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Increased Neovascularization in Advanced Lipid-Rich Atherosclerotic Lesions Detected by Gadofluorine-M-Enhanced MRI

Implications for Plaque Vulnerability

From the Lariboisière University Hospital (M.S.), Assistance Publique-Hôpitaux de Paris, Université Paris 7-Denis Diderot, Paris, France; Translational and Molecular Imaging Institute (M.S., E.V., V.A., Z.A.F.), Mount Sinai School of Medicine, New York, NY; Zena and Michael A. Wiener Cardiovascular Institute and Marie-Josée and Henry R. Kravis Cardiovascular Health Center (M.S., P.R.M., K.-R.P., E.V., P.M., Z.A.F.), Mount Sinai School of Medicine, New York, NY; The Centro Nacional de Investigaciones Cardiovasculares (V.F.), Madrid, Spain; and Bayer Schering Pharma AG (H.-J.W.), Berlin, Germany.

Correspondence to Zahi A. Fayad, PhD, Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1234, New York, NY 10029-6574. E-mail zahi.fayad{at}mssm.edu

Received June 24, 2008; accepted July 6, 2009.

Background— Inflammation and neovascularization may play a significant role in atherosclerotic plaque progression and rupture. We evaluated gadofluorine-M-enhanced MRI for detection of plaque inflammation and neovascularization in an animal model of atherosclerosis.

Methods and Results— Sixteen rabbits with aortic plaque and 6 normal control rabbits underwent gadofluorine-M-enhanced MRI. Eight rabbits had advanced atherosclerotic lesions, whereas the remaining 8 had early lesions. Magnetic resonance atherosclerotic plaque enhancement was meticulously compared with plaque inflammation and neovessel density as assessed by histopathology. Advanced plaques and early atheroma were enhanced after gadofluorine-M injection. Control animals displayed no enhancement. After accounting for the within-animal correlation of observations, mean contrast-to-noise ratio was significantly higher in advanced plaques than compared with early atheroma (4.29±0.21 versus 3.00±0.32; P=0.004). Macrophage density was higher in advanced plaques in comparison to early atheroma (geometric mean=0.50 [95% CI, 0.19 to 1.03] versus 0.25 [0.07 to 0.42]; P=0.05). Furthermore, higher neovessel density was observed in advanced plaques (1.83 [95% CI, 1.51 to 2.21] versus 1.29 [0.99 to 1.69]; P=0.05). The plaque accumulation of gadofluorine-M correlated with increased neovessel density as shown by linear regression analysis (r=0.67; P<0.001). Confocal and fluorescence microscopy revealed colocalization of gadofluorine-M with plaque areas containing a high density of neovessels.

Conclusion— Gadofluorine-M-enhanced MRI is effective for in vivo detection of atherosclerotic plaque inflammation and neovascularization in an animal model of atherosclerosis. These findings suggest that gadofluorine-M enhancement reflects the presence of high-risk plaque features believed to be associated with plaque rupture. Gadofluorine-M plaque enhancement may therefore provide functional assessment of atherosclerotic plaque in vivo.

Key Words: atherosclerosis • MRI • vulnerable plaque • contrast media • molecular imaging