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Androgenic Effects on Ventricular Repolarization: A Translational Study From the International Pharmacovigilance
Joe-Elie Salem1,2,3, Tao Yang2,3, Javid J Moslehi2
1Assitance 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.
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:
URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.
Insights
Androgen-deprivation therapies (ADTs) increase the risk of acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP) in men. Enzalutamide, an ADT, showed a significant association with cardiac events and prolonged QT intervals in stem cell models.
Area of Science:
- Cardiology
- Pharmacology
- Electrophysiology
Background:
- Male hypogonadism and androgen-deprivation therapies (ADTs) are linked to acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP).
- Clinical features and mechanisms of aLQTS associated with ADT require further elucidation.
Purpose of the Study:
- To investigate the association between ADTs and cardiac arrhythmias like aLQTS and TdP.
- To explore the underlying electrophysiological mechanisms of ADT-induced cardiac events.
Main Methods:
- Searched the VigiBase pharmacovigilance database for adverse events associated with ADTs.
- Utilized induced pluripotent stem cell-derived cardiomyocytes to study the electrophysiological effects of ADTs and dihydrotestosterone.
Main Results:
- Identified 184 cases of aLQTS and/or TdP, and 99 sudden deaths linked to ADTs in VigiBase.
- Seven of ten examined ADTs showed a disproportional association with cardiac events; enzalutamide was linked to a higher mortality rate.
- Enzalutamide significantly prolonged action potential duration, induced afterdepolarizations, inhibited potassium currents, and enhanced sodium currents in cardiomyocytes, effects reversed by dihydrotestosterone.
Conclusions:
- QT prolongation and TdP represent a significant risk for men undergoing treatment with enzalutamide and other ADTs.
- The findings highlight the need for careful cardiac monitoring in patients receiving ADT.
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