180Noninvasive ultrasound molecular imaging of the effect of atorvastatin on vascular inflammation

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Purpose: Non-invasive assessment of changes in vascular inflammatory activity may be of use in managing medical therapy in patients with atherosclerotic disease and for developing new candidate therapies. We hypothesized that molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) expression with contrast enhanced ultrasound (CEU) could be used to assess the effects of HMG-CoA reductase inhibitors on vascular inflammation.Methods: Mice deficient for the LDL-receptor and Apobec-1 editing protein that develop atherosclerosis in a time-dependent fashion were studied. Beginning at 12 weeks of age, mice received 8 weeks of either regular chow (n=10) or chow containing atorvastatin (0.01% wt/wt; n=12). At 20 weeks of age, CEU molecular imaging of the ascending aorta was performed after I.V. injection of VCAM-1-targeted (MBV) and control microbubbles (MBC).High frequency transthoracic ultrasound imaging (40MHz) was used for noninvasive assessment of plaque burden by measuring aortic wall thickness. Plasma levels of total cholesterol and LDL+VLDL cholesterol were measured. Histology with Movat's pentachrome was used to quantify plaque burden. Fluorescence immunohistology and Western blot was used to localize and quantify VCAM-1 expression in the aortic wall.Results: Atorvastatin treatment lowered plasma LDL+VLDL cholesterol levels by 20% in statin-treated animals vs control animals (189.1mg/dl vs 233 mg/dl, p=0.03). On histology, plaque burden was reduced by 61% in statin treated animals (3.7% of luminal area vs 9.2%, p<0.005). Aortic VCAM-1 expression on Western blot was reduced by 41% (p<0.01) by atorvastatin, which corresponded to less endothelial expression of VCAM-1 on immunohistology. High frequency ultrasound was unable to detect differences in aortic wall thickness between the two animal groups. In contrast, CEU molecular imaging demonstrated selective signal enhancement for MBV in control animals (MBV 2±1.1 vs MBC 0.7±.08, P<0.01), but not instatin-treated animals (MBV 0.8±0.5 vs MBC 1.0±0.6, p=ns; p<0.01 for the effect of statin treatment on MBV signal).Conclusions: Non-invasive CEU molecular imaging can detect changes in vascular inflammatory phenotype in response to antiatherogenic treatments at a point in time when non-invasive morphologic imaging is unableto detect differences in plaque burden. This technique may be useful in the assessment of treatment effects both in preclinical research as well as in patients.

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