Abstract 931: Mechanisms of Gender-Related Differences in Susceptibility to Torsades de Pointes: Reverse Effects of Estrogen and Progesterone on Cardiac Repolarization
Women are at a greater risk of torsades de pointes (TdP) than men in both congenital and acquired long QT syndrome. The risk of drug-induced TdP varies during the menstrual cycle suggesting that the dynamic change in levels of ovarian steroids, estradiol (E2) and progesterone (Pg), cyclically influence action potential duration (APD). Although we have recently reported that testosterone shortens APD via a non-genomic pathway involving NO release from eNOS, acute effects of ovarian steroids on cardiac ion channels remained unclear. We therefore investigated acute effects of E2 and Pg on cardiac ion currents in whole-cell patch-clamped guinea pig ventricular myocytes and mammalian cell lines. E2 exhibited bi-directional effects on APD: E2 rapidly prolonged APD within physiological E2 levels in women (0.1–1 nM), whereas higher concentrations (>10 nM) of E2 shortened APD via a non-genomic pathway as similar to testosterone. E2-induced APD prolongation was attributable to inhibition of the cardiac IKr channel. E2 inhibited recombinant hERG currents (IC50; 0.72 nM) in HEK293T cells in which the estrogen receptor is not expressed suggesting receptor-independent blockade by a direct binding to the hERG channel. By contrast, Pg acutely enhanced IKs through the Pg receptor in a dose-dependent manner (EC50; 5.7 nM, Imax; 1.4-fold vs. Ctrl). IKs increase by Pg varied in the physiological Pg levels ranging from 3 nM in follicular phase to 25 nM in luteal phase. This is the first report that physiological levels of both ovarian steroids have reverse effects on cardiac repolarization: the Pg-induced IKs enhancement counterbalances the E2-induced IKr inhibition, which may create cyclic variation of cardiac repolarization in women. These data may explain dynamic changes of arrhythmia risk in women during the menstrual cycle and pregnancy, and can provide valid strategy to prevent arrhythmic events in congenital and drug-induced long QT syndrome.