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Evaluation of the Time-Dependent Changes and the Vulnerability of Carotid Plaques Using Contrast-Enhanced Carotid Ultrasonography
ARTICLE IN PRESS
Evaluation of the Time-Dependent Changes and the Vulnerability of Carotid Plaques Using Contrast-Enhanced Carotid Ultrasonography Hirofumi Shimada, MT,* Toshiyasu Ogata, MD,†,‡ Koichi Takano, MD,§ Hiroshi Abe, MD,† Toshio Higashi, MD,† Takaaki Yamashita, MT,* Akira Matsunaga, MD,* and Tooru Inoue, MD†
Background: The association of carotid plaque enhancement on contrastenhanced carotid ultrasound (CEUS) and plaque vulnerability evaluated by magnetic resonance imaging (MRI) was to be determined. Materials and methods: The 103 patients underwent CEUS from May 2013 until June 2016. CEUS images of the carotid plaque were obtained offline. Plaque images obtained at 1, 3, 5, and 10 minutes were compared with the reference image, defined as the image obtained at 0 minute. Plaque brightness was assessed using the gray-scale median during contrast enhancement (GSM-C). Plaque vulnerability was evaluated using T1- and T2-weighted MRI and Volume ISotropic TSE Acquisition (VISTA), with a VISTA cutoff value for the plaque muscle ratio (PMR) of 1.5. Time-dependent changes in the GSM-C were evaluated, and those between 0 and 1 minute were compared with the PMR values determined on MRI. Findings: GSM-C decreased significantly over time, from 32.0 at 0 minute to 28.0 at 1 minute, 25.0 at 3 minutes, and 19.0 at 10 minutes. The greater the increase in the changes in the GSM-C from 0 to 1 minute, the more significant the association with a PMR higher than the median on T1 (GSM-C: 0 minute: 29.0, 1 minute: 24.0, P = .015), a PMR less than or equal to the median on T2 (0 min: 35.0, 1 min: 28.0, P = .003), and a PMR more than 1.5 determined on VISTA (GSM-C: 0 minute: 29.0, 1 minute: 24.0, P = .005). Conclusions: Early changes in the GSM-C evaluated with CEUS indicate significant plaque vulnerability on MRI. Key Words: Carotid plaque—CEUS—MRI—vulnerability. © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction From the *Department of Laboratory Medicine, Fukuoka University Hospital; †Department of Neurosurgery; ‡Department of Neurology, Fukuoka University, Fukuoka, Japan; and §Department of Radiology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan. Received July 28, 2017; revision received August 31, 2017; accepted September 6, 2017. Grant support: This study was partially supported by a grant from the Clinical Research Foundation in Japan. Address correspondence to Toshiyasu Ogata, MD, Department of Neurology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. E-mail: toshiogata@ fukuoka-u.ac.jp. 1052-3057/$ - see front matter © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.09.010
Contrast-enhanced carotid ultrasound (CEUS) has been shown to correlate with the pathological findings of carotid plaque.1-7 This imaging modality can also be used to evaluate intraplaque vessels and the vasa vasorum. Both are important determinants of plaque vulnerability, given that the presence of intraplaque vessels correlates significantly with the frequency of cardiovascular risk factors and the development of cardiovascular disease.8 A CEUS study demonstrated that the density of the plaque shoulder is more significantly associated with plaque vulnerability than that of the area of the plaque core.7 In a previous report,9 we showed that CEUS reveals plaque-surface irregularities, intraplaque hemorrhage, and
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■
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fibrous cap disruption. Ulceration of the carotid arteries is also more effectively detected by CEUS than with standard carotid ultrasound. The addition of magnetic resonance imaging (MRI) to the pathological findings can confirm the vulnerability of carotid-artery plaques.10 A high signal intensity on T1-weighted MRI is a definitive finding indicating the vulnerability of carotid plaques.11-13 However, whether plaque findings on MRI are associated with those determined using CEUS has not been investigated. As plaque brightness that is ultrasonographically evaluated is implicated in the vulnerability of carotid plaque, plaque brightness during CEUS study may also give us some information about its vulnerability. The purpose of this study was to determine the association between plaque brightness on MRI and the CEUS results.
Methods Materials From May 2013 to June 2016, 126 patients with carotid stenosis were prospectively investigated. All the patients had significant carotid stenosis whose degree of stenosis measured by the method of the European Carotid Endarterectomy trial was more than 50% in computed tomography (CT) angiography or ultrasonography and their modified Rankin Scale (mRS) was 0-2. The patients were excluded when they did not agree to the CEUS study (N = 20) or were not able to obtain MRI (N = 3). Thus, a total of 103 patients were registered in this study. The characteristics of the study patients and plaque sections are shown in Table 1. The patients had a high frequency of hypertension and hyperlipidemia. The images were acquired offline by capturing them at the start of contrast enhancement (0 minute) and then 1, 3, 5, and 10 minutes thereafter. The acquired CEUS
Table 1. Background and characteristics of the study patients (n = 103)† Characteristics of patients Age* (y) Male, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Diabetes mellitus, n (%) Smoking, n (%) Antithrombotic agents, n (%) Degree of stenosis (ECST, %)* Interval from MRI to ultrasonography (days)† Symptom, n (%)
Figure 1. Carotid-artery findings in a 68-year-old male with right carotid artery stenosis. (A) Longitudinal view of the carotid plaque on contrastenhanced carotid ultrasound 0 minute after contrast enhancement shows increased contrast. (B) At 1 minute, there is a decrease in enhancement.
images were analyzed by 2 experienced observers (H.S. and T.O.) blinded to the patients’ clinical characteristics. The research protocol was approved by the Human Subjects Committee at Fukuoka University Hospital (number 13-9-03). All patients provided written consent to participate in the study.
Ultrasonographic Study After carotid ultrasound with a GE LOGIQ 7 (GE Healthcare, Milwaukee, WI) to screen patients for enrollment, CEUS was performed using a 7-MHz linear transducer, as described in our previous paper.9 Long-axis images, in which the plaque features were clearly visible, were captured from each patient. First, the boundary of the plaque was drawn with reference to the CEUS image obtained at 0 minute, just after the arrival of contrast medium, which allowed the brightness of the plaque within its boundary to be measured using Photoshop CS6 (Adobe Corp., CA, USA) (Fig 1, A). The median plaque brightness was defined as the gray-scale median during contrast (GSM-C). The GSM-C was similarly determined from the images acquired at 1 (Fig 1, B), 3, 5, and 10 minutes after the injection of contrast.
MRI Protocol 72.2 ± 7.5 92 (89.3%) 72 (69.9%) 81 (78.6%) 39 (37.9%) 27 (26.2%) 83 (80.6%) 73.3 ± 13.2% 6 (2-14) 49 (47.6%)
Abbreviations: ECST, European Carotid Stenosis Trial; MRI, magnetic resonance imaging. *Mean ± SD. †Median (interquartile range).
The carotid plaques of all patients were imaged by MRI within 2 weeks of the CEUS. Scans were obtained using a 1.5-T scanner (ACHIEVA; Philips Medical Systems, Best, the Netherlands) and a SENSE head/neck coil (Philips Medical Systems), in which the quadrate head element had 2 neck elements. The carotid plaque was evaluated, as described previously.14,15 Short-axis 2D turbo spin echo (2D-TSE) T1- and T2-weighted images and Volume ISotropic Turbo spin echo Acquisition (VISTA) were applied using the same equipment.
Image Review Plaque signal intensity was measured with reference to the adjacent sternocleidomastoid muscle. The values
ARTICLE IN PRESS EVALUATION OF THE TIME-DEPENDENT CHANGES AND THE VULNERABILITY OF CAROTID PLAQUES
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Figure 2. The magnetic resonance images of the patient in Figure 1. (A) The T1-weighted image shows an elevated signal in the plaque. (B) The T2weighted image shows a slightly decreased signal. (C) Volume ISotropic turbo spin echo Acquisition analysis shows an increased carotid plaque signal on the T1-weighted image.
were calculated as the signal ratio of the plaque to the sternocleidomastoid muscle, defined as the plaque/ muscle ratio (PMR). The area with the severest degree of stenosis was evaluated by means of 2D-TSE T1- (Fig 2, A) and T2-weighted images (Fig 2, B) and VISTA (Fig 2, C) and the results used to calculate the PMR. In plaques characterized by heterogeneous intensity, the highestintensity component was used.
Statistical Analyses The GSM-C values of the carotid plaques were determined at 0, 1, 3, 5, and 10 minutes. The patients were then divided into 2 groups based on their median PMR values according to the 2D-TSE T1- and T2-weighted images. They were also classified based on a cutoff PMR value of 1.5, established using VISTA. We previously reported that a PMR higher than 1.5 strongly correlated with plaque vulnerability.14 The GSM-C values at 0 and 1 minute were compared with both the PMRs of the T1and T2-weighted images and the cutoff value of 1.5 determined by VISTA. Statistical analyses were performed using the Wilcoxon signed-rank test. A P value < .05 was considered to indicate statistical significance. All data were analyzed using SPSS version 22.0 (IBM, NY, USA).
Results The GSM-C values decreased gradually with time (0 minute: 32.0, 1 minute: 28.0, 3 minutes: 25.0, 5 minutes: 22.0, 10 minutes: 19.0, P = .069 (0 versus 1 minute) and P < .001 (0 versus 3, 5, and 10 minutes). There was no implication between the change of GSM-C values from 0 to 1 minute and the presence of symptoms. No association was also found of the change of the GSM values with degree of stenosis. The medians of the PMR on the T1- and T2-weighted images were 1.69 and 2.72, respectively, while that on the VISTA was 1.82. The patients were classified according to their PMR values and the values determined on the T1- (Fig 3, A) and T2- (Fig 3,
B) weighted images. Those with a higher PMR than the median calculated from the T1-weighted images had a significantly higher GSM-C (GSM-C: 0 minute: 29.0, 1 minute: 24.0, P = .015), whereas in those with the lower PMR on T2-weighted images, the GSM-C values also decreased significantly (GSM-C: 0 minute: 35.0, 1 minute: 28.0, P = .003). According to the PMR cutoff of 1.5 determined with VISTA, 67 patients had a PMR higher than 1.5 and 36 patients had a PMR of 1.5 or lower. The GSM-C of patients with a PMR higher than 1.5 on VISTA decreased significantly from 0 to 1 minute (GSM-C: 0 minute: 29.0, 1 minute: 24.0, P = .005), while that of patients with a PMR of 1.5 or lower was unchanged (GSM-C: 0 minute: 34.5, 1 minute: 33.0, P = .53) (Fig 3, C).
Discussion The main advantages of ultrasonography are its wide availability and ability to be performed at the bedside. Furthermore, unlike the contrast medium used in CT or angiography, the metabolic products of the contrast medium used in CEUS are exhaled from the lungs, such that the contrast medium is relatively safe. In this study, we evaluated whether CEUS can be used to assess plaque vulnerability with the same diagnostic accuracy as MRI. We previously reported the utility of VISTA in discovering vulnerable carotid-artery plaques.14 Based on a metaanalysis showing that the measurement of the degree of neovascularization was a promising tool in plaque evaluation,16 we hypothesized that the GSM-C value would indicate the extent of neovascularization and thus serve as a predictor of vulnerability. Our results showed that a change in the GSM-C was a significant indicator of plaque vulnerability. An increase in the GSM-C is thought to reflect plaque disruption, specifically that of the fibrous cap. However, this remains to be confirmed in further studies. The GSM-C values were compared with the median PMR values determined on the T1- and T2-weighted mag-
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Figure 3. The change in the gray-scale median during contrast enhancement between 0 and 1 minute after contrast injection. The patients were grouped according to the median of the plaque muscle ratio obtained on the T1-weighted (A) and T2weighted (B) images as well as according to the VISTA cutoff of 1.5 (C). Abbreviation: PMR, plaque/muscle ratio.
ARTICLE IN PRESS EVALUATION OF THE TIME-DEPENDENT CHANGES AND THE VULNERABILITY OF CAROTID PLAQUES
netic resonance images. The PMRs from the T1-weighted images and with respect to the VISTA cutoff of 1.5 were positively associated with the GSM-C value, probably because of the good association between the PMRs of the T1-weighted images and determined using VISTA. However, why the PMR of the T2-weighted image correlated inversely with the GSM-C value is unclear. A previous T2 study showed a significant association between intraplaque hemorrhage and a low T2-PMR,17 which may account for the correlation between the latter and a high GSM-C. Intraplaque microvessels can be recognized on CT studies as bright spots or small strings,18 which could explain their low PMR on T2-weighted MRI. According to a review article, intraplaque hemorrhage shows various characteristics on a T2 study,19 such that investigations of carotid plaque vulnerability on T2-weighted imaging may yield ambiguous results. There were several limitations to this study. First, the number of participants was small. Second, the pathological findings of the carotid plaque were not assessed in detail, as this study investigated the relationship between CEUS and MRI findings. Third, the outline of the carotid plaque used in the measurements may have inadvertently included the carotid outer wall or the inner cavity of the carotid artery, resulting in artifacts. Furthermore, mRS was one of the criteria of exclusion in this study, and this could be a selection bias.
Conclusions Early changes in the GSM-C evaluated with CEUS were significantly associated with a high PMR, obtained on the T1-weighted images and using VISTA, and with a low PMR, measured from the T2-weighted images. The degree of neovascularization contributes to the GSM-C and may therefore serve as an indicator of carotid-artery plaque vulnerability. Acknowledgments: We thank Ms. Asuka Ikezaki for her technical assistance.
References 1. Coli S, Magnoni M, Sangiorgi G, et al. Contrast-enhanced ultrasound imaging of intraplaque neovascularization in carotid arteries: correlation with histology and plaque echogenicity. J Am Coll Cardiol 2008;52:223-230. 2. Faggioli GL, Pini R, Mauro R, et al. Identification of carotid “vulnerable plaque” by contrast-enhanced ultrasonography: correlation with plaque histology, symptoms and cerebral computed tomography. Eur J Vasc Endovasc Surg 2011;41:238-248. 3. Shalhoub J, Monaco C, Owen DR, et al. Late-phase contrast-enhanced ultrasound reflects biological features of instability in human carotid atherosclerosis. Stroke 2011;42:3634-3636.
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4. Hoogi A, Adam D, Hoffman A, et al. Carotid plaque vulnerability: quantification of neovascularization on contrast-enhanced ultrasound with histopathologic correlation. AJR Am J Roentgenol 2011;196:431-436. 5. Varetto G, Gibello L, Bergamasco L, et al. Contrast enhanced ultrasound in atherosclerotic carotid artery disease. Int Angiol 2012;31:565-571. 6. Muller HF, Viaccoz A, Kuzmanovic I, et al. Contrastenhanced ultrasound imaging of carotid plaque neovascularization: accuracy of visual analysis. Ultrasound Med Biol 2014;40:18-24. 7. Saito K, Nagatsuka K, Ishibashi-Ueda H, et al. Contrastenhanced ultrasound for the evaluation of neovascularization in atherosclerotic carotid artery plaques. Stroke 2014;45:3073-3075. 8. Staub D, Patel MB, Tibrewala A, et al. Vasa vasorum and plaque neovascularization on contrast-enhanced carotid ultrasound imaging correlates with cardiovascular disease and past cardiovascular events. Stroke 2010;41:41-47. 9. Hamada O, Sakata N, Ogata T, et al. Contrast-enhanced ultrasonography for detecting histological carotid plaque rupture: quantitative analysis of ulcer. Int J Stroke 2016;11:791-798. 10. Yuan C, Mitsumori LM, Ferguson MS, et al. In vivo accuracy of multispectral magnetic resonance imaging for identifying lipid-rich necrotic cores and intraplaque hemorrhage in advanced human carotid plaques. Circulation 2001;104:2051-2056. 11. Moody AR, Murphy RE, Morgan PS, et al. Characterization of complicated carotid plaque with magnetic resonance direct thrombus imaging in patients with cerebral ischemia. Circulation 2003;107:3047-3052. 12. Chu B, Kampschulte A, Ferguson MS, et al. Hemorrhage in the atherosclerotic carotid plaque: a high-resolution MRI study. Stroke 2004;35:1079-1084. 13. Hosseini AA, Kandiyil N, Macsweeney ST, et al. Carotid plaque hemorrhage on magnetic resonance imaging strongly predicts recurrent ischemia and stroke. Ann Neurol 2013;73:774-784. 14. Takemoto K, Ueba T, Takano K, et al. Quantitative evaluation using the plaque/muscle ratio index panels predicts plaque type and risk of embolism in patients undergoing carotid artery stenting. Clin Neurol Neurosurg 2013;115:1298-1303. 15. Takano K, Yamashita S, Takemoto K, et al. Characterization of carotid atherosclerosis with black-blood carotid plaque imaging using variable flip-angle 3D turbo spin-echo: comparison with 2D turbo spin-echo sequences. Eur J Radiol 2012;81:e304-e309. 16. Huang R, Abdelmoneim SS, Ball CA, et al. Detection of carotid atherosclerotic plaque neovascularization using contrast enhanced ultrasound: a systematic review and meta-analysis of diagnostic accuracy studies. J Am Soc Echocardiogr 2016;29:491-502. 17. Narumi S, Sasaki M, Ohba H, et al. Prediction of carotid plaque characteristics using non-gated MR imaging: correlation with endarterectomy specimens. AJNR Am J Neuroradiol 2013;34:191-197. 18. Tateishi Y, Tsujino A, Hamabe J, et al. “Snake fang” sign without carotid stenosis on duplex ultrasonography indicates high risk of artery-to-artery embolic stroke. J Neuroimaging 2014;24:407-410. 19. Singh N, Moody AR, Roifman I, et al. Advanced MRI for carotid plaque imaging. Int J Cardiovasc Imaging 2016;32:83-89.
Evaluation of the Time-Dependent Changes and the Vulnerability of Carotid Plaques Using Contrast-Enhanced Carotid Ultrasonography Hirofumi Shimada, MT,* Toshiyasu Ogata, MD,†,‡ Koichi Takano, MD,§ Hiroshi Abe, MD,† Toshio Higashi, MD,† Takaaki Yamashita, MT,* Akira Matsunaga, MD,* and Tooru Inoue, MD†
Background: The association of carotid plaque enhancement on contrastenhanced carotid ultrasound (CEUS) and plaque vulnerability evaluated by magnetic resonance imaging (MRI) was to be determined. Materials and methods: The 103 patients underwent CEUS from May 2013 until June 2016. CEUS images of the carotid plaque were obtained offline. Plaque images obtained at 1, 3, 5, and 10 minutes were compared with the reference image, defined as the image obtained at 0 minute. Plaque brightness was assessed using the gray-scale median during contrast enhancement (GSM-C). Plaque vulnerability was evaluated using T1- and T2-weighted MRI and Volume ISotropic TSE Acquisition (VISTA), with a VISTA cutoff value for the plaque muscle ratio (PMR) of 1.5. Time-dependent changes in the GSM-C were evaluated, and those between 0 and 1 minute were compared with the PMR values determined on MRI. Findings: GSM-C decreased significantly over time, from 32.0 at 0 minute to 28.0 at 1 minute, 25.0 at 3 minutes, and 19.0 at 10 minutes. The greater the increase in the changes in the GSM-C from 0 to 1 minute, the more significant the association with a PMR higher than the median on T1 (GSM-C: 0 minute: 29.0, 1 minute: 24.0, P = .015), a PMR less than or equal to the median on T2 (0 min: 35.0, 1 min: 28.0, P = .003), and a PMR more than 1.5 determined on VISTA (GSM-C: 0 minute: 29.0, 1 minute: 24.0, P = .005). Conclusions: Early changes in the GSM-C evaluated with CEUS indicate significant plaque vulnerability on MRI. Key Words: Carotid plaque—CEUS—MRI—vulnerability. © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction From the *Department of Laboratory Medicine, Fukuoka University Hospital; †Department of Neurosurgery; ‡Department of Neurology, Fukuoka University, Fukuoka, Japan; and §Department of Radiology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan. Received July 28, 2017; revision received August 31, 2017; accepted September 6, 2017. Grant support: This study was partially supported by a grant from the Clinical Research Foundation in Japan. Address correspondence to Toshiyasu Ogata, MD, Department of Neurology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. E-mail: toshiogata@ fukuoka-u.ac.jp. 1052-3057/$ - see front matter © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.09.010
Contrast-enhanced carotid ultrasound (CEUS) has been shown to correlate with the pathological findings of carotid plaque.1-7 This imaging modality can also be used to evaluate intraplaque vessels and the vasa vasorum. Both are important determinants of plaque vulnerability, given that the presence of intraplaque vessels correlates significantly with the frequency of cardiovascular risk factors and the development of cardiovascular disease.8 A CEUS study demonstrated that the density of the plaque shoulder is more significantly associated with plaque vulnerability than that of the area of the plaque core.7 In a previous report,9 we showed that CEUS reveals plaque-surface irregularities, intraplaque hemorrhage, and
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■
1
ARTICLE IN PRESS H. SHIMADA ET AL.
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fibrous cap disruption. Ulceration of the carotid arteries is also more effectively detected by CEUS than with standard carotid ultrasound. The addition of magnetic resonance imaging (MRI) to the pathological findings can confirm the vulnerability of carotid-artery plaques.10 A high signal intensity on T1-weighted MRI is a definitive finding indicating the vulnerability of carotid plaques.11-13 However, whether plaque findings on MRI are associated with those determined using CEUS has not been investigated. As plaque brightness that is ultrasonographically evaluated is implicated in the vulnerability of carotid plaque, plaque brightness during CEUS study may also give us some information about its vulnerability. The purpose of this study was to determine the association between plaque brightness on MRI and the CEUS results.
Methods Materials From May 2013 to June 2016, 126 patients with carotid stenosis were prospectively investigated. All the patients had significant carotid stenosis whose degree of stenosis measured by the method of the European Carotid Endarterectomy trial was more than 50% in computed tomography (CT) angiography or ultrasonography and their modified Rankin Scale (mRS) was 0-2. The patients were excluded when they did not agree to the CEUS study (N = 20) or were not able to obtain MRI (N = 3). Thus, a total of 103 patients were registered in this study. The characteristics of the study patients and plaque sections are shown in Table 1. The patients had a high frequency of hypertension and hyperlipidemia. The images were acquired offline by capturing them at the start of contrast enhancement (0 minute) and then 1, 3, 5, and 10 minutes thereafter. The acquired CEUS
Table 1. Background and characteristics of the study patients (n = 103)† Characteristics of patients Age* (y) Male, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Diabetes mellitus, n (%) Smoking, n (%) Antithrombotic agents, n (%) Degree of stenosis (ECST, %)* Interval from MRI to ultrasonography (days)† Symptom, n (%)
Figure 1. Carotid-artery findings in a 68-year-old male with right carotid artery stenosis. (A) Longitudinal view of the carotid plaque on contrastenhanced carotid ultrasound 0 minute after contrast enhancement shows increased contrast. (B) At 1 minute, there is a decrease in enhancement.
images were analyzed by 2 experienced observers (H.S. and T.O.) blinded to the patients’ clinical characteristics. The research protocol was approved by the Human Subjects Committee at Fukuoka University Hospital (number 13-9-03). All patients provided written consent to participate in the study.
Ultrasonographic Study After carotid ultrasound with a GE LOGIQ 7 (GE Healthcare, Milwaukee, WI) to screen patients for enrollment, CEUS was performed using a 7-MHz linear transducer, as described in our previous paper.9 Long-axis images, in which the plaque features were clearly visible, were captured from each patient. First, the boundary of the plaque was drawn with reference to the CEUS image obtained at 0 minute, just after the arrival of contrast medium, which allowed the brightness of the plaque within its boundary to be measured using Photoshop CS6 (Adobe Corp., CA, USA) (Fig 1, A). The median plaque brightness was defined as the gray-scale median during contrast (GSM-C). The GSM-C was similarly determined from the images acquired at 1 (Fig 1, B), 3, 5, and 10 minutes after the injection of contrast.
MRI Protocol 72.2 ± 7.5 92 (89.3%) 72 (69.9%) 81 (78.6%) 39 (37.9%) 27 (26.2%) 83 (80.6%) 73.3 ± 13.2% 6 (2-14) 49 (47.6%)
Abbreviations: ECST, European Carotid Stenosis Trial; MRI, magnetic resonance imaging. *Mean ± SD. †Median (interquartile range).
The carotid plaques of all patients were imaged by MRI within 2 weeks of the CEUS. Scans were obtained using a 1.5-T scanner (ACHIEVA; Philips Medical Systems, Best, the Netherlands) and a SENSE head/neck coil (Philips Medical Systems), in which the quadrate head element had 2 neck elements. The carotid plaque was evaluated, as described previously.14,15 Short-axis 2D turbo spin echo (2D-TSE) T1- and T2-weighted images and Volume ISotropic Turbo spin echo Acquisition (VISTA) were applied using the same equipment.
Image Review Plaque signal intensity was measured with reference to the adjacent sternocleidomastoid muscle. The values
ARTICLE IN PRESS EVALUATION OF THE TIME-DEPENDENT CHANGES AND THE VULNERABILITY OF CAROTID PLAQUES
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Figure 2. The magnetic resonance images of the patient in Figure 1. (A) The T1-weighted image shows an elevated signal in the plaque. (B) The T2weighted image shows a slightly decreased signal. (C) Volume ISotropic turbo spin echo Acquisition analysis shows an increased carotid plaque signal on the T1-weighted image.
were calculated as the signal ratio of the plaque to the sternocleidomastoid muscle, defined as the plaque/ muscle ratio (PMR). The area with the severest degree of stenosis was evaluated by means of 2D-TSE T1- (Fig 2, A) and T2-weighted images (Fig 2, B) and VISTA (Fig 2, C) and the results used to calculate the PMR. In plaques characterized by heterogeneous intensity, the highestintensity component was used.
Statistical Analyses The GSM-C values of the carotid plaques were determined at 0, 1, 3, 5, and 10 minutes. The patients were then divided into 2 groups based on their median PMR values according to the 2D-TSE T1- and T2-weighted images. They were also classified based on a cutoff PMR value of 1.5, established using VISTA. We previously reported that a PMR higher than 1.5 strongly correlated with plaque vulnerability.14 The GSM-C values at 0 and 1 minute were compared with both the PMRs of the T1and T2-weighted images and the cutoff value of 1.5 determined by VISTA. Statistical analyses were performed using the Wilcoxon signed-rank test. A P value < .05 was considered to indicate statistical significance. All data were analyzed using SPSS version 22.0 (IBM, NY, USA).
Results The GSM-C values decreased gradually with time (0 minute: 32.0, 1 minute: 28.0, 3 minutes: 25.0, 5 minutes: 22.0, 10 minutes: 19.0, P = .069 (0 versus 1 minute) and P < .001 (0 versus 3, 5, and 10 minutes). There was no implication between the change of GSM-C values from 0 to 1 minute and the presence of symptoms. No association was also found of the change of the GSM values with degree of stenosis. The medians of the PMR on the T1- and T2-weighted images were 1.69 and 2.72, respectively, while that on the VISTA was 1.82. The patients were classified according to their PMR values and the values determined on the T1- (Fig 3, A) and T2- (Fig 3,
B) weighted images. Those with a higher PMR than the median calculated from the T1-weighted images had a significantly higher GSM-C (GSM-C: 0 minute: 29.0, 1 minute: 24.0, P = .015), whereas in those with the lower PMR on T2-weighted images, the GSM-C values also decreased significantly (GSM-C: 0 minute: 35.0, 1 minute: 28.0, P = .003). According to the PMR cutoff of 1.5 determined with VISTA, 67 patients had a PMR higher than 1.5 and 36 patients had a PMR of 1.5 or lower. The GSM-C of patients with a PMR higher than 1.5 on VISTA decreased significantly from 0 to 1 minute (GSM-C: 0 minute: 29.0, 1 minute: 24.0, P = .005), while that of patients with a PMR of 1.5 or lower was unchanged (GSM-C: 0 minute: 34.5, 1 minute: 33.0, P = .53) (Fig 3, C).
Discussion The main advantages of ultrasonography are its wide availability and ability to be performed at the bedside. Furthermore, unlike the contrast medium used in CT or angiography, the metabolic products of the contrast medium used in CEUS are exhaled from the lungs, such that the contrast medium is relatively safe. In this study, we evaluated whether CEUS can be used to assess plaque vulnerability with the same diagnostic accuracy as MRI. We previously reported the utility of VISTA in discovering vulnerable carotid-artery plaques.14 Based on a metaanalysis showing that the measurement of the degree of neovascularization was a promising tool in plaque evaluation,16 we hypothesized that the GSM-C value would indicate the extent of neovascularization and thus serve as a predictor of vulnerability. Our results showed that a change in the GSM-C was a significant indicator of plaque vulnerability. An increase in the GSM-C is thought to reflect plaque disruption, specifically that of the fibrous cap. However, this remains to be confirmed in further studies. The GSM-C values were compared with the median PMR values determined on the T1- and T2-weighted mag-
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Figure 3. The change in the gray-scale median during contrast enhancement between 0 and 1 minute after contrast injection. The patients were grouped according to the median of the plaque muscle ratio obtained on the T1-weighted (A) and T2weighted (B) images as well as according to the VISTA cutoff of 1.5 (C). Abbreviation: PMR, plaque/muscle ratio.
ARTICLE IN PRESS EVALUATION OF THE TIME-DEPENDENT CHANGES AND THE VULNERABILITY OF CAROTID PLAQUES
netic resonance images. The PMRs from the T1-weighted images and with respect to the VISTA cutoff of 1.5 were positively associated with the GSM-C value, probably because of the good association between the PMRs of the T1-weighted images and determined using VISTA. However, why the PMR of the T2-weighted image correlated inversely with the GSM-C value is unclear. A previous T2 study showed a significant association between intraplaque hemorrhage and a low T2-PMR,17 which may account for the correlation between the latter and a high GSM-C. Intraplaque microvessels can be recognized on CT studies as bright spots or small strings,18 which could explain their low PMR on T2-weighted MRI. According to a review article, intraplaque hemorrhage shows various characteristics on a T2 study,19 such that investigations of carotid plaque vulnerability on T2-weighted imaging may yield ambiguous results. There were several limitations to this study. First, the number of participants was small. Second, the pathological findings of the carotid plaque were not assessed in detail, as this study investigated the relationship between CEUS and MRI findings. Third, the outline of the carotid plaque used in the measurements may have inadvertently included the carotid outer wall or the inner cavity of the carotid artery, resulting in artifacts. Furthermore, mRS was one of the criteria of exclusion in this study, and this could be a selection bias.
Conclusions Early changes in the GSM-C evaluated with CEUS were significantly associated with a high PMR, obtained on the T1-weighted images and using VISTA, and with a low PMR, measured from the T2-weighted images. The degree of neovascularization contributes to the GSM-C and may therefore serve as an indicator of carotid-artery plaque vulnerability. Acknowledgments: We thank Ms. Asuka Ikezaki for her technical assistance.
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