Metabolic Profiling of Acute Myocardial Injury in Humans

描述(由申请者提供)：项目概要：本建议的目的是促进候选人发展成为一名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的临床研究人员。刘易斯博士将通过哈佛和麻省理工学院博德研究所与马萨诸塞州总医院之间独特的多学科合作，将基于质谱学的小分子图谱培训与临床研究方法论结合起来。临床上对循环生物标记物的需求尚未得到满足，这些生物标记物可以提供心肌缺血和早期(肌钙蛋白阴性)心肌梗死(ML)的生化证据。新陈代谢图谱技术的最新进展提高了获得整个生物体新陈代谢状态的高通量“快照”的可行性。在过去的两年里，刘易斯博士在建立一个液-质联用平台以监测每个人体血浆样本400多种代谢物方面发挥了核心作用。他建议应用这一平台来识别和验证心肌缺血和ML的代谢特征。具体目标1将确定两个患者队列中ML和缺血的代谢变化：1)接受计划ML治疗肥厚性梗阻性心肌病的患者，以及2)在运动平板试验(ETT)期间发生心肌缺血的患者。在这两个队列中，心肌损伤的受控性质允许在损伤之前和之后获取样本，允许每个患者作为他或她自己的生物对照。冠状静脉窦采样将有助于定位计划中的ML代谢变化的来源。具体目标2将是在第二个ETT队列中前瞻性地验证心肌缺血代谢标志物的诊断效用。具体目标3将是验证这些新的代谢生物标记物在急诊胸痛患者中的诊断效用。具体目标4将是将代谢图谱扩展到缺血之外，以确定心功能不全的代谢调节因素。候选人最终将把这一拟议奖项的培训和结果与他的生理学培训结合起来，以确定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发挥着重要作用。然而，目前使用的标志物在心脏病发作后的头几个小时内在血液中检测不到。这项建议概述了一种新的战略，以捕捉发生在心脏损伤反应中的循环代谢产物的快速变化。这些代谢物可以作为新的损伤标志物，帮助指导及时、适当的治疗以纠正代谢异常。(摘要结束)

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)