Abstract 4145196: The role of extracellular vesicle-mediated interorgan crosstalk in obesity and risk of arrhythmias

Background: The worldwide prevalence of obesity has increased in the past decades. Obesity is known to be epidemiologically associated with an increased risk of sudden cardiac death (SCD). However, the mechanisms underlying this phenomenon are not completely understood. We hypothesize that the crosstalk between metabolic organs, such as adipose tissue, and cardiac tissues may contribute to cardiac electrical and structural remodeling that ultimately increases the propensity for SCD; and that extracellular vesicles (EVs), lipid membrane-delimited particles containing diverse cargo (protein, nucleic acids, and metabolites), are as potential key mediators of these interorgan communications. Method: Plasma samples were obtained from 5 lean and 6 obese patients without a history of arrhythmias or heart failure (patients were matched by age, sex, and comorbidities). Small EVs (sEVs) were extracted from patients’ plasma and characterized. These sEVs were used to treat human induced pluripotent stem cell-derived ventricular cardiomyocytes (iPSC-vCMs). Action potentials of sEV-treated iPSC-vCMs were measured via optical mapping. Lastly, plasma extracellular small RNAs were extracted and sequenced. Results: IPSC-vCMs treated with sEVs derived from obese patients have significantly prolonged action potential duration (APD) at 1-Hz pacing, compared to those treated with EVs from lean counterparts (Figure 1, 589±8 ms vs. 540±11 ms, p < 0.001, n = 2 differentiations) without significant difference in spontaneous contraction rate between the two groups. Preliminary differential gene expression analysis of obese vs. lean plasma extracellular small RNAs demonstrates enrichment in critical signaling pathways, including those involved in calcium homeostasis, reactive oxygen species, fibrosis, and mitochondrial energetics. Conclusion: An increased APD in iPSC-vCMs treated with plasma-derived EVs from obese patients correlates with QT interval prolongation, a known risk factor for SCD which is epidemiologically observed in obese populations. Further in-depth analysis to pinpoint targetable EV cargo may shed light on novel mechanisms responsible for obesity-related SCD and potential preventive strategies for SCD in this patient population.