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Comparative Study
. 2012 Aug;5(8):819-28.
doi: 10.1016/j.jcmg.2011.11.025.

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

Esad Vucic  1 , Claudia Calcagno, Stephen D Dickson, James H F Rudd, Katsumi Hayashi, Jan Bucerius, Erin Moshier, Jessica S Mounessa, Michelle Roytman, Matthew J Moon, James Lin, Sarayu Ramachandran, Tatsuo Tanimoto, Karen Brown, Masakatsu Kotsuma, Sotirios Tsimikas, Edward A Fisher, Klaas Nicolay, Valentin Fuster, Zahi A Fayad
Affiliations
Comparative Study

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

Esad Vucic et al. JACC Cardiovasc Imaging. 2012 Aug.

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 (18)F-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 (18)F-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: (18)F-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 (18)F-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.

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Figures

Figure 1
Figure 1. Study Design
Atherosclerotic New Zealand white rabbits after 4 months of a high cholesterol diet when imaging scans, lipid profiles, and RNA analysis were performed (baseline). Animals were then divided into control, atorvastatin, and R211945 groups. At 5 months (1-month imaging) and at 7 months (3-month imaging), imaging scans, lipid profiles, RNA analysis, and drug pharmacokinetics (PK) determination were performed. After last imaging, all animals were immediately sacrificed and tissue analysis was performed. ABCA1 = ATP-binding cassette transporter A1; DCE-CMR = dynamic contrast-enhanced cardiac magnetic resonance; MC-CMR = multicontrast cardiac magnetic resonance; PET/CT = positron emission tomography/computed tomography.
Figure 2
Figure 2. 18F-Flurodeoxyglucose–PET/CT
(A to I) Coronal PET images through the abdominal aorta (white arrowheads) from 1 representative animal per group. (A, D, G) Baseline of all groups (control, atorvastatin, and R211945, respectively). (B, E, H) All groups at 1 month. (C, F, I) All groups at 3 months. Summary showing scatterplots and standard uptake values versus time slopes (bottom). Abbreviations as in Figure 1.
Figure 3
Figure 3. DCE-CMR
(A to I) Single-slice axial T1-weighted CMR with color-coded overlay of the contrast signal at 1 min of the abdominal aorta with insert of the aorta. (A, D, G) All groups at baseline (control, atorvastatin [Atorva], and R211945, respectively). (B, E, H) All groups at 1 month. (C, F, I) All groups at 3 months. Warm colors (orange to red) indicate higher areas under the curve (AUCs); cool colors (green to blue) indicate lower AUCs. Summary showing scatterplots and AUCs versus time slopes (bottom). Abbreviations as in Figure 1.
Figure 4
Figure 4. MC-CMR
Single-slice axial T2-weighted representative CMR with insert of the aorta with T2-, T1-, and proton density weighing (A to I). (A, D, G) All groups at baseline (control, baseline atorvastatin [Atorva], and baseline R211945, respectively). (B, E, H) All groups at 1 month. (C, F, I) All groups at 3 months. Bar graph summary (right). Values are mean ± SD. Abbreviations as in Figure 1.
Figure 5
Figure 5. Immunohistology
Representative immunohistological images of individual groups of the abdominal aorta at 3 months. Staining (red-brown, red arrowheads) for macrophages (A, E, I), apolipoprotein B (ApoB) (B, F, J), oxidized phospholipids (OxPL) (C, G, K), and smooth muscle actin (SMA) (D, H, L) are shown. Objective magnification: ×10. The lumen is on the right-hand side from the tissue.
Figure 6
Figure 6. Summary Immunohistology
(Left) Macrophages (MAC), ApoB, OxPL, and SMA staining at 3 months in control and atorvastatin- and R211945-treated animals. Inset shows CD-31 staining for neovessels (individual p values between control and treatment group are indicated). (A to C) Representative histological images after CD-31 staining for neovessels: control (A), atorvastatin (B), and R211945 (C). All values are mean ± SD. *p < 0.05; ***p < 0.001. n.s. = nonsignificant; control versus treatment groups. Abbreviations as in Figure 5.
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