Metabolome-wide anaysis for the risk-stratification of sudden cardiac death

心源性猝死风险分层的全代谢组分析

• 批准号: 8722592
• 负责人: Alan Cheng
• 金额: $ 62.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722592
• 关键词: Adverse effects; Affect; Algorithms; Ancillary Study; Arrhythmia; Biological Availability; Biological Markers; Biology; Blood; Blood specimen; Cardiac Myocytes; Cardiomyopathies; Cell physiology; Cessation of life; Characteristics; Clinical Research; Cohort Studies; Collection; Complement; Complex; Defibrillators; Development; Devices; Diet; Disease; EFRAC; Electric Stimulation; Electrocardiogram; Enrollment; Ensure; Equation; Event; Fingerprint; Funding; Future; General Population; Generations; Genetic; Genetic Transcription; Grant; Guidelines; Heart Diseases; Human; Implant; Implantable Defibrillators; Incidence; Individual; Investigation; Left Ventricular Dysfunction; Left Ventricular Ejection Fraction; Life; Measurement; Measures; Metabolic; Myocardial Infarction; National Heart, Lung, and Blood Institute; Nature; Observational Study; Parents; Participant; Pathway interactions; Patients; Pattern; Phase; Phenotype; Physiology; Prevention; Prevention strategy; Primary Prevention; Procedures; Proteins; Public Health; Qualifying; Quality of life; Resources; Risk; Risk Factors; Sample Size; Sampling; Scanning; Secondary to; Serum; Shock; Signal Transduction; Statistical Methods; Stratification; Sudden Death; Techniques; Time; United States; Validation; Ventricular Tachycardia; adjudicate; adjudication; base; case control; cohort; cost; design; enzyme activity; follow-up; genetic risk assessment; heart function; high risk; implantation; injured; insight; liquid chromatography mass spectrometry; metabolomics; novel; novel marker; novel therapeutics; palliative; peripheral blood; programs; prophylactic; prospective; public health relevance; small molecule; sudden cardiac death; tool; validation studies

DESCRIPTION (provided by applicant): Sudden cardiac death (ASD) is a major public health problem affecting over 300,000 individuals in the United States each year. Over 5 million individuals in United States who have advanced left ventricular (LV) dysfunction, usually secondary to myocardial infarction or non-ischemic cardiomyopathy, are considered to be a high-risk of SCD. The current guidelines recommend a prophylactic placement of an implantable cardioverter defibrillator (ICD) in patients with a LV ejection fraction (LVEF) of <35%. The procedure itself is not curative, is associated with high costs, and is not free from short- and long-term adverse effects. Moreover, this preventive strategy, based on LVEF alone, results in 10 times more ICDs implanted than required to save a life, and in general reflects the limited understanding of the biologic pathways predisposing to ASD. In considering these risks, the impaired quality of life, and the increasing burden on the exiting resources due these expensive devices, there is a clear need for the development better risk-stratification techniques. As the currently known risk-factors for SCD are neither sensitive nor specific, this proposal is aimed at developing a novel biomarker panel that will help identify individuals who are at an increased risk of SCD, and thus the ideal candidates for ICD implantation. This proposal is an ancillary study within two of the largest, well-established, RO1-funded, and nationally representative cohort studies of patients undergoing ICD implantation - the PRospective Observational Study of the ICD in SCD (PROSE-ICD, n=1,200) and the Genetic Risk Assessment of Defibrillator Events (GRADE, n=2,000) studies. Both parent cohorts have remarkably similar enrollment criteria, patient characteristics, and availability of biologic material necessary for this study. The ancillary study will leverage the strengths of unbiased metabolome-wide scans, which include thousands of final downstream products of gene transcription, enzyme activity and metabolic products of extraneously administered substances, in order to identify a metabolomic fingerprint associated with at an increased risk of SCD. While the large sample size and the availability of independent discovery and validation cohorts will eliminate false positive associations, the availability of stringently phenotyped parent cohort will provide novel insights into the biologic and mechanistic pathways by which these metabolites may predispose to SCD. As the metabolome is the most proximal 'snapshot', the identification of the proposed metabolite panel will be a significant addition to the currently used risk-prediction algorithms for SCD and perfectly complement the overall specific aims of the parent cohorts. The results of this ancillary study will have direct implication over 5 million individuals who are considered ICD eligible and some findings may be applicable to the general population where majority of SCDs occur.

描述（由申请人提供）： 心源性猝死 (ASD) 是一个重大的公共卫生问题，每年影响美国超过 300,000 人。在美国，有超过 500 万人患有晚期左心室 (LV) 功能障碍（通常继发于心肌梗塞或非缺血性心肌病），被认为是 SCD 的高危人群。目前的指南建议对左心室射血分数 (LVEF) <35% 的患者预防性放置植入式心律转复除颤器 (ICD)。该手术本身没有疗效，成本高昂，并且存在短期和长期的不良影响。此外，这种仅基于 LVEF 的预防策略导致植入的 ICD 数量比挽救生命所需的数量多 10 倍，并且总体上反映了对诱发 ASD 的生物途径的了解有限。考虑到这些风险、生活质量受损以及这些昂贵设备对现有资源造成的日益增加的负担，显然需要开发更好的风险分层技术。 由于目前已知的 SCD 风险因素既不敏感也不特异，该提案旨在开发一种新型生物标志物组合，帮助识别 SCD 风险增加的个体，从而识别 ICD 植入的理想人选。该提案是两项最大的、完善的、由 RO1 资助且具有全国代表性的 ICD 植入患者队列研究中的一项辅助研究，即 ICD 在 SCD 中的前瞻性观察研究 (PROSE-ICD，n=1,200) 和除颤器事件的遗传风险评估 (GRADE，n=2,000) 研究。两个父队列具有非常相似的入组标准、患者特征以及本研究所需的生物材料的可用性。该辅助研究将利用无偏见的全代谢组扫描的优势，其中包括数千种基因转录的最终下游产物、酶活性和外源施用物质的代谢产物，以确定与 SCD 风险增加相关的代谢组指纹。虽然大样本量以及独立发现和验证队列的可用性将消除假阳性关联，但严格表型亲代队列的可用性将为这些代谢物可能诱发 SCD 的生物学和机制途径提供新的见解。由于代谢组是最近的“快照”，因此所提出的代谢物组的识别将是对当前使用的 SCD 风险预测算法的重要补充，并完美补充父群体的总体具体目标。这项辅助研究的结果将对超过 500 万被认为符合 ICD 资格的人产生直接影响，并且一些研究结果可能适用于大多数 SCD 发生的一般人群。