Role of ionic electrodiffusion and ephaptic coupling in cardiac dynamics.

Abstract

Cardiac myocytes coordinate the heart contractions through electrical signaling, facilitated by gap junctions (GJs) in the intercalated disc (ID). GJs provide low-resistance pathways for electrical propagation between myocytes, acting as the main mechanism for electrical communication in the heart. However, studies show that conduction can persist in the absence of GJs. For instance, GJ knockout mice still display slow and discontinuous electrical propagation, suggesting the presence of alternative communication mechanisms. Ephaptic coupling (EpC) serves as an alternative way for cell communication, relying on electrical fields within narrow clefts between neighboring myocytes. Studies show that EpC can enhance conduction velocity (CV) and reduce conduction block (CB), especially when GJs are compromised. Reduced GJs and significant electrochemical gradients are prevalent in various heart diseases. However, existing models often fail to capture their combined influence on cardiac conduction, which limits our understanding of both the physiological and pathological aspects of the heart. Our study aims to address this gap through the development of a two-dimensional (2D) discrete multidomain electrodiffusion model that includes EpC. In particular, we investigated the interplay between EpC and multidomain electrodiffusion on action potential (AP) propagation, morphology, and electrochemical properties. Our findings indicate that under strong EpC, Na + electrodiffusion enhances CV, reduces the occurrence of CB, and sharpens the upstroke phase of the AP, while Ca 2+ and K + diffusion shorten the AP duration, alter the repolarization phase, and elevate the resting membrane potential. Additionally, when EpC is prominent, Na + electrodiffusion helps stabilize AP propagation and promotes its spread into ischemic regions. Strong EpC also significantly alters ionic concentrations in the cleft, markedly increasing [K +], nearly depleting [Ca 2+], and causing moderate changes in [Na +]. This multidomain electrodiffusion model provides valuable insights into the mechanisms of EpC in the heart.