Combined pharmacological block of I_Kr and I_Ks increases short‐term QT interval variability and provokes torsades de pointes

Abstract

Background and purpose: Assessing the proarrhythmic potential of compounds during drug development is essential. However, reliable prediction of drug-induced torsades de pointes arrhythmia (TdP) remains elusive. Along with QT interval prolongation, assessment of the short-term variability of the QT interval (STV(QT)) may be a good predictor of TdP. We investigated the relative importance of I Ks and I Kr block in development of TdP together with correlations between QTc interval, QT interval variability and incidence of TdP. Experimental approach: ECGs were recorded from conscious dogs and from anaesthetized rabbits given the I Kr blocker dofetilide (DOF), the I Ks blocker HMR-1556 (HMR) and their combination, intravenously. PQ, RR and QT intervals were measured and QTc and short-term variability of RR and QT intervals calculated. Key results: DOF increased QTc interval by 20% in dogs and 8% in rabbits. HMR increased QTc in dogs by 12 and 1.9% in rabbits. Combination of DOF þ HMR prolonged QTc by 33% in dogs, by 16% in rabbits. DOF or HMR given alone in dogs or HMR given alone in rabbits induced no TdP. Incidence of TdP increased after DOF þ HMR combinations in dogs (63%) and following HMR þ DOF (82%) and DOF þ HMR combinations (71%) in rabbits. STV(QT) markedly increased only after administration of DOF þ HMR combinations in both dogs and rabbits. Conclusion and implications: STV(QT) was markedly increased by combined pharmacological block of I Kr and I Ks and may be a better predictor of subsequent TdP development than the measurement of QTc interval prolongation.

Contribution of ion currents to beat-to-beat variability of action potential duration in canine ventricular myocytes

“…Therefore, in absence of relevant human cellular electrophysiological data, canine ventricular myocytes were chosen to analyze experimentally the determinants of SV in the present study due to two reasons. (1) Canine ventricular myocytes are believed to resemble human ventricular cells regarding their action potential morphology and kinetics of the underlying ion currents [19,20]; and (2) a large mass of in vitro and in vivo experimental data on beat-to-beat variability have been obtained in this species [1,12,13,15,22,23]. Here is to be mentioned that all action potentials analyzed in the present study were normally driven ones, records taken in myocytes displaying early or delayed afterdepolarizations were excluded from evaluation.…”

Comparison of different proarrhythmia biomarkers in isolated rabbit hearts

“…In accordance with this, Lengyel et al. found that the beat-to-beat variability of the QT interval predicted the occurrence of druginduced TdP in anaesthetized rabbits 68 . In contrast, the beat-to-beat variability of the QT interval failed to predict repolarization-prolonging-drug-induced TdP in two recent investigations with adrenergically stimulated, anaesthetized rabbits 27,69 .…”

“…It has been shown that beatto-beat variability of the repolarization measured in regular rhythm predicted TdP in clinical 24 and experimental 16,25,26 settings. However, beat-to-beat variability of repolarization measured in regular rhythm did not predict drug-induced TdP in anaesthetized rabbits [27][28][29][30] and guinea pigs 31 .…”

“…I Ks may compensate the decreased function of I Kr . However, a multiple hit on repolarization might lead to an excessive APD prolongation and may render the cardiac muscle more susceptible to proarrhythmia 25,73 .…”

“…the slow component of the delayed rectifier K + current (I Ks ), becomes more prominent and compensates the repolarization lengthening and decreases the arrhythmogenic effect of the I Kr blocker [39][40][41][42] . However, the concomitant block of I Kr and I Ks currents constitutes an increased risk to TdP development 25,30,[41][42][43][44][45] .…”