Chrishan J Nalliah1, James R Bell2, Antonia J A Raaijmakers3, Helen M Waddell3, Simon P Wells4, Gabriel B Bernasochi3, Magdalene K Montgomery3, Simon Binny5, Troy Watts5, Subodh B Joshi5, Elaine Lui6, Choon Boon Sim7, Marco Larobina8, Michael O'Keefe8, John Goldblatt8, Alistair Royse8, Geoffrey Lee1, Enzo R Porrello9, Matthew J Watt3, Peter M Kistler10, Prashanthan Sanders11, Lea M D Delbridge12, Jonathan M Kalman13. 1. Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; Department of Medicine and Radiology, University of Melbourne, Melbourne, Victoria, Australia. 2. Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia; Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia. 3. Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia. 4. Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. 5. Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia. 6. Department of Radiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia. 7. Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia. 8. Department of Cardiothoracic Surgery, Royal Melbourne Hospital, Melbourne, Victoria, Australia. 9. Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia. 10. Department of Cardiology, The Alfred Hospital, Melbourne, Victoria, Australia. 11. Australia 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. 12. Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia. Electronic address: lmd@unimelb.edu.au. 13. Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; Department of Medicine and Radiology, University of Melbourne, Melbourne, Victoria, Australia. Electronic address: Jon.Kalman@mh.org.au.
Abstract
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.
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.
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