BIOMARKERS OF ISCHEMIC OUTCOMES IN SYMPTOMATIC INTRACRANIAL STENOSIS (BIOSIS)

有症状颅内狭窄 (BIOSIS) 缺血结局的生物标志物

• 批准号: 7987527
• 负责人: MICHAEL Ross FRANKEL
• 金额: $ 35.16万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987527
• 关键词: Accounting; Address; Angioplasty; Arterial Fatty Streak; Arteries; Atherosclerosis; Biological Markers; Biology; Blood Vessels; Blood specimen; Brain; Cells; Cerebrum; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Coronary Arteriosclerosis; Data; Development; Disease; E-Selectin; Enrollment; Event; Functional disorder; Funding; Goals; Human; Infiltration; Inflammation; Inflammatory; Intracranial Atheroscleroses; Ischemic Stroke; Lead; Life; Link; Lipids; Measures; Medical; National Institute of Neurological Disorders and Stroke; Outcome; Pathogenesis; Pathologic Processes; Patients; Phase III Clinical Trials; Plasminogen Activator Inhibitor 1; Process; Prospective Studies; Randomized; Recurrence; Research Infrastructure; Research Proposals; Risk; Risk Assessment; Risk Factors; Safety; Sample Size; Serum; Stem cells; Stenosis; Stroke; Symptoms; Testing; Time; cost; hazard; high risk; in vivo; intracranial artery; novel; prevent; public health relevance; repaired; vascular inflammation

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.

描述（由申请人提供）：主要的颅内动脉的动脉粥样硬化狭窄是中风的重要原因，在美国，在美国，每年约有50,000次中风，在中风后的第一年，每年的费用为750,000,000美元，在这些患者的一生中增加到45亿美元。动脉粥样硬化归因于三个主要病理过程：生物活性脂质通过生物活性脂质对血管壁的内皮功能障碍，血管炎症和浸润。但是，未知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有关。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与有症状性颅内狭窄患者的重大血管事件风险之间的关系。这项研究建议建立在现有的基础设施和与最近资助的Ninds赞助的试验的密切合作的基础上 - “预防颅内狭窄中的复发性中风的支架和积极的医疗管理”（Sammpris -M.Chimowitz，PI） - 首次随机，多个中心的III期临床试验，并在安全方面进行了竞争，并旨在促进安全的效果，以解决安全性，并在安全方面进行了促进，以解决安全性，并在安全方面进行了促进，以解决安全性。有症状的颅内动脉粥样硬化。当前建议的主要目的是确定有症状性颅内狭窄患者的炎症血清生物标志物是否是复发性中风的独立预测指标。我们假设炎症生物标志物的水平升高（HSCRP，PAI-1和E-选择蛋白）在SAMMPRIS入学时测量，与主要终点的风险增加有关，这定义为在症状狭窄势的领土上的复发性中风。我们的探索目的是确定循环内皮祖细胞的数量（血管修复标记）是否是有症状性狭窄动脉领域复发性中风的独立预测指标。对于探索目的，我们将测试以下假设：循环内皮祖细胞降低水平与主要终点的风险增加有关。其他探索性分析将包括比较强化医疗疗法与血管成形术和支架相结合的功效，仅在减少有或没有生物标志物水平升高的患者群体之间的重大血管事件中，仅比较强化医疗疗法。对于该提案中的主要目的，如果SAMMPRIS确定的样本量（n = 764）提供80％的功率，以找到统计学上的显着结果，如果3个生物标志物中任何一个的真实危险比至少在1.8至2.0范围内（调整了多个比较之后）。预计这项研究的结果将提供有关动脉粥样硬化生物标志物与症状性颅内狭窄患者结果的独特而新颖的数据。颅内动脉粥样硬化患者的风险评估可以导致更量身定制的治疗方法，并更好地了解这种常见和研究的疾病所涉及的病理过程。 公共卫生相关性：狭窄的脑动脉狭窄的患者，称为颅内狭窄，患有特别高风险的疾病，导致中风。每年约有50,000人在美国发生，成本近75万美元。该项目的目的是确定与动脉粥样硬化有关的循环生物标志物（分子和血液样本中测得的细胞）是否是否可以预测哪些由于狭窄的脑动脉狭窄导致的中风症状的患者是否处于发展另一种中风的最高风险。