Research Note

Combined application of 18F-fluorodeoxyglucose positron emission tomography/computed tomography and magnetic resonance imaging in early diagnosis of vulnerable carotid atherosclerotic plaques

Journal of International Medical Research 2014, Vol. 42(1) 213–223 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060513502887 imr.sagepub.com

Xie Lei-xing1,2,*, Gai Jing-jing1,*, Niu Jing-xue3,*, Wang Juan1,*, Li Juan1, Liang Chang-zai1, Wang Xiao-xi1, Yin Da-yi4, Liu Jia-jin4, Zhang Xiong-wei4, Cheng Liu-quan5, Wang Yong5, Liu Dan-qing5 and Liu Hong-bin1

Abstract Objective: To assess the correlations between atherosclerotic plaque characteristics and inflammatory activity by combined use of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI). Methods: Patients underwent 18F-FDG PET/CT and MRI. Target/background ratios (TBR) of axial sections were determined from mean standard uptake values (SUV). Correlations between TBR and mean vessel wall thickness, total vessel area, lumen area, vessel wall area and normalized wall index were calculated. Plaque types were defined as calcified, collagen, lipid or haemorrhage. Plaques were also classified as thick, thin, or ruptured fibrous cap.

5 1

Department of Cardiology, Chinese People’s Liberation Army General Hospital, Beijing, China 2 Department of Cardiology, Hainan Branch of Chinese PLA General Hospital, Sanya, China 3 Department of Neurorehabilitation, China Rehabilitation Research Centre, Beijing, China 4 Department of Nuclear Medicine, Chinese People’s Liberation Army General Hospital, Beijing, China

Department of Radiology, Chinese People’s Liberation Army General Hospital, Beijing, China *These authors contributed equally to this work. Corresponding author: Liu Hong-bin, Department of Cardiology, Chinese People’s Liberation Army General Hospital, Fuxing Road, Haidian District, Beijing 100853, China. Email: [email protected]

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Results: The study included 31 patients (1178 plaque slices). There was a significant decrease in TBR values across the fibrous cap groups, such that ruptured > thin > thick. Lipid and haemorrhage plaques had significantly higher TBR than calcification and collagen plaques. There were weak positive correlations between TBR and mean vessel wall thickness, vessel wall area and normalized wall index. Conclusions: Thin or ruptured plaques, lipid-rich plaques and haemorrhagic plaques possess high inflammatory activity. The combination of 18F-FDG PET/CT and MRI could be useful for qualitative and quantitative diagnosis of carotid atherosclerotic plaques.

Keywords Carotid artery, atherosclerotic plaque, inflammation Date received: 14 January 2013; accepted: 5 February 2013

Introduction Atherosclerosis is the most common cause of death worldwide.1 Accurate assessment of plaque stability, early detection of vulnerable plaques and quantitation of disease are necessary for optimum treatment.2 18Ffluorodeoxyglucose (18F-FDG) positron emission tomography (PET) imaging has become an important tool for assessing the degree of inflammatory activity of carotid plaques.3 This technique can be used to identify plaque inflammation,4 and can also assess and monitor the effect of treatment.5 Criteria for the evaluation of plaque instability include morphology, size and composition; it has been shown that evaluating plaque instability by plaque morphology and size alone is inaccurate, however.4 Magnetic resonance imaging (MRI) cannot identify all vulnerable plaques, and the presence of uncharacterized plaques with high inflammatory activity may be a risk factor for cardiovascular and cerebrovascular events.4 The aim of the present study was to use 18 F-FDG PET/computed tomography (CT) imaging and MRI to evaluate patients with carotid atherosclerosis. The inflammatory activity (18F-FDG uptake) of plaques of different size, composition and fibrous cap

thickness was evaluated in order to explore the feasibility of vulnerable plaque detection by combined 18F-FDG PET/CT and MRI.

Patients and methods Study population The study recruited patients undergoing PET/CT and MRI within a 2-day period at the Department of Cardiology, Chinese People’s Liberation Army General Hospital, Beijing, China, between January 2011 and April 2012. Inclusion criteria were: (i) carotid artery ultrasound examination revealed carotid atherosclerosis within 2 weeks of study entry; (ii) verbal informed consent was provided by patients or their next of kin. Exclusion criteria were: (i) patients who could not undergo MRI due to metal in their body (e.g. cardiac pacemakers, prosthetic valves, metal residues around vital organs), pregnancy, contrast agent allergy, stage 4 or 5 nondialysisdependent chronic kidney disease, carotid bifurcation above the mandible or claustrophobia; (ii) patients who could not undergo PET/CT, including pregnant women and patients with serum glucose levels > 200 mg/dl. The Research Ethics Committee, Chinese People’s Liberation Army General Hospital,

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Beijing, China, provided ethical approval for the study.

The PET Centre of the Chinese People’s Liberation Army General Hospital provided 18 F-FDG with > 95% radiochemical purity. Patients fasted for > 6 h before examination. Following a 30-min rest period, 5.55 mBq/kg (0.15 mCi/kg) 18F-FDG was administered by intravenous injection. After a further 90-min rest period, PET/CT scanning was performed from the middle of the sternum to the upper edge of the ears (Biography 64 HD PET/CT scanner, Siemens, Erlangen, Germany).3,6,7 Plain CT scanning was performed at 120 kV and180 mA. A 3-min PET scan was performed, and three-dimensional (3D)-mode acquired data were used for image construction by the ordered subset expectation maximization method. The display matrix was 128  128; pixel size was 2.16 mm. Transaxial spatial resolution varies between 3.6 mm full width at half-maximal (FWHM) at the centre, 4.6 mm FWHM tangentially and 7.5 mm FWHM radially at R ¼ 10 cm. Average axial resolution changed from 4.6 mm FWHM at the centre to 5.8 mm FWHM at R ¼ 10 cm; the coronal, sagittal and transverse images were displayed and integrated. Images were analysed independently by two nuclear medicine specialists (L.J.J. and Z.X.W.). Regions of interest including the total vessel area were selected and the mean standard uptake value (SUV) of different axial sections was standardized against the contralateral jugular vein SUV, to determine the target/background ratio (TBR).

specified phased array coil. Images were obtained with field-of-view of 13 cm, matrix size of 512 (256 for two-dimensional [2D] time-of-flight [TOF]), slice thickness of 2 mm, and scan time 1.5 min per n slices. A 0-filled Fourier transform was used to reduce pixel size (to 0.25  0.25 mm2). Scanning was performed as follows: (i) bilateral carotid position scanning using gradient echo sequence; (ii) whole scan of the carotid artery using 2D–TOF sequence with thickness 2 mm and spacing 0 mm, flip angle 25, repetition time (TR) ¼ 23 ms, echo time (TE) ¼ 3.8 ms, number of excitations (NEX) 2, number of slices 48; (iii) 3D–TOF sequence with position line in the plaque centre, TR ¼ 9 ms, TE ¼ 2.4 ms, NEX 1, number of slices 40; (iv) horizontal scanning centred on the carotid bifurcation with quadruple inversion recovery T1-weighted imaging (T1WI) sequence, TR ¼ 800 ms, inversion time ¼ 650 ms, TE ¼ 9.3 ms, NEX 2, number of slices 22; (v) oblique sagittal scan of the carotid artery using T1WI sequence; (vi) double-echo axial scanning of plaque to obtain proton density-weighted images and T2-weighted imaging (T2WI), TR ¼ 3000 ms, TE ¼ 20/40 ms, NEX 2, turbo factor (echo train length) 12, number of slices 22; (vii) thin horizontal scan of the plaque with thickness 2 mm and spacing 0 mm, with fat suppression; (viii) thin horizontal scan of the plaque with thickness 2 mm and spacing 0 mm, without fat suppression; (ix) contrast agent (gadoliniumdiethylene triamine penta-acetic acid) was injected and contrast enhanced MRI examinations were undertaken. Full details of MRI scanning sequences and parameters are given in Table 1.

MRI

Quantitative plaque analysis

Each patient underwent MRI of the carotid artery using the 1.5 T Signa Horizon Echospeed MR imaging machine (GE Healthcare, Piscataway, NJ, USA) and

All MRI scans were uploaded to the Advantage Workstation 4.4 (General Electric) and independently analysed by two experienced radiologists (W.Y. and

18

F-FDG PET/CT imaging

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Table 1. Magnetic resonance imaging scanning sequences and parameters in a study to investigate the use of combined 18F-fluorodeoxyglucose positron emission tomography/computed tomography and magnetic resonance imaging for early diagnosis of vulnerable plaques (n ¼ 31). Scan type

2D-TOF

3D-TOF

T1WI

PDWI/T2WI

Acquisition mode Acquisition sequence TR, ms TI, ms TE, ms FOV, cm Matrix Size Slice thickness, mm No. of slices NEX Echo-train length flip angle,

2D gradient-echo 23 – 3.8 13  13 256  256 2 48 2 – 25

3D gradient-echo 9 – 2.4 13  13 512  512 2 40 1 – –

2D Fast spin-echo 800 650 9.3 13  13 512  512 2 22 2 – –

2D Fast spin-echo 3000 – 20/40 13  13 512  512 2 22 2 12 –

TR, repetition time; TE, echo time; TI, inversion time; FOV, field-of-view; NEX, number of excitations; 2D–TOF, twodimensional time-of-flight; 3D–TOF, three-dimensional time-of-flight; T1WI, T1-weighted imaging; PDWI, proton density weighted images; T2WI, T2-weighted imaging.

L.D.Q.). Fibrous caps were examined and classified as ruptured, thick (intact fibrous cap with thickness  200 mm), or thin (intact fibrous cap with thickness < 200 mm).8 The TBR values of each group were calculated.

Plaque composition analysis Each layer of PET/CT image was compared with the corresponding MRI scan by reference to anatomical landmarks such as carotid bifurcation and sternocleidomastoid. Plaques were classified as calcified based on the presence of calcification on CT images. Noncalcified plaques were classified on the basis of arterial wall signal intensity on TOF, T1W, T2W and proton density weighted images into collagen, lipid, or haemorrhage groups.9,10 The TBR values of each group were calculated.

Statistical analyses Data were presented as mean  SD, mean (interquartile range), or n (%). Kruskal–Wallis test was used for analysis

of between-group differences in TBR for the calcified, collagen, lipid and haemorrhage groups, and for the ruptured, thick and thin plaque groups. Spearman’s rank analysis was used to determine correlations between TBR values in the ruptured, thick and thin plaque groups and: (i) mean vessel wall thickness (VWT); (ii) total vessel area (TVA); (iii) lumen area (LA); (iv) vessel wall area (VWA; TVA  LA); (v) normalized wall index (NWI; TWA/TVA). Data were analysed using SPSSÕ version 17.0 (SPSS Inc., Chicago, IL, USA) for WindowsÕ . P-values < 0.05 were considered statistically significant.

Results The study included 31 patients (28 male, three female; mean age 70.90  14.43 years), and 1178 plaque slices. Baseline demographic and clinical data are given in Table 2. Representative PET/CT and MRI scans are shown in Figures 1 and 2. Plaque slices were classified as ruptured (n ¼ 315), thin (n ¼ 584) or thick (n ¼ 279).

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Table 2. Baseline demographic and clinical data for patients with carotid atherosclerosis, included in a study to investigate the use of combined 18 F-fluorodeoxyglucose positron emission tomography/computed tomography and magnetic resonance imaging for early diagnosis of vulnerable plaques (n ¼ 31). Parameter

Value

Age, years BMI, kg/m2 Cerebral ischaemic stroke Diabetesa Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Duration of hypertension,b years LDL, mmol/l HDL, mmol/l TC, mmol/l TG, mmol/l Blood sugar, mmol/l Creatinine, mmol/l Dizzinessc Smoking

70.90  14.43 24.56  2.47 11 (35.5) 13 (41.9) 149.06  23.41 83.81  12.29 10.94  12.89 2.14  0.47 1.07  0.28 3.85  0.63 1.69  0.67 6.10  2.66 72.58  11.44 11 (35.5) 15 (48.4)

Data presented as mean  SD or n (%). BMI, body mass index; LDL, low density lipoprotein; HDL, high density lipoprotein; TC, total cholesterol; TG, triglyceride. a Defined as fasting plasma glucose  7.0 mmol/l. b Defined as systolic blood pressure  140 mmHg and/or diastolic pressure  90 mmHg. c Defined as light-headedness (clouding of consciousness, difficulty in focusing rational thought, or difficulty in concentrating) or vertigo.

There was a significant decrease in TBR values across the groups, such that ruptured > thin > thick (P < 0.001; Table 3). Plaque slices were classified as calcified (n ¼ 333), haemorrhage (n ¼ 205), collagen (n ¼ 293) or lipid (n ¼ 347). TBR values were significantly higher in the haemorrhage group than the calcification and collagen groups (P ¼ 0.002 and 0.004, respectively), and higher in the lipid group than the calcification and collagen groups (P < 0.001 for both comparisons; Table 4). There were no statistically significant differences between the calcification group and

the collagen group, or the haemorrhage group and the lipid group. There were significant positive correlations between TBR and VWT (r ¼ 0.231, P < 0.001), TVA (r ¼ 0.114, P < 0.001), VWA (r ¼ 0.203, P < 0.001) and NWI (r ¼ 0.192, P < 0.001). There was no correlation between TBR and LA (Figure 3).

Discussion It is known that 18F-FDG accumulates in plaque macrophages and positively correlates with macrophage density.11,12 Some inflammatory plaques can be identified by 18 F-FDG PET/CT but not by MRI.4,13 The present study investigated the combined application of MRI and PET/CT imaging in plaque diagnosis. Thinning or rupture of the fibrous cap is caused by an imbalance between matrix degradation and synthesis.14,15 Increased matrix metalloproteinase activity enhances degradation of the extracellular matrix that constitutes the fibrous cap, as well as promoting macrophage infiltration that further encourages metalloproteinase production. This positive feedback mechanism promotes a much more severe inflammatory response in thinned or ruptured fibrous caps than other types.16 Macrophages have been shown to account for 26% of the ruptured fibrous cap plaque in coronary arteries.17 Plaque rupture is not an extensive and diffuse inflammatory response, however; rather it is a local (such as fibrous cap, or even part of the fibrous cap) inflammatory response. This study combined two noninvasive imaging methods to analyse the morphology and inflammatory activity of the plaque fibrous cap, quantitatively. Our results indicated that inflammatory activity was highest in plaques with ruptured fibrous caps, but was also increased in high-risk plaques (i.e., those with a thin fibrous cap).

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Figure 1. Representative 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET; A, B), computed tomography (CT; C), PET/CT (D) and magnetic resonance image (E, F) scans of carotid atherosclerotic plaques. There is an obvious atherosclerotic plaque in the right carotid artery (arrows, images E and F). Despite its size, no 18F-FDG uptake is demonstrated on PET/CT (arrows, images A, B and D). RCA, right carotid artery; LCA, left carotid artery; RCV, right cephalic vein, LCV, left cephalic vein. The colour version of this figure is available at: http://imr.sagepub.com Downloaded from imr.sagepub.com at UCSF LIBRARY & CKM on March 14, 2015

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Figure 2. Representative 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET; A, D), computed tomography (CT; B, E), PET/CT (C, F) and magnetic resonance image (G–L) scans of carotid atherosclerotic plaques. G, H, I: Slices before the carotid artery bifurcation, indicating slight plaque burden (arrows). C, F: A high level of FDG uptake (arrows). J, K, L: Slices after the carotid artery bifurcation, showing an obvious atherosclerotic plaque on the right external carotid artery (arrows). The arrow on panel F highlights an area of high 18F-FDG signal at the same location. T2WI, T2-weighted imaging; post T1, following T1-weighted imaging. The colour version of this figure is available at: http://imr.sagepub.com

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Table 3. 18F-fluorodeoxyglucose positron emission tomography/computed tomography target/ background ratios (TBR) of carotid atherosclerotic plaque slices, stratified according to fibrous cap status Fibrous cap

Plaque, n

TBR

Ruptured Thin Thick

315 584 279

1.366 (1.286–1.457) 1.220 (1.098–1.381) 1.145 (1.080–1.221)

Data presented as mean (interquartile range). Significant decrease in TBR values across the groups: ruptured > thin > thick (P < 0.001; Kruskal–Wallis test).

Table 4. 18F.-fluorodeoxyglucose positron emission tomography/computed tomography target/background ratios (TBR) of carotid atherosclerotic plaque slices, stratified according to plaque composition Plaque type

Plaque, n

TBR

Calcified Haemorrhage Lipid Collagen

333 205 293 347

1.221 (1.113–1.339) 1.338 (1.083–1.473)a,b 1.299 (1.158–1.432)c,d 1.198 (1.094–1.340)

Data presented as mean (interquartile range). a P ¼ 0.002 vs calcified; bP ¼ 0.004 vs collagen; cP ¼ 0.001 vs calcified; dP ¼ 0.001 vs collagen; Kruskal–Wallis test.

In the later stages of plaque development, new blood vessels become the main channels for continuous transport of lipids into the plaques and further mediate the infiltration of inflammatory cells.18 Due to their lack of integrate basilar membranes and other connective tissues, these blood vessels are very brittle and easily broken. This causes plaque haemorrhage, which is a serious complication in advanced atherosclerosis and an extremely dangerous phase of plaque development.19 Inflammatory activity was highest in plaques in the haemorrhage group, in the present study. This may allow early warning of haemorrhagic plaque risk.

In plaques, the lipid core is formed by accumulation of free cholesterol by macrophage-mediated phagocytosis. This lipid may activate macrophage apoptosis.20 The lipid core contains a small number of cells located near the fibrous cap.21,22 In the present study, the inflammatory activity of the lipid group was similar to that of the haemorrhage group, and was significantly higher than that of the calcification and collagen groups. This was likely due to the fact that complex plaque components (such as a thin fibrous cap and ruptured neovascularization) in the lipid core mediated macrophage infiltration, thus showing a greater level of inflammatory infiltration. Calcification occurs during plaque development and can affect plaque stability.23 Failure stress initially concentrates at interfaces between calcified and noncalcified regions within an artery; thus early calcification could promote plaque rupture. As the degree of calcification increases, further calcification decreases the interface area, ultimately reducing the incidence of rupture.24 In accordance with the present findings, the inflammatory activity of calcified plaques has been shown to be lower than that of lipid plaques.25 Since inflammatory infiltration and calcification are independent aetiologies for plaque development, and the correlation between calcification and cardiovascular adverse events is well established,26,27 it is not possible to classify calcified plaques as stable due to their low inflammatory activity alone. Calcification should remain an independent risk factor for vascular events, and can be considered as a noninvasive early warning indicator for atherosclerosis. Fibrous plaque formation is an early stage of atherosclerotic plaque progression. The collagen group in the present study mainly contained these plaque types. The data showed that the inflammatory activity of the collagen group was significantly lower than the haemorrhage and lipid groups, but was similar to that of the calcification group.

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Figure 3. Spearman’s rank correlation analysis of 18F-fluorodeoxyglucose positron emission tomography/ computed tomography target/background ratios (TBR) of carotid atherosclerotic plaque slices, and A: mean vessel wall thickness (VWT); B: total vessel area (TVA); C: vessel wall area (VWA); D: normalized wall index (NWI)

These data confirm the relative stability of such plaques from the perspective of metabolic inflammation. Plaque burden is considered to be one of the factors responsible for plaque vulnerability. VWA and NWI can be used as reliable indicators for atherosclerosis.28 Studies have found that plaque inflammation does not correlate with plaque thickness (VWT) or plaque area (VWA).12 In accordance with the present data, other research has shown weak correlations between plaque inflammation and VWA and TVA.25 In the current study, cases were also found to support these conclusions:

some patients had obvious plaques during the MRI scanning but no significant FDG accumulation on PET/CT (Figure 1), whereas others showed slight plaque burden on MRI but significant FDG accumulation on PET/CT (Figure 2). These data underscore the limitations of determining plaque vulnerability according to plaque burden. The current study had several limitations. First, time and personnel constraints resulted in a small sample size. Further studies, involving substantially larger groups, are required in order to confirm these findings. Secondly, two separate machines performed

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MRI and PET/CT scanning, and images could only be compared by reference to anatomical landmarks. The introduction of a combined PET/MRI imaging system in our centre may alleviate this problem in future. In conclusion, we have combined two noninvasive imaging methods (PET/CT and MRI) to evaluate the atherosclerotic plaque fibrous cap, composition, plaque burden and inflammatory activity. High inflammatory activity was associated with thin or ruptured fibrous caps, as well as lipid or haemorrhage-type plaques.

Declaration of conflicting interest The authors declare that there are no conflicts of interest.

Funding This work was supported by the Research Foundation for Medical Sciences of CPLA (No. 11BJZ19).

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computed tomography and magnetic resonance imaging in early diagnosis of vulnerable carotid atherosclerotic plaques.

To assess the correlations between atherosclerotic plaque characteristics and inflammatory activity by combined use of (18)F-fluorodeoxyglucose ((18)F...
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