1. Introduction
Torsades de Pointes (TdP) are a malignant form of ventricular arrhythmia that can degenerate into ventricular fibrillation and sudden cardiac death. This particular kind of arrhythmia is commonly related to a lengthening of ventricular repolarisation. Consequently, the increase in ventricular repolarisation duration by drug-candidates is a major issue since it is associated with the risk of TdP (Kannankeril et al., 2010). Such QT prolongation has been strongly linked to cardiac hERG channels blocking properties since hERG channels are responsible for an inwardly rectifying outward potassium current, IKR, that largely contributes to action potential repolarisation of ventricular cardiomyocytes. Despite the identification of this mechanism, prediction of the risk for QT prolongation remains uncertain during the preclinical development from hERG blocking properties and QT studies (Park et al., 2018). Similar difficulties are met in the clinic to identify at risk patients affected by Long QT Syndromes (LQTs). Indeed, 25 % approximately of genotyped LQTs patients do not exhibit signs of QT prolongation (Goldenberg et al., 2011). The beat to beat variability of ventricular repolarisation (BVR) also plays a major role in TdPs (Thomsen et al., 2004; Lengyel et al., 2007). In sinusal rhythm, the greatest contributor to BVR is the parasympathetic nervous system through rate dependent mechanisms. Indeed, rhythmic vagal discharges in the High Frequency (HF) band (>0.1 Hz) are responsible for large beat to beat heart rate changes causing in turn an important beat to beat rate dependent adaptation of ventricular repolarisation duration. Suppression of HF oscillations of heart rate (HFHR) and QT interval (HFQT) by a ganglioplegic agent was found to fully prevent dofetilide induced TdPs in cynomolgus monkeys (Champéroux et al., 2015). In beagle dogs, magnitude of HFHR oscillations was found to be increased by several hERG blockers causing TdPs in human. Increases in HFQT oscillations induced by these hERG blockers through parasympathetic raise result from a concomitant sympathetic activation (Champéroux et al., 2016). Altogether, these studies have permitted identification of a particular state of the autonomic control characterised by a coactivation of both the parasympathetic and sympathetic systems named S2 oscillations (Champéroux et al., 2018). However, the mechanism by which torsadogenic hERG blockers causes this coactivation is still unclear. Sympathetic activation often results from reflex compensatory mechanisms. So, we focused on the hemodynamic effects of hERG blocking drugs and their consequences on HF oscillations to determine a possible utility of a refined integrative approach combining hemodynamic, electrophysiological and autonomic biomarkers to predict TdP risk. For this aim, we used a representative set of 20 hERG blockers including 15 compounds incriminated in TdP. To our knowledge, it is the first time that a refined analysis of hemodynamic, electrophysiological and autonomic effects of 20 hERG blocking drugs was presented in one integrative study. Thus, these observations may also serve to future researches on the topic of evaluation and management of TdP risk .