Article

Correlation of Carotid Artery Atherosclerotic Lesion Echogenicity and Severity at Standard US with Intraplaque Neovascularization Detected at Contrast-enhanced US

October 2010
Radiology 258(2):618-26

DOI:10.1148/radiol.10101008

Source
PubMed

Authors:

Universitätsspital Basel

Cleveland Clinic

Arend F L Schinkel

Erasmus MC

Show all 8 authorsHide

To correlate echogenicity and severity of atherosclerotic carotid artery lesions at standard ultrasonography (US) with the degree of intraplaque neovascularization at contrast material-enhanced (CE) US. This HIPAA-compliant study was approved by the local ethics committee, and all patients provided informed consent. A total of 175 patients (113 [65%] men, 62 [35%] women; mean age, 67 years ± 10 [standard deviation]) underwent standard and CE US of the carotid artery. Lesion echogenicity (class I to IV), degree of stenosis, and maximal lesion thickness were evaluated for each documented atherosclerotic lesion. The degree of intraplaque neovascularization at CE US was categorized as absent (grade 1), moderate (grade 2), or extensive (grade 3). Correlation of neovascularization with echogenicity, degree of stenosis, and maximal lesion thickness was made by using Spearman ρ and χ(2) test for trend. In a total of 293 atherosclerotic lesions, echogenicity was inversely correlated with grade of intraplaque neovascularization (ρ = -0.199, P < .001). More echolucent lesions had a higher degree of neovascularization compared with more echogenic ones (P < .001). The degree of stenosis was significantly correlated with grade of intraplaque neovascularization (ρ = 0.157, P = .003). Lesions with higher degree of stenosis had higher grade of neovascularization (P = .008), and maximal lesion thickness increased with the grade of neovascularization (P < .001) and was significantly correlated with grade of neovascularization (ρ = 0.233, P < .001). Neovascularization visualized with CE US correlates with lesion severity and with morphologic features of plaque instability, contributing to the concept that more vulnerable plaques are more likely to have a greater degree of neovascularization. Therefore, CE US may be a valuable tool for further risk stratification of echolucent atherosclerotic lesions and carotid artery stenosis of different degrees. Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10101008/-/DC1.

The utility of ultrasound and computed tomography in the assessment of carotid artery plaque vulnerability–A mini review

Article

Full-text available

Nov 2022

As the burden of cardiovascular and cerebrovascular events continues to increase, emerging evidence supports the concept of plaque vulnerability as a strong marker of plaque rupture, and embolization. Qualitative assessment of the plaque can identify the degree of plaque instability. Ultrasound and computed tomography (CT) have emerged as safe and accurate techniques for the assessment of plaque vulnerability. Plaque features including but not limited to surface ulceration, large lipid core, thin fibrous cap (FC), intraplaque neovascularization and hemorrhage can be assessed and are linked to plaque instability.

Ultrasonography and contrast-enhanced ultrasound for activity assessment in 115 patients with carotid involvement of Takayasu arteritis

Article

Full-text available

Sep 2022

Objectives To evaluate the efficacy of ultrasound and contrast-enhanced ultrasound (CEUS) in disease activity assessment of Takayasu arteritis (TA) with carotid involvement. Methods This is a cohort study of 115 patients of TA with carotid involvement. We investigated correlations between clinical data, sonographic features and CEUS enhancement at the site most prominent lesion of each patient. Disease activity was assessed by the NIH Kerr criteria. Sonographic findings were compared with follow-up examinations. CEUS was repeated after a three to seven months interval in 35 patients to evaluate change of CEUS enhancement after treatment. Results Extensiveness of CEUS enhancement at most prominent carotid lesions had significant correlations with disease activity by the Kerr criteria (P < 0.001). The specificity of extensive enhancement for indicating active disease was 95%, while sensitivity was 67%. Patients with active disease showed greater arterial wall thickness and more prominent reduction of arterial wall thickness after treatment. Most of patients (68%) with subsided active disease after treatment featured decrease of CEUS enhancement. Conclusions Extensiveness of enhancement by CEUS and arterial wall thickness by ultrasonography may be useful markers for initial and follow-up assessment of disease activity of TA with common carotid artery involvement.

Vascular Imaging Techniques to Diagnose and Monitor Patients with Takayasu Arteritis: A Review of the Literature

Article

Full-text available

Oct 2021

Takayasu arteritis (TA) is a large vessel vasculitis that causes stenosis, occlusion, and sometimes the aneurysm of the aorta and its major branches. TA often occurs in young women, and because the symptoms are not obvious in the early stages of the disease, diagnosis is difficult and often delayed. In approximately 10% to 20% of patients, TA is reportedly complicated by ischemic stroke or transient ischemic attack. It is important to diagnose TA early and provide appropriate treatment to prevent complications from stroke. Diagnostic imaging techniques to visualize arterial stenosis are widely used in clinical practice. Even if no signs of cerebrovascular events are present at the time of the most recent evaluation of patients with TA, follow-up vascular imaging is important to monitor disease progression and changes in the cerebrovascular risk. However, the optimal imaging technique for monitoring of TA has not been established. Therefore, the purpose of this review is to describe newly available evidence on the usefulness of conventional imaging modalities (digital subtraction angiography, computed tomography angiography, magnetic resonance imaging/angiography, duplex ultrasound, and positron emission tomography) and novel imaging modalities (optical coherence tomography, infrared thermography, contrast-enhanced ultrasonography, and superb microvascular imaging) in the diagnosis and monitoring of TA.

Contrast-enhanced carotid ultrasound: current status

Article

Full-text available

Dec 2019

Unstable atherosclerotic plaques (ASP) are the cause of acute ischemia in the carotid and coronary systems. Numerous studies have shown a relationship between plaque instability, manifestations, echogenicity, histological findings and its neovascularization. The presence and extent of ASP neovascularization in the carotid arteries can be detected for the first time using contrast-enhanced carotid ultrasound. Contrast-enhanced carotid ultrasound does not have nephrotoxic effect; it also improves the accuracy of plaque ulceration detecting and determining the severity of stenosis. The article presents the opinions of the authors and international experts on contrast ultrasound of peripheral arteries. An analysis of the literature data and our own observations is presented. Significant parameters such as the doses, procedure onset time and duration, methods for the qualitative and quantitative assessment of plaque neovascularization are analyzed. The difficulties of contrast-enhanced ultrasound are described.

The role of intraplaque neovascularization in recent and future ischemic stroke in patients with mild carotid stenosis

Article

Oct 2024

Purpose: There is still insufficient evidence for predicting stroke risk in patients with mild carotid atherosclerotic stenosis. This study aimed to explore the association between carotid intraplaque neovascularization (IPN) in mild stenosis and ischemic stroke, using contrast-enhanced ultrasound (CEUS) imaging. Methods: This retrospective observational study included 369 patients from July 2021 to March 2022. These patients were categorized as symptomatic or asymptomatic based on their recent history of ipsilateral ischemic stroke. Initial parameters of carotid plaques, such as IPN grading and contrast enhancement index, were assessed using B-mode ultrasonography and CEUS. The follow-up period lasted 12 months or until a newly-developed ischemic stroke occurred. Logistic regression models and Cox proportional-hazards regression models were employed to explore the associations between ultrasonic parameters and the incidence of recent and future ischemic strokes. Results: In patients with mild stenosis, both increasing age and grade 2 carotid IPN were significant predictors of recent primary ischemic stroke. Furthermore, grade 2 carotid IPN independently predicted future ischemic strokes in both symptomatic and asymptomatic patients. Conclusion: This study demonstrated that carotid IPN as detected by CEUS imaging holds potential as a useful non-invasive biomarker for predicting recent and future ischemic strokes in patients with mild carotid stenosis.

Contrast-Enhanced Ultrasound Feasibility in Assessing Carotid Plaque Vulnerability—Narrative Review

Article

Full-text available

Oct 2023

The risk assessment for carotid atherosclerotic lesions involves not only determining the degree of stenosis but also plaque morphology and its composition. Recently, carotid contrast-enhanced ultrasound (CEUS) has gained importance for evaluating vulnerable plaques. This review explores CEUS’s utility in detecting carotid plaque surface irregularities and ulcerations as well as intraplaque neovascularization and its alignment with histology. Initial indications suggest that CEUS might have the potential to anticipate cerebrovascular incidents. Nevertheless, there is a need for extensive, multicenter prospective studies that explore the relationships between CEUS observations and patient clinical outcomes in cases of carotid atherosclerotic disease.

Inter and intra-observer agreement of arterial wall contrast-enhanced ultrasonography in giant cell arteritis

Article

Full-text available

Nov 2022

Objective The aim of this study was to analyze inter- and intra-observer agreement for contrast-enhanced ultrasonography (CEUS) for monitoring disease activity in Giant Cell Arteritis (GCA) in the wall of axillary arteries, and common carotid arteries. Methods Giant cell arteritis patients have CEUS of axillary arteries and common carotid. These images were rated by seven vascular medicine physicians from four hospitals who were experienced in duplex ultrasonography of GCA patients. Two weeks later, observers again rated the same images. GCA patients were recruited in from December 2019 to February 2021. An analysis of the contrast of the ultrasound images with a gradation in three classes (grade 0, 1, and 2) was performed. Grade 0 corresponds to no contrast, grade 1 to moderate wall contrast and grade 2 to intense contrast. A new analysis in 2 classes: positive or negative wall contrast; was then performed on new series of images. Results Sixty arterial segments were evaluated in 30 patients. For the three-class scale, intra-rater agreement was substantial: κ 0.70; inter-rater agreement was fair: κ from 0.22 to 0.27. Thirty-four videos had a wall thickness of less than 2 mm and 26 videos had a wall thickness greater than 2 mm. For walls with a thickness lower than 2 mm: intra-rater agreement was substantial: κ 0.69; inter-rater agreement was fair: κ 0.35. For walls with a thickness of 2 mm or more: intra-rater agreement was substantial: κ 0.53; inter-rater agreement was fair: κ 0.25. For analysis of parietal contrast uptake in two classes: inter-rater agreement was fair to moderate: κ from 0.35 to 0.41; and for walls with a thickness of 2 mm or more: inter-rater agreement was fair to substantial κ from 0.22 to 0.63. Conclusion The visual analysis of contrast uptake in the wall of the axillary and common carotid arteries showed good intra-rater agreement in GCA patients. The inter-rater agreement was low, especially when contrast was analyzed in three classes. The inter-rater agreement for the analysis in two classes was also low. The inter-rater agreement was higher in two-class analysis for walls of 2 mm thickness or more.

International Union of Angiology (IUA) consensus paper on imaging strategies in atherosclerotic carotid artery imaging: From basic strategies to advanced approaches

Article

Jun 2022
Atherosclerosis

Cardiovascular disease (CVD) is the leading cause of mortality and disability in developed countries. According to WHO, an estimated 17.9 million people died from CVDs in 2019, representing 32% of all global deaths. Of these deaths, 85% were due to major adverse cardiac and cerebral events. Early detection and care for individuals at high risk could save lives, alleviate suffering, and diminish economic burden associated with these diseases. Carotid artery disease is not only a well-established risk factor for ischemic stroke, contributing to 10%–20% of strokes or transient ischemic attacks (TIAs), but it is also a surrogate marker of generalized atherosclerosis and a predictor of cardiovascular events. In addition to diligent history, physical examination, and laboratory detection of metabolic abnormalities leading to vascular changes, imaging of carotid arteries adds very important information in assessing stroke and overall cardiovascular risk. Spanning from carotid intima-media thickness (IMT) measurements in arteriopathy to plaque burden, morphology and biology in more advanced disease, imaging of carotid arteries could help not only in stroke prevention but also in ameliorating cardiovascular events in other territories (e.g. in the coronary arteries). While ultrasound is the most widely available and affordable imaging methods, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), their combination and other more sophisticated methods have introduced novel concepts in detection of carotid plaque characteristics and risk assessment of stroke and other cardiovascular events. However, in addition to robust progress in usage of these methods, all of them have limitations which should be taken into account. The main purpose of this consensus document is to discuss pros but also cons in clinical, epidemiological and research use of all these techniques.

Use of Contrast-Enhanced Ultrasound Sonography in Giant Cell Arteritis: A Proof-of-Concept Study

Article

Oct 2021
ULTRASOUND MED BIOL

C-Reactive protein and erythrocyte sedimentation rate are crucial parameters used to monitor giant cell arteritis (GCA). Given that tocilizumab is approved for the treatment of GCA, these parameters are less sensitive because of the effects of interleukin-6 receptor blockade. Thus, the optimal method for monitoring GCA patients undergoing tocilizumab therapy, especially patients exhibiting a persistent thickened vessel wall in large vessels, remains unclear. Contrast-enhanced ultrasonography (CEUS) can increase the visibility of tissue perfusion by slow blood flow, which cannot be detected by power color doppler. We used CEUS to investigate patients with active and inactive GCA of the large vessels (active large vessel arteritis [aLVV]/inactive large vessel arteritis [iLVV]) who were not administered tocilizumab in this proof-of-concept study. After injection of the ultrasound contrast agent, the contrasted area (CA) of large vessels in a transverse section was calculated twice: first when the lumen was contrasted completely and once again 4–8 s later. We investigated the value of increase in CA that exhibited the best sensitivity and specificity for aLVV. Twenty-four patients were included in this study: 15 with aLVV and 9 with iLVV. The CA increased from 32.2 ± 16.8 to 52.5 ± 21.3 mm² (p < 0.0001) in aLVV. The mean CA remained unchanged in iLVV. The best cutoff value to differentiate between aLVV and iLVV was a ≥25% increase in CA with a sensitivity and specificity of 91.7% and 100%, respectively. Our study indicates that CEUS can detect aLVV with high sensitivity and specificity. Incorporation of CEUS into routine clinical practice might result in a good method for monitoring disease activity in LVV in GCA patients. The limitation of our study was the small number of patients and the lack of investigator blinding to clinical data.

Detection of Adventitial Vasa Vasorum and Intraplaque Neovascularization in Carotid Atherosclerotic Lesions with Contrastenhanced Ultrasound and their Role in Atherosclerosis

Article

Oct 2011

Superb Microvascular Imaging Ultrasound for Cervical Carotid Artery Stenosis for Prediction of the Development of Microembolic Signals on Transcranial Doppler during Carotid Exposure in Endarterectomy

Article

Full-text available

May 2021

Introduction: During exposure of the carotid arteries, embolism from the surgical site is recognized as a primary cause of neurological deficits or new cerebral ischemic lesions following carotid endarterectomy (CEA), and associations have been reported between histological neovascularization in the carotid plaque and both plaque vulnerability and the development of artery-to-artery embolism. Superb microvascular imaging (SMI) enables accurate visualization of neovessels in the carotid plaque without the use of intravenous contrast. This study aimed to determine whether preoperative SMI ultrasound for cervical carotid artery stenosis predicts the development of microembolic signals (MES) on transcranial Doppler (TCD) during exposure of the carotid arteries in CEA. Methods: Preoperative cervical carotid artery SMI ultrasound followed by CEA under TCD monitoring of MES in the ipsilateral middle cerebral artery was conducted in 70 patients previously diagnosed with internal carotid artery stenosis (defined as ≥70%). First, observers visually identified intraplaque microvascular flow (IMVF) signals as moving enhancements located near the surface of the carotid plaque within the plaque on SMI ultrasonograms. Next, regions of interest (ROI) were manually placed at the identified IMVF signals (or at arbitrary places within the plaque when no IMVF signals were identified within the carotid plaque) and the carotid lumen, and time-intensity curves of the IMVF signal and lumen ROI were generated. Ten heartbeat cycles of both time-intensity curves were segmented into each heartbeat cycle based on gated electrocardiogram findings and averaged with respect to the IMVF signal and lumen ROI. The difference between the maximum and minimum intensities (ID) was calculated based on the averaged IMVF signal (IDIMVF) and lumen (IDl) curves. Finally, the ratio of IDIMVF to IDl was calculated. Results: MES during exposure of the carotid arteries were detected in 17 patients (24%). The incidence of identification of IMVF signals was significantly greater in patients with MES (94%) than in those without (57%; p = 0.0067). The IDIMVF/IDl ratio was significantly greater in patients with MES (0.108 ± 0.120) than in those without (0.017 ± 0.042; p < 0.0001). The specificity and positive predictive value for the IDIMVF/IDl ratio for prediction of the development of MES were significantly higher than those for the identification of IMVF signals. Logistic regression analysis revealed that only the IDIMVF/IDl ratio was significantly associated with the development of MES (95% CI 101.1-3,628.9; p = 0.0048). Conclusion: Preoperative cervical carotid artery SMI ultrasound predicts the development of MES on TCD during exposure of the carotid arteries in CEA.

Carotid Intraplaque Neovascularization on Contrast-Enhanced Ultrasound Correlates with Cardiovascular Events and Poor Prognosis: A Systematic Review and Meta-analysis

Article

Feb 2021
ULTRASOUND MED BIOL

The goal of this meta-analysis is to investigate whether carotid intraplaque neovascularization (IPN) on contrast-enhanced ultrasound (CEUS) correlates with past cardiovascular events (CVEs) and prognosis. The present meta-analysis included 22 studies involving 3232 patients. The pooled analysis revealed that the presence of IPN was significantly associated with a higher incidence of future CVEs (pooled relative risk = 3.28, 95% confidence interval [CI]: 2.28–4.73) and a lower event-free probability (pooled hazard ratio = 2.51, 95% CI: 1.48–4.27). The presence of IPN was significantly associated with higher rates of past cardiac events (odds ratio = 4.25, 95% CI: 2.48–7.29) and past cerebrovascular accidents (odds ratio = 4.83, 95% CI: 2.66–8.78). Our results suggest that carotid IPN on CEUS significantly correlates with past cardiac events and cerebrovascular accidents and can predict future CVEs. Carotid CEUS is useful in CVE risk stratification.

Contrast Imaging Ultrasound for the Detection and Characterization of Carotid Vulnerable Plaque

Article

Full-text available

Aug 2020

Not only the degree of luminal narrowing but also the plaque morphology and composition play an important role in risk stratification of carotid atherosclerotic lesions. During the last few years, carotid contrast-enhanced ultrasound (CEUS) has emerged as a valuable imaging tool to assess such vulnerable carotid plaques. This review article discussed the use of CEUS for the detection of carotid plaque irregularities and ulcerations as well as the quantification of intraplaque neovascularization and its correlation with histology and inflammatory biomarkers. Apart from evaluating for markers of vulnerable carotid plaques, CEUS enhancement is directly associated with past cerebrovascular events. More importantly, preliminary evidence has shown that CEUS could be used to predict future cerebrovascular and cardiovascular events. Despite the progress in CEUS imaging for carotid atherosclerotic disease, past studies still suffer from the retrospective nature, small sample size, and a lack of matched, well controlled prospective studies. In the future, large multi-center prospective studies addressing the relationship between CEUS findings and patient clinical outcomes in carotid atherosclerotic disease are warranted.

Recommendations for the Assessment of Carotid Arterial Plaque by Ultrasound for the Characterization of Atherosclerosis and Evaluation of Cardiovascular Risk: From the American Society of Echocardiography

Article

Jun 2020
J AM SOC ECHOCARDIOG

Atherosclerotic plaque detection by carotid ultrasound provides cardiovascular disease risk stratification. The advantages and disadvantages of two-dimensional (2D) and three-dimensional (3D) ultrasound methods for carotid arterial plaque quantification are reviewed. Advanced and emerging methods of carotid arterial plaque activity and composition analysis by ultrasound are considered. Recommendations for the standardization of focused 2D and 3D carotid arterial plaque ultrasound image acquisition and measurement for the purpose of cardiovascular disease stratification are formulated. Potential clinical application towards cardiovascular risk stratification of recommended focused carotid arterial plaque quantification approaches are summarized.

Advanced ultrasound Methods in assessment of carotid plaque instability: A prospective multimodal study

Preprint

Full-text available

Nov 2019

Background: A significant proportion of ischemic strokes are caused by emboli from atherosclerotic, unstable carotid artery plaques. The selection of patients for endarterectomy in current clinical practice is primarily based on the degree of carotid artery stenosis and clinical symptoms. However, the content of the plaque is known to be more important for stroke risk. Intraplaque neovascularization (IPN) has recently emerged as a possible surrogate marker for plaque instability. Neo-microvessels from the adventitial vasa vasorum grow into the full thickness of the vessel wall in an adaptive response to hypoxia, causing subsequent intraplaque haemorrhage and plaque rupture. Conventional ultrasound cannot detect IPN. Contrast-enhanced ultrasound and Superb Microvascular Imaging (SMI), have, however, shown promise in IPN assessment. Recent research using Shear Wave Elastography (SWE) has also reported reduced tissue stiffness in the artery wall (reduced mean Young’s modulus) in unstable compared to stable plaques. The purpose of this study is to identify unstable carotid artery plaques at risk of rupture and future ischemic stroke risk using multimodal assessments. Methods: Thirty symptomatic and 30 asymptomatic patients >18 years, with >50% carotid stenosis referred to Oslo University Hospital ultrasound lab will be included in this on-going project. Patients will undergo contrast enhanced ultrasound, SMI, carotid-MRI and PET-(18F-FDG). Contrast enhanced ultrasound will be analyzed semi-quantitatively (5-levels of visual classification) and quantitatively by plotting time-intensity curve analyses to obtain plaque peak contrast enhancement intensity. Plaques removed at carotid endarterectomy will be assessed histologically and the number of microvessels, areas of inflammation, granulation, calcification, lipid and fibrosis will be measured. Discussion: This multimodality study will primarily provide information on the clinical value of advanced ultrasound methods (SMI, SWE) for the detection of unstable carotid artery plaque in comparison with other methods including contrast-enhanced ultrasound, carotid-MRI and PET-(18F-FDG) using histology as the gold standard. Secondly, findings from the methods mentioned above will be related to cerebrovascular symptoms, blood tests (leukocytes, CRP, ESR, lipoproteins and inflammatory markers) and cardiovascular risk factors at inclusion and at 1-year follow-up. The overall aim is to optimize detection of plaque instability which can lead to better preventive decisions and reduced stroke rate.

Advanced ultrasound Methods in assessment of carotid plaque instability: A prospective multimodal study

Preprint

Full-text available

Dec 2019

Background: A significant proportion of ischemic strokes are caused by emboli from atherosclerotic, unstable carotid artery plaques. The selection of patients for endarterectomy in current clinical practice is primarily based on the degree of carotid artery stenosis and clinical symptoms. However, the content of the plaque is known to be more important for stroke risk. Intraplaque neovascularization (IPN) has recently emerged as a possible surrogate marker for plaque instability. Neo-microvessels from the adventitial vasa vasorum grow into the full thickness of the vessel wall in an adaptive response to hypoxia, causing subsequent intraplaque haemorrhage and plaque rupture. Conventional ultrasound cannot detect IPN. Contrast-enhanced ultrasound and Superb Microvascular Imaging (SMI), have, however, shown promise in IPN assessment. Recent research using Shear Wave Elastography (SWE) has also reported reduced tissue stiffness in the artery wall (reduced mean Young’s modulus) in unstable compared to stable plaques. The purpose of this study is to identify unstable carotid artery plaques at risk of rupture and future ischemic stroke risk using multimodal assessments. Methods: Forty five symptomatic and 45 asymptomatic patients >18 years, with >50% carotid stenosis referred to Oslo University Hospital ultrasound lab will be included in this on-going project. Patients will undergo contrast enhanced ultrasound, SMI, carotid-MRI and PET-(18F-FDG). Contrast enhanced ultrasound will be analyzed semi-quantitatively (5-levels visual classification) and quantitatively by plotting time-intensity curve analyses to obtain plaque peak contrast enhancement intensity. Plaques removed at carotid endarterectomy will be assessed histologically and the number of microvessels, areas of inflammation, granulation, calcification, lipid and fibrosis will be measured. Discussion: This multimodality study will primarily provide information on the clinical value of advanced ultrasound methods (SMI, SWE) for the detection of unstable carotid artery plaque in comparison with other methods including contrast-enhanced ultrasound, carotid-MRI and PET-(18F-FDG) using histology as the gold standard. Secondly, findings from the methods mentioned above will be related to cerebrovascular symptoms, blood tests (leukocytes, CRP, ESR, lipoproteins and inflammatory markers) and cardiovascular risk factors at inclusion and at 1-year follow-up. The overall aim is to optimize detection of plaque instability which can lead to better preventive decisions and reduced stroke rate.

Advanced ultrasound Methods in assessment of carotid plaque instability: A prospective multimodal study

Preprint

Full-text available

Jan 2020

Background: A significant proportion of ischemic strokes are caused by emboli from atherosclerotic, unstable carotid artery plaques. The selection of patients for endarterectomy in current clinical practice is primarily based on the degree of carotid artery stenosis and clinical symptoms. However, the content of the plaque is known to be more important for stroke risk. Intraplaque neovascularization (IPN) has recently emerged as a possible surrogate marker for plaque instability. Neo-microvessels from the adventitial vasa vasorum grow into the full thickness of the vessel wall in an adaptive response to hypoxia, causing subsequent intraplaque haemorrhage and plaque rupture. Conventional ultrasound cannot detect IPN. Contrast-enhanced ultrasound and Superb Microvascular Imaging (SMI), have, however, shown promise in IPN assessment. Recent research using Shear Wave Elastography (SWE) has also reported reduced tissue stiffness in the artery wall (reduced mean Young’s modulus) in unstable compared to stable plaques. The purpose of this study is to identify unstable carotid artery plaques at risk of rupture and future ischemic stroke risk using multimodal assessments. Methods: Forty five symptomatic and 45 asymptomatic patients >18 years, with >50% carotid stenosis referred to Oslo University Hospital ultrasound lab will be included in this on-going project. Patients will undergo contrast enhanced ultrasound, SMI, carotid-MRI and PET-(18F-FDG). Contrast enhanced ultrasound will be analyzed semi-quantitatively (5-levels visual classification) and quantitatively by plotting time-intensity curve analyses to obtain plaque peak contrast enhancement intensity. Plaques removed at carotid endarterectomy will be assessed histologically and the number of microvessels, areas of inflammation, granulation, calcification, lipid and fibrosis will be measured. Discussion: This multimodality study will primarily provide information on the clinical value of advanced ultrasound methods (SMI, SWE) for the detection of unstable carotid artery plaque in comparison with other methods including contrast-enhanced ultrasound, carotid-MRI and PET-(18F-FDG) using histology as the gold standard. Secondly, findings from the methods mentioned above will be related to cerebrovascular symptoms, blood tests (leukocytes, CRP, ESR, lipoproteins and inflammatory markers) and cardiovascular risk factors at inclusion and at 1-year follow-up. The overall aim is to optimize detection of plaque instability which can lead to better preventive decisions and reduced stroke rate.

Carotid vessel wall imaging on CTA

Article

Feb 2020

Vessel wall imaging has been increasingly used to characterize plaque beyond luminal narrowing to identify patients who may be at the highest risk of cerebrovascular ischemia. Although detailed plaque information can be obtained from many imaging modalities, CTA is particularly appealing for carotid plaque imaging due to its relatively low cost, wide availability, operator independence, and ability to discern high-risk features. The present Review Article describes the current understanding of plaque characteristics on CTA by describing commonly encountered plaque features, including calcified and soft plaque, surface irregularities, neovascularization, and inflammation. The goal of this Review Article was to provide a more robust understanding of clinically relevant plaque features detectable on routine CTA of the carotid arteries.

Advanced ultrasound methods in assessment of carotid plaque instability: A prospective multimodal study

Article

Full-text available

Jan 2020
BMC NEUROL

Background: A significant proportion of ischemic strokes are caused by emboli from atherosclerotic, unstable carotid artery plaques. The selection of patients for endarterectomy in current clinical practice is primarily based on the degree of carotid artery stenosis and clinical symptoms. However, the content of the plaque is known to be more important for stroke risk. Intraplaque neovascularization (IPN) has recently emerged as a possible surrogate marker for plaque instability. Neo-microvessels from the adventitial vasa vasorum grow into the full thickness of the vessel wall in an adaptive response to hypoxia, causing subsequent intraplaque haemorrhage and plaque rupture. Conventional ultrasound cannot detect IPN. Contrast-enhanced ultrasound and Superb Microvascular Imaging (SMI), have, however, shown promise in IPN assessment. Recent research using Shear Wave Elastography (SWE) has also reported reduced tissue stiffness in the artery wall (reduced mean Young's modulus) in unstable compared to stable plaques. The purpose of this study is to identify unstable carotid artery plaques at risk of rupture and future ischemic stroke risk using multimodal assessments. Methods: Forty five symptomatic and 45 asymptomatic patients > 18 years, with > 50% carotid stenosis referred to Oslo University Hospital ultrasound lab will be included in this on-going project. Patients will undergo contrast enhanced ultrasound, SMI, carotid-MRI and PET-(18F-FDG). Contrast enhanced ultrasound will be analyzed semi-quantitatively (5-levels visual classification) and quantitatively by plotting time-intensity curve analyses to obtain plaque peak contrast enhancement intensity. Plaques removed at carotid endarterectomy will be assessed histologically and the number of microvessels, areas of inflammation, granulation, calcification, lipid and fibrosis will be measured. Discussion: This multimodality study will primarily provide information on the clinical value of advanced ultrasound methods (SMI, SWE) for the detection of unstable carotid artery plaque in comparison with other methods including contrast-enhanced ultrasound, carotid-MRI and PET-(18F-FDG) using histology as the gold standard. Secondly, findings from the methods mentioned above will be related to cerebrovascular symptoms, blood tests (leukocytes, CRP, ESR, lipoproteins and inflammatory markers) and cardiovascular risk factors at inclusion and at 1-year follow-up. The overall aim is to optimize detection of plaque instability which can lead to better preventive decisions and reduced stroke rate.

Is the Adventitial Vasa Vasorum in Vulnerable Carotid Plaques Increased or Decreased?

Article

Jan 2025

Exploring Diagnostic Echoes Doppler Ultrasound Performance in Plaque Detection against CT as Gold Standard

Article

Full-text available

Jan 2025

Background: Cerebrovascular stroke is the third leading cause of death globally and is often associated with carotid artery stenosis, particularly in older adults. While ultrasonography is a widely used and non-invasive diagnostic tool, its limitations include operator dependency, potential for misinterpretation, and reduced sensitivity in detecting subtle plaque characteristics compared to computed tomography. Further research is needed to enhance its diagnostic accuracy and standardization. Objective: To evaluate the diagnostic performance of carotid Doppler ultrasound against CT gold standard. Methodology: A retrospective descriptive study was carried out at the Radiology Department of Shifa International Hospital, involving 100 participants categorized into 50 with calcified plaques and 50 with non-calcified plaques. Participants underwent a doppler carotid ultrasound followed by a CT carotid angiogram using non-probability convenient sampling. Data was collected on structured forms and analyzed using IBM SPSS version 23. Results: In a sample of 100 participants, 96 were elderly and 4 were younger adults with a gender distribution of 68 males and 32 females. Ultrasonography (USG) Doppler performed exceptionally well in terms of diagnosis. 88% sensitivity, 84% specificity, 84.6% positive predictive value, 87.5% negative predictive value, and 86% diagnostic accuracy were attained for noncalcified plaques. USG Doppler showed enhanced performance for calcified plaques, with 94% diagnostic accuracy, 92% sensitivity, 96% specificity, 95.8% positive predictive value, and 92.3% negative predictive value. Conclusion: Our study highlights the high sensitivity, specificity, and predictive values of Doppler ultrasound for assessing non-calcified and calcified plaques, emphasizing its utility as a valuable diagnostic tool in atherosclerosis management.

Exclusion of echo-lucent plaque using superb micro-vascular imaging: A case report

Article

Full-text available

Oct 2024

Background In the carotid bulb (CB), the vascular morphology can cause a decrease in blood flow velocity near the vessel wall. In addition, the CB is a common site for plaque formation. Particularly, echo-lucent plaques (ELPs) are known to pose a risk for cerebral embolism, requiring careful attention. In carotid ultrasonography (CU), ELPs may be difficult to distinguish from blood flow within the vessel using only B-mode imaging; thus, the use of color Doppler imaging (CDI) is recommended. However, when blood flow is extremely slow, even CDI may fail to differentiate between ELPs and the flow. We encountered a case where superb micro-vascular imaging (SMI) successfully detected extremely low-velocity blood flow, thereby excluding the presence of an ELP that CDI could not discern. Case Description A 64-year-old male with a history of smoking, hyperlipidemia, and percutaneous coronary intervention for myocardial infarction presented for an atherosclerosis screening. CU with CDI indicated a lesion showing a flow void near the wall of the CB, raising suspicions of significant blood flow stasis or the presence of an ELP or thrombus. He had no neurological findings or carotid bruits. A head magnetic resonance imaging revealed no findings suggestive of cerebral embolization. Using SMI during additional CU, we detected extremely low-velocity blood flow near the wall of the CB, allowing us to exclude an ELP. Conclusion When a flow void is observed with CDI in CU, and it is difficult to differentiate between an ELP and extremely low-velocity blood flow, the application of SMI can sometimes detect the extremely low-velocity blood flow. This approach may help avoid invasive examinations such as CU with contrast agents or cerebral angiography.

Intraplaque neovascularization combined with plaque elasticity for predicting ipsilateral stroke in patients with asymptomatic mild carotid stenosis

Article

Full-text available

Jan 2023

Background Intraplaque neovascularization (IPN) is a biomarker for vulnerable atherosclerotic plaques and can be effectively visualized via contrast-enhanced ultrasound (CEUS). Plaque elasticity is influenced by elements such as lipid core and fibrosis and can be quantitatively assessed on shear wave elastography (SWE). Studies combining the use of CEUS and SWE for the assessment of stroke risk are currently lacking. Our study thus aimed to determine the predictive value of IPN combined with plaque elasticity among patients with asymptomatic carotid plaque. Methods Consecutive patients with mild carotid stenosis who underwent CEUS and SWE were retrospectively analyzed. IPN was graded according to the presence and location of microbubbles within the plaque, while plaque elasticity was measured in terms of mean shear wave velocity (SWV). All patients were followed up for 6 months to monitor the development of ischemic stroke. The predictive values of IPN and SWV, individually and in combination, were assessed. Results A total of 121 patients were included, of whom 95 (78.5%) were male. The mean age was 63.1±10.7 years. Both grade 2 IPN [hazard ratio (HR) =2.37, 95% confidence interval (CI): 1.58–9.65; P=0.039] and SWV (HR =0.43, 95% CI: 0.20–0.95; P=0.038) were independently associated with future ischemic stroke events. The combined model demonstrated a significantly better predictive performance (HR =3.243, 95% CI: 1.87–6.17; P=0.027). Conclusions The combination of IPN and SWV demonstrated significantly better predictive value for the risk of stroke. Our combined model thereby has the potential to guide the clinical stratification and management of patients with asymptomatic mild carotid stenosis.

Assessment of Carotid Plaque Enhancement on Contrast-Enhanced Ultrasound as a Predictor for Severe Coronary Artery Disease

Article

Full-text available

Feb 2024
Indian J Radiol Imag

Background and Aim Contrast-enhanced ultrasound (CEUS) can reliably identify vulnerable plaques. As atherosclerosis is a systemic disease, we evaluated whether contrast enhancement of carotid plaque (CECP) can predict severe coronary artery disease (CAD) by comparing CECP in patients who have had acute coronary syndromes (ACS) recently with asymptomatic individuals. Settings and Design This case–control study was done at a tertiary care center during 2022. Materials and Methods Fourteen participants were recruited in each group, after screening in-patients for carotid plaques and inclusion and exclusion criteria. Those who had history of ACS were enrolled as cases, while those who did not were enrolled as controls. All these patients underwent grayscale, Doppler, and CEUS examination for characterization of the carotid plaque. For cases, findings on CEUS were also compared with the severity of CAD on catheter coronary angiography. Statistical Analysis Diagnostic parameters including sensitivity, specificity, and diagnostic accuracy were calculated and proportions were compared by using Fisher's exact test. Results Eight out of 28 patients showed CECP. CECP and CAD were positively associated with p-Value of 0.033. Eighty-three percent patients with triple vessel disease and 50% patients with double vessel disease on coronary angiography showed CECP. Sensitivity and specificity of CECP for prediction of CAD were 50 and 92.9%, respectively. Conclusion CECP on CEUS can predict CAD and is a more reliable indicator of severe CAD than plaque characteristics on grayscale and Doppler imaging; making it useful for screening of patients at risk of having CAD.

Noninvasive assessment of carotid plaque with subharmonic aided pressure estimation from a US contrast agent: A preliminary study

Article

Full-text available

Jan 2023
CTS-CLIN TRANSL SCI

Stroke is closely associated with carotid plaques. The assessment of carotid plaque is still the key issue of stroke prevention in clinical practice. This prospective cross-sectional study included patients with carotid plaque evaluated by ultrasonography (US). The intima-media thickness (IMT), lumen stenosis severity, thickness, and length of carotid plaque were measured by the routine US, and the amplitudes of subharmonics in the upstream shoulder, top, and downstream shoulder of all plaques and corresponding lumens were observed by Subharmonic Aided Pressure Estimation (SHAPE) US examination from the US contrast agent perflubutane microbubbles (Sonazoid), which analyzed the clinical parameters of patients, the subharmonic amplitude characteristics of all plaques and lumens, and the parameter differences between the ischemic stroke (IS) group and control group. From May 2021 to February 2022, 46 carotid plaques of 23 patients were included. For plaques, the subharmonic amplitude in the plaque (-60.52 ± 4.46) was lower than that in the opposing level lumen (-56.82 ± 5.68 dB), the subharmonic gradient across the plaque cap was negatively correlated with plaque thickness (r = -0.51, p < 0.001), and with the lumen stenosis severity (r = -0.42, p = 0.003). The median IMT of the IS group was thicker than the control group. The subharmonic gradient of the intraplaque of the IS group was larger than the control group (p = 0.004). In this analysis, we use the receiver operating characteristic (ROC) curve to establish the cutoff value of the difference to predict a new monitoring method for plaque without invasion to predict IS. It still needs a large-scale study with long-term follow-up to validate these findings.

Effect of evolocumab on the progression of intraplaque neovascularization of the carotid based on contrast-enhanced ultrasonography (EPIC study): A prospective single-arm, open-label study

Article

Full-text available

Jan 2023

Background and Purpose: The aim of this study was to explore the effect of half a year of evolocumab plus moderate-intensity statin treatment on carotid intraplaque neovascularization (IPN) and blood lipid levels. Methods: A total of 31 patients with 33 carotid plaques who received evolocumab plus statin treatment were included. Blood lipid levels, B-mode ultrasound and contrast-enhanced ultrasonography (CEUS) at baseline and after half a year of evolocumab plus statin therapy were collected. The area under the curve (AUC) reflected the total amount of acoustic developer entering the plaque or lumen within the 180 s measurement period. The enhanced intensity reflected the peak blood flow intensity during the monitoring period, and the contrast agent area reflected the area of vessels in the plaques. Results: Except for high-density lipoprotein cholesterol (HDL-c), all other lipid indices decreased. Compared with baseline, low-density lipoprotein cholesterol (LDL-c) decreased by approximately 57% (p < 0.001); total cholesterol (TC) decreased by approximately 34% (p < 0.001); small dense low-density lipoprotein (sd-LDL) decreased by approximately 52% (p < 0.001); and HDL-c increased by approximately 20% (p < 0.001). B-mode ultrasonography showed that the length and thickness of the plaque and the hypoechoic area ratio were reduced (p < 0.05). The plaque area, calcified area ratio, and lumen cross-sectional area changed little (p > 0.05). CEUS revealed that the area under the curve of plaque/lumen [AUC (P/L)] decreased from 0.27 ± 0.13 to 0.19 ± 0.11 (p < 0.001). The enhanced intensity ratio of plaque/lumen [intensity ratio (P/L)] decreased from 0.37 ± 0.16 to 0.31 ± 0.14 (p = 0.009). The contrast agent area in plaque/area of plaque decreased from 19.20 ± 13.23 to 12.66 ± 9.59 (p = 0.003). The neovascularization score decreased from 2.64 ± 0.54 to 2.06 ± 0.86 (p < 0.001). Subgroup analysis based on statin duration (<6 months and ≥6 months) showed that there was no significant difference in the AUC (P/L) or intensity ratio (P/L) at baseline or after half a year of evolocumab treatment. Conclusion: This study found that evolocumab combined with moderate-intensity statins significantly improved the blood lipid profile and reduced carotid IPN. Clinical Trial Registration: https://www.clinicaltrials.gov; identifier: NCT04423406.

Excessive Adventitial and Perivascular Vascularisation Correlates with Vascular Inflammation and Intimal Hyperplasia

Article

Full-text available

Oct 2022
INT J MOL SCI

Albeit multiple studies demonstrated that vasa vasorum (VV) have a crucial importance in vascular pathology, the informative markers and metrics of vascular inflammation defining the development of intimal hyperplasia (IH) have been vaguely studied. Here, we employed two rat models (balloon injury of the abdominal aorta and the same intervention optionally complemented with intravenous injections of calciprotein particles) and a clinical scenario (arterial and venous conduits for coronary artery bypass graft (CABG) surgery) to investigate the pathophysiological interconnections among VV, myeloperoxidase-positive (MPO+) clusters, and IH. We found that the amounts of VV and MPO+ clusters were strongly correlated; further, MPO+ clusters density was significantly associated with balloon-induced IH and increased at calciprotein particle-provoked endothelial dysfunction. Likewise, number and density of VV correlated with IH in bypass grafts for CABG surgery at the pre-intervention stage and were higher in venous conduits which more frequently suffered from IH as compared with arterial grafts. Collectively, our results underline the pathophysiological importance of excessive VV upon the vascular injury or at the exposure to cardiovascular risk factors, highlight MPO+ clusters as an informative marker of adventitial and perivascular inflammation, and propose another mechanistic explanation of a higher long-term patency of arterial grafts upon the CABG surgery.

3D-Arterial analysis software and CEUS in the assessment of severity and vulnerability of carotid atherosclerotic plaque: a comparison with CTA and histopathology

Article

Full-text available

Sep 2022
RADIOL MED

Purpose Our purpose is to assess Multiparametric Ultrasound (MPUS) efficacy for evaluation of carotid plaque vulnerability and carotid stenosis degree in comparison with Computed Tomography angiography (CTA) and histology. Material and methods 3D-Arterial Analysis is a 3D ultrasound software that automatically provides the degree of carotid stenosis and a colorimetric map of carotid plaque vulnerability. We enrolled 106 patients who were candidates for carotid endarterectomy. Prior to undergoing surgery, all carotid artery plaques were evaluated with Color-Doppler-US (CDUS), Contrast-Enhanced Ultrasound (CEUS), and 3D Arterial analysis (3DAA) US along with Computerized Tomographic Angiography (CTA) to assess the carotid artery stenosis degree. Post-surgery, the carotid specimens were fixed with 10% neutral buffered formalin solution, embedded in paraffin and used for light microscopic examination to assess plaque vulnerability morphological features. Results The results of the CTA examinations revealed 91 patients with severe carotid stenoses with a resultant diagnostic accuracy of 82.3% for CDUS, 94.5% for CEUS, 98.4% for 3DAA, respectively. The histopathological examination showed 71 vulnerable plaques with diagnostic accuracy values of 85.8% for CDUS, 93.4% for CEUS, 90.3% for 3DAA, 92% for CTA, respectively. Conclusions The combination of CEUS and 3D Arterial Analysis may provide a powerful new clinical tool to identify and stratify “at-risk” patients with atherosclerotic carotid artery disease, identifying vulnerable plaques. These applications may also help in the postoperative assessment of treatment options to manage cardiovascular risks.

Diagnostic Performance of Atherosclerotic Carotid Plaque Neovascularization with Contrast-Enhanced Ultrasound: A Meta-Analysis

Article

Full-text available

Mar 2022

Objectives: To evaluate the diagnostic performance of contrast-enhanced ultrasound (CEUS) for atherosclerotic carotid plaque neovascularization. Methods: The electronic databases like PubMed, Embase, OVID, and Web of Science were used to search for the relevant studies, which are involved in the evaluation of the diagnostic parameters of QUS for atherosclerotic carotid plaque neovascularization. Review Manager 5.4 and Stata 14.0 were used to estimate the pooled diagnostic value of CEUS. Forest plots, sensitivity analysis, and Deeks' funnel plots were performed on the included studies. Results: Ten studies eventually met the final inclusion criteria. For diagnostic performance, CUES showed that the pooled values of sensitivity, specificity, positive likelihood odds ratios, negative likelihood odds ratios, and diagnostic odds ratios were 0.83 (95% CI 0.78-0.86), 0.77 (95% CI 0.68-0.84), 3.61 (95% CI 2.59-5.03), 0.23 (95% CI 0.18-0.28), and 16.02 (95% CI 10.02-25.60), respectively. The estimate of the area under curve (AUC) was 0.85 (95% CI 0.82-0.88). Conclusion: Our research supported that CEUS had high sensitivity and specificity in the diagnosis of atherosclerotic carotid plaque neovascularization. More high-quality prospective multicenter studies focusing on the accuracy of CEUS for carotid atherosclerotic plaque should be performed to verify our conclusions.

Carotid Intraplaque Neovascularization and Future Vascular Events in Patients With Asymptomatic Carotid Stenosis

Article

Full-text available

Feb 2022

Objective: Intraplaque neovascularization is a marker of plaque vulnerability and is used to predict the risk of future vascular events in patients with symptomatic carotid stenosis; however, its association with asymptomatic carotid stenosis has not been prospectively evaluated. Therefore, this study aimed to explore the association between intraplaque neovascularization assessed using contrast-enhanced ultrasound and the occurrence of future ischemic events in asymptomatic patients diagnosed with carotid stenosis. Methods: We recruited patients with asymptomatic carotid stenosis from our center. Contrast-enhanced ultrasound was performed at baseline. The outcomes were ischemic stroke and cardiovascular events. We plotted Kaplan-Meier survival curves and performed a log-rank test to compare endpoint event probability in patients with and without grade 2 intraplaque neovascularization. Univariate and multivariate Cox proportional hazards models were used to assess predictors of future vascular events. Results: The data of 50 participants were included in the analysis (median follow-up, 43.7 months). Endpoint events occurred in 12 participants (24%). The Kaplan-Meier survival curves showed that patients with grade 2 intraplaque neovascularization had a higher probability of future vascular events than those with grades 0 and 1 (p < .05). Grade 2 intraplaque neovascularization (hazard ratio: 4.530, 95% confidence interval, 1.337–15.343, p < .05) was an independent predictor of future vascular events in patients with asymptomatic carotid stenosis. Conclusion: Grade 2 intraplaque neovascularization assessed using contrast-enhanced ultrasound independently predicted future ischemic events in patients with asymptomatic carotid stenosis, and contrast-enhanced ultrasound may be an effective screening method to identify high-risk subgroups of patients with asymptomatic carotid stenosis.

Relationship Between Serum Lipid Profiles and Carotid Intraplaque Neovascularization in a High–Stroke‐Risk Population: A Cross‐Sectional Study in China

Article

Full-text available

Nov 2021

Background Evidence of the association between serum lipid profiles and intraplaque neovascularization (IPN) is still limited. We aimed to study the value of a novel Doppler method, superb microvascular imaging, in correlating serum lipid profiles and evidence of IPN in a population with a high risk of stroke. Methods and Results A community‐based cross‐sectional study was conducted in Beijing, China. Residents (aged ≥40 years) underwent questionnaire interviews, physical examinations, and laboratory testing in 2018 and 2019. Subjects with a high risk of stroke were then selected. Standard carotid ultrasound and carotid plaque superb microvascular imaging examinations were then performed on the high–stroke‐risk participants. Logistic regression was used to evaluate the relationship between serum lipid profiles and carotid plaque IPN. Overall, a total of 250 individuals (mean age, 67.20±8.12 years; 66.4% men) met the study inclusion criteria. Superb microvascular imaging revealed carotid plaque IPN in 96 subjects (38.4%). Subjects with IPN were more likely to be current smokers (34.0% versus 46.9%, P =0.046), and their identified carotid plaques were much thicker (2.35±0.63 mm versus 2.75±0.80 mm, P =0.001). Serum lipids, including total cholesterol, non–high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol were positively associated with the presence of IPN (4.33±1.00 mmol/L versus 4.79±1.12 mmol/L, P =0.001; 2.96±0.92 mmol/L versus 3.40±1.01 mmol/L, P =0.001; 2.18±0.76 mmol/L versus 2.46±0.80 mmol/L, P =0.005, respectively), and after adjustment for other confounders, the positive relationship remained significant. Furthermore, non–high‐density lipoprotein cholesterol (odds ratio, 2.62 [95% CI, 1.35–5.06]) was significantly associated with the presence of carotid plaque IPN even after adjusting for low‐density lipoprotein cholesterol. Conclusions Total cholesterol, non–high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol were positively associated with the presence of carotid IPN in a Chinese high–stroke‐risk population. Further prospective studies should be conducted to better understand how much finding IPN adds to current stroke prediction tools.

Carotid intraplaque neovascularisation as a predictive factor for future vascular events in patients with mild and moderate carotid stenosis: an observational prospective study

Article

Full-text available

Jun 2021

Background Intraplaque neovascularisation (IPN) increases the vulnerability of plaques, which makes them more likely to rupture and increases the risk of vascular events. However, it is unclear whether IPN can predict future vascular events (stroke recurrence and cardiovascular events). Previous studies on IPN have focused on patients with severe stenosis but overlooked patients with mild and moderate stenosis. This study aimed to investigate whether IPN assessed by contrast-enhanced ultrasonography (CEUS) in patients with mild and moderate degrees of stenosis is associated with future vascular events. Methods One hundred and twenty-one patients participated in this study. 76 patients who met the inclusion and exclusion criteria were included in the final dataset of the study. IPN was graded from 0 to 2 according to the extent of the microbubbles assessed using CEUS. The degree of carotid stenosis was graded as mild, moderate, or severe. We recorded future vascular events during the follow-up. Univariate and multivariate logistic regression analyses were used to evaluate risk factors for future vascular events. Results After a follow-up period of 30 ± 6 months, 30 patients (39.5%) experienced subsequent vascular events. Compared with the ‘non-recurrent’ group, the ‘recurrent’ group showed a higher proportion of grade 2 neovascularisation ( p < 0.05), and it was an independent predictor of subsequent vascular events (odds ratio 6.066, 95% confidence interval 1.565–23.512, p < 0.05). Furthermore, in patients with mild and moderate stenosis, future vascular events occurred in an unexpectedly high proportion (up to 42.9%). In the ‘recurrent’ group, 55% of patients with mild and moderate stenosis had grade 2 neovascularisation. Conclusion IPN by CEUS was an independent predictor of future vascular events in patients with recent ischemic stroke, and the high proportion of neovascularisation in patients with mild and moderate stenosis requires more attention.

Carotid Atherosclerosis, Ultrasound and Lipoproteins

Article

Full-text available

May 2021

Carotid artery plaques are considered a measure of atherosclerosis and are associated with an increased risk of atherosclerotic cardiovascular disease, particularly ischemic strokes. Monitoring of patients with an elevated risk of stroke is critical in developing better prevention strategies. Non-invasive imaging allows us to directly see atherosclerosis in vessels and many features that are related to plaque vulnerability. A large body of evidence has demonstrated a strong correlation between some lipid parameters and carotid atherosclerosis. In this article, we review the relationship between lipids and atherosclerosis with a focus on carotid ultrasound, the most common method to estimate atherosclerotic load.

Ultrasound Methods in the Evaluation of Atherosclerosis: From Pathophysiology to Clinic

Article

Full-text available

Apr 2021

Atherosclerosis is a key pathological process that causes a plethora of pathologies, including coronary artery disease, peripheral artery disease, and ischemic stroke. The silent progression of the atherosclerotic disease prompts for new surveillance tools that can visualize, characterize, and provide a risk evaluation of the atherosclerotic plaque. Conventional ultrasound methods—bright (B)-mode US plus Doppler mode—provide a rapid, cost-efficient way to visualize an established plaque and give a rapid risk stratification of the patient through the Gray–Weale standardization—echolucent plaques with ≥50% stenosis have a significantly greater risk of ipsilateral stroke. Although rather disputed, the measurement of carotid intima-media thickness (C-IMT) may prove useful in identifying subclinical atherosclerosis. In addition, contrast-enhanced ultrasonography (CEUS) allows for a better image resolution and the visualization and quantification of plaque neovascularization, which has been correlated with future cardiovascular events. Newly emerging elastography techniques such as strain elastography and shear-wave elastography add a new dimension to this evaluation—the biomechanics of the arterial wall, which is altered in atherosclerosis. The invasive counterpart, intravascular ultrasound (IVUS), enables an individualized assessment of the anti-atherosclerotic therapies, as well as a direct risk assessment of these lesions through virtual histology IVUS.

The Role of Carotid and Femoral Plaque Burden in the Diagnosis of Coronary Artery Disease

Article

Full-text available

Aug 2020
Curr Cardiol Rep

With limitations of cardiovascular disease risk stratification by traditional risk factors, the role of noninvasive imaging techniques, such as vascular ultrasound, has emerged as a prominent utility for decision-making in coronary artery disease. A review of current guidelines and contemporary approaches for carotid and femoral plaque assessment is needed to better inform the diagnosis, management, and treatment of atherosclerosis in clinical practice. The recent consensus-based guidelines for carotid plaque assessment in coronary artery disease have been established, supported by some outcomes-based research. Currently, there is a gap of evidence on the use of femoral ultrasound to detect atherosclerosis, as well as predict adverse cardiovascular outcomes. The quantification and characterization of individualized plaque burden are important to stratify risk in asymptomatic or symptomatic atherosclerosis patients. Standardized quantification guidelines, supported by further outcomes-based research, are required to assess disease severity and progression.

Ultrasound detection of cerebral microembolism in carotid stenoses: progress and perspective (A review of the literature)

Article

Full-text available

Jul 2020

M.V. Globa

The review summarizes available information regarding the method of Transcranial doppler sonography (TCD) usage to record microembolism in patients with carotid artery stenosis, search for information was carried out in literature 1997–2020 (PUBMED, MEDLINE). History overview of TCD with embolodetection implementation is presented, as well as ways of its technical and methodological improvement. Evidence-based studies of the method clinical relevance in atherosclerotic carotid stenoses and their surgical treatment are outlined. Observation results of the intraoperative cerebral embolization during carotid endarterectomy and carotid artery stenting are presented along with comparison of TCD-embolodetection data, neuroimaging and clinical outcomes. Individual centres and multicenter study ACES data on prognostic value of registration of embolic signals in asymptomatic carotid stenosis, risk assessment of vascular events in diffe-rent groups of patients and in varying degrees of stenosis of the vessel lumen was analyzed. The role of embolodetection in predicting repeated cerebrovascular disorders in symptomatic carotid stenosis and its importance for monitoring antiplatelet therapy is set out (multicenter study CARESS). The evidence of the reliability of TCD embolodetection as tool for verificarion of at-risk patients with carotid stenosis who may benefit ftom surgical treatment is presented. Recent advances in ultrasound and other imaging techniques for assessing unstable plague are outlined along with prospects for the use of TCD monitoting for cerebrovascular disorders forecasting.

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

Article

Full-text available

Feb 2021

A significant portion of ischemic stroke is on account of emboli caused by fibrous cap rupture of vulnerable plaque with intraplaque neovascularization as a significant triggering factor to plaque vulnerability. Contrast-enhanced ultrasound (CEUS) could offer detailed information on plaque surface and intraplaque microvascular. This study aims to comprehensively assess the value of CEUS for the detection of plaque rupture and neovascularization in histologically verified plaques that had been removed from the patients who had undergone carotid endarterectomy (CEA). Fifty-one consecutive subjects (mean age, 67.0 ± 6.5 years; 43 [84.3%] men) scheduled for CEA were recruited. Standard ultrasound and CEUS were performed prior to surgery. Based on the direction of the contrast agents that diffuse within the plaques, plaques were divided as “inside-out” direction (contrast agents diffuse from the artery lumen towards the inside of the plaque) and non-inside-out direction. Plaque enhancement was assessed by using a semi-quantitative grading scale (grade 1: no enhancement; grade 2: moderate enhancement; grade 3: extensive enhancement). Plaques were evaluated for histopathologic characteristics according to Oxford Plaque Study (OPS) standard postoperative. Intraplaque neovascularization as manifested by the appearance of CD34-positive microvessels was characterized in terms of microvessel density (MVD), microvessel area (MVA), and microvessel shape (MVS). In 51 plaques, the sensitivity, specificity, positive, and negative predictive values of contrast agent inside-out direction diffusion for the detection of plaque fibrous cap rupture were 87.5%, 92.6%, 91.3%, and 89.3%, respectively. The incidence of cap rupture was significantly higher in contrast agent inside-out direction diffusion than non-inside-out direction diffusion (73.9% vs 25.0%, p < 0.001), and inside-out direction diffusion did exhibit higher frequency of vulnerable plaques (OPS grades 3–4) (95.7% vs 53.6%, p = 0.001). Multivariate logistic regression analysis revealed the contrast agent inside-out direction diffusion as an independent correlate to plaque rupture (OR 8.5, 95% CI 2.4–30.1, p = 0.001). With increasing plaque enhancement, plaque MVD (p < 0.001), plaque MVA (p = 0.012), and percentage of highly irregular-shaped microvessels increased (p < 0.001). Contrast agent inside-out direction diffusion could indicate plaque rupture. The increase in plaque enhancement paralleled increased, larger, and more irregular-shaped microvessels, which may suggest an increased risk of plaque vulnerability.

Use of Ultrasound in the Diagnosis and Management of the Vasculitides

Article

Full-text available

Jun 2020
Curr Rheumatol Rep

Purpose of review: The aim of this review paper is to evaluate the current data regarding clinical use of ultrasound (US) for diagnosis of systemic vasculitis. Recent findings: In recent years, US has emerged as an image modality taking a central role in the diagnosis and monitoring of vasculitides by measuring vessel wall inflammation and changes in vessel wall thickness. US has been recognized as an important tool predominantly in the diagnosis of large vessel vasculitis (LVV). Signs like the "halo sign" in temporal arteries of patients with giant cell arteritis (GCA) have demonstrated to be a robust marker. In other types of vasculitides the role of US is not well defined yet but could be of help by diagnosing secondary findings when there is organ involvement, like interstitial lung disease in small vessel vasculitis (SVV). Different modes of ultrasound (US) are being studied for this purpose, especially since it is a non-invasive technique that can limit exposure to ionizing radiation. In conclusion there is clear evidence for the use of US particularly color duplex US (CDS) in the diagnosis of LVV like GCA and Takayasu's arteritis (TAK). Nevertheless, there is urgent need for more data in regard to the use of US in small/medium vessel vasculitis, as well as the role of US in monitoring of patients with LVV.

Assessment of neovascularization in atherosclerotic carotid sinus plaques using quantitative contrast-enhanced ultrasound perfusion imaging

Article

Full-text available

Jun 2020

Aim. To assess the prospects of using quantitative contrast-enhanced ultrasound perfusion imaging of atherosclerotic carotid sinus plaques.Material and methods. The study included 5 men and 1 woman (59-76 years old, median 72) with symptomatic coronary sinus atherosclerosis. The inclusion criterion was history of ischemic stroke due to internal carotid artery lesion (NASCET >60%). We performed contrast-enhanced ultrasound perfusion imaging of the carotid arteries, endarterectomy, studying pathomorphology of the removed plaque with the calculation of the neovascular density and the total number of neovessels with a diameter <40 μm. Neovascularization was assessed by quantitative contrast-enhanced ultrasound 20 seconds after the 1 ml infusion of Sonovia (Bracco, Italy) and subsequent application of the flash. The analysis of dynamics of ultrasonic signal intensity in the atherosclerotic plaque was carried out by creating the curves of the ultrasonic signal intensity (dB)/time (s) over 3 segments of the cross section of the internal carotid artery long axis. The automatic calculation of the intensity dynamics took into account the parameter values in the studied areas within 20 s after the flash. The calculated coefficients (A, B, β) of the exponential equation for 3 atherosclerotic segments were recorded.Results. Perfusion and neovascularization were assessed in 27 segments of atherosclerotic plaques. The correlation relationships between the ultrasonic parameters of plaque perfusion and the severity of neovascularization were assessed according to the histological data. Significant correlations of the exponential curve coefficient β and histological parameters characterizing the prevalence of “young” vessels (<40 microns) in the atherosclerotic plaque were revealed. Spearman’s R for the density of neovessels was 0,54; for the number of neovessels with a diameter <40 μm. —0,66 (p<0,01).Conclusion. Diagnosis of atherosclerotic plaque neovascularization becomes possible to quantify, assessing not only the presence of neovascular vessels, but also the perfusion intensity. The novel approach replaces the qualitative and semi-quantitative method for calculating the number of carotid plaques neovessels in vivo.

Risk Factors of Large Artery Atherosclerotic Ischemic Stroke Based on Carotid Contrast-Enhanced Ultrasonography

Preprint

Full-text available

Apr 2020

Background Ischemic stroke is a serious public health issue with a continuously increasing incidence worldwide. This study explores the risk factors of large artery atherosclerotic (LAA) ischemic stroke based on carotid contrast-enhanced ultrasonography (CEUS). Methods A total of 110 patients with LAA ischemic stroke and 34 patients without stroke were included. All participants underwent standard ultrasonography and CEUS, from which carotid artery plaque characteristics were obtained. The predicted performance of artery plaques was evaluated using the area under the receiver operating characteristics (ROC) curve and sensitivity and specificity at the optimal cut-off point. Results Subjects with LAA ischemic stroke were more likely to have a history of hypertension than the control group (P = 0.009). The area under the ROC curve (AUROC) for plaque echogenicity was 0.609 (95% CI, 0.524–0.689). With a cut-off value of ≤ class II (echolucent or predominantly hypoechogenic plaque), the sensitivity and specificity were 84.55% and 32.35%, respectively. The AUROC for plaque thickness was 0.676 (95% CI, 0.593–0.751). With a cut-off value of > 2.4 mm, the sensitivity and specificity were 41.82% and 88.24%, respectively. The AUROC for intraplaque neovascularization was 0.807 (95% CI, 0.733–0.868). With a cut-off value of > grade 2 (extensive appearance of bubbles within plaque), the sensitivity and specificity were 70.91% and 82.35%, respectively. Conclusions Hypertension, echolucent (or predominantly hypoechogenic) plaque, plaque thickness, and degree of intraplaque neovascularization are significantly relevant to LAA ischemic stroke in adults. These results may be helpful for clinical prediction of ischemic stroke risk.

Novel approaches to assessing the signs of atherosclerotic plaque instability in the carotid arteries

Article

Full-text available

May 2017

Introduction. Application of contrast agents in vascular untrasonography has become a new direction in noninvasive assessment of signs of atherosclerotic plaque (ASP) instability; the type of plaque neovascularization being the major sign. However, questions regarding the accuracy of the methods for quantitative evaluation of plaque neovascularization are still to be answered. Objective. To evaluate signs of ASP instability in the carotid arteries according to the contrast-enhanced duplex scanning data and to elaborate our own approach to quantitative evaluation of neovascularization. Materials and methods. Twenty-six patients with carotid atherosclerosis who had been subjected to carotid endarterectomy (n=27) followed by morphological plaque verification were enrolled in this study. All patients underwent standard duplex scanning and scanning using contrast agent SonoVue. Results. Neovascularization was revealed in all 27 patients with ASP according to the pathomorphological and contrast-enhanced ultrasonography data. The total number of vessels per cm2 of plaque was 651 [2114/cm2] according to the ultrasonography data and 191224 [236249/cm2] according to the pathomorphological examination. According to the ultrasonography data, the absolute values were close to the density of plaque vessels 30 m in diameter determined during pathomorphological examination and did not differ significantly from this value (p = 0.67). The morphology data show that vessels 20 m in diameter, which constituted up to 96% of all microvessels in ASP, cannot be detected by ultrasonography. In one case, ulceration of the ASP surface was detected only by contrast medium injection. Calcified plaques with different degrees of calcination imposed the greatest difficulties when performing ultrasonic assessment of neovascularization. Conclusions. Contrast-enhanced untrasonography can be used as an informative method to noninvasively detect signs of ASP instability enabling rather accurate assessment of neovascularization at microvessel diameter 30 m. Calcification of ASPs may significantly affect the study results.

Novel approaches to assessing the signs of atherosclerotic plaque instability in the carotid arteries

Article

Full-text available

May 2017

Introduction. Application of contrast agents in vascular untrasonography has become a new direction in noninvasive assessment of signs of atherosclerotic plaque (ASP) instability; the type of plaque neovascularization being the major sign. However, questions regarding the accuracy of the methods for quantitative evaluation of plaque neovascularization are still to be answered. Objective. To evaluate signs of ASP instability in the carotid arteries according to the contrast-enhanced duplex scanning data and to elaborate our own approach to quantitative evaluation of neovascularization. Materials and methods. Twenty-six patients with carotid atherosclerosis who had been subjected to carotid endarterectomy (n=27) followed by morphological plaque verification were enrolled in this study. All patients underwent standard duplex scanning and scanning using contrast agent SonoVue. Results. Neovascularization was revealed in all 27 patients with ASP according to the pathomorphological and contrast-enhanced ultrasonography data. The total number of vessels per cm2 of plaque was 651 [2114/cm2] according to the ultrasonography data and 191224 [236249/cm2] according to the pathomorphological examination. According to the ultrasonography data, the absolute values were close to the density of plaque vessels 30 m in diameter determined during pathomorphological examination and did not differ significantly from this value (p = 0.67). The morphology data show that vessels 20 m in diameter, which constituted up to 96% of all microvessels in ASP, cannot be detected by ultrasonography. In one case, ulceration of the ASP surface was detected only by contrast medium injection. Calcified plaques with different degrees of calcination imposed the greatest difficulties when performing ultrasonic assessment of neovascularization. Conclusions. Contrast-enhanced untrasonography can be used as an informative method to noninvasively detect signs of ASP instability enabling rather accurate assessment of neovascularization at microvessel diameter 30 m. Calcification of ASPs may significantly affect the study results.

Progress of Ultrasound Techniques in the Evaluation of Carotid Vulnerable Plaque Neovascularization

Article

Oct 2023

Background: The rupture and detachment of unstable plaques in the carotid artery can cause embolism in the cerebral artery, leading to acute cerebrovascular events. Intraplaque neovascularization (IPN) is a very important contributor to carotid plaque instability, and its evolution plays a key role in determining the outcome of vulnerable plaques. Ultrasound techniques, represented by contrast-enhanced ultrasound and superb microvascular imaging, are reported to be non-invasive, rapid and effective techniques for the semi-quantitative or quantitative evaluation for IPN. Although ultrasound techniques have been widely applied in the detection of carotid plaque stability, it has been limited owing to the lack of unified IPN quantitative standards. Summary: This review summarizes the application and semi-quantitative/quantitative diagnostic standards of ultrasound techniques in evaluating IPN, and looks forward to the prospects of the future research. With the development of novel techniques like artificial intelligence, ultrasound will offer appropriate selections for achieving more accuracy diagnosis. Key messages: A large number of studies have used contrast-enhanced ultrasound and superb microvascular imaging to detect IPN and perform semi-quantitative grading to predict the occurrence of diseases such as stroke, and to accurately assess drug efficacy based on rating changes. These studies have made great progress at this stage, but more accurate and intelligent quantitative imaging methods should become the future development goal.

Comparison of Cardiovascular Disease Risk Factors Between 2 Subclinical Atherosclerosis Measures in Healthy Postmenopausal Women: Carotid Artery Wall Thickness and Echogenicity

Article

Apr 2022

Objectives: Although carotid artery intima media thickness (CIMT) is a widely used determinant of subclinical atherosclerosis, gray-scale median of the intima-media complex (IM-GSM) of the common carotid artery is a relatively novel measure of echogenicity reflecting composition of the arterial wall. It is important to compare cardiovascular disease (CVD) risk factor correlates across CIMT and IM-GSM to determine whether these measures reflect distinct aspects of atherosclerosis. Methods: Baseline information from a completed randomized clinical trial of 643 healthy postmenopausal women without clinically apparent CVD was included in this cross-sectional study. The women were on average ± SD 61 ± 7 years old, and predominantly non-Hispanic White. CIMT and IM-GSM were measured by high-resolution B-mode ultrasonogram in the far wall of the right common carotid artery. CVD risk factors including age, race, body mass index (BMI), smoking, weekly hours of physical activity, systolic (SBP) and diastolic blood pressure (DBP), lipids, glucose, and inflammatory markers were measured at baseline. Linear regression models were used to assess associations of CVD risk factors with CIMT and IM-GSM. Multivariable models included groups of risk factors added one at a time with and withoutbasic demographic factors (age, race, BMI, physical activity) with model R2 values compared between CIMT and IM-GSM. Results: In multivariable analysis, age, Black race, BMI, SBP, and DBP were associated with CIMT (all P < .05), whereas age, Hispanic race, BMI, SBP, physical activity, LDL-cholesterol, and leptin were correlates of IM-GSM (all P < .05). Adjusted for age, race, BMI, and physical activity, the R2 value for SBP was greater for CIMT association, whereas R2 values for lipids, glucose, inflammatory markers, and adipokines were greater for IM-GSM associations. Conclusions: CIMT and IM-GSM assess different attributes of subclinical atherosclerosis. Integrating both measures may provide improved assessment of atherosclerosis in asymptomatic individuals.

The clinical application of ultrasonography with superb microvascular imaging‐a review

Article

Mar 2022

Superb microvascular imaging (SMI) is among the latest doppler ultrasound methods. It uses an advanced clutter filter to eliminate artifacts caused by breathing, movement and retains the low‐speed blood signals in microvessels. The great advantage of SMI is that it can intuitively detect very slow blood signals in microvessels, providing clinicians with more significant information about flow distribution in the target area. Therefore, it is speculated that SMI has important application value. The purpose of this article is to outline the application of SMI in different parts of the body. Superb microvascular imaging (SMI) as the latest Doppler ultrasound method uses an advanced clutter filter to eliminate artifacts caused by breathing, movement and so on and retains the low‐speed blood signals in microvessels. This review offers the application of SMI in various clinical filed.

Blood-Based and Imaging Biomarkers of Atherosclerosis

Article

Jan 2022
Cardiol Rev

Atherosclerosis is the main cause of arterial thrombosis, causing acute occlusive cardiovascular syndromes. Numerous risk prediction models have been developed, that mathematically combine multiple predictors, to estimate the risk of developing cardiovascular events. Current risk models typically do not include information from biomarkers that can potentially improve these existing prediction models especially if they are pathophysiologically relevant. Numerous cardiovascular disease biomarkers have been investigated that have focused on known pathophysiological pathways including those related to cardiac stress, inflammation, matrix remodelling and endothelial dysfunction. Imaging biomarkers have also been studied that have yielded promising results with a potential higher degree of clinical applicability in detection of atherosclerosis and cardiovascular event prediction. To further improve therapy decision-making and guidance, there is continuing intense research on emerging biologically relevant biomarkers. As the pathogenesis of cardiovascular disease is multifactorial, improvements in discrimination and reclassification in risk prediction models will likely involve multiple biomarkers. This article will provide an overview of the literature on potential blood-based and imaging biomarkers of atherosclerosis studied so far, as well as potential future directions.

Studying the Factors of Human Carotid Atherosclerotic Plaque Rupture, by Calculating Stress/Strain in the Plaque, Based on CEUS Images: A Numerical Study

Article

Full-text available

Nov 2020

Carotid plaque neovascularization is one of the major factors for the classification of vulnerable plaque, but the axial force effects of the pulsatile blood flow on the plaque with neovessel and intraplaque hemorrhage was unclear. Together with the severity of stenosis, the fibrous cap thickness, large lipid core, and the neovascularization followed by intraplaque hemorrhage (IPH) have been regarded as high-risk features of plaque rupture. In this work, the effects of these factors were evaluated on the progression and rupture of the carotid atherosclerotic plaques. Five geometries of carotid artery plaque were developed based on contrast-enhanced ultrasound (CEUS) images, which contain two types of neovessel and IPH, and geometry without neovessel and IPH. A one-way fluid-structure interaction model was applied to compute the maximum principal stress and strain in the plaque. For that hyper-elastic and non-linear material, Yeoh 3rd Order strain energy density function was used for components of the plaque. The simulation results indicated that the maximum principal stress of plaque in the carotid artery was higher when the degree of the luminal stenosis increased and the thickness of the fibrous cap decreased. The neovessels within the plaque could introduce a 2.5% increments of deformation in the plaque under the pulsatile blood flow pressure. The IPH also contributed to the increased risk of plaque rupture that a gain of stress was 8.983, 14.526, and 34.47 kPa for the plaque with 50, 65, and 75%, respectively, when comparing stress in the plaque with IPH distributed at the middle to the shoulder of the plaque. In conclusion, neovascularization in the plaque could reduce the stability of the plaque by increasing the stress within the plaque. Also, the risk of plaque rupture increased when large luminal stenosis, thin fibrous cap, and IPH were observed.

Advanced imaging in the diagnosis of cardiovascular diseases: The “ongoing” future

Article

Full-text available

Aug 2020

Luca Saba

Use of Contrast-Enhanced Ultrasound for Detecting the Disease Activity of the Carotid Artery in Takayasu Arteritis

Article

Sep 2020

Objective: To investigate whether contrast-enhanced ultrasound (CEUS) is helpful for assessing the disease activity of Takayasu arteritis (TA).Methods: Eighty-four patients with TA were examined with ultrasound (US) and CEUS. Intima-media thickness (IMT) of both sides of the common carotid artery was measured for each patient. Semiquantitative analyses of contrast enhancement within the arterial wall were performed with a visual interpretation scale. Disease activity was determined by one experienced physician based on Physician Global Assessment criteria.Results: Carotid CEUS revealed that 6 arteries showed no enhancement (7.1%, 6/84) while 78 arteries showed homogeneous enhancement within the thickened wall (92.9%, 78/84). Grade 1 enhancement was noted in 40 patients, and grade 2 in 38 patients. IMT of the active group was significantly thicker than that of the inactive group (2.4 ± 0.9 mm vs. 1.8 ± 0.5 mm, P = 0.001) on B-mode US, and slightly correlated with ESR (r = 0.344, P < 0.05) and CRP (r = 0.261, P < 0.05). Grade 2 enhancement was observed more in the active patients (61.7% vs. 41.3%, P = 0.001) on CEUS.Conclusions: CEUS is a convenient and non-invasive imaging modality that is useful for evaluating disease activity in TA patients by assessing the vascularization within the carotid wall.

B-flow ultrasound imaging of intraplaque blood flow in patients with carotid artery stenosis

Article

Jan 2020

Purpose: Intraplaque neovascularization is reportedly associated with plaque progression and instability. We aimed to determine whether intraplaque blood flow (IPBF) could be visualized without contrast medium using B-flow ultrasound imaging, and to evaluate the relationship between IPBF and ultrasound findings or clinical significance. Methods: We investigated IPBF in 66 carotid arteries with ≥ 30% area stenosis using B-mode ultrasound imaging with a Logiq s8 ultrasound system (GE) and a linear probe (9L). We assessed characteristics such as signal intensity and plaque uniformity, as well as their relationships with IPBF. Results: We visualized IPBF in 20 funicular and linear lesions with either a straight or a tortuous course. Among them, IPBF was connected with the outside of the vessel in 4 lesions, with the vascular lumen in 4 lesions, and with both sides in 9 lesions. Twenty lesions with IPBF had hypoechoic and heterogeneous plaques more frequently than 46 lesions without IPBF. Lesions with IPBF were symptomatic relatively compared with those without IPBF. Conclusion: B-flow ultrasound imaging could detect IPBF without contrast medium. IPBF was observed more frequently in hypoechoic and heterogeneous plaques, and lesions with IPBF were symptomatic relatively, therefore seemed to indicate plaque instability.

Carotid Artery Stenosis: Gray-Scale and Doppler US Diagnosis - Society of Radiologists in Ultrasound Consensus Conference

Article

Full-text available

Nov 2003

The Society of Radiologists in Ultrasound convened a multidisciplinary panel of experts in the field of vascular ultrasonography (US) to come to a consensus regarding Doppler US for assistance in the diagnosis of carotid artery stenosis. The panel's consensus statement is believed to represent a reasonable position on the basis of analysis of available literature and panelists' experience. Key elements of the statement include the following: (a) All internal carotid artery (ICA) examinations should be performed with gray-scale, color Doppler, and spectral Doppler US. (b) The degree of stenosis determined at gray-scale and Doppler US should be stratified into the categories of normal (no stenosis), <50% stenosis, 50%-69% stenosis, > or =70% stenosis to near occlusion, near occlusion, and total occlusion. (c) ICA peak systolic velocity (PSV) and presence of plaque on gray-scale and/or color Doppler images are primarily used in diagnosis and grading of ICA stenosis; two additional parameters, ICA-to-common carotid artery PSV ratio and ICA end-diastolic velocity may also be used when clinical or technical factors raise concern that ICA PSV may not be representative of the extent of disease. (d) ICA should be diagnosed as (i) normal when ICA PSV is less than 125 cm/sec and no plaque or intimal thickening is visible; (ii) <50% stenosis when ICA PSV is less than 125 cm/sec and plaque or intimal thickening is visible; (iii) 50%-69% stenosis when ICA PSV is 125-230 cm/sec and plaque is visible; (iv) > or =70% stenosis to near occlusion when ICA PSV is greater than 230 cm/sec and visible plaque and lumen narrowing are seen; (v) near occlusion when there is a markedly narrowed lumen at color Doppler US; and (vi) total occlusion when there is no detectable patent lumen at gray-scale US and no flow at spectral, power, and color Doppler US. (e) The final report should discuss velocity measurements and gray-scale and color Doppler findings. Study limitations should be noted when they exist. The conclusion should state an estimated degree of ICA stenosis as reflected in the above categories. The panel also considered various technical aspects of carotid US and methods for quality assessment and identified several important unanswered questions meriting future research.

18FDG PET and Ultrasound Echolucency in Carotid Artery Plaques

Article

Full-text available

Mar 2010

The objective was to evaluate inflammation in echolucent carotid artery plaques. Ultrasound echolucency of carotid artery plaques has been proven to differentiate patients at high risk of stroke. On the other hand, positron emission tomography (PET) of plaques with the use of [(18)F]-fluorodeoxyglucose (FDG) identifies highly inflamed plaques, and the combination of molecular imaging and morphology could improve identification of vulnerable plaques. A total of 33 patients with cerebrovascular symptoms and carotid artery plaques were included prospectively for ultrasound and PET imaging. Plaque standardized gray scale medians (GSM) were measured in longitudinal ultrasound images to quantitate echolucency, and GSM values were compared with FDG PET uptake quantified by maximum standardized uptake values (SUV). Symptomatic plaques were compared with contralateral carotid artery plaques considered asymptomatic, and in 17 symptomatic patients, endarterectomized plaque specimens were analyzed for CD68 expression. There was a negative correlation between GSM and FDG SUV (r = -0.56, p < 0.01). Whereas echo-rich plaques tended to show low FDG uptake, echolucent plaques ranged from high to low inflammatory activity, as depicted with PET. Quantitative FDG SUV differentiated asymptomatic from symptomatic plaques, whereas GSM values did not. There was a positive correlation between CD68 expression and FDG uptake (r = 0.50, p = 0.04). Our results substantiate previous findings of an association between plaque FDG uptake and inflammation. Echolucent plaques exhibit a wide range of inflammatory activity, whereas echorich plaques show little inflammation. FDG PET may be useful for further stratification of echolucent plaques being either active (vulnerable) or inactive.

Prevention of Disabling and Fatal Strokes by successful Carotid Endarterectomy in Patients without recent neurological Symptoms: Randomised Controlled Trial

Article

Full-text available

Jun 2004
LANCET

Among patients with substantial carotid artery narrowing but no recent neurological symptom (stroke or transient ischaemia), the balance of surgical risks and long-term benefits from carotid endarterectomy (CEA) was unclear. During 1993-2003, 3120 asymptomatic patients with substantial carotid narrowing were randomised equally between immediate CEA (half got CEA by 1 month, 88% by 1 year) and indefinite deferral of any CEA (only 4% per year got CEA) and were followed for up to 5 years (mean 3.4 years). Kaplan-Meier analyses of 5-year risks are by allocated treatment. The risk of stroke or death within 30 days of CEA was 3.1% (95% CI 2.3-4.1). Comparing all patients allocated immediate CEA versus all allocated deferral, but excluding such perioperative events, the 5-year stroke risks were 3.8% versus 11% (gain 7.2% [95% CI 5.0-9.4], p<0.0001). This gain chiefly involved carotid territory ischaemic strokes (2.7% vs 9.5%; gain 6.8% [4.8-8.8], p<0.0001), of which half were disabling or fatal (1.6% vs 5.3%; gain 3.7% [2.1-5.2], p<0.0001), as were half the perioperative strokes. Combining the perioperative events and the non-perioperative strokes, net 5-year risks were 6.4% versus 11.8% for all strokes (net gain 5.4% [3.0-7.8], p<0.0001), 3.5% versus 6.1% for fatal or disabling strokes (net gain 2.5% [0.8-4.3], p=0.004), and 2.1% versus 4.2% just for fatal strokes (net gain 2.1% [0.6-3.6], p=0.006). Subgroup-specific analyses found no significant heterogeneity in the perioperative hazards or (apart from the importance of cholesterol) in the long-term postoperative benefits. These benefits were separately significant for males and females; for those with about 70%, 80%, and 90% carotid artery narrowing on ultrasound; and for those younger than 65 and 65-74 years of age (though not for older patients, half of whom die within 5 years from unrelated causes). Full compliance with allocation to immediate CEA or deferral would, in expectation, have produced slightly bigger differences in the numbers operated on, and hence in the net 5-year benefits. The 10-year benefits are not yet known. In asymptomatic patients younger than 75 years of age with carotid diameter reduction about 70% or more on ultrasound (many of whom were on aspirin, antihypertensive, and, in recent years, statin therapy), immediate CEA halved the net 5-year stroke risk from about 12% to about 6% (including the 3% perioperative hazard). Half this 5-year benefit involved disabling or fatal strokes. But, outside trials, inappropriate selection of patients or poor surgery could obviate such benefits.

Mannheim Intima-Media Thickness Consensus

Article

Full-text available

Dec 2004

Intima-media thickness (IMT) is increasingly used in clinical trials as a surrogate end point for determining the success of interventions that lower risk factors for atherosclerosis. The necessity for unified criteria to distinguish early atherosclerotic plaque formation from thickening of IMT and to standardize IMT measurements is addressed in this consensus statement. Plaque is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness of > or =1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. Standard use of IMT measurements is recommended in all epidemiological and interventional trials dealing with vascular diseases to improve characterization of the population investigated. The consensus concludes that there is no need to 'treat IMT values' nor to monitor IMT values in individual patients apart from few exceptions. Although IMT has been suggested to represent an important risk marker, it does not fulfill the characteristics of an accepted risk factor. Standardized methods recommended in this consensus statement will foster homogenous data collection and analysis. This will help to improve the power of studies incorporating IMT measurements and to facilitate the merging of large databases for meta-analyses.

Contrast-enhanced ultrasound imaging of atherosclerotic carotid plaque neovascularisation: A new surrogate marker of atherosclerosis?

Article

Full-text available

Dec 2007

An atherosclerotic plaque requires a nutrient blood supply, which is predominantly derived from arterial vasa vasorum. A variety of factors (environmental and genetic) contribute to the initiation and growth of atherosclerosis within vessel walls. Chemotactic factors, such as tissue ischemic and hypoxic factors, stimulate the release of vascular endothelial growth factor (VEGF) proteins, resulting in vessel wall angiogenesis. These developments often precede the formation of the luminal plaque. In this report, we describe the use of contrast-enhanced carotid ultrasound (CECU) imaging for the detection and quantification of intra-plaque neovascularization. The efficacy of CECU was measured against the neovascular density observed within the tissue specimens obtained at the time of carotid endarterectomy surgery. The objective of this study was to provide a histologic correlation between CECU and carotid artery atherosclerotic plaque neovascularization. Fifteen patients with significant atherosclerotic carotid artery disease received a CECU examination prior to undergoing a carotid endarterectomy (CEA). Two patients received bilateral endarterectomies, resulting in a total of 17 cases. At the time of surgery, carotid plaque samples were surgically removed and stained with specific vascular markers (CD31, CD34, von Willebrand factor, and hemosiderin) designed to identify the presence and degree of neovascularization. The intra-plaque neovascularization recorded on preoperative CECU was correlated with the degree of neovascularization noted in the tissue specimens. The CECU neovascularization was correlated to CD31-stained tissue specimens. This correlation value was 0.68 using Spearman's rank method. When CECU results were correlated with the other histologic markers (CD34, von Willebrand factor, and hemosiderin), a correlation of 0.50 was obtained. In conclusion, contrast-enhanced carotid ultrasound correlated to the presence and degree of intra-plaque neovascularization as determined from histology specimens.

Hypoxia, Hypoxia-Inducible Transcription Factor, and Macrophages in Human Atherosclerotic Plaques Are Correlated With Intraplaque Angiogenesis

Article

Full-text available

May 2008

We sought to examine the presence of hypoxia in human carotid atherosclerosis and its association with hypoxia-inducible transcription factor (HIF) and intraplaque angiogenesis. Atherosclerotic plaques develop intraplaque angiogenesis, which is a typical feature of hypoxic tissue and expression of HIF. To examine the presence of hypoxia in atherosclerotic plaques, the hypoxia marker pimonidazole was infused before carotid endarterectomy in 7 symptomatic patients. Also, the messenger ribonucleic acid (mRNA) and protein expression of HIF1 alpha, HIF2 alpha, HIF-responsive genes (vascular endothelial growth factor [VEGF], glucose transporter [GLUT]1, GLUT3, hexokinase [HK]1, and HK2), and microvessel density were determined in a larger series of nondiseased and atherosclerotic carotid arteries with microarray, quantitative reverse transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry. Pimonidazole immunohistochemistry demonstrated the presence of hypoxia, especially within the macrophage-rich center of the lesions. Hypoxia correlated with the presence of a thrombus, angiogenesis, and expression of CD68, HIF, and VEGF. The mRNA and protein expression of HIF, its target genes, and microvessel density increased from early to stable lesions, but no changes were observed between stable and ruptured lesions. This is the first study directly demonstrating hypoxia in advanced human atherosclerosis and its correlation with the presence of macrophages and the expression of HIF and VEGF. Also, the HIF pathway was associated with lesion progression and angiogenesis, suggesting its involvement in the response to hypoxia and the regulation of human intraplaque angiogenesis.

Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis The North American Symptomatic Carotid Endarterectomy Trial Collaborators N Engl J Med 1991 325 445 453 10.1056/NEJM199108153250701

Article

Aug 1991
NEW ENGL J MED

Background. Without strong evidence of benefit, the use of carotid endarterectomy for prophylaxis against stroke rose dramatically until the mid-1980s, then declined. Our investigation sought to determine whether carotid endarterectomy reduces the risk of stroke among patients with a recent adverse cerebrovascular event and ipsilateral carotid stenosis. Methods. We conducted a randomized trial at 50 clinical centers throughout the United States and Canada, in patients in two predetermined strata based on the severity of carotid stenosis—30 to 69 percent and 70 to 99 percent. We report here the results in the 659 patients in the latter stratum, who had had a hemispheric or retinal transient ischemic attack or a nondisabling stroke within the 120 days before entry and had stenosis of 70 to 99 percent in the symptomatic carotid artery. All patients received optimal medical care, including antiplatelet therapy. Those assigned to surgical treatment underwent carotid endarterectomy performed by neurosurgeons or vascular surgeons. All patients were examined by neurologists 1, 3, 6, 9, and 12 months after entry and then every 4 months. End points were assessed by blinded, independent case review. No patient was lost to follow-up. Results. Life-table estimates of the cumulative risk of any ipsilateral stroke at two years were 26 percent in the 331 medical patients and 9 percent in the 328 surgical patients—an absolute risk reduction (±SE) of 17±3.5 percent (P<0.001). For a major or fatal ipsilateral stroke, the corresponding estimates were 13.1 percent and 2.5 percent — an absolute risk reduction of 10.6±2.6 percent (P<0.001 ). Carotid endarterectomy was still found to be beneficial when all strokes and deaths were included in the analysis (P<0.001). Conclusions. Carotid endarterectomy is highly beneficial to patients with recent hemispheric and retinal transient ischemic attacks or nondisabling strokes and ipsilateral high-grade stenosis (70 to 99 percent) of the internal carotid artery. (N Engl J Med 1991; 325:445–53.)

Contrast-Enhanced Ultrasound Imaging of Intraplaque Neovascularization in Carotid Arteries. Correlation With Histology and Plaque Echogenicity

Article

Jul 2008

This study was designed to evaluate contrast-enhanced ultrasound imaging of carotid atherosclerosis as a clinical tool to study intraplaque neovascularization. Plaque neovascularization is associated with plaque vulnerability and symptomatic disease; therefore, imaging of neovascularization in carotid atherosclerosis may represent a useful tool for clinical risk stratification and monitoring the efficacy of antiatherosclerotic therapies. Thirty-two patients with 52 carotid plaques were studied by standard and contrast-enhanced ultrasound imaging. In 17 of these patients who underwent endarterectomy, the surgical specimen was available for histological determination of microvessel density by CD31/CD34 double staining. Plaque echogenicity and degree of stenosis at standard ultrasound imaging were evaluated for each lesion. Contrast-agent enhancement within the plaque was categorized as absent/peripheral (grade 1) and extensive/internal (grade 2). In the surgical subgroup, plaques with higher contrast-agent enhancement showed a greater neovascularization at histology (grade 2 vs. grade 1 contrast-agent enhancement: median vasa vasorum density: 3.24/mm(2) vs. 1.82/mm(2), respectively, p = 0.005). In the whole series of 52 lesions, echolucent plaques showed a higher degree of contrast-agent enhancement (p < 0.001). Stenosis degree was not associated with neovascularization at histology or with the grade of contrast-agent enhancement. Carotid plaque contrast-agent enhancement with sonographic agents correlates with histological density of neovessels and is associated with plaque echolucency, a well-accepted marker of high risk lesions, but it is unrelated to the degree of stenosis. Contrast-enhanced carotid ultrasound imaging may provide valuable information for plaque risk stratification and for assessing the response to antiatherosclerotic therapies, beyond that provided by standard ultrasound imaging.

Management of atherosclerotic carotid artery disease: Clinical practice guidelines of the Society for Vascular Surgery

Article

Aug 2008

The Society for Vascular Surgery (SVS) appointed a committee of experts to formulate evidence-based clinical guidelines for the management of carotid stenosis. In formulating clinical practice recommendations, the committee used systematic reviews to summarize the best available evidence and the GRADE scheme to grade the strength of recommendations (GRADE 1 for strong recommendations; GRADE 2 for weak recommendations) and rate the quality of evidence (high, moderate, low, and very low quality). In symptomatic and asymptomatic patients with low-grade carotid stenosis (<50% in symptomatic and <60% in asymptomatic patients), we recommend optimal medical therapy rather than revascularization (GRADE 1 recommendation, high quality evidence). In symptomatic patients with moderate to severe carotid stenosis (more than 50%), we recommend carotid endarterectomy plus optimal medical therapy (GRADE 1 recommendation, high quality evidence). In symptomatic patients with moderate to severe carotid stenosis (>/=50%) and high perioperative risk, we suggest carotid artery stenting as a potential alternative to carotid endarterectomy (GRADE 2 recommendation, low quality evidence). In asymptomatic patients with moderate to severe carotid stenosis (>/=60%), we recommend carotid endarterectomy plus medical management as long as the perioperative risk is low (GRADE 1 recommendation, high quality evidence). We recommend against carotid artery stenting for asymptomatic patients with moderate to severe (>/=60%) carotid artery stenosis (GRADE 1 recommendation, low quality evidence). A possible exception includes patients with >/=80% carotid artery stenosis and high anatomic risk for carotid endarterectomy.

Inflammation within Carotid Atherosclerotic Plaque: Assessment with Late-Phase Contrast-enhanced US 1

Article

May 2010
RADIOLOGY

To determine if the number of nontargeted microbubbles retained in human carotid plaque is sufficient to be detected with ultrasonography (US). The study protocol was approved by the local research ethics committee. Informed consent was obtained. A total of 37 subjects with carotid atherosclerosis (mean age, 69.9 years; age range, 49-86 years), of whom 27 (73%) were men (mean age, 69.7 years; age range, 58-86 years) and 10 (27%) were women (mean age, 70.3 years; age range, 49-86 years), were studied between December 2008 and May 2009 with late-phase (LP) contrast material-enhanced US by using flash imaging with a nonlinear mode at an intermediate mechanical index of 0.34 6 minutes after bolus contrast agent injection. Plaques were defined as symptomatic if symptoms consistent with stroke, transient ischemic attack, or amaurosis fugax had occurred in the neurovascular territory of the plaque studied within 12 months prior to entry into the study. Plaques were defined as asymptomatic if no such events had ever occurred within the neurovascular territory. Raw linear data were used to quantify echogenicity of the plaque, which was normalized to lumen echogenicity. Gray-scale median score was also calculated. Of the 37 subjects, 16 (43%) had symptomatic plaques and 21 (57%) had asymptomatic plaques. All examinations yielded evaluable LP contrast-enhanced US data. Normalized LP plaque echogenicity was greater in the symptomatic group (0.39; 95% confidence interval: -0.11, 0.89) than in the asymptomatic group (0.69; 95% confidence interval: -1.04, -0.34) (P = .0005). There was a moderate (rho = -0.44, P = .016) inverse correlation between normalized LP plaque echogenicity and gray-scale median score. By quantifying microbubble retention within the carotid plaque, LP contrast-enhanced US depicts clear differences between groups of subjects with plaque ipsilateral to symptoms and asymptomatic plaques. This technique has promise as a tissue-specific marker of inflammation and a potential role in the risk stratification of atherosclerotic carotid stenosis.

The use of Contrast Enhanced Ultrasound in Carotid Arterial Disease

Article

Apr 2010

Traditionally, stroke risk stratification has centred on the degree of internal carotid artery stenosis, and the presence of focal neurological symptoms. However, degree of stenosis alone is a relatively poor predictor of future stroke in asymptomatic patients; the Asymptomatic Carotid Surgery Trial highlighting the need to identify a subgroup of asymptomatics that may benefit from intervention. Attempting to define this subgroup has inspired imaging research to identify, in vivo, high-risk plaques. In addition to pre-operative risk stratification of carotid stenosis, contrast enhanced ultrasound (CEUS) may be employed in monitoring response to plaque-stabilising therapies. Unlike most contrast agents used for computed tomography and magnetic resonance imaging, microbubbles used in CEUS remain within the vascular space and can hence be used to study the vasculature. In addition to improving current carotid structural scans, CEUS has potential to add extra information on plaque characteristics. Furthermore, by targeting microbubbles to specific ligands expressed on vascular endothelium, CEUS may have the ability to probe plaque biology. This review describes the current carotid ultrasound examination and the need to improve it, rationale for imaging neovascularisation, use of CEUS to image neovascularisation, microbubbles in improving the structural imaging of plaque, potential problems with CEUS, and future directions.

Contrast enhanced ultrasound imaging

Article

Nov 2009
J NUCL CARDIOL

Vasa Vasorum and Plaque Neovascularization on Contrast-Enhanced Carotid Ultrasound Imaging Correlates With Cardiovascular Disease and Past Cardiovascular Events

Article

Nov 2009
STROKE

Histological data associate proliferation of adventitial vasa vasorum and intraplaque neovascularization with vulnerable plaques represented by symptomatic vascular disease. In this observational study, the presence of carotid intraplaque neovascularization and adventitial vasa vasorum were correlated with the presence and occurrence of cardiovascular disease (CVD) and events (CVE). The contrast-enhanced carotid ultrasound examinations of 147 subjects (mean age 64+/-11 years, 61% male) were analyzed for the presence of intraluminal plaque, plaque neovascularization (Grade 1=absent; Grade 2=present), and degree of adventitial vasa vasorum (Grade 1=absent, Grade 2=present). These observations were correlated with preexisting cardiovascular risk factors, presence of CVD, and history of CVE (myocardial infarction and transient ischemic attack/stroke). The presence of intraluminal carotid plaque was directly correlated to cardiovascular risk factors, CVD, and CVE (P<0.05). Adventitial vasa vasorum Grade 2 was associated with significant more subjects with CVD than vasa vasorum Grade 1 (73 versus 54%, P=0.029). Subjects with intraplaque neovascularization Grade 2 had significantly more often a history of CVE than subjects with intraplaque neovascularization Grade 1 (38 versus 20%, P=0.031). Multivariate logistic regression analysis revealed that presence of plaque was significantly associated with CVD (odds ratio 4.7, 95% CI 1.6 to 13.8) and intraplaque neovascularization grade 2 with CVE (odds ratio 4.0, 95% CI 1.3 to 12.6). The presence and degree of adventitial vasa vasorum and plaque neovascularization were directly associated with CVD and CVE in a retrospective study of 147 patients undergoing contrast-enhanced carotid ultrasound.

Contrast Carotid Ultrasound for the Detection of Unstable Plaques with Neoangiogenesis: A Pilot Study

Article

Apr 2009

To evaluate whether contrast ultrasonography can be used to distinguish asymptomatic from symptomatic carotid plaques and provide insight into underlying pathophysiological differences. Contrast carotid ultrasound was performed in both symptomatic and asymptomatic patients referred for carotid endarterectomy. Of 77 consecutive patients referred for carotid artery evaluation, 64 underwent carotid endarterectomy for asymptomatic cerebrovascular disease and 9 underwent urgent surgery for acute neurological deficits with hemiparesis. The endarterectomy specimens were assessed immunohistologically. In all 9 patients undergoing urgent surgery, contrast ultrasonography showed the accumulation of diffuse microbubble contrast at the base of the carotid plaque. This pattern was observed only in 1/64 of the patients undergoing surgery for asymptomatic carotid disease. Immunohistologically staining of the endarterectomy specimens showed that the area of microbubble contrast at the base of the symptomatic plaques was associated with an increased number of small diameter (20-30 microm) microvessels staining for vascular endothelial growth factor (VEGF). Contrast carotid ultrasonography may allow the identification of microvessels with neoangiogenesis at the base of carotid plaques, and differentiate symptomatic from asymptomatic plaques.

Novel concepts in atherogenesis: Angiogenesis and hypoxia in atherosclerosis

Article

May 2009
J PATHOL

The clinical complications of atherosclerosis are caused by thrombus formation, which in turn results from rupture of an unstable atherosclerotic plaque. The formation of microvessels (angiogenesis) in an atherosclerotic plaque contributes to the development of plaques, increasing the risk of rupture. Microvessel content increases with human plaque progression and is likely stimulated by plaque hypoxia, reactive oxygen species and hypoxia-inducible factor (HIF) signalling. The presence of plaque hypoxia is primarily determined by plaque inflammation (increasing oxygen demand), while the contribution of plaque thickness (reducing oxygen supply) seems to be minor. Inflammation and hypoxia are almost interchangeable and both stimuli may initiate HIF-driven angiogenesis in atherosclerosis. Despite the scarcity of microvessels in animal models, atherogenesis is not limited in these models. This suggests that abundant plaque angiogenesis is not a requirement for atherogenesis and may be a physiological response to the pathophysiological state of the arterial wall. However, the destruction of the integrity of microvessel endothelium likely leads to intraplaque haemorrhage and plaques at increased risk for rupture. Although a causal relation between the compromised microvessel structure and atherogenesis or between angiogenic stimuli and plaque angiogenesis remains tentative, both plaque angiogenesis and plaque hypoxia represent novel targets for non-invasive imaging of plaques at risk for rupture, potentially permitting early diagnosis and/or risk prediction of patients with atherosclerosis in the near future.

Correlation of Carotid Plaque Neovascularization Detected by Using Contrast-enhanced US with Clinical Symptoms1

Article

Apr 2009
RADIOLOGY

To determine the correlation between the degree of plaque enhancement with contrast agent microbubbles and clinical symptoms in patients with carotid atherosclerotic plaque. The study was approved by the hospital ethical committee, and informed consent was obtained from all patients. One hundred four patients (83 men: mean age, 64 years +/- 9 [standard deviation]; 21 women: mean age, 61 years +/- 10) with carotid plaques were studied with standard and contrast material-enhanced ultrasonography (US). Contrast enhancement in the plaque was evaluated with visual interpretation and quantitative analysis. Among the 104 patients, 35 (34%) had transient ischemic attack and/or cerebrovascular ischemic stroke. Plaque enhancement was found in 28 (80%) of 35 symptomatic patients and in 21 (30%) of 69 asymptomatic patients (P < .001). Enhanced intensity in the plaque (13.9 dB +/- 6.4) and the ratio of enhanced intensity in the plaque to that in the lumen of the carotid artery (0.54 +/- 0.23) in symptomatic patients were significantly greater than those in asymptomatic patients (8.8 dB +/- 5.2 [P < .001] and 0.33 +/- 0.19 [P < .001], respectively). Sensitivity and specificity were 74% and 62%, respectively, for enhanced intensity in the plaque (cutoff value, 10.0 dB) and 74% and 75%, respectively, for ratio of enhanced intensity in the plaque to that in the lumen of the carotid artery (cutoff value, 0.46). Symptomatic patients had more intense contrast agent enhancement in the plaque than asymptomatic patients, suggesting that contrast-enhanced carotid US may be used for plaque risk stratification.

Visual Analysis or Semi-Automated Gray-Scale-Based Color Mapping of the Carotid Plaque: Which Method Correlates the Best with the Presence of Cerebrovascular Symptoms and/or Lesions on MRI ?

Article

Dec 2008
J NEUROIMAGING

To determine the correlation between carotid plaque morphology, assessed by two different ultrasonographic methods, and presence of cerebrovascular events and/or lesions on magnetic resonance imaging (MRI). Visual analysis of plaque echogenicity using a five-type classification was performed. Further, a semi-automated gray-scale-based color mapping of the whole plaque and of its surface was achieved. There were 31 (35%) symptomatic (23 strokes and 8 transitory ischemic attacks [TIAs]) and 58 (65%) asymptomatic carotid stenoses. MRI lesions related to the carotid stenosis if located in the ipsilateral cortical, subcortical, or watershed area, were present in 27 cases (30%). In a multivariate logistic regression model, degree of stenosis (P= .03) and a predominant red color on the surface (P= .04) were independent factors associated with the presence of cerebrovascular events and/or lesions on MRI. Sensitivity and specificity were, respectively, 80% and 63% by combining degree of stenosis and color mapping of plaque surface. Degree of stenosis and a predominant red color on plaque surface were independent factors associated with the presence of cerebrovascular events and/or lesions on MRI. No correlation was observed with any particular type of plaque based on visual analysis alone.

Rapid improvement of carotid plaque echogenicity within 1 month of pioglitazone treatment in patients with acute coronary syndrome

Article

Aug 2008

This study examined whether pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, may stabilize vulnerable plaque with use of ultrasound evaluation of carotid artery plaque echolucency in patients with acute coronary syndrome (ACS) and type 2 diabetes mellitus (DM). Treatment with pioglitazone (15 or 30mg/day, n=31) or placebo (n=30) was randomly assigned and initiated within 5 days after the onset of ACS in 61 patients with type 2 DM and echolucent carotid plaques. Vulnerable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) before, at 2 weeks, and 1 month and 6 months after initiation of treatment. An increase in IBS value reflects an increase in carotid plaque echogenicity. Calibrated IBS value (intima-media IBS value minus adventitia IBS value) of echolucent carotid plaques did not change at 2 weeks but was significantly increased at 1 month after treatment in the pioglitazone group but not in the placebo group. The increase in calibrated IBS value was not significantly correlated with the effect of pioglitazone on glycemia. Pioglitazone rapidly improved carotid plaque echolucency within 1 month of therapy initiation in patients with ACS and type 2 DM.

Increasing Carotid Plaque Echolucency is Predictive of Cardiovascular Events in High-Risk Patients 1

Article

Oct 2008
RADIOLOGY

Carotid plaque echolucency seen at ultrasonography (US) is a potential indicator of plaque instability and may help identify patients at risk for major adverse cardiovascular events (MACEs). The authors performed this study to determine whether decreasing gray-scale median (GSM) levels at repeat carotid US examinations are associated with future MACEs. The study was approved by the institutional ethics committee and all patients provided informed consent. The authors prospectively studied 574 patients with carotid plaques of at least 30% from a group of 1268 consecutive patients who were initially asymptomatic with respect to carotid disease. GSM levels were determined with carotid US at baseline and after a median of 7.5 months (range, 6-9 months), and the mean change of the GSM was calculated. Patients were then followed up clinically for a median of 3.2 years for the occurrence of composite MACE. During the initial period, the median change in carotid GSM was 2.9 (interquartile range [IQR], -6.9 to 11.0). Of 574 study participants, 230 (40%) showed a reduction of GSM levels and 344 (60%) showed an increase. MACEs were observed in 177 (31%) of the 574 patients. Adjusted hazard ratios for the lowest quartile (GSM change less than -6.9), the second quartile (GSM change between -6.9 and 2.9), and the third quartile (GSM change between 3.0 and 11.0) were 1.71 (95% confidence interval [CI]: 1.09, 2.66), 1.36 (95% CI: 0.86, 2.16), and 1.22 (95% CI: 0.77, 1.95), respectively, compared with the highest quartile (GSM change greater than 11.0) (P = .018). Increasing echolucency of carotid artery plaques within a 6- to 9-month interval is predictive of midterm clinical adverse events of atherosclerosis.

Hypoechoic plaque at US of the carotid artery: An independent risk factor for incident stroke in adults aged 65 years or older. Cardiovascular Health Study

Article

Oct 1998

To investigate the association between incident (first) stroke and the echogenicity of internal carotid arterial plaque at ultrasonography (US). A cohort of 4, 886 individuals who, at baseline, were 65 years of age or older and without symptoms of cerebrovascular disease was followed up for an average of 3.3 years. Baseline clinical findings were from color Doppler and duplex US studies of the carotid arteries and a record of traditional risk factors: age, sex, presence of diabetes mellitus, pack-years of cigarette smoking, presence of hypertension, elevated systolic and diastolic blood pressure, elevated low-density lipoprotein cholesterol level. Incident strokes, excluding hemorrhagic strokes and strokes of cardiac origin, were seen in 104 individuals (2.1%) at risk. Age- and sex-adjusted odds ratios for incident stroke were significant for hypoechoic plaque (odds ratio, 2.53; 95% CI, 1,42,4.53). After controlling for risk factors in a Cox proportional hazards model, the relative risk (RR) of incident stroke was 1.72 (p = .015) for hypoechoic plaque and 2.32 (P = .004) for internal carotid arterial narrowing of at least 50%. In addition, hypoechoic plaque (RR, 2.78; CI, 1.36,5.69) and 50%-100% stenosis (RR, 3.08; CI, 1.28, 7.41) were associated with ipsilateral, nonfatal stroke. In asymptomatic adults aged 65 years or older, that risk of incident stroke was associated with two US features: hypoechoic internal carotid arterial plaque and an estimated internal carotid arterial stenosis of 50%-100%.

Carotid Plaque Characterization by Duplex Scanning : Observer Error May Undermine Current Clinical Trials

Article

Feb 1999

Clinical studies currently in progress are using subjective methods to characterize plaque morphology from ultrasound images. However, there are few studies on the intraobserver and interobserver variability of these classifications. This study was designed to assess these variables. Grading of plaque morphology from ultrasound images, stored both digitally and to hard copy, was performed by 2 classification schemes. Interobserver agreement was determined by 4 observers. Within-observer agreement was performed at intervals for up to 6 months. Accuracy of the 2 methods was determined by comparison with histology. Within- and between-observer agreement was moderate to good for full-color digital image analyses, with pooled kappa values of kappap=0.49+/-0.10 and kappap=0.62+/-0.07 for the 2-category method and kappap=0.53+/-0.06 and kappap=0.52+/-0.05 for the 4-category method, respectively. Hard copy data analyses gave lower kappa values. The more experienced observers produced higher within-observer agreements and higher correlation with histology. Reproducible grading of ultrasound images is not consistently achievable among experienced observers, and within-observer agreement may vary with time. The current subjective ultrasound characterization of carotid plaque morphology used in clinical trials may be associated with unacceptable levels of reproducibility in some centers. Variability between observers may be reduced by using the simpler 2-category grading of plaque morphology to interrogate full-color digitally stored images. Observer agreement should be audited regularly.

Leucocyte recruitment in rupture prone regions of lipid-rich plaques: A prominent role for neovascularization?

Article

Mar 1999

Microvessels in atherosclerotic plaques provide an alternative pathway for the recruitment of leucocytes in the lesions. The present study was designed to investigate the potential role of these microvessels in creating vulnerable sites in atherosclerotic plaques. Thirty-four atherosclerotic plaques were obtained from 25 patients undergoing carotid endartherectomy (n = 16), femoral endartherectomy (n = 6) and aortic surgery (n = 12). Plaques were histologically classified as either lipid-rich (rupture prone, n = 21) or fibrous (stable, n = 13). Serial cryostat sections were immunohistochemically investigated using monoclonal antibodies against endothelial cells (ULEX-E and F-VIII), vascular endothelial growth factor (VEGF), endothelial adhesion molecules (ICAM-1, VCAM-1, E-Selectin, CD40) and inflammatory cells (macrophages (CD68) and T lymphocytes (CD3). The microvessel density in lipid-rich plaques was significantly increased as compared to fibrous plaques. Most of these vessels were located in the shoulder-region of the plaque and at the base of the atheroma. Microvessels in lipid-rich plaques also expressed increased levels of ICAM-1, VCAM-1, E-Selectin and CD40. Moreover, inflammation was most abundantly present in the proximity of microvessels. VEGF was only observed on vessels and mononuclear cells in lipid-rich plaques, suggesting that this factor may play a role in microvessels formation. Neovascularisation and expression of adhesion molecules by microvessels at sites of vulnerable lipid-rich plaques may sustain the influx of inflammatory cells and hence, could contribute to plaque destabilization.

Neovascularization in early atherosclerotic lesions of human carotid arteries: Its potential contribution to plaque development

Article

Sep 1999
Hum Pathol

Neovascularization is a prominent feature of late-stage atherosclerotic lesions and their complications but is generally regarded as an insignificant, undetectable component of the earliest stages of plaque development, probably because of relatively poor histological techniques. Using an improved vascular staining procedure, we have examined the extent of neovascularization in the earliest plaque lesions. Combined monoclonal antibodies to CD31, CD34, and von Willebrand factor have provided an ultrasensitive technique with which to visualize blood vessels in early atherosclerotic lesions (n = 55) of human carotid arteries obtained through surgical procedures. Capillary-like microvessels were shown in very early atherosclerotic lesions (type II), where they were associated with the distribution of macrophages and a few immature mast cells. Neovascularization was more prominent in type III lesions with vessels of variable size, often providing a focus around which local accumulations of macrophages and apolipoproteins A-I and B were visualized. Thickened type III lesions usually showed an intricate network of microvessels, together with numerous mast cells. These studies have shown neovascularization as a prominent feature of early stages of atherosclerotic plaque development. Whereas distribution of apolipoproteins A-I and B were observed in the very earliest stages of the plaque intima, these lipids, together with macrophages, foam cells, and mast cells, were observed as perivascular accumulations in a proportion of type II and III lesions. Such findings indicate that neovascularization is an important feature of early plaque development and may provide an additional or alternative source of leukocyte and lipid accumulations relative to the arterial lumen.

Macrophages are associated with lipid-rich carotid artery plaques, echolucency on B-mode imaging, and elevated plasma lipid levels

Article

Jan 2002
J VASC SURG

Atherosclerosis may be regarded as an inflammatory disease dominated by macrophages. We tested whether macrophages in carotid artery atherosclerotic plaques are associated with echolucency on B-mode ultrasound imaging, lipid levels, inflammatory markers, and aspirin use. We studied 106 patients undergoing carotid endarterectomy having >/=50% carotid artery stenosis and previous ipsilateral hemispheric neurologic symptoms. Macrophages were particularly common in plaques with a high content of lipid and hemorrhage and, conversely, rare in plaques dominated by calcification and fibrous tissue. Macrophage density in carotid artery plaques classified by B-mode ultrasound imaging as echolucent (n = 56), intermediate (n = 25), or echorich (n = 25) was 1.8% +/- 0.2%, 1.5% +/- 0.4%, and 1.0% +/- 0.2% (+/-SE), respectively (analysis of variance, P =.02). A computer-generated measure of plaque echolucency, gray-scale median, was associated with increased macrophage density (r = -0.31; P =.002). Furthermore, plasma and low-density lipoprotein cholesterol levels were associated with carotid artery macrophage density (r = 0.26, P =.008 and r = 0.23, P =.02); this was most pronounced in patients with lipid-rich plaques. Macrophage density was not associated with plasma levels of acute-phase reactants. Finally, macrophage density in carotid artery plaques of users (n = 55) and nonusers of aspirin (n = 51) was 1.2% +/- 0.2% and 1.8% +/- 0.2% (t test, P =.01). Increased macrophage density in carotid atherosclerotic plaques was associated with lipid content, plaque echolucency, and increased plasma and low-density lipoprotein cholesterol levels. Furthermore, use of aspirin was associated with reduced macrophage density in carotid artery plaques.

Echolucent rupture-prone plaques

Article

Nov 2003

Routine measurement of echolucency of atherosclerotic plaques, in addition to degree of stenosis, may change clinical practice in the future. Within the context of previous knowledge in this field, we therefore review recent developments in detection and histological characterization of echolucent rupture-prone plaques and risk for ischaemic events associated with them, as well as risk factors and treatment for such plaques. Plaque echolucency is associated with increased lipid content and macrophage density (and sometimes haemorrhage), whereas fibrous tissue (and sometimes calcification) dominates echo-rich plaques. Echolucent carotid plaques are associated with higher risk for future ischaemic stroke, particularly in previously symptomatic individuals, and possibly with risk for restenosis after endarterectomy as well as myocardial infarction. These plaques also associate with elevated levels of triglyceride-rich lipoproteins (and with reduced levels of HDL), but not with elevated levels of LDL or acute phase reactants. Risk factor intervention may be more beneficial for patients with echolucent plaques than in those with echo-rich plaques, whereas coronary stenting may be less efficient in patients with echolucent plaques. If it is to be clinically useful, then the ultrasound method must be further improved such that it may accurately detect echolucent rupture-prone plaques in the individual patient. Furthermore, the possible superior benefit from preventive treatments deployed selectively in patients with echolucent plaques must be better documented in large randomized trials. When these two requirements are met, routine measurement of plaque echolucency could change clinical practice with respect to the preventive treatments that are offered to patients with echolucent plaques as compared with those without such plaques.

Echolucent carotid Plaques predict future coronary events in patients with coronary artery disease

Article

Apr 2004
J AM COLL CARDIOL

The purpose of this study was to examine whether echolucent carotid plaques predict future coronary events in patients with clinically stable coronary artery disease (CAD). Although rupture of coronary plaques is considered a major cause of acute coronary syndromes (ACS), the clinical estimation of coronary vulnerability still remains inconclusive. Ultrasound evaluation of carotid plaques with integrated backscatter (IBS) analysis can indicate the consistency/structure of the plaques. Lipid-rich lesions known as "unstable plaques" appear as echolucent plaques with low IBS values using this technique. We investigated the echogenicity of carotid plaques using ultrasound with IBS in 286 consecutive CAD patients (71 with ACS and 215 with stable CAD). Coronary plaque complexity was also determined angiographically in stable CAD patients followed up for 30 months or until the occurrence of coronary events. The calibrated IBS values of carotid plaques in ACS patients were significantly lower than those in stable CAD patients (p < 0.01). Echolucent carotid plaques accurately predicted the existence of complex coronary plaques (predictive power of 83%). Kaplan-Meier analysis demonstrated a significantly higher probability of coronary events developing in patients with echolucent carotid plaques than in patients without this type of plaque (p < 0.001). The presence of echolucent carotid plaques in stable CAD patients predicted future coronary events independent of other risk factors (odds ratio 7.0, 95% confidence interval 2.3 to 21.4; p < 0.001). Echolucent carotid plaques with low IBS values predicted coronary plaque complexity and the development of future coronary complications in patients with stable CAD. Qualitative evaluation of carotid plaques using ultrasound with IBS is a clinically useful procedure for risk assessment of CAD patients.

The powerful microbubble: From bench to bedside, from intravascular indicator to therapeutic delivery system, and beyond

Article

Sep 2004

Steven Feinstein

This review discusses the development, current applications, and therapeutic potential of ultrasound contrast agents. Microbubbles containing gases act as true, intravascular indicators, permitting a noninvasive, quantitative analysis of the spatial and temporal heterogeneity of blood flow and volumes within the microvasculature. These shelled microbubbles are near-perfect reflectors of acoustic ultrasound energy and, when injected intravenously into the bloodstream, reflect ultrasound waves within the capillaries without disrupting the local environment. Accordingly, microbubble ultrasound contrast agents are clinically useful in enhancing ultrasound images and improving the accuracy of diagnoses. More recently, ultrasound contrast agents have been used to directly visualize the vasa vasorum and neovascularization of atherosclerotic carotid artery plaques, thus suggesting a new paradigm for diagnosis and treatment of atherosclerosis. Future applications of these microscopic agents include the deliver of site-specific therapy to targeted organs in the body. Medical therapies may use these microbubbles as carriers for newer therapeutic options.

Plaque Neovascularization Is Increased in Ruptured Atherosclerotic Lesions of Human Aorta Implications for Plaque Vulnerability

Article

Nov 2004
CIRCULATION

Growth of atherosclerotic plaques is accompanied by neovascularization from vasa vasorum microvessels extending through the tunica media into the base of the plaque and by lumen-derived microvessels through the fibrous cap. Microvessels are associated with plaque hemorrhage and may play a role in plaque rupture. Accordingly, we tested this hypothesis by investigating whether microvessels in the tunica media, the base of the plaque, and the fibrous cap are increased in ruptured atherosclerotic plaques in human aorta. Microvessels, defined as CD34-positive tubuloluminal capillaries recognized in cross-sectional and longitudinal profiles, were quantified in 269 advanced human plaques by bicolor immunohistochemistry. Macrophages/T lymphocytes and smooth muscle cells were defined as CD68/CD3-positive and alpha-actin-positive cells. Total microvessel density was increased in ruptured plaques when compared with nonruptured plaques (P=0.0001). Furthermore, microvessel density was increased in lesions with severe macrophage infiltration at the fibrous cap (P=0.0001) and at the shoulders of the plaque (P=0.0001). In addition, microvessel density was also increased in lesions with intraplaque hemorrhage (P=0.04) and in thin-cap fibroatheromas (P=0.038). Logistic regression analysis identified plaque base microvessel density (P=0.003) as an independent correlate to plaque rupture. Thus, neovascularization as manifested by the localized appearance of microvessels is increased in ruptured plaques in the human aorta. Furthermore, microvessel density is increased in lesions with inflammation, with intraplaque hemorrhage, and in thin-cap fibroatheromas. Microvessels at the base of the plaque are independently correlated with plaque rupture, suggesting a contributory role for neovascularization in the process of plaque rupture.

Arterial Neovascularization and Inflammation in Vulnerable Patients Early and Late Signs of Symptomatic Atherosclerosis

Article

Dec 2004
CIRCULATION

Atherosclerosis is complicated by cardiovascular events such as myocardial infarction, stroke, or peripheral arterial occlusive disease. Inflammation and pathological neovascularization are thought to precipitate plaque rupture or erosion, both causes of arterial thrombosis and cardiovascular events. We tested the hypothesis that arterial inflammation and angiogenic events are increased throughout the arterial tree in vulnerable patients, ie, in patients who suffered from cardiovascular events, compared with patients who never suffered from complications of atherosclerosis. In a postmortem study, we quantified the inflammatory infiltrate and microvascular network in the arterial wall of iliac, carotid, and renal arteries. Tissue microarray technology was adapted to investigate full-thickness arterial sectors. We compared 22 patients with symptomatic atherosclerosis with 27 patients who never had suffered from any cardiovascular event. The absolute intimal macrophage content was 2- to 4-fold higher in vulnerable patients at all 3 arterial sites analyzed (P<0.05). Patients with symptomatic atherosclerosis had a denser network of vasa vasorum than patients with asymptomatic disease (33+/-2 versus 25+/-2 adventitial microvessels per 1 mm2; P=0.008). Hyperplasia of vasa vasorum was an early and macrophage infiltration was a late sign of symptomatic atherosclerosis. High intimal macrophage content and a hyperplastic network of vasa vasorum characterize vulnerable patients suffering from symptomatic atherosclerosis. These changes are uniformly present in different arterial beds and support the concept of symptomatic atherosclerosis as a panarterial disease.

New aspects in the pathogenesis of diabetic atherothrombosis

Article

Jan 2005
J AM COLL CARDIOL

Diabetes mellitus affects 150 million people worldwide and close to 20 million in the U.S. The prevalence of diabetes among U.S. adults has increased by 40% in the past decade, and is expected to increase by 165% between 2000 and 2050 (1 and 2). Furthermore, one-third of the population born in 2000 will develop diabetes, with up to 30% reduction in life expectancy, mostly related to atherosclerosis, which is responsible for up to 80% of all deaths among North American diabetic patients (3 and 4). Mortality from myocardial infarction in patients with diabetes is markedly higher than in nondiabetic patients (5 and 6). As a result, diabetes mellitus imposes a large economic burden on society, estimated to be as much as $100 billion per year in the U.S. alone (7).

The Vulnerable Carotid Artery Plaque: Current Imaging Methods and New Perspectives

Article

Jan 2006
STROKE

Atherosclerosis is a diffuse, chronic inflammatory disorder that involves the vascular, metabolic, and immune systems and leads to plaque vulnerability. The traditional risk assessment relies on clinical, biological, and conventional imaging tools. However, these tools fall short in predicting near-future events in patients with vulnerable carotid artery plaque. In current clinical practice, anatomic imaging modalities, such as B-mode ultrasound, spiral computed tomography angiography, and high-resolution MRI, can identify several morphological features characteristic of the vulnerable plaque but give little or no information regarding molecular and cellular mechanisms. This review is dedicated to factors involved in carotid artery plaque vulnerability and to new imaging methods that target this condition. Our aim is to describe the following: (1) conventional pathologic and imaging markers predictive of plaque vulnerability; (2) the role of relevant biological, genetic, and mechanical factors; (3) the potential of new imaging methods; and (4) current and emerging treatments. A multimodal assessment of plaque vulnerability involving the combination of systemic markers, new imaging methods that target inflammatory and thrombotic components, and the potential of emerging therapies may lead to a new stratification system for atherothrombotic risk and to a better prevention of atherothrombotic stroke.

Stabilization of Carotid Atheroma Assessed by Quantitative Ultrasound Analysis in Nonhypercholesterolemic Patients With Coronary Artery Disease

Article

Dec 2005

Objectives: This study examined whether intensive cholesterol-lowering therapy with statins in nonhypercholesterolemic patients is effective in improving echolucency of vulnerable plaques assessed by ultrasound with integrated backscatter (IBS) analysis. Background: Atherosclerotic plaque stabilization is a promising clinical strategy to prevent cardiovascular events in patients with coronary artery disease (CAD). There is a correlation between coronary and carotid plaque instability, and echolucent plaques are recognized as vulnerable plaques. Methods: Consecutive nonhypercholesterolemic patients with CAD were randomly assigned Adult Treatment Panel-III diet therapy (diet group; n = 30) or pravastatin (statin group; n = 30). Echolucent carotid plaques were monitored by measuring intima-media thickness (IMT) and echogenicity by IBS for six months. Results: Total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-sensitivity C-reactive protein were significantly decreased in the statin group (from 197 +/- 15 mg/dl to 170 +/- 18 mg/dl [p < 0.001]; from 131 +/- 14 mg/dl to 99 +/- 14 mg/dl [p < 0.001]; and from 0.11 [0.04 to 0.22] mg/dl to 0.06 [0.04 to 0.11] mg/dl [p < 0.05]; respectively), whereas only total cholesterol was moderately reduced (from 193 +/- 24 mg/dl to 185 +/- 22 mg/dl [p < 0.05]) and LDL-C and triglycerides insignificantly reduced in the diet group. Significant increases of echogenicity of carotid plaques were noted in the statin group but not in the diet group (from -18.5 +/- 4.1 dB to -15.9 +/- 3.7 dB [p < 0.001] and from -18.2 +/- 4.0 dB to -18.9 +/- 3.5 dB [p = 0.13]; respectively) without significant regression of plaque-IMT values in both groups. Conclusions: Statin therapy is rapidly effective in increasing echogenicity of vulnerable plaques without regression of plaque size in nonhypercholesterolemic patients with CAD. Quantitative assessment of carotid plaque quality by ultrasound with IBS is clinically useful for monitoring atherosclerotic lesions by evaluating vulnerability of atheroma.

Neovascularization in Human Atherosclerosis

Article

Jun 2006
CIRCULATION

In the absence of disease, microvessels provide vessel wall nutrients to the tunica media, while the intima is fed by oxygen diffusion from the lumen. As disease evolves and the tunica intima thickens, oxygen diffusion is impaired, and microvessels become the major source for nutrients to the vessel wall. Microvessels serve as a port of entry for inflammatory cells, from the systemic circulation to the nascent atherosclerotic lesion. As disease progress, microvessels also play a role in intraplaque hemorrhage, lipid core expansion, and plaque rupture. In addition, microvessels are also involved in stent restenosis, and plaque regression. Therefore, microvessels are a pivotal component of atherosclerosis, and proper patient risk-stratification in the near future may include the detection of increased neovascularization in atherosclerotic lesions. This review divided in two parts summarizes the current understanding of atherosclerosis neovascularization, starting with the normal anatomy and physiology and progressing to more advanced stages of the disease. We will review the structure and function of vasa vasorum in health and disease, the mechanisms responsible for the angiogenic process, the role of the immune system, including inflammation and Toll-like receptors, and the pathology of microvessels in early atherosclerotic plaques. Furthermore, the review addresses the advanced stages of atherosclerosis, summarizing the progressive role for microvessels during disease progression, red blood cell extravasation, lipid core expansion, plaque rupture, healing, repair, restenosis, and disease regression, offering the clinician a state-of-the-art, bench to bedside approach to neovascularization in human atherosclerosis.

Contrast Ultrasound Imaging of the Carotid Artery Vasa Vasorum and Atherosclerotic Plaque Neovascularization

Article

Aug 2006

Steven Feinstein

Cardiovascular disease is associated with the aging of the population, obesity, metabolic syndrome, and diabetes. Therefore, it is important to develop non-invasive imaging systems to detect "at-risk" populations. New data suggest that contrast-enhanced ultrasound (CU) imaging of the carotid arteries enhances luminal irregularities (i.e., ulcers and plaques), improves near-wall, carotid intima-media thickness, and uniquely permits direct, real-time visualization of neovasculature of the atherosclerotic plaque and associated adventitial vasa vasorum. With continued clinical investigation, CU imaging of the carotid artery may afford an effective means to non-invasively identify atherosclerosis in "at-risk" populations while providing new standard for therapeutic monitoring.

From Vulnerable Plaque to Vulnerable Patient—Part III: Executive Summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force Report

Article

Jul 2006
AM J CARDIOL

Screening for early-stage asymptomatic cancers (eg, cancers of breast and colon) to prevent late-stage malignancies has been widely accepted. However, although atherosclerotic cardiovascular disease (eg, heart attack and stroke) accounts for more death and disability than all cancers combined, there are no national screening guidelines for asymptomatic (subclinical) atherosclerosis, and there is no government- or healthcare-sponsored reimbursement for atherosclerosis screening. Part I and Part II of this consensus statement elaborated on new discoveries in the field of atherosclerosis that led to the concept of the "vulnerable patient." These landmark discoveries, along with new diagnostic and therapeutic options, have set the stage for the next step: translation of this knowledge into a new practice of preventive cardiology. The identification and treatment of the vulnerable patient are the focuses of this consensus statement. In this report, the Screening for Heart Attack Prevention and Education (SHAPE) Task Force presents a new practice guideline for cardiovascular screening in the asymptomatic at-risk population. In summary, the SHAPE Guideline calls for noninvasive screening of all asymptomatic men 45-75 years of age and asymptomatic women 55-75 years of age (except those defined as very low risk) to detect and treat those with subclinical atherosclerosis. A variety of screening tests are available, and the cost-effectiveness of their use in a comprehensive strategy must be validated. Some of these screening tests, such as measurement of coronary artery calcification by computed tomography scanning and carotid artery intima-media thickness and plaque by ultrasonography, have been available longer than others and are capable of providing direct evidence for the presence and extent of atherosclerosis. Both of these imaging methods provide prognostic information of proven value regarding the future risk of heart attack and stroke. Careful and responsible implementation of these tests as part of a comprehensive risk assessment and reduction approach is warranted and outlined by this report. Other tests for the detection of atherosclerosis and abnormal arterial structure and function, such as magnetic resonance imaging of the great arteries, studies of small and large artery stiffness, and assessment of systemic endothelial dysfunction, are emerging and must be further validated. The screening results (severity of subclinical arterial disease) combined with risk factor assessment are used for risk stratification to identify the vulnerable patient and initiate appropriate therapy. The higher the risk, the more vulnerable an individual is to a near-term adverse event. Because <10% of the population who test positive for atherosclerosis will experience a near-term event, additional risk stratification based on reliable markers of disease activity is needed and is expected to further focus the search for the vulnerable patient in the future. All individuals with asymptomatic atherosclerosis should be counseled and treated to prevent progression to overt clinical disease. The aggressiveness of the treatment should be proportional to the level of risk. Individuals with no evidence of subclinical disease may be reassured of the low risk of a future near-term event, yet encouraged to adhere to a healthy lifestyle and maintain appropriate risk factor levels. Early heart attack care education is urged for all individuals with a positive test for atherosclerosis. The SHAPE Task Force reinforces existing guidelines for the screening and treatment of risk factors in younger populations. Cardiovascular healthcare professionals and policymakers are urged to adopt the SHAPE proposal and its attendant cost-effectiveness as a new strategy to contain the epidemic of atherosclerotic cardiovascular disease and the rising cost of therapies associated with this epidemic.

Histopathology of Carotid Atherosclerotic Disease

Article

Dec 2006
NEUROSURGERY

Stroke is the third leading cause of death in the United States, constituting approximately 700,000 cases each year, of which about 500,000 are first attacks and 200,000 are recurrent attacks. Ischemic stroke accounts for the majority of all strokes (88%), followed by intracerebral hemorrhage (9%) and subarachnoid hemorrhage (3%). Patients with substantial carotid narrowing are at increased risk for major stroke; however, recent studies suggest that factors other than the degree of carotid stenosis are involved in ischemic stroke pathogenesis. Atherosclerotic plaque of the stenotic carotid artery is the underlying cause of the majority of ischemic strokes and specific plaque characteristics have been associated with ischemic brain injury. Several studies have demonstrated that the mechanisms of plaque instability in the carotid circulation are similar to those in the coronary circulation. The purpose of this review is to characterize atherosclerotic carotid disease in light of our knowledge of coronary atherosclerosis and relate carotid plaque morphology to cerebral ischemic syndromes. Histological examination of the carotid plaque specimen should provide insights into the underlying plaque morphology that is responsible for the disease and should help determine the potential treatments that are likely to be beneficial in the prevention of a subsequent event.

Echolucent Carotid Plaques as a Feature in Patients With Acute Coronary Syndrome

Article

Jan 2007

Carotid arterial ultrasound examination may be helpful for screening populations at high risk for acute coronary syndrome (ACS), so the present study was designed to identify the carotid arterial characteristics of patients with ACS. Carotid ultrasound examinations were performed in 172 patients with ACS, 166 patients with stable coronary artery disease (CAD), and 96 control subjects. Common carotid arterial structures were assessed by the intima - media thickness (IMT), interadventitial diameter (IAD), lumen diameter (LD), the IMT to LD ratio (IMT/LD), and the plaque burden based on the plaque score. Plaque morphology was assessed by the echogenecity based on the gray-scale median (GSM). IMT, IAD, IMT/LD, and plaque score did not differ between the ACS and stable CAD groups. The GSM in the ACS group was lower (47.5+/-25.3, p<0.001) than in the control (70.1+/-22.5) and stable CAD (73.7+/-23.4) groups. Multiple logistic regression analysis showed that the presence of carotid echolucent plaques (GSM <or=60) was an independent predictor of ACS. Echolucent carotid plaques were strongly associated with ACS and may be a surrogate marker of high-risk patients.

Statin treated patients have reduced intraplaque angiogenesis in carotid endarterectomy specimens

Article

Jun 2007
Atherosclerosis

Treatment with statins is considered a first line therapy in atherosclerotic disease. Intraplaque angiogenesis is involved in plaque progression and instability. It remains unclear whether the beneficial effect of statin treatment in humans is achieved through reduced intraplaque angiogenesis. The aim of this study was to evaluate the capillaries density in carotid plaques removed from patients treated with statin versus untreated patients. We studied 102 patients who underwent carotid endarterectomy: 98 of them met the inclusion criteria and entered the study; 75 men and 23 women; mean age 66+/-8 years (range 42-83 years). Forty-three patients (44%) were on statin treatment at least 3 months before endarterectomy and 55 (56%) had never received statin treatment. The intensity of intraplaque angiogenesis was evaluated with immunohistochemistry using the antibody CD34. The number of capillaries per mm(2) was measured with a custom designed image tool analysis. With the exception of serum total cholesterol levels and serum low-density cholesterol levels, the two groups of patients did not vary significantly in cardiovascular risk factors and in parameters pertaining to the procedure profile. Patients on statin treatment had less capillaries per mm(2) than patients not receiving this kind of drugs (0.97+/-0.61 per mm(2) versus 1.39+/-0.98 per mm(2), p=0.031). Univariate associations between possible explanatory variables and number of capillaries per mm(2) were tested using Spearman rank R. Variables associated with a p-value <0.20 (age, serum creatinine, serum total cholesterol, serum low-density lipoprotein, serum homocysteine, presence of diabetes mellitus and statin treatment) were entered in a multivariable model. Multivariate analysis showed that statin treatment was the only independent predictor (t=-5.39, p<0.001) of intraplaque angiogenesis. Statin therapy is associated with reduced intraplaque angiogenesis in the carotid arteries. This could provide an explanation for the beneficial effects of this kind of drug on patients with atherosclerotic disease.

Plaque Neovascularization and Antiangiogenic Therapy for Atherosclerosis

Article

Jun 2007

The concept that neovascularization of the vessel wall may play a fundamental role in the pathophysiology of atherosclerosis was proposed more than a century ago. In recent years, supportive experimental evidence for this hypothesis (such as the finding that neointimal microvessels may increase delivery of cellular and soluble lesion components to the vessel wall) has been underscored by clinical studies associating plaque angiogenesis with more rapidly progressive high-grade disease. Attention has also focused on a possible role for microvessel-derived intraplaque hemorrhage in the development of acute lesion instability. The interest of clinicians in this phenomenon has been spurred by the potential to target vessel wall neovascularization with angiogenesis inhibitors, a therapeutic approach that has been associated with impressive reductions in plaque progression in animal models of vascular disease. The rationale for pursuing an "antiangiogenic" strategy in the treatment of patients with vascular disease, and a framework for further preclinical evaluation of such therapy, is presented here.

Rapid Stabilization of Vulnerable Carotid Plaque Within 1 Month of Pitavastatin Treatment in Patients With Acute Coronary Syndrome

Article

Apr 2008

We determined time course of stabilization of echolucent carotid plaques by statin therapy in patients with acute coronary syndrome (ACS). Treatment with 4 mg/d pitavastatin (n = 33) or placebo (n = 32) was initiated within 3 days after onset of ACS in 65 patients with echolucent carotid plaque. Vulnerable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) analysis before and 1 month after treatment in all patients. The calibrated IBS value (intima-media IBS value minus adventia IBS) of vulnerable carotid plaques favorably changed at 1 month after treatment in both groups, but the echolucency at 1 month improved more in the pitavastatin than in the placebo group (pitavastatin group: -18.7 +/- 3.3 dB at pretreatment versus -12.7 +/- 2.3 dB at 1 month *P < 0.001; placebo: -19.0 +/- 3.5 dB versus -16.9 +/- 3.2 dB, P < 0.05, *P < 0.01 versus the value at 1 month in placebo group). Levels of CRP, VEGF, and TNFalpha at 1 month were significantly lower in pitavastatin than placebo group. In conclusion, pitavastatin improved carotid plaque echolucency within 1 month of therapy in patients with ACS, in association with decrease in the inflammatory biomarkers related to vulnerable plaques.

Article

MR imaging findings of early bile duct cancer

December 2008 · Journal of Magnetic Resonance Imaging

To retrospectively evaluate the MR imaging features of early bile duct cancer and to correlate them with the clinicopathologic findings. This retrospective study was approved by our institutional review board, and informed consent was waived. Seventeen patients with surgically proven early bile duct cancer who had undergone preoperative MR cholangiopancreatography with gadolinium-enhanced MR ... [Show full abstract] imaging, were included in this study. Two, experienced radiologists evaluated the MR images in consensus regarding the following findings: tumor number and morphology; signal intensity of the tumor; sharpness of the outer border of the bile duct wall; enhancement pattern of the tumor; and the presence of enlarged peribiliary lymph nodes. Another radiologist measured the SNR of the tumor and bile duct wall on gadolinium-enhanced MRI during the dynamic phases to evaluate the tumor enhancement degree. In all patients, MR imaging demonstrated single or multiple intraluminal bile duct masses showing a sharply defined outer margin. The most common enhancement pattern of the biliary lesions showed heterogeneous amorphous enhancement or heterogeneous enhancement with central, dot-like structures or vascular structures (76.5%, 13/17 patients). The difference of SNR between bile duct and tumor was greatest in the equilibrium phase (P < 0.05). MRCP combined with dynamic contrast-enhanced MRI can be useful for detecting early bile duct cancers. Common MR findings of early bile duct cancer include one or more inhomogeneously enhancing intraductal masses with clear outer margins and preservation of the bile duct wall.

Article

Knowledge , Attitude and Practices among Gynecologists regarding Oral Health of Expectant Mothers of...

June 2013 · International Journal of Health Sciences

To assess the knowledge, attitude and practices among Gynecologists' regarding oral health of expectant mothers of Vadodara city, by using self designed, structured, pre-tested close ended questionnaire. Total of 130 gynaecologists are included in the study. Ethical approval was obtained by the Ethics committee, Sumandeep Vidyapeeth, Vadodara. Prior to study, questionnaire was pre-tested and ... [Show full abstract] validated. Those individuals who participated in the pilot study were not considered for the main study to prevent possible bias. The informed consent was obtained and information sheet was given. The questionnaire was administered on first day of visit and on the next day it was collected back. For statistical analysis SPSS package version 17 and Pearson's Chi Square test was used. The study revealed that majority of gynecologists had good knowledge, attitude and practices regarding oral health of expectant mothers and there is no significant difference in relation with age, sex and years in practice. Majority of gynecologists had good knowledge, attitude and practices but still there is a need for more active participation and involvement of medical specialists like gynecologists and pediatricians, in continuing education programs and forums on dentistry.

Article

Full-text available

Prostate Cancer Ablation with Transrectal High-Intensity Focused Ultrasound: Assessment of Tissue De...

February 2011 · Radiology

To assess contrast material-enhanced ultrasonographic (US) findings seen after high-intensity focused ultrasound (HIFU) ablation of prostate cancer and correlate the US findings with post-HIFU biopsy findings. The study was ethics committee approved. Written informed consent was obtained from all patients. Twenty-eight patients referred for HIFU prostate cancer ablation underwent ... [Show full abstract] contrast-enhanced prostate US before treatment, gadolinium-enhanced magnetic resonance (MR) imaging and repeat contrast-enhanced US 1-3 days after treatment, and contrast-enhanced US-guided biopsy 30-45 days after treatment. The contrast-enhanced US enhancement patterns of the biopsy sites--assigned a score of S0 for no enhancement, S1 for mild and/or patchy enhancement, or S2 for marked enhancement--were compared with corresponding biopsy findings, which were assigned a score of B0 for necrosis and/or fibrosis without viable prostate gland tissue, B1 for vascularized tissue without viable gland tissue, or B2 for viable gland tissue (benign or malignant). Then, six additional patients underwent contrast-enhanced prostate US 15-30 minutes and 1 day after HIFU ablation, and the results of these two US examinations were compared. Contrast-enhanced US performed on days 1-3 and days 30-45 after HIFU ablation depicted a large devascularized zone with peripheral enhancing areas that were localized anteriorly in all 28 patients, posteriorly in nine, laterally in five, and at the apex in 20 patients. MR findings were concordant. At biopsy, viable gland tissue was found at nine (6.2%) of 146 S0 sites, 10 (34%) of 29 S1 sites, and 44 (60%) of 73 S2 sites. The odds ratios for finding viable tissue (score B1 or B2) at S1 and S2 sites as opposed to S0 sites were 21 (95% confidence interval [CI]: 6, 71) and 73 (95% CI: 22, 243), respectively (P < .0001). Contrast-enhanced US performed 15-30 minutes and 1 day after treatment in the six additional patients had similar findings. Contrast-enhanced US is a promising tool for distinguishing between ablated (devascularized) and viable (enhancing) tissue immediately after HIFU treatment.

Article

Subchondral impaction fractures of the non-weight-bearing portion of the lateral femoral condyle

August 2012 · Skeletal Radiology

Objective: To document the first report of intra-articular, non-weight-bearing, impaction fractures of the lateral femoral condyle. Materials & methods: Institutional Review Board and Regional Ethics Committee approval for this study was obtained and patient informed consent deemed unnecessary. We prospectively documented all potential cases of non-weight-bearing posterior subchondral ... [Show full abstract] impaction fractures of the femoral condyles diagnosed on magnetic resonance imaging (MRI) of the knee performed at our institution between January 2006 and December 2011. The cases were reviewed and discussed by three experienced musculoskeletal radiologists and only cases satisfying pre-defined MRI criteria were included. Results: Sixteen cases of intra-articular impaction fractures in a posterior, non-weight-bearing area of the lateral femoral condyle were diagnosed in patients with a mean age of 40. Eight were associated with recreational sports activities and 4 with repeated kneeling. There were no fractures documented in the non-weight-bearing aspect of the medial femoral condyles. Proposed underlying mechanisms for development of this type of fracture are presented. Conclusion: Awareness, along with a high level of suspicion, that non-specific knee pain, especially in patients involved in athletic activities, could be due to intra-articular impaction fractures of the non-weight-bearing posterior aspect of the lateral femoral condyle is essential and MRI is the mainstay of diagnosis.

Last Updated: 22 Oct 2024