Quantitative Contributions to Electrical Propagation in 1D Cable Model

Abstract

From previous experimental and theoretical studies, it is well-known that gap junctional coupling, Na+ channel density, and Na+ channel localization influence the speed of electrical conduction velocity (CV) in multicellular cardiac tissue. However, two recent findings complicate our understanding of electrical conduction: (1) Na+ channels located at the intercalated disk region have different properties than those in the cell center; (2) in disease states, changes in gap junctional coupling occur in tandem with alterations in Na+ channel density, Na+ channel properties, and subcellular structure, which makes it difficult to determine the effects of each change. To gain a greater quantitative understanding of the factors that influence CV, we implemented a one-dimensional mathematical model of electrically coupled human ventricular myocytes. The model accounts for the possibility that electrical fields in the narrow clefts between adjacent cells can influence conduction. To determine how each model variable affects CV, we performed parameter sensitivity analysis under two conditions: (1) normal gap junctional conductance (400 kΩ resistance between cells), and (2) severely reduced gap junctional conductance (40 MΩ resistance between cells). Our simulation results predict the following: (1) Increasing the width of the cleft between adjacent cells increases CV under normal gap junctional conductance conditions but decreases CV when gap junctional coupling is low; (2) reducing cell coupling decreases CV under normal gap junctional conductance conditions, but further changes to coupling have little effect under low gap junctional conductance conditions, (3) Na+ channel activation kinetics and voltage dependence have a greater quantitative effect on CV with low than with normal gap junctional conductance. The simulations generate predictions that can be tested experimentally, and the results provide insight into changes in CV observed in disease.