Epicardial Fat of Patients with Atrial Fibrillation Releases Exosomes with Distinct Molecular and Biological Properties

Background: Exosomes, nano-mediators of cell-to-cell communication, are potential contributors to cardiovascular disease. However, the role of exosomes in the pathogenesis of atrial fibrillation (AF) remains unknown. We aimed to test the hypothesis that exosomes, derived from epicardial fat (eFat),contribute to the myocardial substrate that promotes AF by increasing the expression and release of pro-inflammatory cytokines, which in turn lead to inflammation and fibrosis.

Methods and Results: We obtained eFat specimens from 25 patients (8 with chronic AF, 5 with paroxysmal AF, and 12 without AF [controls]) who underwent open heart surgery. We then cultured the eFat specimens, and collected and analyzed the secreted cytokines and exosomes (Fig. 1A). Demographic and clinical characteristics were similar between patients with and without AF (Fig. 1B). Significantly, eFat specimens from AF patients secreted higher amounts of exosomes compared with controls (Fig. 1C). Increased exosome secretion was primarily related to eFat of patients with chronic AF (Fig. 1D). Notably, eFat from patients with AF had a higher concentration of exosomal pro-inflammatory and pro-fibrotic cytokines, such as IL-1α, TNF-α, IL-6, IL-4 but less IL-10, an anti-inflammatory cytokine, compared with patients without AF (Fig 1E-I). Scratch assay was used to determine whether excess expression of the measured cytokines from eFat exosomes promote the formation of cardiac fibrosis. Fibroblast migration was higher and faster after stimulation with eFat exosomes from patients with vs. those without AF (Fig. 1J), suggesting pro-fibrotic properties of eFat exosomes from patients with AF.

Conclusions: We show, for the first time, that eFat exosomes from patients with AF have a unique pro-inflammatory and pro-fibrotic signature. Our data suggest that atrial fibrosis could be mediated by eFat exosomes. Our findings could be relevant to the pathogenesis and therapy of other diseases such as atherosclerosis, cardiac fibrosis, and heart failure with preserved ejection fraction.