Abstract: Cardiac action potential (AP) propagation occurs through gap junction (GJ)-rich intercalated discs (IDs). However, recent experimental studies show that GJ knockout mice can still maintain heart structure and function, even though GJs are undetectable at IDs. Ephaptic coupling (EpC), an electric field effect across the narrow and tortuous ID, offers an alternative mechanism for cell-to-cell communication when GJs are impaired. Given the current absence of direct experimental evidence for the existence of EpC, modeling studies are essential for understanding its physiological and pathological roles in the heart. Myocardial ischemia, caused by coronary artery blockage, induces major electrophysiological and structural remodeling, including disrupted GJs and steep electrochemical gradients that impair ion channel function and promote arrhythmias. Our research investigates how EpC and ionic electrodiffusion influence conduction and arrhythmogenesis in both healthy and ischemic hearts, with a focus on EpC mechanisms. We developed first two-dimensional (2D) multidomain electrodiffusion model that incorporates EpC, laying the groundwork for future mechanistic studies. Our findings demonstrate that sufficiently strong EpC suppresses the initiation of reentry, leading to absent or nonsustained reentrant activity with a reduced maximum dominant frequency (DF), although it can also introduce transient instability and heterogeneity into cardiac dynamics. In contrast, relatively weak EpC supports sustained reentry, characterized by a stable rotor and high DF. Strong EpC terminates reentry through self-attenuation, while moderate EpC terminates reentry through self-collision. Additionally, strong EpC markedly alters ionic concentrations in the cleft, significantly increasing [K+], nearly depleting [Ca2+], and causing moderate changes in [Na+]. This multidomain electrodiffusion model thus provides new insights into the mechanisms of EpC in the heart.

Contact: Trachette Jackson