Extracellular Space Attenuates the Effect of Gap Junctional Remodeling on Wave Propagation: A Computational Study

Abstract

Ionic channels and gap junctions are remodeled in cells from the 5-day epicardial border zone (EBZ) of the healing canine infarct. The main objective of the study was to determine the effect of gap junctional conductance (Gj) remodeling and Cx43 redistribution to the lateral membrane on conduction velocity (θ) and anisotropic ratio, and how gap junctional remodeling is modulated by the extracellular space. We first implemented subcellular monodomain and two-domain computer models of normal epicardium (NZ) to understand how extracellular space modulates the relationship between Gj and θ in NZ. We found that the extracellular space flattens the Gj-θ relationship, thus θ becomes less sensitive to changes in Gj. We then investigated the functional consequences of Gj remodeling and Cx43 distribution in subcellular computer models of cells of the outer pathway (IZo) and central pathway (IZc) of reentrant circuits. In IZo cells, side-to-side (transverse) Gj is 10% the value in NZ cells. Such Gj remodeling causes a 45% decrease in transverse θ (θT). Inclusion of an extracellular space reduces the decrease in θT to 31%. In IZc cells, Cx43 redistribution along the lateral membrane results in a 29% increase in θT. That increase in θT is a consequence of the decrease in access resistance to the Cx43 plaques that occur with the Cx43 redistribution. Extracellular space reduces the increase in θT to 10%. In conclusion: 1), The extracellular space included in normal epicardial simulations flattens the Gj-θ relationship with θ becoming less sensitive to changes in Gj. 2), The extracellular space attenuates the effects of gap junction epicardial border zone remodeling (i.e., Gj reduction and Cx43 lateralization) on θT.