Carotid Plaque Vulnerability: Quantification of Neovascularization on Contrast-Enhanced Ultrasound With Histopathologic Correlation

ObjectivesThe aim of this study was to evaluate the performance of deep learning-based detection and classification of carotid plaque (DL-DCCP) in carotid plaque contrast-enhanced ultrasound (CEUS).Methods and analysisA prospective multicentre study was conducted to assess vulnerability in patients with carotid plaque. Data from 547 potentially eligible patients were prospectively enrolled from 10 hospitals, and 205 patients with CEUS video were finally enrolled for analysis. The area under the receiver operating characteristic curve (AUC) was used to evaluate the effectiveness of DL-DCCP and two experienced radiologists who manually examined the CEUS video (RA-CEUS) in diagnosing and classifying carotid plaque vulnerability. To evaluate the influence of dynamic video input on the performance of the algorithm, a state-of-the-art deep convolutional neural network (CNN) model for static images (Xception) was compared with DL-DCCP for both training and holdout validation cohorts.ResultsThe AUCs of DL-DCCP were significantly better than those of the experienced radiologists for both the training and holdout validation cohorts (training, DL-DCCP vs RA-CEUS, AUC: 0.85 vs 0.69, p<0.01; holdout validation, DL-DCCP vs RA-CEUS, AUC: 0.87 vs 0.66, p<0.01), that is, also better than the best deep CNN model Xception we had performed, for both the training and holdout validation cohorts (training, DL-DCCP vs Xception, AUC:0.85 vs 0.82, p<0.01; holdout validation, DL-DCCP vs Xception, AUC: 0.87 vs 0.77, p<0.01).ConclusionDL-DCCP shows better overall performance in assessing the vulnerability of carotid atherosclerotic plaques than RA-CEUS. Moreover, with a more powerful network structure and better utilisation of video information, DL-DCCP provided greater diagnostic accuracy than a state-of-the-art static CNN model.Trial registration numberChiCTR1900021846,

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Abstract 11733: Assessment of Carotid Plaque Neovascularization Using Quantitative Analysis of Contrast-Enhanced Ultrasound Imaging is Useful for Risk Stratification in Patients With Coronary Artery Disease

Circulation ◽

10.1161/circ.130.suppl_2.11733 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Jun Nakamura ◽

Takamitsu Nakamura ◽

Juntaro Deyama ◽

Daisuke Fujioka ◽

Ken-ichi Kawabata ◽

...

Keyword(s):

Risk Factors ◽

Heart Failure ◽

Quantitative Analysis ◽

Carotid Artery ◽

Carotid Plaque ◽

Contrast Enhanced Ultrasound ◽

Baseline Model ◽

Contrast Enhanced ◽

Traditional Risk Factors ◽

Artery Disease

Introduction: Extensive neovascularization in atherosclerotic plaque has been shown to be associated with plaque progression and instability, leading to atherosclerotic cardiovascular events. Contrast-enhanced ultrasound (CEUS) of the carotid artery is a potential technique for imaging plaque neovascularization. Hypothesis: Assessment of intra-plaque neovascularization of the carotid artery using quantitative analysis of CEUS provides prognostic information in patients with coronary artery disease (CAD). Methods: This study included 206 patients with stable CAD and with carotid intima-media thickness (IMT) > 1.1 mm. They underwent a CEUS examination of the carotid artery and were followed-up prospectively for < 38 months or until a cardiac event (cardiac death, non-fatal myocardial infarction [MI], unstable angina pectoris [uAP] requiring unplanned coronary revascularization, or heart failure requiring hospitalization). The degree of contrast signals measured within the carotid plaque after the intravenous injection of contrast material was quantified by calculating the increase in mean gray scale level within the region of interest of the carotid plaque, expressed as plaque enhanced intensity. Results: During the follow-up period (3 - 38 months, mean 22.8 ± 11.8 months), 31 events occurred (2 cardiac deaths, 7 non-fatal MIs, 16 uAP, and 6 heart failure). Multivariate Cox proportional hazards analysis showed that plaque enhanced intensity was a significant predictor of cardiac events independent of traditional risk factors (HR, 1.52; 95% CI, 1.20 - 1.94; p = 0.001). The addition of plaque enhanced intensity had a significant incremental effect on the area under the ROC curve (AUC) generated using baseline model of traditional risk factors (AUC: baseline model 0.69 vs. baseline model + plaque enhanced intensity 0.78, p = 0.03). The addition of the plaque enhanced intensity to the baseline risk factors resulted in net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.58, p = 0.003; and IDI 0.078, p = 0.03). Conclusions: The assessment of carotid plaque neovascularization using quantitative analysis of CEUS may be useful for risk stratification in patients with CAD.

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Contrast-enhanced ultrasound imaging of atherosclerotic carotid plaque neovascularization: a new surrogate marker of atherosclerosis?

Vascular Medicine ◽

10.1177/1358863x07083363 ◽

2007 ◽

Vol 12 (4) ◽

pp. 291-297 ◽

Cited By ~ 146

Author(s):

Falak Shah ◽

Prakash Balan ◽

Matthew Weinberg ◽

Vijaya Reddy ◽

Rachel Neems ◽

...

Keyword(s):

Ultrasound Imaging ◽

Carotid Plaque ◽

Surrogate Marker ◽

Contrast Enhanced Ultrasound ◽

Contrast Enhanced

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Molecular Imaging of Carotid Plaque Vulnerability

Cerebrovascular Diseases ◽

10.1159/000369123 ◽

2014 ◽

Vol 39 (1) ◽

pp. 5-12 ◽

Cited By ~ 25

Author(s):

Angelika Alonso ◽

Dimitrios Artemis ◽

Michael G. Hennerici

Keyword(s):

Molecular Imaging ◽

Carotid Endarterectomy ◽

Contrast Enhancement ◽

Phase Contrast ◽

Late Phase ◽

High Grade ◽

Contrast Enhanced Ultrasound ◽

Plaque Vulnerability ◽

Carotid Plaques ◽

Contrast Enhanced

Background: Carotid endarterectomy (CEA) has been shown to be beneficial in patients with high-grade symptomatic carotid artery stenosis. Patients with high-grade asymptomatic stenosis may only exceptionally benefit from CEA during periods of increased plaque vulnerability. Imaging modalities to characterize unstable, vulnerable plaques are strongly needed for better risk stratification in these patients. Summary: Contrast-enhanced ultrasound (CEUS) is a novel and noninvasive technique capable to identify several surrogate markers of vulnerable carotid plaques. The use of specific ultrasound microbubbles allows a reliable detection of microulcerations due to an optimized visualization of the plaque-lumen border. As microbubbles are strictly intravascular tracers, the detection of individual microbubbles within the plaque corresponds to intraplaque neovessels. The accuracy of CEUS in the visualization of newly formed microvessels has been confirmed in histological studies on carotid endarterectomy specimens. Together with the formation of adventitial vasa vasorum, intraplaque neovascularization is a strong predictor for symptomatic disease. The phenomenon of late phase contrast enhancement is based on the adherence of microbubble-containing monocytes on inflamed endothelium. Recent studies suggest that late phase contrast enhancement may reflect endothelial inflammation or activation within carotid plaques. The development of conjugated microbubbles that bind to specific ligands such as thrombotic material or neovessels has led to the term ‘molecular imaging'. CEUS with microbubbles targeted to P-selectin and VCAM-1, key molecules in leukocyte trafficking, was used to detect an inflammatory plaque phenotype, whereas microbubbles coupled to the VEGF-receptor may allow for a detection of neovascularization. Even though imaging with targeted microbubbles is yet in an experimental stage, this technique can visualize active plaque reorganization with increased vulnerability leading to generation of arterio-arterial embolism. Key Messages: The use of contrast-enhanced ultrasound can be recommended to assess atherosclerotic carotid lesions at risk for rupture. Prospective clinical studies are needed to validate the use of CEUS in patients with high risks of recurrent large artery strokes. In particular, this applies to the detection of intraplaque neovascularization, a well-established marker in preclinical and observational studies, while the clinical significance of late phase contrast enhancement still needs to be determined.

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Assessment of Carotid Plaque Stability Using Contrast-Enhanced Ultrasound and Its Correlation With the Expression of CD147 and MMP-9 in the Plaque

Frontiers in Computational Neuroscience ◽

10.3389/fncom.2021.778946 ◽

2021 ◽

Vol 15 ◽

Author(s):

Shanshan Huang ◽

Xinyin Wu ◽

Linlin Zhang ◽

Jianming Wu ◽

Yi He ◽

...

Keyword(s):

Surface Morphology ◽

Positive Predictive Value ◽

Predictive Value ◽

Vulnerable Plaque ◽

Contrast Enhanced Ultrasound ◽

Plaque Vulnerability ◽

Vulnerable Plaques ◽

Contrast Enhanced ◽

2D Ultrasound ◽

Grade Ii

This study aims to investigate the correlation between the enhancement degree of contrast-enhanced ultrasound (CEUS) and the expression of CD147 and MMP-9 in carotid atherosclerotic plaques in patients with carotid endarterectomy and evaluate the diagnostic efficacy of CEUS using pathological results as the gold standard. Thirty-eight patients who underwent carotid endarterectomy (CEA) for carotid stenosis in the Department of Neurovascular Surgery of the Second People’s Hospital of Shenzhen from July 2019 to June 2020 were selected. Preoperatively, two-dimensional (2D) ultrasound scan was performed on all patients to assess the characteristics of the plaque and degree of stenosis, and CEUS was used to evaluate the surface morphology of the plaque and the distribution of neovascularization. Postoperatively, pathological sections and immunohistochemical analysis of CD147 and MMP-9 levels in the plaque were performed on the stripped plaque tissue, and the results were analyzed against the CEUS grading and pathological results. Among the 38 patients, pathological results showed that 10 and 28 were in the stable and vulnerable plaque groups, respectively. There were more smokers in the vulnerable plaque group than in the stable plaque group, with higher intraplaques CD147 and MMP-9. The difference in ultrasound plaque surface morphology grading and CEUS grading between the two groups was statistically significant. There was no significant difference in age, sex, incidence of complications such as hypertension, diabetes, and coronary heart disease between the two groups. CD147 was higher in the CEUS grade IV group than in the grades I (P = 0.040) and II (P = 0.010) groups. MMP-9 was higher in the CEUS grade IV group than in the grade II group (P = 0.017); MMP-9 was higher in the grade III group than in the grade II group (P = 0.015). Intraplaque contrast enhancement intensity was positively correlated with CD147 (r = 0.462, P = 0.003) and MMP-9 (r = 0.382, P = 0.018) levels. There was moderate consistency between the assessment of plaque vulnerability by 2D-ultrasound and by histopathological hematoxylin-eosin (HE) (kappa = 0.457, P > 0.05). 2D diagnosis of vulnerable plaque had a sensitivity of 85.7%, a specificity of 60.0%, a positive predictive value of 85.7%, a negative predictive value of 60.0%, and an accuracy of 78.0%. There was a strong consistency between the assessment of plaque vulnerability by CEUS and histopathological HE (kappa = 0.671, P < 0.01). CEUS had a sensitivity of 89.2%, a specificity of 80.0%, a positive predictive value of 92.6%, a negative predictive value of 72.7%, and an accuracy of 86.8% for the diagnosis of vulnerable plaques; CEUS is a reliable, non-invasive test that can show the distribution of neovascularization within vulnerable plaques, evaluate the vulnerability and risk of intraplaque hemorrhage, with a high consistency with pathological findings. The degree of intraplaque enhancement and the levels of CD147 and MMP-9 in the tissue were positively correlated.

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Evaluation of Carotid Plaque Rupture and Neovascularization by Contrast-Enhanced Ultrasound Imaging: an Exploratory Study Based on Histopathology

Translational Stroke Research ◽

10.1007/s12975-020-00825-w ◽

2020 ◽

Author(s):

Qi Lyu ◽

Xiaojie Tian ◽

Yafang Ding ◽

Yanhong Yan ◽

Yabo Huang ◽

...

Keyword(s):

Ultrasound Imaging ◽

Exploratory Study ◽

Carotid Plaque ◽

Plaque Rupture ◽

Contrast Enhanced Ultrasound ◽

Contrast Enhanced

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A Study on Distribution Features of Neovascularization in Atherosclerotic Carotid Artery Plaques: Comparing Contrast-enhanced Ultrasound with Histopathology

Ultrasonic Imaging ◽

10.1177/0161734618824941 ◽

2019 ◽

Vol 41 (2) ◽

pp. 115-125

Author(s):

Bin Ning ◽

Dong Zhang ◽

Wen He ◽

Li Shu Wang ◽

Zhan Qiang Jin

Keyword(s):

Statistical Difference ◽

Ultrasound Images ◽

Contrast Enhanced Ultrasound ◽

Plaque Vulnerability ◽

Asymptomatic Group ◽

Significant Statistical Difference ◽

Fibrous Cap ◽

Contrast Enhanced ◽

Distribution Features ◽

Histopathological Images

Intraplaque neovascularization (IPNV) is a characteristic feature of the vulnerable plaques. In this study of neovessels of carotid plaques, we assessed intraplaque echogenicity and plaque surface morphology, and performed contrast-enhanced ultrasound (CEUS) to observe the location and grading of neovessels to identify the vulnerability of plaques. The results showed that plaque with a ruptured fibrous cap on the histopathological images presented as a sunken or fissured surface on corresponding ultrasound images. Both in the symptomatic and asymptomatic groups, plaque echogenicity did not correlate with neovessels grading. The neovessels that appeared in the tunica media and base of the plaque in the symptomatic and asymptomatic group on CEUS had no statistical difference ( p > 0.05), but those located in the fibrous cap and shoulders had a significant statistical difference ( p = 0.000). Statistical differences were not found in the locations of IPNV on CEUS and histopathology (all p > 0.05). The sensitivity (82.4%, 56/68) and specificity (77.4%, 24/31) of IPNV location were higher than those (77.9%, 53/68; 45.2%, 14/31) of IPNV grading in the identification of plaque vulnerability. IPNVs located at the fibrous cap and shoulders on CEUS is a reliable indicator for identifying plaque vulnerability.

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Abstract TMP44: Contrast Enhanced Ultrasound Can Detect Small Disruption of Carotid Plaques Related to Symptomatic Internal Carotid Artery Stenosis

Stroke ◽

10.1161/str.47.suppl_1.tmp44 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Soichiro Abe ◽

Kozue Saito ◽

Hatsue Ishibashi-Ueda ◽

Shuichi Tonomura ◽

Kota Mori ◽

...

Keyword(s):

Ischemic Stroke ◽

Carotid Artery ◽

Internal Carotid Artery ◽

Carotid Artery Stenosis ◽

Carotid Plaque ◽

Internal Carotid ◽

Color Doppler ◽

Internal Carotid Artery Stenosis ◽

Contrast Enhanced Ultrasound ◽

Contrast Enhanced

Background: The ulcerated atheroma of the carotid artery is a risk factor of ipsilateral ischemic stroke. Contrast-enhanced ultrasound (CEUS) is a novel noninvasive technique useful for evaluating the morphology of carotid plaques, and can detect small disruptions on plaque surface. However, it remains unclear whether the disrupted carotid plaque detected by CEUS is related to the symptomatic internal carotid artery stenosis (ICS). Methods: A total of 79 ICS patients who underwent carotid endarterectomy (CEA) were enrolled from July 2010 to July 2015. Before operation, ICA lesions were examined by color Doppler ultrasound (CDUS) and CEUS using perflubutane. The ulceration was diagnosed when both of the color Doppler signal on CDUS and the pooling of microbubbles on CEUS were observed within the plaque. The disruption was diagnosed only by CEUS when microbubbles pooled through the fissured surface, unlike the linear delineation of neovessels. We validated findings on ultrasound compared with the histopathological findings of ulceration and present/recent plaque rupture. The associations between ulceration/disruption on ultrasound and symptomatic ICS (with a history of ipsilateral transient ischemic attack and/or ischemic stroke) were investigated. Results: Of 79 subjects (mean age 71.2±6.8 years old, 78 men), 55 had symptomatic ICS. The ulceration by CEUS and CDUS was recognized in 20 patients (25%), and the disruption on plaque surface was seen by CEUS solitary in 26 patients (33%). The sensitivity and specificity of detecting plaque ulceration or disruption using CEUS compared with histopathological findings were 0.57 (45/66) and 1.00 (13/13), respectively. The detection rate of ulceration or disruption using CEUS was higher in symptomatic ICS than in asymptomatic ICS (66% vs 42%, P=0.049). Compared to plaques without ulceration/disruption on ultrasound, prevalence of symptomatic ICS was higher in plaques with the disruption (88% vs 58%, P=0.01), whereas it was similar in plaques with the ulceration (65% vs 58%, P=0.77) Conclusion: Small disruptions on carotid plaque surface detected by CEUS were significantly related to symptomatic ICS and this results may help the detailed assessment of plaque vulnerability.

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