Epicardial adipose tissue drives to macrophages response during the atrial cardiomyopathy

Abstract Background Atrial fibrillation (AF), the most common arrhythmia and the first cause of stroke, is often associated with an atrial cardiomyopathy. The epicardial adipose tissue (EAT) has emerged as a major component of the atrial cardiomyopathy notably in patients with metabolic disorders like obesity and diabetes. Direct arrhythmogenicity of EAT has been attributed to its role played in fibrosis, inflammation or oxidative and metabolic stress of neighbouring myocardium. Hypothesis. The immune response is a mechanistic link between metabolic disorders, EAT and the formation of the atrial cardiomyopathy by favouring fibrosis of EAT and fibro-fatty infiltrations of the atrial myocardium and by modulating recruitment of resident progenitor cells. Research strategies. In atria the subpopulations of immune cells were analyzed with flow cytometry in a high fat diet-induced obesity mouse model that developed an arrythmia, adipogenic and inflammatory phenotype. To characterize the impacts of immune response on atrial remodelling, both deficient mouse models for monocyte-derived macrophages, CCR2KO, and resident macrophages Lyve1Cre+/--Csf1Rfl/fl induced obese with high fat diet. Clinical and obesity parameters was used together with flow cytometer, histology and immunolabeling. Data obtained in mice will be confronted to results from human specimen atria obtained during cardiac surgery in patients suffering of obesity, diabetes or AF and compared to a control group of patients in sinus rhythm without metabolic disorders. In human atrial sections, the identification and localization of immune cells subpopulations will be addressed using Spatial transcriptomic approach. Addition, the dysfunctional human EAT will be characterized with immunolabeling and quantification of adipocytes morphometry. Results Our studies have shown that adipocytes size and their function in EAT was various in specific areas of subepicardium. Hypoxia and vessels of EAT led to inflammatory response. The contribution of macrophages in atria remodeling that lead to a better understand the link between AF and metabolic diseases and that open new avenues of research to prevent the atrial cardiomyopathy.Subepicardium of human atria specimen Macrophages in obese mouse atria