AAA Disease: Mechanism, Stratification and Treatment

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DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) is a common, morbid, and frequently lethal disease of older Americans. Major clinical challenges in AAA disease include the absence of: 1) effective non-surgical therapies to prevent progression of early stage disease, and 2) validated biomarkers or efficient imaging indices to monitor disease activity and guide suppressive medical therapies in small aneurysms. Based on extensive prior evidence demonstrating that variable aortic flow and wall shear stress conditions modulate vascular inflammation, this SCCOR proposes to: 1) Identify and validate novel biomarkers and imaging strategies for AAA disease stratification, 2) Test the ability of exercise therapy to suppress small AAAs, and 3) Investigate key molecular and cellular events present during experimental AAA evolution to identify and refine novel therapeutic strategies. Project I (Thrombin-Cleaved Osteopontin in AAA) will examine the role of thrombin-cleaved osteopontin and its regulation in AAA, and determine if measurements of specific cleaved forms of osteopontin will serve as useful biomarkers for predicting disease progression. Project II (Signature Protein Profile to Identify AAAs) will develop a custom antibody-based protein array to test whether distinct signature protein profiles can be identified that will correlate with AAA of different sizes, and whether changes in these profiles can predict disease progression and response to intervention. Project III (Hemodynamics in AAA Progression) will characterize the hemodynamics in the infrarenal aorta of patients with AAA, under both resting and exercise conditions, using MRI-based imaging techniques. We will examine how the shape, size, or vessel wall structure of the aortic aneurysm influence the hemodynamic parameters in AAA and test whether these changes in flow and vessel wall characteristics predict disease progression and response to intervention. Project IV (Evaluation of Exercise Therapy in Small AAA) is the key project in this SCCOR application. A prospective randomized trial will be carried out to test whether a supervised and sustained exercise program will reduce the rate of expansion of small AAA in patients. This clinical trial will anchor and connect all the other projects of this SCCOR. The proposed SCCOR will enable many accomplished investigators with complementary expertise to develop a coordinated and integrated approach to analysis, stratification and treatment of AAA disease, and fulfills the SCCOR objective of translating knowledge into clinical practice.