Novel Biomarkers to Identify Vulnerable Patients with Coronary Artery Disease

识别易患冠状动脉疾病的患者的新型生物标志物

• 批准号: 7564535
• 负责人: MARC S SABATINE
• 金额: $ 31.51万
• 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: 2009-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564535
• 关键词: Acute; Amino Acids; Angiotensin-Converting Enzyme Inhibitors; Arteries; Atherosclerosis; Basic Science; Biochemical; Biological; Biological Markers; Blood Tests; Blood specimen; Cardiac Myocytes; Cardiovascular system; Cessation of life; Chronic; Clinical Research; Clinical Trials; Cohort Studies; Complication; Coronary; Coronary Arteriosclerosis; Coronary heart disease; Data; Data Set; Detection; Development; Diagnosis; Disease; Disease Progression; Endothelial Cells; Event; Functional disorder; Future; Genes; Genomics; Goals; Heart Diseases; Individual; Injury; Investigation; Leukocytes; Lipids; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Pathway; Monitor; Morbidity - disease rate; Myocardial; Myocardial Infarction; Nested Case-Control Study; Outcome; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Physicians; Platelet Activation; Play; Predictive Value; Process; Proteins; Recurrence; Registries; Research; Risk; Risk Factors; Risk Marker; Role; Rupture; Sampling; Staging; Stroke; Subgroup; Technology; Testing; Transcript; United States; Unstable angina; Validation; Work; atherothrombosis; base; cardiovascular risk factor; cohort; cost; experience; follow-up; genome wide association study; high risk; interest; metabolomics; mortality; novel; outcome forecast; peace; prognostic; protein metabolite; public health relevance; sugar; tool; trandolapril

DESCRIPTION (provided by applicant): Over 16 million patients are estimated to have coronary artery disease (CAD) in the United States alone. Whereas some patients will have quiescent disease, others will suffer plaque rupture and develop acute, overt ischemic complications. Thus, a major challenge for clinicians is to identify which of their patients with apparently stable CAD are, in fact, vulnerable to major adverse outcomes in the ensuing years. Until recently, cardiovascular biomarkers have been primarily limited to cardiomyocyte-derived proteins released during myocardial infarction (MI), and thus have been restricted to diagnosing a major complication of CAD after it has occurred. However, a greater understanding of the complexity of atherothrombosis has catalyzed an interest in examining novel biomarkers that may provide reliable, non-invasive biochemical detection of the underlying pathobiological processes that render patients vulnerable to future cardiovascular events, including oxidative stress, leukocyte recruitment & activation, endothelial cell dysfunction, fibrous cap degradation, and platelet activation. Moreover, candidate biomarker selection can now additionally be informed by data from "omics" profiling including genomics and metabolomics. Specifically, the results from several recently completed genome-wide association studies have implicated several proteins previously not thought to play a role in CAD. Similarly, recent advances in mass spectrometry based metabolic profiling technologies have enabled the monitoring of hundreds of metabolites from biological samples. These lipids, sugars, and amino acids serve as substrates and products for metabolic pathways that may be deranged very early in disease states. The combination of proteins from known, pathobiologically relevant pathways plus proteins and metabolites not previously suspected to play a role in coronary disease but identified and validated through unbiased investigative approaches offers the best chance to develop a biomarker panel that offers substantial rather than simply incremental advances in prognosis. Thus, the overall goal of this proposal is to determine the ability of novel biomarkers to predict major adverse cardiovascular outcomes in patients with chronic CAD. We will utilize a cost-efficient staged approach to assess candidate biomarkers in blood samples from 3778 patients from PEACE, an NIH-sponsored clinical trial of the angiotensin-converting enzyme (ACE) inhibitor trandolapril in patients with chronic CAD. In Aim 1 we will investigate the prognostic utility of 14 novel protein biomarkers for adverse cardiovascular outcomes in a nested case-cohort study of 1100 patients from PEACE. In Aim 2 we will use metabolomics to identify and validate the association of metabolites with adverse cardiovascular outcomes in 2 nested case-control studies. In Aim 3 we will fully characterize the prognostic utility of promising novel biomarkers in the entire trial cohort and combine traditional risk factors and multiple biomarkers to create comprehensive risk prediction tools. PUBLIC HEALTH RELEVANCE: Over 16 million patients are estimated to have coronary artery disease in the United States alone, and despite modern therapy, these patients remain at significant risk for future adverse cardiovascular outcomes such as death, recurrent heart attacks, and strokes. Our greater understanding of what causes plaques to build up in arteries and eventually rupture has created an opportunity to develop blood tests that might better predict which individuals are at high risk for disease progression; such tests might also be used by physicians to target therapy to patients who would reap the greatest benefit. Our goal is to evaluate potential new blood tests that may predict recurrent heart disease and determine which ones offer the greatest value.

描述（由申请人提供）：据估计，仅在美国就有超过 1600 万患者患有冠状动脉疾病 (CAD)。有些患者会出现静止期疾病，而另一些患者则会出现斑块破裂并出现急性、明显的缺血性并发症。因此，临床医生面临的一个主要挑战是确定哪些表面上稳定的 CAD 患者实际上在接下来的几年中容易遭受重大不良后果。直到最近，心血管生物标志物主要局限于心肌梗塞 (MI) 期间释放的心肌细胞衍生蛋白，因此仅限于诊断 CAD 发生后的主要并发症。然而，对动脉粥样硬化血栓形成的复杂性的更多了解促使人们对检查新型生物标志物产生了兴趣，这些生物标志物可以为潜在的病理生物学过程提供可靠的、非侵入性的生化检测，这些病理生物学过程使患者容易受到未来心血管事件的影响，包括氧化应激、白细胞募集和激活、内皮细胞功能障碍、纤维帽降解和血小板活化。此外，候选生物标志物的选择现在还可以通过“组学”分析（包括基因组学和代谢组学）的数据来了解。具体来说，最近完成的几项全基因组关联研究的结果表明，一些以前不被认为在 CAD 中发挥作用的蛋白质。同样，基于质谱的代谢分析技术的最新进展使得能够监测生物样品中的数百种代谢物。这些脂质、糖和氨基酸充当代谢途径的底物和产物，这些代谢途径可能在疾病状态的早期就被扰乱。来自已知病理生物学相关途径的蛋白质加上以前未被怀疑在冠状动脉疾病中发挥作用但通过公正的研究方法识别和验证的蛋白质和代谢物的组合提供了开发生物标志物组的最佳机会，该组在疾病方面提供了实质性的而非简单的增量进展。预后。因此，该提案的总体目标是确定新型生物标志物预测慢性 CAD 患者主要不良心血管结局的能力。我们将利用一种经济高效的分阶段方法来评估来自 PEACE 的 3778 名患者血液样本中的候选生物标志物，PEACE 是一项由 NIH 资助的针对慢性 CAD 患者的血管紧张素转换酶 (ACE) 抑制剂群多普利的临床试验。在目标 1 中，我们将在一项对 1100 名 PEACE 患者进行的巢式病例队列研究中，研究 14 种新型蛋白质生物标志物对不良心血管结局的预后效用。在目标 2 中，我们将在两项嵌套病例对照研究中使用代谢组学来识别和验证代谢物与不良心血管结局的关联。在目标 3 中，我们将充分描述整个试验队列中有前景的新型生物标志物的预后效用，并结合传统风险因素和多种生物标志物来创建全面的风险预测工具。公共健康相关性：据估计，仅在美国就有超过 1600 万患者患有冠状动脉疾病，尽管采用了现代治疗，这些患者仍然面临着未来不良心血管结局（例如死亡、复发性心脏病和中风）的重大风险。我们对导致动脉斑块积聚并最终破裂的原因有了更深入的了解，这为开发血液测试创造了机会，可以更好地预测哪些个体处于疾病进展的高风险；医生也可以使用此类测试来针对能够获得最大益处的患者进行针对性治疗。我们的目标是评估可能预测复发性心脏病的潜在新血液检测，并确定哪些检测提供最大价值。