BIOMARKERS OF ISCHEMIC OUTCOMES IN SYMPTOMATIC INTRACRANIAL STENOSIS (BIOSIS)

描述（由申请人提供）：颅内主要动脉的动脉粥样硬化性狭窄是卒中的重要原因，在美国每年约有50，000例卒中，卒中后第一年的年成本为750，000，000美元，并在这些患者的一生中增加至45亿美元。动脉粥样硬化可归因于三个主要病理过程：内皮功能障碍、血管炎症和生物活性脂质对血管壁的浸润。然而，目前尚不清楚反映这些过程的生物标志物是否与颅内动脉粥样硬化患者相关。为了解决这个问题，我们建议研究动脉粥样硬化的有前途的生物标志物和有症状的颅内狭窄患者的主要血管事件的风险之间的关系。这项研究计划建立在现有的基础设施上，并与最近资助的NINDS赞助的试验密切合作-“支架植入和积极的医疗管理，以预防颅内狭窄复发性卒中”。（SAMMPRIS - M.Chimowitz，PI）-第一个随机，多的中心III期临床试验，旨在评价颅内血管成形术和支架植入术在症状性颅内动脉瘤患者中的安全性和有效性动脉粥样硬化本提案的主要目的是确定症状性颅内狭窄患者的血清炎症生物标志物是否是复发性卒中的独立预测因子。我们假设，在SAMMPRIS入组时测量的炎症生物标志物（hsCRP、派-1和E-选择素）水平升高与主要终点（定义为症状性狭窄动脉区域的复发性卒中）风险增加相关。我们的探索性目的是确定循环内皮祖细胞（血管修复的标志物）的数量是否是症状性狭窄动脉区域内复发性卒中的独立预测因子。出于探索性目的，我们将检验循环内皮祖细胞水平降低与主要终点风险增加相关的假设。其他探索性分析将包括比较强化药物治疗联合血管成形术和支架植入术与单独强化药物治疗在减少生物标志物水平升高和不升高的患者组中主要血管事件方面的疗效。对于本提案中的主要目的，如果3种生物标志物中任何一种的真实风险比至少在1.8至2.0的范围内（调整多重比较后），则SAMMPRIS（n = 764）确定的样本量提供80%的把握度来找到统计学显著性结果。预计本研究的结果将提供关于动脉粥样硬化生物标志物与症状性颅内狭窄患者结局关系的独特和新颖的数据。对颅内动脉粥样硬化患者进行精确的风险评估可能会导致更有针对性的治疗方法，以及更好地了解这种常见和未充分研究的疾病所涉及的病理过程。 公共卫生相关性：患有脑动脉狭窄（称为颅内狭窄）的患者患中风的风险特别高。在美国，每年约有50，000例此类中风发生，花费近750，000，000美元。该项目的目的是确定与动脉粥样硬化（动脉硬化）相关的循环生物标志物（血液样本中测量的分子和细胞）是否可以预测哪些因脑动脉狭窄而出现中风症状的患者患另一次中风的风险最高。

DESCRIPTION (provided by applicant): Atherosclerotic stenosis of the major intracranial arteries is an important cause of stroke, accounting for approximately 50,000 strokes per year in the USA at an annual cost of $750,000,000 in the first year after the stroke, and increasing to $4.5 billion over the life time of these patients. Atherosclerosis is attributable to three main pathological processes: endothelial dysfunction, vascular inflammation, and infiltration of the vascular wall by bioactive lipids. It is unknown, however, whether biomarkers that reflect these processes are relevant in patients with intracranial atherosclerosis. To address this question, we propose to study the relationship between promising biomarkers of atherosclerosis and risk of major vascular events in patients with symptomatic intracranial stenosis. This research proposal builds on the existing infrastructure and close collaboration with the recently funded NINDS sponsored trial - "Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis" (SAMMPRIS - M.Chimowitz, PI) - the first randomized, multi-center Phase III clinical trial designed to evaluate the safety and efficacy of intracranial angioplasty and stenting in patients with symptomatic intracranial atherosclerosis. The Primary Aim of the current proposal is to determine whether serum biomarkers of inflammation in patients with symptomatic intracranial stenosis are independent predictors of recurrent stroke. We hypothesize that elevated levels of inflammatory biomarkers (hsCRP, PAI-1 and E-selectin), measured at the time of enrollment in SAMMPRIS, are associated with an increased risk of the primary endpoint, defined as recurrent stroke in the territory of the symptomatic stenotic artery. Our Exploratory Aim will be to determine whether the number of circulating endothelial progenitor cells (a marker for vascular repair) is an independent predictor of recurrent stroke in the territory of the symptomatic stenotic artery. For the exploratory aim, we will test the hypothesis that decreased levels of circulating endothelial progenitor cells are associated with an increased risk of the primary endpoint. Additional exploratory analyses will include a comparison of the efficacy of intensive medical therapy combined with angioplasty and stenting to intensive medical therapy alone in reducing major vascular events among patient groups with and without elevated levels of biomarkers. For the primary aim in this proposal, the sample size determined for SAMMPRIS (n = 764) provides 80% power to find a statistically significant result if the true hazard ratio for any of the 3 biomarkers is, at a minimum, in the range of 1.8 to 2.0 (after adjusting for multiple comparisons). It is expected that the results of this study will provide unique and novel data on the relationship of atherosclerotic biomarkers with outcome in patients with symptomatic intracranial stenosis. Refining risk assessment in patients with intracranial atherosclerosis could lead to a more tailored approach to treatment as well as a better understanding of the pathological processes involved in this common and understudied disease. PUBLIC HEALTH RELEVANCE: Patients with narrowed brain arteries, known as intracranial stenosis, have a particularly high-risk disease leading to stroke. Approximately 50,000 of these strokes per year occur in the USA at a cost of nearly $750,000,000. The aim of this project is to determine whether circulating biomarkers (molecules and cells measured in blood samples) that are linked to atherosclerosis (hardening of the arteries) can predict which patients with stroke symptoms due to narrowed brain arteries are at highest risk of developing another stroke.