Plasma Osteoprotegerin and Adverse Outcomes in CHD Patients

描述（由申请人提供）：美国有近1630万患者患有冠心病（CHD），这种疾病与显著的发病率和死亡率以及高昂的医疗费用相关。目前迫切需要确定能够预测冠心病患者不良结局的生物标志物，以实现可靠的预后、深入了解病理生理学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管理，因为医生经常面临复杂的选择，涉及二级预防的治疗范围和冠状动脉血管重建术的需要。本应用的目的是研究参与血管紧张素转换酶抑制剂治疗（PEACE）试验的患者血浆中骨保护素（OPG）水平是否能预测不良结局（致命性和非致命性心肌梗死、缺血性中风和心力衰竭）。OPG是一种属于肿瘤坏死因子（TNF）受体超家族的糖蛋白，是核因子- b配体受体激活剂（RANKL）和TNF相关凋亡诱导配体（TRAIL）的可溶性诱饵受体。它与内皮细胞完整性的维持、炎症反应和血管钙化有关。与在心脏和血管组织中局部表达的RANK和RANKL相比，OPG的循环水平很容易测量。我们假设OPG/RANK/RANKL系统的上调是稳定型冠心病患者不良结局的标志。此外，OPG-RANKL通路可能是药物治疗的靶点，以改善冠心病患者的预后。拟议的研究将利用PEACE试验的基础设施和我们在生物标志物研究方面的经验，包括免疫测定的验证。使用先前在申请人实验室建立的免疫测定法，我们将测量3634名参加PEACE试验的稳定型冠心病患者的血浆OPG，并提供基线血浆样本。我们将调查血浆OPG水平是否与不良结局（致死性和非致死性心肌梗死、缺血性中风和心力衰竭）相关，而不受年龄、性别、种族、常规危险因素和肾小球滤过率的影响。此外，我们将评估血浆OPG与不良事件的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、净重分类指数和综合判别改进（IDI）来评估。

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).