title: Ischemia-related subcellular redistribution of sodium channels enhances the proarrhythmic effect of class I antiarrhythmic drugs: a simulation study.
abstract: 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.
authors.affiliation: Department of Pharmacology, Graduate school of Medicine, Osaka University, Suita, Japan.
authors.forename: Kunichika
authors.initials: K
authors.lastname: Tsumoto
authors.affiliation: Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ashihara
authors.affiliation: Department of Medical Informatics, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Haraguchi
authors.affiliation: Laboratory of Biomedical Science and Information Management, Research Institute, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakazawa
authors.affiliation: Department of Pharmacology, Graduate school of Medicine, Osaka University, Suita, Japan; Center for Advanced Medical Engineering and Informatics, Osaka University, Suita, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kurachi
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D017629:Gap Junctions / Q000473:pathology; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015222:Sodium Channels / Q000032:analysis*
chemical_list: D000889:Anti-Arrhythmia Agents; D015222:Sodium Channels