title: Epicardial border zone overexpression of skeletal muscle sodium channel SkM1 normalizes activation, preserves conduction, and suppresses ventricular arrhythmia: an in silico, in vivo, in vitro study.
abstract: BACKGROUND
  In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel (SCN5A) is largely inactivated, contributing to low action potential upstroke velocity (V(max)), slow conduction, and reentry. We hypothesized that a fast inward current such as the skeletal muscle sodium channel (SkM1) operating more effectively at depolarized membrane potentials might restore fast conduction in epicardial border zones and be antiarrhythmic.
  
  
  RESULTS
  Computer simulations were done with a modified Hund-Rudy model. Canine myocardial infarcts were created by coronary ligation. Adenovirus expressing SkM1 and green fluorescent protein or green fluorescent protein alone (sham) was injected into epicardial border zones. After 5 to 7 days, dogs were studied with epicardial mapping, programmed premature stimulation in vivo, and cellular electrophysiology in vitro. Infarct size was determined, and tissues were immunostained for SkM1 and green fluorescent protein. In the computational model, modest SkM1 expression preserved fast conduction at potentials as positive as -60 mV; overexpression of SCN5A did not. In vivo epicardial border zone electrograms were broad and fragmented in shams (31.5 +/- 2.3 ms) and narrower in SkM1 (22.6 +/- 2.8 ms; P=0.03). Premature stimulation induced ventricular tachyarrhythmia/fibrillation >60 seconds in 6 of 8 shams versus 2 of 12 SkM1 (P=0.02). Microelectrode studies of epicardial border zones from SkM1 showed membrane potentials equal to that of shams and V(max) greater than that of shams as membrane potential depolarized (P<0.01). Infarct sizes were similar (sham, 30 +/- 2.8%; SkM1, 30 +/- 2.6%; P=0.86). SkM1 expression in injected epicardium was confirmed immunohistochemically.
  
  
  CONCLUSIONS
  SkM1 increases V(max) of depolarized myocardium and reduces the incidence of inducible sustained ventricular tachyarrhythmia/fibrillation in canine infarcts. Gene therapy to normalize activation by increasing V(max) at depolarized potentials may be a promising antiarrhythmic strategy.
authors.affiliation: Department of Pharmacology, Center for Molecular Therapeutics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Lau
authors.forename: Chris
authors.initials: C
authors.lastname: Clausen
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Sosunov
authors.forename: Iryna N
authors.initials: IN
authors.lastname: Shlapakova
authors.forename: Evgeny P
authors.initials: EP
authors.lastname: Anyukhovsky
authors.forename: Peter
authors.initials: P
authors.lastname: Danilo
authors.forename: Tove S
authors.initials: TS
authors.lastname: Rosen
authors.forename: Caitlin
authors.initials: C
authors.lastname: Kelly
authors.forename: Heather S
authors.initials: HS
authors.lastname: Duffy
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Szabolcs
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.forename: Richard B
authors.initials: RB
authors.lastname: Robinson
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.forename: Sinhu
authors.initials: S
authors.lastname: Kumari
authors.forename: Ira S
authors.initials: IS
authors.lastname: Cohen
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rosen
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D004195:Disease Models, Animal; D004285:Dogs; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006329:Heart Conduction System / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology; D008297:Male; D008955:Models, Cardiovascular; D018482:Muscle, Skeletal / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010400:Penicillin G / Q000378:metabolism; D010496:Pericardium / Q000502:physiology; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D017180:Tachycardia, Ventricular / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D049452:Green Fluorescent Proteins; D010400:Penicillin G