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

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.

Cardiac electrophysiology

Cardiac electrophysiology involves voltage gradients across myocardial cells and their changes during heartbeat cycles. These processes are maintained by ion exchanges across cellular membranes. Their character and dynamics vary for different types of myocytes as well as different layers and strata of cardiac walls. Electrical changes of the cellular membranes of a cell influence neighbouring cells. Electrical excitation that precedes cardiac contraction is propagated throughout the heart in this way, forming the so-called depolarization waveform. The processes of cellular electrical recovery during which the cellular membranes are recharged for the next cardiac cycle do not follow the same path and sequence as the excitation waveform. These recovery processes do not depend on cell-to-cell signal transmission but even during electrical recovery, neighbouring cells influence each other by means of the so-called electrotonic interactions. Abnormalities in electrical excitation due to anatomical blocks and/or functional barriers as well as heterogeneity of the electrical recovery across myocardium may lead to self-perpetuating excitation processes that are the basis of tachyarrhythmias.

Partial IK1 blockade destabilizes spiral wave rotation center without inducing wave breakup and facilitates termination of reentrant arrhythmias in ventricles

It has been reported that blockade of the inward rectifier K+ current ( IK1) facilitates termination of ventricular fibrillation. We hypothesized that partial IK1 blockade destabilizes spiral wave (SW) re-entry, leading to its termination. Optical action potential (AP) signals were recorded from left ventricles of Langendorff-perfused rabbit hearts with endocardial cryoablation. The dynamics of SW re-entry were analyzed during ventricular tachycardia (VT), induced by cross-field stimulation. Intercellular electrical coupling in the myocardial tissue was evaluated by the space constant. In separate experiments, AP recordings were made using the microelectrode technique from right ventricular papillary muscles of rabbit hearts. Ba2+ (10–50 μM) caused a dose-dependent prolongation of VT cycle length and facilitated termination of VT in perfused hearts. Baseline VT was maintained by a stable rotor, where an SW rotated around an I-shaped functional block line (FBL). Ba2+ at 10 μM prolonged I-shaped FBL and phase-singularity trajectory, whereas Ba2+ at 50 μM transformed the SW rotation dynamics from a stable linear pattern to unstable circular/cycloidal meandering. The SW destabilization was not accompanied by SW breakup. Under constant pacing, Ba2+ caused a dose-dependent prolongation of APs, and Ba2+ at 50 μM decreased conduction velocity. In papillary muscles, Ba2+ at 50 μM depolarized the resting membrane potential. The space constant was increased by 50 μM Ba2+. Partial IK1 blockade destabilizes SW rotation dynamics through a combination of prolongation of the wave length, reduction of excitability, and enhancement of electrotonic interactions, which facilitates termination of ventricular tachyarrhythmias.