AUTHOR=Morris Joshua A. , Bardsley Oliver J. , Salvage Samantha C. , Jackson Antony P. , Matthews Hugh R. , Huang Christopher L-H. TITLE=Nernst-Planck-Gaussian modelling of electrodiffusional recovery from ephaptic excitation between mammalian cardiomyocytes JOURNAL=Frontiers in Physiology VOLUME=14 YEAR=2024 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2023.1280151 DOI=10.3389/fphys.2023.1280151 ISSN=1664-042X ABSTRACT=

Introduction: In addition to gap junction conduction, recent reports implicate possible ephaptic coupling contributions to action potential (AP) propagation between successive adjacent cardiomyocytes. Here, AP generation in an active cell, withdraws Na⁺ from, creating a negative potential within, ephaptic spaces between the participating membranes, activating the initially quiescent neighbouring cardiomyocyte. However, sustainable ephaptic transmission requires subsequent complete recovery of the ephaptic charge difference. We explore physical contributions of passive electrodiffusive ion exchange with the remaining extracellular space to this recovery for the first time.

Materials and Methods: Computational, finite element, analysis examined limiting, temporal and spatial, ephaptic [Na⁺], [Cl⁻], and the consequent Gaussian charge differences and membrane potential recovery patterns following a ΔV∼130 mV AP upstroke at physiological (37°C) temperatures. This incorporated Nernst-Planck formalisms into equations for the time-dependent spatial concentration gradient profiles.

Results: Mammalian atrial, ventricular and purkinje cardiomyocyte ephaptic junctions were modelled by closely apposed circularly symmetric membranes, specific capacitance 1 μF cm^-2, experimentally reported radii a = 8,000, 12,000 and 40,000 nm respectively and ephaptic axial distance w = 20 nm. This enclosed an ephaptic space containing principal ions initially at normal extracellular [Na⁺] = 153.1 mM and [Cl⁻] = 145.8 mM, respective diffusion coefficients D_Na = 1.3 × 10⁹ and D_Cl = 2 × 10⁹ nm²s^-1. Stable, concordant computational solutions were confirmed exploring ≤1,600 nm mesh sizes and Δt≤0.08 ms stepsize intervals. The corresponding membrane voltage profile changes across the initially quiescent membrane were obtainable from computed, graphically represented a and w-dependent ionic concentration differences adapting Gauss’s flux theorem. Further simulations explored biological variations in ephaptic dimensions, membrane anatomy, and diffusion restrictions within the ephaptic space. Atrial, ventricular and Purkinje cardiomyocytes gave 40, 180 and 2000 ms 99.9% recovery times, with 720 or 360 ms high limits from doubling ventricular radius or halving diffusion coefficient. Varying a, and D_Na and D_Cl markedly affected recovery time-courses with logarithmic and double-logarithmic relationships, Varying w exerted minimal effects.

Conclusion: We thereby characterise the properties of, and through comparing atrial, ventricular and purkinje recovery times with interspecies in vivo background cardiac cycle duration data, (blue whale ∼2000, human∼90, Etruscan shrew, ∼40 ms) can determine physical limits to, electrodiffusive contributions to ephaptic recovery.