Project Summary/Abstract An abdominal aortic aneurysm (AAA) is a vascular condition where a major blood vessel in the body can degenerate, balloon in size leading to ultimate rupture and sudden death. Currently, an AAA is identified through imaging studies performed as part of a screening study or incidentally when evaluating for other abdominal pathology. Given that the most important clinical parameter in predicting rupture is the maximal aortic diameter, a normal aorta of 2.0 cm or less requires no further evaluation, whereas a large aorta >5.5 cm in men and >5.0 cm in women requires surgery. Based upon a large VA population based prospective analysis, 20% of veterans with small aortas (3.0-5.4 cm) will grow rapidly and may pose a threat to the life of the veteran. Unfortunately, we do not know which small AAAs will grow rapidly, others slowly, and still others not at all. Failure to identify rapidly growing small AAAs will lead to a certain but preventable death. Thus, there is a critical need to develop predictive markers for rapidly growing small AAAs so that surgery can be performed timely. The medical management of small AAA is one of the top research priorities in the care of the Veterans with vascular disease. We hope to establish our central hypothesis that RhoA mediated monocyte adhesion to the aortic endothelium leads to endothelial barrier injury, subsequent monocyte transmigration, increased aortic wall destruction, and ultimate small AAA growth. This hypothesis will be tested by the following specific aims: 1) To determine whether the activation of RhoA in monocytes from Veteran subjects with a growing small AAA will lead to increased monocyte adhesion, and endothelial barrier injury, 2) To determine whether monocyte RhoA plays a causal role in AAA formation in the animal model, 3) To determine whether high RhoA protein activity isolated in the monocytes from Veteran subjects with small AAA will predict the growth of the small AAA (>0.1 cm/year). Current studies have shown the possibility of RhoA as a biomarker for disease in both AAA formation and growth. RhoA and monocyte activity were identified to be highly expressed in both the serum and aortic tissue from subjects with AAA compared to age-matched controls, The role of RhoA in comparing human subjects with growing AAA or stable AAA has yet to be elucidated. To date, there is a lack of translatability of the data obtained from tissue in human subjects (late in the disease process) or findings from animal models to the human patient with small AAAs. The innovation of this project is the connection between the use of RhoA and monocyte activity into an overarching mechanism of biomarkers, leading to future novel therapies to control small AAA growth. This is a translational study using human Veteran subjects with the readily available 1,169 veterans identified with small AAAs (3.0-5.4 cm) collected over a 10-year period to make the completion of the proposed study feasible. Ultimately, we hope that the data collected will open the possibility of identifying approaches to both predicting and limiting small AAA growth.

An abdominal aortic aneurysm (AAA) is a weakening of the major blood vessel that can increase in size to the point where rupture and sudden death can occur. However, it is unclear how to manage small sized AAAs (3.0- 5.4 cm)—before the accepted diameter (5.5 cm) required for repair. This proposal will utilize a large data set of 1,169 Veteran subjects who were diagnosed with a small AAA over the past 10 years. Through this study we plan to understand the natural history of small AAA growth and to test the hypothesis that increased protein (RhoA) expression and white cell infiltration play a role in small AAA growth in human subjects. Simultaneously, novel animal models will be used to test the causal role of RhoA expression in AAA formation and growth. Ultimately, these studies can lead to targeted strategies of using blood biomarkers for following patients at risk for AAA growth, develop pharmacologic methods in preventing small AAA growth, or to streamline patients for early surgery.