Waitlist and Posttransplant Outcomes of Children and Young Adults With Hypertrophic Cardiomyopathy.

BACKGROUND: Heart transplantation (HT) is standard therapy for end-stage hypertrophic cardiomyopathy (HCM); however, few studies have described outcomes of older children and young adults with HCM listed for HT. Our objective was to compare waitlist and post-HT outcomes among pediatric and young adult patients with HCM and dilated cardiomyopathy (DCM). METHODS: The Scientific Registry of Transplant Recipients was queried for patients with HCM and DCM listed at ≤25 years of age. Patient characteristics, waitlist and post-HT survival were compared between younger (≤5 years of age) and older (>5 to ≤25 years of age) HCM patients and between HCM and DCM patients. RESULTS: Among 6252 patients listed for HT at ≤25 years of age with DCM and HCM, 3926 and 250 were in the older cohort and 1944 and 132 were in the younger cohort, respectively. Older HCM patients were less likely to be critically ill at listing compared with younger HCM patients (P = .0001). Waitlist mortality was similar between HCM and DCM patients in both age cohorts. Post-HT survival in HCM patients was similar between the age cohorts. In the younger cohort, early post-HT survival was worse in HCM compared with DCM (P = .009), with no difference in long-term survival. Survival was similar between the older cohorts. CONCLUSIONS: Older children and young adults with HCM are less critically ill than the younger cohort and show waitlist and post-HT survival similar to DCM patients. The young children with HCM had worse early posttransplantation survival, though long-term survival was same as DCM.

Safety of Enalapril in Infants: Data from the Pediatric Heart Network Infant Single Ventricle Trial.

OBJECTIVE: To assess the safety profile of angiotensin-converting enzyme inhibitor therapy in infants with single ventricle. STUDY DESIGN: The Pediatric Heart Network conducted a double-blind trial involving infants with single ventricle physiology randomized to receive enalapril or placebo and followed to 14 months of age. Data including demographics, drug administration, hemodynamic monitoring, laboratory measurements, adverse events, and survival were extracted from the public use data set and compared between the placebo and enalapril-treated groups. RESULTS: The Infant Single Ventricle trial randomized 230 patients, with 115 patients in each group. Initial enalapril dose was 0.10 mg/kg/d and median maximal dose was 0.38 mg/kg/d. There was no significant difference in change in blood pressure at study drug initiation or when resuming study drug after Glenn surgery. The incidence of hyperkalemia and neutropenia did not differ between groups. Renal dysfunction occurred in 3% of the enalapril group and none of the placebo patients, which was not statistically significant. There was a high frequency of serious adverse events in both groups. There was no difference in the frequency of heart transplant or death between groups. CONCLUSIONS: Enalapril did not have sustained hemodynamic effects at initiation or up-titration of drug. Creatinine and potassium were not different between groups, although renal dysfunction occurred more often in the patients on enalapril. Although efficacy of enalapril in neonates with single ventricle has not been demonstrated, the safety profile of angiotensin-converting enzyme inhibitors appears to be low risk in infants and children with significant heart disease.

Early outcomes for low-risk pediatric heart transplant recipients and steroid avoidance: A multicenter cohort study (Clinical Trials in Organ Transplantation in Children - CTOTC-04).

BACKGROUND: Immunosuppression strategies have changed over time in pediatric heart transplantation. Thus, comorbidity profiles may have evolved. Clinical Trials in Organ Transplantation in Children-04 is a multicenter, prospective, cohort study assessing the impact of pre-transplant sensitization on outcomes after pediatric heart transplantation. This sub-study reports 1-year outcomes among recipients without pre-transplant donor-specific antibodies (DSAs). METHODS: We recruited consecutive candidates (<21 years) at 8 centers. Sensitization status was determined by a core laboratory. Immunosuppression was standardized as follows: Thymoglobulin induction with tacrolimus and/or mycophenolate mofetil maintenance. Steroids were not used beyond 1 week. Rejection surveillance was by serial biopsy. RESULTS: There were 240 transplants. Subjects for this sub-study (n = 186) were non-sensitized (n = 108) or had no DSAs (n = 78). Median age was 6 years, 48.4% were male, and 38.2% had congenital heart disease. Patient survival was 94.5% (95% confidence interval, 90.1-97.0%). Freedom from any type of rejection was 67.5%. Risk factors for rejection were older age at transplant and presence of non-DSAs pre-transplant. Freedom from infection requiring hospitalization/intravenous anti-microbials was 75.4%. Freedom from rehospitalization was 40.3%. New-onset diabetes mellitus and post-transplant lymphoproliferative disorder (PTLD) occurred in 1.6% and 1.1% of subjects, respectively. There was no decline in renal function over the first year. Corticosteroids were used in 14.5% at 1 year. CONCLUSIONS: Pediatric heart transplantation recipients without DSAs at transplant and managed with a steroid avoidance regimen have excellent short-term survival and a low risk of first-year diabetes mellitus and PTLD. Rehospitalization remains common. These contemporary observations allow for improved caregiver and/or patient counseling and provide the necessary outcomes data to help design future randomized controlled trials.

Cardiomyopathy in Children: Classification and Diagnosis: A Scientific Statement From the American Heart Association.

In this scientific statement from the American Heart Association, experts in the field of cardiomyopathy (heart muscle disease) in children address 2 issues: the most current understanding of the causes of cardiomyopathy in children and the optimal approaches to diagnosis cardiomyopathy in children. Cardiomyopathies result in some of the worst pediatric cardiology outcomes; nearly 40% of children who present with symptomatic cardiomyopathy undergo a heart transplantation or die within the first 2 years after diagnosis. The percentage of children with cardiomyopathy who underwent a heart transplantation has not declined over the past 10 years, and cardiomyopathy remains the leading cause of transplantation for children >1 year of age. Studies from the National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry have shown that causes are established in very few children with cardiomyopathy, yet genetic causes are likely to be present in most. The incidence of pediatric cardiomyopathy is ≈1 per 100 000 children. This is comparable to the incidence of such childhood cancers as lymphoma, Wilms tumor, and neuroblastoma. However, the published research and scientific conferences focused on pediatric cardiomyopathy are sparcer than for those cancers. The aim of the statement is to focus on the diagnosis and classification of cardiomyopathy. We anticipate that this report will help shape the future research priorities in this set of diseases to achieve earlier diagnosis, improved clinical outcomes, and better quality of life for these children and their families.

Current Topics and Controversies in Pediatric Heart Transplantation: Proceedings of the Pediatric Heart Transplantation Summit 2017.

In October 2017, a pediatric heart transplant summit was held in Seattle-the first of its kind internationally-which focused solely upon controversies in pediatric end-stage heart failure management and pediatric heart transplantation. We selected five of the most popular and contentious topics and asked the speakers to provide a position paper. Worldwide, the vast majority of programs perform only a handful of pediatric heart transplants a year. Because of this, these "orphan" areas of investigation provide an opportunity for us as a community to aggregate our collective knowledge, which may represent the only viable way that we might sort through these complex and controversial issues in the field. We hope this represents the first of many such conferences and that this initial selection of papers encourages us to begin this collaborative process.

The Effect of the Superior Cavopulmonary Anastomosis on Ventricular Remodeling in Infants with Single Ventricle.

BACKGROUND: Infants with single ventricular physiology have volume and pressure overload that adversely affect ventricular mechanics. The impact of superior cavopulmonary anastomosis (SCPA) on single left ventricles versus single right ventricles is not known. METHODS: As part of the Pediatric Heart Network placebo-controlled trial of enalapril in infants with single ventricular physiology, echocardiograms were obtained before SCPA and at 14 months and analyzed in a core laboratory. Retrospective analysis of the following measurements included single ventricular end-diastolic volume (EDV), end-systolic volume (ESV), mass, mass-to-volume ratio (mass/volume), and ejection fraction. Qualitative assessment of atrioventricular valve regurgitation and assessment of diastolic function were also performed. RESULTS: A total of 156 participants underwent echocardiography at both time points. Before SCPA, mean ESV and mass Z scores were elevated (3.4 ± 3.7 and 4.2 ± 2.9, respectively) as were mean EDV and mass/volume Z scores (2.1 ± 2.5 and 2.0 ± 2.9, respectively). EDV, ESV, and mass decreased after SCPA, but mass/volume and the degree of atrioventricular valve regurgitation did not change. Subjects with morphologic left ventricles demonstrated greater reductions in ventricular volumes and mass than those with right ventricles (mean change in Z score: left ventricular [LV] EDV, -1.9 ± 2.1; right ventricular EDV, -0.7 ± 2.5; LV ESV, -2.3 ± 2.9; right ventricular ESV, -0.9 ± 4.6; LV mass, -2.5 ± 2.8; right ventricular mass, -1.3 ± 2.6; P ≤ .03 for all). Approximately one third of patients whose diastolic function could be assessed had abnormalities at each time point. CONCLUSIONS: Decreases in ventricular size and mass occur in patients with single ventricle after SCPA, and the effect is greater in those with LV morphology. The remodeling process resulted in commensurate changes in ventricular mass and volume such that the mass/volume did not change significantly in response to the volume-unloading surgery.

3D Printing to Guide Ventricular Assist Device Placement in Adults With Congenital Heart Disease and Heart Failure.

As the population of adults with congenital heart disease continues to grow, so does the number of these patients with heart failure. Ventricular assist devices are underutilized in adults with congenital heart disease due to their complex anatomic arrangements and physiology. Advanced imaging techniques that may increase the utilization of mechanical circulatory support in this population must be explored. Three-dimensional printing offers individualized structural models that would enable pre-surgical planning of cannula and device placement in adults with congenital cardiac disease and heart failure who are candidates for such therapies. We present a review of relevant cardiac anomalies, cases in which such models could be utilized, and some background on the cost and procedure associated with this process.

Growth Asymmetry, Head Circumference, and Neurodevelopmental Outcomes in Infants with Single Ventricles.

OBJECTIVE: To assess the variability in asymmetric growth and its association with neurodevelopment in infants with single ventricle (SV). STUDY DESIGN: We analyzed weight-for-age z-score minus head circumference-for-age z-score (HCAZ), relative head growth (cm/kg), along with individual growth variables in subjects prospectively enrolled in the Infant Single Ventricle Trial. Associations between growth indices and scores on the Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI) of the Bayley Scales of Infant Development-II (BSID-II) at 14 months were assessed. RESULTS: Of the 230 subjects enrolled in the Infant Single Ventricle trial, complete growth data and BSID-II scores were available in 168 (73%). Across the cohort, indices of asymmetric growth varied widely at enrollment and before superior cavopulmonary connection (SCPC) surgery. BSID-II scores were not associated with these asymmetry indices. In bivariate analyses, greater pre-SCPC HCAZ correlated with higher MDI (r = 0.21; P = .006) and PDI (r = 0.38; P < .001) and a greater HCAZ increase from enrollment to pre-SCPC with higher PDI (r = 0.15; P = .049). In multivariable modeling, pre-SCPC HCAZ was an independent predictor of PDI (P = .03), but not MDI. CONCLUSION: In infants with SV, growth asymmetry was not associated with neurodevelopment at 14 months, but pre-SCPC HCAZ was associated with PDI. Asymmetric growth, important in other high-risk infants, is not a brain-sparing adaptation in infants with SV. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00113087.

Outcomes and risk factors for listing for heart transplantation after the Norwood procedure: An analysis of the Single Ventricle Reconstruction Trial.

BACKGROUND: Infants with hypoplastic left heart syndrome after palliation have the worst survival among heart transplant recipients. Heart transplantation is often reserved for use in patients with sub-optimal results after palliative surgery. This study characterized outcomes after listing in infants with a single ventricle who had undergone the Norwood procedure and identified predictors of the decision to list for heart transplantation. METHODS: The public-use database from the multicenter, prospective randomized Single Ventricle Reconstruction trial was used to identify patients who were listed for heart transplantation. Outcomes on the waiting list and after transplantation were determined. Risk factors were compared between those who were listed and those who survived without listing. RESULTS: Among 555 patients, 33 patients (5.9%) were listed and 18 underwent heart transplantation. Mortality was 39% while waiting for a heart and was 33% after heart transplantation. Overall, 1-year survival after listing (including death after transplantation) was 48%. Factors associated with listing were a lower right ventricular fractional area change at birth, non-hypoplastic left heart syndrome diagnosis, and a more complicated post-Norwood course, defined as a higher need for extracorporeal membrane oxygenation, longer intensive care unit stay, more complications, and a higher number of discharge medications. CONCLUSIONS: Worse right ventricular function, non-hypoplastic left heart syndrome diagnosis, and complex intensive care unit stay were significant risk factors for listing for heart transplantation after the Norwood procedure. Heart transplantation as a rescue procedure after the Norwood procedure in the first year of life carries a significant risk of mortality.

The Fontan operation: the long-term outlook.

PURPOSE OF REVIEW: As perioperative survival following the Fontan procedure has improved and more patients are reaping the benefits of physiologic palliation, the costs of longstanding systemic venous hypertension and the functional limitations of a single ventricle are becoming clearer. Arrhythmias, heart failure, protein-losing enteropathy, hepatic cirrhosis, pulmonary hypertension, and ventricular dysfunction are common in late survivors and result in significant morbidity and mortality. Current research is focused on characterizing late morbidities and developing risk-prediction models for worse outcomes in long-term survivors. RECENT FINDINGS: Ten-year survival following the Fontan procedure is now 94-98%; however, estimated conditional survival in survivors aged above 18 years is 60% at 40 years of age. Atrial arrhythmias and heart failure are the leading causes of morbidity and mortality. Hypoplastic left heart syndrome, hepatic dysfunction, decreased exercise tolerance, lower quality of life, and markers of neurohormonal activation have been associated with worse outcome. Improvements in exercise tolerance are seen with selective pulmonary vasodilator therapy and exercise training. Heart transplant continues to be an effective therapy for end-stage Fontan failure, and reports of the use of traditional mechanical assist devices and the development of right heart assist devices in the setting of passive venous flow are ongoing. SUMMARY: Over a generation has passed since the Fontan procedure revolutionized the care of patients with a single ventricle. Data generated from retrospective and prospective observational studies in long-term survivors are identifying patients at risk.

Effect of copy number variants on outcomes for infants with single ventricle heart defects.

BACKGROUND: Human genomes harbor copy number variants (CNVs), which are regions of DNA gains or losses. Although pathogenic CNVs are associated with congenital heart disease (CHD), their effect on clinical outcomes is unknown. This study sought to determine whether pathogenic CNVs among infants with single ventricle physiology were associated with inferior neurocognitive and somatic growth outcomes. METHODS AND RESULTS: Genomic DNAs from 223 subjects of 2 National Heart, Lung, and Blood Institute-sponsored randomized clinical trials in infants with single ventricle CHD and 270 controls from The Cancer Genome Atlas project were analyzed for rare CNVs>300 kb using array comparative genomic hybridization. Neurocognitive and growth outcomes at 14 months from the CHD trials were compared among subjects with and without pathogenic CNVs. Putatively pathogenic CNVs, comprising 25 duplications and 6 deletions, had a prevalence of 13.9%, significantly greater than the 4.4% rate of such CNVs among controls. CNVs associated with genomic disorders were found in 13 cases but not in controls. Several CNVs likely to be causative of single ventricle CHD were observed, including aberrations altering the dosage of GATA4, MYH11, and GJA5. Subjects with pathogenic CNVs had worse linear growth, and those with CNVs associated with known genomic disorders had the poorest neurocognitive and growth outcomes. A minority of children with pathogenic CNVs were noted to be dysmorphic on clinical genetics examination. CONCLUSIONS: Pathogenic CNVs seem to contribute to the cause of single ventricle forms of CHD in ≥10% of cases and are clinically subtle but adversely affect outcomes in children harboring them.

Superior cavopulmonary anastomosis timing and outcomes in infants with single ventricle.

OBJECTIVES: We sought to identify factors associated with the timing and surgical outcomes of the superior cavopulmonary anastomosis. METHODS: The Pediatric Heart Network's Infant Single Ventricle trial database identified participants who underwent superior cavopulmonary anastomosis. Factors potentially associated with age at superior cavopulmonary anastomosis, length of stay and death by 14 months of age were evaluated. Factors included subject demographics, cardiac anatomy, measures from neonatal hospitalization and pre-superior cavopulmonary anastomosis visit, adverse events, echocardiographic variables, intraoperative variables, superior cavopulmonary anastomosis type, and number of concurrent cardiac surgical procedures. Age at superior cavopulmonary anastomosis was analyzed using Cox proportional hazards regression. Natural log length of stay was analyzed by multiple linear regression. RESULTS: Superior cavopulmonary anastomosis was performed in 193 subjects at 5.2 months of age (interquartile range, 4.2, 6.2) and weight of 5.9 kg (interquartile range, 5.3, 6.6). The median length of stay was 7 days (interquartile range, 6, 10). There were 3 deaths and 1 transplant during the superior cavopulmonary anastomosis hospitalization, and 3 deaths and 3 transplants between discharge and 14 months of age. Age at superior cavopulmonary anastomosis was associated with center and interstage adverse events. A longer length of stay was associated with younger age and greater case complexity. Superior cavopulmonary anastomosis type, valve regurgitation, ventricular ejection fraction, and ventricular end-diastolic pressure were not independently associated with age at superior cavopulmonary anastomosis or the length of stay. CONCLUSIONS: Greater case complexity and more frequent interstage adverse events are associated with an earlier age at superior cavopulmonary anastomosis. Significant variation in age at superior cavopulmonary anastomosis among centers, independent of subject factors, highlights a lack of consensus regarding the optimal timing. Factors associated with length of stay could offer insights for improving presuperior cavopulmonary anastomosis care and surgical outcome.

Early predictors of survival to and after heart transplantation in children with dilated cardiomyopathy.

BACKGROUND: The importance of clinical presentation and pretransplantation course on outcome in children with dilated cardiomyopathy listed for heart transplantation is not well defined. METHODS AND RESULTS: The impact of age, duration of illness, sex, race, ventricular geometry, and diagnosis of myocarditis on outcome in 261 children with dilated cardiomyopathy enrolled in the Pediatric Cardiomyopathy Registry and Pediatric Heart Transplant Study was studied. End points included listing as United Network for Organ Sharing status 1, death while waiting, and death after transplantation. The median age at the time of diagnosis was 3.4 years, and the mean time from diagnosis to listing was 0.62±1.3 years. Risk factors associated with death while waiting were ventilator use and older age at listing in patients not mechanically ventilated (P=0.0006 and P=0.03, respectively). Shorter duration of illness (P=0.04) was associated with listing as United Network for Organ Sharing status 1. Death after transplantation was associated with myocarditis at presentation (P=0.009), nonwhite race (P<0.0001), and a lower left ventricular end-diastolic dimension z score at presentation (P=0.04). In the myocarditis group, 17% (4 of 23) died of acute rejection after transplantation. CONCLUSIONS: Mechanical ventilator use and older age at listing predicted death while waiting, whereas nonwhite race, smaller left ventricular dimension, and myocarditis were associated with death after transplantation. Although 97% of children with clinically or biopsy-diagnosed myocarditis at presentation survived to transplantation, they had significantly higher posttransplantation mortality compared with children without myocarditis, raising the possibility that preexisting viral infection or inflammation adversely affects graft survival.

Outcomes in pediatric cardiac transplantation with a positive HLA cross-match.

Previous studies have shown poor outcomes in pediatric heart transplant recipients with a high PRA or a positive direct donor-recipient cross-match. This study describes outcomes in patients with a positive cross-match at a large pediatric program. Pediatric heart transplant patients at a large single center between January 1993 and July 2009 were reviewed; those with cross-match data were analyzed. Cross-match data were available in 242/262 (92.4%) patients. Indications for transplant were cardiomyopathy (58%), CHD (32%), and retransplant (7%). PRA was ≥10% in 31/213 (14.6%) patients. A retrospective cross-match was positive in 17/31 (55%) patients with PRA ≥10% and 0/182 with PRA <10%. In positive cross-match patients, rejection frequency in the first year post-transplant was higher than negative cross-match patients (1.69 vs. 0.96 episodes/pt year, p = 0.014). There was no difference in rejection frequency after the first year post-transplant (0.18 vs. 0.12 episodes/pt year, p = 0.14). Overall survival was not significantly different between the groups with a median follow-up time of 4.5 yr. Heart transplantation in patients with a positive cross-match may result in good medium-term survival but a higher frequency of early rejection. Further investigation is warranted to define which patients with a positive cross-match will do poorly.

Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle.

BACKGROUND: We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function, and response to enalapril in infants with single ventricle. METHODS AND RESULTS: Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with renin-angiotensin-aldosterone system upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate, and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high risk), and those with <2 homozygous risk genotypes (low risk) at 2 time points: before the superior cavopulmonary connection (pre-SCPC) and at age 14 months. Of 230 trial subjects, 154 were genotyped: Thirty-eight were high risk, and 116 were low risk. Ventricular mass and volume were elevated in both groups pre-SCPC. Ventricular mass and volume decreased and estimated glomerular filtration rate increased after SCPC in the low-risk (P<0.05), but not the high-risk group. These responses were independent of enalapril treatment. Weight and height z-scores were lower at baseline, and height remained lower in the high-risk group at 14 months, especially in those receiving enalapril (P<0.05). CONCLUSIONS: Renin-angiotensin-aldosterone system-upregulation genotypes were associated with failure of reverse remodeling after SCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. Renin-angiotensin-aldosterone system genotype may identify a high-risk subgroup of single ventricle patients who fail to fully benefit from volume-unloading surgery. Follow-up is warranted to assess long-term impact. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00113087.

Cardiac retransplantation in high risk pediatric patients.

Cardiac retransplantation is often the only therapy to treat GV or other causes of allograft failure. Previous reports of retransplantation have conflicting results. In this series of 18 re-transplants in 16 patients from 1984-2005, indications for retransplantation were: GV (67%); GV with cellular rejection (28%); acute graft failure (2.5%); and chronic graft failure (2.5%). Mean age at retransplantation was 12.3 (range: 0.7-22) years with a mean primary graft survival of 5.3 years (range: 8 days-10.5 years). There was no short-term mortality with only three deaths at 4, 10, and 16 years post-retransplantation. Fourteen of 18 patients had risk factors for adverse outcomes following retransplantation: ECMO support in one patient prior to retransplantation; impaired renal function in three patients; elevated panel reactive antibody screen in seven patients; a history of PTLD in five patients; and a recent episode of rejection (13-36 days) in four patients. One-, five- and ten-year survival after retransplantation was 100%, 83% and 66%, respectively, comparable to survival after primary transplantation. Freedom from rejection was not significantly different between primary and retransplantations. All patients who underwent treatment for PTLD had excellent results after retransplantation with one recurrence 16 months after retransplant. Overall, patients had excellent survival after retransplantation even in those with risk factors for poor outcome.