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

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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recent years, the acquired form of the Long QT syndrome (LQTS) has been associated with several major drugs that were withdrawn from the market after being associated with numerous arrhythmic events and cardiac death.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.