雄激素对心室复极的影响：从国际药物警戒数据库到 iPSC 心肌细胞的转化研究。
Androgenic Effects on Ventricular Repolarization: A Translational Study From the International Pharmacovigilance Database to iPSC-Cardiomyocytes.
机构信息
Assitance 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.
Department of Medicine (J-E.S., T.Y., J.J.M., B.C.K., A.M.G., D.M.R.), Vanderbilt University Medical Center, Nashville, TN.
出版信息
Circulation. 2019 Sep 24;140(13):1070-1080. doi: 10.1161/CIRCULATIONAHA.119.040162. Epub 2019 Aug 5.
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; <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%]; <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, <0.001) and 1062.3±28.9 ms (chronic; <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.
背景
男性性腺功能减退症可由多种病因引起，包括雄激素剥夺疗法（ADT），已被报道为获得性长 QT 综合征（aLQTS）和尖端扭转型室性心动过速（TdP）的危险因素。缺乏对与 ADT 相关的 aLQTS 及潜在机制的临床特征的全面描述。
方法
我们在国际药物警戒数据库 VigiBase 中检索了接受 ADT 的男性（n=6560565 例个体病例安全报告）中与 ADT 相关的 aLQTS、TdP 或猝死的报告。在源自男性诱导多能干细胞的心肌细胞中，我们研究了 ADT 和二氢睾酮的电生理效应。
结果
在 VigiBase 中接受 ADT 的受试者中，我们鉴定出 184 例 aLQTS（n=168）和/或 TdP（n=68；11%为致命性）和 99 例猝死。在所检查的 10 种 ADT 药物中，有 7 种与 aLQTS、TdP 或猝死呈不成比例的关联（报告比值比=1.4-4.7；<0.05）。猝死的最短和中位时间分别为 0.25 和 92 天。雄激素受体拮抗剂恩扎鲁胺与更多死亡相关（5430/31896[17%]；<0.0001），而其他用于前列腺癌的 ADT 则更少（4208/52089[8.1%]）。在诱导多能干细胞中，急性和慢性恩扎鲁胺（25µM）显著延长动作电位时程（在 0.5Hz 起搏时 90%动作电位时程；429.7±27.1（对照）与 982.4±33.2（急性，<0.001）和 1062.3±28.9ms（慢性；<0.001），并在药物处理的细胞中产生后除极和/或触发活动（急性 20 例中有 11 例，慢性 15 例中有 8 例）。恩扎鲁胺急性和慢性抑制延迟整流钾电流，并慢性增强晚期钠电流。二氢睾酮（30nM）逆转了恩扎鲁胺对诱导多能干细胞的电生理效应。
结论
QT 间期延长和 TdP 是接受恩扎鲁胺和其他 ADT 的男性的风险。
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