Eddy Vlaminckx

Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines

The regulatory guidelines (ICHS7B) recommending inhibition of the delayed rectifier K+ current (IKr), carried by human ether‐a‐go‐go‐related gene (hERG) channels in cardiac cells (the hERG test), as a ‘first line’ test for identifying compounds inducing QT prolongation, have limitations, some of which are outlined here.

Drug-induced long QT in isolated rabbit Purkinje fibers: importance of action potential duration, triangulation and early afterdepolarizations

In the present study, we investigated three drug-induced long-QT syndromes in isolated rabbit Purkinje fibers in order to identify the relationship of action potential duration (APD), triangulation of action potentials (APD(90)-APD(40)) and early afterdepolarizations. Isolated rabbit Purkinje fibers were superperfused in Tyrode solution with solvent, indapamide (1 x 10 (-4) M, an I(ks) blocker mimicking long QT1), dofetilide (1 x 10 (-9), 1 x 10 (-8) or 1 x 10 (-7) M, an I(kr) blocker mimicking long QT2) or anthopleurin (1 x 10 (-8) M, an inhibitor of the inactivation of the I(Na(+)) current mimicking long QT3) (n=8 per group) for 25 min, and stimulated at 1 Hz for 20 min and at 0.2 Hz for another 5 min. Indapamide did not change APD and triangulation or elicit early afterdepolarizations even in the presence of beta-adrenergic stimulation with isoproterenol. Dofetilide concentration-dependently prolonged APD(90), increased triangulation and elicited early afterdepolarizations. Anthopleurin markedly increased APD(90) as well as triangulation and elicited early afterdepolarizations. The induction of early afterdepolarizations by dofetilide and anthopleurin was associated with a prolongation of APD(90) or an increase in triangulation, but not with a change in APD(40). Moreover, the degree of the increase in the triangulation was larger than that of APD(90) in long QT2 (dofetilide-induced) and long QT3 (anthopleurin-induced) models in isolated rabbit Purkinje fibers. Our present study indicates that rabbit Purkinje fibers can be used as long QT2 (dofetilide-mimicking) and LQT3 (anthopleurin-mimicking) syndrome models, and confirms that drug-induced long QT1 (indapamide-mimicking) is absent. Our present study also shows the relationship between a prolongation of APD(90) or increase in triangulation and the induction of early afterdepolarizations with dofetilide (I(kr) blocker) and anthopleurin (I(Na) modulator) in isolated rabbit Purkinje fibers.

Predicting drug‐induced slowing of conduction and pro‐arrhythmia: identifying the ‘bad’ sodium current blockers

Background and purpose:  The regulatory guidelines (ICHS7B) for the identification of only drug‐induced long QT and pro‐arrhythmias have certain limitations.

Calmodulin antagonist W-7 prevents sparfloxacin-induced early afterdepolarizations (EADs) in isolated rabbit purkinje fibers: importance of beat-to-beat instability of the repolarization.

Introduction: The occurrence of early afterdepolarizations (EADs) has been related to the incidence of torsades de pointes in drug‐induced long QT (LQT). The generation of EADs may be facilitated by Ca2+/calmodulin‐dependent protein kinase II (CaM kinase).