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Dapagliflozin has been associated with euglycemic ketoacidosis in adults with diabetes contributing to poor outcomes when continued prior to surgery. It is unknown if preoperative use of dapagliflozin may lead to adverse events (AE) in nondiabetic children with advanced heart failure (HF) undergoing heart transplantation (HTx). We performed a single-center, matched case-control analysis of nondiabetic primary pediatric HTx recipients < 21 years-old who underwent HTx and followed through postoperative day (POD) 3. Cases who received dapagliflozin leading up to HTx (n = 22) were matched by age and cardiac diagnosis to two historical controls who did not receive dapagliflozin (n = 44). Median age at HTx was 13.8 years (range 0.36-20.7) and 48% were female. Cardiac diagnoses included cardiomyopathy (45%), Fontan failure (41%), and single ventricle status post stage I palliation (14%). Cases received median dapagliflozin dose of 0.17 mg/kg once daily; therapy was stopped one day prior to HTx. There were no significant differences in blood glucose nadirs, arterial blood gas indices including nadirs of pH, bicarbonate, or peaks of arterial blood lactic acid POD0-3. Vasopressor, inotrope, and insulin infusion usage were not different. No patients were treated for severe hypoglycemia, euglycemic ketoacidosis, or urinary tract infections. There were no deaths. Length of stay in ICU and time from HTx to hospital discharge did not differ between cohorts. Use of dapagliflozin in children with advanced HF until HTx is not associated with AE in the immediate postoperative period nor increased length of hospitalization post-HTx. Potential cardiovascular benefits of dapagliflozin in patients awaiting HTx should be prioritized., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The prevalence of iron deficiency and anemia in the setting of modern-day maintenance immunosuppression in pediatric heart transplant (HTx) recipients is unclear. The primary aim was to determine the prevalence of iron deficiency (serum ferritin < 30 ng/mL ± transferrin saturation < 20%) and anemia per World Health Organization diagnostic criteria and associated risk factors., Methods: Single-center, cross-sectional analysis of 200 consecutive pediatric HTx recipients (<21 years old) from 2005 to 2021. Data were collected at 1-year post-HTx at the time of annual protocol biopsy., Results: Median age at transplant was 3 years (IQR .5-12.2). The median ferritin level was 32 ng/mL with 46% having ferritin < 30 ng/mL. Median transferrin saturation (TSAT) was 22% with 47% having TSAT < 20%. Median hemoglobin was 11 g/dL with 54% having anemia. Multivariable analysis revealed lower absolute lymphocyte count, TSAT < 20%, and estimated glomerular filtration rate <75 mL/min/1.73 m 2 were independently associated with anemia. Ferritin < 30 ng/mL in isolation was not associated with anemia. Ferritin < 30 ng/mL may aid in detecting absolute iron deficiency while TSAT < 20% may be useful in identifying patients with functional iron deficiency ± anemia in pediatric HTx recipients., Conclusion: Iron deficiency and anemia are highly prevalent in pediatric HTx recipients. Future studies are needed to assess the impact of iron deficiency, whether with or without anemia, on clinical outcomes in pediatric HTx recipients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Therapies to support small infants in decompensated heart failure that are failing medical management are limited. We have used the hybrid approach, classically reserved for high-risk infants with single ventricle physiology, in patients with biventricular physiology with left ventricular failure. This approach secures systemic circulation, relieves left atrial hypertension, protects the pulmonary vasculature, and allows the right ventricle to support cardiac output. This approach can be used as a bridge to transplantation in select individuals. Infants without single ventricle congenital heart disease who were treated with the hybrid approach between 2008 and 2021 were included in analysis. Eight patients were identified. At the time of hybrid procedure, the median weight was 3.2 kg (range 2.4-3.6 kg) and the median age was 18 days (range 1-153 days). Seventy five percent were mechanically ventilated and 88% were on inotropic support. The median duration from hybrid procedure to transplant was 63 days (range 4-116 days). All patients experienced a good outcome (delisted for improvement or transplanted). The hybrid procedure is an appropriate therapeutic bridge to transplantation in a carefully selected subset of critically ill infants without single ventricle congenital heart disease in whom alternate therapies may confer increased risk for morbidity and mortality., (© 2023. The Author(s).)

Introduction: Previous reports demonstrate racial/ethnic differences in survival for children hospitalized with cardiomyopathy and myocarditis. The impact of illness severity, a potential mechanism for disparities, has not been explored., Methods: Using the Virtual Pediatric Systems (VPS, LLC), we identified patients ≤ 18 years old admitted to the intensive care unit (ICU) for cardiomyopathy/myocarditis. Multivariate regression models were used to evaluate the association between race/ethnicity and Pediatric Risk of Mortality (PRISM 3). Multivariate logistic and competing risk regression was used to examine the relationship between race/ethnicity and mortality, CPR, and ECMO., Results: Black patients had higher PRISM 3 scores on first admission (𝛽 = 2.02, 95% CI: 0.15, 3.90). There was no difference in survival across race/ethnicity over multiple hospitalizations. Black patients were less likely to receive a heart transplant (SHR = 0.65, 95% CI: 0.45-0.92). Black and unreported race/ethnicity had higher odds of CPR on first admission (OR = 1.64, 95% CI: 1.01-2.45; OR = 2.12, 95% CI: 1.11-4.08, respectively)., Conclusion: Black patients have higher severity of illness on first admission to the ICU, which may reflect differences in access to care. Black patients are less likely to receive a heart transplant. Additionally, Black patients and those with unreported race/ethnicity had higher odds of CPR, which was not mediated by severity of illness, suggesting variations in care may persist after admission., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: 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., Methods: Single-center, observational analysis of 135 de novo pediatric HTx recipients ≤21 years old who underwent MPA AUC between 2011 and 2021., Results: 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 AUC 0-24 h (r = .3 and .383, respectively). MPA C0 had weak association (r = .451) with Trapezoidal MPA AUC 0-24 h . LSS with two pharmacokinetic sampling time points at 90 (C 3 ) and 360 (C 5 ) min after MMF administration (estimated AUC 0-24 h  = 32.82 + 4.12 × C 3  + 11.53 × C 5 ) showed strong correlation with Trapezoidal MPA AUC 0-24 h (r = .87)., Conclusion: MMF at fixed or weight-adjusted doses, as well as MPA trough levels, correlate poorly with MPA AUC 0-24 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., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Literature is limited comparing adverse effects (AEs) of the proliferation signal inhibitors (PSIs) sirolimus (SRL) and everolimus (EVL) in pediatric heart transplant (HTx) recipients., Methods: 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., Results: 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., Conclusion: 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., (© 2023 Wiley Periodicals LLC.)

Background: Fontan associated liver disease (FALD) potentially impacts Fontan patients undergoing heart transplant. This multi-center study sought to identify pre-transplant risk factors and characterize any post-transplant liver recovery in those patients undergoing heart-alone transplant., Methods: Review of Fontan patients at 12 pediatric institutions who underwent heart transplant between 2001-2019. Radiologists reviewed pre and post-transplant liver imaging for fibrosis. Laboratory, pathology and endoscopy studies were reviewed., Results: 156 patients underwent transplant due to decreased ventricular function (49%), protein losing enteropathy (31%) or plastic bronchitis (10%); median age at transplant was 13.6 years (interquartile range IQR 7.8, 17.2) with a median of 9.3 years (IQR 3.2, 13.4) between the Fontan operation and transplant. Few patients had pre-transplant endoscopy (18%), and liver biopsy (19%). There were 31 deaths (20%). The median time from transplant to death was 0.5 years (95% Confidence Interval CI 0.0, 3.6). The five-year survival was 73% (95% CI 64%, 83%). Deaths were related to cardiac causes in 68% (21/31) and infection in 6 (19%). A pre-transplant elevation in bilirubin was a predictor of death. Higher platelet levels were protective. Immediate post-transplant elevations in creatinine, AST, ALT, and INR were predictive of death. Advanced liver fibrosis identified on ultrasound, computed tomography, or magnetic resonance imaging was not predictive of death. Liver imaging suggested some improvement in liver congestion post-transplant., Conclusions: Elevated bilirubin, but not fibrosis on liver imaging, was associated with post-heart transplant mortality in Fontan patients in this multicenter retrospective study. Additionally, heart transplant may alter the progression of FALD., (© 2022 Wiley Periodicals LLC.)

Individuals with Fontan circulation are at risk of late mortality from both cardiac and noncardiac causes. Despite the known risk of mortality, referral indications for advanced heart failure care vary between centers, and many individuals die from Fontan circulation-related complications either after late consideration for advanced heart failure therapies or having never seen a heart failure specialist. There is a critical need for guidelines to direct appropriately timed referral for advanced heart failure consultation. The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) Fontan Committee has developed recommended thresholds for advanced heart failure referral to guide primary cardiologists. These recommendations are divided into 4 categories of clinical Fontan circulatory dysfunction including (1) cardiac/systemic ventricular dysfunction, (2) Fontan pathway dysfunction, (3) lymphatic dysfunction, and (4) extracardiac dysfunction.

Objectives: Activated partial thromboplastin time (aPTT) is the primary test used to monitor intravenous (IV) direct thrombin inhibitors (DTIs) but has many limitations. The plasma diluted thrombin time (dTT) has shown better correlation with DTI levels than aPTT. This study compared dose-response curves for dTT and aPTT in pediatric patients receiving argatroban and bivalirudin., Methods: A retrospective review of pediatric patients treated with argatroban (n = 45) or bivalirudin (n = 14) monitored with dTT and aPTT., Results: The dTT assay was calibrated to report DTI concentrations in µg/mL for argatroban and bivalirudin with good analytic sensitivity and specificity. The dTT was fivefold more likely to show a stable dose-response slope than the aPTT (P < .0002; odds ratio, 4.9). For patients in whom both dTT and aPTT showed a significant correlation between dose and assay results, dTT had a higher average correlation factor compared with aPTT (P = .007). Argatroban dose-response slopes showed more inter- and intrapatient variation than bivalirudin (dose-response slope coefficient of variation, 132% vs 52%)., Conclusions: The dTT assay was more likely to show a stable dose response and have a stronger correlation with DTI dose than aPTT. Argatroban shows more variation in dose response than bivalirudin., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pediatric heart failure (HF) is associated with significant morbidity and mortality. Medical treatment for pediatric HF is largely derived from adult studies. Previously, there has been no described use of dapagliflozin in pediatric HF patients. We describe our single-center experience using dapagliflozin in addition to standard HF medical therapy in 38 pediatric HF patients since January 2020. Median age was 12.2 years (interquartile range 6.2-17.5). Majority of patients had dilated cardiomyopathy (68.4%) and reduced left ventricular ejection fraction (LVEF) of 40% or less (65.8%). HF regimens commonly included sacubitril/valsartan, beta-blocker, mineralocorticoid receptor antagonist, and loop diuretic. Median follow-up from dapagliflozin initiation for the whole cohort was 130 days (IQR 76-332). Median B-type natriuretic peptide decreased significantly from 222 to 166 pg/mL at latest clinical follow-up (P = .04). Estimated glomerular filtration rate trended lower at latest follow-up but was not significant from baseline. There were no clinically significant changes in blood chemistries or vital signs after initiation of dapagliflozin. No patients experienced symptomatic hypoglycemia or hypovolemia. Six patients (15.8%) experienced a symptomatic urinary tract infection necessitating antibiotic treatment. In a separate analysis of 16 patients with dilated cardiomyopathy who received dapagliflozin for a median of 313 days (IQR 191-414), median LVEF increased significantly from 32 to 37.2% (P = .006). Dapagliflozin, when added to a background of guideline-directed medical therapy, appears well tolerated in children with HF. Larger studies are needed to evaluate safety and efficacy of dapagliflozin in this population., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: 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., Methods: 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., Results: 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/1.73m 2 , p = .001)., Conclusion: 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., (© 2022 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

The field of pediatric ventricular assist device (VAD) support has expanded significantly over the past 20 years, with one third of pediatric heart transplant recipients currently being bridged to transplant with a VAD. Despite increased pediatric VAD utilization, however, there remains little formalized guidance for patient or device selection. The population of children with advanced heart failure is quite heterogeneous, and the available data suggest that VAD outcomes vary significantly based upon patient size, anatomy, level of illness, and type of device implanted. In an effort to better understand current practice patterns and identify populations for whom there does not appear to be a consensus approach to achieving optimal VAD outcomes, the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) has surveyed clinical decision-making among member sites and conducted a review of the available literature regarding patient population-specific VAD outcomes and center-specific practices related to patient and device selection. Rather than aiming to provide clinical guidelines, this document offers an overview of contemporary approaches to patient and device selection, highlighting specific populations for whom there is not a consensus approach to achieving reliably good VAD outcomes, as these populations may benefit most from future research and quality improvement efforts directed toward identifying best practice., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abnormal dystrophin production due to mutations in the dystrophin gene causes Duchenne Muscular Dystrophy (DMD). Cases demonstrate considerable genetic and disease progression variability. It is unclear if specific gene mutations are prognostic of outcomes in this population. We conducted a retrospective cohort study of DMD patients followed at 17 centers across the USA and Canada from 2005 to 2015 with goal of understanding the genetic variability of DMD and its impact on clinical outcomes. Cumulative incidence of clinically relevant outcomes was stratified by genetic mutation type, exon mutation location, and extent of exon deletion. Of 436 males with DMD, 324 (74.3%) underwent genetic testing. Deletions were the most common mutation type (256, 79%), followed by point mutations (45, 13.9%) and duplications (23, 7.1%). There were 131 combinations of mutations with most mutations located along exons 45 to 52. The number of exons deleted varied between 1 and 52 with a median of 3 exons deleted (IQR 1-6). Subjects with mutations starting at exon positions 40-54 had a later onset of arrhythmias occurring at median age 25 years (95% CI 18-∞), p = 0.01. Loss of ambulation occurred later at median age of 13 years (95% CI 12-15) in subjects with mutations that started between exons 55-79, p = 0.01. There was no association between mutation type or location and onset of cardiac dysfunction. We report the genetic variability in DMD and its association with timing of clinical outcomes. Genetic modifiers may explain some phenotypic variability., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2021 Wiley Periodicals LLC.)

Fontan palliation has improved survival for single ventricle patients, but long-term complications persist including cardiovascular dysfunction, neurohormonal abnormalities, and protein-losing enteropathy (PLE). Although chronic inflammation contributes to morbidity, an association between inflammation and vascular dysfunction has not been studied. We assessed inflammation and vascular function in 31 Fontan-palliated patients (52% male, median age 14.3 years), including 10 PLE+. Fontan circulation was associated with altered inflammatory cytokines (TNF-α: mean 2.5 ± 1.4 vs. 0.7 ± 0.2 pg/ml, p < 0.0001; sTNFR2: 371 ± 108 vs. 2694 ± 884 pg/ml, p < 0.0001) and vascular dysfunction [log-transformed reactive hyperemia index (lnRHI) 0.28 ± 0.19 vs. 0.47 ± 0.26, p < 0.01; augmentation index (AI) -2.9 ± 13.8 vs. -16.3 ± 12.0, p = 0.001; circulating endothelial progenitor cells (cEPCs) 5.0 ± 8.1 vs. 22.8 ± 15.9, p = 0.0002)]. Furthermore, PLE+ patients showed greater inflammation (IFN-γ 6.3 ± 2.2 vs. 11.5 ± 7.9 pg/ml, p = 0.01; sTNFR1: 1181 ± 420 vs. 771 ± 350 pg/ml, p = 0.01) and decreased arterial compliance (AI: 5.4 ± 17.1 vs. -6.8 ± 10.2, p = 0.02) than PLE- patients. Circulating EPCs, but not inflammatory cytokines, were inversely associated with arterial stiffness in Fontan patients. In conclusion, chronic inflammation and vascular dysfunction are observed after Fontan operation, with greater inflammation and arterial stiffness in Fontan patients with active PLE. However, there is no clear association between inflammatory cytokines and vascular dysfunction, suggesting these pathophysiologic processes are not mechanistically linked., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Right heart failure (RHF) is a vexing problem in children after left ventricular assist device (LVAD) implantation that can negatively impact transplant candidacy and survival. Anticipation, prevention, early identification and appropriate medical and device management of RHF are important to successful LVAD outcomes. However, there is limited pediatric evidence to guide practice. This pediatric-focused review summarizes the relevant literature and describes the harmonized approach to RHF from the Advanced Cardiac Therapies Improving Outcomes Network (ACTION). This review seeks to improve RHF outcomes through the sharing of best practices and experience across the pediatric VAD community., (© 2021 Wiley Periodicals LLC.)

Background: Inclusion of BMI as criterion in the determination of heart transplant candidacy in children is a clinical and ethical challenge. Childhood obesity is increasing and children with heart disease are not spared. Currently, many adult heart transplant centers consider class II obesity and higher (BMI > 35 kg/m 2 ) to be a relative contraindication for transplantation due to risk of poor outcome after transplant. No national guidelines exist regarding consideration of BMI in pediatric heart transplant and outcomes data are limited. This leaves decisions about transplant candidacy in obese pediatric patients to individual institutions or on a case-by-case basis, allowing for bias and inequity., Methods: We review (a) the prevalence of childhood obesity, including among heart transplant candidates, (b) the lack of existing BMI guidelines, and (c) relevant literature on BMI and pediatric heart transplant outcomes. We discuss the ethical considerations of using obesity as a criterion using the principles of utility, justice, and respect for persons., Results: Existing transplant outcomes data do not show that obese children have different or poor enough outcomes compared to non-obese children to warrant exclusion. Moreover, obesity in the United States is unequally distributed by race and socioeconomic status. Children already suffering from health disparities are therefore doubly penalized if obesity denies them access to life-saving transplant., Conclusion: Insufficient data exist to support using any BMI cutoff as an absolute contraindication for heart transplant in children. Attention should be paid to health equity issues when considering excluding a patient for transplant based on obesity., (© 2020 Wiley Periodicals LLC.)

Duchenne muscular dystrophy (DMD) is characterized by myocardial fibrosis and left ventricular (LV) dysfunction. Implantable cardioverter defibrillator (ICD) use has not been characterized in this population but is considered for symptomatic patients with severe LV dysfunction (SLVD) receiving guideline-directed medical therapy (GDMT). We evaluated ICD utilization and efficacy in patients with DMD. Retrospective cohort study of DMD patients from 17 centers across North America between January 2, 2005 and December 31, 2015. ICD use and its effect on survival were evaluated in patients with SLVD defined as ejection fraction (EF) < 35% and/ or shortening fraction (SF) < 16% on final echocardiogram. SLVD was present in 57/436 (13.1%) patients, of which 12 (21.1%) died during the study period. Of these 12, (mean EF 20.9 ± 6.2% and SF 13.7 ± 7.2%), 8 received GDMT, 5 received steroids, and none received an ICD. ICDs were placed in 9/57 (15.8%) patients with SLVD (mean EF 31.2 ± 8.5% and SF 10.3 ± 4.9%) at a mean age of 20.4 ± 6.3 years; 8/9 received GDMT, 7 received steroids, and all were alive at study end; mean ICD duration was 36.1 ± 26.2 months. Nine ICDs were implanted at six different institutions, associated with two appropriate shocks for ventricular tachycardia in two patients, no inappropriate shocks, and one lead fracture. ICD use may be associated with improved survival and minimal complications in DMD cardiomyopathy with SLVD. However, inconsistent GDMT utilization may be a significant confounder. Future studies should define optimal indications for ICD implantation in patients with DMD cardiomyopathy.

As survival and neuromuscular function in Duchenne muscular dystrophy (DMD) have improved with glucocorticoid (GC) therapy and ventilatory support, cardiac deaths are increasing. Little is known about risk factors for cardiac and non-cardiac causes of death in DMD. A multi-center retrospective cohort study of 408 males with DMD, followed from January 1, 2005 to December 31, 2015, was conducted to identify risk factors for death. Those dying of cardiac causes were compared to those dying of non-cardiac causes and to those alive at study end. There were 29 (7.1%) deaths at a median age of 19.5 (IQR: 16.9-24.6) years; 8 (27.6%) cardiac, and 21 non-cardiac. Those living were younger [14.9 (IQR: 11.0-19.1) years] than those dying of cardiac [18 (IQR 15.5-24) years, p = 0.03] and non-cardiac [19 (IQR: 16.5-23) years, p = 0.002] causes. GC use was lower for those dying of cardiac causes compared to those living [2/8 (25%) vs. 304/378 (80.4%), p = 0.001]. Last ejection fraction prior to death/study end was lower for those dying of cardiac causes compared to those living (37.5% ± 12.8 vs. 54.5% ± 10.8, p = 0.01) but not compared to those dying of non-cardiac causes (37.5% ± 12.8 vs. 41.2% ± 19.3, p = 0.58). In a large DMD cohort, approximately 30% of deaths were cardiac. Lack of GC use was associated with cardiac causes of death, while systolic dysfunction was associated with death from any cause. Further work is needed to ensure guideline adherence and to define optimal management of systolic dysfunction in males with DMD with hopes of extending survival.

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 >1 year after HTx. Subtherapeutic CNI levels were defined as <50% of the lower limit of target range. The risk of acute, late (>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 = <.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 >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., (© 2019 Wiley Periodicals, Inc.)

Background: As survival and neuromuscular function in Duchenne Muscular Dystrophy (DMD) improve with glucocorticoid therapy and respiratory advances, the proportion of cardiac deaths is increasing. Little is known about the use and outcomes of advanced heart failure (HF) therapies in this population., Methods: A retrospective cohort study of 436 males with DMD was performed, from January 1, 2005-January 1, 2018, with the primary outcome being use of advanced HF therapies including: implantable cardioverter defibrillator (ICD), left ventricular assist device (LVAD), and heart transplantation (HTX)., Results: Nine subjects had an ICD placed, 2 of whom (22.2%) had appropriate shocks for ventricular tachycardia; 1 and 968 days after implant, and all of whom were alive at last follow-up; median 18 (IQR: 12.5-25.5) months from implant. Four subjects had a LVAD implanted with post-LVAD survival of 75% at 1 year; 2 remaining on support and 1 undergoing HTX. One subject was bridged to HTX with ICD and LVAD and was alive at last follow-up, 53 months after HTX., Conclusion: Advanced HF therapies may be used effectively in select subjects with DMD. Further studies are needed to better understand risk stratification for ICD use and optimal candidacy for LVAD implantation and HTX, with hopes of improving cardiac outcomes., Competing Interests: Declaration of interest Carol A. Wittlieb-Weber, MD: None. Chet R. Villa, MD: None. Matthew J. Bock, MD: None. Katheryn E. Gambetta, MD: None. Jonathan N. Johnson, MD: None. Ashwin K. Lal, MD: None. Kurt R. Schumacher, MD: None. Sabrina P. Law, MD: None. Shriprasad R. Deshpande, MD, MS: None. Shawn C. West, MD, MSc: None. Joshua M. Friedland-Little, MD: None. Irene D. Lytrivi, MD: None. Michael A. McCulloch, MD: None. Ryan J. Butts, MD: None. David R. Weber, MD, MSCE: Consulted for Marathon Pharmaceuticals. Kenneth R. Knecht, MD: None.

Post-transplant lymphoproliferative disorder (PTLD) is a significant complication after pediatric heart transplantation (HT), occurring in 5%-15% of patients within 3 years. Data >3 years from HT are limited. We sought to describe the prevalence, risk factors, and outcomes of PTLD occurring late (>3 years) after pediatric HT in the Pediatric Heart Transplant Study from 1993 to 2010. Among 3844 primary HT patients, 110 (3%) developed late, nonrecurrent PTLD. The hazard rate for late PTLD was constant at 0.01 events/year out to 20 years after HT. Risk factors for late PTLD were younger age at HT (HR 1.06, P = 0.003) and Epstein-Barr virus (EBV) naivety (HR 1.65, P = 0.02). Survival after late PTLD was 86% and 68% at 1 and 5 years, with nonwhite race (HR 2.27, P = 0.03) and earlier year of HT (HR 1.03, P = 0.04) independently associated with mortality. Acute rejection and infection were both common after late PTLD, occurring in 26% and 34% of patients. The constant late hazard and contribution of EBV to late PTLD suggest that vigilance for development of PTLD, including for EBV conversion, should persist indefinitely after pediatric HT. The reasons for elevated risk of death for nonwhites after late PTLD are unclear and warrant further investigation., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: 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., Methods: 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., Results: Data from 247 patients from 39 centers were analyzed. Baseline RD (estimated glomerular filtration rate [eGFR] <90 ml/min/1.73 m 2 ) 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., Conclusions: 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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

PH is a risk factor for GL after HTx. However, traditional parameters are not reliable predictors of risk in children. We hypothesized that DPI (dPAP and DPG) are predictive of GL in pediatric HTx recipients. The UNOS/SRTR database was reviewed to identify pediatric HTx recipients (age <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 HTx recipients. Our findings suggest that DPI should be considered as part of routine hemodynamic assessment for pediatric HTx candidates., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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 < .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., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Prolonged graft ischemia may be a risk factor for early rejection post-HTx, but this has not been well studied in children. Furthermore, factors moderating the association between IT and early rejection have not been investigated. From 2004 to 2012, pediatric HTx recipients (n = 2381) were identified from the UNOS database. A ROC curve determined the optimal IT discriminating patients by the presence of early rejection. Separate univariate analyses identified factors associated with: (i) early (prior to hospital discharge) rejection, and (ii) IT. A multivariable logistic regression assessed independent risk factors for early rejection. We included interaction terms to evaluate whether IT's independent risk effect on early rejection is moderated via interaction with associated factors found in univariate analysis. Longer IT was associated with an increased risk of early rejection. In multivariable analysis, IT > 3.1 hours was an independent risk factor for early rejection (AOR 1.44, P = .01). No interaction terms between IT and any associated factors were significant. Longer IT is an independent risk for early rejection in pediatric HTx recipients. Better understanding the association between IT and early rejection may identify interventions to mitigate this risk., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

While VAD use in pediatric patients has previously been associated with anti-HLA antibody production, the clinical significance of these antibodies is unclear. We investigated the clinical impact of anti-HLA antibodies associated with VAD use in a large cohort of pediatric HTx recipients. From 2004 to 2011, pediatric cardiomyopathy patients post-HTx (N=1288) with pre-HTx PRA levels were identified from the United Network for Organ Sharing database. PRA levels were compared between VAD patients and those with no history of MCS. Incidence of rejection and overall survival were compared between VAD and non-MCS groups after stratification by PRA and age. VAD recipients were more likely to produce anti-HLA antibodies than non-MCS patients (25.5% vs 10.5% had PRA>10%, P<.0001). Sensitized VAD patients (PRA>10%) had a higher incidence of rejection within 15 months of HTx compared to sensitized non-MCS patients (57.1% vs 35.9%, P=.02). There was no intergroup difference in 15-month mortality. Among pediatric cardiomyopathy patients supported with a VAD, the presence of anti-HLA antibodies prior to HTx is associated with an increased risk of rejection. The mechanism of the association between VAD-associated antibodies and early rejection is unclear and warrants further investigation., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Infants who require extracorporeal membrane oxygenation (ECMO) support after a Norwood operation are at increased risk for early and late death compared with patients who do not require ECMO post-Norwood. Little is known about the effect that ECMO post-Norwood has on functional status and quality of life among long-term survivors., Methods: We prospectively evaluated functional status and health-related quality of life in 12 surviving patients (cases) and 19 corresponding patients (controls) from a previous retrospective case-control assessment of long-term survival in patients requiring ECMO post-Norwood. Functional status was assessed with the Vineland Adaptive Behavior Scale-II, and health-related quality of life was assessed with the Pediatric Quality of Life Inventory (PedsQL) core and cardiac modules., Results: There were no differences in demographics, extracardiac or genetic anomalies, or age at follow-up assessment between ECMO cases and non-ECMO controls. The Vineland Adaptive Behavior Scale-II scores were comparable between groups, with both groups demonstrating function in the normal range in all four domains tested. The only difference in PedsQL scores between cases and controls was perceived physical appearance, which was lower among ECMO survivors by both patient and proxy report. PedsQL scores of both groups were comparable to published scores for patients with single-ventricle congenital heart disease but generally lower than scores for the healthy population., Conclusions: The requirement for ECMO support after a Norwood operation does not appear to significantly affect functional status or quality of life among the subset of patients who achieve long-term survival., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The impact of nutritional status on HTx waitlist mortality in children is unknown, and there are conflicting data regarding the role of nutrition in post-HTx survival. This study examined the influence of nutrition on waitlist and post-HTx outcomes in children. Children 2-18 yr listed for HTx from 1997 to 2011 were identified from the OPTN database and stratified by BMI percentile. Multivariable logistic regression evaluated the influence of BMI on waitlist mortality. Cox proportional hazard regression assessed the impact of BMI on post-HTx mortality. When all 2712 patients were analyzed, BMI did not impact waitlist, one-, or five-yr mortality. However, when stratified by diagnosis, BMI > 95% (AOR 1.96; 95% CI 1.24, 3.09) and BMI < 1% (AOR 2.17; 95% CI 1.28, 3.68) were independent risk factors for waitlist mortality in patients with CM. BMI did not impact waitlist mortality in CHD and did not impact post-HTx outcomes, regardless of diagnosis. BMI > 95% and BMI < 1% are independent risk factors for waitlist mortality in patients with CM, but not CHD. This suggests differing risk factors based on disease etiology, and an individualized approach to risk assessment based on diagnosis may be warranted., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Repeat heart transplantation (re-HTx) is standard practice in many pediatric centers. There are limited data available on outcomes of third HTx after failure of a second graft. We sought to compare outcomes of third HTx in pediatric and young adult patients with outcomes of second HTx in comparable recipients., Methods: All recipients of a third HTx in whom the primary HTx occurred before 21 years of age were identified in the United Network for Organ Sharing database (1985 to 2011) and matched 1:3 with a control group of second HTx patients by age, era and re-HTx indication. Outcomes including survival, rejection and cardiac allograft vasculopathy (CAV) were compared between groups., Results: There was no difference between third HTx patients (n = 27) and control second HTx patients (n = 79) with respect to survival (76% vs 80% at 1 year, 62% vs 58% at 5 years and 53% vs 34% at 10 years, p = 0.75), early (<1 year from HTx) rejection (33.3% vs 44.3%, p = 0.32) or CAV (14.8% vs 30.4%, p = 0.11). Factors associated with non-survival in third HTx patients included mechanical ventilation at listing or HTx, extracorporeal membrane oxygenation support at listing or HTx, and elevated serum bilirubin at HTx., Conclusions: Outcomes among recipients of a third HTx are similar to those with a second HTx in matched patients, with no difference in short- or long-term survival and comparable rates of early rejection and CAV. Although the occurrence of a third HTx remains relatively rare in the USA, consideration of a third HTx appears reasonable in appropriately selected patients., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Patients requiring extracorporeal membrane oxygenation (ECMO) support after a Norwood operation constitute an extremely high-risk group. Data regarding risk factors for the requirement for ECMO post-Norwood are limited, however. We retrospectively assessed risk factors for requiring ECMO support after a Norwood operation during a 10-year period in a high-volume center., Methods: Retrospective case-control study of 64 consecutive patients requiring ECMO support after a Norwood operation at a single institution during a 10-year period (January 2001-December 2010), with a 3:1 era-matched control group of patients who underwent a Norwood but did not require ECMO., Results: In univariate analysis, ascending aorta less than 2.0 mm, longer cardiopulmonary bypass (CPB) time, intraoperative shunt revision, and right ventricle to pulmonary artery conduit were associated with the need for postoperative ECMO. A single left ventricle was protective compared with single right ventricle anatomy. By multivariate logistic regression, birth weight less than 2.5 kg and longer CPB time were independently associated with the need for postoperative ECMO. Receiver-operating characteristic curve analysis identified a peak lactate of 9 mmol/L and a peak vasoactive inotrope score (VIS) of 27 within 48 hours of surgery as most prognostic of the need for ECMO., Conclusions: Birth weight less than 2.5 kg and longer CPB time are independently associated with the need for ECMO after a Norwood operation. Peak serum lactate and peak VIS may be useful in stratifying risk for ECMO. Risk factors for ECMO post-Norwood appear to be similar to the risk factors for early mortality post-Norwood., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Although nutritional status affects survival after heart transplant (HTx) in adults and older children, its effect on outcomes in young children is unknown. This study aimed to assess the effect of pre-HTx nutrition on outcomes in this population., Methods: Children aged 0 to 2 years old listed for HTx from 1997 to 2011 were identified from the Organ Procurement and Transplantation Network database. Nutritional status was classified according to percentage of ideal body weight at listing and at HTx. Logistic regression analysis evaluated the risk of waitlist mortality. Cox proportional hazard models assessed the effect of nutrition on post-HTx survival., Results: Of 1,653 children evaluated, 899 (54%) had normal nutrition at listing, 445 (27%) were mildly wasted, 203 (12%) were moderate or severely wasted, and 106 (6%) had an elevated weight-to-height (W:H) ratio. Moderate or severe wasting (adjusted odds ratio, 1.9; 95% confidence interval, 1.3-2.7) and elevated W:H (adjusted odds ratio, 1.7; 95% confidence interval, 1.1-2.6) were independent risk factors for waitlist mortality. HTx was performed in 1,167 patients, and 1,016 (87%) survived to 1-year post-HTx. Nutritional status at listing or at HTx was not associated with increased post-HTx mortality. Nutritional status did not affect the need for early reoperation, dialysis, or the incidences of infection, stroke, or rejection before hospital discharge., Conclusions: Moderate or severe wasting and an elevated W:H are independent risk factors for waitlist mortality in patients aged < 2 years but do not affect post-HTx mortality. Optimization of pre-HTx nutritional status constitutes a strategy to reduce waitlist mortality in this age range., (© 2014 International Society for Heart and Lung Transplantation Published by International Society for the Heart and Lung Transplantation All rights reserved.)

Background: Infants supported by extracorporeal membrane oxygenation (ECMO) after a Norwood operation face in-hospital mortality rates of 60% to 70%. There are limited data on completion of staged palliation for the subset of patients who survive to hospital discharge., Methods: We performed a retrospective case-control study of 64 sequential patients at a single institution supported by ECMO after a Norwood operation. Primary endpoints were survival to hospital discharge, stage II palliation, and stage III palliation. Predictors of non-survival to each endpoint were identified with logistic regression. Survival was compared with a 3:1 era-matched group of control patients who underwent a Norwood operation but did not require ECMO., Results: Survival to hospital discharge, stage II palliation, and stage III palliation was 43.8%, 35.9%, and 25.4%, respectively for ECMO cases. Factors independently associated with non-survival to hospital discharge included female gender, ECMO 7 days or greater, and need for renal replacement therapy on ECMO. Non-Caucasian race and ECMO 7 days or greater were independently associated with non-survival to stage II, while non-Caucasian race, lower birth weight, and ECMO 7 days or greater were independently associated with non-survival to stage III. Extracorporeal membrane oxygenation was associated with decreased survival at each endpoint. Patients who survived ECMO had increased interstage mortality between hospital discharge and stage II palliation., Conclusions: Extracorporeal membrane oxygenation after a Norwood operation can be life-saving but ultimate survival through staged palliation remains suboptimal. The elevated mortality risk for patients supported by ECMO persists after hospital discharge. Both socioeconomic factors and ECMO-related morbidity may contribute to midterm mortality., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The developmental mechanisms underlying human congenital heart disease (CHD) are poorly understood. Atrial septal defects (ASDs) can result from haploinsufficiency of cardiogenic transcription factors including TBX5. We demonstrated that Tbx5 is required in the second heart field (SHF) for atrial septation in mice. Conditional Tbx5 haploinsufficiency in the SHF but not the myocardium or endocardium caused ASDs. Tbx5 SHF knockout embryos lacked atrial septum progenitors. We found that Tbx5 mutant SHF progenitors demonstrated cell-cycle progression defects and that Tbx5 regulated cell-cycle progression genes including Cdk6. Activated hedgehog (Hh) signaling rescued ASDs in Tbx5 mutant embryos, placing Tbx5 upstream or parallel to Hh in cardiac progenitors. Tbx5 regulated SHF Gas1 and Osr1 expression, supporting both pathways. These results describe a SHF Tbx5-Hh network required for atrial septation. A paradigm defining molecular requirements in SHF cardiac progenitors for cardiac septum morphogenesis has implications for the ontogeny of CHD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The primary cilium is emerging as a crucial regulator of signaling pathways central to vertebrate development and human disease. We identified atrioventricular canal 1 (avc1), a mouse mutation that caused VACTERL association with hydrocephalus, or VACTERL-H. We showed that avc1 is a hypomorphic mutation of intraflagellar transport protein 172 (Ift172), required for ciliogenesis and Hedgehog (Hh) signaling. Phenotypically, avc1 caused VACTERL-H but not abnormalities in left-right (L-R) axis formation. Avc1 resulted in structural cilia defects, including truncated cilia in vivo and in vitro. We observed a dose-dependent requirement for Ift172 in ciliogenesis using an allelic series generated with Ift172(avc1) and Ift172(wim), an Ift172 null allele: cilia were present on 42% of avc1 mouse embryonic fibroblast (MEF) and 28% of avc1/wim MEFs, in contrast to >90% of wild-type MEFs. Furthermore, quantitative cilium length analysis identified two specific cilium populations in mutant MEFS: a normal population with normal IFT and a truncated population, 50% of normal length, with disrupted IFT. Cells from wild-type embryos had predominantly full-length cilia, avc1 embryos, with Hh signaling abnormalities but not L-R abnormalities, had cilia equally divided between full-length and truncated, and avc1/wim embryos, with both Hh signaling and L-R abnormalities, were primarily truncated. Truncated Ift172 mutant cilia showed defects of the distal ciliary axoneme, including disrupted IFT88 localization and Hh-dependent Gli2 localization. We propose a model in which mutation of Ift172 results in a specific class of abnormal cilia, causing disrupted Hh signaling while maintaining L-R axis determination, and resulting in the VACTERL-H phenotype.

The genesis of the septal structures of the mammalian heart is central to understanding the ontogeny of congenital heart disease and the evolution of cardiac organogenesis. We found that Hedgehog (Hh) signaling marked a subset of cardiac progenitors specific to the atrial septum and the pulmonary trunk in the mouse. Using genetic inducible fate mapping with Gli1(CreERT2), we marked Hh-receiving progenitors in anterior and posterior second heart field splanchnic mesoderm between E8 and E10. In the inflow tract, Hh-receiving progenitors migrated from the posterior second heart field through the dorsal mesocardium to form the atrial septum, including both the primary atrial septum and dorsal mesenchymal protrusion (DMP). In the outflow tract, Hh-receiving progenitors migrated from the anterior second heart field to populate the pulmonary trunk. Abrogation of Hh signaling during atrial septal progenitor specification resulted in atrial and atrioventricular septal defects and hypoplasia of the developing DMP. Hedgehog signaling appeared necessary and sufficient for atrial septal progenitor fate: Hh-receiving cells rendered unresponsive to the Hh ligand migrated into the atrium in normal numbers but populated the atrial free wall rather than the atrial septum. Conversely, constitutive activation of Hh signaling caused inappropriate enlargement of the atrial septum. The close proximity of posterior second heart field cardiac progenitors to pulmonary endoderm suggested a pulmonary source for the Hh ligand. We found that Shh is required in the pulmonary endoderm for atrial septation. Therefore, Hh signaling from distinct pulmonary and pharyngeal endoderm is required for inflow and outflow septation, respectively. These data suggest a model in which respiratory endoderm patterns the morphogenesis of cardiac structural components required for efficient cardiopulmonary circulation.