Androgenic Effects on Ventricular Repolarization: A Translational Study From the International Pharmacovigilance Database to iPSC-Cardiomyocytes
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 un...
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| Published in | Circulation (New York, N.Y.) Vol. 140; no. 13; pp. 1070 - 1080 |
|---|---|
| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
by the American College of Cardiology Foundation and the American Heart Association, Inc
24.09.2019
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0009-7322 1524-4539 1524-4539 |
| DOI | 10.1161/CIRCULATIONAHA.119.040162 |
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| Abstract | 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 µM) 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.
CONCLUSIONS:QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT03193138. |
|---|---|
| AbstractList | 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 µM) 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.
CONCLUSIONS:QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT03193138. 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. 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. 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; <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%]; <0.0001) than other ADT used for prostate cancer (4208/52 089 [8.1%]). In induced pluripotent stem cells, acute and chronic enzalutamide (25 µM) 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, <0.001) and 1062.3±28.9 ms (chronic; <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. QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs. URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138. 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.BACKGROUNDMale 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.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.METHODSWe 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.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 µM) 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.RESULTSAmong 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 µM) 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.QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs.CONCLUSIONSQT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs.URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.CLINICAL TRIAL REGISTRATIONURL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138. |
| Author | Yang, Tao Knollmann, Bjorn C. Hulot, Jean-Sebastien Funck-Brentano, Christian Roden, Dan M. Glazer, Andrew M. Gandjbakhch, Estelle Hidden-Lucet, Francoise Salem, Joe-Elie Moslehi, Javid J. Bachelot, Anne Waintraub, Xavier Lebrun-Vignes, Benedicte |
| AuthorAffiliation | Assitance Publique Hopitaux de Paris, Pitié-Salpêtriére Hospital, Departments of Pharmacology and Cardiology, UNICO-GRECO Cardio-oncology Program, Centre d’investigation clinique-1421, Pharmacovigilance Unit (J-E.S., X.W., E.G., F.H-L., B.L-V., C.F-B.), INSERM, Sorbonne Université, Paris, France. IE3M, Department of Endocrinology and Reproductive Medicine, and Centre de Référence des Maladies Endocriniennes Rares de la croissance et Centre des Pathologies gynécologiques Rares (A.B.), INSERM, Sorbonne Université, Paris, France. Department of Medicine (J-E.S., T.Y., J.J.M., B.C.K., A.M.G., D.M.R.), Vanderbilt University Medical Center, Nashville, TN. Department of Pharmacology (J-E.S., T.Y., B.C.K., D.M.R.), Vanderbilt University Medical Center, Nashville, TN. Department of Biomedical Informatics, Vanderbilt University Medical Center (D.M.R.), Vanderbilt University Medical Center, Nashville, TN. Université Paris-Descartes, Sorbonne Paris Cité Paris Cardiovascular Research Center, Institu |
| AuthorAffiliation_xml | – name: Assitance Publique Hopitaux de Paris, Pitié-Salpêtriére Hospital, Departments of Pharmacology and Cardiology, UNICO-GRECO Cardio-oncology Program, Centre d’investigation clinique-1421, Pharmacovigilance Unit (J-E.S., X.W., E.G., F.H-L., B.L-V., C.F-B.), INSERM, Sorbonne Université, Paris, France. IE3M, Department of Endocrinology and Reproductive Medicine, and Centre de Référence des Maladies Endocriniennes Rares de la croissance et Centre des Pathologies gynécologiques Rares (A.B.), INSERM, Sorbonne Université, Paris, France. Department of Medicine (J-E.S., T.Y., J.J.M., B.C.K., A.M.G., D.M.R.), Vanderbilt University Medical Center, Nashville, TN. Department of Pharmacology (J-E.S., T.Y., B.C.K., D.M.R.), Vanderbilt University Medical Center, Nashville, TN. Department of Biomedical Informatics, Vanderbilt University Medical Center (D.M.R.), Vanderbilt University Medical Center, Nashville, TN. 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 (J-S-.H.) – name: 4 AP-HP, Pitié-Salpêtrière Hospital, IE3M, 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 Universités, F-75013 Paris, France – name: 3 Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA – name: 1 AP-HP, Pitié-Salpêtrière Hospital, Departments of Pharmacology and Cardiology, Cardio-oncology Program, CIC-1421, Pharmacovigilance Unit ; INSERM, Sorbonne Université, F-75013 Paris, France – name: 5 Université Paris-Descartes, Sorbonne Paris Cité; Paris Cardiovascular Research Center (PARCC), INSERM UMRS 970; Hôpital Européen Georges Pompidou, AP-HP, Paris, France – name: 6 Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA – name: 2 Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA |
| Author_xml | – sequence: 1 givenname: Joe-Elie surname: Salem fullname: Salem, Joe-Elie organization: Assitance Publique Hopitaux de Paris, Pitié-Salpêtriére Hospital, Departments of Pharmacology and Cardiology, UNICO-GRECO Cardio-oncology Program, Centre d’investigation clinique-1421, Pharmacovigilance Unit (J-E.S., X.W., E.G., F.H-L., B.L-V., C.F-B.), INSERM, Sorbonne Université, Paris, France. IE3M, Department of Endocrinology and Reproductive Medicine, and Centre de Référence des Maladies Endocriniennes Rares de la croissance et Centre des Pathologies gynécologiques Rares (A.B.), INSERM, Sorbonne Université, Paris, France. Department of Medicine (J-E.S., T.Y., J.J.M., B.C.K., A.M.G., D.M.R.), Vanderbilt University Medical Center, Nashville, TN. Department of Pharmacology (J-E.S., T.Y., B.C.K., D.M.R.), Vanderbilt University Medical Center, Nashville, TN. Department of Biomedical Informatics, Vanderbilt University Medical Center (D.M.R.), Vanderbilt University Medical Center, Nashville, TN. 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 (J-S-.H.) – sequence: 2 givenname: Tao surname: Yang fullname: Yang, Tao – sequence: 3 givenname: Javid surname: Moslehi middlename: J. fullname: Moslehi, Javid J. – sequence: 4 givenname: Xavier surname: Waintraub fullname: Waintraub, Xavier – sequence: 5 givenname: Estelle surname: Gandjbakhch fullname: Gandjbakhch, Estelle – sequence: 6 givenname: Anne surname: Bachelot fullname: Bachelot, Anne – sequence: 7 givenname: Francoise surname: Hidden-Lucet fullname: Hidden-Lucet, Francoise – sequence: 8 givenname: Jean-Sebastien surname: Hulot fullname: Hulot, Jean-Sebastien – sequence: 9 givenname: Bjorn surname: Knollmann middlename: C. fullname: Knollmann, Bjorn C. – sequence: 10 givenname: Benedicte surname: Lebrun-Vignes fullname: Lebrun-Vignes, Benedicte – sequence: 11 givenname: Christian surname: Funck-Brentano fullname: Funck-Brentano, Christian – sequence: 12 givenname: Andrew surname: Glazer middlename: M. fullname: Glazer, Andrew M. – sequence: 13 givenname: Dan surname: Roden middlename: M. fullname: Roden, Dan M. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31378084$$D View this record in MEDLINE/PubMed |
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| Keywords | androgen antagonists torsades de pointes hypogonadism long QT syndrome testosterone |
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| References | e_1_3_4_3_2 e_1_3_4_2_2 Salem J-E (e_1_3_4_30_2) e_1_3_4_9_2 e_1_3_4_8_2 e_1_3_4_7_2 e_1_3_4_6_2 e_1_3_4_5_2 e_1_3_4_4_2 e_1_3_4_22_2 e_1_3_4_23_2 e_1_3_4_20_2 e_1_3_4_21_2 e_1_3_4_27_2 e_1_3_4_24_2 e_1_3_4_25_2 e_1_3_4_28_2 e_1_3_4_29_2 e_1_3_4_11_2 e_1_3_4_34_2 e_1_3_4_12_2 e_1_3_4_33_2 e_1_3_4_32_2 e_1_3_4_10_2 e_1_3_4_31_2 e_1_3_4_15_2 Khan A (e_1_3_4_26_2) 2016; 129 e_1_3_4_38_2 e_1_3_4_16_2 e_1_3_4_37_2 e_1_3_4_13_2 e_1_3_4_36_2 e_1_3_4_14_2 e_1_3_4_35_2 e_1_3_4_19_2 e_1_3_4_17_2 e_1_3_4_18_2 e_1_3_4_39_2 32011924 - Circulation. 2020 Feb 4;141(5):e61-e62 32011925 - Circulation. 2020 Feb 4;141(5):e63-e64 |
| References_xml | – ident: e_1_3_4_5_2 doi: 10.1161/01.CIR.0000048142.85076.A2 – ident: e_1_3_4_18_2 doi: 10.1177/009286150804200501 – ident: e_1_3_4_20_2 doi: 10.1136/heartjnl-2017-312934 – ident: e_1_3_4_21_2 doi: 10.1093/eurheartj/ehi092 – ident: e_1_3_4_7_2 doi: 10.1371/journal.pone.0181875 – ident: e_1_3_4_12_2 doi: 10.1016/j.pharmthera.2016.07.005 – ident: e_1_3_4_14_2 doi: 10.1210/jc.2016-3669 – ident: e_1_3_4_29_2 doi: 10.1126/scitranslmed.3003623 – ident: e_1_3_4_30_2 article-title: Clinical characterization of men with long QT syndrome and torsade de pointes associated with hypogonadism: a review and pharmacovigilance study. publication-title: Arch Cardiovasc Dis – ident: e_1_3_4_8_2 doi: 10.1161/CIRCULATIONAHA.113.007765 – ident: e_1_3_4_32_2 doi: 10.1056/NEJMoa1800536 – ident: e_1_3_4_37_2 doi: 10.1016/j.pharmthera.2018.04.009 – ident: e_1_3_4_24_2 doi: 10.1007/s40262-015-0271-5 – ident: e_1_3_4_39_2 doi: 10.1093/eurheartj/ehz023 – ident: e_1_3_4_25_2 – ident: e_1_3_4_23_2 doi: 10.3389/fphys.2012.00089 – ident: e_1_3_4_11_2 doi: 10.1210/jc.2016-1877 – ident: e_1_3_4_22_2 doi: 10.1093/cvr/cvz020 – ident: e_1_3_4_36_2 doi: 10.1093/eurheartj/ehw211 – ident: e_1_3_4_17_2 doi: 10.1536/ihj.18-127 – ident: e_1_3_4_35_2 doi: 10.1161/CIRCULATIONAHA.109.192695 – ident: e_1_3_4_2_2 doi: 10.1056/NEJMra032426 – ident: e_1_3_4_3_2 doi: 10.1016/0735-1097(94)90410-3 – ident: e_1_3_4_34_2 doi: 10.1002/pds.3474 – ident: e_1_3_4_16_2 doi: 10.1210/js.2018-00039 – volume: 129 start-page: 124 year: 2016 ident: e_1_3_4_26_2 article-title: Life threatening torsades de pointes due to abiraterone-induced hypokaelemia in a patient with metastatic prostate cancer. publication-title: N Z Med J – ident: e_1_3_4_31_2 doi: 10.1056/NEJMoa1405095 – ident: e_1_3_4_19_2 doi: 10.1145/1081870.1081923 – ident: e_1_3_4_9_2 doi: 10.1001/jama.1993.03510210076031 – ident: e_1_3_4_15_2 doi: 10.1161/CIRCULATIONAHA.118.034282 – ident: e_1_3_4_10_2 doi: 10.1016/j.amjcard.2008.11.041 – ident: e_1_3_4_13_2 doi: 10.1001/jamacardio.2018.2251 – ident: e_1_3_4_33_2 doi: 10.1111/bju.13123 – ident: e_1_3_4_28_2 doi: 10.1124/jpet.117.246157 – ident: e_1_3_4_4_2 doi: 10.1097/00005344-200111000-00010 – ident: e_1_3_4_6_2 doi: 10.1038/clpt.2010.51 – ident: e_1_3_4_38_2 doi: 10.1056/NEJM199401133300208 – ident: e_1_3_4_27_2 doi: 10.1038/s41598-017-18650-x – reference: 32011925 - Circulation. 2020 Feb 4;141(5):e63-e64 – reference: 32011924 - Circulation. 2020 Feb 4;141(5):e61-e62 |
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| Snippet | BACKGROUND:Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for... Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT... |
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| SubjectTerms | Androgens - metabolism Antineoplastic Agents - adverse effects Antineoplastic Agents - therapeutic use Cell Differentiation Cells, Cultured Databases, Factual Humans Hypogonadism - drug therapy Hypogonadism - epidemiology Induced Pluripotent Stem Cells - physiology International Cooperation Long QT Syndrome - drug therapy Long QT Syndrome - epidemiology Male Myocytes, Cardiac - physiology Pharmacovigilance Phenylthiohydantoin - adverse effects Phenylthiohydantoin - analogs & derivatives Phenylthiohydantoin - therapeutic use Risk Torsades de Pointes - drug therapy Torsades de Pointes - epidemiology Translational Medical Research |
| Title | Androgenic Effects on Ventricular Repolarization: A Translational Study From the International Pharmacovigilance Database to iPSC-Cardiomyocytes |
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