Metabolomic Biomarkers of Early Myocardial Injury

描述(由申请人提供)：本提案旨在识别和验证新的循环代谢生物标记物，以解决心血管疾病管理中关键的、未得到满足的需求。我们的研究将专门针对心肌缺血和早期损伤，目前还没有合适的和临床实用的血液生物标志物。我们的目标是建立在我们最初的观察和工作假设的基础上，即一个无偏见的代谢组学发现平台将产生新的生物标记物，同时评估检查不同病理生理轴的多个生物标记物将提供补充信息，以改善诊断和明确预后。新开发的代谢组学技术、注释丰富的临床样本以及已经确定的新生物标记物可以作为建议研究的基础：在特定目标1中，我们将使用我们基于LC-MS/MS的代谢组学平台在三个独特的计划性心肌缺血或损伤患者队列中识别新的心肌损伤早期标志物：接受心肌灌注成像运动负荷试验的患者，在心导管室接受起搏诱导心肌缺血的患者，以及因肥厚性心肌病而发生计划心肌梗死的患者。在特定的目标2中，我们将在健康对照组、稳定型冠状动脉疾病(CAD)患者和各种急性冠状动脉综合征(ACS)患者中仔细研究新的心肌损伤早期标志物。在目标3a中，我们将测试新的生物标记物将在两个当前具有挑战性的临床环境中辅助诊断的假设。首先，我们将测试在接受运动负荷测试的患者中测量生物标记物是否能够检测到诱导性心肌缺血。其次，我们检查了在急诊科就诊的胸痛患者的生物标记物的测量是否提高了我们区分非缺血性胸痛和不稳定型心绞痛的能力。在目标3b中，我们将检验这一假设，即新的生物标记物将提供独立的预后价值，而不是传统的临床危险因素和已建立的生物标记物在几种心脏疾病状态下的患者，包括最初出现不稳定心绞痛和最近急性冠脉综合征后稳定。 公共卫生相关性：鉴于越来越多的证据支持对表现为急性冠状动脉综合征的患者进行早期治疗，发现敏感和特异的生物标记物可以提供早期心肌损伤的生化证据，可能会对患者护理产生实质性的积极影响。本项目描述了一种新的代谢组学技术在生物标记物发现中的应用，以满足这一临床需求。

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.