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

描述（由申请人提供）：仅在美国就有超过500万人患有晚期左心室功能障碍，并且突然死亡的风险增加，根据目前的指南，这些患者是植入式心律转复除颤器（ICDs）的候选者。该建议的总体假设是结构（底物）和功能（触发）异常之间的相互作用，其中一些是遗传决定的，可用于识别具有SCD高风险的结构性心脏病患者。本提案的目标有两个：加强对人类SCD易感性的生物学机制的理解，并开发一种实用的生物标志物面板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方面的优势，并将利用一项正在进行的前瞻性队列研究（前瞻性观察研究ICD in SCD， PROSE-ICD），对结构性心脏病和左室射血分数降低的患者进行ICD植入，以一级预防SCD。PROSE- 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的电生理重构、炎症、缺血和心肌损伤的途径以及SCD的遗传因素。ICD中存储的心电图有助于准确诊断潜在致命性室性心律失常，为心律失常性SCD提供了一种特定的替代方法。使用除颤器的患者将进行前瞻性随访，并分为两组，一组因快速症状性室性心动过速或心室颤动而经历适当的ICD触发，另一组在装置植入后三年内没有危及生命的室性心律失常。三年的窗口创造了一个实际的终点，允许在批准期间进行组间比较，但所有患者都将无限期随访。在本研究中，我们将采用一种替代SCD的方法，即心律失常性猝死（ASD），定义为因室性心动过速（VT）或心室颤动（VF）而确定的放电，以及因未经ICD纠正的室性心律失常导致的死亡。PROSE-ICD的大小和设计将通过全队列和病例队列分析，促进晚期结构性心脏病患者ASD遗传易感性、电生理重构、炎症、缺血和心肌损伤途径的新研究。连续的血液采样和心电图记录将允许在同一患者中随时间评估潜在的生物标志物。这将有助于对ASD风险的血清蛋白和心电图标志物的系列分析进行探索性评价。该队列生物样本的详细表型和可用性将允许在其他人群中识别的生物标志物在PROSE-ICD中进行与SCD及其替代品的关联测试。公共卫生相关性：仅在美国就有超过500万人患有晚期心脏病，并且突然死亡的风险增加。本建议的目标有两个：加强对猝死易感性的生物学机制的理解，并开发一个实用的生物标志物小组，以识别具有最大猝死风险的植入除颤器的患者。

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.