Epicardial Adipose Tissue Accumulation Confers Atrial Conduction Abnormality

• Published in: Journal of the American College of Cardiology Vol. 76; no. 10; pp. 1197 - 1211
• Main Authors: Nalliah, Chrishan J, Bell, James R, Raaijmakers, Antonia J A, Waddell, Helen M, Wells, Simon P, Bernasochi, Gabriel B, Montgomery, Magdalene K, Binny, Simon, Watts, Troy, Joshi, Subodh B, Lui, Elaine, Sim, Choon Boon, Larobina, Marco, O'Keefe, Michael, Goldblatt, John, Royse, Alistair, Lee, Geoffrey, Porrello, Enzo R, Watt, Matthew J, Kistler, Peter M, Sanders, Prashanthan, Delbridge, Lea M D, Kalman, Jonathan M
• Format: Journal Article
• Language: English
• Published: United States 08-09-2020
• Subjects: Adipose Tissue - diagnostic imaging; Adipose Tissue - physiopathology; Aged; Animals; Atrial Fibrillation - diagnostic imaging; Atrial Fibrillation - physiopathology; Cells, Cultured; Coculture Techniques; Epicardial Mapping - methods; Female; Heart Conduction System - diagnostic imaging; Heart Conduction System - physiopathology; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Pericardium - diagnostic imaging; Pericardium - physiopathology; Proteomics - methods; atrial fibrillation; electrophysiology; proteomics; epicardial adipose tissue; cardiomyocyte
• ISSN: 1558-3597
• DOI: 10.1016/j.jacc.2020.07.017

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.
The purpose of this study was to identify the underlying mechanisms by which EpAT influences the atrial substrate for AF.
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.
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.
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.