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500万人患有左心室功能障碍，突然死亡的风险增加，并且按照当前的准则是植入可植入的心脏扭矩除颤器（ICDS）的候选人。该提议的总体假设是结构（基板）与功能（触发）异常之间的相互作用（其中一些是遗传确定的）可用于鉴定患有SCD高风险的结构性心脏病患者。该提案的目标是两方面：增强对人类SCD的生物学机制的理解，并开发实用的生物标志物小组以识别有风险的患者。我们利用了遗传学，蛋白质组学，电生理学和流行病学方面的程序性强度，并将利用持续的前瞻性队列研究（SCD中ICD的前瞻性观察性研究，散文ICD，散文ICD）的结构性心脏病患者的患者和左心室散发量减少的ICD植入率降低了ICD植入量。散发性的大量表型和基因分型将使我们能够探索电生理重塑，炎症，缺血和心肌损伤的途径，以及晚期结构心脏病患者SCD的遗传贡献者。 ICD中存储的电图促进了对潜在致命性心律不齐的准确诊断，从而为心律不齐SCD提供了特定的替代物。具有除颤剂的患者将被前瞻性地遵循，并将其分为成群，这些患者经历了适当的ICD射击，以快速症状心室心动过速或心室纤维化，以及那些在装置植入后三年内没有危及生命的心律失常的患者。为期三年的窗口创建了一个实用的终点，可以在授予期间进行比较，但将无限期遵循所有患者。在这项研究中，我们将采用SCD的替代物，将其称为心律不齐突然死亡（ASD），该死亡（ASD）被定义为心室心动过速（VT）或心室纤维化（VF）的裁决点火（VF）和由于无法通过ICD校正的心室心律失常引起的死亡。散文-ICD的大小和设计将促进对ASD遗传易感性，电生理重塑，炎症，缺血和心肌损伤的新途径，该患者使用完整的队列和病例 - 霍特分析。连续采样和心电图记录将允许在同一患者中评估潜在的生物标志物。这将有助于对ASD的血清蛋白和ECG标记的系列分析进行探索性评估。来自该队列的生物样品的详细表型和现成的生物样品将允许在其他种群中鉴定出在散文ICD中测试的生物标志物，以与SCD及其替代物相关。公共卫生相关性：仅在美国，超过500万人就患有心脏病，突然死亡的风险增加。该提案的目标是两方面：增强对易于猝死的生物学机制的理解，并开发一个实用的生物标志物小组，以鉴定具有最大死亡风险的植入植入除颤器的患者。