Resident lyve1+ macrophage regulates adiposity of the atrial myocardium

Background The epicardial adipose tissue (EAT) is a major component of the atrial cardiomyopathy and a risk factor of atrial fibrillation, notably in dysmetabolic patients. The arrhythmogenicity of EAT is mainly caused by its replacement by fibrosis and the resulting fibro-fatty infiltration of subepicardial layers of the atrial wall. Hypothesis. Inflammation is involved fibro-fatty infiltration of the atrial myocardium and the formation of the atrial cardiomyopathy. Methods Identification and localization of immune cells subpopulations using spatial transcriptomic approach and flow cytometry in human right atrial samples. Study of the role of macrophages using high fat diet-induced obesity in mice that develop an atrial cardiomyopathy and atrial fibrillation (AF) vulnerability. Dissection of the role of immune cells using mice deficient for monocyte-derived macrophages, CCR2KO, and resident macrophages Lyve1Cre+/--Csf1Rfl/fl . Adiposity in mouse atria analysed by two photon microscopy imaging. The atrial cardiomyopathy was studied main by echocardiovardipography and burst pacing induced AF in mice. Results Using spatial gene expression analysis, we found that distinct subsets of macrophages were confined in the subepicardial region of the atria depending on the histological aspect of the fat depot and the presence of fibrosis. In obese mice , adipocytes could be directly visualized by two photon microscopy imaging together with macrophages in the atrial subepicardium of obese mice. After one month under a high fat diet, mice depleted of Lyve-1 showed dystrophic atrial myocardium with few adipocytes of small size, enlarged atria cardiomyocytes with little sarcomeres and the absence of extracellular matrix. In contrast, depletion of CCR2 macrophages prevented fibrosis of the atrial myocardium and the development of the atrial cardiomyopathy in obese mice. Conclusion This study reveals the pivotal role played by local inflammation notably resident Lyve1+ macrophage in the atrial adiposity and the formation of the atrial cardiomyopathy.