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Female Gender is a Risk Factor for Drug‐Induced Long QT and Cardiac Arrhythmias in an In Vivo Rabbit Model
Author(s) -
LU HUA RONG,
REMEYSEN PAUL,
SOMERS KATRIEN,
SAELS AN,
CLERCK FRED
Publication year - 2001
Publication title -
journal of cardiovascular electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.193
H-Index - 138
eISSN - 1540-8167
pISSN - 1045-3873
DOI - 10.1046/j.1540-8167.2001.00538.x
Subject(s) - dofetilide , medicine , qt interval , ventricular tachycardia , cardiology , repolarization , ventricular fibrillation , afterdepolarization , torsades de pointes , proarrhythmia , anesthesia , electrophysiology
Gender Differences in Drug‐Induced LQT and TdP.Introduction: 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. Methods and 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 I Kr blocker, in anesthetized rabbits challenged with the α 1 ‐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. Conclusion: 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.