Epicardial adipose layer in the control of cardiomyocyte ion homeostasis: Persistent atrial fibrillation, and semaglutide regulations

Background Epicardial adipose tissue (EAT) is a complex fat depot containing distinct cell types. In addition to being an energy source, it shows paracrine effects over the myocardium. It can be separated into adipose and non-adipose layers, where both detrimental (FABP4) and protective (omentin) markers are secreted1, 2. Although semaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), has been associated with reduced EAT volume3, its effect on epicardium layers and their paracrine activity remains unknown. Purpose This study aimed to investigate the differential paracrine activity of the epicardium layers on cardiomyocytes ion channels, its validation on patients with atrial fibrillation, and its modulation by semaglutide. Methods A total of 163 patients were enrolled after providing written informed consent. Epicardial adipose tissue (EAT) biopsies were obtained from 100 patients: Tissue profiling was performed in 87 biopsies, and 13 were separated into adipose and non-adipose layers based on adiposity and cultured with/out semaglutide (1 nM) for 72 hours. Differential secretome analysis was conducted using TripleTOF mass spectrometry. Paracrine effects on ion channel regulation were studied with hiPSC- atrial cardiomyocytes (hiPSC-aCMs) cultured with epicardium conditioned media. An adipose layer-associated protein was quantified by enzyme-linked immunosorbent assay (ELISA) in left atrial plasma from 43 patients with atrial fibrillation, as well as in peripheral plasma from 20 patients treated with semaglutide for 6 months. Results Separation of adipose and non-adipose layers was confirmed by epithelial markers mRNA levels and multiphotonic microscope. These layers showed different profiles and paracrine effect over cardiomyocytes. While non-adipose layer released more protective-structural proteins, adipose layer released fatty acid metabolism controllers. hiPSC-aCMs cultured with adipose layer conditioned medium showed increased expression levels of sodium and potassium channels and modulated after being treated by semaglutide. ACSL1, one of the identified adipose layer-related protein, was detected higher in plasma from persistent compared to paroxysmal AF patients. This protein was modulated in 65% of patients after being treated with semaglutide for 6 months. Conclusions Proteins derived from epicardial adipose layer modify cardiomyocyte ion channels which may explain the association between high ACSL1 levels and persistent AF. By regulating the adipose layer paracrine activity, semaglutide might reduce the AF burden. These findings identify the epicardial fat–ACSL1 axis as a potential semaglutide target.