Search

The genetic reference population of recombinant inbred BXD mice has been derived from crosses between C57BL/6J and DBA/2J strains. The DBA/2J parent exhibits cardiomyopathy phenotypes, while C57BL/6J has normal heart. BXD mice are sequenced for studying genetic interactions in cardiomyopathies.The study aimed to assess cardiomyopathy traits in BXDs and investigate the quantitative genetic architecture of those traits.Echocardiography, blood pressure, and cardiomyocyte size parameters obtained from 44 strains of BXD family (N5/sex) at 4-5 months of age were associated with heart transcriptomes and expression quantitative trait loci (eQTL) mapping was performed.More than 2-fold variance in ejection fraction (EF%), fractional shortening (FS%), left ventricular volumes (LVVol), internal dimensions (LVID), mass (LVM), and posterior wall (LVPW) thickness was found among BXDs. In male BXDs, eQTL mapping identified Ndrg4 on chromosome 8 QTL to be positively correlated with LVVol and LVID and negatively associated with cardiomyocyte diameter. In female BXDs, significant eQTLs were found on chromosomes 7 and 3 to be associated with LVPW and EF% and FS%, respectively, and Josd2, Dap3 and Tmp3 were predicted as strong candidate genes.Our study found variable cardiovascular traits among BXD strains and identified multiple associated QTLs, suggesting an influence of genetic background on expression of echocardiographic and cardiomyocyte diameter traits. Increased LVVol and reduced EF% and FS% represented dilated cardiomyopathy, whereas increased LV mass and wall thickness indicated hypertrophic cardiomyopathy traits. The BXD family is ideal for identifying candidate genes, causal and modifier, that influence cardiovascular phenotypes.

Not available.

Introduction: Heart rhythm disorders or cardiac arrhythmias can cause sudden death and heart failure. Risk factors for cardiac arrhythmias vary including genetics, age, and other environmental and lifestyle factors. To sought how genetic background affects an expression of cardiac rhythm phenotypes, we assessed electrocardiography (ECG) traits in BXD family of mice derived from crosses between DBA/2J (D2) and C57BL/6J (B6) strains and explored the quantitative genetic architecture of those traits. Methods: ECG tracings were recorded in 44 BXD male (M) and female (F) strains (N >5 mice/sex) at 4-5 months of age anesthetized with 2% isoflurane. Heart rate (HR), ECG parameters, and frequency of arrhythmias in percentile (‰) were associated with blood pressure, echocardiography, and heart transcriptome values followed by quantitative trait loci (QTLs) mapping. Results: Parental D2 strains had the lowest HR and significantly prolonged QT intervals (62.82 ± 9.42 ms in D2F and 53.42 ± 1.73 ms in D2M) compared to sex matched B6 parental strains. Significantly widened QRS complexes were seen in BXD65F (14.27±2.97 ms) compared to 11.67±1.03 ms in B6F controls. In males, BXD83M had the widest QRS (13.48±1.74 ms) vs 10.89±0.41 ms seen in B6M controls. We found a significant association between QRS duration and increased left ventricular internal diameter (LVID) and reduced ejection fraction and fractional shortening. Further, varied cardiac arrhythmias including bradycardia, atrioventricular block (AVB), premature atrial or ventricular complexes (PAC and PVC, respectively), ventricular tachycardia (VT) and sick sinus syndrome (SSS) were seen among BXD strains. PACs were recorded in BXD73F (14.57 ‰), 40M, 101F, 51M, and 101M strains. Strains, BXD79M (14.97 ‰), 83M, 78M, 69F, and 171F, had frequent PVCs compared to B6 controls. AVB II was recorded in BXD48M and BXD66M had SSS. Both PAC and PVC were positively associated with cardiac phenotype burden. Specifically, PVCs were significantly correlated with echocardiographic pulmonary vein peak pressure, LVID and volumes at end-diastole (P = 0.04) among male BXDs. In females, right ventricular internal diameters (RVID) and cardiac output were significantly correlated with PVC and PAC frequencies. Moreover, PVCs were significantly correlated with systolic blood pressure in both male and female mice. QTL mapping identified a significant locus on Chromosome 3 associated with QTC and JT durations, while the same locus was suggestive for association with QT interval, suggesting that Chromosome 3 loci may be associated with repolarization abnormalities such as long QT syndromes. Conclusions: ECG parameters, heart rate, type and frequency of arrhythmias significantly varied between mouse strains of the BXD family suggesting an influence of genetic background on expression of those traits. Abnormal heart rhythms detected in BXD strains mimic cardiac rhythm and conduction disorders in humans. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder of desmosomal dysfunction, and PKP2 (plakophilin-2) has been reported to be the most common disease-causing gene when mutation-positive. In the early concealed phase, the ACM heart is at high risk of sudden cardiac death before cardiac remodeling occurs because of mistargeted ion channels and altered Ca 2+ handling. However, the results of pathogenic PKP2 variants on myocyte contraction in ACM pathogenesis remain unknown. Methods: We studied the outcomes of a human truncating variant of PKP2 on myocyte contraction using a novel knock-in mouse model with insertion of thymidine in exon 5 of Pkp2 , which mimics a familial case of ACM (PKP2-L404fsX5). We used serial echocardiography, electrocardiography, blood pressure measurements, histology, cardiomyocyte contraction, intracellular calcium measurements, and gene and protein expression studies. Results: Serial echocardiography of Pkp2 heterozygous (Pkp2-Het) mice revealed progressive failure of the right ventricle (RV) in animals older than 3 months. By contrast, left ventricular function remained normal. ECGs of 6-month-old anesthetized Pkp2-Het mice showed normal baseline heart rates and QRS complexes. Cardiac responses to β-adrenergic agonist isoproterenol (2 mg/kg) plus caffeine (120 mg/kg) were also normal. However, adrenergic stimulation enhanced the susceptibility of Pkp2-Het hearts to tachyarrhythmia and sudden cardiac death. Histological staining showed no significant fibrosis or adipocyte infiltration in the RVs and left ventricles of 6- and 12-month-old Pkp2-Het hearts. Contractility assessment of isolated myocytes demonstrated progressively reduced Pkp2-Het RV cardiomyocyte function consistent with RV failure measured by echocardiography. However, aging Pkp2-Het and control RV myocytes loaded with intracellular Ca 2+ indicator Fura-2 showed comparable Ca 2+ transients. Western blotting of Pkp2-RV homogenates revealed a 40% decrease in actin, whereas actin immunoprecipitation followed by a 2,4-dinitrophenylhydrazine staining showed doubled oxidation level. This correlated with a 39% increase in troponin-I phosphorylation. In contrast, Pkp2-Het left ventricular myocytes had normal contraction, actin expression and oxidation, and troponin-I phosphorylation. Last, Western blotting of cardiac biopsies revealed that actin expression was 40% decreased in RVs of patients with end-stage ACM. Conclusions: During the early concealed phase of ACM, reduced actin expression drives loss of RV myocyte contraction, contributing to progressive RV dysfunction.

To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10(−16)). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.

Background Understanding the overall variant burden in pediatric patients with left ventricular noncompaction (LVNC) has clinical implications. Whole exome sequencing (WES) allows detection of coding variants in both candidate cardiomyopathy genes and those included on commercial panels. Other lines of evidence, including in silico analysis, are necessary to reduce the overwhelming number of variants to those most likely having a phenotypic impact. Methods Five families, including five pediatric probands with LVNC, 5 other affected, and 10 unaffected family members, had WES performed, followed by bioinformatics filtering and Sanger sequencing. Review of the HGMD, variant classification by ACMG guidelines, and clinical information were used to further refine complex genotypes. Results One nonsense and eleven missense variants were identified. In Family 1, affected siblings carried digenic heterozygous variants: E1350K-MYH7 and A276V-ANKRD1. The proband also carried heterozygous W143X-NRG1. Four affected members of Family 2 carried K184Q-MYH7 while unaffected members did not. In Family 3, homozygous A161T-MYH7 and heterozygous P4935T-OBSCN variants were identified in the proband with the latter being absent in his unaffected brother. In Family 4, proband's father and half-sibling have mild hypertrabeculation and carry T3796I-PLEC. The proband, carrying T3796I-PLEC and V2878A-OBSCN, demonstrated higher trabeculation burden. The proband in Family 5 carried four variants, R3247W-PLEC, C92Y-ERG, T1233M-NCOR2, and E54K-HIST1H4B. Application of ACMG criteria and clinical data revealed that W143X-NRG1, P4935T-OBSCN, and V2878A-OBSCN likely have no phenotypic role. Conclusions We report nine variants, including novel T3796I-PLEC and biallelic A161T-MYH7, likely contributing to phenotypes ranging from asymptomatic hypertrabeculation to severe LVNC with heart failure.

Broad cellular functions and diseases including muscular dystrophy, arrhythmogenic right ventricular cardiomyopathy (ARVC5) and cancer are associated with transmembrane protein43 (TMEM43/ LUMA). The study aimed to investigate biological roles of TMEM43 through genetic regulation, gene pathways and gene networks, candidate interacting genes, and up- or downstream regulators. Cardiac transcriptomes from 40 strains of recombinant inbred BXD mice and two parental strains representing murine genetic reference population (GRP) were applied for genetic correlation, functional enrichment, and coexpression network analysis using systems genetics approach. The results were validated in a newly created knock-in Tmem43-S358L mutation mouse model (Tmem43S358L) that displayed signs of cardiac dysfunction, resembling ARVC5 phenotype seen in humans. We found high Tmem43 levels among BXDs with broad variability in expression. Expression of Tmem43 highly negatively correlated with heart mass and heart rate among BXDs, whereas levels of Tmem43 highly positively correlated with plasma high-density lipoproteins (HDL). Through finding differentially expressed genes (DEGs) between Tmem43S358L mutant and wild-type (Tmem43WT) lines, 18 pathways (out of 42 found in BXDs GRP) that are involved in ARVC, hypertrophic cardiomyopathy, dilated cardiomyopathy, nonalcoholic fatty liver disease, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease were verified. We further constructed Tmem43-mediated gene network, in which Ctnna1, Adcy6, Gnas, Ndufs6, and Uqcrc2 were significantly altered in Tmem43S358L mice versus Tmem43WT controls. Our study defined the importance of Tmem43 for cardiac- and metabolism-related pathways, suggesting that cardiovascular disease-relevant risk factors may also increase risk of metabolic and neurodegenerative diseases via TMEM43-mediated pathways.

Emerging evidence suggests that pediatric and adult dilated cardiomyopathy (DCM) represent distinct diseases. Few diagnostic tools exist for pediatric cardiologists to assess clinical status and prognosis. We hypothesized that pediatric DCM would have a unique biomarker profile compared to adult DCM and controls. We utilized a DNA aptamer array (SOMAScan) to compare biomarker profiles between pediatric and adult DCM. We simultaneously measured 1310 plasma proteins and peptides from 39 healthy children (mean age 3 years, interquartile range (IQR) 1–14), 39 ambulatory subjects with pediatric DCM (mean age 2.7 years, IQR 1–13), and 40 ambulatory adults with DCM (mean age 53 years, IQR 46–63). Pediatric and adult DCM patients displayed distinct biomarker profiles, despite similar clinical characteristics. We identified 20 plasma peptides and proteins that were increased in pediatric DCM compared to age- and sex-matched controls. Unbiased multidimensionality reduction analysis suggested previously unrecognized heterogeneity among pediatric DCM subjects. Biomarker profile analysis identified four subgroups of pediatric DCM with distinguishing clinical characteristics. These findings support the emerging concept that pediatric and adult DCM are distinct disease entities, signify the need to develop pediatric-specific biomarkers for disease prognostication, and challenge the paradigm that pediatric DCM should be viewed as a single disease.

Visual Abstract, Highlights • AM is an important cause of cardiac dysfunction following some viral infections and has been previously linked with genetic host susceptibilities. • Sequencing data for genes related to cardiomyocyte structure and function was compared between patients with AM and sex- and ancestry-matched heart-healthy control subjects. • Putatively DVs among these genes were found in ∼16% of AM cases, contributing to viral susceptibility. • Implicated genes are ones classically associated with cardiomyopathy or neuromuscular disorders with cardiac involvement, suggesting shared mechanistic pathways. • Phenotypes, including outcomes, were similar in subjects who have AM with and without DV, therefore genetic testing will be necessary to uncover this subtype and inform risk in relatives., Summary Impairments in certain cardiac genes confer risk for myocarditis in children. To determine the extent of this association, we performed genomic sequencing in predominantly adult patients with acute myocarditis and matched control subjects. Putatively deleterious variants in a broad set of cardiac genes were found in 19 of 117 acute myocarditis cases vs 34 of 468 control subjects (P = 0.003). Thirteen genes classically associated with cardiomyopathy or neuromuscular disorders with cardiac involvement were implicated, including >1 associated damaging variant in DYSF, DSP, and TTN. Phenotypes of subjects who have acute myocarditis with or without deleterious variants were similar, indicating that genetic testing is necessary to differentiate them.

Cancer survivors who have undergone hematopoietic cell transplantation (HCT) are at risk for myocardial dysfunction. Children who receive allogenic HCT encounter systemic inflammation resulting in tachycardia and hypertension. The effect of these abnormalities on myocardial function is not known. The aim of this study was to determine whether cardiac dysfunction early after HCT can be predicted by tachycardia or hypertension, within a retrospective single-center sample of pediatric HCT recipients. Early tachycardia or hypertension was defined as a majority of values taken from infusion date to 90 days post-infusion being abnormal. Ejection fraction

Background: Survivors of childhood cancer have an increased risk of therapy-related cardiovascular disease. It is not known whether family history of cardiovascular disease further increases risk of adverse cardiovascular outcomes among survivors. Methods: Family history of cardiovascular disease was collected from 1,260 survivors [median age at diagnosis, 8 years (range, 0–23); age at last follow-up, 35 years (range, 18–66)] of childhood cancer in the St. Jude Lifetime Cohort Study. Multivariable risk models evaluated associations with cardiovascular disease (Common Terminology Criteria for Adverse Events grade 2–4 events) and cardiovascular risk factors. Results: Among survivors exposed to chest-directed radiation and/or anthracycline chemotherapy (n = 824), 7% reported a first-degree family history of heart failure, 19% myocardial infarction, 11% stroke, 26% atherosclerotic disease (myocardial infarction and/or stroke), 62% hypertension, and 31% diabetes mellitus. Eighteen percent of exposed survivors developed heart failure, 9% myocardial infarction, 3% stroke, 11% atherosclerotic disease, 30% hypertension, and 9% diabetes mellitus. Having a first-degree family history of atherosclerotic disease was independently associated with development of treatment-related heart failure [RR, 1.38; 95% confidence interval (CI), 1.01–1.88; P = 0.04] among exposed survivors. Risk for hypertension was increased among exposed survivors with a first-degree family history of hypertension (RR, 1.55; 95% CI, 1.26–1.92; P < 0.0001) or of any cardiovascular disease [myocardial infarction, stroke, or heart failure (RR, 1.30; 95% CI, 1.06–1.59; P = 0.01)]. Conclusions: Family history of cardiovascular disease and cardiovascular risk factors independently increased risk of heart failure and hypertension among survivors of childhood cancer exposed to cardiotoxic therapies. Impact: These data show the importance of cardiovascular family history as a risk factor for cardiovascular disease in survivors of childhood cancer.

Cardiomyopathy or disease of the heart muscle involves abnormal enlargement and a thickened, stiff, or spongy-like appearance of the myocardium. As a result, the function of the myocardium is weakened and does not sufficiently pump blood throughout the body nor maintain a normal pumping rhythm, leading to heart failure. The main types of cardiomyopathies include dilated hypertrophic, restrictive, arrhythmogenic, and noncompaction cardiomyopathy. Abnormal trabeculations of the myocardium in the left ventricle are classified as left ventricular noncompaction cardiomyopathy (LVNC). Myocardial noncompaction most frequently is observed at the apex of the left ventricle and can be associated with chamber dilation or muscle hypertrophy, systolic or diastolic dysfunction, or both, or various forms of congenital heart disease. Animal models are incredibly important for uncovering the etiology and pathogenesis involved in this disease. This chapter will describe the clinical and pathological features of LVNC in humans and present the animal models that have been used for the study of the genetic basis and pathogenesis of this disease.

Cardiac mortality is the leading cause of death secondary to malignancy in survivors of cancer. The field of cardio-oncology is dedicated to identifying and, if possible, modifying risk factors that contribute to significant cardiac morbidity and mortality. Many risk factors for the development of cancer-related cardiotoxicity overlap with risk factors in cardiovascular disease such as hypertension, obesity, dyslipidemia, and diabetes among others. These risk factors are usually modifiable while others such as genetics, type of malignancy, and need for chemotherapy are less modifiable. This article summarizes acquired and modifiable risk factors in both pediatric and adult patients treated for cancer.

Hypertrophic cardiomyopathy (HCM), a relatively common, globally distributed, and often inherited primary cardiac disease, has now transformed into a contemporary highly treatable condition with effective options that alter natural history along specific personalized adverse pathways at all ages. HCM patients with disease-related complications benefit from: matured risk stratification in which major markers reliably select patients for prophylactic defibrillators and prevention of arrhythmic sudden death; low risk to high benefit surgical myectomy (with percutaneous alcohol ablation a selective alternative) that reverses progressive heart failure caused by outflow obstruction; anticoagulation prophylaxis that prevents atrial fibrillation-related embolic stroke and ablation techniques that decrease the frequency of paroxysmal episodes; and occasionally, heart transplant for end-stage nonobstructive patients. Those innovations have substantially improved outcomes by significantly reducing morbidity and HCM-related mortality to 0.5%/y. Palliative pharmacological strategies with currently available negative inotropic drugs can control symptoms over the short-term in some patients, but generally do not alter long-term clinical course. Notably, a substantial proportion of HCM patients (largely those identified without outflow obstruction) experience a stable/benign course without major interventions. The expert panel has critically appraised all available data and presented management insights and recommendations with concise principles for clinical decision-making.

Restrictive cardiomyopathy (RCM), a potentially devastating heart muscle disorder, is characterized by diastolic dysfunction due to abnormal muscle relaxation and myocardial stiffness resulting in restrictive filling of the ventricles. Diastolic dysfunction is often accompanied by left atrial or bi-atrial enlargement and normal ventricular size and systolic function. RCM is the rarest form of cardiomyopathy, accounting for 2-5% of pediatric cardiomyopathy cases, however, survival rates have been reported to be 82%, 80%, and 68% at 1-, 2-, and 5-years after diagnosis, respectively. RCM can be idiopathic, familial, or secondary to a systemic disorder, such as amyloidosis, sarcoidosis, and hereditary hemochromatosis. Approximately 30% of cases are familial RCM, and the genes that have been linked to RCM are

Myocarditis remains a clinical challenge in pediatrics. Originally, it was recognized at autopsy before the application of endomyocardial biopsy, which led to a histopathology-based diagnosis such as in the Dallas criteria. Given the invasive and low-sensitivity nature of endomyocardial biopsy, its diagnostic focus shifted to a reliance on clinical suspicion. With the advances of cardiac magnetic resonance, an examination of the whole heart in vivo has gained acceptance in the pursuit of a diagnosis of myocarditis. The presentation may vary from minimal symptoms to heart failure, life-threatening arrhythmias, or cardiogenic shock. Outcomes span full resolution to chronic heart failure and the need for heart transplantation with inadequate clues to predict the disease trajectory. The American Heart Association commissioned this writing group to explore the current knowledge and management within the field of pediatric myocarditis. This statement highlights advances in our understanding of the immunopathogenesis, new and shifting dominant pathogeneses, modern laboratory testing, and use of mechanical circulatory support, with a special emphasis on innovations in cardiac magnetic resonance imaging. Despite these strides forward, we struggle without a universally accepted definition of myocarditis, which impedes progress in disease-targeted therapy.

While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.

BACKGROUND Limited data exist regarding left ventricular remodeling patterns observed in adult survivors of childhood cancer after therapy. METHODS Among 1190 adult survivors diagnosed with childhood cancer (median age at diagnosis, 9 years [interquartile range (IQR), 3.8-14.4 years]; age at evaluation, 35.6 years [IQR, 29.5-42.8 years]), treatment exposures included anthracyclines (n = 346), chest radiotherapy (n = 174), both (n = 245), or neither (n = 425). Prospective echocardiographic assessment compared survivors with 449 noncancer controls classified according to left ventricle geometric patterns. Associations between left ventricle geometric patterns and decreased exercise tolerance were assessed. RESULTS Overall, 28.2% of survivors (95% confidence interval [CI], 25.6%-30.8%) exhibited concentric remodeling, 2.4% (95% CI, 1.6%-3.5%) exhibited eccentric hypertrophy, and 1.1% (95% CI, 0.6%-1.9%) exhibited concentric hypertrophy. A greater proportion of survivors who received only chest radiotherapy (41%) had concentric remodeling compared with those who received only anthracyclines (24%), both (27%), or neither (27%; all P < .001), and all were greater than the proportions in noncancer controls (18%; all P < .05). Concentric remodeling was associated with radiation exposure, but not with anthracycline exposure, in multivariable models. Survivors who had concentric remodeling were more likely to have a maximal oxygen uptake peak

BACKGROUND: Cardiomyopathies are a rare cause of pediatric heart disease, but they are one of the leading causes of heart failure admissions, sudden death, and need for heart transplant in childhood. Reports from the Pediatric Cardiomyopathy Registry (PCMR) have shown that almost 40% of children presenting with symptomatic cardiomyopathy either die or undergo heart transplant within 2 years of presentation. Little is known regarding circulating biomarkers as predictors of outcome in pediatric cardiomyopathy. STUDY DESIGN: The Cardiac Biomarkers in Pediatric Cardiomyopathy (PCM Biomarkers) study is a multi-center prospective study conducted by the PCMR investigators to identify serum biomarkers for predicting outcome in children with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Patients less than 21 years of age with either DCM or HCM were eligible. Those with DCM were enrolled into cohorts based on time from cardiomyopathy diagnosis: categorized as new onset or chronic. Clinical endpoints included sudden death and progressive heart failure. RESULTS: There were 288 children diagnosed at a mean age of 7.2±6.3 years who enrolled in the PCM Biomarkers Study at a median time from diagnosis to enrollment of 1.9 years. There were 80 children enrolled in the new onset DCM cohort, defined as diagnosis at or 12 months prior to enrollment. The median age at diagnosis for the new onset DCM was 1.7 years and median time from diagnosis to enrollment was 0.1 years. There were 141 children enrolled with either chronic DCM or chronic HCM, defined as children ≥2 years from diagnosis to enrollment. Among children with chronic cardiomyopathy, median age at diagnosis was 3.4 years and median time from diagnosis to enrollment was 4.8 years. CONCLUSION: The PCM Biomarkers study is evaluating the predictive value of serum biomarkers to aid in the prognosis and management of children with DCM and HCM. The results will provide valuable information where data are lacking in children. CLINICAL TRIAL REGISTRATION: NCT01873976: https://clinicaltrials.gov/ct2/show/NCT01873976?term=PCM+Biomarker&rank=1

Purpose To evaluate myocardial strain and circumferential transmural strain difference (cTSD; the difference between epicardial and endocardial circumferential strain) in a genotyped cohort with hypertrophic cardiomyopathy (HCM) and to explore correlations between cTSD and other anatomic and functional markers of disease status. Left ventricular (LV) dysfunction may indicate early disease in preclinical HCM (sarcomere mutation carriers without LV hypertrophy). Cardiac MRI feature tracking may be used to evaluate myocardial strain in carriers of HCM sarcomere mutation. Materials and Methods Participants with HCM and their family members participated in a prospective, multicenter, observational study (HCMNet). Genetic testing was performed in all participants. Study participants underwent cardiac MRI with temporal resolution at 40 msec or less. LV myocardial strain was analyzed by using feature-tracking software. Circumferential strain was measured at the epicardial and endocardial surfaces; their difference yielded the circumferential transmural strain difference (cTSD). Multivariable analysis to predict HCM status was performed by using multinomial logistic regression adjusting for age, sex, and LV parameters. Results Ninety-nine participants were evaluated (23 control participants, 34 participants with preclinical HCM [positive for sarcomere mutation and negative for LV hypertrophy], and 42 participants with overt HCM [positive for sarcomere mutation and negative for LV hypertrophy]). The average age was 25 years ± 11 and 44 participants (44%) were women. Maximal LV wall thickness was 9.5 mm ± 1.4, 9.8 mm ± 2.2, and 16.1 mm ± 5.3 in control participants, participants with preclinical HCM (P = .496 vs control participants), and participants with overt HCM (P < .001 vs control participants), respectively. cTSD for control participants, preclinical HCM, and overt HCM was 14% ± 4, 17% ± 4, and 22% ± 7, respectively (P < .01 for all comparisons). In multivariable models (controlling for septal thickness and log-transformed N-terminal brain-type natriuretic peptide), cTSD was predictive of preclinical and overt HCM disease status (P < .01). Conclusion Cardiac MRI feature tracking identifies myocardial dysfunction not only in participants with overt hypertrophic cardiomyopathy, but also in carriers of sarcomere mutation without left ventricular hypertrophy, suggesting that contractile abnormalities are present even when left ventricular wall thickness is normal.

There continues to be controversy on the long-term effects of a patent ductus arteriosus (PDA) and its management. However, the hemodynamic effects of a large PDA in a preterm infant are well known. This article aims to provide insight into the adaptive changes and remodeling effects of a PDA on the myocardium in preterm infants.

BACKGROUND: MEK inhibitor trials in pediatric low-grade glioma (pLGG) have yielded promising results, but there remains room for improvement since objective responses are rarely complete and disease recurrence after completion of therapy is common. Mirdametinib (PD-0325901) is a highly selective MEK1/MEK2 inhibitor that, in preclinical studies, has been reported to have superior blood-brain-barrier penetration compared to other MEK inhibitors. As such, we recently launched the SJ901 clinical trial (NCT04923126) to determine the safety, recommended phase 2 dose, pharmacokinetics, and preliminary efficacy of mirdametinib in patients with pLGG when administered continuously. Here, we present preliminary phase 1 data. METHODS: SJ901 is a multi-arm phase I/II trial of mirdametinib in patients >2 and 25%

Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing ( P =0.005 and P =0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first‐degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01873963.

Emerging evidence suggests that pediatric and adult dilated cardiomyopathy (DCM) represent distinct diseases. Few diagnostic tools exist for pediatric cardiologists to assess clinical status and prognosis. We hypothesized that pediatric DCM would have a unique biomarker profile compared to adult DCM and controls.We utilized a DNA aptamer array (SOMAScan) to compare biomarker profiles between pediatric and adult DCM. We simultaneously measured 1310 plasma proteins and peptides from 39 healthy children (mean age 3 years, interquartile range (IQR) 1-14), 39 ambulatory subjects with pediatric DCM (mean age 2.7 years, IQR 1-13), and 40 ambulatory adults with DCM (mean age 53 years, IQR 46-63).Pediatric and adult DCM patients displayed distinct biomarker profiles, despite similar clinical characteristics. We identified 20 plasma peptides and proteins that were increased in pediatric DCM compared to age- and sex-matched controls. Unbiased multidimensionality reduction analysis suggested previously unrecognized heterogeneity among pediatric DCM subjects. Biomarker profile analysis identified four subgroups of pediatric DCM with distinguishing clinical characteristics.These findings support the emerging concept that pediatric and adult DCM are distinct disease entities, signify the need to develop pediatric-specific biomarkers for disease prognostication, and challenge the paradigm that pediatric DCM should be viewed as a single disease.Pediatric and adult DCM patients displayed distinct biomarker profiles, despite similar clinical characteristics and outcomes. Our findings suggest that pediatric DCM may be a heterogeneous disease with various sub-phenotypes, including differing biomarker profiles and clinical findings. These data provide prerequisite information for future prospective studies that validate the identified pediatric DCM biomarkers, address their diagnostic accuracy and prognostic significance, and explore the full extent of heterogeneity amongst pediatric DCM patients.

Hypertrophic cardiomyopathy (HCM) is a relatively common often inherited global heart disease, with complex phenotypic and genetic expression and natural history, affecting both genders and many races and cultures. Prevalence is 1:200-1:500, largely based on the disease phenotype with imaging, inferring that 750,000 Americans may be affected by HCM. However, cross-sectional data show that only a fraction are clinically diagnosed, suggesting under-recognition, with most clinicians exposed to small segments of the broad disease spectrum. Highly effective HCM management strategies have emerged, altering clinical course and substantially lowering mortality and morbidity rates. These advances underscore the importance of reliable HCM diagnosis with echocardiography and cardiac magnetic resonance. Family screening with noninvasive imaging will identify relatives with the HCM phenotype, while genetic analysis recognizes preclinical sarcomere gene carriers without left ventricular hypertrophy, but with the potential to transmit disease. Comprehensive initial patient evaluations are important for reliable diagnosis, accurate portrayal of HCM and family history, risk stratification, and distinguishing obstructive versus nonobstructive forms.

Cancer survivors who have undergone hematopoietic cell transplantation (HCT) are at risk for myocardial dysfunction. Children who receive allogenic HCT encounter systemic inflammation resulting in tachycardia and hypertension. The effect of these abnormalities on myocardial function is not known. The aim of this study was to determine whether cardiac dysfunction early after HCT can be predicted by tachycardia or hypertension, within a retrospective single-center sample of pediatric HCT recipients. Early tachycardia or hypertension was defined as a majority of values taken from infusion date to 90 days post-infusion being abnormal. Ejection fraction53% determined systolic dysfunction. A composite score of accepted pediatric diastolic abnormalities determined diastolic dysfunction. Among 80 subjects (median age 8 years), early tachycardia, systolic dysfunction, and diastolic dysfunction were present in 64%, 25%, and 48% of the sample, respectively. In multivariable models, early tachycardia was an independent predictor of early systolic dysfunction (OR = 12.6 [1.4-112.8], p = 0.024) and diastolic dysfunction (OR = 3.9 [1.3-11.5], p = 0.013). Tachycardia and cardiac dysfunction are common and associated with one another in the early period after pediatric HCT. Future studies may elucidate the role of tachycardia and myocardial dysfunction early after HCT as important predictors of future cardiovascular dysfunction.

Introduction: Pediatric and adult dilated cardiomyopathy (DCM) represent distinct entities with divergent gene expression, histopathology, and response to medical therapies. Prognostically important serum biomarkers identified in adults have failed to provide similar diagnostic and prognostic information for children with DCM. We hypothesized that pediatric and adult DCM populations display different biomarker profiles. Methods: Pediatric control (≤18y), pediatric DCM, and adult DCM plasma samples were analyzed using the SOMAscan biomarker platform to simultaneously measure over 1300 known protein analytes. Pediatric control and DCM subjects were age- and gender-matched. Most samples were obtained within 2 years of diagnosis. Biomarkers were compared between groups with p-value 2 considered significant. Principal component analysis was used to visualize differences in proteomic data. Results: The study included 39 pediatric control (mean age 3y, IQR 1-14), 39 pediatric DCM (median age 2.7y, IQR 1-13), and 40 adult DCM (median age 53y, IQR 46-63) subjects. Twenty plasma peptides were upregulated in pediatric DCM compared to controls. Plasma renin and 6-phosphogluconate dehydrogenase represented potential pediatric-specific biomarkers. Pediatric DCM subjects clustered into 4 distinct subgroups with unique biomarker profiles and distinguishing clinical characteristics suggesting the pediatric DCM phenotype may represent a heterogeneous group of diseases. Conclusions: This feasibility study provides important evidence that distinct biomarker profiles are present in pediatric and adult DCM patients. These findings provide preliminary data to inform the design of larger prospective studies to validate pediatric DCM specific biomarkers and investigate their prognostic value.

Cardiac mortality is the leading cause of death secondary to malignancy in survivors of cancer. The field of cardio-oncology is dedicated to identifying and, if possible, modifying risk factors that contribute to significant cardiac morbidity and mortality. Many risk factors for the development of cancer-related cardiotoxicity overlap with risk factors in cardiovascular disease such as hypertension, obesity, dyslipidemia, and diabetes among others. These risk factors are usually modifiable while others such as genetics, type of malignancy, and need for chemotherapy are less modifiable. This article summarizes acquired and modifiable risk factors in both pediatric and adult patients treated for cancer.

Background Genetic testing in pediatric primary dilated cardiomyopathy (DCM) patients has identified numerous disease-causing variants, but few studies have evaluated genetic testing outcomes in this population in the context of patient and familial clinical data or assessed the clinical implications of temporal changes in genetic testing results. Methods and Results We performed a retrospective analysis of all patients with primary DCM who presented to our institution between 2008 and 2018. Variants identified by genetic testing were reevaluated for pathogenicity on the basis of current guidelines for variant classification. A total of 73 patients with primary DCM presented to our institution and 63 (86%) were probands that underwent cardiomyopathy-specific gene testing. A disease-causing variant was identified in 19 of 63 (30%) of cases, with at least 9/19 (47%) variants occurring de novo. Positive family history was not associated with identification of a causal variant. Reclassification of variants resulted in the downgrading of a large proportion of variants of uncertain significance and did not identify any new disease-causing variants. Conclusions Clinical genetic testing identifies a causal variant in one third of pediatric patients with primary DCM. Variant reevaluation significantly decreased the number of variants of uncertain significance, but a large burden of variants of uncertain significance remain. These results highlight the need for periodic reanalysis of genetic testing results, additional investigation of genotype-phenotype correlations in DCM through large, multicenter genetic studies, and development of improved tools for functional characterization of variants of uncertain significance.

Thromboembolic events and bleeding are major sources of morbidity among pediatric patients supported on a ventricular assist device (VAD). Pharmacokinetics and pharmacodynamics of enteral antiplatelet agents are affected and variable due to erratic enteral absorption in end-stage heart failure and VAD circulation. Additionally, 20%-40% of the population are poor metabolizers of clopidogrel, a prodrug, making cangrelor an alternative when antiplatelet therapy is crucial. Cangrelor has been used effectively and safely for short durations in adults during percutaneous coronary interventions, but the use of cangrelor is still under investigation in pediatrics. This case series utilized cangrelor, a novel short-acting, reversible, intravenous P2Y12 platelet inhibitor in managing pediatric patients supported with a VAD. We performed a retrospective, single-center review of patients admitted to a tertiary medical center with end-stage heart failure requiring mechanical circulatory support and concomitant cangrelor administration between January 2019 and March 2020. Platelet function testing, cangrelor dose, bleeding complications, thromboembolic events, and frequency of circuit interventions during the use of cangrelor were recorded. Optimal platelet reactivity, defined as P2Y12 < 180 platelet reaction units (PRU), was measured with serial point-of-care testing (VerifyNow). Seven patients, median age of 4.9 years, met the above criteria. Three patients had a diagnosis of complex congenital heart disease. Four patients had dilated or restrictive cardiomyopathy. All patients were on continuous flow VADs. The median VAD duration was 84.5 days (IQR 61.5-103). The median duration on cangrelor was 43 days (IQR 8-70). The median cangrelor dose to reach the therapeutic threshold was 0.75 μg/kg/min with the mean P2Y12 , while on cangrelor of 164.75 PRU. Bleeding complications included mild gastrointestinal bleeding and hematuria. There was one patient with pump thrombosis requiring intervention. There were no cerebrovascular events while on cangrelor. We report the first successful long-term use of cangrelor in pediatric patients. The reversibility and short half-life of cangrelor make it a feasible antiplatelet agent in selected patients. This data supports the use of cangrelor in children as a viable antiplatelet option; with minimal bleeding complications and no cerebrovascular events demonstrated in this cohort.

Objectives: This study sought to delineate clinical phenotype and investigate pathophysiological mechanisms of arrhythmogenic right ventricular cardiomyopathy (ARVC5) in vivo.Background: Mutation p.S358L in TMEM43/LUMA causes ARVC5, a fully penetrant gender- and exercise-dependent disease. Exact pathophysiological mechanisms of ARVC5 remain incomplete and controversial. Methods: Knock-in Tmem43S358L mice were generated using conventional targeting. Assessment of cardiac and intestinal phenotypes, transcriptome and protein analysis were performed. Results: Onset of systolic dysfunction and rhythm asymmetry was apparent in 3-month-old homozygote mutants. Heterozygote 6-month-old mutants displayed systolic dysfunction as well. Biventricular myocardial fibro-fatty infiltration and subcellular abnormalities were found in both mutants, while acute stress caused ventricular tachycardia and death in homozygotes. Microarray revealed that WNT-b-catenin and PPARG signaling-associated genes were differentially expressed between LV and RV. Tmem43S358L mutants displayed significantly reduced PPARG activities and downregulation of PPARG-downstream metabolic genes in the heart. Expression of b-catenin were significantly reduced, while JUP was translocated into nuclei of mutant cardiomyocytes. Conversely in small intestine, b-catenin and PPARG-associated genes responsible for cholesterol, bile acid, and lipid transport were upregulated in Tmem43S358L mutants resulting in elevated lipids absorption, hyperlipidemia, and reciprocal fecal lipids reduction. These abnormalities were associated with elongated villi, fatty infiltrations, and gut epithelial proliferation markers in small intestine. Conclusions: We defined novel distinct effects of the TMEM43-S358L mutation on small intestine homeostasis in addition to cardiac damage. Tmem43-S358L perturbs PPARG and WNT-b-catenin signaling in the heart as well as in intestine, elevating lipids absorption from gut lumen whereby triggering ACM pathophysiology.

BACKGROUND The purpose of this study was to describe the prevalence, characteristics, and outcomes in pediatric patients with chromosomal anomalies (CA) undergoing orthotopic heart transplantation (OHT). METHODS A query of the database of the Pediatric Health Information System, a large administrative and billing database of 43 tertiary children's hospitals, was performed for the Years 2004 to 2016. Pediatric patients who received OHT were analyzed based on presence and type of CA. CA analyzed included: Down syndrome (DS); Turner syndrome (TS)/gonadal dysgenesis; conditions due to anomaly of unspecified chromosome; autosomal deletion; microdeletion; and autosomal anomaly. Healthcare-associated charge analysis during hospitalization for OHT and survival after OHT were assessed. RESULTS A total of 3,080 hospitalizations were identified in which OHTs were performed. Of these OHTs, 64 (2.1%) were performed in patients with a concomitant diagnosis of CA. The presence of CA did not confer a higher risk of in-hospital mortality after OHT (odds ratio 1.2 [0.5 to 3.2], p = 0.651). Differences in in-hospital mortality between different types of CA, including DS and TS, did not reach statistical significance. Survival at 1-year post-OHT was similar in patients with CA compared to those without CA (p = 0.248). Length of stay after OHT was longer in patients with CA: 76 (interquartile range [IQR] 76 to 142 days vs 49 [IQR 21 to 98] days) (p < 0.001), respectively. Overall adjusted hospital charges were significantly higher in the CA group: $1.2 million (IQR $740,000 to $2.2 million) vs $792,000 (IQR $425,000 to $1.5 million] (p < 0.001), respectively. CONCLUSIONS CA is present in ~2% of pediatric patients undergoing OHT. The presence of CA was not associated with increased mortality in pediatric patients undergoing OHT. Limitations of this study include the small number of patients available for analysis and a likely highly selective cohort of patients with CA.

This study aimed to examine the role of nutrition in pediatric dilated cardiomyopathy (DCM).In adults with DCM, malnutrition is associated with mortality, whereas obesity is associated with survival.The National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry was used to identify patients with DCM and categorized by anthropometric measurements: malnourished (MN) (body mass index [BMI] 5% for age ≥2 years or weight-for-length 5% for 2 years), obesity (BMI95% for age ≥2 years or weight-for-length95% for 2 years), or normal bodyweight (NB). Of 904 patients with DCM, 23.7% (n = 214) were MN, 13.3% (n=120) were obese, and 63.1% (n=570) were NB.Obese patients were older (9.0 vs. 5.7 years for NB; p 0.001) and more likely to have a family history of DCM (36.1% vs. 23.5% for NB; p = 0.023). MN patients were younger (2.7 years vs. 5.7 years for NB; p 0.001) and more likely to have heart failure (79.9% vs. 69.7% for NB; p = 0.012), cardiac dimension z-scores2, and higher ventricular mass compared with NB. In multivariable analysis, MN was associated with increased risk of death (hazard ratio [HR]: 2.06; 95% confidence interval [CI]: 1.66 to 3.65; p 0.001); whereas obesity was not (HR: 1.49; 95% CI: 0.72 to 3.08). Competing outcomes analysis demonstrated increased risk of mortality for MN compared with NB (p = 0.03), but no difference in transplant rate (p = 0.159).Malnutrition is associated with increased mortality and other unfavorable echocardiographic and clinical outcomes compared with those of NB. The same effect of obesity on survival was not observed. Further studies are needed investigating the long-term impact of abnormal anthropometric measurements on outcomes in pediatric DCM. (Pediatric Cardiomyopathy Registry; NCT00005391).

The normal function of the human myocardium requires the proper generation and utilization of energy and relies on a series of complex metabolic processes to achieve this normal function. When metabolic processes fail to work properly or effectively, heart muscle dysfunction can occur with or without accompanying functional abnormalities of other organ systems, particularly skeletal muscle. These metabolic derangements can result in structural, functional, and infiltrative deficiencies of the heart muscle. Mitochondrial and enzyme defects predominate as disease-related etiologies. In this review, left ventricular noncompaction cardiomyopathy, which is often caused by mutations in sarcomere and cytoskeletal proteins and is also associated with metabolic abnormalities, is discussed. In addition, cardiomyopathies resulting from mitochondrial dysfunction, metabolic abnormalities, storage diseases, and inborn errors of metabolism are described.

Sickle cell anemia (SCA)-related cardiomyopathy is characterized by diastolic dysfunction and hyperdynamic features. Diastolic dysfunction portends early mortality in SCA. Diastolic dysfunction is associated with microscopic myocardial fibrosis in SCA mice, but the cause of diastolic dysfunction in humans with SCA is unknown. We used cardiac magnetic resonance measurements of extracellular volume fraction (ECV) to discover and quantify diffuse myocardial fibrosis in 25 individuals with SCA (mean age, 23 ± 13 years) and determine the association between diffuse myocardial fibrosis and diastolic dysfunction. ECV was calculated from pre- and post-gadolinium T1 measurements of blood and myocardium, and diastolic function was assessed by echocardiography. ECV was markedly increased in all participants compared with controls (0.44 ± 0.08 vs 0.26 ± 0.02, P < .0001), indicating the presence of diffuse myocardial fibrosis. Seventeen patients (71%) had diastolic abnormalities, and 7 patients (29%) met the definition of diastolic dysfunction. Participants with diastolic dysfunction had higher ECV (0.49 ± 0.07 vs 0.37 ± 0.04, P = .01) and N-terminal pro-brain natriuretic peptide (NT-proBNP; 191 ± 261 vs 33 ± 33 pg/mL, P = .04) but lower hemoglobin (8.4 ± 0.3 vs 10.9 ± 1.4 g/dL, P = .004) compared with participants with normal diastolic function. Participants with the highest ECV values (≥0.40) were more likely to have diastolic dysfunction (P = .003) and increased left atrial volume (57 ± 11 vs 46 ± 12 mL/m2, P = .04) compared with those with ECV

Left ventricular hypertrabeculation (LVHT) or noncompaction is a myocardial abnormality of unknown aetiology, frequently associated with monogenic disorders, particularly neuromuscular disorders, or with chromosomal defects. LVHT is diagnosed usually by echocardiography by the presence of a bilayered myocardium consisting of a thick, spongy, noncompacted endocardial layer and a thin, compacted, epicardial layer. The pathogenesis of LVHT is unsolved, and the diagnostic criteria, prognosis, and optimal treatment of patients with LVHT are under debate. LVHT is categorized as distinct primary genetic cardiomyopathy by the AHA and as unclassified cardiomyopathy by the ESC. LVHT is usually asymptomatic, but can be complicated by heart failure, thromboembolism, or ventricular arrhythmias, including sudden cardiac death. Mortality of patients with LVHT ranges from 5% to 47%. Anticoagulation is indicated if atrial fibrillation, severe heart failure, previous embolism, or intracardiac thrombus formation are present. In patients with LVHT with late gadolinium enhancement, an implantable cardioverter-defibrillator might be considered if systolic dysfunction, a family history of sudden cardiac death, nonsustained ventricular tachycardia, or previous syncope is additionally present. In this Review, we discuss the current findings on the aetiology and pathophysiology of LVHT, and provide an overview of the diagnosis, available treatment, and prognosis of this cardiomyopathy.

Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present.

ObjectiveTo enhance the understanding of cardiovascular care delivery in childhood cancer patients and survivors.Study designA 20-question survey was created by the Pediatric Cardio-oncology Work Group of the American College of Cardiology (ACC) Cardio-oncology Section to assess the care, management, and surveillance tools utilized to manage pediatric/young adult cardio-oncology patients. The survey distribution was a collaborative effort between Cardio-oncology Section and membership of the Adult Congenital and Pediatric Cardiology Section (ACPC) of the ACC.ResultsSixty-five individuals, all self-identified as physicians, responded to the survey. Most respondents (n = 58,89%) indicated childhood cancer patients are regularly screened prior to and during cancer therapy at their centers, predominantly by electrocardiogram (75%), standard echocardiogram (58%) and advanced echocardiogram (50%) (i.e. strain, stress echo). Evaluation by a cardiologist prior to/during therapy was reported by only 8(12%) respondents, as compared to post-therapy which was reported by 28 (43%,p n = 31,48%) and history of chemotherapy exposure (n = 27,42%). Of note, during post-treatment counseling, common cardiovascular risk-factors like blood pressure (31,48%), lipid control (22,34%), obesity & smoking (30,46%) and diet/exercise/weight loss (30,46%) were addressed by fewer respondents than was LV function (72%).ConclusionsThe survey data demonstrates that pediatric cancer patients are being screened by EKG and/or imaging prior to/during therapy at most centers. Our data, however, highlight the potential for greater involvement of a cardiovascular specialist for pre-treatment evaluation process, and for more systematic cardiac risk factor counseling in posttreatment cancer survivors.

Background: Arrhythmogenic cardiomyopathies (ACMs) are heritable diseases characterized by arrhythmias, related sudden death, fibro-fatty infiltration and progressive heart failure. Although the pathogenic variant p.S358L in TMEM43/ LUMA causes fully penetrant ACM (ARVC5) in patients, little in vivo evidence has been reported and the roles of Tmem43 in normal cardiac function and disease remain obscure and controversial. This study explored Tmem43-associated genetic modifiers using forward, reverse, and systems genetics analyses in vivo . Methods: Microarray of cardiac and jejunal tissues were performed in a newly created Tmem43 S358L knock-in mouse and in forty BXD strains, used as a murine genetic reference population (GRP). Levels of plasma and fecal lipids and Pparγ activities were defined in heart and jejunum of Tmem43 animals. Immunohistochemistry was performed in the myocardium of patients with non-TMEM43 origin ACM. Results: BXD strain cardiac tissues demonstrated high levels of Tmem43 expression that was significantly negatively correlated with heart mass and heart rate, while positively correlated with plasma HDL and LDL levels. Expression of Tmem43 was also significantly (r>0.5, pPpargc1a ( Pcg1a ) in the heart and intestine of BXDs and Tmem43 mutants. In the Tmem43 S358L mouse heart, Tmem43 and Ppargc1a were downregulated resulting in reduced Pparγ activities. Conversely, Tmem43 and Ppars- regulated genes, including Mogat2, responsible for cholesterol, bile acid, and lipid absorption and re-esterification, were upregulated in the jejunum, resulting in elevated lipid absorption in the gut lumen and hyperlipidemia in Tmem43 S358L mutants. Expression of TMEM43 was disrupted in cardiomyocyte intercalated disks in ACM patients’ myocardium in contrast to normal controls. Conclusions: Tmem43 is an essential gene for cardiac and small intestine signaling and function. The S358L-Tmem43 pathogenic variant is significantly associated with downregulation of Tmem43 , Ppagc1a and Ppar γ in the myocardium and upregulation of Pparγ and Pparα signaling in small intestine in vivo . Testing plasma lipid levels and TMEM43 expression in ACM patients may provide critical information for personalized predictive care.

Introduction: Pediatric and adult dilated cardiomyopathy (DCM) represent distinct pathological entities, however, the basis of this phenomena remains obscure. The pathogenic variant p.K69R in MLP/ CSRP3 induced DCM in adult Mlp K69R knock-in mice. A noncompacted ventricular wall and dilated ventricles were seen in embryonic and neonatal Mlp K69R hearts, reminiscent of that seen in infant variant carriers. Hypothesis: Mlp- K69R associated genetic modifiers govern DCM phenotypes in neonatal and adult heart. The study was to find genetic modifiers associated with divergent neonatal and adult phenotypes induced by Mlp- K69R. Methods: RNA extracted from neonatal and adult Mlp K69R and Mlp WT mouse myocardium was applied to Affymetrix microarray and QPCR analysis. Data were normalized, subjected to differentially expression genes and gene set enrichment analysis. Results: We found 1024 genes in adult and 252 genes in neonatal heart that were significantly altered in Mlp K69R vs WT littermates. 23 of these genes were mutually altered in adult and neonatal mutants. In adult mutants, 15 sarcomeric genes were significantly over-expressed compared to WT littermates. The mutation altered expression of genes involved in sarcolemmal and desmosomes unity. Calcium handling, integrin-associated networks, and heart failure-associated genes were upregulated in mutants vs WT littermates. In neonates, genes involved in cardiac and vascular development ( Rhox2c, Tbx3, Mir23a, Tbc1d7 ), cell adhesion and migration ( Tff2 ), and apoptosis ( Mir297a-2 ) were significantly altered. Two cardio-protective miRNAs, Mir98 and Mir451a , were highly reciprocally altered in both, adult and neonatal, mutant vs WT hearts. Their expression was increased in mutant adult hearts, but decreased in neonatal mutant hearts, suggesting novel candidates associated with K69R-MLP-induced DCM and noncompaction phenotypes. Conclusions: Differential transcriptomes in neonatal and adult hearts suggest that pathogenic K69R-MLP variant induces DCM and noncompaction phenotypes via distinct underlying genetic modifiers. Contrary to mutant adult mice, mutant newborn hearts show significant decrease in Mir98 and Mir451a, which may predispose them to developing myocardial noncompaction.