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

Abstract

Abstract. 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 druginduced 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 wellcharacterized 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.

Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters

“…The vasodilation effects of estrogen indirectly mask arrhythmic risks by protecting against cardiac ischemia-reperfusion injury (Murphy and Steenbergen, 2008). It has been reported in animal models that estrogen has a profound impact in some drug-induced long QT syndrome mainly by reducing repolarization reserve (Hara et al, 1998;Drici et al, 1998;Kurokawa et al, 2009;Saito et al, 2009). This study's findings clearly support that estrogen predisposes women to the development of druginduced arrhythmias by lengthening the QT interval.…”

Torsades de Pointes in Takotsubo Cardiomyopathy with QT Prolongation

“…Women are more prone to develop TdP than men either congenital or acquired LQTS, and it is similar to the sex difference of occurrence of Takotsubo cardiomyopathy. Although the precise mechanism has not been clarified, female hormone may exert the influence on cardiac repolarization process (Kurokawa et al, 2009). …”

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Diversity in the Excitation–Contraction Mechanisms of the Heart

“…A cardiac ion channel responsible for repolarization is known to be affected by sex hormones (10). This can at least partly explain the observed gender difference in susceptibility to the arrhythmogenic effects of QT-prolonging drugs.…”