Lars Anneken1, Stefan Baumann2, Patrick Vigneault3, Peter Biliczki4, Corinna Friedrich5, Ling Xiao3, Zenawit Girmatsion4, Ina Takac6, Ralf P Brandes6, Stefan Kissler4, Inka Wiegratz7, Sven Zumhagen5, Birgit Stallmeyer5, Stefan H Hohnloser4, Thomas Klingenheben8, Eric Schulze-Bahr5, Stanley Nattel3, Joachim R Ehrlich9. 1. Universitätsklinikum, Goethe-Universität, Frankfurt, Germany Universitätsklinikum Erlangen, Erlangen, Germany. 2. Universitätsklinikum, Goethe-Universität, Frankfurt, Germany Universitätsklinikum Mannheim, Mannheim, Germany. 3. Montreal Heart Institute and Université de Montréal, Montréal, Canada. 4. Universitätsklinikum, Goethe-Universität, Frankfurt, Germany. 5. Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany. 6. Cardiovascular Physiology, Goethe-Universität, Frankfurt, Germany. 7. Universitätsklinikum, Goethe-Universität, Frankfurt, Germany Kinderwunschpraxis am Goetheplatz, Frankfurt, Germany. 8. Universitätsklinikum, Goethe-Universität, Frankfurt, Germany Praxis für Kardiologie, Bonn, Germany. 9. Universitätsklinikum, Goethe-Universität, Frankfurt, Germany Division of Cardiology, St. Josefs-Hospital, Wiesbaden, Germany joachimehrlich@t-online.de.
Abstract
BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
BACKGROUND: 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. METHODS AND RESULTS: We measured hormone levels and QTc intervals in women during clomiphene stimulation for infertility and women before, during, and after pregnancy. Three heterozygous LQT-2patients (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. CONCLUSION: Elevated estradiol levels were associated with shorter QTc intervals in healthy women and female LQT-2patients. 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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