Mechanisms of postpartum-related arrhythmogenesis in long-QT syndrome

长QT综合征产后相关心律失常的机制

• 批准号: 278990290
• 负责人: Professorin Dr. Katja Elisabeth Odening
• 金额: --
• 依托单位: Institut für Experimentelle Kardiovaskuläre Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/278990290?language=en
• 关键词: Mechanisms; postpartum; related; arrhythmogenesis; long

Sudden cardiac death (SCD) in younger, apparently healthy individuals, most often occurs secondary to rare inherited arrhythmogenic channelopathies. The inherited long-QT syndrome type 2 (LQT2) is one of these arrhythmogenic diseases, in which loss-of-function mutations in the gene of repolarizing HERG ion channels prolong cardiac repolarization and increase the risk for ventricular tachyarrhythmia, syncope and SCD. Adult women with LQT2 have a higher risk for lethal arrhythmia than men. During the postpartum phase, this risk is further increased by 4-fold. Despite this clinical observation, no studies have investigated whether and how oxytocin and prolactin that are secreted during the postpartum phase have pro-arrhythmic effects.We hypothesize that oxytocin and prolactin contribute to the heightened postpartal arrhythmogenic risk by modulating the arrhythmogenic substrate (regionally heterogeneous prolongation of cardiac repolarization) as well as the susceptibility to pro-arrhythmic sympathetic stimuli. We have generated transgenic LQT2 rabbit models (HERG-G628S) mimicking the human LQTS phenotype with QT interval prolongations, spontaneous ventricular tachycardia and sudden cardiac death - and similarly as in human subjects - a particularly high mortality during the postpartum phase due to lethal ventricular arrhythmia. These transgenic LQT rabbits are thus useful tools to investigate mechanisms of postpartum-related arrhythmogenesis on in vivo, ex vivo whole heart, tissue, cellular and molecular levels.In this project, we will utilize transgenic LQT2 rabbits to investigate how oxytocin and prolactin affect arrhythmogenesis, (regional) cardiac repolarization and the expression, phosphorylation and function of cardiac ion channels and transporters. To assess mechanisms of postpartum arrhythmia on multiple levels, we will use in vivo ECG monitoring, ex vivo monophasic action potential measurements, real-time PCR and western blot analyses of mRNA and protein expression of cardiac ion channels and Ca2+-handling proteins, and cellular patch clamping. The experimental data will finally be integrated into an in silico LQT2 heart model to test whether the hormone-induced changes predispose to arrhythmia.Our longterm goal is to translate our findings on the mechanisms of postpartum-related arrhythmogenesis into clinical (diagnostic and therapeutic) routines, specifically, use these findings for recommendations regarding breastfeeding and oxytocin administration in LQTS patients.

心源性猝死（SCD）发生在年轻、表面健康的个体中，最常继发于罕见的遗传性血管源性通道病。遗传性长QT综合征2型（LQT 2）是其中一种致心律失常性疾病，其复极化HERG离子通道基因的功能缺失突变延长了心脏复极化，增加了室性快速性心律失常、晕厥和SCD的风险。患有LQT 2的成年女性发生致命性心律失常的风险高于男性。在产后阶段，这种风险进一步增加了4倍。尽管有这种临床观察，没有研究已经调查是否以及如何催产素和催乳素分泌在产后阶段有pro-embryonic effects.We假设，催产素和催乳素有助于提高产后embryogenic风险通过调制embryogenic基板（心脏复极的区域异质性延长），以及pro-embryogenic交感神经刺激的敏感性。我们已经产生了转基因LQT 2兔模型（HERG-G628 S），其模拟了具有QT间期缩短、自发性室性心动过速和心脏性猝死的人LQTS表型-并且与人类受试者相似-由于致死性室性心律失常，产后阶段的死亡率特别高。本研究将利用转基因LQT 2兔研究催产素和催乳素对产后心肌发生、心肌复极化以及心肌离子通道和转运蛋白的表达、磷酸化和功能的影响。为了在多个层面上评估产后心律失常的机制，我们将使用体内ECG监测、离体单相动作电位测量、心脏离子通道和Ca 2+处理蛋白的mRNA和蛋白表达的实时PCR和蛋白质印迹分析以及细胞膜片钳。实验数据最终将被整合到一个计算机模拟的LQT 2心脏模型中，以测试产后引起的变化是否易患心律失常。我们的长期目标是将我们关于产后相关的心律失常发生机制的发现转化为临床（诊断和治疗）常规，特别是，使用这些发现为LQTS患者的母乳喂养和催产素给药提供建议。