Nernst-Planck-Gaussian modelling of electrodiffusional recovery from ephaptic excitation between mammalian cardiomyocytes

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 DNa = 1.3 × 109 and DCl = 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 DNa and DCl 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.

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

“…Adjacent cardiomyocytes are joined end-to-end at specialized perinexal regions including closely apposed adjacent cell membranes ( Rhett and Gourdie, 2012 ; Rhett et al, 2013 ; Veeraraghavan et al, 2014 ) with locally elevated Cx expression and Nav1.5 densities ( Veeraraghavan et al, 2015 ; Hichri et al, 2018 ; Struckman et al, 2021 ) increased by Na v 1.5 clustering ( Salvage et al, 2020b ). Mathematical modeling suggests such structural organization is additionally or alternatively compatible with a direct cell-to-cell ephaptic propagation of excitation ( Sperelakis and Mann, 1977 ; Sperelakis, 2002 ; Mori et al, 2008 ; Carmeliet, 2019 ; Morris et al, 2024 ). An albeit slower propagation of excitation persists even with compromised gap junction coupling under pathological conditions following ischemic insult ( Rohr, 2004 ), atrial fibrillation ( Chaldoupi et al, 2009 ), and experimental loss-of-function Cx43 ( Eloff et al, 2001 ; Gutstein et al, 2001 ) or Cx40 genetic platforms ( Hagendorff et al, 1999 ; Bagwe et al, 2005 ).…”