Increased short-term variability of the QT interval predicts cisapride induced ventricular arrhythmias
█ Original article
Krajcs Nóra1, 2, Tábori Katalin1, Juhász Viktor1, Hornyik Tibor1, Varró András1, 3, Baczkó István1
1Szegedi Tudományegyetem, Farmakológiai és Farmakoterápiai Intézet, Szeged
2MTA, Ökológiai Kutatóközpont, BLI Kísérletes Állattani Osztály, Tihany
3MTA-SZTE, Keringésfarmakológiai Kutatócsoport, Szeged
Aims: Preclinical drug safety tests employ healthy animals and animal tissues for the investigation of the cardiac repolarization prolonging effects of compounds, that do not represent patients exhibiting increased arrhythmia susceptibility, and the degree of repolarization prolongation does not correlate directly with the incidence of arrhythmias. Therefore, the reliable prediction of proarrhythmic potency of compounds is lacking. Here we investigated the effects of cisapride, a drug withdrawn from the market due to its proarrhythmic side effects, on ventricular arrhythmias and ECG parameters in a rabbit model with impaired repolarization reserve.
Methods: In anaesthetized rabbits, cardiac repolarization reserve was reduced by pharmacological block of the IKs current (0.1 mg/kg HMR1556, i.v.). The development of arrhythmias was registered following cisapride (0.5, 1 and 2 mg/kg) or HMR1556 and cisapride combination (n=10 in all groups). Conventional ECG intervals (PQ, RR, QT and QTc), the short term variability of QT and RR (STVQT and STVRR) were measured. STVQT is an ECG parameter suggested for more reliable prediction of arrhythmias.
Results: The IKs blocker HMR1556 did not cause any arrhythmias, did not prolong the QTc and did not increase STVQT. Cisapride induced some arrhythmias, however, the incidence of Torsades de Pointes (TdP) was markedly increased (50%) when cisapride was combined with the IKs blocker. Cisapride alone and with HMR1556 in combination caused similar QTc prolongation. The STVQT was highest following the combination that caused the highest incidence of TdP.
Conclusions: In a rabbit model with reduced repolarization reserve, cisapride increased the incidence of ventricular arrhythmias and the significant elevation of the short term variability of the QT interval preceded the increase in arrhythmia incidence. Our results support the calculation of STVQT during proarrhythmic side effect assessment.