Regression of inflammation in atherosclerosis by the LXR agonist R211945 : a noninvasive assessment and comparison with atorvastatin

E. Vucic, C. Calcagno, S.D. Dickson, J.H.F. Rudd, K. Hayashi, J. Bucerius, E. Moshier, J.S. Mounessa, M. Roytman, M.J. Moon, J. Lin, S. Ramachandran, T. Tanimoto, K. Brown, M. Kotsuma, S. Tsimikas, E.A. Fisher, K. Nicolay, V. Fuster, Z.A. Fayad

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    Abstract

    OBJECTIVES The aim of this study was to noninvasively detect the anti-inflammatory properties of the novel liver X receptor agonist R211945. BACKGROUND R211945 induces reversal cholesterol transport and modulates inflammation in atherosclerotic plaques. We aimed to characterize with F-18-fluorodeoxyglucose (FDG)-positron emission tomography(PET)/computed tomography (CT) and dynamic contrast-enhanced cardiac magnetic resonance (DCE-CMR) inflammation and neovascularization, respectively, in atherosclerotic plaques with R211945 treatment compared with atorvastatin treatment and a control. METHODS Twenty-one atherosclerotic New Zealand white rabbits were divided into 3 groups (control, R211945 [3 mg/kg orally], and atorvastatin [3 mg/kg orally] groups). All groups underwent F-18-FDG-PET/CT and DCE-CMR at baseline and at 1 and 3 months after treatment initiation. Concomitantly, serum metabolic parameters and histology were assessed. For statistical analysis, continuous DCE-CMR and PET/CT outcomes were modeled as linear functions of time by using a linear mixed model, whereas the histological data, animal characteristics data, and nonlinear regression imaging data were analyzed with a 2-tailed Student t test. RESULTS F-18-FDG-PET/CT detected a decrease in mean and maximum standard uptake values (SUV) over time in the R211945 group (both p = 0.001), indicating inflammation regression. The atorvastatin group displayed no significant change (p = 0.371 and p = 0.600, respectively), indicating no progression or regression. The control group demonstrated an increase in SUV (p = 0.01 and p = 0.04, respectively), indicating progression. There was a significant interaction between time and group for mean and maximum SUV (p = 0.0003 and p = 0.0016, respectively). DCE-CMR detected a trend toward difference (p = 0.06) in the area under the curve in the atorvastatin group, suggesting a decrease in neovascularization. There was no significant interaction between time and group (p = 0.6350 and p = 0.8011, respectively). Macrophage and apolipoprotein B immunoreactivity decreased in the R211945 and atorvastatin groups (p <0.0001 and p = 0.0004, respectively), and R211945 decreased oxidized phospholipid immunoreactivity (p = 0.02). CONCLUSIONS Noninvasive imaging with F-18-FDG-PET/CT and DCE-CMR and histological analysis demonstrated significant anti-inflammatory effects of the LXR agonist R211945 compared with atorvastatin. The results suggest a possible role for LXR agonists in the treatment of atherosclerosis. (J Am Coll Cardiol Img 2012; 5: 819-28) (C) 2012 by the American College of Cardiology Foundation
    Original languageEnglish
    Pages (from-to)819-828
    Number of pages10
    JournalJACC: Cardiovascular Imaging
    Volume5
    Issue number8
    DOIs
    Publication statusPublished - 2012

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