The high frequency relationship: implications for torsadogenic hERG blockers.

BACKGROUND AND PURPOSE: Ventricular arrhythmias induced by human ether-a-go-go related gene (hERG; Kv 11.1 channel) blockers are a consequence of alterations in ventricular repolarisation in association with high-frequency (HF) oscillations, which act as a primary trigger; the autonomic nervous system plays a modulatory role. In the present study, we investigated the role of ß1 -adrenoceptors in the HF relationship between magnitude of heart rate and QT interval changes within discrete 10 s intervals (sorted into 5 bpm heart rate increments) and its implications for torsadogenic hERG blockers. EXPERIMENTAL APPROACH: The HF relationship was studied under conditions of autonomic blockade with atenolol (ß1 -adrenoceptor blocker) in the absence or presence of five hERG blockers in beagle dogs. In total, the effects of 14 hERG blockers on the HF relationship were investigated. KEY RESULTS: All the torsadogenic hERG blockers tested caused a vertical shift in the HF relationship, while hERG blockers associated with a low risk of Torsades de Pointes did not cause any vertical shift. Atenolol completely prevented the effects four torsadogenic agents (quinidine, thioridazine, risperidone and terfenadine) on the HF relationship, but only partially reduced those of dofetilide, leading to the characterization of two types of torsadogenic agent. CONCLUSIONS AND IMPLICATIONS: Analysis of the vertical shift in the HF relationship demonstrated that signs of transient sympathetic activation during HF oscillations in the presence of torsadogenic hERG blockers are mediated by ß1 -adrenoceptors. We suggest the HF relationship as a new biomarker for assessing Torsades de pointes liability, with potential implications in both preclinical studies and the clinic.

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

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.