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: 8212015
• 负责人: MARC S SABATINE
• 金额: $ 31.24万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212015
• 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; Health; 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; Research; Risk; Risk Factors; Risk Marker; Role; Rupture; Sampling; Staging; Stroke; Subgroup; Technology; Testing; Transcript; United States; United States National Institutes of Health; Unstable angina; Validation; Work; adverse outcome; atherothrombosis; base; cardiovascular risk factor; cohort; cost; data registry; experience; follow-up; genome wide association study; high risk; interest; metabolomics; mortality; novel; outcome forecast; prognostic; protein metabolite; 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）：仅在美国，估计有超过1600万患者患有冠状动脉疾病（CAD）。尽管有些患者会患有静止的疾病，而另一些患者会遭受斑块破裂并产生急性，明显的缺血并发症。因此，临床医生的一个主要挑战是确定哪些显然稳定的CAD患者实际上很容易受到随后几年的重大不良后果的影响。直到最近，心血管生物标志物主要仅限于心肌梗塞（MI）释放的心肌细胞衍生的蛋白质，因此仅限于诊断发生后CAD的主要并发症。然而，对动脉粥样硬化的复杂性的更深入的了解已引起人们对检查新型生物标志物的兴趣 激活。此外，现在可以通过包括基因组学和代谢组学（包括基因组学和代谢组学）的数据来核对候选生物标志物选择。具体而言，几项最近完成的全基因组关联研究的结果暗示了几种以前未被认为在CAD中起作用的蛋白质。同样，基于质谱的代谢分析技术的最新进展已使从生物样品中监测数百种代谢产物。这些脂质，糖和氨基酸用作代谢途径的底物和产物，这些途径在疾病状态中可能很早就被危险。来自已知的，病原体相关的途径以及蛋白质和代谢产物的蛋白质的组合以前尚未怀疑在冠状动脉疾病中发挥作用，而是通过无偏见的研究方法鉴定和验证和验证，这为开发生物标志物面板提供了最佳机会，它可以开发出实质性的，而不是简单地提供预后的增量进步。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期方法来评估来自和平的3778例患者的血液样本中的候选生物标志物，这是一项由NIH赞助的慢性CAD患者的血管紧张素转化酶（ACE）抑制剂trandolapril的临床试验。在AIM 1中，我们将研究14种新型蛋白质生物标志物的预后效用，以对1100例和平的患者进行嵌套的病例研究中的不良心血管结局。在AIM 2中，我们将使用代谢组学在2个嵌套病例对照研究中识别和验证代谢产物与心血管不良结局的关联。在AIM 3中，我们将充分表征整个试验队列中有希望的新型生物标志物的预后效用，并结合了传统的风险因素和多个生物标志物来创建全面的风险预测工具。公共卫生相关性：据估计，仅在美国，估计有超过1600万患者患有冠状动脉疾病，尽管现代疗法，这些患者仍处于未来不良心血管结局（例如死亡，复发性心脏病发作和中风）的危险中。我们对导致噬菌斑在动脉中积聚和最终破裂的更深入的理解创造了一个机会来开发血液检查，可以更好地预测哪些人有疾病进展的高风险；医生也可以使用此类测试来靶向将获得最大好处的患者。我们的目标是评估可能预测复发性心脏病并确定哪些具有最大价值的潜在新血液检查。

项目成果

Prognostic utility of secretory phospholipase A(2) in patients with stable coronary artery disease.

分泌型磷脂酶 A(2) 在稳定性冠状动脉疾病患者中的预后效用。

• DOI: 10.1373/clinchem.2011.166520
• 发表时间: 2011
• 期刊: Clinical chemistry
• 影响因子: 9.3
• 作者: O'Donoghue,MichelleL;Mallat,Ziad;Morrow,DavidA;Benessiano,Joelle;Sloan,Sarah;Omland,Torbjørn;Solomon,ScottD;Braunwald,Eugene;Tedgui,Alain;Sabatine,MarcS
• 通讯作者: Sabatine,MarcS

Lipoprotein(a) for risk assessment in patients with established coronary artery disease.

• DOI: 10.1016/j.jacc.2013.09.042
• 发表时间: 2014-02-18
• 期刊: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
• 影响因子: 24
• 作者: O'Donoghue, Michelle L.;Morrow, David A.;Tsimikas, Sotirios;Sloan, Sarah;Ren, Angela F.;Hoffman, Elaine B.;Desai, Nihar R.;Solomon, Scott D.;Domanski, Michael;Arai, Kiyohito;Chiuve, Stephanie E.;Cannon, Christopher P.;Sacks, Frank M.;Sabatine, Marc S.
• 通讯作者: Sabatine, Marc S.