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Current challenges in pediatric heart transplantation for congenital heart disease

Kirklin, James K.

Current Opinion in Organ Transplantation: October 2015 - Volume 20 - Issue 5 - p 577–583
doi: 10.1097/MOT.0000000000000238
CARDIAC TRANSPLANTATION: Edited by James K. Kirklin

Purpose of review Pediatric heart transplantation is an established therapy for end-stage cardiac disease without suitable medical or surgical options. However, transplantation for congenital heart disease carries an incremental risk that challenges the pediatric transplant team on multiple levels.

Recent findings With improved outcomes following palliative and corrective congenital cardiac surgery, cardiac transplantation has decreased in recent years as a primary therapy. Nevertheless, congenital heart disease remains the most common indication for cardiac transplantation during infancy. Primary transplantation in infancy is selectively recommended for severe systemic ventricular dysfunction, severe atrioventricular valve insufficiency, and occlusive coronary artery anomalies, particularly with single ventricle physiology. Wait-list mortality remains highest for infants with prior palliative surgery and patients with failing Fontan physiology, both of whom have limited options for effective mechanical circulatory support. The sensitized patient carries an increased risk with prolonged wait times, although virtual cross-matches and single bead assays for donor-specific antigens have facilitated the transplant process. Early and late survival after transplantation for congenital heart disease remain inferior to cardiomyopathy, with prior Fontan procedure as a major risk factor. However, among survivors at 6 months, late outcomes are generally excellent. Major late causes of death include allograft vasculopathy, post-transplant lymphoproliferative disease, and acute rejection. Noncompliance with medications remains a major risk for teenage mortality.

Summary Despite the myriad of evolving challenges, pediatric heart transplantation for congenital heart disease enjoys routine short and long-term success at experienced centers for the vast majority of such patients without other options.

University of Alabama at Birmingham, Birmingham, Alabama, USA

Correspondence to James K. Kirklin, MD, Department of Surgery, Division of Cardiothoracic Surgery, 760 Tinsley Harrison Tower, 1900 University, Boulevard, Birmingham, Alabama 35294, USA. Tel: +1 205 934 3368; e-mail: jkirklin@uab.edu

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INTRODUCTION

Pediatric heart transplantation is an established therapy for end-stage heart disease among infants, children, and adolescents. Short- and long-term survival following transplantation for cardiomyopathy is excellent, with 1- and 10-year survivals of 90–95 and 60–80% for most subsets [1▪]. However, survival following transplantation for complex congenital heart disease is less good (Fig. 1), and numerous challenges present ongoing barriers to successful outcomes. This article will review challenges specific to patients with congenital heart disease who undergo cardiac transplantation.

FIGURE 1

FIGURE 1

Box 1

Box 1

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HISTORICAL PERSPECTIVE

Three days after Christian Barnard electrified the world with the first human-to-human heart transplant on 3 December 1967, Adrian Kantrowitz attempted the first human heart transplant in the USA in an 18-day-old infant with Ebstein anomaly and subvalvular right ventricular outflow tract obstruction. The donor was anencephalic, and unfortunately the recipient died several hours following the procedure [2]. Over the next decade, many forms of complex congenital heart disease were treated with orthotropic cardiac transplantation. In 1984, Madgi Yacoub in London performed a heart transplant on a 10-day-old neonate who survived for 18 days [3]. Denton Cooley is credited with the first successful infant heart transplant, also in 1984, in which the recipient survived for 13 years. However, routine transplant survival in neonates and small infants with complex congenital heart disease would await the fateful Baby Fae experiment in October 1984, when Leonard Bailey and his Loma Linda team transplanted a baboon heart into a neonate with hypoplastic left heart syndrome (HLHS). The baby expired 3 weeks later from nonrejection causes, and Bailey would never perform another xenotransplant. Bailey subsequently performed the first successful newborn heart transplant in 1985. The recipient, transplanted at 4 days of age, is alive and well 25 years later [3].

Bailey and his team rapidly developed a world-class infant cardiac transplant program at Loma Linda, which inspired pediatric heart transplant programs throughout North America and Europe. In the USA, during the latter half of the 1980s, HLHS was the most common infant congenital cardiac malformation listed for cardiac transplantation. However, with progressive improvement in hospital survival following first stage Norwood Procedure, coupled with the ongoing donor shortages and importantly mortality (20–25%) while waiting [4▪▪], heart transplantation become a rare primary therapy for HLHS by 2005.

In the current era, congenital heart disease remains the most common indication for heart transplantation in infancy (55%), but has decreased over time, with the emphasis on surgical correction or palliation for most congenital malformations [1▪]. Congenital heart disease accounts for about 40% of heart transplants between ages 1 and 5 years, 32% between ages 6 and 10, and 23% between ages 11 and 17 years. European transplant centers tend to have a smaller proportion of pediatric transplants with congenital heart disease than the USA [1▪].

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PATIENT SELECTION

Patient selection for cardiac transplantation in the face of complex congenital heart disease (usually with one or more prior operations) involves the complex interplay between the expected survival benefit for a given patient, the obligation to maximize utility of a limited organ resource (transplantation may not be advisable if expected survival falls below some threshold which would suggest inappropriate organ wastage), and the intense regulatory oversight of the transplant outcomes at every institution. Thus, in the current era, the concept of ‘salvage transplantation’, in which the likelihood of death without transplant is a near certainty, but the risk of transplantation is excessive (more than about 25 to 30%), is not considered acceptable. In centers with active and successful pediatric heart transplant programs, difficult discussions are often necessary among members of the transplant team and other caregivers to balance programmatic success (by avoiding excess mortality) against the desire to help desperately ill patients. Nowhere is this dilemma more evident than in patients with complex congenital heart disease and a failing heart.

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INDICATIONS FOR TRANSPLANTATION IN PATIENTS WITH CONGENITAL HEART DISEASE

The major indications for cardiac transplantation with congenital heart disease are refractory heart failure usually following one or more palliative or corrective operations; unreconstructable congenital heart disease in which mortality following palliation or repair is known to be excessively high; and life-threatening arrhythmias.

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Cardiac transplant as primary therapy

Cardiac transplantation is currently rarely indicated as primary therapy for complex congenital heart disease; however, it may be considered for certain malformations with high-risk anatomic features:

  1. Single ventricle physiology (most commonly HLHS) with depressed ventricular function and severe atrioventricular valve insufficiency.
  2. Pulmonary atresia intact ventricular septum with multiple coronary–right ventricular sinusoids combined with severe proximal coronary stenoses or occlusion. Such patients are known to have a mortality exceeding 90% within 6 months [5].
  3. Neonatal Ebstein anomaly with marked cardiomegaly, severe tricuspid insufficiency, poor right ventricular function, and sluggish antegrade flow into the main pulmonary artery. Although usually treated with a palliative operation such as the Starnes procedure [6], a few particularly high-risk cases might be considered for cardiac transplantation.
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Failed single ventricle palliation

Failed single ventricle palliation is the major congenital subset referred for heart transplantation [7]. These high-risk patients will likely be increasingly referred for heart transplant evaluation as greater numbers of single ventricle babies survive initial palliative procedures.

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The failing Fontan

The progressive shift toward transplantation following multiple operations is epitomized by the failing Fontan, which presents one of the greatest challenges in pediatric transplant surgery. As with other forms of congenital cardiac surgery, results after the Fontan operation have progressively improved, such that routine survival for 20 years or more is expected [8]. However, when the physiologic construct necessary for a successful Fontan begins to fail, the fragile line between compensated heart failure and multiorgan dysfunction presents the ultimate challenge for pediatric heart failure/transplant teams. Among patients with a failing Fontan, the most common indications for transplantation are chronic heart failure (40%), protein-losing enteropathy (PLE) (40%), and acute decompensation (10%) [9]. Complete resolution of PLE is the norm following cardiac transplantation.

In the Fontan patient who develops progressive heart failure more than a decade after the Fontan procedure, the potential for hepatic fibrosis becomes an increasing concern as an important risk factor for post-transplant mortality. Many institutions perform a liver biopsy if noninvasive studies suggest possible hepatic fibrosis. However, recent evidence suggests that hepatic ultrasound elastography may have greater sensitivity for the detection of early cirrhosis by measuring liver stiffness [10,11]. A few centers have performed heart–liver transplantation in this situation [12]. However, there is not uniform agreement with this approach, with some reports of similar post-transplant survival whether or not cirrhosis was detected by computed tomography [13▪].

The considerable mortality following transplantation for the failing Fontan has caused some centers to reflect further about patient evaluation following bidirectional cavopulmonary connection, which usually precedes Fontan completion by 1–3 years. Superior survival with cardiac transplantation following the bidirectional cavopulmonary connection stage compared to a failed Fontan has been reported, and some have concluded that cardiac transplantation should be performed as an alternative to the final Fontan stage if the hemodynamic situation is suboptimal for Fontan completion [14].

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Pulmonary vascular resistance

If pulmonary vascular resistance can be measured directly, general guidelines of acceptability for heart transplantation include a transpulmonary gradient less than 15 mmHg and a pulmonary vascular resistance below 6 Wood Units (WU)m2. Some centers have accepted higher degrees of pulmonary vascular resistance, but with a greater risk of early mortality from right ventricular failure [15].

Reversibility of increased pulmonary vascular resistance is also an important consideration, since reversibility may allow successful cardiac transplantation even if the initial pulmonary vascular resistance index exceeds 6 WUm2 or the transpulmonary gradient exceeds 15. The pathophysiology of the increase in pulmonary vascular resistance in patients with congenital heart disease is often more complex than just reactive arteriolar constriction secondary to high left atrial pressure. Thus, a wider array of pharmacologic interventions may be appropriate to investigate reversibility, such as inhaled nitric oxide, prostaglandin infusion, phosphodiesterase-5 inhibitors such as sildenafil, endothelin antagonists, and dobutamine.

Some degree of elevated pulmonary vascular resistance is common in the failing Fontan, possibly related to progressive changes in the structure of the pulmonary vasculature in the absence of pulsatile flow [16]. The abnormal pulmonary vascular resistance in this setting has been documented following successful orthotopic cardiac transplantation [16]. A study of heart transplant patients’ post-Fontan failure showed persistent elevation of transpulmonary gradient (range 10–16 mmHg) and pulmonary vascular resistance (2.8–5.4 WUm2).

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Circulatory support

The poor survival of patients bridged to transplant with extracorporeal membrane oxygenator (ECMO) support (nearly 40% 1-year mortality has prompted re-examination of the appropriate strategy in this patient subset). With the availability of the Berlin Heart EXCOR (Berlin Heart Corp., Berlin, Germany) for infants and children and the HVAD (Heart Ware Inc., Framingham, Massachusetts, USA) and HeartMate II (Thoratec Corp., Pleasanton, California, USA) continuous flow pumps for older children and adolescents (off-label use), survival on the waiting list has improved, but at the possible expense of some increase in early post-transplant mortality [17]. The proportion of patients supported with these durable circulatory support devices increased from below 5% in 2000 to greater than 20% by 2010 (Pediatric Heart Transplant Study, unpublished data). Thus, ECMO-dependent patients with preserved noncardiac organ system function can usually be transitioned to a more durable device as bridge-to-transplant therapy. Many centers no longer consider ECMO a suitable support system for bridging patients to transplantation.

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MANAGEMENT OF THE SENSITIZED PATIENT

Sensitization [development of circulating antibodies against human leukocyte antigen (HLA) proteins] remains an important barrier to successful cardiac transplantation among patients with congenital heart disease who have undergone previous cardiac operations. Exposure to homograft material (most commonly as aortic patch material during the first stage Norwood procedure) is associated with long-term sensitization in greater than 50% of patients [18]. Even though they are processed and cryopreserved, human allografts can remain immunologically active [19]. The other common source of sensitization is blood transfusions at and following cardiac surgery.

Controversy exists over the proper interpretation of anti-HLA antibodies in terms of predicting hyperacute or accelerated acute rejection. HLA antibodies can be divided into those which fix complement (complement-fixing antibodies) and noncomplement-fixing antibodies. Complement-fixing antibodies are known to activate the complement cascade through the classical pathway and are more likely involved in acute allograft antibody-mediated rejection [19].

An additional advance is the C1q single antigen bead (SAB) assay, which detects only complement-fixing antibodies [20]. In clinical studies, the presence of pre-existing C1qSAB-positive donor-specific antibodies correlated highly with a positive cross-match and predicted the development of antibody-mediated rejection [21]. In contrast, noncomplement-fixing antibodies were not detrimental to the cardiac allograft.

Most centers now use virtual cross-matching to make decisions about organ suitability in sensitized patients. A virtual cross-match involves comparing the known anti-HLA antibodies of the recipient against the HLA profile of the donor. A final decision about the suitability of donor-recipient matching often requires decisions about recipient anti-HLA antibody strength and specificity. Although some centers have developed criteria for transplanting against a positive virtual cross-match, the presence of a retrospective positive cross-match portends significantly worse 2-year survival after pediatric heart transplantation.

Therapeutic options for reducing the level of sensitization prior to transplantation include plasmapheresis (applicable down to about 15 kg), intravenous immunoglobin (IVIG), and anti-B-cell agents. No clearly superior regimen has emerged, but increasing interest has focused on the combination of IVIG and either rituximab (a monoclonal antibody against the B-cell marker CD20), which directly depletes B lymphocytes, or Bortezomib (a proteasome inhibitor), which removes plasma cells from the circulation. Plasmapheresis is frequently added immediately before transplant for antibody dilution, with scheduled plasmapheresis exchanges at close intervals early after transplant while monitoring levels of donor-specific antibodies. IVIG is typically continued in the postoperative period. Improved results have been reported with these regimens in highly sensitized patients, but 1-year survival is generally reduced by 10% or more compared to a nonsensitized population [22].

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CHALLENGES IN WAIT-LIST MORTALITY

Among all pediatric age groups, infants awaiting heart transplantation experience the highest wait-list mortality [23]; 25% of infants die before a suitable donor is identified. Risk factors for infant wait-list mortality include a higher level of invasive support (ECMO and ventilator support), weight less than 3 kg, and congenital heart disease with prostaglandin support. This high wait-list mortality results not only from a shortage of available donors but also from inadequate support of seriously ill infants with ECMO and currently available ventricular assist devices. The Berlin Heart EXCOR is the only device specifically approved for infant support, yet the pretransplant mortality among infants with operated congenital heart disease who receive a Berlin Heart EXCOR exceeds 90% [24], emphasizing the critical need for more effective mechanical circulatory support systems for small infants.

‘ABO-incompatible heart transplantation’ was intended to reduce waiting time mortality among suitable recipients. Multiple studies indicate survival and freedom from rejection similar to ABO-compatible transplants [25]. While this strategy has succeeded in reducing wait-list mortality in Canada [26], no reduction in wait-list mortality has yet been documented among infants listed for ABO-incompatible heart transplantation in the USA [23].

Among older patients, the failing Fontan presents critical challenges when the hemodynamic state worsens rapidly. The absence of a pumping chamber for the pulmonary circulation subjects them to the ravages of profound reduction of cardiac output combined with severe systemic venous congestion. In a multi-institutional study from the Pediatric Heart Transplant Study, patients requiring continuous inotropic support or ventilator support had a wait-list mortality exceeding 40% within 6 months of listing [27]. Death before transplant was prominent among patients who developed circulatory failure within 6 months of the Fontan procedure. The absence of an adequate reservoir in the Fontan circuit to provide effective inflow to either pulsatile or continuous flow devices, if right-sided support becomes necessary, has greatly limited the options for mechanical circulatory support in the rapidly deteriorating Fontan patient.

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SURGICAL CHALLENGES

The surgical challenges in heart transplantation for many forms of complex congenital heart disease differ vastly from the usually straightforward transplant operation for cardiomyopathy. The patient with complex congenital heart disease typically has endured multiple prior operations, often with an enlarged heart in close proximity to the sternum. Some degree of hepatic dysfunction is typical, and a severe coagulopathy is standard in these patients. The operations are often performed at night, setting the stage for surgeon fatigue, particularly if graft function is not optimal and ongoing bleeding becomes destabilizing. Reconstructive procedures on the pulmonary arteries, rerouting of anomalous systemic venous drainage, revising previous arch reconstruction, and adapting the new heart to native cardiac positional anomalies can present important technical challenges. Given the importance of warm ischemic time, a common practice at our institution, as well as others [28], is to use other reconstructive materials rather than donor tissue for parts of the cardiac reconstructions at the time of transplant. This allows the donor heart to remain in the transport canister at very low temperatures until the time of actual implantation. With this strategy, bovine pericardial patches are suitable for extensive pulmonary artery reconstruction, and GoreTex (W.L. Gore and Associates, Arizona, USA) patch material is useful for arch repairs, as well as for reconstructing the interatrial septum to accommodate anomalies of systemic or pulmonary venous connection.

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SURVIVAL

By most analyses, a diagnosis of congenital heart disease is an important risk factor for mortality after pediatric cardiac transplantation [1▪]. The decrement in survival is accounted for by the increased mortality in the first 3 months after transplant, after which the survival curve parallels that of transplant for cardiomyopathy. The 1-year mortality for pediatric transplantation for congenital heart disease ranges between 10 and 20%. Data from the International Society for Heart and Lung Transplantation (ISHLT) Pediatric Heart Transplant Registry indicate that 10-year survival for patients transplanted for congenital heart disease is about 10% lower than for cardiomyopathy [1▪].

Among patients with congenital heart disease, risk factors for post-transplant mortality include the need for ECMO support, younger age at listing [29], renal dysfunction, higher bilirubin, mechanical ventilation, lower body surface area, panel reactive antibody greater than 10%, and prior Fontan procedure [30▪,31]. The effect of prior cardiac operations is apparent from another analysis which indicates a similar survival among infants transplanted for unrepaired congenital heart disease compared to those with cardiomyopathy [4▪▪]. However, survival following failed palliation for single ventricle carries the highest mortality for infant cardiac transplantation (particularly when renal dysfunction is present before transplant) [32], with 1-year survival of 70 versus 89% for cardiomyopathy. Major challenges remain in the subset of patients with HLHS who require cardiac transplantation in infancy after previous palliative surgery. The 30% 1-year mortality after transplant has not improved in the current era. Another single-center study found similar favorable outcomes after the Glenn stage of single ventricle palliation compared to other forms of infant congenital heart disease [33▪].

The higher transplant mortality among patients with prior congenital heart operations and in particular the Fontan operation likely reflect the cumulative impact of longer warm ischemic time required for cardiac reconstruction at the time of transplant, a higher incidence of HLA sensitization (particularly with the use of allograft patch material and/or multiple prior operations), and frequent baseline renal insufficiency.

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LATE OUTCOMES AFTER PEDIATRIC HEART TRANSPLANTATION FOR CONGENITAL HEART DISEASE

In a cohort of patients from Loma Linda in which more than 75% had congenital heart disease, 10% of survivors beyond 15 years required either renal transplantation or chronic dialysis [34▪]. The major causes of late mortality were allograft vasculopathy, post-transplant lymphoproliferative disease, and acute rejection. The late survival of patients transplanted during infancy was significantly better than older patients, possibility related to greater immunologic graft acceptance. Somewhat disappointing was the finding that even though over 75% of the patients were transplanted as infants (of which a third were neonates), allograft vasculopathy developed in over 30% of long-term survivors.

Medication noncompliance represents a special challenge in pediatric transplant patients who reach late adolescence and is likely a major root cause of teenage mortality [35]. The incidence of medication nonadherence increases dramatically with the onset of teen years, with a mortality exceeding 30% within 2 years after documented noncompliance. Major programmatic resources are necessary to favorably modify this behavior. Despite these challenges, most long-term survivors of this miraculous intervention enjoy an excellent quality of life and are often working and living independently [36].

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CONCLUSION

Cardiac transplantation for complex congenital heart disease remains one of the greatest triumphs in modern cardiac surgery. Despite seemingly impenetrable barriers, the vast majority of these patients with no other medical options survives and enjoy many years of excellent life quality. Future breakthroughs must include better mechanical circulatory support systems to bridge infants and failing Fontan patients, as well as improved strategies (possibly xenotransplantation) to overcome the deficit of available donors for infants.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

Dr Kirklin has no conflict of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1▪. Dipchand AI, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Seventeenth Official Pediatric Heart Transplantation Report – 2014: Focus Theme: Retransplantation. JHLT 2014; 33:985–995.

Detailed analysis of the world database for pediatric heart transplantation.

2. Kantrowitz A, Haller JD, Joos H, et al. Transplantation of the heart in an infant and an adult. Am J Cardiol 1968; 22:782–790.
3. Chinnock RE, Bailey LL. Heart transplantation for congenital heart disease in the first year of life. Curr Cardiol Rev 2011; 7:72–84.
4▪▪. Hsu DT, Lamour JM. Changing indications for pediatric heart transplantation complex congenital heart disease. Circulation 2015; 131:91–99.

Outstanding overview of current challenges in heart transplantation for congenital heart disease. The authors also discuss specific heart failure issues in this patient population.

5. Calder AL, Peebles CR, Occleshaw CJ. The prevalence of coronary arterial abnormalities in pulmonary atresia with intact ventricular septum and their influence on surgical results. Cardiol Young 2007; 17:387–396.
6. Starnes VA, Pitlick PT, Bernstein D, et al. Ebstein's anomaly appearing in the neonate. A new surgical approach. Thorac Cardiovasc Surg 1991; 101:1082–1087.
7. Voeller RK, Epstein DJ, Guthrie TJ, et al. 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.
8. Dabal RJ, Kirklin JK, Kukreja M, et al. The modern Fontan operation shows no increase in mortality out to 20 years: a new paradigm. J Thorac Cardiovasc Surg 2014; 148:2517–2524.
9. Davies RR, Sorabella RA, Yang J, et al. Outcomes after transplantation for ‘failed’ Fontan: a single-institution experience. J Thorac Cardiovasc Surg 2012; 143:1183–1192.
10. Yoo BW, Choi JY, Eun LY, et al. Congestive hepatopathy after Fontan operation and related factors assessed by transient elastography. J Thorac Cardiovasc Surg 2014; 148:1498–1505.
11. Wu FM, Opotowsky AR, Raza R, et al. Transient elastography may identify Fontan patients with unfavorable hemodynamics and advanced hepatic fibrosis. Congenit Heart Dis 2014; 9:438–447.
12. Vallabhajosyula P, Komlo C, Wallen TJ, et al. Combined heart-liver transplant in a situs-ambiguous patient with failed Fontan physiology. J Thorac Cardiovasc Surg 2013; 145:e39–e41.
13▪. Simpson KE, Esmaeeli A, Khanna G, et al. Liver cirrhosis in Fontan patients does not affect 1-year postheart liver mortality or markers of liver function. J Heart Lung Transplant 2014; 33:170–177.

Provocative study suggesting that Fontan patients with early cirrhosis can be safely transplanted.

14. Razzouk AJ, Bailey LL. Heart transplantation in children for end-stage congenital heart disease. Semin Thorac Cardiovasc Surg Pediatr Card Surg Ann 2014; 17:69–76.
15. Mora BN, Huddleston CB. Heart transplantation in biventricular congenital heart disease: indications, techniques, and outcomes. Curr Cardiol Rev 2011; 7:92–101.
16. Gazit AZ, Canter CE. Impact of pulmonary vascular resistances in heart transplantation for congenital heart disease. Curr Cardiol Rev 2011; 7:59–66.
17. Botha P, Solana R, Cassidy J, et al. The Impact of mechanical circulatory support on outcomes in paediatric heart transplantation. Eur J Cardiothorac Surg 2013; 44:836–840.
18. O’Connor MJ, Lind C, Tang X, et al. Persistence of antihuman leukocyte antibodies in congenital heart disease late after surgery using allografts and whole blood. J Heart Lung Transplant 2013; 32:390–397.
19. Castleberry C, Ryan TD, Chin C. Transplantation in the highly sensitized pediatric patient. Circulation 2014; 129:2313–2319.
20. Chin C, Chen G, Sequeria F, et al. Clinical usefulness of a novel C1q assay to detect immunoglobulin G antibodies capable of fixing complement in sensitized pediatric heart transplant patients. J Heart Lung Transplant 2011; 30:158–163.
21. Zeevi A, Lunz J, Feingold B, et al. Persistent strong anti-HLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients. J Heart Lung Transplant 2013; 32:98–10522.
22. Pollock-BarZiv SM, den Hollander N, Ngan B-Y, et al. Pediatric heart transplantation in human leukocyte antigen sensitized patients. Circulation 2007; 116:172–178.
23. Mah D, Singh TP, Thiagarajan RR, et al. Incidence and risk factors for mortality in infants awaiting heart transplantation in the USA. J Heart Lung Transplant 2009; 28:1292–1298.
24. Almond CS, Gauvreau K, Canter CE, et al. A risk-prediction model for in-hospital mortality after heart transplantation in US children. Am J Transplant 2014; 12:1240–1248.
25. Henderson HT, Canter CE, Mahle WT, et al. ABO-incompatible heart transplantation: analysis of the Pediatric Heart Transplant Study (PHTS) database. J Heart Lung Transplant 2012; 31:173–179.
26. West LJ, Karamlou T, Dipchand AI, et al. Impact on outcomes after listing and transplantation, of a strategy to accept ABO Blood group-incompatible donor hearts for neonates and infants. J Thorac Cardiovasc Surg 2006; 131:455–461.
27. Bernstein D, Naftel DC, Chin C, et al. Outcome of listing for cardiac transplantation for failed Fontan: a multiinstitutional study. Circulation 2006; 114:273–280.
28. Lyengar AJ, Sharma VJ, Weintraub RG, et al. Surgical strategies to facilitate heart transplantation in children after failed univentricular palliations: the role of advanced intraoperative surgical preparation. Eur J Cardiothorac Surg 2014; 46:480–485.
29. Jeewa A, Manlhiot C, Kantor PF, et al. Risk Factors for mortality or delisting of patients from the pediatric heart transplant waiting list. J Thorac Cardiovasc Surg 2014; 147:462–468.
30▪. Schumacher KR, Almond C, Singh TP, et al. Predicting graft loss by 1 year in pediatric heart transplantation candidates. Circulation 2015; 131:890–898.

This multi-institutional study identified risk factors in the current era for mortality after cardiac transplantation for congenital heart disease.

31. Almond CS, Gauvreau K, Cante CE, et al. A risk-prediction model for in-hospital mortality after heart transplantation in US children. Am J Transplant 2012; 12:1240–1248.
32. Everitt MD, Boyle GJ, Schechtman KB, et al. Early survival after heart transplant in young infants is lowest after failed single-ventricle palliation: a multiinstitutional study. J Heart Lung Transplant 2012; 31:509–516.
33▪. Alsoufi B, Deshpande S, McCracken C, et al. Results of heart transplantation following failed staged palliation of hypoplastic left heart syndrome and related single ventricle anomalies. Eur J Cardiothorac Surg 2015; 1–8.[Epub ahead of print].

Outstanding results with cardiac transplantation after failed palliation for hypoplastic left heart syndrome.

34▪. Copeland H, Razzouk A, Chinnock R, et al. Pediatric recipient survival beyond 15 post-heart transplant years: a single-center experience. Ann Thorac Surg 2014; 98:2145–2151.

Nice analysis of transplant outcomes beyond 15 years in a cohort with 75% congenital heart disease.

35. Oliva M, Singh TP, Gauvreau K, et al. Impact of medication nonadherence on survival after pediatric heart transplantation in the USA. J Heart Lung Transplant 2013; 32:881–888.
36. Hollander SA, Chen S, Luikart H, et al. Quality of life and metrics of achievement in long-term adult survivors of pediatric heart transplant. Pediatr Transplant 2015; 19:76–81.
Keywords:

failing Fontan; pediatric cardiac transplantation; pediatric heart failure; single ventricle; uncorrectable congenital heart disease

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