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Nemaline Myopathy (NM) is a disorder of skeletal muscles caused by mutations in sarcomere proteins and characterized by accumulation of microscopic rod or thread-like structures (nemaline bodies) in skeletal muscles. Patients diagnosed with both NM and infantile cardiomyopathy are very rare. A male infant presented, within the first few hours of life, with severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction. A muscle biopsy on the 8th day of life from the right sternocleidomastoid muscle identified nemaline rods. Whole exome sequencing identified a c.1288 delT (homozygous pathogenic variant) in the CAP2 gene (NM_006366), yielding a CAP2 protein (NP_006357.1) with a p.C430fs. Both parents were heterozygous for the same variant but have no history of heart or muscle disease. Analysis of patient derived fibroblasts and cardiomyocytes derived from induced pluripotent stem cells confirmed the p.C430fs mutation (pathogenic variant), which appears to cause loss of both CAP2 protein and mRNA. The CAP2 gene encodes cyclase associated protein 2, an actin monomer binding and filament depolymerizing protein and CAP2 knockout mice develop severe dilated cardiomyopathy and muscle weakness. The patient underwent a heart transplant at 1 year of age. Heart tissue explanted at that time also showed nemaline rods and additionally disintegration of the myofibrillar structure. Other extra cardiac concerns include mild hypotonia, atrophic and widened scarring. This is the first description of a patient presenting with nemaline myopathy associated with a pathogenic variant of CAP2.

Heart failure metrics specific to the pediatric population are required to successfully implement quality improvement initiatives in children with heart failure. Medication use at the time of discharge following admission for decompensated heart failure has been identified as a potential quality metric in this population. This study aimed to report medication use at discharge in the current era for children admitted with acute decompensated heart failure. All patients

The number of potential pediatric heart transplant recipients continues to exceed the number of donors, and consequently the waitlist mortality remains significant. Despite this, around 40% of all donated organs are not used and are discarded. This document (62 authors from 53 institutions in 17 countries) evaluates factors responsible for discarding donor hearts and makes recommendations regarding donor heart acceptance. The aim of this statement is to ensure that no usable donor heart is discarded, waitlist mortality is reduced, and post-transplant survival is not adversely impacted.

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 Endomyocardial biopsy (EMB) is costly and discomforting yet remains a key component of surveillance after pediatric heart transplantation (HT). Donor-derived cell-free DNA (dd-cfDNA) has been histologically validated with high negative predictive value, offering an alternative to surveillance EMB (sEMB). Methods We implemented an alternative surveillance protocol using commercially available dd-cfDNA assays in place of sEMB after pediatric HT. Recipients ≧7 months post-HT with reassuring clinical assessment were referred for dd-cfDNA. When not elevated above the manufacturers' threshold, sEMB was deferred. Subsequent clinical status and results of follow-up EMB were analyzed. Results Over 17 months, 58 recipients [34% female, median age at HT 3.1 years (IQR 0.6-10.6)] had dd-cfDNA assessed per protocol. Median age was 14.8 years (8.4-18.3) and time from HT 6.0 years (2.2-11.2). Forty-seven (81%) had non-elevated dd-cfDNA and 11 (19%) were elevated. During a median of 8.7 months (4.2-15), all are alive without allograft loss/new dysfunction. Among those with non-elevated dd-cfDNA, 24 (51%) had subsequent sEMB at 12.1 months (6.9-12.9) with 23 showing no acute rejection (AR): grade 0R/pAMR0 (n = 16); 1R(1A)/pAMR0 (n = 7). One had AR (grade 2R(3A)/pAMR0) on follow-up sEMB after decreased immunosuppression following a diagnosis of PTLD. All 11 with elevated dd-cfDNA had reflex EMB at 19 days (12-32) with AR in 4: grade 1R(1B-2)/pAMR0 (n = 3); 1R(1B)/pAMR2 (n = 1). Conclusions dd-cfDNA assessment in place of selected, per-protocol EMB decreased surveillance EMB by 81% in our pediatric HT recipient cohort with no short-term adverse outcomes. Individual center approach to surveillance EMB will influence the utility of these findings.

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.

BACKGROUND 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 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 years. We characterized centers by RSB frequency (defined as median biopsies performed among recipients aged ≥12 months without rejection in the first year). We adjusted for potential confounders and center effects with mixed-effects regression analysis. RESULTS We analyzed 2867 patients at 29 centers. After adjusting for patient and center differences, increasing 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 hospital-based cost (US$390 315 vs. $313 248, p

Background Barth Syndrome (BTHS) is a rare, X-linked disease characterized by cardioskeletal myopathy and neutropenia. Comparative outcomes after heart transplantation have not been reported. Methods We identified BTHS recipients across 3 registries (Pediatric Heart Transplant Study Registry [PHTS], Barth Syndrome Research Registry and Repository, and Scientific Registry of Transplant Recipient-Pediatric Health Information System) and matched them 1:4 to non-BTHS, male heart transplant (HT) recipients listed with dilated cardiomyopathy in PHTS. Demographics and survival data were analyzed for all recipients, whereas post-HT infection, malignancy, allograft vasculopathy , and acute rejection were only available for analysis for individuals with PHTS data. Results Forty-seven BTHS individuals with 51 listings and 43 HTs (including 2 re-transplants) were identified. Age at primary HT was 1.7 years (IQR: 0.6-4.5). Mechanical circulatory support at HT was common (ventricular assist device 29%, extracorporeal membrane oxygenation 5%). Over a median follow-up of 4.5 years (IQR 2.7-9.1), survival for BTHS HT recipients was no different than non-BTHS HT recipients (HR 0.91, 95% CI 0.40-2.12, p = 0.85). Among those with PHTS data (n = 28), BTHS HT recipients showed no difference in freedom from infection (HR 0.64, 0.34-1.22; p = 0.18), malignancy (HR 0.22, 0.02-2.01, p = 0.18), and allograft vasculopathy (HR 0.58, 0.16-2.1, p = 0.41). Freedom from acute rejection (HR 0.39, 0.17-0.86, p = 0.02) was greater for BTHS HT recipients despite similar use of induction (61 vs 73%, p = 0.20), steroids at 30-days (75 vs 62%, p = 0.27), and dual/triple drug immunosuppression at 1-year (80 vs 84%, p = 0.55). Conclusions In this largest cohort yet reported, individuals with BTHS have equivalent survival with less acute rejection and no difference in infection or malignancy after HT. When indicated, HT for individuals with BTHS is appropriate.

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.

Discharging children on ventricular assist device (VAD) support offers advantages for quality of life. We sought to describe discharge and readmission frequency in children on VAD support. All VAD-implanted patients aged 10-21 years at Advanced Cardiac Therapies Improving Outcomes Network (ACTION) centers were identified from the Pediatric Health Information System database (2009-2018). Discharge frequency on VAD was calculated. Patients discharged on VAD were compared with those not discharged. Freedom from readmission was assessed using the Kaplan-Meier method. A total of 298 VAD-implanted patients from 25 centers were identified, of which 163 (54.7%) were discharged. Discharges increased over time (36.9% [2009-2012] vs. 59.7% [2013-2018], p = 0.001). Of 144 discharged patients with follow-up, 96 (66.7%) were readmitted for reasons other than transplantation. Heart failure was the most common reason for readmission (27.7%), followed by infection (25.8%) and hematologic concerns (16.8%). In-hospital mortality on readmission was uncommon (1.8%) and the median length of stay was 6 days (interquartile range 2-19 days). Discharge of children on VAD support has increased over time, although variability exists across centers. Readmissions are common with diverse indications; however, the risk of mortality is low. Further interventions, including collaboration in ACTION, are critical to increasing discharges and optimizing outpatient management.

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.

Purpose of review Pediatric transplantation faces unique challenges in implementing dynamic quality improvement measures because of proportionally smaller volumes compared to adults, logistics of being integrated successfully within larger or complex hospital systems, lack of adult-affiliated transplant centers, varying focus in prioritization of relevant outcome metrics, and potential lack of sufficient resources. Recent findings To address these challenges, multiinstitutional collaborations have developed which have proven increasingly effective in driving awareness and quality improvement measures to supplement regulatory efforts in the pediatric population. Relevant work from the Pediatric Heart Transplant Society and Studies in Pediatric Liver Transplantation will be highlighted. The introduction of learning networks such as the Improving Renal Outcomes Collaborative and the Starzl Network for Excellence in Pediatric Transplantation have further focused on continuous learning initiatives in renal and liver transplantation using collaboration and patient informed measures. Summary Optimal transplant performance improvement is fully integrated into health delivery at all points of the patient pathway. Progress in performance improvement will require ongoing integration of big data solutions, improved patient engagement and technology solutions. VIDEO ABSTRACT:.

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.

Elevated plasma norepinephrine levels are a strong independent predictor of mortality in adults with heart failure with systolic dysfunction, and provide the mechanistic basis to its therapeutic paradigm. The pathogenesis of heart failure in the single ventricle circulation is unknown. It remains controversial whether conventional neurohormonal blockade in this population is beneficial. We hypothesize that norepinephrine levels can be elevated in children with single ventricle circulation and that it is associated with a poor outcome. Norepinephrine levels were collected from 22 consecutive single ventricle and 7 control patients at the time of catheterization. The disease group was followed for the development of heart failure and a composite outcome of death or transplant. Median age at norepinephrine level was 2.4 years (interquartile range 93 days–16.8 years) and follow-up duration was 9.8 years (range 75 days–10.5 years), during which 5 patients (23%) met a composite outcome of either death (n = 4) or transplantation (n = 1). While ventricular dysfunction and individual invasive hemodynamic parameters were not predictive of subsequent composite outcome, a norepinephrine level > 369 pg/mL at time of catheterization was associated with a decreased freedom from the composite outcome. In this study of children with single ventricle circulation, elevated norepinephrine levels were observed and were associated with a poor outcome. Consideration should be given to the further study of the role of neurohormonal activation and potentially its blockade, currently used for heart failure from systolic dysfunction, in the management of this high risk congenital heart disease population.

Purpose Patients with congenital heart disease (CHD) account for ∼40% of pediatric heart transplants (HT) performed in the United States. Our aim was to evaluate the overall trends for waitlist and post-transplant survival for children with CHD in the last three decades and identify risk factors for waitlist and post-transplant mortality in the current era. Methods Children (age Results Compared to Era 1, CHD candidates in Eras 2 and 3 were older (mean age 3.5±5.4 vs 4.0±5.5 vs 4.2±5.5 years), more often of non-White race (26.7 vs 39.7 vs 41.6%), more likely on intravenous inotropes (31.1 vs 45.7 vs 46.6%) and on VAD support (1.1 vs 2.3 vs 3.2%). Compared to Era 2, those in Era 3 were less likely to have renal dysfunction (71.5 vs 54.0%) and pulmonary hypertension (27.8 vs 17.1%) or be on ECMO (14.8 vs 8.1%) or ventilator (29.8 vs 23.0%) pre-transplant. Compared to earlier Eras, children with CHD listed for HT in Era 3 had significantly improved 1-year waitlist (59.6 vs 58.4 vs 67.5%) and post-transplant survival (75.3 vs 80.6 vs 88.0%) (Figure) [p Conclusion Children with CHD listed for HT in the U.S. have had significant improvement in waitlist and post-transplant survival particularly in the last decade. Improved candidate selection and post-transplant care may have led to these advances.

Purpose There is a concerted effort to increase discharges of children on ventricular assist device (VAD) support. Optimizing this process represents a quality improvement target of Advanced Cardiac Therapies Improving Outcomes Network (ACTION). We sought to describe discharge and readmission frequency in children on VAD support using a multicenter administrative database. Methods All VAD-implanted patients aged 10-21 years at ACTION centers were identified from the Pediatric Health Information System database (2009-2018). Discharge frequency on VAD was calculated. Patients discharged on VAD were compared to those not discharged. Freedom from readmission was assessed using the Kaplan Meier method, censoring at readmission for transplantation. The indications for readmission were determined using ICD diagnosis codes. Results A total of 298 patients from 25 centers were identified, of which 163 (54.7%) were discharged. The discharge frequency ranged from 8% to 100% across centers. The frequency of discharge increased over time (36.9% [2009-2012] vs. 59.7% [2013-2018], p=0.001). Of 144 discharged patients with follow-up data, 96 (66.7%) were readmitted for reasons other than transplantation with a median time to readmission of 45 days (IQR 18-79) [Figure]. Heart failure was the most common reason for readmission (27.7%), followed by infection (25.8%), hematologic concerns (16.8%), neurologic events (8.6%), arrhythmias (7.8%), and fluid/electrolyte problems (4.7%). In-hospital mortality on readmission was uncommon (1.8%) and the median length of stay was 6 days (IQR 2-19 days). Conclusion Patients discharged with VADs from ACTION centers has increased over time, with high variability across centers. Readmissions are common with diverse indications; however, the risk of mortality during a readmission encounter is low. Further collaboration in ACTION is critical to optimize the outpatient management of this vulnerable 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.

The definition and classification of cardiomyopathies were recently revised by an expert panel of the American Heart Association (Maron et al., Circulation 113:1807–1816, 2006) following the initial classification by the World Health Organization in 1995 (Richardson et al., Circulation 93:841–842, 1996). Cardiomyopathies are considered “a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic” (Maron et al., Circulation 113:1807–1816, 2006). Cardiomyopathies are generally considered as primary (disease solely or predominantly confined to heart muscle) or secondary, showing pathological myocardial involvement secondary to a systemic or multiorgan disease process. Both forms are commonly seen in children, although primary forms predominate.

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.

We sought to characterize the shifting epidemiology and resource utilization of Lyme disease and associated carditis in US children’s hospitals. We hypothesized that the Lyme carditis burden has increased and that hospitalizations for Lyme carditis are costlier than those for Lyme disease without carditis. The PHIS database was queried for Lyme disease encounters between January 1, 2007 and December 31, 2013. Additional diagnostic codes consistent with carditis identified Lyme carditis cases. Demographic, clinical, and resource utilization data were analyzed. All costs were adjusted to 2014 US dollars. Lyme disease was identified in 3620 encounters with 189 (5%) associated with carditis. Lyme disease (360 cases in 2007 vs. 672 in 2013, p = 0.01) and Lyme carditis (17 cases in 2007 vs. 40 in 2013, p = 0.03) both significantly increased in frequency. This is primarily accounted for by their increase within the Midwest region. Carditis frequency among cases of Lyme disease was stable (p = 0.15). Encounters for Lyme carditis are dramatically costlier than those for Lyme disease without carditis [median $9104 (3741–19,003) vs. 922 (238–4987), p

Background:Investigations of ventricular dominance and outcomes after the Fontan procedure have shown conflicting results. This may be due to the inclusion of multiple modifications of the Fontan or the omission of recently identified complications of the procedure. We examined the association between right ventricular dominance (RVD) and morbidity/mortality in a contemporary cohort following the extracardiac (EC) Fontan.Methods:We studied all pediatric patients at our center who underwent a predominantly fenestrated EC Fontan from 2004 to 2016. Outcomes assessed were freedom from (1) Fontan failure (death, takedown, listing for transplantation) and (2) complication (arrhythmia requiring medication, postoperative pacemaker, or implantable cardioverter defibrillator requirement, stroke, thrombosis in the Fontan circuit, protein losing enteropathy, plastic bronchitis, New York Heart Association class >2). We defined the perioperative period as occurring before hospital discharge or within 30 days of the Fontan.Results:A total of 137 patients (median age: 34 months, 62% male, 60% RVD) underwent the EC Fontan. Median duration of follow-up was 5.8 years (interquartile range: 2.4-9.0). Freedom from any event was 82.5% (RVD = 77%, LVD = 91%, χ2(1) = 5.03, P = .025) and RVD was associated with reduced event-free survival (hazard ratio: 2.94, P = .02). No confounders were identified. In the perioperative period, RVD was associated with reduced complication-free survival ( P = .004). After this period, RVD was associated with reduced failure-free survival ( P = .003).Conclusions:In this contemporary, single-center cohort of EC Fontan patients, RVD was associated with inferior outcomes.

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 Allograft rejection is driven by HLA disparity between donor and recipient despite of the use of various immunosuppression protocols. To better define the risk of allograft failure or complications from overt immunosuppression we applied the epitope-based mismatch approach to quantify the degree of HLA disparity in a in a large multi-center pediatric heart transplant (pHTX) cohort that has been followed for 3-5 years. Methods 274 pHTX recipient/donor pairs were retrospectively HLA genotyped by Next-Generation Sequencing and evaluated for HLA allele (alMM) and eplet mismatch (epMM) loads. HLAMatchmaker version 2.2 was used to determine epMM load at HLA-A/B/C, -DRB1/3/4/5, -DQA1/DQB1 and -DPA1/DPB1. Results Overall, the average total alMM was 13(±2). 76% were ≥5 HLA-A/B/C allele mismatches, 67% were ≥3 HLA-DRB and ≥3 HLA-DQ allele mismatch. The average epMM load was 60 (±17), range 16-112 (Table). 94% of cases had >11 HLA-DR or DQ epMM, a threshold previously shown to be associated with development of HLA donor-specific antibody in renal transplantation. While 159 cases (61.6%) had both DR and DQ epMM >11, only DR epMM or only DQ epMM >11 occurred in 31 (12.0%) and 50 (19.4%) cases, respectively (Figure). Therefore, this cohort can be divided into 3 groups for Class II epMM load: 6% (16) of cases with low, 36% (99) with intermediate and 58% (159) with high load. Conclusion Although this pHTx cohort is highly mismatched, for HLA alleles, there is a large range based on epMM, especially for HLA-DR and -DQ indicating that allele level typing is insufficient for determination of the true degree of mismatching. By correlating these data with clinical parameters, we aim to determine risk stratification based on epMM load in pediatric heart transplantation.

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.

Purpose Reduction in circulating alloantibodies is a common goal in treating antibody mediated rejection (AMR) and in desensitization of highly sensitized transplant recipients. There are limited data about safety and efficacy of these treatments in children. We report our experience using combined therapy with rituximab, plasmapheresis (PP), and bortezomib to reduce anti-HLA antibodies (Abs) in AMR and desensitization in pediatric heart transplantation (HT). Methods There were 16 treatment courses for desensitization or AMR at our institution from 5/2012-3/2018: 4 for desensitization and 12 for AMR. A typical cycle consists of PP followed by rituximab (375mg/m2) with 4 subsequent PP cycles, each followed by bortezomib (1.3mg/m2), over 21 days. Cycles may be repeated based on response. AlloAb burden was quantified using the OPTN cPRA calculator for Abs ≥4000 MFI to capture clinically relevant Abs. cPRA prior to treatment and at 3 and 12 months after therapy completion were analyzed. Results Median patient age was 12.6 (2.9-20.4) years. All 4 desensitized candidates achieved HT (3 with negative cytotoxicity crossmatch), with median wait time of 166 (68-412) days from therapy initiation. All are alive and free from >pAMR1 at 341.5 (119-904) days from HT. Of the 12 treated for AMR, 10 are alive and 4 had coronary allograft vasculopathy during median follow-up of 948.5 (40-1483) days from AMR diagnosis. Mean class I and II cPRAs were 28.5% and 51.4%, decreasing to 16.4% (p=0.29) and 20.1% (p bacteremia , 2 with peripheral neuropathy , and one with stroke. Conclusion Combined therapy with rituximab, PP, and bortezomib reduced circulating Abs, both in desensitization and treatment of AMR, in our small pediatric HT series. Survival to HT (for desensitization) and after HT (for AMR) also appear reassuring, with some risk of complications. More detailed and regimented multicenter studies are warranted.

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.

There are limited data available on the bioequivalence of generic and brand-name tacrolimus in pediatric and heart transplant patients. We characterized changes in 12-hour trough concentrations and clinical outcomes after transition from brand to generic tacrolimus in pediatric thoracic organ transplant recipients. Patients with a pharmacy-confirmed date of switch between generic and brand tacrolimus were identified, as well as a matched control group that did not switch for comparison. We identified 18 patients with a confirmed date of switch, and in 12 patients that remained on the same dose, trough concentrations were 14% less than when they were on brand (p = 0.037). The average change was -1.15 ± 1.76 ng/mL (p = 0.045). The control group did not experience a change in trough concentration and was different than the switched group (p = 0.005). There were no differences in dosage changes or kidney or liver function. In the year after switch, 24% of patients who were switched to generic experienced a rejection event vs. 18% in the patients on brand. We suggest a strategy of monitoring around the time of transition, and education of the patient/family to notify the care team when changes from brand to generic or between generics occur.

1. Kataoka M, Inami T, Hayashida K, et al. Percutaneous transluminal pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2012;5:756-62. 2. Inami T, Kataoka M, Shimura N, et al. Pressure-wire-guided percutaneous transluminal pulmonary angioplasty: a breakthrough in the catheter-interventional therapy for chronic thromboembolic pulmonary hypertension. JACC Cardiovasc Interv 2014;7:1297-306. 3. Kreutzer J, Landzberg MJ, Preminger TJ, et al. Isolated peripheral pulmonary artery stenoses in the adult. Circulation 1996;93:1417-23. 4. Rothman A, Levy DJ, Sklansky MS, et al. Balloon angioplasty and stenting of multiple intralobar pulmonary arterial stenoses in adult patients. Catheter Cardiovasc Interv 2003;58:252-60.

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.

There are limited data investigating the epidemiology and resource utilization associated with parenteral prostacyclin use in children. We sought to examine national trends in treatment practices and resource utilization during prostacyclin initiation for pulmonary arterial hypertension (PAH) at children’s hospitals in the United States. Patients with PAH initiated on parenteral epoprostenol and treprostinil (2004–2014) were identified using a nationwide administrative database. Demographics, clinical characteristics, and resource utilization were compared between epoprostenol and treprostinil groups. Costs were indexed in 2014 US dollars. Among 1448 children admitted with a primary or secondary diagnosis of PAH, 280 (19%) were initiated on parenteral prostacyclins (epoprostenol n = 195 and treprostinil n = 85). Epoprostenol predominated early (97% of initiations in 2005); however, treprostinil predominated recently (52–67% of initiations/year). Children initiated on treprostinil had shorter ICU stays (1 [IQR = 0–4] vs. 4 [0–10] days, P

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 NO bioavailability has not been systematically examined in congenital heart disease (CHD). To assess NO in patients with CHD, we measured nasal NO ( nNO ) generated by the nasal epithelia, given blood NO is difficult to measure (half‐life, NO bioavailability with heart failure risk, we hypothesized NO levels may differ with varying severity of CHD physiologic characteristics. Methods and Results Six‐hundred eighteen subjects, 483 with CHD and 135 controls, had nNO measured noninvasively via the nares using American Thoracic Society/European Respiratory Society guidelines. Subjects were dichotomized as having low or normal nNO based on age‐specific cutoff values. Prevalence of low nNO was examined by various CHD physiologic feature types. Low nNO was more prevalent with CHD than controls (odds ratio , 2.28; P =0.001). A logistic regression model showed overall significance ( P =0.035) for single ventricle, systemic right ventricle, ventricular dysfunction, oxygen desaturation, and heterotaxy predicting low nNO , with systemic right ventricle independently having twice the odds of low nNO (odds ratio, 2.04; P =0.014). Patients with low nNO had a higher risk of experiencing heart transplant or death (hazard ratio, 2.75; P =0.048), and heart transplant recipients (N=16) exhibited 5 times the odds of low nNO (69% versus 30%; odds ratio, 5.1; P =0.001). Conclusions Patients with CHD have increased prevalence of low nNO , with highest odds seen with systemic right ventricle and heart transplant. Further studies are needed to investigate heart failure risks in patients with CHD with left versus right systemic ventricle physiologic characteristics and utility of low nNO for predicting heart failure risk.

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.

There is growing acceptance of transplantation across a positive crossmatch for highly allosensitized pediatric HT candidates. While survival may be similar to patients transplanted across a negative crossmatch, costs are unknown. Among 60 HT recipients at our center from 5/07 to 6/12, we analyzed hospital charges and length of stay from the day of HT to discharge and through the first year after transplant. Median age at HT was 6.2 years (15 days-20.5 years). Charges in the first year post-HT were greater for crossmatch-positive patients ($907 678 vs $549 754; P = .017), with a trend toward higher charges for the HT hospitalization ($537 640 vs $407 374; P = .07). Plasmapheresis was more common in crossmatch-positive patients during the HT hospitalization (80% vs 4%, P < .001). In the first year after HT, crossmatch-positive patients had a greater number of endomyocardial biopsies (10 vs 7.5, P = .03) and episodes of treated rejection (2 vs 0, P = .004). Pediatric HT across a positive crossmatch is associated with higher first-year costs, including increased use of plasmapheresis and care around an increased number of rejections. These novel data will help inform decision and policymaking regarding care practices for the growing population of highly sensitized pediatric HT candidates.

Destination ventricular assist device therapy (DT-VAD) is well accepted in select adults with medically refractory heart failure (HF) who are not transplant candidates; however, its use in younger patients with progressive diseases is unclear. We sought to evaluate the cost-effectiveness of DT-VAD in Duchenne muscular dystrophy (DMD) patients with advanced HF. We created a Markov-state transition model (5-year horizon) to compare survival, costs, and quality of life (QOL) between medical management and DT-VAD in DMD with advanced HF. Model input parameters were derived from the literature. We used sensitivity analyses to explore uncertainty around model assumptions. DT-VAD had higher costs ($435,602 vs. $125,696), survival (3.13 vs. 0.60 years), and quality-adjusted survival (1.99 vs. 0.26 years) than medical management. The incremental cost-effectiveness ratio (ICER) for DT-VAD was $179,086 per quality-adjusted life year (QALY). In sensitivity analyses that were widely varied to account for uncertainty in model assumptions, the DT-VAD strategy generally remained more costly and effective than medical management. Only when VAD implantation costs were

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.