title: Ventricular remodelling is a prerequisite for the induction of dofetilide-induced torsade de pointes arrhythmias in the anaesthetized, complete atrio-ventricular-block dog.
abstract: BACKGROUND
  A number of predisposing factors have been suggested to be contributing to drug-induced torsade de pointes (TdP) arrhythmias: short-long-short (SLS) sequence, bradycardia, timing of drug administration, anaesthesia, ventricular remodelling, and altered ventricular activation due to ventricular ectopic beats (SLS) or idioventricular rhythm (IVR). Chronic atrio-ventricular (AV)-block (CAVB) dogs are susceptible to dofetilide-induced TdP.
  
  
  RESULTS
  In 32 anaesthetized animals, the relevance of ventricular remodelling for TdP susceptibility was studied by dofetilide [0.025 mg/kg/5 min intravenously (iv)] during bradycardia in the presence (CAVB, n= 18) or absence [acute atrio-ventricular block (AVB), n= 32] of ventricular remodelling. In sub-protocols, the possible pro-arrhythmic effects of timing of dofetilide administration: prior to (n= 11), or after creation of AVB (n= 9) and relevance of SLS pacing (n= 17) was investigated during IVR. Dofetilide was also given after AVB when the activation of the ventricles was normal: pacing (1000 ms) from the high septum (n= 7) or abnormal but fixed from the left ventricular apex (n= 5). Torsade de pointes inducibility was defined as reproducible (≥ 3 times) occurrence. In acute AV block (AAVB), dofetilide did not induce TdP spontaneously (0 of 32), whereas TdP was seen in 10 out of 18 serially tested dogs in CAVB (P< 0.001). The other factors: timing of dofetilide (0 of 11 vs. 0 of 9), SLS pacing (0 of 17 vs. 1 of 17), or ventricular activation (0 of 7 vs. 0 of 5) did not increase TdP susceptibility. Beat-to-beat variability of repolarization increased after ventricular remodelling and was highest prior to TdP induction.
  
  
  CONCLUSIONS
  In AAVB dogs, TdP is not spontaneously seen, whereas it is present in CAVB. This implies that ventricular remodelling is a prerequisite for TdP induction in this model.
authors.affiliation: Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM Utrecht, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Dunnink
authors.forename: Jurren M
authors.initials: JM
authors.lastname: van Opstal
authors.forename: Peter
authors.initials: P
authors.lastname: Oosterhoff
authors.forename: Stephan K G
authors.initials: SK
authors.lastname: Winckels
authors.forename: Jet D M
authors.initials: JD
authors.lastname: Beekman
authors.forename: Roel
authors.initials: R
authors.lastname: van der Nagel
authors.forename: S
authors.initials: S
authors.lastname: Cora Verduyn
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D054537:Atrioventricular Block / Q000503:physiopathology*; D001919:Bradycardia / Q000503:physiopathology; D004285:Dogs; D005260:Female; D008297:Male; D010627:Phenethylamines / Q000009:adverse effects*; D013449:Sulfonamides / Q000009:adverse effects*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide