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

描述(由申请人提供)： 心脏性猝死(ASD)是一个主要的公共卫生问题，每年影响美国30多万人。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的高危人群。目前的指南建议对左心室射血分数(LVEF)为35%的患者预防性放置植入性心律转复除颤器(ICD)。这一过程本身不能治愈，与高昂的成本相关，而且也不是没有短期和长期的不利影响。此外，这种仅以左心室射血分数为基础的预防策略，导致植入的ICD比挽救生命所需的ICD多10倍，总体上反映了对ASD易患生物途径的有限了解。考虑到这些风险、生活质量的降低以及这些昂贵设备对现有资源的日益沉重的负担，显然有必要开发更好的风险分层技术。由于目前已知的SCD的危险因素既不敏感也不特异，本提案旨在开发一种新的生物标记物小组，以帮助识别SCD风险增加的个体，从而成为ICD植入的理想候选者。这项建议是两项对接受ICD植入的患者进行的最大的、得到RO1资助的、具有全国代表性的队列研究中的一项辅助研究--SCD中ICD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(GRAME，n=2,000)研究。两个父母队列具有非常相似的登记标准、患者特征以及本研究所需生物材料的可用性。辅助研究将利用无偏见的代谢组扫描的优势，包括数千种基因转录的最终下游产物、酶活性和外部给药物质的代谢产物，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，但严格表型的父母队列的可用性将为这些代谢物易患SCD的生物和机制途径提供新的见解。由于代谢组是最接近的“快照”，建议的代谢物小组的鉴定将是对目前使用的SCD风险预测算法的重大补充，并完美地补充了父代队列的总体特定目标。这项辅助研究的结果将对500多万被认为符合ICD资格的个人产生直接影响，一些发现可能适用于大多数SCD发生的普通人群。 公共卫生相关性： 根据目前的指导方针，美国有500多万患有晚期心脏病的人被认为有很高的猝死风险，因此有资格植入心脏转复除颤器以防止心律失常猝死。目前的风险分层算法，仅基于心脏功能，导致每挽救一条生命就植入10个或更多这样的设备。这项提议旨在开发一种新的生物标志物小组，基于对2,000多种下游基因代谢产物、酶活性和外部给药物质(统称为人类代谢组)的无偏见扫描，以确定真正从这些昂贵设备中受益的个人。

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. PUBLIC HEALTH RELEVANCE: Under current guidelines, over five million individuals in the United States with advanced heart disease are considered to be at a high risk of dying suddenly, and therefore eligible for the implantation of cardioverter defibrillators for prevention of arrhythmic sudden cardiac death. The current risk-stratification algorithm, based on heart function alone, results in the implantation of 10 or more of these devices for each life saved. This proposal aims at developing a novel biomarker panel based on unbiased scans of over 2,000 downstream metabolic products of genes, enzyme activity, and extraneously administered substance (collectively known as the human metabolome), in order to identify individuals who will truly benefit from these expensive devices.