Correlation of MMP activity with anatomic changes in the ruptured AAA wall

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DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) is a lethal disease, with significant public health ramifications as the population ages. AAA rupture is associated with a uniformly high mortality rate (80%). While significant strides have been made in understanding the pathophysiology of AAA development and in decreasing the mortality of elective AAA repair, little is known about the series of events leading to AAA rupture. Clinically, multiple risk factors are associated with rupture, including aortic diameter, as well as the coexistence of chronic obstructive pulmonary disease and hypertension. While three contemporary animal models have been developed to examine the molecular events associated with AAA development, few models are available to study the events associated with AAA rupture. From observational cohorts in humans, preliminary data suggests that serine proteases (e.g. plasminogen activators tPA and uPA), in excess of their inhibitors, activate metalloproteinase's (MMP2 and 9) at specific locations in the aortic wall promoting collagen destruction and subsequent aortic wall rupture. Establishing a model of AAA rupture and defining the mechanisms underlying aortic rupture are critical to better define the risk in humans and will be the focus of the present investigation. Understanding temporal differences that occur in the aortic wall leading to and immediately prior to rupture using aortic wall and serum biomarkers, as well as anatomic and functional imaging techniques (ultrasound, FDG-PET scanning and autoradiographs, MRA) will allow us to develop new translational approaches to treat patients prior to aortic rupture. PUBLIC HEALTH RELEVANCE: Abdominal aortic aneurysm (AAA) is a lethal disease, with significant public health ramifications as the population ages and the number of patients at risk for development of AAAs increases. Clinically, AAAs are important because their rupture is associated with a very high risk of death. This study will allow for the development of non-invasive, imaging techniques that can be used to determine when AAAs are prone to rupture or dissection before emergency surgery must be performed.