title: Connexin43 gene transfer reduces ventricular tachycardia susceptibility after myocardial infarction.
abstract: OBJECTIVE
  The aim of this study was to evaluate the links between connexin43 (Cx43) expression, myocardial conduction velocity, and ventricular tachycardia in a model of healed myocardial infarction.
  
  
  BACKGROUND
  Post-infarction ventricular arrhythmias frequently cause sudden death. Impaired myocardial conduction has previously been linked to ventricular arrhythmias. Altered connexin expression is a potential source of conduction slowing identified in healed scar border tissues. The functional effect of increasing border-zone Cx43 has not been previously evaluated.
  
  
  METHODS
  Twenty-five Yorkshire pigs underwent anterior infarction by transient left anterior descending coronary artery occlusion, followed by weekly testing for arrhythmia inducibility. Twenty animals with reproducibly inducible sustained monomorphic ventricular tachycardia were randomized 2:1:1 to receive AdCx43, Adβgal, or no gene transfer. One week later, animals underwent follow-up electrophysiologic study and tissue assessment for several functional and molecular measures.
  
  
  RESULTS
  Animals receiving AdCx43 had less electrogram fractionation and faster conduction velocity in the anterior-septal border zone. Only 40% of AdCx43 animals remained inducible for ventricular tachycardia, while 100% of controls were inducible after gene transfer. AdCx43 animals had 2-fold higher Cx43 protein levels in the anterior-septal infarct border, with similar percents of phosphorylated and intercalated disk-localized Cx43 compared with controls.
  
  
  CONCLUSIONS
  These data mechanistically link Cx43 expression to slow conduction and arrhythmia susceptibility in the healed scar border zone. Targeted manipulation of Cx43 levels improved conduction velocity and reduced ventricular tachycardia susceptibility. Cx43 gene transfer represents a novel treatment strategy for post-infarction arrhythmias.
authors.affiliation: Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109, USA.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Greener
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Sasano
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wan
authors.forename: Tomonori
authors.initials: T
authors.lastname: Igarashi
authors.forename: Maria
authors.initials: M
authors.lastname: Strom
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenbaum
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Donahue
mesh_terms: D000818:Animals; D018031:Connexin 43 / Q000008:administration & dosage / Q000235:genetics*; D004198:Disease Susceptibility / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics* / Q000628:therapy*; D011897:Random Allocation; D013552:Swine; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000235:genetics* / Q000628:therapy*
chemical_list: D018031:Connexin 43