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Abstract
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.
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