Long-term studies on safety of beta-blockers in pediatric heart failure (HF) are scant. We describe the safety profile, dose ranges, and tolerability of carvedilol in pediatric dilated cardiomyopathy (DCM). The Pediatric Cardiomyopathy Registry (PCMR) was used to identify patients with DCM, treated with carvedilol from 1997 to 2005. Descriptive statistics were analyzed and echocardiographic parameters were compared longitudinally using ANOVA. Total 118 patients were included with median age 4.4 years (interquartile range (IQR) 1.0–13.3). The etiology of DCM was idiopathic (66

Ventriculoarterial coupling (VAC), the ratio of arterial elastance (Ea) to LV end-systolic elastance (Ees), measures the relationship between ventricular performance and arterial stiffness. We hypothesized that VAC is abnormal in muscular dystrophy (MD) patients and worsens with disease progression. MD patients < 21 years were included. Demographics, MD phenotype, medications, medical history, and clinical status were collected. Initial and last follow up echocardiograms were reviewed to determine Ea, Ees, and VAC and compared between MD and age-matched males and between the initial and last follow up studies in the MD patients. Univariable and multivariable regression analyses was performed to determine factors independently associated with VAC. Forty-six MD patients, median age at diagnosis 9.8 years (IQR 7 -12.2), followed for a median of 4.1 years (IQR 3–6) were included for study. 41

BACKGROUND:Population-based data on healthcare utilization in adults with congenital heart disease (CHD) are limited. We examined utilization patterns in a multi-site, population-based U.S. cohort of adults with CHD. METHODS:This retrospective cohort linked health and administrative records from five regions (Colorado, North Carolina, Utah, metropolitan Atlanta, and New York). Adults aged 19-64 years with at least one CHD-related ICD-9-CM code recorded during 2011-2013 were included. We evaluated inpatient, emergency department (ED), outpatient, and cardiology outpatient encounters, as well as cardiac diagnostic/imaging, therapeutic/interventional, and vascular procedures. Multivariable mixed-effects logistic regression models compared utilization by CHD severity (severe vs. non-severe), adjusting for sex, race/ethnicity, insurance, comorbidity, and site, and including age group as an effect modifier. RESULTS:Over 3 years, this cohort of 18,877 adults (20.7% severe CHD), 45.9% had at least one hospitalization, 35.1% had an ED visit, 92.1% had an outpatient encounter, and 43.8% had a cardiology outpatient visit. Cardiac diagnostic/imaging procedures occurred in 67.8%, cardiac interventions in 20.3%, and vascular procedures in 10.5%. Severe CHD was associated with higher odds of cardiac procedures but lower odds of ED use than non-severe CHD. Age modified these associations, and site-level variation was marked, with cardiology visit rates ranging from 21% to 59%. CONCLUSIONS:Adults with CHD had high healthcare utilization, including frequent ED use, yet fewer than half saw a cardiology specialist, particularly at older ages. These findings highlight persistent gaps in lifelong care and substantial geographic variation, underscoring the need to improve access to specialized care for adults with CHD.

We evaluated the frequency and patterns of comorbidity and multimorbidity in adolescents with congenital heart disease (CHD) using data from a multisite population-based surveillance project. Adolescents aged 11 to 18 years with at least 1 CHD-related diagnosis code and residing in one of 5 geographic areas in the US were identified using linked clinical and administrative data sources for the years 2011 to 2013. Sites linked data on all inpatient, emergency department, and outpatient visits. Multivariate Poisson regression with robust error estimates was used to assess the association of comorbidity with age, sex, insurance type, race, ethnicity, and CHD severity. The study included 9626 adolescents. Of these, 26% had severe CHDs. Overall, 68% had at least one comorbidity during the study period, and 46% had multiple comorbidities. Noncardiac comorbidities (55%) were more frequent than cardiac comorbidities (40%). Major noncardiac comorbidities included mental health conditions, neurodevelopmental disorders, pulmonary obstructive disease, nutrition-related (overweight, obesity) conditions, and endocrine conditions. Cardiac comorbidities included arrhythmias and residual cardiac disease. Variations by age and sex were minimal, but a higher burden of comorbidity and multimorbidity was associated with CHD severity, multiracial background, and public insurance. Comorbidities, both cardiac and noncardiac, are prevalent in adolescents with CHD, underscoring the need for targeted care strategies in this age group and effective transition programs from pediatric to adult CHD care.

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.

BACKGROUND:Survival of individuals with congenital heart disease (CHD) has improved, leading to a growing and aging population of adults living with these conditions. Over their lifetime, they often face an array of comorbidities that affect outcomes and complicate medical management. However, population-based information on such comorbidities is scarce, reducing opportunities for prevention. METHODS:This population-based, cross-sectional study assessed comorbid conditions in adults with CHD residing in five geographic areas in the United States (in Colorado, Georgia, New York, North Carolina, and Utah). The study included 18,672 adults aged 19 to 64 years who had a healthcare encounter between 2011 and 2013 associated with ≥ 1 CHD-related diagnosis code. Data were derived from linked clinical and administrative sources, reflecting inpatient, outpatient, and emergency department encounters. RESULTS:Most adults with CHD experienced at least one (88.5%) and usually multiple (76%) comorbidities. Overall, noncardiac comorbidities exceeded cardiac comorbidities. The most frequent noncardiac comorbidities were endocrine/metabolic conditions (e.g., diabetes, hyperlipidemia, hypothyroidism), hypertension, and neuropsychiatric conditions (e.g., anxiety, depression). The presence and number of comorbidities varied in different sociodemographic groups. Men and older individuals experienced higher rates of many comorbidities, cardiac and noncardiac, regardless of CHD type. CONCLUSIONS:Preventable and treatable comorbidity and multimorbidity are common in adults with CHD, with patterns shaped by sociodemographic factors and CHD type. Reducing preventable mortality in this growing population will require sustained tracking of health metrics and coordinated, data-driven, and lifelong care.

Medical and surgical advances have resulted in excellent midterm survival following the Fontan procedure; however, heart failure has become an important cause of morbidity and mortality as these patients age. The mechanisms of heart failure are multifactorial and include morphologic abnormalities, chronic exposure of the myocardium and pulmonary vascular bed to cyanosis, pathophysiologic volume- and pressure-loads, and myocardial ischemia. Heart failure following the Fontan can be the result of systolic or diastolic ventricular function; equally important is low flow through the Fontan circuit due to abnormalities of the lymphatic or pulmonary vasculature. The hallmarks of a “failing Fontan” circulation include systemic venous congestion and low cardiac output from an underfilled ventricle. Clinical evaluation of the Fontan patient includes evaluation for signs and symptoms of low output and venous congestion along with noninvasive and invasive assessments of hemodynamics and anatomy. Noncardiac comorbidities are common, and laboratory testing is essential for risk stratification. Treatment of heart failure begins with preventive measures to minimize myocardial damage and pulmonary hypertension. Evidence-based medical therapies are lacking, and treatment of ventricular dysfunction is largely limited to Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Effective interventions to decrease the consequences of venous congestion have not been identified. Increasing use of ventricular assist devices has been reported, and heart transplantation remains the intervention of choice for end-stage heart failure. Significant knowledge gaps exist regarding the mechanisms of heart failure, the effectiveness and safety of heart failure medications, and the optimal timing and management of ventricular assist devices and heart transplants.

INTRODUCTION:Duchenne muscular dystrophy is a devastating neuromuscular disorder characterized by the loss of dystrophin, inevitably leading to cardiomyopathy. Despite publications on prophylaxis and treatment with cardiac medications to mitigate cardiomyopathy progression, gaps remain in the specifics of medication initiation and optimization. METHOD:This document is an expert opinion statement, addressing a critical gap in cardiac care for Duchenne muscular dystrophy. It provides thorough recommendations for the initiation and titration of cardiac medications based on disease progression and patient response. Recommendations are derived from the expertise of the Advance Cardiac Therapies Improving Outcomes Network and are informed by established guidelines from the American Heart Association, American College of Cardiology, and Duchenne Muscular Dystrophy Care Considerations. These expert-derived recommendations aim to navigate the complexities of Duchenne muscular dystrophy-related cardiac care. RESULTS:Comprehensive recommendations for initiation, titration, and optimization of critical cardiac medications are provided to address Duchenne muscular dystrophy-associated cardiomyopathy. DISCUSSION:The management of Duchenne muscular dystrophy requires a multidisciplinary approach. However, the diversity of healthcare providers involved in Duchenne muscular dystrophy can result in variations in cardiac care, complicating treatment standardization and patient outcomes. The aim of this report is to provide a roadmap for managing Duchenne muscular dystrophy-associated cardiomyopathy, by elucidating timing and dosage nuances crucial for optimal therapeutic efficacy, ultimately improving cardiac outcomes, and improving the quality of life for individuals with Duchenne muscular dystrophy. CONCLUSION:This document seeks to establish a standardized framework for cardiac care in Duchenne muscular dystrophy, aiming to improve cardiac prognosis.

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).

With continued medical and surgical advancements, most children and adolescents with congenital heart disease are expected to survive to adulthood. Chronic heart failure is increasingly being recognized as a major contributor to ongoing morbidity and mortality in this population as it ages, and treatment strategies to prevent and treat heart failure in the pediatric population are needed. In addition to primary myocardial dysfunction, anatomical and pathophysiological abnormalities specific to various congenital heart disease lesions contribute to the development of heart failure and affect potential strategies commonly used to treat adult patients with heart failure. This scientific statement highlights the significant knowledge gaps in understanding the epidemiology, pathophysiology, staging, and outcomes of chronic heart failure in children and adolescents with congenital heart disease not amenable to catheter-based or surgical interventions. Efforts to harmonize the definitions, staging, follow-up, and approach to heart failure in children with congenital heart disease are critical to enable the conduct of rigorous scientific studies to advance our understanding of the actual burden of heart failure in this population and to allow the development of evidence-based heart failure therapies that can improve outcomes for this high-risk cohort.

Background: A viral vector recombinant gene transfer therapy (GTT) has recently been approved by the FDA for males of all ages with Duchenne Muscular Dystrophy (DMD) without limitations regarding preexisting cardiac impairment. Acute myocarditis is a potential life-threatening short-term complication that has been reported following GTT. This immune mediated response can range from troponin elevation to rapid cardiovascular compromise and death, particularly in those with abnormal cardiac status at baseline. Early detection of cardiac compromise is essential to optimize outcomes. Objectives: The primary objective of this consensus statement is to advocate for caution with DMD GTT patient selection and to initiate preemptive monitoring for those who may be at increased risk for cardiac adverse events. Secondary objective is to deepen our understanding of short and long-term impact of DMD gene therapies on the heart. Methods: A national learning network of pediatric cardiologists with expertise in DMD developed recommendations for cardiac surveillance of DMD males receiving GTT based on available evidence and expert consensus opinion. A monitoring and treatment plan for standard and high cardiac risk patients was developed. Conclusion: Partnership of cardiologists with GTT prescribers is essential to identify patient-specific considerations that might influence risk for adverse cardiac events and alter post infusion monitoring and management plans. Consistency in cardiac surveillance practices across centers will expedite our knowledge regarding potential short- and long-term cardiac effects of GTT for DMD.

Given the numerous opportunities and the wide knowledge gaps in pediatric heart failure, an international group of pediatric heart failure experts with diverse backgrounds were invited and tasked with identifying research gaps in each pediatric heart failure domain that scientists and funding agencies need to focus on over the next decade.

BackgroundDespite advances in treatment and survival, individuals with congenital heart defects (CHD) have a higher risk of heart failure (HF) compared to the general population.ObjectiveTo evaluate comorbidities associated with HF in patients with CHD with a goal of identifying potentially modifiable risk factors that may reduce HF-associated morbidity and mortality.MethodsFive surveillance sites in the United States linked population-based healthcare data and vital records. Individuals with an ICD-9-CM code for CHD aged 11-64 years were included and were stratified by presence of HF diagnosis code. Prevalence of death and cardiovascular risk factors based on diagnosis codes were compared by HF status using log-linear regression.ResultsA total of 25,343 individuals met inclusion/exclusion criteria. HF was documented for 2.2% of adolescents and 12.9% of adults with CHD. Adolescents and adults with HF had a higher mortality than those without HF. In both age groups, HF was positively associated with coronary artery disease, hypertension, obesity, diabetes, and increased healthcare utilization compared to those without HF.ConclusionsWithin this population-based cohort, over 1 in 50 adolescents and 1 in 8 adults with CHD had HF, which was associated with increased mortality. Modifiable cardiovascular comorbidities were associated with HF.ImpactFive sites in the United States linked population-based healthcare data and vital records to establish surveillance network for identifying the factors which influence congenital heart disease (CHD) outcomes.Survivors of CHD frequently develop heart failure across the lifespan.Over 1 in 50 adolescent and 1 in 8 adult survivors of CHD have heart failure which is associated with increased mortality compared to CHD survivors without heart failure.Heart failure development is associated with potentially modifiable cardiovascular risk factors such as hypertension, coronary artery disease, and diabetes.Controlling modifiable cardiovascular risk factors may serve to lower the risk of heart failure and mortality in survivors of congenital heart disease of all ages.

Background: Clinical genetic testing is increasingly being utilized to establish a molecular diagnosis to help manage children with cardiomyopathy and to assess the risk of cardiomyopathy among family members. However, as evidence and guidelines evolve, variant classification can change with the potential to impact counseling and family screening. Objectives: The main purpose of this study was to investigate whether variants in cardiomyopathy genes previously interpreted by clinical genetic testing laboratories would be reclassified under current guidelines for the interpretation of sequence variants. Methods: In 211 children enrolled in the Pediatric Cardiomyopathy Registry, we compared the results of previous clinical genetic testing with the results of research testing in 37 cardiomyopathy genes. Results: The mean time difference between initial testing and reinterpretation was 7 years. Using the 2015 American College of Medical Genetics and Genomics guidelines for the interpretation of sequence variants, we found that 18 % of the tested population had a change in variant classification. Ninety-two percent of the initial classifications were performed before the publication of the guidelines, with 82 % of reclassifications resulting in a variant downgrade. Most of these were changes from the pathogenic or likely pathogenic category to a variant of uncertain significance. Reclassification frequency was similar across types of cardiomyopathy. Conclusion: Our results highlight that a portion of variants get downgraded, and periodic reinterpretation of genetic testing results is necessary for all types of cardiomyopathy -particularly for variant interpretations prior to 2015. Importantly, variant reclassification has potential impact on the clinical management of at -risk patients.

Even with recent substantive improvements in health care in pediatric populations, considerable need remains for additional safe and effective interventions for the prevention and treatment of diseases in children. The approval of prescription drugs and biological products for use in pediatric settings, as in adults, requires demonstration of substantial evidence of effectiveness and favorable benefit-to-risk. For diseases primarily affecting children, such evidence predominantly would be obtained in the pediatric setting. However, for conditions affecting both adults and children, pediatric extrapolation uses scientific evidence in adults to enable more efficiently obtaining a reliable evaluation of an intervention's effects in pediatric populations. Bridging biomarkers potentially have an integral role in pediatric extrapolation. In a setting where an intervention reliably has been established to be safe and effective in adults, and where there is substantive evidence that disease processes in pediatric and adult settings are biologically similar, a 'bridging biomarker' should satisfy three additional criteria: effects on the bridging biomarker should capture effects on the principal causal pathway through which the disease process meaningfully influences 'feels, functions, survives' measures; secondly, the experimental intervention should not have important unintended effects on 'feels, functions, survives' measures not captured by the bridging biomarker; and thirdly, in statistical analyses in adults, the intervention's net effect on 'feels, functions, survives' measures should be consistent with what would be predicted by its level of effect on the bridging biomarker. A validated bridging biomarker has considerable potential utility, since an intervention's efficacy could be extrapolated from adult to pediatric populations if evidence in children establishes the intervention not only to be safe but also to have substantive effects on that bridging biomarker. Proper use of bridging biomarkers could increase availability of reliably evaluated therapies approved for use in pediatric settings, enabling children and their caregivers to make informed choices about health care.