Clinical outcomes after a biopsy diagnosis of antibody-mediated rejection in pediatric heart transplant recipients.

BACKGROUND: Extending survival after heart transplant (HT) is of paramount importance for childhood recipients of HT. Acute rejection is a significant event, and biopsy remains the most specific means for distinguishing between cellular (ACR) and antibody-mediated rejection (AMR). METHODS: All children in the Pediatric Heart Transplant Society Registry who underwent HT between January 2015 and June 2022 and had ≥1 rejection episode were included. Survival was compared between AMR and ACR-only. Secondary outcomes of infection, malignancy, and cardiac allograft vasculopathy (CAV) were assessed. Risk factors for graft loss after AMR were identified using Cox proportional hazard modeling. RESULTS: Among 906 children with rejection, 697 (77%) with complete biopsy information were included. AMR was present on biopsy in 261 (37%) patients; ACR-only was present in 436 (63%). Time to rejection was earlier for AMR, median time from HT to rejection 0.11 versus 0.29 years, p = 0.0006. Survival after AMR in the 1st year was lower than survival after ACR-only. Predictors of graft loss after AMR were younger age at HT, congenital heart disease, and rejection with hemodynamic compromise. There was no difference in time to CAV, infection, or malignancy after rejection between groups. CONCLUSIONS: The largest analysis of pediatric HT rejection with biopsy data to identify AMR underscores the continued importance of AMR on survival. AMR is associated with higher graft loss versus ACR when occurring in the first-year post-HT. Predictors of graft loss after AMR identify patients who may benefit from increased surveillance or augmented maintenance immunosuppression.

Inclusive ABO-Incompatible Listing for Pediatric Heart Transplantation Results in Comparable Post-Transplant Rejection-Free Survival in a Single-Center Series.

ABO-incompatible (ABOi) heart transplantation (HT) has increased organ availability for infants with end-stage heart failure. Despite increasing adoption of ABOi listing for HT, data remain limited regarding pre- and post-HT immunologic profiles to guide listing practices and post-HT follow-up. Thus, the purpose of this study was to evaluate post-HT outcomes at a single center employing inclusive ABOi listing irrespective of pre-HT isohemagglutinin titers. All HT recipients listed at less than 24 months of age at our institution from 2010-2020 were included. Pre- and post-operative variables were compared for ABOi and ABO-compatible (ABOc) recipients. Separate iso-IgG and iso-IgM titers were monitored pre- and post-HT. Primary outcomes were compared between ABOi versus ABOc groups at mid-term follow-up. 51 HTs were performed on 50 patients from 2010-2020 (ABOi, N = 13; ABOc, N = 38). Six ABOi recipients received intra-operative plasma exchange for elevated titers (greater than 1:8 for IgG or IgM or reverse type greater than 2 +). Treated rejection, DSA, CAV, primary graft failure, need for re-HT, and survival were comparable between ABOi and ABOc groups at mid-term follow-up. An inclusive approach to ABOi HT listing for infants less than 24 months of age results in comparable post-transplant rejection-free survival, CAV, and prevalence of DSA at mid-term follow-up. These data define a potential role for specific IgM and IgG testing to promote understanding of risk stratification in pediatric ABOi listing, and support an inclusive strategy irrespective of high pre-HT titers to expand the number of available donor hearts for infants and older children awaiting HT.

LCP-Tacrolimus Extended-Release (Envarsus XR) Use in Adolescent and Young Adult Solid Organ Transplant Recipients.

INTRODUCTION: Limited published experience describes once daily, extended-release tacrolimus (LCP-Tac) use in pediatric solid organ transplantation (SOT), particularly nonrenal SOT. LCP-Tac can simplify immunosuppression (IS) regimens, minimize immediate release-tacrolimus (IR-Tac)-associated adverse effects, and promote adherence. This study describes the successful use of LCP-Tac in adolescent and young adult (AYA) SOT populations. METHODS: A single-center, retrospective chart review of AYA SOT recipients (age < 25 years) converted from IR-Tac to LCP-Tac. Graft survival, biopsy-proven acute rejection (BPAR), infection rates, estimated glomerular filtration rate (eGFR), and pill burden were assessed at five time points postconversion (1, 3, 6, 12, and 24 months). Intrapatient variability of tacrolimus, as assessed by coefficient of variability (CV%), was also analyzed. RESULTS: Twenty-nine AYA SOT recipients (19 heart, 6 kidney, and 4 liver) were converted to LCP-Tac, with a median age of 17.4 years at conversion. Conversion, mainly due to perceived or identified medication nonadherence, occurred at a median of 5.4 years posttransplant. No graft loss occurred within 24 months of conversion, and BPAR incidence rate was consistent with previous reports for these populations. Only one patient experienced CMV infection. Renal function remained stable postconversion. CONCLUSION: Successful conversion from IR-Tac to LCP-Tac was demonstrated in AYA heart, kidney, and liver transplant recipients. These AYA SOT recipients experienced reduced pill burden and improved tacrolimus trough concentration variability. However, the impact on medication adherence warrants further investigation. Future research should explore the targeted use of LCP-Tac to enhance IS tolerability and medication adherence in young SOT populations.

Non-invasive myocardial tissue deformation and discoordination indices predict cardiac allograft vasculopathy in pediatric heart transplantation patients.

There is an urgent need for non-invasive imaging-based biomarkers suitable for diagnostic surveillance of cardiac allograft vasculopathy (CAV) in pediatric heart transplant (PHT) patients. The purpose of this study was to comprehensively investigate left ventricular (LV) myocardial deformation in conjunction with electromechanical discoordination in PHT. PHT patients with and without CAV were evaluated for echocardiography derived global longitudinal strain (GLS) and electromechanical discoordination indices including systolic stretch fraction (SSF) and diastolic relaxation fraction (DRF). SSF was increased in CAV(+) patients at the time of CAV diagnosis (median CAV(+) 5.0 vs. median CAV(-) 0.0, P = 0.008) and in the echocardiogram preceding the CAV diagnosis (median CAV(+) 29.0 vs. median CAV(-) 0.0, P < 0.001). DRF was also increased in the echocardiogram that preceded CAV diagnosis in CAV(+) patients (0.31 ± 0.08 vs. 0.25 ± 0.05, P = 0.008). The final model using indices 6-12 months prior to CAV diagnosis included GLS, SSF, and DRF providing AUC of 0.94 with sensitivity 98.5%, specificity 80.0%, positive predictive value 85.0%, and negative predictive value 94.1%. Systolic and diastolic electro-mechanical discoordination indices are significantly worse in PHT patients experiencing CAV. Non-invasive imaging guided surveillance using echocardiographic myocardial deformation indices can be improved by adding SSF and DRF to standard GLS measurements.

Genetic Testing Resources and Practice Patterns Among Pediatric Cardiomyopathy Programs.

The use of genetic testing has enhanced the diagnostic accuracy of heritable genetic cardiomyopathies. However, it remains unclear how genetic information is interpreted and incorporated into clinical practice for children with cardiomyopathy. The primary aim of this study was to understand how clinical practice differs regarding sequence variant classifications amongst pediatric cardiologists who treat children with cardiomyopathy. A secondary aim was to understand the availability of genetic testing and counseling resources across participating pediatric cardiomyopathy programs. An electronic survey was distributed to pediatric heart failure, cardiomyopathy, or heart transplantation physicians between August and September 2022. A total of 106 individual providers from 68 unique centers responded to the survey. Resources for genetic testing and genetic counseling vary among large pediatric cardiomyopathy programs. A minority of centers reported having a geneticist (N = 16, 23.5%) or a genetic counselor (N = 21, 31%) on faculty within the division of pediatric cardiology. A total of 9 centers reported having both (13%). Few centers (N = 13, 19%) have a formal process in place to re-engage patients who were previously discharged from cardiology follow-up if variant reclassification would alter clinical management. Clinical practice patterns were uniform in response to pathogenic or likely pathogenic variants but were more variable for variants of uncertain significance. Efforts to better incorporate genetic expertise and resources into the clinical practice of pediatric cardiomyopathy may help to standardize the interpretation of genetic information and better inform clinical decision-making surrounding heritable cardiomyopathies.

Progressive Left Ventricular Remodeling for Predicting Mortality in Children With Dilated Cardiomyopathy: The Pediatric Cardiomyopathy Registry.

BACKGROUND: Pediatric dilated cardiomyopathy often leads to death or cardiac transplantation. We sought to determine whether changes in left ventricular (LV) end-diastolic dimension (LVEDD), LV end-diastolic posterior wall thickness, and LV fractional shortening (LVFS) over time may help predict adverse outcomes. METHODS AND RESULTS: We studied children up to 18 years old with dilated cardiomyopathy, enrolled between 1990 and 2009 in the Pediatric Cardiomyopathy Registry. Changes in LVFS, LVEDD, LV end-diastolic posterior wall thickness, and the LV end-diastolic posterior wall thickness:LVEDD ratio between baseline and follow-up echocardiograms acquired ≈1 year after diagnosis were determined for children who, at the 1-year follow-up had died, received a heart transplant, or were alive and transplant-free. Within 1 year after diagnosis, 40 (5.0%) of the 794 eligible children had died, 117 (14.7%) had undergone cardiac transplantation, and 585 (73.7%) had survived without transplantation. At diagnosis, survivors had higher median LVFS and lower median LVEDD Z scores. Median LVFS and LVEDD Z scores improved among survivors (Z score changes of +2.6 and -1.1, respectively) but remained stable or worsened in the other 2 groups. The LV end-diastolic posterior wall thickness:LVEDD ratio increased in survivors only, suggesting beneficial reverse LV remodeling. The risk for death or cardiac transplantation up to 7 years later was lower when LVFS was improved at 1 year (hazard ratio [HR], 0.83; P=0.004) but was higher in those with progressive LV dilation (HR, 1.45; P<0.001). CONCLUSIONS: Progressive deterioration in LV contractile function and increasing LV dilation are associated with both early and continuing mortality in children with dilated cardiomyopathy. Serial echocardiographic monitoring of these children is therefore indicated. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005391.

Three decades of collaboration through the Pediatric Heart Transplant Society Registry: A journey through registry data with a highlight on children with single ventricle anatomy.

BACKGROUND: The Pediatric Heart Transplant Society (PHTS) Registry was founded 30 years ago as a collaborative effort among like-minded providers of this novel life-saving technique for children with end-stage heart failure. In the intervening decades, the data from the Registry have provided invaluable knowledge to the field of pediatric heart transplantation. This report of the PHTS Registry provides a comprehensive look at the data, highlighting both the longevity of the registry and one unique aspect of the PHTS registry, allowing for exploration into children with single ventricle anatomy. METHODS: The PHTS database was queried from January 1, 1993 to December 31, 2019 to include pediatric (age < 18 years) patients listed for HT. For our analysis, we primarily analyzed patients by era. The early era was defined as children listed for HT from January 1, 1993 to December 31, 2004; middle era January 1, 2005 to December 31, 2009; and recent era January 1, 2010 to December 31, 2019. Outcomes after listing and transplant, including mortality and morbidities, are presented as unadjusted for risk, but compared across eras. RESULTS: Since 1993, 11 995 children were listed for heart transplant and entered into the PHTS Registry with 9755 listed during the study period. The majority of listings occurred within the most recent era. Waitlist survival improved over the decades as did posttransplant survival. Other notable changes over time include fewer patients experiencing allograft rejection or infection after transplant. Waitlist and posttransplant survival have changed dramatically in patients with single ventricle physiology and significantly differ by stage of single ventricle palliation. SUMMARY: Key points from this PHTS Registry summary and focus on patients with single ventricle congenital heart disease in particular, include the changing landscape of candidates and recipients awaiting heart transplant. There is clear improvement in waitlist and transplant outcomes for children with both cardiomyopathy and congenital heart disease alike.

Changes in estimated glomerular filtration rate over the first year following repeat heart transplant in children and young adults.

BACKGROUND: Renal function is reduced in patients undergoing heart transplant due to hemodynamic compromise, cardiorenal syndrome, and nephrotoxin exposure. No current studies evaluate renal function in retransplants. METHODS: We reviewed all heart transplants at our center from 1995 to 2021 and matched first-time heart transplants with retransplants, based on age at transplant, sex, and race. Estimated glomerular filtration rate (eGFR) was derived from CKiD-U25 calculator using creatinine and measured prior to transplant, 1-week post-transplant, 1-3, 6, and 12 months post-transplant, and recent follow-up. Changes in eGFR were measured within and between patients using a piecewise linear mixed effect model with matching. Exploratory univariate analysis was performed to evaluate pre-transplant risk factors for decreased eGFR. RESULTS: The unmatched cohort included 393 heart transplant recipients, with 47 being retransplants. Thirty-eight patients in both groups with at least 1 year of follow-up underwent matching. Both retransplants and first-time transplants had an initial decline in eGFR. eGFR rebounded to baseline or above baseline at 1-3 months post-transplant, but eGFR in retransplants remained significantly lower. At 1-year post-transplant, the average eGFR was 67.8 ± 4.3 mL/min/1.73 m2 versus 104.7 ± 4.3 mL/min/1.73 m2 (p < .001) in the retransplants and first-time transplants group, respectively. CONCLUSION: This study provides data on anticipated renal trajectory following retransplantation.

A Preliminary Study of One Year Safety and Tolerability of Attention-Deficit/Hyperactivity Disorder Medications in Youth with Fontan Palliation or Heart Transplant.

There are no published studies that examine the safety and tolerability of medication to treat attention-deficit/hyperactivity disorder (ADHD) in children with histories of Fontan palliation (Fontan) or heart transplant (HT), despite the high prevalence of ADHD in these populations. To address this gap, we examined the cardiac course, somatic growth, and incidence of side effects for one year after medication initiation amongst children with Fontan or HT and comorbid ADHD. The final sample comprised 24 children with Fontan (12 medication-treated, 12 control) and 20 children with HT (10 medication-treated, 10 control). Demographic, somatic growth (height and weight percentile-for age), and cardiac data (blood pressure, heart rate, results of 24 h Holter monitoring, electrocardiograms) were extracted from electronic medical records. Medication-treated and control subjects were matched by cardiac diagnosis (Fontan or HT), age, and sex. Nonparametric statistical tests were utilized to compare between- and within-group differences prior to, and one year post, medication initiation. There were no differences in somatic growth or cardiac data when comparing medication-treated participants to matched controls, regardless of cardiac diagnosis. Within the medication group, a statistically significant increase in blood pressure was observed, though the group average remained within clinically acceptable limits. While results are preliminary in nature due to our very limited sample size, our findings suggest that ADHD medications can be tolerated with minimal cardiac or somatic growth effects amongst complex cardiac patients. Our preliminary results favor treating ADHD with medication, which has considerable implications for long-term academic/employment outcomes and quality of life for this population. Close collaboration between pediatricians, psychologists, and cardiologists is essential to individualizing and optimizing interventions and outcomes for children with Fontan or HT.

Risk factors for 1-year allograft loss in pediatric heart transplant patients using machine learning: An analysis of the pediatric heart transplant society database.

BACKGROUND: Pediatric heart transplant patients are at greatest risk of allograft loss in the first year. We assessed whether machine learning could improve 1-year risk assessment using the Pediatric Heart Transplant Society database. METHODS: Patients transplanted from 2010 to 2019 were included. The primary outcome was 1-year graft loss free survival. We developed a prediction model using cross-validation, by comparing Cox regression, gradient boosting, and random forests. The modeling strategy with the best discrimination and calibration was applied to fit a final prediction model. We used Shapley additive explanation (SHAP) values to perform variable selection and to estimate effect sizes and importance of individual variables when interpreting the final prediction model. RESULTS: Cumulative incidence of graft loss or mortality was 7.6%. Random forests had favorable discrimination and calibration compared to Cox proportional hazards with a C-statistic (95% confidence interval [CI]) of 0.74 (0.72, 0.76) versus 0.71 (0.69, 0.73), and closer alignment between predicted and observed risk. SHAP values computed using the final prediction model indicated that the diagnosis of congenital heart disease (CHD) increased 1 year predicted risk of graft loss by 1.7 (i.e., from 7.6% to 9.3%), need for mechanical circulatory support increased predicted risk by 2, and single ventricle CHD increased predicted risk by 1.9. These three predictors, respectively, were also estimated to be the most important among the 15 predictors in the final model. CONCLUSIONS: Risk prediction models used to facilitate patient selection for pediatric heart transplant can be improved without loss of interpretability using machine learning.

Cardiac imaging and biomarkers for assessing myocardial fibrosis in children with hypertrophic cardiomyopathy.

BACKGROUND: Myocardial fibrosis, as diagnosed on cardiac magnetic resonance imaging (cMRI) by late gadolinium enhancement (LGE), is associated with adverse outcomes in adults with hypertrophic cardiomyopathy (HCM), but its prevalence and magnitude in children with HCM have not been established. We investigated: (1) the prevalence and extent of myocardial fibrosis as detected by LGE cMRI; (2) the agreement between echocardiographic and cMRI measurements of cardiac structure; and (3) whether serum concentrations of N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) and cardiac troponin-T are associated with cMRI measurements. METHODS: A cross-section of children with HCM from 9 tertiary-care pediatric heart centers in the U.S. and Canada were enrolled in this prospective NHLBI study of cardiac biomarkers in pediatric cardiomyopathy (ClinicalTrials.gov Identifier: NCT01873976). The median age of the 67 participants was 13.8 years (range 1-18 years). Core laboratories analyzed echocardiographic and cMRI measurements, and serum biomarker concentrations. RESULTS: In 52 children with non-obstructive HCM undergoing cMRI, overall low levels of myocardial fibrosis with LGE >2% of left ventricular (LV) mass were detected in 37 (71%) (median %LGE, 9.0%; IQR: 6.0%, 13.0%; range, 0% to 57%). Echocardiographic and cMRI measurements of LV dimensions, LV mass, and interventricular septal thickness showed good agreement using the Bland-Altman method. NT-proBNP concentrations were strongly and positively associated with LV mass and interventricular septal thickness (P < .001), but not LGE. CONCLUSIONS: Low levels of myocardial fibrosis are common in pediatric patients with HCM seen at referral centers. Longitudinal studies of myocardial fibrosis and serum biomarkers are warranted to determine their predictive value for adverse outcomes in pediatric patients with HCM.

Implementation of the Cardiac Inpatient Neurodevelopmental Care Optimization (CINCO) programme: an interdisciplinary, generalisable approach to inpatient neurodevelopmental care.

BACKGROUND: Children with CHD are at risk for neurodevelopmental delays, and length of hospitalisation is a predictor of poorer long-term outcomes. Multiple aspects of hospitalisation impact neurodevelopment, including sleep interruptions, limited holding, and reduced developmental stimulation. We aimed to address modifiable factors by creating and implementing an interdisciplinary inpatient neurodevelopmental care programme in our Heart Institute. METHODS: In this quality improvement study, we developed an empirically supported approach to neurodevelopmental care across the continuum of hospitalisation for patients with CHD using three plan-do-study-act cycles. With input from multi-level stakeholders including parents/caregivers, we co-designed interventions that comprised the Cardiac Inpatient Neurodevelopmental Care Optimization (CINCO) programme. These included medical/nursing orders for developmental care practices, developmental kits for patients, bedside developmental plans, caregiver education and support, developmental care rounds, and a specialised volunteer programme. We obtained data from the electronic health record for patients aged 0-2 years admitted for at least 7 days to track implementation. RESULTS: There were 619 admissions in 18 months. Utilisation of CINCO interventions increased over time, particularly for the medical/nursing orders and caregiver handouts. The volunteer programme launch was delayed but grew rapidly and within six months, provided over 500 hours of developmental interaction with patients. CONCLUSIONS: We created and implemented a low-cost programme that systematised and expanded upon existing neurodevelopmental care practices in the cardiac inpatient units. Feasibility was demonstrated through increasing implementation rates over time. Key takeaways include the importance of multi-level stakeholder buy-in and embedding processes in existing clinical workflows.

Basiliximab as maintenance immunosuppression in heart transplant recipients: A single pediatric center experience.

BACKGROUND: Pediatric heart transplant recipients are at risk for complications from prolonged exposure to immunosuppressive drugs, pharmacokinetic challenges in maintaining consistent immunosuppression, and medication non-adherence. Basiliximab (BAS), an interleukin-2 receptor antagonist, is used for induction therapy across many pediatric heart transplant centers, but use as maintenance immunosuppression has not been well described. METHODS: This was a retrospective, single pediatric center cohort study of heart transplant recipients who received BAS for maintenance immunosuppression (defined as >2 monthly doses) from January 1, 2011, to December 31, 2021. RESULTS: Ten patients met study criteria with a median age of 17.5 (5-22) years and median 9.6 (1.2-18.9) years since transplant at time of BAS initiation. The primary indications for BAS use were recurrent rejection (n = 4), fluctuating immunosuppression levels (n = 3), and renal dysfunction (n = 3). A median of 5.5 (3-32) monthly BAS doses were received. Three patients had a rejection event while on BAS. Calcineurin inhibitor exposure was reduced in 70% of patients. Three of the 10 patients were alive at last follow-up. There was one documented infection during BAS use, and no hypersensitivity reactions. CONCLUSIONS: Monthly BAS infusions were well tolerated and allowed for reduced calcineurin inhibitor exposure in most patients. Mortality commonly occurred despite BAS use, potentially reflecting the acuity of this patient cohort. BAS can be considered for maintenance immunosuppression in pediatric patients with fluctuating immunosuppressive levels and/or renal dysfunction. More studies are needed to determine long-term outcomes and explore expanded use of BAS in the pediatric heart transplant population.

End-stage care for children after heart transplant.

Heart transplant is performed annually in over 600 children worldwide to treat life-limiting cardiac disease. Conversations regarding waitlist mortality, post-transplant morbidity and mortality, and goals of care are commonplace pre-transplant. However, there is a void of information and resources for providers and families when end-stage disease recurs in the long-term transplant recipient. The purpose of this review is to discuss the care of the pediatric heart transplant recipient with chronic cardiac dysfunction occurring years after a successful transplant. This includes a need for transplant providers to have education and training related both to palliative care and medical ethics to improve shared decision making with patients and families.

Clinical approach to antibody-mediated rejection from the pediatric heart transplant society.

OBJECTIVE: This document is designed to outline the definition, pathogenesis, diagnostic modalities and therapeutic measures to treat antibody-mediated rejection in children postheart transplant METHODS: Literature review was conducted by a Pediatric Heart Transplant Society (PHTS) working group to identify existing pediatric and adult studies on antibody-mediated rejection (AMR). In addition, the centers participating in PHTS were asked to submit their approach to diagnosis and management of pediatric AMR. This document synthesizes information gathered from both these sources to highlight a practical approach to diagnosing and managing a child with AMR postheart transplant. This document may not represent the practice at all centers in the PHTS and serves as a starting point to understand an approach to this clinical scenario.

Clinical approach to acute cellular rejection from the pediatric heart transplant society.

BACKGROUND: Early detection of cardiac allograft rejection is crucial for post-transplant graft survival. Despite the progress made in immunosuppression strategies, acute cellular rejection remains a serious complication during and after the first post-transplant year, and there is a continued lack of consensus regarding its treatment, especially in pediatric transplant patients. METHODS: An open request was placed via the listserv to the membership of the Pediatric Heart Transplant Society (PHTS). Along with a broad literature search, numerous institutional protocols were pooled, analyzed and consolidated. A clinical approach document was generated highlighting areas of consensus and practice variation. RESULTS: The clinical approach document divides cellular rejection by International Society for Heart and Lung Transplantation grades and provides management strategies for each, including persistent cellular rejection. CONCLUSIONS: Cellular rejection treatment can be tailored to the clinical status, graft function, and the grade of cellular rejection. A case of mild and asymptomatic rejection may not require treatment, whereas a higher-grade rejection or rejection with graft dysfunction or hemodynamic compromise may require aggressive intravenous therapies, changes to maintenance immunosuppression therapy and augmented surveillance.

Pediatric Heart Transplant Waiting List Times in the US During the COVID-19 Pandemic.

This cohort study investigates the association between the COVID-19 pandemic and waiting list times among pediatric heart transplant recipients in the US.

The genetic architecture of pediatric cardiomyopathy.

To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10-16). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.

Improved heart transplant survival for children with congenital heart disease and heterotaxy syndrome in the current era: An analysis from the pediatric heart transplant society.

BACKGROUND: Challenges exist with heterotaxy due to the complexity of heart disease, abnormal venous connections, and infection risks. This study aims to understand heart transplant outcomes for children with heterotaxy. METHODS: All children with congenital heart disease listed for transplant from 1993 to 2018 were included. Those with and without heterotaxy were compared. Waitlist outcomes and survival post-listing and transplant were analyzed. Post-transplant risk factors were identified using multiphase parametric hazard modeling. RESULTS: There were 4814 children listed, of whom 196 (4%) had heterotaxy. Heterotaxy candidates were older (5.8 ± 5.7 vs 4.2 ± 5.5 years, p < 0.01), listed at a lower urgency status (29.8% vs 18.4%, p < 0.01), more commonly single ventricle physiology (71.3% vs 59.2%, p < 0.01), and less often supported by mechanical ventilation (22% vs 29.1%, p < 0.05) or extracorporeal membrane oxygenation (3.6% vs 7.5%, p < 0.05). There were no differences in waitlist outcomes of transplant, death, or removal. Overall, post-transplant survival was worse for children with heterotaxy: one-year survival 77.2% vs 85.1%, with and without heterotaxy, respectively. Heterotaxy was an independent predictor for early mortality in the earliest era (1993-2004), HR 2.09, CI 1.16-3.75, p = 0.014. When stratified by era, survival improved with time. Heterotaxy patients had a lower freedom from infection and from severe rejection, but no difference in vasculopathy or malignancy. CONCLUSIONS: Mortality risk associated with heterotaxy is mitigated in the recent transplant era. Early referral may improve waitlist outcomes for heterotaxy patients who otherwise have a lower status at listing. Lower freedom from both infection and severe rejection after transplant in heterotaxy highlights the challenges of balancing immune suppression.