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