title: Assessment of age modulated vascular inflammation in ApoE-/- mice by USPIO-enhanced magnetic resonance imaging.
abstract: OBJECTIVE
  Inflammation within atherosclerotic lesions increases the risk for plaque rupture and thrombosis. A functional approach to plaque analysis is the intravenous administration of ultrasmall superparamagnetic particles of iron oxide (USPIO) that enables visualization of macrophages residing in the plaques. In this study, we sought to characterize the age-related inflammatory status associated with atherosclerosis lesion progression in ApoE mice using USPIO-enhanced magnetic resonance imaging (MRI).
  
  
  METHODS
  A total of 24 ApoE mice were divided in 4 groups (N = 6) and were given a high cholesterol diet from 6 weeks of age to the end of the protocol. One group per MR time point was investigated at 10, 16, 24, and 34 weeks of age. Each MR examination was performed on a 4.7 T scanner and consisted of baseline and 48 hours post-USPIO administration imaging sessions. P904, a USPIO contrast agent (Guerbet, Paris, France) with a potential for plaque macrophage targeting, was used.Vessel wall area measurements were performed on high resolution spin echo transverse images. Multi-echo gradient-echo images acquired with the same geometry were used to calculate T2* maps of the vessel wall using a pixel-by-pixel monoexponential fit. A one-way analysis of variance was performed to characterize the temporal variation of vessel wall area, susceptibility artifact area, baseline, and post-USPIO T2* values. MR measurements were correlated with the histologic findings.
  
  
  RESULTS
  A significant increase was found in the aortic wall area from 1.4 ± 0.2 at 10 weeks to 2.0 ± 0.3 mm at 34 weeks of age (P < 0.05). Concerning the post-USPIO MRI, signal loss regions, with patterns spanning from focal to the complete disappearance of the vessel wall, were observed on all postcontrast images. A significant increase in the size of the susceptibility artifact was observed from 0.5 ± 0.2 to 2.4 ± 1.0 at 24 weeks (P < 0.05) and to 2.0 ± 0.9 mm at 34 weeks (P < 0.05).The T2* values calculated on the 48 hours post-USPIO images were shorter compared with baseline. The decrease was 34% ± 16% at 10 weeks, 57% ± 11% at 16 weeks, 57% ± 16% at 24 weeks, and 48% ± 13% at 34 weeks.The Pearson's correlation test between measurement of aortic wall area performed on both MR images and histologic analysis showed a statistically significant correlation (r = 0.695 and P < 0.05). A correlation was also obtained between the signal loss area and the macrophages covered area (r = 0.68 and P < 0.05).
  
  
  CONCLUSIONS
  This study demonstrated the feasibility of USPIO-enhanced MRI in assessing the inflammatory status related to the temporal progression of the atherosclerosis plaque in ApoE transgenic mice model of atherosclerosis. In our experimental conditions, the vascular inflammation peak, for the ApoE mice feeding high-fat/high-cholesterol diet is measured between 16 and 24 weeks of age.
authors.affiliation: Université Lyon 1, CREATIS-LRMN, UMR CNRS 5220, U630 INSERM, Lyon, France.
authors.forename: Monica
authors.initials: M
authors.lastname: Sigovan
authors.forename: Amine
authors.initials: A
authors.lastname: Bessaad
authors.forename: Hasan
authors.initials: H
authors.lastname: Alsaid
authors.forename: Eric
authors.initials: E
authors.lastname: Lancelot
authors.forename: Claire
authors.initials: C
authors.lastname: Corot
authors.forename: Bruno
authors.initials: B
authors.lastname: Neyran
authors.forename: Nicolas
authors.initials: N
authors.lastname: Provost
authors.forename: Zouher
authors.initials: Z
authors.lastname: Majd
authors.forename: Magali
authors.initials: M
authors.lastname: Breisse
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Canet-Soulas
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000473:pathology*; D001057:Apolipoproteins E; D001161:Arteriosclerosis / Q000175:diagnosis* / Q000473:pathology; D018450:Disease Progression; D005240:Feasibility Studies; D007091:Image Processing, Computer-Assisted; D007249:Inflammation / Q000175:diagnosis* / Q000473:pathology; D008264:Macrophages / Q000473:pathology*; D008279:Magnetic Resonance Imaging / Q000295:instrumentation*; D051379:Mice; D008810:Mice, Inbred C57BL; D018570:Risk Assessment; D012421:Rupture; D012984:Software; D013223:Statistics as Topic; D013927:Thrombosis / Q000175:diagnosis* / Q000473:pathology
chemical_list: D001057:Apolipoproteins E