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 (QTcn-B = QT / (RR / f)1/2, f = 150 ms) 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 QTcn-B were in the physiological range. QTcn-B was unrelated to RR (Pearson r = 0.1122, not significant) but the relationship between QTcn-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 QTcn-B was used. Beta-adrenergic stimulation with isoproterenol prolonged, while beta-blockade with bisoprolol shortened QTcn-B. Ivabradine dose-dependently induced bradycardia without altering QT. However, QTcn-B showed false positive shortening at sustained bradycardia. Therefore, adjusted formula for QTcn-B is suitable for QT correction in rats but its use should be considered carefully in case of very low heart rate.