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Acute Binge Alcohol Increases Risk of Arrhythmias and Myocardial Fibrosis in a Mouse Model of Arrhythmogenic Cardiomyopathy.

Emily A. Shiel,Waleed Farra,Steven Medarev,Gallage Hdn Ariyaratne,Elisa N. Cannon,Jennifer L. Steiner,Stephen P. Chelko

Published 2025 in American Journal of Physiology. Heart and Circulatory Physiology

ABSTRACT

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by myocardial inflammation and fibrosis, ventricular dysfunction, and arrhythmias, and is a leading cause of sudden cardiac death in young adults. Acute binge alcohol consumption is a common behavior of young adults and is known to cause transient cardiac stress; however, its impact on ACM remains unclear. Wild-type (WT) and homozygous Desmoglein-2 mutant (Dsg2mut/mut) mice, a robust mouse model of ACM, were gavaged with 5 g/kg of alcohol or equivalent volume/kg of saline (placebo), twice weekly from 8 to 24 weeks of age to determine the effects of repeat binges on ACM disease progression. Survival, cardiac function, ectopic burden, myocardial fibrosis, and inflammatory signaling were evaluated using echocardiography, electrocardiography, histology, and molecular assays, respectively. Of note, alcohol-treated Dsg2mut/mut mice exhibited increased mortality compared to placebo-treated counterparts, accompanied with increased ventricular ectopics in Dsg2mut/mut mice that died prematurely. Increased biventricular fibrosis was noted in alcohol-treated Dsg2mut/mut mice and demonstrated a strong, positive correlation with peak blood alcohol concentration. While alcohol-treated mice displayed decreased phosphorylated NFĸB and JNK2 myocardial levels, elevated levels of cytoplasmic and extracellular localization of HMGB1 were noted. Our findings demonstrate that acute binge alcohol exacerbates disease progression in a desmosomal-linked ACM mouse, likely through enhanced fibrotic remodeling and altered inflammatory signaling. These outcomes highlight the potential danger of binge alcohol consumption in genetically susceptible ACM subjects, further underscoring the role of environmental factors in ACM onset and progression.

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