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.