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

SCD 的基础生物学及其在识别高危患者中的应用

• 批准号: 8067175
• 负责人: Gordon Frank Tomaselli
• 金额: $ 68.36万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-22 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067175
• 关键词: Biological; Biological Assay; Biological Availability; Biological Markers; Biology; Blood specimen; Candidate Disease Gene; Cardiac; Cessation of life; Chronic; Clinical; Cohort Analysis; Cohort Studies; Data Analyses; Defibrillators; Devices; Diagnosis; Electric Stimulation; Electrocardiogram; Electrophysiology (science); Enrollment; Epidemiology; Evaluation; Event; Genetic; Genetic Predisposition to Disease; Genotype; Grant; Guidelines; Health; Heart Diseases; Human; Implant; Implantable Defibrillators; Incidence; Inflammation; Injury; Left Ventricular Dysfunction; Left Ventricular Ejection Fraction; Life; Measurement; Measures; Metric; Modeling; Myocardial; Myocardial Ischemia; Observational Study; Participant; Pathway interactions; Patients; Phenotype; Population; Primary Prevention; Proteins; Proteomics; Qualifying; Resources; Risk; Risk Marker; Sampling; Serum; Serum Proteins; Signal Transduction; Sudden Death; Testing; Time; United States; Variant; Ventricular Arrhythmia; Ventricular Fibrillation; Ventricular Tachycardia; adjudicate; adjudication; base; cohort; design; experience; follow-up; high risk; implantation; inflammatory marker; novel; programs; prophylactic; prospective; sudden cardiac death

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.

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，猝死风险增加，根据现行指南，他们是植入式心律转复除颤器 (ICD) 的候选者。该提案的总体假设是，结构性（基质）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）可用于识别具有 SCD 高风险的结构性心脏病患者。该提案的目标有两个：加强对人类诱发 SCD 的生物学机制的理解，并开发实用的生物标志物组来识别处于危险中的患者。我们利用遗传学、蛋白质组学、电生理学和流行病学方面的规划优势，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，PROSE-ICD），对象是接受 ICD 植入的结构性心脏病和左心室射血分数降低的患者用于 SCD 的一级预防。 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塑、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 SCD 提供特定替代指标。将前瞻性地对使用除颤器的患者进行随访，并将其分为因快速症状性室性心动过速或心室颤动而接受适当的 ICD 触发的组，以及在装置植入后三年内未出现危及生命的室性心律失常的组。三年的窗口期创造了一个实用的终点，允许在授权期间进行各组之间的比较，但所有患者都将被无限期地跟踪。我们将在本研究中采用 SCD 的替代物，称为心律失常性猝死 (ASD)，定义为室性心动过速 (VT) 或心室颤动 (VF) 判定的放电以及由于 ICD 未纠正的室性心律失常导致的死亡。 PROSE-ICD 的规模和设计将有助于利用完整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、电生理重塑、炎症、缺血和心肌损伤途径进行新研究。连续血液采样和心电图记录将允许评估同一患者随时间推移的潜在生物标志物。这将有助于对 ASD 风险的血清蛋白和心电图标记物的系列分析进行探索性评估。该队列中生物样本的详细表型分析和现成可用将允许在 PROSE-ICD 中测试其他人群中鉴定的生物标志物与 SCD 及其替代物的关联。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，突然死亡的风险增加。该提案的目标有两个：增强对猝死倾向的生物学机制的理解，并开发实用的生物标志物组来识别植入除颤器的患者猝死风险最大的情况。