Role of ephaptic coupling in discordant alternans domain sizes and action potential propagation in the heart.

Abstract

Discordant alternans, the spatially out-of-phase alternation of the durations of propagating action potentials in the heart, has been linked to the onset of fibrillation, a major cardiac rhythm disorder. The sizes of the regions, or domains, within which these alternations are synchronized are critical in this link. However, computer models employing standard gap junction-based coupling between cells have been unable to reproduce simultaneously the small domain sizes and rapid action potential propagation speeds seen in experiments. Here we use computational methods to show that rapid wave speeds and small domain sizes are possible when a more detailed model of intercellular coupling that accounts for so-called ephaptic effects is used. We provide evidence that the smaller domain sizes are possible, because different coupling strengths can exist on the wavefronts, for which both ephaptic and gap-junction coupling are involved, in contrast to the wavebacks, where only gap-junction coupling plays an active role. The differences in coupling strength are due to the high density of fast-inward (sodium) channels known to localize on the ends of cardiac cells, which are only active (and thus engage ephaptic coupling) during wavefront propagation. Thus, our results suggest that this distribution of fast-inward channels, as well as other factors responsible for the critical involvement of ephaptic coupling in wave propagation, including intercellular cleft spacing, play important roles in increasing the vulnerability of the heart to life-threatening tachyarrhythmias. Our results, combined with the absence of short-wavelength discordant alternans domains in standard gap-junction-dominated coupling models, also provide evidence that both gap-junction and ephaptic coupling are critical in wavefront propagation and waveback dynamics.