excitatory current (i.e., the source) is less than the current required to maintain

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Figure 8. High-magnification map (400-jim resolution) of depolarization (1-ms isochrones) around the basal tip of the epicardial obstacle (hatched area) during reentrant ventricular tachycardia. Pivoting around the obstacle requires that the reentrant wavefront first propagate transverse to fibers (blue region), then turn parallel to fibers (blue > green > yellow), and finally turn transverse to fibers again (red region). As the wavefront pivots conduction slows (i.e., crowding of isochrones) paradoxically as propagation turns parallel to fibers. Action potential upstrokes recorded from 5 evenly spaced sites around the pivot point are shown to the right. While the wavefront enters the pivot point (A,B) conduction is relatively fast and upstrokes are sharp. However, as the wavefront pivots (C,D) action potential upstrokes become increasingly slowed. After pivoting is complete (E), conduction and action potential upstroke velocity are again normal. See color appendix. Reprinted from Girouard et al. Circulation •\996;93:6Q3-6J\3.

normal propagation (i.e., the sink). Other experimental67'68 and theoretical69 studies have supported this finding. Summary Using high-resolution optical action potential mapping with voltage-sensitive dye, we have demonstrated how systematic, beat-to-beat changes in the spatial and temporal dynamics of ventricular repolarization influence the initiation and maintenance of reentrant arrhythmias. Due to limitations of conventional electrophysiological recording techniques, the influence such heterogeneities of repolarization have on arrhythmia vulnerability in the intact heart has not been well appreciated. We demonstrated that because

of spatial heterogeneities in electrical properties between cells, during premature stimulation repolarization gradients are modulated in a systematic and predictable manner that is highly dependent on premature coupling interval. Importantly, such changes critically influence the substrate for unidirectional block and reentry. Thus, a premature stimulus serves not only as a "trigger" of arrhythmias, but also importantly modulates the electrophysiological substrate for reentry. Spatial heterogeneities of repolarization also appear to play a critical role in the development of arrhythmogenic substrates during repolarization alternans. Heterogeneous ion channel function, as manifest by regional variation in cellular restitution properties, produces a situation in which cellular repolarization within separate regions

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of myocardium alternates with differing amplitude and phase. Regional differences in the phase of alternans (i.e., discordant alternans) produce critical gradients of repolarization that form a suitable substrate for unidirectional block, leading to the initiation of VF. Equally important are changes in the electrophysiological substrate that occur during reentry, as they determine the ultimate stability of the arrhythmia. Using optical mapping to directly measure dynamic changes in wavelength at any point in time, we were able to demonstrate heterogeneity of wavelength within a single reentrant beat. Moreover, high-resolution optical action potential recordings at the pivot points suggest that the underlying mechanism of wavelength heterogeneity is related to conduction slowing associated with wavefront curvature. These findings demonstrate the complexity of arrhythmogenic substrates and indicate that the electrophysiological substrate for reentry is not necessarily static but can potentially form, disappear, and reform in a predictable fashion during the initiation and maintenance of reentry. Obviously, the factors that determine dispersion of repolarization in the heart are dependent on the specific pathophysiological substrate involved. Further studies are required to increase our understanding of how heterogeneities of repolarization in the presence and absence of cardiac pathology influence the electrophysiological substrate for reentry. Undoubtedly, optical mapping will play an important role in these investigations. References 1. Allessie A, Bonke FI, Schopman FJG. Circus movement in rabbit atrial muscle as a mechanism of tachycardia: The role of nonuniform recovery of excitability in the occurrence of unidirectional block as studied with multiple microelectrodes. CircRes 1976;39:169-177.

2. Han J, Moe G. Nonuniform recovery of excitability in ventricular muscle. Circ Res 1964;14:44-60. 3. Gough W, Mehra R, Restivo M, et al. Reentrant ventricular arrhythmias in the late myocardial infarction period in the dog: 13. Correlation of activation and refractory maps. Circ Res 1985;57:432-442. 4. Allessie MA. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. III. The "leading circle" concept: A new model of circus movement in cardiac tissue without the involvement of an anatomic obstacle. CircRes 1977;41:9-18. 5. Litovsky SH, Antzelevitch C. Transient outward current prominent in canine ventricular epicardium but not endocardium. CircRes 1988;62:116-126. 6. Furukawa T, Myerburg RJ, Furukawa N, et al. Differences in transient outward currents of feline endocardial and epicardial myocytes. CircRes 1990;67:1287-1291. 7. Fedida D, Giles WR. Regional variations in action potentials and transient outward current in myocytes isolated from rabbit left ventricle. J Physiol (Lond) 1991;442:191209. 8. Sicouri S, Antzelevitch C. A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle: The M cell. Circ Res 1991;68:1729-1741. 9. Drouin E, Charpentier F, Gauthier C, et al. Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: Evidence for presence of M cells. JAm Coll Cardiol 1995;26:185-192. 10. Sicouri S, Quist M, Antzelevitch C. Evidence for the presence of M cells in the guinea pig ventricle. J Cardiovasc Electrophysiol 1996;7:503-511. 11. Laurita KR, Girouard SD, Rosenbaum DS. Modulation of ventricular repolarization by a premature stimulus: Role of epicardial dispersion of repolarization kinetics demonstrated by optical mapping of the intact guinea pig heart. CircRes 1996;79:493-503. 12. Curran ME, Splawski I, Timothy KW, et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80:795-803. 13. Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805-811. 14. Spach MS, Dolber PC, Heidlage JF. Interaction of inhomogeneities of repolarization with anisotropic propagation in dog atria:

OPTICAL MAPPING OF REPOLARIZATION A mechanism for both preventing and initiating reentry. CircRes 1989;65:1612-1631. 15. Lammers WJEP, Wit AL, Allessie MA: Effects of anisotropy on functional reentrant circuits: Preliminary results of computer simulation studies. In: Sideman S, Beyar R, (eds): Activation, Metabolism, andPerfusion of the Heart: Simulation and Experimental Models. Zoetermeer, The Netherlands: Martinus Nijhoff; 1987:133-149. 16. Kuo C, Munakata K, Reddy CP, Surawicz B. Characteristics and possible mechanisms of ventricular arrhythmia dependent on the dispersion of action potential durations. Circulation 1983;67:1356-1357. 17. Rosenbaum DS, Kaplan DT, Kanai A, et al. Repolarization inhomogeneities in ventricular myocardium change dynamically with abrupt cycle length shortening. Circulation 1991;84:1333-1345. 18. Rosenbaum D, Jalife J, (eds): Optical Mapping of Cardiac Excitation and Arrhythmias. Armonk, NY: Futura Publishing Co.; 2001. 19. Windisch H, Muller W, Tritthart H. Fluorescence monitoring of rapid changes in membrane potential in heart muscle. Biophys J 1985;48:877-884. 20. Loew LM. Design and characterization of electrochromic membrane probes. JBiochem Biophys Methods 1982;6:243. 21. Slavik J. Measurement of Membrane Potential. Fluorescent Probes in Cellular and Molecular Biology. Boca Raton: CRC Press; 1994:155-166. 22. Laurita KR, Singal A. Mapping action potentials and calcium transients simultaneously from the intact heart. Am J Physiol 2001;280:H2053-H2060. 23. Fast VG, Ideker RE. Fast co-local optical recordings of transmembrane potential and intracellular calcium in myocyte cultures. Pacing Clin Electrophysiol 1999;22:702. Abstract. 24. Loew LM, Cohen LB, Dix J, et al. A naphthyl analog of the aminostyryl pyridinium class of potentiometric membrane dyes shows consistent sensitivity in a variety of tissue, cell, and model membrane preparations. JMembrBiol 1992;130:1-10. 25. Baxter WT, Davidenko JM, Loew LM, et al. Technical features of a CCD video camera system to record cardiac fluorescence data. Ann Biomed Eng 1997;25:713-725. 26. Dillon SM, Morad MA. A new laser scanning system for measuring action potential propagation in the heart. Science 1981; 214:453-456.

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27. Knisley SB, Blitchington TF, Hill BC, et al. Optical measurements of transmembrane potential changes during electric field stimulation of ventricular cells. Circ Res 1993;72:255-270. 28. Pastore JM, Rosenbaum DS. Role of structural barriers in the mechanism of alternans-induced reentry. Circ Res 2000;87: 1157-1163. 29. Laurita KR, Rosenbaum DS. Interdependence of modulated dispersion and tissue structure in the mechanism of unidirectional block. Circ Res 2000;87:922-928. 30. Akar FG, Roth BJ, Rosenbaum DS. Optical measurement of cell-to-cell coupling in intact heart using subthreshold electrical stimulation. Am J Physiol (Heart Circ Physiol) 2001;281(2):H533-H542. 31. Eloff BC, Lerner DL, Yamada KA, et al. High resolution optical mapping reveals conduction slowing in connexin43 deficient mice. Cardiovasc Res 2001;51(4):681-690. 32. Laurita K, Libbus I. Optics and detectors used in optical mapping. In: Rosenbaum D, Jalife J (eds): Optical Mapping of Cardiac Excitation and Arrhythmias. Armonk, NY: Futura Publishing Co.; 2001:61-78. 33. Bass BG. Restitution of the action potential in cat papillary muscle. Am J Physiol 1975;228:1717-1724. 34. Carmeliet E. Repolarization and frequency in cardiac cells. J Physiol (Paris) 1977;73:903-923. 35. Girouard SD, Laurita KR, Rosenbaum DS. Unique properties of cardiac action potentials recorded with voltage-sensitive dyes. J Cardiovasc Electrophysiol 1996;7: 1024-1038. 36. Qu Z, Garfinkel A, Chen P, Weiss J. Mechanisms of discordant alternans and induction of reentry in simulated cardiac tissue. Circulation 2000; 102:1664-1670. 37. Kanai A, Salama G. Optical mapping reveals that repolarization spreads anisotropically and is guided by fiber orientation in guinea pig hearts. CircRes 1995;77:784-802. 38. El-Sherif N, Caref EB, Yin H, Restivo M. The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome—tridimensional mapping of activation and recovery patterns. Circ Res 1996;79:474-492. 39. Akar FG, Yan GX, Antzelevitch C, Rosenbaum DS. Unique topograpical distribution of m cells underlies reentrant mechanisms of torsade de pointes in the long-QT syndrome. Circulation 2002;105: 1247-1253.

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with alcoholism and hypomagnesemia. 40. Antzelevitch C, Sicouri S. Clinical releAmJCardiol 1984;53:390-391. vance of cardiac arrhythmias generated by afterdepolarizations. Role of M cells in 53. Platt SB, Vijgen JM, Albrecht P, et al. Occult T wave alternans in long QT synthe generation of U waves, triggered activdrome. J Cardiovasc Electrophysiol 1996;7: ity and torsade de pointes. JAm Coll Car144-148. diol 1994;23:259-277. 41. Yuan S, Wohlfart B, Olsson SB, Blomstrom- 54. Rosenbaum DS, Albrecht P, Cohen RJ. Predicting sudden cardiac death from T Lundqvist C. The dispersion of repolarization wave alternans of the surface electrocarin patients with ventricular tachycardia a diogram: Promise and pitfalls. J Cardiostudy using simultaneous monophasic vasc Electrophysiol 1996;7:1095-1111. action potential recordings from two sites in the right ventricle. Eur Heart J 1995;16: 55. Rubenstein DS, Lipsius SL. Premature beats elicit a phase reversal of mechanoelectrical 68-76. alternans in cat ventricular myocytes: A 42. Vassallo J, Cassidy D, Kindwall E, et al. possible mechanism for reentrant arrhythNonuniform recovery of excitability in the mias. Circulation 1995;91:201-214. left ventricle. Circulation 1988;78:136556. Saitoh H, Bailey J, Surawicz B. Alternans 1372. of action potential duration after abrupt 43. Myerburg RJ, Kessler KM, Castellanos A. shortening of cycle length: Differences Sudden cardiac death: Structure, function, between dog Purkinje and ventricular and time-dependent risk. Circulation 1992; muscle fibers. CircRes 1988;62:1027-1040. 85(SupplI):I-2-I-10. 44. Moe GK, Childers RW, Merideth J. An 57. Karagueuzian HS, Khan SS, Hong K, et al. Action potential alternans and irregappraisal of supernormal A-V conduction. ular dynamics in quinidine-intoxicated Circulation 1968;38:5-28. ventricular muscle cells: Implications for 45. Laurita KR, Girouard SD, Akar FG, ventricular proarrhythmia. Circulation Rosenbaum DS. Modulated dispersion 1993;87:1661-1672. explains changes in arrhythmia vulnerability during premature stimulation of the 58. Kleber AG, Janse MJ, van Capelle FJL, et al. Mechanism and time course of S-T heart. Circulation 1998;98:2774-2780. and T-Q segment changes during acute 46. Boyett MR, Jewell BR. A study of the facregional myocardial ischemia in the pig tors responsible for rate-dependent shortheart determined by extracellular and ening of the action potential in mammalian intracellular recordings. CircRes 1978; 42: ventricular muscle. J Physiol 1978;285:359603-613. 380. 47. Girouard SD, Pastore JM, Laurita KR, et al. 59. Dilly SG, Lab MJ. Electrophysiological alternans and restitution during acute regional Optical mapping in a new guinea pig model ischemia in myocardium of anesthetized pig. of ventricular tachycardia reveals mechJ Physiol (Lond) 1988;402:315-333. anisms for multiple wavelengths in a single reentrant circuit. Circulation 1996;93: 60. Kurz RW, Mohabir R, Ren X-L, Franz MR. Ischaemia induced alternans of action poten603-613. tial duration in the intact heart: Dependence 48. Rosenbaum DS, Jackson LE, Smith JM, on coronary flow, preload, and cycle length. et al. Electrical alternans and vulnerabilEur Heart J 1993;14:1410-1420. ity to ventricular arrhythmias. N Engl J 61. Sutton PMI, Taggart P, Lab M, et al. Med 1994;330:235-241. Alternans of epicardial repolarization as 49. Cheng TC. Electrical alternans: An assoa localized phenomenon in man. Eur ciation with coronary artery spasm. Arch Heart J 1991;12:70-78. Intern Med 1983;143:1052-1053. 50. Salerno JA, Previtali M, Panciroli C, et al. 62. Shimizu W, Yamada K, Arakaki Y, et al. Monophasic action potential recordings Ventricular arrhythmias during acute during T-wave alternans in congenital long myocardial ischemia in man. The role and QT syndrome. Am Heart J 1996;132:699significance of R-ST-T alternans and the prevention of ischemic sudden death by medical 701. 63. Pastore JM, Girouard SD, Laurita KR, et al. treatment. Eur Heart J 1986;7:63-75. Mechanism linking T-wave alternans to the 51. Wayne VS, Bishop RL, Spodick DH. Exergenesis of cardiac fibrillation. Circulation cise-induced ST segment alternans. Chest 1999;99:1385-1394. 1983;83:824-825. 52. Reddy CVR, Kiok JP, Khan RG, El-Sherif 64. Hohnloser SH, Klingenheben T, Zabel M, et al. T wave alternans during exercise N. Repolarization alternans associated

OPTICAL MAPPING OF REPOLARIZATION and atrial pacing in humans. J Cardiovasc Electrophysiol 1997;8:987-993. 65. Konta ,Ikeda K, Yamaki M, et al. Significance of discordant ST alternans in ventricular fibrillation. Circulation 1990;82: 2185-2189. 66. Hirata Y, Toyama J, Yamada K. Effects of hypoxia or low pH on the alteration of canine ventricular action potentials following an abrupt increase in driving rate. Cardiovasc Res 1980; 14:108-115.

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67. Cabo C, Pertsov AM, Baxter WT, et al. Wave-front curvature as a cause of slow conduction and block in isolated cardiac muscle. Circ Res 1994;75:1014-1028. 68. Spach MS, Miller W, Geselowitz D, et al. The discontinuous nature of propagation in normal canine cardiac muscle. Circ Res 1981;48:39-54. 69. Quan W, Rudy Y. Unidirectional block and reentry of cardiac excitation: A model study. Circ Res 1990;66:367-382.

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Chapter 39

Techniques for Mapping Ventricular Fibrillation and Defibrillation William M. Smith, PhD and Raymond E. Ideker, MD, PhD

fibrillation,11 using monophasic action potential electrodes to estimate transmembrane Ventricular fibrillation (VF) and potentials generated by external electrical defibrillation have been studied in a vari- sources applied to intact hearts or isolated ety of ways. For example, the efficacy of tissue preparations,12 applying high temimplantable defibrillators has been greatly poral and spatial resolution techniques to increased by measuring defibrillation estimating transmembrane currents,13-14 thresholds and probability of success curves and attempting to control arrhythmic activfor different electrode configurations, shock ity in isolated tissues15 or the intact heart.16-17 waveforms, and animal models.1-5 Simi- The introduction of high-resolution electrical larly, substantial indirect information about and optical mapping technologies has opened VF has been gleaned from the application the door for intense investigation into the of sophisticated signal processing algo- underlying bioelectrical phenomena associrithms to surface ECGs.6-8 In spite of their ated with fibrillation and defibrillation. great value, these techniques have revealed A complete understanding of fibrillalittle about the mechanisms of either fib- tion and defibrillation will perhaps require rillation or defibrillation, or the determin- a characterization of the transmembrane ing factors for the success or failure of potentials at all points in the myocardium defibrillation shocks. Approaches to more during the arrhythmia and during internal mechanistic investigations include filming or external countershock. Unfortunately, the the surface of the heart at high speeds to instrumentation that will allow that level of record the changes in mechanical contrac- detail will not be available in the foreseeable tion during VF,9 recording from microelec- future. Recent developments in electrical trodes in myocardial cell aggregates during and optical mapping, however, provide a fibrillation-like states10 or in vivo during means for a beginning understanding of the

Introduction

This work is supported in part by research grants HL-33637, HL-28429, HL-42760 from the National Heart, Lung and Blood Institute of the National Institutes of Health. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003. 729

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electrophysiological events associated with fibrillation and defibrillation. The introduction of specialized recording techniques has allowed the extension of traditional electrical mapping methods to the study of the electrophysiological events during fibrillation and successful and unsuccessful defibrillation shocks. New technology has allowed the determination of the nature of cardiac activation during fibrillation before and after shocks and the distribution of currents, potentials, and gradients in the myocardium from externally applied fields. Optical mapping, a complementary approach, exploits the characteristics of voltage-sensitive dyes to acquire signals that are approximations of the action potentials in the myocardium. Optical techniques provide information about electrical recovery of the tissue and the change in transmembrane potential caused by shocks, and are impervious to contamination by shock artifact. Because of the instability of fibrillation, activation mapping must be performed by recording simultaneously from many sites. A single-channel system could hypothetically be used to map the distribution of fields during shocks by making measurements during repeated trials during diastole, but the changes in the tissue with repeated shocks dictate the use of multiple channels. In this chapter we discuss the hardware and software developments that have opened the way to new understandings and hypotheses about these electrophysiological phenomena, we describe the way in which mapping studies have been combined with other electrophysiological techniques to broaden the range of questions that can be addressed, and we discuss some developments that might be important in the design of future mapping systems.

Instrumentation Transducers The first step in electrical or optical mapping of VF is the conversion of the

physiological currents and voltages into forms that are accessible to the analog and digital instrumentation. In the case of electrical mapping, the transducers are simply electrodes that are applied to the intercellular space to convert ionic currents into a flow of electrons that can be processed by standard electrical components or to sense the potentials generated in the tissue by extrinsic stimuli of shocks. Optical mapping requires staining the tissue with a voltage-sensitive dye that can be excited to yield a waveform that is typically an estimate of the intracellular action potential in the underlying tissue. The simplest sensors used in electrical mapping studies are electrodes to record electrograms directly from the cardiac tissue. These are structures of many shapes and materials that can be applied to the epicardium,12,18 the endocardium,19 or intramurally.20-24 The application of electrodes with spacing close enough to determine mechanisms of fibrillation and defibrillation throughout the extent of the myocardium is an unsolved problem. There is evidence to indicate that spatial resolution of approximately 1 mm is adequate for mapping fibrillation wavefronts.25 This spacing might be necessary to resolve some of the questions that are currently unanswered about the nature of fibrillation and the events that occur when defibrillation shocks are unsuccessful.26-27 However, to map the entire myocardial volume of a canine heart with this resolution would require more than 100,000 electrodes. This density of plunge needles would obviously cause unacceptable damage to the tissue, perturbing the activation sequences and potential gradients under measurement in addition to placing demands on the data acquisition system that are currently not technologically feasible. In addition, there is evidence that the very presence of either epicardial28 or intramural 29

MAPPING VF AND DEFIBRILLATION electrode arrays can distort the fields under measurement. An extensive literature exists on the electrochemical characteristics of metals and their interfaces with biological tissue.30 The nature of the metal from which the electrodes are made is less important when measurements are limited to the signals arising from the cardiac generators than when it is necessary to measure potentials resulting from large, externally applied fields, as in defibrillation shocks, either simultaneously or within milliseconds. High-level defibrillation potentials recorded by highly polarizable materials can cause large offsets that saturate the input system. Recovery can take up to seconds, causing loss of information about the nature of the response of the tissue to the shock. Electrodes made of chloridized silver, sintered silver-silver chloride, or other nonpolarizable materials are among the most practical available for recording fibrillation/defibrillation episodes.26 There are several possible configurations of the electrodes, and the choice is largely independent of the electrode material. Unipolar electrodes measure the electrical potential in the heart with respect to a distant point, either on the body surface31 or on a common point within the chest wall.26 When measuring externally generated potentials, it is necessary to refer all of the signals to a common level, so unipolar recording is used. Bipolar recordings are made by referring the signal from one electrode to another electrode very close to it. A unipolar or a bipolar configuration can be used to acquire signals generated by the heart for the purpose of mapping the activation sequence (Figure 1). The morphology of the local activation waveforms in unipolar electrograms is more consistent than in bipolar recordings. Electrical activity from sites distant from the electrode is largely suppressed in bipolar waveforms,

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Figure 1. Cardiac electrograms recorded after 8 seconds of ventricular fibrillation in a canine heart. The signals were recorded from a plunge needle with multiple recording sites along its length. The most distal electrode was just inside the endocardial surface and was always one of the bipolar pairs. For the signals shown, the other electrode of the pair was spaced from 50 microns to 1 cm from the distal point, as indicated. The top tracing is lead II of the EGG.

but the automatic detection of local activation complexes is complicated by the lack of consistent morphology.32 It has been proposed that the distribution of the potential gradient in the myocardium is an important determinant of the success or failure of defibrillation attempts.33,34 Some, but not all, mathematical models indicate that the transmembrane potentials may be predicted from the value of the gradient in the tissue.35'36 If the gradient is a critical variable, it is important to measure its value during a shock with precision and accuracy. Closely spaced triangular arrays have been developed to measure the gradient on the epicardium.26 This is a difficult measurement to make, since the value of the gradient is highly sensitive to errors in the value of the measured voltage and the determination of the coordinates of the electrodes.37 Other mathematical

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models indicate that the derivative of the shock field potential gradient is one of the variables determining the resulting change in transmembrane potential.38 This is an even more difficult measurement to make than the gradient. Other electrode configurations can be used for specialized measurements. For example, very closely spaced electrodes and a data acquisition system with a very high sampling rate have been used to estimate transmembrane ionic currents from extracellular potential gradients.14 A tetrapolar electrode composed of two bipolar pairs39 that has been used for vector mapping of activation in a hand-held probe has been adapted for multichannel use.40 Taccardi et al.41 have developed an intracavitary probe that can be used to identify early sites on the endocardium during arrhythmias. This configuration has been tested to determine whether it is possible to predict shock potentials on the endocardium from those measured in the cavitary blood and vice versa,42-43 and has been used in clinical situations.44 Several groups have developed arrays of electrodes mounted on balloons19,45-47 or extensible baskets48-50 for mapping endocardial activation or ablating endocardial tissue. For repetitive rhythms, a system that uses a hand-held probe has been developed that can map endocardial anatomy and activation sequences.51 The introduction of electrodes fabricated from thin film technologies offers interesting possibilities for very small plunge needles or surface arrays of arbitrary shapes with precise and repeatable electrode arrangements.20-52 These structures have been used successfully in neurophysiological studies53 and there has been some success in incorporating active electronics on the structure.54 Because of the motion of the beating heart and the consistency of the myocardial wall, the use of such needles is more complicated for in vivo cardiac studies than in

neurological tissue. This is an area of active investigation. In optical mapping, the transducer includes the dye, which is sensitive to voltage or other analyte, the light source used to excite the dye, and the instrumentation for converting the photons from the tissue to a voltage or current proportional to the underlying variable. These elements vary from system to system and depend on the desired variable. A typical dye for myocardial staining in optical mapping experiments is di4-ANEPPS.55 This dye binds to the cell membrane in such a way that excitation by light of wavelength less than 520 nanometers induces fluorescence at a wavelength that is proportional to the membrane voltage of myocytes in the underlying tissue. The fluoresced light can be separated from the incident light by filters. The fluorescence shift related to a 100-mV change in action potential can be as much as 10%.56,57 The light to excite the stained tissue can be directed to the area to be mapped by optical fibers58,59 or by a laser beam steered to individual epicardial spots.56,60,61 Spatial resolution is achieved through the manipulation of the laser beam, and the light is collected through a photomultiplier tube56,60 or a single photodiode.61 Alternatively, the tissue can be illuminated by a light source, with spatial information provided by an array of photodiodes62-64 or charged coupled devices.65,66 The use of video imaging systems allows the acquisition of anatomical images at the same time that electrophysiological data are gathered.67 Sampling rates, number of sensor sites, and noise levels differ for the various types of optical mapping systems. Data Acquisition The basic concepts of data acquisition are the same for optical and electrical

MAPPING VF AND DEFIBRILLATION mapping of fibrillation and defibrillation. The primary difference is that optical mapping systems are immune to the effects of shock artifact, while the inputs of electrical mapping systems must accommodate large differences (several orders of magnitude) in input voltage. Conversely, optical mapping does not provide information about the electrical potentials and gradients generated in the myocardium by external or internal shocks. The acquisition of intramural information is more straightforward with electrical mapping than with optical techniques. Acquisition of data during VF and, especially, defibrillation for electrical mapping purposes has required the application of techniques not generally used in biomedical instrumentation. Much has been learned about the response of tissue to countershocks simply by disconnecting the inputs from the amplifiers during the shocks68 or by measuring gradients generated by low-voltage external sources and extrapolating to defibrillation voltage levels.69 For the most complete characterization, it is necessary to provide adequate dynamic range in the inputs for simultaneous, or almost simultaneous, recording of electrograms with amplitudes on the order of millivolts and shock potentials that might be hundreds of volts at the locations of the sensing electrodes. There are currently 2 approaches to this problem in electrical mapping systems. Witkowski et al.26 use parallel input channels for acquiring, respectively, electrograms and shock potentials. Each sensing electrode is directly coupled to 2 amplifiers. One set of amplifiers has a dynamic range of ±130 mV and the other has a dynamic range of ±500 V. This system measures 240 signals from 120 sites. The advantage of this technique is its simplicity and lack of reliance on communications between the defibrillator and the data acquisition system. In addition, the parallel inputs allow each amplifier to

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be operated at a fixed gain, further simplifying system design. A major disadvantage is the fact that only half of the input channels provide useful data at any time. The second method used for electrically mapping fibrillation and defibrillation provides rapid context switching, so that the parameters of the mapping system can be switched between those suitable for recording electrograms and those suitable for recording shock potentials very quickly.70 In one such system, up to 528 electrograms during fibrillation are recorded simultaneously in unipolar or bipolar mode with an appropriate set of gains and input filter settings. Within one sampling period, normally before a shock is to be delivered, the inputs are converted to unipolar mode if not already so set, another set of gains is applied to the variable gain amplifiers, the signals are directly coupled to the inputs, and a voltage divider is switched into each channel. After the shock, the mapping system reverts to its original state to resume recording electrograms. Figure 2 shows an electrogram recorded during a fibrillation/defibrillation episode by one channel of a 128-channel mapping system designed for studying defibrillation. Even though this system is more complicated than the first one described, it has additional flexibility as well as the feature that all channels are recording data from distinct electrode positions. In principle, the 2 approaches provide equivalent information and both have been productively applied to the study of ventricular defibrillation.26,27 Other data can be acquired that can enable or improve the interpretation of mapping data. It is desirable to provide automated, computerized storage of information about the shocks when measuring thresholds or probability of defibrillation curves. These data include the shock voltage, current, and energy of the delivered

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Figure 2. An electrogram recorded from an episode of fibrillation and defibrillation by a specially constructed mapping system. Each channel of the mapping system is capable of rapidly switching from conditions suitable for measuring electrograms to those appropriate for recording shock potentials, then reverting to the original state. The labeled events in the figure are as follows: (A) normal bipolar electrogram recording during fibrillation, with full-scale voltage ±50 mV. (B) Relays inserting voltage dividers into the system are switched on, gains on each channel are modified, and recording mode is switched from bipolar to unipolar. (C) Amplifier settling time. (D) Shock voltage turned on. Full-scale voltage is ±250 V. (E) Shock duration. The amplitude of the generated potential can be measured at each electrode during this period. (F) Trailing edge of the shock. (G) Input restored to bipolar mode with original gain setting. (H) Electrogram recording with transient recovery.

impulses in particular. It is also useful to record the status of the system dynamically within the data stream71 to resolve any uncertainties about the status of the data acquisition system at the time the data are recorded. Another desirable characteristic of mapping systems for fibrillation and defibrillation is the ability to record data continuously for extended periods.72 Since the time of onset of VF is often unpredictable,73 it is often necessary to record the data continuously until an event of interest is identified. In many data acquisition systems, the data acquisition process is controlled by one or more computers.

The amount of data that can be continuously recorded is then limited by the amount of available high-speed computer memory or the speed with which the data can be transferred to a larger storage medium. A simpler approach is to record the data without computer intervention until an event of interest is detected, at which time the data can be transferred to the computer for analysis.74 The high data rates and volumes associated with modern mapping systems impose severe constraints on the hardware and software used for data acquisition. In general, for real time data input, it is not feasible to use operating systems

MAPPING VF AND DEFIBRILLATION that allow many simultaneous users because the computer must be able to respond in a predictable way to external events. In networked computing environments, a machine can be dedicated to the task of controlling acquisition, making the data available for users at other network nodes.75 In this way, the high-speed data acquisition is isolated from the computing demands of data analysis and display. The data acquisition for optical mapping systems can be simpler in some ways, because as stated above, they are generally not constrained to accommodate large voltages associated with shocks. On the other hand, depending on the amount of tissue stained and excited, optically sensed transmembrane potentials can have low signal-to-noise ratios. These issues have been addressed by signal averaging in the time domain56 or by spatially filtering.66 Some of the video imaging systems have been limited by the video rates available,66 but new technology promises to improve substantially the time resolution available.76-78 One limit on achievable noise levels is the occurrence of photobleaching, which limits the time that the light source can illuminate the tissue without undesirable effects.58 Signal Processing The selection of signal processing algorithms that are applied to data from the study of fibrillation and defibrillation depends on the nature of the study and the conditions under which the signals are acquired. It is often necessary to analyze signals recorded from the heart as well as the waveforms delivered to the shocking or defibrillation electrodes. The unique capabilities of optical mapping, in particular the ability of optical systems to measure tissue recovery, create a need for different signal analysis techniques from those used in electrical mapping.

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For complete isochronal and isogradient mapping studies using electrical mapping, the electrograms from bipolar or unipolar sensing electrodes must be analyzed for detection of local activations in each channel and for determination of the field strength at the electrode location during the external shock. VF is of such variability and high rate, especially in smaller experimental animals, that electrograms recorded in the arrhythmia are often confusing. It is sometimes difficult to distinguish conduction block from slow conduction across abnormal tissue and deflections in the electrograms from distant generators can cause ambiguities in the detection and timing of local electrical events. Complicating the analysis is the fact that there are often multiple wavefronts simultaneously existing in the myocardium during fibrillation,73 giving rise to waveform deflections that do not represent local activity and that make grouping activations into beats difficult. Because of the consistent morphology of unipolar electrograms during local activation, some investigators prefer recording in unipolar rather than bipolar mode. The detection of local activations is then limited to comparison of the first derivative of the signal to a threshold, with time of activation determined by the minimum value (maximum absolute value) of the derivative.26,31,79 Unipolar electrodes are subject to more contamination from distant electrical activity than bipolar recordings,80 complicating the selection of a threshold value for the derivative. Bipolar electrograms, while less susceptible to distant electrical generators than unipolar,81 are dependent on the angle of incidence of the wavefront to the axis between the bipolar pair,82 which increases the variability of the waveform morphology. Thus, analysis algorithms for bipolar electrograms are more complex

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for activation detection and determination of activation times than their unipolar counterparts.32 Other algorithms can provide limited information about repolarization from extracellular unipolar electrograms.83 When local activity is difficult to identify, as it often is during fibrillation, it is preferable to study the activation sequence of the myocardium during VF without explicitly identifying and timing local activations.84 This can be accomplished by animating the potential recorded during time of interest. The values of the potentials or their first derivatives are color coded according to their level and displayed dynamically at varying rates. This technique avoids the ambiguities of activation detection and grouping of beats for isochronal displays.85 Figure 3 is adapted from such a display. The potentials generated during a shock or stimulus must be recorded in unipolar mode. To determine the potential in the tissue during the shock, a decision must be made about where in the shock waveform to make the measurement. If the waveform is a truncated exponential, it is possible to fit an exponential to the digitized points and then make a measurement at any desired point along the curve.86 If the signal delivered is a square wave (from a constant voltage source), it is desirable to compute average voltage across several sample points for noise reduction purposes. Activation sequences during fibrillation and after external shocks are also measured in optical mapping studies. Because the optical waveform is a representation of the underlying action potential, the time of activation is generally estimated by the maximum positive derivative of the signal62,76 or a fixed percentage of the action potential upstroke.66 A powerful capability of the optical technique is the ability to estimate repolarization times. These times can be determined

by the return of the action potential to some point near baseline66 or by the point of maximum second derivative during repolarization.62 This measurement becomes problematic during VF because the short cycle lengths often prevent a return to baseline of the signal.87 It is convenient to analyze the signal coming from the defibrillating device by inputting the attenuated and isolated defibrillation waveform into a waveform analyzer or digital oscilloscope instead of dedicating a channel of the mapping system to that signal.88 Waveform analyzers are generally programmable, so that the peak or average voltage and current can be measured and from them impedance, energy, and other defibrillation parameters can be computed. New signal processing algorithms have improved our understanding of fibrillation and defibrillation as studied by both electrical and optical mapping systems, and have added exciting new approaches to extracting the most information possible from the data. One development has been the application of quantitative analysis techniques to multichannel mapping data. These have included assessment of the organizational level of ventricular arrhythmias,76,89,91 estimation of the conduction velocity of propagating wavefronts,92 and automatic and semiautomatic identification of fibrillatory wavefronts and extraction of significant electrophysiological parameters.93,95 The analysis of the phase of the action potential during VF mapped by optical techniques has provided new insight into the mechanisms of VF.96 Many of these techniques have been developed for regular geometric grid patterns in 2 dimensions but are extensible to irregular 3-dimensional arrays.97 As new instrumentation is introduced, it will be necessary to develop new signal processing methods to interpret quantitatively and accurately the new kinds of data acquired.

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Image Not Available

Figure 3. Frames from an animation of activation fronts proceeding across the epicardium beneath a recording plaque with a 22 x 23 array of electrodes with interelectrode spacing of 1.12 mm. The purpose of the study was to electrically capture myocardium during ventricular fibrillation using a pair of pacing electrodes beneath the center of the recording array. Normally the pixels would be color coded according to the value of the derivative of the electrogram at each electrode site, but in this adaptation pixels with a derivative value greater than 0.5 v/s are shaded and others are white. A. The electrogram recorded from the position marked by the circled x. The asterisk marks the spot at which the stimuli begin to capture the myocardium. B, C, and D show, respectively, activation sequence before pacing is begun, after pacing has begun but before the myocardium is captured, and during capture, and correspond to the times indicated by the labels below A. The frames should be read in the top then bottom rows, from left to right. Reprinted with permission from KenKnightetal.16

Visualization Visualization in cardiac mapping encompasses everything from simply plotting electrophysiological waveforms in an intuitive and informative manner to superimposing electrophysiological data on realistic 3-dimensional renderings of the cardiac anatomy.98 As discussed above,

when the sensed sites are from a regularly space 2-dimensional array, animated isopotential or isoderivative maps can be highly effective in either electrical16 or optical76 systems. The most challenging visualization tasks in cardiac mapping arise from electrical mapping studies in which data are acquired within the myocardium.

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These data are inherently 3-dimensional and are superimposed on anatomical structures that are irregular and variable. The electrophysiological quantities are sparsely sampled, at least with the current level of mapping technology, so that interpolation is often needed for interpretation of results. Even though computer software for scientific visualization has improved dramatically over the last several years, there is currently no single solution for the display of data from mapping studies." In addition, accurate and meaningful visualization requires imaging the heart and determining sensor positions, either on a per study basis or in order to define a representative anatomy. Acquisition of anatomy and electrode geometry has progressed from physically slicing and photographing the heart, with data entry using digitizing tablets,88,100 to imaging the whole heart with magnetic resonance imaging techniques and interactively determining boundaries and electrode positions.101 There is a continuing research effort to segment the heart automatically, separating ventricular cavities from myocardium, and to characterize tissue types—normal, fibrotic, ischemic, or acutely infarcted. A rapid, accurate technique for imaging and segmenting the heart either clinically or in experimental studies would improve the quality of results. Anatomical displays can be either surface based or volume based. Surface techniques102 require the extraction of a surface of interest from a 3-dimensional structure. The surface must be defined interactively or automatically on the basis of some characteristic of the image. Surface renderers are capable of providing extremely high-quality visualizations of complex anatomies. For true 3-dimensional visualization, volume rendering techniques are available103 that allow the direct display of volume data without preliminary extraction of a surface.

Volume rendering algorithms often allow exploration of anatomical structures, but are computationally demanding. Surface- and volume-based techniques provide different perspectives on the anatomical data at different costs in processing time and realism. For example, with surface rendering techniques it is possible to display the values of potentials, gradients, or activation times on the epicardial or endocardial surfaces and rotate the heart for different perspective views. Volume rendering preserves information about the interior of the myocardial wall and allows exploration of the data throughout the tissue in a more flexible way (Figures 4 and 5). Because of the sparseness of sensing points, traditional contour maps require interpolation of the variable to be viewed. Often linear interpolation between points is adequate for 2-dimensional displays,104 but discrete smooth interpolation is a robust and flexible method that is readily applied to volumetric data.105-106 The interpolated data can be combined with the anatomy and electrode geometry to display the results realistically107 (Figures 4 and 5), and can incorporate biophysical principles.108 In other instances, presenting the data dynamically can clarify the interactions between variables as the events in fibrillation and defibrillation occur. We have developed software for displaying multivariate data as a function of time and for defining the display parameters quickly and flexibly.98 For example, it is possible with this system to render an activation surface shaded by another variable moving through the cardiac tissue. The surface shading can be derived from the local conduction velocity, from the potentials and gradients generated by a previous defibrillation shock, or by any other measured or computed variable. The goal of the visualization technique chosen is to provide methods of presenting the data from these complex studies that

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Figure 4. Displays of activation sequence of the first beat following a failed defibrillation shock. The times of activation, measured from an arbitrary reference, are shown in the color code at the right of each panel. The top panel shows the epicardial and endocardial sequences separately from a roughly anterior perspective. The epicardial surface is on the left and the left and right ventricular cavities are shown on the right. The left ventricle is to the right and just below the right ventricle and right ventricular outflow tract. The earliest activation is on the apical left ventricle, almost hidden in this 3-dimensional view. The left ventricular epicardium and left atrial appendage are the areas of latest activation. The lower panel shows the same epicardial and endocardial activation sequences, but with the endocardium and epicardium in the proper location with respect to each other. The epicardial surface has been rendered translucent to allow the cavities to be visible. The anatomy and electrode locations for this figure and Figure 5 were derived from magnetic resonance images. The electrophysiological quantities were interpolated using discrete smooth interpolation. See color appendix.

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Figure 5. Potential gradients induced in the same heart as in Figure 4 by a defibrillation shock between an anode in the left ventricular apex and a cathode in the right ventricular outflow tract. The gradients in volts per centimeter are represented by the colors shown in the scale at the right. The 3-dimensional representation allows tissue to be removed for inspection of gradients within the wall. The cubes with X's indicate the recording electrodes. In this view the left and right ventricles have been exposed, with the high-gradient area appearing in the left ventricular apex. See color appendix.

build intuition, increase insight, and lead to new hypotheses about the electrophysiological events of interest. Conclusion Ventricular fibrillation and defibrillation are complex phenomena and the study of their mechanisms can require commensurately complex instrumentation. The tools needed to adequately map these events include sensors for transducing the ionic signals into electronic ones, highspeed electronics for converting the signals into a form that can be analyzed, and modern computers for processing signals, transforming data, and visualizing results. Commercial mapping systems, while adequate for many clinical applications, are limited in mapping defibrillation shocks

and the immediate response of the tissue to the shocks because of their limited dynamic range. Currently, mapping instrumentation appropriate for these studies requires a substantial investment in hardware and software development, but the decreasing cost-to-performance ratio of electronics and computers should lead to the proliferation of electrical and optical mapping systems, and the studies will be limited largely by our imagination and persistence. References I. Chang MS, Inoue H, Kallok MJ, et al. Double and triple sequential shocks reduce ventricular defibrillation threshold in dogs with and without myocardial infarction. J Am Coll Cardiol 1986;8: 1393-1405.

MAPPING VF AND DEFIBRILLATION 2. Dixon EG, Tang ASL, Wolf PD, et al. Improved defibrillation thresholds with large contoured epicardial electrodes and biphasic waveforms. Circulation 1987;76: 1176-1184. 3. Feeser SA, Tang ASL, Kavanagh KM, et al. Strength-duration and probability of success curves for defibrillation with biphasic waveforms. Circulation 1990;82: 2128-2141. 4. Jones DL, Klein GJ, Guiraudon GM, et al. Prediction of defibrillation success from a single defibrillation threshold measurement with sequential pulses and two current pathways in humans. Circulation 1988;78:1144-1149. 5. Kralios AC, Nappi JM, Tsagaris TJ, et al. Paradoxical increase of ventricular fibrillation threshold in response to coronary sinus obstruction. Am Heart J 1988;115:334-339. 6. Kaplan DT, Cohen RJ. Is fibrillation chaos? Circ Res 1990;67:886-892. 7. Goldberger AL. Fractal dynamics of the heartbeat. In: Jalife J (ed): Mathematical Approaches to Cardiac Arrhythmias. New York: New York Academy of Sciences; 1990:402-409. 8. Herbschleb JN, Heethaar RM, Tweel L, et al. Frequency analysis of the ECG before and during ventricular fibrillation. In: Ripley KL, Ostrow HG (eds): Proc Comput Cardiol. Piscataway, NJ: The Institute of Electrical and Electronics Engineers, Inc.; 1980:365-368. 9. Wiggers CJ. Studies of ventricular fibrillation caused by electric shock: Cinematographic and electrocardiographic observations of the natural process in the dog's heart: Its inhibition by potassium and the revival of coordinated beats by calcium. Am Heart J 1930;5:351365. 10. Swartz JF, Jones JL, Jones RE, et al. Conditioning prepulse of biphasic defibrillator waveforms enhances refractoriness to fibrillation wavefronts. Circ Res 1991;68:438-449. 11. Zhou X, Knisley SB, Wolf PD, et al. Prolongation of repolarization time by electric field stimulation with monophasic and biphasic shocks in open chest dogs. Circ Res 1991;68:1761-1767. 12. Daubert JP, Frazier DW, Wolf PD, et al. Response of relatively refractory canine myocardium to monophasic and biphasic shocks. Circulation 1991;84:2522-2538.

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MAPPING VF AND DEFIBRILLATION the right heart using a basket catheter: Acute and chronic animal studies. Pacing Clin Electrophysiol 1997;20:51-59. 49. Eldar M, Ohad DG, Goldberger JJ, et al. Transcutaneous multielectrode basket catheter for endocardial mapping and ablation of ventricular tachycardia in the pig. Circulation 1997;96:2430-2437. 50. Hsu S, Smith MF, Ohad DG, et al. Insights into the mechanism of ventricular tachycardia in a closed-chest porcine model utilizing a multielectrode basket catheter. Pacing Clin Electrophysiol 1996;19:714. Abstract. 51. Smeets JLRM, Ben-Haim SA, Rodriguez L-M, et al. New method for nonfluoroscopic endocardial mapping in humans. Accuracy assessment and first clinical results. Circulation 1998;97:2426-2432. 52. Hofer E, Urban G, Spach MS, et al. Measuring activation patterns of the heart at a microscopic size scale with thin-film sensors. Am J Physiol 1994;266:H2136H2145. 53. Anderson DJ, Najafi K, Tanghe SJ, et al. Batch-fabricated thin-film electrodes for stimulation of the central auditory system. IEEE Trans Biomed Eng 1989;36: 693-704. 54. Ji J, Najafi K, Wise KD. A low-noise demultiplexing system for active multichannel microelectrode arrays. IEEE Trans Biomed Eng 1991;38:75-81. 55. Fluhler E, Burnham VG, Loew LM. Spectra, membrane binding, and potentiometric responses of new charge shift probes. Biochemistry 1985;24:57495755. 56. Knisley SB, Blitchington TF, Hill BC, et al. Optical measurements of transmembrane potential changes during electric field stimulation of ventricular cells. Circ Res 1993;72:255-270. 57. Gross D, Loew LM, Webb WW. Optical imaging of cell membrane potential changes induced by applied electric fields. Biophys J 1986;50:339-348. 58. Dillon SM. Optical recordings in the rabbit heart show that defibrillation strength shocks prolong the duration of depolarization and the refractory period. Circ Res 1991;69:842-856. 59. Neunlist M, Tung L. Optical recordings of ventricular excitability of frog heart by an extracellular stimulating point electrode. Pacing Clin Electrophysiol 1994;17:1641-1654.

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Chapter 40 Disorders of Cardiac Repolarization and Arrhythmogenesis in the Long QT Syndrome Nabil El-Sherif, MD and Gioia Turitto, MD

Introduction The congenital and acquired forms of the long QT syndrome (LQTS) both result from abnormalities (intrinsic, acquired, or both) of the ionic currents underlying repolarization. Prolongation of the repolarization phase acts as a primary step for the generation of early afterdepolarizations (EADs).1 EAD-induced triggered beats arise predominantly from the Purkinje network.1 In LQTS, prolonged repolarization is associated with increased spatial dispersion of repolarization.2,3 The focal EAD-induced triggered beat(s) can infringe on the underlying substrate of inhomogeneous repolarization to initiate polymorphic reentrant ventricular tachycardia (VT).3 Torsades de pointes (TdP) is an ear-pleasing term that describes an eye-catching form of polymorphic VT. The term was first coined by Dessertenne,4 who described its electrocardiographic

pattern of continuously changing morphology of the QRS complexes that seem to twist around an imaginary baseline. The quasi-musical term (Figure 1) and the intriguing electrocardiographic pattern have caught the attention of electrophysiologists for years and have been, to some extent, a driving force behind the recent focused interest into the value of genetics and cardiac ion channelopathy in cardiac arrhythmias in general.5 More importantly, they are helping to refocus attention on the role of dispersion of ventricular repolarization in the genesis of malignant ventricular tachyarrhythmias. There is more than one electrophysiological mechanism for polymorphic VT, and an understanding of these mechanisms can be valuable in the proper care of individual patients. The most appropriate manner in which to classify polymorphic VT is whether it is associated with normal or prolonged QT (or QTU) segment. The electrophysiological

Supported in part by Veterans Administration REAP program. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003. 747

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Figure 1. The daily utterance of the term "torsade" in French refers to different bakery items including bread loaves with characteristic twisting configuration. The above card is an advertisement for such products. Reproduced from reference 40, with permission.

mechanisms of these 2 types of polymorphic VT may be different. The term TdP should be reserved for use with LQTS. However, not all patients with LQTS have polymorphic VT with a characteristic TdP configuration,6 and this classic configuration can be seen in some cases without a prolonged QT interval.7 A Paradigm of TdP from Ion Channels to ECG (Figures 2 through 4) An in vivo canine model of LQTS and TdP was developed using the neurotoxins anthopleurin-A (AP-A)8 or ATX-II.9 These agents act by slowing Na channel inactivation resulting in a sustained inward current during the plateau and prolongation of the action potential duration (APD).10,11 The model anticipated the more recent discovery of a genetic mutation of the Na channel a subunit (SCN5A) in

patients with LQT3.12 The mutant channels were shown to generate a sustained inward current during depolarization quite similar to the Na channel exposed to AP-A or ATX-II.13 Although the model is a surrogate of LQTS, which is a relatively uncommon form of congenital LQTS, the basic electrophysiological mechanism of TdP in this model seems to apply, with some necessary modifications, to all forms of congenital and acquired LQTS. In a series of reports, a paradigm of the mechanisms of TdP that extends from an ion channel abnormality to an arrhythmia with a characteristic ECG morphology was elucidated.3,8,14-16 Figures 2 to 4 illustrate this paradigm in a logical, uninterrupted sequence. Figure 2A illustrates the behavior of single Na channels exposed to AP-A. Figure 2B demonstrates the effects of AP-A on the action potential of a canine Purkinje fiber from an endocardial preparation and a midmyocardial (M) cell from a transmural strip

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Figure 2. A. Sequential recordings of single Na channel current responses during depolarizing steps from -120 to -20 mV from 2 rabbit cardiac myocytes illustrating the behavior of single Na channels exposed to anthopleurin-A (AP-A). The left panel shows recordings under control conditions and the right panel shows recordings from a patch exposed to 1000 nmol/L of AP-A. At -20 mV, control Na channels opened briefly, on average only once, very soon after the potential step. In contrast, Na channels exposed to AP-A showed long-lasting bursts consisting of repetitive long openings interrupted by brief closures. Some of the bursts lasted for the entire duration of the potential step. The ensemble currents from both patches are shown on the bottom. The control ensemble current shows fast relaxation. Conversely, the ensemble current of the Na channel exposed to AP-A shows markedly slowed relaxation, with the current failing to relax completely by the end of the 95-ms step. Kinetic analysis suggested that AP-A results in modal gating behavior of the Na channel. B. Action potential recordings from a Purkinje fiber in an endocardial preparation and from a midmyocardial cell, from a transmural strip; both isolated from the left ventricle of a 10-week-old puppy and placed in the same chamber and perfused with 50 mg/L AP-A. The 2 preparations were stimulated at a cycle length (CL) of 3000 ms. The Purkinje fiber shows a series of early afterdepolarizations (EADs) that increased gradually in amplitude before final repolarization. On the other hand, the first action potential of the midmyocardial cell showed marked prolongation of action potential duration (APD) and low amplitude EADs at the end of phase 2. The subsequent action potential showed the occurrence of a potential at the end of phase 2 that is more representative of an electrotonic interaction rather than an EAD. This observation is emphasized in C, which shows simultaneous recordings from a subepicardial (EPI) cell, midmyocardial (M) cell, and a subendocardial (END) cell from a transmural strip isolated from the left ventricle of a 12-week-old puppy and transfused with 50 mg/L AP-A. The preparation was stimulated at a CL of 4000 ms. Control recordings show the characteristic prolongation of APD of the M cell compared to EPI and END cells. AP-A resulted in prolongation of all 3 cell types, but the effect was more marked in the M cell. In section C, spontaneous regular activity arose in the preparation at a CL of 1200 ms. There was a 1:1 response in the EPI cell but irregular responses in the M and END cells. In particular, the M cell, which had a markedly prolonged APD, showed an inflection on phase 3, suggestive of electrotonic interaction. There was also evidence of asynchronous activation in the preparation (possible substrate for reentrant excitation). In 4 other transmural preparations, M cells showed a steep relation between APD and CL. However, it was uncommon to see oscillatory responses characteristic of EAD in these cells compared to Purkinje fiber at similar CL and concentration of AP-A. Reproduced from reference 40, with permission.

that were placed in the same chamber and superfused with the same concentration of AP-A. The drug resulted in prolongation of the APD of the Purkinje fiber and the development of a series of EADs. On the

other hand, the drug resulted in marked prolongation of APD of the midmyocardial cell and low-amplitude EADs at the end of phase 2. The subsequent action potential showed the occurrence of a

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Figure 2. Continued.

potential at the end of phase 2 that is more representative of an electrotonic interaction rather than an EAD. This observation is emphasized in Figure 2C, which shows simultaneous recordings from a subepicardial (Epi) cell, M cell, and a subendocardial (End) cell from a transmural strip isolated from the left ventricular (LV) free wall of a 12-week-old puppy and transfused with AP-A. The recording illustrates the differential marked lengthening of the action potential of the M cell compared to both Epi and End cells; the development of conduction block between the Epi and M cells and the occurrence of asynchronous activation in the slice are suggestive of reentrant excitation. Figure 3 further investigates the effects of AP-A in the in vivo canine heart using high-resolution 3-dimensional isochronal mapping of both activation and repolarization. To map 3-dimensional repolarization in vivo, activation-recovery intervals (ARIs)17 were measured from unipolar extracellular electrograms recorded by multielectrode plunge needles. The ARI was shown to correspond to local repolarization.3,17 Microelectrode studies

in transmural preparations have shown that Epi, M, and End cells respond differently to changes in cycle length (CL): the M cells had the steepest APD-CL relationship, followed by End cells. The weakest relationship was observed in Epi cells.18,19 Figure 3A shows 8 transmural unipolar electrograms recorded across the basolateral wall of a canine LV during AP-A infusion at 4 different CLs. The figure shows that as the CL lengthened, the calculated ARI at M sites (#3 to #6) increased significantly more compared to End sites (#1 and #2) and Epi sites (#1 and #8). This resulted in a steep gradient of ARI, especially between Epi and M sites. This behavior is illustrated graphically in Figure 3B, which shows composite data of ARI distribution collected from 12 unipolar plunge needle recordings from the same heart. Figure 4 illustrates the final step in the synthesis of the in vivo electrophysiological mechanism of TdP. The figure shows the 3-dimensional activation pattern of a 12-beat run of nonsustained TdP. Figure 4A shows that the initiating beat of TdP arose from a focal subendocardial activity. The activation wavefront

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Figure 3. A. Recordings of 8 transmural unipolar electrograms, 1 mm apart, across the basolateral wall of the left ventricle at cycle lengths (CLs) of 400, 600, 1000, and 1400 ms, from a canine heart illustrating the behavior of single Na channels exposed to anthopleurin-A (AP-A) infusion. The calculated activation-recovery interval (ARI) is shown next to each electrogram (in ms). The figure illustrates the steep ARI-CL relation of midmyocardial sites compared with subepicardial (Epi) and subendocardial (Endo) sites, resulting in steep gradients of ARI at the transition zones at the longer CL. B. Composite data of ARI distribution collected from 12 unipolar plunge needle recordings in the basolateral wall of the left ventricle in a 4 x 10-mm section from the same experiment. After AP-A, ARIs increased 2 to 3 times compared with control at similar CLs. The steepest increase occurred at midmyocardial zones. At 600 ms, ARIs were slightly longer in midmyocardial zones, but the differences were not statistically significant. At 1000 and 1400 ms, a significant increase in ARIs was apparent in midmyocardial electrodes 3 to 6 compared with both subendocardial electrodes 1 and 2 and subepicardial electrodes 7 and 8. There was, however, marked variation in ARI dispersion at the 2 transitional zones between midmyocardial sites and both Epi and Endo sites. Differences in ARIs of up to 80 ms (at a CL of 1400 to 1500 ms) between contiguous sites, 1 mm apart, at the transition zones were not uncommon. C. Diagrammatic illustration of the plunge needle electrode used to collect ARI data. Modified from reference 3, with permission.

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Figure 4. Continues

encountered multiple zones of functional conduction block that developed at contiguous sites with disparate refractoriness as shown in Figure 3. The wavefront proceeded in a very slow counterclockwise

circular pathway around the LV cavity before reactivating sites in sections 3 and 4 at isochrone #20 to initiate the first reentrant cycle. Panels B through E of Figure 4 show that all subsequent beats

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Figure 4. Continues

of TdP resulted from reentrant excitation with varying 3-dimensional activation pattern. The TdP VT terminated when the reentrant wavefront blocked, thus ending the reentrant activity. The twist-

ing of the QRS axis during this run of TdP was more evident in the inferior lead, aVF. The initial transition in QRS axis (between V7 and V10) correlated with the bifurcation of a predominantly single

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Figure 4. (Continued) Three-dimensional ventricular activation patterns of a 12-beat nonsustained torsades de pointes (TdP) ventricular tachycardia (VT). The maps are presented as if the heart was cut transversely into 5 sections, oriented with the basal section on top and the apical section on bottom and labeled 1 to 5. In B to E, section 1 was deleted. The activation isochrones were drawn as closed contour at 20-ms intervals and labeled as 1, 2, 3, and so on to make it easier to follow the activation patterns of successive beats of the VT. Functional conduction block is represented in the maps by heavy solid lines. The thick bars under the surface ECG lead mark the time intervals covered by each of the 3-dimensional maps. The V1 beat arose as a focal subendocardial activity (marked by a star in section 1). A. Selected local electrograms recorded along the reentrant pathway during the V1 illustrating complete diastolic bridging during the first reentrant cycle of 400-ms duration. Bipolar electrograms recorded from the very slow conducting component of the circuit in section 4 had a wide multicomponent configuration. Electrograms recorded in close proximity to arcs of functional conduction block had double potentials representing an electrotonic potential (E) and an activation potential (A), respectively. Note that the electrotonic potentials were synchronous with activation at the opposite side of arcs of functional block (electrograms J, K, and Q). All subsequent beats of TdP were due to reentrant excitation with varying configuration of the reentrant circuit (B to E). The twisting QRS pattern was more evident in lead aVF during the second half of the VT episode. The transition in QRS axis (between V7 and V10) correlated with the bifurcation of a predominantly single rotating wavefront (scroll) into 2 separate simultaneous wavefronts rotating around the left and right ventricular (LV, RV, respectively) cavities. The final transition in QRS axis (between V10 and V11) correlated with the termination of the RV circuit and the reestablishment of a single LV circulating wavefront (both transition zones are marked by the 2 squares in D). P indicates P waves. Modified from reference 16, with permission.

rotating wavefront (scroll) with 2 separate simultaneous wavefronts rotating around the LV and right ventricular (RV) cavities. The final transition in QRS axis (between V10 and VI1) correlated with

the termination of the RV circuit and the reestablishment of a single LV circulating wavefront. In this and other examples of TdP, the initiating mechanism for the bifurcation of the single wavefront frequently

DISORDERS OF REPOLARIZATION AND ARRHYTHMOGENESIS IN LQTS was the development of functional conduction block between the anterior or posterior RV free wall and the interventricular septum. The termination of the RV wavefront was also frequently associated with the development of functional conduction block ahead of the circulating wavefront between the RV free wall and the anterior or posterior border of the septum. In other instances, the RV circulating wavefront was extinguished through collision with an opposing wavefront in the interventricular septum. The RV circulating wavefront usually did not exhibit a localized zone of slow conduction. This may suggest that the conduction block that develops at the border between the thin RV free wall and the much thicker interventricular septum may be, at least in part, secondary to an impedance mismatch mechanism.20 On the other hand, LV circuits frequently encompassed a varying zone of slow conduction, and conduction block usually developed in this slow zone probably secondary to decremental conduction. Although it was more difficult to correlate accurately, there was evidence that a period of transitional complexes covering more than one cycle was associated with gradual dominance of 1 of the 2 circulating wavefronts before termination of the other wavefront (see the transitional QRS complexes labeled V8 and V9 in Figure 4). Short-Long Cardiac Sequence and the Onset of TdP One or more short-long cardiac cycles, usually the result of a ventricular bigeminal rhythm, frequently precede the onset of malignant ventricular tachyarrhythmias. This is seen in patients with organic heart disease and apparently normal QT intervals21 as well as in patients with either the congenital22 or acquired23,24 LQTS. The electrophysiological mechanisms

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that underlie this relationship have not been fully explored. This was recently investigated in the canine AP-A model, a surrogate of LQTS.16 The bigeminal beats consistently arose from a subendocardial focal activity (SFA) from the same or different sites, while TdP was due to encroachment of the SFA on a substrate of dispersion of repolarization to induce reentrant arrhythmias. In the presence of a multifocal bigeminal rhythm, TdP followed the SFA that had both a critical site of origin and local coupling interval in relation to the underlying pattern of dispersion of repolarization that promoted reentry. In the presence of a unifocal bigeminal rhythm, the following mechanisms for the onset of TdP were observed: (1) a second SFA from a different site infringed on the dispersion of repolarization of the first SFA to initiate reentry; (2) a slight lengthening of the preceding CL(s) resulted in increased dispersion of repolarization at key sites due to differential increase of local repolarization at M zones compared to epicardial zones. This resulted in de novo arcs of functional conduction block and slowed conduction to initiate reentry (Figures 5 through 7). Thus, the transition of a bigeminal rhythm to TdP resulted from well-defined electrophysiological changes with predictable consequences that promoted reentrant excitation. QT/T Wave Alternans and TdP It has long been known that tachycardia-dependent T wave alternans occurs in patients with the congenital or idiopathic form of LQTS and may presage the onset of TdP.25,26 Interest in the repolarization alternans is attributed to the hypothesis that it may reflect underlying dispersion of repolarization in the ventricle, a well-recognized electrophysiological substrate for reentrant VT.27 Investigations of the arrhythmogenicity of QT/T

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Figure 5. ECG recordings from a canine anthopleurin-A (AP-A) surrogate model of LQT3 in which ventricular tachycardia was initiated by the ventricular premature beat (V2) that followed the first short-long cardiac sequence. The latter was due to the occurrence of a ventricular premature beat (V1—the short cycle) followed after a compensatory pause by a sinus beat (the long cycle). Note that V1 followed a sudden lengthening of the sinus cycle length. The numbers represent cardiac cycle length in milliseconds. Reproduced from reference 16, with permission.

wave alternans in experimental models of LQTS have provided significant insight into the role of dispersion of ventricular repolarization in the generation of reentrant VT. Chinushi et al.15 studied an in vivo canine surrogate model of LQTS using the neurotoxin AP-A, and analyzed 3dimensional repolarization and activation patterns during tachycardia-induced QT/T alternans (Figures 8 and 9). The arrhythmogenicity of QT/T alternans was primarily due to the greater degree of spatial dispersion of repolarization during alternans than during slower rates not associated with alternans. The dispersion of repolarization was most marked between M and Epi zones in the LV free wall. In the presence of a critical degree of dispersion of repolarization, propagation of the activation wavefront could be blocked between these zones to initiate reentrant excitation and polymorphic VT. Two factors contributed to the modulation of repolarization during QT/T alternans, resulting in greater magnitude of dispersion of repolarization between M and Epi zones at critical short CLs: (1) differences in restitution kinetics at M sites, characterized by larger differences of the AARI, an accurate in vivo marker of the duration of repolar-

ization, and a slower time constant (T) compared with epicardial sites; and (2) differences in the diastolic interval that would result in different input to the restitution curve at the same constant CL. The longer ARI of M sites resulted in shorter diastolic interval during the first short cycle and, thus, a greater degree of ARI shortening. An important observation was that marked repolarization alternans could be present in local electrograms without manifest alternation of the QT/T segment in the surface ECG. The latter was seen at critically short CLs associated with reversal of the gradient of repolarization between Epi and M sites, with a consequent reversal of polarity of the intramyocardial QT wave in alternate cycles. This observation provides the rationale for the digital processing techniques that attempt to detect subtle degrees of T wave alternans. The association of T wave alternans with a greater degree of dispersion of repolarization was later confirmed in 2 other experimental models. Shimizu et al.28 studied an in vitro surrogate model of LQTS using ATX-II and a perfused wedge preparation of canine LV wall. Simultaneous

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Figure 6. Three-dimensional activation maps of the V1 and V2 beats shown in Figure 5 (top) and selected electrograms along the reentrant pathway induced by the V2 beat (bottom). The 2 V beats arose from different sites in section 3 (marked by stars on the maps and electrograms). The V2 beat had a shorter "local" coupling interval than the V1 beat. The V1 beat resulted in multiple zones of functional conduction block, but there was no significant area of slow conduction, and the total ventricular activation time was 100 ms. By contrast, the V2 beat resulted in more extensive zones of functional conduction block and a slow circulating wavefront in section 2 to initiate the first reentrant cycle. Reproduced from reference 16, with permission.

transmembrane action potentials were recorded from Epi, M, and End cells together with a simulated unipolar ECG. When the preparation was paced at a critical fast rate, there was pronounced alter-

nation of APD of M cells, resulting in a reversal of repolarizing sequence across ventricular wall leading to alternation in the polarity of the T wave in the unipolar ECG (Figure 10). The authors concluded

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Figure 7. This image was obtained from the experiment illustrated in Figures 5 and 6, and shows unipolar electrograms recorded from 2 plunge needle electrodes (in sections 1 and 3, respectively). Recordings from electrode sites #1 and #4 in Needle A are not shown. The recordings illustrate the alterations in the repolarization pattern and dispersion of repolarization that followed the lengthening of preceding cycle length (CL) and that created the substrate for reentrant excitation. The numbers in the figure represent the local activation-recovery intervals (ARIs), and the numbers between parentheses are the cardiac CLs. Needle A shows that the increase of the sinus CL preceding V1 resulted in lengthening of ARI of all epicardial (Epi), midmyocardial (Mid), and endocardial (End) sites compared to preceding sinus beats with shorter and relatively constant CLs. The longer compensatory CL following V1 resulted in further lengthening of ARIs of the next sinus beat. Critical analysis revealed that the degree of lengthening of ARI at Epi sites was less compared to subEpi, Mid, and End sites, resulting in greater dispersion between these sites. For Needle A, the dispersion of ARIs between Epi site #8 and "adjacent" subEpi site #7, separated by 1 mm, was 10 ms during the stable sinus rhythm at a CL of 600 ms, and increased to 19 ms following the lengthening of the last sinus cycle before V1 to 700 ms. The ARI dispersion then increased to 37 ms following the longer CL of 833 ms of the S-L sequence. Needle B showed similar directional increases of local ARIs following the lengthening of the preceding CL but the degree of lengthening was more pronounced. Still, the lengthening of ARI at Epi sites was less marked compared to Mid and End sites. The lengthening of the sinus CL from 600 ms to 700 ms resulted in a 19-ms and a 38-ms increase of the ARI at the 2 most Epi sites #8 and #7, respectively, compared to Mid/End sites (ranging from 65 ms at site #6 to 195 ms at site #2). The most illustrative consequence of differential changes in ARI in response to lengthening of preceding CL is seen in the sinus beat following the short-long sequence in Needle B. Conduction block occurred between Mid sites #5 and #4. The ARIs could only be estimated at sites #6 to #8 and showed further lengthening compared to the sinus beat prior to V1. The ARI could not be accurately estimated at sites #1 to #5 because of superimposition of the local activation potential (site #5) or electrotonic potentials (sites #1 to #4) on the repolarization wave. It is clear, however, that the dispersion of local ARI between sites #5 and #4 was the substrate for the resulting functional conduction block. E = electrotonic potential. Reproduced from reference 16, with permission.

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Figure 8. Transmural recording from a plunge needle electrode in the left ventricular free wall from a dog during infusion of anthopleurin-A (AP-A). The recording illustrates unipolar electrograms from endocardial (End), midmyocardial (Mid), and epicardial (Epi) sites. QT alternans was induced by abrupt decrease of the cardiac cycle length (CL) from 1000 ms (S1) to 600 ms (P1, P2, P3, etc.). The numbers represent the activation-recovery interval (ARI) in milliseconds. Note that even though the overall QT interval is shorter at 600 ms compared to 1000 ms, the degree of ARI dispersion between Epi and Mid sites was greater at 600 ms. Also note the reversal of the gradient of ARI between Epi and Mid sites, with a consequent reversal of polarity of the intramyocardial QT wave in alternate cycles. B. Graphic illustration of mean ± SEM of ARI dispersion between Mid and Epi sites and between Mid and End sites during successive short CLs of 600 ms from 12 different sites from the left ventricular free wall from the same experiment. Modified from reference 15, with permission.

that T wave alternans observed at rapid rates under long QT conditions is largely the result of alternation of the M cell APD, leading to exaggeration of transmural dispersion of repolarization during alternate beats and, thus, the potential for development of TdP. The data also suggested that unlike transient forms of T wave alternans that damp out quickly and depend on electrical restitution factors, the steady-state electrical and mechanical alternans demonstrated in their study

appears to be largely the result of beatto-beat alternans of Ica. Pastore et al.29 investigated T wave alternans in a Langendorff-perfused guinea pig heart using optical mapping of epicardial action potentials, and showed that repolarization alternans at the level of the single cell accounts for T wave alternans on the surface ECG. They also showed that discordant alternans produces spatial gradients of repolarization of sufficient magnitude to cause unidirectional block and reentrant VT.

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Figure 9. Recordings obtained from a canine experiment in the presence of anthopleurin-A (AP-A) to create a surrogate model of LQT3. T wave alternans in ECG lead aVF was induced by abrupt shortening of ventricular paced cycle length (CL) from 700 ms (top panel) to 350 ms (bottom panel). Following the fifth paced beat at short CL (P5), polymorphic ventricular tachycardia developed, the first beat of which is labeled V1. The figure illustrates the 3-dimensional activation map during control paced rhythm at 700 ms (S1) (top). Activation began at the pacing site (indicated by star) in section 3. The total ventricular activation time was 80 ms, and there were no arcs of functional conduction block. Selected unipolar electrograms are shown on the right panel. There was no QT/T alternans at this CL at any site. Recordings from the same experiment during abrupt shortening of the cycle length to 350 ms (P) are shown at bottom. The activation map of the P5 beat that initiated reentrant excitation is shown on the left. Selected electrograms along the reentrant pathway that demonstrate complete diastolic bridging are shown on the right. Note the development of QT/T alternans, which was more marked at Mid sites E to H compared to Epi sites B, C, I, and J. The reentrant wavefront circulated around arcs of functional conduction block between Epi and Mid sites in sections 4 and 5 (represented by heavy solid lines) before reactivating a subepicardial site in section 4 at the 220-ms isochrone. Reproduced from reference 15, with permission.

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Figure 10. Cellular basis for alternans in T wave polarity from a canine perfused wedge preparation in the presence of ATX-II (20 nmol/L). The figure shows 7 intramural unipolar electrograms recorded from endocardial (Endo), midmyocardial (M; sites M1-M5), and epicardial (Epi) regions, transmembrane action potentials recorded from M (M2), and epicardial sites together with a transmural EGG. Numbers before and after depolarization of each unipolar electrogram indicate activation time (AT) and activation-recovery intervals. Numbers before and after upstroke of each action potential indicate AT and action potential duration at 90% of repolarization. Numbers associated with each ECG denote transmural dispersion of repolarization. Horizontal lines in each unipolar electrogram show time maximum of the first derivative of T wave. Note that the epicardium is the first to repolarize and the M region is the last when the T wave is positive (first and third beats). When in alternate beats repolarization gradients reverse (the M region repolarizes first and epicardium last), the T wave becomes negative (second beat). Traces were obtained under steadystate conditions (15 seconds after decreasing cycle length from 500 ms to 300 ms). Reproduced from reference 28, with permission.

The Autonomic Nervous System and LQTS Sympathetic imbalance has been involved to explain an arrhythmogenic sub-

strate of LQTS.30 The concept proposes that reduced right cardiac sympathetic innervation, presumably of a congenital basis, results in reflex elevation of left cardiac sympathetic activity. The hypothesis

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was originally based on earlier studies in dogs showing that left stellate ganglion stimulation and right stellate ganglion interruption prolong QT interval.31 The data were obtained from measurement of the QT interval in only one ECG lead. Later studies showed that neuronal or intravenous adrenergic stimulation can transiently prolong the QT interval, followed by shortening.32 Studies in the in vivo model of cesium-induced LQTS suggest that the left stellate ganglion exerts a "quantitatively" greater adrenergic influence on the ventricles than the right stellate ganglion.33 The larger EAD amplitude in monophasic action potential recordings from the LV observed with left or bilateral ansae subclaviae stimulation, compared to right ansae subclaviae stimulation, may simply reflect more epinephrine release or a greater mass of affected myocardium. The potential role of a1-adrenoreceptors in LQTS was highlighted by studies that showed that a1-adrenoreceptor stimulation increased and a1-adrenoreceptor blockade decreased EAD amplitude and incidence of VT in the canine cesium model of LQTS and TdP.34 In a rabbit model of LQTS and TdP, induced by Class III antiarrhythmic agents, the a1-adrenoreceptor agonist methoxamine significantly lengthened the QT interval and increased the incidence of TdP35; however, the effects of a1adrenoreceptor agonists can be complex. In another study,36 when using measurements of ARI in the rabbit, a1-agonist effect resulted in prolongation of ARIs but a decrease of the dispersion of ARIs on the epicardial surface. The latter effect was explained by the a1-agonist improving cellular coupling via enhanced gap-junctional conductance.37 It remains unknown, however, whether a1-agonists can affect dispersion of refractoriness in the 3-dimensional ventricle. Recent preliminary clinical observations suggest that the onset of TdP in LQTS

patients with a mutant Na channel may occur at rest or during sleep rather than during exercise, possibly in association with relative bradycardia.38 On the other hand, patients with mutant K channels, especially LQT1, usually have syncope or cardiac arrest under stressful conditions possibly because of an arrhythmogenic effect of catecholamine and/or differences in the rate and degree of accommodation of the QT interval to CL shortening.38 Schreick et al.39 investigated the differential effects of p-adrenergic stimulation on the frequency-dependent electrophysiological actions of 3 different Class III agents, dofetilide, a pure Ikr blocker, ambasilide, a nonselective Ik blocker, and chromanol 293B, a selective Iks blocker. The actionpotential-prolonging effect of dofetilide was significantly reduced by isoproterenol, while that of ambasilide was much less reduced. In contrast, the action-potentialprolonging effect of chromanol 293B was increased in the presence of isoproterenol. These observations are of interest, since the most significant correlation of autonomic stimulation and the onset of TdP is seen in LQTl patients in whom the Iks channel is mutated. Possible mechanisms for such a reversed effect of isoproterenol in the presence of chromanol remain speculative. From an electrophysiological mechanistic point of view, autonomic manipulations can be arrhythmogenic in LQTS by means of 2 interrelated mechanisms: (1) by enhancing or suppressing the generation of EADs and their conduction in the heart, and (2) by enhancing or suppressing the dispersion of repolarization. The latter mechanism is essential for the occurrence of reentrant excitation. It is possible that, in patients with LQTl, because of depressed Iks, autonomic stimulation results in a differential effect on APD in Epi versus M and End zones, with consequent increase of dispersion of repolarization and onset of reentrant excitation. Given this framework, it becomes obvious that a major limitation

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prolonged ventricular repolarization and increased 3-dimensional dispersion of repolarization (TDK) compared to nonhypertrophied heart.42 Further, the hyper trophied heart is more susceptible to the repolarization-prolonging effects of a Class III antiarrhythmic agent, dofetilide, a selective blocker of I^.43 Dofetilide resulted Acquired LQTS and TdP in significantly more prolongation of venThe clinical syndrome of acquired tricular repolarization of the hypertroLQTS occurs in association with certain phied heart. More importantly, the drug pharmacological agents, electrolyte ab- resulted in differentially greater prolonnormalities, and bradycardic states.40 gation of repolarization at endo/midmyoRecently the electrophysiological mecha- cardial regions, compared to epicardial nism of acquired LQTS was investigated in regions resulting in increased dispersion of a canine model of cardiac hypertrophy41 TDR. The increased TDK at contiguous in which dogs with chronic atrioventricu- myocardial sites represented the primary lar block develop ventricular hypertrophy electrophysiological substrate for the desecondary to chronic volume overload. The velopment of functional conduction block study demonstrated that volume overload and reentrant tachyarrhythmias such as hypertrophy in dogs is associated with TdP (Figures 11 through 14). The study in this area is the lack of quantitative data on the effects of autonomic manipulations on the 3-dimensional spatial dispersion of repolarization in vivo in a surrogate model ofLQTl.

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Figure 11. Electrocardiographic recordings obtained from a dog with chronic atrioventricular block and ventricular hypertrophy following infusion of 10 jj,g/kg of dofetilide. The ventricle was paced at a cycle length (CL) of 1000 ms (S1). A spontaneous ectopic beat (V^ initiated a 9-beat run of torsades de pointes at an average CL of 195 ms. This was followed by a slower run of multifocal ventricular rhythm at an average CL of 430 ms. Reproduced from reference 42, with permission.

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Figure 12. Recordings obtained from the experiment shown in Figure 11. Left: 3-dimensional activation maps of the ventricular paced beat (S-,) and the initiating beat of torsades de pointes (VJ following infusion 10 |ig/kg of dofetilide. Right: Selected local electrograms recorded along the reentrant pathway during V1? which illustrates complete diastolic bridging during the first reentrant cycle (V1 - V2 = 240 ms). Reproduced from reference 42, with permission.

demonstrated that a high dose of dofetilide resulted in prolongation of repolarization, increased TDK, and, uncommonly, TdP in normal heart. On the other hand, the hypertrophied heart is more susceptible to the proarrhythmic consequences of dofetilide at doses that are considered within the clinical range.43 The study provided the electrophysiological basis for the reported doserelated incidence of dofetilide-induced TdP in patients.44 It also justified the current

recommendations for dose-titration and close monitoring of the effects of the drug in the clinical setting.45 Dofetilide-induced prolongation of APD and increased dispersion of repolarization was bradycardia-dependent. However, there seem to be some differences in the extent of CL-dependent prolongation of repolarization and TDR when compared to the canine AP-A surrogate model of LQT3. The CL dependence in

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Figure 13. Repolarization (activation-recovery interval [ARI]) map of section 4 of the ventricular paced beat (SJ before and following dofetilide infusion from the experiment shown in Figures 11 and 12. Repolarization isochrones are drawn at 20-ms intervals. The bottom recordings illustrate selective unipolar electrograms from 2 plunge needle electrodes. The numbers on the electrograms represent the calculated ARI in milliseconds. The drug caused significant differential prolongation of the ARIs of epicardial sites A-B and E-F, compared to midmyocardial sites C-D and G-H, respectively. This resulted in 3-dimensional dispersion of repolarization between contiguous sites (represented by crowded repolarization isochrones). Reproduced from reference 42, with permission.

the LQTS model seems more exaggerated compared to the present model. In other words, the longer the CL, the greater the lengthening of repolarization and TDK in the LQTS model. In the present model, there was a gradual increase of repolarization as the CL prolonged, but the major increase in TDK occurred between CLs of 600 and 1000 ms. This may be related to differences in response of M cells to agents that delay Na+ inactivation (LQTS) versus those that depress IKr (LQT2). In the former situation, the enhanced inward slow Na+ current during the plateau of AP

shows less time dependence of inactivation10 compared to 1^.

Further Refinement of the Mechanism of TdP in LQTS (Role of EAD versus DAD)46 Figure 15 shows that the electrophysiological mechanism of VT in LQTS is somewhat more complex than that described above. The figure illustrates the process of deductive analysis when 2 or more experimental approaches are combined. Panel A

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Figure 14. Repolarization map of section #4 of the S-, beat that preceded the onset of torsades de pointes (TdP) and the activation map of the V-i beat that initiated TdP from the experiment shown in Figures 11 to 13. The bottom left panel shows selected electrograms of 2 S1 beats prior to TdP. The bottom right panel shows the same electrograms of the ST beat that immediately preceded the onset of TdP as well as the first 4 beats of TdP. The figure shows that the functional conduction block induced by the V1 beat between contiguous sites B-C and F-G occurred at those sites with marked spatial dispersion of repolarization as depicted by the crowded repolarization isochrones. Reproduced from reference 42, with permission.

is from one of the classic reviews of cellular mechanisms of cardiac arrhythmias.47 It shows a transmembrane action potential recording from a canine Purkinje fiber superfused with 20 mmol/L cesium chloride (a surrogate experimental model for LQT2). The recording illustrates the classic bradycardia-dependent prolongation of APD associated with membrane oscillation on late phase 2/early phase 3 of the repolarization phase characteristic of EADs. But it also shows that complete repolarization of the action potential is followed by a subthreshold delayed afterdepolariza-

tion (DAD). The latter is simply explained on the basis of increased intracellular Ca2+ associated with the prolonged APD triggering a transient outward current. This almost forgotten observation strongly suggests that some VT and ectopic beats in LQTS could be secondary to DADs. Panel B shows a corroboration of this observation from a different experimental model using different recording techniques. The ECG recordings were obtained from the in vivo canine AP-A surrogate model of LQTS. The top ECG tracing was obtained 10 minutes after infusion of AP-A and

DISORDERS OF REPOLARIZATION AND ARRHYTHMOGENESIS IN LQTS

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Figure 15. A. Transmembrane action potential recording from a Purkinje fiber superfused with 20 mmol/L cesium chloride showing both early and delayed afterdepolarizations. Reproduced from reference 47, with permission. B. ECG recording from an in vivo canine anthopleurin-A surrogate model of long QT syndrome showing both focal and reentrant ventricular tachycardia from the same experiment. See text for details. F = focal discharge; R = reentrant excitation. Reproduced from reference 46, with permission.

shows moderate prolongation of the QT interval and a run of nonsustained monomorphic VT at a rate of 150 beats per minute. The VT starts with a late coupled beat that is well beyond the end of the QT interval of the preceding sinus beat. Threedimensional mapping of activation showed that the VT arose as a focal discharge (F) from the same subendocardial site. For all practical purposes, the focal discharge could be attributed to DAD-triggered activity. The bottom ECG tracing was obtained from the same experiment 10 minutes later, and shows further prolongation of the QT interval. The ectopic beats labeled F now seem to be coupled to the end of the prolonged QT interval of

the preceding sinus beats. The middle of the tracing illustrates a 6-beat run of polymorphic VT, which, at least in lead V1, has a faint resemblance to TdP. Threedimensional mapping shows that the first beat arose from a subendocardial focal site and could be safely attributed to an EADtriggered activity, while subsequent beats resulted from reentrant excitation in the form of continuously varying scroll waves. A vivid graphic display of the subtle interplay between EAD-triggered activity, DAD-triggered activity, dispersion of repolarization, and reentrant excitation in LQTS is shown in Figures 16 through 18, which were obtained from a different canine AP-A experiment. Figure 16 shows

768

CARDIAC MAPPING

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Figure 16. Electrocardiographs recordings from an in vivo canine anthopleurin-A surrogate model of LQT3 illustrating the interaction between delayed afterdepolarization- and early afterdepolarizationtriggered beats in arrhythmia generation in the long QT syndrome. See text for details. Abbreviations as in Figure 15. Reproduced from reference 46, with permission.

ECG recordings obtained after a stable prolongation of the QT interval was achieved during sinus bradycardia. The recordings are arranged chronologically with few minutes between. Panel A shows a stable bigeminal and trigeminal rhythm due to subendocardial discharge attributed to an EAD-triggered activity from the same focus. This was followed several minutes later by runs of 4- or 5-beat polymorphic VT with remarkable repetition of the same QRS morphology. The first beat of each run arose from the same site of the bigeminal/ trigeminal beats in panel A. The second and third beats of each run arose from 2 different

subendocardial focal sites, while the fourth beat was reentrant in origin. The fifth beat in a 5-beat run was again focal in origin, arose well after the end of the reentrant excitation, and could be attributed to DADtriggered activity. After approximately 10 minutes of repetitive nonsustained VT, the same 3 initial focal beats were followed by reentrant excitation that degenerated into ventricular fibrillation (VF) (panel D). Figure 17 shows selected local electrograms of the 5-beat VT shown in Figure 16C (labeled VI to V5) and the activation map of V3, as well as the first 5 beats of the VT that degenerated into VF

DISORDERS OF REPOLARIZATION AND ARRHYTHMOGENESIS IN LQTS 769

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Figure 17. Selected electrograms of the nonsustained ventricular tachycardia (VT) shown in Figure 16C and of the run of VT that degenerated into ventricular fibrillation (VF) in Figure 16D. V1 to V5 refer to the first 5 beats of each run. Also shown are selected 3-dimensional activation maps of the V3 beat of the nonsustained VT and the V3 and V4 beats of the VT/VF run. See text for details. Sections 2 to 4 of the activation maps refer to sections selected out of a traditional representation of 5 transverse sections of the ventricles labeled 1 through 5 from base to apex as shown in Figure 4A. Reproduced from reference 46, with permission.

shown in Figure 16D (also labeled V1-V5) together with the activation maps of V3 and V4. The figure shows a self-terminating single reentrant cycle in the first case as contrasted with a more complex activation pattern induced by the same V3 beat

in the second case with 2 simultaneous reentrant wavefronts that rapidly degenerated into multiple reentrant wavefronts. Figure 18 illustrates the electrophysiological mechanism of the different consequences of the same V3 ectopic beat

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Figure 18. Selected electrograms of the 5-beat nonsustained ventricular tachycardia (VT) and the first 5 beats of the VT that degenerated into ventricular fibrillation (V1-V5) shown in Figures 15 through 17. Also shown is section 4 of the activation maps of both V3 beats. See text for details. The numbers without brackets represent cycle length in milliseconds and the numbers between brackets represent activation-recovery intervals. Reproduced from reference 46, with permission.

in the 2 episodes. It shows that the interectopic intervals VI-V2 and V2-V3 increased by approximately 30 to 40 ms in the second case (the equivalent of a slight slowing in the discharge of the focal activity). This resulted in lengthening of local repolarization following the V2 beat by 30 to 40 ms. However, the degree of lengthening of repolarization was slightly disparate at contiguous sites in section 4, resulting in functional conduction block and the initiation of a secondary reentrant wavefront. Figure 17 shows that the same disparate lengthening of repolarization can also explain the conduction block of the original reentrant wavefront between sites H and I in the VT that degenerated toVF. It is interesting to speculate on the electrophysiological mechanism of the 3 successive focal beats VI to V3. It is rea-

sonable to consider VI as an EAD-triggered beat. The mechanism of V2 and V3 is less certain. If these are also EAD-triggered beats we have to assume the presence of entrance block to the site of these 2 foci. Otherwise, if these foci are captured by the advancing wavefront of the preceding ectopic activity, their action potential will shorten significantly, thus mitigating against the generation of an EAD-triggered discharge. While it is customary for rapid succession of EADs to be generated from phase 2/early phase 3 of action potentials in isolated Purkinje strands subjected to manipulations that prolong action potential duration (see Figure ISA), the situation is different in the in vivo heart. Could the same focus generate fast EAD-triggered activity in vivo? Three-dimensional mapping of experimental LQTS shows that every beat of a fast VT is due to reentrant

DISORDERS OF REPOLARIZATION AND ARRHYTHMOGENESIS IN LQTS

771

excitation, save for the first 1 or 2 initiating strategies including risk stratification and beats. A repetitive unifocal discharge, as the choice of therapeutic modalities. shown in Figure 15B, is relatively slow (usually <150 beats per minute) and has the References characteristics of DAD-triggered rhythm. To conclude, then, the V2 and V3 beats are probably secondary to DAD-triggered activ- 1. El-Sherif N, Craelius W, Boutjdir M, Gough WB. Early afterdepolarizations and ity. It is interesting to note that a slight arrhythmogenesis. J Cardiovasc Electroslowing of this activity was the trigger for physiol 1990; 1:145-160. the induction of a non-self-terminating 2. Antzelevich C, Sicouri S. Clinical relevance of cardiac arrhythmias generated VT/VF. This is the opposite of the requireby afterdepolarizations: Role of M cells in ment to induce reentrant excitation in a the generation of U waves, triggered activpostinfarction heart, for example, where a ity and torsade de pointes. J Am Coll more closely coupled one or more premaCardiol 1994;23:259-277. ture beats are the norm. 3. El-Sherif N, Caref EB, Yin H, Restivo M. Conclusions The primary lesson learned from the above discussion is that minor changes in spatial dispersion of repolarization, secondary to subtle changes in CL (or other modifiers like circulating catecholamines, electrolytes, acid-base changes, pharmaceutical agents, etc.), can have decisive effects on the arrhythmogenicity of LQTS as well as whether LQTS-associated reentrant excitation self-terminates or degenerates into VF. Although the subtle changes in spatial dispersion of repolarization leading to non-self-terminating reentry may sometimes seem stochastic and unpredictable, these changes always have a clear electrophysiological basis. As shown above, a similar subtle change in spatial dispersion of repolarization can also explain the arrhythmogenicity of the short-long-short cardiac cycle sequence as well as that of overt or subtle QT alternans in LQTS. These changes are not limited to LQTS but are operational also in the presence of ischemic or nonischemic organic heart disease. The current limitations of our ability to predict, with some degree of accuracy, the timing of a non-self-terminating reentrant VT clearly require adjustment of our management

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12. Wang Q, Shen J, Splawski I, et al. SCN5A 23. Roden DM, Woosley RL, Primm RK. Incidence and clinical features of the quinidine mutations associated with an inherited carassociated long QT syndrome: Implications diac arrhythmia, long QT syndrome. Cell for patient care. Am Heart J 1986;111: 1995;80:805-811. 1088-1093. 13. Bennett PB, Yazawa K, Makita N, George AL Jr. Molecular mechanism for an inher- 24. Kay GN, Plumb VJ, Arciniegas JG, et al. Torsades de pointes: The long-short initiited cardiac arrhythmia. Nature 1995;376: ating sequence and other clinical features; 683-685. observations in 32 patients. J Am Coll 14. El-Sherif N, ChinushiM, Caref EB, Restivo Cardiol 1990;2:806-817. M. Electrophysiological mechanism of the characteristic electrocardiographic mor- 25. Schwartz PJ, Malliani A Electrical alternation of the T-wave: Clinical and experimental eviphology of torsade de pointes tachyarrhythdence of its relationship with the sympathetic mias in the long QT syndrome. Detailed nervous system and with the long Q-T synanalysis of ventricular tridimensional activadrome. Am Heart J 1975;89:45-50. tion patterns. Circulation 1997;96:4392-4399. 15. Chinushi M, Restivo M, Caref EB, El-Sherif 26. Habbab MA, El-Sherif N. TU alternans, long QTU, and torsade de pointes: CliniN. Electrophysiological basis of the arrhythcal and experimental observations. Pacing mogenicity of QT/T alternans in the long Clin Electrophysiol 1992; 15:916-931. QT syndrome. Tridimensional analysis of the kinetics of cardiac repolarization. Circ 27. Han J, Moe GK. Cumulative effects of cycle length on refractory period of carRes 1998;83:614-628. diac tissues. Am JPhysiol 1969;217:10616. El-Sherif N, Caref EB, Chinushi M, 109. Restivo M. Mechanism of arrhythmogenicity of short-long cardiac sequence that pre- 28. Shimizu W, Antzelevitch C. Cellular and ionic basis for T-wave alternans under long cedes ventricular tachyarrhythmias in the QT conditions. Circulation 1999;99:1499long QT syndrome. J Am Coll Cardiol 1999; 33:1415-1423. 1507. 17. Haws CW, Lux RL. Correlation between 29. Pastore JM, Girouard SD, Laurita KR, et al. Mechanism linking T-wave alternans to the in vivo transmembrane action potential genesis of cardiac fibrillation. Circulation durations and activation recovery intervals 1999;99:1385-1394. from electrograms: Effects of interventions that alter repolarization time. Circulation 30. Schwartz PJ, Locati E, Priori SG, Zaza A. The long QT syndrome. In: Zipes DP, 1991;81:281-288. Jalife J (eds): Cardiac Electrophysiology: 18. Antzelevitch C, Sicouri S, Litovsky SH, et al. Heterogeneity within the ventricular wall: From Cell to Bedside. Philadelphia: WB Electrophysiology and pharmacology of epiSaunders Co.; 1990:589-605. cardial, endocardial, and M cells. Circ Res 31. Yanowitz R, Preston JB, Abildskov JA. Functional distribution of right and left 1991;69:1427-1449. stellate innervation to the ventricles: Pro19. Sicouri S, Antzelevitch C. Electrophysiologic duction of neurogenic electrocardiographic characteristics of M cells in the canine left changes by unilateral alteration of symventricular free wall. J Cardiouasc Electropathetic tone. Circ Res 1966;18:416-428. physiol 1995;6:591-603. 20. Fast VG, ffleber AG. Block of impulse prop- 32. Abildskov JA. Adrenergic effects on the QT interval of the electrocardiogram. Am agation at an abrupt tissue expansion: Evaluation of the critical strand diameter in a Heart J 1976;92:210-216. 2- and 3-dimensional computer models. 33. Ben David J, Zipes DP. Differential response to right and left ansae subclaviae stimulaCardiovasc Res 1995;30:449-459. tion of early afterdepolarizations and ven21. Leclerq JF, Maison-Blanche P, Cauchemez tricular tachycardia induced by cesium in B, Coumel P. Respective role of sympathetic tone and cardiac pauses in the genesis of 62 dogs. Circulation 1988;78:1241-1250. cases of ventricular fibrillation recorded 34. Ben David J, Zipes DP. Alpha adrenoceptor stimulation and blockade modulates during Holter monitoring. Eur Heart J cesium-induced early afterdepolarizations 1988;9:1276-1283. and ventricular tachyarrhythmias in dogs. 22. Viskin S, Alla SR, Barron HV, et al. Mode Circulation 1990;82:225-233. of onset of torsades de pointes in congenital long QT syndrome. J Am Coll Cardiol 1996; 35. Carlsson L, Almgren O, Duker G. QTUprolongation and torsade de pointes induced 28:1262-1268.

DISORDERS OF REPOLARIZATION AND ARRHYTHMOGENESIS IN LQTS by putative class III antiarrhythmic agents in the rabbit: Etiology and interventions. J Cardiovasc Pharmacol 1990; 16:276-285. 36. Dhein S, Gerwin R, Ziskoven V, et al. Propranolol unmasks class III like electrophysiological properties of norepinephrine. Arch Pharmacol 1993;348:643-649. 37. Kolb HA, Somogyi R. Biochemical and biophysical analysis of cell-to-cell channels and regulation of gap junctional permeability. Rev Physiol Biochem Pharmacol 1991;118:l-48. 38. Schwartz PJ, Priori SG, Locati EH, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation 1995; 92:3381-3386. 39. Schreick J, Wang Y, Gjini V, et al. Differential effect of (3-adrenergic stimulation on the frequency-dependent electrophysiologic actions of the new class III antiarrhythmics dofetilide, ambasilide, and chromanol 293B. J Cardiovasc Electrophysiol 1997;8:1420-1430. 40. El-Sherif N, Turitto G. The long QT syndrome and torsade de pointes. Pacing Clin Electrophysiol 1999;22:91-110. 41. Vos MA, Verduyn SC, Gorgels AP, et al. Reproducible induction of early afterdepolarizations and torsade de pointes arrhyth-

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Index

clinical observations of, 577—578 Accessory pathway (AP), 497-516 electrophysiological substrate of, 579 Accuracy, defined, 158 entrainment and mapping of, 91, 94, Action potential amplitude (APA), 294 96, 98, 596-597 Activated clotting time (ACT), in focal activation in, 91 noncontact endocardial mapping, 70 Activating function, 292 invasive therapy for, 578 Activation mapping, description of, 15, magnetic electroanatomical mapping with substrate mapping of, 599, 600 158 methods of mapping for, 596 Analog-to-digital (A/D) converters, 294 new navigation and mapping Animal studies systems for, 599, 601 mapping of atrial flutter in dogs, noncontact endocardial mapping of, 373-381 mapping of normal and 90-98 nonfluoroscopic catheter-based arrhythmogenic activation of rabbit AV node, 383-402 mapping for guided RF atrial compartmentalization of, 581-589 mapping pharmacological effects on reentry around ring of anisotropic pace mapping of, 597 potential utility of substrate mapping myocardium, 311-322 for ablation of, 601 mapping the AV node in restoration and maintenance of sinus experimental settings, 403-425 rhythm and, 578 Anisotropic reentry, 220 APD restitution, 711 RF catheter ablation in, 579-580 substrate mapping of, 597-599 Atrial arrhythmias, role of P wave techniques replicating atrial morphology in mapping of compartmentalization, 580-581 atrial fibrillation, surface ECG of, termination of, 94, 97-98 445-450 Atrial flutter (AFL) future directions in, 450 ablation of, 84, 88, 89, 90 surface ECG of ectopic focal atrial definition of, 540 activity in, 429-438 endocardial catheter mapping of, typical atrial flutter, surface ECG of, 537-559 438-445 Atrial flutter (AFL), mapping of Atrial fibrillation (AF) AF pattern in, 91 (canine) activation and refractory patterns in catheter ablation in humans with, 561-574 RA enlargement model, 374-375 775

776

CARDIAC MAPPING

Atrial flutter (AFL), mapping of (canine) (contd.) clinical implications of, 378—379 intercaval region, electrophysiological properties of, 376, 377 RA pressure and local refractory patterns in, 376, 377 surface EGG and epicardial activation patterns, characteristics of, 377-378, 379, 380 Atriofascicular pathways, variants of preexcitation of, 518-535 Atrio-Hisian connections, 533 Atypical AFL, definition of, 541 AV nodal reentry, description of, 9, 10-11 AV node, mapping in experimental settings of anatomical and electrophysiological aspects of AV nodal area, 404-405 anisotropic conduction in the triangle of Koch in, 406-410 double component action potentials in posterior approach to AV node, 416-421 dual AV nodal physiology in, 405 functional aspects of the AV node, 404-405 mapping normal and arrhythmogenic activation of rabbit AV nodes in, 383-402 methodology of, 405-406 prospects and discussion of, 421-422 reentrant pathway during ventricular echoes confined to the AV node, 410-415 Body surface mapping, in noncontact endocardial mapping, 60-61 Body surface potential mapping (BSPM) applications and discussion of, 477-479 description of, 467-468 intraoperative epicardial mapping and, 471 for localization of WPW and VT, 467-481

localizing preexcitation sites, results of, 471-477 methodology of, 468, 469-471 pace mapping and radiofrequency ablation with, 477, 478 patient population, study of, 469 Boundary element method (BEM), 65-69 BSS algorithm, 22 Cardiac electrograms, interpretation of activation detection in, 16-18, 19 acute myocardial ischemia and infarction, electrograms of, 26-27 artifacts in, 30 chronic MI, electrograms of, 27-29 computer algorithms for, 20—23 continuous electrical activity in, 29 definition of, 15 endocardial electrograms in, 23-24, 29 epicardial electrograms in, 24-25, 27-28 extrinsic and intrinsic deflection in, 17-18 fractionated/fragmented electrograms in, 29-30 general principles of, 16 intracellular leads in, 18-20 intramural electrograms in, 24, 28—29 morphological interpretations of, 23-30 preexcitation syndromes, electrograms of, 25-26 transmembrane potential (TMP) in, 31 unipolar and bipolar electrograms in, 16-18, 19, 21-23 Cardiac mapping, ideal system of, 187-193 Cardiac mapping, methodology of of activation times in infarct regions, 45-48, 49 atrial fibrillation, mapping of, 43, 44-45 contours, generation of, 52-56 current techniques in, 41-43 endocardial and epicardial approaches in, 42 faults in, 44 gridding in, 53-56

INDEX late potentials, mapping of, 43-44 measurements and values in, 41 organization mapping in atrial fibrillation by, 49-51, 52 sequential mapping, systems of, 42-43 unipolar and bipolar measurements in, 41-42 Cardiovascular Research (Rosen), 6 CARTO™, system of, 42, 104, 159, 562, 581, 599-601, 640, 693, 694-695, 702 Catheter ablation of AF in humans electrophysiological effects of catheter ablation of atrial substrate in, 564-565 mapping and ablation of triggers of AF with, 565-573 mapping of atrial tissue substrate in, 561-564 Catheter mapping, 159 Chagasic VT, 681, 685, 686-688, 690-691 Circus movement reentry, history of mapping of, 3-11 Class I drugs, high-resolution epicardial mapping of the effects of, 314-316 Closed-chest mapping, 159 Connexin43, expression of, 219, 227-228 Continuous electrical activity, 29 Contours, generation of, 52-56 Correlation timing, 73 Cycle length (CL), 313, 619-634 Defibrillation shocks, optical mapping the effects of cell boundaries, effects on AVm, 296-297 cell culture studies of, 292 direct stimulation by secondary sources in, 300, 302-303 intercellular clefts, effects on AVm, 297-300, 301 measurements of shock-induced Vm changes, 295-296 microscopic optical mapping of Vm in cell cultures, 292-295 nonlinear AVm, mechanism of, 306-309

777

in shock-induced AVm in cell strands, 302-306, 307 Vm changes during defibrillation, 291-292 Direct myocardial injection, using nonfluoroscopic mapping, 113-115 Direct myocardial revascularization, using nonfluoroscopic mapping, 113 Discordant alternans, 717, 718-720 Disorganization, definition of, 562 Drugs. See Pharmacological interventions Early afterdepolarizations (EADs), 747 Ebstein's anomaly, APs associated with, 498, 500, 501, 502 Echo-wave termination, 320 Efferent autonomic innervation of the atrium, isointegral mapping of atrial incisions, effects of, 367 atrial integral distribution mapping in, 363-365 discussion and conclusion of, 369-370 maze procedure, effects of, 367, 368 stimulation of autonomic neural elements in, 366-367 in stimulation of intrinsic cardiac ganglia in humans, 368, 369 Electrochromic mechanism, 133 Endocardial approach in cardiac mapping, 42 See also Noncontact endocardial mapping Endocardial catheter mapping of atrial flutter anatomical basis of atrial arrhythmias, 538-540 atrial tachycardias, classification of, 540-541 atypical flutter, forms in, 541, 553 catheter-based atrial mapping and, 541-547 entrainment mapping in, 547-548 fibrillatory conduction, forms in, 553, 554 LA macroreentry or flutter in, 551, 553, 554 reverse typical flutter in, 541, 550

778

CARDIAC MAPPING

Endocardial catheter mapping of atrial flutter (contd.) scar-related macroreentry, forms in, 550-551, 552 typical AFL in, 541, 548-550 Endocardial catheter mapping of patients with Mahaim and variants of preexcitation ablation of specialized atriofascicular and AV pathways with, 523, 524-525, 526 of fasciculoventricular fibers, 529-533 history of, 517-518 of nodofascicular and nodoventricular pathways, 525, 527-529 preexcitation, definition of, 517-518 of specialized atriofascicular and AV pathways, 519-524 Endocardial catheter mapping of patients with WPW complications of RF current ablation techniques with, 511-512 Ebstein's anomaly, APs associated with, 498, 500, 501, 502 efficacy of RF current ablation of APs, 511 epicardial APs in, 500-501, 503 Mahaim-type preexcitation, APs associated with, 501-502, 504 potential hazards of RF current catheter ablation, 512-513 in RF ablation of left-sided APs, 510-511 in RF ablation of right-sided APs, 497-504 in RF ablation of septal APs, 504-509, 510 Endocardial electrograms, 23-24, 29 EnSite™, system of, 42-43, 159, 572 Entrainment in AF, 91, 94, 96, 98 Epicardial mapping high-resolution mapping of pharmacological interventions with, 314-316 in intraoperative epicardial mapping in BSPM, 471

transthoracic epicardial mapping and ablation technique in, 681-692 European Study Group for Preexcitation, 532 Explanted hearts, mapping of architecture of interstitial fibrosis and conduction delay in, 355-358, 359 characteristics of infarcted human hearts in, 343 conduction in dilated cardiomyopathy in, 354-355 direction of surviving fibers in, 349, 350 histology of, 343-344 Langendorff perfusion of isolated human hearts with, 342 recording electrical activity of, 343 return path, characteristics of, 347-349 spread of activation during tachycardia in, 345-347 superperfused preparations of, 350-354 Extracellular potassium, epicardial mapping of the effects of, 314-316 Extrinsic deflection, in cardiac electrograms, 17 Fast fluorescent mapping animal studies with, 149-150, 151 approaches to experimental design in, 137-140 areas of applications of, 144-150, 152-153 charge coupled device (CCD) cameras in, 139-140 dyes used in, 134-135 experimental preparations for, 144, 145 history of, 132-133 human heart applications with, 150, 152 laser scanning systems in, 140 light source and filters in, 138—139 limitations of, 150, 152

INDEX mechanical motion artifacts in, 135-136 photodetector design in, 139-140 photodiode arrays (PDAs) in, 139, 141-144 physical principles of fluorescent recordings in, 133-135 signal-to-noise ratios (SNRs) in, 132, 134, 138 software for data acquisition and analysis in, 143-144 voltage-sensitive dyes, effects of, 135 Faults in cardiac mapping, 44 Figure-of-8 model of reentrant ventricular arrhythmias adrenergic stimuli, effects on reentrant excitation in, 259, 260, 261 anatomical or ring models of reentry in, 237-239 anisotropic model and, 239, 240 antiarrhythmic agents, effects on, 259, 262-270 circus movement reentry, classification of, 237 functional models of reentry in, 239, 240 functional obstacle of the reentrant circuit in, 239-244, 245 induced versus spontaneous circus movement reentry in, 247-249 interruption of reentrant circuit of, 250, 253 leading circle model and, 239, 240, 246 modulation, effects on refractoriness in, 253-254 prevention of reentrant excitation by dual stimulation in, 258-259 programmed stimulation of entrainment, termination or acceleration of, 251-253, 254, 255 short-long-short cardiac sequence in induction of, 254-257 spiral wave model and, 239, 240 spontaneous termination of, 250, 251, 252

779

topology of functional circus movement, 244-247 Finite element modeling (FEM), 67 Focal activation, in AF, 91 Focal atrial tachycardia, definition of, 540 45° algorithm, 22 Fractionated/fragmented electrograms, 29-30, 545-546 Fragmentation index S, in MCGs, 124 Garrey, W. E., 5, 7, 8 Gridding in cardiac mapping, 53-56 History of Cardiology, The (Acierno), 9 History of the Disorders of Cardiac Rhythm (Liideritz), 9 Ideal cardiac mapping system, 187-193 Insulation defects, 531 Interpretation of Complex Arrhythmias (Pick and Langendorf), 10 Intraoperative mapping of VT in patients with MI activation patterns of VT in, 606, 607, 608-611 implications and discussion of, 615-616 mapping methodology of, 606, 607 mechanisms of VT, 611-613 septal VTs, studies of, 613-615 Intrinsic deflection, in cardiac electrograms, 17 Isochronal mapping, description of, 15, 16 Isoderivative mapping, 15 Isopotential mapping, 15 KG1 filter, 141 LabVIEW, 143-144 Lambeth Convention (Walker), 341 Laplace's equation, in noncontact endocardial mapping, 65-67

780

CARDIAC MAPPING

Late potentials, mapping of, 43-44 Local activation time (LAT), 103 Long QT syndrome (LQTS), cardiac repolarization and arrhythmogenesis acquired LQTS and TdP in, 763-765, 766 autonomic nervous system and LQTS in, 761-763 paradigm of TdP from ion channels to EGG in, 748-755 QT/T wave alternans and TdP in, 755-757, 759-761 in refinement of mechanism of TdP in LQTS, 765-771 short-long cardiac sequence and onset of TdP in, 755, 756, 757, 758, 759 Macroreentrant tachycardia (MRT), definition of, 540-541 Macroreentry, 275 Magnetocardiographic (MCG) mapping conclusions and discussion of, 491-493 detection by magnetocardiograms (MCG), 119-120 fetal MCGs with, 490-491 findings and discussion of, 127-128 instrumentation in, 121-123 localization of preexcitation and arrhythmias by, 484, 485 myocardial ischemia and viability detected by, 487-490 repolarization analysis in, 124-125 risk stratification after MI with, 484-486 signal processing in, 123-125 source localization in, 125-127 spatial MCG map analysis in, 125 spectrotemporal analysis in, 124 stress MCG studies in, 125 superconducting quantum interference devices (SQUIDs) and, 119, 121-123 theory of, 120-121 time domain analysis in, 123-124 of ventricular hypertrophy, 486, 487 of ventricular repolarization, 486-487

Mahaim-type preexcitation APs associated with, 501-502, 504 concept and description of, 518 endocardial catheter mapping of, 517-535 Mapping of arrhythmias, history of, 3-11 Mapping of normal and arrhythmogenic activation of rabbit AV node AV node activation, microelectrode and surface mapping of, 388-394 future of, 397 limitations of, 396-397 nodal inputs, dual pathway physiology, and reentry in, 386-388 optical mapping of AV node in, 394-396 rate-dependent nodal functional properties in, 383-386 MAS algorithm, 22 Microreentry continuous electrical activity (CEA) in, 279-282 definition of, 275-276 detecting the region of slow conduction in, 278-279 isolated mid-diastolic potentials in, 282-285, 286, 287 location of, 277-278 protected zone with altered connection in, 276-277 terminating VT with interruption of conduction in, 286-287, 288 Microscopic discontinuities curvature of wavefronts, effects of microfibrosis with loss of side-toside cellular interconnections in, 333-336 electrical description of myocardial architecture and application to conduction in, 327-328 electrical loading in normal mature myocardium at microscopic level and, 325-327 excitation spread between and within myocytes and, 328-332 multidimensional spread of excitation at macroscopic level and, 324-325

INDEX proarrhythmic effects of microfibrosis with loss of side-to-side gap junctions, 336, 337 significance and discussion of, 337-339 in Vmax variation within adult ventricular myocytes, 332-333 Mines, George Ralph, 3-11 Morphological algorithms, 22-23 Multi-electrode array (MEA), in noncontact endocardial mapping, 62-77, 83, 98 Myocardial architecture and anisotropy in ventricular arrhythmias in pathological states anisotropic conduction in normal ventricular myocardium and, 198-200 anisotropic reentry in, 220 arrhythmogenesis, normal myocardial architecture and uniform anisotropy with, 211-212 connexin43, altered expression of, 219, 227-228 effects of cardiac disease on anisotropy and arrhythmogenesis, 212-228 gap junctions in, 201-211 intercalated disks in, 200—201 ischemic heart disease, effects of, 212-227 myocardial architecture underlying uniform anisotropic conduction in, 200-211 Myocardial infarction (MI) in dynamic analysis of postinfarction monomorphic and polymorphic VTs, 619-634 in electrograms of acute myocardial ischemia and infarction, 26-27 Nikon, 141, 142 Nodes of Kent, 10 NOGA™, system of, 104 Noncontact endocardial mapping ablation of atrial flutter (AFL) with, 84, 88, 89, 90 applications of, 59-60, 98

781

of atrial fibrillation (AF), 90-98 of atrial flutter, 82-90 body surface mapping in, 60-61 boundary element method (BEM) in, 65-69 catheter locator system in, 64-65, 66 correlation timing in, 73 CS pacing in, 88 endocardial potentials, inverse solution reconstruction of, 65—69 human VT, mapping with, 76-82 initial validation in, 71-76 LV and RA mapping procedures in, 70-71, 72, 73 mapping protocols in, 69-71, 72, 73 materials in, 62-69 multi-electrode array (MEA) in, 62-77, 83, 98 preoperative investigations with, 69-70 solution of the inverse problem in, 60-61 system of, 61-62 Nonfluoroscopic mapping CARTO™ system of, 104, 105-107, 108, 109-110 guidance of interventional procedures with, 113-115 method of, 104-105 NOGA™ system of, 104, 106-107, 109, 110-112, 113 system components of, 104—105 Nonfluoroscopic mapping of SVT of accessory AV connections, 702-704 of atrial fibrillation (AF), 704-707 of ectopic atrial tachycardia, 697-698 electroanatomical mapping in, 694-696, 697 of RA during SR, 697 of RA isthmus in AFL, 698-702 Omega Optical, 141 Optical mapping of cellular repolarization approach of, 709-710 discordant alternans in initiation of reentry, role of, 718-720

782

CARDIAC MAPPING

Optical mapping of cellular repolarization (contd.) findings and discussion of, 723—724 heterogeneity of wavelength during reentrant excitation in, 720—723 optical action potential mapping in, 710-711 during premature stimulus of the heart, 711-716 repolarization alternans in formation of arrhythmogenic substrates, role of, 716-718 voltage sensitive dyes in, 710-711 Oriel Corporation, 141-142 Paraspecific connections, 531 Peak algorithm, 22 Pharmacological interventions Class I drugs, tetrodotoxin, and extracellular potassium, effects of, 314-316 Class III drugs, effects of, 317-318 experimental model of, 311 heptanol, effects of, 316-317 implications and discussion of, 320-322 mapping technique of, 311-322 potassium channel blockers, effects of, 318 reentrant ventricular tachycardia, characteristics of, 312-314 termination of reentrant VT by, 318-320, 321 Postinfarction monomorphic and polymorphic VTs, dynamic analysis of CL dynamics at onset of monomorphic VTs in, 620-622 polymorphic VTs, studies of, 627-631 significance of CL dynamics at onset of tachycardia in, 624-627 spatial stability of activation patterns in, 622-624 Postrepolarization refractoriness, 239 Power-One, 141 Precision and reproducibility of cardiac mapping

in activation times for roving-probe mapping, 164-166 definitions of, 157-158 electrogram signal analysis in, 170-178 induction of arrhythmia in, 161-162 in localization of recording sites, 163-164 in map generation and interpretation of activation sequence, 178-181, 182 mapping techniques in, 158-160 patient selection or experimental model in, 161 problems of analysis of, 160-181 recording of electrograms and, 162-163 role of human observers with, 181, 183 signal conditioning and, 166-169 signal logging and, 169-170 Preexcitation, definition of, 517-518 P wave morphology, role in mapping of atrial arrhythmias, 429-454 Radiofrequency (RF) ablation of atrial fibrillation (AF), 579-580 body surface potential mapping (BSPM) with, 477, 478 implications with endocardial catheter mapping of WPW, 497-516 in transthoracic epicardial mapping and ablation technique, 681-692 Reciprocating rhythm, 10 Repeatability, defined, 157-158 Reproducibility. See Precision and reproducibility of cardiac mapping Reverse typical AFL, definition of, 541 Right ventricular outflow tract (RVOT), in cardiac electrograms, 17 Roving-probe mapping, 158 Rytand, David A., 3-6 Secondary sources, 292 Silicon Graphics workstation, 62-63 Solution of the inverse problem, 60-61 Solvatochromic mechanism, 133

INDEX Specialized pathways, definition of, 523-524

SQUIDS, 119, 121-123 Subthreshold electrical stimulation electrophysiological effects of, 656, 657, 658 evidence of lack of capture during, 657-658, 659, 660, 661 history of, 649-650 implications of, 658-662 low level in subthreshold pulses of, 658 methods and definitions of, 650 patients with orthodromic tachycardias, effects on, 655-656 in patients with sustained monomorphic VT, 650 patients with SVTs, effects on, 652-655 prevention of VT, effects on, 651-652, 653 termination of VT, effects on, 650, 651, 652 Superconducting quantum interference devices (SQUIDs), 119, 121-123 Supraventricular tachycardia (SVT) effects of subthreshold electrical stimulation on, 652-655 nonfluoroscopic mapping of, 693-707 TA-IVC isthmus, 83-84, 85, 86, 87, 89, 90, 579-580 Techniques of cardiac mapping. See Cardiac mapping, methodology of Tetrodotoxin, high-resolution epicardial mapping of the effects of, 314-316 Torsades de pointes (TdP), 747-773 Transcoronary venous mapping of VT accessing coronary venous system during, 668-669 epicardial mapping of VT following MI, 669-670, 673-674, 675 of idiopathic right or left ventricular outflow tract tachycardia, 672, 674, 676, 677 using the coronary venous system for, 668 Transmembrane potential (TMP)

783

in cardiac electrograms, 18-20, 31 in isochronal mapping, 16 Transthoracic epicardial mapping and ablation technique avoiding damage to coronary arteries during, 690 for Chagasic VT, 688-689 criteria for diagnosis of epicardial VT in, 686-687 electrogram patterns defining site for successful epicardial RF ablation in, 687 epicardial mapping during, 684-685 mapping technique of, 682 of post-Mi VT, 689-690 safety of transthoracic epicardial ablation in, 686 transthoracic puncture during, 682-684 Typical AFL, definition, 541 Unstable VT, mapping of in guiding linear ablation with mapping during SR, 640-642 in mapping arrhythmia substrate during SR, 637-642 in multipoint activation sequence, mapping of, 643-644 optimizing hemodynamic support during, 636-637 QRS morphology and pace mapping for, 639-640, 641 slowing VT with antiarrhythmic drugs for, 636-637 SR electrograms for, 637-639 using basket catheters, 643, 644, 646 using noncontact electrogram recording, 643-644 Ventricular fibrillation (VF) and defibrillation, mapping of data acquisition in, 732-735 instrumentation in, 730-732 signal processing algorithms in, 735-736, 737 technique approaches to, 729-730 visualization in, 737-740

784

CARDIAC MAPPING

Ventricular tachycardia (VT) in body surface mapping localization of VT breakthroughs, 467-481 catheter ablation of, 59—60 in dynamic analysis of postinfarction monomorphic and polymorphic VTs, 619-634 in intraoperative mapping in patients with MI, 605-618 substrate mapping for ablation of, 595-604 success rate of ablation of, 595 transcoronary venous mapping of, 667-679 unstable VT, mapping of, 635—647 Ventricular tachycardia (VT), surface ECG mapping of correlating with electrophysiological mapping in, 455-466 future of, 465 history of, 455-456 ofleftseptalVT, 461, 462

limitations of, 463-465 of outflow tract VT, 460-461, 462 ofpostinfarct VT, 456-460 of VTs in absence of structural heart disease, 461-462 of VTs with structural heart disease present, 462-463 Wolff-Parkinson-White (WPW) syndrome body surface mapping localization of, 467-481 description of, 9-10 electrograms of, 25-26 endocardial catheter mapping in patients with, 497-516 findings and description of, 517-518 implications for RF ablation in, 497-516 Zigzag conduction, 322

Appendix Chapter 4

Figure 4-3

Figure 4-4

A-l

Figure 4-5

Figure 4-12a

A-2

Figure 4-12b

Figure 4-13a

A-3

Figure 4-14a

Figure 4-15

A-4

Figure 4-16

A-5

Figure 4-17A

Figure 4-18A

A-6

Figure 4-19A

Chapter 5

Figure 5-2

A-7

Figure 5-3

Figure 5-4

Figure 5-5

A-8

Figure 5-6

Figure 5-7A and B

A-9

Figure 5-7C and D

A-10

Figure 5-8

A-ll

Figure 5-9 Chapter 6

Figure 6-3

A-12

Figure 6-5

Figure 6-5

A-13

Chapter 9

Figure 9-1

Figure 9-2

A-14

Chapter 13

Figure 13-4

A-15

Chapter 16

Figure 16-9

a-16

Figure 16-10

A-17

Chapter 17

Figure 17-2

Figure 17-4

A-18

Figure 17-5

Chapter 24

Figure 24-1

A-19

fIGURE 24-2

Figure 24-3

Figure 24-4

A-20

Figure 24-5 Chapter 29

Figure 29-3

Figure 29-4

A-21

Chapter 30

Figure 30-2

A-22

Chapter 31

Figure 31-2

Figure 31-6

A-23

Figure 31-7

A-24

Chapter 33

Figure 33-1

A-25

Figure 33-6 Chapter 37

Figure 37-1

A-26

Figure 37-2

B

Figure 37-3

A-27

Figure 37-4

Figure 37-5

A-28

Figure 37-6

Figure 37-7

A-29

Figure 37-8

Figure 37-9

A-30

Chapter 38

Figure 38-7

A-31

Chapter 39

Figure 39-4

Figure 39-5

A-32