QTRR Dynamic Coupling in Patients with the Long QT Syndrome

长 QT 综合征患者的 QTRR 动态耦合

• 批准号: 8870417
• 负责人: JEAN-PHILIPPE Y COUDERC
• 金额: $ 35.66万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870417
• 关键词: 11p15.5; 7q36.1; Acoustic Stimulation; Adrenergic Agents; Affect; Age; American; Arousal; Arrhythmia; Cardiac; Cessation of life; Child; Clinical; Clinical Protocols; Clinical Research; Complement; Coupling; Cytogenetics; Data; Defect; Dependency; Diagnosis; Electrocardiogram; Emotions; Enrollment; Epinephrine; Equipment; Event; Exercise; Exogenous Factors; France; Frequencies; Functional disorder; Gender; General Population; Genes; Genetic screening method; Genotype; Health; Heart; Heart Arrest; Heart Rate; Hour; Impairment; Implant; Individual; Inherited; Ion Channel; Ions; Italy; Life; Location; Long QT Syndrome; Measurement; Measures; Medical Genetics; Methods; Molecular; Molecular Biology; Mutation; Patients; Percussion; Phenotype; Play; Potassium; Predisposition; Process; Prospective Studies; Recording of previous events; Registries; Reporting; Reproducibility; Rest; Resuscitation; Retrospective Studies; Risk; Risk Marker; Role; Safety; Scientist; Severities; Sleep; Stimulus; Stratification; Stress; Surface; Syncope; Syndrome; Tachycardia; Techniques; Testing; United States; Ventricular; Work; adrenergic; base; clinical risk; cohort; computerized; digital; imprint; improved; insight; novel; outcome forecast; prospective; response; sudden cardiac death; tool; trafficking; voltage; young adult

DESCRIPTION (provided by applicant): While molecular biology has evidenced gene-specific ion-channel dysfunctions in patients with the Long QT syndrome (LQTS), the clinical studies have described a large spectrum of arrhythmogenic mechanisms involved in the triggering of life-threatening arrhythmias between and within specific gene. Genotyping is considered the most reliable tool to identify the presence of the LQTS, but genetic testing captures only 75% of phenotypically affected LQTS individuals, and negative test in a phenotype-positive patient does not rule out the presence of the syndrome. Importantly, these tests do not fully capture an individual risk to life-threatening arrhythmias that is modulated by exogenous factors. The surface electrocardiogram (ECG) is an investigational tool that could provide insights into the integrated functional defects associated with LQTS mutations. Therefore, we propose to conduct a project to identify ECG features associated with risk in LQTS patients. We will investigate ECG parameters beyond QTc prolongation focusing on capturing dynamic features of the QT and RR intervals coupling. More specifically, we propose to evaluate a method describing the instantaneous components of the QT response to changes in heart rate as a genetically-determined imprint of cardiac repolarization profile in LQTS patients. The proposal relies on a unique set of Holter ECGs recorded from ~1,210 genotyped LQTS patients gathered from three registries (American, Italian and French). We will study the reproducibility of the proposed ECG markers and their association with patients' events based on data from a retrospective and a prospective study. Several methods will be developed to risk stratify LQTS patients for cardiac events, and to estimate their susceptibility to specific triggers such as arousal, sleep/rest, and physical stress. Ultimately, we aim to improve the prognosis and management of LQTS patients.

描述(申请人提供)：虽然分子生物学已经证明长QT综合征(LQTS)患者存在基因特异性离子通道功能障碍，但临床研究描述了涉及触发特定基因之间和特定基因内危及生命的心律失常的大范围心律失常发生机制。基因分型被认为是确定LQTS存在的最可靠的工具，但基因检测只捕捉到75%的表型受影响的LQTS个体，表型阳性患者的阴性测试不能排除该综合征的存在。重要的是，这些测试并不能完全捕捉到由外源性因素调节的危及生命的心律失常的个体风险。体表心电图是一种研究工具，可以深入了解与LQTS突变相关的综合功能缺陷。因此，我们建议开展一个项目，以确定与LQTS患者风险相关的心电特征。我们将研究QT间期延长以外的心电参数，重点是捕捉QT和RR间期耦合的动态特征。更具体地说，我们建议评估一种描述QT对心率变化反应的瞬时分量的方法，作为LQTS患者心脏复极曲线的基因决定印记。该提案依赖于一套独特的Holter心电图记录，这些记录来自来自三个登记处(美国、意大利和法国)的约1210名分型LQTS患者。我们将基于一项回顾和前瞻性研究的数据，研究所建议的心电标记物的重复性及其与患者事件的关系。将开发几种方法来对LQTS患者的心脏事件进行风险分层，并估计他们对特定触发因素的易感性，如唤醒、睡眠/休息和身体压力。最终，我们的目标是改善LQTS患者的预后和治疗。