Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes.
Androgens
/ pharmacology
Cell Differentiation
/ drug effects
Cells, Cultured
Databases, Factual
Death, Sudden, Cardiac
/ epidemiology
Dihydrotestosterone
/ pharmacology
Electrophysiological Phenomena
/ drug effects
Eunuchism
/ drug therapy
Heart Ventricles
/ drug effects
Humans
Induced Pluripotent Stem Cells
/ drug effects
Internationality
Long QT Syndrome
/ chemically induced
Male
Membrane Potentials
/ drug effects
Myocytes, Cardiac
/ drug effects
Pharmacovigilance
Torsades de Pointes
/ chemically induced
Translational Research, Biomedical
Ventricular Function
/ drug effects
Journal
Annales d'endocrinologie
ISSN: 2213-3941
Titre abrégé: Ann Endocrinol (Paris)
Pays: France
ID NLM: 0116744
Informations de publication
Date de publication:
Jun 2021
Jun 2021
Historique:
pubmed:
17
3
2020
medline:
15
12
2021
entrez:
16
3
2020
Statut:
ppublish
Résumé
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; 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 (25μM) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5Hz; 429.7±27.1 (control) versus 982.4±33.2 (acute, P<0.001) and 1062.3±28.9ms (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 (30nM) 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.
Sections du résumé
BACKGROUND
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
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
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 (25μM) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5Hz; 429.7±27.1 (control) versus 982.4±33.2 (acute, P<0.001) and 1062.3±28.9ms (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 (30nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells.
CONCLUSION
CONCLUSIONS
QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs.
CLINICAL TRIAL REGISTRATION
BACKGROUND
URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.
Identifiants
pubmed: 32171470
pii: S0003-4266(20)30031-7
doi: 10.1016/j.ando.2020.02.008
pii:
doi:
Substances chimiques
Androgens
0
Dihydrotestosterone
08J2K08A3Y
Banques de données
ClinicalTrials.gov
['NCT03193138']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
132-133Informations de copyright
Copyright © 2020. Published by Elsevier Masson SAS.