Atrial remodeling of excitation and Ca2+ handling in male mice with cardiac steatosis induced by perilipin 2 overexpression.

BACKGROUND: Diabetes mellitus and obesity are major risk factors for atrial fibrillation (AF). Cardiac steatosis, characterized by excessive lipid droplet (LD) accumulation within cardiomyocytes, is frequently observed in these conditions. However, whether myocardial LD accumulation per se directly promotes atrial proarrhythmogenic remodeling remains unclear. OBJECTIVE: To explore whether myocardial LD accumulation directly induces proarrhythmogenic remodeling of electrophysiological and Ca2+ handling properties in male mice. METHODS: Atrial myocytes from male steatotic transgenic (TG) mice with cardiac-specific perilipin-2 (PLIN2) overexpression and male double transgenic (DTG) mice with normalized atrial LD levels were studied. Action potentials and ionic currents were recorded using patch-clamp techniques. Ca2+ handling was assessed by Rhod-4™-based imaging, and reactive oxygen species (ROS) levels by fluorescence probes. RESULTS: TG atrial myocytes demonstrated reduced action potential duration, increased ultra-rapid delayed rectifier K+ current, decreased L-type Ca2+ current and membrane potential instability. Ca2+ handling was markedly altered, including increased Ca2+ spark density, prolonged Ca2+ transient decay, and elevated sarcoplasmic reticulum Ca2+ content. Both cytosolic and mitochondrial ROS levels were significantly increased. These alterations were absent in DTG myocytes and in TG myocytes treated with a mitochondria-targeted antioxidant. CONCLUSION: Atrial LD accumulation induces electrical remodeling, abnormal Ca2+ handling, and oxidative stress, creating a proarrhythmogenic substrate. These findings identify cardiac steatosis in male mice as a direct contributor to arrhythmogenesis and suggest myocardial lipid metabolism as a therapeutic target for AF in metabolic disease. Whether similar mechanisms operate in female mice require future investigation.