Female gender is a risk factor for drug-induced long QT and cardiac arrhythmias in an in vivo rabbit model.
BACKGROUND
Clinical observations and in vitro experimental data indicate that females have a longer QT interval than males, which is associated with a higher risk of drug-induced cardiac arrhythmias. Little is known about this gender difference in anesthetized animals, which may affect the outcome of in vivo drug tests.


RESULTS
We evaluated potential gender differences in ventricular repolarization (QT, QTc, JT, and JTc interval) and its dispersion, as well as in its response to dofetilide, an IKr blocker, in anesthetized rabbits challenged with the alpha1-adrenoceptor agonist methoxamine. A 12-lead ECG was recorded during the experiments. At baseline, there were no significant gender differences in ventricular repolarization values in male and female rabbits under anesthesia. Dofetilide (0.04 mg/kg/min IV for 60 min; n = 10 per gender) produced marked prolongation of the ventricular repolarization time and its dispersion, associated with a high incidence of polymorphic ventricular tachycardia (PVT; 100% in females vs 80% in males) and ventricular fibrillation (VF; 80% in females vs 50% in males; P > 0.05). QT and JT interval at 2 minutes as well as QT and JT dispersion at 10 and 30 minutes during dofetilide infusion were significantly higher in female than in male rabbits. After 30 minutes of dofetilide infusion, 10 of 10 female rabbits had severe cardiac arrhythmias (complete AV block, PVT, or VF), so ECG parameters were impossible to assess (vs 3/10 males with severe cardiac arrhythmias; P < 0.05). During dofetilide infusion, female rabbits developed complete AV block, PVT, or VF at doses about 50% lower than those given to males.


CONCLUSIONS
The present study indicates that female rabbits are more susceptible to drug-induced long QT and cardiac arrhythmias than are male rabbits; therefore, female rabbits are more appropriate for testing drug-induced cardiac arrhythmias.
Lu
H R
HR
Department of Cardiovascular Safety Pharmacology, Janssen Research Foundation, Beerse, Belgium. hlu@janbe.jnj.com
Remeysen
P
P
Somers
K
K
Saels
A
A
De Clerck
F
F
D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000453:epidemiology; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D015994:Incidence; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000453:epidemiology; D008297:Male; D008729:Methoxamine / Q000008:administration & dosage / Q000819:agonists; D008955:Models, Cardiovascular; D010627:Phenethylamines / Q000008:administration & dosage; D011817:Rabbits; D018340:Receptors, Adrenergic, alpha-1 / Q000008:administration & dosage; D012307:Risk Factors; D012737:Sex Factors; D013449:Sulfonamides / Q000008:administration & dosage; D016896:Treatment Outcome; D016387:Women's Health
D058646:Adrenergic alpha-1 Receptor Agonists; D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides; D008729:Methoxamine; C063533:dofetilide