title: Short-term variability in QT interval and ventricular arrhythmias induced by dofetilide are dependent on high-frequency autonomic oscillations.
abstract: OBJECTIVE
  The present study was undertaken to investigate an effect of dofetilide, a potent arrhythmic blocker of the voltage-gated K(+) channel, hERG, on cardiac autonomic control. Combined with effects on ardiomyocytes, these properties could influence its arrhythmic potency.
  
  
  METHODS
  The short-term variability of beat-to-beat QT interval (STVQT ), induced by dofetilide is a strong surrogate of Torsades de pointes liability. Involvement of autonomic modulation in STVQT was investigated in healthy cynomolgus monkeys and beagle dogs by power spectral analysis under conditions of autonomic blockade with hexamethonium.
  
  
  RESULTS
  Increase in STVQT induced by dofetilide in monkeys and dogs was closely associated with an enhancement of endogenous heart rate and QT interval high-frequency (HF) oscillations. These effects were fully suppressed under conditions of autonomic blockade with hexamethonium. Ventricular arrhythmias, including Torsades de pointes in monkeys, were prevented in both species when HF oscillations were suppressed by autonomic blockade. Similar enhancements of heart rate HF oscillations were found in dogs with other hERG blockers described as causing Torsades de pointes in humans.
  
  
  CONCLUSIONS
  These results demonstrate for the first time that beat-to-beat ventricular repolarization variability and ventricular arrhythmias induced by dofetilide are dependent on endogenous HF autonomic oscillations in heart rate. When combined with evidence of hERG-blocking properties, enhancement of endogenous HF oscillations in heart rate could constitute an earlier and more sensitive biomarker than STVQT for Torsades de pointes liability, applicable to preclinical regulatory studies conducted in healthy animals.
authors.affiliation: Centre de Recherches Biologiques, CERB, Baugy, France.
authors.forename: P
authors.initials: P
authors.lastname: Champeroux
authors.affiliation: Centre de Recherches Biologiques, CERB, Baugy, France.
authors.forename: J
authors.initials: J
authors.lastname: Thireau
authors.affiliation: Centre de Recherches Biologiques, CERB, Baugy, France.
authors.forename: S
authors.initials: S
authors.lastname: Judé
authors.affiliation: Centre de Recherches Biologiques, CERB, Baugy, France.
authors.forename: C
authors.initials: C
authors.lastname: Laigot-Barbé
authors.affiliation: Centre de Recherches Biologiques, CERB, Baugy, France.
authors.forename: A
authors.initials: A
authors.lastname: Maurin
authors.affiliation: Centre de Recherches Biologiques, CERB, Baugy, France.
authors.forename: M L
authors.initials: ML
authors.lastname: Sola
authors.affiliation: Centre de Recherches Biologiques, CERB, Baugy, France.
authors.forename: J S L
authors.initials: JS
authors.lastname: Fowler
authors.affiliation: Centre de Recherches Biologiques, CERB, Baugy, France.
authors.forename: S
authors.initials: S
authors.lastname: Richard
authors.affiliation: Centre de Recherches Biologiques, CERB, Baugy, France.
authors.forename: J Y
authors.initials: JY
authors.lastname: Le Guennec
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001341:Autonomic Nervous System / Q000187:drug effects*; D004285:Dogs; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D005730:Ganglionic Blockers / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects*; D018738:Hexamethonium / Q000494:pharmacology; D008252:Macaca fascicularis; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010627:Phenethylamines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D016171:Torsades de Pointes / Q000139:chemically induced
chemical_list: D000889:Anti-Arrhythmia Agents; D005730:Ganglionic Blockers; D010627:Phenethylamines; D013449:Sulfonamides; D018738:Hexamethonium; C063533:dofetilide