Key result
Absolute QT variability parameters indicated increased proarrhythmic liability in isolated rabbit hearts with reduced repolarization reserve, even when arrhythmias compromised sinus measurements.
Absolute QT variability parameters are sensitive surrogates for torsades de pointes in drug-safety investigations using isolated rabbit hearts with attenuated repolarization reserve.
Isolated hearts with reduced repolarization reserve would be suitable for assessing the proarrhythmic liability of drugs. However, it is not known which proarrhythmia biomarkers indicate the increased susceptibility to torsades de pointes arrhythmia (TdP) in such experimental setting. Thus, we estimated the efficacy of proarrhythmia biomarkers in isolated hearts with attenuated repolarization reserve. Langendorff-perfused rabbit hearts were used. Repolarization reserve was reduced by concomitant inhibition of the rapid (IKr) and slow (IKs) delayed rectifier potassium currents by dofetilide and HMR-1556, respectively. Rate corrected QT (QTc) interval and beat-to-beat variability of the QT interval measured in sinus rhythm or irrespective of rhythm even during arrhythmias (sinus and absolute QT variability, respectively) were tested. QTc failed to predict increased proarrhythmic risk. Sinus QT variability indicated proarrhythmic liability when low concentration of dofetilide was used. However, when arrhythmias compromised sinus variability measurement during coperfusion of catecholamines and elevated concentration of dofetilide, only absolute QT variability indicated increased proarrhythmic risk. Absolute QT variability parameters seem to be the most practical and sensitive biomarkers of proarrhythmic liability in rabbit hearts with reduced repolarization reserve. Absolute QT variability parameters could serve as surrogates for torsades de pointes in drug-safety investigations in isolated rabbit hearts with attenuated repolarization reserve.
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Orosz et al. (2014) studied Attenuated repolarization reserve (experimental proarrhythmia model) (n=52). Dofetilide and HMR-1556 vs. Vehicle or dofetilide alone was evaluated on Efficacy of proarrhythmia biomarkers (QTc, sinus QT variability, absolute QT variability) to indicate increased proarrhythmic liability. Absolute QT variability parameters indicated increased proarrhythmic liability in isolated rabbit hearts with reduced repolarization reserve, even when arrhythmias compromised sinus measurements.
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