Heart rate correction of the QT duration in rats

Duration of heart rate corrected QT interval (QTc) is a crucial and critical factor in the assessment of repolarization changes considering safety of drugs and cardiac disorders. In rats, a validated approach to QT correction is lacking. In this study, we tested the normalization of QTc using normalization factor according to rat's cardiac cycle length (RR). Standard 12-lead ECG was measured in anesthetized rats at basal conditions and at various pharmacological conditions such as beta-adrenergic stimulation with isoproterenol or medication with clarithromycin (single- or repeated dosing for seven days), bisoprolol or ivabradine. For QT correction, standard Bazett's formula (QTc-B=QT/(RR)(1/2)) and Bazett's formula normalized to average rat RR (QTc(n)-B=QT/(RR/f)(1/2), f=150ms) were compared. Duration of QT showed a positive correlation with RR duration (Pearson r=0.7645, P<0.001). Calculated QTc-B gave 2-2.5 fold of values of uncorrected QT, whereas values of normalized QTc(n)-B were in the physiological range. QTc(n)-B was unrelated to RR (Pearson r=0.1122, not significant) but the relationship between QTc(n)-B and QT remained preserved (Pearson r=0.7216, P<0.001). Both single and repeated administration of clarithromycin prolonged QT as compared to the controls but a significant dose-dependent difference between clarithromycin applications was revealed only when QTc(n)-B was used. Beta-adrenergic stimulation with isoproterenol prolonged, while beta-blockade with bisoprolol shortened QTc(n)-B. Ivabradine dose-dependently induced bradycardia without altering QT. However, QTc(n)-B showed false positive shortening at sustained bradycardia. Therefore, adjusted formula for QTc(n)-B is suitable for QT correction in rats but its use should be considered carefully in case of very low heart rate.