TY - JOUR
T1 - Epicardial Adipose Tissue Accumulation Confers Atrial Conduction Abnormality
AU - Nalliah, Chrishan J.
AU - Bell, James R.
AU - Raaijmakers, Antonia J.A.
AU - Waddell, Helen M.
AU - Wells, Simon P.
AU - Bernasochi, Gabriel B.
AU - Montgomery, Magdalene K.
AU - Binny, Simon
AU - Watts, Troy
AU - Joshi, Subodh B.
AU - Lui, Elaine
AU - Sim, Choon Boon
AU - Larobina, Marco
AU - O'Keefe, Michael
AU - Goldblatt, John
AU - Royse, Alistair
AU - Lee, Geoffrey
AU - Porrello, Enzo R.
AU - Watt, Matthew J.
AU - Kistler, Peter M.
AU - Sanders, Prashanthan
AU - Delbridge, Lea M.D.
AU - Kalman, Jonathan M.
N1 - Funding Information:
The authors thank the Melbourne Histology Platform and Australian Phenomics Network for assistance with histological processing, and the Bio21 Mass Spectrometry and Proteomics Facility for support with proteomics procedures.
Funding Information:
Research support for this work has been provided by the National Health and Medical Research Council Project (NHMRC: 1099352 and 1125453 to Drs. Delbridge, Bell, and Kalman) and fellowship (1093830 to Dr. Nalliah; 1143224 to Dr. Montgomery) grants. Dr. Sanders has served on the Advisory Board of Biosense Webster, Medtronic, St. Jude Medical, and Boston Scientific; has received lecture and/or consulting fees from Biosense Webster, Medtronic, St. Jude Medical, and Boston Scientific; and has received research funding from Medtronic, St. Jude Medical, Boston Scientific, Biotronik, and Sorin. Dr. Kalman is the recipient of a Practitioner Fellowship (NHMRC: GNT1155084); has received research support from Biosense Webster, St. Jude Medical, and Medtronic; and has received research and fellowship funding from Medtronic, Abbott, Inc., and Biosense Webster. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Publisher Copyright:
© 2020 American College of Cardiology Foundation
PY - 2020/9/8
Y1 - 2020/9/8
N2 - Background: Clinical studies have reported that epicardial adipose tissue (EpAT) accumulation associates with the progression of atrial fibrillation (AF) pathology and adversely affects AF management. The role of local cardiac EpAT deposition in disease progression is unclear, and the electrophysiological, cellular, and molecular mechanisms involved remain poorly defined. Objectives: The purpose of this study was to identify the underlying mechanisms by which EpAT influences the atrial substrate for AF. Methods: Patients without AF undergoing coronary artery bypass surgery were recruited. Computed tomography and high-density epicardial electrophysiological mapping of the anterior right atrium were utilized to quantify EpAT volumes and to assess association with the electrophysiological substrate in situ. Excised right atrial appendages were analyzed histologically to characterize EpAT infiltration, fibrosis, and gap junction localization. Co-culture experiments were used to evaluate the paracrine effects of EpAT on cardiomyocyte electrophysiology. Proteomic analyses were applied to identify molecular mediators of cellular electrophysiological disturbance. Results: Higher local EpAT volume clinically correlated with slowed conduction, greater electrogram fractionation, increased fibrosis, and lateralization of cardiomyocyte connexin-40. In addition, atrial conduction heterogeneity was increased with more extensive myocardial EpAT infiltration. Cardiomyocyte culture studies using multielectrode arrays showed that cardiac adipose tissue-secreted factors slowed conduction velocity and contained proteins with capacity to disrupt intermyocyte electromechanical integrity. Conclusions: These findings indicate that atrial pathophysiology is critically dependent on local EpAT accumulation and infiltration. In addition to myocardial architecture disruption, this effect can be attributed to an EpAT-cardiomyocyte paracrine axis. The focal adhesion group proteins are identified as new disease candidates potentially contributing to arrhythmogenic atrial substrate.
AB - Background: Clinical studies have reported that epicardial adipose tissue (EpAT) accumulation associates with the progression of atrial fibrillation (AF) pathology and adversely affects AF management. The role of local cardiac EpAT deposition in disease progression is unclear, and the electrophysiological, cellular, and molecular mechanisms involved remain poorly defined. Objectives: The purpose of this study was to identify the underlying mechanisms by which EpAT influences the atrial substrate for AF. Methods: Patients without AF undergoing coronary artery bypass surgery were recruited. Computed tomography and high-density epicardial electrophysiological mapping of the anterior right atrium were utilized to quantify EpAT volumes and to assess association with the electrophysiological substrate in situ. Excised right atrial appendages were analyzed histologically to characterize EpAT infiltration, fibrosis, and gap junction localization. Co-culture experiments were used to evaluate the paracrine effects of EpAT on cardiomyocyte electrophysiology. Proteomic analyses were applied to identify molecular mediators of cellular electrophysiological disturbance. Results: Higher local EpAT volume clinically correlated with slowed conduction, greater electrogram fractionation, increased fibrosis, and lateralization of cardiomyocyte connexin-40. In addition, atrial conduction heterogeneity was increased with more extensive myocardial EpAT infiltration. Cardiomyocyte culture studies using multielectrode arrays showed that cardiac adipose tissue-secreted factors slowed conduction velocity and contained proteins with capacity to disrupt intermyocyte electromechanical integrity. Conclusions: These findings indicate that atrial pathophysiology is critically dependent on local EpAT accumulation and infiltration. In addition to myocardial architecture disruption, this effect can be attributed to an EpAT-cardiomyocyte paracrine axis. The focal adhesion group proteins are identified as new disease candidates potentially contributing to arrhythmogenic atrial substrate.
KW - atrial fibrillation
KW - cardiomyocyte
KW - electrophysiology
KW - epicardial adipose tissue
KW - proteomics
UR - https://www.scopus.com/pages/publications/85089819693
U2 - 10.1016/j.jacc.2020.07.017
DO - 10.1016/j.jacc.2020.07.017
M3 - Article
C2 - 32883413
AN - SCOPUS:85089819693
SN - 0735-1097
VL - 76
SP - 1197
EP - 1211
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 10
ER -