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

描述（由申请人提供）：体表心电图QT间期延长已被认为是心脏事件风险增加的替代标志。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律失常事件和心源性死亡相关后被撤出市场。这种类型的药物靶向人类以太-a-go-go相关基因（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。这些药物与表面心电图上QT间期的非常小的延长有关，显示了这一标记的局限性。因此，设计一种评估药物诱导的复极心脏毒性的方法是很重要的，该方法依赖于QT间期以外的其他参数，并表达IKr阻断的存在。在本应用中，我们将使用FDA从8项药物安全性研究中收集的一组1688张心电图，其中莫西沙星已被用作延长QT间期的阳性对照物质。我们申请的目的是：1)识别复极段的异常，以改进与QT延长相补充的心电图方法，以评估药物心脏毒性；2)研究性别作为ikr相关心室复极异常的易感因素的作用；3)测试莫西沙星诱导的复极异常是否可以在HERG突变携带者的心电图中发现。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。这些重要参数将用于区分长QT综合征LQT2突变的携带者和非携带者，这些突变也涉及受莫西沙星药物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recent years, the acquired form of the Long QT syndrome (LQTS) has been associated with several major drugs that were withdrawn from the market after being associated with numerous arrhythmic events and cardiac death.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.