Reflex sympatho-vagal coactivation and concealed QTc prolongation: Lessons from hERG-blockers and long QT syndromes type 1 and type 2

Background and Purposes: Several hERG blocking molecules known for their propensity in triggering Torsades de Pointes (TdP) were reported as increasing High Frequency QT oscillations (HFQT). This effect was found as reflecting a sympatho-vagal coactivation. The present work aims to characterise the mechanism(s) leading to this particular state of the autonomic nervous system. Experimental approach: Effects of 20 hERG blockers including 15 torsadogenic molecules were assessed by telemetry in beagle dogs. Electrocardiogram and stroke volume modelled from the pulse contour method were analysed at the first dose level causing either QTc prolongation and/or HFQT increase. Cardiac autonomic control was analysed using the High Frequency Autonomic Modulation (HFAM) model in dogs and in untreated genotyped LQT1 and LQT2 individuals, for comparison. Key results: The sympatho-vagal coactivation induced by torsadogenic molecules is elicited by reflex compensatory mechanisms in response to changes in stroke volume or cardiac output related to hemodynamic off-targets and/or QT prolongation. QTc prolongation was concealed or markedly blunted by the sympathetic component activation in a large proportion of tested torsadogenic drugs. Sympathetic reflex mechanisms in LQT patients similar to that found for dofetilide was also revealed in both patients exhibiting QTc prolongation and concealed QTc prolongation, irrespective to LQT type. Conclusions and implications: QTc prolongation and/or drug-induced hemodynamic side effects enhance beat to beat ventricular repolarisation variability via sympatho-vagal reflex compensatory mechanisms. Considering the sympathetic reflex component via analysis of HFQT oscillations dramatically improves prediction, sensitivity and specificity of drug induced Torsades de pointes risk assessment.