Effects of Subcellular Sodium Channel Distribution on the Initiation of Phase-2 Reentry: A Possible Mechanism of Fibrillation Induction in Brugada Syndrome

Abstract

Cardiac sodium (Na+) channels play critical roles in initiating and propagating action potentials in myocardium. We have recently reported that the action potential propagation was greatly affected by the subcellular distribution of Na+ channels in a physiologically-relevant myofiber model, where myocytes were electrically coupled with both gap-junctions and intercellular cleft conductor. Here, we extended the simulation to the initiation of phase-2 reentry in Brugada syndrome. We conducted computer simulations of action potential propagation in the myofiber model, and investigated the effect of spatial and subcellular distributions of Na+ channels on the phase-2 reentry. In the myofiber model with local decrease in Na+ current density, phase-2 reentry was not reproduced. Surprisingly, in the same myofiber model but with a certain type of subcellular Na+ channel remodeling (all Na+ channels were distributed only in the intercalated disks and there were no Na+ channels along the lateral side of each myocyte), the local decrease in Na+ current density resulted in the marked abbreviation of the action potential duration followed by phase-2 reentry. Changes in subcellular Na+ channel distribution in addition to the spatially-heterogeneous Na+ channel density might be required for fibrillation induction in Brugada syndrome.