Charles B. Huddleston and Andrew C. Fiore Cardinal Glennon Children’s Hospital, St. Louis University School of Medicine, St. Louis, MO, USA The era of clinical cardiac transplantation began when Christian Barnard [1] performed the first successful human heart transplant in a 54‐year‐old man on December 3, 1967. This clinical success was based on the extensive laboratory work of Richard Lower and Norman Shumway [2, 3]. During the next year (1968) over 100 cardiac transplant procedures were performed by 64 surgical teams around the world [4]. Most patients had a satisfactory technical procedure followed by fatal allograft rejection or opportunistic infection. With these poor results, only a few centers remained committed to cardiac transplantation, the most notable of which was Stanford University. The evaluation of the transplanted heart for rejection was greatly advanced by the development of percutaneous transvenous right ventricular endomyocardial biopsy by Phillip Caves at Stanford in 1972 [5]. A standardized grading system for cardiac rejection based on the histopathologic interpretation of these biopsies was developed by Margaret Billingham, the pathologist working with the Stanford team [6]. The final advance that launched cardiac transplantation was the introduction of cyclosporine in the early 1980s for immunosuppression, with resultant reduced infectious complications and improved survival [7]. Since that time, there have been incremental improvements in cardiac transplantation outcomes resulting from the use of bicaval technique [8], shorter circulatory arrest for neonates [9, 10], tacrolimus (FK‐506) immunosuppression [11, 12], the use of mycophenolate mofetil [13], reduced steroid dosage or steroid‐free immunosuppression [14, 15] induction therapy with monoclonal antibodies [16], increased attention to cytomegalovirus and Epstein–Barr viral prophylaxis [17], and ABO‐incompatible transplants in infants [18]. Initially, pediatric cardiac transplants were performed chiefly at transplant centers such as Pittsburgh and Stanford [19, 20], but with increasing success with immunosuppressive regimes, more pediatric centers have achieved good results with cardiac transplantation [21–23]. Infant cardiac transplantation was first successfully performed by Leonard Bailey at Loma Linda University on November 20, 1985 [24]. This pioneering effort followed much research and attempts at clinical xenotransplantation [25, 26]. Mavroudis also reported early success with infant cardiac transplantation [27]. Like pediatric cardiac transplantation, infant cardiac transplantation is now performed in many medical centers with good results [28, 29]. Still, infant and pediatric cardiac transplantation accounts for only about 10% of total cardiac transplants [30]. These historical milestones are illustrated in Table 43.1. Approximately 50% of all congenital cardiac centers in the United States have pediatric heart transplant programs. Worldwide nearly 600 transplants are performed annually in children less than 18 years of age [31]. The indications, techniques, pre‐ and postoperative care, and long‐term management have certainly evolved over the past three decades. Table 43.1 Historical milestones in cardiac transplantation. Heart transplantation may be broadly stated as a procedure designed for those whose survival is dependent upon replacement of the heart. Cardiomyopathies and congenital heart disease comprise approximately 80% of all transplants, with nearly equal numbers in each category overall. Retransplantation for graft failure or coronary artery vasculopathy accounts for 5% and a potpourri of other conditions make up the remainder. The indications vary somewhat by the age of the recipient. Congenital heart disease is the predominant diagnosis in infants and cardiomyopathy is the major indication in teenagers. Cardiomyopathic conditions in children (particularly adolescents) are similar to those seen in adults, namely dilated (DCM), hypertrophic (HCM), and restrictive (RCM) cardiomyopathies. Each particular type of cardiomyopathy has its own set of treatment, risk factors for death, natural history, and prognosis. The estimated incidence of pediatric cardiomyopathy in the United States is approximately 1.1–1.5 per 100,000 children who are less than 18 years of age [32]. Transplantation is reserved for those patients in whom all manner of medical therapy has been exhausted. The need for transplantation is related to some extent to the underlying etiology for the cardiomyopathy. This is the most common form of cardiomyopathy and may be due to a neuromuscular disorder (such as muscular dystrophy), postmyocarditis, the toxic effects of certain chemotherapeutic agents, inborn errors of metabolism, familial, ventricular noncompaction, or idiopathic. A variety of medical therapies have emerged for DCM, including angiotensin‐converting enzyme inhibitors, beta blockers, and biventricular pacing. Despite the advancement of medical therapies, the overall prognosis for DCM has not changed appreciably over the past 30 years. The prognosis varies according to the underlying etiology (Table 43.2) [33]. Children with an idiopathic DCM (the most common type) have a transplant‐free survival of 50% at five years [34]. The two most common neuromuscular disorders associated with DCM are Becker and Duchenne muscular dystrophy. The prognosis in this group is generally worse, although this may be influenced by the exclusion of some patients due to concerns related to the underlying diagnosis and how it would impact overall posttransplant rehabilitation and survival [35]. Postmyocarditis‐DCM has the most favorable prognosis [36]. In fact, those presenting with fulminant myocarditis had the best prognosis overall, with as many as 80% recovering normal left ventricular function; fulminant is defined by the severity of clinical presentation [36, 37]. Anthracyclines are potent chemotherapeutic agents used for a variety of malignancies in children and adults. They have a dose‐related cardiotoxic effect on the myocardium and may result in either RCM or DCM, but DCM is more prevalent. This may appear early or late following therapy [38]. Table 43.2 Transplant‐free survival in dilated cardiomyopathy based upon etiology. This diagnosis is the second most common form of cardiomyopathy and accounts for approximately 25% of the total [32]. It is characterized by the presence of severe ventricular hypertrophy without apparent hemodynamic cause. The types of HCM include inborn errors of metabolism, malformation syndromes, neuromuscular disorders, and idiopathic, which includes the familial types. Approximately 75% of patients are classified as idiopathic [39]. The risk factors for death or transplantation are age less than 1 year at diagnosis, lower shortening fraction of the left ventricle, thicker posterior wall dimension at presentation, mixed hypertrophic and dilated appearance of the left ventricle, and an inborn error of metabolism as the underlying cause [40]. The most common disease of inborn error of metabolism associated with HCM is Pompe disease. Noonan and Beckwith–Wiedemann syndromes account for most of the malformation syndromes [39]. The survival rate for these patients is approximately 80% at one year and 74% at five years. Friedreich ataxia is the most common underlying etiology in the HCM group and is related to neuromuscular disorders [39]. These patients have an excellent prognosis, with over 90% surviving beyond five years. This form of cardiomyopathy is relatively rare in children, but accounts for more heart transplants than HCM. The survival at one, five, and ten years following diagnosis is 80%, 39%, and 20%, respectively [41]. Children with RCM have a particularly poor prognosis, in part related to the high incidence of elevated pulmonary vascular resistance that frequently accompanies this diagnosis [42]. These patients have an elevated left ventricular end‐diastolic pressure that presumably leads to elevation of the pulmonary vascular resistance. This elevated pulmonary vascular resistance also has an impact on survival following heart transplantation. This progression may occur without any change in symptoms. It is reasonable to consider transplantation earlier in the clinical process than one might in a patient with DCM. Recognized for 25–30 years, left ventricular noncompaction was officially classified as a cardiomyopathy in 2006 [43]. It is characterized by the presence of prominent trabeculae, intertrabecular recesses, and two distinct layers of compacted and noncompacted myocardium based upon the echocardiographic appearance of the left ventricle [44]. Although it is generally believed to be the result of disrupted embryologic development of the myocardium, the precise etiology of this is unknown. It accounts for approximately 5% of all pediatric cardiomyopathies [42]. The clinical course and age at presentation are quite variable. This disease is broadly categorized into dilated, hypertrophic, and isolated types, with the isolated ventricular noncompaction having the best prognosis [45]. Another unusual form of cardiomyopathy is arrhythmogenic right ventricular dysplasia. As the name implies, this condition predisposes children to arrhythmias, usually ventricular tachycardia. A portion of the right ventricular wall is replaced with fibrofatty tissue. Ablation of the arrhythmogenic focus is the preferred treatment. Unfortunately, extensive ablation associated with extensive involvement of the right ventricle can result in very poor right ventricular function and hence the need for transplantation. This diagnosis has been the most common indication for transplantation in children since heart transplantation was established. This heterogeneous group of patients has changed over the course of the history of pediatric heart transplantation as innovations in surgical and cardiac care of many complex lesions have advanced. The range of conditions may be divided into unrepaired complex lesions, repaired lesions with residual poor ventricular function, and single‐ventricle anomalies at all stages of palliation. Table 43.3 provides an example of the variety of congenital cardiac lesions in patients undergoing heart transplantation. Table 43.3 Congenital cardiac conditions transplanted (n = 173). Source: Adapted from Voeller RK, Epstein DJ, Guthrie TJ, Gandhi SK, Canter CE, Huddleston CB. Trends in the indications and survival in pediatric heart transplants: a 24‐year single‐center experience in 307 patients. Ann Thorac Surg. 2012;94:807–816. In the 1980s and early 1990s, hypoplastic left heart syndrome (HLHS) was the primary lesion in this category. The mortality with early palliation was over 50% even at the most experienced centers in the 1980s, prompting many centers to adopt primary transplantation for this condition following the pioneering work of Leonard Bailey and associates at Loma Linda University [46, 47]. The results with transplantation were generally quite good, with survival at one and five years of 89% and 80%, respectively. However, as more centers established transplant programs for these infants, the waiting times became quite long, resulting in a waitlist mortality of over 20% [48]. In addition, refinement of surgical technique and advancements in pre‐ and postoperative care improved the results with palliative procedures, such that the mortality for the Norwood procedure in an uncomplicated patient with HLHS is now in the order of 10–15% [49]. The practice at most centers is to reserve transplantation as primary therapy for HLHS for those infants with poor right ventricular function, severe tricuspid valve regurgitation, or pulmonary valve disease (either stenosis or insufficiency). In addition, some infants who have HLHS with mitral stenosis and aortic atresia may have severe coronary anomalies that make the Norwood procedure risk prohibitively high [50–52]. Pulmonary atresia with intact ventricular septum and right ventricle–dependent coronary circulation is a congenital lesion for which palliative procedures carry a very high risk [53, 54]. This risk is related to the tenuous coronary perfusion wherein the native coronary arteries are stenotic or occluded, and the myocardial blood supply is derived from the hypertensive right ventricle via sinusoidal connections to the distal native coronaries [55]. Patients identified with significant myocardium are at risk due to proximal native coronary lesions and should be listed for primary transplantation. Arguably, any patient with single‐ventricle anatomy and a concomitant cardiac lesion have a high risk for death and may be poor candidates for single‐ventricle palliation; these patients should be considered for transplantation. An example of this would be a patient with heterotaxy, unbalanced atrioventricular septal defect with a dominant right ventricle, and severe atrioventricular valve regurgitation. Although initial palliation may be a relatively straightforward procedure (i.e., Blalock–Taussig–Thomas shunt), in reality this is somewhat high risk. If the regurgitant valve is not easily reparable, the likelihood that the infant will survive to undergo a bidirectional Glenn shunt and Fontan is very low [56, 57]. In general, the long‐term outcomes of patients with repaired biventricular congenital heart disease is quite good. Having said that, the survival curves for entities such as repaired tetralogy of Fallot do not follow the same curve as the normal population [58]. Some of the diagnoses falling into this category include tetralogy of Fallot, atrial repair of transposition of the great arteries, congenitally corrected transposition of the great arteries, and Shone complex. Atrial repairs of transposition of the great arteries and congenitally corrected transposition of the great arteries have an anatomic right ventricle serving as the systemic ventricle. Progressive right ventricular dilatation and the development of heart failure are common in these patients [59, 60]. In Shone complex, multiple sites of left ventricular outflow tract obstruction may lead to a hypertrophic left ventricle even if the lesions have been repaired. A variety of other lesions may require transplantation as a result of myocardial injury or prolonged myocardial ischemia at the time of repair. These patients are usually those with single‐ventricle anatomy who are failing along the path of reconstructive surgery or are not suitable candidates for the Fontan procedure. An example of this would be a patient with HLHS and severe tricuspid valve regurgitation or modest elevation of the pulmonary vascular resistance following the Glenn shunt procedure. These patients would be considered high risk for the Fontan procedure in both the short and long term and transplantation at this stage may be preferable to staged reconstructive surgery. This diagnostic group now makes up the largest single group within the category of congenital heart disease undergoing heart transplantation, and it is expected that this number will grow with time [61, 62]. This is in part a reflection of the improvement in survival of neonates undergoing palliation, some of whom have borderline hemodynamics or ventricular function and perhaps would not have survived in an earlier era of surgery. Depending upon the clinical circumstances, the most practical approach to a patient with early Fontan failure is to take down the Fontan and revise it to a Glenn shunt. Late failure of the Fontan operation may be due to single‐ventricle dysfunction, elevation of the pulmonary vascular resistance, valve dysfunction, lymphatic derangements (protein‐losing enteropathy and plastic bronchitis), pulmonary arteriovenous malformations, thrombotic circuit occlusion, and intractable arrhythmias. It is also apparent that hepatic dysfunction is an altogether common occurrence late following the Fontan procedure. Single‐ventricular dysfunction is the most common mechanism leading to a late failed Fontan. It may be either diastolic or systolic dysfunction or a combination of the two. Generally speaking, ventricular dysfunction is not particularly responsive to medical therapy. For patients with a classical Fontan circulation (atriopulmonary connection), there may be instances in which conversion to an extracardiac type of Fontan with arrhythmia surgery may substantially improve the clinical situation and avoid transplantation. As with most operations, patient selection is crucial. Those most likely to benefit have arrhythmias, pathway obstructions, or salvageable valve dysfunction [63]. Risk factors for Fontan conversion failure include an anatomic right ventricle and the presence of protein‐losing enteropathy [64]. Some have advocated cardiac resynchronization therapy in patients with heart failure, bundle branch block, and congenital heart disease, including patients with a failing Fontan [65, 66]. There is no clear evidence that benefit is derived in this group of patients. Most patients with a failing Fontan have some elevation of the pulmonary vascular resistance. Many surgeons believe that the underlying etiology is due to vascular remodeling and endothelial dysfunction related to the lack of pulsatile flow [67]. Although this seldom reaches a level that precludes heart transplantation, it certainly contributes to a failing Fontan circulation. These patients may respond to pulmonary vasodilators and this therapy should be evaluated prior to consideration of transplantation [68]. Protein‐losing enteropathy and plastic bronchitis may be manifestations of lymphatic dysfunction seen in the late follow‐up of patients with a failing Fontan circulation. The incidence is approximately 10% and the five‐year survival once the diagnosis is made is approximately 50% [69]. These patients need to be aggressively evaluated and treated for any entity that might cause a rise in the venous pressures. One specific treatment for protein‐losing enteropathy is oral budesonide [70]. Inhaled tissue plasminogen activator is now the recommended therapy for plastic bronchitis [71]. More recently, interventions on the lymphatic system have been used to treat plastic bronchitis [72]. Hepatic dysfunction and fibrosis may be common late conditions following the Fontan procedure. In a recent study, 21 patients undergoing routine cardiac catheterization during late follow‐up also underwent liver biopsy; 18 (85%) were found to have hepatic fibrosis [73]. Whether heart transplantation can reverse this process is unknown. The degree of cirrhosis can reach the point where heart transplantation is contraindicated or where a combined heart–liver transplant is considered. Patients with a Model for End‐Stage Liver Disease (MELD) score of less than 12 are probably suitable candidates for heart transplantation only [74]. As would be expected, this indication is growing as many patients extend their survival to a point where transplant coronary vasculopathy occurs. Although early posttransplant graft failure is another potential reason for retransplantation, this is less common, and not very successful. The contraindications for heart transplantation fall into the categories of general and specific; that is, those clinical issues that would preclude any patient from transplantation and those that are specific to the heart (Table 43.4). Significant dysfunction of another organ (liver or kidney) would exclude patients from cardiac transplantation unless the cause is cardiac related with some reasonable hope of reversal of this process with the institution of normal cardiac output. Placing a ventricular assist device (VAD) is an excellent pretransplant strategy to retrieve patients from irreversible end‐organ dysfunction [75]. As previously stated, severe liver dysfunction is a relatively common finding in the late follow‐up of patients undergoing the Fontan operation. The presence of cirrhosis on a liver biopsy is a contraindication for heart transplantation. Renal failure requiring dialysis is also a contraindication [76]. In some circumstances it may be appropriate to perform a combined heart–liver or heart–kidney transplant to obviate these problems. Table 43.4 Contraindications. The presence of a positive serology for human immunodeficiency virus (HIV) infection has been long considered an absolute contraindication to heart transplantation. However, the success in controlling this disease with antiretroviral therapy has altered the natural history of HIV infection. Most centers still consider this a contraindication because of concerns over the possibility that immunosuppression will result in progression to acquired immunodeficiency syndrome (AIDS), and the scarcity of donor hearts should preclude listing patients deemed high risk. However, at least 18 heart transplants have been performed in HIV‐positive patients, with good results thus far [77]. The presence of other serious infections should dictate waiting until appropriate therapy has been instituted. The presence of an active malignancy is an absolute contraindication to transplantation. The definition of active is the sticking point. If the patient has been in remission for two years, does that mean the malignancy has been cured or is inactive? This would obviously depend upon the specific malignancy and therefore consultation with the appropriate oncologic service is mandatory. The cardiotoxicity of some chemotherapeutic agents (and to some extent the improved cancer survival offered by these agents) has made this a more prevalent issue over the past several years. Most would agree that a five‐year interval between remission and transplantation is probably safe [78]. Severe neurologic derangements are a contraindication to heart transplantation. Developmental delay and other neurologic issues that come up short of severe derangement are separate entities that must be considered on a case‐by‐case basis. If a child has a stroke while being supported on a VAD, does that automatically exclude that patient from transplantation? There are many instances in which excellent recovery has occurred following a major cerebrovascular event in a small child. All of this must be carefully considered when evaluating these patients. The cardiac evaluation must be very thorough, particularly for those children with congenital heart disease. This evaluation includes a detailed evaluation for nontransplant treatment options. Cardiac catheterization is very important in this evaluation to assess the anatomic anomalies as well as the hemodynamic issues, specifically the pulmonary vascular resistance (PVR) and its reactivity to pulmonary vasodilator agents. Elevated PVR not responsive to pulmonary vasodilator therapy is considered a contraindication to isolated heart transplantation. Precisely what degree of elevation of the PVR and precisely what degree of responsiveness to therapy are somewhat controversial and have been relaxed over the years. In the early years of heart transplantation, a PVR of greater than 4 Wood units without response to pulmonary vasodilators was considered a contraindication [79]. However, with the advent of more pulmonary vasodilator agents, the degree of elevation of the PVR that would exclude a patient from heart transplantation has trended upward [80]. Borderline elevations of the PVR are treated for prolonged periods of time with pulmonary vasodilators and/or inotropic agents and then re‐evaluated to assess the effectiveness of this therapy. Failing that, placement of a left VAD effectively lowers the left ventricular end‐diastolic pressure and secondarily the PVR [81]. Combined heart–lung transplantation is an alternative, but has the disadvantages of difficulty obtaining an adequate donor heart and overall poor long‐term results [82]. In general, there are no anatomic contraindications to heart transplantation in children with congenital heart disease. Having said that, patients with small or abnormal pulmonary arteries, such as those with multiple aortopulmonary collaterals, should be carefully evaluated. Most of these patients will have prohibitively high pulmonary artery pressures and most do not respond to pulmonary vasodilators. Patients with pulmonary venous stenosis are poor candidates for transplantation due to the high recurrence rate of pulmonary venous stenosis and PVR instability post repair. Perhaps the most complex congenital cardiac lesion is situs inversus or dextrocardia. Often, patients with these anomalies also have complex single‐ventricle lesions and have been through various stages of palliative operations. This combination certainly complicates any transplant procedure from a technical aspect, but would not be considered a contraindication. There are techniques for dealing with this, as will be discussed in the technique section. Over the past 10 years there has been a steady rise in the percentage of patients undergoing heart transplantation while on mechanical circulatory support [31]. This has gone from 22% in 2005 to 33% in 2014. VADs make up the bulk of the support with extracorporeal membrane oxygenation (ECMO), accounting for approximately 10% of those bridged to transplantation. The majority of these patients have cardiomyopathy as their underlying diagnosis. All potential transplant recipients must go through a thorough multidisciplinary evaluation to assess their candidacy. A variety of tests are performed to assess other organ function, including renal, liver, neurologic, immunologic, and gastrointestinal systems. Panel‐reactive antibody (PRA) testing is particularly important in patients who have undergone prior cardiac surgery, especially when homograft material has been used as part of the repair. A value of greater than 10% reactivity is generally considered a significant level of preformed antibodies, placing the patient at risk of early rejection and graft failure [83]. Given the frequency of positive PRA testing in children with congenital heart disease and multiple prior operations, each center will need its own plan for dealing with these issues. One option is treatment with anti‐B cell drugs such as rituximab along with plasmapheresis to remove existing antibodies. This must be done on a recurring basis pretransplant and obviously has its limitations. Another strategy is to perform pretransplant prospective cross‐match with the donor. This also has its limitations, but there is a possibility of a virtual cross‐match using the donor antigen profile compared with the corresponding recipient antibody data to predict posttransplant reactivity [84]. There are clearly some antibodies that are more problematic than others and if those are negative on a prospective cross‐match but others are positive it is probably safe to proceed. Many patients in whom homograft material was used in reconstructive procedures will have very high PRA levels, approaching 100% in some cases. The likelihood of having a prospective cross‐match that is negative in this situation is very low. Transplanting across a positive cross‐match is another alternative. This can be successfully accomplished, albeit with an aggressive immunosuppressive regimen and the recognition that essentially all patients will have at least one episode of significant rejection in the first six months posttransplant [85]. If the offending homograft material can be replaced with nonhomograft material (such as a right ventricle to pulmonary artery conduit), this could result in a reduction of the antigen load and aid in the pretreatment regimen of rituximab and plasmapheresis. This is obviously not always practical, but we have had a limited anecdotal positive experience with this approach. Serologic testing for prior viral infections (cytomegalovirus, Epstein–Barr virus, hepatitis, and HIV) is also part of the pretransplant evaluation. Prior infection with these agents can be reactivated with immunosuppression.
CHAPTER 43
Pediatric Heart Transplantation
Year
Event
1960
Successful canine orthotopic cardiac transplantation, R. Lower and N. Shumway
1967
Successful human orthotopic cardiac transplantation, C. Barnard
1972
Percutaneous transvenous right ventricular endomyocardial biopsy, P. Caves
1974
Standardized grading system for cardiac biopsy, M. Billingham
1979
Cyclosporin A introduced for clinical immunosuppression
1985
Successful infant orthotopic cardiac transplantation, L. Bailey
2001
ABO‐incompatible transplantation for infants, L. West
Indications
Cardiomyopathy
Dilated Cardiomyopathy
Etiology
1‐Year
5‐Year
Idiopathic
75%
50%
Postmyocarditis
80%
77%
Neuromuscular
65%
25%
Inborn error of metabolism
72%
30%
Hypertrophic Cardiomyopathy
Restrictive Cardiomyopathy
Left Ventricular Noncompaction
Congenital Heart Disease
Single‐ventricle anomalies
138
Hypoplastic left heart syndrome
90
Double‐outlet right ventricle
17
Pulmonary atresia
10
Tricuspid atresia
10
Others
11
Biventricular anomalies
35
Transposition of the great arteries
11
Left ventricular outflow tract stenosis
5
Atrioventricular septal defect
4
Tetralogy of Fallot
3
Ventricular septal defect
3
Others
9
Single‐ventricle surgical history
137
No prior palliation
76
Prior palliation
28
Failed Fontan
33
Unrepaired Congenital Heart Lesions
Repaired Congenital Heart Disease
Previously Palliated Congenital Heart Disease
Failed Fontan
Retransplantation
Contraindications
General
History of poor compliance with medical regimen
Prohibitive psychosocial circumstances
Coexisting condition that limits survival
Specific
Human immunodeficiency virus (HIV) infection
Uncontrolled sepsis/infection
Other organ failure
Renal failure
Liver failure
Central nervous system dysfunction
Significant neurodevelopmental disorder
Severe stroke
Significant psychiatric disorder
Elevated, nonreactive pulmonary vascular resistance
Malignancy
Ventricular Assist Device
Pretransplant Evaluation
Donor Evaluation
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