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

基本信息

批准号：
7817856
负责人：
MARC S SABATINE
金额：
$ 50万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/7817856
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

项目摘要

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）：该应用解决了广泛的挑战领域 (03) 生物标志物发现和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)。他们的预后变化很大，治疗选择也很广泛。肌钙蛋白等坏死的循环生物标志物已被证明不仅有助于诊断，而且有助于预后。然而，当前检测方法在极低浓度下分析性能的局限性限制了我们对大量患者进行风险分层的能力。新型超灵敏肌钙蛋白检测方法正在开发中，其在极低浓度下具有更高的精确度。我们的小组领导了对这些检测的初步研究，这些检测比目前的商业检测灵敏1-2个数量级，并发现它们可以比传统检测更早地识别更多患者的心肌缺血。除了心肌损伤期间释放的心肌细胞衍生蛋白外，人们对可靠反映 ACS 核心其他相关病理学（包括炎症、血栓形成和心室壁应力）的循环生物标志物也越来越感兴趣。此外，代谢分析技术的最新进展已经能够监测数百种代谢物（“代谢组学”），这些代谢物可能在疾病状态的早期就发生紊乱。我们相信，将心肌细胞特异性结构蛋白、相关病理生物学途径的蛋白质和代谢标记物的超灵敏测定相结合，为开发综合生物标记物组合提供了最佳机会，该组合在风险评估方面取得了重大进展。此外，此类生物标志物有望使临床医生能够定制治疗方案，以最大限度地降低发病率和死亡率。因此，该提案的总体目标是验证最先进的生物标志物预测 ACS 的主要不良心血管结局和治疗益处的能力。为了实现这一目标，我们将利用 TIMI 研究组临床试验的优势，该试验提供 (1) 大量经过仔细表型分析的患者和经过判定的临床结果，(2) 大量额外数据，包括缺血动态心电图监测、血管造影、和多种传统生物标志物，以及（3）随机分配到特定的药物疗法。在目标 1 中，我们将研究超灵敏肌钙蛋白测量对不良心血管结局（a）出现时、（b）临床稳定后和（c）经皮冠状动脉介入治疗（PCI）后的预后意义。在目标 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。在目标 3 中，我们将测试新型生物标志物水平与特定药物疗法的益处之间的关联。公共卫生相关性：心脏病发作患者的预后变化很大，治疗选择也很广泛。我们相信，针对心肌损伤的极其灵敏的血液检测以及针对炎症、心肌应激和凝血的其他新型血液检测有可能提高临床医生确定患者预后和调整治疗方案的能力，从而最大限度地减少心脏疾病的并发症。心脏病发作。