Incorrectly corrected? QT interval analysis in rats and mice

Abstract

QT interval, a surrogate measure for ventricular action potential duration (APD) in the surface ECG, is widely used to identify cardiac abnormalities and drug safety. In humans, cardiac APD and QT interval are prominently affected by heart rate (HR), leading to widely accepted formulas to correct the QT interval for HR changes (QT corrected - QTc). While QTc is widely used in the clinic, the proper way to correct the QT interval in small mammals such as rats and mice is not clear. Over the years, empiric correction formulas were developed for rats and mice, which are widely used in the literature. Recent experimental findings obtained from pharmacological and direct pacing experiments in unanesthetized rodents show that the rate-adaptation properties are markedly different from those in humans and the use of existing QTc formulae can lead to major errors in data interpretation. In the present review, these experimental findings are summarized and discussed.

Keywords: ECG; QT interval; action potential duration; effective refractory period; rate-adaptation; rodent cardiac electrophysiology.

FIGURE 1

Absence of QT interval dependence on HR in paced unanesthetized rodents. (A). Data from instrumented, unanesthetized male SD rats that were subjected to atrial pacing at different CL (n = 10): Mean ± SE of measured QT and calculated QTc (based on the formula of Kmecova and Klimas (Kmecova and Klimas, 2010)), plotted as a function of CL. Linear regression data (slope, R²) are presented for both QT and calculated QTc. (B). Data from instrumented, unanesthetized male C57BL/J mice that were subjected to atrial pacing at different CL (n = 9): Mean ± SE of measured QT and calculated QTc [based on the formula of Mitchell et al. (1998)], plotted as a function of CL. Linear regression data (slope, R²) are presented for both QT and calculated QTc. Experimental findings were adapted from Mulla et al. (2018).