Borah J. Hong

With 5-year survival of children with cancer exceeding 80% in developed countries, premature cardiovascular disease is now a major cause of early morbidity and mortality. In addition to the acute and chronic cardiotoxic effects of anthracyclines, related chemotherapeutics, and radiation, a growing number of new molecular targeted agents may also have detrimental effects on the cardiovascular system. Survivors of childhood cancer also may have earlier development of conventional cardiovascular risk factors such as hypertension, dyslipidaemia, and diabetes, which further increase their risk of serious cardiovascular disease. This review will examine the epidemiology of acute and chronic cardiotoxicity relevant to paediatric cancer patients, including genetic risk factors. We will also provide an overview of current screening recommendations, including the evidence regarding both imaging (e.g. echocardiography and magnetic resonance imaging) and blood-based biomarkers. Various primary and secondary prevention strategies will also be discussed, primarily in relation to anthracycline-related cardiomyopathy. Finally, we review the available evidence related to the management of systolic and diastolic dysfunction in paediatric cancer patients and childhood cancer survivors.

The prevalence of obesity in long-term survivors with complex congenital heart disease may be increasing, and little is known about the timing and onset of weight gain and growth patterns in these high-risk patients. Prevalence rates of overweight/obesity and longitudinal changes in body mass index (BMI) with age were determined in 606 patients with Fontan circulation seen at a tertiary care cardiology center from 1992 to 2012. The number of clinic encounters (n) was stratified by age group (n = 401, 2-5 years; n = 333, 6-11 years; n = 217, 12-19 years; and n = 129, >20 years). Among adults, 39% were overweight/obese at last clinic visit; 22% overweight, and 17% obese. Childhood anthropometric data were available for 82 adults, of which 15% (n = 12/82) were overweight/obese in childhood. The likelihood of being overweight/obese as an adult was three times higher if there was a BMI ≥ 85th percentile in childhood (CI 2.1-4.5, P < 0.01). Overweight/obesity in adulthood was associated with lower heart failure rates (4 vs. 19%, P = 0.03). Pediatric rates of overweight/obesity were comparable to national data (NHANES 2011-2012) in every age group: at 2-5 years, (25 vs. 23%), 6-11 years (26 vs. 34%), and 12-19 years (15 vs. 35%). Systolic blood pressure was higher in overweight/obese children as young as 2-5 years of age. Childhood and adult survivors with Fontan circulation have high rates of overweight/obesity. Childhood obesity is a strong predictor of future adiposity and is linked to changes in systolic blood pressure at a very young age.

Adult survivors of childhood cancer are at risk for cardiovascular events.In this study, we sought to determine the risk for mortality after a major cardiovascular event among childhood cancer survivors compared with noncancer populations.All-cause and cardiovascular cause-specific mortality risks after heart failure (HF), coronary artery disease (CAD), or stroke were compared among survivors and siblings in the Childhood Cancer Survivor Study (CCSS) and participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Cox proportional hazard regression models were used to estimate HRs and 95% CIs between groups, adjusted for demographic and clinical factors.Among 25,658 childhood cancer survivors (median age at diagnosis 7 years, median age at follow-up or death 38 years) and 5,051 siblings, 1,780 survivors and 91 siblings had a cardiovascular event. After HF, CAD, and stroke, 10-year all-cause mortalities were 30% (95% CI: 26%-33%), 36% (95% CI: 31%-40%), and 29% (95% CI: 24%-33%), respectively, among survivors vs 14% (95% CI: 0%-25%), 14% (95% CI: 2%-25%), and 4% (95% CI: 0%-11%) among siblings. All-cause mortality risks among childhood cancer survivors were increased after HF (HR: 7.32; 95% CI: 2.56-20.89), CAD (HR: 5.54; 95% CI: 2.37-12.93), and stroke (HR: 3.57; 95% CI: 1.12-11.37). CAD-specific mortality risk was increased (HR: 3.70; 95% CI: 1.05-13.02). Among 5,114 CARDIA participants, 345 had a major event. Although CARDIA participants were on average decades older at events (median age 57 years vs 31 years), mortality risks were similar, except that all-cause mortality after CAD was significantly increased among childhood cancer survivors (HR: 1.85; 95% CI: 1.16-2.95).Survivors of childhood cancer represent a population at high risk for mortality after major cardiovascular events.

We have developed new surface to ensure a proper spacing between immobilized biomolecules. While DNA microarray on this surface provided each probe DNA with ample space for hybridization with incoming target DNAs, the microarray showed enhanced discrimination efficiency for various types of single nucleotide polymorphism. The high discrimination efficiency holds for all tested cases (100:<1 for internal mismatched cases; 100:<28 for terminal mismatched ones). In addition, by investigating influence of hybridization temperature and washing condition on the fluorescence intensity and the discrimination efficiency with and without controlled mesospacing, it was observed that the nanoscale-controlled surface showed good discrimination efficiency in a wide range of temperature (37-50 degrees C), and hybridization behavior on the surface was in agreement with the solution one. Intriguingly, it was found that washing process after the hybridization was critical for the high discrimination efficiency. For the particular case, washing process was so efficient that only 30 s washing was sufficient to reach the optimal discrimination ratio.

BackgroundInfants with hypoplastic left heart syndrome (HLHS) are susceptible to pre-Norwood comorbidities (PCs) and complications. This study aimed to describe the effect of PCs on timing and survival of Norwood palliation (NP).MethodsA single-center, retrospective review of infants with HLHS who underwent initial NP between 2003 and 2010 was performed. PCs included intact atrial septum, ≥ moderate atrioventricular regurgitation (AVVR), no antenatal diagnosis, mitral stenosis/aortic atresia subtype, genetic abnormality, and prematurity. Complications included pre-NP mechanical ventilation, inotropic support, infection, arrhythmia, and end-organ injury. The primary outcome measure was survival after NP.Results113 patients were included with 78 (69%) patients having at least one PC and 61 (78%) of those patients having at least one complication. Patients with PCs underwent NP later than those without PCs (7 vs 6 days, P = .036) as well as when associated with a complication (8 vs 5 days, P < .001). Patients with PCs had similar post-Norwood hospital length of stay (P = .116) except when the PC occurred in conjunction with a complication (28 vs 21 days; P = .015). In-hospital mortality post-NP was 10% and interstage mortality was 15%. On multivariable analysis, ≥ moderate AVVR was associated with increased overall mortality (OR 2.8, 95% CI 1.3-6.2). Age at NP was not associated with mortality (P = .638).ConclusionsAlthough PCs are common in infants with HLHS, only ≥ moderate AVVR was associated with increased mortality in this single-center experience. Older age at NP was not a significant risk factor for interstage mortality. Infants with hypoplastic left heart syndrome (HLHS) are susceptible to pre-Norwood comorbidities (PCs) and complications. This study aimed to describe the effect of PCs on timing and survival of Norwood palliation (NP). A single-center, retrospective review of infants with HLHS who underwent initial NP between 2003 and 2010 was performed. PCs included intact atrial septum, ≥ moderate atrioventricular regurgitation (AVVR), no antenatal diagnosis, mitral stenosis/aortic atresia subtype, genetic abnormality, and prematurity. Complications included pre-NP mechanical ventilation, inotropic support, infection, arrhythmia, and end-organ injury. The primary outcome measure was survival after NP. 113 patients were included with 78 (69%) patients having at least one PC and 61 (78%) of those patients having at least one complication. Patients with PCs underwent NP later than those without PCs (7 vs 6 days, P = .036) as well as when associated with a complication (8 vs 5 days, P < .001). Patients with PCs had similar post-Norwood hospital length of stay (P = .116) except when the PC occurred in conjunction with a complication (28 vs 21 days; P = .015). In-hospital mortality post-NP was 10% and interstage mortality was 15%. On multivariable analysis, ≥ moderate AVVR was associated with increased overall mortality (OR 2.8, 95% CI 1.3-6.2). Age at NP was not associated with mortality (P = .638). Although PCs are common in infants with HLHS, only ≥ moderate AVVR was associated with increased mortality in this single-center experience. Older age at NP was not a significant risk factor for interstage mortality.

ObjectiveThe study objective was to evaluate risk factors for poor weight gain in infants with hypoplastic left heart syndrome after stage 1 palliation.MethodsWe reviewed all term infants with hypoplastic left heart syndrome who had stage 1 palliation and stage 2 palliation at Texas Children's Hospital between 2000 and 2011 (n = 120). Predictor variables included age at stage 1 palliation, intensive care unit factors, calories delivered, and echocardiographic findings. Outcome variables included weight for age Z scores at hospital discharge, stage 2 palliation, and change in weight for age Z scores between stage 1 palliation and hospital discharge.ResultsComplete nutritional data were available for 47 of 120 patients. Median total parenteral nutrition duration was 6 days (range, 1-43 days), and median intensive care unit calories delivered was 53.9 kcal/kg/d (range, 22.3-119.6 kcal/kg/d). Before hospital discharge, the median caloric intake was 106.7 kcal/kg/d (range, 70.0-152.0 kcal/kg/d). Median weight for age Z scores was −0.59 (range, −3.6 to 0.5) at stage 1 palliation, −1.62 (range, −4.5 to −0.1) at intensive care unit transfer, and −1.81 (range, −4.9 to −0.5) at hospital discharge. A total of 46 of 47 patients had a negative change in weight for age Z scores between stage 1 palliation and hospital discharge, with a median change of −1.14 (range, −2.3 to 0.6). Change in weight for age Z scores from stage 1 palliation to discharge was directly associated with calories delivered and indirectly associated with hospital length of stay and moderate tricuspid regurgitation (P < .001).ConclusionsPostoperative nutrition fails to meet the needs of infants with hypoplastic left heart syndrome despite increased focus on nutritional support. Modifiable factors (eg, nutritional intake) and hemodynamic factors (eg, tricuspid regurgitation) may play roles in the poor weight gain of these infants. The study objective was to evaluate risk factors for poor weight gain in infants with hypoplastic left heart syndrome after stage 1 palliation. We reviewed all term infants with hypoplastic left heart syndrome who had stage 1 palliation and stage 2 palliation at Texas Children's Hospital between 2000 and 2011 (n = 120). Predictor variables included age at stage 1 palliation, intensive care unit factors, calories delivered, and echocardiographic findings. Outcome variables included weight for age Z scores at hospital discharge, stage 2 palliation, and change in weight for age Z scores between stage 1 palliation and hospital discharge. Complete nutritional data were available for 47 of 120 patients. Median total parenteral nutrition duration was 6 days (range, 1-43 days), and median intensive care unit calories delivered was 53.9 kcal/kg/d (range, 22.3-119.6 kcal/kg/d). Before hospital discharge, the median caloric intake was 106.7 kcal/kg/d (range, 70.0-152.0 kcal/kg/d). Median weight for age Z scores was −0.59 (range, −3.6 to 0.5) at stage 1 palliation, −1.62 (range, −4.5 to −0.1) at intensive care unit transfer, and −1.81 (range, −4.9 to −0.5) at hospital discharge. A total of 46 of 47 patients had a negative change in weight for age Z scores between stage 1 palliation and hospital discharge, with a median change of −1.14 (range, −2.3 to 0.6). Change in weight for age Z scores from stage 1 palliation to discharge was directly associated with calories delivered and indirectly associated with hospital length of stay and moderate tricuspid regurgitation (P < .001). Postoperative nutrition fails to meet the needs of infants with hypoplastic left heart syndrome despite increased focus on nutritional support. Modifiable factors (eg, nutritional intake) and hemodynamic factors (eg, tricuspid regurgitation) may play roles in the poor weight gain of these infants.

Kidney disease is common after pediatric heart transplantation. Serum creatinine-based glomerular filtration rate is the most frequently reported measure of kidney function. Albuminuria is an additional marker of kidney dysfunction and is not well described in this population. In this study, we evaluate the prevalence and degree of albuminuria and describe clinical factors associated with albuminuria in a cohort of pediatric heart transplant recipients.This was a cross-sectional study of pediatric heart transplant recipients. Albuminuria was assessed using spot urine albumin-to-creatinine ratio collected at the most recent annual screening cardiac catheterization through August 2019.In 115 patients at a median duration of 10.2 years post-transplant, 39% had albuminuria. Stage 3 or greater chronic kidney disease was present in 6%. The immunosuppressive regimen at the time of measurement contained a calcineurin inhibitor (CNI) in 88% and a proliferation signal inhibitor (PSI) in 62%. In multivariable modeling, lower eGFR, PSI use, and younger age at transplant were associated with higher levels of albuminuria, whereas CNI use was associated with lower levels of albuminuria.Albuminuria is a prevalent finding in medium-term follow up of pediatric heart transplant recipients, reflecting kidney injury, and is associated with other markers of kidney dysfunction, such as low eGFR. Younger age at transplant, lower eGFR, and PSI use were among the associations with albuminuria.

Acute myocardial infarction (AMI) can occur suddenly, which may induce deadly outcomes, and the population suffering from AMI presents a younger trend. Necroptosis, the new cell necrosis type, is associated with the pathogenic mechanisms of diverse cardiovascular diseases (CVDs). Its diagnostic value and molecular mechanisms in AMI are still unclear. Objective: This study focused on determining key necroptosis-related genes as well as immune infiltration in AMI.We first examined the GSE66360 dataset for identifying necroptosis-related differentially expressed genes (NRDEGs). Thereafter, GO and functional annotation were performed, then a PPI network was built. In addition, "CIBERSORT" in R was applied in comparing different immune infiltration degrees in AMI compared with control groups. The receiver operating characteristic (ROC) curve was plotted to evaluate whether hub NRDEGs could be used in AMI diagnosis. Associations of immune cells with candidate NRDEGs biomarkers were examined by Spearman analysis. Finally, hub NRDEGs were validated by cell qPCR assays and another two datasets.A total of 15 NRDEGs were identified and multiple enrichment terms associated with necroptosis were discovered through GO and KEGG analysis. Upon module analysis, 10 hub NRDEGs were filtered out, and the top six hub NRDEGs were identified after ROC analysis. These top six NRDEGs might have a certain effect on modulating immune infiltrating cells, especially for mast cells activated, NK cells activated and neutrophils. Finally, two AMI datasets and qPCR assay came to identical findings.Our results offer the reliable molecular biomarkers and new perspectives for necroptosis in AMI, which lay a certain foundation for developing novel anti-AMI therapeutic targets.

Though pediatric cardiomyopathy is rare in children, there is significant associated morbidity and mortality. Etiology varies from inborn errors of metabolism to familial genetic mutations and myocyte injury. Major classes include dilated, hypertrophic, restrictive, and non-compaction. Diagnosis generally involves a combination of clinical history and echocardiography. The use of cross-sectional imaging is gaining popularity. Management varies between subtype and may involve a combination of medical and surgical interventions depending on clinical status.

Human leukocyte antigen (HLA) sensitization of pediatric heart recipients increases their risk of rejection and graft loss. As more children are placed on mechanical circulatory support (MCS) as a bridge to transplant, the risk factors for development of sensitization warrant further study. A single-center retrospective review of 36 children who received MCS identified 22 patients supported with either extracorporeal membrane oxygenation (ECMO) (n = 15) or ECMO-ventricular assist device (VAD) (n = 7) with paired (pre-MCS/post-MCS) panel reactive antibodies (PRA) or only negative post-MCS PRAs. Four patients (18%) became sensitized post-MCS (one ECMO-only patient, three ECMO-VAD patients). No difference was found between sensitized and nonsensitized patients in terms of congenital heart disease versus primary cardiomyopathy (p = 0.096), duration of MCS (38 days vs. 14 days, p = 0.233), or volume of blood product transfusions (358.6 ml/kg vs. 612.7 ml/kg, p = not significant). By multivariable analysis, the association of sensitization with older age at MCS (p = 0.076) and history of homograft (p = 0.064) approached significance. Pediatric patients supported with MCS are at low risk of developing HLA sensitization. Diagnosis, MCS duration, and volume of transfused blood products do not appear to be associated with HLA sensitization, but there is a suggestion of an association with older age at MCS and history of a homograft.

Renal dysfunction (RD) is prevalent among pediatric patients with advanced heart failure. Data are limited regarding changes in renal function after left ventricular assist device (LVAD) placement in this population.Pediatric LVAD recipients enrolled in the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) between September 19, 2012 and June 30, 2016 were included. Longitudinal changes in renal function were analyzed for the entire cohort as well as subgroups stratified by patient and device characteristics. Logistic regression was used to attempt to identify factors associated with lack of improvement in renal function after LVAD placement. Post-LVAD outcomes were assessed using the Kaplan‒Meier method.Data from 247 patients from 39 centers were analyzed. Baseline RD (estimated glomerular filtration rate [eGFR] <90 ml/min/1.73 m2) was present in 150 (61%) patients. Overall, eGFR improved post-LVAD, peaking at 1 month post-implant. There was an inverse relationship between baseline eGFR and the degree of improvement at 1 month. Degree of improvement in eGFR at 1 month was not impacted by device type, age, Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile, or diagnosis. Failure to normalize renal function at 1 week was correlated with persistent RD at 1 month. Post-implant outcomes did not differ among patients stratified by pre-implant renal function.Renal function improves post-LVAD placement in pediatric patients regardless of age, diagnosis, illness severity, or device type, with improvement most pronounced in patients with baseline RD. Identifying patients with irreversible renal dysfunction before LVAD placement remains difficult. Pre-LVAD renal function does not appear to impact survival to transplant.

Although tremendous advances in pediatric cancer treatment have improved the survival of many children, these patients remain at increased risk of early morbidity and mortality with cardiovascular disease as a leading cause of death. Heightened awareness in providers with increased surveillance and improvement in cardiovascular imaging modalities have led to earlier detection of cardiac dysfunction, but the outcomes remain poor once this has dysfunction developed. A great deal of work remains to be done to refine screening and identify high-risk patients more precisely, and to develop more evidence-based strategies for effective primary and secondary cardioprotection and treatment.

Iron deficiency (FeD), with or without anemia, in adults with heart failure (HF) is associated with poor outcomes, which can be improved with replacement therapy. A similar therapeutic opportunity may exist for children; however, iron laboratory measurements and FeD have not been described in pediatric patients with HF. A single-center, retrospective study was conducted on 28 patients <21 years old with a diagnosis of dilated cardiomyopathy and HF who had iron laboratories (serum iron, iron saturation, and ferritin) performed. The mean (standard deviation) age at time of laboratory collection was 10.3 (5.5) years. Twenty-seven patients (96.4%) met the criteria for FeD. Serum iron and iron saturation were significantly associated with inpatient hospitalization, being on inotropic medications, or having stage D HF. Low-serum iron was associated with a higher left ventricular end-diastolic dimension and left ventricular end-systolic dimension z-score by echocardiography ((β −2.58, 95% confidence interval [CI] −4.76, −0.40, p = 0.02) and (β −2.43, 95% CI −4.70, −0.17, p = 0.04)), respectively. Low ferritin was associated with higher mortality (relative risk 0.29, 95% CI 0.12, 0.70, p = 0.006). In conclusion, FeD was common in this pediatric cohort with more advanced HF. Iron profile abnormalities were associated with worse HF severity and outcomes including mortality. Iron deficiency (FeD), with or without anemia, in adults with heart failure (HF) is associated with poor outcomes, which can be improved with replacement therapy. A similar therapeutic opportunity may exist for children; however, iron laboratory measurements and FeD have not been described in pediatric patients with HF. A single-center, retrospective study was conducted on 28 patients <21 years old with a diagnosis of dilated cardiomyopathy and HF who had iron laboratories (serum iron, iron saturation, and ferritin) performed. The mean (standard deviation) age at time of laboratory collection was 10.3 (5.5) years. Twenty-seven patients (96.4%) met the criteria for FeD. Serum iron and iron saturation were significantly associated with inpatient hospitalization, being on inotropic medications, or having stage D HF. Low-serum iron was associated with a higher left ventricular end-diastolic dimension and left ventricular end-systolic dimension z-score by echocardiography ((β −2.58, 95% confidence interval [CI] −4.76, −0.40, p = 0.02) and (β −2.43, 95% CI −4.70, −0.17, p = 0.04)), respectively. Low ferritin was associated with higher mortality (relative risk 0.29, 95% CI 0.12, 0.70, p = 0.006). In conclusion, FeD was common in this pediatric cohort with more advanced HF. Iron profile abnormalities were associated with worse HF severity and outcomes including mortality.

Significant inter-centre variability in the intensity of endomyocardial biopsy surveillance for rejection following paediatric cardiac transplantation has been reported. Our aim was to determine if low-intensity biopsy surveillance with two scheduled biopsies in the first year would produce outcomes similar to published registry outcomes.A retrospective study of paediatric recipients transplanted between 2008 and 2014 using a low-intensity biopsy protocol consisting of two surveillance biopsies at 3 and 12-13 months in the first post-transplant year, then annually thereafter. Additional biopsies were performed based on echocardiographic and clinical surveillance. Excluded were recipients that were re-transplanted or multi-organ transplanted or were followed at another institution.A total of 81 recipients in the first 13 months after transplant underwent an average of 2 (SD ± 1.3) biopsies, 24 ± 6.8 echocardiograms, and 17 ± 4.4 clinic visits per recipient. During the 13-month period, 19 recipients had 24 treated rejection episodes, with the first at an average of 2.8 months post-transplant. The 3-, 12-, 36-, and 60-month conditional on discharge graft survival were 100%, 98.8%, 98.8%, and 90.4%, respectively, comparable to reported figures in major paediatric registries. At a mean follow-up of 4.7 ± 2.1 years, four patients (4.9%) developed cardiac allograft vasculopathy, three (3.7%) developed a malignancy, and seven (8.6%) suffered graft loss.Rejection surveillance with a low-intensity biopsy protocol demonstrated similar intermediate-term outcomes and safety measures as international registries up to 5 years post-transplant.

Literature is limited comparing adverse effects (AEs) of the proliferation signal inhibitors (PSIs) sirolimus (SRL) and everolimus (EVL) in pediatric heart transplant (HTx) recipients.Single-center, observational cohort analysis assessing first use of SRL or EVL in pediatric HTx recipients <21 years of age with up to 2 years follow-up between 2009 and 2020.Eighty-seven patients were included, with 52 (59.8%) receiving EVL and 35 (40.2%) receiving SRL. Tacrolimus with PSI was the most common regimen. Intergroup comparison revealed lower baseline estimated glomerular filtration rate (eGFR) and greater increase in eGFR from baseline to 6 months and latest follow-up in SRL cohort compared to EVL cohort. There was greater increase in HDL cholesterol in SRL cohort compared to EVL cohort. Intragroup analysis revealed eGFR and HDL cholesterol increased significantly within SRL cohort, triglycerides and glycosylated hemoglobin increased in EVL cohort, and LDL cholesterol and total cholesterol increased in both cohorts (all p < .05). There were no differences in hematological indices or rates of aphthous ulcers, effusions, or infections between cohorts. Incidence of proteinuria was not significantly different among those screened within cohorts. Of those included in our analysis, one patient in SRL cohort (2.9%) and two in EVL cohort (3.8%) had PSI withdrawn due to AE.Low-dose PSIs in calcineurin inhibitor minimization regimens appear well-tolerated with low withdrawal rate secondary to AE in pediatric HTx recipients. While incidence of most AE was similar between PSI, our results suggest EVL may be associated with less favorable metabolic impact than SRL in this population.

ABO-i heart transplantation can be performed in infants with end-stage heart failure to increase organ availability. The development of newly detected DSAs is associated with decreased cardiac graft survival, and the effect of ABO-i transplantation on DSA production is unknown. We examined DSA production and rejection frequency in infant recipients of ABO-i and ABO-c heart transplants via a retrospective cohort study of infant heart transplant recipients transplanted at a single pediatric center between January 2004 and November 2014. Patients were included if they were less than 1 year of age at transplant and had a minimum of 6 months follow-up. DSA positivity was examined under two categories, either the lowest level detectable (MFI > 500) or a level presumed to have clinical relevance in our immunogenetics laboratory (MFI > 5000). Of 52 patients, 36 received ABO-c transplants and 16 received ABO-i transplants. Compared to ABO-c recipients, the ABO-i group showed a consistent but statistically non-significant finding of less frequent ndDSA positivity (69.4% ABO-c vs 43.8% ABO-i with MFI >500, P = 0.122; 41.7% ABO-c vs 25% ABO-i with MFI >5000, P = 0.353). Additionally, ABO-i patients were less likely to have any form of rejection (12.5% vs 47.2%, P = 0.027) or acute cellular rejection (6.3% vs 38.9%, P = 0.021). Our data suggest that infants receiving ABO-i heart transplants may be less likely to develop ndDSAs or have rejection compared to same age ABO-c recipients. Larger multicenter studies are needed to confirm results from this single center study.

Abstract Outcomes of ACR after pediatric HTx have been well described, but less has been reported on outcomes of AMR. We compared the clinical characteristics and cardiovascular outcomes (composite end‐point of death, retransplantation, or allograft vasculopathy) of pediatric HTx recipients with AMR, ACR, and no rejection in a retrospective single‐center study of 104 recipients. Twenty were treated for AMR; 15 were treated for ACR. Recipients with AMR had an increased frequency of congenital heart disease (90% vs ACR 67% vs no rejection 59%, P = .03), homograft (68% vs 7% vs 18%, P &lt; .001), HLA sensitization (45% vs 13% vs 13%, P = .008), and positive cross‐match (30% vs 7% vs 9%, P = .046). AMR caused hemodynamic compromise more often than ACR (39% vs 4%, P = .02). AMR recipients had worse cardiovascular outcome than recipients with ACR or no rejection (40% vs 20% vs 8.6%, P = .003). In bivariate Cox analysis, AMR (HR 4.1, CI 1.4‐12.0, P = .009) and ischemic time (HR 1.6, CI 1.1‐2.3, P = .02) were associated with worse cardiovascular outcome; ACR was not. In summary, pediatric HTx recipients who develop AMR have worse cardiovascular outcome than recipients who develop only ACR or experience no rejection at all.

While mismatching between donor and recipient human leukocyte antigen (HLA) alleles has been associated with increased graft loss in pediatric heart recipients, it is actually the surface amino acid structures, termed eplets, which determine the antigenicity of each HLA molecule. We hypothesized that HLA eplet mismatch analysis is a better predictor of adverse outcomes after pediatric heart transplant than conventional allele mismatch comparison.A retrospective review of the Pediatric Heart Transplant Society database identified pediatric heart recipients (<18 years at listing) with complete donor and recipient HLA typing (A, B, and DR). Imputed high-resolution HLA genotypes were entered into HLAMatchmaker software which then calculated the number of eplet mismatches between each donor-recipient pair. Multivariable Cox regression analysis was used to examine associations between allele or eplet mismatching and adverse outcomes.Compared to those with <20 HLA class I eplet mismatches, recipients with 20 or more HLA class I eplet mismatches had an increased risk of graft loss (HR 1.46 [1.01-2.12], p = .049). HLA class I eplet mismatching was also associated with rejection (>20 mismatches: HR 1.30 [1.03-1.65], p = .030), while HLA class II eplet mismatching was associated with specified antibody-mediated rejection (10-20 mismatches: HR 1.57 [1.06-2.34], p = .025; >20 mismatches: HR 3.14 [1.72-5.71], p < .001). Neither HLA class I nor class II allele mismatching was significantly associated with graft loss or rejection.Eplet mismatch analysis was more predictive of adverse post-transplant outcomes (including graft loss and rejection) than allele mismatch comparison. Further study, including prospective high-resolution HLA typing, is warranted.

Left ventricular non-compaction cardiomyopathy (LVNC) is a rare cardiomyopathy characterized by hypertrabeculation of the left ventricle with deep intertrabecular recesses and a thin, compacted layer of myocardium. The clinical phenotype can be heterogeneous with a benign or severe course, including life-threatening arrhythmias, thromboembolism, skeletal myopathy, and immune deficiencies, most notably neutropenia. 1 Brescia S.T. Rossano J.W. Pignatelli R. et al. Mortality and sudden death in pediatric left ventricular noncompaction in a tertiary referral center. Circulation. 2013; 127: 2202-2208 Crossref PubMed Scopus (180) Google Scholar , 2 Arbustini E. Weidemann F. Hall J.L. Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases?. J Am Coll Cardiol. 2014; 64: 1840-1850 Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar , 3 Towbin J.A. Left ventricular noncompaction: a new form of heart failure. Heart Fail Clin. 2010; 6: 453-469 Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Prior studies of cardiomyopathy outcomes in children listed for heart transplant (HT) did not assess patients with LVNC, 4 Dipchand A.I. Naftel D.C. Feingold B. et al. Outcomes of children with cardiomyopathy listed for transplant: a multi-institutional study. J Heart Lung Transplant. 2009; 28: 1312-1321 Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar and a recent evaluation of LVNC outcomes using the United Network for Organ Sharing database combined pediatric and adult outcomes. 5 Al-Kindi S.G. El-Amm C. Ginwalla M. Hoit B.D. Park S.J. Oliveira G.H. Heart transplant outcomes in patients with left ventricular non-compaction cardiomyopathy. J Heart Lung Transplant. 2015; 34: 761-765 Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar We sought to describe the characteristics and course of children with LVNC listed for HT.

Abstract Background: Children with decompensated heart failure are at high risk for arrhythmias, and ventricular assist device placement is becoming a more common treatment strategy. The impact of ventricular assist devices on arrhythmias and how arrhythmias affect the clinical course of this population are not well described. Methods and results: A single-centre retrospective analysis of children receiving a ventricular assist device between 1998 and 2011 was performed. In all, 45 patients received 56 ventricular assist devices. The median age at initial placement was 13 years (interquartile range 6–15). The median duration of support was 10 days (range 2–260). The aetiology of heart failure included cardiomyopathy, transplant rejection, myocarditis, and congenital heart disease. In all, 32 patients (71%) had an arrhythmia; 19 patients (42%) had an arrhythmia before ventricular assist device and eight patients (18%) developed new arrhythmias on ventricular assist device. Ventricular tachycardia was most common (25/32, 78%). There was no correlation between arrhythmia and risk of death or transplantation (p=0.14). Of the 15 patients who weaned from ventricular assist device, post-ventricular assist device arrhythmias occurred in nine (60%), with five (33%) having their first arrhythmia after weaning. Patients with ventricular dysfunction after ventricular assist device were more likely to have arrhythmias (p&lt;0.02). Conclusions: Arrhythmias, especially ventricular, are common in children requiring ventricular assist device. They frequently persist for those able to wean from ventricular assist device.

PurposeDapagliflozin recently received FDA-approval for use in adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure (HF). This is the first report describing safety and use of dapagliflozin in children with HF.MethodsThis is a single-center, observational, retrospective analysis assessing safety of dapagliflozin when added to a background of guideline-directed medical therapy in 9 pediatric patients (age < 21 years) with HF. Only patients with dapagliflozin at steady-state and with follow-up data were included. Univariate comparisons were made using Wilcoxan signed rank test before and after addition of dapagliflozin.ResultsMedian age was 14.2 years (IQR 11.2-17.7; range 9-18). Of the 9 patients, 6 had dilated cardiomyopathy, 2 had single ventricle physiology, and 1 had diastolic HF. NYHA functional class was as follows: 6 were class II, 2 were class III, and 1 was class IV. Median baseline hemoglobin A1c was 5.5% (IQR 5.3-5.75). Most (78%) were started on dapagliflozin during a HF-related hospitalization. Median starting dose of dapagliflozin was 5 mg once daily (IQR 5-10). Mean follow-up was 30.6 days (SD 21.6). Median dose at follow-up was 10 mg once daily (IQR 7.5-10). Urine glucose was negative at baseline and 1+ to 3+ at follow-up confirming the pharmacodynamic effect of dapagliflozin. Total daily dose of loop diuretic was decreased 50% for 3 patients at follow-up. There were no significant differences in weight, blood pressure, heart rate, ejection fraction, B-type natriuretic peptide, estimated glomerular filtration rate or blood chemistries at follow-up. No adverse events such as urinary tract infections, hypoglycemia, fractures, hypovolemia or renal injury were observed. Dapagliflozin was discontinued in 1 patient due to receipt of a heart transplant.ConclusionDapagliflozin appears to be safe in the short term when added to guideline-directed medical therapy for children with heart failure. Dapagliflozin recently received FDA-approval for use in adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure (HF). This is the first report describing safety and use of dapagliflozin in children with HF. This is a single-center, observational, retrospective analysis assessing safety of dapagliflozin when added to a background of guideline-directed medical therapy in 9 pediatric patients (age < 21 years) with HF. Only patients with dapagliflozin at steady-state and with follow-up data were included. Univariate comparisons were made using Wilcoxan signed rank test before and after addition of dapagliflozin. Median age was 14.2 years (IQR 11.2-17.7; range 9-18). Of the 9 patients, 6 had dilated cardiomyopathy, 2 had single ventricle physiology, and 1 had diastolic HF. NYHA functional class was as follows: 6 were class II, 2 were class III, and 1 was class IV. Median baseline hemoglobin A1c was 5.5% (IQR 5.3-5.75). Most (78%) were started on dapagliflozin during a HF-related hospitalization. Median starting dose of dapagliflozin was 5 mg once daily (IQR 5-10). Mean follow-up was 30.6 days (SD 21.6). Median dose at follow-up was 10 mg once daily (IQR 7.5-10). Urine glucose was negative at baseline and 1+ to 3+ at follow-up confirming the pharmacodynamic effect of dapagliflozin. Total daily dose of loop diuretic was decreased 50% for 3 patients at follow-up. There were no significant differences in weight, blood pressure, heart rate, ejection fraction, B-type natriuretic peptide, estimated glomerular filtration rate or blood chemistries at follow-up. No adverse events such as urinary tract infections, hypoglycemia, fractures, hypovolemia or renal injury were observed. Dapagliflozin was discontinued in 1 patient due to receipt of a heart transplant. Dapagliflozin appears to be safe in the short term when added to guideline-directed medical therapy for children with heart failure.

The immunosuppressant tacrolimus is a first-line agent to prevent graft rejection following pediatric heart transplant; however, it suffers from extensive inter-patient variability and a narrow therapeutic window. Personalized tacrolimus dosing may improve transplant outcomes by more efficiently achieving and maintaining therapeutic tacrolimus concentrations. We sought to externally validate a previously published population pharmacokinetic (PK) model that was constructed with data from a single site.Data were collected from Seattle, Texas, and Boston Children's Hospitals, and assessed using standard population PK modeling techniques in NONMEMv7.2.While the model was not successfully validated for use with external data, further covariate searching identified weight (p < 0.0001 on both volume and elimination rate) as a model-significant covariate. This refined model acceptably predicted future tacrolimus concentrations when guided by as few as three concentrations (median prediction error = 7%; median absolute prediction error = 27%).These findings support the potential clinical utility of a population PK model to provide personalized tacrolimus dosing guidance.

Pharmacokinetics of mycophenolic acid (MPA) display substantial interpatient variability, with up to 10-fold difference of exposure in individual patients under a fixed-dose regimen. MPA trough level (C0) monitoring is common in clinical practice but has not proven sufficiently informative in predicting MPA exposure or patient outcomes, especially in children. No limited sampling strategies (LSSs) have been generated from pediatric heart transplant (HTx) recipients to estimate MPA AUC.Single-center, observational analysis of 135 de novo pediatric HTx recipients ≤21 years old who underwent MPA AUC between 2011 and 2021.Median age was 4 years (IQR .6-12.1). Median time from transplant to MPA AUC sampling was 15 days (IQR 11-19). MMF doses (mg or mg/day) had low, negative Pearson correlation coefficients (r) while doses adjusted for weight or body surface area had low correlation with Trapezoidal MPA AUC0-24 h (r = .3 and .383, respectively). MPA C0 had weak association (r = .451) with Trapezoidal MPA AUC0-24 h . LSS with two pharmacokinetic sampling time points at 90 (C3 ) and 360 (C5 ) min after MMF administration (estimated AUC0-24 h = 32.82 + 4.12 × C3 + 11.53 × C5 ) showed strong correlation with Trapezoidal MPA AUC0-24 h (r = .87).MMF at fixed or weight-adjusted doses, as well as MPA trough levels, correlate poorly with MPA AUC0-24 h . We developed novel LSSs to estimate Trapezoidal MPA AUC from a large cohort of pediatric HTx recipients. Validation of our LSSs should be completed in a separate cohort of pediatric HTx recipients.

Aspirin (ASA) remains the most common antiplatelet agent used in children. VerifyNow Aspirin Test® (VN) assesses platelet response to ASA, with therapeutic effect defined by the manufacturer as ≤ 549 aspirin reaction units (ARU). Single-center, observational, analysis of 195 children (< 18 years-old) who underwent first VN between 2015 and 2020. Primary outcome was proportion of patients with ASA biochemical resistance (> 549 ARU). Secondary outcomes included incidence of new clinical thrombotic and bleeding events during ≤ 6 months from VN in those who received ASA monotherapy (n = 113). Median age was 1.8 years. Common indications for ASA included cardiac anomalies or dysfunction (74.8%) and ischemic stroke (22.6%). Median ASA dose before VN was 4.6 mg/kg/day. Mean VN was 471 ARU. ASA biochemical resistance was detected in 14.4% (n = 28). Of 113 patients receiving ASA monotherapy, 14 (12.4%) had a thrombotic event and 2 (1.8%) had a bleeding event. Mean VN was significantly higher at initial testing in patients experiencing thrombotic event compared to those without thrombosis (516 vs 465 ARU, [95% CI: 9.8, 92.2], p = 0.02). Multivariable analysis identified initial VN ASA result ≥ 500 ARU at initial testing as the only significant independent risk factor for thrombosis (p < 0.01). VN testing identifies ASA biochemical resistance in 14.4% of children. VN ASA ≥ 500 ARU rather than ≥ 550 ARU at initial testing was independently associated with increased odds of thrombosis. Designated cut-off of 550 ARU for detecting platelet dysfunction by ASA may need reconsideration in children.

Abstract Bortezomib is approved for the treatment of multiple myeloma but increasingly used in heart transplant (HTx) recipients with antibody‐mediated rejection (AMR). Severe pulmonary toxicity is a rare complication in multiple myeloma patients treated with bortezomib, but has not been described in a solid organ transplant recipient. A 20‐year‐old man 7 years post‐HTx presented with acute rejection with hemodynamic compromise. Endomyocardial biopsy showed mixed rejection (ISHLT grade 2R‐3R acute cellular rejection (ACR) and pAMR 1 (I+) with diffuse C4d staining). Two new high MFI circulating MHC class‐II donor‐specific antibodies (DSA) were detected. Treatment included corticosteroids, antithymocyte globulin, plasmapheresis, IVIG, rituximab, and bortezomib (1.3 mg/m 2 ). Due to rebound in DSA, a second course of bortezomib was started. Thrombocytopenia and peripheral neuropathy prompted a 50% dose reduction during the 2nd course. Shortly after the 3rd reduced dose, the patient developed hypoxemic respiratory failure. Bronchoscopy revealed pulmonary hemorrhage with negative infectious studies. Chest CT showed bilateral parenchymal disease with bronchiectasis and alveolar bleeding. Despite treatment with high‐dose steroids, severe ARDS ensued with multisystem organ failure. The patient expired 23 days after the final dose of bortezomib. Post‐mortem lung histology revealed diffuse alveolar damage, pulmonary fibrosis, and hemorrhage. Cardiac histology showed resolving/residual ACR 1R and pAMR 1 (I+). While rare, bortezomib‐induced lung toxicity (BILT) can occur in HTx recipients and can carry a high risk of mortality. Drug reaction and immediate drug withdrawal should be considered in patients who develop respiratory symptoms, though optimal management of BILT is unclear.

Rejection remains a significant cause of morbidity and mortality after pediatric heart transplantation (HTx). Outcomes after acute cellular rejection (ACR) have been well described, but less has been reported on outcomes after antibody mediated rejection (AMR). We sought to compare the clinical characteristics and outcomes of pediatric HTx recipients with AMR, ACR and no rejection. A retrospective chart review identified 104 patients <21yo who underwent HTx at a single center from 2006-14. Twenty recipients had histologic or immunopathologic findings of AMR and 15 had only histologic findings of ACR on endomyocardial biopsy. All 35 were treated for rejection. Recipients with mixed AMR/ACR or recipients that experienced both AMR and ACR, but at different time intervals, were included in the AMR group. Clinical characteristics and cardiovascular outcome, defined as a composite end point of either allograft loss (death or retransplantation) or cardiac allograft vasculopathy, were compared between the 3 groups by Fisher’s exact test and bivariate Cox proportional hazard analysis. There was no difference in age, gender, pretransplant mechanical circulatory support or ischemic time between recipients with AMR, ACR and no rejection. Recipients with AMR had an increased frequency of congenital heart disease (90% vs ACR 67% vs no rejection 59%, p=0.03), homograft from surgical palliation (68% vs 7% vs 18%, p<0.001), HLA sensitization (45% vs 13% vs 13%, p=0.008) and positive B or T cell crossmatch (30% vs 7% vs 9%, p=0.046). AMR patients had worse cardiovascular outcome than recipients with ACR or no rejection (40% vs 20% vs 8.6%, p= 0.003). In the univariate Cox proportional hazard model AMR, ischemic time and HLA-sensitization were associated with worse outcome after HTx. In bivariate Cox analysis, AMR (HR 4.1, CI 1.4-12.0, p=0.009) and ischemic time (HR 1.6, CI 1.1-2.3, p=0.02) were associated with worse outcome. ACR was not. Of note, fractional shortening on most recent echo was not significantly different between the 3 groups. Pediatric HTx recipients who develop AMR have worse cardiovascular outcome than recipients who develop only ACR or experience no rejection at all. Recipients with congenital heart disease, homograft material, HLA sensitization or positive crossmatch are at increased risk for developing AMR.

An overall outcome of children bridged to heart transplant (HT) with VAD at the time of transplant is associated with superior post-transplant survival than ECMO support. Limited outcomes information is available on mechanical circulatory support device (MCSD) in patients with single ventricle (SV). We analyzed data from the Pediatric Heart Transplant Study (PHTS) registry to evaluate the outcome of children with SV physiology who are supported with MCSD as a bridge to HT and their post-HT outcomes. Of the 3631 PHTS patients listed for HT between 2005 and 2014, 1825 (50%) had congenital heart disease (CHD) [SV= 1381 (76%) and biventricular (Bi-V) = 444 (24%)]. Of these, 906 (65%) SV patients and 298 (67%) Bi-V underwent HT; 233 (17%) and 80 (18%) died while waiting. 57% of all SV patients had hypoplastic left heart syndrome. MCSD support was more prevalent in Bi-V patients (46%: 24% ECMO & 22% VAD) compared to SV (14%: 9% ECMO & 5% VAD) (p<.01). Overall, 40% of SV patients (45.3% of VAD group & 38.6% of ECMO group) with MCSD received transplantation by 6 months compared to 59% of those without MCSD. SV waitlist mortality was 11% among no-MCSD support, 35% in VAD group, and 47% in ECMO group at 6 months (p <.01). SV patients on MCSD were more likely to remain on support until HT if they received VAD 22/60 (36%) compared to ECMO 10/127 (8%); p<.01. After HT, 12 month survival was significantly different between SV groups with no MCSD at listing or while listed (88%), VAD (78%) and ECMO (69%); p<.01. However, there was no difference in survival between SV patients on VAD at the time of HT (74%) vs those on ECMO (80%); p=0.9 (figure). Waitlist mortality for SV patients supported with MCSD remains unacceptably high. SV patients receiving MCSD are more likely to stay on support until HT if they had VAD compared to ECMO. However, for those SV patients on MCSD support at HT, there was no significant difference in survival outcomes between ECMO and VAD.

Purpose Extensive variability in tacrolimus pharmacokinetics (PK) influences attainment of therapeutic immunosuppression following pediatric heart transplant. Population PK (popPK) model-based personalized dosing of tacrolimus can reduce the need for tacrolimus titration and improve long-term pediatric heart transplant outcomes. The objective of this study was to externally evaluate a previously described single-center popPK model for personalized tacrolimus therapy. Methods A multicenter, retrospective analysis utilized demographics, tacrolimus dosing and concentration data, and laboratory values collected from pediatric inpatients during the first 6 weeks post-transplant, or until discharge, from three sites. PopPK analysis used the modeling software NONMEM v7.2. Observed concentration data were compared to data simulated with our single-center popPK model, using median prediction error (MPE, a measure of bias, <15% acceptable) and median absolute prediction error (MAPE, a measure of accuracy, <30% acceptable). Results A total of 285 children: 115 female, 196 white, 32 black, were included. Median age and creatinine clearance were 9.1 years and 101 mL/min/1.73m2, respectively. Fluconazole use was rare, occurring in only 6 subjects. When utilizing all data the MPE and MAPE (interquartile range) were acceptable, at -3% (-25%, 10%) and 18% (5%, 49%), respectively, and not different by institution. However, when allowed only 3 concentrations (i.e. the minimum number to adequately predict future concentrations in our prior single-center study) the model poorly predicted future concentrations at all sites (MPE=31%; MAPE=47%). MPE and MAPE varied by site, ranging from 7 to 61% and 30 to 63%, respectively. Including site as a covariate in the popPK model improved predictions (MPE=21%; MAPE=37%) and decreased variability in predictive ability between sites (MPE: 11 to 34%; MAPE: 32 to 45%). Conclusion Our single-center popPK model did not adequately predict tacrolimus concentrations from external institutions. Study site appears to drive some of the poor model performance. Future directions include identifying study site differences that influence model performance, as well as identifying additional patient-specific factors affecting tacrolimus dosing requirements. Extensive variability in tacrolimus pharmacokinetics (PK) influences attainment of therapeutic immunosuppression following pediatric heart transplant. Population PK (popPK) model-based personalized dosing of tacrolimus can reduce the need for tacrolimus titration and improve long-term pediatric heart transplant outcomes. The objective of this study was to externally evaluate a previously described single-center popPK model for personalized tacrolimus therapy. A multicenter, retrospective analysis utilized demographics, tacrolimus dosing and concentration data, and laboratory values collected from pediatric inpatients during the first 6 weeks post-transplant, or until discharge, from three sites. PopPK analysis used the modeling software NONMEM v7.2. Observed concentration data were compared to data simulated with our single-center popPK model, using median prediction error (MPE, a measure of bias, <15% acceptable) and median absolute prediction error (MAPE, a measure of accuracy, <30% acceptable). A total of 285 children: 115 female, 196 white, 32 black, were included. Median age and creatinine clearance were 9.1 years and 101 mL/min/1.73m2, respectively. Fluconazole use was rare, occurring in only 6 subjects. When utilizing all data the MPE and MAPE (interquartile range) were acceptable, at -3% (-25%, 10%) and 18% (5%, 49%), respectively, and not different by institution. However, when allowed only 3 concentrations (i.e. the minimum number to adequately predict future concentrations in our prior single-center study) the model poorly predicted future concentrations at all sites (MPE=31%; MAPE=47%). MPE and MAPE varied by site, ranging from 7 to 61% and 30 to 63%, respectively. Including site as a covariate in the popPK model improved predictions (MPE=21%; MAPE=37%) and decreased variability in predictive ability between sites (MPE: 11 to 34%; MAPE: 32 to 45%). Our single-center popPK model did not adequately predict tacrolimus concentrations from external institutions. Study site appears to drive some of the poor model performance. Future directions include identifying study site differences that influence model performance, as well as identifying additional patient-specific factors affecting tacrolimus dosing requirements.

Purpose Pediatric heart transplant recipients who experience antibody mediated rejection (AMR) are at increased risk for poor graft outcomes. We report the incidence, treatment, and outcomes of AMR at our center. Methods Transplant recipients treated for AMR between 2010 and 2021 were identified. We reviewed AMR episodes, therapies, and graft outcomes. Results Of 183 transplants performed, 25 patients experienced 37 episodes of AMR, representing an incidence of 14%. 89% of patients were transplanted for congenital heart disease, 40% were sensitized pre-transplant, and 28% had a crossmatch positive transplant. In 33 of 37 episodes (89%), there was both strong DSA (>4,000 mfi) and findings of pathologic AMR (pAMR) on endomyocardial biopsy. Two patients had DSA <4,000 mfi with pAMR findings, one had strong DSA but died prior to biopsy, and one had strong DSA with negative pAMR but with graft dysfunction without other explanation. The first rejection episode occurred at a median of 50 days (IQR 17-635 days) from transplant. 19% of episodes were with hemodynamic compromise and 36% of patients had recurrence of AMR. Biopsy findings showed pAMR 0 in 3%, pAMR 1 (H+) in 47%, pAMR 1 (I+) in 17%, and pAMR 2 in 33%. 75% had mixed ACR/pAMR. Therapy included anti-thymocyte globulin in 13% (predominately for rejection with hemodynamic compromise), methylprednisolone in 92%, IVIG in 97%, bortezomib in 78%, rituximab in 73%, plasmapheresis in 35%, and eculizumab in 22%. A combination of 2 or greater antibody directed therapies was used in 89% of episodes and 3 or greater therapies in 70%. IVIG/bortezomib/rituximab was the most common therapy combination, used in 32% of episodes. pAMR findings resolved in 64% at 3 months and 79% at 1 year. During a median follow up of 4 years (IQR 1-6 years) from first AMR, there were 8 graft losses (2 retransplants and 6 deaths). The median time from AMR to graft loss was 7 months (IQR 2 months - 4.5 years). 20% of patients developed cardiac allograft vasculopathy at a median duration of 4.8 years (IQR 4-7) from AMR and 8 years (IQR 5-9) from transplant. Retransplant free survival from first AMR was 83% at 1 year, 76% at 3 years, and 63% at 5 years. Conclusion AMR occurred early post-transplant and recurrence was common. Treatment strategies varied, however combination therapy was nearly always employed. Despite relatively early graft loss after first AMR, AMR can be treated to prolong graft survival. Pediatric heart transplant recipients who experience antibody mediated rejection (AMR) are at increased risk for poor graft outcomes. We report the incidence, treatment, and outcomes of AMR at our center. Transplant recipients treated for AMR between 2010 and 2021 were identified. We reviewed AMR episodes, therapies, and graft outcomes. Of 183 transplants performed, 25 patients experienced 37 episodes of AMR, representing an incidence of 14%. 89% of patients were transplanted for congenital heart disease, 40% were sensitized pre-transplant, and 28% had a crossmatch positive transplant. In 33 of 37 episodes (89%), there was both strong DSA (>4,000 mfi) and findings of pathologic AMR (pAMR) on endomyocardial biopsy. Two patients had DSA <4,000 mfi with pAMR findings, one had strong DSA but died prior to biopsy, and one had strong DSA with negative pAMR but with graft dysfunction without other explanation. The first rejection episode occurred at a median of 50 days (IQR 17-635 days) from transplant. 19% of episodes were with hemodynamic compromise and 36% of patients had recurrence of AMR. Biopsy findings showed pAMR 0 in 3%, pAMR 1 (H+) in 47%, pAMR 1 (I+) in 17%, and pAMR 2 in 33%. 75% had mixed ACR/pAMR. Therapy included anti-thymocyte globulin in 13% (predominately for rejection with hemodynamic compromise), methylprednisolone in 92%, IVIG in 97%, bortezomib in 78%, rituximab in 73%, plasmapheresis in 35%, and eculizumab in 22%. A combination of 2 or greater antibody directed therapies was used in 89% of episodes and 3 or greater therapies in 70%. IVIG/bortezomib/rituximab was the most common therapy combination, used in 32% of episodes. pAMR findings resolved in 64% at 3 months and 79% at 1 year. During a median follow up of 4 years (IQR 1-6 years) from first AMR, there were 8 graft losses (2 retransplants and 6 deaths). The median time from AMR to graft loss was 7 months (IQR 2 months - 4.5 years). 20% of patients developed cardiac allograft vasculopathy at a median duration of 4.8 years (IQR 4-7) from AMR and 8 years (IQR 5-9) from transplant. Retransplant free survival from first AMR was 83% at 1 year, 76% at 3 years, and 63% at 5 years. AMR occurred early post-transplant and recurrence was common. Treatment strategies varied, however combination therapy was nearly always employed. Despite relatively early graft loss after first AMR, AMR can be treated to prolong graft survival.

Background: Cytomegalovirus (CMV) is an important complication of heart transplantation and has been associated with graft loss in adults. The data in pediatric transplantation, however, is limited and conflicting. We conducted a large-scale cohort study to better characterize the relationship between CMV serostatus, CMV antiviral use, and graft survival in pediatric heart transplantation. Methods: 4,968 pediatric recipients of solitary heart transplants from the Scientific Registry of Transplant Recipients were stratified into three groups based on donor or recipient seropositivity and antiviral use: CMV seronegative (CMV-) transplants, CMV seropositive (CMV+) transplants without antiviral therapy, and CMV+ transplants with antiviral therapy. The primary endpoint was retransplantation or death. Results: CMV+ transplants without antiviral therapy experienced worse graft survival than CMV+ transplants with antiviral therapy (10-year: 57 vs 65%). CMV+ transplants with antiviral therapy experienced similar survival as CMV- transplants. Compared to CMV seronegativity, CMV seropositivity without antiviral therapy had a hazard ratio of 1.21 (1.07-1.37 95% CI, p-value = .003). Amongst CMV+ transplants, antiviral therapy had a hazard ratio of .82 (0.74-.92 95% CI, p-value < .001). During the first year after transplantation, these hazard ratios were 1.32 (1.06-1.64 95% CI, p-value .014) and .59 (.48-.73 95% CI, p-value < .001), respectively. Conclusions: CMV seropositivity is associated with an increased risk of graft loss in pediatric heart transplant recipients, which occurs early after transplantation and may be mitigated by antiviral therapy.

Infants listed for heart transplant are at high risk for waitlist mortality. While waitlist mortality for children has decreased in the current era of increased ventricular assist device use, outcomes for small infants supported by ventricular assist device remain suboptimal. We evaluated morbidity and survival in critically ill infants listed for heart transplant and managed without ventricular assist device support.Critically ill infants (requiring ≥1 inotrope and mechanical ventilation or ≥2 inotropes without mechanical ventilation) listed between 2008 and 2019 were included. During the study period, infants were managed primarily medically. Mechanical circulatory support, specifically extracorporeal membrane oxygenation, was utilized as "rescue therapy" for decompensating patients.Thirty-two infants were listed 1A, 66% with congenital heart disease. Median age and weight at listing were 2.2 months and 4.4 kg, with 69% weighing <5 kg. At listing, 97% were mechanically ventilated, 41% on ≥2 inotropes, and 25% under neuromuscular blockade. Five patients were supported by ECMO after listing. A favorable outcome (transplant or recovery) was observed in 84%. One-year posttransplant survival was 92%. Infection was the most common waitlist complication occurring in 75%. Stroke was rare, occurring in one patient who was supported on ECMO. Renal function improved from listing to transplant, death, or recovery (eGFR 70 vs 87 ml/min/1.73m2 , p = .001).A strategy incorporating a high threshold for mechanical circulatory support and acceptance of prolonged mechanical ventilation and neuromuscular blockade can achieve good survival and morbidity outcomes for critically ill infants listed for heart transplant.

There is considerable variability in practice among pediatric centers for treatment of myocarditis. We report outcomes using high dose steroids in conjunction with IVIG. This is a single center retrospective study of children < 21 years of age diagnosed with myocarditis and treated with high dose steroids and IVIG from January 2004-April 2021. Diagnostic criteria for myocarditis included positive endomyocardial biopsy, cardiac magnetic resonance (CMR) imaging meeting Lake Louise criteria, or strictly defined clinical diagnosis. Forty patients met inclusion criteria. Median age at diagnosis was 11.6 years (0.7-14.6). Diagnosis was made clinically in 70% of cases (N = 28), by CMR in 12.5% (N = 5) and by biopsy in 17.5% (N = 7). Median ejection fraction (EF) at diagnosis was 35% (IQR 24-48). Median duration of IV steroids was 7 days (IQR 4-12) followed by an oral taper. Median cumulative dose of IV immunoglobulin (IVIG) was 2 g/kg. There were no serious secondary bacterial infections after steroid initiation. Ten patients (25%) required mechanical circulatory support. Overall transplant free survival was 92.5% with median follow-up of 1 year (IQR 0-6 years). Six patients required re-admission for cardiovascular reasons. By 3 months from diagnosis, 70% of patients regained normal left ventricular function. High dose steroids in conjunction with IVIG to treat acute myocarditis can be safe without significant infections or long-term side effects. Our cohort had excellent recovery of ventricular function and survival without transplant. Prospective comparison of a combination of high dose steroids with IVIG versus other therapies is needed.

In the combustion treatment of explosive gases with a high heating value such as H2 and NH3 used in semiconductor and chemical processes, the heat recovery modeling and exergy analysis of the process using the Aspen Plus simulator and its thermodynamic data were performed to examine the recovery of high temperature thermal energy. The heat recovery process was analyzed through this process modeling while the exergy results clearly confirmed that the rigorous reaction mainly occurs in the condenser and the chamber. In addition, the process modeling demonstrated that approximately 95% of the exergy is destructed on the basis of the exergies injected and the exergy being exhausted. Using the exergy technique, which can quantitatively analyze the energy, we could understand the energy flow in the process and confirm that our heat recovery process was efficiently designed.

Abstract PH is a risk factor for GL after HT x. However, traditional parameters are not reliable predictors of risk in children. We hypothesized that DPI ( dPAP and DPG ) are predictive of GL in pediatric HT x recipients. The UNOS / SRTR database was reviewed to identify pediatric HT x recipients (age &lt;18 years) between 1994 and 2013. Recipients with pretransplant hemodynamic data were grouped by diagnosis ( CMP or CHD ), and the groups were analyzed separately. Bivariate Cox regression analysis examined the association between hemodynamic variables and GL . DPI showed the strongest association with early GL in recipients with CMP ( dPAP : HR = 1.25 [1.09‐1.42]; DPG : 1.24 [1.11‐1.38]). Among CHD recipients, DPI were associated with early GL in those with preexisting PH ( dPAP : HR = 1.16 [1.01‐1.33]; DPG : HR = 1.10 [1.00‐1.21]). No cutoff values for “high‐risk” DPI were identified, but a continuous relationship between higher DPI and risk of early GL was observed. DPI are associated with early GL in select pediatric HT x recipients. Our findings suggest that DPI should be considered as part of routine hemodynamic assessment for pediatric HT x candidates.

Infections in adult ventricular assist device patients increase subsequent mortality and stroke risk. Less is known about outcomes after infections in younger patients, where diabetes and obesity, risk factors associated with poor outcomes, are less prevalent. The purpose of this study was to examine outcomes after infections in adolescents and young adults with continuous-flow left ventricular assist devices (VAD) bridged to transplant. From Pediatric Interagency Registry for Mechanically Assisted Circulatory Support and Interagency Registry for Mechanical Circulatory Support registries, we identified patients aged 12–29 years with continuous-flow VADs implanted as bridged to transplant from September 2012 to March 2016. The primary predictor variable was first reported infection. The primary outcome was death on VAD support; secondary outcome was clinical stroke. Kaplan–Meier and Cox proportional hazard methods were used to compare outcomes between patients before or without infection and patients after infection. Ninety-two adolescents (12–18 years of age) and 224 young adults (19–29 years of age) with 3,748 patient-months of follow-up were included. Adolescents were smaller (body surface area 1.7 vs . 2.0 m 2 , p &lt; 0.01) and implanted at higher Interagency Registry for Mechanical Circulatory Support profiles ( p = 0.005); there were no differences in diabetes and obesity, and survival on VAD was similar ( p = 0.22). Among adolescents but not young adults, mortality increased after infection (hazard ratio 8.2, 95% confidence interval 1.6–42.6, p = 0.01). In contrast, stroke risk increased after infection in young adults (hazard ratio 3.1, 95% confidence interval 1.3–7.6, p = 0.01) but not in adolescents. Despite similar underlying risk factors, adolescents have increased mortality after infections, whereas young adults have increased strokes after infections. Both pre- and postimplant factors likely contribute to the discrepancy in outcomes between the two age cohorts.

Abstract CNIs are the mainstay of immunosuppressive therapy after pediatric HTx. While regular laboratory surveillance is performed to ensure blood levels are within targeted range, the risk of acute rejection associated with subtherapeutic CNI levels has never been quantified. This is a retrospective single‐center review of 8413 CNI trough levels in 138 pediatric HTx recipients who survived &gt;1 year after HTx. Subtherapeutic CNI levels were defined as &lt;50% of the lower limit of target range. The risk of acute, late (&gt;12 months post‐transplant) rejection following recipients' subtherapeutic CNI levels was assessed using time‐varying multivariable Cox proportional hazards analysis. We found that 79 of 138 recipients (57%) had at least one subtherapeutic CNI level on routine surveillance laboratories during a mean follow‐up of 5.5 ± 3.6 years. Following an episode of subtherapeutic levels, 17 recipients (22%) had biopsy‐proven rejection within the next 3 months; the majority (9/17) within the first 2 weeks. After presenting with subtherapeutic CNI levels, recipients incurred a 6.1 times increased risk of acute rejection in the following 3 months (HR = 6.11 [2.41, 15.51], P = &lt;.001). Age at HTx, HLA sensitization, or positive crossmatch were not associated with acute late rejection, but rejection in the first post‐transplant year was (HR 2.61 [1.27, 5.35], P = .009). Thus, maintaining therapeutic CNI levels is the most important factor in preventing acute rejection in recipients who are &gt;12 months after pediatric HTx. Recipients who present with subtherapeutic CNI levels on surveillance monitoring are 6.1 times more likely to develop rejection in the following 3 months.

The influence of hospital environment on pediatric transplant outcomes is unknown. We investigated the association of hospital type (pediatric vs. general) with pre-transplant ventricular assist device (VAD) utilization and heart transplant outcome measures. Data from all patients < 21 years of age reported to the HCUP-KID Inpatient Database from 2003-2012 were analyzed. Pediatric heart transplant recipients were segregated into two groups based on hospital environment: pediatric hospital vs. pediatric ward within a general hospital. Multivariate models examining pre-transplant use of mechanical circulatory support, complications, post-transplant length of stay, post-transplant hospital survival, and hospital charges were examined. Of the 1559 transplant patients analyzed, 889 (57%) underwent transplantation in a pediatric hospital and 670 (43%) underwent transplantation in a general hospital. A higher proportion of neonatal (< 28 days: 10.6% vs. 4.8%) and infant (28-365 days: 16.1% vs. 13.4%) transplants were performed in pediatric hospitals (p=0.05). In addition, a higher proportion of patients with structural congenital heart disease (51.7% vs. 36.5%, p<0.01) or single ventricle physiology (21.5% vs. 12.7%, p<0.01) underwent transplantation in a pediatric hospital. VADs were used more commonly in pediatric hospitals (14.4% vs. 9.0% in general hospitals, p=0.02), with the largest difference being in children > 1 year of age (18.0% vs. 9.8% in general hospitals, p<0.01). In multivariate models, patients who underwent transplantation in pediatric hospitals were more likely to receive a VAD prior to transplantation (OR=2.33, 95% CI=1.41-3.85), whereas ECMO usage across hospital environments was similar (5.5% pediatric vs. 4.3% general, p=0.40). Hospital type was not associated with hospital mortality, complication rate, length of stay, or hospital charges in multivariate models. Overall hospital survival following heart transplant is similar in pediatric and general hospitals. Waiting list mortality is unknown but children who survive to heart transplantation are more likely to receive pre-transplant VAD support in pediatric hospitals than general hospitals. These data suggest that hospital environment may impact pre-transplant support strategy and potentially waiting list mortality.

A prior study showed lack of production of donor specific antibodies to HLA antigens (DSAs) in non-sensitized ABO-incompatible (ABO-i) and similar age ABO-compatible (ABO-c) recipients. We examined whether ABO compatibility has an effect on de novo DSA production in an American cohort regardless of pre-transplant sensitization status. A retrospective cohort study of recipients < 1 year of age at transplant with > 6 months of follow-up, transplanted between 1/2004-10/2013 at a single U.S. pediatric heart transplant center. Outcomes included development of DSAs and history of rejection. DSA positivity was defined as either the lowest level detectable by assay, mean fluorescence intensity (MFI) >500, or suggestive of clinical relevance, MFI>5000. Of 47 patients, 33 received ABO-c transplants and 14 received ABO-i transplants (median age 5.5 mo vs. 4.2 mo, p=0.577). Median duration of follow-up was 45 mo for ABO-c and 47 mo for ABO-i (p=0.745). There were no significant differences between the two groups in gender, cardiac diagnosis, prior open heart surgery, prior homograft, crossmatch, pre-transplant sensitization to anti-HLA antibodies, number of HLA mismatches, and immunosuppression regimen. Compared to ABO-c recipients, the ABO-i group consistently showed a trend of less frequent de novo DSA positivity and rejection (see Table). For the entire cohort, there was a significant association between antibody-mediated rejection and DSA positivity (36.8% in DSA-positive vs. 7.1% in DSA-negative using MFI>5000 as the cutoff, p=0.021; and 31% vs. 0% using MFI>500, p=0.008). A similar though not statistically significant trend was seen for cellular rejection. Our data suggest that patients receiving ABO-i heart transplants within the first year of life develop fewer DSAs compared to recipients of ABO-c transplants, which may lead to fewer rejections. Larger sample sizes with adjustment for covariates will be needed to confirm results from this pilot study.

Cardiac allograft vasculopathy (CAV) is one of the leading causes of late mortality in pediatric heart transplant patients. Many do not survive to retransplantation, and a subset die suddenly. The purpose of this study is to determine risk factors associated with sudden death (SD) in pediatric patients with CAV. This is a single center retrospective review of all pediatric patients transplanted from 1984 to 2012 who died or were retransplanted following a diagnosis of CAV. The diagnosis of CAV was made by coronary angiography, explant pathology, or autopsy. Data including demographics, episodes of rejection, cardiac catheterization and echocardiographic data, time to CAV diagnosis, and cause of death were collected to compare SD patients to those who died of end-stage heart failure. Of the 54 patients with CAV, 40 died or underwent retransplantation (RT) and 14 are alive. Three patients were excluded as their causes of death were unknown or noncardiac. Of the 37 patients who met inclusion criteria, 9 patients (24%) died suddenly. The other 28 patients died of heart failure (12/28 patients) or were retransplanted (16/28 patients). Comparison of the SD group to the heart failure death/RT group did not find any differences in age at transplant, episodes of cellular or antibody mediated rejection, or time to CAV diagnosis or death. Systolic function was significantly better in the SD group with a median ejection fraction of 62% (range 50-70%) compared to 50% (range 24-75%) in the heart failure death/RT group (p=0.045). Hemodynamics also differed, with a median right ventricular end diastolic pressure of 8 mmHg (range 3-16 mmHg) in the SD group compared to a median of 14 mmHg (range 4-24 mmHg) in the heart failure death/RT group (p=0.011) and a median pulmonary capillary wedge pressure of 9 mmHg (range 4-16 mmHg) in the SD group compared to a median of 14 mmHg (range 7-27 mmHg) in the heart failure death group/RT (p=0.027). B-type natriuretic peptide (BNP) levels before death or retransplantation were lower in the SD group with a median of 260 pg/ml (range 81-953 pg/ml) compared to the heart failure death/RT group with a median of 1081 pg/ml (range 207-5258 pg/ml) (p=0.013). Sudden death occurred in 24% of CAV associated patient or organ deaths. The SD patients were more likely to have normal hemodynamics and a lower BNP. Normal hemodynamics may not be reassuring in the setting of CAV.

PurposeCardiac allograft vasculopathy (CAV) is an important cause of graft failure in heart transplant (HTx) recipients. The purpose of this study was to identify the effect of medication regimens (MR) on the development of CAV in pediatric HTx recipients.MethodsPatients (pts) <19 yrs of age whose first transplant was between 1996 and 2012 at Texas Children’s Hospital were included in the study. Pts MR were followed to 1 of 3 endpoints: date of first CAV diagnosis, retransplantation (RTx), or death. CAV was determined by angiography/imaging or pathology. MR data included: cyclosporine, tacrolimus, mycophenolate mofetil (MMF), sirolimus, prednisone, statin, beta-blockers and angiotensin converting enzyme inhibitors (ACEi) use. MR in those that developed CAV was compared to pts that did not develop CAV. Pts were excluded if death occurred prior to first clinic visit, not transplanted at our institution, had multi-organ transplantation, or RTx. Statistical analysis included univariate and multivariate hazard models.ResultsOf the 148 pts identified, 57% were males, with a median age of 3.2 yrs (0.1 - 18.4) at HTx. Graft loss occurred in 27% (n=40) and CAV was present in 24% (n=35) pts. Median time to CAV was 5.52 yrs (1.0 - 12.3). No difference was seen in pts who developed CAV to those who did not with respect to age at HTx, sex, or CMV status. Of those who developed CAV, 97% were on steroids compared to 78% without CAV (p=0.01) and 26% who developed CAV were on MMF compared to 60% without CAV (p=0.01). Multivariate Hazard ratios (HR) showed that statins and MMF were protective from the development of CAV (HR: 0.39 CI: 0.18-0.89; p=0.02 and HR: 0.45 CI: 0.2-0.98, p=0.04) (Figure 1). Prior sirolimus, type of calcineurin inhibitor, or beta-blocker/ACEi use did not appear to be protective for the development of CAV.Conclusion PurposeCardiac allograft vasculopathy (CAV) is an important cause of graft failure in heart transplant (HTx) recipients. The purpose of this study was to identify the effect of medication regimens (MR) on the development of CAV in pediatric HTx recipients. Cardiac allograft vasculopathy (CAV) is an important cause of graft failure in heart transplant (HTx) recipients. The purpose of this study was to identify the effect of medication regimens (MR) on the development of CAV in pediatric HTx recipients. MethodsPatients (pts) <19 yrs of age whose first transplant was between 1996 and 2012 at Texas Children’s Hospital were included in the study. Pts MR were followed to 1 of 3 endpoints: date of first CAV diagnosis, retransplantation (RTx), or death. CAV was determined by angiography/imaging or pathology. MR data included: cyclosporine, tacrolimus, mycophenolate mofetil (MMF), sirolimus, prednisone, statin, beta-blockers and angiotensin converting enzyme inhibitors (ACEi) use. MR in those that developed CAV was compared to pts that did not develop CAV. Pts were excluded if death occurred prior to first clinic visit, not transplanted at our institution, had multi-organ transplantation, or RTx. Statistical analysis included univariate and multivariate hazard models. Patients (pts) <19 yrs of age whose first transplant was between 1996 and 2012 at Texas Children’s Hospital were included in the study. Pts MR were followed to 1 of 3 endpoints: date of first CAV diagnosis, retransplantation (RTx), or death. CAV was determined by angiography/imaging or pathology. MR data included: cyclosporine, tacrolimus, mycophenolate mofetil (MMF), sirolimus, prednisone, statin, beta-blockers and angiotensin converting enzyme inhibitors (ACEi) use. MR in those that developed CAV was compared to pts that did not develop CAV. Pts were excluded if death occurred prior to first clinic visit, not transplanted at our institution, had multi-organ transplantation, or RTx. Statistical analysis included univariate and multivariate hazard models. ResultsOf the 148 pts identified, 57% were males, with a median age of 3.2 yrs (0.1 - 18.4) at HTx. Graft loss occurred in 27% (n=40) and CAV was present in 24% (n=35) pts. Median time to CAV was 5.52 yrs (1.0 - 12.3). No difference was seen in pts who developed CAV to those who did not with respect to age at HTx, sex, or CMV status. Of those who developed CAV, 97% were on steroids compared to 78% without CAV (p=0.01) and 26% who developed CAV were on MMF compared to 60% without CAV (p=0.01). Multivariate Hazard ratios (HR) showed that statins and MMF were protective from the development of CAV (HR: 0.39 CI: 0.18-0.89; p=0.02 and HR: 0.45 CI: 0.2-0.98, p=0.04) (Figure 1). Prior sirolimus, type of calcineurin inhibitor, or beta-blocker/ACEi use did not appear to be protective for the development of CAV. Of the 148 pts identified, 57% were males, with a median age of 3.2 yrs (0.1 - 18.4) at HTx. Graft loss occurred in 27% (n=40) and CAV was present in 24% (n=35) pts. Median time to CAV was 5.52 yrs (1.0 - 12.3). No difference was seen in pts who developed CAV to those who did not with respect to age at HTx, sex, or CMV status. Of those who developed CAV, 97% were on steroids compared to 78% without CAV (p=0.01) and 26% who developed CAV were on MMF compared to 60% without CAV (p=0.01). Multivariate Hazard ratios (HR) showed that statins and MMF were protective from the development of CAV (HR: 0.39 CI: 0.18-0.89; p=0.02 and HR: 0.45 CI: 0.2-0.98, p=0.04) (Figure 1). Prior sirolimus, type of calcineurin inhibitor, or beta-blocker/ACEi use did not appear to be protective for the development of CAV. Conclusion

Introduction: Renal dysfunction (RD) is prevalent among pediatric patients with advanced heart failure. Data are limited regarding changes in renal function following left ventricular assist device (LVAD) placement in this population. Hypothesis: Renal function will improve following pediatric LVAD placement, but degree and durability of improvement may vary based upon patient and device characteristics. Methods: Pediatric LVAD recipients enrolled in the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS) between September 19, 2012 and December 31, 2015 were included. The Schwartz equation was used to calculate eGFR and longitudinal changes in renal function were analyzed for the entire cohort as well as subgroups stratified by patient and device characteristics. Results: Data from 218 patients from 39 centers were analyzed. Mean age at implant was 9.2 years and total follow up time was 768 patient-months. There were 117 (54%) durable continuous flow LVADs, 60 (27%) durable pulsatile flow LVADs, and 41 (19%) temporary LVADs. The underlying diagnosis was cardiomyopathy in 162 (74%) patients and congenital heart disease in 47 (22%) patients. Baseline RD (eGFR &lt; 90 mL/min/1.73 m 2 ) was present in 140 (64%) patients. Overall, eGFR improved post-LVAD, peaking at 1 month post-implant (Figure 1). There was an inverse relationship between baseline eGFR and the degree of improvement at 1 month (mean increase in eGFR of 45 +/- 16 for patients with baseline RD vs. mean increase of 16 +/- 58 for patients with normal eGFR pre-LVAD, p=0.001). Degree of improvement in eGFR at 1 month did not appear impacted by device type, age, or diagnosis. There was a downward trend in eGFR after 1 month, although eGFR remained over baseline for patients with pre-implant RD. Conclusions: Renal function improves post-LVAD placement in pediatric patients regardless of age, diagnosis or device type, with improvement most pronounced in patients with baseline RD.

Totally thoracoscopic closure of a VSD was performed in 119 patients without the aid of a robotically assisted surgical system.Technical success was achieved in all patients.One patient required insertions of a permanent pacemaker.Transthoracic echocardiography 5.2 months after the operation showed complete closure of the VSD in all patients.

Cardiac allograft vasculopathy (CAV) is a leading cause of late mortality in pediatric heart transplant patients.Sudden death (SD) is a known phenomenon in CAV.This study aims to characterize factors associated with SD versus heart failure death (HFD) in pediatric patients with CAV.This single center retrospective review identified 37 pediatric patients who died or were retransplanted as a result of CAV. 9 (24%) of those patients died suddenly.There were no differences in rejection episodes between SD patients and HFD/retransplant patients.Ejection fraction (EF) was significantly higher in the SD group, median EF 62% versus 50% in the HFD/retransplant group (p=0.045).Hemodynamics also differed, with a median right ventricular end diastolic pressure of 8 mmHg in the SD group versus 14 mmHg in the HFD/retransplant group (p=0.011) and a median pulmonary capillary wedge pressure of 9 mmHg in the SD group versus 14 mmHg in the HFD/ retransplant group (p=0.027).Brain natriuretic peptide (BNP) was lower in the SD group, median 260 pg/ml versus 1081 pg/ml in the HFD/retransplant group (p=0.013).SD patients were more likely to have lower BNP levels, normal hemodynamics, and normal systolic function, none of which should be reassuring in the setting of CAV.

Background: Elevated body mass index (BMI) is a major independent risk factor for cardiovascular disease. The prevalence of obesity in patients with Fontan physiology is unknown and the added disease burden is unclear. There are no longitudinal studies on weight trends in Fontan patients. Objective: To determine the prevalence of overweight (OW) and obesity (OB) and to track longitudinal changes in BMI in children and adults treated with Fontan palliative surgery at a major tertiary care center. Design and Methods: We performed a retrospective chart review of all patients who underwent the Fontan operation between 1992 - 2012. Subjects were categorized by age as outlined by the NHANES database (2-5 y, 6-11 y, 12-19 y, adults) and growth records were reviewed. BMI percentiles were calculated for children using the US Centers for Disease Control (CDC) growth charts. CDC definitions of OW and OB were used. Results: Anthropometric data were available for 701 subjects (n=401, age 2-5 y; n= 333, age 6-11 y; n=217, age 12-19 y; and n=128, adult). Among adults, 38% (n=49) were OW or OB at last clinic visit, with 21.1% (n=27) OW and 17.2% (n=22) OB. Longitudinal data were available for 83 adult subjects. Of this subset, 14.5% (n=12) were OW or OB in childhood, 85.5% (n=71) had BMI &lt; 85th percentile. Forty seven percent of OB adults were OW or OB in childhood (n=9/19). The likelihood of being OW/OB as an adult was 2.5 times higher if there was OW/OB present during childhood (CI 1.8-3.6, p =&lt;0.001). Within children, the total rates of OW and OB in age groups 2-5 y, 6-11 y and 12-19 y were 24.7% (n=99), 26.4% (n=88) and 13.3% (n=29), respectively. Childhood OB rates were 13.4 % (n=54), 12% (n=40), and 4.6% (n=10), respectively, compared to national obesity rates of 10.4%, 19.6%, and 18.1% (NHANES 2007-2008). Conclusion: In this high-risk population, obesity rates for adults are nearly as high as those reported in national data, and are higher than national rates for children ages 2-5y. Longitudinal data in adult Fontan patients show that increased weight begins in childhood. The impact of early-onset obesity especially in young children with complex congenital heart disease is unknown. Assessment of the additional disease burden of obesity in this population requires additional study.

HLA sensitization increases risk of rejection and graft loss post-transplant. As more children are placed on mechanical circulatory support (MCS) as a bridge to transplant, the development of HLA sensitization needs further study. We determined the frequency and risk factors for HLA sensitization in children placed on MCS.

Recently the environmental regulations require automobile makers not only to set up the open loop resource recycling system by promoting the material recycling and remanufacturing in disposal phase, but also to apply Eco-design to their products in design phase. Hyundai Motor Group applies DfD(Design for Disassembly) and DfR(Design for Recycling) from conceptual design stage to production stage with the aspect of concurrent engineering. Eco-design guideline helps engineering designers to understand the necessity of Eco-design. The recyclability check sheets that include detailed design ideas classified by the polymer parts enable each designer to verify the product design by oneself. Furthermore, virtual recyclability inspection is performed in the digital product inspection stage which handles the virtual 3D modeling of products. All these activities became the official procedure in product development process. The DOROSY(Design for Recycling Optimizing SYstem) which is developed to help designers evaluate and modify their 3D design to generate the redesign alternatives and finally analyze the effect of environmental design change within a short time. Because DOROSY is based in CATIA which is familiar to engineering designers using the parametric designed template, engineering designer can apply the Eco-friendly idea to product design efficiently.

Surveillance endomyocardial biopsy (SEMB) is the accepted standard in monitoring for rejection following cardiac transplant. However, biopsy-reliant surveillance (BRS) remains costly and invasive. Our aim is to demonstrate that an echocardiographic predominant surveillance (EPS) protocol which utilizes fewer SEMBs can produce non-inferior outcomes in pediatric heart recipients.

To examine outcomes after infections in adolescents and young adults with continuous flow left ventricular assist devices (CF-LVAD) bridged to transplant (BTT). Our hypothesis was that patients with an infection have lower survival on VAD compared to those who remain without infection.

Purpose VerifyNow Aspirin assay (VN) assesses platelet response to ASA, with therapeutic effect defined as ≤ 549 aspirin reaction units (ARU). We aim to evaluate its clinical efficacy in children of all ages, by identifying biochemical resistance (> 549 ARU) and association with clinical thrombosis or bleeding. Methods Single-center, observational, analysis of 195 children (< 21 yo) who underwent first VN between 2015-2020 after receiving ≥ 1 enteral ASA dose. Primary outcome was proportion of these patients with ASA biochemical resistance. Secondary outcomes included incidence of new clinical thrombotic and bleeding events in 113 patients receiving ASA monotherapy for ≤ 1 year from VN. Patients receiving concomitant anticoagulation (n=61), dual antiplatelet therapy (n=7), had no follow-up (n=8), or had ASA held (n=6) were excluded from secondary outcome analysis. Results Of 195 patients, 56% were male and 53% were Caucasian. At time of VN, median age was 1.8 yrs (IQR 0.08 - 11.9), weight 10 kg (3.5 - 39.1), and BSA 0.47 m2 (0.23 - 1.25). Indications for ASA included single ventricle with shunt (36.4%), ischemic stroke (22.6%), Glenn/Fontan (9.7%), vascular disease (7.2%), valvular heart disease (6.7%), VAD (6.2%), coronary disease (2%), RV-PA conduit (3.1%), intracardiac thrombus (2%), ventricular dysfunction (1.5%), and other (2.6%). Median ASA dose before VN was 4.6 (2.6 - 5.8) mg/kg/day; 36% received 1 and 64% ≥ 2 doses. Mean VN was 471 ARU (±66). 14.4% (n=28) had VN > 549 ARU. There were no significant differences in age, weight, BSA, ASA dose, platelet count, hemoglobin, or hematocrit between patients with VN ≤ 549 vs > 549 ARU. Of 113 patients receiving ASA only, mean VN was 471 (±69). Over a median of 252 days (89 - 365), 14 (12.4%) had a thrombotic event after 9 days (3.5-118) and 9 (8%) had a bleeding event after 80 days (25-150) from VN. Mean VN was significantly higher at initial testing in thrombotic (516 ARU, p=0.03) but not bleeding groups (472 ARU, p=0.97). 20% of patients in thrombotic and 33% in bleeding groups had repeat VN performed, with results not significantly different from the group as a whole (482 ARU, p=0.45, and 461 ARU, p=0.39, respectively). Conclusion VN platelet function testing identifies biochemical resistance in 14.4% of children. Higher ARU at initial testing may be associated with thrombosis; in contrast, there was no association between ARU and bleeding. VerifyNow Aspirin assay (VN) assesses platelet response to ASA, with therapeutic effect defined as ≤ 549 aspirin reaction units (ARU). We aim to evaluate its clinical efficacy in children of all ages, by identifying biochemical resistance (> 549 ARU) and association with clinical thrombosis or bleeding. Single-center, observational, analysis of 195 children (< 21 yo) who underwent first VN between 2015-2020 after receiving ≥ 1 enteral ASA dose. Primary outcome was proportion of these patients with ASA biochemical resistance. Secondary outcomes included incidence of new clinical thrombotic and bleeding events in 113 patients receiving ASA monotherapy for ≤ 1 year from VN. Patients receiving concomitant anticoagulation (n=61), dual antiplatelet therapy (n=7), had no follow-up (n=8), or had ASA held (n=6) were excluded from secondary outcome analysis. Of 195 patients, 56% were male and 53% were Caucasian. At time of VN, median age was 1.8 yrs (IQR 0.08 - 11.9), weight 10 kg (3.5 - 39.1), and BSA 0.47 m2 (0.23 - 1.25). Indications for ASA included single ventricle with shunt (36.4%), ischemic stroke (22.6%), Glenn/Fontan (9.7%), vascular disease (7.2%), valvular heart disease (6.7%), VAD (6.2%), coronary disease (2%), RV-PA conduit (3.1%), intracardiac thrombus (2%), ventricular dysfunction (1.5%), and other (2.6%). Median ASA dose before VN was 4.6 (2.6 - 5.8) mg/kg/day; 36% received 1 and 64% ≥ 2 doses. Mean VN was 471 ARU (±66). 14.4% (n=28) had VN > 549 ARU. There were no significant differences in age, weight, BSA, ASA dose, platelet count, hemoglobin, or hematocrit between patients with VN ≤ 549 vs > 549 ARU. Of 113 patients receiving ASA only, mean VN was 471 (±69). Over a median of 252 days (89 - 365), 14 (12.4%) had a thrombotic event after 9 days (3.5-118) and 9 (8%) had a bleeding event after 80 days (25-150) from VN. Mean VN was significantly higher at initial testing in thrombotic (516 ARU, p=0.03) but not bleeding groups (472 ARU, p=0.97). 20% of patients in thrombotic and 33% in bleeding groups had repeat VN performed, with results not significantly different from the group as a whole (482 ARU, p=0.45, and 461 ARU, p=0.39, respectively). VN platelet function testing identifies biochemical resistance in 14.4% of children. Higher ARU at initial testing may be associated with thrombosis; in contrast, there was no association between ARU and bleeding.

Purpose The role of non-HLA antibodies, such as MICA and AT1R, in pediatric heart transplant (HTx) is not well delineated. While both may contribute to worse outcomes after HTx, regular surveillance monitoring and B-cell treatment is generally reserved for recipients with HLA-DSA. Methods Case report describing the development of non-HLA DSA in a patient who is s/p second HTx with concern for CAV in both allografts. Results We introduce a 16-yo male who received a HTx for familial DCM in 2007, at age 2yo. Prior to HTx he was mechanically supported with ECMO (10 dys) and a Berlin Heart (6 wks). PRA were negative and his retrospective cross match (XM) was invalid due to auto-reactivity. Immunosuppression (ISX) was maintained with tacrolimus and sirolimus. Three years (2010) after HTx de novo HLA-DSA (DQ8, DR53) were detected following a period of medical non-compliance; HLA-DSA gradually increased in strength to 20,000 MFI. While all surveillance biopsies since transplant remained without evidence of ACR or AMR, he required treatment for clinical rejection in 2011 (pulse steroids, IVIG) and 2015 (pulse steroids, ATG) and MMF was added to his ISX. He eventually developed micro-vascular CAV, presenting as heart block and diastolic dysfunction, and received a second HTx in 2016. His retrospective XM again showed autoreactivity; he had a negative virtual XM and never developed new HLA-DSA. A recent biopsy, prompted by mild diastolic dysfunction, revealed new endothelial swelling (ACR 1R, AMR 1H, C4D neg). Additional analysis showed high levels of donor-specific MICA, and AT1R antibodies; both remained high despite initiation of B-cell therapy (rituximab, bortezomib, IVIG). Further retrospective analysis revealed that the MICA antibodies were developed de novo against his first heart (targeting a common epitope present on both donors’ MICA) alongside the HLA-DSA, while AT1R antibodies were already present before his first HTx. Thus, MICA-DSA may have contributed to accelerated CAV in his first allograft, and cause endothelial swelling and AMR in his second allograft. This may have been further exacerbated by the ongoing presence of AT1R, though their role in our patient's clinical course remains less clear. Conclusion Non-HLA DSA can be injurious to cardiac allografts, and the presence of AMR or CAV without HLA-DSA warrants further evaluation for MICA-DSA and AT1R antibodies. The role of non-HLA antibodies, such as MICA and AT1R, in pediatric heart transplant (HTx) is not well delineated. While both may contribute to worse outcomes after HTx, regular surveillance monitoring and B-cell treatment is generally reserved for recipients with HLA-DSA. Case report describing the development of non-HLA DSA in a patient who is s/p second HTx with concern for CAV in both allografts. We introduce a 16-yo male who received a HTx for familial DCM in 2007, at age 2yo. Prior to HTx he was mechanically supported with ECMO (10 dys) and a Berlin Heart (6 wks). PRA were negative and his retrospective cross match (XM) was invalid due to auto-reactivity. Immunosuppression (ISX) was maintained with tacrolimus and sirolimus. Three years (2010) after HTx de novo HLA-DSA (DQ8, DR53) were detected following a period of medical non-compliance; HLA-DSA gradually increased in strength to 20,000 MFI. While all surveillance biopsies since transplant remained without evidence of ACR or AMR, he required treatment for clinical rejection in 2011 (pulse steroids, IVIG) and 2015 (pulse steroids, ATG) and MMF was added to his ISX. He eventually developed micro-vascular CAV, presenting as heart block and diastolic dysfunction, and received a second HTx in 2016. His retrospective XM again showed autoreactivity; he had a negative virtual XM and never developed new HLA-DSA. A recent biopsy, prompted by mild diastolic dysfunction, revealed new endothelial swelling (ACR 1R, AMR 1H, C4D neg). Additional analysis showed high levels of donor-specific MICA, and AT1R antibodies; both remained high despite initiation of B-cell therapy (rituximab, bortezomib, IVIG). Further retrospective analysis revealed that the MICA antibodies were developed de novo against his first heart (targeting a common epitope present on both donors’ MICA) alongside the HLA-DSA, while AT1R antibodies were already present before his first HTx. Thus, MICA-DSA may have contributed to accelerated CAV in his first allograft, and cause endothelial swelling and AMR in his second allograft. This may have been further exacerbated by the ongoing presence of AT1R, though their role in our patient's clinical course remains less clear. Non-HLA DSA can be injurious to cardiac allografts, and the presence of AMR or CAV without HLA-DSA warrants further evaluation for MICA-DSA and AT1R antibodies.

Calcineurin inhibitors (CNI) are the mainstay of immunosuppressive therapy after pediatric heart transplant. While clinical management centers around regular lab surveillance to ensure blood levels are within targeted range, the risk of rejection associated with the detection of subtherapeutic CNI levels has never been quantified.

Children admitted for heart failure has an increased risk of morbidity, mortality, and cost as previously reported. Angiotensin converting enzyme inhibitor (ACEI) is the mainstay of medical management. However, in the admitted patient, adverse effects such as hypotension, hyperkalemia, uremia, and worsening renal function can limit its use. The combination of isosorbide dinitrate/hydralazine (ISDN/HYD) is approved for use in heart failure in African Americans adults, but it has also been shown to be effective in the general adult heart failure population and is attractive in that it does not possess the laboratory side effect profile of ACEI. Given the lack of published reports of its use in children, we report our preliminary experience with ISDN/HYD.

No study has ever described the long-term outcomes of adult survivors of primary pediatric heart transplantation. We sought to describe their co-morbidities, outcomes, and risk factors.

Determine risk factors that predict poor outcomes including death, transplant, or readmission following initial hospitalization for acute decompensated heart failure (ADHF) in pediatric patients.

Appropriate mycophenolate mofetil (MMF) dosing and monitoring is challenging due to complex pharmacokinetics/dynamics with high intra- and inter-patient variability. Area under the curve (AUC) is the gold standard in measuring drug exposure and has been shown to be clinically meaningful in solid organ transplant recipients. We hypothesize trough (C0) levels do not accurately reflect drug exposure as measured by AUC in the pediatric heart transplant (HTx) population.

Purpose No single agent has been found to adequately treat AMR after heart transplant (HTx). Bortezomib, which can reduce donor-specific antibody (DSA) production by elimination of plasma cells, has been used as adjunctive AMR treatment in adults, but its use in pediatric HTx recipients has not been well described. Methods Single center retrospective review of 27 consecutive patients (<21yo) diagnosed with AMR and treated with bortezomib from 1/2011-10/2017. Clinical and immunogenic data were reviewed. Results Median age at HTx was 36 months (IQR 9-108) and time from HTx to AMR was 308 days (35-2231). Majority of cases (81.5%) had an underlying diagnosis of CHD. Diagnosis was by biopsy in 23 patients (11 pAMR1, 11 pAMR2, and 1 pAMR3), while 4 were based on clinical evidence. Echocardiogram showed systolic dysfunction in 8 (29.6%). All 27 patients had circulating DSAs at diagnosis. Each received at least 1 course of bortezomib (1.3 mg/m2 x4 doses), while 10 had 2 courses, and 2 had 3 courses. Other intensive treatments for AMR were also administered. DSA production decreased in patients receiving bortezomib, more noticeably for HLA-I than HLA-II, with partial rebound noted after treatment.(Figure). Follow-up biopsy (median 68 days [41-122] after diagnosis) showed resolution of AMR in 21 (78%). At median follow-up of 603 days (79-1400), graft survival was 63%; 2 required retransplant (1 directly attributed to AMR) and 8 died (4 directly attributed to AMR). Adverse events leading to discontinuation or adjustment of dosing included headache (2), thrombocytopenia (2), elevated transaminases (3), neuropathy (2), and flash pulmonary edema leading to ARDS/death (1). Conclusion Bortezomib can reduce DSA production and may be a viable adjunctive therapeutic option for AMR in pediatric HTx recipients. However, risk of adverse effects requires close monitoring, with early intervention to adjust or discontinue dosing. Further study is needed to determine the precise role of bortezomib in pediatric AMR. No single agent has been found to adequately treat AMR after heart transplant (HTx). Bortezomib, which can reduce donor-specific antibody (DSA) production by elimination of plasma cells, has been used as adjunctive AMR treatment in adults, but its use in pediatric HTx recipients has not been well described. Single center retrospective review of 27 consecutive patients (<21yo) diagnosed with AMR and treated with bortezomib from 1/2011-10/2017. Clinical and immunogenic data were reviewed. Median age at HTx was 36 months (IQR 9-108) and time from HTx to AMR was 308 days (35-2231). Majority of cases (81.5%) had an underlying diagnosis of CHD. Diagnosis was by biopsy in 23 patients (11 pAMR1, 11 pAMR2, and 1 pAMR3), while 4 were based on clinical evidence. Echocardiogram showed systolic dysfunction in 8 (29.6%). All 27 patients had circulating DSAs at diagnosis. Each received at least 1 course of bortezomib (1.3 mg/m2 x4 doses), while 10 had 2 courses, and 2 had 3 courses. Other intensive treatments for AMR were also administered. DSA production decreased in patients receiving bortezomib, more noticeably for HLA-I than HLA-II, with partial rebound noted after treatment.(Figure). Follow-up biopsy (median 68 days [41-122] after diagnosis) showed resolution of AMR in 21 (78%). At median follow-up of 603 days (79-1400), graft survival was 63%; 2 required retransplant (1 directly attributed to AMR) and 8 died (4 directly attributed to AMR). Adverse events leading to discontinuation or adjustment of dosing included headache (2), thrombocytopenia (2), elevated transaminases (3), neuropathy (2), and flash pulmonary edema leading to ARDS/death (1). Bortezomib can reduce DSA production and may be a viable adjunctive therapeutic option for AMR in pediatric HTx recipients. However, risk of adverse effects requires close monitoring, with early intervention to adjust or discontinue dosing. Further study is needed to determine the precise role of bortezomib in pediatric AMR.

Introduction: Plasma B-type natriuretic peptide (BNP) is a biomarker used to diagnose and monitor ventricular dysfunction and heart failure. However, the response of the allograft to produce BNP from ventricular wall stress and inflammation may be different, particularly in an understudied population such as pediatric recipients. Hypothesis: BNP levels decrease over time after transplant as the allograft recovers; but BNP will be higher during rejection. Methods: Enrolled all heart recipients from January 2007 to December 2016. Rejection surveillance included serial echocardiography, annual biopsy, and BNP q 1-3 months. Rejection is defined as requiring augmentation of immunosuppression from biopsy grade ≥ 2R or ≥ pAMR2 or from clinical diagnosis. Results: Among 114 patients studied, 60% were male with age at transplant 5.8 ± SD 6.5 yrs. Follow-up was 3.7 ± 2.7 yrs and 37 patients (32%) experienced 75 episodes of rejection. A total of 8358 BNP samples were obtained. BNP decreased linearly after transplant leveling off after 2 years (Fig 1). BNP was 671 ± 1115 (n=75) at rejection vs. 187 ± 423 pg/mL (n=501) without rejection confirmed by biopsy. By multivariable analysis, Ln BNP was associated with rejection (RR 1.56; 95% CI 1.35-1.80). Figure 2 shows the relationship between change in BNP and risk of rejection. Multivariable longitudinal Cox proportional model incorporating BNPs leading to 1 st rejection showed Ln BNP to be associated with rejection (HR 2.22; 95% CI 1.53-3.23, p&lt;0.001). Conclusion: BNP continues to decrease in the 1 st 2 years after transplant. At rejection, BNP is elevated, and this test can be further developed to screen for rejection.

Purpose Infants listed for heart transplant (HTx) are at high risk for waitlist (WL) mortality. While WL mortality for children has decreased overall in the current era of increased VAD use, outcomes for small infants supported by VAD remain suboptimal. We evaluated survival and morbidity in a cohort of critically ill infants listed for HTx and managed without VAD support. Methods Critically ill infants (defined as age Results Thirty-two critically ill infants were listed 1A for HTx during the study period, 66% with congenital heart disease. Mean age and weight at listing were 2.8 (±2) months and 4.4 (±1.3) kg, with the majority (69%) weighing 0.1). A favorable outcome was observed in 27 patients (84%) (26 HTx and 1 de-listed due to recovery of left ventricular function). Five patients (16%) died, including 3/5 patients supported with ECMO. Among patients who received a HTx, 24 (92%) survived to 1 year, with median post-HTx length of stay of 43 days. Two patients required tracheostomy post-HTx. Higher peak vasoactive-inotropic score (27 vs 16, p Conclusion A strategy incorporating a high threshold for mechanical circulatory support and acceptance of prolonged mechanical ventilation and neuromuscular blockade can achieve good short-term survival and morbidity outcomes for critically ill infants listed for HTx.

Purpose Renal dysfunction is a common complication of heart transplantation (HTx) in children that affects overall outcome. Proteinuria reflects renal glomerular and tubular damage and is an early marker of renal dysfunction, even when excreted in small amounts, termed microalbuminuria. The prevalence of microalbuminuria in pediatric HTx has not been previously described. We report the prevalence of proteinuria as measured by microabuminuria to creatinine ratio (UACR) and its associated risk factors in pediatric HTx recipients. Methods Since 2015, UACR is collected annually at rejection surveillance catheterization. Patients aged Results 116 patients were identified, of whom 51 (44%) were female and 68 (58%) Caucasian. Mean age at HTx was 5.4 ± 6.2 years. Ninety-two (79%) were listed status 1A, and 74 (64%) had congenital heart disease. Perioperative therapies included mechanical circulatory support in 23 (20%), dialysis in 4 (3%), mechanical ventilation in 34 (29%). No patients had insulin dependent diabetes pre-HTx and 2 (2%) developed diabetes in the first year post-HTx. Mean pre-HTx eGFR was 99 ± 35.5 ml/min/1.73m2. At a latest follow-up of 5.8 ± 3.8 years, 7 (6%) patients developed diabetes, 42% (n=35) had an abnormal UACR (≥ 31 units). Mean UACR was 85 ± 182.5 and 25% had eGFR Conclusion Microalbuminuria as a marker of renal injury is a highly prevalent finding in medium-term follow up of pediatric HTx. Post-Htx dialysis and diabetes is a risk factor for developing microalbuminuria and younger age at transplant may be protective. These observations may have implications on early identification of chronic renal disease and its medical intervention.

Introduction: While CMV infection has been associated with graft loss in adult heart transplants, its role in children is less understood. We aim to better understand the effect of donor and recipient CMV immune status at transplant on survival in pediatric recipients. Methods: We analyzed 6,951 pediatric heart-only transplants in the Scientific Registry of Transplant Recipients (1987-2019). Patients were stratified by recipient and donor CMV status at transplant. The primary endpoint was freedom from graft loss. Results: Of the various donor and recipient CMV statuses, only CMV-positive recipients had decreased graft survival compared to CMV-negative ones (at 15-yrs: 47% vs. 53%, HR 1.14). However, when fully adjusted by Cox regression, recipient status was no longer a risk factor ( p = 0.12). In this model, anti-CMV treatment with ganciclovir or valganciclovir was associated with a lower risk of graft loss (HR 0.80, CI 0.71 - 0.90, p &lt; 0.005). When stratified by the four donor-recipient CMV status combinations, antiviral use was associated with improved survival in both donor-positive groups: most strongly in donor-positive/recipient-positive transplants (at 15-yrs: 51% vs. 39%, p &lt; 0.005) and to a lesser extent in donor-positive/recipient-negative transplants (at 15-yrs: 53% vs. 51%, p &lt; 0.005). The association is maintained when examined by era, such as with more frequent use of anti-CMV therapy after 1995. No association with antiviral use was observed in either donor-negative transplant group. Conclusion: CMV-positive recipients had greater long-term graft loss, although this may be confounded by other transplant characteristics. Anti-CMV therapy is associated with improved long-term graft survival in transplants with CMV-positive donors. This finding may explain the lack of association between donor CMV status and graft loss in that an association may be masked by antiviral use. Further investigation of anti-CMV therapy may mitigate risk of graft loss.

Introduction: Iron deficiency (FeD) is common in adults with heart failure and is associated with worse outcomes. Parenteral iron therapy improves outcomes in this population, but this has not been described in the pediatric population. Methods: We conducted a prospective observational cohort study of heart failure patients with FeD, defined as ferritin &lt;100 ng/mL or ferritin = 100-300 with iron saturation &lt;20%, who received parenteral iron sucrose between 01/2007-12/2019. Iron dosing and frequency were based on initial and subsequent iron profiles using a standard replacement protocol. Monthly follow-up lab and clinical data up to 6 months were obtained and analyzed to characterize the effect on iron biomarkers and association with clinical outcomes (B-type natriuretic peptide (BNP), death, transplant, and mechanical circulatory support). Results: Among 61 patients who received parenteral iron therapy, 49% were male, with a median age of 23 months (IQR 7 - 117). 30 (49%) had primary cardiomyopathy; 31 (51%) had congenital heart disease with systolic dysfunction, 14 (45%) of which with cyanotic disease. 56 (92%) of the patients had a follow-up iron profile at timepoint 1 (TP 1) at a mean of 24 SD + 9 days. The interval between the 1st dose of iron and last follow-up (TP Last) was 61 + 50 days. The cumulative number of iron doses received was 3.5 + 1.5 at TP 1 and 4.1 + 2.4 at TP Last. Figure 1 shows the trend in iron biomarkers and BNP. There was a statistically significant increase in ferritin, iron saturation and serum iron levels, as well as a decrease in BNP over time. Clinical outcomes were examined by multivariable analysis. Only an increase in ferritin was associated with a decrease in BNP (p=0.012). Conclusions: Parenteral iron therapy for FeD under a standard protocol led to improvement in iron biomarkers in children with heart failure. Our study was limited by a small sample size and further study to assess clinical outcomes specifically related to iron therapy is warranted.

12073 Background: The direct impact of a major cardiovascular (CV) event on mortality among childhood cancer survivors is not well described. We hypothesized that mortality following a major CV event would be higher among survivors compared with siblings and that mortality would be influenced by primary cancer treatment. Methods: The CCSS cohort has conducted longitudinal follow-up of 25,658 survivors of childhood cancer and 5,051 siblings. All-cause and CV-cause specific mortality after a first event of heart failure (HF), coronary artery disease (CAD), or stroke occurring at least 5 years after cancer diagnosis, was estimated using the Kaplan-Meier method. The relative hazards (HR) and 95% confidence intervals (CI) between survivors and siblings as well as the influence of demographic (sex, age, race/ethnicity) and cancer treatment factors were estimated via Cox regression. Results: In total, 1780 survivors and 91 siblings experienced a serious CV event. Total deaths included 706 survivors (271 cardiac causes, 381 non-cardiac causes, 54 unknown causes) and 14 siblings. Survivors were a median age of 31.5 years (range 6.5-61.5) and 20.0 years (range 5.0-44.6) since cancer diagnosis at time of CV event. After a CV event, estimated 10- and 20-y all-cause mortality was significantly higher among survivors than siblings (Table). The HR for all-cause mortality was significantly higher among survivors than siblings after HF (HR 5.2, CI 2.1-13.0), CAD (HR 4.2, CI 2.0-9.0), and stroke (HR 4.6, CI 1.5-14.6). HF and stroke-specific mortality were not significantly increased among survivors versus siblings, in contrast to CAD-specific mortality (HR 3.5, CI 1.1-11.0). Among survivors, heart dose from radiotherapy (per 10 Gy) was associated with increased all-cause and cause-specific mortality after HF (HR 1.2, CI 1.0-1.3; HR 1.3, CI 1.0-1.7), all-cause mortality after CAD (HR 1.2, CI 1.0-1.3), and cause-specific mortality after stroke (HR 2.5, CI 1.2-4.9). Brain dose from radiotherapy was associated with increased all-cause mortality (HR 1.1, CI, 1.0-1.2, per 10 Gy) after stroke. Anthracycline dose was not associated with increased overall or cause-specific mortality risk after a CV event. Conclusions: After a CV event, mortality is higher among survivors than siblings. In survivors, mortality is primarily driven by non-cardiac causes. CAD and prior radiotherapy exposure to the heart and brain also influenced mortality.[Table: see text]