Secretome of atrial epicardial adipose tissue facilitates reentrant arrhythmias by myocardial remodeling

Auriane C. Ernault, Arie O. Verkerk, Jason D. Bayer, Kedar Aras, Pablo Montañés-Agudo, Rajiv A. Mohan, Marieke Veldkamp, Mathilde R. Rivaud, Rosan de Winter, Makiri Kawasaki, Shirley C. M. van Amersfoorth, Eva R. Meulendijks, Antoine H. G. Driessen, Igor R. Efimov, Joris R. de Groot, Ruben Coronel

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Background: Epicardial adipose tissue (EAT) accumulation is associated with cardiac arrhythmias. The effect of EAT secretome (EATs) on cardiac electrophysiology remains largely unknown. Objective: The purpose of this study was to investigate the arrhythmogenicity of EATs 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, subcutaneous adipose tissue secretome (SATs), and cardiomyocytes conditioned medium (CCM) for 72 hours. We implemented the electrophysiological changes observed after EATs incubation into a model of human left atrium and tested arrhythmia inducibility. Results: Incubation of NRVMs with EATs decreased expression of the potassium channel subunit Kcnj2 by 26% and correspondingly reduced the inward rectifier K+ current IK1 by 35% compared to incubation with CCM, resulting in a depolarized resting membrane of cardiomyocytes. EATs decreased expression of connexin43 (29% mRNA, 46% protein) in comparison to CCM. Cells incubated with SATs showed no significant differences in Kcnj2 or Gja1 expression in comparison to CCM, and their resting potential was not depolarized. Cardiomyocytes incubated with EATs showed reduced conduction velocity and increased conduction heterogeneity compared to SATs and CCM. Computer 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 potential, alters electrical cell–cell coupling, and facilitates reentrant arrhythmias.
Original languageEnglish
Pages (from-to)1461-1470
Number of pages10
JournalHeart Rhythm
Issue number9
Early online date2022
Publication statusPublished - Sept 2022


  • Arrhythmias
  • Atrial fibrillation
  • Epicardial adipose tissue
  • Ion channels
  • Obesity

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