Metabolic Profiling of Acute Myocardial Injury in Humans

项目概述：该提案的目的是促进候选人向临床医生的发展 能够将心肌缺血和功能障碍的代谢特征转化为临床的研究人员 适用的生物标志物。刘易斯博士将结合基于质谱学的小分子图谱方面的培训 和临床研究方法之间通过广泛的独特的多学科合作 哈佛和麻省理工学院和马萨诸塞州综合医院。 临床上对循环生物标记物的需求尚未得到满足，这些生物标记物可提供心肌梗塞的生化证据。 缺血和早期(肌钙蛋白阴性)心肌梗死(Ml)。代谢谱研究的最新进展 技术已经提高了获得整个生物体的高通量“快照”的可能性 新陈代谢状态。在过去的两年里，刘易斯博士在建立一种液体 色质联用平台，可监测每个人体血浆样本400多种代谢物。 他建议应用这一平台来识别和验证心肌缺血和 毫升。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)患者 接受计划的ML治疗肥厚型梗阻性心肌病，以及2)患者经历 运动平板试验(ETT)中的心肌缺血。在这两个群体中，受控的自然 心肌损伤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防治。冠状静脉窦采样将有助于定位 计划毫升的代谢变化。具体目标2将是前瞻性地验证 第二个ETT队列中心肌缺血的代谢标记物。具体目标3将是验证 这些新的代谢生物标志物在急诊科就诊患者中的诊断价值 伴随着胸痛。具体目标4将是将代谢图谱扩展到缺血之外以识别新陈代谢 心功能不全的调节剂。应聘者最终将整合培训和由此产生的结果 建议授予他的生理学培训奖，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使 对心脏病发作的诊断和指导适当的治疗。然而，当前使用的标记不是 在心脏病发作后的头几个小时内可以在血液中检测到。这份提案勾勒出了一个新颖的战略。 以捕捉心脏损伤后循环代谢产物的快速变化。这些代谢物 可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 异常现象。

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 ofmyocardial 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 novelstrategy 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.