title: Determinants and mechanisms of flecainide-induced promotion of ventricular tachycardia in anesthetized dogs.
abstract: BACKGROUND
  Class IC antiarrhythmic agents such as flecainide are known to have potentially significant ventricular proarrhythmic actions, but the underlying mechanisms are incompletely understood. While some studies have reported proarrhythmia in both healthy dogs and dogs that previously have had a myocardial infarction (MI), there are no published, controlled studies comparing proarrhythmia in healthy dogs vs in dogs with MI. In addition, the concentration dependence of proarrhythmia is unknown and the electrophysiological changes associated with proarrhythmia are not well established.
  
  
  METHODS
  We administered successive loading and maintenance infusions of flecainide until ventricular tachyarrhythmia or death occurred in 13 healthy dogs and 19 dogs with 72-hour-old MIs (MI dogs). Ventricular proarrhythmia, defined as reproducible ventricular tachycardia absent under control conditions and occurring in the presence of flecainide, was observed in 4 of 13 healthy dogs (31%) and 15 of 19 MI dogs (79%, P = .02), and drug-induced spontaneous ventricular tachycardia occurred in 8 of 19 MI dogs but in no healthy dogs (P = .007). Activation data at the time of proarrhythmia were available for 11 MI dogs and provided evidence for reentry in 9, with a complete epicardial reentry circuit identified in 4 dogs and a partial circuit in 5. While flecainide slowed ventricular conduction in both the longitudinal and transverse directions, there were no significant differences between overall drug-induced conduction changes in MI dogs compared with healthy dogs. However, in 7 MI dogs for whom activation data were available during ventricular pacing at concentrations comparable to those causing proarrhythmia, flecainide induced a new arc of block in 6 of 7, whereas an arc of block was never observed in the absence of proarrhythmia. Conduction block was induced transverse to fiber orientation in a rate-dependent fashion and was caused by a regionally-specific effect of the drug. No differences were noted between refractory periods proximal and distal to the site of block.
  
  
  CONCLUSIONS
  Prior MI strongly predisposes dogs to flecainide proarrhythmia, which occurs in the majority of such dogs in a concentration-related way. In most cases, activation data suggest that anisotropic reentry around a localized arc of rate-dependent transverse conduction block underlies proarrhythmia. These results provide insights into the conditions and mechanisms underlying the ability of flecainide to promote the occurrence of ventricular tachycardia.
authors.affiliation: Department of Medicine, Montreal Heart Institute, Quebec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Ranger
authors.forename: S
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000818:Animals; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005424:Flecainide / Q000008:administration & dosage / Q000633:toxicity*; D006327:Heart Block / Q000139:chemically induced / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D009203:Myocardial Infarction / Q000503:physiopathology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D017180:Tachycardia, Ventricular / Q000139:chemically induced* / Q000503:physiopathology
chemical_list: D005424:Flecainide