Vascular diseases, including aortic aneurysm, are major causes of morbidity and mortality in the US. Matrix metalloproteinases (MMPs) play a key role in the pathogenesis of aortic aneurysm and its major complications, rupture and dissection. Inflammatory cells are a major source of MMP activity in the vessel wall. Complications of aneurysm occur more frequently in large or symptomatic aneurysms, which as a preventive measure, are usually referred for surgical or endovascular repair. However, a large number of complications occur in smaller aneurysms which do not meet the criteria for surgical repair. The development of a non-invasive imaging approach for detection of vessel wall proteolytic activity and inflammation in aneurysm may help identify the subset of small aneurysms at high risk for morbid complications. Classically, 18Ffluorodeoxyglucose (18F-FDG) imaging is used for detection of enhanced metabolism associated with inflammatory conditions, and despite its lack of specificity for inflammation, 18F-FDG imaging is under clinical investigation for detection of inflamed, thus high risk abdominal aortic aneurysm. We hypothesize that vessel wall inflammation in aortic aneurysm may be detected by molecular imaging of MMP activation, and targeting MMP proteolytic activity is superior to targeting enhanced metabolism by 18F-FDG for detection of vessel wall inflammation and predicting outcome in aneurysm.
Our specific aims are to establish and validate MMP targeted single photon emission tomography (SPECT)/ computed tomography (CT) imaging for detection of vessel wall inflammation in murine aneurysm, compare its performance in comparison with 18F-FDG for detection of inflammation in aneurysm, and evaluate MMP-targeted imaging for detection of the effect of antiproteolytic and anti-inflammatory treatments on vessel wall biology and outcome in aneurysm. Aneurysm will be induced in the mouse aorta through angiotensin II infusion. MMP-targeted microSPECT imaging will be followed by histomorphometric analysis to establish an association between tracer uptake and vessel wall inflammation. The effect of modulating monocyte function through genetic intervention and monocyte depletion on tracer uptake will be addressed. The performance of an MMP-targeted tracer in comparison with 18F-FDG for prediction of outcome in aneurysm will be addressed in animals injected with both tracers. Finally, a group of animals with aneurysm will be placed on anti-proteolytic or anti-inflammatory treatment and undergo repeated MMP-targeted imaging to establish the performance of molecular imaging for detection of vessel wall inflammation, proteolytic activity and outcome under such conditions. The development of an imaging modality for detection of vessel wall inflammation in aneurysm may have a major impact on public health by identifying high risk patients who may benefit from early invasive treatment. Furthermore, this approach may be applied to risk assessment and management of other vascular diseases, which together with aneurysm,are leading causes of mortality amongst veterans.
The patient population at the VA healthcare system is characterized by the high prevalence of cardiovascular disease, including aneurysm. By developing a method to detect proteolytic activity and inflammation in aneurysm, this project will help identify patients who are at high ris for complications of aortic aneurysm and guide intensive therapy to reduce the risk of complications. Ultimately, this will improve the health of veterans and reduce healthcare costs.
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