Investigation of arterial changes in the Circle of Willis during intracranial aneurysm growth in humans

项目摘要/摘要 据估计，西方人群中囊性颅内动脉瘤(IA)的患病率约为3%。 在临床上，IA呈现两难境地，因为它们通常是无症状的；然而，如果 他们破裂，导致蛛网膜下腔出血(约50%的死亡率)。有令人信服的证据表明 动脉粥样硬化的增长增加了破裂的风险(12-24倍)。为了更好地监控和预测IA进展，有一个 迫切需要更好地了解临床上的IA增长(动脉瘤样重塑)。90%的IA发生在 威利斯环的动脉(奶牛)。尽管有压倒性的证据表明奶牛血管 重塑与IA病，大多数IA研究仅集中在IA部位，而不考虑 连通动脉的贡献。奶牛动脉中特定的血管重塑可能提供额外的 用于监测IA进展的指标。在IA现场发生的生化过程包括 炎症和细胞外基质重塑导致细胞死亡和管壁退化。分析 在动物模型中，动脉壁切应力(WSS)是这些过程的触发因素， 导致IA的启动和重塑。以患者为中心的研究进一步将低WSS与IA联系在一起 成长。由于奶牛血管在IA生长过程中会发生变化，因此进入IA的血流会发生变化，并可能 创造一个新的WSS水平，以稳定重塑过程。更好地了解人类IA如何 自然稳定与预测IA进展高度相关，而改变WSS的作用将是 在这项拨款中进行了调查。在我们最近对520名临床监测的IA进行的研究中，我们发现，尽管许多IA增长 始终如一地，按照预期的增长路径，其他国家变得稳定。我们还发现，IA的增长速度是 女性的速度要快得多。考虑到IA与性别、家族史和疾病的关联，不同 血管重塑的模式可能发生在具有不同遗传或病史的群体中。我们建议 一项临床转化研究，以研究不同遗传和病史组的IA生长。我们假设 IA的生长可能与奶牛体内血管重塑的模式有关。我们将使用以下工具来验证我们的假设 具体目标如下：(1)IA生长是局部现象还是与血管重塑有关 在奶牛体内？(2)遗传相似的个体是否经历相似的血管重塑模式？(3) 奶牛体内的血液流动是否与血管重塑有关？通过确定IA疾病是如何 进展可能与奶牛体内的其他重塑相关，这项研究可以确定新的成像 能够改进IA治疗决策的生物标记物。这项提议意义重大，因为有一个未得到满足的 需要准确评估IA疾病进展和风险变化。这项建议具有创新性，因为它 将扩展现有的IA研究，以包括更多相关的脑血管和纵向数据，同时 实施针对此问题的几项技术创新，可转化为临床跟踪 脑血管改变

PROJECT SUMMARY/ABSTRACT Prevalence of saccular intracranial aneurysms (IA) in western populations is estimated at around ~3%. Clinically, IA present a dilemma, in that they are usually asymptomatic; however, IA are extremely dangerous if they rupture, causing subarachnoid hemorrhage (~50% mortality). There is convincing evidence that continued IA growth increases the risk of rupture (12-24 times). To better monitor and predict IA progression, there is a compelling need to better understand clinical IA growth (aneurysmal remodeling). 90% of IA occur within the arteries of the Circle of Willis (CoW). Despite there being overwhelming evidence connecting CoW vascular remodeling and IA disease, the majority of IA research focuses only on the IA site, and does not consider the contribution of connected arteries. Specific vascular remodeling in the CoW arteries may provide an additional indicator for monitoring IA progression. The biochemical processes that occur at the IA site include inflammation and extracellular matrix remodeling leading to cell death and vessel wall degeneration. Analyses in animal models have strongly connected arterial wall shear stress (WSS) as a trigger of these processes, leading to IA initiation and remodeling. Patient-oriented research has further linked areas of low WSS with IA growth. Because CoW vasculature can change during IA growth, the blood flow entering IA changes and may create a new level of WSS to stabilize the remodeling process. Better understanding how human IA may naturally stabilize is highly relevant to predicting IA progression, and the role of changing WSS will be investigated in this grant. In our recent study of 520 clinically monitored IA, we found that while many IA grew consistently, following a projected growth path, others became stable. We also found that IA growth speed is significantly faster in women. Given the association of IA with sex, family history, and disease, different patterns of vascular remodeling may occur within groups with different genetics or medical history. We propose a clinical translational study to study IA growth in different genetic and medical history groups. We hypothesize IA growth may associate with patterns of vascular remodeling within the CoW. We will test our hypothesis with the following specific aims: (1) Is IA growth a local phenomenon or it associated with vascular remodeling within the CoW? (2) Do genetically similar individuals undergo similar patterns of vascular remodeling? (3) Does blood flow within the CoW associate with vascular remodeling? By identifying how IA disease progression may associate with other remodeling within the CoW, this study can identify new imaging biomarkers that enable improved IA treatment decisions. This proposal is significant because there is an unmet need to accurately assess IA disease progression and changes in risk. This proposal is innovative because it will extend existing IA studies to include more, relevant cerebrovascular arteries and longitudinal data, while implementing several technical innovations specific to this problem which can translate to clinical tracking of cerebrovascular changes