Valvular heart disease is responsible for ~23,000 deaths per year in the US. Aortic stenosis is the most common cause of valvular heart disease and calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Pathological hallmarks of CAVD are Inflammation, extracellular matrix remodeling (including fibrosis) and calcification. Mechanical stress, atherosclerotic risk factors, deposition of lipid particles, and other factors induce focal inflammation which in turn triggers osteoblastic transformation of valvular interstitial cells. Matix metalloproteinases (MMPs) mediate matrix remodeling and turnover. Expression profiling of healthy and calcific human aortic valve has identified several MMPs (including MMP- 12) amongst the top 10 genes upregulated in CAVD. Monocyte-macrophages are major sources of MMP production and activation and MMP expression and activation appear to be closely linked to inflammation in CAVD. Here, we hypothesize that hallmarks of CAVD, inflammation and remodeling, can be detected by targeting MMP activation in vivo, thus providing a non-invasive imaging approach for early detection and tracking the effect of therapeutic intervention.
Our specific aims are to validate MMP imaging for detection of inflammation and remodeling in CAVD, investigate MMP-targeted SPECT imaging for predicting outcome and tracking the effect of therapeutic interventions in CAVD, and evaluate MMP-12 as target for molecular imaging of early CAVD. Using two complementary murine models of CAVD we will evaluate aortic valve anatomy, function and biology by echocardiography, CT and MMP-targeted microSPECT or MMP-12 near infrared fluorescent imaging. This will be followed by histological analysis of aortic valve composition and biology. MMP tracer uptake in vivo will be correlated with markers of inflammation and valvular remodeling. Animals with early CAVD will be randomly assigned to therapeutic interventions and aortic valve anatomy, function and biology will be investigated by serial imaging followed by histological analysis. The effect of therapeutic interventions on tracer uptake and CAVD will be addressed and the ability of early imaging to predict outcome in individual animals will be determined. The effect of MMP-12 gene deletion and MMP-12 inhibition on the development and progression of CAVD and MMP-12 probe uptake will be addressed. In line with the main purpose of the RFA, the proposed experiments are primarily designed to validate MMP-targeted imaging for early diagnosis of CAVD. In parallel, aspects of CAVD pathobiology will be addressed. As such, the proposal is expected to facilitate the development of novel therapeutic measures by establishing the role of MMPs in CAVD and providing non-invasive tools for early assessment of treatment efficacy.

Public Health Relevance

We plan to develop a novel imaging approach for early detection of calcific aortic valve disease. This should facilitate the development of novel treatments and lead to a reduction in valve-related deaths.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL114703-03
Application #
8697125
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Evans, Frank
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
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