Androgenic Effects on Ventricular Repolarization: A Translational Study From the International Pharmacovigilance Database to iPSC-Cardiomyocytes

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: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.

Keywords: androgen antagonists; hypogonadism; long QT syndrome; testosterone; torsades de pointes.

Fig.1

Number of acquired long QT syndrome (aLQTS) including Torsades de pointes (TdP); and sudden death associated with androgen deprivation therapies (ADT) reported over time within VigiBase. Each ADT is noted below the year corresponding to its first associated individual case safety report (ICSR) related to aLQTS, TdP or sudden death reported in VigiBase.

Fig.2

In cardiomyocytes derived from induced pluripotent stem cells from 3 different male lines (A,B,C), acute (D,E,F) and chronic (G,H,I) exposure to enzalutamide prolonged action potential duration (J,K,L). **p<0.01 vs. control (n=5-7 each)

Fig.3

Panels A-C are typical action potential traces in three groups of men cardiomyocytes derived from induced pluripotent stem cells in the absence and presence of dihydrotestosterone (DHT). Panel D is the summary of these groups of cells. Acute and chronic enzalutamide (Enza) prolonged action potentials whereas DHT had opposite effect. **p<0.01 (n=4-5 each)

Fig.4

In Chinese-hamster-ovary cells, acute (A-D) and chronic (E-J) exposure to enzalutamide (A,C,E,H,I) decreased I_Kr. Conversely, exposure to dihydrotestosterone (DHT) increased I_Kr (B,D,G,H,I). A p-value <0.005 was deemed significant to account for multiple comparisons (Bonferroni adjustment; H,I). *p<0.05 vs. control, **p<0.01 vs. control, # p<0.005 vs. enzalutamide (n=5 each)

Fig.5

Chronic exposure to enzalutamide increased ventricular peak (I_Na) and late (I_Na-L) sodium current in cardiomyocytes derived from induced pluripotent stem cells (A-D). **p<0.01 vs. control (n=4 each)