Biomarkers of Prognosis and Response to Therapy in Acute Coronary Syndromes

急性冠脉综合征预后和治疗反应的生物标志物

• 批准号: 7933931
• 负责人: MARC S SABATINE
• 金额: $ 49.85万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933931
• 关键词: Address; Amino Acids; Angiography; Area; Arts; Biological; Biological Assay; Biological Markers; Blood; Blood Tests; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular system; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Coagulation Process; Coronary Arteriosclerosis; Creatine Kinase MB Isoenzyme; Data; Detection; Diagnosis; Diagnostic; Disease; Event; Functional disorder; Generations; Goals; Holter Electrocardiography; Individual; Inflammation; Injury; Ischemia; Lipids; Measurement; Measures; Metabolic; Metabolic Pathway; Monitor; Morbidity - disease rate; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Necrosis; Outcome; Pathway interactions; Patients; Performance; Pharmacotherapy; Phenotype; Proteins; Randomized; Respiratory System; Respiratory tract structure; Risk; Risk Assessment; Sampling; Stress; Structural Protein; Technology; Testing; Therapeutic; Thrombosis; Time; Tissues; Troponin; United States; Validation; Ventricular; acute coronary syndrome; adjudicate; case control; clinical application; clinically relevant; cohort; improved; interest; metabolomics; mortality; muscle stress; novel; outcome forecast; percutaneous coronary intervention; prognostic; protein metabolite; public health relevance; response; sugar

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-HL-101: Identify and Validate Clinically Relevant, Quantifiable Biomarkers of Diagnostic and Therapeutic Responses to Blood, Vascular, Cardiac, and Respiratory Tract Dysfunction. Each year 1.4 million individuals have an acute coronary syndrome (ACS). Their prognosis is highly variable and therapeutic options broad. Circulating biomarkers of necrosis such as troponin have proven invaluable in aiding not only with diagnosis but also prognosis. However, limitations to the analytical performance of current assays at very low concentrations have constrained our ability to risk stratify a substantial number of patients. New, ultrasensitive troponin assays are being developed that have far greater precision at very low concentrations. Our group has led initial studies with these assays, which are 1-2 orders of magnitude more sensitive than current commercial assays, and found that they allow for the identification of myocardial ischemia earlier and in more patients than conventional assays do. In addition to cardiomyocyte-derived proteins released during myocardial injury, there is also growing interest in circulating biomarkers that reliably reflect other relevant pathobiologies central to ACS including inflammation, thrombosis, and ventricular wall stress. Moreover, recent advances in metabolic profiling technologies have enabled the monitoring of hundreds of metabolites ("metabolomics"), that may be deranged very early in disease states. We believe the combination of an ultrasensitive assay for a cardiomyocyte-specific structural protein plus proteins and metabolite markers from relevant pathobiological pathways offers the best chance to develop a comprehensive biomarker panel that offers significant advances in risk assessment. Moreover, such biomarkers hold the promise of enabling clinicians to tailor therapy so as to minimize morbidity and mortality. Thus, the overall goal of this proposal is to validate the ability of state-of-the-art biomarkers to predict major adverse cardiovascular outcomes and benefit of therapy in ACS. To achieve this goal, we will leverage the strength of our TIMI Study Group clinical trials, which offer (1) large numbers of carefully phenotyped patients and adjudicated clinical outcomes, (2) a wealth of additional data including Holter monitoring for ischemia, angiograms, and multiple traditional biomarkers, and (3) randomized allocation to specific pharmacotherapies. In Aim 1, we will investigate the prognostic significance of ultrasensitive troponin measurements for adverse cardiovascular outcomes (a) at the time of presentation, (b) after clinical stabilization, and (c) following percutaneous coronary intervention (PCI). In Aim 2 we will investigate the prognostic significance of novel circulating protein and metabolic biomarkers. In Aim 3 we will test the association between levels of novel biomarkers and the benefit of specific pharmacotherapies. Public Health Relevance: The prognosis in patients suffering a heart attack is highly variable and the therapeutic options broad. We believe extremely sensitive blood tests for damage to heart muscle plus other novel blood tests for inflammation, heart muscle stress, and clotting offer the potential to improve a clinician's ability to determine a patient's prognosis and to tailor therapy so as to minimize the complications of a heart attack.

描述（由申请人提供）： 该申请解决了广泛的挑战领域（03）生物标志物发现，验证以及特定挑战主题，03-HL-101：识别和验证对血液，血管，心脏，心脏和呼吸道功能障碍的诊断和治疗反应的临床相关，可量化的生物标志物。每年有140万人患有急性冠状动脉综合征（ACS）。它们的预后是高度可变的，治疗方案广泛。循环的坏死生物标志物（如肌钙蛋白）在不仅可以诊断和预后方面有证明是宝贵的。但是，在非常低浓度的当前测定法分析性能的局限性限制了我们风险将大量患者分层的能力。正在开发新的，超敏感的肌钙蛋白测定，在非常低的浓度下精确得多。我们的小组对这些测定法进行了初步研究，比目前的商业测定法对1-2个数量级，并发现它们允许早期鉴定心肌缺血，并且在患者中比常规测定更大。除了在心肌损伤期间释放的心肌细胞衍生的蛋白质外，对循环生物标志物的兴趣也日益增加，这些生物标志物可靠地反映了其他相关病态生物学，包括ACS，包括炎症，血栓形成和心室壁应力。此外，代谢分析技术的最新进展使监测数百种代谢产物（“代谢组”），这在疾病状态下可能很早就被危险。我们认为，来自相关病理生物学途径的心肌细胞特异性结构蛋白以及蛋白质和代谢物标记的超敏化测定法提供了开发全面的生物标志物面板的最佳机会，从而在风险评估方面提供了重大进展。此外，这种生物标志物具有使临床医生能够量身定制治疗以最大程度地减少发病率和死亡率的希望。因此，该提案的总体目标是验证最先进的生物标志物预测主要不良心血管结局和ACS治疗的好处的能力。为了实现这一目标，我们将利用TIMI研究组临床试验的强度，该试验提供（1）大量精心型表型患者和裁决的临床结果，（2）大量其他数据，包括缺血，血管疾病，血管疾病和多个传统生物标志物以及（3）特定特定药物治疗的随机分配。在AIM 1中，我们将研究超敏感性肌钙蛋白测量值对不良心血管结局的预后意义（a）在临床稳定后（b）和（c）经皮冠状动脉干预（PCI）之后（c）。在AIM 2中，我们将研究新型循环蛋白和代谢生物标志物的预后意义。在AIM 3中，我们将测试新型生物标志物水平与特定药物疗法的好处之间的关联。 公共卫生相关性： 患有心脏病发作的患者的预后是高度可变的，并且治疗方案广泛。我们认为，对心脏损伤的血液测试非常敏感，以及其他新型的炎症，心肌压力和凝结的血液检查，为提高临床医生确定患者预后和调整治疗的能力提供了潜力，以最大程度地减少心脏病发作的并发症。