INTRODUCTION: The anesthetized @entity840 (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 @entity299 . 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 @entity3652 / @entity4763 ANES GP. METHODS: Atrial pacing (n=10), @entity15726 or @entity6358 (n=6/group) infusions were used, respectively to evaluate the effects of a wide range of @entity299 . 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 @entity299 . RESULTS: From 100 to 220bpm, QTcb underestimated the change in QT interval duration ( @entity299 =0.35 to 0.67). However, QTcVdW was more appropriate in this HR range ( @entity299 =-0.07 and 0.09). At higher HRs (>220bpm), QTcb performed better ( @entity299 =-0.02 and 0.07) as compared to QTcf ( @entity299 =-0.18 to -0.1) and QTcVdW ( @entity299 =-0.2 to -0.17) (p<0.01). All the correction formulas identified @entity2781 - and @entity2778 -dependent repolarization delay (n=6/group) but QTcb and QTcf demonstrated reduced sensitivity as compared to fixed @entity299 (p<0.01). In contrast, QTcVdW resulted in an apparent underestimation of the QT interval duration at HR levels above the basal @entity3652 / @entity4763 ANES GP HRs (>220bpm) with @entity6358 (n=6). DISCUSSION: The best fit correction formula in the ANES GP was highly dependent on the HR range. In the @entity3652 / @entity4763 model, QTcVdW performed best with HR <220bpm and QTcb performed best with HR >220bpm. The QTcVdW correction formula was thus selected in the @entity3652 / @entity4763 ANES GP since HRs in this model are generally within the optimal range for this correction formula.

QT interval correction assessment in the anesthetized XXXX .

@entity2781 :: ('MESH:C063533', 'Chemical') :: ['dofetilide'] @entity6358 :: ('MESH:D004809', 'Chemical') :: ['ephedrine'] @entity840 :: ('10141', 'Species') :: ['guinea pig'] @entity3652 :: ('MESH:D007649', 'Chemical') :: ['ketamine'] @entity4763 :: ('MESH:D014991', 'Chemical') :: ['xylazine'] @entity2778 :: ('MESH:D013015', 'Chemical') :: ['sotalol'] @entity299 :: ('MESH:D006331', 'Disease') :: ['QT/HR relationship', 'HRs on the QT/HR relationship', 'QT/HR slope', 'slope of their QT-HR linear relationship', 'cardiac pacing'] @entity15726 :: ('MESH:C088408', 'Chemical') :: ['ivabradine']
@entity840 :: (10141,Species) :: ['guinea pig']
