Improving Cerebral Aneurysm Risk Assessment through Understanding Wall Vulnerability and Failure Modes

项目摘要和相关性 在美国，每50个成年人中至少有1个患有颅内动脉瘤（IA），这是一种大脑的病理性外凸 动脉即使临床管理有所改善，IA破裂对大约45%的患者是致命的， 50%的幸存者患有残疾，无法恢复正常生活。治疗以防止 破裂过程中，通过机械夹闭IA颈部， 开放性脑手术或通过使用血管内弹簧圈或支架植入诱导血栓形成。这些治疗 有显著的并发症风险，可能高于自然破裂风险，包括1-2%的风险 mortality.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 识别需要立即治疗并避免不必要的破裂风险的脆弱动脉瘤的方法 别人的待遇。 该项目的临床重点是具有局灶性生长区域（水泡）的动脉瘤，如这些IA 高临床患病率（约30%），是破裂的已知危险因素。尽管临床上 重要的是，很少有人知道为什么水泡形成或水泡增加破裂的实际机制 风险我们先前的工作表明，动脉瘤与泡可以有不同的壁结构和失败 与其他动脉瘤不同。即使在这一亚组中，也存在广泛的壁类型和风险 因素目前的临床实践没有区分不同类型的滤过泡或其失效模式， 平等对待所有水泡。 拟议的研究是创新的，因为它试图改变这种常见的动脉瘤临床方法 将所有水泡作为一组进行评估。此外，我们的研究也是创新的，因为 它改变了动脉瘤的研究方式，直接关注动脉瘤壁的脆弱性及其 而不是寻找不同因素与动脉瘤破裂之间的相关性。 该项目的目标是通过识别临床可测量的特征来改善风险评估， 使一些颅内动脉瘤易于形成水泡，然后确定哪些血管壁特征决定了这些颅内动脉瘤的破裂风险。 内部审计处。具体而言，本项目的目标是i）识别有形成滤过泡风险的动脉瘤，ii） 确定动脉瘤囊泡壁脆弱性的原因，iii）了解牙齿和动脉瘤之间的联系。 病原体和IA壁脆弱性。我们将采用多方面的方法来实现这些目标， 将人体动脉瘤组织的生物成像和力学测试与计算机模拟患者特定建模相结合 动脉瘤内的血流和动脉瘤壁内的应力。我们将利用我们的多- 由脑动脉瘤领域的世界领导者组成的学科团队，其中包括七名神经外科医生， 患者特定CFD建模、计算生物力学、IA壁生物学、生物成像和 软组织的力学测试。 拟议研究的基本原理是，通过将具有水泡的IA识别为具有不同 我们将改善风险评估，并能针对患者进行治疗。此外，委员会认为， 通过识别与水泡形成相关的可改变的风险因素（例如，牙齿病原体），我们可以 开始对颅内动脉瘤进行预防性治疗。在这个研究项目的成功完成，我们将有i） 已确定的滤过泡形成的风险因素（风险的早期指示），ii） 以及iii）确定牙齿病原体如何影响壁结构以及与可测量的患者的相关性 因素这些结果预计将对人类健康产生积极影响，因为它们将改善风险 评估IA，为药物治疗提供目标，并确定IA治疗的预防方法。

Project Summary and Relevance At least 1 in 50 adults in the US harbor an intracranial aneurysm (IA), a pathological outpouching of a brain artery. Even with improvements in clinical management, IA rupture is fatal for approximately 45% of patients and 50% of survivors suffer from disabilities that prevent them from returning to a normal life. Treatment to prevent rupture strives to shield the wall from blood pressure induced loads by mechanically clipping the IA neck during open brain surgery or by inducing thrombosis using endovascular coiling or stent implantation. These treatments have significant risks of complications that can be higher than the natural rupture risk, including 1-2% risk of mortality. 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. The clinical focus of this project is aneurysms that have focal areas of growth (blebs) as these IA have high clinical prevalence (approximately 30%) and are a known risk factor for rupture. Despite this clinical importance, very little is known about why blebs form nor the actual mechanisms by which blebs increase rupture risk. Our prior work demonstrates that aneurysms with blebs can have different wall structures and failure mechanisms than other aneurysms. Even within this subgroup, there are a wide range of wall types and risk factors. Current clinical practice does not distinguish between different types of blebs or their failure modes and treats all blebs equally. The proposed research is innovative because it seeks to change this common clinical approach for aneurysm evaluation where all blebs are treated as a single group. Furthermore, our research is also innovative because it changes the way aneurysms are studied by focusing directly on the vulnerability of the aneurysm wall and its failure modes instead of searching for correlations between different factors and aneurysm rupture. The goal of this project is to improve risk assessment by identifying clinically measurable features that predispose some IAs to bleb formation and then determine which walls features determine rupture risk in these IAs. Specifically, the goals of this project are to i) Identify aneurysms that are at risk for developing blebs, ii) Determine causes for wall vulnerability in aneurysms with blebs, iii) Understand the connection between dental pathogens and IA wall vulnerability. We will achieve these objectives using a multi-faceted approach that combines bioimaging and mechanical testing of human aneurysm tissue with in silico patient specific modeling of the blood flow inside the aneurysms and stresses within the aneurysm wall. We will leverage our multi- disciplinary team of world leaders in the field of cerebral aneurysms which includes seven neurosurgeons and experts in patient specific CFD modeling, computational biomechanics, biology of the IA wall, bioimaging and mechanical testing of soft tissues. The rationale for the proposed research is that by recognizing IAs with blebs as a distinct group with different causes for formation and rupture, we will improve risk assessment and can target patient treatment. Furthermore, by identifying modifiable risk factors that are associated with bleb formation (e.g. dental pathogens), we can initiate preventative treatment for IAs. At the successful completion of this research program we will have i) identified risk factors for bleb formation (an early indication of risk), ii) direct causes for increased rupture risk in blebs, and iii) determined how dental pathogens affect the wall structure and association with measurable patient factors. These results are expected to have a positive impact on human health because they will improve risk assessment in IAs, provide targets for drug therapy and identify preventative approaches for IA treatment.