Estradiol regulates human QT-interval: acceleration of cardiac repolarization by enhanced KCNH2 membrane trafficking

Modulation of cardiac repolarization by sexual hormones is controversial and hormonal effects on ion channels remain largely unknown. In the present translational study, we therefore assessed the relationship between QTc duration and gonadal hormones and studied underlying mechanisms. We measured ho...

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Published in:European heart journal 2016-02, Vol.37 (7), p.640-650
Main Authors: Anneken, Lars, Baumann, Stefan, Vigneault, Patrick, Biliczki, Peter, Friedrich, Corinna, Xiao, Ling, Girmatsion, Zenawit, Takac, Ina, Brandes, Ralf P, Kissler, Stefan, Wiegratz, Inka, Zumhagen, Sven, Stallmeyer, Birgit, Hohnloser, Stefan H, Klingenheben, Thomas, Schulze-Bahr, Eric, Nattel, Stanley, Ehrlich, Joachim R
Format: Article
Language:English
Subjects:
Adult
Basic Science
Benzoquinones - pharmacology
Clomiphene - therapeutic use
Electrocardiography
Enzyme Inhibitors - pharmacology
ERG1 Potassium Channel - genetics
ERG1 Potassium Channel - metabolism
Estradiol - metabolism
Estradiol - physiology
Female
Fertility Agents, Female - therapeutic use
Healthy Volunteers
Heart Conduction System - drug effects
Heterozygote
Humans
Infertility, Female - genetics
Lactams, Macrocyclic - pharmacology
Long QT Syndrome - genetics
Menstrual Cycle
Mutation, Missense - genetics
Pregnancy
Pregnancy Complications, Cardiovascular - genetics
Prospective Studies
Protein Transport - genetics
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Summary:Modulation of cardiac repolarization by sexual hormones is controversial and hormonal effects on ion channels remain largely unknown. In the present translational study, we therefore assessed the relationship between QTc duration and gonadal hormones and studied underlying mechanisms. We measured hormone levels and QTc intervals in women during clomiphene stimulation for infertility and women before, during, and after pregnancy. Three heterozygous LQT-2 patients (KCNH2-p.Arg752Pro missense mutation) and two unaffected family members additionally were studied during their menstrual cycles. A comprehensive cellular and molecular analysis was done to identify the mechanisms of hormonal QT-interval regulation. High estradiol levels, but neither progesterone nor estradiol/progesterone ratio, inversely correlated with QTc. Consistent with clinical data, in vitro estradiol stimulation (60 pmol/L, 48 h) enhanced IKCNH2. This increase was mediated by estradiol receptor-α-dependent promotion of KCNH2-channel trafficking to the cell membrane. To study the underlying mechanism, we focused on heat-shock proteins. The heat-shock protein-90 (Hsp90) inhibitor geldanamycin abolished estradiol-induced increase in IKCNH2. Geldanamycin had no effect on KCNH2 transcription or translation; nor did it affect expression of estradiol receptors and chaperones. Estradiol enhanced the physical interaction of KCNH2-channel subunits with heat-shock proteins and augmented ion-channel trafficking to the membrane. Elevated estradiol levels were associated with shorter QTc intervals in healthy women and female LQT-2 patients. Estradiol acts on KCNH2 channels via enhanced estradiol-receptor-α-mediated Hsp90 interaction, augments membrane trafficking and thereby increases repolarizing current. These results provide mechanistic insights into hormonal control of human ventricular repolarization and open novel therapeutic avenues.
ISSN:0195-668X
1522-9645
DOI:10.1093/eurheartj/ehv371