Abstract 2537: Molecular Imaging of Matrix Metalloproteinase in Atherosclerotic Lesions: Resolution with Dietary Modification and Statin Therapy
Background: Matrix metalloproteinase (MMP) expression in atherosclerotic plaques leads to fibrous cap attenuation and positive vascular remodeling, and hence vulnerability of plaque to rupture. We evaluated the feasibility of noninvasive detection of MMP activity in experimental atherosclerotic lesions using Tc-99m-labeled broad MMP inhibitor (MPI) determined the effect of dietary modification and statin treatment in MMP activity.
Methods: Atherosclerosis was produced in =0 New Zealand White rabbits by balloon deendothelialization and hypercholesterolemic diet for 4 months; 12 unmanipulated rabbits on normal chow were used as controls. In the last month, 6 of the 30 atherosclerotic rabbits were changed to normal chow, and 6 received fluvastatin (1mg/kg) once a day. MPI imaging was performed using micro-SPECT/micro-CT. After in vivo imaging, aortas were explanted to acquire ex vivo images and calculate percent injected dose per gram (%ID/g) uptake. Histological and immunohistochemical characterization and extent of MMP were evaluated in representative aortic samples.
Results: Radiotracer uptake was clearly visualized in the atherosclerotic lesions by noninvasive imaging; No uotake was observed in the diet withdrawal, fluvastatin, and normal control groups. The %ID/g MPI uptake in the atherosclerotic lesions (0.10 ±0.03%) was significantly higher than the uptake in control abdominal aorta (0.016 ± 0.004%; P<0.0001). The quantitative uptake in fluvastatin (0.056 ± 0.011%; P<0.0005) and diet withdrawal (0.043 ± 0.011%; P<0.0001) groups was statistically significantly lower compared to diet uninterrupted group. Histological and immunohistochemical studies revealed a significant correlation of MPI uptake with macrophage infiltration and the extent of MMP-2 and 9 expression. MMP-2 and 9 activity was also characterized by gel zymography or ELISA.
Conclusions: The present data confirmes the feasibility of noninvasive detection of MMP activity in atherosclerotic plaques, and reconfirms previous belief that dietary modification and statin therapy abrogate MMP activity.