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

描述（由申请人提供）： 心源性猝死（ASD）是美国每年影响超过30万人的主要公共卫生问题。在美国，超过500万人患有晚期左心室（LV）功能障碍，通常继发于心肌梗死或非缺血性心肌病，被认为是SCD的高风险。目前的指南建议在左心室射血分数（LVEF）<35%的患者中预防性放置植入式心律转复除颤器（ICD）。该手术本身并不具有治愈性，费用高昂，而且并非没有短期和长期的不良影响。此外，仅基于LVEF的这种预防策略导致植入的ICD比挽救生命所需的多10倍，并且通常反映了对ASD易感生物学途径的有限理解。考虑到这些风险、生活质量受损以及这些昂贵器械对现有资源造成的日益加重的负担，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，因此该提案旨在开发一种新的生物标志物面板，以帮助识别SCD风险增加的个体，从而确定ICD植入的理想候选人。该提案是两项最大的、成熟的、由RO 1资助的、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-ICD在SCD中的前瞻性观察性研究（PROSE-ICD，n= 1，200）和除颤器事件的遗传风险评估（GRADE，n= 2，000）研究。两个母队列的入组标准、患者特征和本研究所需生物材料的可用性非常相似。辅助研究将利用无偏代谢组全扫描的优势，包括数千种基因转录的最终下游产物，酶活性和非药物给药物质的代谢产物，以确定与SCD风险增加相关的代谢组学指纹。虽然大样本量和独立发现和验证队列的可用性将消除假阳性关联，但严格表型父队列的可用性将为这些代谢物可能易患SCD的生物学和机制途径提供新的见解。由于代谢物组是最接近的“快照”，因此拟定代谢物组的鉴定将是对目前使用的SCD风险预测算法的重要补充，并完美地补充了母体队列的总体特定目标。这项辅助研究的结果将直接影响超过500万名被认为符合ICD条件的个体，一些结果可能适用于大多数SCD发生的一般人群。

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.