Improving cerebral aneurysm risk assessment through understanding wall vulnerability andfailure modes

描述：项目总结和相关性 颅内动脉瘤影响相当大一部分成人人群。它们很少破裂，但在颅内 由于脑动脉瘤破裂引起的出血具有毁灭性的影响，具有高死亡率和残疾率。 由于治疗的风险可能超过破裂的自然风险，因此迫切需要一种可靠的方法 识别有破裂风险的脆弱动脉瘤，需要立即治疗，避免不必要的 别人的待遇。 以前的工作主要集中在寻找破裂和临床可达到的量之间的相关性 例如几何形状、血液动力学和患者特征。然而，迄今为止，这些努力 有希望，但尚未充分发挥其潜力。我们的团队和其他人认为这是因为 动力学在壁劣化中起着不止一种作用，而且存在多种壁失效模式。 因此，在没有关于墙本身的进一步信息的情况下识别相关性是非常具有挑战性的。 在我们看来，这项研究是创新的，因为它试图改变动脉瘤病理学的方式。 通过将焦点转向临床相关的易损动脉瘤壁并通过直接评估 血液动力学改变壁的可能多种机制， 结构性故障这种方法是可能的，因为我们已经花了前R21期i）建立一个 在动脉瘤研究方面具有不同技能的世界领导者的协作团队，ii）获得所有需要的IRB， MTA文件，这将使我们能够获得超过350个IA圆顶在这个计划中，和iii）开发 许多创新的方法，利用获得一系列重要的实验， 设施 了解区分坚固的动脉瘤壁与组织良好的胶原纤维的因素 和脆弱或脆弱的动脉瘤壁与胶原蛋白结构的各种变化是必不可少的， 有效预测动脉瘤脆弱性和设计治疗以减缓或逆转这种变化。 具体而言，该项目的目标是：1）确定结构合理的动脉瘤壁的特征， 2)确定动脉瘤壁脆弱性的结构原因，3）确定血液动力学条件， 促进内皮功能障碍和血管壁改变，以及4）开发用于评估血管壁损伤风险的框架。 脆弱 这项工作的贡献是重大的，因为它将创造一个范式转变， 研究了动脉瘤。重点破裂作为终点将转移到墙的脆弱性使用的方法 我们在R21时期开发的。我们将利用这些数据，结合患者特征，制定一个 评估墙体脆弱性风险的框架。这些结果将为更大规模的跨国公司提供基础。 使用我们的风险分层框架进行试验。 拟议项目的临床相关性：本项目的结果将立即适用于 临床实践，特别是我们将为社区提供一个量表，以分级动脉瘤的风险， 具有脆弱的壁。此外，这些结果将指导未来的研究，旨在开发新的临床 成像技术和/或造影剂，通过向它们提供与易受损害的血管壁相关的壁变化， 墙通过进一步了解坚固和脆弱的墙壁之间的差异，我们将提供一个目标， 对于针对利用壁的自然能力的药理学疗法， 胶原结构这些进步都将有助于改善患者护理。

Description: Project Summary and Relevance Intracranial aneurysms affect a substantial portion of the adult population. They rarely rupture, but intracranial hemorrhage due to a ruptured brain aneurysm has devastating effects with high mortality and disability rates. Since the risk of treatment may exceed the natural risk of rupture, there is an urgent need for a reliable method to identify fragile aneurysms at risk of rupture that require immediate treatment and avoid unnecessary treatment in others. Prior work has largely focused on looking for correlations between rupture and clinically attainable quantities such as geometry, hemodynamics and patient characteristics. However, to date, these efforts have been promising but have not reached their full potential. Our group and others believe this is because the flow dynamics play more than one role in wall degradation and further there are multiple modes of wall failure. Therefore, it is extremely challenging to identify correlations without further information about the wall itself. The proposed research is innovative in our opinion because it seeks to shift the way aneurysm pathology is studied by turning the focus to the clinically relevant vulnerable aneurysm wall and by directly assessing the possibly multiple mechanisms by which hemodynamics alters the wall and studying the mechanisms of structural failure. This approach is possible because we have spent the prior R21 period i) building a collaborative team of world leaders with diverse skills in aneurysm research, ii) acquiring all needed IRB and MTA documents that will enable us to obtain over 350 IA domes during this program, and iii) developing the numerous innovations in methodology that take advantage of access to an array of important experimental facilities. Understanding the factors that discriminate between robust aneurysm walls with well-organized collagen fibers and vulnerable or fragile aneurysm walls with diverse changes to the collagen architecture is essential for effective prediction of aneurysm vulnerability and design of treatments to slow or reverse this change. Specifically, the goals of this project are: 1) determine the characteristics of structurally sound aneurysm walls, 2) determine structural causes of aneurysm wall vulnerability, 3) determine the hemodynamic conditions that promote endothelial dysfunction and wall alteration, and 4) develop a framework for assessing risk of wall fragility. The contribution of the proposed work is significant because it will create a paradigm shift in how cerebral aneurysms are studied. The focus on rupture as the end point will be shifted to wall vulnerability using methods we developed during the R21 period. We will use this data, combined with patient characteristics, to develop a framework for assessing risk of wall vulnerability. These results will provide he basis for a larger multi-national trial using our framework for risk stratification. Clinical relevance of the proposed project: The results of this project will be immediately applicable to the clinical practice, in particular we will provide the community with a scale to grade the risk of an aneurysm of having fragile walls. Additionally, these results will guide future research aiming at developing new clinical imaging techniques and/or contrast agents by providing them with wall changes associated with vulnerable walls. Further by understanding the differences between robust and vulnerable walls, we will provide a target for pharmacological therapies directed at harnessing the natural ability of the wall the maintain a robust collagen structure. These advancements will all contribute to the improvement of patient care.