Metabolic Profiling of Acute Myocardial Injury in Humans

人类急性心肌损伤的代谢分析

• 批准号: 8123295
• 负责人: Gregory Dyer Lewis
• 金额: $ 14.24万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-22 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123295
• 关键词: Accident and Emergency department; Acute; Award; Biochemical; Biological; Biological Markers; Blood; Blood Tests; Chest Pain; Clinical; Clinical Investigator; Clinical Research; Collaborations; Complement; Coronary Angiography; Coronary sinus structure; Couples; Data; Development; Diagnosis; Diagnostic; Exercise; Exercise stress test; Fostering; Functional disorder; General Hospitals; Heart; Heart Injuries; Heart failure; Hormones; Hour; Human; Hypertrophic Cardiomyopathy; Image; Injury; Institutes; Ischemia; K-Series Research Career Programs; Left; Lighting; Liquid Chromatography; Lung; Mass Spectrum Analysis; Massachusetts; Measurement; Measures; Metabolic; Metabolic Marker; Metabolic Pathway; Molecular Weight; Monitor; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocardial perfusion; Nature; Patients; Performance; Physiology; Plasma; Play; Publishing; Pulmonary Vascular Resistance; Radionuclide Ventriculography; Reporting; Research; Research Methodology; Research Personnel; Right Ventricular Dysfunction; Right Ventricular Function; Role; Sampling; Signal Transduction; Source; Specificity; Technetium Tc 99m Sestamibi; Technology; Testing; Time; Training; Translating; Treadmill Tests; Troponin; Unstable angina; Venous; Ventricular; Ventricular Dysfunction; Whole Organism; abstracting; base; blood pressure regulation; candidate identification; cohort; experience; hemodynamics; improved; liquid chromatography mass spectrometry; metabolomics; novel; novel marker; novel strategies; outcome forecast; programs; response; small molecule; tandem mass spectrometry

DESCRIPTION (provided by applicant): PROJECT SUMMARY: The purpose of this proposal is to foster the candidate's development into a clinical investigator capable of translating metabolic signatures of myocardial ischemia and dysfunction into clinically applicable biomarkers. Dr. Lewis will couple training in mass-spectrometry based small molecule profiling and clinical research methodology through a unique, multi-disciplinary collaboration between the Broad Institute of Harvard & MIT and the Massachusetts General Hospital. There is an unmet clinical need for circulating biomarkers that provide biochemical proof of myocardial ischemia and early (troponin negative) myocardial infarction (Ml). Recent advances in metabolic profiling technologies have enhanced the feasibility of obtaining high throughput "snapshots" of a whole organism's metabolic state. Over the past 2 years, Dr. Lewis has played a central role in establishing a liquid chromatography-mass spectrometry platform to monitor over 400 metabolites per human plasma sample. He proposes to apply this platform to identify and validate metabolic signatures of myocardial ischemia and Ml. Specific Aim 1 will be to identify metabolic changes of Ml and ischemia in two patient cohorts: 1) patients undergoing planned Ml to treat hypertrophic obstructive cardiomyopathy, and 2) patients experiencing myocardial ischemia during exercise treadmill testing (ETT). In both of these cohorts, the controlled nature of the myocardial insult permits samples to be obtained before and after the insult, allowing each patient to serve as his or her own biological control. Coronary sinus sampling will aid in localizing the source of metabolic changes in planned Ml. Specific Aim 2 will be to prospectively validate the diagnostic utility of metabolic markers of myocardial ischemia in a second ETT cohort. Specific Aim 3 will be to validate the diagnostic utility of these novel metabolic biomarkers in patients presenting to the emergency department with chest pain. Specific Aim 4 will be to extend metabolic profiling beyond ischemia to identify metabolic modulators of ventricular dysfunction. The candidate will ultimately integrate training and results from this proposed award with his physiology training to define metabolic signatures of ischemia and heart failure. RELEVANCE: Blood tests that measure markers of heart damage play an important role in making the diagnosis of heart attack and in guiding appropriate treatments. Currently used markers, however, are not detectable in the blood for the first several hours after a heart attack. This proposal outlines a novel strategy to capture rapid changes in circulating metabolites that occur in response to heart injury. These metabolites may serve as new markers of injury to help to guide prompt, appropriate treatments to correct metabolic abnormalities. (End of Abstract)

描述（由申请人提供）：项目摘要：该提案的目的是将候选人的发展促进临床研究者，该研究人员能够将心肌缺血和功能障碍的代谢特征转化为临床适用的生物标志物。刘易斯博士将通过基于质谱法的小分子分析和临床研究方法进行培训，通过哈佛大学广泛研究所和马萨诸塞州综合医院之间的独特的多学科合作。对循环生物标志物的临床需求未满足，这些生物标志物提供了心肌缺血的生化证明和早期（肌钙蛋白阴性）心肌梗塞（ML）。代谢分析技术的最新进展增强了获得整个生物体代谢状态的高吞吐量“快照”的可行性。在过去的两年中，刘易斯博士在建立液相色谱 - 质谱平台方面发挥了核心作用，可以根据人血浆样品监测超过400个代谢产物。他建议应用此平台来识别和验证心肌缺血和ML的代谢特征。具体目的1将是在两个患者队列中鉴定ML和缺血的代谢变化：1）接受计划的ML治疗肥厚性阻塞性心肌病的患者，以及2）运动跑步机期间患有心肌缺血的患者（ETT）。在这两个队列中，心肌侮辱的受控性质允许在侮辱之前和之后获得样本，使每个患者都可以作为他自己的生物控制。冠状动脉鼻窦抽样将有助于定位计划的ML代谢变化的来源。具体目标2将是前瞻性验证第二个ETT队列中心肌缺血代谢标记的诊断效用。具体目的3将是验证这些新型代谢生物​​标志物在胸痛向急诊科发给急诊科的患者中的诊断效用。具体目标4将是将代谢谱扩展到缺血之外，以鉴定心室功能障碍的代谢调节剂。候选人最终将将该拟议奖的培训和结果与他的生理培训相结合，以定义缺血和心力衰竭的代谢特征。相关性：测量心脏损伤标志物的血液测试在诊断心脏病发作和指导适当治疗方面起着重要作用。但是，目前使用的标记在心脏病发作后的头几个小时内无法在血液中检测到。该提案概述了一种新的策略，以捕获响应心脏损伤而发生的循环代谢产物的快速变化。这些代谢产物可能是损伤的新标志，以帮助指导迅速，适当的治疗以纠正代谢异常。 （抽象的结尾）