Female Gender is a Risk Factor for Drug-Induced Long QT and Early Afterdepolarizations (EADS) in Anesthetized Dogs

Abstract

Clinical observations and experimental data in isolated rabbit and dog Purkinje fibers and in vivo in rabbits indicate that female gender is more sensitive to drug-induced long QT and cardiac arrhythmia. However, to-date there has been no demonstration of a gender difference in vivo in dogs and therefore male dogs tend to be the chosen sex for cardiovascular safety pharmacology tests. As such, this may potentially lead to wrong conclusions on the QT-related arrhythmogenic risk of a new chemical entity. Methods and Results We evaluated potential gender differences in the following variables, in neuromuscular blocked, mechanically ventilated anesthetized dogs: ventricular repolarization (ECG lead II, QT and QTcV; right ventricular endocardial monophasic action potential (MAP), duration at 90% repolarization, APD90 and APD90cV), spatial dispersion of the T wave (Tp-Te), instability of QTend (QT TI: total instability) and occurrence of EADs on the MAP signal. These parameters were derived from continuous recording of ECG and MAP signals. 20 female and 18 male dogs were treated with dofetilide (0.05 mg/kg i.v. infusion over 10 min). At baseline, there was no statistically significant gender difference observed in the values of the various parameters, while dofetilide infusion produced marked prolongation. Median maximum percentage changes of baseline in females versus males were respectively: heart rate (+3% / +6%, ns ), QT (+23% / +14%, p = 0.003 ), QTcV (+20% / +15%, p = 0.03 ), APD90 (+26% / +17%, p = 0.006 ), and APD90cV (+24% / +18%, p = 0.009 ). In addition, dofetilide tended to differently increase Tp-Te (+40% / +23%, ns ) and QT TI (+150% / +104%, ns ), more in female than in male animals. Furthermore, dofetilide infusion elicited more incidences of EADs on the MAP signal in female than in male dogs (73% versus 48%). Conclusion The present study confirms that female gender may be a risk factor for drug-induced long QT in the dog. Indeed, since significant alterations in additional markers beyond QT interval itself are more pronounced in female dogs and EADs occur more frequently in this sex, female dogs could be more sensitive to induction of polymorphic ventricular tachycardia (TdP). As such, consideration should be given to incorporation of female dogs into standard cardiovascular safety evaluations, or at least be the chosen single sex for drug safety evaluation for the identification of QT/TdP related adverse effects.