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Background: Sarcopenia is an increasingly recognized marker of frailty in cardiac patients. Patients with a history of congenital heart disease and Fontan procedure have a higher risk of developing progressive muscle wasting. Our objective was to determine if we could use routine cardiac MRI (CMR) for the surveillance of muscle wasting. Methods: A retrospective study of all Fontan patients (n = 75) was conducted at our institution, with CMR performed from 2010 to 2022 and exercise stress testing performed within 12 months (4.3 ± 4.2 months). The skeletal muscle area (SMA) for the posterior paraspinal and anterior thoracic muscles were traced and indexed for body surface area (BSA). Patients were stratified by percentile into the upper and lower quartiles, and the two groups were compared. Multivariable regression was performed to control for sex and age. Results: There was a significant positive association of both anterior (r = 0.34, p = 0.039) and paraspinal (r = 0.43, p = 0.007) SMA to peak VO2. Similarly, paraspinal but not anterior SMA was negatively associated with the VE/VCO2 (r = –0.45, p = 0.006). The upper quartile group had significantly more males (18/19 vs. 8/20; p = 0.0003) and demonstrated a significantly higher peak VO2 (32.2 ± 8.5 vs. 23.8 ± 4.7, p = 0.009), a higher peak RER (1.2 ± 0.1 vs. 1.1 ± 0.04, p = 0.007), and a significantly lower VE/VCO2 (32.9 ± 3.6 vs. 40.2 ± 6.2, p = 0.006) compared to the lowest quartile. The association of SMA to VO2 peak and VE/VCO2 was redemonstrated after controlling for sex and age. Conclusion: Thoracic skeletal muscle area may be an effective surrogate of muscle mass and is correlated to several measures of cardiorespiratory fitness post-Fontan. CMR would be an effective tool for the surveillance of sarcopenia in post-Fontan patients given its accessibility and routine use in these patients.

Background There is currently no clear consensus on screening techniques to evaluate the presence or severity of Fontan-associated liver disease (FALD). Cardiac MRI (CMR) is used routinely for post-Fontan surveillance, but CMR-derived measures that relate to the severity of FALD are not yet defined. Methods This was a cross-sectional single-center study of post-Fontan patients who underwent a CMR. CMR exams were re-analyzed by a single pediatric cardiologist. Surrogates of FALD included Gamma-Glutamyl Transferase (GGT), Fibrosis-4 laboratory score (FIB-4), and imaging findings. Findings consistent with cirrhosis on liver ultrasound included increased liver echogenicity and/or nodularity. Statistical analyses were performed to investigate potential relationships between CMR parameters and markers of FALD. Results Sixty-one patients were included. A larger inferior vena cava cross-sectional area (IVC-CSA) indexed to height was significantly associated with a higher FIB-4 score (Spearman’s ρ = 0.28, P = 0.04), a higher GGT level (Spearman’s ρ = 0.40, p = 0.02), and findings consistent with cirrhosis on liver ultrasound (OR 1.17, 95% CI: (1.01, 1.35), p = 0.04). None of the other CMR parameters were associated with markers of FALD. A larger indexed IVC-CSA was associated with higher systemic ventricle end-diastolic pressure (EDP) on cardiac catheterization (Spearman’s ρ = 0.39, p = 0.018) as well as older age (Spearman’s ρ = 0.46, p =

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).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.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.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.

Echocardiographic parameters assessing left and right heart function were evaluated in children with established pulmonary hypertension (PH) from bronchopulmonary dysplasia (BPD) to look for correlations with each other, and pulmonary artery pressure (PAPs) from right heart catheterizations (RHC). Data were retrospectively collected on patients with BPD and PH and correlations were performed between various objective echocardiographic and RHC measurements. A total of 31 patients with BPD were found to have PH by echocardiogram and RHC after chart review. Median age of evaluation was 0.58 years. Correlations were noted between measurements of right heart function, indirect measures of pulmonary artery pressures and left ventricular dimensions. A trend was noted between the tricuspid annular plane systolic excursion obtained at echocardiography and systolic pulmonary artery pressure, obtained during RHC. Significant correlations were found between objective echocardiographic measurements of left and right heart function, in patients with PH from BPD.

BACKGROUND: Cardiomyopathies are a rare cause of pediatric heart disease, but they are one of the leading causes of heart failure admissions, sudden death, and need for heart transplant in childhood. Reports from the Pediatric Cardiomyopathy Registry (PCMR) have shown that almost 40% of children presenting with symptomatic cardiomyopathy either die or undergo heart transplant within 2 years of presentation. Little is known regarding circulating biomarkers as predictors of outcome in pediatric cardiomyopathy. STUDY DESIGN: The Cardiac Biomarkers in Pediatric Cardiomyopathy (PCM Biomarkers) study is a multi-center prospective study conducted by the PCMR investigators to identify serum biomarkers for predicting outcome in children with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Patients less than 21 years of age with either DCM or HCM were eligible. Those with DCM were enrolled into cohorts based on time from cardiomyopathy diagnosis: categorized as new onset or chronic. Clinical endpoints included sudden death and progressive heart failure. RESULTS: There were 288 children diagnosed at a mean age of 7.2±6.3 years who enrolled in the PCM Biomarkers Study at a median time from diagnosis to enrollment of 1.9 years. There were 80 children enrolled in the new onset DCM cohort, defined as diagnosis at or 12 months prior to enrollment. The median age at diagnosis for the new onset DCM was 1.7 years and median time from diagnosis to enrollment was 0.1 years. There were 141 children enrolled with either chronic DCM or chronic HCM, defined as children ≥2 years from diagnosis to enrollment. Among children with chronic cardiomyopathy, median age at diagnosis was 3.4 years and median time from diagnosis to enrollment was 4.8 years. CONCLUSION: The PCM Biomarkers study is evaluating the predictive value of serum biomarkers to aid in the prognosis and management of children with DCM and HCM. The results will provide valuable information where data are lacking in children. CLINICAL TRIAL REGISTRATION: NCT01873976: https://clinicaltrials.gov/ct2/show/NCT01873976?term=PCM+Biomarker&rank=1

Background: Reports focused on adult heart transplant (HTx) recipients with COVID-19 suggest an increased risk of severe disease, however; it is unclear if this holds true for pediatric HTx patients, given the typically milder course of illness in children in general with COVID-19. We sought to rapidly implement a system for multi-center data collection on pediatric HTx candidates and recipients, with the aim of describing the patient population and infection related outcomes. Methods: The Pediatric Heart Transplant Society (PHTS) is a multi-center collaboration that seeks to improve the outcomes of children who are listed and undergo HTx. The society consists of pediatric HTx centers in North America (n=53), UK (n=2), and Brazil (n=1). In response to the pandemic, PHTS developed a web-based platform to collect COVID-19 specific data on pediatric HTx candidates and recipients. Non-PHTS centers were also invited to submit data. Data fields included pre-and post-HTx patient characteristics, presumed versus documented infection, need for hospitalization (including ICU and ventilator use), treatments administered, and 30-day outcome (resolution, death, sequelae, and or unresolved) Results: Data collection was initiated on 4/30/20. As of 03/15/21 there were 225 patients [19 pre-HTx and 206 post-HTx, median age 14 years (IQR 7, 18)] reported from 41 centers. Hospitalization occurred in 42% (n=8) of the pre-HTx and 21% (n=43) of the post-HTx patients. Among the patients listed for HTx, 21% (n=4) required ICU and 10.5% (n=2) were mechanically ventilated. Among post-HTx patients, 7% (n=14) required ICU and 1% (n=3) were mechanically ventilated. At 30 days, the majority of patients had resolution of symptoms (94.7% pre-HTx, 95.6% post-HTx). One death was reported in a post-HTx patient prior to 30 days from onset of COVID-19 illness. Conclusions: These data demonstrate the ability to rapidly adapt the PHTS data collection infrastructure in response to a novel infection and represent the first known multi-center report of characteristics and early outcomes for patients listed and following pediatric HTx with COVID-19. Hospitalization appears to be more common for both candidates and recipients due to COVID-19 than for the general pediatric population though stays were short and mortality minimal.

Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in

Introduction: Barth Syndrome (BTHS) is a rare (~1/350,000), X-linked mitochondrial disease characterized by cardioskeletal myopathy and neutropenia. Reported outcomes after heart transplant (HT) are limited to case reports. We sought to identify a large cohort of BTHS HT recipients to describe clinical outcomes. Hypothesis: HT in BTHS is associated with non-inferior survival, acute rejection (AR), infection, and vasculopathy (CAV) relative to non-BTHS dilated cardiomyopathy (DCM). Methods: We analyzed data from the Barth Syndrome Registry and Repository (BRR), Pediatric Heart Transplant Society (PHTS), and Scientific Registry of Transplant Recipients (SRTR). To avoid recounting patients occurring in >1 source, we used years of birth, listing, and HT and listing/HT city to link records across registries. BTHS HT recipients were matched 1:4 on age, era, urgency status, and use of ECMO/VAD to male, non-BHTS, DCM HT recipients in PHTS. Survival was analyzed for all BTHS HT recipients. Because BRR and SRTR morbidity data are limited, AR, infection, malignancy, and CAV were analyzed only for those with PHTS data. Results: Forty-seven BTHS patients with 51 listings and 43 HTs (including 2 re-transplants) were identified; 29 BTHS HTs (1 re-transplant) had data in PHTS. Median age at HT was 1.9 yrs (IQR: 0.6-5.8) with 35% Conclusions: In this largest cohort yet reported, BTHS HT recipients show equivalent survival and freedom from infection, malignancy, and CAV, with a lower risk of acute rejection. Thus, individuals with BTHS should not be excluded from HT solely based on the diagnosis of BTHS.

In children with single ventricle physiology, the Glenn procedure is performed to redirect venous return from the superior vena cava directly to the pulmonary arteries and route venous return from the inferior vena cava exclusively to the systemic circulation. Although this surgery successfully palliates the hemodynamic stress experienced by the single ventricle, patients frequently develop pulmonary arteriovenous malformations (PAVMs). Interestingly, PAVMs may regress upon rerouting of hepatic venous effluent to the pulmonary vasculature, suggesting the presence of a circulating “hepatic factor” that is required to prevent PAVMs. Here, we test the hypothesis that hepatic factor is bone morphogenetic protein 9 (BMP9) and/or BMP10. These circulating ligands are produced by the liver and activate endothelial endoglin (ENG)/ALK1 signaling, and mutations in ENG and ALK1 cause hereditary hemorrhagic telangiectasia, a genetic disease associated with AVM development. However, we found no within-subject variation in BMP9, BMP10, or BMP9/10 plasma concentrations when sampled from five cardiovascular sites, failing to support the idea that the Glenn would limit access of these ligands to the lung vasculature. Unexpectedly, however, we found a significant decrease in all three ligand concentrations in Glenn cases versus controls. Our findings suggest that BMP9/BMP10/ENG/ALK1 signaling may be decreased in the Glenn vasculature but fail to implicate these ligands as hepatic factor.

INTRODUCTION: Right ventricular (RV) failure is a potentially fatal complication following heart transplantation (HTx). Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator that is used to decrease pulmonary vascular resistance immediately post-HTx to reduce the risk of RV failure. The aim of this study was to describe utilization patterns, costs, and outcomes associated with post-transplant iNO use in children. METHODS: All pediatric HTx recipients (2002–2016) were identified from a unique linked PHIS/SRTR dataset. Post-HTx iNO use was determined based on hospital billing data. Utilization patterns and associated costs were described. The association of iNO support with post-HTx survival was assessed using the Kaplan-Meier method and a multivariable Cox proportional hazards model was used to adjust for risk factors. RESULTS: A total of 2893 pediatric HTx recipients from 28 centers were identified with 1057 (36.5%) receiving iNO post-HTx. Post-HTx iNO use showed significant increase overall (17.2% to 54.7%, p < 0.001) and wide variation among centers (9% – 100%, p < 0.001). Patients with congenital heart disease (aOR 1.4, 95% CI 1.2, 1.6), requiring mechanical ventilation at HTx (aOR 1.3, 95% CI 1.1, 1.6), and pre-transplant iNO (aOR 9.3, 95% CI 5.4, 16) were more likely to receive iNO post-HTx. The median daily cost of iNO was $2,617 (IQR $1,843 – $3,646). Patients who required > 5 days of iNO post-HTx demonstrated inferior 1-year post-HTx survival (p < 0.001) and iNO use > 5 days was independently associated with worse post-HTx survival (AHR 1.6, 95% CI 1.2, 2.1; p < 0.001). CONCLUSION: There is wide variation in iNO use among centers following pediatric HTx with use increasing over time despite significant incremental cost. Prolonged iNO use post-HTx is associated with worse survival, likely serving as a marker of residual illness severity. Further research is needed to define the populations that derive the greatest benefit from this costly therapy.

There are limited published data addressing the costs associated with pediatric heart transplantation and no studies evaluating the variation in costs across centers. We aimed to describe center variation in pediatric heart transplant costs and assess the association of transplant hospitalization costs with patient outcomes. Using a linkage between the Pediatric Health Information System and Scientific Registry of Transplant Recipients databases, hospital costs were assessed for patients (

BACKGROUND Despite significant changes in the past decade for children undergoing heart transplantation, including the evolution of mechanical circulatory support and increasing patient complexity, costs and resource utilization have not been reassessed. We sought to use a novel linkage of clinical-registry and administrative data to examine changes in hospitalization costs over time in this population. METHODS We identified all pediatric heart transplant recipients in a unique linked Pediatric Health Information System/Scientific Registry of Transplant Recipients data set (2002-2016). Hospital costs were estimated from charges using cost-to-charge ratios, inflated to 2016 dollars. Severity-adjusted costs were calculated using generalized linear mixed-effects models. Costs were compared across 3 eras (era 1, 2002-2006; era 2, 2007-2011; and era 3, 2012-2016). RESULTS A total of 2896 pediatric heart transplant recipients were included: era 1, 649 (22.4%); era 2, 1028 (35.5%); and era 3, 1219 (42.1%). Extracorporeal membrane oxygenation support at transplant decreased over time, concurrent with an increase in ventricular assist device-supported patients. Between era 1 and era 2, there was an increase in pretransplant hospitalization costs (US $343 692 vs US $435 554; P < 0.001). However, between era 2 and era 3, there was a decline in total (US $906 454 vs US $767 221; P < 0.001), pretransplant (US $435 554 vs US $353 364; P < 0.001), and posttransplant (US $586 133 vs US $508 719; P = 0.002) hospitalization costs. CONCLUSIONS Concurrent with the increase in utilization of ventricular assist device support, there has been an increase in pretransplant costs associated with pediatric heart transplantation. However, in the most recent era, costs have declined. These findings suggest the evolution of more cost-effective management strategies, which may be related to shifts in the approach to pediatric mechanical circulatory support.

Purpose Routine surveillance biopsy (RSB) is performed to detect asymptomatic acute rejection (AR) after heart transplantation (HT). Variation in pediatric RSB across institutions is high. We examined center-based variation in RSB use and its relationship to graft loss, AR, coronary artery vasculopathy (CAV), and cost of care during the first year post-HT. Methods We linked the Pediatric Health Information System (PHIS) and Scientific Registry of Transplant Recipients (SRTR, 2002-2016), including all primary-HT aged 0-21. We scored institutional RSB strategy by the median number of first-year biopsies in recipients aged ≥12 months without rejection. Mixed effects regression analysis was used to adjust for potential confounders and center effects. Results Of 2,867 patients at 29 centers, we identified an inflection at the top-tertile of centers (834 patients at 10 centers with RSB-score≥4). Higher-RSB centers (i.e. those in the top-tertile) had more patients on pre-HT ventilator/ECMO (23% vs 18% p=0.04) and fewer with a positive crossmatch (13% vs 17% p=0.007). After adjusting for patient and center differences, higher RSB frequency was associated with diagnosed AR (OR 1.15 p=0.004), a trend toward treated AR (OR 1.09 p=0.083) and higher cost (US$450,708 vs 342,170, p Conclusion Higher RSB frequency is associated with increased diagnosis, but not treatment, of AR one-year post-HT. Graft survival and CAV appear unchanged at medium term follow-up. De-intensification at high-frequency institutions may be safe and reduce costs, but further study of differences in treated rejections are necessary.

Background Large clinical, research, and administrative databases are increasingly utilized to facilitate pediatric heart transplant (HTx) research. Linking databases has proven to be a robust strategy across multiple disciplines to expand the possible analyses that can be performed while leveraging the strengths of each dataset. We describe a unique linkage of the Scientific Registry of Transplant Recipients (SRTR) database and the Pediatric Health Information System (PHIS) administrative database to provide a platform to assess resource utilization in pediatric HTx. Methods All pediatric patients (1999-2016) who underwent HTx at a hospital enrolled in the PHIS database were identified. A linkage was performed between the SRTR and PHIS databases in a stepwise approach using indirect identifiers. To determine the feasibility of using these linked data to assess resource utilization, total and post-HTx hospital costs were assessed. Results A total of 3188 unique transplants were identified as being present in both databases and amenable to linkage. Linkage of SRTR and PHIS data was successful in 3057 (95.9%) patients, of whom 2896 (90.8%) had complete cost data. Median total and post-HTx hospital costs were $518,906 (IQR $324,199-$889,738), and $334,490 (IQR $235,506-$498,803) respectively with significant differences based on patient demographics and clinical characteristics at HTx. Conclusions Linkage of the SRTR and PHIS databases is feasible and provides an invaluable tool to assess resource utilization. Our analysis provides contemporary cost data for pediatric HTx from the largest US sample reported to date. It also provides a platform for expanded analyses in the pediatric HTx population.

Optimal management of pediatric cardiac donors is essential in order to maximize donor heart utilization and minimize the rate of discarded organs. This review was performed after a systematic literature review and gives a detailed overview on current practices and guidelines. The review focuses on optimal monitoring of pediatric donors, donor workup, hormonal replacement, and obliterating the adverse effects of brain death. The current evidence on catecholamine support and thyroid hormone replacement is also discussed. Recognizing and addressing this shall help in a standardized approach toward donor management and optimal utilization of pediatric heart donors organs.

Rehospitalization following pediatric heart transplantation is common. However, existing data remain somewhat limited. Using a novel linkage between administrative and clinical databases, pediatric heart transplant (HT) recipients from 29 centers who survived to discharge were retrospectively reviewed to determine the frequency, timing of, and indication for all-cause rehospitalizations in the year following transplant discharge. Of 2870 pediatric HT recipients, 1835 (63.9%) were rehospitalized in the first year post-discharge (5429 total readmissions). Rehospitalization rates varied significantly across centers (46% to 100%) and were inversely correlated to center transplant volume (r(2) 0.25, p < 0.01). The median number of rehospitalizations per patient was 2 (IQR 1–4) and the median time to first rehospitalization was 29 days (IQR 9–99 days). Independent risk factors for rehospitalization included younger age at HT (HR 0.99, 95% CI 0.97–0.99), congenital heart disease (HR 1.2, 95% CI 1.1–1.4), listing status 1B at transplant (HR 1.3, 95% CI 1.1–1.5), and post-transplant complications including rejection prior to discharge (HR 1.5 95% CI 1.3–1.8) and chylothorax (HR 1.3, 95% CI 1.0–1.6). Cardiac diagnoses were the most common indication for rehospitalization (n = 1600, 29.5%), followed by infection (n = 1367, 25.2%). These findings may serve to guide the development of interventions aimed at reducing post-HT hospitalizations.

Objectives This study examined how ECV and GLS relate to each other and to outcomes. Background Among myriad changes occurring in diseased myocardium, left ventricular imaging metrics of either the interstitium (e.g., extracellular volume [ECV]) or contractile function (e.g., global longitudinal strain [GLS]) may consistently associate with adverse outcomes yet correlate minimally with each other. This scenario suggests that ECV and GLS potentially represent distinct domains of cardiac vulnerability. Methods The study included 1,578 patients referred for cardiovascular magnetic resonance (CMR) without amyloidosis, and it quantified how ECV associated with GLS in linear regression models. ECV and GLS were then compared in their associations with incident outcomes (death and hospitalization for heart failure). Results ECV and GLS correlated minimally (R2 = 0.04). Over a median follow-up of 5.6 years, 339 patients experienced adverse events (149 hospitalizations for heart failure, 253 deaths, and 63 with both). GLS (univariable hazard ratio: 2.07 per 5% increment; 95% CI: 1.86 to 2.29) and ECV (univariable hazard ratio: 1.66 per 4% increment; 95% CI: 1.51 to 1.82) were principal variables associating with outcomes in univariable and multivariable Cox regression models. Similar results were observed in several clinically important subgroups. In the whole cohort, ECV added prognostic value beyond GLS in univariable and multivariable Cox regression models. Conclusions GLS and ECV may represent principal but distinct domains of cardiac vulnerability, perhaps reflecting their distinct cellular origins. Whether combining ECV and GLS may advance pathophysiological understanding for a given patient, optimize risk stratification, and foster personalized medicine by targeted therapeutics requires further investigation.

The frequency, indications, and outcomes for readmission following pediatric heart transplantation are poorly characterized. A better understanding of this phenomenon will help guide strategies to address the causes of readmission. Data from the Clinical Trials in Organ Transplantation for Children (CTOTC-04) multi-institutional collaborative study were utilized to determine incidence of, and risk factors for, hospital readmission within 30 days and 1 year from initial hospital discharge. Among 240 transplants at 8 centers, 227 subjects were discharged and had follow-up. 129 subjects (56.8%) were readmitted within one year; 71 had two or more readmissions. The 30-day and 1-year freedom from readmission were 70.5% (CI: 64.1%, 76.0%) and 42.2% (CI: 35.7%, 48.7%), respectively. The most common indications for readmissions were infection followed by rejection and fever without confirmed infection, accounting for 25.0%, 10.6%, and 6.2% of readmissions, respectively. Factors independently associated with increased risk of first readmission within 1 year (Cox proportional hazard model) were as follows: transplant in infancy (P = .05), longer transplant hospitalization (P = .04), lower UNOS urgency status (2/IB vs 1A) at transplant (P = .04), and Hispanic ethnicity (P = .05). Hospital readmission occurs frequently in the first year following discharge after heart transplantation with highest risk in the first 30 days. Infection is more common than rejection as cause for readmission, with death during readmission being rare. A number of patient factors are associated with higher risk of readmission. A fuller understanding of these risk factors may help tailor strategies to reduce unnecessary hospital readmission.

US Pediatric Heart Allocation Policy was recently revised, deprioritizing candidates with cardiomyopathy while maintaining status 1A eligibility for congenital heart disease (CHD) candidates on "high-dose" inotropes. We compared waitlist characteristics and mortality around this change. Status 1A listings decreased (70% to 56%, P < .001) and CHD representation increased among status 1A listings (48% vs 64%, P < .001). Waitlist mortality overall (subdistribution hazard ratio [SHR] 0.96, P = .63) and among status 1A candidates (SHR 1.16, P = .14) were unchanged. CHD waitlist mortality trended better (SHR 0.82, P = .06) but was unchanged for CHD candidates listed status 1A (SHR 0.92, P = .47). Status 1A listing exceptions increased 2- to 3-fold among hypertrophic and restrictive cardiomyopathy candidates and 13.5-fold among dilated cardiomyopathy (DCM) candidates. Hypertrophic (SHR 6.25, P = .004) and restrictive (SHR 3.87, P = .03) cardiomyopathy candidates without status 1A exception had increased waitlist mortality, but those with DCM did not (SHR 1.26, P = .32). Ventricular assist device (VAD) use increased only among DCM candidates ≥1 years old (26% vs 38%, P < .001). Current allocation policy has increased CHD status 1A representation but has not improved their waitlist mortality. Excessive DCM status 1A listing exceptions and continued status 1A prioritization of children on stable VADs potentially diminish the intended benefits of policy revision.

Purpose Reports focused on adult heart transplant (HT) recipients with COVID-19 suggest an increased risk of severe disease. It is unclear if this holds true for pediatric HT patients, given the reported milder course of illness in children in general with COVID-19. We sought to rapidly implement a system for multi-center data collection on pediatric HT recipients and candidates, with the aim of describing the patient population and infection related outcomes. Methods The Pediatric Heart Transplant Society (PHTS) is a multi-center collaboration whose main goal is to improve the outcomes of children who are listed and undergo HT. The society consists of pediatric HT centers in North America (n=53), UK (n=2), and Brazil (n=1). In response to the pandemic, PHTS developed a web-based platform to collect COVID-19 specific data in pediatric HT candidates and recipients. Non-PHTS centers were also invited to submit data. Data fields included pre-and post-HT patient characteristics, presumed vs. documented infection, need for hospitalization (including ICU and ventilator use), treatments administered, and 30-day outcome (death, resolution, sequelae, ongoing treatment). Results Data collection was initiated on 4/30/20. As of 9/28/20, there were 72 patients (7 pre-HT and 65 post-HT, median age 13 years) reported from 27 centers. Of these, 67 were PCR+ by nasal swab and 5 were presumed positive. Complete data with 30-day follow-up was available for 60 patients (7 pre and 53 post HTx). Hospitalization was common and occurred in 71% of the pre-HT and 32% of the post HTx patients. Of the pre-Tx patients, 43% required ICU and 14% were ventilated. In the post HTx group, 13% required ICU and 4% were ventilated. At 30 days a majority of pre-Tx had resolution of symptoms (n=6/7). Among post HTx patients, resolution occurred in 87%% (46/53) with 1 death at 30 days. Conclusion The PHTS remains the most robust source of data on pediatric HT and this effort shows the adaptability of the registry. Although likely limited by reporting bias, these data represent the first known report of characteristics and early outcomes for pediatric HT candidates and recipients with COVID-19. As data collection continues, we aim to better understand the characteristics of patients with more severe disease in order to improve risk characterization and decrease the knowledge gap that currently exists in this unique population.

Primary graft dysfunction following heart transplantation (HTx) is associated with significant morbidity and mortality. This study aimed to assess the incidence of, risk-factors for, and outcomes of children requiring ECMO within 24-hours of HTx. This study utilized a linked PHIS/SRTR database of pediatric HTx recipients (2002–2016). Post-HTx ECMO was identified using inpatient billing data. Logistic regression assessed risk-factors for post-HTx ECMO. Kaplan-Meier analyses assessed in-hospital mortality and post-discharge survival. A total of 2,820 patients were included with 224 (7.9%) requiring ECMO. Independent risk-factors for post-HTx ECMO include age

BACKGROUND: DiGeorge syndrome (DGS) is commonly associated with both congenital heart disease (CHD) and immunologic abnormalities. While CHD may prompt consideration for heart transplantation (HTx), little is known about HTx management or outcomes in this group. The aim of this study was to describe the spectrum of patients with DGS who undergo HTx and report post-HTx outcomes. METHODS: All pediatric HTx recipients (2002–2016) with DGS were identified using ICD codes from a linked billing and clinical registry database. Patient characteristics and outcomes were described and compared to non-DGS HTx recipients with CHD. Kaplan-Meier methods were used to assess overall survival, freedom from infection, and freedom from rejection. RESULTS: A total of 17 patients with DGS who underwent HTx at 12 different centers were included. Median age at HTx was 5yrs (IQR 0–13yrs). Steroids were used for induction in all patients in addition to thymoglobulin in 13/17 (76%) and IL2R antagonists in 3/17 (18%). Maintenance immunosuppression was a combination of tacrolimus or cyclosporine and mycophenolate or azathioprine in 16/17 (94%). Half received steroids at the time of discharge. There were 6 deaths (35%). The median post-HTx survival was 5.4yrs with no difference in freedom from rejection, infection, or overall survival between patients with and without DGS. CONCLUSIONS: Patients with DGS syndrome undergoing HTx receive standard immunosuppression. We found no difference in freedom from infection, rejection, or overall post-HTx survival compared to non-DGS patients, although the small size of our study resulted in limited statistical power. Given the potential for favorable outcomes, patients with DGS may be considered for HTx in the appropriate clinical setting.

Identify pediatric heart transplant (HT) recipients with heterotaxy and other complex arrangements of cardiac situs (heterotaxy/situs anomaly) and compare mortality, morbidities, length of stay (LOS), and costs to recipients with congenital heart disease without heterotaxy/situs anomaly.Using linked registry data (2001-2016), we identified 186 HT recipients with heterotaxy/situs anomaly and 1254 with congenital heart disease without heterotaxy/situs anomaly. We compared post-HT outcomes in univariable and multivariable time-to-event analyses. LOS and cost from HT to discharge were compared using Wilcoxon rank-sum tests. Sensitivity analyses were performed using stricter heterotaxy/situs anomaly group inclusion criteria and through propensity matching.HT recipients with heterotaxy/situs anomaly were older (median age, 5.1 vs 1.6 years; P .001) and more often black, Asian, Hispanic, or "other" nonwhite (54% vs 32%; P .001). Heterotaxy/situs anomaly was independently associated with increased mortality (hazard ratio, 1.58; 95% confidence interval, 1.19-2.09; P = .002), even among 6-month survivors (hazard ratio, 1.86; 95% confidence interval, 1.09-3.16; P = .021). Heterotaxy/situs anomaly recipients more commonly required dialysis (odds ratio, 2.58; 95% confidence interval, 1.51-4.42; P = .001) and cardiac reoperation (odds ratio, 1.91; 95% confidence interval, 1.17-3.11; P = .010) before discharge. They had longer ischemic times (19.2 additional minutes [range, 10.9-27.5 minutes]; P .001), post-HT intensive care unit LOS (16 vs 13 days; P = .012), and hospital LOS (26 vs 23 days; P = .005). Post-HT hospitalization costs were also greater ($447,604 vs $379,357; P = .001).Heterotaxy and other complex arrangements of cardiac situs are associated with increased mortality, postoperative complications, LOS, and costs after HT. Although increased surgical complexity can account for many of these differences, inferior late survival is not well explained and deserves further study.

Elevated serum soluble (s) suppressor of tumorigenicity-2 is observed during cardiovascular and inflammatory bowel diseases. To ascertain whether modulated ST2 levels signify heart (HTx) or small bowel transplant (SBTx) rejection, we quantified sST2 in serially obtained pediatric HTx (n = 41) and SBTx recipient (n = 18) sera. At times of biopsy-diagnosed HTx rejection (cellular and/or antibody-mediated), serum sST2 was elevated compared to rejection-free time points (1714 ± 329 vs. 546.5 ± 141.6 pg/mL; p = 0.0002). SBTx recipients also displayed increased serum sST2 during incidences of rejection (7536 ± 1561 vs. 2662 ± 543.8 pg/mL; p = 0.0347). Receiver operator characteristic (ROC) analysis showed that serum sST2 > 600 pg/mL could discriminate time points of HTx rejection and nonrejection (area under the curve [AUC] = 0.724 ± 0.053; p = 0.0003). ROC analysis of SBTx measures revealed a similar discriminative capacity (AUC = 0.6921 ± 0.0820; p = 0.0349). Quantitative evaluation of both HTx and SBTx biopsies revealed that rejection significantly increased allograft ST2 expression. Pathway and Network Analysis of biopsy data pinpointed ST2 in the dominant pathway modulated by rejection and predicted tumor necrosis factor-α and IL-1β as upstream activators. In total, our data indicate that alloimmune-associated pro-inflammatory cytokines increase ST2 during rejection. They also demonstrate that routine serum sST2 quantification, potentially combined with other biomarkers, should be investigated further to aid in the noninvasive diagnosis of rejection.

Anti-HLA donor-specific antibodies are associated with worse outcomes after organ transplantation. Among sensitized pediatric heart candidates, requirement for negative donor-specific cytotoxicity crossmatch increases wait times and mortality. However, transplantation with positive crossmatch may increase posttransplantation morbidity and mortality. We address this clinical challenge in a prospective, multicenter, observational cohort study of children listed for heart transplantation (Clinical Trials in Organ Transplantation in Children-04 [CTOTC-04]). Outcomes were compared among sensitized recipients who underwent transplantation with positive crossmatch, nonsensitized recipients, and sensitized recipients without positive crossmatch. Positive crossmatch recipients received antibody removal and augmented immunosuppression, while other recipients received standard immunosuppression with corticosteroid avoidance. This first CTOTC-04 report summarizes study rationale and design and relates pretransplantation sensitization status using solid-phase technology. Risk factors for sensitization were explored. Of 317 screened patients, 290 were enrolled and 240 underwent transplantation. Core laboratory evaluation demonstrated that more than half of patients were anti-HLA sensitized. Greater than 80% of sensitized patients had class I (with or without class II) HLA antibodies, and one-third of sensitized patients had at least 1 HLA antibody with median fluorescence intensity of ≥8000. Logistic regression models demonstrated male sex, weight, congenital heart disease history, prior allograft, and ventricular assist device are independent risk factors for sensitization.

OBJECTIVES Bone marrow suppression is a common adverse effect of the immunosuppressive drug azathioprine. Polymorphisms in the gene encoding thiopurine S-methyltransferase (TPMT) can alter the metabolism of azathioprine, resulting in marrow toxicity and life-threatening infection. In a multicenter cohort of pediatric heart transplant (HT) recipients, we determined the frequency of TPMT genetic variation and assessed whether azathioprine-treated recipients with TPMT variants were at increased risk of infection. METHODS We genotyped TPMT in 264 pediatric HT recipients for the presence of the TPMT*2, TPMT*3A, and TPMT*3C variant alleles. Data on infection episodes and azathioprine use were collected as part of each patient's participation in the Pediatric Heart Transplant Study. We performed unadjusted Kaplan-Meier analyses comparing infection outcomes between groups. RESULTS TPMT variants were identified in 26 pediatric HT recipients (10%): *3A (n = 17), *3C (n = 8), and *2 (n = 1). Among those with a variant allele, *3C was most prevalent in black patients (4 of 5) and *3A most prevalent among white and Hispanic patients (16 of 20). Among 175 recipients (66%) who received azathioprine as part of the initial immunosuppressive regimen, we found no difference in the number of infections at 1 year after HT (0.7 ± 1.3; range, 0–6 versus 0.5 ± 0.9; range, 0–3; p = 0.60) or in freedom from infection and bacterial infection between non-variant and variant carriers. There was 1 infection-related death in each group. CONCLUSIONS In this multicenter cohort of pediatric HT recipients, the prevalence of TPMT variants was similar across racial/ethnic groups to what has been previously reported in non-pediatric HT populations. We found no association between variant alleles and infection in the first year after HT. Because clinically detected cytopenia could have prompted dose adjustment or cessation, we recommend future studies assess the relationship of genotype to leukopenia/neutropenia in the pediatric transplantation population.

Allosensitized children who require a negative prospective crossmatch have a high risk of death awaiting heart transplantation. Accepting the first suitable organ offer, regardless of the possibility of a positive crossmatch, would improve waitlist outcomes but it is unclear whether it would result in improved survival at all times after listing, including posttransplant. We created a Markov decision model to compare survival after listing with a requirement for a negative prospective donor cell crossmatch (WAIT) versus acceptance of the first suitable offer (TAKE). Model parameters were derived from registry data on status 1A (highest urgency) pediatric heart transplant listings. We assumed no possibility of a positive crossmatch in the WAIT strategy and a base-case probability of a positive crossmatch in the TAKE strategy of 47%, as estimated from cohort data. Under base-case assumptions, TAKE showed an incremental survival benefit of 1.4 years over WAIT. In multiple sensitivity analyses, including variation of the probability of a positive crossmatch from 10% to 100%, TAKE was consistently favored. While model input data were less well suited to comparing survival when awaiting transplantation across a negative virtual crossmatch, our analysis suggests that taking the first suitable organ offer under these circumstances is also favored.

BACKGROUND: Pediatric mechanical circulatory support (MCS) has evolved considerably over the past decade. Though marked improvements in waitlist survival have been realized, costs have not been reassessed. This project aimed to assess contemporary MCS costs in children bridged to heart transplant (HT). METHODS: All pediatric HT recipients (2002–2016) were identified from a unique, linked PHIS/SRTR dataset. Costs were calculated from hospital charges, inflated to 2016 Dollars and adjusted for patient-specific characteristics using generalized linear mixed-effects models. Costs and length of stay (LOS) were compared across support strategies at the time of HT (no MCS, VAD, or ECMO) with select subgroup analyses. RESULTS: A total of 2873 pediatric HT recipients were included; no MCS: 2268 (78.9%), VAD: 470 (16.4%), and ECMO: 135 (4.7%). Both VAD and ECMO were associated with greater total hospitalization costs compared to no MCS ($755,345 and $808,771 vs. $457,086; p

Recent Organ Procurement and Transplantation Network bylaw revisions mandate that US transplant programs have an "approved pediatric component" in order to perform heart transplantation (HT) in patients18 years old. The impact of this change on adolescents, a group known to be at high risk for graft loss and nonadherence, is unknown. We studied all US primary pediatric (age18 years) HT from 2000 to 2015 to compare graft survival between centers organized mainly for adult versus pediatric care. Centers were designated as pediatric- or adult-specialty care according to the ratio of pediatric:adult HT performed and minimum age of HT (pediatric-specialty defined as ratio0.7; adult-specialty ratio0.05 and minimum age8 years). In propensity score-matched cohorts, we observed no difference in graft loss by center type (median survival: adult 12.4 years vs pediatric 9.2 years, P = .174). Compared to the matched pediatric cohort, adult-specialty center recipients lived closer to their transplant center (31 vs 45 miles, P = .012), and trended toward fewer out-of-state transplants (15 vs 25%, P = .082). Our data suggest that select adolescents can achieve similar midterm graft survival at centers organized primarily for adult HT care. Regardless of post-HT setting, the development of care models that demonstrably improve adherence may be of greatest benefit to improving survival of this high-risk population.

BACKGROUND: Turner syndrome (TS) patients with hypoplastic left heart syndrome (HLHS) have poor single ventricle palliation outcomes; therefore, consideration of other potential management strategies is important. Little is known about heart transplantation (HTx) in this group, as standard HTx databases do not allow for identification of TS. This study describes experiences and outcomes of HTx in TS using a unique linkage between the Scientific Registry of Transplant Recipients (SRTR) and the Pediatric Health Information System (PHIS) databases. METHODS: All pediatric HTx recipients (2002–2016) with TS were identified in the database using ICD-9 code 758.6 (gonadal dysgenesis) in conjunction with female sex. Patient characteristics and outcomes were described. RESULTS: Fourteen patients with TS were identified who underwent 16 HTx procedures at 8 centers. For initial HTx, HLHS was the most common indication (10/14) with a median age of 10 months (IQR 3–73 months). Median transplant-free survival following initial HTx was 4.1 years (IQR: 16 days–10.5 years), with all deaths occurring in the first year post-HTx. For patients that survived past 1 year (8/14), follow-up ranged from 4.1 to 10.9 years (median 8.0 years) with no deaths observed. CONCLUSIONS: Our cohort demonstrates that while there is a clear risk for early mortality, there is the potential for favorable outcomes following HTx in patients with TS. Therefore, TS should not be viewed as an absolute contraindication to HTx, but careful assessment of candidate risk is needed. Primary palliation with HTx for HLHS and TS may be a reasonable consideration given the poor outcomes of single ventricle palliation in this group. Further research is needed to fully delineate the outcomes and characteristics of this unique population.

Data on the clinical importance of newly detected donor-specific anti-HLA antibodies (ndDSAs) after pediatric heart transplantation are lacking despite mounting evidence of the detrimental effect of de novo DSAs in solid organ transplantation. We prospectively tested 237 pediatric heart transplant recipients for ndDSAs in the first year posttransplantation to determine their incidence, pattern, and clinical impact. One-third of patients developed ndDSAs; when present, these were mostly detected within the first 6 weeks after transplantation, suggesting that memory responses may predominate over true de novo DSA production in this population. In the absence of preexisting DSAs, patients with ndDSAs had significantly more acute cellular rejection but not antibody-mediated rejection, and there was no impact on graft and patient survival in the first year posttransplantation. Risk factors for ndDSAs included common sensitizing events. Given the early detection of the antibody response, memory responses may be more important in the first year after pediatric heart transplantation and patients with a history of a sensitizing event may be at risk even with a negative pretransplantation antibody screen. The impact on late graft and patient outcomes of first-year ndDSAs is being assessed in an extended cohort of patients.

For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes.

Fibrosis is commonly described in heart allografts lost late after transplantation. CMR-derived ECV is a validated measure of DMF in native adult hearts that may predict heart failure and mortality. We explored associations of ECV with histologic myocardial fibrosis and clinical features after pediatric heart transplantation. Twenty-five recipients (7.0±6.3 years at transplant and 10.7±6.5 years post-transplant) were prospectively recruited for CMR and BNP measurement at the time of surveillance biopsy. All had normal ejection fractions and lacked heart failure symptoms. Fibrosis was quantified on biopsy after picrosirius red staining as CVF. ECV was quantified using contemporaneous hematocrit on basal and mid-short-axis slices. ECV was moderately correlated with CVF (r=.47; P=.019). We found no associations of ECV with hemodynamics, ischemic time, time since transplantation, or number of prior biopsies or acute rejections. Compared to healthy non-transplant controls, there was no significant difference in ECV (25.1±3.0 vs 23.7±2.0%, P=.09). Log-transformed BNP was correlated with ECV (recipients: r=.46, P=.02; recipients and controls: r=.45, P=.006). These findings suggest ECV quantifies DMF and relates to biological indicators of cardiac function after pediatric heart transplantation.

To compare the outcomes and comorbidities of children with mitochondrial disease undergoing heart transplantation with children without mitochondrial disease.Using a unique linkage between the Pediatric Health Information System and Scientific Registry of Transplant Recipients databases, pediatric heart transplantation recipients from 2002 to 2016 with a diagnosis of cardiomyopathy were included. Post heart transplantation survival and morbidities were compared between patients with and without mitochondrial disease.A total of 1330 patients were included, including 47 (3.5%) with mitochondrial disease. Survival after heart transplantation was similar between patients with and without mitochondrial disease over a median follow-up of 4 years. Patients with mitochondrial disease were more likely to have a stroke after heart transplantation (11% vs 3%; P = .009), require a longer duration of mechanical ventilation after heart transplantation (3 days vs 1 day; P .001), and have a longer intensive care unit stay after heart transplantation (10 vs 6 days; P = .007). The absence of a hospital readmission within the first post-transplant year was similar among patients with and without mitochondrial disease (61.7% vs 51%; P = .14). However, patients with mitochondrial disease who were readmitted demonstrated a longer length of stay compared with those without (median, 14 days vs 8 days; P = .03).Patients with mitochondrial disease can successfully undergo heart transplantation with survival comparable with patients without mitochondrial disease. Patients with mitochondrial disease have greater risk for post-heart transplantation morbidities including stroke, prolonged mechanical ventilation, and longer intensive care unit and readmission length of stay. These results suggest that the presence of mitochondrial disease should not be an absolute contraindication to heart transplantation in the appropriate clinical setting.

EMB, the gold standard for diagnosis of ACR, poses unique risks in children. Limited cross-sectional data have associated LV MPI with ACR. We hypothesize that a relative change in MPI from baseline without ACR to the time of ACR will better detect ACR than an absolute threshold LV MPI value. We identified 40 children with ACR ≥60 days post-transplant matching them by age and time from transplantation to 40 children without ACR. There was a significant increase in LV MPI at time of ACR vs. baseline (0.59 ± 0.17 vs. 0.41 ± 0.11; p

As methods for human leukocyte antigens (HLA) antibody detection have evolved and newer solid phase assays are much more sensitive, the last 15 years has seen a renewed focus on the importance of HLA antibodies in solid organ transplant rejection. However, there is still much controversy regarding the clinical significance of antibody level as depicted by the mean fluorescence intensity of a patient’s neat serum. Emerging techniques, including those that identify antibody level and function, show promise for the detection of individuals at risk of allograft rejection, determination of the effectiveness of desensitization prior to transplant, and for monitoring treatment of rejection. Here, we review current publications regarding the relevance of donor-specific HLA antibodies (DSA) in adult and pediatric heart transplantation (HT) with graft survival, development of antibody-mediated rejection and cardiac allograft vasculopathy (CAV). The negative impact of DSA on patient and allograft survival is evident in adult and pediatric HT recipients. Many questions remain regarding the most appropriate frequency of assessment of pre- and posttransplant DSA as well as the phenotype of DSA memory vs. true de novo antibody using large multicenter adult and pediatric cohorts and state-of-the-art methodologies for DSA detection and characterization.