Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes

J E Salem; T Yang; J J Moslehi; X Waintraub; E Gandjbakhch; A Bachelot; F Hidden-Lucet; J S Hulot; B C Knollmann; B Lebrun-Vignes; C Funck-Brentano; A M Glazer; D M Roden

doi:10.1016/j.ando.2020.02.008

Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes

Ann Endocrinol (Paris). 2021 Jun;82(3-4):132-133. doi: 10.1016/j.ando.2020.02.008. Epub 2020 Feb 29.

Authors

J E Salem¹, T Yang², J J Moslehi³, X Waintraub⁴, E Gandjbakhch⁴, A Bachelot⁵, F Hidden-Lucet⁴, J S Hulot⁶, B C Knollmann², B Lebrun-Vignes⁴, C Funck-Brentano⁴, A M Glazer³, D M Roden⁷

Affiliations

¹ 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; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: [email protected].
² Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴ 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.
⁵ 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 Université, Paris, France.
⁶ 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.
⁷ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Vanderbilt University Medical Center, Nashville, TN, USA.

PMID: 32171470
DOI: 10.1016/j.ando.2020.02.008

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 (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: 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.

MeSH terms

Androgens / pharmacology
Androgens / therapeutic use
Cell Differentiation / drug effects
Cell Differentiation / physiology
Cells, Cultured
Databases, Factual
Death, Sudden, Cardiac / epidemiology
Dihydrotestosterone / pharmacology*
Dihydrotestosterone / therapeutic use
Electrophysiological Phenomena / drug effects
Eunuchism / drug therapy
Eunuchism / epidemiology
Eunuchism / physiopathology
Heart Ventricles / drug effects
Heart Ventricles / physiopathology
Humans
Induced Pluripotent Stem Cells / drug effects
Induced Pluripotent Stem Cells / physiology
Internationality
Long QT Syndrome / chemically induced
Long QT Syndrome / epidemiology
Long QT Syndrome / pathology
Long QT Syndrome / physiopathology
Male
Membrane Potentials / drug effects
Myocytes, Cardiac / drug effects*
Myocytes, Cardiac / pathology
Pharmacovigilance
Torsades de Pointes / chemically induced
Torsades de Pointes / epidemiology
Torsades de Pointes / pathology
Torsades de Pointes / physiopathology
Translational Research, Biomedical
Ventricular Function / drug effects*

Substances

Androgens
Dihydrotestosterone

Associated data

ClinicalTrials.gov/NCT03193138