Metabolomic Biomarkers of Early Myocardial Injury

早期心肌损伤的代谢组生物标志物

• 批准号: 8040031
• 负责人: ROBERT E GERSZTEN
• 金额: $ 75.88万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8040031
• 关键词: Accident and Emergency department; Address; Biochemical; Biochemical Markers; Biochemistry; Biological; Biological Assay; Biological Markers; Biology; Blood; Cardiac; Cardiac Catheterization Procedures; Cardiovascular Diseases; Catheters; Chest Pain; Citric Acid Cycle; Clinical; Clinical Trials; Coronary Arteriosclerosis; Detection; Diagnosis; Diagnostic; Disease Management; Early treatment; Exercise stress test; Goals; Heart Diseases; Human; Hypertrophic Cardiomyopathy; Image; Injury; Intervention; Isotopes; Kinetics; Link; Liquid Chromatography; Mass Spectrum Analysis; Measurement; Metabolic; Metabolic Pathway; Monitor; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial perfusion; Nature; Pathway interactions; Patient Care; Patients; Pentosephosphate Pathway; Phenotype; Physiology; Pilot Projects; Plasma; Protocols documentation; Research; Risk Factors; Sampling; Surveys; Techniques; Technology; Testing; Time; Unstable angina; Validation; Work; acute coronary syndrome; base; cohort; experience; human disease; improved; metabolomics; novel; nutrition; outcome forecast; prognostic; public health relevance; purine metabolism; tandem mass spectrometry; validation studies

DESCRIPTION (provided by applicant): This proposal aims to identify and validate novel circulating metabolic biomarkers to address critical, unmet needs in cardiovascular disease management. Our studies will specifically focus on myocardial ischemia and early injury, for which no suitable and clinically practical blood biomarkers presently exist. Our goal is to build on our initial observations and working hypotheses that an unbiased metabolomics discovery platform will yield novel biomarkers, and that simultaneous assessment of multiple biomarkers examining different pathophysiological axes will provide complementary information to improve diagnosis and clarify prognosis. Newly developed metabolomics techniques, richly-annotated clinical samples, as well as novel biomarkers already identified serve as the underpinnings for the proposed studies: In Specific Aim 1, we will use our LC- MS/MS-based metabolomics platform to identify novel early markers of myocardial injury in three unique cohorts of patients experiencing planned myocardial ischemia or injury: patients undergoing cardiac exercise stress testing with myocardial perfusion imaging, patients subjected to pacing-induced myocardial ischemia in the cardiac catheterization suite, and patients experiencing a planned myocardial infarction for hypertrophic cardiomyopathy. In Specific Aim 2, we will then characterize novel early markers of myocardial injury in carefully phenotyped cohorts of healthy controls, patients with stable coronary artery disease (CAD), and patients presenting across the spectrum of acute coronary syndromes (ACS). In Aim 3a, we will test the hypothesis that the novel biomarkers will aid diagnosis in two currently challenging clinical settings. First, we will test whether measurement of the biomarkers in patients undergoing exercise stress testing will enable the detection of inducible myocardial ischemia. Second, we examine whether measurement of the biomarkers in patients presenting to the Emergency Department with chest pain improves our ability to discriminate between non-ischemic chest pain versus unstable angina. In Aim 3b, we will test the hypothesis that the novel biomarkers will offer independent prognostic value beyond traditional clinical risk factors and established biomarkers in patients across several cardiac disease states including initial presentation with unstable angina and recent stabilization after ACS. PUBLIC HEALTH RELEVANCE: Given the mounting evidence in favor of early treatments for patients presenting with acute coronary syndromes, discovering sensitive and specific biomarkers that provide biochemical evidence of early myocardial injury could have a substantial positive impact on patient care. This project describes the application of a new metabolomics technology for biomarker discovery to address this clinical need.

描述（由申请人提供）：该提案旨在识别和验证新颖的循环代谢生物标志物，以满足心血管疾病管理中关键，未满足的需求。我们的研究将特别关注心肌缺血和早期损伤，目前不存在合适和临床实用的血液生物标志物。我们的目标是建立我们的最初观察结果和工作假设，即公正的代谢组学发现平台将产生新颖的生物标志物，并且对多种生物标志物的同时评估了多种生物标志物检查不同的病理生理轴，将提供互补的信息，以改善诊断和澄清预后。新开发的代谢组学技术，丰富的临床样本以及已经确定的新型生物标志物是拟议的研究的基础：在特定的目标1中，我们将使用基于LC-MS/MS的代谢组学平台来使用我们的心肌症患者的三个独特的肌肉症患者的新型早期损伤（在经历过的肌肉症患者）中进行，以识别肌肉疾病的新型早期标记：心肌灌注成像，在心脏导管套件中患有起搏引起的心肌缺血的患者，以及患有肥厚性心肌病的心肌梗塞的患者。在特定的目标2中，我们将在精心表现的健康对照组中，稳定的冠状动脉疾病（CAD）患者以及在急性冠状动脉综合征（ACS）范围内出现的患者中，表征了心肌损伤的新型早期标记。在AIM 3A中，我们将检验以下假设：新型生物标志物将在两个当前具有挑战性的临床环境中有助于诊断。首先，我们将测试接受运动胁迫测试的患者中生物标志物的测量是否能够检测到可诱导的心肌缺血。其次，我们检查了出现在急诊室疼痛的患者中生物标志物的测量是否可以提高我们区分非缺血性胸痛与不稳定心绞痛的能力。在AIM 3B中，我们将检验以下假设：新型生物标志物将在几种心脏病状态的患者中提供超出传统临床风险因素和确定的生物标志物，包括具有不稳定的心绞痛的初始呈现以及ACS后最近稳定。 公共卫生相关性：鉴于对患有急性冠状动脉综合征的患者进行早期治疗的越来越多的证据，发现敏感和特定的生物标志物提供了早期心肌损伤的生化证据，可能会对患者护理产生重大积极影响。该项目描述了一种新的代谢组学技术在生物标志物发现中的应用来满足这一临床需求。