Discovery of modifier genes and molecular mechanisms in arrhythmogenic cardiomyopathy - arrhythmogenic cardiomyopathies (acms) are inherited heart muscle diseases characterized life-threatening…

The National Institutes of Health National Heart, Lung, and Blood Institute awarded the University of Tennessee Health Science Center $769,447 on September 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to discover modifier genes and molecular mechanisms in arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathies are inherited heart muscle diseases characterized by life-threatening arrhythmias, sudden cardiac death, fibro-fatty infiltrations in the myocardium, and heart failure. The research addresses the challenge that while lifestyle, sex, age, diet, and environmental factors influence disease presentation, clinical heterogeneity remains difficult to predict. The project hypothesizes that genes modifying metabolic homeostasis partly control variance in vulnerability or resilience to arrhythmias and that identifying these modifier genes impacting severity and outcomes of arrhythmogenic cardiomyopathy and arrhythmogenic dilated cardiomyopathy remains challenging in humans. The recipient will employ a murine genetic reference population of BXD mice maintained in controlled laboratory environment for systems genetics analysis to identify and characterize modifier genes. Prior pilot studies identified genes involved in energy and lipid metabolism as shared common genetic regulators, and transmembrane protein 43 (TMEM43), a target of PPARG, as a critical participant in cardiac and metabolic pathways.

The award period runs through May 31, 2030, with work performed in Memphis, Tennessee.

Discovery of modifier genes and molecular mechanisms in arrhythmogenic cardiomyopathy - arrhythmogenic cardiomyopathies (acms) are inherited heart muscle diseases characterized life-threatening arrhythmias, sudden cardiac death (SCD), fibro-fatty infiltrations in the myocardium and heart failure (HF). While lifestyle, SEX, age, diet, and/or environment factors are shown to influence clinical heterogeneity of acms, IT is still difficult to fully explain and predict disease onset, phenotypes, and severity and establish a personalized prevention and treatment for patients. The likely reason for this is that compared to other familial CMS like hypertrophic cardiomyopathy (HCM) with SCD, acms exhibit much lower penetrance of causal genes, while modifier genes and epistatic (gene-gene) interactions have additional risks for causing SCD. Our pilot studies have identified the genes involved in energy and lipid metabolism (PPARGC1A, LEP) as shared common genetic regulators of top common causal genes in patients with ACM and arrhythmogenic dilated cardiomyopathy (adcm) with common arrhythmogenic features. Based on these data, we hypothesized that the genes modifying the metabolic homeostasis (AKA modifier genes) partly control the variance in vulnerability or resilience to arrhythmias. However, identification of those modifier genes impacting the severity and outcomes of ACM and adcm remains challenging in humans. Simulating genetic heterogeneity of human populations, we utilized a murine genetic reference population (GRP) of BXD mice maintained in controlled laboratory environment for systems genetics analysis. This approach identified a transmembrane protein 43 (TMEM43), a target of pparγ, as a critical participant that plays key roles for both cardiac- and metabolic- related pathways via enhancing expression of genes involved in fatty acid and cholesterol uptake in the small intestine. Further, we have demonstrated that a fully penetrant ACM-causal TMEM43 p.S358L mutation induces both arrhythmogenic and metabolic abnormalities in knock-in (KI) mice bred in the same environment as the bxds, confirming shared S358L-induced mechanisms that underlie arrhythmias and disturbed energy and lipid metabolism in vivo. The goals of this study will focus on the identification of such modifier genes and molecular pathways that strongly influence the susceptibility (or resilience) and severity in acms and adcm. In this study, we will introduce the TMEM43 S358L mutation in murine GRP of BXD mice and identify shared genes and molecular mechanisms underlying arrhythmogenic and metabolic phenotypes in mice under the S358L mutation using the power of systems genetics methods (aim 1). In aim 2, the mouse results will then be assessed and validated in our registries by correlating cardiac- and metabolic-related phenotypes and genotypes in ACM and adcm patients. The major achievements of translating preclinical and cross-species and cross-tissue findings into a clinical setting will be a fuller understanding of arrhythmogenic disease spectrum, including fibro-fatty infiltrations in the myocardium, identifying novel realistic strategies for risk stratification, diagnostics and, potentially, improving SCD prevention and personalized care of patients.