Résumé
Background and Purposes: Several hERG blocking drugs known for their propensity to trigger Torsades de Pointes (TdP) were reported to induce a sympatho-vagal coactivation and to enhance High Frequency heart rate (HFHR) and QT oscillations (HFQT) from telemetric data. The present work aims to characterise the underlying mechanism(s) leading to these autonomic changes.Experimental approach: Effects of 15 torsadogenic hERG blocking drugs (astemizole, chlorpromazine, cisapride, droperidol, ibutilide, dofetilide, haloperidol, moxifloxacin, pimozide, quinidine, risperidone, sotalol, sertindole, terfenadine, thioridazine) were assessed by telemetry in beagle dogs. Hemodynamic effects on diastolic and systolic arterial pressure were analysed from the first doses causing QTc prolongation and/or HFQT oscillations enhancement. Autonomic control changes were analysed with the High Frequency Autonomic Modulation (HFAM) model.Key results: Except moxifloxacin and quinidine, all torsadogenic hERG blockers induced parasympathetic activation or sympatho-vagal coactivation combined with enhancement of HFQT oscillations. These autonomic effects result from reflex compensatory mechanisms in response to mild hemodynamic side effects. These hemodynamic mechanisms were characterised by transient HR acceleration during HF oscillations. A phenomenon of concealed QT prolongation was unmasked for several torsadogenic hERG blockers under β-adrenoceptors blockade by atenolol. Resulting enhancement of HFQT oscillations was shown to contribute directly to triggering of dofetilide induced ventricular arrhythmias.Conclusions and implications: This work supports for the first time a contribution of hemodynamic side properties to ventricular arrhythmias triggering by torsadogenic hERG blocking drugs. These hemodynamic side effects may constitute a second component of their arrhythmic profile acting as a trigger alongside their intrinsic arrhythmogenic electrophysiological properties.