Increased arrhythmic risk in obesity is transduced by adipose tissue-derived extracellular vesicles

Here, we demonstrate prolongation of the action potential duration (APD) is human atrial myocytes obtained from obese but not lean patients indicating obesity-associated electrical remodeling. Consistent with this observation, visceral adipose tissue-derived extracellular vesicles (VAT EVs) from obese individuals similarly prolong action potential duration (APD) and impair calcium handling in human stem cell-derived cardiomyocytes, activate human cardiac fibroblasts and drive macrophages toward a pro-inflammatory phenotype, promoting a pro-arrhythmic substrate.

We observed this communication in vivo, where adipose-derived EVs directly target cardiac cells in obese mice more than in lean mice, implicating a fat-heart communication axis in obesity. Human functional genomics anchored on genes differentially expressed in human cardiomyocytes, fibroblasts, and macrophages after human obese VAT-EV exposure identified targets causally linked to both QT interval (n=117,532) and atrial fibrillation (n= 181,446).