Epicardial Fat Drives Macrophage Response in Atrial Cardiomyopathy

BACKGROUND: Inflammation is associated with atrial fibrillation, but its precise impact on the long-term progression of the atrial fibrillation substrate, also called atrial cardiomyopathy, remains debated. METHODS AND RESULTS: Here, using spatial gene expression analysis, macrophage subpopulations mainly confined to the epicardial fat tissue were identified in the human atria. In a mouse model of obesity and atrial cardiomyopathy, macrophage recruitment was associated with atrial adiposity. Single-cell RNA sequencing allowed the identification of Lyve1 + -resident and CCR2 + monocyte-derived macrophages in obese mouse atria. In obese mice, depleting Lyve1 + -macrophages prevented early fat expansion and led to myocardial dystrophy, while CCR2 + -macrophage depletion prevented fibro-fatty remodeling, atrial dilation, and atrial fibrillation. CONCLUSIONS: These data highlight the pivotal role of macrophages in atrial adiposity, in particular that of Lyve1 + -macrophages during adipose tissue expansion.