Plasma Osteoprotegerin and Adverse Outcomes in CHD Patients

描述(申请人提供)：美国有近1630万患者患有冠心病(CHD)，这种疾病与严重的发病率和死亡率以及高昂的医疗费用有关。迫切需要确定预测冠心病患者不良结局的生物标志物，以实现可靠的预测、对病理生理学的洞察和发现新的治疗靶点。经过验证的预后标志物将有助于冠心病的治疗，因为医生经常面临关于二级预防的治疗范围和冠状动脉血运重建的需要的复杂选择。这项应用的目的是调查血浆骨保护素(OPG)水平是否可以预测参加血管紧张素转换酶抑制物疗法预防事件试验的患者的不良结果(致命性和非致命性心肌梗死、缺血性中风和心力衰竭)。OPG是一种肿瘤坏死因子受体超家族的糖蛋白，是核因子B受体激活剂(RANKL)和肿瘤坏死因子相关凋亡诱导配体(TRAIL)的可溶性诱骗受体。它与维持内皮细胞完整性、炎症反应和血管钙化有关。与局部在心脏和血管组织中表达的RANK和RANKL相比，循环中的OPG水平很容易测量。我们假设OPG/RANK/RANKL系统上调是稳定性冠心病患者不良结局的标志。此外，OPG-RANKL通路可能是改善冠心病患者预后的药物治疗的靶点。拟议的研究将利用和平试验的基础设施和我们在生物标记物研究方面的经验，包括免疫分析的验证。使用申请人实验室先前建立的免疫测定法，我们将检测参加和平试验的3634名稳定性冠心病患者的血浆OPG，并提供可用的基线血浆样本。我们将调查血浆OPG水平是否与年龄、性别、种族、常规危险因素和估计的肾小球滤过率无关的不良结局(致命性和非致命性心肌梗死、缺血性中风和心力衰竭)有关。此外，我们将评估血浆OPG与不良事件的任何关联是否独立于循环C-反应蛋白和NT-proBNP水平。增量预测效用将通过c统计量、净重分类指数和综合判别改进(IDI)进行评估。

DESCRIPTION (provided by applicant): Nearly 16.3 million patients in the United States have coronary heart disease (CHD), a condition associated with significant morbidity and mortality and high healthcare costs. There is an urgent need to identify biomarkers that predict adverse outcomes in patients with CHD to enable reliable prognostication, insights into pathophysiology, and discovery of new targets for therapy. Validated prognostic markers will facilitate management of CHD since physicians often face complex choices concerning the range of therapies for secondary prevention and the need for coronary revascularization. The goal of this application is to investigate whether plasma levels of osteoprotegerin (OPG) predict adverse outcomes (fatal and nonfatal myocardial infarction, ischemic stroke and heart failure) in patients participating in the Prevention of Events with Angiotensin-Converting Enzyme Inhibitor Therapy (PEACE) trial. OPG is a glycoprotein belonging to the tumor necrosis factor (TNF) receptor superfamily, and a soluble decoy receptor for the receptor activator of nuclear factor-B ligand (RANKL) and TNF-related apoptosis inducing ligand (TRAIL). It has been implicated in maintenance of endothelial cell integrity, inflammatory response, and vascular calcification. Circulating levels of OPG are easily measured, in contrast to RANK and RANKL that are expressed locally in the cardiac and vascular tissue. We hypothesize that an upregulated OPG/RANK/RANKL system is a marker of adverse outcomes in patients with stable CHD. Furthermore, OPG-RANKL pathway may be target for drug therapy to improve outcomes in patients with CHD. The proposed research will leverage the infrastructure of the PEACE trial and our experience in biomarker research including validation of immunoassays. Using an immunoassay previously established in the applicant's laboratory, we will measure plasma OPG in 3634 patients with stable CHD participating in the PEACE trial and with available baseline plasma samples. We will investigate whether plasma levels of OPG are associated with adverse outcomes (fatal and nonfatal myocardial infarction, ischemic stroke, and heart failure) independent of age, sex, ethnicity, conventional risk factors, and estimated glomerular filtration rate. In addition, we will assess whether any association of plasma OPG with adverse events is independent of circulating levels of C-reactive protein and NT-proBNP. Incremental predictive utility will be assessed by the c-statistic, net reclassification index, and integrated discriminaton improvement (IDI).