Elsevier

Atherosclerosis

Volume 228, Issue 2, June 2013, Pages 339-345
Atherosclerosis

Monitoring plaque inflammation in atherosclerotic rabbits with an iron oxide (P904) and 18F-FDG using a combined PET/MR scanner

https://doi.org/10.1016/j.atherosclerosis.2013.03.019Get rights and content

Highlights

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    Combined PET/MR scanner can be used to assess plaque inflammation.

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    Correlation between SUV or R2* and macrophages density were good.

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    FDG-PET seems to be more sensitive than USPIO enhanced MRI.

Abstract

Purpose

The aim of this study was to compare the ability of 18F-FDG PET and iron contrast-enhanced MRI with a novel USPIO (P904) to assess change in plaque inflammation induced by atorvastatin and dietary change in a rabbit model of atherosclerosis using a combined PET/MR scanner.

Materials and methods

Atherosclerotic rabbits underwent USPIO-enhanced MRI and 18F-FDG PET in PET/MR hybrid system at baseline and were then randomly divided into a progression group (high cholesterol diet) and a regression group (chow diet and atorvastatin). Each group was scanned again 6 months after baseline imaging. R2* (i.e. 1/T2*) values were calculated pre/post P904 injection. 18F-FDG PET data were analyzed by averaging the mean Standard Uptake Value (SUVmean) over the abdominal aorta. The in vivo imaging was then correlated with matched histological sections stained for macrophages.

Results

18F-FDG PET showed strong FDG uptake in the abdominal aorta and P904 injection revealed an increase in R2* values in the aortic wall at baseline. At 6 months, SUVmean values measured in the regression group showed a significant decrease from baseline (p = 0.015). In comparison, progression group values remained constant (p = 0.681). R2* values showed a similar decreasing trend in the regression group suggesting less USPIO uptake in the aortic wall. Correlations between SUVmean or Change in R2* value and macrophages density (RAM-11 staining) were good (R2 = 0.778 and 0.707 respectively).

Conclusion

This experimental study confirms the possibility to combine two functional imaging modalities to assess changes in the inflammation of atherosclerotic plaques. 18F-FDG-PET seems to be more sensitive than USPIO P904 to detect early changes in plaque inflammation.

Introduction

Rupture of atherosclerotic plaques may trigger the onset of clinical events such as myocardial infarction or ischemic stroke. Macrophages are inflammatory cells that have been shown to play a critical role in plaque formation and contribute to plaque instability and rupture [1]. Inflammation exerts detrimental effects by degrading the fibrous cap, increasing apoptosis of the resident smooth muscle cells and increasing neovascularization in the plaque. The beneficial effects of several therapeutics, such as statins, on plaque inflammation have been previously established both in clinical and preclinical settings [2], [3]. Therefore, there is increasing interest in the development of non-invasive imaging techniques to visualize macrophage burden, and to monitor plaque activity as well as the efficacy of therapeutic interventions. 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG-PET), used in combination with computed tomography (CT) or magnetic resonance imaging (MRI), and iron contrast-enhanced MRI with ultra small superparamagnetic iron oxides (USPIOs) are two established methods that have been used to visualize the inflammation/macrophage burden in both preclinical and clinical settings [4], [5].

The aim of this study was to compare the ability of 18F-FDG PET and iron contrast-enhanced MRI with a novel USPIO (P904) to assess change in plaque inflammation induced by atorvastatin and dietary change in a rabbit model of atherosclerosis.

Section snippets

Animal protocol

The Mount Sinai Institute of Animal Care and Use Committee approved all experiments.

Atherosclerotic lesions were induced in the aorta of New Zealand White rabbits (n = 14; mean age 3 months; mean body weight, 3.0–4.0 kg; Covance, Princeton, NJ) by combination of high cholesterol diet and aortic denudation. Aortic injury was induced under general anesthesia by an intramuscular injection of ketamine (20 mg/kg; Fort Dodge Animal Health, Overland Park, KS) and xylazine (5 mg/kg; Bayer, Shawnee

USPIO and FDG uptake

At baseline we observed an increase of R2* values post P904 injection and a strong uptake of FDG in the abdominal aorta indicating atherosclerotic plaque inflammation. At baseline, R2* values and SUVmean were similar in Regression and Progression group (p = 0.936 for R2* change, p = 0.701 for SUVmean).

At 6 months we observed a lesser increase in R2* values post P904 injection in the regression group compared to baseline (32.91% vs 48.12%) but without significant difference (p = 0.602). In the

Discussion

Combined FDG PET and USPIO contrast enhanced MRI can be used to monitor the effect of statin therapy and dietary change in atherosclerotic rabbits. FDG PET mean SUV reduction in atherosclerotic plaque was significant after 6 months while USPIO MRI signal change also showed a decrease in macrophage infiltration but without statistical significance.

Human prospective studies have already shown the ability of USPIO contrast enhanced MRI or FDG PET to monitor the effect of statin therapy at

Conflict of interest

E.L., S.B., P.R. and C.C. are employees of Guerbet; Z.A.F. received partial funding from Guerbet.

Acknowledgments

Partial funding for this research was provided in part by NIH/NHLBI R01 HL07102, NIH/NBIB R01 EB009638, NIH/NCATS CTSA UL1TR000067 (Imaging Core) and Guerbet Laboratories.

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