Decreased intercellular coupling via connexin43 knockdown in fibrotic rat ventricular myocardium models increased arrhythmia incidence and complexity by promoting spatially discordant action potential duration alternans.
Does reduced intercellular coupling and fibrosis promote reentrant arrhythmias through spatially discordant APD alternans in ventricular myocardium models?
The combination of myocardial fibrosis and reduced intercellular coupling promotes complex reentrant arrhythmias through the formation of spatially discordant alternans phase islands.
Fibrosis and altered gap junctional coupling are key features of ventricular remodelling and are associated with abnormal electrical impulse generation and propagation. Such abnormalities predispose to reentrant electrical activity in the heart. In the absence of tissue heterogeneity, high-frequency impulse generation can also induce dynamic electrical instabilities leading to reentrant arrhythmias. However, because of the complexity and stochastic nature of such arrhythmias, the combined effects of tissue heterogeneity and dynamical instabilities in these arrhythmias have not been explored in detail. Here, arrhythmogenesis was studied using in vitro and in silico monolayer models of neonatal rat ventricular tissue with 30% randomly distributed cardiac myofibroblasts and systematically lowered intercellular coupling achieved in vitro through graded knockdown of connexin43 expression. Arrhythmia incidence and complexity increased with decreasing intercellular coupling efficiency. This coincided with the onset of a specialized type of spatially discordant action potential duration alternans characterized by island-like areas of opposite alternans phase, which positively correlated with the degree of connexinx43 knockdown and arrhythmia complexity. At higher myofibroblast densities, more of these islands were formed and reentrant arrhythmias were more easily induced. This is the first study exploring the combinatorial effects of myocardial fibrosis and dynamic electrical instabilities on reentrant arrhythmia initiation and complexity.
Majumder et al. (Wed,) conducted a other in Arrhythmogenesis in fibrotic ventricular myocardium. Connexin43 knockdown and diffuse cardiac fibrosis vs. Normal Connexin43 expression and non-fibrotic cultures was evaluated on Arrhythmia incidence and complexity. Decreased intercellular coupling via connexin43 knockdown in fibrotic rat ventricular myocardium models increased arrhythmia incidence and complexity by promoting spatially discordant action potential duration alternans.