Genetic Predictors of QT Response During Exercise

描述(由申请人提供)： 项目概述：对运动压力的反应是心脏病预后的一个公认的预测因子。这项K23提案的总体目标是建立在我以前在这一领域的经验基础上，确定对运动应激反应的遗传和其他预测因素，从而开始开发一个新的框架，以接近由于心律失常而导致的猝死风险。这些特定的目的将决定已定义的和新的多态在调节中间电生理表型的变异性方面的作用，包括对运动应激和内在心率的反应。在具体目标1中，我将对正常人在运动和恢复过程中的QT和RR反应进行表型分析，并测试基因多态在调节这些反应的变异性中的作用。在特定的目标2中，我将对正常人在运动和恢复过程中的内在QT和RR反应进行表型，并测试基因多态在调节这些反应的变异性中的作用。在具体目标3中，我将确定延长QT的药物对固有心率和QT间期的影响。让我进一步发展成为一名临床研究员并测试这些目标背后的假设的资源已经到位。这个奖项将通过临床研究、明确的教育计划以及在高度支持和富有成效的研究和指导环境中的正式指导过程来增强我作为临床研究人员的技能。通过这种方式，最大可能实现我的目标，即发展成为一名拥有强大研究计划的独立调查员。 相关性：每年有42万美国人死于心脏性猝死。这项研究有可能识别有心脏性猝死风险的个人，因此对公共卫生具有重要的相关性。(摘要结束)

DESCRIPTION (provided by applicant): Project Summary: Response to exercise stress is a well-recognized predictor of outcome in heart disease. The overall goal of this K23 proposal to is build on my previous experience in this area to identify genetic and other predictors of response to exercise stress, and thereby begin to develop a new framework for approaching risk of sudden death due to arrhythmias. The Specific Aims will determine the role of defined and new polymorphisms in modulating variability in intermediate electrophysiologic phenotypes, including responses to exercise stress and intrinsic heart rate. In Specific Aim 1, I will phenotype QT and RR responses during exercise and recovery in normal subjects, and test the role of genetic polymorphisms in mediating variability in these responses. In Specific Aim 2, I will phenotype intrinsic QT and RR response during exercise and recovery in normal subjects, and test the role of genetic polymorphisms in mediating variability in these responses. In Specific Aim 3, I will determine the effect of a QT-prolonging drug on intrinsic heart rate and QT interval. The resources for me to develop further as a clinical investigator and to test the hypotheses underlying these aims are in place. This award will enhance my skills as a clinical investigator through clinical research, a defined educational program, and a formal mentoring process in a highly supportive and productive research and mentoring environment. In this way, the likelihood is maximized that my goal of developing as an independent investigator with a robust research program will be achieved. Relevance: Sudden cardiac death kills 420,000 Americans each year. This research has the potential to permit identification of individuals at risk for sudden cardiac death and therefore has significant relevance to public health. (End of Abstract)