New aspects for the treatment of cardiac diseases based on the diversity of functional controls on cardiac muscles: Acute effects of female hormones on cardiac ion channels and cardiac repolarization

Regulation of cardiac ion channels by sex hormones accounts for gender differences in susceptibility to arrhythmias associated with QT prolongation (TdP). Women are more prone to develop TdP than men with either congenital or acquired long-QT syndrome. The risk of drug- induced TdP varies during the menstrual cycle, suggesting that dynamic changes in levels of ovarian steroids, estradiol and progesterone, have cyclical effects on cardiac repolarization. Although increasing evidence suggests that the mechanism of this involves effects of female hormones on cardiac repolarization, it has not been completely clarified. In addition to well- characterized transcriptional regulation of cardiac ion channels and their modifiers through nuclear hormone receptors, we recently reported that physiological levels of female hormones modify functions of cardiac ion channels in mammalian hearts. In this review, we introduce our recent findings showing that physiological levels of the two ovarian steroids have opposite effects on cardiac repolarization. These findings may explain the dynamic changes in risk of arrhythmia in women during the menstrual cycle and around delivery, and they provide clues to avoiding potentially lethal arrhythmias associated with QT prolongation.