Objective: Extracorporeal membrane oxygenation (ECMO) before ventricular assist device (VAD) implantation as a “double-bridge” strategy to heart transplantation is often used for the most acutely ill patients with decompensated heart failure. This cohort of patients has worse outcomes than those with primary VAD. Early crossover from ECMO to VAD has shown to have better survival in adults who are double-bridged. This study aims to evaluate the outcomes of early versus late crossover in pediatric patients who were double-bridged using the Advanced Cardiac Therapies Improving Outcomes Network registry. Methods: All patients <18 years of age in the Advanced Cardiac Therapies Improving Outcomes Network database who were double-bridged were identified. Patients were categorized into early or delayed crossover groups. Univariate and multivariate Cox regression analysis identified independent risk factors of outcomes. Kaplan-Meier and competing risk analyses assessed survival. Results: Of 1360 patients, 334 (24%) underwent double-bridging. Median ECMO support was 6 days, leading to an early crossover group (≤6 days) of ECMO (n = 168) and a delayed crossover group (>6 days) of ECMO support (n = 166). Univariate analysis showed that patients who were double-bridged were considerably sicker than the primary VAD group. Multivariable analysis revealed that a diagnosis of dilated cardiomyopathy/myocarditis and bridge to candidacy device intent were independent predictors of outcome. Duration of ECMO support/timing of crossover (early vs late) was not independently associated with outcomes. Conclusions: The timing of crossover from ECMO to VAD in pediatric patients subject to the double-bridge strategy does not affect outcomes. Focus on the patient selection and reversibility of risk factors rather than the duration of ECMO support may improve outcomes in this high-risk population.

This study was designed to identify genes for further study as modifiers of the severity of cardiomyopathy in DMD-related Duchenne Muscular Dystrophy (DMD). We evaluated genome sequencing results in a well-phenotyped DMD cohort with severe cardiomyopathy against those with less severe cardiomyopathy. Using combined annotation-dependent depletion variant annotation to look at variant burden, we created a difference between group mean (DBGM) summative C-Scores by gene. We completed analyses on three groups. For each analysis, we normalized DBGM summative C-Score and determined which genes had a value > three standard deviations from the mean in all three analyses. There were 54 DMD males in this analysis. 18 individuals (33

Duchenne muscular dystrophy (DMD) is an X-linked genetic neuromuscular disorder that is caused by a mutation in the dystrophin gene. The disease is characterized by progressive weakness of skeletal muscle, resulting in loss of ambulation and eventually respiratory insufficiency. Cardiac muscle is also involved, and cardiomyopathy is a prominent feature of DMD. The care of patients with DMD has changed in important ways over the past 15 years, with the use of chronic steroid therapy combined with noninvasive respiratory support such as continuous positive airway pressure for home use. More recently, therapies targeting specific genetic mutations in DMD have been approved, using gene-skipping oligonucleotides, and many other novel therapies are being evaluated in clinical trials, including mini-dystrophin genes delivered by viral vectors. In view of this new era in care and outcomes, it is appropriate to review the role of advanced cardiac therapies such as ventricular assist devices and heart transplantation in the care of this population. In September 2024, a group of healthcare professionals with expertise in DMD and heart failure convened to review this topic; the consensus opinion of this group (DMD Cardiac Care Consortium) is presented in this manuscript.

Introduction Desmoplakin (DSP) genetic variants cause various cardio-cutaneous phenotypes. DSP related cardiomyopathy (DSP-CM) is a cause of arrhythmogenic cardiomyopathy (ACM). Patient presentation is highly variable, and dermatologic manifestations are often the first sign of impending cardiac dysfunction. A subset DSP-CM patients require advanced cardiac therapies (ACT) such as heart transplantation (HTx). Case description Patient 1 is a male neonate who presented at birth with tense bullae and erosions scattered on the body. Genetic panel disclosed two DSP variants. He was diagnosed with DSP-related skin fragility. At age 2.5 years, DSP-CM developed, leading to aborted cardiac arrest and HTx at age 4.Patient 2 is a 15-year-old male who presented with new onset dilated cardiomyopathy and wooly hair, hypodontia, and onychodystrophy. Genetic testing revealed a DSP variant, which was diagnostic for DSP-CM with woolly hair, keratoderma, and tooth agenesis. He underwent HTx 1 month after presentation. Discussion DSP variants cause a distinct form of ACM. Left dominant cardiomyopathy and systolic dysfunction were the primary manifestations in our patients. Pediatric DSP-CM cases are sparse in the literature. We demonstrate that patients with DSP-CM can successfully undergo HTx with special attention to treatment of their dermatologic disease.

This study seeks to understand cardiac medication use in a large cohort of males with Duchenne Muscular Dystrophy (DMD) followed prospectively with focus on current practices and adherence to consensus directed medical therapy (CDMT). DMD patients have been enrolled in the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) Dystrophinopathy Registry since 2021. Cardiac medication use was analyzed at enrollment and most recent follow-up. CDMT was defined as concurrent use of angiotensin-converting-enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) /angiotensin receptor-neprilysin inhibitor (ARNI) plus beta-blocker (BB) plus mineralocorticoid receptor antagonist (MRA). Two hundred sixty-five males with DMD (median age 17.5 (IQR 14.5–21.5) years) were prospectively followed; median follow-up was 11.5 (IQR 6.2–15.6) months. At most recent follow-up, 153 patients (57.7%) had decreased LV systolic function, 67 (25.3% of the cohort) had moderate or severe dysfunction. For patients with moderate or severe dysfunction, CDMT was used for 49/67 (73.1%) at most recent follow-up, similar to 36/51 (70.6%) at enrollment (p = 0.92). Target doses of CDMT were achieved for 27% of males on ACEi/ARB/ARNI, 28% on BB, and 23% on MRA. Initial analysis of a prospective registry of males with DMD showed that ~ 30% of patients with moderate or severe LV dysfunction were not on CDMT at most recent follow-up and the majority did not reach target dosing. Further understanding regarding the optimal combination of cardiac medications for DMD cardiomyopathy is needed, as is a better understanding of the barriers to CDMT optimization given increasing cardiac causes of death for DMD patients.

Hypertrophic cardiomyopathy (HCM) is an inherited disease present in 1 in 500 individuals and is the most common cause of sudden cardiac death in children. We present the case of a 17-year-old boy with HCM and a primary prevention subcutaneous implantable cardioverter-defibrillator (S-ICD) who developed left ventricular outflow tract obstruction and a myocardial bridge of the left anterior descending coronary artery. The patient underwent a septal myectomy/myotomy and muscular bridge unroofing. The S-ICD system was undisturbed during the surgery, with no loss of function. Septal myectomy may be accomplished in pediatric HCM patients following optimal S-ICD placement with maintained S-ICD function.

BACKGROUND:Studies evaluating the prevalence and impact of recurrent rejection (RR) in pediatric heart transplant (HT) are sparse. OBJECTIVES:The purpose of this study was to describe prevalence and impact of RR on cardiac allograft vasculopathy (CAV) and graft loss after pediatric HT. METHODS:Data on HT from January 1, 2000, to June 30, 2020, in the Pediatric Heart Transplant Society database were included. Freedom from RR (≥2 rejection episodes) was compared by era (early: 2000-2009; current: 2010-2020). Outcomes for children experiencing RR were compared with those experiencing 0 or 1 rejection episodes and by type of RR (antibody-mediated rejection [AMR], acute cellular rejection [ACR], mixed [ACR/AMR]). RESULTS:Of 6,342 HT recipients, 1,035 (17%) experienced RR. In the current era, pediatric HT recipients were less likely to experience RR (P < 0.001). Freedom from CAV was similar for those experiencing RR to those experiencing 0 or 1 episode (96.6% vs 95.3% vs 96.6%); and similar regardless of the type of RR (AMR, ACR, or mixed) (65.5% vs 82.9% vs 100%) (P > 0.05). Freedom from graft loss was significantly lower for those experiencing RR to those experiencing 0 or 1 episode (56.3% vs 72.3% vs 82.3%) and lower for those experiencing recurrent mixed rejection or recurrent AMR compared with those experiencing recurrent ACR (65.3% vs 50% vs 81.8%). Black children experiencing RR subsequently had lower freedom from CAV and graft loss than White children (P < 0.05 for all). CONCLUSIONS:Although prevalence of RR has decreased, children experiencing RR are at greatly increased risk for losing their graft, particularly those who have recurrent mixed or antibody-mediated rejection.

We report the largest pediatric multicenter experience with Impella pump use and peripheral veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support. Utilizing the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) collaborative database, we conducted a retrospective, multicenter study of all patients with cardiogenic shock requiring VA-ECMO support with subsequent Impella implant between October 2014 and December 2021. The primary outcome was defined as death while on Impella support. Secondary outcomes were recovery, transplantation, and transition to durable ventricular assist device (VAD) at the time of Impella explantation. Adverse events were defined according to the ACTION registry criteria. Twenty subjects were supported with Impella; Impella 2.5 (n = 3), CP (n = 12), 5.0/5.5 (n = 5). The median Interquartile range (IQR) age, weight, and body surface area at implantation were 15.6 years (IQR = 13.9-17.2), 65.7 kg (IQR = 53.1-80.7), and 1.74 m2 (IQR = 1.58-1.98). Primary cardiac diagnoses were dilated cardiomyopathy/myocarditis in nine (45%), congenital heart disease in four (20%), graft failure/rejection in four (20%), and three (15%) others. Most common adverse events included hemolysis (50%) and bleeding (20%). There were two deaths (10%) in the cohort. Nine patients (45%) were explanted for recovery, eight (40%) were transitioned to a durable VAD, and one (5%) underwent heart transplantation. Impella percutaneous pump support should be considered in the older pediatric population supported with peripheral VA-ECMO, as a means of left heart decompression, and a strategy to come off ECMO to achieve endpoints of myocardial recovery, transition to a durable VAD, or transplantation.

Introduction: Duchenne muscular dystrophy (DMD) has cardiac phenotype variability ranging from mild ventricular dysfunction to death from heart failure in the second decade. This variability has not been explained by specific DMD variants. Question: This study was designed to identify target genes, other than DMD , as cardiomyopathy (CMP) severity modifiers. Methods: Genome sequencing results were analyzed from 54 well phenotyped DMD males and either severe CMP (cardiac mortality or left ventricular ejection fraction (EF) < 40% at < 20 years of age, n = 18) or mild CMP (EF > 40% at > 20 years of age, n = 36). We compared variants within CMP groups as follows: 1) all study subjects, 2) siblings discordant for CMP severity, and 3) subjects without relatives. Combined Annotation-Dependent Depletion (CADD) was used to assess individual rare variant burden by filtering to retain coding variants with a raw CADD-generated C-Score >2.5. Using the C-Score, we calculated the difference between group mean (DBGM) between the CMP groups for each gene. For each of the three analyses groups, we normalized DBGM summative C-Score and determined which genes had a DBGM summative C-Score >3 standard deviations from the mean (SDM). We evaluated genes that were present on the gene list for all three analyses. Results: The cohort by CMP severity is depicted in Figure 1a. Comparisons yielded 8,155 genes with a C-Score > 2.5 in at least one patient. Number of genes with DBGM >3SDM in respective CMP group analysis above: 1) 159 genes 2) 134 genes 3) 136 genes. Nine genes had DBGM summative C-Scores >3 SDM in all three analyses. Of these, 5 genes, ANKLE1 , ESRRA , GXYLT1 , MTCH2 , and QRFPR, had scores suggestive that these genetic variants could be protective against severe CMP. Whereas 4 genes, FRAS1 , GEMIN4 , PKD1L2 , and PRSS2 had scores suggestive that these genetic variants could be a risk factor for severe CMP. Conclusion: DBGM summative C-Scores from DMD genome sequencing generated 9 candidate genes from 8,155 genes for stratifying CMP phenotypic variability. Further translational evaluation of these genes as modifiers of DMD CMP severity is warranted. If confirmed, these modifiers could provide therapeutic insight specific to DMD CMP.

SARS-CoV-2 is a novel coronavirus that has rarely been associated with chylothorax. Patients with Noonan syndrome are at risk for developing chylothorax, especially after cardiothoracic interventions. We present the case of SARS-CoV-2 infection triggering the underlying tendency of a patient with Noonan syndrome to develop chylothorax who did not develop it even after prior cardiothoracic interventions. Patient presented in respiratory distress without hypoxia and was found, on imaging, to have a large right-sided pleural effusion, which was eventually classified as chylothorax. The patient was then started on a low-fat diet. Chest tube drainage substantially reduced the effusion in size, and it remained stable. Our report highlights that SARS-CoV-2 infection can cause the development of a chylothorax or a chylous effusion in patients with Noonan syndrome or among populations with a similar predisposition. A high index of suspicion in vulnerable patients or those not responding to traditional therapy should exist with providers, thus leading to the testing of the fluid to confirm the diagnosis.

Objectives: Lack of defined diagnostic criteria for acute myocarditis makes its diagnosis dependent on clinical suspicion. The objective of this study was to the current trends in demographics, clinical manifestations, treatments, and outcomes in the United States for children hospitalized with acute myocarditis. Methods: This retrospective study was conducted using data collected from the Pediatric Health Information System (PHIS) database for the years 2014-2020. We included patients 21 years or younger with acute myocarditis. The statistical analysis was performed using Chi-squared and continuous variables using Mann-Whitney U-test for continuous data comparisons. Results: We found 1199 patients with acute myocarditis. About 60% of patients required admission to the intensive care unit (ICU). The median hospital length of stay was four days for all patients and six days for ICU patients. Two hundred sixty-five (22.1%) patients required invasive mechanical ventilation, 127 (10.6%) required Extracorporeal membrane oxygenation, 33 (2.8%) required Ventricular assist device and 22 (1.8%) required cardiac transplantations. Milrinone was the most used vasoactive agent. The overall hospital mortality was 2.3%. IVIG infusion use decreased during the study period. On multivariate analysis, vasoactive medication use, (p< 0.01) and arrhythmia (p = 0.02) were independently associated with increased odds of mortality. IVIG use (p=0.01) was associated with decreased odds of mortality. Conclusions: Despite high morbidity and frequent need for advanced life support measures, the survival outcomes of acute myocarditis in children are favorable. Vasoactive medication support and occurrence of arrythmia were independently associated with mortality, most likely due to disease severity. Administration of IVIG was independently associated with reduced mortality.

BACKGROUND:We report current outcomes in patients supported with the HeartMate 3 (HM3) ventricular assist device in a multicenter learning network. METHODS:The Advanced Cardiac Therapies Improving Outcomes Network database was queried for HM3 implants between 12/2017 and 5/2022. Clinical characteristics, postimplant course, and adverse events were collected. Patients were stratified according to body surface area (BSA) (<1.4 m2, 1.4-1.8 m2, and >1.8 m2) at device implantation. RESULTS:During the study period, 170 patients were implanted with the HM3 at participating network centers, with median age 15.3years; 27.1% were female. Median BSA was 1.68 m2; the smallest patient was 0.73 m2 (17.7 kg). Most (71.8%) had a diagnosis of dilated cardiomyopathy. With a median support time of 102.5days, 61.2% underwent transplantation, 22.9% remained supported on device, 7.6% died, and 2.4% underwent device explantation for recovery; the remainder had transferred to another institution or transitioned to a different device type. The most common adverse events included major bleeding (20.8%) and driveline infection (12.9%); ischemic and hemorrhagic stroke were encountered in 6.5% and 1.2% of patients, respectively. Patients with BSA <1.4 m2 had a higher incidence of infection, renal dysfunction, and ischemic stroke. CONCLUSIONS:In this updated cohort of predominantly pediatric patients supported with the HM3 ventricular assist device, outcomes are excellent with <8% mortality on device. Device-related adverse events including stroke, infection, and renal dysfunction were more commonly seen in smaller patients, highlighting opportunities for improvements in care.

Pediatric transplant centers are faced with the difficult task of maximizing the benefit of organs donated for transplantation while also ensuring that all patients undergoing transplant evaluation are fairly considered for this life-saving therapy. Children with neurodevelopmental disabilities are a complex patient population that on occasion may face the need for a solid organ transplant. Several concerns exist regarding transplantation in this population, yet standard transplant inclusion and exclusion criteria do not exist. Here we explore important factors regarding organ transplantation for children with neurodevelopmental disorders, including patient outcomes, quality of life considerations, and the fundamental ethical principles underlying this complex medical decision-making.

BACKGROUND:Cardiac allograft vasculopathy (CAV) is a leading cause of graft failure in pediatric heart transplant recipients (HTRs). Early statin use has been shown to reduce CAV incidence and all-cause mortality in adult HTRs. We sought to evaluate the contemporary prevalence and trends of statin use in pediatric HTRs and the association between statin use with CAV development and graft failure. METHODS:Patients aged <17 years at the time of primary heart transplant who survived to ≥3 years without CAV were identified from the Pediatric Heart Transplant Society database (2001-2018). Statin use in the first 3 years posttransplant was defined as consecutive, intermediate, or absent. Kaplan-Meier survival, multivariable modeling, and propensity score-matched analyses evaluated associations between statin use and CAV incidence and graft survival, with subanalyses performed on subjects aged ≥10 years at transplant. RESULTS:Among 3,485 (of which 1,086 aged ≥10 years) HTRs, 584 (17%) received consecutive statin therapy, 647 (19%) received intermediate use, and 2,254 (65%) received no statin therapy. Statin use varied widely between sites, with increasing use in the ≥10-year-old cohort over time. By multivariate analysis, statin use was not associated with graft loss. Consecutive statin use was also not associated with graft survival or freedom from CAV development when compared to absent statin use in unmatched or propensity-matched analyses. CONCLUSIONS:While statins remain commonly utilized in pediatric HTRs, early consecutive statin therapy did not decrease CAV incidence or graft loss. The differing effects of statins on CAV development and progression in pediatric vs adult HTRs suggest differing risk and mediating factors and require further study.

BACKGROUND Genetic defects in the RAS/mitogen-activated protein kinase pathway are an important cause of hypertrophic cardiomyopathy (RAS-HCM). Unlike primary HCM (P-HCM), the risk of sudden cardiac death (SCD) and long-term survival in RAS-HCM are poorly understood. OBJECTIVES The study's objective was to compare transplant-free survival, incidence of SCD, and implantable cardioverter-defibrillator (ICD) use between RAS-HCM and P-HCM patients. METHODS In an international, 21-center cohort study, we analyzed phenotype-positive pediatric RAS-HCM (n = 188) and P-HCM (n = 567) patients. The between-group differences in cumulative incidence of all outcomes from first evaluation were compared using Gray's tests, and age-related hazard of all-cause mortality was determined. RESULTS RAS-HCM patients had a lower median age at diagnosis compared to P-HCM (0.9 years [IQR: 0.2-5.0 years] vs 9.8 years [IQR: 2.0-13.9 years], respectively) (P < 0.001). The 10-year cumulative incidence of SCD from first evaluation was not different between RAS-HCM and P-HCM (4.7% vs 4.2%, respectively; P = 0.59). The 10-year cumulative inci-dence of nonarrhythmic deaths or transplant was higher in RAS-HCM compared with P-HCM (11.0% vs 5.4%, respec-tively; P = 0.011). The 10-year cumulative incidence of ICD insertions, however, was 5-fold lower in RAS-HCM compared with P-HCM (6.9% vs 36.6%; P < 0.001). Nonarrhythmic deaths occurred primarily in infancy and SCD primarily in adolescence. CONCLUSIONS RAS-HCM was associated with a higher incidence of nonarrhythmic death or transplant but similar incidence of SCD as P-HCM. However, ICDs were used less frequently in RAS-HCM compared to P-HCM. In addition to monitoring for heart failure and timely consideration of advanced heart failure therapies, better risk stratification is needed to guide ICD practices in RAS-HCM. (J Am Coll Cardiol 2023;81:1035-1045) (c) 2023 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).