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. 2015 Jul 8;88(1053):20150167. doi: 10.1259/bjr.20150167

MRI study of atherosclerotic plaque progression using ultrasmall superparamagnetic iron oxide in Watanabe heritable hyperlipidemic rabbits

C Kaneko 1,✉, N Nitta 1, K Tsuchiya 1, S Watanabe 1, A Nitta-Seko 1, S Ohta 1, H Otani 1, A Sonoda 1, K Murata 1, M Shiomi 2
PMCID: PMC4743577  PMID: 26083261

Abstract

Objective:

The purpose of this study was to evaluate plaque progression by using MRI with ultrasmall superparamagnetic iron oxide (USPIO) and by histopathological studies.

Methods:

We divided 12 Watanabe heritable hyperlipidemic (WHHL) rabbits into 4 groups based on their age (3, 9, 14 and 26 months) and injected them intravenously with 0.8 mmol (Fe) kg−1 of USPIO (size, 32 nm; concentration, 15 mg dl−1). On the fifth post-injection day, they were again given an intravenous injection with 40 μmol kg−1 of the same USPIO, and MR angiography (MRA) was performed. The signal-to-noise ratio (SNR) in regions of interest in the wall of the upper abdominal aorta was calculated on coronal images. Specimens from the same level of the aorta were subjected to iron staining and RAM-11 immunostaining and used for histopathological study. For statistical analysis of the MRA and histopathological findings, we used analysis of variance [Tukey's honest significant difference (HSD) test].

Results:

In 9-month-old rabbits, the SNR was significantly lower than in rabbits of the other ages (p < 0.01), and the area of RAM-11 (DAKO Corporation, Glostrup, Denmark) and iron uptake in the aortic wall was significantly larger (RAM-11, p < 0.01; iron, p < 0.05). These areas were the smallest in 3-month-old rabbits.

Conclusion:

Histopathologically, the number of macrophages was the greatest in 9-month-old rabbits. Our findings indicate that the SNR on MRI scans reflects the number of macrophages in the aortic wall of WHHL rabbits.

Advances in knowledge:

USPIO-enhanced MRI visualized the accumulation of macrophages in early atherosclerotic plaques of WHHL rabbits in the course of natural progression.

INTRODUCTION

Atherosclerosis is a chronic inflammation of the arterial wall and a leading cause of diseases such as acute coronary syndrome and myocardial and cerebral infarction. Macrophages play an important role in the progression of atherosclerosis; they produce molecules that promote inflammation and trigger plaque disruption and subsequent thrombus formation.1–3 Therefore, the evaluation of target molecular components in atherosclerotic plaques is important.

The uptake of superparamagnetic iron oxide particles (SPIOs) by the mononuclear phagocytic system (MPS) results in hepatic, splenic, bone marrow and nodal iron accumulation.4 Unlike SPIOs with a diameter of a few hundred nanaometres, ultrasmall iron oxide particles (USPIOs), whose mean diameter is 30 nm, are not immediately recognized by the hepatic and splenic MPS.4–6 The capillary permeability of USPIOs facilitates their uptake by macrophages and they have been used in the study of multiple sclerosis, arthritis and atherosclerotic plaques.7–9 The blood half-life of USPIOs is longer than that of SPIOs and their T1-shortening property has led to their use in low concentrations in MR angiography (MRA) studies. Owing to their T2/T2*-shortening effect, at high injection concentrations, the accumulation of USPIO in the aortic wall results in a very low signal after 4–5 days, and this facilitates the acquisition of excellent vascular wall images.4

The aim of this study was to evaluate spontaneous atherosclerosis plaque progression in the aorta of Watanabe heritable hyperlipidemic (WHHL) rabbits using MRI and USPIOs. We also compared imaging and histological findings made at identical aortic wall sites in rabbits of different ages.

METHODS AND MATERIALS

All experimental protocols were approved by our animal experimentation committee, and all experiments were conducted in accordance with the Animal Care Guidelines of Shiga University of Medical Science, Otsu, Shiga, Japan.

Iron oxide nanoparticles

USPIO (particle diameter, 32 nm; iron concentration, 15 mg dl−1) was supplied by Meito Sangyo, Kiyosu, Aichi, Japan.

Animal model

We obtained 12 (WHHL) rabbits from the Institute for Experimental Animals at Kobe University, Hyogo, Japan. They were 3–26 months old and weighed approximately 3 kg. They were divided into four equal groups based on their age (3, 9, 14 and 26 months).

MRI studies

The animals were anesthetized with ketamine (Ketalar 50; Sankyo Yell Yakuhin, Tokyo, Japan) and medetomidine (Domitor; Meiji Seika, Tokyo, Japan) (25 and 0.1 mg kg−1 body weight, respectively). USPIOs were injected into an ear vein (0.8 mmol Fe kg−1), and 5 days later, the animals were again injected with USPIO (40 μmol Fe kg−1). The low dose, 40 μmol Fe kg−1, was administered for its T1-shortening effect that renders the signal bright in the aortic lumen.

MRA scans were obtained on a 1.5-T MRI system (Signa® Excite HDx; GE Healthcare, Milwaukee, WI) (maximum amplitude, 33 mT m−1; slew rate, 120 mT m−1 ms−1) using a single-channel birdcage head coil. Scanning was performed with a three-dimensional fast spoiled gradient echo protocol; the scanning parameters were TR, 9.0 ms; TE, 1.4 ms; receiver bandwidth, 62.5  kHz; slices, 106; flip angle, 25°; field of view (FOV), 320 × 240 mm; matrix size, 256 × 256; slice thickness, 1 mm; average, 1; acquisition time, 159 s.

MR image analysis

The MR images were analysed on a workstation (Ziostation2; Ziosoft, Inc., Tokyo, Japan) and post-processed. Multiplanar reformatting images were acquired.

For quantitative analysis, the signal-to-noise ratio (SNR) was calculated on coronal images at three regions of interest (ROIs) in the wall of the upper abdominal aorta, the same areas used in the histopathological studies. The ROI (2 × 10 pixels) was set in the aortic wall on coronal images (Figure 1) using Photoshop CS6 (Adobe Systems Inc., San Jose, CA), and the signals were recorded. We measured the aortic segments 2 cm down from the celiac artery level, using the celiac and the superior mesenteric artery as markers. Image background noise was also evaluated by measuring the standard deviation of the ROI. For each animal, the SNR of the aortic wall was calculated as SNR = SI/BN, where SI is the signal intensity of the aortic wall, and BN the background noise. At least 5 months after the first evaluation, this analysis was performed twice by a single radiologist blinded to the pathological data.

Figure 1.

Figure 1.

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Curved planar reconstruction of ultrasmall superparamagnetic iron oxide-enhanced MR images obtained under a three-dimensional fast spoiled gradient echo protocol. The aortas of four Watanabe heritable hyperlipidemic rabbits aged 3 (a), 9 (b), 14 (c) and 26 months (d) are shown. The aortic wall was relatively smooth in 3-month-old rabbits. Some irregularities are apparent in 14- and 26-month-old rabbits (c, d). The insets show regions of interest placed in the aortic wall.

Care was taken to ensure that ROIs of identical size, as large as possible, were placed at identical locations in the different animals. The thinness of the arterial wall of our relatively small rabbits dictated the use of large ROIs.

In addition, USPIO-induced magnetic susceptibility artefact was quantified by the size of signal loss in the aortic walls. The lengths of signal loss area were measured in the reconstructed transverse plane (Figure 2). The lengths were measured in two directions that crossed perpendicularly. Two radiologists (CK and NN, with 16 and 26 years' experience, respectively) measured levels below the celiac artery in three different slices of the aorta. The mean values of each group (n = 12 per one animal) were then calculated.

Figure 2.

Figure 2.

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Axial MR images of the abdominal aorta in rabbits obtained after ultrasmall superparamagnetic iron oxide injection. The white lines indicate the measurement of lengths of the vessel wall area. The aortas of four Watanabe heritable hyperlipidemic rabbits aged 3 (a), 9 (b), 14 (c), and 26 months (d) are shown. Note that the area of signal loss of the aortic wall in 9-month-old rabbits is relatively diffuse and in 14- and 26-month-old rabbits is relatively spotty.

Histological examination

The rabbits were euthanized and the aortic specimens were removed. The abdominal aorta, 2 cm down from the diaphragm, was fixed in 10% paraformaldehyde. For general morphologic analysis, we stained 4-μm thick serial sections (sagittal plane; mean, 22.5 slices per animal) with haematoxylin–eosin and Elastica van Gieson stains. We used Prussian blue staining to visualize accumulated iron oxide. Immunostaining was with monoclonal antibodies against rabbit macrophages (RAM-11; DAKO Corporation, Denmark). For quantitative assessments, we measured the Prussian blue and RAM-11 stained areas in one FOV (magnification ×200) in three different lesions on each section and calculated the average values. Histology sections corresponding to the MRI-scanned regions were located on the MRI scans using the celiac artery and superior mesenteric artery as references.

Statistical analysis

Differences in the SNR values among the four age groups and in the stain-positive areas were analysed by one-way analysis of variance and by Tukey's honest significance difference test. To assess the variability in the recorded SNR of the vessel wall, we compared the two sets of measurements using the Pearson test. A value of p < 0.05 was considered statistically significant.

RESULTS

MRI findings

With respect to luminal SI, the low-dose (40 μmol Fe kg−1) injection of USPIO produced an angiographic T1-shortening effect. The aortic lumen was bright, and the aortic walls were clearly visualized. While curved planar reconstruction revealed no aortic wall abnormalities in 3- and 9-month-old rabbits, in the older animals, we observed contour irregularities with some degree of stenosis visualized as spotty signal voids (Figure 1).

The high-dose (0.8 mmol Fe kg−1) injection of USPIO resulted in T2* effects that led to a signal loss in the aortic wall. The MRI-derived SNR and the lengths of vessel wall areas of 3-, 9-, 14- and 26-month-old rabbits are summarized in Table 1.

Table 1.

Signal-to-noise ratio (SNR) and length of vessel wall area studied by MRI in four different age groups (n = 3 each)

Watanabe heritable hyperlipidemic rabbit age (months) 3 9 14 26
SNR 25.43 ± 14.15a,b 6.19 ± 2.72c,d,b 25.92 ± 3.26a,b 40.82 ± 7.80c,a,d
Length of vessel wall area (mm) 0.98 ± 0.36d,b 1.06 ± 0.34d,b 0.72 ± 0.46c,a 0.75 ± 0.31c,a
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All measurements are the mean ± standard deviation.

a

Significantly different (p < 0.05) from 9-month-old rabbits.

b

Significantly different (p < 0.05) from 26-month-old rabbits.

c

Significantly different (p < 0.05) from 3-month-old rabbits.

d

Significantly different (p < 0.05) from 14-month-old rabbits.

Quantitative assessment of USPIO showed that all images provided a sufficient SNR for atherosclerotic lesions. The SNR of the aortic wall was significantly lower in 9-month-old rabbits than in rabbits of the other ages (p < 0.01) (Figure 3). As shown in Table 1, there were significant differences when we compared the SNR in 3- and 26-month-old animals (p = 0.002) and in 14- and 26-month-old rabbits (p = 0.003). The Pearson correlation coefficient calculated to evaluate interobserver variability in the SNR measurements was 0.77 (p < 0.01).

Figure 3.

Figure 3.

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Signal-to-noise ratio (SNR) in the aortic wall of rabbits injected with ultrasmall superparamagnetic iron oxides. SNR was significantly lower in 9-month-old rabbits than in rabbits of the other age groups (*p < 0.01).

The lengths of signal loss area in the aortic wall were significantly lower in 9-month-old rabbits than in rabbits of 14- and 26-month-old animals (p < 0.01). There were significant differences when we compared the lengths in 3- and 14-month-old animals and in 3- and 26-month-old rabbits (p < 0.05, respectively).

Histological findings

Prussian blue and RAM-11 staining confirmed the uptake of iron- and RAM-11 by the arterial wall of all 12 rabbits. The localization of iron coincided with the observed accumulation of macrophages in the neointima of the aortic wall (Figure 4). In 3-month-old rabbits, thickening of the intima was mild and their aortic wall was smooth. As the age of the animals increased, so did intimal thickening and the uptake of USPIOs. In 14-month-old rabbits, intimal thickening was advanced while the uptake of USPIOs and the number of macrophages declined. Calcification and plaque disruption were evident in 26-month-old rabbits; RAM-11 and iron were taken up in a small area, and the degree of intimal thickening was greater than in 14-month-old animals.

Figure 4.

Figure 4.

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Histology of the abdominal aorta of four rabbits aged 3 (a, e), 9 (b, f), 14 (c, g) and 26 months (d, h). Prussian blue (a–d, blue) and RAM-11 (DAKO Corporation, Glostrup, Denmark) staining (e–h, red) at identical sites. The localization of iron coincided with the accumulation of macrophages in rabbits of all ages. Note intimal hyperplasia and moderate ultrasmall superparamagnetic iron oxide (USPIO) uptake in the neointima of the 3-month-old rabbits (a, e). In 9-month-old animals, there is greater USPIO uptake and progressive intimal thickening (b, f). The USPIO uptake and the number of macrophages were lower in 14-month-old rabbits (c, g). RAM-11 staining and the uptake of USPIOs were seen in small areas in 26-month-old rabbits (d, h). Intimal thickening progressed with increasing age. Bars = 100 μm (magnification, ×200).

By quantitative analysis, the iron- and RAM-11-positive areas were significantly larger in 9-month-old rabbits than in animals of the other ages (RAM-11, p < 0.01; iron, p < 0.05); they were the smallest in 3-month-old rabbits (Figures 5 and 6).

Figure 5.

Figure 5.

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The area of iron uptake in the aortic wall of rabbits injected with ultrasmall superparamagnetic iron oxides was significantly larger in 9-month-old rabbits than in the other age groups (*p < 0.05; **p < 0.01).

Figure 6.

Figure 6.

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The RAM-11-positive areas (DAKO Corporation, Glostrup, Denmark) in the aortic wall of rabbits injected with ultrasmall superparamagnetic iron oxides were significantly larger in 9-month-old rabbits than in the other age groups (*p < 0.01).

DISCUSSION

Our study shows that USPIOs were phagocytosed by macrophages in the early atherosclerotic plaques in the abdominal aorta of WHHL rabbits.

Assessment on images of USPIOs in the arterial wall and histopathological and immunopathological study of the areas of USPIO uptake showed a significant accumulation of macrophages in atherosclerotic plaques of 9-month-old rabbits. These animals did not manifest marked intimal thickening. While no aortic wall abnormalities were observed on images of 3-month-old rabbits, in 14- and 26-month-old animals, we observed aortic wall irregularities and the older rabbits harboured several ruptured plaques. Our findings suggest that the neointimal USPIO uptake and the accumulation of macrophages observed in 9-month-old rabbits may be predictive of vulnerable plaques.

Previous experimental4,10 and clinical6,11 pathological studies revealed that USPIOs are taken up by macrophage-laden atherosclerotic plaques. Those findings coincide with ours. However, no MRI data using USPIOs have been published on the natural progression of atherosclerosis in WHHL rabbits. Wang et al,12 who evaluated the natural progression of atherosclerosis in WHHL rabbits on unenhanced MRI scans by measuring the abdominal aortic wall thickness and the vascular lumen, reported good agreement between their MRI observations and pathological findings on the wall thickness and plaque components reported by others.13,14 We noted many macrophages in the aortic wall of rabbits up to the age of 9 months. This confirms that macrophages play an important role in early atherosclerosis. Ruehm et al4 documented the presence of USPIOs in the aortic wall of 6-month-old WHHL rabbits. According to Wang et al,12 the aortic wall thickness of WHHL rabbits increased rapidly as their age increased from 20 to 50 weeks; it continued to increase slowly up to an age of 73 weeks. Their and our observations are indicative of active atherosclerosis at around 9 months; however, they did not address changes in the activity of macrophages. As the evaluation of intimal thickening and of the vascular stenosis rate alone does not help to identify vulnerable plaques, the quantification of macrophages, cells that play an important role in the development of atherosclerosis, may be more useful.

The developmental process of atherosclerosis is similar in rabbits and humans,15 and our use of WHHL rabbits, in whom the disease progresses in the course of a few months, made it possible to observe its progression over a relatively short time. We followed the natural course of atherosclerosis progression on USPIO-enhanced images of rabbits without balloon-induced vessel wall injury who were fed a normal diet.

There are several techniques for the quantitative analysis of USPIO signal changes. We chose the SNR because it can be used even when the imaging methods and the measured areas are different.6,11,16,17 Hyafil et al10 reported that magnetic susceptibility artefacts, which generate signal voids on MRI scans, extended periadventitially and intraluminally to outside the anatomic borders of the aortic wall. Sigovan et al18 used the area of signal loss for their quantitative analysis. We hypothesized that we could use the vessel wall areas for USPIO quantification. Millon et al19 prepared R2* maps to calculate the mean R2* value in rabbit plaques. Positive-contrast approaches after USPIO injection, e.g. gradient echo acquisition of superparamagnetic particles (GRASP), have been studied.20,21

Atherosclerosis can also be evaluated with invasive imaging techniques such as X-ray angiography and intravascular ultrasound. Because MRI is non-invasive and does not require ionizing radiation, USPIOs can be used in patients with renal dysfunction. USPIO-enhanced MRI is therefore more suitable in clinical settings. In fact, the ability of USPIO-enhanced MRI to detect vulnerable human atherosclerotic plaques has been well documented.6,22,23

Our study has some limitations. First, the number of rabbits was too small to assess interindividual differences. Second, signal loss owing to motion, partial voluming, calcification and haemorrhage rendered SNR measurements difficult. Third, our imaging sequence was not optimized. We are in the process of evaluating the usefulness of other sequences such as a more T2* weighted GRE sequence, T2 weighted spin-echo axial images of high-resolution MRI and positive-contrast techniques such as the GRASP sequence.20,21

In conclusion, USPIO-enhanced MRI visualized the accumulation of macrophages in the early atherosclerotic plaques of WHHL rabbits. We consider it a promising technique for the detection of vulnerable plaques and for the assessment of the effects of therapy.

FUNDING

This study was supported by a research grant from the Japan Radiological Society supported by Bayer.

Contributor Information

C Kaneko, Email: sugimori@belle.shiga-med.ac.jp.

N Nitta, Email: r34nitta@yahoo.co.jp.

K Tsuchiya, Email: keikot@belle.shiga-med.ac.jp.

S Watanabe, Email: swat@belle.shiga-med.ac.jp.

A Nitta-Seko, Email: ayumis@belle.shiga-med.ac.jp.

S Ohta, Email: junryuhei@belle.shiga-med.ac.jp.

H Otani, Email: otani@belle.shiga-med.ac.jp.

A Sonoda, Email: akinagasonoda@yahoo.co.jp.

K Murata, Email: murata@belle.shiga-med.ac.jp.

M Shiomi, Email: ieakusm@med.kobe-u.ac.jp.

REFERENCES

  • 1.Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801–9. doi: 10.1038/362801a0 [DOI] [PubMed] [Google Scholar]
  • 2.Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell 2011; 145: 341–55. doi: 10.1016/j.cell.2011.04.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685–95. doi: 10.1056/NEJMra043430 [DOI] [PubMed] [Google Scholar]
  • 4.Ruehm SG, Corot C, Vogt P, Kolb S, Debatin JF. Magnetic resonance imaging of atherosclerotic plaque with ultrasmall superparamagnetic particles of iron oxide in hyperlipidemic rabbits. Circulation 2001; 103: 415–22. doi: 10.1161/01.CIR.103.3.415 [DOI] [PubMed] [Google Scholar]
  • 5.Weissleder R, Elizondo G, Wittenberg J, Rabito CA, Bengele HH, Josephson L. Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiology 1990; 175: 489–93. doi: 10.1148/radiology.175.2.2326474 [DOI] [PubMed] [Google Scholar]
  • 6.Kooi ME, Cappendijk VC, Cleutjens KB, Kessels AG, Kitslaar PJ, Borgers M, et al. Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging. Circulation 2003; 107: 2453–8. doi: 10.1161/01.CIR.0000068315.98705.CC [DOI] [PubMed] [Google Scholar]
  • 7.Corot C, Petry KG, Trivedi R, Saleh A, Jonkmanns C, Le Bas JF, et al. Macrophage imaging in central nervous system and in carotid atherosclerotic plaque using ultrasmall superparamagnetic iron oxide in magnetic resonance imaging. Invest Radiol 2004; 39: 619–25. doi: 10.1097/01.rli.0000135980.08491.33 [DOI] [PubMed] [Google Scholar]
  • 8.Lutz AM, Seemayer C, Corot C, Gay RE, Goepfert K, Michel BA, et al. Detection of synovial macrophages in an experimental rabbit model of antigen-induced arthritis: ultrasmall superparamagnetic iron oxide-enhanced MR imaging. Radiology 2004; 233: 149–57. doi: 10.1148/radiol.2331031402 [DOI] [PubMed] [Google Scholar]
  • 9.Simon GH, von Vopelius-Feldt J, Wendland MF, Fu Y, Piontek G, Schlegel J, et al. MRI of arthritis: comparison of ultrasmall superparamagnetic iron oxide vs. Gd-DTPA. J Magn Reson Imaging 2006; 23: 720–7. doi: 10.1002/jmri.20556 [DOI] [PubMed] [Google Scholar]
  • 10.Hyafil F, Laissy JP, Mazighi M, Tchétché D, Louedec L, Adle-Biassette H, et al. Ferumoxtran-10-enhanced MRI of the hypercholesterolemic rabbit aorta. Arterioscler Thromb Vasc Biol 2006; 26: 176–81. doi: 10.1161/01.ATV.0000194098.82677.57 [DOI] [PubMed] [Google Scholar]
  • 11.Trivedi RA, Mallawarachi C, U-King-Im JM, Graves MJ, Horsley J, Goddard MJ, et al. Identifying inflamed carotid plaques using in vivo USPIO-enhanced MR imaging to label plaque macrophages. Arterioscler Thromb Vasc Biol 2006; 26: 1601–6. doi: 10.1161/01.ATV.0000222920.59760.df [DOI] [PubMed] [Google Scholar]
  • 12.Wang YX, Kuribayashi H, Wagberg M, Holmes AP, Tessier JJ, Waterton JC. Gradient echo MRI characterization of development of atherosclerosis in the abdominal aorta in Watanabe Heritable Hyperlipidemic rabbits. Cardiovasc Intervent Radiol 2006; 29: 605–12. doi: 10.1007/s00270-005-0073-5 [DOI] [PubMed] [Google Scholar]
  • 13.Zimmermann-Paul GG, Quick HH, Vogt P, von Schulthess GK, Kling D, Debatin JF. High-resolution intravascular magnetic resonance imaging: monitoring of plaque formation in heritable hyperlipidemic rabbits. Circulation 1999; 99: 1054–61. doi: 10.1161/01.CIR.99.8.1054 [DOI] [PubMed] [Google Scholar]
  • 14.Hänni M, Edvardsson H, Wågberg M, Pettersson K, Smedby O. Quantification of atherosclerosis with MRI and image processing in spontaneously hyperlipidemic rabbits. J Cardiovasc Magn Reson Imaging 2004; 6: 675–84. [DOI] [PubMed] [Google Scholar]
  • 15.Gallagher PJ, Nanjee MN, Richards T, Roche WR, Miller NE. Biochemical and pathological features of a modified strain of Watanabe heritable hyperlipidaemic rabbits. Atherosclerosis 1988; 71: 173–83. doi: 10.1016/0021-9150(88)90141-4 [DOI] [PubMed] [Google Scholar]
  • 16.Tang TY, Howarth SP, Miller SR, Graves MJ, U-King-Im JM, Li ZY, et al. Correlation of carotid atheromatous plaque inflammation using USPIO-enhanced MR imaging with degree of luminal stenosis. Stroke 2008; 39: 2144–7. doi: 10.1161/STROKEAHA.107.504753 [DOI] [PubMed] [Google Scholar]
  • 17.Tsuchiya K, Nitta N, Sonoda A, Nitta-Seko A, Ohta S, Takahashi M, et al. Evaluation of atherosclerotic lesions using dextran- and mannan-dextran-coated USPIO: MRI analysis and pathological findings. Int J Nanomed 2012; 7: 2271–80. doi: 10.2147/IJN.S29417 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Sigovan M, Boussel L, Sulaiman A, Sappey-Marinier D, Alsaid H, Desbleds-Mansard C, et al. Rapid-clearance iron nanoparticles for inflammation imaging of atherosclerotic plaque: initial experience in animal model. Radiology 2009; 252: 401–9. doi: 10.1148/radiol.2522081484 [DOI] [PubMed] [Google Scholar]
  • 19.Millon A, Dickson SD, Klink A, Izquierdo-Garcia D, Bini J, Lancelot E, et al. Monitoring plaque inflammation in atherosclerotic rabbits with an iron oxide (P904) and (18)F-FDG using a combined PET/MR scanner. Atherosclerosis 2013; 228: 339–45. doi: 10.1016/j.atherosclerosis.2013.03.019 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Mani V, Briley-Saebo KC, Itskovich VV, Samber DD, Fayad ZA. Gradient echo acquisition for superparamagnetic particles with positive contrast (GRASP): sequence characterization in membrane and glass superparamagnetic iron oxide phantoms at 1.5T and 3T. Magn Reson Med 2006; 55: 126–35. doi: 10.1002/mrm.20739 [DOI] [PubMed] [Google Scholar]
  • 21.Briley-Saebo KC, Mani V, Hyafil F, Cornily JC, Fayad ZA. Fractionated Feridex and positive contrast: in vivo MR imaging of atherosclerosis. Magn Reson Med 2008; 59: 721–30. doi: 10.1002/mrm.21541 [DOI] [PubMed] [Google Scholar]
  • 22.Metz S, Beer AJ, Settles M, Pelisek J, Botnar RM, Rummeny EJ, et al. Characterization of carotid artery plaques with USPIO-enhanced MRI: assessment of inflammation and vascularity as in vivo imaging biomarkers for plaque vulnerability. Int J Cardiovasc Imaging 2011; 27: 901–12. doi: 10.1007/s10554-010-9736-7 [DOI] [PubMed] [Google Scholar]
  • 23.Tang T, Howarth SP, Miller SR, Trivedi R, Graves MJ, King-Im JU, et al. Assessment of inflammatory burden contralateral to the symptomatic carotid stenosis using high-resolution ultrasmall, superparamagnetic iron oxide-enhanced MRI. Stroke 2006; 37: 2266–70. doi: 10.1161/01.STR.0000236063.47539.99 [DOI] [PubMed] [Google Scholar]

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