Increased Arrhythmic Risk in Obesity Is Transduced by Adipose Tissue–Derived Extracellular Vesicles

Abstract

Obesity drives atrial fibrillation and ventricular arrhythmias, yet whether direct fat-heart communication mediates this risk is unknown. The authors demonstrate that human atrial myocytes from obese individuals exhibit prolonged action potential duration, a pro-arrhythmic phenotype reproduced by treating induced pluripotent stem cell–derived cardiomyocytes with visceral adipose tissue–derived extracellular vesicles (VAT EVs) from obese donors. VAT EVs also impaired calcium handling, activated cardiac fibroblasts, and shifted macrophages toward a pro-inflammatory activation state—collectively promoting an arrhythmogenic substrate. Using a transgenic adipose-specific EV-tracking mouse model, the authors confirmed preferential adipose-to-myocardial EV trafficking in obese vs lean mice in vivo. Transcriptome-wide association studies anchored on VAT EV–induced gene expression changes identified causal links to QT interval and atrial fibrillation in large genome-wide association studies. Pharmacologic inhibition of TRPC3, an ion channel upregulated by VAT EVs, restored action potential duration toward normal, identifying a novel therapeutic target in obesity-associated arrhythmia.