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Review
. 2016 Dec:168:23-28.
doi: 10.1016/j.pharmthera.2016.09.004. Epub 2016 Sep 4.

Sex hormonal regulation of cardiac ion channels in drug-induced QT syndromes

Junko Kurokawa  1 , Masami Kodama  2 , Colleen E Clancy  3 , Tetsushi Furukawa  2
Affiliations
Review

Sex hormonal regulation of cardiac ion channels in drug-induced QT syndromes

Junko Kurokawa et al. Pharmacol Ther. 2016 Dec.

Abstract

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. Clinical and experimental evidences suggest that the gender differences may be due to, at least in part, gender differences in regulation of rate-corrected QT (QTC) interval between men and women. In adult women, both QTC 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 actions, and sex differences in drug responses and metabolisms. In particular, non-genomic actions of testosterone and progesterone on cardiac ion channels are likely to contribute to the gender differences in cardiac repolarization processes. This review summarizes current knowledge on sex hormonal regulation of cardiac ion channels which contribute to cardiac repolarization processes and its implication for gender differences in drug-induced long QT syndromes.

Keywords: Arrhythmias; Cardiac repolarization; Gender difference; Sex hormones.

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Conflict of interest statement

Statement The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Scheme for mechanism underlying sex hormonal regulation of the L-type Ca2+ (ICa,L) channel, the rapid delayed rectifier K+ (IKr) channel and the slow delayed rectifier K+ (IKs) channel. HR; hormone receptor, βAR; beta-adrenergic receptor, AC; adenylate cyclase, PDE; phosphodiesterase, L-Arg; L-arginine, L-Cit; L-citrulline, sGC; soluble guanylyl cyclase. βAR stimulation involves in modulation of ICa,L through a non-genomic pathway of progesterone receptor(Nakamura et al., 2007).
Figure 2
Figure 2
Site specific effect of estrogen alters sensitivity of a selective HERG blocker, E4031. A. A scheme shows that Phe656 (F656) but not Tyr652 (Y652), a common drug-binding site for the hERG, is important for the suppression by some estrogens (E2 and E1S)(Kakusaka et al., 2009; Kurokawa et al., 2008). B. E2 but not DHT (dihydrotestosterone) shifted concentration-dependent curves of HERG inhibition by E4031.. HERG currents were recorded from HEK293 cells overexpressing the hERG channel. E2 at 0.3, 1, 3 nM increased the E4031-induced fractional inhibition (*P<0.05 vs. control, and vs. DHT), while DHT did not (n.s. vs. control)(Kurokawa et al., 2008). C. Estrogen-null in CYP19 KO mice reduced the E-4031-induced QTc prolongation. Prolongation of QTc intervals in response to the cumulative administration of E-4031 were compared between late-proestrus female mice (open circles) and aromatase knockout mice (CYP19 KO, closed circles). Modified from(Kurokawa et al., 2015).
See this image and copyright information in PMC

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