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Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes
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ANDO-1159; No. of Pages 2
Annales d’Endocrinologie xxx (2020) xxx–xxx
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Klotz communication 2020: Heart and Hormones
Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes夽 J.E. Salem a,b,c,∗ , T. Yang b,c , J.J. Moslehi b , X. Waintraub a , E. Gandjbakhch a , A. Bachelot d , F. Hidden-Lucet a , J.S. Hulot e , B.C. Knollmann b,c , B. Lebrun-Vignes a , C. Funck-Brentano a , A.M. Glazer b , D.M. Roden b,c,f a Assistance Publique Hopitaux de Paris, Pitié-Salpêtriére Hospital, Departments of Pharmacology and Cardiology, UNICO-GRECO Cardio-oncology Program, Centre d’investigation clinique-1421, Pharmacovigilance Unit, Inserm, Sorbonne Université, Paris, France b Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA c Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA d IE3 M, Department of Endocrinology and Reproductive Medicine, and Centre de Référence des Maladies Endocriniennes Rares de la croissance et Centre des Pathologies gynécologiques Rares, Inserm, Sorbonne Université, Paris, France e Université Paris-Descartes, Sorbonne Paris Cité Paris Cardiovascular Research Center, Institut national de la santé et de la recherche médicale UMRS 970, Hôpital Européen Georges Pompidou, AP-HP, Paris, France f Department of Biomedical Informatics, Vanderbilt University Medical Center, Vanderbilt University Medical Center, Nashville, TN, USA
a r t i c l e
i n f o
a b s t r a c t Background. – Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. Methods. – We searched the international pharmacovigilance database VigiBase for men (n = 6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone. Results. – Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n = 168) and/or TdP (n = 68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio = 1.4–4.7; P < 0.05) with aLQTS, TdP, or sudden death. The minimum and median times to sudden death were 0.25 and 92 days, respectively. The androgen receptor antagonist enzalutamide was associated with more deaths (5430/31 896 [17%]; P < 0.0001) than other ADT used for prostate cancer (4208/52 089 [8.1%]). In induced pluripotent stem cells, acute and chronic enzalutamide (25 M) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5 Hz; 429.7 ± 27.1 (control) versus 982.4 ± 33.2 (acute, P < 0.001) and 1062.3 ± 28.9 ms (chronic; P < 0.001), and generated afterdepolarizations and/or triggered activity in drug-treated cells (11/20 acutely and 8/15 chronically). Enzalutamide acutely and chronically inhibited delayed rectifier potassium current, and chronically enhanced late sodium current. Dihydrotestosterone (30 nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells. Conclusion. – QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs. Clinical trial registration. – URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138. © 2020 Published by Elsevier Masson SAS.
夽 Please cite this abstract as: Androgenic Effects on Ventricular Repolarization: A Translational Study From the International Pharmacovigilance Database to iPSCCardiomyocytes. Salem JE, Yang T, Moslehi JJ, Waintraub X, Gandjbakhch E, Bachelot A, Hidden-Lucet F, Hulot JS, Knollmann BC, Lebrun-Vignes B, Funck-Brentano C, Glazer AM, Roden DM. Circulation. 2019 Sep 24;140(13):1070-1080. doi: 10.1161/CIRCULATIONAHA.119.040162. Epub 2019 Aug 5. ∗ Corresponding author at: Hôpital La Pitié-Salpêtrière, Centre d’Investigation Clinique Paris-Est, 47–83, boulevard de l’Hôpital, 75651 Paris, France. E-mail address: [email protected] (J.E. Salem). https://doi.org/10.1016/j.ando.2020.02.008 0003-4266/© 2020 Published by Elsevier Masson SAS.
Please cite this article in press as: Salem JE, et al. Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes. Ann Endocrinol (Paris) (2020), https://doi.org/10.1016/j.ando.2020.02.008
G Model ANDO-1159; No. of Pages 2
ARTICLE IN PRESS J.E. Salem et al. / Annales d’Endocrinologie xxx (2020) xxx–xxx
2
Disclosure of interest The author declares that he has no competing interest.
Please cite this article in press as: Salem JE, et al. Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes. Ann Endocrinol (Paris) (2020), https://doi.org/10.1016/j.ando.2020.02.008
ARTICLE IN PRESS
ANDO-1159; No. of Pages 2
Annales d’Endocrinologie xxx (2020) xxx–xxx
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
Klotz communication 2020: Heart and Hormones
Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes夽 J.E. Salem a,b,c,∗ , T. Yang b,c , J.J. Moslehi b , X. Waintraub a , E. Gandjbakhch a , A. Bachelot d , F. Hidden-Lucet a , J.S. Hulot e , B.C. Knollmann b,c , B. Lebrun-Vignes a , C. Funck-Brentano a , A.M. Glazer b , D.M. Roden b,c,f a Assistance Publique Hopitaux de Paris, Pitié-Salpêtriére Hospital, Departments of Pharmacology and Cardiology, UNICO-GRECO Cardio-oncology Program, Centre d’investigation clinique-1421, Pharmacovigilance Unit, Inserm, Sorbonne Université, Paris, France b Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA c Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA d IE3 M, Department of Endocrinology and Reproductive Medicine, and Centre de Référence des Maladies Endocriniennes Rares de la croissance et Centre des Pathologies gynécologiques Rares, Inserm, Sorbonne Université, Paris, France e Université Paris-Descartes, Sorbonne Paris Cité Paris Cardiovascular Research Center, Institut national de la santé et de la recherche médicale UMRS 970, Hôpital Européen Georges Pompidou, AP-HP, Paris, France f Department of Biomedical Informatics, Vanderbilt University Medical Center, Vanderbilt University Medical Center, Nashville, TN, USA
a r t i c l e
i n f o
a b s t r a c t Background. – Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. Methods. – We searched the international pharmacovigilance database VigiBase for men (n = 6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone. Results. – Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n = 168) and/or TdP (n = 68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio = 1.4–4.7; P < 0.05) with aLQTS, TdP, or sudden death. The minimum and median times to sudden death were 0.25 and 92 days, respectively. The androgen receptor antagonist enzalutamide was associated with more deaths (5430/31 896 [17%]; P < 0.0001) than other ADT used for prostate cancer (4208/52 089 [8.1%]). In induced pluripotent stem cells, acute and chronic enzalutamide (25 M) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5 Hz; 429.7 ± 27.1 (control) versus 982.4 ± 33.2 (acute, P < 0.001) and 1062.3 ± 28.9 ms (chronic; P < 0.001), and generated afterdepolarizations and/or triggered activity in drug-treated cells (11/20 acutely and 8/15 chronically). Enzalutamide acutely and chronically inhibited delayed rectifier potassium current, and chronically enhanced late sodium current. Dihydrotestosterone (30 nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells. Conclusion. – QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs. Clinical trial registration. – URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138. © 2020 Published by Elsevier Masson SAS.
夽 Please cite this abstract as: Androgenic Effects on Ventricular Repolarization: A Translational Study From the International Pharmacovigilance Database to iPSCCardiomyocytes. Salem JE, Yang T, Moslehi JJ, Waintraub X, Gandjbakhch E, Bachelot A, Hidden-Lucet F, Hulot JS, Knollmann BC, Lebrun-Vignes B, Funck-Brentano C, Glazer AM, Roden DM. Circulation. 2019 Sep 24;140(13):1070-1080. doi: 10.1161/CIRCULATIONAHA.119.040162. Epub 2019 Aug 5. ∗ Corresponding author at: Hôpital La Pitié-Salpêtrière, Centre d’Investigation Clinique Paris-Est, 47–83, boulevard de l’Hôpital, 75651 Paris, France. E-mail address: [email protected] (J.E. Salem). https://doi.org/10.1016/j.ando.2020.02.008 0003-4266/© 2020 Published by Elsevier Masson SAS.
Please cite this article in press as: Salem JE, et al. Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes. Ann Endocrinol (Paris) (2020), https://doi.org/10.1016/j.ando.2020.02.008
G Model ANDO-1159; No. of Pages 2
ARTICLE IN PRESS J.E. Salem et al. / Annales d’Endocrinologie xxx (2020) xxx–xxx
2
Disclosure of interest The author declares that he has no competing interest.
Please cite this article in press as: Salem JE, et al. Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes. Ann Endocrinol (Paris) (2020), https://doi.org/10.1016/j.ando.2020.02.008