BIOMARKERS OF ISCHEMIC OUTCOMES IN SYMPTOMATIC INTRACRANIAL STENOSIS (BIOSIS)

描述（由申请人提供）：颅内大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7.5亿美元，在这些患者的一生中增加到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浸润血管壁。然而，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尚不清楚。为了解决这个问题，我们建议研究有希望的动脉粥样硬化生物标志物与症状性颅内狭窄患者主要血管事件风险之间的关系。这项研究计划建立在现有的基础上，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预防颅内狭窄复发性卒中”（SAMMPRIS - M.Chimowitz， PI） -这是第一个随机，多中心III期临床试验，旨在评估颅内血管成形术和支架植入对症状性颅内动脉粥样硬化患者的安全性和有效性。本研究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卒中复发的独立预测因子。我们假设，在SAMMPRIS入组时测量的炎症生物标志物（hsCRP， PAI-1和e -选择素）水平升高与主要终点风险增加有关，主要终点定义为症状性狭窄动脉区域复发性卒中。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）的数量是否是有症状的狭窄动脉区域中风复发的独立预测因子。为了探索性目的，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。额外的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的主要血管事件方面的疗效。对于本提案的主要目标，SAMMPRIS确定的样本量（n = 764）提供了80%的能力，如果3种生物标志物中的任何一种的真实风险比至少在1.8至2.0的范围内（经过多次比较调整后），则可以找到具有统计学意义的结果。预计本研究结果将为有症状的颅内狭窄患者的动脉粥样硬化生物标志物与预后的关系提供独特和新颖的数据。改进颅内动脉粥样硬化患者的风险评估可能导致更有针对性的治疗方法，以及更好地了解这种常见且研究不足的疾病的病理过程。

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.