Abstract
BackgroundCardiomyocytes 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.MethodsComputer 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.ResultsWe 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.ConclusionsProarrhythmia of Na+ channel blockade in patients with old myocardial infarction might be partly attributable to the ischemia-related subcellular Na+ channel redistribution.
Highlights
Class I antiarrhythmic drugs, which block cardiac sodium (Na+) channels, have been used to treat premature ventricular contractions (PVCs), which degenerate into tachyarrhythmias
Effects of subcellular Na+ channel redistribution on conduction velocity (CV) Figures 2A and 2B show the relative ratios of CV (%CV)
The major findings of the present study are as follows: (1) a decrease in the number of Na+ channels from the lateral surface membrane (LM) of each ventricular myocyte was a major cause of the conduction slowing in the ischemic border zone (IBZ); (2) in the presence of electric field (EF) mechanism, the relative contribution of the INa,LM to the total INa in a myocyte that makes up myofibers was greater than that of INa,junctional membrane (JM); (3) an IBZ accompanied by the subcellular redistribution of Na+ channels was highly vulnerable to reentry under Na+ channel blockade
Summary
Class I antiarrhythmic drugs, which block cardiac sodium (Na+) channels, have been used to treat premature ventricular contractions (PVCs), which degenerate into tachyarrhythmias. Previous experimental studies [3,4,5,6,7,8,9] showed that electrophysiological remodeling occurs in cardiomyocytes located at the ischemic border zone (IBZ) of infarcted ventricles. 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 shown that sodium (Na+) channels are redistributed within myocytes located in the ischemic border zone. The roles of the subcellular redistribution of Na+ channels in the arrhythmogenicity under ischemia remain unclear
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