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Hypertrophic cardiomyopathy (HCM) remains the most common cardiomyopathy in humans and cats with few preclinical pharmacologic interventional studies. Small-molecule sarcomere inhibitors are promising novel therapeutics for the management of obstructive HCM (oHCM) patients and have shown efficacy in left ventricular outflow tract obstruction (LVOTO) relief. The objective of this study was to explore the 6-, 24-, and 48-hour (h) pharmacodynamic effects of the cardiac myosin inhibitor, CK-586, in six purpose-bred cats with naturally occurring oHCM. A blinded, randomized, five-treatment group, crossover preclinical trial was conducted to assess the pharmacodynamic effects of CK-586 in this oHCM model. Dose assessments and select echocardiographic variables were assessed five times over a 48-h period. Treatment with oral CK-586 safely ameliorated LVOTO in oHCM cats. CK-586 treatment dose-dependently eliminated obstruction (reduced LVOTOmaxPG), increased measures of systolic chamber size (LVIDs Sx), and decreased select measures of heart function (LV FS% and LV EF%) in the absence of impact on heart rate. At all tested doses, a single oral CK-586 dose resulted in improved or resolved LVOTO with well-tolerated, dose-dependent, reductions in LV systolic function. The results from this study pave the way for the potential use of CK-586 in both the veterinary and human clinical setting.

Background. Our knowledge regarding the epidemiology of pediatric cardiomyopathy is based on large national population studies reporting an annual incidence of 1 case per 100,000 children, with a higher incidence observed in infancy and among selected populations. The aim here is to document the epidemiology of pediatric cardiomyopathy in a Mediterranean population. Methods. Children younger than 18 years of age living on the Mediterranean island of Crete, Greece, who have been evaluated since the establishment of tertiary pediatric cardiology services (2002–2022) were included in this retrospective study. Results. A total of 40 children were included, corresponding to an average annual incidence of pediatric cardiomyopathy of 1.59 cases (95% CI: 1.4–2.3) and a prevalence of 26 cases per 100,000 children. In decreasing order of frequency, most cases corresponded to dilated (50%), followed by hypertrophic (42.5%), arrhythmogenic (5%), and restrictive (2.5%) cardiomyopathy. An etiology was identified in 40%, including a genetic diagnosis in 22.5%. Conclusions. The incidence of pediatric cardiomyopathy in the Mediterranean island of Crete is higher compared with that reported previously for other Caucasian populations. Further study is needed to investigate the exact prevalence and specific genetic factors associated with the epidemiology of pediatric cardiomyopathy in Mediterranean populations. [ABSTRACT FROM AUTHOR]

BackgroundHypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM.MethodsWe performed a comprehensive multiomics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts).ResultsIntegrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in creatine kinase and ATP synthesis. Accompanying these metabolic derangements, electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance.ConclusionsOverall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.

Background. Our knowledge regarding the epidemiology of pediatric cardiomyopathy is based on large national population studies reporting an annual incidence of 1 case per 100,000 children, with a higher incidence observed in infancy and among selected populations. The aim here is to document the epidemiology of pediatric cardiomyopathy in a Mediterranean population. Methods. Children younger than 18 years of age living on the Mediterranean island of Crete, Greece, who have been evaluated since the establishment of tertiary pediatric cardiology services (2002–2022) were included in this retrospective study. Results. A total of 40 children were included, corresponding to an average annual incidence of pediatric cardiomyopathy of 1.59 cases (95% CI: 1.4–2.3) and a prevalence of 26 cases per 100,000 children. In decreasing order of frequency, most cases corresponded to dilated (50%), followed by hypertrophic (42.5%), arrhythmogenic (5%), and restrictive (2.5%) cardiomyopathy. An etiology was identified in 40%, including a genetic diagnosis in 22.5%. Conclusions. The incidence of pediatric cardiomyopathy in the Mediterranean island of Crete is higher compared with that reported previously for other Caucasian populations. Further study is needed to investigate the exact prevalence and specific genetic factors associated with the epidemiology of pediatric cardiomyopathy in Mediterranean populations.

Cardiomyopathies are a heterogeneous group of myocardial diseases representing the first cause of heart transplantation in children. Diagnosing and classifying the different phenotypes can be challenging, particularly in this age group, where cardiomyopathies are often overlooked until the onset of severe symptoms. Cardiovascular imaging is crucial in the diagnostic pathway, from screening to classification and follow-up assessment. Several imaging modalities have been proven to be helpful in this field, with echocardiography undoubtedly representing the first imaging approach due to its low cost, lack of radiation, and wide availability. However, particularly in this clinical context, echocardiography may not be able to differentiate from cardiomyopathies with similar phenotypes and is often complemented with cardiovascular magnetic resonance. The latter allows a radiation-free differentiation between different phenotypes with unique myocardial tissue characterization, thus identifying the presence and extent of myocardial fibrosis. Nuclear imaging and computed tomography have a complementary role, although they are less used in daily clinical practice due to the concern related to the use of radiation in pediatric patients. However, these modalities may have some advantages in evaluating children with cardiomyopathies. This paper aims to review the strengths and limitations of each imaging modality in evaluating pediatric patients with suspected or known cardiomyopathies. [ABSTRACT FROM AUTHOR]

Pediatric cardiomyopathies (CM) are rare and challenging to diagnose due to the complex and mixed phenotypes. With the advent of next-generation sequencing (NGS), variants in several genes associated with CM have been identified, such as Troponin C (TnC), encoded by the TNNC1 gene. De novo variants in TNNC1 have been associated with different types of CM, including dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). The American College of Medical Genetics and Genomics recently added TNNC1 to their recommended list of genes for reporting secondary findings. In this study, we report a de novo variant, c.100G > C (p.Gly34Arg) in the TNNC1 gene identified in three siblings with a diagnosis of severe DCM causing infant death for one of the siblings and stillbirth in the other two pregnancies. The identification of the same de novo variant in all affected siblings is suggestive of germline mosaicism in this family. [ABSTRACT FROM AUTHOR]

TAF1A , a gene encoding a TATA-box binding protein involved in ribosomal RNA synthesis, is a candidate gene for pediatric cardiomyopathy as biallelic TAF1A variants were reported in two families with affected individuals. Here, we report a third family with two siblings who presented with infantile restrictive cardiomyopathy and carried biallelic missense variants in TAF1A (NM_001201536.1:c.1021G>A p.(Gly341Arg) and c.781A>C p.(Thr261Pro)). Additional shared clinical features in the siblings included feeding intolerance, congenital leukoencephalopathy, ventriculomegaly and concern for primary immunodeficiency. The first-born sibling passed away at 6 months of age due to complications of hemophagocytic lymphohistiocytosis (HLH) whereas the second sibling underwent cardiac transplantation at 1 year of age and is currently well. We compare the clinical and molecular features of all the TAF1A associated cardiomyopathy cases. Our study adds evidence for the gene-disease association of TAF1A with autosomal recessive pediatric cardiomyopathy. [ABSTRACT FROM AUTHOR]

There are limited data that can explain the earlier penetrance and the different expressivity of pediatric cardiomyopathy (pCM) compared to adult-onset cardiomyopathy (aCM). In addition, the relationship between genotype and pCM results is poorly described. We compared the genotypes between a cohort of aCM and a cohort of pCM to propose hypotheses on the earlier penetrance and expressivity of pCM. Finally, we report how genetic testing was used to guide genetic counseling in pCM. 253 pCM (<18 years old) and 1466 aCM patients were sequenced on a panel of 67 cardiomyopathy genes. Risk factors for death and heart transplantation were analyzed. In pCM, the variant of interest (VOI) yield was 53.7 % including 24.2 % carrying two VOI. De novo variants represented 11 % of VOI in pCM and 50 % in restrictive pCM. An age at diagnosis younger than 1 year (HR = 2.07, p = 0.029), restrictive phenotype (HR = 2.87, p = 0.03) and the presence of two VOI (HR = 2.97, p = 0.001) were independent risk factors for death or heart transplantation. In comparison with aCM, pCM patients harbored more frequently two VOI (p = 0.02), or de novo variants (p = 4.10−13). In addition, the distribution of VOI was different in aCM and pCM. Genotyping of pCM improved genetic counseling in families and led to ten prenatal-diagnosis. Conclusions: Genetic testing provides clues for earlier penetrance of pCM. The presence of two VOI in children with CM is a risk factor for severe and early cardiac events. • Carrying 2 variants and an age of onset before 1 year old are risk factors associated with severe outcomes in pCM • pCM patients harbored a different spectrum of genes and variants compare to adult cardiomyopathies cohorts • A higher rate of patients carrying 2 or de novo variants, and specific genetic spectrum could explain pediatric onset of CM [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. 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. • Genetic variants from clinical genetic testing results can be reclassified. • Results older than 2015 or from racial/ethnic minorities should be verified. • Downgrading variants can have implications for clinical care. [ABSTRACT FROM AUTHOR]

OBJECTIVES This exploratory mixed-methods study explored the barriers to physical activity, daily physical activity and submaximal exercise capacity among children with and at risk for cardiomyopathy and children with atrial septal defects. METHODS The study followed a convergent parallel mixed methodology design. Semi-structured interviews explored physical activity barriers. Seven-day accelerometry assessed moderate-to-vigorous physical activity, and an intermittent cardiopulmonary exercise test measured submaximal exercise capacity. RESULTS Twenty children, including 5 with cardiomyopathy (n=2 females, 14.2 ± 2.7 years old), 7 who were genotype-positive phenotype-negative for cardiomyopathy (n=5 females, 10.6 ± 3.3 years old) and 8 with atrial septal defects (n=4 females, 9.4 ± 3.8 years old) were recruited. Children with cardiomyopathy reported disease-specific physical activity barriers, while children who were genotype-positive phenotype-negative perceived barriers related to lack of time, parent support or activity motivation. The average daily moderate-to-vigorous physical activity was less than the recommended 60-minutes/day (n=20, mean 48.1 ± 18.0 minutes). Children with cardiomyopathy participated a median of 141.2 [interquartile range (IQR): 98.8) minutes of light-intensity physical activity and a median of 55.6 (IQR: 34.6) minutes of moderate-to-vigorous physical activity. The average submaximal exercise capacity was low (n=16, 25.2 ± 5.7 mL/kg/min). Estimated submaximal exercise capacity, including metabolic equivalent (4.5 ± 3.1 METs), respiratory exchange ratio (median = 1.0, IQR: 0.09) and ratings of perceived exertion (median = 7, IQR: 5) at peak exercise suggest that children with cardiomyopathy appear to have the exercise capacity to participate in low-to-moderate intensity activities. CONCLUSIONS These novel data suggest that a diagnosis of cardiomyopathy may not preclude children from participating in a healthy, active lifestyle. However, they perceive disease-specific physical activity barriers and may require support to optimize their level of participation for optimal health.

Mutations in MYBPC3, the gene encoding cardiac myosin binding protein C (cMyBP-C), are a major cause of hypertrophic cardiomyopathy (HCM). While most mutations encode premature stop codons, missense mutations causing single amino acid substitutions are also common. Here we investigated effects of a single proline for alanine substitution at amino acid 31 (A31P) in the C0 domain of cMyBP-C, which was identified as a natural cause of HCM in cats. Results using recombinant proteins showed that the mutation disrupted C0 structure, altered sensitivity to trypsin digestion, and reduced recognition by an antibody that preferentially recognizes N-terminal domains of cMyBP-C. Western blots detecting A31P cMyBP-C in myocardium of cats heterozygous for the mutation showed a reduced amount of A31P mutant protein relative to wild-type cMyBP-C, but the total amount of cMyBP-C was not different in myocardium from cats with or without the A31P mutation indicating altered rates of synthesis/degradation of A31P cMyBP-C. Also, the mutant A31P cMyBP-C was properly localized in cardiac sarcomeres. These results indicate that reduced protein expression (haploinsufficiency) cannot account for effects of the A31P cMyBP-C mutation and instead suggest that the A31P mutation causes HCM through a poison polypeptide mechanism that disrupts cMyBP-C or myocyte function.

There is wide variability in the timing of heart transplant (HTx) after pediatric VAD implant. While some centers wait months before listing for HTx, others accept donor heart offers within days of VAD surgery. We sought to determine if HTx within 30 days versus ≥ 30 after VAD impacts post-HTx outcomes. Children on VAD pre-HTx were extracted from the Pediatric Heart Transplant Study database. The primary endpoints were post-HTx length of hospital stay (LOS) and one-year survival. Confounding was addressed by propensity score weighting using inverse probability of treatment. Propensity scores were calculated based on age, blood type, primary cardiac diagnosis, decade, VAD type, and allosensitization status. A total of 1064 children underwent VAD prior to HTx between 2000 to 2018. Most underwent HTx ≥ 30 days post-VAD (70%). Infants made up 22% of both groups. Patients ≥ 12 years old were 42% of the < 30 days group and children 1 to 11 years comprised 47% of the ≥ 30 days group (p < 0.001). There was no difference in the prevalence of congenital heart disease vs. cardiomyopathy (p = 0.8) or high allosensitization status (p = 0.9) between groups. Post-HTx LOS was similar between groups (p = 0.11). One-year survival was lower in the < 30 days group (adjusted mortality HR 1.76, 95% CI 1.11-2.78, p = 0.016). A longer duration of VAD support prior to HTx is associated with a one-year survival benefit in children, although questions of patient complexity, post-VAD complications and the impact on causality remain. Additional studies using linked databases to understand these factors will be needed to fully assess the optimal timing for post-VAD HTx. [ABSTRACT FROM AUTHOR]

Cardiomyopathy is a risk factor for poor prognosis in pediatric patients with mitochondrial disease. However, other risk factors including genetic factors related to poor prognosis in mitochondrial disease has yet to be fully elucidated. Between January 2004 and September 2019, we enrolled 223 consecutive pediatric mitochondrial disease patients aged <18 years with a confirmed genetic diagnosis, including 114 with nuclear gene mutations, 89 patients with mitochondrial DNA (mtDNA) point mutations, 11 with mtDNA single large-scale deletions and 9 with chromosomal aberrations. Cardiomyopathy at baseline was observed in 46 patients (21%). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for all-cause mortality. Over a median follow-up of 36 months (12–77), there were 85 deaths (38%). The overall survival rate was significantly lower in patients with cardiomyopathy than in those without (p < 0.001, log-rank test). By multivariable analysis, left ventricular (LV) hypertrophy (HR = 4.6; 95% CI: 2.8–7.3), neonatal onset (HR = 2.9; 95% CI: 1.8–4.5) and chromosomal aberrations (HR = 2.9; 95% CI: 1.3–6.5) were independent predictors of all-cause mortality. Patients with LV hypertrophy with neonatal onset and/or chromosomal aberrations had higher mortality (100% in 21 patients) than those with LV hypertrophy alone (71% in 14 patients). In pediatric patients with mitochondrial disease, cardiomyopathy was common (21%) and was associated with increased mortality. LV hypertrophy, neonatal onset and chromosomal aberrations were independent predictors of all-cause mortality. Prognosis is particularly unfavorable if LV hypertrophy is combined with neonatal onset and/or chromosomal aberrations. • Cardiomyopathy is related to poor prognosis in pediatric mitochondrial disease patients. • However, other risk factors including genetic factors related to poor prognosis has yet to be fully elucidated. • We assessed the prognosis and genetic background of cardiomyopathy in 223 pediatric mitochondrial disease patients. • Cardiomyopathy was common (22%) and was associated with increased mortality. • Left ventricular (LV) hypertrophy, neonatal onset and chromosomal aberrations were independent predictors of mortality. • Prognosis is particularly unfavorable if LV hypertrophy is combined with neonatal onset and/or chromosomal aberrations. [ABSTRACT FROM AUTHOR]

Pediatric patients on the waiting list for heart transplantation incur the highest risk of death for any organ transplantation. Berlin Heart EXCOR provides a reliable support as a bridge to heart transplantation or recovery for all pediatric age groups. We report the first successful experience of Berlin Heart EXCOR mechanical circulatory support and heart transplantation in pediatric patients in Saudi Arabia. The purpose of this report is to highlight the clinical events and share lessons learned from this endeavor. [ABSTRACT FROM AUTHOR]

Endomyocardial biopsy (EMB) is a well-known diagnostic tool for the investigation and treatment of myocardial diseases and remains the gold standard for the diagnosis of myocarditis. Due to its invasiveness, with a complication rate ranging from 1 to 15%, its role in the diagnostic work-up of pediatric heart failure is not well established. The aim of this review is to define the role of EMB as diagnostic technique in the work up of children presenting with severe left ventricular dysfunction with the support of our center experience.

The ACMG/AMP variant classification framework was intended for highly penetrant Mendelian conditions. While it is appreciated that clinically relevant variants exhibit a wide spectrum of penetrance, accurately assessing and expressing the pathogenicity of variants with lower penetrance can be challenging. The vinculin (VCL) gene illustrates these challenges. Model organism data provide evidence that loss of function of VCL may play a role in cardiomyopathy and aggregate case‐control studies suggest low penetrance. VCL loss of function variants, however, are rarely identified in affected probands and therefore there is a paucity of family studies clarifying the clinical significance of individual variants. This study, which aggregated data from >18,000 individuals who underwent gene panel or exome testing for inherited cardiomyopathies, identified 32 probands with VCL loss‐of‐function variants and confirmed enrichment in probands with dilated cardiomyopathy (odds ratio [OR] = 9.01; confidence interval [CI] = 4.93–16.45). Our data revealed that the majority of these individuals (89.5%) had pediatric onset of disease. Family studies demonstrated that heterozygous loss of function of VCL alone is insufficient to cause cardiomyopathy but that these variants do contribute to disease risk. In conclusion, VCL loss‐of‐function variants should be reported in a diagnostic setting but need to be clearly distinguished as having lower penetrance. [ABSTRACT FROM AUTHOR]

Aim: The aim of the study was to assess predictors of outcome in patients hospitalized for dilated cardiomyopathy (DCM) and severe left ventricular dysfunction. Patients & methods: 83 pediatric patients hospitalized for heart failure due to DCM with coexistent left ventricular dysfunction were enrolled.Results: Overall, 5-year survival free from heart transplantation was 69.8%. Normalization of left ventricular function was achieved in 39.8% of patients during follow-up: younger age, less necessity of inotropic support and other than idiopathic DCM predicted left ventricular function, while familial history for cardiac disease or sudden death and inotropic support during hospitalization were associated with poorer outcome.Conclusion: Almost 40% of patients with DCM experienced a complete normalization of cardiac function. Outcome was extremely variable according to the type of DCM. [ABSTRACT FROM AUTHOR]

Successful therapy in a cohort with early onset Danon disease (DD) highlights the potential importance of earlier disease recognition. We present experience from the largest National Pediatric Center in Russia for cardiomyopathy patients. This report focuses on identification of early clinical features of DD in the pediatric population by detailed pedigree analysis and review of medical records. Nine patients (3 females) were identified with DD at the Russian National Medical Research Center of Children's Health ("National Pediatric Center") aged birth to 16 years. At presentation/evaluation: all patients had left ventricular hypertrophy (LVH), ECG features of Wolff-Parkinson-White (WPW), and an increase in hepatic enzymes (particularly lactate dehydrogenase (LDH)); three had marked increase in NT-proBNP; two had HCM with impaired LV function; one had LVH with LV noncompaction; five had arrhythmia with paroxysmal supraventricular and/or ventricular tachycardia. Two teenagers died at ages 16–17 from refractory heart failure and two underwent heart transplantation. All patients were found to have a pathogenic/likely pathogenic variant in the LAMP2 gene, six patients had no family history and a de novo evolvement was documented in 4/6 of those available for genetic tested. Retrospective review related to family background and earlier clinical evaluations revealed a definitive or highly suspicious family history of DD in 3, early clinical presentation with cardiac abnormalities (ECG, echo) in 3, and cerebral, hepatic and/or neuromuscular symptoms in 5. Abnormalities were detected 9,5 months to 5,8 years, median 3,5 years prior to referral to the National Pediatric Center. The earliest clinical manifestations of Danon disease occur in the first 12 years of life with symptoms of skeletal muscle and cerebral disease, raised hepatic enzymes, and evidence of cardiac disease on ECG/echo. • Danon disease develops in patients of both sexes, despite the X-linked variant of inheritance. • Pediatric red flags for early diagnosis are: intracellular enzyme elevation in blood tests which are associated with Wolff-Parkinson-White-like patterns on ECG and myocardial hypertrophy. • The positive Phase 1 study results of Danon gene therapy treatment makes early diagnosis in children particularly important and might help to avoid the typically rapid progression of Danon disease that leads to patients requiring heart transplantation. [ABSTRACT FROM AUTHOR]

Pediatric cardiomyopathies are rare. The disease can be a chronic, debilitating illness and is often progressive. There are many unknowns related to the heritability of cardiomyopathy, acute risks of disease, disease progression, and treatment efficacy that are unique to this population. These disease-related confounders may be important determinants of quality of life for PCM patients and families. Few studies have evaluated health-related quality of life and its determinants in pediatric cardiomyopathy patients. In this review, we will describe the epidemiology and natural history of pediatric cardiomyopathy and outcomes in these patients. We will highlight the clinical and scientific utility of health-related quality of life assessments in pediatric patients with cardiomyopathy and describe the screening tools that are currently in use and their potential roles in improving outcomes in pediatric patients living with cardiomyopathy. Finally, we will suggest potential, disease specific, modifiers of health-related quality of life in pediatric cardiomyopathy patients that may serve as a focus for clinical care and future research endpoints. [ABSTRACT FROM AUTHOR]

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heritable cardiomyopathy characterized by fibro-fatty replacement of right ventricular myocardium. Diagnostic criteria, established in 1994 and modified in 2010, are based on predominately adult manifestations of ARVC/D. The goal of this paper is to review a single-center experience with pediatric ARVC/D and propose modifications of current diagnostic criteria to appropriately include pediatric ARVC/D. We identified 16 pediatric cases of ARVC/D from our tertiary care center. Patient demographics, presentation, course, genetic testing, and family history were reviewed. Sixteen patients were diagnosed with ARVC/D through the modified diagnostic criteria, genetic testing, and pathology. Five patients had positive family histories. Five patients presented with cardiac arrest, and six were found to have ventricular tachycardia. Two patients presented with heart failure. Six autopsies, six explanted hearts, and three biopsies found massive fibro-fatty infiltration of the right ventricular wall. Six patients underwent heart transplantation, and two have received automatic implantable cardioverter defibrillator. Two patients had identifiable genetic mutations previously noted in the literature. One patient had a novel mutation of a known ARVC/D gene. Many pediatric patients do not meet the current ARVC/D diagnostic criteria, resulting in delays in diagnosis and treatment. The current criteria need further revision to encompass pediatric manifestations of ARVC/D. In our opinion, pathological and clinical findings alone are sufficient for accurate diagnosis of pediatric ARVC/D. Creating modified pediatric criteria would facilitate prompt diagnosis and management of ARVC/D and facilitate structured research with the goal of improving outcomes. [ABSTRACT FROM AUTHOR]

Cardiomyopathy is the leading diagnosis for pediatric heart transplantation in children over 1 year of age. The majority of these patients usually have dilated cardiomyopathy. Children with hypertrophic and restrictive types of cardiomyopathy comprise less than 20% of the total children transplanted. Hypertrophic cardiomyopathy is the smallest subgroup to receive a cardiac transplant (6%). The mean age at listing in the Pediatric Heart Transplant Study (PHTS) was 7.6 years; however, 39% were infants listed at a mean of 3.2 ± 2.8 months of age. A patient with hypertrophic cardiomyopathy older than 1 year had low waitlist mortality and survival after transplant was no different than dilated or non-cardiomyopathy patients. The infant subgroup had the poorest overall survival with waitlist mortality of 33%, within a few months after listing. Restrictive cardiomyopathy is the rarest type of cardiomyopathy (2–5%) but accounts for 11% of children transplanted with cardiomyopathy in PHTS. Survival after listing in infants < 1 year of age with either hypertrophic or restrictive cardiomyopathy was poor, 50% at 1 year compared with 80% in infants with dilated cardiomyopathy. The mean age at listing for restrictive patients in PHTS was 8.1 years, 81% were transplanted and 9% died waiting (40% of pre-transplant deaths were infants < 1 year). The 1 and 5 year survival was 89 and 77%, similar to other cardiomyopathy patients and better than non-cardiomyopathy patients. Risk factors and clinical profiles leading to listing are discussed. [ABSTRACT FROM AUTHOR]

Ventricular assist device ( VAD) support induces reverse remodeling of failing myocardium that leads to occasional functional recovery of the adult heart. While there have been numerous clinical reports in adult patients with end-stage cardiomyopathy, little is known about reverse remodeling in children, which has increasing clinical potential with the recent expansion of pediatric VADs in the setting of static organ supply for heart transplantation. Pediatric myocardium also promises theoretical advantages for recovery over adult myocardium due to its greater abundance of cardiac progenitor cells. To identify potential targets of future studies, we conducted a literature review with two aims: (i) to summarize clinical cases of pediatric patients who exhibited cardiac recovery following VAD support; and (ii) to analyze genetic changes in pediatric myocardium induced by VAD support compared with those observed in adult patients. Several clinical series of pediatric VAD cases report that small proportions of their cohorts were weaned off from device support, but a lack of information about the etiology and support duration of these patients limits the ability to determine whether they represent reverse remodeling of myocardial structure or just recovery from acute illness. A comparison of pediatric and adult gene expression changes with VAD support reveals approximately 40% of genes to be oppositely regulated, indicating that the pediatric genetic response is distinct. These observations highlight a necessity to better understand reverse remodeling specific to pediatric myocardium, which is crucial to improving clinical strategies for bridge-to-recovery in children. [ABSTRACT FROM AUTHOR]

Heart failure remains a significant contributor to morbidity and mortality in pediatric patients with congenital and acquired heart diseases. However, there are several new promising therapies for acute and chronic heart failures including the development of new pediatric specific ventricular assist devices. There remains a need for collaborative research including the creation of a large-scale registry of pediatric heart failure, increased utilization of genetic testing, and an improved understanding of the optimal model of disease management that maximizes quality care. [ABSTRACT FROM AUTHOR]

Cardiomyopathy (CM) in children shares some features with cardiomyopathy in adults but also has many important unique features. Heretofore, genetic testing panels, testing strategies, and treatment recommendations have largely been based on studies in adult populations. In general, CMs in children are much more likely to be genetic and to have extracardiac manifestations that should be medically addressed. Therefore, genetic testing in children with CM is an essential part of their initial evaluation and the ongoing care of the child and family. CMs in children are more genetically heterogeneous, and many of the genes that are rare causes of CM in children are not currently included in testing panels, and future genetic testing is likely to increasingly utilize more comprehensive approaches such as whole exome/whole genome sequencing with focused analysis of all the genes that can cause CM in children. [ABSTRACT FROM AUTHOR]

Coronary and congenital heart malformations contribute to and overlap with clinical cardiomyopathy. As cellular mechanisms and gene associations are better understood, overlap is becoming apparent between cardiomyopathies such as left ventricular non-compaction, hypertrophic cardiomyopathy and congenital heart disease. In current studies and registries, patients with clinical overlap are excluded limiting our understanding of the synergy of disease. We review contributing lesions and discuss genetic contributions to overlapping disease. [ABSTRACT FROM AUTHOR]