Surgical Options for the Management of Congestive Heart Failure

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Surgical Options for the Management of Congestive Heart Failure

Guest Editor

Malek G. Massad, (Chicago, Ill.)

43 ﬁgures, and 36 tables, 2004

Basel • Freiburg • Paris • London • New York • Bangalore • Bangkok • Singapore • Tokyo • Sydney

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S. Karger Medical and Scientiﬁc Publishers Basel • Freiburg • Paris • London New York • Bangalore • Bangkok Singapore • Tokyo • Sydney

Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant ﬂow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.

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Vol. 101, No. 1–3, 2004

Contents

61 Ventricular Reconstruction Surgery for Congestive

Editorial

Heart Failure 5 Surgical Options for the Management of Congestive

Heart Failure Massad, M.G. (Chicago, Ill.)

7 Aortic Valve Replacement in Patients with Severely

Reduced Left Ventricular Function Paul, S.; Mihaljevic, T.; Rawn, J.D.; Cohn, L.H.; Byrne, J.G. (Boston, Mass.) 15 Mitral Valve Surgery in Patients with Ischemic and

Nonischemic Dilated Cardiomyopathy Geha, A.S.; El-Zein, C.; Massad, M.G. (Chicago, Ill.) 21 Outcomes of Coronary Artery Bypass Grafting

versus Percutaneous Coronary Intervention and Medical Therapy for Multivessel Disease with and without Left Ventricular Dysfunction Caines, A.E.B.; Massad, M.G.; Kpodonu, J. (Chicago, Ill.); Rebeiz, A.G. (Durham, N.C.); Evans, A.; Geha, A.S. (Chicago, Ill.) 29 Revascularization Options for Ischemic

Cardiomyopathy: On-Pump and Off-Pump Coronary Artery Bypass Surgery Khabbaz, K.R.; DeNofrio, D.; Kazimi, M.; Carpino, P.A. (Boston, Mass.) 37 Mechanisms and Results of Transmyocardial Laser

Revascularization Horvath, K.A. (Chicago, Ill.) 48 Clinical Trials in the Surgical Management of

Congestive Heart Failure: Surgical Ventricular Restoration and Autologous Skeletal Myoblast and Stem Cell Cardiomyoplasty

Lee, R.; Hoercher, K.J.; McCarthy, P.M. (Cleveland, Ohio) 72 Cardiac Resynchronization Pacing Therapy Casey, C.; Knight, B.P. (Chicago, Ill.) 79 Current Trends in Heart Transplantation Massad, M.G. (Chicago, Ill.) 93 Ventricular Assist Devices as a Bridge to Transplant

or Recovery Kherani, A.R. (Durham, N.C./New York, N.Y.); Maybaum, S.; Oz, M.C. (New York, N.Y.) 104 Destination Therapy with Ventricular Assist Devices Raman, J.; Jeevanadam, V. (Chicago, Ill.) 111 Use of the Flowmaker (Jarvik 2000) Left Ventricular

Assist Device for Destination Therapy and Bridging to Transplantation Frazier, O.H.; Shah, N.A.; Myers, T.J.; Robertson, K.D.; Gregoric, I.D.; Delgado, R. (Houston, Tex.) 117 The Total Artificial Heart: Where We Stand Frazier, O.H. (Houston, Tex.); Dowling, R.D.; Gray, L.A., Jr. (Louisville, Ky.); Shah, N.A.; Pool, T.; Gregoric, I. (Houston, Tex.) 122 Genetics and Gene Manipulation Therapy of

Premature Coronary Artery Disease Chaer, R.A.; Billeh, R.; Massad, M.G. (Chicago, Ill.) 131 Therapeutic Angiogenesis: A Biologic Bypass Syed, I.S.; Sanborn, T.A.; Rosengart, T.K. (Evanston, Ill./Chicago, Ill.) 144 Cardiac Xenotransplantation: Future and Limitations Ogata, K.; Platt, J.L. (Rochester, Minn.)

McConnell, P.I.; Michler, R.E. (Columbus, Ohio) 156 Author Index and Subject Index

© 2004 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

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Editorial Cardiology 2004;101:5–6 DOI: 10.1159/000075979

Surgical Options for the Management of Congestive Heart Failure

Congestive heart failure (CHF) continues to be recognized as the most common killer worldwide, and remains the most important medical condition affecting the world today. It is a syndrome that is the end product of heart conditions of different etiologies. CHF is becoming more prevalent as the population continues to age. Populationbased studies from North America and Europe have estimated the prevalence of CHF at about 10–20/1,000 population and the incidence at about 2–3/1,000 population [1]. These figures become quite alarming when extrapolated to the 6,216 million world population at large. About 62–124 million people worldwide suffer from CHF and there are about 12.5–18.6 million new cases each year. It is surmised that an increase in the overall prevalence of CHF is expected worldwide as a result of the advances in the early detection and treatment of coronary artery disease and the improving survival following acute myocardial infarction as well as the overall increased longevity in the developed countries. The disease is fatal in the long term, as about 60% of the patients affected die by 5 years from the time of diagnosis. In the developed countries, the cost of management of CHF is estimated to constitute about 2% of the total health care expenditure worldwide, with 60–70% of that being spent on hospitalizations. This figure is much less dramatic among developing or underdeveloped countries, which have a limited health care expenditure budget and nonabundance of hospitals and tertiary care centers to treat these patients. Several advances in medical therapy, with the introduction of angiotensin-converting enzyme inhibitors, selective beta-blockers, type III antiarrhythmic agents, natriuretic peptides and lipid therapy as well as the liberal

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use of pacemakers and internal defibrillators, have improved the survival of patients suffering from CHF. However, despite all the advances in medical therapy and despite early recognition, the outcome of CHF remains poor. This has prompted investigators to consider newer surgical options for the management of CHF. The small number of heart transplants performed worldwide (between 3,500 and 4,500 transplants annually) makes heart transplantation a limited option that is only available to a privileged section of the world population, primarily confined to developed countries. Over 95% of the heart transplants performed worldwide are performed in North America and Europe, while less than 5% are performed in the three heavily populated continents, namely Asia, Africa and South America, where over 75% of the world population lives. In view of these limitations, several surgical alternatives for the treatment of CHF are being investigated with the aim of improving the quality of life of these patients in the short term, and also improving the long-term outcome. It has been almost 4 decades since the first experiments with the development of mechanical assist devices to replace the human heart. Ever since, several world centers and investigators have become involved and numerous devices have been developed, although many of them have faded into the past. This issue of Cardiology is the result of the generous contribution of a select cast of investigators and experts in the surgical management of CHF from premier centers who were invited to participate and kindly accepted. Drs. John Byrne, Lawrence Cohn and associates from the Brigham and Women’s Hospital in Boston discuss the

indications and outcomes of valve replacement for aortic valvular cardiomyopathy. Dr. Alexander Geha from the University of Illinois discusses the topic of mitral valve repair in patients with ischemic and nonischemic cardiomyopathy. The topic of myocardial revascularization in patients with ischemic cardiomyopathy and left ventricular dysfunction is discussed in two papers from Tufts University and the University of Illinois. In the first paper, Dr. Kamal Khabbaz and associates from Tufts-New England Medical Center discuss the pros and cons of beating heart versus on-pump coronary artery bypass grafting in patients with ischemic cardiomyopathy and viable myocardium. The second paper provides a summary of the clinical trials comparing coronary artery bypass grafting to percutaneous coronary interventions and medical therapy in patients with left ventricular dysfunction. Dr. Robert Michler and his group from Ohio State University summarize the different ongoing clinical trials in the surgical management of CHF. Dr. Patrick McCarthy and associates from the Cleveland Clinic provide a valuable update on their experience with ventricular reduction and remodeling surgery for CHF. This special issue also provides an update on the current status of heart transplantation with alarming statistics about the limited utilization of this treatment option in developing and underdeveloped countries, and about the gender disparity among heart transplant recipients worldwide, with three quarters of the transplants performed in men. Dr. Bradley Knight and his associate from the University of Chicago provide an update on the current status of resynchronization therapy and biventricular pacing for CHF. From the same institution, Drs. Jai Raman and Val Jeevanandam update the reader on the use of left ventricular assist devices as destination therapy. Dr. Mehmet Oz and associates from Columbia University in New York provide a very interesting report on the use of assist devices as a bridge to

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transplant and to recovery. Dr. O. Howard Frazier and his group at the Texas Heart Institute update the reader on the clinical experience with the Jarvik 2000 left ventricular assist device for destination therapy and bridging to transplantation. Also, Dr. Frazier and his group along with Drs. Robert Dowling and Laman Gray from the University of Louisville provide a valuable update on the world’s clinical experience, to date, with the AbioCor total artificial heart. On the genetic level, Dr. Chaer and associates discuss the biologic basis for gene manipulation therapy of premature coronary artery disease. Dr. Todd Rosengart and associates from Northwestern University provide an update on the current trials in gene therapy in their elegant paper entitled ‘Therapeutic angiogenesis: a biologic bypass’. From the same institution, Dr. Keith Horvath talks about the current status and the future of transmyocardial laser revascularization for the ischemic myocardium with nonbypassable coronaries. Dr. Jeffery Platt and associates from the Mayo Clinic provide an intriguing update on the present status and the future of cardiac xenotransplantation. We hope that this special issue will give the journal a new impact in the sense that it will acquaint the current readers and subscribers, who are primarily cardiologists, with these surgical alternatives for the management of CHF and at the same time bring into the journal readership a stronger surgical presence. Malek G. Massad, MD Guest Editor, Chicago, Ill.

Reference 1 Murdoch DR, McMurray JJV: Epidemiological perspective on heart failure: Common, costly, disabling, deadly; in Sharpe N (ed): Heart Failure Management. London, Martin Dunitz, 2000, pp 1–14.

Massad

Cardiology 2004;101:7–14 DOI: 10.1159/000075980

Aortic Valve Replacement in Patients with Severely Reduced Left Ventricular Function Subroto Paul Tomislav Mihaljevic James D. Rawn Lawrence H. Cohn John G. Byrne Division of Cardiac Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass., USA

Key Words Aortic stenosis W Aortic regurgitation W Cardiomyopathy W Aortic valve replacement

Abstract Aortic valve replacement (AVR) can be done safely in patients with severe aortic stenosis (AS) and depressed ventricular function (ejection fraction ^35%). Dobutamine echocardiography is useful to identify AS patients with contractile reserve who will benefit from AVR and can be used for risk stratification of these patients. AVR can also be undertaken in patients with severe aortic regurgitation and depressed ventricular function with an acceptable operative mortality. AVR in both groups results in a 5-year survival of approximately 70%, which is similar to that of orthotopic heart transplantation. Due to the comorbidities of immunosuppression and limited donor organ supply, AVR should be attempted prior to transplantation in both these high-risk groups. Copyright © 2004 S. Karger AG, Basel

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Introduction

The prevalence of congestive heart failure (CHF) continues to rise. Improvements in the medical and surgical treatment for acute coronary syndromes combined with advances in the understanding and medical and surgical treatment of valvular heart disorders have led to an increasing number of patients surviving with their disease. These improvements, combined with other advances in health and technology, have now allowed the average US life expectancy to rise to an all-time high of 77 years on average for both sexes and have also contributed to the rise in the number of patients with heart failure [1]. There are approximately 5 million Americans living with heart failure, with an additional 400,000 patients newly diagnosed each year. CHF is associated not only with a decreased quality of life, but also significant mortality. Recent statistics show that CHF carries a mortality rate of at least 40% within 2 years of diagnosis [2]. New York Heart Association (NYHA) class IV failure is associated with a 50% or greater mortality at 1 year [3–5]. The associated medical and societal costs of CHF are high as well. Medical costs for treating CHF are estimated to be over USD 10 billion a year [6]. The most common causes of CHF are ischemic heart disease, idiopathic dilated cardiomyopathy and hyperten-

John G. Byrne, MD Brigham and Women’s Hospital, Division of Cardiac Surgery 75 Francis Street Boston, MA 02215 (USA) Tel. +1 617 732 7678, Fax +1 617 732 6559, E-Mail [email protected]

sion [7]. A small minority of patients, approximately 5%, have CHF as a result of valvular disorders [8]. Regardless of the etiology, chronic CHF results in compensatory myocardial hypertrophy and remodeling of the cardiac ventricles with resultant increased wall stress, increased risk of arrhythmias and poor effective contractility. Pharmacologic therapies, which constitute the majority of treatment plans, can reverse the adaptive remodeling process to a degree. Medical treatment regimens, which typically incorporate multiple drugs such as diuretics, digoxin, angiotensin-converting enzyme inhibitors and most recently beta-blockers, have all been shown to improve and extend patients’ lives. A subset of CHF patients, however, may benefit from direct surgical interventions. These include patients with ischemic cardiomyopathy with revascularizable myocardium, valvular disorders such as aortic stenosis (AS), aortic regurgitation (AR) and mitral regurgitation with or without concomitant coronary disease, and end-stage cardiomyopathies who are candidates for heart transplantation, left ventricular assist devices, either as end-stage devices or as a bridge to transplant, or new innovative reconstructive cardiac operations that directly remodel the ventricle [9, 10]. In this review, we will focus on the role of aortic valve replacement (AVR) in patients with CHF and reduced left ventricular function.

Aortic Stenosis

AS is found more often in men than in women. Numerous etiologies exist, with the most common being agerelated degeneration of the aortic valve followed by a congenitally bicuspid valve and then rheumatic disease [11– 14]. Other, less common causes include renal failure, hyperparathyroidism and other metabolic causes [15–17]. Regardless of the etiology, the resulting left ventricular obstruction from chronic AS leads to chronic pressure overload of the left ventricle, leading to compensatory hypertrophy. Left ventricular hypertrophy and adaptation to the pressure overload is mediated by the stressmediated activation of a fetal gene expression pattern leading to myocyte hypertrophy. The exact molecular mechanisms are unknown but involve the upregulation of protein kinases, such as protein kinases A and C [18–20]. This is an area of active investigation. Progress in this area may one day make it possible to modulate the hypertrophic response and hence pharmacologically remodel the ventricle.

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Progressive pressure overload in uncorrected AS eventually leads to myocardial dysfunction as the hypertrophied myocardium eventually cannot compensate for the increased wall stress generated. Increasing degrees of diastolic dysfunction result, leading to cardiac dysfunction. Continuing pressure overload eventually leads to fibroblast proliferation and collagen deposition in cardiac tissue and apoptosis of cardiac myocytes, leading to progressive and irreversible cardiac dysfunction and subsequent development of CHF symptoms. AVR is possible in these patients with severe AS and CHF. The main prerequisite for successful valve replacement in these patients is the presence of reversible myocardial dysfunction. Determining which patients with AS and CHF, especially those with low-gradient AS (valve gradient ^30 mm Hg), will benefit from AVR is especially challenging. Only a few published series have been undertaken to examine the outcomes of those patients with severe AS (valve area ^0.75 cm2 ) and left ventricular dysfunction [ejection fraction (EF) ^35%] or NYHA class IV symptoms who undergo AVR (table 1), given that they represent !5% of the patient population with AS [8]. Earlier studies had small numbers of patients, typically as part of larger studies, with varied outcomes. One early study of a series of 19 patients with severe AS and severely reduced EF by Smith et al. [2] found an operative mortality of 21% with a 3-year survival of 74 B 10%, with 13 of the survivors changing two NYHA classes from III–IV to I–II. Based upon these results, Smith et al. [2] recommended AVR in this patient group. A subsequent study by Carabello et al. [21] confirmed these findings in 14 patients by finding an operative mortality of 21%, with 10 of the 11 surviving patients undergoing functional NYHA class improvement from NYHA class III–IV to I–II. Subsequently, Connolly et al. [8] in their study of 154 patients found an operative mortality of 9% with the majority of patients improving their functional NYHA class after surgery, thereby supporting earlier studies. In another study of 112 patients with critical AVR and NYHA class III and IV failure, Obadia et al. [22] found only a 7% operative mortality and a 5-year survival of 77%. Hence, AVR was favored in this study as well. However, it should be noted that the EF was not measured in this study, which focused only on the functional status of the patients. In more recent series, AVR was associated with a high perioperative risk and poor overall prognosis in long-term follow-up. One such series, reported by Powell et al. [23], had an operative mortality of 18%, with prior myocardial infarction being a risk factor for perioperative mortality.

Paul/Mihaljevic/Rawn/Cohn/Byrne

Table 1. AVR for severe AS with left ventricular dysfunction

Smith et al. [2] Carabello et al. [21] Connolly et al. [8] Obadia et al. [22] Powell et al. [23] Connolly et al. [25]a Monin et al. [30]a, b Pereira et al. [29]a Nishimura et al. [34]c

a b c

n

AV area, cm2

19 14 154 112 55 52 45

0.32 cm2/m2 0.4 0.60 0.40 cm2/m2 ^0.75 0.7 0.7

37 !45 27 NA ^30 ^35 29

^0.75 ^1.2

^35 ^40

39 21

EF, %

Operative mortality, %

NYHA Survival improvement benefit

21 21 9 7.14 18 21 8 (with reserve) 8 7 (with reserve)

yes yes yes yes yes yes yes

no NA NA NA NA NA yes

yes yes

yes NA

AV = Aortic valve; NA = not applicable. Assessed low-gradient AS. Dobutamine echocardiography used to stratify patients. Dobutamine catheterization used to stratify patients.

Powell et al. [23] did not recommend AVR in this patient group, based on high operative mortality. Despite the recommendations from this study, the overall consensus is that AVR should be undertaken in those patients with severe AS and depressed function despite the high perioperative mortality ranging around 20% at most centers, since those patients who survived had substantial symptomatic improvement. In two studies of patients undergoing AVR, survival at 5 years has been shown to be approximately 70%, which is better than the expected life expectancy of 2 years in medically treated patients [2, 22, 24]. This survival benefit from AVR has been implied, but not statistically demonstrated in these studies in comparison to medical therapy. A more controversial subset of patients with severe AS is those who also have left ventricular dysfunction (EF ^35%), as well as a low transvalvular gradient (valve gradient ^30 mm Hg). In this subset of patients, left ventricular dysfunction may be secondary to superimposed myocardial fibrosis from longstanding AS or prior ischemic cardiac disease and hence irreversible and not rectifiable by AVR. In the initial study by Carabello et al. [21], of the 4 patients in their study who met these criteria, 3 died in the perioperative period and the other did not improve symptomatically. Hence, AVR was not recommended for this patient population. A recent study by Connolly et al. [25] examined the results of AVR in this most controversial group of patients. In their series of 52 patients, the operative mortali-

ty was 21%, with 3- and 5-year survival rates of 71% each for those without coronary disease, and 58 and 29%, respectively, for those with coronary disease [25]. The increased long-term mortality of AVR in combination with coronary disease has been noted before [26–28]. Most patients in the study also had symptomatic improvement, with 77% of surviving patients at follow-up improving by greater than one functional NYHA class [25]. AVR was recommended in this subset despite the high operative mortality as the majority of surviving patients had symptomatic improvement. Pereira et al. [29] used propensity score analysis to assess the survival benefit of AVR in this patient population. In this series, propensity score analysis was used to compare a cohort of 39 from a pool of 68 patients who underwent AVR to 56 control patients from a pool of 89 patients who were treated medically. This study found that the AVR group had markedly improved 1- and 4-year survival rates in comparison to the control group (82 vs. 41% and 78 vs.15%, respectively, p ! 0.0001), with AVR being the main predictor of survival in multivariate analysis [29]. Operative mortality in the AVR group was only 8%, while the control group had a 14% in-hospital mortality rate. Only 2 of the 30 patients in the AVR group who were of preoperative NYHA class III–IV did not improve to class I–II symptomatology [29]. This is only one of two studies to show a mortality benefit with AVR in this patient population [29, 30].

Aortic Valve Replacement and Reduced Left Ventricular Function

Cardiology 2004;101:7–14

9

Other studies of patients with severe AS and low valve gradients, but not necessarily low EFs, have also found AVR to have a high operative mortality but with symptomatic improvement. In one such study, Brogan et al. [31] retrospectively studied 18 patients and found an operative mortality of 33%, with 10 patients improving in functional class to NYHA class I–II at follow-up. Despite the high operative mortality, these investigators also recommended AVR for this group of patients. Blitz et al. [32], in their series of 52 patients, found an operative mortality of 11% with an 8-year survival of 29% and hence also recommended AVR as being superior to medical therapy. In order to better identify the surgical candidates for AVR in this high-risk population and thereby lower the operative mortality, attempts have been made to identify patients with reversible left ventricular dysfunction [30, 33]. One such study has recently been published that uses dobutamine echocardiography to differentiate between those patients with severe AS, left ventricular dysfunction and a low transvalvular gradient with irreversible myocardial damage versus those with ‘afterload mismatch’ and hence reversible myocardial dysfunction from the pressure-overloaded state of AS [30]. Dobutamine echocardiography allows the determination of aortic valve area in two different flow states (baseline and dobutamine), so that severe AS which is fixed can be distinguished from AS that is flow-dependent [30, 33]. Those patients with flow-dependent AS will demonstrate a decrease in valve area with the increased flows caused by the enhanced inotropic-mediated contractile state. In these patients, AVR is more likely to be beneficial as the depressed contractility is due to increased afterload, which is termed ‘afterload mismatch’ [30, 33]. Monin et al. [30] used dobutamine echocardiography to stratify 45 patients into two groups, 32 with recruitable myocardium versus 13 without. Twenty-four of the 32 patients with, and 6 of the 13 patients without recruitable myocardium underwent AVR. The operative mortality was 8% in those patients with contractile reserve and 50% in those without (p = 0.014). In comparison to medical therapy, at a median follow-up of 24 months, AVR patients had improved long-term survival, with a hazard ratio for death of 0.13 (p = 0.003). In contrast, those patients with no contractile reserve had a poorer prognosis when compared with medical therapy, with a hazard ratio for death of 19.6 (p = 0.003) [30]. This study, along with that of Pereira et al. [29], clearly demonstrates a survival benefit with AVR in comparison to medical therapy in this high-risk patient population [29, 30].

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Dobutamine challenge has also been used in the cardiac catheterization laboratory to determine flow-dependent gradients in patients with critical AS and low outputs in order to stratify risk. In one such study, Nishimura et al. [34] identified 32 patients with NYHA class III–IV heart failure, ‘critical’ AS and low EF (!40%). Twentyone of these patients underwent surgery at the discretion of the treating physicians. Patients with preserved systolic function (n = 15), which was defined as 120% increase in stroke volume, were found to have better outcomes than those who did not. The operative mortality was 7% in patients with contractile reserve (n = 15), compared to 33% in patients without reserve (n = 6). At follow-up, all of the survivors in the group with preserved systolic function had improved symptoms and were NYHA class I–II, while 2 more patients in the other group had died of progressive heart failure [34]. Although the results and hence utility of dobutamine stress catheterization rest on one study, it confirms the published results of dobutamine stress echocardiography and provides another means of stratifying high-risk patients, especially those who may have ambiguous echocardiography data. However, it is clear that more studies are needed to validate this method. This study, along with that of Monin et al. [30], demonstrates the utility of dobutamine challenge in assessing this high-risk patient population. There are limitations with all the studies presented. Most of these studies involve a small number of patients and often represent operative techniques and valve prostheses which are no longer in use, or included patients who had undergone AVR with concomitant coronary artery disease, who are known to have decreased longterm survival [26, 27, 33]. All but one of the studies (that of Monin et al. [30]) are retrospective in nature, and no randomized prospective studies exist that directly compare AVR to medical therapy in this patient population [8, 21–23, 25, 29, 30, 32]. Prospective randomized studies are difficult in this small subset of patients with AS and are unlikely to be performed. However, both Pereira et al. [29] and Monin et al. [30] attempted to eliminate as many confounding variables as possible in their studies. Pereira et al. [29] attempted to eliminate selection bias as best as possible using propensity analysis in their retrospective study. Monin et al. [30], in turn, attempted to eliminate bias in the prospective design of their trial. This group of studies, especially the most recent studies by Pereira et al. [29] and Monin et al. [30], illustrate a few important points concerning AVR in this high-risk population:

Paul/Mihaljevic/Rawn/Cohn/Byrne

(1) AVR can be performed safely in this patient population with an operative mortality in the range of 10–15%, especially if dobutamine stress echocardiography is performed to identify patients with contractile reserve and hence most likely to benefit from AVR. (2) AVR in this patient group leads to symptomatic improvement in most patients who survive surgery. (3) AVR in this patient population confers a short- and long-term survival benefit in comparison to medical therapy. The caveat to this point is that dobutamine echocardiography must show contractile reserve in order for there to be a benefit. Whether AVR should be recommended in patients with AS and a valvular cardiomyopathy with left ventricular function ^35% or NYHA class III or IV symptoms as opposed to heart transplantation remains unclear. Most patients in this subgroup are elderly and hence generally not candidates for heart transplantation. Thus, AVR should be recommended for these elderly patients as long as dobutamine echocardiography shows evidence of contractile reserve. For those patients younger than 65 years of age, heart transplantation is typically associated with 1-year survival rates of 70–80% and 5-year survival rates of 60–70% for all patients [35, 36]. No studies have specifically addressed the outcomes of those patients with strictly valvular cardiomyopathy from AS. The transplantation survival rates, however, are similar to the survival rates reported by Pereira et al. [29] and Monin et al. [30] for AVR in a considerably more elderly population with a median age of 70 years for both studies. Hence, it can also be recommended that younger patients would likely benefit from AVR provided that contractile reserve is present in dobutamine stress studies, since there is no increased survival benefit from transplantation. The survival benefit from AVR is probably greater in patients less than 65 years old, as the survival data come from a considerably older set of patients who are likely to have more comorbidities. Also, transplantation is not without its own comorbidities, such as those associated with immunosuppression, and is limited by the availability of suitable donor organs. Furthermore, by having AVR as the first operation, transplantation remains as an option should symptoms progress.

Aortic Regurgitation

AR results from improper coaptation of the aortic valve leaflets, leading to regurgitant blood flow into the left ventricle. Unlike AS, the pathophysiology of AR

Aortic Valve Replacement and Reduced Left Ventricular Function

involves both volume and pressure overload of the left ventricle. AR has numerous etiologies, including calcific aortic disease, degenerative disease, rheumatic disease, endocarditis, anorectic medications such as fenfluramine, and aortic annular dilatation as a result of connective tissue disorders such as Marfan’s syndrome, hypertension or even trauma [37–42]. Chronic AR leads to left ventricular eccentric hypertrophy to compensate for the volume and pressure overload. Furthermore, as for AS, the exact molecular mechanisms that underlie the transduction of mechanical stress in AR to myocardial hypertrophy and eccentric hypertrophy are unknown. As for AS, numerous protein kinases are activated in the mechanical transduction of wall stress. Recent evidence implicates various calcium-dependent protein kinases, such as calcineurin, the molecular target of cyclosporine, in these pathways [43, 44]. Better understanding of these pathways may one day lead to the modulation of the eccentric hypertrophic response in AR patients much in the same way as has been discussed for AS previously. With continued uncorrected AR, myocardial fibrosis eventually occurs, resulting either from subclinical ischemia from increased wall stress and diminished diastolic coronary flow or stress-triggered myocyte apoptosis. The exact mechanisms are an area of active investigation. Progressive fibrosis leads to irreversible cardiac dysfunction and subsequent CHF symptomatology in patients. The natural history of patients with chronic AR and low EF (^35%) or NYHA class III–IV symptoms treated medically is extremely poor. Survival for medically treated severe AR at 5 years has been reported to be between 20 and 66% [5, 45]. Current guidelines for patients with AR recommend AVR for symptomatic patients and those asymptomatic patients who show signs of deteriorating left ventricular function or have an EF !55% or diastolic diameter approaching 75 mm or an end-systolic diameter approaching 55 mm. AVR is well tolerated in these patients, with preserved or slightly disturbed ventricular function and acceptable morbidity and mortality [24, 46]. Hence, AVR is currently recommended in severe AR even when EF is slightly depressed. However, preoperative EF has been shown to be an indicator of postoperative prognosis after AVR, and current guidelines make no recommendations for AVR in those patients with markedly depressed ventricular function (EF ^35%) or NYHA class III–IV symptoms. Clearly defining the risks and benefits of AVR in this patient population would allow us to better differentiate among the various treatment options for this subset of patients

Cardiology 2004;101:7–14

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Table 2. AVR for severe AR with left ventricular dysfunction

Henry et al. [47] Bonow et al. [48] Klodas et al. [51] Chaliki et al. [50]

n

EF, %

Operative Survival mortality, %

14 50 128 43

! 55 37 NA ! 35

14 0 7.8 14

NA 63% at 5 years 72% at 5 years 72% at 4 years

NA = Not applicable.

with AR, which include medical vasodilator therapy, cardiac transplantation and end-stage ventricular assist device placement. Very few studies have been done on AVR in this group of patients as they represent a small percentage of patients with AR, and most undergo AVR prior to marked ventricular decompensation (table 2). Earlier studies had small numbers of patients as part of larger studies. One such early study by Henry et al. [47] evaluated 14 patients with AR and severely reduced ventricular function, originally assessed by echocardiographic fractional shortening. The operative mortality for this group was 14%, with the remaining 7 patients subsequently dying of CHF [47]. In another series of 80 patients, there was no operative mortality, but in patients with depressed EF (!37%; n = 50), 5-year survival rates were less than those with preserved EF (52%; n = 30): 96 B 3% versus 63 B 12% (p ! 0.001) [48]. These results were confirmed by Klodas et al. [49], who examined AVR in 289 patients with AR, of whom 161 had NYHA class I–II symptoms, while the remaining 128 patients had NYHA class III–IV symptoms. The EF of the group with class III–IV symptoms was slightly lower than in those with class I–II symptoms, but not markedly so (49 B 14% vs. 53 B 11%, respectively, p = 0.013) [49]. In this study, patients with NYHA class III–IV symptoms had a higher operative mortality than those with class I–II symptoms (7.8 vs. 1.2%, respectively, p = 0.005). Also, the class III–IV group had lower 5- and 10-year survival (72 B 4% and 45 B 4% vs. 92 B 2% and 78 B 7%, respectively, p ! 0.0001) [49]. However, it should be noted that at baseline, the patients with class III–IV symptoms were older, had more comorbidities and underwent more concomitant coronary artery bypass grafting (41 vs. 14%, p ! 0.0001), all of which have been associated with decreased survival [49]. Hence, the results of this study are somewhat questionable, as the higher operative mortality and

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lower late of survival could be explained solely by the differences outlined. The most comprehensive study in the literature to date examining the outcomes of isolated AVR in patients with severe AR and depressed ventricular function was published by Chaliki et al. [50]. This study examined 450 patients over 15 years. Patients were subdivided into three groups based on EF: group 1 had 43 patients with markedly depressed EF (!35%); group 2 had 135 patients with moderately depressed EF (35–50%), and group 3 had 273 patients with normal EF (6 50%) [50]. In their analysis, they found that the operative mortality was higher in those patients with markedly depressed EF (!35%) than in those with moderately depressed EF (35–50%) or normal EF (150%): 14 versus 6.7 and 3.7%, respectively (p = 0.02) [50]. Late survival was also reduced in the group with markedly depressed EF, with 4- and 10-year survival rates being 72 and 48%, in comparison to 4- and 10-year survival rates of 81 and 60% and 85 and 73% (p ! 0.0001), respectively, for the groups with moderately depressed EF and normal EF [50]. Postoperative EF improved in all but the normal EF group, as is expected, since ‘afterload mismatch’ is probably improved the most in those with markedly and moderately reduced EF. A few important points concerning AVR in patients with AR and depressed ventricular function can be made: (1) AVR can be performed in patients with AR with marked ventricular dysfunction with an operative mortality of approximately 8–15%, which is greater than that in patients with AR and preserved or slightly decreased ventricular function. (2) AVR in this subset of patients is associated with decreased survival compared to patients undergoing AVR with preserved or slightly decreased ventricular function. Survival of this subset is approximately 70% at 5 years, which is better than with no treatment and medical treatment alone, as inferred from natural history studies. However, no studies that directly compare medical therapy to AVR in this subgroup exist, and probably will not exist, as the prognosis of medical treatment alone for dilated cardiomyopathy secondary to AR is extremely poor. (3) AVR should be performed prior to left ventricular decompensation, since operative and long-term results worsen with decreasing left ventricular dysfunction as measured by EF. With these recommendations, what is still unclear is whether AVR should be performed in patients with AR and a valvular cardiomyopathy with left ventricular function ^35% and NYHA class III–IV symptoms as op-

Paul/Mihaljevic/Rawn/Cohn/Byrne

posed to heart transplantation or medical vasodilator therapy. Although there are no direct comparative studies, it can be concluded that AVR is better than medical therapy in this group of patients, as discussed before. Heart transplantation at high-volume centers is associated with 1- and 5-year survival rates of 70–80% and 60– 70%, respectively, for all patients, which is comparable to those with AVR in these patients with AR and severe ventricular dysfunction [35, 36]. As with AS, no studies have specifically addressed the transplant outcomes of those patients with strictly valvular cardiomyopathy from AR, as they represent a minority of heart transplant patients. However, as these survival rates are similar to the survival rates with AVR in AR patients and given the comorbidities associated with transplantation from immunosuppression and the lack of availability of suitable organ donors, it is reasonable to favor AVR as the first surgical therapy in this patient population as well. As with AVR for AS, by having AVR as the first operation, transplantation remains as a viable option if AVR were to fail in these patients.

Conclusions

AVR is feasible in patients with severe AS or AR with depressed ventricular function (EF ^35%). In patients with severe AS with depressed ventricular function and low valve gradients, dobutamine echocardiography is useful to identify patients with contractile reserve who will benefit from AVR. Operative mortality is acceptable and there is a mortality benefit associated with AVR in this patient population. AVR can also be undertaken in patients with severe AR and depressed ventricular function, with an acceptable operative mortality. AVR in this group has an implied mortality benefit over medical therapy. AVR in both groups results in a 5-year survival of approximately 70%, which is similar to that with orthotopic heart transplantation. Due to the associated comorbidities of immunosuppression and limited donor organ availability, AVR should be attempted first prior to transplantation. Transplantation should be used only when and if AVR starts to fail or is not feasible in these patients.

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22 Obadia JF, Eker A, Rescigno G, Flamens C, Chassignolle JF: Valvular replacement for aortic stenosis on patients in NYHA class III and IV. Early and long term results. J Cardiovasc Surg (Torino) 1995;36:251–256. 23 Powell DE, Tunick PA, Rosenzweig BP, Freedberg RS, Katz ES, Applebaum RM, Perez JL, Kronzon I: Aortic valve replacement in patients with aortic stenosis and severe left ventricular dysfunction. Arch Intern Med 2000; 160:1337–1341. 24 Tarasoutchi F, Grinberg M, Filho JP, Izaki M, Cardoso LF, Pomerantezeff P, Nuschbacher A, da Luz PL: Symptoms, left ventricular function, and timing of valve replacement surgery in patients with aortic regurgitation. Am Heart J 1999;138:477–485. 25 Connolly HM, Oh JK, Schaff HV, Roger VL, Osborn SL, Hodge DO, Tajik AJ: Severe aortic stenosis with low transvalvular gradient and severe left ventricular dysfunction: Result of aortic valve replacement in 52 patients. Circulation 2000;101:1940–1946. 26 He GW, Acuff TE, Ryan WH, Douthit MB, Bowman RT, He YH, Mack MJ: Aortic valve replacement: Determinants of operative mortality. Ann Thorac Surg 1994;57:1140–1146. 27 Hochrein J, Lucke JC, Harrison JK, Bashore TM, Wolfe WG, Jones RH, Lowe JE, White WD, Glower DD: Mortality and need for reoperation in patients with mild-to-moderate asymptomatic aortic valve disease undergoing coronary artery bypass graft alone. Am Heart J 1999;138:791–797. 28 Collins JJ Jr, Aranki SF: Management of mild aortic stenosis during coronary artery bypass graft surgery. J Card Surg 1994;9:145–147. 29 Pereira JJ, Lauer MS, Bashir M, Afridi I, Blackstone EH, Stewart WJ, McCarthy PM, Thomas JD, Asher CR: Survival after aortic valve replacement for severe aortic stenosis with low transvalvular gradients and severe left ventricular dysfunction. J Am Coll Cardiol 2002;39:1356–1363. 30 Monin JL, Monchi M, Gest V, Duval-Moulin AM, Dubois-Rande JL, Gueret P: Aortic stenosis with severe left ventricular dysfunction and low transvalvular pressure gradients: Risk stratification by low-dose dobutamine echocardiography. J Am Coll Cardiol 2001;37:2101– 2107. 31 Brogan WC 3rd, Grayburn PA, Lange RA, Hillis LD: Prognosis after valve replacement in patients with severe aortic stenosis and a low transvalvular pressure gradient. J Am Coll Cardiol 1993;21:1657–1660. 32 Blitz LR, Gorman M, Herrmann HC: Results of aortic valve replacement for aortic stenosis with relatively low transvalvular pressure gradients. Am J Cardiol 1998;81:358–362.

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33 deFilippi CR, Willett DL, Brickner ME, Appleton CP, Yancy CW, Eichhorn EJ, Grayburn PA: Usefulness of dobutamine echocardiography in distinguishing severe from nonsevere valvular aortic stenosis in patients with depressed left ventricular function and low transvalvular gradients. Am J Cardiol 1995;75:191– 194. 34 Nishimura RA, Grantham JA, Connolly HM, Schaff HV, Higano ST, Holmes DR Jr: Lowoutput, low-gradient aortic stenosis in patients with depressed left ventricular systolic function: The clinical utility of the dobutamine challenge in the catheterization laboratory. Circulation 2002;106:809–813. 35 Smits JM, De Meester J, Deng MC, Scheld HH, Hummel M, Schoendube F, Haverich A, Vanhaecke J, van Houwelingen HC; COCPIT Study Group; Eurotransplant heart transplant programs: Mortality rates after heart transplantation: How to compare center-specific outcome data? Transplantation 2003;75:90–96. 36 Campana C, Gavazzi A, Berzuini C, Larizza C, Marioni R, D’Armini A, Pederzolli N, Martinelli L, Vigano M: Predictors of prognosis in patients awaiting heart transplantation. J Heart Lung Transplant 1993;12:756–765. 37 Mast ST, Jollis JG, Ryan T, Anstrom KJ, Crary JL: The progression of fenfluramine-associated valvular heart disease assessed by echocardiography. Ann Intern Med 2001;134:261–266. 38 Khan MA, Herzog CA, St Peter JV, Hartley GG, Madlon-Kay R, Dick CD, Asinger RW, Vessey JT: The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med 1998; 339:713–718. 39 Roberts WC: Aortic dissection: Anatomy, consequences, and causes. Am Heart J 1981;101: 195–214. 40 Waller B: Rheumatic and nonrheumatic conditions producing valvular heart disease; in Frankl W, Brest AN (eds): Cardiovascular Clinics. Valvular Heart Disease: Comprehensive Evaluation and Management. Philadelphia, Davis, 1986, pp 30–31. 41 Tonnemacher D, Reid C, Kawanishi D, Cummings T, Chandrasoma P, McKay CR, Rahimtoola SH, Chandraratna PA: Frequency of myxomatous degeneration of the aortic valve as a cause of isolated aortic regurgitation severe enough to warrant aortic valve replacement. Am J Cardiol 1987;60:1194–1196. 42 Stein PD, Sabbah HN: Turbulent blood flow in the ascending aorta of humans with normal and diseased aortic valves. Circ Res 1976;39: 58–65.

43 Zhou YQ, Faerestrand S, Matre K: Velocity distributions in the left ventricular outflow tract in patients with valvular aortic stenosis. Effect on the measurement of aortic valve area by using the continuity equation. Eur Heart J 1995;16:383–393. 44 Sussman MA, Lim HW, Gude N, Taigen T, Olson EN, Robbins J, Colbert MC, Gualberto A, Wieczorek DF, Molkentin JD: Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science 1998;281:1690–1693. 45 Dujardin KS, Enriquez-Sarano M, Schaff HV, Bailey KR, Seward JB, Tajik AJ: Mortality and morbidity of aortic regurgitation in clinical practice. A long-term follow-up study. Circulation 1999;99:1851–1857. 46 Bonow RO, Carabello B, de Leon AC Jr, Edmunds LH Jr, Fedderly BJ, Freed MD, Gaasch WH, McKay CR, Nishimura RA, O’Gara PT, O’Rourke RA, Rahimtoola SH, Ritchie JL, Cheitlin MD, Eagle KA, Gardner TJ, Garson A Jr, Gibbons RJ, Russell RO, Ryan TJ, Smith SC Jr: Guidelines for the management of patients with valvular heart disease: Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). Circulation 1998;98:1949–1984. 47 Henry WL, Bonow RO, Borer JS, Ware JH, Kent KM, Redwood DR, McIntosh CL, Morrow AG, Epstein SE: Observations on the optimum time for operative intervention for aortic regurgitation. I. Evaluation of the results of aortic valve replacement in symptomatic patients. Circulation 1980;61:471–483. 48 Bonow RO, Picone AL, McIntosh CL, Jones M, Rosing DR, Maron BJ, Lakatos E, Clark RE, Epstein SE: Survival and functional results after valve replacement for aortic regurgitation from 1976 to 1983: Impact of preoperative left ventricular function. Circulation 1985;72: 1244–1256. 49 Klodas E, Enriquez-Sarano M, Tajik AJ, Mullany CJ, Bailey KR, Seward JB: Optimizing timing of surgical correction in patients with severe aortic regurgitation: Role of symptoms. J Am Coll Cardiol 1997;30:746–752. 50 Chaliki HP, Mohty D, Avierinos JF, Scott CG, Schaff HV, Tajik AJ, Enriquez-Sarano M: Outcomes after aortic valve replacement in patients with severe aortic regurgitation and markedly reduced left ventricular function. Circulation 2002;106:2687–2693. 51 Klodas E, Enriquez-Sarano M, Tajik AJ, Mullany CJ, Bailey KR, Seward JB: Aortic regurgitation complicated by extreme left ventricular dilation: Long-term outcome after surgical correction. J Am Coll Cardiol 1996;27:670–677.

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Cardiology 2004;101:15–20 DOI: 10.1159/000075981

Mitral Valve Surgery in Patients with Ischemic and Nonischemic Dilated Cardiomyopathy Alexander S. Geha Chawki El-Zein Malek G. Massad Division of Cardiothoracic Surgery, The University of Illinois Medical Center at Chicago, Chicago, Ill., USA

Key Words Mitral valve repair W Mitral valve replacement W Cardiomyopathy, ischemic W Cardiomyopathy, nonischemic

Abstract Congestive heart failure (CHF) is a chronic, progressive disease and its central element is the remodeling of the cardiac chamber associated with ventricular dilatation. Secondary mitral regurgitation is a complication of endstage cardiomyopathy and is associated with a poor prognosis. It is due to progressive mitral annular dilatation and alteration in the geometry of the left ventricle. A vicious cycle of continuing volume overload, ventricular dilatation, progression of annular dilatation, increased left ventricular wall tension and worsening mitral regurgitation and CHF occurs. The mainstays of medical therapy are diuretics and afterload reduction, which are associated with poor long-term survival in these patients. Historically, the surgical approach to patients with mitral regurgitation was mitral valve replacement, but these patients were not considered operative candidates because of their high morbidity and mortality. Heart transplantation is now considered standard treatment for select patients with end-stage heart disease; however, it

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is applicable only to a small number of patients. Mitral valve replacement in these patients is associated with adverse consequences on left ventricular systolic function resulting from interruption of the annulus-papillary muscle continuity. Preserving the mitral valve apparatus and left ventricle in mitral valve repair enhances and maintains left ventricular function and geometry with an associated decrease in wall stress. Using these operative techniques to alter the shape of the left ventricle, in combination with optimal medical management for heart failure, improves survival and may avoid or postpone transplantation. Copyright © 2004 S. Karger AG, Basel

Introduction

Congestive heart failure (CHF) is the commonest heart problem in the USA and is currently one of the leading causes of death and hospitalization in the older age group. As life expectancy increases worldwide, an escalating number of patients presenting with CHF are encountered. Badhwar and Bolling [1] reported that 4.7 million patients are suffering from heart failure in the USA, and 500,000 new patients are diagnosed every year. According to Tavazzi [2], half of the patients presenting with CHF will die

Alexander S. Geha, MD, MS Division of Cardiothoracic Surgery, The University of Illinois at Chicago 840 S. Wood Street, CSB 417 (MC 958) Chicago, IL 60612 (USA) Tel. +1 312 996 4942, Fax +1 312 996 2013, E-Mail [email protected]

within 3 years despite significant improvements in medical therapy; those with CHF and mitral regurgitation have a life expectancy of less than 12 months [3]. Cardiac transplantation has been the standard treatment for patients with severe CHF associated with endstage heart disease. However, this therapeutic modality has limited applicability, particularly in the elderly population or in patients with comorbid diseases. Organ shortage further limits the applicability of heart transplantation to approximately 2,000–2,500 patients annually in the United States [4]. This limitation is further compounded by the fact that there are contraindications due to concurrent disease, when patients with cardiomyopathy cannot be considered for transplantation. Alternate surgical strategies to manage patients with severe endstage heart disease have been applied over the last decade or more, including resynchronization therapy [5], electrical therapy [6], coronary artery revascularization [7], cardiomyoplasty [8], left ventricular myoreduction surgery [9] and mitral valve repair [10–14]. It is well established that secondary mitral regurgitation worsens both symptoms and prognosis in patients with left ventricular dysfunction of ischemic and nonischemic etiology. Volume overload resulting from mitral valve regurgitation leads to ventricular dilatation and dysfunction, which subsequently lead to further regurgitation through annular dilatation. Thus, a vicious downhill cycle is perpetuated whereby ventricular dilatation potentiates mitral regurgitation and mitral regurgitation potentiates ventricular dilatation. Once medical therapy has been maximized, these patients face an extremely poor probability of survival unless they undergo cardiac transplantation. With the already mentioned limitations of cardiac transplantation, Bolling et al. [15] advocated open mitral valve repair as a potential surgical option to interrupt this vicious cycle by eliminating mitral regurgitation. They hypothesized that correction of the mitral regurgitation and the ensuing reduction in concomitant ventricular volume overload allow the ventricle to recover and stabilize; if instituted early enough, valve repair potentially could achieve these results before irreversible dysfunction occurs. Historically, the surgical approach to mitral regurgitation had been replacement of the valve; however, in patients with a low ejection fraction, this approach, with removal of the subvalvular apparatus, was associated with prohibitively high mortality rates [16]. In all likelihood, this resulted from the lack of understanding of the interdependence of ventricular function and annulus-papillary muscle continuity [17]. It was originally thought that

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mitral incompetence provided a low-pressure relief during systolic ejection from the failing ventricle, and that removal of this ‘pop-off’ effect through mitral replacement was responsible for deterioration of ventricular function. The rationale of Bolling et al. [15] for open mitral valve repair in these patients was based on the observation that preservation of the mitral valve apparatus during mitral surgery resulted in improved ventricular geometry, decreased wall stress and improved systolic and diastolic function [18]; furthermore, repair of the valve, according to the principles first proposed by Carpentier [19], preserves left ventricular function, maintains the geometric integrity of the subvalvular complex and in general has a lower surgical mortality than mitral valve replacement. The purpose of this paper is to review the structural and functional alterations in patients with ischemic and nonischemic cardiomyopathy associated with mitral regurgitation, and to summarize the clinical and therapeutic correlates of this pathophysiological situation. We also review the currently reported experience, as well as our own, with mitral valve repair in patients with CHF and functional mitral regurgitation.

Anatomic and Functional Alterations

Functional mitral regurgitation occurs in the absence of structural mitral valve disease. By potentiating ventricular dilatation, it exacerbates left ventricular remodeling and subsequent activation of neurohormonal and cytokine system factors which contribute to further left ventricular hypertrophy and enlargement. While some pharmacologic interventions have been successful in transiently reducing functional mitral regurgitation in patients with dilated cardiomyopathy, one would expect long-term success to depend on interventions which effectively address anatomic changes responsible for functional regurgitation and its progression [20]. The mitral valve is an anatomically complex structure consisting of two leaflets separated at the annulus by the posteromedial and anterolateral commissures, and attached to the mitral annulus on one side and, through the chordae tendineae, to the papillary muscle on the other side. The posterior aspect of the left ventricular wall and papillary muscles together play a very important role in valvular competence and leaflet coaptation. The mitral valve annulus assumes an elliptical shape during systole and a more circular shape in diastole. The annulus, particularly its posterior aspect, is flexible, allowing increased

Geha/El-Zein/Massad

Table 1. Currently used techniques of mitral valve repair or replace-

Table 2. Available options for annuloplasty of the dilated mitral

ment

valve annulus

Reconstruction with or without annuloplasty Prosthesis implantation with preservation of the subvalvular apparatus/chordal sparing Prosthesis implantation with preservation of one or both leaflets (usually posterior leaflet) Replacement with resection of both leaflets and the chordae tendineae

Flexible or rigid circular rings Carpentier-Edwards classic annuloplasty ring (Edwards Lifesciences LLC, Irvine, Calif., USA) Medtronic Duran flexible annuloplasty ring (Medtronic Inc., Minneapolis, Minn., USA) St. Jude SJM Tailor annuloplasty ring (St. Jude Medical Inc., Minneapolis, Minn., USA) Carbomedics AnnuloFlex and AnnuloFlo rings (SulzerMedica, Austin, Tex., USA)

leaflet coaptation during systole and increased annular orifice area during diastole. In mitral regurgitation associated with cardiomyopathy, dilatation typically occurs along the more flexible posterior aspect of the annulus. Additionally, the posterior aspect of the left ventricular wall and papillary muscles play an important role in valvular competence and leaflet coaptation. During ventricular contraction, the leaflets are pulled down and together. Dilatation of the left ventricle may alter the alignment and tension on the papillary muscles, and may contribute to valvular incompetence [21]. Thus, there may be some difference in the mechanism of mitral regurgitation in idiopathic dilated and ischemic cardiomyopathy. In a study of patients with dilated cardiomyopathy, Strauss et al. [22] concluded that the primary anatomic alteration responsible for functional mitral regurgitation is increased annular size and, to a lesser extent, increased left ventricular size. Although mitral annular dilatation has been reported to be less severe in ischemic than idiopathic dilated cardiomyopathy [22], Yiu et al. [23] demonstrated that systolic mitral valve tenting and, to a lesser extent, loss of systolic annular contraction are the major determinants of functional mitral regurgitation in both ischemic and nonischemic cardiomyopathy. The same authors emphasize that in view of the loss of systolic annular contraction that contributes to regurgitation, mitral ring annuloplasty can reduce the regurgitation; however, they postulate that in the future, surgical correction of apical and posterior displacement of papillary muscle should probably be combined with annuloplasty in order to minimize mitral valve tenting and correct regurgitation [23]. It should also be pointed out that secondary mitral regurgitation also affects coronary flow characteristics. Coronary flow reserve appears to be limited in patients with mitral regurgitation due to an increase in baseline coronary flow and flow velocity (related to left ventricular volume overload, hypertrophy and left ventricular wall

Mitral Valve Repair in Cardiomyopathy

Posterior annuloplasty bands or partial rings Cosgrove-Edwards annuloplasty band (Edwards Lifesciences LLC) Medtronic Duran flexible annuloplasty band (Medtronic Inc.) St. Jude SJM Tailor partial annuloplasty ring (St. Jude Medical Inc.) Carbomedics AnnuloFlex partial ring (SulzerMedica) Posterior pericardial plication Autologous pericardium Periguard graft (Baxter Healthcare Corp., Irvine, Calif., USA)

stress). After valve reconstruction, ventricular preload, work and mass were reduced, with a resulting decrease in baseline coronary flow and flow velocity [21]. In addition, it also appears likely that patients who have secondary mitral regurgitation have restriction in coronary flow reserve, and improvement in flow reserve and velocity would be expected after mitral valve repair.

Surgical Options for Valve Repair or Replacement

From the technical point of view, a list of the currently used techniques of mitral valve repair or replacement is given in table 1. Table 2 provides a list of the currently available options for annuloplasty of the dilated mitral valve annulus, and table 3 lists the surgical options for repair of the mitral valve apparatus. When cardiomyopathy is the primary factor, the valve is usually structurally intact, and an annuloplasty suffices to achieve valvular competence. However, when structural abnormalities of the valve mechanism are present or account for the primary functional defect, they must be corrected in order to restore competence. Depending on the etiology of the mitral regurgitation, one or more of the techniques listed in table 3 are performed, usually in combination with a partial or complete ring annuloplasty.

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Table 3. Surgical options for repair of the mitral valve apparatus (usually performed in combination with a ring annuloplasty)

Quadrangular resection of the posterior leaflet with or without sliding annuloplasty Triangular resection of the middle scallop of the anterior leaflet Chordal transfer or transposition Papillary muscle shortening or reimplantation Edge-to-edge leaflet approximation (Alfieri repair) Leaflet cleft closure Primary closure or patch reconstruction of leaflet perforation Commissural plication

Clinical and Therapeutic Correlates

Mitral regurgitation frequently develops as left ventricular remodeling progresses in both ischemic and nonischemic cardiomyopathy. Using echocardiographic evaluation of left ventricular function, Blondheim et al. [3] reported that 57% of patients with a left ventricular ejection fraction of less than 40% had functional mitral regurgitation. The presence of this complication predicted a poor prognosis and was often grossly underestimated by physical examination. It was extremely labile and heavily dependent on cardiac loading conditions. The prevalence of mitral regurgitation increases as left ventricular remodeling progresses. Regardless of the initial etiology where mitral regurgitation is attributed to papillary or lateral wall muscle dysfunction in ischemic heart failure and to annular dilatation and chordal tethering in nonischemic myopathy, the regurgitation sets up the vicious cycle described earlier. It exacerbates the volume overload of the already dilated ventricle with further progression of annular dilatation, increased left ventricular wall tension, worsening mitral regurgitation and increased failure, which predicts a poor outcome. Bolling et al. [10] were the first to report the early outcome of remodeling mitral annuloplasty with a flexible posterior ring in 16 patients with severe CHF and mitral regurgitation in 1995. Twelve of their patients had a nonischemic cardiomyopathy and the other 4 an ischemic cardiomyopathy without ongoing ischemia. Functional capacity was improved in all patients, and their mean left ventricular ejection fraction rose from 16 to 25%, with reduction in regurgitation volume and left ventricular volume. The most impressive result of this study was that patients with severe left ventricular systolic dysfunction, in whom left ventricular ejection fraction was probably overestimated by the presence of severe mitral regurgita-

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tion, were able to tolerate the major surgical procedure of correction of mitral regurgitation. This observation was instrumental in reversing the widely held opinion that corrective surgery should not be performed in patients with severe mitral regurgitation and an ejection fraction less than 30%. Bolling et al. [15] subsequently reported the intermediate outcome of mitral annuloplasty with an undersized flexible ring in 48 patients with severe CHF, and recently, Bolling [4] reported the results in 150 patients who underwent this therapy between 1993 and 2000 at the University of Michigan in Ann Arbor. The overall operative mortality was 5% and the 1- and 2-year actuarial survival was 80 and 70%, respectively. At the 2-year follow up, all patients were in New York Heart Association (NYHA) class I/II, with a mean ejection fraction of 26%. Bishay et al. [24] reported the experience of the Cleveland Clinic with 44 patients with mitral regurgitation and a left ventricular ejection fraction !35% operated on between 1990 and 1998. Seven of those 44 patients (16%) were initially referred for consideration for transplantation. The 1-, 2and 5-year survival rates were 89, 86 and 67%, respectively. The mean NYHA class improved from 2.8 to 1.3 at a mean follow-up of 40 months. Of interest, freedom from readmission for heart failure was 88, 82 and 72% at 1, 2 and 5 years, respectively. Mitral valve surgery in that patient population was associated with improved survival and also improved quality of life with a significantly lower need for rehospitalization. Chen et al. [13] reported the experience of the Brigham and Women’s Hospital in 81 patients with ischemic cardiomyopathy. Of those, 77% had concomitant coronary bypass graft surgery and 13% had structural abnormalities of the mitral valve. Left ventricular ejection fraction improved to the same extent in patients who underwent only ring annuloplasty and those who in addition underwent coronary bypass grafting. The 11% surgical mortality in this group was attributed by the authors to the inclusion of actively ischemic patients. Szalay et al. [25] reported a somewhat similar experience from Bad Nauheim in Germany among 121 patients with mitral regurgitation and cardiomyopathy having a left ventricular ejection fraction less than 30%. Seventyfive percent of their patients had ischemic cardiomyopathy. All patients underwent a flexible posterior ring annuloplasty. Additional procedures included tricuspid valve repair and coronary bypass grafting. Eighty-six percent of the ischemic cardiomyopathy patients had concomitant coronary artery grafting. The results were similar to those reported by Bolling [4], where early mortality was 6.6% in

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either group, and the 1- and 2-year actual survival was no different in dilated or ischemic patients. In the 33-month period between November 2000 and July 2003, we operated on 28 patients with mitral regurgitation and a left ventricular ejection fraction below 30%. Of those, 13 patients (11 female, 2 male) had dilated cardiomyopathy and 15 (11 male, 4 female) had ischemic cardiomyopathy. Their age ranged from 48 to 82 years (mean 62 years). All patients received a flexible ring posterior annuloplasty with undersizing by 2–4 mm. Coronary bypass grafting was performed in 12 of the 15 patients with ischemic cardiomyopathy; the other 3 did not have active ongoing ischemia. Tricuspid valve repair with or without a ring was performed in 9 of the 13 patients with dilated myopathy and 2 of the 15 with ischemic myopathy. There was no surgical mortality in this group, and no late mortality, thus far, at a mean follow-up of 18 months. Our experience in a relatively small group of patients is in line with that reported by Bolling [4] and others in that mitral valve reconstruction can be performed fairly safely in these patients with severe left ventricular dysfunction. We have combined the procedure with coronary bypass grafting in patients showing evidence of active ischemia. Whether coronary revascularization contributes to improvement in papillary and lateral wall muscle function in these patients is difficult to assess. Should such an improvement result, it will add to the beneficial effect of the annuloplasty in reversing the remodeling of the left ventricle. Bolling [1, 4, 10, 15] has emphasized in many presentations the importance of the undersizing of the flexible ring in reestablishing the ellipsoid shape and somewhat normal geometry of the left ventricular base. Whether implantation of an undersized ring by itself reverses remodeling or attenuates its progression in the long run is still not clear, but early and intermediate results are quite encouraging. The survival at that level of follow-up is comparable to that following cardiac transplantation. Rothenburger et al. [14] recently reported a series of 31 patients with mitral regurgitation and an ejection fraction below 30% who underwent isolated repair [16] or replacement [15]. They reported comparable results between the two groups, with 1-, 2- and 5-year survival rates of 91, 84 and 77%, respectively. Functional results were also equally good. This brings into question whether mitral valve replacement with preservation of the subvalvular apparatus and chordae tendineae might achieve similar results as valve repair. Such a procedure can be performed, especially with the use of bioprosthetic valves, with total pres-

ervation of the mitral valve apparatus. Early available data from David et al. [26] indicate that replacement of the mitral valve with preservation of the subvalvular structures can result in postoperative left ventricular systolic function that is comparable to that with valvular repair. In situations where the native valve leaflet(s) is (are) excised, this can be achieved by incorporating the chordal leaflet attachments between the annular suture line and the prosthetic cloth rim. In other situations where one or both valve leaflets are kept intact, this can be achieved by incorporating the plicated leaflet structure with transannular sutures. In these latter instances, clinical and functional studies have shown that preservation of the posterior leaflet is more important in maintaining left ventricular systolic function. Although preservation of the anterior leaflet is technically feasible, obstruction of the left ventricular outflow tract is possible if too much of the anterior leaflet structure is left intact [26]. Such outcomes with chordae-preserving mitral valve replacement are certainly at odds with the previously reported superiority of repair over replacement [19]. The efficacy of such a valve replacement approach will need to be demonstrated in randomized trials. Menicanti et al. [27] recently reported combining a posterior annulopasty with a left ventricular restoration procedure in 46 patients with ischemic cardiomyopathy after an old anteroseptal myocardial infarction. However, the operative mortality was 15.2%, and although the late functional outcomes were reported to be good, the followup was relatively too short to allow adequate evaluation of this approach in this subgroup of patients at this time.

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Cardiology 2004;101:15–20

Conclusion

Functional mitral regurgitation commonly occurs in patients with left ventricular dysfunction and ongoing remodeling of the left ventricle, whether the etiology is ischemic or idiopathic dilated myopathy. Early and intermediate results with implantation of an undersized flexible ring in the posterior mitral annulus suggests that correction of functional regurgitation results in partial reversal of left ventricular remodeling and in symptomatic improvement. Intermediate results are superior to medical treatment alone and comparable to cardiac transplantation. The long-term benefit of this procedure remains to be demonstrated, and the insertion of a prosthetic valve with total preservation of the native mitral valve needs to be evaluated.

19

References 1 Badhwar V, Bolling S: Mitral valve surgery in the patient with left ventricular dysfunction. Semin Thorac Cardiovasc Surg 2002;14:133– 136. 2 Tavazzi L: Epidemiology of dilated cardiomyopathy: A still undetermined entity. Eur Heart J 1997;18:4–6. 3 Blondheim DS, Jacobs LE, Kotler MN, Costacurta GA, Parry WR: Dilated cardiomyopathy with mitral regurgitation: Decreased survival despite a low frequency of left ventricular thrombus. Am Heart J 1991;122:763–771. 4 Bolling S: Mitral reconstruction in cardiomyopathy. J Heart Valve Dis 2002;11:S25–S31. 5 Gras D, Ruffy R, Cebron JP, Brunel P, Leurent B, Banus Y: Treatment of refractory congestive heart failure by cardiac resynchronization. Minerva Cardioangiol 2003;2:185–195. 6 Engelstein ED: Prevention and management of chronic heart failure with electrical therapy. Am J Cardiol 2003;91:62F–73F. 7 Dreyfus GD, Duboc D, Blasco A, Vigoni F, Dubois C, Brodaty D, de Lentdecker P, Bachet J, Goudot B, Guilmet D: Myocardial viability assessment in ischemic cardiomyopathy: Benefits of coronary revascularization. Ann Thorac Surg 1994;57:1402–1408. 8 Carpentier A, Chachques JC, Acar C, Relland J, Mihaileanu S, Bensasson D, et al: Dynamic cardiomyoplasty at seven years. J Thorac Cardiovasc Surg 1993;106:42–54. 9 Batista RJV, Santos JLV, Takeshita N, Bocchino L, Lima PN, Cunha MA: Partial left ventricular function in end-stage heart disease. J Card Surg 1996;11:96–97. 10 Bolling SF, Deeb GM, Brunsting LA, Bach DS: Early outcome of mitral valve reconstruction in patients with end-stage cardiomyopathy. J Thorac Cardiovasc Surg 1995;109:676–683.

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11 Bolling SF: Mitral reconstruction for cardiomyopathy. Nippon Geka Gakkai Zasshi 1995; 24:226–227. 12 Bach DS, Bolling SF: Improvement following correction of secondary mitral regurgitation in end-stage cardiomyopathy with mitral annuloplasty. Am J Cardiol 1996;78:966–969. 13 Chen F, Adams D, Aranki S, Collins J, Couper G, Rizzo R, Cohn L: Mitral valve repair in cardiomyopathy. Circulation 1998;98(19 suppl):II-124–II-127. 14 Rothenburger M, Rukosujew A, Hammel D, Dorenkamp A, Schmidt C, Schmid C, Wichter T, Scheld HH: Mitral valve surgery in patients with poor left ventricular function. Thorac Cardiovasc Surg 2002;6:351–354. 15 Bolling S, Pagani F, Deeb G, Bach D: Intermediate-term outcome of mitral reconstruction in cardiomyopathy. J Thorac Cardiovasc Surg 1998;115:381–388. 16 Phillips HR, Levine FH, Carter JE, Boucher CA, Osbakken MD, Okada RD, Akins CW, Daggett WM, Buckley MJ, Pohost GM: Mitral valve replacement for isolated mitral regurgitation: Analysis of clinical course and late postoperative left ventricular ejection fraction. Am J Cardiol 1981;48:647–654. 17 Pitarys CJ II, Forman MB, Panayiotou H, Hansen DE: Long-term effects of excision of the mitral apparatus on global and regional ventricular function in humans. J Am Coll Cardiol 1990;15:557–563. 18 Sarris GE, Cahill PD, Hansen DE, Derby GC, Miller DC: 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.

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19 Carpentier A: Cardiac valve surgery: The ‘French correction.’ J Thorac Cardiovasc Surg 1983;109:676–683. 20 Lachmann J, Shirani J, Pletis K, Frater R, Le Jemtel T: Mitral ring annuloplasty: An incomplete correction of functional mitral regurgitation associated with left ventricular remodeling. Curr Cardiol Rep 2001;3:241–246. 21 Crawford M: Cardiology. New York, Harcourt, 2000. 22 Strauss RH, Stevenson LW, Dadourian BA, Child JS: Predictability of mitral regurgitation detected by Doppler echocardiography in patients referred for cardiac transplantation. Am J Cardiol 1987;59:892–894. 23 Yiu SF, Enriquez-Sarano M, Tribouilloy C, Seward JB, Tajik AJ: Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunction. Circulation 2000;102:1400–1406. 24 Bishay ES, McCarthy PM, Cosgrove DM, Hoercher KJ, Smedira NG, Mukherjee D, White J, Blackstone EH: Mitral valve surgery in patients with severe left ventricular dysfunction. Eur J Cardiothorac Surg 2000;17:213– 221. 25 Szalay ZA, Civelek A, Hobe S, Brunner-LaRocca HP, Klovekorn WP, Knez I, Vogt PR, Bauer EP: Mitral annuloplasty in patients with ischemic versus dilated cardiomyopathy. Eur J Cardiothorac Surg 2003;4:567–572. 26 David TE, Armstrong S, Sun Z: Left ventricular function after mitral valve surgery. J Heart Valve Dis 1995;4(suppl 2):S175–S180. 27 Menicanti L, Di Donato M, Frigiola A, Buckberg G, Santambrogio C, Ranucci M, Santo D; RESTORE Group: Ischemic mitral regurgitation: Intraventricular papillary muscle imbrication without mitral ring during left ventricular restoration. J Thorac Cardiovasc Surg 2002; 123:1041–1050.

Geha/El-Zein/Massad

Cardiology 2004;101:21–28 DOI: 10.1159/000075982

Outcomes of Coronary Artery Bypass Grafting versus Percutaneous Coronary Intervention and Medical Therapy for Multivessel Disease with and without Left Ventricular Dysfunction Amitra E.B. Caines a Malek G. Massad b Jacques Kpodonu b Abdallah G. Rebeiz c Alexander Evans b Alexander S. Geha b Departments of a Medicine and b Surgery, University of Illinois at Chicago, Chicago, Ill., c Division of Cardiology, Duke University Medical Center, Durham, N.C., USA

Key Words Coronary artery bypass grafting W Stenting W Ejection fraction W Multivessel coronary artery disease

of CABG and the recent advances in PCI, will be needed to assess the proper role and outcome of these two interventions. Copyright © 2004 S. Karger AG, Basel

Abstract Multiple randomized trials support the treatment of patients with multivessel coronary artery disease (CAD) and relatively normal left ventricular (LV) ejection fraction (EF) by either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). However, there has been a paucity of trials in the recent literature that have compared the outcomes of patients with multivessel CAD and low EF who undergo PCI or CABG. This review examines some of the clinical trials and series in this subgroup of patients and also compares the outcome of patients undergoing either procedure in the absence and presence of LV dysfunction. These trials and series support the notion that PCI can be successfully performed in patients with low EF with relatively low mortality, but that CABG is associated with greater freedom from repeat revascularization and from angina or congestive heart failure symptoms. In addition, most of the data published thus far indicate a long-term survival advantage among patients with ventricular dysfunction who have undergone CABG. Further studies, including randomized trials incorporating the evolving techniques

ABC

© 2004 S. Karger AG, Basel 0008–6312/04/1013–0021$21.00/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/crd

Introduction

It is well established that one of the major determinants of morbidity during and after coronary artery bypass grafting (CABG) is low left ventricular ejection fraction (LVEF) [1]. The results of numerous CABG trials performed in the 1970s and 1980s show that despite the increased morbidity, the benefits of this procedure outweigh the risks in patients with multivessel coronary artery disease (CAD) and decreased left ventricular (LV) systolic function. This is particularly true in situations where there is a hibernating myocardium that may recover following revascularization, thereby augmenting the reduced LV systolic function [2]. For many years, CABG was the preferred mode of revascularization for these patients. However, since the late 1970s, percutaneous coronary intervention (PCI) has evolved alongside with CABG and has become an increasingly effective modality of treatment [3]. With the advent of drug-eluting stents and the increasingly effective antiplatelet agents, many patients who in the past would have been destined for CABG now undergo

Malek G. Massad, MD Division of Cardiothoracic Surgery, The University of Illinois at Chicago 840 S. Wood Street, Suite 417 (MC 958) Chicago, IL 60612 (USA) Tel. +1 312 996 6215, Fax +1 312 996 2013, E-Mail [email protected]

PCI instead. While several groups have addressed the issue of surgery versus stenting in the past decade, there is a paucity of trials in the recent literature comparing the outcomes of patients with multivessel CAD and low LVEF who undergo CABG or PCI. This review examines the findings of some of the early and recent clinical trials and series that have tackled this issue.

Early CABG versus Medical Therapy Trials

The early classic surgical trials that dealt with patient subgroups with multivessel CAD and low ejection fraction (EF) are the Veterans Administration Trial of Coronary Bypass Surgery for Stable Angina (VA Trial), the Veterans Administration Unstable Angina Cooperative Study (VA Study), the European Coronary Surgery Study (European Study) and the Coronary Artery Surgery Study (CASS). The Veterans Administration Trial of Coronary Bypass Surgery for Stable Angina The VA cooperative trial of CABG for patients with stable angina was conducted between 1972 and 1974 at 13 VA sites and included 686 patients with stable angina of more than 6 months duration. The inclusion and exclusion criteria for enrollment have been published previously [4]. Briefly, patients were excluded if they had a myocardial infarction (MI) within 6 months, or if they had refractory diastolic hypertension, unstable angina or uncompensated congestive heart failure (CHF). In that study, 354 patients were randomly assigned to receive medical therapy and 332 patients to have surgery (CABG). The patient cohorts were all men. Of the 354 patients randomly assigned to medical treatment, 38% had CABG during a mean follow-up of 11 years (crossovers). The study showed an overall survival advantage with surgery at 7 years for all patients. However, that survival advantage was not maintained at 11 years of followup. In the subgroup of patients with multivessel disease and impaired LV function (LVEF !50%), there was a statistically significant difference in survival between the medically and the surgically treated groups at 7 years (52 vs. 76%, respectively, p = 0.002) and at 11 years of followup (38 vs. 50%, respectively, p = 0.026). That landmark study lends proof that, compared to medical therapy at that time, CABG improved survival in patients with multivessel CAD, regardless of the status of the LV function, and led to fewer subsequent hospitalizations. The difference in survival was maintained for up to 10 years from

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the time of enrollment, following which the difference in survival was no longer apparent. It is possible that the observed decrease in long-term survival of the CABG patients by 10 years from the time of revascularization could have been attributed to the progression of native vessel disease as well as to vein graft failure due to atherosclerosis, since vein grafts were the standard mode of revascularization at that time. The Veterans Administration Unstable Angina Cooperative Study The VA Study of unstable angina was a prospective randomized study that compared CABG to medical therapy alone in patients with unstable angina pectoris [5]. In that study, unstable angina was classified either as exertional angina that progressed in frequency and severity (type I) or recurring episodes of angina at rest (type II). Four hundred and sixty-eight patients were enrolled in the study, which involved 11 VA sites; 237 patients were randomly assigned to medical therapy and 231 to CABG. The patient cohorts were men, with an average age of 56 years, and with similar baseline characteristics. Twenty-nine percent had abnormal LV function, defined as EF !50%. Similar to the original VA trial [4], 45% of the patients assigned to the medical arm crossed over to CABG within 8 years from the time of randomization. Among patients with type II unstable angina and EF !50%, there were no deaths in the surgical cohort during the first 5 years of follow-up, whereas the medically treated group had a 5-year mortality of 27% (p ! 0.03). That difference in mortality continued to be significant after 8 years of follow-up (13 vs. 46%, respectively, p ! 0.04). From these two VA studies, it became apparent that patients with multivessel disease and impaired LV function who have stable angina or those with unstable angina at rest do better with surgery, with improved long-term survival compared to those who are treated medically. Of note is the fact that the initial VA trial also demonstrated a survival advantage up to 11 years of follow-up in patients with left main CAD regardless of whether they did or did not have LV dysfunction. The European Coronary Surgery Study The European Study (EURO) looked at patients with stable angina who had two- and three-vessel CAD disease and absence of marked LV dysfunction [6]. The study randomized 767 patients to receive medical therapy (373 patients) or CABG (394 patients). The two treatment groups were compared on the basis of ‘intention to treat’, although that entailed the risk that the potential effect of

Caines/Massad/Kpodonu/Rebeiz/Evans/ Geha

CABG might have been diluted by crossovers. Of the 373 patients assigned to medical treatment, 36% subsequently underwent CABG (i.e. crossed over to surgery). At the projected 5-year follow-up interval, there was a significantly higher survival in the group assigned to surgery compared to the group assigned to medical therapy alone (92 vs. 83%, respectively, p = 0.0001). At 12 years of follow-up, the survival advantage was still apparent (70.6 vs. 66.7%, respectively, p = 0.04), although the decrease in the percentage of survival among the surgically treated group was more rapid after the initial 5-year period of follow-up [7]. When patients were stratified into those who were low risk or high risk, i.e. elderly, had signs of ischemia or previous MI on ECG, markedly abnormal exercise testing, peripheral vascular disease or left anterior descending coronary artery (LAD) disease, the high-risk patients with three-vessel disease were found to benefit more from surgery compared to medical therapy. The Coronary Artery Surgery Study The CASS trial was a randomized trial of CABG versus medical therapy for patients with chronic stable angina and CAD [8]. Seven hundred and eighty patients were randomized, of whom 160 patients had an EF ! 50% but 135%. Among the exclusion criteria for that study was an EF !35%. At the 7-year follow-up, there was no significant difference in survival between the two intervention groups. When the subgroup of patients with low EF was examined, a significant survival advantage was noted in the surgical group. Survival was 84% in the CABG group and 70% in the medical group (p = 0.012). When low EF was combined with three-vessel CAD, survival was 88% in the surgical group and 65% in the medical group (p = 0.0094) [8]. That survival benefit was maintained up to 10 years of follow-up [9]. A similar survival benefit was noted in patients with low EF who had proximal LAD disease. The above four studies set a precedent for CABG as the preferred intervention for patients with three-vessel disease and low EF. It is important to note, however, that these studies were performed in the pre-PCI or early PCI era.

CABG versus PCI Trials

Several landmark trials examined the outcomes of CABG versus PCI in patients with multivessel CAD. These are the Arterial Revascularization Therapies Study (ARTS), the Argentine Randomized Study: Coronary Angioplasty with Stenting Versus Coronary Bypass Surgery

Coronary Bypass vs. Percutaneous Intervention

Table 1. Clinical trials of CABG versus PCI or medical therapy in patients with and without LV dysfunction

Early CABG versus medical therapy trials Veterans Administration Trial of CABG for Stable Angina (VA Trial) Veterans Administration Unstable Angina Cooperative Study (VA Study) European Coronary Surgery Study (EURO) Coronary Artery Surgery Study (CASS) CABG versus PCI trials Arterial Revascularization Therapies Study (ARTS) Argentine Randomized Study (ERACI II) Stent or Surgery (SoS) Trial Emory Angioplasty versus Surgery Trial (EAST) Bypass Angioplasty Revascularization Investigation (BARI) Coronary Angioplasty versus Bypass Revascularization Investigation (CABRI) First Randomized Intervention Treatment of Angina (RITA-1) Trial First German Angioplasty Bypass Investigation (GABI-1) Angina with Extremely Serious Operative Mortality Evaluation (AWESOME)

in Patients with Multiple-Vessel Disease (ERACI II), the Stent or Surgery (SoS) trial, the Emory Angioplasty versus Surgery Trial (EAST), the Bypass Angioplasty Revascularization Investigation (BARI) trial, the Randomized Intervention Trial of Angina (RITA), the German Angioplasty Bypass Investigation (GABI), and the Angina with Extremely Serious Operative Mortality Evaluation (AWESOME) trial (tables 1, 2). The Arterial Revascularization Therapies Study The ARTS was a randomized trial that compared the clinical outcomes and costs of PCI versus CABG [10]. In that trial, 1,205 patients were randomized; 600 patients were randomized to have PCI with stenting and 605 patients to have CABG. The patients were predominantly males with an average age of 61 years. Mean LVEF in that cohort was 60%, and 30% of the patients had three-vessel CAD. Among the exclusion criteria were an LVEF !30%, overt symptoms of CHF, history of a cerebrovascular accident (CVA) or transmural MI within 1 week of enrollment. The primary end points of the trial were freedom from major adverse cardiac and cerebrovascular events such as death, CVA, transient ischemic attack, reversible neurological deficits and nonfatal MI 1 year after the procedure. Other end points included cost effectiveness and quality of life. The study was well powered at 92%. Overall, there was no statistically significant difference be-

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Table 2. Demographics of patients enrolled

in clinical trials of CABG versus PCI or medical therapy in patients with and without LV dysfunction

Trial

Years conducted

Men %

VA Trial VA Study EURO CASS ARTS ERACI II SoS EAST BARI CABRI RITA-1 GABI-1 AWESOME

1972–1974 1976–1982 1973–1976 1975–1979 1997–1998 1996–1998 1996–1999 1987–1990 1988–1991 1988–1993 1988–1991 1986–1991 1995–2000

100 100 100 90 72 80 79 73 73 76 81 78 100

tween the two groups with respect to the incidence of death at 1 year (2.5% in the PCI group vs. 2.8% in the CABG group), CVA (1.7% in the PCI group vs. 2.1% in the CABG group) or MI (6.2% in the PCI group vs. 4.8% in the CABG group). Patients who underwent CABG had a significantly lower rate of repeat revascularizations [3.8% in the CABG group vs. 21% in the PCI group; relative risk 5.52, 95% confidence interval (CI) 3.59–8.49], and also had a higher event-free survival at 1 year (87.8% in the CABG group vs. 73.8% in the PCI group; relative risk of any event 2.14, 95% CI 1.66–2.75, p ! 0.001). In the short term, stenting was the more cost-effective strategy at 1 year (p ! 0.001) [10]. From that study, one might conclude that PCI and CABG offer comparable protection from death, CVA and MI up to 1 year after the procedure. Furthermore, CABG appeared to provide superior relief from angina whereas patients undergoing PCI were 5 times more likely to require repeat revascularizations within the first year after the intervention. Thus, the costeffectiveness of PCI might have diminished after 1 year. The Argentine Randomized Study The ERACI II was a randomized trial of 450 patients who underwent CABG or PCI between 1996 and 1998 [11]. The primary end points of the trial were a combination of death, Q-wave MI, CVA and the need for emergent or repeat revascularizations. Secondary end points were angina status, completeness of revascularization and associated costs. Among the exclusion criteria were single-vessel CAD, previous CABG, previous percutaneous transluminal coronary angioplasty (PTCA) or stenting within 1

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Mean age years 50s 56 !65 51 61 62 61 61 61 60 57 60 67

Patients

686 468 767 780 1,205 450 988 392 1,829 1,054 1,011 359 454

Follow-up years 11 8 12 10 1 1 3 3 5 1 5 1 5

year, LVEF ^35% and acute MI. There were no significant differences in the baseline characteristics between the two study groups. At 30 days, the CABG group had a significantly greater incidence of the primary end points (p = 0.002). This trend continued into the 1-year followup period, where the PCI group again displayed better survival (p ! 0.017) as well as greater freedom from MI (p ! 0.017). However, CABG patients did fare better in terms of the need for repeat revascularization (p ! 0.001) and freedom from angina (p = 0.01). Overall, there was no significant difference in costs between the two groups in the short term [11]. Recently, an additional retrospective analysis of a cohort of 230 patients from the ERACI II study with multivessel CAD and severe stenosis of the proximal LAD was published [12]. One hundred and thirteen patients were randomized to the PCI group, and 117 to the CABG group. The two groups were similar with respect to baseline characteristics. At 30 days, there were no significant differences with respect to the major adverse cardiovascular events (death, MI, repeat revascularization, CVA). At 6 months, CABG patients were shown to have a significantly lower rate of revascularization than those who underwent PCI. Freedom from revascularization was 97% for the CABG patients compared to 73% for those who had PCI (p = 0.0002). There were no significant differences in survival or MI incidence between the two groups. The investigators concluded that PCI in patients with multivessel CAD who had significant proximal LAD disease was associated with higher rates of future revascularization compared to CABG.

Caines/Massad/Kpodonu/Rebeiz/Evans/ Geha

The Stent or Surgery Trial The SoS trial was a randomized trial of 988 patients that aimed to compare PCI with stenting versus CABG in patients with multivessel CAD [13]. In that study, 500 patients were randomized to CABG and 488 patients to PCI. The majority of the study cohort were men (80%), approximately 62 years of age, and 24% of them presented with an acute coronary syndrome. Mean LVEF was 57%. Forty-two percent of the patients had three-vessel CAD. Seventy-eight percent of the PCI procedures were undertaken with stent placement. In the CABG group, the mean number of bypass grafts per patient was 2.8. The major end point of the study was the need for repeat revascularization. At the 2-year follow up, a higher proportion of PCI patients required revascularization compared to patients who had CABG (21 vs. 6%, p ! 0.0001). There were no significant differences in the hazard ratios for death or non-Q-wave MI between the two groups, although there did appear to be a survival advantage with CABG over PCI (p = 0.01). The SoS trial investigators suggested that this latter observation might have been partially due to the favorable surgical risk profile of their patient population [13]. However, it is difficult to dismiss these disparities in mortality given that the study was a well-designed randomized trial. The Emory Angioplasty versus Surgery Trial EAST was a single-center study that randomized 392 patients to CABG or PTCA between 1987 and 1990 [14]. This cohort was predominantly male, aged in their sixties, with an EF of about 60%. The primary end points were adverse events such as death, MI or large ischemic defect. At the 8-year follow-up, there was no significant difference in survival between the two groups (CABG 82.7%, PTCA 79.3%, p = 0.40). Patients in the CABG group with diabetes and LAD disease had a tendency to have better late survival than their peers in the PTCA group, although this result was not statistically significant [14]. The Bypass Angioplasty Revascularization Investigation Trial The BARI trial was a large study that randomized 1,829 patients with multivessel CAD and severe angina or ischemia to CABG or PTCA between 1988 and 1991 [15]. At 5 years, the cardiac mortality rate was 8% in the PTCA group versus 4.9% in the CABG group (relative risk 1.55, 95% CI 1.07–2.23, p = 0.022). The two groups had comparable event rates for the combined end point of cardiac death and MI. However, contrary to the previous studies, when the subgroups of diabetic patients, patients with

Coronary Bypass vs. Percutaneous Intervention

normal or impaired LV function, and patients with singlevessel or multivessel CAD were examined, there were no significant differences in cardiac mortality between the two intervention groups [15]. To summarize, the studies discussed above generally agree that patients with multivessel CAD with relatively normal LVEF may be treated effectively by either contemporary PCI or CABG. Those who undergo PCI appear more prone to repeat revascularization. However, although these trials were well planned and executed, they are not without their limitations. One shortcoming that ARTS, ERACI II and the SoS trials all share is that they predominantly involved patients with normal LVEF and had a short follow-up period of 1–2 years. The Coronary Angioplasty versus Bypass Revascularization Investigation The Coronary Angioplasty versus Bypass Revascularization Investigation (CABRI) was a multinational, multicenter European randomized trial comparing revascularization by CABG and PCI in patients with symptomatic multivessel CAD [16, 17]. The study recruited 1,054 patients (820 men and 234 women) from 26 centers. The average age was 60 years, and 62% presented with angina of class 3 or greater. Of the 1,054 patients randomized, 513 were assigned to CABG and 541 to PCI. Of those randomized, 93 and 96%, respectively, were allocated. Data were analyzed by intention to treat and document all deaths, major cardiac events and the symptom status of the patients 1 year after randomization. At 1 year of follow-up, 2.7% of those randomized to CABG and 3.9% of those randomized to PCI had died. Patients randomized to PCI required significantly more reinterventions; only 66.4% reached 1 year with a single revascularization procedure, compared with 93.5% of the patients randomized to CABG (p ! 0.001). The patients in the PCI group took significantly more medications at 1 year. They were also more likely to have clinically significant angina. Interestingly, this latter association was present in both sexes but was significant only in females. The CABRI trial results were consistent with the previous studies comparing CABG to PCI. In 1995, Sim et al. [18] performed a meta-analysis of 5 randomized trials comparing CABG to PCI. The metaanalysis included the ERACI trial, EAST, CABRI, the first RITA trial (RITA-1) and the first GABI (GABI-1) [19, 20]. These trials primarily included patients with normal or subnormal EF. The overall risks of death and nonfatal MI over a follow-up of 1–3 years were not different between the groups randomized to CABG or PCI. Pa-

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tients randomized to CABG tended to have a higher risk of death or MI in the early periprocedural period, but a lower risk in subsequent follow-up. CABG patients were much less likely to undergo another revascularization procedure and were more likely to be free of angina [18]. The Angina with Extremely Serious Operative Mortality Evaluation Trial The only prospective multicenter randomized trial published to date that compared PCI and CABG in a high-risk patient population was the AWESOME trial [21]. That 5-year randomized study was conducted at 16 VA hospitals. Patients were selected based on the presence of one or more risk factors for adverse outcome with CABG, including prior open-heart surgery, age 170 years, LVEF !35%, MI within 7 days, or use of an intra-aortic balloon pump. The primary end point was survival. In that trial, 232 patients were randomized to CABG and 222 patients to PCI. Of the CABG patients, 73.2% received internal mammary artery grafts, and 2.9% received radial artery grafts. Within the PCI group, stents were used increasingly from a rate of 26% in 1995 to 88% in 1999/2000, as were glycoprotein IIb/IIIa receptor blocking agents (1% in 1995, 51% in 1999/2000). The inpatient mortality was 4% for the patients who had CABG and 1% for those who had PCI. The 30-day mortality was 5% for CABG patients and 3% for PCI patients. The survival rates for CABG and PCI were 90 and 94% at 6 months, and 79 and 80% at 36 months (log rank test, p = 0.46). Patients in the CABG group had significantly less angina than those in the PCI group (p = 0.001) [21]. The trial was limited by its low statistical power and its male patient cohort. In addition, important determinants of successful revascularization such as postprocedure MI and graft patency rates were not considered. Valid conclusions that one might draw from that investigation are that patients with one or two high risk factors for MI do have comparable 3-year survival rates with both CABG and PCI, but have less freedom from angina with PCI.

Recent Clinical Series in Patients with Ventricular Dysfunction

A recent study by Keelan et al. [22] attempted to address the issue of whether new advances in interventional cardiology have decreased the risk of PCI in patients with significantly impaired LV function. That retrospective study looked at in-hospital and 1-year outcomes among 1,158 patients with EFs ranging from !40

26

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to 50% who underwent PCI. Patients with acute MI were excluded from that study. Composite end points included death, need for CABG, death/MI and death/MI/CABG. Patients were stratified into three groups: EF !40% (14%), EF 41–49% (11%), and EF 650% (75%). There were many significant differences in the baseline characteristics between the three groups. Lower EFs were more positively associated with diabetes mellitus, CHF and other comorbidities. Three-vessel CAD and total occlusion of one or more coronary arteries or grafts were also more prevalent in patients with EFs !40%. Stents were used in approximately 59–74% of the patients in each of the three EF groups. In terms of adverse in-hospital outcomes, the end points of death and death/MI were more common in patients with EF !40% (95% CIs 2.29–10.97 and 1.21–3.32, respectively). That group also had longer hospital stays. In-hospital mortality was 3% in the group with EF !40%, 1.6% in the group with EF 41–49%, and 0.1% in the group with EF 650% (p ! 0.001). At 1 year, patients with EF !40% again had the worst outcomes for death (p ! 0.001) and death/MI (p = 0.024) [22]. In 2002, Li et al. [23] published the results of a retrospective series of 74 patients with LVEF ^40% who underwent PCI. Forty-six percent of these patients were stented. Patients with acute MI within 3 weeks of the onset of the study or left main CAD were excluded. In that cohort, 86% of the patients had a prior MI, 74% had multivessel CAD (45% had three-vessel disease), 58% had angina and 61% had symptoms of CHF. The mean LVEF was 30%. The investigators noted that the procedures were performed from 1990 to 1997 and that stenting was not attempted routinely at their institution until January 1993. Prior to December 1995, patients who received stents were also treated with aspirin, dipyridamole, dextran, heparin and warfarin. After that time, high-pressure dilatation was introduced and only aspirin and ticlopidine were used. Clinical success, defined as angiographic success in a minimum of 1 vessel, symptomatic improvement and the absence of MI, rescue CABG or death, was achieved in 89.2% of the patients upon review of the immediate results. Procedure-related complications, including death and MI, occurred in 2.7% of the patients. PCI-related mortality was 1.4%. The positive effects of the intervention continued to be apparent at long-term follow-up (mean 29 months, range 6–96 months). Among the successfully treated patients, there was an improvement in NYHA functional class from an average of approximately 1.9 prior to the procedure to 1.5 afterwards (p ! 0.01). The 4-year survival was 81%. More importantly, at an average of 29 months, 23.5% of the

Caines/Massad/Kpodonu/Rebeiz/Evans/ Geha

patients who received stents suffered cardiac events (3 cardiac deaths, 1 fatal ischemic CVA) and 3% underwent repeat PTCA [23]. The generalizability of that study was limited by the size of the cohort, which weakened the power of the study, as well as the lack of gender diversity (95% male) and also presumably ethnic diversity of the group. The results of that study did, however, support the contention that patients with severe LV dysfunction may be stented successfully with low periprocedural mortality using contemporary interventional techniques. Toda et al. [2] recently published a retrospective analysis that looked at a cohort of 117 patients with severe LV dysfunction (LVEF 15–30%) who underwent CABG or PCI between 1992 and 1997. Fifty-nine percent of the patients underwent CABG and 41% underwent PCI. Patients were excluded from the study if they underwent emergency CABG within 6 h after failed PCI or if they had PCI because of cardiogenic shock post-MI. CABG and PCI patients were similar in terms of comorbidities. The mean EF for both groups was 24%. A higher percentage of patients who underwent CABG had NYHA class III/IV CHF symptoms (p = 0.117), as well as a greater extent of CAD (p = 0.0003). A greater proportion of PCI patients had had previous revascularizations. Sixty-seven percent of the patients undergoing PCI were stented. The results showed that CABG achieved more complete revascularization overall. There were no significant differences in mortality and morbidity at the 30-day follow-up. At 1 year, there was no significant change in EF in the PCI group, but there was an improvement in the mean EF from approximately 25 to 37% in the CABG group (p ! 0.001). At 3 years, cardiac event-free survival was 52% among CABG patients and 25% among PCI patients (p = 0.0011). The rate of target vessel revascularization was higher in the PCI group at 3 years (p ! 0.0001). Survival was not significantly different at 3 years. When adjusted hazard ratios were compared, CABG patients younger than 65 years and those with significant proximal LAD lesions had significantly higher freedom from death and cardiac events compared with PCI patients. That study was limited by its nonrandomized nature as well as by the baseline differences within the cohort, beside the fact that it excluded patients who acutely failed PCI and were salvaged by CABG. The results of that study indicated that patients with poor EF (15–30%) received a more complete revascularization, and had improved EF and a decreased rate of cardiac events and target vessel revascularization with CABG, although there was no survival benefit. Given the small number of patients, no meaningful conclusion could be made about long-term survival.

Table 3. Conclusions of the clinical trials of CABG versus PCI and medical therapy in patients with multivessel disease and LV dysfunction

Coronary Bypass vs. Percutaneous Intervention

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Survival advantage with CABG compared to PCI or medical therapy alone in patients with low EFs More freedom from angina symptoms and heart events with CABG More complete revascularization with CABG More need for revascularization with PCI More periprocedural morbidity with CABG PCI more cost-effective within the first year after intervention PCI less cost-effective after 1 year of intervention because of need for repeat interventions

Table 4. Limitations of some of the clinical trials of CABG versus PCI and medical therapy in patients with multivessel disease and LV dysfunction

Lack of recent large multicenter, prospective, randomized, blinded trials Short follow-ups for most PCI trials and some CABG trials Most recent studies are weakly powered because of small numbers Lack of gender diversity in some studies Exclusion of patients who acutely failed PCI and were salvaged with CABG Crossovers from medical therapy or PCI to CABG were excluded in some trials Vein grafts have lower patency rates compared to currently used arterial conduits Some PCIs were PTCA without stenting Newer drug-eluting stents were not available at the time of the studies

The authors suggest that incomplete revascularization by PCI may prolong intermediate survival to the same extent as CABG, although these patients will likely require repeated interventions [2].

Conclusions

Most of the PCI trials discussed above were weakly powered, with short periods of follow-up. They do support the contention that PCI can be successfully performed in patients with low LVEF with relatively low mortality, but that CABG may result in improved EF and greater freedom from repeat revascularization (tables 3, 4). It is unclear whether there is a significant survival benefit with PCI in this patient population as compared to medical therapy alone, or if any improvement in EF or NYHA functional class can be expected in the long

27

term. In order to elucidate the proper role of CABG and PCI in patients with CAD and poor LVEF, additional studies, including long-term prospective randomized control trials, are needed. Regardless of what we may be able to achieve through percutaneous intervention in the future, it is likely that there will always be a role for some type of surgical intervention, particularly in patients with LV dysfunction. At this point in time, we have few better options for correc-

tion of left main disease or ostial and bifurcated lesions. Future studies should take into account the new methods for coronary bypass including the liberal use of multiple arterial conduits and minimally invasive and off-pump beating heart procedures for CABG, and should also factor in the latest innovations in PCI such as paclitaxel- and sirolimus-coated stents. Such studies will provide an important framework for treatment protocols involving patients with poor LVEF in the future.

References 1 Kurki TS, Kataja M: Preoperative prediction of postoperative morbidity in coronary artery bypass grafting. Ann Thorac Surg 1996;61: 1740–1745. 2 Toda K, Mackenzie K, Mehra M, DiCorte C, Davis J, McFadden M, Ochsner J, White C, Van Meter C Jr: Revascularization in severe ventricular dysfunction (15% ^ LVEF ^ 30%): A comparison of bypass grafting and percutaneous intervention. Ann Thorac Surg 2002;74:2082–2087. 3 Poyen V, Silvestri M, Labrunie P, Valeix B: Indications of coronary angioplasty and stenting in 2003: What is left to surgery? J Cardiovasc Surg (Torino) 2003;44:307–312. 4 Eleven-year survival in the Veterans Administration Randomized Trial of Coronary Bypass Surgery for Stable Angina. The Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group. N Engl J Med 1984; 311:1333–1339. 5 Sharma GV, Deupree RH, Khuri SF, Parisi AF, Luchi RJ, Scott SM: Coronary bypass surgery improves survival in high-risk unstable angina. Results of a Veterans Administration Cooperative Study with an 8-year follow-up. Veterans Administration Unstable Angina Cooperative Study Group. Circulation 1991; 84(5 suppl):III260–III267. 6 Long-term results of prospective randomised study of coronary artery bypass surgery in stable angina pectoris. European Coronary Surgery Study Group. Lancet 1982;ii:1173–1180. 7 Varnauskas E, and The European Coronary Surgery Study Group: Twelve-year follow-up of survival in the randomized European Coronary Surgery Study. N Engl J Med 1988;319: 332–337. 8 Killip T, Passamani E, Davis K, CASS Principal Investigators and Their Associates: Coronary Artery Surgery Study (CASS): A randomized trial of coronary bypass surgery. Eight years follow-up and survival in patients with reduced ejection fraction. Circulation 1985;72: V102–V109. 9 Chaitman BR, Ryan TJ, Kronmal RA, Foster ED, Frommer PL, Killip R, CASS Investigators: Coronary Artery Surgery Study (CASS): Comparability of 10-year survival in randomized and randomizable patients. J Am Coll Cardiol 1990;16:1071–1078.

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10 Serruys P, Unger F, Sousa JE, Jatene A, Bonnier H, Schonberger J, Buller N, Bonser R, van den Brand M, van Herwerden L, Morel M, van Hout B: Comparison of coronary artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med 2001;344:1117– 1124. 11 Rodriguez A, Bernardi V, Navia J, Baldi J, Grinfield L, Martinez J, Vogel D, Grinfield R, Delacasa A, Garrido M, Oliveri R, Mele E, Palacios I, O’Neill W: Argentine Randomized Study: Coronary Angioplasty with Stenting versus Coronary Bypass Surgery in patients with Multiple-Vessel Disease (ERACI II): 30day and one-year follow-up results. ERACI II Investigators. J Am Coll Cardiol 2001;37:51– 58. 12 Rodriguez A, Baldi J, Navia J, Delcasa A, Vogel D, Oliveri R, Fernandez P, Bernardi V, O’Neill W, Palacios I: Coronary stenting versus coronary bypass surgery in patients with multiple vessel disease and significant proximal LAD stenosis: Results from the ERACI II study. Heart 2003;89:184–188. 13 SoS Investigators: Coronary artery bypass surgery versus percutaneous coronary intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): A randomized controlled trial. Lancet 2002;360:965–970. 14 King SB III, Kosinski AS, Guyton RA, Lembo NJ, Weintraub WS: Eight-year mortality in the Emory Angioplasty Versus Surgery Trial (EAST). J Am Coll Cardiol 2000;35:1116– 1121. 15 Chaitman BR, Rosen AD, Williams DO, Bourassa MG, Aguirre FV, Pitt B, Rautaharju P, Rogers WJ, Sharaf B, Attubato M, Hardison RM, Srivatsa S, Kouchoukos NT, Stocke K, Sopko G, Detre K, Frye R: Myocardial infarction and cardiac mortality in the Bypass Angioplasty Revascularization Investigation (BARI) randomized trial. Circulation 1997;96:2162– 2170. 16 First-year results of CABRI (Coronary Angioplasty versus Bypass Revascularization Investigation). CABRI Trial Participants. Lancet 1995;346:1179–1184. 17 Wahrborg P on behalf of the CABRI Trialists: Quality of life after coronary angioplasty or bypass surgery: 1-year follow up in the Coro-

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nary Angioplasty versus Bypass Revascularization Investigation (CABRI) trial. Eur Heart J 1999;20:653–658. Sim I, Gupta M, McDonald K, Bourassa MG, Hlatky MA: A meta-analysis of randomized trials comparing coronary artery bypass grafting with percutaneous trans-luminal coronary angioplasty in multi-vessel coronary artery disease. Am J Cardiol 1995;76:1025–1029. Henderson RA, Pocock SJ, Sharp SJ, Nanchahal K, Sculpher MJ, Buxton MJ, Hampton JR , for the Randomized Intervention Treatment of Angina (RITA-1) trial participants: Long-term results of RITA-1 trial: Clinical and cost comparisons of coronary angioplasty and coronary artery bypass grafting. Lancet 1998;352:1419– 1425. Hamm CW, Remers J, Ischinger T, Rupprecht HJ, Berger J, Bleifeld W: German Angioplasty Bypass Surgery Investigation (GABI). A randomized study of coronary angioplasty compared with bypass surgery in patients with symptomatic multivessel coronary disease. N Engl J Med 1994;331:1044–1050. Morrison DA, Sethi G, Sacks J, Henderson W, Grover F, Sedlis S, Esposito R, Ramanathan K, Weiman D, Saucedo J, Antakli T, Paramesh V, Pett S, Vernon S, Birjiniuk V, Welt F, Krucoff M, Wolfe W, Lucke JC, Mediratta S, Booth D, Barbiere C, Lewis D: Percutaneous coronary intervention versus coronary artery bypass graft surgery for patients with medically refractory myocardial ischemia and risk factors for adverse outcomes with bypass: A multicenter, randomized trial. Investigators of the Department of Veterans Affairs Cooperative Study #385, the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME). J Am Coll Cardiol 2001;38:143–149. Keelan PC, Johnston JM, Koru-Sengul T, Detre K, Williams DO, Slater J, Block PC, Holmes DR Jr, Dynamic Registry Investigators: Comparison of in-hospital and one-year outcomes in patients with left ventricular ejection fractions ^40%, 41–49%, and 650% having percutaneous coronary revascularization. Am J Cardiol 2003;91:1168–1172. Li C, Jia G, Guo W, Li W: Stent supported coronary angioplasty in patients with severe ventricular dysfunction. Chin Med J (Engl) 2002; 115:355–358.

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Cardiology 2004;101:29–36 DOI: 10.1159/000075983

Revascularization Options for Ischemic Cardiomyopathy: On-Pump and Off-Pump Coronary Artery Bypass Surgery Kamal R. Khabbaz a David DeNofrio b Marwan Kazimi a Philip A. Carpino a Divisions of a Cardiothoracic Surgery and b Cardiology, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Mass., USA

Key Words Cardiomyopathy W Heart failure W Coronary artery bypass surgery W Beating heart surgery

Abstract Patients with ischemic cardiomyopathy and markedly reduced left ventricular (LV) function should be evaluated for coronary artery bypass surgery (CABG) before other surgical options are considered. The success of surgery depends on the presence of viable myocardium and target coronary arteries of acceptable quality. Longterm survival in this setting may be comparable to that with cardiac transplantation. Off-pump CABG can be safely and reproducibly performed in patients with diminished LV function. Off-pump beating heart surgery may provide additional benefits to these patients by reducing some of the complications that are associated with cardiopulmonary bypass.

cal revascularization. There is growing evidence that coronary artery bypass surgery (CABG) in this population of patients offers a survival benefit over medical therapy [1– 3]. Long-term survival following CABG in this subgroup of patients with depressed LV function may be comparable to that seen with cardiac transplantation [1, 4]. A satisfactory outcome hinges on the quality of the target vessels, the presence of ‘viable’ myocardium in the territory of bypassed vessels and the absence of significant associated comorbidities. Off-pump beating heart surgery has emerged as yet another option in the revascularization of the severely depressed left ventricle [5]. Recent evidence indicates that some of the associated morbidities encountered with the on-pump arrested heart technique may be reduced with beating heart surgery [5–7].

Myocardial Viability Assessment in Patients with LV Dysfunction

Copyright © 2004 S. Karger AG, Basel

Introduction

Cardiac surgeons are increasingly faced with the challenge of evaluating patients with ischemic cardiomyopathy and severe left ventricular (LV) dysfunction for surgi-

ABC

© 2004 S. Karger AG, Basel 0008–6312/04/1013–0029$21.00/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/crd

Myocardial ‘Stunning’ and ‘Hibernation’ Myocardial dysfunction in patients with coronary artery disease is usually due to impaired blood flow to the myocardium, resulting in an imbalance between oxygen supply and metabolic demand of the cardiac tissue. This supply and demand imbalance leads to myocardial stunning, hibernation and/or scarring and results in progres-

Kamal R. Khabbaz, MD Division of Cardiothoracic Surgery, Tufts-NEMC 750 Washington Street Boston, MA 02111 (USA) Tel. +1 617 636 8736, Fax +1 617 636 7616, E-Mail [email protected]

sive LV dysfunction and ultimately heart failure [8, 9]. Prolonged absence of blood flow due to an acute coronary thrombosis may result in irreversible damage to myocardial tissue causing infarction and scar formation. The extent of the infarcted tissue is often a function of the size of the myocardium at risk, the degree of collaterals and the time of ischemia. Myocardial stunning is defined as persistent cardiac dysfunction despite restoration of normal blood flow following a short episode of ischemia [9]. Myocardial stunning has been frequently observed in patients with acute ischemia who undergo reperfusion therapy with thrombolytic agents or angioplasty to restore a normal or near normal coronary perfusion. The return to normal contractile function after stunning occurs in days to weeks following ischemia. Hibernating myocardium results from a chronic imbalance of the myocardial oxygen supply and demand relationship and results in impaired contractility. Impaired myocardial contractility may function to limit the metabolic requirements of the myocardial tissue as an adaptive mechanism to prevent worsening of the ischemic injury [10]. In hibernation, recovery of contractility after revascularization can take months in contrast to days and weeks with myocardial stunning. Numerous studies over the last decade have demonstrated that LV dysfunction secondary to myocardial stunning and hibernation can be a reversible phenomenon following coronary revascularization [11, 12]. Therefore, it is important that the selection of patients who have coronary artery disease and LV dysfunction for surgical revascularization is based on the presence of viable myocardium. Evaluation of Myocardial Viability Several of the methods that provide evidence of myocardial viability have a great value in predicting recovery of the LV function following surgical revascularization. The techniques employed for the detection of viable myocardium usually provide confirmation of preserved metabolic activity, cell membrane integrity or contractile reserve in dysfunctional regions [13–15]. Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose (FDG) imaging has long been considered the gold standard for the assessment of myocardial viability. FDG PET has a sensitivity and specificity of approximately 90 and 70%, respectively. The major limitations of this technique are its high cost and limited availability. Myocardial perfusion and the integrity of cell membranes can be assessed with quantitative single photon emission tomography (SPECT) with thallium-201, technetium-99m sestamibi or technetium-99m tetrofosmin imaging. These

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nuclear imaging techniques have a sensitivity and specificity for detecting viable myocardium similar to that of FDG PET. In general, the disadvantages of SPECT include low spatial resolution, poor image quality in obese patients and attenuation artifacts. More recently, dobutamine stress echocardiography (DSE) has emerged as an important diagnostic method for the detection of viable myocardium. This technique utilizes a combination of low- and high-dose dobutamine infusion. A biphasic response (increased contractility at low doses and decreased at high doses) is considered most predictive of myocardial recovery after revascularization. DSE has a lower sensitivity than PET or SPECT but a higher specificity and greater positive predictive value with respect to improved wall motion and LV ejection fraction (LVEF) following revascularization. The choice between PET, SPECT or DSE imaging often reflects the availability of the technique in an individual institution and the comfort level with interpretation of the study. The implications of distinguishing viable from nonviable myocardium are important in determining which patients may benefit from coronary revascularization. To date, no prospective randomized trial has been completed that examines this question. Allman et al. [16] undertook a meta-analysis pooling 24 studies with a total of 3,088 patients to examine the survival of patients with coronary artery disease and LV dysfunction who underwent revascularization with prior testing for viability. The pooled analysis demonstrated an increased annual mortality rate of 16% in the medically treated group compared to 3.2% in the revascularized group (p ! 0.0001), with a 79.6% relative risk reduction. In the revascularized group, there was a lower annual mortality of 3.2% in patients with viable myocardium compared to 7.7% in the group with no viability. Medical treatment demonstrated a higher annual mortality of 16% in the group with viable myocardium compared to 6.2% in the group with nonviable myocardium. This analysis suggests that viable myocardium may represent an unstable substrate leading to improvement in survival with revascularization. The Surgical Treatment of Ischemic Heart Failure trial began enrollment in 2002 and will provide much needed prospective clinical data that will help determine the actual benefit of revascularization in this high-risk patient population. Although prospective randomized data are not yet available, patients with coronary artery disease and LV dysfunction with significant myocardial viability should be strongly considered for coronary revascularization.

Khabbaz/DeNofrio/Kazimi/Carpino

Table 1. Survival statistics from 5 different series investigating on-pump CABG in patients with reduced LVEF

Report

Year

Patients

Pigott et al. [18] Kron et al. [2] Elefteriades et al. [1] Hausmann et al. [4] Mickleborough et al. [3]

1985 1989 1997 1997 2000

77 39 125 514 125

On-Pump CABG in Patients with Depressed LV Function

LVEF range % 15–35 10–20 10–30 10–30 !20

Operative Survival mortality, % % 1.3 2.6 5.2 7.1 4.0

76 (5-year) 83 (3-year) 71 (5-year) 78.9 (6-year) 72 (5-year)

Although there is no strict agreement as to what constitutes a ‘poor ventricle’, most reports have addressed patients with an LVEF of less than 35%. The ideal surgical candidate for revascularization in the setting of severely reduced function is the patient with documented myocardial viability in the distribution of good-quality target vessels with proximal discrete stenoses. Cardiac transplantation or other surgical therapies discussed in this issue may be considered if the patient has predominance of myocardial scarring, severely depressed right ventricular function, markedly elevated LV end diastolic pressures or poor-quality ungraftable coronary arteries. Previous cardiac surgery may also be a relative contraindication. An early series on medical versus surgical therapy for end-stage coronary artery disease reported by Alderman et al. [17] demonstrated a 5-year survival rate of 41% for the medically treated group and a corresponding 5-year survival rate of 62% for the surgical group. Since that time, improvements in anesthetic and surgical management as well as postoperative intensive care have made it possible for patients with LV dysfunction to undergo CABG with acceptable risk and clear benefit. In the past decade, both observational and prospective randomized trials have conclusively shown that these ‘high-risk’ patients who undergo CABG can expect not only a better long-term survival compared to those treated with medicine alone, but also improvement in ventricular function, angina status and congestive heart failure symptoms. Multiple groups have reported their experience with CABG in patients with LVEF less than 35% (table 1). In 1985, Pigott et al. [18] reported on 192 patients with coronary artery disease and depressed LVEF; 77 had CABG and 115 had medical therapy alone. LV volumes and

LVEF were calculated by biplane ventriculography. Seven-year actuarial survival was 63% in the surgical group and 34% in the medical group. Survival free of myocardial infarction at 7 years in the two groups was 62 and 33%, respectively (p ! 0.001). For the subset of patients with an LVEF of 25% or less, the 7-year survival rates were 46 and 15%, respectively (p ! 0.001). The authors concluded that if CABG can be accomplished with an operative risk of less than 5% in cases of depressed LV function, survival and freedom from nonfatal myocardial infarction are enhanced. Elefteriades et al. [1] published their surgical results for CABG in patients with an LVEF !30%. First presented in 1993 and updated in 1997 [1], the findings of the Yale group regarded analysis of 135 consecutive patients over an 8-year period. LVEF, determined preoperatively by either contrast angiography or radionuclide ventriculography, ranged from 10 to 30% with a mean of 23.6%. The overall operative mortality was 5.2%, and survival was 87, 81 and 71% at 1, 3 and 4.5 years, respectively. The authors concluded that CABG should be encouraged in ischemic patients with advanced LV dysfunction and may provide a viable alternative to cardiac transplantation in a selected subgroup. Kron et al. [2] described their results with 39 patients with a preoperative LVEF !20% who underwent CABG between 1983 and 1989. The mean preoperative EF was 18% (range 10–20%). There was 1 operative death and 8 late deaths (a total mortality rate of 21%). Seven of the deaths were due to arrhythmias. Three patients continued to have severe heart failure symptoms, one of whom underwent successful cardiac transplantation. By life table analysis, the 3-year survival rate was 83%. Mickleborough et al. [3] from the University of Toronto presented their experience with 125 patients with LVEF !20%. Forgoing preoperative viability studies in favor of more liberal selection criteria, the group instead

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focused on optimizing myocardial protection, as advocated by Kaul et al. [19]. Results in this group of patients who underwent CABG with temperature mapping were then compared to a case-controlled group of patients who were operated on by various cooling methods but without temperature mapping. The operative mortality in this high-risk group of patients was 4% in the study patients and 11% in the controls (p = 0.03). The incidence of perioperative complications including myocardial infarction, stroke, reoperation for bleeding and sternal infection was not significantly different between the two groups. The authors concluded that patients with graftable coronary disease, poor LV function and akinetic or dyskinetic regions of the ventricle may benefit from surgery even without preoperative ventriculography. In an attempt to identify differential indications for CABG versus cardiac transplantation, Hausmann et al. [4] in Berlin studied patients with end-stage ischemic cardiomyopathy and LVEF between 10 and 30% who underwent CABG. The 225 study patients had been referred as possible cardiac transplant candidates. The major criteria for bypass grafting at their institution was ischemia diagnosed by myocardial thallium scintigraphy and echocardiography – the so-called ‘hibernating myocardium’ [20]. The operative mortality for the Berlin group was 7.1%, with an actuarial survival of 90.8% at 2 years, 87.6% at 4 years and 78.9% at 6 years. During the same time period, 231 patients with end-stage coronary artery disease and a mean LVEF of 21% underwent orthotopic heart transplantation. The operative mortality in the transplant group was 18.2%, and the actuarial survival at 6 years was 68.9%. Significant causes of early death in the transplant group were infection (40.5%) and early rejection (26.2%). Among their observations, the authors noted that an area of 20% or more of the total heart mass defined as viable by preoperative testing portends promising results after CABG.

Beating Heart CABG in Patients with Depressed LV Function

CABG has traditionally been performed using cardiopulmonary bypass on an arrested heart. It has been thought that cardiac arrest is needed to afford the surgeon full exposure of the coronary circulation and a bloodless and motionless field for the construction of the delicate vascular anastomoses. The period of aortic cross-clamping and cardioplegic arrest may be deleterious to the myocardium by creating an environment of global ischemia.

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Multiple myocardial protection techniques and additives have been proposed to reduce the risk of ischemia during the period of aortic cross-clamping. In the patient with reduced ventricular function and minimal myocardial reserve, the issue of myocardial protection becomes even more important. Furthermore, avoidance of cardiac arrest and global ischemia may be beneficial in the patient with a ‘poor ventricle’ who undergoes surgical revascularization. Technical Considerations in Off-Pump Surgery Off-pump beating heart CABG is typically performed by total avoidance of cardiopulmonary bypass and aortic cross-clamping. In some instances, beating heart CABG could also be performed on a beating heart that is supported by cardiopulmonary bypass to decompress its chambers. Multiple exposure devices and stabilizing platforms have been developed to allow the cardiac surgeon to reconstruct the coronary circulation while the heart is beating. For most multivessel procedures, the operation is performed through a median sternotomy with the patient in the Trendelenburg position and tilted to the right. The right pleural space is opened to allow rightward displacement of the heart. The apex of the heart is also displaced cephalad by using an apical suction device or by placing deep pericardial sutures for traction (fig. 1). The role of the anesthesiologist in the hemodynamic monitoring and management of these cases cannot be overemphasized. Continuous cardiac output and mixed venous monitoring is very important in such cases and so is the judicious use of fluids, pressors and inotropes. With such maneuvers, exposure of the entire coronary circulation is usually possible. The coronary artery to be grafted is either shunted or is temporarily occluded and stabilized with an arm that is attached to the sternal retractor (fig. 1). Visualization is enhanced by blowing a fine jet of misted carbon dioxide that clears the anastomotic field. Benefits of Off-Pump Surgery The benefits of off-pump beating heart CABG have been extensively investigated in the surgical literature. Most reports comparing the off-pump and on-pump techniques have done so in a retrospective, nonrandomized fashion. There are a number of prospective trials that have been reported, but those generally represent relatively small cohorts [5, 21, 22]. However, off-pump CABG has never been shown to carry a higher risk than on-pump CABG. An early mortality benefit has been documented in a number of comparisons; most notable among them are the analysis of the Society of Thoracic Surgeons’ data-

Khabbaz/DeNofrio/Kazimi/Carpino

Fig. 1. Off-pump CABG. Posterior descending artery being grafted on the inferior wall of the heart. The heart is eviscerated from the pericardial space, the apex pointing cephalad. A stabilizer with vessel loop control of the coronary artery is also seen.

base by Cleveland et al. [23] and the report by Mack et al. [6]. Transfusion requirements, blood loss and reoperation for bleeding as well as postoperative neurocognitive impairment may all be reduced with the off-pump technique [7, 24–27]. There is also a reduced incidence of perioperative myocardial injury and infarction with off-pump surgery as assessed by cardiac enzyme elevation postoperatively [5, 22]. This may be related to the avoidance of prolonged global myocardial ischemia seen with on-pump surgery. In some studies, graft patency was not shown to be reduced with the off-pump technique [5, 28, 29], whereas the incidence of renal dysfunction was reduced [7, 24, 25]. Off-Pump CABG in Patients with a ‘Poor Ventricle’ The adoption of off-pump CABG for revascularization in patients with reduced LV function has been slow. However, in centers with experience in off-pump or beating heart surgery, favorable results in this population of patients have emerged. Arom et al. [30] showed that offpump CABG in patients with LVEF !30% was ‘appropriate and applicable’. However, when that group of 45 patients was compared to 177 patients who were operated on using conventional on-pump CABG, perioperative blood loss and peak cardiac enzyme leak were less in the

off-pump cohort. Operative mortality was lower in the off-pump group, but that did not reach statistical significance. That study showed no noted benefit to the onpump technique in this group of patients. A report by Meharwal and Trehan [31] showed a non-statistically significant reduction in mortality for patients with LVEF !30% operated on using the off-pump method. The incidence of postoperative atrial fibrillation, the length of stay and the postoperative ventilation time were lower in the off-pump group. Shennib et al. [32] documented the feasibility of off-pump surgery in patients with poor LV function (EF !35%). When off-pump patients were compared to on-pump patients, there was a trend towards a reduction in mortality in the off-pump group. Again, perioperative complications were not increased in the off-pump group. A recent report by Dewey et al. [33] from Dallas showed an early survival benefit in multivessel CABG patients with poor LV function. In that series, 204 offpump patients with LVEF !30% were compared to 715 on-pump patients who had a lower predicted risk. The offpump group had a lower operative mortality (2.9 vs. 6.4%, p = 0.05), a significantly lower incidence of reoperation for bleeding, less blood product usage and decreased postoperative ventilator time as well as fewer days in the

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33

intensive care unit. The use of cardiopulmonary bypass in that study was an independent risk factor for mortality by logistic regression analysis. The authors concluded that avoidance of cardiopulmonary bypass in patients with severe LV dysfunction improves early survival.

The Tufts-New England Medical Center Off-Pump CABG Experience

Fig. 2. Distribution by LVEF of 511 Tufts-New England Medical

Center patients who underwent off-pump CABG. Ninety-two patients had EFs less than 35%.

We review the first 511 consecutive off-pump CABG procedures that were performed at our institution between October 1999 and July 2001 (table 2). The demographics of the patients were similar to most of those reported elsewhere. The mean age in this group of patients was 66 years. The mean LVEF was 50%. Figure 2 shows the breakdown of the patients by LVEF. Ninety-two patients (18%) had LVEF !35%, of whom 60 patients

Table 2. Demographics and preoperative risk factors of the TuftsNew England Medical Center off-pump CABG patients (n = 511)

Table 3. Complications in the Tufts-New England Medical Center

Demographics Males Females Age, years LVEF, % Number of grafts

Operative 381 (77) 130 (23) 66B11 50B12.3 3.4B0.9

Preoperative risks Smoking Diabetes Hypercholesterolemia Renal failure HTN CVA COPD PVD Urgent Emergent Redo Preoperative MI Angina Preoperative IABP Left main disease (1 60%)

105 (21) 141 (28) 225 (44) 20 (4) 284 (56) 23 (4) 23 (4) 50 (10) 80 (16) 20 (4) 9 (2) 142 (28) 353 (70) 14 (3) 103 (20)

Figures show the number of patients (percentage in parentheses), except where otherwise indicated. HTN = Hypertension; CVA = cerebrovascular accident; COPD = chronic obstructive pulmonary disease; PVD = peripheral vascular disease; MI = myocardial infarction; IABP = intra-aortic balloon pump.

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off-pump CABG patients (n = 511) Reexploration/bleeding Reexploration/other Neurologic CVA TIA Mental status changes Renal ATN (creatinine 1 2.0) ATN requiring dialysis Infection Sternal Leg Sepsis Pneumonia UTI Pulmonary Prolonged intubation (1 48 h) Tracheostomy Cardiac Low output Atrial fibrillation VT/VF - AICD Operative mortality Readmission (30 days) Recatheterization (30 days)

2 2 2 1 7 12 0 1 1 1 12 2 19 3 2 75 (18%) 1 0 0 0

CVA = Cerebrovascular accident; TIA = transient ischemic attack; ATN = acute tubular necrosis; UTI = urinary tract infection; VT/VF = ventricular tachycardia/ventricular fibrillation; AICD = automatic internal cardioverter – defibrillator.

Khabbaz/DeNofrio/Kazimi/Carpino

had LVEF under 30% and some as low as 10%. There were no operative deaths in this series. The overall complication rates were quite low (table 3). More importantly, no increase in the rate of complications was seen after adoption of the off-pump technique. The mean number of grafts performed was 3.4 per patient, not different from our practice patterns with on-pump surgery. Thus, from our experience, we can conclude that off-pump CABG could be performed safely and with reproducible results in patients with poor LV function.

Conclusions

CABG is definitely an option to consider for the patient with multivessel coronary artery disease who has an ischemic cardiomyopathy. The selection of patients is important in determining the operative outcomes. Conventional on-pump CABG offers acceptable short-term results and affords such patients long-term survival benefits similar to those seen with cardiac transplantation. Reports are emerging from centers experienced with offpump CABG suggesting that this technique is an option to consider for the patient with a poor left ventricle as it may ameliorate some of the risk factors that may be associated with conventional bypass.

References 1 Elefteriades JA, Morales DL, Gradel C, Tollis G, Levi E, Zaret BL: Results of coronary artery bypass grafting by a single surgeon in patients with left ventricular ejection fractions ^30%. Am J Cardiol 1997;79:1573–1578. 2 Kron IL, Flanagan TL, Blackbourne LH, Schroeder RA, Nolan SP: Coronary revascularization rather than cardiac transplantation for chronic ischemic cardiomyopathy. Ann Surg 1989;210:348–352. 3 Mickleborough LL, Carson S, Tamariz M, Ivanov J: Results of revascularization in patients with severe left ventricular dysfunction. J Thorac Cardiovasc Surg 2000;119:550–557. 4 Hausmann H, Topp H, Siniawski H, Holz S, Hetzer R: Decision-making in end-stage coronary artery disease: Revascularization or heart transplantation? Ann Thorac Surg 1997;674: 1296–1302. 5 Puskas JD, Williams WH, Duke PG, Staples JR, Glas KE, Marshall JJ, Leimbach M, Huber P, Garas S, Sammons BH, McCall SA, Petersen RJ, Bailey DE, Chu H, Mahoney EM, Weintraub WS, Guyton RA: Off-pump coronary artery bypass grafting provides complete revascularization with reduced myocardial injury, transfusion requirements, and length of stay: A prospective randomized comparison of two hundred unselected patients undergoing offpump versus conventional coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003; 125:797–808. 6 Mack M, Bachand D, Acuff T, Edgerton J, Prince S, Dewey T, Magee M: Improved outcomes in coronary artery bypass grafting with beating-heart techniques. J Thorac Cardiovasc Surg 2002;124:598–607. 7 Sabik JF, Gillinov AM, Blackstone EH, Vacha C, Houghtaling PL, Navia J, Smedira NG, McCarthy PM, Cosgrove DM, Lytle BW: Does off-pump coronary surgery reduce morbidity and mortality? J Thorac Cardiovasc Surg 2002; 124:698–707.

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8 Schulz R, Heusch G: Characterization of hibernating and stunned myocardium. Eur Heart J 1995;16(suppl J):19–25. 9 Bonow RO: The hibernating myocardium: Implications for management of congestive heart failure. Am J Cardiol 1995;75:17A–25A. 10 Marwick T: The viable myocardium: Epidemiology, detection, and clinical implications. Lancet 1998;341:815–819. 11 Braunwald E, Rutherford JD: Reversible ischemic left ventricular dysfunction: Evidence for the hibernating myocardium. J Am Coll Cardiol 1986;8:1467–1470. 12 Bax JJ, Wijns W, Cornel JH, Visser FC, Boersma E, Fioretti PM: Accuracy of currently available techniques for prediction of functional recovery after revascularization in patients with left ventricular dysfunction due to chronic coronary artery disease: A comparison of pooled data. J Am Coll Cardiol 1997;30:1451– 1460. 13 Iskandrian AS, Heo J, Schelbert HR: Myocardial viability: Methods of assessment and clinical relevance. Am Heart J 1996;132:1226– 1235. 14 Bax JJ, Poldermans D, Allhendy A, Boersma E, Rahimtoola SH: Sensitivity, specificity, and predictive accuracy of various noninvasive techniques for detecting hibernating myocardium. Curr Probl Cardiol 2001;26:141–186. 15 Bonow RO: Identification of viable myocardium. Circulation 1996;94:2674–2680. 16 Allman K, Shaw L, Hachamovitch R, Udelson JE: Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: A meta-analysis. J Am Coll Cardiol 2002;39:1151–1158. 17 Alderman EL, Fisher LD, Litwin P, Kaiser GC, Myers WO, Maynard C, Levine F, Schloss M: Results of coronary artery surgery in patients with poor left ventricular function (CASS). Circulation 1983;68:785–795.

18 Pigott JD, Kouchoukos NT, Oberman A, Cutter GR: Late results of surgical and medical therapy for patients with coronary artery disease and depressed left ventricular function. J Am Coll Cardiol 1985;5:1036–1045. 19 Kaul TK, Agnihotri AK, Fields BL, Riggins LS, Wyatt DA, Jones CR: Coronary artery bypass grafting in patients with an ejection fraction of twenty percent or less. J Thorac Cardiovasc Surg 1996;111:1001–1012. 20 Dreyfus GD, Duboc D, Blasco A, Vigoni F, Dubois C, Brodaty D, Lentdecker P, Bachet J, Goudot B, Guilmet D: Myocardial viability assessment in ischemic cardiomyopathy: Benefits of coronary revascularization. Ann Thorac Surg 1994;57:1402–1408. 21 Angelini GD, Taylor FC, Reeves BC, Ascione R: Early and midterm outcome after off-pump and on-pump surgery in Beating Heart Against Cardioplegic Arrest Studies (BHACAS 1 and 2): A pooled analysis of two randomised controlled trials. Lancet 2002;359:1194–1199. 22 van Dijk D, Nierich AP, Jansen EW, Nathoe HM, Suyker WJ, Diephuis JC, van Boven WJ, Borst C, Buskens E, Grobbee DE, Robles De Medina EO, de Jaegere PP, Octopus Study Group: Early outcome after off-pump versus on-pump coronary bypass surgery: Results from a randomized study. Circulation 2001; 104:1761–1766. 23 Cleveland JC Jr, Shroyer AL, Chen AY, Peterson E, Grover FL: Off-pump coronary artery bypass grafting decreases risk-adjusted mortality and morbidity. Ann Thorac Surg 2001;72: 1282–1288. 24 Hernandez F, Cohn WE, Baribeau YR, Tryzelaar JF, Charlesworth DC, Clough RA, Klemperer JD, Morton JR, Westbrook BM, Olmstead EM, O’Connor GT; Northern New England Cardiovascular Disease Study Group: Inhospital outcomes of off-pump versus on-pump coronary artery bypass procedures: A multicenter experience. Ann Thorac Surg 2001;72: 1528–1533.

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25 Berson A, Smith JM, Woods S: Off-pump versus on-pump coronary artery bypass surgery: Does the pump influence outcomes? J Am Coll Cardiol 2002;195:524. 26 Puskas JD, Thourani VH, Marshall JJ, Dempsey SJ, Steiner MA, Sammons BH, Brown WM 3rd, Gott JP, Weintraub WS, Guyton RA: Clinical outcomes, angiographic patency, and resource utilization in 200 consecutive offpump coronary bypass patients. Ann Thorac Surg 2001;71:1477–1483. 27 Lancey RA, Soller BR, Vander Salm TJ: Offpump versus on-pump coronary artery bypass surgery: A case-matched comparison of clinical outcomes and costs. Heart Surg Forum 2000;3: 277–281.

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28 Lund O, Christensen J, Holme S, Fruergaard K, Olesen A, Kassis E, Abildgaard U: On-pump versus off-pump coronary artery bypass: Independent risk factors and off-pump graft patency. Eur J Cardiothorac Surg 2001;20:901–907. 29 Jara FM, Kalush J, Kahn ML: Electron beam coronary angiography to assess patency in the off-pump coronary bypass graft. Ann Thorac Surg 2002;74:S1395–S1397. 30 Arom KV, Flavin TF, Emery RW, Kshettry VR, Petersen RJ, Janey PA: Is low ejection fraction safe for off-pump coronary bypass operation? Ann Thorac Surg 2000;70:1021– 1025.

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31 Meharwal ZS, Trehan N: Off pump coronary artery bypass grafting in patients with left ventricular dysfunction. Heart Surg Forum 2002; 5:41–45. 32 Shennib H, Munemoto E, Benhamed O, Morin JF: Surgical revascularization in patients with poor left ventricular function: On- or offpump? Ann Thorac Surg 2002;74:S1344– S1347. 33 Dewey TM, Magee MJ, Edgerton JR, Herbert MA, Prince SL, Trachiotis G, Alexander EP, Mack MJ: Avoidance of cardiopulmonary bypass improves early survival in multi-vessel coronary artery bypass patients with poor ventricular function. Heart Surg Forum 2003; 6(suppl 1):S26.

Khabbaz/DeNofrio/Kazimi/Carpino

Cardiology 2004;101:37–47 DOI: 10.1159/000075984

Mechanisms and Results of Transmyocardial Laser Revascularization Keith A. Horvath Northwestern University, Chicago, Ill., USA

Key Words Transmyocardial laser revascularization W Angina W Reversible ischemia

Abstract Transmyocardial laser revascularization (TMR) is a technique that has been performed on over 10,000 patients around the world. Most of the patients were not suffering from heart failure. TMR is principally used for the treatment of angina, but in patients with significant reversible ischemia that is not amenable to conventional therapy, TMR may also improve myocardial function. The results of using TMR as a treatment for angina show a dramatic improvement in symptoms and quality of life. This paper reviews the current status of TMR techniques, mechanisms and results. Copyright © 2004 S. Karger AG, Basel

Introduction

History Numerous patients with coronary artery disease have been successfully treated with conventional methods, such as coronary artery bypass grafting (CABG) or percutaneous coronary interventions, but there is a significant

ABC

© 2004 S. Karger AG, Basel 0008–6312/04/1013–0037$21.00/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/crd

and increasing number of patients who have exhausted the ability to undergo these procedures repeatedly, due to the diffuse nature of their coronary artery disease. As a result, they have chronic disabling angina that is often refractory to medical therapy. Transmyocardial laser revascularization (TMR) was developed to treat these patients. For patients with severe ischemia that leads to diminished myocardial function, TMR will help. For those with heart failure for other reasons, TMR is of limited utility. Although Mirhoseini et al. [1, 2] and Okada et al. [3, 4] pioneered the use of a laser to perform this type of revascularization in conjunction with CABG in the early 1980s, establishment of the efficacy of the use of a laser as sole therapy required advancements in the technology. Since then, over 10,000 patients have been treated with TMR around the world, and results from individual institutions, multicenter studies and prospective randomized controlled trials have been reported [5–18]. Clinical Results The significant angina relief seen in such patients enrolled in nonrandomized trials led to prospective randomized studies to further demonstrate the efficacy of TMR. In these pivotal trials, over 1,000 patients were enrolled and randomized to receive TMR or medical management for their severe angina [12–17]. The six trials employed a 1:1 randomization in which one half of

Keith A. Horvath, MD Division of Cardiothoracic Surgery, Northwestern University The Feinberg School of Medicine, 201 E. Huron Street, Galter 10-105 Chicago, IL 60611 (USA) Tel. +1 312 695 3121, Fax +1 312 695 1903, E-Mail [email protected]

Line of incision in 5th intercostal space for open TMR

Fig. 1. Sole-therapy TMR performed as an

open surgical procedure is typically done through a left anterolateral thoracotomy in the 5th intercostal space. Exposure of the heart through this incision can typically be achieved without division of the ribs or costal cartilages.

the patients were treated with laser and the other half continued on maximal medical therapy. All patients were followed for 12 months.

Methods Patients The entry criteria for these studies were as follows. Patients had refractory angina that was not amenable to standard methods of revascularization as verified by a recent angiogram. They had evidence of reversible ischemia based on myocardial perfusion scanning, and their left ventricular ejection fractions were greater than 25%. The typical patient profile of TMR patients is listed in table 1. Because the patients were equally randomized to the medical management group there were no significant demographic differences between the TMR and the control groups for any of these trials. Three studies [12–14] employed a holmium:yttrium-aluminum-garnet (Ho:YAG) laser and three [15–17] used a carbon dioxide (CO2) laser. Two of the trials [12, 15] permitted a crossover from the medical management group to laser treatment for the presence of unstable angina that necessitated intravenous antianginal therapy from which they were unweanable over a period of at least 48 h. By definition, these crossover patients were less stable and significantly different from those who had been initially randomized to TMR or medical management alone. Operative Technique For sole-therapy TMR, patients undergo a left anterior thoracotomy in the fifth intercostal space (fig. 1). Once the ribs are spread by a retractor, the lung is deflated and the pericardium is opened to expose the epicardial surface of the heart (fig. 2). Channels are created starting near the base of the heart and then serially in a line approximately 1 cm apart toward the apex, starting inferiorly and working superiorly to the anterior surface of the heart. The number of channels created depends on the size of the heart and on the size of the ischemic area.

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Table 1. Baseline characteristics of TMR

patients Average age, years Women, % CCS angina class III, % CCS angina class IV, % Ejection fraction (mean B SD), % Previous MI, % Previous CABG, % Previous PTCA, % IDDM, %

62 14 39 61 48B10 72 83 37 32

CCS = Canadian Cardiovascular System; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty; IDDM = insulin-dependent diabetes mellitus.

The handpiece in figure 2 is from a CO2 laser and illustrates one of the differences between the two lasers employed for TMR. The CO2 laser energy is delivered via hollow tubes and is reflected by mirrors to reach the epicardial surface. 1-mm channels are made with a 20- to 30-joule pulse. The firing of the laser is synchronized to occur on the r wave of the EKG to avoid arrhythmias. The transmural channel is created by a signal pulse in 40 ms and can be confirmed by transesophageal echocardiography (TEE). The vaporization of blood by the laser energy as the laser beam enters the ventricle creates an obvious and characteristic acoustic effect as noted on TEE. The Ho:YAG laser achieves a similar 1-mm channel by manually advancing a fiber through the myocardium while the laser fires. Typical pulse energies are 2 J for this laser, with 20–30 pulses being required to traverse the myocardium. Detection of transmural penetration is primarily by tactile and auditory feedback.

Horvath

Laser handpiece

Open TMR

Fig. 2. Channels are created in a distribution

of one per square centimeter, starting inferiorly and then working superiorly to the anterior surface of the heart. The number of channels created depends on the size of the heart and on the size of the ischemic area.

Laser channels in left ventricle

End Points The principal subjective end point for all of the trials was a change in angina symptoms. This was assessed by the investigator and/or a blinded independent observer. In addition to assigning an angina class, other tools such as the Seattle Angina Questionnaire, the Short Form Questionnaire 36 (SF-36) and the Duke Activity Status Index were employed. Objective measurements consisted of repeated exercise tolerance testing as well as repeat myocardial perfusion scans. Patients were reassessed 3, 6 and 12 months after randomization.

Results

Mortality Prior to the randomized studies, mortality rates in the 10–20% [5–11] range were reported for TMR patients. In the randomized trials, lower perioperative mortality rates were reported, ranging from 1 to 5% [12–17]. One of the important lessons learned from these controlled trials that differs from the earlier studies was a decrease in the mortality when patients taken to the operating room were not unstable, specifically not on intravenous heparin or nitroglycerine. When patients were allowed to recover from their most recent episode of unstable angina and were

Transmyocardial Laser Revascularization

able to be weaned from intravenous medications such that their operation could be performed 2 weeks later, the mortality dropped to 1% [15]. The 1-year survival for TMR patients was 85–95%, and for medical management patients, it was 79–95%. Meta-analysis of the 1-year survival demonstrated no statistically significant difference between the patients treated with a laser and those who continued on medical therapy. Morbidity Unlike mortality, the exact definitions of various complications varied from one study protocol to the next, and therefore, morbidity data are difficult to pool. Nevertheless, the typical postoperative course had a lower incidence of myocardial infarction, heart failure and arrhythmias than what has been documented in a similar cohort of patients, i.e. those that have reoperative CABG [12– 17]. Angina Class The principal reason for performing TMR is to reduce the patient’s anginal symptoms. This can be quantified by assessing the angina class before and after the procedure.

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Table 2. One-year success rates for randomized trials of TMR versus

medical management Study

Laser

Success rate, % medical TMR management

Aaberge et al. [17] Schofield et al. [16] Burkhoff et al. [13] Frazier et al. [15] Allen et al. [12]

CO2 CO2 Ho:YAG CO2 Ho:YAG

0 4 11 13 32

39 25 61 72 76

Success rate refers to the proportion of patients who experienced a decrease of two or more angina classes.

Angina class assessment was performed by a blinded independent observer in all studies. Significant symptomatic improvement was seen in all studies for patients treated with the laser. Using a definition of success of a decrease of two or more angina classes, all of the studies demonstrated a significant success rate after TMR, with success rates ranging from 25 to 76% (table 2). Significantly fewer patients in the medical management group experienced symptomatic improvement, and the success rate for these patients ranged from 0 to 32%. The seemingly broad range of success is due to differences between the baseline characteristics of the patients in the studies. It is more difficult to achieve an improvement of two angina classes if the baseline angina class is III. Studies in which most of the patients started in angina class III not surprisingly showed the lowest success rates. In contrast, the highest success rate for TMR was seen in the trial in which all of the patients were in class IV at enrollment. Of note, the medical management group in this study also showed the highest success rate [12]. This underscores some of the baseline differences between the studies. Quality of Life and Myocardial Function Quality of life indices as assessed by the Seattle Angina Questionnaire, the SF-36 and Duke Activity Status Index demonstrated significant improvement for TMR-treated patients versus patients on medical management in every study. Global assessment of myocardial function by ejection fraction using echocardiography or radionuclide multigated acquisition scans showed no significant change in the overall ejection fraction for any of the patients, regardless of group assignment or study.

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Hospital Admission Another indicator of the efficacy of TMR was demonstrated in a reduction in hospital admissions for unstable angina or cardiac-related events after the procedure. A meta-analysis of the data provided indicates that the 1year hospitalization rate of patients in the laser-treated group was statistically significantly lower than for those treated medically. Medical management patients were admitted four times more frequently than TMR patients over the year of follow-up [19]. Exercise Tolerance Additional functional test assessment using exercise tolerance was also performed in three of the trials [13, 16, 17]. While the method of treadmill testing differed between the trials, the results demonstrate an improvement in exercise tolerance for TMR-treated patients. Two studies showed an average of 65- to 70-second improvement in the TMR group at 12 months compared to their baseline values, while the medical management group had either an average of 5-second improvement or a 46-second decrease in exercise time over the same interval [16, 17]. One additional trial demonstrated that the time to chest pain during exercise increased significantly and fewer patients were limited by chest pain in the TMR group, whereas the medical management group showed no improvement [17]. Medical Treatment All of the studies employed protocols that continued all of the patients on maximal medical therapy. TMR patients, as a result of their symptomatic improvement, had a reduction in their medication use over the year of follow-up. The overall medication use decreased or remained unchanged in 83% of the TMR patients, and conversely, the use of medications increased or remained unchanged in 86% of the medical management patients [15]. Myocardial Perfusion As previously stated, myocardial perfusion scans were obtained preoperatively to verify the extent and severity of reversible ischemia. The four largest randomized trials included follow-up scans as part of their study [12, 13, 15, 16]. These results reflect over 800 of the patients randomized. The methodology of recording and analyzing these results differed in each study, so it is difficult to pool the data. Nevertheless, review of the results demonstrated an improvement in perfusion for CO2 TMR-treated patients. Fixed (scar) and reversible (ischemic) defects were tallied

Horvath

Fig. 3. a Distribution of Ho:YAG TMR-treated patients by decrease in Canadian Cardiovascular System angina class; baseline versus 3 years. b Distribution of CO2 TMR-treated patients by decrease in Canadian Cardiovascular System angina class; baseline versus 5 years.

for both the TMR-treated patients and the medical management groups. A CO2 study demonstrated a significant decrease in the number of reversible defects for both the TMR and the medical management patients [16]. This improvement in the reversible defects in the TMR group was seen without a significant increase in the fixed defects at the end of the study. However, the number of fixed defects in the medical management group had nearly doubled over the same interval. Similarly, there was a 20% improvement in the perfusion of previously ischemic areas in the CO2 TMR group of another trial, and in that same trial, there was a 27% worsening of the perfusion of the ischemic areas in the medical management group at 12 months [15]. There was no difference in the number of fixed defects between the groups at 12 months, nor was there a significant change in the number of fixed defects for each patient compared with their baseline scans. The remaining two Ho:YAG studies that obtained follow-up scans showed no significant difference between the TMR and the medical management groups at 12 months and no significant improvement in perfusion in the TMR-treated patients over the same interval [12, 13].

Long-Term Results Long-term results of Ho:YAG and CO2 TMR also differ. As noted, after Ho:YAG TMR, significant short-term angina relief was demonstrated at 1 year, as the average angina class fell from 3.5 B 0.5 at baseline to 1.8 B 0.8 at 1 year (p ! 0.01). However, the average angina class 3 years after Ho:YAG TMR has been reported to significantly increase to 2.2 B 0.7 (p = 0.003 vs. at 1 year) [20, 21]. Additionally, at 3 years, only 30% of the patients had a two-class improvement in angina compared to baseline and 70% had a one-class improvement (fig. 3a). Longterm results with the CO2 laser were markedly different. As reported, these results demonstrate a decrease in angina class from 3.7 B 0.4 at baseline to 1.6 B 1.0 at 5 years (p = 0.0001) [22]. This was unchanged from the average angina class of 1.5 B 1.0 at 1 year of follow-up (not significant vs. at 5 years). Additionally, 68% of the patients at 5 years had an improvement of two or more angina classes, and 17% had no angina with a length of follow-up of up to 7 years (fig. 3b). As would be expected, the patients’ improvements in terms of quality of life were also maintained long-term. Additionally, one report of late clinical follow-up of another of the randomized control trials also

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Cardiology 2004;101:37–47

41

Fig. 4. Sequential photography of the firing of a single pulse from a CO2 laser and a Ho:YAG laser into water. The pulse duration and

energy levels are the same as those being used clinically.

demonstrated continued symptomatic improvement with CO2 TMR [23]. This study is noteworthy in that the medical management arm of the original randomized trial was also followed long-term. In this study with up to 5 years of follow-up, the average angina class for CO2 TMR-treated patients decreased from 3.3 at baseline to 2.0 at follow-up. Over the same interval, the average angina class for the medical management group increased from 3.2 to 3.7. Only 3% of the medical management group showed a twoclass angina reduction at 5 or more years, whereas 24% of the TMR-treated patients maintained a reduction in angina of two or more classes. Additionally, medical management patients were hospitalized twice as frequently for unstable angina as those treated with CO2 TMR.

Mechanisms of TMR

Understanding the mechanism of TMR starts with understanding the laser-tissue interaction. While numerous devices [24, 25], including ultrasound [26], cryoablation [27], radio frequency [28, 29] and heated needles [30, 31], as well as hollow and solid needles have been used, none have engendered the same response that is seen with a laser. Additionally, numerous wavelengths of laser light have also been employed [32–36]. Only CO2 and Ho:YAG are used clinically for TMR. The result of any laser-tissue interaction is dependent on both laser and tissue variables [35–37]. CO2 has a wavelength of 10,600 nm, whereas Ho:YAG has a wavelength of 2,120 nm. These infrared wavelengths are primarily absorbed in water and therefore rely on thermal energy to

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ablate tissue. One significant difference, however, is that the Ho:YAG laser is pulsed, and the arrival of two successive pulses must be separated in time to allow for thermal dissipation, otherwise the accumulated heat will cause the tissue to explode under pressure. Such explosions create acoustic waves, which travel along the planes of lower resistance between muscle fibers and cause structural trauma as well as thermocoagulation [38]. The standard operating parameters for the Ho:YAG laser are pulse energies of 1–2 J and 6–8 W/pulse. The energy is delivered at a rate of 5 pulses/s through a flexible 1-mm optical fiber. It takes approximately 20 pulses to create a transmural channel. Despite the low energy level and short pulse duration, there are very high levels of peak power delivered to the tissue, so that with each pulse there is an explosion (fig. 4). Additionally, the fiber is advanced manually through the myocardium and it is therefore impossible to know whether the channel is being created by the kinetic energy delivered via the mechanical effects of the fiber or whether there has been enough time for thermal dissipation prior to the next pulse. In contrast, the CO2 laser is used at an energy level of 20–30 J/pulse with a pulse duration of 25–40 ms. At this level, the laser photons do not cause explosive ablation and the extent of structural damage is limited. Additionally, a transmural channel can be created with a single pulse (fig. 4). Confirmation of this transmuralality is obtained by observing the vaporization of blood within the ventricle using TEE. Finally, the CO2 laser is synchronized to fire on the r wave, and with its short pulse duration, arrhythmic complications are minimized. The Ho:YAG device is un-

Horvath

Fig. 5. a, b The CO2 laser creates a transmural channel with a single 20-joule pulse. Conceptually direct perfusion may occur via the channel. Evidence indicates that the laser stimulates angiogenesis in and around the channel, which leads to improved perfusion.

synchronized, and due to the motion of the fiber through the myocardium over several cardiac cycles, it is more prone to ventricular arrhythmias. Patent Channels As noted, the original concept of TMR was to create perfusion via channels connecting the ventricle with the myocardium. Clinical work demonstrated some evidence of long-term patency [39, 40]. Additional experimental work showed some evidence of patency as well [41–44]. There are also significant reports from autopsy series and laboratories that indicate that the channels do not remain patent [45–49]. What evidence there is that channel patency may be a mechanism was only obtained following CO2 TMR (fig. 5). There has never been any evidence that Ho:YAG TMR channels stay patent.

neurons to regulate regional cardiac function by reflex action. This intrinsic system contains afferent neurons, sympathetic efferent postganglionic neurons, and parasympathetic efferent postganglionic neurons. Because of this complex system, it is difficult to demonstrate true denervation. However, several experimental studies have demonstrated that denervation may indeed play a role in Ho:YAG TMR [50–52]. Experimental evidence to the contrary was provided in a nonischemic animal model [53]. Regardless of the methodology employed in the laboratory, there is significant evidence of sympathetic denervation following positron emission tomography of Ho:YAG TMR-treated patients [54]. Although the studies were carefully carried out, it is difficult to isolate the sympathetic afferent nerve fibers, and the experiments were in the acute setting and only addressed the shortterm effects.

Denervation In contrast to the open-channel mechanism, damage to the sympathetic nerve fibers may explain the angina relief noted in clinical trials. The nervous system of the heart can function independently of inputs from extracardiac

Angiogenesis The likely underlying mechanism for the clinical efficacy of TMR is the stimulation of angiogenesis. This mechanism fits the clinical picture of significant improve-

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43

ment in symptoms over time as well as a concomitant improvement in perfusion, as seen with the CO2 laser. Numerous reports have demonstrated a histologic increase in neovascularization as a result of TMR channels [46, 48, 55–61]. More molecular evidence of this angiogenic phenomenon was derived from work that demonstrated an upregulation of vascular endothelial growth factor messenger RNA and expression of fibroblast growth factor 2 as well as matrix metalloproteinases following TMR [62–64]. Histologically, similar degrees of neovascularization have been noted after mechanical injury of various types. Needle injury has been demonstrated by immunohistochemistry to also stimulate growth factor expression and angiogenesis. The conclusion is that TMR-induced angiogenesis is a nonspecific response to injury [25, 65, 66]. Investigation of this using hot and cold needles, radiofrequency energy and laser energy to perform TMR clearly demonstrates a spectrum of tissue response to the injury [30]. The results in a model of chronic myocardial ischemia to mimic the clinical scenario indicate that neovascularization can indeed occur after mechanical TMR, but if these new blood vessels grow in the midst of a scar, there will be little functional contribution from blood flow through these new vessels. The recovery of function with laser TMR was due to a minimization of scar formation and a maximization of angiogenesis. There then arises the critical question that if TMR induces angiogenesis, is there an ensuing improvement in function? Clinically, this has been demonstrated subjectively with quality of life assessments, but more importantly, it has been demonstrated objectively with multiple techniques, including dobutamine stress echocardiography [67], positron emission tomography [68] and cardiac MRI [69, 70]. As further evidence of the angiogenic response, experimental data have mirrored the clinical perfusion results noted, with improvements in perfusion in porcine models of chronic ischemia where the ischemic zone was treated with CO2 TMR [44, 71–73]. This improved perfusion did lead to an improvement in myocardial function as well.

Conclusion

Myocardial laser revascularization has been performed percutaneously [74–76], thoracoscopically [77], via thoracotomy [12–18] and via sternotomy [78–80]. Aside from the percutaneous approach, all of the other surgical approaches have yielded similar symptomatic improve-

44

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ment. A recent double-blinded randomized controlled trial showed no benefit to the percutaneously treated patients compared to the untreated control group [76]. As the patients were blinded to their treatment, the possibility of a significant placebo effect for percutaneous laser myocardial revascularization (PMR) has been raised. Of note, the morbidity and mortality with PMR is reportedly similar to that seen with TMR. As a result, the United States Food and Drug Administration recently rendered PMR unapprovable. The failure of PMR to achieve the same clinical results that have been seen with TMR may be due to several significant limitations. The first is the partial-thickness treatment of the left ventricle. Even at the maximal estimated depth of 6 mm that has been reported with PMR, this is significantly less than the fullthickness treatment of the myocardium that is achieved with an open TMR approach. Furthermore, there are typically fewer of these partial thickness channels created with PMR. The exact location of the channel and the establishment of a wide distribution of the channels from inside a moving ventricle is also problematic. Finally, the limitations of Ho:YAG TMR are also applicable to PMR, as that is the wavelength of light that has been employed. While the results of sole-therapy TMR are encouraging, and were necessary to confirm the efficacy of the procedure, the future of TMR is in combination therapy [78– 80]. Perhaps prescient, the description of Mirhoseini et al. [1, 2] of using TMR with CABG provides the likely clinical scenario for the future. As percutaneous coronary intervention techniques improve and evolve, the patients who undergo CABG will more likely than not have more diffuse disease and more occluded coronary arteries. As a result, some territories may be bypassable, but others may be better suited for TMR. A combination of both of these methods will provide a more complete revascularization. Early results with a randomized trial comparing CABG to CABG plus TMR indicated a mortality benefit with the combined procedure [78]. Unfortunately, the mortality rate for the CABG only patients in that study was high at 7.5% and may be the key contributing factor in the results. Additionally, the patients were randomized based on their angiograms and prior to investigation in the operating room. Nevertheless, these results indicate that the combined procedure is feasible, and in fact, longer-term outcomes of CABG plus TMR patients indicate that significant angina relief and low morbidity and mortality can be achieved in such high-risk patients [79, 80]. Other applications include the use of TMR in the treatment of cardiac transplant graft atherosclerosis. While performed on only a small number of patients, the results

Horvath

have indicated a benefit following TMR [81, 82]. Finally, the combination of TMR plus other methods of angiogenesis may provide an even more robust response. Experimental work investigating these combinations has verified a synergistic effect with regard to histologic evidence

of significant angiogenesis and perhaps more importantly an improvement in myocardial function with a combination of TMR and gene therapy versus either therapy alone [83–87].

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48 Burkhoff D, Fisher PE, Apfelbaum M, Kohmoto T, DeRosa CM, Smith CR: Histologic appearance of transmyocardial laser channels after 4 ½ weeks. Ann Thorac Surg 1996;61:1532– 1535. 49 Sigel JE, Abramovitch CM, Lytle BW, Ratliff NB: Transmyocardial laser revascularization: Three sequential autopsy cases. J Thorac Cardiovasc Surg 1998;115:1381–1385. 50 Kwong KF, Kanellopoulos GK, Nikols JC, Sundt TR III: Transmyocardial laser treatment denervates canine myocardium. J Thorac Cardiovasc Surg 1997;114:883–890. 51 Kwong KF, Schuessler RB, Kanellopoulos GK, Saffitz JE, Sundt TM: Nontransmural laser treatment incompletely denervates canine myocardium. Circulation 1998;98:1167–1171. 52 Hirsch GM, Thompson GW, Arora RC, Hirsch KJ, Sullivan JA, Armour JA: Transmyocardial laser revascularization does not denervate the canine heart. Ann Thorac Surg 1999;68:460– 468. 53 Minisi AJ, Topaz O, Quinn MS, Mohanty LB: Cardiac nociceptive reflexes after transmyocardial laser revascularization: Implications for the neural hypothesis of angina relief. J Thorac Cardiovasc Surg 2001;122:712–719. 54 Al-Sheikh T, Allen KB, Straka SP, et al: Cardiac sympathetic denervation after transmyocardial laser revascularization. Circulation 1999;100:135–140. 55 Yamamoto N, Kohmoto T, Gu A, DeRosa C, Smith CR, Burkhoff D: Angiogenesis is enhanced in ischemic canine myocardium by transmyocardial laser revascularization. J Am Coll Cardiol 1998;31:1426–1433. 56 Fisher PE, Khomoto T, DeRosa CM, Spotnitz HM, Smith CR, Burkhoff D: Histologic analysis of transmyocardial channels: Comparison of CO2 and holmium:YAG lasers. Ann Thorac Surg 1997;64:466–472. 57 Zlotnick AY, Ahmad RM, Reul RM: Neovascularization occurs at the site of closed laser channels after transmyocardial laser revascularization. Surg Forum 1996;48:286–287. 58 Kohmoto T, Fisher PE, DeRosa C, Smith CR, Burkhoff D: Evidence of angiogenesis in regions treated with transmyocardial laser revascularization. Circulation 1996;94:1294. 59 Spanier T, Smith CR, Burkhoff D: Angiogenesis. A possible mechanism underlying the clinical benefits of transmyocardial laser revascularization. J Clin Laser Med Surg 1997;15:269– 273. 60 Mueller XM, Tevaearai HT, Chaubert P, Genton CY, von Segesser LK: Does laser injury induce a different neovascularization pattern from mechanical or ischemic injuries? Heart 2001;85:697–701. 61 Hughes GC, Lowe JE, Kypson AP, et al: Neovascularization after transmyocardial laser revascularization in a model of chronic ischemia. Ann Thorac Surg 1998;66:2029–2036. 62 Horvath KA, Chiu E, Maun DC, Lomasney JW, Greene R, Pearce WH, Fullerton DA: Upregulation of VEGF mRNA and angiogenesis after transmyocardial laser revascularization. Ann Thorac Surg 1999;68:825–829.

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63 Li W, Chiba Y, Kimura T, et al: Transmyocardial laser revascularization induced angiogenesis correlated with the expression of matrix metalloproteinase and platelet-derived endothelial cell growth factor. Eur J Cardiothorac Surg 2001;19:156–163. 64 Pelletier MP, Giaid A, Sivaraman S, et al: Angiogenesis and growth factor expression in a model of transmyocardial revascularization. Ann Thorac Surg 1998;66:12–18. 65 Chu V, Kuang J, McGinn A, Giai A, Korkola S, Chiu RC: Angiogenic response induced by mechanical transmyocardial revascularization. J Thorac Cardiovasc Surg 1999;118:849–856. 66 Chu VF, Giaid A, Kuagn JQ, et al: Angiogenesis in transmyocardial revascularization: Comparison of laser versus mechanical punctures. Ann Thorac Surg 1999;68:301–307. 67 Donovan CL, Landolfo KP, Lowe JE, Clements F, Coleman RB, Ryan T: Improvement in inducible ischemia during dobutamine stress echocardiography after transmyocardial laser revascularization in patients with refractory angina pectoris. J Am Coll Cardiol 1997;30: 607–612. 68 Frazier OH, Cooley DA, Kadipasaoglu KA, et al: Myocardial revascularization with laser. Preliminary findings. Circulation 1995; 92(suppl):II58–II65. 69 Laham RJ, Simons M, Pearlman JD, Ho KKL, Baim DS: Magnetic resonance imaging demonstrates improved regional systolic wall motion and thickening and myocardial perfusion of myocardial territories treated by laser myocardial revascularization. J Am Coll Cardiol 2002; 39:1–8. 70 Kim RJ, Rafael A, Chen E, Wu E, Parker MA, Horvath KA, Simonetti O, Finn P, Bonow RO, Klocke FJ, Judd RM: Contrast-enhanced MRI predicts wall motion improvement after coronary revascularization. Circulation 1999; 100(suppl):I-797. 71 Horvath KA, Greene R, Belkind N, Kane B, McPherson D, Fullerton DA: Left ventricular functional improvement after transmyocardial laser revascularization. Ann Thorac Surg 1998; 66:721–725. 72 Hughes GC, Kypson AP, St Louis JD, et al: Improved perfusion and contractile reserve after transmyocardial laser revascularization in a model of hibernating myocardium. Ann Thorac Surg 1999;67:1714–1720. 73 Krabatsch T, Modersohn D, Konertz W, Hetzer R: Acute changes in functional and metabolic parameters following transmyocardial laser revascularization: An experimental study. Ann Thorac Cardiovasc Surg 2000;6:383–388. 74 Oesterle SN, Sanborn TA, Ali N, et al: Percutaneous transmyocardial laser revascularization for severe angina: The PACIFIC randomised trial. Potential Class Improvement From Intramyocardial Channels. Lancet 2000;356:1705– 1710.

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75 Stone GW, Teirstein PS, Rubenstein R, et al: A prospective, multicenter, randomized trial of percutaneous transmyocardial laser revascularization in patients with nonrecanalizable chronic total occlusions. J Am Coll Cardiol 2002;39:1581–1587. 76 Leon MB, Baim DS, Moses JW, et al: A randomized blinded clinical trial comparing percutaneous laser myocardial revascularization vs. placebo in patients with refractory coronary ischemia. Circulation 2000;102:II-565. 77 Horvath KA: Thoracoscopic transmyocardial laser revascularization. Ann Thorac Surg 1998; 65:1439–1441. 78 Allen KB, Dowling RD, DelRossi AJ, et al: Transmyocardial laser revascularization combined with coronary artery bypass grafting: A multicenter, blinded, prospective, randomized, controlled trial. J Thorac Cardiovasc Surg 2000;119:540–549.

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84 Sayeed-Shah U, Mann MJ, Martin J, et al: Complete reversal of ischemic wall motion abnormalities by combined use of gene therapy with transmyocardial laser revascularization. J Thorac Cardiovasc Surg 1998;116:763–768. 85 Doukas J, Ma CL, Craig D, et al: Therapeutic angiogenesis induced by FGF-2 gene delivery combined with laser transmyocardial revascularization. Circulation 2000;102:1214. 86 Lutter G, Dern P, Attmann T, et al: Combined use of transmyocardial laser revascularization with basic fibroblastic growth factor in chronically ischemic porcine hearts. Circulation 2000;102:3693. 87 Horvath KA, Doukas J, Lu CJ, Belkind N, Greene R, Pierce GF, Fullerton DA: Myocardial functional recovery after fibroblast growth factor 2 gene therapy as assessed by echocardiography and MRI. Ann Thorac Surg 2002;74: 481–487.

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Cardiology 2004;101:48–60 DOI: 10.1159/000075985

Clinical Trials in the Surgical Management of Congestive Heart Failure: Surgical Ventricular Restoration and Autologous Skeletal Myoblast and Stem Cell Cardiomyoplasty Patrick I. McConnell Robert E. Michler The Ohio State University Medical Center, Columbus, Ohio, USA

Key Words Ventricular remodeling W Left ventricular dysfunction W Congestive heart failure W Surgical ventricular restoration W Autologous skeletal myoblast transplantation

Abstract Despite continued advances in medical and surgical approaches for patients with ischemic cardiomyopathy, congestive heart failure (CHF) remains a growing cause of morbidity and mortality. Historically, surgical options for end-stage CHF have been limited. However, there are several surgical therapies now under clinical investigation that appear promising in the effort to reverse or restore the remodeled left ventricle. This review will focus on early but current clinical studies examining surgical ventricular restoration and autologous skeletal myoblast and stem cell transplantation. Although these emerging therapeutic options remain in the early stages of study and development, they hold promise in providing options to those patients with end-stage CHF. Copyright © 2004 S. Karger AG, Basel

Conflict of interest: research relationship with the for profit organization GenVec Inc.

ABC

© 2004 S. Karger AG, Basel 0008–6312/04/1013–0048$21.00/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/crd

Introduction

Immediate survival after myocardial infarction may be predicated by the timeliness and adequacy of appropriate reperfusion, but long-term prognosis is ultimately dependent on subsequent changes in left ventricular (LV) shape and function (fig. 1) [1–6]. Regional myocardial dysfunction, if sufficiently large, results in a progressive process of global cardiac remodeling and LV dilatation [4, 5]. If early intervention and therapy are unable to reverse or prevent LV dilatation, the end result is a progressive process leading to congestive heart failure (CHF) and death [1, 4]. Despite continued advances in medical and surgical approaches for patients with ischemic cardiomyopathy, CHF remains a growing cause of morbidity and mortality in the United States and worldwide [7, 8]. Historically, surgical options have been few for patients with end-stage CHF who are not eligible for heart transplantation [9–11]. Although options are limited currently, there are several surgical therapies now under investigation that appear promising in the effort to reverse or restore the remodeled LV towards a more normal shape and function. This clinical trial review will focus on surgical ventricular restoration (SVR) with reference to the National Heart, Lung, and Blood Institute’s Surgical Treatment for Ischemic Heart Failure (STICH) trial, and the investigational and clinical highlights of both autologous skeletal myoblast

Robert E. Michler, MD Karl P. Klassen Professor of Surgery, Chief Division of Cardiothoracic Surgery N843 Doan Hall, 410 W. 10th Avenue Columbus, OH 43210 (USA) Tel. +1 614 293 5502, Fax +1 614 293 4726, E-Mail [email protected]

and stem cell cellular cardiomyoplasty (CCM) for the treatment of ischemic cardiomyopathy and CHF. This review will also describe the institutional insights of the authors, who have been involved in clinical trials and basic science research in each of these three areas.

LV Dilatation: Cardiac Physiology ‘behind the Eight Ball’

Though oversimplified, the complex physical processes of progressive LV remodeling and dilatation can be understood through Laplace’s law. LV wall stress/tension (‰) is proportional to the radius (r) and pressure (P) within the LV chamber and inversely proportional to LV wall thickness (T), with average wall stress estimated by the following equation: ‰ = rP/(2)T. Whether approaching the concept from the level of the individual myocyte (tensionlength) or at the level of the LV chamber (pressure-volume), increasing LV volume translates to increasing cardiac myocyte stress, which becomes an impediment to effective contraction. Cardiac myocytes, particularly in areas immediately adjacent to and also remote from myocardial injury (e.g. myocardial infarction), are pushed beyond their individual reserves as those cells/tissues are forced to respond to the global (LV chamber) effects of regional LV dysfunction [12, 13]. Physiologically, this results in impaired myocyte energetics placing individual myocytes in an intra-/extracellular milieu of increased oxidative stress and relative ischemia [14]. Such multifactorial stresses progressively activate local and systemic neurohormonal responses, altering cardiac gene expression and producing myocyte hypertrophy, apoptosis and fibrosis [15–18]. Hypertrophied cardiac myocytes along with concomitant fibrosis contribute directly to altered diastolic and systolic function, further driving these same compensatory processes (vicious cycle) [19]. Therefore, logical solutions to increased wall stress would be to either reduce the radius/volume of the LV chamber, thereby reducing myocardial wall stress, or to replace LV scar with functional myocytes, thus restoring LV regional function. However, little is known about whether a restoration of global wall stress/chamber size or regional myocardial function can facilitate the chronically remodeled myocardium to revert back to functional or contractile normalcy.

SVR, Myoblasts and Stem Cells

Fig. 1. Increasing LV size after myocardial infarction is associated with worsening prognosis. ESV = End-systolic volume. Reproduced with permission from White et al. [5].

Surgical Ventricular Restoration

LV volume reduction surgery, though recently sensationalized by the work of Dr. Randas Batista in Brazil [20], was first a concept born from experiences in treating LV aneurysms. Under the auspices of LV aneurysmectomy, technically refined most notably by Cooley [21], Jatene [22] and Dor et al. [23], LV volume reduction surgery had its beginning in the early 1970s. The SVR procedure (also known as the Dor procedure or endoventricular circular patch plasty) is by far the most extensively applied technique for reshaping and excluding regions of functional asynergy (akinesis and dyskinesis). Unlike aneurysmectomy per se, which targets areas of dyskinesis (thinned, bulging LV aneurysm), SVR attempts to directly address areas of both akinesis and/or dyskinesis (asynergy) [24, 25]. SVR restores/reshapes the endoventricular contour by placing a patch (Dacron or bovine pericardium) at the level of a purse-string suture,

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thereby encircling and excluding the transition zone of myocardial asynergy (fig. 2, 3) [23, 26]. This technique is most suitable for anterior wall infarctions, which typically involve areas of asynergy from the mid to distal septum and also involve portions of the anteroapical LV. This technique has also been applied to inferior wall asynergic areas with promising results. Beyond the restoration of LV size, additional important and key features are (1) complete revascularization, including a graft to the left anterior descending artery, and (2) ventricular sizing (60 ml/m2 for ventricles with preoperative end-diastolic volumes !150 ml/m2, and 70 ml/m2 for ventricles with volumes 1150 ml/m2) to avoid postoperative restrictive ventricular physiology [27]. By grafting the left anterior descending artery, the high septum is preserved and thereby enhances postoperative circumferential shortening. In an attempt to avoid a box-like ventricle, Menicanti and Di Donato [27] have recommended orienting the purse-string suture and patch at an oblique angle towards the aortic outflow tract while still excluding intraventricular (septal) akinetic segments. The trade-off comes in the extent to which the longitudinal axis of the LV can be reduced and is ultimately determined by the position of the new apex. This may require inferior wall suture plication to relocate the LV apex (fig. 3). Magnetic resonance imaging (MRI) has proven very valuable in the pre- and postoperative evaluation of these patients. There are reports of a dramatic enhancement in the function of the remote nonischemic myocardium following SVR, documented by improved global function (ejection fraction; EF) as well as improvement in remote regional contractility [28]. Experience at The Ohio State University Medical Center has confirmed these findings, as illustrated in figure 4. This improvement in remote

Fig. 2. Intraoperative photos of LV restoration surgery (SVR) in a patient with anteroseptal asynergy (akinesis) and LV dilatation. A An area of asynergy at the site of prior myocardial infarction is seen just lateral to the left anterior descending artery. B A ventriculotomy was created within the area of asynergy. Septal stitches are placed at the level of a Fontan stitch (yellow arrows) delineating the area of normal myocardium from that exhibiting akinesis. C An endoventricular bovine pericardial patch (Cor Restore™, Somanetics Corp., Troy, Mich., USA) is seen in position just prior to tying the sutures and closing the free edges of the LV. Photos in B and C courtesy of Somanetics Corp.

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Fig. 3. In order to avoid a box-like ventricle, care must be taken to properly orient the Fontan stitch (pursestring) and endoventricular patch. Shown conceptually: plicating the posterior wall can further enable the surgeon to avoid overreducing ventricular volume and misshaping the ventricle (box-like ventricle). Reproduced with permission from Menicanti and Di Donato [27].

myocardial performance is likely due to reduced myocardial stress (Laplace’s law) allowing cardiac myocytes to perform within a given preload reserve, and to some extent, effective and complete revascularization. The Reconstructive Endoventricular Surgery, returning Torsion Original Radius Elliptical Shape to the LV (RESTORE) group (an 11-center multinational group of surgeons and cardiologists organized in 1998 in an effort to evaluate the durability and efficacy of the SVR procedure for ischemic dilated cardiomyopathy [29, 30]) demonstrated that by reducing the LV end-systolic volume index (LVESVI) by 35–40%, there is a corresponding 30– 35% improvement in EF. Furthermore, there does not appear to be a difference in operative outcome based on whether the indication for SVR was dyskinetic or akinetic myocardium [25, 30].

In 439 patients undergoing SVR, Athanasuleas et al. [30] (RESTORE group) reported a reduction in the mean LVESVI from 109 ml/m2 to a mean of 69 ml/m2 postoperatively and an 18-month rate of freedom from readmission for CHF of 85%. Of course, the goal of incremental reductions in LV volume is likewise a reduction in longterm mortality, and such data continue to accrue (fig. 1, table 1).

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Fig. 4. End-systolic long-axis MRI of a patient before (A) and after (B) ventricular restoration surgery at the Ohio State University Med-

ical Center. Note the significant decrease in LV volume (LVESVI) and increased septal and posterior lateral wall thickening after the procedure. RV = Right ventricle.

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Table 1. Experience with SVR Procedure

SVR

Study

Patients

Di Donato et al. (2001) [23] Menicanti and Di Donato (2002) [27] RESTORE (2001) [29]

225 985 439

LVESVI, ml/m2

EF, %

pre

pre

post

early (months) late (months)

mitral

35 25 29

48 35 39

8 (hospital) NR 6.6 (1)

5 15 26

post

112 46 188 (ml) 107 (ml) 109 69

Mortality, %

18 (60) NR 11 (18)

Mitral = Mitral valve repair or replacement; NR = not reported; pre = preoperative; post = postoperative.

SVR and coronary artery bypass grafting (CABG), though extensively applied for the treatment of LV asynergy (table 1), have not been prospectively studied in a randomized fashion against standard medical therapy alone or CABG alone in patients with CHF and coronary artery disease. To this end, the National Heart, Lung, and Blood Institute’s multicenter, international, randomized STICH trial (table 2) began enrolling patients with CHF and coronary artery disease in the spring of 2002. Three critical questions define the rationale for this trial: (1) Should CABG surgery be performed in patients with coronary artery disease and CHF? (2) Does SVR need to be added to CABG in patients with regional myocardial dysfunction, and what magnitude of dysfunction must be present to justify the additional surgery? (3) Should viability of akinetic myocardium affect the decision regarding CABG in patients with LV failure? The goal of the STICH trial is to determine whether a benefit over medical therapy can be found for coronary revascularization and whether this benefit can be enhanced by ventricular restoration surgery in patients with heart failure and coronary artery disease. In the STICH trial, patients with NYHA class II–IV CHF (symptomatic CHF is not a necessary criterion for enrollment), LVEF ^35% and evidence of coronary artery disease amenable to revascularization will be randomized into three possible strata: (1) medical therapy alone versus CABG alone, (2) medical therapy alone versus CABG alone versus CABG plus SVR, or (3) CABG alone versus CABG plus SVR (fig. 5). A critical future finding of this study will be the analysis of data from stratum A, which compares the benefits of medical therapy alone versus CABG surgery for patients with heart failure. Data from the Duke Databank for Cardiovascular Disease confirms the fact that many patients across the nation are managed predominantly medically for this condition. Should surgery prove more beneficial, a significant change in patient management will occur,

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Table 2. National Heart, Lung, and Blood Institute’s STICH trial Selected eligibility criteria1 Age 1 18 years Coronary artery disease suitable for revascularization Evidence of LV systolic dysfunction (LVEF ^35%) as assessed by either: echocardiography gated SPECT imaging contrast ventriculogram CMR ventriculogram Dominant akinesia or dyskinesia of the anterior LV wall amenable to SVR Selected exclusion criteria1 Aortic valvular heart disease requiring aortic valve replacement Recent acute myocardial infarction accounting for depressed LV function More than one previous coronary artery bypass procedure Left main coronary artery stenosis/disease (1 50% stenosis) Canadian Cardiovascular Society class III angina or significant lifestylelimiting angina Noncardiac illness imposing significant operative mortality or that would have a life expectancy of ! 3 years Previous organ transplantation Randomization Medical treatment alone2 Medical treatment + CABG Medical treatment + CABG + SVR CMR = Cardiac MRI. Please contact the National Heart, Lung, and Blood Institute for the complete listing. 2 Patient must not have left main coronary artery stenosis or lifestyle-limiting angina (see exclusion criteria). 1

resulting in an increase in the number of patients referred for CABG surgery. Though comprehensive results are not available at this early stage of patient accrual, of the initial 41 patients randomized, 95% have NYHA class II, III or IV heart failure, the average preoperative EF is 25 B 7%, and the average LVESVI is 95 B 48 ml/m2. Over 80% of patients have left anterior descending artery stenosis 675%; 37% of patients have mild mitral regurgitation, and 10% have moderate or severe mitral regurgitation. Of those patients

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SVR Stratification and Randomization

CAD / CHF EF <– 0.35

SVR Eligible? 2,200 Pts

R 600 Pts

1 MED

2 CABG

3 MED

4 CABG

800 Pts

800 Pts

200 Pts

200 Pts

Stratum A

No

Not in Trial

Yes

R 1,600 Pts

determine if SVR offers any additional benefit over revascularization alone in those patients with ischemic dilated CHF. The trial will also determine the effectiveness of revascularization versus standard medical therapy in the same patient population. CAD = Coronary artery disease; MED = medical therapy.

SVR Eligible?

Medical Eligibility

Yes

No

Fig. 5. The focus of the STICH trial is to

No

Yes

Stratum B

R 600 Pts

5 CABG + SVR 200 Pts

6 CABG

300 Pts

7 CABG + SVR 300 Pts

Stratum C

undergoing CABG surgery, 99% have had 62 distal anastomoses. Exclusion criteria for the trial are provided in table 2. It should be emphasized that patients ineligible for medical treatment and patients with lifestyle-limiting angina or significant coronary artery disease (650% stenosis), involving the left main coronary artery, will automatically be enrolled in stratum C and receive coronary revascularization. Furthermore, to be an appropriate candidate for SVR, the patient must have significant LV dilatation as assessed by the surgeon, which for most surgeons is an LVESVI 160 ml/m2 (table 2). In order to enable safe and feasible reconstruction of the LV, there must exist significant septal and anterior wall asynergy (135% akinesis/dyskinesis of these regions), which would ideally not involve significant portions of the posterior/inferior LV. In addition, the STICH trial will determine the longterm outcome and durability of SVR surgery. Emerging evidence demonstrates that further remodeling and LV redilatation may occur over time following SVR surgery [26]. This yet to be understood phenomenon may be attributed to (1) progression of LV remodeling in terms of cardiac myocyte hypertrophy and fibrosis [31], (2) further

progression of coronary artery disease, or (3) iatrogenic causes, in that the reduction in LV volume may be too large to allow for adequate diastolic function (LV restrictive physiology). It is likely, given the chronicity of disease prior to surgical therapy (mean time to surgery from the point of myocardial infarction has historically been 36 months [27]) and the preexistence of remodeled remote myocardium, that despite decreased systolic wall stress there may not be an adequate augmentation of diastolic performance in some patients to allow for reversal or attenuation of the progression of LV remodeling. The surgeon, though able to reduce LV chamber size dramatically, cannot reduce chamber volume to normal values (normal LVESVI = 25–30 ml/m2 versus RESTORE group postprocedure LVESVI = 69 ml/m2) [30]. Better survival rates and less physiological derangements are seen in those patients with better preoperative function, less LV dilatation and less delay to surgical therapy [26, 27, 29, 30]. Therefore, it may be that the intrinsic properties within the chronically remodeled myocardium limit the surgeon’s ability to completely return LV chamber size (wall stress) to normal without risking too small a ventricle and compromised diastolic function. If the promise of earlier intervention can be realized, it may be

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possible to surgically exclude areas of asynergy prior to the patient crossing that yet to be defined threshold that inevitably leads to progressive and possibly irreversible ventricular remodeling, dilatation and LV dysfunction.

Cellular Cardiomyoplasty

As was discussed in the prior section, injury to cardiac myocytes by ischemia can lead to myocyte death with replacement by fibrous scar and eventual CHF. CHF currently affects over 5 million people in the United States, with heart transplantation being the only long-term, clinically effective therapy [32]. Current organ shortages and transplant program listing criteria restrictions have acted to decrease the number of heart transplants performed over the last several years [33]. Though the decline in whole organ heart transplants is concerning, the fact remains that heart transplantation never offered any significant epidemiological impact given the disparity between organ availability and the vast number of patients with progressive or end-stage CHF. Therefore, a recent conceptual alternative to end-stage heart failure and heart transplantation is the concept of cellular transplantation (CCM) [34, 35]. Immature cells or tissues are grafted to the heart in key areas of myocardial dysfunction with the goal of angiogenesis, vasculogenesis and/or myogenesis to promote functional restoration. Animal Studies with Autologous Skeletal Myoblast CCM Unlike cardiac myocytes, skeletal muscle when injured retains the ability to regenerate. It is now well established that the regenerative capacity of skeletal muscle resides in cells known as satellite cells (myoblasts), which were first described in 1961 by Mauro [36]. These myoblasts tolerate ischemia well and can remain viable in scars for several months, which we have demonstrated in a sheep model of heart failure (fig. 6) [37–39]. Myofibers derived from myoblast grafts will contract in vitro with electrical stimulation and can differentiate into fatigue-resistant slowtwitch fibers, which would make them well suited for cardiac activity [34, 40, 41]. It remains to be determined whether these myoblast-derived myofibers will contract independently of electrical stimulation or synchronously with adjacent cardiac myocytes. Experimental work in animals subjected to either LV cryolesions or coronary artery ligation to induce LV dysfunction demonstrated that cardiac function measured by noninvasive techniques improved after myoblast trans-

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plantation [42–46]. Ghostine et al. [45] demonstrated by echocardiography that LVEF was reduced but stable after left circumflex coronary artery embolization (LVEF 48%) in sheep transplanted with myoblasts. Early LVEF (after left circumflex coronary artery embolization) was 48% and late (after 4 months) LVEF was 50% in transplanted animals, compared to early LVEF of 43% and late LVEF of 33% in control animals [45]. Tissue Doppler imaging in these same animals indicated decreased myocardial velocity gradients in control animals with infarcts, compared to increased myocardial velocity gradients at 4 months in myoblast-transplanted animals. These findings were maintained at 1 year in the sheep receiving myoblast transplants after coronary embolization. Myoblasts from predominately fast-twitch skeletal muscle can selectively differentiate into myofibers expressing myosin heavy chain isoforms and, uniquely, into myofibers expressing fatigue-resistant slow-twitch isoforms [38, 45]. The capacity for myoblasts to fuse into myotubules, differentiate into myofibers and selectively differentiate into slow-twitch isoforms appears to occur in response to the physiologic milieu into which the myoblasts are placed [47, 48]. As yet, there is no evidence to suggest that skeletal myoblasts are capable of forming gap junctions with native cardiac myocytes or of expressing connexin 43 (a cardiac-specific gap junction protein presumed necessary for coordinated cardiomyocyte function). Furthermore, to date, no large animal studies have been performed in recipient animals with abnormal cardiac hemodynamics prior to myoblast transplantation comparable to end-stage ischemic CHF seen in humans. The survival and function of implanted myoblasts under these requisite stresses is of fundamental importance. Now that early human studies are under way (next section), it is increasingly important to continue further basic laboratory studies focused on addressing the myriad of questions associated with this burgeoning technology. Phase One Human Trials of Autologous Skeletal Myoblast CCM Considering the number of patients with end-stage CHF, the lack of effective therapeutic alternatives and the promise of early animal studies, the incentive is tremendous for advancing CCM in humans. Human autologous skeletal myoblast transplantation has been undertaken in both Europe and the United States. In 2001, Menasche et al. [49] reported the first human autologous myoblast transplantation in a patient undergoing concomitant CABG [49]. Encouraging findings with both transthoracic echocardiography and positron emission tomography

McConnell/Michler

Fig. 6. In a sheep with experimental isch-

emic CHF transplanted with autologous skeletal myoblasts at The Ohio State University Medical Center, viable skeletal muscle is evident (A) within an area of myocardial fibrosis 6 weeks after transplantation. Myogenin, a nuclear protein specific for skeletal muscle, is seen staining nuclei of muscle cells (B), whose location coincides with cells that stain for myosin heavy chain (C). These panels demonstrate the ability of transplanted autologous skeletal myoblasts to survive and differentiate into skeletal muscle.

(PET) demonstrated improved regional function and viability in key areas (nonrevascularized segments) after skeletal myoblast transplantation. As part of the first phase one trial in Europe, Menasche et al. [50] reported on 10 patients with LVEF !35% who were evaluated and found to be candidates for coronary revascularization. These patients were concomitantly transplanted with approximately 800 million autologous skeletal myoblasts at the time of CABG. On average, there was an improvement in

LVEF from 24 to 32% after CCM and CABG. Blinded echocardiographic assessment of regional wall function demonstrated improvement in 63% of implanted scars. Four of the 10 patients required automatic internal cardiac defibrillator (AICD) implantation during the followup period (range 5–17.5 months). These early results are promising; however, the local functional improvement secondary to engraftment cannot be unequivocally attributed to the autologous myoblast transplant since these

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Fig. 7. Viable autologous skeletal myotubules are seen within fibrotic

(scarred) myocardium from an LVAD recipient 6 days after myoblast transplant. A Trichrome staining demonstrates native cardiac myocytes (asterisk) along the border of fibrosis with viable multinucleated myotubules (white and black arrows) engrafted within this area of fibrosis. B Immunostaining with skeletal muscle-specific myogenin confirms that the myotubules are skeletal in origin. Myoblast transplantation was carried out at the time of implantation of an LVAD. Photos courtesy of GenVec Inc. (Boston, Mass., USA).

patients underwent concomitant coronary revascularization. In addition, the molecular, cellular and arrhythmogenic impact of CCM remains unclear and requires careful additional study. A recently completed United States Food and Drug Administration (FDA) phase 1 multiinstitutional human clinical trial (The Ohio State University, Arizona Heart Institute, University of California at Los Angeles, Temple University, Cleveland Clinic Foundation and University

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of Michigan) reported on 10 patients who underwent both coronary revascularization (average 2.5 grafts/patient) and autologous myoblast transplantation, and 4 patients who underwent both implantation of an LV assist device (LVAD) and autologous myoblast transplantation [51]. This trial identified an improvement in LVEF from approximately 23% prior to surgery to 34% 12 weeks following revascularization and autologous myoblast implantation, with a corresponding symptomatic improvement in NYHA class from II (2.1) to !I (0.8), respectively [46–48]. In those patients with MRI follow-up, there was an increase in wall thickness in areas injected with myoblasts, indirectly suggesting improved perfusion and function. Two of 5 patients who underwent nuclear myocardial perfusion and PET studies demonstrated improved regional myocardial viability. Histologic evidence of autologous myoblast survival and differentiation was confirmed in 3 of the 4 LVAD-implanted patients who subsequently underwent heart transplantation and pathologic examination of the transplanted heart (fig. 7) [40, 51]. As part of this phase 1 FDA clinical trial, Pagani et al. [40] made several important observations in three recipient hearts made available after heart transplantation and LVAD explant. In summary, autologous myoblasts survived transplantation (positive staining for skeletal muscle-specific myosin heavy chain), autologous myoblasts had differentiated into both myofibers and slow-twitch myosin isoforms (positive staining for myosin heavy chain beta), autologous myofibers were aligned in parallel with host myocardial fibers, and in one patient, there was an increase in the number of blood vessels in the area of the grafted scar [40]. As with the European experience, post-myoblast transplant arrhythmias were encountered in these patients. Whether these ventricular arrhythmias were causally related to the myoblasts remains to be investigated, since many of these low-LVEF patients have underlying arrhythmic substrates. Two patients of the 10 undergoing concomitant CABG demonstrated nonsustained ventricular tachycardia, with another patient requiring rehospitalization and eventually AICD placement for inducible monomorphic ventricular tachycardia. In this patient, the recurrent ventricular tachycardia may have been independent of myoblast transplantation, based upon coronary angiography, coronary blood flow assessment and electrophysiology studies demonstrating technical issues with the bypass grafts postoperatively, presumably resulting in local ischemia leading to inducible arrhythmia. One additional patient, who underwent planned AICD placement as part of a biventricular pacing regimen for CHF,

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had their device discharged twice 9 months postoperatively. Currently, two new FDA phase 1 trials (one using direct injection at the time of CABG and the second employing a catheter-based endoventricular implantation technique) are under way in the United States. The original US FDA clinical trial utilized successive increases in cell number, beginning at 2 million and ending at 300 million cells [incidentally, 300 million cells is approximately 1/3 of the number used in the European trial (approximately 800 million)]. A major focus for the latest FDA clinical trial involving direct myocardial injection will be to use a fixed dose of cells (300 million) targeted to areas of scar remote from the area of revascularization. Other modifications of the previous study involve improved pre- and postoperative evaluation in determining areas of hibernation from advanced scar (MRI, PET and perfusion imaging). Moreover, the effects of revascularization as distinguished from the effects of CCM should be better accounted for with the more rigorous evaluation practices and targeting cell transplants to nonrevascularized areas of myocardial scar. However, the optimal number of transplanted cells still has yet to be determined, and this is particularly important since recent evidence suggests that !1% of injected myoblasts are retained within the human myocardium after injection [40]. Information gained from the few patients involved in these phase 1 trials will likely not be sufficient to determine ideal cell numbers, particularly given the multitude of variables that could and most certainly will impact on cell survival (e.g. injection technique(s), cardioplegia, concomitant drug therapy, adequacy of revascularization, degree of CHF/LV dilatation, AICD/BiVentricular pacing, patient age). The issue of cell leakage from the injection tract at the time of injection has technically been an issue with the direct injection methods, but has been improved with modifications to the amount of media injected with the cells per injection site, as well as patience, i.e. allowing time for absorption prior to removal of the delivery needle (approx 30 s/injection). Little information exists regarding the efficacy and adequacy of cell delivery via catheter-based, intraventricular delivery methods. Though intraventricular delivery methods are less invasive, insight gained from experience with direct injection in preventing media and cell leakage will undoubtedly be helpful using these catheter-based techniques. The potential leakage of cells back into the LV cavity with intracavitary delivery methods may be accentuated with the short needles used in these catheter-based techniques. The time required and the adequacy of verify-

ing the appropriate area within the LV to be injected and then to inject upwards of 20–30 appropriate sites (typical number of injections used with direct injection procedures) may be prohibitive with respect to time for both the technician and patient. Furthermore, if only a fraction of those cells remain within the myocardium, the benefit may be reduced over more direct injection techniques. The issue of efficiency of injection methods as well as the number of cells to be transplanted has not been systematically studied in animals and will need to be an area of study that receives adequate attention either in an appropriate animal model or in patients as experience with this technology progresses.

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Stem Cells and Beyond

Though skeletal myoblasts possess the potential to differentiate into myofibers, they lack the potential to differentiate into cardiac muscle with its vitally important capacity for cell-to-cell integration and synchronous contraction. Improvement in myocardial function has been demonstrated in animal models treated with other types of CCM, including cardiomyocytes [42, 43, 46], embryonic stem cells [52] and adult-derived stem cells [53– 55]. Autologous bone marrow-derived adult stem cells (BM-SCs) are one source of stem cells (less controversial than embryonic stem cells) and have the potential for cardiac myocyte differentiation, angiogenesis and vasculogenesis, without the need for immunosuppression [56, 57]. Each of these cell types have drawbacks to their use, which include availability and sensitivity to ischemia for cardiomyocytes, ethical issues and consistent directed differentiation for embryonic stem cells, and inefficiency of generating cardiomyocytes for adult stem cells. Many of these limitations will hopefully be overcome with time and investigation. A number of animal studies have demonstrated that myocardial function can improve following CCM with adult-derived stem cells. Tomita et al. [53] demonstrated in rats transplanted with BM-SCs and pretreated with 5azacytidine (promotes myogenic differentiation) that capillary density increased and muscle-like cells appeared in injected scars when compared to control animals. Furthermore, those animals transplanted with 5-azacytidinetreated BM-SCs had greater wall thickness, smaller ventricular chambers and improved cardiac performance in an isolated heart preparation (Langendorff) than control animals [53]. In a pig model of myocardial infarction,

57

functional studies using sonomicrometry demonstrated attenuation of contractile dysfunction (systolic wall thickening 5.5% versus 3.4% in controls at 4 weeks) and less wall thinning in those animals that received mesenchymal stem cell transplants [54]. Recently, autologous bone marrow and stem cell transplants in humans have been reported in the lay press, which obviously foreshadows the importance of this emerging area of cell therapy [58]. In humans, Strauer et al. [55] delivered BM-SCs via a transcoronary approach into the infarct-related artery at the time of percutaneous transcoronary intervention (stent in 19/20 patients). These authors found that intracoronary administration of BM-SCs with stent/angioplasty intervention resulted in improved functional indices 3 months after the procedure [stroke volume index, fiber shortening and Psys/ESV (pressure systolic/end systolic volume) (contractility index)], improved regional perfusion and decreased LV chamber size [55]. Endoventricular catheter-based delivery methods have been employed to transplant BM-SCs in selected patients. Fuchs et al. [59] successfully transplanted BM-SCs in 10 patients using a catheter-based endoventricular injection technique guided by electromechanical mapping to identify areas of ischemia. Procedural time was reported for both mapping and injection to average less than 1 h in these 10 patients. Three-month follow-up did not demonstrate any statistically significant differences in objective indices of myocardial function or perfusion, and these findings call into question whether a sufficient volume of cells was transplanted into the myocardium. As was discussed in the previous section, leakage of cells occurs with

direct visualization surgical techniques, and this is likely to be compounded by catheter-based techniques. Techniques for labeling cells with ferrous compounds or other paramagnetic particles prior to CCM are emerging and would permit patients to be followed postoperatively to ensure proper localization of the injected cells and, potentially, the viability and function of those transplanted cells. MRI-compatible labeling techniques have been developed for stem cells injected into animals, demonstrating proof of the concept for this technique [60, 61]. However, myocardial function studies have not yet been reported in animals with heart failure treated with paramagnetic labeled cells. In addition, the detection of labeled cells following transplantation has not yet been demonstrated to correlate with survival of those cells. By now, the reader is likely to have come to the conclusion that future therapies for heart failure will probably include cell-based treatment strategies combined with other procedures such as ventricular restoration or mechanical devices. The combination of a mechanical device and CCM is particularly intriguing, since it offers the potential of resting the heart while transplanted cells grow and differentiate in the hemodynamically unloaded heart. These therapies will require the close collaboration of both cardiologists and cardiac surgeons in treating and offering CHF patients appropriate options. Therefore, the imperative need to understand the rational basis and utilization of these emerging therapeutics is increasingly important as heart failure specialists trudge the road towards realistic and suitable epidemiological solutions for patients with end-stage CHF.

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4 Pfeffer MA, Pfeffer JM: Ventricular enlargement and reduced survival after myocardial infarction. Circulation 1987;75(suppl IV):IV93–IV-97. 5 White HD, Norris RM, Brown MA, Brandt PWT, Whitlock RML, Wild CJ: Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987;76:44–51. 6 Zijlstra F, de Boer MJ, Hoorntje JC, Reiffers S, Reiber JH, Suryapranata A: A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. Circulation 1994;89:68–75. 7 Bolling SF, Pagani FD, Deeb GM, Bach DS: Intermediate-term outcome of mitral reconstruction in cardiomyopathy. J Thorac Cardiovasc Surg 1998;115:381–388.

8 National Heart, Lung, and Blood Institute: National Institutes of Health Data Fact Sheet: Congestive Heart Failure in the United States: A New Epidemic. NHLBI web site: http:// www/nhlbi.nih.gov/health/public/heart/other/ CHF.htm. 9 Demirovic J, Prineas R, Rudolph M: Epidemiology of congestive heart failure in three ethnic groups. Congest Heart Fail 2001;7:93–96. 10 Cope JT, Kaza AK, Reade CC, Shockey KS, Kern JA, Tribble CG, Kron IL: A cost comparison of heart transplantation versus alternative operations for cardiomyopathy. Ann Thorac Surg 2001;72:1298–1305. 11 Trachiotis GD, Weintraub WS, Johnston TS Jones EL, Guyton RA, Craver JM: Coronary artery bypass grafting in patients with advanced left ventricular dysfunction. Ann Thorac Surg 1998;66:1632–1639.

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12 Bodi V, Sanchis J, Berenguer A, Insa LD, Chorro FJ, Llacer A, Lopez-Merino V: Wall motion of non-infarcted myocardium: Relationship to regional and global systolic function and to early and late left ventricular dilatation. Int J Cardiol 1999;71:157–165. 13 Mitchell GF, Lamas GA, Vaughan DE, Pfeffer MA: Left ventricular remodeling in the year after first anterior myocardial infarction: A quantitative analysis of contractile segment lengths and ventricular shape. J Am Coll Cardiol 1992;19:1136–1144. 14 Paulus WJ: How are cytokines activated in heart failure? Eur J Heart Fail 1999;1:309– 312. 15 Baumgarten G, Knuefermann P, Kalra D, Feng G, Taffet GE, Michael L, Blackshear PJ, Carballo E, Sivasubramanian N, Mann DL: Loaddependent and -independent regulation of proinflammatory cytokine and cytokine receptor gene expression in the adult mammalian heart. Circulation 2002;105:2192–2197. 16 Crilley JG, Farrer M: Left ventricular remodeling and brain natriuretic peptide after first myocardial infarction. Heart 2001;86:638– 642. 17 Richards AM, Nichols MG, Yandle TG, Ikram H, Espiner EA, Turner JG, Baltimore RC, Lainchbury JG, Elliot JM, Frampton C, Crozier IG, Smyth DW: Neuroendocrine prediction of left ventricular function and heart failure after acute myocardial infarction. Heart 1999;81:114–201. 18 Serneri GGN, Modesti PA, Boddi M, Cecioni I, Paniccia R, Coppo M, Galanti G, Simonetti I, Vanni S, Papa L, Bandinelli B, Miglioroni A, Modesti A, Maccharini M, Sani G, Toscano M: Cardiac growth factors in human hypertrophy: Relations with myocardial contractility and wall stress. Circ Res 1999;85:57–67. 19 Pfeffer MA, Braunwald E: Ventricular remodeling after myocardial infarction: Experimental observations and clinical implications. Circulation 1990;81:1161–1172. 20 Altman l: Brazil surgeon develops a bold, promising operation for patients with heart failure. New York Times, June 14, 1996, section A:16. 21 Cooley D: Ventricular endoaneurysmorrhaphy: A simplified repair for extensive postinfarction aneurysm. J Card Surg 1989;4:200– 205. 22 Jatene AD: Left ventricular aneurysmectomy: Resection or reconstruction. J Thorac Cardiovasc Surg 1985;89:321–331. 23 Di Donato M, Toso A, Maioli M, Sabatier M, Stanley AWH, Dor V: Intermediate survival and predictors of death after surgical ventricular restoration. Semin Thorac Cardiovasc Surg 2001;13:468–475. 24 Buckberg G: Defining the relationship between akinesia and dyskinesia and the cause of left ventricular failure after anterior infarction and reversal of remodeling to restoration. J Thorac Cardiovasc Surg 1998;116:47–49.

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25 Di Donato M, Sabatier M, Dor V, Toso A, Maioli M, Fantini F: Akinetic versus dyskinetic postinfarction scar: Relation to surgical outcome in patients undergoing endoventricular circular patch plasty repair. J Am Coll Cardiol 1997;29:1569–1575. 26 Dor V, Sabatier M, Di Donato M, Montiglio F, Toso A, Maioli M: Efficacy of endoventricular patch plasty in large postinfarction akinetic scar and severe left ventricular dysfunction: Comparison with a series of large dyskinetic scars. J Thorac Cardiovasc Surg 1998;116:50– 59. 27 Menicanti L, Di Donato M: The Dor procedure: What has changed after fifteen years of clinical practice? J Thorac Cardiovasc Surg 2002;124:886–890. 28 Di Donato M, Sabatier M, Toso A, Barletta G, Baroni M, Dor V, Fantini F: Regional myocardial performance of non-ischemic zones remote from anterior wall left ventricular aneurysm: Effects of aneurysmectomy. Eur Heart J 1995;16:1285–1292. 29 Athanasuleas CL, Stanley AWH, Buckberg GD, Dor V, Di Donato M, Siler W: Surgical anterior ventricular endocardial restoration for dilated ischemic cardiomyopathy. Semin Thorac Cardiovasc Surg 2001;13:448–457. 30 Athanasuleas CL, Stanley AWH, Buckberg GD, Dor V, Di Donato M, Blackstone EH: Surgical anterior ventricular endocardial restoration in the dilated remodeled ventricle after anterior myocardial infarction. RESTORE group. Reconstructive Endoventricular Surgery, returning Torsion Original Radius Elliptical Shape to the LV. J Am Coll Cardiol 2001; 37:1999–1209. 31 Beltrami CA, Finato N, Rocco M, Fergulio GA, Puricelli C, Cigola E, Sonnenblick EW, Olivetti G, Anversa P: The cellular basis of dilated cardiomyopathy in humans. J Mol Cell Cardiol 1995;27:291–305. 32 Hunt SA, Baker DW, Chin MH, Cinquegrani M, Feldmanmd AM, Francis GS, Ganaits TG, Goldstein S, Gregoratos G, Jessup M, Noble RJ, Packer M, Silver MA, Stevenson LW, Gibbons RJ, Altman EM, Alpert JS, Faxon DP, Fuster V, Jacobs AK, Hiratzka LF, Russell RO, Smith SC: ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary. 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): Developed in Collaboration with the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America. Circulation 2001;104:2996–3007. 33 Hertz MI, Taylor DO, Trulock EP, Boucek MM, Mahasci PJ, Edwards LB, Keck BM: The registry of the international society of heart and lung transplantation: Nineteenth official report – 2002. J Heart Lung Transplant 2002;21:950– 970.

34 Chiu RCJ, Zibaitis A, Koa RL: Cellular cardiomyoplasty: Myocardial regeneration with satellite cell implantation. Ann Thorac Surg 1995; 60:12–18. 35 Reinlib L, Field L: Cell transplantation as future therapy for cardiovascular disease? Circulation 2000;101:e182–e187. 36 Mauro A: Satellite cell of skeletal muscle fibers. J Biophys Biochem Cytol 1961;9:493–495. 37 Atkins BZ, Hueman MT, Meuchel J, Hutcheson KA, Glower DD, Taylor DA: Cellular cardiomyoplasty improves diastolic properties of the injured heart. J Surg Res 1999;85:234– 242. 38 Jain M, DerSimonian H, Brenner DA, Ngoy S, Teller P, Edge ASB, Zawadzka A, Wetzel K, Sawyer DB, Colucci WS, Apstein CS, Liao R: Cell therapy attenuates deleterious ventricular remodeling and improves cardiac performance after myocardial infarction. Circulation 2001; 103:1920–1927. 39 Hutcheson KA, Atkins BZ, Hueman MT, Hopkins MB, Glower DD, Taylor DA: Comparison of benefits on myocardial performance of cellular cardiomyoplasty with skeletal myoblasts and fibroblasts. Cell Transplant 2000;9:359– 368. 40 Pagani FD, DerSimonian H, Zawadzka A, Wetzel K, Edge ASB, Jacoby DB, Dinsmore JH, Wright S, Aretz TH, Eisen HJ, Aaronson KD: Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. J Am Coll Cardiol 2003;41:879–888. 41 Reinecke H, MacDonald GH, Hauschka SD, Murry CE: Electromechanical coupling between skeletal and cardiac muscle: Implication for infarct repair. J Cell Biol 2000;149:731– 740. 42 Li RK, Jia ZQ, Weisel RD, Mickle DAG, Zhang J, Mohabeer MK, Rao V, Ivanov J: Cardiomyocyte transplantation improves heart function. Ann Thorac Surg 1996;62:654–661. 43 Scorsin M, Hagege A, Vilquin JT, Fiszman M, Marotte F, Samuel JL, Rappaport L, Schwartz K, Menasche P: Comparison of effects of fetal cardiomyocyte and skeletal myoblast transplantation on postinfarction left ventricular function. J Thorac Cardiovasc Surg 2000;119: 1169–1175. 44 Taylor DA, Atkins BZ, Hungspreugs P, Jones TR, Reedy MC, Hutcheson KA, Glower DD, Kraus WE: Regenerating functional myocardium: Improved performance after skeletal myoblast transplantation. Nat Med 1998;4: 929–933. 45 Ghostine S, Carrion C, Souza LCG, Richard P, Bruneval P, Vilquin JT, Pouzet B, Schwartz K, Menasche P, Hagege AA: Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction. Circulation 2002;106(suppl I):I131–I136. 46 Yoo KJ, Li RK, Weisel RD, Mickle DAG, Jia ZQ, Kim EJ, Tomita S, Yau TM: Heart cell transplantation improves heart function in dilated cardiomyopathic hamsters. Circulation 2000;102(suppl 3):III204–III209.

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47 Dorfman J, Duong M, Zibaitis A, Pelletier MP, Shum-Tim D, Li C, Chui RC: Myocardial tissue engineering with autologous myoblast implantation. J Thorac Cardiovasc Surg 1998; 116:744–751. 48 Atkins BZ, Lewis CW, Kraus WE, Hutcheson KA, Glower DD, Taylor DA: Intracardiac transplantation of skeletal myoblasts yields two populations of striated cells in situ. Ann Thorac Surg 1999;67:124–129. 49 Menasche P, Hagege AA, Scorsin M, Pouzet B, Desnos M, Duboc D, Schwartz K, Vilquin JT, Marolleau JP: Myoblast transplantation for heart failure. Lancet 2001;357:279–280. 50 Menasche P, Hagege AA, Vilquin JT, Desnos M, Abergel E, Pouzet B, Bel A, Sarateanu S, Scorsin M, Schwartz K, Bruneval P, Benbunan M, Marolleau JP, Duboc D: Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 2003;41:1078–1083. 51 Dib N, McCarthy P, Campbell A, Yeager M, Pagani F, Wright S, MacLellan R, Fonarow G, Eisen HJ, Furukawa S, Michler RE, Binkley P, Buchele D, Korn R, Ghazoul M, Dinsmore J, Diethrich E: Initial results of the safety and feasibility of autologous myoblasts transplantation in patients with ischemic cardiomyopathy: The United States experience. Circulation, in review.

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52 Klug MG, Soonpaa MH, Koh GY, Field LJ: Genetically selected cardiomyocytes from differentiating embryonic stem cells form stable intracardiac grafts. J Clin Invest 1996;98:216– 224. 53 Tomita S, Li RK, Weisel RD, Mickle DAG, Kim EJ, Sakai T, Jia ZQ: Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 1999;100 (suppl II):II-247–II-256. 54 Shake JG, Gruber PJ, Baumbartner WA, Senechal G, Meyers J, Redmond M, Pittenger MF, Martin BJ: Mesenchymal stem cell implantation in a swine myocardial infarct model: Engraftment and functional effects. Ann Thorac Surg 2002;73:1919–1926. 55 Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P: Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002; 106:1913–1918. 56 Kamihata H, Matsubara H, Nishiue T, Fugiyama S, Tsutsumi Y, Ozono R, Masaki H, Mori Y, Iba O, Tateishi E, Kosaki A, Shintani S, Muroharo T, Imaizumi T, Iwasaka T: Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands and cytokines. Circulation 2001;104:1046–1052.

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57 Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S: Neovascularization of ischemic myocardium by human bone marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001;7:430–436. 58 Associated Press: Stem cells transplanted to teen’s heart: Experimental procedure aims to grow new muscle, vessels. CNN.com, March 6, 2003. 59 Fuchs S, Satler LF, Kornowski R, Okubagazi P, Weisz G, Baffour R, Waksman R, Weissmen NJ, Cerqueiria M, Leon MB, Epstein SE: Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: A feasibility study. J Am Coll Cardiol 2003;41:1721–1724. 60 Kraitchman DL, Heldman AW, Atalar E, Amado LC, Martin BJ, Pittenger MF, Hare JM, Bulte JWM: In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 2003;107:2290– 2293. 61 Garot J, Unterseeh T, Teiger E, Champagne S, Chazaud B, Gherardi R, Hittinger L, Gueret P, Rahmouni A: Magnetic resonance imaging of targeted catheter based implantation of myogenic precursor cells into infarcted left ventricular myocardium. J Am Coll Cardiol 2003;41: 1841–1846.

McConnell/Michler

Cardiology 2004;101:61–71 DOI: 10.1159/000075986

Ventricular Reconstruction Surgery for Congestive Heart Failure Richard Lee Katherine J. Hoercher Patrick M. McCarthy Department of Thoracic and Cardiovascular Surgery, George M. and Linda H. Kaufman Center for Heart Failure, Cleveland Clinic Foundation, Cleveland, Ohio, USA

Key Words Left ventricular reconstruction W Heart failure W Cardiomyopathy

Abstract The significant increase in the prevalence of heart failure in the United States has made this disease a major health problem. The continued shortage of donor organs has prevented heart transplantation from becoming an effective solution for the treatment of end-stage heart failure, and as a result, surgical treatments for heart failure have been reexamined. Surgical therapies represent the evolution of conventional operations, such as coronary artery bypass surgery, and the application of the more novel left ventricular (LV) reconstruction operations which address the geometry of the LV, the important component in the failing heart. Copyright © 2004 S. Karger AG, Basel

Introduction

The evolving epidemiology and demographics of cardiovascular disease have resulted in radical changes in the practice of cardiovascular medicine [1]. The significant increase in the prevalence, morbidity and mortality of

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Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

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congestive heart failure has made this disease a major health problem in the United States [2, 3]. The limited supply of donor organs has prevented heart transplantation from becoming an effective solution for the treatment of heart failure, and as a result, all patients with cardiomyopathy should be assessed for nontransplant alternatives. Improved surgical outcomes with sicker patients have caused an increase in the application of surgery to treat this terminal disease. Surgical correction of cardiac pathology in congestive heart failure is no longer practiced only when all medical options have failed. Rather, surgery has become an important adjunct to medical therapy and is applied earlier in order to improve symptoms and survival [4]. One important component of the surgical treatment of congestive heart failure addresses the geometry of the left ventricle (LV). In the failing heart, the normal elliptical ventricular shape is lost. A dilated, spherical muscle or a pathologically ‘remodeled’ ventricle results. LV chamber enlargement is a compensatory response commonly seen after many forms of myocardial injury, and although this is initially beneficial, eventually this pathological remodeling actually limits the ability of the heart to pump efficiently. The remodeled shape progresses from being an effect of heart failure to a contributing cause of heart failure [5]. In an effort to improve symptoms and survival in these patients, procedures and devices to arrest or reverse

Patrick M. McCarthy, MD Department of Thoracic and Cardiovascular Surgery 9500 Euclid Avenue, F25 Cleveland, OH 44195 (USA) Tel. +1 216 444 0648, Fax +1 216 445 3272, E-Mail [email protected]

remodeling and improve cardiac function are at the forefront of surgical management for heart failure. Attempts at geometrical restoration have been applied to heart failure caused by multiple etiologies. Surgical reconstruction attempts to restore normal geometry to the dysfunctional ischemic LV. This involves exclusion of the noncontributing part of the ventricle. The concept of surgical LV reconstruction in ischemic cardiomyopathy has existed since 1944. Dr. Claude Beck developed an animal model of an LV aneurysm, attached strips of fascia lata to the aneurysm, and plicated the fascia lata as a means of repair [6]. He applied this technique to one patient who died from empyema 5 weeks postoperatively. The first successful surgical correction of an LV aneurysm did not occur until 1957. Via a left thoracotomy without cardiopulmonary bypass, Charles Bailey placed a large clamp on the base of a ventricular aneurysm, passed a horizontal mattress suture beneath and excised the aneurysm. One year later, Denton Cooley performed a resection of an LV aneurysm on cardiopulmonary bypass using a technique that remained unchanged for nearly 30 years [7]. With the application of novel techniques, surgical reconstruction of the dysfunctional LV has made tremendous advances in recent years. Ventricular reconstruction now includes the LV septum, which had been neglected with conventional aneurysmectomy. Whatever variation of this technique is employed, restoration of LV geometry is critical to optimize LV function. Nonischemic cardiomyopathy is a different problem and has been studied with three techniques: the dynamic cardiomyoplasty (DCMP), the partial left ventriculectomy (PLV) and the Acorn CorCap. Although originally intended as a method of providing mechanical support to the failing heart, DCMP, which wrapped the patient’s own latissimus dorsi around the heart, became the first widely used operation to inhibit ventricular remodeling. Carpentier and Chachques [8] performed the first successful surgery on a human in 1985. Since that time, improvements in patient selection, surgical technique and optimal cardiostimulator settings have occurred. Although this procedure improved the functional status of many of the survivors, evidence of improvement of accompanying hemodynamic parameters was inconsistent [9, 10]. Further, the operative mortality in very end-stage disease was prohibitively high, and as a result, DCMP is not currently being performed. PLV was introduced by Randas Batista in 1994. This procedure has for the most part also been abandoned due to unacceptable perioperative mortality and morbidity [11]. However, this procedure is still performed with

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improving results at a few select centers in Europe and Asia [12]. More importantly, both these experiences spawned a new generation of devices designed to change LV shape and reduce wall stress. This chapter will discuss the theory and technique of LV reconstruction surgery for both ischemic and nonischemic cardiomyopathy.

LV Reconstruction for Ischemic Cardiomyopathy

In patients with ischemic cardiomyopathy, anterior myocardial infarction is a common initiating event, leading to loss of function of the anterior LV and parts of the interventricular septum [13]. As necrotic muscle is slowly replaced by fibrous tissue, significant scarring occurs and often an area of relative thinning following the distribution of the occluded artery [14]. LV aneurysm has been reported to occur in 4–20% of patients following transmural myocardial infarction [15]. In areas remote from the initial infarct, progressive LV remodeling occurs in order to compensate for the loss of contractile function in the infarcted segment. The consequences of LV chamber dilatation are heart failure, associated ventricular arrhythmias, repeated hospitalizations and ultimately death. Research in the 1990s has taught us that LV size and shape is a critical correlate in the progression of heart failure and associated mortality. In 382 patients with New York Heart Association (NYHA) class III and IV heart failure referred for cardiac transplantation, Lee et al. [16] found that LV dilation as measured by the LV index (LV end-diastolic dimension/estimated body surface area) was a predictor of sudden death which was independent of disease etiology and ejection fraction (EF). In patients with massively dilated LVs greater than 4 cm/m2, 2-year survival was 49%; patients with LVs less than 4 cm/m2 had a 2-year survival of 75% [16]. Ventricular volume predicts survival after medical revascularization. As part of the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries trial, Migrino et al. [17] evaluated end-systolic volume at 90– 180 min into reperfusion during acute myocardial infarction. An LV end-systolic volume index greater than 40 ml/m2 was a powerful predictor of adverse outcomes, including early and late death. Ventricular volume is also a prognostic indicator even after surgical revascularization. Coronary artery bypass surgery improves or relieves angina and prolongs the life expectancy of patients with ischemic cardiomyopathy. However, recent studies have demonstrated that in the

Lee/Hoercher/McCarthy

subset of patients with grossly increased LV volumes, the benefits of revascularization are limited. Yamaguchi et al. [18] identified an LV end-systolic volume index greater than 100 ml/m2 as an independent risk factor for the development of congestive heart failure after coronary artery bypass grafting. More importantly, the actuarial survival of these patients was significantly worse. These reports support the concept of surgical LV reconstruction in an effort to reduce the chamber volume and to decrease wall stress with the goal of improving overall cardiac performance, which will hopefully translate into improvement of both function and long-term survival. The challenge has been to identify the patients who benefit most. Infarcted areas are of two general morphological types: (1) dyskinesia and (2) akinesia. Dyskinetic segments are true LV aneurysms. They are transmural LV infarcts with thin walls that lead to paradoxical segmental outward bulging during LV systole. Akinetic segments are LV infarcts generally with a thin rim of viable myocardium. These segments do not move during systole but have enough myocardium to prevent paradoxical bulging [19]. The development of a classic dyskinetic aneurysm or significant akinesis appears to be related to many factors, including time to development of the scarring and the extent of collateral circulation, as well as the influence of age, gender and comorbid conditions [14]. Additionally, patients with akinetic segments may be more likely to have other noninfarcted dysfunctional LV segments and worse baseline hemodynamics than patients with dyskinesia [19, 20]. For nearly 30 years, surgeons attempted to reproducibly resect an LV aneurysm to improve LV function. However, the technique that they employed was the same technique described by Cooley et al. [7] in 1958. The surgery involved excision of the grossly thinned (usually anterior) LV segment with subsequent linear closure of the two edges. However, the unpredictable clinical outcomes associated with the surgical resection of LV aneurysms appear to have been reflected in the small numbers of these procedures being performed. Indeed, the surgical risk from LV aneurysectomy appeared to be much higher than one would expect from a procedure that in theory should immediately improve LV function. Thus, as recently as the 1980s, repair of ventricular aneurysms was recommended only in cases with symptoms refractory to optimal medical management [21]. As our understanding of LV aneurysm pathology and its role in the development of heart failure evolved, newer surgical approaches were developed. In 1985, Jatene [25]

and Dor et al. [26] reported repair techniques that excluded the dysfunctional segment of the ventricular septum, as well as the free ventricular wall. This restored LV geometry to as close to normal as possible [22–24]. After changing his technique, Jatene [25] reduced his hospital mortality from 11.6 to 4.3%, and his late mortality from 12.6 to 3.5%. Dor et al. [26] applied their technique to areas of akinesia as well as dyskinesia. Although operative mortality was 12% in patients with large areas of akinesia, it was 0% in patients with small akinetic wall motion abnormalities [26]. However, in the subgroup of survivors with large akinetic areas, EF increased from 25 to 41%. Although several contemporary reports suggested an inferior outcome after reconstruction of akinetic segments as compared to dyskinetic segments, these surgeons used the traditional methods of aneurysm resection and linear closure [27, 28]. Currently, both akinetic and dyskinetic segments are repaired at centers with experienced surgeons. At present, essentially four variations of LV reconstruction are used that exclude the septum. These include linear closure by Jatene, modified linear closure by Mickleborough, circular closure with a patch by Dor, and double-cerclage circular closure without a patch by McCarthy. All of these techniques involve an incision into the diseased segment, exclusion of the entire diseased segment and a reduction in ventricular cavity size. In the majority of patients, the infarct, and therefore the reconstruction, is on the anterior portion of the LV. However, reconstruction has also been performed on the posterior aspect. Usually, the reconstruction is one of multiple interventions on the diseased heart. Most of these patients undergo concomitant coronary artery bypass and a variable number undergo mitral valve interventions. Indications for LV reconstruction include ischemic cardiomyopathy with heart failure, angina or arrhythmias, as well as a localized dyskinetic or akinetic area, regardless of size. Most commonly, these areas are in the left anterior descending distribution (from previous anterior myocardial infarction). Cox [29] and Dor et al. [30] have argued for a more aggressive and early approach to akinetic segments to prevent irreversible damage. Traditionally, patients have presented with heart failure and undergo LV reconstruction, but supporting the notion that early intervention before the development of heart failure is beneficial, we currently consider asymptomatic patients with LV enlargement and deteriorating LV function after an anterior myocardial infarction for this procedure. Patients with diffuse, nonlocalized scarring of the LV are generally not candidates for reconstruction.

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Fig. 1. Survival of 224 patients following LV reconstruction at the Cleveland Clinic. Overall survival at 30 days and 1, 2 and 3 years was 98, 92, 90 and 86%, respectively.

Fig. 2. Freedom from readmission at 1, 2 and 3 years was 80, 70 and

Several groups have reported large series of patients undergoing LV reconstruction with excellent results. The Reconstructive Endoventricular Surgery, returning Torsion Original Radius Elliptical shape to the LV group reported a series of 662 patients undergoing ventricular reconstruction for apical segments of akinesia and dyskinesia using the Dor or double-cerclage closure without patch technique [31]. Concomitant procedures included coronary artery bypass grafting in 92% of patients, mitral valve repair in 22% and mitral valve replacement in 3%. Hospital mortality was 7.7%. In patients with only coronary artery bypass grafting and reconstruction, mortality was 4.9%. Postoperatively, EF increased from 30 to 40%, and LV end-systolic volume decreased from 96 to 62 ml/m2. At 3 years, survival was 89.4%. Survival was lower for patients with preoperative LV volumes greater than 80 ml/m2. Freedom from hospital readmission for heart failure was 88.7%. Mickleborough et al. [32] recently reported their results with a modified linear closure. One hundred and ninety-six patients with akinetic (57%) and dyskinetic (43%) segments underwent repair. Concomitant coronary artery bypass grafting was performed in 91%. Preoperatively, 83% of patients were in NYHA class III or IV. Hospital mortality was 2.6%. Actuarial survival at 1 and 5 years was 91 and 84%, respectively. Risk factors for a poor outcome at 5 years were preoperative mitral regurgitation of 2+ or greater, congestive heart failure and ventricular tachycardia. Among the survivors, 80% were in NYHA class I or II.

At the Cleveland Clinic (Cleveland, Ohio, USA), LV reconstruction is performed in patients with a discrete left anterior descending scar, usually detected by preoperative magnetic resonance imaging scan and three-dimensional echocardiography, with compensated heart failure or other indications for surgery such as severe coronary artery disease or mitral regurgitation. Currently, our technique of LV reconstruction is predominately that of a doublecerclage circular closure no-patch repair on the beating heart. One hundred and two consecutive patients operated on with this technique were reported in 2001 [33], with a 1% hospital mortality. A patch is utilized only in patients with a calcified aneurysm in whom the pursestring sutures may not create a neck, or in patients with a small LV cavity, to avoid creating too small a cavity with a low stroke volume. Since January 1997, 224 patients (80% male, mean age 62 B10 years) have undergone LV reconstruction at the Cleveland Clinic, 69% for dyskinetic and 31% for akinetic regions, as part of comprehensive surgical management of ischemic cardiomyopathy. Before surgery, 66% were in NYHA class III or IV. The mean preoperative EF was 26 B 8.5%, and QRS duration was 121.8 B 31.6 ms. Concomitant procedures included coronary artery bypass grafting in 85% and mitral valve repair in 43%. Overall survival at 30 days and 1, 2 and 3 years was 98, 92, 90 and 86%, respectively (fig. 1). Freedom from readmission at 1, 2 and 3 years was 80, 70 and 61%, respectively (fig. 2). Readmission was more common in older patients and those with a longer QRS duration, higher

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61%, respectively, following LV reconstruction among 224 Cleveland Clinic patients.

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preoperative pulmonary artery diastolic pressures and postoperative pulmonary artery systolic pressures, and longer cardiopulmonary bypass times. Freedom from adverse events [transplant listing, return to NYHA class IV, LV assist device (LVAD) and death] at 1, 2 and 3 years was 89, 85 and 83%, respectively. We found that preoperative ventricular dysrhythmia was a powerful predictor of worse outcomes. The rates of both adverse events (p = 0.002) and readmission (p = 0.02) were significantly higher in patients with a longer QRS duration (fig. 3, 4). The presence of a preoperative automatic internal cardiac defibrillator was also associated with early mortality (p = 0.001) (fig. 5). On the other hand, preoperative NYHA class, LVEF, preoperative ventricular volumes, prior cardiac surgery and need for mitral valve repair were not risk factors for worse outcomes once the conduction disturbances were taken into account. The experience of Dor has shown that patients with akinetic ventricles do not do as well as those with dyskinetic aneurysms; however, this was of borderline significance in the Cleveland Clinic series. Outcomes in the akinetic versus the dyskinetic group were investigated by propensity analysis, and in our experience, the difference in survival between the akinetic and dyskinetic group was 80 versus 95% at 3 years (p = 0.06). These large series demonstrate that excellent results can be achieved after LV reconstruction in ischemic cardiomyopathy and further support the argument for an aggressive approach to ventricular reduction. In the future, we need to define the most appropriate candidates

Ventricular Reconstruction Surgery for Congestive Heart Failure

3

Fig. 4. Higher preoperative QRS (in ms) was associated with rehospitalization for heart failure following LV reconstruction

100 AICD 80 Survival (%)

Fig. 3. Freedom from composite events (listing for heart transplant, return to NYHA class IV and LVAD support) was associated with a higher QRS (in ms) preoperatively.

2 Years

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Fig. 5. The presence of a preoperative automatic implantable cardiac

defibrillator (AICD) was found to be a risk factor for death following LV reconstruction.

for this intervention. With the advances in imaging technology, we should be better able to predict which patients will benefit from reconstruction and which would benefit from revascularization and valvular correction alone. In addition, the distinction between akinetic and dyskinetic segments must be clearly defined. Although there are several different methods of defining segment function, a simple, reproducible method has not yet been established. Lastly, the effect of the location of the aneurysm, the effect of a patch and the indications for postoperative arrhythmia treatment need to be more completely under-

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stood. As our understanding improves, the broader application of ventricular reconstruction to patients with endstage ischemic heart disease should help provide better outcomes in this devastating disease.

LV Reconstruction for Dilated Cardiomyopathy

Dynamic Cardiomyoplasty The DCMP became the first widely used operation to inhibit ventricular remodeling. Carpentier and Chachques [8] performed the first successful surgery on a human in 1985. This breakthrough was accomplished by understanding that skeletal muscle could be transformed into slow, fatigue-resistant muscle. By developing a pacing device that was capable of stimulating skeletal muscle in synchrony with cardiac contractions, the latissimus dorsi muscle was transformed into a muscle that could contract with the beating heart [10]. The latissimus dorsi muscle was wrapped around the heart and the pacing device was implanted. Initially, the procedure was designed to support the failing LV by augmenting systolic ejection, and thus improve hemodynamics and symptoms of heart failure. However, it has been found that much of the benefit after DCMP appeared to be derived from the girdling effect of the wrap, which stabilized the remodeling process of the LV [34]. In the past 15 years, more than 800 patients have undergone DCMP. Reports from single centers have helped to refine both patient selection and operative technique. Early in the experience with DCMP, it was noted that patients with NYHA class IV heart failure experienced a prohibitively high operative mortality [35, 36]. More encouraging results were obtained in the patients with NYHA class II and III heart failure, where an improved functional status for many of the survivors was noted following the procedure. However, in most instances, evidence of improvement of accompanying hemodynamic parameters was inconsistently reproducible. Despite the modest success of this procedure, it has failed to gain widespread acceptance due to the high early mortality in those patients with advanced heart failure and lack of a demonstrated survival advantage over medical therapy. Results from a controlled randomized trial entitled Cardiomyoplasty-Skeletal Muscle Assist Randomized Trial will be released in the near future and will be useful in determining the role, if any, of DCMP in the field of heart failure surgery. However, at present, the procedure is not routinely practiced, and the pacer is no longer commercially available.

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Acorn CorCap The modest success of the DCMP inspired the creation of the Acorn CorCap. The Acorn CorCap is a custommade polyester mesh that is wrapped around the ventricles and girdles the heart (fig. 6). It is designed to provide both flexibility and strength. The design of the mesh permits bidirectional compliance of the fabric, which allows it to conform easily to the heart, and also allows it to return to a more normal ellipsoidal shape in a procedure that carries less morbidity than the DCMP [37]. Acorn CorCap placement is usually performed with concomitant valve repair or coronary artery bypass. Encouraging early clinical results led to a randomized clinical trial of the Acorn. Konertz et al. [38] examined the safety and efficacy of the Acorn in a series of 27 patients suffering from cardiomyopathy with a mean NYHA class of 2.6 B 0.1. Of these, 16 received concomitant cardiac surgery, principally mitral valve repair or replacement. The remaining 11 patients received the Acorn only. In the Acorn-only group, 5 of the 11 patients experienced adverse events, including 2 deaths during an average follow-up of 12.2 B 1.1 months, but none of the events were related to the device. Follow-up at 3 and 6 months reflected a significant improvement from pretreatment values for EF (from 21 to 28 and 33%) and NYHA functional class (from 2.5 to 1.6 and 1.7), as well as a significant decrease in LV end-diastolic dimension (from 74 to 68 and 65 mm) and LV end-systolic dimension (from 65 to 62 and 57 mm). Raman et al. [39] reported similar findings in a cohort of 5 patients undergoing Acorn placement with concomitant coronary artery bypass grafting. Midterm outcomes at 12 months of follow-up demonstrated a significant decrease in LV end-diastolic dimension and LV end-systolic dimension, with an improvement in EF and NYHA functional class [39]. From these early safety/feasibility studies, it appears that the Acorn CorCap is useful for preventing further cardiac dilation and improves symptoms of heart failure without device-related morbidity or mortality. A randomized, prospective clinical trial of the device is currently under way in Europe, the United States and Australia. This device may play a role in the treatment of dilated cardiomyopathy in the future. Partial Left Ventriculectomy In 1996, Randas Batista [40] proposed the concept of ventricular volume reduction or PLV. Initially, the procedure and its promoter drew a great deal of attention and interest from both physicians and the thousands of pa-

Lee/Hoercher/McCarthy

tients suffering from heart failure. This procedure offered an alternative to patients who were not considered candidates for cardiac transplantation or LVADs or preferred to avoid or delay transplantation. More importantly, it encouraged physicians to look for more unconventional approaches to end-stage heart failure, and with the contemporaneous success of mitral valve repair in patients with end-stage cardiomyopathy, surgeons were emboldened to attempt surgery in these very high-risk patients. Indeed, the discipline of heart failure surgery within cardiovascular surgery appeared to ‘come of age’ at this time. The concept of PLV was based on the law of Laplace and attempted to restore a normal diameter to the LV by excising a portion of the lateral LV wall, thus reducing the radius and the wall stress. The resected segment was the myocardium between the papillary muscles, or included papillary muscle transection and reimplantation. The procedure was most often performed with concomitant mitral valve repair. Among the centers performing this operation, different surgical techniques have been applied, postoperative outcomes have been variable, and long-term survival and effects are heterogenous. Follow-up of the earliest series of patients from Batista was inadequate, and hence any conclusions about the success of this surgery were impossible to ascertain. However, in 1997, Batista et al. [41] reported on their combined experience of 120 patients undergoing PLV. Operative mortality was 22% and survival at 2 years was 55%. Preoperatively, all patients were in NYHA class IV, and of the survivors, 57% were in NYHA class I and 33% in NYHA class II at follow-up. In general, the outcomes following PLV at other centers are generally poor. Varying patient selection and surgical techniques make comparison between centers difficult. However, there are several modest-sized single-institution series that give insight into some of the outcomes after PLV. Between May 1996 and December 1998, 62 patients at the Cleveland Clinic underwent PLV for the treatment of advanced refractive heart failure [11]. All but 3 in this group were candidates for cardiac transplantation and had either NYHA class III (39%) or NYHA class IV heart failure (61%). In general, this was a severely ill population with a mean EF of 13.5%, peak oxygen consumption of 10.7 ml/kg/min and LV end-diastolic volume index of 330 ml/m2. Thirty-seven percent were inotrope-dependent. The operative technique included excision of the lateral LV between the papillary muscles with mitral valve repair and papillary muscle reimplantation as

Ventricular Reconstruction Surgery for Congestive Heart Failure

Fig. 6. Illustration depicting the Acorn CorCap on the heart.

needed. Left ventricular end diastolic index was reduced from 8.4 to 5.9 cm. Left ventricular end systolic index was reduced from 133 to 64 ml. EF increased from 16 to 31%. There were only two hospital deaths (3.2%). Unfortunately, these excellent perioperative results were not long-lasting. In our experience, PLV for dilated cardiomyopathy was associated with a significant early failure rate and an event-free survival at 3 years of only 26%. We observed 80% survival at 1 year, which compares favorably with survival reported from other centers [41–44]. However, since the freedom from composite events at the same time was only 49%, this indicates that the aggressive use of an LVAD and transplantation accounts for this seemingly high survival rate at 1 year. This is corroborated by the fact that 3-year overall survival was only 60%. In this group of 62 patients, we were able to identify preoperative risk factors, including increased systolic pulmonary artery pressure, decreased maximum exercise oxygen consumption and increased left atrial pressure. Emergency surgery [44], preoperative poor ventricular compliance (i.e. diastolic dysfunction) [45], increased myocardial cell diameter [46, 47] and a left dominant coronary artery system [48] are other suggested risk factors for failure. The influence of mitral valve repair in PLV is of interest, and in our experience, we were very aggressive with

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100

Survival (%)

80 PLV survival 60 40

PLV event free

20 LVAD

OMM 0 0

1

2

3

4

5

Years

Fig. 7. We recently compared the results of our PLV experience to

the results of the REMATCH trial. In patients with similar NYHA classifications as the patients undergoing PLV, 2-year survival was 23% after LVAD placement in the REMATCH trial. In comparison, at the Cleveland Clinic, 5-year event-free survival for patients after PLV was 23%. OMM = Optimal medical management.

Fig. 8. The Myocor Myosplint. Three tension members are positioned to bisect the long axis of the LV.

valve repair to avoid chronic volume overload, which we thought might lead to late redilatation and failure. It is well understood that mitral valve repair can reverse LV remodeling and dysfunction in patients with dilated or ischemic cardiomyopathy combined with severe (4+) mitral regurgitation [49, 50]. Our analysis of risk factors could not distinguish any favorable effects of PLV and mitral valve repair in patients with moderately severe (3+) or severe (4+) mitral regurgitation compared to patients with mild (1+) to moderate (2+) mitral regurgitation. We also found that late redilatation was unusual and, therefore, not the cause of failure. Additionally, the modest improvement in LVEF decreased very slowly but again was not associated with failure. A few patients did receive a benefit in our series. In order to put the results into perspective, we recently compared them to the results of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial (fig. 7). In patients with similar NYHA classifications as the patients undergoing PLV, 2-year survival was 23% after LVAD placement in the REMATCH trial. In comparison, at the Cleveland Clinic, 5-year event-free survival for patients after PLV was 23% [51]. Unfortunately, we do not believe that we can accurately predict who will benefit, and thus do not perform PLV, and currently, most other centers have also abandoned this therapy. However, a small number of

other groups have persisted with this procedure, especially when transplantation is not a realistic therapeutic option. In one of the largest single series, Suma [52] reported the outcome of 82 patients undergoing PLV for nonischemic cardiomyopathy. Forty percent of the patients were in NYHA class III and 60% were in class IV. During his experience, Suma changed several aspects of his approach. These included a change to ventriculectomy onpump on a beating heart, mitral valve replacement via the left ventriculotomy, resection limited to the area between the papillary muscles and a more targeted resection location based on intraoperative echocardiography. This led to an anterior resection in 12 patients. Overall hospital mortality was 20%, but was only 8% for elective surgeries. When the site was selectively chosen rather than the standard site, hospital mortality decreased from 33 to 15%. Four-year survival was 53% overall, but 0% for emergencies and 69% for elective procedures. The survivors remained in NYHA class I or II, with only one patient with an LVAD awaiting transplant. Other groups have reported demonstrable improvements in hemodynamic parameters with PLV, but high perioperative mortality. A recent report from Sao Paulo included 37 patients with dilated cardiomyopathy who underwent PLV, with an operative mortality of 18.9% and actuarial survival of 56.7% at 24 months [46]. For the survivors, NYHA class improved form 3.5 B 0.5 to 1.8 B

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0.9 (p ! 0.001), and LVEF increased from 17.1 B 4.6 to 23 B 8% (p ! 0.001). In England, Angelini et al. [42] demonstrated a perioperative mortality of 22.5%, but only 1 late death in 14 patients. A study from Yugoslavia included 22 patients, with 3 early deaths (13.6%) and 4 late deaths and 1-year survival of 68 B 10% [53]. EF increased from 23.9 B 6.8 to 40.7 B 12.5% (p ! 0.001). Further study showed a decrease in LV circumferential end-systolic and end-diastolic stresses (p = 0.0014) [53, 54]. We have seen astonishing successes and dismal failures following PLV. A number of reports have attempted to identify factors for the failure of the surgery. The Partial Left Ventriculectomy 2nd International Registry analyzed outcomes in 287 patients from 48 institutions in an effort to standardize inclusion and exclusion criteria and predict risk factors for failure following PLV [55]. Eventfree survival (defined as freedom from death, LVAD or listing for transplantation) was significantly reduced when PLV was performed as an emergent rather than an elective procedure (p ! 0.001). Event-free survival at 2 years was 39% for patients in NYHA class IV, but 59% for patients in all other NYHA classes (p = 0.002). Centers with experienced surgeons also achieved improved outcomes. After 20 cases, the 1-year event-free survival was 69%. Before 20 cases, it was 46%. Other indicators for a worse outcome included fractional shortening !5% and duration of preoperative symptoms 19 years. Individual centers have also implicated degree of postoperative mitral regurgitation [56] and extent of interstitial fibrosis [57] as adverse factors affecting outcome. However, it still remains difficult to predict which candidates are virtually guaranteed a successful outcome. In summary, PLV has shown us that even patients with end-stage heart failure respond to ventricular reconstruction with sustained benefit for years. However, the price to be paid for this surgical intervention is generally high, with early failures and mortality. Until we can define the appropriate candidates, transplantation listing remains a superior option in the US. Much remains to be unraveled regarding the mystery of why PLV is of benefit to some patients and not others. However, the Batista ‘concept’ of LV reconstruction for idiopathic dilated cardiomyopathy may prove to be a useful adjunct for selected patients with congestive heart failure if patient selection, surgical techniques and therapeutic devices can be refined.

decrease wall stress and improve hemodynamics. The device consists of two epicardial pads and a transventricular tension wire (fig. 8). The two pads are located on the surface of the heart. The wire passes through the ventricle and connects the pads. Under tension, the ventricular walls are drawn toward one another. Typically, 3 Myosplints are placed through the posterior intraventricular septum on a beating heart. The splints are then tightened to create a bilobular shape. Early successes in the lab led to the introduction of the Myosplint into the clinical arena. Chronic human studies were first performed in seven patients with dilated cardiomyopathy and NYHA class III or IV heart failure [58]. Four patients underwent concomitant mitral valve repair. At the 3-month follow-up, 6 of the 7 patients showed an improvement in heart failure symptoms. Two of the patients have been removed from the transplant waiting list. Only one patient had worsening of heart failure symptoms. This was attributed to uncorrected mitral regurgitation. This early experience has opened the door for future studies. However, the long-term effect of Myosplint therapy on cardiac function awaits results from a larger, randomized study. Currently, the Myosplint is undergoing US FDA feasibility testing.

Conclusion

The current treatments of congestive heart failure are inadequate. As this problem has become more prevalent, surgery has become an integral part of a multidisciplinary approach to improve outcomes. Instead of being withheld as a last resort, it is now one of the earliest interventions for end-stage heart disease. Anatomical correction of pathology is a critical component of the treatment of this disease. Ventricular reconstruction attempts to restore the geometry of the diseased heart to that of a healthy one. In ischemic cardiomyopathy, the results are excellent, and more widespread application is inevitable. In nonischemic disease, there is a beneficial effect in selected patients. However, the appropriate patients and techniques are still being defined. Nonetheless, restoration of ventricular geometry already has an important role in the surgical treatment of congestive heart failure. We believe that we have only seen the infancy of its development.

Myosplint As an outgrowth of the Batista concept, the Myosplint was designed to change the geometry of the LV in order to

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32 Mickleborough LL, Carson S, Ivanov J: Repair of dyskinetic or akinetic left ventricular aneurysm: Results obtained with a modified linear closure. J Thorac Cardiovasc Surg 2001;121: 675–682. 33 Caldeira C, McCarthy PM: A simple method of left ventricular reconstruction without patch for ischemic cardiomyopathy. Ann Thorac Surg 2001;72:2148–2149. 34 Patel HJ, Lankford EB, Polidori DJ, et al: Dynamic cardiomyoplasty: Its chronic effects on the failing heart. J Thorac Cardiovasc Surg 1997;14:169–178. 35 Grandjean PA, Austin L, Chan S, Terpstra B: Dynamic cardiomyoplasty: Clinical follow-up results. J Cardiac Surg 1991;6(suppl):80–88. 36 Carpentier A, Chachques JC, Acar C, et al: Dynamic cardiomyoplasty at seven years. J Thorac Cardiovasc Surg 1993;106:42–54. 37 Oz MC: Passive ventricular constraint for the treatment of congestive heart failure. Ann Thorac Surg 2001;71:S185–S187. 38 Konertz WF, Shapland JE, Hotz H, et al: Passive containment and reverse remodeling by a novel textile cardiac support device. Circulation 2001;104:I-270–I-275. 39 Raman JS, Hata M, Storer M, et al: The midterm results of ventricular containment (Acorn Wrap) for end-stage ischemic cardiomyopathy. Ann Thorac Cardiovasc Surg 2001;7:278–281. 40 Batista RJV, Santos JLV, Takeshita N, et al: Partial left ventriculectomy to improve left ventricular function in end-stage heart disease. J Card Surg 1996;11:96–97. 41 Batista RJV, Verde J, Nery P, et al: Partial left ventriculectomy to treat end stage heart disease. Ann Thorac Surg 1997;64:634–638. 42 Angelini GD, Pryn S, Mehta D, Izzat MB, Walsh C, Wilde P, Bryan AJ: Left-ventricularvolume reduction for end-stage heart failure. Lancet 1997;350:489. 43 Moreira LFP, Stolf NAG, Bocchi EA, Bacal F, Giorgi MCP, Parga JR, Jatene AD: Partial left ventriculectomy with mitral valve preservation in the treatment of patients with dilated cardiomyopathy. J Thorac Cardiovasc Surg 1998; 115:800–807. 44 Suma H, Isomura T, Horii T, Sato T, Kikuchi N, Iwahashi K, Hosokawa G: Two-year experience of the Batista operation for non-ischemic cardiomyopahty. J Cardiol 1998;32:269–276. 45 Fukamachi K, McCarthy PM, Smedira NG, Buda T, Wong J, Starling RC, et al: Effects of ventriculectomy on left ventricular performance: One year follow up. Circulation 1998; 68(suppl):I-1201. 46 Stolf NAG, Moreira LFP, Bocchi EA, Higuchi ML, Bacal F, Bellotti G, Jatene AD: Determinants of midterm outcome of partial left ventriculectomy in dilated cardiomyopathy. Ann Thorac Surg 1998;66:1585–1591. 47 Barry WH: Load-dependent myocyte dysfunction. Circulation 1998;97:2297–2298.

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48 Frazier OH, Gradinac S, Segura AM, Przybylowski P, Popovic Z, Vasiljevic J, et al: Partial left ventriculectomy: Which patients can be expected to benefit? Ann Thorac Surg 2000;69: 1836–1841. 49 Bach D, Bolling SF: Early improvement in congestive heart failure after correction of secondary mitral regurgitation in end-stage cardiomyopathy. Am Heart J 1995;129:1165–1170. 50 Bishay ES, McCarthy PM, Cosgrove DM, Hoercher KJ, Smedira NG, Mukherjee D, White J, Blackstone EH: Mitral valve surgery in patients with severe left ventricular dysfunction. Eur J Cardiothorac Surg 2000;19:1–9.

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51 Hoercher KJ, Starling RC, McCarthy PM, Blackstone EH, Young JB: Partial left ventriculectomy: Lessons learned and future implications for surgical trials. Circulation 2002;106: II-418 (abstract). 52 Suma H, and the RESTORE Group: Left ventriculoplasty for nonischemic dialted cardiomyopathy. Semin Thorac Cardiovasc Surg 2001;13:514–521. 53 Gradinac S, Miric M, Popovic Z, Popovic AD, Neskovic AN, Jovovic L, et al: Partial left ventriculectomy for idiopathic dilated cardiomyopathy: Early results and six-month follow-up. Ann Thorac Surg 1998;66:1963–1968. 54 Popovic Z, Miric M, Gradinac S, et al: Effects of partial left ventriculectomy on left ventricular performance in patients with nonischemic dilated cardiomyopathy. J Am Coll Cardiol 1998;32:1801–1808.

55 Kawaguchi AT, Suma H, Konertz W, et al: Partial left ventriculectomy: The 2nd International Registry Report 2000. J Card Surg 2001;16:10– 23. 56 Bhat G, Dowling RD: Evaluation of predictors of clinical outcome after partial left ventriculectomy. Ann Thorac Surg 2001;72:91–95. 57 Kawaguchi AT, Bergsland J, Ishibashi-Ueda H, et al: Partial left ventriculectomy in patients with dilated failing ventricle. J Card Surg 1998; 13:335–342. 58 Schenk S, Reichenspurner H, Boehm DH, et al: Myosplint implant and shape-change procedure: Intra- and peri-operative safety and feasibility. J Heart Lung Transplant 2002;21:680– 686.

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Cardiology 2004;101:72–78 DOI: 10.1159/000075987

Cardiac Resynchronization Pacing Therapy Cash Casey Bradley P. Knight Division of Cardiology, Department of Internal Medicine, University of Chicago, Chicago, Ill., USA

Key Words Congestive heart failure W Biventricular pacing W Pacemaker W Ventricular dyssynchrony W Implantable cardioverter defibrillator

pacing device that also provides defibrillation therapy. This paper reviews biventricular pacing for congestive heart failure, including results of acute hemodynamic studies and randomized clinical trials, patient and device selection, and procedural issues. Copyright © 2004 S. Karger AG, Basel

Abstract Approximately one third of patients with congestive heart failure and systolic dysfunction have an intraventricular conduction delay that is manifested as a QRS duration 1 120 ms. An intraventricular conduction delay adversely affects ventricular performance by causing dyssynchrony in ventricular activation. When ventricular dyssynchrony is present, simultaneous left and right ventricular pacing or cardiac resynchronization therapy can improve ventricular synchrony. This can lead to an improvement in hemodynamics, ventricular remodeling, mitral regurgitation, exercise capacity and quality of life. Candidates for cardiac resynchronization therapy include patients with advanced congestive heart failure that is refractory to medical therapy, a QRS duration 1130 ms, left ventricular ejection fraction ! 0.35 and sinus rhythm. Because patients who are candidates for biventricular pacing are at high risk of sudden death, they should be considered for implantation of a biventricular

B.P.K. has a research relationship with Guidant Corporation and Medtronic Corporation.

ABC

© 2004 S. Karger AG, Basel 0008–6312/04/1013–0072$21.00/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/crd

Introduction

Intraventricular conduction disturbances are common in patients with congestive heart failure. Up to one third of patients with heart failure have a bundle branch block and a QRS duration greater than 120 ms. An intraventricular conduction delay is a marker of more severe myocardial disease, but also causes a reduction in cardiac output and worsening heart failure by causing inter- and intraventricular dyssynchrony. In addition, a bundle branch block can worsen mitral regurgitation by changing the ventricular activation sequence. The severity of the intraventricular conduction delay has been shown to correlate directly with mortality in patients with heart failure [1]. The principle behind resynchronization pacing therapy is to simultaneously pace at two or more ventricular sites to minimize the time required for ventricular activation and improve cardiac synchrony. This paper reviews biventricular pacing for congestive heart failure, including results of acute hemodynamic studies and randomized clinical trials, patient and device selection, and procedural issues.

Bradley P. Knight, MD University of Chicago Hospitals 5758 South Maryland, MC 9024 Chicago, IL 60637 (USA) Tel. +1 773 702 5988, Fax +1 773 702 4666, E-Mail [email protected]

Early Studies of Pacing for Heart Failure

Pacing studies for congestive heart failure began in the late 1980s. Hochleitner et al. [2] reported clinical improvement with standard dual-chamber pacing and a short atrioventricular (AV) delay in patients with severe heart failure awaiting heart transplantation. Similar results were reported in patients with congestive heart failure and first-degree AV block [3, 4], especially when presystolic mitral regurgitation was present. However, subsequent larger, randomized trials did not reproduce these findings [5, 6]. It is likely that the improvements associated with shortening the PR interval were offset by the detrimental hemodynamic effects of right ventricular pacing in patients who had a normal QRS duration at baseline.

Acute Multisite Pacing Hemodynamic Studies

Acute atrio-biventricular pacing was first tested at the time of cardiac surgery using epicardial pacing electrodes and was shown to increase cardiac output and decrease pulmonary capillary wedge pressure [7]. Subsequent acute hemodynamic studies of temporary biventricular pacing, including the work of Daubert et al. [8], were performed percutaneously. Left ventricular pacing was accomplished either endocardially using a retrograde aortic approach or epicardially via a branch of the coronary sinus. Kass et al. [9] reported the acute effects of transvenous atrio-biventricular pacing in 18 patients with advanced ventricular dysfunction and a mean QRS duration of 157 ms. They showed a significant increase in systolic blood pressure, pulse pressure and maximum contractility. Pressure-volume loops were also shown to improve. The degree of hemodynamic improvement correlated with the severity of baseline ventricular dyssynchrony. Several acute hemodynamic studies have shown that biventricular pacing improves inter- and intraventricular synchrony, mitral regurgitation and diastolic function [10, 11]. Biventricular pacing has also been shown to improve cardiac efficiency by increasing cardiac work without increasing myocardial oxygen consumption [12]. This is in contrast to previous pharmacologic therapies for heart failure that increased systolic function, at the expense of also increasing oxygen demand, arrhythmia frequency and mortality [13].

Cardiac Resynchronization Pacing Therapy

Clinical Trials of Permanent Biventricular Pacing

Multiple clinical trials have been performed to measure the effect of permanent biventricular pacing in patients with advanced heart failure and ventricular dyssynchrony. The trials can be divided into two groups based on whether or not the patients had an indication for defibrillator therapy. The Cardiac Resynchronization for Heart Failure Patients (InSync) trial was a prospective, multicenter trial of biventricular pacing in 117 patients with New York Heart Association (NYHA) class III/IV heart failure symptoms, left ventricular ejection fraction !0.35 and a QRS duration 1150 ms. This trial demonstrated an improvement in ejection fraction, functional class, exercise tolerance and quality of life scores after 12 months [14]. However, it was uncontrolled and unblinded. One of the first randomized biventricular pacing trials was the Pacing Therapies for Congestive Heart Failure study, which was a single-blinded, crossover trial of biventricular pacing that included 42 patients with NYHA class III/IV congestive heart failure [15]. An interim analysis showed trends toward superiority for biventricular pacing, but the results were limited by a small sample size. The Multisite Stimulation In Cardiomyopathies (MUSTIC) study was a randomized, blinded, crossover design trial of 58 patients with NYHA class III symptoms and sinus rhythm with a QRS duration 1150 ms [16]. After a run-in period, patients were randomized to pacing on or off for 12 weeks and then were crossed over. In longterm follow-up, atrio-biventricular pacing was associated with a 20% improvement in the 6-min walk distance, a 36% improvement in quality of life scores, an 11% increase in peak oxygen uptake, a 65% reduction in heart failure classification and seven times fewer hospitalizations. Also, active pacing was preferred by 85% of the patients at the end of the study. The improvements in exercise tolerance and quality of life questionnaire scores found in the MUSTIC trial were significantly greater than those found in the angiotensin-converting enzyme inhibitor trials that enrolled patients with congestive heart failure and similar characteristics. The major limitation of the MUSTIC trial, however, was that it was only singleblinded. There are four randomized permanent biventricular pacing trials that have been completed in the United States: the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) and MIRACLE Implantable Cardioverter Defibrillator (ICD) trials, which were spon-

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Table 1. Patient selection criteria for resynchronization pacing ther-

apy Advanced heart failure Ventricular dyssynchrony Ventricular dysfunction Baseline rhythm

NYHA CHF class III or IV despite optimal medical therapy QRS duration 6130 ms LVEF ^0.35 sinus rhythm or AF with slow ventricular response or complete AV block

AF = Atrial fibrillation; CHF = congestive heart failure; LVEF = left ventricular ejection fraction.

sored by Medtronic Inc., and the Contak CD and Comparison Of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trials, which were sponsored by Guidant Inc. The MIRACLE trial was a randomized, doubleblinded, parallel-controlled trial [17]. The primary endpoints were NYHA class, quality of life score and 6-min walk distance. Secondary endpoints were a composite clinical response, maximum VO2, ejection fraction and QRS duration. The trial enrolled 453 patients with NYHA class III/IV symptoms, ejection fraction !0.35 and a QRS duration 1130 ms. Patients were randomized to atrio-biventricular pacing or no pacing for 6 months. In the pacing group, the NYHA class improved by 1.0, quality of life score improved by 18 points, 6-min walk distance increased by 39 m and the ejection fraction increased by 4.6%. The MIRACLE trial also reported a significant decrease in systolic mitral regurgitation area from 7 to 4 cm2 after 6 months of biventricular pacing. The MIRACLE ICD trial was a multicenter, randomized, double-blind, parallel-controlled study to determine whether patients who had an indication for an ICD and ventricular dyssynchrony benefit from atrio-biventricular pacing. At the 6-month follow-up, the atrio-biventricularly paced group had a statistically significant improvement in quality of life scores and heart failure classification. There was also a trend toward longer 6-min walk distance and fewer hospitalizations with pacing [18]. The Contak CD trial was a randomized, parallel, double-blinded, controlled trial of 581 patients with NYHA functional class II–IV, ejection fraction !0.35, QRS duration 1120 ms and an indication for an ICD [19]. There was a 21% decrease in the primary endpoint of combined mortality and morbidity, but the results were not statistically significant (p = 0.17). There was, however, a signifi-

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cant improvement in maximum oxygen consumption and quality of life scores. Data from this trial led to approval of the Guidant biventricular pacing defibrillator by the Food and Drug Administration. The COMPANION trial is the only biventricular pacing trial that was designed to measure the effect of resynchronization therapy on mortality [20, 21]. Patients were required to have a dilated cardiomyopathy, left ventricular end diastolic dimension 160 mm, NYHA functional classification III/IV symptoms, ejection fraction !0.35, QRS duration 1120 ms, a PR interval 1150 ms and at least one hospitalization for congestive heart failure in the previous 12 months. Patients were randomized to one of three arms: biventricular pacemaker, an implantable defibrillator with biventricular pacing, or no device, in a 2:2:1 ratio. The trial was recently stopped prematurely after 1,600 of the anticipated 2,200 patients were enrolled, due to a statistically significant 20% reduction in the primary endpoint of combined all-cause mortality and hospitalizations in the biventricular pacing arm (one half biventricular pacemakers and one half biventricular pacing defibrillators) as compared to no pacing. The absolute mortality rates after 1 year of follow-up were 19, 15 and 11% for the no pacing, biventricular pacing and biventricular pacing defibrillator groups, respectively. The results of the trial are expected to be presented at the Scientific Sessions of the American College of Cardiology in March 2003. A recently published meta-analysis [22] of the four major randomized trials before the COMPANION trial revealed a significant 51% reduction in mortality from progressive heart failure in the 1,634 patients studied. There is also evidence from the randomized trials that biventricular pacing is also associated with cardiac remodeling [23].

Patient Selection

The following factors must be considered when evaluating a patient for biventricular pacing: severity of heart failure symptoms, extent of ventricular dyssynchrony, left ventricular function and the baseline rhythm (table 1). Heart Failure Severity Patients who have the most severe symptoms have the most to gain from an effective intervention. For example, a relatively small improvement in cardiac output in a patient with class IV symptoms can mean the difference between being ambulatory instead of bed-bound. Patients

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should be considered for biventricular pacing only after optimal medical therapy has been instituted. Most trials of biventricular pacing have included patients who have NYHA class III/IV symptoms and have been hospitalized in the past year. From a clinical standpoint, however, recent hospitalizations should not be considered mandatory before consideration of biventricular pacing. Ventricular Dyssynchrony Most data suggest that the severity of ventricular dyssynchrony correlates with the improvement in symptoms in patients treated with biventricular pacing, and is one of the most important criteria in identifying patients for resynchronization therapy. The most convenient assessment of ventricular dyssynchrony is the QRS duration on the 12-lead electrocardiogram (ECG). Many biventricular pacing studies have included only patients with a QRS duration 1150 ms. However, a cutoff QRS duration of 6130 ms was used in the MIRACLE trial and is a reasonable cutoff to be used clinically. Interestingly, however, the baseline QRS duration did not correlate with the degree of symptomatic improvement in the MIRACLE trial [17]. The QRS duration can be prolonged as a result of a left bundle branch block, a right bundle branch block or a nonspecific intraventricular conduction delay. Few patients with a right bundle branch block have been included in clinical trials, because it is uncommon. Furthermore, it would seem that patients with a right ventricular conduction delay would not benefit from left ventricular pacing. However, the data that are available suggest that the type of bundle branch block pattern does not predict the response to biventricular pacing [17]. Thus, patients with advanced heart failure and a QRS duration 6130 ms due to any type of conduction delay should be considered for biventricular pacing. Ventricular pacing itself leads to ventricular dyssynchrony, regardless of the baseline QRS duration. Patients with advanced heart failure who require ventricular pacing should also be considered for biventricular pacing as an alternative to right ventricular pacing. Although patients with a class I indication for a pacemaker were not included in most biventricular pacing trials, a recent study of patients who had undergone prior AV node ablation and right ventricular pacemaker implantation demonstrated a significant improvement in heart failure symptoms after an upgrade to a biventricular pacemaker [24]. Because there are limitations to the use of the QRS duration in the quantification of ventricular dyssynchro-

Cardiac Resynchronization Pacing Therapy

ny, other techniques are being developed. Tissue Doppler imaging has been used successfully to grade ventricular dyssynchrony. Basal mechanical dyssynchrony established using tagged magnetic resonance imaging has been shown to be a good predictor of response to biventricular pacing [25]. However, because the surface ECG is noninvasive, inexpensive and widely used, it will likely remain the most commonly used tool in the identification of heart failure patients with ventricular dyssynchrony. Biventricular pacing is usually performed using a VDD pacing mode during sinus rhythm, so that ventricular pacing is triggered by an atrial-sensed event. Therefore, biventricular pacing can be used to optimize ventricular filling as well as to synchronize ventricular contraction. Because patients with significant first-degree AV block frequently have diastolic mitral regurgitation, manipulation of the paced AV interval can also be used to minimize mitral regurgitation. Ventricular Dysfunction Most patients with moderate or severe heart failure symptoms have significant left ventricular systolic dysfunction. Patients with heart failure caused by diastolic dysfunction have not been included in clinical trials. Therefore, only patients with at least moderate ventricular systolic dysfunction should be considered for biventricular pacing. A left ventricular ejection fraction ^0.35 is a reasonable cutoff point and has been used in many biventricular pacing trials. Because the etiology of heart failure does not appear to be predictive of a response to biventricular pacing, patients with or without coronary artery disease are candidates for biventricular pacing. Baseline Rhythm Biventricular pacing is usually achieved by simultaneously pacing the right ventricle and the left ventricle. In patients who are in sinus rhythm, a right atrial lead is placed for atrial sensing to allow ventricular stimulation to occur shortly after atrial systole. Patients who are in sinus rhythm are usually paced in a VDD mode with an AV delay that is shorter than the PR interval to maintain constant biventricular capture. Patients with atrial fibrillation who are treated with biventricular pacing may benefit from ventricular resynchronization but do not receive the potential benefit of AV optimization. Successful resynchronization therapy depends on continuous biventricular capture. It is difficult to maintain ventricular capture in patients with atrial fibrillation unless the ventricular response is slow or there is complete heart block. AV conduction during atrial fibrillation not

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only inhibits biventricular pacing, but can also lead to sensing problems for patients with a biventricular pacing defibrillator. Some biventricular pacing defibrillators occasionally sense each conducted QRS complex twice, because ventricular activation is detected at different times by each ventricular lead. So-called ‘double-counting’ can lead to inappropriate defibrillator shocks but is no longer a problem with newer devices that sense only from the right ventricle. In general, patients with atrial fibrillation and intact AV conduction are candidates for biventricular pacing when AV conduction can be depressed with medications or catheter ablation. Recently, it has been shown that biventricular pacing in patients with permanent atrial fibrillation and complete heart block is associated with an improvement in functional class, 6-min walk distance and a reduction in hospitalizations compared to right ventricular pacing [21].

Device Selection

The recently published Multicenter Automatic Defibrillator Implantation Trial II found that prophylactic defibrillator therapy reduced overall mortality in patients with an ischemic cardiomyopathy and a left ventricular ejection fraction !0.30 [26]. Because patients who are candidates for biventricular pacing usually have severe ventricular dysfunction, it is not clear which patients are candidates for a biventricular pacemaker without defibrillator capabilities. The advantages of a biventricular pacemaker compared to a biventricular pacing defibrillator include smaller device size, no risk of inappropriate defibrillator shocks and substantially lower cost. The COMPANION study may help answer the question of whether defibrillation therapy is needed in a population with advanced heart failure treated with biventricular pacing [27]. Recently released devices have independent left ventricular lead pacing outputs. This provides more programming flexibility and may improve the battery longevity. Devices that have programmable timing offset between the right and left ventricle are also being evaluated in clinical trials to determine whether or not this function can further improve ventricular synchrony.

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Implantation Techniques and Technical Issues

There are six steps during implantation of a transvenous, atrio-biventricular pacing device: implantation of the standard right-sided pacing or defibrillation leads, cannulation of the coronary sinus with a guiding sheath, coronary sinus venography, placement of a pacing lead in the coronary vein for left ventricular pacing, removal of the guiding sheath, and attachment of the leads to the pacing generator. A biventricular pacing device requires standard right atrial and ventricular leads that are placed via the subclavian or cephalic vein. A defibrillator lead is placed in the right ventricle for patients undergoing implantation of a biventricular pacing defibrillator. The right-sided leads are usually placed before the coronary sinus lead to prevent dislodgement of the coronary sinus lead. For patients who already have a pacing device and are undergoing an upgrade of the system, the previously placed leads can be used with the new system if the leads are intact. To provide support during placement of the coronary sinus lead, the coronary sinus is usually cannulated with a guiding sheath. The left anterior oblique view is useful during cannulation of the coronary sinus. This part of the procedure can be difficult when the coronary sinus ostium is displaced inferiorly and posteriorly, as occurs commonly when the atrium dilates in patients with heart failure, but several different shapes of preformed guide sheaths are now commercially available to make this step easier. The sheath can be directly advanced into the ostium, or more commonly, the coronary sinus is cannulated with an electrophysiology catheter or guide wire and the sheath is advanced over the catheter or wire. The advantage of using an electrode catheter to cannulate the coronary sinus is that the intracardiac electrograms can be displayed to assist identification of the ostium. After sheath placement, coronary sinus venography can be performed to document the coronary sinus anatomy and to create a guide that can be used during lead placement (fig. 1). A balloon occlusion catheter can improve retrograde filling of the coronary sinus and its branches. However, to prevent perforation of the coronary sinus, care must be taken before balloon inflation to assure that the catheter is coaxial to the vein and that the balloon is not overinflated. There are a variety of leads that can be used to pace the left ventricular from the coronary sinus. Recently, leads that can be placed over a standard angioplasty wire have been approved by the Food and Drug Administration. This advance in technology has allowed lead placement in branches that were previously not accessible and has

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increased the success rate of coronary sinus lead implantation. An angioplasty guide wire is first advanced into the desired coronary vein. The lead is then advanced as far as possible, and the guide wire is removed (fig. 2). There are several considerations when selecting which vein to place the pacing electrode in. There are hemodynamic data that suggest that the preferred pacing site is the mid-lateral free wall of the left ventricle [28]. Therefore, initial attempts are usually made to place the lead laterally. Other factors that influence the lead placement are the pacing threshold and whether or not there is capture of the diaphragm. Pacing sites distal in a posterolateral coronary vein frequently result in phrenic nerve stimulation. When a suitable left ventricular pacing site cannot be obtained from the coronary veins, permanent epicardial lead placement should be considered. New pericardial approaches and robotics are under development to achieve minimally invasive epicardial pacing. After the left ventricular lead is positioned in a stable, desirable coronary vein, the guide sheath is removed. This step must be done carefully to avoid dislodgement of the coronary sinus lead. The Guidant over-the-wire lead has a unique terminal pin that is low profile because it has no sealing rings. The guide sheath can be pulled directly over the Guidant lead after a finishing wire is placed to stabilize the lead. The Medtronic over-the-wire lead has a standard IS-1 connector pin and the sheath must be split with a special splitter as it is removed over the lead. After the lead collars are secured to the pectoral fascia, the leads are attached to the pacing device and the device is placed subcutaneously or in some cases submuscularly. For patients undergoing implantation of a biventricular pacing defibrillator, induction of ventricular fibrillation and testing the defibrillation energy requirements should be done before completion of the procedure. The AV delay should be programmed to a value that provides optimal cardiac performance. This can be determined using echocardiography to optimize the time velocity integral of the left ventricular outflow tract or to optimize the mitral inflow pattern. The AV delay can also be programmed empirically using a formula that involves the intracardiac AV interval.

Fig. 1. A coronary sinus venogram is shown in the left anterior oblique projection. A guide sheath is positioned in the mid-coronary sinus from the left subclavian vein. A large posterolateral branch can be seen (arrow). Also note two guide wires that were used to place the right-sided pacing leads and the sternotomy wires to the left, prosthetic valve rings in the mitral and aortic positions, and an external defibrillation patch to the right.

Conclusions

Cardiac resynchronization therapy is a promising new treatment option for patients with heart failure and ventricular dyssynchrony and should be considered for patients with medically refractory heart failure, ventricular

Cardiac Resynchronization Pacing Therapy

Fig. 2. A pacing lead is shown in the posterolateral coronary vein. It

was introduced through a guide sheath placed over a guide wire to achieve epicardial capture of the left ventricular free wall. The projection is more anterior-posterior compared to figure 1.

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dysfunction and an intraventricular conduction delay with a QRS duration 1130 ms. Biventricular pacing has been shown to improve hemodynamics, heart failure symptoms and functional capacity. Recent evidence from the COMPANION trial suggests that it may also improve

mortality. Future studies are needed to determine better ways to identify which patients respond to biventricular pacing, and more work is needed to improve the coronary sinus leads and delivery systems.

References 1 Shamim W, Francis DP, Yousufuddin M, Varney S, Pieopli MF, Anker SD, Coats AJ: Interventricular conduction delay: A prognostic marker in chronic heart failure. Int J Cardiol 1999;70:171–178. 2 Hochleitner M, Hortnagl H, Hortnagl H, Fridrich L, Gschnitzer F: Long-term efficacy of physiologic dual-chamber pacing in the treatment of end-stage idiopathic dilated cardiomyopathy. Am J Cardiol 1992;70:1320–1325. 3 Brecker SJD, Ziao HB, Sparrow J, Gibson DG: Effects of dual chamber pacing with short atrioventricular delay in dilated cardiomyopathy. Lancet 1992;340:1308–1312. 4 Nishimura RA, Hayes DL, Holmes DR Jr, Tajik AJ: Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: An acute Doppler and catheterization hemodynamic study. J Am Coll Cardiol 1995;25:281–288. 5 Linde C, Gadler F, Edner M, Norlander R, Rosenqvist M, Ryden L: Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure. Am J Cardiol 1995;75:919–923. 6 Gold MR, Feliciano Z, Gottlieb SS, Fisher ML: Dual-chamber pacing with a short atrioventricular delay in congestive heart failure: A randomized study. J Am Coll Cardiol 1995;26: 967–973. 7 Foster AH, Gold MR, McClaughlan JS: Acute hemodynamic effects of atrio-biventricular pacing in humans. Ann Thorac Surg 1995;59: 294–300. 8 Daubert JC, Ritter P, Le Breton H, Gras D, Leclercq C, Lazarus A, Mugica J, Mabo P, Cazeau S: Permanent left ventricular pacing with transvenous leads inserted into the coronary veins. Pacing Clin Electrophysiol 1998; 21:239–245. 9 Kass D, Chen-Haun C, Curry C, Talbot M, Berger R, Fetics B, Nevo E: Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 1999;99: 1567–1573. 10 Cazeau S, Ritter P, Bakdach S, Lazarus A, Limousin M, Henao L, Mundler O, Daubert JC, Mugica J: Four chamber pacing in dilated cardiomyopathy. Pacing Clin Electrophysiol 1994;17:1974–1979. 11 Leclercq C, Cazeau S, Le Breton H, Ritter P, Mabo P, Gras D, Pavin D, Lazarus A, Daubert JC: Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. J Am Coll Cardiol 1998;32:1825–1831. 12 Nelson GS, Berger RD, Fetics BJ, Talbot M, Spinelli JC, Hare JM, Kass DA: Left ventricular or

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biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block. Circulation 2000;102:3053–3059. Cohn JN, Goldstein SO, Greenberg BH, Lorell BH, Bourge RC, Jaski BE, Gottlieb SO, McGrew F 3rd, DeMets DL, White BG: A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. N Engl J Med 1998;339:1810–1816. Gras D, Cazeau S, Ritter P: Long term results of cardiac resynchronization for heart failure patients: The InSync clinical trial. Circulation 1999;100:I–515. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, Huth C, Schondube F, Wolfhard U, Bocker D, Krahnefeld O, Kirkels H: The Pacing Therapies for Congestive Heart Failure (PATH-CHF) Study: Rationale, design, and endpoints of a prospective randomized multicenter study. Am J Cardiol 1999;83: 130D–135D. Linde C, Leclercq C, Rex S, Garrigue S, Lavergne T, Cazeau S, McKenna W, Fitzgerald M, Deharo JC, Alonso C, Walker S, Braunschweig F, Bailleul C, Daubert JC, on behalf of the Multisite Stimulation In Cardiomyopathies (MUSTIC) study group: Long-term benefits of biventricular pacing in congestive heart failure: Results from the Multisite Stimulation In Cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002;40:111–118. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J, MIRACLE Study Group; Multicenter InSync Randomized Clinical Evaluation: Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. The Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD). Presented at the late-breaking clinical trials segment of the 51st annual American College of Cardiology Scientific Sessions, March 20, 2002. Available at: http://www.medtronic.com/newsroom/ news_20020320a.html. Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA, Boehmer JP, Higginbotham MB, De Marco T, Foster E, Yong PG: Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol 2003;42:1454–1459. Bristow M, Feldman A, Saxon L: Heart failure management using implantable devices for ventricular resynchronization: Comparison of

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Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial. COMPANION Steering Committee and COMPANION Clinical Investigators. J Card Fail 2000;6:276–285. Guidant: Landmark heart failure therapy study sponsored by Guidant achieves primary endpoint. News release, November 21, 2002. http:/ / www . guidant . com / news / 300 / web_release/ nr_000307.shtml Bradley DJ, Bradley EA, Baughman KL, Berger RD, Calkins H, Goodman SN, Kass DA, Powe NR: Cardiac resynchronization and death from progressive heart failure: A metaanalysis of randomized controlled trials. JAMA 2003;289:730–740. Yu CM, Chau E, Sanderson JE, Fan K, Tang MO, Fung WH, Lin H, Kong SL, Lam YM, Hill MR, Lau CP: 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. Leon AR, Greenberg JM, Kanuru N, Baker CM, Mera FV, Smith AL, Langberg JJ, DeLurgio DB: Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation: Effect of upgrading to biventricular pacing after chronic right ventricular pacing. J Am Coll Cardiol 2002;39:1258–1263. Nelson GS, Curry CW, Wyman BT, Kramer A, Declerck J, Talbot M, Douglas MR, Berger RD, McVeigh ER, Kass DA: Predictors of systolic augmentation from left ventricular preexcitation in patients with dilated cardiomyopathy and intraventricular conduction delay. Circulation 2000;101:2703–2709. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML: Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. For the Multicenter Automatic Defibrillator Implantation Trial II Investigators. N Engl J Med 2002;346:877–883. Saxon LA, Boehmer JP, Hummel J, Kacet S, De Marco T, Naccarelli G, Daoud E: Biventricular pacing in patients with congestive heart failure: Two prospective randomized trials. The VIGOR CHF and VENTAK CHF Investigators. Am J Cardiol 1999;83:120D–123D. Auricchio A, Klein H, Tockman B, Sack S, Stellbrink C, Neuzner J, Kramer A, Ding J, Pochet T, Maarse A, Spinelli J: Transvenous biventricular pacing for heart failure: Can the obstacles be overcome? Am J Cardiol 1999;83: 136D–142D.

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Cardiology 2004;101:79–92 DOI: 10.1159/000075988

Current Trends in Heart Transplantation Malek G. Massad Division of Cardiothoracic Surgery, Department of Surgery, The University of Illinois at Chicago, Chicago, Ill., USA

Key Words Heart transplantation W End-stage heart disease W Heart failure

Abstract With the introduction of cyclosporin A in the early 1980s, heart transplantation was transformed from an experimental procedure into a successful therapeutic option for patients with end-stage heart disease. Since then, constant progress has extended the benefits of the procedure to an increasing number of patients. Despite all this progress, heart transplantation is not an option that can be offered to the vast majority of the world population, in particular to the over 5 billion inhabitants of underdeveloped or developing countries in the three most populated continents, namely, Asia, Africa and South America. While the North American continent and Europe account for only 17% of the world population, they donate and receive over 95% of the heart transplants performed worldwide. In addition, the number of transplant candidates continues to exceed the number of available donors, and the donor shortage is not expected to improve. Opportunistic infections, rejection, malignancy and graft coronary artery disease continue to plague heart transplantation and remain the Achilles heel of the procedure. With the beginning of the new millennium, new perspectives are arising in heart transplantation. Strategies addressing donor-specific tolerance and the development of selective immunosuppressive

ABC

© 2004 S. Karger AG, Basel 0008–6312/04/1013–0079$21.00/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/crd

therapies are on the horizon and could improve the quality of life after transplantation and also prolong survival. Copyright © 2004 S. Karger AG, Basel

Introduction

Scope of the Problem Congestive heart failure (CHF) affects 4.7 million people in the US, with an estimated 400,000 new cases diagnosed each year. It is the most important medical problem facing America and the world today. Deaths from CHF are four times more common than deaths from HIV infection and three times more common than deaths from breast cancer. The incidence and prevalence of the disease are expected to increase as the population ages, accounting for an annual cost of USD 34 billion and constituting 6.5% of US health care dollars. The disease is associated with an 80% mortality at 5 years from the time of diagnosis. Predictors of Compromised Survival in CHF Although CHF has always been looked upon as a welldefined single disease process, it is better defined as a clinical syndrome that impacts on many organ systems. Its etiology is quite diverse, and thus the rapidity and progression of the disease is, by and large, unpredictable. Several advances in our understanding of CHF on the biomolecular and biochemical levels have helped identify some of the predictors of compromised survival. These predic-

Malek G. Massad, MD Division of Cardiothoracic Surgery, The University of Illinois at Chicago 840 S. Wood Street, CSB 417 (MC 958) Chicago, IL 60612 (USA) Tel. +1 312 996 6215, Fax +1 312 996 2013, E-Mail [email protected]

Table 1. Indications for heart transplantation

Cardiogenic shock or low cardiac output state with reversible endorgan dysfunction requiring mechanical support (ventilator, intraaortic balloon pump, left and/or right ventricular assist device) Low cardiac output state or refractory heart failure requiring inotropic support. Hemodynamic monitoring to be utilized as necessary to initiate and maintain optimal hemodynamics and to adjust inotrope dosage Any end-stage heart disease with a limited prognosis (i.e. less than 50% expected survival at 1 year). This includes: Left ventricular dysfunction with an EF of less than 20% and maximum VO2 treadmill ! 15 ml/kg/min. A peak VO2 ! 10 ml/kg/min for adults is considered as a definitive indication for transplant listing NYHA classes III and IV heart failure signs and symptoms not responding to medical therapy Ventricular arrhythmia not responsive to medical therapy and/or AICD implantation Ischemic cardiomyopathy not manageable by medications, PTCA or conventional coronary artery bypass surgery where the long-term prognosis is poor and the patient is symptomatic Valvular cardiomyopathy not amenable to medical or surgical therapy Restrictive or hypertrophic cardiomyopathy not amenable to conventional therapy and with severely impaired functional capacity as measured by peak oxygen uptake Dilated nonischemic cardiomyopathy not amenable to conventional therapy Congenital heart disease not amenable to surgical palliation or correction AICD = Automatic internal cardioverter defibrillator; PTCA = percutaneous transluminal coronary angioplasty.

tors include the following: (1) symptomatic patients who are in New York Heart Association (NYHA) classes III and IV heart failure have respective mortality rates of 10– 20 and 20–50% at 1 year. (2) Ejection fraction (EF) has also been correlated with risk of death. About 30% of patients with EFs between 10 and 20%, and most of those with EFs below 10%, die within 1 year. (3) Patients with electrical abnormalities, both ventricular tachycardia and interventricular conduction delays, and those on antiarrhythmic drugs for ventricular arrhythmias. (4) Patients with secondary pulmonary hypertension. (5) Patients who perform poorly on metabolic stress testing with maximum peak oxygen consumption (VO2) below 14 ml/kg/min. (6) Patients who have failed medical therapy. (7) Patients with hemodynamic abnormalities such as elevated right atrial and pulmonary capillary wedge pressures and low

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cardiac indices !2.5 liters/min/m2. (8) Patients with plasma norepinephrine levels 1800 pg/ml often have correlating high resting heart rates and are prone to have increased mortality. Furthermore, due to the underlying coronary artery disease, it has also been shown that patients with an ischemic cardiomyopathy tend to do worse compared to those with a nonischemic cardiomyopathy. Indications for Transplant Listing The question then arises, why should we recommend heart transplantation? The most important reasons are survival benefit and quality of life. Heart failure mortality in patients in NYHA class IV may be as high as 50% at 1 year. This is compared to a heart transplant mortality of 10–15% at 1 year. Who should then be listed for a heart transplant? Sick patients with hemodynamic instability requiring dependence on one or more intravenous inotropic agent or mechanical circulatory support in the form of an intraaortic balloon pump or ventricular assist device. Outpatients with poor prognostic indicators of survival, referred to as ‘high-risk ambulatory’ patients (table 1). These include patients with severe left or biventricular dysfunction and a poor EF (left ventricular EF !20%) whose maximum attained peak VO2 is !15 ml/kg/min on metabolic stress testing. It also includes patients with burned out cardiomyopathy of various etiologies who have NYHA class III or IV heart failure symptoms not responding to conventional medical therapy, or patients with malignant ventricular dysrhythmias who are at increased risk of sudden death, or patients with diffuse nonsurgically correctable coronary artery disease who do not respond to other nontransplant treatment modalities. Having identified the groups of patients who would qualify as potential heart transplant candidates based on their cardiac status alone, several factors may play a role in identifying those patients who would be good candidates for transplant with low operative risk and good longterm outcome, and several other factors may identify those who have an increased operative risk and poor outcome (table 2). In general, patients who have irreversible pulmonary hypertension or pulmonary parenchymal disease, those with irreversible renal or hepatic dysfunction, severe peripheral or cerebrovascular disease, or insulindependent diabetes mellitus with end-organ damage, patients with coexisting cancer and those who are noncompliant or have persistent substance abuse despite counseling are not candidates for heart transplantation.

Massad

Organ Resources

Donor Shortage The demand for heart donors has been steadily on the rise, and the number of patients with end-stage heart disease on the waiting list of the United Network for Organ Sharing (UNOS) has almost tripled over the past decade, from 2,000 patients in 1991 to nearly 7,000 patients in 1996. However, in view of the improvements in medical therapy and with the emerging alternative nontransplant surgical options that have become available, the number of active patients on the waiting list dropped significantly to about 3,750 as of June 2003. What continues to be concerning is the steady leveling off in the number of available heart donors. It is estimated that the number of potential heart donors would increase to about 5,000– 7,000 annually if the organ acceptance criteria were liberalized to include marginal donors. With this limited pool of organ donors, the Institute of Medicine estimates that over 15,000 patients would potentially benefit from a heart transplant if the acceptance criteria were liberalized to include all qualified patients below 55 years of age, and about 40,000–70,000 patients would benefit if the acceptance age were extended to 65 years. Fortunately, with aggressive medical management and the introduction of newer heart failure pharmacotherapy such as angiotensin-converting enzyme inhibitors and receptor blockers, the death rate for patients on the waiting list has dropped significantly by almost half over the past decade, with a similar trend for patients waiting for heart-lung transplantation.

Table 2. Contraindications to heart transplantation

Absolute contraindications Age greater than 65–70 years (depending on transplant center) Diabetes mellitus with peripheral end-organ damage (other than retinopathy) Pulmonary hypertension with pulmonary vascular resistance 1 6 Wood units Active infection or sepsis Positive HIV antibodies Irreversible hepatic or renal dysfunction Active malignancy Recent substance abuse Peripheral vascular disease Psychological or social contraindications such that a patient is unable to follow a drug regimen or maintain health care Any other disease process that would limit the life span or result in a poor quality of life for an otherwise healthy transplant recipient Poor compliance Relative contraindications Age greater than 65 years Diabetes mellitus without end-organ damage Active peptic ulcer disease Peripheral vascular disease Preformed antibodies Previous malignancy Psychological and social concerns Musculoskeletal wasting Renal and/or hepatic insufficiency Recent diverticulitis Recent pulmonary infarction Obesity Ventilatory support Active smoking Indications for retransplantation Advanced graft atherosclerosis

Demographics Almost all heart transplant centers worldwide report their transplant procedures to the Registry Database of the International Society for Heart and Lung Transplantation (ISHLT), which in turn analyzes the data and reports the outcomes on an annual basis. In the US, all transplant centers are required to report their transplant procedures and outcomes to UNOS. Thus far, and as of June 2003, there have been over 62,000 heart transplants that have been reported to the ISHLT registry from over 200 heart transplant centers worldwide, 135 of which are in the US. The age distribution of the recipients of these transplants follows a bell-shaped curve, with the vast majority of these procedures being performed in recipients between 35 and 64 years of age [1]. About 52% of the transplant recipients are in the 50- to 64-year age group and about 23% are in the 35- to 49-year age group. More transplants are now being performed on older recipients

who are 65 years of age or more (8% between 1997 and 2001 compared to 3% between 1985 and 1996). Heart transplantation continues to be a valuable option for the treatment of end-stage heart disease. Despite the growing and aging world population, the number of heart transplants had been steady since the early 1990s at about 2,500–2,700 procedures performed annually in the US and about 3,500–4,300 procedures worldwide. However, a close look at the recent total number of patients who have been transplanted worldwide (US and non-US) and who have been reported to the ISHLT registry indicates that the number of transplants performed worldwide has dropped over the past few years to about 3,200 procedures annually. This has been attributed, at least in part, to a decrease in the reporting of heart transplants by non-US centers. However, there are other factors that

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Table 3. Possible factors contributing to the recent downward trend in the number of heart transplants performed worldwide

Improvement in medical therapy for CHF Availability of other nontransplant surgical options for patients with end-stage heart disease Decline in donor availability in some countries Organ wastage in donor supply and uptake [2] Pressing socioeconomic issues in developing and third world countries Underreporting of procedures to the ISHLT by non-US centers Lack of facilities such as operating room time, beds and specialized nurses and physicians/surgeons in some centers, states or countries [2] Insufficient institutional resources Lack of governmental funding in most countries Poor reimbursement by third party insurers Variation in activity of individual surgeons, centers and countries [2] Disaffection among new trainees toward transplantation in general (long training, low pay) [2]

have contributed to this recently observed downward trend (table 3) [2]. A major reason for this is the fact that, unfortunately, heart transplantation continues to be confined, to a very large extent, to the affluent nations. Whereas the North American continent and Europe account for only 17% of the world population, they donate and receive over 95% of the heart transplants performed worldwide (table 4). At present, heart transplantation is not an option that can be offered to the vast majority of the world population, in particular to the over 5 billion inhabitants of underdeveloped or developing countries in the three most populated continents, namely South America, Africa and Asia. More interesting is the more or less universal role that gender plays in determining who receives a heart transplant. Over 73–80% of transplants performed worldwide are performed in men, with women receiving less than one fourth of the transplants worldwide. It is believed that several socioeconomic factors might have influenced this difference and have contributed to this gender disparity. The two most common disease etiologies leading to cardiac transplantation are ischemic cardiomyopathy secondary to end-stage coronary artery disease and dilated cardiomyopathy secondary to a viral or an iatrogenic etiology. In the US, these constituted 43.7 and 41.1%, respectively, of the heart transplants performed in 2001. This is contrasted with the European continent, where 53.7% of the heart transplants performed in 2001 were for a viral or iatrogenic cardiomyopathy and only 30.8% were

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performed for an ischemic cardiomyopathy. The same trend seen in Europe is also seen in Asia, Australia and in South America, where dilated cardiomyopathy constitutes the etiology in about 60% of the total transplants. In Brazil alone, it is estimated that between 7 and 10 million people have Chagas disease, with some degree of cardiomyopathy developing in about 10% of the patients affected. Other heart diseases that may lead to transplantation include valvular or hypertrophic cardiomyopathy, sarcoidosis and primary cardiac amyloidosis, although many centers shy away from transplantation in patients with the latter disease due to their increased postoperative mortality and their decreased long-term survival. Donor Identification The criteria for brain death and organ donation have been established in the US since 1968. Cadaver donors are declared brain dead based on set and well-defined neurological criteria. The attending physician or local hospital where the brain death occurs then informs the local organ procurement organization, which, in turn, decides whether to send a transplant coordinator to evaluate that particular case as a potential organ donor. In general, brain dead patients are deemed suitable for donation if they satisfy certain criteria with regard to age, medical condition, cause of death and their psychosocial history. Those who have a known history of heart disease or an active infection, or a positive serology for hepatitis B or C or for HIV, and those with an active malignancy or an active psychosocial history including intravenous drug use at the time of evaluation are usually turned down as potential donors. Although some centers have accepted donors with positive serology for hepatitis C in particular instances when the potential recipient is hepatitis C positive or when that recipient is quite sick and cannot wait for a more suitable donor, such practice is not encouraged. Thus far, there have been no heart transplants reported to UNOS from patients with HIV who have controlled viral counts and who have not demonstrated any manifestations of AIDS. Once these conditions have been ruled out, a battery of testing and screening is then initiated by the local organ procurement organization coordinator to identify the status of the donor’s heart. Usually, it is advisable that potential donors who are over 40 years of age undergo, beside a routine ECG and a surface echocardiogram, a coronary angiogram to evaluate the status of their coronary arteries. This is particularly important in the potential donor who has a strong family history of coronary artery disease or who has one or more risk factors for developing coronary

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Table 4. Continent-specific numbers of heart transplants performed during 2001 based on UNOS/ISHLT data as of March 14, 2003 (source: www.ishlt.org/registries/)

Population, millions Percentage of world population Number of heart Txs Percentage of total heart Txs

North America

Europe

South America1

Africa1

Asia/ Australia1

Entire ISHLT registry

318 5.0

728 12.0

532 8.5

840 13.5

3,798 61

6,216 (world population) 100

5 !1

0 0

5 !1

– – –

80.0 60 40

74.9 46.3 38.5

NA NA

77.0 NA

83.8 77.3

2,302 75

743 24

Heart Tx demographics Male, % DCM, % ICMP, %

73.0 43.7 41.1

79.9 53.7 30.8

80.0 60 40

Heart Tx survival, % At 1 year At 3 years

85.3 77.3

80.5 74.8

77 NA

1

3,055 100

Tx = Transplant; DCM = dilated cardiomyopathy; ICMP = ischemic cardiomyopathy; NA = not available. From countries with heart transplant centers that report to the ISHLT registry.

artery disease. Based on the results of the coronary angiography, the decision is then made on whether to accept that heart for transplantation. In some cases, the local hospital where that potential donor is does not have the facilities or the specialized personnel to perform coronary angiography. In such instances, it is up to the transplant surgeon to make the decision whether to accept or turn down the organ based on his or her own personal assessment of the organ on site. In an effort to increase the number of heart transplant procedures performed worldwide, several centers have considered expanding the donor pool by liberalizing the donor acceptance criteria to include donors who are not considered optimal by the standard criteria. These donors are often referred to as ‘marginal donors’. The interest in this group has increased in view of more recent data indicating that the outcome of heart transplant recipients who have received so-called ‘marginal organs’ is not significantly different from that of patients who received ideal organs. In view of that, several centers now consider donors who are older (aged up to 65 years or more), who have had periods of cardiopulmonary arrest and were successfully resuscitated (down time of 25–30 min), who are on pressors due to some hyperdynamic state related to their injury, who are distant (outside the 1,000-mile procurement radius, particularly for pediatric transplants), who have an estimated expected cold ischemia time exceeding the 4-hour mark, and also those who have

Current Trends in Heart Transplantation

Table 5. Criteria for acceptable heart donation from marginal do-

nors Age up to 65 years Undersizing or oversizing by more than 20% body weight Prolonged hospitalization History of chest trauma Open cardiac massage Elevation of myocardial enzyme levels Prolonged cardiopulmonary resuscitation (1 5 min) Transient hypotension (1 30 min) High-dose pressor requirement Wall motion abnormality by echocardiography Long-distance procurement (over the 1,000-mile radius) Persistent conduction disturbance Cold ischemia time up to 4–5 h Bypassable one- or two-vessel coronary artery disease Correctable valvular dysfunction by echocardiography

bypassable coronary disease or some correctable valvular dysfunction (table 5) [3, 4]. Organ Allocation In the US, the UNOS has been designated to assume the role of equitable distribution of cadaveric organs nationwide. Although this model has its own limitations and shortcomings, many other developed countries view it as ideal for equitable placement and distribution of

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donor organs. This organizational scheme divides the US into 11 geographic regions, each region consisting of several neighboring states with local organ procurement organizations that communicate with the local hospitals to evaluate potential donors and also with the UNOS. In this model, and in order to minimize organ wastage or suboptimal outcomes, the donated organs would be offered to the local transplant centers first, as these organs would have the shortest ischemia time, and also better chances for an optimal outcome. If no local recipients are identified, these organs are then placed within the region or outside of it as a last resort. In addition to the distance between the organ donor and the potential recipient, other organ allocation criteria that are also considered include blood group compatibility, size and weight difference between the donor and the potential recipient (usually within 20%) and the medical condition of the potential recipient at that time. Patients on the waiting list are classified into one of three classes based on their clinical status, defined as follows: UNOS status 1 patients are those patients who have either (1) been on mechanical ventricular assist for less than 30 days [total artificial heart, left ventricular assist device (LVAD) or extracorporeal membrane oxygenation], or have an intraaortic balloon pump or are on highdose inotropic agents with continuous hemodynamic monitoring (Swan-Ganz catheter), or are expected to live less than 1 week (subgroup 1a), or (2) been on mechanical circulatory support for over 30 days or are on continuous low-dose inotropic support (without Swan-Ganz monitoring) on an inpatient or outpatient basis (subgroup 1b). UNOS status 2 includes all other active patients on the waiting list, namely those who are homebound and on no mechanical or inotropic support, and UNOS status 7 are patients who have been placed on the list because they satisfied the criteria for listing but who were inactivated because of some recent medical condition. At the time of evaluation for listing, a panel reactive antibody (PRA) assay is obtained. In this assay, the recipient’s serum is tested by complement-dependent lymphocytotoxicity against a comprehensive 25- to 50-member cell panel of human leukocyte antigen (HLA)-typed donors selected to represent most of the defined HLA specificities. Using cytotoxicity by standard dye exclusion assay, positive reactions are expressed as a percentage of the total cell panel. Patients who will be placed on the waiting list are considered sensitized if their PRA is over 10%. In general, HLA sensitization occurs secondary to previous pregnancies or a previously transplanted organ, or due to recent or remote blood transfusions as is the case

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during implantation of an LVAD [5]. Thus, it is quite important that frequent PRA assays are obtained for the patients on the waiting list anytime they receive blood transfusions or following implantation of an LVAD as a bridge to transplant. In this latter group of patients, who are bridged to transplantation on an LVAD, most antibodies that develop following LVAD implantation are antibodies against non-HLA antigens that may be related to the device’s biocompatibility (autosensitization). Most antibodies against non-HLA antigens have a relatively short half-life of about 2–3 months on average. In addition, a significant number of such patients develop antibodies against HLA antigens (allosensitization), related to the blood and blood product transfusions they receive during and after LVAD implantation [5]. Notorious among these blood products are pooled platelet transfusions that contain class I antigens. In general, prospective cross-matching is not usually required in patients who have no PRAs upon screening and on follow-up. However, patients with PRA 110% require prospective cross-matching to assure that they have no HLA antibodies against the potential donor. In some instances, the degree of HLA sensitization becomes problematic in the sense that the patients would need to wait longer on the list for a suitable donor. This is particularly so when bridged patients waiting for an organ develop very high PRA levels (up to 100%). In that group of patients, several strategies can be adopted to decrease their level of sensitization and prepare them for the transplant. These include performing frequent sessions of plasmapheresis as they move up the waiting list, as well as administering intravenous immunoglobulin infusions, or both, before and after the transplant [6]. These highly sensitized patients are more predisposed to develop frequent and more severe cellular and humoral-mediated rejection episodes after the transplant, hence the need to continue their desensitization protocols after the procedure. Such patients are also prone to develop graft vasculopathy and as a result have decreased long-term survival.

Graft Procurement and Techniques of Transplantation

Once a suitable heart donor is identified and the organ is allocated, a timetable is set and organized to keep the transportation time and cold ischemia time of the procured organ to a minimum. At the time of procurement, the procuring surgeon dissects and exposes the major vessels (aorta, pulmonary vessels and cavae). Once the other

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surgical teams have completed their dissection for procuring the abdominal organs, a small catheter is placed in the ascending aorta for antegrade cardioplegia delivery. The aorta is then cross-clamped near the innominate artery takeoff, the superior vena cava is ligated and the heart is arrested with 2 liters of high-potassium (30–40 mEq/l) cold crystalloid cardioplegia solution [7–12]. The inferior vena cava is divided above the level of the diaphragm to decompress the right heart. Incising one of the pulmonary veins if the lungs were not procured, or the tip of the left atrial appendage if the lungs were procured, decompresses the left heart. The heart is arrested and covered with ice slush in preparation for explantation. The donor’s heart is then excised by completely dividing the superior and inferior vena cavae, the right and left pulmonary venous confluences, the main pulmonary artery at its bifurcation and the aorta near the arch. The heart is then inspected for any septal defects or abnormality and is placed in sterile bags containing cold saline and ice slush, then packed in ice and transported to the transplant center. At the local transplant center, the recipient has already been prepared, the mediastinum has been opened and the native heart has been exposed. The recipient is placed on cardiopulmonary bypass. Once the donated heart arrives, cardiectomy is then performed in the recipient and the new heart is sewn in. The implantation technique adopted by most transplant surgeons is the standard biatrial technique that was described by Lower and Shumway in the early 1960s. With this technique, the native heart is excised, leaving right and left atrial cuffs that are then anastomosed to the donor’s right and left atrial cuffs with running nonabsorbable sutures. More recently, several surgeons have adopted the bicaval technique for ease of use, particularly in patients who have had no previous heart operations. With this technique, the donor’s superior and inferior vena cavae are sewn separately to those of the recipient. The advantage of the latter technique is that it maintains the geometry of the right atrium and, by doing so, minimizes the amount of tricuspid regurgitation and also atrial arrhythmias following the procedure. It is usually uncommon for atrial fibrillation to develop in the immediate postoperative period outside of the context of rejection, and if it does develop, then rejection should be ruled out by endomyocardial biopsy. Modifications of the bicaval technique have been described whereby the native superior and inferior vena cavae of the recipient are kept in continuity by preserving the posterior strip of the recipient’s right atrial tissue connecting the two structures [13].

Table 6. Endomyocardial biopsy schedule for surveillance of cellular

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rejection after heart transplantation Postoperative interval

Endomyocardial biopsies

First month Second month 3–6 months After 6 months Long term (1 1 year) After rejection treatment

weekly biweekly monthly every 3–4 months yearly 10–14 days

Table 7. The ISHLT grading system for cellular rejection (modified

Billingham’s criteria as adopted by the Heart Transplant Rejection Study Group) Grade of rejection

Histologic findings

0 1A 1B 2 3A 3B 4

no inflammation focal perivascular or interstitial infiltration minimal diffuse single aggressive multifocal aggressive diffuse with possible myocyte damage diffuse polymorphous infiltrate; myocyte damage and possible hemorrhage and vasculitis

Rejection Grading and Surveillance

Following the transplant, acute cellular rejection is surveyed by obtaining endomyocardial biopsies, usually weekly during the first month, then monthly for a period of 6 months, then yearly thereafter (table 6). The cellular rejection is then graded according to a histological grading system that was initially developed by Margaret Billingham at Stanford University and was later adopted by the Heart Transplant Rejection Study Group and the ISHLT (table 7). Other criteria for identifying rejection, such as ECG voltage criteria, cardiac enzymes and troponin levels, glycolipid antibodies and echocardiography, have been found to be less specific and less accurate and, therefore, cannot be depended on at this time to identify rejection [14–16]. Endomyocardial biopsy schedules for surveillance of rejection vary between transplant centers. Rejection is considered significant by most centers when it is grade 3 or more or when it is accompanied by any hemodynamic changes. Once rejection is detected and deemed signifi-

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cant, the patient is then treated accordingly. When planning a strategy for treating transplant rejection, the following variables should be considered: (1) the histological grade of rejection; (2) evidence of hemodynamic compromise by EF or right heart catheterization; (3) the severity of previous rejection episodes and types of immunosuppressive agents used, and (4) risk factors for rejection [17].

Immunosuppressive Therapy

Induction and Maintenance For most patients undergoing heart transplantation, immunosuppression consists of triple drug therapy which is based on a calcineurin inhibitor that blocks interleukin-2 gene transcription, usually cyclosporin A (CSA) or FK506 (Tacrolimus/Prograf). A purine synthesis inhibitor (antimetabolite) such as azathioprine (Imuran) or mycophenolate mofetil (Cellcept) would then be a secondline drug in addition to steroids. Steroids work by inhibiting interleukin-2 production and by suppressing T celldependent immunity. The patient would typically receive a preoperative oral dose of CSA (5–10 mg/kg) and azathioprine (4 mg/kg) or mycophenolate (1–1.5 gm) prior to the procedure. In addition, an intravenous dose of methylprednisolone (500 mg) is administered intraoperatively prior to release of the aortic cross-clamp and reperfusion of the transplanted heart. Postoperatively, CSA can be continued in an oral form (through the nasogastric tube at a dose of 5–10 mg/kg/day in two divided doses, with the goal of achieving 12-hour trough blood levels of 200– 300 ng/ml, as assessed by high-performance liquid chromatography). More commonly, however, CSA is given in the immediate postoperative period as a continuous intravenous infusion to minimize its effects on the kidneys. The intravenous dose is usually about one third of the oral dose. Imuran is continued at a dose of 2–4 mg/kg/day as a single daily dose or, alternatively, mycophenolate at 1– 1.5 mg twice daily. Methylprednisolone is continued for the initial 24-hour period after the transplant at a dose of 125 mg every 8 h for three doses, following which the patient is switched to prednisone and later tapered gradually to about 20–25 mg/day. There are no data, thus far, demonstrating the safety of steroid-free immunosuppression in the long term for heart transplant recipients as is the case in renal transplantation, although the prednisone dose could potentially be tapered down 1 year after the transplant to about 10–15 mg daily. Patients who develop renal dysfunction after transplantation with CSA or with FK506 (at a dose of 0.15–

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0.30 mg/kg/day given in two divided doses 12 h apart) may be switched to a less nephrotoxic agent such as rapamycin (sirolimus) in addition to azathioprine or mycophenolate and steroids. Rapamycin works by inhibiting T cell proliferation and by suppressing proliferation from the G1 to the S phase of the cell cycle. It is given as a loading dose of 6 mg followed by 2 mg/day once daily. Therapeutic blood levels should be maintained between 5 and 10 ng/ml. Its effects on the cellular and humoral responses of the host make it a promising drug for the treatment of refractory acute rejection and graft vasculopathy [18, 19]. In patients with compromised renal function prior to the transplant, ‘induction therapy’ with OKT3 could be considered for a period of 10–14 days either in addition to a low dose of CSA or without a calcineurin inhibitor. ‘Sequential therapy’ with CSA or another calcineurin inhibitor is then started after completion of OKT3 therapy. One of the recent advances in the field of immunosuppression therapy is the development of molecularly engineered humanized monoclonal antibodies. At present, two such drugs are in clinical use after passing clinical trials that demonstrated their efficacy in preventing cellular rejection. These are basiliximab (Simulect, Novartis Pharmaceuticals) and daclizumab (Zenapax, Roche Pharmaceuticals). These monoclonal antibodies act by blocking the interleukin-2 receptor. Although the data regarding the use of these two drugs come primarily from their use in the renal transplant population, some encouraging reports regarding their use in the cardiac transplant population have started to surface [20]. In a randomized trial of daclizumab at the Columbia-Presbyterian Hospital in New York, 55 heart transplant recipients were randomized to receive either standard immunosuppression consisting of CSA, mycophenolate and prednisone or the standard therapy plus daclizumab. Acute cellular rejection developing within 8 weeks of the induction period and defined as ISHLT grades 2 or more developed in 63% of the patients who were treated with the standard immunosuppression and in only 18% of those treated with the standard immunosuppression plus daclizumab [20]. More recent data from the same center have demonstrated that the effect of interleukin-2 receptor blockade seems to be influenced by the degree of donor-recipient HLA-DR mismatching [21]. In a study of 70 adult heart transplant recipients who received an interelukin-2 receptor blocker (daclizumab), treatment with daclizumab significantly prevented development of high-grade acute rejection in recipients with at least one donor HLA-DR locus match during the first 3 months after the transplant

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[21]. Recent data from the ISHLT registry indicate that approximately 47% of patients undergoing heart transplantation between 1999 and 2001 received some form of antibody-based induction therapy (polyclonal, monoclonal or interleukin-2 receptor blocker). Triple drug immunosuppression with cyclosporine, mycophenolate and corticosteroids remains the most frequently used combination of immunosuppressive agents 1 and 5 years after the transplant [1]. Management of Acute Cellular Rejection The initial episode of acute rejection is usually treated with a bolus corticosteroid therapy or what is referred to as a ‘steroid pulse’. This is achieved either by increasing the oral prednisone dose to 1.5–15 mg/kg given over a 3- to 10-day period then tapering it to baseline, or, alternatively, the baseline oral prednisone dose is switched to intravenous methylprednisolone at a dose of 5–15 mg/kg per day for 3 consecutive days, followed by return to the baseline dose of oral prednisone. This is usually accomplished in an inpatient setting, although some centers treat the first episode of rejection on an outpatient basis, particularly when it is of low to intermediate grade (grades 2–3A) and is not associated with any hemodynamic compromise. The endomyocardial biopsy is usually repeated 10–14 days after the steroid pulse (table 6). If the biopsy shows persistent rejection, another steroid pulse is usually administered, followed by a repeat biopsy. A third steroid pulse may be administered. However, in most centers, persistent rejection that does not respond to two or more steroid pulses, or rejection that is accompanied by hemodynamic compromise is treated on an inpatient basis with antilymphocyte therapy either in the form of OKT3 monoclonal antibody, which binds to the CD3 antigen, or with polyclonal antisera such as horse antithymocyte globulin or rabbit antithymocyte globulin [22]. Other modalities to treat persistent or recurrent rejection despite the above include lowdose methotrexate therapy, total lymphoid irradiation, photopheresis or switching immunosuppression to other newer immunosuppressive agents such as tacrolimus (FK506 or Prograf), sirolimus (rapamycin), everolimus, mycophenolate mofetil (Cellcept) or others.

circulation. Humoral rejection is B cell mediated, in contrast to cellular rejection, which is T cell mediated. It requires special immunohistochemical staining for detection on endomyocardial biopsies, which often show the typical findings of endothelial cell activation, immune complex deposition and interstitial fibrin deposition in the absence of significant lymphocytic infiltration [23]. In the cardiac allograft, it often manifests as graft coronary artery disease, which is detected either by annual angiography or more accurately by intravascular coronary ultrasound. Treatment for humoral rejection is prescribed with the aim of suppressing new antibody formation, removing circulating antibody and improving coronary blood flow [25]. The initial management strategy is prevention in the high-risk group of patients who usually present prior to the transplant with elevated PRA levels secondary to blood transfusions or in association with LVAD implants [5, 26]. These patients usually receive plasmapheresis and/or immunoglobulin therapy around the time of the transplant and in the postoperative period. Oral cyclophosphamide has been used for the treatment of chronic vascular rejection, but the long-term outcome remains poor, with many of these patients requiring retransplantation.

Management of Humoral Rejection Humoral rejection is not as common as cellular rejection and has been reported to occur in over 8% of transplant recipients [23, 24]. It is more difficult to control than cellular rejection and usually appears as chronic vascular rejection that leads to graft vasculopathy manifesting as diffuse small vessel disease that targets the coronary

Prevention of Graft Vasculopathy Coronary artery vasculopathy is the leading cause of late death in heart transplant recipients. It manifests on the endothelial level and within the coronary arterial lumen with release of profibrotic cytokines, recruitment of circulating leukocytes, proliferation of smooth muscle cells and deposition of extracellular matrix proteins within the lumen of small coronary vessels [27]. A strong correlation between the number and intensity of cellular and vascular rejection episodes has been established. Likewise, vasculopathy has also been associated with prolonged organ ischemia time and the development of cytomegalovirus (CMV) infection, particularly in the highrisk group, as well as abnormal lipid profiles following the transplant. As a result, it has been demonstrated that calcium channel blockers, newer cholesterol-lowering agents (statins), ganciclovir, newer immunosuppressive agents such as mycophenolate and rapamycin, and photophoresis may be helpful in ameliorating this condition or slowing down its progression [28]. Graft arteriosclerosis develops in about 10% of heart transplant recipients within the first year after the transplant. The incidence increases to 24% by 2 years, 29% by 3 years and 50% by 5 years after the transplant. In a review of 2,546 patients who underwent heart transplantation between April 1994 and De-

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cember 1998 and were reported to the ISHLT registry, Hertz et al. [1] identified some of the risk factors for the development of angiographic coronary artery vasculopathy of any severity within 3 and 7 years after the transplant. These included a donor history of hypertension, younger recipient, older donor and an increasing recipient body mass index [1]. In order to decrease the incidence and severity of graft arteriosclerosis, a lot of emphasis should be placed on targeting B cell-mediated humoral rejection, which is considered the main culprit and predisposing factor. Newer immunosuppressive drugs on the market, such as mycophenolate mofetil and rapamycin, have been shown, in vitro and in vivo, to demonstrate a significant effect on B cell-mediated rejection. Their impact on long-term graft arteriosclerosis is yet to be determined pending longitudinal studies of transplant outcomes with these newer immunosuppressive agents. Induction of Tolerance The ability to induce lifelong donor-specific tolerance to alloantigens in vivo is essential to progress in organ transplantation. Although most immunosuppressive drugs are capable of reducing the incidence and severity of acute rejection, they all appear to be less effective in preventing loss of the allograft in the long term, as many other factors come into play and contribute to this untoward outcome. The induction of tolerance to the histocompatibility antigens of the organ donor in the long term after transplantation would eliminate the need for longterm administration of these nonspecific immunosuppressive agents, and as a result would significantly decrease the incidence of infectious and immunosuppression-related complications [29]. Several strategies for induction of immune tolerance are currently being explored. However, many of the tolerance protocols that have shown some success in small animal models such as rodent models have failed when attempted in larger animal models or in humans [30]. An attractive concept that is currently being investigated is the induction of mixed hematopoietic chimerism, although this strategy in itself can be associated with significant complications related to host conditioning [30].

Management of Pulmonary Hypertension

Irreversible pulmonary hypertension is a contraindication to heart transplantation. Pulmonary hypertension is considered irreversible despite aggressive challenge if the

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pulmonary vascular resistance persists above 4 Wood units (pulmonary vascular resistance index over 6 Wood units) with a transpulmonary gradient of 115 mm Hg. When evaluating the patient with end-stage heart disease and elevated pulmonary artery pressures, it is imperative that aggressive challenge with one or more pulmonary vasodilators such as oxygen, nitric oxide, sodium nitroprusside, milrinone or dobutamine over a prolonged period of time is performed. This challenge should not be limited to a brief period of a few minutes in the heart catheterization laboratory setting. Rather, it should be performed over an extended period of several hours and even several days in an intensive care unit setup while constantly monitoring the pulmonary hemodynamics using a Swan-Ganz catheter, before excluding patients from listing based on the degree of pulmonary hypertension. Furthermore, it is mandatory that patients on the waiting list have repeat hemodynamic testing and right heart catheterization at various intervals while on the list to ensure that the degree of elevation in the pulmonary artery pressures has not progressed to unacceptable or irreversible levels. Adopting such a strategy insures that patients with elevated but reversible pulmonary artery pressures are given the chance to have a transplant, but at the same time, it identifies a high-risk group of transplant recipients who will require very close monitoring and management in the postoperative period in order to insure a favorable outcome. Pulmonary hypertension continues to be one of the leading causes of death immediately after transplantation. Thus, it is important that all measures be taken to accept an allograft that can provide adequate right ventricular contractile function in the face of the elevated pulmonary pressures. In such instances, when identifying a suitable organ, consideration should be given to hearts from large donors. In addition, and in order to keep the pulmonary pressures within acceptable limits, transplant recipients with preoperative pulmonary hypertension may need to be continued on inotropic agents that have salutary vasodilatory effects on the pulmonary pressures. Dobutamine at doses of up to 15 Ìg/kg/min and/or milrinone at doses of up to 0.75 Ìg/kg/min are two such drugs. Their effects on the pulmonary vasculature could be augmented by the use of supplemental oxygen as well as agents such as nitric oxide at doses of 10–80 parts per million or a continuous infusion of prostaglandin E (100–200 ng/kg/min). The effects of dobutamine on right heart contractility and the pulmonary vasculature should be weighed against its potent chronotropic characteristic, as it can precipitate significant tachycardia that may overburden the newly implanted heart and interfere with left ventricular filling.

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Outcomes

Survival Data Survival rates after heart transplantation rose in the 1980s with the introduction of cyclosporine into clinical use and have remained relatively constant since then [31]. Among the US heart transplant recipients during 1999, the 1-year survival rate was 84% [32]. After the first year of transplantation, survival declines at a relatively constant rate of approximately 4–5% per year [1, 33]. The 5-year survival rate for transplants performed in 1995 was 71% [32]. The patient half-life, defined as the time to 50% survival, for all patients transplanted between 1982 and 2001 remains constant at about 10 years [1]. In one report, the survival rate was 23% at 19 years after the transplant [32]. In a study by Bennett et al. [32], about 66% of heart transplant recipients did not require rehospitalization during the first year after transplantation. In another study of 1,853 patients from the ISHLT network who survived the initial hospitalization and for whom 1-year follow-up data were available, more than 40% of survivors required rehospitalization during the first year after the transplant, and at least one third of those required admission to the intensive care unit [34]. Infection and rejection were the most common reasons for rehospitalization, each accounting for about 20% [34]. Early donor heart failure accounts for approximately 26% of the deaths of heart transplant recipients, with a steep rise in mortality associated with storage times in excess of 2 h (9.8% mortality for !2 h of storage, rising to 17.6% for 14 h of storage) [35]. The causes of death after heart transplantation among 39 patients who underwent postmortem examination after their death were investigated by Alexander and Steenbergen [24] and are summarized in table 8. Although the presence of diabetes mellitus at the time of transplantation seems to impact on the long-term survival, the data still justify offering heart transplantation to diabetic patients with end-stage heart failure [36]. Czerny et al. [36] analyzed 773 consecutive primary adult heart transplant recipients at their institution. Of those, 140 patients had diabetes and 633 did not have diabetes at the time of transplantation. Although the patients with diabetes were older (54.9 versus 49.7 years, p = 0.0001) and had a higher incidence of ischemic cardiomyopathy prior to the transplantation (52 versus 30%, p = 0.0001), the incidence of transplant coronary artery disease was comparable at 10 years (28 versus 22%, respectively, logrank = 0.625). However, the presence of diabetes at the

Current Trends in Heart Transplantation

Table 8. Causes of death after heart transplantation

Cause of death

Percent of autopsies

Right-sided heart failure Infection Multisystem organ failure Complications of noncardiac surgery Acute rejection Graft vascular disease Malignant neoplasm Preservation injury during procurement Cardiac arrhythmia Other Undetermined

15 13 10 8 8 8 8 8 5 14 8

Summarized from Alexander and Steenbergen [24].

time of transplantation was associated with reduced longterm survival at 10 years (40 versus 58%, respectively, log-rank = 0.025). Multivariate Cox proportional hazard analysis performed by these authors showed that diabetes but not age was an independent predictor affecting longterm survival [36]. Noninfectious Complications Noninfectious complications after heart transplantation can be divided into immunosuppression-related and non-immunosuppression-related complications. Immunosuppression-related complications include malignancy, lymphoproliferative disease and complications relating to each specific immunosuppressive drug. Hypertension, renal dysfunction, hirsutism, gum hyperplasia, tremor and seizures are seen mostly with the calcineurin inhibitors. Hyperlipidemia, obesity, diabetes, gout, osteoporosis and bone fractures and peptic ulcer are primarily related to steroid use. Gastrointestinal (liver, diarrhea) and blood abnormalities (leukopenia, anemia) are primarily related to the use of one of the antimetabolites, although calcineurin inhibitors can also precipitate a rise in liver enzymes. A clinical and radiographic picture consistent with interstitial pneumonitis has been attributed to rapamycin (sirolimus), particularly when the blood levels are high. Non-immunosuppression-related complications include a variety of morbidities that are associated with the transplant but not necessarily related to the immunosuppression protocol in use. These include graft coronary artery disease, drug interactions and additive toxicities, complications related to CMV and other opportunistic infections, and abdominal complications such as peptic ulcer

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Table 9. Incidence of post-transplant morbidities for survivors of heart transplants performed between 1994 and 2001 as reported by the 19th annual report of the ISHLT registry

Morbidity

Incidence, %

Hypertension Hyperlipidemia Abnormal renal function Diabetes Coronary artery vasculopathy Need for chronic dialysis

at 1 year

at 5 years

73 49 25 24 8 1.2

95 81 31 32 33 2.5

disease, cholecystitis and increased incidence of diverticulitis, among others. Complications during the first year after transplantation occur in 10% or more of survivors and include hypertension, diabetes, renal dysfunction and hyperlipidemia [34]. Table 9 shows the cumulative incidence of posttransplant comorbidities at 1 and 5 years after the transplant for survivors of heart transplants performed between 1994 and 2001 as reported in the 2002 annual report of the ISHLT registry [1]. By 7 years after the transplant, Hertz et al. [1] reported a 29% incidence of malignancy, including a 16% incidence of skin malignancy and a 4.4% incidence of lymphoma.

Prophylactic Strategies for Infections

CMV and Other Opportunistic Infections CMV infections are the most common viral infections after transplantation. Among the risk factors for the development of CMV infections are the use of non-leukocytefiltered or CMV-positive blood products in CMV-negative recipients, and the CMV statuses of the donor and recipient. Preemptive treatment strategies are based on early detection or identification of a high-risk subset of patients [37]. Four risk groups are identified according to the CMV status of the donor and recipient: (1) CMV-negative donor and CMV-negative recipient; (2) CMV-positive donor and CMV-negative recipient; (3) CMV-negative donor and CMV-positive recipient, and (4) CMV-positive donor and CMV-positive recipient. CMV-negative recipients have a particularly increased risk of CMV infection when they receive an organ from a CMV-positive donor. More interesting, in this latter subgroup of patients, is the reportedly increased incidence of graft vasculopathy.

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Several prophylactic strategies have been evaluated for prevention of CMV and other opportunistic infections. These include antiviral agents, globulin preparations such as pooled immunoglobulins or CMV-specific hyperimmune globulins (Gamimune, CytoGam) or combinations of these therapies. Once CMV infection develops, the treatment of choice is ganciclovir (Cytovene), given intravenously for 2–4 weeks with the dose adjusted to renal function or bone marrow suppression. Although earlier outcome analyses of the ISHLT registry showed that CMV mismatch is a risk factor for 1-year mortality, this is no longer true, according to the most recent report from 2002 [1]. Line Sepsis and Bacterial Infections Line sepsis and bacterial infections are not uncommon in the immediate postoperative period. Therefore, it is imperative that meticulous care be taken while the patient is recovering in the intensive care and cardiac units. Access lines need to be changed quite frequently. Once the patient is stable and is off drips, we have found the use of peripherally placed central venous lines quite useful, and they can eliminate the need for multiple venous punctures. Nosocomial pneumonia can develop early on, particularly in the setup of continued need for mechanical ventilator support after the transplant. Sternal or groin wound infections may develop after the transplant, and these require early intervention with empiric broad-spectrum antibiotic coverage until the offending organism has been isolated and targeted with the appropriate antibiotic therapy. Patients who are confined to bed and are on vasoconstrictors after the transplant are prone to develop pressure ulcers in the skin and soft tissue, and this needs to be avoided, first and foremost, by frequent positioning of the patient and use of special air mattresses or both. Should these develop, they need to be identified early and managed with appropriate wound care and occlusive dressings. Fungal and Protozoal Infections Fungal infections are not uncommon after transplantation. The most common of these include infections caused by Candida albicans, and these are usually superficial. However, systemic infections with candida or with other fungi such as Cryptococcus and coccidioides still account for 5–7% of infections and are usually treated with systemic antifungal medications (amphotericin B). Among the protozoal infections, Pneumocystis carinii pneumonia is the most common. Treatment is usually with high-dose trimethoprim-sulfamethoxazole (Bactrim) for 4–6 weeks.

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Toxoplasmosis may also occur in this patient population and is often transmitted through an infected organ.

Living with a Transplant

Functional and Employment Status Several studies about the quality of life after heart transplantation have been published during the past two decades [38]. The current body of literature suggests that quality of life is better overall, but varies based on demographic characteristics, clinical problems, time after the transplant and other life events [38]. Approximately 90% of patients return to NYHA class I 1 year after the transplant [39]. Based on the 2002 report of the ISHLT registry, the functional status of surviving heart transplant recipients is excellent, with 190% having no activity limitations 5 years after the transplant [1]. However, fewer than 40% of these patients report full- or part-time employment [1]. Similar data on the functional status and return to work of transplant recipients from the United Kingdom were evaluated by Kavanagh et al. [40]. The clinical and employment status of 62 transplant recipients from a single center were evaluated by interviews at 1, 5 and 12 years after transplantation. The employment pattern was reported as good, with 69% (of 55 survivors) and 57% (of 35 survivors) of the group working at 5 and 12 years, respectively [40]. The subgroups of patients who were older and had a poor pretransplant work history were less successful in finding work and were more likely to be unemployed. Cost At a time when institutional support and Medicare and other third party reimbursements have been dwindling, heart transplantation has fallen into the back seat relative to other health care priorities. This is true in the US, but even more so in countries with limited access to medical care and health care providers. This constraint has been complicated by a process that requires providers and centers to assume risk and accept economic responsibility and fiscal consequences for clinical decisions [41]. While the need for transplantation as well as other modalities to treat end-stage heart disease is considerable, there are both clinical and economic factors limiting the overall level of activity. This is particularly important when looking at the group of patients who require implantation of LVADs as a bridge to transplantation, as the costs of transplantation and care for that group may escalate significantly from an average of USD 100,000–120,000, in

Current Trends in Heart Transplantation

the case of a straightforward nonbridged transplant, to between USD 250,000 and 500,000 or more in some instances when an LVAD is required for bridging. This puts a lot of pressure on the transplant center as well as on the patients and their third party insurance carriers. It is through the process of streamlining of services and designating centers based on price and quality considerations, in addition to governmental agencies overseeing this process, that procedural expenses could be reduced. Compliance and Other Post-Transplant Issues Compliance continues to be an important issue that affects the long-term outcome after heart transplantation. Grady et al. [39] evaluated patient compliance among 120 patients who were transplanted and followed up for 1 year and 76 patients who were followed up for 2 years. At both 1 and 2 years, patients had no difficulty following the heart transplant regimen and complied almost all of the time with taking medications, attending clinics and completing scheduled tests. However, patient compliance was lower with regard to following diet and exercising regimes [39]. Close follow-up is essential for a successful outcome following heart transplantation. Transplantation in itself does not provide a cure for the disease but rather palliation. It substitutes one disease process, namely heart failure, with another (the actual transplant) with all that entails in regard to uninterrupted immunosuppression, continued monitoring and treatment of developing infections and other complications. It entails a lifelong commitment from the patient and the transplant team. It also entails a very close working relationship with the referring physician to insure continuity of care and also to coordinate primary care closer to home.

Conclusions

Advances in surgical techniques and immunosuppressive therapy have rendered heart transplantation an effective treatment for patients with end-stage heart disease. Donor availability continues to limit the number of transplants in an aging population. Drugs targeting B cellmediated humoral rejection, developing selective immunosuppressive agents with a good safety profile and low number of side effects in the short term, and establishing donor-specific tolerance in the long term are important milestones that will hopefully bring heart transplantation up to par with the technologic advances of the new millennium.

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References 1 Hertz MI, Taylor DO, Trulock EP, Boucek MM, Mohacsi PJ, Edwards LB, Keck BM: The registry of the International Society for Heart and Lung Transplantation: Nineteenth Official Report – 2002. J Heart Lung Transplant 2002; 21:950–970. 2 Large SR: Is there a crisis in cardiac transplantation? Lancet 2002;359:803–804. 3 Massad M, Smedira NG, Hobbs R, Hurscher K, Vandervoot P, McCarthy PM: Bench repair of donor mitral valve before heart transplantation. Ann Thorac Surg 1996;61:1833–1835. 4 Drinkwater DC, Laks H, Blitz A, Kobashigawa J, Sabad A, Moriguchi J, Hamilton M: Outcomes of patients undergoing transplantation with older donor hearts. J Heart Lung Transplant 1996;15:684–689. 5 Massad M, Cook DJ, Schmitt S, Smedira NG, McCarthy JF, Vargo R, McCarthy PM: Factors influencing HLA sensitization in implantable LVAD recipients. Ann Thorac Surg 1997;64: 1120–1125. 6 Mehra MR, Uber PA, Uber WE, Scott RL, Park MH: Allosensitization in heart transplantation. Implications and management strategies. Curr Opin Cardiol 2003;18:153–158. 7 Dzielak DJ, Raju S, Woollex S: Enhanced myocardial viability with hypothermic storage in Euro-Collins solution. Transplant Proc 1989; 21:1364–1365. 8 Drinkwater DC, Ziv ET, Laks H, Lee JR, Bhuta S, Rudis E, Chang P: Extracellular and standard University of Wisconsin solutions provide equivalent preservation of myocardial function. J Thorac Cardiovasc Surg 1995;110: 738–745. 9 Jahania MS, Sanchez JA, Narayan P, Lasley RD, Mentzer RM: Heart preservation for transplantation: Principles and strategies. Ann Thorac Surg 1999;68:1983–1987. 10 Galinanes M, Murashita T, Hearse DJ: Longterm hypothermic storage of the mammalian heart for transplantation: A comparison of three cardioplegic solutions. J Heart Lung Transplant 1992;11:624–635. 11 Donnelly AJ, Djuric M: Cardioplegia solutions. Am J Hosp Pharm 1991;48:2444–2460. 12 Michel P, Vial R, Rodriguez C, Ferrera R: A comparative study of the most widely used solutions for cardiac graft preservation during hypothermia. J Heart Lung Transplant 2002; 21:1030–1039. 13 Tsilimingas NB: Modification of bicaval anastomosis: An alternative technique for orthotopic cardiac transplantation. Ann Thorac Surg 2003;75:1333–1334. 14 Gleissner CA, Klingenberg R, Nottmeyer W, Zipfel S, Sack FU, Schnabe PA, Haass M, Dengler TJ: Diagnostic efficiency of rejection monitoring after heart transplantation with cardiac troponin T is improved in specific patient subgroups. Clin Transplant 2003;17:284– 291.

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15 Harada K, Reller MD, Shiota T, Marcella CP, Sahn DJ: Echocardiographic indexes of rejection in pediatric cardiac transplant recipients managed without maintenance steroid immunosuppression. Am J Cardiol 1997;79:693– 696. 16 Laguens RP, Vigliano CA, Argel MI, Chambo JG, Rozlosnik JA, Perrone SV, Favaloro RR: Anti-skeletal muscle glycolipid antibodies in human heart transplantation as predictors of acute rejection: Comparison with other risk factors. Transplantation 1998;65:1345–1351. 17 Cotts WG, Johnson MR: The challenge of rejection and cardiac allograft vasculopathy. Heart Fail Rev 2001;6:227–240. 18 Goggins WC, Fisher RA, Cohen DS, Tawes JW, Grimes MM: Effect of single-dose rapamycin-based immunosuppression on the development of heart allograft vasculopathy. J Heart Lung Transplant 1996;15:790–795. 19 Radovancevic B, Vrtovec B: Sirolimus therapy in cardiac transplantation. Transplant Proc 2003;35(3 suppl):S171–S176. 20 Beniaminovitz A, Itescu S, Lietz K, Donovan M, Burke EM, Groff BD, Edwards N, Mancini DM: Prevention of rejection in heart transplantation by blockade of the interleukin-2 receptor with a monoclonal antibody. N Engl J Med 2000;34:613–619. 21 Lietz K, John R, Beniaminovitz A, Burke EM, Suciu-Foca N, Mancini DM, Edwards NM, Itescu S: Interleukin-2 receptor blockade in cardiac transplantation: Influence of HLA-DR locus incompatibility on treatment efficacy. Transplantation 2003;75:781–787. 22 Hausen B, Demertzis S, Rohde R, Gohrband B, Wahlers T, Pethig K, Schafers HJ: Treatment of recurrent rejection in heart transplantation: Cytolytic therapy or bolus steroids? Eur J Cardiothorac Surg 1996;10:905–911. 23 Olsen SL, Wagoner LE, Hammond EH, Taylor DO, Yowell RL, Ensley RD, Bristow MR, O’Connell JB, Renlund DG: Vascular rejection in heart transplantation: Clinical correlation, treatment options, and future considerations. J Heart Lung Transplant 1993;12:S135–S142. 24 Alexander RT, Steenbergen C: Cause of death and sudden cardiac death after heart transplantation. An autopsy study. Am J Clin Pathol 2003;119:740–748. 25 Costello JM, Pahl E: Prevention and treatment of severe hemodynamic compromise in pediatric heart transplant patients. Paediatr Drugs 2002;4:705–715. 26 Massad M, McCarthy PM, Navia J, Smedira NG, Ratliff N, Cook DJ, Goormastic M, Young JB, Stewart RW: Does successful bridging with the implantable left ventricular assist device affect cardiac transplantation outcome? J Thorac Cardiovasc Surg 1996;112:1275– 1283.

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27 Waller J, Brook NR, Nicholson ML: Cardiac allograft vasculopathy: Current concepts and treatment. Transpl Int 2003;16:367–375. 28 Young JB: Perspectives on cardiac allograft vasculopathy. Curr Atheroscler Rep 2000;2: 259–271. 29 Wood KJ: Induction of tolerance to cardiac allografts. Curr Opin Cardiol 1996;11:208– 213. 30 Wekerle T: Transplantation tolerance induced by mixed chimerism. J Heart Lung Transplant 2001;20:816–823. 31 Hunt SA: Current status of cardiac transplantation. JAMA 1998;280:1692–1698. 32 Bennett LE, Keck BM, Hertz MI, Trulock EP, Taylor DO: Worldwide thoracic organ transplantation: A report from the UNO/ISHLT international registry for thoracic organ transplantation. Clin Transplant 2001;15:25–40. 33 Massad M, McCarthy PM: Will permanent LVADs be better than heart transplantation. Eur J Cardiothorac Surg 1997;11(suppl):S11– S17. 34 Brann WM, Bennett LE, Keck BM, Hosenpud JD: Morbidity, functional status, and immunosuppressive therapy after heart transplantation: An analysis of the joint International Society for Heart and Lung Transplantation/ United Network for Organ Sharing Thoracic Registry. J Heart Lung Transplant 1998;17: 374–382. 35 Wheeldon D: Thoracic organ preservation. Perfusion 1991;6:191–202. 36 Czerny M, Sahin V, Fasching P, Zuckermann A, Zimpfer D, Kilo J, Wolner E, Grimm M: The impact of diabetes mellitus at the time of heart transplantation on long-term survival. Diabetologia 2002;45:1498–1508. 37 Avery RK: Prevention and treatment of cytomegalovirus infection and disease in heart transplant recipients. Curr Opin Cardiol 1998; 13:122–129. 38 Grady KL: Quality of life after heart transplantation: Are things really better? Curr Opin Cardiol 2003;18:129–135. 39 Grady KL, Jalowiec A, White-Williams C: Patient compliance at one and two years after heart transplantation. J Heart Lung Transplant 1998;17:383–394. 40 Kavanagh T, Yacoub MH, Kennedy J, Austin PC: Return to work after heart transplantation: 12-year follow-up. J Heart Lung Transplant 1999;18:846–851. 41 Evans RW: Socioeconomic aspects of heart transplantation. Curr Opin Cardiol 1995;10: 169–179.

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Cardiology 2004;101:93–103 DOI: 10.1159/000075989

Ventricular Assist Devices as a Bridge to Transplant or Recovery Aftab R. Kherani a, b Simon Maybaum d Mehmet C. Oz b, c, e a Department

of Surgery, Duke University Medical Center, Durham, N.C.; b Division of Cardiothoracic Surgery, of Surgery, d Division of Circulatory Physiology, Columbia University College of Physicians and Surgeons, New York, N.Y.; e The Cardiovascular Institute, New York Presbyterian Hospital, Columbia Presbyterian Medical Center, New York, N.Y., USA

c Department

Key Words Ventricular assist device W Bridge to transplantation W Bridge to recovery

Abstract Ventricular assist devices have emerged as the standard of care in treating end-stage heart failure. Their success in bridging patients to transplantation is well documented. The data supporting their ability to bridge patients to recovery is sparser. However, as technology continues to advance, these devices will offer a high quality of life both in and out of the hospital setting, making them options for a broader spectrum of heart failure patients. Copyright © 2004 S. Karger AG, Basel

Introduction

Heart failure (HF) affects 4.7 million patients in the United States and is responsible for approximately 1 million hospitalizations and 300,000 deaths annually [1]. The total annual costs associated with this disorder have been estimated to exceed USD 22 billion [2]. Whereas the prevalence of most cardiovascular disorders has been declining over the last 15 years, the impact of HF has increased more than 4-fold during the same period. HF is

ABC

© 2004 S. Karger AG, Basel 0008–6312/04/1013–0093$21.00/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/crd

a progressive, relentless disease. However, over the last decade, developments in the medical therapy of HF have led to improvements in quality of life and survival. When the disease enters its terminal phase, the condition of some patients may be rescued with the use of heart transplantation, but unfortunately this procedure can only be offered to a small fraction of the patients who need it, due to a shortage of donor hearts. Approximately 2,000 heart transplants are performed in the United States each year, while it is estimated that 15,000 patients would benefit and one third of the patients die while waiting for a suitable donor [3, 4]. The left ventricular assist device (LVAD) is a novel therapy that was devised to support the failing heart in critically ill patients with end-stage HF. It is a mechanical pump that is surgically implanted to take over the work of the left side of the heart. LVADs are now frequently used in transplant candidates with advanced HF who are considered to be too unstable to await a suitable donor. Patients bridged with an LVAD demonstrate impressive survival to transplantation and posttransplant survival [5]. Furthermore, LVADs allow the opportunity for rehabilitation in both the in- and outpatient setting, so those patients may undergo cardiac transplantation in a more stable condition. In transplant candidates with refractory HF, LVADs have improved quality of life and allowed time for appropriate donor selection. Three devices are currently approved by the Food and Drug Administration

Aftab R. Kherani, MD Division of Cardiothoracic Surgery, MHB 7GN-435 177 Ft. Washington Avenue New York, NY 10032 (USA) Tel. +1 212 305 5108, Fax +1 212 305 2439, E-Mail [email protected]

(FDA) for use as a bridge to cardiac transplantation in those patients listed for transplant who become refractory to medical therapy. Since their introduction to the medical community, LVADs have benefited from numerous technological advances and have evolved to the standard of care in the treatment of these patients. Recently, the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) study demonstrated the benefits of an LVAD as longterm or ‘destination’ therapy in patients with end-stage HF who are not eligible for cardiac transplantation [6]. One device [HeartMate vented electric (VE), Thoratec Corporation, Pleasanton, Calif., USA] is already approved for use for this indication, and a number of other devices are currently being evaluated in clinical trials for destination therapy.

Ventricular Assist Devices in Clinical Use

Extracorporeal Pulsatile Devices This category includes both the Thoratec ventricular assist device (VAD) system (Thoratec Corporation) [7] and the ABIOMED BVS-5000 (ABIOMED, Danvers, Mass., USA). These devices are large and cumbersome, rendering them a suitable support system solely for inpatients and hindering the rehabilitation process. However, they do possess certain advantages, including the ability to provide biventricular support, and they may be used for children and adults with small body size. These systems are also less expensive than the other devices, adding to their cost-efficiency. Extracorporeal devices are generally indicated for left or right ventricular support during acute hemodynamic decompensation, such as postcardiotomy shock, acute myocardial infarction, acute myocarditis, acute right HF (after LVAD implantation) and rarely graft failure posttransplantation. These devices may also be used by referring centers to transport their patients to a tertiary care center for cardiac transplantation or for conversion to a longer-term implantable device [8]. Implantable Pulsatile Devices Implantable VADs differ from extracorporeal devices in that they facilitate patient rehabilitation and allow outpatient support [9]. First utilized in 1986, these devices have allowed for more than 90% of patients to be discharged from the hospital with a 74% rate of survival to transplantation [10]. During implantation, the inflow cannula is placed in the left ventricular apex, the outflow

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graft is anastomosed to the ascending aorta and the pumping chamber is placed in the abdomen either pre- or intraperitoneally [11]. The three most commonly used devices in this category are the HeartMate Implantable Pneumatic (IP) and HeartMate VE (Thoratec Corporation) and the Novacor (World Heart Corporation, Ottawa, Canada); these devices are approved by the FDA for use as bridge to cardiac transplantation. Thoratec HeartMate IP The HeartMate IP received FDA approval in 1994, making it the first VAD to gain acceptance as a bridge to transplantation. The unique feature of the HeartMate devices is the textured blood-contacting pump surface. This textured surface promotes the deposition of blood products and the development of a biologically active lining that resembles vascular endothelium. The activated ‘endothelium’ results in a degree of chronic autoanticoagulation, obviating the need for anticoagulation [12]. Patients supported with HeartMate devices who are not treated with anticoagulants have a favorably low thromboembolic complication rate as compared to the use of other devices in this class (0.011 events per patient month [13]). The HeartMate IP has a portable pneumatic console on a cart so that the patient may ambulate, and is therefore less restrictive than the extracorporeal devices. Thoratec HeartMate VE The HeartMate VE (fig. 1) was designed to offer further mobility by allowing patients up to 4 h of portable battery power without the need for connection to the console. The HeartMate VE replaced the pneumatic device with an electrical one, thereby eliminating the need for a bulky console. Its uniqueness comes from the internal motor, which provides 12 V of direct-current power controlled by a microprocessor. There are two external components to this device, but they are easily portable. The VE model requires a small system controller, which is worn on a belt, and a battery pack, worn on a shoulder holster [14]. The HeartMate systems represent the most widely used devices on the market, with 1,306 implants of the IP worldwide and 2,098 implants of the VE, providing mean support of 100 and 154 days, respectively, as of December 2002 [15]. Novacor Left Ventricular Assist System The Novacor left ventricular assist system (LVAS) (fig. 2) is similar to the HeartMate VE. It is small, portable and electrically driven. However, the Novacor requires systemic anticoagulation. Stanford Medical Center has

Kherani/Maybaum/Oz

Fig. 1. The HeartMate VE LVAD. Courtesy of Thoratec Corporation (Pleasanton, Calif., USA).

reported on its extensive experience with this device [16]. As of 2000, they had 53 patients with a mean duration of support of 56 B 76 days, with two thirds successfully bridged to transplantation. The major complications were bleeding (43%), infection (30%) and embolic cerebrovascular events (24.5%). Thus far, the worldwide experience with this device has shown promising results [17]. In a recent series of 768 patients, the mean duration of support was 85 days; 3% of patients were weaned from support (bridge to recovery), 58% were transplanted and 89% were discharged home at some point in time. The Novacor LVAS and the Thoratec HeartMate VE are the two most commonly used LVADs for bridge to transplantation. El-Banayosy et al. [18] prospectively compared the outcomes with these two devices. There were no significant differences with respect to postoperative hemodynamics, organ recovery, outpatient support and survival to transplantation. However, the HeartMate was associated with a higher infection rate, but a lower incidence of neurologic complications.

Fig. 2. The Novacor LVAS. Courtesy of World Heart Corporation (Ottawa, Canada).

CardioWest Total Artificial Heart The design of the CardioWest total artificial heart (CardioWest Technologies, Inc., Tucson, Ariz., USA) was based upon the Jarvik-7 device developed in the 1980s. There have been 150 device implantations since this tech-

nology was revived in 1993. The limitation of this device is similar to that of the extracorporeal devices, in that the console is not portable and patients are restricted to a hospital setting with diminished potential for rehabilitation. For these reasons, the CardioWest was developed as a bridge to transplantation, unlike the AbioCor (ABIOMED), which is intended for destination therapy [19]. The total artificial heart has the obvious advantage of complete right- and left-sided heart support. The University of Arizona has reported the most extensive experience with this device [20]. Between 1985 and 1999, 176 CardioWest devices were implanted with an overall survival of 83%. Although 4 patients died during device support (17%), there was no operative mortality associated with implantation, and all 19 patients who were transplanted survived. The linearized stroke rate was 0.6 events per patient year. The US multicenter trial of the CardioWest total artificial heart enrolled patients on high-dose inotropic support who had failed conventional therapies and had similarly positive results [21].

Ventricular Assist Devices

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Comparison of LVAD with Optimal Medical Management for Bridge to Transplantation The HeartMate VE was compared to optimal medical management in a prospective multicenter study using historical controls. A prospective trial was designed to investigate this necessary comparison [22]. Twenty-four centers throughout the United States enrolled 280 transplant candidates who had been unresponsive to inotropic support with or without intra-aortic balloon counterpulsation. The median age of these patients was 55 years; each had pulmonary capillary wedge pressures of at least 20 mm Hg and either a systolic blood pressure below 80 mm Hg or a cardiac index of less than 2.0 liters/min/m2. Patients were compared to a historical control group of 48 patients (median age 50 years) who had not received device support. The two groups were similar with respect to age, gender, underlying cardiac pathology and baseline renal and hepatic function. However, patients in the LVAD group had more advanced HF, with significantly lower baseline systolic blood pressure (75.5 B 9.7 vs. 86.1 B 15.4 mm Hg, p ! 0.0001) and lower cardiac index (1.67 B 0.41 vs. 2.03 B 0.72 liters/min/m2, p ! 0.0001). LVAD support was maintained for a mean duration of 112 days. Device support led to significant improvement in renal and hepatic function as compared to baseline. Devicerelated complications of infection (40%), bleeding (11%) and thromboembolism (6%) were not infrequent. However, the study demonstrated a survival advantage for LVAD as compared to optimal medical management in this patient population. Only 29% of the VAD patients expired prior to transplantation, compared to 67% of the optimal medical management patients (p ! 0.0001). Timing of LVAD Implantation In a recent report from Muenster University in Germany, patients were stratified according to the urgency of their need for LVAD implantation and outcomes were compared [23]. Thirty-nine patients undergoing VAD implantation as a bridge to transplantation were classified into three subgroups: elective VAD, i.e. those patients who received their VADs in an attempt to minimize expected end organ damage from worsening HF; urgent VAD, i.e. those patients who had rapidly progressive HF and who received VAD implantation within 48 h of being listed for transplant and who required an intervention such as ventilation or dialysis; and emergency VAD, i.e. those patients who were emergently implanted for cardiogenic shock following cardiac surgery, myocarditis or myocardial infarction. Overall, survival to transplantation was 77%. Survival in the urgent group was 56%, as

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compared to 33% in the emergent group. Patients in the elective group had a superior survival rate to those patients who were felt to be too well to require device support prior to transplantation. The overall results endorse the use of early, elective VAD implantation when possible. The Hub and Spoke Network In the postcardiotomy setting, when patients are receiving emergent mechanical circulatory support, VADs have a proven role in effective treatment. However, in the early phase of VAD development, this was not so. At that time, a voluntary registry of 965 patients requiring VAD support reported a hospital discharge rate of 25% [24]. The mandatory New York State cardiac surgery database also reported similarly low survival rates with LVAD implantation for postcardiotomy shock [25]. In an effort to improve outcomes, a bridge-to-transplant ‘hub and spoke’ network was established. This network was intended to provide community hospitals with a way of rapidly transferring patients to a hub institution adept at managing such a patient population. These hubs were intended to be hospitals that had established LVAD and transplantation programs. Our hub and spoke network was recently evaluated, with a favorable outcome [8]. There were 44 total referrals, of which 29 (66%) survived to discharge. Just over half of these patients (n = 23) received an implantable device, and 74% of them survived to hospital discharge. Similarly favorable results were reported by the University of Michigan using LVAD support as a bridge to transplant. Patients who required extracorporeal membrane oxygenation for extreme hemodynamic instability and multiorgan injury [26] were successfully converted from extracorporeal membrane oxygenation to LVAD implantation. The 1-year survival rate in the extracorporeal membrane oxygenation patients was similar to a less sick population of patients who required LVAD support alone. LVAD Implantation in Younger and Older Patients We recently evaluated our LVAD experience with 12 patients under 21 years of age [27]. The mean age of the patients was 16 years (range 11–20 years), and the mean body surface area was 1.8 m2 (range 1.4–2.2 m2). Each of the patients received a Thoratec HeartMate as a bridge to transplant. More than half (58%) were discharged home supported with an LVAD, with an average duration of LVAD support of 123 days. Two patients underwent device explantation for recovery (15%), 8 (62%) underwent transplantation and 3 (23%) died. For smaller pa-

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tients, prosthetic graft material (polytetrafluoroethylene) was sutured to the edges of the divided linea alba to facilitate abdominal wall closure [28]. There have been varying reports about outcomes of LVAD implantation in older patients. Smedira et al. [29] reviewed the Cleveland Clinic experience to examine whether advanced age was a significant risk factor for poor outcome following LVAD implantation. Most of the patients were over the age of 60, the oldest being 69 years of age. In this analysis, age was not a significant risk factor for poor outcome following implantation of the Thoratec HeartMate device. When comparing the survival to transplantation rate and the rate of discharge from hospital, no significant difference was found between this population and that of the younger patients [29]. Similarly, Wareing and Kouchoukos [30] reported comparable survival of younger and older patients who required mechanical support for postcardiotomy shock. However, in contrast, multivariate analysis of the Novacor European Registry concluded that age was an independent risk factor (odds ratio 3.01) for poor outcome after device implantation. Of note, in this analysis, older age was defined as greater than 65 years, as compared to the Cleveland Clinic report, which defined older age as greater than 60 years. Other risk factors identified by the Novacor European Registry included respiratory failure in the setting of sepsis (odds ratio 11.2), right-sided HF (odds ratio 3.2), acute postcardiotomy (odds ratio 1.8) and acute myocardial infarction (odds ratio 1.7) [31].

patient and family in care and management of the device, including how to deal with the possibility of device malfunction; (3) patient and family are able to manage the device driveline exit site; (4) the patient has successfully completed an adequate number of day trips away from the hospital; (5) echocardiographic evidence exists that the native heart could temporarily provide adequate flow to sustain life in the event of major device malfunction. A more recent review reported on 471 patients who were discharged home on a device, representing 61,237 days of support [33]. The mortality rate was determined to be 0.012 per outpatient year, with only 2 patients dying while at home. The standard daily outpatient maintenance cost was found to be USD 27.

Use of Assist Devices as a ‘Bridge to Recovery’

LVADs in the Outpatient Setting With the development of convenient wearable devices, patients may be discharged home while on LVAD support. We reviewed our outpatient experience with the Thoratec HeartMate VE [32]. Between the years 1993 and 1997, 19 of 32 patients implanted with the HeartMate were discharged home on device support to await transplantation. The mean duration of support was 122 B 26 days (the longest amount of time on the VAD was 466 days, and 2 patients were implanted for 320 days). The mean duration of time spent in the hospital prior to discharge was 41 B 4 days, and the mean duration of outpatient VAD support was 108 B 30 days. The rate of survival to transplantation approached 80%. While at home, the patients’ lives were often filled with activities, including playing tennis, dancing, bicycling and gardening. Many of these patients returned to work and/or school, and the majority resumed normal sexual activity. We propose that discharge home is a viable option when the following conditions are met: (1) clinical stability; (2) training of

Potential for Recovery of the Failing Myocardium The structural and functional changes in the heart that occur in response to cardiac injury have been termed ‘remodeling’. An increase in chamber radius or intracavitary pressure induces compensatory mechanisms in an attempt to normalize wall stress. When compensation is insufficient, reduction in the arterial perfusion pressure prompts systemic activation of vasoconstrictor neurohormonal systems and the adaptive remodeling process turns maladaptive, leading to the changes in myocardial structure, cellular function and gene expression of chronic HF. LVADs offer a unique opportunity to study these mechanisms of HF, utilizing a simple experimental approach consisting of the analysis of paired myocardial samples harvested at the time of implantation and explantation. While the changes of end-stage HF were initially thought to be irreversible, a number of investigators have demonstrated biological and structural evidence for recovery during LVAD support. Chronic mechanical unloading has been shown to reverse the abnormal gene expression that is present in failing myocardium, including normalization of genes that regulate calcium handling [34], tumor necrosis factor [35] and cytoskeleton proteins [36]. In addition, there is now clear evidence for the regression of fibrosis and cellular hypertrophy [37, 38], improved in vitro contractile function [34, 39], improved adrenergic responses [39, 40] and favorable changes in cardiac electrophysiology [41] and cardiac signaling pathways [42]. These changes favor a trend to normal cardiac physiology that has been termed ‘reverse remodeling’ [43].

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Clinical Significance of Cardiac Recovery – The Controversy The utility of mechanical support to bridge patients to recovery for acute HF syndromes is well established. LVADs have been used for this purpose with success in the acute postcardiotomy setting [44] (although some concern exists regarding bypass graft patency during LVAD support [45]), as well as in patients with acute myocarditis and peripartum cardiomyopathy [46–50]. However, despite the experimental evidence for reverse remodeling during LVAD support, the clinical significance for patients with chronic HF remains uncertain. Most investigators agree that patients with chronic ischemic cardiomyopathy, with evidence of extensive scarring, are unlikely to recover. However, in patients with nonischemic cardiomyopathy, experience has been varied, with contrasting reports regarding the frequency with which patients may undergo LVAD explantation for recovery and the degree to which recovery is sustained after LVAD explantation. We have reported a low incidence of sustained recovery during LVAD support in patients with chronic HF [51]. A retrospective chart review revealed that out of 111 patients who had undergone LVAD implantation, only 5 demonstrated sufficient recovery to permit LVAD explantation without transplantation. Of these 5, 2 patients required a second LVAD for recurrent HF, 1 died from rapidly progressive HF 3 months after explantation and 1 patient remained stable for 27 months and then died suddenly. Only 1 patient was stable without recurrent HF 15 months after device explantation. We have also described in a further report the natural history of reverse remodeling and recurrent remodeling in two patients with chronic HF who underwent device explantation for recovery and subsequently required a second LVAD [52]. The low rate of cardiac recovery in patients with chronic HF has not changed at our center since publication of these reports. In contrast, Berlin Heart has reported that over one third of patients with chronic dilated cardiomyopathy supported with an LVAD may undergo device explantation for recovery and that the majority of these patients do not develop recurrent HF [53]. Over a 5-year period, 65 patients with chronic nonischemic cardiomyopathy (mean duration of chronic HF 6 years) were supported with an apical drainage LVAD. Twenty-three out of the 65 patients underwent device explantation for recovery. Thirteen of these 23 patients remained stable without recurrent chronic HF for a mean follow-up of 23 months (11 patients were followed for at least 1 year). Seven patients developed recurrent chronic HF after LVAD explantation, 6 of whom required cardiac transplantation.

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Three patients died of noncardiac causes after device explantation. The LVAD Working Group Recovery Study was established in response to these contrasting reports of recovery during LVAD support [45]. In this prospective multicenter study, cardiac function is uniformly assessed at monthly intervals during LVAD support. Preliminary results were available at the time of preparation of this paper. Forty-one LVAD patients had been followed for a mean of 101 days. While serial echocardiographic assessment during LVAD support demonstrated significant improvement in left ventricular ejection fraction and reduction in left ventricular diameters and cardiac mass as compared to before LVAD, none of the patients with chronic HF demonstrated sufficient improvement to undergo device explantation. However, 2 patients with acute ischemic syndromes did undergo LVAD explantation for recovery. Continued enrollment and follow-up in this important study will better define the frequency, time course and durability of cardiac recovery and identify markers that may be used to select appropriate candidates for explantation. Time Course of Cardiac Recovery Only limited data are available regarding the time course of changes in cardiac function during LVAD support. One study utilizing paired myocardial tissue analysis has suggested that the optimal duration of device support for reverse remodeling is approximately 40 days [54]. Hetzer et al. [55] observed that optimal improvement in left ventricular size and function occurred within approximately 90 days of LVAD implantation, but noted a gradual deterioration with longer periods of support. A trend to reduction in heart mass over time in LVAD-supported patients [56] has been demonstrated in serial echocardiographic studies, and investigators have also shown a decrease in mean myocyte area after LVAD implantation [57, 58]. These data have raised concerns over the possibility of disuse atrophy during longer periods of device support [59, 60]. Conversely, changes in the United Network of Organ Sharing listing guidelines have favored earlier transplantation for patients supported with an LVAD, and the resultant shorter duration of support may be insufficient for optimal cardiac recovery. For these reasons, a deeper understanding of the time course of changes in cardiac function during LVAD support is important. Prospective studies like that of the LVAD Working Group will be able to better define these changes.

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Methods to Assess Recovery Echocardiography is the most useful imaging modality for assessing cardiac function in patients with VADs. It is portable and safe for use in patients with large metallic implants and provides important information about cardiac morphology, flow, valvular function and device function in these patients [61]. Performed acutely after institution of LVAD support, echocardiographic studies have shown a reduction in left ventricular volumes, with leftward displacement of the interventricular septum, as well as a decrease in atrial size [62, 63] and in mitral regurgitant volume [64]. Diastolic filling also improves, with prolongation of the deceleration time and a decrease in the early to atrial contraction filling ratio [65]. Serial echocardiographic studies performed after LVAD implantation have demonstrated progressive reduction in left ventricular cavity diameter and a significant reduction in left ventricular mass [38]. Echocardiography is also useful in evaluating right ventricular function in LVAD patients [66]. The frequency and extent of aortic valve opening, as determined by M-mode and 2-dimensional echocardiography, can be used to evaluate cardiac ejection during reduction of LVAD flow and are markers of cardiac function [51]. While resting studies of cardiac function during device support may screen patients for recovery, reliable tests of cardiac reserve are needed to identify patients who might tolerate device explantation. Some centers utilize ‘pumpoff’ studies, where the LVAD is turned off during echocardiographic or hemodynamic measurements. These studies are limited by the very short period that the pump can be left with no flow, because of the risk of thromboembolic events. There are currently no uniform guidelines regarding the level of anticoagulation and the frequency of intermittent manual pumping required, or the maximum duration that the pump can be at no flow. The role of dobutamine stress echocardiography has been well established in patients with coronary artery disease. This test can be used to determine contractile reserve by measuring the improvement in the segmental wall motion index score during administration of low doses of dobutamine. Investigators have recently recommended the use of dobutamine stress echocardiography to measure cardiac reserve during LVAD support, and there are preliminary data to suggest that this technique may identify patients with sufficient recovery to tolerate device explantation [67]. Patients are considered ‘favorable responders’ and suitable for device explantation if they show a consistent rise in cardiac output and left ventricular ejection fraction without an increase in pulmonary capillary wedge pressure above 15 mm Hg. We have de-

scribed the use of exercise testing with simultaneous hemodynamic and echocardiographic measurements to measure cardiac reserve during LVAD support [51]. Patients undergo cardiopulmonary exercise testing with the device giving full support, and then exercise is repeated in those patients who tolerate weaning of flow to 2 liters/ min. Hemodynamic measurements are taken with a Swan-Ganz catheter simultaneously with echocardiographic measurements performed at rest and during each stage of exercise. Patients were considered for device explantation if they were able to exercise at low LVAD flows and achieve a maximal oxygen consumption of 20 ml/kg/min or cardiac output greater than 10 liters/min.

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Future Perspectives on Cardiac Recovery Current experience would suggest that in patients with long-standing cardiomyopathy, only a few would demonstrate substantial and sustained cardiac recovery from mechanical unloading alone. Future research will be directed at adjuvant therapies that could be applied while the left ventricle is unloaded in order to enhance recovery. Therapies under active investigation include novel pharmacological agents, stem cell therapy and cell transplantation. One such pharmacological therapy under investigation is clenbuterol, a selective ß-2 agonist used for the treatment of asthma in Europe, but not currently approved for use in the United States. Clenbuterol has a potent anabolic effect on skeletal muscle and has been used extensively by athletes to enhance muscle strength [68–71]. Furthermore, there are animal data suggesting that clenbuterol may have positive effects on cardiac myocytes, causing physiological myocyte hypertrophy which results in ventricular hypertrophy, without deleteriously affecting cardiac filling properties [72]. An intriguing preliminary report from investigators at Harefield Hospital (UK) describes the use of clenbuterol in patients with end-stage chronic HF supported with an LVAD [73, 74]. In this series, 19 patients were supported with an LVAD for a mean of 276 days. Eleven out of 15 surviving patients (there were 4 perioperative deaths) showed significant improvement of cardiac function during device support, and 9 of these 15 patients underwent LVAD explantation for recovery. During 144–496 days of postexplantation follow-up, there were no episodes of recurrent HF. This series represents a rate of myocardial recovery that is more than double that of any previously reported study. Further investigation will define the role of this and other therapies in the management of patients supported with an LVAD.

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Fig. 3. The MicroMed Debakey VAD. Courtesy of MicroMed Technology, Inc. (Houston, Tex., USA).

The clinical trials have yielded a 30-day survival rate following implantation of 81%. Also, adequate circulatory support, maintenance of end organ function and a low incidence of perioperative bleeding (6.3%) have been observed [75]. In a small study investigating the incidence of intracranial thromboembolic events, five patients with the DeBakey VAD were followed for 10 weeks. Only one demonstrated evidence of microembolic signals; this patient also had microembolic signals preoperatively [76]. None of the first nine VAD recipients had a device-related thromboembolic event, although one did die of a left ventricular thrombus that resulted in pump failure [77]. Other studies have focused on the immunologic and inflammatory consequences of continuous flow. The level of interleukin-6 is markedly higher in these patients compared to that in patients with a pulsatile device [78]. A separate investigation also found a transitory immunologic response following implantation, but normalization to baseline occurred within 7 weeks and there was no evidence of blood-borne infection seen in any of the six patients who were followed for 10 weeks [79]. Thus, although much investigation into the long-term ramifications of continuous flow in particular is still necessary, early clinical experience supports the DeBakey pump as a safe and effective means of providing circulatory support.

Jarvik 2000 Heart DeBakey VAD

The DeBakey VAD (MicroMed Technology, Inc., Houston, Tex., USA) (fig. 3) was the product of collaboration between the Baylor College of Medicine and NASA that began in 1988. Clinical trials began in Europe in November 1998, with the US trial following in June 2000. To qualify for the trial, patients must be eligible for transplantation. The device is composed of four subsystems: an axial flow pump system, a controller system, a clinical data acquisition system and a patient home support system. Systemic anticoagulation is required. The pump is titanium and electromagnetically actuated. It weighs only 95 g, and measures 1.2 inches in diameter and 3.0 inches in length. Maximum output is 10 liters/min. The impeller/inducer, housed in the pump unit, is the only moving part. Continuous axial flow is provided, but pulsatile flow is possible if there is a large pressure gradient between the left ventricle and aorta, which exists with native contractility.

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The Jarvik 2000 (Jarvik Heart, Inc., New York, N.Y., USA) [80] is the product of collaboration between the Texas Heart Institute and Jarvik Heart, Inc. that began in 1989. Clinical trials began in 2000. The device weighs a scant 90 g, displaces 25 cm3 and measures 2.5 cm in diameter. Unlike the DeBakey VAD, whose outflow graft is anastomosed to the ascending aorta, the outflow graft of the Jarvik 2000 is connected to the descending aorta, allowing implantation via left thoracotomy (median sternotomy is used for the DeBakey VAD). The impeller is electromagnetically actuated and can rotate from 8,000 to 12,000 rpm, producing a maximum output of 7 liters/ min. The first version of the device is the percutaneous model, which has a power cable brought out through the abdominal wall. The cable is attached to an external controller. External batteries are connected to the controller and power the device. Another model has a power cable that is externalized at the back of the head and has a connector that is attached to the skull base. The power cable

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is connected to a titanium pedestal that is screwed onto the skull. The goal of this design is to minimize infection, as scalp tissue is highly vascularized. Success in this area has been demonstrated by cochlear implants, which employ similar technology. All variants of the Jarvik 2000 are based upon the same pump unit. In three of the first four patients, the device served as a bridge to transplantation. One had a localized infection of the power cable exit site (abdominal) that responded to antibiotic and local treatment, and another had a bleeding duodenal ulcer that responded to discontinuation of anticoagulation. The device (skull mounted) served as a destination therapy for the fourth patient in the United Kingdom. None of the four patients experienced a devicerelated complication. Early experience with the Jarvik 2000 has demonstrated safe circulatory support in and out of the hospital.

In Development

The HeartMate II is another axial flow rotary VAD which includes a pump unit, percutaneous lead, external power source and system driver. Its outflow graft is anastomosed to the ascending aorta. The pump measures 124 cm3, may be placed within the abdominal musculature or preperitoneally, and has only one moving part. Manual and automatic modes are possible [81]. A version of the HeartMate II with no percutaneous connections is also being developed. It utilizes a transcutaneous electrical transmission system (TETS) and can provide up to 1 h of untethered support [82]. At this time, the clinical trial is on hold to work out technical details. Also under development is the HeartMate III (Thoratec Corporation) [83]. It is distinguished from the HeartMate II by its magnetically raised impeller. The absence of mechanical bearings confers potential advantages with regard to durability. The remainder of the device is similar to the HeartMate II, and the same two configurations will be available (i.e. percutaneous and transcutaneous).

The Kriton VAD (Kriton Medical Inc., Miramar, Fla., USA) is a small, centrifugal, pulsatile pump currently undergoing long-term animal testing. The pump’s displaced volume is 48 cm3, and it is capable of an output of 15 liters/min. Since the pump’s bearings are magnetically suspended, the pump should last for years with minimal wear [84]. Another unique pump, the Terumo DuraHeartTM LVAS (Terumo Cardiovascular Systems, Ann Arbor, Mich., USA), incorporates a unique centrifugal pump with a magnetically raised impeller. The pump provides contact-free rotation of the impeller to offer maximum durability. More than 50 animal experiments have been conducted and development of this pump is still in the early stages.

Conclusion

LVADs are now well established as bridge to transplantation, and these devices are the standard of care for transplant candidates who cannot be supported with conventional medical management alone. Extracorporeal devices provide an excellent short-term bridge, particularly useful in community hospitals that may not have an active VAD program. Implantable pulsatile devices offer longer-term support, which is viable in the outpatient setting. On the strength of the REMATCH study [6], one device has already been approved for use in the United States as destination therapy for patients ineligible for transplantation. Other devices are currently being investigated for this indication in clinical trials. The promise in the future of smaller, more durable pumps with no percutaneous connections will further expand the indications for these devices for a broad spectrum of HF patients.

Acknowledgment This work was supported in part by the Foundation for the Advancement of Cardiac Therapies (FACT).

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5 El-Banayosy A, Korfer R, Arusoglu L, Minami K, Kizner L, Fey O, Schutt U, Morshuis M: Bridging to cardiac transplantation with the Thoratec Ventricular Assist Device. Thorac Cardiovasc Surg 1999 Feb;47 Suppl 2:307– 310. 6 Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, Long JW, Ascheim DD, Tierney AR, Levitan RG, Wat-

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34 Heerdt PM, Holmes JW, Cai B, Barbone A, Madigan JD, Reiken S, Lee Dl, Oz MC, Marks AR, Burkhoff D: Chronic unloading by left ventricular assist device reverses contractile dysfunction and alters gene expression in endstage heart failure. Circulation 2000;102:2713– 2719. 35 Torre-Amione G, Stetson SJ, Youker KA, Durand JB, Radovancevic B, Delgado RM, Frazier OH, Entman ML, Noon GP: Decreased expression of tumor necrosis factor-alpha in failing human myocardium after mechanical circulatory support: A potential mechanism for cardiac recovery. Circulation 1999;100:1189– 1193. 36 Wolff MR, Buck SH, Stoker SW, Greaser ML, Mentzer RM: Myofibrillar calcium sensitivity of isometric tension is increased in human dilated cardiomyopathies: Role of altered betaadrenergically mediated protein phosphorylation. J Clin Invest 1996;98:167–176. 37 Bruckner BA, Stetson SJ, Perez-Verdia A, Youker KA, Radovancevic B, Koerner MM, Entman ML, Frazier OH, Noon GP, TorreAmione G: Regression of fibrosis and hypertrophy in failing myocardium following mechanical circulatory support. J Heart Lung Transplant 2001;20:457–464. 38 Zafeiridis A, Jeevanandam V, Houser SR, Margulies KB: Regression of cellular hypertrophy after left ventricular assist device support. Circulation 1998;98:656–662. 39 Dipla K, Mattiello JA, Jeevanandam V, Houser SR, Margulies KB: Myocyte recovery after mechanical circulatory support in humans with end-stage heart failure. Circulation 1998;97:2316–2322. 40 Ogletree-Hughes ML, Stull LB, Sweet WE, Smedira NG, McCarthy PM, Moravec CS: Mechanical unloading restores beta-adrenergic responsiveness and reverses receptor down-regulation in the failing human heart. Circulation 2001;104:881–886. 41 Harding JD, Piacentino V III, Gaughan JP, Houser SR, Margulies KB: Electrophysiological alterations after mechanical circulatory support in patients with advanced cardiac failure. Circulation 2001;104:1241–1247. 42 Flesch M, Margulies KB, Mochmann HC, Engel D, Sivasubramanian N, Mann DL: Differential regulation of mitogen-activated protein kinases in the failing human heart in response to mechanical unloading. Circulation 2001; 104:2273–2276. 43 Levin H, Oz M, Chen J, Packer M, Rose E, Burkhoff D: Reversal of chronic ventricular dilation in patients with end-stage cardiomyopathy by prolonged mechanical unloading. Circulation 1995;91:2717–2720. 44 Hoy FBY, Mueller DK, Geiss DM, Munns JR, Bond LM, Linett CE, Gomez RC: Bridge to recovery for postcardiotomy failure: Is there still a role for centrifugal pumps? Ann Thorac Surg 2000;70:1259–1263.

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45 Maybaum S, Frazier OH, Starling RC, Miller L, Murali S, Aaronson KD, Margulies K, McRee S, Torre G, on behalf of the LVAD Working Group: Cardiac recovery during 30 days of support with a left ventricular assist device. J Am Coll Cardiol 2003;41:165A. 46 Maybaum S, Stockwell P, Naka Y, Catanese K, Flannery M, Fisher P, Oz M, Mancini D: Assessment of myocardial recovery in a patient with acute myocarditis supported with a left ventricular assist device: A case report. J Heart Lung Transplant 2003;22:202–209. 47 Rockman HA, Adamson RM, Dembitsky WP, Bonar JW, Jaski BE: Acute fulminant myocarditis: Long-term follow-up after circulatory support with a left ventricular assist device. Am Heart J 1991;121:922–926. 48 Jett GK, Miller A, Savino D, Gonwa T: Reversal of acute fulminant lymphocytic myocarditis with combined technology of OKT3 monoclonal antibody and mechanical circulatory support. J Heart Lung Transplant 1992;11: 733–738. 49 Holman WL, Bourge RC, Kirklin JK: Case report: Circulatory support for seventy days with resolution of acute heart failure. J Thorac Cardiovasc Surg 1991;102:932–934. 50 Reiss N, El-Banayosy A, Posival H, Morshuis M, Minami K, Korfer R: Management of acute fulminant myocarditis using circulatory support systems. Artif Organs 1996;20:964–970. 51 Mancini DM, Beniaminovitz A, Levin H, Catanese K, Flannery M, DiTullio M, Savin S, Cordisco ME, Rose E, Oz M: Low incidence of myocardial recovery after left ventricular assist device implantation in patients with chronic heart failure. Circulation 1998;98:2383–2389. 52 Helman D, Maybaum S, Morales D, Williams M, Beniaminovitz A, Edwards N, Mancini D, Oz M: Recurrent remodeling after ventricular assistance: Is long-term myocardial recovery attainable? Ann Thorac Surg 2000;70:1255– 1258. 53 Hetzer R, Muller JH, Weng YG, Loebe M, Wallukat G: Midterm follow-up of patients who underwent removal of a left ventricular assist device after cardiac recovery from endstage dilated cardiomyopathy. J Thorac Cardiovasc Surg 2000;120:843–853. 54 Madigan JD, Barbone A, Choudhri AF, Morales DL, Cai B, Oz MC, Burkhoff D: Time course of reverse remodeling of the left ventricle during support with a left ventricular assist device. J Thorac Cardiovasc Surg 2001;121: 902–908. 55 Hetzer R, Mueller J, Weng Y, Wallukat G, Spiegelsberger S, Loebe M: Cardiac recovery in dilated cardiomyopathy by unloading with a left ventricular assist device. Ann Thorac Surg 1999;68:742–749. 56 Zwas D, DiTullio M, Flannery M, et al: Time course of left ventricular mass regression following left ventricular assist device implantation (abstract). J Am Coll Cardiol 1999;33: 208A. 57 Kinoshita M, Takano H, Taenaka Y, et al: Cardiac disuse atrophy during LVAD pumping. ASAIO Trans 1988;34:208–212.

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58 Kinoshita M, Takano H, Takaichi S, Taenaka Y, Nakatani T: Influence of prolonged ventricular assistance on myocardial histopathology in intact heart. Ann Thorac Surg 1996;61:640– 645. 59 Schenin S, Capek P, Radovancevic B, Duncan J, McAllister J, Frazier O: The effect of prolonged left ventricular assist device support on myocardial histopathology in patients with end-stage cardiomyopathy. ASAIO J 1992;38: M271–M274. 60 Soloff L: Atrophy of myocardium and its myocytes by left ventricular assist device (letter). Circulation 1999;100:1012. 61 Scalia GM, McCarthy PM, Savage RM, Smedira NG, Thomas JD: Clinical utility of echocardiography in the management of implantable ventricular assist devices. J Am Soc Echocardiogr 2000;13:754–763. 62 McCarthy PM, Nakatani S, Vargo R, KottkeMarchant K, Harasaki H, James KB, Savage RM, Thomas JD: Structural and left ventricular histologic changes after implantable LVAD insertion. Ann Thorac Surg 1995;59:609–613. 63 Farrar DJ, Homan WR, McBride LR, Kormos RL, Icenogle TB, Hendry PJ, Moore CH, Loisance DY, El-Banayosy A, Frazier H: Longterm follow-up of Thoratec ventricular assist device bridge-to-recovery patients successfully removed from support after recovery of ventricular function. J Heart Lung Transplant 2002;21:516–521. 64 Holman WL, Bourge RC, Fan P, Kirklin JK, Pacifico AD, Nanda NC: Influence of longer term left ventricular assist device support on valvular regurgitation. ASAIO J 1994;40: M454–M459. 65 Nakatani S, Thomas JD, Vandervoort PM, Zhou J, Greenberg NL, Savage RM, McCarthy PM: Left ventricular diastolic filling with an implantable ventricular assist device: Beat to beat variability with overall improvement. J Am Coll Cardiol 1997;30:1288–1294. 66 Mandarino WA, Morita S, Kormos RL, Kawai A, Deneault LG, Gasior TA, Losken B, Griffith BP: Quantitation of right ventricular shape changes after left ventricular assist device implantation. ASAIO J 1992;38:M228–M231. 67 Khan T, Delgado RM, Radovancevic B, TorreAmione G, Abrams J, Miller K, Myers T, Okerberg K, Stetson SJ, Gregoric I, Hernandez A, Grazier OH: Dobutamine stress echocardiography predicts myocardial improvement in patients supported by left ventricular assist devices (LVADs): Hemodynamic and histologic evidence of improvement before LVAD explantation. J Heart Lung Transplant 2003;22: 137–146. 68 Beckett AH: Clenbuterol and sport (letter). Lancet 1992;340:1165. 69 Palmer JBD, Shepherd GL, Cifelli AT: Muscling in on salbutamol (letter). Lancet 1992; 340:1407. 70 Perry H: Clenbuterol: A medal in tablet form? (letter). Br J Sports Med 1993;27:141. 71 Broadley KJ, Spencer PSJ: Muscling in on salbutamol (letter). Lancet 1993;341:313.

72 Wong K, Boheler K, Bishop J, Petrou M, Yacoub M: Clenbuterol induces cardiac hypertrophy with normal functional morphological and molecular features. Cardiovasc Res 1998;37: 115–122. 73 Yacoub M: A novel strategy to maximize the efficacy of left ventricular assist devices as a bridge to recovery. Eur Heart J 2001;22:534– 540. 74 Yacoub M, Tansley P, Birks E, Hipkin M, Hardy J, Bowles C, Banner N, Khaghani A: Interim results of left ventricular assist device combination therapy for inducing clinical and hemodynamic recovery of end stage dilated cardiomyopathy (abstract). Circulation 2002;106:II-606. 75 Noon GP, Morley DL, Irwin S, Abdelsayed S, Benkowski RJ, Lynch BE: Clinical experience with MicroMed Debakey Ventricular Assist Device. Ann Thorac Surg 2001;71:S133–S138. 76 Potapov EV, Nasseri BA, Loebe M, Kukucka M, Koster A, Kuppe H, Noon GP, DeBakey ME, Hetzer R: Transcranial detection of microembolic signals in patients with a novel nonpulsatile implantable LVAD. ASAIO J 2001; 47:249–253. 77 Wilhelm MJ, Hammel D, Schmid C, Stypmann J, Asfour B, Kemper D, Schmidt C, Morley D, Noon GP, Debakey ME, Scheld HH: Clinical experience with nine patients supported by the continuous flow Debakey VAD. J Heart Lung Transplant 2001;20:201. 78 Loebe M, Koster A, Sanger S, Potapov EV, Kuppe H, Noon GP, Hetzer R: Inflammatory response after implantation of a left ventricular assist device: Comparison between the axial flow MicroMed DeBakey VAD and the pulsatile Novacor device. ASAIO J 2001;47:272– 274. 79 Ankersmit HJ, Wiesenthaler G, Moser B, Gerlitz S, Roth G, Boltz-Nitulescu G, Wolner E: Transitory immunologic response after implantation of the DeBakey VAD continuous flow pump. J Thorac Cardiovasc Surg 2002; 123:557–561. 80 Frazier OH, Myers TJ, Jarvik RK, Westaby S, Pigott DW, Gregoric ID, Khan T, Tamez DW, Conger JL, Macris MP: Research and development of an implantable, axial-flow left ventricular assist device: The Jarvik 2000 Heart. Ann Thorac Surg 2001;71:S125–S132. 81 Griffith BP, Kormos RL, Borovetz HS, Litwak K, Antaki JF, Poirier VL, Butler KC: HeartMate II Left Ventricular Assist System: From concept to first clinical use. Ann Thorac Surg 2001;71:S116–S120. 82 Burke DJ, Burke E, Parsaie F, Poirier V, Butler K, Thomas D, Taylor L, Maher T: The HeartMate II: Design and development of a fully sealed axial flow left ventricular assist system. Artif Organs 2001;15:380–385. 83 Maher TR, Butler KC, Poirier VL, Gernes DB: HeartMate Left Ventricular Assist Devices: A multigeneration of implanted blood pumps. Artif Organs 2001;25:422–426. 84 Boyce SW: An anatomically compatible, wearless, reliable, and nonthrombogenic centrifugal blood pump. Ann Thorac Surg 2001;71:S190.

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Cardiology 2004;101:104–110 DOI: 10.1159/000075990

Destination Therapy with Ventricular Assist Devices Jai Raman Valluvan Jeevanadam Section of Cardiothoracic Surgery, University of Chicago Medical Center, Chicago, Ill., USA

Key Words Destination therapy W Heart failure W Ventricular assist devices

Abstract Despite extensive research and great strides over the past 40 years, the ideal permanent mechanical assist device remains elusive. The incidence of heart failure is increasing, and the number of heart transplants has remained constant. The HeartMate and Novacor are two pulsatile, long-term ventricular assist devices (VADs) commonly used as a bridge to transplantation. Randomized Evaluation of Mechanical Assistance in the Treatment of Congestive Heart Failure is a randomized study of device therapy in heart failure with treatment either with device (HeartMate) therapy or maximal medical therapy which was recently completed and demonstrated a Kaplan-Meier survival rate at 1 year of 52% for the device group compared to 25% in the medical therapy group. The TCI HeartMate is the only device approved for destination therapy, while others such as the Novacor device are in the process of evaluation. Most of these devices are still plagued by mechanical problems, bleeding, thromboembolism and infection. Other promising new devices include smaller VADs using impeller pump technology, such as the Arrow LionHeart, Micromed Debakey pump and Jarvik 2000 pump. The CardioVAD is an interesting chronically implantable balloon pump inserted into the descending thoracic aorta. While experi-

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ence with the newer implantable pumps is growing, most of them require some manipulation of the heart perioperatively, in addition to anticoagulation postoperatively and careful monitoring for complications and infection. Copyright © 2004 S. Karger AG, Basel

Introduction

The Holy Grail of the permanent mechanical assist device remains elusive. Despite extensive research over the past 40 years and billions of dollars spent in research and development, there are few if any long-term options for permanent circulatory assistance of the failing heart. At the same time, the incidence of heart failure is increasing and the number of transplants, the only other heart failure solution, has remained constant. No wonder a number of journal and textbook articles parrot the same line about ‘thousands of patients a year in the USA who could benefit from chronic ventricular support with a mechanical device’ [1].

The HeartMate Left Ventricular Assist Device

Most current devices were developed with the intention for use for permanent implantation. However, due to FDA study requirements, especially the desire to obtain device performance data over a defined period of time,

Jai Raman, MD Section of Cardiothoracic Surgery, University of Chicago Medical Center 5841 S. Maryland Avenue, MC 5040 Chicago, IL 60637 (USA) Tel. +1 773 834 2807, E-Mail [email protected]

Fig. 1. The HeartMate left VAD. Reprinted with permission from Thoratec Corporation.

these devices were first evaluated and have been approved for bridge to transplant. The HeartMate (Thoratec Inc., Pleasanton, Calif., USA) and Novacor (WorldHeart Corporation, Ottawa, Canada) are two commonly used devices approved by the FDA for ventricular assistance as a bridge to transplantation (fig. 1, 2). They are both pulsatile, long-term devices that are implanted in a pocket below the diaphragm and under the skin. They are paracorporeal devices, i.e. they are attached to the left ventricular apex and propel blood to the ascending aorta. They have an external driveline that connects to a system controller and the power supply. They are implanted at cardiopulmonary bypass following a median sternotomy. They have some differentiating properties. The blood-contacting surface of the HeartMate left ventricular assist system (LVAS) is textured with sintered titanium spheres on the rigid surface and textured polyurethane on the movable surfaces, to encourage deposition of a nonthrombogenic neointimal layer. This allows for use without mandatory anticoagulation. The thromboembolic rate of the device is very low at 0.01% per patient-month according to a recent multicenter study among 223 patients on aspirin alone [2]. Two bioprosthetic valves (Medtronic Hancock) maintain unidirectional blood flow. This pulsatile blood pump can be powered either by a pneumatic pump (the HeartMate IP-1000 LVAS) or an

Destination Therapy with Ventricular Assist Devices

Fig. 2. The Novacor LVAS. Photograph

courtesy of WorldHeart Corporation.

electric motor (VE LVAS and XVE LVAS). The VE versions allow maximum mobility and support of patients outside the hospital. The percutaneous driveline is covered with a polyester velour fabric that promotes tissue

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bonding and is designed to create a barrier to infection. The control algorithm is designed to maintain a stroke volume of 75 ml. Therefore, it will automatically adjust the rate depending on the amount of blood that the rightsided circulation can deliver to the LVAS. The maximum amount of flow is 10 liters/min, and this is easily achieved during exercise [3]. The HeartMate LVAS has been in use since 1994, and over 3,300 patients have had this device implanted worldwide. Since the results for bridge to transplantation were encouraging, a study [Randomized Evaluation of Mechanical Assistance in the Treatment of Congestive Heart Failure (REMATCH)] was initiated with funding from the National Heart, Lung, and Blood Institute. It randomized nontransplant patients to either HeartMate therapy or maximal medical therapy. It is the only randomized study of device therapy in heart failure. It was recently completed and demonstrated a KaplanMeier survival rate at 1 year of 52% for the device group compared to 25% in the medical therapy group, and a 2year survival of 23 and 8%, respectively. However, the patients in the device group had 2.5 times more adverse events than the medical therapy group, the predominant problems being infection, bleeding and malfunction of the device. The probability of device failure was over 35% at 24 months in the survivors. The perioperative implantation and index hospitalization mortalities approached 20 and 28%, respectively. Despite great results in the bridge to transplantation trials, permanent use in nontransplant patients revealed some weaknesses of the device. There was a shorter than anticipated lifespan of the bioprosthetic valves, leading to ventricular assist device (VAD) regurgitation and heart failure. In addition, there was a high incidence of infection as the driveline sites did not heal well in this group of elderly malnourished patients. Thoratec has addressed these issues with a special housing for the valve and a softer driveline in their newer model, the HeartMate XVE. As this article was being written, the HeartMate XVE LVAS was approved by the FDA for destination therapy. This is the first VAD to be approved for this indication.

lation, but up to 20% of patients may still experience a thromboembolic event, necessitating the use of coumadin with this device [4]. This device is connected by a percutaneous lead to a wearable console, thus enhancing patient mobility. The maximum stroke volume is 70 ml. Like the HeartMate, the system is self-regulating, responding to the recipient’s changing heartbeat and circulatory demands, especially in special circumstances like exercise. There have been over 1,350 Novacor LVAS implanted worldwide. A total of 288 patients were supported over 6 months, 106 for more than a year and 23 for more than 2 years. Long-term results of this device are eagerly awaited as the Investigation of Non-Transplant Eligible Patients who are Inotrope Dependent study, which is studying implant experience with the Novacor LVAS, is nearing completion. The manufacturers and implanting surgeons always comment on how well this device responds to demands placed by patients when they exercise.

The Thoratec Ventricular Assist System

The Thoratec ventricular assist system is an extracorporeal, pneumatically powered, pulsatile system which utilizes a seamless polyurethane blood sac contained in a rigid polycarbonate housing (fig. 3). This system utilizes an external drive console that pumps pressurized air. The devices can be configured for left, right or biventricular support, allowing for maximum flexibility. There is a portable drive console that is useful in enhancing the mobility of patients and facilitates their discharge from hospital [5]. The Thoratec VAD has been approved by the FDA as a bridge to transplantation or recovery. This device is now being tested for home or destination therapy, with a portable driver, as part of a study. The device resides outside the chest and patients are not as comfortable and ambulatory as with the Novacor or HeartMate. However, this device has the ability to provide biventricular support.

Arrow LionHeart LVAS The Novacor LVAS

The Novacor LVAS is also a portable, implantable assist device designed for long-term support (fig. 2). It utilizes a system of opposing pusher plates that compress a seamless polyurethane blood sac causing ejection of blood in one direction. Bioprosthetic valves are housed in the inflow and outflow cannulae. Patients require anticoagu-

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This device was designed by the Division of Artificial Organs at the Pennsylvania State University College of Medicine. The Arrow LionHeart (similar in design to the Thoratec pump) is completely implanted in the body and has no lines or cables protruding through the skin of the patient. The device operates via transcutaneous energy transmission to charge internal batteries that power a

Raman/Jeevanadam

Fig. 3. The Thoratec VAD. Reprinted with

permission from Thoratec Corporation.

4

Fig. 4. The MicroMed DeBakey pump. Reprinted with permission

from MicroMed Technology, Inc. Fig. 5. The HeartMate II left VAD. Reprinted with permission from

Thoratec Corporation.

5

blood pump. This device is predominantly designed for destination therapy. More than 10 patients have had this device implanted in Germany alone, and a phase I study for the FDA has just been approved in the USA. The preliminary experience with the LionHeart LVD 2000 VAD

in 6 patients was reported recently, with a 50% survival at 18 months [6]. A recent report looking at all major adverse clinical events showed an incidence of 3.59/ patient-year for the LionHeart versus 6.45/patient-year in the REMATCH trial. Actuarial survival looking at im-

Destination Therapy with Ventricular Assist Devices

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plant experience in 7 European centers with 22 enrolled patients showed an actuarial survival of 86% at 1 month, 45% at 6 months and 41% at 1 year. Six of the 22 patients were alive at a mean of 400 days. This is a promising device but it is bulky and limited to use in large patients. The other exciting ventricular replacement therapy is the Abiocor (Abiomed, Danvers, Mass., USA) total artificial heart. It is undergoing clinical trials in nontransplant patients with biventricular failure. This device is discussed in detail in this issue of Cardiology by Dr. Frazier and his associates [7]. Despite the promise shown by these devices, they are beset with a cluster of problems, namely size, bleeding, infection, thromboembolism and reliability. Consequently, the Devices and Technology Branch of the National Heart, Lung, and Blood Institute invited and promoted the development of innovative left ventricular support systems in 1994. As a result, an array of smaller, efficient devices have been developed with the following desirable features in mind: (1) reduced size and weight, which allows the pump to be implanted in smaller patients; (2) reduced blood-foreign surface interface to decrease activation of coagulation and immune proteins, and (3) simple blood propulsion with less movable parts or prosthetic valves. Most of these devices are nonpulsatile. Continuous flow pumps can be made smaller and at less expense and may potentially use less energy. However, nonpulsatile flow is not physiological and may have consequences such as end organ edema. The two other challenges are the presence of regurgitation through the device should it stop and the inability to control the device easily. For instance, should the pump be running at a high rpm and the patient become dehydrated, the left ventricle could collapse into the device. The next few paragraphs deal with some of the new devices, their applicability and limitations.

MicroMed DeBakey Pump

The MicroMed DeBakey pump is a small impeller pump measuring 3.5 cm in diameter and 7.6 cm in length that is totally implanted between the left ventricular apex and the ascending aorta (fig. 4). This device is a nonpulsatile, extracardiac axial flow pump that was developed as a joint project between the Baylor College of Medicine and the National Aeronautics Space Administration. The impeller pump rotates at speeds of 7,500–12,500 rpm and is capable of generating up to 5 liters of flow per minute. There is implant experience with well over 110 patients, with satisfactory results [8]. Patients do require antico-

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agulation, but the infection rate is very low. In addition, to prevent massive regurgitation should the device fail, there is an emergency shut-off valve in case of pump stoppage. Trials utilizing this device for bridge to transplantation and destination therapy are under way in Europe and the USA.

Jarvik 2000

The Jarvik 2000 is also an impeller pump, but it does not have an inlet cannula. Rather, it is placed directly in the left ventricle [9]. This decreases the potential for stasis of blood and thromboembolic events. The Texas Heart Institute has the largest experience with the device, and they place it via left thoracotomy with the outflow going to the descending aorta [10]. This impeller pump has a fixed speed with a flow of about 2–3 liters/min. This device may be most effective in postcardiotomy pump failure and bridge to recovery. It is also undergoing clinical trials as long-term treatment for heart failure [11].

The HeartMate II

The HeartMate II is an impeller pump developed by Thoratec Corp. (fig. 5). It utilizes the cannula developed for the HeartMate XVE, but without the bioprosthetic valve [12]. The advantage of the device over the other two above-mentioned devices is a control algorithm that senses when the ventricle is getting empty. It checks the electrical impedance of the pump, which is a reflection of the afterload. It then controls its speed by allowing for some pulsatility. Since the native left ventricle is ejecting blood, the device assumes that there is adequate volume in the ventricle. This allows for autoregulation of VAD flow depending on blood return to the left ventricle. All of the above devices are smaller than the first generation of VADs but still have some common drawbacks: (1) they are all obligatory, in the sense that they have to keep working continuously – any period of stoppage, however brief, is likely to result in thrombosis and VAD regurgitation; (2) they all have large cannulae sitting in a major cardiac chamber, and (3) they all require anticoagulation. Despite these limitations, a coordinated management of end-stage heart failure, with a combination of fluid management, inotropes and medical management, does make room for miniaturized and partial support pumps that provide support but cannot replicate the pumping capacity of the heart.

Raman/Jeevanadam

Fig. 6. The Kantrowitz CardioVAD System. Reprinted with permis-

sion from L.VAD Technology, Inc.

The CardioVAD

There are other devices that can provide partial permanent circulatory assistance. Perhaps the most novel device with the least manipulation of the heart is the Kantrowitz CardioVAD. This is a permanent intra-aortic balloon pump that is sutured to the descending thoracic aorta. As mentioned above, most devices are electrically driven, and have valves. Some propel blood in a pulsatile fashion while others do not. The CardioVAD utilizes the principles of the intra-aortic balloon pump, and does not contain valves. The pump is designed to displace as much blood as possible during diastole without occluding the aortic lumen. This device was designed by Dr. Kantrowitz and consists of three components: a blood pump, a percutaneous access device (PAD) and drive consoles (fig. 6). The blood pump is implanted by being sutured into the descending thoracic aorta and works in series with the patient’s left ventricle. It acts by increasing diastolic blood pressure

Destination Therapy with Ventricular Assist Devices

and flow, decreasing the afterload of the left ventricle, increasing coronary blood flow, increasing mean arterial blood pressure and decreasing the workload of the left ventricle. The lining of the blood pump is similar to that of the HeartMate and fosters formation of a nonthrombogenic pseudointima. The device utilizes no valves and can be turned on or off at the desire of the patient. To minimize infection, the PAD is lined with autologous fibroblasts. This creates a biologic seal between the PAD and the skin. The PAD provides a connection between the internal blood pump and the external console, allowing pneumatic and electrical signals to pass between the two. The balloon is implanted in the descending thoracic aorta, between clamps, with the patient supported on partial cardiopulmonary bypass. Cardiac manipulation is not required and the patients are not required to be anticoagulated. Preliminary results in the phase I trial have been satisfactory; 5 out of the 6 patients enrolled were discharged home, with a median survival of 8 months [13]. The CardioVAD is ideally suited to the advanced class III or early class IV patient who is failing medical therapy. The extent of cardiac support is only partial, and hence, this device cannot be used in end-stage class IV heart failure. Studies have demonstrated an increase in cardiac performance by about 50% during CardioVAD support. This device has recently been redesigned to improve implantation into a single period of aortic clamping. In addition, the device has been streamlined to conform to the shape of the native aorta, without compromising the shape and profile of the balloon. This minimizes the risk of balloon fatigue and rupture, which were encountered in some of the phase I trial patients. The FDA has approved the new version of the CardioVAD, which is soon to be evaluated in patients.

Conclusions

The evidence presented above is an attempt to summarize the most up-to-date experience with mechanical assist devices in their role as destination therapy. Despite great strides made in technology and improved survival, long-term implants are still hindered by problems of infection, mechanical failure and thromboembolism. However, with the aging population, declining numbers of donor organs and increasing numbers of patient with heart failure, destination therapy with devices will have an important role in the future management of patients with end-stage heart disease.

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References 1 Franco KL: New implantable pulsatile blood pumps; in Franco KL, Verrier ED (eds): Advanced Therapy in Cardiac Surgery, ed 2. London, BC Decker, 2003, pp 537–545. 2 Slater JP, Rose EA, Levin HR, Frazier OH, Roberts JK, Weinberg AD, Oz MC: Low thromboembolic risk without anticoagulation using advanced-design left ventricular assist devices. Ann Thorac Surg 1996;62:1321– 1328. 3 Branch KR, Dembitsky WP, Peterson KL, Adamson R, Gordon JB, Smith SC Jr, Jaski BE: Physiology of the native heart and Thermo Cardiosystems left ventricular assist device complex at rest and during exercise: Implications for chronic support. J Heart Lung Transplant 1994;13:641–651. 4 El-Banaysosy A, Deng M, Loisance DY, Vetter H, Gronda E, Loebe M, Vigano M: The European experience of Novacor left ventricular assist (LVAS) therapy as a bridge to transplant: A retrospective multi-centre study. Eur J Cardiothorac Surg 1999;15:835–844.

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5 Farrar DJ, Buck KE, Coulter JH, Kupa EJ: Portable pneumatic biventricular driver for the Thoratec ventricular assist device. ASAIO J 1997;43:M631–M634. 6 El-Banayosy A, Arusoglu L, Kizner L, Morshuis M, Tenderich G, Pae WE, Korfer R: Preliminary experience with the LionHeart left ventricular assist device in patients with endstage heart failure. Ann Thorac Surg 2003;75: 1469–1475. 7 Frazier OH, Dowling RD, Gray LA Jr, Shah NA, Pool TP, Gregoric I: The total artificial heart: Where we stand. Cardiology 2004;101: 117–121. 8 Westaby S: The new rotary blood pumps: An alternative to cardiac transplantation; in Franco KL, Verrier ED (eds): Advanced Therapy in Cardiac Surgery, ed 2. London, BC Decker, 2003, chapter 49, p 504. 9 Frazier OH, Shah NA, Myers TJ, Robertson KD, Gregoric ID, Delgado R: Use of the Flowmaker (Jarvik 2000) left ventricular assist device for destination therapy and bridging to transplantation. Cardiology 2004;101:111– 116.

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10 Frazier OH, Myers TJ, Gregoric ID, Khan T, Delgado R, Croitoru M, Miller K, Jarvik R, Westaby S: Initial clinical experience with the Jarvik 2000 implantable axial-flow left ventricular assist system. Circulation 2000;105:2855– 2860. 11 Westaby S, Banning A, Saito S, Pigott DW, Jin XY, Catarino PA, Robson D, Moorjani N, Kardos A, Poole-Wilson PA, Jarvik R, Frazier OH: Circulatory support for long-term treatment of heart failure: Experience with an intraventricular continuous flow pump. Circulation 2000;105:2588–2591. 12 Maher TR, Butler KC, Poirier VL, Gernes DB: HeartMate left ventricular assist devices: A multigeneration of implanted blood pumps. Artif Organs 2001;25:422–426. 13 Jeevanandam V, Jayakar DV, Anderson A, Martin S, Piccione W Jr, Wynne J, Stephenson LW, Freed PS, Kantrowitz A: Circulatory assistance with a permanent implantable IABP: Initial human experience. Circulation 2002;106 (12 suppl 1):I183–I188.

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Cardiology 2004;101:111–116 DOI: 10.1159/000075991

Use of the Flowmaker (Jarvik 2000) Left Ventricular Assist Device for Destination Therapy and Bridging to Transplantation O.H. Frazier Nyma A. Shah Timothy J. Myers Kimberly D. Robertson Igor D. Gregoric Reynolds Delgado Cardiopulmonary Transplant Service and Cullen Cardiovascular Research Laboratories, Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, Tex., USA

Key Words Flowmaker W Left ventricular assist devices W Congestive heart failure W Heart transplantation W Destination therapy

Abstract The Flowmaker left ventricular assist device (formerly known as the Jarvik 2000) is an axial-flow pump that provides continuous flow from the left ventricle to the aorta. Designed for either temporary or permanent use, the Flowmaker is undergoing clinical trials in the United States and Europe. The goal of this therapy is to provide adequate circulatory flow while partially reducing the left ventricular size and end-diastolic pressure. This gives the native ventricle an opportunity to remodel itself. Those who benefit the most from this technology are patients who require only true left ventricular assistance rather than total capture of the left ventricular output. Because of the Flowmaker’s simplicity and safety of implantation, as well as the absence of late pump failure, its use may be justified in severely impaired class III and IV (but not preterminal) heart failure patients. Copyright © 2004 S. Karger AG, Basel

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Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/crd

Introduction

Clinical studies have shown that left ventricular assist devices (LVADs) are safe and effective as temporary bridges to heart transplantation [1] or as destination therapy [2]. These implantable pulsatile assist systems are becoming widely used in Europe and the United States. Smaller, axial-flow pumps have been developed to provide circulatory support for patients with advanced heart failure not amenable to conventional medical or surgical treatment [3]. These pumps are silent, reliable and simple to operate. They require relatively low power, which is supplied by wearable lithium batteries via a thin percutaneous power cable. One such pump, the Flowmaker (formerly known as the Jarvik 2000 LVAD; Jarvik Heart, Inc., New York, N.Y., USA) (fig. 1), is an axial-flow LVAD that provides continuous flow from the left ventricle to the aorta. Designed for either temporary or permanent circulatory support, the Flowmaker is undergoing clinical trials in the United States and Europe. The results so far have shown it to be a valuable true assist device for selected critically ill patients with severe heart failure [4, 5]. In such patients, some complications can be expected with the use of any new technology, and the Flowmaker is no exception [6]. However, in the light of increasing clinical experience, this device appears to have significant therapeutic potential for expanded use in patients with advanced heart failure.

O.H. Frazier, MD Texas Heart Institute PO Box 20345, MC 3-147 Houston, TX 77225-0345 (USA) Tel. +1 832 355 3000, Fax +1 832 355 6798, E-Mail [email protected]

Fig. 1. The main components of the Flow-

maker LVAD.

Materials and Methods Device Description The Flowmaker LVAD is a compact axial-flow pump that provides continuous blood flow from the left ventricle to the descending or ascending aorta. The device measures 2.4 cm in diameter by 5.5 cm in length and weighs 85 g. The only blood pump to be placed within the native heart, this LVAD requires no inflow cannula [7]. The pump comprises a single rotating impeller, which is located in the center of the titanium housing (fig. 2). A brushless, direct-current motor, also positioned within the housing, creates the electromagnetic force necessary to rotate the impeller. The impeller consists of a neodymium-iron-boron magnet and 2 titanium impeller blades that are suspended by ceramic bearings. All the blood-contacting surfaces are of smooth titanium. Blood is directed through the outflow graft by stator blades located near the pump outlet. The continuous flow eliminates the need for valves, an external vent or a compliance chamber. In addition to the blood pump, the system consists of a 16-mm outflow graft, percutaneous power cable, speed controller and directcurrent power supply. The external speed controller powers the pump via a series of wires contained in a silicone tube, which is covered with Dacron. The motor speed is manually adjusted and is regulated by a pulse width-modulated, speed control circuit. Lead acid or lithium ion batteries provide the 12-volt direct-current power supply. The pump can be operated at 8,000–12,000 rpm. Under optimal conditions, it can produce an output of up to 6 liters/min. Implantation Technique The Flowmaker LVAD is inserted into the apex of the left ventricle via a thoracotomy or sternotomy [8, 9]. The standard implant procedure utilizes partial cardiopulmonary bypass, but 3 of our cases have been safely implanted without cardiopulmonary bypass [10].

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Fig. 2. The Flowmaker pump comprises a single rotating impeller, which is located in the center of the titanium housing.

The implant procedure and its variations have been detailed elsewhere [8–10]. When the device is implanted via a thoracotomy, the outflow graft from the blood pump is sewn onto the descending aorta (fig. 3a). When a median sternotomy is used, however, the outflow graft is sewn onto the ascending aorta (fig. 3b). The pump is secured in place by a Silastic sewing cuff anastomosed to the apex of the left ventricle. The percutaneous power cable is externalized through the right side of the patient’s abdomen (fig. 4a) and is then connected to the controller and battery system. When permanent cardiac assistance is the goal at the time of implantation, an alternative approach may be considered. The cable is brought through the left pleural cavity to the apex of the chest and is then tunneled subcutaneously across

Frazier/Shah/Myers/Robertson/Gregoric/ Delgado

Fig. 3. a When the pump is implanted via a thoracotomy, the outflow graft is sewn onto the descending aorta. b When

a median sternotomy is used, however, the outflow graft is sewn onto the ascending aorta.

the neck to the base of the skull, behind the mastoid process. The power cable passes from the pump to a titanium pedestal attached to the skull (fig. 4b). The durability of the percutaneous pedestal has been shown by cochlear implants [11], some of which have been safely used for more than 20 years.

United States In the United States, the Flowmaker LVAD is being investigated as a bridge to transplantation under a Food and Drug Administration (FDA)-approved protocol. In April 2000, the Texas Heart Institute initiated clinical trials for this purpose, and the Flowmaker was first implanted clinically at that time. Eight other United States centers have received the training necessary to begin clinical trials, and 4 of them have begun implanting

the device (table 1). So far in this study, 35 patients have received the Flowmaker. This group includes 8 women (23%) and 27 men (77%) with a mean age of 52 years. Twenty-one patients (60%) had idiopathic cardiomyopathy, 13 patients (37%) had ischemic cardiomyopathy and 1 patient (3%) had postpartum cardiomyopathy. Preoperatively, the mean cardiac index was 1.7 liters/min/m2, the mean pulmonary capillary wedge pressure was 24 mm Hg and the mean peripheral vascular resistance was 2.8 Wood units. The average support period has been 67 days and the cumulative support period 2,348 days. Eighteen patients underwent successful transplantation, and 12 patients died during the support period. In 1 patient, the Flowmaker was explanted and exchanged for a HeartMate® LVAD (Thoratec Corporation, Pleasanton, Calif., USA). Four patients are still being supported by the Flowmaker pump.

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Cardiology 2004;101:111–116

Results

113

Fig. 4. The percutaneous power cable is externalized through the right side of the abdomen (a) or, in patients with permanent implants, at the base of the skull (b). Figure 4b reproduced with the permission of the Society of Thoracic Surgeons from Frazier et al. [5].

Table 1. United States investigational sites authorized to implant the Flowmaker (n = 8)

Investigational site

Patients

Texas Heart Institute (Houston, Tex.) University of Maryland Medical Center (Baltimore, Md.) Cleveland Clinic Foundation (Cleveland, Ohio) Stanford Hospital and Clinic (Stanford, Calif.) UCLA Medical Center (Los Angeles, Calif.) Yale New Haven Heart Center-Yale University (New Haven, Conn.) Mount Sinai Medical Center (New York, N.Y.) Inova Fairfax Hospital (Falls Church, Va.)

29 3 2 1 –

Total

35

UCLA = University of California at Los Angeles.

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– – –

Early in 2002, the United States FDA granted approval for patients to be discharged home with the Flowmaker. To be eligible for this arrangement, the patient must pass a pump-off hemodynamic stability test. The power is turned off for 3 min, during which echocardiographic monitoring must show that the native heart has sufficient function to maintain the circulation. The patient must remain alert and awake. At the end of the 3 min, he or she should be able to change the controller and batteries. Three patients have been discharged home with the Flowmaker. All of them remain well and in a stable condition. Europe In Europe, 9 centers have undergone the necessary training for clinical trials of the Flowmaker LVAD, and 5 of them have initiated clinical programs (table 2). Seventeen implants have been performed to date, 3 implants for

Frazier/Shah/Myers/Robertson/Gregoric/ Delgado

Table 2. European investigational sites authorized to implant the Flowmaker (n = 9)

Investigational site

Patients

Freiburg (Germany) Oxford (UK) Gothenburg (Sweden) Lund (Sweden) Bern (Switzerland) Harefield (UK) Newcastle (UK) Papworth (UK) Rome (Italy)

7 4 3 2 1 – – – –

Total

17

bridging to transplantation and 14 for destination therapy. All 17 patients have been men, with a mean age of 56 years. Fourteen patients (82%) had idiopathic cardiomyopathy, and 3 patients, respectively, had amyloid cardiomyopathy, acute viral cardiomyopathy and dermatomyositis. At device implantation, all the patients had New York Heart Association (NYHA) functional class IV heart failure and were receiving maximal medical therapy. Preoperatively, they had a mean cardiac index of 1.81 liters/ min/m2, mean pulmonary capillary wedge pressure of 23 mm Hg and mean pulmonary vascular resistance of 3 Wood units. Postoperatively, 10 patients have been discharged home with the Flowmaker. Of the 14 patients in the destination therapy cohort, 2 patients underwent successful transplantation after support durations of 290 and 385 days, respectively. Seven patients died during the support period, after an average support duration of 111 days. In 1 patient, the Jarvik 2000 was explanted and exchanged for a pusher-plate pump. Four patients are continuing to be supported, with an average support duration of 630 days. Of the 3 patients who received the Flowmaker as a bridge to transplantation, 2 patients are still being supported (3 and 706 days, respectively), and the remaining patient underwent successful transplantation after 349 days of support.

Fig. 5. Regression analysis of cardiac output and systemic vascular resistance data, showing the effect of the afterload on the total cardiac output. Cardiac output support by the Flowmaker is optimized with a decreased afterload; conversely, the total cardiac output decreases with an increased afterload.

The Flowmaker LVAD is an effective, reliable option for both destination therapy and bridging to transplantation. This particular pump has several benefits over conventional pulsatile LVADs. Because of its simplicity and

small size, implantation is easier and involves a shorter cardiopulmonary bypass time, reducing the risk of serious complications such as bleeding related to coagulopathy and end organ failure [12]. In addition, minimization of the surface area of foreign material and of device movement inside the body reduces the risk of infection. The patients who receive the maximum benefit from this device are those who require only true left ventricular assistance rather than total capture of the left ventricular output. Continuous offloading of the ventricle is most effective when the patient has enough residual myocardial function to maintain pulsatility, aortic root ejection and (with nonpulsatile support) a normal cardiac index [13]. The goal of this therapy is to provide adequate circulatory flow while partially reducing the left ventricular size and end-diastolic pressure. This gives the native ventricle an opportunity to remodel itself [14]. At lower pump speeds, ejection occurs through the aortic valve, and the workload of the ventricle can be varied to accommodate each individual patient’s needs. The ability to adjust the response and, thus, the pump flow simply, safely and progressively may allow a more simplified approach to left ventricular weaning and recovery [14]. Myocardial recovery followed by device removal is a developing strategy applicable to selected patients with dilated cardiomyopathy, viral myocarditis or postrevascularization ischemic cardiomyopathy [15]. If an effective

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Cardiology 2004;101:111–116

Discussion

115

LVAD with minimal complications such as this one can be employed earlier in the disease process, before extensive myocardial fibrosis ensues, more hearts may achieve recovery [12]. The physiology of continuous-flow pumps interfacing with the normal pulsatility of the native heart adds another unique dimension to circulatory support. As the ventricle is offloaded throughout the cardiac cycle, the normal phase of isometric contraction time is lost, giving rise to a unique pressure-volume loop. This continual offloading minimizes cardiac work, and our preliminary data show accelerated recovery. However, this technology has certain clinical limitations that must be considered in its use. The flow is afterload sensitive (fig. 5), so care must be given to pressure control and active clinical follow-up. If blood return to the left ventricle is inadequate because of high pulmonary vascular resistance manifesting as right ventricular dysfunction, increasing the speed of the Flowmaker may create negative pressure, distort the septum and further compromise left ventricular inflow. This scenario has invariably led to mortality in cases of rapid intervention in which right ventricular support was not initiated. In 1 such patient, we implanted the Flowmaker on the right side to counteract the septal shift and enhance left ventricular filling. In some cases, the phasic flow of a conventional pulsatile pump may be required.

Stasis with thrombus formation in the aortic root has been seen in 2 patients with an outflow graft anastomosis to the descending aorta. Such stasis may be lessened by minimizing pump flow to allow opening of the aortic valve and by administering anticoagulation therapy when a descending aortic anastomosis is used for the outlet graft. This problem has not been seen with outlet grafts anastomosed to the ascending aorta. The axial-flow technology offers many advantages. The fact that implantation involves minimal surgery is a decided advantage in these critically ill patients. The Flowmaker has been particularly successful in Europe when implanted in homebound class IV cardiac patients. One such patient has had a Flowmaker for more than 3 years and has remained in NYHA class I since hospital discharge. During the 9 months before LVAD implantation, he had been hospitalized 6 times for progressive congestive heart failure. Patients who are intensive care unitbound and are receiving pharmacologic and IABP support are more challenging to treat, as they may lack sufficient cardiac function to fill a continuous-flow pump. To date, the Flowmaker has resulted in no pump failures and no clinically significant infections. Its simplicity and safety of implantation, as well as the absence of late pump failure, may justify implantation in severely impaired class III and IV (but not preterminal) heart failure patients.

References 1 Frazier OH, Rose EA, Oz MC, et al: Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation. J Thorac Cardiovasc Surg 2001;122:1186–1195. 2 Rose EA, Gelijns AC, Moskowitz AJ, et al: Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001;15:345:1435–1443. 3 Frazier OH, Gregoric ID, Delgado R, et al: Initial clinical experience with the Jarvik 2000 left ventricular assist system as a bridge to transplantation: Report of 4 cases. J Heart Lung Transplant 2001;20:201. 4 Philips WS, Burton NA, MacManus Q, et al: Surgical complications in bridging to transplantation: The Thermo Cardiosystems LVAD. Ann Thorac Surg 1992;53:482–486. 5 Frazier OH, Myers TJ, Jarvik RK, et al: Research and development of an implantable, axial-flow left ventricular assist device: The Jarvik 2000 Heart. Ann Thorac Surg 2001;71: S125–S132.

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6 Myers TJ, Kahn T, Frazier OH: Infectious complications with ventricular assist systems. ASAIO J 2000;46:S28–S36. 7 Westaby S, Frazier OH, Beyersdorf F, et al: The Jarvik 2000 Heart. Clinical validation of the intraventricular position. Eur J Cardiothorac Surg 2002;22:228–232. 8 Siegenthaler MP, Martin J, Frazier OH, Beyersdorf F: Implantation of the permanent Jarvik-2000 left ventricular-assist-device: Surgical technique. Eur J Cardiothorac Surg 2002; 21:546–548. 9 Westaby S, Frazier OH, Pigott DW, Saito S, Jarvik R: Implant technique for the Jarvik 2000 Heart. Ann Thorac Surg 2002;73:1337– 1340. 10 Frazier OH: Implantation of the Jarvik 2000 left ventricular assist device without the use of cardiopulmonary bypass. Ann Thorac Surg 2003;75:1028–1030.

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11 Westaby S, Jarvik R, Freeland A, et al: Postauricular percutaneous power delivery for permanent mechanical circulatory support. J Thorac Cardiovasc Surg 2002;123:977–983. 12 Westaby S, Banning AP, Saito S, et al: Circulatory support for long-term treatment of heart failure: Experience with an intraventricular continuous flow pump. Circulation 2002;105: 2588–2591. 13 Frazier OH, Myers TJ, Westaby S, Gregoric ID: Use of the Jarvik 2000 left ventricular assist system as a bridge to heart transplantation or as destination therapy for patients with chronic heart failure. Ann Thorac Surg 2003; 237:631–637. 14 Frazier OH, Myers TJ, Gregoric ID, et al: Initial clinical experience with the Jarvik 2000 implantable axial-flow left ventricular assist system. Circulation 2002;105:2855–2860. 15 Westaby S, Takahiro K, Houel R, et al: Jarvik 2000 heart: Potential for bridge to myocyte recovery. Circulation 1998;98:1568–1574.

Frazier/Shah/Myers/Robertson/Gregoric/ Delgado

Cardiology 2004;101:117–121 DOI: 10.1159/000075992

The Total Artificial Heart: Where We Stand O.H. Frazier a, b Robert D. Dowling c Laman A. Gray, Jr. c Nyma A. Shah b Toni Pool b Igor Gregoric a a Cardiopulmonary

Transplant Service, b Cardiovascular Surgical Research Laboratories, Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, Tex., c Department of Surgery, Division of Thoracic and Cardiovascular Surgery, University of Louisville School of Medicine, Louisville, Ky., USA

Key Words Congestive heart failure W Mechanical circulatory support W Total artificial heart

ure. Further investigation with regard to its primary clinical applicability, i.e. as a rescue device for sudden catastrophic heart failure, is warranted. Copyright © 2004 S. Karger AG, Basel

Abstract The AbioCor® total artificial heart (TAH) is undergoing clinical feasibility testing as destination therapy in patients with end-stage congestive heart failure. So far, the device has been implanted in 11 of a projected 15 patients. The TAH has performed reliably, providing adequate circulatory support while extending survival and improving quality of life in most recipients. Thromboembolism remains a problem but is being addressed by optimizing device and patient management and refining the anticoagulation protocol. Because the device is totally implantable and requires no penetration of the skin, infection has been minimized. All recipients so far have been men. The device is large and this limits its use in smaller patients (i.e. women, small men and children). A smaller version is being developed. Although it has yet to receive Food and Drug Administration approval, the early clinical results suggest that the AbioCor TAH may become an accepted alternative to heart transplantation for selected patients with end-stage congestive heart fail-

ABC

© 2004 S. Karger AG, Basel 0008–6312/04/1013–0117$21.00/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/crd

Introduction

Despite advances in medical therapy, the mortality for patients with end-stage congestive heart failure remains high. Heart transplantation is the only definitive therapeutic option for many of these patients. The effectiveness of heart transplantation is severely diminished by the constant shortage of donor hearts [1, 2]. One response to this situation has been the development of the AbioCor® Implantable Replacement Heart (ABIOMED, Danvers, Mass., USA), a total artificial heart (TAH) that is now undergoing clinical testing in a Food and Drug Administration (FDA)-approved feasibility trial at several centers in the United States [3, 4].

O.H. Frazier, MD Cardiopulmonary Transplant Service and Cardiovascular Surgical Research Laboratories Texas Heart Institute at St. Luke’s Episcopal Hospital PO Box 20345, MC 2-114A, Houston, TX 77030 (USA) Tel. +1 832 355 3000, Fax +1 832 355 6798, E-Mail [email protected]

Development and Design

Fig. 1. The AbioCor® Implantable Replacement Heart. Courtesy of

ABIOMED, Danvers, Mass., USA.

Fig. 2. Internal and external components of the AbioCor. Reprinted

with the permission of McGraw-Hill Publishers from Frazier et al. [6, p 1512].

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The early development of and experience with the TAH have been reviewed elsewhere [5, 6]. There are currently 2 types of TAH in clinical use in the United States, and both are being used under investigational device exemptions granted by the FDA. The CardioWest TAH (SynCardia Systems Inc., Tucson, Ariz., USA), formerly known as the Jarvik-7 and Symbion, is used as a bridge to transplantation [7]. The AbioCor (fig. 1) is used as destination therapy [8]. Both devices are direct outgrowths of the National Heart Institute’s Artificial Heart Program, established in 1964 to foster the development of the TAH and other mechanical circulatory support devices. In the current study, the AbioCor is intended for use in patients who have irreversible biventricular heart failure that does not respond to optimal medical management and who are ineligible for heart transplantation. The device, made of titanium and plastic, is designed to fit inside the body and operate without penetrating the skin, thus providing the recipient with continued mobility and a good quality of life. Its smooth plastic construction and unique totally implantable design have been specifically engineered to reduce the risk of hemolysis, clotting and infection. The AbioCor system has internal and external components (fig. 2). The internal components include a thoracic unit or pump weighing about 2 pounds, an internal transcutaneous energy transfer (TET) coil, a controller and a battery. The pump itself consists of a motor-driven electrohydraulic energy system and 2 chambers that fill and empty alternately. A rotary switching valve alternates hydraulic flow between the right chamber, which couples with the right blood pump to supply blood to the lungs, and the left chamber, which couples with the left blood pump to supply blood to other vital organs and the rest of the body. The pump’s motor operates at 3,000– 10,000 rpm and can generate a flow of up to 8 liters/min. A miniaturized electronics package implanted in the abdomen monitors and controls the right-left hydraulic fluid balance, motor speed and pump rate. An internal rechargeable battery, also placed abdominally, functions as an emergency or backup power source. This battery is continually recharged by external power received through the internal TET coil and can provide up to 20 min of operation while disconnected from the main power source. The external components include a computer console, radiofrequency communication system, external TET coil and portable external battery and power transfer packs.

Frazier/Dowling/Gray/Shah/Pool/Gregoric

The console communicates with the internal components via the radiofrequency communication system. The external TET coil provides power to the pump from the console or from the external power transfer pack transcutaneously via the internal TET coil. Each external battery pack can power the AbioCor TAH for 2–4 h.

Feasibility Trial

Study Design The initial feasibility trial of the AbioCor TAH began in June 2001 with a planned enrollment of 15 patients and is still ongoing [3, 4, 8, 9]. The inclusion and exclusion criteria for the trial are summarized in table 1. Eligible patients are those who would imminently die from biventricular failure and are not transplant candidates at the time of evaluation. Ineligible patients are those with a predicted life expectancy of more than 30 days, or who are undergoing chronic hemodialysis, have irreversible liver failure, have potential for myocardial recovery or have had a recent cerebrovascular event. Patients with significant coagulation disorders are ineligible until their coagulation status is normalized. Although AbioCor recipients are not eligible for heart transplantation, they may become eligible later if their condition improves sufficiently during the period of support. The initial study end points are 60-day survival and assessment of quality of life.

Table 1. Inclusion and exclusion criteria for the FDA-approved clin-

ical trial of the AbioCor TAH Inclusion criteria Age 1 18 years Ineligibility for heart transplantation Acceptable device fitting evaluation Biventricular failure Optimized medical management Inability to be weaned if on a temporary mechanical circulatory support system Exclusion criteria ! 70% probability of death within 30 days Significant potential for reversibility of heart failure Chronic dialysis Recent cerebrovascular accident Irreversible liver failure Blood dyscrasia Suspected or active systemic infection Positive serum pregnancy test results Severe peripheral vascular disease No adequate social support system

Implantation and Patient Management Eligible candidates are screened for device fit using a proprietary software program (AbioFit, ABIOMED) [8]. The purpose of this screening is to determine before surgery whether the TAH will fit comfortably in the chest without compressing critical soft tissue structures such as the pulmonary veins. The implantation procedure has been described in detail elsewhere [3, 4]. The internal TET coil is placed first, anterior to the pectoral muscle via an infraclavicular incision. The thoracic unit is implanted orthotopically in the chest after excision of the left and right ventricles. Because the natural heart is totally replaced by a mechanical system, AbioCor recipients have no electrocardiogram to assess and no need for inotropic support. Recipients are monitored for intravascular pressures, thrombosis, infection and hemolysis. Though the AbioCor TAH does not normally require strict control of pulmonary and systemic vascular resistance, maintaining proper intravascular volume is critical. Excessive intravascular volume may result in manifestation of severe

right-sided heart failure or hepatic congestion. Left-sided heart failure should not occur in patients supported with a properly functioning device. Left atrial and central venous pressures are maintained as close to normal as possible. Systemic vasoactive agents are used as needed to control arterial blood pressure to avoid hemorrhagic complications especially under hypertensive conditions. To minimize thrombotic complications, the typical anticoagulation regimen is a combination of low-molecular-weight dextran, heparin, warfarin, dipyridamole and aspirin. Anticoagulation is routinely monitored with platelet aggregation, partial thromboplastin time and international normalized ratio. Some centers perform daily thromboelastograms. Infections are managed aggressively to prevent chronic device infections, which can lead to serious complications and death. The AbioCor’s TET system helps prevent such infections by precluding skin penetration. Antimicrobial therapy for AbioCor recipients is the same as that for any patient undergoing cardiac surgery. Rehabilitation through nutritional support, exercise and physical therapy is important for improving quality of life after TAH implantation. Restoring the patient’s ability to walk requires early aggressive physical therapy. Since one of the main goals after implantation is a return to life outside the hospital, the patient and family must also be taught how to operate the AbioCor system properly. Though it requires more training, care and mainte-

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Table 2. Results of the AbioCor feasibility trial1

Patient Sex Age Diagnosis No. years

Implant date

1 2 3 4 5

M M M M M

58 70 68 74 51

ICM 7/2/2001 ICM 9/13/2001 ICM 9/26/2001 ICM 10/17/2001 IdCM, PH 11/05/2001

6 7 8 9 10 11

M M M M M M

79 61 79 65 69 64

ICM ICM ICM ICM ICM ICM

11/27/2001 4/10/2001 1/7/2003 1/22/2003 2/24/2003 5/1/2003

Institution/city

Number Outcome of days supported

Cause of death

Jewish Hospital, Louisville, Ky. Jewish Hospital, Louisville, Ky. Texas Heart Institute, Houston, Tex. UCLA, Los Angeles, Calif. Hahnemann University Hospital, Philadelphia, Pa. Texas Heart Institute, Houston, Tex. Jewish Hospital, Louisville, Ky. Jewish Hospital, Louisville, Ky. Jewish Hospital, Louisville, Ky. Texas Heart Institute, Houston, Tex. Texas Heart Institute, Houston, Tex.

151 512 142 56 293

died died died died died

CVA device membrane wear2 CVA MOSF CVA

0 0 100 53 110 ongoing

died died died died died alive

bleeding thrombosis MOSF CVA MOSF NA

CVA = Cerebrovascular accident; ICM = ischemic cardiomyopathy; IdCM = idiopathic cardiomyopathy; MOSF = multiple organ system failure; NA = not applicable; PH = pulmonary hypertension. 1 As of August 8, 2003. 2 This problem was anticipated and has since been addressed. Device replacement was not elected.

nance than other MCS systems because of its increased complexity, the AbioCor system has been designed to be maintained as much as possible by the patient and family. Clinical Experience So far, 11 patients have had the AbioCor implanted. Two patients died of operative complications at the time of surgery. Nine patients have survived for periods ranging from 53 to 512 days. Two patients have lived outside of the hospital. The longest time spent outside the hospital was approximately 9 months. Six patients became ambulatory. There have been no serious device-related infections. Five patients have died of sequelae of thromboembolic events, partly because of their inability to tolerate anticoagulation (table 2). To date, the AbioCor system itself has performed very reliably. There have been no pump failures and only minor technical problems. The system has functioned as intended, and hemodynamic stability is easily achieved. The TET system has functioned reliably with no interruptions in power. One patient underwent elective replacement of the internal battery 11 months after initial device implantation. Few problems with maintenance of the AbioCor system have been reported in the home environment. One patient lived outside the hospital with minimal medical supervision for approximately 9 months.

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Improvements

In response to problems encountered in the ongoing feasibility trial, changes have been made in the design of the inflow sewing cuff of the device and in the postimplantation anticoagulation protocol. Thromboembolism has been a recurring problem in the clinical trial. Autopsies of 4 early recipients who died of a cerebrovascular accident revealed thrombus on support struts within the atrial cuffs. The struts have since been removed. However, it has not yet been determined if this modification will resolve the thromboembolic events. Four recent patients have been supported with the new strutless design. One of those patients died of causes unrelated to thromboembolism. Another died of multiple organ system failure, with evidence of multiple microemboli. The fourth patient, who is still alive, has not had a major cerebrovascular event after 99 days of support.

Conclusion

In the clinical experience so far, the AbioCor TAH has performed reliably and well. In most cases, it has met the circulatory needs of its recipients while extending survival well beyond the expected 30 days and improving quality of life. Thromboembolism remains a problem but is being

Frazier/Dowling/Gray/Shah/Pool/Gregoric

addressed through changes in device and patient management and the anticoagulation protocol. Because the AbioCor is totally implantable and requires no skin penetration, infection is less of a problem than with other mechanical circulatory support devices. The large size of the device precludes its use in smaller patients (i.e. women, small men and children), but a smaller version based on an earlier design from the Pennsylvania State University is being developed by ABIOMED. Though the AbioCor has yet to receive FDA approval as an alternative to

heart transplantation, the promising early results suggest that in the future it may indeed become an accepted alternative to cardiac transplantation for patients with endstage congestive heart failure. Beyond that, the future hope is that it will be used as an ‘off-the-shelf’ orthotopic biventricular cardiac replacement system that will provide a safe and reliable means of rescuing patients at risk of premature death from acute heart failure usually related to acute myocardial infarction.

References 1 United Network for Organ Sharing: Critical data. U.S. facts about transplantation. Available at http://www.unos.org, accessed August 7, 2003. 2 Evans RW: Cardiac replacement: Estimation of need, demand, and supply; in Rose EA, Stevenson LW (eds): Management of End-Stage Heart Disease. Philadelphia, LippincottRaven, 1998, pp 13–24. 3 Dowling RD, Gray LA, Etoch SW, et al: Initial experience with the AbioCor implantable replacement heart system. J Thorac Cardiovasc Surg, in press.

Total Artificial Heart

4 Dowling RD, Gray LA Jr, Etoch SW, Laks H, Marelli D, Samuels L, Entwistle J, Couper G, Vlahakes GJ, Frazier OH: The AbioCor implantable replacement heart. Ann Thorac Surg 2003;75(6 suppl):S93–S99. 5 Cooley DA: The total artificial heart. Nat Med 2003;9:108–111. 6 Frazier OH, Shah NA, Myers TJ: Total artificial heart; in Cohn LH, Edmunds LH Jr (eds): Cardiac Surgery in the Adult. New York, McGraw-Hill, 2003, pp 1507–1514.

7 Copeland JG, Arabia FA, Tsau PH, Nolan PE, McClellan D, Smith RG, Slepian MJ: Total artificial hearts: Bridge to transplantation. Cardiol Clin 2003;21:101–113. 8 Samuels LE, Dowling R: Total artificial heart: Destination therapy. Cardiol Clin 2003;21: 115–118. 9 Myers TJ, Robertson K, Pool T, Shah N, Gregoric I, Frazier OH: Continuous flow pumps and total artificial hearts: Management issues (review). Ann Thorac Surg 2003;75(6 suppl): S79–S85.

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Cardiology 2004;101:122–130 DOI: 10.1159/000075993

Genetics and Gene Manipulation Therapy of Premature Coronary Artery Disease Rabih A. Chaer Rana Billeh Malek G. Massad Division of Cardiothoracic Surgery, Department of Surgery, The University of Illinois College of Medicine at Chicago, Chicago, Ill., USA

Key Words Coronary artery disease, premature W Genetics W Gene therapy

Abstract Despite the notable recent scientific advances, our ability to detect and prevent premature coronary artery disease (CAD) remains limited, and the identification of patients at risk is yet to be based on objective scientific testing. Eliciting a family history of CAD currently remains the only available screening tool to identify patients with a genetic predisposition. The risk of CAD attributable to genes appears to be most significant at younger ages, and this may explain the lack of definite markers for the disease. Candidate gene association studies focusing on young patients with CAD will, therefore, be more likely to identify a true genetic risk. In this report, we review the known genetic risk factors for premature CAD. We also discuss the potential gene manipulation therapy of CAD as well as of vein graft atherosclerosis following coronary artery bypass surgery. Copyright © 2004 S. Karger AG, Basel

ABC

© 2004 S. Karger AG, Basel 0008–6312/04/1013–0122$21.00/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/crd

Introduction

Atherosclerotic coronary artery disease (CAD) is the leading cause of morbidity and mortality in the United States and Europe. In the US alone, it affects at least 13 million people. An additional 1 million will have a new or recurrent myocardial infarction (MI) each year, resulting in over 500,000 deaths annually [1]. The majority of these new attacks will occur in older patients, with the lifetime risk of developing CAD after the age of 40 being 49% for men and 32% for women [1]. However, at least 5–10% of these new events will occur in younger patients, prior to their 50th birthday. In a recent report, Doughty et al. [2] outlined the profile of young MI victims at their institution; 10% of their MI patients were 45 years of age and younger, with atherosclerosis still being the most common etiology in this patient population. Although associated with a favorable prognosis, premature MI remains a substantial personal and societal burden. Given the current advanced state of therapeutic strategies, the major impact clearly lies in prevention and should depend on early detection and aggressive risk factor modification. Moreover, the identification of patients with a genetic predisposition to CAD should translate into more aggressive therapeutic interventions to improve long-term outcomes.

Malek G. Massad, MD Division of Cardiothoracic Surgery, The University of Illinois at Chicago 840 South Wood Street, Suite 417 (MC 958) Chicago, IL 60612 (USA) Tel. +1 312 996 6215, Fax +1 312 996 2013, E-Mail [email protected]

Genetic Contribution to CAD Risk

It has long been known that premature heart disease runs in families [3–5], and like most other common chronic diseases, CAD is multifactorial and has an important hereditary component. A variety of study designs have been used to quantify the size of the genetic component of the susceptibility for CAD. Classic twin studies compared concordance for disease status between members of monozygotic twin and dizygotic twin pairs. The Swedish Twin Registry study showed that the relative risk of fatal CAD in the second male twin among pairs where the first twin had died of CAD before the age of 55 was 8.1 (95% confidence interval 2.7–24.5) for monozygotic twins and 3.8 (95% confidence interval 1.4–10.5) for dizygotic twins [4]. These results indicate a significant genetic contribution to the risk of CAD. However, despite the current assessment of the known risk factors such as hypertension, diabetes and hypercholesterolemia, our ability to diagnose the genetic risk for CAD is still limited to establishing a family history for the disease. The complex pathophysiologic processes likely involve an interaction between many genetic variations of molecular and biochemical pathways and environmental factors. It is estimated that the overall contribution of genetics to the etiology of cardiovascular disease ranges from 20 to 60%, based on epidemiological studies [6]. Genetic factors probably have a greater influence in younger people, whereas environmental factors become more important in older people. Yet, although it is believed that all major causal risk factors for CAD have been identified, we still have a very limited ability to predict the development of clinically evident cardiovascular disease, even after the assessment of known cardiovascular risk factors. Cigarette smoking, hypertension, abnormal serum cholesterol and diabetes account for 50% of the variability of risk in high-risk populations [7]. The remaining risk is likely a combination of several, yet to be identified, minor risk factors and genetic influences [6].

General Approaches to Identifying Genetic Risk Factors for CAD

The investigation of the inherited components of such a complex genetic disease involves searches for genes in two general classes: causative genes and disease susceptibility genes [6]. Two broad categories of study design can be used to address the genetics of complex traits: linkage studies and association studies. Linkage studies examine

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the coinheritance of chromosomal segments with disease in families. They have been highly successful in the detection of monogenic disorders, but are tedious and complicated when used to investigate polygenic diseases such as CAD. Association studies provide an alternative method for detecting genetically complex diseases by using the candidate gene approach. Based on the known pathophysiologic characteristics of a disease, assumptions are made about the genes involved in its process and the hypothesis of the association of these genes with the disease is then tested. Such studies have greater power to resolve small genetic effects than do linkage studies. They compare the frequency of a genetic variation, often a single nucleotide polymorphism (SNP), in individuals with the phenotype [here coronary heart disease (CHD)]. However, although there are already several hundred published association studies in the literature looking at SNPs in candidate genes and the presence of CHD, few SNPs have actually been shown to be associated with CAD and/or MI, and in many cases, the results of the initial reports have not been reproduced in larger follow-up studies. Several factors are believed to account for this, mainly mismatches between the case and control groups, phenotypic heterogeneity, small studies and failure to recognize possible gene-gene interactions or gene-environmental interactions.

Candidate Gene Studies for CAD

Like other common diseases of adulthood, most genetic factors that contribute to CAD are prevalent in the population and have low penetrance [8]. Many gene polymorphisms have actually been linked to the development of atherosclerosis. These are usually genes from biochemical pathways implicated in the development and progression of atherosclerosis. They include hypertension, lipid metabolism, the coagulation cascade, smooth muscle proliferation and vascular growth, inflammation and oxidation/antioxidation balance in the arterial wall, glucose metabolism and control, insulin resistance, and other metabolic factors such as homocysteine.

Specific Gene Polymorphisms and Risk for CAD

Lipid Metabolism The study of genetic abnormalities related to lipid metabolism has identified some causative factors in premature CAD. The study of the genetics of lipid metabo-

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lism has focused in the past on rare mutations leading to the well-known familial forms of severe dyslipidemia. It is well established that the principal role of low-density lipoprotein (LDL) cholesterol in patients with familial hypercholesterolemia is secondary to a codominant mutation in the LDL receptor gene [9]. These defects represent a major independent risk factor for the development of CAD, and affected individuals typically have cholesterol concentrations twice the population average. However, they occur at a low prevalence, affect 0.2% of the general population [10] and have little impact from a population perspective. The more common variants of these genes result in moderate hypercholesterolemia, also a wellestablished independent risk factor for CAD. Because of such findings, some of the candidate gene variants involved in cholesterol homeostasis have become a major focus. These include variations in the genes for apolipoprotein B and E (apoE), and lipoprotein lipase. The apolipoprotein molecule is synthesized in the liver and intestine, and is the ligand for removal of triglyceride-rich lipoproteins [11]. Of the candidate genes involved in determining plasma lipid levels and CAD risk, apoE is probably the most comprehensively studied and involves different variations in the apoE gene (E2, E3 and E4) [12, 13]. ApoE acts as a ligand for the LDL receptor, and E3 is the most common isoform, with a frequency of 0.77 in Caucasians [13]. The apoE4 variant occurs in up to 30% of the population [14] and is an established genetic risk factor for CHD [12, 13]. It is reported to increase the risk of coronary death by 1.8-fold [15, 16], whereas individuals carrying the E2 allele show protection from coronary disease, carotid disease and stroke [17]. On the other hand, the risk of CAD is reported to be 7 times higher in people with the R3500Q mutation of the apolipoprotein B gene, normally coding for the component of LDL that binds the receptor [18]. However, these findings were not reproduced in larger prospective studies [19]. Another example is provided by lipoprotein lipase, the function of which is to hydrolyze triglyceride-rich particles with the resultant production of high-density lipoprotein (HDL) cholesterol. Any mutation causing partial deficiency of lipoprotein lipase would thus result in a modest increase in plasma triglyceride concentration and reduced HDL cholesterol levels [20]. Two common amino acid variants of the lipoprotein lipase gene have been identified: the D9N variant, resulting in a substitution of the aspartic acid residue at codon 9 with asparagine, and N291S, resulting in substitution of asparagine at codon 291 with serine [20, 21]. In the Second Northwick Park Heart Study (NPHS-II), a prospective survey of healthy

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middle-aged men drawn from nine general practices throughout the UK, there was no evidence that the N291S allele had any effect on CHD risk. However, the association with the D9N allele was significant and led to a relative risk of CAD of 2.33 in carriers [21]. Coagulation, Fibrinolysis and Endothelial Function Unregulated thrombotic events have always been implicated in the pathogenesis of atherosclerosis, but the expectations raised by early reports have been inconsistent [22]. The plasminogen activator inhibitor-1 serum level has been shown to be a risk factor for MI and successful fibrinolysis [23, 24]. A guanine insertion/deletion polymorphism in the gene promoter region was reported to increase expression of the protein [25]. Yet, studies attempting to link this genotype with the risk of MI have produced conflicting results with no uniform consensus [26]. On the other hand, polymorphism of another member of this gene family, PA1-2, has been associated with an increased risk for MI [27]. Formation of platelet thrombi at the site of plaque rupture is another culprit in the pathogenesis of the acute coronary syndrome. Several SNPs of the platelet surface proteins, notably the glycoprotein (GP) IIb-IIIa receptor involved in fibrinogen binding, have been investigated. Although P1A polymorphism in codon 196 resulting in proline for leucine substitution in the GPIIIa molecule may affect platelet aggregation [28], the association with MI was not confirmed in large case-controlled and prospective studies [29, 30]. In another study, a silent polymorphism (C807T) in the coding region of GPIa of the collagen receptor on platelets resulted in an increased thrombotic risk for carriers [31]. The risk of MI among these individuals increased significantly in the youngest 10% of a large series of men undergoing coronary angiography but did not increase in the entire study sample [31]. In the GeneQuest study, Topol et al. [27] investigated various platelet surface protein gene variants and their association with CAD. They identified 398 families with CAD before the age of 45 in men and the age of 50 in women. A total of 62 vascular biology genes and 72 SNPs were assessed. Eleven (15%) of these SNPs showed statistically significant differences in frequency between cases and controls. Notably, a missense variant of thrombospondin-4 (A387P) and thrombospondin-1 (N700S) of the thrombospondin family of 5 extracellular matrix glycoproteins showed the strongest statistical association with premature CAD, with an adjusted odds ratio for MI of 1.89 for the A387P carriers and 11.90 for the N700S carriers. In homozygote carriers of the N700S allele, there was a 10-fold increase in the risk of

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MI. However, these novel SNPs still need to be validated in larger prospective studies. Vascular Homeostasis and Endothelial Function The renin-angiotensin-aldosterone system plays a key role in maintaining vascular homeostasis. Excess angiotensin II appears to be detrimental, and its inhibition is protective against the complications of CAD [32]. The angiotensin-converting enzyme (ACE) insertion/deletion gene polymorphism has been extensively studied. An intron 16 insertion/deletion polymorphism is associated with plasma ACE activity, and individuals with the DD genotype have been shown to have a higher plasma level of ACE [33]. The DD allele has been linked to an increased risk for MI, especially in a low-risk subgroup of MI survivors without the traditional risk factors for CAD [34]. However, only a modest risk for MI was reproduced in larger studies [35]. Similarly, the common variant of the angiotensinogen gene (AGT M235T), though resulting in increased levels of circulating angiotensinogen, did not confer an increased risk for premature CAD as initially suspected [36]. Endothelial function also plays a key role in the pathogenesis of atherosclerotic disease. The association between polymorphism of the endothelial constitutive nitric oxide synthase gene and CAD has been well established. Hooper et al. [37] investigated the association of the polymorphic dinucleotide repeats found on intron 4 of the endothelial cell nitric oxide synthase gene and the platelet GPIIIa PLA(1)/A(2) polymorphism with MI in African Americans. Twenty-three percent of their patients with a diagnosis of MI prior to the age of 45 years were homozygous for the 393-allele coding for a dysfunctional endothelial cell nitric oxide synthase enzyme. They suggested that this genotype could be useful as a genetic screening tool for premature CHD given the association between impaired endothelium-dependent dilatation and premature MI. Metabolic Factors and Inflammatory Cytokines The genetic association of other factors with the clinical phenotypes of CAD or MI is not as well established. Mild elevation of plasma homocysteine is associated with an increased risk of coronary, cerebral and peripheral atherosclerotic disease [38]. However, although it is well documented that severe hyperhomocysteinemia caused by rare inborn errors of metabolism leads to early-onset atherosclerosis and thromboembolic events, the association of genetically determined mild hyperhomocysteinemia with these life-threatening events is less clear [39].

Gene Therapy of Premature Coronary Artery Disease

Similarly, inflammation is a key component of atherosclerosis, and genes coding for inflammatory cytokines may confer an increased risk for CAD. Elevated levels of IL-6 have been associated with the development [40, 41] and severity of CAD [28]. In the NPHS-II cohort, men with the G1C polymorphism of the –174 allele of the IL-6 gene had higher plasma levels of IL-6 and a relative risk of 1.54 for CAD compared to men homozygous for the G allele [42]. Yet, although these initial results are encouraging, the association still needs confirmation in larger studies.

Molecular Approaches for the Treatment of Atherosclerosis

With the knowledge of the genetic susceptibility to CAD, identifying important biologic differences could improve disease management and prevention through the use of targeted therapies. Most currently available interventions fall in the realm of damage control, with admittedly fewer in-hospital complications and a lower mortality rate for young patients with premature MI [2]. Nevertheless, despite the good short-term prognosis and the low risk and morbidity of surgical revascularization [43], younger age at infarction also indicates a relatively aggressive atherosclerotic process in the majority of the patients [44]. The key to better long-term outcomes, therefore, lies in prevention of the onset of the disease, early aggressive interventions and prevention of complications after disrupting or bypassing flow-limiting lesions. Moreover, in addition to their use to correct certain discrete inherited defects, as in cases of LDL receptor deficiency, gene therapies are now being sought as an avenue to improve the treatment of complex common acquired disorders such as CAD. Genetic manipulation is generally achieved through the introduction of foreign DNA into cells in a process known as transduction or transfection. It can involve the delivery of whole active genes or the blockade of native genes by the transfection of cells with short chains of nucleic acids known as oligonucleotides (ODNs). Vascular gene therapy using a variety of different vectors was first reported by Nabel et al. [45] in 1989. However, the ideal vector to efficiently deliver genetic material to a targeted tissue with minimal local or systemic toxicity while allowing a sustained desired level of gene expression has yet to be discovered. Once delivered into a cell, expression of the inserted genetic material is dependent on the cell’s normal tran-

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Table 1. Vectors used for cardiovascular gene therapy

Viral vectors Retrovirus (Moloney murine leukemia virus, lentivirus) Parvovirus: adeno-associated virus Lentivirus (HIV-1, HSV-1) Epstein-Barr virus Nonviral vectors Naked plasmid DNA Ligand DNA DNA liposome Oligonucleotides (e.g. E2F ODN decoy) Fusigenic-liposome (hemagglutinating virus of Japan)

scription and translation mechanisms to generate the final product. The form of the delivered genetic material, which varies depending on the type of vector used, must be converted to a double-stranded DNA template to be acted on by the native cell’s transcription machinery. The ideal vector for gene therapy would have to meet several desirable attributes. Safety concerns obviously come first, and the vector used should induce little or no host inflammatory response. Its distribution should also be ideally restricted to the target tissue of interest. A vector should be easily produced, handled and stored without loss of potency. It should be able to efficiently transduce nondividing cells, and should provide sustained stable transgene expression for at least a few weeks. Gene delivery vectors can be viral or nonviral (table 1). Nonviral vectors include naked plasmid DNA, and DNAliposome or ligand-DNA complexes. Gene inhibition can be achieved by transfection of cells with short chains of DNA known as antisense ODNs, which bind to mRNA in a sequence-specific fashion and block protein translation [46]. Ribozymes, segments of RNA that act like enzymes, have also been used to destroy specific sequences of target mRNA [47]. A third type of gene inhibition involves the blockade of gene-regulatory proteins known as transcription factors. Double-stranded ODNs have been designed to mimic the transcription factor chromosomal binding sites and act as ‘decoys’, binding the transcription factor and preventing the activation of its target genes [48]. Small synthetic ODNs can, therefore, be delivered to cells and tissues without the use of a vector. Indeed, the use of nondistending pressure has been shown to result in the rapid uptake of ODN by more than 80% of cells in the saphenous vein wall during a 10-min exposure [49]. Recombinant viral vectors have been engineered to become replication deficient by means of deletion of sev-

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eral genes that are crucial to the viral life cycle. They also contain the genetic information of interest. Exposure to these systems is usually well tolerated; however, host immunologic responses may occur to either the viral gene product or the viral particle itself. Several viral vectors have been studied in vascular gene therapy. These include retroviral, adenoviral and adeno-associated viral vectors. The first recombinant vectors used for gene transfer were based on retroviruses. These, however, require target cell proliferation and are not suitable for direct intraoperative treatment. Since then, adenoviral vectors have become the most widely used viral vectors for in vivo gene transfer [50]. They can effectively infect nondividing cells and do not usually integrate into the host genome. However, the immunogenicity of these vectors has been limiting in terms of tissue toxicity and reduced transgene expression. Recombinant adeno-associated viruses contain no viral sequences and are thus much less pathogenic and immunogenic to humans. Although less efficient than adenoviral vectors, and more cumbersome to produce, they can yield long-term expression by integrating into the genome of even nonreplicating cells [51]. Other viral vectors still under active preclinical investigation are lentiviruses. These include HIV-1 [52] and HSV-1 [53]. Experience with these vectors in cardiovascular tissues is still limited. Viral vectors remain the most common vehicles for exogenous gene delivery into mammalian cells. Therapeutic genes are cloned into the recombinant genome and coupled to the required regulatory elements. Interestingly enough, with the development of virus-mediated gene delivery elements, some investigators have used these systems ex vivo in autologous vein grafts in animal [54] and human organ culture [55] models. However, the safety and efficacy of these approaches remain to be verified in clinical trials.

Specific Clinical Applications (table 2)

Hyperlipidemia Hyperlipidemia has clearly been established as an independent risk factor for CAD, MI and stroke. The current pharmacological regimens have their limitations in the treatment of inherited disorders such as apoE deficiency and familial hypercholesterolemia. Gene therapy directed to the liver in patients with familial hypercholesterolemia attempted to correct the deficit in LDL receptor [56]. The reduction in serum LDL levels was not, however, as encouraging as that achieved in the animal model

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[57]. Treatment of apoE-deficient mice with adenoviral gene transfer of the human apoE3 gene resulted in a shift in the plasma lipoprotein distribution to predominantly HDL in transfected mice [58]. However, further development of vector technology will be necessary before the permanent correction of these diseases is achieved. Therapeutic Angiogenesis The use of angiogenic growth factors to promote the growth of collateral blood vessels in ischemic tissue has been termed therapeutic angiogenesis. Angiogenic gene therapy might provide an alternative treatment to patients with peripheral vascular disease or CAD who are not candidates for conventional revascularization therapies. Potential therapeutic agents include vascular endothelial growth factor (VEGF), and two members of the fibroblast growth factor (FGF) family, acidic FGF (FGF1) and basic FGF (FGF-2). VEGF is a family of angiogenic growth factors specific for endothelial cells; however, despite this theoretical selectivity, experimental use of VEGF in animal models may be associated with smooth muscle cell proliferation and exacerbation of neointimal hyperplasia [59]. The Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis study was the first large doubleblind placebo-controlled randomized study of therapeutic angiogenesis to be conducted in humans [60]. The trial was designed to determine the safety and efficacy of intracoronary and intravenous recombinant human VEGF protein (rhVEGF) for therapeutic angiogenesis in patients with chronic myocardial ischemia not amenable to standard revascularization techniques. The primary end point of the trial, change in exercise treadmill test time from baseline to day 60, was negative. There was no improvement in myocardial perfusion, but high-dose rhVEGF resulted in significant improvement in angina and favorable trends in exercise treadmill test time and angina frequency by day 120. As shown in other clinical trials [61], rhVEGF was well tolerated and appeared to be safe for human use. However, larger trials with longer-term follow-up are required in order to determine the long-term efficacy and safety of VEGF. Concerns remain regarding the consequences of potential systemic exposure, namely the growth of occult neoplasms, worsening of diabetic retinopathy and even occlusive arterial disease itself. Gene Therapy for Vein Graft Failure The long-term success of lower extremity and coronary bypass revascularization has been limited by autologous vein graft failure. After surgical manipulation, vein grafts

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Table 2. Potential targets of gene therapy for cardiovascular disease

Hyperlipidemia Therapeutic angiogenesis Postangioplasty restenosis Vein graft failure: thrombosis, ischemia reperfusion injury, intimal hyperplasia Bioprosthetic graft conduits Congestive heart failure Hypertension Transplant immunomodulation

undergo structural changes leading to intimal hyperplasia and wall thickening, the end point of which is thrombosis and bypass failure. Smooth muscle cell proliferation is the hallmark of intimal hyperplasia after both arterial injury and vein grafting. By targeting smooth muscle cell proliferation, intimal hyperplasia could potentially be prevented, and this could be used for the treatment of native arterial atherosclerosis, restenosis and transplant vasculopathy. Several approaches are available for this purpose. Gene therapy could be delivered through endovascular devices or through transduction of the outer wall or adventitia of blood vessels. Stents coated with a hydrogel containing genetic material are still in the developmental phase and are an attractive means for gene delivery, and because of the vasoprotective properties of nitric oxide, delivery of inducible nitric oxide synthase into the coronary bed has been approved by the National Institutes of Health and the Food and Drug Administration for the treatment of restenosis following angioplasty or stenting. The antiproliferative effects of nitric oxide are complemented by its additional vasoprotective properties; moreover, the effects of liposome-mediated inducible nitric oxide synthase gene transfer are currently being investigated for the prevention of restenosis in the coronary bed after angioplasty [62]. Local gene delivery to the peripheral circulation could be performed at the time of surgical exposure for intervention. Similarly, saphenous vein bypass grafts could be easily transduced ex vivo prior to implantation in the arterial circulation [63]. Intraoperative transfection of the vein graft combines intact tissue DNA transfer with the safety of ex vivo transfection. A single intraoperative E2F decoy ODN treatment of human vein grafts in patients undergoing peripheral bypass surgery has resulted in resistance to neointimal hyperplasia and fewer graft occlusions at 12 months of follow-up [64]. The E2F decoy treatment has also been applied to coronary vein grafts in the PREVENT II trial (Project in

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Ex-Vivo Vein Graft Engineering via Transfection [PREVENT], unpublished data). The study randomized 200 patients to the E2F decoy treatment or placebo, and transfection was achieved via a nondistending pressure-mediated device. Although the study lacked statistical power to detect differences in patient-level end points, the graftlevel analysis revealed increased patency and positive vascular remodeling in the treated group [65]. On the basis of preclinical and phase I/II clinical data, multicenter, randomized, double-blinded, placebo-controlled trials of E2F decoy ODN for the prevention of lower extremity vein graft failure and coronary vein graft failure (PREVENT IV trial) have been initiated. These studies are adequately powered to detect significant reduction in the primary end point of graft failure at 1 year. Other Vascular Applications for Gene Therapy Prosthetic materials are often used as arterial substitutes or in the construction of arteriovenous grafts. However, their long-term use has been limited due to their thrombogenic surfaces. Cellular and genetic engineering of bioprosthetic grafts has been achieved, and successful endothelialization of a graft with autologous endothelial cells transduced with a recombinant retrovirus encoding the beta-galactosidase gene has been reported [66]. This intervention still awaits successful clinical application. Gene and cell therapy for heart failure could be introduced at the time of surgery and may be an adjunct therapy for myocardial revascularization. The beta-adrenergic receptor is downregulated in the failing myocardium, and the transfer of the receptor gene into the ailing myocardium has been achieved in animal models with subsequently improved myocardial function [67]. The implantation of functional cardiomyocytes into the myocardium for therapeutic purposes is another attractive approach.

Bone marrow stromal cells may contain cardiac stem cells that can differentiate into adult cardiomyocytes [68]. These could potentially be harvested and cultured for clinical use.

Conclusions

This discussion is by no means complete, given the rapid advances in laboratory and molecular technology. Investigating complex genetic diseases such as CAD to potentially impact on the diagnosis and treatment of individual patients is surely becoming a reality. The tools for this type of genetic analysis are currently available: clinical information from large series, technology for genotyping and analytic methods to identify genes in individuals and families. Nevertheless, eliciting a family history of CAD is currently the only available screening tool to identify patients with a genetic predisposition for the disease. Despite the abundance of positive reports published to date, the association between SNPs and CAD has been inconsistent, with the exception of apoE polymorphism. As mentioned earlier, the risk of CAD attributable to genes appears to be most significant at younger ages, and this may explain the lack of definite markers for the disease. Candidate gene association studies focusing on young patients with CAD will, therefore, be more likely to identify a true genetic risk. As such, patients who are more susceptible to end organ damage because of a more virulent disease will be identified and more aggressively treated with risk factor modification and earlier surgical intervention. With this molecular armamentarium and the multidisciplinary approach to vascular disease, it is only a matter of time before genetic studies of CAD find clinical applications.

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35 Keavney B, McKenzie C, Parish S, Palmer A, Clark S, Youngman L, Delepine M, Lathrop M, Peto R, Collins R: Large scale test of hypothesized associations between the angiotensin converting enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. International Studies of Infarct Survival (ISIS) Collaborators. Lancet 2000;355:434–442. 36 Ludwig EH, Borecki IB, Ellison RC, Folsom AR, Heiss G, Higgins M, Lalouel JM, Province MA, Rao DC: Associations between candidate loci angiotensin-converting enzyme and angiotensinogen with coronary heart disease and myocardial infarction: The NHLBI Family Heart Study. Ann Epidemiol 1997;7:3–12. 37 Hooper WC, Lally C, Austin H, Benson J, Dilley A, Wenger NK, Whitsett C, Rawlins P, Evatt BL: The relationship between polymorphism in the endothelial cell nitric oxide synthase gene and the platelet GPIIIa gene with myocardial infarction and venous thromboembolism in African Americans. Chest 1999;116: 880–886. 38 Meleady R, Ueland PM, Blom H, Whitehead AS, Refsum H, Daly LE, Vollset SE, Donohue C, Giesendorf B, Graham IM, Ulvik A, Zhang Y, Bjorke Monsen AL, EC Concerted Action Project: Homocysteine and Vascular Disease: Thermolabile methylenetetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: The European Concerted Action Project. Am J Clin Nutr 2003;77:63–70. 39 Brattstrom L, Wilcken EL, Ohrvik J, Brudin L: Common methylene-tetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a metaanalysis. Circulation 1998;98:2520–2526. 40 Lane DA, Grant PJ: Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 2000;95:1517–1532. 41 Goodall AH, Curzen N, Panesar M, Hurd C, Knight CJ, Ouwehand WH, Fox KM: Increased binding of fibrinogen to glycoprotein IIIa-proline33 (HPA-1b, Pla2, Zwb) positive platelets in patients with cardiovascular disease. Eur Heart J 1999;20:742–747. 42 Humphries SE, Luong LA, Ogg MS, Hawe E, Miller GJ: The interleukin-6-174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. Eur Heart J 2001;22:2243– 2252. 43 Sim EK, Lee CN, Mestres CA, Lim LC, Adebo OA, Tan CT: Coronary artery bypass surgery in young patients. Aust NZ J Surg 1992;62:618– 621. 44 Choudhury L, Marsh JD: Myocardial infarction in young patients. Am J Med 1999;107: 254–261. 45 Nabel EG, Plautz G, Boyce FM, Stanley JC, Nabel GJ: Recombinant gene expression in vivo within endothelial cells of the arterial wall. Science 1989;244:1342–1344. 46 Colman A: Antisense strategies in cell and developmental biology. J Cell Sci 1990;97:399– 409.

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56 Grossman M, Raper SE, Kozarsky KF, Stein EA, Engelhardt JF, Muller D, Lupien PJ, Wilson JM: Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolemia. Nat Genet 1994;6:335–341. 57 Chowdhury JR, Grossman M, Gupta S, Chowdhury NR, Baker JR Jr, Wilson JM: Long term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits. Science 1991;254:1802–1805. 58 Stevenson SC, Marshall-Neff J, Teng B, Lee CB, Roy S, McClelland A: Phenotypic correction of hypercholesterolemia in apoE-deficient mice by adenovirus-mediated in vivo gene transfer. Arterioscler Thromb Vasc Biol 1995; 15:479–484. 59 Banai S, Jaklitsch MT, Shou M, Lazarous DF, Scheinowitz M, Biro S, Epstein SE, Unger EF: Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation 1994;89:2183–2189. 60 Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, Giordano FJ, Shah PK, Willerson JT, Benza RL, Berman DS, Gibson CM, Bajamonde A, Rundle AC, Fine J, McCluskey ER; VIVA Investigators: The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation 2003;107: 1359–1365. 61 Henry TD, Rocha-Singh K, Isner JM, Kereiakes DJ, Giordano FJ, Simons M, Losordo DW, Hendel RC, Bonow RO, Eppler SM, Zioncheck TF, Holmgren EB, McCluskey ER: Intracoronary administration of recombinant human vascular endothelial growth factor to patients with coronary artery disease. Am Heart J 2001;142:872–880.

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62 Kuntz RP: Restenosis gene therapy trial: Phase I study. NIH RAC online database. Bethesda, Office of Biotechnology Activities, National Institutes of Health, 2001. 63 Zuckerbraun BS, Tzeng E: Vascular gene therapy: A reality of the 21st century. Arch Surg 2002;137:854–861. 64 Mann MJ, Whittemore AD, Magruder CD, Belkin M, Conte MS, Polak JF, Orav EJ, Ehsan A, Dell’Acqua G, Dzau VJ: Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: The PREVENT single-centre, randomized, controlled trial. Lancet 1999;354:1493– 1498. 65 Kandzari DE, Kay J, O’Shea JC, Trichon BH, Donahue M, Liao L, Rao SV: Highlights from the American Heart Association annual scientific sessions 2001:November 11 to 14, 2001. Am Heart J 2002;143:217–228. 66 Wilson JM, Birinyi LK, Salomon RN, Libby P, Callow AD, Mulligan RC: Implantation of vascular grafts lined with genetically modified endothelial cells. Science 1989;244:1344–1346. 67 Maurice JP, Hata JA, Shah AS, White DC, McDonald PH, Dolber PC, Wilson KH, Lefkowitz RJ, Glower DD, Koch WJ: Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery. J Clin Invest 1999;104:21– 29. 68 Tomita S, Li RK, Weisel RD, Mickle DA, Kim EJ, Sakai T, Jia ZQ: Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 1999;100(suppl):II247–II-256.

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Cardiology 2004;101:131–143 DOI: 10.1159/000075994

Therapeutic Angiogenesis: A Biologic Bypass Imran S. Syed Timothy A. Sanborn Todd K. Rosengart Evanston Northwestern Healthcare, Evanston, Ill., Feinberg School of Medicine of Northwestern University, Chicago, Ill., USA

Key Words Gene therapy W Angiogenesis W Atherosclerosis W Coronary artery disease

Abstract The use of angiogenic factors to effect therapeutic angiogenesis may be an attractive treatment modality for a substantial number of patients who have diffuse coronary artery disease and who are not candidates for traditional revascularization procedures. Delivery of angiogenic factors as a protein or gene encoding for the respective protein product has been shown to induce angiogenesis in numerous animal models, and expression of a functioning product has been demonstrated. Various early clinical trials of therapeutic angiogenesis have shown reduction in anginal symptoms and increases in exercise time, as well as objective evidence of improved perfusion, left ventricular function and angiographic appearance following such angiogenic treatments. Copyright © 2004 S. Karger AG, Basel

Introduction

Coronary artery disease remains the leading cause of morbidity and mortality in the industrialized world. In 1990, it was responsible for 6.3 million deaths around the world. In patients with coronary artery disease and symp-

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toms refractory to medical treatment, percutaneous coronary intervention and coronary artery bypass surgery (CABG) improve long-term survival and provide relief from symptoms. However, bypass grafts suffer from progressive atherosclerotic occlusion, and the procedure is limited by a finite number of conduits available for subsequent revascularizations. Percutaneous coronary interventions are subject to relatively high rates of restenosis at the current time, although these outcomes can be expected to improve in the near future with advancements in the field. Moreover, a large number of individuals have an unfavorable occlusive pattern, diffuse coronary atherosclerosis, small distant vessels and comorbidities that may preclude the application of one or both of these treatments. This is consistent with these observations, a recent study found that approximately 12% of patients with symptomatic obstructive coronary artery disease with documented ischemia, who were referred for coronary angiograms, were not candidates for percutaneous coronary intervention or CABG [1]. It has been estimated that 6,750,000 Americans have angina pectoris, and that 350,000 more will develop new-onset angina each year. The implications of the above data are clear. A very large number of patients, possibly in the realm of 100,000–200,000 patients each year, could benefit from an alternative revascularization approach. Against this backdrop, the field of therapeutic angiogenesis has emerged as an attractive treatment strategy for patients with diffuse atherosclerotic disease who are otherwise not candidates for conventional revasculariza-

Todd K. Rosengart, MD 2650 Ridge Avenue, Burch 100 Evanston, IL 60201 (USA) Tel. +1 847 570 2868, Fax +1 847 570 2899 E-Mail [email protected]

tion procedures. Therapeutic angiogenesis can be defined as the delivery of angiogenic cytokines, either by direct injection of protein or by gene therapy, to cause neovascularization and promote the development of supplemental collateral blood vessels that will act as endogenous bypass conduits around occluded native arteries. In addition to various poudrage techniques, the first recorded attempt at surgical (mechanical) angiogenesis can be traced back to 1946, when one of the pioneers of cardiovascular surgery, Arthur Vineberg [2], recommended and first used implantation of the arteria mammaria interna into ischemic myocardium. The result after a few weeks was a network of capillary collaterals, visible angiographically, that developed between the implanted thoracic wall artery and the myocardium. A similar result was obtained when omental grafts were applied to the ischemic myocardium [3]. The Vineberg technique was fairly successful in alleviating anginal complaints [4–6], but fell into disfavor soon after the initiation of aortocoronary venous bypass. The theoretical foundation of modern angiogenesis was based on two important discoveries. The first, in 1971, was that of Folkman [7, 8] and his collaborators, who documented the dependence of tumor growth on neovascularization and attributed this process to the existence of a tumor angiogenesis factor that served to establish and maintain an essential vascular supply for tumors. These investigations succeeded in isolating this angiogenic factor from Walker tumor cells and demonstrated that it induced the growth of new capillaries in a dorsal air sac model in rats. Until then, tumor hypervascularity was thought to reflect inflammatory vasodilation of preexisting host vessels, a response to tumor metabolites and necrotic tumor products that was of no benefit to the tumor. Folkman’s work paved the way for the identification of several angiogenic molecules, including vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) that subsequently proved to have important biologic properties and significant therapeutic potentials. The second important development in the establishment of the modern era of therapeutic angiogenesis concerned the elucidation of the coronary collateral circulation. While the development of collateral vessels after coronary occlusion had been familiar to cardiologists for many years, the functional significance of this process had remained uncertain and a matter for debate. The coronary collateral circulation is a complex network of interconnecting vessels, most of which are !200 Ìm in diameter. Highly variable amongst individuals, this network develops from the recruitment and enlargement of existing vessels as well as the creation of new vessels. The main

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stimulants for collateral growth was understood to be ischemia, shear stresses on the arterial wall and inflammation included by gradually developing vascular stenosis [9]. More recently, several studies demonstrated the functional significance of these conduits [9–11]. In patients with myocardial infarcts, the presence of collateral circulation decreases the infarct size, decreases the likelihood of aneurysm formation, improves left ventricular function, decreases wall motion abnormalities and improves survival [10, 11]. In patients undergoing CABG, a well developed collateral circulation is associated with a reduced perioperative infarct rate and a reduced mortality [11]. In the context of these two discoveries – that neovascularization can be potentially induced by angiogenic growth factors, and that the presence of such neovascularization in the heart as evidenced by coronary collaterals has benefit – the field of angiogenesis emerged. In the past 20 years, successful therapeutic angiogenesis has been demonstrated in various animal models of peripheral and myocardial ischemia using a number of growth factors administered either as protein or by gene transfer. Proof of concept in humans was established in severely symptomatic patients with critical limb ischemia by the pioneering work of Isner et al. [12] at St. Elizabeth Hospital. Shortly thereafter, clinical trials were extended to severely symptomatic patients with coronary artery disease not amenable to revascularization. Successful preclinical studies and promising early results in clinical trials have created great excitement about the potential of therapeutic angiogenesis. However, many important questions remain to be addressed. For example, it is still unclear what will be the optimal angiogenic growth factor or combination of factors, method of delivery, route of administration and dosing schedule. It is still uncertain whether pathological angiogenesis be a problem. In addition, data from the few larger randomized double-blinded trials that have been conducted so far have not yet conclusively demonstrated the efficacy of therapeutic angiogenesis for myocardial ischemia, although these studies may be limited by flaws in the delivery strategies employed in these trials. Based on these considerations, the objectives of this article are to: (1) briefly review the biology of angiogenesis and those angiogenic factors that might have a therapeutic effect, (2) discuss the relative merits of various methods of delivery and routes of administration, (3) review experimental and clinical studies using angiogenic protein or gene therapy, and (4) discuss potential risks associated with angiogenesis and future directions of the field.

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Angiogenesis, Arteriogenesis and Vasculogenesis

When Leonardo da Vinci first speculated about the circulatory system, he suggested that the vasculature developed like a tree from a seed (the heart) by sprouting roots (the liver capillary meshwork) and a trunk with major branches (the aorta and arteries) [13]. Actually, three distinct processes may contribute to the growth of new blood vessels – angiogenesis, vasculogenesis and arteriogenesis [14–19]. Angiogenesis is defined as the process by which new capillaries develop from the extension of preexisting vasculature. Vasculogenesis, in contrast, is defined as the de novo formation of a primitive vascular network from differentiating precursor mesodermal cells (angioblasts or endothelial progenitor cells). While vasculogenesis had long been considered to be primarily an embryonic process, new evidence suggests that postnatal vasculogenesis occurs as well. Finally, arteriogenesis defines the process of collateral vessel enlargement caused by remodeling or growth of preexisting arteriolar collateral connections. Angiogenesis involves the migration and proliferation of previously differentiated endothelial cells residing within the parent vessel in response to such stimuli as hypoxia, mechanical shear stress and inflammation. In the embryo, angiogenesis is though to act as an important complement to vasculogenic development processes. In the adult, endothelial cells have an extremely low turnover, probably measurable over ‘thousands of days’, but a proliferative response to hypoxia, sheer stress or inflammation involving as few as !1 to 6% of vascular endothelial cells may induce substantially new blood vessel formation, or angiogenesis. Angiogenesis in the postnatal state is associated with certain physiological conditions such as ovulation, placental development and wound healing. Angiogenesis also occurs in such pathologic conditions as ischemia and inflammation, and in disease states such as vascular retinopathies, tumor growth, rheumatoid arthritis and psoriasis. As opposed to the angiogenic process, embryonic vasculogenesis involves the formation of multiple embryonic blood islands, with hematopoietic stem cells destined to form circulating blood cells situated in the center, and endothelial progenitor cells destined to give rise to the vessel itself situated in the periphery. Subsequent recruitment of other cell types completes the process of vessel formation. New evidence suggests that bone marrowderived endothelial progenitor cells in the peripheral blood of adult animals proliferate in response to tissue ischemia, localize to and become incorporated in sites of

Therapeutic Angiogenesis

neovascularization and thereby enhance vasculature development through vasculogenesis in the adult. Arteriogenesis, finally, is the vascular development process which gives rise to medium-sized arteries that are large enough to be visualized angiographically, and which possess a fully developed tunica media consisting of smooth muscle cells. Both flow-mediated maturation of collateral conduits and growth factor modulation are believed to be responsible for such remodeling. It is currently thought that the main stimulus for arteriogenesis is a change in shear stress within an occluded vessel and interconnecting arterioles caused by flow and pressure shifts associated with such an occlusion. Increased shear stress is known to induce various functional changes in vascular endothelium, inducing modification of cell-cell as well as cell-extracellular matrix (ECM) junctions and upregulating growth factors that can induce vascular remodeling. Although all three of the above-noted vascular development processes may be relevant to the therapeutic induction of neovascularization, the focus of recent clinical activities has been in the area of angiogenesis. It is thus important to understand the basics of the molecular biology of angiogenesis, accepting that vasculogenesis and arteriogenesis overlap these mechanisms only in part, and the elucidation of the biologic mechanisms underlying these pathways may ultimately also advance our clinical capabilities.

Cellular and Molecular Biology of Angiogenesis

Angiogenesis is a complex process that begins with the activation of endothelial cells by a local angiogenic stimulus, such as hypoxia, ischemia or inflammation. Two distinct mechanisms of angiogenesis have been described: sprouting and intussusception [13]. Intussusceptive angiogenesis is a process of splitting preexisting vessels by the insertion of interstitial cellular pillars into their lumen. Subsequent growth and stabilization of these pillars partitions the vessel and leads to remodeling of the local vasculature. Sprouting angiogenesis involves a number of steps that can be thought of as involving an initial phase and a stabilization phase. The initial phase begins with endothelial cell activation, which induces morphologic modifications of these cells and proceeds along the following steps: (1) proteolytic degradation of the basement membrane and the surrounding ECM by activated proteases, including collagenases and plasminogen activator, produced by the endothelial cells; (2) migration, proliferation and sprouting of endothelial cells induced by chemotactic fac-

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tors and mitogens produced by a variety of cells, and (3) lumen formation within the endothelial sprout. The stabilization phase is associated with the reestablishment of the quiescent endothelial cell phenotype and consists of (1) cessation of endothelial cell proliferation, (2) reestablishment of endothelial cell-cell contact and migration of pericytes so that they invest and cover the neocapillary, and (3) production by endothelial cells and pericytes of a basement membrane around the neocapillary. A large number of molecules have been shown to play a role at different times in the angiogenic sequence [18–20]. Whereas angiogenic growth factors, such as VEGF and the FGFs, act as stimulators of the process and are essential for the growth phase of angiogenesis, other growth factors and cofactors, such as transforming growth factorbeta, platelet-derived growth factor-beta, angiopoietin-1 and their respective receptors, are essential for the stabilization of angiogenesis. Additional positive and negative modulators of angiogenesis effect this process through a variety of amplification loops which affect levels of expression of growth factors and their receptors, and through interactions with the ECM that modulate the effectiveness of activated angiogenic molecules. These complex actions have lead to the concept of the ‘angiogenic balance’, by which the expression and activity of angiogenic or angiostatic factors control endothelial cell quiescence or activate angiogenesis.

Vascular Endothelial Growth Factor

While Folkman [7, 8] proposed the existence of a tumor angiogenesis factor as early as 1971, it was in 1983 that Senger et al. [21] first reported the existence of a tumor-secreted protein that enhanced vascular permeability, which they named vascular permeability factor. In 1989, Ferrara and Henzel [22] and Ploüet et al. [23] independently reported isolating and sequencing a 45-kD protein that was mitogenic for cultured endothelial cells, and which they named ‘vascular endothelial growth factor’ (VEGF). This molecule was later shown to be identical to vascular permeability factor. VEGF is actually the prototypical member of a family of structurally and functionally related glycoproteins, of which VEGF (VEGF-1, or VEGF-A) has been the subject of most interest in angiogenesis trials [21–30]. The other family members include VEGF-B (or VEGF-3), VEGF-C (or VEGF-2), VEGF-D, VEGF-E and placental growth factor. All further references in this review will be to VEGF-1 (VEGF).

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Alternative splicing of the VEGF gene results in the generation of 5 isoforms of VEGF with 121, 145, 165, 189 or 206 amino acids (VEGF121, VEGF145, VEGF165, VEGF189 and VEGF206). VEGF165 is the predominant molecular species, whereas VEGF206 is a very rare form. VEGF121 and VEGF189 are detected in the majority of tissues expressing the VEGF gene. The isoforms differ with respect to permeability and heparin-binding capacity. For example, VEGF121 does not bind heparin and is freely diffusible. In contrast, VEGF189 and VEGF206 bind heparin avidly, and for this reason are almost completely sequestered in the ECM. The ECM-bound VEGF isoforms can be released as a soluble and bioactive form by heparinase and plasmin, among other factors, and may represent an important store of VEGF. Importantly, however, VEGF121, VEGF165 and VEGF189 have all been shown to possess similar angiogenic potency, but the expression of genomic VEGF has been shown to be more potent than the administration of single isoforms. As opposed to other angiogenic growth factors, all VEGF isoforms contain a secretory signal sequence that permits their active secretion from intact cells. This is important because the potency of VEGF is in large part due to paracrine and autocrine effects. When activated under hypoxic conditions, the autocrine loop serves to amplify and protract the response in endothelial cells stimulated by exogenously administered VEGF. In addition, the localization of the high-affinity VEGF receptors only to endothelial cells results in fidelity of the VEGF response to this cell type, as opposed to the activity of FGF, which is mitogenic for fibroblasts and vascular smooth muscle cells in addition to endothelial cells. VEGF is secreted from a variety of cell types, and its production is upregulated in ischemic tissues. Hypoxia appears to regulate VEGF protein expression at both the transcriptional and posttranscriptional level [31–34]. At the transcriptional level, hypoxia stimulates VEGF and VEGF receptor protein expression by inhibiting the destruction of the otherwise labile protein, hypoxia-inducible factor-alpha, thus allowing it to bind to a 28-base pair hypoxia response element in the 5) promoter region of the VEGF gene and thereby activate its expression. Hypoxiainduced stabilization of the messenger RNA encoding VEGF via a sequence in its 3)-untranslated region underlies the intrinsically short half-life of VEGF messenger RNA and, additionally, the increase in VEGF activity in hypoxic conditions. The biological activities of VEGF are mediated by two high-affinity transmembrane tyrosine receptor tyrosine kinases termed VEGFR-1 (flt-1) and VEGFR-2 (flk-1/

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KDR) that are localized to endothelial cells and their embryonic precursors (angioblasts), hence accounting for the specificity of the VEGF response to endothelial cells alone [35, 36]. The expression of VEGF receptors is also upregulated by hypoxia. Though VEGFR-1 is a higheraffinity receptor for VEGF, VEGFR-2 is thought to be the dominant mediator of angiogenesis. VEGFR-2 is a common receptor for VEGF-1 and VEGF-2 and is responsible for transduction signals required for vasculogenesis and angiogenesis. Although it has been suggested that VEGFR-1 may be a ‘decoy’ receptor, able to regulate the activity of VEGF in a negative fashion by sequestering it and making it less available to VEGFR-2, other more recent studies now suggest that VEGFR-1 generates signals that organize the assembly of endothelial cells into functional tubes and vessels [17]. VEGFR-3 principally mediates lymphangiogenesis. More recently, the existence of two new receptors, neuropilin-1 and neuropilin-2, has been demonstrated, which selectively bind VEGF165 (in the case of neuropilin-2, also VEGF145) but not VEGF121. The neuropilins are thought to enhance the binding of VEGF165 to VEGFR-2 and improve the resulting signal transduction. This may explain the somewhat greater mitogenic potency of VEGF165 compared with VEGF121. Aside from VEGF inducing the proliferation and migration of endothelial cells, it also inhibits apoptosis in endothelial cells by inducing expression of the antiapoptotic genes bcl-2 and A1, and VEGF is thus believed to play a role in vascular stabilization [37]. VEGF has also recently been shown to increase the number of circulating endothelial progenitor cells and regulate differentiation of the hemangioblast into an endothelial cell lineage, thereby helping to induce vasculogenesis as well as angiogenesis [38]. At concentrations much higher than those required to induce angiogenesis, VEGF also enhances vascular permeability, in part by inducing fenestrations in endothelial cells, and it also induces vasodilation, primarily via endothelial cell-derived nitric oxide [39]. The importance of VEGF in angiogenesis and vasculogenesis has been highlighted in studies of VEGF knockout mice, where inactivation of even a single VEGF allele (i.e. heterozygous genotype) resulted in abnormal vascular development and in embryonic lethality by early gestation [40, 41]. Equally importantly, models of experimental vascular occlusion and evidence of upregulated endogenous VEGF expression in the setting of tissue ischemia and growth, as well as the potency of administering exogenous VEGF or VEGF antagonists, highlight the importance of VEGF in postnatal vascular development and stabilization.

Therapeutic Angiogenesis

FGF and Its Receptors

The FGF family of angiogenic growth factors includes at least nine polypeptides, of which acidic FGF (aFGF or FGF-1) and basic FGF (bFGF or FGF-2) are the most extensively characterized members [42]. The other seven members of the FGF family are designated FGF-3 to FGF-9. The FGFs exhibit a high degree of protein homology; all bind to heparin avidly; all have a high affinity for heparan sulfate proteoglycans, and all require heparan sulfate to enhance binding to one of their four high-affinity cell surface tyrosine kinase receptors (FGFR-1, FGFR-2, FGFR-3, FGFR-4). This binding explains the rapid extraction of injected FGF from the circulation, particularly in the lungs, and its localization on cells and in the ECM. The concentration of FGF available to cellbound receptors may also vary depending upon the production of secreted FGF receptors. Both aFGF and bFGF have been shown to be mitogenic for endothelial cells and to induce angiogenesis in vitro and in vivo. Like VEGF, the FGFs also induce endothelial cell synthesis of proteases such as plasminogen activator and metalloproteinases, which digest ECM, an important step in the process of angiogenesis. In addition to their isolated angiogenic potential, bFGF and VEGF acting in concert have been shown to have a potent synergistic effect on the induction of angiogenesis in vitro and in vivo [43]. Also, like VEGF, acidic FGF and basic FGF are produced by a variety of cells, but differ from VEGF in two important aspects. As noted above, FGF is not specifically mitogenic for endothelial cells, having receptors on many other cells, including fibroblasts and vascular smooth muscle cells. Secondly, both aFGF and bFGF lack a classical secretory signal sequence and are consequently nonsecreted growth proteins. In this regard, it has been shown that heat shock induces aFGF release in vitro, and it is thought that cell death or damage results in extracellular release of FGF in vivo [44]. Clinical trials of FGF gene transfer have, however, commonly utilized either modification of the FGF gene, or use of another member of the FGF family with a signal sequence because of this lack of a secretory signal sequence [45–47].

Angiogenic Delivery Strategies

Angiogenic factors may be administered as recombinant proteins or as the genes encoding these proteins [48– 51]. Data from clinical studies suggest that both protein

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and gene delivery approaches are generally safe and well tolerated, but that local tissue delivery of either proteins or genes yields a superior safety and efficacy profile. As opposed to the standard pharmacologic considerations relevant to angiogenic protein administration, gene transfer makes use of either viral or nonviral vectors to introduce genes into target cells, with the aim of achieving high levels of sustained transgene expression [52, 53]. The most commonly used viral delivery system in cardiovascular gene therapy is the adenoviral vector, which has been deleted of the sequences necessary for viral replication (E1 and E3), thus rendering it ‘replication incompetent’, while nonviral gene transfer vectors involve the use of DNA alone, most commonly in the form of a plasmid, or complexed with liposomes. Nonviral gene transfer, such as that provided by a plasmid, is relatively inefficient compared with viral vector systems, but the administration of relatively large quantities of plasmid appears sufficient to overcome this inefficiency and induce angiogenesis. The duration of transgene expression varies according to the method of gene delivery. Plasmid DNA and firstgeneration adenoviral vectors mediate a fairly short duration of expression, whereas other viral vectors such as adeno-associated and lentiviral vectors, which result in the incorporation of the transfected DNA into the host cell chromosome, can result in a rather long duration of expression. The ideal therapeutic angiogenic gene transfer regimen has yet to be delineated, but excessively prolonged angiogenic therapy has been shown to induce hemangioma formation. The primary theoretical disadvantage of gene therapy compared to a protein-based strategy is that of vectorinduced cytotoxicity. Concerns about a deleterious inflammatory response inducing cell loss remain controversial, and have not yet been substantiated in human clinical trials of angiogenesis, although the recently reported death of a patient receiving a relatively high dose of a recombinant adenovirus vector to the liver may have been attributable to systemic immunogenicity. Newer generations of adenoviral vectors have additional sequence deletions (E4) that may limit potential vector toxicity by reducing the production of viral proteins and consequent inflammatory responses. Because the immune response is probably partly responsible for limiting the duration of transgene expression, however, these vectors may yield longer durations of transgene expression and protein production, which may consequently give rise to safety concerns associated with prolonged angiogenic stimulation. As noted above, a variety of delivery methods have been employed to induce therapeutic angiogenesis. These

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include intravenous, selective intracoronary, intramyocardial (transendocardial and transepicardial) and intrapericardial approaches. The ideal delivery strategy would provide high local concentrations of angiogenic factor(s), specifically target ischemic myocardium, yield adequate exposure time, minimize systemic exposure, be minimally invasive and allow readministration. Each of the delivery strategies noted above has distinct advantages and disadvantages, and it is currently unknown which is the safest and most effective delivery strategy to induce a clinically important therapeutic response in ischemic myocardium. Thus far, clinical trials have suggested the potential benefit of selective intracoronary or intramyocardial routes compared to systemic delivery, likely on the basis of standard pharmacokinetic principles [48–54]. More specifically, intravenous delivery is clearly the most practical and simple route; however, such a systemic approach results in a relatively low efficiency of myocardial uptake. Intravenous bFGF has been shown to be ineffective in inducing an angiogenic response in a canine model of myocardial ischemia, in contrast to the efficacy of the intracoronary approach in the same model [55–57]. This is believed to be due to ‘first-pass’ uptake in the lungs, where bFGF binds to low-affinity receptors (containing heparan sulfates), resulting in a marked lowering of the peak concentration delivered to the myocardium. Intravenous VEGF has similarly been shown to be ineffective in yielding a therapeutic angiogenic response in a porcine model of hibernating myocardium, although intramyocardial administration of VEGF in the same model was effective [58, 59]. Intracoronary administration of FGF-5 and FGF-4 via an adenoviral vector has likewise been shown to increase myocardial perfusion, with approximately 95% first-pass myocardial uptake of the viral vector being reported [46]. Consistent with these findings, Lazarous et al. [57] evaluated differential regional uptake of [165I]-labeled bFGF after bolus intravenous, left atrial, intracoronary or pericardial delivery in a canine model and demonstrated that 0.5, 1.3, 3–5 and 19%, respectively, of the bFGF dose was recovered from the hearts of these dogs. Compared to intravascular delivery of angiogenic agents, intrapericardial delivery offers the theoretical advantage of providing prolonged exposure of myocardial tissue to the administered agent from a pericardial ‘reservoir’, and high myocardial uptake has also been demonstrated with this approach [57]. Animal studies have, however, yielded conflicting results in regard to the efficacy of this approach. Ultimately, direct intramyocardial injection of angiogenic growth factors or genes possesses

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the advantage of delivering the angiogenic material directly into the target tissue, which appears to increase concentrations of the angiogenic agent at the treatment site, and thereby minimizes potential side effects. The appeal of this mode of delivery also includes the possibility of selectively targeting desired (i.e. ischemic) areas of the heart, a higher efficiency of delivery and prolonged tissue retention. Of the two means of intramyocardial delivery described, transepicardial delivery requires the use of either a thoracotomy or thoracoscopy. Catheter-based transendocardial injection of angiogenic factors directly into the myocardium may provide benefit equivalent to that of the transepicardial approach without the risks of surgery. In order to improve localization of angiogenic delivery, endocardial delivery can be integrated with left ventricular electromechanical mapping to allow delivery into ischemic zones or may simply require fluoroscopic guidance to enhance anatomic localization.

Experimental Studies in Animals

with the known effects of these factors in the natural biology of angiogenic pathways. These findings may be particularly relevant in that patients with advanced ischemic heart disease are usually older and often have diabetes, hypercholesterolemia or other as yet undetermined characteristics that may likewise limit their ability to upregulate angiogenic cytokine expression in response to tissue ischemia. Endothelial cell dysfunction as is seen with advanced age or as an accompaniment of various coronary risk factors may further obtund the responsiveness of endothelium to hypoxic stimuli or angiogenic growth factors, and may constitute a potentially limiting factor in strategies designed to promote angiogenesis in ischemic tissues. Complementary strategies to increase the production of relevant angiogenic agents or the availability of endothelial progenitor cells would hence be a potentially advantageous therapeutic strategy, supplemental to the initial clinical efforts described below.

Clinical Angiogenesis Trials for Advanced Coronary Artery Disease

Therapeutic angiogenesis has been accomplished utilizing a variety of delivery routes to administer angiogenic proteins on gene vectors in several different animal models of coronary ischemia, as well as peripheral ischemia. The effectiveness of these strategies has been documented by angiography, myocardial perfusion studies, measurement of left ventricular function at rest or during stress and histologic assessment of the number and size of arterioles or capillaries. Most studies of FGF efficacy have involved the administration of aFGF or bFGF protein, but several studies have also evaluated the efficacy of FGF gene transfer. Animal studies have also been performed utilizing the delivery of proteins on genes encoding for VEGF165, VEGF121 and VEGF-2. Although concern has been expressed over potential myocardial inflammation/myocarditis with the use of an adenovirus vector, such an effect has generally not been seen, especially with the use of more purified viral preparations. In contrast, side effects that have been associated with the systemic delivery of angiogenic proteins have included hypotension, renal toxicity and bone marrow depression. A clinically relevant increase in neovascularization in animal studies has been demonstrated by almost all of the assays listed above. Interestingly, old age, diabetes and hypercholesterolemia have been shown to limit the effectiveness of administered angiogenic agents, consistent

Successful preclinical studies in animals paved the way for the first human studies exploring therapeutic angiogenesis. Proof of concept in humans was established in severely symptomatic patients with critical limb ischemia [12], following which investigations have explained the use of therapeutic angiogenic strategies in patients with coronary artery disease. Patients in these trials have typically been included on the basis of advanced coronary artery disease for which conventional CABG or percutaneous coronary interventions have been unsuccessful or contraindicated (tables 1, 2). The results of these studies need to be interpreted with caution, since most were small Phase 1 trials, lacking control groups and designed primarily to establish safety and describe optimal doses. Nevertheless, the results of these studies have been encouraging in terms of efficacy, and especially in terms of safety. The first reported clinical study of angiogenic therapy for the treatment of coronary artery disease was a randomized trial of 40 patients involving the intramyocardial administration of recombinant FGF-1 protein into the distal anterior wall as an adjunct to coronary bypass surgery [60]. The 20 patients randomized to FGF demonstrated evidence of increased neovascularization in the treated territory on digital angiography compared to control (bypass only) patients. At the 3-year follow-up, the FGF group of patients continued to demonstrate improved functional

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Table 1. Clinical trials using recombinant proteins for myocardial angiogenesis Report

Type of trial

Protein

Route

Treated/ controls

Outcomes

Schumacher et al. [60] (1998) and Stegmann et al. [61] (2000)

phase 1

FGF-1 + heparin + fibrin glue

intramyocardial during CABG

20/20

decreased angina decreased use of antianginals increased flow (digital scale) angiographic improvement

Sellke et al. [62] (1998)

phase I

FGF-2 + heparin alginate

periadventitial during CABG

8/0

all patients free of angina after surgery variable changes on stress perfusion scans 1 perioperative myocardial infarction

Laham et al. [63] (1999)

phase I

FGF-2 + heparin alginate

periadventitial during CABG

16/8

2 operative deaths; 3 myocardial infarctions decreased angina in high-dose (100-Ìg) group reduced defect size on stress perfusion scans in high-dose group reduction in ischemic area on MRI

Stegmann et al. [75] (2000)

phase I

FGF-1 + heparin + fibrin glue

intramyocardial at thoracotomy

20/0

reduction of angina compared to baseline increased exercise time compared to baseline perfusion improved on SPECT compared to baseline

Unger et al. [76] (2000)

phase I

FGF-2

intracoronary

17/8

short-term dilation of epicardial arteries no change in exercise time hypotension, bradycardia, transient mild thrombocytopenia and proteinuria

Udelson et al. [77] (2000) and Laham et al. [78] (2000)

phase I

FGF-2

intracoronary (52 patients) or intravenous (14 patients)

66/0

decreased angina/improved quality of life increased exercise time improved LV function improved nuclear perfusion scans reduction in ischemic area on MRI

Hendel et al. [70] (2000) and Henry et al. [71] (2001)

phase I

VEGF165

intracoronary

15/0

decreased angina in 13 of 15 patients improvement in rest and stress nuclear perfusion defects in high-dose group

Henry and Abraham [79] (2000)

phase I

VEGF165

intravenous

28/0

improvement on 40% of rest and 20% of stress nuclear perfusion scans

Henry et al. [80, 81] (1999 and 2000)

phase II (VIVA multicenter study)

VEGF165

intracoronary for 20 min and intra-venous for 4 h on days 3, 6 and 9

115/63

at 60 days: similar decrease in anginal grade and quality of life and increase in exercise time as placebo; no change on nuclear perfusion scans or angiography at 120 days: decreased anginal grade with high dose; trend towards increased exercise time but not significant at 1 year: trend towards increased exercise time; placebo group: 3 cases of cancer and 1 of retinopathy

Simons et al. [72] (2002)

phase II FGF-2 (FIRST multicenter study)

intracoronary

251/86

at 90 days: no significant difference in exercise times; no significant changes in nuclear perfusion scans; trend towards decreased anginal symptoms in treatment groups compared to placebo at 180 days: no significant difference in any parameter

LV = Left ventricular.

class, reduction in nitrate consumption and an increase in left ventricular ejection fraction compared to controls [61]. Several other studies utilizing intramyocardial FGF-2 administration of recombinant protein with fibrin

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glue at the time of bypass surgery have yielded similar results, including improvements in anginal symptoms, exercise time and/or nuclear perfusion scans in the treated groups compared to baseline or controls [62, 63].

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Table 2. Clinical trials using gene therapy for myocardial angiogenesis Report

Type of trial

Gene

Route

Treated/ controls

Outcomes

Losordo et al. [82] (1998) Symes et al. [64] (1999)

phase I

phVEGF165

intramyocardial via minithoracotomy

30/0

60 days: improved rest and stress nuclear perfusion scans; increased function on EMM 1 year: reduced angina; decreased use of antianginals; increased exercise time and exercise time to angina; 2 late deaths, 1 cardiac transplant

Rosengart et al. [67] (1999)

phase I

Ad.VEGF121

intramyocardial during CABG/ minithoracotomy

21/0

30 days: decreased angina in all patients; increase in exercise time in patients receiving gene therapy alone without CABG); improved Rentrop collateral scores; improved function on 99mTc-sestamibi scans; no change in blood flow on perfusion scans; 2 perioperative deaths, 1 late death 6 months: improvement in angina, use of antianginals and exercise time in patients with gene therapy alone

Rosengart et al. [68] (1999)

phase I

Ad.VEGF121

intramyocardial at thoracotomy/ thoracoscopy

10/4

outcomes not reported

Vale et al. [65] (2000)

phase I

phVEGF-2

intramyocardial at thoracotomy

30/0

90 days: reduced angina; decreased use of antianginals; increased exercise time; improved nuclear perfusion scans; improved function on EMM; 1 perioperative death

Vale et al. [83] (2001)

phase I

phVEGF-2

intramyocardial via EMM catheter

6

Losordo et al. [69] (2002)

phase 1/2

phVEGF-2

intramyocardial via EMM catheter

12/7

significantly reduced angina compared to controls nonsignificant improvement in exercise time positive trends towards decrease in ischemic area on nuclear perfusion scans positive trends in function on EMM

Grines et al. [73] (2002)

phase 1/2 (AGENT)

Ad.FGF-4

intracoronary

60/19

nonsignificant increase in exercise time compared with placebo at 4 weeks (1.3 vs. 0.6 min) and 12 weeks (1.6 vs. 0.9 min) patients with low neutralizing titers had significantly better response than those with high titers no effect on time to angina no difference in stress echocardiograms 2 patients had transient liver enzyme elevations administration of adenoviral vector appeared safe

60 days: reduced angina; decreased use of antianginals 90 days: reduced angina and use of antianginals; improved nuclear perfusion scans; improved function on EMM

EMM = Electromechanical mapping; Ad. = adenovirus.

The first report of direct myocardial gene transfer as sole therapy for patients with refractory angina was that by the late Jeffrey Isner and the St. Elizabeth group [64] describing a Phase 1, dose-escalating, 30-patient study in which naked plasmid DNA encoding VEGF was injected directly into ischemic myocardium via a minithoracotomy. Dramatic improvements in sublingual nitrate use and exercise time were seen at 90 days. At the 1-year followup, sublingual nitrate use had fallen from 60/week to 3/

week, accompanied by a reduction in anginal episodes from 56/week to 4/week. Exercise time had increased by 98 s, and exercise time to angina had increased by 2.5 min over baseline. At 60 days, improvements in rest and stress perfusion were documented in 22 of 29 patients on SPECT-sestamibi perfusion scans. This observation of improvement in rest as well as stress images was supported by the findings of left ventricular electromechanical mapping, utilized in the final 13 patients. Foci of elec-

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tromechanical coupling (reduced fractional wall shortening with preserved viability) identified preoperatively had improved significantly at 60 days. A multicenter clinical trial of VEGF-2 plasmid DNA in 30 patients with severe coronary artery disease and refractory angina also reported favorable results [65, 66]. Patients received direct myocardial injection of phVEGF-2 via thoracotomy as the sole therapeutic intervention. At 12 months, the mean number of angina episodes and nitroglycerin consumption had decreased significantly, and improvements in nuclear perfusion and electromechanical mapping were also reported. The use of an adenovirus vector to transfer angiogenic genes for the treatment of coronary artery disease has also been reported. In studies utilizing the direct myocardial administration of an adenovirus expressing VEGF as an adjunct to conventional CABG (n = 15) or as sole therapy (n = 6) via a minithoracotomy, Rosengart et al. [67, 68] reported no evidence of systemic or cardiac-related adverse effects related to adenoviral vector administration. Patients in the sole-therapy study (as well as the CABG study) reported a marked reduction in the frequency and severity of angina, and an improvement in angiographic appearance, stress-induced nuclear perfusion and wall motion was noted in the area of vector administration 30 days after therapy. More, recently, the results of a phase 1/2 placebo-controlled, double-blind, dose-escalating trial of catheterbased plasmid VEGF-2 transfer were reported, addressing the study design limitations of these phase 1 studies [69]. The primary efficacy end point of this VEGF-2 study was Canadian Cardiovascular Society (CCS) anginal class status. At 12 weeks, there was a statistically significant improvement in CCS anginal class in phVEGF-2-treated patients compared to placebo-treated patients. Changes in exercise duration (91.8 versus 3.9 s) and Seattle Angina Questionnaire data also showed favorable improvements with phVEGF-2 versus placebo, although these were not found to be significant. Further a phase 2 multi-centered and randomized trial comparing optimized medical therapy to ‘sole’ angiogenic therapy with adenoviral mediated transfer of VEGF121 delivered via a mini-thoracotomy demonstrated significant improvement in time to 1 mm ST depression during exercise tolerance testing 3 and 6 months after angiogenic therapy compared to medical group controls [69a]. These trials of intramyocardial delivery have thus demonstrated some evidence of efficacy, but are confounded by the performance of concomitant coronary bypass surgery. Although most have included objective

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study end points, the absence of placebo controls are a second major limitation of these studies. Clinical trials utilizing intravenous and intracoronary growth factor administration, which typically have included placebo controls, have generally demonstrated less impressive improvements in angina, exercise time and myocardial function and perfusion, and a greater incidence of side effects compared to the intramyocardial studies. Side effects likely related to the use of systemic distribution of growth factor in these studies have included hypotension, bradycardia, transient mild thrombocytopenia and proteinuria. It is as yet unclear whether differences between the intramyocardial and the systemic therapy groups are related to the impact of the pharmacokinetics of these two delivery strategies described above, or the lack or presence of appropriate placebo controls, respectively. More specifically, the Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis (VIVA) study was the first and only prospective, randomized, placebo-controlled study to evaluate the efficacy of VEGF in coronary disease [70, 71]. A total of 178 patients enrolled at 20 US centers received 20-min intracoronary infusions of escalating doses of VEGF165 protein or placebo followed by 4-hour intravenous infusions on days 3, 6 and 9. Treatment was limited by hypotension, which developed at higher doses, and no significant differences in treadmill exercise times or angina scores were noted at 60 days in these studies, although the highest-dose group demonstrated a significant reduction in angina grade compared to the placebo group 120 days after treatment. Angiographic and SPECT-sestamibi scans also failed to show significant changes in any group at up to 1 year of followup. Interestingly, despite the exclusion of patients with evidence of malignancy, cancer was diagnosed in 3 placebo patients within the 120-day follow-up period. One placebo patient also experienced a worsening of retinopathy. The FGF Initiating RevaScularization Trial (FIRST) was a multicenter, randomized, double-blind, placebocontrolled trial of a single 20-min intracoronary infusion of recombinant FGF-2 at escalating doses or placebo in 337 enrollees [72]. FGF-treated subjects did not differ significantly from placebo controls with respect to the primary end point of exercise time (65 vs. 45 s, p = 0.64), or with respect to rest or stress nuclear perfusion. Angina frequency as measured by the Seattle Angina Questionnaire was reduced in the FGF-2 infusion group at 90 days, but this difference was no longer apparent at 180 days. A retrospective analysis of these data showed that FGF treatment resulted in a significant improvement in exercise

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time only in patients older than 63 years of age (80 vs. 40 s, p = 0.03). The Angiogenic GENe Therapy (AGENT) study was the first double-blind, placebo-controlled trial of gene therapy for myocardial angiogenesis, but this study used intracoronary administration of adenovirus [73]. Patients in this study were randomized to receive a single infusion of either one of five ascending doses of an adenovirus vector expressing FGF-4 or placebo. Nonsignificant increases in exercise treadmill time with FGF-4 treatment compared with placebo were observed at 4 and 12 weeks, with subgroup analysis demonstrating exercise improvement only in patients with baseline exercise performance of ^10 min. As noted above, additional studies using catheter delivery techniques to allow more studies with appropriate controls for intramyocardial delivery should help resolve the questions raised by these initial studies regarding the optimal means of providing angiogenic therapy.

evidence of new retinopathy or changes in acuity at up to 4 years of follow-up [74]. Finally, clinical studies have also failed to show any evidence of angiogenic cytokines contributing to accelerated atherosclerosis, although documentation of this complication would probably not be obvious. Therapeutic angiogenesis also entails risks specific to the activity profiles of specific growth factors. As noted above, hypotension has been described with intravenous and intracoronary administration of both FGF and VEGF, but hypotension does not appear to occur after localized angiogenic therapy. The administration of FGF has also been associated with proteinuria, anemia and thrombocytopenia, and VEGF has been shown to cause transient peripheral edema in patients with critical limb ischemia due to its ability to enhance vascular permeability. Essentially, all of these side effects have, however, been shown to be mild and transient.

Conclusions Potential Risks and Clinical Safety Concerns with Angiogenic Therapy

Although clinical studies to date have yielded limited evidence of toxicity associated with angiogenic therapy, several potential concerns still exist in this regard. As previously noted, angiogenesis is believed to play a role in several diseases, including tumor growth, proliferative or hemorrhagic retinopathy, rheumatoid pannus formation and progression of atherosclerosis or plaque destabilization resulting from neovascularization of atherosclerotic plaques. Pathologic angiogenesis induced by the administration of growth factors is thus a relevant safety concern despite encouraging initial clinical data. Based on the above considerations, patients with a history of cancer have been excluded from angiogenic therapy trials. Although new neoplasms have been seen in the clinical angiogenesis clinical trials reported to date, an increased risk in treated compared to placebo patients has not been seen. Longer-term follow-up data are of course essential to resolve this matter. Most Phase 1 and Phase 2 trials have also included formal ophthalmological examinations as part of their protocol, and demonstration of new retinopathy in patients receiving angiogenic growth factors has likewise not been seen. At St. Elizabeth’s Medical Center, more than 100 patients (one third with diabetes or remote retinopathy) receiving VEGF-1 or VEGF-2 underwent serial funduscopic examination before and after gene transfer, with no

The use of angiogenic factors to effect therapeutic angiogenesis is an attractive treatment modality for a substantial number of patients who have diffuse coronary artery disease and who are not candidates for traditional revascularization procedures. Over the past decade, substantial progress has been made in this field. In animal models of ischemia, proof of principle showing that protein or gene delivery results in expression of a functioning product has been demonstrated. Clinical trials of therapeutic angiogenesis have shown reduction in anginal symptoms and increases in exercise time, as well as objective evidence of improved perfusion, left ventricular function and angiographic appearance. Recently, the safety and efficacy of targeted catheter-mediated myocardial gene therapy have been reported, which may have important implications for the widespread applicability of this technique. As noted above, the results of the small, nonrandomized early studies reported to date must, however, be interpreted with caution. The negative primary end point results of larger trials like the VIVA, FIRST and AGENT studies underscore this concern, despite the possibility that adverse pharmacokinetics have handicapped these studies. Despite encouraging early results, there thus remain many questions and considerations that need to be addressed before therapeutic angiogenesis becomes a new option for the treatment of ischemic heart disease. These issues include selection of optimal doses and ideal delivery strategies and angiogenic factor or combinations of

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factors in inducing the formation of new blood vessels, elucidation of the stability of newly formed vessels and development of appropriate definitions of efficacy. It nevertheless appears that myocardial therapeutic angiogenesis has great potential for the treatment of refractory angina and advanced coronary artery disease,

and may provide a ‘natural bypass’ in such patients who are otherwise not candidates for either surgical revascularization or angioplasty. Future clinical studies will determine the efficacy of this new novel therapy for the treatment of the ischemic heart.

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Therapeutic Angiogenesis

thelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart. J Thorac Cardiovasc Surg 1998; 115;168–177. 60 Schumacher B, Pecher P, von Specht B, et al: Induction of neoangiogenesis in ischemic myocardium by human growth factors. Circulation 1998;97:645–650. 61 Stegmann TJ, Hoppert T, Schlurmann W, et al: First angiogenic treatment of coronary artery disease by FGF-1: Long term results after 3 years. Card Vasc Regen 2000;1:5–10. 62 Sellke FW, Laham RJ, Edelman ER, et al: Therapeutic angiogenesis with basic fibroblast growth factor: Technique and early results. Ann Thorac Surg 1998;65:1540–1544. 63 Laham RJ, Sellke FW, Edelman ER, et al: Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: Results of a phase I randomized double-blind, placebo controlled trial. Circulation 1999;100:1865–1871. 64 Symes JF, Losordo DW, Vale PR, et al: Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Ann Thorac Surg 1999;68:830–836. 65 Vale PR, Milliken CE, Fortuin FD, et al: Effective gene transfer of phVEGF-2 for therapeutic angiogenesis in chronic myocardial ischemia as assessed by NOGA left ventricular electromechanical mapping. Circulation 2000;102:II689. 66 Hendel RC, Vale PR, Losordo DW, et al: The effects of VEGF-2 gene therapy on rest and stress myocardial perfusion: Results of serial SPECT imaging. Circulation 2000;102:II-769. 67 Rosengart TK, Lee LY, Patel SR, Sanborn TA, Parikh M, Bergmann GW, Hachamovitch R, Szulc M, Kligfield PD, Okin PM, Hahn RT, Devereux RB, Post MR, Hackett NR, Foster T, Grasso TM, Lesser ML, Isom OW, Crystal RG: Angiogenesis gene therapy: Phase I assessment of direct intramyocardial administration of an adenovirus vector expressing the VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation 1999;100:468–474. 68 Rosengart TK, Lee LY, Patel SR, Kligfield PD, Okin PM, Hackett NR, Isom OW, Crystal RG: Six-month assessment of a phase I trial of angiogenic gene therapy for the treatment of coronary artery disease using direct intramyocardial administration of an adenovirus vector expressing the VEGF121 cDNA. Ann Surg 1999;230:466–472. 69 Losordo DW, Vale PR, Hendel RC, et al: Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation 2002;105:2012–2018. 69a Stewart DJ, et al: A phase 2, randomized, multi-center, 26-week study to assess the efficacy and safety of BIOBYPASS (Adgv VEGF121.10) delivered through minimally invasive surgery versus maximum medical treatment in patients with severe angina, advanced coronary artery disease, and no options for revascularization. Circulation 2000;106:1.

70 Hendel RC, Henry TD, Rocha-Singh K, et al: Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: Evidence for a dose-dependant effect. Circulation 2000;102:965–974. 71 Henry TD, Rocha-Singh K, Isner JM, et al: Intracoronary administration of recombinant human vascular endothelial growth factor (rhVEGF) to patients with coronary artery disease. Am Heart J 2001;142:872–880. 72 Simons M, Annex BH, Laham RJ, et al: Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2. Circulation 2002;105:788–793. 73 Grines CL, Watkins MW, Helmer G, et al: Angiogenic gene therapy (AGENT) trial in patients with stable angina pectoris. Circulation 2002;105:1291–1297. 74 Isner JM: Myocardial gene therapy. Nature 2002;415:234–239. 75 Stegmann TJ, Hoppert T, Schneider A, et al: Induction of myocardial neoangiogenesis by human growth factors. A new therapeutic approach in coronary artery disease. Herz 2000; 25:589–599. 76 Unger EF, Gonclaves L, Epstein SE, et al: Effects of a single intracoronary injection of basic fibroblast growth factor in stable angina pectoris. Am J Cardiol 2000;85:1414–1419. 77 Udelson JE, Dilsizian V, Laham RJ, et al: Therapeutic angiogenesis with recombinant fibroblast growth factor-2 improves stress and rest myocardial perfusion abnormalities in patients with severe symptomatic chronic coronary artery disease. Circulation 2000;102: 1605–1610. 78 Laham RJ, Chronos NA, Pike M, et al: Intracoronary basic fibroblast growth factor (FGF2) in patients with severe ischemic heart disease: Results of a phase I open-label dose escalation study. J Am Coll Cardiol 2000;36:2132– 2139. 79 Henry TD, Abraham JA: Review of preclinical and clinical results with vascular endothelial growth factors for therapeutic angiogenesis. Curr Interv Cardiol Rep 2000;2:228–241. 80 Henry TD, Annex BH, Azrin MA, et al: Final results of the VIVA trial of rhVEGF for human therapeutic angiogenesis (abstract). Circulation 1999;100:I-476. 81 Henry TD, McKendall GR, Azrin MA, et al: VIVA trial: One year follow up (abstract). Circulation 2000;102:II-309. 82 Losordo DW, Vale PR, Symes JF, et al: Gene therapy for myocardial angiogenesis: Initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 1998;98:2800–2804. 83 Vale PR, Losordo DW, Milliken CE, et al: Randomized, single-blind, placebo-controlled pilot study of catheter-based myocardial gene transfer for therapeutic angiogenesis using left ventricular electromechanical mapping in patients with chronic myocardial ischemia. Circulation 2001;103:2138–2143.

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Cardiology 2004;101:144–155 DOI: 10.1159/000075995

Cardiac Xenotransplantation: Future and Limitations Kiyoshi Ogata a Jeffrey L. Platt a–d a Transplantation Biology, Departments of b Surgery, c Immunology and d Pediatrics, Mayo Clinic, Rochester, Minn., USA

Key Words Transplantation W Xenotransplantation W Endothelium W Rejection, organ

Abstract Despite improvements in pharmacological therapies, the outlook for patients with severe cardiac disease remains poor. At present, only transplantation can ‘cure’ endstage cardiac failure. However, fewer than 5% of those who need a cardiac transplant receive one in the United States each year. To address this problem, some propose using animals as a source of organs for transplantation, that is, xenotransplantation. Here, we discuss the rationale for xenotransplantation beyond overcoming the shortage of human organs, and we weigh xenotransplantation against other new technologies that might be used for the treatment of cardiac failure. Copyright © 2004 S. Karger AG, Basel

Introduction

Despite the apparent improvement of pharmacological therapies, such as angiotensin-converting enzyme inhibitors, ß-blockers and spironolactone, for treatment of cardiac failure, the outlook for patients with severe cardiac disease remains poor. Approximately 550,000 new cases of cardiac failure occur annually in the United States, and 38% of these end in death within 2 years [1]. The only ‘cure’ for end-stage cardiac failure is transplantation of donated human hearts. Although cardiac allotransplantation is very effective, the number of patients who can benefit is severely limited by the number of human organs donated. Thus, by one estimate, only 5% of the transplants needed are carried out [2]. Therefore, alternative approaches for treating cardiac failure are still very much needed. In this communication, we discuss the potential of xenotransplantation and other approaches that might be applied for treatment of cardiac failure and the hurdles that remain.

Rationale for Cardiac Xenotransplantation

This work was supported by grants from the National Institutes of Health.

ABC Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

© 2004 S. Karger AG, Basel

Accessible online at: www.karger.com/crd

The use of animals as a source of organs and tissues for transplantation into humans has been a goal of investigators in the field of transplantation for decades [3, 4]. The main reason for interest in xenotransplantation is the

Jeffrey L. Platt, MD Director, Transplantation Biology Mayo Clinic Rochester, 200 First Street SW Medical Science Building 2-66, Rochester, MN 55905 (USA) Tel. +1 507 538 0313, Fax +1 507 284 4957, E-Mail [email protected]

hope that it would alleviate the shortage of organs for transplantation. Other reasons, however, impel interest in xenotransplantation. For example, xenotransplantation might be used to treat certain diseases, such as pericarditis or myocarditis, caused by viruses that could infect a human allograft but spare a xenograft. Thus, xenotransplantation could one day offer a way of dealing with epidemic viruses. Analogous to this, xenotransplantation has been proposed for the treatment of human subjects with viral hepatitis [5] and AIDS [6]. Xenotransplantation might also be used to deliver genes. Since gene expression can be achieved at higher levels and controlled more effectively through genetic engineering of animals than conventional approaches to gene transfer [7, 8], cells harvested from genetically engineered animals may one day be used as vehicles for gene delivery. Finally, xenotransplantation might be used to enable the growth of human stem cells into organs, i.e. organogenesis, as discussed in detail elsewhere [9].

devices [13]. While implantable cardiac devices in their current form are not preferred over transplantation, it is possible that devices might be preferred if improvements in technology continue. While implantable devices might be viewed as competing with transplantation, the application of these devices could conceivably increase the need for transplantation. For example, transplantation might be used to rescue individuals who fail to thrive on devices. Furthermore, implantable devices may not be the best alternative for some diseases of the heart. For example, the ventricular assist device may not address the problem of diffuse myocardial dysfunction, and no device may be suitable for application in infants and children. Finally, the preferred therapeutic approach in parts of the world with limited technological resources might well be transplantation rather than implantable devices.

Implantable Devices Devices such as the ventricular assist device or total artificial heart might be used to augment or replace cardiac function. Ventricular assist devices appear to dramatically modify the course of severe cardiac failure [10] and are now in common use. However, the largest study of ventricular assist devices was undertaken in subjects who were not suitable for cardiac transplantation. While the outcome of ventricular assistance in these patients was better than the outcome of medical therapy, it does not approach the outcome of transplantation. The implantable artificial heart, AbioCor, has also been tested, although not so extensively, in seven human subjects [11, 12]. The device appears to offer some promise; however, thrombotic complications were recently reported in the lay press. Assuming that the technology will continue to improve, this limited experience suggests that some day the heart might be preferentially replaced by implantable

Cellular Transplants More recent attention has focused on using cellular transplantation to augment, replace or improve vascularization of damaged myocardium. The concept of isolating and transplanting cells is hardly new; indeed, the transplantation of bone marrow and hematopoietic stem cells is a standard therapy. However, the past few years have brought cellular transplantation for diseases of the heart closer to application. Cells used for transplantation might, in principle, consist of mature differentiated cells or immature cells, the latter having the capacity to differentiate and acquire function after transplantation. Mature myocytes have not been used for treatment of cardiac disease because the cells survive poorly after isolation. This problem can be averted by using immature cells, such as myoblasts or stem cells, or by engineering mature cells to allow for controlled proliferation or generation of cell lines [14, 15]. Immature cells or stem cells might be harvested from a fetus [16] or from mature individuals [17]. Stem cells acquire mature properties during specialized conditions of growth in culture or following transplantation. One advantage of using stem cells is that the cells can be made to proliferate in culture (in this regard, stem cells from a fetus are thought to have far greater potential for proliferation than stem cells from mature individuals). Because stem cells harvested from a fetus would be allogeneic, the recipient would likely need ongoing immunosuppression. Instead, most would favor obtaining stem cells from the individual with organ disease, thus overcoming the need for immunosuppression. Recently, skeletal myoblasts (and hematopoietic stem cells) have been used to repair

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Competing Technologies

Some approaches other than xenotransplantation might improve the outcome for patients with cardiac failure. These approaches, including implantable devices, stem cells, transplantation and tissue engineering, might be viewed as competing with xenotransplantation. Hence, it is useful to consider each application in comparison to xenotransplantation.

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focal defects induced in myocardium in experimental animals [18] and in human subjects [19]. Although myoblast transplantation has been the focus of much attention, there is no compelling evidence that cardiac myocytes can be effectively replaced with myoblasts, as cell coupling may not occur. On the other hand, stem cells may undergo cell-cell coupling as they mature into myocytes. Also uncertain is whether transplanted cells generate myocardium de novo or whether the cells fuse with existing myocytes [20]. An alternative approach may be the use of stem cells, such as mesenchymal stem cells, as a means of revascularizing ischemic myocardium or promoting myocardial healing [21]. This sort of therapy is only in its infancy, but, if successful, it could significantly reduce the need for organ allotransplantation. However, regenerative therapies such as these may not ultimately decrease the total demand for cardiac transplantation, but rather shift the need for transplantation to an older age. Tissue Engineering An important limitation of cellular transplantation is that the transplanted cells may not assume anatomical localization that would allow optimum function. Thus, it is difficult to imagine how a random orientation of stem cells injected into myocardium could give rise to fully functional cardiac tissue. One potential solution to this problem is tissue engineering. In tissue engineering, synthetic or biological polymers are used to support the growth and differentiation of the cells of interest and to direct histogenesis. Efforts in tissue engineering have included generation of blood vessels [22, 23], heart valves [24] and cardiac muscle [25–27]. While tissue engineering may be used to repair focal defects in diseased or injured tissues, it is not applicable for organ replacement. Hence, cardiac replacement will require other technologies. Organogenesis Despite advances in cellular transplantation and tissue engineering, there are no apparent means by which cellular transplants or engineered tissues can be used for replacement of the entirety of anatomically complex organs, such as the heart. What appears to be needed are intact, whole organs. One potential way to obtain such organs is by organogenesis – the growing of organs. Organogenesis has been considered a way to obtain organs for transplantation for many years. The concept of organogenesis is based, at least in part, on observations that primitive cells are capable of assembling into tissues

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and organs that resemble more or less normal, mature tissues and organs [28]. Organogenesis provides a context in which stem cells potentially derived from an individual with organ failure might be used to ‘grow’ a new organ. The main limitations of organogenesis in vitro are that the tissues formed in this way are very small, too small to be of physiologic relevance, and the tissues may lack vascularization [29]. The limitations of organogenesis in vitro might be overcome if the organs were to be grown in vivo. The possibility of in vivo organogenesis is suggested by work in experimental embryology demonstrating that primitive organ rudiments can be coaxed to mature in apposition to chick embryos and in the renal capsule. This idea was recently extended in experiments demonstrating that fetal tissues implanted in the capsule of the kidney and omentum spontaneously mature and even exhibit function [30– 32]. Various investigators have attempted in vivo organogenesis, as such, over the years, and, although arguably successful in the cases noted, it may be difficult to achieve for technical reasons. Technical considerations aside, however, there is the question of where organogenesis would be conducted. The individual with cardiac failure and metabolic stress might not tolerate or support organogenesis. Instead, we have thought that a human organ might be grown in an animal [9]. Such an organ would be a xenograft during growth (the hurdles to xenografting will be summarized below). However, vascularization of the graft would be derived from the xenogeneic host. In this case, the immune system of the affected individual could act on the blood vessels of the newly developed organ. We have discussed these considerations elsewhere [33]. For the present, it should suffice to point out that the technology needed to apply organogenesis for the replacement of organs is not close to being available, even for experimental testing.

Xenotransplantation

Because of the limitations of other technologies, xenotransplantation of the heart might be considered where organ replacement, as opposed to repair, is sought. Xenotransplantation has been used, or rather attempted, at various times during the past century for replacement of organ function [34, 35]. Attempts at cardiac xenotransplantation are summarized in table 1. Below, we discuss in detail the barriers that have prevented application of cardiac xenotransplantation.

Ogata/Platt

Table 1. Clinical experience in cardiac xenotransplantation

Year

Surgeon

Donor

Type

Patient survival

References

1964

Hardy

chimpanzee

OHT

110

1968

Cooley

sheep

OHT

1968

Ross

pig

HHT

1968

Ross

pig

1969

Marion

chimpanzee

perfused with human blood but not transplanted OHT?

functioned for 2 h (heart too small) immediate cessation of function (vascular rejection?) cessation of function within 4 min (vascular rejection?) immediate cessation of function (vascular rejection?)

114

1977

Barnard

baboon

HHT

1977

Barnard

chimpanzee

HHT

1984

Bailey

baboon

OHT

1992

Religa

pig

OHT

rapid failure (4 h; raised pulmonary vascular resistance?) functioned for 5 h (heart too small) functioned for 4 days (probably vascular rejection) functioned for 20 days (vascular rejection) functioned for 24 h (cause of failure uncertain)

111 112, 113

115 115 116 117

Adapted from Cooper et al. [118]. OHT = Orthotopic heart transplantation; HHT = heterotopic heart transplantation.

Barriers to Xenotransplantation

The barriers to cardiac xenotransplantation include the immune response of the recipient against the graft, the physiological limitations of the transplant in the foreign host, the possibility of transferring infectious agents from the graft to the recipient and other factors such as regulatory, ethical and religious matters. Because xenotransplantation has been attempted on a number of occasions over the past 100 years, much more is known about these barriers than the barriers to other technologies discussed above. Accordingly, in discussing this subject and in envisioning clinical application, one should not assume that obstacles of equal difficulty will not be observed for competing technologies. In addressing the biological hurdles to xenotransplantation, we must emphasize the importance of distinguishing between grafted cells and tissues on the one hand and grafted organs on the other. The biological hurdles to xenotransplantation depend to a significant extent on the way in which the graft is connected to the recipient (fig. 1). It will be seen that while clinical xenotransplantation of the intact heart may be remote, clinical xenotrans-

Cardiac Xenotransplantation

plantation of myoblasts or other cells for repair of the heart might be undertaken today. Because we believe that the immune response to xenotransplantation is the most difficult of the hurdles, we shall focus especially on this subject. The elements of the immune system involved in xenograft recognition have been reviewed recently by us [33]. The immune responses to xenotransplantation are much more severe than the immune responses to allotransplantation, for what we believe are at least three reasons. First, all individuals have innate immunity against xenogeneic cells, and this innate immune response includes xenoreactive natural antibodies, complement and natural killer cells [33]. Second, xenogeneic transplants carry a diverse set of foreign antigens against which cellular and humoral immune responses can be elicited (in allotransplants, the main foreign antigens are MHC antigens) [36]. Third, immune regulation, which might partially control responses to allografts, may fail in responses to xenografts.

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Fig. 1. Outcome of xenografts of various types. The figure shows the various types of rejection to which cellular and organ xenografts are subject in the approximate order in which they are observed. The outcome of xenografts depends to a large extent on whether the graft consists of isolated cells, such as myoblasts, or an intact organ, such as the heart. Isolated cells are subject to primary non-function, caused by local inflammation, early immunity or failure of angiogenesis. Subsequently, cellular xenografts (B) are subject to cellular rejec-

tion, mediated by T lymphocytes. Organ xenografts (A) are subject to various types of vascular disease, which in sequence are hyperacute rejection, acute vascular rejection and chronic rejection. These forms of vascular disease may be mediated by humoral factors, such as antibodies and complement, directed against endothelium in the graft. Under some conditions, grafts may acquire resistance to humoral injury, a condition known as ‘accommodation’. Organ xenografts are also subject to cellular rejection, mediated by T lymphocytes.

The Barriers to Xenotransplantation of Cells and Tissues Transplantation of isolated cells, such as myoblasts or stem cells, have been proposed for the repair of myocardial disease. Grafts of isolated cells are nourished and maintained by the microenvironment, growth factors and capillaries of the recipient. These components, particularly the recipient blood vessels, establish a barrier between the immune system of the recipient and the foreign cells [37, 38]. Following the transplantation of isolated cells, the first biological barrier is known as ‘primary non-function’ (fig. 1) [39]. We believe that primary non-function of xenogeneic transplants is caused by one or more of three factors: (1) the inability of growth factors of the recipient to support newly implanted cells and/or failure of graft factors to support angiogenesis by host vessels [40]; (2) the action of natural killer cells or recently activated T cells on the newly implanted graft, and (3) the action of complement on xenogeneic cells and tissues introduced into the blood (e.g. pancreatic islets injected into the portal vein) [41]. Primary non-function can be overcome in at least some systems by increasing the number of cells transplanted.

The main hurdle to xenotransplantation of cells and tissues is cellular rejection. Cell-mediated immune responses to xenotransplantation are thought to be especially severe [36, 42, 43] and may be further amplified by the humoral immune reactions and by failure of immune regulation between species [7, 33]. Some fundamental aspects of the cellular immune response to xenotransplantation have been reviewed by us [33, 44] and others [45, 46]. What is pertinent here is that, despite the severity of cellmediated rejection of cell and tissue transplants between disparate species, the responses appear to be subject to control by the immunosuppressive agents currently available [47–50].

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The Barriers to Xenotransplantation of Vascularized Organs Many investigators have studied the transplantation of porcine hearts into non-human primates [51–56]. Most of the cardiac xenografts studied to date have been heterotopic grafts with anastomosis of the donor aorta to the abdominal aorta and the pulmonary artery to the inferior vena cava; however, many would believe the same hurdles apply to hearts placed in the orthotopic position. Transplanted organs are confronted by very different and potentially difficult barriers. The transplanted organ

Ogata/Platt

Table 2. Approaches to prevention of

hyperacute rejection

Approaches

Method

References

Depletion of xenoreactive antibodies Inhibition of complement Genetic engineering for expression of complement-regulatory proteins Genetic engineering to decrease antigen expression

column absorption cobra venom factor, sCR1 DAF, CD59, MCP

51, 119 120, 121 64, 122, 123

knock-out of the ·1,3-galactosyltransferase gene and possibly other genes in pigs

78–80

DAF = Decay-accelerating factor; MCP = membrane cofactor protein; sCR1 = soluble complement receptor type 1.

receives blood through donor blood vessels, and the endothelial lining of blood vessels is thus the target of the immune response. Interaction of the immune system with donor blood vessels gives rise to distinct forms of vascular disease, as listed in figure 1. These types of vascular disease can also be seen in cardiac allografts, albeit less frequently. We shall describe the vascular types of rejection and potential treatments below. Vascularized organs, including hearts, are initially subject to hyperacute rejection. Hyperacute rejection destroys a xenograft within minutes to a few hours [44, 47, 52]. Hyperacute rejection of porcine organs transplanted into primates is triggered by the binding of xenoreactive natural antibodies to Gal·1–3Gal, a saccharide expressed by pigs and other lower mammals [57]. Binding of these antibodies activates complement, which in turn causes graft destruction. The mechanisms underlying susceptibility to hyperacute rejection have been a subject of controversy, since binding of antidonor antibodies occurs in a variety of conditions, including some xenografts in which hyperacute rejection is not observed [58]. We believe that hyperacute rejection is caused by the rapid insertion of terminal complement complexes in the cell membranes of the endothelial lining of blood vessels in the donor organ [47], and anything that modifies the kinetics of complex formation modifies susceptibility to rejection (table 2). Among the factors that may influence the rate of complement reactions is the availability and function of complement-regulatory proteins [59, 60]. We had postulated that activation of complement in xenografts is amplified because complement-regulatory proteins, such as decayaccelerating factor (CD55), CD59 and membrane cofactor protein, which function more effectively against homologous than against heterologous complement, fail to protect the xenograft against complement-mediated inju-

ry [44]. However, based on studies using isolated cells, some have questioned whether complement-regulatory proteins, particularly CD59, indeed function in a speciesspecific fashion [61]. We contend that this controversy is addressed by xenotransplantation. Thus, expression of decay-accelerating factor [58], but not CD59, prevents hyperacute rejection [62], suggesting that insertion of C5b67 complexes may be sufficient to induce changes in endothelium underlying hyperacute rejection [63]. Also, porcine organs expressing human complement-regulatory proteins at very low levels are protected from hyperacute rejection, thus establishing the idea that failure of complement control is an important hurdle to xenotransplantation [64]. These observations further establish that the safest and perhaps the most clinically applicable approach to preventing hyperacute rejection is expression in the graft of complement-regulatory proteins compatible with the complement system of the recipient and that where a molecular hurdle to xenotransplantation is identified, that hurdle can potentially be addressed by genetic engineering. Some have proposed knocking out ·1,3galactosyltransferase, the enzyme that synthesizes Gal·1–3Gal, to avert hyperacute rejection [65]. However, given the success of other approaches, knocking out ·1,3galactosyltransferase for this purpose hardly seems warranted. If hyperacute rejection is prevented, an organ xenograft becomes susceptible to acute vascular rejection [66, 67]. Similar or identical to acute humoral rejection, acute vascular rejection is the main hurdle to clinical application of xenotransplantation [68–70]. Acute vascular rejection appears to be caused by xenoreactive antibodies that bind to the xenograft, causing ‘activation’ of endothelium in the graft [66, 71, 72] (fig. 2). Whereas the endothelium of normal blood vessels promotes blood flow and inhibits thrombosis and inflammation, the activated endothelium

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Fig. 2. Vascularization of transplants. Cellular grafts are vascularized by recipient blood vessels. Tissue grafts, such as skin, are vascularized by spontaneous anastomosis of donor and recipient capillaries and by the ingrowth of recipient blood vessels. Organ grafts are vascularized exclusively by the surgical anastomosis of donor and recipient blood vessels. As illustrated in figure 1, grafts are subject to humoral injury, depending on the type of vascularization that occurs. Thus, organ grafts, containing donor blood vessels, are subject to humoral rejection, whereas cellular grafts, containing recipient blood vessels, are not.

Fig. 3. Cloning as a means of genetic modification. Cloning can be used to introduce genetic modifications, such as eliminating genes, from lines of animals. Toward this end, cultured somatic cells can be genetically manipulated, and the cells in which genetic change has occurred can be selected. The cells containing genetic manipulations can be used a source of nuclei, which are introduced into enucleated eggs. The ‘new’ embryo so produced contains the genetic material of the cultured cells and cytoplasmic material of the donor egg. The cytoplasmic material causes ‘reprogramming’ of the nuclear material of the donors so that it can yield new, cloned animal. This sequence of events is referred to as reproductive cloning.

of xenografts promotes vasoconstriction, thrombosis and inflammation, giving rise to the picture of ischemia and thrombosis characteristic of acute vascular rejection of xenografts [67, 73]. These pathophysiologic changes in endothelium are due, at least in part, to coordinate elaboration of tissue factor, plasminogen activator inhibitor type 1, E-selectin and thromboxane A2, and other products of genes induced by xenoreactive antibodies and small amounts of complement or platelets [44, 69, 71, 73, 74]. Because acute vascular rejection is thought to be the main biological obstacle to xenotransplantation of organs, much effort is now directed at developing the means to prevent or treat this disorder (table 3). Here we summarize the main approaches. One way to prevent acute vascular rejection may be to induce immunological tolerance to the xenotransplant donor. Xenogeneic tolerance might be induced by engraftment of donor bone marrow or stem cells [75, 76]. Unfortunately, the biological hurdles to engraftment of xenogeneic bone marrow cells, which include the action of

antibodies and complement on the cells and the incompatibility of host growth factors mentioned above [40, 77], and the possibility that some relevant antigens are not expressed in bone marrow, may make induction of tolerance to organ xenografts difficult to achieve. Another way to prevent acute vascular rejection might be to eliminate the antigens targeted by xenoreactive antibodies. Recent progress in the cloning of pigs [78–80] and in gene targeting [81] makes it possible for the first time to knock out porcine antigens targeted by xenoreactive antibodies [65, 82, 83] (fig. 3). Most of the efforts toward this end have focused on knocking out ·1,3galactosyltransferase, which catalyzes the synthesis of Gal·1–3Gal, shown to be the target of some of the antibodies that cause acute vascular rejection [84]. However, as already mentioned, some have questioned whether knocking out this enzyme would eradicate the sugar [85]. In addition, while it may be possible to eliminate this one antigen from xenograft donors, it may not be possible to eliminate a myriad of other xenogeneic antigens [86, 87].

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Table 3. Approaches to prevention of acute

vascular rejection

Method

Result

References

Pretransplant infusion with donor hematopoietic cells Knock-out of ·-1,3-galactosyltransferase and possibly other genes in pigs Suppression of procoagulant or proinflammatory genes Transient depletion of xenoreactive antibodies

tolerance to Gal-·-1,3Gal and other xenospecific antigens decreased antigen expression

75, 124

inhibition of endothelial cell activation induction of accommodation

74

64, 122, 123

44, 84, 90

A third approach to preventing acute vascular rejection involves the inducing of ‘accommodation’. First described in organs allografted across ABO blood group barriers [88, 89], accommodation refers to a condition in which the transplanted organ acquires resistance to immune-mediated injury [44]. Since it may prove difficult or impossible to prevent humoral responses to xenotransplants, there is hope that accommodation can be used to avert the consequences of humoral rejection [44, 70, 74]. Accommodation has been used to prevent acute vascular rejection in rodent and in pig-to-bamboon xenografts [84, 90]. Because accommodation may be vital to the success of xenotransplantation and might be exploited for treatment or prevention of vascular disease, there is much interest in understanding how it can be reliably induced and what mechanisms underlie it. Accommodation of xenotransplants has been induced by temporary depletion of xenoreactive antibodies followed by the return of those antibodies without causing humoral rejection [84]. In this setting, accommodation might be brought about by a change in xenoreactive antibodies or a change in the antigens in the graft [91]. Another possibility is that the binding of xenoreactive antibodies in subtoxic amounts induces changes in the graft, which make the graft inured to humoral injury. Consistent with this mechanism are experiments showing that endothelial cells exposed to xenoreactive antibodies acquire resistance to complementmediated injury, owing to increased expression of CD59 [92] and other inhibitors of injury [93]. Studies in rodents have shown that accommodation is associated with expression of genes such as Bcl-2 that inhibit apoptosis and hemoxygenase-1 (HO-1), which confer protection against toxic injury [94]. Organ grafts deficient in HO-1 or in functional complement-regulatory proteins appear to be subject to severe vascular injury [95], and current studies suggest that the regulatory function of HO-1 is related to

carbon monoxides generated by HO-1 [96]. However, efforts to prevent vascular injury by induction of these genes have not yielded full success, as grafts with increased expression of HO-1 and/or CD59 still undergo acute vascular rejection [62, 97] [unpubl. observations]. This suggests that accommodation is multifactorial and still incompletely understood. While here we discuss accommodation in the context of acute vascular rejection, it is possible accommodation will be found to mediate resistance to other forms of tissue injury [98]. When acute vascular rejection is prevented, xenografts are susceptible to cellular rejection, as discussed above, and presumably to chronic rejection [99]. If chronic rejection is caused by an immune response to the graft, as some experimental evidence suggests [100], then it may be more common and more severe in xenotransplants. If chronic rejection is caused by qualities of the graft, such as preservation time, ischemia and donor age, then it should not be much of a problem. In any case, since xenotransplantation offers an unlimited supply of organs, the impact of chronic rejection may be less serious, as the chronically rejected organ can be replaced.

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Physiologic Hurdles to Xenotransplantation Whether a porcine heart would function adequately in a human patient is a question with obvious bearing on the clinical application of cardiac xenotransplantation. Studies in non-human primates suggest that the kidneys, hearts and lungs of pigs would function sufficiently in a human to sustain life [53, 101, 102]. The main functional impairment of these xenogeneic organ grafts is from rejection. The presumed incompatibilities between the complex metabolic systems of the pig and human liver would appear much more important as a barrier to hepatic xenotransplantation.

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Infectious Agents Another barrier to xenotransplantation is infection [103, 104]. A regular complication of cardiac allotransplantation, infection should, in principal, be less severe a risk in the recipient of a xenograft since the animal source can, in principal, be fully characterized and made free of known pathogens before harvesting the organ and because some pathogens are species-restricted. However, much attention has been devoted to the possibility that an animal organ or tissue might carry pathogens in the genome and that such pathogens would be transmitted vertically within the source species and horizontally to the human recipient. The porcine endogenous retrovirus (PERV) may be one such agent [105]. PERV is found in the genome of all pigs, and it can be transmitted from porcine to human cells in culture. Were PERV to be transmitted from a xenotransplant to a recipient and were the agent to then be spread more widely in the population, the infection would become a matter of public health. Although PERV can be transmitted in cell culture systems in a pigto-mouse model [106], the study of various human recipients with various types of xenotransplants has failed to reveal even a single instance in which PERV has been transmitted to a human subject [107]. A recent study suggests that those viruses known at present could be eradicated from pig herds being bred for xenotransplantation [108]. While the question of the relevance of PERV to public health cannot be entirely dismissed, the question may now be viewed as one that might be resolved by careful attention to the recipients of xenografts, rather than as a reason for abandoning xenotransplantation [104]. Other Hurdles to Xenotransplantation of the Heart Among the further hurdles to xenotransplantation are ethical, religious and governmental considerations. Some ethical and religious groups object to the use of organs from pigs, even when offered as a lifesaving measure. Some oppose xenotransplantation because they regard it as interfering with nature. Some would object to genetic modification of pigs and some question whether so many intellectual and financial resources should be concentrated on developing this technology. In our view, these concerns are personal more than societal and are unlikely to pose an absolute barrier to clinical application. Ethical objections to xenotransplantation have to be weighed against the potential benefit for patients dying of endstage cardiac failure [4]. Of greater concern, in our view, are commercial and regulatory barriers. We have discussed these barriers in detail elsewhere [109]. Briefly put, the application of

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xenotransplantation may depend on genetic engineering of pigs, an undertaking that is quite expensive and technically challenging. While genetic engineering for this purpose has been supported by industry, such efforts may be waning because clinical application seems remote and because there is the impression that application would engender legal liability. Added to the cost and liability are severe regulatory hurdles. Thus, the financial and technical impetus may be deserting the field and this, in turn, poses a barrier.

Prospects for Application

Recent years have brought progress in a number of fields, the technologies of which might be applied to the problem of cardiac failure. Implantable devices have achieved a commendable level of success, but do not yet offer a permanent solution. With improvements in technology, it seems reasonable to think that a fully implantable device may become a preferred treatment. Transplants of myoblasts or stem cells appear promising for focal defects, but may not address diffuse myocardial disease. In light of these advances, one might be inclined to question whether there exists a future for cardiac allo- or xenotransplantation. We think there is. New technologies such as stem cell transplants seem to us most likely to shift the age at which myocardial replacement is needed, rather than eliminate that need. Cardiac transplantation is the most effective treatment for severe, permanent cardiac failure, and it is likely to remain so for the foreseeable future. If xenotransplantation can be made to succeed at a comparable level, it will surely be applied. Furthermore, xenotransplantation might be applied in individuals who fail treatment with a device. It is not inconceivable, and we think it is likely, that further approaches will be forthcoming. Some of these approaches may be complementary. For example, stem cells might be used to fashion new hearts by organogenesis, and the fashioning might have to take place in an animal, i.e. as a xenograft [9]. As another example, cells harvested from animals genetically engineered to express angiogenic factors on demand might be introduced into the ischemic heart to promote revascularization. As still another example, an engineered or xenogeneic heart might someday be used to rescue the recipient of a poorly functioning implantable device. Thus, we believe the best options for replacing or augmenting the function of the heart will be achieved by simultaneous advancement of multiple technologies, including xenotransplantation.

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97 Imai T, Morita T, Shindo T, Nagai R, Yazaki Y, Kurihara H, Suematsu M, Katayama S: Vascular smooth muscle cell-directed overexpression of heme oxygenase-1 elevates blood pressure through attenuation of nitric oxideinduced vasodilation in mice. Circ Res 2001; 89:55–62. 98 Holzknecht ZE, Platt JL: Accommodation and the reversibility of biological systems. Transplantation 2001;71:594–595. 99 Sebille F, Guillet M, Brouard S, Gagne K, Petzold T, Blancho G, Vanhove B, Soulillou JP: T-cell-mediated rejection of vascularized xenografts in the absence of induced antidonor antibody response. Am J Transplant 2001;1:21–28. 100 Hancock WW, Buelow R, Sayegh MH, Turka LA: Antibody-induced transplant arteriosclerosis is prevented by graft expression of antioxidant and anti-apoptotic genes. Nat Med 1998;4:1392–1396. 101 Sablinski T, Lorf T, Monroy R, Bailin M, Gianello P, Cosimi AB, Sachs DH: Absorption of preformed primate anti-swine antibodies by extracorporeal perfusion through gal·(1,3)gal columns. 1995;poster-33 No. 115:18. 102 Daggett CW, Yeatman M, Lodge AJ, Chen EP, Gullotto C, Frank MM, Platt JL, Davis RD: Total respiratory support from swine lungs in primate recipients. J Thorac Cardiovasc Surg 1998;115:19–27. 103 Takeuchi Y, Weiss RA: Xenotransplantation: Reappraising the risk of retroviral zoonosis. Curr Opin Immunol 2000;12:504–507. 104 Boneva R, Folks TM, Chapman LE: Infectious disease issues in xenotransplantation. Clin Microbiol Rev 2001;14:1–14. 105 Patience C, Takeuchi Y, Weiss RA: Zoonosis in xenotransplantation. Curr Opin Immunol 1998;10:539–542. 106 Van der Laan LJW, Lockey C, Griffeth BC, Frasier FS, Wilson CA, Onions DE, Hering BJ, Long Z, Otto E, Torbett BE, Salomon DR: Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID mice. Nature 2000;407:501–504. 107 Paradis K, Langford G, Long Z, Heneine W, Sandstrom P, Switzer WM, Chapman LE, Lockey C, Onions D: Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. Science 1999;285:1236–1241. 108 Clark DA, Fryer JF, Tucker AW, McArdle PD, Hughes AE, Emery VC, Griffiths PD: Porcine cytomegalovirus in pigs being bred for xenograft organs: Progress towards control. Xenotransplantation 2003;10:142–148. 109 Platt J, DiSesa V, Gail D, Massicot-Fisher J: Recommendations of the National Heart, Lung, and Blood Institute Heart and Lung Xenotransplantation Working Group. Circulation 2002;106:1043–1047. 110 Hardy JD, Chavez CM, Kurrus FD, Neely WA, Eraslan S, Turner MD, Fabian LW, Labecki TD: Heart transplantation in man: Developmental studies and report of a case. JAMA 1964;188:1132–1140.

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Cardiology 2004;101:144–155

155

Author Index Vol. 101, No. 1–3, 2004

Billeh, R. 122 Byrne, J.G. 7 Caines, A.E.B. 21 Carpino, P.A. 29 Casey, C. 72 Chaer, R.A. 122 Cohn, L.H. 7 Delgado, R. 111 DeNofrio, D. 29 Dowling, R.D. 117 El-Zein, C. 15 Evans, A. 21 Frazier, O.H. 111, 117 Geha, A.S. 15, 21 Gray, L.A., Jr.. 117

Gregoric, I.D. 111, 117 Hoercher, K.J. 61 Horvath, K.A. 37 Jeevanadam, V. 104 Kazimi, M. 29 Khabbaz, K.R. 29 Kherani, A.R. 93 Knight, B.P. 72 Kpodonu, J. 21 Lee, R. 61 McCarthy, P.M. 61 McConnell, P.I. 48 Massad, M.G. 5, 15, 21, 79, 122 Maybaum, S. 93 Michler, R.E. 48

Mihaljevic, T. 7 Myers, T.J. 111 Ogata, K. 144 Oz, M.C.M. 93 Paul, S. 7 Platt, J.L. 144 Pool, T. 117 Raman, J. 104 Rawn, J.D. 7 Rebeiz, A.G. 21 Robertson, K.D. 111 Rosengart, T.K. 131 Sanborn, T.A. 131 Shah, N.A. 111, 117 Syed, I.S. 131

Subject Index Vol. 101, No. 1–3, 2004

Angina 37 Angiogenesis 131 Aortic regurgitation 7 – stenosis 7 – valve replacement 7 Atherosclerosis 131 Autologous skeletal myoblast transplantation 48 Beating heart surgery 29 Biventricular pacing 72 Bridge to recovery 93 – – transplantation 93 Cardiomyopathy 7, 29, 61 –, ischemic 15 –, nonischemic 15 Congestive heart failure 48, 72, 111, 117

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Coronary artery bypass grafting 21 – – – surgery 29 – – disease 131 – –, premature 122 Destination therapy 104, 111 Ejection fraction 21 Endothelium 144 End-stage heart disease 79 Flowmaker 111 Gene therapy 122, 131 Genetics 122 Heart failure 29, 61, 79, 104 – transplantation 79, 111 Implantable cardioverter defibrillator 72 Left ventricular assist devices 111 – – dysfunction 48 – – reconstruction 61

Mechanical circulatory support 117 Mitral valve repair 15 – – replacement 15 Multivessel coronary artery disease 21 Pacemaker 72 Rejection, organ 144 Reversible ischemia 37 Stenting 21 Surgical ventricular restoration 48 Total artificial heart 117 Transmyocardial laser revascularization 37 Transplantation 144 Ventricular assist device 93, 104 – dyssynchrony 72 – remodeling 48 Xenotransplantation 144