Author + information
- Received May 4, 2020
- Revision received July 2, 2020
- Accepted July 9, 2020
- Published online August 31, 2020.
- Chrishan J. Nalliah, MBBS, PhDa,b,∗,
- James R. Bell, PhDc,d,∗,
- Antonia J.A. Raaijmakers, PhDd,
- Helen M. Waddell, BScd,
- Simon P. Wells, MResd,e,
- Gabriel B. Bernasochi, PhDd,
- Magdalene K. Montgomery, PhDd,
- Simon Binny, MBBSa,
- Troy Watts, BSca,
- Subodh B. Joshi, MBBSa,
- Elaine Lui, MMed, MBBSf,
- Choon Boon Sim, PhDg,
- Marco Larobina, MBBSh,
- Michael O’Keefe, MBBSh,
- John Goldblatt, MBBSh,
- Alistair Royse, MBBSh,
- Geoffrey Lee, MBChB, PhDa,b,
- Enzo R. Porrello, PhDd,g,
- Matthew J. Watt, PhDd,
- Peter M. Kistler, MBBS, PhDi,
- Prashanthan Sanders, MBBS, PhDj,
- Lea M.D. Delbridge, PhDd,∗∗,† (, )@DelbridgeLea@LabBell and
- Jonathan M. Kalman, MBBS, PhDa,b,∗,† ()
- aDepartment of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
- bDepartment of Medicine and Radiology, University of Melbourne, Melbourne, Victoria, Australia
- cDepartment of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia
- dDepartment of Physiology, University of Melbourne, Melbourne, Victoria, Australia
- eInstitute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- fDepartment of Radiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
- gMurdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Victoria, Australia
- hDepartment of Cardiothoracic Surgery, Royal Melbourne Hospital, Melbourne, Victoria, Australia
- iDepartment of Cardiology, The Alfred Hospital, Melbourne, Victoria, Australia
- jAustralia Centre for Heart Rhythm Disorders (CHRD), South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide and Royal Adelaide Hospital, Adelaide, South Australia, Australia
- ↵∗Address for correspondence:
Prof. Jonathan M. Kalman, Department of Medicine, University of Melbourne, Department of Cardiology, Grattan Street, Parkville, Victoria 3050, Australia.
- ↵∗∗Prof. Lea M.D. Delbridge, Department of Physiology, University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia.
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.
↵∗ Drs. Nalliah and Bell are joint first authors.
↵† Profs. Delbridge and Kalman are joint senior authors.
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.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.
- Received May 4, 2020.
- Revision received July 2, 2020.
- Accepted July 9, 2020.
- 2020 American College of Cardiology Foundation
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