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Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance
J E Salem1, T Yang2, J J Moslehi3
1Assistance 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.
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.
Insights
Androgen-deprivation therapies (ADTs) increase the risk of acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). Enzalutamide, an ADT, showed a higher association with adverse cardiac events and sudden death in men.
Area of Science:
- Cardiology
- Pharmacology
- Electrophysiology
Background:
- Male hypogonadism, often treated with androgen-deprivation therapies (ADTs), is linked to acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP).
- Limited data exists on the clinical presentation and mechanisms of aLQTS associated with ADT.
Purpose of the Study:
- To investigate the association between ADTs and cardiac events like aLQTS and TdP.
- To explore the underlying electrophysiological mechanisms of these adverse events.
Main Methods:
- Searched the VigiBase pharmacovigilance database for cases of aLQTS, TdP, or sudden death linked to ADT.
- Utilized induced pluripotent stem cell-derived cardiomyocytes to study the electrophysiological effects of ADT and dihydrotestosterone.
Main Results:
- Identified 184 cases of aLQTS and/or TdP, with 99 sudden deaths among men receiving ADT.
- Seven of ten examined ADT drugs showed a disproportional association with cardiac events.
- Enzalutamide was linked to a higher incidence of deaths compared to other ADTs and demonstrated significant QT prolongation and altered ion channel activity in cardiomyocytes.
Conclusions:
- QT prolongation and TdP represent a significant risk for men undergoing treatment with enzalutamide and other ADTs.
- Enzalutamide's proarrhythmic effects are mediated by inhibition of potassium currents and enhancement of sodium currents.
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