Improving cerebral aneurysm risk assessment through understanding wall vulnerability andfailure modes

通过了解壁的脆弱性和失效模式来改进脑动脉瘤风险评估

• 批准号: 9156209
• 负责人: Anne Marie Robertson
• 金额: $ 65.65万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9156209
• 关键词: Adult; Affect; Age; Aneurysm; Architecture; Arteries; Biology; Blood Pressure; Brain; Brain Aneurysms; Caring; Cerebral Aneurysm; Characteristics; Clinical; Clinical Management; Clinical Treatment; Clip; Collagen; Collagen Fiber; Communities; Contrast Media; Custom; Data; Development; Devices; Electron Microscopy; Endothelial Cells; Ethnic Origin; Evaluation; Exploratory/Developmental Grant; Failure; Functional disorder; Geometry; Goals; Health; Human; Hypertension; Image; Imaging Techniques; Inflammation; Institutional Review Boards; Intracranial Aneurysm; Intracranial Hemorrhages; Knowledge; Lead; Lipids; Maintenance; Mechanics; Methodology; Methods; Neck; Pathology; Patient Care; Patients; Pharmacological Treatment; Play; Population; Process; Protocols documentation; Research; Resected; Resolution; Risk; Risk Assessment; Role; Rupture; Smoking; Smooth Muscle Myocytes; Stents; Stratification; Structure; Survivors; Testing; Textiles; Thrombosis; Tissues; Vulnerable Populations; Work; base; bioimaging; biomechanical model; brain surgery; calcification; clinical decision-making; clinical practice; clinically relevant; cohort; computer studies; disability; endothelial dysfunction; hemodynamics; imaging biomarker; implantation; improved; innovation; microCT; mortality; prevent; programs; repaired; shear stress; skills; soft tissue; sound; targeted treatment; therapy design; unnecessary treatment

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.

描述：项目摘要和相关性 颅内动脉瘤影响大部分成人人群。它们很少破裂，但颅内 由于脑动脉瘤破裂而导致的出血具有毁灭性的影响，死亡率高和残疾率。 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 识别需要立即治疗的破裂风险的脆弱动脉瘤，并避免不必要 其他治疗。 先前的工作主要集中在寻找破裂与临床上可达到数量之间的相关性 例如几何学，血液动力学和患者特征。但是，迄今为止，这些努力一直在 有希望，但没有发挥全部潜力。我们的小组和其他人认为这是因为流程 动态在墙壁降解中起多个角色，进一步有多种模式的墙壁故障。 因此，在没有有关隔离墙本身的更多信息的情况下，确定相关性是极其挑战的。 在我们看来，拟议的研究具有创新性，因为它试图改变动脉瘤病理的方式 通过将重点转移到临床相关的脆弱性动脉瘤壁上，然后直接评估 血流动力学改变壁并研究机制的多种机制 结构失败。这种方法可能是可能的，因为我们已经花费了上一段R21时期i）建造一个 世界领导者的合作团队在动脉瘤研究方面具有多种技能，ii）获取所有需要的IRB和 MTA文档将使我们能够在此程序中获得超过350个IA域，并且iii）开发 方法论的大量创新，这些创新利用了访问一系列重要实验的渠道 设施。 了解用良好的胶原蛋白纤维区分稳健动脉瘤壁的因素 对于胶原蛋白体系结构的变化，易受伤害或脆弱的动脉瘤墙对于 有效预测动脉瘤脆弱性和治疗方法，以减慢或扭转这种变化。 具体而言，该项目的目标是：1）确定结构听起来的动脉瘤壁的特征， 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隔壁改变，以及4）制定一个评估墙风险的框架 脆弱性。 拟议工作的贡献很重要，因为它将在脑的方式上产生范式转变 研究动脉瘤。对破裂的重点是使用方法将终点转移到墙壁脆弱性时 我们在R21时期开发。我们将使用这些数据，并结合患者特征来开发 评估墙壁脆弱性风险的框架。这些结果将为更大的跨国公司提供基础 使用我们的框架进行风险分层的试验。 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，尤其是我们将为社区提供一个规模，以评估动脉瘤的风险 有脆弱的墙壁。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/或对比剂通过为墙壁变化与脆弱的隔壁变化来 墙。进一步了解强大和脆弱墙之间的差异，我们将提供一个目标 对于旨在利用墙壁自然能力的药理疗法，保持坚固 胶原蛋白结构。这些进步都将有助于改善患者护理。