Title: Exploring the Effects of Conduction Reserve and Ephaptic Coupling in Cardiac Cells
Abstract: Many cardiomyopathies are associated with reduced gap junctional (GJ) coupling, which is an important determinant of conduction velocity (CV) in the heart. However, the relationship between phenotype and functional expression of the connexin GJ family of proteins is controversial. There have been reports of little to no CV loss secondary to 50% reduction of GJ coupling. It has been theorized that reducing GJ coupling increases sodium entry into the cell to maintain slower but safer CV, a phenomenon that is called conduction reserve. On the other hand, ephaptic coupling (EpC) theorizes that with low GJ, conduction is enhanced by electrical fields generated in the sodium channel rich, restricted clefts between neighboring myocytes. Using our previously published mathematical model of cardiac cells that includes variations on the cellular level, such GJ coupling strength and distribution, cleft width (Wp), and ionic channel distributions, we ran simulations for a strand of cells with lowered GJ under varying conditions to elucidate the effects of EpC or conduction reserve. These simulations were compared against experimental data gathered under similar circumstances. The computational simulations and experimental data supported the same conclusions: reducing GJ coupling decreased sodium entry into the cell, which indicates that conduction reserve may not be the main mechanism through which decoupled cells maintain conduction. Additionally, we found that the action potential (AP) upstroke was faster with smaller Wp and was more sensitive to changes in Wp than GJ coupling, supporting the hypothesis of EpC.