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Short‐term variability in QT interval and ventricular arrhythmias induced by dofetilide are dependent on high‐frequency autonomic oscillations
Author(s) -
Champeroux P,
Thireau J,
Judé S,
LaigotBarbé C,
Maurin A,
Sola M L,
Fowler J S L,
Richard S,
Le Guennec J Y
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13093
Subject(s) - dofetilide , qt interval , term (time) , afterdepolarization , cardiology , autonomic nervous system , medicine , herg , electrophysiology , potassium channel , heart rate , physics , blood pressure , repolarization , quantum mechanics
Background and Purpose 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. Experimental Approach The short‐term variability of beat‐to‐beat QT interval ( STV QT ), induced by dofetilide is a strong surrogate of T orsades de pointes liability. Involvement of autonomic modulation in STV QT was investigated in healthy cynomolgus monkeys and beagle dogs by power spectral analysis under conditions of autonomic blockade with hexamethonium. Key Results Increase in STV QT 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 h ERG blockers described as causing T orsades de pointes in humans. Conclusions and Implications 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 h ERG ‐blocking properties, enhancement of endogenous HF oscillations in heart rate could constitute an earlier and more sensitive biomarker than STV QT for T orsades de pointes liability, applicable to preclinical regulatory studies conducted in healthy animals.