BIOMARKERS OF ISCHEMIC OUTCOMES IN SYMPTOMATIC INTRACRANIAL STENOSIS (BIOSIS)

描述(申请人提供)：主要颅内动脉的动脉粥样硬化性狭窄是中风的一个重要原因，在美国每年约有5万例中风，中风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的病理过程：内皮功能障碍、血管炎症和生物活性脂类对血管壁的渗透。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发生主要血管事件的风险之间的关系。这项研究建议建立在现有基础设施的基础上，并与NINDS最近资助的试验--“支架植入和积极医疗管理预防颅内狭窄复发中风”(SAMMPRIS-M.Chimowitz，PI)--密切合作，这是第一个随机、多中心的第三阶段临床试验，旨在评估颅内血管成形术和支架植入治疗症状性颅内动脉硬化患者的安全性和有效性。目前建议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中风复发的独立预测因素。我们假设，在SAMMPRIS注册时测量的炎性生物标记物(hsCRP、PAI-1和E-选择素)水平的升高与主要终点风险的增加有关，主要终点被定义为症状性狭窄动脉区域内的复发性中风。我们的探索性目标将是确定循环内皮祖细胞的数量(血管修复的标志)是否是症状性狭窄动脉区域复发卒中的独立预测因素。为了探索性的目的，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在生物标志物水平升高的患者组中比较强化药物治疗结合血管成形术和支架植入与单独强化药物治疗在减少重大血管事件方面的效果。对于本建议的主要目的，SAMMPRIS(n=764)确定的样本量提供了80%的力量来找到统计上显著的结果，如果3个生物标记物中的任何一个的真实危险比至少在1.8至2.0的范围内(经多次比较调整后)。预计这项研究的结果将为动脉粥样硬化生物标志物与症状性颅内狭窄患者预后的关系提供独特和新颖的数据。完善对颅内动脉粥样硬化患者的风险评估可能会导致一种更有针对性的治疗方法，以及更好地了解这种常见且未被研究的疾病的病理过程。

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.