Sex Hormones Prolong the QT Interval and Downregulate Potassium Channel Expression in the Rabbit Heart

BACKGROUND: Sex hormones are known to exert direct and indirect effects on cardiovascular function, but their effects on cardiac repolarization have not been elucidated. The repolarization phase of the cardiac action potential or QT interval of the ECG is regulated largely by potassium channels such as the delayed rectifier currents HK2 and IsK. METHODS AND RESULTS: The effects of ovariectomy (OVX) and estradiol (E2) or dihydrotestosterone (DHT) treatment were evaluated on HK2, HERG, and IsK mRNA levels, QT duration, and quinidine-induced changes in QT interval in isolated rabbit hearts. HK2 and 0.7-kilobase IsK mRNA were downregulated in cardiac ventricular tissue from OVX rabbits treated with either E2 or DHT. The QT interval was prolonged in E2- and DHT-treated animals (OVX + vehicle, 223 +/- 6 ms; OVX + DHT, 236 +/- 10 ms; and OVX + DHT, 245 +/- 6 ms; P < .05). CONCLUSIONS: The association between hormone-induced changes in baseline QT interval and the mRNA level for these channels suggests that sex hormones may play a critical role in regulating cardiac repolarization. However, the changes in baseline QT and potassium channel mRNA after hormone treatment were not concordant with the changes in QT interval after the infusion of quinidine, after which E2-treated animals responded similarly to controls (18.4 +/- 4.6% and 19.3 +/- 4.6% increase in QT interval, respectively) and DHT-treated animals exhibited less QT prolongation (11.4 +/- 3.8% increase; P < .03).