Epicardial fat drives macrophage response in atrial cardiomyopathy

Inflammation is associated with atrial fibrillation (AF), but its precise impact on the long-term progression of AF substrate, also called atrial cardiomyopathy (ACM), remains debated. Here, using spatial gene expression analysis, macrophage subpopulations mainly confined to the epicardial fat depots were identified in human atria. In a mouse model of obesity and ACM, macrophage recruitment was associated with atrial adiposity. Single-cell RNA sequencing identified Lyve1+ resident and CCR2+ monocyte-derived macrophages in obese mouse atria. In obese mice, depleting Lyve1+ macrophages prevented early fat expansion and caused myocardial dystrophy, while CCR2+ macrophage depletion prevented fatty-fibrotic remodeling, atrial dilation, and AF. These data highlighted the pivotal role of epicardial adipose tissue in macrophage activation during ACM development and identified Lyve1+ macrophages as key regulators of atrial adiposity.