Discussion
This set of 15 hERG blocking drugs reported as causing TdP includes 9 of
the most potent hERG blockers of the Kramer list (Kramer et al., 2013).
All these torsadogenic drugs induced hemodynamic effects activating in
turn autonomic reflex mechanisms. These hemodynamic effects were
different depending on drug and dose levels. In most of cases, they were
more or less compensated by reflex mechanisms making them difficult to
detect directly from blood pressure changes only. In parallel, combining
QTc prolongation and HFQT oscillations analysis allowed detection of all
tested torsadogenic drugs since visible from at least one of these two
biomarkers. In the absence of QTc prolongation, enhancement of HFQT
oscillations also constitutes a sensitive surrogate for suspicion of
possible concealed QTc prolongation at low doses of torsadogenic hERG
blockers. This paradigm is due to specific off-targets which conceal the
hERG blockade induced QTc prolongation by activating the sympathetic
system during HF cycles. This phenomenon likely involves the recruitment
of the IKs repolarisation reserve by β-adrenoceptors
mediated sympathetic activation (Volders et al., 2003). The α1
adrenoceptors blocking property is by far the most common off-target
among torsadogenic drugs. This is not the only one since drugs like
pimozide and cisapride also induced autonomic coactivation while they
were not reported as exhibiting this α1 adrenoceptors blocking property.
The milrinone profile shows that phosphodiesterase inhibition could also
constitute an off-target leading to an autonomic coactivation and
increase in HFQT oscillations. This example is important because it
demonstrates that increase in HFQT oscillations do not require
necessarily any mechanism lengthening the ventricular repolarisation
since milrinone is devoid of hERG blocking properties and even causes
QTc shortening. First of all, this work demonstrates that HFQT
oscillations magnitude is a sensitive biomarker of the sympathetic
activity on autonomic beat to beat variability of ventricular
repolarisation. This biomarker is particularly useful when the
parasympathetic system activity is predominant as with dofetilide at a
low dose or in LQT patients with concealed QT prolongation. This dataset
of hERG blockers also shows that this biomarker is more sensitive for
detection of drug torsadogenic profile than short term QT variability
that rather reflects instability of ventricular repolarisation in its
principle.
Specificity for TdP risk assessment appears promising too. Indeed,
increases in HFQT oscillations were found with torsadogenic hERG
blockers only whereas non torsadogenic hERG blockers did not increase
HFQT oscillations. However, two non arrhythmic drugs, prazosin and
milrinone, were found sharing this ability to enhance this biomarker.
Investigating available data from literature about sudden cardiac death
risk reveals that milrinone (Packer et al, 1991), prazosin and other α1
adrenoceptors antagonists (O’ Connell et al., 2014) were reported to
unexplainably worsen mortality in patients with heart failure. Despite
its hERG blocking properties (Thomas et al., 2004), we failed to find
clinical reports of Tdp induced by prazosin. Conversely, milrinone was
recently cited as involved in TdP events in humans (Chiba et al., 2020)
although devoid of hERG blocking properties (Yunomae et al., 2007) and
considered as a non torsadogenic drug. Milrinone was also reported as
causing cardiotoxicity resulting from adrenergic hyperactivity (Chiba et
al., 2020). Their propensity to cause excess mortality in the context of
heart failure is certainly not a coincidence. Indeed, ventricular
repolarization is lengthened in heart failure due to down regulation of
potassium current (Näbauer & Kääb, 1998) and enhancement of the late
sodium current (Maltsev et al., 2007) creating as well favourable
conditions for the triggering of ventricular arrhythmias by sympathetic
activation as in LQT syndromes. These two examples of molecules open new
perspectives for sudden cardiac death risk assessment out the area of
TdP induced by arrhythmic drugs.
One of the most important finding in this work is the central role
played by the stroke volume and cardiac output changes in reflex
mechanisms leading to autonomic coactivation and increase in beat to
beat ventricular repolarisation variability. This autonomic coactivation
corresponds to an enhancement of oscillatory reflex mechanisms aimed to
maintain stable the mean diastolic arterial pressure during HF
parasympathetic cycles elicited by mild increases or decreases in stroke
volume. Transient drops in diastolic arterial pressure following large
RR pauses during HF cycles support involvement of the baroreflex in this
autonomic coactivation phenomenon. However, mechanoreceptors sensitive
to ventricular distension and volume could also be involved. They were
shown to trigger large sympathetic burst following transient drop in
arterial pressure in particular following premature ventricular
contraction where the systolic pressure peak required to trigger
arterial baroreceptors to terminate sympathetic outflow is absent (Zamir
et al., 2012). Lowering in stroke volume induced by α1 adrenoceptors
blocking drugs and other peripheral vasodilator drugs is considered as
due to blood pooling in peripheral venous compartments below the
diaphragm causing in turn a reduction in venous return and cardiac
output (Brignole et al., 2018). Conversely, outcomes of dofetilide at a
high dose under β-adrenoceptors blockade support that QT prolongation
may result in a mild increase in stroke volume. Accordingly, positive
inotropic effects correlated to their effects on ventricular
repolarisation duration were reported for dofetilide and E4031 in
ventricular muscle preparations (Tande et al., 1990; Abrahamsson et al.,
1993).
This work establishes for the first time complex relationships between
hemodynamic effects leading to sympathetic compensatory reflexes with
arrhythmic electrophysiological mechanisms related to ventricular
repolarisation prolongation. These relationships very well fit with the
concept of the Coumel’s triangle and allow to dramatically refining and
update (Figure 8) the model based on the Coumel’s triangle proposed
earlier (Champéroux et al., 2015). According to this concept, TdP
triggering involves 1/ a modulator: the autonomic nervous system: its
contribution is featured by an enhancement of HF oscillations through a
sympathetic coactivation in response to hemodynamic off-targets in case
of vaso-active torsadogenic and/or due to ventricular repolarisation
prolongation itself for drugs acting selectively on ventricular
repolarization and in LQT syndromes, 2/ a substrate: the lengthening in
ventricular repolarisation due to genetic mutations in LQT syndromes or
related to intrinsic electrophysiological (off-)targets in case of
torsadogenic drugs, 3/ a trigger: the sympathetic system that increases
the probability of rate dependent arrhythmias under conditions of
ventricular repolarization prolongation (Shimizu & Antzlevitch, 1999)
during acceleration phases of HF cycles or following large RR pause,
reminding that 80% of TdP published in the clinical literature are
pause dependent (Viskin et al., 2000).
Finally, two specific further features common to torsadogenic hERG
blocking drugs, LQT1 and LQT2 syndromes should be emphasized. First, the
magnitude of HFQT oscillations is increased in LQT1 and LQT2 syndromes
as with most of torsadogenic hERG blockers causing QTc prolongation. In
both cases, this enhancement of HFQT oscillations reflects an increase
in sympathetic activity. In LQT syndromes, TdPs are mainly triggered in
humans by sympathetic activation achieved in various situations such as
physical exercice, swimming, fear reaction or arousal events (Schwartz
et al., 2001, Kim et al., 2010, ). Like in LQT syndromes, these
compensatory sympathetic reflexes caused torsadogenic drugs also appear
as playing a key role for their arrhythmic profile. Besides, the
proposed sympathetic reflex mechanisms provide a robust rational support
to current therapeutic strategies applied in LQT syndromes based on use
of β-blockers or sympathetic left stellate ganglia ablation (Priori et
al., 2015). Secondly, drug induced QTc prolongation potency can be
concealed as in LQT1 and LQT2 syndromes. This latter feature should have
strong implications for preclinical safety pharmacology and drug safety.
Indeed, the current preclinical strategy based on risk assessment of QT
prolongation and hERG blockade showed a poor sensitivity in the 1x-10x
exposure multiple range (Park et al., 2018). Combining QTc prolongation
potency assessment, hemodynamic and autonomic modelling and HFQT
oscillations analysis offers real opportunity for better estimation of
drug safety margins and improving preclinical assessment of TdP risk and
sudden cardiac death.