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 .