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.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.From 100 to 220bpm, 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 (220bpm), 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) (p0.01). 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 (p0.01). In contrast, QTcVdW resulted in an apparent underestimation of the QT interval duration at HR levels above the basal ketamine/xylazine ANES GP HRs (220bpm) with ephedrine (n=6).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 HR220bpm and QTcb performed best with HR220bpm. 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.
