TY - JOUR T1 - Evaluation of Antiatherogenic Properties of Ezetimibe Using <sup>3</sup>H-Labeled Low-Density-Lipoprotein Cholesterol and <sup>99m</sup>Tc-cAbVCAM1–5 SPECT in ApoE<sup>−/−</sup> Mice Fed the Paigen Diet JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1088 LP - 1093 DO - 10.2967/jnumed.116.177279 VL - 58 IS - 7 AU - Laurent S. Dumas AU - François Briand AU - Romain Clerc AU - Emmanuel Brousseau AU - Christopher Montemagno AU - Mitra Ahmadi AU - Sandrine Bacot AU - Audrey Soubies AU - Pascale Perret AU - Laurent M. Riou AU - Nick Devoogdt AU - Tony Lahoutte AU - Gilles Barone-Rochette AU - Daniel Fagret AU - Catherine Ghezzi AU - Thierry Sulpice AU - Alexis Broisat Y1 - 2017/07/01 UR - http://jnm.snmjournals.org/content/58/7/1088.abstract N2 - The addition of ezetimibe, an intestinal cholesterol absorption inhibitor, to statin therapy has recently shown clinical benefits in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial by reducing low-density-lipoprotein (LDL) cholesterol levels more than statin therapy alone. Here, we investigated the mechanisms by which inhibition of intestinal cholesterol absorption might contribute to the clinically observed reduction in cardiovascular events by evaluating its effect on inflammatory plaque development in apolipoprotein E−/− mice. Methods: Apolipoprotein E−/− mice were fed the Paigen diet (1.25% cholesterol, 0.5% cholic acid, and 15% fat) without or with ezetimibe (7 mg/kg/d) for 6 wk. In a first set of mice (n = 15), we intravenously injected 3H-cholesteryl oleate–labeled human LDL to test whether ezetimibe promotes LDL-derived cholesterol fecal excretion. In a second set (n = 20), we used the imaging agent 99mTc-cAbVCAM1–5 to evaluate expression of an inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1), in atherosclerotic plaques. In a third set (n = 21), we compared VCAM-1 expression with 99mTc-cAbVCAM1–5 uptake in various tissues. Results: Mice treated with ezetimibe showed a 173% higher LDL–cholesteryl ester plasma disappearance rate (P &lt; 0.001 vs. control) after 3H-cholesteryl oleate–labeled LDL injection. At 96 h after injection, the hepatic fraction of 3H-tracer was 61% lower in mice treated with ezetimibe (P &lt; 0.001). Meanwhile, LDL-derived 3H-cholesterol excretion in the feces was 107% higher (P &lt; 0.001). The antiatherogenic effect of ezetimibe monitored by 99mTc-cAbVCAM1–5 SPECT showed a 49% reduction in aortic tracer uptake (percentage injected dose per cubic centimeter, 0.95 ± 0.04 vs. 1.87 ± 0.11; P &lt; 0.01). In addition to hypercholesterolemia, the proinflammatory Paigen diet significantly increased VCAM-1 expression with respect to the control group in various tissues, including the aorta, and this expression correlated strongly with 99mTc-cAbVCAM1–5 uptake (r = 0.75; P &lt; 0.05). Conclusion: Inhibition of intestinal cholesterol absorption with ezetimibe promotes antiatherosclerotic effects through increased LDL cholesterol catabolism and LDL-derived cholesterol fecal excretion and reduces inflamed atherosclerotic plaques. These mechanisms may contribute to the benefits of adding ezetimibe to a statin therapy. ER -