BPS2026 – Modeling the response of a cardiac cell pair to an external electric field generates testable predictions to evidence ephaptic coupling with optical mapping experiments

It has been proposed that ephaptic coupling modulates cardiac action potential propagation. Ephaptic coupling is mediated by large negative extracellular potentials arising in intercalated disc clefts due to sodium currents. However, such potentials have never been evidenced experimentally. In this setting, high-resolution optical mapping of transmembrane potential may be suitable to provide such evidence. To examine the feasibility of such an approach, we used a finite element model of a pair of longitudinally abutting cardiomyocytes and investigated its response to an extracellular electric field pulse. The membranes incorporated a Hodgkin-Huxley-type sodium current and a potassium current. To generate testable predictions, we simulated optical signals at different locations. Suprathreshold field pulses (0.5 ms duration) applied along the cell pair axis induced complex spatiotemporal behaviors of membrane potential and sodium current. However, the intracellular space of each cell remained essentially isopotential. After the pulse, the extracellular potential returned rapidly to 0 except in the intercalated disc cleft, where sodium currents caused large negative potentials. Hence, comparing the upstrokes of the transmembrane potentials in the lateral and intercalated disc membranes permits to ascertain the extracellular potential in the cleft. Our approach was to plot the lateral and intercalated disc optical signals against each other and evaluate the deviation from the identity line. This deviation was robustly apparent over a broad range of cleft widths (10–100 nm), gap junctional coupling levels (0%–100% of normal) and field strengths (1%–50% above threshold). Similar results were obtained when the field was applied transversely. Therefore, our results can orient future experiments to provide direct evidence of negative extracellular potentials in intercalated disc clefts, and hence of ephaptic coupling, a still debated mechanism.