Fundamental Biology of SCD and its Application to Identify Patients at Risk

描述(申请人提供)：仅在美国就有500多万人患有晚期左心功能不全，猝死风险增加，根据目前的指南，他们是植入型心律转复除颤器(ICD)的候选者。这一建议的总体假设是，结构性(底物)和功能性(触发)异常之间的相互作用，其中一些是由基因决定的，可以用来识别结构性心脏病患者，具有SCD的高风险。这项建议的目标有两个：加强对人类SCD易感生物学机制的了解，以及开发一个实用的生物标记物小组来识别有风险的患者。我们利用遗传学、蛋白质组学、电生理学和流行病学的编程优势，并将利用一项正在进行的前瞻性队列研究(SCD中ICD的前瞻性观察研究，散文-ICD)，对结构性心脏病和左心室射血分数降低的患者进行ICD植入，作为SCD的一级预防。对散文-ICD队列的广泛表型和基因分型将使我们能够探索晚期结构性心脏病患者电生理重构、炎症、缺血和心肌损伤的途径，以及SCD的遗传贡献者。ICD中存储的心电图有助于对潜在致命性室性心律失常的准确诊断，为心律失常的SCD提供了一种特殊的替代方法。使用除颤器的患者将接受前瞻性跟踪，并将其分为两组，一组是因快速症状性室性心动过速或室颤而经历适当的ICD放电的患者，另一组是在装置植入后三年内没有危及生命的室性心律失常的患者。为期三年的窗口创建了一个实际的终点，允许在授予期间进行组间比较，但所有患者都将被无限期跟踪。在这项研究中，我们将使用SCD的替代物，称为心律失常猝死(ASD)，定义为室性心动过速(VT)或室颤(VF)以及因室性心律失常而未经ICD纠正的死亡。SPOSE-ICD的大小和设计将有助于利用全队列和病例队列分析，对晚期结构性心脏病患者的ASD遗传易感性、电生理重构、炎症、缺血和心肌损伤的途径进行新的研究。连续的血液采样和心电记录将允许随着时间的推移对同一患者的潜在生物标志物进行评估。这将有助于对ASD风险的血清蛋白和心电标记物系列分析的探索性评估。来自这个队列的生物样本的详细表型和现成的可用性将允许在其他人群中确定的生物标记物在散文-ICD中进行测试，以与SCD及其替代物相关联。与公共卫生相关：仅在美国就有500多万人患有晚期心脏病，猝死的风险增加。这项提议的目标有两个：加强对易导致猝死的生物学机制的了解，并开发一个实用的生物标记物小组，以确定植入除颤器的患者具有最大的猝死风险。

DESCRIPTION (provided by applicant): More than 5 million people in the United States alone have advanced left ventricular dysfunction with an increased risk of dying suddenly and by current guidelines are candidates for implantable cardioverter defibrillators (ICDs). The overall hypothesis of this proposal is that interactions between structural (substrate) and functional (trigger) abnormalities, some of which are genetically-determined, can be used to identify patients with structural heart disease at high risk of SCD. The objectives of this proposal are two-fold: to enhance understanding of the biological mechanisms that predispose to SCD in humans, and to develop a practical biomarker panel to identify patients at risk. We exploit programmatic strengths in genetics, proteomics, electrophysiology, and epidemiology and will leverage an ongoing prospective cohort study (PRospective Observational Study of the ICD in SCD, PROSE-ICD) of patients with structural heart disease and reduced left ventricular ejection fraction undergo ICD implantation for primary prevention of SCD. The extensive phenotyping and genotyping of the PROSE- ICD cohort will allow us to explore pathways of electrophysiological remodeling, inflammation, ischemia and myocardial injury, and genetic contributors to SCD in patients with advanced structural heart disease. Stored electrograms in the ICD facilitate the accurate diagnosis of potentially lethal ventricular arrhythmias providing a specific surrogate for arrhythmic SCD. Patients with defibrillators will be followed prospectively and divided into groups who experience an appropriate ICD firing for rapid symptomatic ventricular tachycardia or ventricular fibrillation, and those who remain free of life-threatening ventricular arrhythmias for a period of three years after device implantation. The three-year window creates a practical endpoint that will allow comparisons between groups during the granting period but all patients will be followed indefinitely. We will employ a surrogate of SCD in this study that will be referred to as arrhythmic sudden death (ASD) defined as adjudicated firings for ventricular tachycardia (VT) or ventricular fibrillation (VF) and deaths due to ventricular arrhythmia not corrected by the ICD. The size and design of PROSE-ICD will facilitate novel studies of pathways of genetic predisposition to ASD, electrophysiological remodeling, inflammation, ischemia and myocardial injury in patients with advanced structural heart disease using full cohort and case-cohort analyses. Serial blood sampling and ECG recording will allow for evaluation of potential biomarkers over time in the same patient. This will facilitate exploratory evaluation of serial analysis of serum protein and ECG markers of risk of ASD. The detailed phenotyping and ready availability of biological samples from this cohort will permit biomarkers identified in the other populations to be tested in PROSE-ICD for association with SCD and it surrogates. PUBLIC HEALTH RELEVANCE: More than 5 million people in the United States alone have advanced heart disease with an increased risk of dying suddenly. The objectives of this proposal are two-fold: to enhance understanding of the biological mechanisms that predispose to sudden death and to develop a practical biomarker panel to identify patients with implanted defibrillators at greatest risk of sudden death.