Accurate detection of drug-induced delayed ventricular repolarization with a suitable correction formula in Langendorff guinea pig heart

Abstract

-The aims of this study were to determine a suitable method to correct the ventricular repolarization period against the RR interval in isolated perfused Langendorff guinea pig heart and to clarify the reliability of this model using several drugs. QT and RR intervals from an electrocardiogram and the epicardial monophasic action potential duration (MAP 90 ) were measured. Two drugs clinically known to be QT-prolonging (E-4031, moxifloxacin) and two known to be non-QT-prolonging (verapamil, zatebradine) were used for the study. To determine a method of correcting the ventricular repolarization period against RR interval, heart rates were slowed with 0.3 µM zatebradine, a specific bradycardiac agent, and then accelerated with atrial pacing to obtain a wide range of MAP 90 /RR relationships. An exponential rate-correction model elicited the most appropriate algorithm for the relationship among the four models tested. Based on linear regression analysis, the exponential showed superior dissociation of corrected MAP 90 s against RR intervals than generic Bazett's and Fridericia's formulae. E-4031 and moxifloxacin prolonged the corrected QT (QTc) intervals and MAP 90 under atrial pacing at a cycle length of 0.25 sec (MAP 90(pacing) ) dose-dependently; verapamil and zatebradine failed to prolong them, indicating that the reliability of this model was excellent. MAP 90(pacing) prolongation by moxifloxacin, the positive compound in the clinical "Thorough QT/QTc Study", was seen at around QTc-prolonging concentrations in clinic, suggesting that the sensitivity would be appropriate for QT evaluation. We therefore concluded that the isolated guinea pig heart model is sufficiently sensitive and useful for assessing the potential QT prolongation of drugs.

Development and Validation of an Automated High-Throughput System for Zebrafish In Vivo Screenings

“…An example of the advantage of using zebrafish for cardiotoxicity detection was found in the classification of Verapamil. While in vitro assays target this compound as a potent HERG blocker [40], [41], studies in mammals show that it does not induce a prolongation of the QT-segment [42], [43]. This result agrees with our data indicating that Verapamil does not cause an AV block in zebrafish embryos.…”

Assessment of Testing Methods for Drug-Induced Repolarization Delay and Arrhythmias in an iPS Cell–Derived Cardiomyocyte Sheet: Multi-site Validation Study

“…These results are in good accordance with a previous observation in patients with supraventricular tachyarrhythmias (15), in which E-4031 at a plasma concentration of 4.85 ± 1.35 ng/ml (11 nM) modestly prolonged RR interval, but it did not achieve statistical significance. Meanwhile in the single sinoatrial nodal cells of rabbits, E-4031 at a concentration of 100 nM suppressed or blocked the spontaneous activity (16), and moreover in the Langendorff-perfused whole hearts of guinea pig, E-4031 at concentrations of 30 -300 nM or 5 mM significantly reduced the heart rate (17,18). Thus, our testing method using the human iPS cell-derived cardiomyocytes can be considered to be more sensitive than currently available in vitro nonclinical models in detecting the E-4031-induced negative chronotropic effect.…”

Conduction and contraction properties of human iPS cell-derived cardiomyocytes: analysis by motion field imaging compared with the guinea-pig isolated heart model

“…The experimental method was described previously (Tabo et al, 2010). Briefly, guinea pigs were pretreated with heparin (1,000 unit/kg, i.p.)…”