Multimodality and Molecular Imaging of Matrix Metalloproteinase Activation in Calcific Aortic Valve Disease

Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Matrix metalloproteinases (MMPs) are upregulated in CAVD and contribute to valvular remodeling and calcification. We investigated the feasibility and correlates of MMP-targeted molec- ular imaging for detection of valvular biology in CAVD. Methods: Apolipoprotein E–deficient (apoE−/−) mice were fed a Western diet (WD) for 3, 6, and 9 mo (n 5 108) to induce CAVD. Wild-type mice served as the control group (n 5 24). The development of CAVD was tracked with CT, echocardiography, MMP-targeted small- animal SPECT imaging using 99mTc-RP805, and histologic analysis. Results: KeyfeaturesofCAVD—leaflet thickening and valvular calcification—were noted after 6 mo of WD and were more pro- nounced after 9 mo. These findings were associated with a signifi- cant reduction in aortic valve leaflet separation and a significant increase in transaortic valve flow velocity. On in vivo SPECT/CT images, MMP signal in the aortic valve area was significantly higher at 6 mo in WD mice than in control mice and decreased thereafter. The specificity of the signal was demonstrated by blocking, using an excess of nonlabeled precursor. Similar to MMP signal, MMP ac- tivity as determined by in situ zymography and valvular inflammation by CD68 staining were maximal at 6 mo. In vivo 99mTc-RP805 up- take correlated significantly with MMP activity (R2 5 0.94, P , 0.05) and CD68 expression (R2 5 0.98, P , 0.01) in CAVD. Conclusion: MMP-targeted imaging detected valvular inflammation and remod- eling in a murine model of CAVD. If this ability is confirmed in humans, the technique may provide a tool for tracking the effect of emerging medical therapeutic interventions and for predicting outcome in CAVD.