Abstract
Rationale: Fibro-fatty infiltration of sub-epicardial layers of the atrial wall has been shown to contribute to the substrate of atrial fibrillation (AF). Objective: Here, we examined if the epicardium that contains multipotent cells is involved in this remodeling process. Methods and Results: 109 human surgical right atrial specimens were evaluated. There was a relatively greater extent of epicardial thickening and dense fibrofatty infiltrates in atrial tissue sections from patients aged over 70 years who had mitral valve disease or AF when compared to patients aged less than 70 years with ischemic cardiomyopathy as indicated using logistic regression adjusted for age and gender. Cells co-expressing markers of epicardial progenitors and fibroblasts were detected in fibro-fatty infiltrates. Such epicardial remodeling was reproduced in an experimental model of atrial cardiomyopathy in rat and in Wilm's Tumor-1 (WT1)CreERT2/+;ROSA-tdT+/- mice. In the latter, genetic lineage tracing demonstrated the epicardial origin of fibroblasts within fibro-fatty infiltrates. A subpopulation of human adult epicardial-derived cells (aEPDCs) expressing Platelet-derived growth factor receptor-alpha (PDGFRalpha were isolated and differentiated into myofibroblasts in the presence of angiotensin-II. Furthermore, single cell RNA-seqencing analysis identified several clusters of aEPDCs and revealed their specification from adipogenic to fibrogenic cells in the rat model of atrial cardiomyopathy. Conclusions:Epicardium is reactivated during the formation of the atrial cardiomyopathy. Subsets of aEPDCs, pre-programmed towards a specific cell fate, contribute to fibro-fatty infiltration of sub-epicardium of diseased atria. Our study reveals the biological basis for chronic atrial myocardial remodeling that paves the way of AF.