GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE314nnn/GSE314750/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE314750GEOGSEfalseIncreased arrhythmic risk in obesity is transduced by adipose tissue-derived extracellular vesiclesWhile obesity is associated with atrial fibrillation and ventricular arrhythmias, whether direct communication from excess fat transduces this risk to the heart is unknown. 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). Pharmacological blockade of a VAT-EV induced ion channel TRPC3 in cardiomyocytes restored the APD toward normal. These results collectively implicate an EV-mediated direct communication pathway between adipose tissue and the heart in arrhythmogenesis that activates both known and novel pathways, offering a new paradigm to identify mediators of cardiovascular disease in obesity.2026/06/30GSE314750GSM9410051GSM9410050GSM9410031GSM9410053GSM9410030GSM9410052GSM9410055GSM9410033GSM9410032GSM9410054GSM9410035GSM9410057GSM9410034GSM9410056GSM9410037GSM9410058GSM9410036GSM9410039GSM9410038GSM9410040GSM9410042GSM9410041GSM9410044GSM9410043GSM9410046GSM9410045GSM9410048GSM9410047GSM9410049GSM94100293017334284314750Homo sapiens