Venoarterial extracorporeal membrane oxygenation (VA ECMO) offers vital support to children with cardiopulmonary failure. Echocardiography is commonly used to assess readiness for decannulation, however pediatric data supporting utility is limited. This is a retrospective, single-center study analyzing echoes during pediatric VA ECMO clamp trials from 2012 ̶ 2024. Subjects were categorized as cardiomyopathy/myocarditis (CM), persistent pulmonary hypertension of the newborn (PPHN), or congenital heart disease (CHD). Subjects were grouped as those who did (+ decan) and did not (− decan) tolerate decannulation within 24 h of the trial. 103 subjects (median age 9.1 days (3.7–109.5 days), 39

BACKGROUND:Late graft survival after pediatric heart transplantation (HT) remains inadequate, with chronic rejection being a major contributor. Daratumumab has shown promise treating antibody-mediated rejection (ABMR) with limited published experience in HT. METHODS:We retrospectively analyzed all HT recipients at our center treated with daratumumab (16 mg/kg × 4 doses) for ABMR identified by elevated donor-derived cell-free DNA (dd-cfDNA) without graft dysfunction or hemodynamic compromise and confirmed by endomyocardial biopsy gene expression profiling (EMB-GEP). HLA-DSA and non-HLA antibodies, including angiotensin II type 1 receptor (AT1R) antibody, were assessed pre- and post-treatment. RESULTS:Ten recipients were identified and treated with daratumumab, including 4 without HLA-DSA at diagnosis. dd-cfDNA decreased (1.6% to 0.04%; p=0.002) post-treatment. Among 8 with post-treatment EMB, ABMR resolved (n=6) or showed only possible ABMR (n=2) after treatment. HLA-DSA total MFI (p=0.031), non-HLA antibody burden (p=0.004), and AT1R Ab concentration (p=0.004) declined post-treatment. Six patients experienced subsequent elevations of dd-cfDNA at a median of 246 days (IQR, 239-283) with ABMR recurrence on EMB and responded to retreatment. No T-cell mediated rejection occurred after treatment. CONCLUSIONS:Daratumumab was associated with significant improvements in dd-cfDNA, EMB-GEP, and antibody burden in pediatric and young adult HT recipients with ABMR. Response among patients without circulating HLA-DSA or with reduced but persistent HLA-DSA after treatment implies effects beyond plasma cell depletion. Rebound ABMR was common but responded to retreatment, suggesting periodic maintenance dosing may be required. Prospective studies are needed to define optimal treatment strategies and long-term outcomes.

Background:Primary graft dysfunction (PGD) remains one of the leading causes of early mortality after pediatric heart transplant (HT). While neurodevelopmental impacts of congenital heart disease (CHD) are well-characterized, the effect of PGD on long-term neurodevelopmental outcomes in pediatric HT recipients remains unknown. We sought to determine the association between PGD and neurodevelopmental outcomes in this population. Methods:We performed a retrospective cohort study using the United Network for Organ Sharing (UNOS) database. All pediatric (age <18 years) isolated heart transplant recipients from 2010-2025 were included. The most recent pre- and post-transplant neurodevelopmental outcomes including cognitive delay, motor development, academic progress, and function status (stratified by age) were compared between PGD (n=434) and non-PGD groups (n=6956). Results:PGD patients had significantly worse pre-transplant functional status and motor development. Post-transplant, PGD was associated with worse motor development (18.8% vs. 13.0% definite motor delay; p=0.01) and functional status in younger children (39.5% vs. 57.8% able to keep up with peers; p<0.001). Post-transplant stroke occurred 3.5 times more frequently in PGD patients (11.5% vs. 3.3%; p<0.001). Cognitive development (p=0.94) and academic progress (p=0.09) did not differ significantly. Thirty-day (7.8% vs. 1.9%) and 1-year mortality (20.3% vs. 6.4%) were significantly higher in PGD patients (both p<0.001). Conclusions:This is the first study to characterize neurodevelopmental outcomes in pediatric patients undergoing HT with PGD. PGD is associated with significantly worse motor development and functional status independent of pre-transplant baseline. There is a 3.5-fold higher stroke rate providing a plausible neurological mechanism. The findings support targeted developmental surveillance recommendations and early intervention for this high-risk population.

Introduction: Monogenic causes of dilated cardiomyopathy (DCM) are commonly identified in children. While DCM frequently presents with symptomatic heart failure (HF), whether an identified genetic cause of DCM implies disease severity or eventual outcome in children is unclear. Goals/Aims: To assess whether clinical or phenotypic disease severity is different in children with an identifiable pathogenic or likely pathogenic (P/LP) variant in a cardiomyopathy gene, using a multi-institutional cohort of children with DCM, and to determine the association of these variants with disease outcomes. Methods: Children (0-18 yrs) from 14 pediatric centers in North America with an echo diagnosis of non-syndromal DCM were studied: phenotypic features included ancestry, family history, presentation age, severity of LV dilation, ejection fraction (EF), and clinical HF. A panel of 37 known cardiomyopathy-associated genes was interrogated by exome sequencing with targeted analysis for P/LP variants. Outcomes of death, cardiac transplant, and continuing LV dysfunction vs echo normalization were assessed prospectively. Results: Between 2012-2016, 279 DCM probands (47% male) were enrolled with a median (IQR) age at diagnosis of 1.6 (0.4-10.4) yrs. Median follow-up time was 1.1 (0.2-4.0) yrs, Gene variants designated as P/LP were identified in 18 of the 37 genes evaluated, with TTN (17%), TNNT2 (15%), MYH7 (15%), RBM20 (9%), and LMNA (8%) being the most frequently implicated genes. Only 19% of the overall cohort yielded an identifiable genetic cause, without any difference between ancestries. Children >12 yrs old had the highest genetic yield at 34% (p<0.05). Symptoms of HF occurred in 62% of pts at or within 12 months of presentation who carried P/LP genetic variant, but presentation HF symptoms, LVEF, or LV dilation were not associated with an identifiable genetic cause. The rate of death or cardiac transplant did not differ with P/LP variant presence or absence and exceeded 60% at 10 yrs after diagnosis. On competing risks analysis (Figures 1 and 2), a trend (p=0.09) towards greater echo normalization, reaching 25% vs 10%, was noted in P/LP variant-negative pts by 10 yrs after diagnosis. Conclusions: A genetic etiology was not associated with the phenotypic severity of DCM at diagnosis. Echo normalization of LV function over time was noted more frequently in patients who did not have an identified P/LP variant.

Importance:Studies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking. Objective:To evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant. Design, Setting, and Participants:Multicenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023. Interventions:Participants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months. Main Outcomes and Measures:The primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder. Results:Among 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, -0.32; 95% CI, -0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, -0.40; 95% CI, -1.81 to 0.93), meeting the success criterion for safety (noninferiority margin <3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93). Conclusions and Relevance:Among 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection. Trial Registration:ClinicalTrials.gov Identifier: NCT03386539.

BACKGROUND:Congenital long QT syndrome (LQTS) is rare but significant, as it carries a risk for ventricular arrhythmias and sudden cardiac death. Its diagnosis can be made clinically by serial ECGs, ambulatory ECG monitoring, and exercise stress testing; however, genetic testing is confirmatory in the majority of cases. METHODS:Here, we describe a rare case of phenotype-positive LQTS in a 6-year-old heart transplant recipient, confirmed 5 years after transplantation to be genotype-positive and thus "acquired" from the transplanted heart. RESULTS:Recognition of a persistently prolonged QTc interval on the recipient's serial ECGs led to ambulatory ECG monitoring and exercise stress testing-both of which were suspicious for LQTS. Ultimately, genetic evaluation and cardiac biopsy were obtained and resulted positive for a KCNQ1 pathogenic variant associated with Type 1 LQTS. CONCLUSION:Recognition of persistent, otherwise unexplained, ECG abnormalities can prompt genetic analysis of the allograft, leading to the potential life-saving diagnosis of a channelopathy.

BACKGROUND:Fontan circulatory failure (FCF) is a chronic state in palliated single ventricle heart disease with high morbidity and mortality rates, including heart failure, multisystem end-organ disease, and need for heart transplant. Specific FCF morbidities have not been rigorously defined, limiting study of how FCF morbidities affect pre-heart transplant and post-heart transplant outcomes. We hypothesized that FCF-related morbidities affect survival from heart transplant waitlisting through 1 year after heart transplant.METHODS:This 20-center, retrospective cohort study collected demographic, medical/surgical history, waitlist, and peri- and post-heart transplant data, and a priori defined FCF-specific morbidities, in Fontan patients who were listed for heart transplant from 2008 through 2022. Univariate 2-group statistics compared surviving individuals with those who died anytime from waitlisting to 1 year after heart transplant, died on the waitlist, or underwent transplant and died within 1 year after transplant. Using covariates from both univariate analyses, multivariable logistic regression determined the primary study outcome of independent FCF risk factors for death between waitlist and 1 year after heart transplant.RESULTS:Of 409 waitlisted patients, 24 (5.9%) died on the waitlist. Of the 341 (83.4%) who underwent transplant, 27 (8.5%) did not survive to 1 year. Univariate risk factors for waitlist death included higher aortopulmonary collateral burden, >1 hospitalization in the previous year, younger age, sleep apnea, higher New York Heart Association class, nonenrollment in school or work, and single-parent home. Risk factors for 1-year post-heart transplant mortality included hypoplastic left heart syndrome diagnosis, patent fenestration, anatomic Fontan obstruction, clinical cyanosis (pulse oximetry <90%), polycythemia, portal variceal disease, mental health condition requiring treatment, and higher human leukocyte antigen class II panel reactive antibody. Of the patients not surviving from waitlisting to 1 year after heart transplant, independent risk factors for death included >1 hospitalization in the year before waitlisting (adjusted odds ratio, 2.0 [95% CI, 1.0-4.1]; P=0.05) and clinical cyanosis (adjusted odds ratio, 5.0 [95% CI, 1.8-13.4]; P=0.002).CONCLUSIONS:Patients with Fontan palliation selected for heart transplant have substantial mortality rates from waitlisting through transplant. Among FCF-specific morbidities, cyanosis is associated with worsened survival and necessitates further study. Clinical morbidity of any type requiring repeated hospital admission also should prompt consideration of heart transplant.

Barth syndrome (BTHS) is a rare X-linked recessive disorder characterized by mutations in the TAFAZZIN gene, leading to mitochondrial dysfunction, cardioskeletal myopathy, neutropenia, exercise intolerance, and growth delay. While cardiac transplantation can improve heart function in BTHS patients, the metabolic effects of this procedure remain poorly understood. This study aimed to compare skeletal muscle morphology, substrate metabolism, energetics, and exercise tolerance in individuals with BTHS who had undergone cardiac transplantation (BTHS-T) versus BTHS patients without transplantation (BTHS-noT) and healthy controls. Six (n = 6) BTHS-T participants (3 adolescents, 3 adults) were compared with n = 29 BTHS-noT and n = 28 healthy controls. All participants underwent graded exercise testing, echocardiography, body composition analysis, and clinical metabolism studies, including 31P-MRS to assess mitochondrial energetics. No significant differences were observed in fat-free mass between BTHS-T participants and BTHS-noT. Exercise capacity (V̇O2peak) was significantly lower in both BTHS groups compared to controls, with lower heart rate responses during peak exercise. In addition, plasma lactate was higher in both BTHS groups compared to healthy controls. Skeletal muscle energetics showed slower phosphocreatine recovery and reduced ATP production in BTHS participants, regardless of cardiac transplantation status. Findings suggest while cardiac transplantation in BTHS may improve heart function, it may not normalize skeletal muscle mass and energetics, metabolic abnormalities, and exercise intolerance. The study enhances our understanding of long-term metabolic consequences of BTHS and potential limitations of cardiac transplantation in ameliorating these dysfunctions. Further research is needed to explore targeted therapies to address underlying metabolic abnormalities in BTHS patients.

Implantable cardioverter-defibrillators (ICDs) are increasingly used in patients with congenital heart disease, most commonly in surgically repaired Tetralogy of Fallot (rTOF). Studies have examined patient outcomes after ICD implantation; however, the cost-effectiveness of ICDs in rTOF is unknown. We sought to evaluate the cost-effectiveness of typical medical management plus ICD (TMM + ICD) for primary prevention of sudden cardiac death (SCD) compared to typical management alone (TMM) in high-risk patients with rTOF. We created a Markov model to compare costs and quality of life (QOL) of TMM + ICD vs TMM for a hypothetical adolescent with rTOF and higher than average risk of SCD over 20 years. Model parameters were derived from the literature and institutional data. We assumed that SCD risk increased from 0.4

Background: Cardiomyocyte proliferation, the fundamental mechanism of heart development and regeneration, is active in infants. We investigated cardiomyocyte proliferation in infants with heart disease. Objective/Hypothesis: Infants with tetralogy of Fallot (ToF, the most common type of cyanotic congenital heart disease) or heart failure (HF) exhibit altered cardiomyocyte proliferation. Methods: The DNA replication marker, 15 N-thymidine, was administered to infants with unrepaired ToF (n = 13) and to infants with heart failure waiting for transplantation (n = 5). One of the infants with ToF was also treated with the beta-blocker, propranolol. Myocardial samples were ascertained at the time of ToF surgery, placement or removal of left ventricular assist devices (LVAD), and heart transplantation. Retention of 15 N-thymidine in cells that had undergone DNA replication was assessed using Multi-Isotope Imaging Mass Spectrometry (MIMS). Polyploidy was quantified to identify post-mitotic, non-dividing cardiomyocytes. Results: Within the first 4 months after birth, 0.74 billion new cardiomyocytes were generated—3.4-fold higher than after the age of 4 months (P = 0.0417). Average per nucleus DNA content in 15 N-labeled cardiomyocytes in ToF infants (n = 11) and HF infants (n = 3) was significantly greater (1.38-fold) than that in individuals without heart disease (n = 11, P = 0.0358), indicating increased formation of post-mitotic cardiomyocytes in diseased hearts. An infant with HF received 15 N-thymidine while on LVAD. Despite clinical improvement and LVAD removal, cardiomyocyte generation remained below age-appropriate levels. In contrast, a ToF infant treated with propranolol, showed a reduced incidence of polyploid nuclei, suggesting enhanced cardiomyocyte division in response to β-blockade. Conclusion: Infants with heart disease generate new cardiomyocytes, with the majority of this occurring in the first four months after birth, which identifies a window for regenerative therapies. Beta-blockade may promote cardiomyocyte division, highlighting a direction for regenerative therapy.

Background: Children with dilated cardiomyopathy (DCM) are at high risk for morbidity and death. There are few data on the utility of biomarkers in this population. Research Question/Hypothesis: We aimed to evaluate a panel of cardiac biomarkers as predictors of death or heart transplant within 2 years of diagnosis. Methods: Patients <21 years of age at DCM diagnosis were enrolled at 15 North American pediatric cardiomyopathy centers within one year of diagnosis with collection of serum, echocardiographic and clinical data at enrollment. Results: Data from 74 subjects were analyzed, median age 2.1 years at enrollment [interquartile range (IQR 0.7-12.8)], 40 (54%) female, and 56 (76%) enrolled within 90 days of diagnosis. The primary endpoint of death or heart transplant was met in 13 subjects (18%). Several cardiac biomarkers of heart failure (HF), N-terminal pro B-type natriuretic peptide, growth differentiation factor-15, interleukin-6, and C-reactive protein were associated with the primary endpoint (p <0.05 for all) in the univariate analysis. In multivariable analysis, growth differentiation factor-15 was independently associated with the primary endpoint (hazard ratio 5.23, 95% confidence interval 2.20, 12.44; p <0.001). Conclusion: Growth differentiation factor-15, an emerging circulating biomarker for HF, was independently associated with death or heart transplantation within 2 years in children with a recent diagnosis of DCM. Traditional biomarkers such as NT pro-BNP were found to be less predictive on single point assessment. If validated in further studies, this biomarker could serve as an endpoint for prospective clinical trials.

Background: Resilience describes an individual’s ability to leverage internal strengths, external support, and acquired skills to maintain wellbeing amidst stressors. Individuals with Fontan-palliated congenital heart disease (CHD) often face physical and psychological stressors, yet some report resilience amidst these circumstances. While resilience is linked to important physical and psychological outcomes in other chronic illnesses, it is underexplored in pediatric and young adult CHD. Research Question: This prospective study aimed to 1) characterize self-reported resilience in a multi-center sample of children and young adults with Fontan circulatory failure (FCF) and 2) identify demographic, physical, and psychological factors correlated with resilience. Methods: Pediatric and young adult patients with Fontan circulation referred for heart failure evaluation at 20 North American pediatric heart centers were eligible. Participants completed the Connor-Davidson Resilience Scale (CD-RISC©). CD-RISC© scores range from 0-40. In adults, scores < 29 represent the lowest quartile. In pediatric cancer and adult CHD, mean scores of 29 have been reported. Participants also completed a measure of disease burden/benefit and NIH PROMIS surveys assessing life satisfaction, purpose in life, depression, and anxiety. Medical data was obtained from chart reviews, and frailty was assessed using the Lurz-Wilde pediatric frailty criteria. Results: The study included 131 participants (60% male, 78% White, median age 16.1 years) with a mean CD-RISC score of 27.2 (SD=7.2; Figure 1). Lower resilience was associated with younger age (p<0.0001), female sex (p=0.01), and hypoplastic left heart syndrome (HLHS; p=0.049). Lower resilience (p=0.001), higher anxiety (p=0.01), and high self-reported disease burden (p=0.02) correlated with frailty. Few objective FCF comorbidities were associated with resilience. In univariate analysis, protein losing enteropathy (PLE; p=0.04) and clinical cyanosis (p=0.053) were associated with lower resilience. In multivariate analysis including age, sex, HLHS diagnosis, and PLE, only younger age and female sex remained independently associated with lower resilience. Conclusion: Although young people with FCF report high resilience, many indicate opportunities for intervention. The study underlines resilience as a modifiable, critical target for intervention in complex CHD, highlighted by its strong link with frailty over less modifiable comorbidities.

Purpose: The TEAMMATE Trial is the first randomized clinical trial of immunosuppression in pediatric heart transplant (HT) recipients. We aimed to describe coronary angiography results from the trial (currently embargoed).

BACKGROUND:Troponin I is a blood biomarker of cardiac injury and levels measured using a high-sensitivity assay after pediatric heart transplantation (HT) have not been described. We sought to assess the association between high-sensitivity troponin I (hsTnI) and N-terminal pro-B-type natriuretic peptide (NTproBNP) with treated acute rejection (AR) and graft loss in pediatric heart transplant (HT) recipients. METHODS:Serum was collected and banked from pediatric HT recipients prior to cardiac catheterization. Patients with samples drawn within 365 days post-HT were included and followed for up to 5 years. Generalized linear mixed-effect models examined the association between hsTnI and treated AR using a random intercept per patient. Cox proportional hazards models tested the association between maximal hsTnI and NT-proBNP and death/graft loss. RESULTS:HsTnI and NTproBNP values decline in the weeks following HT, after which these biomarkers stabilize. HsTnI was higher in AR versus no AR (6.2 vs. 3.5 ng/L, p < 0.001); doubling of hsTnI increased the odds of AR by 33% (p = 0.004). HsTnI showed moderate discrimination for AR with an AUC of 0.811 (95% CI 0.76, 0.87) and a NPV of 96.4% (95% CI 93.0, 98.1). Elevation in NT-proBNP was not associated with AR. In multivariable Cox modeling, a doubling of maximal NT-proBNP was associated with graft loss (HR 8.96, p = 0.014). CONCLUSIONS:In this pediatric HT cohort, HsTnI was moderately discriminative for AR and higher maximal NT-proBNP was associated with graft loss. HsTnI may add value in pediatric HT non-invasive AR surveillance, and elevated NTproBNP could suggest an increased risk of graft loss.

BACKGROUND:We have developed a new clinical research approach for the quantification of cellular proliferation in human infants to address unanswered questions about tissue renewal and regeneration. The approach consists of oral 15N-thymidine administration to label cells in S-phase, followed by Multi-isotope Imaging Mass Spectrometry for detection of the incorporated label in cell nuclei. To establish the approach, we performed an observational study to examine uptake and elimination of 15N-thymidine. We compared at-home label administration with in-hospital administration in infants with tetralogy of Fallot, a form of congenital heart disease, and infants with heart failure. METHODS:We examined urine samples from 18 infants who received 15N-thymidine (50 mg/kg body weight) by mouth for five consecutive days. We used Isotope Ratio Mass Spectrometry to determine enrichment of 15N relative to 14N (%) in urine. RESULTS/FINDINGS:15N-thymidine dose administration produced periodic rises of 15N enrichment in urine. Infants with tetralogy of Fallot had a 3.2-fold increase and infants with heart failure had a 4.3-fold increase in mean peak 15N enrichment over baseline. The mean 15N enrichment was not statistically different between the two patient populations (p = 0.103). The time to peak 15N enrichment in tetralogy of Fallot infants was 6.3 ± 1 hr and in infants with heart failure 7.5 ± 2 hr (mean ± SEM). The duration of significant 15N enrichment after a dose was 18.5 ± 1.7 hr in tetralogy of Fallot and in heart failure 18.2 ± 1.8 hr (mean ± SEM). The time to peak enrichment and duration of enrichment were also not statistically different (p = 0.617 and p = 0.887). CONCLUSIONS:The presented results support two conclusions of significance for future applications: (1) Demonstration that 15N-thymidine label administration at home is equivalent to in-hospital administration. (2) Two different types of heart disease show no differences in 15N-thymidine absorption and elimination. This enables the comparative analysis of cellular proliferation between different types of heart disease.

The cone operation has revolutionized care for patients with Ebstein anomaly; however, acute post-operative right ventricular dysfunction (RVD) is common in this patient population. A single-center, retrospective review of 28 patients with Ebstein anomaly who underwent cardiac MRI (CMR) prior to cone reconstruction of the tricuspid valve was conducted. Measurements of atrial and ventricular size/function were assessed. Post-operative RVD was defined as the presence of moderate or severe systolic dysfunction on discharge echo. A two-tail t test was employed to compare the two groups. The average age at operation was 21.4 years (range 1.6–57.8) and 14 (50