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

doi:10.1016/j.hrthm.2022.05.011

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

^*Corresponding author for this work

Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

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 I_K1 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 language	English (US)
Pages (from-to)	1461-1470
Number of pages	10
Journal	Heart rhythm
Volume	19
Issue number	9
DOIs	https://doi.org/10.1016/j.hrthm.2022.05.011
State	Published - Sep 2022

Funding

Funding Sources: This work was supported by the FRM (Fondation pour la Recherche Médicale, PBR201810007613 ) to Auriane C. Ernault; French National Research Agency ( ANR-10-IAHU-04 and ANR-19-ECVD-0006 ) to Dr Bayer; NIH Grants 3OT2OD023848 and 5K99HL148523-02 to Drs Efimov and Aras ; and Leducq Foundation Grant RHYTHM to Drs Efimov and Coronel (16CVD02).

Keywords

Arrhythmias
Atrial fibrillation
Epicardial adipose tissue
Ion channels
Obesity

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.hrthm.2022.05.011

Cite this

Ernault, A. C., Verkerk, A. O., Bayer, J. D., Aras, K., Montañés-Agudo, P., Mohan, R. A., Veldkamp, M., Rivaud, M. R., de Winter, R., Kawasaki, M., van Amersfoorth, S. C. M., Meulendijks, E. R., Driessen, A. H. G., Efimov, I. R., de Groot, J. R., & Coronel, R. (2022). Secretome of atrial epicardial adipose tissue facilitates reentrant arrhythmias by myocardial remodeling. Heart rhythm, 19(9), 1461-1470. https://doi.org/10.1016/j.hrthm.2022.05.011

@article{ee6eb7a401c44848bffd1debe24bf775,

title = "Secretome of atrial epicardial adipose tissue facilitates reentrant arrhythmias by myocardial remodeling",

abstract = "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.",

keywords = "Arrhythmias, Atrial fibrillation, Epicardial adipose tissue, Ion channels, Obesity",

author = "Ernault, {Auriane C.} and Verkerk, {Arie O.} and Bayer, {Jason D.} and Kedar Aras and Pablo Monta{\~n}{\'e}s-Agudo and Mohan, {Rajiv A.} and Marieke Veldkamp and Rivaud, {Mathilde R.} and {de Winter}, Rosan and Makiri Kawasaki and {van Amersfoorth}, {Shirley C.M.} and Meulendijks, {Eva R.} and Driessen, {Antoine H.G.} and Efimov, {Igor R.} and {de Groot}, {Joris R.} and Ruben Coronel",

note = "Publisher Copyright: {\textcopyright} 2022 Heart Rhythm Society",

year = "2022",

month = sep,

doi = "10.1016/j.hrthm.2022.05.011",

language = "English (US)",

volume = "19",

pages = "1461--1470",

journal = "Heart rhythm",

issn = "1547-5271",

publisher = "Elsevier",

number = "9",

}

Ernault, AC, Verkerk, AO, Bayer, JD, Aras, K, Montañés-Agudo, P, Mohan, RA, Veldkamp, M, Rivaud, MR, de Winter, R, Kawasaki, M, van Amersfoorth, SCM, Meulendijks, ER, Driessen, AHG, Efimov, IR, de Groot, JR & Coronel, R 2022, 'Secretome of atrial epicardial adipose tissue facilitates reentrant arrhythmias by myocardial remodeling', Heart rhythm, vol. 19, no. 9, pp. 1461-1470. https://doi.org/10.1016/j.hrthm.2022.05.011

TY - JOUR

T1 - Secretome of atrial epicardial adipose tissue facilitates reentrant arrhythmias by myocardial remodeling

AU - Ernault, Auriane C.

AU - Verkerk, Arie O.

AU - Bayer, Jason D.

AU - Aras, Kedar

AU - Montañés-Agudo, Pablo

AU - Mohan, Rajiv A.

AU - Veldkamp, Marieke

AU - Rivaud, Mathilde R.

AU - de Winter, Rosan

AU - Kawasaki, Makiri

AU - van Amersfoorth, Shirley C.M.

AU - Meulendijks, Eva R.

AU - Driessen, Antoine H.G.

AU - Efimov, Igor R.

AU - de Groot, Joris R.

AU - Coronel, Ruben

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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.

KW - Arrhythmias

KW - Atrial fibrillation

KW - Epicardial adipose tissue

KW - Ion channels

KW - Obesity

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DO - 10.1016/j.hrthm.2022.05.011

M3 - Article

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SN - 1547-5271

VL - 19

SP - 1461

EP - 1470

JO - Heart rhythm

JF - Heart rhythm

IS - 9

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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