Key result
Small extracellular vesicles from epicardial fat of patients with atrial fibrillation induced inflammation, fibrosis, and sustained re-entry in experimental models compared to those without AF.
Why the study?
Epicardial fat is linked to AF, but the role of small extracellular vesicles in the pathogenesis of AF had not been studied.
Do small extracellular vesicles from epicardial fat of patients with AF induce inflammation, fibrosis, and arrhythmias compared to those from patients without AF?
Do small extracellular vesicles from epicardial fat of patients with AF induce inflammation, fibrosis, and arrhythmias compared to those from patients without AF?
Small extracellular vesicles from epicardial fat of patients with atrial fibrillation exhibit unique pro-inflammatory, pro-fibrotic, and pro-arrhythmic properties, suggesting a novel mechanism for AF pathogenesis.
Should not change practice; hypothesis-generating for vesicle-targeted AF therapies.
Background and aim Epicardial fat (eFat) has been linked to atrial remodeling and fibrillation (AF). Small extracellular vesicles (sEVs) are heterogeneous membrane vesicles released by all cell types. They can both protect and damage tissues by the delivery of multiple different messengers. Surprisingly, the role of sEVs in the pathogenesis of AF has not been studied. Thus, we aimed to determine whether sEVs derived from eFat play a role in the pathogenesis of AF. Methods and results We collected eFat specimens from patients with and without chronic or paroxysmal AF undergoing open-heart surgery. Isolated eFat specimens were cut into small pieces and incubated as organ cultures. We isolated sEVs from the medium of the explant by differential ultra-centrifugation, high-density gradient or size exclusion chromatography (SEC), and characterized vesicle size distribution, morphology, specific markers, histology and molecular cargo. Immunostaining for macrophage accumulation, fibrosis and apoptosis confirmed the pro-inflammatory and pro-fibrotic properties of eFat sEVs from patients with AF (Fig. 1). eFat sEVs labeled with PKH26 were massively up taken by endothelial cells (Fig. 2). Real-time PCR showed an increased level of oxidative stress genes in endothelial cells. eFat sEVs from patients with AF caused more fibrosis after injection into rat hearts than those without AF. (Fig. 3). Finally, while eFat sEVs from patients with and without AF induced shorter action potential duration, only eFat sEVs from patients with AF induced sustained re-entry (rotor) in human induced pluripotent stem cell (iPS)-derived cardiomyocytes (Fig. 4) Conclusion We show, for the first time, that sEVs from eFat of patients with AF demonstrate unique pro-inflammatory, pro-fibrotic and pro-arrhythmic properties. Our findings suggest that eFat sEVs can induce cellular, molecular and electrophysiological remodeling that can subsequently lead to the development of AF. Funding Acknowledgement Type of funding source: None
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Shaihov–Teper et al. (2020) studied Atrial fibrillation. Small extracellular vesicles from epicardial fat of patients with atrial fibrillation vs. Small extracellular vesicles from epicardial fat of patients without atrial fibrillation was evaluated on Inflammation, fibrosis, and re-entrant arrhythmias. Small extracellular vesicles from epicardial fat of patients with atrial fibrillation induced inflammation, fibrosis, and sustained re-entry in experimental models compared to those without AF.
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