QT interval correction assessment in the anesthetized guinea pig

Introduction: The anesthetized guinea pig (ANES GP) has proven to be an effective small animal model to evaluate cardiac electrophysiologic effects of drug-candidate molecules during lead optimization. While heart rate (HR) corrected QT interval (QTc) is a key variable to determine test article-dependent repolarization effects, ideal correction methods are an area of constant debate given the potential influence of anesthesia, autonomic tone, species, strain and gender on the QT/HR relationship. The aim of this study was to characterize the ability of common correction formulas to normalize rate-dependent effects on the QT interval in the ketamine/xylazine ANES GP. Methods: Atrial pacing (n = 10), ivabradine or ephedrine (n = 6/group) infusions were used, respectively to evaluate the effects of a wide range of HRs on the QT/HR relationship. Correction formulas (Bazett [QTcb], Fridericia [QTcf] and Van de Water [QTcVdW]) were applied and the best fit formula was determined with the aid of the slope of their QT-HR linear relationship. Results: From 100 to 220 bpm, QTcb underestimated the change in QT interval duration (QT/HR slope = 0.35 to 0.67). However, QTcVdW was more appropriate in this HR range (QT/HR slope=-0.07 and 0.09). At higher HRs (>220 bpm), QTcb performed better (QT/HR slope = -0.02 and 0.07) as compared to QTcf (QT/HR slope = -0.18 to -0.1) and QTcVdW(QT/HR slope = -0.2 to -0.17) (p < 0.01). All the correction formulas identified dofetilide-and sotalol-dependent repolarization delay (n= 6/group) but QTcb and QTcf demonstrated reduced sensitivity as compared to fixed cardiac pacing (p < 0.01). In contrast, QTcVdW resulted in an apparent underestimation of the QT interval duration at HR levels above the basal ketamine/xylazine ANES GP HRs (>220 bpm) with ephedrine (n= 6). Discussion: The best fit correction formula in the ANES GP was highly dependent on the HR range. In the ketamine/xylazine model, QTcVdW performed best with HR <220 bpm and QTcb performed best with HR >220 bpm. The QTcVdW correction formula was thus selected in the ketamine/xylazine ANES GP since HRs in this model are generally within the optimal range for this correction formula. (C) 2015 Elsevier Inc. All rights reserved.