Role of Sex Hormones in Gender Differences in Cardiac Repolarization and Arrhythmogenesis in Transgenic Long QT Syndrome 2 (LQT2) Rabbits

性激素在转基因长 QT 综合征 2 (LQT2) 兔心脏复极和心律失常发生性别差异中的作用

• 批准号: 70755745
• 负责人: Professorin Dr. Katja Elisabeth Odening
• 金额: --
• 依托单位: Professur für Translationale Kardiologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 无数据
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/70755745?language=en
• 关键词: Role; Sex; Hormones; Gender; Differences

The inherited long QT syndrome 2 (LQT2) is an arrhythmogenic disease with a prolonged cardiac repolarization caused by loss-of-function mutations in HERG channels (IKr). Adult women with LQT2 are at a higher risk than men for clinical events such as polymorphic ventricular tachycardia (pVT) and sudden cardiac death (SCD). In our lab we have created transgenic LQT2 rabbits over-expressing a loss-of-function mutant of HERG in the heart. My preliminary data show the same gender differences in transgenic LQT2 rabbits with a prolonged QT-index and a steeper QT/RR ratio in females. This prolonged cardiac repolarization can be mimicked by estrogen in ovariectomized rabbits. In our female LQT2 rabbits SCD only occurred after sexual maturation, partly associated with postpartum, but estrogen predisposed even prepubertal LQT2 rabbits to spontaneous pVT. I hypothesize that sex hormones modulate regional and transmural expression of cardiac ion channels, and α1- and β1-adrenergic receptors and are responsible for the gender differences in cardiac repolarization and arrhythmogenesis. I propose to elucidate the underlying mechanisms that predispose female LQT2 rabbits to cardiac arrhythmias by treating prepubertal rabbits with sex hormones and analyzing the hormone-related changes.

遗传性长QT综合征2 （LQT2）是一种由HERG通道（IKr）功能缺失突变引起的心脏复极延长的心律失常性疾病。患有LQT2的成年女性比男性有更高的临床事件风险，如多形性室性心动过速（pVT）和心源性猝死（SCD）。在我们的实验室中，我们创造了转基因LQT2兔子，在心脏中过度表达HERG的功能丧失突变体。我的初步数据显示转基因LQT2家兔的性别差异相同，雌性的QT-指数延长，QT/RR比更陡。这种延长的心脏复极可以用雌激素在切除卵巢的家兔体内模拟。在我们的雌性LQT2兔中，SCD仅在性成熟后发生，部分与产后有关，但雌激素甚至使青春期前的LQT2兔易发生自发性pvt。我假设性激素调节心脏离子通道和α1-和β1-肾上腺素能受体的区域和跨壁表达，并负责心脏复极和心律失常的性别差异。我建议通过对青春期前兔进行性激素治疗并分析激素相关变化来阐明雌性LQT2兔易患心律失常的潜在机制。