A role of extracellular vesicle-mediated inter-organ communication in obesity-related arrhythmia

Abstract

Obesity contributes to the risk of cardiac arrhythmias, but the exact mechanism remains unclear. Here, we show visceral adipose tissue-derived extracellular vesicles (VAT EVs) from individuals with obesity prolong action potential duration (APD) and impair calcium handling in stem cell-derived cardiomyocytes, in addition to activating fibroblasts and macrophages towards a pro-fibrotic/inflammatory state, thereby creating pro-arrhythmic substrate. Adipose-derived EVs target the heart in obese mice, suggesting the potential for direct communication. Transcriptome-wide genetic association (TWAS) and epigenetic studies anchored on genes differentially expressed in cardiomyocytes, fibroblasts, and macrophages after VAT-EV exposure identified genes significantly associated with QT interval and atrial fibrillation. Finally, as a proof-of-principle, we pharmacologically blocked TRPC3 (a VAT-EV-induced ion channel) in cardiomyocytes, restoring the APD towards normality. This molecular genetic evidence supports an EV-mediated direct communication pathway between adipose tissue and the heart in arrhythmogenesis, offering a new paradigm to identify mediators of cardiovascular disease in obesity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/676027v1_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@114b230org.highwire.dtl.DTLVardef@1be7926org.highwire.dtl.DTLVardef@3d6b0org.highwire.dtl.DTLVardef@3ef15_HPS_FORMAT_FIGEXP M_FIG C_FIG