Ischemia-Related Subcellular Redistribution of Sodium Channels Enhances the Proarrhythmic Effect of Class I Antiarrhythmic Drugs: A Simulation Study

BACKGROUND: Cardiomyocytes located at the ischemic border zone of infarcted ventricle are accompanied by redistribution of gap junctions, which mediate electrical transmission between cardiomyocytes. This ischemic border zone provides an arrhythmogenic substrate. It was also shown that sodium (Na(+)) channels are redistributed within myocytes located in the ischemic border zone. However, the roles of the subcellular redistribution of Na(+) channels in the arrhythmogenicity under ischemia remain unclear. METHODS: Computer simulations of excitation conduction were performed in a myofiber model incorporating both subcellular Na(+) channel redistribution and the electric field mechanism, taking into account the intercellular cleft potentials. RESULTS: We found in the myofiber model that the subcellular redistribution of the Na(+) channels under myocardial ischemia, decreasing in Na(+) channel expression of the lateral cell membrane of each myocyte, decreased the tissue excitability, resulting in conduction slowing even without any ischemia-related electrophysiological change. The conventional model (i.e., without the electric field mechanism) did not reproduce the conduction slowing caused by the subcellular Na(+) channel redistribution. Furthermore, Na(+) channel blockade with the coexistence of a non-ischemic zone with an ischemic border zone expanded the vulnerable period for reentrant tachyarrhythmias compared to the model without the ischemic border zone. Na(+) channel blockade tended to cause unidirectional conduction block at sites near the ischemic border zone. Thus, such a unidirectional conduction block induced by a premature stimulus at sites near the ischemic border zone is associated with the initiation of reentrant tachyarrhythmias. CONCLUSIONS: Proarrhythmia of Na(+) channel blockade in patients with old myocardial infarction might be partly attributable to the ischemia-related subcellular Na(+) channel redistribution.