Heart Transplantation: Indications and Contraindications, Procedures and Complications : Indications and Contraindications, Procedures and Complications [1 ed.] 9781608765911, 9781607412281

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Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. Heart Transplantation: Indications and Contraindications, Procedures and Complications : Indications and Contraindications, Procedures and

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. Heart Transplantation: Indications and Contraindications, Procedures and Complications : Indications and Contraindications, Procedures and

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved.

HEART TRANSPLANTATION: INDICATIONS AND CONTRADICTIONS, PROCEDURES AND COMPLICATIONS

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Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. Heart Transplantation: Indications and Contraindications, Procedures and Complications : Indications and Contraindications, Procedures and

HEART TRANSPLANTATION: INDICATIONS AND CONTRADICTIONS, PROCEDURES AND COMPLICATIONS

CATHERINE T. FLEMING Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved.

EDITOR

Nova Biomedical Books New York

Heart Transplantation: Indications and Contraindications, Procedures and Complications : Indications and Contraindications, Procedures and

Copyright © 2009 by Nova Science Publishers, Inc.

All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers‘ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Library of Congress Cataloging-in-Publication Data Available upon request

ISBN: H%RRN

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Heart Transplantation: Indications and Contraindications, Procedures and Complications : Indications and Contraindications, Procedures and

Contents

Preface Chapter I

Chapter II

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Chapter III

Chapter IV

Chapter V

Chapter VI

Chapter VII

vii Management of Tricuspid Regurgitation After Cardiac Transplantation Mitesh V. Badiwala and Vivek Rao Virtual Histology Intravascular Ultrasound in Coronary Allograft Vasculopathy G. Sarno, W. Wijns and M. Vanderheyden. Gene Therapy for Prevention of Acute and Chronic Cardiac Rejection Jun-ichi Suzuki, Mitsuaki Isobe, Ryuichi Morishita and Ryozo Nagai

1

11

17

Prevention of Heart Allograft Rejection by Immunotherapy with Ex Vivo-Expanded Foxp3+CD4+CD25+ Natural Regulatory T Cells Guliang Xia, Zheng Zhang and Bryon D Johnson

25

Addressing the Shortage of Donor Cardiac Allografts – Use of Marginal Grafts Silvana F Marasco, M. Bioeth and Andrew E Newcomb

51

Dendritic Cell Modulation for Therapeutic Immunoregulation in Heart Transplantation Giuseppe Vassalli, Marc-Estienne Roehrich, Manuel Pascual, Ludwig K. Von Segesser, Pierre Vogt, Giovanni B. Pedrazzini, Tiziano Moccetti Heart Transplantation: Indications and Contradictions, Procedures and Complications Katharina Kerschan-Schindl and Peter Pietschmann

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63

81

vi

Contents

Chapter VIII

The Role of Statins in Heart Transplantation Nikolaos Bessias, Panagiotis Georgakis and Kosmas I. Paraskevas

Chapter IX

Heart Transplantation from Non-Heart-Beating Donors; Future Transplantation Masanori Hirota and Shunji Sano

Chapter X

Chapter XI

Chapter XII

An Innovative Treatment for Cardiac Failure: Autologous Stem Cell Transplantation Gloria Invernici, Silvia Cristini, Stefania Navone, Laura Canzi and Eugenio A. Parati Continuous, Normothermic Heart Preservation in a Modified Langendorff Perfusion System — Ultrastructural Findings and Functional Morphology in a Pig Model Heike Aupperle, Jens Garbade, Christian Krautz, Cris Ullmann, Sven Lehmann, Jörg Kempfert, Michael A. Borger, Stefan Dhein, Jan F. Gummert and Friedrich-Wilhelm Mohr Surgical Alternatives to Heart Transplantation Andrew E Newcomb, Silvana F Marasco and Nikunj Powar

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Index

Heart Transplantation: Indications and Contraindications, Procedures and Complications : Indications and Contraindications, Procedures and

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101

143

207

231 273

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Preface Cardiac transplantation is a widely accepted therapy for the treatment of end-stage congestive heart failure. Most candidates for cardiac transplantation have not been helped by conventional medical therapy and are excluded from other surgical options because of the poor condition of the heart. About 45% of the candidates have ischemic cardiomyopathy; however, this percentage is rising because of the increase in coronary artery disease in younger age groups. Of the candidates, 54% have some form of dilated cardiomyopathy, which often has an unclear origin. The remaining 1% of candidates fall into the category of other diseases, including congenital heart disease, that are not amenable to surgical correction. Candidacy determination and evaluation are key components of the process, as is postoperative follow-up care and immunosuppression management. This new book presents leading research from around the world. Chapter 1 - Tricuspid valve regurgitation is the most frequent valvular complication following orthotopic cardiac transplantation. It leads to diminished quality of life and predicts shortened long-term survival. The optimal surgical management of refractory tricuspid valve regurgitation in this setting is unclear. Recent findings: Tricuspid valve regurgitation following cardiac transplantation is likely related to accumulated injury from repeated endomyocardial biopsies. Durability of repair in this setting was shown to be suboptimal. Replacement with a bioprosthesis was found to be durable and relieves symptoms of heart failure associated with tricuspid valve regurgitation in the majority of patients. Prophylactic tricuspid valve annuloplasty at transplantation was found to significantly decrease the incidence of early and late tricuspid valve regurgitation. Summary: Results of tricuspid valve repair in the post-cardiac transplant setting are not ideal, and this strategy is better suited to treating functional tricuspid valve regurgitation resulting from annular dilatation. Tricuspid valve replacement with a bioprosthesis is a safe, durable, and effective method of treating tricuspid valve regurgitation following transplantation and allows for future endomyocardial biopsies to be performed. Mechanical valves should be avoided. Consideration of prophylactic tricuspid annuloplasty is warranted as a means of prevention. Chapter 2 - Coronary allograft vasculopathy (CAV) remains the major cause of morbidity and mortality in patients after heart transplantation.[1–3] It is characterized initially by progressive intimal proliferation and later by luminal narrowing and occlusion of small

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arteries.[4–6] The etiology of CAV is complex with the involvement of immunologic (e.g. HLA), infectious (e.g. cytomegalovirus) and classic risk (e.g. lipid status and diabetes) factors.[7–14] Chapter 3 - Cardiac transplantation has been established in humans; however, acute rejection and graft arterial disease (GAD) are still problems. Several cytokines and adhesion molecules enhance acute rejection; the arteriopathy is characterized by intimal thickening comprised of proliferative smooth muscle cells. Strategies that target in the attenuation of acute rejection and GAD formation were not well studied in cardiac transplantation. Recent progress in the DNA technology, such as antisense oligodeoxynucleotides (ODNs) to regulate the transcription of disease-related genes, has important roles in therapeutic applications. We, for the first time, reported that antisense cdk2 kinase ODN transfection prevented the arteriopathy in murine cardiac allografts. Recently, transfection of cis-element doublestranded DNA, named as "decoy", has been reported to be a useful method for gene therapy. This decoy strategy has been not only a useful method for the experimental studies of endogenous gene regulation but also a novel clinical strategy for gene therapy. E2F plays a pivotal role in the coordinated transcription of cell cycle regulatory genes; nuclear factorkappa B (NF-kB) is critical in the transcription of multiple inflammatory genes. Therefore, we investigated the effects of E2F decoy and NF-kB decoy for prevention of cardiac acute allograft rejection and GAD. In this article, the authors reviewed the experimental results of NF-kB decoy, E2F decoy and other ODNs using the experimental heart transplant models. Chapter 4 - The role of Foxp3+CD4+CD25+ regulatory T (Treg) cells has increasingly been demonstrated in modulating allograft rejection and mediating allograft tolerance in rodents. In humans, a favorable transplantation outcome is frequently associated with increased frequencies of Foxp3+CD4+CD25+ Treg cells. Over the past several years, we have been interested in using natural CD4+CD25+ Treg (nTreg) as cellular therapy to prevent heart allograft rejection in mice. Due to low frequencies in fresh tissues, ex vivo expansion is essential for generating sufficient numbers of CD4+CD25+ nTreg cells to target the large repertoire of alloreactive effector T (Teff) cells in transplant recipients. Strategies for ex vivo expansion have evolved from alloantigen (alloAg)-nonspecific (e.g., anti-CD3/CD28 mAbcoated beads) approaches to alloAg-specific (e.g., live donor bone marrow-derived dendritic cells [BM-DC]) methods, with reasonable cell expansion after 20 days of culture. An unexpected observation was a gradual decrease of the transcription factor Foxp3, a critical regulator for suppressive function during ex vivo expansion, when in vitro cultures were supplemented with only interleukin (IL)-2. We systemically examined the kinetics of Foxp3 expression in CD4+CD25+ and CD4+Foxp3+ nTreg cells (FACS-sorted from Foxp3green fluorescence protein [GFP] knock-in mice) during ex vivo expansion, and confirmed the activation of T cell receptors (TCR), leading to the loss of Foxp3 from the original Foxp3+ precursors. We have made significant progress towards preserving Foxp3 expression by modifying expansion protocols to include transforming growth factor (TGF)-β, all-trans retinoic acid (RA), histone deacetylase inhibitor trichostatin A (TSA), or combinations of these reagents. Importantly, fresh CD4+CD25+ nTreg cells expanded by the ―modified‖ culture conditions (e.g., RA/TSA/TGF-β/IL-2) not only expressed high Foxp3 in vitro (~45%) but also retained high Foxp3 expression in vivo (~91%) during prevention of heart allograft rejection. As a result, long-term survival of fully major histocompatibility complex (MHC)-

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mismatched heart allografts was successfully achieved in wild-type mice without using conventional immunosuppressants. Further optimization of protocols for expanding CD4+CD25+ nTreg cells ex vivo may be essential for the successful use of these cells in preventing heart allograft rejection in immune competent mice. Chapter 5 - Worldwide, cardiac transplant numbers are decreasing due to donor shortages. Attempts to ameliorate these shortages have focused on expanding the traditional criteria for organ donors. This chapter reviews our experience with cardiac transplantation using marginal donors and compares our experience with that of other centres. In particular our marginal donors have largely consisted of long ischemic time organs which has largely been dictated by geographical factors. We have found an increased risk of primary graft failure in this population but have achieved good outcomes with early institution of mechanical support. The use of cardiac allografts from non heart beating donors, and continuous perfusion storage are also explored. Chapter 6 - Dendritic cells (DCs) pick up antigens at peripheral sites and migrate to lymph nodes and spleen, where they present antigenic peptides to T cells. As such, DCs initiate innate and adaptive immune responses to microorganisms and other antigens, including alloantigens. However, DCs can also inhibit T-cell responses depending on the subset of DCs involved and their degree of activation and maturation. Mature myeloid DCs typically stimulate T cells, whereas plasmacytoid DCs and immature myeloid DCs have been associated with immunoregulation under certain circumstances. Data in cardiac transplant models suggest that alloantigen-presenting plasmacytoid DCs migrating preferentially to lymph nodes, rather than spleen, induce the generation of regulatory T cells (Treg). Bidirectional links between regulatory DCs and Treg modulate alloreactive T-cell functions. Initial clinical data in cardiac transplant recipients also suggest that circulating plasmacytoid DCs may play immunoregulatory roles. Therefore, several approaches have been evaluated for therapeutic enhancement of regulatory DCs in transplantation. These approaches involve genetic manipulation of DCs with immunosuppressive genes and in vitro exposure of DCs to agents that prevent their maturation in response to inflammatory cytokines. Importantly, several agents used in cardiac transplant recipients, including corticosteroids, cyclosporine A, mycophenolate mofetil and rapamycin attenuate DC activation in several contexts. Aspirin also inhibits DC activation, a potentially beneficial effect in transplantation. Thus several agents that primarily act by inhibiting T-cells concomitantly regulate DC activation. An improved understanding of the mechanisms by which immunosuppressive agents modulate DC activation and induce regulatory DCs will likely assist in the development of improved treatments in transplantation. Chapter 7 - Osteoporosis is a systemic skeletal disease characterized by low bone mass and deterioration in the microarchitecture of bone tissue, resulting in fragility of bone and susceptibility to fractures. Bone disease is a clinically significant complication, frequently observed in patients suffering from terminal heart failure as well as in heart transplant recipients. Approximately half of the patients with severe congestive heart failure (CHF) have a reduced bone mineral density, osteopenia or osteoporosis. During the first year after heart transplantation (HTX) the reported bone loss is 10 %, leading to a higher percentage of HTX recipients suffering of osteoporosis and a higher percentage of patients suffering of vertebral fractures compared to

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HTX candidates. Disturbances of bone metabolism in both patient groups are multifactorial. In HTX candidates, increased bone resorption may be caused partly by existing low-grade renal insufficiency, the regular intake of loop diuretics, and restricted mobility. After HTX, the majority of patients no longer need loop diuretics and mobility increases soon. However, HTX recipients need several types of immunosuppressive drugs which negatively influence bone turnover. During the first months after transplantation the typical effects of high doses of corticosteroids on bone metabolism can be observed. Different immunosuppressive regimens seem to have a different impact on bone metabolism. Thus, hopefully changes of these regimens in the future may be able to reduce the rate of post-transplant fragility fractures. However, each fragility fracture is a serious complication and we need to take steps to prevent this complication. Chapter 8 - Cardiac allograft vasculopathy comprises a considerable limitation in the long–term success of heart transplantation. Statins (3–hydroxy, 3–methyl glutaryl coenzyme A reductase inhibitors) have been proposed to prevent the progression of transplant vasculopathy and cardiac rejection rates in heart transplant recipients. Additionally, statins are associated with a significant reduction in perioperative and long–term mortality rates in these patients. A recent meta–analysis showed that routine statin treatment is associated with an almost 12% improved mortality in patients undergoing heart transplantation. Besides these effects, it has been demonstrated that statins reduce the number of post–operative complications and clinical events, revascularization rates and post–operative hospital stay. These actions are associated with considerable cost–related advantages. Statins are cost– effective and safe agents with few adverse side–effects. Current evidence suggests that a large percentage of heart transplant recipients are under–treated with respect to statins. It is important to ensure that all heart transplant recipients are on routine statin treatment in order to reduce cardiac allograft vasculopathy and peri–operative mortality rates. Chapter 9 - Background: Heart transplantation is an alternative treatment for cardiac failure. However, increasing demand for donor hearts has lead to extension of donor criteria. Thus, our final purpose is to achieve heart transplantation from non-heart-beating donors (NHBDs). However, cardiac function of NHBDs is uncertain due to severe myocardial damage, resulting in primary graft failure. To utilize NHBDs for heart transplantation, it is critically important to minimize cardiac damage with many myocardial protections and also to evaluate resuscitated hearts from NHBDs before transplantation. We developed isolated myocardial perfusion system to resuscitate the NHBD hearts and attempted to predict functional recovery of 60-min warm ischemic hearts by analyzing systolic and diastolic functions. Methods: Hypoxic cardiac arrest was induced in eight mongrel dogs without any pretreatments. After 60-min ischemia, intracoronary microthrombi were flushed out by retrograde blood cardiopledia with tissue-type plasminogen activator. Coronary arteries were initially perfused from the aortic root with tepid hyperkalemic blood (20 mmol/L) at low pressure (20 mm Hg) for the first 60 min and then with normothermic blood for the next 60 min. After 120 min of reperfusion, preload was increased for ejection against an 80 mm Hg of afterload. Pressure-volume loops were recorded to obtain end-systolic pressure-volume relationship (ESPVR) and end-diastolic pressure-volume relationship (EDPVR). Stroke volume at given preload was calculated from averaged ESPVR, EDPVR and afterload

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identical to averaged baseline value. Frank-Starling relationship was obtained and cardiac status was classified by Forrester‘s hemodynamic subset. Results: End-systolic elastance was significantly decreased to about 60% of the baseline and time constant of isovolumic relaxation was significantly prolonged by about 20%. Cardiac index was decreased to about 50% and cardiac status was classified in Forrester‘s III or IV subset. Conclusions: An extent of functional recovery of NHBD hearts is predictable by cardiac output. Although 120 min of recovery time may be short for 60-min ischemic damage, this system may be feasible to predict posttransplant cardiac function before transplantation. Chapter 10 - Heart failure results from the inability of the heart to pump enough blood to maintain physiological functions. It is one of the most common cardiovascular disorders in the world. In the final stage of heart failure, heart transplantation is the elective treatment. However, the availability of donor organs and immunological rejection limit this choise. Although immunosuppression agents can prevent rejection, they are associated with several complications including wound healing, opportunistic infections, drug-related toxicities, skin malignancies and low-grade lymphomas. Thus, current treatment is far from adequate. The most promising future treatment option is stem cell transplantation therapy for the repair of the damaged myocardium. This is based on the principle of enhancing the insufficient intrinsic repair mechanisms of the damaged heart and the employment of either fetal or post-natal stem cells. The discovery of pluripotent stem cells with their ability to repair adult tissue has prompted novel research into repair of the heart and blood vessels. This finding offers immense therapeutic possibilities but also problems that have never been encountered before. The use of stem cells for treatment of the heart, because of its simplicity in function and accessibility, is more advanced than in other organs. The initial report of an improvement in cardiac function in a mouse model of myocardial infarction treated with bone-marrow-derived progenitor cells led to a series of clinical studies in human beings. However, the significance of the results still remains unclear. In this context, human adult skeletal muscle stem cells represent an important and alternative source for cell therapy since they can be obtained easily from a small muscle biopsy and allow autologous transplantation. The pre-differentiating treatment is aimed to avoid side-effects which have been observed with undifferentiated myoblasts or embryonic stem cells transplantation. This source of stem cells could represent a new source for heart failure cell therapy. Skeletal muscle stem cells (SkmSCs), differentiated under GMP (Good Manufactory Practice) conditions, in the future could be injected into patients with acute myocardial infarction. The route of delivery of these stem cells could vary and include intracoronary, percutaneous intramyocardial or direct intramyocardial at the time of coronary artery bypass grafting. First protocols to amplify in vitro the SkmSCs population, and to drive their differentiation toward cardiomyogenic lineage must be optimized. Then Skm stem cells transplantation can be considered. Chapter 11 - Objective: Efficient organ preservation is an important precondition for functional recovery during heart transplantation and may be improved with continuous blood

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perfusion. The aim of this study was to investigate the effectiveness of continuous, normothermic heart reperfusion in a modified Langendorff system by the use of ultrastructural findings and functional parameters. Methods: Hearts of twelve pigs were randomly assigned to two groups receiving a constant pressure perfusion in a modified Langendorff system after different preparation techniques. (Group 1) Six hearts were arrested with Bretschneider HTK cardioplegia (4°C) and then reperfused with a circulating pressure of 80–90 mmHg using leukocyte depleted autologous blood. (Group 2) Beating hearts of six pigs were explanted while immediately being reperfused. Perfusion protocol was equivalent to Group 1, except for a lower circulating pressure (40–50 mm Hg). At different time points (in situ, 1, 6 and 12 hours after reperfusion) myocardial biopsies were taken and contractility was assessed by measuring the maximum rate of left ventricular pressure rise (Δp/Δt (max)). In all biopsies ATP concentration was measured using a bioluminescence technique. Additionally, specimens were fixed in 2.5% glutaraldhyde, embedded in glycidether 100 and ultrathin sections were prepared for transmission electron microscopy. A quantitative method was applied to evaluate and to statistically analyze progressive ultrastructural alterations, which were summarized in alterations scores of 0–3.0. Results: Hypothermic cardioplegia and a higher reperfusion pressure (Group 1) were associated with an earlier and sharper decline of contractile function and intracellular ATP concentration. After cardioplegia and hypothermic ischemia, all ultrastructural alteration scores of Group 1 increased significantly (Score 1.75 vs. 0.25, P=0.031) compared to normal in situ biopsies. , Especially endothelial edema was leading to an obliteration of the capillary lumina. Cardiomyocytes developed mild to moderate mitochondrial edema. In contrast, ultrastructural alteration scores in Group 2 did not exceed 1.0. Six hours after reperfusion, ultrastructural lesions were mainly affected the cardiomyocytic mitochondria (6 h: Score 2.75) and myofibrils (6 h: Score 2.7) of Group 1. In contrast, alterations in Group 2 were less intensive and scores did not exceed 1.75 and endothelial cells were damaged only mildly. Twelve hours after reperfusion, a total loss of cellular structures was apparent in samples of Group 1 (scores ranged from 2.5 to 3.0). In Group 2, all scores increased but did not exceed 2.25. Alterations affected predominantly the myofibrils. Conclusion: The results demonstrate that extracorporeal blood reperfusion provided protection against severe ischemic damage for a limited time. The use of a lower perfusion pressure, as well as avoiding cardioplegia and hypothermia, led to a significantly better and longer preservation of the reperfused hearts. Ultrastructural investigations gave important informations concerning the causes and pathogenesis of the functional findings, leading to further modifications of our experimental design. Chapter 12 - Cardiomyopathy is an expanding clinical problem, and is one of the leading causes of hospitalization worldwide. The use of heart transplantation is well established as the treatment of choice in appropriate patients. This in itself poses a problem, as the donor rate in many countries remains constant in spite of increasing numbers of potential recipients.

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There are many surgical options available to patients in this situation including high-risk coronary bypass surgery (i.e. Grade 4 LV, or LVEF≤30%) for those patients with ischemic cardiomyopathy and severe coronary artery disease with associated viability. High-risk valve repair or replacement is undertaken for valvular cardiomyopathy. Surgical ventricular restoration may be performed in conjunction with other forms of surgery, and all of the above should be accompanied by surgical implantation of LV epicardial leads for future biventricular pacing in the setting of widened QRS complex. Ventricular Assist Device implantation is better positioned as a precursor to cardiac transplantation, and is comprised of the 2 main categories of destination therapy or as a bridge to either recovery or transplantation. There is also a great deal of research and interest in cardiac splinting procedures and devices, although these are still only experimental in nature. In the future, surgical units that do not offer cardiac transplantation are likely to provide more surgical support to multidisciplinary heart failure clinics as the population ages, and the numbers of patients with cardiomyopathy increases.

Heart Transplantation: Indications and Contraindications, Procedures and Complications : Indications and Contraindications, Procedures and

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. Heart Transplantation: Indications and Contraindications, Procedures and Complications : Indications and Contraindications, Procedures and

In: Heart Transplantation Ed: Catherine T. Fleming

ISBN: 978-1-60741-228-1 ©2009 Nova Science Publishers, Inc.

Chapter I

Management of Tricuspid Regurgitation After Cardiac Transplantation Mitesh V. Badiwala and Vivek Rao* Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada

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Abstract Tricuspid valve regurgitation is the most frequent valvular complication following orthotopic cardiac transplantation. It leads to diminished quality of life and predicts shortened long-term survival. The optimal surgical management of refractory tricuspid valve regurgitation in this setting is unclear. Recent findings: Tricuspid valve regurgitation following cardiac transplantation is likely related to accumulated injury from repeated endomyocardial biopsies. Durability of repair in this setting was shown to be suboptimal. Replacement with a bioprosthesis was found to be durable and relieves symptoms of heart failure associated with tricuspid valve regurgitation in the majority of patients. Prophylactic tricuspid valve annuloplasty at transplantation was found to significantly decrease the incidence of early and late tricuspid valve regurgitation. Summary: Results of tricuspid valve repair in the post-cardiac transplant setting are not ideal, and this strategy is better suited to treating functional tricuspid valve regurgitation resulting from annular dilatation. Tricuspid valve replacement with a bioprosthesis is a safe, durable, and effective method of treating tricuspid valve regurgitation following transplantation and allows for future endomyocardial biopsies to be performed. Mechanical valves should be avoided. Consideration of prophylactic tricuspid annuloplasty is warranted as a means of prevention.

* Corresponding Author: Vivek Rao, MD, PhD, FRCSC, FAHA, Alfredo and Teresa deGasperis Chair in Heart Failure Surgery, Surgical Director – Heart Transplant Program, Associate Professor of Surgery, 4N-464, Toronto General Hospital, 200 Elizabeth St , Toronto, Ontario, M5G 2C4, E-mail [email protected] , Tel. 416-340-3562, Fax. 416-340-3337 Heart Transplantation: Indications and Contraindications, Procedures and Complications : Indications and Contraindications, Procedures and

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Mitesh V. Badiwala and Vivek Rao

Keywords/Phrases: Cardiac transplantation, Tricuspid valve regurgitation, Tricuspid valve replacement, Tricuspid valve repair

Introduction Tricuspid valve regurgitation (TR) is the most frequent valvular abnormality that occurs following orthotopic cardiac transplantation, with a prevalence ranging from 47% to 98%.[1] World-wide experience with surgery to correct TR following cardiac transplantation is limited. When severe and/or symptomatic TR refractory to medical management occurs following cardiac transplantation, tricuspid valve repair or replacement are current strategies used to treat this difficult condition. Recently published retrospective studies provide us with some evidence that tricuspid valve replacement may offer better durability and symptomatic relief for TR in this situation.[2-4]

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Pathophysiology of Tricuspid Valve Regurgitation Following Cardiac Transplantation It is important to understand the pathophysiology of the TR that occurs following cardiac transplantation in order to optimally treat this condition surgically when medical management fails, and to potentially avoid this condition altogether. Two types of TR generally occur in the post-transplant setting. Annular dilatation, due to right ventricular remodelling, results in a central regurgitant jet due to incomplete leaflet coaptation. Alternatively, excessive leaflet motion from prolapsing or flail leaflets is thought to occur either secondary to altered geometric alignment of the right atrium, tricuspid valve and right ventricle, or from damage to the leaflet or chordal structures. Factors thought to influence the occurrence and/or severity of post cardiac transplant TR include: (1) the technique of allograft implantation (biatrial versus bicaval versus total orthotopic),[5, 6] (2) frequency of endomyocardial biopsy,[7-9] (3) length of biopsy bioptome sheath,[2, 10] (4) infection leading to endocarditis, (5) ischemic injury to the right ventricle, and (6) size mismatch between the donor heart and pericardial cavity. Endomyocardial biopsy currently remains the gold standard for surveillance of allograft rejection, however, it has been implicated in the development of TR.[8] Mild to moderate TR may progress to severe TR by biopsy induced damaged to the chordae tendineae resulting in a flail leaflet.[11] Repeated biopsies may exacerbate the situation and result in further damage and increasing TR. Nguyen et al. recently examined the relationship between number of endomyocardial biopsies and severity of tricuspid regurgitation.[8] In their series, of the 101 patients who had undergone orthotopic heart transplantation and survived more than 1 year, 25% developed severe TR and 4% ultimately required tricuspid valve replacement for refractory right heart failure due to severe TR. There were no cases of severe TR in patients who had less than 18 biopsies, whereas beyond 31 biopsies 60% of patients developed severe TR. Thus, the authors suggest that 31 biopsies be a cut-off to avoid a higher incidence of severe TR. It is important to note that in their series, all patients underwent endomyocardial

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Management of Tricuspid Regurgitation after Cardiac Transplantation

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biopsy with a standard short sheath (12 cm) for access. More recent use of a longer 45 cm sheath that crosses the tricuspid valve may improve results with less damage to the tricuspid valve. Further direct evidence linking endomyocardial biopsy to damage of the tricuspid valve which leads to significant TR is provided by Meilniczuk et al.[7] They examined the endomyocardial biopsy specimens of patients who were found to have significant TR post cardiac transplantation. Histological findings of chordal tissue were found in the biopsies of 47% of patients with significant TR. The degree of TR also increased post biopsy. These findings strongly suggest that chordal damage at the time of endomyocardial biopsy does indeed lead to significant TR.

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Management of Refractory Tricuspid Regurgitation While the majority of TR that occurs in patients is mild and asymptomatic, retrospective studies have revealed that the prevalence of moderate to severe TR may be as high as 34%.[12] Though symptoms of TR including fatigue, diminished exercise capacity, and peripheral edema occur more frequently with severe TR, patients with moderate TR post cardiac transplantation may also have significant symptoms that affect quality of life. Mishra notes that as the severity of TR reaches that point where quality of life is affected, its management is both difficult and controversial, and medical management is clearly not satisfying.[13] Recent retrospective reviews indicate that between 2.0% and 5.8% of patients postcardiac transplantation present with severe TR that is symptomatic and refractory to medical management.[2-4, 8, 10] These patients subsequently undergo surgical management for symptomatic relief and to prevent progression to end stage heart failure. TR secondary to annular dilatation, i.e. functional TR, conceptually would benefit from a downsizing annuloplasty type repair. However, TR secondary to flail leaflets due to chordal damage is the more frequent cause of TR requiring surgical management in these patients. This type of TR may be amenable to reconstructive repair. However, replacement may be a superior option to avoid recurrent TR from recurrent chordal damage in this population who require multiple endomyocardial biopsies.[2]

Recent Experience with Repairs and Replacements A number of recent retrospective analyses provide insight into the results of strategies to surgically manage TR post cardiac transplant (see Table 1). Yankah et al. published a retrospective study examining tricuspid valve dysfunction within 647 heart transplanted patients surviving more than 30 days post-transplantation.[4] The unique aspect of their patient population is their immunologic monitoring consisting of intramyocardial

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Mitesh V. Badiwala and Vivek Rao

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electrocardiography (IMEG) via a telemetric bipolar pacemaker that monitors changes in the amplitude of the QRS-complex. IMEG has recently been demonstrated to safely reduce the need for endomyocardial biopsy by approximately 45%.[14] Endomyocardial biopsy was only performed if there were concerns about the day-by-day IMEG results and/or echocardiography data. This strategy has yielded a biopsy rate of 4.8 per patient in the first two years following transplantation during the period from 1991 to 1999. During a mean follow-up period of 5.1 years (31 days to 13.3 years) moderate tricuspid regurgitation occurred in 3.1% of patients and severe tricuspid regurgitation occurred in 2.5% of patients. Overall survival to 5 and 13 years was 59% and 50% respectively. These results are important to consider, as they suggest that the strategy of IMEG may reduce the incidence and severity of TR while not adversely affecting long term survival which in this series is comparable to world-wide experience.[15] All of the 16 patients with severe TR ultimately required tricuspid valve surgery. Six patients underwent tricuspid valve repair (DeVega or KayWhooler annuloplasty) with one early repair failure requiring replacement. Eleven patients underwent tricuspid valve replacement (4 bioprostheses and 7 mechanical valves). Injury of the chordae tendineae (presumably biopsy induced) was observed at surgery in 15 (94%) of the 16 patients. There was one early death 3 days following tricuspid valve replacement, however this patient had a combined tricuspid replacement and right lower lobe resection for cancer and died in pulmonary failure on an extracorporeal membrane oxygenator. There were 5 late deaths (mean 13 months), none related to the tricuspid valve surgery or directly related to a cardiac cause. At a mean follow-up of 29.9 months, nine out of ten surviving patients improved to an NYHA functional class I or II. Thus, although overall survival is suboptimal in this group of patients, durability and efficacy of tricuspid valve replacement is acceptable. Moreover, the overall need for tricuspid valve surgery was lower in this group compared to other published reports and may be due to the use of IMEG for rejection surveillance. Table 1. Summary of tricuspid valve surgery durability after cardiac transplantation Authors

Time Period

Total # of patients

Yankah et al.[4] Filsoufi et al.[2] Alharethi et al.[3]

19861999 19852005 19921999

Overall

Total # of repairs

647

Number (%) with TR requiring surgery 16 (2.5%)

Total # of replacements

Rereplacements (%)

6

Repair failures requiring replacement (%) 1 (16.7%)

11

0 (0%)

138

8 (5%)

6

3 (50%)

5

0 (0%)

871

17 (2%)

2

0 (0%)

15

1 (6.7%)

1656

41 (2.5%)

14

4 (28.6%)

31

1 (3.2%)

Filsoufi et al. recently reported their results following surgical management of severe TR in heart transplant recipients.[2] In their series examining 138 cardiac transplant patients over a period of 7 years, 8 patients (5.8%) developed severe symptomatic TR requiring surgical management. Four patients exhibited TR consistent with regurgitation secondary to annular dilatation. The remaining 4 exhibited TR consistent with regurgitation secondary to leaflet prolapse due to cordal rupture from injury during endomyocardial biopsy. Endomyocardial

Heart Transplantation: Indications and Contraindications, Procedures and Complications : Indications and Contraindications, Procedures and

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Management of Tricuspid Regurgitation after Cardiac Transplantation

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biopsies were utilized in all of these patients for routine rejection surveillance, weekly for the first month post-transplant, bi-weekly in the second month, then monthly for the remainder of the first year and then every 3 months during the second year post-transplant. Six patients underwent tricuspid valve repair and 2 underwent replacement. Three repairs failed requiring replacement with a bioprosthetic valve (2 were early failures within 14 days post-op; the third was over 4 years post-op). One of the primary replacements was with a pulmonary allograft and this failed at 10 months requiring re-replacement with a bioprosthesis. At a mean followup of 55 months, all of the bioprostheses were functioning normally with no evidence of deterioration. The 3 remaining tricuspid valve repairs were free of symptomatic regurgitation at a mean follow-up of 72 months. In summary, their series demonstrated a 50% failure rate with repair, in contrast to complete durability of replacement with bioprostheses out to 55 months. Alharethi et al. also recently reported their results of tricuspid valve replacement after cardiac transplantation, and this series is the largest reported to date.[3] Amongst 871 orthotopic heart transplants at their institution between 1985 and 2004, 17 patients (2%) developed severe tricuspid regurgitation requiring surgical management. All 17 patients had undergone transplantation by the standard bi-atrial technique. Two patients underwent tricuspid valve repair and 15 patients underwent primary tricuspid valve replacement (14 with bioprosthesis). Sixteen of the valves (94%) were noted to have a flail leaflet at the time of operation. One patient underwent replacement with a mitral homograph that failed within 4 months and was re-replaced with a bioprosthesis. One early post-operative death occurred after replacement due to cardiogenic shock and another death occurred at 8 months due to progressive right heart failure. At a mean follow-up of 32.9 ± 49.3 months 12 of the 15 surviving patients (80%) were benefiting from improvement in their heart failure symptoms and there was an overall mean decrease in furosemide dose from 48 mg/day to 27 mg/day (p=0.009). Thus, these results suggest that tricuspid valve replacement with a bioprosthesis for post transplant TR is effective at ameliorating heart failure symptoms in the majority of patients with an acceptable (6%) early mortality.

Repair or Replacement? The series reported by Yankah et al.[4] and more recently by Alharethi et al.[3] provide further evidence to support the suspicion that damage to the chordae tendineae, resulting in a flail leaflet, is a common mechanism leading to severe symptomatic tricuspid. Surgery to correct severe TR needs to take this mechanism into account. As endomyocardial biopsy currently remains the gold standard in rejection surveillance, patients will undoubtedly require biopsies after any tricuspid repair or replacement.[8] Tricuspid repair with a downsizing annuloplasty may actually increase the chance of damage to the chordal structures as they are brought closer together into the path of the bioptome. As such, its role may be more suitable in functional TR where the annulus is dilated to begin with, and where downsizing annuloplasty merely restores a normal valve size.[2] The series reported by Filsoufi et al. raises some concern about durability of repair as 50% of repairs failed requiring subsequent replacement. If repair is chosen, no residual regurgitation should be accepted

Heart Transplantation: Indications and Contraindications, Procedures and Complications : Indications and Contraindications, Procedures and

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Mitesh V. Badiwala and Vivek Rao

post-repair intraoperatively, as these patients are clearly at risk of recurrent regurgitation. Tricuspid valve replacement should be performed immediately when repair is demonstrated to be suboptimal intraoperatively. Some have suggested that choice of mechanical versus bioprosthetic valve for replacement may be influenced by the possibility of future chronic renal failure in a patient, since this may lead to premature calcification and failure of bioprostheses.[4] However, others have suggested that given the limited survival of heart transplant patients in ideal circumstances this deciding factor may be of limited value. Moreover, since the gold standard for surveillance of rejection is endomyocardial biopsy, more credence should probably be given to facilitating future biopsies with the use of a bioprosthetic valve since mechanical valves impede obtaining an endomyocardial biopsy. [2] Thus, the more logical choice for tricuspid valve replacement is arguably to use a bioprosthetic valve.

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Preventing Post-Transplant TR The occurrence of TR after heart transplantation may result from tension on the atrial anastomosis and/or mismatch of the donor heart size to pericardial cavity size, resulting in misalignment between the right atrium, tricuspid valve and right ventricle. Thus, surgical factors that may prevent significant tricuspid regurgitation after heart transplantation include (1) matching donor heart size to pericardial cavity size with a reduction pericardial closure, (2) a tensionless atrial anastomosis, or alternatively (3) using bicaval anastomosis or (4) total orthotopic (bicaval and pulmonary venous anastomoses) technique to maintain native right atrial to ventricular geometry. Sun et al. at the Cleveland Clinic Foundation recently reported the 1-month post-transplant prevalence of moderate or severe TR after standard atrial anastomotic technique (n=293) to be 22.5% compared to 15.4% after bicaval transplant technique (n=322).[16] Park et al. have reported the late prevalence of moderate or severe TR after standard atrial anastomotic technique to be 36.4% compared to 10.5% after bicaval transplant technique in 43 patients at their institution.[6] Similarly, Koch et al. have reported the prevalence of moderate and severe TR to be lower at 5 years following transplantation with the total orthotopic technique versus the standard biatrial technique (moderate TR 14% vs. 39%, P