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 Ca 2+ 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. Ca 2+ 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 Ca 2+ current and membrane potential instability. Ca 2+ handling was markedly altered, including increased Ca 2+ spark density, prolonged Ca 2+ transient decay, and elevated sarcoplasmic reticulum Ca 2+ 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 Ca 2+ 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.