Improving cerebral aneurysm risk assessment through understanding wall vulnerability andfailure modes

描述：项目摘要和相关性 颅内动脉瘤影响了相当大一部分成年人。它们很少破裂，但在颅内 脑动脉瘤破裂导致的出血具有破坏性，死亡率和致残率很高。 由于治疗风险可能超过破裂的自然风险，迫切需要一种可靠的方法。 识别有破裂风险的脆弱动脉瘤，需要立即治疗并避免不必要的 其他人的治疗。 以前的工作主要集中在寻找破裂与临床可获得的数量之间的相关性。 例如几何形状、血流动力学和患者特征。然而，迄今为止，这些努力一直是 前景看好，但尚未充分发挥潜力。我们团队和其他人认为这是因为 动力作用在墙体破坏中起着不止一种作用，而且墙体的破坏有多种模式。 因此，在没有关于长城本身的进一步信息的情况下确定相关性是极其具有挑战性的。 这项拟议的研究在我们看来是创新的，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 可能有多种血流动力学改变室壁的机制，并研究了 结构性故障。这种方法是可能的，因为我们在之前的R21期间i)构建了一个 在动脉瘤研究方面拥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和 MTA文件，使我们能够在该计划期间获得350多个IA穹顶，以及iii)开发 方法论上的许多创新，利用了一系列重要的实验 设施。 了解区分具有良好组织的胶原纤维的坚固的动脉瘤壁的因素 而脆弱或脆弱的动脉瘤壁胶原蛋白结构有不同的变化是必不可少的 有效预测动脉瘤的易损性，并设计减缓或逆转这种变化的治疗方法。 具体地说，该项目的目标是：1)确定结构健全的动脉瘤壁的特征， 2)确定动脉瘤壁脆性的结构性原因；3)确定满足以下条件的血流动力学条件 促进内皮功能障碍和室壁改变，以及4)建立评估室壁风险的框架 脆弱。 这项拟议的工作的贡献是重大的，因为它将在大脑 对动脉瘤进行了研究。将使用方法将重点转移到墙体易损性上 我们是在R21时期开发的。我们将利用这些数据，结合患者的特征，开发出一种 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：该项目的结果将立即适用于 临床实践，特别是我们将为社会提供一个量表，以分级动脉瘤的风险。 有脆弱的墙壁的。此外，这些结果将指导未来旨在开发新临床的研究。 通过向成像技术和/或造影剂提供与易损性相关的壁变化 墙壁。通过进一步了解坚固和脆弱墙之间的区别，我们将提供一个目标 对于旨在利用墙的自然能力的药物疗法来说，保持一个强大的 胶原蛋白结构。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.