Assessing QT prolongation in conscious dogs: Validation of a beat-to-beat method

Abstract

A model of sling-trained, conscious mongrel dogs instrumented with telemetric arterial pressure transmitters and ECG leads was validated for assessment of the QT–RR interval relationship at clinically used free and total plasma concentrations of positive and negative standards with known outcomes. The beat-to-beat technique for assessing the dynamic boundaries of the individual cardiac cycles was compared to the same data with typically used averaging techniques and corrections applied. Positive standards E-4031, cisapride, terodiline, and terfenadine showed increased sensitivity toward detection at clinically relevant levels when an outlier analysis of beats beyond the normal autonomic boundary is applied. Since methods to correct the QT interval for heart rate are often confounded with changes in autonomic state, a validation of the changes with reflex tachycardia induced by vasodilatation after nitroprusside and reflex bradycardia induced by sudden vasoconstriction with phenylephrine where shown to be differentiated from direct effects of repolarization with E-4031. These changes were also demonstrated to be identical to effects observed in humans after standing or challenged with a similar dose of phenylephrine. The conscious dog is also a sensitive model for studying the arrhythmia liability induced by beat-to-beat changes in cardiac ECG restitution (the relationship between QT and TQ intervals) and hysteresis. However, some caveats based on observations may need to be considered due to inherent differences in QT intervals and sinus arrhythmia between canines and humans.