1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899
DIASTOLOGY: CLINICAL APPROACH TO DIASTOLIC HEART FAILURE
ISBN: 978-1-4160-3754-5
Copyright © 2008 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail:
[email protected]. You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions.
Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioners, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher Library of Congress Cataloging-in-Publication Data Diastology : clinical approach to diastolic heart failure / [edited by] Allan L. Klein, Mario J. Garcia.—1st ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4160-3754-5 1. Congestive heart failure. 2. Heart—Left ventricle—Pathophysiology. 3. Diastole (Cardiac cycle) I. Klein, Allan L. II. Garcia, Mario J. III. Title: Clinical approach to diastolic heart failure. [DNLM: 1. Heart Failure, Congestive. 2. Diagnostic Techniques, Cardiovascular. 3. Diastole— physiology. 4. Ventricular Dysfunction, Left. WG 370 D541 2008] RC685.C53D53 2008 616.1′29—dc22 2007042084
Executive Publisher: Natasha Andjelkovic Project Manager: Mary B. Stermel Design Direction: Karen O’Keefe Owens Marketing Manager: Todd Liebel Developmental Editor: Pamela Hetherington
Working together to grow libraries in developing countries www.elsevier.com | www.bookaid.org | www.sabre.org
Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1
Contributors NASER M. AMMASH, MD, FACC
ROBERT O. BONOW, MD, FACC
Associate Professor of Medicine Mayo Clinic Rochester, Minnesota
Goldberg Distinguished Professor Northwestern University Feinberg School of Medicine Chief, Division of Cardiology Co-Director Bluhm Cardiovascular Institute Northwestern Memorial Hospital Chicago, Illinois
CHRISTOPHER P. APPLETON, MD, FACC Professor of Medicine Division of Cardiovascular Diseases Mayo Clinic Arizona Phoenix, Arizona
CRAIG R. ASHER, MD, FACC Cardiology Fellowship Director Cleveland Clinic Florida Weston, Florida
GERARD P. AURIGEMMA, MD, FACC, FASE, FAHA Professor of Medicine and Radiology Director, Cardiology Fellowship Program University of Massachusetts Medical School Director, Non-Invasive Cardiology Umass Memorial Healthcare Worcester, Massachusetts
CATALIN F. BAICU, PhD Assistant Professor of Medicine Gazes Cardiac Research Institute Medical University of South Carolina Charleston, South Carolina
AJAY BHARGAVA, MD Staff Cardiologist Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
EDMUND A. BERMUDEZ, MD, MPH, FACC Assistant Professor of Medicine Tufts University School of Medicine Boston, Massachusetts Consultant, Cardiac and Vascular Disease Florida Cardiac Consultants Sarasota, Florida
D. DIRK BONNEMA, MD Cardiology Fellow Division of Cardiology Department of Medicine Medical University of South Carolina Charleston, South Carolina
BARRY A. BORLAUG, MD Assistant Professor of Medicine Division of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota
SHEMY CARASSO, MD University of Toronto HCM Clinic, Division of Cardiology Department of Medicine, Toronto General Hospital University Health Network University of Toronto Toronto, Ontario, Canada
MANUEL D. CERQUEIRA, MD, FACC, FAHA Professor of Radiology Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Chairman, Department of Nuclear Medicine and Staff Cardiologist Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
KRISHNASWAMY CHANDRASEKARAN, MD Professor of Medicine Consultant, Division of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota
HSUAN-HUNG CHUANG, MBBS, MRCP (UK), FAMS, FESC, FACC Consultant Cardiologist Mount Elizabeth Hospital Visiting Consultant Heart Failure and Transplantation Program National Heart Center Singapore
v
vi
Contributors
RONAN CURTIN, MD, MSc
BRIAN D. HOIT, MD, FACC, FASE
Associate Staff Cardiologist Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
Professor of Medicine and Physiology and Biophysics Case Western Reserve University Director of Echocardiography University Hospitals Case Medical Center Cleveland, Ohio
BENJAMIN W. EIDEM, MD
JERRY M. JOHN, MD, MS
Associate Professor of Pediatrics Divisions of Pediatric Cardiology and Cardiovascular Diseases Mayo Clinic Rochester, Minnesota
Cardiovascular Fellow Division of Cardiovascular Medicine University of Toledo Toledo, Ohio
KANIZ FATEMA, MBBS, PhD
TRACI L. JURRENS, MD
Research Fellow in Cardiovascular Diseases Mayo School of Graduate Medical Education Mayo Clinic Rochester, Minnesota
Cardiovascular Fellow Mayo Clinic Rochester, Minnesota
ANNE S. KANDERIAN, MD
GARY S. FRANCIS, MD
Advanced Fellow in Cardiovascular Imaging Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Head, Section of Clinical Cardiology Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
HIDEKATSU FUKUTA, MD, PhD Postdoctoral Research Fellow Wake Forest University School of Medicine Wake Forest University Baptist Medical Center Winston-Salem, North Carolina Department of Cardio-Renal Medicine and Hypertension Nagoya City University Graduate School of Medical Sciences Nagoya, Japan
WILLIAM H. GAASCH, MD, FACC Professor of Medicine University of Massachusetts Medical School Worcester, Massachusetts Senior Consultant in Cardiology Director of Cardiovascular Research Lahey Clinic Burlington, Massachusetts
MARIO J. GARCIA, MD, FACC, FACP Professor of Medicine and Radiology Mount Sinai School of Medicine Director of Cardiac Imaging Mount Sinai Heart Institute New York, New York
RICHARD A. GRIMM, DO, FACC, FASE Director, Echocardiography Laboratory Staff Cardiologist Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
DAVID A. KASS, MD Abraham and Virginia Weiss Professor of Cardiology Professor of Medicine Professor of Biomedical Engineering Johns Hopkins Medical Institutions Attending Physician Division of Cardiology, Department of Medicine Johns Hopkins Hospital Baltimore, Maryland
DALANE W. KITZMAN, MD, FACC Professor of Internal Medicine, Cardiology and Gerontology Wake Forest University Health Sciences Winston-Salem, North Carolina
ALLAN L. KLEIN, MD, FRCP(C), FACC, FAHA, FASE Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Director, Cardiovascular Imaging Research Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
LIVIU KLEIN, MD, MS Fellow in Cardiovascular Disease Northwestern University, The Feinberg School of Medicine Bluhm Cardiovascular Institute Northwestern Memorial Hospital Chicago, Illinois
SANJAY KUMAR, MD Hospitalist Department of Hospital Medicine Ohio Permanente Medical Group Kaiser Permanente Cleveland, Ohio
Contributors
DOUGLAS S. LEE, MD, PhD, FRCP(C)
SHERIF F. NAGUEH, MD, FACC
Assistant Professor of Medicine, University of Toronto Scientist, Institute for Clinical Evaluative Sciences Attending Physician, Division of Cardiology, University Health Network Toronto, Ontario, Canada
Professor of Medicine Weill Cornell Medical College Associate Director, Echocardiography Laboratory Methodist DeBakey Heart Center Houston, Texas
STEVEN J. LESTER, MD, FACC, FRCPC, FASE
SATOSHI NAKATANI, MD, PhD, FACC
Associate Professor of Medicine, Mayo Clinic Director, Cardiovascular Ultrasound Imaging and Hemodynamic Laboratory Consultant Division of Cardiovascular Diseases Mayo Clinic Arizona Scottsdale, Arizona
Staff Cardiologist Department of Cardiology National Cardiovascular Center Suita, Osaka, Japan
BENJAMIN D. LEVINE, MD, FACC Professor of Medicine University of Texas Southwestern Medical Center at Dallas Director, Institute for Exercise and Environmental Medicine S. Finley Ewing Jr. Chair for Wellness at Presbyterian Hospital of Dallas Harry S. Moss Heart Chair for Cardiovascular Research Presbyterian Hospital of Dallas Dallas, Texas
WILLIAM C. LITTLE, MD, FACC McMichael Professor and Vice Chair of Internal Medicine Chief of Cardiology Wake Forest University School of Medicine Winston-Salem, North Carolina
VOJTECH MELENOVSKY, MD, PhD Department of Cardiology Institute for Clinical and Experimental Medicine-IKEM Prague, Czech Republic
ARUMUGAM NARAYANAN, MD Research Fellow Cardiology Division, Department of Medicine University of Massachusetts Medical School University of Massachusetts Memorial Health Care Worcester, Massachusetts
M. GARY NICHOLLS, MD, ChB, FAHA, FACC, FRCP Professor of Medicine Department of Medicine Christchurch School of Medicine and Health Sciences University of Otago Christchurch, New Zealand
JAE K. OH, MD, FACC, FAHA Professor of Medicine Codirector, Echocardiography Laboratory Director, Pericardial Clinic Consultant, Division of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota
MARTIN OSRANEK, MD, MSc ANNITTA J. MOREHEAD, BA, RDCS, CCRC, FASE Manager, Cardiovascular Imaging Core, C5 Research Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
JAMES P. MORGAN, MD, PhD Professor of Medicine Tufts University Chief of Cardiovascular Medicine Caritas Carney Hospital and Caritas St. Elizabeth’s Medical Center Director of the Cardiovascular Center Caritas Christi Healthcare System Boston, Massachusetts
ROSS MURPHY, MD Consultant Cardiologist St James’s Hospital Dublin, Ireland
Assistant Professor of Medicine Research Associate, Cardiovascular Disease Mayo Clinic Rochester, Minnesota
YUTAKA OTSUJI, MD, PhD, FACC Professor of Medicine The Second Department of Internal Medicine Director Department of Cardiovascular and Renal Disease University of Occupational and Environmental Health, Japan School of Medicine Kitakyushu, Japan
ZORAN B. POPOVIĆ, MD, PhD Project Staff Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
vii
viii
Contributors
ANAND PRASAD, MD
SRIKANTH SOLA, MD, FACC, FAHA
Interventional Cardiology Fellow Department of Medicine, Division of Cardiology University of California–San Diego San Diego, California
Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Staff Cardiologist Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
MIGUEL A. QUINONES, MD, FACC Professor of Medicine Weill Cornell Medical College Chairman, Department of Cardiology The Methodist Hospital Houston, Texas
AMBEREEN QURAISHI, MD Clinical Instructor Senior Cardiovascular Fellow Department of Cardiovascular Medicine Caritas St. Elizabeth Medical Center Boston, Massachusetts
HARRY RAKOWSKI, MD, FRCPC, FACC, FASE Professor of Medicine Department of Medicine University of Toronto Douglas Wigle Research Chair in Hypertrophic Cardiomyopathy Development Director Peter Munk Cardiac Imaging Centre, Division of Cardiology, Department of Medicine Toronto General Hospital, University Health Network Toronto, Ontario, Canada
JAY RITZEMA-CARTER, BM, MRCP Cardiology Research Fellow Department of Medicine Christchurch School of Medicine and Health Sciences University of Otago Christchurch, New Zealand
L. LEONARDO RODRIGUEZ, MD, FACC Director, Stress Laboratory Program Director, Advanced Cardiovascular Imaging Fellowship Program Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
JAMES B. SEWARD, MD, FACC John M. Nasseff Sr. Professorship in Cardiology and Professor of Medicine and Pediatrics Consultant, Division of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota
DAVID H. SPODICK, MD, DSc, FACC Professor of Medicine Cardiovascular Medicine University of Massachusetts Medical School St. Vincent Hospital Worcester, Massachusetts
RANDALL C. STARLING, MD, MPH, FACC Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Vice Chairman, Department of Cardiovascular Medicine Section Head, Heart Failure and Cardiac Transplant Medicine Medical Director, Kaufman Center for Heart Failure Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
A. JAMIL TAJIK, MD, FACC Thomas J. Watson, Jr. Professor in honor of Dr. Robert L. Frye Professor of Medicine and Pediatrics Chairman (Emeritus) Zayed Cardiovascular Center Mayo Clinic Rochester, Minnesota Consultant, Division of Cardiovascular Diseases, Internal Medicine and Pediatric Cardiology Mayo Clinic Scottsdale, Arizona
W. H. WILSON TANG, MD, FACC, FAHA Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Staff Cardiologist, Section of Heart Failure and Cardiac Transplantation Medicine Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
CHUWA TEI, MD, FACC Professor and Chairman Department of Cardiovascular, Respiratory, and Metabolic Medicine Graduate School of Medicine, Kagoshima University Kagoshima, Japan
Contributors
JAMES D. THOMAS, MD, FACC, FAHA, FESC
RAMACHANDRAN S. VASAN, MD, DM, FACC, FAHA
Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Charles and Lorraine Moore Chair of Cardiovascular Imaging Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio
Professor of Medicine Boston University School of Medicine Framingham Heart Study Framingham, Massachusetts
FILIPPOS TRIPOSKIADIS, MD, FESC, FACC Professor of Cardiology Director, Department of Cardiology Larissa University Hospital Larissa, Greece
RICHARD W. TROUGHTON, MB, ChB, PhD Associate Professor Department of Medicine Christchurch School of Medicine and Health Sciences University of Otago Christchurch, New Zealand
TERESA S. M. TSANG, MD Professor of Medicine Consultant, Division of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota
MICHAEL R. ZILE, MD, FACC Charles Ezra Daniel Professor of Medicine Attending Physician Department of Medicine, Division of Cardiology Medical University of South Carolina Director of the Medical Intensive Care Unit Ralph H. Johnson Department of Veteran’s Affairs Medical Center Charleston, South Carolina
WILLIAM A. ZOGHBI, MD, FACC Professor of Medicine Weill Medical College of Cornell University William L. Winters Chair in Cardiovascular Imaging Director, Cardiovascular Imaging Center The Methodist DeBakey Heart Center Houston, Texas
ix
Foreword
Doctors Klein and Garcia have attacked a controversial yet extraordinarily problematic clinical challenge with aggressiveness, insight, and thoroughness. Their text, Diastology: Clinical Approach to Diastolic Heart Failure, is one of the few organized efforts to bring together noted experts and synthesize today’s knowledge base regarding this fascinating problem. The depth and breadth of topics covered in this text are extraordinary, and the editors and individual contributors are to be congratulated. The importance of this subject cannot be overemphasized because it is now well established that almost half of all patients admitted to the hospital for symptomatic congestive heart failure have relatively preserved or normal left ventricular systolic function. It is assumed that some degree of abnormality in diastolic function contributes to the presentation of these patients and, indeed, predicts decompensation. Knowing that well over 5 million patients in North America alone have heart failure makes, then, the importance of this syndrome high. The debate about syndrome nomenclature has been entertaining. Should we be referring to the difficulty as “diastolic heart failure” or “heart failure in the setting of preserved left ventricular systolic function”? Doctors Klein and Garcia are not shy about their opinion of facts, as the title of the text indicates. Diastolic dysfunction can be defined as the inability of the heart to perform adequately under a normal filling pressure, and this generally results in impaired exercise tolerance resulting from varying combinations of inadequate forward cardiac output and elevated left ventricular end-diastolic pressure. Perhaps the most
important intrinsic left ventricular abnormality is slowing of the rate of left ventricular relaxation and increased stiffness of the chamber. The nuances of this finding and, indeed, the spectrum of definitions are well characterized and addressed in this text. Recognition of the importance of diastolic heart failure has been relatively recent, but there is now a large spectrum of data that gives us more precise information regarding the pathophysiology, epidemiology, and prognosis, and there are even a few recent trials studying therapy in these patients. Perhaps the latter is the most disappointing with little to guide us regarding the best approaches for reducing the substantive morbidity and mortality seen with this syndrome. Again, Doctors Klein and Garcia and their contributing authors are to be applauded for their thorough review of the current knowledge base regarding diastolic dysfunction and heart failure in the setting of preserved or relatively normal left ventricular systolic function. This text will capture the interests of clinicians, clinical investigators, and basic scientists interested in gaining insight into heart failure more generally. James B. Young, MD Chairman, Medicine Division Professor and Chairman George and Linda Kaufman Chair Cleveland Clinic Cleveland, Ohio
xiii
Foreword
In the past two decades, there have been remarkable advances in our appreciation of how cardiac diastolic function is important for patient well being. My first encounter with this occurred as a fellow in training in the early 1980s, when in Baltimore we were seeing so many elderly, predominantly females, with hypertension and hypercontractile left ventricles—but the seemingly paradoxical presentation with heart failure. It is interesting to reflect back on how ignorant we were back then with respect to the primacy of cardiac filling and relaxation and how far we have come since that time. In this book, the field of diastolic function and dysfunction is fully dissected. All of the major intersecting processes, such as hypertension, coronary artery disease, pericardial disease, valvular abnormalities, diabetes, and so many others, are tackled. The recent surge in the use of biventricular “resynchronization” and atrio-ventricular optimization has markedly accentuated the role of the interaction of systole and diastole in clinical practice—and we still have much to learn in selecting patients who will benefit from this “big ticket” technology. The simple notion that ideal patients would have a markedly dilated heart with left bundle branch block certainly has not held up for long. Our enhanced understanding of ventricular interaction and diastole, per se, should make a difference. New and improved imaging modalities
xiv
such as tissue Doppler imaging and strain rate imaging have given us a keener ability to quantify and differentiate “normal” and abnormal diastolic function. A variety of new indices, methods, and innovative imaging tools including torsion imaging will undoubtedly help illuminate the field in the years ahead. The book is as good as it gets in laying out a comprehensive assessment of where we are and where we are going in the comprehensive field of diastology. Drs. Klein and Garcia and the superb group of authors they have engaged have done quite an exceptional job in providing a panoramic view of a very dynamic field. Cardiologists in training, those in practice who have an interest in cardiac physiology, and virtually all academic cardiologists and sonographers who want to enhance their understanding of the implications of cardiac relaxation and filling will benefit from this fine contribution to cardiovascular medicine. Eric J. Topol, MD Professor of Translational Genomics, TSRI Director, Scripps Translational Science Institute Chief Academic Officer, Scripps Health Senior Consultant, Division of Cardiovascular Diseases Scripps Clinic La Jolla, California
Preface
A 65-year-old woman with hypertension presents to the emergency room with shortness of breath. Chest x-ray shows interstitial edema, and two-dimensional and Doppler echocardiography demonstrate an ejection fraction of 60%, concentric left ventricular (LV) hypertrophy, atrial enlargement, and stage 2 (moderate) LV diastolic dysfunction. The brain natriuretic peptide level is elevated at 800 pg/dl. This prototypic patient has evidence of classical diastolic heart failure, which is the inability to fill the left ventricle with normal filling pressures. This timely book addresses how diastolic heart failure is diagnosed and treated. It also comprehensively discusses the general principles of diastolic dysfunction, including the molecular biology, hemodynamics, epidemiology, clinical presentation, and principles of treatment. The contents of this book are targeted to a broad audience encompassing noninvasive and invasive cardiologists, physiology scientists, cardiology fellows, and cardiac sonographers. Multiple cardiovascular disorders cause diastolic dysfunction and subsequent diastolic heart failure. There is a raging controversy about whether diastolic heart failure exists as an independent entity or whether it is always accompanied by systolic dysfunction in the setting of a normal ejection fraction. In this book, we have elected to use the term diastolic heart failure; however, we recognize that systolic-ventricular interaction and arterial stiffening can definitely play a significant role in causing symptoms of heart failure in these patients. Why study diastolic heart failure? The answer is that a complete understanding of the pathophysiology of LV filling is essential to managing the patient with congestive heart failure syndromes. There has been a tremendous interest in diastology during the past 50 years, with over 16,000 original manuscripts published during this period.
Historical Perspective Since the heart was determined to be a pump, most biologists and physicians have focused on the study of systolic function. However, as early as in the renaissance period, Leonardo da Vinci described that the lower cardiac chambers of the heart filled with blood by drawing it from the upper chambers. In the 1940s, Carl J. Wiggers proposed the term inherent elasticity to describe the passive properties of the heart. In the 1970s, cardiac physiologists assessed the properties of active ventricular relaxation and passive filling using invasive quantification of intracavity pressure and volume. During the following decade, clinicians recognized that diastolic heart failure was an important cause of congestive heart failure, and Doppler echocardiography emerged as an important noninvasive method to assess the diastolic filling properties of the heart. The term “diastology” was coined in the early 1990s; imaging modalities, such as Doppler tissue imaging, color Mmode Doppler, and magnetic resonance imaging (MRI), advanced
our understanding of diastolic function. Over the past 10 years, new techniques and indices for assessing diastolic function have continued to evolve. Recent epidemiology-based studies have shown that diastolic heart failure is increasing in prevalence and that it is as common as systolic heart failure and just as fatal. In the past 5 years, there has been a shift from research in developing diagnostic techniques to large-scale clinical trials to determine targeted treatment for patients with diastolic heart failure.
Our Interest in the Field In the late 1980s, Allan Klein started his interest in this field as a Canadian Heart Foundation fellow at the Mayo Clinic studying Doppler assessment of LV filling during acute myocardial infarction and after reperfusion. His first impression was that the quick bedside echocardiographic evaluation, including the mitral E/A ratio and deceleration time, was a simple but powerful measure of LV diastolic filling, relaxation, and prognosis. Also, he was struck by how the stages of diastolic filling related to the clinical exam, including the extra heart sounds (S3 and S4). As a student of the field, he also learned that the study of diastolic function was more complex than the simple analysis of the mitral E/A ratio. During his training, Dr. Klein was very fortunate to have excellent mentors, including Liv Hatle, Jamil Tajik, and James Seward. Dr. Mario Garcia developed his interest in the field while at the Cleveland Clinic in the early days of tissue Doppler echocardiography, color M-mode Doppler, and strain rate imaging. His clinical observations and hemodynamic validation of early annular velocities (Em) and the slope of the flow propagation (Vp) as well as the relationship of mitral early filling/annular e wave (E/Em) and mitral early filling/flow propagation slope (E/vp) as measures of LV filling pressure were important for the advancement of the field. Their interest led to many diastology symposiums where leaders congregated in Cleveland, Ohio, and Scottsdale, Arizona, to discuss their advances. These summits sparked our interest to publish a state-of-the-art book on diastology.
Contents of the Book This book is organized into five main sections: basic determinants, diagnosis, specific cardiac diseases, emerging topics, and treatment. It includes a comprehensive analysis of the major areas of knowledge in this field from the molecular, genetic, and cellular mechanisms to clinical presentation and treatment of diastolic heart failure. This book discusses conventional and newer methods of diagnosis, including two-dimensional and Doppler echocardiographic techniques as well as cardiac MRI. An important practical chapter of how to actually perform a diastolic function examination written by one of the leading cardiac sonographers in the field xv
xvi
Preface is also included. A review of the prototypical diseases that manifest diastolic dysfunction, including hypertension, coronary artery disease, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and pericardial diseases, provides an important clinical perspective. Newer topics that are addressed include the role of neurohormones, pacing, aging, and vascular cardiac interactions in diastolic heart failure. Finally, the general treatment, echocardiographic guided therapy, and ongoing clinical trials are covered in depth by the leading experts in the field. In the past, treatment of heart failure has focused purely on the treatment of systolic heart failure. However, there have been an increasing number of clinical trials, including The Candesartan in Heart Failure, Assessment of Reduction in Mortality and Morbidity (CHARM) preserved trial, the Perindopril for Elderly Patients with Chronic Heart Failure (PEP-CHF) trial, as well as
ongoing studies, including the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) and the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trials, that address the treatment of diastolic heart failure. The importance of new drugs including endothelial receptor antagonists and glucose cross-link breakers that evaluate the targeted treatment of diastolic heart failure is also reviewed in this book. Finally, it is important to recognize that the field of diastology is a fast-moving target and we have tried to be as current as possible while also avoiding overlap in the chapters. We surely hope that you enjoy this exciting book. Allan L. Klein Mario J. Garcia
Acknowledgments
We would like to thank Marilyn, Jared, Lauren, and Jordan Klein and Cheryl, Melinda, and Olivia Garcia as well as our parents for their encouragement and support while editing this book. We especially would like to express our thanks to Marie Campbell, who helped and guided us in the journey of putting this book together. Finally, we would like to express our gratitude to the editors of Elsevier for their guidance in making this book a great success.
xvii
1
AMBEREEN QURAISHI, MD JAMES P. MORGAN, MD, PhD
Molecular, Gene, and Cellular Mechanisms INTRODUCTION PATHOPHYSIOLOGY Excitation-Contraction and RepolarizationRelaxation Coupling The Failing Human Heart Abnormal Calcium Regulation in Heart Failure Sarcolemmal Receptors and Mechanisms Sarcoplasmic Reticulum Altered Calcium Responsiveness of Myofibrillar Tension TREATMENT, GENE THERAPY, AND THE FUTURE
INTRODUCTION Heart failure is an ancient diagnosis. Some of the earliest known descriptions are attributed to Hippocrates, circa 460–370 bce. He reported dozens of clinical case histories with examples of dyspnea, as seen in left heart failure, and dropsy, as seen in right heart failure.1 Over the centuries, it has become apparent that the symptoms of heart failure are the result of complex pathophysiologic processes that alter both anatomic and physiologic properties of the heart. In the United States alone, approximately 5 million people are afflicted by heart failure, with an annual incidence of 500,000 new diagnoses and 300,000 deaths.2,3 One third of patients with symptomatic heart failure have a normal ejection fraction, and only in the last decade has there been a shift in the paradigm, focusing attention on diagnosing and understanding diastolic dysfunction. In many cases, diastolic dysfunction is caused by one or more abnormalities of cardiac structure, such as hypertrophy, fibrosis, infiltrative disease, or pericardial constriction. However, many patients appear to have diastolic dysfunction due to cellular abnormalities of myocyte relaxation, which is reversible and transient and occurs mainly in the setting of ischemia or hypoxia. Other causes include cellular calcium overload or ATP depletion.
Metabolic processes such as alkalosis, cardiovascular drugs, and the hypertrophy process itself can also alter the contractile and metabolic phenotype.4 This chapter will focus on the cellular mechanisms of normal and impaired myocardial relaxation. Calcium plays a crucial role in this process. Its movement into the cytosol, caused by excitation at the surface membrane, stimulates contraction. This physiologic phenomenon is appropriately termed excitation-contraction coupling. The reverse of this process, which is dependent on the movement of calcium and sodium, can be thought of as repolarization-relaxation coupling.4 In normal hearts, sympathetic stimulation can increase contractility by exerting a positive inotropic effect as part of the excitation-contraction (E-C) process and can also increase the rate of relaxation, a positive lusitropic (relaxation-enhancing) effect, by facilitating Ca2+ removal from the sarcoplasm. Myocyte control of relaxation occurs through the regulation of calcium concentrations within the cytosol via four main pathways involving sarcoplasmic reticulum (SR) Ca2+ATPase, sarcolemmal Na+/Ca2+ exchange, sarcolemmal Ca2+ATPase, or mitochondrial Ca2+ uniport.5 The latter two pathways have been studied and appear to have no significant effect on the beat-to-beat regulation of intracellular calcium.6,7 We will discuss the other two mechanisms in detail along with myofibrillar calcium responsiveness, as much research is being directed in trying to develop novel therapeutic interventions targeted toward repolarization-relaxation coupling in an effort to maximize positive lusitropic effects.
PATHOPHYSIOLOGY Excitation-Contraction and RepolarizationRelaxation Coupling The E-C coupling process activates contraction by coupling the signal generated by the action potential (excitation) at the myocyte cell surface to the delivery of calcium into the cytosol that initiates contraction.1 After spontaneous depolarization of the surface membrane, Ca2+ enters the myocyte through voltage-gated L-type channels (which are dihydropyridine receptive and will be referred 3
Ch001-X3754.indd 3
1/17/2008 6:02:21 PM
4
Chapter 1 • Molecular, Gene, and Cellular Mechanisms to as DHRs). This influx serves as a trigger for the release of stored Ca2+ from the SR via Ca2+ release channels called ryanodine receptor 2 (RyR2). This process is known as calcium-induced calcium release (CICR).8,9 The transverse tubule system, unique to the mammalian heart, allows for the close proximity of the DHRs to clusters of RyR2. The initial influx of calcium through L-type channels activates the RyR2 channels within its domain in a synchronized fashion, spontaneously increasing local concentration of calcium and producing a Ca2+ spark (named according to its appearance by confocal microscopy), which can also be thought of as a local Ca2+ transient.10 During E-C coupling, several thousand Ca2+ sparks occur in synchrony, overlapping in time and space, thus allowing for a global and uniform calcium transient that is sufficient for myocardial contraction. Another channel within the SR membrane, inositol triphosphate, has been reported to induce the release of calcium, but the rate and extent of release is much lower, and it is not triggered by CICR. It is important to understand the cardiac contractile apparatus from the vantage point of troponin-C, the Ca2+ receptor protein. When cytosolic calcium levels are low, there is minimal or no calcium bound to troponin-C. The troponin-tropomyosin complex inhibits the formation of the actomyosin complex. Once calcium is released from the SR, Ca2+ binds to troponin-C, changing the configuration of the troponin-tropomyosin complex, removing the inhibition of the actin-myosin interaction, and thus allowing cross-bridge cycling and contraction. Another important messenger that modulates E-C coupling is cyclic adenosine monophosphate (cAMP). This pathway is initiated by activation of the β-adrenergic receptors, which then activate adenylate cyclase and generate cAMP. This nucleotide activates a series of phosphorylating enzymes (i.e., protein kinases). Protein kinase A (PKA) binds to A-kinase anchoring proteins (AKAPs)11,12 and phosphorylate calcium regulatory proteins at multiple subcellular sites. Phosphorylation of both the voltagegated L-type channels and RyR2 channels (Ca2+ release channels) leads to a net effect of increased Ca2+ entry and a greater calcium release (a function of the amount of Ca2+ stored) from the SR, producing an increase in the rate and magnitude of force generation (positive inotropic effect).13 This is balanced by the phosphorylation of phospholamban on the SR, which regulates the sarcoendoplasmic reticulum Ca2+ (SERCA)-ATPase pump and allows for greater reuptake of calcium from the cytosol, enhancing the rate of relaxation (positive lusitropic effect). Finally, the phosphorylation of troponin-I, part of the regulatory complex of the contractile apparatus, facilitates the dissociation of calcium from troponin-C by altering the myofilament calcium sensitivity, also causing a positive lusitropic effect. These changes increase the amplitude of the systolic Ca2+ transient and decrease its duration, thus increasing myocyte contractility and generation of force. When the β-adrenergic pathway is activated in times of increased cardiac output demand, there is an increased heart rate and simultaneous increase in force (positive force frequency)14 and an increase in rate of relaxation, which ensures that sufficient calcium is available from the SR for the next beat.
The Failing Human Heart In the failing human heart, adrenergic effects are blunted.13 Numerous studies of mammalian heart models have been done to better understand the mechanism that leads to abnormal adrenergic signaling. The normal human atrial and ventricular myocardium expresses β1- and β2-adrenergic receptors at a ratio of about
Ch001-X3754.indd 4
70:30.15 In the early stages of heart failure, there is an increase in sympathetic stimulation in order to maintain adequate blood pressure and cardiac output. As the syndrome progresses, the continuous activation eventually leads to a downregulation of β1 receptors by almost 60% to 70% and desensitization of the remaining receptors, which depresses cAMP levels, hence contributing to altered calcium regulation and reducing intracellular calcium levels.16–18 The overall effect is a depressed and negative force-frequency relationship. In vitro studies of nonfailing and failing human myocytes have been done of contractility under varying conditions (i.e., varying muscle length and loading conditions as seen with pressure or volume changes in vivo, slow rates, [Ca2+], and catecholamine stimulation).19,20 These studies concluded that during basal conditions, the contractile properties of normal and failing myocytes is similar. Conversely, the same is not true during increased inotropic stimulation. The normal myocyte is able to increase force generation, but in failing myocytes, the developed force either decreases or remains unchanged. Therefore, during low workload states, contractility is preserved, but “contractility reserve” (the ability to increase contractility with heart rate or sympathetic stimulation) is severely reduced in failing myocytes.13 The proposed mechanism at this time is that the amount of calcium that is released by the SR of failing myocytes is less than in normal myocytes, which may be due to decreased SR Ca2+ stores or abnormal SR Ca2+ loading21; however, there is a need for more investigational studies to fully understand the mechanisms behind the E-C coupling defects that contribute to dysfunctional Ca2+ handling.
Abnormal Calcium Regulation in Heart Failure Abnormal modulation of intracellular calcium is a major mechanism that underlies both systolic and diastolic dysfunction and develops with cardiac hypertrophy and failure. The heart spends more than half of its time in diastole (i.e., relaxation and filling), yet there is controversy in the definition of diastolic dysfunction and diastolic heart failure. Abnormal calcium regulation comprises a spectrum of changes that include slowed force (or pressure) decline and cellular re-lengthening (increased ventricular stiffness), increased (or decreased) early filling rates and deceleration, an elevated diastolic pressure-volume relationship, and a filling-rate–dependent pressure elevation (increased end-diastolic pressure).22 These changes occur due to abnormal regulation of Ca2+ homeostasis within the myocyte. Although the cellular and molecular regulation of calcium in failing myocardium has been studied, the exact mechanism of abnormal calcium regulation is still not well understood (Fig. 1-1). Normally, the systolic calcium transient occurs with the release of calcium from the SR, which is triggered by the L-type channel Ca2+ influx. The magnitude of calcium release is dependent on the Ca2+ influx and the amount of calcium stored in the SR.23 Calcium reuptake is mediated by the SR Ca2+-ATPase pump and the sarcolemmal Na+-Ca2+ exchanger (NCX), which results in the decay of the Ca2+ transient and normal relaxation. In failing myocytes, there are numerous changes (e.g., expression levels of these membrane proteins), which result in abnormal Ca2+ transient, particularly in its termination. This also causes a prolonged action-potential duration and delayed relaxation. At slow pacing rates, the Ca2+ transients of normal and failing myocytes are very similar. However, when the heart rate increases, the Ca2+ transient becomes significantly different due to a negative force-frequency relationship and decreased SR Ca2+ release, as discussed earlier.
1/16/2008 2:31:17 PM
Chapter 1 • Molecular, Gene, and Cellular Mechanisms
B-ar
P
5
NCX LTC Na+
cAMP 2 1
P
Figure 1-1 Major Cellular Mechanisms of Diastolic Dysfunction. 1. Inhibition of cyclic AMP (cAMP) formation via adenylate cyclase. cAMP mediates phosphorylation of SERCA2 and the myofilaments, which reduces Ca2+ uptake and increases myofilament Ca2+ responsiveness (MyoCAr), respectively. Ca2+ entry via the L-type Ca2+ channels (LTC) is also increased. 2. Enhancement of Na+/Ca2+ exchange. 3. Blockade of reuptake of Ca2+ by SERCA2 by non–cAMPdependent mechanisms. 4. Decreased myofilament Ca2+ responsiveness by non–cAMP-dependent mechanisms. B-ar, β-adrenergic receptor; p, phosphorylation site; SR, sarcoplasmic reticulum.
Ca2+
SERCA2 SR Re-uptake X3 Released Ca2+ Ca2+
Sarcolemmal Receptors and Mechanisms The cardiac sarcolemma is a complex structure that contains multiple channels, exchangers, and pumps that are necessary for normal E-C coupling and myocyte contraction. In recent years, the sarcolemmal NCX has surfaced as one of the primary agents necessary to extrude calcium with each heart beat to allow normal relaxation. By virtue of the NCX mechanism, the role of the electrochemical sodium gradient has also been studied in various mammalian species as a potential determinant of [Ca2+]i.24,25 The NCX is a bidirectional electrogenic ion transporter that utilizes the Na+ electrochemical gradient to exchange one calcium for three sodium ions. During repolarization, the negative membrane potential and elevated [Ca2+]i drive the NCX toward a forward mode (Na+ in/Ca2+ out), resulting in extrusion of calcium from the cell in diastole. When the membrane potential is positive ([Na+]i is increased), the NCX functions in reverse mode (Na+ out/Ca2+ in), resulting in calcium influx, which may help regulate SR Ca2+ load and also, in conjunction with the Ca2+ current induced by activated DHRs, regulate SR Ca2+ release.21,26 There still remain some conflicting data in regard to the effects of CICR on SR by the reverse mode INaCa. CICR occurs mainly in the dyadic cleft space in the T-tubular regions.27 Several studies using the detubulation method in rat ventricular myocytes concluded that a majority of the NCX was localized to the T-tubules.28 However, Scriven et al. studied the distribution of these proteins using high-resolution imaging and showed that the NCX was localized to areas outside of the dyadic cleft space and that the spatial proximity of DHR with RyR2 was higher than with NCX29; therefore, any triggered SR Ca2+ release by the reverse mode INaCa seems highly inefficient.30 Several animal models with myocyte hypertrophy demonstrated elevated [Na+]i compared with normal. Pieske and Houser measured [Na+]i in failing and nonfailing human myocytes using multiple techniques and were the first to report elevated [Na+]i levels in failing human myocytes.24 The exact mechanism of this is under further investigation. Several studies have tried to describe the processes that lead to Na+ influx in the failing
Ch001-X3754.indd 5
Ca2+
X
4
“MyoCar”
Myofilaments
myocyte and the role of this influx in governing calcium homeostasis. One proposed mechanism suggests that sodium influx occurs through sodium channels and raises levels within the Na+ microdomain activating the NCX in reverse mode (Ca2+ influx), which is complementary to the influx generated by L-type calcium channels. Because the NCX is dependent on the Na+ electrochemical gradient for functioning, any changes that occur in sodium regulation in heart failure, when taken to an extreme, can result in [Ca2+]i overload and diastolic dysfunction. Few studies have addressed the role of the Na+-H+ exchanger in failing myocytes, which has a 1:1 stoichiometry of Na+ influx for H+ efflux. Its stimulation may be increased in heart failure and lead to elevated [Na+]i. Decrease in intracellular pH (which increases H+) can also increase Na+ by means of the Na+-H+ exchanger, secondarily increasing Ca2+ by means of the NCX. Alteration of these exchanges may contribute to prolongation of the action potential, slowed decay of the Ca2+ transient, and a delayed relaxation in failing myocardium. Several models of heart failure and hypertrophy have also shown an increase in expression of NCX,31,32 which may be partially controlled by the decreased sympathetic stimulation, leading to decreased SERCA activity.33 Terraciano et al.25,34 showed that in myocytes from transgenic (heterozygous) mice with upregulation of NCX, there was an increase in reverse-mode function resulting in an increase in SR calcium stores compared with wildtype myocytes. It is important to remember that in smaller mammals (mice and rats), the action potential is shorter than the duration of the calcium transient, which means that repolarization is occurring during most of the calcium transient, favoring forwardmode NCX.35 In these species there are lower levels of NCX, so any efflux via NCX makes a very small contribution to the decay of the calcium transient, even when overexpressed.20 However, there is a high [Na+]i in smaller mammals,36 favoring Ca2+ entry by reverse mode during the latter part of the calcium transient, which becomes more pronounced in myocytes overexpressing NCX, explaining the findings reported by Terraciano’s group. In normal human myocytes, the action-potential duration is prolonged, and SERCA release and reuptake occur during the
1/16/2008 2:31:17 PM
6
Chapter 1 • Molecular, Gene, and Cellular Mechanisms plateau phase, when NCX is not in forward mode, indicating that most of the elimination of cytosolic calcium is dependent on reuptake by the SERCA pump. However, in failing myocardium, the interaction between these two proteins changes due to an increase in the ratio of NCX to SERCA levels. To better understand whether increased NCX activity in the setting of reduced SERCA activity affects diastolic function, a study discriminating failing human hearts into three groups based on diastolic dysfunction with increased stimulation rate was performed.37 The investigators discovered three different phenotypes with varying expression of SERCA and NCX with impaired systolic function, but the overall trend in the ratio of NCX to SERCA was an increase by a factor of 2 to 4 in all groups of failing myocytes compared with normal. The phenotypes at either end of the spectrum ranged from increased levels of NCX and unchanged SERCA levels (group I) to decreased levels of SERCA and unchanged NCX levels (group III). Only the latter phenotype demonstrated both systolic and diastolic dysfunction, suggesting that both SR calcium uptake and the capacity to eliminate calcium from the cytosol are impaired, whereas in group I, the SR calcium uptake is impaired (causing systolic dysfunction), and global capacity to eliminate calcium is higher (preserving diastolic dysfunction). Therefore, the overexpression of NCX has positive correlation with diastolic function in failing myocytes.
Sarcoplasmic Reticulum The SR is an intracellular structure that is the most important store of calcium in the mammalian heart. The sarcoplasmic membrane proteins (RyR2 and SERCA) maintain a tight control of calcium release and uptake in E-C coupling, contractility, and relaxation. There is a 10,000-fold Ca2+ gradient maintained across the SR membrane by the SR Ca2+-ATPase pump.38 Molecular analysis has identified three homologous genes (SERCA1, SERCA2, and SERCA3) encoding the SERCA pumps. The SERCA2 gene is spliced into four variants that encode the isoforms. SERCA2a is the primary isoform expressed in cardiac muscle39 at high levels; however, there are regional differences, age-related effects, and variation due to thyroid hormone levels that affect expression levels. Experimental models in animals and humans have demonstrated that the expression level of SERCA in the atrium versus the ventricle is twofold and may account for shorter contraction time in atria versus ventricles.40 In fact, in heart failure models, it is well established that defective SR Ca2+ uptake correlates with decreased contractility, which could be attributed to significant decline in SERCA protein levels or an alteration in SR Ca2+ transport function.41 Several studies induced left ventricular pressure overload hypertrophy/failure in rats by thoracic aortic banding and consistently found an overall decrease in SERCA mRNA levels,42–44 suggesting that downregulation of SERCA2a gene expression in these models partly occurs at the transcriptional level.38 Feldman et al. also deduced that decreased SERCA mRNA levels could be a marker of transition from compensated hypertrophy to decompensated hypertrophy/failure.43 In human heart models, SERCA mRNA levels are reduced in failing compared with nonfailing hearts, yet there remains controversy regarding simultaneous decrease in SERCA protein expression.29 Recently, data from larger studies have successfully shown a reduction of SERCA protein levels in failing human hearts, but not in compensated hypertrophied human hearts, suggesting that perhaps a decrease in protein level is a sign of developing failure.6,45,46 A decrease in
Ch001-X3754.indd 6
SERCA2a expression at the level of mRNA or protein is inversely related to duration of cardiac contraction,47–49 correlates with decreased myocardial function, alters the force-frequency response,50 and may also slow the velocity of relaxation, suggesting the importance of SERCA pump level in maintaining myocardial function. Yet it is still difficult to describe the actual relationship between cardiac muscle and the SERCA pump because of the complexity of its regulation and all the changes in other calcium-regulating proteins (such as NCX) that occur in concert with each other within the myocyte and the heart as the syndrome of heart failure progresses. The SERCA pump is modulated by both direct and indirect factors. Phospholamban is the primary indirect regulator that activates the SERCA2a pump. In its dephosphorylated state, phospholamban inhibits SERCA2a affinity for calcium. The phosphorylation of phospholamban can occur at three different sites—serine-16 by cAMP-dependent PKA, threonine-17 by Ca2+/calmodulin-dependent protein kinase II, and serine-10 by Ca2+-activated phospholipid-dependent protein kinase.34 When phospholamban is phosphorylated by cAMP-dependent PKA (the most important mediator), the inhibitory effect is removed and the calcium affinity (not the maximal velocity of SERCA2a) increases, resulting in enhanced relaxation and an increase in SR Ca2+ load. Ca2+/calmodulin-dependent protein kinase II (CaMK II) is the other modulator, which directly phosphorylates SERCA2 and increases Vmax (maximal activity) without altering the calcium affinity of SERCA2.51 CaMK II also phosphorylates the threonine-17 site in phospholamban, which also increases the calcium affinity of SERCA2a. In heart failure, the blunting of the β-adrenergic pathway leads to alteration not only in phosphorylation of phospholamban at the serine-16 site, but also in CaMK-dependent phosphorylation, ultimately altering SERCA2a activity. Most studies of human heart failure have suggested that although there is a decrease in phospholamban mRNA levels, there is no difference in protein expression between failing and nonfailing myocytes.52,53 Therefore, protein expression of SERCA2a in relation to phospholamban is always diminished in heart failure, which may explain the increased phospholamban-to-SERCA2a ratios, leading to an increase in inhibition of the SERCA2a pump and an overall decrease in its basal activity level and contributing to abnormal calcium handling.
Altered Calcium Responsiveness of Myofibrillar Tension Cardiac contractility and relaxation are altered not only because of changes in calcium availability, but also because of changes in myofilament responsiveness to calcium. In fibers rendered hypermeable to Ca2+, a change in responsiveness can manifest as either a change in sensitivity or potency or as maximal Ca2+-activated force. The actual mechanism responsible for this effect has not been definitively determined, but based on numerous studies, it appears that isoform composition and phosphorylation status of the contractile proteins are altered, which increases the Ca2+ sensitivity of the contractile apparatus in end-stage heart failure. Most studies have concentrated on changes of a single factor. Van der Velden et al.54 focused on a combination of contractile protein changes that occur during heart failure by studying isometric force and its Ca2+ sensitivity in left ventricular myocytes from nonfailing and end-stage failing donor hearts. They concluded that the combined decrease in phosphorylation status of
1/16/2008 2:31:17 PM
Chapter 1 • Molecular, Gene, and Cellular Mechanisms troponin-I and myosin light chain 2 resulted in an increase in Ca2+ sensitivity, and not due to contractile protein isoform change. However, other studies have shown that the phosphorylation of myosin light chain 2 increases Ca2+ responsiveness.55 Earlier reports showed that end-stage heart failure in humans is not associated with myofibrillar Ca2+ sensitivity.56–58 Until now, no real consensus has been reached to explain if, why, and how Ca2+ sensitivity increases in heart failure patients. Therapeutically, Ca2+ sensitizers pose a problem due to the mechanism of action. An increased affinity of Ca2+ for troponin-C would enhance the actin-myosin interaction, which, theoretically, prolongs relaxation. This has been shown in vivo and in vitro in animals and in humans.57
TREATMENT, GENE THERAPY, AND THE FUTURE Congestive heart failure is a leading cause of morbidity and mortality in the United States. The remodeling process that occurs after myocyte injury from multiple causes leads to contractile dysfunction and abnormal intracellular calcium handling, which delays normal relaxation, as discussed in detail thus far. Although there is no universal agreement regarding the mechanisms, it is generally accepted that calcium handling is altered in failing hearts. The NCX and the SERCA2a pump are the two main players that regulate cytosolic calcium levels during relaxation on a beat-to-beat basis. Therefore, multiple studies using gene transfer methodologies are exploring the overexpression of these two mechanisms that could potentially return calcium handling to normal, as most of the conventional therapies that we currently offer utilize mainly multiple medications, the actions of which are not completely understood.59 The sodium-calcium exchanger is a complex transport protein that functions in reverse and forward modes. In normal mice myocytes, it is the most dominant Ca2+ efflux mechanism that helps maintain calcium homeostasis.60 In humans, only 25% of the calcium is extruded by the NCX, and the other 75% is removed by SERCA2a pumps.61 Some models of heart failure have described an increase in expression of NCX in response to the pathologic decrease in SERCA2a pumps attributed to the delayed and smaller Ca2+ transient.14 This is felt to be a compensatory mechanism for the decreased efficiency of SR calcium re-uptake. Because the actual quantitative contribution of the two regulatory mechanisms under pathologic conditions is poorly understood, so is the relationship between the changes in protein expression and the functional consequences.34 Terraciano et al. noted that the degree of compensation that may be achieved with a two- to threefold increase of NCX, the same measured in failing human hearts, has not been tested.34 They compared transgenic mice overexpressing NCX with nontransgenic mice and confirmed that a reduction in SERCA2a function can be compensated by overexpression of NCX. A 2.4-fold increase in the function of NCX compensated for a 28% reduction in SERCA2a and maintained Ca2+ transient. Although these findings may not necessarily be extrapolated to human hearts, it is a starting point for understanding such mechanisms and developing future therapies. The expression of SERCA2a pump level has also been an increasing area of interest given its central role in SR Ca2+ handling. Several models utilizing in vitro adenoviral-mediated gene transfer have been created to express varying levels of SERCA2a, which has allowed for a better understanding of the role of SERCA2a pump levels in maintaining Ca2+ homeostasis and
Ch001-X3754.indd 7
7
cardiac function.62–64 As discussed earlier, decrease in SERCA2a activity and/or expression has been identified as one of the major defective mechanisms responsible for impaired relaxation. By disrupting the SERCA2a gene using homologous recombination, Periasamy et al.65 obtained a better understanding of how the pathologic decrease in SERCA2a pump levels can alter cardiac function. In homozygous mice, the outcome was lethal. Heterozygous mice were able to function, but the Vmax of SR Ca2+ uptake was decreased by 35%. The peak amplitude of the Ca2+ transients in normal heterozygous myocyte was decreased by more than 30%, which led to a decrease in the maximal rate of contraction and relaxation, as confirmed by measurements obtained via transducers in the left ventricles and right femoral arteries of anesthetized mice. These findings prove that there is a direct relationship between SERCA2a level and cardiac contractility. Therefore, recent studies have used the adenoviral-mediated gene transfer to increase SERCA2a pump activity as a potential means for therapy. Hajjar et al.66 showed that increased expression of SERCA2a in rat myocytes led to increased contractility and faster decay of the Ca2+ transient. The question remained in the ability to restore function in failing human myocytes. Del Monte et al.67 addressed this very question by isolating human cardiomyocytes from the left ventricles of 10 patients with end-stage heart failure. Gene transfer of SERCA2a led to an increase in protein expression and pump activity, induced a faster contraction velocity, and enhanced relaxation velocity, thus reversing contractile abnormalities of the failing heart. Although the results were promising in the in vitro model, this method did not predict the outcome in vivo. Hajjar and colleagues used a catheter-based technique of gene transfer to allow for global overexpression of SERCA2a in an animal model of pressure-overload hypertrophy in transition to failure. SERCA2a overexpression restored both systolic and diastolic dysfunction to normal levels, decreased left ventricular size, and restored the slope of the end-systolic pressure-dimension relationship to that of control levels.68 The SERCA gene therapy studies described above demonstrate not only that it is possible to increase the expression of SERCA protein but that its effects can normalize the abnormalities of calcium handling and contraction. However, this raises several important concerns, such as the long-term effects of inducing these changes, impacts on the phospholamban and SERCA interaction, and the effect on the NCX. As heart failure continues to pose a major clinical challenge for patients and physicians, the limitations of current treatment modalities are reflected in the grave statistics of minimal improvement in overall mortality within the last century. Gene transfer targeted toward specific pathways in the failing human heart is a novel therapeutic option that can potentially reverse the abnormalities of diastolic dysfunction and transform heart failure into a chronic survivable condition.
REFERENCES 1. Katz AM: Heart failure: Pathophysiology, molecular biology, and clinical management. Philadelphia, Lippincott Williams & Wilkins, 2000:6. 2. Owan TE, Redfield MM: Epidemiology of diastolic heart failure. Prog Cardiovasc Dis 2005;47:320. 3. Hunt HA, Baker DW, Chin MH, et al: ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee to revise the 1995 guidelines for the evaluation and management of heart failure). Circulation 2001;104: 2996–3007.
1/16/2008 2:31:17 PM
8
Chapter 1 • Molecular, Gene, and Cellular Mechanisms 4. Apstein CS, Morgan JP: Diastolic relaxation of the heart, 2nd ed. London, Lea and Febiger, 1994:3–24. 5. Bers DM: Cardiac excitation-contraction coupling. Nature 2002;415: 198–205. 6. Hasenfuss G, Pieske B: Calcium cycling in congestive heart failure. J Molec Cell Cardiol 2002;34:951–969. 7. Bassani RA, Bassani JWM, Bers DM: Mitochondrial and sarcolemmal Ca transport can reduce [Ca]i during caffeine contractures in rabbit cardiac myocytes. J Physiol (London) 1992;453:591–608. 8. Scoote M, Poole-Wilson PA, Williams AJ: The therapeutic potential of new insights into myocardial excitation-contraction coupling. Heart 2003;89: 371–376. 9. Fabiato A: Calcium induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 1983;245:C1–C14. 10. Cheng H, Lederer WJ, Cannell MB: Calcium sparks: Elementary events underlying excitation-contraction coupling in the heart muscle. Science 1993;262:740–744. 11. Bauman AL, Scott JD: Kinase- and phosphatase-anchoring proteins: Harnessing the dynamic duo. Nature (Cell Biol) 2002;4:E203–E206. 12. Fink MA, Zakhary DR, Mackey JA, et al: AKAP-mediated targeting of protein kinase A regulates contractility in cardiac myocytes. Circ Res 2001;88:291–297. 13. Houser SR, Margulies KB: Is depressed myocyte contractility involved in heart failure? Circulation 2003;92:350–358. 14. Gwathmey JK, Copelas L, MacKinnon R, et al: Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res 1987;61:70–76. 15. Lohse MJ, Engelhardt S, Eschenhagen T: What is the role of β-adrenergic signaling in heart failure? Circ Res 2003;93:896–906. 16. Brodde OE: β-adrenoreceptors in cardiac disease. Pharmacol Ther 1993;60:405–430. 17. Bristow MR: The adrenergic nervous system in heart failure. NEJM 1984;311:850–851. 18. Ungerer M, Bohm M, Elce JS, et al: Altered expression of β-adrenergic receptor kinase and β1-adrenergic receptors in the failing human heart. Circulation 1993;87:454–463. 19. Houser SR, Piacentino V 3rd, Mattiello J, et al: Functional properties of failing human ventricular myocytes. Trends Cardiovasc Med 2000;10: 101–107. 20. Houser SR, Piacentino V 3rd, Weisser J: Abnormalites of calcium cycling in the hypertrophied and failing heart. J Mol Cell Cardiol 2000;32: 1595–1607. 21. Pieske B, Maier LS, Bers DM, et al: Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium. Circ Res 1999;85:38–46. 22. Kass DA, Bronzwaer JGF, Paulus WJ: What mechanisms underlie diastolic dysfunction in heart failure? Circ Res 2004;94:1533–1542. 23. Bassani JW, Yuan W, Bers DM: Fractional SR Ca2+ release is regulated by trigger Ca2+ and SR Ca2+ content in cardiac myocytes. Am J Physiol 1995;268:C1313–C1319. 24. Pieske B, Houser SR: [Na+]i handling in the failing human heart. Cardiovasc Res 2003;57:874–886. 25. Blaustein MP, Lederer WJ: Sodium/calcium exchange: Its physiologic implications. Physiol Rev 1999;79:763–854. 26. Goldhaber JI, Scott TL, Walter DO, et al: Local regulation of the threshold for calcium sparks in rat ventricular myocytes: Role of sodium-calcium exchange. J Physiol (London) 1999;520(pt 2):431–438. 27. Reuter H, Pott C, Goldhaber JI, et al: Na+-Ca2+ exchange in the regulation of cardiac excitation-contraction coupling. Cardiovasc Res 2005;67: 198–207. 28. Kawai M, Hussain M, Orchard CH: Excitation-contraction coupling in rat ventricular myocytes after formamide-induced detubulation. Am J Physiol 1999;277:H603–H609. 29. Scriven DR, Dan P, Moore ED: Distribution of proteins implicated in excitation-contraction coupling in rat ventricular myocytes. Biophys J 2000;79:2682–2691. 30. Sipido K, Macs M, van de Werf F: Low efficiency of Ca2+ entry through the Na+-Ca2+ exchanger as triggers for Ca2+ release from the sarcoplasmic reticulum. A comparison between L-type Ca2+ current and reverse-mode Na+Ca2+ exchange. Circ Res 1982;50:651–662. 31. Hasenfuss G: Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res 1998;37:279–289. 32. Flesch M, Schwinger RHG, Schiffer F, et al: Evidence for functional relevance of an enhanced expression of the Na(+)-Ca2+ exchanger in failing human myocardium. Circulation 1996;94:992–1002.
Ch001-X3754.indd 8
33. Golden KL, Ren J, O’Connor J, et al: In vivo regulation of Na/Ca exchanger expression by adrenergic effectors. Am J Physiol (Heart Circ Physiol) 2001;280:H1376–H1382. 34. Terraciano CM, Philipson KD, MacLeod KT: Overexpression of the Na(+)/ Ca(2+) exchanger and inhibition of the sarcoplasmic reticulum Ca(2+)ATPase in ventricular myocytes from transgenic mice. Cardiovasc Res 2001;49:38–47. 35. Piacentino V 3rd, Weber CR, Gaughan JP, et al: Modulation of contractility in failing human myocytes by reverse-mode Na/Ca exchange. Ann NY Acad Sci 2002;976:466–471. 36. Hasenfuss G, Pieske B: Calcium cycling in congestive heart failure. J Molec Cell Cardiol 2002;34:951–969. 37. Hasenfuss G, Schillinger W, Lehnert SE, et al: Relationship between Na+Ca2+ exchanger protein levels and diastolic function of failing human myocardium. Circulation 1999;99:641–648. 38. Frank KF, Bölck B, Erdmann E, et al: Sarcoplasmic reticulum Ca2+-ATPase modulates cardiac contraction and relaxation. Cardiovasc Res 2003;57:20–27. 39. Zarain-Herzberg A, MacLennan DH, Periasamy M: Characterization of rabbit cardiac sarco(endo)-plasmic reticulum Ca2+-ATPase gene. J Biol Chem 1990;265:4670–4677. 40. Luss I, Boknika P, Jones LR, et al: Expression of cardiac calcium regulatory proteins in atrium v ventricle in different species. J Molec Cell Cardiol 1999;31:1299–1314. 41. Periasamy M, Huke S: SERCA pump level is a critical determinant of Ca2+ homeostasis and cardiac contractility. J Molec Cell Cardiol 2002;33: 1053–1063. 42. Dumas AR, Wisnewsky C, Boheler KR, et al: The sarco(endo)plasmic reticulum Ca2+-ATPase gene is regulated at the transcriptional level during compensated left ventricular hypertrophy in the rat. Academie des sciences 1997;320:963–969. 43. Feldman AM, Weinberg EO, Ray PE, et al: Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation in rats with chronic aortic banding. Circ Res 1993;73: 184–192. 44. Aoyagi T, Yonekura K, Eto Y, et al: The sarcoplasmic reticulum Ca2+ATPase (SERCA2) gene promoter activity is decreased in response to severe left ventricular pressure-overload hypertrophy in rat hearts. J Molec Cell Cardiol 1999;31:919–926. 45. Dash R, Frank KF, Carr AN, et al: Gender influences on sarcoplasmic reticulum Ca2+ handling in failing human myocardium. J Molec Cell Cardiol 2001;33:1345–1353. 46. Di Paola NR, Sweet WE, Stull LB, et al: Beta-adrenergic receptors and calcium cycling protein in non-failing, hypertrophied and failing human hearts: Transition from hypertrophy to failure. J Molec Cell Cardiol 2001;33:1283–1295. 47. Chen F, Ding S, Lee BS, Wetzel GT: Sarcoplasmic reticulum Ca(2+)ATPase and cell contraction in developing rabbit heart. J Molec Cell Cardiol 2000;32:745–755. 48. Gombosova I, Bokník P, Kirchhefer U, et al: Postnatal changes in contractile time parameters, calcium regulatory proteins and phosphatases. Am J Physiol 1998;274:H2123–H2132. 49. Cain BS, Meldrum DR, Joo KS, et al: Human SERCA2a levels correlate inversely with age in senescent human myocardium. J Am Coll Cardiol 1998;32:458–467. 50. Hasenfuss G, Reinecke H, Studer R, et al: Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+ATPase in failing and nonfailing myocardium. Circ Res 1994;75: 434–442. 51. Toyofuku T, Kurzydlowski K, Narayanan N, et al: Identification of Ser38 as a site in cardiac sarcoplasmic reticulum Ca2+-ATPase that is phosphorylated by Ca2+/calmodulin-dependent protein kinase. J Biol Chem 1991;266:11144–11152. 52. Schwinger RH, Böhm M, Schmidt U, et al: Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca2+-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with non-failing hearts. Circulation 1995;92:3220–3228. 53. Meyer M, Schillinger W, Pieske B, et al: Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation 1995;92:778–784. 54. Van der Velden J, Papp Z, Zaremba R, et al: Increased Ca2+-sensitivity of the contractile apparatus in end-stage human heart failure results from altered phosphorylation of contractile proteins. Cardiovas Res 2003;57: 37–47.
1/16/2008 2:31:17 PM
Chapter 1 • Molecular, Gene, and Cellular Mechanisms 55. Morano I, Arndt H, Gärtner C, et al: Skinned fibers of human atrium and ventricle: Myosin isoenzymes and contractility. Circ Res 1988;62: 632–639. 56. Hajjar RJ, Gwathmey JK, Briggs GM, et al: Differential effect of DPI 201– 206 on the sensitivity of myofilaments to Ca2+ in intact and skinned trabeculae from control and myopathic human hearts. J Clin Invest 1988;82:1578. 57. Wankerl M, Böhm M, Morano I, et al: Calcium sensitivity and myosin light chain pattern of atrial and ventricular stunned cardiac fibers from patients with various kinds of cardiac disease. J Molec Cell Cardiol 1990;22:1425. 58. D’Angelo A, Luciani GB, Mazzucco A, et al: Contractile properties and Ca2+ release activity of the sarcoplasmic reticulum in dilated cardiomyopathy. Circulation 1992;85:518–525. 59. Hoshijima M: Gene therapy targeted at calcium handling as an approach to the treatment of heart failure. Pharmacol Ther 2005;105:211– 228. 60. Goldhaber JI, Henderson SA, Reuter H, et al: Effects of Na+-Ca2+ exchange expression on excitation-contraction coupling in genetically modified mice. Ann NY Acad Sci 2005;1047:122–126. 61. Hasenfuss G: Calcium pump overexpression and myocardial function: Implications for gene therapy of myocardial failure. Circ Res 1998; 83:966–968.
Ch001-X3754.indd 9
9
62. He H, Giordano FJ, Hilal-Dandan R, et al: Overexpression of the rat sarcoplasmic reticulum Ca2+-ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation. J Clin Invest 1997;100:380–389. 63. Baker DL, Hashimoto K, Grupp IL, et al: Targeted expression of the sarcoplasmic reticulum Ca2+-ATPase increases cardiac contractility in transgenic mouse hearts. Circ Res 1998;83:1205–1214. 64. Müeller OJ, Katus HA, Bekeredjian R: Targeting the heart with gene therapy-optimized gene delivery methods. Cardiovasc Res 2007;73: 453–462. 65. Periasamy M, Reed TD, Liu LH, et al: Impaired cardiac performance in heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) gene. J Biol Chem 1999;274: 2556–2562. 66. Hajjar RJ, Kang JX, Gwathmey JK, et al: Physiological effects of adenoviral gene transfer of sarcoplasmic reticulum calcium ATPase in isolated rat myocytes. Circulation 1997;95:423–429. 67. Del Monte F, Harding SE, Schmidt U, et al: Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation 1999;100:2308–2311. 68. Miyamoto MI, del Monte F, Schmidt U, et al: Adenoviral gene transfer of SERCA2a improves left ventricular function in aortic-banded rats in transition to heart failure. Proc Natl Acad Sci USA 2000;97:793–798.
1/16/2008 2:31:18 PM
D. DIRK BONNEMA, MD CATALIN F. BAICU, PhD MICHAEL R. ZILE, MD
2
Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness INTRODUCTION PATHOPHYSIOLOGY Normal Diastolic Function Measurements of Diastolic Function Left Ventricular Diastolic Function During Exercise CARDIOVASCULAR STRUCTURE AND FUNCTION IN DIASTOLIC HEART FAILURE Left Ventricular Chamber Remodeling Left Ventricular Diastolic Function in Diastolic Heart Failure Cardiomyocyte Diastolic Function in Diastolic Heart Failure
Left Ventricular Systolic Function in Diastolic Heart Failure Abnormal Diastolic Function in Decompensated Diastolic Heart Failure Abnormal Diastolic Function in Diastolic Heart Failure During Exercise CLINICAL RELEVANCE Ischemic Diastolic Dysfunction Left Ventricular Concentric Hypertrophy Trigger Mechanisms of Noncardiac Factors in Acute Decompensated Diastolic Heart Failure FUTURE RESEARCH
INTRODUCTION Heart failure (HF) can be defined physiologically as an inability of the heart to provide sufficient forward output to meet the perfusion and oxygenation requirements of the tissues while maintaining normal filling pressures. Chronic heart failure can be divided into two broad categories: systolic heart failure (SHF) and diastolic heart failure (DHF). Classifying patients in these two broad categories should be based on characteristic changes in cardiovascular structure and function (see Chapter 28).1,2 SHF is characterized by progressive chamber dilation, eccentric remodeling, and dominant abnormalities in systolic properties. Clinical manifestations of left ventricular (LV) systolic dysfunction include decreased cardiac output, increased heart rate, and peripheral vasoconstriction. However, patients with SHF frequently have additional symptoms of shortness of breath at rest or with exertion.3 These symptoms of pulmonary congestion are due, at least in part, to LV diastolic dysfunction.4–6 Therefore, patients with SHF (particularly when they have
symptomatic decompensation) do not have an “isolated” abnormality in systolic properties; rather, from the pathophysiologic point of view, they have predominant abnormalities in systolic properties and eccentric remodeling, with associated or secondary abnormalities in diastolic function. By contrast, patients with DHF are characterized by normal LV volume, concentric remodeling, and normal LV chamber systolic properties, but dominant abnormalities in diastolic properties.2,7–11 These patients have abnormalities in diastolic relaxation, filling, and/or distensibility. Clinical manifestations of LV diastolic dysfunction include shortness of breath at rest or with exertion and peripheral edema. However, abnormalities in regional systolic shortening have also been identified in some patients with DHF.2,11 Therefore, patients with DHF do not have “isolated” abnormalities in diastolic properties; rather, from the pathophysiologic point of view, they have predominant abnormalities in diastolic properties and concentric remodeling. “Diastolic dysfunction” and “diastolic heart failure” are not synonymous terms.12 Diastolic dysfunction indicates a functional abnormality of diastolic relaxation, filling, or distensibility of the 11
12
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness left ventricle—regardless of whether the ejection fraction is normal or abnormal and regardless of whether the patient is asymptomatic or has symptoms and signs of HF. Thus, diastolic dysfunction comprises abnormal mechanical (diastolic) properties of the ventricle and is present in virtually all patients with heart failure. Diastolic heart failure denotes signs and symptoms of clinical heart failure with normal ejection fraction and LV diastolic dysfunction. Similar distinctions apply to the terms “systolic dysfunction” and “systolic heart failure” (Boxes 2-1 and 2-2).
PATHOPHYSIOLOGY The pathophysiology of diastolic heart failure will be reviewed here, beginning with a discussion of the factors involved in normal diastolic relaxation and filling. Understanding normal diastolic function permits an easier understanding of some of the clinical features of DHF.
Normal Diastolic Function Cardiac function is critically dependent upon diastolic physiologic mechanisms to provide adequate LV filling (cardiac input) in Box 2-1
Definitions Diastolic Dysfunction: Abnormal diastolic properties of LV (abnormal relaxation, filling dynamics, distensibility) • EF may be normal or low. • Patient may be symptomatic or asymptomatic. Diastolic Heart Failure: Clinical heart failure, normal ejection fraction, abnormal diastolic function Systolic Dysfunction: Abnormal systolic properties of LV (abnormal performance, function, contractility)
parallel with LV ejection (cardiac output) both at rest and during exercise. Adequate pulmonary function is also dependent upon LV diastolic function. During diastole, the left ventricle, left atrium, and pulmonary veins form a “common chamber” that is continuous with the pulmonary capillary bed. LV diastolic pressure is determined by the volume of blood in the left ventricle during diastole and the diastolic distensibility or compliance of the entire cardiovascular system, principally the left ventricle (but it may also include the left atrium, pulmonary vessels, right ventricle, and systemic arteries). Thus, an increase in LV diastolic pressure (whether this occurs at rest or during exercise) will increase pulmonary capillary pressure, which, if high enough, causes dyspnea, exercise limitation, pulmonary congestion, and edema (Fig. 2-1). Relaxation of the contracted myocardium begins at the onset of diastole. This is a dynamic process that takes place during isovolumic relaxation (the period between aortic valve closure and mitral valve opening during which LV pressure declines with no change in volume) and then continues during auxotonic relaxation (the period between mitral valve opening and mitral valve closure during which the left ventricle fills at variable pressure) (Fig. 2-2). The rapid pressure decay and the concomitant “untwisting” and elastic recoil of the left ventricle produce a suction effect that augments the left atrial-ventricular pressure gradient and pulls blood into the ventricle, thereby promoting diastolic filling. During exercise in normal patients, relaxation rate is increased and early diastolic pressures decrease, augmenting elastic recoil and diastolic suction and resulting in more rapid filling during a shortened diastolic filling period at increasing heart rates (Fig. 2-3). During the later phases of diastole, the normal left ventricle is composed of completely relaxed cardiomyocytes and is very compliant and easily distensible, offering minimal resistance to LV filling over a normal volume range. Atrial contraction near the end of diastole contributes 20%–30% to total LV filling volume and increases diastolic pressures by less than 5 mmHg. As a result,
• EF is low (and diastolic dysfunction may coexist). • Patient may be symptomatic or asymptomatic. Pulmonary capillaries
Systolic Heart Failure: Clinical heart failure, low ejection fraction, abnormal systolic function (From Circulation 2006;113:296–304.)
Pulmonary vein
Box 2-2
Diastolic Heart Failure—Diagnostic Criteria Required Criteria 1. Clinical evidence of heart failure • Framingham or Boston criteria • Plasma brain natriuretic peptide and/or chest x-ray • Cardiopulmonary exercise testing 2. Normal ejection fraction (= 50%) Confirmatory Evidence 1. LVH or concentric remodeling 2. Left atrial enlargement (in absence of atrial fibrillation) 3. Echo Doppler or catheter evidence of diastolic dysfunction Exclusion Nonmyocardial disease
Ao
LA
LV
Figure 2-1 Elevated left ventricular end diastolic pressure causes pulmonary congestion. The heart is seen in diastole when the mitral valve open and the left ventricle (LV), left atrium (LA), and pulmonary veins form a common chamber, continuous with the pulmonary capillary bed. The left ventricular end diastolic pressure determines the pulmonary capillary pressure and the presence or absence of pulmonary congestion or edema. Ao, aorta.
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness REST
EXERCISE
20
Isovolumic pressure decline
Left atrium Systole
PLA 0
mL/sec
Left ventricle
PLV
mmHg
Aorta
150
dV/dt
Minimum PLV
E
0 500 msec
Diastole
LV volume
CHF REST
CHF EXERCISE
40
I
Isovolumic relaxation
Slow filling
Atrial filling
Auxotonic relaxation
Figure 2-2 Changes in left ventricular pressure and volume throughout the cardiac cycle. The cardiac cycle is divided into systole, the time period from mitral valve closure (MVC) to aortic valve closure (AVC), and diastole. Diastole is further divided into isovolumic relaxation (the time period from AVC to mitral valve opening [MVO] during which LV pressure declines with no change in volume) and auxotonic relaxation (the time period from MVO to MVC during which LV volume increases at variable pressure). AVO, atrial valve opening.
LV filling can normally be accomplished by very low filling pressures in the left atrium and pulmonary veins, preserving a low pulmonary capillary pressure (<12 mmHg) and a high degree of lung distensibility. Loss of normal LV diastolic relaxation and distensibility, from structural and functional causes, impairs LV pressure decline and filling, resulting in increases in LV diastolic, left atrial (LA), and pulmonary venous pressures, which directly increase pulmonary capillary pressure.
Measurements of Diastolic Function Complete characterization of LV diastolic properties requires simultaneous measurement (often using a high-fidelity micromanometer) of LV diastolic pressure and LV volume using invasive and/or noninvasive methods. Diastolic function can be assessed using the following measurements: ❒
❒
❒
Rate of isovolumic relaxation: peak (−)dP/dt, the time constant of the isovolumic LV pressure decay (Tau) and the isovolumic relaxation time (IVRT). When relaxation rate is decreased, (−)dP/dt and Tau are increased (Fig. 2-4). Rate and extent of LV filling: filling rate, the time-to-peak filling rate (TPFR), transmitral flow velocity, tissue velocity, and strain and strain rate. When there is prolonged relaxation, the early filling rate and extent are decreased, TPFR is prolonged, and the filling rate and extent that results from atrial contraction are increased (Fig. 2-5). Passive elastic stiffness properties: diastolic pressure-volume (P-V) relationship. When stiffness is increased (distensibility is decreased) the diastolic pressure versus volume relationship is shifted upward (Fig. 2-6).
mL/sec
Rapid MVO filling AVC
mmHg
PLV MVC AVO
E
PLA 0 150
Minimum PLV E E
dV/dt 0
Figure 2-3 Effects of exercise on left ventricular (LV) filling dynamics. Changes in LV pressure (PLV), left atrial pressure (PLA), and the rate of change of LV volume (dV/dt) at rest and during exercise. Top panel: During exercise in normal patients, minimal PLV decreases without any change in PLA, leading to an increase in the peak mitral valve gradient and producing a higher peak filling rate (E). Bottom panel: In congestive heart failure (CHF), the peak LV filling rate (E) increases during exercise due to an increase in the early transmitral valve pressure gradient. However, the gradient is produced by an increase in PLA instead of a reduction in PLV as occurs in normal patients. (From Cheng CP et al: Mechanism of augmented rate of left ventricle filling during exercise. Circ Res 1992;70:9.)
Left Ventricular Pressure Decline Isovolumic relaxation can be quantified by measurement of LV pressure with a high-fidelity micromanometer catheter and calculation of the peak instantaneous rate of LV pressure decline (peak − dP/dt) and the time constant of LV isovolumic pressure decline (Tau).13 When the natural log of LV diastolic pressure is plotted versus time, Tau equals the slope of this linear relationship. Stated in more conceptual terms, Tau is the time required for LV pressure to fall by approximately two thirds of its initial value. When isovolumic pressure decline is slowed, Tau is prolonged and its numerical value increases. Noninvasive estimates of the total IVRT can be made using echocardiographic techniques. However, no index of relaxation (isovolumic or auxotonic) can be considered an index of “intrinsic” relaxation rate unless loading conditions (and other modulators) are held constant or are at least specified. Therefore, changes in afterload (systolic pressure) and diastolic load (LA diastolic pressures) may change measurements of isovolumic and auxotonic relaxation without changing intrinsic relaxation properties.
Left Ventricular Filling A detailed description of the Doppler echocardiographic assessment of diastolic dysfunction is provided in other chapters (10–12 and 15). The normal left ventricle has a characteristic
13
14
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness 5 LV pressure
Left ventricular pressure (mmHg)
Left ventricular pressure (mmHg)
AVC
100
Peak (–)dP/dt
50
Abnormal τ = 55 msec
4
3 Normal τ = 34 msec 2
1
MVO
LV dP/dt
P = P0e–t/τ
0
0 0
500
1000
0
Time (msec)
50
100
Time (msec)
Time to peak filling rate
Figure 2-4 Left ventricular (LV) isovolumic relaxation. LV pressure versus time and the rate of change of LV pressure (dP/dt) in a normal subject (solid line) versus a patient with diastolic heart failure (dashed line). Isovolumic relaxation can be quantified by calculating the peak instantaneous rate of LV pressure decline (peak −dP/dt) and the time constant of LV isovolumic pressure decline (Tau). When the natural log of LV diastolic pressure is plotted versus time, Tau equals the slope of this linear relationship (right panel). Stated in more conceptual terms, Tau is the time required for LV pressure to fall by approximately two thirds of its initial value. When isovolumic relaxation is abnormal, LV pressure decline is slower, −dP/dt has a more negative value; the time constant Tau is prolonged, and its numerical value is increased (depicted by the dashed lines in both figure panels).
Peak rapid filling rate
Peak atrial filling rate
LV dV/dt
LV volume
Contribution of atrial systole to LV filling
End diastole
Total LV stroke volume
Rapid filling fraction End systole
Rapid filling
Slow filling (diastatis)
pattern of filling and inflow velocities. LV inflow velocity and the rate of LV filling are greatest early (E) in diastole, immediately after mitral valve opening, and are responsible for the normally tall E wave of the transmitral inflow Doppler echocardiogram (Fig. 2-7). Since most atrial-to-ventricular transfer of blood occurs in early and mid-diastole, the amount of blood transported by atrial contraction is relatively small, the velocity imparted by the atrial contraction (the A wave of the transmitral inflow Doppler echocardiogram) is relatively low, and the normal E/A wave ratio is greater than 1 and approaches a value of 2 in younger individuals. Doppler echocardiographic assessment of LV filling has limitations, since diastolic filling parameters are influenced by multiple
Atrial systole
Figure 2-5 Left ventricular (LV) filling dynamics. LV volume versus time and the rate of change of LV volume (dV/dt) in a normal subject (solid line) versus a patient with diastolic heart failure (dashed line). With the onset of systole, the LV volume decreases and reaches its minimum at the end systole. Diastolic filling has three distinct phases: rapid filling of the left ventricle, during which dV/dt reaches it maximum and the peak filling rate occurs; a slow filling phase (diastasis), during which there is little change in LV volume; and an atrial systole phase, during which active atrial contraction fills the left ventricle and allows it to attain its end diastolic volume. Important diastolic parameters include the peak filling rate, the time to peak filling rate, the rapid filling fraction (percent of total stroke volume reached during rapid filling), and the percent contribution of atrial systole to LV filling.
factors, the most important of which are loading conditions. The typical, but nonspecific, mitral filling pattern associated with diastolic dysfunction (termed abnormal relaxation) is a pattern of increased IVRT and decreased E/A ratio. However, this pattern can be altered or pseudonormalized by changes in LA pressure. When diastolic dysfunction occurs, relaxation is slowed and incomplete, early LV diastolic pressures rise, early diastolic suction falls, and LV filling becomes increasingly dependent on an increase in LA pressure to push blood into the left ventricle during diastole. As LA pressures rise, the value of the E wave increases and E/A increases to a “normal” (or pseudonormal) value. When LA pressures are severely increased, a “restrictive” pattern may develop in which the IVRT may be decreased and the E/A ratio further
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness
LV diastolic pressure (mmHg)
30 DHF
25 20
SHF 15 10 Normal
5 0 0
50
100
150
200
250
300
LV diastolic volume (ml) Figure 2-6 Diastolic pressure versus volume relationships in patients with heart failure. Left ventricular (LV) diastolic pressure-volume data from normal controls (solid line), patients with diastolic heart failure (DHF) (dotted line), and patients with systolic heart failure (SHF) (dashed line). In patients with DHF, the diastolic pressure-volume curve is shifted up and left, indicating an increase in passive stiffness and a decrease in distensibility of the left ventricle. In contrast, in patients with SHF, the diastolic pressure-volume curve is shifted down and right, indicating a decrease in passive stiffness and an increase in distensibility of the left ventricle. These data clearly indicate that all patients with heart failure, whether diastolic or systolic, have a significant increase in LV diastolic pressure; however, the mechanisms responsible for these increased pressures are different between these two different patient groups. (From Aurigemma GP et al: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296.)
Diastolic dysfunction Normal
Impaired relaxation Stage 1 Mild
LV press
Pseudonormal Stage 2 Moderate
Restrictive Stage 3 Severe
LA press E A
E
E
E
A
A
Mitral Doppler velocity
A
Decel IVRT S Doppler tissue imaging
A' E'
E' E'
A'
E'
A'
A'
Figure 2-7 Doppler findings in diastolic heart failure. Schematic representation of left ventricular (LV) and left atrial (LA) pressures during diastole (top panel), transmitral Doppler LV inflow velocity (middle panel), and Doppler tissue velocity (bottom panel) in normal patients and in different types of diastolic dysfunction. This schema divides patients into four filling patterns: normal pattern of relaxation and filling (column 1 far left); impaired relaxation or stage I mild diastolic dysfunction; pseudonormal relaxation, or stage II moderate diastolic dysfunction; and restrictive filling pattern, or stage III severe diastolic dysfunction. Patients with an impaired filling pattern have a reduced E′, a prolonged E decel of early diastolic filling, and an increased A. A pseudonormal filling pattern is denoted by an increased E wave in the face of a decreased E′. A restrictive filling pattern is denoted by an even larger E wave and even smaller E′, with a shortened IVRT and a decreased E decel. It should be noted that these abnormal filling patterns may also be seen in patients with systolic heart failure. In all patients with heart failure, these filling patterns have important prognostic value. For example, the presence of a restrictive pattern predicts an increase in mortality rate, particularly in patients with systolic heart failure. E, peak early diastolic flow velocity; A, peak late diastolic flow velocity caused by atrial contraction; E decel, E-wave diastolic deceleration time; IVRT, isovolumic relaxation time; S, myocardial velocity during systole; E′, myocardial velocity during early filling; and A′, myocardial velocity during filling produced by atrial contraction. (From Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387.)
15
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness increased.14 Recently developed echocardiographic and Doppler echocardiographic techniques can be used to distinguish these three patterns of abnormal LV filling.15 When transmitral Doppler flow patterns are examined in concert with more recently developed Doppler echocardiographic techniques, patterns of normal versus impaired relaxation versus pseudonormal versus restriction can be determined because these newer techniques provide information about LV filling pressure and the LA/LV diastolic pressure gradient. These techniques include measuring pulmonary venous flow velocity, tissue Doppler myocardial velocity, strain and strain rate, and color M-mode flow acceleration patterns. In particular, measures of myocardial velocities made by tissue Doppler imaging (TDI) appear less sensitive to alteration in LV loading conditions (Fig. 2-8). E′ measures the rate of early diastolic myocardial lengthening and, when combined with transmitral Doppler E-wave data, can be used to estimate pulmonary capillary wedge pressure (PCWP) = 2 + 1.3 (E/E′).16
nondistensible ventricle will require higher pressures to achieve filling of a given volume. Thus, an increase in LV diastolic chamber stiffness or a decrease in distensibility shifts the LV diastolic P-V curve upward and often increases its slope. Defining the entire LV filling curve throughout diastole requires the simultaneous measurement of LV diastolic pressure and volume either throughout a single cardiac cycle (to define the diastolic P-V relationship) or by way of the end diastolic P-V coordinate over variably loaded cardiac cycles (to define the end diastolic P-V relationship). The volume measurements can be made by angiography, echocardiography, or radionuclide imaging techniques simultaneous with invasive measurements of LV diastolic pressure. Alternatively, noninvasive Doppler echocardiographic techniques can be used to estimate PCWP (see earlier description). Together with echocardiographically measured end diastolic volume, an index of instantaneous diastolic stiffness (ratio of PCWP-to-end diastolic volume) can be derived.17
Left Ventricular Stiffness/Distensibility
Left Ventricular Diastolic Function During Exercise
LV ventricular diastolic stiffness and distensibility are quantified by the position and shape of the LV diastolic P-V relationship, which plots LV diastolic pressure as a function of LV diastolic volume throughout diastole (see Fig. 2-6). A relatively stiff,
A detailed description of the mechanisms and clinical relevance of diastolic dysfunction during exercise is provided in Chapter 17. The cardiac output can increase several fold during exercise, an appropriate response to the enhanced needs of exercising muscle.
TISSUE DOPPLER IMAGING DHF patient Velocity (cm/sec)
4 0 –4 –8
4 0 –4 –8
0
0
–5
–5
Strain (%)
Strain (%)
Velocity (cm/sec)
Normal patient
–10 –15 –20 Systole
–10 –15 –20
Diastole
3
Systole
Diastole
3 Strain rate (sec–1)
Strain rate (sec–1)
16
2 1 0 –1 –2 0
0.2
0.4
0.6
Time (sec)
0.8
1
2 1 0 –1 –2
0
0.2
0.4
0.6
0.8
1
Time (sec)
Figure 2-8 Examples of tissue Doppler imaging. Derived velocity (top), strain (middle), and strain rate (bottom) in a normal control patient (left) and a patient with diastolic heart failure (DHF) (right). These tissue Doppler images were taken from the mitral annulus. The relaxation pattern during early diastolic filling is marked by the block arrows. The strain data are similar to a left ventricular (LV) filling curve. The patient with DHF had a slow filling pattern, as evidenced by a marked decrease in the slope of the line during early diastolic filling compared with the normal patient. The velocity and the strain rate are both reduced. The relaxation pattern during late diastolic filling is marked by the thin arrows. The strain data show that the patient with DHF had a more robust filling as a result of atrial contraction than had the normal patient. This indicates a shift in LV filling pattern from early to late diastole. The velocity and the strain rate are both increased during atrial contraction. (From Aurigemma GP et al: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296.)
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness Multiple factors contribute to this response, including an increase in heart rate, a modest rise in stroke volume, a reduction in peripheral vascular resistance, and an elevation in contractile force, which increases LV, arterial systolic pressure, and the force of ejection. The increase in LV output must be matched by a rise in LV input. The left ventricle cannot accomplish this task by the same mechanisms that increase output during exercise. For example, tachycardia shortens the duration of diastole, the time during which LV filling must occur. As a result, the diastolic filling rate during exercise may be increased out of proportion to cardiac output. A rise in flow rate across the mitral valve requires an increase in the transmitral diastolic pressure gradient. If this were achieved by increasing the pressure in the left atrium, this would have the deleterious effects of increasing pulmonary capillary pressure and causing pulmonary congestion, dyspnea, and respiratory compromise. Rather, the normal left ventricle permits a remarkable increase in diastolic filling rate during exercise by rapidly and markedly decreasing LV pressure during early diastole, thereby creating a relative LV “suction” effect, which enhances the transmitral pressure gradient without increasing LA pressure (see Fig. 2-3).18–21 Several mechanisms contribute to the left ventricular diastolic suction effect during exercise: ❒
❒
The increased force of contraction during systole enhances early diastolic myocardial elastic recoil due to greater systolic shortening forces and the extent of systolic fiber shortening, which is manifested as a smaller end systolic volume (ESV).20 Thus, an increase in systolic shortening results in an increase in restoring forces during diastole, which allow enhanced diastolic filling. Acceleration of myocyte relaxation occurs during exercise, due to an increased rate of calcium uptake by the sarcoplasmic reticulum (SR). Increased cyclic adenosine monophosphate (cAMP), generated by the β-adrenergic response to exercise, phosphorylates the regulatory SR membrane protein, phospholamban, to increase the rate of calcium uptake by the SR during diastole.22
Some of the mechanisms that allow an increase in cardiac output and in cardiac input during exercise act in concert on systolic and diastolic functions: ❒
❒
The Treppe effect creates a relationship between the heart rate (or frequency of contraction)/LV pressure (or systolic force development) and ejection fraction (or shortening) such that in a normal heart, an increase in heart rate is associated with an increase in stroke volume over a physiologic range of heart rate. This has been called the systolic force-frequency relationship. In addition, the same mechanism governs the relationship between heart rate and diastolic relaxation rate where increased heart rate in a normal heart is associated with an increased relaxation rate, which in part allows LV diastolic pressures and PCWP to remain normal during exercise. A second example of the determinants of systolic and diastolic function acting in concert during exercise is the relationship between increased stroke volume and diastolic distensibility. During normal exercise, end systolic volume decreases and end diastolic volume increases. The increase in end diastolic volume allows the left ventricle to use the Frank-Starling mechanism to augment stroke volume.
However, it is the normal stiffness and distensibility of the left ventricle that allows an increase in end diastolic volume with a negligible change in late diastolic pressure and no significant change in PCWP. In summary, the normal heart during exercise has an elegant balance of physiologic mechanisms to ensure that cardiac input keeps pace with cardiac output, with preservation of a low pulmonary capillary pressure. These mechanisms result in an increase in measured LV distensibility, as manifested by a downward shift of the LV diastolic P-V curve, especially during early diastole (Fig. 2-9).23,24
CARDIOVASCULAR STRUCTURE AND FUNCTION IN DIASTOLIC HEART FAILURE DHF is typically associated with significant remodeling that affects the LV and LA chambers, the cardiomyocytes, and the extracellular matrix. The structural remodeling that occurs in DHF differs dramatically from that in SHF.
Left Ventricular Chamber Remodeling Patients with DHF generally exhibit a concentric pattern of LV remodeling and a hypertrophic process that is characterized by a normal or near-normal end diastolic volume, increased wall thickness, and an increased ratio of mass-to-volume with an increased ratio of wall thickness-to-chamber radius. By contrast, patients with SHF exhibit a pattern of eccentric remodeling with an increase in end diastolic volume (which is usually progressive over time), an increase in LV mass but little increase in wall thickness, and a substantial decrease in the ratios of mass to volume and thickness to radius (Fig. 2-10).1,2,9,11,17,25,26
Cardiomyocyte and Extracellular Matrix Remodeling The dramatic differences in organ morphology and geometry noted previously are paralleled by anatomic differences at the microscopic level. In DHF, the cardiomyocyte exhibits an increased diameter, with little or no change in length; this corresponds to the increase in LV wall thickness with no change in LV volume (Fig. 2-11). By contrast, in SHF, the cardiomyocytes are elongated, with little or no change in diameter; this corresponds to the increase in LV volume with no change in LV wall thickness. It is easy to imagine how the geometric structural remodeling of these cardiomyocytes causes the remodeling seen in the LV chambers that they populate. In DHF, there is an increase in the amount of collagen, with a corresponding increment in the width and continuity of the fibrillar components of the extracellular matrix (Fig. 2-12). In SHF, at least early in its development, there is degradation and disruption of the fibrillar collagen.2,25,26 In end-stage SHF, replacement fibrosis and ischemic scarring may result in an overall increase in fibrillar collagen within the extracellular matrix.
Left Ventricular Diastolic Function in Diastolic Heart Failure Abnormal LV diastolic function is a universal finding in patients with DHF. Indeed, these abnormalities in diastolic function form
17
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness CONTROL
ISCHEMIA
Rest Exercise
20
30
20
10
10
60
120
160
Left ventricular volume (ml)
200
30
20
10
0
0
Rest Exercise
40 LV pressure (mmHg)
30
SCAR
Rest Exercise
40 LV pressure (mmHg)
40 LV pressure (mmHg)
18
0 100
140
180
Left ventricular volume (ml)
220
140
180
220
260
Left ventricular volume (ml)
Figure 2-9 Left ventricular (LV) pressure-volume (P-V) relationships. Shown are the relationships at rest and during exercise at early, mid-, and end diastole. The simultaneous measurements of LV diastolic pressure and volume define distensibility or compliance. In the normal individual with normal compliance (left panel), exercise causes a downward shift of the diastolic P-V curve in early diastole, indicating an increase in LV distensibility; the increase in cardiac output occurs without an increase in LV diastolic pressure. In a patient with ischemia (middle panel), exercise causes a marked upward shift in the curve, indicating a reduction in LV distensibility, or diastolic dysfunction, and there is a significant increase in LV and pulmonary capillary wedge pressures as LV volume or cardiac output increases. This may result in the development of pulmonary congestion and respiratory symptoms. In the patient with a previous myocardial infarction and an LV scar (right panel), the early increase in diastolic distensibility with exercise is lost, but there is no change in the P-V curve in the absence of ischemia. (From Carroll JD et al: Dynamics of left ventricular filling at rest and during exercise. Circulation 1983;68:59.)
Normal
Systolic heart failure
Disastolic heart failure
Figure 2-10 Left ventricular (LV) remodeling in heart failure. Autopsy examples of the left ventricle imaged at the midventricular cross section in a normal heart (left), systolic heart failure (center), and diastolic heart failure (right). Diastolic heart failure is characterized by a pattern of concentric LV remodeling with a normal or near-normal end diastolic volume, increased wall thickness and mass, and a high ratio of mass to volume. By contrast, patients with systolic heart failure exhibit eccentric remodeling with an increased end diastolic volume, little change in wall thickness, and a low ratio of mass to volume. (From Aurigemma GP et al: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296.)
the dominant pathophysiologic basis for the development of DHF.7–11,15,17,25,26 The major abnormalities in LV diastolic function that contribute to or occur during the development of DHF include: ❒ ❒ ❒ ❒ ❒ ❒
Slowed, delayed, and incomplete myocardial relaxation Impaired rate and extent of LV filling Shift of filling from early to late diastole Decreased early diastolic suction/recoil Augmented LA pressure during the early filling Altered passive elastic properties of the ventricle, resulting in increased passive stiffness and decreased diastolic distensibility
❒ ❒ ❒ ❒
Inability to sufficiently augment cardiac output during exercise Inability to sufficiently augment relaxation during exercise Inability to utilize the Frank-Starling mechanism during exercise Increased diastolic LV, LA, and pulmonary venous pressures at rest or during exercise
In a given patient, impairment of one or more of these parameters will result in decreased LV chamber distensibility, as manifested by an increase in diastolic pressure at any given LV volume. When myocardial relaxation is impaired in diastolic dysfunction,
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness POH-Diastolic heart failure
POH-Diastolic heart failure
Normal
Normal
DCM-Systolic heart failure
DCM-Systolic heart failure Figure 2-11 Cardiomyocyte remodeling in heart failure. Isolated cardiac muscle cells taken from (bottom) an animal model of dilated cardiomyopathy (DCM) that produces systolic heart failure; (middle) a normal heart; and (top) an animal model of pressure-overload hypertrophy (POH) that produces diastolic heart failure, in which the cardiomyocyte diameter is increased. By contrast, in systolic heart failure, the cardiomyocyte length is increased. (From Aurigemma GP et al: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296.)
the rate and amount of early diastolic LV filling are reduced, with a relative shift of LV filling to the later part of diastole (see Fig. 2-5). The Doppler E wave is decreased, the hemodynamic load on the atrium is increased, and atrial contraction makes a more important contribution to ventricular filling than in normal subjects. This is reflected by an increase in the Doppler A wave and a decrease in the E/A ratio (see Fig. 2-7). The chronic atrial overload may eventually result in atrial fibrillation, which can result in the loss of atrial contraction; dramatic reductions in LA emptying, LV filling, and LV stroke volume; and a significant increase in LV diastolic pressures. The redistribution of filling from early to late diastole also means that LV filling and LA emptying are compromised more in patients with diastolic dysfunction than in normal patients by the occurrence of tachycardia. An increase in heart rate shortens the duration of diastole and truncates the important late phase of diastolic filling.
Cardiomyocyte Diastolic Function in Diastolic Heart Failure The significant abnormalities in LV diastolic function observed at the chamber level are paralleled by the abnormalities in cardiomyocyte diastolic function observed at the cellular level. Cardiomyocyte diastolic function was directly addressed in two studies in which patients with DHF underwent endomyocardial biopsy and single cardiomyocytes were isolated to assess cellular diastolic performance.25,26 The cardiomyocytes had an increased resting tension in the absence of calcium that was almost twice as high
Figure 2-12 Extracellular matrix remodeling in heart failure. Scanning electron micrographs taken from (bottom) an animal model of dilated cardiomyopathy (DCM) that produces systolic heart failure; (middle) a normal heart; and (top) an animal model of pressure-overload hypertrophy (POH) that produces diastolic heart failure, in which there is an increase in the amount of collagen, with a corresponding increment in the width and continuity of the fibrillar components of the extracellular matrix. By contrast, in systolic heart failure, there is degradation and disruption of the fibrillar collagen. (From Aurigemma GP et al: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296.)
as control cardiomyocytes. These in vitro cell data corresponded to an in vivo increase in LV end diastolic pressure in these patients with DHF. These data indicate that cardiomyocytes from patients with DHF have increased stiffness and decreased distensibility compared with normal cardiomyocytes. Therefore, these clinical studies, along with studies using animal models of DHF, showed that there are clear parallels in the abnormalities in diastolic function between the LV chamber and individual cardiac muscle cells that constitute the myocardium.27
Left Ventricular Systolic Function in Diastolic Heart Failure A detailed description of the systolic function in patients with DHF is provided in Chapter 28. The dominant functional abnormality in patients with SHF is abnormal LV systolic function. Ejection fraction is normal in patients with DHF, but whether
19
20
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness abnormalities in LV systolic properties contribute to the pathophysiology of DHF has remained an area of active investigation. Recent studies have carefully examined LV global and regional systolic properties in patients with definite DHF. These studies have clearly demonstrated that global LV systolic properties are normal in patients with DHF. The most commonly used index of LV systolic properties is the ejection fraction; however, a full assessment of the contractile behavior of the ventricle requires the combined use of indices that reflect LV systolic performance, function, and contractility, as well as a consideration of global and regional functions. The following measurements have been made in patients with definite DHF: ❒ ❒
LV performance measured as stroke work LV function measured as ejection fraction and preload recruitable stroke work LV contractility measured as peak (+)dP/dt, end systolic elastance, and the endocardial stress-shortening relationship
❒
Patients with DHF have no significant change in any of these measurements compared with age- and gender-matched normal control subjects.11 While these global measurements of LV systolic properties are normal in patients with DHF, regional systolic properties such as midwall fractional shortening and long axis shortening extent and rate may be abnormal in some patients (>50%) with DHF. However, these regional abnormalities do not appear to be causally linked to either the pathophysiology of diastolic dysfunction or the development of DHF.2
As previously discussed, abnormal LV diastolic function is a universal finding in patients with DHF. Indeed, these abnormalities in diastolic function form the dominant pathophysiologic basis for the development of DHF. Even in patients with “compensated” DHF (NYHA classes II–III), abnormal relaxation, filling, and stiffness lead to increased diastolic pressures (Fig. 2-13). Further changes in diastolic function occur when patients develop decompensated DHF.28,29 For example, atrial fibrillation, tachycardia, or uncontrolled hypertension can lead to rapid increases in LA pressures and the development of decompensated DHF. Under these circumstances, the rise in pressure causes a significant change in transmitral Doppler flow pattern (as previously described). There is pseudonormalization of the ratio of ventricular to atrial filling velocities (E to A ratio) and when atrial pressures are extremely increased, to a frankly restrictive pattern. These changes in relaxation and filling are associated with changes in distensibility. During compensated DHF, the LV diastolic P-V relationship shifts upward, indicating decreased diastolic distensibility. During the initial development of decompensated DHF (during the phase of “worsening DHF”), LV volume may increase along a similar abnormal diastolic P-V curve (from point A to point B). Later, when acute pulmonary edema develops in decompensated DHF, there may be a marked upward shift in the diastolic P-V relationship (from point B to point C), indicating a further decrease in LV distensibility. Once patients with decompensated
WORSENING DHF
33 A 22 Normal 11
LV pressure (mmHg)
COMPENSATED DHF
LV pressure (mmHg)
Abnormal Diastolic Function in Decompensated Diastolic Heart Failure
0
B
33 A 22
11
0 0
20
40
60
80
100
0
20
40
60
LV volume (ml)
ACUTE PULMONARY EDEMA
POST TREATMENT
LV pressure (mmHg)
B
33
100
C
C LV pressure (mmHg)
80
LV volume (ml)
22
11
0
33 A 22
11
0 0
20
40
60
LV volume (ml)
80
100
0
20
40
60
LV volume (ml)
80
100
Figure 2-13 Left ventricular (LV) diastolic pressure-volume (P-V) relationship in compensated and decompensated diastolic heart failure (DHF). During compensated DHF, the LV diastolic P-V relationship shifts upward, indicating decreased diastolic distensibility. During the development of decompensated DHF initially (during the phase of “worsening DHF”), LV volume may increase along a similar abnormal diastolic P-V curve (from point A to point B). Later, when acute pulmonary edema develops in decompensated DHF, there may be a marked upward shift in the diastolic P-V relationship (from point B to point C), indicating a further decrease in LV distensibility. Once patients with decompensated DHF are adequately treated—for example, with diuretics and nitrates—the LV diastolic P-V relationship moves back to the compensated DHF state (from point C to point A).
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness DHF are adequately treated—for example, with diuretics and nitrates—the LV diastolic P-V relationship moves back to the compensated DHF state (from point C to point A). Decompensated DHF may be caused by both cardiovascular and noncardiovascular factors (or triggers) that act on the already existing structural and functional abnormalities (composing a substrate) to precipitate the development of acute pulmonary edema (Fig. 2-14). The substrate in patients with DHF consists of structural remodeling of the LV chamber and of the constituent cardiomyocytes and extracellular matrix that compose the chamber. These structural changes are associated with significant abnormalities in LV diastolic function, including decreased LV distensibility. These changes in LV structure and function form the substrate from which patients develop the clinical syndrome of DHF. There are a number of comorbid conditions that may act as triggers for the development of acute decompensated DHF. These include uncontrolled hypertension, increased salt and water intake, tachyarrhythmias, chronic renal failure, anemia, and coexistent lung disease.1,3,30–36 These comorbidities act upon the substrate to precipitate acute decompensated DHF. It should be noted, however, that in the absence of this substrate, these triggers do not result in DHF. For example, an increase in salt and water
intake in the absence of concentric remodeling or diastolic dysfunction does not result in DHF.
Abnormal Diastolic Function in Diastolic Heart Failure During Exercise While studies consistently show that diastolic function is abnormal in patients with DHF at rest, these abnormalities become even more exaggerated during exercise (see Chapter 17).37–39 Specifically, patients with DHF are not able to increase LV end diastolic volume, recruit Frank-Starling forces, increase relaxation rate, or increase filling rate. Consequently, exercise results in a marked increase in diastolic pressure, a limited ability to increase cardiac output, and marked truncation of exercise capacity. These abnormal responses to exercise are made worse by the exaggerated increase in arterial blood pressure that frequently accompanies exercise in patients with DHF. Abnormal diastolic function also plays a role in exercise intolerance suffered by patients with SHF, in which systolic dysfunction causes the left ventricle to lose the ability to augment diastolic filling in response to exercise by the normal mechanism of accentuated elastic recoil and early diastolic suction, previously
LV diastolic pressure (mmHg)
Normal
Diastolic heart failure
30
DHF Normal control
25 20
Decreased distensibility
15 10 5 0 0
20
40
60
80
100
120
LV diastolic volume (ml)
Substrate LV structure LV function
Triggers HTN, ↑ Na2/H2O, Tachy, CRF, ↓ HgB lung disease
Diastolic heart failure
Figure 2-14 Diastolic heart failure (DHF) substrate versus trigger. Patients with DHF have structural remodeling of the left ventricular (LV) chamber and of the constituent cardiomyocytes and extracellular matrix that compose the chamber. These structural changes are associated with significant abnormalities in LV diastolic function, including decreased LV distensibility. These changes in LV structure and function form the substrate from which patients develop the clinical syndrome of DHF. There are a number of comorbid conditions that may trigger the development of acute decompensated DHF. These include uncontrolled hypertension, increased salt and water intake, tachyarrhythmias, chronic renal failure (CRF), anemia, and coexistent lung disease. These comorbidities act upon the substrate to precipitate acute decompensated DHF. It should be noted, however, that in the absence of this substrate, these triggers do not result in DHF. For example, an increase in salt and water intake in the absence of concentric remodeling or diastolic dysfunction does not result in DHF.
21
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness described.18–20 Early diastolic filling in HF can be increased during exercise by a different mechanism: an elevation in LA pressure to create the requisite transmitral gradient rather than the normal decline in early diastolic LV pressure. The increase in LA pressure results in pulmonary congestion with exercise, a hallmark of HF (see Fig. 2-3).
sure, indicating a “paradoxical” increase in diastolic compliance.41 By contrast, during demand ischemia, diastolic compliance falls acutely.41–43 These opposite initial compliance changes with demand and supply ischemia may be explained by differences in the pressure and volume within the coronary vasculature, by the mechanical effects of the normal myocardium adjacent to the ischemic region, and by tissue metabolic factors.
CLINICAL RELEVANCE
Ischemia/Reperfusion Causing Diastolic Dysfunction
A variety of cardiac diseases can cause the development of abnormal diastolic function, abnormal cardiovascular remodeling, and the development of DHF. The mechanisms by which cardiovascular disease causes these outcomes include (but are not limited to) hemodynamic alterations, nonhomogeneous contraction and relaxation, myocardial ischemia, and LV concentric remodeling and hypertrophy. These mechanisms can act individually to alter diastolic function but often act in concert to cause the development of DHF. For ease of understanding, these mechanisms will first be discussed individually.
Ischemic Diastolic Dysfunction Ischemia can cause a reversible impairment of myocyte relaxation and diastolic function. The resultant slowing or failure of myocyte relaxation causes a fraction of actin-myosin cross-bridges to persist and continue to generate tension throughout diastole, especially in early diastole, creating a state of “partial persistent systole.” Two kinds of ischemia can alter diastolic function: demand ischemia, created by an increase in energy utilization that outstrips the necessary supply (such as during exercise or stress), and supply ischemia, created by a decrease in myocardial blood flow without a change in energy utilization (such as a myocardial infarction or coronary artery spasm). The differences between supply and demand ischemia are transient. After more sustained ischemia of 30 to 60 minutes or longer, both types result in decreased diastolic compliance.
Ischemic diastolic dysfunction can continue during and after reestablishment of normal myocardial blood flow (i.e., reperfusion). Reperfusion after a period of ischemia may result in a phase of post-ischemic diastolic “stunning,” analogous to post-ischemic stunning of contractile function. For example, diastolic dysfunction may be present early after cardiac surgery, after the myocardium has been exposed to cardioplegic arrest, or after thrombolytic or percutaneous treatment of an acute myocardial infarction. In each of these circumstances, reversible diastolic dysfunction follows reperfusion after a period of ischemia despite normal blood flow, with slow recovery to normal levels (Fig. 2-15).44–46 Post-ischemic mechanical dysfunction results in both systolic and diastolic dysfunction, and the latter may be a more sensitive parameter of ischemic injury.41 During reperfusion, LV diastolic chamber stiffness is increased.44,45 Over time, diastolic dysfunction resolves, and it is therefore reasonable to refer to this process as post-ischemic diastolic stunning. Recognition of this phenomenon is important because a reduced cardiac output or elevated PCWP in the early postoperative period or early after treatment of acute coronary syndrome may reflect an increase in LV diastolic chamber stiffness rather than a reduction in contractile function. This distinction can be made readily with echocardiography.
Demand Ischemia During demand ischemia, diastolic dysfunction may be related to myocardial ATP depletion, with a concomitant increase in ADP, resulting in rigor (rigor bond formation).29 Although ischemia is also associated with the persistence of an increased intracellular calcium concentration during diastole, one study found that ischemic diastolic dysfunction was not directly mediated by an increase in calcium concentration and a calcium-activated tension.40 As a result of the rigor, LV pressure decay, as assessed by Tau, is impaired, and the left ventricle is functionally stiffer than normal during diastole. Typically demand ischemia occurs during exercise or pharmacologically induced stress; it results from an increase in oxygen demand in the setting of limited coronary flow reserve caused by coronary stenosis and/or ventricular hypertrophy.
Supply Ischemia Supply ischemia results from a marked reduction in coronary flow. The net effect is inadequate coronary perfusion even in the resting state. Acute supply ischemia causes an initial transient downward and rightward shift of the diastolic P-V curve such that end diastolic volume increases relative to end diastolic pres-
Post CABG
20 PCWP (mmHg)
22
Pre CABG 14
9.5
10
10.5
11
11.5
LV end diastolic area
12
12.5
(cm2)
Figure 2-15 Coronary artery bypass graft (CABG) decreases left ventricular (LV) compliance. The relationship between LV end diastolic area, measured by two-dimensional echocardiography, and the pulmonary capillary wedge pressure (PCWP), which reflects LV compliance, before and after CABG. The PCWP and LV diastolic areas were increased with volume loading using isotonic saline. After CABG, the LV diastolic area was smaller at each level of PCWP, as reflected by a leftward shift of the pressure-area relationship; this indicates a reduction in LV compliance. (From McKenney P, et al: Increased left ventricular diastolic chamber stiffness immediately after coronary artery bypass surgery. J Am Coll Cardiol 1994;24:1189.)
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness
Ischemia-Induced Pulmonary Symptoms Ischemia, either spontaneous or during exercise, prevents the normal increase in LV distensibility and, as previously mentioned, can cause a rapid and marked increase in LV diastolic chamber stiffness. In the latter setting, LV diastolic pressures quickly increase, resulting in acute pulmonary congestion (“flash” pulmonary edema). This upward shift of the LV diastolic P-V curve is completely reversible with recovery of myocardial perfusion.24 The effects of ischemia explain why many patients with coronary disease have respiratory symptoms with their anginal pain, including wheezing, an inability to take a deep breath, or shortness of breath. Such respiratory symptoms may occur in the absence of anginal pain and are often referred to as anginal equivalents. These symptoms are similar to those of HF, which is not surprising, since the responsible mechanism is an elevation in pulmonary capillary pressure. One study, for example, showed that the acute decrease in LV distensibility and increase in diastolic pressure during angina caused an increase in airway resistance and a reduction in lung compliance.47 A similar symptom complex can occur in patients with concentric LV hypertrophy (LVH), even in the absence of epicardial coronary artery disease.
Left Ventricular Concentric Hypertrophy Widespread use of noninvasive methods of cardiac imaging has led to the recognition that LV diastolic dysfunction and DHF are commonly induced by the myocardial hypertrophy associated with hypertensive, coronary, or valvular heart disease. Resistance to diastolic filling is usually the result of common structural abnormalities, including concentric LV remodeling, cardiomyocyte hypertrophy, altered structure and composition of the extracellular matrix, and increased fibrillar collagen. All of these hypertrophy-associated changes lead to impaired cellular and myocardial relaxation (see Fig. 2-9). LVH and ischemia have important interactions. For a given degree of ischemia, a greater decline in diastolic function is seen in hypertrophied hearts.9,48 Hearts with concentric LVH are highly susceptible to subendocardial ischemia for several reasons49: ❒
❒
❒
❒
There is some evidence of inadequate coronary growth relative to muscle mass, with a resultant decrease in capillary density.50 The ensuing increase in capillary-to-myocyte oxygen diffusion distance renders the hypertrophied myocyte more susceptible to ischemia. The increase in ventricular wall thickness raises the epicardial-endocardial distance. Coronary arterial circulation consists of epicardial vessels that penetrate transmurally, giving rise to mid-myocardial branches that perfuse the thickened LV wall before supplying the subendocardium. Thus, coronary perfusion pressure is dissipated in proportion to LV wall thickness, leaving the subendocardium as the region most vulnerable to ischemia.49 Coronary arterial remodeling accompanies concentric hypertrophy and is manifested by an increase in coronary arterial medial thickness and perivascular fibrosis, which can restrict the extent of coronary arterial vasodilatation. Vascular tone at rest is often abnormally reduced, and coronary flow at rest is increased in the hypertrophied heart.51,52 Enhanced coronary flow is required in the resting state to supply the increased muscle mass. However, since maximal achievable coronary flow is similar to that of normal ventricles, coronary flow reserve is diminished. Endothelial
❒
❒
dysfunction also may contribute to the reduction in coronary reserve, although the response to exogenous nitric oxide is preserved.53,54 Thus, when metabolic demand and the need for oxygen increase, coronary reserve is often inadequate to meet the increased oxygen requirements, and ischemia ensues.52 Increased LV diastolic pressures can cause vascular compression, thereby reducing coronary flow and perfusion of the subendocardial layer.49 The incidence and severity of coronary atherosclerosis is increased in the presence of systemic arterial hypertension, a frequent cause of concentric LVH. Thus, patients with concentric LVH on a hypertensive basis often have significant concomitant coronary artery disease.
These factors make the heart with concentric LVH exquisitely sensitive to subendocardial ischemia. The hypertrophied ventricle also cannot relax normally in diastole with exercise. Thus, to produce the necessary increase in ventricular input, there is an increase in LA pressure, rather than the normal reduction in ventricular pressure, which produces a suction effect, as previously described. This can lead to an elevation in pulmonary capillary pressure that is sufficient to induce pulmonary congestion. Exercise-induced subendocardial ischemia can produce an “exaggerated” impairment of diastolic relaxation of the hypertrophied myocardium (see Fig. 2-15). These factors often act in concert. For a given degree of ischemia, the functional impairment in relaxation is more severe in the hypertrophied than in the nonhypertrophied heart.9,48 Thus, patients with concentric LVH secondary to chronic hypertension or aortic stenosis are particularly susceptible to ischemic diastolic dysfunction.
Genetic and Infiltrative Diseases Genetic disease processes, such as hypertrophic cardiomyopathy, and infiltrative diseases, such as amyloidosis, cause diastolic dysfunction and lead to the development of DHF. These disease processes are discussed in detail in Chapters 21 and 23.
Trigger Mechanisms of Noncardiac Factors in Acute Decompensated Diastolic Heart Failure Patients with DHF are older and have a large number of coexistent, comorbid disease processes, each of which may act on the structural and functional substrate that occurs in patients with DHF and may trigger the development of acute decompensated DHF (see Fig. 2-14). For example, present in patients with DHF may be advanced age, poorly controlled diabetes, chronic renal insufficiency, anemia, atrial fibrillation, selected drugs (e.g., glitazones, acidic nonsteroidal anti-inflammatory drugs [ANSAIDs], calcium channel blockers), abnormal sodium and water balance, chronic lung disease, increased arterial blood pressure, and increased effective arterial elastance. When present chronically, some of these factors may contribute to development of the structural and functional changes that form the substrate from which DHF develops. For example, diabetes may be associated with increases in advanced glycation endproduct–induced collagen cross-links, in collagen content, and in myocardial stiffness. The changes in the structure and function of cardiomyocytes and extracellular matrix that are common to advanced age may make the myocardium more vulnerable to
23
24
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness the effects of hypertension and coronary artery disease, making the development of DHF more frequent. In addition, once the structural and functional substrate of DHF has formed (i.e., concentric remodeling and abnormal diastolic function), the factors previously listed can act on this substrate to precipitate (or trigger) the development of acute decompensated DHF. However, in the absence of the substrate structure/function changes of DHF, these factors by themselves will not result in its development.
FUTURE RESEARCH There are many aspects of the pathophysiology of DHF and acute decompensated DHF that remain to be completely understood. In particular, the cellular and extracellular mechanisms causing the pathophysiologic changes in LV and LA structure and function remain to be completely defined. The independent effects of aging and the relationship between advancing age and the development of diastolic dysfunction and DHF must be addressed, as must also the question of whether diastolic dysfunction is an inevitable consequence of aging or can be avoided by a “successful” aging process, without these abnormalities (particularly as regards diastolic function). We must define whether and how aging plus disease processes (hypertension, diabetes, etc.) common in an aging population result in DHF. Finally, we must define the factors that cause the transition from asymptomatic diastolic dysfunction (with or without compensated LVH or concentric remodeling) to symptomatic DHF. In particular, we must define clinically applicable, noninvasive methods to detect and predict this transition. Only with an increased knowledge and understanding of the pathophysiology of DHF can effective management strategies that target this pathophysiology be developed and successfully applied to patients with DHF to decrease mortality and morbidity of this important cause of congestive heart failure. REFERENCES 1. Quiñones MA, Zile MR, Massie BM, Kass DA, for the Participants of the Dartmouth Diastole Discourses: Chronic heart failure: A report from the Dartmouth Diastole Discourses. Congest Heart Fail 2006;12:162–165. 2. Aurigemma GP, Zile MR, Gaasch WH: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296–304. 3. Bhatia RS, Tu JV, Lee DS, et al: Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355:260–269. 4. Redfield MM, Jacobsen SJ, Burnett JC Jr, et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202. 5. Kitzman DW, Little WC, Brubaker PH, et al: Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–2150. 6. Brucks S, Little WC, Chao T, et al: Contribution of left ventricular diastolic dysfunction to heart failure regardless of ejection fraction. Am J Cardiol 2005;95:603–606. 7. Zile MR, Gaasch WH, Carroll JD, et al: Heart failure with a normal ejection fraction. Is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? Circulation 2001;104:779–782. 8. Zile MR: Heart failure with preserved ejection fraction: Is this diastolic heart failure? J Am Coll Cardiol 2003;41:1519. 9. Aurigemma GP, Gaasch WH: Clinical practice. Diastolic heart failure. N Engl J Med 2004;351:1097–1105. 10. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure—abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 2004;350:1953–1959.
11. Baicu CF, Zile MR, Aurigemma GP, et al: Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation 2005;111:2306–2312. 12. Zile MR, Baicu CF, Bonnema DD: Diastolic heart failure: Definitions and terminology. Prog Cardiovasc Dis 2005;47:307–313. 13. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387–1393. 14. Yusuf S, Pfeffer MA, Swedberg K, et al. and CHARM Investigators and Committees: Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet 2003;362:777–781. 15. Oh JK, Hatale L, Tajik AJ, et al: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506. 16. Nagueh SF, Mikati I, Kopelen HA, et al: Doppler estimation of left ventricular filling pressure in sinus tachycardia. A new application of tissue Doppler imaging. Circulation 1998;98:1644–1650. 17. Ahmen SH, Clark LL, Pennington WR, et al: Matrix metalloproteinases/ tissue inhibitors of metalloproteinases: Relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation 2006;113:2089–2096. 18. Cheng CP, Igarashi Y, Little WC: Mechanism of augmented rate of left ventricular filling during exercise. Circ Res 1992;70:9–19. 19. Cheng CP, Noda T, Nozawa T, et al: Effect of heart failure on the mechanism of exercise induced augmentation of mitral valve flow. Circ Res 1993;72:795–806. 20. Little WC, Cheng CP: Modulation of diastolic dysfunction in the intact heart. In Lorell BH, Grossman W (eds): Diastolic Relaxation of the Heart: The biology of diastole in health and disease, 2d ed. Boston, Kluwer Academic Publishers, 1994:167–176. 21. Little WC: Diastolic dysfunction beyond distensibility: Adverse effects of ventricular dilatation. Circulation 2005;112:2888–2890. 22. Katz AM: Physiology of the Heart. New York, Raven Press, 1992: 178. 23. Carroll JD, Hess OM, Hirzel HO, et al: Dynamics of left ventricular filling at rest and during exercise. Circulation 1983;68:59–67. 24. Carroll JD, Hess OM, Hirzel HO, et al: Exercise-induced ischemia: The influence of altered relaxation on early diastolic pressures. Circulation 1983;67:521–528. 25. Borbély A, van der Velden J, Papp Z, et al: Cardiomyocyte stiffness in diastolic heart failure. Circulation 2005;111:774–781. 26. Van Heerebeek L, Borbély A, Niessen HWM, et al: Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 2006;113:1966–1973. 27. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part II. Causal mechanisms and treatment. Circulation 2002;105:1503–1508. 28. Gandhi SK, Powers JC, Nomeir AM, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001;344: 17–22. 29. Vinch CS, Aurigemma GP, Hill JC, et al: Usefulness of clinical variables, echocardiography, and levels of brain natriuretic peptide and norepinephrine to distinguish systolic and diastolic causes of acute heart failure. Am J Cardiol 2003;91:1140–1143. 30. Owan TE, Hodge DO, Herges RM, et al: Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251–259. 31. Yancy CW, Lopatin M, Stevenson LW, et al for the ADHERE Scientific Advisory Committee and Investigators: Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: A report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol 2006;47:76–84. 32. Brucks S, Little WC, Chao T: Relation of anemia to diastolic heart failure and the effect on outcome. Am J Cardiol 2004;93:1055–1057. 33. Fukuta H, Sane DC, Brucks S, et al: Statin therapy may be associated with lower mortality in patients with diastolic heart failure: A preliminary report. Circulation 2005;112:357–363. 34. O’Meara E, Clayton T, McEntegart MB, et al: Clinical correlates and consequences of anemia in a broad spectrum of patients with heart failure: Results of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program. Circulation 2006;113:986–994.
Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness 35. Zile MR: Treating diastolic heart failure with statins. “Phat” chance for pleiotropic benefits (editorial). Circulation 2005;112:300–303. 36. Katz AM, Zile MR: New molecular mechanism in diastolic heart failure (editorial). Circulation 2006;113:1922–1925. 37. Little WC, Zile MR, Klein A, et al: Effect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and left ventricular diastolic dysfunction. Am J Cardiol 2006;98:383–385. 38. Warner JG Jr, Metzger DC, Kitzman DW, et al: Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999;33:1567–1572. 39. Little WC, Wesley-Farrington DJ, Hoyle J, et al: Effect of candesartan and verapamil on exercise tolerance in diastolic dysfunction. J Cardiovasc Pharmacol 2004;43:288–293. 40. Eberli FR, Stromer H, Ferrell MA, et al: Lack of direct role for calcium in ischemic diastolic dysfunction in isolated hearts. Circulation 2000;102:2643–2649. 41. Apstein CS, Grossman W: Opposite initial effects of supply and demand ischemia on left ventricular diastolic compliance: The ischemia-diastolic paradox. J Mol Cell Cardiol 1987;19:119–128. 42. Varma N, Eberli FR, Apstein CS: Increased diastolic chamber stiffness during demand ischemia: Response to quick length change differentiates rigor-activated from calcium-activated tension. Circulation 2000;101: 2185–2192. 43. Varma N, Eberli FR, Apstein CS: Left ventricular diastolic dysfunction during demand ischemia: Rigor underlies increased stiffness without calcium-mediated tension. Amelioration by glycolytic substrate. J Am Coll Cardiol 2001;37:2144–2153. 44. McKenney PA, Apstein CS, Mendes LA, et al: Increased left ventricular diastolic chamber stiffness immediately after coronary artery bypass surgery. J Am Coll Cardiol 1994;24:1189–1194.
45. McKenney PA, Apstein CS, Mendes LA, et al: Immediate effect of aortic valve replacement for aortic stenosis on left ventricular diastolic chamber stiffness. Am J Cardiol 1999;84:914–918. 46. Bolli R: Myocardial “stunning” in man. Circulation 1992;86:1671. 47. Pepine CJ, Wiener L: Relationship of anginal symptoms to lung mechanics during myocardial ischemia. Circulation 1972;46:863– 869. 48. Eberli FR, Apstein CS, Ngoy S, et al: Exacerbation of left ventricular ischemic diastolic dysfunction by pressure-overload hypertrophy. Modification by specific inhibition of cardiac angiotensin converting enzyme. Circ Res 1992;70:931–943. 49. Isayama S: Interplay of hypertrophy and myocardial ischemia. In Lorell BH, Grossman W (eds): Diastolic Relaxation of the Heart: The biology of diastole in health and disease, 2d ed. Boston, Kluwer Academic, 1994:203–212. 50. Tomanek RJ, Wessel TJ, Harrison DG: Capillary growth and geometry during long-term hypertension and myocardial hypertrophy in dogs. Am J Physiol 1991;261:H1011–H1018. 51. Eberli FR, Ritter M, Schwitter J, et al: Coronary reserve in patients with aortic valve disease before and after successful aortic valve replacement. Eur Heart J 1991;12:127–138. 52. Marcus ML, Koyanagi S, Harrison DG, et al: Abnormalities in the coronary circulation that occur as a consequence of cardiac hypertrophy. Am J Med 1983;75:62–66. 53. Ishihara K, Zile MR, Nagatsu M, et al: Coronary blood flow after the regression of pressure-overload left ventricular hypertrophy. Circ Res 1992;71:1472–1481. 54. MacCarthy PA, Shah AM: Impaired endothelium-dependent regulation of ventricular relaxation in pressure-overload cardiac hypertrophy. Circulation 2000;101:1854–1860.
25
3
DAVID H. SPODICK, MD
Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure INTRODUCTION PATHOPHYSIOLOGY CLINICAL RELEVANCE AND FUTURE RESEARCH ABBREVIATIONS
INTRODUCTION Pericardologists1 were concerned almost exclusively with diastole (for good reasons of pericardial constriction and cardiac tamponade) before the late 1980s, when diastolic dysfunction (DD) started to attract widespread attention among other cardiologists. In many respects, acute and subacute constrictive pericarditis (CP) and cardiac tamponade epitomize DD, usually in the presence of normal systolic cardiac function. Indeed, both often have normal or high ejection fractions (EFs)—a consequence of ventricular underfilling with basically normal or compensatorily hyperfunctional myocardium.2 However, the normal pericardium also affects the cardiac filling dynamics of both normal and diseased hearts, although to a lesser degree.3
PATHOPHYSIOLOGY The normal pericardium becomes more important in dilated hearts and with increased central circulatory volume and less so with hypovolemia and normal responses to other influences that reduce cardiac size, like head-up tilt (HUT), lower body negative pressure (LBNP), and administration of such agents as nitroprusside and nitroglycerine.3 With the often low compliance of hearts with DD, the influence on filling of the normally stiff, lowcompliance pericardium may be either less than normal or additive, but this relationship has not been investigated. In the absence of formal, specifically targeted investigations of the influence of the pericardium on DD and diastolic heart failure
(DHF), the current state of knowledge permits only reasonable extensions and hypothesis generation from what we know of pericardial function and behavior during normal cardiac function and to some extent during systolic cardiac impairments. Box 3-1 summarizes the macrophysiology of the normal pericardium, many elements of which—subject to investigation—may affect DD and DHF. Box 3-2 summarizes the many cardiac effects of pericardiectomy or sufficiently extensive pericardiotomy.4 Patients who have had pericardiectomy for any indication grossly appear to function quite well, although the subject has not been intensively studied in human patients and certainly not compared for individual patients acutely and especially chronically, which would permit a better estimate of the pericardium’s dispensability. In considering the many effects of pericardiectomy and pericardiotomy sufficiently widespread to remove pericardial mechanical influence (see Box 32), the apparent benignity of pericardiectomy/otomy is at least superficially surprising because it implies that there are either widespread and adequately compensatory adjustments or that the pericardium is really not indispensable. Nonindispensability would be especially surprising when one considers the items in Box 3-1, as well as the very rich pericardial microphysiology5 (not a subject of this discussion). There is, however, broad and deep experience with experimental pericardiectomy and pericardiotomy (see Box 3-2) in hearts without cardiac disease, which, like the macro functions of the normal pericardium (see Box 3-1), should be considered in evaluating and further investigating DD and DHF. All pericardial investigations must always be considered in the light of the varied investigational protocols, which have definitely affected experimental results. Thus, it matters quantitatively and even qualitatively whether the experimental subjects are intact and conscious with a closed chest and having recovered from surgery, versus open chest, anesthetized, and/or autonomically blocked experimental subjects, as well as the species of the subjects.3 For example, dog, rabbit, and human pericardial structures differ significantly; the canine pericardium is much more anisotropic than the human pericardium.6 Moreover, within the intact pericardium, it matters quantitatively whether the pressure is 27
28
Chapter 3 • Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure Box 3-1
Macrophysiology of the Normal Pericardium* Mechanical Functions: Promotion of Cardiac Efficiency, Especially during Hemodynamic Overloads I. Relatively inelastic cardiac envelope A. Maintenance of normal ventricular compliance (volume-elasticity relation) B. Defense of the integrity of any Starling curve: Starling mechanism operates uniformly at all intraventricular pressures because presence of pericardium 1. Maintains ventricular function curves. 2. Limits effect of increased left ventricular end diastolic pressure. 3. Supports output responses to: a. Venous inflow loads and atrioventricular valve regurgitation (particularly when acute) b. Rate fluctuations 4. Hydrostatic system (pericardium plus pericardial fluid) distributes hydrostatic forces over epicardial surfaces. a. Favors equality of transmural end diastolic pressure throughout ventricle, therefore uniform stretch of muscle fibers (preload) b. Constantly compensates for changes in gravitational and inertial forces, distributing them evenly around the heart C. Limitation of excessive acute dilation D. Protection against excessive ventriculoatrial regurgitation (atrial support) E. Ventricular interaction: relative pericardial stiffness 1. Provides a mutually restrictive chamber favoring balanced output from right and left ventricles integrated over several cardiac cycles 2. Permits either ventricle to generate greater isovolumic pressure from any volume 3. Reduces ventricular compliance with increased pressure in the opposite ventricle (e.g., limits right ventricular stroke work during increased impedance to left ventricular outflow) F. Maintenance of functionally optimal cardiac (especially left ventricular) shape
II. Provision of closed chamber with slightly subatmospheric pressure in which: A. The level of transmural cardiac pressures will be low, relative to even large increases in “filling pressures” referred to atmospheric pressure. B. Pressure changes aid atrial filling via more negative pericardial pressure during ventricular ejection. C. Diastolic suction can accelerate filling following systole. III. “Feedback” cardiocirculatory regulation via pericardial servomechanisms A. Neuroreceptors detect lung inflation and (via vagus): alter heart rate and blood pressure. B. Mechanoreceptors: Lower blood pressure and contract spleen. IV. Limitation of hypertrophy associated with chronic exercise Membranous Functions I. Reduction of external friction due to heart movements A. Production of pericardial fluid B. Generation of phospholipid surfactants II. Buttressing of thinner portions of the myocardium: Myocardial thickness varies reciprocally with parietal pericardial thickness. A. Atria B. Right ventricle III. Defensive immunologic constituents in pericardial fluid IV. Fibrinolytic activity in mesothelial lining V. Prostacyclin (PGE2, PG12 and eicosanoids) released into pericardial sac in response to stretch, hypoxia and increased myocardial loading/work VI. Synthesis and release of endothelin, increased by angiotensin III stimulation VII. Barrier to inflammation from contiguous structures Ligamentous Function I. Limits undue cardiac displacement II. Modifies pericardial stress/strain by limiting directions of traction of its fibers
*Condensed from Spoclick DH: The pericardium: A comprehensive textbook. New York, Marcel Dekker, 1997.
measured by an open-ended catheter or a flat balloon transducer, with balloons yielding higher levels of pericardial constraint (specifically radial epicardial stress), especially significant at very low effusion volumes.7 Most of the pathophysiologic effects of pericardiectomy or sufficiently extensive pericardiotomy must be considered in light of the fact that the pericardium, specifically the parietal pericardium, constrains the heart, which is immediately recognizable by retraction of the in situ pericardial tissue when it is incised.3 (The visceral pericardium may also have some constraining effect, but this is incompletely investigated.) Indeed, in 1898 Barnard incised the pericardium and observed that the heart herniated through the incision, especially in diastole and more so when he squeezed the abdomen, elevating vena cava pressure.8 Thus it is no surprise that pericardial constraint accounts for about 90% of right atrial (RA) and 80% of right ventricular (RV) cavitary pressure.9 The immediate filling pressures of the cardiac chambers are their transmural pressures (TMPs): cardiac chamber pressures minus
normally negative—therefore numerically additive—intrapericardial pressure.3 TMPs are created by having an intact pericardium and are approximately equal over both ventricles, although there may be local effects causing small local differences.10 The right ventricular end diastolic pressure-dimension (RVEDPD) relation, for example, is not flat or zero because of this, and as noted in Box 3-2, at matched left ventricular end-diastolic (LVED) volume, pericardiectomy causes a fundamental alteration in otherwise normal RV, but not left ventricular (LV), filling.11 Finally, transmural LVED pressure is a more important determinant of LV mechanoreceptor activity than absolute LVED pressure.3,12 Mechanoreceptors are sensitive to changes in ventricular stretch, determined by ventricular volume and TMP; pericardial constraint may attenuate their activity by limiting cardiac distension.3 Whereas, with an intact pericardium, the right ventricle dominates direct ventricular diastolic interaction (ventricular interdependence), after pericardiectomy or sufficiently extensive
Chapter 3 • Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure Box 3-2
Pericardiectomy/Pericardiotomy*: Pathophysiologic Effects A. General Considerations 1. Reduced or absent constraint of the cardiac chambers 2. At matched LVEDV, pericardiectomy causes a fundamental alteration in RV but not LV filling. 3. Pericardiectomy shifts LVEDP-V curve to the right. 4. Pericardiectomy decreases RVEDP-V slope. 5. Reduced atrioventricular and ventricular interaction (i.e., parallel interaction, due to pericardium); left ventricle dominates. (With an intact pericardium, the right ventricle dominates.) 6. Decreased suction (less negative pressure) during ventricular systole B. Specific Effects 1. Decreased: a. RA mean pressure b. RA filling rate c. Pulmonary volume overload with intravascular volume loading d. Excess intravascular volume redistribution from pulmonary systemic circulation e. Decreased ventricular isovolumic pressure generation from any volume f. Decreased base to apex intraventricular pressure gradient; filling velocity shifts toward the base g. E/A and E′ h. Decreased LV mechanoreceptor activity12 2. Increased: a. Cardiac chamber transmural pressures b. RV size c. LV stroke volume, SWI and CI due to Frank-Starling response to increased preload d. LA compliance with greater increase in conduit than reservoir function e. LV compliance f. Peak dp/dt g. Early LV filling velocity (A) and filling fraction h. LV end diastolic diameter and volume i. LV early filling rate j. Ventricular series interactions (relative to direct interaction) k. LV mechanoreceptor activity l. Rate of myocardial protein synthesis producing increased LV mass m. Exercise responses i. Maximal O2 consumption ii. Maximal stroke volume and cardiac output iii. LA pressure and SV and LASV iv. LV end diastolic pressure n. Ventricular pressure-volume curves: Ventricular pressure begins its sharp rise later (at a higher cardiac volume) and increases more gradually thereafter. *Pericardiotomy = sufficiently wide incision/excision.
pericardiotomy, the left ventricle dominates the relationship; thus LV isovolumic pressure generation from any LV volume is decreased and, comparably, after pericardiectomy ventricular pressure-volume (P-V) curves show their customary sharp rise later (i.e., at a higher chamber volume) and thereafter also increase more gradually than before pericardiectomy.13
After pericardiectomy, the cardiac chambers operate at different TMPs because of the normally slightly negative intrapericardial pressure (unless, subject to investigation, the ambient pleural and pulmonary pressures of the cardiac fossa could substitute for this). With DHF, pericardial influence would also be subject to investigation to characterize cardiac filling in relation to the TMPs. Moreover, the force balance affecting cardiac chambers and their corresponding systolic performance is described by the transmural difference between intracavitary and extramural pressures.14 Indeed, the chamber collapses seen in cardiac tamponade can be attributed to sometimes even negative transmural diastolic pressures (i.e., intrapericardial pressure intermittently sufficiently higher than subjacent chamber pressures). In pericardial constriction (usually completely obliterative), there can be no truly transmural pressures.2 Ventricular interaction (ventricular interdependence) reflects the influence, particularly the filling characteristics, of the contralateral ventricle.4 Direct interaction occurs immediately via the ventricular septum, while indirect interaction (series interaction) is by way of the pericardium. For series interaction, an immediate change in one ventricle is not transmitted as directly as through the septum but is transmitted sequentially in subsequent heartbeats. Series and direct interaction influence P-V relations, pulmonary-cardiac contact pressure, and coronary engorgement. Of these, the P-V relations are the most important to producing LV diastolic pressure. Hypertrophied hearts, which are characterized by DD, especially with ventricular failure, should be a natural subject for further investigation of interaction. Draining a noncompressing hydropericardium, as occurs in heart failure, induces a state analogous to removing the normal pericardial constraint, or at least reducing it considerably, since it has been shown that any size, small to large, of even clinically nontamponading effusions significantly exaggerate respiratory effects on cardiac dynamics when measured with appropriate instruments.15 These are a quantitatively small counterpart to the effusions producing cardiac tamponade, which more strongly couple the parietal pericardium to the chamber surfaces, grossly exaggerating ventricular interaction, especially the respiratory effects due to the existence of an intact pericardium, notably pulsus paradoxus.16 A particular advantage of an intact pericardium, which could be investigated in DD and DHF, is the pericardial contribution to diastolic suction. Diastolic suction, specifically ventricular suction, occurs in early diastole and must exist in normal as well as abnormal hearts.17 The intensity of diastolic suction is proportional to the kinetic energy of the preceding systole. Moreover, diastolic suction is greatest when the heart size is least, after the end of systole, precisely when it is needed for filling. (Systolic suction may also exist in the atria during reduction of intrapericardial contents by ventricular ejection.3) Presence of the pericardium thus permits the kinetic energy acquired during systole to be applied to filling. Moreover, diastolic suction is more important at the rapid heart rates common to cardiac failure, which amputate the late to mid-diastolic diastasis interval so that there is less “passive” filling. In any case, suction must be necessary for even normal cardiac filling because, although the Frank-Starling relation implies that cardiac output should be determined by venous filling of the right heart, RA pressure is normally low, and small changes should not affect the entire heart. Indeed, changes in body position and breathing may cause larger changes in pressure.18 This is dramatically seen when excised mammalian hearts in buffered solutions continue to empty and refill, where pericar-
29
30
Chapter 3 • Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure dial absence ensures that there can be no change in extramural pressure. Yet, diastolic suction is directly observed, indeed obvious. In such hearts, an intact pericardium would facilitate or magnify suction. In these isolated hearts, diastolic filling pressure thus does not uniquely determine fiber length and cannot entirely explain the cardiac “output.” In DD, one might predict that decreased myocardial compliance, epitomized by hypertensive hearts, would reduce macrophysiologic pericardial effects by analogy to pericardial effects on the normal right and left ventricles; the normal right ventricle is thinner and far more compliant than the left—especially with LV hypertrophy—and thus much more directly subject to pericardial constraint and to changing intrapericardial pressure. Indeed, normal RV compliance is three to four times LV compliance,19 a relationship predictably affected by DHF but subject to investigation. Another target for investigation in DD and DHF would be the effect of the pericardium in restricting acute chamber dilation (as of the left atrium following papillary muscle rupture with acute mitral regurgitation). Constraint is illustrated in reverse in those cases of “pericardial shock” with severe hypotension immediately after pericardiocentesis, usually in patients with concomitant heart disease who develop acute LV failure after pericardial drainage due to acute LV dilation.20 Indeed, some of these patients also develop acute pulmonary edema. One could assume that the pericardium and pericardial effusion fluid, especially with cardiac tamponade, had resisted ventricular dilation, following which drainage left a lax, nonconstraining, and therefore no longer resisting (constraining) pericardium. The effects of pericardiectomy could also be investigated in DHF on a purely mechanistic basis because pericardiectomy shifts the LVED P-V relationship to the right or down (Box 3-2), while DHF shifts it to the left.21 Some of the major considerations are condensed in Box 3-3. Box 3-3
Selected Major Pericardial Functions Potentially* Applicable to Investigating Diastolic Dysfunction and Diastolic Failure I. Mechanical effects due to mainly the parietal pericardium and minimal in euvolemic individuals with normal hearts A. Decreased by hypovolemia B. Exaggerated by central hypervolemia (and pericardial effusion with or without tamponade) and by cardiac dilation C. Comparative effects in DD/DHF uninvestigated II. Normally, RV and LV volumes are equally restrained by the pericardium. (Though perhaps due to regional pericardial effects, cavitary pressures fall more in RV than LV after pericardiectomy.) Effects with DD/DHF uninvestigated. III. Differences in RV and LV filling partly relate to differences in atrial compliance and ventricular distensibility. (Volume loading and pericardiectomy affect A-V pressure gradient.) Effects in DD/DHF uninvestigated. IV. Nitroglycerine and nitroprusside decrease ventricular diastolic pressures, reflecting loss of pericardial constraint when decreased venous return shrinks cardiac volume. Applications in DD/DHF uninvestigated. *Pending formal, specific investigation.
CLINICAL RELEVANCE AND FUTURE RESEARCH Pericardial pathophysiology as capsulated in Boxes 3-1 and 3-2 applies to investigations of the pericardium and its effect on the normal heart, usually the left ventricle. There are as yet no formal investigations of the role of the pericardium in patients and animal models with DD or DHF. Although one may generate hypotheses (e.g., see Box 3-3) and make reasonable projections from the foregoing data, clinical relevance can emerge only from specifically designed, controlled investigations tested in appropriate clinical contexts. For example, does the stiffness of the normal pericardium, accounting for its normal constraint,13 add to or otherwise modify the reduced compliance of the hypertensive left ventricle with DD or DHF? In some circumstances, structural pericardial modifications may be a therapeutic option. When pericardiectomy was tried some years ago for dilated cardiomyopathy, it proved to be more detrimental than helpful. The recent development, however, of a pericardial “garment” for the ventricles (e.g., the Acorn mesh) actually compensates for pericardial anisotropy since it is constructed with special fiber orientations that oppose the differing directional tensions in the underlying pericardial fibers.22 In addition, there is currently an enlarging field of intrapericardial drug and instrumental therapy for investigation in diastolically as well as systolically and rhythmically abnormal hearts.23
ABBREVIATIONS HUT: Head-up tilt LBNP: lower body negative pressure DD: diastolic dysfunction DHF: diastolic heart failure TMP: transmural pressure: cardiac chamber pressures minus normally negative—therefore additive—pericardial pressure (e.g., LVTMP = left ventricular transmural pressure, and so on) PTMP: pericardial transmural pressure: intrapericardial pressure minus pleural pressure LV: left ventricle LA: left atrium RV: right ventricle RA: right atrium EDP: end diastolic intracavitary pressure (e.g., LVEDP = left ventricular end diastolic pressure, and so on) EDPV relation: end diastolic pressure-volume relation EDPD relation: end diastolic pressure-dimension relation Ventricular interaction (interdependence): Effects of physical changes and movements in one ventricle on the other. Direct interaction: septal movement (as during breathing phases) imposed by pericardial constraint (series interaction is the effect via the vasculature and lungs of one ventricle on the other). Pericardium-dependent ventricular interactions are almost entirely diastolic, although systolic and atrioventricular interactions also exist. Suction: filling of a cardiac chamber because of negative/relatively negative pressure “leading” the direction of blood flow. Ventricular diastolic suction is especially important, especially at small/relatively small chamber/heart volumes. Most suction is facilitated by an intact pericardium. CP: constrictive pericarditis CT: cardiac tamponade EF: ejection fraction
Chapter 3 • Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure REFERENCES 1. Seferovic PM, Spodick DH, Maisch B (eds): Pericardiology. Belgrade, Science, 1999. 2. Haffty BG, Singh JB, Spodick DH: Tracking left ventricular performance noninvasively: Response of the peak ear pulse derivative during cardiac catheterization. Chest 1983;83:543–546. 3. Spodick DH: Threshold of pericardial constraint: The pericardial reserve volume and auxiliary pericardial functions. J Am Coll Cardiol 1985;6: 296–297. 4. Spodick DH: Pericardial diseases. In Braunwald E, Zipes DP, Libby P (eds) Heart Disease, 6th ed. Philadelphia, WB Saunders, 2001:1823–1866. 5. Spodick DH: Macro and microphysiology and anatomy of the pericardium. Am Heart J 1992;124:1046–1051. 6. Janicki JS, Weber KT: The pericardium and ventricular interaction, distensility, and function. Am J Physiol 1980;238:H494–H503. 7. Tyberg JV, Misbach GA, Glantz SA, et al: A mechanism for shifts in the diastolic left ventricular pressure-volume curve: The role of the pericardium. Euro J Cardiol 1978;7:163–175. 8. Spodick DH: Acute pericarditis. New York, Grune Stratton, 1959:182. 9. Hamilton DR, Dani RS, Semlacher RA, et al: Right atrial and right ventricular transmural pressures in dogs and humans: Effects of the pericardium. Circulation 1994;90:2492–2500. 10. Spadaro J, Bing OHL, Gaasch WH, Weintraub RM: Pericardial modulation of right and left ventricular diastolic interaction. Circ Res 1981; 48:233–238. 11. Gaasch WH, Zile MR: Left ventricular diastolic dysfunction and diastolic heart failure. Annu Rev Med 2004;55:373–394. 12. Wang SY, Sheldon RS, Bergman DW, Tyberg JV: Effects of pericardial constraint on left ventricular mechanoreceptor activity in cats. Circulation 1995;92:3331–3336.
13. Spodick DH: Progress in investigation of effusion and tamponade, immunosuppression, and constriction in pericarditis and pericardial diseases. Curr Op Cardiol 1992;7:476–481. 14. Boltwood CM: Ventricular performance related to transmural filling pressure in clinical cardiac tamponade. Circulation 1987;75:941–947. 15. Wayne VS, Bishop RL, Spodick DH: Dynamic effects of nontamponading pericardial effusion: Respiratory responses in the absence of pulsus paradoxus. Br Heart J 1984;51:202–204. 16. Spodick DH: Pathophysiology of cardiac tamponade. Chest 1998;113: 1372–1378. 17. Myers RBH, Spodick DH: Constrictive pericarditis: Clinical and pathophysiologic characteristics. Am Heart J 1999;138:219–232. 18. Robinson TF, Factor SM, Sonnenblick EH: The heart as a suction pump. Scient Amer 1981;210:84–98. 19. Belenkie I, Dani R, Smith ER, Tyber JV: The importance of pericardial constraint in experimental pulmonary embolism and volume loading. Am Heart J 1992;123:733. 20. Spodick DH: The pericardium: A comprehensive textbook. New York, Dekker, 1997. 21. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387–1393. 22. Saavedra WF, Tunin RS, Paolocci N, et al: Reverse remodeling and enhanced adrenergic reserve from passive external support in experimental dilated heart failure. J Am Coll Cardiol 2002;39:2069–2076. 23. Spodick DH: Direct therapy for coronary disease, myocardial disease, and severe cardiac arrhythmias. In Spodick DH (ed): Intrapericardial therapeutics and diasgnostics (IPTD). Clin Cardiol 1999;22:I–1, I–42.
31
BRIAN D. HOIT, MD
4 Left Atrial Function: Basic Physiology INTRODUCTION PATHOPHYSIOLOGY Atrial Function in Health Left Atrial Reservoir Function Left Atrial Conduit Function Global Left Atrial Function LEFT ATRIAL FUNCTION IN DISEASE Left Atrial Function and Systolic Left Ventricular Dysfunction
Left Atrial Function and Diastolic Left Ventricular Dysfunction Left Atrial Function in a Model of Atrial Systolic Failure Importance of Left Atrial Functions and Their Interplay in Left Ventricular Systolic Dysfunction FUTURE RESEARCH ACKNOWLEDGMENT
INTRODUCTION A resurgence of interest in atrial function has enhanced our understanding of the atrial contributions to cardiovascular performance in health and disease (see Chapter 13). The reasons for this “renaissance” are multifactorial and include (1) the recognition that atrial function is an important, at times critical, determinant of left ventricular (LV) filling, (2) the increasing number of drugs, devices, ablative procedures, and surgeries available for the treatment of atrial fibrillation,1–3 (3) the considerable interest in dual- and three-chamber pacemakers that maintain atrioventricular and biventricular synchrony, respectively,4–6 (4) the pathophysiological and clinical relevance of chamber-specific structural, electrical, and ionic remodeling,7–9 (5) the clinical impact of atrial distensibility and stunning, particularly postcardioversion,10,11 and (6) the important prognostic role of atrial function in heart failure.12,13 Despite this attention, quantifying atrial function is difficult, in part because the atria are geometrically complex. Because of the obliquity of the atrial septum, the right atrium projects anteriorly, inferiorly, and to the right of the left atrium. The broad, triangular, muscular right atrial (RA) appendage protrudes anteriorly, the superior vena cava opens into the dome of the right atrium, and the inferior vena cava opens into its inferior and posterior portion. The body of the left atrium is smaller and thicker than the right atrium. The chamber has been modeled as a sphere, cube, or ellipse. The left atrial (LA) appendage is longer and narrower than the right appendage and contains all the pectinate muscles of the
left atrium. The four pulmonary veins, upper and lower from each lung (the left pair frequently opening via a common channel), enter the posterior aspect of the left atrium.14 The atrial walls consist of two muscular layers, the fascicles of which both originate and terminate at an atrioventricular ring and follow nearly perpendicular courses. Fascicles in the inner layer ascend vertically through a pectinate muscle, change depth and course circumferentially in the outer layer, encircle the atrium, dive into the inner layer, and descend vertically within a pectinate muscle. While some fascicles are intrinsic to one atrium, others are shared. The muscular terminations of the veins are also composed of two layers, the inner longitudinal and the outer circular.15 Ultrastructurally, atrial myocardium differs significantly from ventricular myocardium. For example, myocytes are smaller in diameter and have fewer T-tubules and more abundant Golgi apparatus in the atrium than in the ventricle.16 Rates of contraction and relaxation and of conduction velocity and anisotropy differ, as do their respective biophysical underpinnings (i.e., myosin isoform composition and qualitative and quantitative differences in a wide assortment of ion transporters, channels, and gap junctional proteins).17–19 While there are important differences between left and right atrial structures and functions at various organizational hierarchies, the function of the left atrium at the organ level will be used in this chapter to illustrate the atrial contributions to ventricular filling. The discussion is drawn largely from studies our group has performed over the past 15 years. 33
34
Chapter 4 • Left Atrial Function: Basic Physiology
PATHOPHYSIOLOGY
Pressure-Volume Relations of the Atrium
Atrial Function in Health
A time-independent representation of the atrial events during the cardiac cycle can be obtained by plotting instantaneous atrial pressure and volume (Fig. 4-1). During ventricular systole, atrial relaxation and descent of the ventricular base lower atrial pressure (the “x” descent) and assist in atrial filling; the latter results in a “v” wave on the atrial pressure tracing. Thus, during ventricular systole, the atrium operates as a reservoir, storing systemic and pulmonary venous return. When the atrioventricular valves open, blood stored in the atria empties into the ventricles, and atrial pressure falls (the “y” descent), during which time the atria act as conduits for venous blood flow into the ventricles. Atrial contraction, denoted by an “a” wave on the atrial pressure tracing, actively assists ventricular filling. The resultant P-V loop inscribes a “figure-eight” that consists of a clockwise “V” loop due to atrial filling and passive emptying, and a counterclockwise “A” loop due to active atrial contraction. Although Alexander et al. described instantaneous LA P-V relations by a time-varying elastance in the isolated left atrium using computer-simulated LA loading conditions,25 assessment of atrial systolic elastance in vivo was hampered by the lack of an accurate measurement of LA volume with an adequate sampling frequency. Therefore, as a critical initial step, we demonstrated that cast-validated LA volumes could be estimated accurately with high temporal resolution sonomicrometry using two nearly orthogonal atrial dimensions.26,27 The left atrium was assumed to be a general ellipsoid of revolution:
Left Atrial Booster Pump Function
LA pressure (mmHg)
34
v
where SAX is the short or mediolateral axis, and LAX is the long or anteroposterior axis. Coupled with high-fidelity micromanometers, instantaneous P-V loops of the intact left atrium were generated (Fig. 4-2). The maximum slope of the isochronal P-V relation was measured every 10 msec during the “A” loop (from
a
0
MVO
16.0 28
20.5
16.5 ECG
LAed A LAes MVC
V
8.0 6.0
4.0
A BC D 1 sec.
A
LA volume = π/6(SAX)2(LAX),
LA pressure (mmHg)
LA short axis (mm)
40
LA long axis (mm)
The principal role of the left atrium is to modulate LV filling and cardiovascular performance through the interplay of atrial reservoir, conduit, and booster pump functions. Typically, the importance of the atrial booster pump function (i.e., the augmented ventricular filling resulting from active atrial contraction) has been estimated by measurements of (1) cardiac output and LV diastolic volume both with and without effective atrial systole,20 (2) relative LV filling (e.g., early to late [E/A] filling ratios) using steady-state Doppler echocardiographic transmitral flow or radionuclide angiography,21 and (3) atrial shortening using methods such as two-dimensional echocardiography, angiography, and sonomicrometry.22 Booster pump function is also evaluated echocardiographically by estimating the kinetic energy and force generated with atrial contraction.23,24 However, measurements of atrial systolic function and the importance of the atrial booster pump are dependent on a multiplicity of factors, including the timing of atrial systole, vagal stimulation, the magnitude of venous return (i.e., atrial preload), LV end diastolic pressures (i.e., atrial afterload), and LV systolic reserve. Not surprisingly, despite considerable study, the magnitude and relative importance of the atrial contribution to LV filling and cardiac output remain controversial. Analogous to end systolic elastance measurements in the left ventricle (where end systolic elastance is calculated as the slope of the ventricular end systolic pressure-volume [P-V] relation), a load-independent index of atrial contraction based on the instantaneous atrial P-V relation has the potential to explain and minimize the discrepancies and confusion that exist in the literature. Accordingly, understanding and deriving atrial elastance require a consideration of the relation between instantaneous atrial pressure and volume.
LA volume (ml)
B
Figure 4-1 A, Analog recording of left atrial (LA) pressure and dimensions in the time domain. The vertical lines indicate times of mitral valve opening (A), end of passive atrial emptying and onset of atrial diastasis (B), atrial end diastole (C), and atrial end systole (D). “a” and “v” represent respective venous pressure waves. B, LA pressure-volume loop from a single beat illustrating the characteristic figure-eight configuration. Arrows indicate direction of loop as a function of time. “A” loop represents active atrial contraction. “V” loop represents passive filling and emptying of the left atrium. MVO, time of mitral valve opening; LAed, left atrial end diastole; Laes, left atrial end systole. (From Hoit BD et al: Circulation 1994;89:1829–1838.)
Chapter 4 • Left Atrial Function: Basic Physiology BASELINE
POST CALCIUM Slope = 3.6
Slope = 5.4
26.6
LA pressure (mmHg)
LA pressure (mmHg)
17.7
35
6.9
6.7 5.7
8.9
5.0
LA volume (ml)
10.1 LA volume (ml)
A Slope 3.6
Slope = 5.4 23
LA pressure (mmHg)
Figure 4-2 A, Five left atrial pressure-volume loops at baseline (left) and after calcium infusion (right). Note the linearity of the end systolic pressure-volume relations, the greater extent of atrial systolic shortening, and the increase in the end systolic pressure-volume slope after calcium infusion (the latter indicating a positive inotropic effect). B, Loops are computersmoothed for clarity. (From Hoit BD et al: Circulation 1994;89:1829–1838.)
LA pressure (mmHg)
18
7
7 6
9 LA volume (ml)
5
10 LA volume (ml)
B
atrial diastasis to atrial end systole) from five variably loaded beats and were fitted to a time-varying elastance model: E(t) = P(t)/[V(t) − V(o)], where E(t) is time-varying elastance, V(o) is the volume axis intercept, and P(t) and V(t) are instantaneous isochronal pressure and volume, respectively. Loading conditions were altered with either phenylephrine boluses or vena caval occlusions. Time-dependent changes in E(t) and maximal atrial systolic elastance (Emax) were found to be highly linear and sensitive to pharmacologically induced changes in inotropic state. In addition, LA systolic P-V relations using either the non-isochronal maximal P-V ratio (Emax P/V) or end systole (Ees) were shown to be useful estimates of Emax. In addition to assisting the quantitation of ejection phase (i.e., ejection fraction, stroke volume, mean normalized systolic ejection rate [MNSER], and velocity of circumferential shortening [Vcf ]) and load-independent indices of contraction (i.e., Emax, Ees, and Emax P/V), P-V loops of the left atrium offered possibilities for study of atrial energetics in vivo. Specifically, the planimetered “A” loop P-V area (total mechanical work done by the atrium) minus the “V” loop P-V area (work done on the atrium by pulmonary venous blood flow during ventricular systole) represents the net
atrial mechanical work. In a study using normal, open-chest dogs, A- and V-loop areas were similar and did not change with increased atrial preload, suggesting that booster pump and reservoir functions of the atrium were balanced over a wide range of LA pressures. However, calcium-induced increases in contractility and subsequent volume loading produced significant increases in the A- but not the V-loop area, indicating that net atrial mechanical work was greater and load dependent after calcium infusion. Calcium infusion was also associated with a change in the trajectory of the A loop resulting in a decrease in the time from Emax to end systole; thus the atrial A loop, which resembled a right ventricular (RV) P-V loop before, looked like the LV P-V loop after calcium infusion, suggesting an effect of calcium on ventricular input impedance. While atrial P-V loops can be generated in humans using invasive and semi-invasive means,28–31 these methods are cumbersome, time consuming, and difficult to apply. Clearly, there is a need for an objective, noninvasive measurement of atrial myocardial performance and contractility. Measurement of myocardial strain and strain rate, which represent the magnitude and rate of myocardial deformation, are indices that have the potential to overcome these limitations.32
Chapter 4 • Left Atrial Function: Basic Physiology
Left Atrial Reservoir Function Grant et al. estimated that 42% of the LV stroke volume and its associated energy are stored in the left atrium during LV systole.33 The subsequent dissipation of this energy during the reservoir phase acts as a ventricular restorative force during the ensuing LV diastole. Reservoir function is governed by atrial distensibility during ventricular systole (although LA reservoir function has been shown to be related to LA contraction and descent of the LV base during systole34 and to LA systolic shortening and LV end systolic volume35), which is measured rigorously by fitting atrial pressures and dimensions—taken either at the time of mitral valve opening over a range of atrial pressures and volumes or from one of the limbs of the “V” loop in a static P-V loop—to an exponential equation.36,37 Although atrial dimensions and pressures are required for its measurement, the relative reservoir function can be estimated simply with pulmonary vein Doppler (Fig. 4-3). Thus, the proportion of LA inflow during ventricular systole provides an index of the reservoir capacity of the atrium.38 In this regard, we showed that LA compliance is an important independent determinant of the pattern of pulmonary venous flow, using an experimental protocol that excluded the LA appendage and produced an isolated decrease in atrial compliance and relative reservoir-to-conduit flow.22 As a consequence, alterations in atrial compliance in various disease stages should be considered when the pattern of pulmonary venous flow is used to estimate LA pressure, assess LV diastolic function, or quantify mitral regurgitation. Suga showed that atrial compliance was a significant determinant of cardiac performance in a circulatory analog model.39 Specifically, decreased atrial compliance was associated with greater phasic and mean atrial pressures but a lower mean level of atrial pressure during ventricular filling; this resulted in a smaller LV end diastolic volume and decreased venous return. We confirmed earlier mathematical predictions that early LV filling (i.e., Doppler
mitral E velocity) increases directly with operative atrial compliance.40 Thus it is interesting to speculate that regions of increased distensibility in the left atrium may facilitate early diastolic filling of the left ventricle. One such region of the left atrium with increased distensibility is the atrial appendage. In isolated canine atria, the slope of the P-V relation for the left atrium without the appendage is significantly greater than with the appendage intact.41 We subsequently showed that in the intact dog, the pressure-strain relation is steeper (i.e., more stiff or less distensible) in the body than in the appendage of the left atrium (Fig. 4-4). Atrial systolic shortening and reservoir capacity (measured as the change in dimension during atrial systole, and the maximum minus minimum dimension, respectively) increased in both the body and the appendage during volume infusion and were greater in the appendage than in the body of the left atrium. Thus, for a given increase in LA pressure, there was a greater increase in the end diastolic atrial dimension, with greater utilization of the Frank-Starling mechanism by the appendage than by the body of the left atrium. Moreover, biochemical studies indicate that atrial natriuretic factor is concentrated in the LA appendage,42 which may, by virtue of its increased distensibility, be better suited for the regulation of intravascular volume. In addition, greater distensibility of the appendage than the body of the left atrium would be potentially beneficial in the context of increased LV filling pressures and decreased global atrial distensibility. It is interesting that relative blood flow to the LA appendage was increased with experimental LA hypertrophy,43 and the appendage-to-nonappendage LA blood flow ratio was increased during severe exercise in dogs, further suggesting that the LA appendage may become functionally important during stress. These data suggest that the substantial contributions of the appendage to overall LA compliance may have important negative implications for routine atrial appendectomy at the time of mitral valve surgery and for the use of percutaneous appendage exclusion devices.44,45
1 sec
J
K
PV Doppler (cm/sec)
40
KVTI
200
0 0
1 sec 40 J
JVTI 0
ECG
K
KVTI
PV flow (ml/min)
JVTI
PV Doppler (cm/sec)
36
Figure 4-3 Representative pulmonary vein (PV) Doppler with flow-probe waveform superimposed (top panel) and a schematic of the pulmonary venous flow velocity (bottom panel). J and K are peak systolic and diastolic velocities; Jvti and Kvti are systolic and diastolic integrals, respectively. The ratio of systolic-to-diastolic velocities (and integrals) represents the relative reservoir-to-conduit function of the left atrium. (From Hoit BD et al: Circulation 1992;86:651–659.)
Chapter 4 • Left Atrial Function: Basic Physiology 20
LA APP
Mean LA pressure (mmHg)
Mean LA pressure (mmHg)
20
10
LA APP
18
*
16 14
*
12 10 8
* 6
0 0.0
0.1
0.2
0.3
0.4
0.5
0.0
0.6
0.2
0.3
0.4
0.5
Natural strain (ln[D/Dmin])
Natural strain (ln[D/Dmin])
A
0.1
B
Figure 4-4 A, Representative mean left atrial (LA) pressure–natural strain relationships for the LA body and appendage from a single dog. Data are fitted to an exponential function. Pressure-strain relationship of appendage is shifted to the right of the body. B, Mean pressure–natural strain data for 12 dogs. Error bars represent SE. Data indicate that the appendage is more distensible than the body of the left atrium. (From Hoit BD, Walsh RA, Am J Physiol 1992;262: H1356–H1360.)
Myocardial strains can be obtained noninvasively using either tissue Doppler imaging (TDI) or 2D speckle imaging. Recently, atrial strain and strain rates (representing the magnitude and rate of myocardial deformation, respectively) during ventricular systole predicted the 9-month atrial fibrillation recurrence rate in patients with lone atrial fibrillation after a successful cardioversion.11 Coupled with an estimate of atrial pressure,46 strain has the potential to estimate atrial distensibility noninvasively.
Left Atrial Conduit Function Atrial conduit function occurs primarily, but not exclusively, during ventricular diastole and represents the volume of blood that passes through the left atrium that cannot be attributed to reservoir or booster pump functions; in a well-characterized model, atrial conduit function accounted for 35 ± 8% of all flow through the atrium.47 A reciprocal relationship exists between conduit and reservoir functions of the left atrium. Indeed, the redistribution of atrial functions was reported as an important compensatory mechanism that facilitates LV filling in patients with myocardial ischemia, acute myocardial infarction, hypertensive heart disease, and mitral stenosis.48–51 Although it has been postulated that a more distensible atrium reduces atrial conduit flow, we showed that while pericardiectomy decreased the atrial stiffness constant (increased distensibility), the relative conduit function, measured as the ratio of flow probedetermined systolic-to-diastolic pulmonary vein flow, actually increased.38 However, it should be noted that the LA reservoir volume (max − min LA volume) and absolute systolic pulmonary venous flow also increased post pericardiectomy. In addition, removal of the pericardium was associated with an increase in the peak early velocity and deceleration time of transmitral diastolic flow, consistent with the increase in LV compliance after pericardiectomy. Thus it is possible that the decreased systolic to diastolic P-V ratio reflects a greater change in compliance of the left ventricle than of the atrium. Irrespective of the mechanisms, these data underscore the complexity of pericardial influences on atrial and ventricular filling and the multifactorial determinants of P-V relations.
Global Left Atrial Function Although it is clear that atrial reservoir, conduit, and booster pump functions (and their modulation by the pericardium) play important roles in maintaining ventricular filling, a global measure (i.e., throughout the entire atrial cycle) of atrial function is lacking. A potential candidate property suitable for quantitation is synchrony. Therefore, we correlated time-tissue Doppler velocity curves from the lateral left and right atria and the lateral left atrium and interatrial septum over three cycles every 10 msec to obtain indices of inter- and intra-atrial phase heterogeneity, respectively. The intra-atrial phase heterogeneity index was 0.90 ± 0.06, indicating that the time-velocity curves over the entire cardiac cycle for the septum and lateral LA segments were highly correlated (i.e., in phase). In contrast, the inter-atrial phase index of 0.66 ± 0.10 indicated a greater degree of heterogeneity between the lateral LA and RA segments. These indices may be particularly useful to understand the effect of altered atrial conduction on atrial function and ventricular filling in various pathological states.
LEFT ATRIAL FUNCTION IN DISEASE Although LV adaptation to chronic hemodynamic loading has been studied extensively, the mechanisms by which the left atrium compensates for sustained increases in pressure and volume are less clear. We considered that adaptation may be due to the addition of contractile units (hypertrophy), an alteration in the molecular composition of the contractile machinery (e.g., protein isoform transitions), or a reduction of atrial systolic stress by structural remodeling. In pathological studies of human atria, increases in the amount of the slow, β-myosin isoform were correlated with the severity and duration of pressure and volume overload. In this context, a switch from the fast (α) to the slow (β) myosin heavy chain (MHC) isoform in the ventricles of small mammals is accompanied by decreased myosin ATPase activity and velocity of contraction, reduced oxygen consumption, and a greater efficiency of contraction. Thus, these isoform switches are likely to represent adaptations to the functional requirements
37
38
Chapter 4 • Left Atrial Function: Basic Physiology imposed by sustained hemodynamic loads in a chamber such as the left atrium, which contains predominantly α MHC.
Left Atrial Function and Systolic Left Ventricular Dysfunction Experimental studies that examine atrial adaptation use models of mitral regurgitation,36 myocardial infarction,12 LV diastolic dysfunction,52 and pacing-induced myocardial failure (ventricular and atrial tachypacing53,54). In the ventricular tachypacing model of heart failure, we found a significant upregulation of β MHC in the LA body that was associated with LA hypertrophy, increased atrial mechanical work (A-loop area, Fig. 4-5), maintained force generation (Emax and Ees), and decreased velocity of LA contraction. Another important finding of our study was that atrial MHC isoform switches vary by region. Despite hypertrophy of the appendage, the percent of β MHC did not increase in comparison with controls, suggesting that adaptation to hemodynamic overload includes differentially determined quantitative (e.g., hypertrophy) and qualitative (e.g., isoform switch) components and that there are fundamental differences in the atrial response to stress hypertrophy, which occurs in the body, versus “strain” hypertrophy, which occurs in the appendage.
Left Atrial Function and Diastolic Left Ventricular Dysfunction In carefully studied animal models, the improvement in systolic function that occurs after cessation of tachypacing is associated with residual abnormalities of LV isovolumic relaxation and chamber compliance, and in some instances, the development of LV hypertrophy. Since LV diastolic dysfunction represents a source of excess afterload on the left atrium, we examined the gravimetric, myosin biochemical, and functional changes in the left atrium that accompany regression of pacing-induced heart failure. Animals were rapidly paced for 3 weeks to produce heart failure, and hemodynamic and functional studies were performed 3 weeks after pacing cessation.52 We showed that improvement of LV systolic dysfunction was associated with persistent LV
24.0
Left Atrial Function in a Model of Atrial Systolic Failure We examined global and regional LA pump functions after one week of isolated atrial flutter (atrial pacing at 400 bpm) in closedchest, sedated dogs.55 LV function, as assessed by the echocardiographic LV area shortening fraction, was preserved. Global and regional atrial pump functions were determined by mitral and LA appendage waveform analysis, and relative conduit and reservoir functions by pulmonary venous waveform analysis with Doppler velocimetry. We found that after one week of rapid atrial pacing, global and regional atrial booster pump functions (i.e., body and appendage) were impaired, and relative reservoir-to-conduit function of the left atrium was reduced (Fig. 4-6). Similar changes in the absence of atrial hypertrophy were noted in a highly instrumented preparation treated with similar atrial tachypacing for 6 weeks.
Importance of Left Atrial Functions and Their Interplay in Left Ventricular Systolic Dysfunction The redistribution of atrial reservoir and conduit functions and an augmented booster pump function are important compensatory mechanisms that facilitate LV filling in patients with myocardial ischemia, acute myocardial infarction, and hypertensive heart disease. However, considerably less is known about how these mechanisms operate in the setting of LV dysfunction. Therefore, we tested the hypothesis that in contrast to dogs with a normal left ventricle, cardiac output falls with the loss of atrial
Left atrial pressure (mmHg)
Left atrial pressure (mmHg)
22.4
V
V
A
A
10.0
9.5 5.5
8.4
17.4
Left atrial volume (ml)
A
diastolic dysfunction and normalization of both atrial Ees and net atrial work despite the persistent abnormalities of loaddependent indices of LA systolic function (e.g., ejection fraction, systolic ejection rate). LA stiffness and reservoir volumes also remained abnormal. Changes in systolic and diastolic function of the left atrium were accompanied by persistent upregulation of the atrial β MHC isoform and incomplete regression of LA hypertrophy, indicating an apparent dissociation of myosin isoform shifts, myocardial hypertrophy, and atrial work.
21.4 Left atrial volume (ml)
B
Figure 4-5 Left atrial pressure-volume loops from three variably loaded beats in a control dog (A) and in a dog with pacing-induced heart failure (B). The A loop represents active atrial contraction; the V loop represents passive filling and emptying of the left atrium. The increase in A loop area after pacing indicates increased atrial systolic work. Loops are computer-smoothed for clarity. (From Hoit BD et al: Cardiovasc Res 1995;29:469–474.)
Chapter 4 • Left Atrial Function: Basic Physiology Baseline
1 week rap
MV velocity
A A E 80 cm/sec
E
e
a e
40 cm/sec
40 cm/sec a
LAA velocity
Figure 4-6 Doppler waveforms of transmitral (MV, top panel), left atrial appendage (LAA, middle panel), and pulmonary vein (PV, bottom panel) flows at baseline and after one week of rapid atrial pacing (RAP). E, early transmitral diastolic velocity; A, late transmitral diastolic velocity; e, early LAA emptying velocity; a, late LAA emptying velocity; J1 and J2, systolic velocities; K, diastolic PV velocities. The corresponding electrocardiogram is shown in each panel. (From Hoit BD et al: J Am Soc Echo 1997;10:805–810.)
80 cm/sec
J2
40 cm/sec J1
K 40 cm/sec J2
PV velocity
systolic contraction in dogs with concomitant LV dysfunction because atrial compensatory mechanisms fail. Chronic atrial and ventricular dysfunction (both singly and in combination) were modeled with rapid pacing in dogs with radiofrequency atrioventricular nodal ablation and implantation of RA and RV pacing catheters.56 Serial echocardiographic analyses of global and regional LA pump function were estimated from mitral and LA appendage Doppler velocimetry, and relative reservoir and conduit functions of the left atrium were determined from pulmonary venous Doppler. Right heart catheterization studies were performed simultaneously to assess right heart pressures and cardiac output. Isolated atrial systolic failure was produced by 1 week of rapid atrial pacing (400 bpm), and moderate
K
J1
LV dysfunction was produced by 2 weeks of rapid RV pacing (220 bpm). Two weeks of rapid ventricular pacing superimposed on rapid atrial pacing during the second week produced combined LA and LV dysfunction. As previously noted, isolated LV dysfunction increased atrial booster pump and reservoir functions, whereas isolated rapid atrial pacing decreased atrial booster pump and increased the relative conduit function of the left atrium. In contrast, the decreased atrial booster pump function in animals with combined atrial and ventricular dysfunction was incompletely compensated by the redistribution of the reservoir and conduit functions of the left atrium. As a result, cardiac output decreased and right heart pressures increased only after superimposed atrial and ventricular pacing.
39
40
Chapter 4 • Left Atrial Function: Basic Physiology
FUTURE RESEARCH While knowledge of atrial function lags considerably behind that of the ventricle, the chasm is rapidly closing. The studies discussed herein describe the role of atrial function to ventricular filling in normal physiology and provide a framework for understanding mechanical, energetic, and biochemical mechanisms responsible for atrial adaptation to chronic hemodynamic loading. Important future directions include distinguishing the role of atrial function in early versus late LV systolic dysfunction, investigating the role of matrix metalloproteinases (and other molecules) in structural remodeling of the atria, characterizing the biochemical and molecular biological changes that accompany atrial adaptation and failure, and identifying the relation between structural and electrical remodeling of the left atrium. These goals are likely to be met with the development of novel techniques to evaluate atrial reservoir, conduit, and booster pump functions of the atrium.
ACKNOWLEDGMENT This work was supported in part by a Grant in Aid award from the American Heart Association Ohio Valley Affiliate (0355198B). REFERENCES 1. Hersi A, Wyse DG: Management of atrial fibrillation. Curr Probl Cardiol 2005;30:175–233. 2. Marine JE, Dong J, Calkins H: Catheter ablation therapy for atrial fibrillation. Prog Cardiovasc Dis 2005;48:178–192. 3. Gillinov AM, Wolf RK: Surgical ablation of atrial fibrillation. Prog Cardiovasc Dis 2005;48:169–177. 4. Frielingsdorf J, Gerber AE, Hess OM: Importance of maintained atrioventricular synchrony in patients with pacemakers. Eur Heart J 1994;15:1431–1440. 5. McComb JM, Gribbin GM: Effect of pacing mode on morbidity and mortality: Update of clinical pacing trials. Am J Cardiol 1999;83:211D–213D. 6. Vural A, Agacdiken A, Ural D, et al: Effect of cardiac resynchronization therapy on left atrial appendage function and pulmonary venous flow pattern. Int J Cardiol 2005;102:103–109. 7. Nattel S, Shiroshita-Takeshita A, Cardin S, Pelletier P: Mechanisms of atrial remodeling and clinical relevance. Curr Opin Cardiol 2005;20: 21–25. 8. Yue L, Melnyk P, Gaspo R, et al: Molecular mechanisms underlying ionic remodeling in a dog model of atrial fibrillation. Circ Res 1999;84:776–784. 9. Wijffels MC, Kirchhof CJ, Dorland R, et al: Electrical remodeling due to atrial fibrillation in chronically instrumented conscious goats: Roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation. Circulation 1997;96:3710–3720. 10. Grimm RA, Leung DY, Black IW, Thomas JD: Left atrial appendage “stunning” after spontaneous conversion of atrial fibrillation demonstrated by transesophageal Doppler echocardiography. Am Heart J 1995;130:174–176. 11. Di Salvo G, Caso P, Lo Piccolo R, et al: Atrial myocardial deformation properties predict maintenance of sinus rhythm after external cardioversion of recent-onset lone atrial fibrillation: A color Doppler myocardial imaging and transthoracic and transesophageal echocardiographic study. Circulation 2005;112:387–395. 12. Kono T, Sabbah HN, Rosman H, et al: Left atrial contribution to ventricular filling during the course of evolving heart failure. Circulation 1992;86:1317–1322. 13. Bruch C, Gotzmann M, Sindermann J, et al: Prognostic value of a restrictive mitral filling pattern in patients with systolic heart failure and an implantable cardioverter-defibrillator. Am J Cardiol 2006;97:676–680. 14. Strandring S, ed: Gray’s Anatomy, 39th ed. London, Elsevier, 2005.
15. Thomas CE: The muscular architecture of the atria of hog and dog hearts. Am J Anat 1959;104:207–236. 16. McNutt NS, Fawcett DW: The ultrastructure of the cat myocardium. II. Atrial muscle. J Cell Biol 1969;42:46–67. 17. Thomas C, Coker B, Zellner J, et al: Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation 1998;97:1708–1715. 18. Li GR, Lau CP, Shrier A: Heterogeneity of sodium current in atrial vs epicardial ventricular myocytes of adult guinea pig hearts. J Mol Cell Cardiol 2002;34:1185–1194. 19. Tuteja D, Xu D, Timofeyev V, et al: Differential expression of smallconductance Ca2+-activated K+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes. Am J Physiol Heart Circ Physiol 2005;289: H2714–H2723. 20. Mitchell JH, Gupta DN, Payne RM: Influence of atrial systole on effective ventricular stroke volume. Circ Res. 1965;17:11–18. 21. Hoit BD, Rashwan M, Verba J, et al: Instantaneous transmitral flow using Doppler and M-mode echocardiography: Comparison with radionuclide ventriculography. Am Heart J 1989;118:308–314. 22. Hoit BD, Shao Y, Tsai LM, et al: Altered left atrial compliance after atrial appendectomy. Influence on left atrial and ventricular filling. Circ Res 1993;72:167–175. 23. Stefanadis C, Dernellis J, Lambrou S, Toutouzas P: Left atrial energy in normal subjects, in patients with symptomatic mitral stenosis, and in patients with advanced heart failure. Am J Cardiol 1998;82:1220– 1223. 24. Manning WJ, Silverman DI, Katz SE, Douglas PS: Atrial ejection force: A noninvasive assessment of atrial systolic function. J Am Coll Cardiol 1993;22:221–225. 25. Alexander J, Sunagawa K, Chang N, Sagawa K: Instantaneous pressurevolume relation of the ejecting canine left atrium. Circ Res 1987;61: 209–219. 26. Hoit BD, Shao Y, McMannis K, et al: Determination of left atrial volume using sonomicrometry: A cast validation study. Am J Physiol 1993;264: H1011–H1016. 27. Hoit BD, Shao Y, Gabel M, Walsh RA: In vivo assessment of left atrial contractile performance in normal and pathological conditions using a timevarying elastance model. Circulation 1994;89:1829–1838. 28. Stefanadis C, Dernellis J, Toutouzas P: Evaluation of the left atrial performance using acoustic quantification. Echocardiography 1999;16: 117–125. 29. Stefanadis C, Dernellis J, Stratos C, et al: Assessment of left atrial pressurearea relation in humans by means of retrograde left atrial catheterization and echocardiographic automatic boundary detection: Effects of dobutamine. J Am Coll Cardiol 1998;31:426–436. 30. Dernellis JM, Stefanadis CI, Zacharoulis AA, Toutouzas PK: Left atrial mechanical adaptation to long-standing hemodynamic loads based on pressure-volume relations. Am J Cardiol 1998;81:1138–1143. 31. Tse HF, Hettrick DA, Mehra R, Lau CP: Improved atrial mechanical efficiency during alternate- and multiple-site atrial pacing compared with conventional right atrial appendage pacing: Implications for selective site pacing to prevent atrial fibrillation. J Am Coll Cardiol 2006;47:209–212. 32. Pislaru C, Abraham TP, Belohlavek M: Strain and strain rate echocardiography. Curr Opin Cardiol 2002;17:443–454. 33. Grant C, Bunnell IL, Green DG: The reservoir function of the left atrium during ventricular systole. Am J Med 1964;37:36–43. 34. Barbier P, Solomon SB, Schiller NB, Glantz SA: Left atrial relaxation and left ventricular systolic function determine left atrial reservoir function. Circulation 1999;100:427–436. 35. Hoit BD, Shao Y, Gabel M, Walsh RA: Influence of loading conditions and contractile state on pulmonary venous flow. Validation of Doppler velocimetry. Circulation 1992;86:651–659. 36. Kihara Y, Sasayama S, Miyazaki S: Role of the left atrium in adaptation of the heart to chronic mitral regurgitation in conscious dogs. Circ Res 1988;62:543–553. 37. Hoit BD, Walsh RA: Regional atrial distensibility. Am J Physiol 1992;262: H1356–H1360. 38. Hoit BD, Shao Y, Gabel M, Walsh RA: Influence of pericardium on left atrial compliance and pulmonary venous flow. Am J Physiol 1993;264: H1781–H1787. 39. Suga H: Importance of atrial compliance in cardiac performance. Circ Res 1974;35:39–43. 40. Hoit BD, LeWinter M, Lew WY: Independent influence of left atrial pressure on regional peak lengthening rates. Am J Physiol 1990;259: H480–H487.
Chapter 4 • Left Atrial Function: Basic Physiology 41. Davis CA, Rembert JC, Greenfield JC: Compliance of the left atrium with and without left atrium appendage. Am J Physiol 1990;259: H1006–H1008. 42. Hintze TH, McIntyre JJ, Patel MB, et al: Atrial wall function and plasma atriopeptin during volume expansion in conscious dogs. Am J Physiol 1989;256:H713–H719. 43. Bauman RP, Rembert JC, Greenfield JC: Regional atrial blood flow in dogs. J Clin Invest 1989;83:1563–1569. 44. Kamohara K, Fukamachi K, Ootaki Y, et al: A novel device for left atrial appendage exclusion. J Thorac Cardiovasc Surg 2005;130:1639–1644. 45. Ostermayer SH, Reisman M, Kramer PH, et al: Percutaneous left atrial appendage transcatheter occlusion (PLAATO system) to prevent stroke in high-risk patients with non-rheumatic atrial fibrillation: Results from the international multi-center feasibility trials. J Am Coll Cardiol 2005;46:9–14. 46. Nagueh SF: Noninvasive evaluation of hemodynamics by Doppler echocardiography. Curr Opin Cardiol 1999;14:217–224. 47. Hitch DC, Nolan SP: Descriptive analysis of instantaneous left atrial volume—with specific reference to left atrial function. J. Surg Res 1981;30:110–120. 48. Sigwart U, Grbic M, Goy J, Kappenberger L: Left atrial function in acute transient left ventricular ischemia produced during percutaneous transluminal coronary angioplasty of the left anterior descending coronary artery. Am J Cardiol 1990;65:282–286.
49. Matsuda Y, Toma Y, Moritani K, et al: Assessment of left atrial function in patients with hypertensive heart disease. Hypertension 1986;8:779– 785. 50. Matsuda Y, Toma Y, Ogawa H: Importance of left atrial function in patients with myocardial infarction. Circulation 1983;65:566–571. 51. Triposkiadis F, Wooley CF, Boudoulas H: Mitral stenosis: Left atrial dynamics reflect altered passive and active emptying. Am Heart J 1990;120:124–132. 52. Hoit BD, Shao Y, Gabel M, et al: Left atrial systolic and diastolic function after cessation of pacing in tachycardia-induced heart failure. Am J Physiol 1997;273:H921–H927. 53. Hoit BD, Shao Y, Gabel M: Left atrial systolic and diastolic function accompanying chronic rapid pacing–induced atrial failure. Am J Physiol 1998;275: H183–H189. 54. Hoit BD, Shao Y, Gabel M, Walsh RA: Left atrial mechanical and biochemical adaptation to pacing induced heart failure. Cardiovasc Res 1995;29:469–474. 55. Hoit BD, Shao Y, Gabel M: Global and regional atrial function after rapid atrial pacing: An echo Doppler study. J Am Soc Echocardiogr 1997;10:805–810. 56. Hoit BD, Gabel M: Influence of left ventricular dysfunction on the role of atrial contraction: An echocardiographic-hemodynamic study in dogs. J Am Coll Cardiol 2000;36:1713–1719.
41
JAMES D. THOMAS, MD ZORAN B. POPOVIC´, MD
5
Physical Determinants of Diastolic Flow INTRODUCTION PATHOPHYSIOLOGY Mechanical Properties of Left Ventricular Chamber Diastole CLINICAL RELEVANCE Physical Factors Governing Left Ventricular Filling Velocities
Understanding Pulmonary Vein Flow Through Computer Modeling of the Heart Lumped Parameter Model of the Heart and Circulation Understanding Intraventricular Flow FUTURE RESEARCH ABBREVIATIONS
INTRODUCTION Comprehensive assessment of ventricular diastolic function is a complex process. Full elucidation generally requires invasive measurements, such as left ventricular (LV) end diastolic pressure, the time constant of isovolumic LV relaxation (τ), the pressurevolume (P-V) relationship of the ventricle at end diastole, and mean left atrial (LA) pressure. Such invasive measurements are inappropriate for routine clinical purposes, and thus diastolic function is generally assessed using Doppler echocardiography, largely through the observation of transmitral and pulmonary venous flow, supplemented by myocardial velocity and color M-mode Doppler information. In order to intelligently use these noninvasive indices to infer actual diastolic function of the heart, however, it is critical that a conceptual framework be in place that reflects the physical and physiological determinants of intracardiac blood flow. In this chapter, we will outline in both basic physical principles and computer simulations the relationship between basic parameters of diastolic function and the intracardiac flow patterns that can be obtained clinically.
PATHOPHYSIOLOGY Mechanical Properties of Left Ventricular Chamber Diastole The major function of the heart in diastole is to let the blood column flow from the antechambers (left atrium and pulmonary
veins) into the left ventricle, while keeping filling pressures to a minimum. During exercise, this task is compounded by the shortening of time allowed for filling and the increase of volume needed to get into the left ventricle. Of the various chamber-wall properties that affect this process, we will briefly cover three: chamber stiffness, relaxation, and early diastolic suction.
Chamber Stiffness Chamber stiffness can be defined as the instantaneous change of pressure for a given volume increment, mathematically the first derivative of LV pressure by volume (dP/dV). LV pressure is a complex nonlinear function of LV volume, meaning that stiffness changes with diastolic volume. Although the LV P-V relationship was initially considered to be exponential in shape (concave upward),1 more recent work suggests that it is sigmoidal in shape (Fig. 5-1), with a concave downward portion to the left of the usual rising exponential.2,3 This sigmoidal curve can be expressed as: P = A ∗ e(V−Vd0)Kp+ + Pb+ V ≥ Vd0 P = −B ∗ e(Vd0−V)Kp− + Pb− V < Vd0, where Vd0 is the inflection point, A and B are the exponential curve multipliers of the upper and lower part, Pb+ and Pb− are pressure offsets of the upper and lower part, while Kp+ and Kp− are the diastolic chamber stiffness indices, determining the overall steepness of the end diastolic P-V relationship (EDPVR) above and below the inflection volume. Frequently, EDPVR is conceptually simplified by assuming that Vd0 equals 0,1 and even further 43
Chapter 5 • Physical Determinants of Diastolic Flow 120 LV pressure (mmHg)
44
90 60 30 0 0
50 LVd0
100
150
LV volume (ml) Figure 5-1 Passive pressure-volume (P-V) loop relationships. The thick continuous and thick dotted lines represent the upper and lower part of the sigmoid end diastolic pressure-volume relationship, respectively. The curvature of the upper part is determined by the chamber stiffness index, which can be interpreted as the inverse of the volume needed to increase the steepness of the P-V curve by a factor of 2.72.
simplified by neglecting Pb+, leaving us with the equation P = AeK×EDV, or in other words ln P = a + K × EDV (see also Chapter 2).1 By differentiating this equation, we see that end diastolic stiffness dP/dV is K × AeK×EDV or K × PEDV. Another parameter of note is the average stiffness,4 that is, the stroke volume divided by the LV pressure increment during diastole, a simple overall measure of how stiff the patient’s LV is during diastole over a given (working) set of conditions.5 The fact that myocardial relaxation is a continuous process throughout diastole results in changing relationships between pressure and volume from very stiff end systole P-V relationships to much more compliant EDPVR.
Relaxation Myocardial relaxation occurs because of calcium reuptake at the end of systole, producing a shift downward and rightward, leading to a fall in LV pressure (at a given volume). The rate of pressure decrease during relaxation depends on the velocity of calcium reuptake and on the LV volume: The smaller the volume, the lower the potential for pressure to fall,2 limited by the end diastolic pressure curve shown in Figure 5-1. Rate of calcium reuptake is further modified by LV lengthening during relaxation, so true relaxation can be measured only during the isovolumic period.6 Several equations have been proposed to describe the rate of isovolumic pressure decay,7 the most general being: P(t) = (Po − Pb) × e−t/τ + Pb, which can be, with some caveats, simplified to: P(t) = Po × e−t/τ, and further to8,9: τ ≈ IVRT/(ln PAVC − ln PMVO), where IVRT is the isovolumic relaxation time (the time between aortic valve closure and mitral valve opening), and PAVC and PMVO are LV pressure at aortic valve closure (AVC) and mitral valve opening (MVO), respectively, which can be approximated nonin-
vasively by systolic blood pressure and an estimate of LA pressure. Importantly, LV relaxation is a never-ending process that critically affects the end diastolic pressure that the patient achieves, particularly during exercise. Consider Figure 5-2A, showing a series of P-V curves representing successive intervals of τ, and Figure 5-2B, the same curves magnified on diastolic pressures. Note that after 6τ, the filling curve is virtually indistinguishable from the end diastolic P-V curve, as relaxation is 99.8% complete. When relaxation rate is normal, the end diastolic filling curve is completely relaxed at normal heart rates (12.5τ, 2C) and almost complete during exercise (5τ, 2D); with delayed relaxation, however, while the EDPV curve is fully relaxed at rest (6.25τ, 2E), it becomes stiff with exercise (3τ, 2F). The combination of relaxation and the EDPVR results in a dynamic P-V relationship, represented by the round dots in Figure 5-2A. Note that in early diastole, LV pressure continues to fall even though volume is increasing, meaning that the instantaneous stiffness is actually negative, which some consider diastolic suction. Two other definitions of “diastolic suction” are also relevant. Consider ventricular filling from a very low end systolic volume (where the EDPVR is concave downward). If relaxation is very rapid or filling is delayed (by mitral stenosis or experimentally with a mitral occluder2), then LV pressure can fall below atmospheric pressure.2,10 Alternatively, suction has been used to refer to the small (1 to 3 mmHg) differences in pressure between the base and the apex, which assist in the low-pressure filling of the ventricle, particularly with exercise, and which will be discussed later.11
Determinants of Intracardiac Blood Flow In the most general sense, the motion of blood inside the heart, as the motion of any fluid, is determined by the Navier-Stokes equations, a complex set of four multidimensional partial differential equations, which must be solved simultaneously at every point in space and moment in time: 䉮·v = 0 and
ρ
Dv = −∇P + B + μ∇2 v Dt
These equations appear deceptively simple but contain such complex mathematical concepts that except in the simplest of geometries, they can never be solved either analytically or with powerful supercomputers. Fortunately, considerable simplifications can be made to these equations that will facilitate a conceptual and computational approach. The most important simplification is to take the distribution of blood throughout the heart and replace it with just a few measurements at specific points inside the heart. For instance, instead of describing pressure in every cubic millimeter inside the left ventricle, we assume that LV pressure can be approximated by an average of these and give a single number for LV pressure, which is precisely how we measure and report LV pressure in practice. Similarly, instead of describing the direction and speed of blood flow at every point within the heart, we focus on points where blood velocity is
Chapter 5 • Physical Determinants of Diastolic Flow
2τ 100 3τ 4τ
50
100
4τ 5τ 6τ 25 Diastole
0 0
150
Volume (ml)
Systole
Systole
50 2τ
2τ
1τ
3τ 4τ 5τ 6τ
25 12.5τ Diastole
Pressure (mmHg)
1τ Pressure (mmHg)
150
B
50
3τ 4τ 5τ 6τ
25 Diastole
0
0 0
100
50
100
50
150
150
Volume (ml)
Volume (ml)
τ = 40 msec, HR = 150, DFP = 200 msec
τ = 40 msec, HR = 75, DFP = 500 msec
C
D
Systole
Systole
50 2τ
1τ
2τ
1τ
3τ 4τ 5τ 6τ
25 Diastole
Pressure (mmHg)
50
Pressure (mmHg)
100
50
Volume (ml)
A
3τ 4τ 5τ 6τ
25 Diastole
0
0 0
100
50
0
150
100
50
150
Volume (ml)
Volume (ml) τ = 80 msec, HR = 75, DFP = 500 msec
E
3τ
5τ 6τ
Diastole
0 50
2τ
1τ
1τ
150
0
Systole
50
Systole
Pressure (mmHg)
Pressure (mmHg)
200
τ = 80 msec, HR = 120, DFP = 240 msec
F
Figure 5-2 Diastolic pressure-volume (P-V) relationships shown as a function of the duration of diastole. Duration of diastole is measured by the multiples of a time constant of relaxation (τ). Panel A shows a series of P-V relationships that occur after successive intervals of τ, while panel B shows the same curves zoomed on diastolic pressures. The combination of relaxation and the end diastolic P-V (EDPV) relationship results in a dynamic diastolic part of the P-V loop represented by the round dots in A. Note that in early diastole, left ventricular pressure continues to fall even though volume is increasing, meaning that the instantaneous stiffness is actually negative, which some consider diastolic suction. When relaxation rate is normal, the end diastolic filling curve is completely relaxed at normal heart rates (arrow 12.5τ, C) and almost complete during exercise (arrow 5τ, D); with delayed relaxation, however, while the EDPV curve is fully relaxed at rest (arrow 6.25τ, E), it becomes stiff with exercise (arrow 3τ, F).
45
46
Chapter 5 • Physical Determinants of Diastolic Flow maximum, such as the tips of the mitral leaflets and the pulmonary vein orifices. Finally we assume fluid incompressibility and zero viscosity and heat conduction losses. In this way, the thousands of partial differential equations that would have to be solved simultaneously throughout the heart are replaced by a few ordinary differential equations that can be solved quite easily on a personal computer. To understand how these equations can model the flow within the heart, we first start by replacing the Navier-Stokes equations with the well-known Bernoulli equation, which applies to flow across discrete points such as valves. Here we present it with its inertial and convective terms (we still omit the viscous term, since it is negligible in almost every intracardiac situation): Δp = M
dv 1 + ρΔ v2 , dt 2
( )
where Δp is the pressure difference between two points; M is the inertial constant and represents the “effective” mass being accelerated; dv/dt is the instantaneous temporal acceleration of flow through the region; ρ is blood density; and Δ(v2) is the change in the square of velocity from one point to another (with pressure in mmHg and velocity in m/sec, 1/2ρv2 reduces to 4v2 in the simplified Bernoulli equation). The first product is the inertial term of the Bernoulli equation and corresponds to the energy used accelerating and decelerating flow; the second term is the convective term and represents kinetic energy of flow. The effective mass of blood in a narrow orifice is small, and thus M is a negligible quantity in, for example, valve stenosis, but the dominant term when flow is not obstructed, such as in the normal mitral valve. For constant flow through an orifice of minimal diameter D, the inertial constant M varies approximately in proportion to D, while the kinetic term 1/2ρv2 varies inversely to D4. For nonobstructive flow through the body of heart chambers, where pressure changes gradually over a distance, not at a discrete point, we must use the Euler equation, a differential version of the Bernoulli equation for pressure change along a streamline of flow: ∂p ∂v ⎞ ⎛ ∂v = −ρ ⋅ ⎜ + v ⋅ ⎟ , ⎝ ∂t ∂s ⎠ ∂s where the inertial and convective terms are in the same order as in the Bernoulli equation, but the discrete terms (Δp and Δ(v2)) have been replaced by their spatial derivatives, yielding the rate of pressure change per centimeter of distance along the streamline. To return the total pressure drop between points A and B along the streamline, this equation must be integrated numerically: B ⎛ ∂v ∂v ⎞ Δp = − ρ ⋅ ∫ ⎜ + v ⋅ ⎟ ds. A ⎝ ∂t ∂s ⎠
Figure 5-3 shows schematically how these partial derivatives are summed together to produce the pressure gradient map.12 Another practical fact is that we can obtain the same map by applying the Euler equation to a color Doppler M-mode tracing.
CLINICAL RELEVANCE In this section, we will demonstrate how interaction of solid and fluid mechanics determines intracardiac flow within three specific
Inertial term Convective term Figure 5-3 Combination of convective (right) and inertial (left) term to produce an intraventricular pressure gradient. (From Thomas JD, Popovic ZB: Intraventricular pressure differences: A new window into cardiac function. Circulation 2005;112:1684–1686.)
regions of the heart: mitral valve, pulmonary vein, and left ventricle.
Physical Factors Governing Left Ventricular Filling Velocities To describe mathematically flow through the mitral valve, we first consider a very simplified construct, consisting of the left ventricle, which has pressure as a function of time pV(t); the left atrium, which has pressure as a function of time (pA(t)); and the mitral valve, which has area AMV and contains a mass of blood M that is accelerating in passing from the left atrium to the left ventricle. To a first approximation, M is the blood within a cylinder that can fit inside the narrowest portion of the mitral leaflet tips and whose length is approximately the diameter of the valve. In reality, though, since pressure is applied across the mitral valve, the most relevant hydrodynamic concept is the length of this cylinder, termed the mitral inertance, related linearly to the diameter of that structure. We will use this construct to discuss three parameters of transmitral flow: mitral acceleration, peak mitral flow, and mitral deceleration.
Acceleration of Mitral Flow To understand the acceleration of blood across the mitral valve, we apply Newton’s second law of motion: The rate at which an object accelerates is given by the force exerted on that object divided by its mass. In this case, the acceleration would be recorded by Doppler echocardiography as the velocity acceleration detected for mitral inflow, while the force is the difference in pressure on either side of the mitral valve multiplied by the area of the valve13: a=
F ΔpA Δp = ≈ . m ρM ρL
Here we have taken advantage of the fact that valve area appears in both the numerator and the denominator (through the definition of inertial mass) to simplify the relationship. Clearly the higher the pressure difference across the valve and the smaller the length of the blood column within the mitral valve, the more rapidly the velocity will accelerate. This is why mitral velocity
Chapter 5 • Physical Determinants of Diastolic Flow increases almost instantaneously in mitral stenosis, which has a very high pressure gradient across the valve and a very small blood mass, due to the small diameter of the mitral orifice. If the blood within the mitral valve were subject to an instantaneously applied pressure difference (as if the relaxation of the left ventricle occurred suddenly), mitral velocity would start to rise linearly. In the physiological situation, the pressure gradient is not abruptly applied but rather increases gradually (roughly linearly) with time as the ventricle relaxes, resulting in a roughly parabolic mitral velocity acceleration curve.14
Peak E-Wave Velocity and Conservation of Energy Mitral valve acceleration eventually decreases over time because the maximal velocity generated by a pressure difference is limited by conservation of energy (expressed in the Bernoulli equation). Within the heart, energy in the blood takes on three principal forms: pressure (a form of potential energy), kinetic energy, and heat; the total energy in the system must remain constant. In the left atrium, where blood velocity is low, most of the energy is in the form of pressure, but as it moves toward the mitral valve, its velocity rises and it acquires a kinetic energy (1/2ρv2), which causes the local blood pressure to fall. If no energy losses appear, pressure difference and velocity are related by the simplified Bernoulli relation, which becomes roughly Δp = 4v2 when pressure is measured in millimeters of mercury and velocity in meters per second. The velocity reaches the target gradient asymptotically, but this is delayed by the amount of inertance present. Reaching the asymptote can be even further delayed by the gradient not being imposed abruptly but slowly, as seen in a normally relaxing left ventricle.
Deceleration of Mitral Flow Returning to our general model of the mitral valve, once flow has been accelerated to maximal velocity by the pressure difference across the mitral valve, it begins falling as the pressure difference between the left atrium and the left ventricle equilibrates. This is analogous to flow between two tanks stopping when the level of water in the two tanks becomes the same. When we speak of the change in pressure with a change in volume, we are dealing with the concept of compliance or its inverse, stiffness, the change in pressure for a given change in volume, which is a major determinant of the deceleration of flow across the mitral valve. Since the stiffer the ventricle, the more rapidly the pressure equilibrates across the mitral valve to decelerate the flow, we can understand why short deceleration time across the mitral valve is associated with increased ventricular stiffness. Note that in this situation, we must consider atrial and ventricular stiffness together, since both chambers are involved in determining how quickly pressure equilibrates across the mitral valve. For ventricular stiffness SV and atrial stiffness SA, the net atrioventricular stiffness Sn is simply SA + SV. To obtain a mathematical expression for mitral velocity deceleration rate, we first note that for a restrictive mitral valve with area A (i.e., mitral stenosis, though even for a normal mitral valve), the overall principle holds: 1 Δp = ρv2 , 2 which simplifies to 4v2 when Δp is in mmHg and v in m/sec. Differentiating this yields:
dΔp/dt = ρv dv/dt. But dΔp/dt can also be expressed in terms of flow across the mitral valve (Av) and net atrioventricular stiffness: dΔp/dt = −AvSn. Substituting for dΔp/dt yields: ρv dv/dt = −AvSn, or, rearranging, dv/dt = ASn/ρ. Thus, the stiffer the ventricle (or atrium) and the larger the valve area, the faster the deceleration. Alternatively, one can represent this as a purely inertial system (with a nonrestrictive orifice), which yields a simple harmonic motion, in which case the velocity across the valve is described roughly by a sine wave: ⎛ t ⎞ v (t ) = v0 sin ⎜ ⎟, ⎝ m k⎠ where v0 is the peak E-wave velocity, m is mitral inertance, and k is the stiffness constant of the ventricle. The deceleration time (time for the E wave to fall from its peak to zero velocity) can be solved for as: tdec =
π 2
ρ⋅L 1 ⋅ , A k
where ρ, L, and A are blood viscosity, mitral valve length, and mitral valve area, respectively. Therefore, the stiffer the ventricle, the shorter the deceleration time. This is intuitively very understandable: Tighter springs oscillate fast. Note that in this simplification, one assumes that active relaxation is complete at the time of interest.13 Modeling of Mitral Valve Flow Up until now, we have been discussing specific features of the transmitral E wave through significant simplifications that allow closed-form mathematical solutions. To permit more realistic modeling of transmitral flow, however, one needs more general equations that can be solved only numerically. A generalized equation for blood flow through the mitral valve and its interaction with the transmitral gradient is15: 1 dv dt = ⎛ PA − Pv − ρv2 ⎞ M , ⎝ ⎠ 2 where v is velocity, t is time, PA and Pv are instantaneous atrial and ventricular pressures, and M is mitral inertance. Conversely, the impact of mitral flow on LA and LV pressures is expressed through the equations dPA/dt = −Av/CA and dPv/dt = Av/Cv + ∂Pv/∂t, where A is mitral valve area, and CA and CV are atrial and ventricular compliance (inverse of stiffness), respectively. By solving these three differential equations, we can assess how changing the parameters of the equation that represent passive diastolic properties, LV relaxation, mitral inertance, and preload can affect transmitral flow. We start with a preliminary discussion of these interactions before presenting an even more
47
Chapter 5 • Physical Determinants of Diastolic Flow detailed model that includes pulmonary vein flow in addition to transmitral flow. Impact of Relaxation: Changes in relaxation affect the earliest part of the mitral flow (Fig. 5-4A and B). They have a profound effect on the peak values of E-wave velocity. The overall effect of relaxation on the descending phase of the E wave is more complex: When τ is very short, relaxation is essentially complete
by the time of the peak of the E wave, and small changes in τ have little effect on deceleration; on the other hand, if τ is significantly longer, the relaxation remains an important aspect of the deceleration phase, and further lengthening of τ will cause a decrease in the deceleration rate (that is, prolongation in deceleration time). Passive Diastolic Properties of the Left Ventricle: Increasing the steepness of the diastolic P-V curve affects
LV RELAXATION CONSTANT (MSEC)
LV RELAXATION CONSTANT (MSEC) 140
20
Velocity (cm/sec)
LV pressure (mmHg)
25
15 10
40
5
60
20 30
100
50
70
90
110
A 16.2 12.3 10.0
D 7.8 6.9 5.8
VTI 13.1 12.7 12.0
60 40
20
40
60
20
0
130
100
200
300
400
500
Time (msec)
A
B LV VOLUME CONSTANT
(CM3)
LV VOLUME CONSTANT (CM3) 140
20 15 40
10
60 90
5
Velocity (cm/sec)
25 LV pressure (mmHg)
E 91 82 73
80
LV volume (cm3)
Vvk 40 60 90
120 100 80
E 58 82 93
A 9.2 12.3 13.7
D 8.4 6.9 4.8
VTI 6.6 12.7 16.3
60 40
40
60
90
20 0
0 30
50
70
90
110
0
130
100
LV volume (cm3)
200
300
400
500
Time (msec)
C
D LA PRESSURE (mmHg)
LA PRESSURE (mmHg) 140
20 5
10
20
15 10 5
Velocity (cm/sec)
25
LAP E A 5 40 4.5 10 82 12.3 20 124 24.1
120 100
20
80 60
D 3.5 6.9 9.6
VTI 6.9 12.7 17.7
10
40
5
20 0
0 30
50
70
90
LV volume
E
TAU 20 40 60
LV relaxation constant (msec)
120
0
0
LV pressure (mmHg)
48
110
130
0
(cm3)
100
200
300
400
500
Time (msec)
F
Figure 5-4 Effect of left ventricular relaxation constant (τ; panels A and B), volume constant (inverse of chamber stiffness index; panels C and D) and left atrial pressure (preload; panels E and F) on a left ventricular pressure volume curve (left panels) and mitral valve velocity profile (right panels). Prolonged relaxation blunts the lower left corner of pressure volume curve and decreases peak mitral valve flow. Increased stiffness (i.e., decreased volume constant) moves lower left corner of the pressure volume loop to the left and upwards, decreases peak mitral valve flow and increases its deceleration rate. Finally, increased left atrial pressure shifts lower right corner of the pressure volume loop to the right while increasing peak mitral valve flow. E, peak velocity of E wave (cm/sec); A, peak acceleration rate of E wave (m/sec2); D, peak deceleration rate of the E wave (m/sec2); VTI, E wave velocity time integral (cm). (From Thomas JD, Weyman AE: Echocardiographic Doppler evaluation of left ventricular diastolic function. Physics and physiology. Circulation 1991;84: 977–990.)
Chapter 5 • Physical Determinants of Diastolic Flow primarily deceleration time, that is, operative chamber stiffness (Fig. 5-4C and D). However, a caveat has to be introduced. The ventricular P-V curve (as well as the atrial P-V curve) is exponential in shape. Since operative chamber stiffness is equal to the slope of these curves, stiffness and mitral deceleration rise when operative chamber volumes increase. This change is indistinguishable from the change that may arise from material properties of the ventricle, leading to a steeper curve at all pressures (that is, a true change in the diastolic properties of the ventricle). Preload Alterations: Preload affects all components of the mitral velocity curve (Fig. 5-4E and F). However, its most prominent effect is on the E wave. For mitral deceleration, the effects depend on the initial position of the P-V curve. If the preload increase does not move the P-V loop too much into the steeper portion of the EDPVR, the effects may be negligible. It is not so in the severely diseased ventricles operating close to the limit of the preload reserve. Mitral Inertance: Mitral inertance affects both acceleration and deceleration of the mitral valve. It changes acceleration of mitral valve inflow and leads to flattening of the parabolic curve of velocity rise. Mitral inertance essentially acts by introducing the time lag between the transmitral pressure gradient and the mitral velocity curve: It makes the peak of the velocity curve occur after the peak of the transmitral pressure gradient curve (Fig. 5-5). It also introduces the difference between the true mitral valve pressure gradient and the pressure gradient calculated from application of the simplified Bernoulli equation to transmitral velocity (see Fig. 5-5). As it correlates with the mitral valve area, it can be largely neglected in patients with mitral stenosis, but it is an important factor in the nonstenotic valve. We have shown, by using the combination of echocardiography and direct pressure recordings, that the average value of mitral inertance in humans is 3.82 ± 1.22 g/cm2, corresponding to an effective length of the blood column of about 3.6 cm within the mitral valve.16 Future research may allow direct estimation of inertance from echocardiography data alone. Interaction of Ventricular Compliance and Relaxation: Importance of Heart Rate: During early filling, relaxation is not yet complete. This means that filling occurs while the dynamic P-V curve continuously shifts downward and toward the right. Thus, as the ventricle fills, it moves to the steeper part of the EDPVR, which in turn becomes progressively “flatter.” These two
P underestimation Actual ΔP by catheter Calculated ΔP from velocity
Phase lag Figure 5-5 Impact of mitral inertance: Transmitral velocities lag behind transmitral pressure differences. (From Nakatani S et al: Mitral inertance in humans: Critical factor in Doppler estimation of transvalvular pressure gradients. Am J Physiol Heart Circ Physiol 2001;280:H1340–1345.)
trends may offset each other, with the result that diastolic pressures are constant or falling despite an increase in LV volume, giving the impression of negative stiffness in early diastole. Figure 5-4A and B show how τ effects mitral valve flow and end diastolic P-V relationships.15 We reiterate here that while τ affects the early part of the diastolic P-V curve, τ has an effect on end diastolic volume only when dramatically prolonged. The situation is different during exercise, where shortening of the diastolic interval and the increase of arterial blood pressures produce incomplete relaxation (with a rise in end diastolic pressure) rather than simply delayed relaxation (which has little impact on LV end diastolic pressure).17
Understanding Pulmonary Vein Flow Through Computer Modeling of the Heart Such conceptual thought experiments as those previously discussed can be helpful in understanding general trends in the relationship between invasive parameters and noninvasive measurements, but a more comprehensive approach can be obtained with a computer model that invokes realistic descriptions of chamber and valvular functions. The reason for this is that the flows of blood through different parts of the circulatory system are interdependent. A change in a single parameter (e.g., resistance in systemic arterioles) affects flow throughout the system. Thus, changes in pulmonary circulation affect systemic circulation even if not assuming any ventricular-ventricular interactions.
Lumped Parameter Model of the Heart and Circulation Since the mid-1980s, the authors and colleagues have worked to develop models of the heart with increasing complexity, beginning from a very simple isolated model of the mitral valve used to understand the mitral pressure half-time; to models incorporating more realistic diastolic characteristics of the ventricle and atrium; to models that simulated all the cardiac chambers and valves, as well as the peripheral and pulmonary vasculature; to most recently a simulation that links knowledge of basic myocyte and fiber function to the gross architecture of the heart. We will use a lumped parameter model to explore some of the determinants of transmitral and pulmonary venous flow inside the heart.3 The lumped parameter approach assumes that blood flow is similar to the flow of a current through an electric circuit, which can be represented at specific nodes of the circuit (left atrium, left ventricle, aortic valve, etc.). Each of these nodes is represented by a specific ordinary differential equation. The principle of the conservation of flow (Kirchoff ’s first law) is applied throughout the circuit, and the parameters of the system are obtained by simultaneously solving all differential equations. Our model consists of 24 coupled differential equations representing eight different chambers (the right atrium and ventricle, pulmonary arteries and veins, left atrium and ventricle, aorta, and systemic veins) as well as the valves and vascular beds connecting them (Fig. 5-6), giving time-varying flows and pressures throughout the model. Figure 5-7 displays normal Doppler velocity tracing of pulmonary vein and transmitral flow recorded in the normal subject by transesophageal echocardiography (left) and a model output of corre-
49
50
Chapter 5 • Physical Determinants of Diastolic Flow Pulmonary capillaries Pulmonary artery
Pulmonary vein
Pulmonic valve
Left atrium
Right ventricle
Tricuspid valve
Mitral valve
Left ventricle
Right atrium
tions have opposite effects. Mitral valve regurgitation (through the parameter MV ERO) has its effect mostly on the systolic waveform, while Kp+ and τ have effect mostly on AR. The results of this sensitivity analysis illustrate the complexities of these relationships, which are not intuitively apparent. In contrast, for the mitral inflow, as expected, the greatest influence was exerted by preload. Importantly, τ showed the opposite effects on E and A waves, in congruence with the E/A ratio being reversed in the setting of impaired relaxation. Table 5-1 should be kept in mind, as very often pulmonary vein flow is used as a surrogate marker of LA function, with S, D, and AR reflecting the LA reservoir, conduit, and pump functions, respectively. Our table indicates that for none of these is there a straightforward relationship between the specific waveform and specific material parameters of the pulmonary vein flow waveform.
Aortic valve Venae cavae
Systemic capillaries
Aorta
Figure 5-6 A lumped parameter model of the heart. (From Thomas JD et al: Physical and physiological determinants of pulmonary venous flow: Numerical analysis. Am J Physiol 1997;272:H2453–H2465.)
sponding pulmonary vein and transmitral flow velocities, along with simulated pressure curves. Starting from this normal shape of velocity and pressure tracings, we first modeled a delayed relaxation pattern, by increasing τ from 50 to 120 msec. Then, to model restrictive filling, we shifted the end systolic P-V relationship by 10 ml to the right and decreased contractility from 4.0 to 2.5 mmHg/ml, thus moving the P-V loop toward the steeper part of the EDPVR. The model outputs are displayed in Figure 5-7, along with actual Doppler and pressure tracings of a representative patient with delayed relaxation (panel B) and restrictive filling (panel C). One can observe a close correspondence between the modeled and actual shapes, with a correlation coefficient approaching 1. Figure 5-8 shows the impact of some of the model parameters on pulmonary vein and mitral valve flow. LA systolic and diastolic function had opposing effects on the S and AR waves of the pulmonary vein, with minimal effect on the D wave (panels A through D). Finally, all waveforms showed strong positive response to preload (panels E and F). Worse LV relaxation decreases the mitral valve E/A ratio and blunts diastolic waves of pulmonary vein flow (panels G and H). These observations are analyzed in depth in Table 5-1, by showing the sensitivities of peak velocity of the three pulmonary vein flow waves and of two mitral inflow waves on model parameters. The sensitivities represented here were obtained by calculating a normalized Jacobian matrix, showing the proportional change in an output index for a given incremental change in an input parameter. A sensitivity of 1 means that for each 1% change of a model parameter value, the output variable will change by 1%. A value of 2 indicates a 2% change for a 1% increase. Negative numbers indicate inverse relationships. Because of the highly nonlinear nature of the model, these observations are relevant to only very small increments but do provide an overall sense of the dependency of Doppler indices on hemodynamic parameters. For example, one can readily observe the dramatic effect of preload on all three pulmonary vein flow waves, in particular AR, which increases almost 6-fold the increment in blood volume. Furthermore, one can observe that LA diastolic and systolic func-
Impact of Pulmonary Vein–Left Atrial Pressure Gradient and Left Atrium Size Similar to mitral valve inertance is pulmonary vein inertance. Its effect on pulmonary vein flow is similar to its effect on transmitral flow. Inertance leads to a lag of pulmonary vein flow behind the PV–LA pressure gradient. This is intuitively understandable: the pressure is needed to push the blood column, which then keeps moving because of its kinetic energy.18 Another interesting observation is the impact of the change of LA size, induced by clipping of the LA appendage, on pulmonary vein flow. The only affected pulmonary vein flow wave was the S wave, indicating that LA size affects primarily LA reservoir function.19
Understanding Intraventricular Flow The previous model formulations seem like child’s play when one is confronted with the task of simulating intraventricular flow with its demands for representing pressure and velocity throughout the chamber. Three major phenomena develop simultaneously during filling: An intraventricular gradient appears at the beginning of LV filling, the blood column slows after exiting the mitral valve while continuing as laminar flow toward the apex, and finally vortices start appearing due to propagation of the blood column past the tips of the mitral leaflets, while the left ventricle continually changes its size. It is well documented that a small LV base-to-apex pressure gradient develops in early diastole (Fig. 5-9A). We have already discussed that this gradient is of utmost importance for the lowpressure filling of the ventricle and is commonly termed diastolic “suction.” However, the exact mechanisms causing it are unclear. The most probable mechanisms are isovolumic conformational changes in LV shape that are driven by elastic forces within the myocyte and/or the myocardial interstitium, explored in greater depth below. As blood emerges from the mitral valve, it slows down as the flow stream expands to fill the left ventricle. Interestingly, within the first four centimeters of the left ventricle, the velocity of propagation of the blood column is fairly constant, despite the dramatic change of the chamber size, but it is generally less than the actual velocities within the bolus of blood traversing the mitral valve. For example, pulsed-wave Doppler may record a velocity of 100 cm/sec, while the normal propagation velocity will be only 60 or 70 cm/sec, and even lower in diseased hearts, due to the bleeding off of vortices at the front of the bolus of blood. We and others have shown that in heart disease, the amount of slowing
Chapter 5 • Physical Determinants of Diastolic Flow
50 E
100 0
Δ = –1.53±9.38 cm/sec
A
0.5
Velocity (cm/s)
y = 0.95x r = 0.94 p < 0.0001
Velocity (cm/s)
Velocity (cm/s)
0
0
A
E 100
1.0
0
Time (sec)
0.5
S
60
y = 1.02x r = 0.92 p < 0.0001
D
0 AR –60 0
1.0
0.5
Δ = 0.76±7.69 cm/sec
Velocity (cm/s)
PULMONARY VENOUS FLOW
TRANSMITRAL FLOW
60
S
0 AR –60
1.0
0
Time (sec)
Time (sec)
D
0.5
1.0
Time (sec)
A
0
0.5
A 100
1.0
0
Time (sec)
0.5
A
40
0
1.0
Δ = 3.52±8.65 cm/sec
E
80
Time (sec)
0.3
0
y = 1.02x r = 0.96 p < 0.0001 Δ = –1.54±3.32 AR cm/sec
–40 0
0.5
40 D
S 0
AR
–40
1.0
0
0.5
80
0.6
y = 0.96x r = 0.91 p < 0.0001 Δ = 3.72±11.81 cm/sec
S 0 AR –60
1.0
0
0
20
0 0
1
0
1 Time (sec)
B
0.3
0.6
Time (sec)
y = 1.16x r = 1.0 p < 0.0001 Δ = 1.99±1.61 mmHg
0 0
1
30
0
0.6
0
Time (sec)
Pressure (mmHg)
0
AR
0.6 Time (sec)
LV PRESSURE Pressure (mmHg)
Pressure (mmHg)
Δ = –3.63±11.30 mmHg
D
0
0
LV PRESSURE y = 0.94x r = 0.96 p < 0.0001
S
0.3 0.6
30
Time (sec)
Time (sec)
120
80
Time (sec)
Pressure (mmHg)
0
0.6
LA PRESSURE Pressure (mmHg)
Pressure (mmHg)
Δ = –1.04±1.04 mmHg
0.3
–60
LA PRESSURE y = 0.84x r = 0.97 p < 0.0001
0
Time (sec)
D
Time (sec)
Time (sec)
20
E
100
PULMONARY VENOUS FLOW Velocity (cm/s)
D
Velocity (cm/s)
Velocity (cm/s)
S
A
Time (sec)
PULMONARY VENOUS FLOW 40
Velocity (cm/s)
100
E
y = 0.95x r = 0.92 p < 0.0001
Velocity (cm/s)
A Δ = 0.70±8.35 cm/sec
0
Pressure (mmHg)
E
50
0
0
120
0 0
1
100
y = 0.80x r = 0.99 p < 0.0001 Δ = –5.01±8.69 mmHg
0 0
Time (sec)
0.6 Time (sec)
Pressure (mmHg)
y = 0.99x r = 0.93 p < 0.0001
TRANSMITRAL FLOW Velocity (cm/s)
0
Velocity (cm/s)
Velocity (cm/s)
TRANSMITRAL FLOW
100
0 0
0.6 Time (sec)
C
Figure 5-7 Actual and modeled pressures and filling patterns in a normal subject (A), patient with delayed relaxation (B), and patient with restrictive filling (C). Note similarities between observed and modeled data. (From Thomas JD et al: Physical and physiological determinants of pulmonary venous flow: Numerical analysis. Am J Physiol 1997;272:H2453–H2465.)
51
Chapter 5 • Physical Determinants of Diastolic Flow TRANSMITRAL FLOW
PULMONARY VEIN 60
A
Velocity (cm/sec)
Velocity (cm/sec)
90 E 60 30 0
S
0.5
0.48* 0.64 AR
1
0
1
B 90
60 A
E
Velocity (cm/sec)
Velocity (cm/sec)
0.5 LA end-systolic elastance (mmHg/ml)
A
60 30 0
30
D
S
0.2* 0.25
0
0.3 AR –30
0
0.5
1
0
LA end-diastolic elastance (mmHg/ml)
0.5
1
LA end-diastolic elastance (mmHg/ml)
C
D 150 E
Velocity (cm/sec)
100 A
100 50 0
S
D
50
3800* 0 4180 –50
4560 AR
–100 0
0.5
1
0
0.5
Preload (ml)
1
Preload (ml)
E
F 60 E
Velocity (cm/sec)
120 A
80 40
D
S 30
0.05* 0
0.10 AR
0.15
–30
0 0
0.5
0
1
LV relaxation time constant (sec)
G
0.32
0
LA end-systolic elastance (mmHg/ml)
Velocity (cm/sec)
D
30
–30 0
Velocity (cm/sec)
52
0.5
1
LV relaxation time constant (sec)
H
Figure 5-8 Simultaneous modeling of pulmonary vein and transmitral velocities using lumped-parameter approach. Increased left atrial systolic elastance (i.e., higher contractility) increases A wave of the transmitral flow and AR wave of the pulmonary vein flow (panels A and B); increased left atrial diastolic elastance (i.e., higher passive stiffness) has the opposite effect (panels C and D); increased preload increases all components of transmitral and pulmonary vein flow (panels E and F); finally, prolongation of ventricular relaxation decreases E and increases A wave velocities of the transmitral flow and decreases diastolic pulmonary vein flow (panels G and H). (From Thomas JD et al: Physical and physiological determinants of pulmonary venous flow: Numerical analysis. Am J Physiol 1997;272:H2453–H2465.)
Chapter 5 • Physical Determinants of Diastolic Flow of the blood column relative to the component velocity (that is, the so-called E/Vp ratio) is related to LV filling pressures,20,21 though the exact mechanistic relationship between these two phenomena is unclear (Fig. 5-9B). As noted, intraventricular flow during diastole characteristically forms circular eddies lateral to the main flow, which can be seen when the heart is imaged by echocardiography with highfrequency transducers, or after the contrast injection, and can be quantified by magnetic resonance velocity mapping (Fig. 5-9C).22 Creation of vortices plays a crucial role in mitral valve closure and in the transfer of blood toward the apex and then into the LV outflow tract. Again, full elucidation of vortex generation and movement is unclear.
TABLE 5-1 RESULTS OF SENSITIVITY ANALYSIS FOR THE PULMONARY VEIN AND TRANSMITRAL FLOW PULMONARY VEIN FLOW
Parameters Preload LV compliance index LV systolic elastance LV τ LA systolic elastance LA diastolic stiffness Mitral valve area MV ERO
TRANSMITRAL FLOW
S
D
AR
E
A
2.38 –0.45 –0.2 0.05 0.8 –0.79 –0.06 –2.73
2.33 –0.12 0.05 –0.19 –0.14 0.6 0.12 0.17
5.88 –1.15 –0.44 –1.76 0.97 –1.27 –0.16 –0.18
1.53 –0.24 –0.09 –0.33 –0.38 –0.11 0.07 0.32
1.9 –0.04 –0.19 0.16 –0.25 0.97 –1.02 –0.11
Modeling of the Intraventricular Flow by Fluid-Mechanical Computer Modeling of the intraventricular flow is demanding because ventricular motion effects blood flow, but blood flow itself effects ventricular motion. Some simplification is possible with compu-
A, atrial wave; AR, atrial reversal wave; D, diastolic wave; E, early wave; ERO, effective regurgitant orifice; LA, left atrial; LV, left ventricular; MV, mitral valve; S, systolic wave. From Thomas JD et al: Physical and physiological determinants of pulmonary venous flow: Numerical analysis. Am J Physiol 1997;272:H2453–H2465.
25
P
ECG
Pressure (mmHg)
20 MVO
15 10
LVP Base LA
LVP Apex 5 0
IVPG
–5
A 30
MV
pw (mmHg)
25 20 15 10
r = 0.80 p < 0.001 y = 5.27x+4.66 SEE = 3.1
5
LV
0 0.5
1
1.5
2
2.5
3
3.5
4
E/vp ratio
B
C
Figure 5-9 Three consecutive early diastolic intraventricular phenomena: A, Intraventricular pressure gradient formation in early diastole; B, relationship between the slowing of the blood column in the early diastole with preload; and C, formation of vortices. (B, From Garcia MJ et al: An index of early left ventricular filling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29:448–454; C, From Kilner PJ et al: Asymmetric redirection of flow through the heart. Nature 2000;404:759–761.)
53
54
Chapter 5 • Physical Determinants of Diastolic Flow tational fluid dynamics (CFD) models, where LV motion is prescribed based on images from echocardiography or magnetic resonance imaging, but these models lack fluid feedback on the myocardium. Full fluid-structure interaction (FSI) models are being developed in which movement of the blood and muscle is not known a priori but is computed during the simulation on a ∼mm three-dimensional grid at ∼msec intervals, an extraordinary computational challenge. Furthermore, most commercially available software programs allow only small strain deformations (up to 5%) and are inadequate for cardiac modeling, where strains may exceed 50%. Fortunately, large strain solvers recently have been implemented in commercial codes, which enabled several researchers to begin true fluid-solid interaction modeling of LV function.23–25 Although these models have simplified geometry and muscle properties, they give us insight into the flow propagation in the normal heart. Flow Propagation Inside the Ventricle We will first discuss the filling modeled by an axi-symmetric thin-walled FSI model of the left ventricle containing both LV outflow and inflow.26 During the rapid filling phase, a jet starts its propagation through the mitral valve into the ventricular chamber. Driven by this jet, a doughnut-shaped vortex is formed around the jet just downstream from the mitral orifice. During filling, the vortex ring travels toward the middle of the expanding ventricle, while a weak vortex is formed within the aortic outflow tract, which dissipates late during diastasis. After the vortex ring reaches the middle of the ventricle, its anterior part becomes stationary while the posterior part continues forward. During atrial contraction, a new, weaker vortex ring that encompasses a part of the outflow tract is formed, while the posterior side of the initial vortex ring continues to move into the posterior apical region of the ventricle. At the end of the filling, the posterior part of the second vortex ring merges with the first one, forming a large vortex in the posterior apex (Fig. 5-10). Effect of Ventricular Dilation on Flow A fascinating conundrum in echocardiography is the possibility of having very high velocities of mitral valve inflow, while the flow propagation velocity (velocity of the blood column inside the left ventricle) may be several times slower. Baccani et al. created a simple CFD simulation of this problem in dilated cardiomyopathy.27 They showed that LV dilation slows down flow propagation velocity. Furthermore, they have shown that this is associated with the initial vortex staying attached to the mitral valve (Fig. 5-11). Pressure Propagation Inside the Ventricle Flow and velocity propagation, though tightly linked, are separate phenomena. To analyze this relationship, we developed a two-dimensional axi-symmetric thick-walled FSI model. The fluid domain was represented by 6321 triangular elements, while the solid domain was represented by 1206 bricklike quadrilateral elements. The time-varying pressure at the mitral valve opening was generated by the numerical simulations of the lumped parameter model. The fluid domain was represented by incompressible Navier-Stokes equations. The LV wall was given time-varying stiffness properties, with strains calculated using a large strain deformation code. Finally, the decrease in stiffness of the wall during ventricular relaxation was modeled as an exponential decay from systolic stiffness to diastolic stiffness.28,29 The baseline ventricular filling pattern is illustrated in Figure 5-12, showing the E wave entering the cavity, with formation of
Figure 5-10 Computer modeling of vortices during left ventricular filling. During the rapid filling phase, initial inflow through the mitral valve forms a doughnut-shaped vortex downstream from the mitral orifice. This vortex ring then travels toward the middle of the expanding ventricle, while a weak vortex of brief duration is formed within the aortic outflow tract. After the initial vortex ring reaches the middle of the ventricle, its anterior part becomes stationary while the posterior part continues forward. During the atrial contraction, a new, weaker vortex ring that encompasses a part of the outflow tract is formed, while the posterior side of the initial vortex ring continues to move into the posterior apical region of the ventricle. In the end of the filling, the posterior part of the second vortex ring merges with the first, forming a large vortex in the posterior apex. (From Cheng Y et al: Fluid-structure coupled CFD simulation of the left ventricular flow during filling phase. Ann Biomed Eng 2005;33:567–576.)
a vortex off the tips of the mitral valve that propagates beside the E wave into the ventricle. The ventricle expands under the influence of decreased elasticity and increased strain due to LV filling. As the relaxation finishes after about 200 msec, the E wave loses strength, and velocity slowly decreases as the expansion of the ventricle ceases. After the E wave ends, atrial pressure increases and the A wave enters the ventricular cavity, forming another vortex off the mitral valve. As the A wave propagates toward the apex, this vortex is taken up by the first vortex that is still present. By now, ventricular stresses have significantly increased, raising LV pressure and slowing down filling. The filling behavior described here corresponds with clinically observed behavior. Using this fluid-structure interaction model, we have investigated the influence of changes in relaxation (τ) and end diastolic stiffness. In Figure 5-12, color Doppler M-mode images are shown from four different conditions: (A-B) baseline, (C-D) shorter τ, (E-F) longer τ, and (G-H) increased ventricular diastolic stiffness. At baseline, the E and A waves are roughly balanced (equal color-mapped peak velocities). Intraventricular pressure gradients (IVPGs) are slightly above normal due to the
Chapter 5 • Physical Determinants of Diastolic Flow 0
0.02
1
0.02
0.01
0.5
0.04
0
z
0 0.01
0.06
0.02
0.08
–0.5 0.08
0.06
0.04
0.02
0
0
0.2
0.4
0.6
0.8
1
–1
t
0 0.02 0.03 0
z
Figure 5-11 Impact of ventricular dilation on flow. Images represent a computer model of left ventricular flow in mid-diastole. In a normal ventricle (upper left panel), the proximal vortex becomes unattached and freely moves toward the apex, enabling prompt filling of the ventricle, as evidenced by high flow propagation velocity (upper right panel). In contrast, left ventricular dilation prohibits the movement of vortices toward the apex (lower left panel), and slows down flow propagation velocity (lower right panel). (From Baccani B et al: Fluid dynamics of the left ventricular filling in dilated cardiomyopathy. J Biomech 2002;35:665–671.)
0.06 0.02
mild mitral stenosis inherent in the model. With shorter τ, the E-wave velocity, Vp, and IVPG increase, while a longer τ produces the classic appearance of delayed relaxation (i.e., low E velocity, slow propagation, large A wave, and reduced IVPG).29–32 Because of the mild mitral stenosis, E-wave deceleration time is prolonged; for very large time constants, the E wave is no longer separated from the A wave.29 With a stiffer ventricle, velocities and IVPG are reduced, reflecting lower stroke volume, the expected behavior when atrial pressure is held at baseline so no pseudonormalization will occur. The A wave is particularly blunted, reflecting ineffective filling of the stiff ventricle.31,33 As support for these findings, we have recently shown that in humans, IVPG in the elderly becomes blunted with worsened relaxation.9 In addition, elderly people with preserved ventricular compliance (i.e., a less stiff ventricle), still had worsened IVPGs, reflecting the dependence of IVPGs on intact relaxation, without an impact of compliance.
Insights from Experimental Studies Currently, no model can predict the impact of structural changes of LV shape on flow propagation within the LV. In that situation, we are left with some experimental studies. We will discuss briefly some of them. Presence of Ischemia Acute ischemia delays apical filling34,35 and is associated with the loss of IVPGs.36,37 Beppu et al. described the altered apical blood flow pattern in dogs with apical akinesis after coronary ligation.38 Ischemia decreases the maximal distance of mitral flow into the ventricle during diastole, with blood flow in the region of the infarction becoming either static or eddied.38,39
0.09 0
0.2
0.4
0.6
0.8
1
Distorted Left Ventricular Geometry In a recent sheep study, myocardial aneurysm was induced by the ligation of coronary arteries subtending the LV apex.40 Flow propagation velocity abruptly decreased when blood flow column entered LV aneurysms and the point of this deceleration coincided with the edge of the aneurysm (Fig. 5-13). The infarct size correlated with the distance from the apex to the point of the deceleration of flow propagation. However, no point of abrupt decrease was detected when myocardial infarct was induced by circumflex occlusion. Also, significantly, the presence of breakpoint coincided with loss of the IVPG. In a clinical study that is congruent with these findings, we have shown that removal of the aneurysm by infarct exclusion surgery improves IVPGs.41 These data show that in order for flow to enter the heart cavity, heart walls have to be compliant. Effect of Isovolumic Processes During the isovolumic period of LV relaxation, the left ventricle changes its shape in the absence of any change of volume. The most dramatic aspect of this is that the left ventricle untwists, a process that is linked to the elastic elements of the ventricle that induce early LV suction. Untwisting is a necessary successor to systolic torsion (twist). Systolic torsion and diastolic untwisting occur because myocardial fibers form a leftward helix in the subepicardium.42 The contraction of these fibers rotates the base and the apex of the left ventricle clockwise and counterclockwise, respectively. However, unlike systolic torsion that increases proportional to systolic volume change, untwisting is a phenomenon that peaks prior to the opening of the mitral valve.11,43 The reason this occurs is that systolic torsion builds potential energy within the elastic elements of the heart.44 With relaxation, energy is released, and elastic elements promptly restore the original, untwisted LV shape. It is no surprise that untwisting is inversely
55
Chapter 5 • Physical Determinants of Diastolic Flow A LV
2
VP
5
1
4
0.6
MV
0
LA
–1 0
0.1
0.2
0.3 0.4 Time (s)
0.5
0.6
0.7
1
0.2
0
1
4
3
0.8
2
0.6
1
0.4
1
0
0.2
0
0.3 0.4 Time (s)
0.5
0.6
0.7
Distance (cm)
4
0.2
0
4
3
0.8
2
0.6
1
0.4
1
0
0.2
0
0.5
0.6
0.7
Distance (cm)
1
0.3 0.4 Time (s)
0
4
3
0.8
2
0.6
1
0.4
1
0
0.2
0
0.5
0.6
0.7
0
Distance (cm)
1
0.3 0.4 Time (s)
6
2 0
0.1
0.2
0.3 0.4 Time (s)
0.5
0.6
0.7
–2 10
F
8 6
2 0
0.1
0.2
0.3 0.4 Time (s)
0.5
0.6
0.7
–2 10
H 8 6
3 4 2
–1 0
2 0
0.1
0.2
0.3 0.4 Time (s)
0.5
0.6
0.7
Relative pressure (mmHg)
4
Velocity (m/s)
5
0.2
8
–1 0
1.2
0.1
10
4
5
–1 0
–2
2
6
G
0.7
3
1.4
6
0.6
Relative pressure (mmHg)
4
Velocity (m/s)
5
0.2
0.5
D
–1 0
1.2
0.1
0.3 0.4 Time (s)
4
5
–1 0
0.2
2
6
E
0.1
3
1.4
6
0
Relative pressure (mmHg)
5 Velocity (m/s)
1.2
0.1
2
–1 0
5
–1 0
6 4
6
C
8
2
0.4
0
10
B
3
1.4
6
Distance (cm)
1.2
0.8
3
1
Distance (cm)
6
Velocity (m/s)
4
1.4
Relative pressure (mmHg)
E-wave
5 Distance (cm)
A-wave
Distance (cm)
6
Distance (cm)
56
–2
Figure 5-12 Modeling of fluid-structure interaction showing influence of changes in relaxation (τ) and end diastolic stiffness. Pseudo–M-mode images of time-velocity (left panels) and time-pressure data from four different conditions: A and B, baseline; C and D, shorter τ; E and F, longer τ; and G and H, increased ventricular diastolic stiffness. At baseline, the E and A waves are roughly balanced (equal color-mapped peak velocities). IVPGs are slightly above normal due to the mild mitral stenosis inherent in the model. With shorter τ, the E-wave velocity, Vp, and IVPG increase, while longer τ produces the classic appearance of delayed relaxation (low E velocity, slow propagation, large A-wave and reduced IVPG). Because of the mild mitral stenosis, E-wave deceleration time is prolonged and for very large time constants no longer fully separated from the A wave. With a stiffer ventricle, velocities and IVPG are reduced, reflecting lower stroke volume, the expected behavior when atrial pressure is held at baseline to prevent pseudonormalization. The A wave is particularly blunted, reflecting ineffective filling of the stiff ventricle.
Chapter 5 • Physical Determinants of Diastolic Flow
7 IVPG (mmHg)
: r2 = 0.99 5 3 1 –1 4 Normal
2
0
Apex-to-base distance (cm)
Apex (A) A-D (23 mm) IVPG (mmHg)
Abrupt decrease in propagation velocity (D)
related to τ, and its magnitude may be used as a surrogate measure of relaxation. Events during early diastole in a normal left ventricle can be summarized in the following way. Relaxation leads to prompt LV untwisting, the peak of which coincides with mitral valve opening; this is immediately followed by peak early mitral annulus velocity; finally, formation of the IVPG facilitates early LV filling. We have shown a strong correlation between untwisting and IVPG at rest and during exercise.11 Furthermore, we have shown that essentially the same slope of untwisting-IVPG relationship exists in patients with severe hypertrophic cardiomyopathy (Fig. 5-14). This indicates that untwisting and the IVPG are tightly coupled and that either untwisting is necessary to produce the IVPG or that some strong third factor binds them, expressed simultaneously by untwisting and by the IVPG. Thus, it seems that three major factors determine flow propagation and IVPGs: chamber dilation, worsened relaxation, and loss of compliance.
: r2 = 0.97 : r2 = 0.67
4 3 2 1 0 –1 4
2
4
p < 0.00001 Normal exercise p < 0.00001
2 Normal rest
HCM exercise P = NS
HCM rest P = NS 0 0
FUTURE RESEARCH The number of flow-based diastolic parameters that are proposed to be helpful in clinical practice is staggering. Still, more and more indices are proposed every year. This review of the physics behind diastolic flows aims to elucidate common underlying processes that are manifested through various diastolic parameters. In this manner, we are trying to bring another “Rosetta stone” to the cardiology community.45 In the remainder of this book, many of these indices will be shown in application to various diseases of
0
LV aneurysm
Peak IVPG (mmHg)
Figure 5-13 Effect of apical aneurysm on intraventricular flow propagation. Flow propagation velocity decreases abruptly when blood enters the aneurysm. This sudden deceleration coincides with the loss of intraventricular pressure gradient. (From Asada-Kamiguchi J et al: Intraventricular pressure gradients in left ventricular aneurysms determined by color M-mode Doppler method: An animal study. J Am Soc Echocardiogr 2006;19:1112–1118.)
5
–5 Peak untwisting velocity (rad/s)
Figure 5-14 Relationship between left ventricular untwisting and intraventricular pressure gradients (IVPGs) at rest (open markers) and during exercise (closed markers). Normal subjects are marked by squares, while hypertrophic cardiomyopathy patients are marked by triangles. While the same slope of untwisting-IVPG relationship exists in normal hearts and in those with severe hypertrophic cardiomyopathy, hearts of patients with hypertrophic cardiomyopathy cannot generate the increase of untwisting during the exercise, leading to smaller IVPG increase. (From in Notomi Y et al: Enhanced ventricular untwisting during exercise: A mechanistic manifestation of elastic recoil described by Doppler tissue imaging. Circulation 2006;113:2524–2533.)
57
58
Chapter 5 • Physical Determinants of Diastolic Flow diastolic function; it is hoped that by keeping these physical principles in mind, the reader will better be able to assess diastolic dysfunction clinically. Despite numerous published studies, our current understanding of physical properties is limited. One field that is largely undefined is the modeling of structural-fluid relationships within the left ventricle, which is a structure so complex that to accurately calculate mechanical events during diastole, one needs several days even with the use of the most powerful supercomputers. Therefore, until computer processing power is increased by an order of magnitude, we will lack the ability to answer such seemingly simple questions as: Is torsion necessary to LV contraction? and What happens to end diastolic pressure if we eliminate an increase in the IVPG during diastole? To paraphrase Sir Isaac Newton, we are still like children playing on the seashore and diverting ourselves now and then, finding a smoother pebble or a prettier shell than ordinary, whilst the great ocean of truth lies all undiscovered before us.
ABBREVIATIONS A: atrial AR: atrial reversal CFD: computational fluid dynamics D: diastolic E: early EDPVR: end diastolic pressure-volume relationships FSI: fluid-structure interactions IVPG: intraventricular pressure gradient LA: left atrium LV: left ventricular MV: mitral valve P-V: pressure-volume PV: pulmonary vein(s) S: systolic Vp: flow propagation velocity τ: time constant of isovolumic pressure decay (Tau) t: time REFERENCES 1. Glantz SA, Parmley WW: Factors which affect the diastolic P-V curve. Circ Res 1978;42:171–180. 2. Nikolic S, Yellin EL, Tamura K, et al: Passive properties of canine left ventricle: Diastolic stiffness and restoring forces. Circ Res 1988;62: 1210–1222. 3. Thomas JD, Zhou J, Greenberg N, et al: Physical and physiological determinants of pulmonary venous flow: Numerical analysis. Am J Physiol 1997;272:H2453–2465. 4. Ohno M, Cheng CP, Little WC: Mechanism of altered patterns of left ventricular filling during the development of congestive heart failure. Circulation 1994;89:2241–2250. 5. Matsubara H, Nakatani S, Nagata S, et al: Salutary effect of disopyramide on left ventricular diastolic function in hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 1995;26:768–775. 6. Nikolic S, Yellin EL, Tamura K, et al: Effect of early diastolic loading on myocardial relaxation in the intact canine left ventricle. Circ Res 1990;66: 1217–1226. 7. Senzaki H, Fetics B, Chen CH, Kass DA: Comparison of ventricular pressure relaxation assessments in human heart failure: Quantitative influence on load and drug sensitivity analysis. J Am Coll Cardiol 1999;34: 1529–1536. 8. Scalia GM, Greenberg NL, McCarthy PM, et al: Noninvasive assessment of the ventricular relaxation time constant (t) in humans by Doppler echocardiography. Circulation 1997;95:151–155.
9. Popovic ZB, Prasad A, Garcia MJ, et al: Relationship between diastolic intraventricular pressure gradients, relaxation, and preload: Impact of age and fitness. Am J Physiol Heart Circ Physiol 2005. 10. Nikolic SD, Yellin EL, Dahm M, et al: Relationship between diastolic shape (eccentricity) and passive elastic properties in canine left ventricle. Am J Physiol 1990;259:H457–H463. 11. Notomi Y, Martin-Miklovic MG, Oryszak SJ, et al: Enhanced ventricular untwisting during exercise: A mechanistic manifestation of elastic recoil described by Doppler tissue imaging. Circulation 2006;113:2524–2533. 12. Thomas JD, Popovic ZB: Intraventricular pressure differences: A new window into cardiac function. Circulation 2005;112:1684–1686. 13. Thomas JD, Weyman AE: Echocardiographic Doppler evaluation of left ventricular diastolic function. Physics and physiology. Circulation 1991;84:977–990. 14. Courtois M, Kovacs SJ Jr, Ludbrook PA: Transmitral pressure-flow velocity relation: Importance of regional pressure gradients in the left ventricle during diastole. Circulation 1988;78:661–671. 15. Thomas JD, Newell JB, Choong CY, Weyman AE: Physical and physiological determinants of transmitral velocity: Numerical analysis. Am J Physiol 1991;260:H1718–H1731. 16. Nakatani S, Firstenberg MS, Greenberg NL, et al: Mitral inertance in humans: Critical factor in Doppler estimation of transvalvular pressure gradients. Am J Physiol Heart Circ Physiol 2001;280:H1340–H1345. 17. Hay I, Rich J, Ferber P, et al: Role of impaired myocardial relaxation in the production of elevated left ventricular filling pressure. Am J Physiol Heart Circ Physiol 2005;288:H1203–H1208. 18. Firstenberg MS, Greenberg NL, Smedira NG, et al: Doppler echo evaluation of pulmonary venous–left atrial pressure gradients: Human and numerical model studies. Am J Physiol Heart Circ Physiol 2000;279: H594–H600. 19. Kamohara K, Fukamachi K, Ootaki Y, et al: Evaluation of a novel device for left atrial appendage exclusion: The second-generation atrial exclusion device. J Thorac Cardiovasc Surg 2006;132:340–346. 20. Garcia MJ, Ares MA, Asher C, et al: An index of early left ventricular filling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29:448–454. 21. Firstenberg MS, Vandervoort PM, Greenberg NL, et al: Noninvasive estimation of transmitral pressure drop across the normal mitral valve in humans: Importance of convective and inertial forces during left ventricular filling. J Am Coll Cardiol 2000;36:1942–1949. 22. Kilner PJ, Yang GZ, Wilkes AJ, et al: Asymmetric redirection of flow through the heart. Nature 2000;404:759–761. 23. Vierendeels JA, Dick E, Verdonck PR: Hydrodynamics of color M-mode Doppler flow wave propagation velocity V(p): A computer study. J Am Soc Echocardiogr 2002;15:219–224. 24. Vierendeels JA, Riemslagh K, Dick E, Verdonck PR: Computer simulation of intraventricular flow and pressure gradients during diastole. J Biomech Eng 2000;122:667–674. 25. Verdonck P, Vierendeels J, Riemslagh K, Dick E: Left-ventricular pressure gradients: A computer-model simulation. Med Biol Eng Comput 1999;37:511–516. 26. Cheng Y, Oertel H, Schenkel T: Fluid-structure coupled CFD simulation of the left ventricular flow during filling phase. Ann Biomed Eng 2005;33:567–576. 27. Baccani B, Domenichini F, Pedrizzetti G, Tonti G: Fluid dynamics of the left ventricular filling in dilated cardiomyopathy. J Biomech 2002;35: 665–671. 28. Mirsky I: Assessment of diastolic function: Suggested methods and future considerations. Circulation 1984;69:836–841. 29. Thomas JD, Zhou J, Greenberg N, et al: Physical and physiological determinants of pulmonary venous flow: Numerical analysis. Am J Physiol 1997;272:H2453–H2465. 30. Lemmon JD, Yoganathan AP: Computational modeling of left heart diastolic function: Examination of ventricular dysfunction. J Biomech Eng 2000;122:297–303. 31. Takatsuji H, Mikami T, Urasawa K, et al: A new approach for evaluation of left ventricular diastolic function: Spatial and temporal analysis of left ventricular filling flow propagation by color M-mode Doppler echocardiography [see comments]. J Am Coll Cardiol 1996;27:365–371. 32. Garcia MJ, Smedira NG, Greenberg NL, et al: Color M-mode Doppler flow propagation velocity is a preload insensitive index of left ventricular relaxation: Animal and human validation. J Am Coll Cardiol 2000;35: 201–208. 33. Appleton CP, Hatle LK, Popp RL: Relation of transmitral flow velocity patterns to left ventricular diastolic function: New insights from a combined
Chapter 5 • Physical Determinants of Diastolic Flow
34. 35. 36. 37. 38.
39.
hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol 1988;12:426–440. Stugaard M, Smiseth OA, Risoe C, Ihlen H: Intraventricular early diastolic filling during acute myocardial ischemia. Circulation 1993;88:2705– 2713. Steine K: Mechanisms of retarded apical filling in acute ischemic left ventricular failure. Circulation 1999;99:2048–2054. Steine K, Stugaard M, Smiseth OA: Mechanisms of retarded apical filling in acute ischemic left ventricular failure. Circulation 1999;99:2048– 2054. Steine K, Flogstad T, Stugaard M, Smiseth OA: Early diastolic intraventricular filling pattern in acute myocardial infarction by color M-mode Doppler echocardiography. J Am Soc Echocardiogr 1998;11:119–125. Beppu S, Izumi S, Miyatake K, et al: Abnormal blood pathways in left ventricular cavity in acute myocardial infarction. Experimental observations with special reference to regional wall motion abnormality and hemostasis. Circulation 1988;78:157–164. Delemarre BJ, Visser CA, Bot H, Dunning AJ: Prediction of apical thrombus formation in acute myocardial infarction based on left ventricular spatial flow pattern. J Am Coll Cardiol 1990;15:355–360.
40. Asada-Kamiguchi J, Jones M, Greenberg NL, et al: Intraventricular pressure gradients in left ventricular aneurysms determined by color M-mode Doppler method: An animal study. J Am Soc Echocardiogr 2006;19: 1112–1118. 41. Firstenberg MS, Smedira NG, Greenberg NL, et al: Relationship between early diastolic intraventricular pressure gradients, an index of elastic recoil, and improvements in systolic and diastolic function. Circulation 2001;104: I330–I335. 42. Ingels NB Jr, Hansen DE, Daughters GT 2nd, et al: Relation between longitudinal, circumferential, and oblique shortening and torsional deformation in the left ventricle of the transplanted human heart. Circ Res 1989;64: 915–927. 43. Gibbons Kroeker CA, Ter Keurs HE, Knudtson ML, et al: An optical device to measure the dynamics of apex rotation of the left ventricle. Am J Physiol 1993;265:H1444–H1449. 44. Bell SP, Nyland L, Tischler MD, et al: Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res 2000;87:235–240. 45. Nishimura RA, Tajik AJ: Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta Stone. J Am Coll Cardiol 1997;30:8–18.
59
HIDEKATSU FUKUTA, MD, PhD WILLIAM C. LITTLE, MD
6
General Principles, Clinical Definition, and Epidemiology INTRODUCTION PATHOPHYSIOLOGY Systolic Performance Diastolic Performance Definition of Systolic and Diastolic Heart Failure Terminology CLINICAL APPLICATIONS Diagnosis of Diastolic Heart Failure Timing of Ejection Fraction Measurement
Is Measurement of Diastolic Function Necessary? Prognostic Utility of Doppler Echocardiography Practical Recommendations EPIDEMIOLOGY Epidemiology of Diastolic Dysfunction Epidemiology of Diastolic Heart Failure CONCLUSIONS AND FUTURE RESEARCH
INTRODUCTION Heart failure (HF) is defined as the pathological state in which the heart is unable to pump blood at a rate required by the metabolizing tissues or can do so only with an elevated filling pressure. Inability of the heart to pump blood sufficiently to meet the needs of the body’s tissues may be due to the inability of the left ventricle to fill (diastolic performance) or eject blood (systolic performance) or both. Thus, consideration of the systolic and diastolic performance of the left ventricle provides a conceptual basis to classify and understand the pathophysiology of HF.
PATHOPHYSIOLOGY Systolic Performance Left ventricular (LV) systolic performance is the ability of the left ventricle to empty, which can be quantified as an emptying frac-
tion, or an ejection fraction (EF): a ratio of stroke volume-to-end diastolic volume. Thus, LV systolic dysfunction is defined as a decreased EF. The EF can be obtained by determining the LV volume by use of two-dimensional echocardiography with or without contrast, radionuclide ventriculography, or magnetic resonance imaging. The EF has been used as an index of myocardial contractile performance. However, it is influenced not only by myocardial contractility but also by LV afterload.1 Furthermore, in the presence of a left-sided valvular regurgitation (mitral or aortic regurgitation) or a left-to-right shunt (ventricular septal defect or patent ductus arteriosus), the LV stroke volume may be high, while the forward stroke volume (stroke volume minus regurgitant volume or shunt volume) is lower. Thus, the effective EF is defined as the forward stroke volume divided by end diastolic volume.2 The effective EF is a useful means to quantify systolic function, for two reasons: First, the effective EF represents the functional emptying of the left ventricle that contributes to cardiac 63
Chapter 6 • General Principles, Clinical Definition, and Epidemiology output. Second, the effective EF is relatively independent of LV end diastolic volume over the clinically relevant range. An operational definition of systolic dysfunction is an effective EF of less than 0.50.2 When defined in this manner, systolic dysfunction results from impaired myocardial function, increased LV afterload, structural abnormalities of the left ventricle, or a combination thereof.2
Diastolic Performance For the left ventricle to function effectively as a pump, it must be able not only to eject but also to fill, which is its diastolic function. Diastolic function conventionally has been assessed on the basis of the LV end diastolic pressure-volume (P-V) relation (see Chapter 7).3 A shift of the curve upward and to the left has been considered to be the hallmark of diastolic dysfunction (Fig. 6-1, curve A). In this situation, each LV end diastolic volume is associated with a high end diastolic pressure, and thus the left ventricle is less distensible. Decreased LV distensibility is caused by aging, systemic hypertension, and hypertrophic or restrictive cardiomyopathy.2 Diastolic function also has been assessed based on LV filling patterns by use of Doppler echocardiography.4,5 In the absence of mitral stenosis, three patterns of LV filling indicate progressive impairment of diastolic function: (1) reduced early diastolic filling with a compensatory increase in importance of atrial filling (impaired relaxation); (2) most filling early in diastole but with rapid deceleration of mitral flow (pseudonormalization); and (3) almost all filling of the left ventricle occurring very early in diastole in association with very rapid deceleration of mitral flow (restrictive filling) (Fig. 6-2).6 These Doppler LV filling patterns, however, are influenced not only by LV diastolic properties but also by left atrial (LA) pressure. In contrast, tissue Doppler measurement of mitral annular velocity and color M-mode measurement of the velocity of propagation of mitral inflow to the apex appear to be less load sensitive. The peak early diastolic mitral annular velocity (EM) provides a relatively load insensitive measure of LV relaxation.7 EM is decreased with increasing severity of diastolic dysfunction.8,9 The color M-mode imaging performed from the apex provides a temporal and spatial map of the velocities of blood flow in early diastole along the long axis of the left ventricle. The velocity of
LV end diastolic pressure
64
A Normal
B
ΔP ΔV
LV end diastolic volume Figure 6-1 A shift of the curve to A indicates that a higher left ventricular (LV) pressure will be required to distend the LV to a similar volume, indicating that the ventricle is less distensible. The slope of the LV end diastolic pressure-volume relation indicates the passive chamber stiffness. Since the relation is exponential in shape, the slope (ΔP/ΔV) increases as the end diastolic pressure increases. (Data from Little WC: Diastolic dysfunction beyond distensibility: Adverse effects of ventricular dilatation. Circulation 2005;112:2888–2890.)
propagation of mitral inflow to the apex (VP) is reduced in conditions with impaired LV relaxation.9 A pseudonormalized LV filling pattern can be distinguished from a normal filling pattern by demonstrating reduced EM and VP. Furthermore, since early diastolic mitral inflow velocity (E) becomes higher and relaxation-related parameters (EM and Vp) remain reduced as filling pressure increases, the E/EM and E/VP can estimate LV filling pressure with a reasonable accuracy over a wide range of an EF.10–12 Last, color M-mode imaging provides a noninvasive measurement of the diastolic intraventricular pressure gradient between the apex and the base during early diastole.13 Finally, analysis of pulmonary venous flow patterns provides useful information on LV compliance and LA pressure.14 With increase in LV end diastolic pressure, the reversal velocity of pulmonary venous atrial flow increases, and duration increases longer than that of mitral late diastolic velocity. With decrease in LV compliance and increase in mean LA pressure, the systolic component of pulmonary venous flow decreases and the diastolic component of pulmonary venous flow increases. Table 6-1 and Figure 6-2 show stages of diastolic dysfunction incorporatingpulmonary venous flow, tissue Doppler, and color M-mode indices.9
Definition of Systolic and Diastolic Heart Failure When the HF is associated with a reduced EF, the pathological state may be called systolic HF. In contrast, when the HF is associated with diastolic dysfunction in the absence of a reduced EF, the pathological state may be called diastolic HF. It is important to recognize that the HF, whether it results from systolic or diastolic dysfunction, is a clinical syndrome and that both systolic HF and diastolic HF are heterogeneous disorders. Patients with systolic HF have abnormalities of diastolic function,2,3 and those with diastolic HF may have abnormalities of systolic contractile function that are not detected by measurement of an EF.15
Terminology Diastolic Dysfunction and Diastolic Heart Failure The term diastolic dysfunction is used to describe abnormal mechanical (diastolic) properties of the ventricle and includes decreased LV distensibility, delayed relaxation, and abnormal filling, regardless of whether the EF is normal or reduced and whether the patient is symptomatic or asymptomatic. In contrast, the term diastolic HF is used to describe patients with the symptoms and signs of HF and a normal EF and diastolic dysfunction.
Diastolic Heart Failure and Heart Failure with Normal Ejection Fraction There are many clinical conditions that cause HF with a normal EF. These include diastolic dysfunction, valvular diseases, pericardial diseases, and intracardiac mass; among them, diastolic dysfunction is the most common cause of HF with a normal EF. Diastolic HF is associated with LV diastolic abnormalities. It is important to recognize that although patients with diastolic HF have diastolic dysfunction, frequently they also have systolic contractile abnormalities (despite the normal EF). In addition, comorbidities such as hypertension, anemia, and renal dysfunction are commonly seen in patients with diastolic HF and may contribute to the development of HF.
Chapter 6 • General Principles, Clinical Definition, and Epidemiology Normal
Impaired relaxation
E
E
Pseudonormal
Restrictive E
E Mitral inflow velocity
A
A
A A
D S
S
D
D
D
Figure 6-2 Transmitral inflow velocity, pulmonary vein flow velocity, mitral annular velocity, and color M-mode imaging in stages of diastolic dysfunction. E, early diastolic mitral inflow velocity; A, late diastolic mitral inflow velocity; S, systolic pulmonary vein velocity; D, diastolic pulmonary vein velocity; SM, systolic mitral annular velocity; EM, early diastolic mitral annular velocity; AM, late diastolic mitral annular velocity; and Vp, velocity of propagation of mitral inflow to the apex. (Data from Fukuta H, Little WC: Diastolic versus systolic heart failure. In Smiseth OA, Tendera M (eds): Diastolic Heart Failure. London, Springer, 2007.)
S
S
Pulmonary vein velocity SM
SM
SM
SM
Mitral annular velocity EM EM Color M-mode imaging
AM
AM
EM
AM
EM
AM
VP
TABLE 6-1 STAGES OF DIASTOLIC DYSFUNCTION PARAMETER
NORMAL (YOUNG)
NORMAL (ADULT)
DELAYED RELAXATION
PSEUDONORMAL FILLING RESTRICTIVE FILLING
E/A DT (msec) IVRT (msec) S/D AR (cm/sec) Vp (cm/sec) Em (cm/sec)
>1 <220 <100 <1 <35 >55 >10
>1 <220 <100 ≥1 <35 >45 >8
<1 >220 >100 ≥1 <35 <45 <8
1–2 150–200 60–100 <1 ≥35 <45 <8
>2 <150 <60 <1 ≥25* <45 <8
*Unless atrial mechanical failure is present. AR, pulmonary venous peak atrial contraction reversed velocity; DT, early left ventricular filling deceleration time; E/A, early-to-atrial left ventricular filling ratio; Em, peak early diastolic myocardial velocity; IVRT, isovolumic relaxation time; S/D, systolic-to-diastolic pulmonary venous flow ratio; Vp, color M-mode flow propagation velocity. From Garcia MJ et al: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865–875.
Comparison of Pathophysiology in Systolic and Diastolic Heart Failure Table 6-2 shows the comparison of LV structural and functional characteristics in systolic and diastolic HF (see Chapter 2). Systolic HF and diastolic HF have several similarities in LV structural and functional characteristics, including increased LV mass and increased LV end diastolic pressure. The most significant difference between the two forms of HF is in LV geometry and LV function: Systolic HF is characterized by LV dilatation, eccentric LV hypertrophy, and abnormal systolic and diastolic function, whereas diastolic HF is characterized by concentric LV hypertrophy, a normal EF, and abnormal diastolic function. Thus, the pathophysiology of systolic HF is dependent predominantly on progressive LV dilatation and abnormal systolic function. On the
other hand, the pathophysiology of diastolic HF is dependent predominantly on concentric LV hypertrophy and abnormal diastolic function.
CLINICAL APPLICATIONS Diagnosis of Diastolic Heart Failure A distinction between systolic and diastolic HF is important because these two forms have different pathophysiologies and thus might potentially require different therapeutic approaches.5 Nevertheless, clinical symptoms and signs are similar in systolic and diastolic HF (Table 6-3).16,17 This may be because systolic HF is often accompanied by diastolic dysfunction, by which
65
66
Chapter 6 • General Principles, Clinical Definition, and Epidemiology TABLE 6-2
TABLE 6-3
COMPARISON OF LEFT VENTRICULAR (LV) STRUCTURAL AND FUNCTIONAL FEATURES BETWEEN SYSTOLIC AND DIASTOLIC HEART FAILURE (HF)
RPREVALENCE OF SPECIFIC SYMPTOMS AND SIGNS IN SYSTOLIC AND DIASTOLIC HEART FAILURE (HF)
CHARACTERISTICS Remodeling LV end diastolic volume LV end systolic volume LV mass Relative wall thickness Cardiomyocyte Extra cellular matrix collagen Diastolic properties LV end diastolic pressure Relaxation time constant Filling rate Chamber stiffness Myocardial stiffness Systolic properties Performance Stroke volume Stroke work Function Ejection fraction Ejection rate PRSW Contractility Positive dp/dt Ees FS vs. stress Preload reserve Ea Arterial-ventricular coupling (Ea/Ees)
SYSTOLIC HF
DIASTOLIC HF
↑ ↑ ↑ eccentric ↓ ↑ length ↓
N N ↑ concentric ↑ ↑ diameter ↑
↑↑ ↑ ↓ N–↓ N–↑
↑↑ ↑↑ ↓↓ ↑ ↑
↓ ↓
N–↓ N
↓ ↓ ↓
N N N
↓ ↓ ↓ Exhausted ↓ ↓
N N–↑ N Limited ↑ N
Ea, effective arterial elastance; EEs, end systolic elastance; FS, fractional shortening; PRSW, preload-recruitable stroke work. Data from Zile MR, Baicu CF, Bonnema DD: Diastolic heart failure: Definitions and terminology. Prog Cardiovasc Dis 2005;47:307–313.
symptoms and signs related to pulmonary congestion are commonly observed.2 Thus, clinical history and physical examination do not provide useful information in discriminating between systolic and diastolic HF. Several criteria have been proposed for the diagnosis of diastolic HF.18,19 In summary, for the diagnosis of diastolic HF to be made, the following evidence is required: ❒ ❒ ❒
clinical evidence of HF, normal systolic function (LV EF >0.50), and objective evidence of impaired LV relaxation or LV passive stiffness.
If strictly applied, the definition of diastolic HF would include patients with acute mitral or aortic regurgitation, mechanical causes of diastolic dysfunction (mitral stenosis or constrictive pericarditis), right-sided HF, intracardiac mass, or congenital heart diseases; these conditions could be avoided by additional echocardiographic screening.5
Timing of Ejection Fraction Measurement Vasan and Levy criteria require a normal EF within 72 hours of an episode of pulmonary congestion to make a definite diagnosis of diastolic HF.19 It is possible, however, that the acute pulmonary
Symptoms Dyspnea on exertion Paroxysmal nocturnal dyspnea Orthopnea Physical examination Jugular venous distension Rales Displaced apical impulse S3 S4 Hepatomegaly Edema Chest radiograph Cardiomegaly Pulmonary venous hypertension
SYSTOLIC HF (%)
DIASTOLIC HF (%)
96 50 73
85 55 60
46 70 60 65 66 16 40
35 72 50 45 45 15 30
96 80
90 75
From Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure. Part I: Diagnosis, prognosis, and measurement of diastolic function. Circulation 2002;105:1387–1393.
congestion may be due to transient systolic dysfunction or acute mitral regurgitation produced by hypertension and/or myocardial ischemia that had resolved by the time the LV EF was measured. To address this issue, Gandhi et al. used Doppler echocardiography to evaluate LV EF, regional wall motion, and mitral regurgitation in 38 patients both during an acute episode of hypertensive pulmonary edema and 24 to 72 hours later, after treatment and resolution of the hypertension and pulmonary congestion.20 They found that LV EF and regional wall motion were similar, both during the acute episode of hypertensive pulmonary edema and after resolution of the congestion and control of blood pressure (Fig. 6-3).21 No patient had severe mitral regurgitation during the acute episode. They also found that 50% of the patients had an EF equal to or greater than 0.50 during their presentation with acute pulmonary edema and that 88% of the patients with an EF equal to or greater than 0.50 after treatment had an EF equal to or greater than 0.50 during the acute episode, and all of these patients had an EF of at least 0.43. Thus, they concluded that the EF obtained 1–3 days after the acute presentation of patients with hypertensive pulmonary edema accurately identified patients with a preserved EF during acute presentation. This study suggests that measuring the EF within 72 hours of an acute episode of pulmonary congestion is sufficient to meet the diagnostic criteria proposed by Vasan and Levy. However, measurements of diastolic filling could have changed within the 72-hour period.
Is Measurement of Diastolic Function Necessary? Recognizing the difficulties inherent in the clinical assessment of LV diastolic performance, Zile et al. tested the hypothesis that measurements of LV relaxation and passive stiffness were not necessary to make the diagnosis of diastolic HF.22 They studied 47 patients with a history of HF, a normal LV EF (>0.50), and at least mild LV hypertrophy (LV mass ≥125 g/m2) or concentric LV remodeling (LV chamber dimension <55 mm combined with LV wall thickness ≥11 mm and relative wall thickness ≥0.45).
Chapter 6 • General Principles, Clinical Definition, and Epidemiology LV EJECTION FRACTION SYSTOLIC BLOOD PRESSURE 0.9 260 0.8 240 0.7
220
0.6
mmHg
200
198 0.5
180
0.50
0.50
0.4
160 140
138
0.3 0.2
120 100
0.1 During acute pulmonary oedema
After treatment
During acute pulmonary oedema
After treatment
Figure 6-3 The systolic arterial pressure of patients at presentation with hypertensive acute pulmonary edema and after treatment 24–72 hours later. Despite the substantial difference in blood pressure, the left ventricular (LV) ejection fraction was similar on admission with acute pulmonary edema and after treatment. (From Little WC: Hypertensive pulmonary oedema is due to diastolic dysfunction. Eur Heart J 2001; 22:1961–1964.)
DIASTOLIC FUNCTION 1.0
Normal
EF = 0.4–0.5
Grade 1
Fraction alive
Fraction alive
1.0
EJECTION FRACTION
0.9 Grade 2 0.8
0.9 EF >0.5
0.8
EF <0.4
Grade 3 p = 0.19
p = 0.0077
0.7 0
250
500
750
1000
0.7 1250
Time (days)
0
250
500
750
1000
1250
Time (days)
Figure 6-4 Kaplan-Meier survival curves for 104 heart failure (HF) patients with an ejection fraction (EF) less than 0.50 and 102 HF patients with an EF equal to or greater than 0.50. Progressively more severe diastolic dysfunction is strongly associated with decreased survival. The EF does not significantly affect survival. For stages of diastolic dysfunction, see Table 6-1 and Figure 6-2. (Data from Brucks S et al: Contribution of left ventricular diastolic dysfunction to heart failure regardless of ejection fraction. Am J Cardiol 2005;95:603–606.)
The authors then assessed LV diastolic function during cardiac catheterization and found that all the patients had evidence of abnormalities of LV relaxation and passive stiffness.22,23 Thus, they concluded that objective evidence of abnormalities of LV relaxation or distensibility during cardiac catheterization was unnecessary to make the diagnosis of diastolic HF if there was evidence of LV hypertrophy or concentric remodeling.
Prognostic Utility of Doppler Echocardiography Noninvasive assessment of diastolic dysfunction using Doppler echocardiography provides useful information on the severity of HF and prognosis.15,24–27 Specifically, Brucks et al. examined the association of systolic and diastolic function with severity of HF assessed by plasma B-type natriuretic peptide levels and prognosis in 104 HF patients with an EF less than 0.50 and in 102 HF patients with an EF equal to or greater than 0.50.15 They found that an increasing grade of diastolic dysfunction but not a reduced EF was associated with increased plasma B-type natriuretic
peptide levels. They also found that greater diastolic dysfunction but not a reduced EF was associated with worse 2-year survival (Fig. 6-4). When analysis was limited to HF patients with an EF less than 0.50, both reduced EF and the greater diastolic dysfunction were associated with worse survival. Rihal et al. examined the association of systolic and diastolic function with HF symptoms and 3-year survival in 102 patients with dilated cardiomyopathy and an EF of 0.23 ± 0.08.25 They found that markers of diastolic dysfunction, including short deceleration time and increased peak early diastolic LV inflow velocity, were more strongly associated with symptoms than was reduced EF. They also found that the short (<130 msec) deceleration time had incremental prognostic value to the reduced (<0.25) EF. Similarly, Wang et al. showed that the reduced (<3 cm/sec) EM was a powerful predictor for 4-year mortality and provided incremental prognostic value to other clinical risk factors and Doppler echocardiographic variables in 182 HF patients with an EF less than 0.50.26 Recently, Troughton et al. showed in the ADEPT study that the newer diastolic indices of E/EM and E/VP
67
Chapter 6 • General Principles, Clinical Definition, and Epidemiology provide independent prediction of clinical outcomes in systolic HF (EF <35%) that are equal or additive to conventional markers including, EF and E deceleration time.28 These observations suggest that diastolic dysfunction is associated with the severity of HF and prognosis independent of the EF. Thus, although measurement of diastolic function may not be necessary for the diagnosis of diastolic HF, its measurement with Doppler echocardiography is critical for risk stratification in all HF patients.
Practical Recommendations If patients have clinical evidence of HF, the EF should be measured within 72 hours of an acute episode of pulmonary congestion. If the EF is less than or equal to 0.50, the diagnosis of systolic HF can be made. If the EF is greater than 0.50 and there is evidence of LV hypertrophy or concentric remodeling, the diagnosis of diastolic HF can be suggested. In the absence of LV hypertrophy or concentric remodeling, the diagnosis of diastolic HF may be supported by the presence of left atrial enlargement.29 When the diagnosis of diastolic HF needs confirmation, Doppler echocardiography or cardiac catheterization provides a definitive diagnosis. Furthermore, assessment of diastolic function using Doppler echocardiography, particularly with tissue Doppler imaging, provides useful information on the severity of HF and prognosis regardless of the EF. Thus, it is important to evaluate both systolic and diastolic functions not only for making a definitive diagnosis of diastolic HF but also for identifying high-risk patients.
[SD] age, 51 [14] years) in Augsburg, Germany.31 The prevalence of diastolic abnormalities in the setting of a preserved EF (≥0.45), as defined by the European Study Group on Diastolic Heart Failure (i.e., normal isovolumic relaxation time, 92–105 msec; normal ratio of early-to-late LV filling [E/A ratio], 1:0.5, depending on age), was 11.1%. The prevalence of diastolic dysfunction, defined as diastolic abnormalities with LA enlargement or treatment with diuretics, was 3.1%. Of the subjects with diastolic abnormalities, only 2.3% had an EF less than 0.45. Independent predictors for diastolic abnormalities or diastolic dysfunction included hypertension, LV hypertrophy, myocardial infarction, obesity (body mass index ≥27.3), diabetes, ratio of fat mass-tofat-free mass greater than 0.70, and male gender. Smoking and low-density-lipoprotein cholesterol levels were not predictors for diastolic abnormalities or dysfunction. Importantly, in the absence of these risk factors, diastolic abnormalities and diastolic dysfunction were rare even in the subjects older than 50 years of age (4.6% and 1.2%, respectively). The prevalence of diastolic abnormalities is lower in the study by Fischer et al.31 than in the study by Redfield et al.30 This may be due to the difference in age between cohorts studied and the diagnostic criteria for diastolic dysfunction using Doppler echocardiography. These observations suggest that diastolic dysfunction is more common than systolic dysfunction in community-dwelling patients and that risk factors for diastolic dysfunction are similar to those for systolic dysfunction. Thus, treatment of these risk factors may reduce the prevalence of both diastolic and systolic dysfunction, thereby reducing the incidence of overt HF.
Prognosis of Diastolic Dysfunction EPIDEMIOLOGY For assessment of the prevalence and prognosis of diseases, large unselected subjects should be evaluated at a given time and followed prospectively. Thus, in this section, we review populationbased cohort studies reporting the frequency of diastolic dysfunction and/or HF with normal EF in the community.
Epidemiology of Diastolic Dysfunction
Three studies have shown that diastolic dysfunction is associated with increased morbidity and mortality in the community. In the Cardiovascular Health Study,32 standard Doppler echocardiographic variables, including the Doppler E/A ratio, were measured in 2671 participants who were free of coronary artery disease, chronic HF, or atrial fibrillation. Both high (>1.5) and low (<0.7) E/A ratios were predictive of the incidence of HF during a mean follow-up of 5.2 years (Fig. 6-5). After adjustment for covariates including age, blood pressure, stress-corrected LV systolic function, and LV mass, the predictive value of both high
Prevalence of Diastolic Dysfunction Two studies have shown that diastolic dysfunction assessed by Doppler echocardiography is more common than systolic dysfunction in the community. Specifically, Redfield et al. investigated the prevalence of diastolic dysfunction assessed by comprehensive tissue Doppler imaging in 2042 randomly sampled subjects aged 45 years and older (mean [SD] age, 63 [11] years) in Olmsted County, Minnesota.30 Overall, 28% had diastolic dysfunction (20.8%, mild; 6.6%, moderate; 0.7%, severe), whereas 6% had an EF less than or equal to 0.50 and 2% had an EF less than or equal to 0.40. An EF of 0.50 or less was present in 1.4% of participants with normal, 10.5% with mild, 19.5% with moderate, and 61.5% with severe diastolic dysfunction. The prevalence of diastolic dysfunction increased with age. Diastolic dysfunction was equally common in men and women and more common in participants with hypertension, diabetes, coronary artery disease, and obesity. Similarly, Fischer et al. investigated the prevalence of diastolic dysfunction assessed by standard Doppler echocardiography in 1274 randomly sampled subjects aged 25 years or older (mean
16 14 % with incident CHF
68
12 10 8 6 4 2 0 < 0.7
0.7–1.5
> 1.5
Doppler E/A ratio Figure 6-5 Unadjusted incident congestive heart failure (CHF) rates by Doppler E/A ratio. Incident CHF is higher at the extreme values of this ratio. (From Aurigemma GP et al: Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: The Cardiovascular Study. J Am Coll Cardiol 2001;37:1042–1048.)
Chapter 6 • General Principles, Clinical Definition, and Epidemiology and low E/A ratios remained significant (adjusted hazard ratios [HRs] [95% CI] of high and low E/A ratios, 3.50 [1.80–6.80] and 1.88 [1.33–2.68], respectively). Similarly, in the Strong Heart Study,33 the prognostic value of high and low E/A ratios was investigated in 3008 American Indian participants. Both high (>1.5) and low (<0.6) E/A ratios were predictive of all-cause and cardiac mortality during a mean follow-up of 3 years (Fig. 6-6). After adjustment for age, sex, body mass index, systolic blood pressure, cholesterol level, hypertension, diabetes, coronary artery disease, smoking, LV hypertrophy, and low (<0.40) EF, high E/A ratio was an independent predictor for all-cause and cardiac mortality (adjusted HRs [95% CI] for all-cause and cardiac death, 1.73 [0.99–3.03] and 2.8 [1.19– 6.75], respectively). However, low E/A ratio was not an independent predictor for either all-cause or cardiac mortality (adjusted HRs [95% CI] for all-cause and cardiac death, 1.2 [0.8–1.6] and 1.2 [0.7–2.1], respectively). Finally, in the study by Redfield et al.,30 the prognostic value of diastolic dysfunction assessed by comprehensive tissue Doppler imaging was investigated. Both mild and moderate or severe diastolic dysfunctions were predictive of all-cause death during a median of 3.5 person-years of follow-up (Fig. 6-7). After adjustment for age, sex, and EF, both mild and moderate or 25 20 15 10 5 0 All-cause death
Cardiac death
Figure 6-6 Incidence of all-cause and cardiac death among participants with E/A less than 0.6 (blue bars), 0.6 to 1.5 (purple bars), and greater than 1.5 (green bars). (From Bella JN et al: Mitral ratio of peak early to late diastolic filling velocity as a predictor of mortality in middle-aged and elderly adults: The Strong Heart Study. Circulation 2002;105:1928–1933.)
69
severe diastolic dysfunction were independent predictors for death (adjusted HRs [95% CI] of mild and moderate or severe diastolic dysfunction, 8.31 [3.00–23.1] and 10.2 [3.28–31.0], respectively). These observations suggest that diastolic dysfunction, particularly of moderate or severe degree, is a powerful predictor for increased morbidity and mortality in the community. Regression of LV hypertrophy by antihypertensive agents has been shown to improve LV diastolic filling.34 The impact of these interventions on clinical outcomes requires further studies.
Epidemiology of Diastolic Heart Failure Reported frequency of diastolic HF in overt HF and that of diastolic HF in the community vary widely.35 This may be due to the difference in diagnostic criteria for diastolic HF between studies. Thus, in this section, we review community-based cohort studies that used the Framingham criteria for a diagnosis of HF and 0.50 for separating a normal EF from a reduced EF.
Prevalence of Diastolic Heart Failure Four studies have shown that nearly half of patients with HF have a normal EF. Specifically, Senni et al.36 evaluated all patients receiving first diagnosis of HF in Olmsted County, Minnesota, in 1991 (n = 216), of whom 137 had an assessment of EF within 3 weeks before or after the diagnosis of HF. In these patients, 59 (43%) had a normal EF (≥0.50) and 78 (57%) had a reduced EF (<0.50). Compared with HF patients with a reduced EF, those with a normal EF were older and more likely to be female and less likely to have had prior myocardial infarction and left bundle branch block. Similarly, Vasan et al.37 evaluated the echocardiograms of 73 Framingham Heart Study subjects with HF. They found that 37 (51%) had a normal EF (≥0.50) and 36 (49%) had a reduced EF (<0.50). Compared with HF patients with a reduced EF, those with a normal EF were more likely to be female and less likely to have had prior myocardial infarction. These studies, however, did not enumerate the base population. Thus, the prevalence of diastolic HF in the community cannot be estimated from these studies. Two other studies have reported both the frequency of a normal EF in overt HF and the prevalence of HF with a normal EF in
25
Diastolic function Moderate or severe dysfunction Mild dysfunction Normal
Mortality (%)
20 15
Log rank p <.001
10 5
Figure 6-7 Kaplan-Meier survival curves for participants with normal diastolic function versus subjects with mild or moderate or severe diastolic dysfunction. Progressively more severe diastolic dysfunction is strongly associated with decreased survival. For stages of diastolic dysfunction, see Table 6-1 and Figure 6-2. (Data from Redfield MM et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202.)
0 0
1
2
3
4
5
885 246 94
404 122 39
38 8 5
Year No. at risk Normal Mild Moderate or severe
1277 371 131
1277 366 129
1275 361 126
Chapter 6 • General Principles, Clinical Definition, and Epidemiology the community. In the study by Redfield et al.,30 the prevalence of HF was 2.2%. They also found that among the HF patients, 44% had an EF greater than 0.50 and 56% had an EF equal to or less than 0.50. Similarly, Cortina et al. assessed the prevalence of HF in 391 randomly selected subjects aged 40 years or older (mean [SD] age, 60 [13] years) in Asturias, northern Spain.38 They found that the prevalence of HF was 5% and that among the HF patients, 59% had an EF greater than or equal to 0.50 and 41% had an EF less than 0.50. These studies, however, have the limitation that the EF was not determined at the onset of HF. Taken together, these observations suggest that the prevalence of diastolic HF is similar to that of systolic HF and that the prevalence of diastolic HF in adult and elderly populations may be 1%–3%. These studies also suggest that patients with diastolic HF are older and more likely to be female than those with systolic HF.
Prognosis of Diastolic Heart Failure Two studies have shown that both patients with a normal EF and those with a reduced EF have poor prognosis. Specifically, in the study by Senni et al.,36 the prognosis of patients with a new diagnosis of HF was worse than age- and gender-matched controls. Survival of HF patients was 86 ± 2% at 3 months, 76 ± 3% at 1 year, and 35 ± 3% at 5 years. There was no significant difference in unadjusted survival between HF patients with an EF greater than or equal to 0.50 and those with an EF less than 0.50 (Fig. 6-8). After adjustment for age, sex, functional class, and coronary artery disease, survival did not significantly differ between the two groups (adjusted HR of normal EF vs. reduced EF, 0.8, p = 0.37). In the study by Vasan et al.,37 during a median follow-up of 6.2 years, HF patients with a reduced EF (<0.50) had significantly higher annual mortality than age- and gender-matched cases (18.9% vs. 4.1%; adjusted HR [95% CI], 4.31 [1.98–9.36]). Similarly, HF patients with a normal EF (≥0.50) had significantly higher annual mortality than age- and gender-matched cases (8.7% vs. 3.0%; adjusted HR [95% CI], 4.06 [1.61–10.3]).
1.0 0.8 Survival
70
0.6 0.4 Expected EF < 50% EF ≥ 50%
0.2
p = 0.279
0.0 0
1
2
3
4
6
5
Years EF < 50% EF ≥ 50%
78 59
58 44
51 35
44 32
36 29
16 15
Figure 6-8 Survival of heart failure patients with an ejection fraction (EF) of equal to or greater than 50% and less than 50%. (Data from Senni M et al: Congestive heart failure in the community: A study of all incident cases in Olmsted County, Minnesota in 1991. Circulation 1998;98:2282–2289.)
Importantly, survival (adjusted for age, sex, and other covariates, including diabetes, smoking, and blood pressure) did not significantly differ between HF patients with a normal EF and those with a reduced EF (adjusted HR [95% CI] of normal EF vs. reduced EF, 0.65 [0.31–1.35], p = 0.25). These observations suggest that both patients with diastolic HF and those with systolic HF have poor prognosis and that the mortality difference between the two groups may be minimal.
CONCLUSIONS AND FUTURE RESEARCH Diastolic function can noninvasively be assessed by Doppler echocardiography. Diastolic dysfunction assessed by Doppler echocardiography is more common than systolic dysfunction in the community and is associated with increased morbidity and mortality. Risk factors for diastolic dysfunction are similar to those for systolic dysfunction and include hypertension, LV hypertrophy, myocardial infarction, diabetes, and obesity. Thus, treating these risk factors may reduce the prevalence of both systolic and diastolic dysfunction and may ultimately reduce the incidence of overt HF. A diagnosis of diastolic HF can be made by clinical evidence of HF in the setting of a normal EF, and objective evidence of diastolic dysfunction and abnormal biomarkers can help confirm the diagnosis (Fig. 6-9). However, assessment of diastolic function using Doppler echocardiography provides useful information on the severity of HF and prognosis regardless of the EF. Thus, it is important to evaluate both systolic and diastolic function not only for making a definite diagnosis of diastolic HF but also for identifying high-risk patients. Diastolic HF and systolic HF are similarly prevalent in the community, and both patients with diastolic HF and those with systolic HF have a poor prognosis.39,40 Patients with diastolic HF are older and more likely to be female than those with systolic HF. Thus, given the aging population, the public health burden of diastolic HF is substantial. Nevertheless at the present time, there is no known therapy for the improvement of survival in diastolic HF, thus emphasizing the urgent need for the establishment of optimal treatment for this condition. Although evidence has accumulated for the contribution of diastolic abnormalities to diastolic HF, the pathophysiology of diastolic HF remains to be fully understood. 1. What causes the transition of asymptomatic diastolic dysfunction to overt diastolic HF? 2. Does mild contractile dysfunction, which is not detected by measurement of an EF, contribute to diastolic HF? 3. Do systemic factors including neurohumoral activation and renal dysfunction contribute to diastolic HF? 4. What are the common causes of death in patients with diastolic HF? 5. Despite the similarities in the clinical manifestations of HF, why are the dramatic differences in the type of LV remodeling seen in diastolic HF and systolic HF? A better understanding of the pathophysiology of diastolic HF will provide a rationale for the development of the plausible therapeutic strategies for the disorder.
Chapter 6 • General Principles, Clinical Definition, and Epidemiology HOW TO DIAGNOSE HFNEF Symptoms or signs of heart failure
Normal or mildly reduced left ventricular systolic function LVEF >50% and LVEDVI <97 ml/m2
Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness Figure 6-9 Diagnostic flow chart showing how to diagnose heart failure with normal ejection fraction (HFNEF) in a patient suspeted of HFNEF, diastolic heart failure. LVEDVI, left ventricular enddiastolic volume index; mPCW, mean pulmonary capillary wedge pressure; LVEDP, left ventricular end-diastolic pressure; τ, time constant of left ventricular relaxation; b, time constant of left ventricular chamber stiffness; TD, tissue Doppler; E, early mitral valve flow velocity; E′, early TD lengthening velocity; NTproBNP, N-terminal-pro brain natriuretic peptide; BNP, brain natriuretic peptide; E/A, ratio of early (E) to late (A) mitral valve flow velocity; DT, deceleration time; LVMI, left ventricular mass index; LAVI, left atrial volume index; Ard, duration of reverse pulmonary vein atrial systole flow; Ad, duration of mitral valve atrial wave flow. (From Paulus WJ, Tschope C, Sanderson JE, et al: How to diagnose diastolic heart failure: A consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007; 28(21):2686.)
Invasive Hemodynamic measurements mPCW >12 mmHg or LVEDP >16 mmHg or τ >48 msec or b >0.27
REFERENCES 1. Kass DA, Maughan WL: From “Emax” to pressure-volume relations: A broader view. Circulation 1988;77:1203–1212. 2. Little WC, Applegate RJ: Congestive heart failure: Systolic and diastolic function. J Cardiothor Vasc Anesthesia 1993;7:2–5. 3. Little WC: Diastolic dysfunction beyond distensibility: Adverse effects of ventricular dilatation. Circulation 2005;112:2888–2890. 4. Little WC, Warner JG Jr., Rankin KM, et al: Evaluation of left ventricular diastolic function from the the pattern of left ventricular filling. Clin Cardiol 1998;21:5–9. 5. Oh JK, Hatle L, Tajik AJ, et al: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506. 6. Fukuta H, Little WC: Diastolic versus systolic heart failure. In Smiseth OA, Tendera M (eds): Diastolic Heart Failure. London, Springer, 2007. 7. Hasegawa H, Little WC, Ohno M, et al: Diastolic mitral annular velocity during the development of heart failure. J Am Coll Cardiol 2003;41: 1590–1597. 8. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 9. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865–875.
TD E/E' >15
15 > E/E' > 8
Biomarkers NT-proBNP >220 pg/ml or BNP >200 pg/ml
Biomarkers NT-proBNP >220 pg/ml or BNP >200 pg/ml
Echo–bloodflow doppler E/A>50 yr <0.5 and DT>50 yr >280 msec or Ard–Ad >30 msec or LAVI >40 ml/m2 or LVMI >122 g/m2 ( ); >149 g/m2 ( ) or Atrial fibrillation
TD E/E' >8
HFNEF
10. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527– 1533. 11. Nagueh SF, Mikati I, Kopelen HA, et al: Doppler estimation of left ventricular filling pressure in sinus tachycardia. Circulation 1998;98:1644– 1650. 12. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. 13. Greenberg NL, Vandervoort PM, Firstenberg MS, et al: Estimation of diastolic intraventricular pressure gradients by Doppler M-mode echocardiography. Am J Physiol 2001;280:H2507–H2515. 14. Oh JK, Appleton CP, Hatle LK, et al: The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 1997;10:246–270. 15. Brucks S, Little WC, Chao T, et al: Contribution of left ventricular diastolic dysfunction to heart failure regardless of ejection fraction. Am J Cardiol 2005;95:603–606. 16. Kitzman DW, Little WC, Brubaker PH, et al: Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–2150. 17. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure. Part I: Diagnosis, prognosis, and measurement of diastolic function. Circulation 2002;105:1387–1393.
71
72
Chapter 6 • General Principles, Clinical Definition, and Epidemiology 18. European Study Group on Diastolic Heart Failure. How to diagnose heart failure. Eur Heart J 1998;20:990–1003. 19. Vasan RS, Levy D: Defining diastolic heart failure: A call for standardized diagnostic criteria. Circulation 2000;101:2118–2121. 20. Gandhi SK, Powers JC, Nomeir AM, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001;344:17–22. 21. Little WC: Hypertensive pulmonary oedema is due to diastolic dysfunction. Eur Heart J 2001;22:1961–1964. 22. Zile MR, Gaasch WH, Carroll JD, et al: Heart failure with a normal ejection fraction: Is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? Circulation 2001;104:779–782. 23. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure—abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 2004;350:1953–1959. 24. Vanoverschelde JL, Raphael DA, Robert AR, et al: Left ventricular filling in dilated cardiomyopathy: Relation to functional class and hemodynamics. J Am Coll Cardiol 1990;15:1288–1295. 25. Rihal CS, Nishimura RA, Hatle LK, et al: Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy: Relation to symptoms and prognosis. Circulation 1994;90:2772–2779. 26. Wang M, Yip G, Yu CM, et al: Independent and incremental prognostic value of early mitral annulus velocity in patients with impaired left ventricular systolic function. J Am Coll Cardiol 2005;45:272–277. 27. Dokainish H, Zoghbi WA, Lakkis NM, et al: Incremental predictive power of B-type natriuretic peptide and tissue Doppler echocardiography in the prognosis of patients with congestive heart failure. J Am Coll Cardiol 2005;45:1223–1226. 28. Troughton RW, Prior DL, Frampton CM, et al: Usefulness of tissue doppler and color M-mode indexes of left ventricular diastolic function in predicting outcomes in systolic left ventricular heart failure (from the ADEPT Study). Am J Cardiol 2005;96:257–262. 29. Yturralde RF, Gaasch WH: Diagnostic criteria for diastolic heart failure. Prog Cardiovasc Dis 2005;47:314–319.
30. Redfield MM, Jacobsen SJ, Burnett JC Jr., et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202. 31. Fischer M, Baessler A, Hense HW, et al: Prevalence of left ventricular diastolic dysfunction in the community. Results from a Doppler echocardiographic-based survey of a population sample. Eur Heart J 2003;24: 320–328. 32. Aurigemma GP, Gottdiener JS, Shemanski L, et al: Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: The cardiovascular study. J Am Coll Cardiol 2001;37:1042–1048. 33. Bella JN, Palmieri V, Roman MJ, et al: Mitral ratio of peak early to late diastolic filling velocity as a predictor of mortality in middle-aged and elderly adults: The Strong Heart Study. Circulation 2002;105:1928–1933. 34. Wachtell K, Bella JN, Rokkedal J, et al: Change in diastolic left ventricular filling after one year of antihypertensive treatment: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study. Circulation 2002;105:1071–1076. 35. Owan TE, Redfield MM: Epidemiology of diastolic heart failure. Prog Card Dis 2005;47:320–332. 36. Senni M, Tribouilloy CM, Rodeheffer RJ, et al: Congestive heart failure in the community: A study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation 1998;98:2282–2289. 37. Vasan RS, Larson MG, Benjamin EJ, et al: Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: Prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999; 33:1948–1955. 38. Cortina A, Reguero J, Segovia E, et al: Prevalence of heart failure in Asturias (a region in the north of Spain). Am J Cardiol 2001;87:1417– 1419. 39. Bursi F, Weston SA, Redfield MM, et al: Systolic and diastolic heart failure in the community. JAMA 2006;296:2209–2216. 40. Bhatia RS, Tu JV, Lee DS, et al: Outcomes of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;335: 260–269.
JAMES B. SEWARD, MD KRISHNASWAMY CHANDRASEKARAN, MD MARTIN OSRANEK, MD, MSc KANIZ FATEMA, MBBS, PhD TERESA S. M. TSANG, MD
7
Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction INTRODUCTION PATHOPHYSIOLOGY Clinical Diastolic Dysfunction Pressure and Volume INVASIVE VERSUS NONINVASIVE ASSESSMENT Systolic Function Diastolic Function STATE-OF-THE-ART INVASIVE AND NONINVASIVE PHYSIOLOGY Myocardial Relaxation Ventricular Stiffness Filling Pressures Comprehensive Diastolic Function Assessment NORMAL DIASTOLIC MYOCARDIAL PHYSIOLOGY Temporal-Spatial Pressure and Flow: Suction of Blood into the Left Ventricle Left Atrial Pressure and Left Ventricular Suction
CLINICAL RELEVANCE Epidemic of Diastolic Heart Failure Myocardial Disease and Diastolic Dysfunction Arterial Stiffening and Diastolic Dysfunction Physiologic Coupling of the Cardiovascular System Forward Dysfunction: End-Organ and Microvascular Damage Vascular Stiffening: Summary CLUSTERING OF CARDIOVASCULAR RISK Diastolic Heart Failure With Normal Ejection Fraction and Systolic Heart Failure: Pathophysiologic Subgroups FUTURE RESEARCH GLOSSARY ABBREVIATIONS
73
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction
INTRODUCTION In the era of classical cardiovascular (CV) medicine (ending around the year 2000), CV function was validated predominantly by invasive means.1,2 Classic studies established the end systolic and end diastolic pressure-volume relationships as a meaningful and useful way of characterizing intrinsic ventricular pump properties.3 These concepts then evolved such that they could be applied to basic and clinical research. In the present era of CV intervention (projected to last until approximately 2020), CV imaging and molecular science are emphasized. Mathematical modeling and further clarification of diastolic function through the use of invasive and noninvasive technologies is evolving.2,4 Around 2020, CV medicine is envisioned to evolve toward an “era of CV disease prevention.”5 Prevention will emphasize system physiology complemented by mathematical probability. A portfolio of physiologic models will be used as surrogate expressions of disease, and primary prevention of disease will be based on the intensity or burden of a physiologic or molecular/chemical risk model. Information acquisition will move from invasive to noninvasive. Research and clinical physiologic approaches2,6,7 are currently evolving from invasive to noninvasive means to elucidate fundamental CV physiology.4,8,9 Clinical physiology is no longer limited to catheterization, and the noninvasive echocardiologist can be redefined as an “echophysiologist.” This chapter attempts to relate classical invasive physiology to the current evolution toward Doppler echocardiographic physiology. It is increasingly recognized and emphasized that contraction (systolic function) is dependent on relaxation (diastolic function). It is important to appreciate the two distinct, although intimately interrelated, aspects of the assessment of cardiac properties: (1) of the ventricle as a hemodynamic pump and (2) of the intrinsic properties of the cardiac muscle.3 Systolic and diastolic ventricular properties are dependent on systolic and diastolic myocardial properties, as well as muscle mass, chamber architecture, and chamber geometry. Pressure-volume constructs are used to directly assess ventricular properties.
PATHOPHYSIOLOGY Cardiac dysfunction, with or without systolic dysfunction, is associated with diastolic dysfunction (i.e., elevation of filling pressure). Cardiac dysfunction can be broadly viewed as a derivative of altered cardiac geometry and cardiomyocyte dysfunction or altered extracardiac loading, which is most commonly attributed to arterial stiffening. Once the sentinel cardiac or arterial perturbation is initiated, the dysfunctional state is propagated throughout the contiguous CV system (arteries, pump, and reservoir), becomes cyclical and self-perpetuating, and accounts for the clustering of a portfolio of common adverse events (e.g., heart failure [HF], atrial fibrillation, stroke, cognitive dysfunction).
Clinical Diastolic Dysfunction Diastolic dysfunction refers to abnormal mechanical relaxation (diastolic) properties of the ventricle, which are present in the majority of patients with congestive heart failure (CHF). The term diastolic heart failure (DHF) is conventionally used to
describe patients with CHF symptoms and normal systolic contractility (i.e., normal ejection fraction [EF]), although a preferred term would be HF associated with preserved systolic function. Thus, the distinction between DHF and diastolic dysfunction is merely the presence of CHF symptoms. The CHF symptom complex associated with systolic HF (SHF) or DHF is most strongly correlated with the elevation of filling pressure. In order for the left ventricle to function as an effective pump, it must be able to empty and fill without requiring abnormal elevation of left atrial (LA) pressure. Atrial pressure is directly related to the ability of the left atrium to expel its contents into the ventricle during diastole. Thus, the principal determinant of risk and symptoms of CHF is the increased pressure reflected backward into the left atrium and pulmonary veins during diastolic filling of the ventricle.10 The stroke volume must be able to increase in response to stress, such as exercise, without any appreciable increase in LA pressure (Fig. 7-1).6 Drugs that produce a sustained decrease in ventricular filling pressures enhance effort tolerance, breathing capacity, and HF outcome.11
Pressure and Volume Diastolic function conventionally has been assessed on the basis of the left ventricular (LV) diastolic pressure-volume relationship and an upward shift of the curve or increase in LV end diastolic pressure (LVEDP) (Figs. 7-2 and 7-3).6,7 The LV end diastolic pressure-volume relationship is the most important means of characterizing global filling properties. The pressure-volume loop (see Fig. 7-2) depicts the amount of diastolic filling (ml of blood) relative to a specified filling pressure (mmHg) and is therefore a key physiologic determinant of preload.13 Any delay or impedance
200 Exercise
150 LV pressure (mmHg)
74
Rest
100
50
0
20
28
36
44
52
LV volume (ml) Figure 7-1 Left ventricular (LV) pressure-volume loops at rest and during exercise. Each loop was generated by averaging the data obtained during a 15-second recording of simultaneous pressure and volume, spanning several respiratory cycles. During exercise, the early diastolic portion of the LV pressure-volume loop is shifted downward (arrow) so that the early diastolic LV pressure is lower during exercise than at rest. (From Cheng CP et al: Mechanism of augmented rate of left ventricular filling during exercise. Circ Res 1992;70:9–19. Used with permission.)
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 160 160
Ejection
120
Isovolumic relaxation
Isovolumic contraction
80
Pressure (mmHg)
120 Pressure (mmHg)
ESPVR
End systole
End diastole
20
40
A
60
80
100
120
0
140
B
Volume (ml)
EDPVR
0
0 0
Ees
40
40 Filling
80
20 Vo
40
60
80
100
120
140
Volume (ml)
160
Pressure (mmHg)
120
80
40
0 0
C
20
40
60
80
100
120
140
Volume (ml)
of myocardial relaxation will increase the filling pressure, which will be reflected backward into the left atrium and pulmonary veins. The end diastolic pressure-volume relationship is intrinsically nonlinear (see Fig. 7-3), a characteristic attributed to the different types of structural fibers being stretched in different pressurevolume ranges.14 In the low pressure-volume range, with only a small increase in pressure for a given increment in volume, the stretch of compliant elastin fibers and of the myocytes with sarcomeric titin molecules15 is believed to account for stiffness. As volume is increased to a higher range, pressure rises more steeply as slack lengths of collagen fibers and titin are exceeded and stretch is more strongly resisted by these stiff elements. Therefore, chamber stiffness increases as end diastolic pressure or volume increases.3 With diastolic dysfunction, any abnormal increase in diastolic filling pressure corresponds to a less distensible or less compliant ventricle during the filling phase of the cardiac cycle. Consequently, a “stiff ” ventricle is less able to increase its stroke volume without further elevation of LA pressure. Pressure reflected backward through the open mitral valve into the atrium and pulmonary veins can cause shortness of breath, elevation of pulmonary
Figure 7-2 The hemodynamic events occurring during the cardiac cycle are displayed by plotting instantaneous pressure versus volume. A, A normal pressure-volume loop. The four phases of the cardiac cycle are displayed on the pressure-volume loop, which is constructed by plotting instantaneous pressure and volume. The loop repeats with each cardiac cycle and shows how the heart transitions from its end diastolic state to the end systolic state and back. B, Decrease in filling pressure (preload). With a constant contractile state and afterload resistance, a progressive reduction in ventricular filling pressure causes the loops to shift toward lower volumes at both end systole and end diastole. When the resulting end systolic pressure-volume points are connected, a reasonably linear end systolic pressure-volume relationship (ESPVR) is obtained. The linear ESPVR is characterized by a slope (Ees, ventricular elastance) and a volume axis intercept (Vo). EDVPR denotes end diastolic pressure-volume relationship. C, Increased afterload (blood pressure). When afterload resistance is increased at a constant preload, the loops get narrower and longer, and under ideal conditions the end systolic pressure-volume points fall on the same ESPVR as obtained with preload reduction. (From Burkhoff D et al: Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: A guide for clinical, translational, and basic researchers. Am J Physiol Heart Circ Physiol 2005;289:501–512.)
venous pressure, secondary pulmonary hypertension, and decrease in clinical exercise capacity.15–18
INVASIVE VERSUS NONINVASIVE ASSESSMENT Systolic Function Cardiac function assessment traditionally has focused on decreased contractility and the measure of EF. The noninvasive measure of systolic function, EF, is almost exclusively used in clinical trials and medical practice. Although EF is clinically considered an important index of LV systolic function, it is not exclusively governed by LV properties. Rather, EF is determined by the interaction of arterial and ventricular properties.20–23 A normal EF suggests that contractility and arterial stiffness are well matched. EF is very load dependent and normally increases up to 30% during stress.24 EF is thus limited by many factors, including marked preload dependence25 and low reproducibility when measured by different imaging modalities.26 Furthermore, EF greater than 45% does not contribute to assessment of CV risks in patients with HF.27 In patients with CHF and elevated filling pressure, diastolic dysfunction correlates better with B-type natriuretic peptde concentration and mortality than with EF or LV volume.12,26
75
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction
A Normal
LV end diastolic pressure
76
B
ΔP
ΔP ΔV
ΔP
ΔV
ΔV
LV end diastolic volume Figure 7-3 Left ventricular (LV) end diastolic pressure-volume curves showing the relationship between end diastolic volume and pressure. Stiffness, at different points on the curve, is reflected as the change in pressure (ΔP) divided by the change in volume (ΔV). During normal LV filling, the myocardium must efficiently relax in order to prevent resistance to atrial emptying and elevation of atrial pressure. As the left ventricle relaxes, the diastolic volume and pressure increase. The ventricular filling pressure is reflected backward into the left atrium. Flow ultimately stops or transiently reverses when the atrial and ventricular pressures equilibrate. Normal atrial emptying thus must occur without requiring significant elevation of left atrial pressure. In this early period of diastole more than two thirds of the LV stroke volume normally enters the left ventricle. The severity of heart failure and prognosis are related to the severity of filling abnormalities regardless of the ejection fraction.12 A shift of the curve upward and to the left is considered the hallmark of diastolic dysfunction (curve A). A “stiff ” left ventricle in early diastole disturbs the normal suction gradient between the left ventricle and the left atrium (see Fig. 7-6C). The LV pressure increases rapidly, thus impeding the normal filling of the ventricle. Pressure is reflected backward into the left atrium, increasing atrial wall stress and pulmonary venous pressure. This pressure-volume curve is typical for isolated diastolic dysfunction with preserved ejection fraction and delayed relaxation, elevated diastolic pressure, and near-normal ventricular volume. In a heart with abnormal geometry, as found in dilated, ischemic, or hypertrophic cardiomyopathy, the LV end diastolic pressure-volume curve is shifted to the right (curve B). Decreased diastolic suction (see Fig. 7-6B) is disturbed because of abnormal chamber geometry, which is commonly associated with uncoordinated wall motion or impaired myocardial contractility. The disturbed LV suction forces the left ventricle and left atrium to function at a higher filling pressure, decreasing ventricular filling and increasing atrial and pulmonary venous pressure. (From Little WC: Diastolic dysfunction beyond distensibility: Adverse effects of ventricular dilatation. Circulation 2005;112:2888–2890.)
Diastolic Function Although the invasive research “testing ground” has made important contributions to the understanding of pressure-volume relationships and diastolic physiology,3,10 only recently has assessment of diastolic function been extensively incorporated into clinical practice. Assessment of diastolic function was neglected because there was no reliable noninvasive method to assess diastolic dysfunction, and invasive confirmation of elevated filling pressure was deemed impractical if not unethical. Invasive monitoring through a pulmonary artery catheter or implantable transducer can provide continuous data. Pulmonary artery catheters, however, appear to contribute to morbidity and mortality29 and contribute little to clinical assessment.30 Even when LV cardiac catheterization is performed, the principal measure of diastolic function is LVEDP, which measures only the load-dependent filling pressure and reflects conditional physiologic circumstances only at the time of data acquisition. With the advent of noninvasive Doppler echocardiography, clinical assessment of diastolic function has become increasingly attainable and validated. However, early impediments to clinical use of Doppler echocardiographic diastolic function assessment became apparent. The first measures of diastolic function, which relied on mitral and pulmonary vein flow, were load dependent—similar to EF and LVEDP—and changed dynamically even during the examination. Because of the dynamic nature of these physiologic events, measures of diastolic function were limited for use in the assessment of long-term morbidity and mortality.
STATE-OF-THE-ART INVASIVE AND NONINVASIVE PHYSIOLOGY Diastolic function assessment by both invasive2 and noninvasive means is plagued by ambiguities surrounding the dynamic nature, indirectness, and difficulty of reproducibly measuring everchanging diastolic function. Dynamic measures include: 1. Decrease in pressure during the period of isovolumic relaxation (invasive: time constants of relaxation; noninvasive: deceleration time and longitudinal fiber relaxation) 2. Passive and active chamber stiffness or, its inverse, compliance (invasive: elastance; noninvasive: diastolic grade and LA volume) 3. End diastolic pressure (invasive: LVEDP; noninvasive: Doppler E/E′ ratio, end diastolic mitral versus pulmonary vein Doppler flow) (Table 7-1)
Myocardial Relaxation Invasive Assessment Pressure relaxation can be measured invasively by placing a micromanometer catheter into the left ventricle. The rate of pressure decrease, which begins during the isovolumic period, is influenced by several physiologic factors2: 1. Capacity and rapidity with which the sarcoplasmic reticulum and sarcolemmal Na+/Ca2+ exchanger restores cellular Ca2+ levels to low diastolic levels
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction TABLE 7-1 DIASTOLIC FUNCTION ASSESSMENT BY INVASIVE AND NONINVASIVE MEANS METHOD Functional parameter Myocardial relaxation Ventricular and arterial stiffness
Invasive Mathematical models of pressure-volume loops2 Analysis of viscoelastic properties2: simultaneous measurement of pressure, volume, and flow Vascular: pulse pressure, central blood pressure
Filling pressure
Left ventricular end diastolic pressure40
2. Extent of elastic recoil (suction) within the heart caused by compression by myocyte contraction during the prior systole and history of prior systolic ejection, which is largely determined by the aortic input impedance (stiffness) 3. Other chamber-level factors, such as dyscoordination and heterogeneity Isovolumic pressure relaxation traditionally starts when pressure decay is maximal, generally occurring shortly after aortic valve closure, and extends to a point when LV pressure decreases just below a threshold equal to the end diastolic pressure plus 5 mmHg. Recorded pressure-time curves can be mathematically analyzed to extract the rate of pressure decrease.2 However, the type of model used to describe relaxation can have marked influences on the apparent changes with drug and chamber-loading interventions.2 Model-dependent analysis of relaxation is commonly fraught with systematic deviations from the real data, particularly with depressed cardiac function.30 Some diseases, including hypertrophic cardiomyopathy, are characterized by regional heterogeneity of loading and material properties, which result in nonuniform relaxation. Diseases with a complex process of pressure decrease, such as hypertrophic cardiomyopathy, in general cannot be easily expressed in a single time constant.
Noninvasive Assessment Diastolic dysfunction is associated with substantial abnormalities of active relaxation and passive stiffness of the ventricle.31 Doppler transmitral velocity deceleration time (DT) and tissue Doppler early diastolic mitral annular velocity (E′) are commonly used noninvasive indices of myocardial relaxation. DT fluctuates with the dynamic changes in ventricular loading pressure, whereas E′ is relatively load independent. DT is useful for estimating intensity32,33 or “grade” of dysfunction34 at the time of the examination. Tissue Doppler E′ velocity is touted as less load dependent and can distinguish pseudonormal from normal filling patterns. The pseudonormal filling pattern is commonly encountered when using mitral inflow Doppler to characterize diastolic function grade.32 Active (e.g., Ca2+-dependent) and passive (e.g., fibrosis) structural mechanisms regulate the rates of ventricular pressure decay and early diastolic ventricular filling.35 Active relaxation represents the speed of transition from the contracted state (systole) to the relaxed state (diastole) and is strongly related to the uptake of calcium for the contracted myocyte. Passive relaxation is most strongly related to myocardial compliance and the effects of tissue fibrosis. Load-dependent measures reflect the dynamic physio-
Noninvasive ultrasonography Tissue Doppler annular velocity, E′31–33 Measures of “stiffness”9,34–36: effective arterial elastance (Ea), end systolic elastance (Ees); Doppler-derived diastolic dysfunction. Vascular stiffness37–39: pulse wave velocity, augmentation index Doppler E/E′31,41–45: acute load-dependent filling pressure Left atrial volume46–48: chronic average increase in filling pressure
logic state of filling pressure under the conditions existing at the time of the examination as well as the likelihood of a favorable response to a therapeutic manipulation (modifiability).32,36–40 The tissue Doppler E′ velocity reflects the relaxation velocity of the myocardium and expresses both passive and active myocardial relaxation.31 Variations in long-axis shortening have relatively little effect on the EF or stroke volume. Most of the stroke volume is produced by shortening of the minor axis dimension,41 which explains why either decreased diastolic (E′) or decreased systolic annular tissue Doppler can be observed in the presence of a normal EF.
Ventricular Stiffness Invasive Assessment Ideally, to analyze the viscoelastic properties of the ventricle, one should take simultaneous measurements of chamber pressure, volume, and flow. Passive elastic properties are those that relate a change in pressure to a given change in volume, whereas viscous properties are those that relate change in pressure to the rate of change in volume or flow. As opposed to noninvasive Doppler, no invasive methods are readily applicable for measuring flow rates of filling in the human heart. Therefore, most analyses must obtain flow data from the derivative of volume.2 The invasive measurement of pressure uses a high-fidelity micromanometer catheter. Measurement of volume is more challenging, with investigators commonly using various imaging-based methods to construct a volume-time curve. This approach is labor intensive, typically yielding a limited number of samplings of volumes during the diastolic period, and is subject to various sources of noise given the extensive processing required.2 A notable alternative is intracardiac electrical impedance, which can serve as a continuous measure of chamber volume.42–45 The association between diastolic pressure and volume from a single cardiac cycle does not necessarily follow a simple mathematic relationship.2 Only limited filling property data can be obtained from a single cardiac cycle. Various solutions have been used to overcome these limitations. After a diastolic pressurevolume curve is obtained, these data are typically subjected to a mathematical curve-fitting process to extract parameters of chamber or muscle stiffness. As with relaxation analysis, there are important limitations of such fitting when applied to a diastolic curve, owing to the nature of the mathematics.2 Unless the diastolic data are perfectly monoexponential, which is rarely the case, simply evaluating the same curve or restricting analysis to slightly
77
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction loading amplification associated with age.48,55 Diastolic HF with preserved EF appears to be best correlated with increased ventricular-arterial stiffness. Relaxation of the “stiff ” ventricular myocardium is delayed when the ventricle is exposed to increased systolic pressure during ejection (i.e., increased afterload).58 Diastolic dysfunction, as reflected in increased filling pressure, is directly related to greater prolongation of diastolic relaxation and increased ventricular-vascular stiffening.55,59 A major hemodynamic consequence of arterial stiffening is widening of the arterial pulse pressure, which also increases cyclic changes in arterial flow. Increased arterial stiffness increases systolic pressure and decreases diastolic pressure. Coronary perfusion occurs principally during diastole; thus, in persons with stiff conduit vessels and lower diastolic pressure, coronary microvascular perfusion is adversely affected.60 Impaired myocyte relaxation of the subendocardial longitudinal fibers is an ageassociated finding. Reduced myocardial relaxation is best measured as a decrease in tissue Doppler E′ velocity. Structural remodeling and functional disturbances are essential to the development of diastolic dysfunction and HF, but acute or subacute decompensation with CHF generally requires a precipitant, or “trigger.”61 The stiff arterial system is particularly sensitive to acute dysfunction, as occurs with excessive sodium intake, hypertension, atrial fibrillation, myocardial infarction, or marked bradycardia (prolonged diastasis). High arterial pulsatility is noted to have detrimental effects on blood flow regulation62 and contributes to adverse mechanical forces, which affect vascular tone, atherogenesis, angiogenesis, hemostasis, and microvascular autoregulation.
different ranges of volume and pressure can influence the derived parameters. Ultimately, derived stiffness parameters must be viewed cautiously, particularly if the data themselves do not clearly follow an exponential rise waveform.2 Even if directly measured by invasive pressures and volumes, the relationship between the two variables during filling does not necessarily provide information solely related to the cardiac chamber.
Noninvasive Assessment Limited success has been achieved in replicating pressure-volume loops by noninvasive Doppler echocardiography.8,46,47 However, several noninvasive studies have identified a relationship between limitation of exercise capacity, increased CV stiffness,48–51 and DHF.52,53 Noninvasive Doppler echocardiographic assessment of “stiffness” appears to be an excellent means of expressing ventricular and arterial stiffening.9,54 Effective arterial elastance (Ea), which reflects vascular stiffening, and end systolic elastance (Ees), which reflects ventricular stiffening, can be calculated noninvasively9,54 and validated against invasive assessment (Fig. 7-4).21,46,54–56 Ea, Ees, and diastolic stiffness increase with age and correlate with one another.21 Normally, there is an inverse relationship between Ees and Ea. As arterial compliance decreases (increased stiffness), ventricular compliance would be expected to increase (decreased stiffness).55 In order for EF to increase during exercise, the coupling ratio of Ea and Ees must decrease. However, with aging, the increase in exercise EF becomes blunted,23,57 suggesting ageassociated differences in the coupling ratio (Ea/Ees) and its components. Both arterial and ventricular stiffness tend to increase to a similar degree—Ea/Ees remains constant despite an increase in arterial stiffness (see Fig. 7-4). Thus, ventricular stiffness tends to increase with age. As ventricular and arterial stiffness increase, the system becomes more pressure labile and sensitive to loading conditions.21 This physiologic change is most evident with aging, as reflected in increased systolic and pulse pressure after age 50 to 60 years. These changes explain decreased exertional capacity and pressure-
Invasive Assessment LVEDP is the most common measure of diastolic dysfunction recorded during clinical cardiac catheterization. Increased filling pressure is not a requisite of diastolic dysfunction but is a universal
Elderly
150
180
Ea
Ees Ees
Filling Pressures
Ea
100
50
Systolic pressure (mmHg)
Young
LV pressure (mmHg)
78
0
150 120
90
Young
60 0
A
Elderly
50
100
LV volume (ml)
0
50
40
100
LV volume (ml)
B
60
80
100 120
LV EDV
Figure 7-4 Graphs showing the relationship between left ventricular (LV) pressure and volume. A, Pressure-volume loops from a 19-year-old man (Young) and an 87-year-old woman (Elderly) show increases in ventricular elastance or stiffness (Ees, solid line) that match increases in arterial elastance or stiffness (Ea, dashed line). Ea and Ees are normally equal in absolute magnitude, which yields optimal and efficient matching of the heart and artery. However, the elderly patient shows marked increases in both Ea and Ees (arterial and ventricular stiffening). The change in loop shape in the elderly patient reflects stiff arteries with a wider pulse pressure. B, As is shown by plotting systolic pressure versus LV end diastolic volume (EDV), the diastolic pressure-volume relationship also becomes steeper in the elderly patient. Ea, Ees, and diastolic stiffness increase with age and correlate with one another.22 Patients with decreased arterial compliance (Ea) show increased ventricular stiffness (Ees), which has important implications for blood pressure lability and loading sensitivity. These findings help explain heart failure with preserved ejection fraction.68,69 (From Kass DA: Ventricular arterial stiffening: Integrating the pathophysiology. Hypertension 2005 Jul;46:185–193.)
feature of both systolic and diastolic dysfunction.63 Increased filling pressure is not specifically representative of either systolic or diastolic dysfunction64 but is a potent marker of evolution toward overt CHF and hospitalization.65 Diastolic filling pressure reflects the load-dependent changes in chamber stiffness, with diastolic dysfunction uniformly occurring before or coincident with overt systolic dysfunction.63 The decrease in cyclic adenosine monophosphate needed to impair diastolic relaxation is much smaller than is required to impair contractility. Abnormal diastolic dysfunction is thus an earlier and more sensitive marker of a deficient energy state in HF than are abnormalities of systolic performance.66 For example, if EF is greater than 45%, it does not further contribute to assessment of CV risk in patients with HF.26 The principal determinant of HF risk is the inability of the ventricle to properly fill during diastole (i.e., inability to “prime the pump”).
Noninvasive Assessment The easiest and most reproducible noninvasive measure of filling pressure elevation is the ratio of early diastolic transmitral inflow velocity (E) to E′ (Doppler E/E′ ratio).32,36,37,67–69 The E/E′ ratio has been well correlated with invasive measures of LV filling pressure and pulmonary capillary wedge pressure.36,67,68 The ratio depicts the relationship between dynamic changes in LA pressure and LV compliance. As LA pressure increases, E increases, depicting the increased pressure gradient between atrium and ventricle. Conversely, myocardial relaxation, as depicted by tissue Doppler E′ velocity of the mitral annulus, is unchanging and relatively unaffected by loading dynamics.31 The E/E′ ratio, which is load dependent, reflects filling pressure at the time of the recording. An E/E′ ratio greater than 10 is highly sensitive (92%) and specific (80%) for the prediction of pulmonary wedge pressure greater than 15 mmHg.37,70 Filling pressure is dynamic; thus, it is common to record a normal filling pressure at rest and an elevated filling pressure with exercise. E/E′ should be viewed as a measure of the intensity of the filling pressure abnormality at the time of recording. Increased LA size reflects the average burden of volume or pressure overload or both. Atrial volume index is the preferred means of expressing atrial size because the atria enlarge asymmetrically and in direct relationship to the body surface area. Atrial enlargement because of abnormal pressure overload is substantiated by the coexistence of abnormal tissue relaxation (i.e., low E′ velocity) (Fig. 7-5); conversely, atrial enlargement because of benign volume overload is associated with a normal Doppler E′ velocity. LA volume index increases slowly and changes little with acute pressure or volume overload.71,72 Indexing LA volume to body surface area accounts for plasma volume throughout life.73–75 LA volume index best reflects “chronicity,” or average filling pressure, and the E/E′ ratio best reflects the “intensity” of filling pressure elevation at the time of the recording.76–78 For example, persons with chronic, yet intermittent, elevation of filling pressure (increased LA volume index and abnormal E′) can have a normal E/E′ at rest and an abnormal E/E′ with exertion. Clinical outcome is more strongly related to the average burden of filling pressure elevation as reflected in the atrial volume79 and not the resting grade of diastolic dysfunction.34
Comprehensive Diastolic Function Assessment The pressure-volume loop and tissue Doppler echocardiography both demonstrate the close link between systolic and diastolic
Average LA filling pressure (mmHg)
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 30 25 20 15
Atrial volume and pressure begin to exceed the LA and pulmonary vein reservoir capacity
10 5
Normal
LA enlargement
0 16
28
40
LA volume index (ml/m2) Figure 7-5 Graph showing the relationship of left atrial (LA) size (LA volume index) to average filling pressure. Pressure overload of the left atrium is present if the medial mitral annular tissue Doppler E′ velocity falls below 10 cm/sec (i.e., abnormal myocardial relaxation) and the atrial volume exceeds 28 ml/m2 (i.e., increased atrial wall tension). The cumulative burden of increased volume and/or pressure overload is related to the magnitude of atrial enlargement. The atrial volume remodels slowly and best reflects burden. Filling pressure at the time of examination (intensity) is best reflected in the E/E′ ratio, whereas atrial enlargement due to pressure overload reflects the chronicity or average burden of increased LA filling pressure. Conversely, atrial enlargement with a normal E′ velocity is consistent with “benign” isolated atrial volume overload, as seen in athletes, chronic disease, and anemia.
function.3,80 Patients with compensated systolic dysfunction have lesser degrees of diastolic dysfunction. Conversely, patients with overt CHF have higher grades of diastolic dysfunction.81 Diastolic dysfunction82,83 is not a part of “normative aging” but an age-related risk associated with the development of increased total CV risk, including increased HF, atrial fibrillation, and mortality,63,84 independent of age and sex.85 As advances in noninvasive methods continue to evolve,86–88 reliance on invasive methods will continue to decrease.2 The invasive examination remains the physiologic testing ground for understanding instantaneous physiology. However, the Doppler echocardiographic examination, although not ideal, is now the gold standard for clinical assessment of diastolic function and physiologic CV burden, in addition to complementing CV research.68,89
NORMAL DIASTOLIC MYOCARDIAL PHYSIOLOGY During LV contraction, potential energy is normally stored as the myocytes are compressed and the elastic elements in the LV wall are compressed and twisted.6,90,91 Relaxation of the myocardial contraction allows this potential energy to be released as the elastic elements recoil.6,92 The release of wall tension (potential energy) is normally rapid enough to cause the LV pressure to decrease despite an increase in LV volume (see Fig. 7-1).93 Although there is a relative decrease in early diastolic enhanced LV relaxation and elastic recoil from tachycardia and adrenergic stimulation during exercise,94–97 LA pressure does not increase to an abnormal level.98–101 Neither an increase in atrial pressure nor more vigorous atrial contraction contributes to the increased mitral valve pressure gradient and resulting increase in dV/dtmax that occurs during exercise.93 The intraventricular pressure gradient is greater in normal subjects than in patients with HF.102,103
79
80
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction In order for LV contraction to release the store of elastic potential energy, LV volume must decrease below a critical value during contraction. The minimum end systolic volume required to generate suction equals the equilibrium volume, the volume of the fully relaxed ventricle at zero pressure.97 If either the equilibrium volume decreases or the end systolic volume increases, the ventricle will be unable to release potential energy capable of suctioning blood into the ventricle.91,97,104 Other determinants of suction are the time constant of LV relaxation105 and the degree of largescale LV torsion and twist.91
Temporal-Spatial Pressure and Flow: Suction of Blood into the Left Ventricle Peak flow across the mitral valve normally equals or exceeds the peak flow rate across the aortic valve. The rapid movement of blood from the left atrium into the left ventricle in early diastole is due to a pressure gradient from the left atrium all the way to the LV apex (Fig. 7-6A).102 Ventricular filling is thus primed by a rapidly developing pressure envelope extending between the left atrium (highest pressure) and the LV apex (lowest pressure).106 As a consequence of the early diastolic intraventricular gradient between the left atrium and ventricular apex, blood is virtually “sucked” into the left ventricle. Suction is initiated during isovolumic ventricular relaxation and continues during early rapid filling.105 The lower the early diastolic LV pressure, the greater the suction, which allows the heart to function at lower LA pressure.95,107 Diastolic suction contributes to filling more than one order of magnitude greater than does passive atrial decompression.105
A
B
Left Atrial Pressure and Left Ventricular Suction The ability to dynamically decrease early LV filling pressure is particularly important in response to stress, which allows an increase in LV stroke volume without an appreciable increase in LA pressure.95,97,106,108–114 Diastolic intraventricular pressure gradients are the result of the interaction of inertial (local) and convective forces caused by unsteady intracardiac flow and pressure distribution.102 Inertial forces are caused by the impulse (potential pressure) developed by myocardial restoring forces related to the inotropic state (LV contraction and the creation of potential energy).97,115 Convective deceleration is determined by spatialtemporal filling flow velocity and, most particularly, the presence of a normal cone-shaped ventricular geometry (see Fig. 7-6A).116 When the mitral valve opens and blood is normally sucked into the left ventricle, the gradient between that ventricle and the left atrium begins to decrease, and flow ultimately stops or transiently reverses when these pressures equilibrate. Under normal circumstances, relaxation is completed during rapid filling as the LV pressure attains its near minimum.58,117 More than two thirds of the LV stroke volume normally enters the left ventricle during this earliest phase of diastole. The time of pressure deceleration is determined by normal vigorous suction (active force) or by “stiff ” noncompliant LV muscle (passive force) associated with disease states.118–120 The normal response to stress is an increase in the gradient between the left atrium and the LV apex.102 βadrenergic stimulation increases contractility, myocardial restoring forces, and the resulting enhanced ventricular suction.97,110,115 Increased diastolic suction facilitates rapid filling and lowers minimum LV pressure.108,113 Enhanced diastolic suction acts as a
C
Figure 7-6 Diagrams of diastolic left ventricular (LV) filling. The relative spacing and shape of the dots reflect pressure (widely spaced = low pressure) and velocity (elongated = fast). A, In the normal heart, recoil of elastic elements produces a pressure gradient from the LV apex (lowest pressure) to the left atrium (higher pressure). This results in acceleration (suction) of blood out of the left atrium, which produces rapid diastolic filling that quickly propagates to the LV apex. The release of diastolic wall tension (potential energy) is normally rapid enough to cause the LV pressure to decrease despite an increase in LV volume.97 B, Dilated, ischemic, and hypertrophic cardiomyopathy typically contribute to heart failure. The normal intraventricular diastolic pressure gradient, which sucks blood from the left atrium into the left ventricle, is disturbed. The dilated, hypocontractile, or geometrically abnormal left ventricle produces a lower intraventricular pressure gradient in early diastole as a result of decreased elastic recoil and increased convective deceleration (i.e., decreased blood velocity with respect to distance). The pressure envelope in early diastole becomes dispersed, decreasing the pressure gradient between the left atrium and the left ventricle.106 The left atrium enlarges in response to increased filling pressure. Early forward flow from the pulmonary veins is commonly replaced by flow and pressure reversal in late diastole (arrows). C, Heart failure with preserved systolic function and a normal-sized left ventricle more commonly occurs in older persons, often in the absence of apparent clinical CV disease. The increased filling pressure (often due to arterial-ventricular stiffening) is transmitted backward from the aorta to the left ventricle, impeding the efficient transit of blood from the left atrium to the left ventricle. The increased filling pressure is transmitted backward to the left atrium causing LA enlargement and increased pulmonary venous pressure.34 Early forward flow from the pulmonary veins (large arrows) is commonly replaced by reversal of flow and pressure into the pulmonary veins (small arrows) in late diastole.
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction compensatory mechanism to maintain low pulmonary venous and arterial pressure in situations of increased contractility.102 The gradient between the left atrium and the LV apex is determined by inertial acceleration (elastic recoil) and convective deceleration (chamber geometry) of blood.102 Inertial acceleration is the change in velocity with respect to time, and convective deceleration is proportional to the decrease in velocity with respect to distance.121 Convective deceleration is increased when the distance or architecture of the left ventricle is altered and intraventricular blood flow is diverted away from the longitudinal axis of the left ventricle. An increase in convective deceleration caused by altered ventricular geometry thus decreases the normal gradient between the left atrium and the LV apex (see Fig. 7-6). Late in diastole, atrial contraction produces a second LA-to-LV pressure gradient that again propels blood into the left ventricle. After atrial systole, as the left atrium relaxes, its pressure drops below LV pressure, which initiates closure of the mitral valve. The onset of ventricular systole produces a rapid increase in LV pressure that seals the mitral valve and ends diastole.
CLINICAL RELEVANCE A thorough understanding of normal and abnormal myocardial physiology is vital to the determination of cause and effect. CHF and the clustering of associated risk factors cannot be assumed to represent cause and effect. Although risk factors modify and enhance the severity of the physiologic condition, most risk events, such as CHF, atrial fibrillation, and stroke, are best viewed as consequences and not causes. In particular, age-associated CV disease appears to have a common physiologic basis, which best accounts for the clustering of common adverse events.83,85,122
Epidemic of Diastolic Heart Failure As the world’s population has increased, the average life expectancy has also increased by approximately 3 months per year since 1840.123,124 This fact best accounts for the existence of an artifactual age-associated global epidemic of CV risk.5,125,126 HF is the most common indication for hospitalization of older persons. However, it is also well known that at least 50% of patients with CHF have a normal EF,127–131 and two studies report that more than 70% of older patients with symptomatic HF have a normal EF and fit the diagnosis of DHF.131,132 In addition, more than half of patients with CHF are relatively asymptomatic, which contributes to a substantial underestimation of the true incidence of HF, particularly in older persons. However, patients with HF and preserved EF (i.e., DHF) have exercise intolerance,19 shortness of breath on exertion, episodes of pulmonary edema requiring hospitalization, and increased mortality, similar to patients with SHF.52,53,133–135 In general, mortality with CHF is approximately 50% at 5 years.136 Patients with DHF tend to be older and more likely to have a history of hypertension, atrial fibrillation, and fewer symptoms, whereas patients with SHF are more likely to have a longer history of CHF, ventricular arrhythmias, and clinical manifestations of coronary artery disease.131 Clinical and research emphasis is increasingly placed on the physiology of cardiac dysfunction and not merely systolic contractility (i.e., EF). State-of-the-art noninvasive Doppler echocardiographic physiology has become the standard of clinical and investigative assessment of CV function. Thus, any discussion of CV function must incorporate the strengths and unique attri-
butes of invasive and noninvasive cardiac and vascular physiology used in the assessment and understanding of diastolic and systolic function. Symptoms of CHF are strongly related to the elevation of filling pressure, which accounts for breathlessness, exercise intolerance, and reduced quality of life.133,137–139 CV dysfunction leading to elevation of filling pressure and the clustering of adverse events can be broadly grouped as a consequence of either altered cardiomyocyte function accompanied by distorted ventricular geometry81,140 or abnormal cardiac loading, which most commonly begins as a consequence of extracardiac stiffening of the conduit arterial system (see Fig. 7-2).54,81,133,137,140–142 Diastolic disorders from cardiomyocyte dysfunction include dilated cardiomyopathy, hypertrophic cardiomyopathy, and ischemic heart disease. Diastolic disorders beginning with increased pressure loading are most commonly ascribed to increased pulse pressure and central systolic blood pressure (i.e., hypertension).141,143–145 Energy-dependent myocardial relaxation (diastolic function) is metabolically more vulnerable than systolic contraction. Resistance to ventricular filling reflects pressure backward into the atria and the pulmonary veins during diastole when the atria and ventricles are directly exposed to each other. As the volume in the atrium and pulmonary vein increases, their combined reservoir capacity is ultimately exceeded. The dynamics of the left atrium and pulmonary veins undergo a transition from physiologic volume overload to abnormal pressure overload (see Fig. 7-5). The transition from a state of benign atrial volume overload to pressure overload is commonly slow and intermittent. The transition to a pressure overload state is clinically more apparent with stress intolerance and acute congestive symptoms after a stressful trigger (e.g., illness, surgery, infarction). Stress-induced increase in atrial pressure accounts for breathlessness and exercise intolerance. Sustained increase in pulmonary venous pressure accounts for symptoms ascribed to the syndrome of CHF.
Myocardial Disease and Diastolic Dysfunction Abnormal suction of blood into the left ventricle has been replicated with various HF models,91,108 such as myocardial ischemia114,146,147 and hypertrophic cardiomyopathy (see Fig. 7-6B).148 Any condition that interferes with normal regional systolic function might be expected to modify the pattern of the normal early diastolic intraventricular pressure gradients.147 With LV muscle disease, the end diastolic pressure-volume curve is shifted substantially to the right, and the diastolic pressure curve is shifted upward, reflecting the increase in filling pressure (see Fig. 7-3B).6 Abnormal LV filling dynamics are seen, along with increased LA pressure and inability to increase stroke volume without abnormal elevation of LA pressure. In patients with dilated cardiomyopathy, the normal pressure gradient from the left atrium to the LV apex is substantially decreased.102 Hypertrophic cardiomyopathy is a myocardial disease with abnormal ventricular geometry and preserved systolic function and is also accompanied predominantly by abnormal diastolic function. Diastolic suction is disturbed because of abnormal changes in chamber geometry, which are commonly associated with uncoordinated wall motion or impaired myocardial contractility. The decreased capacity to generate suction contributes to the abnormal increase in filling pressure.102 Limited suction response to stress causes LV filling pressure to increase disproportionately and causes exercise-related shortness of breath.102 Decreased
81
82
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction suction shifts the pressure-volume curve toward a higher minimum diastolic pressure (see Fig. 7-3B). With dobutamineinduced stress, the gradient between the left atrium and the LV apex can be demonstrated to be impaired.102 Altered geometry of the ventricle impairs inertial acceleration (decreased global elastic recoil) and enhances convective deceleration. Myocardial disease, associated with impaired elastic recoil and enhanced convective deceleration, is proportional to the magnitude of altered LV geometry.118 Cardiomyopathic ventricles show abnormal suction at baseline and have a limited ability to recruit suction when undergoing inotropic stimulation.102 The minimum diastolic pressure of the failing heart increases during exercise.108 Although the increase in filling pressure accounts for the symptoms of CHF (i.e., increased filling pressure and decreased EF), it is not directly related to the hemodynamic cause of decreased cardiac output and distorted LV geometry. Thus, simply decreasing filling pressure will decrease symptoms but will fall short of eliminating the primary problem. Lasting clinical improvement requires reversal of the LV remodeling and return of the cardiac output and renal perfusion to near-normal values to prevent relapse of fluid retention and subsequent clinical deterioration.139
Arterial Stiffening and Diastolic Dysfunction Widening of the arterial pulse is common to aging and generally reflects the stiffening or senescence of the conduit arteries49,54,149–151 and a dominant hemodynamic risk for cardiac dysfunction.141,152–154 In response to an increase in preload volume, the increase in systolic and diastolic blood pressure is exaggerated, which accounts for the shortness of breath, exercise intolerance, and hypertensive pulmonary edema seen in patients with DHF.53 The blood vessels are coupled in tandem with the ventricle (pump), which undergoes simultaneous systolic and diastolic stiffening (see Figs. 7-3 and 7-6C).21,55 Combined stiffening alters how the heart-arterial system interacts at rest, but particularly under stress by exertional demands,54 and is particularly evident in patients with CHF and preserved EF, smaller-than-normal end diastolic volume,31 and normal ventricular geometry.55 Delayed active and passive relaxation of the stiff left ventricle in early diastole disturbs the normal suction gradient between the left ventricle and the left atrium. HF with preserved EF and a normalsized and -shaped left ventricle more commonly occurs in older persons, women,151,155–157 and obese persons81,133,137,140,142 and is associated with a lower rate of myocardial infarction.158 Vascular stiffness affects CV reserve, coronary and peripheral flow regulation, endothelial function, and mechanical signaling and causes blood pressure lability and diastolic dysfunction. Ageassociated ventricular systolic and diastolic stiffness occurs even in the absence of other CV disease and is thought to be the dominant cause of age-related HF with preserved EF.9,49,55,151,159,160 Stiffening of arterial-ventricular function is referred to as coupling disease and is considered to be the principal contributor to the epidemic of age-associated CV adverse events such as HF, atrial fibrillation, stroke, and cognitive dysfunction.54
Physiologic Coupling of the Cardiovascular System Reservoir, Pump, and Arteries The concept of “continuity disease” has been proposed to describe the relationship and shared physiology between the arteries and the rest of the CV system.54 The CV system is best viewed as a
contiguous system, analogous to a conventional water pump. The heart is a pump delivering pulsatile flow to the arterial system. The arterial and capillary vascular system is an extensive hydraulic filter, which converts pulsatile flow to continuous flow at the end organ. The atria and veins act as a distensible reservoir that stores blood during ventricular contraction and fills the ventricle during diastole, thus initiating the conversion of continuous flow back to pulsatile flow. Any abnormality that interferes with efficient forward-directed flow initiates deterioration in the forward and backward directions to the adjoining components of the contiguous system. The age-associated epidemic of HF appears to be principally related to an increase in arterial stiffness. Increased arterial stiffness affects the ventricle (reverse direction) and distal arterial bed (forward direction). The concept of coupling disease54 can be expanded to include the interdependence of the whole CV system (i.e., arteries, pump, and reservoir).
Arterial-Ventricular Coupling It is necessary to address the interaction of the whole CV system as a discipline in order to understand the vascular and cardiac regulatory mechanisms associated with the contiguous relationship of ventricular and arterial function.57 The interaction of ventricular and arterial properties, or coupling, is an important and largely underappreciated determinant of cardiac performance.19–22,161 Elastance is the change in pressure for a given change in volume of the ventricle. Arterial elastance (Ea) indexed to body surface (EaI) represents a steady-state arterial property that characterizes the functional properties of the arterial system (see Fig. 7-4).20 Ea is a lumped parameter that accounts for aortic impedance, peripheral resistance, and arterial compliance. Ea is equal to the LV end systolic pressure divided by the stroke volume. Ea shares common units with elastance measures of ventricular function (Ees or Ees indexed to body surface [EesI]); their ratio (EaI/EesI), an index of arterial-ventricular coupling,20 is inversely related to EF.162 In healthy subjects free of CV disease, EF increases by up to 30% during exercise.23 However, in order for the EF to increase during exercise, the coupling ratio, EaI/EesI, must decrease (Fig. 7-7).19 Studies show that with aging, the normal increase in EF during exercise (i.e., EF reserve) becomes blunted,23,57 suggesting ageassociated differences in the shift of coupling ratio and its components during exercise. Suboptimal vascular-ventricular coupling helps explain the age-associated blunting of maximal exercise EF and its underlying mechanisms.19
Stiffening Stiffening of any component of the CV system signals the dysfunctional state to contiguous (i.e., coupled) systems. Stiffening within the CV system is accompanied by changes that do not require renal disease or cardiac hypertrophy to be present.21 Patients with low arterial compliance (e.g., increased stiffness; Ea) have increased ventricular stiffening (Ees),55 which has important implications regarding blood pressure lability and loading sensitivity. To maintain optimal interaction with the stiffened arterial system, the LV itself must also develop greater systolic stiffness.21,163–166 Arterial-ventricular stiffening alters the way in which the CV system responds to stress demands and changes in volume and pressure loading.54 The physiologic changes of increased stiffness are associated with decreased exertional capacity, which contributes to the clinical complex of CHF with preserved systolic EF.48
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 90
0.7
85
0.6
<40 yr
0.5
75
>60 yr
Eal/Eesl
EF (%)
80
70
0.3
65
0.2
60
A
Sit
50% max
Max
B
<40 yr
Supine
Sit
50% max
Max
30 >60 yr <40 yr >60 yr
2.8 2.6
<40 yr
2.4
25
<40 yr
20 Eesl
3.0
Eal
>60 yr
0.1 Supine
3.2
2.2
15
<40 yr
10
>60 yr
5
2.0 1.8
C
0.4
0 Supine
Sit
50% max
Max
D
Supine
Sit
50% max
Max
Figure 7-7 Comparison of ejection fraction (EF), ventricular-vascular coupling index (EaI/EesI), arterial elastance index (EaI), and ventricular elastance index (EesI) by analysis of variance. Men aged <40 years (red circles) and >60 years (yellow squares) and women aged <40 years (blue circles) and >60 years (green squares) were compared at rest (Supine Sit) and at half-maximal (50% max) and maximal (Max) exercise capacities. A, The EF is augmented with exercise in both age groups and sexes. B, Correspondingly, the EaI/EesI (i.e., the inverse of EF) decreases in both age groups and sexes. In both men and women, the decrease in EaI/EesI ratio at maximal exercise is greater (improved function) in younger than in older subjects. C, At maximal exercise, EaI is greater in older women (stiffer arteries) than in younger women, even though heart rate, which is a determinant of EaI, is greater at peak exercise in younger versus older women. In contrast, there is no difference in the EaI between the two age groups in men, even though heart rate is also significantly higher in younger than in older men at peak exercise. D, EesI increases with exercise in both age groups and sexes. At maximal exercise, EesI is greater (better) in younger men than in older men and is slightly greater in younger women than in older women. These results show that EF increase in older persons is blunted and associated with less corresponding decrease in the ventricular-vascular index with exercise. With aging, women show a smaller decrease in both arterial (Ea) and ventricular (Ees) elastance than men. However, both men and women show similar blunting in EF augmentation and decrease in EaI/EesI ratio with aging. Increased stiffness (lower compliance) of the ventricular myocardium accounts for age-associated delay in myocardial relaxation, increased filling pressure, and atrial enlargement, which contribute to the onset of adverse cardiovascular events. (From Najjar SS et al: Age and gender affect ventricularvascular coupling during aerobic exercise. J Am Coll Cardiol 2004;44:611–617.)
Diastole and Stiffness Cardiac relaxation is delayed when the heart (pump) is exposed to increased systolic pressure during ejection (i.e., increased afterload), as occurs with vascular stiffening or enhanced systemic resistance.54,58 Ejecting into a stiff thoracic aorta decreases total compliance and substantially increases pulse pressure.167 Arterialventricular stiffening changes the mechanical forces to which the endothelial cells and arterial smooth muscles are exposed. These mechanical forces have key roles in regulating wall tone, atherogenesis, angiogenesis, and other features of vascular hemostasis. Cardiac maladaptations such as hypertrophy and increased ventricular Ees make the net effects of vascular stiffening even worse, particularly from the standpoint of net CV reserve, blood pressure regulation, and blood volume distribution.54 Coupling between altered systems helps explain the cause-and-effect physiologic manifestations observed in many CV disease states.143 Severe cardiac dysfunction can occur in spite of normal LV contractility (i.e., EF) and geometry.168 In patients with LV diastolic dysfunction and preserved EF caused by arterial stiffening, the abnormal increase in LV filling
pressure is directly related to the primary hemodynamic abnormality. In these patients, an absolute change in LV filling pressure and cardiac output are potent predictors of clinical outcome. Intravascular volume depletion should be avoided, and therapy should concentrate on blood pressure reduction with vasodilators that affect the renin-angiotensin-aldosterone system and sympathetic nervous system.138,139
Forward Dysfunction: End-Organ and Microvascular Damage End-Organ Pulsatility A complex network of small arteries and arterioles represents the resistance vasculature. Increased vascular capillary resistance may result from decreased lumen diameter, a longer vessel length, or rarefaction (decreased number of vessels connected in parallel).144,149 High resistance at the capillary level decreases both pulsatile flow and steady flow, resulting in a steady blood flow through resistance vessels and tissue. Arterial pulsations, which
83
84
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction cannot enter the high-resistance vessels, are reflected backward and summate with the pressure of the approaching waves. The distribution of these phenomena is not identical along the arterial tree and differs according to age, anatomy, and physiology of the vascular bed in question.144 In elderly people, increased vascular stiffness and higher systolic blood pressure and pulse pressure increase arterial pulsatility closer to the end organ, which favors end-organ damage, particularly in the heart, brain, and kidneys.144 Pressure pulsatility has major effects on microvascular structure and function. Deleterious effects on vascular reactivity and end-organ function are amplified in the setting of increased arterial stiffness and elevated pulse pressure. Reduced regional vascular resistance can diminish the decrease in pressure in the precapillary arterioles and expose the capillaries to potentially harmful levels of pressure pulsatility.169 If changes in the relationship between mean arterial pressure and flow involve microvascular structural remodeling or rarefaction, as opposed to a reversible change in microvascular tone, impaired responsiveness to metabolic demand may result, causing altered autoregulatory flow modulation.170
artery pulsations are normally transmitted through the pulmonary capillaries to the left atrium.15,16,178 The notable feature of the kidney and brain, compared with the heart, is that they are continually and passively perfused at high-volume flow throughout both systole and diastole,145 whereas the heart is perfused principally during diastole. The vascular capillary resistance in these organs is very low, so that in comparison with other vascular beds, resistance is closer to input and characteristic impedance. Wave reflections from the brain and kidney are very low, and pulsatile pressure and flow extend well into these organs, similar to the lungs.15,16 The brain and kidneys thus literally “throb” with each beat of the heart.145 Whereas other organs are protected by relatively intense vasoconstriction upstream, the brain and kidneys are susceptible to influences upstream that can increase fluctuations in flow and pressure and contribute to age-associated end-organ or microvascular damage.179–181 As with the lungs, exposure of the small vessels of the brain and kidneys to highly pulsatile pressure and flow can explain microvascular damage151 and the resulting cognitive and renal dysfunction commonly encountered in the aging population.145
Heart and Coronary Perfusion
Vascular Stiffening: Summary
Coronary circulation is autoregulated but with two particularities.144,171 First, because of nearly exclusive coronary perfusion during diastole, perfusion pressures are determined by diastolic blood pressure and not mean arterial pressure. Flow into the coronary arteries during systole is caused entirely by passive distention of the epicardial arteries.172 Second, as arterial stiffness increases in association with systolic hypertension, atherosclerosis, or both, aortic branches with decreased lumen diameter and shorter height cause the arterial pressure reflections to arrive in the aortic root in late systole, rather than in diastole. The consequence is systolic pressure summation closer to the aortic valve, which impairs diastolic coronary perfusion.21,151,161,173 Age-associated increase in arterial vascular stiffness thus contributes to decreased coronary perfusion and secondary myocardial dysfunction, which begins as an abnormality in diastolic function (elevation of filling pressure).36 The ensuing alteration in myocardial relaxation causes a measurable increase in ventricular stiffness (decreases active and passive relaxation), initiating a cascade of physiologic and structural changes, which lower the threshold for the occurrence of adverse CV events.
Age-associated vascular stiffening increases systolic blood pressure and pulse pressure. Pulsatile forces acting on large and small arteries, down to the microvessels, contribute substantially to increased CV risk and selective end-organ damage in addition to diastolic dysfunction.179,182
Brain and Kidney Mean arterial blood pressure normally decreases by less than 1 mmHg between the ascending aorta and a peripheral artery such as the cerebral and renal arteries.145,174,175 Exposure of small vessels to highly pulsatile arterial pressure and flow can explain microvascular damage and can result in stroke and cognitive dysfunction,145,176 as well as renal insufficiency.177 Normally pulsatile arterial energy is restricted to the major arteries and is absorbed in these vessels as a consequence of blood and arterial wall elastance. However, the renal, brain, lung, and coronary beds are different from all other vascular beds.145 The brain and myocardium receive (relatively) torrential flow at rest to sustain sensitive brain cells and maintain cardiac function, respectively. The heart pulsates because it fills and empties, but the brain and kidneys also pulsate because of the high pulsatile flow into and within these organs. The lungs also pulsate in a similar manner, and pulmonary
Reverse Continuity Disease (Aorta to Coronary Artery, Ventricle, and Atrial Reservoir) The age-associated increase in arterial stiffness is not explained on the basis of vascular disease such as atherosclerosis, which is commonly encountered in older persons; instead, the most unifying feature is that of major conduit vessels becoming larger and physiologically stiffer.144 Stiffening of the vascular system causes an increase in systolic blood pressure due to reflected pulse waves.144 Antegrade energy is “reflected” backward, with the incident and reflected waves summating. Summated pressure progressively increases the afterload in the aortic root, coronary arteries, ventricle, and atrial reservoir.
Coronary Perfusion A stiff aorta causes pressure reflections to arrive more rapidly and reach the aortic root in late systole, instead of in diastole as they normally do, thus impairing coronary perfusion. The coronary ischemia causes altered Ca2+ regulation, which appears to have a fundamental role in diverse age-associated diseases and associated increased cardiac stiffness.57,183 With age, mitochondrial sequestration of Ca2+ decreases, release of Ca2+ from stores is greatly enhanced, and extrusion of intracellular Ca2+ is diminished. These changes delay the myocyte transition from a contracted to a relaxed state. Thus, when the atrioventricular valve opens, the atrium is confronted with a variable degree of increased ventricular myocardial stiffness and filling pressure. After age 50, aortic diastolic blood pressure and coronary artery perfusion tend to decrease, whereas systolic blood pressure and pulse pressure increase.184 For example, increased central pulse pressure is superior to peripheral pulse pressure in the pre-
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction diction of myocardial infarction.182 Conduit arterial physiology and morphology have strong relationships to age-associated decrease in coronary perfusion, which in turn can account for the delay in myocyte relaxation and increase in filling pressure.
ture (rarefaction) and surrounding tissue (tissue fibrosis). Endorgan perfusion is particularly vulnerable to diastolic hypotension and volume depletion. The natural history of CV dysfunction “forward continuity disease” revolves around end-organ damage, which is most evident in the heart, kidney, and brain.
Ventricular and Atrial Reservoir Stiffness Age- or disease-associated increase in vascular stiffening and arterial afterload cause ventricular systolic and diastolic stiffening. The induced cascade of altered filling dynamics is typified by abnormal myocardial relaxation and increased filling pressure. The atrial appendage and pulmonary veins are normally three to four times more distensible than the body of the atrium.185,186 Distensibility of the atrium plays a major role in normal cardiac function. Increased atrial distensibility benefits cardiac hemodynamics and increasing cardiac output187 through augmented atrial reservoir function.188 An increase in atrial distensibility prevents an increase in atrial pressure.189 Thus, a highly compliant left atrium, with large reservoir capacity, low pressure during atrial filling, and relatively high mean atrial pressure during ventricular filling, best maintains ventricular hemodynamics.187 A stiff ventricle and increased filling pressure is reflected backward into the atrial reservoir. During ventricular diastole, the atrium and ventricle are directly exposed to each other, and any increase in filling pressure is reflected backward, causing atrial and pulmonary vein walls to become stretched. The normal reservoir capacity and distensibility of the atrium and pulmonary veins can become exceeded.190 Atrial pressure overload causes atrial myocyte stretch, upregulation of the local renin-angiotensin system, cell death, and collagen deposition.78,88,191–193 A stiff, noncompliant atrial reservoir has decreased capacity to store blood during ventricular systole and is unable to increase output on demand. In older persons, incremental increase of atrial volume more commonly represents the burden of pressure overload caused by the inability of a stiff ventricle to efficiently receive blood during diastole.78,194
Pulmonary Venous Stiffness and Pulmonary Artery Pressure Increase The symptom of breathlessness is caused by backward transition of the increased atrial pressure into the pulmonary veins, capillaries, and arteries.15,16 Dyspnea is typically caused by an increase in either pulmonary interstitial fluid17 or physiologic dead space.18 The stiff hypertrophied LV, coupled with increased LA and pulmonary venous pressures, produces shortness of breath.17,18 As the resistance to forward flow increases, variable resting or exerciseinduced pulmonary artery hypertension develops.
Forward Continuity Disease (Aorta to Arteries, Arterioles, and Capillaries) Increased conduit stiffness is characterized by increased central systolic pressure and decreased diastolic pressure. The systolic pressure is augmented by pressure waves reflected from the periphery. The increased pulsatile pressure is transmitted into the arteries. The brain and kidney, which are not protected by an extensive compliant precapillary arterial bed, are particularly vulnerable to pressure-induced microvascular damage and perfusion deficits. In response to increased systolic pressure, the microvessels increase their intima at the expense of the lumen (i.e., the intima-to-lumen ratio increases) and the normal autoregulatory function of the microvasculature. Increased pressure damages the microvascula-
CLUSTERING OF CARDIOVASCULAR RISK Is is apparent that CV dysfunction potentiates the development of adverse CV events. Heart failure (cause: altered myocardial geometry and/or ventricular stiffening), atrial fibrillation (cause: atrial stretch, cell death, fibrosis, and electrical heterogeneity), cognitive and renal dysfunction (cause: microvascular end-organ damage), and stroke (cause: atrial stretch/dysfunction, reduced circulating nitroso products, increased thrombosis) all “cluster” around age- and disease-associated CV dysfunction. Today, CV investigators are much closer to a physiologic understanding of a common causal relationship among these diverse yet interrelated, commonly age-associated, adverse CV events.
Diastolic Heart Failure with Normal Ejection Fraction and Systolic Heart Failure: Pathophysiologic Subgroups Although HF with normal EF is commonly thought to be the result of a single hemodynamic mechanism, data indicate that subgroups exist with distinctly different underlying pathophysiologies.159,195 Diastolic dysfunction refers to mechanical and functional abnormalities present during relaxation and filling, which is usually associated with concentric hypertrophy. DHF refers to clinical syndromes in which patients with HF have little or no ventricular dilation, dominant diastolic dysfunction, and preserved EF. Systolic dysfunction refers to the decreased ability of the ventricle to develop tension and shorten, which generally leads to eccentric hypertrophy. The mechanisms leading to HF with normal EF differ among patient subgroups. Subjects with preserved EF fall into two distinct subgroups: those who are nonhypertensive (e.g., idiopathic hypertrophic cardiomyopathy, infiltrative diseases) and those who are hypertensive.159 Subjects in the nonhypertensive group have an upward or leftward shift of the end diastolic pressure-volume curve, indicative of passive diastolic dysfunction and the classical paradigm of DHF. The LV chamber is normal or smaller than normal and hypertrophied. The hypertensive group also has an increase in LV mass and in LV end diastolic volume and a normal or even rightward shift in the end diastolic pressure-volume relationship. Within the hypertensive subgroup of patients, some have significantly higher than normal values of ventricular and arterial elastance. The rightward shift of the pressure-volume curve may not always be the predominant factor contributing to HF in patients with hypertension. The extracardiac factors, including renal dysfunction, obesity, and anemia, among others, are speculated to account for the volume overload state. Plasma volume overload may be an important factor contributing to HF.159 SHF is the clinical syndrome in which patients with HF have distorted ventricular geometry, ventricular enlargement, and reduced EF. Diastolic dysfunction, which is closely related to elevation of filling pressure, is found in patients with both DHF and SHF and relates most closely to symptoms of breathlessness and exercise intolerance196 but does not accurately reflect the underlying pathophysiology or HF phenotype.195,197 DHF and SHF
85
86
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction share many clinical and hemodynamic features but are increasingly recognized to be caused by different pathophysiologic mechanisms.195,197 LV systolic performance (stroke work), function (EF), and contractility (dP/dt, stress vs. shortening and ventricular elastance) are not significantly different in patients with DHF and in normal controls.168 SHF is characterized by eccentric hypertrophy, progressive LV dilation, and abnormal systolic properties. DHF exhibits concentric hypertrophy, normal or reduced LV volume, concentric remodeling, and abnormal diastolic function (i.e., reduced LV long-axis shortening,198 decreased tissue Doppler myocardial systolic velocity,199 disturbed ventriculoarterial coupling,55 slow LV relaxation, and high LV stiffness31). However, DHF and elevation of filling pressure also occur in patients with SHF in whom diastolic abnormalities correlate better with symptoms than with LV EF.196 The most striking difference between SHF and DHF is the tendency of the end diastolic volume to increase in SHF. Cardiomyocyte diameter is larger in DHF, and collagen volume is larger in DHF but increases similarly in SHF and DHF as fibrosis progresses.195 The excess cardiomyocyte hypertrophy in DHF is strongly related to a history of arterial hypertension, which in one study was present in 73% of DHF patients and only 13% of SHF patients.195 This distinction, which can be attributed to activation of different proliferative signaling mechanisms, has important implications, because therapy that improves prognosis of SHF may not slow progression in DHF.197 Evidence suggests that cardiomyocytes in SHF and DHF express different gene products. Van Heerebeek et al.195 described an abnormal distribution of titin isoforms in the hearts of patients with these two clinical syndromes. Titin is a huge cytoskeletal protein found in the cardiomyocyte. Mammalian hearts contain either or both of two titin isoforms, N2BA and N2B.200 A key difference is that the N2B isoform is stiffer than the N2BA isoform. N2B tends to predominate in stiffer ventricles, whereas N2BA occurs in more compliant hearts. The less stiff N2BA isoform has been reported in human dilated cardiomyopathy,201 and the stiffer N2B is more prominent in DHF with high diastolic stiffness.195 The cardiomyocyte stiffness observed in DHF could be attributed to the titin isoform shift. The myocardial structure and function differ in SHF and DHF because of distinct cardiomyocyte abnormalities. Given the profound differences in LV volume, mass geometry, and systolic properties in patients with SHF and DHF, long-term treatment will likely be fundamentally different.168 Elevated filling pressure, common to both SHF and DHF, best accounts for symptoms, rather than the fundamental pathologic abnormality causing the symptoms. Thus, fluid manipulation and alleviation of breathlessness may not adequately address the problem, which may account for the high incidence of rehospitalization of HF patients. In patients with SHF, therapies that reverse eccentric remodeling (i.e., reverse remodeling) by decreasing LV volume and restoring LV EF result in decreased morbidity and mortality.202,203 Treatment of DHF should be directed at reversing the cellular and extracellular mechanisms that lead to concentric remodeling, fibrosis, and abnormal diastolic function.168 A reversal of collagen turnover—decreasing its synthesis while increasing its degradation—would appear to accompany pharmacologic inhibition of angiotensin II, through the use of angiotensin-converting enzyme inhibition and antagonism of its AT1 receptor.204 Because a high percentage of patients with DHF have diabetes mellitus, collagen cross-links formed by advanced-glycation end products205 could also contribute to increased myocardial stiffness.
FUTURE RESEARCH Diastolic function assessment by invasive2 and/or noninvasive means is plagued by ambiguities surrounding the dynamic nature, lack of directness, and difficulty of reproducibly measuring everchanging diastolic function. Advances in noninvasive methods continue to erode the need for invasive validation. The invasive examination remains the physiologic “testing ground” for understanding instantaneous physiology. However, the Doppler echocardiographic examination is now the gold standard for clinical assessment of dynamic and chronic manifestations of diastolic function. Energy-dependent diastolic relaxation is more vulnerable to dysfunction than is systolic contraction. Thus, diastolic dysfunction is expectedly found with both systolic and diastolic cardiac dysfunction. Understanding of the complexities and redundancies of the CV system is being translated into clinical practice. Forward and reverse coupling, CV stiffness, risk factor clustering, elastance, distensibility, and other terms are becoming incorporated into the vernacular of the “echophysiologist.” The future of CV medicine hinges on the acquisition and understanding of the physiologic model(s) of disease. Filling pressure, myocyte contraction and relaxation, and spatial-temporal event recording are increasingly viewed as the keys to determining systolic and diastolic function and the development of primary prevention and physiologic treatment scenarios.
GLOSSARY Terms Clustering: Common risk factors attributed to cause diastolic dysfunction cluster around one another, which suggests the existence of a common underlying physiologic perturbation. Continuity disease: Dysfunction in one component of the cardiovascular system (arteries, ventricle, or atria) is transmitted to an adjoining system(s) Forward continuity: Example: Arterial stiffening causes contiguous stiffening of the distal arterial, arteriolar, and microvascular systems. Reverse continuity: Example: Arterial stiffening causes contiguous stiffening of coronary, ventricular, atrial, and pulmonary venous functions. Coupling disease: Stiffening of the contiguous arterial-ventricular system function Echophysiologist: A diagnostician who uses noninvasive ultrasonography to assess and model physiologic function. Stiffening: Increased rigidity; decreased compliance and elastance
ABBREVIATIONS CHF, congestive heart failure CV, cardiovascular
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction DHF, diastolic heart failure DT, deceleration time E, early diastolic transmitral inflow velocity E′, early diastolic mitral annular velocity Ea, effective arterial elastance EaI, effective arterial elastance index Ees, end systolic elastance EesI, end systolic elastance index EF, ejection fraction HF, heart failure LA, left atrial LV, left ventricular LVEDP, LV end diastolic pressure SHF, systolic heart failure REFERENCES 1. Baim DS, Grossman W: Grossman’s cardiac catheterization, angiography, and intervention, 5th ed. Philadelphia, Lippincott, Williams & Wilkins, 1996. 2. Kass DA. Assessment of diastolic dysfunction: Invasive modalities. Cardiol Clin 2000;18:571–586. 3. Burkhoff D, Mirsky I, Suga H: Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: A guide for clinical, translational, and basic researchers. Am J Physiol Heart Circ Physiol 2005;289: 501–512. 4. Fox JM, Maurer MS: Ventriculovascular coupling in systolic and diastolic heart failure. Curr Heart Fail Rep 2005;2:204–211. 5. Braunwald E: The Simon Dack lecture. Cardiology: The past, the present, and the future. J Am Coll Cardiol 2003;42:2031–2041. 6. Little WC: Diastolic dysfunction beyond distensibility: Adverse effects of ventricular dilatation. Circulation 2005;112:2888–2890. 7. Grossman W: Diastolic dysfunction in congestive heart failure. N Engl J Med 1991;325:1557–1564. 8. Klotz S, Hay I, Dickstein ML, et al: Single beat estimation of the end-diastolic pressure-volume relationship: A novel method with the potential for noninvasive application. Am J Physiol Heart Circ Physiol 2006 Jan 20. 9. Redfield MM, Jacobsen SJ, Borlaug BA, et al: Age- and gender-related ventricular-vascular stiffening: A community-based study. Circulation 2005 Oct 11;112:2254–2262. 10. Packer M: How should we judge the efficacy of drug therapy in patients with chronic congestive heart failure? The insights of six blind men. J Am Coll Cardiol 1987;9:433–438. 11. Packer M: Abnormalities of diastolic function as a potential cause of exercise intolerance in chronic heart failure. Circulation 1990;81 Suppl: III78–III86. 12. Jacob R, Kissling G: Ventricular pressure-volume relations as the primary basis for evaluation of cardiac mechanics: Return to Frank’s diagram. Basic Res Cardiol 1989;84:227–246. 13. Diamond G, Forrester JS, Hargis J, et al: Diastolic pressure-volume relationship in the canine left ventricle. Circ Res 1971;29:267–275. 14. Labeit S, Kolmerer B: Titins: Giant proteins in charge of muscle ultrastructure and elasticity. Science 1995;270:293–296. 15. Bergel DH, Milnor WR: Pulmonary vascular impedance in the dog. Circ Res 1965;16:401–415. 16. Milnor WR, Conti CR, Lewis KB, et al: Pulmonary arterial pulse wave velocity and impedance in man. Circ Res 1969;25:637–649. 17. Myers J, Froelicher VF: Hemodynamic determinants of exercise capacity in chronic heart failure. Ann Intern Med 1991;115:377–386. 18. Sullivan MJ, Higginbotham MB, Cobb FR: Increased exercise ventilation in patients with chronic heart failure: Intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation 1988;77:552–559. 19. Najjar SS, Schulman SP, Gerstenblith G, et al: Age and gender affect ventricular-vascular coupling during aerobic exercise. J Am Coll Cardiol 2004;44:611–617. 20. Sunagawa K, Maughan WL, Burkhoff D, et al: Left ventricular interaction with arterial load studied in isolated canine ventricle. Am J Physiol 1983;245: H773–H780. 21. Chen CH, Nakayama M, Nevo E, et al: Coupled systolic-ventricular and vascular stiffening with age: Implications for pressure regulation and cardiac reserve in the elderly. J Am Coll Cardiol 1998;32:1221–1227.
22. Saba PS, Roman MJ, Ganau A, et al: Relationship of effective arterial elastance to demographic and arterial characteristics in normotensive and hypertensive adults. J Hypertens 1995;13:971–977. 23. Fleg JL, O’Connor F, Gerstenblith G, et al: Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Physiol 1995;78:890–900. 24. Kumar A, Anel R, Bunnell E, et al: Preload-independent mechanisms contribute to increased stroke volume following large volume saline infusion in normal volunteers: A prospective interventional study. Crit Care 2004 Jun;8: R128–R136. 25. Bellenger NG, Burgess MI, Ray SG, et al: Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance: Are they interchangeable? Eur Heart J 2000;21:1387–1396. 26. Solomon SD, Anavekar N, Skali H, et al: Candesartan in Heart Failure Reduction in Mortality (CHARM) Investigators. Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients. Circulation 2005 Dec 13;112:3738–3744. 27. Lim TK, Ashrafian H, Dwivedi G, et al: Increased left atrial volume index is an independent predictor of raised serum natriuretic peptide in patients with suspected heart failure but normal left ventricular ejection fraction: Implication for diagnosis of diastolic heart failure. Eur J Heart Fail 2006 Jan;8:38–45. 28. Connors AF Jr, Speroff T, Dawson NV, et al: SUPPORT Investigators. The effectiveness of right heart catheterization in the initial care of critically ill patients. JAMA 1996;276:889–897. 29. U.S. Department of Health and Human Services. National Institutes of Health. No increase in deaths or hospitalizations for heart failure patients who have a pulmonary artery catheter [updated 2004 Nov 9; cited 2006 Apr 26]. Available from: http://www.nhlbi.nih.gov/new/press/04–11–09.htm. 30. Senzaki H, Fetics B, Chen CH, et al: Comparison of ventricular pressure relaxation assessments in human heart failure: Quantitative influence on load and drug sensitivity analysis. J Am Coll Cardiol 1999;34:1529– 1536. 31. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure: Abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 2004;350:1953–1959. 32. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527–1533. 33. Rivas-Gotz C, Manolios M, Thohan V, et al: Impact of left ventricular ejection fraction on estimation of left ventricular filling pressures using tissue Doppler and flow propagation velocity. Am J Cardiol 2003;91:780–784. 34. Nishimura RA, Tajik AJ: Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta stone. J Am Coll Cardiol 1997;30:8–18. 35. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure. Part I: Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387–1393. 36. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. 37. Nagueh SF, Mikati I, Kopelen HA, et al: Doppler estimation of left ventricular filling pressure in sinus tachycardia: A new application of tissue Doppler imaging. Circulation 1998;98:1644–1650. 38. Sohn DW, Kim YJ, Park YB, et al: Clinical validity of measuring time difference between onset of mitral inflow and onset of early diastolic mitral annulus velocity in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 2004;43:2097–2101. 39. Diwan A, McCulloch M, Lawrie GM, et al: Doppler estimation of left ventricular filling pressures in patients with mitral valve disease. Circulation 2005 Jun 21;111:3281–3289. Epub 2005 Jun 13. Erratum in: Circulation 2005;112:e76. 40. Temporelli PL, Giannuzzi P, Nicolosi GL, et al: GISSI-3 Echo Substudy Investigators. Doppler-derived mitral deceleration time as a strong prognostic marker of left ventricular remodeling and survival after acute myocardial infarction: Results of the GISSI-3 Echo Substudy. J Am Coll Cardiol 2004;43:1646–1653. 41. Lewis RP, Sandler H: Relationship between changes in left ventricular dimensions and the ejection fraction in man. Circulation 1971;44: 548–557. 42. Baan J, van der Velde ET, de Bruin HG, et al: Continuous measurement of left ventricular volume in animals and humans by conductance catheter. Circulation 1984;70:812–823.
87
88
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 43. Burkhoff D, van der Velde E, Kass D, et al: Accuracy of volume measurement by conductance catheter in isolated, ejecting canine hearts. Circulation 1985;72:440–447. 44. Kass DA: Clinical evaluation of left heart function by conductance catheter technique. Eur Heart J 1992;13 Suppl E:57–64. 45. Kass DA, Yamazaki T, Burkhoff D, et al: Determination of left ventricular end-systolic pressure-volume relationships by the conductance (volume) catheter technique. Circulation 1986;73:586–595. 46. Chen CH, Fetics B, Nevo E, et al: Noninvasive single-beat determination of left ventricular end-systolic elastance in humans. J Am Coll Cardiol 2001;38:2028–2034. 47. Senzaki H, Chen CH, Kass DA: Single-beat estimation of end-systolic pressure-volume relation in humans: A new method with the potential for noninvasive application. Circulation 1996;94:2497–2506. 48. Hundley WG, Kitzman DW, Morgan TM, et al: Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796–802. 49. Vaitkevicius PV, Fleg JL, Engel JH, et al: Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation 1993;88:1456– 1462. 50. Lakatta EG: Cardiovascular aging research: The next horizons. J Am Geriatr Soc 1999;47:613–625. 51. Chen CH, Nakayama M, Talbot M, et al: Verapamil acutely reduces ventricular-vascular stiffening and improves aerobic exercise performance in elderly individuals. J Am Coll Cardiol 1999;33:1602–1609. 52. Kitzman DW, Higginbotham MB, Cobb FR, et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17: 1065–1072. 53. Gandhi SK, Powers JC, Nomeir AM, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001; 344:17–22. 54. Kass DA: Ventricular arterial stiffening: Integrating the pathophysiology. Hypertension 2005 Jul;46:185–193. 55. Kawaguchi M, Hay I, Fetics B, et al: Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: Implications for systolic and diastolic reserve limitations. Circulation 2003;107:714–720. 56. Kelly RP, Ting CT, Yang TM, et al: Effective arterial elastance as index of arterial vascular load in humans. Circulation 1992;86:513–521. 57. Lakatta EG: Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 1993;73:413–467. 58. Leite-Moreira AF, Correia-Pinto J, Gillebert TC: Afterload induced changes in myocardial relaxation: A mechanism for diastolic dysfunction. Cardiovasc Res 1999;43:344–353. 59. Takimoto E, Soergel DG, Janssen PM, et al: Frequency- and afterloaddependent cardiac modulation in vivo by troponin I with constitutively active protein kinase A phosphorylation sites. Circ Res 2004 Mar 5;94:496–504. 60. Davies JE, Whinnett ZI, Francis DP, et al: Evidence of a dominant backward-propagating “suction” wave responsibe for diastolic coronary filling in humans, attenuated in left ventricular hypertrophy. Circulation 2006 Apr 11;113:1768–1778. 61. Aurigemma GP, Zile MR, Gaasch WH: Contractile behavior of the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296–304. 62. Kass DA, Saeki A, Tunin RS, et al: Adverse influence of systemic vascular stiffening on cardiac dysfunction and adaptation to acute coronary occlusion. Circulation 1996;93:1533–1541. 63. Aurigemma GP, Gaasch WH: Clinical practice: Diastolic heart failure. N Engl J Med 2004;351:1097–1105. 64. Redfield MM, Jacobsen SJ, Burnett JC Jr, et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202. 65. Verdecchia P, Angeli F, Gattobigio R, et al: Asymptomatic left ventricular systolic dysfunction in essential hypertension: Prevalence, determinants, and prognostic value. Hypertension 2005 Mar;45:412–418. 66. Katz AM: Role of the basic sciences in the practice of cardiology. J Mol Cell Cardiol 1987;19:3–17. 67. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 68. Dokainish H, Zoghbi WA, Lakkis NM, et al: Optimal non-invasive assessment of left ventricular filling pressures: A comparison of tissue
69. 70. 71.
72. 73. 74. 75. 76. 77. 78.
79. 80. 81. 82. 83. 84. 85. 86.
87. 88. 89.
90. 91. 92.
Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation 2004 May 25;109:2432– 2439. Dokainish H, Zoghbi WA, Lakkis NM, et al: Comparative accuracy of Btype natriuretic peptide and tissue Doppler echocardiography in the diagnosis of congestive heart failure. Am J Cardiol 2004;93:1130–1135. Agricola E, Galderisi M, Oppizzi M, et al: Doppler tissue imaging: A reliable method for estimation of left ventricular filling pressure in patients with mitral regurgitation. Am Heart J 2005;150:610–615. Barberato SH, Mantilla DE, Misocami MA, et al: Effect of preload reduction by hemodialysis on left atrial volume and echocardiographic Doppler parameters in patients with end-stage renal disease. Am J Cardiol 2004;94:1208–1210. Tsang TS, Barnes ME, Gersh BJ, et al: Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90:1284–1289. Messerli FH: Cardiovascular effects of obesity and hypertension. Lancet 1982;1:1165–1168. De Divitiis O, Fazio S, Petitto M, et al: Obesity and cardiac function. Circulation 1981;64:477–482. Wang TJ, Parise H, Levy D, et al: Obesity and the risk of new-onset atrial fibrillation. JAMA 2004;292:2471–2477. Tsang TS, Barnes ME, Gersh BJ, et al: Prediction of risk for first age-related cardiovascular events in an elderly population: The incremental value of echocardiography. J Am Coll Cardiol 2003;42:1199–1205. Douglas PS: The left atrium: A biomarker of chronic diastolic dysfunction and cardiovascular disease risk. J Am Coll Cardiol 2003;42:1206– 1207. Appleton CP, Galloway JM, Gonzalez MS, et al: Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease: Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993;22:1972–1982. Tsang TS, Barnes ME, Gersh BJ, et al: Risks for atrial fibrillation and congestive heart failure in patients ≥65 years of age with abnormal left ventricular diastolic relaxation. Am J Cardiol 2004;93:54–58. Robinson TF, Factor SM, Sonnenblick EH: The heart as a suction pump. Sci Am 1986;254:84–91. Yip GW, Ho PP, Woo KS, et al: Comparison of frequencies of left ventricular systolic and diastolic heart failure in Chinese living in Hong Kong. Am J Cardiol 1999;84:563–567. Gerstenblith G, Frederiksen J, Yin FC, et al: Echocardiographic assessment of a normal adult aging population. Circulation 1977;56:273–278. Fleg JL, Shapiro EP, O’Connor F, et al: Left ventricular diastolic filling performance in older male athletes. JAMA 1995;273:1371–1375. Tsang TS, Gersh BJ, Appleton CP, et al: Left ventricular diastolic dysfunction as a predictor of the first diagnosed nonvalvular atrial fibrillation in 840 elderly men and women. J Am Coll Cardiol 2002;40:1636–1644. Tsang TS, Barnes ME, Bailey KR, et al: Left atrial volume: Important risk marker of incident atrial fibrillation in 1655 older men and women. Mayo Clin Proc 2001;76:467–475. Appleton CP, Hatle LK, Popp RL: Relation of transmitral flow velocity patterns to left ventricular diastolic function: New insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol 1988;12:426–440. Nishimura RA, Abel MD, Hatle LK, et al: Assessment of diastolic function of the heart: Background and current applications of Doppler echocardiography. Part II. Clinical studies. Mayo Clin Proc 1989;64:181–204. Rossvoll O, Hatle LK: Pulmonary venous flow velocities recorded by transthoracic Doppler ultrasound: Relation to left ventricular diastolic pressures. J Am Coll Cardiol 1993;21:1687–1696. Redfield MM, Rodeheffer RJ, Jacobsen SJ, et al: Plasma brain natriuretic peptide to detect preclinical ventricular systolic or diastolic dysfunction: A community-based study. Circulation 2004 Jun 29;109:3176– 3181. Sengupta PP, Khandheria BK, Korinek J, et al: Apex-to-base dispersion in regional timing of left ventricular shortening and lengthening. J Am Coll Cardiol 2006 Jan 3;47:163–172. Bell SP, Nyland L, Tischler MD, et al: Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res 2000;87:235– 240. Brutsaert DL, Sys SU, Gillebert TC: Diastolic failure: Pathophysiology and therapeutic implications. J Am Coll Cardiol 1993;22:318–325. Erratum in: J Am Coll Cardiol 1993;22:1272.
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 93. Cheng CP, Freeman GL, Santamore WP, et al: Effect of loading conditions, contractile state, and heart rate on early diastolic left ventricular filling in conscious dogs. Circ Res 1990;66:814–823. 94. Yellin EL, Nikolic S, Frater RW: Left ventricular filling dynamics and diastolic function. Prog Cardiovasc Dis 1990;32:247–271. 95. Yellin EL, Hori M, Yoran C, et al: Left ventricular relaxation in the filling and nonfilling intact canine heart. Am J Physiol 1986;250:H620– H629. 96. Gilbert JC, Glantz SA: Determinants of left ventricular filling and of the diastolic pressure-volume relation. Circ Res 1989;64:827– 852. 97. Nikolic S, Yellin EL, Tamura K, et al: Passive properties of canine left ventricle: Diastolic stiffness and restoring forces. Circ Res 1988;62:1210–1222. Erratum in: Circ Res 1988;62:1059. 98. Vatner SF, Pagani M: Cardiovascular adjustments to exercise: Hemodynamics and mechanisms. Prog Cardiovasc Dis 1976;19:91–108. 99. Poliner LR, Dehmer GJ, Lewis SE, et al: Left ventricular performance in normal subjects: A comparison of the responses to exercise in the upright and supine positions. Circulation 1980;62:528–534. 100. Higginbotham MB, Morris KG, Williams RS, et al: Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res 1986;58:281–291. 101. Nonogi H, Hess OM, Ritter M, et al: Diastolic properties of the normal left ventricle during supine exercise. Br Heart J 1988;60:30–38. 102. Yotti R, Bermejo J, Antoranz JC, et al: A noninvasive method for assessing impaired diastolic suction in patients with dilated cardiomyopathy. Circulation 2005;112:2921–2929. 103. Rovner A, Greenberg NL, Thomas JD, et al: Relationship of diastolic intraventricular pressure gradients and aerobic capacity in patients with diastolic heart failure. Am J Physiol Heart Circ Physiol 2005 Nov;289:H2081– H2088. 104. Solomon SB, Nikolic SD, Glantz SA, et al: Left ventricular diastolic function of remodeled myocardium in dogs with pacing-induced heart failure. Am J Physiol 1998;274:H945–H954. 105. Wang Z, Jalali F, Sun YH, et al: Assessment of left ventricular diastolic suction in dogs using wave-intensity analysis. Am J Physiol Heart Circ Physiol 2005 Apr;288;H1641–H1651. Erratum in: Am J Physiol Heart Circ Physiol 2005;288:H3017. 106. Courtois M, Kovacs SJ Jr, Ludbrook PA: Transmitral pressure-flow velocity relation: Importance of regional pressure gradients in the left ventricle during diastole. Circulation 1988;78:661–671. 107. Sabbah HN, Stein PD: Pressure-diameter relations during early diastole in dogs: Incompatibility with the concept of passive left ventricular filling. Circ Res 1981;48:357–365. 108. Cheng CP, Noda T, Nozawa T, et al: Effect of heart failure on the mechanism of exercise-induced augmentation of mitral valve flow. Circ Res 1993;72:795–806. 109. Katz LN: The role played by the ventricular relaxation process in filling the ventricle. Am J Physiol 1930;95:542–553. 110. Bell SP, Fabian J, LeWinter MM: Effects of dobutamine on left ventricular restoring forces. Am J Physiol 1998;275:H190–H194. 111. Ling D, Rankin JS, Edwards CH II, et al: Regional diastolic mechanics of the left ventricle in the conscious dog. Am J Physiol 1979;236: H323–H330. 112. Falsetti HL, Verani MS, Chen CJ, et al: Regional pressure differences in the left ventricle. Cathet Cardiovasc Diagn 1980;6:123–134. 113. Nikolic SD, Feneley MP, Pajaro OE, et al: Origin of regional pressure gradients in the left ventricle during early diastole. Am J Physiol 1995;268: H550–H557. 114. Firstenberg MS, Smedira NG, Greenberg NL, et al: Relationship between early diastolic intraventricular pressure gradients, an index of elastic recoil, and improvements in systolic and diastolic function. Circulation 2001;104 Suppl 1:I330–I335. 115. Udelson JE, Bacharach SL, Cannon RO III, et al: Minimum left ventricular pressure during beta-adrenergic stimulation in human subjects: Evidence for elastic recoil and diastolic “suction” in the normal heart. Circulation 1990;82:1174–1182. 116. Pasipoularides A, Shu M, Shah A, et al: RV instantaneous intraventricular diastolic pressure and velocity distributions in normal and volume overload awake dog disease models. Am J Physiol Heart Circ Physiol 2003 Nov;285: H1956–1965. Erratum in: Am J Physiol Heart Circ Physiol 2004;287: H2367. 117. Weisfeldt ML, Frederiksen JW, Yin FC, et al: Evidence of incomplete left ventricular relaxation in the dog: Prediction from the time constant for isovolumic pressure fall. J Clin Invest 1978;62:1296–1302.
118. Little WC, Ohno M, Kitzman DW, et al: Determination of left ventricular chamber stiffness from the time for deceleration of early left ventricular filling. Circulation 1995;92:1933–1939. 119. Marino P, Faggian G, Bertolini P, et al: Early mitral deceleration and left atrial stiffness. Am J Physiol Heart Circ Physiol 2004 Sep;287: H1172–H1178. 120. Lisauskas JB, Singh J, Bowman AW et al: Chamber properties from transmitral flow: Prediction of average and passive left ventricular diastolic stiffness. J Appl Physiol 2001;91:154–162. 121. Thomas JD, Popovic ZB: Intraventricular pressure differences: A new window into cardiac function. Circulation 2005;112:1684–1686. 122. Vita JA, Keaney JF Jr, Larson MG, et al: Brachial artery vasodilator function and systemic inflammation in the Framingham Offspring Study. Circulation 2004 Dec 7;110:3604–3609. 123. Hadler NM: A ripe old age. Arch Intern Med 2003;163:1261–1262. 124. Oeppen J, Vaupel JW: Demography: Broken limits to life expectancy. Science 2002;296:1029–1031. 125. Braunwald E: Shattuck lecture. Cardiovascular medicine at the turn of the millennium: Triumphs, concerns, and opportunities. N Engl J Med 1997;337:1360–1369. 126. Rich MW: Heart failure in the 21st century: A cardiogeriatric syndrome. J Gerontol A Biol Sci Med Sci 2001;56:M88–M96. 127. Gottdiener JS, McClelland RL, Marshall R, et al: Outcome of congestive heart failure in elderly persons: Influence of left ventricular systolic function. The Cardiovascular Health Study. Ann Intern Med 2002;137:631–639. 128. Senni M, Tribouilloy CM, Rodeheffer RJ, et al: Congestive heart failure in the community: A study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation 1998;98:2282–2289. 129. Vasan RS, Larson MG, Benjamin EJ, et al: Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: Prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999;33:1948–1955. 130. Kitzman DW, Gardin JM, Gottdiener JS, et al: Cardiovascular Health Study Research Group. Importance of heart failure with preserved systolic function in patients ≥65 years of age. Am J Cardiol 2001;87:413–419. 131. Kelly RV, Tan WA, Cho H, et al: Prevalence of symptomatic diastolic heart failure in patients hospitalized with cerebral or peripheral vascular disease. Congest Heart Fail 2005;11:256–261. 132. Vasan RS, Benjamin EJ, Levy D: Prevalence, clinical features and prognosis of diastolic heart failure: An epidemiologic perspective. J Am Coll Cardiol 1995;26:1565–1574. 133. Smith GL, Masoudi FA, Vaccarino V, et al: Outcomes in heart failure patients with preserved ejection fraction: Mortality, readmission, and functional decline. J Am Coll Cardiol 2003;41:1510–1518. 134. Senni M, Redfield MM: Heart failure with preserved systolic function: A different natural history? J Am Coll Cardiol 2001;38:1277–1282. 135. McAlister FA, Teo KK, Taher M, et al: Insights into the contemporary epidemiology and outpatient management of congestive heart failure. Am Heart J 1999;138:87–94. 136. Kupari M, Lindroos M, Iivanainen AM, et al: Congestive heart failure in old age: Prevalence, mechanisms and 4-year prognosis in the Helsinki Ageing Study. J Intern Med 1997;241:387–394. 137. Jaarsma T, Halfens R, Abu-Saad HH, et al: Quality of life in older patients with systolic and diastolic heart failure. Eur J Heart Fail 1999;1:151– 160. 138. Stevenson LW: Are hemodynamic goals viable in tailoring heart failure therapy? Hemodynamic goals are relevant. Circulation 2006;113: 1020–1027. 139. Le Jemtel TH, Alt EU: Are hemodynamic goals viable in tailoring heart failure therapy? Hemodynamic goals are outdated. Circulation 2006;113:1027–1032. 140. Tsutsui H, Tsuchihashi M, Takeshita A: Mortality and readmission of hospitalized patients with congestive heart failure and preserved versus depressed systolic function. Am J Cardiol 2001;88:530–533. 141. Safar ME: Pulse pressure, arterial stiffness, and cardiovascular risk. Curr Opin Cardiol 2000;15:258–263. 142. Philbin EF, Rocco TA Jr, Lindenmuth NW, et al: Systolic versus diastolic heart failure in community practice: Clinical features, outcomes, and the use of angiotensin-converting enzyme inhibitors. Am J Med 2000;109: 605–613. 143. Safar ME, Thomas F, Blacher J, et al: Metabolic syndrome and agerelated progression of aortic stiffness. J Am Coll Cardiol 2006 Jan 3;47: 72–75. 144. Safar ME: Peripheral pulse pressure, large arteries, and microvessels. Hypertension 2004 Aug;44:121–122.
89
90
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 145. O’Rourke MF, Safar ME: Relationship between aortic stiffening and microvascular disease in brain and kidney: Cause and logic of therapy. Hypertension 2005 Jul;46:200–204. 146. Bell SP, Fabian J, Watkins MW, et al: Decrease in forces responsible for diastolic suction during acute coronary occlusion. Circulation 1997;96: 2348–2352. 147. Courtois M, Kovacs SJ, Ludbrook PA: Physiological early diastolic intraventricular pressure gradient is lost during acute myocardial ischemia. Circulation 1990;81:1688–1696. 148. Rovner A, Smith R, Greenberg NL, et al: Improvement in diastolic intraventricular pressure gradients in patients with HOCM after ethanol septal reduction. Am J Physiol Heart Circ Physiol 2003 Dec;285:H2494– H2499. 149. Nichols WW, O’Rourke MF: McDonald’s blood flow in arteries: Theoretical, experimental and clinical principles, 5th ed. London, Hodder Arnold, 2005. 150. Kelly R, Hayward C, Avolio A, et al: Noninvasive determination of agerelated changes in the human arterial pulse. Circulation 1989;80:1652– 1659. 151. Mitchell GF, Parise H, Benjamin EJ, et al: Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: The Framingham Heart Study. Hypertension 2004 Jun;43:1239– 1245. 152. Asmar R, Rudnichi A, Blacher J, et al: Pulse pressure and aortic pulse wave are markers of cardiovascular risk in hypertensive populations. Am J Hypertens 2001;14:91–97. 153. Miura K, Dyer AR, Greenland P, et al: Chicago Heart Association. Pulse pressure compared with other blood pressure indexes in the prediction of 25-year cardiovascular and all-cause mortality rates: The Chicago Heart Association Detection Project in Industry Study. Hypertension 2001;38: 232–237. 154. Haider AW, Larson MG, Franklin SS, et al. for Framingham Heart Study: Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med 2003;138:10–16. 155. Smulyan H, Asmar RG, Rudnicki A, et al: Comparative effects of aging in men and women on the properties of the arterial tree. J Am Coll Cardiol 2001;37:1374–1380. 156. Gatzka CD, Kingwell BA, Cameron JD, et al: ANBO2 Investigators, Australian comparative outcome trial of angiotensin-converting enzyme inhibitor- and diuretic-based treatment of hypertension in the elderly. Gender differences in the timing of arterial wave reflection beyond differences in body height. J Hypertens 2001;19:2197–2203. 157. Hayward CS, Kelly RP: Gender-related differences in the central arterial pressure waveform. J Am Coll Cardiol 1997;30:1863–1871. 158. Yancy CW, Lopatin M, Stevenson LW, et al: ADHERE Scientific Advisory Committee and Investigators. Clinical presentation, management, and inhospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: A report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol 2006 Jan 3;47:76–84. 159. Maurer MS, King DL, El-Khoury Rumbarger L, et al: Left heart failure with a normal ejection fraction: Identification of different pathophysiologic mechanisms. J Card Fail 2005;11:177–187. 160. Avolio AP, Deng FQ, Li WQ, et al: Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: Comparison between urban and rural communities in China. Circulation 1985;71: 202–210. 161. Kass DA: Age-related changes in ventricular-arterial coupling: Pathophysiologic implications. Heart Fail Rev 2002;7:51–62. 162. Cohen-Solal A, Caviezel B, Laperche T, et al: Effects of aging on left ventricular-arterial coupling in man: Assessment by means of arterial effective and left ventricular elastances. J Hum Hypertens 1996;10:111– 116. 163. Little WC, Cheng CP: Left ventricular-arterial coupling in conscious dogs. Am J Physiol 1991;261:H70–H76. 164. Burkhoff D, de Tombe PP, Hunter WC, et al: Contractile strength and mechanical efficiency of left ventricle are enhanced by physiological afterload. Am J Physiol 1991;260:H569–H578. 165. Van der Velde ET, Burkhoff D, Steendijk P, et al: Nonlinearity and load sensitivity of end-systolic pressure-volume relation of canine left ventricle in vivo. Circulation 1991;83:315–327. 166. Saba PS, Ganau A, Devereux RB, et al: Impact of arterial elastance as a measure of vascular load on left ventricular geometry in hypertension. J Hypertens 1999;17:1007–1015.
167. Saeki A, Recchia F, Kass DA: Systolic flow augmentation in hearts ejecting into a model of stiff aging vasculature: Influence on myocardial perfusiondemand balance. Circ Res 1995;76:132–141. 168. Baicu CF, Zile MR, Aurigemma GP, et al: Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation 2005 May 10;111:2306–2312. 169. Loutzenhiser R, Bidani A, Chilton L: Renal myogenic response: Kinetic attributes and physiological role. Circ Res 2002;90:1316–1324. 170. Mitchell GF, Vita JA, Larson MG, et al: Cross-sectional relations of peripheral microvascular function, cardiovascular disease risk factors, and aortic stiffness: The Framingham Heart Study. Circulation 2005 Dec 13;112:3722–3728. 171. Hoffman JI: A critical view of coronary reserve. Circulation 1987;75: I6–I11. 172. Douglas JE, Greenfield JC Jr: Epicardial coronary artery compliance in the dog. Circ Res 1970;27:921–929. 173. Lakatta EG, Levy D: Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises. Part I. Aging arteries: A “set up” for vascular disease. Circulation 2003;107:139–146. 174. Pauca AL, Wallenhaupt SL, Kon ND, et al: Does radial artery pressure accurately reflect aortic pressure? Chest 1992;102:1193– 1198. 175. Pauca AL, O’Rourke MF, Kon ND: Prospective evaluation of a method for estimating ascending aortic pressure from the radial artery pressure waveform. Hypertension 2001;38:932–937. 176. Laurent S, Katsahian S, Fassot C, et al: Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke 2003 May;34:1203–1206. 177. Safar ME, London GM, Plante GE: Arterial stiffness and kidney function. Hypertension 2004 Feb;43:163–168. 178. Smiseth OA, Thompson CR, Lohavanichbutr K, et al: The pulmonary venous systolic flow pulse: Its origin and relationship to left arterial pressure. J Am Coll Cardiol 1999;34:802–809. 179. Rizzoni D, Porteri E, Boari GE, et al: Prognostic significance of small-artery structure in hypertension. Circulation 2003 Nov 4;108:2230– 2235. 180. Schofield I, Malik R, Izzard A, et al: Vascular structural and functional changes in type 2 diabetes mellitus: Evidence for the roles of abnormal myogenic responsiveness and dyslipidemia. Circulation 2002;106:3037– 3043. 181. Verhave JC, Fesler P, du Cailar G, et al: Elevated pulse pressure is associated with low renal function in elderly patients with isolated systolic hypertension. Hypertension 2005 Apr;45:586–591. 182. Safar ME, Levy BI, Struijker-Boudier H: Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation 2003;107:2864–2869. 183. Apstein CS, Morgan JP: Cellular mechanisms underlying left ventricular diastolic dysfunction. In Gaasch WH, LeWinter MM (eds): Left ventricular diastolic dysfunction and heart failure. Philadelphia, Lea & Febiger, 1994:3–24. 184. Rizzoni D, Palombo C, Porteri E, et al: Relationships between coronary flow vasodilator capacity and small artery remodelling in hypertensive patients. J Hypertens 2003;21:625–631. 185. Goto M, Arakawa M, Suzuki T, et al: A quantitative analysis of reservoir function of the human pulmonary “venous” system for the left ventricle. Jpn Circ J 1986;50:222–231. 186. Hoit BD, Walsh RA: Regional atrial distensibility. Am J Physiol 1992;262: H1356–H1360. 187. Suga H: Importance of atrial compliance in cardiac performance. Circ Res. 1974;35:39–43. 188. Nagano T, Arakawa M, Tanaka T, et al: Diastolic compliance of the left atrium in man: A determinant of preload of the left ventricle. Heart Vessels 1989;5:25–32. 189. Kihara Y, Sasayama S, Miyazaki S, et al: Role of the left atrium in adaptation of the heart to chronic mitral regurgitation in conscious dogs. Circ Res 1988;62:543–553. 190. Davis CA III, Rembert JC, Greenfield JC Jr: Compliance of left atrium with and without left atrium appendage. Am J Physiol 1990;259: H1006–H1008. 191. Basnight MA, Gonzalez MS, Kershenovich SC, et al: Pulmonary venous flow velocity: Relation to hemodynamics, mitral flow velocity and left atrial volume, and ejection fraction. J Am Soc Echocardiogr. 1991;4:547– 558. 192. Little WC, Downes TR: Clinical evaluation of left ventricular diastolic performance. Prog Cardiovasc Dis 1990;32:273–290.
Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 193. Matsuda Y, Toma Y, Matsuzaki M, et al: Change of left atrial systolic pressure waveform in relation to left ventricular end-diastolic pressure. Circulation 1990;82:1659–1667. 194. Simek CL, Feldman MD, Haber HL, et al: Relationship between left ventricular wall thickness and left atrial size: Comparison with other measures of diastolic function. J Am Soc Echocardiogr 1995;8: 37–47. 195. Van Heerebeek L, Borbely A, Niessen HW, et al: Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 2006 Apr 25;113:1966–1973. 196. Skaluba SJ, Litwin SE: Mechanisms of exercise intolerance: Insights from tissue Doppler imaging. Circulation 2004 Mar 2;109:972–977. 197. Katz AM, Zile MR: New molecular mechanism in diastolic heart failure. Circulation 2006;113:1922–1925. 198. Yip G, Wang M, Zhang Y, et al: Left ventricular long axis function in diastolic heart failure is reduced in both diastole and systole: time for a redefinition? Heart 2002;87:121–125.
199. Yu CM, Lin H, Yang H, et al: Progression of systolic abnormalities in patients with “isolated” diastolic heart failure and diastolic dysfunction. Circulation 2002;105:1195–1201. 200. LeWinter MM: Titin isoforms in heart failure: Are there benefits to supersizing? Circulation 2004;110:109–111. 201. Nagueh SF, Shah G, Wu Y, et al: Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation 2004 Jul 13;110:155–162. 202. Konstam MA, Udelson JE, Anand IS, et al: Ventricular remodeling in heart failure: A credible surrogate endpoint. J Card Fail 2003;9:350–353. 203. Udelson JE, Patten RD, Konstam MA: New concepts in post-infarction ventricular remodeling. Rev Cardiovasc Med 2003;4 Suppl 3:S3–S12. 204. Weber KT: Are myocardial fibrosis and diastolic dysfunction reversible in hypertensive heart disease? Congest Heart Fail 2005;11:322–324. 205. Herrmann KL, McCulloch AD, Omens JH: Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy. Am J Physiol Heart Circ Physiol 2003;284:H1277–H1284.
91
SRIKANTH SOLA, MD
8
Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging INTRODUCTION PRINCIPLES OF MAGNETIC RESONANCE IMAGING Physics of Magnetic Resonance Imaging Basic Imaging Sequences CLINICAL RELEVANCE Hypertropic Cardiomyopathy Hypertension and Aortic Stenosis Coronary Artery Disease
Dilated Cardiomyopathy Constrictive Pericarditis Restrictive Cardiomyopathy Cardiac Amyloidosis Cardiac Sarcoidosis Hemochromatosis LIMITATIONS OF CARDIAC MAGNETIC RESONANCE IMAGING FUTURE RESEARCH
INTRODUCTION Recent advances in image acquisition techniques and scanner hardware have allowed magnetic resonance imaging (MRI) to become a useful tool in the noninvasive assessment of cardiovascular diseases. In addition to high-resolution anatomical images, cardiovascular magnetic resonance (CMR) provides quantitative assessment of ventricular function, myocardial perfusion, viability, and shunt flow and measurements of valvular velocities and gradients.1–3 In addition, coronary, pulmonary, and systemic vasculatures can be assessed with contrast-enhanced magnetic resonance angiography (MRA) without the use of ionizing radiation or nephrotoxic contrast agents. CMR’s comprehensive ability to image the heart also makes it a useful tool in the evaluation of diastolic function.
PRINCIPLES OF MAGNETIC RESONANCE IMAGING Physics of Magnetic Resonance Imaging All atoms have nuclei that are composed of one or more protons. These protons have a small positive electric charge and spin at a rapid rate. The rapid spinning motion of a positively charged proton produces a very small but measurable magnetic field that in a sense is like a tiny bar magnet. Normally, the magnetic fields of these protons are randomly oriented throughout the body. When placed within an MRI scanner, the protons within the body will align themselves with the external magnetic field of the scanner, just like a compass would align itself with Earth’s magnetic field. By applying specific radiofrequency (RF) waves, some of these protons will change their alignment (“resonate”) to a more 93
Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging
RV LV
RV LV
LV Liver
Liver
Liver
A
C
B
Basic Imaging Sequences MRI depends on using gradient coils within the scanner to send RF pulses in specific patterns to stimulate the 1H protons within the body. As these protons relax, they emit signals that are detected by receiver coils placed over the surface of the body. Pulse sequences are combinations of different types of RF pulses that are placed together to create images with specific characteristics. Combinations of different pulse sequences can be used to evaluate parameters that define both global and regional diastolic functions. These parameters include: flow mapping of the mitral valve, pulmonary vein, and tricuspid valve; global and regional rotation; translation and radial motion; peak filling rate (PFR) and timeto-peak filling rate (TPFR) of contrast; and phosphorus-31 magnetic resonance (31P-MR) spectroscopy to measure myocardial energy content. The most common types of pulse sequences relevant to diastolic function are the following.
Spin Echo or “Black Blood” Images These pulse sequences are designed so that flowing blood produces no signal and appears black (Fig. 8-1A). However, because of the time required to stimulate and then saturate the signal emitted from the flowing blood, spin echo pulse sequences produce still images. Spin echo sequences can be “weighted” to highlight different relaxation properties of the protons, resulting in T1 (T1w) or T2 (T2w) weighted images. Although spin echo sequences are not used specifically to evaluate cardiac diastolic function, they do provide good tissue contrast and anatomical detail, making them useful for visualizing morphology.
A
140
MVC
AVC
AVO
excited state. As these protons relax and return to their original alignment, they give off an RF signal that can be measured and used to generate a clinical image. Since hydrogen (1H) is the most abundant atom in the body capable of generating a clinically useful image, 1H protons form the basis of clinical MRI.
MVO
Figure 8-1 Hypertrophic obstructive cardiomyopathy. A, Short axis spin echo image. Moving blood is black, whereas myocardium and fat have intermediate and high signal intensities, respectively. Note the prominent interventricular septum (arrow). The right ventricle is not well seen on this image. B, GRE still-frame image at the same level. Blood is bright (white) on this image. C, DE-MRI image at the same level. Note the area of hyperenhanced (bright) myocardium in the inferoseptal wall (arrow) near the right ventricular (RV) insertion point, which represents scarred or fibrotic tissue. LV, left ventricle.
B
C
D
E
F
130 LV cavity volume (ml)
94
120 110 100 90 80 70 60 50 0
100
200
300
400
500
600
700
Time (msec) A: Ejection B: Isovolumic relaxation C: Early filling D: Diastasis E: Atrial contraction F : Isovolumic contraction Figure 8-2 Volume-time curve of the left ventricle during the cardiac cycle in a 27-year-old healthy volunteer. Cine MRI, using a GrE (balanced steadystate-free precession) technique, was used to generate a stack of short axis images encompassing the left ventricle. Planimetry of the left ventricular (LV) endocardial border of each short axis image creates a time-volume curve. The onset of ejection (A), characterized by decrease in LV volume, coincides with aortic valve opening (AVO). At aortic valve closure (AVC), the minimal LV volume is obtained. The difference in volume between AVO and AVC represents the stroke volume (SV). The time period between AVC and mitral valve opening (MVO) is the isovolumic relaxation (B). At the moment of MVO, ventricular filling starts. This is characterized by an early, fast-filling phase (C), a period with nearly no filling (diastasis, D), and a final phase of filling caused by atrial contraction (E). The last part (i.e., isovolumic contraction) starts with mitral valve closure (MVC) and ends with AVO. (From Bogaert J: Cardiac function. In Bogaert J et al (eds): Clinical Cardiac MRI. Springer-Verlag, 2005:99–141.)
Gradient Echo or “White Blood” Images These pulse sequences are fast enough to “catch” the signal coming from excited blood so that blood appears white (Fig. 8-1B). Gradient echo (GRE) sequences produce cine images with good temporal resolution (typically 20–30 fps; up to 70 fps for perfusion imaging). GRE sequences are used for evaluating cardiac function as well as turbulent flow due to valvular disease or intracardiac shunts.
GRE sequences yield accurate and highly reproducible measurements of ventricular volumes and indices of cardiac systolic function without the need for geometric assumptions.4,5 From the contours describing the endocardial and epicardial borders of the myocardium, time-volume curves can be derived that assess global diastolic function (Fig. 8-2). The peak filling rate (PFR) from
Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging these curves describes the maximum change in cm2 per second during the rapid filling phase of ventricular systole, whereas time to PFR is measured between end systole and the point at which PFR occurs. Both PFR and time to PFR are typically prolonged when diastolic function is impaired.6,7
Phase Velocity or Phase Contrast Imaging As hydrogen nuclei move through a magnetic field, they shift their particular phase (the manner in which protons rotate about a particular axis) in a way that is proportional to their velocity. Phase-contrast MRI (PC-MRI), which is somewhat analogous to pulsed-wave Doppler echocardiography, takes advantage of this change in phase with velocity to measure the velocity of blood moving through an area of interest. Clinically, PC-MRI is used to calculate transvalvular velocities as well as gradients, regurgitant volumes, and ratios of pulmonary-to-systemic blood flows (Qp/Qs). Flow mapping of mitral and tricuspid valve inflow
95
using PC-MRI allows accurate assessment of peak velocities and volume flow of early (E) and late or atrial (A) filling waves (Fig. 8-3), showing good correlation with Doppler-derived data.8–10 Similar techniques are also used to map pulmonary and caval venous flow (Fig. 8-4).11 More recently, PC-MRI measurements of tissue velocities have been used to quantify myocardial velocities, enabling calculation of local strain. Strain rate can also be quantified for regions of myocardium as well as for each myocardial voxel.12
Myocardial Tagging A unique feature of CMR is that it allows the myocardium to be magnetically labeled with a rectangular or radial grid that acts as a marker of myocardial deformation during contraction (Fig. 8-5) and also shows abnormal myocardial tagging. The creation of tags requires the application of specific RF pre-pulses in one or more planes perpendicular to the imaging plane, prior to the application 30
35 E
25
30 20
20
Velocity cm/sec
Velocity cm/sec
25 A
15 10
15
S
D
10 5 0
5
–5
0
–10
A
–15
–5 0
100
200
300
400
500
600
85 170 255 340 425 510 595 680 765 850 935 Time (msec)
A
Time (msec)
A
0
700 30
25
A 25 20 Velocity cm/sec
Velocity cm/sec
20 15 10 E 5
D 15 S 10 5 0 A –5
0
–10 0 0
B
100
200
300
400
500
600
700
Time (msec)
Figure 8-3 A, Mitral inflow pattern using PC-MRI in a 24-year-old healthy subject, depicting normal E/A ratio. B, Severe myocardial relaxation disturbance leading to reversal of the E/A ratio. The early filling velocities are strongly decreased (E), whereas the late-filling velocities are increased (A). (From Bogaert J: Cardiac Function. In Bogaert J et al (eds): Clinical Cardiac MRI. Springer-Verlag, 2005:99–141.)
B
85 170 255 340 425 510 595 680 765 850 935 Time (msec)
Figure 8-4 Venous flow patterns using PC-MRI in a 39-year-old healthy subject through the inferior vena cava (A) and pulmonary vein (B). In the inferior vena cava, the systolic (S) forward-flow velocity is slightly larger than the diastolic (D) flow. Line A represents the reversed flow caused by atrial contraction. In the pulmonary vein (B), diastolic forward-flow velocities slightly exceed systolic forward-flow velocities. (From Bogaert J: Cardiac Function. In Bogaert J et al (eds): Clinical Cardiac MRI. Springer-Verlag, 2005:99–141.)
96
Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging of RF pulses that are used for cine (bright blood) imaging.13 The tagging pre-pulses cause the tissue in the tag planes to be “saturated” so that they appear as hypointense or black lines compared with the normal surrounding tissue. By measuring tag displacement and deformation during the cardiac cycle, myocardial deformation can be analyzed, which serves as the basis for strain and strain rate analysis using CMR (Fig. 8-6).14–16 Images can be obtained every 20 msec, allowing very high temporal resolution.17 Clinically, myocardial tagging is used in the evaluation of diastolic function, of abnormal myocardial deformation in patients with hypertrophic cardiomyopathy (HCM) or complex congenital heart disease, and of pericardial motion in patients with suspected constrictive pericarditis and in the differentiation of solid structures (e.g., muscular tissue from tumor or thrombus).18–20 Different myocardial tagging techniques are currently available that allow
RV
LV
B
A
Delayed Hyperenhancement In areas where the myocardium is scarred or fibrotic, there is delayed “wash-in” and “wash-out” of MRI contrast agents. These fibrotic or scarred areas show up as bright or “hyperenhanced” areas of myocardium when “delayed” images are taken, typically 10–15 minutes after injection of gadolinium-DTPA (diethylenetriamine penta-acetic acid) (see Fig. 8-1C). A special inversion signal given prior to the main pulse sequence is used to “null” the signal from the normal myocardium so that it can be more easily distinguished from abnormal, hyperenhanced myocardium. Specific patterns of hyperenhancement correspond with certain cardiovascular diseases and can be used to distinguish ischemic from non-ischemic cardiomyopathy, as well as to differentiate among different forms of infiltrative cardiomyopathies (Fig. 8-7).
Magnetic Resonance Spectroscopy
RV LV
evaluation of myocardial deformation in both two-dimensions and three-dimensions.21
Figure 8-5 Myocardial tagging in a healthy individual demonstrating normal patterns of myocardial deformation between end diastole (A) and end systole (B).
Besides 1H, other magnetic nuclei in the human body, such as 23 Na, 13C, 19F, and 31P, can also generate MRI signals, though normally with much less intensity and under much more technically demanding conditions. 31P-MR spectroscopy provides a profile of regional adenosine triphosphate (ATP) and phosphocreatine (PCr) contents and thus an estimate of energy status and viability A-wave (SRA) E-wave (SRE)
E-wave (SRE)
A-wave (SRA)
1.5
1.5 Strain rate (1/sec)
Strain rate (1/sec)
1.0 1.0 0.5 0 –0.5
0.5 0 –0.5 –1.0
–1.0
–1.5
Peak systolic strain rate (SRS)
Peak systolic strain rate (SRS)
5
5 0 Strain (%)
Strain (%)
0 –5 –10
–10 –15
–15
–20
–20 0
A
–5
200
400
600 Time (msec)
800
1000
0
1200
B
200
400
600
800
1000
1200
Time (msec)
Figure 8-6 A, Representative strain rate (upper) and strain (lower) profiles from a healthy subject. Profiles were measured using tagged GrE images from the anterior wall segment of a short axis slice at a midventricular level. The markers on the strain and strain rate traces represent the time resolution (54 msec). B, Strain rate (upper) and strain (lower) from a person with left ventricular hypertrophy. Note the depressed SRE lower than 1.0 s−1 and the intact systolic function. (From Edvardsen T et al: Regional diastolic dysfunction in individuals with left ventricular hypertrophy measured by tagged magnetic resonance imaging—the Multi-Ethnic Study of Atherosclerosis (MESA). Am Heart J 2006;151:109–114.)
Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging HYPERENHANCEMENT PATTERNS Ischemic
A. Subendocardial infarct
Non-ischemic
A. Mid-wall HE
• Idiopathic dilated • Hypertrophic cardiomyopathy cardiomyopathy • Myocarditis • Right ventricular pressure overload (e.g. congenital heart disease, pulmonary HTN)
• Sarcoidosis • Myocarditis • Anderson-Fabry • Chagas disease
B. Epicardial HE B. Transmural infarct
• Sarcoidosis, myocarditis, Anderson-Fabry, Chagas disease
C. Global endocardial HE Figure 8-7 Hyperenhancement (HE) patterns seen in common clinical conditions. If hyperenhancement is present, the endocardium should be involved in patients with ischemic disease. Isolated midwall or epicardial hyperenhancement strongly suggests a non-ischemic etiology. (From Shah et al, in Edelman RR et al (eds): Clinical Magnetic Resonance Imaging, 3rd ed. Elsevier, 2005.)
of the myocardium.22 Myocardial relaxation is an active, energydependent process, and changes in the ratio of myocardial PCr and ATP levels (PCr/ATP) by 31P-MR spectroscopy are seen in abnormal diastolic function.23 On a cellular level, these abnormalities in PCr/ATP ratios are thought to result in impaired Ca2+ sequestration, leading to impaired relaxation in cardiac myocytes.
CLINICAL RELEVANCE This section reviews the role of CMR in evaluating diastolic function in a spectrum of cardiac disorders, including HCM, ischemic heart disease, constrictive pericarditis, and restrictive cardiomyopathies.
Hypertrophic Cardiomyopathy The characteristic finding of HCM is an inappropriate myocardial hypertrophy in the absence of an obvious cause, such as aortic stenosis or hypertension. Although transthoracic echocardiography is the primary imaging modality in HCM, CMR is an excellent alternative in the diagnosis and follow-up of patients. The array of MRI sequences used in the evaluation of HCM includes spin echo MRI, GRE MRI, PC-MRI, MRI tagging, delayed enhancement (DE), and MR spectroscopy. A combination of these sequences is used to identify the presence and severity of
• Amyloidosis, systemic sclerosis, post cardiac transplantation
hypertrophied myocardium,24–26 to distinguish different forms of HCM,27,28 to differentiate obstructive from nonobstructive forms of the disease,29 and to define prognosis.30,31 Diastolic dysfunction is thought to be one of the major pathophysiological mechanisms in patients with HCM,32 frequently leading to diastolic heart failure. These diagnostic abnormalities can be evaluated using cine tagging, DE, PC-MRI, and MRI spectroscopy sequences. The effect of myocardial hypertrophy on regional and global left ventricular (LV) and right ventricular (RV) function can be precisely characterized by MRI. Global systolic function in HCM is often increased with high ejection fractions and low end systolic volumes. In the hypertrophied myocardium, however, cine tagging sequences demonstrate reduced or absent systolic wall thickening, which is related to muscle disorganization (Fig. 8-8).33 Strain analysis in these same regions show that systolic myocardial strains are invariably decreased, with reduced longitudinal and circumferential shortening.34,35 Three-dimensional CMR tagging demonstrates specific patterns of myocardial deformation among the different forms of HCM, although all forms have abnormally small circumferential curvatures in hypertrophied segments.36,37 Abnormal DE of the myocardium after imaging by gadolinium-DTPA is found in approximately 80% of patients with HCM.38,39 Invariably, the enhancement occurs in the hypertrophied regions, with a mean volume of enhancement of 8% to 11% of LV mass. The pattern of enhancement is usually patchy
97
98
Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging data demonstrate a delay and prolongation of diastolic untwisting, as well as a reduction in regional strain in patients with LV hypertrophy in comparison with normals.48,49 RV LV
A
Coronary Artery Disease
B
Figure 8-8 Abnormal myocardial deformation in hypertrophied myocardium in patients with hypertrophic cardiomyopathy. Short axis view of the heart during diastole (A) and systole (B). Note the decreased pattern of deformation in the hypertrophied anteroseptal wall of the left ventricle (arrow) compared with the normal surrounding areas of myocardium during systole.
with multiple foci, predominantly involving the middle third of the ventricular wall, especially near the insertion points of the RV free walls onto the interventricular septum (see Fig. 8-1C).37 This pattern of enhancement is distinct from the predominantly subendocardial distribution of hyperenhancement seen in patients with coronary artery disease. Histologically, these abnormally enhanced areas of myocardium are thought to represent scarred myocardium due to microinfarction or are in relation to myocardial disarray and consequent interstitial expansion.40 In a highly select group of patients with HCM, the degree of myocardial enhancement was associated with progressive disease and increased risk for sudden cardiac death.36 It has been proposed that the degree of diastolic dysfunction is linked to the extent of myocardial fibrosis quantified by DE-MRI.41 Impaired myocardial relaxation can be identified using GRE-derived time-volume curves of the left ventricle, which demonstrate prolonged time-to-peak rapid filling and time-to-peak wall thickness thinning rates. In 31 patients with HCM, regional prolongation of time-to-peak wall thinning rate was detected in segments with extensive myocardial fibrosis and decreased perfusion.42 Other MRI techniques, such as 31P-MR spectroscopy, demonstrate abnormal myocardial high-energy phosphate metabolites in both symptomatic43 and asymptomatic patients44 with HCM. Lower myocardial energy content is thought to contribute to relaxation abnormalities in hypertrophied hearts. Finally, PCMRI of flow patterns in the caval and pulmonary veins, as well as the diastolic inflow in the tricuspid/mitral valves, can be used to evaluate diastolic function, similar to echocardiography.
Resting impairment of diastolic function is common in ischemic heart disease. Such diastolic dysfunction precedes systolic dysfunction and occurs as the earliest sign of myocardial ischemia. Diastolic filling patterns in ischemic heart disease are often complex, reflecting regional heterogeneity of myocardial function due to different degrees of ischemia, infarction, postinfarction remodeling, and myocardial stunning and hibernation. Three-dimensional tagging by CMR is well suited to assess these regional changes in diastolic function. In a model of postinfarction LV remodeling, a reduction of regional strains was observed in both the infarcted region and, to a lesser extent, the remote regions.50 Diastolic untwisting tended to be nonuniform, delayed, and prolonged in areas of both infarcted and hibernating myocardium.51 Similar changes were seen in an animal model of transmural ischemia,52 with restoration of the normal untwisting motion after reperfusion. PC-MRI can be used to evaluate regional diastolic function by quantifying tissue velocities in patients with previous myocardial infarction. PC-MRI measurements of mitral valve inflow after myocardial infarction demonstrate the typical changes in transvalvular flow patterns and closely correlate with Doppler echocardiography.53
Dilated Cardiomyopathy While the diagnosis of dilated cardiomyopathy can be easily made with transthoracic echocardiography, CMR can provide a comprehensive evaluation of cardiac function, myocardial stress perfusion, and viability. CMR has been shown to reliably discriminate between ischemic and non-ischemic causes of cardiomyopathy, and CMR remains the gold standard for the evaluation of LV and RV volumes, masses, ejection fractions, and viabilities.54,55 Diastolic dysfunction is common in dilated cardiomyopathy, and its severity is related to prognosis. The same CMR techniques previously described can be used for the comprehensive evaluation of both systolic and diastolic function in these patients— GRE-based time-volume curves for analysis of global diastolic function; PC-MRI to determine inflow curves as well as tissue velocities; myocardial tagging to evaluate strain and, more recently, ventricular dyssynchrony; and 31P-MR spectroscopy to determine PCr/ATP ratios as a measure of myocardial energy content.
Hypertension and Aortic Stenosis Chronic pressure overload in systemic hypertension and aortic stenosis leads to hypertrophy of the left ventricle, with the addition of new sarcomeres in parallel to existing ones to normalize wall tension.45 Hypertrophy, coupled with a variable degree of altered passive elastic properties of the myocardium, leads to diastolic dysfunction. In LV hypertrophy, changes in ventricular time-volume curves, including prolonged TPFR, early-to-late filling ratio, and early filling percentage measured from GRE sequences, can be demonstrated before changes in the classical mitral Doppler pattern.46 Other early changes include a decreased PCr/ATP ratio on 31P-MR spectroscopy, even before the development of evident LV hypertrophy.22 Later in hypertrophy, PCMRI demonstrates typical changes in mitral valve inflow that are similar to the classical mitral Doppler patterns.47 CMR-tagged
Constrictive Pericarditis The pericardium is well characterized by CMR because of its excellent contrast resolution and multiplanar imaging capability. Typically, T1- and T2-weighted spin echo, GRE, and tagged cine sequences are used in patients with suspected pericardial disease to evaluate cardiac function and morphology, pericardial thickness and tethering, and the presence of ventricular interdependence. In patients with acute pericarditis, T2-weighted spin echo or DE images after administration of gadolinium-DTPA can be used to detect pericardial inflammation and edema.56 On T1-weighted spin echo images, the normal pericardium is most easily identified over the right ventricle and appears as a thin band of low signal intensity between the high signal intensities of the external pericardial fat and the internal epicardial fat
Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging (Fig. 8-9). The low signal intensity of the pericardium on CMR images is attributable to the fibrous, low proton density component of the pericardium in combination with a small quantity of pericardial fluid.57 The normal pericardial thickness is approximately 2 mm, although thicknesses of up to 4 mm are not necessarily abnormal. The appearance of pericardial effusions may vary depending on the protein and cellular content of the effusion; transudative pericardial effusions appear dark on T1-weighted spin echo images and bright on T2-weighted images due to their high water content. Exudative effusions, which have relatively lower water content, have the opposite appearance.58 In patients with pericardial effusions, GRE sequences are useful to distinguish the pericardium from pericardial fluid. The latter typically has a bright appearance on GRE sequences. Characteristic findings of constrictive pericarditis by CMR are described in Box 8-1. The classical CMR finding in patients with constrictive pericarditis is tethering or adhesion of the parietal pericardium to the visceral pericardium/epicardial surfaces.59 This finding is best appreciated on cine tagged sequences and differs markedly from the normal free sliding motion of the parietal pericardium over the visceral pericardium/epicardium in normal individuals (Fig. 8-10). Other techniques, such as freebreathing cine GRE sequences, can be used to evaluate ventricular interdependence. In patients with constrictive pericarditis, the interventricular septum can be seen to shift toward the left ventricle during inspiration, whereas the opposite motion occurs with expiration. The characteristic septal shift is often most prominent on the first heart beat that follows the beginning of inspiration. PC-MRI, while useful for evaluating flow patterns across the cavae and atrioventricular valves, is less useful in evaluating peri-
cardial constriction due to its inability to differentiate respiratory changes in flow patterns. Although a normal-thickness pericardium does not necessarily exclude constriction,60 irregular thickening of the pericardium is seen in up to 80% of individuals with constrictive pericarditis. A pericardial thickness of 5–6 mm has a high specificity for constrictive pericarditis. Pericardial thickening is often not generalized, and focal pericardial thickening in strategic locations such as the atrioventricular grooves can give rise to a full clinical picture of constrictive pericarditis even when the morphological abnormalities are not that impressive. In patients with extensive fibrosis or calcification, the pericardium will have low signal intensity (black) on T1-weighted and T2-weighted spin echo images. However, the extent of pericardial calcification or fibrosis is often better depicted by computed tomography, due to the signal loss of calcified tissues by MRI.
Restrictive Cardiomyopathy Diastolic dysfunction and restrictive filling patterns are common to all of the restrictive cardiomyopathies. By CMR, the abnormal diastolic function is evident on cine tagged images, PC-MRI, ventricular time-volume curves, and 31P-MR spectroscopy using the techniques we have described. Although it is often not feasible to differentiate among different restrictive cardiomyopathies on Box 8-1
Characteristic Findings of Constrictive Pericarditis by Cardiovascular Magnetic Resonance (CMR) • • • • • • •
A
B
Figure 8-9 Normal pericardium in a healthy individual, four-chamber view. A, The pericardium appears as a thin band of low signal intensity (black) on a spin echo image. B, The pericardium appears as a band of intermediate signal intensity (grey) on a GRE image.
• • • •
Pericardial tethering Pericardial calcification Increased pericardial thickness (>4 mm) Tubular or conical narrowing of one or both ventricles Enlargement of one or both atria Dilatation of the vena cava and hepatic vein Abnormal flow across the vena cava and atrioventricular valves on phase-contrast sequences of magnetic resonance imaging Diastolic restraint Abnormal diastolic motion Pericardial effusion (in patients with effusive-constrictive pericarditis) Pleural effusion
RV LV RA LA
A
B
C
Figure 8-10 Characteristic CMR findings in a patient with constrictive pericarditis. A, Four-chamber GRE image depicting the common tubular-shaped deformity of the ventricles and atrial dilatation. Note the thickened fibrous pericardium over the right ventricular free wall (arrows) and the darker area of calcified pericardium over the lateral wall of the left ventricle (arrowheads). B, C, Diastolic and systolic still frame from cine tagged four-chamber images shows the characteristic tethering of the pericardium to the epicardial surface during diastole. RV, right ventricle. RA, right atrium. LV, left ventricle. LA, left atrium.
99
100
Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging the basis of diastolic filling patterns alone, CMR can help to identify the etiology of restrictive cardiomyopathy based on its functional and morphological characteristics.
Cardiac Amyloidosis Cardiac involvement is common in certain forms of systemic amyloidosis and is a major determinant of treatment options and prognosis. Several CMR findings have been described in cardiac amyloidosis, but the most characteristic feature of this disorder is a diffuse pattern of hyperenhancment on DE-MRI images that occurs in a noncoronary distribution (Fig. 8-11). Maceira et al. evaluated 29 patients by CMR who had biopsy-proven systemic amyloidosis and were considered to have cardiac amyloidosis on the basis of the presence of morphological and diastolic filling changes on echocardiography. They found a global subendocardial pattern of hyperenhancment in 20 of the 29 patients (69%) by CMR.61 In addition, the distribution of gadolinium-DTPA within both the myocardium and the LV blood pool was abnormally prolonged, with a modest correlation between T1 relaxation times of gadolinium-DTPA and diastolic function (r = −0.42, p = 0.025). Morphologically, the infiltration by amyloid protein results in a homogeneously increased thickness of ventricular and atrial walls, with occasional involvement of the papillary muscles and valve leaflets. Ventricular cavity size is usually normal or decreased, but the atria are usually enlarged due to the diastolic dysfunction, valvular dysfunction from amyloid deposition, or both. Approximately 5% to 15% of patients develop asymmetric septal hypertrophy in combination with a systolic anterior motion of the mitral valve in a pattern that may mimic HCM.62 Pleural and pericardial effusions are not infrequent. Systolic function is usually preserved or mildly impaired until late in the disease.
Cardiac Sarcoidosis Myocardial involvement of sarcoidosis is present at autopsy in 20% to 30% of patients with this disease, although clinical involvement is evident in only 5%. GRE sequences may demonstrate normal or impaired LV systolic function, often with regional wall motion abnormalities, depending on the degree of sarcoid involvement of the heart. In the early stages of sarcoidosis, the myocardium may demonstrate patchy areas of high signal intensity on T2-weighted black blood images due to localized inflammation, along with focal, patchy areas of hyperenhancement (i.e. bright) that occur in a noncoronary distribution. The latter corresponds to areas of noncaseating granulomas that are the typical histological findings of sarcoidosis. These areas of hyperenhancement are also seen in more chronic cases of cardiac sarcoidosis, along with ventricular wall thinning and aneurysms, most commonly along the basal anteroseptal wall (Fig. 8-12).
Hemochromatosis Initially, myocardial iron overload in patients with primary or secondary hemochromatosis is asymptomatic. There is a mild increase in LV wall thickness and end diastolic chamber diameter. Diastolic dysfunction usually precedes systolic dysfunction and is characterized by a restrictive filling pattern.63,64 Global systolic abnormalities do not occur until the iron concentration reaches a critical level, but then there is often a rapid deterioration in systolic function. At the time of diagnosis, these patients typically have a dilated cardiomyopathy on GRE sequences, as well as evidence of abnormal myocardial deformation on cine tagged images. In addition, both the myocardium and the liver appear dark on T2-weighted spin echo sequences due to loss of signal as a result of iron accumulation in these tissues (Fig. 8-13).
LIMITATIONS OF CARDIAC MAGNETIC RESONANCE IMAGING
RV RA LV LA
Figure 8-11 Four-chamber delayed hyperenhancement image in a patient with amyloidosis. The diffuse pattern of hyperenhancement in the left ventricle is characteristic of amyloidosis and distinguishes this condition from other causes of hyperenhancement, such as ischemic heart disease, hypertrophic cardiomyopathy, and sarcoidosis.
Despite its increasing robustness, important limitations still remain in CMR imaging. The electromagnetic forces created by the MRI scanner can induce important thermal and nonthermal effects in some patients. Therefore, the presence of contraindications to MRI must be identified before the patient enters the scanner (Table 8-1). Pacemakers and defibrillators are increasingly common in the cardiac population, although these devices should pose less of a hazard as experience in CMR imaging of these patients increases and new, MRI-compatible devices become available. Nonferromagnetic metallic devices, such as mechanical heart valves, sternal wires, and retained (nonlooped) pacing wires after cardiac surgery, are safe to image, although they are often a source of image artifact. Patient cooperation is critical to successful cardiac imaging. Patient movement during image acquisition can result in degraded image quality, and uncooperative patients may require oral or intravenous sedation to prevent unwanted motion artifacts. Multiple breath holds of 10–15 seconds each are often utilized in adults to limit cardiac motion caused by respiration. Children and adult patients who are unable to hold their breaths can still be imaged successfully, although acquisition times are often increased to preserve image quality. As previously noted, clinically available PC-MRI sequences are unable to distinguish respiratory variation in flow patterns across the systemic veins or atrioventricular
Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging
LV
LV
B
A
Figure 8-12 Two-chamber (A) and midventricular short axis (B) delayed hyperenhancement images of a patient with cardiac sarcoidosis. Note the typical patchy pattern of hyperenhancement that occurs in a noncoronary distribution. Cine GrE images (not shown) demonstrated reduced systolic function with regional wall motion abnormalities.
RV
LV
RV LV
Figure 8-13 Secondary hemochromatosis in a patient with iron overload due to recurrent blood transfusions for hereditary anemia. A, Short axis GrE image demonstrates the characteristic low signal over the liver due to accumulation of iron particles. B, Axial T2-weighted spin echo image demonstrates the abnormally low signal intensity of the myocardium due to iron accumulation within myocardial tissue.
RA LA
Liver
A
B
TABLE 8-1 CONTRAINDICATIONS TO MAGNETIC RESONANCE IMAGING (MRI) CONCERN ABSOLUTE CONTRAINDICATIONS Cerebral aneurysm clips Implanted neural stimulator; cochlear implant; implanted insulin or other drug pump Cardiac pacemaker or defibrillator
Ocular foreign body; metal shrapnel or bullet fragment Temporary pacemaker wires or pulmonary artery catheters RELATIVE CONTRAINDICATIONS Hearing aids Pregnancy Claustrophobia
May become displaced by the strong external magnetic field of the scanner, causing severe local injury. Aneurysm clips that are “nonferromagnetic” or “weakly ferromagnetic” are safe to image. Most implantable devices employ a strong internal magnet or electronic circuitry that can be damaged by the strong external magnetic field of the scanner. Pacemakers/defibrillators are important contraindications to MRI due to the potential for device malfunction. Small studies suggest that some non–pacer-dependent patients with pacemakers can be imaged, although the devices must be interrogated and potentially reprogrammed before and after imaging. MRIcompatible devices are in development. Metallic foreign objects within the body can become displaced by the strong external magnetic field of the scanner, causing severe local tissue injury. Wires and catheters contain metallic tips that may become heated during MRI, causing local tissue damage. Same concerns as cochlear implants; must be removed prior to entering the scanner. Considerable evidence suggests that exposure to MRI is safe. However, exposure during the first trimester, particularly to MRI contrast agents, should be avoided. Some claustrophobic patients may have difficulty within the confines of an MRI scanner. Oral anxiolytics (e.g., alprazolam) may be useful in such patients.
101
102
Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging valves. Arrhythmias are problematic due to image degradation and make velocity assessment and flow quantification by PCMRI unreliable.
FUTURE RESEARCH Several exciting applications in CMR are under development, including real-time sequences that allow comprehensive, highresolution images of the heart without the need for breath holding, as well as real-time PC-MRI evaluation of flow. Other applications include improved software analytical tools for tagged cine MRI sequences, allowing for easier quantification of strain and strain rate data. Newer therapeutic applications are also being developed, which include specific MRI-compatible catheters for electrophysiology studies/ablation, as well as interventional cardiology-related procedures, which may change the way that interventional cardiology procedures are practiced in the future. REFERENCES 1. Lima JA, Desai M: Cardiovascular magnetic resonance imaging: Current and emerging applications. J Am Coll Cardiol 2004;44:1164–1171. 2. Pennell DJ, Sechtem UP, Higgins CB, et al: Clinical indications for cardiovascular magnetic resonance (CMR): Consensus Panel report. Eur J Cardiol 2004;25:1940–1965. 3. Hundley W, Gregory L, Hong F, et al: Assessment of left-to-right intracardiac shunting by velocity-encoded, phase-difference magnetic resonance imaging: A comparison with oximetric and indicator dilution techniques. Circulation 1995;91:2955–2960. 4. Grothues F, Smith GC, Moon JCC, et al: Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol 2002;90:29–34. 5. Pujadas S, Reddy GP, Weber O, et al: Imaging assessment of cardiac function. J Magn Reson Imaging 2004;19:789–799. 6. Suzuki JI, Caputo GR, Masui T, et al: Assessment of right ventricular diastolic and systolic function in patients with dilated cardiomyopathy using cine magnetic resonance imaging. Am Heart J 1991;122:1035–1040. 7. Fujita N, Hartiala J, O’Sullivan M, et al: Assessment of left ventricular diastolic function in dilated cardiomyopathy with cine magnetic resonance imaging: Effect of an angiotensin converting enzyme inhibitor, benazepril. Am Heart J 1993;125:171–178. 8. Hartiala JJ, Mostbeck GH, Foster E, et al: Velocity-encoded cine MRI in the evaluation of left ventricular diastolic function. Measurement of mitral valve and pulmonary vein flow velocity and flow volume across the mitral valve. Am Heart J 1993;125:1056–1066. 9. Kayser HWM, Stoel BC, van der Wall EE, et al: MR velocity mapping of tricuspid flow: Correction for through-plane motion. J Magn Reson Imaging 1997;7:669–673. 10. Mohiaddin RH, Gatehouse PD, Henien M, et al: Cine MR Fourier velocimetry of blood flow through cardiac valves: Comparison with Doppler echocardiography. J Magn Reson Imaging 1997;7:657–663. 11. White RD, Hardy PA, Van Dyke CE, et al: Diastolic dysfunction: Dynamic MRI velocity-mapping of related flow pattern in the superior vena cava. J Magn Reson Imaging 1993;3:65. 12. Wedeen VJ: Magnetic resonance imaging of myocardial kinematics: Technique to detect, localize, and quantify strain rates of the active human myocardium. Magn Reson Med 1992;27:52–67. 13. Zerhouni EA, Parish DM, Rogers WJ, et al: Human heart: Tagging with MR imaging—a new method for noninvasive assessment of myocardial motion. Radiology 1988;169:59–63. 14. Edvardsen T, Rosen BD, Pan L, et al: Regional diastolic dysfunction in individuals with left ventricular hypertrophy measured by tagged magnetic resonance imaging: The Multi-Ethnic Study of Atherosclerosis (MESA). Am Heart J 2006;151:109–114. 15. Young AA, Axel L: Three-dimensional motion and deformation of the heart wall: Estimation with spatial modulation of magnetization—a model-based approach. Radiology 1992;185:241–247. 16. Young AA, Axel L, Dougherty L, et al: Validation of tagging with MR imaging to estimate material deformation. Radiology 1993;188:101–108.
17. Fischer SE, McKinnon GC, Scheidegger MB, et al: True myocardial motion tracking. Magn Reson Med 1994;31:401–1413. 18. Hatabu H, Gefter WB, Axel L: MR imaging with spatial modulation of magnetization in the evaluation of chronic central pulmonary thromboemboli. Radiology 1994;190:791–796. 19. Naito H, Arisawa J, Harada K, et al: Assessment of right ventricular regional contraction and comparison with the left ventricle in normal humans: A cine magnetic resonance study with presaturation myocardial tagging. Br Heart J 1995;74:186–191. 20. Kojima S, Yamada N, Goto Y: Diagnosis of constrictive pericarditis by tagged cine magnetic resonance imaging. N Engl J Med 1999;341: 373–374. 21. Ryf S, Spiegel MA, Gerber M, Boesiger P: Myocardial tagging with 3DCSPAMM. J Magn Reson Imaging 2002;16:320–325. 22. Friedrich J, Apstein CS, Ingwall JS: 31P nuclear magnetic resonance spectroscopic imaging of regions of remodeled myocardium in the infarcted rat heart. Circulation 1995;92:3527–3538. 23. Lamb HJ, Beyerbacht HP, van der Laarse A, et al: Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism. Circulation 1999;99:2261–2267. 24. Posma JL, Blanksma PK, van der Wall EE, et al: Assessment of quantitative hypertrophy scores in hypertrophic cardiomyopathy: Magnetic resonance imaging versus echocardiography. Am Heart J 1996;132:1020–1027. 25. Devlin AM, Moore NR, Ostman-Smith I: A comparison of MRI and echocardiography in hypertrophic cardiomyopathy. Br J Radiol 1999;72: 258–264. 26. Pons-Llado G, Carreras F, Borras X, et al: Comparison of morphologic assessment of hypertrophic cardiomyopathy by magnetic resonance versus echocardiographic imaging. Am J Cardiol 1997;79:1651–1656. 27. Moon JC, Fisher NG, McKenna WJ, Pennell DJ: Detection of apical hypertrophic cardiomyopathy by cardiovascular magnetic resonance in patients with non-diagnostic echocardiography. Heart 2004;90:645–649. 28. Rickers C, Wilke NM, Jerosch-Herold M, et al: Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation 2005;112:855–861. 29. Park JH, Kim YM, Chung JW, et al: MR imaging of hypertrophic cardiomyopathy. Radiology 185;441–446. 30. Spirito P, Bellone P, Harris KM, et al: Magnitude of left ventricular hypertrophy predicts the risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med 2000;342:1778–1785. 31. Elliott PM, Poloniecki J, Dickie S, et al: Sudden death in hypertrophic cardiomyopathy: Identification of high risk patients. J Am Coll Cardiol 2000;36:2212–2218. 32. Steward S, Mason D, Braunwald E: Impaired rate of left ventricular filling in idiopathic hypertrophic subaortic stenosis and valvular aortic stenosis. Circulation 1968;37:8–14. 33. Arrive L, Assayag P, Russ G, et al: MRI and cine MRI of asymmetric septal hypertrophy. J Comput Assist Tomogr 1994;18:376–382. 34. Kramer CM, Reichek N, Ferrari VA, et al: Regional heterogeneity of function in hypertrophic cardiomyopathy. Circulation 1994;90:186–194. 35. Maier SE, Fischer SE, McKinnon GC, et al: Evaluation of left ventricular segmental wall motion in hypertrophic cardiomyopathy with myocardial tagging. Circulation 1992;86:1919–1928. 36. Young AA, Kramer CM, Ferrari VA, et al: Three-dimensional left ventricular deformation in hypertrophic cardiomyopathy. Circulation 1994;90: 854–867. 37. Petrank YF, Dong SJ, Tyberg J, et al: Regional differences in shape and load in normal and diseased hearts studied by three dimensional tagged magnetic resonance imaging. Int J Card Imaging 1999;l15:309–321. 38. Moon JCC, McKenna WJ, McCrohon JA, et al: Toward clinical risk assessment in hypertrophic cardiomyopathy with gadolinium cardiovascular magnetic resonance. J Am Coll Cardiol 2003;41:1561–1567. 39. Choudhury L, Marhold H, Wagner A, et al: Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;40:2156–2164. 40. Kim RJ, Judd RM: Gadolinium-enhanced magnetic resonance imaging in hypertrophic cardiomyopathy. In vivo imaging of the pathologic substrate for premature cardiac death? (editorial comment). J Am Coll Cardiol 2003;41:1568–1572. 41. Motoyasu M, Sukuma H, Uemura S, et al: Correlation between hyperenhancement on delayed contrast enhanced MRI and diastolic function in hypertrophic cardiomyopathy. J Cardiovasc Magn Reson 2004;6:245. 42. Yamanari H, Kakishita M, Fujimoto Y, et al: Regional myocardial perfusion abnormalities and regional myocardial early diastolic dysfunction in patients with hypertrophic cardiomyopathy. Heart Vessels 1997;12:192–198.
Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging 43. DeRoos A, Doornbos J, Luyten PR, et al: Cardiac metabolism in patients with dilated and hypertrophic cardiomyopathy: Assessment with protondecoupled P-31 MR spectroscopy. J Magn Reson Imaging 1992;2: 711–719. 44. Jung WI, Sieverding L, Breuer J, et al: 31P NMR spectroscopy detects metabolic abnormalities in asymptomatic patients with hypertrophic cardiomyopathy. Circulation 1998;97:2536–2542. 45. Stuber M, Scheidegger MB, Fischer SE, et al: Alterations in the local myocardial motion pattern in patients suffering from pressure overload due to aortic stenosis. Circulation 1999;100:361–368. 46. Hartiala JJ, Foster E, Fujita N, et al: Evaluation of left atrial contribution to left ventricular filling in aortic stenosis by velocity-encoded cine MRI. Am Heart J 1994;127:593–600. 47. Kudelka AM, Turner DA, Liebson PR, et al: Comparison of cine magnetic resonance imaging and Doppler echocardiography for evaluation of left ventricular diastolic function. Am J Cardiol 1997;80:384–386. 48. Nagel E, Stuber M, Burkhard B, et al: Cardiac rotation and relaxation in patients with aortic valve stenosis. Eur Heart J 2000;21:582–589. 49. Edvardsen T, Rosen BD, Pan L, et al: Regional diastolic dysfunction in individuals with left ventricular hypertrophy measured by tagged magnetic resonance imaging—the Multi-Ethnic Study of Atherosclerosis (MESA). Am Heart J 2006;151:109–114. 50. Bogaert J, Bosmans H, Maes A, et al: Remote myocardial dysfunction after acute anterior myocardial infarction: Impact of left ventricular shape on regional function. J Am Coll Cardiol 2000;35:1525–1534. 51. Nagel E, Stuber M, Lakatos M, et al: Cardiac rotation and relaxation after anterolateral myocardial infarction. Coron Artery Dis 2000;10:261–267. 52. Kroeker CA, Tyberg JV, Beyar R: Effects of ischemia on left ventricular apex rotation. An experimental study in anesthetized dogs. Circulation 1995; 92:3539–3548. 53. Karwatowski SP, Brecker SJD, Yang GZ, et al: Mitral valve flow measured with cine MR velocity mapping in patients with ischemic heart disease:
54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64.
Comparison with Doppler echocardiography. J Magn Reson Imaging 1995;5:89–92. Benjelloun H, Cranney GB, Kirk KA, et al: Interstudy reproducibility of biplane cine nuclear magnetic resonance measurements of left ventricular function. Am J Cardiol 1991;67:1413–1420. Bottini PB, Carr AA, Prisant LM, et al: Magnetic resonance imaging compared to echocardiography to assess left ventricular mass in the hypertensive patient. Am J Hypertens 1995;8:221–228. Bogaert J, Taylor AM, Van Kerkhove F, et al: Use of the inversion-recovery contrast-enhanced MRI technique for cardiac imaging: Spectrum of diseases. Am J Roentgenol 182:609–615. White CS: MR evaluation of the pericardium. Top Magn Reson Imaging 1995;7:258–266. Watanabe A, Hara Y, Hamada M, et al: A case of effusive-constrictive pericarditis: An efficacy of Gd-DTPA enhanced magnetic resonance imaging to detect a pericardial thickening. Magn Reson Imaging 1998;16:347–350. Kojima S, Yamada N, Goto Y: Diagnosis of constrictive pericarditis by tagged cine magnetic resonance imaging. N Engl J Med 1999;341: 373–374. Talreja DR, Edwards WD, Danielson GK, et al: Constrictive pericarditis in 26 patients with histologically normal pericardial thickness. Circulation 2003;108:1852–1857. Maceira AM, Joshi J, Prasad SK, et al: Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111:186–193. Siqueira-Filho AG, Cunha CLP, Tajik AJ, et al: M-mode and twodimensional echocardiographic features in cardiac amyloidosis. Circulation 63:188–196. Benson L, Liu P, Olivieri N, et al: Left ventricular function in young adults with thalassemia. Circulation 1989;80:274. Liu P, Stone J, Collins A, et al: Is there a predictable relationship between ventricular function and myocardial iron levels in patients with hemachromatosis? Circulation 1993;88:183.
103
MANUEL D. CERQUEIRA, MD
9
Evaluation of Diastolic Function by Radionuclide Techniques INTRODUCTION PATHOPHYSIOLOGY Basic Principles of Radionuclide Assessment of Diastolic Function Equilibrium Radionuclide Angiocardiography Methods in Diastolic Assessment First Pass Radionuclide Angiography
Coronary Artery Disease Heart Failure Hypertrophic Cardiomyopathy Hypertension Aging LIMITATIONS FUTURE RESEARCH
CLINICAL RELEVANCE
INTRODUCTION For over 30 years, in the diagnosis and management of patients with known or suspected heart disease, nuclear cardiology procedures have made extensive use of radioactive tracers that can be injected as a bolus and tracked during first pass through the vascular system, attached to red blood cells and in equilibrium within the vascular space or as myocardial perfusion tracers that define the endocardial borders of the left ventricle.1 First pass radionuclide angiography (FPRNA) and equilibrium radionuclide angiocardiography (ERNA) have been the most commonly used techniques capable of assessing global and regional systolic and diastolic function at rest and following supine or upright exercise. They were used extensively in the 1970s and 1980s. The advantages of these modalities over other cardiac tests available at that time included counts based on true three-dimensional measurements (independent of geometric assumptions), high accuracy, reproducibility, and absolute quantitation. However, such accurate measurements of diastolic function were difficult to perform using the standard methods of acquisition, and processing in clinical practice and efforts to achieve greater accuracy and reproducibility were time consuming, computer intensive, and not practical in most clinical settings.2 Echocardiography provides
similar information on diastolic function and is portable and highly flexible, which offers practical advantages. In addition, echocardiography provides assessment of valves, wall thickness, left ventricular (LV) mass, chamber pressures, flow dynamics, and the integrity of the pericardium from the same study, which makes it much more valuable for patient evaluation and management. For these reasons, echocardiography has been the most practical method for the assessment of diastolic function. Due to practical and economic factors, FPRNA and ERNA techniques are rarely performed in general clinical practice, and even less for evaluation of diastolic function. However, many of the concepts and methods developed for diastolic function analysis for FPRNA and ERNA in the 70s and 80s may be applicable today to the information available from the 8 million radionuclide myocardial perfusion imaging studies performed annually in the United States. Early radionuclide perfusion imaging did not allow the assessment of systolic or diastolic ventricular function. In the mid-1990s, several methods for assessment of systolic ventricular function using 8 time frames in the heart cycle were developed, and recently this technique has been modified to allow greater temporal sampling through 16 time frames, which can be used for the evaluation of diastolic function.3,4 This may provide incremental 105
106
Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques information to the assessment of perfusion and systolic function. In some circumstances, diastolic dysfunction may identify preclinical abnormalities in the absence of alterations of systolic function. Given the current limited utilization of FPRNA and ERNA for assessment of diastolic function, this review will focus on the concepts and methods that have been found to be useful in the past and will then look at the opportunities for obtaining diastolic information from radionuclide myocardial perfusion studies that are currently being performed in such large numbers.
PATHOPHYSIOLOGY Basic Principles of Radionuclide Assessment of Diastolic Function All radionuclide approaches for assessing systolic and diastolic LV function require the generation of a curve plotting the changes in radioactivity, which is proportional to changes in LV volume over time, as shown in Figure 9-1. From this time-activity curve (TAC), the first derivative, which measures the change in volume over time, is derived and used to calculate the most rapid changes in ejection and filling and the time when the maximal rate occurs. The typical ranges of normal values for these diastolic parameters in humans are shown in Box 9-1.5 The left side of the curve prior to end systole (ES) in Figure 9-1 provides information on the systolic function of the ventricle as expressed by the rate of ejection, measured as end diastolic
Box 9-1
Important Radionuclide Parameters of Diastolic Function and Normal Values 1. Peak filling rate (PFR) (>2.5 end diastolic volumes/ second) 2. Time to peak filling rate (TPFR) (<180 msec) 3. Filling fraction (% of stroke volume at one third, one half, or two thirds of diastole) 4. E/A ratio, 1 : 40
Atrial systole
Volume EDV/sec
ED
ED
Diastasis
PER
PFR ES IR
Time (msec) Figure 9-1 The relationship between left ventricular volume over time and the derived systolic and diastolic parameters. ED, end diastole; EDV, end diastolic volume; PER, peak ejection rate; ES, end systole; IR, isovolumic relaxation; PFR, peak filling rate.
volumes per second (EDV/sec), and the time at which this peak ejection occurs, expressed as time to peak filling rate (TPFR). For ventricles with muscle damage or infiltration, pericardial abnormalities, or ischemia, the rate of emptying is decreased and there is prolongation of the time when the peak emptying rate is achieved. Diastole is represented to the right of end systole in Figure 9-1 and is a much more complicated process, which consists of four distinct phases: 1. 2. 3. 4.
Isovolumic relaxation Peak filling rate (PFR) Diastasis Atrial systole
Isovolumic relaxation starts at end systole, is an energydependent process, has a short duration (usually <50 msec), and ends when pressures in the left ventricle fall below the left atrial (LA) pressure, the mitral valve opens, and rapid filling begins. PFR represents the most rapid ventricular filling and is normalized to EDV/sec, which is normally greater than 2.5. Generally, it has been shown to be rapid in young and healthy hearts but declines in the elderly, even in the absence of pathology.6,7 TPFR is an important measure of diastolic function and is less than 180 milliseconds in normal ventricles. There have also been attempts to look at the percent of stroke volume filling that occurs during the rapid filling phase as an indicator of disease. Generally, more than 69% of the stroke volume should fill during the rapid filling portion. Following rapid filling, there is a separate phase, diastasis, with minimal changes in volume, which is followed by atrial systole. At slower heart rates, a distinct atrial component can be identified and the peak measured to calculate an E/A ratio similar to that obtained by echocardiography. For nuclear techniques, a ratio of less than 1 : 4 is normal but increases with age. At faster heart rates, the duration of diastasis decreases and the rapid ventricular filling and atrial systolic portions of the TAC merge, making it difficult to calculate ratios and assess the relative contribution of the two phases. This chapter will focus on disorders of diastolic function resulting from abnormalities of the myocardium and ischemia and not address abnormalities resulting from valvular or pericardial disease. Caution must be used in applying these normal value ranges to a particular patient, as the method of acquisition and processing, as well as patient-specific parameters, will result in great variability in the values independent of any changes caused by cardiac pathology. As shown above, factors such as age, heart rate, systolic function (ejection fraction [EF]), end diastolic volume, adrenergic state, and medications will alter these parameters in the absence of pathology.2 Given the influence of these multiple factors on the derived diastolic values, it is easy to see that single or even multiple variables may not accurately identify the presence or absence of pathology in a given individual. Figure 9-2 is a schematic representation of a normal TAC in the presence of diastolic dysfunction, shown as the dashed line. With decreased relaxation, the rate of filling, expressed as EDV/sec, decreases and the TPFR is delayed and shifted to the left. Under such circumstances, the contribution of atrial systole may be increased and the E/A ratio shifted to a greater reliance on atrial filling. In patients with very stiff ventricles, such as in hypertrophic cardiomyopathy (HCM) or diminished systolic ventricular function, the loss of the atrial contribution to filling caused by rhythms other than sinus can rapidly lead to pulmonary edema.
Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques Atrial systole
ED
ED
Diastolic function
Volume EDV/sec
Normal Diastasis
Abnormal
PFR
PER ES IR
Time (msec) Figure 9-2 Schematic of normal and abnormal diastolic function timeactivity curves. The blue line shows that PFR has a flatter slope and is shifted to the right, indicating a delay in filling in comparison with the normal curve. ED, end diastole; EDV, end diastolic volume; PER, peak ejection rate; ES, end systole; IR, isovolumic relaxation; PFR, peak filling rate. Box 9-2
Basics of Equilibrium Radionuclide Angiocardiography (ERNA) Acquisition for Diastolic Function Analysis 1. 20–30 millicuries Tc-99m labeled red blood cells 2. Labeling methods a. In vivo: fastest and least expensive but lowest binding efficiency b. Modified in vivo/in vitro: compromise with good labeling efficiency c. In vitro: longest time and expense but best labeling efficiency 3. Planar or single photon emission computed tomography (SPECT) 4. Positioning: Best septal separation, left anterior oblique (LAO) 5. Arrhythmia rejection: ±10% of mean R-R interval and drop postpremature beat 6. Temporal resolution: <50 milliseconds or 16–32 frames/cycle 7. Acquisition a. Frame mode: simplest and least data intensive b. List mode: optimal but adds considerable processing time and data storage c. Forward-backward with buffered beat: compromise
Equilibrium Radionuclide Angiocardiography Methods in Diastolic Assessment Data Acquisition Important variables for performing diastolic function analysis using ERNA are listed in Box 9-2. Technetium (Tc)-99m pertechnetate is the radioisotope of choice and is attached to the patient’s own red blood cells using one of three possible labeling methods, which vary in the time to perform labeling, expense, and labeling efficiency.1 Both planar and single photon emission computed tomography (SPECT) methods of acquisition are available, but nearly all studies are performed using planar techniques, with the patient positioned in the left anterior oblique (LAO) view, which
Figure 9-3 Left anterior oblique planar equilibrium radionuclide angiocardiogram at end diastole (ED) and end systole (ES) in a patient with normal systolic and diastolic function. The time-activity curves for analysis are obtained from sequential definition of the edges of the left ventricle.
allows the best separation of the right and left ventricles for independent and accurate volume measurements in each chamber.8,9 An example of a typical LAO view is shown in Figure 9-3. The labeled red blood cells circulate in the vascular space, and the patient’s electrocardiographic (ECG) signal is used to set the timing for acquisition of each heart beat at individual time points, which may vary from 10 to 150 msec, depending on heart rate and the preset parameters. Information for each time point for each beat (usually >400 beats are acquired) is summed so that the final TAC is an average rather than information from a single beat or a small number of beats, as is provided by other modalities. For this reason, this technique may be more representative of overall function than are other methods, due to the large number of beats averaged. Unlike systolic function analysis, where changes in heart rate and arrhythmias have relatively little influence on the time to end systole and EF, diastolic parameters are markedly affected by heart rate variability during acquisition and processing. To avoid volume and filling inconsistencies due to heart rate variability and arrhythmias from such a large number of beats, the R-R interval is sampled prior to acquisition and the parameters set up to reject individual beats that vary by ±10% of the mean R-R. Since the beat following a rejected beat has a longer filling period and will add variability to the measurements due to differences in end diastolic volume and EF, it is also rejected. There are three computer methods used to acquire ERNA studies: frame, list, and buffered beat acquisition. Frame mode is the simplest method. It samples the R-R interval prior to acquisition, determines the number of time frames for each beat, and puts data into the appropriate time frame in real time for each beat using the set parameters until a new ECG gating signal identifies the beginning of a new contraction. Once a beat has been added to the particular time bin, it cannot be removed. If there is an early beat, a new ECG trigger resets the acquisition so that the time bins toward the end of the heart cycle will have fewer beats contributing counts. The TAC generated from this method of acquisition suffers from count dropoff in the terminal frame(s) due to heart rate variability; and although accurate for EF measurements, these curves cannot be analyzed for diastolic parameters using harmonic analysis. Although this is not the best method, it is universally used because of its simplicity and the small storage size of the retained data. List mode acquisition is the best method. It retains the X,Y spatial distribution of the radiotracer for every millisecond of acquisition, along with the ECG trigger signal so that the data set
107
108
Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques can be reformatted into any timing interval and use the appropriate arrhythmia rejection during postprocessing. It provides maximal flexibility relative to heart rate variability, but unfortunately at the expense of prolonged processing time and massive data storage. This technique was used exclusively for all studies performed by the group at the U.S. National Institutes of Health.10 A hybrid method, the buffered beat approach, is an attempt to provide realistic flexibility for heart rate variability while keeping data size to a manageable limit. It uses a temporary memory buffer to examine each beat and the ECG gating signal with regard to the set baseline parameters and makes an instant decision to keep or reject the beat.6,7 An additional feature of this method is a forward-backward curve generation technique to avoid discontinuities or count dropoff in the last several frames, which precludes harmonic analysis of the TAC.
Data Analysis For analysis of diastolic indices, there needs to be adequate temporal sampling of LV volume to capture the fine detail required to detect minor or subtle alterations in diastolic filling. The actual sampling interval will vary with heart rate. To achieve a temporal resolution under 50 msec usually requires 16–32 frames per heart cycle with frame mode or buffered beat. At slow heart rates, more frames are required than at faster heart rates. The processed images are filtered to reduce statistical noise, the edges of the left ventricle are defined using manual or automated edge detection software, and background subtraction is performed. The radioactive counts within these boundaries represent the total volume in the ventricle and are used to produce a TAC. A TAC from a frame mode of 16 time intervals acquired from a clinical study is shown in Figure 9-4. All the fine detail shown schematically in Figure 9-1 is retained in this curve, which does not have any dropoff in counts in the terminal frames that may be seen in the presence of even minor sinus arrhythmias but is much more pronounced in the presence of atrial or ventricular arrhythmias. Figure 9-5 is from a study with 32 frame intervals. In comparison with the 16-frame study shown in Figure 9-4, the higher temporal
resolution results in even more detail during the diastolic filling period. Once the TAC has been generated, there are two general methods of diastolic function analysis: digital filtering and mathematical curve fitting.10 With digital filtering or harmonic analysis, three to five harmonics are applied to smooth noise in the TAC, and the first derivative is taken to define the point at which the greatest change in volume is present; this change and the time at which it occurs represents the PFR and TPFR. An example is shown in Figure 9-6. An absolute requirement for harmonic analysis is that the EDV from the TAC start and end at the same volume point. Figure 9-7 shows an example of count dropoff due to arrhythmias in a study acquired by frame mode. In the presence of count dropoff, error is introduced into the derived values from harmonic analysis. Discontinuity occurs in the terminal frames with frame mode acquisition, and for this reason, list or buffered beat acquisition with forward and backward reconstruction of the TAC is required to use harmonic methods of analysis. Diastolic function values derived using a mathematical curve fitting technique generally take the available data and apply a third-order polynomial equation to derive PFR and TPFR from the slope changes in the TAC. This method is less susceptible to discontinuities in the TAC. The basic concepts of diastolic function analysis for ERNA were developed and performed in the late 1970s and early 1980s, when the technical requirements were recognized and observed. Currently, most software packages on nuclear cardiology workstations are capable of generating diastolic function values from any
70000
A 20000
50000 40000 Count (count)
Count (count)
60000
30000 20000 10000
15000
10000
5000
0 0
50
150
250
350
450
0
550
0
100
300
500
700
900
1100
Time (msec) Figure 9-4 A 16 time interval frame mode time-activity curve from the study in Figure 9-3. The individual time points and triangles and the fitted curve are shown. All the fine diastolic detail shown in the schematics for Figures 9-1 and 9-2 can be seen in this curve, even though the 16 time intervals provide less temporal sampling than a 24- or 32-frame study.
B
Time (msec)
Figure 9-5 An equilibrium radionuclide angiocardiogram, shown in representative end diastole and end systole for the actual study and with the 32 time frame derived curve. With 32 frames, finer detail can be seen for all four phases of diastole.
Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques 8.00e4
FITTING RESULTS ED PER
Figure 9-6 The graph shows the third harmonic fitted curve superimposed by the first derivative curve with the peak ejection rate and peak filling rate. To the right is the print-out of all the variables that can be derived from the data. ED, end diastole; PER, peak ejection rate; ES, end systole; PFR, peak filling rate.
(dv/dt ⫻ 10) : (count)
6.00e4
ES
4.00e4 2.00e4 0 –2.00e4 –4.00e4 –6.00e4
Item EDC (count) ESC (count) TES (msec) TPE (msec) PER(/SV) (%/sec) TPE/T (%) 1/3EF(/SV) (%) 1/3ER(/SV) (%/sec) TPF (msec) PFR(/SV) (%/sec) TPF/TF (%) 1/3FF(/SV) (%) 1/3FR(/SV) (%/sec) 1/2FF(/SV) (%)
Value 64162 36386 202 92 718.8 15.5 31.7 471.4 94 637.2 24.0 59.8 460.2 11.2
–8.00e4 0
50 100 150 200 250 300 350 400 450 500 550 Time (msec)
Box 9-3
30000 25000
Basics of First Pass Radionuclide Angiography (FPRNA) Acquisition for Diastolic Function Analysis
20000 Counts
PFR
15000 10000 5000 0 0
100
200
300
400
500
600
700
800
Time (msec) Figure 9-7 Time-activity curve from a 32-frame study showing terminal frame dropoff in the last two frames due to an arrhythmia.
TAC obtained from ERNA or ECG gated SPECT studies. A typical print-out of results is shown in the right-hand panel of Figure 9-5. Unfortunately, details such as the accuracy of the ECG gating mechanism, the presence or absence of count dropoff in the terminal frames, information density, and temporal resolution are ignored. These systems are capable of generating values for diastolic function indices but are not used clinically.
First Pass Radionuclide Angiography Data Acquisition A method for diastolic radionuclide analysis involves FPRNA. At one time this technique was being performed with equal frequency to myocardial perfusion imaging and ERNA for detection of coronary artery disease (CAD) and systolic function assessment. Today it is rarely performed. First pass techniques for assessment of diastolic function require administration of a compact intravenous (IV) bolus of radioactivity and use of a very high temporal resolution and high count rate camera system to follow the radioactivity as it traverses the right and left ventricles. Serial gated images at 25–50 msec of temporal resolution are acquired, and the resultant TACs allow systolic and diastolic function analysis of the
1. Radiopharmaceutical a. 10–30 millicuries of Tc-99m sulfur colloid, DTPA b. Bolus injection of Tc-99m sestamibi or tetrofosmin in conjunction with perfusion, given rapidly in small volume c. Total dose injected adjusted for count rate capabilities of camera 2. Injection site a. Antecubital vein or external jugular with minimum of 18-gauge IV cannula 3. Camera types a. Multicrystal preferred due to high count rates b. Single crystal must be capable of 150,000 counts/sec 4. Temporal resolution: Usually 25 msec 5. Acquire images in anterior position
right and left ventricles at rest or following exercise or pharmacologic stress. There was a dramatic decline in the use of this technique in the 1980s and 1990s due to a lack of high count rate multicrystal camera systems, which are optimal for the technique. Performing FPRNA studies with a conventional single crystal gamma camera system is not optimal due to the low count rate. The basic requirements for performing studies are shown in Box 9-3 and will be discussed in the following section. Any Tc-99m radiolabeled compound can be used for bolus administration. When assessment is to be made at rest and following stress on one day, an agent that is cleared by the kidneys (Tc-99m DMSO or DTPA) can be given first, followed by an agent that is cleared by the liver (Tc-99m sulfur colloid) or a heart perfusion tracer (Tc-99m tetrofosmin or sestamibi), so that there is no interference during the second study from the initial dose. The total dose administered can be lower when a multicrystal camera is used, but with a single crystal camera that is not capable of high count rates, 25–30 millicuries are required. The total dose must be given as a tight IV bolus over 2 or 3 seconds, which requires at least an 18-gauge IV in the antecubital fossa or the external jugular. If such venous access is not available, the study should not be attempted.
109
110
Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques Anterior images are acquired with the patient supine or upright with the chest directly on the camera head. Exercise is best performed on a bicycle, which allows the chest to be relatively stationary and the images free of motion artifacts. Studies have been acquired during treadmill exercise, but this requires placement of external radioactive markers that can be used to correct for motion. Since only eight to ten beats can be used to analyze right ventricular (RV) or LV function without having bolus overlap in the chambers, heart rate variability or arrhythmias will further limit the number of beats that can be processed and will result in sampling bias or overlap of tracer activity in more than one chamber. These sampling limitations may result in poor study quality and limit the conclusions that can be reached. Echocardiography, computed tomography (CT) ventriculography, and cardiac magnetic resonance have similar sampling limitations. ERNA, which averages more than 400 beats, provides a more robust assessment of overall function. Depending on the count rate capabilities, diastolic and systolic parameters can be acquired from a single beat, or beats can be summed using ECG gating to give higher information density and allow better edge detection. Conventional gamma camera acquisition provides low counts and generally requires gating and summing of multiple beats for accurate results.
Data Analysis From a single beat or summed beats, the data are Fourier filtered using a third- to fifth-order harmonic with appropriate background subtraction, and the first derivative of the resultant TAC is used to measure filling rates and the time to peak filling. This technique remains the most accurate for assessment of RV function and for the detection of pulmonary hypertension.
CLINICAL RELEVANCE Radionuclide methods for diastolic function analysis have been performed predominantly on a research basis in specific patient populations and are not used on a day-to-day basis in general clinical cardiology practice. This is due, in part, to the lack of appropriate equipment, difficulty in accurately performing the measurements, and variability in the measurements due to factors other than cardiac pathology, such as age-related changes and the effects of medications. This variability makes it difficult to measure diastolic parameters in a given patient and meaningfully apply the values for purposes of diagnosis, management, or monitoring of therapy. Is the abnormal value due to the patient’s age, systolic function, myocardial stiffness, ischemia, or other variables? Even with all of these limitations, the technique has been useful in certain disease states and clinical scenarios, as listed in Box 9-4. These will be discussed in detail.
Coronary Artery Disease Diagnosis Although CAD diagnosis using radionuclide methods is usually performed by measuring myocardial perfusion or changes in systolic function at baseline and following stress, analysis of diastolic function alone or in conjunction with these other measures provides an accurate diagnosis5 based on the induction of LV ischemia, which causes a transient increase in myocardial “stiffness”
Box 9-4
Clinical Patient Populations Evaluated Using Radionuclide Diastolic Function Analysis 1. Coronary artery disease (CAD) a. Diagnosis of CAD b. Monitoring therapy 2. Heart failure a. Normal systolic function b. Abnormal systolic function 3. Hypertrophic cardiomyopathy 4. Hypertension 5. Aging
and a decrease in relaxation reflected in a decreased PFR and an increased TPFR. These are usually measurements of global changes, but regional analysis can also be performed in an attempt to increase sensitivity by measuring the small changes that may not be detected by a global filling value or time.11 Using ERNA, Bonow et al. found a very high percentage of abnormal diastolic function in the resting state in patients with documented CAD.12 In 231 patients with chronic CAD, PFR and TPFR were abnormal in 91%, in 85% of those without Q waves, and in 82% of patients with normal resting LV EFs, no resting regional wall motion abnormalities, and no Q waves. These findings suggest a high rate of abnormalities in patients with CAD at rest independent of LV systolic function or previous myocardial infarction. Using FPRNA, Reduto et al. performed rest and bicycle exercise measurements of PFR and of PFR in the first third of diastole in 32 normal and 68 CAD patients.13 In comparison with normals, patients with CAD had a lower PFR overall and a lower PFR in the first third of diastole during exercise. Although the CAD patients also had an abnormal EF response to exercise, diastolic parameters were more sensitive for detection of disease. It has also been shown among patients with CAD and with normal LV systolic function at rest that impaired LV filling and regional asynchrony predict a greater degree of exercise-induced ischemia, suggesting a greater extent of jeopardized myocardium.14,15 Despite the documented efficacy of diastolic function analysis for CAD diagnosis, it is not being used in the practice of cardiology today due to the limitations previously listed. With the potential for deriving similar information from 16-frame ECG gated perfusion studies, the technique may provide ancillary information beyond perfusion that may have a role for diagnosis and monitoring. This needs to be validated.
Monitoring Treatment of Coronary Artery Disease Once a diagnosis of CAD has been made, diastolic function analysis has also been used to document the response to treatment. Bonow et al. documented improvement in abnormal diastolic function following revascularization.16 Again, diastolic abnormalities were present in the resting state and did not require stress to provoke dysfunction. In a study of only 25 patients with singlevessel CAD, all had abnormal resting diastolic dysfunction despite normal systolic function. With exercise, 23 of the 25 developed a drop in EF, indicating the development of ischemia. Following percutaneous transluminal coronary angioplasty, resting diastolic function normalized in all patients; and with exercise, EF
Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques increased. These findings suggest that resting diastolic dysfunction is a very sensitive indicator of significant CAD, even in the absence of systolic abnormalities, and that following successful revascularization, resting diastolic dysfunction improves.
Heart Failure
normal contribution to ventricular filling in these abnormal ventricles. However, at this stage of our understanding of the etiology and management of HCM, it is accepted that diastolic dysfunction is present and that there is no need to document its existence independently of the results available from echocardiography, which is an essential test in HCM.
Normal Systolic Function Patients with clinical symptoms of congestive heart failure generally have abnormal systolic function, but as many as 30% to 40% of these patients may have normal systolic function and their symptoms are on the basis of diastolic dysfunction.17,18 Common causes of diastolic dysfunction include increased resistance to ventricular inflow caused by constrictive and restrictive pericardial disease, hypertrophy, scarring due to infarction, and volume overloading. Two other causes include impaired myocardial relaxation due to ischemia or cardiomyopathies and increased resistance to atrial emptying in patients with mitral stenosis. Although radionuclide methods may be useful for detection of diastolic abnormalities in these groups, the information provided is less useful than that provided by echocardiography, which should be the first diagnostic test performed. Soufer was able to show in 58 patients with congestive heart failure and normal systolic function that 38% had a reduction in PFR below 2.5 EDV/sec, and an additional 24% had probable diastolic dysfunction with values of 2.5–3.0 EDV/sec. The etiology was CAD and hypertension in the majority of patients.
Abnormal Systolic Function Although it has been shown using ECG techniques that patients with heart failure and abnormal systolic function also have diastolic abnormalities, radionuclide methods have not been investigated in this population.19,20 In these patients, diagnostic abnormalities were associated with worse symptoms and increased event rate. Due to complex hemodynamics, neurohumoral factors, arrhythmias, and medications, the values for diastolic indices are difficult to measure and interpret. For these reasons, radionuclide methods have limited application.
Hypertrophic Cardiomyopathy Patients with HCM have been extensively evaluated in terms of diagnosis and management using radionuclide techniques because of the interest and expertise of the group at the National Institutes of Health.21–26 The major abnormalities in HCM patients include prolonged isovolumic relaxation caused by myocardial ischemia and intracellular calcium overloading, as well as delayed rapid ventricular filling and a greater dependence on the atrial contribution to filling. In addition to documenting these abnormalities, radionuclide techniques have been used to monitor the effects of treatment. The calcium blockers verapamil and nifedipine have been shown to improve LV relaxation and filling with IV administration and with long-term oral administration. In addition to improving hemodynamic parameters, there are also clinical improvements in exercise tolerance and heart failure symptoms.21,22 It was shown that the early and late improvement in symptoms with verapamil was related to the extent of improvement in diastolic filling. These findings also explain why HCM patients can go into severe heart failure when they are not in sinus rhythm and lose atrial contraction, which makes a larger than
Hypertension In the presence of hypertension, there are alterations in diastolic function independent of alterations in systolic function or the presence of CAD that can be measured by radionuclide methods.27,28 Cuocolo et al. evaluated 41 essential hypertensive patients without CAD at rest and with exercise by ERNA.27 With exercise, 22 patients had an appropriate increase in EF and 19 had a drop in EF. In the patients with a drop in EF, resting PFR and TPFR were reduced. This suggests that resting diastolic function detects early changes in myocardial function at rest in patients with essential hypertension that predict an abnormal response during stress. These changes were not directly related to previously identified modifiers of diastolic parameters such as age, heart rate, and the extent and severity of hypertension. Abnormalities were directly related to myocardial mass. The acute effects of verapamil on diastolic function in hypertensive patients have also been studied in the cardiac catheterization laboratory. Patients had resting diastolic abnormalities that improved with the acute administration of verapamil.29 These studies suggest that diastolic function analysis may be used for preclinical detection of myocardial dysfunction in patients with hypertension.
Aging There are age-related changes in ventricular relaxation and filling that are independent of the increasing prevalence of hypertension, CAD, increased LV mass, and altered response to catecholamines and that suggest that there are primary effects of aging on diastolic function.7,30,31 It has been documented by many methods that with increasing age, there is a decrease in PFR and TPFR and an increase in the atrial component of diastole. The etiology of these changes is multifactorial but may be reversed, in part, through exercise training and with the use of calcium blockers.7,30 It is also possible that fibrosis or protein deposition within the myocardium may mediate the abnormalities.32 Documentation of these abnormalities is most useful when diastolic radionuclide parameters are being used to diagnose ischemia, in order not to confuse age-related changes with the presence of CAD. Adjusting for age is critical.
LIMITATIONS Despite the extensive literature on the use of radionuclide methods for analysis of diastolic function, the technique is not being used in clinical settings due to several factors. These include the lack of clinical utilization of these techniques for diagnosis of CAD and systolic function and the absence of special gamma cameras that optimize performance of the measurements. Such measurements were difficult to perform using the standard methods of acquisition and processing in clinical practice, and efforts to achieve greater accuracy and reproducibility were time consum-
111
112
Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques ing, computer intensive, and not practical in most clinical settings.2 In addition, techniques such as echocardiography and cardiovascular magnetic resonance provide similar information on diastolic function and much more information on heart valves, wall thickness, LV mass, chamber pressures, flow dynamics, and the integrity of the pericardium. This additional information makes these techniques much more valuable for patient evaluation and management. Other studies have brought into question the value of measuring relaxation rates and time intervals. Studies have shown that despite the improvement in these parameters with the use of calcium channel blockers, there may be an increase in LV end diastolic pressure as well as an overall prolongation of the time constant of relaxation.2
FUTURE RESEARCH Given the widespread use of ECG gated SPECT perfusion imaging and the relative lack of utilization of ERNA and FPRNA, the ability to assess diastolic function analysis from perfusion data would allow screening of diastolic dysfunction in a larger patient population during the assessment for obstructive CAD. In order to correctly perform diastolic function analysis from gated SPECT perfusion images, there are limitations to overcome. These include the low temporal resolution, failure to perform optimal arrhythmia rejection, and poor edge detection due to the low information density contained in the perfusion data. Despite these limitations, there are several groups that have shown the feasibility of such an approach.3,9,33–36 Unlike ERNA and FPRNA, in which the injected radioactivity remains in the intravascular space, Tc-99m perfusion agents are cleared by the liver and empty into the gastrointestinal tract. This means that a smaller percentage of the injected dose is actually in the myocardium when imaging is performed and that the counts are low, mandating that the time intervals for each beat be relatively long to achieve adequate information density in each frame. Increasing the imaging time will improve counts but decrease quality, as patients are likely to move. Most studies are acquired for 8 time frames. If the heart rate is 60 beats/minute, each time frame will be 125 msec, which does not allow sufficient temporal resolution to adequately separate out the various components of diastole. If 16 frames are used, each frame will have a temporal resolution of 63 msec and half the counts, but adequate edge definition can still be performed.3 The other problem that requires resolution is getting a TAC without terminal frame count dropout. Currently, arrhythmia rejection for ECG gated perfusion SPECT uses ±50% of the mean R-R interval to avoid compromising the perfusion study, which would either drop beats and lower total counts or prolong the acquisition time to achieve adequate counts. Some of the newer camera/workstation systems allow multiple acquisition windows so that arrhythmia rejection can be performed on one set of data while a separate window can be used for the perfusion data without arrhythmia rejection. Additional time is not added to the acquisition. If arrhythmias are present, the ECG gated data set will still be compromised, and quality control needs to be performed. The final hurdle is getting appropriate edge definition from the available algorithms to accurately track the endocardial borders of the ventricle. Existing software packages have been shown to handle the lower counts in 16-frame acquisition.3 Definition of
the mitral valve plane at the base of the heart is also difficult, as the transition from the left atrium, which has little uptake, to the myocardium in the area of the valves and membranous septum is difficult to identify. Failure to clearly delineate this separation will result in error in the volume of the cavity and the resultant TAC. Using this approach in ECG gated SPECT studies, normal value ranges were developed for PFR (2.62 ± 0.46 and −2 SD <1.71 EDV/s) and TPFR (164.6 ± 21.7 and −2 SD >216.7 msec) in 90 patients without CAD or hypertension. PFR had significant correlations with age, EDV, and EF, but TPFR did not. This suggests that TPFR may be a more robust measurement by this technique, as it is independent of these other factors that influence PFR. These normal ranges were then applied to a validation set of patients and showed similar results. From the combined populations, normal threshold values for PFR of greater than 1.70 EDV/sec and for TPFR under 208 msec were established.3 These results need to be validated in a larger population.
REFERENCES 1. Cerqueira M: Nuclear Cardiology. Boston, Blackwell Scientific, 1994. 2. Arrighi JA, Soufer R: Left ventricular diastolic function: Physiology, methods of assessment, and clinical significance. J Nucl Cardiol 1995;2: 525–543. 3. Akincioglu C, Berman DS, Nishina H, et al: Assessment of diastolic function using 16-frame 99mTc-sestamibi gated myocardial perfusion SPECT: Normal values. J Nucl Med 2005;46:1102–1108. 4. Germano G, Kiat H, Kavanagh PB, et al: Automatic quantification of ejection fraction from gated myocardial perfusion SPECT. J Nucl Med 1995;36:2138–2147. 5. Bonow RO: Radionuclide angiographic evaluation of left ventricular diastolic function. Circulation 1991;84:I208–I215. 6. Johannessen KA, Cerqueira M, Veith RC, Stratton JR: The relation between radionuclide angiography and Doppler echocardiography during contractile changes with infusions of epinephrine. Int J Cardiol 1991;33: 149–157. 7. Levy WC, Cerqueira MD, Abrass IB, et al: Endurance exercise training augments diastolic filling at rest and during exercise in healthy young and older men. Circulation 1993;88:116–126. 8. Updated imaging guidelines for nuclear cardiology procedures, part 1. J Nucl Cardiol 2001;8:G5–G58. 9. Higuchi T, Taki J, Nakajima K, et al: Left ventricular ejection and filling rate measurement based on the automatic edge detection method of ECG-gated blood pool single-photon emission tomography. Ann Nucl Med 2004;18:507–511. 10. Bacharach SL, Green MV, Borer JS: Instrumentation and data processing in cardiovascular nuclear medicine: Evaluation of ventricular function. Semin Nucl Med 1979;9:257–274. 11. Bonow RO, Vitale DF, Bacharach SL, et al: Asynchronous left ventricular regional function and impaired global diastolic filling in patients with coronary artery disease: Reversal after coronary angioplasty. Circulation 1985;71:297–307. 12. Bonow RO, Bacharach SL, Green MV, et al: Impaired left ventricular diastolic filling in patients with coronary artery disease: Assessment with radionuclide angiography. Circulation 1981;64:315–323. 13. Reduto LA, Wickemeyer WJ, Young JB, et al: Left ventricular diastolic performance at rest and during exercise in patients with coronary artery disease. Assessment with first-pass radionuclide angiography. Circulation 1981;63:1228–1237. 14. Perrone-Filardi P, Bacharach SL, Dilsizian V, Bonow RO: Effects of regional systolic asynchrony on left ventricular global diastolic function in patients with coronary artery disease. J Am Coll Cardiol 1992;19:739– 744. 15. Perrone-Filardi P, Bacharach SL, Dilsizian V, Bonow RO: Impaired left ventricular filling and regional diastolic asynchrony at rest in coronary artery disease and relation to exercise-induced myocardial ischemia. Am J Cardiol 1991;67:356–360.
Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques 16. Bonow RO, Kent KM, Rosing DR, et al: Improved left ventricular diastolic filling in patients with coronary artery disease after percutaneous transluminal coronary angioplasty. Circulation 1982;66:1159–1167. 17. Soufer R, Wohlgelernter D, Vita NA, et al: Intact systolic left ventricular function in clinical congestive heart failure. Am J Cardiol 1985;55: 1032–1036. 18. Watanabe J, Levine MJ, Bellotto F, et al: Effects of coronary venous pressure on left ventricular diastolic distensibility. Circ Res 1990;67:923–932. 19. Rihal CS, Nishimura RA, Hatle LK, et al: Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy. Relation to symptoms and prognosis. Circulation 1994;90:2772–2779. 20. Shen WF, Tribouilloy C, Rey JL, et al: Prognostic significance of Dopplerderived left ventricular diastolic filling variables in dilated cardiomyopathy. Am Heart J 1992;124:1524–1533. 21. Bonow RO, Dilsizian V, Rosing DR, et al: Verapamil-induced improvement in left ventricular diastolic filling and increased exercise tolerance in patients with hypertrophic cardiomyopathy: Short- and long-term effects. Circulation 1985;72:853–864. 22. Bonow RO, Rosing DR, Bacharach SL, et al: Effects of verapamil on left ventricular systolic function and diastolic filling in patients with hypertrophic cardiomyopathy. Circulation 1981;64:787–796. 23. Bonow RO, Vitale DF, Maron BJ, et al: Regional left ventricular asynchrony and impaired global left ventricular filling in hypertrophic cardiomyopathy: Effect of verapamil. J Am Coll Cardiol 1987;9:1108–1116. 24. Cannon RO 3rd, Rosing DR, Maron BJ, et al: Myocardial ischemia in patients with hypertrophic cardiomyopathy: Contribution of inadequate vasodilator reserve and elevated left ventricular filling pressures. Circulation 1985;71:234–243. 25. Maron BJ, Bonow RO, Cannon RO 3rd, et al: Hypertrophic cardiomyopathy. Interrelations of clinical manifestations, pathophysiology, and therapy (2). N Engl J Med 1987;316:844–852. 26. Maron BJ, Spirito P, Green KJ, et al: Noninvasive assessment of left ventricular diastolic function by pulsed Doppler echocardiography in patients
27. 28. 29. 30. 31. 32. 33. 34.
35. 36.
with hypertrophic cardiomyopathy. J Am Coll Cardiol 1987;10:733– 742. Cuocolo A, Sax FL, Brush JE, et al: Left ventricular hypertrophy and impaired diastolic filling in essential hypertension. Diastolic mechanisms for systolic dysfunction during exercise. Circulation 1990;81:978–986. Inouye I, Massie B, Loge D, et al: Abnormal left ventricular filling: An early finding in mild to moderate systemic hypertension. Am J Cardiol 1984;53:120–126. Brush JE Jr, Udelson JE, Bacharach SL, et al: Comparative effects of verapamil and nitroprusside on left ventricular function in patients with hypertension. J Am Coll Cardiol 1989;14:515–522. Arrighi JA, Dilsizian V, Perrone-Filardi P, et al: Improvement of the agerelated impairment in left ventricular diastolic filling with verapamil in the normal human heart. Circulation 1994;90:213–219. Bonow RO, Vitale DF, Bacharach SL, et al: Effects of aging on asynchronous left ventricular regional function and global ventricular filling in normal human subjects. J Am Coll Cardiol 1988;11:50–58. Topol EJ, Traill TA, Fortuin NJ: Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med 1985;312:277–283. Kikkawa M, Nakamura T, Sakamoto K, et al: Assessment of left ventricular diastolic function from quantitative electrocardiographic-gated 99mTctetrofosmin myocardial SPET. Eur J Nucl Med 2001;28:593–601. Kumita S, Cho K, Nakajo H, et al: Assessment of left ventricular diastolic function with electrocardiography-gated myocardial perfusion SPECT: Comparison with multigated equilibrium radionuclide angiography. J Nucl Cardiol 2001;8:568–574. Higuchi T, Nakajima K, Taki J, et al: Assessment of left ventricular systolic and diastolic function based on the edge detection method with myocardial ECG-gated SPET. Eur J Nucl Med 2001;28:1512–1516. Sakamoto K, Nakamura T, Zen K, et al: Identification of exercise-induced left ventricular systolic and diastolic dysfunction using gated SPECT in patients with coronary artery disease. J Nucl Cardiol 2004;11:152– 158.
113
10
CHRISTOPHER P. APPLETON, MD
Evaluation of Diastolic Function by TwoDimensional and Doppler Assessment of Left Ventricular Filling Including Pulmonary Venous Flow INTRODUCTION LEFT VENTRICULAR FILLING: A HISTORICAL PERSPECTIVE RELATION BETWEEN DIASTOLIC PROPERTIES AND LEFT VENTRICULAR FILLING PATTERNS EXERCISE AND LEFT VENTRICULAR DIASTOLIC FUNCTION DOPPLER MITRAL FLOW VELOCITY PATTERNS Changes in Mitral Flow Velocity Patterns with Aging and Disease States Left Ventricular Filling and Changing Cardiac Loading Conditions Grading the Degree of Left Ventricular Diastolic Dysfunction by Mitral Flow Velocity Alone Grading the Degree of Left Ventricular Diastolic Dysfunction in Epidemiology Studies
PULMONARY VENOUS FLOW VELOCITY Relation of Mitral to Pulmonary Venous A-Wave Duration CLINICAL APPLICATIONS: INTERPRETATION OF INDIVIDUAL MITRAL FLOW VELOCITY VARIABLES Left Ventricular Isovolumic Relaxation Time Left Ventricular Intracavitary Flow During Isovolumic Relaxation Time Mitral Time-Velocity Integral Peak Mitral E-Wave Velocity Mitral Deceleration Time Mitral Flow Velocity at the Start of Atrial Contraction Peak Mitral A-Wave Velocity Mitral A-Wave Duration Mitral Peak E/A Wave Velocity Ratio
115
116
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling ANCILLARY DATA THAT HELP THE INTERPRETATION OF MITRAL FLOW VELOCITY PATTERNS M-Mode and Two-Dimensional Echocardiography Tricuspid Flow Velocity Mitral Annular Velocities in Tissue Doppler Imaging and Relation to Left Ventricular Filling Pulmonary Artery Pressures PERFORMING AN ECHO-DOPPLER EVALUATION OF LEFT VENTRICULAR DIASTOLIC FUNCTION MITRAL FLOW VELOCITY PATTERNS: INTERPRETIVE CHALLENGES Mitral E/A Ratio Less Than 1
Mitral Regurgitation and Stenosis Sinus Tachycardia: Effect on Left Ventricular Filling Uncommon Mitral Valve Velocity Patterns Increased Mitral Respiratory Flow Velocity Variation Atrial Flutter and Fibrillation Diastolic Mitral and Tricuspid Regurgitation RIGHT VENTRICULAR DIASTOLIC FUNCTION USING LEFT VENTRICULAR FILLING PATTERNS FOR PATIENT MANAGEMENT FUTURE RESEARCH
INTRODUCTION The cardiac cycle is continuous. The filling of the ventricle (diastole) is followed by ventricular contraction (systole) to provide an adequate cardiac output during both rest and exercise to meet the body’s metabolic demands. Systole and diastole affect each other in an intimate manner to accomplish this goal. The normal elastic recoil after left ventricular (LV) contraction aids early filling of the ventricle, with the late diastolic atrial contraction ensuring that the myocardial sarcomeres are adequately stretched to optimize contractile force. Exercise tests the health of this integrated system by shortening the time for filling and myocardial perfusion, and a normally functioning cardiac electrical system is also needed for optimal performance. The “new” epidemiology of LV diastolic dysfunction has been discussed in Chapter 6 of this volume. Diastolic heart failure is now recognized as a major national health problem, especially in the elderly, who have a high incidence of LV hypertrophy (LVH). These patients present with symptomatic heart failure despite a normal LV ejection fraction (LVEF) and have morbidity and mortality that is nearly equal to that of patients with reduced systolic function. Diastolic heart failure patients are also at risk for first-onset atrial fibrillation and a higher incidence of stroke. Although LVEF is normal in diastolic heart failure, ventricular contractile mechanics have been altered in a way that lengthens the isovolumic contraction and relaxation period so that the period for diastolic filling becomes shorter and may be inadequate. In both systolic and diastolic heart failure, the degree of diastolic dysfunction is a powerful predictor of prognosis. Despite this new appreciation of the importance of both systole and diastole in maintaining normal cardiovascular physiology, the role of LV diastolic function in health and disease is incompletely understood and underappreciated by many primary care physicians and cardiologists. As discussed in Chapter 2, diastole is a complex phenomenon with many determinants that are difficult to study individually and several phases that encompass both the relaxation and the filling of the ventricle. Physical examination, echocardiography (ECG), chest radiographs, and laboratory studies are unreliable in diagnosing diastolic heart failure in most individuals, and invasive measurements of LV diastolic properties and pressures are impractical in clinical practice. Therefore, at present, assessing the type and degree of LV diastolic dysfunction relies on evaluating the pattern of LV filling. Although this can be accomplished by radionuclide and computed tomography
(CT) angiographic and magnetic resonance imaging (MRI) techniques, cardiac ultrasound is currently the method of choice because of its noninvasive and portable nature. Evaluating LV filling by two-dimensional anatomic findings, Doppler flow, and tissue Doppler imaging (TDI) have emerged as powerful clinical techniques to predict adverse cardiovascular events such as newonset atrial fibrillation and heart failure, as well as mortality regardless of LVEF. The purpose of this chapter will be to describe the various LV filling patterns encountered in clinical practice, and what these patterns and their measurable variables reveal about LV diastolic function. In cases of possible ambiguity, ancillary variables such as left atrial (LA) volume, pulmonary venous (PV) flow velocity, and TDI that help in interpreting mitral flow velocity patterns will be discussed.
LEFT VENTRICULAR FILLING: A HISTORICAL PERSPECTIVE In 100 bc, Galen proposed that the heart is filled by dilation of the right ventricle. Sixteen hundred years later, in 1628, William Harvey described the heart as a central pump in a circulatory system with both arteries and veins. Logically, most cases of heart failure were ascribed to damage or weakening of the heart muscle and a decrease in pumping function. Diastole was considered simply the interval in which the cardiac chambers filled passively between each pumping cycle and therefore was largely ignored. Gradually, evidence emerged that abnormalities of ventricular filling could cause symptoms and that diastolic and systolic functions were interrelated. About 1915, Wiggers described the phases of the entire cardiac cycle, and the Frank-Starling mechanism was described, whereby LV end diastolic volume helps regulate forward stroke volume on a beat-to-beat basis. In 1930, Katz recognized the role of LV relaxation in the filling of the ventricle, suggesting that the normal heart acts like a “suction” pump, a concept proven 60 years later.1 A limitation in cardiac filling, not pumping function, with resultant reduced cardiac output was recognized as the cardinal feature of constrictive pericarditis, further emphasizing that disorders of filling could also cause cardiac symptoms and disease. In the 1960s, the study of ventricular biomechanics accelerated. Although most research continued to focus on LV contractile function, cardiac diseases with thickened and noncompliant
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling
RELATION BETWEEN DIASTOLIC PROPERTIES AND LEFT VENTRICULAR FILLING PATTERNS The numerous factors that affect LV diastolic properties and the filling of the left ventricle are described in Chapter 5 of this volume. Although the interaction of these factors is complex, their sum reflects the diastolic transmitral pressure gradient, which
Transmitral pressure gradient
LV TMPG Elastic recoil LV relaxation LV-LA compliance Mitral valve LA pressure Viscoelasticity LV pressure LV-RV interaction Atrial contractility Electrical system Pericardial constraint
LA
LV filling Mitral flow velocity
ventricles with good pumping function, such as restrictive2 and hypertrophic3 cardiomyopathies, were described. Angiographic differences in LV filling patterns between normals and patients with various heart diseases were reported even when the LVEFs were similar,4 and these phenomena were subsequently studied by M-mode echocardiography.5,6 At the same time, the importance of LV systolic function in determining diastolic restoring forces and rate of LV relaxation was appreciated. Our current view that systole and diastole are an intertwined continuum, with each part affecting all others, gradually began to emerge. In the mid-1980s, echocardiographic studies showed that 20% to 40% of elderly patients with heart failure had a normal LVEF and, therefore, presumably “isolated” diastolic dysfunction.7,8 However, difficulties in quantitating individual LV diastolic properties9 caused the clinical study of LV diastolic dysfunction to proceed slowly. LV filling patterns were analyzed by digitized M-mode,10 angiographic,11 and radionuclide12 methods. In 1982, pulsed wave (PW) Doppler study of mitral flow velocities to study LV filling was first reported.13,14 Doppler ultrasound, a noninvasive technique that could determine dynamic changes in LV filling after interventions and over time, revolutionized the study of LV diastolic function. Age-related changes in LV filling were quickly described,15–18 followed by the description of three basic abnormal mitral flow filling patterns that were correlated to LV diastolic variables and filling pressures.19 The three abnormal mitral filling patterns were found to be independent of disease type19 and to have clinical significance and prognostic value regardless of cardiac disease type,20–23 suggesting that different pathology altered the same basic diastolic properties. PV flow velocity helped assess the filling of the left atrium, and variables were found to aid the interpretation of LV filling patterns and pressures.24–27 Using the two flow velocities, a “natural history” of LV filling in normals and with disease patterns was described.24–27 Manipulation of preload and afterload demonstrated the dynamic nature of LV filling patterns in response to changes in loading conditions,28–30 and these changes also had prognostic significance in patients with cardiac disease.31,32 Additional Doppler methods followed, such as TDI of mitral annular motion (MAM) and the rate of color Doppler mitral inflow propagation (Vp), and modelbased image processing continued to improve diagnostic accuracy and advance the new field of “diastology.”33–46 These continue to enhance our basic knowledge regarding clinical observations. Although all echo-Doppler variables have limitations in interpreting diastolic function, the aggregate sum of the twodimensional echo and Doppler findings provides us a powerful and practical way to noninvasively assess LV diastolic function and to objectively follow serial changes after medical intervention or with disease progression.47–49 These methods are powerful prognostic tools in asymptomatic50 as well as symptomatic patients with various diseases, like dilated21,51 and restrictive31 cardiomyopathies. As a result, the clinical syndrome of diastolic heart failure is now more readily recognized, and studies on improved diagnosis and the best treatment strategies for such patients are under way.
Figure 10-1 Determinants of LV filling. In sum, they affect the transmitral pressure gradient, which determines the LV filling pattern. When LV pressure falls below LA pressure, a positive pressure gradient occurs and early diastolic filling begins (hatching). Pressure in the ventricle rises and then briefly exceeds LA pressure, which decelerates mitral flow velocity. A positive pressure gradient occurs again at atrial contraction and results in flow in late diastole, just before systole begins. (Modified from Appleton CP et al: The echo-Doppler evaluation of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–46, ix.)
ultimately determines mitral inflow and the LV filling pattern, as shown in Figure 10-1.49 Positive gradients in diastole result in flow across the mitral valve, while negative gradients decelerate or stop flow.52–54 The different LA and LV pressures that are determined by LV diastolic properties and filling are shown in Figure 10-2. Understanding that LV end diastolic pressure (LVEDP) can be elevated before mean LA pressure is increased is essential to understanding and interpreting diastolic function. Two key diastolic properties, the rate of LV relaxation (diastolic pressure fall) and of LV compliance (throughout all of diastole), are especially important in understanding pressures and LV filling.55 Normal LV contraction and relaxation are vigorous and rapid, resulting in diastolic elastic recoil that augments early diastolic filling through a suction effect (chamber volume increasing while pressure is initially still decreasing).38,56,57 This promotes an early mitral valve opening and helps maximize the diastolic filling period and myocardial perfusion. Rapid ejection and a predominance of early diastolic filling leaves a period of diastasis before atrial contraction as a reserve that can help maintain adequate filling when exercise shortens cardiac cycle length. The first hemodynamic abnormality seen in nearly all cardiac diseases is a slower rate of LV relaxation.14,52,55,58,59 This is commonly associated with hypertension or LVH.60 Both systole and diastole are affected, even if the LVEF remains normal. In systole, the LV isovolumic contraction and ejection times become prolonged. In diastole, the slower fall in LV pressure causes the mitral valve to open later and the early diastolic transmitral pressure gradient and proportion of filling to decline.55 The diastasis period often disappears, and a greater
117
118
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling LV
LA
LV + LA
LV
LV V-wave LV A-wave
LA
LV EDP
LV RFW
A-wave Mean LAP
LA TMPG
LV pre-A
LVmin
A
B
C
Figure 10-2 The left atrial (LA) and left ventricular (LV) pressures that are influenced by LV diastolic properties are shown. The transmitral pressure gradient (TMPG, C) determines the LV filling pattern, while other hemodynamic variables relate to mitral and other echo-Doppler flow velocity variables. LV pressure falls after aortic valve closure, and its rate of decline and minimum LV pressure (LVmin, A) reflects the rate of LV relaxation and elastic recoil. As blood fills the left ventricle, there is a rapid increase in pressure from the rapid filling wave (RFW), which decelerates blood inflow. Low-level filling causes pressure to increase slowly in mid-diastole, and then an increase in pressure is seen in both chambers with atrial contraction (A wave). The first diastolic abnormality seen in nearly all cardiac diseases is a slower rate of LV relaxation. As LV compliance decreases, an abnormal increase in LV pressure is initially confined to late diastole and is seen as an increased LV A-wave pressure rise and LV end diastolic pressure (LV EDP). When LV compliance is further reduced, filling of the ventricle causes an increase in pressure throughout the diastolic filling period, which is manifest as an increase in mean LA pressure (B) and its surrogate LV preA pressure. In these cases, LV EDP is obligatorily elevated. (From Appleton CP et al: The echo-Doppler evaluation of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–546, ix.)
proportion of filling at atrial contraction is needed to reach an optimal end diastolic volume. These changes can markedly alter the length of the diastolic filling period and resting LV filling pattern, as shown in the two individuals in Figure 10-3. One is normal and one has hypertensive heart disease with LVH. Both have identical heart rates and LVEFs. At this stage, if LV compliance is reduced, the abnormal increase in pressure is seen initially only in late diastole at the time of atrial contraction, and mean LA pressure remains normal, so that patients are usually asymptomatic.47,49,61,62 A comparison of the durations of mitral and PV flow velocities at atrial contraction indicates this earliest abnormality of ventricular compliance and hemodynamics.63–66 With more advanced disease, LV relaxation remains abnormal, but a decrease in LV compliance occurs throughout diastole, which increases mean LA pressure and size and begins to result in symptomatic heart failure. The increased LA pressure will oppose the effect of a slower rate of LV relaxation, causing an earlier mitral valve opening and a higher transmitral pressure gradient,52,67 so that the LV filling pattern appears more “normal.” However, in this case the increase in early diastolic LV filling is caused by increased driving pressure rather than suction created by normal ventricular elastic recoil. Patients with this “pseudonormal” LV filling19 begin to have heart failure symptoms and show moderate functional limitation.48,49,68,69 With a severe decrease in LV compliance, the marked elevation in LA pressure causes early diastolic filling to predominate, while the left atrium fails and provides little additional late diastolic filling. This third and most abnormal LV filling pattern is termed “restrictive.”70 Patients with restrictive filling patterns also have impaired LV relaxation, but the severe decrease in LV compliance results in a marked elevation of LA pressure, which promotes a rapid initial flow of blood into the ventricle in early diastole. However, the increased proportion of early filling has an abrupt, premature termination due to a rapid increase in LV pressure with only minimal filling occurring at atrial contraction. The
reduced atrial contribution indicates that LA systolic failure is present due to the chronic pressure overload. Patients with this pattern are markedly symptomatic, demonstrate a severe functional impairment, and have a poor prognosis.21,31,51 Because both the rate of LV relaxation and LA pressures may have many different values that are not necessarily related, many different transmitral gradient profiles and LV filling patterns are possible.49,67 As a result, a similar-appearing LV filling pattern may occur with different combinations of these two key diastolic properties, with clinically significant differences in LV filling pressures. In these instances, the degree of abnormality of LV relaxation and compliance is indicated by anatomic abnormalities such as reduced LVEF, LVH, LA enlargement or altered PV flow, and annular TDI velocities.49
EXERCISE AND LEFT VENTRICULAR DIASTOLIC FUNCTION An increase in heart rate, as with exercise, is the heart’s diastolic “stress test.” As heart rate increases, diastolic filling time shortens. In normal individuals, several adaptations help keep early and late diastolic filling separated, a coordination of the electrical and mechanical systems that provide for increased filling and cardiac output without an elevation of diastolic pressures.71,72 Most importantly the P-R interval shortens.73 At the same time, faster heart rates trigger the Treppe (or “staircase”) effect, which increases LV contractility and rate of relaxation. LVEF increases and LV end systolic volume decreases. The overall effect is an earlier mitral valve opening, increased elastic recoil, and a larger early diastolic transmitral pressure gradient.71 LV contractility is also increased by sympathetic tone, while systemic vascular resistance falls with muscular vasodilation. Impaired relaxation may reduce the cardiac output achieved by reducing the diastolic filling time below that needed for optimal LV filling74 and myocardial perfusion. A premature fusion of early
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling NORMAL
Figure 10-3 The effect of impaired left ventricular (LV) relaxation on LV diastolic filling time (DFT) and LV filling patterns. A, Echocardiography (ECG), pulsed wave (PW) Doppler of mitral flow velocity and highfidelity LV pressure recordings are shown in two individuals at rest. Both individuals have heart rates of 75 bpm and a normal LV ejection fraction. In the normal subject (left), LV pressure increases and decreases rapidly so that the diastolic filling time (DFT) is longer than systole (SYS), with a period of diastasis in mid-diastole. In contrast, with impaired LV relaxation (right), longer isovolumic contraction and relaxation times result in the DFT being longer than systole. As a result, the LV filling pattern is markedly altered to reach the same end diastolic volume, with less filling in early diastole, the disappearance of a diastasis period, and a larger contribution of filling at atrial contraction. B, The effect of increased heart rates on diastolic filling time. LV pressure (LVP) is shown in the same two individuals at rest and with exercise. At a heart rate of 125 bpm compared with the normal subject (left), the DFT with impaired LV relaxation (right) is markedly abbreviated, and only 25% as long as systole, making it difficult to maintain adequate LV filling. The result is a reduced LV end diastolic volume, blunted cardiac output, and reduced functional aerobic capacity.
IMPAIRED LV RELAXATION
LV filling pattern
LV filling pattern
HR 75
HR 75
DFT SYS
DFT SYS
A HR 75
HR 125
HR 75
HR 125
LVP
DFT
DFT Exercise
DFT
DFT Exercise
B
and late diastolic filling often occurs (see Fig. 10-3) with an inability to increase LV end diastolic volume.72,74 LV and LA filling and PV flow increase with atrial contraction of an incompletely relaxed left ventricle. Patients are affected by reduced aerobic capacity and may complain of abnormal exertional dyspnea. Those with pseudonormal and restrictive filling patterns have a significant decrease in exercise capacity. However, in these individuals, it is the increase in mean LA pressure and pulmonary congestion due to reduced LV compliance that limits exercise rather than a blunted increase in LV end diastolic volume.
DOPPLER MITRAL FLOW VELOCITY PATTERNS Because of their noninvasive nature and ease of use, echo-Doppler techniques have become the accepted clinical standard for assessing LV diastolic function. LV filling is assessed with both continuous wave (CW) and PW Doppler techniques. Figure 10-4 shows mitral flow velocity obtained with the PW Doppler technique and the variables that are measured.75 These include: LV isovolumic relaxation time (IVRT); peak mitral flow velocity in early diastole (E wave) and at atrial contraction (A wave); the mitral deceleration time (DT); the E-wave velocity just before atrial contraction (E at A), also sometimes referred to as preA velocity; and the duration of mitral A-wave velocity (Adur). An E-at-A wave velocity of more than 20 cm/sec results in a peak A-wave velocity that is larger than it would have been at a slower heart rate, when mitral flow velocity has time to drop to a lower level
before atrial contraction.73 In these cases, the E/A wave ratio may be reduced compared with values obtained at a slower heart rate, so that more reliance on other echo-Doppler variables is needed when interpreting the “fused” LV filling pattern.
Changes in Mitral Flow Velocity Patterns with Aging and Disease States Elastic recoil and rapid LV relaxation in adolescents and young adults result in a predominance of early diastolic filling (E wave) with much less filling (10%–15%) due to atrial contraction. With normal aging, LVEF changes little, but LV relaxation slows in most individuals. The slower relaxation appears to be due largely to a gradual increase in systolic blood pressure and LV mass (hypertrophy). The result is reduced LV filling in early diastole and increased filling at atrial contraction.16–18 In most individuals, the peak E- and A-wave velocities become approximately equal during the sixth and seventh decade of life, with atrial filling contributing up to 35% to 40% of LV diastolic stroke volume. In individuals who maintain lower blood pressures and have no increase in LV mass, the age-related changes of decreasing E/A ratio in asymptomatic “normal” patients used in most reference studies are less pronounced, and normal E-wave predominance can occasionally be seen into the seventh decade of life. In these individuals, normal two-dimensional findings, LA size, and annular TDI variables confirm that diastolic function is normal. Normal age-related values for mitral variables are listed in Table 10-1.
119
120
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling
E
E
A
A
LV RV
Sample volume
Ac RA
E at A
LA
Ac
0 LV IVRT
Mdt
Adur
Mdt
LV IVRT
Adur
Figure 10-4 Mitral flow velocity variables. These are obtained with PW Doppler by placing a 1–2 mm sample volume between the mitral leaflet tips as shown. Variables measured include peak E- and A-wave velocities, as well as the E-wave velocity just prior to atrial contraction (E-at-A velocity). The left ventricular (LV) isovolumic relaxation time (IVRT) is the time interval from aortic valve closure (Ac) to mitral valve opening. Mitral deceleration time (Mdt) is from peak E-wave velocity to a line extrapolated down the decreasing velocity to the zero baseline. The duration of mitral A wave (Adur) is from the E-at-A (preA) velocity to the time the A wave returns to the zero baseline. (From Appleton CP et al: The echo-Doppler evaluation of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–46, ix.)
TABLE 10-1 MITRAL FLOW VELOCITY IN NORMALS: AGE-RELATED CHANGES AGE (yr)
n
IVRT (msec)
E (mmHg)
A (mmHg)
MDT (msec)
ADUR (msec)
2–20 21–40 41–60 >60
46 51 33 10
50 ± 9 67 ± 8 74 ± 7 87 ± 7
88 ± 14 75 ± 13 71 ± 13 71 ± 11
49 ± 12 51 ± 11 57 ± 13 75 ± 12
142 ± 19 166 ± 14 181 ± 19 200 ± 29
113 ± 17 127 ± 13 133 ± 13 138 ± 19
Normal age-related values for mitral E- and A-wave velocities, and mitral E/A wave ratios are shown ± SD. All individuals were free of cardiac disease and had a normal blood pressure, physical exam, and electrocardiography. Left ventricular hypertrophy was excluded, and all E-at-A velocities were <20 cm/sec, so that the peak A-wave velocity was not increased above that expected for the aging process. IVRT = isovolumic relaxation time; Mdt = mitral deceleration time; Adur = duration of mitral A wave. From Hatle LH; unpublished, with permission.
LV FILLING PATTERNS E A IVRT Normal
Impaired relaxation
Pseudonormal
Restrictive
Diastolic abnormalities:
Abnormal relaxation + Normal LA pressure
Abnormal relaxation ↓ compliance + ↑ LAP ↑ LV RFW
Abnormal relaxation ↓↓ compliance + ↑ LAP ↑ LV RFW
The three basic abnormalities of LV filling patterns were discussed previously and are shown in Figure 10-5, where the arrows indicate that abnormal mitral filling patterns are a dynamic continuum and may worsen or become more normal with changes in loading conditions. Common usage describes the three abnormal filling patterns as “impaired,” “pseudonormal,” and “restrictive” relaxation. The diastolic property of impaired LV relaxation is
Figure 10-5 Normal and abnormal LV filling patterns and their associated LV diastolic abnormalities. The degree of abnormality increases from left to right. The arrows indicate their dynamic nature in response to loading conditions and other variables. IVRT, isovolumic relaxation time; LA, left atrial; LAP, LA pressure; RFW, LV rapid filling wave in early diastole.
present in all patterns, the difference being that with pseudonormal and restrictive filling, progressively reduced LV compliance raises mean LA pressure to levels that mask their effects on the transmitral pressure gradient and filling. The changes in LV filling with normal aging and with cardiac disease states can be combined into a “natural history of LV filling,” which is shown together with their corresponding PV
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling THE NATURAL HISTORY OF LV FILLING Impaired LV relaxation Normal Young m/sec 1
Middle age
Decrease in LV compliance Older
Mild
Moderate
Severe
E A IVRT
0 0.5
PVs PVd
0 PVa Figure 10-6 The “natural history” of left ventricular (LV) filling patterns with normal aging and with progressive diastolic dysfunction, as assessed by PW Doppler mitral and pulmonary venous flow velocity recordings. Several abnormal LV filling patterns have E/A wave velocity ratios that are similar to those seen in normal individuals. This can occur because different combinations of LV relaxation and left atrial (LA) pressures may result in the same early diastolic transmitral pressure gradient and hence a similar mitral flow velocity pattern. For this reason, additional data, such as pulmonary venous flow velocity, is often helpful in distinguishing normal from abnormal mitral filling patterns, especially of the pseudonormal type. The dashed lines in pulmonary venous flow represent common variations. A, peak mitral flow velocity at atrial contraction; E, peak mitral flow velocity in early diastole; IVRT, LV isovolumic relaxation time; PVa, reverse pulmonary venous flow at atrial contraction; PVd, pulmonary venous flow velocity in diastole; PVs, pulmonary venous flow velocity in systole. (Modified from Appleton CP: The natural history of left ventricular filling abnormalities: Assessment by two-dimensional and Doppler echocardiography. Echocardiography 1992;9:437–457.)
flow velocities in Figure 10-6. Although theoretical when proposed in 1992,24 the progression of abnormalities in LV filling patterns with disease states (from impaired relaxation to pseudonormal to restrictive), together with changes in LV relaxation and compliance, has been documented in experimental models of congestive heart failure76 and clinically observed in patients with restrictive cardiomyopathies.20 Many variations of LV filling patterns that do not exactly match the three “classical” abnormal patterns are common because of the multiple combinations of the rate of LV relaxation and compliance. However, the abnormal LV filling patterns remain specific to the alterations in diastolic properties rather than to the type of cardiac disease, with all three patterns, depending on disease stage, being seen in disorders as diverse as restrictive and dilated cardiomyopathies. This “natural history” of LV filling explains how both young normal individuals and patients with severe disease and a restrictive filling pattern can have a high proportion of filling in early diastole and an audible S3 gallop.77 It also shows that PV flow velocity has its own changes that occur with normal aging and in cardiac disease states (discussed below) and that these associated PV filling patterns are more distinctive than some similar-appearing normal and abnormal mitral flow velocity patterns.26
Left Ventricular Filling and Changing Cardiac Loading Conditions Simple maneuvers in the echo laboratory to reduce (Valsalva) or increase (leg raising) preload demonstrate that mitral flow velocity patterns are a dynamic continuum.28–30 Plotting the changes in E-wave velocity and mitral DT in individuals after altering loading conditions has even been proposed as a load-independent index of normal and abnormal diastolic filling.78 During the strain phase of a Valsalva maneuver, preload (mean LA pressure) is reduced, and in normals peak mitral E-wave velocity decreases by at least 20% during maximum strain with a smaller decrease in peak A-wave velocity (Fig. 10-7). Similarly, in patients with an impaired relaxation filling pattern, mean LA
pressure is normal, so that with preload reduction, the whole diastolic transmitral pressure gradient decreases and both E- and A-wave velocities decrease. In patients with reduced systolic function and an impaired relaxation pattern, increasing preload by leg raising may result in no change in the filling pattern. However, if a pseudonormal mitral flow velocity pattern results, it indicates a higher cardiovascular morbidity than if their E/A ratio remains less than 1.28 With pseudonormal mitral flow patterns, the Valsalva strain lowers the elevated LA pressure and “unmasks” the underlying impaired LV relaxation.29 A notable feature of this change is the increase in mitral A-wave velocity and duration as the left atrium ejects into a ventricle that has a lower pressure. Preload-sensitive patients with restrictive filling patterns will revert to a pseudonormal filling pattern. In individuals who perform an adequate Valsalva and yet remain restrictive, LV stiffness is markedly increased, even at the more normal filling pressures. These patients have a poor prognosis.32
Grading the Degree of Left Ventricular Diastolic Dysfunction by Mitral Flow Velocity Alone A simplified grading system for diastolic function based on the three abnormal mitral flow velocity patterns alone is shown in Figure 10-848 and has been found to be useful in many patients. Grades Ia and Ib represent an impaired relaxation filling pattern with normal mean LA pressure and LA size. The difference is whether all LV filling pressures are normal (Ia) or whether LV pressure increase with atrial contraction is abnormal and increases LVEDP (Ib). This is important because an increase in LVEDP is the first hemodynamic abnormality of diastolic dysfunction (see Fig. 10-2). Grade II indicates pseudonormal filling with increased mean LA pressure, and grade III is a restrictive LV filling pattern. Grade IV is restrictive filling that does not revert to pseudonormal with preload reduction, indicating the most advanced LV diastolic dysfunction and the worst prognosis. Although grading LV diastolic dysfunction by mitral flow velocity pattern alone can be helpful, many patients (especially the
121
122
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling LV FILLING PATTERNS: RESPONSE TO PRELOAD REDUCTION (VALSALVA) Normal
Pattern
Pseudonormal
Valsalva
Baseline
Maximum
Interpretation
Normal
Normal
Impaired relaxation
Normal pressures
Impaired relaxation
↑ LV A wave, ↑ EDP
Pseudonormal
Pseudonormal
Restrictive
Preload sensitive partially reversible
Restrictive
Fixed restrictive
Valsalva
B
A
Figure 10-7 Changes in mitral flow velocity patterns to preload reduction using the Valsalva maneuver. A, PW Doppler mitral flow velocity recordings from a normal individual and a patient with pseudonormal left ventricular (LV) filling. After Valsalva, the normal has both E- and A-wave velocity decrease with little change in E/A ratio, while the lowering of left atrial (LA) pressure in the pseudonormal patient “unmasks” an impaired LV relaxation filling pattern. B, In tabular form the different responses seen in mitral LV filling patterns with a Valsalva maneuver after approximately 10 seconds of strain. In all but fixed restrictive, the E-wave velocity should decrease at least 20%. When mean LA pressure is normal, the mitral A-wave velocity also decreases. No A-wave change with an impaired relaxation filling pattern suggests an elevated LV end diastolic pressure (EDP). With mean LA pressure increased, pseudonormal filling reverts to impaired relaxation filling, and most restrictive patterns to pseudonormal. The exception is irreversibly restrictive, where advanced disease results in no change in filling, even with a moderate decrease in mean LA pressure. (A, From Dumesnil JG et al: Use of Valsalva maneuver to unmask left ventricular diastolic function abnormalities by Doppler echocardiography in patients with coronary artery disease or systemic hypertension. Am J Cardiol 1991;68:515– 519. B, From Appleton CP: The echo-Doppler evaluation of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–546, ix.)
SIMPLIFIED LV DIASTOLIC FUNCTION CLASSIFICATION Normal Grade DHF
IR Ia
IR+ Ib
PN II
III
Restrictive IV*
*No change with Valsalva Figure 10-8 A simplified grading system for diastolic dysfunction is shown that assigns each abnormal mitral flow velocity pattern to a progressively more advanced grade of diastolic heart failure. Impaired relaxation Ia has normal filling pressures, while IR + Ib has an increase in left ventricular (LV) end diastolic pressure, the first hemodynamic abnormality that occurs in diastolic dysfunction. Grade III is restrictive, which will revert to a pseudonormal pattern with Valsalva maneuver and left atrial pressure (preload) reduction, while grade IV diastolic heart failure will not, an ominous prognostic sign. (From Oh JK et al: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506.)
elderly) may be misclassified. The rate of LV relaxation and LV compliance and filling pressures are a continuum, and similar LV filling patterns are possible with different combinations of these diastolic properties.48,49 A major area of misinterpretation concerns patients with markedly impaired LV relaxation where LA pressures are elevated with an increase in the E-wave velocity, yet the filling pattern appears to be impaired (E/A ratio <1) because of partial fusion of early and late diastole (see Fig. 10-3) or because LV relaxation is so abnormally slow that only marked increases in mean LA pressure will result in pseudonormal filling. Figure 10-9 shows an example of this latter phenomenon. In this case, three patients with hypertrophic cardiomyopathy have different combinations of the speed of LV relaxation and LA pressure,
giving similar mitral E/A wave ratios of approximately 2, yet the mean LA pressure varies threefold because of the markedly different rates of LV relaxation.59 In these cases, ancillary data such as two-dimensional anatomic abnormalities, LVEF reduction, LVH, LA enlargement, or altered PV flow or annular TDI velocities are indicators that abnormal diastolic function and pressures are present.47–49,79 Also some mitral filling patterns are “atypical,” meaning that a biphasic mitral DT, a mid-diastolic filling “hump,” or some other unusual feature is present. These less common LV filling patterns do not fit well into a grading scheme for diastolic dysfunction that uses only the mitral flow velocity pattern and are best understood by evaluating the abnormal diastolic properties and physiology that the altered LV filling reflects.
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling
LV relaxation
Figure 10-9 An illustration of how different combinations of impaired left ventricular (LV) relaxation and left atrial (LA) pressure can result in mitral flow velocity patterns with similar E/A ratios but markedly different filling pressures. The pulsed wave (PW) mitral recordings shown are from three patients with hypertrophic cardiomyopathy. The patient on the left is the most normal, with the least impaired LV relaxation and a normal mean LA pressure. The patient on the right has a similar LV filling pattern but marked diastolic dysfunction, with severely impaired LV relaxation and a mean LA pressure of 30 mmHg. In these cases, the grading system of diastolic dysfunction in Figure 10-8 would not work well, and other ancillary variables indicate the true degree of diastolic dysfunction present. (From Nishimura RA et al: Noninvasive Doppler echocardiographic evaluation of left ventricular filling pressures in patients with cardiomyopathies: A simultaneous Doppler echocardiographic and cardiac catheterization study. J Am Coll Cardiol 1996;28:1226–1233.)
LV pressure 7 All combinations = 7 (i.e., LV relaxation + LV pressure = the same filling pattern) E 150 mmHg
E
E
0.2 m/sec
150 mmHg
A
LV
100 mmHg
LV
A
LA
LA
0 mmHg
0 mmHg
0 mmHg
A
LV relaxation LA pressure
9
Grading the Degree of Left Ventricular Diastolic Dysfunction in Epidemiologic Studies Recent landmark studies show that many asymptomatic individuals with a normal LVEF have abnormal diastolic function that is a risk factor for future development of adverse cardiovascular events such as new-onset heart failure, a first episode of atrial fibrillation or stroke, and death.50,80 In an effort to improve predictive value beyond that of analyzing mitral flow velocity alone, the classification of the degree of LV diastolic abnormality in these studies included mitral inflow velocity variables (especially the E/A wave ratio), their response to the Valsalva maneuver, PV flow velocity, and TDI of the mitral annulus. Figure 10-10 shows the multiple echo-Doppler criteria for grading diastolic dysfunction in these epidemiologic studies and provides a preview of the ancillary variables that aid in this interpretation (discussed later in this chapter).
PULMONARY VENOUS FLOW VELOCITY PV velocity, usually obtained with PW Doppler from the right upper pulmonary vein during transthoracic apical imaging, reflects the filling dynamics of the left atrium. With experience, high-quality PW Doppler transthoracic recordings can be obtained in approximately 85% to 90% of patients.75 Within a short time after mitral flow velocity patterns were correlated with hemodynamics, it became apparent that PV flow velocity could be of additional help in assessing LV filling patterns,26 especially impaired relaxation filling with increased LVEDP and pseudonormal LV filling.64–66
14
30
mmHg
While there are now several additional echo-Doppler variables to help identify pseudonormal filling (LA size, color M-mode [CMM] inflow propagation velocity, mitral annular TDI), PV flow velocity analysis remains unique and indispensable to identifying an abnormal increase in LV pressure at atrial contraction. The various components of PV flow velocity change with age, mitral flow velocity, and disease states and can be matched to their corresponding mitral Doppler patterns (see Fig. 10-6). The hemodynamic determinants of PV flow velocity have been studied in vivo81–84 and clinically26,85–87 and related to individual variables (Fig. 10-11). These include peak forward flow velocity in early systole (PVs1), late systole (PVs2), and early diastole (PVd) and peak reverse flow velocity at atrial contraction (PVa) and its duration (PVa dur). A dip or “notch” between PVs1 and PVs2 in early LV systole represents the C wave seen in LA pressure recordings at the time of mitral valve closure. PVs1 blends with PVs2 velocity, and this “notch” is not distinctly seen in most (about 70%) transthoracic flow velocity recordings75 but is observed more often with a first-degree atrioventricular (AV) block and in virtually all transesophageal-echo (TEE) recordings in patients in sinus rhythm.86 PVs1 occurs in early ventricular systole as a result of LA relaxation and a decrease in downstream LA pressure at a time when PV pressure is relatively constant. PVs2 peaks later in systole and is due to the increase in PV flow and pressure that results from systolic right ventricular (RV) stroke volume. Maximal PVs2 velocity, its time-velocity integral (TVI), and deceleration of flow reflect the pressure difference between PV and downstream LA pressure as blood fills both vascular systems. The descent of the
123
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling
Mitral inflow at peak Valsalva maneuver
Doppler tissue imaging of mitral annular motion
Pulmonary venous flow
Velocity (m/sec) Velocity (m/sec)
Mitral inflow
Velocity (m/sec)
Severe diastolic dysfunction
Velocity (m/sec)
124
Normal diastolic function
Mild diastolic dysfunction Impaired relaxation
Moderate diastolic dysfunction Pseudonormal
Reversible restrictive
Fixed restrictive
0.75 < E/A < 1.5 DT >140 msec
E/A < 0.75
0.75 < E/A < 1.5 DT > 140 msec
E/A >1.5 DT< 140 msec
E/A >1.5 DT < 140 msec
ΔE/A < 0.5
ΔE/A ≥ 0.5
ΔE/A ≥ 0.5
ΔE/A < 0.5
E/E′ < 10
E/E′ ≥ 10
E/E′ ≥ 10
E/E′ ≥ 10
2.0
E A
0 Adur ΔE/A < 0.5 2.0 E
A
0 E/E′ < 10 0 0.15
E′
A′
S≥D ARdur < Adur 1.0
S
S>D ARdur < Adur
S < D or S < D or S < D or ARdur > Adur + 30 msec ARdur > Adur + 30 msec ARdur > Adur + 30 msec
D ARdur
0
Left ventricular relaxation Left ventricular compliance Atrial pressure
AR Time (msec)
Time (msec)
Time (msec)
Time (msec)
Time (msec)
Normal Normal Normal
Impaired Normal to ↓ Normal
Impaired ↓↓ ↑↑
Impaired ↓↓↓ ↑↑↑
Impaired ↓↓↓↓ ↑↑↑↑
Figure 10-10 A more complicated grading system for left ventricular (LV) diastolic dysfunction that incorporates multiple mitral flow velocity variables, their response to Valsalva maneuver, pulmonary venous flow velocity variables and tissue Doppler imaging of the septal mitral annulus. These criteria have been used in epidemiologic studies to assess the asymptomatic prevalence of diastolic dysfunction in the community and also how LV diastolic dysfunction increases the risk for future adverse cardiac events. (From Redfield MM et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202.)
AV rings with ventricular systole increases LA size and compliance while helping decrease the downstream LA pressure. PV diastolic flow velocity (PVd) initially follows early diastolic mitral flow velocity; but in mid-diastole, LV filling slows while PVd flow continues with ongoing LA enlargement and appendage filling. PV flow reversal due to atrial contraction (PVa) is determined by LA contractility and LV compliance, with more and longer reverse flow seen as LV compliance decreases. Changes in PV flow velocity and their relation to LV compliance and LA pressures are shown in Figure 10-12. In patients with impaired relaxation filling, decreased LV compliance, and normal mean LA pressure, early diastolic filling (mitral E wave) is reduced. In these cases, LA hypertrophy (LAH) provides a sufficient atrial “kick” to fill the left ventricle to its optimal end diastolic volume. An important benefit of LAH is that it confines the abnormal pressure rise in the atrium, ventricle, and pulmonary veins to the short period associated with atrial contraction so that mean LA pressure remains normal (see Fig. 10-2). PVs1 is increased so that the PV systolic-to-diastolic flow velocity ratio remains above 50%. If LV compliance decreases further, the atrium may begin to decompensate, enlarge, and have contractile dysfunction. A reduced systolic fraction of PV antegrade flow
(<40%) indicates LA systolic dysfunction (decline in PVs1) and has a high specificity for a pseudonormal LV filling pattern and increased mean LA pressure (see Fig. 10-12).28,87 The PV A wave and its relation to mitral A-wave duration are of special importance and are discussed in detail below.
Relation of Mitral to Pulmonary Venous A-Wave Duration As shown in Figure 10-13, when both A-wave flow velocity durations are accurately recorded, this relation is an important indication of LV A-wave pressure increase and LV end diastolic pressure,64–66,88,89 even in the pediatric age group.90 Laboratories that do not routinely record PV flow velocity will miss the unique aspects of this derived variable. Unlike other Doppler variables, the relation is independent of age, meaning that mitral A-wave duration remains equal to or longer than PV A-wave duration throughout life in normal individuals. Secondly, the relation of the two A-wave durations is our only echo-Doppler variable that directly relates to the rise in LV pressure at atrial contraction, thereby separating patients with impaired relaxation who have normal filling pressures from those who have an increased LVEDP
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling PVs2 PVd PVs1 ECG PVs2
PVd
PVs1
0
PVa
PVa
PVa dur
A
PVd
80
200 msec 8 PVs2
PVs2
40
PV LA
PVs1
LA
6
PVd
PVs1
0 –20
PV
PVa mmHg
PV velocity (cm/sec)
Figure 10-11 A, Pulmonary venous (PV) variables obtained with the pulsed wave Doppler technique include peak flow velocity and early systole (PVs1), late systole (PVs2), and early diastole (PVd) and peak reverse flow velocity (PVa) and its duration (PVa dur) at atrial contraction. B, Panel 1 shows simultaneously recording of PV flow velocity together with PV and left atrial (LA) pressures. Panel 2 is a schematic drawing of PV and left atrial (LA) pressures showing the different hemodynamic pressure gradients (hatched areas) that determine the four individual PV flow velocity components. These components are described in the text. (A, From Appleton CP et al: The echo-Doppler evaluation of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–546, ix. B, From Appleton CP: Hemodynamic determinants of Doppler pulmonary venous flow velocity components: New insights from studies in lightly sedated normal dogs. J Am Coll Cardiol 1997;30:1562–74.)
PVa dur PVa PVa dur
4
B PULMONARY VENOUS FLOW VELOCITY
PVs PVd
PVa Normal
↓ LV compliance ↑ LAP
Impaired relaxation
↓ LV compliance ↑↑ LAP
A
PWP (mmHg)
40
1 m/sec
30
0.4
20 10
0
0 0
20
40
60
80
100 0.4
PV systolic fraction (%)
B
C
Figure 10-12 A, Schematic drawing of pulmonary venous (PV) flow velocity patterns obtained with PW Doppler from normal to most abnormal (left to right). With impaired relaxation, the proportion of PV systolic flow (PVs) increases as PV diastolic flow (PVd) decreases, paralleling the decrease in mitral E-wave velocity. Reverse flow back into the pulmonary veins with atrial contraction (PVa) is variable, being increased in velocity (>35 cm/sec) and duration (>30 msec greater than mitral A-wave duration) if left ventricular (LV) end diastolic pressure is elevated. As LV compliance decreases, and left atrial pressure (LAP) increases, the proportion of PVs flow decreases. At the same time, PVd and E-wave velocity increase with pseudonormal and restrictive LV filling being seen. All mitral and their corresponding PV patterns are shown together in Figure 10-6. B, The relation of PV systolic fraction (in % of total forward flow) to pulmonary wedge pressure (PWP). When PVs is <40% in a patient with heart disease, PWP is elevated. C, PW Doppler mitral and PV flow velocity in a patient with pseudonormal to restrictive filling who has an enlarged left atrium and whose contractile function is failing. PVs is decreased with a systolic fraction <40%, PVd is increased, and the velocity and duration of PVa exceed those of the mitral A-wave (vertical lines). This indicates that mean LA pressure, LV A-wave pressure rise, and LV end diastolic pressure are all increased. (B, From Kuecherer HF et al: Pulmonary venous flow patterns by transesophageal pulsed Doppler echocardiography: Relation to parameters of left ventricular systolic and diastolic function. Am Heart J 1991;122:1683–1693.)
125
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling MITRAL VS. PULMONARY VENOUS A - WAVE DURATION: RELATION TO LVEDP
40
S D Svti
PVa-d
Dvti
30
LVEDP
Velocity
–30
20
PVa-vti Ddt
10
PVa
0 –100
A
Velocity
E
–50
0
50
100
MVA dur – PVa dur
B Edt
Adur
m/sec
EDP
LVa
Pulmonary venous
Mitral
1– Pressure
126
0.5–
0
Pre-a 0 Adur 121 msec
A
0.5–
PVa Adur 200 msec
C
Figure 10-13 A, Schematic diagram of the relation of pulmonary venous (PVa-d) and mitral flow velocity A-wave duration (Adur), which relates to the left ventricular (LV) pressure rise at atrial contraction (LVa). The graph combines Doppler data from three separate studies (from references 64–66) and shows that when the reverse duration of PV compared with mitral A-wave flow exceeds 30 msec, LV end diastolic pressure (LVEDP) is usually >15 mmHg. C, PW Doppler mitral and PV flow velocity from a patient with LV hypertrophy and impaired relaxation filling. The mitral A-wave duration is 121 msec and PV Awave duration 200 msec, so that flow backward into the pulmonary vein continues for 80 msec after flow into the left ventricle stops. This indicates that LV A-wave pressure increases and LV end diastolic pressure is elevated. (A, From Kuecherer HF et al: Pulmonary venous flow patterns by transesophageal pulsed Doppler echocardiography: Relation to parameters of left ventricular systolic and diastolic function. Am Heart J 1991;122:1683–1693.)
(>12 mmHg), the first hemodynamic abnormality seen with diastolic dysfunction. Under normal circumstances when the left atrium contracts, the net volume and duration of flow should be greater forward into the left ventricle than backward into the pulmonary veins. If the PV A wave is increased in either velocity (>35 cm/sec) or duration (>30 msec longer than mitral A wave), LV A-wave pressure is increased and LVEDP is elevated (see Fig. 10-13). Even in cases where the atrium is enlarged, markedly hypokinetic, and failing, the PV A-wave duration of reverse flow continues to be more than 30 msec longer than the abbreviated mitral A-wave inflow duration. If the PV A-wave duration is difficult to measure due to a suboptimal recording, referencing the end of both A-wave flows to the QRS complex is helpful, as PV flow duration is abnormal if it exceeds that of the mitral A wave. A detailed guide to obtaining high-quality PW Doppler PV flow velocity recordings has been published.75 The interpretation of mitral versus PV A-wave duration may not be reliable if the mitral velocity at the start of atrial contraction is greater than 20 cm/sec,88 or if atrial contraction occurs before PVd has reached the zero velocity baseline.49 In the first case, the peak mitral A-wave velocity, TVI, and A-wave duration are longer than normal to accommodate the increased atrial stroke volume that is present; and in the second case, the PV Adur is
shorter because it starts above the conventional measuring point of the zero velocity baseline.
CLINICAL APPLICATIONS: INTERPRETATION OF INDIVIDUAL MITRAL FLOW VELOCITY VARIABLES Studying the factors that influence individual mitral flow velocity variables is often useful in interpreting LV filling patterns in difficult or uncommon cases. It is also a powerful tool for deciding which diastolic property is most abnormal, which helps in the planning of possible clinical interventions in individual patients.
Left Ventricular Isovolumic Relaxation Time LV IVRT is the interval from aortic valve closure to mitral valve opening and the start of mitral inflow (see Fig. 10-4). This interval can be a powerful tool for physicians in helping to evaluate diastolic dysfunction and filling pressures, especially when the mitral E wave is increased or atrial fibrillation is present. We suggest it be measured on all echo-Doppler studies.91 In normal patients, IVRT varies with age, being shorter in the young, who have rapid LV relaxation that results in an earlier mitral valve opening, and then becoming lengthened as relaxation
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling slows with age.17 Figure 10-14 compares the effect of changes in the rate of LV relaxation and LA pressure on the IVRT interval, timing of the mitral valve opening, and LV filling pattern using a normal subject and a patient with impaired LV relaxation. The IVRT interval is most helpful when it is at its extremes, meaning farthest from expected norms, being either short (<60 msec) or long (>110 msec). It is less useful in-between these values. A normal IVRT for a middle-aged adult is approximately 80 msec. A short IVRT (<60 msec) indicates an early mitral valve opening; a long IVRT (>100 msec), a delayed LV relaxation and a late valve opening. In patients with impaired relaxation filling and normal pressures, a prolonged IVRT is an early indicator of LV diastolic dysfunction.60,92 If mean LA pressures remain normal, extremely slow LV relaxation can result in IVRT values that approach 200 msec. The higher filling pressure in pseudonormal filling patterns causes the mitral valve to open earlier, so the IVRT shortens. More normal values of 60 to 100 msec are usually seen, and the IVRT value is less useful. A short IVRT of 40 to 60 msec can be seen in young, healthy, normal individuals or in patients with very high mean LA pressure and restrictive filling. This clinical distinction is easily made by normal versus abnormal two-dimensional anatomic findings, especially of LA size and contractile function. Effect of the speed of LV relaxation on TMPG and LV IVRT
A common instance when IVRT duration can be very helpful is when heavy mitral annular calcification is present and there is a question of mild calcific mitral stenosis versus LV diastolic dysfunction. The mitral annular narrowing may increase E-wave velocity, the E/A wave velocity ratio, and LA size, making the assessment of LV diastolic dysfunction difficult. If the pressure half-time is normal or borderline but the IVRT is short (20 msec less than expected for age), LA pressure is likely elevated due to a noncompliant left ventricle. Conversely, if E-wave velocity is increased but the IVRT is normal, mild annular narrowing is likely the cause for the increased velocity. A markedly prolonged pressure half-time indicates calcific mitral stenosis, in which case a short IVRT would also indicate increased mean LA pressure, similar to the auscultatory findings of a short opening snap interval.
Left Ventricular Intracavitary Flow During Isovolumic Relaxation Time LV IVRT flow is usually apically directed, from one part of the ventricle to another, occurring when both aortic and mitral valves are closed during IVRT.93 The importance of recognizing IVRT flow is twofold; it indicates that abnormal, dyssynchronous LV
LV pressure
Mitral flow velocity Abnormal relaxation
LV
Ac LAP Abnormal relaxation
LV IVRT
C
A Effect of LAP on TMPG and LV IVRT
Mitral flow velocity Ao
Ao
1 m/sec LV c m/sec
LV
–50 LV Ac LAP Normal relaxation
LV IVRT
B
Abnormal relaxation
D
Figure 10-14 The left ventricular (LV) isovolumic relaxation time (IVRT). A, The effect of the speed of LV relaxation on early diastolic (E-wave) transmitral pressure gradient (TMPG) and IVRT with constant left atrial (LA) pressure. The slower the LV relaxation, the longer the IVRT interval and the smaller the TMPG (E wave). B, The effect of different LA pressures (LAP) on LV IVRT with a constant rate of LV relaxation. The higher the LAP, the shorter the IVRT and the earlier the mitral valve opening. C, D, Schematic of LV pressure and mitral flow velocity (top) and PW Doppler mitral flow velocity recordings in two subjects (bottom), illustrating the principles in the left panel. The normal subject shows rapid relaxation, a normal LV filling pattern, and normal IVRT of 70 msec (small vertical arrows). The patient on the left has hypertension and slower LV relaxation. With a normal mean LAP, this results in a longer IVRT (110 msec), lower E-wave, increased A-wave velocity, and the familiar impaired LV relaxation filling pattern. (C, D, From Hatle LK et al: Differentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370.)
127
128
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling relaxation is present between apex and base and that its peak velocity should not be confused with the mitral E-wave velocity that immediately follows it. In the normal situation, no significant LV flow is detected during the IVRT period. When present, IVRT flow is most easily detected from an apical transducer position with CW or CMM Doppler because both techniques scan the long axis of the ventricle. PW Doppler can then be used for better velocity definition. When present, IVRT flow is usually 20 to 60 cm/sec but can occasionally be as high as 1 to 2 m/sec, as seen in Figure 10-15. When IVRT flow is present, the most common cause is systolic LV narrowing at the papillary muscle level, due to either LVH or hyperdynamic systolic function, which increases late systolic flow velocities. The increased mid- or late systolic load placed on the LV apical segments causes the apex to relax prematurely before the basal myocardial segments, with blood flow moving toward the lower pressure in the apex before the mitral valve opens. “Bidirectional” IVRT flow is occasionally seen when apical directed flow “turns around,” flowing back toward the annulus as basilar relaxation reduces pressure below that in the apex. IVRT flow can also be observed in the left ventricle with dyssynchronous LV relaxation due to coronary artery disease (CAD) with a left bundle branch block (LBBB) and in the RV apex when it is hyperdynamic and exhibits systolic cavity obliteration.
stroke volume. Cardiac output is this stroke volume times the heart rate. Since the mitral orifice is larger than the aortic annulus, the mitral TVI should be smaller than the LV outflow tract (LVOT) TVI, typically by about 30%. If cardiac output is either elevated or decreased, the mitral-toLVOT TVI ratio should remain normal. With significant mitral regurgitation (MR) or mitral stenosis (MS), the mitral TVI will increase and be as large or larger than the LVOT TVI. With isolated aortic regurgitation, the reverse relation may exist, increasing the difference from aortic to mitral TVI. As early and late diastolic mitral TVIs represent the sum of LV filling, an inverse relation exists. A large early diastolic mitral TVI will be associated with a smaller TVI at atrial contraction. Conversely, when the E-wave TVI is decreased, the ventricle can reach a normal end diastolic volume only if there is a corresponding increase in A-wave TVI. If mitral E and A waves are partially fused at rest, a low proportion of E-wave versus A-wave TVIs may be present. Patients often have a reduced functional aerobic capacity because of an inability to increase LV diastolic volume adequately with exercise.72
Peak Mitral E-Wave Velocity The early diastolic transmitral pressure gradient52 (see Fig. 10-1) determines peak mitral E-wave velocity, whose values in normals of various ages have been published but have wide confidence limits.16–18 These studies were performed before additional variables such as LA volume or TDI annular velocities were routinely performed, which would verify that normal cardiac physiology was present. Table 10-1 lists E-wave velocities in individuals of various ages without histories of cardiac disease, in whom these newer variables were included, and who also had normal blood
Mitral Time-Velocity Integral Though rarely considered when discussing the assessment of LV diastolic function, the absolute value of the mitral TVI is often helpful in interpreting mitral flow velocity patterns. In the absence of significant mitral or aortic regurgitation, mitral TVI multiplied by the mitral valve cross-sectional orifice area represents the LV
CMM DOPPLER IVRT flow PW DOPPLER MID-LV CAVITY 1.5 m/sec
IVRT flow
E
A
Sys
1.0
E 1.0
A
1.5 0.5 CW DOPPLER
E
Sys [m/sec]
IVRT flow
–0.5 1.0 MR
1.5
2.0 100 mm/sec
83 HR
Figure 10-15 Isovolumic relaxation time (IVRT) flow in the mid–left ventricular (LV) cavity in a patient with LV hypertrophy and near systolic cavity obliteration. All recordings are from an apical transducer position. The color M-mode (CMM, top left) is directed through the mitral valve. Midcavity systolic flow (Sys) is followed by bidirectional IVRT flow, first toward the apex (orange) and then a shorter period toward the base (blue, arrows). This is followed by mitral E and A waves. CW Doppler shows the apically directed IVRT flow, followed by mitral E-wave and mild mitral regurgitation. PW Doppler at the mid-LV cavity shows late peaking systolic flow acceleration at the area of LV narrowing (papillary muscle level), and then very prominent IVRT flow first toward the apex (1.6 m/sec, arrow above baseline) and then lower velocity toward the base (0.3 m/sec, arrow below baseline).
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling pressure, ECG, and echo-derived LV mass. Therefore, although sample sizes are much smaller in terms of absolute patient numbers, the confidence limits are smaller and the results more likely to represent true normal values. Since E-wave and LVOT velocities are related to stroke volume and orifice area, a predictable ratio between these variables exists in normals regardless of heart rate and cardiac output. The normal LVOT velocity is approximately 1 m/sec. Table 10-1 shows that the mitral/LVOT velocity ratio is about 80% in younger individuals, decreasing to 70% in middle age and 60% in the elderly as LV relaxation slows slightly and E-wave velocity decreases. Routinely checking this E-wave/LVOT velocity ratio improves the assessment of LV filling patterns and diastolic function. An Ewave/LVOT velocity ratio lower than expected indicates impaired LV relaxation and normal mean LA pressure. A normal ratio with increased or decreased E- and A-wave velocities is seen with reduced or increased cardiac output. Higher than expected ratios indicate that peak E-wave velocity is elevated, which may occur for several reasons. These include MS, MR, or increased mean LA pressure. Patients with MS or MR have increased E-wave velocities that may not reflect diastolic dysfunction. Mean transvalvular gradient and pressure half-times help assess the severity of MS, while IVRT reflects mean LA pressure. Significant MR increases Ewave velocity due to the regurgitant volume recrossing the mitral valve in early diastole. Normally the ventricle and left atrium become more compliant as they undergo chamber enlargement and eccentric hypertrophy through a rightward shift in the pressure-volume relation. Mitral DT and PA pressures remaining normal despite the volume overload reflect this normal adaptation. A shortening of mitral DT or increased pulmonary artery pressures suggest acute MR or an abnormal decrease in LV compliance due to additional pathology. Many elderly patients with hypertension and LVH have an elevated E-wave velocity of 1 m/sec or greater with a mitral E/A wave ratio of less than 1. Using a diastolic function assessment by mitral filling pattern alone frequently labels these patients as having “impaired LV relaxation,” suggesting that mean LA pressure is normal when in fact the increased E-wave velocity is due to increased mean LA pressure. The higher A-wave velocity reflects LAH or partial fusion of E- and A-wave velocities due to a relatively fast heart rate or first-degree AV block. Clues that patients with an impaired relaxation pattern actually have moderate diastolic dysfunction and elevated mean LA pressure equivalent to pseudonormal filling are: marked LVH, LA enlargement, and a preA velocity greater than 20 cm/sec. The differentiation between a normal and a pseudonormal filling pattern can be made by two-dimensional findings (vigorous LV and RV contraction, normal LA size) or other ancillary variables, such as PV systolic fraction, CMM mitral inflow propagation velocity, and mitral annular TDI. The change to a less abnormal LV filling pattern with a Valsalva maneuver (see Fig. 10-7) reveals the preload sensitivity of the abnormal diastolic function. Figure 10-16 shows increased E-wave velocities from expected values in several patients, illustrating the concepts we have discussed.
Mitral Deceleration Time Mitral DT is arguably the most important mitral variable for prognosis when heart disease is present, regardless of LVEF.21,32,94,95 In cardiac patients, mitral DT relates to LV chamber stiffness96;
the shorter the mitral DT and the more “restrictive” the LV filling pattern, the higher the mortality. The acceleration of E-wave mitral flow velocity is related to the maximum early diastolic transmitral pressure gradient. The deceleration of this flow, the mitral DT, is related to how fast (or slow) LV pressure increases in early diastole as volume enters the ventricle (the rapid filling wave as shown in Figs. 10-1 and 10-2). As with other mitral flow velocity variables, mitral DT changes with age, lengthening as the rate of LV relaxation slows and less volume is transferred to the ventricle in early diastole (see Table 10-1). A short mitral DT (140–160 msec) is normal in healthy, young individuals due to the high proportion of filling in early diastole that occurs because of LV elastic recoil. As E-wave velocity and the proportion of early diastolic filling declines with age, mitral DT increases to about 200 msec by age 65 (see Table 10-1). With impaired LV relaxation and normal mean LA pressure, early diastolic filling is reduced (E/A wave ratio <1) and mitral DT is prolonged roughly in proportion to the slowing in the rate of LV relaxation.97 With pseudonormal mitral filling, the elevated mean LA pressure increases filling in early diastole into the noncompliant ventricle, and the rapid filling wave shortens the DT, with values that appear more normal for age. More advanced disease and further decreases in LV compliance cause such high LA pressure that blood is forced rapidly into a stiff ventricle in early diastole, which causes a very rapid, abnormal rise in LV pressure.19 A short mitral DT (<140 msec) characterizes this restrictive filling, which is most commonly seen in advanced dilated or restrictive cardiomyopathies. In these cases, and despite the widely variable LVEFs, mitral DT is strongly related to both the elevated filling pressures51 and survival.21,94 Mitral DT is dynamic and will change with alterations in preload and afterload that change the transmitral pressure gradient. Patients who are volume overloaded may lengthen their DT with diuresis. Similarly, mitral DT may lengthen and become less restrictive in response to a Valsalva maneuver (see Fig. 10-7) that lowers preload.30 Persistence of a restrictive LV filling pattern in a cardiomyopathy despite a Valsalva maneuver or after maximum medical therapy is the most severe form of diastolic dysfunction (grade IV; Figs. 10-7, 10-8, and 10-10), an ominous prognostic sign that indicates a very high mortality.32 Mitral DT is also useful in patients with MR, where the welladapted ventricle will retain a normal DT. Shortening of the mitral DT from expected normal values for age indicates increased ventricular stiffness and is a better indicator of myocardial pathology than is peak E-wave velocity (see Fig. 10-16).
Mitral Flow Velocity at the Start of Atrial Contraction Although rarely measured, or even considered, mitral flow velocity at the start of atrial contraction (see Fig. 10-4) is important because it affects peak mitral A-wave velocity, the mitral E/A wave ratio, and the mitral A-wave duration. Therefore, we encourage its routine measurement along with those of the other mitral flow velocity variables to improve the accuracy of assessing LV diastolic function. In normal individuals, the heart rate at rest is slow enough to keep this velocity at under 20 cm/sec. This maximizes early and mid-diastolic ventricular filling and minimizes the proportion of filling associated with the booster pump function of atrial contraction. With exercise, fusion of early and late diastolic filling will occur, but only at relatively rapid heart rates because of the effects
129
130
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling m/sec 2.0
1.5
1.0
0.5
0 NI
IR
PN
PN-V
RST
MR
MS
Figure 10-16 PW Doppler recordings of mitral flow velocity in seven individuals (left to right panels), illustrating how different E-wave velocities compared with expected values aid in the interpretation of left ventricular (LV) filling patterns, some of which might be misdiagnosed by a scheme of grading diastolic dysfunction by E/A wave ratio alone. All individuals had a left ventricular outflow tract (LVOT) velocity of approximately 1 m/sec. The last two subjects have mitral valve disease. The 35-year-old normal (NI) has a mitral E-wave/LVOT velocity ratio of 85%. This ratio is reduced to 50% in the second patient, who has impaired LV relaxation. The patient with pseudonormal filling has a normal-appearing E/A wave ratio, but the E-wave velocity of 1.2 m/sec is 20% higher than LVOT velocity, indicating the increase in mean LA pressure. The next patient appears to have an impaired relaxation filling pattern with an E/A wave ratio <1 but really has a pseudonormal pattern variant (PN-V) caused by the partial fusion of early and late diastolic filling. Pseudonormal abnormalities present include an E-wave velocity elevated at 1 m/sec and an A-wave that would be much smaller (with a higher E/A ratio) if the heart rate were slower and atrial contraction had occurred after the mitral flow velocity had fallen below 20 cm/sec. The next patient has a dilated cardiomyopathy and restrictive (RST) filling with a short mitral DT (130 msec) and diminished atrial filling contribution. The last two patients have an increased E-wave velocity due to mitral valve disease. The patient with severe mitral regurgitation (MR) has an E-wave velocity of 1.4 m/sec, 40% higher than LVOT velocity. A shorter than expected mitral DT (170 msec) indicates reduced LV compliance, in this case from coronary artery disease and diabetes. The last patient has rheumatic mitral stenosis (MS), a high E-wave velocity, increased mean gradient, and prolonged pressure half-time.
of shortening of the P-R interval and faster LV relaxation (see Fig. 10-3). If mitral flow velocity does not have sufficient time to fall below 20 cm/sec before atrial contraction, early and late diastolic filling (E and A waves) begin to merge, as shown in Figure 10-17. This decreases fluid dynamic and filling efficiency and may increase the workload and size of the left atrium. The fusion of early and late diastolic filling most often occurs when the heart rate is too fast for a diastolic filling period that is shortened by impaired LV relaxation from LVH, an LBBB, or CAD. A first-degree AV block may also cause mitral E- and A-wave fusion due to atrial contraction occurring only shortly after mitral valve opening instead of later in diastole. Depending on the physiology present, fusion can occur at heart rates as low as 70 to 80 bpm. In both cases, the A velocity is higher than if no fusion were present, and the E/A ratio is reduced compared with early and late diastolic filling that are separated. The consequences of resting or premature fusion of early and late diastolic filling are frequently seen in a “limited” ability to increase mitral TVI (the LV stroke volume) and LV end diastolic volume during exercise, with associated decrease in exercise capacity.72,74 The ability to see if the resting heart rate is well matched to the cardiac physiology present in individual patients by observing the LV filling pattern is one of the great strengths of the echo-Doppler technique that cannot be determined by physical exam. If possible, altering the heart rate to restore a normal separation between early and late diastolic filling frequently improves patient symptoms and exercise capacity.
Peak Mitral A-Wave Velocity The mitral A-wave velocity is determined by the late diastolic transmitral pressure gradient (see Fig. 10-1) and varies from 50 cm/sec in younger individuals to 75 cm/sec in normals over
60 years (see Table 10-1). In patients with impaired relaxation filling and reduced E-wave velocity, an increased A-wave velocity and TVI are expected and necessary to maintain a normal LV end diastolic volume and cardiac output. When LV relaxation is slowed, the reduced filling in early diastole results in less LV pressure increase after LV minimum pressure, so that the atrium contracts into a relatively low pressure, compliant chamber. By two-dimensional echo, the left atrium is usually normal in size and appears “hypercontractile,” with exaggerated annular movement superiorly toward the pulmonary veins. The A-wave peak velocity is increased, A-wave TVI is relatively large, and the flow duration is increased, usually to more than 140 msec. An A-wave velocity below 1 m/sec or atrial DT that is unusually short (<110 msec) may indicate a decrease in late diastolic LV chamber compliance and an increase in LV A-wave and end diastolic pressures.
Mitral A-Wave Duration The importance of mitral A-wave duration is in what it reveals about late diastolic LV compliance. It is best used in conjunction with PV A-wave duration, as discussed previously. Like all mitral variables, A-wave duration varies with age in normals, being about 120 msec in the young and 140 msec in individuals over 60 (see Table 10-1). In general, when viewed in patients with cardiovascular disease, the longer the mitral A-wave duration, the more likely filling pressures are normal, while a shortened A-wave duration indicates increased LVEDP. Mitral A-wave duration, like peak A-wave velocity, is determined by the transmitral pressure gradient at atrial contraction (see Fig. 10-1). Under normal circumstances, the pressure increase in the atrium is larger than that in the ventricle. In pseudonormal or restricted LV filling patterns, the mitral A-wave duration is shortened because the reduced LV compliance results in an
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling P wave HR 70 preA 15 cm/sec A E HR 82 preA 70 cm/sec
E
A
HR 74 1° AVB LBBB preA 90 cm/sec A HR 105 1° AVB A wave only
E
E
A
A
HR 78 PR 276 LBBB preA 1 m/sec followed by PVC PVC
Figure 10-17 Variable mitral E-wave velocity at the start of atrial contraction (preA velocity, dotted vertical line) and how it affects the left ventricular (LV) filling pattern and especially E/A wave ratio and A-wave duration. PW Doppler recordings of mitral flow velocity in five separate patients are shown, and referred to from top to bottom. The echocardiography at the bottom relates to the bottom-most patient only. These fused LV filling patterns make assessment of diastolic dysfunction more challenging but are important because these patients are frequently symptomatic. For reference, the vertical dashed line (p wave) is aligned to the start of atrial contraction in all recordings. Only the top patient with an impaired relaxation mitral pattern has a preA velocity <20 cm/sec, the cutoff value at which E/A ratio, peak A velocity, and A-wave duration are unaffected by partial “fusion” of early and late diastolic LV filling. Patients 2 and 3 are in their 70s and have histories of hypertension. They have higher E-wave velocities than expected for age, yet the high preA velocity increases the peak A-wave velocity and makes the E/A ratio <1. Since the mitral time-velocity integral (TVI) represents LV filling volume, the higher pre-A velocity reduces E-wave TVI, which results in a larger A-wave TVI and A-wave duration. Slower heart rates would decrease peak A-wave velocity and increase the E/A wave ratio. Patient 4 has sinus tachycardia so that only an A wave is present. The A-wave velocity is high (1.6 m/sec) because all LV filling must occur during the P-R interval. Finally, patient 5 shows how after a premature ventricular contraction (PVC) and compensatory pause, the longer R-R interval markedly changes the E/A ratio and LV filling pattern. 1º AVB, first-degree atrioventricular block; LBBB, left bundle branch block. (From Hatle LK: Differentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370.)
excessive rise in LV pressure with atrial contraction, which abruptly terminates transmitral flow (Fig. 10-18).98 The reduced time of a positive transmitral pressure gradient is indicated by a shorter mitral A-wave duration whose DT is shorter than its acceleration time.99 Observing changes in A-wave duration over time (or after changes in loading conditions or medical therapy [see Fig. 10-18]) may confirm that LV diastolic function is improving more easily than examining other Doppler variables. For instance, in patients with hypertensive heart disease and an impaired LV relaxation filling pattern, a lengthening of A-wave duration after medical therapy is helpful in confirming if an increase in peak E-wave velocity represents improved LV relaxation and not increased LA pressure.100 Conditions that affect mitral A-wave duration and make it more difficult for use in assisting the evaluation of LV diastolic function include partial fusion of early and late diastolic filling101 (see Fig. 10-17), variation in cardiac cycle length due to sinus arrhythmia, premature atrial or ventricular beats, second- or third-degree AV block, and a short (<120 msec) P-R interval. Longer cycles result in more mid-diastolic LV filling and pressure
increase, so that when the atrium finally contracts, A-wave duration and velocity integral are reduced. Conversely, shorter R-R intervals result in longer A-wave durations. A short P-R interval (<120 msec) will have a reduced A-wave duration because the rise in LV pressure soon after atrial contraction will result in mitral valve closure and abrupt termination of A-wave flow. Advanced degrees of heart block continually change the relation between early and late diastolic filling so that virtually every A wave has a different velocity and duration.
Mitral Peak E/A Wave Velocity Ratio Peak E/A ratio has been the single most important variable used to help characterize the overall mitral flow velocity pattern47–49,79,102–105 and define diastolic function in patient groups in previous research studies (see Figs. 10-8 and 10-10).80,106 In patients with systolic heart failure, the E/A ratio is related to filling pressures and prognosis. While the diastolic function evaluation by E/A wave ratio “pattern recognition” is quick, using it without consideration of the individual variables for mitral velocities previously described, other two-dimensional findings, and
131
132
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling LA-LV pressure gradient
LV
mmHg 20
20
20
LA
10
A wave 140 msec (+) TMPG
90 msec
75 msec
A Nitroglycerin
Angina at rest 1 min
5 min
1 m/sec
Mitral DT A duration
120 msec 80 msec
140 msec 100 msec
160 msec 140 msec
B Figure 10-18 The hemodynamic determinants of mitral A-wave peak velocity and duration (top), and an example of their dynamic variation in a patient with rest angina treated with sublingual nitroglycerin (bottom). A, High-fidelity recordings of left ventricular (LV) and left atrial (LA) pressure show the positive late diastolic transmitral pressure gradient (TMPG) associated with LA contraction (dotted lines) in three individuals. In the normal subject (left), LA pressure rise at atrial contraction exceeds that seen in the ventricle, so that the positive (+) A-wave TMPG goes on until LA pressure falls below LV pressure during atrial relaxation. The patient in the middle panel has a decrease in LV compliance. The maximal LA-LV pressure gradient at atrial contraction is approximately the same, but the rise in LV pressure exceeds LA pressure at 90 msec, shortening the (+) A-wave TMPG and A-wave duration but not its peak velocity. The patient on the right has a marked decrease in LV compliance. LV pressure increases rapidly after LA contraction, so the maximum (+) TMPG and duration is further shortened, resulting in a lower peak A-wave velocity with a shorter duration. B, Patient with angina at rest. The pulsed wave mitral flow velocity shows a high E-wave velocity, a short, “restrictive” like mitral DT, and a low A-wave velocity and duration, which are partially “masked” by some fusion of early and late diastolic filling (velocity at the start of atrial contraction >20 cm/sec). One minute after taking sublingual nitroglycerin, LV hemodynamics are improving, as evidenced by a longer diastolic filling period, lower E-wave velocity, longer mitral deceleration (DT), and wider A-wave duration. By 5 minutes, the improvement in mitral filling variables are even more obvious. (A, From Matsuda Y et al: Change of left atrial systolic pressure waveform in relation to left ventricular end-diastolic pressure. Circulation 1990;82:1659–67. B, From Hatle LK et al: Differentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370.)
ancillary Doppler variables will lead to a certain number of patients being misclassified. The E/A ratio is most helpful when the mitral DT is linear and preA velocity is below 20 cm/sec. If mitral DT is curved or biphasic or if there is partial fusion of Eand A-wave velocities, then the LV filling pattern needs a careful assessment in relation to the other echo-Doppler findings.
ANCILLARY DATA THAT HELP THE INTERPRETATION OF MITRAL FLOW VELOCITY PATTERNS A criticism of the assessment of LV diastolic dysfunction by mitral flow velocity variables and LV filling pattern is that they are affected by multiple confounding variables and therefore are unsuitable for determining LV diastolic properties,107 and by implication LV diastolic dysfunction. This discounts the large body of evidence now accumulated on the predictive value of these variables in clinical medicine21,28,31,32,80,94,108–113 and the fact
that additional ancillary data are available to further document the cardiac abnormalities present for both diagnosis and treatment.49
M-Mode and Two-Dimensional Echocardiography There is considerable information about LV diastolic function and filling pressures available from M-mode and two-dimensional cardiac ultrasound recordings to complement Doppler variables.5,49,114 With practice, the visual interpretation of these anatomic findings usually will suggest what Doppler LV filling patterns are present. From the parasternal long axis view, observing the movement at the AV groove helps identify the cardiac rhythm, LA size, and contractility. In the parasternal short axis, the normal left atrium appears approximately the same size or slightly larger than the aorta. From apical views, the sizes of both atria in relation to their respective ventricles can be determined, as well as comparisons made of their respective sizes and contractilities. Differences are usually obvious. A normal-sized left atrium
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling that appears “hypercontractile” indicates reduced LV filling in early diastole, increased filling at atrial contraction, and an impaired relaxation pattern. LA enlargement and reduced contractility are often associated with elevated pressures and pseudonormal or restrictive mitral filling patterns as long as there have been no recent atrial arrhythmias. At the same time, noting asymmetry in the rate of LV and RV contractility and relaxation, and the excursion of AV longitudinal plane movement, often indicates the abnormalities of ventricular diastolic filling that will be seen on Doppler exam. LVH slows LV relaxation independent of other cardiac abnormalities and results in an impaired relaxation that is often obvious in M-mode LV recordings (Fig. 10-19). In the absence of MR, arrhythmias, or cardiac conduction system disease, LA enlargement usually indicates an elevated mean LA pressure associated with pseudonormal and restrictive mitral flow velocity patterns.86,106,115 Because maximal LA volume is strongly associated with adverse cardiac events such as new-onset atrial fibrillation, congestive heart failure, and stroke,106,115,116 we agree that it should be measured according to the guidelines of the American Society of Echocardiography and the European Society of Cardiology117 in all patients. Conversely, normal LA size suggests that mean LA pressure is normal. Left atrial minimum volume is related to pulmonary wedge pressure with a correlation coefficient equal to that of most other Doppler variables.89
Tricuspid Flow Velocity Tricuspid and mitral flow velocity patterns are normally qualitatively similar, and in RV pathology the alterations are similar to
those seen on the left side of the heart. Since the tricuspid leaflet orifice is larger, tricuspid velocities are slightly lower. Tricuspid flow velocity increases significantly with respiration, which differs from left heart filling (this aspect will be discussed in the section on assessing RV diastolic function). Differences between mitral and tricuspid filling patterns usually reflect cardiac pathology. Since most cardiac diseases affect the left heart, the more abnormal filling pattern is usually seen in LV filling, although the right heart is also affected through the involvement of the intraventricular septum. For instance, in an individual with an ischemic cardiomyopathy who has a pseudonormal LV filling pattern, tricuspid filling often “lags behind,” showing an impaired relaxation pattern.49
Mitral Annular Velocities in Tissue Doppler Imaging and Relation to Left Ventricular Filling The recently developed TDI ultrasound modality (discussed in detail in Chapter 12 of this volume) has underlying physics and principles similar to those of conventional PW spectral Doppler. From the apical views, the velocities are related to LV contraction and relaxation. In interpreting LV filling patterns, TDI of myocardial velocities has its greatest use in distinguishing normal and pseudonormal LV filling.39 The ratio of peak mitral E-wave velocity to myocardial E′ velocity is used to estimate mean LA pressure.64,118–120 The normal diastolic velocity pattern of myocardial velocities obtained from TDI is similar to that of transmitral flow in patients in sinus rhythm, except inverted.39,121–127 There is positive (above the zero velocity baseline) movement toward the apex with
LV DIASTOLIC FUNCTION
1 m/sec
1 m/sec
IVRT - 70 msec Normal
A
IVRT - 110 msec LVH abnormal relaxation
B
IVRT - 95 msec LVH ↑ LVEDP
C
Figure 10-19 Pulsed wave mitral flow velocity together with M-mode recordings of the left ventricular (LV) cavity in three individuals, illustrating how the diastolic wall motion pattern helps in interpreting the LV filling pattern. Compared with the normal subject (A), the patient in B with LV hypertrophy (LVH) has impaired relaxation filling. Their longer isovolumic relaxation time (IVRT) and reduced E-wave velocity matches the slower rate of early diastolic LV filling seen in the LV posterior wall (arrow). The patient in C has a mitral pattern that may appear similar to the normal so as to be difficult to interpret without additional data. However, the M-mode recording shows marked LVH, very delayed early diastolic filling with relaxation, and mid-diastolic LV cavity expansion continuing to occur up to the time of atrial contraction. These findings, along with the increased E-wave velocity (1 m/sec), indicate pseudonormal LV filling and moderate diastolic dysfunction. Small vertical arrows indicate LV IVRT period and mitral A-wave duration for comparison. (From Hatle LK et al: Differentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370.)
133
134
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling systolic contraction and negative movement back toward the pulmonary veins with LV filling in early (E′) and late diastole (A′). In patients with normal ventricular diastolic function, the E′/A′ and mitral E/A flow velocity wave ratios are similar. Patients with impaired relaxation filling have a myocardial velocity E′/A′ ratio of under 1, again mirroring the findings seen with mitral flow velocity. However, in pseudonormal mitral flow velocity patterns, a myocardial velocity E′/A′ ratio of less than 1, rather than higher than 1, is present, reflecting the impaired LV relaxation that separates these patients from true normals. This is similar to the relaxation abnormality seen in the myocardial M-mode in Figure 10-19, despite the “normal”-appearing Doppler LV filling pattern. With restrictive LV filling, the E′/A′ ratio frequently is greater than 1 because the majority of filling occurs in early diastole, with little contribution from atrial contraction. Figure 10-20 shows a schematic diagram of normal and abnormal mitral LV filling patterns together with LV pressure, TDI myocardial velocity, and PV flow velocity for reference. The interpretation of TDI myocardial velocities is enhanced by an awareness of the factors that influence these annular movements. The E′/A′ ratio is higher in the lateral as compared with the septal annulus because the septal is tethered to the right ventricle and other structures in the middle of the heart. The E′ diastolic annular movement predominates in normals because LV longitudinal movement at the base in both systole and diastole is greater than displacement in a radial direction. In patients with a normal LVEF and pseudonormal filling, a reduced E′ is present because LVH causes an increase in systolic radial movement that is reversed (outward LV motion) in early diastole. The E′/A′ ratio will be less abnormal if there is another reason for the reduced LV compliance than LVH or if the LVEF is decreased. Regardless of LVH, a large volume of blood flow across the mitral valve in early diastole due to MR will fill the ventricle and increase upward annular movement and E′ velocity so that the E′/A′ ratio will appear more normal.
As shown in Figure 10-3 and discussed (see the section “Exercise and Left Ventricular Diastolic Function”), impaired relaxation reduces the time available for diastolic filling and myocardial perfusion and sets in motion a process that leads to limitation in cardiac output (Fig. 10-21).72,74 In patients presenting with exertional dyspnea, examining changes in the ratio of mitral E-wave and TDI E′ velocity at rest and exercise has been proposed as a diastolic stress.128 Using supine bicycle exercise and classifying points by E/E’ of more than 10, exercise duration was significantly longer in patients whose E/E′ ratios were equal to or greater than 10 and did not increase with exercise. These preliminary results suggest that the hemodynamic consequences of exercise-induced increase in diastolic filling pressure may be possible noninvasively with exercise Doppler ECG (see Chapter 17).
Pulmonary Artery Pressures The estimation of PA systolic and diastolic pressures is a valuable adjunct to assessing LV filling patterns. Using the modified Bernoulli equation, this can be accomplished in a high percentage of patients with right-sided valvular regurgitation. The velocity of pulmonary regurgitation at end diastole together with an estimate of central venous pressure (physical exam, size of inferior vena cava, and degree of respiratory collapse) is used to estimate PA diastolic pressure. In the absence of pulmonary vascular disease, this is a surrogate estimate of mean LA pressure. Similarly, peak velocity of tricuspid regurgitation (TR) together with central venous pressure helps estimate PA systolic pressure. Patients with impaired relaxation in LV filling are expected to have normal or at worst borderline increases in PA pressure in the absence of pulmonary parenchymal or vascular disease. Pseudonormal filling is associated with elevated mean LA pressure, and so PA pressures are passively elevated. With the higher left heart pressures seen in restrictive filling, PA systolic pressure can be quite elevated, in the 50–70 mmHg range.
LV FILLING PATTERNS Decrease in compliance Normal
Abnormal relaxation
Moderate
Marked
Irreversible
Normal
IR
PN
RST
Irreversible RST
LV pressure Mitral flow velocity Tissue Doppler
Pulmonary vein
Figure 10-20 Schematic diagram showing the correlation of pulsed wave tissue Doppler imaging (TDI) recordings of the mitral annulus with normal and abnormal left ventricular (LV) filling patterns, LV pressures, and pulmonary venous (PV) flow velocity; IR, impaired relaxation; PN, pseudonormal; RST, restrictive. TDI is especially helpful in distinguishing normal from PN LV filling in most circumstances. Note that in normal and IR filling, the mitral and TDI patterns are inverted but similar in terms of early and late diastolic ratios. In contrast, PN filling has a markedly disparate TDI with reduced longitudinal movement in early diastole and increased movement at atrial contraction, a pattern that reflects the impaired LV relaxation. The TDI patterns in RST filling can be variable depending on disease process and LV ejection fraction, with the most typical shown. The dashed lines and arrows in impaired relaxation filling in LV pressure and PV A-wave refer to patients with decreased LV compliance in late diastole who have an increase in LV end diastolic pressure.
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling HOCM 68F s/p myectomy
HR 57 TVI-16 CO 4.4 L/min
Pulmonary wedge pressure (mmHg)
B
A
Reduced FAC Normal subjects
30 Peak exercise 20
Peak exercise
10 Rest
0 60
140
LV end-diastolic volume (ml)
HR 87 TVI-17 CO 6.7 L/min
C
100
D
Figure 10-21 Reduced functional aerobic capacity in a patient due to left ventricular (LV) diastolic rather than systolic dysfunction. The patient has hypertrophic obstructive cardiomyopathy (HOCM) (A) and is status postsurgical septal myectomy with resultant gradient reduction but also a left bundle branch block (LBBB). At rest, an impaired relaxation pattern is present (B). With exercise, (C) an increase in heart rate (HR) to 87 bpm, a premature fusion of early and late diastolic filling is seen with only a small increase in mitral time-velocity integral (TVI), which represents LV filling. Therefore, the cardiac output increase is mostly from the increase in heart rate. As shown in the graph (D), the inadequate diastolic filling blunts the normal increase in end diastolic volume, reducing cardiac output while also causing an increase in pulmonary pressures and venous congestion. (B, From Kitzman DW et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17: 1065–1072.)
PERFORMING AN ECHO-DOPPLER EVALUATION OF LEFT VENTRICULAR DIASTOLIC FUNCTION The assessment of LV diastolic function requires high-quality two-dimensional images and Doppler recordings of mitral, PV, and TDI flow velocities. Guides are available for optimizing these recordings and avoiding pitfalls, with many examples.91 Techniques for optimizing CMM mitral inflow velocity propagation and TDI of the mitral annulus are covered in Chapter 18 of this volume. Organizing an echo-Doppler assessment of LV diastolic function into a standard routine helps both the sonographer (Chapter 17) and the physician improve their technical and interpretive skills.61,69,129 We recommend starting with M-mode and twodimensional anatomic imaging to obtain measurements of chamber sizes, maximal LA volume, and LV diastolic and systolic volumes. LV mass, relative wall thickness,130 and LVEF are then calculated. Variables of special importance include absolute LV mass and LV relative wall thickness (normal <42%) and maximal LA size (normal <32 ml/m2).
After the two-dimensional exam is finished, an apical fourchamber color Doppler screen is performed to check for significant valvular regurgitation. CMM of mitral inflow and LV outflow is then used to preview the LV filling pattern and mitral E-wave flow velocity propagation, as well as whether systolic LV intracavitary gradients or IVRT flow is present. CW Doppler is activated to profile the LV filling and ejection velocities throughout the ventricle. CW technique is used before PW Doppler because CW profiles the mitral inflow pattern, provides a reference for the peak E- and A-wave velocities that will be obtained during the subsequent PW Doppler interrogation, and displays IVRT flow and the magnitude of any systolic intracavitary gradients. PW Doppler mitral inflow velocity, mitral velocity response to Valsalva maneuver, and PW Doppler of PV flow is then performed. If confusion still exists regarding the normalcy of the LV filling pattern, TDI spectral Doppler of mitral annular motion (lateral, medial, or both) will usually help make this distinction, and together with peak mitral E-wave velocity may indicate whether normal or increased mean LA pressure is present. Before leaving the left side of the heart, any LV intracavitary gradients or IVRT flow seen on
135
136
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling the CMM screen are located and quantified by PW Doppler. The transducer is then moved medially toward the sternum, and PW Doppler of tricuspid inflow along with estimation of PA systolic pressures using peak TR velocity by CW Doppler is performed. Finally, PW analysis of Doppler hepatic veins and superior vena caval flow throughout respiration is recorded.131 With practice and performing a complete diastolic function exam on every patient, the components we have listed can be completed with only an additional 5 to 10 minutes of scanning time. The information derived not only helps assess LV diastolic function, filling pressures, and future possible adverse cardiovascular events, but also aids patient management decisions.
MITRAL FLOW VELOCITY PATTERNS: INTERPRETIVE CHALLENGES Mitral E/A Ratio Below 1 The most common mitral filling pattern is also the one most frequently misinterpreted and therefore deserves special mention. The “true” impaired relaxation filling pattern is due to slow LV relaxation with normal mean LA pressure (see Fig. 10-14). Criteria include normal LA volume, with “hypercontractile”appearing LA systolic function (especially in the parasternal long axis view) due to ejection into a ventricle with a lower than normal preA pressure. Compared with normal age-related values, the LV IVRT and mitral DT should be prolonged, mitral E-wave velocity should be lower than expected for age and LVOT velocity, and the preA velocity should be below 20 cm/sec. If the analysis stops here, the interpretation is incomplete, for it has not been determined whether LV end diastolic compliance and pressure are normal or abnormal, the latter being the first indication of elevated LV filling pressures (see Fig. 10-2). This can be determined only by comparing the duration of mitral and PV flow velocity A waves, as previously described. If PVa duration is more than 30 msec longer than mitral A-wave duration, LVED pressure is elevated and LV compliance is reduced, indicating that early diastolic dysfunction is present (see Fig. 10-13). There are two common instances where the E/A wave velocity ratio is less than 1, implying an impaired relaxation filling pattern, and yet the diastolic abnormalities are more severe and closer to pseudonormal with decreased LV compliance and increased mean LA pressure. The first occurs when the mitral velocity at atrial contraction is above 20 cm/sec and there is fusion of early and late diastolic LV filling (see Figs. 10-16, 10-17, and 10-21). In this case, the A-wave velocity is higher than it would be at a slower heart rate or shorter P-R interval, which reduces the E/A wave ratio to below 1. A premature beat or slower heart rate will reveal the pseudonormal filling pattern. An E/A ratio of less than 1 with increased filling pressures can also be seen in patients with marked LVH and severely impaired LV relaxation. In these cases, a markedly elevated LA pressure may be needed before the filling pattern appears pseudonormal (see Fig. 10-9). In both instances, the presence of moderate or severe LVH, increased LA volume, E-wave velocity that approaches or exceeds LVOT velocity, and increased E/E′ ratio are all clues that despite the E/A wave ratio of below 1, mean LA pressure is elevated.
Mitral Regurgitation and Stenosis Hemodynamically significant MR will increase the volume returning through the mitral valve in early diastole and increase
the mitral E-wave velocity. LA size and the mitral E-wave/LVOT velocity ratio will both be increased. However, LV diastolic dysfunction and filling pressures are not necessarily abnormal since the normal adaptation of the left atrium and ventricle to chronic volume overload is a rightward shift in the pressure-volume relation, which makes both chambers more compliant. A normal mitral DT is the best indicator of a healthy adaptation to the chronic volume overload of MR. Conversely, a shortened mitral DT indicates an abnormal rise in early diastolic LV pressure from reduced LV chamber compliance. This finding is expected in acute MR because of a lack of time for the ventricle to adapt, but in chronic regurgitation it signifies an increase in myocardial stiffness from a process unrelated to the valve disease. A shortened mitral IVRT, decrease in PV systolic fraction, and increase in TR velocity are other indicators of increased left heart filling pressures. MS increases E-wave velocity by reducing orifice size and is associated with a prolonged mitral pressure half-time as well as LA enlargement. Impaired LV relaxation may prolong the mitral DT, while reduced LV myocardial compliance may shorten it independent of valve area. When MS is present, a clinically useful approach is to measure the LV IVRT (whose shortening indicates the degree of mean LA pressure elevation), calculate the mean mitral gradient while noting the heart rate, estimate the mitral valve area by the pressure half-time method, and estimate the PA pressure by TR velocity. If mitral preA velocity is greater than 20 cm/sec, slowing the heart rate may improve the hemodynamic abnormalities and patient symptoms. In patients with mixed MS and MR, the focus is on the valve disease and its consequences rather than LV diastolic dysfunction. The LV IVRT, mitral valve area, and PA pressures become important objective data to relate to patient symptoms.
Sinus Tachycardia: Effect on Left Ventricular Filling Previous animal studies link the normal cardiac pathophysiology that occurs as heart rate increases with changes in mitral flow velocity (see Fig. 10-14). The method by which heart rate is increased (withdrawal of parasympathetic tone, increase in sympathetic tone or exercise) markedly affects when mitral E and A waves begin to fuse and when complete fusion (A-wave flow only) occurs. In normal dogs, withdrawal of parasympathetic tone with atropine administration results in complete fusion of E and A waves at 160 bpm, while with isoproterenol infusion this is not observed until a heart rate of 220 bpm. These differences relate to the effect of each intervention on LV contractility and the degree of shortening of the P-R interval. Increased contractility shortens the LV isovolumic contraction, ejection, and relaxation times so that diastolic filling time is maximized, while shortening of the P-R interval provides for more diastolic filling before atrial contraction. With exercise, increased venous return and LA pressure also result in an earlier mitral valve opening, which also helps keep early and late diastolic filling separated. LVH, systolic dysfunction, increased wall stress, and cardiac conduction system disease (first-degree or LBBB) prolong systolic periods and shorten the diastolic filling time so that Eand A-wave fusion occur at lower heart rates (see Fig. 10-3). This may limit LV filling and result in a reduced exertional cardiac output and functional aerobic capacity, as previously discussed (see Fig. 10-21).
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling
Uncommon Mitral Valve Velocity Patterns Variations in LV filling patterns are seen where impaired LV relaxation persists into mid-diastole, or altered compliance is present only in early diastole rather than throughout the diastolic filling period. This physiology is most commonly present with marked LVH, especially in the elderly with severe and longstanding hypertension132 or in patients with hypertrophic cardiomyopathy. Figure 10-22 shows examples of uncommon mitral LV filling patterns in five such patients. Most typically the initial mitral E-wave velocity is increased compared with LVOT velocity, and there is a short initial mitral DT. The predominant abnor-
mality present is markedly impaired LV relaxation, which causes a severe decrease in LV compliance (the short initial mitral DT) but is confined to early diastole, perhaps because of delayed actinmyosin cross-bridge detachment. In mid-diastole there is continued LV relaxation and a fall in pressure so that the mitral DT markedly slows and becomes nonlinear, or a mid-diastolic filling hump is seen. The width of the A wave is variable depending on the end diastolic compliance of the ventricle. Because of the profound relaxation abnormality, these patients often do well with very slow (40–55 bpm) resting heart rates, while faster heart rates result in inadequate LV filling, exercise intolerance, and pulmonary congestion.
m/sec 1.0
0.5
0
A
B
C
LV pressure
60 cm/sec
D
E
Figure 10-22 Five patients (A to E) with markedly impaired left ventricular (LV) relaxation that results in unusual PW Doppler mitral flow velocity recordings that do not fit conventional LV filling patterns of diastolic dysfunction. All patients are in normal sinus rhythm. Each peak E-wave velocity is followed by an initial restrictive-like mitral DT and then variable degrees of additional filling in mid-diastole and with atrial contraction, indicating profound myocardial relaxation abnormalities and dynamic changes in LV compliance throughout diastole. Patient A has marked LV hypertrophy (LVH) from long-standing hypertension and a normal LV ejection fraction (LVEF). The initial mitral deceleration time (DT) is 100 msec, which then dramatically changes slope to 280 msec in mid-diastole with A-wave duration of 100 msec. LV posterior wall M-mode motion showed continuous filling throughout mid-diastole, indicating ongoing LV relaxation. Patient B is a 35-year-old on dialysis with LVH and normal LVEF. Without the abnormal mid-diastolic filling “hump,” the mitral pattern might be mistaken for normal. Patient C is elderly with hypertension and slight sinus arrhythmia. With a slower heart rate, the filling pattern would be similar to B, but the slightly faster heart rate results in the mid-diastolic filling blending into the A wave, making its true duration difficult to measure except on the first beat. Patient D has a 50-year history of nonobstructive hypertrophic cardiomyopathy with a giant left atrium. The initial mitral DT is only 80 msec, with over two thirds of LV filling occurring in mid-diastole (middle hump) and then with atrial contraction. The patient reports feeling best with a resting heart rate of 40–45 bpm. Functional aerobic capacity is severely reduced with any increase in heart rate. Patient E has a mitral flow velocity somewhat similar to patient D. Patient E’s LV pressure recording shows an initial rapid filling wave correlating with the restrictive early diastolic mitral DT, but then LV pressure declines in mid-diastole with reestablishment of transmitral flow. The cellular mechanisms that result in these marked derangements of LV relaxation and early diastolic restrictive physiology, which are transient rather than fixed, are under investigation.
137
138
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling
Increased Mitral Respiratory Flow Velocity Variation The diagnosis of a number of important conditions is dependent on a measure of increased variations in mitral respiratory flow velocity. The presence of these conditions would be missed in laboratories that do not record mitral flow velocity initially at the slower sweep speed of 50 cm/sec to observe whether increased respiratory variation is present. Although respiratory variation in tricuspid E-wave flow velocity is expected to be 15% to 25%, the respiratory change in mitral E-wave velocity in normals is less than 5%.133 Increased changes in both mitral and tricuspid inflow velocities with respiration can be seen in patients with acute or chronic pulmonary disease134 or pericardial abnormalities, including tamponade,135,136 constriction,133,134,137 and pericardial restraint due to acute cardiac dilation from RV infarction, pulmonary embolus, or acute valvular regurgitation. So that abnormal respiratory mitral changes are not overlooked, we recommend recording mitral flow velocity using CW Doppler from the apical transducer position at a sweep speed of 50 mm/ sec. Any variation greater than 10% with a regular heart rate is considered abnormal. Accompanying changes in the LV IVRT verify that the alterations in velocity are due to alterations in LA pressure and the timing of mitral valve opening. A PW Doppler exam of mitral flow velocity with a respirometer is then performed. The clinical history and characteristic two-dimensional findings (such as an inspiratory septal shift) are noted, along with the exact timing of the flow velocity changes. This will help determine whether pulmonary or pericardial disease is present. The hepatic venous Doppler is especially important and should always be recorded because in primary pericardial disease the heart has difficulty filling normally (low velocities), while with pulmonary disease the heart overfills due to the excessive swings in intrathoracic pressure and RV minimum pressure.134
Atrial Flutter and Fibrillation Regardless of whether there is 2 : 1 or higher-degree AV block, almost no assessment of LV diastolic function can be made from mitral flow velocity when atrial flutter is present. All LV filling is due to atrial contractions, so that no E velocity, E/A wave ratio, or mitral DT is available for measurement. If 3 : 1 or 4 : 1 AV block is present, multiple filling waves are seen with diastolic MR interspersed between each. PA pressure calculated from peak TR velocity may be the best indicator of increased left heart filling pressures if no lung disease is present. New-onset “coarse” atrial fibrillation may resemble atrial flutter in that multiple pulses of blood flowing from atrial contraction enter the ventricle in diastole. This makes the interpretation of peak E-wave velocity and mitral DT difficult to relate to LV diastolic properties. Chronic atrial fibrillation, when LA mechanical function is negligible and the rate is <100 bpm, is easier to interpret. In patients with heart disease, the mitral E wave to TDI E′ ratio119 or LV IVRT is a good indicator of whether filling pressures are elevated. Since all LV filling must occur without an atrial booster pump, mean LA pressure and peak E-wave velocity are usually slightly higher than normal for age, except in young patients with lone atrial fibrillation and vigorous elastic recoil. Mitral DT is generally about 20 msec shorter than in normal sinus rhythm, and PV flow should have a reduced but not absent systolic fraction, since the S1 component due to atrial relaxation is absent. In adult cardiac patients, a short LV IVRT (<60 msec),
mitral E-wave velocity equal to LVOT velocity, short mitral DT (<160 msec), and reduced (<25%) PV systolic fraction and increased E/E′ ratio all suggest reduced LV compliance and increased filling pressures. A mitral DT under 140 msec has been shown to have the same unfavorable prognosis as for patients in sinus rhythm.95 When recording atrial fibrillation, CW technique is again suggested first to display the maximum velocities and measure the LV IVRT. PW Doppler is used for mitral DT, and five beats are averaged to assess mitral variables. Beats with short R-R intervals should be excluded, especially if systole causes an abrupt cessation of mitral inflow. Examples of mitral flow velocity in atrial flutter and atrial fibrillation are shown in Figure 10-23.
Diastolic Mitral and Tricuspid Regurgitation Regurgitation occurs when there is a reverse diastolic transmitral pressure gradient where LV pressure exceeds LA pressure in diastole. Although the magnitude of the reverse transmitral pressure gradient can exceed the normal forward-flow gradient, the amount of regurgitation is hemodynamically insignificant because it is limited by a small AV valve orifice area.138 There are several situations in which diastolic MR and aortic regurgitation can be seen. By far the most common is with first-, second-, or third-degree AV block,139 or with atrial flutter and greater than 2 : 1 AV block (see Fig. 10-23). In these cases, the atrium contracts, and atrial and ventricular pressures both increase. However, in the absence of a normal P-R interval and properly timed ventricular systole, atrial relaxation causes its pressure to fall below ventricular pressure, and diastolic regurgitation occurs. Diastolic MR due to first-degree AV block is usually not seen until the P-R interval exceeds 280 msec. The Doppler findings of first-degree AV block are worth noting, especially if it is causing partial fusion of early and late diastolic filling. Diastolic MR is more pathologic when associated with advanced restrictive LV filling. After filling in mid-diastole or after atrial contraction, there is a marked increase in LV pressure that not only decelerates, but transiently reverses transmitral flow in mid-diastole or after atrial contraction. Aortic regurgitation with marked bradycardia or atrial fibrillation and a very slow ventricular rate is an additional uncommon etiology.
RIGHT VENTRICULAR DIASTOLIC FUNCTION The same Doppler analysis and variables used for mitral flow velocity can be applied to tricuspid inflow and RV filling (see Chapter 14 in this volume).91,140 Because inspiration increases RV filling, changes in tricuspid flow velocity are seen throughout the respiratory cycle, while on the left side of the heart, Doppler mitral variables vary only about 5%.133 This increase in inspiratory RV filling can be used, in conjunction with hepatic and superior vena cava flow velocities, to assess the diastolic properties of the right ventricle. PW Doppler tricuspid DT is about 25 msec longer than its mitral counterpart. With normal RV diastolic function, this value changes little with the increased flow during inspiration, and hepatic A-wave reversals decrease in velocity and duration. With a decrease in late diastolic RV compliance, hepatic venous A-wave velocity and duration increase with inspiration. An inspiratory shortening of tricuspid DT, diastolic predominance of hepatic venous flow with prominent V- and A-wave reversals are signs of
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling ATRIAL FIBRILLATION Mitral Figure 10-23 PW Doppler mitral flow velocity in a patient with atrial flutter and atrial fibrillation. In atrial flutter, left ventricular (LV) filling is a regular pulsation of A waves (arrows), often with mild diastolic mitral regurgitation (dMR) during atrial relaxation. Left atrial (LA) size is often enlarged from the arrhythmia, the isovolumic relaxation time (IVRT) is affected by the atrial contractions, and there is no E wave or mitral deceleration (DT) to measure, making the assessment of diastolic function problematic. In atrial fibrillation (Af ), peak E-wave velocity and mitral DT can be measured but can also be affected by the fibrillatory contractions of the atrium (Af flow = arrows). It is likely that this patient does have an increase in mean LA pressure because the LV IVRT is short (50 msec) and pulmonary venous systolic (PVs) filling is negligible, a sign of reduced LA compliance.
Pulmonary vein
Atrial flutter E
PVd
A A Af
A
Af
–3
–2
dMR
PVs
2
1
a marked decrease in RV compliance and increased diastolic filling pressures.140 The early diastolic slope and A-wave decrease in velocity in pulmonary regurgitation Doppler signals can also be used to assess early and late diastolic RV compliance. The assessment of right heart pressures from inferior vena cava size141 and systemic venous flow (hepatic vein and superior vena cava) has also been described.142,143
USING LEFT VENTRICULAR FILLING PATTERNS FOR PATIENT MANAGEMENT If the only information available from examining LV filling patterns is whether the patient has elevated LA pressure, this can be usually ascertained from the patient’s history, physical examination, chest x-ray, and brain natriuretic peptide level (see Chapter 32). Unique information available from an echo-Doppler study is the identification of early diastolic dysfunction (impaired relaxation filling pattern with elevated LVEDP), with the relation of LV systolic to diastolic function identifying which diastolic property (relaxation or compliance) is most abnormal and which parts of diastole are most affected by these abnormalities. In addition, seeing whether the patient’s heart rate at rest is well matched to the cardiac physiology present is a great strength of the echoDoppler technique that cannot be done reliably by physical exam. Using this information is a powerful tool for intervening to prevent progression of diastolic abnormalities and for treating patients with symptoms of diastolic heart failure to improve their functional status and prognosis. After the echo-Doppler study is completed, the first question is, What is the main cardiac abnormality present: systolic dysfunction, diastolic dysfunction, or valvular heart disease? In patients with a reduced LVEF, diastolic dysfunction is expected and is usually “matched” to the reduction in LVEF. For example, patients with a moderate reduction in LVEF (30%–35%) often have a pseudonormal mitral filling pattern, while patients with severe reduction in LVEF (<20%) commonly demonstrate restrictive filling. A “mismatch” between these expected relations is
notable. Better diastolic than systolic function suggests a welladapted, compliant ventricle. Such individuals often have a good functional capacity and a favorable prognosis.28 Conversely, a pseudonormal or restrictive mitral filling pattern with mild systolic function suggests volume overload (easily detected by imaging of the inferior vena cava) or pathology, which increases myocardial stiffness. Why patients with LV systolic dysfunction have such variability in LV compliance remains a key enigma that requires further investigation. In patients with normal LV systolic function and diastolic heart failure, questions to be answered include whether abnormalities of LV relaxation or compliance predominate, and during what part(s) of diastole are the abnormalities present. This gives an idea of the best approach for short-term therapy and whether altering the heart rate is likely to improve the patient’s symptoms. Although classifying patients as having one of the three abnormal filling patterns is often useful for this purpose, enough variations in LV filling patterns and combinations of LA pressure and rates of LV relaxation exist that the choice of treatments to benefit the patient are still best determined by carefully examining the mitral flow velocity pattern and its individual Doppler variables, as in the patients in Figures 10-15 through 10-19 and Figures 10-21 and 10-22.
FUTURE RESEARCH The greatest limitation to the echo-Doppler assessment of LV diastolic dysfunction is the experience to discern from the information available which of the key diastolic properties (LV relaxation or compliance) is most abnormal, how these are related to LV systolic function, and how both interact to affect the overall LV filling pattern. When first learning to interpret LV diastolic function, there is a tendency to try to make all variables fit into one abnormal LV filling pattern or another, when in reality there are nearly endless variations and exceptions to defined “criteria.” This is why we believe that examining the mitral filling pattern
139
140
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling together with all available two-dimensional and Doppler information is most helpful for patient management. This approach acknowledges that the variables used are imperfect indicators of individual diastolic filling properties or pressures and can sometimes appear contradictory, but in aggregate they usually provide sufficient information to be clinically useful in the great majority of patients. Another common limitation is the lack of technical experience in acquiring high-quality Doppler recordings so that all variables are accurately measured. It can be expected that even when performing a routine diastolic-function examination on every patient undergoing ECG, it could take at least 6 months for sonographers and physicians to master these skills. With the advent of Doppler annular TDI recordings and measurement of LA volume, the problem of identifying patients with pseudonormal LV filling has improved. However, the number of labs that routinely obtain PV flow velocity recordings has likely declined, decreasing the likelihood of identification of an elevated LVEDP at its earliest stage. Therefore, additional and simpler ways to identify LV diastolic dysfunction at its earliest and most treatable stages are needed, as are load-independent indices of LV diastolic filling.78 Atrial fibrillation is becoming increasingly prevalent. More research is needed on ways to assess LV diastolic dysfunction and filling pressures in this important group. Pediatric patients present their own challenges. Isolated diastolic dysfunction is rare in this group, and there is much less literature available to establish when abnormal diastolic properties are present.
ACKNOWLEDGMENTS I am grateful to Dr. Liv Hatle for her help editing the manuscript and figures and the expert preparation of the figures by my friend Marvin Ruona.
ABBREVIATIONS 2D: two-dimensional (echo) bpm: beats per minute CMM: color M-mode (Doppler) CW Doppler: continuous wave Doppler (technique) DHF: diastolic heart failure HF: heart failure IR: impaired relaxation (LV filling) IVRT: isovolumic relaxation time LA: left atrial LBBB: left bundle branch block LV: left ventricular LVEF: LV ejection fraction LVEDP: LV end diastolic pressure LVOT: LV outflow tract LA A-wave: LV pressure rise due to atrial contraction LVH: LV hypertrophy MAM: mitral annular motion Mitral Adur: duration if mitral A-wave velocity Mitral DT: mitral deceleration time MR: mitral regurgitation MS: mitral stenosis PA: pulmonary artery
PN: pseudonormal (LV filling) PV: pulmonary venous PVs1: PV flow velocity in early systole PVs2: PV flow velocity in middle and late systole PVa: flow pulmonary venous flow PV Adur: reverse PV flow velocity at atrial contraction PW Doppler: pulsed wave Doppler (technique) RST: restrictive (LV filling) RV: right ventricular SHF: systolic heart failure TDI: tissue Doppler imaging TMPG: transmitral pressure gradient TR: tricuspid regurgitation REFERENCES 1. Ingels NB Jr., Daughters GT 2nd, Nikolic SD, et al: Left atrial pressureclamp servomechanism demonstrates LV suction in canine hearts with normal mitral valves. Am J Physiol 1994;267:H354–362. 2. Child JS, Perloff JK: The restrictive cardiomyopathies. Cardiol Clin 1988;6:289–316. 3. Braunwald E: Hypertrophic cardiomyopathy—continued progress. N Engl J Med 1989;320:800–802. 4. Hammermeister KE, Warbasse JR: The rate of change of left ventricular volume in man. II. Diastolic events in health and disease. Circulation 1974;49:739–747. 5. Gibson DG, Brown DJ: Measurement of peak rates of left ventricular wall movement in man. Comparison of echocardiography with angiography. Br Heart J 1975;37:677–683. 6. Upton MT, Gibson DG, Brown DJ: Echocardiographic assessment of abnormal left ventricular relaxation in man. Br Heart J 1976;38: 1001–1019. 7. Soufer R, Wohlgelernter D, Vita NA, et al: Intact systolic left ventricular function in clinical congestive heart failure. Am J Cardiol 1985;55: 1032–1036. 8. Topol EJ, Traill TA, Fortuin NJ: Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med 1985;312:277–283. 9. Little WC, Applegate RJ: Invasive evaluation of left ventricular diastolic performance. Herz 1990;15:362–376. 10. Hanrath P, Mathey, DG, Siegert, R, Bleifeld, W: Left ventricular relaxation and filling pattern in different forms of left ventricular hypertrophy: An echocardiographic study. Am J Cardiol 1980;45:15–23. 11. Rokey R, Kuo LC, Zoghbi WA, et al: Determination of parameters of left ventricular diastolic filling with pulsed Doppler echocardiography: Comparison with cineangiography. Circulation 1985;71:543–550. 12. Spirito P, Maron BJ, Bonow RO: Noninvasive assessment of left ventricular diastolic function: Comparative analysis of Doppler echocardiographic and radionuclide angiographic techniques. J Am Coll Cardiol 1986;7: 518–526. 13. Kitabatake A, Inoue M, Asao M, et al: Transmitral blood flow reflecting diastolic behavior of the left ventricle in health and disease—a study by pulsed Doppler technique. Jpn Circ J 1982;46:92–102. 14. Tanouchi J, Kitabatake A, Asao M, et al: Role of left ventricular relaxation on transmitral flow dynamics during early diastole: Pulsed Doppler flowmetry. J Cardiogr 1983;13:301–307. 15. Kuo LC, Quinones MA, Rokey R, et al: Quantification of atrial contribution to left ventricular filling by pulsed Doppler echocardiography and the effect of age in normal and diseased hearts. Am J Cardiol 1987;59: 1174–1178. 16. Gardin JM, Drayer JI, Weber M, et al: Doppler echocardiographic assessment of left ventricular systolic and diastolic function in mild hypertension. Hypertension 1987;9:I190–I196. 17. Klein AL, Burstow DJ, Tajik AJ, et al: Effects of age on left ventricular dimensions and filling dynamics in 117 normal persons. Mayo Clin Proc 1994;69:212–224. 18. Miyatake K, Okamoto, M, Kinoshita, N, et al: Augmentation of atrial contribution to left ventricular inflow with aging as assessed by intracardiac Doppler flowmetry. Am J Cardiol 1984;70:586–589. 19. Appleton CP, Hatle LK, Popp RL: Relation of transmitral flow velocity patterns to left ventricular diastolic function: New insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol 1988;12:426–440.
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 20. Klein AL HL, Taliercio CP, Oh JK, et al: Prognostic significance of diastolic function in cardiac amyloidosis. A Doppler echocardiographic study. Circulation 1991;83:808–816. 21. Pinamonti B, Di Lenarda A, Sinagra G, Camerini F: Restrictive left ventricular filling pattern in dilated cardiomyopathy assessed by Doppler echocardiography: Clinical, echocardiographic and hemodynamic correlations and prognostic implications. Heart Muscle Disease Study Group. J Am Coll Cardiol 1993;22:808–815. 22. Rich MW, Stitziel NO, Kovacs SJ: Prognostic value of diastolic filling parameters derived using a novel image processing technique in patients > or = 70 years of age with congestive heart failure. Am J Cardiol 1999;84:82–86. 23. Xie GY, Berk MR, Smith MD, et al: Prognostic value of Doppler transmitral flow patterns in patients with congestive heart failure. J Am Coll Cardiol 1994;24:132–139. 24. Appleton CP: The natural history of left ventricular filling abnormalities: Assessment by two-dimensional and Doppler echocardiography. Echocardiography 1992;9:437–457. 25. Keren G, Pardes A, Miller HI, et al: Pulmonary venous flow determined by Doppler echocardiography in mitral stenosis. Am J Cardiol 1990;65: 246–249. 26. Klein AL: Doppler assessment of pulmonary venous flow in healthy subjects and patients with heart disease. J Am Soc Echocardiogr 1991;4:379– 392. 27. Kuecherer HF, Muhiudeen IA, Kusumoto FM, et al: Estimation of mean left atrial pressure from transesophageal pulsed Doppler echocardiography of pulmonary venous flow. Circulation 1990;82:1127–1139. 28. Pozzoli M, Traversi E, Cioffi G, et al: Loading manipulations improve the prognostic value of Doppler evaluation of mitral flow in patients with chronic heart failure. Circulation 1997;95:1222–1230. 29. Dumesnil JG, Gaudreault G, Honos GN, Kingma JG Jr: Use of Valsalva maneuver to unmask left ventricular diastolic function abnormalities by Doppler echocardiography in patients with coronary artery disease or systemic hypertension. Am J Cardiol 1991;68:515–519. 30. Hurrell DG, Nishimura RA, Ilstrup DM, Appleton CP: Utility of preload alteration in assessment of left ventricular filling pressure by Doppler echocardiography: A simultaneous catheterization and Doppler echocardiographic study. J Am Coll Cardiol 1997;30:459–467. 31. Klein AL, Hatle LK, Taliercio CP, et al: Prognostic significance of Doppler measures of diastolic function in cardiac amyloidosis. A Doppler echocardiography study. Circulation 1991;83:808–816. 32. Pinamonti B, Zecchin M, Di Lenarda A, et al: Persistence of restrictive left ventricular filling pattern in dilated cardiomyopathy: An ominous prognostic sign. J Am Coll Cardiol 1997;29:604–612. 33. Brun P, Tribouilloy C, Duval AM, et al: Left ventricular flow propagation during early filling is related to wall relaxation: A color M-mode Doppler analysis. J Am Coll Cardiol 1992;20:420–432. 34. Garcia MJ, Rodriguez L, Ares M, et al: Differentiation of constrictive pericarditis from restrictive cardiomyopathy: Assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol 1996;27:108–114. 35. Garcia MJ, Smedira NG, Greenberg NL, et al: Color M-mode Doppler flow propagation velocity is a preload insensitive index of left ventricular relaxation: Animal and human validation. J Am Coll Cardiol 2000;35: 201–208. 36. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32: 865–875. 37. Kovacs SJ Jr, Barzilai B, Perez JE: Evaluation of diastolic function with Doppler echocardiography: The PDF formalism. Am J Physiol 1987;252: H178–187. 38. Kovacs SJ, Meisner JS, Yellin EL: Modeling of diastole. Cardiol Clin 2000;18:459–487. 39. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 40. Yellin EL, Meisner JS: Physiology of diastolic function and transmitral pressure-flow relations. Cardiol Clin 2000;18:411–433, vii. 41. Thomas JD, Newell JB, Choong CY, Weyman AE: Physical and physiological determinants of transmitral velocity: Numerical analysis. Am J Physiol 1991;260:H1718–H1731. 42. Choong CY, Abascal VM, Thomas JD, et al: Combined influence of ventricular loading and relaxation on the transmitral flow velocity profile in dogs measured by Doppler echocardiography. Circulation 1988;78:672– 683.
43. Greenberg NL, Vandervoort PM, Firstenberg MS, et al: Estimation of diastolic intraventricular pressure gradients by Doppler M-mode echocardiography. Am J Physiol Heart Circ Physiol 2001;280:H2507– H2515. 44. Greenberg NL, Vandervoort PM, Thomas JD: Automated assessment of color Doppler M-mode flow velocity propagation features. Computers in Cardiology 1996:201–204. 45. Riordan MM, Kovacs SJ: Quantitation of mitral annular oscillations and longitudinal “ringing” of the left ventricle: A new window into longitudinal diastolic function. J Appl Physiol 2006;100:112–119. 46. Riordan MM, Kovacs SJ: Absence of diastolic mitral annular oscillations is a marker for relaxation-related diastolic dysfunction. Am J Physiol Heart Circ Physiol 2007;292:H2952–H2958. 47. Garcia MJ: Comprehensive echocardiographic assessment of diastolic function. Heart Fail Clin 2006;2:163–178. 48. Oh JK, Hatle L, Tajik AJ, Little WC: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506. 49. Appleton CP, Firstenberg MS, Garcia MJ, Thomas JD: The echo-Doppler evaluation of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–546, ix. 50. Bursi F, Weston SA, Redfield MM, et al: Systolic and diastolic heart failure in the community. JAMA 2006;296:2209–2216. 51. Giannuzzi P, Temporelli PL, de Vito F, et al: Doppler-derived mitral deceleration time of early filling as a strong predictor of pulmonary wedge pressure in postinfarction patients with left ventricular dysfunction. J Am Coll Cardiol 1994;23:1630–1637. 52. Ishida Y, Meisner JS, Tsujioka K, et al: Left ventricular filling dynamics: Influence of left ventricular relaxation and left atrial pressure [published erratum appears in Circulation 1986 Sep;74(3):462]. Circulation 1986;74:187–196. 53. Nishimura RA, Rihal CS, Tajik AJ, Holmes DR Jr: Accurate measurement of the transmitral gradient in patients with mitral stenosis: A simultaneous catheterization and Doppler echocardiographic study. J Am Coll Cardiol 1994;24:152–158. 54. Thomas JD, Choong CY, Flachskampf FA, Weyman AE: Analysis of the early transmitral Doppler velocity curve: Effect of primary physiologic changes and compensatory preload adjustment. J Am Coll Cardiol 1990;16:644–655. 55. Nishimura RA, Housmans PR, Hatle LK, Tajik AJ: Assessment of diastolic function of the heart: Background and current applications of Doppler echocardiography. Part I. Physiologic and pathophysiologic features. Mayo Clin Proc 1989;64:71–81. 56. Cheng CP, Freeman GL, Santamore WP, et al: Effect of loading conditions, contractile state, and heart rate on early diastolic left ventricular filling in conscious dogs. Circ Res 1990;66:814–823. 57. Ingels NB Jr, Daughters GT, Nikolic SD, et al: Left ventricular diastolic suction with zero left atrial pressure in open-chest dogs. Am J Physiol 1996;270:H1217–1224. 58. Takagi S, Yokota M, Iwase M, et al: The important role of left ventricular relaxation and left atrial pressure in the left ventricular filling velocity profile. Am Heart J 1989;118:954–962. 59. Nishimura RA, Schwartz RS, Tajik AJ, Holmes DR Jr: Noninvasive measurement of rate of left ventricular relaxation by Doppler echocardiography. Validation with simultaneous cardiac catheterization. Circulation 1993;88: 146–155. 60. Snider AR, Gidding SS, Rocchini AP, et al: Doppler evaluation of left ventricular diastolic filling in children with systemic hypertension. Am J Cardiol 1985;56:921–926. 61. Oh JK, Appleton CP, Hatle LK, et al: The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 1997;10:246–270. 62. Redfield MM: Understanding “diastolic” heart failure. N Engl J Med 2004;350:1930–1931. 63. Appleton CP, Gonzalez MS, Basnight MA: Relationship of left atrial pressure and pulmonary venous flow velocities: Importance of baseline mitral and pulmonary venous flow velocity patterns studied in lightly sedated dogs. J Am Soc Echocardiogr 1994;7:264–275. 64. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. 65. Rossvoll O, Hatle LK: Pulmonary venous flow velocities recorded by transthoracic Doppler ultrasound: Relation to left ventricular diastolic pressures. J Am Coll Cardiol 1993;21:1687–1696.
141
142
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 66. Yamamoto K, Nishimura RA, Burnett JC Jr, Redfield MM: Assessment of left ventricular end-diastolic pressure by Doppler echocardiography: Contribution of duration of pulmonary venous versus mitral flow velocity curves at atrial contraction. J Am Soc Echocardiogr 1997;10:52–59. 67. Nishimura RA, Appleton CP, Redfield MM, et al: Noninvasive Doppler echocardiographic evaluation of left ventricular filling pressures in patients with cardiomyopathies: A simultaneous Doppler echocardiographic and cardiac catheterization study. J Am Coll Cardiol 1996;28:1226– 1233. 68. Vanoverschelde JL, Raphael DA, Robert AR, Cosyns JR: Left ventricular filling in dilated cardiomyopathy: Relation to functional class and hemodynamics. J Am Coll Cardiol 1990;15:1288–1295. 69. Rakowski H, Appleton C, Chan KL, et al: Canadian consensus recommendations for the measurement and reporting of diastolic dysfunction by echocardiography: From the Investigators of Consensus on Diastolic Dysfunction by Echocardiography. J Am Soc Echocardiogr 1996;9:736–760. 70. Appleton CP, Hatle LK, Popp RL: Demonstration of restrictive ventricular physiology by Doppler echocardiography. J Am Coll Cardiol 1988;11: 757–768. 71. Cheng CP, Igarashi Y, Little WC: Mechanism of augmented rate of left ventricular filling during exercise. Circ Res 1992;70:9–19. 72. Kitzman DW, Higginbotham MB, Cobb FR, et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17: 1065–1072. 73. Appleton CP: Influence of incremental changes in heart rate on mitral flow velocity: Assessment in lightly sedated, conscious dogs. J Am Coll Cardiol 1991;17:227–236. 74. Cuocolo A, Sax FL, Brush JE, et al: Left ventricular hypertrophy and impaired diastolic filling in essential hypertension. Diastolic mechanisms for systolic dysfunction during exercise. Circulation 1990;81:978–986. 75. Jensen JL, Williams FE, Beilby BJ, et al: Feasibility of obtaining pulmonary venous flow velocity in cardiac patients using transthoracic pulsed wave Doppler technique. J Am Soc Echocardiogr 1997;10:60–66. 76. Ohno M, Cheng CP, Little WC: Mechanism of altered patterns of left ventricular filling during the development of congestive heart failure. Circulation 1994;89:2241–2250. 77. Manson AL, Nudelman SP, Hagley MT, et al: Relationship of the third heart sound to transmitral flow velocity deceleration. Circulation 1995;92:388–394. 78. Shmuylovich L, Kovacs SJ: Load-independent index of diastolic filling: Model-based derivation with in vivo validation in control and diastolic dysfunction subjects. J Appl Physiol 2006;101:92–101. 79. Nishimura RA, Tajik AJ: Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta Stone. J Am Coll Cardiol 1997;30:8–18. 80. Redfield MM, Jacobsen SJ, Burnett JC Jr, et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202. 81. Hoit BD, Shao Y, Gabel M, Walsh RA: Influence of loading conditions and contractile state on pulmonary venous flow. Validation of Doppler velocimetry. Circulation 1992;86:651–659. 82. Basnight MA, Gonzalez MS, Kershenovich SC, Appleton CP: Pulmonary venous flow velocity: Relation to hemodynamics, mitral flow velocity and left atrial volume, and ejection fraction. J Am Soc Echocardiogr 1991;4:547–558. 83. Appleton CP: Hemodynamic determinants of Doppler pulmonary venous flow velocity components: New insights from studies in lightly sedated normal dogs. J Am Coll Cardiol 1997;30:1562–1574. 84. Smiseth OA, Thompson CR, Lohavanichbutr K, et al: The pulmonary venous systolic flow pulse—its origin and relationship to left atrial pressure. J Am Coll Cardiol 1999;34:802–809. 85. Keren G, Sherez J, Megidish R, et al: Pulmonary venous flow pattern—its relationship to cardiac dynamics. A pulsed Doppler echocardiographic study. Circulation 1985;71:1105–1112. 86. Bartzokis T, Lee R, Yeoh TK, et al: Transesophageal echo-Doppler echocardiographic assessment of pulmonary venous flow patterns. J Am Soc Echocardiogr 1991;4:457–464. 87. Kuecherer HF, Kusumoto F, Muhiudeen IA, et al: Pulmonary venous flow patterns by transesophageal pulsed Doppler echocardiography: Relation to parameters of left ventricular systolic and diastolic function. Am Heart J 1991;122:1683–1693. 88. Klein AL, Abdalla I, Murray RD, et al: Age independence of the difference in duration of pulmonary venous atrial reversal flow and transmitral A-wave flow in normal subjects. J Am Soc Echocardiogr 1998;11:458–465.
89. Appleton CP, Galloway JM, Gonzalez MS, et al: Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993;22:1972–1982. 90. O’Leary PW, Durongpisitkul K, Cordes TM, et al: Diastolic ventricular function in children: A Doppler echocardiographic study establishing normal values and predictors of increased ventricular end-diastolic pressure. Mayo Clin Proc 1998;73:616–628. 91. Appleton CP, Jensen JL, Hatle LK, Oh JK: Doppler evaluation of left and right ventricular diastolic function: A technical guide for obtaining optimal flow velocity recordings. J Am Soc Echocardiogr 1997;10:271– 292. 92. Nishimura RA, Abel MD, Hatle LK, Tajik AJ: Assessment of diastolic function of the heart: Background and current applications of Doppler echocardiography. Part II. Clinical studies. Mayo Clin Proc 1989;64: 181–204. 93. Sasson Z, Hatle L, Appleton CP, et al: Intraventricular flow during isovolumic relaxation: Description and characterization by Doppler echocardiography. J Am Coll Cardiol 1987;10:539–546. 94. Klein AL, Hatle LK, Taliercio CP, et al: Serial Doppler echocardiographic follow-up of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1990;16:1135–1141. 95. Hurrell DG, Oh JK, Mahoney DW, et al: Short deceleration time of mitral inflow E velocity: Prognostic implication with atrial fibrillation versus sinus rhythm. J Am Soc Echocardiogr 1998;11:450–457. 96. Little WC, Ohno M, Kitzman DW, et al: Determination of left ventricular chamber stiffness from the time for deceleration of early left ventricular filling. Circulation 1995;92:1933–1939. 97. Hirota Y: A clinical study of left ventricular relaxation. Circulation 1980;62:756–763. 98. Matsuda Y, Toma Y, Matsuzaki M, et al: Change of left atrial systolic pressure waveform in relation to left ventricular end-diastolic pressure. Circulation 1990;82:1659–1667. 99. Tenenbaum A, Motro M, Hod H, et al: Shortened Doppler-derived mitral A wave deceleration time: An important predictor of elevated left ventricular filling pressure. J Am Coll Cardiol 1996;27:700–705. 100. Nishimura RA, Schwartz RS, Holmes DR Jr, Tajik AJ: Failure of calcium channel blockers to improve ventricular relaxation in humans. J Am Coll Cardiol 1993;21:182–188. 101. Sohn DW, Choi YJ, Oh BH, et al: Estimation of left ventricular enddiastolic pressure with the difference in pulmonary venous and mitral A durations is limited when mitral E and A waves are overlapped. J Am Soc Echocardiogr 1999;12:106–112. 102. Appleton CP: Doppler assessment of left ventricular diastolic function: The refinements continue. J Am Coll Cardiol 1993;21:1697–1700. 103. Garcia MJ: Diastolic dysfunction and heart failure: Causes and treatment options. Cleve Clin J Med 2000;67:727–729, 733–738. 104. Nishimura RA, Appleton CP: “Diastology”: Beyond E and A. J Am Coll Cardiol 1996;27:372–374. 105. Quinones MA: Assessment of diastolic function. Prog Cardiovasc Dis 2005;47:340–355. 106. Tsang TS, Barnes ME, Gersh BJ, et al: Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90:1284–1289. 107. Maurer MS, Spevack D, Burkhoff D, Kronzon I: Diastolic dysfunction: Can it be diagnosed by Doppler echocardiography? J Am Coll Cardiol 2004;44: 1543–1549. 108. Badano LP, Albanese MC, De Biaggio P, et al: Prevalence, clinical characteristics, quality of life, and prognosis of patients with congestive heart failure and isolated left ventricular diastolic dysfunction. J Am Soc Echocardiogr 2004;17:253–261. 109. Moller JE, Poulsen SH, Sondergaard E, et al: Impact of early changes in left ventricular filling pattern on long-term outcome after acute myocardial infarction. Int J Cardiol 2003;89:207–215. 110. Oh JK, Ding ZP, Gersh BJ, et al: Restrictive left ventricular diastolic filling identifies patients with heart failure after acute myocardial infarction. J Am Soc Echocardiogr 1992;5:497–503. 111. Ommen SR, Tsang TS, Ammash NM, et al: Usefulness of serial echocardiographic parameters for predicting the subsequent occurrence of atrial fibrillation. Am J Cardiol 2001;87:1298–1301. 112. Rihal CS, Nishimura RA, Hatle LK, et al: Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy. Relation to symptoms and prognosis. Circulation 1994;90:2772–2779.
Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 113. Tsang TS, Gersh BJ, Appleton CP, et al: Left ventricular diastolic dysfunction as a predictor of the first diagnosed nonvalvular atrial fibrillation in 840 elderly men and women. J Am Coll Cardiol 2002;40:1636– 1644. 114. Gibson DG, Prewitt TA, Brown DJ: Analysis of left ventricular wall movement during isovolumic relaxation and its relation to coronary artery disease. Br Heart J 1976;38:1010–1019. 115. Abhayaratna WP, Seward JB, Appleton CP, et al: Left atrial size: Physiologic determinants and clinical applications. J Am Coll Cardiol 2006;47: 2357–2363. 116. Tsang TS, Barnes ME, Bailey KR, et al: Left atrial volume: Important risk marker of incident atrial fibrillation in 1655 older men and women. Mayo Clin Proc 2001;76:467–475. 117. Lang RM, Bierig M, Devereux RB, et al: Recommendations for chamber quantification: A report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–1463. 118. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527– 1533. 119. Nagueh SF, Kopelen HA, Quinones MA: Assessment of left ventricular filling pressures by Doppler in the presence of atrial fibrillation. Circulation 1996;94:2138–2145. 120. Nagueh SF, Mikati I, Kopelen HA, et al: Doppler estimation of left ventricular filling pressure in sinus tachycardia. A new application of tissue Doppler imaging. Circulation 1998;98:1644–1650. 121. Alam M, Wardell J, Andersson E, et al: Characteristics of mitral and tricuspid annular velocities determined by pulsed wave Doppler tissue imaging in healthy subjects. J Am Soc Echocardiogr 1999;12:618–628. 122. Garcia MJ, Rodriguez L, Ares M, et al: Myocardial wall velocity assessment by pulsed Doppler tissue imaging: Characteristic findings in normal subjects. Am Heart J 1996;132:648–656. 123. Garcia MJ, Thomas JD: Tissue Doppler to assess diastolic left ventricular function. Echocardiography 1999;16:501–508. 124. Oki T, Tabata T, Mishiro Y, et al: Pulsed tissue Doppler imaging of left ventricular systolic and diastolic wall motion velocities to evaluate differences between long and short axes in healthy subjects. J Am Soc Echocardiogr 1999;12:308–313. 125. Oki T, Tabata T, Yamada H, et al: Clinical application of pulsed Doppler tissue imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 1997;79:921–928. 126. Rodriguez L, Garcia M, Ares M, et al: Assessment of mitral annular dynamics during diastole by Doppler tissue imaging: Comparison with mitral Doppler inflow in subjects without heart disease and in patients with left ventricular hypertrophy. Am Heart J 1996;131:982–987. 127. Nagueh SF, Rao L, Soto J: Hemodynamic mechanisms that account for the variable effect of preload on tissue Doppler early diastolic velocity. Circulation 2002;107:2306.
128. Ha JW, Oh JK, Pellikka PA, et al: Diastolic stress echocardiography: A novel noninvasive diagnostic test for diastolic dysfunction using supine bicycle exercise Doppler echocardiography. J Am Soc Echocardiogr 2005;1 8:63–68. 129. Cohen GI, Pietrolungo JF, Thomas JD, Klein AL: A practical guide to assessment of ventricular diastolic function using Doppler echocardiography. J Am Coll Cardiol 1996;27:1753–1760. 130. Koren MJ, Casale PN, Savage DD, Laragh JH: Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114:345–352. 131. Appleton CP, Hatle LK, Popp RL: Superior vena cava and hepatic vein Doppler echocardiography in healthy adults. J Am Coll Cardiol 1987;10:1032–1039. 132. Ha JW, Oh JK, Redfield MM, et al: Triphasic mitral inflow velocity with middiastolic filling: Clinical implications and associated echocardiographic findings. J Am Soc Echocardiogr 2004;17:428–431. 133. Hatle LK, Appleton CP, Popp RL: Differentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370. 134. Boonyaratavej S, Oh JK, Tajik AJ, et al: Comparison of mitral inflow and superior vena cava Doppler velocities in chronic obstructive pulmonary disease and constrictive pericarditis. J Am Coll Cardiol 1998;32:2043– 2048. 135. Burstow DJ, Oh JK, Bailey KR, et al: Cardiac tamponade: Characteristic Doppler observations. Mayo Clin Proc 1989;64:312–324. 136. Appleton CP, Hatle LK, Popp RL: Cardiac tamponade and pericardial effusion: Respiratory variation in transvalvular flow velocities studied by Doppler echocardiography. J Am Coll Cardiol 1988;11:1020–1030. 137. McCully RB, Higano ST, Oh JK: Diagnosis of constrictive pericarditis. Circulation 1999;99:2476. 138. Appleton CP, Basnight MA, Gonzalez MS: Diastolic mitral regurgitation with atrioventricular conduction abnormalities: Relation of mitral flow velocity to transmitral pressure gradients in conscious dogs. J Am Coll Cardiol 1991;18:843–849. 139. Schnittger I, Appleton CP, Hatle LK, Popp RL: Diastolic mitral and tricuspid regurgitation by Doppler echocardiography in patients with atrioventricular block: New insight into the mechanism of atrioventricular valve closure. J Am Coll Cardiol 1988;11:83–88. 140. Klein AL, Hatle LK, Burstow DJ, et al: Comprehensive Doppler assessment of right ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1990;15:99–108. 141. Simonson JS, Schiller NB: Sonospirometry: A new method for noninvasive estimation of mean right atrial pressure based on two-dimensional echographic measurements of the inferior vena cava during measured inspiration. J Am Coll Cardiol 1988;11:557–564. 142. Nageh MF, Kopelen HA, Zoghbi WA, et al: Estimation of mean right atrial pressure using tissue Doppler imaging. Am J Cardiol 1999;84:1448–1451, A8. 143. Nagueh SF, Kopelen HA, Zoghbi WA: Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function. Circulation 1996;93:1160–1169.
143
L. LEONARDO RODRIGUEZ, MD
11
Evaluation of Diastolic Function by Color M-Mode Doppler INTRODUCTION BACKGROUND Obtaining and Measuring Flow Propagation Color M-Mode Intraventricular Pressure Gradients Pathophysiology
CLINICAL RELEVANCE Pseudonormal Filling Patterns Estimation of Left Atrial Pressures Use of Color M-Mode in Clinical Settings Limitations of Color M-Mode Indices FUTURE RESEARCH
COLOR M-MODE DOPPLER AND DIASTOLIC FUNCTION
INTRODUCTION Pulsed-wave Doppler velocities of mitral inflow are the most commonly used indices of diastolic function. Their application is nevertheless limited by their load dependency. Flow propagation (Vp) using Doppler color M-mode (CMM) has been proposed as a complementary technique to evaluate left ventricular (LV) relaxation. Color Doppler M-mode echocardiography provides a spatiotemporal map of blood distribution (v(s,t)) within the heart, with a typical temporal resolution of 5 ms, a spatial resolution of 300 microns, and a velocity resolution of 3 cm/s. By aligning the cursor parallel to the streamlines of flow, we can observe the propagation of flow from the mitral valve to the apex (Fig. 11-1). Assessment of diastolic flow propagation has offered novel information about LV filling dynamics and has been applied in a variety of clinical conditions. Since the initial descriptions by Jacobs1 and later Brun,2 computer simulation,3 in vitro modeling,4 and animal5,6 and clinical studies2,5–8 have improved our understanding of the determinant of Vp but also have shown the complexity of this index. Vp appears to be relatively independent of loading conditions and therefore may overcome one of the main limitations of Doppler-based techniques.2,5,7,9 In this chapter we will review the current understanding of how flow propagates from the base to the apex of the left ventricle, its major determinants, how to properly obtain a color M-mode
tracing, and clinical situations in which this technique may be applied. We will also describe its application in the calculation of intraventricular pressure gradients (IVPGs).
BACKGROUND It is now well recognized that in early diastole small but significant intraventricular mitral-to-apex pressure gradients are generated.10,11 These IVPGs are related to elastic recoil12–14 and apical untwisting. They represent one of the driving forces of the blood entering the left ventricle (ventricular “suction”). As a result, when the mitral valve opens, a column of blood accelerates from the atrium toward the ventricular apex. In normal ventricles, flow propagates very rapidly, while in dilated, poorly contracted ventricles it occurs comparatively slowly (Fig. 11-2, right).2 Mitral inflow propagation displayed by CMM has a complex pattern. The earliest CMM velocities often occur during isovolumic relaxation. After the mitral valve opens, there is a rapid initial component (phase I), often followed by a slower component (phase II). Finally, the last component in late diastole is associated with atrial contraction (see Fig. 11-1). Computer and in vitro modeling have studied the phenomenon of flow propagation. During phase I, blood moves almost simultaneously in the whole left ventricle, behaving as an incompressible fluid column (columnar flow).3,4 Phase II is a flow wave thought to be caused by 145
146
Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler propagation of a ring vortex formed at the ventricular base.3,4,15,16 Vortices are formed during the acceleration phases of the early and atrial filling waves. During the deceleration phases, the vortices are amplified and convected into the ventricle (Figs. 11-3 and 11-4).3 The formation of a vortex is affected by the size of the inlet (mitral orifice)4 and the geometry and size of the receiving chamber. In small, tubular ventricles there is predominant columnar flow with no space from the mitral leaflets to the ventricular wall for vortex formation. In dilated ventricles with decreased ratio of mitral valve orifice to ventricular diameter, there would be predominant vortex formation and propagation.4 In this circumstance, flow velocities at the mitral tips can be relatively high, but the velocity of the front wave propagation remains slow. This explains why patients with a restrictive filling pattern can have a peak E-wave velocity greater than 1 m/sec at the level of the mitral level tips and at the same time a flow velocity propagation of 40 cm/sec or less. In in vitro modeling, the ratio of flow velocity to vortex propagation is around 2 : 1.4
Obtaining and Measuring Flow Propagation CMM flow propagation is usually measured from the apical fourchamber view. The M-mode cursor is carefully aligned with direc.45
Late (A Wave) Color M-Mode Flow Propagation
.75 22
tion of flow, maximizing the distance from mitral tips to apex. At least 4 cm of CMM depth should be obtained and displayed at 100 cm/sec sweep speed. In the initial description by Brun,2 CMM flow propagation was measured as the slope of colornoncolor interface. The use of the slope of the color-noncolor interface is limited by its interference with isovolumic flow. Since then, several other methods have been proposed. This constitutes one of the main limitations of this technique, as it is difficult to compare studies among different authors. The slope of the first aliasing velocity has also been used by several authors, setting the aliasing velocity at a percentage (40%–70%) of the maximal inflow velocity (see Fig. 11-2).5,17 An aliasing velocity of 40% of the peak E-wave velocity appears to be more reproducible and to better reflect the velocity of propagation.17 There are no consensus guidelines as to whether phase I or phase II should be measured. Garcia et al. proposed the use of phase II when present.18 Stugaard et al. used a computer algorithm to detect the maximal velocities along the center of the flow propagation wave and measured the time delay between the velocity at mitral tips and apex.8 This method is attractive, for it appears to be more objective, but it is not widely available. An automated way to measure the slope of Vp has been described.19 Normal values depend on the methodology used. With the slope of first aliasing (40%–50% of peak E velocity), values greater than 45 cm/sec are considered normal. The interobserver variability of Vp measurements has been reported to be around 12%20 but can be as high as 20%.15
Cal = 10mm I
II
IVF AC
Most of the studies have focused in the propagation of early mitral inflow. There are limited data about the importance and clinical significance of the propagation of flow during atrial contraction. There is a fundamental difference between early and late flow propagation. During early propagation, blood is pulled into the ventricle, while during late propagation, it is pushed (atrial contraction). A ratio of early to late flow propagation has been reported in patients with pseudonormal filling patterns,21 although the advantage of this over early Vp alone or E/Vp is unclear.
133
Figure 11-1 Color M-mode of mitral inflow obtained from the apical window. Several components can be appreciated from this tracing. Phase I is faster, followed by the slower phase II (vortex) component. A short flow during isovolumic relaxation (IVF) is also seen, as well as late flow during atrial contraction (AC).
Color M-Mode Intraventricular Pressure Gradients Given the complexity of CMM inflow patterns and the variability of the measurements of flow propagation, a more objective analysis of LV filling is desirable. It is well known that the presence of
Figure 11-2 Example of a young normal individual (left) and a patient with delayed relaxation (right). Note the difference in Vp slope between the two.
Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler
Figure 11-3 Computer simulation of vortex formation, flow patterns, and calculated 2D color Doppler echocardiograms at six different points in time during filling. Note that the vortex is amplified during the deceleration phase of the early filling wave and moves into the left ventricle toward the apex. (From Vierendeels JA et al: Hydrodynamics of color M-mode Doppler flow wave propagation velocity V(p): A computer study. J Am Soc Echocardiogr 2002;15: 219–224.)
Figure 11-4 In vitro model of diastolic flow obtained by injecting liquid dye of the same density as water from two opposing thin needles placed at the top and bottom of the orifice. This model produced a succession of vortex rings. The driving waveforms resulted in trailing vortex rings in addition to a primary ring. (From Cooke J et al: Characterizing vortex ring behavior during ventricular filling with Doppler echocardiography: An in vitro study. Ann Biomed Eng 2004;32:245–256.)
regional pressure differences in the left ventricle is related to LV relaxation and suction. Ling et al. demonstrated in a canine model the presence of regional diastolic IVPGs between the base and the apex of the left ventricle. These gradients resulted in the active filling of the ventricle. Courtois et al.11,22 validated these findings and later demonstrated a reduction in IVPG during myocardial ischemia in an animal model. These IVPGs are related to elastic recoil and to apical untwisting.23 Greenberg and Thomas24 used the Euler equation to calculate local pressure gradients, ∂p ∂v ⎤ ⎡ ∂v = −ρ ⎢ + ν ⎥ , ∂s ∂s ⎦ ⎣ ∂t where p, s, t, and v are pressure, distance, time, and velocity, respectively. Integrating the Euler equation from the LV base to apex IVPG can be estimated by
ΔPIV (t ) =
apex
∂p ds ∂s base
∫
where ΔPIV(t) represents IVPG.25 This methodology has been reproduced by others26 and opens the possibility of evaluating diastole in a more fundamental way by measuring one of the driving forces of early filling.
Pathophysiology In abnormal ventricles, IVPGs are blunted22 or even reversed— the initial, faster phase is then lost; vortex formation predominates, slowing the progression of the wavefront toward the apex (see Fig. 11-2). Factors that can affect the formation of IVPGs
147
148
Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler include regional wall motion abnormalities, increased end systolic volume, and dyssynchrony of relaxation.15 The magnitude of pressure gradient formation also depends on ventricular size. In small ventricles, intraventricular gradient formation is enhanced. Vortex formation and propagation require that the ventricular diameter exceed the mitral diameter.4 In dilated, spherical ventricles, the difference in axial velocity between the blood already in the ventricle and blood coming through the mitral valve creates a larger vortex.4
COLOR M-MODE DOPPLER AND DIASTOLIC FUNCTION Human and animal studies have shown that flow propagation velocity of early transmitral flow (Vp) correlates well with the time constant of isovolumic relaxation (Tau, τ).2,5,6,27 This correlation is maintained under a variety of loading and inotropic5 conditions and also in children.28 The strength of the correlation varies according to the technique used to measure Vp, with r values ranging from 0.5 to 0.9.5,6,27,28 Vp is also related to −dP/dt and minimal LV diastolic pressure.27 Vp appears to be a more complex parameter than a simple index of ventricular relaxation.29,30 Vp is influenced not only by the rate of LV relaxation, but also by ventricular geometry,31 the ratio between mitral orifice size and LV cavity size, and dyssynchrony of relaxation.4,30,32 Because Vp correlates well with tau, which is preload independent, CMM flow propagation has been proposed as a loadinsensitive method of assessing LV relaxation.5,7 Although most clinical studies have found that Vp is relatively load independent, there is still some controversy, particularly regarding patients with normal systolic function and hypertrophy.30,33–36 In this group of patients, LV geometry may play a predominant role. It has also been reported that in patients with congestive heart failure, Vp may decrease after medical treatment and is correlated with changes in pulmonary capillary wedge pressure (PCWP).37
CLINICAL RELEVANCE Pseudonormal Filling Pattern In patients with elevated left atrial (LA) pressure, the mitral inflow Doppler pattern can be indistinguishable from normal diastolic function. This important limitation of pulsed Doppler regarding mitral inflow has led to a search for other techniques. One of the early applications of CMM was to differentiate normal from pseudonormal filling patterns. In patients with a pseudonormal mitral filling pattern, CMM will show slow flow propagation.27,38 Takatsuji et al. studied patients with decreased ejection fractions and mitral E/A ratios less than 1 and equal to or greater than 1 and compared them with a group with normal ejection fractions. The rate of velocity propagation of CMM was significantly lower in patients with low ejection fractions, regardless of the mitral inflow pattern.27
Estimation of Left Atrial Pressures The main determinants of Doppler peak E-wave velocity (E) are LA pressure (LAP) and relaxation. By using 1/Vp as a surrogate for relaxation, it is in theory possible to estimate LA pressure, by substituting Vp α 1/τ in E α LAP/τ to yield E α LAP × Vp, which is then rearranged LAP α E/Vp.
This method has been investigated in patients under several conditions, in sinus rhythm and atrial fibrillation.39 Garcia et al. studied 45 patients and found a robust correlation of E/Vp with PCWP (r = 0.80) with a regression equation: PCWP = 5.27 × [E/Vp] + 4.6. The limitations of this method to calculate a numerical value for LA pressure lie in the difficulty in measuring a reliable and reproducible slope of the CMM. As an example, the same group published the relation of CWP and Vp in normal subjects. The regression equation in this group was: PCWP = 25.6 × Vp − 26.1 (r = 0.81). Adding isovolumic relaxation time (IVRT) to the calculation appears to improve the correlation with CWP. Gonzales-Vilchez and Ares40 modified the Weiss equation to derive: PCWP = (0.9 × SBP) × e−IVRT×Vp, where SBP is systolic blood pressure. Using this equation, they found an improved correlation compared with the E/Vp ratio alone (r = 0.80 vs. 0.55).40 Another approach is to use the ratio of E/Vp to identify patients with normal versus elevated PCWP. An E/Vp of less than 1.4 or 1.5 appears to have high sensitivity and reasonable specificity to identify PCWP under 15 mmHg in patients in sinus rhythm or even in atrial fibrillation.39 Other authors have used a ratio of 2.540 to predict elevated CWP, once again reflecting variability in measuring the slope of Vp.
Use of Color M-Mode in Clinical Settings Abnormalities in Vp have been described in ischemic heart disease,6,8,38,41,42 before cardiac resynchronization43 and constrictive pericarditis,44 and in dilated,1,21 hypertrophic,45 and restrictive cardiomyopathies.46,47 In all clinical conditions with abnormal relaxation, the velocity of propagation is diminished. In patients with isolated constrictive physiology, where the intrinsic properties of the myocardium are normal and the left ventricle has small end systolic volume, Vp is normal or even augmented despite elevated filling pressures.44 The prognostic value of Vp has been investigated in patients after their initial myocardial infarction. Patients with a pseudonormal pattern, defined by normal E/A ratio and slow Vp, had an adverse prognosis.38 The researchers found that an E/Vp greater than 1.5 was a strong predictor of in-hospital heart failure in patients with acute myocardial infarction (Fig. 11-5).48 The Vp has been studied in patients with congestive heart failure. The E/Vp ratio has a modest correlation with brain natriuretic peptide (BNP) levels.49 In patients with hypertensive heart disease and normal function who present with dyspnea to the emergency room, E/Vp has a sensitivity of 73%, a specificity of 75%, and an accuracy of 74.3% for diagnosis of heart failure for the optimal cutoff of 1.5.50 Others have found that an E/Vp of 1.8 has a sensitivity of 83% and a specificity of 86% to predict pulmonary congestion in patients with normal or low ejection fraction and correlated with LV end diastolic pressure (r = 0.73).51 As mentioned previously, in patients with heart failure, Vp may show some dependency on loading conditions,37,52 and Vp can be lower after heart failure treatment. This may limit the application of Vp for assessing therapy in patients with congestive heart failure. In this situation, E/Vp appears to be still useful, as E decreases more than Vp, and therefore the ratio diminishes in the
Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler 100 E/Vp < 1.5
FUTURE RESEARCH Automatic or semiautomatic methods are necessary to introduce more objectivity into the measurements of Vp.19 A better understanding of the hydrodynamic and mechanical phenomena occur-
E/Vp > 1.5
50 40 30 20 10
Log rank 28; p < 0.00001
0 0
3
6
9
12
15
18
21
24
27
30
33
Days
IVPG = 3.5 – 0.056*t0 + 0.11*PCW p < 0.001 r = 0.58 4
2
80 60 40
s)
The main limitation of Vp is its high variability in measuring the slope of CMM. There is no agreement in how to measure it, and even if there were, the color display is often complex, bifurcated, and curvilinear. In some patients, prominent isovolumic flow interferes with measurement of the slope. Normal or increased Vp in patients in whom we expect delayed relaxation has been described,34 a condition named by some authors as pseudonormalization of Vp.15 This appears to be limited to small, hypertrophic ventricles with small end systolic volumes.
60
(m
Limitations of Color M-Mode Indices
70
τ0
direction of hemodynamic improvement. Further research in this area is necessary. In patients with systolic heart failure, E/Vp greater than 2.7 independently predicts the composite end point of death, transplantation, or hospitalization.52 The calculation of IVPG using CMM has yielded important information in patients with hypertrophic cardiomyopathy and has been used as a tool to study basic physiologic changes of aging25 and exercise.23,25,53 Rovner et al.53 found that exercise capacity and its maximum oxygen use, VO2 max, have a tight relationship with changes in IVPG with exercise. Notably, basal IVPG was not related to exercise capacity. Normal aging impairs the relationship between IVPGs and preload, probably through age-dependent decline in relaxation, and is independent of changes in ventricular compliance.25 IVPGs appear to be influenced by τ and preload (Fig. 11-6).25,51 More recently, a close relation between IVPGs and velocity of apical untwisting has been shown at rest and with exercise.23 The increase in IVPGs during exercise appears to be an essential mechanism to augment stroke volume during this condition. The precise relationship between CMM-derived IVPGs and Vp has not yet been well characterized. This relationship is probably complex, involving not only the absolute pressure difference but also the temporal and spatial location of local pressure gradients. In an animal model of ischemia, time delay of Vp from base to apex correlated closely with IVPGs (r = 0.94).
80
IVPG (mmHg)
Figure 11-5 Kaplan-Meier curves showing the effect of the ratio of peak E-wave velocity and flow propagation velocity (E/Vp) on cardiac survival in patients after first myocardial infarction. (From Moller JE et al: Ratio of left ventricular peak E-wave velocity to flow propagation velocity assessed by color M-mode Doppler echocardiography in first myocardial infarction: Prognostic and clinical implications. J Am Coll Cardiol 2000;35:363–370.)
Cumulative survival (%)
90
8
20
4 0
P PCW
12
16
20
24
Hg)
(mm
Elderly sedentary Young Figure 11-6 Three-dimensional scatterplot that shows correlation between time constant of ventricular relaxation (τ0, x-axis), pulmonary capillary wedge pressure (PCWP) (y-axis), and intraventricular pressure gradient (IVPG) (z-axis). Data are from both elderly (solid circles) and young (open circles) subjects around the regression plane. A highly significant, moderately strong correlation of IVPG with relaxation and preload was observed. Note that separation of young and elderly subjects according to their IVPG values disappears when both τ0 and PCWP are taken into account. (From Popovic ZB et al: Relationship among diastolic intraventricular pressure gradients, relaxation, and preload: Impact of age and fitness. Am J Physiol Heart Circ Physiol 2006;290:H1454–H1459.)
ring during isovolumic relaxation and early filling will allow development of more precise methods to quantitate flow propagation and may explain the discrepancies among studies—in particular, the load dependency of this technique. Further research into the correlation of Vp with ventricular torsion in clinical situations will greatly help us understand the determinants of Vp.23 The estimation of IVPG using CMM has been used only in limited clinical conditions but is a promising technique if calculations can be automatized and widely available in different echocardiographic machines.
149
150
Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler The issue of preload independence of CMM is not settled, and further studies are necessary. Larger numbers of patients in different clinical conditions and with a variety of LV volumes and ejection fractions need to be studied. The Vp and IVPG under different loading conditions may be useful to our understanding of the discrepancies among studies. REFERENCES 1. Jacobs LE, Kotler MN, Parry WR: Flow patterns in dilated cardiomyopathy: A pulsed-wave and color flow Doppler study. J Am Soc Echocardiogr 1990;3:294–302. 2. Brun P, Tribouilloy C, Duval AM, et al: Left ventricular flow propagation during early filling is related to wall relaxation: A color M-mode Doppler analysis. J Am Coll Cardiol 1992;20:420–432. 3. Vierendeels JA, Dick E, Verdonck PR: Hydrodynamics of color M-mode Doppler flow wave propagation velocity V(p): A computer study. J Am Soc Echocardiogr 2002;15:219–224. 4. Steen T, Steen S: Filling of a model left ventricle studied by colour M mode Doppler. Cardiovasc Res 1994;28:1821–1827. 5. Garcia MJ, Smedira NG, Greenberg NL, et al: Color M-mode Doppler flow propagation velocity is a preload insensitive index of left ventricular relaxation: Animal and human validation. J Am Coll Cardiol 2000;35: 201–208. 6. Stugaard M, Smiseth OA, Risoe C, Ihlen H: Intraventricular early diastolic velocity profile during acute myocardial ischemia: A color M-mode Doppler echocardiographic study. J Am Soc Echocardiogr 1995;8:270–279. 7. Garcia MJ, Palac RT, Malenka DJ, et al: Color M-mode Doppler flow propagation velocity is a relatively preload-independent index of left ventricular filling. J Am Soc Echocardiogr 1999;12:129–137. 8. Stugaard M, Brodahl U, Torp H, Ihlen H: Abnormalities of left ventricular filling in patients with coronary artery disease: Assessment by colour M-mode Doppler technique. Eur Heart J 1994;15:318–327. 9. Abali G, Tokgozoglu L, Ozcebe OI, et al: Which Doppler parameters are load independent? A study in normal volunteers after blood donation. J Am Soc Echocardiogr 2005;18:1260–1265. 10. Ling D, Rankin JS, Edwards CH 2nd, et al: Regional diastolic mechanics of the left ventricle in the conscious dog. Am J Physiol 1979;236: H323–H330. 11. Courtois M, Kovacs SJ Jr, Ludbrook PA: Transmitral pressure-flow velocity relation. Importance of regional pressure gradients in the left ventricle during diastole. Circulation 1988;78:661–671. 12. Nikolic SD, Feneley MP, Pajaro OE, et al: Origin of regional pressure gradients in the left ventricle during early diastole. Am J Physiol 1995;268: H550–H557. 13. Suga H, Goto Y, Igarashi Y, et al: Ventricular suction under zero source pressure for filling. Am J Physiol 1986;251:H47–H55. 14. Ingels NB Jr, Daughters GT, Nikolic SD, et al: Left ventricular diastolic suction with zero left atrial pressure in open-chest dogs. Am J Physiol 1996;270:H1217–H1224. 15. De Boeck BW, Oh JK, Vandervoort PM, et al: Colour M-mode velocity propagation: A glance at intra-ventricular pressure gradients and early diastolic ventricular performance. Eur J Heart Fail 2005;7:19–28. 16. Nakamura M, Wada S, Mikami T, et al: Computational study on the evolution of an intraventricular vortical flow during early diastole for the interpretation of color M-mode Doppler echocardiograms. Biomech Model Mechanobiol 2003;2:59–72. 17. Seo Y, Ishimitsu T, Ishizu T, et al: Assessment of propagation velocity by contrast echocardiography for standardization of color Doppler propagation velocity measurements. J Am Soc Echocardiogr 2004;17:1266– 1274. 18. Garcia MJ, Ares MA, Asher C, et al: An index of early left ventricular filling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29:448–454. 19. Greenberg NL, Firstenberg MS, Cardon LA, et al: Automated assessment of noninvasive filling pressure using color Doppler M-mode echocardiography. Comput Cardiol. 2001;28:601–604. 20. Khan S, Bess RL, Rosman HS, et al: Which echocardiographic Doppler left ventricular diastolic function measurements are most feasible in the clinical echocardiographic laboratory? Am J Cardiol 2004;94:1099–1101. 21. Patrianakos AP, Parthenakis FI, Mavrakis HE, et al: Late left ventricular color M-mode Doppler in the assessment of diastolic dysfunction in patients with dilated cardiomyopathy. J Am Soc Echocardiogr 2005;18:979.
22. Courtois M, Kovacs SJ, Ludbrook PA: Physiological early diastolic intraventricular pressure gradient is lost during acute myocardial ischemia. Circulation 1990;81:1688–1696. 23. Notomi YM, Oryszak SJ, Shiota T, et al: Enhanced ventricular untwisting during exercise: A mechanistic manifestation of elastic recoil described by Doppler tissue imaging. Circulation 2006;113:2524–2533. 24. Greenberg NL, Vandervoort PM, Firstenberg MS, et al: Estimation of diastolic intraventricular pressure gradients by Doppler M-mode echocardiography. Am J Physiol Heart Circ Physiol 2001;280:H2507–H2515. 25. Popovic ZB, Prasad A, Garcia MJ, et al. Relationship among diastolic intraventricular pressure gradients, relaxation, and preload: Impact of age and fitness. Am J Physiol Heart Circ Physiol 2006;290:H1454–H1459. 26. Bermejo J, Antoranz JC, Yotti R, et al: Spatio-temporal mapping of intracardiac pressure gradients. A solution to Euler’s equation from digital postprocessing of color Doppler M-mode echocardiograms. Ultrasound Med Biol 2001;27:621–630. 27. Takatsuji H, Mikami T, Urasawa K, et al: A new approach for evaluation of left ventricular diastolic function: Spatial and temporal analysis of left ventricular filling flow propagation by color M-mode Doppler echocardiography. J Am Coll Cardiol 1996;27:365–371. 28. Border WL, Michelfelder EC, Glascock BJ, et al: Color M-mode and Doppler tissue evaluation of diastolic function in children: Simultaneous correlation with invasive indices. J Am Soc Echocardiogr 2003;16: 988–994. 29. Stoylen A, Skjelvan G, Skjaerpe T: Flow propagation velocity is not a simple index of diastolic function in early filling: A comparative study of early diastolic strain rate and strain rate propagation, flow and flow propagation in normal and reduced diastolic function. Cardiovasc Ultrasound 2003;1:3. 30. Barbier P, Grimaldi A, Alimento M, et al: Echocardiographic determinants of mitral early flow propagation velocity. Am J Cardiol 2002;90:613– 619. 31. Baccani B, Domenichini F, Pedrizzetti G, Tonti G: Fluid dynamics of the left ventricular filling in dilated cardiomyopathy. J Biomech 2002;35: 665–671. 32. Smiseth OA, Thompson CR: Atrioventricular filling dynamics, diastolic function and dysfunction. Heart Fail Rev 2000;5:291–299. 33. Ie EH, Vletter WB, ten Cate FJ, et al: Preload dependence of new Doppler techniques limits their utility for left ventricular diastolic function assessment in hemodialysis patients. J Am Soc Nephrol 2003;14:1858– 1862. 34. Alegret JM, Borras X, Carreras F, et al: Restrictive left ventricular filling and preserved ventricular function: A limitation in the noninvasive estimation of pulmonary wedge pressure by Doppler echocardiography. J Am Soc Echocardiogr 2002;15:334–338. 35. Hsiao SH, Huang WC, Lee TY, et al: Preload and flow propagation velocity: Insight into patients with uremia and different left ventricular systolic function. J Am Soc Echocardiogr 2005;18:1254–1259. 36. Hsiao SH, Huang WC, Sy CL, et al: Doppler tissue imaging and color Mmode flow propagation velocity: Are they really preload independent? J Am Soc Echocardiogr 2005;18:1277–1284. 37. Seo Y, Ishimitsu T, Ishizu T, et al: Preload-dependent variation of the propagation velocity in patients with congestive heart failure. J Am Soc Echocardiogr 2004;17:432–438. 38. Moller JE, Sondergaard E, Poulsen SH, Egstrup K: Pseudonormal and restrictive filling patterns predict left ventricular dilation and cardiac death after a first myocardial infarction: A serial color M-mode Doppler echocardiographic study. J Am Coll Cardiol 2000;36:1841–1846. 39. Nagueh SF, Kopelen HA, Quinones MA: Assessment of left ventricular filling pressures by Doppler in the presence of atrial fibrillation. Circulation 1996;94:2138–2145. 40. Gonzalez-Vilchez F, Ares M, Ayuela J, Alonso L: Combined use of pulsed and color M-mode Doppler echocardiography for the estimation of pulmonary capillary wedge pressure: An empirical approach based on an analytical relation. J Am Coll Cardiol 1999;34:515–523. 41. De Sutter J, De Mey S, De Backer J, et al: Diastolic dysfunction, infarct size, and exercise capacity in remote myocardial infarction: A combined approach of mitral E-wave deceleration time and color M-mode flow propagation velocity. Am J Cardiol 2002;89:593–595. 42. Stugaard M, Smiseth OA, Risoe C, Ihlen H: Intraventricular early diastolic filling during acute myocardial ischemia, assessment by multigated color M-mode Doppler echocardiography. Circulation 1993;88:2705–2713. 43. Waggoner AD, Faddis MN, Gleva MJ, et al: Cardiac resynchronization therapy acutely improves diastolic function. J Am Soc Echocardiogr 2005;18:216–220.
Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler 44. Rajagopalan N, Garcia MJ, Rodriguez L, et al: Comparison of new Doppler echocardiographic methods to differentiate constrictive pericardial heart disease and restrictive cardiomyopathy. Am J Cardiol 2001;87:86–94. 45. Nishihara K, Mikami T, Takatsuji H, et al: Usefulness of early diastolic flow propagation velocity measured by color M-mode Doppler technique for the assessment of left ventricular diastolic function in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2000;13:801–808. 46. Palecek T, Linhart A, Lubanda JC, et al: Early diastolic mitral annular velocity and color M-mode flow propagation velocity in the evaluation of left ventricular diastolic function in patients with Fabry disease. Heart Vessels 2006;21:13–19. 47. Salemi VM, Picard MH, Mady C: Assessment of diastolic function in endomyocardial fibrosis: Value of flow propagation velocity. Artif Organs 2004;28:343–346. 48. Moller JE, Sondergaard E, Seward JB, et al: Ratio of left ventricular peak E-wave velocity to flow propagation velocity assessed by color M-mode Doppler echocardiography in first myocardial infarction: Prognostic and clinical implications. J Am Coll Cardiol 2000;35:363–370. 49. Troughton RW, Prior DL, Pereira JJ, et al: Plasma B-type natriuretic peptide levels in systolic heart failure: Importance of left ventricular diastolic func-
50.
51.
52.
53.
tion and right ventricular systolic function. J Am Coll Cardiol 2004;43: 416–422. Arques S, Roux E, Sbragia P, et al: Comparative accuracy of color M-mode and tissue Doppler echocardiography in the emergency diagnosis of congestive heart failure in chronic hypertensive patients with normal left ventricular ejection fraction. Am J Cardiol 2005;96:1456– 1459. Schwammenthal E, Popescu BA, Popescu AC, et al: Association of left ventricular filling parameters assessed by pulsed wave Doppler and color M-mode Doppler echocardiography with left ventricular pathology, pulmonary congestion, and left ventricular end-diastolic pressure. Am J Cardiol 2004;94:488–491. Troughton RW, Prior DL, Frampton CM, et al: Usefulness of tissue Doppler and color M-mode indexes of left ventricular diastolic function in predicting outcomes in systolic left ventricular heart failure (from the ADEPT study). Am J Cardiol 2005;96:257–262. Rovner A, Greenberg NL, Thomas JD, Garcia MJ: Relationship of diastolic intraventricular pressure gradients and aerobic capacity in patients with diastolic heart failure. Am J Physiol Heart Circ Physiol 2005;289: H2081–H2088.
151
MARIO J. GARCIA, MD
12
Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis INTRODUCTION PATHOPHYSIOLOGY Tissue Doppler Velocities Myocardial Strain and Strain Rate Left Ventricular Torsion CLINICAL APPLICATIONS Assessment of Left Ventricular Relaxation Evaluation of Left Ventricular Filling Pressures
Ischemic Heart Disease Dilated Cardiomyopathies Restrictive Cardiomyopathies Constrictive Pericarditis Hypertrophy Cardiomyopathies Transplant Rejection Diabetes and Myocardial Disease Tissue Doppler Parameters and Prognosis FUTURE RESEARCH
INTRODUCTION Early Doppler echocardiographic indices of left ventricular (LV) diastolic function have studied the mechanics of left atrial (LA) and ventricular filling. These filling indices have been proven to be useful, providing prognostic information in heart failure patients.1–3 However, filling indices have limited accuracy predicting intrinsic parameters of diastolic function due to the confounding effects of extrinsic loading conditions and valvular hemodynamic performance. Doppler ultrasound and more recently two-dimensional speckle tracking may be applied to study LV myocardial mechanics. Since myocardial mechanical events precede LA and LV filling, they may be potentially less dependent on extrinsic variables and therefore more accurate in characterizing intrinsic myocardial properties. In this chapter, we will review the role of tissue Doppler and two-dimensional particle tracking–derived myocardial velocities and their derivatives for the assessment of LV diastolic function.
PATHOPHYSIOLOGY Tissue Doppler Velocities In technical terms, tissue Doppler echocardiography (TDE) differs from standard Doppler by eliminating the highpass filter and using low gain amplification to display the velocities of the myocardium. TDE velocities may be displayed in spectral pulsed mode or in color-encoded two-dimensional maps superimposed on structural images (Figs. 12-1 and 12-2).4 The technical principles and limitations of these modalities are similar to those encountered with standard Doppler flow systems. Myocardial velocities may be obtained from multiple locations of the myocardium. In a typical spectral display, the myocardial velocity is a positive waveform representing ventricular systole (SM) and two waves corresponding to early filling (EM) and atrial contraction (AM). From the apical acoustic windows, the diastolic myocardial velocities obtained from any of the LV myocardial segments appear as a mirror image of the mitral inflow early (E) and atrial (A) filling velocities. In normal humans, the peak of EM precedes 153
154
Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis
2
SM 1
3 Figure 12-1 Longitudinal axis tissue Doppler velocities obtained using spectral Doppler from the basal lateral left ventricular segment. AM, atrial contraction velocity; EM, early diastolic velocity; SM, systolic velocity.
AM EM
A
B
the peak of LV filling E velocity, suggesting that active relaxation of the myocardium generates negative pressures in the LV cavity that initiate LV filling. TDE velocities are affected not only by regional LV mechanical events, but also by global translation and rotation of the heart. Accordingly, spectral TDE velocities are usually obtained from the apical acoustic window, since LV longitudinal velocities are less affected by translational motion (Figs. 12-3 and 12-4).5 Alternatively, translational motion may be corrected by offline analysis from color-encoded TDE velocities. One method plots the velocity of each adjacent scan line from the distance of the epicardium to the endocardium. From a parasternal color M-mode image, the rates of circumferential fiber shortening and lengthening are proportional to the slope of the velocity/distance regression line. The value of this slope has been referred to as the myocardial velocity gradient (MVG).
Figure 12-2 Color-encoded tissue Doppler velocities obtained from the four-chamber view during systole (A) and diastole (B).
SM
AM EM
MYOCARDIAL STRAIN AND STRAIN RATE The change in length of the myocardial fiber (end diastolic length, end systolic length/end diastolic length) is also known as myocardial strain. The spiral architecture of the myocardial fiber bundles determines strain deformation in multiple directions. Thus,
Figure 12-3 Regional values derived from the color-encoded velocities obtained from different regions of the myocardium. Notice that velocities that are obtained closer to the base have a higher magnitude, due to the added translation produced by the contraction and relaxation of middle and apical segments. AM, atrial contraction velocity; EM, early diastolic velocity; SM, systolic velocity.
Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis changes in LV geometry during LV systole relate primarily to radial (short axis), longitudinal (long axis), and meridional (LV torsion) strain (Fig. 12-5). Myocardial strain may be quantified noninvasively using magnetic resonance imaging (MRI), TDE, or high-frame-rate two-dimensional echocardiography with speckle tracking. (Strain analysis using MRI is described in detail in a separate chapter.) TDE-derived strain quantifies tissue deformation based on Doppler velocity shifts. Unlike tissue Doppler velocities, tissue strain is less affected by segmental tethering and translational motion; therefore, it reflects primarily the intrinsic deformation of the myocardial segment within the sample region. The strain rate (SR) of a segment of a given length (L0) is given
by: SR = (V1 − V2)/L0, where V1 and V2 are the tissue Doppler velocities at each end of the segment (L0). Strain (ε) represents the percent deformation for the given segment over its initial value, and is obtained by integrating SR over the systolic (shortening) or diastolic interval (lengthening) of the cardiac cycle (Figs. 12-6 and 12-7). Recent studies have demonstrated a closed correlation between SR and indices of LV contractility and between ε and LV stroke volume.6,7 Unfortunately, Doppler-derived strain is limited to interrogating segments aligned in parallel with the Doppler angle of incidence. More recently, strain analysis derived from two-dimensional speckle tracking has become available. This method promises to be more robust than Doppler-derived strain,
SM εl εl : Longitudinal strain εr εr : Radial strain εc
εc : Circumferential strain
EM AM
Figure 12-4 Regional values derived from the color-encoded velocities obtained from different regions of the myocardium from a patient with abnormal relaxation. AM, atrial contraction velocity; EM, early diastolic velocity; SM, systolic velocity.
Figure 12-5 Diagram indicating the direction of different myocardial strain vectors.
Velocity
Strain rate
d
V2 V1
Strain rate = (V2−V1)/d Strain
Strain rate
Systolic strain
Systolic strain rate
Diastolic strain rate
Figure 12-6 Diagram indicating the mathematical steps used to derive strain rate and strain from tissue velocities. d, distance; V, velocity.
∫ (Strain rate) δ time = strain
Diastolic strain
155
156
Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis Time
AL
+
BL
AS ML
ML AL
MS BL BS
AS MS BS SRI M-mode/curved M-mode
–
Figure 12-7 Curved M-mode display of the strain rate derived from different myocardial segments. The vertical axis indicates the spatial location. The horizontal axis represents time, according to the electrocardiographic tracing above. The colors represent the magnitude of tissue deformation: Red corresponds to systolic contraction, blue corresponds to diastolic expansion, and green indicates absence of deformation. BS, basal septum; MS, midseptum; AS, apical septum; AL, apical lateral; ML, midlateral; BL, basal lateral.
Figure 12-8 Diagram indicating the vectors of apical counterclockwise and basal clockwise twist. Torsion is the sum of both components. (From Notomi Y et al. Measurement of ventricular torsion by two-dimensional ultrasound speckle tracking imaging. J Am Coll Cardiol 2005;45:2034–2041.)
and may provide strain analysis in multiple directions, from virtually any echocardiographic image.
LEFT VENTRICULAR TORSION In addition to radial and longitudinal deformation, there is torsional deformation of the left ventricle during the cardiac cycle due to the helical orientation of the myocardial fibers.8–15 During systole, the basal segments of the LV myocardium rotate or twist in counterclockwise direction, whereas the apical segments twist in clockwise direction. During diastole, untwisting occurs in the opposite direction. Systolic torsion represents the net effect of basal and apical twist. Apical twisting is the main component of global LV systolic torsion, and in the next diastole, the apical untwisting also plays the dominant role, whereas basal rotation is of less importance. Torsional deformation may be quantified by MRI or by either TDE velocities or high-frame-rate twodimensional echocardiography with speckle tracking (Fig. 12-8). Systolic LV torsion tends to equalize sarcomere shortening between endocardial and epicardial layers of the left ventricle and is a possible mechanism by which potential energy can be stored during ejection and then released during early diastole to generate suction and rapid filling by “elastic recoil.” LV untwisting has been shown to be dissociated from filling and accentuated by catecholamines, with the untwisting rate related to LV pressure decay. The magnitude of the restoring force appears to be inversely related to end systolic volume.16,17 Epicardial contraction dominates the direction of torsion because these fibers are at larger radii and therefore produce greater torque than
do those in the inner layers. The process can be viewed as a global LV spring between the epicardium and endocardium that is stretched during systole, storing potential energy for release in early diastole. Accordingly, LV myocardial contraction and relaxation are tightly interconnected: The potential energy stored during systole is converted to kinetic energy during diastole, thus effectively bridging the two periods. Peak LV untwisting velocity occurs approximately 60 msec earlier than long-axis lengthening and short-axis expansion18 and may be accentuated by catecholamine infusion. Left ventrical untwisting is 40% to 50% completed by the time of mitral valve opening and continues during early LV filling.14
CLINICAL APPLICATIONS Doppler myocardial velocities and, to a lesser extent, strain analysis have been used to evaluate myocardial relaxation in a variety of cardiac diseases associated with LV diastolic dysfunction. In addition, TDE combined with LV filling Doppler indices has been used to evaluate LV filling pressures.
Assessment of Left Ventricular Relaxation Several studies have shown an inverse relationship between EM and LV relaxation (τ)19,20 in patients with both normal and elevated preload. Tissue Doppler EM has been shown to be less influenced by preload alterations than standard Doppler LV filling indices, particularly in the presence of slow ventricular relaxation.21 Clinical studies suggest that EM is a better discrimi-
Evaluation of Left Ventricular Filling Pressures Several investigators have studied the utility of Doppler ECG for the assessment of LV filling pressures.24–27 Previous studies have demonstrated a relationship between mean LA pressure and pulmonary venous systolic (S)/diastolic (D) ratio, mitral E/A ratio, isovolumic relaxation time (IVRT), and deceleration time (DT). All pulsed Doppler–based methods are accurate when applied to groups of patients with homogeneously impaired LV relaxation since they assume that reduction in IVRT, atrial filling fraction, pulmonary venous S/D ratio, and DT will occur solely as a consequence of elevated LA pressure. However, when these methods are applied to younger patients and those with minimal structural heart disease with a normal ejection fraction (EF), they overestimate actual LV filling pressure since they cannot separate the effect of LV relaxation and preload as confounding variables. TDE velocities used as an index of LV relaxation may be combined with standard Doppler flow indices in order to separate these confounding effects. Since pulsed Doppler E velocity is determined equally by both LA pressure and LV relaxation, whereas TDE EM is related primarily to LV relaxation, the ratio of E/EM may be used to predict LA pressure. This concept has been developed and validated in relatively heterogeneous groups of patients undergoing right heart catheterization.28 In subjects with normal LV relaxation and normal LA pressure, both E and EM are elevated. In subjects with impaired relaxation and normal LA pressure, both E and EM are decreased. In patients with impaired relaxation and elevated LA pressure, E is elevated but EM is reduced. An E/EM ratio greater than 15 is almost invariably associated with a mean LA pressure greater than 15 mmHg. The combined E/EM ratio also appears to be an important independent predictor of exercise capacity. In 121 subjects who were studied with Doppler echocardiography before maximal exercise testing, exercise capacity was similar in the population with a normal mitral inflow pattern (E/A >1) and those with a slow relaxation pattern (E/A <1) only when E/Ea was less than 10 (Fig. 12-9).29 However, those subjects with slow relaxation and E/Ea less than 10 had reduced exercise tolerance. Compared with other echocardiographic and clinical parameters, E/Ea had the best correlation with exercise capacity (r = 0.684, p < 0.001) and was the strongest independent predictor of exercise capacity less than 7 metabolic equivalents (METs) by multivariate analysis.
20
p < 0.001
n = 85
15 n = 36
10 5 0
≥ 10
< 10 E/EM
A Exercise performance (METs)
nator between diastolic dysfunction and normal patients, compared with any other single or combined index of transmitral filling and pulmonary venous Doppler flows.22 LV torsion and untwisting also correlate well with the relaxation time constant15 and with the early LV diastolic intraventricular pressure gradient (IVPG) (that is, LV suction). Delayed LV untwisting has been reported in patients with severe aortic stenosis and impaired LV relaxation.13 Enhanced LV torsion during exercise is associated with increased IVPG.18 We have recently demonstrated that the ability to increase IVPG during exercise is directly related to aerobic capacity in normals and in heart failure patients.23
Exercise performance (METs)
Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis
20
n = 44
p < 0.001 n = 40*
15 n = 19†
10
n = 18
5 0 Normal
Slow relaxation *E/EM < 10
†E/E ≥ M
Pseudonormal/ restrictive 10
B Figure 12-9 A, Exercise capacity in patients with normal or increased E/EM (<10 vs. ≥10). Exercise capacity was greater by a mean of 5.0 METs in patients with E/EM ≥10. B, Exercise capacity in patients categorized by their mitral inflow pattern. Patients in slow relaxation group were subdivided into those with normal and increased E/Ea. Box plot shows median (center line), first and third quartiles (top and bottom of box), and lowest and highest values (vertical lines) of exercise performance. (Modified from Skaluba SJ, Litwin SE: Mechanisms of exercise intolerance: Insights from tissue Doppler imaging. Circulation 2004;109:972–977.)
to a pattern of impaired LV relaxation. Doppler LV filling patterns will vary according to the extent, duration, and severity of ischemia. These patterns have been shown to carry important prognostic information after an acute myocardial infarction30 and in chronic ischemic heart disease.24 TDE myocardial velocities and strain indices may identify myocardial ischemia and viability during pharmacologic stress testing (Fig. 12-10).31 Strain rate imaging may be used to identify not only the magnitude but also the time of peak systolic myocardial contraction. Postsystolic shortening is a sensitive marker of ischemia. In pigs subjected to acute myocardial ischemia during angioplasty balloon inflation, there is a strong direct correlation between the spatial distributions of postsystolic shortening measured by strain rate imaging and myocardium at risk.32 In patients with ischemic cardiomyopathy, an increase of peak systolic strain rate from rest to dobutamine stimulation by more than −0.23 s−1 allowed accurate discrimination of viable from nonviable myocardial segments, as determined by 18-fluorodeoxyglucose positron emission tomography with a sensitivity of 83% and a specificity of 84%. In this study, strain imaging was superior to TDE and two-dimensional wall thickening subjective assessment.
Dilated Cardiomyopathies Ischemic Heart Disease Ischemia affects relaxation by limiting the availability of energy substrates in the form of adenosine triphosphate (ATP). The reabsorption of Ca++ ions by the sarcoplasmic reticulum is an energy-dependent process, which is required for the deactivation of the troponin-tropomyosin complex. In the presence of normal systolic function at baseline, ischemia is manifested by a change
In many patients with dilated cardiomyopathies, conduction abnormalities result in the late activation and contraction of the LV lateral wall. This ventricular dyssynchrony and associated mechanical abnormalities result in an inefficient global contraction that in turn results in reduced stroke volume.33 Cardiac resynchronization therapy (CRT), via biventricular pacing, can restore electrical and mechanical synchrony. Clinical studies have
157
158
Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis
Figure 12-10 Regional strain derived from speckle tracking in a patient with a lateral wall infarct. Notice the dyskinetic (+) systolic strain in the basal lateral wall.
shown that CRT may reduce symptoms, increase exercise capacity, reduce hospitalizations for heart failure, induce ventricular reverse remodeling, and improve survival in symptomatic heart failure patients.34–37 However, a significant proportion of eligible patients do not respond, some may experience increased event rates after CRT,38 and it appears that a significant number of patients who have a wide QRS do not have significant mechanical dyssynchrony. The mechanical delay or dyssynchrony is not always evident by visual assessment of regional wall motion. TDE may be used to determine mechanical dyssynchrony in heart failure patients who are being evaluated for CRT. An intraventricular delay of greater than 65 msec measured by TDE before CRT identifies patients who experience superior outcomes, including improved 6-minute walk time and greater reduction in LV end systolic volume. Changes in LV end systolic volume after CRT are strong predictors of long-term survival and heart failure events in these patients.39
Restrictive Cardiomyopathies The restrictive cardiomyopathies are a group of primary and secondary myocardial diseases characterized by small LV cavity size, abnormal LV relaxation, and increased LV stiffness. Commonly, in restrictive cardiomyopathies, LV wall thickness is normal or increased due to infiltration or fibrosis. Systolic function is abnormal only in advanced stages of disease. Pulsed Doppler LV filling patterns vary according to the severity of the disease. Initially, a pattern of delayed relaxation is seen, progressing to pseudonormal and finally to restrictive filling patterns in advanced disease. Therefore, early diagnosis by conventional echocardiography is often difficult. Tissue Doppler early diastolic myocardial velocity (EM) is abnormally reduced in patients with restrictive cardiomyopathies.5 A recent study also demonstrated reduced myocardial systolic strain in patients with amyloidosis, even before the development of congestive heart failure symptoms.40
Constrictive Pericarditis Diastolic dysfunction in constrictive pericarditis results from increased pericardial constraint on the LV that is related to the
thickness and rigidity of the pericardium. Patients present with signs and symptoms of right-sided heart failure, which are similar to those found in restrictive cardiomyopathy.41 Two-dimensional echocardiogrpahy does not always demonstrate increased pericardial thickness and the typical interventricular septal bounce. Right ventricular (RV) and LV Doppler filling patterns may demonstrate respiratory variability. However, these findings are not always present and are not specific. Acute respiratory illnesses can increase intrathoracic pressure swings, increasing also respiratory flow variability. Excessive preload may attenuate the effect of intrathoracic pressure swings and decrease respiratory variability, whereas low preload can decrease the constraining effect of the pericardium, also masking the characteristic Doppler signs of constriction. Tissue Doppler myocardial velocities are useful in differentiating restrictive cardiomyopathy from constrictive pericarditis. In restrictive cardiomyopathy patients, both relaxation and stiffness are abnormal. On the other hand, relaxation is preserved in pure constrictive pericarditis, in the absence of other myocardial disease. Patients with constrictive pericarditis and normal systolic function have normal or elevated EM velocities (>8 cm/sec), probably reflecting their preserved ventricular relaxation.5 In a study that included 30 consecutive patients with suspected pericardial constriction versus restrictive myocardial disease, an EM greater than 8.0 cm/sec differentiated patients with constriction from restriction with 89% sensitivity and 100% specificity (Fig. 12-11).42
Hypertrophy Cardiomyopathies The most common form of hypertrophic cardiomyopathy is characterized by prominent increase in global or segmental LV wall thickness and histologically by myocardial fiber disarray.43 Diastolic function is characterized by increased LV chamber stiffness and decreased relaxation of variable severity due to the asynchronous deactivation of the muscle fibers.44,45 Patients with hypertrophic cardiomyopathies can have symptoms even in the absence of systolic obstruction of the LV outflow tract (LVOT), although recent studies suggest that relief of the LVOT gradient after alcohol embolization may be accompanied by an improvement in LV relaxation.46,47 Pulsed Doppler LV filling usually shows
Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis
30
Peak EM (cm/sec)
25 20 15 10
Y = 8.0 cm/sec
These abnormalities can often be found in asymptomatic carriers of genetic mutations, even in the absence of phenotypic expression (Fig. 12-13).50 In hypertrophic cardiomyopathy patients with β-myosin heavy chain (β-MHC) mutation, genotype (+) individuals with LVH and genotype (+) individuals without LVH have lower EM than gender- and age-matched controls. Similar findings have been reported in Fabry’s disease, a cardiomyopathy secondary to α-galactosidase A deficiency. Mutation-positive Fabry’s patients have significant reduction of EM and higher E/EM compared with normal control subjects, even before the development of LVH.51 TDE has been used to study myocardial performance in patients with Friedreich’s ataxia, a 25
Averaged EM velocity (cm/sec)
impaired relaxation or pseudonormal patterns and rarely restrictive patterns because of the markedly increased wall thickness and impaired relaxation. Two-dimensional echocardiography can establish the diagnosis in patients with either asymmetric hypertrophy or LVOT obstruction. However, many patients with hypertrophic cardiomyopathies have concentric hypertrophy without obstruction, which is indistinguishable from the physiologic hypertrophy seen in endurance athletes or in patients with hypertensive heart disease. TDE velocities may help to differentiate myocardial hypertrophy seen in athletes from hypertrophic cardiomyopathy, where these velocities are abnormally decreased.48 Tissue Doppler can also identify abnormal regional strain, predominantly in areas of localized hypertrophy (Fig. 12-12).49 In fact, it appears that the greater the extent of segmental wall thickness, the greater the reduction in myocardial strain.
20 *†
15
*
10
5 0 CP RCM Figure 12-11 Peak early longitudinal axial velocities (EM) in patients with constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM). A value of greater than 8.0 cm/sec differentiated patients with constrictive pericarditis with 89% sensitivity and 100% specificity. (Modified from Rajogopalan N et al: Comparison of new Doppler echocardiographic methods to differentiate constrictive pericardial heart disease and restrictive cardiomyopathy. Am J Cardiology 2001;87:86–94.)
Figure 12-12 Regional strain obtained at the septum from a patient with hypertrophic cardiomyopathy. The thicker midseptal segment (blue line) is dyskinetic (+ strain in systole). (Modified from Yang H et al: Use of strain imaging in detecting segmental dysfunction in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2003;16:233–239.)
5 G+/LVH– Controls G+/LVH+ Figure 12-13 Averaged EM velocity in two hypertrophic cardiomyopathy subgroups and normal control subjects. Mean values (䊉) and SD (vertical line) are indicated. *p < 0.0001 compared with control subjects; †p < 0.0001 compared with β-myosin gene (+) and left ventricular hypertrophy group (G+/LVH+). (Modified from Ho CY et al: Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105:2992–2997.)
159
Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis neurodegenerative disorder associated with cardiomyopathy and impaired glucose tolerance (Fig. 12-14). The genetic basis for this inherited disease is a glucosidase acid alpha (GAA) trinucleotide repeat expansion in the first intron of gene X25, which encodes a 210–amino acid protein, frataxin. It appears that the GAA expansion leads to reduced levels of frataxin, resulting in abnormalities of mitochondrial iron transport and antioxidant systems. Asymptomatic patients who are homozygous for the GAA expansion in the Friedreich’s ataxia gene have reduced MVGs during systole and in early diastole.52 There appears to be a strong relationship between age-corrected early diastolic MVG and the GAA expansion in the smaller allele of the Friedreich’s ataxia gene, suggesting that TDE-derived MVGs may be used to determine the extent of genotypic expression.
Transplant Rejection Heart transplant patients often receive serial echocardiography in an effort to detect abnormalities related to organ rejection. It has been proposed that serial echocardiographic studies may help in reducing the frequency of surveillance biopsies. Transplant rejection is associated with lymphocytic infiltration and edema, resulting in increased myocardial stiffness and abnormal relaxation. Diastolic myocardial velocities measured by TDE may be reduced in heart transplant patients with rejection and may return to normal after successful treatment.53,54 One caution that has to be taken, however, when interpreting these results is that factors other than rejection may affect LV relaxation and EM in these patients, such as the age of the donor heart and the time after transplantation. Thus lower velocities may not imply rejection if the organ belonged to an older donor or if these velocities are obtained several years following transplantation. One way to circumvent this problem would be to compare the results of serial studies obtained in the same patient. In most circumstances, however, the diagnosis of rejection requires the integration of clinical data in addition to the detection of several echocardiographic markers, such as pericardial effusions, increased wall thickness, and diastolic abnormalities.55
Diabetes and Myocardial Disease Glycemic control in diabetic patients has been associated with microvascular complications. Microvascular disease may lead to ischemia and subsequent impaired LV relaxation and increased myocardial stiffness. Advanced glycation end-products (AGEs) have been associated with microvascular complications of type 1 diabetes mellitus and may be a pathophysiologic mechanism for diastolic dysfunction in these patients. Advanced glycation end-products may lead to early reversible glycation products, followed by irreversible Amadori products and subsequent diabetic cardiomyopathy. We performed echocardiographic studies on 25 patients with type 1 diabetes without clinical evidence of heart disease.56 Compared with 26 nondiabetic controls, type 1 diabetic subjects had worse diastolic function with lower tissue Doppler EM. Furthermore, glycosylated hemoglobin (HgbA1C) was correlated with E/EM (r = 0.68, p = 0.0002). These results demonstrate that asymptomatic diastolic dysfunction is common in patients with type 1 diabetes mellitus and that its severity is correlated with glycemic control. Furthermore, our data suggest that asymptomatic diabetic patients have increased LV filling pressure as measured by E/EM, and a larger LA size.
Tissue Doppler Parameters and Prognosis A reduced EM has been associated with reduced survival in patients with cardiac disease. In a study that followed for 2 years 165 normals and 353 patients with hypertension, ischemic heart disease, valvular heart disease, heart failure, diabetes, and obstructive sleep apnea, a reduced EM was independently predictive of cardiac death (Fig. 12-15).57 In another recent study, which followed 225 patients with symptomatic systolic heart failure, E/EM was associated with an increased risk of death or transplant (p < 0.05) (Fig. 12-16).58 Those patients with an E/EM ratio 1.0
.9 Cum survival
15 MVG in early diastole (s–1), age corrected
160
r = –0.68 p < 0.001 10
.8 5 Em > 5 cm/sec 3 < Em ≤ 5 cm/sec Em ≤ 3 cm/sec
0 0
250
500
750
1000
1250
GAA repeats on smaller frataxin allele Figure 12-14 Relationship between size of GAA expansion in smaller allele of Friedreich’s ataxia gene and myocardial velocity gradients in early diastole, corrected for age. (Modified from Dutka JP et al: Echocardiographic characterization of cardiomyopathy in Friedreich’s ataxia with tissue Doppler echocardiographically derived myocardial velocity gradients. Circulation 2000;102:1276–1282.)
.7 0
10
20
30
40
Follow time (months) Figure 12-15 Cumulative cardiac death by tertiles of EM in patients with cardiac disease. (Modified from Wang M et al: Peak early diastolic mitral annulus velocity by tissue Doppler imaging adds independent and incremental prognostic value. J Am Coll Cardiol 2003;41:820–826.)
Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis
E/Vp < 2.7 0.9 0.8 E/Vp > 2.7
0.7 P < 0.01 0.6 0
greater than 17 had a mortality of approximately 40% at 36 months compared with 5% in those with an E/EM ratio of less than 17 (p < 0.001). In a study that included 250 nonselected patients who had had an echocardiogram 1.6 days after a myocardial infarction followed up for a median of 13 months, the most powerful predictor of survival was an E/EM ratio of greater than 15.59 In this study, E/EM was a stronger predictor than other Doppler echocardiographic indices, including the LV filling pulsed Doppler DT.
FUTURE RESEARCH The introduction of tissue Doppler techniques has led to significant advance in our understanding of cardiac physiology. However, more studies are needed to help understand the relationship between TDE indices and myocardial morphology and cellular function. In addition, it will be important to better define how these indices are related to exercise performance. We foresee that TDE will become a valuable tool for the evaluation of novel therapeutic interventions. REFERENCES 1. Klein AL, Hatle LK, Burstow DJ, et al: Doppler characterization of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1989;13:1017–1026. 2. Rihal CS, Nishimura RA, Hatle LK, et al: Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy. Relation to symptoms and prognosis. Circulation 1994;90:2772–2779. 3. Redfield MM, Jacobsen SJ, Burnett JC Jr, et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202. 4. Miyatake K, Yamagishi M, Tanaka N, et al: New method for evaluating left ventricular wall motion by color-coded tissue Doppler imaging: In vitro and in vivo studies. J Am Coll Cardiol 1995;25:717–724. 5. Garcia MJ, Rodriguez L, Ares MA, et al: Differentiation of constrictive pericarditis from restrictive cardiomyopathy: Assessment of left ventricular diastolic velocities in the longitudinal axis by tissue Doppler imaging. J Am Coll Cardiol 1996;27:108–114. 6. Greenberg NL, Firstenberg MS, Castro PL, et al: Doppler-derived myocardial systolic strain rate is a strong index of left ventricular contractility. Circulation 2002;105:99–105. 7. Weidemann F, Jamal F, Sutherland GR, et al: Myocardial function defined by strain rate and strain during alterations in inotropic states and heart rate. Am J Physiol 2002;283:H792–H799. 8. Streeter DD Jr, Spotnitz HM, Patel DP, et al: Fiber orientation in the canine left ventricle during diastole and systole. Circ Res 1969;24:339–347. 9. Arts T, Reneman RS: Dynamics of left ventricular wall and mitral valve mechanics—a model study. J Biomech 1989;22:261–271. 10. Beyar R, Yin FC, Hausknecht M, et al: Dependence of left ventricular twistradial shortening relations on cardiac cycle phase. Am J Physiol 1989;257: H1119–H1126.
12
24 Months
36
Death or heart transplant
Figure 12-16 Cumulative survival by the ratio of LV filling pulsed Doppler E to color M-mode propagation velocity (VP) and E to EM. (Modified from Troughton RW et al: Usefulness of tissue Doppler and color M-mode indexes of left ventricular diastolic function in predicting outcomes in systolic left ventricular heart failure (from the ADEPT study). Am J Cardiol 2005;96:257–262.)
Death or heart transplant
1
161
1 E/EM < 17 0.9 0.8 E/EM > 17 0.7 P < 0.001 0.6 0
12
24
36
Months
11. Ingels NB Jr, Hansen DE, Daughters GT 2nd, et al: Relation between longitudinal, circumferential, and oblique shortening and torsional deformation in the left ventricle of the transplanted human heart. Circ Res 1989;64:915–927. 12. Rademakers FE, Buchalter MB, Rogers WJ, et al: Dissociation between left ventricular untwisting and filling. Accentuation by catecholamines. Circulation 1992;85:1572–1581. 13. Stuber M, Scheidegger MB, Fischer SE, et al: Alterations in the local myocardial motion pattern in patients suffering from pressure overload due to aortic stenosis. Circulation 1999;100:361–368. 14. Bell SP, Nyland L, Tischler MD, et al: Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res 2000;87:235–240. 15. Dong SJ, Hees PS, Siu CO, et al: MRI assessment of LV relaxation by untwisting rate: A new isovolumic phase measure of tau. Am J Physiol Heart Circ Physiol 2001;281:H2002–H2009. 16. Nikolic S, Yellin EL, Tamura K, et al: Passive properties of canine left ventricle: Diastolic stiffness and restoring forces. Circ Res 1988;62:1210–1222. 17. Yellin EL, Hori M, Yoran C, et al: Left ventricular relaxation in the filling and nonfilling intact canine heart. Am J Physiol 1986;250:H620–629. 18. Notomi Y, Martin-Miklovic MG, Oryszak SJ, et al: Enhanced ventricular untwisting during exercise: A mechanistic manifestation of elastic recoil described by Doppler tissue imaging. Circulation 2006;113:2524– 2533. 19. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by tissue Doppler imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 20. Oki T, Tabata T, Yamada H, et al: Clinical application of pulsed tissue Doppler imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 1997;79:921–928. 21. Firstenberg MS, Greenberg NL, Main ML, et al. Determinants of diastolic myocardial tissue Doppler velocities: Influences of relaxation and preload. J Appl Physiol 2001;90:299–307. 22. Farias CA, Rodriguez L, Garcia MJ, et al: Assessment of diastolic function by tissue Doppler echocardiography: Comparison with standard transmitral and pulmonary venous flow. J Am Soc Echocardiogr 1999;12:609–617. 23. Rovner A, Greenberg NL, Thomas JD, et al: Relationship of diastolic intraventricular pressure gradients and aerobic capacity in patients with diastolic heart failure. Am J Physiol Heart Circ Physiol 2005;289:H2081– H2088. 24. Vanoverschelde JL, Raphael DA, Robert AR, et al: Left ventricular filling in dilated cardiomyopathy: Relation to functional class and hemodynamics. J Am Coll Cardiol 1990;15:1288–1295. 25. Stork TV, Muller RM, Piske GJ, et al: Noninvasive measurement of left ventricular filling pressures by means of transmitral pulsed Doppler ultrasound. Am J Cardiol 1989;64:655–660. 26. Mulvagh S, Quinones, MA, Kleiman NS, et al: Estimation of left ventricular end-diastolic pressure from Doppler transmitral flow velocity in cardiac patients independent of systolic performance. J Am Coll Cardiol 1992;20:112–119. 27. Vanoverschelde JL, Robert AR, Gerbaux A, et al: Noninvasive estimation of pulmonary arterial wedge pressure with Doppler transmitral flow velocity pattern in patients with known heart disease. Am J Cardiol 1995;75:383–389. 28. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527–1533. 29. Skaluba SJ, Litwin SE: Mechanisms of exercise intolerance: Insights from tissue Doppler imaging. Circulation 2004;109:972–977.
162
Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis 30. Oh JK, Ding ZP, Gersh BJ, et al: Restrictive left ventricular diastolic filling identifies patients with heart failure after acute myocardial infarction. J Am Soc Echocardiogr 1992;5:497–503. 31. Hoffmann R, Altiok E, Nowak B, et al: Strain rate measurement by Doppler echocardiography allows improved assessment of myocardial viability in patients with depressed left ventricular function. J Am Coll Cardiol 2002;39:3:443–449. 32. Pislaru C, Belohlavek M, Bae RY, et al: Regional asynchrony during acute myocardial ischemia quantified by ultrasound strain rate imaging. J Am Coll Cardiol 2001;37:1141–1148. 33. Prinzen FW, Augustijn CH, Arts T, et al: Redistribution of myocardial fiber strain and blood flow by asynchronous activation. Am J Physiol 1990;259: H300–H308. 34. Cazeau S, Ritter P, Lazarus A, et al: Multisite pacing for end-stage heart failure: Early experience. Pacing Clin Electrophysiol 1996;19:1748–1757. 35. Cazeau S, Leclercq C, Lavergne T, et al: Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873–880. 36. Abraham WT, Fisher WG, Smith AL, et al: Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 37. Cleland JG, Daubert JC, Erdmann E, et al: The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–1549. 38. Bax JJ, Bleeker GB, Marwick TH, et al: Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol 2004;44:1834–1840. 39. Yu CM, Bleeker GB, Fung JW, et al: Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation 2005;112:1580–1586. 40. Koyama J, Ray-Sequin PA, Falk RH: Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis. Circulation 2003;107:2446–2452. 41. Oh JK, Hatle LK, Seward JB, et al: Diagnostic role of Doppler echocardiography in constrictive pericarditis. J Am Coll Cardiol 1994;23:154– 162. 42. Rajogopalan N, Garcia MJ, Rodriguez L, et al: Comparison of new Doppler echocardiographic methods to differentiate constrictive pericardial heart disease and restrictive cardiomyopathy. Am J Cardiology 2001;87: 86–94. 43. Wigle ED: Diastolic dysfunction in hypertrophic cardiomyopathy. In Gaasch WH, Lewinter MM (eds): Left Ventricular Diastolic Dysfunction and Heart Failure. Philadelphia, Lea and Febiger, 1994:373–389. 44. Brutsaert DL, Rademakers FE, Sys SU: Triple control of relaxation: Implications in cardiac disease. Circulation 1984;69:190–196. 45. Brutsaert DL, Sys SU, Gillebert TC: Diastolic failure: Pathophysiology and therapeutic implications. J Am Coll Cardiol 1993;22:318–325.
46. Nagueh SF, Lakkis NM, Middleton KJ, et al: Changes in left ventricular diastolic function 6 months after nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. Circulation 1999;99:344– 347. 47. Rovner A, Smith R, Greenberg NL, et al: Improvement in diastolic intraventricular pressure gradients in patients with HOCM after ethanol septal reduction. Am J Physiol 2003;285: H2492–H2499. 48. Palka P, Lange A, Fleming AD et al: Differences in myocardial velocity gradient measured throughout the cardiac cycle in patient with hypertrophic cardiomyopathy, athletes and patients with left ventricular hypertrophy due to hypertension. J Am Coll Cardiol 1997;30:760–768. 49. Yang H, Sun JP, Lever HM, et al: Use of strain imaging in detecting segmental dysfunction in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiog 2003;16:233–239. 50. Ho CY, Sweitzer NK, McDonough B, et al: Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105:2992–2997. 51. Pieroni M, Chimenti C, Ricci R, et al: Early detection of Fabry cardiomyopathy by tissue Doppler imaging. Circulation 2003;107:1978– 1984. 52. Dutka JP, Donnelly JE, Palka P, et al: Echocardiographic characterization of cardiomyopathy in Friedreich’s ataxia with tissue Doppler echocardiographically derived myocardial velocity gradients. Circulation 2000;102: 1276–1282. 53. Mankad S, Murali S, Mandarino WA, et al: Assessment of acute cardiac allograft rejection by quantitative tissue Doppler echocardiography. Circulation 1997;96:I–342. 54. Puleo JA, Aranda JM, Weston MW, et al: Noninvasive detection of allograft rejection in heart transplant recipients by use of Doppler tissue imaging. J Heart Lung Transplant 1998;17:176–184. 55. Sun JP, Abdalla IA, Asher CR, et al: Non-invasive evaluation of orthotopic heart transplant rejection of echocardiography. J Heart Lung Transplant 2005;24:160–165. 56. Shishehbor MH, Hogwerf BJ, Schoenhagen P, et al: Relation of hemoglobin A1C to left ventricular relaxation in patients with type 1 diabetes mellitus and without overt heart disease. Am J Cardiol 2003;91:1514– 1517. 57. Wang M, Yip GWK, Wang AYM, et al: Peak early diastolic mitral annulus velocity by tissue Doppler imaging adds independent and incremental prognostic value. J Am Coll Cardiol 2003;41:820–826. 58. Troughton RW, Prior DL, Frampton CM, et al: Usefulness of tissue Doppler and color M-mode indexes of left ventricular diastolic function in predicting outcomes in systolic left ventricular heart failure (from the ADEPT study). Am J Cardiol 2005;96:257–262. 59. Hillis GS, Moller JE, Pellikka PA, et al: Noninvasive estimation of left ventricular filling pressure by E/e’ is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol 2004;43:360–367.
13
SATOSHI NAKATANI, MD, PhD
Assessment of Left Atrial Size and Function INTRODUCTION PATHOPHYSIOLOGY Quantification of Left Atrial Size Assessment of Left Atrial Function
diseases. For example, increased LA size is associated with atrial fibrillation, stroke, and adverse cardiovascular outcomes.5,8,9–15 LA size has also been known to correlate with overall mortality after myocardial infarction16,17 and risk of death and hospitalization in patients with dilated cardiomyopathy.18–21
CLINICAL RELEVANCE Diastolic Dysfunction and Left Atrial Size FUTURE RESEARCH
PATHOPHYSIOLOGY Quantification of Left Atrial Size Measurement of Left Atrial Diameter
INTRODUCTION The left atrium is an oval chamber with thin, muscular walls, located between the aorta and the esophagus. Because of this location, it is easily recognized not only by transthoracic but also by transesophageal echocardiography. The left atrium collects blood from the pulmonary veins and ejects it into the left ventricle. The left atrial (LA) chamber changes its size during a cardiac cycle, being largest at ventricular systole and smallest at atrial systole. This phasic change involves mainly the anteroposterior and supero-inferior diameters, while the mediolateral diameter does not change significantly. The left atrium has three functions in a cardiac phase (see Chapter 4). During ventricular systole, the left atrium functions as a reservoir that collects pulmonary venous flow; and during early diastole, following passive atrial emptying, it functions as a conduit allowing the passage of stored blood from the left atrium to the left ventricle. During atrial contraction, the left atrium acts as a contractile pump that delivers as much as one-third of the left ventricular (LV) filling.1 This atrial contraction makes a significant contribution to maintaining cardiac output, especially in patients with LV dysfunction.2–4 Because the left atrium is connected to the left ventricle, enlargement of LA size suggests the presence of elevated filling pressure and diastolic dysfunction.5–7 Thus, LA size has been noted to be a good prognosticator in various cardiovascular
LA size is usually measured at end systole, when the left atrium is most dilated. Traditionally, it is measured at the parasternal long-axis view using M-mode or B-mode echocardiography (Fig. 13-1). When the M-mode technique is used, the cursor should pass through the aortic valve. The largest anteroposterior diameter is measured from the trailing edge of the posterior aortic wall to the leading edge of the posterior LA wall. Although the convention for M-mode is to measure from the leading edge to the leading edge, the trailing edge of the posterior aortic root is recommended by the American Society of Echocardiography, to avoid the variable extent of space between the left atrium and the aortic root.22 When the M-mode cursor is not perpendicular to the posterior aortic wall or the posterior LA wall, measurement based on B-mode echocardiography should be done.
Measurement of Left Atrial Area by Echocardiography The left atrium can be observed at multiple views besides the parasternal long axis. It can also be observed at apical two- and four-chamber views and a parasternal short-axis view, and a diameter can be measured at each. Anteroposterior and supero-inferior diameters can be measured at the parasternal long-axis view. Anteroposterior and mediolateral diameters can be measured at the parasternal short-axis view, and supero-inferior and mediolateral diameters can be measured at the four-chamber view (Fig. 13-2). The normal values for each diameter are shown in Table 13-1.23 163
164
Chapter 13 • Assessment of Left Atrial Size and Function
Measurement of Left Atrial Volume by Echocardiography Linear measurements have been reported to correlate with the angiographically determined LA size.24,25 However, the left atrium has an oval shape that changes asymmetrically according to disease state and loading conditions. Therefore, it is not always the case that the anteroposterior diameter represents LA size.26,27 For example, patients with mitral stenosis have an enlarged anteroposterior diameter, but patients with mitral regurgitation due to mitral valve prolapse often have an enlarged supero-inferior diameter. Thus, the measurement of LA anteroposterior diameter may be misleading, and LA volume, instead of diameter, should be determined in both clinical practice and research. LA volume can be calculated using either an ellipsoid method or Simpson’s method.5,8,15,16,24–26,28–30 In the ellipsoid method, the left atrium is assumed to be represented as a prolate ellipse, and the volume can be calculated by Volume = 4π/3 (L/2) (D1/2) (D2/2), where L is the LA long-axis diameter at the four-chamber view, and D1 and D2 are anteroposterior and mediolateral diameters
obtained at the parasternal long- and short-axis views, respectively.30–32 The method based on diameter measurements is dependent on selection of the location and direction of the minoraxis diameters and has been shown to significantly underestimate LA volume.30 Alternatively, volume can be calculated using the biplane ellipsoid area-length method: Volume = 8 (A1) (A2)/3π (L), where A1 and A2 represent the maximal LA area acquired from the apical four- and two-chamber views, respectively. L is the shortest LA long-axis diameter, determined as the distance of the perpendicular line connecting the mitral annular plane and the superior aspect of the left atrium at either the four-chamber or the two-chamber view. The ellipsoid method assumes that the atrium can be represented by an ellipsoid. However, this assumption often fails when the atrium is deformed by external compression or ventricular distortion. On such occasions, Simpson’s method is more appropriate. Simpson’s method states that the volume of a large figure can be calculated from the sum of the volumes of a series of smaller figures of similar shape. Thus, the LA volume can be obtained as the sum of the volumes of a series of smaller elliptic cylinders of known height (h): Volume = π/4 (h) Σ (D1) (D2),
TABLE 13-1 NORMAL VALUES FOR LEFT ATRIAL DIAMETER MEAN ± SD (cm)
RANGE (cm)
Parasternal long-axis view Anteroposterior diameter Supero-inferior diameter
3.0 ± 0.3 4.8 ± 0.8
2.3–3.8 3.1–6.8
Parasternal short-axis view Anteroposterior diameter Mediolateral diameter
2.9 ± 0.4 4.2 ± 0.6
2.2–4.1 3.1–6.0
Apical 4-chamber view Supero-inferior diameter Mediolateral diameter
4.1 ± 0.6 3.8 ± 0.4
2.9–5.3 2.9–4.9
0
Left atrial diameter
40 Figure 13-1 Measurement echocardiography.
of
left
atrial
diameter
by
M-mode
D1
From Weyman AE: Normal cross-sectional echocardiographic measurements. In Weyman AE (ed): Principles and Practice of Echocardiography, 2nd ed. Philadelphia, Lea & Febiger, 1994:1289–1298.
D1 D3
D3
D2
D2
A
B
C
Figure 13-2 Left atrial diameter measures. A, In the parasternal long-axis view; B, in the parasternal short-axis view; and C, in the apical four-chamber view. D1, anteroposterior diameter; D2, mediolateral diameter; D3, supero-inferior diameter.
Chapter 13 • Assessment of Left Atrial Size and Function where D1 and D2 are orthogonal minor and major axes of each cylinder (Fig. 13-3). For these calculations, the planimetered LA areas at the orthogonal views, such as apical four-chamber and two-chamber, are required. The pulmonary veins and the LA appendage should be excluded, and the inferior border should be represented by the mitral annular plane when the LA border is traced. Normal LA volume determined by echocardiography in a number of studies is 22 ± 6 ml/m2.5,32–34 Table 13-2 shows reference limits and partition values for LA measurements obtained from a Framingham Heart Study cohort.22 Because the entire left atrium cannot always fit into the image sector when using the transesophageal approach, measurements of LA volume cannot be reliably performed. However, LA diameter can be estimated combining measurements from different imaging planes.
Measurement of Left Atrial Volume by Other Methods LA volume has been determined by computed tomography, biplane contrast ventriculography, and magnetic resonance imaging.24,28,29,35,36 LA volume determined by echocardiography has been shown to correlate well with or to underestimate measurements by these methods.24,28,29,36 In a dog model, LA volume can be estimated accurately with two pairs of sonomicrometers sewn into the anteroposterior and mediolateral walls of the left atrium.37
Assessment of Left Atrial Function The left atrium has several physiologic functions. During LV systole, the left atrium collects and stores blood (a reservoir func-
TABLE 13-2 REFERENCE LIMITS AND PARTITION VALUES FOR LEFT ATRIAL DIMENSION AND VOLUME WOMEN
LA diameter, cm LA diameter/BSA, cm/m2 LA area LA volume, mL LA volume/BSA, ml/m2
MEN
REFERENCE RANGE
MILDLY ABNORMAL
MODERATELY ABNORMAL
SEVERELY ABNORMAL
REFERENCE RANGE
MILDLY ABNORMAL
MODERATELY ABNORMAL
SEVERELY ABNORMAL
2.7–3.8 1.5–2.3
3.9–4.2 2.4–2.6
4.3–4.6 2.7–2.9
≥4.7 ≥3.0
3.0–4.0 1.5–2.3
4.1–4.6 2.4–2.6
4.7–5.2 2.7–2.9
≥5.2 ≥3.0
≤20 22–52 22 ± 6
20–30 53–62 29–33
30–40 63–72 34–39
>40 ≥73 ≥40
≤20 18–58 22 ± 6
20–30 59–68 29–33
30–40 69–78 34–39
>40 ≥79 ≥40
LA, left atrial; BSA, body surface area. Bold italic values: Recommended and best validated. From Lang RM et al: Recommendations for chamber quantification: A report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–1463.
A
B
Figure 13-3 Measurement of left atrial volume using modified Simpson’s method. Apical four-chamber view (left) and two-chamber view (right) are obtained at end systole to obtain maximum left atrial size.
165
Chapter 13 • Assessment of Left Atrial Size and Function tion). During LV early diastole, a part of the blood in the left atrium flows into the left ventricle, helping rapid ventricular filling (passive emptying); and from rapid filling to mid-diastolic slow filling, the left atrium helps the passage of blood from the pulmonary veins to the left ventricle (a conduit function). During atrial systole, the left atrium expels blood to the left ventricle against LV diastolic pressure (a contractile function). To facilitate understanding of LA function, the instantaneous changes in LA pressure and volume during a cardiac cycle are shown in Figure 13-4. LA volume increases during LV systole due to LA active relaxation just after atrial active contraction, LV shrinkage by LV contraction, and caudal movement of the inferior aspect of the left atrium. LA pressure decreases after mitral valve closure (“c”) and makes the “x” trough. Then, receiving blood from the right heart, the left atrium is passively expanded, and both volume and pressure increase, making the “v” wave in the pressure tracing. With mitral valve opening, blood flows into the left ventricle rapidly, and LA volume decreases (passive atrial emptying). During this phase, LA pressure also decreases and makes the “y” trough. During mid-diastole, blood from the pulmonary veins flows into the left ventricle (a conduit function). LA volume and pressure increases only a little at this phase in the normal compliant heart. However, in the noncompliant heart, LA pressure increases rapidly. At late diastole, LA volume decreases and LA pressure increases rapidly, making the “a” wave with atrial active contraction. A part of the blood flows back into the pulmonary veins. The atrial pressure-volume relationship has a “figure 8” shape (Fig. 13-5). It has an “a-loop” during atrial contraction and a “vloop” during the other phase. The ascending limb of the v-loop corresponds to the period between the “x” trough and the peak of the “v” wave and represents LA passive expansion. There have been some studies to calculate LA compliance by fitting the limb to an exponential curve: P = beaV, where P is LA pressure, b is a constant, a is a chamber stiffness parameter, and V is LA volume.38–40 LA compliance can be determined as a reciprocal of a chamber stiffness parameter. It has been
reported to be 1.60 ± 0.41 ml/mmHg/m2, one-half to one-third of LV compliance.39,40 LA compliance is an important determinant of diastolic filling and atrial function. Hoit et al. showed that LA compliance was affected by the presence of the LA appendage (see Chapter 4). They found that in a canine model, the diastolic pressure-volume relation of the left atrium was shifted upward and leftward after appendectomy, suggesting that the LA appendage was more distensible than the LA body. Larger compliance of the appendage may be beneficial when LV filling pressure is increased and atrial distensibility is decreased.41 It has been reported that blood volume ejected by atrial contraction has a linear relationship with LA volume just before atrial contraction.42 This supports the presence of the Frank-Starling mechanism in the atrium. We have recently demonstrated a linear relationship between LA peak change in pressure by time (dP/dt) and LA pressure just before atrial contraction.43 The blood volume ejected by atrial contraction is related to LV function. It is about 20% in normal subjects but is about 35% in patients with myocardial infarction.2 Thus, LA contractile function seems to compensate the reduced LV stroke volume in LV dysfunction. However, when LV end diastolic pressure is very high, with significant LV dysfunction, much of the blood ejected by LA contraction goes back to the pulmonary veins, leading to an inefficient LA contraction.
CLINICAL RELEVANCE Diastolic Dysfunction and Left Atrial Size It has been reported that about half of patients with chronic heart failure have preserved LV ejection fraction (diastolic heart failure).44–47 Hypertension, LV hypertrophy, ischemic heart disease, aging, and other cardiovascular disease can potentially cause diastolic dysfunction. Diastolic dysfunction elevates filling pressures leading to atrial enlargement. Doppler parameters such as transmitral flow and mitral annulus velocity, considered to be useful to assess diastolic function, reflect filling pressures at one time and would be altered if loading conditions changed. In contrast, an enlarged atrium may better reflect the cumulative effect of elevated filling pressures over time. Thus, atrial size has been suggested as a marker of the severity and duration of diastolic 17
ECG
15 a-loop LA pressure (mmHg)
166
LAV
v
13
v-loop
11 9 7
a LVP LAP
c
y
d
x Figure 13-4 Echocardiography (ECG) shows instantaneous changes in left atrial pressure (LAP) and left atrial volume (LAV), along with left ventricular pressure (LVP) during a cardiac cycle.
5
20
30
40
50
60
LA volume (ml) Figure 13-5 Left atrial (LA) pressure-volume relationship.
70
80
Chapter 13 • Assessment of Left Atrial Size and Function
Left Atrial Size and Prognosis Since diastolic heart failure has a poor prognosis, similar to systolic heart failure, enlarged LA size may potentially indicate a worse outcome.55 Tsang et al. noted that LA volume was associated with poor outcome in a community-based elderly population.8 They found that an LA volume index of more than 32 ml/m2 was an independent predictor of cardiovascular events, including congestive heart failure, myocardial infarction, and stroke. However, it has been suggested in another study that LA volume might not be a better predictor than diastolic dysfunction grade.49 Pritchett et al. found that the LA volume index was highly sensitive and specific for the detection of severe diastolic dysfunction but was not a robust marker of mild or moderate diastolic dysfunction. In addition, they found that although diastolic function grade had prognostic importance, the LA volume index added no
incremental prognostic value beyond that provided by diastolic dysfunction grade.49 The significance of LA enlargement in cardiovascular diseases has been demonstrated in many studies. LA enlargement has been reported to be an early sign of hypertensive heart disease.50 LA size is associated with the outcomes in patients with myocardial infarction. Møller et al. found that an LA volume index of greater than 32 ml/m2 measured a median of one day after admission was a powerful and independent predictor of mortality in patients with acute myocardial infarction.16 Moreover, LA volume of greater than 32 ml/m2 has been reported in another study to be an independent predictor of 5-year mortality in patients with acute myocardial infarction (Fig. 13-6).17 These results are well explained by the fact that LA size reflects chronically elevated filling pressure. A recent paper using stress echocardiography suggested that normal resting LA volume (≤28 ml/m2) predicts a normal stress echocardiogram and identifies patients with low ischemic risk.58 This is an interesting observation and should be further assessed for its complementary role in stress testing.
100
90
Survival (%)
dysfunction. There is a famous analogy: Serum glucose is used to assess transient diabetic control, and hemoglobin A1C is used as a long-term biomarker of average metabolic state. Similarly, LV filling pressure is used to assess transient loading conditions, and LA size is used as a long-term biomarker of average LV diastolic pressure.48 In fact, Pritchett et al. have shown that LA volume increased with worsening of diastolic dysfunction in a general population, as shown in Table 13-3.49 They found that the grade of diastolic dysfunction was positively associated with the LA volume index. Thus, diastolic dysfunction has been considered to contribute to LA remodeling. LA size can be evaluated by diameter and volume. Which is suitable for the assessment of diastolic dysfunction? Previous investigations used mainly LA diameter as an index of the size of the left atrium.10,13,50–52 For example, Vaziri et al. demonstrated that there was a significant association between elevated systolic pressure and increased LA diameter in the Framingham Heart Study.53 In contrast, recent studies have demonstrated that LA volume may be more suitable to reflect morbid conditions.26,54 Tsang et al. followed 423 patients who had a general medical consultation for subsequent development of new atrial fibrillation, congestive heart failure, stroke, transient ischemic attack, myocardial infarction, coronary revascularization, and cardiovascular death. They found that LA volume was a more robust marker of cardiovascular events than was LA diameter or area.55 LA volume has been related to the occurrence of atrial fibrillation54,56 and other cardiovascular events, such as myocardial infarction, congestive heart failure, and stroke.8 It has been shown that both body size and aging influence LA size.1,54,57 The influence of body size on LA size is typically corrected by indexing to body surface area.
167
80
70
60
LA volume index < 32 ml/m2 LA volume index ≥ 32 ml/m2
50 0
1
2
3
4
5
Time (years) Figure 13-6 Kaplan-Meier survival curves of patients with acute myocardial infarction with left atrial (LA) volume index ≥32 ml/m2 and with <32 ml/m2. They were adjusted for age, gender, Killip class ≥2, primary reperfusion, diabetes, systemic hypertension, paroxysmal atrial fibrillation, previous myocardial infarction, left ventricular ejection fraction, moderate and severe mitral regurgitation, and left ventricular filling pattern. p = 0.02. (From Beinart R et al: Long-term prognostic significance of left atrial volume in acute myocardial infarction. J Am Coll Cardiol 2004;44:327–334.)
TABLE 13-3 LEFT ATRIAL VOLUME INDEX ACCORDING TO DIASTOLIC FUNCTION GRADE DIASTOLIC GRADE
n
% OF COHORT
LEFT ATRIAL VOLUME INDEX, ml/m2
% MEETING CRITERIA FOR LEFT ATRIAL ENLARGEMENT
Normal Grade I Grade II Grade III to IV
1212 315 118 12
73 19 7 1
23 ± 6 25 ± 8 31 ± 8 48 ± 12
9 17 48 100
Left atrial enlargement, ≥30 ml/m2 in women or ≥33 ml/m2 in men. From Pritchett AM et al: Diastolic dysfunction and left atrial volume: A population-based study. J Am Coll Cardiol 2005;45:87–92.
168
Chapter 13 • Assessment of Left Atrial Size and Function S-v
S-sr
S-s
E-s
E-v E-sr A-sr
A-v
A
B
C
Figure 13-7 A, Left atrial (LA) tissue velocity; B, LA strain; C, LA strain rate. These traces were obtained with a region of interest placed in the midseptum at the four-chamber view. S-v, peak velocity in systole; E-v, peak velocity in early diastole; A-v, peak velocity in late diastole; S-s, peak strain in systole; E-s, peak strain in early diastole; S-sr, peak strain rate in systole; E-sr, peak strain rate in early diastole; A-sr, peak strain rate in late diastole.
LA volume is also helpful to determine prognosis in patients with dilated cardiomyopathy having systolic dysfunction as well as diastolic dysfunction. In the Studies Of Left Ventricular Dysfunction (SOLVD) population, a left atrium larger than 4.17 cm in diameter was closely associated with increased risk of death and cardiovascular hospitalization.18 Rossi et al. showed that determinants of LA volume in patients with dilated cardiomyopathy include LV volume, ejection fraction, the degree of mitral regurgitation, and diastolic dysfunction.19 These parameters all related to the outcome. However, compared with all of these determinants, LA volume has an independent and incremental prognostic value.
FUTURE RESEARCH Since LA size is closely linked to cardiac risk and prognosis, its evaluation, that is, LA volume indexed to body surface area, should be measured routinely in the echocardiographic laboratory. However, the measurement is still cumbersome and may be affected by LA morphology. Sometimes the left atrium is compressed by a marked dilation of the aortic root or extracardiac masses, causing asymmetric atrial morphology. On these occasions, the accuracy of measurements of LA size may be questionable. Recently, real-time three-dimensional echocardiography has emerged as a tool for accurate volume measurements in clinical assessment. Further development of three-dimensional echocardiography would allow accurate and easy measurment of LA volume independent of LA shape. There are a number of articles that show that LA size reflects the burden and chronicity of elevated LV filling pressure and is a strong predictor of outcome. However, there are scant data that show the clinical significance of changes in LA size. For example, how much and how sensitively does LA volume decrease after treatment of diastolic dysfunction? How soon does the left atrium shrink following the reduction of filling pressure? Does the degree of shrinkage relate to the etiology and severity of cardiovascular conditions? Further work should be done to answer these questions.59 The development of new echocardiographic techniques, such as tissue Doppler imaging and strain and strain rate imaging, enables us to quantitate LA function noninvasively (Fig. 13-7). Although tissue Doppler imaging provides accurate measure-
ments of local velocities, it is affected by motion of the adjacent tissues and Doppler incident angle. Since strain and strain rate parameters are determined based on spatial differences in velocities or moving distance between two different regions, they are independent of cardiac translational motion and the tethering effect. Recently, these indexes could be obtained not only by tissue Doppler imaging but also by speckle tracking imaging, which is independent of Doppler incident angle. LA strain and strain rate can be obtained by placing a region of interest on the midsegment of the LA walls at the apical views. It has been reported that LA systolic and early diastolic strain rates are correlated with age.60 Moreover, LA peak systolic strain rate is significantly lower in patients with atrial fibrillation than in age-matched control subjects. LA late diastolic strain rate, which corresponds to atrial contraction, is also lower in patients with atrial fibrillation, and this increases gradually after cardioversion.61 LA strain and strain rate have been reduced in various conditions, such as amyloidosis62 and postsurgical correction of atrial septal defect.63 They did not reduce when closure of the atrial septal defect was done with a catheter-based device, suggesting that this was a less invasive procedure to the left atrium. Strain and strain rate imaging is promising because the parameters obtained may reflect subtle changes in LA function that are not readily assessed with conventional echocardiography. REFERENCES 1. Spencer KT, Mor-Avi V, Gorcsan J, et al: Effects of aging on left atrial reservoir, conduit, and booster pump function (a multi-institution acoustic quantification study). Heart 2001;85:272–277. 2. Rahimtoola SH, Ehsani A, Sinno MZ, et al: Left atrial transport function in myocardial infarction: Importance of its booster pump function. Am J Med 1975;59:686–94. 3. Matsuda Y, Toma Y, Ogawa H, et al: Importance of left atrial function in patients with myocardial infarction. Circulation 1983;67:566–571. 4. Ruskin J, McHale PA, Harley A, et al: Pressure-flow studies in man: Effect of atrial systole on left ventricular function. J Clin Invest 1970;49:472– 478. 5. Tsang TS, Barnes ME, Gersh BJ, et al: Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90:1284– 1289. 6. Simek CL, Feldman MD, Haber HL, et al: Relationship between left ventricular wall thickness and left atrial size (comparison with other measures of diastolic function). J Am Soc Echocardiogr 1995;8:37–47.
Chapter 13 • Assessment of Left Atrial Size and Function 7. Appleton CP, Galloway JM, Gonzalez MS, et al: Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease: Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993;22:1972–1982. 8. Tsang TS, Barnes ME, Gersh BJ, et al: Prediction of risk for first age-related cardiovascular events in an elderly population: The incremental value of echocardiography. J Am Coll Cardiol 2003;42:1199–2005. 9. Kizer JR, Bella JN, Palmieri V, et al: Left atrial diameter as an independent predictor of first clinical cardiovascular events in middle-aged and elderly adults (the strong heart study). Am Heart J 2006;151:412–418. 10. Benjamin EJ, D’Agostino RB, Belanger AJ, et al: Left atrial size and the risk of stroke and death: The Framingham Heart study. Circulation 1995;92:835–841. 11. Di Tullio MR, Sacco RL, Sciacca RR, et al: Left atrial size and the risk of ischemic stroke in an ethnically mixed population. Stroke. 1999;30: 2019–2024. 12. Flaker GC, Fletcher KA, Rothbart RM, et al: Clinical and echocardiographic features of intermittent atrial fibrillation that predict recurrent atrial fibrillation (Stroke Prevention in Atrial Fibrillation [SPAF] investigators). Am J Cardiol 1995;76:355–358. 13. Vaziri SM, Larson MG, Benjamin EJ, et al: Echocardiographic predictors of nonrheumatic atrial fibrillation: The Framingham Heart study. Circulation 1994;89:724–730. 14. Tsang TS, Barnes ME, Gersh BJ, et al: Risks for atrial fibrillation and congestive heart failure in patients >/=65 years of age with abnormal left ventricular diastolic relaxation. Am J Cardiol 2004;93:54–58. 15. Tsang TS, Gersh BJ, Appleton CP, et al: Left ventricular diastolic dysfunction as a predictor of the first diagnosed nonvalvular atrial fibrillation in 840 elderly men and women. J Am Coll Cardiol 2002;40:1636–1644. 16. Møller JE, Hillis GS, Oh JK, et al: Left atrial volume. A powerful predictor of survival after acute myocardial infarction. Circulation 2003;107: 2207–2212. 17. Beinart R, Boyko V, Schwammenthal E, et al: Long-term prognostic significance of left atrial volume in acute myocardial infarction. J Am Coll Cardiol 2004;44:327–334. 18. Quinones MA, Greenberg BH, Kopelen HA, et al: Echocardiographic predictors of clinical outcome in patients with left ventricular dysfunction enrolled in the SOLVD registry and trials: Significance of left ventricular hypertrophy: Studies of left ventricular dysfunction. J Am Coll Cardiol 2000;35:1237–1244. 19. Rossi A, Cicoira M, Zanolla L, et al: Determinants and prognostic value of left atrial volume in patients with dilated cardiomyopathy. J Am Coll Cardiol 2002;40:1425. 20. Dini FL, Cortigiani L, Baldini U, et al: Prognostic value of left atrial enlargement in patients with idiopathic dilated cardiomyopathy and ischemic cardiomyopathy. Am J Cardiol 2002;89:518–523. 21. Sabharwal N, Cemin R, Rajan K, et al: Usefulness of left atrial volume as a predictor of mortality in patients with ischemic cardiomyopathy. Am J Cardiol 2004;94:760–763. 22. Lang RM, Bierig M, Devereux RB, et al: Recommendations for chamber quantification: A report from the American Society of Echocardiography’s guidelines and standards committee and the chamber quantification writing group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–1463. 23. Weyman AE. Normal cross-sectional echocardiographic measurements. In Weyman AE (ed): Principles and Practice of Echocardiography, 2nd ed. Philadelphia, Lea & Febiger, 1994:1289–1298. 24. Schabelman S, Schiller NB, Silverman NH, et al: Left atrial volume estimation by two-dimensional echocardiography. Catheter Cardiovasc Diagn 1981;7:165–178. 25. Wade MR, Chandraratna PA, Reid CL, et al: Accuracy of nondirected and directed M-mode echocardiography as an estimate of left atrial size. Am J Cardiol 1987;60:1208–1211. 26. Lester SJ, Ryan EW, Schiller NB, et al: Best method in clinical practice and in research studies to determine left atrial size. Am J Cardiol 1999;84:829–832. 27. Loperfido F, Pennestri F, Digaetano A, et al: Assessment of left atrial dimensions by cross sectional echocardiography in patients with mitral valve disease. Br Heart J 1983;50:570–578. 28. Rodevan O, Bjornerheim R, Ljosland M, et al: Left atrial volumes assessed by three- and two-dimensional echocardiography compared to MRI estimates. Int J Card Imaging 1999;15:397–410.
29. Vandenberg BF, Weiss RM, Kinzey J, et al: Comparison of left atrial volume by two-dimensional echocardiography and cine-computed tomography. Am J Cardiol 1995;75:754–757. 30. Khankirawatana B, Khankirawatana S, Porter T: How should left atrial size be reported? Comparative assessment with use of multiple echocardiographic methods. Am Heart J 2004;147:369–374. 31. Hiraishi S, DiSessa TG, Jarmakani JM, et al: Two-dimensional echocardiographic assessment of left atrial size in children. Am J Cardiol 1983;52: 1249–1257. 32. Jessurun ER, van Hemel NM, Kelder JC, et al: The effect of maze operations on atrial volume. Ann Thorac Surg 2003;75:51–56. 33. Wang Y, Gutman JM, Heilbron D, et al: Atrial volume in a normal adult population by two-dimensional echocardiography. Chest 1984;86:595– 601. 34. Gutman J, Wang YS, Wahr D, et al: Normal left atrial function determined by 2-dimensional echocardiography. Am J Cardiol 1983;51:336–340. 35. Thomas L, Levett K, Boyd A, et al: Compensatory changes in atrial volumes with normal aging: Is atrial enlargement inevitable? J Am Coll Cardiol. 2002;40:1630–1635. 36. Kircher B, Abbott JA, Pau S, et al: Left atrial volume determination by biplane two-dimensional echocardiography: Validation by cine computed tomography. Am Heart J 1991;121:864–871. 37. Hoit BD, Shap Y, McMannis K, et al: Determination of left atrial volume using sonomicrometry: A cast validation study. Am J Physiol 1993;264(3 Pt 2):H1011–H1016. 38. Nakajima K, Iizuka M, Natsume T, et al: Assessment of left atrial stiffness in man. Circulation 1982;66(suppl):327. 39. Nagano T, Arakawa M, Tanaka T, et al: Diastolic compliance of the left atrium in man: A determinant of preload of the left ventricle. Heart Vessels 1989;5:25–32. 40. Arakawa M, Tanaka T, Hirakawa S. Pressure-volume relation of the left atrium in man. In Hori M, Suga H, Baan J, et al. (eds): Cardiac Mechanics and Function in the Normal and Diseased Heart. New York, SpringerVerlag, 1989:147–154. 41. Hoit BD, Shao Y, Tsai LM, et al: Altered left atrial compliance after atrial appendectomy. Influence of left atrial and ventricular filling. Circulation Res 1993;72:167–175. 42. Yamaguchi M, Arakawa M, Tanaka T, et al: Study on left atrial contractile performance: Participation of Frank-Starling mechanism. Jpn Circ J 1987; 51:1001–1009. 43. Nakatani S, Garcia MJ, Firstenberg MS, et al: Noninvasive assessment of left atrial maximum dP/dt by a combination of transmitral and pulmonary venous flow. J Am Coll Cardiol 1999;34:795–801. 44. Senni M, Tribouilloy CM, Rodeheffer RJ, et al: Congestive heart failure in the community. A study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation 1998;98:2282–2289. 45. Oh JK, Hatle L, Tajiki AJ, et al: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506. 46. Aurigemma GP, Gaasch WH: Diastolic heart failure. N Engl J Med 2004;351:1097–1105. 47. Cleland JGF, Swedberg K, Follath F, et al: The EuroHeart Failure survey programme—A survey on the quality of care among patients with heart failure in Europe. Part 1: Patient characteristics and diagnosis. Eur Heart J 2003;24:442–463. 48. Douglas PS: The left atrium: A biomarker of chronic diastolic dysfunction and cardiovascular disease risk. J Am Coll Cardiol 2003;42:1206– 1207. 49. Pritchett AM, Mohoney DW, Jacobson SJ, et al: Diastolic dysfunction and left atrial volume: A population-based study. J Am Coll Cardiol 2005;45:87–92. 50. Miller JT, O’Rourke RA, Crawford MH: Left atrial enlargement: An early sign of hypertensive heart disease. Am Heart J 1988;116:1048–1051. 51. Gottdiener JS, Reda DJ, Williams DW, et al: Left atrial size in hypertensive men: Influence of obesity, race and age. Department of Veterans Affairs cooperative study group on antihypertensive agents. J Am Coll Cardiol 1997;29:651–658. 52. Psaty BM, Manolio TA, Kuller LH, et al: Incidence of and risk factors for atrial fibrillation in older adults. Circulation 1997;96:2455–2461. 53. Vaziri SM, Larson MG, Lauer MS, et al: Influence of blood pressure on left atrial size. The Framingham Heart Study. Hypertension 1995;25: 1155–1160. 54. Pritchett AM, Jacobson SJ, Mahoney DW, et al: Left atrial volume as an index of left atrial size: A population-based study. J Am Coll Cardiol 2003;41:1036–1043.
169
170
Chapter 13 • Assessment of Left Atrial Size and Function 55. Tsang TSM, Abhayaratna WP, Barnes ME, et al: Prediction of cardiovascular outcomes with left atrial size. Is volume superior to area or diameter? J Am Coll Cardiol 2006;47:1018–1023. 56. Tsang TS, Barnes ME, Bailey KR, et al: Left atrial volume: Important risk marker of incident atrial fibrillation in 1655 older men and women. Mayo Clin Proc 2001;76:467–475. 57. 10Vasan RS, Levy D, Larson MG, et al: Interpretation of echocardiographic measurements: A call for standardization. Am Heart J 2000;139:412– 422. 58. Alsaileek AA, Osranek M, Fatema K, et al: Predictive value of normal left atrial volume in stress echocardiography. J Am Coll Cardiol 2006;47: 1024–1028. 59. Abhayaratna WP, Seward JB, Appleton CP, et al: Left atrial size: Physiologic determinants and clinical applications. J Am Coll Cardiol 2006;47: 2357–2363.
60. Inaba Y, Yuda S, Kobayashi N, et al: Strain rate imaging for noninvasive functional quantification of the left atrium: Comparative studies in controls and patients with atrial fibrillation. J Am Soc Echocardiogr 2005;18: 729–736. 61. Thomas L, McKay T, Byth K, Marwick TH: Abnormalities of left atrial function after cardioversion: An atrial strain rate study. Heart Online, July 3, 2006. 62. Modesto KM, Dispenzieri A, Cauduro SA, et al: Left atrial myopathy in cardiac amyloidosis: Implications of novel echocardiographic techniques. Eur Heart J 2005;26:173–179. 63. Di Salvo G, Drago M, Pacileo G, et al: Atrial function after surgical and percutaneous closure of atrial septal defect: A strain rate imaging study. J Am Soc Echocardiogr 2005;18:930–933.
SHERIF F. NAGUEH, MD WILLIAM A. ZOGHBI, MD
14 Evaluation of Right Ventricular Diastolic Function INTRODUCTION PATHOPHYSIOLOGY Right Atrial and Ventricular Dimensions Inferior Vena Cava Diameter and Respiratory Collapse Tricuspid and Pulmonary Regurgitation Signals by Continuous Wave Doppler Tricuspid Inflow Hepatic Venous Flow Tissue Doppler Imaging FUTURE RESEARCH
INTRODUCTION Assessment of right ventricular (RV) function is an important component of the comprehensive evaluation of cardiac function in patients with known or suspected heart disease. RV function may be normal when left ventricular (LV) function is depressed, and conversely, RV dysfunction may occur in the presence of normal LV function. Therefore, a careful evaluation of RV function is essential irrespective of LV functional status. In this chapter, we will discuss the assessment of RV diastolic function with echocardiographic and Doppler techniques.
PATHOPHYSIOLOGY RV diastolic function is determined by a number of factors at the cellular, myocardial, and cardiac chamber levels. Therefore, RV
filling patterns and RV filling pressures reflect the net balance of many variables. Active relaxation is among the important determinants of RV diastolic function and is dependent on calcium uptake by the sarcoplasmic reticulum, intrinsic contractility, uniformity of relaxation, and the load-dependent properties of relaxation. Ventricular suction and active myocardial relaxation in health lead to a small positive pressure gradient between the right atrium and the right ventricle, hence the predominant RV filling in early diastole. In addition, recent animal studies with threedimensional real-time echocardiography have drawn attention to the presence of vortical motion during early diastolic RV filling, which is reduced with chamber dilatation.1 This vortical motion can facilitate RV filling by shunting kinetic energy that could otherwise lead to increased convective deceleration and therefore a reduced right atrial (RA) to RV pressure gradient. With impaired RV relaxation, an increase in RA pressure is needed to maintain adequate RV filling and stroke volume. Myocardial stiffness, RV chamber geometry (dimensions and wall thickness), and RA systolic function determine RV filling later in diastole. In particular, RA systolic function appears to play an important compensatory role in preventing heart failure in the presence of pulmonary hypertension.2 In addition, factors extrinsic to the right ventricle determine RV filling, including pericardial properties, LV filling, and extrinsic compression by mediastinal masses or large pleural effusions. In turn, RV filling can affect LV diastolic volume and pressure.3 It is possible to assess RV relaxation invasively by using highfidelity pressure catheters to measure peak negative pressure/time change (dP/dt) and the time constant of pressure decay during isovolumic relaxation (τ). Both measurements, however, are load dependent,4,5 with an inverse linear relation to systolic load. There is a paucity of data with respect to human measurements that 171
172
Chapter 14 • Evaluation of Right Ventricular Diastolic Function include small numbers of patients with coronary artery disease,6 pulmonary hypertension,5 and hypertrophic cardiomyopathy.7 RV chamber stiffness can also be quantified using the combination of RV diastolic pressures and volumes.4,8 In comparison with invasive measurements, echocardiography has the advantages of safety, versatility, and portability, and therefore is the modality that is most frequently utilized to gain insight into RV diastolic function and filling pressures (Table 14-1).
Right Atrial and Ventricular Dimensions The assessment of RV diastolic function should begin with the evaluation of RV dimensions and systolic function, as patients with reduced RV systolic performance have diastolic dysfunction. RV systolic function is usually assessed in a qualitative manner by paying attention to RV dimensions and fractional area change. This is done utilizing two-dimensional echocardiography, with images acquired from the parasternal, apical, and subcostal views. Likewise, the presence of RV hypertrophy is associated with diastolic dysfunction. RA volume is another useful parameter obtained with twodimensional echocardiography. It is usually increased in patients with RV diastolic dysfunction. RA volumes should be considered when drawing conclusions about RA pressure in patients with
TABLE 14-1 ECHO DOPPLER INDICES FOR ASSESSMENT OF RIGHT VENTRICULAR DIASTOLIC FUNCTION 1. Right atrial volumes (maximum, minimum, and emptying fraction) 2. Inferior vena cava diameter and collapse index 3. Downslope of tricuspid regurgitation jet by continuous wave (CW) Doppler 4. Deceleration rate of pulmonary regurgitation jet by CW Doppler 5. Tricuspid inflow velocities (E, A, E/A ratio, and deceleration time of E velocity) 6. Hepatic venous flow (systolic, diastolic, and atrial reversal velocities) 7. Tricuspid annulus early (Ea) and late (Aa) diastolic velocities by tissue Doppler (TD) 8. Isovolumic relaxation time by TD: time between end of systolic velocity and onset of Ea 9. Early (SRe) and late (Sra) diastolic strain rate
NORMAL RA VOLUME
RA
equivocal findings in Doppler parameters. Although RA volumes can be measured at any time during the cardiac cycle, maximal RA volumes (Fig. 14-1) are most frequently measured before tricuspid valve opening at end systole; RA minimum volume is measured after tricuspid valve closure at end diastole. RA emptying fraction can be computed as the difference between RA maximum and minimum volumes/RA maximum volume. In patients with increased mean RA pressure, RA maximum and minimum volumes are increased, whereas RA emptying fraction is decreased.9 The correlation of RA volumes with RA pressure, however, is weak and is heavily modified by RA stiffness and contractility. In addition, RA volumes may be increased for reasons other than diastolic dysfunction, such as atrial fibrillation and tricuspid valve disorders.
Inferior Vena Cava Diameter and Respiratory Collapse Inferior vena cava (IVC) diameter and its change during inspiration are useful indicators of RA pressure. Previous studies have noted that the segment within 2 cm of the RA-IVC junction is the region most responsive to changes in respiratory effort.10,11 In particular, IVC expiratory and inspiratory diameters as well as percent collapse were reported to have significant relations with RA pressure in patients with spontaneous respiration.9–11 Clinically, IVC imaging is acquired in the subcostal view at rest and with inspiratory effort, or a “sniff test.” The presence of at least 50% collapse is usually seen with an RA pressure less than 10 mmHg, whereas patients with RA pressure greater than 10 mmHg typically exhibit less than 50% IVC collapse.11 Figure 14-2 is from a patient with an increased RA mean pressure (>20 mmHg) who exhibits a dilated IVC and minimal change in IVC diameter with inspiration. The limitations of this method occur in patients with dyspnea and those on mechanical ventilation. In patients on mechanical ventilation, IVC percent collapse relates poorly (Fig. 14-3) to mean RA pressure,9,12 whereas IVC diameter at expiration has a somewhat better correlation (r = .58). An IVC diameter no greater than 12 mm appears highly accurate in identifying patients with an RA pressure less than 10 mmHg, whereas a diameter greater than 12 mm has no predictive value in this population.12 In addition, it is possible to image the left hepatic vein from the same window. In one study, the transverse diameter of this vein at expiration and inspiration, as well as end expiratory apnea, was shown to relate significantly to mean RA pressure in a group
MARKEDLY ENLARGED RA
RA
Figure 14-1 Right atrial (RA) end systolic volume from two patients: one with normal RA volume at 26 ml (left) and the other with pulmonary hypertension, a dilated and hypertrophied right ventricle, and a markedly enlarged right atrium, with a maximum volume of 156 ml.
Chapter 14 • Evaluation of Right Ventricular Diastolic Function Expiration
Inspiration
Normal RAP
Figure 14-2 Examples of inferior vena cava (IVC) diameter changes with inspiration (between arrows) from a patient with normal right atrial pressure (RAP) (upper panel) and another with increased RAP (lower panel). In the upper panel, there is complete collapse of the IVC with inspiration, whereas in the lower panel, the IVC is dilated with minimal change in its diameter with inspiration. The latter observation is consistent with an RAP >20 mmHg.
Mean right atrial pressure by catheter (mmHg)
30
Overall
Increased RAP
r = –0.63, y = 16.6 – 0.16x n = 35, SEE = 4.4 mmHg
25 – vent r = –0.76, SEE = 4.1 mmHg + vent r = 0.24, p = ns
20
15
10
5
0 0
20
40
60
80
100
IVC collapse index (%) Figure 14-3 Relation between mean right atrial pressure and inferior vena cava (IVC) percent collapse. Patients on mechanical ventilation are shown as blue circles, whereas those with spontaneous breathing are shown as red circles. A significant inverse correlation was present only in the group with spontaneous breathing. (From Nagueh SF et al: Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function. Circulation 1996;93:1160–1169.)
of 32 patients presenting with acute myocardial infarction.13 Assessment of the left hepatic vein diameter could be helpful in patients where the IVC is not well visualized. However, there is a paucity of data on the clinical application of this approach in patients on mechanical ventilation.
Tricuspid and Pulmonary Regurgitation Signals by Continuous Wave Doppler The rate of rise and fall in tricuspid regurgitation (TR) jet velocity by continuous wave (CW) Doppler parallels the corresponding events in RV pressure, assuming minimal fluctuations of RA pressure throughout the cardiac cycle. Therefore, it is possible to calculate RV peak positive and peak negative dP/dt by using the TR jet and applying the modified Bernoulli equation to convert the TR velocity to RV pressure. In one study,14 a strong correlation was observed between the invasive measurement and the noninvasive estimate of peak negative dP/dt. The limitations of this approach include the need for a complete TR signal and the underestimation of peak negative dP/dt in patients with an RA “v” wave pressure of at least 10 mmHg. For clinical application, one depends more on the shape of the signal (slow decay of the peak velocity to baseline) than the actual measurement, as shown in Figure 14-4. A pulmonary regurgitation (PR) signal by CW Doppler can be recorded in many patients, particularly in the presence of pulmonary hypertension. In addition, it is possible to enhance the signal by using intravenous contrast.15 Once an adequate signal is recorded, its peak velocity can be used to estimate mean pulmonary artery pressure, whereas its end diastolic velocity in conjunction with mean RA pressure can be used to estimate pulmonary artery diastolic pressure.16 Discrepancies may occur if RV end diastolic pressure is significantly different than mean RA pressure. In addition, in the absence of significant PR, the deceleration slope and the pressure half-time of the PR jet by CW Doppler can provide unique insight into RV diastolic function. Patients with increased RV stiffness and rapidly rising RV diastolic pressure have a rapid equalization of the pressure gradient between the pulmonary artery and the right ventricle and therefore a short pressure half-time (Fig. 14-5). In one study, which used right heart catheterization, a pressure half-time of no greater than
173
174
Chapter 14 • Evaluation of Right Ventricular Diastolic Function NORMAL RV FUNCTION
DEPRESSED RV FUNCTION
Figure 14-4 Example of tricuspid regurgitation jets by CW Doppler from two patients: one with normal right ventricular (RV) function (left) and the other with depressed RV function (right). Notice the slow decay of the peak velocity to the baseline from the patient with depressed RV systolic function compared with the normal, as indicated by the slope of the yellow arrows.
Figure 14-5 Example of pulmonary regurgitation jets by CW Doppler from two patients: one with normal right ventricular (RV) diastolic pressure (left) and the other with highly increased RV diastolic pressures (right). Notice the very steep deceleration of pulmonary regurgitation from the patient in the right panel as indicated by slope of the yellow arrows.
150 ms was the best predictor of RV involvement in patients presenting with acute inferior wall myocardial infarction.17 The same investigators reported that this parameter was the only predictor of overall in-hospital clinical events in the same patient population.18
Tricuspid Inflow Pulsed-wave (PW) Doppler recording of tricuspid inflow is essential for the assessment of RV filling. Care should be exercised to obtain the best alignment with the direction of blood flow, which typically requires a medial movement of the transducer from the conventional apical position.19 The recording is obtained by placing a 1–2 mm sample volume at the valve annulus and tips with filter and gain adjustments to obtain a clear signal. Respiratory variability is an additional factor that needs to be considered with measurements taken at end expiratory apnea or as the average of five to seven consecutive cardiac cycles. The latter approach has been shown to yield identical results to those obtained at end expiratory apnea.20
Similar to mitral inflow, tricuspid inflow (Fig. 14-6) is analyzed for peak early (E) and late (A) diastolic velocity, deceleration time (DT) of E velocity, duration of A velocity, and the fraction of RA contribution to RV filling (the atrial filling fraction [AFF]). All measurements except for the A duration are obtained from the Doppler recordings at the level of the valve tips. The A duration is measured from the recording at the level of the tricuspid annulus. Because the tricuspid and pulmonary valves are in different planes, isovolumic relaxation time (IVRT) is measured by Doppler using two time intervals, as the difference between the duration from the QRS complex to onset of tricuspid inflow and the interval from the QRS complex to end of pulmonic flow. Alternatively, IVRT can be calculated by subtracting the time between the QRS complex and the end of pulmonic ejection from the duration of the TR jet. Early diastolic RV filling is reduced with normal aging,20,21 which should be considered when drawing conclusions about RV diastolic function using tricuspid inflow velocities. In general, patients with impaired RV relaxation have a reduced E/A ratio, a prolonged IVRT and DT, and an increased AFF. As RA pres-
Chapter 14 • Evaluation of Right Ventricular Diastolic Function
Hepatic Venous Flow The flow in the hepatic veins is largely determined by RA pressure during the cardiac cycle. In normal subjects, antegrade flow from the hepatic veins to the RA occurs in systole (S) and diastole (D). With RA contraction, as well as in late ventricular systole (Vr), brief retrograde flow (Ar) occurs into the hepatic veins.23 It is feasible to record high-quality signals by transthoracic imaging from the subcostal window. It is also possible to record them by transesophageal echocardiography (TEE) in the course of a transesophageal examination.24 The sample volume (3–4 mm) is placed 1–2 cm in the hepatic veins, close to their entrance into the IVC. Similar to tricuspid inflow velocities, flow should be recorded for five to seven consecutive cardiac cycles or at end expiratory apnea. E VAR
VVR A
AR dur
VS AT
DT
A wave duration
30 r = 0.66 n = 35 y = –1 + 9.6x SEE = 3.8 mmHg
25
20
15
10
5
VD
Figure 14-6 Schematic diagram of tricuspid inflow (left) and hepatic venous flow (right). E, peak early diastolic velocity; A, peak late diastolic velocity; AT, acceleration time of E velocity; DT, deceleration time of E velocity; VS, peak systolic velocity; VD, peak diastolic velocity; VVR, midsystolic reversal velocity; VAR, peak atrial reversal velocity; AR dur, duration of atrial reversal velocity. (From Nagueh M et al: Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function. Circulation 1996;93:1160–1169.)
Figure 14-7 Examples of normal tricuspid inflow (left), impaired relaxation (middle), and restrictive filling (right). E, early velocity; A, velocity with atrial contraction.
Quantitative measurements include the peak velocity, the duration, and the time-velocity integral (TVI) of velocity at each of the phases (see Fig. 14-6), as well as the proportion of forward flow during systole and diastole, using either peak velocity or TVI measurements. Such parameters can be used to assess mean RA pressure in patients who are in sinus rhythm.9 This is based on the following premise: Systolic forward flow from the hepatic veins to the RA depends on RA relaxation, RV systolic function, and RA pressure. In the presence of a normal RA pressure, predominant flow occurs in systole (Fig. 14-9). As the RA pressure increases, the pressure gradient between the hepatic veins and the right atrium decreases, and correspondingly forward systolic flow decreases.9,25 This abnormal pattern of flow is most exaggerated in patients with restrictive physiology with large atrial and venous reversals.22 Systolic forward flow parameters, particularly systolic filling fraction (systolic flow/total antegrade flow), derived from either TVIs or maximal velocities, have been successfully applied to estimate RA pressure noninvasively in patients with a variety of diseases, including those on mechanical ventilation (Fig. 14-10). Ar duration is also of value, as it has been shown to
Mean right atrial pressure by catheter (mmHg)
sure increases, E/A ratio increases and DT shortens (Fig. 14-7). However, the individual response is highly variable and dependent on the interplay between many hemodynamic parameters, such that the E/A ratio has a significant positive relation with mean RA pressure but with a wide scatter (Fig. 14-8). Nevertheless, in patients with RV systolic dysfunction, a short DT is usually associated with increased filling pressures.9 In addition, diastolic TR, when present and in the absence of atrioventricular (AV) block, indicates the presence of increased RV stiffness and highly increased RV filling pressures.22
175
0 0
1
2
3
Tricuspid E/A ratio Figure 14-8 Relation between tricuspid E/A ratio and mean right atrial pressure. (From Nagueh SF et al: Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function. Circulation 1996;93:1160–1169.)
Chapter 14 • Evaluation of Right Ventricular Diastolic Function
Figure 14-9 Examples of hepatic venous flow. In the example shown on the left, forward flow occurs predominantly in systole, which corresponds to a mean right atrial (RA) pressure ≤5 mmHg. In the example on the right, the peak systolic and diastolic velocities are similar, corresponding to mean RA pressure of 5–10 mmHg.
SYSTOLIC FILLING FRACTION 30 r = –0.86 n = 35 y = 21.6 – 24x SEE = 2.5 mmHg
25
20
15
10
5
0
Mean right atrial pressure by catheter (mmHg)
30 Mean right atrial pressure by catheter (mmHg)
176
r = –0.85 n = 35 y = 23 – 29x SEE = 3 mmHg
25
20
15
10
5
0 0.0
0.2
0.4
0.6
0.8
1.0
TVIS/(TVIS + TVID)
0.0
0.2
0.4
0.6
0.8
1.0
VS/(VS + VD)
Figure 14-10 Correlation between mean right atrial pressure and right atrial systolic filling fraction calculated using the time-velocity integral (left) and peak systolic velocity (right). (From Nagueh SF et al: Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function. Circulation 1996;93:1160–1169.)
relate to RA pressure9,26 and late diastolic RV pressures (Fig. 14-11). These principles are not applicable to patients in nonsinus rhythms or with cardiac transplants, tricuspid valve disease (significant stenosis or regurgitation and prosthetic valves), or pericardial compression syndromes (tamponade or constriction). However, hepatic venous flow may still be helpful in these conditions. For example, patients with severe TR usually exhibit systolic flow reversal (Fig. 14-12) into the hepatic veins.27 Likewise, hepatic venous flow can help differentiate pericardial constriction from restrictive cardiomyopathy. In patients with constrictive physiology, a predominant systolic or biphasic flow pattern is frequently recorded. In addition, respiratory flow variation presents unique insight into RV and LV filling, where RA and RV filling increase with inspiration and the Vr and Ar velocities become more prominent with expiration.28 The latter observation is
dependent upon increased LV filling with expiration in the presence of a taut pericardium, which leads to reduced RV filling with RA contraction. Accordingly, RA contraction results in increased flow into the hepatic veins during expiration. Table 14-2 shows a practical summary for estimating mean RA pressure using an IVC collapse index and hepatic venous flow.
Tissue Doppler Imaging Tissue Doppler imaging (TDI) allows the recording of myocardial velocity during the cardiac cycle, including velocities at the tricuspid annulus. In addition, using TDI or recently developed speckle tracking technology, one can measure local rates of systolic compression and early and late diastolic expansion of the myocardium (systolic and diastolic strain rates, respectively). For assessment of RV global diastolic function, tricuspid annulus velocities
Chapter 14 • Evaluation of Right Ventricular Diastolic Function
Figure 14-11 Hepatic venous flow from a patient with pulmonary hypertension and increased late diastolic right ventricular pressures and stiffness. Notice the prominent AR (atrial reversal) velocity.
Figure 14-13 Example of tissue Doppler recording of myocardial velocities from the right ventricular free wall in a normal subject. The inset shows the location of the sample volume at the right side of the tricuspid annulus. Notice the presence of an Sa peak velocity of 15 cm/s, a peak Ea velocity of 18 cm/s, and an Ea/Aa ratio >1. IVRT, isovolumic relaxation time between end of Sa and onset of Ea; Sa, systolic ejection velocity; Ea, early diastolic velocity; Aa, late diastolic velocity.
examination of function of multiple segments simultaneously, in the same beat; however, an estimate of mean myocardial velocities is provided. The velocity measured by color TDI is therefore lower than the maximal velocity measured by PW Doppler, which should always be considered when normal values and results are compared among different studies. The following indices of diastolic function are measured by TDI at the tricuspid annulus: ❒ ❒ ❒ ❒ ❒ ❒ Figure 14-12 Hepatic venous flow from a patient with severe tricuspid regurgitation. Notice the presence of flow reversal during systole.
TABLE 14-2 SUMMARY OF RIGHT ATRIAL PRESSURE (RAP) ESTIMATION USING INFERIOR VENA CAVA (IVC) COLLAPSE INDEX AND HEPATIC VENOUS FLOW MEAN RAP (mmHg)
IVC % COLLAPSE
HEPATIC VEINS
0–5 5–10 10–15 ≥20
≥50 ≥50 <50 <50
VS > VD VS = VD VS < VD Flow only with VD
VS = systolic velocity; VD = diastolic velocity.
are recorded by placing the PW Doppler sample volume (4– 5 mm) at the right border of the annulus. It is also possible to use color Doppler two-dimensional images to obtain a display of myocardial and annular velocities. The advantages of the PW approach include online beat-to-beat evaluation and the spectral display of velocities. On the other hand, color TDI allows the
Early diastolic velocity (Ea) Late diastolic velocity (Aa) Ea/Aa ratio RV regional IVRT (Fig. 14-13) Early diastolic strain rate Late diastolic strain rate
A number of studies have evaluated the utility of Ea, Aa, and the Ea/Aa ratio to assess RV diastolic function. Patients with RV diastolic dysfunction usually have reduced Ea velocity and a reduced Ea/Aa ratio. Aa velocity may be increased in the early course of diastolic dysfunction, whereas with increased RV late diastolic pressures, it may decrease. Using these simple and reproducible velocity measurements, a number of investigators have reported on RV diastolic function in several cardiac disorders. These included patients with coronary artery disease,29 inferior wall myocardial infarction and RV involvement,30 dilated cardiomyopathy,31 hypertrophic cardiomyopathy,32 obesity,33,34 congenital heart disease,35 and systemic36 and pulmonary hypertension.37 While the observations in this chapter support an important clinical role for TDI-derived velocities, there have been no direct validation studies in animals or humans against invasive measurements of negative dP/dt or τ. Similar to early diastolic velocity at the mitral annulus, tricuspid Ea is load dependent in normal ventricles.38 On the other hand, the tricuspid Ea/Aa ratio appears unchanged with preload reduction.38 Notwithstanding, existing studies support the conclusion that tricuspid annulus Ea velocity is not positively affected by preload in patients with RV dysfunction, given the presence of an inverse correlation between Ea and mean RA pressure in cardiac patients.39 Accordingly, the ratio of
177
178
Chapter 14 • Evaluation of Right Ventricular Diastolic Function tricuspid E velocity to annular Ea velocity has been applied to predict RV filling pressures (Figs. 14-14 and 14-15), in an analogous manner to the use of mitral velocities, in both animal40 and human studies.39,41 In the human studies, different groups of patients were evaluated, and overall an E/Ea ratio greater than 6 had a sensitivity of 79% and a specificity of 73% for mean RA pressure of at least 10 mmHg.39 The good correlation of tricuspid E/Ea ratio to mean RA pressure was noted in patients with and without RV systolic dysfunction, as well as in those on mechanical ventilation.39
TRICUSPID INFLOW
100 80
E
cm/sec
60
A
40 20 0 –20 TISSUE DOPPLER 20
cm/sec
Sa
In cardiac transplant recipients, the ratio of E to Ea is also useful (Fig. 14-16), where a ratio greater than 8 had a sensitivity of 78% and a specificity of 85% for RA pressure of at least 10 mmHg.41 Furthermore, Ea of the tricuspid annulus had no significant relation to RA pressure and was not altered by pressure changes. Accordingly, the E/Ea ratio readily detected changes in mean RA pressure of at least 5 mmHg (Fig. 14-17) with a sensitivity of 70% and a specificity of 75%.41 These observations are in contrast to the limited role of hepatic venous flow in the transplant population as a result of mechanical dissociation between the donor and recipient atria, which alters the systolic and diastolic components of hepatic venous flow and renders their interpretation more challenging. A recent study reported on the clinical application of another TDI-derived measurement, namely the time interval between the end of tricuspid annular systolic velocity and the onset of annular Ea. The latter time interval had a significant inverse correlation with mean RA pressure. In a study of 21 patients, a time interval of less than 59 ms had a sensitivity of 80% and a specificity of 88% in identifying patients with RA pressure greater than 8 mmHg.42 There are advantages to determining mean RA pressure by using TDI. In the case of RV regional IVRT, this is a single measurement that is not affected by angulation. In addition, the tricuspid E/Ea ratio and the above time interval are particularly helpful in patients without subcostal windows where there is concomitant inability to image the IVC and acquire hepatic venous flow. However, these methods may not be accurate in the presence of nonsinus rhythms and tricuspid valve disease.
0
FUTURE RESEARCH
Ea
Aa
–20 Figure 14-14 Upper panel shows early (E) and late (A) diastolic tricuspid inflow velocities. Lower panel shows the annular velocities during systolic ejection (Sa) and early (Ea) and late (Aa) diastole. The E/Ea ratio is 6.75, predicting a mean right atrial pressure of 12 mmHg (catheter pressure 11 mmHg). (From Nageh MF et al: Estimation of mean right atrial pressure using tissue Doppler imaging. Am J Cardiol 1999;84:1448–1451.)
35
y = 0.8 + 1.7x r = 0.75 n = 62
20 (Doppler RAP – Catheter RAP)
30 25 RAP (mmHg)
Evaluation of RV diastolic function is important clinically. Echocardiography and Doppler provide several complementary methods for evaluation of RV diastolic function and prediction of mean RA pressure. These include the evaluation of cardiac structure and function; RV, RA, and IVC size; myocardial velocities; strain rate with tissue Doppler and speckle tracking technology; and hepatic venous flow patterns. These parameters allow a
20 15 10 5 0
15 10 5 0 –5 –10 –15 –20
0
2
4
6
8 E/Ea
10
12
14
16
0
5
10
15
20
25
30
35
(Doppler RAP + Catheter RAP)/2
Figure 14-15 Upper panel: regression plot between mean right atrial pressure (RAP) and tricuspid E/Ea ratio in 62 patients with simultaneous invasive and echocardiographic measurements. Lower panel: Bland-Altman plot of Doppler-derived RAP versus catheter RAP. Mean difference between Doppler and catheter pressures was 0.3 ± 3.7 mmHg. Upper and lower lines represent mean + and mean −2 SDs, respectively. (From Nageh MF et al: Estimation of mean right atrial pressure using tissue Doppler imaging. Am J Cardiol 1999;84:1448–1451.)
Chapter 14 • Evaluation of Right Ventricular Diastolic Function 25
20 (Doppler – Catheter RAP) (mmHg)
r = 0.79 n = 38 y = 1.76× – 3.7
RAP (mmHg)
20
15
10
5
0
15 10 5 0 –5 –10 –15 –20
0
5
10
15
0
E/Ea
5
10
15
20
25
(Doppler + Catheter RAP)/2
Figure 14-16 Left, relation between mean right atrial pressure (RAP) and tricuspid E/Ea ratio in patients who have undergone cardiac transplantation. Right, Bland-Altman plot of Doppler-derived RAP versus catheter RAP. (From Sundereswaran L et al: Estimation of left and right ventricular filling pressures after heart transplantation by tissue Doppler imaging. Am J Cardiol 1998;82:352–357.)
Δ Doppler RAP (mmHg)
10
15
r = 0.83 n = 18 y = x – 0.2
(Δ Doppler – Δ Catheter RAP) (mmHg)
15
5 0 –5 –10
10 5 0 –5 –10 –15
–15 –15
–10
–5
0
5
10
15
Δ Catheter RAP (mmHg)
–15
–10
–5
0
5
10
15
(Δ Doppler + Δ Catheter RAP)/2
Figure 14-17 Left: relation between changes in mean right atrial pressure (RAP) and those predicted by Doppler in patients who have undergone cardiac transplantation. Right: Bland-Altman plot of changes in RAP by Doppler and changes in mean RAP by right heart catheterization. (From Sundereswaran L et al: Estimation of left and right ventricular filling pressures after heart transplantation by tissue Doppler imaging. Am J Cardiol 1998;82:352–357.)
comprehensive approach to the evaluation of RV diastolic function and its effect on filling pressures. The availability of threedimensional technology will undoubtedly improve quantification of RV volumes and systolic function. Whether three-dimensional technology will further improve the evaluation of RV diastolic function remains to be determined. In addition, the presence of sensitive indices of RV diastolic function such as early diastolic strain rate may help in the earlier diagnosis of RV dysfunction in cardiomyopathic disorders, as in patients with arrhythmogenic RV dysplasia, where conventional echocardiography may not be diagnostic of RV disease. Furthermore, there is a need to study the presence of systolic and diastolic RV intraventricular dyssynchrony, its impact on global RV diastolic function, and the effect of different RV pacing sites on RV performance. Finally, these different methods to assess RV function can be used to track functional changes in response to medical/surgical therapy for
several cardiovascular disorders that affect the right ventricle, including congenital heart disease and pulmonary hypertension. REFERENCES 1. Pasipoularides A, Shu M, Shah A, et al: Diastolic right ventricular filling vortex in normal and volume overload states. Am J Physiol Heart Circ Physiol 2003;284:H1064–H1072. 2. Gaynor SL, Maniar HS, Bloch JB, et al: Right atrial and ventricular adaptation to chronic right ventricular pressure overload. Circulation 2005;112: I212–I218. 3. Moore TD, Frenneaux MP, Sas R, et al: Ventricular interaction and external constraint account for decreased stroke work during volume loading in CHF. Am J Physiol Heart Circ Physiol 2001;281:H2385–H2391. 4. Leeuwenburgh BP, Steendijk P, Helbing WA, Baan J: Indexes of diastolic RV function: Load dependence and changes after chronic RV pressure overload in lambs. Am J Physiol Heart Circ Physiol 2002;282: H1350–H1358.
179
180
Chapter 14 • Evaluation of Right Ventricular Diastolic Function 5. Stein, PD, Sabbah HN, Mazilli M, Anbe DT: Effect of chronic pressure overload on the maximal rate of pressure fall of the right ventricle. Chest 1980;78:10–15. 6. Darsinos, JT, Evagelou AM, Rassidakis AN: Rate of pressure fall in right ventricle during isovolumic relaxation. Angiology 1974;25:520–526. 7. Maeda, M, Yamakado T, Nakano T: Right ventricular diastolic function in patients with hypertrophic cardiomyopathy—an invasive study. Jpn Circ J 1999;63:681–687. 8. Pasipoularides A, Shu M, Shah A, et al: Right ventricular diastolic function in canine models of pressure overload, volume overload, and ischemia. Am J Physiol Heart Circ Physiol 2002;283:H2140–H2150. 9. Nagueh SF, Kopelen HA, Zoghbi WA: Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function. Circulation 1996;93:1160–1169. 10. Simonson JS, Schiller NB: Sonospirometry: A non-invasive method for estimation of mean right atrial pressure based on two dimensional echocardiographic measurements of the inferior vena cava during measured inspiration. J Am Coll Cardiol 1988;11:557–564. 11. Kircher BJ, Himelman RB, Schiller NB: Non-invasive estimation of right atrial pressure from the inspiratory collapse of the inferior vena cava. Am J Cardiol 1990;66:493–496. 12. Jue J, Chung W, Schiller NB: Does inferior vena caval size predict right atrial pressure in mechanically ventilated patients? J Am Soc Echocardiogr 1992;5:613–619. 13. Luca L, Mario P, Giansiro B, et al: Noninvasive estimation of mean right atrial pressure utilizing the 2-D echo transverse diameter of the left hepatic vein. Int J Card Imaging 1992;8:191–195. 14. Imanishi T, Nakatani S, Yamada S, et al: Validation of continuous wave Doppler–determined right ventricular peak positive and negative dP/dt: Effect of right atrial pressure on measurement. J Am Coll Cardiol 1994;23:1638–1643. 15. Tanabe K, Asanuma T, Yoshitomi H, et al: Doppler estimation of pulmonary artery end-diastolic pressure using contrast enhancement of pulmonary regurgitant signals. Am J Cardiol 1996;78:1145–1148. 16. Masuyama T, Kodama K, Kitabatake A, et al: Continuous-wave Doppler echocardiographic detection of pulmonary regurgitation and its application to noninvasive estimation of pulmonary artery pressure. Circulation 1986;74:484–492. 17. Cohen A, Guyon P, Chauvel C, et al: Relations between Doppler tracings of pulmonary regurgitation and invasive hemodynamics in acute right ventricular infarction complicating inferior wall left ventricular infarction. Am J Cardiol 1995;75:425–430. 18. Cohen A, Logeart D, Costagliola D, et al: Usefulness of pulmonary regurgitation Doppler tracings in predicting in-hospital and long-term outcome in patients with inferior wall acute myocardial infarction. Am J Cardiol 1998;81:276–281. 19. Appleton CP, Jensen JL, Hatle LK, Oh JK: Doppler evaluation of left and right ventricular diastolic function: A technical guide for obtaining optimal flow velocity recordings. J Am Soc Echocardiogr 1997;10:271–292. 20. Zoghbi WA, Habib JB, Quiñones MA: Doppler assessment of right ventricular filling in a normal population: Comparison with left ventricular filling dynamics. Circulation 1990;82:1316–1324. 21. Berman G, Reicheck N, Brownson D, Douglas PS: Effects of sample volume location, imaging view, heart rate and age on tricuspid velocimetry in normal subjects. Am J Cardiol 1990;65:1026–1030. 22. Appleton CP, Hatle LK, Popp RL: Demonstration of restrictive ventricular physiology by Doppler echocardiography. J Am Coll Cardiol 1988;11: 757–768. 23. Appleton CP, Hatle LK, Popp RL: Superior vena cava and hepatic vein Doppler echocardiography in healthy adults. J Am Coll Cardiol 1987;10: 1032–1039.
24. Pinto FJ, Wranne B, St Goar FG, et al: Hepatic venous flow assessed by transesophageal echocardiography. J Am Coll Cardiol 1991;17:1493– 1498. 25. Sivaciyan V, Ranganathan N: Transcutaneous Doppler jugular venous flow velocity recording. Circulation 1978;57:930–939. 26. Ommen SR, Nishimura RA, Hurrell DG, Klarich KW: Assessment of right atrial pressure with 2-dimensional and Doppler echocardiography: A simultaneous catheterization and echocardiographic study. Mayo Clin Proc 2000;75:24–29. 27. Gonzalez-Vilchez F, Zarauza J, Vazquez de Prada JA, et al: Assessment of tricuspid regurgitation by Doppler color flow imaging: Angiographic correlation. Int J Cardiol 1994;44:275–283. 28. Oh JK, Hatle LK, Seward JB, et al: Diagnostic role of Doppler echocardiography in constrictive pericarditis. J Am Coll Cardiol 1994;23:154–162. 29. Alam M, Hedman A, Nordlander R, Samad B: Right ventricular function before and after an uncomplicated coronary artery bypass graft as assessed by pulsed wave Doppler tissue imaging of the tricuspid annulus. Am Heart J 2003;146:520–526. 30. Dokainish H, Abbey H, Gin K, et al: Usefulness of tissue Doppler imaging in the diagnosis and prognosis of acute right ventricular infarction with inferior wall acute left ventricular infarction. Am J Cardiol 2005;95: 1039–1042. 31. McMahon CJ, Nagueh SF, Eapen RS et al: Echocardiographic predictors of adverse clinical events in children with dilated cardiomyopathy: A prospective clinical study. Heart 2004;90:908–915. 32. Severino S, Caso P, Cicala S, et al: Involvement of right ventricle in left ventricular hypertrophic cardiomyopathy: Analysis by pulsed Doppler tissue imaging. Eur J Echocardiogr 2000;1:281–288. 33. Willens HJ, Chakko SC, Lowery MH, et al: Tissue Doppler imaging of the right and left ventricle in severe obesity (body mass index >35 kg/m2). Am J Cardiol 2004;94:1087–1090. 34. Wong CY, O’Moore-Sullivan T, Leano R, et al: Association of subclinical right ventricular dysfunction with obesity. J Am Coll Cardiol 2006;47:611– 616. 35. Watanabe M, Ono S, Tomomasa T, et al: Measurement of tricuspid annular diastolic velocities by Doppler tissue imaging to assess right ventricular function in patients with congenital heart disease. Pediatr Cardiol 2003;24:463–467. 36. Cicala S, Galderisi M, Caso P, et al: Right ventricular diastolic dysfunction in arterial systemic hypertension: Analysis by pulsed tissue Doppler. Eur J Echocardiogr 2002;3:135–142. 37. Moustapha A, Lim M, Saikia S, et al: Interrogation of the tricuspid annulus by Doppler tissue imaging in patients with chronic pulmonary hypertension: Implications for the assessment of right-ventricular systolic and diastolic function. Cardiology 2001;95:101–104. 38. Pela G, Regolisti G, Coghi P, et al: Effects of the reduction of preload on left and right ventricular myocardial velocities analyzed by Doppler tissue echocardiography in healthy subjects. Eur J Echocardiogr 2004;5: 262–271. 39. Nageh MF, Kopelen HA, Zoghbi WA, et al: Estimation of mean right atrial pressure using tissue Doppler imaging. Am J Cardiol 1999;84:1448– 1451. 40. Boissiere J, Gautier M, Machet MC, et al: Doppler tissue imaging in assessment of pulmonary hypertension-induced right ventricle dysfunction. Am J Physiol Heart Circ Physiol 2005;289:H2450–H2455. 41. Sundereswaran L, Nagueh SF, Vardan S, et al: Estimation of left and right ventricular filling pressures after heart transplantation by tissue Doppler imaging. Am J Cardiol 1998;82:352–357. 42. Abbas A, Lester S, Moreno FC, et al: Noninvasive assessment of right atrial pressure using Doppler tissue imaging. J Am Soc Echocardiogr 2004;17: 1155–1160.
MIGUEL A. QUINONES, MD
15
Evaluation of Intracardiac Filling Pressures INTRODUCTION PATHOPHYSIOLOGY Definition of Left Ventricular Filling Pressure Two-Dimensional Echocardiography Doppler Echocardiography—Transmitral and Pulmonary Vein Velocities CLINICAL ASSESSMENT Estimation of Filling Pressures Limitations of Transmitral and Pulmonary Vein Velocities
Combination of Transmitral Velocity with Newer Indices of Left Ventricular Relaxation Estimation of Filling Pressures Newer (Less Validated) Methods A Recommended Algorithm for Estimation of Filling Pressures FUTURE RESEARCH
INTRODUCTION
PATHOPHYSIOLOGY
Normal diastolic function allows a ventricle to fill to an adequate volume while maintaining normal diastolic pressures at rest, during exercise, and through a wide range of heart rates. This occurs through the interaction of multiple intracardiac and extracardiac factors (which have been discussed in detail in previous chapters). Failure of these factors to properly operate results in the elevation of left ventricular (LV) diastolic (or filling) pressures at rest or with exertion and consequently the occurrence of cardiac dyspnea, a common denominator in all forms of heart failure regardless of the resting systolic function. However, there are as many pulmonary causes of dyspnea as there are cardiac, and even in patients with known heart disease, the dyspnea may be of a pulmonary origin. Likewise, elevations of right ventricular (RV) filling pressures and right atrial pressures (RAPs) result in rightsided failure and edema as its common manifestation; as with dyspnea, edema has also a common list of noncardiac etiologies. Thus, over the past 20 years, there has been great interest in the development of noninvasive methods to estimate left- and rightsided filling pressures. In this chapter, we will discuss the estimation of left-sided filling pressures and propose an integrated approach. Assessment of right-sided pressures is discussed in detail in Chapter 14.
Definition of Left Ventricular Filling Pressure Several pressure measurements are collectively referred to as filling pressures. They include mean left atrial pressure (LAP), mean pulmonary capillary wedge pressure (PCWP) as a corollary of LAP, and LV end diastolic pressure (LVEDP). In addition, diastolic LV pressure (LVP) prior to atrial contraction has been shown to relate closely with mean LAP.1 It is important, however, to understand the clinical difference between mean LAP (or PCWP) and LVEDP. Although a high LVEDP is indicative of increased LV stiffness at end diastole, many of these patients have normal diastolic LVP prior to atrial contraction, and consequently a normal mean LAP. Therefore, when evaluating patients with dyspnea, it is preferable to utilize indices that provide an estimate of mean LAP rather than LVEDP.
Two-Dimensional Echocardiography Echocardiography plays a pivotal role in the evaluation of patients presenting with dyspnea of suspected cardiac origin. It provides an accurate assessment of LV size, regional wall motion, and ejection fraction (EF); allows recognition of patterns of LV hypertrophy and remodeling; and provides an accurate assessment of left 181
182
Chapter 15 • Evaluation of Intracardiac Filling Pressures atrial (LA) enlargement, an extremely frequent finding in heart failure. The anteroposterior LA dimension has been used for decades to determine LA size, primarily because it was the only measurement available in the era of M-mode echocardiography. However, enlargement of the left atrium does not occur symmetrically, and the anteroposterior dimension consistently underestimates the true LA volume (Fig. 15-1).2 A more accurate assessment is obtained with two-dimensional echocardiography by deriving the volume of the left atrium from planimetry of the chamber in the apical views, using either single or biplane methods.3,4 These volume estimates compare well with measurements obtained with three-dimensional–cine computed tomography and magnetic resonance imaging.5,6 All subsequent reference in this chapter to the value of determining LA size for the estimation of filling pressures implies that volumes, rather than dimensions, are used. Using echocardiography, the upper limit of normal LA volume, indexed to body surface area, is 28 ml/m2.4 Echocardiography is currently the most widely used imaging technique to distinguish patients with systolic heart failure from those with diastolic heart failure; the former is characterized by LV dilatation, eccentric hypertrophy (dilated cavity with normal ratio of radius to wall thickness), and depressed EF, and the latter by absence of LV dilatation, preservation of EF (≥50%), and often concentric hypertrophy or remodeling7 (see Chapters 2 and 6). Concentric LV hypertrophy is defined as increased mass with an increased radius/thickness ratio (R/Th), and concentric remodeling is defined as normal mass with increased R/Th. Another frequent finding in patients with diastolic heart failure is a reduction (<8 mm) in the extent of mitral annular descent, an index of the longitudinal vector of contraction and relaxation.8,9 If the echocardiogram in the evaluation of dyspnea demonstrates normal LV size without hypertrophy, normal EF and regional wall motion, normal annular descent, and normal LA size, the cause of dyspnea is unlikely to be cardiac. The contrary may not always be the case, since patients may present with abnormalities of cardiac structure and function, including depressed EF, and have dyspnea of a noncardiac etiology. Perhaps the most reliable finding is the LA size, since, in the absence of atrial fibrillation or mitral regurgitation/stenosis, it represents a “poor man’s” index of the diastolic load imposed by the left ventricle on the atrium10,11 (see Chapters 10 and 18). In our experience at the
ASSESSMENT OF LEFT ATRIAL SIZE
Methodist DeBakey Heart Center over the past year, 95% of 2500 patients with echo-Doppler evidence of elevated filling pressures had an enlarged LA volume (unpublished observation).
Doppler Echocardiography—Transmitral and Pulmonary Vein Velocities Determinants of Transmitral Velocity With the advent of pulsed-wave (PW) Doppler echocardiography, recordings of transmitral velocity from the apical window at the tips of the mitral leaflets provided an easy-to-use noninvasive tool for the evaluation of diastolic filling. The peak early velocity (E) and its deceleration time (DT), the atrial (A) velocity, and the E/A ratio became popular indices of diastolic function (Fig. 15-2). E/A ratio is a normalized index that reflects early diastolic filling relative to atrial contraction. Isovolumic relaxation time (IVRT) is the interval between the end of ejection and the onset of mitral inflow. IVRT is obtained by recording velocities from an intermediate position between mitral inflow and LV outflow with either PW or continuous wave (CW) Doppler (Fig. 15-3) (see Chapter 10). The determinants of transmitral velocity and its components have been described in detail elsewhere in this volume. Briefly, transmitral velocity is driven by two major factors: flow and the instantaneous transvalvular pressure gradient (see Fig. 15-2).12,13 During early diastole, active relaxation and LA pressure are the principal determinants of flow and transvalvular gradients. With normal relaxation, LVP decay during isovolumic relaxation occurs rapidly (thus a shorter time constant of relaxation, or Tau), and early ventricular suction is enhanced. This results in a higher E velocity and a shorter DT and IVRT; the opposite occurs with impaired relaxation (longer Tau): less suction, lower E velocity, and longer DT and IVRT. Likewise, with increasing LAP (and a higher LV-LA crossover pressure), IVRT shortens, the early LALV transmitral gradient and E velocity increase, and DT shortens; the opposite occurs with a fall in LA pressure.14,15 The influence of relaxation and LA pressure on transmitral velocity explains the different transmitral patterns described in the literature (Fig. 15-4): the normal healthy pattern seen in young hearts; the “impaired relaxation” pattern, also referred to as ↓ Relaxation
Normal
↓ Relaxation elevated LVFP
IVRT
E
E LAd
A
A
A
E
LA DT
Figure 15-1 Example of a patient in whom the anteroposterior left atrial dimension (LAd) is mildly increased (4.0 cm), whereas in the apical view the left atrium is severely dilated with a volume derived from planimetry of 160 ml (80 ml/m2).
Figure 15-2 Relation of transmitral velocity to the pressure gradient between the left atrium and the left ventricle in three common hemodynamic conditions: normal relaxation, impaired (↓) relaxation, and impaired relaxation with elevated left atrial pressure. No pseudonormal noted. IVRT, isovolumic relaxation time; E, peak early velocity; A, atrial velocity; DT, deceleration time; LVFP, left ventricular filling pressure.
Chapter 15 • Evaluation of Intracardiac Filling Pressures PW-DOPPLER
CW-DOPPLER
IVRT
IVRT
A
B
Figure 15-3 Recording of left ventricular outflow and transmitral velocity. A, PW Doppler; B, CW Doppler. Both recordings provide a measurement of isovolumic relaxation time (IVRT) as the interval from the end of ejection to the onset of mitral inflow.
Figure 15-4 Examples of normal transmitral velocity with the three stages of diastolic dysfunction patterns. Range of values is listed under each pattern. IVRT, isovolumic relaxation time; E, peak early velocity; A, atrial velocity; DT, deceleration time; LVFP, left ventricular filling pressure.
E/A >1 DT 150–240 IVRT <90 msec
stage I diastolic dysfunction13; and both the pseudonormal (stage II) and restrictive (stage III) patterns associated with high filling pressures. As discussed later, the relation of these patterns to LAP occurs best in patients with depressed EF.
Determinants of Pulmonary Vein Velocity Recordings of pulmonary vein velocity (PVV) by PW Doppler are readily obtained in close to 80% of patients during routine examinations. The determinants of the different components of PVV are described in detail in Chapter 10. In brief, atrial relaxation combined with the normal descent of the annulus during ventricular systole contributes to a rapid decline in LAP (the x-descent) that drives flow into the atrium. This is depicted in the PVV recording as an antegrade flow velocity (S-wave) (Fig. 15-5). Following mitral valve opening, there is a second antegrade velocity (D-wave) coincident with the transmitral E velocity. During atrial contraction, there is a small retrograde velocity (AR) into the pulmonary vein. When the x-descent is replaced by an elevated v-wave (as seen frequently during decompensated systolic heart failure), the S-wave becomes diminished and D becomes accentuated in concert with the increase in E velocity previously described. An S/D ratio of less than 1 (S/D derived
↓ RELAXATION STAGE I
PSEUDO-NORMAL STAGE II
E/A <1 DT >240 IVRT >90 msec
Pulmonary Mitral inflow vein (cm/sec) (cm/sec)
NORMAL
RESTRICTIVE STAGE III
E/A 1–2 DT 150–240 IVRT <90 msec
E/A >2 DT <150 IVRT <70 msec
E E
100
100
A
S
E
S
D
A A
D
D S
AR Normal relaxation
AR Normal Lap
High Lap
AR
Impaired LV relaxation
Figure 15-5 Diagrammatic illustration of transmitral and pulmonary vein velocities in normal relaxation, impaired left ventricular (LV) relaxation with normal left atrial pressure (LAP), and impaired relaxation with high LAP. Values of deceleration time for pseudonormal should be 150–240; for restrictive, <150. E, peak early velocity; A, atrial velocity; S, systolic; D, diastolic; Ar, retrograde A velocity.
183
184
Chapter 15 • Evaluation of Intracardiac Filling Pressures using the integral of the velocities) is an index of elevated mean PCWP that, like the E/A ratio and DT, performs more accurately in patients with depressed LVEF.16,17
CLINICAL ASSESSMENT Estimation of Filling Pressures Given that impaired relaxation is present in the vast majority of patients with conditions leading to or associated with heart failure (Box 15-1),18–22 the influence of LAP on transmitral velocity depends on how much LAP (and LV stiffness) overcomes the opposite effect of impaired relaxation (Fig. 15-6). This opposite interaction can be seen even in patients with normal hearts, in whom a very low LAP or preload results in a lowering of the E velocity and E/A ratio despite normal relaxation. A subtle difference between stage I diastolic dysfunction and normal relaxation with low preload is that the reduction in early filling induced by impaired relaxation results in a greater residual volume in the left atrium at the time of atrial contraction and a compensatory increase in A velocity that often brings the E/A ratio to less than 0.8. In addition, stage I diastolic dysfunction frequently has a DT of greater than 240 msec. Box 15-1
Conditions Associated with Impaired Relaxation Increased afterload Aging Systemic hypertension Pathologic secondary left ventricular hypertrophy Hypertrophic cardiomyopathy Ischemia Myocardial diseases Infiltrative cardiomyopathies
↓ Relaxation
↑ LA pressure
↓ E-velocity
↑ E-velocity
Measured E-velocity
Figure 15-6 Influence of impaired (↓) left ventricular relaxation and elevated (↑) left atrial (LA) pressure on the transmitral E velocity.
In patients with depressed LVEF (<40%), the presence of a stage I pattern is usually associated with normal (<15 mmHg) resting mean LAPs and a PVV S/D ratio greater than 1.13,23 In contrast, the pseudonormal (stage II) and restrictive (stage III) patterns are associated with increasing elevation of filling pressures. The stage III pattern is often associated with a diminished A-wave due to the high afterload imposed on the atrium by the elevated LVEDP. In these patients, an S/D ratio of less than 1 in the PVV also implies elevated mean LAP.13,16 Although patients with stage I diastolic dysfunction are often asymptomatic at rest, they are more prone to develop exerciseinduced dyspnea and are at risk for developing heart failure over time, particularly the group with a dilated left atrium.24,25 These patients often have auscultatory evidence of a fourth heart sound and may have a prominent A-wave in LVP tracing. In patients with systolic dysfunction (EF <40%), the presence of stage II and III diastolic dysfunction represents a progression of disease and implies a worsening of LV stiffness and higher LAP. Therefore, a gross estimate of mean LAP or PCWP can be inferred from these patterns: Stage I is associated with pressures less than 15 mmHg; stage II is usually associated with pressures between 15 and 25 mmHg; and stage III is associated with pressures greater than 25 mmHg. Several equations have been proposed in the literature to derive mean PCWP.11,23,26–27 They all incorporate multiple measurements from transmitral velocity, and some of them add measurements from the pulmonary veins, LA volume, or both. They all have better accuracy in patients with depressed EF and perform poorly in those with normal systolic function. We have found that the equation Mean PCWP = 17 + (5 × E/A) − (0.11 × IVRT) is simple to use and performs well in the estimation of mean PCWP in patients with depressed EF (Fig. 15-7).23 When estimating mean PCWP, we have not found additional value from recordings of the PVV in patients with systolic heart failure. In contrast, PVV is useful in estimating the LVEDP. During atrial contraction with an elevated LVEDP, LVP may rise over LA pressure, producing a reverse gradient that shortens the duration of the transmitral A velocity (AMV) relative to the pulmonary vein retrograde A velocity (AR) (Fig. 15-8). The interval AR–AMV has been found to relate directly with LVEDP; whenever AR–AMV exceeds 20 msec, LVEDP is likely to be higher than 20 mmHg.28 This finding is fairly reliable as long as the P-R interval is within a normal range, that is, is neither too short nor too long. The progression from stage I diastolic dysfunction to stage II and III is a “two-way street,” meaning that patients may decompensate into the advanced stages and with proper treatment regress back to stage I (i.e., lower filling pressures). The preceding equation has been shown to track well changes in mean PCWP in response to therapy. Application of the Valsalva maneuver can be used to assess reversibility, since the increased intrathoracic pressure during the maneuver causes a decrease in preload and a shift in transmitral velocity from stage III to stage II or from II to I.29 Stage IV diastolic dysfunction represents a restrictive pattern that fails to reverse with either Valsalva or heart failure therapy.13 In patients with systolic heart failure, this pattern appears to be a marker of very high LV stiffness and fibrosis and is associated with poor prognosis.30,31 In animal models of systolic heart failure, DT has been shown to relate well with LV chamber stiffness.15 Likewise, in patients with ischemic cardiomyopathy,
Chapter 15 • Evaluation of Intracardiac Filling Pressures 40
20 15
30
Doppler (mmHg)
Doppler (mmHg)
r = 0.88 y = 4 + 0.7x
20
10
n = 30 r = 0.87 y = 0.2 + 1.2x
5 0 –5 –10
10
–15 = 5 points –20
0 0
10
20
30
40
–20 –15 –10 –5
Catheter pressure (mmHg)
5
10
15
20
Catheter pressure (mmHg)
Mean PCWP = 17 + (5 × E/A) – (0.11 × IVRT)
A
0
Mean PCWP = 17 + (5 × E/A) – (0.11 × IVRT)
B
Figure 15-7 A, Correlation of mean pulmonary capillary wedge pressure (PCWP) estimated by Doppler. B, Correlation of changes in mean PCWP with therapy estimated by Doppler versus catheter measurement. E/A, ratio of peak early velocity to atrial velocity; IVRT, isovolumic relaxation time. (Modified from Nagueh SF et al: Feasibility and accuracy of Doppler echocardiographic estimation of pulmonary artery occlusive pressure in the intensive care unit. Am J Cardiol 1995;75:1256–1262.)
ARPV – AMV = 50 msec Figure 15-8 Transmitral and pulmonary vein velocity recorded in a patient with elevated left ventricular end diastolic pressure. Notice the prolonged duration of the pulmonary vein retrograde A-wave (ARPV ) relative to the mitral A-wave (AMV ).
we have demonstrated an inverse relation between DT and the amount of LV scarring detected by thallium20 scintigraphy.32 Patients with a shorter DT (<150 msec) also had less evidence of viability by dobutamine stress, less recovery of function, more heart failure, and a shorter 12-month survival after coronary revascularization.
Limitations of Transmitral and Pulmonary Vein Velocities As mentioned, the effect of impaired relaxation is to reduce the E velocity, while that of an elevated LAP is to increase the E velocity; thus, the absolute E velocity recorded is the net summation of these two opposing forces (see Fig. 15-6). In patients with
a depressed LVEF and dilated ventricles, the high atrial pressure and prominent v-wave predominate, resulting in changes in transmitral velocity and PVV, as previously discussed. By contrast, patients with diastolic dysfunction but normal LV size and EF often have elevated minimal LV diastolic pressure, greater preservation of the x-descent in the LAP, and increased filling pressures without prominence of the v-wave. This can result in a stage I pattern despite the presence of elevated filling pressures. In these instances, the transmitral and the pulmonary vein velocities lose sensitivity for detection of high filling pressures,20,33,34 with the exception of the AR–AMV interval, which is less accurate but can provide an estimate of LVEDP.33 Although infrequent, a pseudonormal or restrictive transmitral velocity pattern may be seen in patients with diastolic heart failure and mistakenly interpreted as normal diastolic function. Application of the Valsalva maneuver can help by showing regression to stage I diastolic dysfunction.29 These patients usually have other clues of diastolic heart failure, such as concentric LV remodeling, LA enlargement, or both, and may also demonstrate a prolonged AR–AMV. Because of the complex interaction of LV relaxation and LAP, transmitral velocity cannot detect elevated filling pressures in normal hearts subjected to a high volume load, such as in acute mitral regurgitation, and is also very limited in the absence of sinus rhythm.
Combination of Transmitral Velocity with Newer Indices of Left Ventricular Relaxation As discussed at length elsewhere in this volume, there are currently two noninvasive indices of LV relaxation that have gained considerable clinical interest because they are less affected by changes in LAP or preload. They are the flow propagation velocity, derived with color M-mode Doppler, and the early diastolic mitral annular velocity, derived with tissue Doppler (see Chapters 11 and 12). We will discuss them in brief.
185
186
Chapter 15 • Evaluation of Intracardiac Filling Pressures
Flow Propagation Velocity Following mitral valve opening and under the influence of relaxation and ventricular suction, a sequence of intracavitary pressure gradients develop from base to apex that promote the propagation of mitral inflow toward the LV cavity. The velocity of this flow propagation can be assessed with color Doppler by placing the M-mode cursor within the center of the mitral inflow and obtaining a color M-mode recording, preferably at a sweep speed of 100 mm/s (Fig. 15-9) (see Chapter 11). The recording should contain an edge of uniform color during early filling, the slope of which represents the flow propagation velocity (Vp). Shifting the color Doppler zero baseline to an aliasing velocity near 70% of the E velocity has been proposed as a method to obtain a distinct color border that improves reproducibility of this measurement.35 Vp has been shown to be fairly insensitive to changes in LAP36 and to relate inversely with Tau.37 A reduced Vp (<40 cm/s) implies impaired relaxation and can be used to distinguish a pseudonormal mitral inflow pattern from a normal one.38
aging, concordant with other indices of relaxation,42 and is inversely affected by increasing afterload.40,43 In the normally contracting and relaxing heart, Ea is directly altered by changes in preload.40 However, this relation virtually disappears in abnormal hearts with impaired relaxation.44 A reduced Ea (<8 cm/s) implies impaired relaxation (whether caused by LV disease or advanced age) and can be used to distinguish a pseudonormal mitral inflow pattern from a normal one.
Estimation of Filling Pressures Transmitral E velocity relates directly with LAP and inversely with Tau. This can be expressed mathematically as: E α LAP/Tau or LAP α E × Tau. Since Vp and Ea relate inversely with Tau, the above equation can be expressed as: LAP α E (1/Vp)
Early Annular Diastolic Velocity The left ventricle has two major vectors of contraction, circumferential and longitudinal. The longitudinal vectors result in shortening of the LV long axis and descent of the mitral annulus toward the apex. The velocity of this motion can be readily obtained with tissue Doppler by placing the sample volume at a corner of the annulus; the recorded velocities reflect the longitudinal vector of contraction and relaxation of that particular wall at its base (Fig. 15-10). Although one can obtain recordings from the septal, lateral, anterior, and inferior corners of the annulus, in routine clinical practice the septal and lateral corners provide most of the needed information.39 The early diastolic velocity (referred to in the literature as Ea, Em, or E′) has been shown in experimental animal work and in humans to relate well with invasive indices of relaxation such as Tau, (−)dP/dt, and the lowest diastolic LVP.40–41 In addition, Ea declines gradually with
or LAP α E (1/Ea). From these derivations, one should expect E/Vp and E/Ea to relate directly with LAP. In 1997, Garcia et al. reported a good relation between E/Vp and mean PCWP in patients in sinus rhythm.38 As noted in Figure 15-11, an E/Vp greater than 1.8 is predictive of a mean PCWP of at least 15 mmHg; however, the specificity is greater when the ratio is greater than 2.5. E/Vp has the added advantage that it can be applied to patients in atrial fibrillation.45 Likewise, in 1996, our laboratory reported a good correlation between E/Ea and mean PCWP (Fig. 15-12A).44 An estimate of mean PCWP can be obtained with the equation Mean PCWP = 1.25E/Ea + 1.9.
FLOW PROPAGATION VELOCITY
A
B
C
Figure 15-9 A, Color Doppler image obtained in an apical four-chamber view with the M-mode cursor positioned through the center of the mitral inflow. B, Transmitral velocity with a measurement of the E velocity. C, The color M-mode tracing was obtained with the aliasing velocity set at 70% of E. Vp (flow propagation velocity) is measured as the slope of the aliasing velocity.
Chapter 15 • Evaluation of Intracardiac Filling Pressures ANNULAR VELOCITY WITH TISSUE DOPPLER 5
4.3 MHz
.21
5
4.3 MHz 10
10 15
15 15 –.21 10
Sa
5 [cm] –5 –10 Ea
Aa
–15 –20
–1.5
A
–1.0
–0.5
100mm/s
Septal
0
–1.5
B
–1.0
–0.5
100mm/s
0.0
Lateral
Figure 15-10 Recordings of annular velocity from the A, septal and B, lateral corners using tissue Doppler. Sa, peak systolic velocity; Ea, early diastolic velocity (also referred to as Em and E′); Aa, atrial velocity.
Figure 15-11 At left is the transmitral velocity and flow propagation velocity (Vp) from a patient with clinical heart failure and an ejection fraction of 35%; E/Vp is 6.0. At right (top) is the correlation between mean pulmonary capillary wedge pressure (PW) and Vp reported by Garcia, with (bottom) 95% confidence limits. (Modified from Garcia MJ et al: An index of early left ventricular filling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997; 29:448–454.)
Our findings have been confirmed by other investigators.46 An E/Ea ratio of no greater than 8 is over 90% predictive of a mean PCWP less than 15 mmHg, while a ratio of at least 15 is over 90% predictive of a mean PCWP of at least 15 mmHg. In the range between 9 and 14, the presence of LA enlargement, a pseudonormal transmitral velocity, or prolonged AR–AMV can be very helpful in supporting a diagnosis of elevated filling pressures. Importantly, E/Ea can predict filling pressures fairly well in patients with normal ejection fraction, including those with hypertrophic cardiomyopathy (see Fig. 12B).34,39 It can also be applied to patients with sinus tachycardia and atrial fibrillation.47,48 When tested against several other indices, E/Ea was
found by Ommen et al. to be the most accurate in estimating filling pressures.46
Limitations of E/Vp E/Vp performs particularly well in dilated ventricles. However, it is limited in patients with concentric hypertrophy and small hyperdynamic ventricles with little space for flow propagation to occur (see Chapter 11). Consequently, these patients can have normal Vp and E/Vp despite having impaired relaxation and elevated LAPs (Fig. 15-13). Recent studies have shown that in
187
188
Chapter 15 • Evaluation of Intracardiac Filling Pressures 35
45 r = 0.87 n = 60
r = 0.76 n = 35
30 LV pre-A pressure (mmHg)
Mean PCWP (mmHg)
40 35 30 25 20 15 10 5
25 20 15 10 5 0
0 0
5
10
15
20
25
30
5
E/Ea
A
10
15 E/Ea
B
E/Vp = 1.3
patients with normal LV size and EFs, E/Ea estimates filling pressures with more accuracy than does E/Vp (Fig. 15-14).39,46 Vp is also limited by a lower reproducibility resulting from variation in positioning of the M-mode cursor and in the actual measurement of the slope. Quantitative computerized techniques have been applied with excellent results, but they are not available commercially.49 Vp cannot be applied in the presence of mechanical inflow obstruction.
Limitations of E/Ea Although measurements of Ea are easy to obtain with good reproducibility using PW tissue Doppler, it is essential that the settings used provide a clear tracing with distinct edges. Some of the older ultrasound systems produced a blurred recording that significantly limited the accuracy of the measurements. Some newer systems allow derivation of a recording of annular or myocardial velocities from a color tissue Doppler by placing a small region of interest in the particular segment. However, Ea with this
E/Ea = 16
20
Figure 15-12 A, Correlation of mean pulmonary capillary wedge pressure (PCWP) with E/Ea in a heterogeneous population of patients with a wide range of ejection fractions. B, Correlation of left ventricular pressure before atrial contraction (pre-A) with the ratio of the mitral peak Doppler E-wave to peak mitral annular velocity (E/Ea) in a group of patients with hypertrophic cardiomyopathy. (Modified from Nagueh SF et al: Doppler estimation of left ventricular filling pressures in patients with hypertrophic cardiomyopathy. Circulation 1999;99:254–261; Nagueh SF et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527–1535.)
Figure 15-13 Example of a patient with systemic hypertension, diastolic heart failure, and a small end systolic left ventricular (LV) volume with an ejection fraction greater than 65%. Note the normal flow propagation velocity (Vp) of 60 cm/s. The mitral E velocity (left upper panel) is 80 cm/s, resulting in an E/Vp of 1.3, consistent with normal mean pulmonary capillary wedge pressure (PCWP). In contrast, peak mitral annular velocity (Ea) from the lateral wall (left lower panel) is much reduced (5 cm/s), and the E/Ea ratio is 16, indicative of an elevated mean PCWP.
new technology is consistently lower than when derived with PW Doppler; this results in a different set of normal values. Given that all of the literature relating E/Ea to filling pressures has been obtained using PW tissue Doppler, this technology should be the one used for this purpose. Although Ea relates to global indices of LV relaxation, one must realize that it is a regional index. Errors can, therefore, occur when one extrapolates a single measurement to the entire ventricle, particularly in patients with regional wall motion abnormalities and in those with excessive cardiac translation (since the velocities are measured relative to transducer position). For instance, a patient with acute myocardial infarction can have a depressed Ea in the affected wall and an augmented one in a distant site that is compensating with hyperdynamic motion.39 Because of the preload dependency of Ea in normal hearts, the ratio E/Ea does not reflect filling pressures accurately in normal young subjects or in patients with primary mitral regurgitation or pericardial constriction.50,51 However, the presence of functional mitral regurgitation in a depressed ventricle does not affect the
Chapter 15 • Evaluation of Intracardiac Filling Pressures accuracy of this index.50 Preliminary observations in our laboratory using animal experiments suggest that even in depressed ventricles, Ea still has some preload dependency, particularly at the extremes of high LAPs.52 The clinical correlate of this is seen occasionally in young patients with dilated cardiomyopathy and severe heart failure, who, despite having a restrictive mitral inflow pattern, continue to have a normal Ea at the lateral base. Ea in the septum, however, is usually reduced. These limitations lead to the question of where Ea should be measured: septum, lateral wall, or both? In a recent study from our laboratory, an average of the two sites provided a good estimate of mean PCWP in dilated ventricles with a depressed EF;
IMPACT OF LVEF ON ESTIMATION OF FILLING PRESSURES USING TISSUE DOPPLER AND FLOW PROPAGATION VELOCITY r = 0.5 p < 0.001 PCWP (mmHg)
PCWP (mmHg)
30
30
20
r = 0.7 p < 0.001
10
0 0
1
2
3
4
E/Vp
Newer (Less Validated) Methods With a decline in myocardial relaxation, not only does Ea fall, but its onset gets delayed relative to that of transmitral velocity (Fig. 15-15).53,54 The time interval between onset of mitral inflow and onset of Ea (TEa-E) relates directly with Tau (r = 0.93) in experimental animal studies and is not altered by changes in LAP.54 TEa-E is derived by subtracting Q-Ea (the interval from the Q-wave on electrocardiogram to the onset of Ea) from Q-E (the interval from the Q-wave to the onset of mitral inflow) (see Fig. 15-15). Previous studies have shown that mean LAP can be derived from the equation LAP = LVes × e−IVRT/Tau,
20
10 0
the same was true for patients with regional wall motion abnormalities.39 However, in patients with normal wall motion and EF, the lateral wall was found to provide a better estimate of mean PCWP. Like E/Vp, E/Ea cannot be used in the presence of mitral inflow obstruction. The new European guidelines on diastolic heart failure suggest averaging the septal and lateral annuli.52a
5
10
15
20
25
E/Ea-lateral LVEF > 50%
Figure 15-14 Correlation of mean pulmonary capillary wedge pressure (PCWP) with ratio of mitral peak Doppler E-wave and flow propagation velocity (E/Vp) and with ratio of E to peak mitral annular velocity (E/Ea) in a population of patients with ejection fractions greater than 50%. Note the larger scatter and lower correlation coefficient for E/Vp. (Modified from Rivas-Gotz C et al: Impact of left ventricular ejection fraction on estimation of left ventricular filling pressures using tissue Doppler and flow propagation velocity. Am J Cardiol 2003;91:780–784.)
where LVes = end systolic LVP.55 Our group has tested a noninvasive version of this equation that substitutes TEa-E for Tau and 0.9 × systolic blood pressure for LVes. The results were accurate across a wide range of LVEFs (Fig. 15-16).54 A simplified approach consisting of the ratio of IVRT to TEa-E related inversely with mean PCWP and allowed separation of patients with normal versus elevated (≥15 mmHg) pressures with a sensitivity and specificity of 91% and 89%, respectively (Fig. 15-17). Since this new method does not require a measurement of the transmitral E velocity, it is applicable in the presence of inflow obstruction and in patients with mitral regurgitation.56 However, as with all new methods, it requires validation by other investigators. Its main limitation is that TEa-E is a small time interval derived from two different intervals measured at separate times, and this may limit its reproducibility. Future developments may allow simultaneous recording of annular motion and mitral inflow, facilitating the measurement of this interval.
TRANSMITRAL VELOCITY
Figure 15-15 Transmitral velocity, lateral annular velocity, and isovolumic relaxation time (IVRT) in a 75-year-old hypertensive woman with concentric left ventricular hypertrophy, a normal ejection fraction, and diastolic heart failure. The transmitral velocity is elevated (180 cm/sec) in part because of annular calcification resulting in some inflow stenosis. Note the delay in onset of Ea relative to the onset of the transmitral velocity; TEa-E was 40 msec and IVRT/TEa-E was 1.05.
LATERAL ANNULAR VELOCITY
TEa-E = 40 msec IVRT/TEa-E = 1.05
189
190
Chapter 15 • Evaluation of Intracardiac Filling Pressures RELATION OF TEa–E TO FILLING PRESSURES 40
Doppler PCWP – Catheter PCWP
35 Doppler PCWP (mmHg)
20
r = 0.84 n = 33 p < 0.01
30 25 20 15 10 5
15 10 5 0 –5 –10 –15 –20
0
5
10 15
20 25
30 35 15
5
Catheter PCWP (mmHg)
10
15
PCWP = LVes × e–IVRT/Tau = LVes × e–IVRT/TEa–E where LVes = 0.9 × SBP
25
30
35
40
tively simple to use. The use of E/Vp or E/Ea may not be required but can provide valuable confirmation of the findings derived from the transmitral velocity. However, there are instances where E/Ea and E/Vp should be used. These include: (1) an E/A less than 1.0 with E greater than 80 cm/sec (E/Ea may be elevated if Ea is <8 cm/sec); (2) E and A in close proximity due to a reduced diastolic filling time; and (3) junctional or pacemaker rhythm in the presence of atrial fibrillation (in these instances, a very short DT [<150 msec] and/or IVRT [<60 msec] are specific for elevated LAP).
40 Sens = 91% Spec = 89% 30 Mean PCWP (mmHg)
20
(Doppler PCWP + Catheter PCWP)/2
Figure 15-16 Relation of cathetermeasured mean pulmonary capillary wedge pressure (PCWP) to PCWP derived by Doppler using the equation LVes × e−IVRT/Ea–E and substituting TEa-E for Tau. The 95% confidence limits obtained with the BlandAltman analysis are shown on the right. SBP, systolic blood pressure. (Modified from Rivas-Gotz C et al: Time interval between onset of mitral inflow and onset of early diastolic velocity by tissue Doppler: A novel index of left ventricular relaxation. Experimental studies and clinical application. J Am Coll Cardiol 2003;42:1463–1470.)
20
Patients with a Preserved Ejection Fraction
The following comprehensive approach can provide an excellent clinical tool for the estimation of filling pressures in patients presenting with symptoms suggestive of heart failure.
In the presence of near-normal (>40%) EF, E/Vp or E/Ea is recommended for the estimation of mean PCWP, with the latter preferred in hypertrophic hearts with small LV cavities. An enlarged left atrium is a sensitive marker of diastolic dysfunction in these patients, particularly when confirmed by observing a reduced Ea or Vp. Likewise, LAP is almost always less than 15 mmHg when LA size and systolic descent of the annulus are normal (E/Ea is usually also normal). Although transmitral velocity is insensitive to an elevated LAP, we have found that when E/A is less than 0.70 and E is no greater than 60 cm/sec, mean PCWP is seldom, if ever, higher than 15 mmHg.57 The transmitral and the pulmonary vein velocities remain specific for elevated LAP when the E/A ratio is at least 2.0 or S/D is less than 1, as long as the left atrium is enlarged and Vp or Ea confirm the presence of impaired relaxation. AR–AMV may be used to estimate LVEDP, although with less sensitivity than in the presence of a low EF. In a prospective study of patients presenting with possible heart failure, we found that a comprehensive approach that combined echocardiographic and Doppler findings was superior to measurements of B-type natriuretic peptide (BNP) in detecting heart failure in patients with a normal EF.58 Using the Framingham criteria as the clinical standard, a BNP greater than 150 pg/ml was 79% sensitive and 85% specific, whereas a comprehensive echo-Doppler evaluation was 85% sensitive and 96% specific.
Patients with a Depressed Ejection Fraction
Evaluating Discrepant Results
In the presence of a depressed EF (<40%), the mitral E/A ratio, IVRT, and DT are excellent indicators of mean PCWP and are rela-
All of the currently available methods of estimating filling pressures are imperfect, and consequently there are times when these
10
0 0
5
10
15
20
IVRT/TEa − E Figure 15–17 Correlation between catheter-measured mean pulmonary capillary wedge pressure (PCWP) and isovolumic relaxation time (IVRT)/ TEa-E. The vertical line demarcates a cutoff of 2 for IVRT/ TEa-E, and the horizontal line demarcates a cutoff of 15 for PCWP. TEa-E, time interval between onset of mitral inflow and onset of early diastolic velocity; Sens, sensitivity; Spec, specificity. (Modified from Rivas-Gotz C et al: Time interval between onset of mitral inflow and onset of early diastolic velocity by tissue Doppler: A novel index of left ventricular relaxation. Experimental studies and clinical application. J Am Coll Cardiol 2003;42:1463–1470.)
A Recommended Algorithm for Estimation of Filling Pressures
Chapter 15 • Evaluation of Intracardiac Filling Pressures methods yield discrepant results, their findings are in a “gray area” (such as an E/Ea in the 10–15 range), or their estimates of filling pressure do not match the clinical findings. In all of these instances, it helps to look for other supporting data. For instance, in a patient with dyspnea, if several echocardiographic or clinical findings (see Box 15-1) indicate a very high probability for abnormal LV relaxation and one sees a stage II diastolic dysfunction pattern with short (<90 ms) IVRT, mean LAP is likely to be elevated even if E/Ea is between 10 and 15. In day-to-day practice, we find the estimation of pulmonary artery systolic pressure (PASP) from the peak velocity of tricuspid regurgitation (TR) to be crucial in resolving difficult cases and helping confirm our estimates of filling pressures. This requires obtaining a good CW Doppler recording of TR, which may need at times signal enhancement with injections of agitated saline. Since PASP = 4(peak TR velocity)2 + mean RAP, it is important to learn well how to estimate mean RAP (see Chapters 10 and 14). As a general rule, it can be stated that an elevated LAP results in an increased PASP and vice versa (with the exception of instances where cardiac output is extremely reduced). For instance, a dyspneic patient with LA enlargement and an estimated PASP of greater than 40 mmHg is likely to have an elevated mean LAP until proven otherwise. An accurate estimate of PASP can therefore serve as the decisive factor in establishing the presence or absence of an elevated LAP in difficult cases. With the proper use of the concepts described in this chapter, one can establish a cardiac source of dyspnea in the vast majority of patients evaluated.
FUTURE RESEARCH Recent technological improvements have allowed measurements of myocardial strain and strain rate along different vectors of contraction and relaxation. Strain is tissue deformation in response to an applied force (see Chapter 12). It represents a fractional change in length (i.e., ΔL/Li). Strain rate is the fractional rate of deformation (i.e., [ΔL/Li]/t). Measurements of systolic and diastolic strain rates provide a new approach to the quantitation of regional function. Because strain is derived from the movement of two adjacent points in the myocardium, the values obtained are less sensitive to cardiac translation. Preliminary studies suggest that strain rate may be superior to myocardial velocities in detecting relaxation abnormalities.59–62 Similarly, other new developments allow an assessment of the clockwise rotation of the base and the counterclockwise rotation of the apex during contraction. This twisting motion of the heart (also referred to as torsion) is an integral part of ventricular ejection, while the untwisting that occurs during LV relaxation is an integral part of rapid ventricular filling.63,64 Quantification of this motion may provide a more accurate global assessment of contraction and relaxation.65,66 Conceivably, one might be able to combine standard indices such as E velocity or IVRT with these newer markers of relaxation to derive a more accurate estimation of LV filling pressures. REFERENCES 1. Rahimtoola SH, Loeb HS, Ehsani A, et al: Relationship of pulmonary artery to left ventricular diastolic pressures in acute myocardial infarction. Circulation 1972;46:283–290. 2. Schabelman S, Schiller NB, Silverman NH, et al: Left atrial volume estimation by two-dimensional echocardiography. Cathet Cardiovasc Diagn 1981;7:165–178.
3. Lester SJ, Ryan EW, Schiller NB, et al: Best method in clinical practice and in research studies to determine left atrial size. Am J Cardiol 1999; 84:829–832. 4. Lang RM, Bierig M, Devereux RB, et al: Recommendation for chamber quantification: A report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–1463. 5. Kircher B, Abbott JA, Pau S, et al: Left atrial volume determination by biplane two-dimensional echocardiography: Validation by cine-computed tomography. Am Heart J 1991;121:864–871. 6. Rodevan O, Bjornerheim R, Ljosland M, et al: Left atrial volumes assessed by three- and two-dimensional echocardiography compared to MRI estimates. Int J Card Imaging 1999;15:397–410. 7. Zile MR, Baicu CF, Bonnema DD: Diastolic heart failure: Definitions and terminology. Prog Cardiovasc Dis 2005;47:307–313. 8. Simonson JS, Schiller NB: Descent of the base of the left ventricle: An echocardiographic index of left ventricular function. J Am Soc Echocardiogr 1989;2:25–35. 9. Barbier P, Solomon SB, Schiller NB, et al: Left atrial relaxation and left ventricular systolic function determine left atrial reservoir function. Circulation 1999;100:427–436. 10. Basnight MA, Gonzalez MS, Kershenovich SC, et al: Pulmonary venous flow velocity: Relation to hemodynamics, mitral flow velocity and left atrial volume, and ejection fraction. J Am Soc Echocardiogr 1991;4:547–558. 11. Appleton CP, Galloway JM, Gonzalez MS, et al: Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993; 22:1972–1982. 12. Ishida Y, Meisner JS, Tsujioka K, et al: Left ventricular filling dynamics: Influence of left ventricular relaxation and left atrial pressure. Circulation 1986; 74:187–196. 13. Nishimura RA, Tajik AJ: Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta stone. J Am Coll Cardiol 1997;30:8–18. 14. Choong CY, Abascal VM, Thomas JD, et al: Combined influence of ventricular loading and relaxation on the transmitral flow velocity profile in dogs measured by Doppler echocardiography. Circulation 1988;78:672–683. 15. Little WC, Ohno M, Kitzman DW, et al: Determination of left ventricular chamber stiffness from the time for deceleration of early left ventricular filling. Circulation 1995;92:1933–1939. 16. Kuecherer HF, Muhiudeen IA, Kusumoto FM, et al: Estimation of mean left atrial pressure from transesophageal pulsed Doppler echocardiography of pulmonary venous flow. Circulation 1990;82:1127–1139. 17. Yamamoto K, Nishimura RA, Chaliki HP, et al: Determination of left ventricular filling pressure by Doppler echocardiography in patients with coronary artery disease: Critical role of left ventricular systolic function. J Am Coll Cardiol 1997;30:1819–1826. 18. Habib GB, Zoghbi WA: Doppler assessment of right ventricular filling dynamics in systemic hypertension: Comparison with left ventricular filling. Am Heart J 1992;124:1313–1320. 19. Wachtell K, Bella JN, Rokkedal J, et al: Change in diastolic left ventricular filling after one year of antihypertensive treatment: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study. Circulation 2002;105:1071–1076. 20. Nishimura R, Appleton C, Redfield M, et al: Noninvasive Doppler echocardiographic evaluation of left ventricular filling pressures in patients with cardiomyopathies: A simultaneous Doppler echocardiographic and cardiac catheterization study. J Am Coll Cardiol 1996;28:1226–1233. 21. Quiñones MA: Doppler assessment of left ventricular diastolic function. In Navin C (ed): Doppler echocardiography, 2nd ed. Philadelphia, Lea & Febiger, 1992:197–215. 22. Sartori MP, Quiñones MA, Kuo LC: Relation of Doppler-derived left ventricular filling parameters to age and radius/thickness ratio in normal and pathologic states. Am J Cardiol 1987;59:1179–1182. 23. Nagueh SF, Kopelen HA, Zoghbi WA: Feasibility and accuracy of Doppler echocardiographic estimation of pulmonary artery occlusive pressure in the intensive care unit. Am J Cardiol 1995;75:1256–1262. 24. Aurigemma GP, Gottdiener JS, Shemanski L, et al: Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: The Cardiovascular Health Study. J Am Coll Cardiol 2001;37: 1042–1048.
191
192
Chapter 15 • Evaluation of Intracardiac Filling Pressures 25. Tsang TS, Barnes ME, Gersh BJ, et al: Risks for atrial fibrillation and congestive heart failure in patients ≥65years of age with abnormal left ventricular diastolic relaxation. Am J Cardiol 2004;93:54–58. 26. Vanoverschelde JL, Robert AR, Gerbaux A, et al: Noninvasive estimation of pulmonary arterial wedge pressure with Doppler transmitral flow velocity pattern in patients with known heart disease. Am J Cardiol 1995; 75:383–389. 27. Pozzoli M, Capomolla S, Pinna G, et al: Doppler echocardiography reliably predicts pulmonary artery wedge pressure in patients with chronic heart failure with and without mitral regurgitation. J Am Coll Cardiol 1996;27: 883–893. 28. Rossvoll O, Hatle LK: Pulmonary venous flow velocities recorded by transthoracic Doppler ultrasound: Relation to left ventricular diastolic pressures. J Am Coll Cardiol 1993;21:1687–1696. 29. Hurrell DG, Nishimura RA, Ilstrup DM, et al: Utility of preload alteration in assessment of left ventricular filling pressure by Doppler echocardiography: A simultaneous catheterization and Doppler echocardiographic study. J Am Coll Cardiol 1997;30:459–467. 30. Temporelli PL, Corra U, Imparato A, et al: Reversible restrictive left ventricular diastolic filling with optimized oral therapy predicts a more favorable prognosis in patients with chronic heart failure. J Am Coll Cardiol 1998;31:1591–1597. 31. Hansen A, Haass M, Zugck C, et al: Prognostic value of Doppler echocardiographic mitral inflow patterns: Implications for risk stratification in patients with chronic congestive heart failure. J Am Coll Cardiol 2001; 37:1049–1055. 32. Yong Y, Nagueh SF, Shimoni S, et al: Deceleration time in ischemic cardiomyopathy: Relation to echocardiographic and scintigraphic indices of myocardial viability and functional recovery after revascularization. Circulation 2001;103:1232–1237. 33. Yamamoto K, Nishimura RA, Chaliki HP, et al: Determination of left ventricular filling pressure by Doppler echocardiography in patients with coronary artery disease: Critical role of left ventricular systolic function. J Am Coll Cardiol 1997;30:1819–1826. 34. Nagueh SF, Lakkis NM, Middleton KJ, et al: Doppler estimation of left ventricular filling pressures in patients with hypertrophic cardiomyopathy. Circulation 1999;99:254–261. 35. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32: 865–875. 36. Takatsuji H, Mikami T, Urasawa K, et al: A new approach for evaluation of left ventricular diastolic function: Spatial and temporal analysis of left ventricular filling flow propagation by color M-mode Doppler echocardiography. J Am Coll Cardiol 1996;27:365–371. 37. Brun P, Tribouilly C, Duval AM, et al: Left ventricular flow propagation during early filling is related to wall relaxation: A colour M-mode Doppler analysis. J Am Coll Cardiol 1992;20:420–432. 38. Garcia MJ, Ares MA, Asher C, et al: An index of early left ventricular filling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29:448–454. 39. Rivas-Gotz C, Manolios M, Thohan V, et al: Impact of left ventricular ejection fraction on estimation of left ventricular filling pressures using tissue Doppler and flow propagation velocity. Am J Cardiol 2003;91: 780–784. 40. Nagueh SF, Sun H, Kopelen HA, et al: Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol 2001;37:278–285. 41. Oki T, Tabata T, Yamada H, et al: Clinical application of pulsed Doppler tissue imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 199;79:921–928. 42. Rodriguez L, Garcia M, Ares M, et al: Assessment of mitral annular dynamics during diastole by Doppler tissue imaging: Comparison with mitral Doppler inflow in subjects without heart disease and in patients with left ventricular hypertrophy. Am Heart J 1996;131:982–987. 43. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 44. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527–1535. 45. Nagueh SF, Kopelen HA, Quiñones MA: Doppler estimation of left ventricular filling pressure in atrial fibrillation. Circulation 1996;94:2138– 2145. 46. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of
47. 48. 49.
50. 51.
52. 52a.
53. 54.
55.
56. 57.
58.
59. 60.
61. 62.
63. 64. 65. 66.
left ventricular filling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. Nagueh SF, Mikati I, Middleton KJ, et al: Doppler estimation of left ventricular filling pressure in sinus tachycardia: A new application of tissue Doppler imaging. Circulation 1998;98:1644–1650. Sohn DW, Song JM, Zo JH, et al: Mitral annulus velocity in the evaluation of left ventricular diastolic function in atrial fibrillation. J Am Soc Echocardiogr 1999;12:927–931. Stügaard M, Smiseth OA, Risoe C, et al: Intraventricular early diastolic filling during acute myocardial ischemia, assessment by multigated color M-mode Doppler echocardiography. Circulation 1993;88:2705– 2713. Bruch C, Stypmann J, Gradaus R, et al: Usefulness of tissue Doppler imaging for estimation of filling pressures in patients with primary or secondary pure mitral regurgitation. Am J Cardiol 2004;93:324–328. Ha JW, Oh JK, Ling LH, et al: Annulus paradoxus: Transmitral flow velocity to mitral annular velocity ratio is inversely proportional to pulmonary capillary wedge pressure in patients with constrictive pericarditis. Circulation 2001 28;104:976–978. Nagueh SF, Rao L, Soto J, et al: Hemodynamic mechanisms that account for the variable effect of preload on tissue Doppler early diastolic velocity [abstract]. Circulation 2002;107(Suppl 3):2306. Paulus WJ, Tschope C, Sanderson JE, et al: How to diagnose diastolic heart failure: A consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28:2539–2550. Hasegawa H, Little WC, Ohno M, et al: Diastolic mitral annular velocity during the development of heart failure. J Am Coll Cardiol 2003;41: 1590–1597. Rivas-Gotz C, Khoury DS, Manolios M, et al: Time interval between onset of mitral inflow and onset of early diastolic velocity by tissue Doppler: A novel index of left ventricular relaxation. Experimental studies and clinical application. J Am Coll Cardiol 2003;42:1463–1470. Thomas JD, Flachskampf FA, Chen C, et al: Isovolumic relaxation time varies predictably with its time constant and aortic and left atrial pressure: Implications for the noninvasive evaluation of ventricular relaxation. Am Heart J 1992;124:1305–1313. Diwan A, McCulloch M, Lawrie GM, et al: Doppler estimation of left ventricular filling pressures in patients with mitral valve disease. Circulation 2005;111:3281–3289. Dokainish H, Zoghbi WA, Lakkis NM, et al: Optimal noninvasive assessment of left ventricular filling pressures: A comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation 2004;20:2432–2439. Dokainish H, Zoghbi WA, Lakkis NM, et al: Comparative accuracy of B-type natriuretic peptide and tissue Doppler echocardiography in the diagnosis of congestive heart failure. Am J Cardiol 2004;93:1130– 1135. Stoylen A, Slordahl S, Skjelvan GK, et al: Strain rate imaging in normal and reduced diastolic function: Comparison with pulsed Doppler tissue imaging of the mitral annulus. J Am Soc Echocardiogr 2001;14:264–274. Kukulski T, Jamal F, D’Hooge J, et al: Acute changes in systolic and diastolic events during clinical coronary angioplasty: A comparison of regional velocity, strain rate, and strain measurement. J Am Soc Echocardiogr 2002;15:1–12. Takemoto Y, Pellikka PA, Wang J, et al: Analysis of the interaction between segmental relaxation patterns and global diastolic function by strain echocardiography. J Am Soc Echocardiogr 2005;18:901–906. Kato TS, Noda A, Izawa H, et al: Discrimination of nonobstructive hypertrophic cardiomyopathy from hypertensive left ventricular hypertrophy on the basis of strain rate imaging by tissue Doppler ultrasonography. Circulation 2004;110:3808–3814. Helle-Valle T, Crosby J, Edvardsen T, et al: New noninvasive method for assessment of left ventricular rotation: Speckle tracking echocardiography. Circulation 2005;112:3149–3156. Notomi Y, Lysyansky P, Setser RM, et al: Measurement of ventricular torsion by two-dimensional ultrasound speckle tracking imaging. J Am Coll Cardiol 2005;45:2034–2041. Notomi Y, Setser RM, Shiota T, et al: Assessment of left ventricular torsional deformation by Doppler tissue imaging: Validation study with tagged magnetic resonance imaging. Circulation 2005;111:1141–1147. Notomi Y, Martin-Miklovic MG, Oryszak SJ, et al: Enhanced ventricular untwisting during exercise: A mechanistic manifestation of elastic recoil described by Doppler tissue imaging. Circulation 2006;113:2524–2533.
CHUWA TEI, MD YUTAKA OTSUJI, MD, PhD
16
Evaluation of Tei Index in Heart Failure INTRODUCTION Concept of the Tei Index PATHOPHYSIOLOGY Measurement of the Tei Index CLINICAL RELEVANCE Load Dependency of the Tei Index The Tei Index and Prognosis
Detection of Cardiac Dysfunction in Various Diseases Hemodynamic Assessment Evaluation of Right Ventricular Function Effects of Interventions Evaluation of Patients with Tachycardia Limitations FUTURE RESEARCH
INTRODUCTION In clinical practice, we use many indices of cardiac function, such as left ventricular ejection fraction (LVEF), maximal positive or negative pressure/time change (dP/dt), Tau (τ), stiffness, maximum elastance, and others. The number of indices of cardiac function indicates that the left ventricle performs multiple roles during a single cardiac cycle, and each index of cardiac function expresses only a partial aspect of a heterogeneous process. This can explain frequent discrepancies between patients’ status and the value of functional indices. One such example is relatively preserved LVEF in patients with end-stage chronic heart failure due to cardiac amyloidosis (Fig. 16-1).1,2 Why is LVEF often discrepant with patient status in cardiac amyloidosis? There can be two reasons: (1) LVEF does not express left ventricular (LV) diastolic function, which is severely impaired in this pathology,3 and (2) LVEF does not express true ventricular systolic function, especially in the presence of increased LV wall thickness. Increased LV wall thickness, typically seen in patients with cardiac amyloidosis, hypertrophic cardiomyopathy, or hypertensive heart disease, decreases wall tension, which allows for good wall motion and ejection even in the presence of significant myocardial systolic dysfunction.4 Therefore, relatively preserved LVEF or wall motion in patients with cardiac amyloidosis does not mean that their systolic function is only mildly impaired. Severely prolonged isovolumic contraction time (ICT) (see Fig. 16-1), despite normal LVEF in patients with cardiac amyloidosis, highly suggests that systolic function is severely impaired. Further, normal LVEF in the presence of LV hypertrophy (LVH), typically seen in patients with “diastolic heart failure,” may not mean
normal systolic function. Figure 16-2 shows a patient with typical diastolic heart failure, with heart failure symptoms, a normal EF, and LVH. Cardiac time interval analysis demonstrates abnormally prolonged ICT and isovolumic relaxation time (IRT), indicating significant impairment of both systolic and diastolic functions.5 Therefore, normal LVEF does not mean normal systolic function in patients with so-called diastolic heart failure, which is one of the most common causes of chronic heart failure (HF).6 The 2005 guidelines of the American Heart Association/ American College of Cardiology prefers “HF and Normal LVEF” for this entity and does not use the phrase “diastolic heart failure.”7 Even in patients with dilated cardiomyopathy, frequently considered as pure systolic dysfunction,8 it is known that LVEF only fairly correlates with exercise capacity, which is closely related to patient status and prognosis.9 Being the most representative index of cardiac function, LVEF expresses only systolic ejection among multiple aspects of systolic and diastolic functions. Therefore, we often encounter discrepancies between values of cardiac functional indices and patient status. Physicians need to evaluate patient status subjectively by combining multiple sources of information, including various indices of cardiac function. In this context, it is reasonable to create an index of cardiac function, which can be a global expression combining systole and diastole or multiple aspects of heterogeneous LV function.
Concept of the Tei Index Due to the big clinical need for an index expressing global cardiac function, the concept of the Tei index has been postulated.10 193
194
Chapter 16 • Evaluation of Tei Index in Heart Failure LV-Tei index
Aortic pressure LV pressure LA pressure
ICT
ET
IRT
Tei index = (a – b)/b = (ICT + IRT)/ET
a Mitral inflow Figure 16-1 End-stage chronic heart failure despite relatively preserved left ventricular ejection fraction (73%) in a patient with cardiac amyloidosis. IVCT (isovolumic contraction time) and IVRT (isovolumic relaxation time) are severely prolonged. ET (ejection time) is severely shortened.
b Aorta outflow
Figure 16-3 Concept of the Tei index. Isovolumic contraction time (ICT) and isovolumic relaxation time (IRT) express systolic and diastolic functions. Ejection time (ET) expresses stroke volume. ICT/ET and IVRT/ET can be sensitive and heart-rate-independent indices of systolic and diastolic function, respectively. Therefore, the sum of ICT/ET and IRT/ET, which is the Tei index, expresses combined systolic and diastolic, therefore global, cardiac function. (From Tei C: New non-invasive index for combined systolic and diastolic ventricular function. J Cardiol 1995;26:135–136.)
PATHOPHYSIOLOGY Measurement of the Tei Index The Tei index can be measured practically with conventional Doppler echocardiography.10,11 Interval a between cessation and re-onset of mitral filling flow includes ICT, ET, and IRT (Fig. 16-4). Interval b between onset and cessation of aortic ejection flow equals ET. Therefore, the Tei index can be obtained by the following formula: Tei index = (a − b)/b = (ICT + IRT)/ET. Figure 16-2 Abnormally prolonged ICT (isovolumic contraction time) and IRT (isovolumic relaxation time) despite normal left ventricular ejection fraction (78%) in a patient with “diastolic heart failure” due to left ventricular hypertrophy.
ICT is inversely proportional to LV peak positive dP/dt and expresses systolic contraction (Fig. 16-3).12 LV ejection time (ET) is proportional to stroke volume, which can be reduced either by systolic or diastolic dysfunction.13 IRT is inversely proportional to LV peak negative dP/dt and expresses diastolic relaxation.12 However, these cardiac time intervals are heart rate dependent. Systolic dysfunction can result in prolonged ICT and shortened ET. Therefore, ICT/ET (which is ICT corrected by ET) can be a sensitive index to express systolic dysfunction. ICT/ET is also expected to be heart rate independent, due to the cancellation of heart rate dependencies of ICT and ET. For the same reason, IRT/ET (which is IVT corrected by ET) can be a sensitive and heart-rate-independent index to express diastolic function. The sum of ICT/ET and IRT/ET is the Tei index.10,11 Therefore, the Tei index has the potential to express combined systolic and diastolic or global cardiac function.
This measurement is simple, practical, and reproducible. Multiple investigators in multiple institutions have measured the Tei index with almost identical normal values with a narrow range both for the LV and the right ventricular (RV) Tei index.14,15 The normal LV and RV Tei indices in our institution are 0.38 ± 0.04 and 0.28 ± 0.04, respectively. Although standard pulsed Doppler echocardiographic measurement of the Tei index is practical and reproducible, multiple investigators have applied alternative approaches. One such approach is to utilize pulsed tissue Doppler annular velocity to measure the Tei index.16,17 This method has the merit of measuring intervals a and b simultaneously in a single cardiac cycle, while standard pulsed flow Doppler echocardiography requires measurement of intervals a and b in different cardiac cycles. Multiple investigators have reported that the Tei index by pulsed tissue Doppler echocardiography correlates well with that by pulsed flow Doppler echocardiography.16,18 However, discrepancy between the tissue Doppler Tei index and the flow Doppler Tei index has also been reported.19–21 It may be questionable whether the Tei index from tissue Doppler annular velocity expresses global cardiac function. Other approaches, including M-mode color tissue Doppler echocardiogram of mitral leaflets and conventional M-mode echocardiogram of mitral and aortic leaflets, have been utilized to measure the Tei index, with good agreement
Chapter 16 • Evaluation of Tei Index in Heart Failure
Figure 16-4 How to measure the Tei index. Interval a between cessation and onset of mitral filling flow includes isovolumic contraction time (ICT), ejection time (ET), and isovolumic relaxation time (IRT). Interval b from onset to cessation of aortic ejection flow is ET. Therefore, the Tei index (0.35) can be simply calculated as (a − b)/b.
Figure 16-5 Measurement of the left ventricular Tei index in a patient with dilated cardiomyopathy. Tei index was clearly abnormal with a value of 0.99.
with the standard pulsed Doppler flow method.22,23 The LV area/ time curve by automated border detection was also utilized to measure the Tei index, with good agreement with the standard pulsed flow Doppler method.24
CLINICAL RELEVANCE The Tei index was initially measured in normal subjects as well as in patients with clear RV or LV dysfunction.10,11 The value of the Tei index has a narrow range in normal subjects. The RV Tei index is clearly increased (0.67 ± 0.20) in patients with RV dysfunction, such as those with RV infarction, dysplasia, or cor pulmonale. The LV Tei index is also clearly increased (0.92 ± 0.22) in patients with idiopathic or ischemic cardiomyopathies (Fig. 16-5). There is no overlap of values between normal subjects and patients with clear RV or LV dysfunction. Therefore, the Tei index is clearly abnormal in patients with a significant level of such dysfunction.
Load Dependency of the Tei Index Because load dependency needs to be evaluated for all indices of cardiac function, the Tei index has also been evaluated regarding its load dependency. Studies have shown no significant correlation between heart rate and the Tei index in normal subjects.10 Dependency for heart rate has further been investigated by changing heart rate in patients with a pacemaker implantation.25 The Tei index significantly increased with elevation of heart rate in this study. However, the increase was subtle, from a mean value of 0.40 at 50 bpm to 0.51 at 100 bpm. Therefore, the Tei index is generally heart rate independent in clinical practice. The Tei index has also been evaluated during preload modifications such as the Valsalva maneuver, leg lifting, or sublingual nitroglycerin administration in normal subjects as well as in patients with prior myocardial
infarction.26 These preload alterations caused an increase in the Tei index, but only to a small degree (0.034 ± 0.05) in normal subjects, and did not cause significant changes in the Tei index in patients with prior myocardial infarction. Therefore, the Tei index is relatively preload independent in patients with cardiac disease. In addition, the Tei index has no significant correlation with blood pressure in patients with LV dysfunction.11,27 Although these investigations indicate that the Tei index is generally load independent, aortic stenosis causes it to significantly reduce. After surgery for valvular heart disease, patients with aortic stenosis showed a significant 29% increase in the Tei index, while those with aortic regurgitation, mitral stenosis, or regurgitation showed only minor changes.28 Correction of the prolongation of ET by aortic stenosis was the main cause of increase in the Tei index after surgical valve replacement.
The Tei Index and Prognosis Because the Tei index is a global expression, it is related to multiple pathophysiologic parameters of cardiac function. The prognostic utility of the Tei index was initially evaluated in patients with cardiac amyloidosis.29 In this study, patients with a greater Tei index had significantly worse survival (Fig. 16-6). Of note is that the Tei index enabled better separation of patients with poorer and better survival compared with LVEF. After this initial study, many studies have demonstrated the utility of the Tei index to evaluate prognosis in dilated cardiomyopathy, prior or acute myocardial infarction, chronic HF, and others.30–37 A strong relation between the Tei index and prognosis in patients with coronary artery disease suggests that the index may enable prediction of complications after acute myocardial infarction. An increased Tei index at admission to a coronary care unit predicted subsequent development of complications (Fig. 16-7).38–40 An increased Tei index greater than 0.70 before mitral valvuloplasty is also a risk factor, doubling postoperative mortality.41 Recently, the utility
195
196
Chapter 16 • Evaluation of Tei Index in Heart Failure of the Tei index to predict development of chronic HF or cardiac death has been demonstrated in a population-based cohort of elderly men.42,43 Therefore, an increased Tei index is a risk factor for the development of chronic HF as well as cardiac death. 1.0 0.8
(11)
0.6
(10)
(10)
(4)
0.4 0.2 0.0 0.0
0.5
1.0
1.5
2.0
2.5
3.0
Years Tei index ≤ 0.77 Tei index > 0.77 Figure 16-6 Relation between Tei index and survival in patients with cardiac amyloidosis. Increased Tei index was a significant risk factor of later mortality. (From Tei C, et al: Doppler index combining systolic and diastolic myocardial performance: Clinical value in cardiac amyloidosis. J Am Coll Cardiol 1996;28:658–664.)
0.6 0.5 0.4
ia
c
de
ry eu Ca
An
at h VT Br ad , Vf yc ar di Ru a No p co tu re m pl ica tio ns
sm
F
F
,A Af
CH
Sh
oc
k
Upper Normal Range
rd
Tei index
1.0
Figure 16-7 Relation between initial Tei index at admission to coronary care unit and subsequent complications in patients with acute anteroseptal myocardial infarction. (From Yuasa T, et al: Noninvasive prediction of complications with anteroseptal acute myocardial infarction by left ventricular Tei index. J Am Soc Echocardiogr 2005;18:20–25.)
Detection of Cardiac Dysfunction in Various Diseases Multiple studies have reported that rejection after cardiac transplantation can cause myocardial damage and result in an increase in the Tei index.44–47 The Tei index is also significantly correlated with exercise capacity in several studies.48–52 Dobutamine stress echocardiography often requires subjective evaluation in patients with unclear response of LV wall motion. The Tei index showed significant increase at peak stress only in patients with positive response for ischemia, suggesting an incremental role of the Tei index in evaluation by dobutamine stress echocardiography.53 Reperfusion in patients with acute myocardial infarction results in an improvement in cardiac function. An increased Tei index of greater than 0.50 suggests absence of adequate reperfusion with thrombolysis in myocardial infarction (TIMI) grade 3 in patients with acute anteroseptal myocardial infarction (Fig. 16-8).37,54 Because abnormalities in ICT, ET, and IRT by cardiac dysfunction can be augmented in ICT/ET and IRT/ET, the Tei index has the potential to express subtle changes in cardiac function. Many investigators have applied the Tei index to detect small changes in cardiac function by various conditions, including hypothyroidism,56 diabetes mellitus,57 acromegaly,58 preconditioning with preceding angina,59 sleep apnea syndrome,60 and others.
Hemodynamic Assessment As expected from its definition, the Tei index has close correlation with both systolic and diastolic functions, such as maximal + and − LV dP/dt, maximum mitral E-wave velocity, and τ.10,61 Although the Tei index does not include mid- to late-diastolic components, it has fair but significant correlation with LV stiffness.62,63 The Tei index is also significantly correlated with LV diastolic filling pressure. However, the correlation with pressure is modest, potentially due to the fact that LV filling pressure is determined by both ventricular function and loading.27,64,65 Nevertheless, the Tei index enables practical evaluation of impaired hemodynamics in patients with acute myocardial infarction with potentially minimal modification of loading in the acute phase before aggressive interventions to alter loading.32,67 A Tei index greater than 0.6 suggests impaired hemodynamics with Forrester classifications II–IV in patients with acute anteroseptal myocardial infarction (Fig. 16-9). Further, the Tei index enables practical differentiation of normal from pseudonormal mitral flow, defined by mitral E/A greater than 1.0 with elevated
LV-Tei index
0.7
0.5
0.3
0.1
#6 #6 (–) (+) Reperfusion
#7 #7 (+) (–) Reperfusion
#8 #8 (+) (–) Reperfusion
#9 (–)
Figure 16-8 Relation between Tei index at admission to the coronary care unit and coronary reperfusion with thrombolysis in myocardial infarction, grade 3, immediately evaluated by angiography in patients with acute anteroseptal myocardial infarction. (From Kuwahara E, et al: Increased Tei index suggests absence of adequate coronary reperfusion in patients with first anteroseptal acute myocardial infarction. Circ J 2006;70:248–253.)
Chapter 16 • Evaluation of Tei Index in Heart Failure ❒
1.0
❒
Tei index
0.8
0.6
0.4
Upper normal
0.2
0 I
II
III
IV
Forrester class
High
Category III (uncommon)
Category IV (common)
Low
Left ventricular filling pressure
Figure 16-9 Relation between Tei index and Forrester’s hemodynamic classification evaluated by catheterization in patients with acute anteroseptal myocardial infarction. (From Takasaki K, et al: Noninvasive estimation of impaired hemodynamics in patients with acute myocardial infarction by Tei index. J Am Soc Echocardiogr 2004;17:615–621.)
Category I (common)
Category II (not uncommon)
Good
Poor Left ventricular function
Figure 16-10 Relation between cardiac function or Tei index and left ventricular filling pressure. Categories II and III cause discrepancy between cardiac function and the filling pressure. Patients in category III are uncommon, and those in category II cause discrepancy between left ventricular function and filling pressure. (From Zhang H, et al: Noninvasive estimation of left ventricular diastolic filling pressure from Doppler Tei index: Different feasibilities in patients with higher and lower early to late diastolic mitral flow velocity ratio. J Echocardiogr 2003;1:15–22.)
LV filling pressure.64,65 It may seem strange that the Tei index practically separates patients with mitral E/A greater than 1.0 with or without elevated LV filling pressure, while the index is only fairly correlated with filling pressure. The Tei index shows significant and better correlation with LV filling pressure in patients with mitral E/A greater than 1.0 compared with those with mitral E/A no greater than 1.0 because LV function and its filling pressure can be placed into four categories (Fig. 16-10)68–69: ❒ ❒
Category I: normal LV function and normal filling pressure Category II: poor LV function and normal filling pressure
Category III: normal LV function and high filling pressure Category IV: poor LV function and high filling pressure
Patients in category III are not common, and those in category II seem to be the main reason for significant but only fair correlation between the Tei index and LV filling pressure. Normal LV filling pressure despite LV dysfunction in category II suggests no significant increase in preload, and most patients with a discrepant Tei index and filling pressure have mitral E/A of less than 1.0,68 being related to reduced preload.70 Therefore, the Tei index has significant and good correlation with the LV filling pressure in patients with mitral E/A greater than 1.0 and enables feasible differentiation of normal from pseudonormal mitral flow.64,65,71 A significant correlation between the Tei index and brain natriuretic peptide concentration also indicates significant relation between the Tei index and degree of chronic HF.72,73
Evaluation of Right Ventricular Function Due to the complex geometry of the right ventricle, it is still difficult to evaluate RV function. Measurement of RVEF seems not to be common practice in many institutions. However, the RV Tei index can be measured independently from chamber geometry by cardiac time interval analysis with tricuspid filling and pulmonary ejection flow. An increased RV Tei index predicts poor outcome in patients with primary pulmonary hypertension.74 Of note is that prediction of outcome is better with the Tei index compared with prediction on the basis of systolic pulmonary artery pressure. This indicates that RV dysfunction with increased pulmonary artery resistance rather than increased pulmonary artery pressure per se is more important to evaluate the severity of the disease. Clinical evaluation of the degree of RV dysfunction was proportional to the increase in the RV Tei index in patients with Ebstein’s anomaly.75 RV involvement of cardiac amyloidosis has also been evaluated by the Tei index.76 The RV Tei index is also significantly correlated with EF, measured by radionuclide angiography or cine magnetic resonance imaging.77,78 Further, an increased RV Tei index in patients with left-sided chronic HF is related to poor prognosis.79
Effects of Interventions Because the Tei index expresses global cardiac function with a sensitive nature, it is reasonable to apply the index to evaluate interventions, especially with potentially minor influences. The most common application of the Tei index to evaluate therapeutic intervention is probably cardiac resynchronization. Multiple investigators uniformly reported an improved Tei index with improvement in patient status.80–85 The Tei index has also been applied to guide pacemaker treatment to achieve maximal benefit.86–90 The Tei index is inversely proportional to quality of life or cardiac output in these patients. Significant but relatively small effects of various pharmacologic agents have been evaluated by the Tei index.91–93 A decrease in the Tei index after administration of carvedilol is an early sign of improvement of chronic HF.94 Improvement in exercise capacity by exercise training in patients with recent myocardial infarction is not associated with changes in EF but may be detected by the Tei index.95 An improved Tei index with low-dose dobutamine is associated with myocardial viability.96 Improvement in RV function can also be evaluated by an RV Tei index in patients with pulmonary hypertension.97,98
197
Chapter 16 • Evaluation of Tei Index in Heart Failure Worsening cardiac function following procedures can also be sensitively evaluated by the Tei index. An increase in the Tei index with low-dose dobutamine in patients with acute myocardial infarction suggests poorer outcome with progressive remodeling and doubled events or mortality.99,100 Early detection of cardiac toxicity by anthracycline can also be detected with the Tei index before the development of abnormality in EF.101–103 Adverse effects of RV pacing with augmented dyssynchrony can also be evaluated by the Tei index.104,105 Therefore, many investigators or clinical physicians utilize the Tei index to evaluate effects of various interventions in multiple disease entities.
40
PCWP (mmHg)
198
r = 0.59 p < 0.0001 SEE = 6.0
30
20
10
0 0.2
Evaluation of Patients with Tachycardia Measurement of LV volumes by two-dimensional echocardiography can be a problem in the presence of high heart rate and relatively low echocardiographic frame rate. However, pulsed Doppler echocardiography has excellent temporal resolution, suggesting that the Tei index is suitable to evaluate cardiac function even in the presence of advanced heart rate, such as in fetuses or small animal models. The Tei index has been reported to be heart rate independent in the fetus.106 Both the LV and RV Tei indices are abnormally increased in fetuses with intrauterine growth retardation.106,107 An increased LV Tei index suggests poor prognosis in fetuses with severe tricuspid valve disease,108 and an increased RV Tei index is a marker of poor prognosis in fetuses with tetralogy of Fallot and absent pulmonary valve.109 The Tei index is correlated with both systolic and diastolic functions in small animal models of chronic HF or myocardial infarction.110–112 Both the LV and RV Tei indices are sensitive measures to detect cardiac dysfunction in mice and rats.113,114
0.4
0.6
0.8
1
Tei index Figure 16-11 Relation between pulmonary capillary wedge pressure (PCWP) and Tei index in consecutive patients with acute anteroseptal myocardial infarction. A marked increase in Tei index is usually associated with significant increase in the filling pressure, and normal or only small increase in the index is associated with normal or only finite increase in the filling pressure. There is a wide scatter of left ventricular filling pressure in patients with mild to moderate increase in the Tei index. A significant increase in the filling pressure despite only mild increase in the index suggests that the Tei index may be pseudonormalized in these patients.
Not severe RV infarction
Normal
Severe RV infarction
Limitations Because the Tei index utilizes cardiac time intervals, it may not accurately express global cardiac function when ICT, ET, or IRT does not express cardiac function. One such example is the case with a paradoxically shortened IRT caused by a marked increase in left atrial pressure.115 A scattergram between LV filling pressure and the Tei index in consecutive patients with acute anteroseptal myocardial infarction demonstrated (1) an advanced increase in the Tei index with a significant increase in the filling pressure, (2) a normal or only small increase in the index with a normal or only finite increase in the filling pressure, and (3) a mild to moderate increase in the Tei index with a wide scatter of the filling pressure (Fig. 16-11). A marked increase in the filling pressure despite only a mild increase in the Tei index suggests that the Tei index may be pseudonormalized in these patients.116,117 Most of these patients had shortened mitral E deceleration time, which combined with the Tei index may enable better evaluation of hemodynamics in patients with HF. Of note is that no patient showed a totally normal Tei index despite advanced HF, although some showed a modest increase. The Tei index is expected to be more resistant to pseudonormalization compared with IRT per se because the component of the Tei index or ratio of IRT to ET is more difficult to be pseudonormalized, as ET usually shortens with elevation of the filling pressure. In addition, the Tei index is a sum of ICT/ET and IRT/ET, which seems to be further resistant to pseudonormalization.69 In the right ventricle, elevation of RV end diastolic pressure causes approximate equalization of diastolic pulmonary artery
ICT ET
IRT
Figure 16-12 Mechanism of pseudonormalized right ventricular Tei index in patients with severe right ventricular infarction. Severely elevated right ventricular end diastolic pressure results in advanced shortening of isovolumic contraction time (ICT) despite clear right ventricular systolic dysfunction. ET, ejection time; IRT, isovolumic relaxation time. (From Yoshifuku S, et al: Pseudonormal Doppler Tei index in patients with right ventricular acute myocardial infarction. Am J Cardiol 2003;91:527.)
and RV pressure, with extreme shortening of ICT despite severely impaired RV systolic contraction (Fig. 16-12).118
FUTURE RESEARCH We often see discrepancies between values of cardiac functional indices and patient status. The reason is often due to the fact that conventional indices express only one aspect of heterogeneous systolic or diastolic function. The Tei index enables evaluation of combined systolic and diastolic function, and therefore global cardiac function. The Tei index is related to patient prognosis. Because it sensitively expresses global cardiac function, evaluation of interventions in cardiac function is feasible with this index and should be an area of future research. The Tei index also enables practical evaluation of RV function with geometric complexity and clinical difficulty with other approaches. Other potential clinical applications of the Tei index will require further investigation.
Chapter 16 • Evaluation of Tei Index in Heart Failure REFERENCES 1. Cueto-Garcia L, Reeder GS, Kyle RA, et al: Echocardiographic findings in systemic amyloidosis: Spectrum of cardiac involvement and relation to survival. J Am Coll Cardiol 1985;6:737–743. 2. Swanton RH, Brooksby IAB, Davies MJ, et al: Systolic and diastolic ventricular function in cardiac amyloidosis. Am J Cardiol 1977;39:658–664. 3. Klein AL, Hatle LK, Burstow DJ, et al: Doppler characterization of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1989;13:1017–1026. 4. Shimizu G, Hirota Y, Kita Y, et al: Left ventricular midwall mechanics in systemic arterial hypertension. Myocardial function is depressed in pressureoverload hypertrophy. Circulation 1991;83:1676–1684. 5. Bruch C, Gradaus R, Gunia S, et al: Doppler tissue analysis of mitral annular velocities: Evidence for systolic abnormalities in patients with diastolic heart failure. J Am Soc Echocardiogr 2003;16:1031–1036. 6. Vasan RS, Larson MG, Benjamin EJ, et al: Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: Prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999;33: 1948–1955. 7. Hunt SA, Abraham WT, Chin MH, et al: ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation 2005;20:112: e154–e235. 8. Andersson B, Caidahl K, Waagstein F: An echocardiographic evaluation of patients with idiopathic heart failure. Chest 1995;107:680–689. 9. Sakate Y, Yoshiyama M, Hirata K, et al: Relationship between Dopplerderived left ventricular diastolic function and exercise capacity in patients with myocardial infarction. Am J Cardiol 2001;65:627–631. 10. Tei C: New non-invasive index for combined systolic and diastolic ventricular function. J Cardiol 1995;26:135–136. 11. Tei C, Ling LH, Hodge DO, et al: New index of combined systolic and diastolic myocardial performance: A simple and reproducible measure of cardiac function—a study in normals and dilated cardiomyopathy. J Cardiol 1995;26:357–366. 12. Tei C, Nishimura RA, Seward JB, Tajik AJ: Noninvasive Doppler-derived myocardial performance index: Correlation with simultaneous measurements of cardiac catheterization measurements. J Am Soc Echocardiogr 1997;10:169–178. 13. Le Feuvre C, Baubion N, Berdah J, et al: Doppler parameters of systolic function and heart rate. Arch Mal Coeur Vaiss 1992;85:199–202. 14. Eto G, Ishii M, Tei C, et al: Assessment of global left ventricular function in normal children and in children with dilated cardiomyopathy. J Am Soc Echocardiogr 1999;12:1058–1064. 15. Eidem BW, Edwards JM, Cetta F: Quantitative assessment of fetal ventricular function: Establishing normal values of the myocardial performance index in the fetus. Echocardiography 2001;18:9–13. 16. Harada K, Masamichi T, Toyono M, et al: Assessment of global left ventricular function by tissue Doppler imaging. Am J Cardiol 2001;88: 927–932. 17. Bahler RC, Mohyuddin T, Finkelhor RS, Jacobs IB: Contribution of Doppler tissue imaging and myocardial performance index to assessment of left ventricular function in patients with Duchenne’s muscular dystrophy. J Am Soc Echocardiogr 2005;18:666–673. 18. Abd el Rahman MY, Hui W, Dsebissowa F, et al: Comparison of the tissue Doppler–derived left ventricular Tei index to that obtained by pulse Doppler in patients with congenital and acquired heart disease. Pediatr Cardiol 2005;26:391–395. 19. Gaibazzi N, Petrucci N, Ziacchi V: Left ventricle myocardial performance index derived either by conventional method or mitral annulus tissueDoppler: A comparison study in healthy subjects and subjects with heart failure. J Am Soc Echocardiogr 2005;18:1270–1276. 20. Rojo EC, Rodrigo JL, Perez de Isla L, et al: Disagreement between tissue Doppler imaging and conventional pulsed wave Doppler in the measurement of myocardial performance index. Eur J Echocardiogr 2006;7:356–364. 21. Voon WC, Su HM, Yen HW, et al: Left ventricular Tei index: Comparison between flow and tissue Doppler analyses. Echocardiography 2005;22: 730–735. 22. Kjaergaard J, Hassager C, Oh JK, et al: Measurement of cardiac time intervals by Doppler tissue M-mode imaging of the anterior mitral leaflet. J Am Soc Echocardiogr 2005;18:1058–1065.
23. Tham EB, Silverman NH: Measurement of the Tei index: A comparison of M-mode and pulse Doppler methods. J Am Soc Echocardiogr 2004;17: 1259–1265. 24. Spencer KT, Weinert L, Avi VM, et al: Automated calculation of the Tei index from signal averaged left ventricular acoustic quantification wave forms. J Am Soc Echocardiogr 2002;15:1485–1489. 25. Poulsen SH, Nielsen JC, Andersen HR: The influence of heart rate on the Doppler-derived myocardial performance index. J Am Soc Echocardiogr 2000;13:379–384. 26. Moller JE, Poulsen SH, Egstrup K: Effect of preload alterations on a new Doppler echocardiographic index of combined systolic and diastolic performance. J Am Soc Echocardiogr 1999;12:1065–1072. 27. Bruch C, Schmermund A, Marin D, et al: Tei-index in patients with mild-to-moderate congestive heart failure. Eur Heart J 2000;21:1888– 1895. 28. Haque A, Otsuji Y, Yoshifuku S, et al: Effects of valve dysfunction on Doppler Tei index. J Am Soc Echocardiogr 2002;15:877–883. 29. Tei C, Dujardin KS, Hodge DO, et al: Doppler index combining systolic and diastolic myocardial performance: Clinical value in cardiac amyloidosis. J Am Coll Cardiol 1996;28:658–664. 30. Dujardin KS, Tei C, Yeo TC, et al: Prognostic value of a Doppler index combining systolic and diastolic performance in idiopathic-dilated cardiomyopathy. Am J Cardiol 1998;82:1071–1076. 31. Harjai KJ, Scott L, Vivekananthan K, et al: The Tei index: A new prognostic index for patients with symptomatic heart failure. J Am Soc Echocardiogr 2002;15:864–868. 32. Poulsen SH, Jensen SE, Tei C, et al: Value of the Doppler index of myocardial performance in the early phase of acute myocardial infarction. J Am Soc Echocardiogr 2000;13:723–730. 33. Poulsen SH, Jensen SE, Nielsen JC, et al: Serial changes and prognostic implications of a Doppler-derived index of combined left ventricular systolic and diastolic myocardial performance in acute myocardial infarction. Am J Cardiol 2000;85:19–25. 34. Moller JE, Egstrup K, Kober L, et al: Prognostic importance of systolic and diastolic function after acute myocardial infarction. Am Heart J 2003;145: 147–153. 35. Anavekar NS, Mirza A, Skali H, et al: Risk assessment in patients with depressed left ventricular function after myocardial infarction using the myocardial performance index—Survival and Ventricular Enlargement (SAVE) experience. J Am Soc Echocardiogr 2006;19:28–33. 36. Acil T, Wichter T, Stypmann J, et al: Prognostic value of tissue Doppler imaging in patients with chronic congestive heart failure. Int J Cardiol 2005;103:175–181. 37. Kato M, Dote K, Sasaki S, et al: Myocardial performance index for assessment of left ventricular outcome in successfully recanalised anterior myocardial infarction. Heart 2005;91:583–588. 38. Ascione L, De Michele M, Accadia M, et al: Myocardial global performance index as a predictor of in-hospital cardiac events in patients with first myocardial infarction. J Am Soc Echocardiogr 2003;16:1019–1023. 39. Yuasa T, Otsuji Y, Kuwahara E, et al: Noninvasive prediction of complications with anteroseptal acute myocardial infarction by left ventricular Tei index. J Am Soc Echocardiogr 2005;18:20–25. 40. Yilmaz R, Celik S, Baykan M, et al: Pulsed wave tissue Doppler–derived myocardial performance index for the assessment of left ventricular thrombus formation risk after acute myocardial infarction. Am Heart J 2004;148:1102–1108. 41. Al-Mukhaini M, Argentin S, Morin JF, et al: Myocardial performance index as predictor of adverse outcomes following mitral valve surgery. Eur J Echo 2003;4:128. 42. Arnlov J, Lind L, Andren B, et al: A Doppler-derived index of combined left ventricular systolic and diastolic function is an independent predictor of cardiovascular mortality in elderly men. Am Heart J 2005;149: 902–907. 43. Arnlov J, Ingelsson E, Riserus U, et al: Myocardial performance index, a Doppler-derived index of global left ventricular function, predicts congestive heart failure in elderly men. Eur Heart J 2004;25:2220–2225. 44. Mooradian SJ, Goldberg CS, Crowley DC, Ludomirsky A: Evaluation of a noninvasive index of global ventricular function to predict rejection after pediatric cardiac transplantation. Am J Cardiol 2000;86:358–360. 45. Vivekananthan K, Kalapura T, Mehra M, et al: Usefulness of the combined index of systolic and diastolic myocardial performance to identify cardiac allograft rejection. Am J Cardiol 2002;90:517–520. 46. Leonard GT Jr, Fricker FJ, Pruett D, et al: Increased myocardial performance index correlates with biopsy-proven rejection in pediatric heart transplant recipients. J Heart Lung Transplant 2006;25:61–66.
199
200
Chapter 16 • Evaluation of Tei Index in Heart Failure 47. Tona F, Caforio AL, Piaserico S, et al: Abnormal total ejection isovolume index as early noninvasive marker of chronic rejection in heart transplantation. Transpl Int 2005;18:303–308. 48. Sato T, Harada K, Tamura M, et al: Cardiorespiratory exercise capacity and its relation to a new Doppler index in children previously treated with anthracycline. J Am Soc Echocardiogr 2001;14:256–263. 49. Parthenakis FI, Kanakaraki MK, Kanoupakis EM, et al: Value of Doppler index combining systolic and diastolic myocardial performance in predicting cardiopulmonary exercise capacity in patients with congestive heart failure: Effects of dobutamine. Chest 2002;121:1935–1941. 50. Skaluba SJ, Bray BE, Litwin SE: Close coupling of systolic and diastolic function: Combined assessment provides superior prediction of exercise capacity. J Card Fail 2005;11:516–522. 51. Norozi K, Buchhorn R, Bartmus D, et al: Elevated brain natriuretic peptide and reduced exercise capacity in adult patients operated on for tetralogy of Fallot is due to biventricular dysfunction as determined by the myocardial performance index. Am J Cardiol 2006;97:1377–1382. 52. Kasikcioglu E, Oflaz H, Akhan H, Kayserilioglu A: Right ventricular myocardial performance index and exercise capacity in athletes. Heart Vessels 2005;20:147–152. 53. Ling LH, Tei C, McCully RB, et al: Analysis of systolic and diastolic time intervals during dobutamine-atropine stress echocardiography: Diagnostic potential of the Doppler myocardial performance index. J Am Soc Echocardiogr 2001;14:978–986. 54. Kuwahara E, Otsuji Y, Takasaki K, et al: Increased Tei index suggests absence of adequate coronary reperfusion in patients with first anteroseptal acute myocardial infarction. Circ J 2006;70:248–253. 55. Reference deleted in proofs. 56. Doin FL, Borges Mda R, Campos O, et al: Effect of central hypothyroidism on Doppler-derived myocardial performance index. J Am Soc Echocardiogr 2004;17:622–629. 57. Andersen NH, Poulsen SH, Helleberg K, et al: Impact of essential hypertension and diabetes mellitus on left ventricular systolic and diastolic performance. Eur J Echocardiogr 2003;4:306–312. 58. Bruch C, Herrmann B, Schmermund A, et al: Impact of disease activity on left ventricular performance in patients with acromegaly. Am Heart J 2002;144:538–543. 59. Baykan M, Yilmaz R, Celik S, et al: Assessment of left ventricular systolic and diastolic function by Doppler tissue imaging in patients with preinfarction angina. J Am Soc Echocardiogr 2003;16:1024–1030. 60. Dursunoglu D, Dursunoglu N, Evrengul H, et al: Impact of obstructive sleep apnoea on left ventricular mass and global function. Eur Respir J 2005;26:283–288. 61. Morgan EE, Faulx MD, McElfresh TA, et al: Validation of echocardiographic methods for assessing left ventricular dysfunction in rats with myocardial infarction. Am J Physiol Heart Circ Physiol 2004;287: H2049–H2053. 62. Cannesson M, Jacques D, Pinsky MR, Gorcsan J 3rd: Effects of modulation of left ventricular contractile state and loading conditions on tissue Doppler myocardial performance index. Am J Physiol Heart Circ Physiol 2006;290: H1952–H1959. 63. LaCorte JC, Cabreriza SE, Rabkin DG, et al: Correlation of the Tei index with invasive measurements of ventricular function in a porcine model. J Am Soc Echocardiogr 2003;16:442–447. 64. Zhang H, Otsuji Y, Matsukida K, et al: Noninvasive differentiation of normal from pseudonormal/restrictive mitral flow using TEI index combining systolic and diastolic function. Circ J 2002;66:831–836. 65. Abd el-Rahim AR, Otsuji Y, Yuasa T, et al: Noninvasive differentiation of pseudonormal/restrictive from normal mitral flow by Tei index: A simultaneous echocardiography-catheterization study in patients with acute anteroseptal myocardial infarction. J Am Soc Echocardiogr 2003;16:1231–1236. 66. Reference deleted in proofs. 67. Takasaki K, Otsuji Y, Yoshifuku S, et al: Noninvasive estimation of impaired hemodynamics in patients with acute myocardial infarction by Tei index. J Am Soc Echocardiogr 2004;17:615–621. 68. Zhang H, Otsuji Y, Matsukida K, et al: Noninvasive estimation of left ventricular diastolic filling pressure from Doppler Tei index: Different feasibilities in patients with higher and lower early to late diastolic mitral flow velocity ratio. J Echocardiogr 2003;1:15–22. 69. Otsuji Y, Tei C: Evaluation of left ventricular filling pressure by the Tei index. J Am Soc Echocardiogr 2004;17:710. 70. Courtois M, Vered Z, Barzilai B, et al: The transmitral pressure-flow velocity relation. Effect of abrupt preload reduction. Circulation 1988;78: 1459–1468.
71. Su HM, Lin TH, Voon WC, et al: Differentiation of left ventricular diastolic dysfunction, identification of pseudonormal/restrictive mitral inflow pattern and determination of left ventricular filling pressure by Tei index obtained from tissue Doppler echocardiography. Echocardiography 2006;23: 287–294. 72. Ono M, Tanabe K, Asanuma T, et al: Doppler echocardiography–derived index of myocardial performance (TEI index): Comparison with brain natriuretic peptide levels in various heart disease. Jpn Circ J 2001;65: 637–642. 73. Okawa M, Kitaoka H, Matsumura Y, et al: Functional assessment by myocardial performance index (Tei index) correlates with plasma brain natriuretic peptide concentration in patients with hypertrophic cardiomyopathy. Circ J 2005;69:951–957. 74. Yeo TC, Dujardin KS, Tei C, et al: Value of a Doppler-derived index combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension. Am J Cardiol 1998;81:1157– 1161. 75. Eidem BW, Tei C, O’Leary PW, et al: Nongeometric quantitative assessment of right and left ventricular function: Myocardial performance index in normal children and patients with Ebstein anomaly. J Am Soc Echocardiogr 1998;11:849–856. 76. Kim WH, Otsuji Y, Yuasa T, et al: Evaluation of right ventricular dysfunction in patients with cardiac amyloidosis using Tei index. J Am Soc Echocardiogr 2004;17:45–49. 77. Miller D, Farah MG, Liner A, et al: The relation between quantitative right ventricular ejection fraction and indices of tricuspid annular motion and myocardial performance. J Am Soc Echocardiogr 2004;17:443–447. 78. Salehian O, Schwerzmann M, Merchant N, et al: Assessment of systemic right ventricular function in patients with transposition of the great arteries using the myocardial performance index: Comparison with cardiac magnetic resonance imaging. Circulation. 2004;110:3229–3233. 79. Meluzin J, Spinarova L, Hude P, et al: Prognostic importance of various echocardiographic right ventricular functional parameters in patients with symptomatic heart failure. J Am Soc Echocardiogr 2005;18:435– 444. 80. Saxon LA, De Marco T, Schafer J, et al, for VIGOR Congestive Heart Failure Investigators: Effects of long-term biventricular stimulation for resynchronization on echocardiographic measures of remodeling. Circulation 2002;105:1304–1310. 81. Yu CM, Chau E, Sanderson JE, et al: Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation 2002;105:438–445. 82. Breithardt OA, Stellbrink C, Franke A, et al: Acute effects of cardiac resynchronization therapy on left ventricular Doppler indices in patients with congestive heart failure. Am Heart J 2002;143:34–44. 83. Sutton MG, Plappert T, Abraham WT, et al: Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003;22:1985–1990. 84. Yu CM, Lin H, Fung WH, et al: Comparison of acute changes in left ventricular volume, systolic and diastolic functions, and intraventricular synchronicity after biventricular and right ventricular pacing for heart failure. Am Heart J 2003;145:E18. 85. Sutton MG, Plappert T, Hilpisch KE, et al: Sustained reverse left ventricular structural remodeling with cardiac resynchronization at one year is a function of etiology: Quantitative Doppler echocardiographic evidence from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). Circulation 2006;113:266–272. 86. Toda N, Ishikawa T, Nozawa N, et al: Doppler index and plasma level of atrial natriuretic hormone are improved by optimizing atrioventricular delay in atrioventricular block patients with implanted DDD pacemakers. Pacing Clin Electrophysiol 2001;24:1660–1663. 87. Kato M, Dote K, Sasaki S, et al: Determination of the optimal atrioventricular interval in sick sinus syndrome during DDD pacing. Pacing Clin Electrophysiol 2005;28:892–897. 88. Moro E, Caprioglio F, Berton G, et al: DDD versus VVIR versus VVI mode in patients with indication to dual-chamber stimulation: A prospective, randomized, controlled, single-blind study. Ital Heart J 2005;6:728–733. 89. Bernheim A, Ammann P, Sticherling C, et al: Right atrial pacing impairs cardiac function during resynchronization therapy: Acute effects of DDD pacing compared to VDD pacing. J Am Coll Cardiol 2005;45: 1482–1487. 90. Porciani MC, Dondina C, Macioce R, et al: Echocardiographic examination of atrioventricular and interventricular delay optimization in cardiac resynchronization therapy. Am J Cardiol 2005;95:1108–1110.
Chapter 16 • Evaluation of Tei Index in Heart Failure 91. Karvounis HI, Zaglavara TA, Parharidis GE, et al: An angiotensinconverting enzyme inhibitor improves left ventricular systolic and diastolic function in transfusion-dependent patients with beta-thalassemia major. Am Heart J 2001;141:281. 92. Harada K, Tamura M, Toyono M, Yasuoka K: Effect of dobutamine on a Doppler echocardiographic index of combined systolic and diastolic performance. Pediatr Cardiol 2002;23:613–617. 93. Nearchou NS, Tsakiris AK, Lolaka MD, et al: Influence of perindopril on left ventricular global performance during the early phase of inferior acute myocardial infarction: Assessment by Tei index. Echocardiography 2003; 20:319–327. 94. Palloshi A, Fragasso G, Silipigni C, et al: Early detection by the Tei index of carvedilol-induced improved left ventricular function in patients with heart failure. Am J Cardiol 2004;94:1456–1459. 95. Ueshima K, Suzuki T, Nasu M, et al: Effects of exercise training on left ventricular function evaluated by the Tei index in patients with myocardial infarction. Circ J 2005;69:564–566. 96. Palmieri V, Innocenti F, Agresti C, et al: Traditional and color M-mode parameters of left ventricular diastolic function during low-dose dobutamine stress echocardiography: Relations to contractility reserve. J Am Soc Echocardiogr 2006;19:483–490. 97. Sebbag I, Rudski LG, Therrien J, et al: Effect of chronic infusion of epoprostenol on echocardiographic right ventricular myocardial performance index and its relation to clinical outcome in patients with primary pulmonary hypertension. Am J Cardiol 2001;88:1060–1063. 98. Seyfarth HJ, Pankau H, Hammerschmidt S, et al: Bosentan improves exercise tolerance and Tei index in patients with pulmonary hypertension and prostanoid therapy. Chest 2005;128:709–713. 99. Norager B, Husic M, Moller JE, et al: The Doppler myocardial performance index during low-dose dobutamine echocardiography predicts mortality and left ventricular dilation after a first acute myocardial infarction. Am Heart J 2005;150:522–529. 100. Norager B, Husic M, Moller JE, et al: Changes in the Doppler myocardial performance index during dobutamine echocardiography: Association with neurohormonal activation and prognosis after acute myocardial infarction. Heart 2006;92:1071–1076. 101. Ishii M, Tsutsumi T, Himeno W, et al: Sequential evaluation of left ventricular myocardial performance in children after anthracycline therapy. Am J Cardiol 2000;86:1279–1281. 102. Eidem BW, Sapp BG, Suarez CR, Cetta F: Usefulness of the myocardial performance index for early detection of anthracycline-induced cardiotoxicity in children. Am J Cardiol 2001;87:1120–1122. 103. Belham M, Kruger A, Pritchard C: The Tei index identifies a differential effect on left and right ventricular function with low-dose anthracycline chemotherapy. J Am Soc Echocardiogr 2006;19:206–210. 104. Tantengco MV, Thomas RL, Karpawich PP: Left ventricular dysfunction after long-term right ventricular apical pacing in the young. J Am Coll Cardiol 2001;15:2093–2100.
105. Lin MS, Lin JL, Liu YB, et al: Immediate impairment of left ventricular mechanical performance and force-frequency relation by rate-responsive dual-chamber, but not atrial pacing: Implications from intraventricular isovolumic relaxation flow. Int J Cardiol 2005;26. 106. Niewiadomska-Jarosik K, Lipecka-Kidawska E, Kowalska-Koprek U, et al: Assessment of cardiac function in fetuses with intrauterine growth retardation using the Tei Index. Med Wieku Rozwoj 2005;9:153– 160. 107. Ichizuka K, Matsuoka R, Hasegawa J, et al: The Tei index for evaluation of fetal myocardial performance in sick fetuses. Early Hum Dev 2005;81: 273–279. 108. Inamura N, Taketazu M, Smallhorn JF, Hornberger LK: Left ventricular myocardial performance in the fetus with severe tricuspid valve disease and tricuspid insufficiency. Am J Perinatol 2005;22:91–97. 109. Inamura N, Kado Y, Nakajima T, Kayatani F: Left and right ventricular function in fetal tetralogy of Fallot with absent pulmonary valve. Am J Perinatol 2005;22:199–204. 110. Broberg CS, Pantely GA, Barber BJ, et al: Validation of the myocardial performance index by echocardiography in mice: A noninvasive measure of left ventricular function. J Am Soc Echocardiogr 2003;16:814–823. 111. Jegger D, Jeanrenaud X, Nasratullah M, et al: Noninvasive Doppler-derived myocardial performance index in rats with myocardial infarction: Validation and correlation by conductance catheter. Am J Physiol Heart Circ Physiol 2006;290:H1540–H1548. 112. Schaefer A, Meyer GP, Hilfiker-Kleiner D, et al: Evaluation of tissue Doppler Tei index for global left ventricular function in mice after myocardial infarction: Comparison with pulsed Doppler Tei index. Eur J Echocardiogr 2005;6:367–375. 113. Santos RA, Castro CH, Gava E, et al: Impairment of in vitro and in vivo heart function in angiotensin-(1–7) receptor MAS knockout mice. Hypertension 2006;47:996–1002. 114. Boissiere J, Gautier M, Machet MC, et al: Doppler tissue imaging in assessment of pulmonary hypertension-induced right ventricle dysfunction. Am J Physiol Heart Circ Physiol 2005;289:H2450–H2455. 115. Appleton CP, Hatle LK, Popp RL: Relation of transmitral flow velocity patterns to left ventricular diastolic function: New insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol 1988;12:426–440. 116. Nearchou NS, Tsakiris AK, Tsitsirikos MD, et al: Tei index as a method of evaluating left ventricular diastolic dysfunction in acute myocardial infarction. Hellenic J Cardiol 2005;46:35–42. 117. Abd el Rahman MY, Abdul-Khaliq H, Vogel M, et al: Value of the new Doppler-derived myocardial performance index for the evaluation of right and left ventricular function following repair of tetralogy of Fallot. Pediatr Cardiol 2002;23:502–507. 118. Yoshifuku S, Otsuji Y, Takasaki K, et al: Psedonormalized Doppler Tei index in patients with right ventricular acute myocardial infarction. Am J Cardiol 2003;91:527–531.
201
DALANE W. KITZMAN, MD JERRY M. JOHN, MD
17
Exercise Intolerance in Diastolic Heart Failure INTRODUCTION PATHOPHYSIOLOGY OF EXERCISE INTOLERANCE Determinants of Oxygen Consumption Exercise Intolerance in Systolic Versus Diastolic Heart Failure Hemodynamic Alterations During Exercise in Heart Failure Patients
Angiotensin Receptor Blockers Calcium Channel Blockers Aldosterone Inhibitors Glucose Cross-Link Breakers Pacemaker Therapy Exercise Training FUTURE RESEARCH ACKNOWLEDGMENT
CLINICAL RELEVANCE: INTERVENTIONS TO IMPROVE EXERCISE TOLERANCE
INTRODUCTION Exercise intolerance is the primary symptom of chronic diastolic heart failure (DHF). This chapter discusses the fundamental aspects of exercise physiology and the assessment, pathophysiology, and potential treatment of exercise intolerance associated with DHF. Exercise intolerance is central to the very definition of heart failure, as well as its pathophysiology, diagnosis, prognosis, and therapy. Heart failure is defined as a syndrome in which cardiac output is insufficient to meet metabolic demands. Inherent in this definition is that consequences of insufficient cardiac output will be expressed symptomatically. Indeed, while the natural history of heart failure is punctuated by occasional episodes of acute decompensation with overt systemic volume overload and pulmonary edema,1,2 the primary chronic symptoms in patients with chronic heart failure, whether associated with reduced or normal ejection fraction, are exertional fatigue and dyspnea.3 In addition, these symptoms are the primary determinants of patients’ healthrelated quality of life. Furthermore, measures of exercise tolerance are powerful independent predictors of mortality.4,5 The severity of exercise intolerance can be quantified by a variety of methods. These include semiquantitative assessments, such as interviews (New York Heart Association [NYHA] classification) and surveys (the Minnesota Living with Heart Failure and Kansas City Cardiomyopathy questionnaires), and quantita-
tive methods, including timed walking tests (6-minute walk distance) and graded exercise treadmill or bicycle exercise tests. Cardiopulmonary exercise testing on a motorized treadmill or a bicycle ergometer provides the most accurate and reliable assessment of exercise tolerance and yields multiple important outcomes, including exercise time, exercise workload, rate-pressure product, and metabolic equivalents (METs). Peak oxygen consumption (VO2) and carbon dioxide generation (VCO2) can be measured simultaneously by expired gas analysis using instruments that are reliable and highly automated. The quality of the exercise data, and in particular whether the patient gave a maximal or near-maximal effort, can be assessed not only by perceived exertion scales, such as the Borg scale, and percent age-predicted maximal heart rate, but also by the respiratory exchange ratio, which is unbiased by other variables. In addition to assessing peak exercise capacity with peak VO2, submaximal exercise capacity can be assessed by determining the ventilatory anaerobic threshold. Submaximal exercise capacity is more applicable to everyday life and is relatively effort independent. We have shown that measurements of both peak and ventilatory anaerobic threshold with automatic instruments are valid and highly reproducible in elderly patients with diastolic as well as systolic heart failure (Fig. 17-1). In addition to these key variables, cardiopulmonary exercise testing with expired gas analysis can assess the slope of expired ventilation (VE)/VCO2, which is a powerful predictor of survival, independent of VO2.6 203
204
Chapter 17 • Exercise Intolerance in Diastolic Heart Failure
PATHOPHYSIOLOGY OF EXERCISE INTOLERANCE
Determinants of Oxygen Consumption Assessment of peak VO2 gives insight into the pathophysiology of exercise intolerance, since, by the Fick equation, it is the product of cardiac output and arteriovenous oxygen (A-V O2) difference. Thus, exercise intolerance will be closely related to one or both of these factors and to the factors that comprise them. Measurement of peak exercise VO2 and at least one of these other two factors (cardiac output or A-V O2) allows one to calculate the remaining unknown factor and therefore to isolate specific factors that contribute to exercise intolerance within individual patients and groups (Fig. 17-3). We performed a series of cardiopulmonary exercise studies in order to examine the determinants of exercise performance in normal humans and in patients with heart failure.7–13 The methods included symptom-limited upright bicycle exercise with indwelling pulmonary artery and brachial artery catheters, and simultaneous expired gas analysis and radionuclide ventriculography.7–15 Cardiac output was determined by the Fick principle for oxygen and was indexed to body surface area. The left ventricular (LV) end diastolic volume index (EDVI) and end systolic volume index (ESVI) were calculated from the Fick stroke volume index (SVI) and the radionuclide LV ejection fraction (LVEF), according to the formulas: EDVI = SVI/LVEF, and ESVI = EDVI − SVI. During upright bicycle exercise in healthy young and middleaged male volunteers, VO2 increased 7.7-fold from rest to peak exercise.7 This was achieved by a 3.2-fold increase in cardiac output and a 2.5-fold increase in A-V O2 difference. The increase in cardiac output resulted from a 2.5-fold increase in heart rate and a 1.4-fold increase in stroke volume. Stroke volume increased during the initial low levels of exercise via the Frank-Starling mechanism, whereas end diastolic volume increased with small
In a comparative study from our laboratory, maximal exercise testing with expired gas was performed in 119 older subjects divided among three groups: heart failure with severe LV systolic dysfunction (mean ejection fraction [EF], 30%); isolated DHF (EF >50%; no significant coronary, valvular, pericardial, or pulmonary disease; and no anemia); and age-matched controls.3 In comparison with the normal controls, peak VO2, an objective measure of exercise capacity, was severely reduced in the patients with DHF, and to a similar degree as in those with systolic heart failure (SHF) (Fig. 17-2).3 In addition, submaximal exercise capacity, as measured by the ventilatory anaerobic threshold, was similarly reduced in patients with DHF versus those with SHF, and this was accompanied by reduced health-related quality of life.3
Test 2 (VO2max, ml/min)
2000 1800 1600 1400 1200 1000 800
r = 0.92 p ≤ 0.0004
600 400 400
600
800
1000 1200 1400 1600 1800 2000
Test 1 (VO2max, ml/min)
VO2 (ml/min)
1500 Start of exercise
1000
Heart rate: Chronotropic incompetence
500
Test 1 Test 2
Stroke volume: ↓ Contractility (systolic dysfunction: ESV) ↓ LV filling (diastolic dysfunction: EDV)
0 0
0.08 3
0.16 7
0.25
0.33 3
0.41 7
0.5
0.58 3
Arteriovenous O2 difference: ↓ Peripheral vascular function ↓ Skeletal muscle bulk and function ↓ Hemoglobin (anemia)
Time (min) Figure 17-1 Excellent reproducibility of peak exercise VO2 in older patients with heart failure, including those with normal LV ejection fraction. Group data shown in top panel; representative patient with 15-second averaged data shown in bottom. (From Marburger et al: Reproducibility of cardiopulmonary exercise testing in elderly heart failure patients. Am J Cardiol 1998;82:905–909.)
SUBMAXIMAL
25 20 15
‡
‡
SD
DD
10 5 0 NO
VO2 (ml/min/kg) at AT
Peak VO2 (ml/kg/min)
PEAK
Figure 17-3 Potential mechanisms of exercise intolerance from the factors of the Fick equation. ESV, end systolic volume; LV, left ventricular; EDV, end diastolic volume.
16 14 12 10 8 6 4 2 0 NO
‡
‡
SD
DD
Figure 17-2 Exercise oxygen consumption (VO2) during peak exhaustive exercise (left panel) and during submaximal exercise at the ventilatory anaerobic threshold (right panel) in age-matched normal subjects (NO), elderly patients with heart failure due to systolic dysfunction (SD), and elderly patients with heart failure with normal systolic function and presumed diastolic dysfunction (DD). Exercise capacity is severely reduced in patients with diastolic heart failure compared with normals (p < 0.001) and to a similar degree as in those with systolic heart failure. Overall, peak exercise VO2 was 33% lower in the women compared with the men (not shown). (Modified from Kitzman et al: Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–2150.)
Chapter 17 • Exercise Intolerance in Diastolic Heart Failure increases in pulmonary wedge pressure. During higher levels of exercise, stroke volume increased predominantly because of increased contractility with decreases in end systolic volume; end diastolic volume may even decline slightly because of tachycardia and limited filling time. A similar hemodynamic exercise response occurs in healthy women.14 Aging is known to be accompanied by reduced peak exercise VO2. This is due to age-related declines in peak exercise cardiac output, heart rate, stroke volume, LVEF, and end diastolic volume, while pulmonary wedge pressure is relatively unaffected.8,9 Thus, stroke volume and end diastolic volume response are important contributors to the increase in VO2 and cardiac output during upright exercise in normal subjects and are altered by normal aging but not by gender.
Exercise Intolerance in Systolic Versus Diastolic Heart Failure In order to examine the cardiovascular response to exercise in classic SHF, 30 patients with heart failure associated with severe LV systolic dysfunction (mean LVEF = 24 ± 8%) were compared with 12 healthy volunteers of similar gender and age group.11 Exercise tolerance was severely reduced in the patients, whose mean peak workload was 50% of that achieved by the healthy subjects. Maximal VO2 was reduced by 53%, and this was associated with a 53% reduction in cardiac output; maximal A-V O2 difference was lower but not significantly different from normals. Maximal stroke volume was severely reduced in the patients. In addition, maximal heart rate was mildly reduced, a finding that has been reported by others as well. When the patients were grouped according to whether their exercise was limited by fatigue or by dyspnea, the peak pulmonary capillary wedge pressure (PCWP) was similar in both groups. Furthermore, in a significant fraction of patients, pulmonary wedge pressure was normal during rest and exercise, even though all had marked exercise intolerance and early lactate formation at submaximal workloads. These data suggest that in patients with chronic heart failure and severe systolic LV dysfunction, exercise intolerance is closely related to reduced exercise cardiac output, which is caused by severely reduced stroke volume and mildly reduced heart rate responses during exercise. A subsequent report in 40 patients with severe LV systolic dysfunction confirmed that stroke volume was reduced during rest and exercise compared with normal subjects.8 However, the relative increase in stroke volume from rest to peak exercise was similar and was 48% in patients and 42% in normal subjects.8 While some of the increase in stroke volume during exercise was attributable to increased contractility, stroke volume increased in patients in whom there was no change in LVEF. Furthermore, there was a significantly greater increase in EDVI during exercise in the patients compared with the normal subjects, and the increase in LV end diastolic volume per increase in PCWP was nearly threefold greater in patients compared with normal subjects. Shen et al.16 reported similar findings, although some patients do not increase end diastolic volume during exercise, due either to diastolic LV dysfunction or to pericardial constraint.8 Thus, in most patients with heart failure caused by systolic LV dysfunction, the Frank-Starling mechanism not only contributes significantly to the increase in stroke volume during exercise but also partially compensates for reduced inotropic and chronotropic reserves. With these background data in SHF, we sought to examine the cardiovascular response to exercise in patients with DHF by per-
forming similar cardiopulmonary exercise testing in seven patients with severe but stable chronic heart failure (NYHA functional class III or IV). Six of the patients had had at least one episode of clinically and radiographically documented pulmonary edema.10 No patient was included who had significant coronary artery disease by coronary angiography, abnormal LVEF (<50%), wall motion abnormalities by radionuclide ventriculography, or clinical or echocardiographic evidence of valvular or pericardial disease. Most of the patients had a history of chronic systemic hypertension; there was also increased LV wall thickness and mass by echocardiography compared with normal controls (107 ± 27 vs. 79 ± 14 g/m2; p < 0.01). Ten age-matched and gender-matched healthy volunteers underwent similar testing to serve as normal controls. The patients with DHF exhibited marked exercise intolerance, indicated by a reduction in peak workload compared with the normal subjects. This corresponded to a 48% reduction in peak VO2 (11.6 ± 4.0 vs. 22.7 ± 6.1 ml/kg/min; p < 0.001). In all patients and normal subjects, exercise was limited primarily by leg fatigue, although dyspnea was also frequently reported at peak exercise.10 The peak respiratory exchange ratio was similar in patients and normal subjects (1.24 ± 0.15 vs. 1.33 ± 0.16; p = 0.24), suggesting a near-maximal exercise effort in both groups. Arterial lactate concentration increased from 0.5 ± 0.3 mmol/ liter at rest to 3.7 ± 2.8 mmol/liter at peak exercise in the patients and from 0.5 ± 0.4 mmol/liter to 7.2 ± 2.0 mmol/liter in the normal subjects. During submaximal exercise at 50 watts, where VO2 was similar in patients and normals, lactate concentration tended to be higher in the patients compared with the normal subjects (2.2 ± 1.1 vs. 1.4 ± 0.7 mmol/liter; p < 0.07). At rest, there were no differences in cardiac output, central A-V O2 difference, SVI, or heart rate between the two groups. However, during exercise in the patients compared with normal subjects, cardiac output was significantly reduced at comparable submaximal workloads and was markedly reduced by 41% at peak exercise (p < 0.001), in proportion to the reduction in peak VO2 (Fig. 17-4A). Central A-V O2 difference was increased by approximately 10% in the patients during the submaximal exercise workloads, partially compensating for the reduced cardiac output (Fig. 17-4B). However, at peak exercise, this mechanism was outstripped, and A-V O2 difference was reduced by 13% compared with the normal subjects (p = 0.08). In the patients, the change in cardiac output from rest to peak exercise correlated closely with the increase in VO2 during exercise (r = 0.81, p < 0.03), but the change in A-V O2 difference did not (r = 0.34, p = 0.43).
Hemodynamic Alterations During Exercise in Heart Failure Patients Stroke Volume The indexed stroke volume is reduced by 26% in heart failure patients compared with the normal subjects during submaximal exercise (p < 0.01) (Fig. 17-4C). In contrast to the increase in SVI during low levels of exercise followed by a plateau observed in the normal subjects, a flat stroke volume response was observed in these patients.10 Heart rate increased slightly in patients compared with controls during submaximal exercise, but was reduced by 18% compared with controls at peak exercise (p < 0.01) (Fig. 17-4D). The change in SVI from rest to peak exercise correlated closely with the increase in cardiac output during exercise (r = 0.86, p < 0.01) in heart failure patients, but the change in heart rate did not (r = 0.60, p = 0.14). Thus, in patients with DHF at
205
Arteriovenous O2 difference (ml/dl)
Chapter 17 • Exercise Intolerance in Diastolic Heart Failure
Cardiac index (l/min/m2)
206
10.0 8.0 6.0 4.0 2.0
*
* †
0
12 10 8 6 4 2
Rest 150 300 450 600 750
Rest 150 300 450 600 750
B
60
200 Heart rate (min –1)
Stroke volume index (ml/m2)
A
50 40 30 20
*
† †
†
160 * 120 80 40
10
0 Rest 150 300 450 600 750 PT max
Rest 150 300 450 600 750
NL max
PT max
Workload (kpm/min)
C
NL max
Workload (kpm/min)
D
peak exercise, reduced SVI was the primary factor responsible for reduced cardiac output, and reduced peak cardiac output was the primary factor responsible for the 48% reduction in peak VO2 observed in our study.10 Factors that could contribute to the abnormal stroke volume response in patients with DHF are displayed in Figure 17-5. The LVEF and ESVI during rest and exercise and the change from rest to peak exercise were not different from those in the normal subjects (see Fig. 17-5A and B). In contrast, EDVI was reduced markedly during submaximal and at peak exercise in patients compared with normal subjects. This results in an abnormal, flattened curve that is similar to the abnormal stroke volume response (see Fig. 17-5C). In patients with DHF, the change in EDVI from rest to peak exercise correlated strongly with the change in SVI (r = 0.97, p < 0.0001) and in cardiac output (r = 0.80, p < 0.03) during exercise.10
Left Ventricular Filling Pressures Pulmonary wedge pressure was mildly increased in patients with DHF compared with normal subjects at rest and became markedly elevated during exercise (see Fig. 17-5D). However, the change in pulmonary wedge pressure from rest to peak exercise did not correlate significantly with the change in SVI or the increase in VO2 during exercise.
Left Ventricular Compliance Although the LV end diastolic pressure-volume ratio tended to be elevated in patients with DHF compared with normal subjects
Figure 17-4 Cardiovascular function assessed by invasive cardiopulmonary exercise testing in patients with heart failure and normal systolic function (blue boxes) and age-matched normals (red boxes). A, B, The primary components of the Fick equation for oxygen consumption: cardiac output and arteriovenous oxygen difference. C, D, The components of cardiac output: stroke volume and heart rate. The x-axis is exercise workload in kpm/min; 150 kpm/min is equivalent to 25 watts. (From Kitzman et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17:1065–1067.)
(0.12 ± 0.11 vs. 0.03 ± 0.03 mmHg/ml; p = 0.07) at rest, during exercise this ratio became markedly elevated in the patients compared with the normal subjects (peak, 0.28 ± 0.15 vs. 0.06 ± 0.05 mmHg/ml; p < 0.0001). The abnormal LV end diastolic pressure-volume relationship demonstrated by patients with DHF is further illustrated in Figure 17-6. At rest, the patients demonstrated a shift upward and to the left. In contrast to the normal subjects, who demonstrated approximately linear increases in end diastolic volume and pulmonary wedge pressure during exercise, the patients’ exaggerated and progressive increases in pulmonary wedge pressure were not accompanied by increases in end diastolic volume.10 Thus, these patients with normal rest and exercise LVEF demonstrated an abnormal pressure-volume relationship during exercise and an inability to augment stroke volume by means of the FrankStarling mechanism, suggesting that their exercise intolerance was due primarily to diastolic LV dysfunction. This is in contrast to patients with heart failure and reduced systolic function, who have an operating pressure-volume relationship that is shifted upward and to the right during exercise.17
Noninvasive Measures of Left Ventricular Filling Pressures The pattern of invasively assessed LV filling pressures offers key insights into exercise intolerance; however, their invasive nature limits their overall utility. Noninvasive Doppler mitral filling indices have given substantial insight into LV diastolic function but are confounded by many variables. The more recently developed tissue Doppler indices are relatively free of confounding
Chapter 17 • Exercise Intolerance in Diastolic Heart Failure End systolic volume index (ml/m2)
80 60 40 20 0
Figure 17-5 A–D, The components of the LV stroke volume response during exercise, LV ejection fraction, end systolic volume, end diastolic volume, and LV filling pressure. Not shown are systolic and mean arterial pressure, which were not different between groups. The x-axis is exercise workload in kpm/min; 150 kpm/min is equivalent to 25 watts. (From Kitzman et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17:1065–1067.)
End diastolic volume index (ml/m2)
A
90 75 60 45 *
30
C
Pulmonary capillary wedge pressure (mmHg)
30 Peak exercise
20 15 Peak exercise
10 Rest 5 0 60
80
100
120
30 20 10 0
40 †
†
32 †
24 16
*
8 0
D
35
25
40
B Pulmonary wedge pressure (mmHg)
L.V. ejection fraction (%)
100
140
160
Left ventricular end diastolic volume (ml) Figure 17-6 LV diastolic function assessed by invasive cardiopulmonary exercise testing. The pressure-volume relation was shifted upward and leftward at rest. In the patients with exercise, LV diastolic volume did not increase despite marked increase in diastolic (pulmonary wedge) pressure. Due to diastolic dysfunction, failure of the Frank-Starling mechanism resulted in severe exercise intolerance. The x-axis is exercise workload in kpm/min; 150 kpm/min is equivalent to 25 watts. (From Kitzman et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17:1065–1067.)
influence. Further, the time constant of isovolumic pressure decline (τ) can be estimated noninvasively by measuring the early diastolic velocity of the mitral annulus (E′).18 In addition, the ratio of early LV diastolic filling velocity (E) to E′ correlates well with invasively measured LV end diastolic pressures.19 Notably, an increased E/E′ ratio at rest has been correlated with maximal and submaximal exercise intolerance.20,21
Moreover, an increase in E/E′ during exercise correlates with exercise intolerance.22 M-mode color Doppler has been used to noninvasively estimate the intraventricular pressure gradient (IVPG) from the left atrium to the left ventricle, a correlate of τ and an analogue of ventricular “suction.” Changes in the IVPG from rest to peak exercise are powerful independent predictors of maximal exercise tolerance in patients with heart failure and systolic dysfunction.23 These eloquent noninvasively obtained data confirm findings from invasive studies and show that individuals with heart failure as a group have increased LV filling pressures at rest and during exercise associated with impaired diastolic function and that impaired myocardial relaxation is associated with reduced diastolic suction during exercise. It is instructive to compare and contrast the exercise cardiovascular responses in the two different groups of heart failure patients described: those with normal EFs10 and those with reduced EFs.8,10,11 Both heart failure patient groups have severe exertional symptoms and objective evidence of exercise intolerance, as well as markedly reduced peak cardiac output and stroke volume, mildly reduced peak heart rate, and slightly reduced peak A-V O2 difference (Fig. 17-7). In addition, both groups had mildly elevated resting and markedly elevated exercise mean PCWPs. However, the mechanisms by which LV stroke volume was reduced differed markedly between the two groups. In one group,8,11 patients had profound systolic contractile dysfunction and were able to utilize markedly increased LV filling pressure to produce greater than normal use of the Frank-Starling mechanism to partially compensate and maintain some increase in exercise stroke volume. In the other group, despite normal systolic contractile function,10 patients were unable to use the FrankStarling mechanism to increase stroke volume during exercise and had markedly increased LV filling pressure. These data highlight the pivotal influence of the end diastolic pressure-volume response during exercise in healthy subjects and in patients with heart failure (see Fig. 17-7).24
207
208
Chapter 17 • Exercise Intolerance in Diastolic Heart Failure CENTRAL HEMODYNAMIC RESPONSE TO UPRIGHT BICYCLE EXERCISE IN SHF vs. DHF COMPARED WITH NORMALS SHF (EF 30%) Sullivan 1989, Higginbotham 1987 • RER 1.18 • Peak VO2 ↓ 50% • CO ↓ 40% • A-V O2 diff ↓ 12% • SV ↓ 30% • Heart rate ↓ 13% • Upright resting PCWP ↑ at 9 mmHg (normal = 3) • Peak PCWP ↑ 27 mmHg (nl = 12) • Unable to decrease ESV (↑ contractility) during exercise
DHF (EF 56%) Kitzman 1991 • RER 1.24 • Peak VO2 ↓ 48% • CO ↓ 41% • A-V O2 diff ↓ 13% • SV ↓ 26% • HR ↓ 18% • Upright resting PCWP ↑ at 9 mmHg (normal = 3) • Peak PCWP ↑ at 25 mmHg (nl = 12) • Unable to increase EDV (↑ diastolic filling) during exercise
Group
Young Normal
Old Normal
Elderly Diastolic HF
VO2 Max (ml/kg/min)
28.6
22.6
12.7
Aortic distensibility (10–3 mmHg)–1
9.1
4.7
0.2
Ascending aortic wall thickness (mm)
2.1
2.2
Arterial Compliance Abnormal afterload and abnormal ventricular-vascular coupling are prime candidates to be responsible for the abnormal FrankStarling response seen in patients with DHF. Nearly all (88%) of such patients have a history of chronic systemic hypertension.25–27 In animal models, diastolic dysfunction develops early in systemic hypertension, and LV diastolic relaxation is very sensitive to increased afterload.28–33 Increased afterload may impair relaxation, leading to increased LV filling pressures, decreased stroke volume, and subsequently in patients, symptoms of dyspnea and congestion.1,2,31 From studies in animal models and humans it is known that chronic systolic hypertension accelerates and magnifies the agerelated increase in fibrotic thickening of the aortic wall and the resultant increase in aortic stiffness, which in turn is a major determinant of LV afterload and ventricular-vascular coupling.34,35 In order to test the hypothesis that abnormally decreased aortic distensibility contributes to the severe exercise intolerance in heart failure with normal EF, we performed magnetic resonance imaging and maximal exercise testing with expired gas analysis in a group of elderly patients with so-called isolated DHF, as previ-
3.3
Figure 17-7 Comparison of characteristic central and peripheral cardiovascular response to exercise in patients with heart failure associated with severe LV systolic dysfunction versus normal LV ejection fraction. RER, respiratory exchange ratio.
Figure 17-8 MRI data and images from representative subjects from healthy young, healthy elderly, and elderly patients with diastolic heart failure (HF). Maximal exercise oxygen consumption (VO2 max), aortic distensibility at rest, and left ventricular mass/volume ratio. Patients with diastolic heart failure have severely reduced exercise tolerance (VO2 max) and aortic distensibility and increased aortic wall thickness. (Modified from Hundley et al: Cardiac cycle dependent changes in aortic area and aortic distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796–802.)
ously defined (in the section “Pathophysiology of Exercise Intolerance”). Young healthy subjects and age-matched healthy subjects were studied as healthy normal controls. The patients with DHF had severe exercise intolerance that was associated with increased pulse pressure and concentric hypertrophic LV remodeling. Thoracic aortic wall thickness was increased 50%, and there was markedly decreased aortic distensibility (Fig. 17-8). In univariate analysis, decreased aortic distensibility correlated closely with patients’ severely decreased peak exercise VO2 (Fig. 17-9).36 In multivariate analysis, decreased aortic distensibility was the strongest independent predictor of reduced exercise capacity. These data support a potentially important role of increased aortic stiffness, due to underlying aging and amplified by chronic hypertension, in the pathophysiology of chronic heart failure symptoms.37
Chronotropic Response In addition to reduced stroke volume, decreased heart rate response can also contribute to reduced peak exercise cardiac output and thence reduced peak exercise VO2. Indeed, chrono-
Chapter 17 • Exercise Intolerance in Diastolic Heart Failure
209
Figure 17-9 There is a close relationship between peak exercise VO2 (horizontal axis) and proximal aortic distensibility (vertical axis) in a group of 30 subjects (10 healthy young, 10 healthy old, and 10 elderly DHF patients). Each symbol represents the data from one participant. (From Hundley et al: Cardiac cycle dependent changes in aortic area and aortic distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796–802.)
10 9.5 9 8.5 8 7.5 7 6.5 6 5.5 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0
tropic incompetence has been a frequent finding during cardiopulmonary exercise studies in SHF. However, few if any data had been available in older patients and particularly those with normal EFs. Accordingly, we examined heart rate and expired gas analysis responses in elderly patients with DHF in comparison with a group of age- and gender-matched patients with SHF and healthy normal controls. Using the most standard definition of chronotropic incompetence, we found that it was present in 20% to 25% of older heart failure patients, that the prevalence was similar in DHF compared with SHF, that the presence of chronotropic incompetence was a significant contributor to the degree of exercise intolerance, measured as maximal VO2, and that this was independent of medications, including beta-adrenergic antagonists.38 The important contribution of chronotropic incompetence to exercise intolerance in patients with DHF was confirmed by Borlaug et al., who studied a cohort of primarily elderly, African American women with hypertension and heart failure with a preserved EF. The researchers reported significant reductions in heart rate increase during exercise, which was a primary contributor to reduced peak cardiac output and maximal exercise VO2 (Fig. 17-10).39 Despite the many physiological exercise studies that have been performed with heart failure patients, there has remained uncertainty regarding the final stimulus that causes heart failure patients to stop exercising at lower workloads than healthy subjects.40,41 It has been thought that increased exercise pulmonary wedge pressure and stimulation of pulmonary J-receptors cause reflex hyperventilation and hypoxia, leading to the sensation of severe dyspnea, causing the patient to stop exercise prematurely. However, about 50% of patients with heart failure, whether systolic or diastolic, discontinue exercise, due primarily to general fatigue or leg fatigue rather than dyspnea. In addition, investigators15,42 have demonstrated that arterial hypoxia does not occur
y = 0.0002x − 0.0021, r = 0.665
0
10
30
20
40
Peak VO2 (ml/kg/min)
HEART RATE ACCELERATION 110 p = 0.02 100 Beats per minute
Aortic distensibility (10 –3 mmHG–1)
RELATIONSHIP OF AORTIC DISTENSIBILITY WITH EXERCISE CAPACITY
Con
90 HFpEF 80
70
60 0
30
60
90
Seconds Figure 17-10 Chronotropic incompetence during exercise. Blunted increase in heart rate during exercise in 7 patients with heart failure and preserved ejection fraction >50% (HFpEF) compared with 14 matched control subjects. (From Borlaug BA et al: Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 2006;114:2138–2147.)
during exercise in patients with heart failure and that excess ventilation is related to pulmonary hypoperfusion and reduced cardiac output rather than elevated LV filling pressures. The decreased exercise cardiac output likely causes skeletal muscle hypoperfusion, a potent stimulus for early anaerobic metabolism, and subsequent generation of muscle lactate and other metabolites, which could produce the sensation of peripheral and central fatigue.43,44
210
Chapter 17 • Exercise Intolerance in Diastolic Heart Failure In a randomized, crossover, blinded trial, Little et al. compared the calcium channel antagonist verapamil with the angiotensin receptor antagonist candesartan with the outcomes of peak exercise blood pressure, exercise time, and quality of life.62 While both agents blunted the peak systolic blood pressure response to exercise, only candesartan, and not verapamil, improved exercise time and quality of life (Fig. 17-12).62 In a subsequent trial with similar randomized, crossover, blinded design, the diuretic hydrochlorothiazide was compared with the angiotensin receptor antagonist losartan on the outcomes of peak exercise blood pressure, exercise time, and quality of life.63 While both agents blunted the peak systolic blood pressure response to exercise, only losartan, not hydrochlorothiazide, improved exercise time and quality of life.63
CLINICAL RELEVANCE: INTERVENTIONS TO IMPROVE EXERCISE TOLERANCE Angiotensin Receptor Blockers Pulse pressure can provide a crude estimate of the stiffness of the central large arteries, and its major determinant is systolic blood pressure.45 During exercise in normal subjects, systolic and pulse pressures increase substantially, and this response is magnified by increased arterial stiffness. Data from animal models suggest that the exercise-related increase in systolic blood pressure is mediated in part by exercise-induced increases in circulating angiotensin II. Indeed, in a randomized, double-blind, placebocontrolled crossover trial, angiotensin receptor blockade reduced the exaggerated exercise increase in systolic and pulse pressures, resulting in significantly improved exercise treadmill time and quality of life (Fig. 17-11).46 Aronow et al. showed in a group of patients with NYHA class III heart failure and presumed diastolic dysfunction (EF >50%) that the angiotensin converting enzyme (ACE) inhibitor enalapril significantly improved functional class, exercise duration, EF, diastolic filling, and LV mass.47
Aldosterone Inhibitors The addition of low-dose spironolactone (12.5–50.0 mg daily) to standard therapy has been shown to improve exercise tolerance in patients with severe SHF. Aldosterone antagonism has numerous potential benefits in patients with DHF, including LV remodeling, reversal of myocardial fibrosis, and improved LV diastolic and vascular function.64–66 However, few data are presently available regarding aldosterone antagonism in DHF. In one small study, low-dose spironolactone was well tolerated and appeared to improve exercise capacity and quality of life in older women with isolated DHF.67 In another, spironolactone improved measures of myocardial function in hypertensive patients with DHF.68
Calcium Channel Blockers In hypertrophic cardiomyopathy, a disorder in which diastolic dysfunction is common, verapamil appears to improve symptoms and objectively measured exercise capacity.48–51 This agent also improves ventricular-vascular coupling and exercise performance in aged individuals with hypertension.52 In laboratory animal models, calcium antagonists, particularly dihydropyridines, prevent ischemia-induced increases in LV diastolic stiffness53 and improve diastolic performance in pacing-induced heart failure.54–56 However, negative inotropic calcium antagonists significantly impair early relaxation56–60 and have in general shown a tendency toward adverse outcome in patients with SHF.56 Setaro et al. examined 22 men (mean age 65) with clinical heart failure despite an EF greater than 45% in a randomized, doubleblind, placebo-controlled crossover trial of verapamil.61 There was a 33% improvement in exercise time and significant improvements in clinico-radiographic heart failure scoring and peak filling rate.
PEAK SYSTOLIC BP DURING EXERCISE
Glucose Cross-Link Breakers Glucose cross-links increase with aging and presence of diabetes, and they cause increased vascular and myocardial stiffness. Alagebrium, a novel cross-link breaker, improved vascular and LV stiffness in dogs. In a small, open-label, 4-month trial of this agent in elderly patients, LV mass, quality of life, and tissue Doppler diastolic function indices improved, but there were no significant improvements in exercise capacity or aortic distensibility, the primary outcomes of the trial.69 A variety of other agents and strategies are currently being evaluated or are under consideration for this syndrome, including a selective endothelin antagonist.
EXERCISE TIME
300 18 16 250
Exercise time (min)
Peak systolic BP (mmHg)
275
225 200 175 150 125
p = ns p<0.05 p<0.05 Baseline
Placebo
Losartan
14 12 10 8 6
p = ns
p<0.05 p<0.05
4 Baseline
Placebo
Losartan
Figure 17-11 Plots of peak systolic blood pressure and exercise duration during baseline, during placebo, and during losartan therapy in a randomized, controlled, crossover trial. Treatment with the angiotensin II antagonist losartan increased exercise time. (From Warner et al: Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999;33:1567–1572.)
Chapter 17 • Exercise Intolerance in Diastolic Heart Failure 40
300 200 100 0 –100
p<0.05
Control
Candesartan
30 20 10 0 –10 –20 –30 –40 p<0.05
p = ns
–200
A
Change in quality of life score (# of symptoms)
Change in exercise time (sec)
400
–50 Verapamil
B
p = ns
Control
Candesartan
Verapamil
Figure 17-12 Effect of candesartan angiotensin receptor antagonist compared with verapamil calcium channel blocker on A, exercise time and B, quality of life in patients with diastolic dysfunction. From survival of patients admitted with congestive heart failure by ejection fraction. (From Little WC et al: Effect of candesartan and veramapil on exercise tolerance in diastolic dysfunction. J Cardiovasc Pharmacol 2004;43:288–293.)
Pacemaker Therapy The substantial chronotropic incompetence seen in DHF and its correlation with reduced exercise capacity we have described provide a rationale for electronic pacing interventions to improve exercise capacity. Indeed, one modest-sized single-center study used such a strategy in selected patients with hypertensive LV hypertrophy with supranormal systolic ejection and distal cavity obliteration who had debilitating exertional fatigue and dyspnea and demonstrated substantially improved exercise performance.70 These data merit confirmation in larger, multicenter, randomized, controlled trials. Thus, a variety of pharmacological and other interventions in small studies have shown improvements in exercise tolerance with verapamil,61 enalapril,47 angiotensin receptor antagonism,46,62 and aldosterone antagonism.67 It should be remembered that in patients with SHF, some types of pharmacological interventions that improve exercise tolerance have had paradoxical effects on long-term survival.71,72 Because of this, the VE/VCO2 slope during exercise, which is a powerful predictor of survival independent of VO2, should be included in future intervention trials of exercise tolerance.6
Exercise Training Aerobic exercise training has the potential to improve a variety of key abnormalities in patients with heart failure and normal EF, including LV diastolic compliance, aortic distensibility, blood pressure, and skeletal muscle function.73–75 Indeed, in SHF, aerobic exercise training has been shown to improve exercise tolerance, likely via favorable effects on multiple factors.12,76,77 A recent report indicates that LV diastolic compliance is preserved in older master athletes compared with their age-matched and young counterparts, suggesting that exercise training may be beneficial in DHF as well.78 A preliminary report indicates that exercise training improves exercise tolerance and quality of life in older patients with heart failure and normal EF.79 Although the role of exercise training in the clinical management of this syndrome remains to be defined, as is the accepted practice in SHF, it would seem prudent to recommend regular, moderate physical activity as tolerated. The effect of exercise training on survival in patients with SHF is being examined in a
large, multicenter, randomized, controlled trial (HF-ACTION) sponsored by the U.S. National Institutes of Health. Presently, there is no trial examining this issue in patients with heart failure and normal EF.
FUTURE RESEARCH Patients with heart failure and normal EF have severe, chronic exercise intolerance. The pathophysiology of exercise intolerance in this syndrome is incompletely understood, but as in SHF, it is likely multifactorial. Current data suggest that important contributors include decreased LV diastolic compliance, decreased aortic distensibility, exaggerated exercise systolic blood pressure, relative chronotropic incompetence, and possibly anemia and skeletal muscle remodeling. Exercise intolerance is an attractive therapeutic target because it is a primary determinant of quality of life, can be quantified objectively, is reproducible, and is modifiable. Based on lengthy experience seeking to understand exercise intolerance in patients with SHF, it is likely that several factors in addition to those discussed in this chapter may contribute to exercise intolerance in patients with DHF, including chronotropic incompetence, abnormal peripheral arterial vasodilation, anemia, and skeletal muscle bulk, fiber type, and function.11,80–88 This will likely be a fruitful area for future research. A number of pharmacological and other interventions appear to improve exercise intolerance in DHF. Although it is unknown whether these will be accompanied by improved survival, the concomitant findings of improved quality of life confirm the clinical relevance of exercise performance outcomes.
ACKNOWLEDGMENTS This work was supported in part by NIH R37 AG18915. REFERENCES 1. Gandhi SK, Powers JE, Fowle KM, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2000;344:17–22. 2. Powers JE, Gandhi SK, Kramer RK, et al: Predictors of poor outcome in patients with hypertensive pulmonary edema. J Am Coll Cardiol 2004;43: 227A.
211
212
Chapter 17 • Exercise Intolerance in Diastolic Heart Failure 3. Kitzman DW, Little WC, Brubaker PH, et al: Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–2150. 4. Bol E, de Vries WR, Mosterd WL, et al: Cardiopulmonary exercise parameters in relation to all-cause mortality in patients with chronic heart failure. Int J Cardiol 2000;72:255–263. 5. Jones RC, Francis GS, Lauer MS: Predictors of mortality in patients with heart failure and preserved systolic function in the Digitalis Investigation Group trial. J Am Coll Cardiol 2004;44:1025–1029. 6. Francis DP, Shamin W, Davies LC, et al: Cardiopulmonary exercise testing for prognosis in chronic heart failure: Continuous and independent prognostic value from VE/VCO2 slope and peak VO2. Eur Heart J 2000;21: 154–161. 7. Higginbotham MB, Morris KG, Williams RS, et al: Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res 1986;58:281–291. 8. Kitzman DW, Sullivan M, Cobb FR, Higginbotham MB: Exercise cardiac output declines with advancing age in normal subjects. J Am Coll Cardiol 1989;13:241A. 9. Higginbotham MB, Morris KG, Williams RS, et al: Physiologic basis for the age-related decline in aerobic work capacity. Am J Cardiol 1986;57: 1374–1379. 10. Kitzman DW, Higginbotham MB, Cobb FR, et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17: 1065–1072. 11. Sullivan M, Knight JD, Higginbotham MB, Cobb FR: Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure: Muscle blood flow is reduced with maintenance of arterial perfusion pressure. Circulation 1989;80:769–781. 12. Sullivan M, Higginbotham MB, Cobb FR: Exercise training in patients with chronic heart failure delays ventilatory anaerobic threshold and improves submaximal exercise performance. Circulation 1989;79:324–329. 13. Higginbotham MB, Sullivan M, Coleman RE, Cobb FR: Regulation of stroke volume during exercise in patients with severe left ventricular dysfunction: Importance of Starling mechanism. J Am Coll Cardiol 1987;9:58A. 14. Sullivan M, Cobb FR, Knight JD, Higginbotham MB: Stroke volume increases by similar mechanisms in men and women. Am J Cardiol 1991;67:1405–1412. 15. Sullivan M, Higginbotham MB, Cobb FR: Increased exercise ventilation in patients with chronic heart failure: Intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation 1988;77:552– 559. 16. Shen WF, Roubin GS, Hirasawa K, et al: Left ventricular volume and ejection fraction response to exercise in chronic congestive heart failure: Difference between dilated cardiomyopathy and previous myocardial infarction. Am J Cardiol 1985;55:1027–1031. 17. Sullivan M, Cobb FR: Central hemodynamic response to exercise in patients with chronic heart failure. Chest 1992;101:340S–346S. 18. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527–1533. 19. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. 20. Hadano Y, Murata K, Yamamoto T, et al: Usefulness of mitral annular velocity in predicting exercise tolerance in patients with impaired left ventricular systolic function. Am J Cardiol 2006;97:1025–1028. 21. Skaluba SJ, Litwin SE: Mechanisms of exercise intolerance: Insights from tissue Doppler imaging. Circulation 2004;109:972–977. 22. Ha JW, Oh JK, Pellikka PA, et al: Diastolic stress echocardiography: A novel noninvasive diagnostic test for diastolic dysfunction using supine bicycle exercise Doppler echocardiography. J Am Soc Echocardiogr 2005;18: 63–68. 23. Rovner A, Greenberg NL, Thomas JD, Garcia MJ: Relationship of diastolic intraventricular pressure gradients and aerobic capacity in patients with diastolic heart failure. Am J Physiol Heart Circ Physiol 2005;289(5): H2081–H2088. 24. Kitzman DW, Sullivan M: Exercise intolerance in patients with heart failure: Role of diastolic dysfunction. In Lorell BH, Grossman W (eds): Diastolic Relaxation of the Heart. Boston, Kluwer Academic, 1994: 295–302. 25. Kitzman DW, Gardin JM, Gottdiener JS, et al: Importance of heart failure with preserved systolic function in patients > or = 65 years of age. CHS
26. 27. 28. 29. 30.
31. 32. 33. 34. 35. 36.
37.
38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51.
Research Group. Cardiovascular Health Study. Am J Cardiol 2001;87: 413–419. Iriarte M, Murga N, Morillas M, et al: Congestive heart failure from left ventricular diastolic dysfunction in systemic hypertension. Am J Cardiol 1993;71:308–312. Iriarte MM, Perez OJ, Sagastagoitia D, et al: Congestive heart failure due to hypertensive ventricular diastolic dysfunction. Am J Cardiol 1995;76: 43D–47D. Little WC: Enhanced load dependence of relaxation in heart failure: Clinical implications. Circulation 1992;85:2326–2328. Gelpi RJ: Changes in diastolic cardiac function in developing and stable perinephritic hypertension in conscious dogs. Circ Res 1991;68:555–567. Shannon RP, Komamura K, Gelpi RJ, Vatner SF: Altered load: An important component of impaired diastolic function in hypertension and heart failure. In Lorell BH, Grossman W (eds): Diastolic Relaxation of the Heart. Boston, Kluwer Academic, 1994:177–185. Little WC, Braunwald E: Assessment of cardiac performance. In Braunwald E (ed): Heart Disease. Philadelphia, WB Saunders, 1999. Hoit BD, Walsh RA: Diastolic dysfunction in hypertensive heart disease. In Gaasch WH, LeWinter MM (eds): Left Ventricular Diastolic Dysfunction and Heart Failure. Philadelphia, Lea & Febiger, 1994:354–372. Little WC, Ohno M, Kitzman DW, et al: Determination of left ventricular chamber stiffness from the time for deceleration of early left ventricular filling. Circulation 1995;92:1933–1939. Lakatta E: Cardiovascular aging research: The next horizons. J Am Geriatr Soc 1999;47:613–625. Lakatta EG, Levy D: Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises. Part I: Aging arteries: A “set up” for vascular disease. Circulation 2003;107:139–146. Hundley WG, Kitzman DW, Morgan TM, et al: Cardiac cycle dependent changes in aortic area and aortic distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796–802. Rerkpattanapipat P, Hundley WG, Link KM, et al: Relation of aortic distensibility determined by magnetic resonance imaging in patients = 60 years of age to systolic heart failure and exercise capacity. Am J Cardiol 2002;90: 1221–1225. Brubaker PH, Joo KC, Stewart KP, et al: Chronotropic incompetence and its contribution to exercise intolerance in older heart failure patients. J Cardiopulm Rehabil 2006;26:86–89. Borlaug BA, Melenovsky V, Russell SD, et al: Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 2006;114:2138–2147. Myers J, Froelicher V: Hemodynamic determinants of exercise capacity in chronic heart failure. Ann Intern Med 1991;115:377–386. Franciosa JA: Role of ventricular function in determining exercise capacity in patients with chronic left ventricular failure. Adv Cardiol 1986;34: 170–8:170–178. Fink LI, Wilson JR, Ferraro N: Exercise ventilation and pulmonary artery wedge pressure in chronic stable congestive heart failure. Am J Cardiol 1966;57:249–253. Sullivan M, Cobb FR: The anaerobic threshold in chronic heart failure. Circulation 1990;81:II-47–II-58. Green HJ: Manifestations and sites of neuromuscular fatigue. Biochem Exercise 1990;VII:13–35. Deedwania PC, Gottlieb S, Ghali JK, et al: Efficacy, safety and tolerability of beta-adrenergic blockade with metoprolol CR/XL in elderly patients with heart failure. Eur Heart J 2004;25:1300–1309. Hornig B, Maier V, Drexler H: Physical training improves endothelial function in patients with chronic heart failure. Circulation 1996;93:210–214. Sanders P, Kistler PM, Morton JB, et al: Remodeling of sinus node function in patients with congestive heart failure: Reduction in sinus node reserve. Circulation 2004;110:897–903. Nagaya N, Moriya J, Yasumura Y, et al: Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation 2004;110:3674–3679. Sullivan JJ, Green HJ, Cobb FR: Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 1990;81: 518–527. Adamopoulos S, Coats A, Brunotte F, et al: Physical training improves skeletal muscle metabolism in patients with chronic heart failure. J Am Coll Cardiol 1993;21:1101–1106. Stratton J, Dunn JF, Adamopoulos S, et al: Training partially reverses skeletal muscle metabolic abnormalities during exercise in heart failure. J Appl Physiol 1994;76:1575–1582.
Chapter 17 • Exercise Intolerance in Diastolic Heart Failure 52. Kouba EJ, Hundley WG, Brubaker PH, et al: Skeletal muscle remodeling and exercise intolerance in elderly patients with diastolic heart failure. Am J Geriatr Cardiol 2003;12:135. 53. Felker GM, Adams KF Jr, Gattis WA, O’Connor CM: Anemia as a risk factor and therapeutic target in heart failure. J Am Coll Cardiol 2004; 44:959–966. 54. Chae CU, Pfeffer MA, Glynn RJ, et al: Increased pulse pressure and risk of heart failure in the elderly. JAMA 1999;281:634–639. 55. Warner JG, Metzger C, Kitzman DW, et al: Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999;33:1567–1572. 56. Aronow WS, Kronzon I: Effect of enalapril on congestive heart failure treated with diuretics in elderly patients with prior myocardial infarction and normal left ventricular ejection fraction. Am J Cardiol 1993;71: 602–604. 57. Vandenberg VF, Rath LS, Stuhlmuller P, et al: Estimation of left ventricular cavity area with on-line, semiautomated echocardiographic edge detection system. Circulation 1992;86:159–166. 58. Bonow RO, Leon MB, Rosing DR, et al: Effects of verapamil and propranolol on left ventricular systolic function and diastolic filling in patients with coronary artery disease: Radionuclide angiographic studies at rest and during exercise. Circulation 1981;65:1337–1350. 59. Bonow RO, Dilsizian V, Rosing DR, et al: Verapamil-induced improvement in left ventricular diastolic filling and increased exercise tolerance in patients with hypertrophic cardiomyopathy: Short- and long-term effects. Circulation 1985;72:853–864. 60. Udelson J, Bonow RO: Left ventricular diastolic function and calcium channel blockers in hypertrophic cardiomyopathy. In Gaasch WH (ed): Left Ventricular Diastolic Dysfunction and Heart Failure. Philadelphia, Lea & Febiger, 1996:465–489. 61. Chen CH, Nakayama M, Talbot M, et al: Verapamil acutely reduces ventricular-vascular stiffening and improves aerobic exercise performance in elderly individuals. J Am Coll Cardiol 1999;33:1602–1609. 62. Serizawa T, Shin-Ichi M, Nagai Y, et al: Diastolic abnormalities in low-flow and pacing tachycardia-induced ischemia in isolated rat hearts—modification by calcium antagonists. In Lorell BH, Grossman W (eds): Diastolic Relaxation of the Heart. Boston, Kluwer Academic, 1996:266–274. 63. Cheng CP, Pettersson K, Little WC: Effects of felodipine on left ventricular systolic and diastolic performance in congestive heart failure. J Pharma and Exper Thera 1994;271:1409–1417. 64. Cheng CP, Noda T, Ohno M, Little WC: Differential effects of enalaprilat and felodipine on diastolic function during exercise in dogs with congestive heart failure. Circulation 1993;88:I-294. 65. Little WC, Cheng CP, Elvelin L, Nordlander M: Vascular selective calcium entry blockers in the treatment of cardiovascular disorders: Focus on felodipine. Cardiovasc Drugs Ther 1995;9:657–663. 66. Ten Cate FJ, Serruys PW, Mey S, Roelandt JR: Effects of short-term administration of verapamil on left ventricular filling dynamics measured by a combined hemodynamic-ultrasonic technique in patients with hypertrophic cardiomyopathy. Circulation 1983;68:1274–1279. 67. Hess OM, Murakami T, Krayenbuehl HP: Does verapamil improve left ventricular relaxation in patients with myocardial hypertrophy? Circulation 1996;74:530–543. 68. Brutsaert DL, Rademakers F, Sys SU, et al: Analysis of relaxation in the evaluation of ventricular function of the heart. Prog Cardiovasc Dis 1985;28:143–163. 69. Brutsaert DL, Sys SU, Gillebert TC: Diastolic failure: Pathophysiology and therapeutic implications. J Am Coll Cardiol 1993;22:318–325.
70. Setaro JF, Zaret BL, Schulman DS, Black HR: Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance. Am J Cardiol 1990;66:981–986. 71. Little WC, Wesley-Farrington DJ, Hoyle J, et al: Effect of candesartan and verapamil on exercise tolerance in diastolic dysfunction. J Cardiovasc Pharmacol 2004;43:288–293. 72. Little WC, Zile MR, Klein AL, et al: Effect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and diastolic dysfunction. Am J Cardiol 2006;98:383–385. 73. Pitt B, Reichek N, Willenbrock R, et al: Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: The 4E–left ventricular hypertrophy study. Circulation 2003;108:1831–1838. 74. Rajagopalan S, Pitt B: Aldosterone as a target in congestive heart failure. Med Clin North Am 2003;87:441–457. 75. Zannad F, Alla F, Dousset B, et al: Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: Insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation 2000;102:2700–2706. 76. Daniel KR, Wells GL, Fray B, et al: The effect of spironolactone on exercise tolerance and quality of life in elderly women with diastolic heart failure. Am J Geriatr Cardiol 2003;12:131. 77. Mottram PM, Haluska B, Leano R, et al: Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 2004;110:558–565. 78. Little WC, Zile MR, Kitzman DW, et al: The effect of alagebrium chloride (ALT–711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail 2005;11:191–195. 79. Kass DA, Chen CH, Talbot MW, et al: Ventricular pacing with premature excitation for treatment of hypertensive-cardiac hypertrophy with cavityobliteration. Circulation 1999;100:807–812. 80. Packer M, Carver JR, Chesebro J, et al: Effect of oral milrinone on mortality in severe chronic heart failure: The Prospective Randomized Milrinone Survival Evaluation (PROMISE). N Engl J Med 1991;325:1468–1475. 81. Creager MA, Massie BM, Faxon DP, et al: Acute and long-term effects of enalapril on the cardiovascular response to exercise and exercise tolerance in patients with congestive heart failure. J Am Coll Cardiol 1985;6:163–173. 82. Peters DG, Mitchell HL, McCune SA, et al: Skeletal muscle sarcoplasmic reticulum Ca(2+)-ATPase gene expression in congestive heart failure. Circ Res 1997;81:703–710. 83. Sullivan M: Role of exercise conditioning in patients with severe systolic left ventricular dysfunction. In Fletcher GF (ed): Cardiovascular Response to Exercise. New York, Futura, 1994:359–372. 84. Vaitkevicius PV, Fleg J, Engel JH, et al: Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation 1993;88:1456–1462. 85. Pina IL, Apstein CS, Balady GJ, et al: Exercise and heart failure: A statement from the American Heart Association committee on exercise, rehabilitation, and prevention. Circulation 2003;107:1210–1225. 86. Coats A, Adamopoulos S, Radaelli A, et al: Controlled trial of physical training in chronic heart failure. Circulation 1992;85:2119–2131. 87. Arbab-Zadeh A, Dijk E, Prasad A, et al: Effect of aging and physical activity on left ventricular compliance. Circulation 2004;110:1799–1805. 88. Kitzman DW, Brubaker PH, Abdelahmed A, Stewart KP: Effect of exercise training on exercise capacity, quality of life, and flow-mediated arterial dilation in elderly patients with diastolic heart failure. J Am Coll Cardiol 2004;110:III-558.
213
ANNITTA J. MOREHEAD, BA, RDCS
18
Sonographer’s Perspective of Evaluating Diastolic Function INTRODUCTION TECHNIQUE OF PERFORMING A DIASTOLIC ECHOCARDIOGRAPHIC DOPPLER EXAMINATION Atrial Chamber Size Left Ventricular Inflow Isovolumic Relaxation Time Pulmonary Venous Flow Color M-Mode Evaluation of Left Ventricular Inflow Tissue Doppler Imaging Right Ventricular Inflow Hepatic Veins Inferior Vena Cava
Superior Vena Cava Sonographic Approach to Imaging Strain, Strain Rate, and Torsion TOOLS USED TO ASSIST THE SONOGRAPHER IN GAINING ADDITIONAL INFORMATION Respirometer Doppler Enhanced Contrast Echocardiography Maneuvers SUMMARY AND FUTURE DIRECTIONS ABBREVIATIONS
INTRODUCTION Heart failure, a common ailment in older adults, is a major public health epidemic in the United States1–3 that affected 5.2 million people in 2006.4 Diagnosis of systolic heart failure with a reduced ejection fraction is well documented, while diastolic heart failure in the presence of a normal ejection fraction is less understood.5–8 The cardiac sonographer plays a crucial role in the evaluation process of patients with both systolic and diastolic heart disease. There is truly an art to collecting accurate and reproducible imaging data in the evaluation of these patients. One must possess high technical competence, sufficient knowledge of left ventricular (LV) filling mechanics, and a thorough understanding of Doppler principles in order to obtain high-quality flow velocity data that are required for obtaining an accurate and reproducible diastolic function examination. Echocardiographic diastolic function information, when collected correctly, can yield meaningful results that will help guide patient management.9–15 Sonographers should
routinely perform a diastolic examination on all patients to perfect their imaging skills and establish a consistent examination protocol. A comprehensive and systematic approach to performing a diastolic examination is outlined in this chapter and involves the use of echocardiographic tools, such as M-mode, twodimensional echo, conventional Doppler, and tissue Doppler. A skilled sonographer must be proficient in these techniques and be able to recognize common pitfalls. When armed with this knowledge, the sonographer plays an important role in the noninvasive assessment of diastolic function. A diastolic echocardiographic evaluation begins with a careful review of the patient’s medical chart. Diastolic dysfunction is associated with a wide array of common clinical presentations and related diseases. Common clinical presentations and related disorders should alert the sonographer that a diastolic echocardiographic examination is indicated. The sonographer should pay close attention to obvious and subtle two-dimensional clues indicating potential diastolic heart disease, such as increased LV wall thickness, left atrial (LA) enlargement, a “ground glass” or 215
216
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function speckled myocardium, a thickened pericardium, and reduced atrioventricular (AV) motion (Table 18-1).
TECHNIQUE OF PERFORMING A DIASTOLIC ECHOCARDIOGRAPHIC DOPPLER EXAMINATION In combination with a standard echocardiographic examination, a diastolic evaluation includes two-dimensional, M-mode, pulsedwave (PW) Doppler, and color Doppler modalities (see Chapter 10).16,17 An attribute of color Doppler is that it can help reduce the length of time needed to perform the examination by aiding the sonographer in locating the center of ventricular inflow, the pulmonary veins, the hepatic vein, and the superior vena cava (SVC). Additionally, color Doppler M-mode (CMM) is a useful tool in displaying a preview of the LV filling pattern. The examination should also include evaluation of chamber size, especially the left atrium and right atrium, LV wall thickness, myocardial tissue characterization (i.e., ground glass appearance), movement of the AV groove from the apical four-chamber view, increased pericardial thickness, and abnormal septal bounce.
lateral mitral annulus. Commence tracing the chamber until reaching the opposite mitral annulus, subsequently closing the area automatically from one annulus to the other. Avoid inclusion of the LA appendage, pulmonary veins, and the mitral tenting area to prevent overestimation of the LA volume measurement (Fig. 18-1).16,18
Left Ventricular Inflow The LV inflow Doppler is probably the most commonly used measurement in the diastolic echo examination because the
Atrial Chamber Size Increased atrial size in a patient without valvular disease or atrial fibrillation may be an indicator of increased LA pressures associated with diastolic dysfunction. A diastolic evaluation should always include an assessment of LA and RA volumes. The sonographer should assess LA size by panning and using slight rotational manipulation of the transducer with biplane images from the apical four-chamber and two-chamber views to “fully open” the LA area. LA volume measurement should be obtained at end systole, when the chamber is at its fullest. The LA volume is planimetered by placing the cursor at either the medial or the
Figure 18-1 Biplane left atrial (LA) area and volume are measured at end ventricular systole (maximum atrial area) from the apical four- and twochamber views. Depicted by arrows, trace from the lateral annulus outlining the atrium to the medial annulus using the automatic tracing feature to “close” the tracing at the annular level. Avoid including the area between the mitral annulus and the closed mitral leaflets as this will falsely increase the atrial measurement. RV, right ventricle; LV, left ventricle; LA, left atrum; RA, right atrium.
TABLE 18-1 STAGES OF DIASTOLIC DYSFUNCTION
NORMAL YOUNG
NORMAL ADULT
STAGE I DELAYED, IMPAIRED, OR ABNORMAL RELAXATION
E/A ratio
1–2
1–2
DT (msec) IVRT (msec) PV S/D ratio MVa / PVa duration PVs2 / PVd ratio AR (cm/sec) CMM (cm/sec) TDI (cm/sec) Anatomic abnormalities
<240 70–90 <1 ≥1
STAGE II PSEUDONORMAL FILLING
STAGE III RESTRICTIVE FILLING
<1.0
1–1.5 (reverses with Valsalva maneuver)
>1.5
150–240 70–90 ≥1 ≥1
≥240 >90 ≥1 ≥1 or <1
150–200 <90 <1 <1
<150 <70 <1 <1
1.5–2.0 (Doppler values similar to stage III except no change with preload reduction maneuvers) <150 <70 <1 <1
≥1 or <1
≥1
>>1
<1
<<1
<<1
<35 >55 >10 None
<35 >55 >8 None
<35 >45 <8 Normal or mildly enlarged LA
≥35 <45 <8 Mild to moderate LA enlargement, LVH, normal or abnormal EF
≥35 <45 <8 Severe LA enlargement, LV systolic dysfunction, MV or TV regurgitation
≥35 <45 <8 Severe LA enlargement, LV systolic dysfunction, MV or TV regurgitation with possible MV systolic regurgitation
STAGE IV IRREVERSIBLE RESTRICTIVE
From Bursi F, Weston SA, Redfield MM: Systolic and diastolic heart failure in the community. JAMA 2006:296;2209–2216. Yamada H, et al: Prevalence of left ventricular diastolic dysfunction by Doppler echocardiography: Clinical application of the Canadian consensus guidelines. J Am Soc Echocardiogr 2002;15:1238–1244. Garcia MJ, et al: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865–875.
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function SV too close to MV annulus
SV too far away from MV tips
LV Figure 18-2 A, Pulsed Doppler sample volume (SV) placed too far away from the mitral valve (MV) leaflet tips (49 cm/ sec) into the left ventricle demonstrating blunted “E” wave velocities with a thick course spectral envelope. B, Pulsed Doppler sample volume placed too close to the mitral annulus (60 cm/sec), resulting in blunted “E” wave velocities with a thick course spectral envelope as well. C, Pulsed wave Doppler sample volume correctly placed at the mitral valve leaflet tips of left ventricular inflow with a Doppler spectral display of 70 cm/sec. Strive for the highest obtainable velocity signals. Note the clean spectral envelope of panel C as compared with panels A and B.
Perfect!
LV
LV
LA
LA
LA
E
E 49 cm/sec
E 60 cm/sec A
70 cm/sec A
A
A
various patterns represent increasing degrees of LV diastolic impairment. LV filling patterns are easily recognized. The sonographer is able to record transmitral velocity using PW Doppler. The routine measurements performed are the early diastolic (E) and atrial contraction (A) peak velocities, as well as early filling deceleration time.17 The sonographer should obtain these by using color Doppler as a guide to align the pulsed Doppler cursor parallel with the center of the LV inflow. Attention must be given to appropriate sizing and placement of the Doppler sample volume box between the tips of the mitral valve in the middle of the color Doppler velocity map. Placing the sample volume box too far into the left ventricle or too close to the mitral annulus will result in underestimated LV inflow Doppler velocities (Fig. 18-2). Using a sample volume box that is too large is likely to produce a coarse velocity profile due to spectral broadening from wall motion artifact, thus yielding an incorrect velocity recording. A low filter setting is required as well to allow the operator to obtain timing information at the zero-velocity baseline. The sonographer should adjust sample volume at 1–2 mm, velocity filter at 200 Hz, sweep speed at 50–100 mm/sec, and optimize the Doppler gain. The sonographer should then measure the peak E- and A-wave velocities, as well as the E-wave deceleration time (Fig. 18-3). To measure mitral A-wave duration, place the sample volume box approximately 5 mm closer to the mitral annulus and collect additional pulsed Doppler waveforms. The same Doppler settings previously described are recommended. The A-wave duration is a measure of time that must be taken from the beginning to the end of the A wave using the leading-edge-to-leadingedge approach (Fig. 18-4).
Isovolumic Relaxation Time Isovolumic relaxation time (IVRT) is a measure of time (in milliseconds) from the onset of the aortic valve closure spike artifact to the onset of the mitral valve opening spike artifact (Figs. 18-5 and 18-6).17 The IVRT is obtained from the apical five-chamber view by aligning the Doppler beam midway between the LV inflow and the LV outflow (see Fig. 18-5). Using PW
B
C
Decel
E A
Figure 18-3 Example of measurement of peak velocities E (early filling) and A (atrial contribution) and E-wave deceleration time from the slope of peak “E” to baseline. Note that deceleration time is measured from peak E wave following the descent to the zero baseline. Be careful not to include signal noise. BPM, beats per minute.
Doppler, the sample volume is adjusted to 3–4 mm and placed midway between the mitral valve leaflet tips and the LV outflow tract until both the aortic valve closure and the mitral valve opening spikes are visualized above and below the zero-Doppler baseline. Alternatively, continuous wave (CW) Doppler may be used if the operator is unable to obtain clear aortic valve closure and mitral valve opening spikes. The velocity filter setting should be adjusted at 200–400 Hz, the chart speed at 100 mm/sec, and Doppler gain optimized. An IVRT interval that is prolonged is representative of impaired relaxation, while an IVRT that is short may be indicative of increased LA pressure.
Pulmonary Venous Flow Pulmonary venous (PV) flow occurs during both systole and diastole, as well as with atrial contraction (see Chapter 10). Systolic PV flow occurs while the mitral valve is closed. Diastolic PV flow occurs while the mitral valve is open. While in the apical
217
218
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function
A E
RV
LV
RA
LA
A Dur
Figure 18-4 Example of measurement of atrial duration (A Dur). Move sample volume approximately 5 mm nearer to the mitral annulus from the peak left ventricular inflow velocities measurements. This technique results in a smaller E wave and a slightly better defined A wave, making clearer visualization of the onset of the A wave and mitral valve closure. Measure the A-wave duration time from these two points.
four-chamber view, one can assess PV flow using PW Doppler. The right upper PV is most frequently visualized and accessible from the transthoracic echo examination.17 Color Doppler should be used as a guide to find the strongest PV flow signal, which has been described as appearing like a candle flame. The sample volume box should be placed approximately 1–2 cm into the pulmonary vein to obtain the purest forward-flow Doppler signal (Fig. 18-7). The sonographer must take care to ensure that the sample volume box is indeed in the pulmonary vein and not in the left atrium or at the junction of the left atrium and the pulmonary vein, or the resulting signal will be contaminated by other blood flow velocities. The Doppler sample volume box should be adjusted to 3–4 mm in size, and the Doppler filter should be set to 200 Hz to allow full visualization of the spectral Doppler signal to the zero baseline. Sweep speed is then adjusted to 50–100 mm/sec. There are several components of the PV Doppler waveform. These components are PVs1, PVs2, PVd, and PVa. PVs1 occurs during early systolic filling and is representative of LA relaxation. PVs2 occurs during late systolic filling and is representative of LA compliance and pressure. PVd occurs during diastolic filling and is representative of LV filling properties. Finally, PVa represents atrial reversal and is representative of flow reversal due to atrial contraction. PVs1 and PVs2 are commonly merged. PVs1 is more likely to be observed with a slower heart rate. The sonographer measures peak PVs1, PVs2, and PVa velocities as well as PVar duration (Fig. 18-8).
Figure 18-5 Place the Doppler cursor between the mitral and aortic valves panning between apical four- and five-chamber views to obtain isovolumic relaxation time. Adjust Doppler filter and gain settings to optimize the aortic valve closure and mitral valve opening spike artifacts.
IVRT 60 MV Flow
40 20 cm/s
AoV Flow
-20 -40 -60 75 BPM
Figure 18-6 Measure isovolumic relaxation time (IVRT) from the end of aortic valve (AoV) closure to the beginning of mitral valve (MV) opening.
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function
Color M-Mode Evaluation of Left Ventricular Inflow As described earlier in this chapter, CMM is a useful tool in that it provides an instant display of the LV filling pattern. CMM can be used to measure the rate of propagation of LV peak filling velocity during early diastole, with representative “E” and “A” CMM propagation signals or waves that represent distance/time (velocity). CMM propagation velocity (Vp) is reduced with impaired LV relaxation and may be used to differentiate restriction from constriction, as well as normal from pseudonormal diastolic function.12,17–19 To obtain a quality CMM examination of LV filling, begin with an apical four-chamber view and avoid foreshortening the apex. Then reduce the two-dimensional depth to approximately 16 cm or at least to a depth that includes the entire left ventricle and a portion of the left atrium. Finally, adjust the color sector to fit over the entire LV chamber, including the mitral valve annulus. Reducing the color sector maximizes the color frame rate and provides a better-quality CMM. Place the CMM cursor through the center of the LV flow, aligned as parallel as possible to the direction of the inflow jet (Fig. 18-9). One of the most common errors in obtaining a CMM is incorrect placement of the cursor. The sonographer should align it with the aliasing color of mitral inflow, being conscientious not to cut off the tips of the E and A waves. Attention to detail will make the difference between accurate and inaccurate waveforms and subsequent measurements.
LV RV
RA LA
Figure 18-7 Pulmonary venous (PV) flow may be visualized using two-dimensional color Doppler guided imaging to depict the “flame” appearance of forward PV flow. The Doppler sample volume is placed approximately 1–2 cm into the right upper pulmonary vein (RUPV).
0.8 S1
LV
S2 0.6
D AR dur
0.4 RV
0.2
[m/s]
-0.2 AR -0.4
0
49 HR
Figure 18-8 Pulsed wave Doppler spectral display of pulmonary vein flow with correct sample volume placement. Clear distinction of pulmonary vein flow systolic (S1, S2), diastolic (D), and atrial reversal (AR) is demonstrated. Measure the peak S, D, and AR velocities as well as the AR duration.
Figure 18-9 Use two-dimensional color Doppler to guide placement for the highest-velocity signals. Place the M-mode cursor in left ventricular (LV) flow propagation, demonstrating appropriate alignment of M-mode cursor.
219
220
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function Keep in mind that the left ventricle fills from the base in a lateral direction as blood flow propagates toward the apex. It is important to avoid crossing the myocardial boundary regions. The sonographer needs to set the color gain just at subsaturation and proceed to CMM display. He or she should adjust the color velocity scale for color aliasing by shifting the baseline up so that it is in the 30–40 cm/sec range, or approximately 70% of the aliasing velocity from the zero baseline (Fig. 18-10).19 The CMM sweep should be recorded at a speed of 100 mm/sec. The goal is to obtain the longest column of color from the base of the mitral annulus to the LV apex with an edge of uniform color during early filling. Measure the Vp slope starting from the aliasing velocity during early filling from the mitral valve plane to 4 cm into the LV cavity as illustrated in Figure 18-11. Ideally five or six high-quality consecutive cardiac cycles should be averaged. Normal CMM has a vertical slope with distinct “E” and “A” waves that resemble conventional PW Doppler E and A waves of ventricular filling.
color two-dimensional—and can be collected from either the longitudinal apical images (to collect annular velocities from the apical four- and two-chamber views with spectral Doppler data) or short-axis images (to collect myocardial Doppler velocities from 2D color) (Fig. 18-12). Color myocardial TDI data can be collected from the apical views as well. A diastolic echocardiographic assessment includes TDI data. The sonographer begins with an apical four-chamber view, initiates TDI mode, and places a 5 mm sample volume on the lateral mitral annulus. This can be repeated at the medial mitral annulus. The right ventricular free wall annulus also can be interrogated using TDI.21 Attention should be given to ensure proper placement of the Doppler sample volume on the annulus, avoiding the basal segments of the ventricular myocardium (Figs. 18-13 and 18-14).
Tissue Doppler Imaging Tissue Doppler imaging (TDI) is a modality that measures myocardial velocity, in contrast to traditional Doppler, which measures blood flow velocity. While in the TDI mode, the ultrasound system is programmed to amplify and display low-velocity signals generated by the myocardium and to filter out higher-velocity signals generated by blood flow. This is the opposite of the traditional use of Doppler imaging to measure blood flow, where lower-velocity signals generated by the myocardium are suppressed and only the high-velocity signals from moving blood are displayed. TDI is a sensitive tool in the assessment of diastolic function in that it can differentiate normal from pseudonormal diastolic dysfunction. TDI spectral waveforms mimic diastolic and systolic patterns of conventional ventricular filling and ventricular outflow pulsed Doppler flow signals in that it includes two diastolic (E′ and A′) peaks and one systolic (S′) peak.17,20,21 TDI can be displayed in the same three formats as conventional Doppler—(1) pulsed (spectral display), (2) CMM, and (3) +58
+42
–58 cm/sec
–68 cm cm/sec
Figure 18-10 Diagram depicting color Doppler baseline before and after adjustment for color M-mode.
Figure 18-11 Example of color M-mode of left ventricular (LV) inflow propagation velocity (Vp). Measure Vp from the intersection of the anterior mitral valve leaflet M-mode extending along the first edge of uniform color or aliasing velocity approximately 4 cm into the left ventricle. Schematic diagram in upper left corner represents color M-mode measurement of LV inflow propagation. E, early LV filling; A, late filling or atrial contribution.
Figure 18-12 Example of tissue Doppler image displayed from the short-axis view used to collect myocardial Doppler velocities from twodimensional color images.
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function
Right Ventricular Inflow PW Doppler assessment of right ventricular (RV) inflow is performed while in the apical four-chamber view to obtain information on RV diastolic function. This is obtained by using color Doppler to find the highest RV inflow velocity (Fig. 18-15). Next, a PW Doppler cursor is aligned parallel with the center of the RV color Doppler inflow. The sonographer may need to move the transducer slightly more medial to obtain correct alignment. The two-dimensional image in this slightly off axis view may not be aesthetically pleasing; however, the Doppler signal will be more accurate. The Doppler cursor must not cross the LV apex, as this will result in a blunted Doppler signal (Fig. 18-16). The sample volume box should be adjusted at 1–2 mm and placed between the tips of the tricuspid valve. The velocity filter is set to approximately 200 Hz, and the Doppler gain optimized to display a clean spectral envelope. Some respiratory variation (up to 15%) is normal and commonly observed in the RV outflow pattern.17 The chart speed is set at 50–100 mm/sec. A biphasic Doppler spectral
display that includes an E and A wave during the diastolic phase should be obtained. The peak E- and A-wave velocities are measured, as well as RV inflow deceleration time (Fig. 18-17). The sonographer should avoid sampling the RV inflow by crossing the LV apex. This will result in unreliable Doppler data (Fig. 18-18).
Hepatic Veins Pulsed Doppler assessment of the hepatic venous (HV) flow is obtained from the short-axis subcostal view. Color Doppler is used to guide the transducer and cursor placement to locate the highest flow velocity (Fig. 18-18A). The sonographer should place the sample volume in the center of the highest flow velocity so that it is parallel with flow and approximately 2–3 cm into the hepatic vein beyond the junction of the inferior vena cava (IVC).
Correct SV placement
LV
RV
RV
LV RV
LV a′
RA
LA e′
A A
B
B
Figure 18-13 Example of tissue Doppler with a 5 mm sample volume (SV) correctly placed at the lateral mitral annulus. Note that early left ventricular (LV) filling is represented by e′ wave and late LV filling or atrial contribution is represented by a′ wave. Measure the peak e′ and a′.
Figure 18-15 A, Correct pulsed wave Doppler cursor and sample volume placement. B, Use of color Doppler guided cursor placement. Note that the cursor crosses the right apex and is parallel with right ventricular inflow and that the sample volume is appropriately placed at the tricuspid valve leaflet tips.
Incorrect SV placement
LV
Figure 18-14 Example of incorrectly placed tissue Doppler sample volume (SV) near the lateral mitral annulus. Note that the SV was placed in the left ventricular (LV) basal lateral wall segment rather than at the lateral mitral annulus. This results in a tissue Doppler velocity signal that is blunted, yielding an inaccurate estimation of tissue velocity.
RA
A
a′ LA
e′
B
221
222
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function 0
SV Angle 0º Dep 9.6 cm Size 1.0 mm Freq 2.0 MHz WF Low Dop 68% Map 3 Prf 2500 Hz
+67.3
5 10 15
-67.3 cm/s
70 60 50 40 30 20 10 cm/s -10 -20 51 BPM
RV E LV A Decel
A
B
Figure 18-16 Example of correct pulsed wave spectral Doppler cursor alignment and correct sample volume placement at the tips of the tricuspid valve leaflets, resulting in the clean “E” and “A” Doppler waveforms.
1.0.65 A
E
The sonographer should adjust the sample volume at 1–3 mm, optimize the Doppler gain, and adjust the sweep speed to 50– 100 cm/sec. The systolic (S) and diastolic (D) filling components, as well as venous reversal (VR) and atrial reversal (AR), are displayed and measured (see Fig. 18-18B). It is common to observe mild respiratory variation in the HV Doppler profile in normal patients.17
Inferior Vena Cava A diastolic echocardiographic examination includes an M-mode interrogation of the IVC to determine its diameter and to rule out plethora. The IVC is generally best visualized while in the short-axis subcostal view. The two-dimensional depth is reduced to improve visualization. The M-mode cursor is placed so that it crosses and is perpendicular to the IVC. Once in M-mode, the gain is optimized and the sweep speed is recorded at 25–50 cm/ sec. Several regular respiratory cycles should be included during M-mode interrogation. The patient is instructed, “Take several quick, short sniffs, as if you have a stuffy nose,” while the sonographer records the IVC diameter via M-mode sweep (Fig. 18-19A). This maneuver allows the sonographer to observe and evaluate the IVC for collapse during quick forceful inspirations. A lack of 50% collapse of the IVC during the “sniff ” test is considered IVC plethora (see Fig. 18-19B).
0.5
LV
RV
[m/s] -0.5
0.0 -0.5
A
-1.0 78 HR
B
Figure 18-17 Incorrect pulsed wave Doppler cursor placement of right ventricular inflow with the Doppler cursor crossing the left ventricular apex, resulting in blunted peak E and A waves.
A
HV
IVC
A
Col 84% Map 1 WF High PRF 4000 Hz Flow Opt: FR 30 20 10 cm/s -10 -20 -30 -40 -50
AR VR
D S
B
Figure 18-18 A, Example of color Doppler guided cursor placement of hepatic vein flow. B, Pulsed wave spectral Doppler of hepatic vein flow demonstrating measurement of peak S (systolic) and D (diastolic) waves, VR (venous reversal), and AR (atrial reversal.)
B Figure 18-19 A, Normal response to the “sniff ” test with M-mode representation of inferior vena cava (IVC) diameter during “sniffing” maneuver. The double arrow illustrates the IVC diameter at end expiration as compared with the change in diameter during the sniff test. The IVC is considered plethoric if during the sniff test it collapses only minimally or does not collapse at all, indicating increased right atrial pressures. B, Abnormal response to the sniff test with M-mode representation of IVC diameter during “sniffing” maneuver. Note minimal or no IVC collapse during the test.
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function
Superior Vena Cava The SVC flow is obtained by positioning the patient flat on his or her back without a pillow for head support. The patient is then asked to extend his or her chin slightly up and to the left. This position helps to better expose the SVC for transducer placement and subsequent Doppler assessment. The transducer is placed in the right supraclavicular fossa (Fig. 18-20A). Using color Doppler as a guide, the sonographer should search for a vertical blue column of color flow, indicating blood flow toward the right atrium via the SVC (see Figs. 18-20B and 18-20C). The PW Doppler cursor is placed in the center of the blue, parallel to the highest flow velocity. The sample volume size is adjusted to 4–5 mm and the sample volume placed at approximately 5–8 cm in depth (close to the junction of the SVC and the right atrium, although well into the SVC). The Doppler filter is set at 200 Hz and the Doppler gain optimized. The sonographer should use a sweep speed of 50–100 cm/sec to collect and measure peak S and D waves, as well as AR (see Fig. 18-20D). As with other right-heart Doppler evaluations, it is common to observe respiratory variation in the SVC Doppler profile.
Sonographic Approach to Imaging Strain, Strain Rate, and Torsion When a stress is imposed on myocardial muscle, it will deform, or change shape and often change volume. Deformation is defined as a change in shape due to an applied force. This can be the result of pulling, pushing, or twisting. The change in shape as a result of imposing a stress is referred to as strain.22,23 Strain in echo Doppler is defined as the change in length of the myocardial fiber. Strain imaging is derived from TDI (one-dimensional strain) or from speckle tracking (two-dimensional strain). Strain occurs in radial and longitudinal directions. The myocardial muscle shortens and thickens during ventricular contraction. Negative strain is demonstrated by myocardial muscle shortening in the circumferential and longitudinal dimensions, and positive strain is demonstrated by thickening or lengthening in the radial direction. Strain imaging is particularly useful to assess geometric changes of LV function. Strain rate is the measure of deformation of myocardial muscle over time.22,23 LV torsion is a measure of energy and is used to
understand the energy expended during the cardiac cycle, in both systolic and diastolic phases. The definition of torsion is to twist or turn. Torsion imaging, also known as torsional deformation, is used to measure the energy expended throughout systole and diastole.24–26 As the ventricles contract and relax, the myocardium thickens and thins in the radial, circumferential, and longitudinal directions. At the same time, the ventricles move in a twisting or coiling (torsion) motion. The respiratory cycle further contributes to cardiac motion by translating the heart in the chest cavity without affecting strain. Strain imaging requires additional skill and understanding of Doppler principles pertinent to optimization of strain Doppler data (Table 18-3). Keep in mind that the heart is moving in multiple directions during the course of the cardiac cycle. Special attention to detail will help avoid collection of inaccurate data. The sonographer can avoid common pitfalls by incorporating technical tips in the strain image examination to improve Doppler data quality.23 One must bear in mind that strain measurement is angle dependent. The sonographer must acquire the data by aligning the LV walls as much as possible along the insonation angle (Fig. 18-21). Sometimes, it is necessary to separately image two opposing LV walls. Finally, one has to take care to maximize the acquisition frame rate: with TDI, one should strive to acquire the data at 60–100 fps. Strain may also be displayed by speckle tracking (see Fig. 18-22), where multiple natural acoustic speckles are automatically tracked in the two-dimensional image.27 Speckle tracking images are not derived from TDI, so images are often easier to acquire because they are not angle dependent. Speckle tracking can be obtained from the basal, mid-, and apical shortaxis levels of the left ventricle, where the resulting 18 segments can be displayed as a bull’s-eye diagram (Fig. 18-23). Table 18-2 provides a summary that may be used as a pocket guide for quick reference.
TOOLS USED TO ASSIST THE SONOGRAPHER IN GAINING ADDITIONAL INFORMATION Respirometer A respirometer is a useful tool in the evaluation of diastolic function. While not necessary, it is recommended and can enhance the interpretation of a diastolic examination by providing respiratory VR
20 2
AR
10 SVC Color Doppler
4
cm/s -10 -20
D
-30 -40 -50
SVC
-60
S
-70
A
B
C
D
Figure 18-20 A, Transducer placement at the right supraclavicular fossa for interrogation of superior vena cava (SVC) flow. B, 2D image of SVC. C, 2D color flow Doppler guided cursor placement in the SVC. The sonographer should obtain solid blue color demonstrating flow away from the transducer. D, Typical SVC pulsed wave Doppler spectral display demonstrating measured peak S, D, and AR velocities.
223
224
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function TABLE 18-2 DIASTOLIC EXAM: COLLECTING AND MEASURING LEFT- AND RIGHT-HEART PARAMETERS
OBSERVATION
VIEW
MODALITY
AV groove LA size (volume/ area) LV inflow
PLAX A4Ch and A2Ch
2D 2D
A4Ch
PWD
A-wave duration
A4Ch
PWD
PV flow
A4Ch
PWD
LV inflow CMM
A4Ch
CMM
IVRT
Between A4Ch and A5Ch
PWD or CWD
MV lateral annulus MV medial annulus
A4Ch A4Ch
TDI TDI
RV inflow
A4Ch
PWD
HV
Subcostal SAX
PWD
TV free wall annulus IVC
A4Ch
TDI
Subcostal SAX
2D guided M-mode
SVC
Right supraclavicular fossa
PWD
Strain
Apical Views
Strain rate
Apical Views
Torsion
SAX and Apical Views
TDI or 2D speckle tracking TDI or 2D speckle tracking TDI or 2D speckle tracking
SAMPLE VOLUME PLACEMENT OR CURSOR PLACEMENT OR FRAMES/SEC
SAMPLE VOLUME SIZE (mm)
VELOCITY FILTER (Hz)
SWEEP SPEED (mm/sec)
SV between mitral valve leaflet tips SV 5 mm nearer to mitral annulus than where sampled for LV inflow SV 1–2 cm into pulmonary vein Activate color Doppler in LV. Cursor placement in highest velocity color signal. Activate M-mode Cursor placement intermediate between LV inflow and LV outflow SV lateral mitral annulus SV medial mitral annulus
1–2
200
50 or 100
1–2
200
50 or 100
3–4
200
50 or 100
Between tricuspid valve leaflet tips 2–3 cm into hepatic vein beyond junction of IVC SV free wall annulus
Left Heart
100
200–400
50 or 100
5 5
100 100
50 or 100 50 or 100
1–2
200
50 or 100
3–4
200
50 or 100
5
100
50 or 100
Right Heart
Place M-mode cursor perpendicular to IVC SV 5–8 cm depth and close to the junction of the right atrium
25 or 50 3–4
200
50 or 100
Strain Imaging
cycle timing information in relation to other dynamics influencing intracardiac pressure, as described in detail in Chapter 15. To collect accurate respiratory timing information, the nasal thermistor must be place appropriately in the patient’s nostril (Fig. 18-24). Once the thermistor is comfortably placed, the sonographer should perform a practice maneuver by instructing the patient to inhale and exhale through the nose. The sonographer must observe the respiratory signal on the screen display and adjust the gain enough to ensure that inhalation and exhalation are recognized. He or she should then identify positive and negative deflections of the respiratory waveform to ensure correct interpretation. Upon completion of use, the nasal thermistor should be cleaned with alcohol prep pads and allowed to air dry. Alternatively, electrodes placed on the chest wall can detect respiratory variation by motion of the chest wall with breathing.
60–100 frames/sec 60–100 frames/sec 60–100 frames/sec
Doppler Enhanced Contrast Echocardiography Myocardial contrast echocardiography (MCE) is an excellent tool for optimizing LV endocardial borders in technically difficult cases; however, it can also be used to enhance a diastolic Doppler evaluation. It is particularly helpful in improving PV Doppler signals if the sonographer is struggling with an examination. Because contrast is used for LV opacification (LVO), it is important to allow the contrast effect to visually dissipate in order to avoid Doppler signal blooming or overcompensation in the Doppler spectral signal. After contrast administration, the sonographer should continue with the image examination until 2D visualization of contrast effect subsides (which can take up to 5 minutes), then proceed with the PV Doppler evaluation (Fig. 18-25). In most cases, the two-dimensional contrast effect will appear to have disappeared; however, there will still be an
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function
Base
A
Figure 18-21 A, Correctly aligned versus B, incorrectly aligned left ventricular wall segments. C, Upper panel is an example of the color M-mode display of strain rate values in the left ventricular (LV) septum. Lower panel represents strain rate obtained in the middle of the LV septum (represented by the green line). Note that the S, E, and A waves appear like mirrored images of the septal tissue velocities. If the transducer is not aligned correctly with the LV septum, peak values of strain rate waves will be decreased (represented by the yellow line).
Apex
S
B
C
-2 -9 -10 Figure 18-22 Example of two-dimensional speckle tracking longitudinal strain.
Figure 18-23 Example of two-dimensional speckle tracking representing all 18 segments in a bull’s-eye diagram.
9 3
-5
E
A
225
226
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function TABLE 18-3 TO OPTIMIZE STRAIN IMAGE DATA, THE THE FOLLOWING TECHNIQUES SHOULD BE EMPLOYED To optimize Doppler velocity signal, avoid reverberation artifacts, and minimize signal noise
To avoid underestimation To avoid angle dependence To avoid respiratory drift and angle changes
Include harmonic image mode Use an appropriate pulse repetition frequency to avoid aliasing Use a narrow sector to improve spatial resolution Ensure that the sample volume tracks within the myocardium throughout the entire cardiac cycle and avoid tracking the left ventricular blood pool Select a high frame rate (greater than 100 frames per second) Align the axis of cardiac motion with the scan lines Acquire strain data at end expiration
From Marwick TH: Measurement of strain and strain rate by echocardiography: Ready for prime time? J Am Coll Cardiol 2006;47:1313–1327.
S
D
AR
A
S D
B
AR
Figure 18-25 A, A technically difficult pulmonary venous (PV) Doppler signal. B, The improved contrast enhanced PV Doppler signals.
(Fig. 18-26). Clinically these techniques can enhance or suppress cardiac sounds and murmurs. LV filling patterns are known to have preload dependence and alterations in preload indices and can be useful in detecting increased filling pressures. Attention must be paid to the mitral A wave, as it will increase during maneuvers due to increased filling pressures (Fig. 18-27). Close attention should also be given to the relationship between the Doppler and the respiratory variation when evaluating patients with constrictive pericarditis versus restrictive cardiomyopathy (see Chapter 24). Reducing preload with an upright positioning maneuver should be done if needed. If mitral E-wave respiratory variation greater than 25% is not present in a patient with suspected constriction, this may be secondary to a marked increase in LA pressure. Reduction of preload, as with upright sitting positioning, may bring out this respiratory variation.
Valsalva Maneuver Figure 18-24 Demonstration of appropriate placement of the nasal thermistor, resulting in an accurate respiratory signal display that can be superimposed on the spectral Doppler display.
adequate amount of contrast to enhance the Doppler signal to yield reproducible high-quality Doppler waveforms. The risks and benefits of administering echo contrast must always be considered and the decision to give echo contrast must be made by a physician on a case-by-case basis.28
Maneuvers Techniques of manipulation may be performed to aid in the assessment of filling pressures and subsequently of diastolic function during an echocardiographic examination.8,13 Valsalva, postural changes, isometric exercise, and respiration are maneuvers that can be used to temporarily alter cardiac hemodynamics
The mitral E/A ratio alone does not differentiate normal from pseudonormal filling patterns. This is where the Valsalva maneuver is indicated. It is probably the most useful maneuver and is achieved by straining against a closed glottis for 10–15 seconds after deep inspiration. Intrathoracic pressure should be elevated to about 40 mmHg. The Valsalva maneuver can also be particularly helpful when determining reversible from irreversible restrictive filling patterns. The Valsalva maneuver can be performed by either having the patient blow into a tube connected to a dial sphygmomanometer (Fig. 18-28) or by bearing down. Performed incorrectly, the maneuver will result in equivocal data. It is the sonographer’s responsibility to thoroughly explain the Valsalva maneuver to the patient and then to conduct a practice session to coach the patient on how to fully participate in the maneuver with expectations of full compliance. The sonographer should explain to the patient that prior to actually recording it he or she will first practice the
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function
Figure 18-26 Demonstration of the Valsalva effect on heart rate, blood pressure, and left ventricular filling pressures. In this example, the A wave increases in velocity during Valsalva and returns to baseline upon release of Valsalva. Heart rate and blood pressure return to baseline as well.
Figure 18-27 A, Note the increasing A-wave response to the Valsalva maneuver while pulsing left ventricular inflow. B, Note the relationship of the E and A waves as they return to baseline peak velocities once Valsalva effect subsides.
maneuver once or twice while the sonographer checks the placement of the cursor and the sample volume. If using the sphygmomanometer, the patient should be instructed to exert enough forward airflow to increase the gauge to approximately 40 mmHg. The sonographer should use the following analogies to help the patient understand what a Valsalva maneuver should feel like:
Figure 18-28 Example of a patient “blowing” into the sphygmomanometer tube to achieve a Valsalva effect.
“Bear down as if you were going to have a bowel movement.” “Push as if you were pushing a lawn mower up a big hill.” “Simulate the act of blowing up a large balloon.” The patient’s abdomen should be observed for verification of active contraction of abdominal muscles. The sonographer’s hand should be placed on the abdomen to ensure adequacy of strain.
227
228
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function The jugular veins are examined to confirm distention of strain phase. An adequate amount of expiratory effort is needed to cause physiologic changes. The sonographer should strive for about a 40 mmHg change from baseline. Though not mandatory, a manometer is most commonly used during research protocols to document the exact measurement and change in expiratory effort from baseline. Contraindications to performing Valsalva are unstable angina or recent myocardial infarction, severe valvular disease, recent transient ischemic attack or stroke, and uncontrolled hypertension.
Isometric Hand Exercise Isometric exercise such as a sustained handgrip is used to increase afterload. The patient should be instructed to squeeze rolled towels or tennis balls simultaneously in a squeeze/release, squeeze/ release pattern and continue performing it until the maneuver yields an adequate response. The patient should not hold his breath or perform Valsalva while doing isometric exercise. Physiologically, the hemodynamic effects of an isometric handgrip are related to decreased vagal tone and increased sympathetic tone. In a patient with normal diastolic function, performing an isometric handgrip causes increased heart rate, blood pressure, cardiac output, and venous reversal. Individual response depends on the amount of exercise, baseline LV function, and baseline hemodynamic state. In patients with baseline LV dysfunction, isometric exercise will increase LV filling pressures.
Respiratory Maneuvers Respiratory changes are divided into two categories: those that increase with inspiration due to increased venous reversal and those that increase with expiration due to decreased lung volume. Physiologically, during deep inspiration, intrathoracic pressure decreases, causing increased venous reversal while augmenting right-heart preload, which increases RV stroke volume. During deep expiration, lung volume decreases as air leaves the lungs, and the heart moves closer to the thoracic wall. PV flow enters the left atrium secondary to increased intrathoracic pressures. Vascular resistance is not solely a result of respiration but depends on the position of the patient. A supine position increases venous reversal; a standing position decreases venous reversal; sitting or standing accentuates respiratory induced changes. Right-sided velocities increase with inspiration, and left-sided velocities decrease with inspiration. Ischemic heart disease and arrhythmias are contraindicated for respiratory maneuvers. As mentioned, a respirometer is a useful tool in the assessment of timing Doppler data during the respiratory cycle to determine respiratory induced changes. Doppler data should be recorded during inspiration and expiration to better define the respiratory effect on intracardiac chamber filling pressures. A respirometer is particularly useful in evaluating respiratory variation to help differentiate between constriction and restriction, for assessing pericardial effusion, and for ruling out IVC plethora. A nasal thermistor is appropriately placed, and the cable is connected to the respirometer port of the ultrasound system. Some ultrasound systems incorporate a respiratory sensing device in the echocardiographic leads. The respirometer signal is displayed as a cine wave superimposed on the echo Doppler images. When using a nasal thermistor, the patient is asked to breath through the nose. The sonographer should always test the respirometer by first practicing to demonstrate the inspiration and expiration signal on the screen.
Figure 18-29 Demonstration of image evaluation during upright sitting position maneuver.
Postural Maneuvers Postural changes, such as sitting or standing from a supine position, decrease venous reversal (Fig. 18-29). Physiologically, gravity causes pooling in the venous beds of the legs, decreasing venous reversal. RV and LV stroke volumes also fall, causing hypotension. This in turn causes reflex tachycardia and an increase in vascular resistance.
Leg Raising Maneuver Passive leg raising is the opposite of those maneuvers described earlier in this chapter, causing increased intra-abdominal pressure, venous reversal, stroke volume, cardiac output, and central aortic pressure (Fig. 18-30). This will cause reflex bradycardia, as in phase IV of the Valsalva maneuver.
Figure 18-30 Demonstration of image evaluation during leg elevation maneuver.
SUMMARY AND FUTURE DIRECTIONS Echocardiography is the workhorse of cardiac imaging and requires skillful sonographers. Echocardiography provides a diagnostic examination that is noninvasive, portable, and able to be repeated multiple times without risk to the patient while yielding unique functional and hemodynamic information. The cardiac sonographer plays an extremely important role in the diagnosis of diastolic heart disease. In-depth knowledge regarding cardiac
Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function hemodynamics and Doppler principles and high-quality imaging skills are required to yield useful clinical data. The growing heart failure epidemic necessitates the demand for competent sonographers who are a critical part of the diagnostic team. Newer technology is being developed that will enhance the information yielded from a diastolic exam, allowing for earlier recognition of impaired diastolic dysfunction. Advances in imaging strain, strain rate, torsion, and tissue or speckle tracking will provide the sonographer with more sensitive and accurate tools; however, this necessitates advanced levels of training and education and should always be consistently practiced. Formal education through medical diagnostic training curricula as well as continuing education programs must include core training in diastolic heart failure assessment by echocardiography.
ABBREVIATIONS 2D A2Ch A4Ch A5Ch ALAX AoV AR CO CMM CWD E/A EF DT HV HR ITP IVC IVRT LA LV LVH MV MVa / PVa PLAX PP PSAX PV PV S/D PVs2 / PVd PWD RA RV SV SVC TDI TV VR
two-dimensional apical 2-chamber apical 4-chamber apical 5-chamber apical long axis aortic valve atrial reversal cardiac output color M-mode continuous wave Doppler LV inflow E and LV inflow A ratio ejection fraction deceleration time hepatic vein heart rate intrathoracic pressure inferior vena cava isovolumetric relaxation time left atrial left ventricular left ventricular hypertrophy mitral valve mitral valve A wave and pulmonary vein A wave ratio parasternal long axis pulse pressure parasternal short axis pulmonary venous pulmonary vein systolic / diastolic ratio pulmonary vein systolic peak 2 and pulmonary vein diastolic pulsed wave Doppler right atrial right ventricular sample volume superior vena cava tissue Doppler imaging tricuspid valve venous reversal
REFERENCES 1. Barker HB, Mullooly JP, Getchell W: Changing incidence and survival for heart failure in a well-defined older population, 1970–1974 and 1990– 1994. Circulation 2006;113:799–804.
2. Gutierrez C, Blanchard DG: Diastolic heart failure: Challenges of diagnosis and treatment. Am Fam Physician 2004;69:2609–2616. 3. Appleton CP, Jensen JL, Hatle LK, et al: Doppler evaluation of left and right ventricular diastolic function: A technical guide for obtaining optimal flow velocity recordings. J Am Soc Echocardiogr 1997:10:271–292. 4. Rosamond W, Flegal K, Friday G, et al: Heart disease and stroke statistics—2007 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115: e69–e171. 5. Bursi F, Weston SA, Redfield MM, et al: Systolic and diastolic heart failure in the community. JAMA 2006;296:2209–2216. 6. Hawkins NM, Wang D, McMurray JJ, et al: Prevalence and prognostic implications of electrocardiographic left ventricular hypertrophy in heart failure: Evidence from the CHARM programme. Heart 2007;93:59–64. 7. Galderisi M: Diastolic dysfunction and diabetic cardiomyopathy: Evaluation by Doppler echocardiography. J Am Coll Cardiol 2006;48: 1548–1551. 8. Oh JK, Appleton CP, Hatle LK, et al: The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 1997;10:246–270. 9. Appleton CP, Jensen JL, Hatle LK, et al: Doppler evaluation of left and right ventricular diastolic function: A technical guide for obtaining optimal flow velocity recordings. J Am Soc Echocardiogr 1997:10:271–292. 10. Vasan RS, Benjamin EJ: Diastolic heart failure—no time to relax. N Engl J Med 2001;344:56–59. 11. Maurer MS, Spevack D, Burkhoff D, et al: Diastolic dysfunction: Can it be diagnosed by Doppler echocardiography? J Am Coll Cardiol 2004;44: 1543–1549. 12. Quiñones MA: Assessment of diastolic function. Prog Cardiovasc Dis 2005;47:340–355. 13. Mottram PM, Marwick TH: Assessment of diastolic function: What the general cardiologist needs to know. Heart 2005;91:681–695. 14. Garcia MJ: Comprehensive echocardiographic assessment of diastolic function. Heart Failure Clin 2006;2:163–178. 15. Oh JK, Hatle L, Tajik AJ, et al: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506. 16. Lang RM, Bierig M, Devereux RB, et al: Recommendations for chamber quantification: A report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–1463. 17. Quiñones MA, Otto CM, Stoddard M, et al: Recommendations for quantification of Doppler echocardiography: A report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15: 167–168. 18. Gilman G, Nelson TA, Hansen WH, et al: Diastolic function: A sonographer’s approach to the essential echocardiographic measurements of left ventricular diastolic function. J Am Soc Echocardiogr 2007;20:199–209. 19. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865–875. 20. Ho CY, Solomon SD: A clinician’s guide to tissue Doppler imaging. Circulation 2006;113:e396–e398. 21. Dokainish H, Sengupta R, Patel R, et al: Usefulness of right ventricular tissue Doppler imaging to predict outcome in left ventricular heart failure independent of left ventricular diastolic function. Am J Cardiol 2007;99:961–965. 22. Abraham TP, Nishimura RA: Myocardial strain: Can we finally measure contractility? J Am Coll Cardiol 2001;37:731–734. 23. Marwick TH: Measurement of strain and strain rate by echocardiography: Ready for prime time? J Am Coll Cardiol 2006;47:1313–1327. 24. Galderisi M. Can technical limitations of strain rate imaging be overtaken by particular arrangements? J Am Coll Cardiol 2006;48:1729. 25. Notomi Y, Setser RM, Shiota T, et al: Assessment of left ventricular torsional deformation by Doppler tissue imaging: Validation study with tagged magnetic resonance imaging. Circulation 2005;111:1141–1147. 26. Notomi Y, Lysyansky P, Setser RM, et al: Measurement of ventricular torsion by two-dimensional ultrasound speckle tracking imaging. J Am Coll Cardiol 2005;45:2034–2041. 27. Perk G, Tunick PA, Kronzon I: Non-Doppler two-dimensional strain imaging by echocardiography—from technical considerations to clinical applications. J Am Soc Echocardiogr 2007;20:234–243. 28. FDA online: Available at http://www.fda.gov/
229
DOUGLAS S. LEE, MD, PhD RAMACHANDRAN S. VASAN, MD, DM
19
Hypertension and Valvular Heart Disease INTRODUCTION PATHOPHYSIOLOGY AND CLINICAL RELEVANCE OF DIASTOLIC DYSFUNCTION IN HYPERTENSION Mechanical Considerations Cellular and Molecular Bases of Left Ventricular Diastolic Dysfunction in Hypertension Clinical Basis of Hypertensive Heart Disease
PATHOPHYSIOLOGY AND CLINICAL RELEVANCE OF DIASTOLIC DYSFUNCTION IN VALVULAR DISEASE Acute Aortic Insufficiency Chronic Aortic Insufficiency Aortic Stenosis Acute Mitral Regurgitation Chronic Mitral Regurgitation Mitral Stenosis FUTURE RESEARCH
INTRODUCTION Hypertension and valve disease are key risk factors for heart failure. Uncontrolled hypertension results in left ventricular (LV) remodeling, often with an increase in LV mass. Valve disease is associated with pressure or volume overload of the left ventricle, depending on its etiology. Significant valve disease is associated with LV remodeling, usually with LV hypertrophy (LVH). The pattern of LV remodeling and its severity vary depending on the nature, severity, and chronicity of valve disease. LV remodeling is a fundamental substrate for overt heart failure. Thus, an overlap exists between the pathophysiology of LV remodeling in hypertensive heart disease and severe valve disease. The hypertrophic response in patients with valve disease results from the activation of biological pathways that also play a key role in the evolution of hypertensive heart disease. LV diastolic impairment occurs in patients with hypertension or valve disease, even in those without evidence of LVH or systolic dysfunction. Cases of heart failure due to hypertension and valve disease both frequently manifest with a preserved LV ejection fraction. When heart failure occurs in association with a normal LV ejection fraction but with concomitant LV diastolic filling abnor-
malities, the term diastolic heart failure (DHF) has been used.1,2 In cases of heart failure on the basis of hypertension, blood pressure control may lead to amelioration or resolution of abnormal LV diastolic function, and therefore may change the natural progression to hypertension-associated DHF.3–6 In the case of valve disease, medical management and/or surgical correction of the condition is associated with resolution of heart failure and LV diastolic dysfunction. In this chapter, we discuss pathophysiologic and clinical considerations in DHF due to hypertension or valvular heart disease. Although valvular heart disease constitutes an exclusion in some definitions of DHF,7 we employ a broader view by examining these conditions in the context of the syndrome of heart failure with preserved LV systolic function.
PATHOPHYSIOLOGY AND CLINICAL RELEVANCE OF DIASTOLIC DYSFUNCTION IN HYPERTENSION Mechanical Considerations Hypertension increases the load on the left ventricle, with a resultant increase in LV mass (referred to as hypertrophy). The LV 233
Chapter 19 • Hypertension and Valvular Heart Disease 160
Laplace’s law: Wall stress = p × r/2 × h.
120
Hypertension and Left Ventricular Mass Systolic blood pressure is an important determinant of LV mass in hypertension.15 LV mass (LVM), in grams, is calculated by echocardiography using the following equation16:
25
50
75
100
125
150
125
150
125
150
LV volume (ml)
A 160
120
80
40
0 0
25
50
75
100
LV volume (ml)
B 160
120
80
40
0
LVM = 39.95 + 14.61 × height (m2.7) + 0.65 × SW (grams-meters/beat) − 17.17 × sex, where male sex is assigned a value of 1 and female sex is assigned a value of 2. An inappropriately increased LV mass was defined as an observed to predicted ratio of LV mass greater than approximately 1.3. Such individuals, who have inappropriately increased LV mass that exceeds the compensatory needs for a given workload, have been found to exhibit further abnormalities of systolic and diastolic function. These abnormalities include delayed LV relaxation with prolonged isovolumic relaxation time (IVRT), increased myocardial stiffness, and mild systolic dysfunction of the midwall and LV chamber (see the section “Echocardiographic Features of Hypertensive Left Ventricular Hypertrophy”).27
40
0
LVM (g) = 1.04 × [(IVS + LVEDD + PWT)3 − LVEDD3] − 13.6, where IVS = thickness of interventricular septum, LVEDD = LV end diastolic dimension, and PWT = posterior wall thickness. Indexed for body surface area, an LV mass index greater than 131 g/m2 for men and greater than 100 g/m2 for women represents LVH.15 Other cutpoints for LVH have also been suggested, indexing for height raised to a power.17–19 LVH is one of the most common causes of isolated diastolic dysfunction and is an important independent risk factor for heart failure.20–22 The patterns of diastolic filling and its relation to LV pressure in chronic hypertension are shown in Figure 19-1. Early diastolic filling abnormalities in hypertension correlate with increased LV mass.23–26 In hypertensive individuals, observed LV mass may be significantly greater than that which is predicted based on demographic, clinical, and hemodynamic factors (e.g., systolic blood pressure, stroke volume, sex, height). For instance, de Simone et al. calculated predicted LV mass as27:
80
0
LV pressure (mmHg)
To normalize wall stress in the presence of pressure overload, LV wall thickness increases, and this concept is applicable to both hypertension and valvular disease. Initially, this response to increased wall tension occurs with thickening of the LV walls within the “normal” range. However, progression toward an abnormal increase in LV wall thickness occurs with prolonged exposure. The development of LVH is not only load dependent but multifactorial and may be influenced by endocrine, autocrine, paracrine, and genetic factors. It is of interest that both blood pressure and LV mass exhibit familial aggregation and are heritable quantitative traits.8–11 Additionally, familial aggregation of LV diastolic measures12,13 and left atrial (LA) size14 (a marker of diastolic dysfunction) has also been reported, suggesting that LV diastolic dysfunction in response to stressors such as pressure overload may be modulated in part by genetic influences and shared environmental factors.
LV pressure (mmHg)
response to increased load is to normalize wall tension. According to Laplace’s law, wall stress is defined by its relationship with pressure (p), chamber radius (r), and wall thickness (h), thus:
LV pressure (mmHg)
234
0
25
50
75
100
LV volume (ml)
C Figure 19-1 Ventricular systolic and diastolic pressure-volume loops associated with heart failure (HF) with normal ejection fraction (normal conditions shown in black). A, Diastolic HF that is not due to hypertensive etiology, with normal end systolic pressure-volume relationship (ESPVR), an upward and left-shifted end diastolic pressure-volume relationship (EDPVR), and normal or low blood pressure (red loop). B, Pressure-volume loops of HF with normal ejection fraction and chronic hypertension (note elevated blood pressure). ESPVR is elevated and EDPVR is shifted upward and to the left (blue loop). C, Same as B, except that ESPVR is normal or near-normal and EDPVR is normal or shifted to the right (green loop). (From Maurer J et al: Left heart failure with a normal ejection fraction: Identification of different pathophysiologic mechanisms. J Card Failure 2005;11:177.)
Chapter 19 • Hypertension and Valvular Heart Disease Regression of increased LV mass is correlated with reduction particularly in systolic blood pressure and parallels similar changes in the electrocardiogram (ECG).28 In patients with regression of LVH on ECG with treatment, there is regression of LV mass.29
Hypertension and Left Ventricular Geometry The effect of hypertension on LV diastolic dysfunction is also partly dependent on LV geometry (see the section “Echocardiographic Features of Hypertensive Left Ventricular Hypertrophy”), a phenotype defined on the basis of presence versus absence of LVH, and the relative wall thickness (RWT). The RWT has been calculated as: RWT = 2 × PWT/LVEDD. The RWT is considered to be increased if greater than 0.42.30,31 Alternatively, RWT has also been calculated as: RWT = (IVS + PWT)/LVEDD and is considered increased if greater than 0.45.32 In those without LVH, normal LV geometry is represented by normal LV mass and normal RWT, whereas concentric LV remodeling is defined by normal LV mass and increased relative wall thickness. Concentric remodeling represents the early adaptive changes to decrease LV wall tension in response to an increase in pressure overload. In the presence of LVH, LV geometry may be concentric or eccentric. Concentric hypertrophy occurs when RWT is increased and LVH is present, often in the presence of reduced ventricular internal dimensions. Eccentric hypertrophy is characterized by ventricular enlargement and an increase in LV mass, where wall tension is increased by virtue of an increase in radius so that RWT is normal.
Hypertensive Overload and Left Ventricular Diastolic Dysfunction In hypertension, ventricular hypertrophy occurs to compensate for elevated wall stress and increased ventricular stiffness, and impaired LV relaxation may ensue.33 Impairment in LV relaxation decreases early LV filling, and the atrial contribution to ventricular filling increases. In hypertensive states, due to increased afterload from vascular or valvular etiologies, increased LV chamber stiffness may result from an increase in myocyte hypertrophy and/or alterations in the cardiac interstitium. An increase in LV stiffness or reduction in ventricular compliance results in increased LV diastolic pressure for any degree of ventricular preload, and subsequent pulmonary venous congestion with symptoms of dyspnea. In adult patients with diastolic,24 isolated systolic,25 borderline isolated systolic,34 and combined systolic and diastolic hypertension,35 as well as in children with hypertension,36 an abnormal diastolic filling pattern characterized by impaired early diastolic ventricular filling with an enhancement in late diastolic filling (due to atrial systole) has been reported, indicating subnormal LV relaxation with normal ventricular compliance.37 A prolonged IVRT has also been demonstrated in hypertensive persons.38 Possible contributing factors for the LV diastolic dysfunction observed in hypertensive patients include myocardial fibrosis and increased LV mass (see the sections “Cellular and Molecular Basis of Left Ventricular Diastolic Dysfunction in Hypertension” and
“Clinical Epidemiology of Hypertensive Heart Disease”) although they do not always accompany hypertension.39,40 An indication that diastolic dysfunction may be present in the context of the pressure-overloaded ventricle is the identification of LVH or an abnormal increase in LV mass. Although diastolic filling abnormalities often occur when LV mass is increased, ventricular hypertrophy is not a requisite for LV diastolic dysfunction, which may also occur at an earlier stage in hypertensive patients without overt LVH. Early diastolic filling abnormalities in hypertension correlate with increased LV mass.23–26 As noted previously, LVH is one of the most common causes of isolated LV diastolic dysfunction and is an important independent risk factor for heart failure.20–22 Myocardial fibrosis with increased interstitial collagen deposition is another mechanism underlying LV diastolic dysfunction in hypertensive subjects. There is a strong relation between LV stiffness and myocardial collagen content41,42 and plasma levels of fibrosis markers43 in hypertensive persons. Improvement of LV diastolic function during antihypertensive treatment is related to regression in myocardial collagen content.41,42 This may indicate that LV mass is determined mainly by loading conditions, whereas myocardial fibrosis and LV diastolic dysfunction may be the consequence of the detrimental effects of neurohormonal activation. The hypothesis that LVH and myocardial fibrosis are regulated independently of each other, and to some extent of blood pressure, is supported by limited experimental evidence.44–46
Left Atrial Function in Hypertension Compensatory changes in the left atrium reflect functional changes due to LVH that occur as a result of hypertensive load. Because the impairment in LV relaxation decreases early LV filling, the contribution of the left atrium to ventricular filling in later diastole increases. These changes may operate under the Frank-Starling principle, to prevent marked changes in mean LA pressure that can occur with elevated LV diastolic pressure or with an increase in LA preload.47,48 Increases in LA size and systolic force have been associated with aging, and both have been suggested as a compensatory response to age-related reduction of ventricular relaxation.49,50 LA systolic force (LASF), can be calculated echocardiographically as: LASF = 0.53 × MOA × (peak A velocity)2, where MOA = mitral orifice area. The degree of change in LA size and systolic force in the pressure- or volume-overloaded left ventricle is highly dependent on the degree of LV diastolic dysfunction, reflected by an impairment of active ventricular relaxation.51 A change in LA size over time is not a feature of “normal aging.”52 The left atrium enlarges in response to changes in LV filling patterns that characterize abnormal LV relaxation, with a reduction in the emptying volume from the left atrium to the left ventricle and a reduced flow from the pulmonary veins into the left ventricle in early diastole.52,53 The left atrium may compensate by an increase in its size, an augmentation of active contraction, and an increase in late diastolic emptying.52–54 Therefore, LA size or volume is an indicator of LV diastolic dysfunction in patients without valve disease or atrial fibrillation. In one study, patients with an LA volume index of less than 27 ml/m2 had a similar future risk of atrial fibrillation or heart failure as those with normal LV diastolic filling.55
235
236
Chapter 19 • Hypertension and Valvular Heart Disease Impaired LA contractility arising from a loss of LA systolic force or atrial arrhythmia will result in a further reduction in LV preload, a decrease in cardiac output, and increased LA pressure. Hypertension is associated with LA enlargement, depression of LA contractile function, and an increased risk for atrial fibrillation,56,57 all of which can precipitate overt heart failure in patients with underlying LV diastolic dysfunction.58
Effect of Associated Metabolic Risk Factors on Left Ventricular Diastolic Function in Hypertension The concomitant presence of other cardiovascular disease risk factors can worsen the impairment of LV diastolic function in hypertension.59 Metabolic factors such as dyslipidemia and dysglycemia may be important in this regard. Indices of LV mass and diastolic function have been correlated with lipid profile.60 Additionally, elevated glucose levels, insulin resistance, and hyperinsulinemia have been associated with LV diastolic dysfunction in hypertensive patients.61–64 The development of LV diastolic dysfunction with elevated glucose levels in persons with and without diabetes has been reported in hypertensive patients, and even slight elevations in fasting glucose levels have been reported to affect LV diastolic function.65 Experimental treatment interventions with thiazolidinediones and insulin-sensitizing agents have been found to inhibit cardiac hypertrophy and improve LV diastolic function. These effects are thought to be mediated in part by activation of the peroxisome proliferator-activated receptor-γ (PPAR-γ).66–68 Additionally, these treatments may decrease cardiac fibrosis by inhibiting collagen synthesis, mediated by a decrease in the ratio of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs).69,70
Effect of Obesity on Left Ventricular Diastolic Function in Hypertension Obesity may also modulate the development of LV diastolic filling abnormalities in hypertensive patients. In a study of lean (body mass index [BMI] <25 kg/m2), overweight (BMI 26– 29 kg/m2), and obese (BMI >30 kg/m2) persons with hypertension, LV mass itself and LV mass indexed to height increased progressively with higher BMI.71,72 The LA diameter, which reflects LA diastolic filling abnormalities, is also significantly increased in obese individuals.72 An increasing trend of E-wave deceleration time and IVRT with increasing BMI has been observed, and the E/A ratio was significantly lower in overweight and obese versus lean hypertensive individuals.71 When those with normal and abnormal LV diastolic function were compared, the major differences were older age and higher LV mass in the latter group.71
Aortic Stiffness and Left Ventricular Diastolic Dysfunction in Hypertension Among hypertensive patients, aortic stiffness has been identified as a predictor of cardiovascular mortality and all-cause death.73 Aortic stiffness has been closely linked with DHF in hypertension and may contribute to the pathophysiology and progression of diastolic dysfunction: Patients with DHF have stiff, large arteries and increased blood pressure lability.74–76 Mechanisms of increased aortic stiffness in hypertension include hemodynamic stress caused by high pressure in the arterial walls, structural
alterations in the vasculature, and atherosclerotic disease.77 However, hypertension may increase aortic stiffness even in the absence of coronary artery disease.78 LV diastolic function in hypertension is associated with indices of aortic stiffness and may be even further increased by the coexistence of other conditions, such as diabetes.78 Given the associations demonstrated in early studies, evaluation of aortic stiffness may take on greater importance in future studies of DHF. Evaluation of aortic stiffness includes assessment of aortic strain and distensibility, which are aortic elasticity parameters and can be calculated as: Aortic strain (%) = (AoSD − AoDD) × 100/AoDD Distensibility (cm2/dyne) = 2 × aortic strain/(SBP − DBP), where AoSD = aortic systolic diameter, AoDD = aortic diastolic diameter, dyne = dynamic measurement, SBP = systolic blood pressure, and DBP = diastolic blood pressure.78,79 Aortic strain and distensibility were related positively with E/A ratio and inversely with deceleration time and IVRT in one study.78 Although other factors, such as age, sex, blood pressure, and LVH, may also influence arterial compliance, analyses adjusted for these variables suggest a significant independent relationship between arterial compliance and LV diastolic dysfunction.80 Pulse wave velocity (PWV) is a measure of large artery stiffness, based on the principle that PWV is inversely related to the elasticity of the vascular wall and directly related to arterial stiffness. PWV is calculated by dividing the pulse transmission time, in milliseconds, typically from carotid to femoral arteries by the distance traveled by the pulse wave using body surface measurements.81 The augmentation index (AI) is a manifestation of the early return of the reflected wave from the periphery to the heart during systole, when the heart is ejecting blood. Both increased PWV and AI increase with greater arterial stiffness and increase cardiac afterload. Prior studies have reported that LV concentric remodeling and hypertrophy are associated with vascular stiffness in hypertensive patients.82,83 Even in those with recently diagnosed hypertension without evidence of LVH, there is demonstrable increased aortic stiffness that occurs concurrently with the presence of LV diastolic dysfunction.84 Aortic stiffness is associated not only with indices of LV diastolic dysfunction, but with the occurrence of heart failure with normal LV ejection fraction.85 Despite what we have discussed, it is not known whether these findings indicate a causal mechanistic link between DHF and vascular stiffness or simply the coexistence of systemic changes in hypertension. A number of potential mechanisms link aortic stiffness in hypertensive patients with diastolic dysfunction (Fig. 19-2)80: 1. It is possible that increased aortic stiffness may increase afterload, resulting in LV changes, including ventricular hypertrophy and delayed LV relaxation.86 2. Increased vascular stiffness is associated with a higher velocity of transmission of the pulse wave ejected by the left ventricle, and early return of reflected waves may augment the amplitude of the central aortic pressure wave. This would further increase LV afterload and central pulse pressure.87 3. The reduction in central aortic diastolic pressure may also reduce coronary perfusion, which, coupled with ventricular hypertrophy, may increase subendocardial ischemia.
Chapter 19 • Hypertension and Valvular Heart Disease Aortic stiffening
↓ Central aortic DBP
↑ Central aortic SBP
↓ Coronary perfusion
↑ LV afterload
Myocyte hypertrophy
Subendocardial ischemia
Impaired relaxation
Myocardial fibrosis
Diastolic dysfunction Figure 19-2 Pathophysiological pathways through which aortic stiffness may contribute to the development of diastolic dysfunction. DBP, diastolic blood pressure; SBP, systolic blood pressure. (From Mottram et al: Relation of arterial stiffness to diastolic dysfunction in hypertensive heart disease. Heart 2005;91:1551.)
The association of arterial stiffness and LV diastolic dysfunction may also be modulated by sex, since there may be differential degrees of concentric remodeling with increased afterload in women versus men and a higher prevalence of DHF in women.88,89 In a large community-based study, age and female sex were associated with the vascular elastance index (Ea) normalized to body surface area,90 calculated as: Ea = Pes/SV, where Pes = end systolic pressure and SV = stroke volume.91 Similar associations were observed for age, female sex, and LV diastolic elastance (Ed),90 calculated as: Ed = E/E′, where, E = early mitral inflow diastolic filling velocity and E′ = mitral annular early diastolic velocity measured by tissue Doppler.92–94 It was speculated that the ventricular-vascular stiffening profiles may contribute to DHF.90 Genetic and environmental factors may also influence the development of aortic stiffness. Arterial stiffness is increased in those with a parental history of essential hypertension95 and also varies according to race.96 Polymorphism of the GNB3 gene, which encodes the G protein β3 subunit, has been associated with increased PWV and AI.97 Although regular resistance and aerobic exercise programs do not affect PWV,98 a regimen of intensive, long-term blood pressure control may decrease arterial stiffness.99
Cellular and Molecular Bases of Left Ventricular Diastolic Dysfunction in Hypertension A number of cellular processes regulate or affect LV diastolic function. In myocytes, relaxation of the ventricle is dependent on calcium (Ca2+) traffic that is influenced by the activity of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2) and its regulator, phospholamban.100,101 Dephosphorylation of phospholamban reduces SERCA2 activity, resulting in impaired relaxation, and in contrast, phosphorylation has a lusitropic effect.102 Neuro-
hormonal factors also contribute to LV diastolic dysfunction. Angiotensin II acts via the angiotensin II type 1 (AT1) receptor to stimulate myocardial atrial natriuretic peptide (ANP) gene expression, endothelin (ET-1) production, and collagen accumulation. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers reduce DHF, presumably partly via the inhibition of this mechanism.103 Blockade of the AT1 receptor may improve LV diastolic function by a decrease in myocardial stiffness, an increase in SERCA expression, promotion of phosphorylation of phospholamban, and attenuation of the prolongation of Tau (τ, the time constant of LV relaxation).104,105 A number of other prohypertrophic factors may contribute to the development of LV diastolic dysfunction. Pathways that may alter LV hypertrophic remodeling include guanosine 3′,5′-cyclic monophosphate (cGMP) and phosphodiesterase-5A (PDE5A) signaling.106,107 Sildenafil, an inhibitor of cGMP catabolism and a PDE5A inhibitor, prevented the development of myocyte and cardiac hypertrophy and reversed preexisting hypertrophy in an animal model.108 The ET-1 pathway may also contribute to the pathogenesis of LV diastolic dysfunction and DHF. The ETA receptor mediated an increase in myocardial stiffness in hypertensive animal models,109 and upregulation of myocardial ET-1 is present in hypertrophied ventricles that transition to progressive LV diastolic dysfunction.110 Signaling pathways activated in hypertension include members of the mitogenactivated protein kinase (MAPK) superfamily (the p38 MAPK, the extracellular regulated kinases [ERK] and c-Jun kinases), the gp130 family (the JAK/STAT pathway), and the calcineurin pathway.111 The transition from compensated LVH to heart failure occurs by remodeling processes, which may involve myocardial fibrosis, myocyte degeneration, autophagic cell death, oncosis, an increase in length, and reduction in cross-sectional area.112,113 Abnormal collagen deposition and accumulation may contribute to increased LV stiffness in DHF. These interstitial changes are mediated by excessive collagen synthesis and an increase in the ratio of type I to type III collagen subtypes.104,114 In patients with hypertension, greater turnover of type III collagen was associated with increased LV mass and impairment of diastolic function.115 DHF is associated with reduced TIMP gene expression and increased MMP-2 and MMP-9 activity.116 In patients with hypertension, circulating TIMP-1 levels correlated with indices of LV diastolic filling, including E′, which is an indicator of load-independent early diastolic relaxation and ventricular wall movement in early diastole.117
Clinical Basis of Hypertensive Heart Disease Epidemiology Hypertension is a prevalent condition with significant implications for the development of heart failure. Data from the Framingham Heart Study found that hypertension often preceded the onset of heart failure in those in the third to sixth decades of life.118 Since the incidence of hypertension and heart failure both increase with age, the coexistence of these conditions in later years may be of even greater importance.119 In a study of the transition from hypertension to congestive heart failure, hypertension was present in 91% of new heart failure cases.120 The risk of heart failure was increased twofold in men and threefold in women, and the population attributable risk associated with hypertension was 39% in men and 59% in women.120 Survival after the onset of
237
238
Chapter 19 • Hypertension and Valvular Heart Disease hypertensive heart failure was poor, with only 24% of men and 31% of women surviving 5 years.120 A common precursor of DHF is a condition referred to as hypertensive hypertrophic cardiomyopathy of the elderly.121 This term refers to elderly patients who frequently are female, have systolic hypertension, and present with marked ventricular hypertrophy, a supernormal LV ejection fraction, and a propensity for developing pulmonary edema.
Clinical Presentation Diastolic dysfunction due to hypertension may be asymptomatic, may manifest as exercise intolerance, or may present acutely with the clinical syndrome of decompensated heart failure with preserved LV ejection fraction. Thus, LV diastolic dysfunction that occurs in concert with hypertension and associated LVH may have an insidious course. Some hypertensive persons with LVH are asymptomatic under resting conditions but may experience exertional dyspnea due to a relative inability to augment their LV end diastolic volume upon exercise.122 The decreased cardiac output arising from LV diastolic filling abnormalities may result in symptoms of “fatigue.” There may be a slow progression of exercise intolerance, and finally rest symptoms may develop.123 At the other end of the spectrum, some patients present with severe uncontrolled hypertension and acute pulmonary edema, which can be reversed by lowering blood pressure.124,125 Clinically, it is difficult to reliably distinguish acute decompensated heart failure on the basis of LV diastolic dysfunction from primarily systolic heart failure.126,127 The pathophysiologic bases for these abnormalities are (1) the increased left-sided filling pressures arising as a result of impaired LV relaxation and (2) subsequent pulmonary interstitial edema. Patients may also present with evidence of myocardial ischemic symptoms, which may or may not be associated with significant epicardial coronary stenosis. In patients with hypertension and LVH, an increase in wall tension decreases subendocardial perfusion. Therefore, patients with hypertensive heart failure may develop ischemic symptoms in the presence of normal epicardial coronary arteries on angiography.128 It is highly likely that patients with hypertensive LV diastolic dysfunction may also develop ischemic symptoms from epicardial coronary artery disease, particularly in the setting of an adverse coronary risk profile, since hypertension is an important component of atherosclerotic disease risk.
Echocardiographic Features of Hypertensive Left Ventricular Hypertrophy Mitral Inflow Parameters The diastolic properties of the left ventricle are often estimated in clinical practice by Doppler indices of early and late peak flow velocities, the latter representing atrial contraction. In hypertensive LVH, the ratio of early to late peak flow velocities (E/A ratio) is reduced as the LV relaxation phase is prolonged.129,130 The E/A ratio in the hypertensive condition is a reflection of LV active relaxation, myocardial passive stiffness, and LA work needed for diastolic LV filling.131–134 Hypertensive patients have their diastolic function significantly influenced by the presence of LVH compared with such patients without increased LV mass and compared with normotensive patients. In hypertensive patients with LVH in particular, there is a decrease in E/A ratio of mitral inflow velocities, an increase
in E-wave deceleration time, an increase in IVRT, and an increase in the ratio of the magnitude of motion due to atrial systole relative to total diastolic atrioventricular plane displacement (AVLA/AV-mean) (Fig. 19-3A).135 Measures of LV wall thickness (including interventricular wall thickness and posterior wall thickness), relative wall thickness, and blood pressure are inversely associated with LV diastolic function, independent of blood pressure. Thus, the E/A ratio and the IVRT exhibit a linear pattern of correlation with blood pressure, interventricular septum thickness, relative wall thickness, and LV mass index (see Fig. 19-3B).135 Stepwise regression analysis of the determinants of LV diastolic function suggests that age, systolic blood pressure, heart rate, and relative wall thickness are significant predictors of both the E/A ratio and the E-wave deceleration time, with model R2 of 0.43 and 0.23, respectively. Among these factors, age and systolic blood pressure explain most of the variation in E/A ratio and E-wave deceleration time. Predictors of IVRT are relative wall thickness, systolic blood pressure, and age, in decreasing order of importance (model R2 0.22).135 In addition to the effects of LV mass, LV geometry also has an effect on ventricular diastolic function, as noted previously. Hypertensive patients with concentric LVH manifest echocardiographically with a lower transmitral peak E velocity, prolonged E deceleration, increased IVRT, and an increase in LA size and systolic force, in comparison with those with a normal LV geometry.136–138 In contrast, those with eccentric LV geometry have different diastolic properties—in particular, an attenuation of the delay in LV relaxation.49 In eccentric LV geometry, the association with abnormal LA structure and function is also attenuated, further suggesting that LA changes are a reflection of impaired LV filling in myocardial hypertrophic states. LV diastolic filling abnormalities (e.g., prolonged IVRT and E deceleration time, lower E/A ratio) are also associated with greater propensity to a reduction in midwall fractional shortening, a subtle abnormality of ventricular contractile function.139,140 Limitations of Mitral Inflow Parameters Although the most common method for evaluation of diastolic function in hypertension is derived from transmitral flow velocities using pulsed-wave (PW) Doppler echocardiography, there are a number of potential limitations to this approach. The E/A ratio, which is widely adopted as an index of diastolic function, is subject to “pseudonormalization” with increasing age.141 Additionally, mitral inflow parameters are dependent on changes in preload, afterload, and contractility. Interpretation of transmitral flow may be aided by information obtained from pulmonary venous flow velocities. The normal pulmonary venous flow consists of forward flow during systole (S wave) and diastole (D wave) and retrograde flow during atrial systole (AR). The S/D pulmonary venous flow velocity ratio is increased in isolated relaxation abnormality conditions and is decreased, together with increased retrograde flow, during atrial contraction (AR) as LV diastolic compliance abnormalities advance.142 PW tissue Doppler imaging (TDI) measured in the myocardium and at the mitral annulus in systole and diastole may be a better method to identify load-independent changes in LV relaxation. These TDI measures correlate with τ, the time constant of isovolumic relaxation; and early studies suggest that the early (Em) and late (Am) tissue Doppler waves at the mitral annulus may change directionally in response to antihypertensive treatment.143 The Em/Am ratio, a global TDI index of diastolic dysfunction, tracked with the reduction in LV mass that occurred with ACE inhibitor therapy in hypertensive patients.143,144
Chapter 19 • Hypertension and Valvular Heart Disease *** **
1.8
*
***
1.4 E/A ratio
E/A ratio
1.8
1.0
1.4 1.0
0.6 *
0.6
* E-dec (msec)
250 200
250 200 150
***
***
150
130
IVRT (msec)
IVRT (msec)
150
110 90 0.65 ***
AV-LA/AVmean (%)
0.35 HT without LVH
Effects of Treatment Hypertension Treatment Hypertension is a key risk factor for the development of cardiovascular disease. Studies have found that systolic blood pressure and pulse pressure, which are both highly correlated, are major predictors of heart failure.146–149 By comparison, diastolic blood pressure was not found to be a risk factor for future heart failure. In the Systolic Hypertension in the Elderly Program (SHEP), which was designed to reduce blood pressure in those with systolic hypertension, one of the major cardiovascular endpoints was the reduction of heart failure events.150 Treatment of hypertension has been shown in multiple randomized trials to reduce cardiovascular events irrespective of age at treatment initiation.151 Reduction in systolic blood pressure has been proposed as the primary mechanism by which these benefits occur, since neither the change nor the achieved diastolic blood
130 110
0.65
0.45
Color M-mode Doppler echocardiography, which evaluates all velocities along a scan line aligned with mitral inflow, may also be used to supplement information from transmitral filling patterns.145 The velocity of flow propagation (Vp) into the left ventricle can be determined by the slope of the color wave front. A left ventricle with normal relaxation demonstrates rapid flow propagation, whereas a slowly relaxing ventricle is associated with blunted flow propagation.
*
90
*
0.55
NT
A
**
300
150
AV-LA/AV-mean (%)
Figure 19-3 A, Evaluation of left ventricular (LV) diastolic function in normotensives (NT, n = 38), hypertensive patients without LV hypertrophy (HT without LVH, n = 38), and hypertensive patients with LV hypertrophy (HT with LVH, n = 114). E/A ratio, ratio of peak early (E) and peak of late (A) mitral inflow velocities; E-dec, Ewave deceleration time; IVRT, isovolumic relaxation time; AV-LA/AV-mean, ratio of the magnitude of motion due to atrial systole to the total diastolic atrioventricular plane displacement. Mean and standard deviations are shown. *p < 0.05, **p < 0.01, ***p < 0.001. B, Evaluation of LV diastolic function in those with normal geometry (normal, n = 63), LV remodeling (LV remod, n = 13), eccentric LV hypertrophy (Ecc LVH, n = 47), and concentric LV hypertrophy (Conc LVH, n = 64). (From Muller-Brunotte R et al: Blood pressure and left ventricular geometric pattern determine diastolic function in hypertensive myocardial hypertrophy. J Hum Hypertens 2003;17:841–849.)
E-dec (msec)
300
HT with LVH
*
0.55 0.45 0.35
B
Normal LV remod Ecc LVH Conc LVH
pressure correlate with the beneficial effects of hypertension treatment.151 Reduction of Cardiac Fibrosis Cardiac fibrosis in hypertensive patients has been identified as a potential contributor to LV stiffness. ACE inhibitors and AT II receptor antagonists may regress myocardial fibrosis and decrease LV stiffness in hypertension.152,153 Aldosterone antagonism also has a prominent effect on inhibiting cardiac fibrosis, which improves diastolic function and decreases LV stiffness.154 Aldosterone antagonism also may improve subtle abnormalities in systolic function that may be present in hypertensive patients with preserved ejection fractions (>50%) and diastolic dysfunction, including increases in strain rate, peak systolic strain, and cyclic variation of integrated backscatter.154
PATHOPHYSIOLOGY AND CLINICAL RELEVANCE OF DIASTOLIC DYSFUNCTION IN VALVULAR DISEASE Valvular heart disease may contribute to the syndrome of heart failure with preserved systolic function. However, it is important to delineate with patient history, physical examination, and cardiac imaging studies whether the syndrome is attributable to severe or to symptomatic valvular disease, since the management principles
239
240
Chapter 19 • Hypertension and Valvular Heart Disease differ. One of the primary differences is the potential for surgical correction of valve disease, which can alleviate the underlying structural cause of heart failure. The natural history of severe aortic or mitral valve lesions has been well described, and a wide array of surgical options is available. It is recognized that DHF has been defined by an absence of significant valvular heart disease.7 It is also relatively uncommon as an underlying etiology for the syndrome of heart failure with preserved LV function. In elderly patients, aged 65 years and older, who were hospitalized for heart failure and met the Framingham diagnostic criteria for congestive heart failure, less than 10% with preserved systolic function had severe aortic or mitral valvular disease.155 However, the left-sided valvular lesions largely share features of LV diastolic dysfunction and/or hypertrophy with hypertensive DHF and therefore merit discussion in this chapter alongside the topic of hypertension. We will here describe the features of left-sided valvular disease as they pertain to heart failure syndromes with potential for diastolic dysfunction. We have limited the scope of this section to a discussion of the more commonly occurring conditions of acute or chronic regurgitation or stenosis of the mitral and aortic valves.
Acute Aortic Insufficiency Acute aortic insufficiency may be the underlying cause in some cases of heart failure with preserved systolic function. Unlike chronic aortic insufficiency, where the ventricle may undergo enlargement and eccentric hypertrophy, the left ventricle does not have the opportunity to accommodate a sudden increase in preload from the regurgitant volume. Therefore, the widened pulse pressure and the myriad of signs and symptoms of chronic aortic insufficiency are not present in the acute setting. Instead, there is an increase in LV end diastolic pressure and a decrease in forward cardiac output and stroke volume; consequently, a drop in blood pressure may be observed. In acute aortic insufficiency, the left ventricle operates at the high end of the pressure-volume relationship (Fig. 19-4C). In the setting of acute aortic insufficiency, overt pulmonary edema may be partly attenuated by preclosure of the mitral valve, which occurs due to the regurgitant jet and increase in LV pressures during the diastolic filling phase.
A
B
Chronic aortic insufficiency is often observed clinically in the context of LV enlargement and eccentric hypertrophy. Chronic volume overload results in increases in myocyte length and LV volume, thereby accommodating the increased regurgitant volume. Despite larger end diastolic volumes, LV compliance remains normal, so that LV end diastolic pressure is not elevated. The increased stroke volume accompanied by an increase in systolic force, via the Frank-Starling mechanism, results in an elevation of systolic blood pressure and a widened pulse pressure. The filling pressures in chronic aortic insufficiency are decreased, and therefore pulmonary congestive symptoms may be minimal to none. As LV dilation progresses, the ventricle operates on a higher segment of the pressure-volume curve, with minimal symptomatic burden. In chronic aortic insufficiency, there may be elevated afterload; and in response to increased wall tension, there may be initial concentric followed by eccentric hypertrophy.156,157 The concentric hypertrophy that develops may have an adverse effect on LV diastolic function, which could result in development of congestive symptoms.158 The adverse effect of increased afterload in chronic severe aortic regurgitation is illustrated by the association of systolic hypertension (defined as a systolic blood pressure >140 mmHg) with increased risk of cardiovascular events, including heart failure onset.159,160 The adverse effects of systolic hypertension in aortic regurgitation remained even after accounting for other risk factors, including age, gender, diastolic blood pressure,
DIASTOLIC DYSFUNCTION
Left ventricular volume
Left ventricular volume
Chronic Aortic Insufficiency
Pressure
NORMAL
Pressure
Pressure
SYSTOLIC DYSFUNCTION
Infective endocarditis or a structurally compromised native or prosthetic aortic valve is a common underlying etiology for acute aortic insufficiency. Medical therapy targeted at the underlying condition, such as treatment with antibiotics, may be required. Other medical therapies are generally temporizing measures, and emergency surgery is often required. Vasodilators may unload the left ventricle to increase forward flow but may compromise diastolic coronary perfusion. Pressor agents that increase blood pressure by increasing peripheral vasoconstriction may worsen the degree of aortic regurgitation. Avoidance of bradycardia may also decrease aortic runoff time and ameliorate acute aortic insufficiency. The intra-aortic balloon pump is contraindicated because it may exacerbate the degree of aortic insufficiency.
Left ventricular volume
C
Figure 19-4 Left ventricular pressure-volume loops in systolic and diastolic dysfunction. A, In systolic dysfunction, LV contractility is depressed, the end systolic pressure-volume relationship (ESPVR) is displaced downward and to the right (black arrow), and the end diastolic pressure is normal (open arrow). B, Normal left ventricular pressure-volume loop. C, In diastolic dysfunction, the diastolic pressure-volume relationship is shifted upward and to the left (black arrow), there is diminished capacity to fill at low left atrial pressures, and the end diastolic pressure is elevated (open arrow). (From Aurigemma G: Diastolic heart failure. NEJM 2004;351:1097.)
Chapter 19 • Hypertension and Valvular Heart Disease LV diastolic dimension, and LV ejection fraction at rest.160 Changes in the extracellular matrix may engender an increase in LV stiffness that is observable in chronic aortic insufficiency as well.161 Treatment for chronic aortic insufficiency may require surgery. The primary management issue is the timing of surgical intervention, which is influenced by the natural history of the condition, prevention of often irreversible myocardial damage, and technical considerations at surgery. In relatively asymptomatic individuals with preserved LV ejection fraction, nifedipine delayed time to surgery, which was indicated on the basis of symptoms or LV systolic dysfunction.162 However, there are relatively few trials of medical therapy in this condition. Once symptoms develop, surgical therapy is generally indicated, because prognosis worsens dramatically after symptom onset.163 Undue delay of surgery once symptoms have developed may lead to worsened LV function and poor surgical outcome.
Aortic Stenosis Hemodynamically significant aortic valve obstruction increases LV pressure and increases the LV work to eject blood out of the narrowed valve. By Laplace’s law, an increase in ventricular pressure leads to an increase in LV wall thickness to maintain wall stress. However, ventricular hypertrophy leads to LV diastolic filling abnormalities and increased chamber stiffness, resulting in the need for increased filling pressure to attain any given ventricular volume when compared with the nonhypertrophied state. Ventricular hypertrophy in chronic aortic stenosis may also be accompanied by subendocardial ischemia. Chronically, ongoing aortic valve obstruction leads to a decline in LV systolic and diastolic function and potentially a reduction in the transaortic valve gradient, due to reduced LV ejection fraction. Patients with aortic valvular stenosis frequently present with heart failure symptoms with a normal LV ejection fraction, suggesting an important role of diastolic dysfunction in the pathogenesis of the symptoms.164 In the pressure-overloaded heart of aortic stenosis, myocardial fibrosis occurs, and there are increased levels of enzymes that reflect greater collagen deposition.165,166 In aortic stenosis, there is an increase in collagen synthesis relative to collagen degradation, procollagen endopeptidase, and lysine and proline hydroxylases, compared with controls without valve disease.167 Expression of TIMPs and MMPs are increased in patients with aortic stenosis compared with controls, and increased TIMP/MMP ratios have been noted in humans.167 Increased TIMPs can stimulate fibroblast growth and may have a direct stimulatory effect on collagen production by cardiac fibroblasts.168,169 As noted previously, the diastolic dysfunction in hypertensive LVH and chronic aortic stenosis are parallel in many aspects. However, one very important difference is the impact of surgical intervention on LV systolic and diastolic function. Aortic valve surgery relieves LV pressure overload and decreases afterload. In patients with systolic dysfunction due to severe aortic stenosis without concomitant cardiomyopathy, LV ejection fraction may return to normal. In patients with dominant aortic stenosis, replacement of the aortic valve has been demonstrated to decrease LV mass.170,171 In dominant aortic insufficiency, aortic valve surgery decreases both LV dimension and mass.172 The beneficial effects of surgery may be measurable as early as one week after the procedure.173 The degree of reverse LV remodeling after aortic valve replacement is partly dependent on the type of valve employed. In the case of the pulmonary autograft or Ross procedure, the relative stenosis is
small and the effective orifice area large. Although significant regression of LV mass may be realized with such surgical procedures, incomplete reversal of LVH may occur, particularly in patients with elevated blood pressure, smokers, and those with high presurgical LV mass index at baseline.174 The abnormalities of LV diastolic dysfunction that were present in aortic stenosis may also be reversed after surgical relief of valvular obstruction, but this may occur over a period of years after the procedure. Reduction in LV diastolic stiffness and normalization of relaxation are accompanied by reduction of interstitial fibrosis.175
Acute Mitral Regurgitation Acute mitral regurgitation may also present as heart failure with preserved systolic function. In acute mitral regurgitation, there is acute volume overload of the left atrium and left ventricle, which have not accommodated to the regurgitant volume by chamber enlargement. As a result of mitral regurgitation, forward cardiac output is also reduced, resulting in the potential for lowered systemic blood pressure and an increase in peripheral resistance, which may further increase regurgitation. There is an acute rise in LA and LV diastolic pressures, leading to pulmonary congestion. The ejection fraction may be supranormal because of the increased stretch of ventricular myocytes arising from an increase in LV volume. In acute mitral regurgitation, medical therapy with arterial vasodilators may decrease afterload and also diminish regurgitant volume.176 However, hypotension may be present, limiting the use of vasodilators, and in some cases, an intra-aortic balloon pump may be required as a bridge to surgical repair of the structurally abnormal mitral valve. The intra-aortic balloon pump may decrease afterload while maintaining mean arterial blood pressure in such cases. In acute, severe mitral regurgitation due to a flail leaflet, mortality rate was high with medical therapy and markedly increased in those who even transiently had New York Heart Association class III or IV symptoms. Surgical correction was associated with a significant reduction in mortality rate.177 In asymptomatic individuals with perhaps less severe degrees of mitral regurgitation, the best management strategy is not elucidated. Uncorrected mitral regurgitation may lead to eccentric hypertrophy with progressive chamber enlargement and a decrease in LV ejection fraction, which may render later surgical correction untenable. There may also be an increased risk of sudden death in such individuals.178,179
Chronic Mitral Regurgitation In chronic, severe mitral regurgitation, there is an increase in ventricular preload that over time may lead to the development of eccentric hypertrophy. Enlargement of the LV chamber and increased wall thickness are accompanied by LA enlargement. Initially, chronic mitral regurgitation is compensated by chamber enlargement, and the patient may be asymptomatic. LV diastolic function is altered in chronic mitral regurgitation: Early diastolic filling is enhanced, τ remains unchanged, but chamber stiffness decreases.180–182 The enhanced diastolic function returns to normal after mitral valve replacement.182 The major clinical issue is deciding whether surgical intervention is required, while systolic function is still relatively preserved and ventricular dilation is minimized. A regurgitant fraction of 40%–50% may be an indication that surgery will ultimately be required, since mitral
241
242
Chapter 19 • Hypertension and Valvular Heart Disease valve repair that can reduce this fraction to less than 35% reversed myocardial dysfunction in an animal model.183 Once symptoms develop, even if mild, the prognosis of mitral regurgitation worsens.177 Additionally, if LV ejection fraction decreases below 60% or if the LV end diastolic dimension is greater than 45 mm, there is worsened prognosis,184,185 and surgery is warranted. Valve repair or replacement should be performed, and ideally the former is the preferred procedure because preservation of the subvalvular apparatus improves LV ejection fraction and decreases the likelihood of development of symptomatic heart failure postoperatively.186–189
Mitral Stenosis Mitral stenosis causes pulmonary congestion by inhibiting filling of the left ventricle across the stenosed orifice. LA and pulmonary venous pressures become elevated, and cardiac filling and output are decreased. Subsequently, pulmonary hypertension may develop. Factors affecting LV filling in mitral stenosis are an increased pulmonary driving pressure and elevated LA pressure. Intrinsic LV diastolic dysfunction, therefore, does not contribute to this syndrome of heart failure with preserved LV function. Medical management consists primarily of diuretics and slowing of heart rate, to maximize the period available for diastolic LV filling. Surgical intervention with mitral balloon valvulotomy or valve replacement may be required if symptoms are uncontrolled by medical management.
FUTURE RESEARCH Investigations into the role of hypertension in DHF should include studies of pathophysiology, longitudinal analyses, and treatment. The relative importance of risk factors and prognostic factors for systolic and diastolic heart failure is also not elucidated. It is unknown, for example, whether hypertension is more (or equally) important for the development of diastolic versus systolic heart failure. Such studies are needed to develop preventative strategies and improve treatment for the condition. It is conceivable that hypertension will be an important risk factor in both types of heart failure, given the association of hypertension with increased LV mass and its role as a coronary disease risk factor. The relative importance of systolic blood pressure, pulse pressure, and other measures of vascular stiffness in determining future DHF risk, and their interactions with other known cardiovascular risk factors, require further research. Ventricular-vascular coupling in the setting of vascular stiffness and LV diastolic dysfunction has not been delineated adequately. In particular, causality has not been determined but may be important if therapeutic targets are to be identified. The sex-related differences in incidence of DHF and vascular stiffness have been described, but further study may provide greater insights into the mechanisms of DHF and vascular stiffness. The transition from preclinical disease to clinically overt DHF has not been well characterized. Thus, the factors that promote transition from a state of compensated hypertrophy to DHF have not been determined. This is of importance because targeting the driving pathway for this transition may enable prevention with early, specific treatment strategies. Furthermore, the factors that determine whether a hypertensive patient remains in a state of
LV diastolic dysfunction or progresses to systolic heart failure have not been described adequately. The primary treatment strategy for diastolic dysfunction in hypertensive patients is blood pressure control. However, the significant degree of cardiac fibrosis in DHF may present a therapeutic target to improve LV diastolic dysfunction. Whether LV diastolic dysfunction and stiffness can be reversed significantly, and whether this translates into a clinical effect (such as reduced symptom burden or improved outcome), may provide valuable insights. Valvular heart diseases with a significant component of cardiac fibrosis may also represent a potential therapeutic target of antifibrotic regimens. Ultimately, the clinical effectiveness of such novel therapies targeted toward decreasing ventricular stiffness will need to be tested in controlled clinical trials. More study is required in the longitudinal follow-up of preclinical hypertrophic states with evidence of LV diastolic dysfunction but without overt heart failure. It is known that once the initial onset of heart failure has occurred, the prognostic outlook is grim. Greater efforts are needed to study these patients and possibly prevent DHF. One area of investigation may be in the setting of LVH and LV diastolic dysfunction, whether “how” blood pressure is reduced is more important than the “magnitude” of blood pressure reduction. For example, would drugs that target putative myoproliferative pathways (e.g., ACE inhibitors, angiotensin receptor blockers) be better preventatively than antihypertensive agents that are not pathophysiologically specific? Additionally, it is unknown whether different degrees of diastolic dysfunction at baseline should be treated differently. Specifically, it is unknown whether more severe degrees of diastolic dysfunction in hypertensive patients should be treated more aggressively using multimodality drug therapy. It is also unknown how such patients should be followed longitudinally. To this end, echocardiography and other imaging studies can identify the presence of LV diastolic dysfunction, but whether these modalities can be used serially to assess progress over time has not been determined. REFERENCES 1. Vasan RS, Levy D: Defining diastolic heart failure: A call for standardized diagnostic criteria. Circulation 2000;101:2118–2121. 2. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387–1393. 3. Topol EJ, Traill TA, Fortuin NJ: Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med 1985;312:277–283. 4. Fouad-Tarazi FM, Liebson PR: Echocardiographic studies of regression of left ventricular hypertrophy in hypertension. Hypertension 1987;9: II65–II68. 5. Smith VE, White WB, Meeran MK, Karimeddini MK: Improved left ventricular filling accompanies reduced left ventricular mass during therapy of essential hypertension. J Am Coll Cardiol 1986;8:1449–1454. 6. Schulman SP, Weiss JL, Becker LC, et al: The effects of antihypertensive therapy on left ventricular mass in elderly patients. N Engl J Med 1990;322:1350–1356. 7. Hunt SA, Abraham WT, Chin MH, et al: ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation 2005;112: e154–e235. 8. Grandi AM, Poletti L, Tettamanti F, et al: Left ventricular anatomy and function in normotensive young adults with hypertensive parents. Study at rest and during handgrip. Am J Hypertens 1995;8:154–159.
Chapter 19 • Hypertension and Valvular Heart Disease 9. Kuznetsova T, Staessen JA, Olszanecka A, et al: Maternal and paternal influences on left ventricular mass of offspring. Hypertension 2003; 41:69–74. 10. Garner C, Lecomte E, Visvikis S, et al: Genetic and environmental influences on left ventricular mass. A family study. Hypertension 2000;36: 740–746. 11. Levy D, DeStefano AL, Larson MG, et al: Evidence for a gene influencing blood pressure on chromosome 17: Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the Framingham Heart Study. Hypertension 2000;36:477–483. 12. Bielen E, Fagard R, Amery A: The inheritance of left ventricular structure and function assessed by imaging and Doppler echocardiography. Am Heart J 1991;121:1743–1749. 13. Tang W, Arnett DK, Devereux RB, et al: Sibling resemblance for left ventricular structure, contractility, and diastolic filling. Hypertension 2002;40: 233–238. 14. Palatini P, Amerena J, Nesbitt S, et al: Heritability of left atrial size in the Tecumseh population. Eur J Clin Invest 2002;32:467–471. 15. Levy D, Anderson KM, Savage DD, et al: Echocardiographically detected left ventricular hypertrophy: Prevalence and risk factors. The Framingham Heart Study. Ann Intern Med 1988;108:7–13. 16. Devereux RB, Reichek N: Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation 1977;55:613–618. 17. Daniels SR, Kimball TR, Morrison JA, et al: Indexing left ventricular mass to account for differences in body size in children and adolescents without cardiovascular disease. Am J Cardiol 1995;76:699–701. 18. de Simone G, Daniels SR, Devereux RB, et al: Left ventricular mass and body size in normotensive children and adults: Assessment of allometric relations and impact of overweight. J Am Coll Cardiol 1992;20: 1251–1260. 19. Lauer MS, Anderson KM, Larson MG, Levy D: A new method for indexing left ventricular mass for differences in body size. J Am Coll Cardiol 1994;74:487–491. 20. Aronow WS, Ahn C, Kronzon I, Koenigsberg M: Congestive heart failure, coronary events and atherothrombotic brain infarction in elderly blacks and whites with systemic hypertension and with and without echocardiographic and electrocardiographic evidence of left ventricular hypertrophy. Am J Cardiol 1991;67:295–299. 21. Gardin JM, McClelland R, Kitzman D, et al: M-mode echocardiographic predictors of six- to seven-year incidence of coronary heart disease, stroke, congestive heart failure, and mortality in an elderly cohort (The Cardiovascular Health Study). Am J Cardiol 2001;87:1051–1057. 22. Gottdiener JS, Arnold AM, Aurigemma GP, et al: Predictors of congestive heart failure in the elderly: The Cardiovascular Health Study. J Am Coll Cardiol 2000;35:1628–1637. 23. Bonaduce D, Breglio R, Conforti G, et al: Myocardial hypertrophy and left ventricular diastolic function in hypertensive patients: An echo Doppler evaluation. Eur Heart J 1989;10:611–621. 24. Inouye I, Massie B, Loge D, et al: Abnormal left ventricular filling: An early finding in mild to moderate systemic hypertension. Am J Cardiol 1984;53:120–126. 25. Pearson AC, Gudipati C, Nagelhout D, et al: Echocardiographic evaluation of cardiac structure and function in elderly subjects with isolated systolic hypertension. J Am Coll Cardiol 1991;17:422–430. 26. Ren JF, Pancholy SB, Iskandrian AS, et al: Doppler echocardiographic evaluation of the spectrum of left ventricular diastolic dysfunction in essential hypertension. Am Heart J 1994;127:906–913. 27. de Simone G, Kitzman DW, Palmieri V, et al: Association of inappropriate left ventricular mass with systolic and diastolic dysfunction: The HyperGEN study. Am J Hypertens 2004;17:828–833. 28. Verdecchia P, Angeli F, Gattobigio R, et al: Does the reduction in systolic blood pressure alone explain the regression of left ventricular hypertrophy? J Hum Hypertens 2004;18(Suppl 2):S23–S28. 29. Okin PM, Devereux RB, Liu JE, et al: Regression of electrocardiographic left ventricular hypertrophy predicts regression of echocardiographic left ventricular mass: The LIFE study. J Hum Hypertens 2004;18:403– 409. 30. Reichek N, Devereux RB: Reliable estimation of peak left ventricular systolic pressure by M-mode echographic-determined end-diastolic relative wall thickness: Identification of severe valvular aortic stenosis in adult patients. Am Heart J 1982;103:202–203. 31. Ganau A, Devereux RB, Roman MJ, et al: Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol 1992;19:1550–1558.
32. Krumholz HM, Larson M, Levy D: Prognosis of left ventricular geometric patterns in the Framingham Heart Study. J Am Coll Cardiol 1995;25: 879–884. 33. Hess OM, Ritter M, Schneider J, et al: Diastolic stiffness and myocardial structure in aortic valve disease before and after valve replacement. Circulation 1984;69:855–865. 34. Sagie A, Benjamin EJ, Galderisi M, et al: Echocardiographic assessment of left ventricular structure and diastolic filling in elderly subjects with borderline isolated systolic hypertension (The Framingham Heart Study). Am J Cardiol 1993;72:662–665. 35. Fouad FM, Slominski JM, Tarazi RC: Left ventricular diastolic function in hypertension: Relation to left ventricular mass and systolic function. J Am Coll Cardiol 1984;3:1500–1506. 36. Snider AR, Gidding SS, Rocchini AP, et al: Doppler evaluation of left ventricular diastolic filling in children with systemic hypertension. Am J Cardiol 1985;56:921–926. 37. Devereux RB: Left ventricular diastolic dysfunction: Early diastolic relaxation and late diastolic compliance. J Am Coll Cardiol 1989;13:337– 339. 38. Andren B, Lind L, Hedenstierna G, Lithell H: Left ventricular diastolic function in a population sample of elderly men. Echocardiography 1998;15:433–450. 39. Volders PG, Willems IE, Cleutjens JP, et al: Interstitial collagen is increased in the non-infarcted human myocardium after myocardial infarction. J Mol Cell Cardiol 1993;25:1317–1323. 40. Brilla CG, Pick R, Tan LB, et al: Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res 1990;67:1355–1364. 41. Brilla CG, Funck RC, Rupp H: Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation 2000;102:1388–1393. 42. Diez J, Querejeta R, Lopez B, et al: Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 2002;105:2512–2517. 43. Lindsay MM, Maxwell P, Dunn FG: TIMP-1: A marker of left ventricular diastolic dysfunction and fibrosis in hypertension. Hypertension 2002; 40:136–141. 44. Jalil JE, Doering CW, Janicki JS, et al: Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res 1989; 64:1041–1050. 45. Weber KT, Brilla CG: Pathological hypertrophy and cardiac interstitium. Fibrosis and renin- angiotensin-aldosterone system. Circulation 1991; 83:1849. 46. Yamamoto K, Masuyama T, Sakata Y, et al: Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart. Cardiovasc Res 2002;55:76–82. 47. Stott DK, Marpole DG, Bristow JD, et al: The role of left atrial transport in aortic and mitral stenosis. Circulation 1970;41:1031–1041. 48. Braunwald E, Frahm CJ, Ross JJ: Studies on Starling’s law of the heart. V. Left ventricular function in man. J Clin Invest 1961;40:1882–1890. 49. Cioffi G, Mureddu GF, Stefenelli C, de Simone G: Relationship between left ventricular geometry and left atrial size and function in patients with systemic hypertension. J Hypertens 2004;22:1589–1596. 50. Mattioli AV, Sansoni S, Lucchi GR, Mattioli G: Serial evaluation of left atrial dimension after cardioversion for atrial fibrillation and relation to atrial function. Am J Cardiol 2000;85:832–836. 51. Chinali M, de Simone G, Liu JE, et al: Left atrial systolic force and cardiac markers of preclinical disease in hypertensive patients: The Hypertension Genetic Epidemiology Network (HyperGEN) Study. Am J Hypertens 2005;18:899–905. 52. Thomas L, Levett K, Boyd A, et al: Compensatory changes in atrial volumes with normal aging: Is atrial enlargement inevitable? J Am Coll Cardiol 2002;40:1630–1635. 53. Triposkiadis F, Tentolouris K, Androulakis A, et al: Left atrial mechanical function in the healthy elderly: New insights from a combined assessment of changes in atrial volume and transmitral flow velocity. J Am Soc Echocardiogr 1995;8:801–809. 54. Tsang TS, Barnes ME, Gersh BJ, et al: Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90:1284–1289. 55. Tsang TS, Barnes ME, Gersh BJ, et al: Risks for atrial fibrillation and congestive heart failure in patients >/= 65 years of age with abnormal left ventricular diastolic relaxation. Am J Cardiol 2004; 93:54–58. 56. Barbier P, Alioto G, Guazzi MD: Left atrial function and ventricular filling in hypertensive patients with paroxysmal atrial fibrillation. J Am Coll Cardiol 1994;24:165–170.
243
244
Chapter 19 • Hypertension and Valvular Heart Disease 57. Benjamin EJ, Levy D, Vaziri SM, et al: Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA 1994;271:840–844. 58. Shah PM, Pai RG: Diastolic heart failure. Curr Probl Cardiol 1992;17:781–868. 59. de Simone G, Palmieri V, Bella JN, et al: Association of left ventricular hypertrophy with metabolic risk factors: The HyperGEN study. J Hypertens 2002;20:323–331. 60. Horio T, Miyazato J, Kamide K, et al: Influence of low high-density lipoprotein cholesterol on left ventricular hypertrophy and diastolic function in essential hypertension. Am J Hypertens 2003;16:938–944. 61. Watanabe K, Sekiya M, Tsuruoka T, et al: Effect of insulin resistance on left ventricular hypertrophy and dysfunction in essential hypertension. J Hypertens 1999;17:1153–1160. 62. Nagano N, Nagano M, Yo Y, et al: Role of glucose intolerance in cardiac diastolic function in essential hypertension. Hypertension 1994;23: 1002–1005. 63. Jain A, Avendano G, Dharamsey S, et al: Left ventricular diastolic function in hypertension and role of plasma glucose and insulin. Comparison with diabetic heart. Circulation 1996;93:1396–1402. 64. Liu JE, Palmieri V, Roman MJ, et al: The impact of diabetes on left ventricular filling pattern in normotensive and hypertensive adults: The Strong Heart Study. J Am Coll Cardiol 2001;37:1943–1949. 65. Miyazato J, Horio T, Takishita S, Kawano Y: Fasting plasma glucose is an independent determinant of left ventricular diastolic dysfunction in nondiabetic patients with treated essential hypertension. Hypertens Res 2002;25:403–409. 66. Yamamoto K, Ohki R, Lee RT, et al: Peroxisome proliferator-activated receptor gamma activators inhibit cardiac hypertrophy in cardiac myocytes. Circulation 2001;104:1670–1675. 67. Asakawa M, Takano H, Nagai T, et al: Peroxisome proliferator-activated receptor gamma plays a critical role in inhibition of cardiac hypertrophy in vitro and in vivo. Circulation 2002;105:1240–1246. 68. Zhu P, Lu L, Xu Y, Schwartz GG: Troglitazone improves recovery of left ventricular function after regional ischemia in pigs. Circulation 2000; 101:1165–1171. 69. Laviades C, Varo N, Fernandez J, et al: Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation 1998;98:535–540. 70. Lindsay MM, Maxwell P, Dunn FG: TIMP-1: A marker of left ventricular diastolic dysfunction and fibrosis in hypertension. Hypertension 2002;40: 136–141. 71. Parrinello G, Licata A, Colomba D, et al: Left ventricular filling abnormalities and obesity-associated hypertension: Relationship with overproduction of circulating transforming growth factor beta1. J Hum Hypertens 2005;19:543–550. 72. Krishnan R, Becker RJ, Beighley LM, Lopez-Candales A: Impact of body mass index on markers of left ventricular thickness and mass calculation: Results of a pilot analysis. Echocardiography 2005;22:203–210. 73. Laurent S, Boutouyrie P, Asmar R, et al: Aortic stiffness is an independent predictor of all–cause and cardiovascular mortality in hypertensive patients. Hypertension 2001; 37:1236–1241. 74. Hundley WG, Kitzman DW, Morgan TM, et al: Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796–802. 75. Kawaguchi M, Hay I, Fetics B, Kass DA: Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: Implications for systolic and diastolic reserve limitations. Circulation 2003;107:714–720. 76. Kitzman DW, Little WC, Brubaker PH, et al: Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–2150. 77. Blacher J, Asmar R, Djane S, et al: Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 1999;33: 1111–1117. 78. Eren M, Gorgulu S, Uslu N, et al: Relation between aortic stiffness and left ventricular diastolic function in patients with hypertension, diabetes, or both. Heart 2004;90:37–43. 79. Lacombe F, Dart A, Dewar E, et al: Arterial elastic properties in man: A comparison of echo-Doppler indices of aortic stiffness. Eur Heart J 1992;13:1040–1045. 80. Mottram PM, Haluska BA, Leano R, et al: Relation of arterial stiffness to diastolic dysfunction in hypertensive heart disease. Heart 2005;91: 1551–1556.
81. Breithaupt-Grogler K, Ling M, Boudoulas H, Belz GG: Protective effect of chronic garlic intake on elastic properties of aorta in the elderly. Circulation 1997;96:2649–2655. 82. Roman MJ, Ganau A, Saba PS, et al: Impact of arterial stiffening on left ventricular structure. Hypertension 2000;36:489–494. 83. Palmieri V, Bella JN, Roman MJ, et al: Pulse pressure/stroke index and left ventricular geometry and function: The LIFE Study. J Hypertens 2003; 21:781–787. 84. Tsioufis C, Chatzis D, Dimitriadis K, et al: Left ventricular diastolic dysfunction is accompanied by increased aortic stiffness in the early stages of essential hypertension: A TDI approach. J Hypertens 2005;23:1745– 1750. 85. Kawaguchi M, Hay I, Fetics B, Kass DA: Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: Implications for systolic and diastolic reserve limitations. Circulation 2003;107:714–720. 86. Leite-Moreira AF, Correia-Pinto J, Gillebert TC: Afterload induced changes in myocardial relaxation: A mechanism for diastolic dysfunction. Cardiovasc Res 1999;43:344–353. 87. O’Rourke MF: Diastolic heart failure, diastolic left ventricular dysfunction and exercise intolerance. J Am Coll Cardiol 2001;38:803–805. 88. Krumholz HM, Larson M, Levy D: Sex differences in cardiac adaptation to isolated systolic hypertension. Am J Cardiol 1993;72:310–313. 89. Aurigemma GP, Gaasch WH: Gender differences in older patients with pressure-overload hypertrophy of the left ventricle. Cardiology 1995; 86:310–317. 90. Redfield MM, Jacobsen SJ, Borlaug BA, et al: Age- and gender-related ventricular-vascular stiffening: A community-based study. Circulation 2005; 112:2254–2262. 91. Kelly RP, Ting CT, Yang TM, et al: Effective arterial elastance as index of arterial vascular load in humans. Circulation 1992;86:513–521. 92. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. 93. Dokainish H, Zoghbi WA, Lakkis NM, et al: Optimal noninvasive assessment of left ventricular filling pressures: A comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation 2004;109:2432– 2439. 94. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 95. Yasmin, Falzone R, Brown MJ: Determinants of arterial stiffness in offspring of families with essential hypertension. Am J Hypertens 2004;17: 292–298. 96. Zion AS, Bond V, Adams RG, et al: Low arterial compliance in young African-American males. Am J Physiol Heart Circ Physiol 2003;285: H457–H462. 97. Nurnberger J, Opazo SA, Mitchell A, et al: The T-allele of the C825T polymorphism is associated with higher arterial stiffness in young healthy males. J Hum Hypertens 2004;18:267–271. 98. Stewart KJ, Bacher AC, Turner KL, et al: Effect of exercise on blood pressure in older persons: A randomized controlled trial. Arch Intern Med 2005;165:756–762. 99. Ichihara A, Hayashi M, Koura Y, et al: Long-term effects of intensive bloodpressure lowering on arterial wall stiffness in hypertensive patients. Am J Hypertens 2003;16:959–965. 100. Luo W, Grupp IL, Harrer J, et al: Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. Circ Res 1994;75:401–409. 101. Kadambi VJ, Ball N, Kranias EG, et al: Modulation of force-frequency relation by phospholamban in genetically engineered mice. Am J Physiol 1999;276:H2245–H2250. 102. Wegener AD, Simmerman HK, Lindemann JP, Jones LR: Phospholamban phosphorylation in intact ventricles. Phosphorylation of serine 16 and threonine 17 in response to beta-adrenergic stimulation. J Biol Chem 1989;264:11468–11474. 103. Kim S, Yoshiyama M, Izumi Y, et al: Effects of combination of ACE inhibitor and angiotensin receptor blocker on cardiac remodeling, cardiac function, and survival in rat heart failure. Circulation 2001;103:148–154. 104. Sakata Y, Yamamoto K, Mano T, et al: Angiotensin II type 1 receptor blockade prevents diastolic heart failure through modulation of Ca(2+) regulatory proteins and extracellular matrix. J Hypertens 2003;21: 1737–1745.
Chapter 19 • Hypertension and Valvular Heart Disease 105. Sakata Y, Yamamoto K, Mano T, et al: Temocapril prevents transition to diastolic heart failure in rats even if initiated after appearance of LV hypertrophy and diastolic dysfunction. Cardiovasc Res 2003;57:757–765. 106. Knowles JW, Esposito G, Mao L, et al: Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A–deficient mice. J Clin Invest 2001;107:975–984. 107. Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA: Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 2003;93: 280–291. 108. Takimoto E, Champion HC, Li M, et al: Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 2005;11:214–222. 109. Yamamoto K, Masuyama T, Sakata Y, et al: Prevention of diastolic heart failure by endothelin type A receptor antagonist through inhibition of ventricular structural remodeling in hypertensive heart. J Hypertens 2002;20:753–761. 110. Iwanaga Y, Kihara Y, Hasegawa K, et al: Cardiac endothelin-1 plays a critical role in the functional deterioration of left ventricles during the transition from compensatory hypertrophy to congestive heart failure in salt-sensitive hypertensive rats. Circulation 1998;98:2065–2073. 111. Lips DJ, deWindt LJ, van Kraaij DJ, Doevendans PA: Molecular determinants of myocardial hypertrophy and failure: Alternative pathways for beneficial and maladaptive hypertrophy. Eur Heart J 2003;24:883–896. 112. Hein S, Arnon E, Kostin S, et al: Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: Structural deterioration and compensatory mechanisms. Circulation 2003;107:984–991. 113. Peterson JT, Hallak H, Johnson L, et al: Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure. Circulation 2001;103:2303–2309. 114. Fielitz J, Hein S, Mitrovic V, et al: Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease. J Am Coll Cardiol 2001;37:1443–1449. 115. Olsen MH, Christensen MK, Wachtell K, et al: Markers of collagen synthesis is [sic] related to blood pressure and vascular hypertrophy: A LIFE substudy. J Hum Hypertens 2005;19:301–307. 116. Nishikawa N, Yamamoto K, Sakata Y, et al: Differential activation of matrix metalloproteinases in heart failure with and without ventricular dilatation. Cardiovasc Res 2003;57:766–774. 117. Tayebjee MH, Lim HS, Nadar S, et al: Tissue inhibitor of metalloproteinase-1 is a marker of diastolic dysfunction using tissue doppler in patients with type 2 diabetes and hypertension. Eur J Clin Invest 2005;35:8–12. 118. Kannel WB, Castelli WP, McNamara PM, et al: Role of blood pressure in the development of congestive heart failure. The Framingham study. N Engl J Med 1972;287:781–787. 119. Vasan RS, Beiser A, Seshadri S, et al: Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study. JAMA 2002;287:1003–1010. 120. Levy D, Larson MG, Vasan RS, et al: The progression from hypertension to congestive heart failure. JAMA 1996;275:1557–1562. 121. Topol EJ, Traill TA, Fortuin NJ: Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med 1985;312:277–283. 122. Cuocolo A, Sax FL, Brush JE, et al: Left ventricular hypertrophy and impaired diastolic filling in essential hypertension. Diastolic mechanisms for systolic dysfunction during exercise. Circulation 1990;81:978–986. 123. Fouad-Tarazi FM: Left ventricular diastolic dysfunction in hypertension. Curr Opin Cardiol 1994;9:551–560. 124. Given BD, Lee TH, Stone PH, Dzau VJ: Nifedipine in severely hypertensive patients with congestive heart failure and preserved ventricular systolic function. Arch Intern Med 1985;145:281–285. 125. Gandhi SK, Powers JC, Nomeir AM, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001; 344:17–22. 126. Thomas JT, Kelly RF, Thomas SJ, et al: Utility of history, physical examination, electrocardiogram, and chest radiograph for differentiating normal from decreased systolic function in patients with heart failure. Am J Med 2002;112:437–445. 127. Badgett RG, Lucey CR, Mulrow CD: Can the clinical examination diagnose left-sided heart failure in adults? JAMA 1997;277:1712–1719. 128. Houghton JL, Frank MJ, Carr AA, et al: Relations among impaired coronary flow reserve, left ventricular hypertrophy and thallium perfusion defects in hypertensive patients without obstructive coronary artery disease. J Am Coll Cardiol 1990;15:43–51. 129. de Simone G, Greco R, Mureddu G, et al: Relation of left ventricular diastolic properties to systolic function in arterial hypertension. Circulation 2000;101:152–157.
130. Wachtell K, Smith G, Gerdts E, et al: Left ventricular filling patterns in patients with systemic hypertension and left ventricular hypertrophy (the LIFE study). Losartan Intervention For Endpoint. Am J Cardiol 2000; 85:466–472. 131. Stoddard MF, Pearson AC, Kern MJ, et al: Left ventricular diastolic function: Comparison of pulsed Doppler echocardiographic and hemodynamic indexes in subjects with and without coronary artery disease. J Am Coll Cardiol 1989;13:327–336. 132. Kuo LC, Quinones MA, Rokey R, et al: Quantification of atrial contribution to left ventricular filling by pulsed Doppler echocardiography and the effect of age in normal and diseased hearts. Am J Cardiol 1987;59: 1174–1178. 133. Bonow RO, Frederick TM, Bacharach SL, et al: Atrial systole and left ventricular filling in hypertrophic cardiomyopathy: Effect of verapamil. Am J Cardiol 1983;51:1386–1391. 134. Channer KS, Jones JV: The contribution of atrial systole to mitral diastolic blood flow increases during exercise in humans. J Physiol 1989;411: 53–61. 135. Muller-Brunotte R, Kahan T, Malmqvist K, Edner M: Blood pressure and left ventricular geometric pattern determine diastolic function in hypertensive myocardial hypertrophy. J Hum Hypertens 2003;17:841– 849. 136. Simek CL, Feldman MD, Haber HL, et al: Relationship between left ventricular wall thickness and left atrial size: Comparison with other measures of diastolic function. J Am Soc Echocardiogr 1995;8:37–47. 137. Cioffi G, Stefenelli C: Comparison of left ventricular geometry and left atrial size and function in patients with aortic stenosis versus those with pure aortic regurgitation. Am J Cardiol 2002;90:601–606. 138. de Simone G, Kitzman DW, Chinali M, et al: Left ventricular concentric geometry is associated with impaired relaxation in hypertension: The HyperGEN study. Eur Heart J 2005;26:1039–1045. 139. Wachtell K, Papademetriou V, Smith G, et al: Relation of impaired left ventricular filling to systolic midwall mechanics in hypertensive patients with normal left ventricular systolic chamber function: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Am Heart J 2004;148:538–544. 140. Bella JN, Palmieri V, Liu JE, et al: Relationship between left ventricular diastolic relaxation and systolic function in hypertension: The Hypertension Genetic Epidemiology Network (HyperGEN) Study. Hypertension 2001;38:424–428. 141. Yamakado T, Takagi E, Okubo S, et al: Effects of aging on left ventricular relaxation in humans. Analysis of left ventricular isovolumic pressure decay. Circulation 1997;95:917–923. 142. Nishimura RA, Tajik AJ: Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta stone. J Am Coll Cardiol 1997;30:8–18. 143. Di Bello V, Giorgi D, Pedrinelli R, et al: Left ventricular hypertrophy and its regression in essential arterial hypertension. A tissue Doppler imaging study. Am J Hypertens 2004;17:882–890. 144. Edner M, Jarnert C, Muller-Brunotte R, et al: Influence of age and cardiovascular factors on regional pulsed wave Doppler myocardial imaging indices. Eur J Echocardiogr 2000;1:87–95. 145. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998; 32:865–875. 146. Chen YT, Vaccarino V, Williams CS, et al: Risk factors for heart failure in the elderly: A prospective community-based study. Am J Med 1999;106:605–612. 147. Gottdiener JS, Arnold AM, Aurigemma GP, et al: Predictors of congestive heart failure in the elderly: The Cardiovascular Health Study. J Am Coll Cardiol 2000;35:1628–1637. 148. Haider AW, Larson MG, Franklin SS, Levy D: Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med 2003;138:10–16. 149. Kostis JB, Lawrence-Nelson J, Ranjan R, et al: Association of increased pulse pressure with the development of heart failure in SHEP. Systolic Hypertension in the Elderly (SHEP) Cooperative Research Group. Am J Hypertens 2001;14:798–803. 150. Kostis JB, Davis BR, Cutler J, et al: Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. JAMA 1997;278:212–216. 151. Wang JG, Staessen JA, Franklin SS, et al: Systolic and diastolic blood pressure lowering as determinants of cardiovascular outcome. Hypertension 2005;45:907–913.
245
246
Chapter 19 • Hypertension and Valvular Heart Disease 152. Brilla CG, Funck RC, Rupp H: Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation 2000;102:1388–1393. 153. Diez J, Querejeta R, Lopez B, et al: Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 2002;105:2512–2517. 154. Mottram PM, Haluska B, Leano R, et al: Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 2004;110:558–565. 155. Pedersen F, Raymond I, Mehlsen J, et al: Prevalence of diastolic dysfunction as a possible cause of dyspnea in the elderly. Am J Med 2005;118:25–31. 156. Wisenbaugh T, Spann JF, Carabello BA: Differences in myocardial performance and load between patients with similar amounts of chronic aortic versus chronic mitral regurgitation. J Am Coll Cardiol 1984;3:916–923. 157. Taniguchi K, Nakano S, Kawashima Y, et al: Left ventricular ejection performance, wall stress, and contractile state in aortic regurgitation before and after aortic valve replacement. Circulation 1990;82:798–807. 158. Feiring AJ, Rumberger JA: Ultrafast computed tomography analysis of regional radius-to-wall thickness ratios in normal and volume-overloaded human left ventricle. Circulation 1992;85:1423–1432. 159. Spagnuolo M, Kloth H, Taranta A, et al: Natural history of rheumatic aortic regurgitation. Criteria predictive of death, congestive heart failure, and angina in young patients. Circulation 1971;44:368–380. 160. Supino PG, Borer JS, Herrold EM, et al: Prognostic impact of systolic hypertension on asymptomatic patients with chronic severe aortic regurgitation and initially normal left ventricular performance at rest. Am J Cardiol 2005;96:964–970. 161. Borer JS, Truter SL, Herrold EM, et al: The cellular and molecular basis of heart failure in regurgitant valvular diseases: The myocardial extracellular matrix as a building block for future therapy. Adv Cardiol 2002;39:7–14. 162. Scognamiglio R, Rahimtoola SH, Fasoli G, et al: Nifedipine in asymptomatic patients with severe aortic regurgitation and normal left ventricular function. N Engl J Med 1994;331:689–694. 163. Klodas E, Enriquez-Sarano M, Tajik AJ, et al: Surgery for aortic regurgitation in women. Contrasting indications and outcomes compared with men. Circulation 1996;94:2472–2478. 164. Dineen E, Brent BN: Aortic valve stenosis: Comparison of patients with to those without chronic congestive heart failure. Am J Cardiol 1986;57:419–422. 165. Krayenbuehl HP, Hess OM, Monrad ES, et al: Left ventricular myocardial structure in aortic valve disease before, intermediate, and late after aortic valve replacement. Circulation 1989;79:744–755. 166. Villari B, Campbell SE, Hess OM, et al: Influence of collagen network on left ventricular systolic and diastolic function in aortic valve disease. J Am Coll Cardiol 1993;22:1477–1484. 167. Heymans S, Schroen B, Vermeersch P, et al: Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation 2005;112:1136–1144. 168. Visse R, Nagase H: Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistry. Circ Res 2003; 92:827–839. 169. Lovelock JD, Baker AH, Gao F, et al: Heterogeneous effects of tissue inhibitors of matrix metalloproteinases on cardiac fibroblasts. Am J Physiol Heart Circ Physiol 2005;288:H461–H468. 170. Monrad ES, Hess OM, Murakami T, et al: Time course of regression of left ventricular hypertrophy after aortic valve replacement. Circulation 1988;77:1345–1355.
171. Pantely G, Morton M, Rahimtoola SH: Effects of successful, uncomplicated valve replacement on ventricular hypertrophy, volume, and performance in aortic stenosis and in aortic incompetence. J Thorac Cardiovasc Surg 1978;75:383–391. 172. Roman MJ, Klein L, Devereux RB, et al: Reversal of left ventricular dilatation, hypertrophy, and dysfunction by valve replacement in aortic regurgitation. Am Heart J 1989;118:553–563. 173. Djavidani B, Schmid FX, Keyser A, et al: Early regression of left ventricular hypertrophy after aortic valve replacement by the Ross procedure detected by cine MRI. J Cardiovasc Magn Reson 2004;6:1–8. 174. Duebener LF, Stierle U, Erasmi A, et al: Ross procedure and left ventricular mass regression. Circulation 2005;112:I415–I422. 175. Villari B, Vassalli G, Monrad ES, et al: Normalization of diastolic dysfunction in aortic stenosis late after valve replacement. Circulation 1995;91: 2353–2358. 176. Yoran C, Yellin EL, Becker RM, et al: Mechanism of reduction of mitral regurgitation with vasodilator therapy. Am J Cardiol 1979;43: 773–777. 177. Ling LH, Enriquez-Sarano M, Seward JB, et al: Clinical outcome of mitral regurgitation due to flail leaflet. N Engl J Med 1996;335:1417–1423. 178. Grigioni F, Enriquez-Sarano M, Ling LH, et al: Sudden death in mitral regurgitation due to flail leaflet. J Am Coll Cardiol 1999;34:2078– 2085. 179. Carabello BA: Sudden death in mitral regurgitation: Why was I so surprised? J Am Coll Cardiol 1999;34:2086–2087. 180. Corin WJ, Murakami T, Monrad ES, et al: Left ventricular passive diastolic properties in chronic mitral regurgitation. Circulation 1991;83:797– 807. 181. Zile MR, Tomita M, Nakano K, et al: Effects of left ventricular volume overload produced by mitral regurgitation on diastolic function. Am J Physiol 1991;261:H1471–H1480. 182. Zile MR, Tomita M, Ishihara K, et al: Changes in diastolic function during development and correction of chronic LV volume overload produced by mitral regurgitation. Circulation 1993;87:1378–1388. 183. Nagatsu M, Ishihara K, Zile MR, et al: The effects of complete versus incomplete mitral valve repair in experimental mitral regurgitation. J Thorac Cardiovasc Surg 1994;107:416–423. 184. Enriquez-Sarano M, Tajik AJ, Schaff HV, et al: Echocardiographic prediction of survival after surgical correction of organic mitral regurgitation. Circulation 1994;90:830–837. 185. Wisenbaugh T, Skudicky D, Sareli P: Prediction of outcome after valve replacement for rheumatic mitral regurgitation in the era of chordal preservation. Circulation 1994;89:191–197. 186. Enriquez-Sarano M, Schaff HV, Orszulak TA, et al: Valve repair improves the outcome of surgery for mitral regurgitation. A multivariate analysis. Circulation 1995;91:1022–1028. 187. Rozich JD, Carabello BA, Usher BW, et al: Mitral valve replacement with and without chordal preservation in patients with chronic mitral regurgitation. Mechanisms for differences in postoperative ejection performance. Circulation 1992;86:1718–1726. 188. David TE, Uden DE, Strauss HD: The importance of the mitral apparatus in left ventricular function after correction of mitral regurgitation. Circulation 1983;68:II76–II82. 189. Sarris GE, Cahill PD, Hansen DE, et al: Restoration of left ventricular systolic performance after reattachment of the mitral chordae tendineae. The importance of valvular-ventricular interaction. J Thorac Cardiovasc Surg 1988;95:969–979.
HSUAN-HUNG CHUANG, MBBS FILIPPOS TRIPOSKIADIS, MD RANDALL C. STARLING, MD, MPH
20
Dilated Cardiomyopathy and Cardiac Transplantation INTRODUCTION PATHOPHYSIOLOGY Diastolic Dysfunction in Dilated Cardiomyopathy Diastolic Dysfunction in the Transplanted Heart CLINICAL RELEVANCE Prognostic Significance of Left Ventricular
Diastolic Dysfunction in Dilated Cardiomyopathy Prognostic Significance of Right Ventricular Diastolic Dysfunction in Dilated Cardiomyopathy Impact on Treatment Strategies in Dilated Cardiomyopathy FUTURE RESEARCH
INTRODUCTION Dilated cardiomyopathy (DCM) is a heterogeneous disease of the myocardium that is characterized by left ventricular (LV) or biventricular dilatation and systolic dysfunction. In the classification of the World Health Organization/International Society and Federation of Cardiology Task Force, DCM in its primary (e.g., idiopathic, familial) and secondary forms (most commonly ischemic, hypertensive, valvular, alcohol-related, or viral or autoimmune in origin) is the most common cause of the clinical syndrome of heart failure (HF).1 Familial DCM accounts for approximately 20% to 35% of DCM cases and has been linked to a diverse group of loci and genes.2 The reported annual incidence of the primary form of DCM varies between five and eight cases per 100,000 population3,4; true incidence is likely underestimated, since many asymptomatic cases remain unrecognized. Primary DCM can occur at any age but is first seen mostly between the ages of 20 and 50 years.5,6
Blacks and males have a 2.5-fold increase in risk compared with Caucasians and females. The natural history of DCM is often progressive, and the clinical picture at the time of diagnosis can vary widely, with the most common initial manifestation being HF in 75% to 85% of patients.6–8 Echocardiography plays an essential role in the diagnosis and the follow-up of DCM. A portion of patients fortunately experience recovery of function and “reverse remodeling,” which can be documented with serial echocardiographic examinations.
PATHOPHYSIOLOGY Diastolic Dysfunction in Dilated Cardiomyopathy In patients with DCM, there are abnormalities in the LV systolic pressure-volume (P-V) relationship, which are almost always associated with changes in the diastolic portion of that relationship. Indeed, nearly all patients with systolic dysfunction have 247
248
Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation impaired relaxation and variable decreases in ventricular compliances.9 LV diastolic dysfunction may lead to an increase in LV diastolic pressure and greatly influence the symptomatic status and outcome of patients.10 Despite improved treatment, the mortality rate in DCM remains high, accounting for 10,000 deaths annually in the United States.3 Diastolic function has traditionally been evaluated by cardiac catheterization with direct measurement of filling pressures and relaxation. This invasive approach, describing LV filling pressures, compliance, and relaxation as major determinants of LV diastolic function, is neither feasible nor suitable for routine evaluation. The development and validation of several noninvasive Doppler echocardiographic techniques that are relatively load independent have made echocardiography the clinical standard for the assessment of LV diastolic function.
Pathomorphology and Pathogenesis of Dilated Cardiomyopathy DCM is heterogeneous in its morphology. Common to the whole group is a poorly contracting dilated LV with a normal or reduced LV wall thickness. The lack of an increase in LV wall thickness often masks a significant increase in LV mass. The histological changes are variable and nonspecific, including (a) increased myocyte diameter and nuclear size, (b) myofibrillary loss, (c) focal myocyte apoptosis and death, (d) increase in interstitial Tlymphocytes/macrophages, and (e) interstitial fibrosis.11 The pathogenesis of DCM remains uncertain despite intense research. Four basic mechanisms have been hypothesized, including familial and genetic factors, chronic viral infection of the myocardium and other cytotoxic insults, immune abnormalities leading to cellular and humorally mediated myocyte damage, and metabolic, energetic, and contractile abnormalities.12,13 With the onset of failure of the heart’s intrinsic mechanisms for sustaining a reasonable ejection fraction (EF) (e.g., contractile protein and excitation-contraction coupling mechanisms, cellular remodeling, bioenergetics), the cardiac remodeling process gradually becomes maladaptive. This is compounded by the effects of endogenous bioactive chemicals (e.g., hormones, neurotransmitters, cytokines) and cell loss via myocyte apoptosis or necrosis compounds, which alter the expression of genes regulating contractility, contributing to the progressive myocardial dysfunction in DCM.
below approximately 30%.15 To maintain cardiac output, relaxation begins to prolong, becomes more afterload dependent, and eventually leads to elevation in LV end diastolic pressure (LVEDP).16 Thus, while the diastolic P-V relationship may reflect a more compliant chamber, the other abnormal diastolic indices support the conclusion that all patients with systolic HF and elevated diastolic pressures in fact have combined systolic and diastolic HF (Fig. 20-1).10 Alternatively, some patients may have only a modest decrease in LV EF and a modest increase in end diastolic volume, but a marked increase in LVEDP and a diastolic P-V relationship, reflecting decreased chamber compliance. Conversely, improvement in systolic function following treatment often leads to concomitant improvement in relaxation, especially if these changes are mediated through the β-adrenergic pathways.
Echocardiographic Indices of Left Ventricular Diastolic Dysfunction Abnormal ventricular contractility and dilatation are the hallmarks of DCM. Although DCM is usually a diffuse process, LV dysfunction can exist independently of concomitant right ventricular (RV) involvement in some patients. The early opening of mitral valve leaflets on M-mode echocardiography (the so-called C-hump) may reflect a high LVEDP. A large body of literature has accrued describing the various Doppler echocardiographic techniques in assessment of diastolic function. These techniques can be used alone or in combination, but most of them are dependent on heart rate, preload, and afterload. The LV filling or transmitral flow pattern remains the starting point. The pulmonary venous flow signal should always be sought as an adjunct to the mitral inflow pattern. These have been described in great detail in Chapters 2, 10, and 18. Briefly, most patients can be categorized into one of the three patterns based on the following Doppler indices and timing (Fig. 20-2): ❒
❒
Diastolic Dysfunction and the Pressure-Volume Relationship In patients with DCM and systolic HF, the abnormalities in the P-V relationship occur during systole, including decreased LV EF, stroke volume, and stroke work. As diastolic function is critically important to systolic function and is linked to it symbiotically, virtually all patients with symptomatic HF have abnormalities in diastolic function. Conversely, as diastolic function worsens and filling pressures increase, systolic function is affected by the FrankStarling mechanism. This is often called the “yin and yang” of cardiac function. Ventricular diastole involves the complex interplay of numerous components, including LV relaxation, diastolic suction, stiffness or compliance of the myocardium, pericardial restraint, ventricular interaction, and atrial contribution.14 LV relaxation is related to the time constant of intracavitary pressure decay during isovolumic relaxation, whereas LV compliance and stiffness are related more to the local slope of the diastolic P-V curve. LV relaxation remains relatively intact until LV EF falls
❒
Impaired relaxation (IR) pattern. Intracardiac pressures are unaffected, but less effective suction from LV relaxation results in a delayed and diminished left atrial (LA)-to-LV early diastolic pressure gradient. This is characterized by long isovolumic relaxation time (IVRT), prolonged deceleration time (DT) of the early diastolic E wave, a high late diastolic A-wave velocity, and a decreased E/A ratio. Pseudonormal (PN) pattern. Increased LA pressure offsets the reduced flow related to impaired relaxation. Transmitral flow pattern appears normal in terms of E/A ratio and DT. Restrictive filling (RF) pattern. LV distensibility is reduced because of increased intrinsic stiffness or decreased operating compliance, and LA pressure is increased. The elevated LA pressure results in an increased E velocity. The decrease in mid-to-late diastolic distensibility produces a more rapid transmitral pressure equilibration, creating a “dip-andplateau” effect. This is characterized by short IVRT, high E velocity and short DT, and reduced A velocity. This pattern can be further stratified into “reversible” and “irreversible” subgroups with loading manipulations, resulting in incremental prognostic value.17,18
Because the majority of patients with DCM are studied while on medications, drug effects must also be considered. A study by Makhoul et al.19 demonstrated a direct relationship between changes in pulmonary capillary wedge pressure (PCWP) induced by intravenous isosorbide dinitrate and the transmitral E/A ratio.
Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation LV PRESSURE-VOLUME LOOP
LV pressure (mmHg)
LV pressure (mmHg)
LV PRESSURE-VOLUME LOOP
LV pressure (ml/m2)
A
LV volume (ml/m2)
Normal Systolic HF NYHA class III–IV Systolic HF following treatment
B
Normal Combined systolic and diastolic HF NYHA class III–IV Combined systolic and diastolic HF after treatment
Figure 20-1 Pressure-volume (P-V) loops in A, systolic heart failure (HF) and B, combined systolic and diastolic HF. A normal left ventricular (LV) P-V loop is shown on the left side of the curve (red loop). Systolic HF manifests as an increase in LV end diastolic volume and a reduction in stroke volume. LV end diastolic pressure (LVEDP) is increased. As a result, the diastolic portion of the curve simply shifts to the right, along the same P-V relationship (green loop). This returns to an intermediate state following treatment (blue loop). In panel B, illustrating combined diastolic and systolic HF, the LVEDP is elevated. Owing to a decrease in LV distensibility, whereby a higher diastolic pressure is necessary to achieve the same diastolic volume, there is a significant upward shift of the diastolic P-V relationship. This is in contrast to pure diastolic HF, where there is only an upward shift in P-V relationship, but no change in LV end diastolic volume. (Modified from Zile MR et al: New concepts in diastolic dysfunction and diastolic heart failure: Part I. Diagnosis, prognosis, and measurements of diastolic function. Circ 2002;105:1387–1393.)
Diastolic
Normal
Mild DD
Moderate DD
Severe DD
Function
Normal Impaired relaxation Pseudonormal Reversible restrictive Fixed restrictive E A
Mitral inflow
E Mitral inflow after Valsalva
A
Sa DTI mitral annulus Aa Ea Pulmonary venous flow
S E
LV relaxation
Normal
Impaired
Impaired
Impaired
Impaired
LV compliance
Normal
Normal to ↓
↓↓
↓↓↓
↓↓↓↓
Atrial pressure Tau
Normal
Normal ↑
↑↑ ↑
↑↑↑ ↑↑
↑↑↑↑ ↑↑↑
Figure 20-2 Doppler parameters in progressive diastolic dysfunction. DD, diastolic dysfunction; TDI, tissue Doppler imaging; LV, left ventricle; E, early diastolic velocity (cm/sec); A, late diastolic velocity (cm/sec); Sa, myocardial systolic velocity (cm/sec); Ea, myocardial early diastolic velocity (cm/sec); Aa, myocardial late diastolic velocity. (Modified from Redfield MM et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202.)
249
250
Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation The initial high E/A ratio, typical of the RF pattern, was reduced by more than 50% after administration of nitrates in nearly all patients with New York Heart Association class IV HF. In addition to analysis of filling pattern, the mean LA pressure (MLAP) may be accurately predicted from the DT of the pulmonary venous diastolic (DTD) flow slope, using the following regression equation20: MLAP = 53.236 − [0.302 DTD] + [0.000484 (DTD2)]. Other echocardiographic indices of diastolic function pertaining to DCM include rate of LV pressure decline, the Tei index, color kinesis, and flow propagation velocity (Vp). Rate of LV Pressure Decline This can be obtained by tracing the deceleration phase of the mitral regurgitation Doppler spectral signal and applying the Bernoulli equation to obtain the instantaneous pressure gradient between the left ventricle and the left atrium. This derivative of Tau (τ) from the velocity curve, validated in human studies as a standard for assessment of active relaxation, is not applicable to those cases of DCM without a complete mitral regurgitant envelope. The Tei Index This is a combined myocardial performance index (isovolumic contraction time plus IVRT divided by ejection time) that may be more effective for analysis of global cardiac dysfunction than for systolic and diastolic measures alone. Although it may be a sensitive indicator of overall cardiac dysfunction in patients with mild to moderate HF,21 it has variable prognostic significance in both adults and children with DCM22–24 (see Chapter 16). Color Kinesis Color kinesis is an echocardiographic technique based on acoustic quantification that allows color encoding of endocardial motion in real time.25–27 The regional LV filling properties can be derived from segmental analysis of diastolic color kinesis images. Increased diastolic asynchrony has been found in patients with DCM and severe mitral regurgitation, which are known to adversely affect global diastolic function.28–30 However, this technique is dependent on the quality of two-dimensional images and may be affected by significant cardiac translation and/or rotation. Flow Propagation Velocity This method offers a glance at different intrinsic LV properties that determine LV filling, such as geometry and LV synchrony. The color M-mode velocity propagation of early diastolic flow correlates with intraventricular pressure gradients and has been proposed as a load-independent indicator of LV diastolic function. Brun et al. were the first to show that Vp is related to LV relaxation.31 The progressive decrease of Vp runs in parallel with the increase of τ, irrespective of rising filling pressure.32 It is therefore free of pseudonormalization, unlike transmitral flow. Compared with the brisk Vp in normal patients, there is often significantly delayed propagation and prolongation of the duration of inflow in patients with DCM.33 In fact, continuous apical flow can be visualized in 25% of DCM. The ratio of E/Vp is a widely used index in the estimation of filling pressure. Coelho et al. found that in patients with severe LV dysfunction, Vp correlated closely with E/A ratio, IVRT, DT, and the Tei index.34 In a heterogeneous group comprising normal, ischemic, and dilated hearts,35 PCWP was calculated as: PCWP = [5.27 × E/Vp] + 4.6 (mmHg).
Reported positive and negative predictive values for E/Vp greater than 1.5 to predict PCWP greater than 12 mmHg were 93% and 70%, respectively. Correlation between E/Vp and PCWP outperformed correlations with maximal E and E/A, independent of LV EF (see Chapter 11).
Tissue Doppler Imaging Early diastolic LV longitudinal expansion, as represented by mitral annular velocity (Ea), and late diastolic mitral annular velocity (Aa) correspond fairly to the E and A waves on mitral inflow. Although Ea has been suggested as being less load sensitive than mitral inflow variables, this remains debatable.36,37 Ea is often reduced to less than 8 cm/sec in the RF pattern. Blunting of the magnitude of Ea correlates closely with diastolic dysfunction established invasively.36 Tissue Doppler imaging (TDI) may even be of value in the presence of atrial fibrillation, where there is no A wave. The ratio of transmitral peak inflow E velocity to Ea has also been shown to correlate significantly with invasively derived mean PCWP using a regression equation, Mean PCWP = 1.24 (E/Ea) + 1.9 (mmHg), and shows better correlation with LVEDP (r = 0.87) than do other Doppler variables38,39 (see Chapter 12). As a general clinical guideline, an E/Ea ratio greater than 10 is predictive of a mean PCWP above 15 mmHg with a sensitivity and specificity of 92% and 80%, respectively. The interval between the onset of mitral E and annular Ea by TDI (TE–Ea) has also been used to estimate LV filling pressure and correlate with τ.40 It has been proposed that PCWP is closely related to IVRT/TE–Ea. In fact, IVRT/ TE–Ea less than 2 was found to have a sensitivity of 91% and a specificity of 89% for detecting PCWP greater than 15 mmHg in other disease states.41 However, the cutoff limit for this index in DCM requires further evaluation. Finally, it is noteworthy that TDI may reveal subtle abnormalities of systolic and diastolic function in asymptomatic relatives of patients with familial DCM with LV enlargement and preserved LV EF and therefore may help predict those who will go on to develop clinical DCM.41
Diastolic Dysfunction in the Transplanted Heart With advances in surgical techniques and immunosuppression, the survival rate following orthotropic heart transplantation (OHT) significantly exceeds that of medical therapy for advanced HF. However, the transplanted heart does not provide the recipient with normal cardiac function, as posttransplant cardiac physiology and hemodynamics differ significantly from those in healthy subjects. Despite anticipated 1- and 5-year survival rates of 90% and 70%, respectively, acute and chronic allograft rejections have remained major determinants of patient outcome. Other important perioperative issues are persistently elevated pulmonary hypertension and RV dysfunction. As acute rejection is initially asymptomatic, regular rejection surveillance is obligatory. For detecting allograft rejection and monitoring immunosuppressive treatment, clinical and laboratory examinations, along with endomyocardial biopsies (EMBs), are conducted following a predetermined time schedule. Despite the inherent limitations and complications associated with biopsy, current noninvasive surveillance methods, though preferable, have yet to match EMBs in terms of sensitivity and specificity. These limitations have fueled the continuing challenge
Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation to develop noninvasive methods to detect acute rejection and to monitor response to therapy. Serial echocardiography, with each individual patient serving as his or her own control, appears to be most promising.
Surgical Techniques and Physiology of the Transplanted Heart It is important to recognize the expected anatomical and physiological changes of a transplanted heart. For more than 30 years, OHT has been performed mostly with biatrial anastomoses, a technique first described by Lower and Shumway.42,43 Using this technique, systemic and pulmonary venous communications between the donor and recipient hearts are simplified with biatrial anastomoses. The downside of this technique includes enlargement of the atria with abnormal geometry; asynchronous contraction of the donor and recipient atria with alteration in ventricular filling; tendency for thrombus formation, arrhythmias, and conduction disturbances in 10%–30% of patients; and residual atrioventricular valve regurgitation.44–47 More recently, bicaval and total techniques to improve cardiac anatomy, physiology, and postoperative outcome have gained popularity.48 The bicaval technique consists of complete excision of the recipient atria and direct anastomoses of the left and right pulmonary veins and the inferior and superior vena cavae.49 This technique reconstitutes atrial geometry with the theoretical advantage of preserving atrial contractility and reduction in valvular regurgitation.50 There is also less sinus node dysfunction and reduced need for chronic pacemaker post-OHT. Immediately after OHT, the heart is relatively noncompliant, with significantly elevated filling pressures and abnormal LV isovolumic relaxation.51,52 The early postoperative noncompliance is attributed to factors such as ischemic myocardial injury, high peripheral vascular resistance, denervation, donor-recipient size mismatch, interaction between donor and recipient atria, allograft rejection, preexistent recipient pulmonary hypertension, and volume overload.53–57 Long-term studies of OHT recipients suggest that these hemodynamics remain mildly abnormal months after the procedure,58,59 while others with an initial RF pattern may become nonrestrictive in the first 6 weeks after OHT.60 Young et al. showed that abnormal PCWP and right atrial (RA) and pulmonary artery pressures improved markedly during the fourth to eighth weeks.61 The average PCWP was 19 mmHg immediately after OHT and improved to 12 mmHg at 4–8 weeks. In contrast, Greenberg et al. demonstrated that LV filling pressures improved but never completely normalized.58 At 1 year after OHT, PCWP and RA and pulmonary artery pressures were elevated in comparison with age-matched controls. Likewise, Valantine et al. found that up to 15% of patients exhibited restrictive physiology at 6 years post-OHT.62 The functional significance is that although the exercise capacity of OHT recipients usually improves in comparison with their pretransplant status, this is only about 60%– 70% of that found in healthy subjects.63,64 The LVEDP during exercise is often normal or elevated in comparison with control subjects, suggestive of a leftward shift of the P-V curve, which is consistent with diastolic dysfunction.65
Alterations in Diastolic Function During Allograft Rejection The noninvasive evaluation of the transplanted heart, particularly echocardiographic measures of diastolic function, has become an
integral part of long-term follow-up. Changes in myocardial structure caused by rejection-induced edema, lymphocyte infiltration, increased mass, and myocardial necrosis have been shown to compromise myocyte function, resulting in increased myocardial stiffness and abnormal relaxation.66–68 With mild or even early rejection, two-dimensional echocardiographic changes are subtle and are not accurate or reproducible enough. Pathophysiologically, rejection-induced myocardial edema manifested by an echocardiographically discernible increase in wall thickness is a rather late event. During episodes of rejection, restrictive physiology of the allograft becomes more prominent. Commonly cited Doppler changes in acute rejection include (1) decreased pressure half-time of the early diastolic E wave, (2) decreased IVRT, and (3) increased E velocity. Using the patient as his or her own baseline, a significant change—defined as greater than 20% for E velocity and greater than 15% for pressure half-time or IVRT—is fairly consistent with rejection.67,69 Valantine et al. evaluated 64 patients undergoing hemodynamic and Doppler echocardiographic studies as part of the routine follow-up 1–13 years after OHT.70 Ten patients were found to have strikingly abnormal (restrictive) transmitral flow patterns. This group had a higher incidence of rejection as the only identifiable clinical difference. RF pattern was associated with impaired systolic performance, and there was correlation between transtricuspid (RV IVRT) and transmitral (LV IVRT) flow patterns and degree of rejection. Barba et al. studied 56 OHT recipients 6 weeks postoperatively and found that during acute rejection, LV wall thickness significantly increased compared with negative biopsies, while IVRT and pressure half-time significantly decreased.71 However, the increase in mitral E velocity was significantly associated with only severe rejection. The progressive shortening of IVRT as a marker of graft rejection showed a high sensitivity (85%) and low specificity (57%). In another prospective study, Berwing et al. reported that parameters of systolic function such as percent fractional shortening and systolic wall thickness of the posterior wall remained without significant changes at moderate (grade 2) and severe (grade 3) rejections.72 The same is valid for relaxation parameters such as maximum velocity of posterior wall reduction (in terms of peak thinning rate [PTR]), the time interval of end systole to maximum velocity of posterior wall reduction (tESPTR), and IVRT. Although LV filling parameters such as mitral E velocity increased significantly from 73.3 + 15.2 cm/sec in the rejection-free interval (grade 0) to 103.9 + 15.0 cm/sec at grade 2 rejection and 101.1 + 9.2 cm/sec at grade 3 rejection, these parameters are too insensitive to diagnose or exclude a moderate or severe acute rejection in the individual case. Analyses of transmitral Doppler and pulmonary venous flow velocity have not lived up to their promise to detect rejection-related diastolic dysfunction for two main reasons. Firstly, transmitral Doppler indices are influenced by variables other than ventricular diastolic function, such as age, heart rate, and, most importantly, ventricular loading conditions.73 Pulmonary venous flow velocities are particularly variable, even in individuals without heart disease. Secondly, denervation of the transplanted heart, with its lack of autonomic regulation and the usual sinus tachycardia, leads to a form of RF filling pattern that amounts to diastolic dysfunction in the absence of acute rejection.74 TDI and Vp measurements appear promising in allowing earlier and more accurate detection of LV dysfunction in the transplanted heart. Derumeaux et al. found values for sensitivity and specificity of 92% using mitral annular Ea velocity during mild or moderate and severe rejection.75 With increasing rejection grade, Ea decreased
251
252
Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation significantly. Puleo et al. tested 121 OHT recipients who underwent TDI at the time of EMB surveillance.68 These investigators found a significant decrease in mitral annular Ea at the inferior wall during moderate allograft rejection but no change in peak systolic velocity in comparison with nonrejecting allograft recipients, with a sensitivity of 76% and a specificity of 88%. In 78 OHT recipients (among whom 75 histological analyses revealed no significant rejection), Mankad et al. found a reduction in posterior wall peak systolic and diastolic velocity gradients with rejection, as well as a reduction in mitral annular systolic Sa and diastolic Ea velocities, with a sensitivity of 93% and a specificity of 71%.76 Dandel et al. also reported that in all patients with acute rejection, a significant reduction in Ea velocity was obtained from the basal LV posterior wall in the short axis. They suggested that absence of such a change could practically exclude acute transplant rejection. In 91.7% of cases, the pulsed Doppler findings reverted completely during antirejection therapy within 65 hours.77 Stengel et al. found that late diastolic mitral annular Aa velocity and mitral annular systolic Sa velocity were higher in patients with rejection grade less than 3A compared with those of 3A or greater (Aa, 8.8 cm/sec vs. 7.7 cm/sec; Sa, 19.3 cm/sec vs. 9.3 cm/sec). Sensitivity and specificity of Aa less than 8.7 cm/ sec in predicting significant allograft rejection were 82% and 53%, respectively.78 Unlike findings in other studies, neither early diastolic mitral annular Ea velocity nor Vp was associated with the histological degree of allograft rejection, though there was a trend toward lower Ea values during episodes of rejection. Although an Aa velocity can reliably exclude severe rejection, the fact that the best threshold of an Aa velocity less than 9 cm/sec falsely detected rejection in almost 50% of cases indicates that it is not specific enough and that the pathophysiological problem of restriction to allograft LV filling impairs the reliability of any tool assessing diastolic function during the early rejection process. In our own series at the Cleveland Clinic, Sun et al. noted that in pericardial effusion, with IVRT less than 90 msec and mitral inflow E/A ratio greater than 1.7, the diameter of the inferior vena cava and the duration of pulmonary venous reversal were independently associated with rejection by multivariate analysis. However, no single predictor or combination of predictors was powerful enough to eliminate surveillance EMB.79 Palka et al. analyzed TDI-derived early diastolic indices of LV and RV function.80 They found that significant differences in the late isovolumic relaxation myocardial velocity gradient, as well as differences in timing between onsets of mitral E and mitral annular Ea waves and between mitral and tricuspid annular Ea, might help identification of those with acute rejection, with a sensitivity and specificity greater than 0.80. They attributed these differences to altered early diastolic untwisting of the oblique LV fibers and the delay in early diastolic RV relaxation. More refined approaches to ultrasonic tissue characterization appear promising, since they may detect interstitial edema early in the course of rejection. Preferential adherence of intercellular adhesion molecule-1–targeted microbubbles may also offer a noninvasive imaging technique for detection of acute rejection that may be characterized by endothelial dysfunction.
CLINICAL RELEVANCE Prognostic Significance of Left Ventricular Diastolic Dysfunction in Dilated Cardiomyopathy Although the overall prognosis of DCM patients is most clearly related to the severity of LV systolic dysfunction, it alone is insuf-
ficient to predict symptoms, exercise tolerance, or outcome or to identify those who may benefit the most from OHT, particularly when the LV EF falls under 25%.81–85 Combination of available clinical, laboratory, hemodynamic, electrophysiological, and functional parameters for each individual may more accurately predict survival.86–88 Doppler-derived diastolic abnormalities have shown additional prognostic values.89–93 An RF filling pattern is common in patients (37%–58%) with DCM and is associated with elevated LVEDP and PCWP, more atrioventricular valvular regurgitation and symptoms, and markedly depressed biventricular systolic function.86,89–91,94–96 Studies by Xie et al. and Werner et al. have shown the RF pattern to predict a higher mortality rate in patients with systolic dysfunction.89,92 Both series found that patients with a DT less than 140 msec and an E/A ratio greater than 2.0 had a 2-year survival rate of approximately 50%, compared with those without this pattern, who had a survival rate of greater than 90%. This was independent of the degree of mitral regurgitation, often found in these DCM patients. Whalley et al. attempted to further distinguish the prognostic implication of the PN filling pattern in 115 HF patients with mixed etiologies.97 The one-year follow-up results showed that (1) all-cause mortality in RF, PN, and IR patterns was 37.5%, 23.4%, and 17.4%, respectively; (2) hospital readmission for HF in the three patterns was 40.7%, 30.9%, and 15.2%, respectively; and (3) death/HF hospital readmission was 62.9%, 47.6%, and 26.1%, respectively. These data are consistent with the notion that the PN pattern reflects a less advanced disease state compared with the RF pattern in the continuum of diastolic dysfunction. Dini et al. reported that the difference in duration of pulmonary venous flow and mitral flow at atrial contraction (ARd-Ad) provided an incremental prognostic value to predict outcome in HF patients.98 The index of ARd-Ad has been shown to directly reflect LVEDP.99 They found that patients with a nonrestrictive pattern and ARd-Ad greater than 30 msec had an intermediate prognosis between patients with a restrictive pattern (worse) and those with a nonrestrictive pattern and ARd-Ad less than 30 msec (better) in terms of survival and event rates. Exercise tolerance is often reduced in DCM, and resting PCWP as well as resting LA volume and systolic function correlate with and influence peak oxygen consumption (VO2) and exercise capacity.39,100–102 Abnormal ventilatory response has been shown to correlate with M-mode IVRT. Studies by Vanoverschelde et al. and Xie et al. have demonstrated a clear relationship between LV filling pattern and functional class.91,103 Patients with increased transmitral E wave or shortened DT, or both, had poorer treadmill performance compared with those who had an IR pattern. This is consistent with the notion that the RF pattern represents increased preload and abnormal LV compliance. Hansen et al. evaluated the incremental value of transmitral flow patterns to peak VO2, as obtained by cardiopulmonary exercise testing, in determining the prognosis of patients with systolic dysfunction (LV EF <40%).104 In this study of 311 consecutive patients (of which 223 had DCM) evaluated for OHT, independent predictors of mortality were transmitral flow pattern, peak VO2, and LV end diastolic diameters. In patients with an RF pattern, peak VO2 was lower (13.2 ± 4.2 ml/min/kg) than in those without an RF pattern (16.6 ± 5.8 ml/min/kg, p < 0.0001). In patients with peak VO2 less than 14 ml/min/kg body weight, the outcome was markedly poorer in the presence of the RF pattern compared with its absence (2-year survival rate, 52% vs. 80%). Similarly, despite peak VO2 greater than 14 ml/ min/kg, the outcome was less favorable in the presence of the RF
Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation pattern (2-year survival rate, 80% vs. 94%) (Fig. 20-3). The severity of diastolic dysfunction is thus closely related to survival. However, one must keep in mind that even though the RF pattern has prognostic value, there is substantial overlap of filling indices between survivors and nonsurvivors. Although Dopplerderived diastolic function may have important prognostic information for the patient groups as a whole, it may not be applicable to an individual patient. Others have attempted to use TDI data to predict exercise capacity, though results have been conflicting, possibly related to different patient subsets and treatment strategies. Some have found that mitral annular Ea velocity was not better at predicting exercise capacity than was conventional
100
Non-RFP
Survival (%)
80
Total 60
RFP
40
20 p = 0.005 0 0
1
2
3
34 20 14
6 4 3
t (years) Total Non-RFP RFP
n = 140 n = 61 n = 79
84 45 41
A 100
Non-RFP Total
80 Survival (%)
RFP 60
Prognostic Significance of Right Ventricular Diastolic Dysfunction in Dilated Cardiomyopathy The presence of RV dilatation and systolic dysfunction is known to significantly worsen the prognosis of patients with DCM, and several echocardiographic RV systolic parameters, such as tricuspid annular plane systolic excursion (TAPSE) less than 14 and peak systolic tricuspid annular velocity (Sa) less than 10.8 cm/sec, have been shown to possess independent prognostic power106–109 (see Chapter 14). RV diastolic dysfunction is also common, but less is known about its prognostic impact.110,111 The peak early diastolic velocity (EaTri) and peak late velocity (AaTri) of the tricuspid annulus, as well as their ratio EaTri /AaTri, may be used. Significant decrease in EaTri and EaTri /AaTri were found in disease states including DCM.111 These velocities are also dependent on age112 and RV systolic function,113 with an inverse relationship to RV filling pressures. The RV EaTri /AaTri ratio was significantly correlated to the LV Ea/Aa ratio, and there is no pseudonormalization of EaTri during progressive increase in RV filling pressure, indicating that these parameters are not load dependent.113 Yu et al. examined RV Doppler filling parameters and defined RV diastolic dysfunction by a shortening of DT of the transtricuspid early diastolic E wave to less than 143 msec, and by a reversal in EaTri /AaTri.114 They showed that the presence of RV diastolic dysfunction significantly predicted cardiac morbidity, including nonfatal hospitalization for HF or angina, but no mortality. Meluzin et al. evaluated the prognostic impact of combination of RV systolic and diastolic function in 177 consecutive patients with symptomatic HF due to ischemic or idiopathic DCM and mean LV EF of 23%.115 Over a mean follow-up of 16 months, RV systolic and diastolic functions were found to be independent predictors of event-free survival on multivariate analysis. The survival pattern was, however, determined mainly by the EaTri value, with EaTri of less than 8.9 cm/sec predicting a high risk of cardiacrelated death irrespective of RV systolic function.
40
Impact on Treatment Strategies in Dilated Cardiomyopathy
20 p = 0.03
0 0
1
2
3
41 31 10
7 4 4
t (years) Total Non-RFP RFP
E-wave velocity.105 In contrast, mitral annular Aa velocity correlated significantly with peak VO2, whereas transmitral A velocity did not reflect exercise capacity. Aa velocity might be a better marker of LA function, reflecting the adaptive capacity of the left atrium to compensate for increased diastolic volume and LV filling pressures.
n = 125 n = 82 n = 43
86 62 25
B Figure 20-3 Mitral inflow patterns provide prognostic information incremental to that of peak VO2 in patients with ischemic or dilated cardiomyopathy. The outcome is significantly poorer in the presence of a restrictive filling pattern (RFP) than in its absence, both in A, patients with peak VO2 ≤14 ml/min/kg and in B, patients with peak >14 ml/min/kg. (Modified from Hansen A et al: Prognostic value of Doppler echocardiographic mitral inflow patterns: Implications for risk stratification in patients with chronic congestive heart failure. J Am Coll Cardiol. 2001;37:1049–1055.)
Therapies targeting the interruption of persistent neurohormonal activation have formed the cornerstone in the management of DCM and HF over the last decade. These therapies, directly or indirectly, play an influential role in the improvement of diastolic function. There is growing evidence that beta blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers, as well as nitric oxide donors, can be beneficial. Patients with DCM and HF have elevated circulating and tissue concentrations of angiotensin II, which may promote hypertrophy, apoptosis, interstitial fibrosis, ventricular and vascular remodeling, and secretion of aldosterone. Aldosterone itself promotes fibroblast proliferation and collagen deposition, leading to an increase in passive stiffness of the ventricles and the arterial bed, and thus ventricular filling and arterial compliance.116 Thus various inhibitors of the renin-angiotensin-aldosterone system
253
254
Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation have all been found to have salutary effects on improving diastolic function. Beta blocker therapy is now recommended for all but the most advanced cases of symptomatic systolic HF. In addition to the improvement of systolic function, beta blockers have been shown to lengthen diastole and affect neurohormonal activation, thereby improving outcome.117 Capomolla et al. reported improvement in diastolic filling following therapy with carvedilol, with concomitant significant reduction in effective regurgitant orifice area and mitral regurgitation.118 Similar findings were reported by Andersson et al. among the patients enrolled in the Metoprolol in Dilated Cardiomyopathy (MDC) study.119 The authors reported a good correlation between decrease in heart rate and prolongation of DT at 3 months in the metoprolol group. Although short-term studies did not reveal any change in chamber stiffness, Kim et al. found a reduction in chamber stiffness after a longer follow-up period of 6 months.120 This is not unexpected, as, unlike the improvement in relaxation and contractility that can occur over a shorter duration,121 a longer treatment period with beta blockers would be necessary before any significant change in geometry and chamber stiffness, as the regression of hypertrophy and interstitial remodeling is a slower process.121,122 In those with mild to moderate LV dysfunction, beta blockers seem to improve exercise capacity through improvement in LV compliance and diastolic function. Likewise, the benefits have recently been demonstrated in those with moderate to severe LV dysfunction. Therapy can be tailored to the individual patient with the use of noninvasive hemodynamic information obtained. For example, there is diastolic ventricular interaction in DCM patients with the RF pattern,123 and volume unloading in this setting allows for increased LV filling. Such patients generally receive significant symptomatic benefit from diuretics and venodilator therapy. On the other hand, patients with normal or only mildly elevated filling may have further deterioration of cardiac output with the use of diuretics and preload reduction. In such patients, management should be directed at optimizing cardiac output with afterload reduction using ACE inhibitors and/or other vasodilators. Studies are ongoing to ascertain the value of this noninvasive hemodynamically based or echo-guided management of HF.
FUTURE RESEARCH Although much is known about the mechanisms underlying diastolic dysfunction in HF, many basic issues remain to be resolved. Clinically relevant diastolic dysfunction integrates abnormalities emanating from sarcomere, extracellular matrix, vasculature, and various cardiac structures. Much work is still needed to clarify which abnormalities are the most meaningful as primary clinical targets for therapeutic intervention. Disparities among various echocardiographic parameters of diastolic function may not be uncommon. Overall Doppler flow measurements are operator dependent and more prone to measurement errors, though in some cases there is genuine disparity. In addition, patient’s age must be considered, as it has a significant influence on mitral inflow, pulmonary vein, mitral annular TDI, and propagation velocity. Other methods of noninvasive quantification of diastolic dysfunction, including myocardial characterization using ultrasonic backscatter, need further evaluation. The “holy grail” of diastolic dysfunction is to find that loadindependent parameter that can be reliably used to monitor disease progression and evaluation of response to therapy. The
clinical applications of TDI in the assessment of LV diastolic function, loading conditions, and synchronization have moved from the experimental lab to clinical practice. Further advances, particularly in strain and strain rate imaging, will establish the use of this technique to quantify LV systolic and diastolic function. In the field of advanced HF therapeutics, biventricular pacing has been shown to alleviate symptoms effectively, improve cardiac function, and reverse LV remodeling (see Chapter 29). Studies have shown that systolic asynchrony, but not QRS complex duration, is a better predictor of acute hemodynamic, echocardiographic, or clinical response. Similar to systolic asynchrony, diastolic asynchrony also occurred in more than 40% of DCM patients with narrow QRS complexes and in about 70% of those with wide QRS complexes. Another observed predictor of diastolic asynchrony is the degree of diastolic dysfunction, as illustrated by the negative correlation with mitral annular Ea velocity. Since cardiac output is dependent on both systolic emptying and diastolic filling, systolic and diastolic asynchrony may cause additive hemodynamic compromise in the failing heart. This relationship between diastolic asynchrony and cardiac resynchronization therapy needs further evaluation. The mean survival rate for DCM was approximately 50% at 5 years, but this has improved with the advent of neurohormonal blockade. When all other treatment options prove unsuccessful and the patient is deemed to have end-stage HF, OHT may be considered. Because the supply of donor organs is limited and many of those on the waiting list die before finding a donor, risk stratification in individual patients is important; Doppler-derived information on diastolic function may thus aid in better prognostication and selection of patients likely to benefit the most from OHT. Lastly, mild hemodynamic abnormalities characterize the transplanted heart. Early recognition of acute rejection episodes in cardiac allograft recipients remains a major challenge during follow-up after OHT. Echocardiography cannot supplant invasive methods for monitoring acute rejection but is a useful adjunct for surveillance and monitoring of allograft function after OHT. Protocols now combine routine biopsies with supplemental biopsy in the event of echocardiographic evidence of acute restrictive physiology.124 Recently gene expression profiling (GEP) has been utilized in heart transplant recipients to determine a state of quiescence and to exclude significant cardiac allograft rejection.125 New algorithms are currently being evaluated in clinical trials to determine whether GEP combined with echocardiography can reduce the need for invasive monitoring with EMB. REFERENCES 1. Richardson P, McKenna W, Bristow M, et al: Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies. Circulation 1996;93:841–842. 2. Maron BJ, Towbin JA, Thiene G, et al: Contemporary definitions and classification of the cardiomyopathies: An American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006;113:1807–1816. 3. Gillum RF: Idiopathic cardiomyopathy in the United States, 1970–1982. Am Heart J 1986;111:752–755. 4. Codd MB, Sugrue DD, Gersh BJ, et al: Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975–1984. Circulation 1989;80:564–572.
Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation 5. Johnson RA, Palacios I: Dilated cardiomyopathies of the adult (first of two parts). N Engl J Med 1982;307:1051–1058. 6. Komajda M, Jais JP, Reeves F, et al: Factors predicting mortality in idiopathic dilated cardiomyopathy. Eur Heart J 1990;11:824–831. 7. Sugrue DD, Rodeheffer RJ, Codd MB, et al: The clinical course of idiopathic dilated cardiomyopathy. A population-based study. Ann Intern Med 1992;117:117–123. 8. Diaz RA, Obasohan A, Oakley CM: Prediction of outcome in dilated cardiomyopathy. Br Heart J 1987;58:393–399. 9. Sutherland GR, Lange A, Palka P, et al: Does Doppler myocardial imaging give new insights or simply old information revisited? Heart 1996;76: 197–199. 10. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387–1393. 11. Williams RS: Apoptosis and heart failure. N Engl J Med 1999;341:759– 760. 12. Zisman LS, Asano K, Dutcher DL, et al: Differential regulation of cardiac angiotensin converting enzyme binding sites and AT1 receptor density in the failing human heart. Circulation 1998;98:1735–1741. 13. Davies CH, Davia K, Bennett JG, et al: Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure. Circulation 1995;92:2540–2549. 14. Nishimura RA, Tajik AJ: Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta stone. J Am Coll Cardiol 1997;30:8–18. 15. Eichhorn EJ, Willard JE, Alvarez L, et al: Are contraction and relaxation coupled in patients with and without congestive heart failure? Circulation 1992;85:2132–2139. 16. Eichhorn EJ, Hatfield B, Marcoux L, et al: Functional importance of myocardial relaxation in patients with congestive heart failure. J Card Fail 1994;1:45–56. 17. Pozzoli M, Traversi E, Cioffi G, et al: Loading manipulations improve the prognostic value of Doppler evaluation of mitral flow in patients with chronic heart failure. Circulation 1997;95:1222–1230. 18. Capomolla S, Pinna GD, Febo O, et al: Echo-Doppler mitral flow monitoring: An operative tool to evaluate day-to-day tolerance to and effectiveness of beta-adrenergic blocking agent therapy in patients with chronic heart failure. J Am Coll Cardiol 2001;38:1675–1684. 19. Makhoul N, Hasanein J, Dagan T, et al: Doppler diastolic transmitral flow patterns in severe heart failure: Response to controlled changes in filling pressure using intravenous isosorbide dinitrate. Cardiology 1994;85: 235–243. 20. Kinnaird TD, Thompson CR, Munt BI: The deceleration time of pulmonary venous diastolic flow is more accurate than the pulmonary artery occlusion pressure in predicting left atrial pressure. J Am Coll Cardiol 2001;37:2025–2030. 21. Bruch C, Schmermund A, Marin D, et al: Tei-index in patients with mildto-moderate congestive heart failure. Eur Heart J 2000;21:1888– 1895. 22. Dujardin KS, Tei C, Yeo TC, et al: Prognostic value of a Doppler index combining systolic and diastolic performance in idiopathic-dilated cardiomyopathy. Am J Cardiol 1998;82:1071–1076. 23. Tei C, Dujardin KS, Hodge DO, et al: Doppler index combining systolic and diastolic myocardial performance: Clinical value in cardiac amyloidosis. J Am Coll Cardiol 1996;28:658–664. 24. McMahon CJ, Nagueh SF, Eapen RS, et al: Echocardiographic predictors of adverse clinical events in children with dilated cardiomyopathy: A prospective clinical study. Heart 2004;90:908–915. 25. Lang RM, Vignon P, Weinert L, et al: Echocardiographic quantification of regional left ventricular wall motion with color kinesis. Circulation 1996;93:1877–1885. 26. Vandenberg BF, Oren RM, Lewis J, et al: Evaluation of color kinesis, a new echocardiographic method for analyzing regional wall motion in patients with dilated left ventricles. Am J Cardiol 1997;79:645–650. 27. Bednarz J, Vignon P, Mor-Avi VV, et al: Color kinesis: Principles of operation and technical guidelines. Echocardiography 1998;15:21–34. 28. Godoy IE, Mor-Avi V, Weinert L, et al: Use of color kinesis for evaluation of left ventricular filling in patients with dilated cardiomyopathy and mitral regurgitation. J Am Coll Cardiol 1998;31:1598–606. 29. Vignon P, Mor-Avi V, Weinert L, et al: Quantitative evaluation of global and regional left ventricular diastolic function with color kinesis. Circulation 1998;97:1053–1061. 30. Gaasch WH, Blaustein AS, Bing OH: Asynchronous (segmental early) relaxation of the left ventricle. J Am Coll Cardiol 1985;5:891–897.
31. Brun P, Tribouilloy C, Duval AM, et al: Left ventricular flow propagation during early filling is related to wall relaxation: A color M-mode Doppler analysis. J Am Coll Cardiol 1992;20:420–432. 32. Takatsuji H, Mikami T, Urasawa K, et al: A new approach for evaluation of left ventricular diastolic function: Spatial and temporal analysis of left ventricular filling flow propagation by color M-mode Doppler echocardiography. J Am Coll Cardiol 1996;27:365–371. 33. Jacobs LE, Kotler MN, Parry WR: Flow patterns in dilated cardiomyopathy: A pulsed-wave and color flow Doppler study. J Am Soc Echocardiogr 1990;3:294–302. 34. Coelho L, Pires R, Costa M, et al: Mitral flow propagation velocity assessed with M-mode color Doppler in patients with dilated cardiomyopathy. Rev Port Cardiol 2001;20:39–44. 35. Garcia MJ, Ares MA, Asher C, et al: An index of early left ventricular filling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29:448–454. 36. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 37. Yalcin F, Kaftan A, Muderrisoglu H, et al: Is Doppler tissue velocity during early left ventricular filling preload independent? Heart 2002;87:336–339. 38. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527–1533. 39. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. 40. Garcia MJ, Rodriguez L, Ares M, et al: Differentiation of constrictive pericarditis from restrictive cardiomyopathy: Assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol 1996;27:108–114. 41. Rivas-Gotz C, Khoury DS, Manolios M, et al: Time interval between onset of mitral inflow and onset of early diastolic velocity by tissue Doppler: A novel index of left ventricular relaxation: Experimental studies and clinical application. J Am Coll Cardiol 2003;42:1463–1470. 42. Lower RR, Shumway NE: Studies on orthotopic homotransplantation of the canine heart. Surg Forum 1960;11:18–19. 43. Shumway NE, Lower RR, Stofer RC: Transplantation of the heart. Adv Surg 1966;2:265–284. 44. Leyh RG, Jahnke AW, Kraatz EG, et al: Cardiovascular dynamics and dimensions after bicaval and standard cardiac transplantation. Ann Thorac Surg 1995;59:1495–1500. 45. Sievers HH, Leyh R, Jahnke A, et al: Bicaval versus atrial anastomoses in cardiac transplantation. Right atrial dimension and tricuspid valve function at rest and during exercise up to thirty-six months after transplantation. J Thorac Cardiovasc Surg 1994;108:780–784. 46. Deleuze PH, Benvenuti C, Mazzucotelli JP, et al: Orthotopic cardiac transplantation with direct caval anastomosis: Is it the optimal procedure? J Thorac Cardiovasc Surg 1995;109:731–737. 47. Triposkiadis F, Starling RC, Haas GJ, et al: Timing of recipient atrial contraction: A major determinant of transmitral diastolic flow in orthotopic cardiac transplantation. Am Heart J 1993;126:1175–1181. 48. Dreyfus G, Jebara V, Mihaileanu S, et al: Total orthotopic heart transplantation: An alternative to the standard technique. Ann Thorac Surg 1991;52:1181–1184. 49. Blanche C, Valenza M, Czer LS, et al: Orthotopic heart transplantation with bicaval and pulmonary venous anastomoses. Ann Thorac Surg 1994;58: 1505–1509. 50. Laske A, Carrel T, Niederhauser U, et al: Modified operation technique for orthotopic heart transplantation. Eur J Cardiothorac Surg 1995;9: 120–126. 51. Hausdorf G, Banner NR, Mitchell A, et al: Diastolic function after cardiac and heart-lung transplantation. Br Heart J 1989;62:123–132. 52. Paulus WJ, Bronzwaer JG, Felice H, et al: Deficient acceleration of left ventricular relaxation during exercise after heart transplantation. Circulation 1992;86:1175–1185. 53. Skowronski EW, Epstein M, Ota D, et al: Right and left ventricular function after cardiac transplantation. Changes during and after rejection. Circulation 1991;84:2409–2417. 54. Frist WH, Stinson EB, Oyer PE, et al: Long-term hemodynamic results after cardiac transplantation. J Thorac Cardiovasc Surg 1987;94:685–693. 55. Braith RW, Mills RM Jr, Wilcox CS, et al: Fluid homeostasis after heart transplantation: The role of cardiac denervation. J Heart Lung Transplant 1996;15:872–880.
255
256
Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation 56. Valantine HA, Appleton CP, Hatle LK, et al: Influence of recipient atrial contraction on left ventricular filling dynamics of the transplanted heart assessed by Doppler echocardiography. Am J Cardiol 1987;59: 1159–1163. 57. McClurken JB, Todd BA, Mather PJ, et al: Recipient-donor atrial synchronization benefits acute hemodynamics after orthotopic heart transplantation. J Heart Lung Transplant 1996;15:368–370. 58. Greenberg ML, Uretsky BF, Reddy PS, et al: Long-term hemodynamic follow-up of cardiac transplant patients treated with cyclosporine and prednisone. Circulation 1985;71:487–494. 59. Verani MS, George SE, Leon CA, et al: Systolic and diastolic ventricular performance at rest and during exercise in heart transplant recipients. J Heart Transplant 1988;7:145–151. 60. St Goar FG, Gibbons R, Schnittger I, et al: Left ventricular diastolic function. Doppler echocardiographic changes soon after cardiac transplantation. Circulation 1990;82:872–878. 61. Young JB, Leon CA, Short HD 3rd, et al: Evolution of hemodynamics after orthotopic heart and heart-lung transplantation: Early restrictive patterns persisting in occult fashion. J Heart Transplant 1987;6:34–43. 62. Valantine HA, Appleton CP, Hatle LK, et al: A hemodynamic and Doppler echocardiographic study of ventricular function in long-term cardiac allograft recipients. Etiology and prognosis of restrictive-constrictive physiology. Circulation 1989;79:66–75. 63. Mandak JS, Aaronson KD, Mancini DM: Serial assessment of exercise capacity after heart transplantation. J Heart Lung Transplant 1995; 14:468–478. 64. Stevenson LW, Sietsema K, Tillisch JH, et al: Exercise capacity for survivors of cardiac transplantation or sustained medical therapy for stable heart failure. Circulation 1990;81:78–85. 65. Kao AC, Van Trigt P 3rd, Shaeffer-McCall GS, et al: Allograft diastolic dysfunction and chronotropic incompetence limit cardiac output response to exercise two to six years after heart transplantation. J Heart Lung Transplant 1995;14:11–22. 66. Sagar KB, Hastillo A, Wolfgang TC, et al: Left ventricular mass by M-mode echocardiography in cardiac transplant patients with acute rejection. Circulation 1981;64:II217–II220. 67. Amende I, Simon R, Seegers A, et al: Diastolic dysfunction during acute cardiac allograft rejection. Circulation 1990;81:III66–III70. 68. Puleo JA, Aranda JM, Weston MW, et al: Noninvasive detection of allograft rejection in heart transplant recipients by use of Doppler tissue imaging. J Heart Lung Transplant 1998;17:176–184. 69. Seacord LM, Miller LW, Pennington DG, et al: Reversal of constrictive/ restrictive physiology with treatment of allograft rejection. Am Heart J 1990;120:455–459. 70. Valantine HA, Fowler MB, Hunt SA, et al: Changes in Doppler echocardiographic indexes of left ventricular function as potential markers of acute cardiac rejection. Circulation 1987;76:V86–V92. 71. Barba J, Gomez JA, Abecia AC, et al: Changes in diastolic function in heart rejection: Role of Doppler echocardiography. Rev Esp Cardiol 1992;45: 652–656. 72. Berwing K, Friedl A, Schaper J, et al: Doppler and echocardiography parameters in detection of acute graft rejection after heart transplantation. Z Kardiol 1994;83:225–233. 73. Seiler C, Aeschbacher BC, Meier B: Quantitation of mitral regurgitation using the systolic/diastolic pulmonary venous flow velocity ratio. J Am Coll Cardiol 1998;31:1383–1390. 74. Hausmann B, Muurling S, Stauch C, et al: Detection of diastolic dysfunction: Acoustic quantification (AQ) in comparison to Doppler echocardiography. Int J Card Imaging 1997;13:301–310. 75. Derumeaux G, Douillet R, Redonnet M, et al: Detection of acute rejection of heart transplantation by Doppler color imaging. Arch Mal Coeur Vaiss 1998;91:1255–1262. 76. Mankad S, Murali S, Kormos RL, et al: Evaluation of the potential role of color-coded tissue Doppler echocardiography in the detection of allograft rejection in heart transplant recipients. Am Heart J 1999;138:721–730. 77. Dandel M, Hummel M, Muller J, et al: Reliability of tissue Doppler wall motion monitoring after heart transplantation for replacement of invasive routine screenings by optimally timed cardiac biopsies and catheterizations. Circulation 2001;104:I184–I191. 78. Stengel SM, Allemann Y, Zimmerli M, et al: Doppler tissue imaging for assessing left ventricular diastolic dysfunction in heart transplant rejection. Heart 2001;86:432–437. 79. Sun JP, Abdalla IA, Asher CR, et al: Non-invasive evaluation of orthotopic heart transplant rejection by echocardiography. J Heart Lung Transplant 2005;24:160–165.
80. Palka P, Lange A, Galbraith A, et al: The role of left and right ventricular early diastolic Doppler tissue echocardiographic indices in the evaluation of acute rejection in orthotopic heart transplant. J Am Soc Echocardiogr 2005;18:107–115. 81. Franciosa JA, Park M, Levine TB: Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure. Am J Cardiol 1981;47:33–39. 82. Ikram H, Williamson HG, Won M, et al: The course of idiopathic dilated cardiomyopathy in New Zealand. Br Heart J 1987;57:521–527. 83. Franciosa JA, Wilen M, Ziesche S, et al: Survival in men with severe chronic left ventricular failure due to either coronary heart disease or idiopathic dilated cardiomyopathy. Am J Cardiol 1983;51:831–836. 84. Griffin BP, Shah PK, Ferguson J, et al: Incremental prognostic value of exercise hemodynamic variables in chronic congestive heart failure secondary to coronary artery disease or to dilated cardiomyopathy. Am J Cardiol 1991;67:848–853. 85. Saxon LA, Stevenson WG, Middlekauff HR, et al: Predicting death from progressive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1993;72:62–65. 86. Fuster V, Gersh BJ, Giuliani ER, et al: The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981;47:525–531. 87. Kuhn H, Becker R, Fischer J, et al: The etiology, course and prognosis of dilated cardiomyopathy. Z Kardiol 1982;71:497–508. 88. Romeo F, Pelliccia F, Cianfrocca C, et al: Determinants of end-stage idiopathic dilated cardiomyopathy: A multivariate analysis of 104 patients. Clin Cardiol 1989;12:387–392. 89. Xie GY, Berk MR, Smith MD, et al: Prognostic value of Doppler transmitral flow patterns in patients with congestive heart failure. J Am Coll Cardiol 1994;24:132–139. 90. Pinamonti B, Di Lenarda A, Sinagra G, et al: Restrictive left ventricular filling pattern in dilated cardiomyopathy assessed by Doppler echocardiography: Clinical, echocardiographic and hemodynamic correlations and prognostic implications. Heart Muscle Disease Study Group. J Am Coll Cardiol 1993;22:808–815. 91. Vanoverschelde JL, Raphael DA, Robert AR, et al: Left ventricular filling in dilated cardiomyopathy: Relation to functional class and hemodynamics. J Am Coll Cardiol 1990;15:1288–1295. 92. Werner GS, Schaefer C, Dirks R, et al: Prognostic value of Doppler echocardiographic assessment of left ventricular filling in idiopathic dilated cardiomyopathy. Am J Cardiol 1994;73:792–798. 93. St Goar FG, Masuyama T, Alderman EL, et al: Left ventricular diastolic dysfunction in end-stage dilated cardiomyopathy: Simultaneous Doppler echocardiography and hemodynamic evaluation. J Am Soc Echocardiogr 1991;4:349–360. 94. Shen WF, Tribouilloy C, Rey JL, et al: Prognostic significance of Dopplerderived left ventricular diastolic filling variables in dilated cardiomyopathy. Am Heart J 1992;124:1524–1533. 95. Rihal CS, Nishimura RA, Hatle LK, et al: Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy. Relation to symptoms and prognosis. Circulation 1994;90:2772–2779. 96. Takenaka K, Dabestani A, Gardin JM, et al: Pulsed Doppler echocardiographic study of left ventricular filling in dilated cardiomyopathy. Am J Cardiol 1986;58:143–147. 97. Whalley GA, Doughty RN, Gamble GD, et al: Pseudonormal mitral filling pattern predicts hospital re-admission in patients with congestive heart failure. J Am Coll Cardiol 2002;39:1787–1795. 98. Dini FL, Michelassi C, Micheli G, et al: Prognostic value of pulmonary venous flow Doppler signal in left ventricular dysfunction: Contribution of the difference in duration of pulmonary venous and mitral flow at atrial contraction. J Am Coll Cardiol 2000;36:1295–1302. 99. Rossvoll O, Hatle LK: Pulmonary venous flow velocities recorded by transthoracic Doppler ultrasound: Relation to left ventricular diastolic pressures. J Am Coll Cardiol 1993;21:1687–1696. 100. Packer M: Abnormalities of diastolic function as a potential cause of exercise intolerance in chronic heart failure. Circulation 1990;81:III78– III86. 101. Franciosa JA, Leddy CL, Wilen M, et al: Relation between hemodynamic and ventilatory responses in determining exercise capacity in severe congestive heart failure. Am J Cardiol 1984;53:127–134. 102. Triposkiadis F, Trikas A, Pitsavos C, et al: Relation of exercise capacity in dilated cardiomyopathy to left atrial size and systolic function. Am J Cardiol 1992;70:825–827. 103. Xie GY, Berk MR, Smith MD, et al: Relation of Doppler transmitral flow patterns to functional status in congestive heart failure. Am Heart J 1996;131:766–771.
Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation 104. Hansen A, Haass M, Zugck C, et al: Prognostic value of Doppler echocardiographic mitral inflow patterns: Implications for risk stratification in patients with chronic congestive heart failure. J Am Coll Cardiol 2001;37:1049–1055. 105. Witte KK, Nikitin NP, De Silva R, et al: Exercise capacity and cardiac function assessed by tissue Doppler imaging in chronic heart failure. Heart 2004;90:1144–1150. 106. Meluzin J, Spinarova L, Dusek L, et al: Prognostic importance of the right ventricular function assessed by Doppler tissue imaging. Eur J Echocardiogr 2003;4:262–271. 107. Ghio S, Recusani F, Klersy C, et al: Prognostic usefulness of the tricuspid annular plane systolic excursion in patients with congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol 2000;85:837–842. 108. Ghio S, Gavazzi A, Campana C, et al: Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001;37:183–188. 109. de Groote P, Millaire A, Foucher-Hossein C, et al: Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure. J Am Coll Cardiol 1998;32:948–954. 110. Yu CM, Sanderson JE, Chan S, et al: Right ventricular diastolic dysfunction in heart failure. Circulation 1996;93:1509–1514. 111. Meluzin J, Spinarova L, Bakala J, et al: Pulsed Doppler tissue imaging of the velocity of tricuspid annular systolic motion; a new, rapid, and non-invasive method of evaluating right ventricular systolic function. Eur Heart J 2001;22:340–348. 112. Kukulski T, Hubbert L, Arnold M, et al: Normal regional right ventricular function and its change with age: A Doppler myocardial imaging study. J Am Soc Echocardiogr 2000;13:194–204. 113. Nageh MF, Kopelen HA, Zoghbi WA, et al: Estimation of mean right atrial pressure using tissue Doppler imaging. Am J Cardiol 1999;84:1448–1451, A8. 114. Yu HC, Sanderson JE: Different prognostic significance of right and left ventricular diastolic dysfunction in heart failure. Clin Cardiol 1999;22: 504–512.
115. Meluzin J, Spinarova L, Hude P, et al: Combined right ventricular systolic and diastolic dysfunction represents a strong determinant of poor prognosis in patients with symptomatic heart failure. Int J Cardiol 2005;105: 164–173. 116. Weber KT: Aldosterone in congestive heart failure. N Engl J Med 2001;345:1689–1697. 117. Eichhorn EJ, Bedotto JB, Malloy CR, et al: Effect of beta-adrenergic blockade on myocardial function and energetics in congestive heart failure. Improvements in hemodynamic, contractile, and diastolic performance with bucindolol. Circulation 1990;82:473–483. 118. Capomolla S, Febo O, Gnemmi M, et al: Beta-blockade therapy in chronic heart failure: Diastolic function and mitral regurgitation improvement by carvedilol. Am Heart J 2000;139:596–608. 119. Andersson B, Caidahl K, di Lenarda A, et al: Changes in early and late diastolic filling patterns induced by long-term adrenergic beta-blockade in patients with idiopathic dilated cardiomyopathy. Circulation 1996;94:673–682. 120. Kim MH, Devlin WH, Das SK, et al: Effects of beta-adrenergic blocking therapy on left ventricular diastolic relaxation properties in patients with dilated cardiomyopathy. Circulation 1999;100:729–735. 121. Hall SA, Cigarroa CG, Marcoux L, et al: Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol 1995;25:1154–1161. 122. Lowes BD, Gill EA, Abraham WT, et al: Effects of carvedilol on left ventricular mass, chamber geometry, and mitral regurgitation in chronic heart failure. Am J Cardiol 1999;83:1201–1205. 123. Atherton JJ, Moore TD, Thomson HL, et al: Restrictive left ventricular filling patterns are predictive of diastolic ventricular interaction in chronic heart failure. J Am Coll Cardiol 1998;31:413–418. 124. Burgess MI, Bhattacharyya A, Ray SG: Echocardiography after cardiac transplantation. J Am Soc Echocardiogr 2002;15:917–925. 125. Starling RC, Pham M, Valantine H, et al: Molecular testing in the management of cardiac transplant recipients: Initial clinical experience. J Heart Lung Transplant 2006;25:1389–1395.
257
CRAIG R. ASHER, MD ALLAN L. KLEIN, MD
21
Primary Restrictive, Infiltrative, and Storage Cardiomyopathies INTRODUCTION PATHOPHYSIOLOGY CLINICAL RELEVANCE Primary Restrictive Cardiomyopathies Infiltrative Cardiomyopathies Storage Cardiomyopathies FUTURE RESEARCH
“A classification serves to bridge the gap between ignorance and knowledge.” J. F. Goodwin1
INTRODUCTION Historically, restrictive cardiomyopathies were among the three primary forms of idiopathic heart muscle disease characterized by the World Health Organization as “restrictive filling and reduced diastolic volume of either or both ventricles with normal or nearnormal systolic function.”2,3 This early grouping of cardiomyopathies highlighted the readily evident morphological and functional features of these disorders, which were largely of unknown cause. With advances in diagnostic testing (biochemistry, genetics, immunology, and pathology) and cardiac imaging techniques (echocardiography, computed tomography [CT], magnetic resonance imaging [MRI]), the etiology of many cardiomyopathies can now be identified. The most recent classification proposal of the American Heart Association (AHA) defines primary (involving predominantly the heart) and secondary (related to systemic disorders) cardiomyopathies.4 Using this new classification, except for primary restrictive cardiomyopathy, the entity of “restrictive
cardiomyopathy” no longer exists, and most infiltrative and storage disorders are considered specific secondary cardiomyopathies (i.e., amyloid cardiomyopathy). From the point of view of the clinician, however they are compiled, these are disorders in which diastolic dysfunction is at least initially the predominant pathophysiological derangement. They are rare diseases, generally with a poor prognosis and often presenting with advanced right- or left-sided heart failure. Much of the data regarding these diseases are based on observational retrospective studies from tertiary centers with little prospective and randomized information. Although a cardiologist will often initiate testing, a multidisciplinary team of geneticists, pathologists, radiologists, hematologists, and oncologists is often required to refine the diagnosis and determine management strategies. Since infiltrative and storage cardiomyopathies occur as part of a multisystem disorder, treatments with chemotherapeutic agents, stem cells, and enzyme replacement are increasingly becoming options. This chapter will review primary restrictive cardiomyopathy and the most prevalent forms of infiltrative and storage disorders encountered among patients surviving into adulthood. A practical approach to diagnosis, differentiation, and exclusion of other, more common disorders with similar pathophysiology and structural appearance will be presented along with current treatment options.
PATHOPHYSIOLOGY Most primary restrictive cardiomyopathies are characterized by at most mild degrees of increased wall thickness on gross inspection.5–7 Cardiac biopsy will distinguish whether at the cellular level there is myocyte hypertrophy (increased myocte diameter and nuclear area), endocardial and interstitial fibrosis (increased collagen to muscle ratio), or both (Fig. 21-1).8,9 Exclusion of fiber disarray, inflammation, eosinophilia, lymphocytes, amyloid or iron deposits, and pericardial disease via light and electron micros259
260
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies
Figure 21-1 Idiopathic restrictive cardiomyopathy in a 63-year-old woman. Left panel: Gross specimen, shown in four-chamber format, demonstrating prominent biatrial enlargement with normal-sized ventricles. Right panel: Light microscopy showing marked interstitial fibrosis (light pink areas) (hematoxylin and eosin; magnification ×120). (From Ammash NM et al: Clinical profile and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000;101:2490–2496.)
copy is required to distinguish primary restrictive diseases. Absence of an endocardial fibrotic shell with extension into the myocardium excludes endomyocardial disease. Structural characteristics of primary restrictive cardiomyopathies include (a) biatrial enlargement, (b) nondilated or reduced left ventricular (LV) cavity size, and (c) normal or mild wall thickness.10 The pathogenesis of diastolic impairment may be secondary to myocyte abnormalities, including abnormal calcium handling, accumulation of desmin (a cytoskeletal component), myocyte hypertrophy, and extracellular matrix interstitial fibrosis with proliferation of collagen fibers and elastic elements.11–13 A marked increase in stiffness of the myocardium or endocardium causes the ventricular pressure to rise dramatically with only small changes in volume, causing an upward shift of the LV pressurevolume relationship and a “dip and plateau” or “square root” hemodynamic pattern.14 Both ventricles are affected by the process, but usually the pressures are higher on the left than the right, which may reflect the relatively decreased compliance of the left ventricle compared with the right ventricle. Secondary infiltrative and storage cardiomyopathies result from the presence of myocardial cellular or extracellular substances that impair diastolic function. In infiltrative diseases, there is localization to the interstitium (between myocardial cells), as with cardiac amyloidosis; whereas in storage disorders, the deposits are within cells, as with hemochromatosis and Fabry’s disease.15 The infiltrative and storage cardiomyopathies may have heterogeneous morphological and hemodynamic findings, depending on the specific underlying process and the stage of disease, which often involves LV dysfunction, increased wall thickness, and nonrestrictive diastolic filling patterns.
CLINICAL RELEVANCE Primary Restrictive Cardiomyopathies Case 1 A 23-year-old woman presents to her family physician complaining of fatigue, exercise intolerance, muscle aches, and dyspnea
with exertion. No other past medical history (PMH) is present. Family history is significant for an aunt with hypertrophic cardiomyopathy (HCM). On examination, she is found to be tachycardic. The cardiac exam is notable for an elevated jugular venous pressure of 10 cm H2O, an S3 gallop, and 1+ lower extremity pitting edema. An electrocardiogram (ECG) shows first-degree atrioventricular (AV) block with a P-R interval of 240 msec. A chest x-ray (CXR) shows mild pulmonary congestion. Brain natriuretic peptide (BNP) level is 750 pg/ml, and the creatine phosphokinase (CPK) level is 280 units/L. An echocardiogram shows normal LV and RV size and function, with moderately dilated atria, stage 3 diastolic dysfunction (restrictive filling pattern), E/E′ of 15, and a delayed color M-mode slope of 35 cm/ sec. Cardiac MRI shows normal pericardial thickness and reduced tissue signal intensity. Subsequent cardiac catheterization is notable for pressures (mmHg) as follows: right atrial, 15; right ventricular end diastolic, 17; left ventricular end diastolic, 24; pulmonary artery systolic pressure, 55; pulmonary capillary wedge pressure, 25; and cardiac index, 2.3 L/min/m2. Cardiac biopsy confirms idiopathic restrictive cardiomyopathy and excludes specific infiltrative and storage diseases. Diagnosis Primary (or idiopathic) restrictive cardiomyopathy is a rare disorder of advanced diastolic impairment, often leading to biventricular diastolic heart failure and sudden cardiac death. It was first described by Benotti et al. in nine patients with heart failure, elevated RV and LV filling pressures, normal systolic function, and dip-and-plateau hemodynamic tracing.16 In children, the disease is more common in females, and the prognosis is worse compared with adults.17,18 Familial autosomal dominant transmission and the association with skeletal myopathies (predominantly distal) and heart block have been reported in several generations of families.8,19,20 Other associations include family members with HCM and Noonan’s syndrome.21 Genetic linkage analysis studies have shown mutations in cardiac troponin-I (TNNI3) and defects in genes coding for myocyte desmin accumulation in patients with restrictive cardiomyopathy.22 The clinical signs and symptoms of primary restrictive cardiac disease relate closely to the degree of left atrial (LA) hypertension required to compensate for reduced ventricular filling.5,23 Initially, there is exercise intolerance and fatigue, progressing to dyspnea with minimal effort. Exertional chest pain is usually absent. Atrial fibrillation is common due to the atrial enlargement. Ventricular arrhythmias or heart block are commonly present in advanced cases and are often the causes of death. Symptoms of proximal or distal myopathy may be present. Cardiac examination may reveal pulmonary congestion, jugular venous distention with a prominent X and Y descent, an S3 depending on the filling characteristics, hepatomegaly, ascites, peripheral edema, and anasarca in advanced cases.5,10 Kussmaul’s sign can be detected, while apical retraction (as in constrictive pericarditis) is not seen. Laboratory testing may provide supportive information. BNP levels are elevated proportional to the level of filling pressures and stage of diastolic dysfunction. Elevated BNP levels also may aid in excluding constrictive physiology.24 CPK levels may be elevated with concomitant myopathy. No data are available on troponin levels in patients with idiopathic restrictive cardiomyopathy. Echocardiography is often the first-line test and may be virtually diagnostic.25,26 Atrial enlargement with nondilated ventricles with near normal systolic function is uniformly present on echo-
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies cardiography. Mild LV dysfunction may develop among patients with advanced disease requiring transplantation. Generally, if hypertrophy is present, it is mild. The pathophysiological findings of advanced diastolic dysfunction are evident with a comprehensive echocardiographic Doppler study (elevated filling pressures ± restrictive physiology). Restrictive physiology may not be present, depending on the stage of disease and loading conditions, but abnormal diastolic function should be evident by evaluation of mitral and tricuspid inflow patterns, pulmonary and hepatic venous flows, and isovolumic relaxation time (IVRT).27,28 Tissue Doppler echocardiography (TDE) E and A annular velocities are low, with mitral E/E annular ratios elevated consistent with high filling pressures.29 Concomitantly, the color M-mode propagation slope is slow.29 TDE and color M-mode, along with pulsed Doppler flow patterns with a respirometer, can help distinguish restrictive from constrictive physiology. MRI and CT may be useful to exclude increased pericardial thickness, septal bounce, or conical compression.30,31 Cine MRI may show abnormal filling patterns in early and advanced stages of restrictive cardiomyopathy similar to echocardiography. MRI is capable of distinguishing tissue characteristics and shows a diffuse reduction in signal intensity due to fibrosis in idiopathic restrictive cardiomyopathy, with more specific patterns in other infiltrative processes like amyloidosis or hemochromatosis.31 Cardiac catheterization is often used as a confirmatory test. Using strict criteria, either right- or left-sided filling pressures are elevated, with a typical dip-and-plateau RV and LV filling pattern and an “M”- or “W”-shaped venous filling pattern with prominent X and Y descents.6 LV diastolic pressures are greater than 5 mmHg more than RV filling pressures. Cardiac index is reduced, and pulmonary artery pressure is greater than 50 mmHg in most patients with a ratio of RV systolic to diastolic pressure greater than 1/3. Often RV endomyocardial biopsy is done at the same time as hemodynamic assessment and importantly excludes other specific etiologies.7,32
Texas Children’s Hospital found that predictors of sudden death included female sex, chest pain, syncope, and ischemia on Holter monitor. The annual mortality rate was 7%, with sudden death occurring in 28% of patients.34 Predictors of poor outcome in the pediatric population include age, female sex, ischemic manifestations, decreased cardiac index, pulmonary venous congestion, and elevated pulmonary vascular resistance.8,18,35,36 Beta blockers are the primary therapy to reduce the risk of sudden death. Additional medical therapy includes diuretics for symptomatic relief and consideration of antiplatelet agents or anticoagulation, due to the high risk of atrial fibrillation and embolism reported in some series.33 Vasodilators should be used cautiously unless LV dysfunction is present, since they may cause hypotension. Pacemakers are often required for heart block. Implantable cardioverter-defrillators are recommended for any patients with ischemic manifestations, along with listing for transplantation.34 Transplantation can substantially improve survival and is usually required within 4 years of diagnosis, optimally before pulmonary vascular resistance is irreversibly high.37 Heartlung transplantation is an option for some children.37 When concomitant skeletal myopathy is present, the benefits of transplantation may be partial. Idiopathic restrictive cardiomyopathy may also be diagnosed in adults after exclusion of secondary causes of restrictive physiology (Fig. 21-2). A large series of 94 patients (mean age, 64 years) was identified from 1979 to 1996 at the Mayo Clinic, with typical structural and hemodynamic features of restrictive cardiomyopathy.38 At follow-up of 68 months, 50% of patients had died, primarily from cardiac causes, and 4 required heart transplantation. Using multivariate analysis, predictors of death included male sex, LA dimension greater than 60 mm, age older than 70 years, and advanced New York Heart Association class (Fig. 21-3).
Management The prognosis of idiopathic restrictive cardiomyopathy depends most on the age of the patient and presenting hemodynamic factors. Although variable, the course is usually progressive and generally poor among the pediatric population, with survival rates of less than 50% over 2 years.17,33 A serial study of 18 children (9 male; mean age, 4.3 years) evaluated over a course of 31 years at
Using the most recent AHA classification, cardiac amyloidosis is the most important infiltrative cardiomyopathy in adults. Sarcoidosis has been recategorized as a secondary inflammatory disorder.4 The exceedingly rare infiltrative disorders—Gaucher’s, Hurler’s, and Hunter’s diseases—are familial defects in metabolism that involve multiple systems, including the heart, and will not be discussed in this chapter.
Infiltrative Cardiomyopathies
Diastolic dysfunction Restrictive physiology
Primary restrictive (Predominant cardiac involvement)
Figure 21-2 Algorithm with differential diagnosis of restrictive physiology determined either by cardiac catheterization or echocardiogram. TR, tricuspid regurgitation; RV, right ventricular; MR, mitral regurgitation.
Secondary restrictive
End stage other primary cardiomyopathy (Predominant cardiac involvement)
End stage other secondary cardiomyopathy (Systemic involvement)
“Restrictive-like diastolic filling” (catheterization/echocardiogram)
• Severe TR (right side) • RV dysfunction (right side) • Severe MR • Constriction • Atrial fibrillation
261
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 100
100 79%
60
45% Women
44%
40 20
p = 0.033 0
1
2
3
4
A
5
6
7
8
9
60
I
40
II
20
27% Men
0
p = 0.007
80 Survival
Survival
80
III IV
0
10
0
1
2
3
4
B
Years
5
6
7
8
9
10
Years
100
100 78% 47% No
51%
60 40 20
80 Survival
80 Survival
262
29% Yes
p = 0.026
69%
60
20
0
42% No
33%
40
11% Yes
p = 0.027
0 0
C
1
2
3
4
5
6
7
8
9
10
Years
0
D
1
2
3
4
5
6
7
8
9
10
Years
Figure 21-3 Kaplan-Meier survival curves in relation to A, sex; B, New York Heart Association functional class (I or II); C, pulmonary venous congestion; and D, left atrial dimension >60 mm. (From Ammash NM et al: Clinical profile and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000;101:2490–2496.)
Cardiac Amyloidosis Case 2 A 44-year-old man presents to a cardiologist for a second opinion regarding amyloid cardiomyopathy. He complains of dyspnea with exertion, orthopnea, orthostasis, abdominal distention, and lower extremity swelling and numbness. No other PMH is present. The man is African American. Family history is significant for his father and brother, who died in their forties with cardiomyopathy. On examination, he appears cachectic and has a supine blood pressure of 96/64 and upright 80/68 mmHg. The cardiac exam is notable for jugular venous distention to the jaw. There is S3 gallop, reduced intensity heart sounds and a moderate apical regurgitant murmur. There is ascites and 3+ lower extremity pitting edema. An ECG shows low voltage in the limb leads and an intraventricular conduction delay. CXR shows a globular heart silhouette and mild pulmonary congestion. BNP level is 4000 pg/ml. An echocardiogram shows severe biventricular increased wall thickness with moderately impaired systolic function. The atria are dilated and the pulmonary artery pressure is 60 mmHg. There is moderate mitral regurgitation. There is stage 2 diastolic dysfunction (pseudonormal filling pattern), E/E′ of 18, with a delayed color M-mode slope of 40 cm/sec. There is a moderate-sized pericardial effusion. Serum and urine electrophoresis with immunofixation and bone marrow biopsy shows no evidence of abnormal immunoglobulin. A laboratory analysis shows a mutation in transthyretin (TTR) protein, confirming the diagnosis of familial TTR amyloidosis. Etiology and Classification Cardiac amyloidosis is the prototype of infiltrative cardiomyopathies and the most frequently encountered in clinical practice.39–41 There are several types of cardiac amyloidoses, each with its own clinical presentations, treatment strategies, and prognosis (Table 21-1).39 Amyloidosis is a multisystem disease in which
linear, nonbranching, aggregated protein fibrils with a cross-β pleated configuration are deposited in various organs of the body, including the heart.42 Within the heart, the amyloid particles can infiltrate the myocardium (atria and ventricles), valves, pericardium, conduction system, and coronary arteries.41 The fibrils deposit between cells (interstitial), with a replacement of the normal tissue structures. When stained with Congo red, this material shows apple-green birefringence under a polarizing microscope. Alcian blue can also be used to diagnose amyloid.39,43 Amyloidosis can be classified by the type of protein deposited. The primary type is the most common form, occurring in 85% of patients with fibrils composed of kappa or lambda immunoglobulin light chains (AL type for amyloid light chain), often associated with a plasma cell dyscrasia such as multiple myeloma.39,43 There may be extracellular deposition of amyloid protein in the kidney, heart, liver, nerves, skin, and tongue, resulting in tissue damage and organ malfunction.42 The most common manifestations include nephrotic syndrome or renal failure, congestive heart failure, sensorimotor peripheral neuropathy, and orthostatic hypotension. Nearly half of patients have cardiac involvement, including congestive heart failure; however, the heart is involved in most all patients by pathological examination.43 Death from cardiac involvement secondary to congestive heart failure or arrhythmia occurs in greater than 50% of patients with systemic amyloidosis.44,45 Familial amyloidosis results from the production of a mutant pre-albumin protein (i.e., TTR), and there are different types, which present with cardiomyopathy, neuropathy, or nephropathy.46 TTR is made up of 125 pairs of amino acids, and more than 100 mutations have been recognized.47 This type of amyloidosis is important to recognize because liver transplantation may be lifesaving, though optimally it should be performed before cardiac involvement has occurred. Laboratory testing should be performed to test for TTR if a family history is present or there is
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies TABLE 21-1 MAJOR FORMS OF AMYLOIDOSIS CARDIAC INVOLVEMENT
OTHER ORGAN INVOLVEMENT
ASSOCIATED DISORDERS
TREATMENT
Immunoglobulin light chain (λ, κ)
Common
Plasma cell dyscrasias (e.g., multiple myelomas)
Chemotherapy; cardiac transplant if isolated cardiac
AA (secondary)
Nonimmunoglobulin, serum protein A
Rare
Liver, kidney, nervous system, gastrointestinal tract, skin Kidney
Underlying disease
ATTR (familial)
Nonimmunoglobulin, transthyretin Nonimmunoglobulin, transthyretin
Common
Nervous system
Inflammatory diseases (e.g., rheumatoid arthritis, familial Mediterranean fever, tuberculosis) None
Common
None
Congestive heart failure
Nonimmunoglobulin, atrial natriuretic peptide
Common
None
Atrial fibrillation
TYPE
PROTEIN
AL (primary)
SSA (senile)
AANP (atrial)
Liver transplant if no cardiac involvement Supportive treatment for congestive heart failure Supportive treatment for atrial fibrillation
Modified from Falk RH: Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112:2047–2060.
no evidence of AL type amyloid on biopsy. In familial amyloidosis, cardiac involvement occurs in 28% of patients at the time of diagnosis; however, it usually presents later in the course of the disease and is less ominous prognostically compared with AL (primary) amyloidosis.46 Peripheral neuropathy may be the presenting feature, but cardiac manifestations may subsequently predominate.48 The disease was reported over 30 years ago in a Danish family but has also been described in several other families of different ethnic origin and has an autosomal dominant expression.49,50 Cardiac failure or cardiac arrhythmia is responsible for the deaths in over 50% of patients.46 Familial amyloidosis has been reported in African Americans as a cause of heart failure secondary to a mutation in TTR isoleucine-122 (substitution for valine).51 This mutation has been found in nearly 4% of African Americans in the United States and in approximately one-quarter of elderly patients with cardiac amyloidosis. Senile systemic amyloidosis (SSA) occurs in elderly men from the production of a wild-type TTR and has been associated with congestive heart failure without significant noncardiac involvement.52,53 Survival is reasonably good relative to AL amyloid or other etiologies of congestive heart failure.52,54 There may be extensive deposits in the heart producing congestive heart failure, or there may be minor deposits in the atria with no symptoms. The prevalence of senile amyloid at autopsy appears to be highest in African Americans. It is important to differentiate senile cardiac amyloidosis from immunoglobulin-derived amyloidosis (AL type) and familial amyloidosis because the treatment regimens differ. The favorable prognosis of SSA relative to AL is concordant with the accumulating evidence that light chains are responsible for toxicity and poor outcome in AL amyloidosis.55 Secondary amyloidosis (AA type) is rare, with the fibrils consisting of protein A, a nonimmunoglobulin acute phase reactant resulting from a multitude of chronic inflammatory conditions (e.g., tuberculosis, familial Mediterranean fever, rheumatoid arthritis, inflammatory bowel disease).56 Cardiac involvement is unusual in secondary amyloidosis, with renal manifestations being predominant.57 Isolated atrial amyloidosis is often found limited to the atria at autopsy in the elderly and derives from atrial
natriuretic peptide.58 It is more common in females and seems to be associated with the presence of atrial fibrillation.59,60 Clinical Presentation Cardiac amyloidosis may present with a spectrum of disease severity. In the nonfamilial forms, it generally affects males over age 30.44,61 In early cardiac amyloidosis, patients may be asymptomatic, while those with advanced disease will have the typical evidence of restrictive cardiomyopathy with severe right-heart failure, ascites, and peripheral edema.62,63 Left-heart failure is a less common manifestation. Additional symptoms include chest pain, presyncope/syncope, and sudden cardiac death. Chest pain resembling angina pectoris may be present despite normal epicardial coronary arteries due to partial obliteration of the distal coronary arteries by amyloid infiltration or intramyocardial vessels.64,65 Orthostatic hypotension occurs in 10%–15% of patients secondary to amyloid infiltration of the autonomic nervous system, with symptoms of syncope, diarrhea, lack of sweating, and impotence.42,66 Renal involvement with nephrotic syndrome and adrenal disease may aggravate postural hypotension. Syncope may be due to postural hypotension or supraventricular or ventricular arrhythmias. Other symptoms may be attributable to peripheral neuropathy, macroglossia, or carpal tunnel syndrome.39,67 Physical examination may reveal signs of cardiac cachexia in advanced disease. Low cardiac output may cause decreased blood pressure, and orthostatic hypotension may still occur. Macroglossia, periorbital edema, petechia, and bruising may be evident on general examination.39 The cardiac exam may reveal an S4 (very early disease) or S3 (advanced disease) on auscultation from either the right or the left heart.68 Mitral and tricuspid valvular regurgitation may also be present, though usually not severe. There is often evidence of biventricular heart failure with predominant right-heart failure.63 The jugular venous pulse will be elevated with a prominent X and Y descent, and hepatomegaly, ascites, and peripheral edema will be present, especially in the advanced disease.39 Neurological examination may reveal findings consistent with peripheral neuropathy.
263
264
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies The cardiac silhouette on CXR is usually enlarged in patients with advanced disease with evidence of pulmonary congestion or pericardial effusion.69 The electrocardiogram typically has low voltage in the limb leads and shows a pseudoinfarction pattern with Q waves simulating a myocardial infarction in the precordial leads (∼50% of patients).70,71 More specifically, patients with cardiac amyloidosis have a low ratio of electrocardiographic voltage to LV wall thickness.72 However, the usefulness of this ratio is limited by the presence of coexisting diseases that may result in reduced voltage. Arrhythmias, especially atrial fibrillation, are common, and sick-sinus syndrome may be present.39 AV conduction defects may be present, especially in familial amyloidosis associated with myopathy, though right and left bundle branch block is uncommon.73 Ventricular arrhythmias are not as common as expected and are not often the cause of sudden cardiac death in nonfamilial forms.74 Echocardiography Two-dimensional and Doppler echocardiography are the procedures of choice for diagnosis, serial follow-up, and prognostic determination of patients with cardiac amyloidosis,75–82 which gives a distinctive appearance on two-dimensional echocardiography and is associated with abnormal LV and RV diastolic function. The findings of a normal or small LV cavity size with markedly thickened myocardium associated with a highly abnormal texture often described as “granular sparkling” in appearance is the classical presentation (Fig. 21-4). Other disorders that cause increased LV wall thickness must be considered (Fig. 21-5). The sparkling appearance is thought to be due to the acoustic mismatch between the highly reflective amyloid deposits in the endocardium, myocardium, and pericardium and the normal tissue.83,84 Moreover, autopsy and clinical biopsy series have demonstrated the presence of amyloid fibrils in the myocar-
dium at the site of the sparkling echoes. However, the specificity of this finding is reduced with improved echocardiographic imaging techniques, including harmonic imaging. Global LV systolic function is usually preserved in early disease, whereas systolic function is usually impaired in advanced disease. The interatrial septum and valve leaflets are thickened. Both atria are enlarged, and small to moderate pericardial effusions are usually present.80,82
Figure 21-4 Apical four-chamber view of patient with cardiac amyloidosis demonstrating severe increased wall thickness of the left and right ventricles, dilated atria, and a pericardial effusion. The myocardium has a “granular sparkling” appearance caused by hyperrefractile amyloid particles intermixed with normal myocardium.
↑ LV wall thickness
Hypertrophy
Primary
• Hypertrophic CM • LV noncompaction
Cardiomyopathy
Secondary
Physiological
Athlete’s heart
Myocardial
Pathological
• HTN • ESRD
Valvular
• AS • AR
Endomyocardial
Secondary
• EMF/Loffler’s • Carcinoid • Radiation
Storage
Inflammatory
Infiltrative
• Fabry’s • Hemochromatosis • Glycogen storage
Sarcoidosis
Amyloidosis
Primary
Idiopathic restrictive
Figure 21-5 Algorithm with differential diagnosis of increased left ventricular (LV) wall thickness. CM, cardiomyopathy; HTN, hypertension; ESRD, end-stage renal disease; AS, aortic stenosis; AR, aortic regurgitation; EMF, endomyocardial fibrosis.
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies Cardiac amyloidosis has traditionally been considered to require a restrictive pattern of ventricular filling. However, a spectrum of LV filling abnormalities using pulsed-wave Doppler echocardiography is detected in patients with cardiac amyloidosis.68,77,85 In a study of 53 patients with the classic echocardiographic features of cardiac amyloidosis, those with advanced disease demonstrated a mean LV wall thickness greater than 15 mm and a “restrictive” physiology pattern of LV filling.68 Furthermore, in serial studies of individual patients, the “impaired relaxation” pattern gradually evolved into a “restrictive” pattern through a “pseudonormal,” or intermediate, phase in the progression of the disease.77 The mechanism for this serial change in LV filling pattern is thought to be the gradual decrease in the compliance of the left ventricle with progressive deposition of amyloid fibrils in the myocardium, leading to loss of myocardial cells from pressure necrosis.86 When the duration of the pulmonary venous atrial reversal wave is longer than the mitral A-wave duration, filling pressures are elevated and the disease is advanced with restrictive physiology.87 Eventually the pulmonary atrial reversal wave may be lost due to atrial involvement of amyloid infiltration. RV diastolic impairment also may occur in patients with cardiac amyloidosis.76 The RV filling pattern is often similar to that of the left ventricle or may be less advanced. In early cases, there is an RV free wall thickness of less than 7 mm and abnormal relaxation. In advanced cases, the RV wall is greater than 7 mm in thickness, with restrictive physiology present. The systolic forward flows by Doppler echocardiography in the superior vena cava and hepatic vein are also decreased with advanced disease, and the diastolic flow is increased compatible with restrictive physiology. Newer diagnostic techniques, including TDE, strain and strain rate, and two-dimensional strain imaging, have been utilized to characterize early systolic dysfunction in patients with cardiac amyloidosis before the onset of congestive symptoms or reduced LV ejection fraction.88,89 Using these methods, it has been shown that there are differences between the longitudinal basal peak systolic strain rate and strain among amyloid patients with no cardiac involvement, cardiac involvement and no symptoms, and cardiac involvement with symptoms (Figs. 21-6 and 21-7).89 This finding allows for detection of patients with early amyloid heart disease to be targeted for therapy. Other Diagnostic Tools Cardiac amyloidosis can be diagnosed noninvasively antemortem in most cases from the typical features obtained from the history, examination, ECG, and echocardiogram. However, confirmatory testing is needed before treatment is initiated, and further classification of the subtype of amyloid is necessary. Serum and urine protein immunofixation and electrophoresis are recommended to assess for the secretion of a monoclonal protein associated with a plasma cell dyscrasia.39,43,44,66,90 Although some patients with AL amyloid will have multiple myeloma, a greater proportion may have unassociated monoclonal gammopathies of uncertain significance. In 10% of cases, there is no monoclonal protein secreted (nonsecretory primary amyloidosis). Laboratory testing of antisera against TTR, the kappa and lambda light chains, and protein A in biopsy or blood samples can be performed. A serum free–light chain assay is available to assess the ratio of kappa-to-lambda free light chains and may be more sensitive than immunofixation.43,91 A positive serum immunofixation plus an abnormal kappa/lambda ratio are highly sensitive to diagnose AL amyloidosis.90
Noncardiac sites of biopsy can include the bone marrow, fat pad, rectum, gingiva, kidney, and liver, though fat aspirate may detect amyloidosis in most patients (>70%).44,92,93 If the echocardiogram is not diagnostic or the fat pad aspirate is negative and cardiac amyloidosis is still suspected, an endomyocardial biopsy can be performed to make the diagnosis. A confirmatory cardiac biopsy may be particularly important if there are other confounding causes of increased LV mass, such as LV hypertrophy (LVH) or HCM. The presence of low electrocardiographic voltage favors a diagnosis of amyloidosis rather than hypertensive or
Figure 21-6 Color-coded map of myocardial long-axis strain recorded from the ventricular septum. Top left image is from the apical four-chamber view, with a bar representing a key to the color-coding. The numbers on the ventricular septum correspond to the numbers on the map; the apical septal strain is represented on the top part of the map, and the base is represented on the bottom. A, Recording from a normal subject. Immediately after the onset of systole (arrow indicates R wave), there is a brief light blue vertical line, representing isovolumic systole, followed by a broad, uniform orange/red-coded band, representing ventricular contraction. This is followed by early relaxation in blue, diastasis in green, and a late diastolic relaxation in a second blue area. B, Strain map from a patient with cardiac amyloid, heart failure, and a mildly reduced ejection fraction. The arrow again represents the onset of the QRS complex. There is almost no longitudinal motion in any portion of the septum, with the large area of green representing absent motion and the brief patches of color representing slight elongation in late diastole (light blue). Systolic longitudinal motion at the base and a brief, reduced contraction in midsystole near the apical septum are yellowish orange. (From Falk RH: Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112:2047–2060.)
265
266
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies hypertrophic cardiomyopathy; however, endomyocardial biopsy may be necessary in some cases to give a definitive diagnosis because of the grim prognostic implications of a diagnosis of cardiac amyloidosis.94 Although systolic anterior motion (SAM) of the mitral valve on echocardiogram is thought to be patho-
Figure 21-7 Speckle tracking image of a patient with advanced cardiac amyloidosis showing decreased longitudinal systolic strain. Top left image is from the apical four-chamber view with a bar representing a key to the color-coding varying from −20% to 20%. Each apical segment is color coded. The global strain is −4.3%. Lower right image shows the actual peak systolic strain values for each segment. For example, the basal septum has a peak strain of −1% (n = −20%). The apical segments have greater peak systolic strain values. Top right image (graph) and lower right image (anatomic M-mode) show decreased peak systolic strain over the cardiac cycle. All the segments in different colors show decreased systolic strain. Basal and midventricular segments have the worst systolic strain, while the apical segment has the best systolic strain.
pneumonic of hypertrophic cardiomyopathy, it has also been recognized in a series of patients with cardiac amyloidosis.95 MRI can be used to identify the increased myocardial thickness and small LV cavity in cardiac amyloidosis. It can be used to demonstrate the lack of increased pericardial thickening with the ancillary findings of biatrial enlargement and inferior vena cava dilatation, similar to echocardiography. Myocardial wall thickening due to hypertrophy or amyloid infiltration may be distinguishable.96–98 A pattern of global and subendocardial late gadolinium enhancement and specific features of T-1 blood pool kinetics are seen in patients with suspected amyloidosis.99 Subendocardial late enhancement involves the right and left ventricles, including the septum, causing the so-called zebra appearance of the septum (Fig. 21-8). This subendocardial late enhancement matches the deposition of amyloid seen histologically. The sensitivity of this finding in a series of 30 patients with echocardiographic features of amyloid was 69%. Nuclear medicine techniques have been used to diagnose cardiac amyloidosis, including technetium-99m pyrophosphate scintigraphy and imaging of indium-labeled antimyosin antibodies, though the reported sensitivities of these techniques are low.100–102 However, a recent small study with technetium-99m dicarboxypropane diphosphonate (DPD) was 100% specific for differentiating TTR amyloid from AL type.103 Figure 21-9 shows the diagnostic evaluation of suspected amyloidosis. Prognosis The prognosis of cardiac amyloidosis is generally poor, but it depends on the type of disease, with AL (primary) amyloidosis having the worst prognosis.43,44,46,57,61,104 In a serial study of over 800 patients with primary amyloidosis over a 10-year period, the median survival was 2.1 years and less than 6 months once congestive heart failure had occurred.104 Several prognostic indicators have been determined (Table 21-2). Mean LV wall thickness and
Figure 21-8 Cardiovascular magnetic resonance (CMR) image of a patient with systemic AL amyloidosis. Top row shows diastolic frames from cines (vertical long axis, horizontal long axis, and short axis, respectively), showing a thickened left ventricle (LV) and pleural effusion (Pl eff ) and pericardial effusion (Pc eff ) (arrows) associated with heart failure. Bottom row shows late gadolinium enhancement images in the same planes. The CMR sequence forces the myocardium remote from the pathology to be nulled (black) such that the abnormal region is enhanced. In cardiac amyloidosis, however, the region of greatest abnormality is enhanced, as the entire myocardium is affected with amyloid infiltration, and the result is diffuse global subendocardial enhancement (straight arrows). The endocardium of the right ventricle (RV) is also heavily loaded with amyloid, and therefore the septum in the horizontal long-axis view shows biventricular subendocardial enhancement with a dark midwall (zebra appearance; dotted arrows). The right ventricular free wall is also enhanced (curved arrow). Note that the blood pool is dark, which does not occur in other reported conditions, including abnormal gadolinium handling in these patients. LA, left atrium; RA, right atrium. (From Maceira AM et al: Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111:186–193.)
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies Suspected cardiac amyloidosis (e.g. heart failure with typical echocardiogram)
Careful physical exam seeking other potential organ involvement (e.g. proteinuria, periorbital purpura)
Biopsy of selected cardiac or non-cardiac tissue
Biopsy positive: amyloidosis confirmed
Where feasible, special stains such as immunogold
Special stains unavailable
Serum and urine IFE, FLC assay, bone marrow biopsy
One or (usually) more positive
All negative
Genetic testing for mutant TTR or ApoA1
Amyloid type confirmed
TTR
AL amyloidosis
Positive
Negative
Familial
Probably SSA
Therapy as below Quantify light chains (as baseline for follow-up) and exclude concomitant myeloma
Genetic testing for mutant TTR
Positive
Negative
Familial amyloidosis Supportive therapy. Assess for liver transplant and need for cardiac transplant.
SSA Supportive therapy.
AL amyloidosis Chemotherapy and supportive therapy.
Figure 21-9 Flow diagram outlining the evaluation of a patient with suspected cardiac amyloidosis. Clinical evaluation may reveal clues that strengthen the likelihood of amyloidosis, but a tissue diagnosis is mandatory. Although special staining of the biopsy may confirm the type of amyloid, further workup of AL amyloid is required to exclude myeloma and to quantify free light chains. If the biopsy stains positive for transthyretin (TTR), further testing is needed to determine whether this is a wild type or mutant. ApoA1, apolipoprotein A1; IFE, immunofixation electrophoresis; FLC, free–light chain assay; SSA, senile systemic amyloidosis. (From Falk RH: Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112:2047–2060.)
267
268
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies TABLE 21-2 ECHOCARDIOGRAPHIC/LABORATORY PROGNOSTIC DETERMINANTS IN AMYLOIDOSIS Left ventricular wall thickness ≥15 mm Right ventricular wall thickness >7 mm Mitral inflow deceleration time ≤150 msec Left ventricular dysfunction Right ventricular enlargement Abnormal Tei index >0.77 ↑ Troponin level ↑ Brain natriuretic peptide level
LV impairment have been suggested as useful variables in assessing the degree of cardiac involvement and prognosis. In a study of 132 patients with biopsy-proven amyloidosis, those with a mean wall thickness of 15 mm had a median survival of 0.4 year compared with 2.4 years for those with a mean wall thickness of 12 mm.80 Doppler echocardiography has also been shown to be useful in prognostic stratification of patients with cardiac amyloidosis. Patients with a deceleration time of the mitral early filling wave at a baseline study of no greater than 150 msec had significantly reduced survival compared with those whose deceleration time was greater than 150 msec (1-year probability of survival, 49% vs. 92%; p < 0.001).78 Bivariate analysis showed that the combination of a shortened deceleration time of no greater than 150 msec and an increased mitral E/A ratio were stronger predictors of cardiac death than were two-dimensional variables of mean LV wall thickness and fractional shortening. A Doppler echocardiographic derived parameter, the Tei index, combining systolic and diastolic performance, has been determined to have significant prognostic importance in cardiac amyloidosis (see Chapter 16 in this volume).105 RV enlargement and LV dysfunction have also been identified as independent predictors of poor outcome among patients with primary amyloidosis.45,79 Both elevated troponin and BNP levels have been associated with a poorer prognosis.106 Treatment The mainstay of treatment is relief of symptoms, though efforts are being undertaken to suppress the principal disease process. The definitive treatment for cardiac amyloidosis (AL type) involves antiplasma cell therapy that stops production of light chains and includes alkylating agents, such as melphalan and prednisone.39,104 Few randomized trials of chemotherapy have shown benefit in AL amyloidosis.107,108 A trial of 100 patients with primary amyloidosis using melphalan, prednisone, and colchicine showed improvement of systemic disease when the major features were not cardiac or renal.108 A subsequent trial randomized 220 patients to colchicine, melphalan, prednisone, or combined therapy. A median duration of survival of 17–18 months occurred in the regimens including melphalan, with only 15% of patients surviving for at least 5 years. Colchicine has also been used to prevent amyloidosis associated with familial Mediterranean fever; however, there is no evidence that it halts the progression of amyloid deposition in primary amyloidosis.104 Various dosing regimens of melphalan have been used with modest success, including among patients with cardiac disease without significant LV dysfunction or advanced heart failure.109 Chemotherapy has been associated with
a high morbidity and mortality in patients with advanced cardiac disease. Autologous stem cell transplantation has shown favorable results, mostly in patients without cardiac disease or early cardiac involvement, and is the treatment of choice for AL amyloidosis.110,111 The toxicity of blood cell transplantation, however, limits its use to a minority of patients. Diuretics are the main drugs used to treat the cardiac symptoms. Avoidance of digoxin has been suggested because of concern for digoxin binding to amyloid fibrils and the risk of arrhythmias, although the data to support this recommendation are mostly experimental or anecdotal.112 With careful monitoring, digoxin has been used for heart rate control in patients with atrial fibrillation.61 Patients with cardiac amyloidosis may also be very sensitive to the negative inotropic effects of calcium-channel blockers, either because of their abnormal binding to amyloid fibrils or because of their vasodilator effects.113 Vasodilator agents such as angiotensin converting enzyme (ACE) inhibitors or angiotensin II inhibitors are poorly tolerated, with a risk of significant hypotension.39 Pacemakers may be useful to treat symptomatic high AV block. Anticoagulation should be considered because of the risk of thrombus formation with atrial amyloid involvement and atrial standstill, even among patients in sinus rhythm.114,115 Cardiac transplantation is generally not performed in patients with AL type amyloid, since systemic involvement of other organs is usually present and may progress.116–120 It has been considered in select patients without extracardiac disease (<5% of cases), since the transplanted heart is usually not clinically affected.119,120 In this situation, heart transplantation is coupled to chemotherapy and stem cell transplantation. Liver transplantation has been performed for the familial type (TTR variant), since the circulating TTR is produced in the liver.121–123 Thus, the new liver will replace the variant TTR with a normal TTR. Ideally, this is performed before cardiac involvement occurs. Nonsteroidal antiinflammatory drugs, such as Diflunisal, that can stabilize TTR and prevent the formation of amyloid are being evaluated.124 There is no specific treatment for the senile type of amyloid, though usually patients can be managed medically.
Storage Cardiomyopathies There has been a growing recognition that cardiac storage disorders often go unrecognized and may be frequent mimics of HCM.4,125,126 Intracellular accumulation of various substances within myocytes generally results from defects in genes coding for metabolic pathways. It is likely that the list of these disorders continues to expand rapidly. Currently, primary cardiomyopathies due to PRKAG2 and LAMP2 proteins have been described, and secondary cardiomyopathies include Fabry’s, Pompe’s, and Nieman-Pick diseases and hemochromatosis.4 Fabry’s disease and the primary cardiomyopathies will be discussed, since they are most prevalent in adults. Hemochromatosis, though more likely to manifest as a dilated cardiomyopathy, will also be reviewed.
Fabry’s Disease Case 3 A 48-year-old man presents with dyspnea on exertion. He has been diagnosed with nonobstructive HCM. There is a family history of Fabry’s disease. On cardiac examination, there is a moderate intensity ejection murmur that is unchanged with Valsalva. ECG shows a short P-R interval and LVH. Echocardio-
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies gram shows severe symmetric hypertrophy (interventricular septum, 1.9 cm; posterior wall, 1.8 cm). There is no SAM of the mitral valve or the LV outflow tract gradient at rest or with exercise echocardiogram. A laboratory test for alpha-galactosidase shows levels less than 10% of normals. Genetic testing confirms Fabry’s disease with a mutation in the gene coding for alphagalactosidase. An endomyocardial biopsy shows inclusion bodies in the sarcoplasmic reticulum. The patient is referred for enzyme replacement therapy. Etiology and Presentations Fabry’s disease is a rare X-linked recessive disorder of metabolism due to gene mutations coding for alpha-galactosidase. This defect results in a deficiency in the enzyme alpha-galactosidase A that leads to accumulation of glycosphingolipids, the most common of which is globotriaosylceramide, Gb(3), in lysosomes.127 Although described decades ago, isolated cardiac manifestations have not been widely recognized until the past decade, and enzyme replacement therapy has only recently become available.128,129 Fabry’s disease most severely affects homozygous males, with generally milder symptoms occurring in females.130–133 Abnormal deposition of glycolipid occurs in the cardiovascular system (myocardium, valves, conduction system, blood vessels), nerves, skin, and kidney.134 Lysosomal inclusions are seen by electron microscopy with vacuolization of myocytes, endothelial and smooth muscle cells with a concentric lamellar configuration.133 The noncardiac manifestations of Fabry’s disease include angiokeratoma, acroparesthesias, hypohidrosis, and corneal opacities.132 Among children in the European Fabry Outcome Survey (FOS), the most frequent symptoms were acroparesthesias, altered temperative sensitivity, gastrointestinal effects, vertigo, tinnitus, and fatigue.135Adults may present with renal failure and stroke, though cardiac-related symptoms alone may occur, including dyspnea, chest pain, syncope, and congestive heart failure.136 Recent studies have shown that Fabry’s disease may be the cause of LVH in 4%–6% of men with late-onset HCM.130,131 Furthermore, 12% of
females (mean age, 51.5 years) with late-onset hypertrophy were demonstrated to have Fabry’s disease by endomyocardial biopsy, despite electrocardiographic and echocardiographic appearances of HCM (Fig. 21-10).132 Among female patients with Fabry’s disease screened for LVH in one study, 63% had evidence of concentric or eccentric hypertrophy, suggesting cardiac involvement.133 In the same study, among females older than 45 years of age with Fabry’s, hypertrophy was evident in all patients. The diagnosis of Fabry’s disease in adults is first suspected by findings on the ECG and echocardiogram. The ECG may show AV block and a short P-R interval with evidence of LVH.137 Cardiac manifestations described by echocardiography include increased aortic dimension, mitral regurgitation with mitral valve prolapse, and increased LV wall thickness.138–143 Although most often the pattern of increased LV wall thickness is concentric hypertrophy or remodeling, asymmetric hypertrophy has been described.132 The systolic function is usually preserved. SAM of the mitral valve has been described.142 Diastolic function, though typically abnormal, is usually not restrictive.144 The diagnosis of Fabry’s disease can be confirmed in hemizygous males by detection of reduced levels of leukocyte alphagalactosidase levels.136 Heterozygous females may have normal or mildly decreased levels, and therefore tissue biopsy or gene testing of affected tissue for diagnosis may be required.132 Efforts have been made to use different imaging modalities to screen patients with LVH for Fabry’s disease, including echocardiography and MRI, since treatment to reduce the accumulation of cardiac infiltration with glycolipid has become available.144–146 Echocardiographic screening of mutation-positive patients for Fabry’s disease, though negative for LVH, has shown reduced tissue Doppler systolic, E-annular, and A-annular velocities compared with controls.144 MRI has also shown abnormalities in patients with Fabry’s plus LVH with reduced radial and longitudinal strain and strain rate relative to controls and improvement in strain and strain rate with concomitant reduction in wall thickness with treatment.147 MRI studies show a mildly increased
Figure 21-10 Fabry’s cardiomyopathy. A, 12-lead electrocardiogram showing signs of left ventricular (LV) hypertrophy and ST-segment depression with giant negative T waves in precordial leads, suggesting apical hypertrophic cardiomyopathy. B, End diastolic (left) and end systolic (right) echocardiographic apical four-chamber view showing severe wall hypertrophy and cavity obliteration of ventricular apex. C, LV angiography in right anterior oblique (30˚) view showing massive apical hypertrophy of LV. D, LV endomyocardial biopsy showing normal cells (arrows) intermingled with cells containing glycolipid inclusion vacuoles (arrowheads) (hematoxylin and eosin; ×200). (From Chimenti C et al: Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy. Circulation 2004;110:1047–1053.)
269
270
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies signal intensity of the myocardium but no specific pattern except a tendency toward posterior-basal late enhancement with gadolinium.147,148 Reduction in radial and longitudinal strain determined echocardiographically in patients with Fabry’s disease shows a correlation between hypertrophy and late enhancement by MRI.149 Thus far, the most accurate and promising finding to distinguish LVH due to hypertension and HCM from Fabry’s cardiomyopathy is the presence of a binary appearance of the LV endocardium border.145 In one study, the sensitivity and specificity of this finding was 94% and 100%, respectively. The finding is demonstrated histologically by compartmentalization of glycosphingolipids to the endocardium (Fig. 21-11). Once cardiac involvement with Fabry’s disease has been confirmed, treatment with enzyme replacement (recombinant human alpha-galactosidase A) can be initiated. Several studies have demonstrated a reduction in LVH and improvement in cardiac function with galactose infusion therapy.147,150,151
liver function tests.125,126 The clinical course progresses rapidly, with premature death. PRKAG2 has a less ominous prognosis. There is a dominant inheritance pattern and lack of noncardiac involvement, with patients surviving to adulthood, though often with arrhythmias and conduction disease.125 A study of 50 unselected patients (mean age, 6 years) with the diagnosis of HCM who underwent gene analysis for LAMP2 found 2 (4%) with mutations. Both of these patients had WolffParkinson White syndrome and skeletal myopathy.126 A similar study of 75 unselected patients with HCM found 3 (4%) with LAMP2 or PRKAG2 mutations.125 The same investigators performed a subgroup analysis of 24 patients with LVH and preexcitation and found 11 with mutations in LAMP2 or PRKAG2 with associated findings of LAMP2, including male sex, severe hypertrophy, early onset of HCM, preexcitation, and elevated liver and muscle enzymes. An algorithm for the diagnosis of patients with suspected LAMP2 or PRKAG 2 mutations is proposed in Figure 21-12.
Glycogen Storage Disorders
Hemochromatosis
Two gene mutations (PRKAG2 and LAMP2) causing glycogen storage disease have recently been recognized as primary cardiomyopathies mimicking HCM.125,126 PRKAG2 codes for a regulatory gene for cyclic adenosine monophosphate (cAMP)–activated protein kinase, and LAMP2 (also called Danon’s disease) codes for a lysosome membrane protein.4 Neither of these diseases is associated with myocyte disarray or interstitial fibrosis, but rather glycogen-rich vacuoles. Additional gene mutations affecting nonsarcomeric proteins involved in metabolism are likely to be discovered. Danon’s disease occurs as an X-linked gene affecting male children younger than 20 years of age, though females are usually detected as adults. Noncardiac manifestations include skeletal myopathy, mental retardation, behavioral changes, and ocular abnormalities.125,126 Cardiac manifestations include early onset of HCM, preexcitation, and elevated creatine kinase, troponins, and
Case 4 A 50-year-old man is undergoing consideration for liver transplantation due to primary hemochromatosis. He has no known cardiac disease and no cardiac risk factors. On examination, his skin is bronze. The cardiac examination is notable for a positive S4 gallop. ECG shows low voltage in the limb leads. An echocardiogram shows normal LV size and function with abnormal diastolic function (stage 2 filling pattern) and reduced tissue Doppler systolic annular (6 cm/sec) and E-annular velocities (4 cm/sec). A cardiac MRI is done and shows abnormalities consistent with hemochromatosis. A cardiac biopsy confirms iron overload in the myocardium. Etiology and Presentations Hemochromatosis is an iron storage disease that affects the heart, pancreas, liver, gonads, joints, and skin.152 Primary idio-
Figure 21-11 Two-dimensional echocardiography in four-chamber apical view and left ventricular (LV) endomyocardial biopsy from two patients with Fabry’s disease cardiomyopathy (A, D and B, E, respectively) and a patient with hypertrophic cardiomyopathy (C, F). Comparison of the three echocardiographic frames reveals the presence of a binary appearance of the LV endocardial border in the two Fabry patients (A, B). This echocardiographic finding reflects glycosphingolipid compartmentalization involving a thickened endocardium (End) with enlarged and engulfed smooth muscle cells (SMC), a subendocardial empty space (SES), and a prominent involvement of subendocardial myocardial layer (SL), while the middle layer (ML) appears partially spared (D, E). The echocardiographic pattern is absent in hypertrophic cardiomyopathy (C), despite a similar thickening of the endocardium (F). (From Pieroni M et al: Fabry’s disease cardiomyopathy: Echocardiographic detection of endomyocardial glycosphingolipid compartmentalization. J Am Coll Cardiol 2006;47:1663–1671. )
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies Unexplained left ventricular hypertrophy: is ventricular preexcitation present? No
Yes
Analyze sarcomere-protein genes; is mutation present?
Young, male patient prominent left ventricular voltage; massive hypertrophy? No
Yes
Hypertrophic cardiomyopathy
No
Analyze PRKAG2; is mutation present?
Yes
No
Measure alanine aminotransferase and creatine phosphokinase; elevated? Yes
Yes
No
Glycogen-associated cardiomyopathy
Analyze LAMP2; is mutation present? Yes
Cardiac Danon’s disease
No
Consider other glycogen storage disease
Figure 21-12 Algorithm for the diagnostic evaluation of patients with unexplained hypertrophy, where hypertrophic cardiomyopathy may not be the etiology. A family history of the dominant inheritance of left ventricular (LV) hypertrophy, unaccompanied by systemic manifestations or electrocardiographic findings of ventricular preexcitation, suggests hypertrophic cardiomyopathy; the identification of a sarcomeric mutation confirms the diagnosis. In young patients with echocardiographic findings of unexplained LV hypertrophy and electrocardiograms with prominent LV voltage and short P-R intervals, delta waves, or both, glycogen storage disease should be suspected. Dominant inheritance and an absence of systemic disease suggest the presence of glycogen-associated cardiomyopathy due to PRKAG2 mutations. Male sex and abnormalities in liver, musculoskeletal, or neurologic function suggest a diagnosis of Danon’s disease, although systemic manifestations can be modest or absent in the cardiac form of this disease. When the cause is not established by genetic analyses, a tissue biopsy and a biochemical study may be helpful. (From Arad M et al: Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 2005;352:362–372.)
pathic hemochromatosis is an autosomal recessive disorder related to the human leukocyte antigen on chromosome 6 that results in excessive iron absorption.152,153 It is the most common autosomal recessive disease in Caucasians.154 Both men and women are affected in middle age (fifties/sixties), with women usually presenting after menstruation has ceased.155 Secondary hemochromatosis results from hemoglobin synthesis abnormalities leading to ineffective erythropoiesis, chronic liver disease, excessive intake of iron, or multiple blood transfusions.153 Histologically, iron is deposited in the sarcoplasmic reticulum, mostly within the subepicardium and to a lesser extent the subendocardium of the myocardium.155 Interstitial iron is not seen, characterizing hemochromatosis as a storage, not an infiltrative, disorder.4 The ventricles and conduction system are most often affected.155 The degree of myocardial iron correlates with the severity of cardiac dysfunction.156–159 Manifestations of cardiac involvement occur when there is a large amount of iron deposited over a long period of time. Onethird of patients manifest cardiac symptoms with evidence of congestive heart failure, supraventricular or ventricular arrhythmias, and conduction defects.152 Cardiac involvement is usually recognized after a noncardiac diagnosis is already known. Less often, patients will present with a cardiomyopathy of unknown etiology without known hemochromatosis. Laboratory tests will show an elevated serum ferritin and increased ratio of plasma iron
level to total iron binding capacity, urinary iron, liver iron, and saturation of transferrin.160 Cardiomegaly may be seen on CXR. Electrocardiographic findings have included arrhythmias, conduction disorders, and low voltage. Echocardiography is a useful noninvasive technique in the assessment of cardiac involvement in primary hemochromatosis, detecting clinically occult heart involvement, following patients serially, and assessing LV function after phlebotomy.156,161–163 A retrospective review from the Mayo Clinic described 19 patients with primary hemochromatosis and demonstrated that 7 (37%) had chamber dilatation and systolic dysfunction secondary to hemochromatosis, while 12 patients did not.157 Increased ventricular wall thickness was not evident in this cohort of patients. Patterns consistent with dilated or restrictive cardiomyopathy or mixed patterns have been described in patients with primary hemochromatosis, though the earliest finding is usually a restrictive pattern.155,159 Ventricular dysfunction and increased ventricular mass may normalize after successful phlebotomy.163–165 The presence of systolic dysfunction usually signifies a poor prognosis.156 Manifestations of secondary hemochromatosis in the heart include increased LV wall thickness and mass, increased cavity dimension, and LA enlargement.166 Specific Doppler filling indexes and TDE are useful to differentiate patients with hereditary hemochromatosis from normal subjects and therefore may be useful for screening.167 Exercise radionu-
271
272
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies Figure 21-13 Middle-aged man with hemochromatosis developed congestive heart failure and a dilated cardiomyopathy. He was treated with deferoxamine and phlebotomy. A, Systolic frame illustrating systolic dysfunction. B, Mitral inflow pattern illustrating Stage 2 diastolic dysfunction. Thirteen months later, systolic frame illustrated normal systolic function (C), and mitral inflow pattern illustrated reversion to Stage 1 diastolic dysfunction (D).
.69
.69 PW:2MHz 1.0
m/s
A
B
1.0
1.6MHZ
C
D
clide cine angiography demonstrating exercise-related LV dysfunction in patients with normal baseline function has also been shown to be sensitive to detect preclinical disease.168 Other noninvasive tests, including CT and MRI, may be useful in demonstrating subclinical involvement of hemochromatosis (Fig. 21-13).169,170 The MRI may show a low myocardial signal on the cine gradient echo, consistent with myocardial iron deposition.169 Endomyocardial biopsy may be useful to exclude the diagnosis, especially when echocardiographic or clinical features are not evident.171 Treatment by repeat phlebotomies in primary hemochromatosis or the use of chelating agents (desferoxamine) in secondary hemochromatosis may result in improvement of cardiac involvement, making early diagnosis important.163–165 Thus, cardiac hemochromatosis is a potentially reversible form of cardiomyopathy. Heart transplantation may be considered when the heart involvement is life threatening, or combined heart and liver transplantation may be useful in patients with heart and liver failure.155,172–174
FUTURE RESEARCH The AHA 2006 reclassification of cardiomyopathies has shifted the focus toward understanding the genetic and cellular causes of specific heart muscle diseases.4 Ultimately, the most effective approach to early diagnosis and targeted treatment will be guided by knowledge of the basic underpinnings of the disease processes. Meanwhile, until these advances occur, echocardiography and MRI have risen to the forefront as noninvasive tests with the potential to detect preclinical myocardial disease and differentiate various disorders. These modalities have begun to uncover specific fingerprints for each disease and should continue to be utilized during the evaluation and screening of cardiomyopathies. Most of the disorders discussed in this review continue to be associated with a poor prognosis and often are managed as pallia-
1.2 0.8 0.4 0.0 0.4 0.8 1.2 1.6
+ m / s –
tive diseases. Furthermore, over the past few decades, it is not readily evident to most physicians that progress has occurred. Advances in studying uncommon problems rely on reminding clinicians that treatment investigations are ongoing. Patients and their doctors should be encouraged to pursue evaluations at specialty referral centers, allowing them to receive the latest therapies and to be participants in prospective registries or clinical trials. Many of these centers, such as Amyloid or Fabry’s Cardiomyopathy Clinics, exist both nationally and internationally and are essential for promoting excellence in care and future research. At the present time, there is reason for modest optimism. Patients with idiopathic restrictive or amyloid cardiomyopathy without significant noncardiac disease can be considered for cardiac or liver transplantation. Storage cardiomyopathies such as Fabry’s disease and hemochromatosis may be largely reversible with known accepted therapies. Amyloid cardiomyopathy still presents a difficult challenge; however, a better recognition of non-AL forms of amyloid has allowed more patients to be eligible for treatment. Although at one time the diseases encompassed by the entity of “restrictive cardiomyopathy” were considered the topic of case presentations and few therapeutic options, in the future we anticipate earlier diagnosis, enhanced understanding of pathophysiological mechanisms, and increasing options for treatment and clinical research, with the ultimate goal of improved outcomes. REFERENCES 1. Goodwin JF: The frontiers of cardiomyopathy. Br Heart J 1982;48:11–18. 2. Report of the WHO/ISFC task force on the definition and classification of cardiomyopathies. Br Heart J 1980;44:672–673. 3. Richardson P, McKenna W, Bristow M, et al: Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation 1996;93:841–842. 4. Maron BJ, Towbin JA, Thiene G, et al: Contemporary definitions and classification of the cardiomyopathies. Circulation 2006;113:1807–1816.
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 5. Kushawa SS, Fallon JT, Fuster V: Restrictive cardiomyopathy. N Engl J Med 1997;336:267–276. 6. Keren A, Popp RL: Assignment of patients into the classification of cardiomyopathies. Circulation 1992;86:1622–1633. 7. Siegel RJ, Shah PK, Fishbein MC: Idiopathic restrictive cardiomyopathy. Circulation 1984;70:165–169. 8. Katritsis D, Wilmshurst PT, Wendon JA, et al: Primary restrictive cardiomyopathy: Clinical and pathologic characteristics. J Am Coll Cardiol 1991;18:1230–1235. 9. Angelini A, Calzolari V, Thiene G, et al: Morphologic spectrum of primary restrictive cardiomyopathy. Am J Cardiol 1997;80:1046–1050. 10. Ammash NM, Seward JB, Bailey KR, et al: Clinical profile and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000;101:2490–2496. 11. Hirota Y: Restrictive cardiomyopathy, cardiac amyloidosis and hypereosinophilic heart disease. In Braunwald E (ed): Cardiomyopathies, myocarditis, and pericardial disease: Atlas of heart diseases, vol 2. Philadelphia, Current Medicine, 1995;5.1–5.15. 12. Zhang J, Kumar A, Stalker HF, et al: Clinical and molecular studies of a large family with desmin associated restrictive cardiomyopathy. Clin Genet 2001;59:248–256. 13. Hayashi T, Shimomura H, Terasaki F, et al: Collagen subtypes and matrix mettaloproteinase in idiopathic restrictive cardiomyopathy. Int J Cardiol 1998;64:109–116. 14. Abelmann WH, Lorell BH: The challenge of cardiomyopathy. J Am Coll Cardiol 1989;13:1219–1239. 15. Klein AL, Oh JK, Miller FA, et al: Two-dimensional and Doppler echocardiographic assessment of infiltrative cardiomyopathy. J Am Soc Echocardiogr 1988;1:48–59. 16. Benotti JR, Grossman W, Cohn PF: Clinical profile of restrictive cardiomyopathy. Circulation 1980;61:1206–1212. 17. Lewis AB: Clinical profile and outcome of restrictive cardiomyopathy in children. Am Heart J 1992;123:1589–1593. 18. Cetta F, O’Leary PW, Seward JB, et al: Idiopathic restrictive cardiomyopathy in childhood: Diagnostic features and clinical course. Mayo Clinic Proceedings 1995;70:634–640. 19. Fitzpatrick AP, Shapiro LM, Rickards AF, Poole-Wilson PA: Familial restrictive cardiomyopathy with atrioventricular block and skeletal myopathy. Br Heart J 1990;63:114–118. 20. Ishiwata S, Nishiyama S, Seki A, et al: Restrictive cardiomyopathy and complete atrioventricular block and distal myopathy with rimmed vacuoles. Jpn Circ J 1993;57:928–933. 21. Cooke RA, Chambers JB, Curry PV: Noonan’s cardiomyopathy: A nonhypertrophic variant. Br Heart J 1994;71:561–565. 22. Mogensen J, Kubo T, Duque M, et al: Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest 2003;111:175–178. 23. Child JS, Perloff JK: The restrictive cardiomyopathies. Cardiol Clin 1988;6:289–316. 24. Leya FS, Arab D, Joyal D, et al: The efficacy of brain natriuretic peptide levels in differentiating constrictive pericarditis from restrictive cardiomyopathy. J Am Coll Cardiol 2005;45:1900–1902. 25. Klein AL, Asher CR: Diseases of the pericardium, restrictive cardiomyopathy and diastolic dysfunction. In Topol EJ, ed, Textbook of cardiovascular medicine, 2nd ed. Philadelphia, Lippincott-Raven 2004:595–646. 26. Leung DL, Klein AL: Restrictive cardiomyopathy: Diagnosis and prognostic implications. In Otto CM, ed, The practice of clinical echocardiography. Philadelphia, WB Saunders, 1996:473–493. 27. Klein AL, Cohen GI, Pietrolungo JF, et al: Differentiation of constrictive pericarditis from restrictive cardiomyopathy by Doppler transesophageal echocardiographic measurements of respiratory variations in pulmonary venous flow. J Am Coll Cardiol 1993;22:1935–1943. 28. Hatle LK, Appleton CP, Popp RL: Differentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370. 29. Rajagopalan N, Garcia MJ, Rodriguez L, et al: Comparison of new Doppler echocardiographic methods to differentiate constrictive pericardial heart disease and restrictive cardiomyopathy. Am J Cardiol 2001;87:86–94. 30. Soler R, Rodriguez E, Remuinan C, et al: Magnetic resonance imaging of primary cardiomyopathies. J Comput Assis Tomo 2003;27:724–734. 31. Celletti F, Fattori R, Napoli G, et al: Assessment of restrictive cardiomyopathy of amyloid or idiopathic etiology by magnetic resonance imaging. Am J Cardiol 1999;83:798–801. 32. Hosenpud JD, Niles NR: Clinical, hemodynamic and endomyocardial biopsy findings in idiopathic restrictive cardiomyopathy. West J Med 1986;144:303–306.
33. Denfield SW, Rosenthal G, Gajarski RJ, et al: Restrictive cardiomyopathies in childhood: Etiologies and natural history. Tex Heart Inst J 1997; 24:38–44. 34. Rivenes SM, Kearney DL, Smith EO, et al: Sudden death and cardiovascular collapse in children with restrictive cardiomyopathy. Circulation 2000;102:876–882. 35. Russo LM, Webber SA: Idiopathic restrictive cardiomyopathy in children. Heart 2005;91:1199–2002. 36. Weller RJ, Weintraub R, Addonizio LF, et al: Outcome of idiopathic restrictive cardiomyopathy in children. Am J Cardiol 2002;90:501–506. 37. Fenton MJ, Chubb H, McMahon AM, et al: Heart and heart-lung transplantation for idiopathic restrictive cardiomyopathy in children. Heart 2006;92:85–89. 38. Ammash NM, Seward JB, Bailey KR, et al: Clinical profile and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000;101:2490–2496. 39. Falk RH: Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112:2047–2060. 40. Gertz MA, Rajkumar SV: Primary systemic amyloidosis. Curr Treat Options Oncol 2002;3:261–271. 41. Kholova I, Niessen HW: Amyloid in the cardiovascular system: A review. J Clin Pathol 2005;58:125–133. 42. Kyle RA, Greipp PR: Amyloidosis (AL): Clinical and laboratory features in 229 cases. Mayo Clin Proc 1983;58:665–683. 43. Kyle RA: Amyloidosis. Circulation 1995;91:12769–12771. 44. Gertz MA, Kyle RA: Primary systemic amyloidosis—a diagnostic primer. Mayo Clin Proc 1989;64:1505–1519. 45. Kyle RA, Gertz MA: Primary systemic amyloidosis: Clinical and laboratory features in 474 cases. Semin Hematol 1995;32:45–59. 46. Gertz MA, Kyle RA, Thibodeau SN: Familial amyloidosis: A study of 52 North American–born patients examined during a 30-year period. Mayo Clin Proc 1992;67:428–440. 47. Connors LH, Lim A, Prokaeva T, et al: Tabulation of human transthyretin (TTR) variants, 2003. Amyloid 2003;10:160–184. 48. Booth DR, Tan SY, Hawkins PN, et al: A novel variant of transthyretin, 59Thr—>Lys, associated with autosomal dominant cardiac amyloidosis in an Italian family. Circulation 1995;91:962–967. 49. Fredericksen T, Gotzsche H, Harboe N, et al: Familial primary amyloidosis with severe amyloid heart disease. Am J Med 1962;33:328–348. 50. Benson MD, Wallace MR, Tejada E, et al: Hereditary amyloidosis: Description of a new American kindred with late onset cardiomyopathy. Appalachian amyloid. Arth & Rheum 1987;30:195–200. 51. Jacobson DR, Pastore RD, Yaghoubian R, et al: Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 1997;366:466–473. 52. Kyle RA, Spittell PC, Gertz MA, et al: The premortem recognition of systemic senile amyloidosis with cardiac involvement. Am J Med 1996;101:395–400. 53. Olson LJ, Gertz MA, Edwards WD, et al: Senile cardiac amyloidosis with myocardial dysfunction. Diagnosis by endomyocardial biopsy and immunohistochemistry. N Engl J Med 1987;317:738–742. 54. Ng B, Connors LH, Davidoff R, et al: Senile systemic amyloidosis presenting with heart failure: A comparison with light chain associated amyloidosis. Arch Intern Med 2005:165:1425–1429. 55. Liao R, Jain M, Teller P, et al: Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts. Circulation 2001;104:1594–1597. 56. Dubrey SW, Cha K, Simms RW, et al: Electrocardiography and Doppler echocardiography in secondary (AA) amyloidosis. Am J Cardiol 1996; 77:313–315. 57. Gertz MA, Kyle RA: Secondary systemic amyloidosis: Response and survival in 64 patients. Medicine 1991;70:246–256. 58. Pucci A, Wharton J, Arbustini E, et al: Atrial amyloid deposits in the failing human heart display both atrial and brain natriuretic peptide–like immunoreactivity. J Pathol 1991;165:235–241. 59. Goette A, Rocken C: Atrial amyloidosis and atrial fibrillation: A genderdependent “arrhythmogenic substrate”? Eur Heart J 2004;25:1237–1241. 60. Rocken C, Peters B, Juenemann G, et al: Atrial amyloidosis: An arrhythmogenic substrate for persistent atrial fibrillation. Circulation 2002; 106:2091–2097. 61. Gertz MA, Lacy MQ, Dispenzieri A: Amyloidosis. Hematol Oncol Clin North Am 1999;13:1211–1233. 62. Cueto-Garcia L, Tajik AJ, Kyle RA, et al: Serial echocardiographic observations in patients with primary systemic amyloidosis: An introduction to the concept of early (asymptomatic) amyloid infiltration of the heart. Mayo Clin Proc 1984;59:589–597.
273
274
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 63. Spyrou N, Foale R: Restrictive cardiomyopathies. Curr Opin Cardiol 1994;9:344–348. 64. Barth RF, Willerson JT, Buja LM, et al: Amyloid coronary artery disease, primary systemic amyloidosis and paraproteinemia. Arch Intl Med 1970;126:627–630. 65. Mueller PS, Edwards WD, Gertz MA: Symptomatic ischemic heart disease resulting from obstructive intramural coronary amyloidosis. Am J Med 2000;109:181–188. 66. Bernardi L, Passino C, Porta C, et al: Widespread cardiovascular autonomic dysfunction in primary systemic amyloidosis: Does spontaneous hyperventilation have a compensatory role against postural hypotension? Heart 2002;88:615–621. 67. Rubinow A, Cohen AS: Skin involvement in generalized amyloidosis. A study of clinically involved and uninvolved skin in 50 patients with primary and secondary amyloidosis. Ann Intern Med 1978;88:781–785. 68. Klein AL, Hatle LK, Burstow DJ, et al: Doppler characterization of left ventricular diastolic function in cardiac amyloidosis. J Am Coll of Cardiol 1989;13:1017–1026. 69. Shabetai R: Pathophysiology and differential diagnosis of restrictive cardiomyopathy. Cardiovasc Clin 1988;19:123–132. 70. Dubrey SW, Cha K, Skinner M, et al: Familial and primary (AL) cardiac amyloidosis: Echocardiographically similar diseases with distinctly different clinical outcomes. Heart 1997;78:74–82. 71. Murtagh B, Hammill SC, Gertz MA, et al: Electrocardiographic findings in primary systemic amyloidosis and biopsy-proven cardiac involvement. Am J Cardiol 2005;95:535–537. 72. Carroll JD, Gaasch WH, McAdam KP: Amyloid cardiomyopathy: Characterization by a distinctive voltage/mass relation. Am J Cardiol 1982; 49:9–13. 73. Dubrey SW, Cha K, Anderson J, et al: The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM 1998;91:141–157. 74. Falk RH, Rubinow A, Cohen AS: Cardiac arrhythmias in systemic amyloidosis: Correlation with echocardiographic abnormalities. J Am Coll Cardiol 1984;3:107–113. 75. Klein AL, Oh JK, Miller FA, et al: Two-dimensional and Doppler echocardiographic assessment of infiltrative cardiomyopathy. J Am Soc Echocardiogr 1988;1:48–59. 76. Klein AL, Hatle LK, Burstow DJ, et al: Comprehensive Doppler assessment of right ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1990;15:99–108. 77. Klein AL, Hatle LK, Taliercio CP, et al: Serial Doppler echocardiographic follow-up of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1990;16:1135–1141. 78. Klein AL, Hatle LK, Taliercio CP, et al: Prognostic significance of Doppler measures of diastolic function in cardiac amyloidosis. A Doppler echocardiography study. Circulation 1991;83:808–816. 79. Patel AR, Dubrey SW, Mendes LA, et al: Right ventricular dilation in primary amyloidosis: An independent predictor of survival. Am J Cardiol 1997;80:486–492. 80. Cueto-Garcia L, Reeder GS, Kyle RA, et al: Echocardiographic findings in systemic amyloidosis: Spectrum of cardiac involvement and relation to survival. J Am Coll Cardiol 1985;6:737–743. 81. Falk RH, Plehn JF, Deering T, et al: Sensitivity and specificity of the echocardiographic features of cardiac amyloidosis. Am J Cardiol 1987; 59:418–422. 82. Siqueira-Filho AG, Cunha CL, Tajik AJ, et al: M-mode and twodimensional echocardiographic features in cardiac amyloidosis. Circulation 1981;63:188–196. 83. Chiaramida SA, Goldman MA, Zema MJ, et al: Real-time cross-sectional echocardiographic diagnosis of infiltrative cardiomyopathy due to amyloid. J Clin Ultra 1980;8:58–62. 84. Chandrasekaran K, Aylward PE, Fleagle SR, et al: Feasibility of identifying amyloid and hypertrophic cardiomyopathy with the use of computerized quantitative texture analysis of clinical echocardiographic data. J Am Coll Cardiol 1989;13:832–840. 85. Chew C, Ziady GM, Raphael MJ, Oakley CM: The functional defect in amyloid heart disease. The “stiff heart” syndrome. Am J Cardiol 1975;36:438–444. 86. St. John Sutton MG, Reichek N, Kastor JA, Giuliani ER: Computerized M-mode echocardiographic analysis of left ventricular dysfunction in cardiac amyloid. Circulation 1982;66:790–799. 87. Abdalla I, Murray RD, Lee JC, et al: Duration of pulmonary venous atrial reversal flow velocity and mitral inflow A wave: New measure of severity of cardiac amyloidosis. J Am Soc Echocardiogr 1998;11:1125–1133.
88. Koyama J, Ray-Sequin PA, Davidoff R, Falk RH: Usefulness of pulsed tissue Doppler imaging for evaluating systolic and diastolic left ventricular function in patients with AL (primary) amyloidosis. Am J Cardiol 2002;89:1067–1071. 89. Koyama J, Ray-Sequin PA, Falk RH: Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis. Circulation 2003;107:2446–2452. 90. Katzmann JA, Abraham RS, Dispenzieri A, et al: Diagnostic performance of quantitative kappa and lambda free light chain assays in clinical practice. Clin Chem 2005;51:878–881. 91. Abraham RS, Katzmann JA, Clark RJ, et al: Quantitative analysis of serum free light chains. A new marker for the diagnostic evaluation of primary systemic amyloidosis. Am J Clin Pathol 2003;119:274–278. 92. Gertz MA, Lacy MQ, Dispenzieri A: Amyloidosis: Recognition, confirmation, prognosis, and therapy. Mayo Clin Proc 1999;74:490–494. 93. Libbey CA, Skinner M, Cohen AS: Use of the abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis. Arch Intern Med 1983;143: 1549–1552. 94. Ardehali H, Qasim A, Cappola T, et al: Endomyocardial biopsy plays a role in diagnosing patients with unexplained cardiomyopathy. Am Heart J 2004;147:919–923. 95. Oh JK, Tajik AJ, Edwards WD, et al: Dynamic left ventricular outflow tract obstruction in cardiac amyloidosis detected by continuous-wave Doppler echocardiography. Am J Cardiol 1987;59:1008–1010. 96. Sechtem U, Higgins CB, Sommerhoff BA, et al: Magnetic resonance imaging of restrictive cardiomyopathy. Am J Cardiol 1987;59:480–482. 97. Von Kemp K, Beckers R, Vandenweghe J, et al: Echocardiography and magnetic resonance imaging in cardiac amyloidosis. Acta Cardiologica 1989;44:29–36. 98. Celletti F, Fattori R, Napoli G, et al: Assessment of restrictive cardiomyopathy of amyloid or idiopathic etiology by magnetic resonance imaging. Am J Cardiol 1999;83:798–801, A10. 99. Maceira AM, Joshi J, Prasad SK, et al: Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111:186–193. 100. Hongo M, Fujii T, Hirayama J, et al: Radionuclide angiographic assessment of left ventricular diastolic filling in amyloid heart disease: A study of patients with familial amyloid polyneuropathy. J Am Coll Cardiol 1989;13:48–53. 101. Hongo M, Hirayama J, Fujii T, et al: Early identification of amyloid heart disease by technetium-99m–pyrophosphate scintigraphy: A study with familial amyloid polyneuropathy. Am Heart J 1987;113:654–662. 102. Lekakis J, Nanas J, Moustafellou C, et al: Cardiac amyloidosis detected by indium-111 antimyosin imaging. Am Heart J 1992;124:1630–1631. 103. Perugini E, Guidalotti PL, Salvi F, et al: Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol 2005;46:1076–1084. 104. Gertz MA, Kyle RA: Amyloidosis: Prognosis and treatment. Semin Arthritis Rheum 1994;24:124–138. 105. Tei C, Dujardin KS, Hodge DO, et al: Doppler index combining systolic and diastolic myocardial performance: Clinical value in cardiac amyloidosis. J Am Coll Cardiol 1996;28:658–664. 106. Dispenzieri A, Kyle RA, Gertz MA, et al: Survival in patients with primary systemic amyloidosis and raised serum cardiac troponins. Lancet 2003; 361:1787–1789. 107. Kyle RA, Gertz MA, Greipp PR, et al: A trial of three regimens for primary amyloidosis: Colchicine alone, melphalan and prednisone, and melphalan, prednisone and colchicine. N Engl J Med 1997;336:1202– 1207. 108. Skinner M, Anderson JJ, Simms R, et al: Treatment of 100 patients with primary amyloidosis: A randomized trial of melphalan, prednisone, and colchicine versus colchicine alone. Am J Med 1996;100:290–298. 109. Palladini G, Perfetti V, Obici L, et al: Association of melphalan and highdose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplant. Blood 2004;103:2936–2938. 110. Skinner M, Sanchorawala V, Seldin DC, et al: High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: An 8-year study. Ann Intern Med 2004;140:85–93. 111. Comenzo RL, Vosburgh E, Falk RH, et al: Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: Survival and responses in 25 patients. Blood 1998;91:3662– 3670. 112. Rubinow A, Skinner M, Cohen AS: Digoxin sensitivity in amyloid cardiomyopathy. Circulation 1981;63:1285–1288.
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 113. Pollak A, Falk RH: Left ventricular systolic dysfunction precipitated by verapamil in cardiac amyloidosis. Chest 1993;104:618–620. 114. Willens HJ, Levy R, Kessler KM: Thromboembolic complications in cardiac amyloidosis detected by transesophageal echocardiography. Am Heart J 1995;129:405–406. 115. Plehn JF, Southworth J, Cornwell GG: Brief report: Atrial systolic failure in primary amyloidosis. N Engl J Med 1992;327:1570–1573. 116. Hosenpud JD, DeMarco T, Frazier OH, et al: Progression of systemic disease and reduced long-term survival in patients with cardiac amyloidosis undergoing heart transplantation. Follow-up results of a multicenter survey. Circulation 1991;84(5 Suppl):III338–343. 117. Dubrey S, Simms RW, Skinner M, Falk RH: Recurrence of primary (AL) amyloidosis in a transplanted heart with four-year survival. Am J Cardiol 1995;76:739–741. 118. Kpodonu J, Massad MG, Caines A, Geha AS: Outcome of heart transplantation in patients with amyloid cardiomyopathy. J Heart Lung Transplant 2005;24:1763–1765. 119. Dubrey SW, Burke MM, Hawkines PN, et al: Cardiac transplantation for amyloid heart disease: The United Kingdom experience. J Heart Lung Transplant 2004;23:1142–1153. 120. Pelosi F Jr, Capehart J, Roberts WC: Effectiveness of cardiac transplantation for primary (AL) cardiac amyloidosis. Am J Cardiol 1997;79:532–535. 121. Suhr OB, Herlenius G, Friman S, Ericzon BG: Liver transplantation for hereditary transthyretin amyloidosis. Liver Transpl 2000;6:263–276. 122. Skinner M, Lewis LD, Jones LA, et al: Liver transplantation as treatment for familial amyloidotic polyneuropathy. Ann Intern Med 1994;120: 133–134. 123. Holmgren G, Ericzon BG, Groth CG, et al: Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 1993;341:1113–1116. 124. Miller SR, Sekijima Y, Kelly JW: Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants. Lab Invest 2004;84:545–552. 125. Arad M, Maron BJ, Gorham JM, et al: Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 2005;352:362–372. 126. Yang Z, McMahon CJ, Smith LR, et al: Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children. Circulation 2005;112:1612–1617. 127. Brady RO, Gal AE, Bradley RM, et al: Enzymatic defect in Fabry’s disease. Ceramidetrihexosidase deficiency. N Engl J Med 1967;276:1163–1167. 128. Von Scheidt W, Eng CM, Fitzmaurice TF, et al: An atypical variant of Fabry’s disease with manifestations confined to the myocardium. N Engl J Med 1991;324:395–399. 129. Eng CM, Guffon N, Wilcox WR, et al: Safety and efficacy of recombinant human alpha-galactosidase A—-replacement therapy in Fabry’s disease. N Engl J Med 2001;345:9–16. 130. Nakao S, Takenaka T, Maeda M, et al: An atypical variant of Fabry’s disease in men with left ventricular hypertrophy. N Engl J Med 1995;333: 288–293. 131. Sachdev B, Takenaka T, Teraguchi H, et al: Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation 2002;105:1407–1411. 132. Chimenti C, Pieroni M, Morgante E, et al: Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy. Circulation 2004;110:1047–1053. 133. Kampmann C, Baehner F, Whybra C, et al: Cardiac manifestations of Anderson-Fabry disease in heterozygous females. J Am Coll Cardiol 2002;40:1668–1674. 134. Desnick RJ, Ioannou YA, Eng CM: Alpha-galactosidase A deficiency: Fabry disease. In Scriver CH et al (eds): The metabolic and molecular bases of inherited diseases. New York, McGraw-Hill 2001:3733–3774. 135. Ramaswami U, Whybra C, Parini R, et al: Clinical manifestations of Fabry disease in children: Data from the Fabry Outcome Survey. Acta Paediatr 2006;95:86–92. 136. Desnick RJ, Brady R, Barranger J, Collins AJ: Fabry disease, an underrecognized multisystemic disorder: Expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 2003;138:338–346. 137. Pochis WT, Litzow JT, King BG, Kenny D: Electrophysiologic findings in Fabry’s disease with a short PR interval. Am J Cardiol 1994;74:203–204. 138. Sakuraba H, Yanagawa Y, Igarashi T, et al: Cardiovascular manifestations in Fabry’s disease. A high incidence of mitral valve prolapse in hemizygotes and heterozygotes. Clin Genet 1986;29:276–283. 139. Bass JL, Shrivastava S, Grabowski GA, et al: The M-mode echocardiogram in Fabry’s disease. Am Heart J 1980;100:807–812.
140. Cohen IS, Fluri-Lundeen J, Wharton TP: Two dimensional echocardiographic similarity of Fabry’s disease to cardiac amyloidosis: A function of ultrastructural analogy? J Clin Ultra 1983;11:437–441. 141. Linhart A, Palecek T, Bultas J, et al: New insights in cardiac structural changes in patients with Fabry’s disease. Am Heart J 2000;139:1101– 1108. 142. Morimoto S, Sugiura A, Iwase M, et al: Relief of left ventricular outflow obstruction by cibenzoline in a patient with Fabry’s disease—a case report. Angiology 2006;57:241–245. 143. Goldman ME, Cantor R, Schwartz MF, et al: Echocardiographic abnormalities and disease severity in Fabry’s disease. J Am Coll Cardiol 1986;7: 1157–1161. 144. Pieroni M, Chimenti C, Ricci F, et al: Early detection of Fabry cardiomyopathy by tissue Doppler imaging. Circulation 2003;107:1978–1984. 145. Pieroni M, Chimenti C, De Cobelli F, et al. Fabry’s disease cardiomyopathy: Echocardiographic detection of endomyocardial glycosphingolipid compartmentalization. J Am Coll Cardiol 2006;47:1663–1671. 146. Matsui S, Murakami E, Takekoshi N, et al: Myocardial tissue characterization by magnetic resonance imaging in Fabry’s disease. Am Heart J 1989;117:472–474. 147. Weidemann F, Breunig F, Beer M, et al: Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: A prospective strain rate imaging study. Circulation 2003;108:1299– 1301. 148. Moon JC, Sachdev B, Elkington AG, et al: Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease: Evidence for a disease specific abnormality of the myocardial interstitium. Eur Heart J 2003;24: 2151–2155. 149. Weidemann F, Breunig F, Beer M, et al: The variation of morphological and functional cardiac manifestation in Fabry disease: Potential implications for the time course of the disease. Eur Heart J 2005;26:1221–1227. 150. Frustaci A, Chimenti C, Ricci R, et al: Improvement in cardiac function in the cardiac variant of Fabry’s disease with galactose-infusion therapy. N Engl J Med 2001;345:25–32. 151. Kalliokoski RJ, Kantola I, Kalliokoski KK, et al: The effect of 12-month enzyme replacement therapy on myocardial perfusion in patients with Fabry disease. J Inherit Metab Dis 2006;29:112–118. 152. Hauser SC: Hemochromatosis and the heart. Heart Dis Stroke 1993;2:487–491. 153. Buja LM, Roberts WC: Iron in the heart. Etiology and clinical significance. Am J Med 1971;51:209–221. 154. Adams PC, Halliday JW, Powell LW: Early diagnosis and treatment of hemochromatosis. Adv Intern Med 1989;34:111–126. 155. Case Records of the Massachusetts General Hospital (Case 31–1994). N Engl J Med 1994;331:460–466. 156. Olson LJ, Baldus WP, Tajik AJ: Echocardiographic features in idiopathic hemochromatosis. Am J Cardiol 1987;60:885–889. 157. Olson LJ, Edwards WD, Holmes DR, et al: Endomyocardial biopsy in hemochromatosis: Clinicopathologic correlates in six cases. J Am Coll Cardiol 1989;13:116–120. 158. Olson LJ, Edward WD, McCall JT, et al: Cardiac iron deposition in idiopathic hemochromatosis: Histologic and analytic assessment of 14 hearts from autopsy. J Am Coll Cardiol 1987;10:1239–1243. 159. Dabestani A, Child JS, Henze E, et al: Primary hemochromatosis: Anatomic and physiologic characteristics of the cardiac ventricles and their response to phlebotomy. Am J Cardiol 1984;54:153–159. 160. Bonkovsky HL, Slaker DP, Bills EB, Wolf DC: Usefulness and limitation of laboratory and hepatic imaging studies in iron-storage disease. Gastroenterology 1990;99:1079–1091. 161. Candell-Riera J, Lu L, Seres L, et al: Cardiac hemochromatosis: Beneficial effects of iron removal therapy. An echocardiographic study. Am J Cardiol 1983;52:824–829. 162. Short EM, Winkle RA, Billingham ME: Myocardial involvement in idiopathic hemochromatosis. Morphologic and clinical improvement following venesection. Am J Med 1981;70:1275–1279. 163. Rivers J, Garrahy P, Robinson W, Murphy A: Reversible cardiac dysfunction in hemochromatosis. Am Heart J 1987;113:216–217. 164. Rahko PS, Salerni R, Uretsky BF: Successful reversal by chelation therapy of congestive cardiomyopathy due to iron overload. J Am Coll Cardiol 1986;8:436–440. 165. Easley RM Jr, Schreiner BF Jr, Yu PN: Reversible cardiomyopathy associated with hemochromatosis. N Engl J Med 1972;287:866–867. 166. Henry WL, Nienhuis AW, Wiener M, et al: Echocardiographic abnormalities in patients with transfusion-dependent anemia and secondary myocardial iron deposition. Am J Med 1978;64:547–555.
275
276
Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 167. Palka P, Macdonald G, Lange A, Burstow DJ: The role of Doppler left ventricular filling indexes and Doppler tissue echocardiography in the assessment of cardiac involvement in hereditary hemochromatosis. J Am Soc Echocardiogr 2002;15:884–890. 168. Leon MB, Borer JS, Bacharach SL, et al: Detection of early cardiac dysfunction in patients with severe beta-thalassemia and chronic iron overload. N Engl J Med 1979;21:1143–1148. 169. Blankenberg F, Eisenberg S, Scheinman MN, Higgins CB: Use of cine gradient echo (GRE) MR in the imaging of cardiac hemochromatosis. J Comput Assist Tomo 1994;18:136–138. 170. Niwano S, Yokoyama J, Niwano H, Aizawa Y: Images in cardiovascular medicine. Iron deposition in myocardium documented on standard computed tomography in cardiac hemochromatosis. Circulation 1998;97:2371.
171. Przybojewski JZ: Endomyocardial biopsy: A review of the literature. Cath & Cardiovasc Diag 1985;11:287–330. 172. Westra WH, Hruban RH, Baughman KL, et al: Progressive hemochromatotic cardiomyopathy despite reversal of iron deposition after liver transplantation. Am J Clin Path 1993;99:39–44. 173. Caines AE, Kpodonu J, Massad MG, et al: Cardiac transplantation in patients with iron overload cardiomyopathy. J Heart Lung Transplant 2005;24:486–488. 174. Ocel JJ, Edwards WD, Tazelaar HD, et al: Heart and liver disease in 32 patients undergoing biopsy of both organs, with implications for heart or liver transplantation. Mayo Clin Proc 2004;79:492–501.
22
ARUMUGAM NARAYANAN, MD GERARD P. AURIGEMMA, MD
Coronary Artery Disease INTRODUCTION PATHOPHYSIOLOGY Acute Ischemia Postinfarction Left Ventricular Remodeling CLINICAL RELEVANCE Diagnosis by Doppler Echocardiography FUTURE RESEARCH
INTRODUCTION While the importance of hypertension in the pathogenesis of diastolic dysfunction and diastolic heart failure is well known,1–6 relatively less attention has been paid to the interaction between coronary artery disease (CAD) and diastolic dysfunction. Accordingly, this chapter will be devoted to reviewing aspects of diastolic dysfunction in patients with coronary disease, with an emphasis on the role of Doppler echocardiography in elucidating aspects of the pathogenesis of heart failure. Diastolic heart failure is a condition characterized by signs and symptoms of heart failure, where “the dominant abnormality resides in diastole.”2 Cross-sectional and population-based studies indicate that at least one-third of all patients with congestive heart failure (CHF) have a normal or near-normal ejection fraction (EF) and that most have diastolic heart failure.1–3 The prevalence is highest in patients over age 75.1,2,7 Historically it has been assumed that the mortality rate of diastolic heart failure is less than that of systolic heart failure, ranging from 5% to 8% annually, compared with 10% to 15% in patients with systolic heart failure.2 However, recent data8–10 have challenged this notion. As is the case with systolic heart failure, the mortality rate of diastolic heart failure is directly related to age and the presence of coronary disease.2 The reported prevalence of diastolic heart failure depends not only on age, but on the diagnostic criteria used to define diastolic dysfunction, the etiology of the disease, and the methods and design of the particular study in question.2,7
The prevalence of coronary disease in patients who develop diastolic heart failure is high. This conclusion is based on data compiled from several types of studies: cross-sectional studies; randomized, placebo-controlled, clinical trials; and community-based studies. Gottdiener et al. studied over 5000 community-based individuals, age 65 or greater, enrolled in the multicenter Cardiovascular Health Study (CHS). These investigators tabulated incidence rates of heart failure over a 5-year period. Prevalent CAD was associated with more than a threefold higher rate of incident CHF (15.3% vs. 41%). Other predictors of CHF include other indicators of prevalent atherosclerotic disease, such as reduced ankle-brachial index, history of stroke, and increased levels of C-reactive protein. The populationattributable risk of prevalent CAD in this study was roughly equivalent to that of arterial hypertension, which itself is epidemiologically important.5–9 In a subsequent analysis of CHF by EF in the CHS database,11 prevalent coronary heart disease was present in 58% of patients with CHF and normal EF and in 78% of patients with CHF and reduced EF. Framingham Study investigators confirmed the importance of CAD in patients with diastolic heart failure, using the concept of population-attributable risk. When adjusting for age and heart failure risk factors in proportional hazards regression models, hypertension accounted for 39% of cases in men and 59% of cases in women.5 Among hypertensive subjects, CAD (in this instance, a history of myocardial infarction) was associated with increased risk for CHF in both sexes.5 Similarly high rates of CAD have been reported in a survey of clinical characteristics of patients hospitalized in New York City with diastolic heart failure reported by Klapholz et al.,6 as well as those enrolled in the “Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity” (CHARM)–Preserved study, the only published randomized clinical trial to date of treatment for diastolic heart failure.12 In the study by Klapholz et al., roughly one half of patients hospitalized in New York City for CHF who had a normal EF had a history of CAD. In the CHARM study, roughly one fifth had a prior coronary artery bypass graft; one half, myocardial infarction; and one quarter, angina.12 These data demonstrate the importance of coronary heart disease in the pathogenesis of diastolic heart failure. 277
278
Chapter 22 • Coronary Artery Disease the rate of LV pressure decline.16–17 This subject is reviewed in detail elsewhere.18
PATHOPHYSIOLOGY As is reviewed in Chapter 2 of this volume, diastolic function is determined by the passive elastic properties of the left ventricle and the process of active relaxation.1,2 Active relaxation is an energy-dependent process that is affected by ischemia. By contrast, abnormal passive elastic properties are generally caused by a combination of increased myocardial mass and alterations in the extramyocardial collagen network.2 The effects of impaired active myocardial relaxation, caused by acute ischemia, can lead to further stiffness. The interplay between this impaired relaxation and passive stiffness determines left ventricular (LV) filling pressure.2
Acute Ischemia It has been demonstrated that acute myocardial ischemia effects changes in both global and regional LV diastolic properties.13 The results of these alterations include a slower LV pressure decay with a consequent slowing of diastolic filling. Acute changes in the passive properties of the left ventricle result in an upward shift in the diastolic pressure-volume relationship (Fig. 22-1). As a result, the LV diastolic pressure-volume relationship changes: Chamber compliance is reduced, the time course is altered, and diastolic pressure is elevated. Under these circumstances, a relatively small increase in central blood volume or an increase in venous tone or arterial stiffness can produce a substantial increase in filling pressures and may result in acute pulmonary edema.14 The slowed relaxation following acute ischemia or infarction may persist for days.15 However, a slower rate of LV pressure fall is not the only result of direct effects of ischemia on myocardial relaxation. Ischemia may also affect contractility, loading conditions, and may worsen nonuniformity, which may also act to slow
Diastolic pressure (mmHg)
30
Angina
20
10
Postinfarction Left Ventricular Remodeling The subject of postinfarction LV remodeling is complicated, and excellent reviews of this topic have been published.19–21 To summarize briefly, myocardial infarction produces global and regional changes in ventricular function in both infarcted and noninfarcted regions, resulting in alterations in LV shape and geometry. The immediate changes following infarction involve mainly the infarcted region. Subsequently, over weeks to months, further changes occur, and these involve the noninfarcted region. This constellation of changes is known as ventricular remodeling. In the consensus paper by Cohn et al., LV remodeling is defined as “changes in size, shape, and function of the heart after cardiac injury. [The process] . . . is influenced by hemodynamic load, neurohumoral activation, and other processes.”20 A review of the processes involved in LV remodeling make it clear that what may begin as an adaptive process can have malefic consequences for LV diastolic function. During acute ischemia, injury, and the attendant reduction in systolic function, the region undergoing infarction may develop systolic expansion and perform a reduced amount of effective work.18,20 Following a large myocardial infarction, LV end diastolic pressures remain elevated, and the volume of viable myocardium increases approximately 30% because of increases in both myocyte cell length and diameter.18 In some instances, the ventricle may undergo progressive infarct expansion, usually within the first 24–72 hours.18–21 In part, this expansion and volume increase help to compensate for the reduction in effective work via the Frank-Starling mechanism.18–21 Even in the absence of acute LV expansion, LV dilation may develop, usually over several months after myocardial infarction18–21 involving both the infarcted and the noninfarcted regions. Given the curvilinear diastolic pressure-volume relationship, lengthening/dilation of noninfarcted regions is associated with an increase in LV end diastolic pressure.18–21 High wall stresses and ventricular remodeling may provide the stimuli for deleterious changes and further remodeling.21 The signal for progressive remodeling in the postinfarction ventricle may be diastolic wall stress, with parallels between this process and what is observed in chronic volume overload due to valvular regurgitation.21 Myocyte hypertrophy and changes in the extracellular matrix also are part of the remodeling process.18–21
CLINICAL RELEVANCE Diagnosis by Doppler Echocardiography
Control
20
40
60
80
100
Diastolic volume (cc/m2) Figure 22-1 The acute effect of ischemia on the pressure-volume relationship. These data are taken from the study of a 60-year-old individual undergoing catheterization. The control diastolic pressure-volume relationship is shown. During the procedure, the patient developed angina; volume assessment and hemodynamic measures were repeated. As can be seen, the pressure-volume relationship shifted dramatically upward, so that at any given diastolic volume, the pressure during the angina episode is higher; note that the ejection fraction has not changed dramatically. (Figure courtesy of Dr. William H. Gaasch.)
Doppler echocardiography plays a critical diagnostic role in all patients with heart failure for a variety of reasons. First, diagnostically, it should be emphasized that the physical examination, electrocardiogram, and chest roentgenogram do not reliably distinguish diastolic from systolic heart failure. Second, an accurate EF determination is essential for the diagnosis of diastolic heart failure. Echocardiography can also rapidly exclude diagnoses such as acute mitral or aortic regurgitation or constrictive pericarditis, conditions also associated with signs and symptoms of heart failure and a normal EF. Finally, Doppler echocardiography can be used in many instances to reliably estimate filling pressures.
Chapter 22 • Coronary Artery Disease
General Principles As is reviewed in Chapter 5 of this volume, Doppler echocardiography measures the velocity of intracardiac blood flow. Doppler transmitral flow analysis has become the mainstay of the clinical assessment of diastolic function. In normal sinus rhythm, diastolic flow from the left atrium to the left ventricle across the mitral valve occurs in two phases, denoted by two distinct waves: the E wave, which reflects early diastolic filling, and the A wave, in late diastole, which reflects atrial contraction. Because the velocity of blood flow across the mitral valve depends on the transmitral pressure gradient, the E-wave velocity is influenced by both the rate of early diastolic relaxation and left atrial (LA) pressure. Alterations in the pattern of these velocities give insight into LV diastolic function and prognosis.22–25 As has been pointed out previously (see Chapter 10), standard mitral inflow patterns are extremely sensitive to loading conditions, particularly LA pressure. Stated another way, early diastolic filling rates might be increased by elevated LA pressure. Therefore, just as a “normal” (E > A) filling pattern does not necessarily indicate normal diastolic function, a reduced E-wave velocity and E/A ratio might be found in the presence of elevated filling pressures. As we have come to realize over the past decade, other data are necessary to give a complete picture of diastolic function. Such other data are
generally provided by pulmonary vein velocities26,27 and tissue Doppler analysis.25 Tissue Doppler techniques appear to be somewhat less sensitive to loading conditions than standard Doppler velocities (Fig. 22-2). It is important to bear in mind, in this connection, that the height of the transmitral E wave merely reflects the early diastolic LA-LV gradient. As is shown in Figure 22-3, it is possible that the E-wave height and E/A ratio may be low, not necessarily because of low LA pressure, but because of a protracted decline in LV diastolic pressure.28 As we will see, such a protracted decline in diastolic pressure may be caused by acute ischemia.
Acute Effects of Ischemia on Doppler Inflow Patterns There have been a number of studies of mitral inflow patterns in patients with acute myocardial ischemia (Table 22-1). Labovitz et al. studied functional changes by Doppler echocardiography in 32 patients during transient myocardial ischemia induced by percutaneous transluminal coronary angioplasty (PTCA).29 Ventricular filling during coronary occlusion showed significant change, evident within 15 seconds of balloon occlusion; there was an acute decrease in peak E velocity as well as E/A ratio (Fig. 22-4A and B), with a return to baseline values within 15 seconds Diastolic dysfunction
LV pressure (mmHg)
50
Figure 22-2 A, End diastolic pressurevolume relationship (EDPVR) curves in normal, diastolic dysfunction, and remodeling groups. Inserted in the figure are the mitral inflow and tissue Doppler recordings for the three groups. The EDPVR is shifted left-upward for diastolic dysfunction compared with a right-downward shift for a heart that has remodeled. B, While mitral inflow velocity appears similar in all three groups, mitral annulus tissue Doppler early diastolic velocities are reduced in patients with diastolic dysfunction or remodeling. Two-dimensional echo shows completely normal cardiac structures for the normal subject at the center and increased wall thickness and LA enlargement but normal left ventricular size in the left panel, consistent with diastolic heart failure. On the right is displayed left ventricular (LV) enlargement typical of the remodeling heart. (A, Modified from Maurer MS, Spevack D, Burkhoff D, et al: Diastolic dysfunction: Can it be diagnosed by Doppler echocardiography? J Am Coll Cardiol 2004;44:1543–1549. B, From Oh JK et al: Diastolic heart failure can be diagnosed by comprehensive twodimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506.)
Normal
40
Remodeling
30 20 10 0 0
A
50
100
150
LV volume (ml)
200
250
279
280
Chapter 22 • Coronary Artery Disease TABLE 22-1 TRANSMITRAL INFLOW (E AND A WAVES) IN ACUTE ISCHEMIA AUTHOR
NUMBER OF PATIENTS (n)
Labovitz et al.29 Snow et al.30
32 22
Iliceto et al.31
9
PATIENT POPULATION
E
A
E/A
AFF
DT
IVRT
Patients undergoing PTCA Patients in the unstable angina group who underwent elective PTCA* Patients with significant CAD who developed ischemic ECG changes with transesophageal atrial pacing
NA NA
NA NA
↓ ↔
NA ↔
NA ↓
NA ↓
↓
↑
↓
↑
NA
NA
*Doppler echocardiography performed 43 ± 27 hours after PTCA. E, early diastolic filling; A, atrial contraction in late diastole; E/A, ratio of E wave to A wave; AFF, atrial filling fraction; DT, deceleration time; IVRT, isovolumic relaxation time; PTCA, percutaneous transluminal coronary angioplasty; CAD, coronary artery disease; ECG, electrocardiogram.
LVP
LAP
MVF
Normal (1)
Impaired relaxation (2)
“Hyperabnormal relaxation” (3)
Figure 22-3 Schematic representation of simultaneous recordings of left ventricular pressure (LVP), left atrial pressure (LAP), and Doppler mitral flow velocity (MVF) in (1) a normal subject, (2) a patient with impaired relaxation without clinical heart failure, and (3) a patient with acute heart failure and a delayed relaxation. This figure illustrates that under certain conditions, such as acute ischemia, a low E/A ratio can be associated with elevated filling pressures. (From Bogaty P et al: New insights into diastolic dysfunction as the cause of acute leftsided heart failure associated with systemic hypertension and/or coronary artery disease. Am J Cardiol 2002;89:341–345.)
1.8 1.7 1.6 Baseline
E
Inflation
Recovery
1.5 1.4
A
1.3
1 m/sec– E/A
1.2 1.1 1.0 .9
V2
V2
.8
V2
.7 .6 .5
p < .001
0
A
B
Baseline
15 seconds
Figure 22-4 A, Simultaneous recording of pulsed Doppler left ventricular inflow velocities with accompanying electrocardiographic lead V2 during left anterior descending coronary occlusion/balloon inflation during percutaneous transluminal coronary angioplasty. There is a marked diminution in early (E) and the E/A ratio, which coincides with ST segment elevation induced by coronary occlusion. The flow profile returned to the baseline state in recovery. B, There was a significant decrease in the ratio of peak early to peak atrial diastolic velocities (E/A) by 15 seconds after coronary occlusion, with the E/A ratio falling in the vast majority of patients. (From Labovitz AJ et al: Evaluation of left ventricular systolic and diastolic dysfunction during transient myocardial ischemia produced by angioplasty. J Am Coll Cardiol 1987;10:748–755.)
Chapter 22 • Coronary Artery Disease following balloon deflation. The diastolic changes occurred prior to systolic and other clinical changes.29 Snow et al. prospectively evaluated 42 patients undergoing elective PTCA for severe ischemia (22 patients with unstable angina pectoris and 20 patients with post–acute myocardial infarction [AMI] ischemia).30 Doppler echocardiographic studies were performed before (8 ± 5 hours) and after (43 ± 27 hours) PTCA. Patients with severe ischemia (both the unstable angina and the postinfarction ischemia groups) showed abnormal diastolic filling patterns before PTCA, characterized by prolonged isovolumic relaxation time (IVRT) and mitral deceleration time (DT), decreased E/A peak velocity ratio, and increased atrial filling fraction (AFF). Following PTCA, IVRT and DT decreased in both groups; the decrease in IVRT was significant. The E/A ratio increased, and AFF decreased in the post-AMI ischemia group at the same time.30 It is noteworthy that both studies demonstrated a reduced E/A ratio following acute ischemia, induced by either PTCA or the acute ischemia. The improvement in diastolic function and transmitral flow velocities post-PTCA likely reflects early recovery of diastolic determinants, active ventricular relaxation, and compliance. These data may be interpreted in light of the hypothesis of Bogaty28: The reduced peak E is probably the result of reduced “driving pressure” between the left atrium and the left ventricle in
early diastole. It is conceivable that an acute ischemia–related reduction in peak E is more related to a slow decline in LV diastolic pressure than to reduced LA pressure. Iliceto et al.31 evaluated the effect of atrial pacing-induced ischemia on Doppler-derived LV filling parameters in 17 patients with significant CAD (Fig. 22-5A). The patients were divided into two groups on the basis of ischemic changes on electrocardiography (ECG) (ST depression ≥1.5 mm) immediately after cessation of atrial pacing. Group 1 (without ischemic changes) showed no significant changes in LV filling variables, while group 2 (with ischemic changes) showed a significant decrease in early peak flow velocity from rest to postpacing, along with a compensatory increase in the atrial component of the mitral inflow velocities. As was observed in the studies headed by Labovitz and Snow, the E/A ratio decreased and the atrial fraction of the timevelocity integral increased in the group with manifest ischemia. The filling alterations gradually returned to baseline levels one minute after cessation of atrial pacing. The changes in LV filling occurring only in group 2 possibly reflect significant ischemia noted by ECG changes and indicate that a threshold for these changes may exist (see Fig. 22-5B). In a more recent investigation using tissue Doppler imaging techniques, Donal and coworkers studied 28 consecutive patients with AMI involving either the left anterior descending or the right
PRE-AP E
POST-AP 17 th
POST-AP 1st Min
A
A GROUP 1
GROUP 2 1.5
1.0
1.0 E/A ratio
1.5
E/A ratio
Figure 22-5 A, Sequential recording of the transmitral flow velocities before atrial pacing, at the 3rd beat, the 17th beat, and 1 minute postatrial pacing (PAP), demonstrating changes with ischemia and recovery in a patient in group 2 (which developed ischemic electrocardiographic changes on pacing). The first panel at left shows normal left ventricular (LV) filling characteristics at rest before atrial pacing (PRE-AP). The next recording (second panel), at the 3rd postatrial pacing beat, shows a significant decrease in the early peak flow velocity, along with an increase in atrial peak flow velocity. At the 17th postatrial pacing beat (third panel), a gradual tendency toward recovery of the LV filling values is observed. At 1 minute after pacing (fourth panel), transmitral flow velocities are very similar to those of the 17th beat. B, Illustration comparing early/atrial (E/A) peak flow velocity ratio changes with atrial pacing in group 1 (no pacing-induced ischemia) and group 2 (pacing-induced ischemia). Early/atrial peak flow velocity ratio demonstrated a significant decrease in group 2 patients, without any significant change in group 1 patients, paralleling electrocardiographic ischemic changes. (From Iliceto S et al: Doppler echocardiographic evaluation of the effect of atrial pacing-induced ischemia on left ventricular filling in patients with coronary artery disease. J Am Coll Cardiol 1988;11:953–961.)
POST-AP 3rd
.5
.5
P: <.001
P: NS
B
Rest
Pacing
Rest
Pacing
281
282
Chapter 22 • Coronary Artery Disease coronary artery territory treated by primary PTCA.32 Echocardiographic studies were performed within 24 hours of angioplasty. A control group comprised 17 individuals with normal coronary angiography and transesophageal echocardiography. The authors recorded systolic (S), early diastolic (E), late diastolic (A), isovolumic contraction (IVC), and isovolumic relaxation (IVR) peak velocities by tissue Doppler. Not surprisingly, estimated LV filling pressures were significantly higher in the two AMI groups compared with controls.32 The IVR peak velocities were significantly lower in each of the two AMI populations compared with controls.32 The combination of IVC greater than 0 and IVR less than 1 separated ischemic from non-ischemic segments with 82% sensitivity and 85% specificity. Notably, among the two AMI groups, even non-ischemic segments or walls showed significantly decreased velocities and displacements.32
Doppler Filling Profiles in Acute Myocardial Infarction Doppler echocardiography has been used to estimate prognosis in acute infarction (Table 22-2). Temporelli et al.33 showed that
DT was a strong prognostic marker both for LV remodeling and for survival following AMI (Fig. 22-6). A subset of 571 patients with confirmed AMI and serial Doppler echo performed at 24 to 48 hours (baseline) from symptom onset, at hospital discharge, and at 6 months enrolled in the GISSI-3 (Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto) substudy formed the basis of the sample. Patients were assigned to two groups based on mitral DT, either restrictive (DT <130 msec) or nonrestrictive (DT >130 msec). During follow-up, the end diastolic volume index (EDVi) and the end systolic volume index (ESVi) increased, and percent of wall motion abnormality decreased in both groups. The magnitude of these changes was more pronounced in patients with a short DT compared with those with DT greater than 130 msec. A progressive impairment in EF was limited to patients with restrictive filling. LV dilation was twofold in the baseline restrictive filling group compared with the nonrestrictive filling group.33 By multivariate analysis, baseline EDVi and percent wall motion abnormality, along with predischarge persistent short DT, demonstrated a higher likelihood of severe late LV dilation (an increase in EDVi of more than 20%).33 These Doppler parameters also had prognostic importance. Follow-up at 4 years showed that
1.05
1.00
Survival (%)
0.95 p < 0.06 0.90
0.85 Baseline DT ≤130 msec (restrictive group) Baseline DT >130 msec (nonrestrictive group)
0.80
0.75 0
200
400
600
800
1000
1200
1400
1600
Time (days) 1.05
1.00
Survival (%)
0.95
0.90 p < 0.0003 0.85
Pre-discharge persistent short (≤130 msec) DT Pre-discharge prolonged (>130 msec) DT
0.80
0.75 0
200
400
600
800 Time (days)
1000
1200
1400
1600
Figure 22-6 Cumulative survival rates for all-cause mortality according to baseline and predischarge deceleration time (DT). The predischarge persistent short DT predicted a higher mortality. (From Temporelli PL et al: Doppler-derived mitral deceleration time as a strong prognostic marker of left ventricular remodeling and survival after acute myocardial infarction: Results of the GISSI-3 echo substudy. J Am Coll Cardiol 2004; 43:1646–1653.)
Chapter 22 • Coronary Artery Disease TABLE 22-2 PREDICTIVE VALUE OF DOPPLER ECHOCARDIOGRAPHIC PARAMETERS IN ACUTE MYOCARDIAL INFARCTION AUTHOR
NUMBER OF PATIENTS (n)
PATIENT POPULATION
Temporelli et al.33
571
AMI
PARAMETERS DT ≤130 msec predischarge persistent
FOLLOW-UP PERIOD 6 months
ENDPOINTS
RESULTS
Severe LV dilation and death from any cause
Severe dilation (>20%) was increased 1.6fold (patients with predischarge persistent restrictive filling vs. reversible restrictive filling; p < 0.04). All-cause mortality rate was 2.9-fold higher (patients with predischarge persistent restrictive filling vs. reversible restrictive filling; p < 0.0003). CHF was 1.4 times more common and NYHA class was higher; p < .01 (patients with restrictive LV filling vs. impaired relaxation). All 6 deaths were observed in patients with restrictive LV filling pattern. DT <170 msec was 2.4fold more often observed in patients with events than in patients without events; p < 0.001. E/e′ >10 was observed 13.2-fold more often in patients with events than in those without events; p < 0.0001. Two thirds of the deaths occurred in patients with E/e′ >15. Patients with E/e′ >15 were 2.2 times more likely to present with CHF; p < 0.001. Patients with E/e′ >15 had a 5.5-fold increase in indexed LV diastolic volume; p < .01.
4 years
Poulsen et al.34
58
First AMI (ST elevation)
DT ≤140 msec
12 months
In-hospital CHF or cardiac death
Naqvi et al.35
59
First AMI (ST elevation) who underwent primary PCI within 12 hours
DT <170 msec E/e′ ratio >10 of noninfarct–related mitral annulus
6 months
In-hospital events: cardiac death, CHF, sustained VT, or urgent surgical revascularization
Hillis et al.37
250
AMI
E/e′ ratio >15
13 months
All-cause mortality
Hillis et al.36
47
First AMI with TIMI grade III flow in infarctrelated coronary artery by angiography and akinesia of the arterial territory
E/e′ ratio >15
8 weeks
Remodeling (>15% increase in indexed LV end diastolic volume)
AMI, acute myocardial infarction; DT, deceleration time; LV, left ventricular; CHF, congestive heart failure; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; VT, ventricular tachycardia; TIMI, thrombolysis in myocardial infarction.
283
Chapter 22 • Coronary Artery Disease predischarge persistent restrictive filling (DT ≤130 msec) was the best predictor of mortality, compared with other clinical and Doppler echocardiographic variables.33 Poulsen et al. studied longitudinal changes and prognostic implications of LV diastolic function in patients with first AMI and found similar results.34 They evaluated 58 consecutive patients admitted with first AMI prospectively by two-dimensional and Doppler echocardiography, along with clinical evaluation on day 1 and day 5 and at 3 months and 12 months. The patients were classified into three groups based on the LV diastolic filling pattern at admission: normal, impaired relaxation, and pseudonormal/ restrictive patterns. CHF during hospitalization was noted more often in patients with the restrictive pattern than in patients with impaired relaxation at baseline (71% vs. 50%). Those with a restrictive pattern had more severe CHF by New York Heart Association class compared with normal and impaired relaxation filling patterns. Mitral E-wave DT less than 140 msec and age were determined as independent predictors of development of in-hospital CHF and cardiac death by multivariate regression analysis. Naqvi et al. evaluated 85 consecutive patients with a first STelevation AMI, who underwent primary percutaneous coronary intervention (PCI) within 12 hours of hospital admission by echocardiography within 24 hours of primary PCI. The subjects were divided into two groups based on development (group A) or no development (group B) of in-hospital events, including cardiac death, CHF, sustained ventricular tachycardia (VT), and urgent surgical revascularization after primary PCI. Group A had restrictive mitral inflow and lower diastolic mitral annular Doppler tissue imaging (DTI) velocities, resulting in a high E/e′ (mitral inflow peak early velocity/mitral annular peak early velocity of the noninfarct annulus) ratio. Using peak early diastolic velocity of the lateral mitral annulus instead of the averaged peak early diastolic velocity of the non-infarcted annulus resulted in a higher E/e′ in group A versus B.35 The E/e′ ratio and mitral inflow E-wave DT were shown to be independent predictors of an in-hospital event on multivariate stepwise logistic regression analysis. E/e′ ratio less than 10 and a DT less than 170 msec were highly specific (98%) for absence of an in-hospital event. At the 6month follow-up echocardiographic assessment, baseline mitral inflow DT was the most important determinant of later LV EF. The E/e′ ratio (estimate of myocardial wall relaxation) and mitral inflow E-wave DT (estimate of global LV filling and relaxation) were superior to other echocardiographic parameters in determining in-hospital events and follow-up LV EF at 6 months.35 Hillis et al.36 examined the prognostic value of E/e′. The study group consisted of all 250 patients who had both Doppler transmitral flow velocities and DTI performed among patients admitted for AMI at the Mayo Clinic with a clinically indicated echo during the index admission. Patients with E/e′ greater than 15 were older, more likely female, more likely to present with CHF, and more often had diabetes and a history of MI. These investigators found that patients with an E/e′ ratio greater than 15 had lower EF and a shorter DT. Twenty-nine patients died during a median follow-up period of 13 months, two thirds of whom had an E/e′ ratio greater than 15. After stratifying patients based on LV EF, E/e′ ratio of at least 15 predicted decreased survival in patients with an EF of 40% or greater. When DT was used to further delineate the groups, E/e′ ratio greater than 15 was a powerful predictor of mortality only in patients with DT greater than 140. The E/e′ ratio was the most powerful independent prognostic indicator of survival after AMI on stepwise multivariate analysis (Fig. 22-7). The E/e′ ratio more importantly
1.0
E/e′ ≤ 15
.9
Survival
284
.8
.7
.6
E/e′ > 15
.5 0 Number at risk 250
6
12
18
24
195
113
49
16
Duration of follow-up (months) Figure 22-7 Kaplan-Meier plot demonstrating decreased survival in patients with E/e′ ratio >15 compared with those with E/e′ ratio <15. (From Hillis GS et al: Noninvasive estimation of left ventricular filling pressure by E/e′ is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol 2004;43:360–367.)
complements the prognostic value of a combination of other clinical and echocardiographic parameters.36 The same researchers, in a more recent study, investigated the relationship between echocardiographic indices of acute and chronic LV filling pressures and dilation in 47 patients after their first AMI.37 All patients demonstrated a patent infarct-related artery with a thrombolysis in myocardial infarction grade III flow on coronary angiography and akinesia within this arterial territory on baseline echo. Patients were prospectively designated as remodeling (>15%) and nonremodeling (≤15%) groups based on the increase in indexed LV end diastolic volume at follow-up echocardiography at approximately 8 weeks. In this study, E/e′ was higher among the remodeling group, with a moderate correlation between basal E/e′ and changes in indexed LV diastolic volume (Fig. 22-8). Interestingly, LA volume index (LAVi) did not predict LV dilation. Both receiver operating characteristic (ROC) curve analysis and multivariate regression analysis confirmed that E/e′ ratio greater than 15 was a strong predictor of remodeling, as defined above. Finally, Sakata et al. investigated the prognostic value of Doppler transmitral flow velocity patterns in AMI. Two hundred and six patients with first AMI recruited to the study underwent two-dimensional and Doppler echocardiography on admission, and hemodynamic measurements (pulmonary capillary wedge pressure [PCWP] and cardiac index) were obtained by using a thermodilution catheter.38 The A-wave velocity was significantly lower in nonsurvivors than in survivors. The E-wave velocity and the E/A ratio were significantly higher, while DT was significantly shorter in survivors with heart failure and nonsurvivors than in survivors without heart failure. Comparing patients with low A and those without a low A, the low A group had a significantly higher frequency of mitral regurgitation, incidence of three-vessel coronary disease, PCWP, cardiogenic shock, and a higher mortality after angioplasty or thrombolytic therapy. Cardiac index and LV EF, on the other hand, were significantly lower in the low A group. The low A was strongly associated with heart failure in the acute phase as well as
