Short‐term variability in QT interval and ventricular arrhythmias induced by dofetilide are dependent on high‐frequency autonomic oscillations

• Published in: British journal of pharmacology Vol. 172; no. 11; pp. 2878 - 2891
• Main Authors: Champeroux, P, Thireau, J, Judé, S, Laigot‐Barbé, C, Maurin, A, Sola, M L, Fowler, J S L, Richard, S, Le Guennec, J Y
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-06-2015; Wiley; BlackWell Publishing Ltd
• Subjects: Animals; Anti-Arrhythmia Agents - pharmacology; Arrhythmias, Cardiac - chemically induced; Autonomic Nervous System - drug effects; Cardiac arrhythmia; Cardiology and cardiovascular system; Cynomolgus; Dogs; Electrocardiography; Electrophysiological Phenomena - drug effects; Ganglionic Blockers - pharmacology; Heart rate; Heart Ventricles - drug effects; Hexamethonium - pharmacology; Human health and pathology; Life Sciences; Macaca fascicularis; Myocytes, Cardiac - drug effects; Pharmaceutical sciences; Pharmacology; Phenethylamines - pharmacology; Research Papers; Studies; Sulfonamides - pharmacology; Torsades de Pointes - chemically induced
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13093

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 (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.
Key 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 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 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.