Background: Obesity is a significant risk factor for arrhythmic cardiovascular death. Interactions between Epicardial Adipose Tissue (EAT) and myocytes are thought to play a key role in the development of arrhythmias. Cross talk between EAT and the heart has various component. First, adipose tissue infiltration within the myocardium constitutes an anatomical obstacle to cardiac excitation. It causes activation delay and increases the risk of arrhythmias. Intercellular electrical coupling between cardiomyocytes and adipocytes can further slow conduction and increase the risk of block, favouring reentry and arrhythmias. Finally, EAT secretes multiple substances that influence cardiomyocyte electrophysiology either by modulating ion currents and electrical coupling, or by stimulating fibrosis. However, the effect of EAT secretome (EATs) on cardiac electrophysiology is largely unknown. We investigated the arrhythmogenicity of EAT secretome and its underlying molecular and electrophysiological mechanisms.
Methods: We collected atrial EAT and subcutaneous adipose tissue (SAT) from 30 patients with atrial fibrillation (AF), and EAT from 3 donors without AF. The secretome was collected after a 24-hour incubation of the adipose tissue explants. We cultured neonatal rat ventricular myocytes (NRVMs) with EATs, SAT secretome (SATs) and cardiomyocytes conditioned medium (CCM) for 72H. We implemented the electrophysiological changes observed after EATs incubation into a model of human left atrium and tested in silico arrhythmia inducibility.
Results: Cardiomyocytes incubated with EATs showed reduced conduction velocity and increased conduction heterogeneity compared to SATs and CCM. This was associated with a decreased expression of the potassium channel subunit Kcnj2 by 26% and correspondingly reduced the inward rectifier K+ current (IK1) by 35% in comparison to incubation with CCM, and resulted in a depolarized resting membrane of cardiomyocytes. EATs caused decreased expression of connexin43 (29% mRNA, 46% protein) in comparison to CCM. Cells incubated with SATs showed no significant differences in Kcnj2 nor Gja1 expression in comparison to CCM, and their resting membrane was not depolarized. In silico modeling of human left atrium revealed that the electrophysiological changes induced by EATs promote sustained reentrant arrhythmias if EAT partially covers the myocardium.
Conclusion: EAT slows conduction, depolarizes the resting membrane, alters electrical cell-cell coupling and facilitates reentrant arrhythmias.