Jae-Joon Jung, Mahmoud Razavian, Azariyas A. Challa, Lei Nie, Reza Golestani, Jiasheng Zhang, Yunpeng Ye, Kerry S. Russell, Simon P. Robinson, Donald D. Heistad, Mehran M. Sadeghi

Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Matrix metalloproteinases (MMP) are upregulated in CAVD and contribute to valvular remodeling and calcification. We investigated the feasibility and correlates of MMP-targeted molecular imaging for detection of valvular biology in CAVD. ApoE-/- mice were fed a Western diet (WD) for 3, 6 and 9 months (n = 108) to induce CAVD. Wild-type mice served as the control group (n = 24). The development of CAVD was tracked with CT, echocardiography, MMP-targeted microSPECT imaging using RP805, a (99m)Tc-labeled tracer, and histological analysis. Key features of CAVD, leaflet thickening and valvular calcification were noted after 6 months of WD, and were more pronounced after 9 months. This was associated with a significant reduction in aortic valve leaflet separation and increase in trans-aortic valve flow velocity. On in vivo microSPECT/CT images, aortic valve area MMP signal was significantly increased in mice on WD for 6 months compared to control animals and decreased thereafter. The specificity of the signal was demonstrated by blocking using excess non-labeled precursor. Similar to MMP signal, MMP activity by in situ zymography and valvular inflammation by CD68 staining were maximal at 6 months. There was a significant correlation between RP805 uptake in vivo, and MMP activity (R(2) = 0.94, P < 0.05) or CD68 expression (R(2) = 0.98, P < 0.01) in CAVD. MMP-targeted imaging detects valvular inflammation and remodeling in CAVD. If confirmed in humans, this may provide a tool for tracking the effect of emerging medical therapeutic interventions and predicting outcome in CAVD.