The convergence of experimental and pathological evidence supports the understanding that extracellular matrix (ECM) degeneration and inflammation are central to the pathogenesis of abdominal aortic aneurysm (AAA). Although the risk of AAA rupture relates to the maximum cross- sectional diameter, rapid expansion of the aortic diameter and rupture have been observed in patients with AAA independent of the initial cross-sectional diameter. This information notwithstanding, current diagnostic modalities stratify risk of AAA rupture solely on the basis of the diameter of the aneurysm without including potentially critical information derivable from the degree of aneurysmal wall inflammatory response. Similarly, there has been no comprehensive evaluation of the role of systemic biomarkers of ECM degeneration for risk prediction in AAA patients. The overriding hypothesis of our proposal is that the progression of AAA and the risk of adverse events are related to the degree of arterial wall inflammation as determined by in vivo molecular imaging, and to the degree of ECM degeneration as inferred from a serum biomarker of proteolysis. First, we propose to utilize 18F-fluorodeoxyglucose (FDG) positron emission tomography imaging co-registered with structural computerized tomography (PET/CT) images for the in vivo localization and quantification of arterial wall inflammation in patients with AAA, in order to determine the relationship between inflammation within the walls of the aneurysm and the growth of AAA and/or risk of adverse outcomes: symptoms, thrombosis, or intervention for ruptured, leaking, rapidly expanding, or painful AAA. Second, we will conduct assays of systemic levels of matrix metalloproteinase (MMP-9)-a biomarker of ECM degeneration-in order to determine whether it is predictive of AAA growth and risk of adverse outcomes. This prospective longitudinal evaluation of a cohort of AAA patients using FDG-PET/CT molecular imaging of arterial wall inflammation and the assay of MMP-9, will also provide important information on the intra- and inter-patient variation of these imaging and systemic biomarkers while evaluating their relevance for patient stratification and individualization of therapeutic intervention. This proposed investigation, by addition of physiological data to the classic anatomic information from size alone, will determine the significance of both local aneurysmal wall inflammatory response and ECM degradation. Overall, these studies will potentially pave the path towards optimal risk prediction, targeted intervention and resource allocation to our Veteran patients, and thereby reduce the morbidity and mortality of AAA in the US Veteran population.
One in 20 United States (US) Veterans over age 50 have AAA, and of the 35,000 annual AAA repair operations performed in the US, 1200 (3.5%) occur in the Department of Veterans Affairs (VA). Most abdominal aortic aneurysms (AAA) are asymptomatic until rupture, resulting in death approximately 90% of the time, thus making AAA the thirteenth leading cause of death in the US. However, there are limited strategies for predicting the progression or risk of AAA rupture. The purpose of this research is to determine whether the degree of aneurysmal wall inflammation and breakdown as determined by positron emission tomography imaging and serum biomarkers can help predict the risk of progression and/or adverse events in AAA patients, and thereby address the significant burden of AAA a leading preventable cause of death in the US Veteran population.
