Are Interactions between Epicardial Adipose Tissue, Cardiac Fibroblasts and Cardiac Myocytes Instrumental in Atrial Fibrosis and Atrial Fibrillation?

Abstract

Atrial fibrillation is very common among the elderly and/or obese. While myocardial fibrosis is associated with atrial fibrillation, the exact mechanisms within atrial myocytes and surrounding non-myocytes are not fully understood. This review considers the potential roles of myocardial fibroblasts and myofibroblasts in fibrosis and modulating myocyte electrophysiology through electrotonic interactions. Coupling with (myo)fibroblasts in vitro and in silico prolonged myocyte action potential duration and caused resting depolarization; an optogenetic study has verified in vivo that fibroblasts depolarized when coupled myocytes produced action potentials. This review also introduces another non-myocyte which may modulate both myocardial (myo)fibroblasts and myocytes: epicardial adipose tissue. Epicardial adipocytes are in intimate contact with myocytes and (myo)fibroblasts and may infiltrate the myocardium. Adipocytes secrete numerous adipokines which modulate (myo)fibroblast and myocyte physiology. These adipokines are protective in healthy hearts, preventing inflammation and fibrosis. However, adipokines secreted from adipocytes may switch to pro-inflammatory and pro-fibrotic, associated with reactive oxygen species generation. Pro-fibrotic adipokines stimulate myofibroblast differentiation, causing pronounced fibrosis in the epicardial adipose tissue and the myocardium. Adipose tissue also influences myocyte electrophysiology, via the adipokines and/or through electrotonic interactions. Deeper understanding of the interactions between myocytes and non-myocytes is important to understand and manage atrial fibrillation.

Direct oral anticoagulation and severe obesity – One size fits all?

“…One master switch linking adiposity, thrombosis and pro-arrhythmic atrial remodeling is inflammation. Particularly inflammatory and metabolic remodeling of the epicardial fat depot and its inter-organ communication with the atrial myocardium and blood compartment is increasingly considered to govern obesity-driven AF and thrombosis [13] , [14] . DOAC interfere in this self-perpetuating cross-talk to suppressing obesity-driven inflammatory sequelae and reducing atrial fibrosis and electrical remodeling in various experimental models (reviewed in [15] ).…”

Serum and Adipose Dipeptidyl Peptidase 4 in Cardiovascular Surgery Patients: Influence of Dipeptidyl Peptidase 4 Inhibitors

“…The extent and status of EAT have also been shown to be positively correlated with AF [ 45 , 46 ]. Krishnan et al [ 47 ] reported that the adipokines secreted by adipocytes stimulate myofibroblast differentiation in association with the generation of reactive oxygen species, causing pronounced fibrosis in the EAT and myocardium. In addition, adipose tissue influences cardiomyocyte electrophysiology through adipokines.…”

The Role and Implications of Epicardial Fat in Coronary Atherosclerotic Disease

“…In addition to these two layers of fatty tissue, anatomical data from many histological species indicate that fatty infiltrate is also present at the level of the myocardium, although the fat distribution in the atrial and ventricular myocardium is extremely diverse. In particular, atrial appendages have fat deposits, particularly around the left posterior atrium [ 8 ]. Whereas such fat distributions are deemed normal, fatty infiltration is considered arrhythmogenic, and a variety of pathological cardiac disorders are associated with increased myocardial fat deposits, particularly in the epicardium [ 9 ].…”