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

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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.