First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany; DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Mannheim, Germany.
First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany; DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Mannheim, Germany; Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China.
Int J Cardiol. 2018 Mar 1;254:195-202. doi: 10.1016/j.ijcard.2017.11.007. Epub 2018 Jan 28.
Previous studies revealed that Takotsubo cardiomyopathy (TTC), a transient disorder of ventricular dysfunction affecting predominantly postmenopausal women, is associated with acquired long QT syndrome and arrhythmias, but the exact pathophysiologic mechanism is unknown. Our aim is to investigate the electrophysiological mechanism for QT-prolongation in TTC-patients by using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
hiPSC-CMs, which were generated from human skin fibroblasts of three healthy donors, were treated by estradiol (10μM for one week) and a toxic concentration of isoprenaline (Iso, 1mM for 2h). Patch clamp techniques, qPCR and fluorescence-activated cell sorting (FACS) were employed for the study.
Iso enhanced late I and suppressed I and thus prolonged the action potential duration (APD), suggesting possible reasons for arrhythmias in TTC. Iso elevated the production of reactive oxygen species (ROS). N-acetylcystein (1mM), a ROS-blocker, abolished the effects of Iso on late I and I. HO (100μM) mimicked Iso effects on late I and I. These data indicate that the effects of Iso were mediated by ROS. Metoprolol (1mM), a beta-blocker, prevented the effects of Iso on late I and APD, confirming the adrenoceptor-dependent effects of Iso. Estradiol treatment prevented the APD-prolongation, attenuated the enhancement of I, diminished the reduction of I, suppressed ROS-production induced by Iso and reduced the expression levels of adrenoceptors, suggesting protective effects of estragon against toxic effects of catecholamine.
Estradiol has protective effects against catecholamine excess and hence reduction in estrogen level may increase the risk of acquired long QT syndrome in TTC.
先前的研究表明，Takotsubo 心肌病（TTC）是一种影响绝经后女性为主的短暂性心室功能障碍疾病，与获得性长 QT 综合征和心律失常有关，但确切的病理生理机制尚不清楚。我们的目的是通过使用人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）来研究 TTC 患者 QT 延长的电生理机制。
从 3 名健康供体的人皮肤成纤维细胞中生成 hiPSC-CMs，用雌二醇（10μM 处理一周）和毒浓度的异丙肾上腺素（Iso，1mM 处理 2 小时）处理。采用膜片钳技术、qPCR 和荧光激活细胞分选（FACS）进行研究。
Iso 增强晚期 I 并抑制 I，从而延长动作电位持续时间（APD），提示 TTC 中心律失常的可能原因。Iso 升高活性氧物质（ROS）的产生。ROS 阻断剂 N-乙酰半胱氨酸（1mM）消除了 Iso 对晚期 I 和 I 的作用。HO（100μM）模拟 Iso 对晚期 I 和 I 的作用。这些数据表明 Iso 的作用是通过 ROS 介导的。β受体阻滞剂美托洛尔（1mM）可预防 Iso 对晚期 I 和 APD 的作用，证实了 Iso 对肾上腺素受体的作用。雌二醇处理可防止 APD 延长，减弱 I 的增强，减少 I 的减少，抑制 Iso 诱导的 ROS 产生，并降低肾上腺素受体的表达水平，提示雌二醇对儿茶酚胺毒性的保护作用。
雌二醇对儿茶酚胺过量有保护作用，因此雌激素水平降低可能会增加 TTC 中获得性长 QT 综合征的风险。
