• 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.

Pediatric dilated cardiomyopathy (DCM) is the most common indication for heart transplantation in children. Despite similar genetic etiologies, medications routinely used in adult heart failure patients do not improve outcomes in the pediatric population. The mechanistic basis for these observations is unknown. We hypothesized that pediatric and adult DCM comprise distinct pathological entities, in that children do not undergo adverse remodeling, the target of adult heart failure therapies. To test this hypothesis, we examined LV specimens obtained from pediatric and adult donor controls and DCM patients. Consistent with the established pathophysiology of adult heart failure, adults with DCM displayed marked cardiomyocyte hypertrophy and myocardial fibrosis compared with donor controls. In contrast, pediatric DCM specimens demonstrated minimal cardiomyocyte hypertrophy and myocardial fibrosis compared with both age-matched controls and adults with DCM. Strikingly, RNA sequencing uncovered divergent gene expression profiles in pediatric and adult patients, including enrichment of transcripts associated with adverse remodeling and innate immune activation in adult DCM specimens. Collectively, these findings reveal that pediatric and adult DCM represent distinct pathological entities, provide a mechanistic basis to explain why children fail to respond to adult heart failure therapies, and suggest the need to develop new approaches for pediatric DCM.

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 cTnT, cTnI, MyBP-C, MYH7, MYL2, MYL3, DES, MYPN, TTN, BAG3, DCBLD2, LNMA, and FLNC. Increased Ca2+ sensitivity, sarcomere disruption, and protein aggregates are some of the few mechanisms of pathogenesis that have been revealed by studies utilizing cell lines and animal models. Additional exploration into the pathogenesis of RCM is necessary to create novel therapeutic strategies to reverse restrictive cardiomyopathic phenotypes.

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 (Tmem43^S358L) 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 Tmem43^S358L mutant and wild-type (Tmem43^WT) 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 Tmem43^S358L mice versus Tmem43^WT 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.

To investigate the regulation of Myopalladin (Mypn) and identify its gene network involved in restrictive cardiomyopathy (RCM). Gene expression values were measured in the heart of a large family of BXD recombinant inbred (RI) mice derived from C57BL/6J and DBA/2J. The proteomics data were collected from Mypn knock-in and knock-out mice. Expression quantitative trait locus (eQTL) mapping methods and gene enrichment analysis were used to identify Mypn regulation, gene pathway and co-expression networks. A wide range of variation was found in expression of Mypn among BXD strains. We identified upstream genetic loci at chromosome 1 and 5 that modulate the expression of Mypn. Candidate genes within these loci include Ncoa2, Vcpip1, Sgk3, and Lgi2. We also identified 15 sarcomeric genes interacting with Mypn and constructed the gene network. Two novel members of this network (Syne1 and Myom1) have been confirmed at the protein level. Several members in this network are already known to relate to cardiomyopathy with some novel genes candidates that could be involved in RCM. Using systematic genetics approach, we constructed Mypn co-expression networks that define the biological process categories within which similarly regulated genes function. Through this strategy we have found several novel genes that interact with Mypn that may play an important role in the development of RCM.