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).