Download Another jigsaw piece in the complex picture of hormonal regulation

EDITORIAL
European Heart Journal (2016) 37, 651–653
doi:10.1093/eurheartj/ehv475
Another jigsaw piece in the complex picture of
hormonal regulation of cardiac repolarization
Katja E. Odening*
Heart Center University of Freiburg, Department of Cardiology and Angiology I, Freiburg, Germany
Online publish-ahead-of-print 20 September 2015
This editorial refers to ‘Estradiol regulates human
QT-interval: acceleration of cardiac repolarization by
enhanced KCNH2 membrane trafficking’†, by L. Anneken
et al., on page 640.
Albert Einstein once said, ‘The important thing is not to stop questioning
. . . It is enough if one tries merely to comprehend a little of this mystery
every day’. In this spirit, in their study presented in this issue, Anneken
et al.1 tried to add another jigsaw piece in the intriguing and complex
puzzle of sex hormones and cardiac repolarization.
For quite a while, sex differences in cardiac repolarization, with
longer QT intervals in adult women than in men, have been appreciated clinically. This phenomenon can be found in healthy subjects
and in patients with inherited long QT syndrome (LQTS) harbouring mutations in repolarizing ion channel genes.2 In addition, changes
in QT duration and the concomitant long QT –related arrhythmogenic risk have been observed during the menstrual cycle, pregnancy
and the post-partum phase,3,4 strongly suggesting a major role of sex
hormones in regulating cardiac repolarization.
The more we investigate potential mechanisms underlying these
sex hormone effects, however, the more complex is the picture that
emerges4 (Figure 1). This may be partly due to the fact that studies
have been performed in various species using various hormone concentrations,5 which can exert opposing effects on cardiac repolarization and arrhythmogenic risk,6,7 and partly due to the fact that
most studies focus on one ion channel/current at a time without
systematically assessing and integrating data on all ion currents.
Based on studies in rabbits and guinea pigs, it has been postulated
that sex differences in repolarizing voltage-gated rapid delayed
rectifier current IKr (HERG/KCNH2) are of major importance for
the observed sex differences in cardiac repolarization. Larger IKr
current densities have been observed in males than in females due
to a testosterone-mediated increase in IKr8 and an oestradiolmediated decrease in IKr,6 causing a longer QT/action potential
duration (APD) and a higher propensity of female hearts for long
QT –related arrhythmia. Similarly, in human cardiac tissue, reduced
mRNA and protein expression of KCNH2/HERG has been demonstrated in females compared vs. males.9 In addition, sex hormone
effects on voltage-gated slow delayed rectifier current IKs (increased
by testosterone and progesterone10,11) and on L-type Ca2+ current
ICa,L (decreased by testosterone and progesterone;7,10 – 12 increased
by oestradiol12,13) have been identified. These progesterone effects
on IKs and ICa,L and the consecutive QT/APD shortening are thought
to mainly account for the observed changes of QT interval during
the menstrual cycle and pregnancy.
Here, another seemingly diverging piece is introduced to this
complex picture by Anneken et al.1 In their detailed, elegantly performed study, they investigate the effect of oestradiol (physiological
levels during pregnancy and post-partum and high oestradiol levels
during clomiphene stimulation for infertility) on QT duration in
human subjects and assess oestradiol effects on IKr and KCNH2/
HERG channel trafficking in vitro in human embryonic kidney
(HEK) cells. Unexpectedly, and in contrast to our current knowledge, they identify a QT shortening with increasing oestradiol levels
along with increased KCNH2/HERG channel trafficking to the
membrane and increased IKr current densities. Even more intriguingly, no such effect on QT duration is seen with increasing progesterone levels, although the data of patients during pregnancy suggest a
negative correlation between progesterone levels and QT duration.
Here, further studies in larger patient cohorts are clearly warranted.
This study, and its pronounced differences compared with previous studies in animal models, demonstrates the importance of investigating mechanisms of sex hormone effects on repolarization in
human subjects and human tissue/cells to solve the complex riddle
of hormonal regulation of cardiac repolarization and arrhythmogenic risk. In the future, novel techniques such as induced pluripotent stem cell – derived cardiomyocytes might further help us to
reveal sex hormone effects in a ‘cardiomyocyte-like’ environment
rather than in heterologous expression systems.
The clinically observed distinct sex differences in cardiac repolarization and known sex hormone effects on various repolarizing ion
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
†
doi:10.1093/eurheartj/ehv371.
* Corresponding author. Heart Center University of Freiburg, Department of Cardiology and Angiology I, Hugstetter Str. 55, 79106 Freiburg, Germany. Tel: +49 761 270 32470,
Fax: +49 761 270 73090, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
652
Editorial
Figure 1 Oestradiol effects on cardiac ion channels/currents and action potential duration. Illustration of oestradiol effects on KCNH2/HERG
(IKr) and Cav1.2a channels (ICa,L) that are mediated either via oestradiol receptors or in a receptor-independent manner (information based
on1,6,12,13). Consecutive changes in action potential duration (APD) are depicted in insets. E2, oestradiol; E2 receptor, oestradiol receptor a;
HRE, hormone responsive element; Hsp90, heat-shock protein 90; ICa,L, L-type Ca2+ current; IK1, inward rectifier current; IKr, rapid delayed rectifier K+ current; IKs, slow delayed rectifier K+ current; INa, depolarizing Na+ current; Ito, transient outward K+ current; +, increase; –, decrease/
blockade; , prolongation of APD; , shortening of APD.
channels/currents suggest that, in the future, sex hormone – based
drugs might be utilized as novel anti-arrhythmic therapies. The
authors also state that the observed oestradiol-induced QT shortening could potentially be exploited as a therapeutic approach in LQTS.
However, this suggestion should be considered very cautiously and
might even be premature since oestradiol also exerts a contrasting
pronounced pro-arrhythmic effect, increasing the incidence of
ventricular arrhythmia and sudden cardiac death in transgenic
LQT2 rabbits due to increased ICa,L currents and early afterdepolarization formation.12 Before we better understand this complex interaction and species-dependent variations, it might be too early to
exploit hormonal treatment as an anti-arrhythmic therapeutic option.
Moreover, in general, it will be challenging to establish future sex hormone–based anti-arrhythmic therapies due to potential systemic side
effects via steroid receptors expressed in other organs and since
different synthetic hormone derivatives may have unspecific actions
via other sex hormone receptors. Several cases and clinical studies
have demonstrated that in contrast to pure progesterone,12 synthetic
progesterone derivatives that have additional partial oestradiolmimicking effects lack any anti-arrhythmic effects14 and that combined oestradiol–gestagene treatment as it is used for contraception
lacks effects on cardiac repolarization and arrhythmogenic risk.15
Overall, the complex hormonal impact on all major repolarizing
ion channels/currents and Ca2+ handling proteins, and their partly
contrasting and thus (simultaneously) pro- and anti-arrhythmic
effects, clearly warrant further detailed investigation. This article
adds an interesting, yet only partially fitting, piece to the puzzle.
However, if we listen to Isaac Asimov, who said ‘The most exciting
phrase to hear in science . . . is not ‘Eureka!’ but ‘That’s funny . . . ,’ ”
exciting times are ahead.
Acknowledgements
Special thanks to Dr Michael Brunner for his valuable comments
regarding this editorial.
Conflict of interest: The author declares no conflict of interest.
Editorial
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