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 (theta) 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 theta in NZ. We found that the extracellular space flattens the Gj-theta relationship, thus theta 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 theta (theta(T)). Inclusion of an extracellular space reduces the decrease in theta(T) to 31%. In IZc cells, Cx43 redistribution along the lateral membrane results in a 29% increase in theta(T). That increase in theta(T) 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 theta(T) to 10%.

In conclusion: 1), The extracellular space included in normal epicardial simulations flattens the Gj-theta relationship with theta 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 theta(T).

Figure 1

Myocardial architecture.

Figure 2

Relationship between cell-to-cell conductance (Gj) and longitudinal conduction velocity (A), transverse conduction velocity (B), and ANR (C), for a two-dimensional monodomain and two-domain model of normal (NZ) epicardial cells.

Figure 3

Effect of reduced side-to-side conductance (Gj remodeling) on propagation in the outer pathway of figure-of-eight reentrant circuits (IZo cells). Comparison of longitudinal velocity (left), transverse velocity (center), and ANR (right) between a nonremodeled IZo substrate (dashed line) and a remodeled IZo substrate (solid line) in a monodomain (A) and a two-domain model (B). (See text for explanation.)

Figure 4

Effect of redistribution of Cx43 to the lateral membrane (Cx43 lateralization) on propagation in the central pathway of figure-of-eight reentrant circuits (IZc cells). Comparison of longitudinal velocity (left), transverse velocity (center), and ANR (right) between a nonremodeled IZc substrate (dashed line) and a remodeled IZc substrate (solid line) in a monodomain (A) and a two-domain model (B). (See text for explanation.)

Figure 5

(A) Top: Plot of Vm decay in the four IZo models in Fig. 3 (Gj = 6.7 μs) to calculate the transverse space constant. Bottom: Plot of the transverse space constants versus transverse resistivity for the four IZo models in Fig. 3 (Gj = 6.7 μs). (B) Top: Plot of Vm decay in the four IZc models in Fig. 4 (Gj = 6.7 μS) to calculate the transverse space constant. Bottom: Plot of the transverse space constants versus transverse resistivity for the four IZc models in Fig. 4 (Gj = 6.7 μS). See text for explanation.

Figure 6

Junctional and access resistance between cell pairs coupled side-to-side. (A) Isopotential lines when node A (A and A′ in structure 3) in cell1 is clamped to 10 mV and node B (B and B′ in structure 3) in cell2 is clamped to 0 mV in three structures with different Cx43 plaque distributions. Isopotential lines are drawn every 0.5 mV. (B) Side-to-side junctional resistance, R_junct, between cell1 and cell2 for the three structures (1, 2, and 3,) in panel (A) as a function of the Cx43 plaque resistance (R_plaque) between cell1 and cell2. See text for explanation.