Pediatric heart transplantation: Looking forward after five decades of learning.

Heart transplantation has become the standard of care for pediatric patients with end-stage heart disease throughout the world. Since the first transplant was performed in 1967, the number of transplants has grown dramatically with 13 449 pediatric heart transplants being reported to The International Society of Heart and Lung Transplant (ISHLT) between January 1992 and June 30, 2018. Outcomes have consistently improved over the last few decades, specifically short-term outcomes. Most recent survival data demonstrate that recipients who survive to 1-year post-transplant have excellent long-term survival with more than 60% of those who were transplanted as infants being alive 25 years later. Nonetheless, the rates of graft loss beyond the first year have remained relatively constant over time; driven primarily by our poor understanding and lack of treatments for chronic allograft vasculopathy (CAV). Acute rejection, CAV, graft failure, and infection continue to be the major causes of death within the first 5 years post-transplant. In addition, renal dysfunction, malignancy, and the need for re-transplantation remain as significant issues that require close follow-up. Looking forward, key challenges include improving donor utilization rates (including donation after cardiac death (DCD) and the use of ex vivo perfusion devices), the development of non-invasive biomarkers for rejection, efforts to mitigate the long-term effects of immunosuppression, and prevention of CAV. It is not possible to cover the entire evolution of pediatric heart transplantation over the last five decades, but in this review, we hope to touch on key observations, lessons learned, and practice changes that have advanced the field, as well as glance ahead to the next decade.

The IPTA Nashville Consensus Conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: III - Consensus guidelines for Epstein-Barr virus load and other biomarker monitoring.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein-Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre-emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre-emptive interventions in patients who are EBV seronegative pre-transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre-transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre-emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority.

Impact of donor-specific anti-HLA antibody on cardiac hemodynamics and graft function 3 years after pediatric heart transplantation: First results from the CTOTC-09 multi-institutional study.

The aim of this study (CTOTC-09) was to assess the impact of "preformed" (at transplant) donor-specific anti-HLA antibody (DSA) and first year newly detected DSA (ndDSA) on allograft function at 3 years after pediatric heart transplantation (PHTx). We enrolled children listed at 9 North American centers. The primary end point was pulmonary capillary wedge pressure (PCWP) at 3 years posttransplant. Of 407 enrolled subjects, 370 achieved PHTx (mean age, 7.7 years; 57% male). Pre-PHTx sensitization status was nonsensitized (n = 163, 44%), sensitized/no DSA (n = 115, 31%), sensitized/DSA (n = 87, 24%), and insufficient DSA data (n = 5, 1%); 131 (35%) subjects developed ndDSA. Subjects with any DSA had comparable PCWP at 3 years to those with no DSA. There were also no significant differences overall between the 2 groups for other invasive hemodynamic measurements, systolic graft function by echocardiography, and serum brain natriuretic peptide concentration. However, in the multivariable analysis, persistent first-year DSA was a risk factor for 3-year abnormal graft function. Graft and patient survival did not differ between groups. In summary, overall, DSA status was not associated with worse allograft function or inferior patient and graft survival at 3 years, but persistent first-year DSA was a risk factor for late graft dysfunction.

Heart transplantation in neonatal Marfan syndrome: Saving life in a rare and fatal condition.

BACKGROUND: Neonatal Marfan syndrome is a rare disease with mortality in the first year of life reported as high as 95% predominantly due to progressive heart failure from valvar regurgitation and cardiomyopathy. Multisystem involvement and uncertain prognosis have historically precluded transplant candidacy, and current management options are of limited success. CASE REPORT: We present a baby girl with a postnatal diagnosis of neonatal Marfan syndrome who at 1 year of age underwent mitral valve and tricuspid valve repair with postoperative profound left ventricular and moderate right ventricular dysfunction necessitating biventricular assist device (BiVAD) support and subsequent heart transplant. A number of noncardiac issues persisted in our patient; however, she enjoyed a good quality of life for the initial 3 years posttransplant. Unfortunately, she subsequently developed rapidly progressive coronary allograft vasculopathy (CAV) with progressive deterioration in function and cardiac arrest. CONCLUSION: To our best knowledge, this is only the second case of neonatal Marfan syndrome to undergo heart transplant reported in the literature and the first with BiVAD support as a bridge to candidacy. This is also the first case of neonatal Marfan syndrome associated with intragenic duplication. This case though demonstrating that earlier listing, ventricular assist device (VAD) support and even primary transplant as treatment in neonatal Marfan syndrome should all be considered viable options but also portends a cautionary tale given the spectrum of comorbidities in this rare and severe disorder.

Assessment of liver fibrosis using a 3-dimensional high-resolution late gadolinium enhancement sequence in children and adolescents with Fontan circulation.

OBJECTIVES: To assess abnormal liver enhancement on 15-20 min delayed 3D high-resolution late gadolinium enhancement (3D HR LGE) sequence in patients with Fontan circulation. METHODS: Retrospective study of pediatric Fontan patients (< 18 years old) with combined cardiac-liver MRI from January 2018 to August 2021. Abnormal hepatic enhancement was graded (0-3) for each lobe, summed for a total liver enhancement score (0-6), and compared to repaired tetralogy of Fallot (rTOF) patients. Correlations with other hepatic imaging biomarkers were performed. Temporal relationships of enhancement compared to traditional early portal venous and 5-7-min delayed phase liver imaging were analyzed. RESULTS: The Fontan group (n = 35, 13 ± 3.4 years old, median time from Fontan 10 (9-12) years) had 23/35 (66%) with delayed 3D HR LGE total liver enhancement score > 0 (range 0-5), with greater involvement of the right lobe (1 (0-1) vs 0 (0-1), p < 0.01). The rTOF group (n = 35, 14 ± 2.6 years old) had no abnormal enhancement. In the Fontan group, total liver enhancement was 3 (2-4) in the early portal venous phase, lower at 1 (1-2) in the 5-7-min delayed phase (p < 0.01), and lowest at 1 (0-2) in the 15-20-min delayed phase (p = 0.03). 3D HR LGE enhancement correlated inversely with portal vein flow (rs = - 0.42, p = 0.01) and positively with left lobe stiffness (rs = 0.51, p < 0.01). The enhancement score decreased in 13/35 (37%) between the 5-7- and 15-20-min delayed phases. CONCLUSIONS: Liver fibrosis can be assessed on 3D HR LGE sequences in patients with Fontan circulation, correlates with other imaging biomarkers of Fontan liver disease, and may add information for hepatic surveillance in this population. KEY POINTS: • Abnormal liver enhancement on 3D HR LGE sequences in Fontan patients likely represents liver fibrosis and is seen in up to 66% of children and adolescents with variable distribution and severity. • The degree of 3D HR LGE liver enhancement correlates with decreased portal vein flow and increased left hepatic lobe stiffness.

International practice heterogeneity in pre-transplant management of pulmonary hypertension related to pediatric left heart disease.

BACKGROUND: Elevated pulmonary vascular resistance (PVR) in the setting of left heart failure may contribute to poor outcomes after pediatric heart transplant (HTx), but peri-transplant management is variable. METHODS: We sought to characterize international practice by surveying physicians at pediatric HTx centers. RESULTS: We received 49 complete responses from 39 centers in 16 countries. Most respondents are pediatric cardiologists (90%), practice at centers offering heart (86%) and lung (55%) transplant, and perform pre-HTx acute vasoreactivity testing (AVT, 88%) in patients with elevated PVR. Half (51%) reported defining a PVR cutoff for HTx eligibility as ≤6 WU m2 (56%) post-AVT (84%). The highest post-AVT PVR ever accepted for HTx ranged from 3-14.4 (median 6) WU m2 . To treat elevated pre-transplant PVR, phosphodiesterase type 5 inhibitors are most common (65%) followed by oxygen (31%), nitric oxide (14%), endothelin receptor antagonists (11%), and prostacyclins (6%). Nearly a third (31%) do not routinely use pulmonary vasodilators without implantation of a left ventricular assist device (LVAD). Case scenarios highlight treatment variability: in a restrictive cardiomyopathy scenario, HTx listing with post-transplant vasodilator therapy was favored, whereas in a Shone's complex patient with fixed PVR, LVAD ± pulmonary vasodilators followed by repeat catheterization was most common. Management of dilated cardiomyopathy with reactive PVR was variable. Most continue vasodilator therapy until HTx (16%), PVR normalizes (16%) or ≤6 months. CONCLUSIONS: Management of elevated PVR in children awaiting HTx is heterogenous. Evidence-based guidelines are needed to allow for longitudinal determination of optimal outcomes and standardized care.

Allocation to pediatric recipients around the world: An IPTA global survey of current pediatric solid organ transplantation deceased donation allocation practices.

BACKGROUND: There has not been a comprehensive global survey of pediatric-deceased donor allocation practices across all organs since the advent of deceased donor transplantation at the end of the 20th century. As an international community that is responsible for transplanting children, we set out to survey the existing landscape of allocation. We aimed to summarize current practices and provide a snapshot overview of deceased donor allocation practices to children across the world. METHODS: The International Registry in Organ Donation and Transplantation (IRODAT, www.irodat.org) was utilized to generate a list of all countries in the world, divided by continent, that performed transplantation. We reviewed the published literature, published allocation policy, individual website references and associated links to publicly available listed allocation policies. Following this, we utilized tools of communication, relationships, and international fellowship to confirm deceased donation pediatric centers and survey pediatric allocation practices for liver, kidney, heart, and lung across the world. We summarize pediatric allocation practices by organ when available using source documents, and personal communication when no source documents were available. RESULTS: The majority of countries had either formal or informal policies directed toward minimizing organ distribution disparity among pediatric patients. CONCLUSION: Children have long-term life to gain from organ donation yet continue to die while awaiting transplantation. We summarize global strategies that have been employed to provide meaningful and sustained benefit to children on the waitlist.

Quantification of lymphatic burden in patients with Fontan circulation by T2 MR lymphangiography and associations with adverse Fontan status.

AIMS: To quantify thoracic lymphatic burden in paediatric Fontan patients using MRI and correlate with clinical status. METHODS AND RESULTS: Paediatric Fontan patients (<18-years-old) with clinical cardiac MRI that had routine lymphatic 3D T2 fast spin echo (FSE) imaging performed from May 2017 to October 2019 were included. 'Lymphatic burden' was quantified by thresholding-based segmentation of the 3D T2 FSE maximum intensity projection image and indexed to body surface area, performed by two independent readers blinded to patient status. There were 48 patients (27 males) with median age at MRI of 12.9 (9.4-14.7) years, time from Fontan surgery to MRI of 9.1 (5.9-10.4) years, and follow-up time post-Fontan surgery of 9.4 (6.6-11.0) years. Intraclass correlation coefficient between two observers for lymphatic burden was 0.96 (0.94-0.98). Greater lymphatic burden correlated with post-Fontan operation hospital length of stay and duration of chest tube drainage (rs = 0.416, P = 0.004 and rs = 0.439, P = 0.002). Median lymphatic burden was greater in patients with chylous effusions immediately post-Fontan (178 (118-393) vs. 113 (46-190) mL/m2, P = 0.028), and in patients with composite adverse Fontan status (n = 13) defined by heart failure (n = 3), transplant assessment (n = 2), recurrent effusions (n = 6), Fontan thrombus (n = 2), and/or PLE (n = 6) post-Fontan (435 (137-822) vs. 114 (51-178) mL/m2, P = 0.003). Lymphatic burden > 600 mL/m2 was associated with late adverse Fontan status with sensitivity of 57% and specificity of 95%. CONCLUSION: Quantification of MR lymphatic burden is a reliable tool to assess the lymphatics post-Fontan and is associated with clinical status.

The IPTA Nashville consensus conference on post-transplant lymphoproliferative disorders after solid organ transplantation in children: I-Methodology for the development of consensus practice guidelines.

The International Pediatric Transplant Association (IPTA) Consensus Conference on Practice Guidelines for the Diagnosis, Prevention, and Management of Post-Transplant Lymphoproliferative Disorders after Solid Organ Transplantation in Children took place on March 12-13, 2019, and the work of conference members continued until the end of December 2021. The goal was to produce evidence-based consensus guidelines on the definitions, diagnosis, prevention, and management of PTLD and related disorders based on the critical review of the literature and consensus of experts. This report describes the goals, organization, and methodology of the consensus conference and follow-up activities. The results of each working group (Definitions, Prevention, Management, and Epstein-Barr viral [EBV] load/Biomarker Monitoring) are presented in separate manuscripts within this volume of Pediatric Transplantation.

The IPTA Nashville consensus conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: II-consensus guidelines for prevention.

The International Pediatric Transplant Association (IPTA) convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorder after solid organ transplantation in children. In this report from the Prevention Working Group, we reviewed the existing literature regarding immunoprophylaxis and chemoprophylaxis, and pre-emptive strategies. While the group made a strong recommendation for pre-emptive reduction of immunosuppression at the time of EBV DNAemia (low to moderate evidence), no recommendations for use could be made for any prophylactic strategy or alternate pre-emptive strategy, largely due to insufficient or conflicting evidence. Current gaps and future research priorities are highlighted.

Eplet matching in pediatric heart transplantation: The SickKids experience.

BACKGROUND: Epitope-based tissue matching may be superior to HLA antigen matching. We compared antigen to molecular-level HLA matching on outcomes following pediatric heart transplantation (HTx). METHODS: This is a retrospective, single centre cohort study (2013-2020). HLA antigen and eplet mismatch analyses were performed in HTx patients <18 years old. Primary endpoint was graft loss; secondary endpoints were rejection and cardiac allograft vasculopathy (CAV). A multivariable Cox regression analysis was used to examine associations between eplet or antigen mismatching and outcomes. A logistic regression analysis was performed to examine associations between eplet or antigen mismatching and outcomes. RESULTS: Seventy-seven patients (40% males) were included, with a median age at HTx 4.3 years [range 0.05-18]. Median HLA class I and II eplet mismatches were 10 (1-22) and 11 (1-23). Median class I and II antigen mismatches were 5 (1-6) and 4 (0-6). 9 patients (11.7%) died [median time 4 months (range 0.1-46)]. Eight (10.4%) patients developed AMR [median time 22 days (IQR = 168)]. Twenty-one patients (27.3%) had acute cellular rejection [median time 40 days (IQR = 85.5)]. In univariate analysis, patients with HLA Class II DPB eplet mismatches above the median for this cohort had an increased risk of graft loss (OR 5.3 [95%CI: 1.03-27.5], p = 0.039). HLA eplet mismatching was not associated with rejection; antigen mismatching was not associated with either graft loss or rejection. In multivariable analysis, patients with HLA Class II DPB eplet mismatches above the median had an increased risk of graft loss (HR 8.14 [95% CI: 1.26-49], p = 0.02). HLA eplet mismatching was not associated with rejection; antigen mismatching was not associated with graft loss or rejection. A logistic regression analysis including 'number of HLA Class II DPB eplet mismatches' correctly predicted 95.8% of the outcomes. CONCLUSION: In our cohort of pediatric heart transplant recipients, the number of HLA Class II DPB eplet mismatches was associated with graft loss. Molecular-level HLA matching is an emerging tool for graft loss risk stratification, but further study is required.

Experience of ethical dilemmas among professionals working in pediatric transplantation: An international survey.

BACKGROUND: Professionals working in pediatric transplantation commonly encounter complex ethical dilemmas. Most ethical research in transplantation is related to adult practice. We aimed to gain insight into ethical issues faced by transplant professionals when dealing with pediatric transplant recipients. METHODS: A two-stage study was designed; the first part was a questionnaire completed by 190 (80%) members of the International Pediatric Transplant Association (IPTA) from over 30 different countries. This was followed by a multidisciplinary focus group that explored the preliminary data of the survey. RESULTS: A total of 38% (56 of 149) respondents of the questionnaire had experienced an ethical issue between 2016 and 2018. Surgeons were more likely to have encountered an ethical issue as compared with physicians (60% vs. 35.7%, p = .035). Clinicians from Europe were more likely to have experienced an ethical issue in living organ donation compared with those from North America (78.9% vs. 52.5%, p = .005), with common ethical concerns being psychosocial evaluation and follow-up care of donors. The focus group highlighted the importance of a multidisciplinary approach to ethical issues. CONCLUSION: The results of this study can direct future research into pediatric transplantation ethics with the aim of producing educational resources, policies, and ethical guidelines.

MRI Phase-Contrast Blood Flow in Fasting Pediatric Patients with Fontan Circulation Correlates with Exercise Capacity.

Purpose: To assess regional blood flow in fasting pediatric patients with Fontan circulation by using MRI and to explore associations with clinical parameters. Materials and Methods: In this retrospective study, pediatric patients who had undergone the Fontan procedure (<18 years of age) and had undergone clinical cardiac MRI, performed after at least 4 hours of fasting, between 2018 and 2021 were included. Regional blood flow was compared with published healthy volunteer data (n = 19) and assessed in relation to hemodynamic parameters and clinical status. Data are presented as medians, with first to third quartiles in parentheses. Mann-Whitney U, Kruskal-Wallis, χ2, and Spearman rank correlation tests were used. Results: Fifty-five patients (38 boys) with median age at MRI of 14 years (IQR, 11-16 years) and median time from Fontan procedure to MRI of 10 years (IQR, 8-12 years) were included. Patients after Fontan procedure had lower ascending aortic, inferior vena cava, and total systemic blood flow compared with healthy volunteers (3.00 L/min/m2 [IQR, 2.75-3.30 L/min/m2] vs 3.61 L/min/m2 [IQR, 3.29-4.07 L/min/m2]; 1.73 L/min/m2 [IQR, 1.40-1.94 L/min/m2] vs 2.24 L/min/m2 [IQR, 2.06-2.75 L/min/m2]; 2.78 L/min/m2 [IQR, 2.45-3.10 L/min/m2] vs 3.95 L/min/m2 [IQR, 3.20-4.30 L/min/m2], respectively; P < .001). Portal vein flow was greater than hepatic vein flow in 25% of patients. Fontan blood flow was inversely correlated with pre-Fontan mean pulmonary artery pressure (Spearman rank correlation coefficient [rs ]= -0.42, P = .005) and ventricular end diastolic pressure (rs = -0.33, P = .04) and positively correlated with post-Fontan percent predicted oxygen consumption at peak workload (rs = 0.34, P = .02). Conclusion: Reference ranges are provided for regional systemic blood flow derived by using MRI in fasting pediatric patients with Fontan circulation, who had lower systemic blood flow compared with healthy volunteers. Lower fasting Fontan blood flow correlated with lower exercise capacity.Keywords: Pediatrics, Heart, Congenital, MR Imaging, Hemodynamics/Flow Dynamics, Cardiac Supplemental material is available for this article. © RSNA, 2022.

The evolution of pediatric heart retransplantation over three decades: An analysis from the PHTS.

BACKGROUND: Retransplantation is rare and associated with worse survival and more morbidity. The study aim is to describe an updated cohort of pediatric retransplants, determine if there has been an era effect on outcomes, and understand if identified trends are explained by changes in patient selection. METHODS: Pediatric Heart Transplant Society database analysis of retransplantation patients <18 years of age (Era 1: 1993-2001, Era 2: 2002-2010, Era 3: 2011-2018). Multivariate analysis identified risk factors for graft loss. Multiphase parametric hazard modeling was used to depict era and risk factor effect. RESULTS: Survival was lower (p < .0001) for retransplant (n = 222) compared to primary transplant (n = 6548) (median 9.3 vs 20.2 years). Median survival increased from Era 1 to 2 (4.8 vs 9.3 years; p < .0001) with no incremental change in Era 3. Era 2 and 3 retransplants had a longer inter-transplant interval (p < .0001), were less frequently for early graft failure (p = .0004) or acute rejection (p = .007), more frequently from a ventricular assist device (p = .0014), and less frequently from extracorporeal membrane oxygenation (p = .0024). Predictors of graft loss included Era 1 (HR 10.55, p = .001), congenital heart disease (HR 4.42, p = .01), inter-transplant interval <1 year (HR 5.34, p = .002), and mechanical support (ventricular assist device HR 7.47, p = .0042; extracorporeal membrane oxygenation HR 10.09, p < .0001). For each 1-year increase in inter-transplant interval, graft loss risk decreased by 1.15 (p = .0002). Retransplantation was associated with more rejection, infection, and allograft vasculopathy. CONCLUSIONS: Graft survival has improved in pediatric retransplants making it a viable option in select patients. Retransplantation should be avoided in the setting of early graft failure especially requiring mechanical support.

"Acquired" Brugada syndrome in a cardiac allograft.

INTRODUCTION: Brugada syndrome is an inherited channelopathy characterized by arrhythmia and an increased risk of sudden cardiac death (SCD). Implantation of a defibrillator for primary or secondary prevention is the only effective strategy to decrease the risk of SCD in Brugada syndrome. We present a case in which a cardiac donor had a pathogenic variant for Brugada syndrome, discovered on genetic testing after transplantation. CASE REPORT: A young child with dilated cardiomyopathy underwent orthotopic heart transplantation from a donor with in-hospital cardiac arrest in the context of fever and a normal ECG. Approximately 1 month after transplant, the donor's post mortem genetic testing revealed a pathogenic loss-of-function SCN5A variant associated with Brugada syndrome, which was confirmed on genetic testing on a post-transplant endomyocardial biopsy from the recipient. The recipient's post-transplant electrocardiographic monitoring revealed persistent right bundle branch block and progressive, asymptomatic sinus node dysfunction. The recipient was managed with precautionary measures including aggressive fever management, avoidance of drugs that increase arrhythmia risk in Brugada syndrome, and increased frequency of arrhythmia surveillance. The recipient remains asymptomatic at over 3 years post-transplant with preserved graft function and no documented ventricular arrhythmias. CONCLUSION: We describe the clinical course of "acquired" Brugada syndrome in a cardiac allograft recipient, which has not been previously reported. The time-sensitive nature of donor organ selection, especially in critically ill recipients, combined with the growing use of molecular autopsies in patients with unexplained etiologies for death may increasingly result in important donor genetic information being made available after transplantation.

Early experience with varicella vaccination in pediatric heart transplant recipients.

International consensus guidelines to vaccinate children after solid organ transplant with the live-attenuated varicella (VZV) vaccine exclude pediatric heart transplant recipients due to insufficient evidence for safety, seroconversion rate, or adverse event profile. Caution is also recommended in the setting of mycophenolate mofetil (MMF) immunosuppression. However, VZV infection in these patients can be serious or even fatal. We report our novel early experience with VZV vaccination in a cohort of 31 children following heart transplantation, 42% of who were on MMF. The early seroconversion rate was 16/17 (94%) with no major adverse events. Though a rash of some description was reported in 29%, spots were few and self-resolving in 1-3 days. Select pediatric heart transplant patients can be safely vaccinated with VZV vaccine with a high early seroconversion rate and a mild adverse event profile.

Heart Transplant Indications, Considerations, and Outcomes in Fontan Patients: Age-Related Nuances, Transplant Listing, and Disease-Specific Indications.

In the current era, 5%-10% of Fontan patients die or need a transplant in childhood, and approximately 50% will experience the same fate by age 40 years. Heart transplant (HTx) can be successful for selected children and adults with Fontan circulatory failure of any mechanism, with a 1-year post-transplant survival rate approaching 90% in children and 80% in the largest single-centre adult Fontan HTx experience. Protein-losing enteropathy and plastic bronchitis can be expected to resolve post-transplant, and limited data suggest patients with Fontan-associated liver disease who survive HTx can expect improvement in liver health. Early Fontan failure, within 12 months of Fontan completion, is not easily rescued by HTx, and late referrals and failure to refer adult patients remain problematic. Very little is known about the numbers of patients who are not referred, are turned down following assessment for HTx, or die on the waiting list-numbers that are needed to understand the complete picture of HTx in the Fontan population and to identify where best to focus quality-improvement efforts. Recent revisions to listing prioritization in Canada with considerations specific to the Fontan population aim to mitigate the fact that the status-listing criteria are not tailored to the congenital heart population. Transplanting high-risk children prior to Fontan completion, developing adult congenital heart disease transplant centres with expertise that can also offer combined heart-liver transplant when appropriate, and improving single-ventricle mechanical support options and criteria for both adults and children may help mitigate the early post-listing mortality.

Coagulation and Anticoagulation in Fontan Patients.

Patients with a Fontan circulation for single-ventricle physiology are at increased risk of developing thromboembolic events. Thromboembolic events can lead to failure of the Fontan circulation, chronic sequelae in case of stroke, and early mortality. Controversies exist regarding the substrates, risk factors, and optimal detection methods for thromboembolic events. Despite the major clinical implications, there is currently no consensus regarding the optimal antithrombotic therapy to prevent or treat thromboembolic events after the Fontan procedure. In this review we aimed to untangle the available literature regarding antithrombotic prophylaxis and treatment for pediatric and adult Fontan patients. A decision-tree algorithm for thromboprophylaxis in Fontan patients is proposed. Additionally, the current state of knowledge is reviewed with respect to the epidemiology, pathophysiology, and detection of thromboembolic events in Fontan patients, and important evidence gaps are highlighted.

Rejection surveillance in pediatric heart transplant recipients: Critical reflection on the role of frequent and long-term routine surveillance endomyocardial biopsies and comprehensive review of non-invasive rejection screening tools.

BACKGROUND: Despite significant medical advances in the field of pediatric heart transplantation (HT), acute rejection remains an important cause of morbidity and mortality. Endomyocardial biopsy (EMB) remains the gold-standard method for diagnosing rejection but is an invasive, expensive, and stressful process. Given the potential adverse consequences of rejection, routine post-transplant rejection surveillance protocols incorporating EMB are widely employed to detect asymptomatic rejection. Each center employs their own specific routine rejection surveillance protocol, with no consensus on the optimal approach and with high inter-center variability. The utility of high-frequency and long-term routine surveillance biopsies (RSB) in pediatric HT has been called into question. METHODS: Sources for this comprehensive review were primarily identified through searches in biomedical databases including MEDLINE and Embase. RESULTS: The available literature suggests that the diagnostic yield of RSB is low beyond the first year post-HT and that a reduction in RSB intensity from high-frequency to low-frequency can be done safely with no impact on early and mid-term survival. Though there are emerging non-invasive methods of detecting asymptomatic rejection, the evidence is not yet strong enough for any test to replace EMB. CONCLUSION: Overall, pediatric HT centers in North America should likely be doing fewer RSB than are currently performed. Risk factors for rejection should be considered when designing the optimal rejection surveillance strategy. Noninvasive testing including emerging biomarkers may have a complementary role to aid in safely reducing the need for RSB.