Epicardial Fat Drives Macrophage Response in Atrial Cardiomyopathy

BACKGROUND: Inflammation is associated with atrial fibrillation (AF), but its precise impact on the long-term progression of the AF substrate, also called atrial cardiomyopathy (ACM), remains debated. METHODS: Human atria specimens were used for spatial transcriptomic, histology, epicardial progenitor cell (EPDCs) culture and immunofluorescence. Atria removed from B6J mice fed a high fat diet (HFD) were evaluated at 2 and 4 months of diet with single-cell RNA sequencing, microscopy and flow cytometer. Lyve1-resident macrophages deficient and CCR2 (C-C chemokine receptor type 2) knockout mice and their wild type littermates were evaluated in terms of ACM, cardiac structure, metabolic diseases, histology, immune cells characterization and key molecular markers. Olink assay was performed to screen plasma samples and the cellular secretome for various cytokines. Primary THP1-derived macrophages were cocultured with EPDCs and evaluated for myofibroblast differentiation. RESULTS: Macrophage subpopulations were mainly confined in the EAT of human atria. In a mouse model of obesity and ACM, macrophage recruitment was associated with atrial adiposity. In addition, Lyve1 + -resident and CCR2+ monocyte-derived macrophages were identified in obese mouse atria. Depleting Lyve1 + -macrophages in mice prevented early fat expansion and led to myocardial dystrophy, while CCR2 + -macrophage depletion prevented fibro-fatty remodeling, atrial dilation, and AF. CONCLUSIONS: These data highlight the pivotal role of macrophages in atrial adiposity, in particular that of Lyve1 + -macrophages during adipose tissue expansion.