Torsadogenic drugs combined with blunted QTc prolongation or
concealed QTc prolongation
In the opposite to drugs causing QTc prolongation, all the other
torsadogenic hERG blocking showed signs of blunted QTc prolongation or
no QTc prolongation. In parallel, they all showed signs of uncompensated
hemodynamic effects associated with an autonomic coactivation and
increases in HFQT oscillations. The term “uncompensated hemodynamic
effects” means that changes in hemodynamic parameters are visible and
was not maintain unchanged by the autonomic reflex mechanisms. For six
of them (chlorpromazine, droperidol, haloperidol, risperidone,
sertindole and thioridazine), this pattern was associated with a
sustained decrease in SV (Figure 3). Since all these latter drugs share
alpha-1 adrenoceptors blocking properties (Nedergaard et al., 1988;
Sleight et al., 1993; Nourian et al., 2008), their profile was compared
to a selective alpha-1 adrenoceptors blocker, prazosin. This drug was
found causing the same profile of lowering in SV with the same
consequences in terms of autonomic coactivation and increases in HFQT
oscillations (Figure 3). Milrinone, a phosphodiesterase 3 inhibitor,
also caused an autonomic coactivation related to lowering in SV
associated with an increase in HFQT oscillations (Figure 3) like
prazosin and torsadogenic alpha-1 adrenoceptors and hERG blocking drugs.
Decrease in SV is attributed to peripheral vasodilation resulting from
phosphodiesterase inhibition in vascular smooth muscles. Interestingly,
milrinone caused QTc shortening (Supplemental Figures 70 to 72) showing
that this increase in ventricular repolarisation variability (HFQT) can
occur even when ventricular repolarisation is shortened. According to
the reflex mechanism described earlier inside HF oscillations, this
lowering in SV related to alpha-1 adrenoceptors blockade or
phosphodiesterase inhibition could be the trigger for a sympathetic
activation followed by compensatory parasympathetic activation to
maintain stable mean SV and DAP levels during HF oscillations.
Conversely, cisapride and pimozide caused both a mild increase in BP
combined with an increase in cardiac output (Figure 4). As stated
earlier for dofetilide, this kind of hemodynamic effect is expected to
induce a baroreflex parasympathetic activation with the similar reflex
consequences during the HF cycles. These data further support the
concept according which these oscillatory mechanisms are aimed to
maintain stable mean DAP during the HF cycles in case of mild drug
induced lowering or increase in SV. Unlike torsadogenic alpha-1
adrenoceptors blocking drugs, off-target(s) responsible for this
particular profile remain unidentified from the literature for pimozide
and cisapride.
In the opposite to hERG blocking drugs causing non blunted QTc
prolongation, expected QTc prolongation was dramatically blunted or
absent although all these molecules induced an increase in HFQT
oscillations. QTc prolongation was revealed under conditions of β
adrenoceptors blockade (Figure 5) applied to 7 drugs of this group
except for chlorpromazine. In other words, QTc prolongation was
concealed for these 6 torsadogenic drugs. This also means that
hemodynamic effects responsible for this sympathetic reflex mechanism
appear at doses at which the ventricular repolarisation prolongation due
to hERG blockade is low or absent (chlorpromazine) and can be concealed
by a sympathetic activation. Reciprocally, drugs causing non blunted QTc
prolongation are molecules devoid of hemodynamic effects due to
off-targets at dose levels causing ventricular repolarisation
prolongation. These findings demonstrate that this phenomenon of
concealed QTc prolongation described earlier with thioridazine at a high
dose (Champéroux et al., 2010) is shared by several other torsadogenic
hERG channel blocking drugs (droperidol, risperidone, sertindole,
pimozide and terfenadine). In the case of terfenadine at least, QTc
prolongation is likely also blunted because of opposite
electrophysiological properties on ventricular repolarization related to
its hERG and calcium/sodium channels blocking profile (Champéroux et
al., 2005). This is the second main mechanism responsible for concealed
QTc prolongation. Terfenadine cumulates both phenomena.