Non-genomic Action of Sex Steroid Hormones and Cardiac Repolarization

Abstract

Gender differences play a major role in the manifestation of cardiovascular disease including cardiac arrhythmias. In particular, female sex is an independent risk factor for development of torsade de pointes (TdP) arrhythmias not only in congenital long QT syndromes but also in acquired long QT syndromes which occur as adverse effects of existing drugs. Recent clinical and experimental studies suggest that the gender differences may stem, at least in part, from gender differences in cardiac repolarization process, that is longer rate-corrected QT (QT(C)) interval in women than in men. In women, QT(C) interval and arrhythmic risks in TdP alter cyclically during menstrual cycle, suggesting a critical role of female sex hormones in cardiac repolarization process. These gender differences in fundamental cardiac electrophysiology result from variable ion channel expression and diverse sex hormonal regulation via long term genomic and acute non-genomic pathways, and sex differences in drug responses and metabolisms. In particular, non-genomic actions of testosterone and progesterone on cardiac ion channels likely to contribute to the gender differences in cardiac repolarization processes.

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

“…Thus, these in vitro data strongly suggest that the direct binding of estrogen to the hERG channel results in hERG suppression and increased E-4031 sensitivity. These data are consistent with the previously shown E2-induced delay of cardiac repolarization in rabbits and ibutilide-induced QT C prolongation in the late follicular phase of women (Kurokawa and Furukawa, 2013;Hara et al, 1998;Rodriguez et al, 2001). However, there is no in vivo proof-of-concept that supports the impact of estrogen-induced hERG suppression on repolarization process of the heart.…”

Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women

“…Numerous medications can prolong the QT interval, such as antiarrhythimcs, anti‐infective drugs, antipsychotics, gastrokinetic stimulants, antihistaminics and opioid analgesics. Notably, the SGDs in QT duration are age‐ and hormone‐dependent (Kurokawa and Furukawa, ). Susceptibility to drug‐induced arrhythmias is higher when the oestrogen level is higher (James et al ., ) and lower when the progesterone level is high (Janse de Jonge et al ., ; Nakagawa et al ., ).…”

Sex differences in cardiac electrophysiology

“…Approximately 65 -75 % of all drug-induced LQTS occur in women (Kurokawa and Furukawa 2013;Makkar et al 1993). The drugs involved are not only medications for treatment of cardiovascular diseases (e.g.…”

“…The question whether the increased risk of drug-associated arrhythmia in women is due to the ~20-ms longer baseline QTc value (Kurokawa and Furukawa 2013) or is related to an intrinsic female property of the cardiovascular system has been addressed by investigating the response to a single oral dose of racemic sotalol (d,lsotalol) in men and women (Darpo et al 2014). In women, mean peak plasma concentration after a therapeutic dose of 160 mg was 128.5 % and the plasma concentration-time integral (area-under-the curve, AUC) was 117.1% of that in men.…”