Interest of IKr-related Abnormalities of ECGs to Improve Drug-safety Evaluation

描述（由申请方提供）：体表ECG上的QT间期延长已被认为是心脏事件风险增加的替代标志物。近年来，获得性长QT综合征（LQTS）与几种主要药物有关，这些药物在与许多心源性事件和心源性死亡相关后退出市场。这种类型的药物靶向人类ether-a-go-go-related基因（HERG），导致心肌细胞（Ikr）中特定钾电流的减少和心室复极过程的延迟。这些药物与体表ECG上QT间期的极轻微延长相关，揭示了该标志物的局限性。因此，重要的是设计一种方法来评估药物诱导的复极心脏毒性，依赖于其他参数而不是QT间期，并表示存在IKr阻滞。在本申请中，我们将使用FDA从8项药物安全性研究中收集的1，688个ECG，其中阿托沙星被用作延长QT间期的阳性对照物质。本申请的目的是：1）识别复极段的异常，以改进与QT延长互补的ECG方法，用于评估药物心脏毒性，2）研究性别作为IKr相关心室复极异常的诱发因素的作用，以及3）测试是否可以在HERG突变携带者的ECG中发现阿托伐他汀诱导的复极异常。本研究将利用描述T波形态的新T波复极化参数来增强识别药物诱导的复极化效应的能力。将研究基于T波标量测量、T环矢量量化和T波数学建模的技术。重要参数将用于区分长QT综合征的LQT 2突变的患者携带者和非携带者，所述长QT综合征也涉及受药物阿氟沙星影响的相同离子通道。

DESCRIPTION (provided by applicant): A prolongation of the QT interval on the surface ECG has been recognized as a surrogate marker for an increased risk of cardiac events. In the recent years, the acquired form of the Long QT syndrome (LQTS) has been associated with several major drugs that were withdrawn from the market after being associated with numerous arrhythmic events and cardiac death. This type of drug targets the human ether-a-go-go-related gene (HERG) leading to a reduction of specific potassium currents in the myocardial cells (Ikr) and a delay in the ventricular repolarization process. These drugs were associated with very small prolongation of the QT interval on the surface ECGs revealing the limit of this marker. Consequently, it is important to design a method for the assessment of drug-induced repolarization cardiotoxicity that relies on other parameters than QT interval, and that expresses the presence of an IKr blockade. In this application, we will use a set of 1,688 ECGs gathered by the FDA from eight drug-safety studies in which moxifloxacin has been used as a positive control substance for prolonging the QT interval. The objectives of our application are 1) to identify abnormalities of the repolarization segment in order to improve ECG methods complementary to QT prolongation for the assessment of drug cardiotoxicity, 2) to investigate the role of gender as a predisposing factor for IKr-related abnormalities of the ventricular repolarization, and 3) to test whether the moxifloxacin-induced abnormalities of repolarization can be found in ECGs of carriers of a HERG mutation. This study will utilize new T-wave repolarization parameters describing T-wave morphology to enhance the ability to identify drug-induced repolarization effects. Techniques based on scalar measurements of T-wave, vectorial quantification of T-loop and T-wave mathematical modeling will be investigated. The important parameters will be used to discriminate patient carriers and non-carriers of a LQT2 mutation of the long QT syndrome that also involve the same ion channel affected by the drug moxifloxacin.