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Abstract Cardiovascular disease continues to be the leading cause of death in the United States. A major contributing factor is cardiac arrhythmia, which results from irregular electrical activity in the heart. On a tissue level, cardiac conduction involves the spread of action potentials (AP) across the heart, enabling coordinated contraction of the myocardium. On a cellular level, the transmission of signals between cells is facilitated by low-resistance pathways formed by gap junctions (GJs). Recent experimental studies have sparked discussion on whether GJs play a dominant role in cell communication. Interestingly, research has revealed that GJ knockout mice can still demonstrate signal propagation in the heart, albeit more slowly and discontinuously, indicating the presence of an alternative mechanism for cardiac conduction. Unlike GJ-mediated propagation, ephaptic coupling (EpC) has emerged as a distinct form of electrical transmission, characterized by contactless electrochemical signaling across the narrow intercalated discs (IDs) between cardiomyocytes. Advancements in cardiac research have highlighted the crucial role of EpC in restoring conduction by increasing conduction velocity (CV), reducing conduction block (CB), and terminating reentry arrhythmias, particularly when GJs are impaired. However, most EpC studies are either numerical or experimental, while analytical studies on ephaptic conduction–an equally important aspect of understanding EpC–remain extremely limited. In this paper, we applied asymptotic theory to calculate the CV in the presence of weak EpC. To achieve this, we developed both continuous and discrete models to describe ephaptic conduction along a strand of cells. Ionic dynamics were modeled using the piecewise linear and cubic functions. The resulting system represents a bistable system with weak EpC. We calculated an expression for CV in the presence of weak EpC for both models, and validated our analytical results with numerical simulations. Additionally, we showed that under weak EpC, CV can increase if the distribution of INa is more prominent on the end membrane.
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This content will become publicly available on August 19, 2026
The role of ephaptic coupling and gap junctional coupling in modulating the initiation and dynamics of reentrant arrhythmias
Cardiac myocytes synchronize through electrical signaling to contract heart muscles, facilitated by gap junctions (GJs) located in the intercalated disc (ID). GJs provide low-resistance pathways for electrical impulse propagation between myocytes, considered the primary mechanism for electrical communication in the heart. However, research indicates that conduction can persist without GJs. Ephaptic coupling (EpC), which depends on electrical fields in the narrow ID between adjacent myocytes, offers an alternative mechanism for cardiac conduction when GJs are impaired. Research suggests that EpC can enhance conduction velocity (CV) and reduce the likelihood of conduction block (CB), particularly when GJs are impaired, demonstrating the anti-arrhythmic potential of EpC. Reduced GJ communication increases the susceptibility of heart to arrhythmias due to ectopic or triggered activity, highlighting the pro-arrhythmic effect of GJ uncoupling. However, the interplay between GJs and EpC, and their roles in the initiation, dynamics, and termination of arrhythmias, remain unclear. Reentry, characterized by a loop of electrical activity, is a common mechanism underlying arrhythmogenesis in the heart. This study aims to explore the interplay between EpC and GJs on reentry initiation and its underlying dynamics. Specifically, we employed a two-dimensional (2D) discrete bidomain model that integrates EpC to simulate ephaptic conduction during reentry. We quantitatively assessed the outcomes of reentry initiation and the resulting dynamics across different levels of EpC, GJs, and initial perturbations. The results show that sufficiently strong EpC (i.e., sufficiently narrow clefts) tends to suppress reentry initiation, resulting in absent or non-sustained reentrant activity, while also introducing transient instability and heterogeneity into the cardiac dynamics. In contrast, relatively weak EpC (wide clefts) support sustained reentry with a stable rotor. Furthermore, we found that sufficiently strong EpC can lower the maximal dominant frequency observed during reentrant activity. Overall, this suggests that strong EpC exerts an anti-arrhythmic effect.
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- PAR ID:
- 10632268
- Editor(s):
- Loppini, Alessandro
- Publisher / Repository:
- Public Library of Science (PLOS)
- Date Published:
- Journal Name:
- PLOS One
- Volume:
- 20
- Issue:
- 8
- ISSN:
- 1932-6203
- Page Range / eLocation ID:
- e0330016
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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