Acute binge alcohol increases risk of arrhythmias and myocardial fibrosis in a mouse model of arrhythmogenic cardiomyopathy

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 and homozygous desmoglein-2 mutant (<i>Dsg2</i>^mut/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 wk 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 <i>Dsg2</i>^mut/mut mice exhibited increased mortality compared with placebo-treated counterparts, accompanied by increased ventricular ectopics in <i>Dsg2</i>^mut/mut mice that died prematurely. Increased biventricular fibrosis was noted in alcohol-treated <i>Dsg2</i>^mut/mut mice and demonstrated a strong, positive correlation with peak blood alcohol concentration. Although alcohol-treated mice displayed decreased phosphorylated NF-κB 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 subjects with ACM, further underscoring the role of environmental factors in ACM onset and progression.<b>NEW & NOTEWORTHY</b> We report that acute binge alcohol consumption in a robust mouse model of arrhythmogenic cardiomyopathy (ACM) significantly elevated ventricular arrhythmias, mortality, cardiomyocyte cell death via the loss of nuclear HMGB1, and extensive myocardial fibrosis. These findings demonstrate that binge drinking may serve as an environmental factor that contributes to disease progression in subjects with ACM, highlighting the need for clinical awareness regarding alcohol use in this vulnerable population.