Torsadogenic hERG blockers combined with non blunted QTc
prolongation
6 torsadogenic hERG blockers caused QTc prolongation without evidence of
blunting of QTc prolongation. 2 of them (moxifloxacin and quinidine)
were found to induce a mild QTc prolongation only at a low dose. No
autonomic and hemodynamic changes were seen with these two drugs at this
low dose. Alternatively, 4 hERG blockers (astemizole, dofetilide,
ibutilide, sotalol) caused larger QTc prolongation combined with signs
of autonomic control changes and increases in HFQT oscillations. No
apparent changes in hemodynamic parameters were observed in parallel. In
this group, autonomic variations involved increases in S1 and/or S2
oscillations and reciprocal decrease in S3 oscillations depending on
drugs and dose level. Increases in S1 oscillations seen with sotalol are
consistent with its β adrenoceptors blocking properties. For the 3 other
hERG blockers causing QTc prolongation, changes in autonomic control
could reflect compensatory mechanisms aimed to counterbalance direct
hemodynamic effects. The only detected hemodynamic change being possibly
responsible for triggering a baroreflex response was an increase in SV
induced by dofetilide at a high dose under β adrenoceptors blockade
(Figure 1). As a reminder, atenolol is fully devoid of hemodynamic
effect in healthy dogs causing a lowering in HFHR and S2 oscillations
only (Supplemental Figures 106 to 108) due to the suppression of the
coactivation mode of the autonomic control (Champéroux et al., 2016).
This effect of dofetilide on SV under β adrenoceptors blockade was
independent on mean heart rate, this latter parameter being unchanged
between control and the dofetilide+atenolol combination sessions during
the period where SV was increased by dofetilide. Such an effect of
dofetilide on SV could be the trigger for a baroreflex parasympathetic
activation since this kind of effect is expected inducing an increase in
cardiac output and BP in the absence of this compensatory baroreflex
response. To better comprehend the relationship between the effect seen
with dofetilide at a high dose on SV and the activation of the
sympathetic component during S2 oscillations, changes in BP and SV were
investigated during S2 oscillations. As shown from the Figure 2A
obtained in a control dog, large drops in DAP occur during the
deceleration phase within 1 to 2 beats only during S2 oscillations. They
are associated with an increase in SV showing a greater left ventricle
filling during deceleration. Drops in DAP reach up to -50 mmHg or more
during S2 oscillations and are followed by compensatory increases in DAP
of the same magnitude during acceleration phases to maintain constant
mean DAP levels during HF oscillations. Building the DAP/HFHR and
SV/HFHR relationships at peak and minimum heart rate during HF
oscillations (Figure 2) shows that this reflex mechanism contributes to
maintain almost constant mean DAP and SV levels during HF cycles.
Interestingly, the largest HF oscillations of systolic arterial pressure
(HFSAP) are much less pronounced than HFDAP oscillations. Taken
together, these findings strongly support that this state of sympathetic
and parasympathetic coactivation results from a reflex sympathetic
activation during parasympathetic driven oscillations aimed to maintain
constant mean DAP levels during HF cycles when parasympathetic activity
is increased in response to an increase in SV and/or a decrease in DAP
at the end of the deceleration phase. Besides, dofetilide induced effect
on SV appears related to the magnitude of QT prolongation. Indeed, this
effect was detected only at a high dose of dofetilide (Supplemental
Figures 91 to 93) causing a large QT prolongation, likely because of its
additional property of late INa enhancement (Yang T et al., 2014). At a
lower dose , dofetilide induced QTc prolongation was less important and
β adrenoceptors blockade did not reveal any increase in SV (Supplemental
Figures 13 to 15). Likewise, low level of QTc prolongation such those
induced by moxifloxacin (Supplemental Figures 1 to 3) and quinidine
(Supplemental Figures 4 to 6) did not trigger this compensatory reflex
suggesting that the magnitude of QTc prolongation caused by these drugs
at a low dose was not large enough to cause this hemodynamic effect on
SV and trigger this reflex mechanism. At a higher dose, these two drugs
induced larger QTc prolongation (Supplemental material, Figure 94 to
99). However, they also caused large decrease in SV combined with
lowering in cardiac output. Blunted S3 oscillations were largely
increased suggesting a more important sympathetic activation in response
to these hemodynamic effects at high dose. This hemodynamic profile of
moxifloxacin and quinidine at a high dose characterised by a lowering in
cardiac function efficiency (cardiac output and SV) is consistent with
their sodium and calcium channel blocking properties (Le Guennec et al.,
2016).