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

项目总结/摘要 在西方人群中，囊状颅内动脉瘤（IA）的患病率估计约为3%。 临床上，IA呈现出一种两难境地，因为它们通常无症状;然而，如果 它们破裂，引起蛛网膜下腔出血（~50%死亡率）。有令人信服的证据表明 IA增长增加破裂的风险（12 - 24倍）。为了更好地监测和预测IA进展， 迫切需要更好地了解临床IA生长（动脉瘤重塑）。90%的IA发生在 Willis环（CoW）尽管有压倒性的证据表明牛的血管 由于动脉重构和IA疾病的关系，大多数IA研究仅关注IA部位，而不考虑 连接动脉的贡献。牛冠状动脉中的特定血管重塑可能提供额外的 用于监测IA进展的指标。在IA位点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血管壁变性。分析 在动物模型中，动脉壁剪切应力（WSS）作为这些过程的触发因素， 导致IA启动和重塑。以患者为导向的研究进一步将低WSS的区域与IA联系起来 增长由于牛脑血管系统在动脉瘤生长过程中会发生变化，因此进入动脉瘤的血流也会发生变化， 创建一个新的WSS水平，以稳定重塑过程。更好地理解人类IA如何 自然稳定与预测IA进展高度相关，改变WSS的作用将是 在这次调查中，在我们最近对520例临床监测的IA的研究中，我们发现，尽管许多IA的生长 其他国家的情况也一直稳定下来，并沿着预期的增长道路前进。我们还发现，IA的增长速度是 在女性中更快。考虑到IA与性别、家族史和疾病的关系， 血管重塑的模式可能发生在具有不同遗传学或病史的群体中。我们提出 一项临床转化研究，旨在研究不同遗传和病史组中的IA生长。我们假设 IA生长可能与牛内的血管重塑模式相关。我们将测试我们的假设， 本研究的具体目的如下：（1）IA生长是局部现象还是与血管重塑有关 在牛？(2)基因相似的个体是否经历相似的血管重塑模式？（三） 牛体内的血流是否与血管重塑有关？通过识别IA疾病如何 进展可能与CoW内的其他重塑相关，这项研究可以识别新的成像 生物标志物，能够改善IA治疗决策。这一建议意义重大，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。这是一项创新，因为它 将扩展现有的IA研究，以纳入更多相关的脑血管和纵向数据， 实施针对该问题的几项技术创新，这些技术创新可以转化为临床跟踪， 脑血管病变

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