Systemic Delivery of Extracellular Vesicles Attenuates Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction

BACKGROUND Atrial fibrillation (AF) is a common comorbidity in heart failure with preserved ejection fraction (HFpEF) patients. To date, treatments for HFpEF-related AF have been limited to anti-arrhythmic drugs and ablation. Here we examined the effects of immortalized cardiosphere-derived extracellular vesicles (imCDCevs) in rats with HFpEF. OBJECTIVES This study sought to investigate the mechanisms of AF in HFpEF and probe the potential therapeutic efficacy of imCDCevs in HFpEF-related AF. METHODS Dahl salt-sensitive rats were fed a high-salt diet for 7 weeks to induce HFpEF and randomized to receive imCDCevs (n 1/4 18) or vehicle intravenously (n 1/4 14). Rats fed a normal-salt diet were used as control animals (n 1/4 26). A comprehensive characterization of atrial remodeling was conducted using functional and molecular techniques. RESULTS HFpEF-verified animals showed significantly higher AF inducibility (84%) compared with control animals (15%). These changes were associated with prolonged action potential duration, slowed conduction velocity (connexin 43 lateralization), and fibrotic remodeling in the left atrium of HFpEF compared with control animals. ImCDCevs reversed adverse electrical remodeling (restoration of action potential duration to control levels and reorganization of connexin 43) and reduced AF inducibility (33%). In addition, fibrosis, inflammation, and oxidative stress, which are major patho-logical AF drivers, were markedly attenuated in imCDCevs-treated animals. Importantly, these effects occurred without changes in blood pressure and diastolic function. CONCLUSIONS Thus, imCDCevs attenuated adverse remodeling, and prevented AF in a rat model of HFpEF. (C) 2023 by the American College of Cardiology Foundation.