Akdis Deniz, Saguner Ardan M, Shah Khooshbu, Wei Chuanyu, Medeiros-Domingo Argelia, von Eckardstein Arnold, Lüscher Thomas F, Brunckhorst Corinna, Chen H S Vincent, Duru Firat
Department of Cardiology, University Heart Center Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.
Development, Aging and Regeneration Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA.
Eur Heart J. 2017 May 14;38(19):1498-1508. doi: 10.1093/eurheartj/ehx011.
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized by fibrofatty infiltration of the myocardium and ventricular arrhythmias that may lead to sudden cardiac death. It has been observed that male patients develop the disease earlier and present with more severe phenotypes as compared to females. Thus, we hypothesized that serum levels of sex hormones may contribute to major arrhythmic cardiovascular events (MACE) in patients with ARVC/D.
The serum levels of five sex hormones, sex hormone-binding globulin, high sensitivity troponin T, pro-brain natriuretic peptide, cholesterol, triglycerides, insulin, and glucose were measured in 54 ARVC/D patients (72% male). Twenty-six patients (48%) experienced MACE. Total and free testosterone levels were significantly increased in males with MACE as compared to males with a favourable outcome, whereas estradiol was significantly lower in females with MACE as compared to females with a favourable outcome. Increased testosterone levels remained independently associated with MACE in males after adjusting for age, body mass index, Task Force criteria, ventricular function, and desmosomal mutation status. Furthermore, an induced pluripotent stem cell-derived ARVC/D cardiomyocyte model was used to investigate the effects of sex hormones. In this model, testosterone worsened and estradiol improved ARVC/D-related pathologies such as cardiomyocyte apoptosis and lipogenesis, strongly supporting our clinical findings.
Elevated serum testosterone levels in males and decreased estradiol levels in females are independently associated with MACE in ARVC/D, and directly influence disease pathology. Therefore, determining the levels of sex hormones may be useful for risk stratification and may open a new window for preventive interventions.
致心律失常性右室心肌病/发育不良（ARVC/D）的特征是心肌纤维脂肪浸润和室性心律失常，可能导致心源性猝死。据观察，与女性相比，男性患者发病更早，且表现出更严重的表型。因此，我们推测性激素水平可能与ARVC/D患者的主要心律失常性心血管事件（MACE）有关。
对54例ARVC/D患者（72%为男性）测定了五种性激素、性激素结合球蛋白、高敏肌钙蛋白T、脑钠肽前体、胆固醇、甘油三酯、胰岛素和葡萄糖的血清水平。26例患者（48%）发生了MACE。发生MACE的男性患者的总睾酮和游离睾酮水平显著高于预后良好的男性患者，而发生MACE的女性患者的雌二醇水平显著低于预后良好的女性患者。在调整年龄、体重指数、工作组标准、心室功能和桥粒基因突变状态后，男性患者睾酮水平升高仍与MACE独立相关。此外，利用诱导多能干细胞衍生的ARVC/D心肌细胞模型研究性激素的作用。在该模型中，睾酮加重了ARVC/D相关病变，如心肌细胞凋亡和脂肪生成，而雌二醇则改善了这些病变，有力地支持了我们的临床研究结果。
男性血清睾酮水平升高和女性雌二醇水平降低与ARVC/D患者的MACE独立相关，并直接影响疾病病理。因此，测定性激素水平可能有助于风险分层，并可能为预防性干预打开一扇新窗口。
