Stijn C.H. van den Oord

Carotid intima-media thickness for cardiovascular risk assessment: Systematic review and meta-analysis

OBJECTIVE B-mode ultrasound measurement of the carotid intima-media thickness (CIMT) is a widely used marker for atherosclerosis and is associated with future cardiovascular events. This article provides a review and meta-analysis of the published evidence on the association of CIMT with future cardiovascular events and its additional value to traditional cardiovascular risk prediction models. METHODS A systematic review and meta-analysis of the evidence on the association of CIMT with future cardiovascular events and the additional value of CIMT to traditional cardiovascular risk prediction models was conducted. The association of CIMT with future cardiovascular events and the additional value of CIMT were calculated using random effects analysis. RESULTS The literature search yielded 1196 articles of which 15 articles provided sufficient data for the meta-analysis. A 1 SD increase in CIMT was predictive for myocardial infarction (HR 1.26, 95% CI 1.20-1.31) and for stroke (HR 1.31, 95% CI 1.26-1.36). A 0.1 mm increase in CIMT was predictive for myocardial infarction (HR 1.15, 95% CI 1.12-1.18) and for stroke (HR 1.17, 95% CI 1.15-1.21). The overall performance of risk prediction models did not significantly increase after addition of CIMT data. The areas under the curve increased from 0.726 to 0.729 (p = 0.8). CONCLUSIONS CIMT as measured by B-mode ultrasound is associated with future cardiovascular events. However, the addition of CIMT to traditional cardiovascular risk prediction models does not lead to a statistical significantly increase in performance of those models.

Current status and future developments of contrast-enhanced ultrasound of carotid atherosclerosis.

B-mode and Doppler ultrasound are commonly used for the evaluation of atherosclerosis in the carotid arteries. Recently, contrast-enhanced ultrasound (CEUS) has been introduced as a technique to improve the detection of carotid atherosclerosis and evaluate the presence of intraplaque neovascularization, which is considered a marker of plaque vulnerability. The present review focuses on the role of CEUS for the assessment of atherosclerosis and plaque instability. Currently available literature and future developments with CEUS are discussed.

Utility of contrast-enhanced ultrasound for the assessment of the carotid artery wall in patients with Takayasu or giant cell arteritis

AIMS Carotid contrast-enhanced ultrasound (CEUS) was recently proposed for the evaluation of large-vessel vasculitides (LVV), particularly to assess vascularization within the vessel wall. The aim of this pilot study was to evaluate the potential of carotid colour Doppler ultrasound (CDUS) and CEUS in patients with LVV. METHODS AND RESULTS This prospective study included seven patients (mean age 48 ± 14 years, all females) with established LVV (Takayasu arteritis or giant cell arteritis). All patients underwent CDUS and CEUS (14 carotid arteries). Intima-media thickness, lumen diameter, Doppler velocities, vessel wall thickening, and lesion thickness were assessed. CEUS was used to improve visualization of the lumen-to-vessel wall border, and to visualize carotid wall vascularization. Four (57%) patients [7 (50%) carotid arteries] exhibited lesions, and the average lesion thickness was 2.0 ± 0.5 mm. According to the Doppler peak systolic velocity, 5 (35%) carotid arteries had a <50% stenosis, 1 (7%) had a 50-70% stenosis, and 1 (7%) had a ≥70% stenosis. The contrast agent improved the image quality and the definition of the lumen-to-vascular wall border. Carotid wall vascularization was observed in 5 (71%) patients [9 (64%) carotid arteries]. Five (36%) carotid arteries had mild-to-moderate vascularization, and 4 (29%) had severe wall vascularization. CONCLUSION Carotid CDUS allows the assessment of anatomical features of LVV, including vessel wall thickening and degree of stenosis. Carotid CEUS improves the visualization of the lumen border, and allows dynamic assessment of carotid wall vascularization, which is a potential marker of disease activity in patients with LVV.

High-Definition Imaging of Carotid Artery Wall Dynamics

The carotid artery (CA) is central to cardiovascular research, because of the clinical relevance of CA plaques as culprits of stroke and the accessibility of the CA for cardiovascular screening. The viscoelastic state of this artery, essential for clinical evaluation, can be assessed by observing arterial deformation in response to the pressure changes throughout the cardiac cycle. Ultrasound imaging has proven to be an excellent tool to monitor these dynamic deformation processes. We describe how a new technique called high-frame-rate ultrasound imaging captures the tissue deformation dynamics throughout the cardiac cycle in unprecedented detail. Local tissue motion exhibits distinct features of sub-micrometer displacements on a sub-millisecond time scale. We present a high-definition motion analysis technique based on plane wave ultrasound imaging able to capture these features. We validated this method by screening a group of healthy volunteers and compared the results with those for two patients known to have atherosclerosis to illustrate the potential utility of this technique.

New Quantification Methods for Carotid Intra-plaque Neovascularization Using Contrast-Enhanced Ultrasound

Carotid intraplaque neovascularization (IPN) has been associated with progressive atherosclerotic disease and plaque vulnerability. Therefore, its accurate quantification might allow early detection of plaque vulnerability. Contrast enhanced ultrasound (CEUS) can detect these small microvessels. To quantify IPN, we developed quantitative methods based on time intensity curve (TIC) and maximum intensity projection (MIP), micro-vascular structure analysis (VSA), and statistical segmentation (SS). Plaque region of interest (ROI) is manually drawn and motion compensation is applied before each analysis. In TIC and MIP, we examine perfusion dynamics and regions within plaques. In VSA, we detect and track contrast spots to examine the microvessel network. In SS, we classify plaque intensities into different components for quantification of IPN. Through an iterative expectation-maximization algorithm, plaque pixels are initially labeled into artifacts, contrast, intermediate, and background class. Next, spatiotemporal and neighborhood information is used to relabel intermediate class pixels, remove artifacts and correct false-contrast. From the applied analyses, we derived several parameters - e.g. MIP based IPN surface area (MIPNSA), MIP based surface ratio (MIPNSR), SS based IPN surface area (SSIPNSA), plaque mean intensity, mean plaque contrast percentage, and number of microvessels (MVN) - and compared them to consensus of visual grading of IPN by two independent physicians. We analyzed 45 carotid arteries with stenosis. To verify if SSIPNSA improves the suppression of artifacts, we analyzed 8 plaques twice, with saturation artifacts included and excluded from the ROI. Five parameters were found to be significantly correlated to visual scoring and may thus have the potential to replace qualitative visual scoring and to measure the degree of carotid IPN. The MIPNSA & SSIPNSA parameters gave the best distinction between visual scores. SSIPNSA proved less sensitive for artifacts than MIPNSA.

Assessment of subclinical atherosclerosis and intraplaque neovascularization using quantitative contrast-enhanced ultrasound in patients with familial hypercholesterolemia.

OBJECTIVE Patients with heterozygous familial hypercholesterolemia (FH) are at severely increased risk of developing atherosclerosis at relatively young age. The aim of this study was to assess the prevalence of subclinical atherosclerosis and intraplaque neovascularization (IPN) in patients with FH, using contrast-enhanced ultrasound (CEUS) of the carotid arteries. METHODS The study population consisted of 69 consecutive asymptomatic patients with FH (48% women, mean age 55 ± 8 years). All patients underwent carotid ultrasound to evaluate the presence and severity of carotid atherosclerosis, and CEUS to assess IPN. IPN was assessed in near wall plaques using a semi-quantitative grading scale and semi-automated quantification software. RESULTS Carotid plaque was present in 62 patients (90%). A total of 49 patients had plaques that were eligible for the assessment of IPN: 7 patients (14%) had no IPN, 39 (80%) had mild to moderate IPN and 3 (6%) had severe IPN. Semi-automated quantification software showed no statistical significant difference in the amount of IPN between patients > 50 years and patients ≤ 50 years and between patients with a defective low-density lipoprotein receptor (LDLR) mutation and patients with a negative LDLR mutation. Plaques with irregular or ulcerated surface had significantly more IPN than plaques with a smooth surface (p < 0.05). CONCLUSION Carotid ultrasound demonstrated atherosclerotic plaque in 90% of asymptomatic patients with FH without known atherosclerosis. IPN assessed with CEUS, was present in 86% of these patients. Irregular and ulcerated plaques exhibited significantly more IPN than plaques with a smooth surface.

Quantitative Analysis of Ultrasound Contrast Flow Behavior in Carotid Plaque Neovasculature

Intraplaque neovascularization is considered as an important indication for plaque vulnerability. We propose a semiautomatic algorithm for quantification of neovasculature, thus, enabling assessment of plaque vulnerability. The algorithm detects and tracks contrast spots using multidimensional dynamic programming. Classification of contrast tracks into blood vessels and artifacts was performed. The results were compared with manual tracking, visual classification and maximal intensity projection. In 28 plaques, 97% of the contrast spots were detected. In 89% of the objects, the automatic tracking determined the contrast motion with an average distance of less than 0.5 mm from the manual marking. Furthermore, 75% were correctly classified into artifacts and vessels. The automated neovascularization grading agreed within 1 grade with visual analysis in 91% of the cases, which was comparable to the interobserver variability of visual grading. These results show that the method can successfully quantify features that are linked to vulnerability of the carotid plaque.

Assessment of carotid atherosclerosis, intraplaque neovascularization, and plaque ulceration using quantitative contrast-enhanced ultrasound in asymptomatic patients with diabetes mellitus.

AIMS Patients with diabetes mellitus (DM) are at severely increased risk of developing atherosclerosis. Intraplaque neovascularization (IPN) and plaque ulceration are markers of the vulnerable plaque, which is at an increased risk of rupture and may lead to cardiovascular events. The aim of this study was to assess the prevalence of subclinical carotid atherosclerosis, intraplaque neovascularization (IPN), and plaque ulceration in asymptomatic patients with DM. METHODS AND RESULTS A total of 51 asymptomatic patients with DM underwent standard carotid ultrasound in conjunction with contrast-enhanced ultrasound (CEUS) to assess the prevalence of subclinical atherosclerosis, IPN, and plaque ulceration. Subclinical atherosclerosis was defined as the presence of atherosclerotic plaque, according to the Mannheim consensus. Semi-automated quantification software was used to assess IPN in suitable plaques. Plaque ulceration was defined as a disruption of the plaque-lumen border of ≥ 1 × 1 mm. A total of 408 carotid segments in 102 carotid arteries were investigated. Forty-six (90%) patients had subclinical atherosclerotic plaques, with a median plaque thickness of 2.4 mm (inter-quartile range 1.9-3.0). CEUS revealed IPN in 88% of the patients. In 10 carotid segments (8%), the plaque had an ulcerated surface. The presence of IPN could not be predicted by the presence of clinical characteristics including complications of DM (P > 0.05). CONCLUSION Patients with DM have a high prevalence (90%) of subclinical carotid atherosclerosis. Severe IPN and plaque ulceration, which are markers of the vulnerable plaque type, were detected in, respectively, 13 and 9% of these patients.

Effect of Carotid Plaque Screening Using Contrast-Enhanced Ultrasound on Cardiovascular Risk Stratification

Cardiovascular risk stratification of asymptomatic patients is based on the assessment of risk factors. Noninvasive imaging of subclinical atherosclerosis may improve cardiovascular risk stratification, especially in patients with co-morbidities. The aim of this study was to investigate the effect of contrast-enhanced ultrasound (CEUS) of the carotid arteries on cardiovascular risk assessment. The study population consisted of 100 consecutive asymptomatic patients with ≥1 clinical risk factor for atherosclerosis. Cardiovascular risk was estimated by calculating the Prospective Cardiovascular Münster Heart Study (PROCAM) risk score. This score was divided into 3 subgroups: low (≤5%), intermediate (6% to 19%), and high (≥20%). Subclinical carotid atherosclerosis was assessed using standard ultrasound for intima-media thickness and plaque screening and CEUS for additional plaque screening. CEUS was performed using SonoVue contrast agent. Patients with subclinical atherosclerosis were considered to be at high cardiovascular risk. McNemars test was used to compare PROCAM score to ultrasound findings. The mean PROCAM risk score was 9 ± 10; the PROCAM risk score was low in 72 patients (72%), intermediate in 17 patients (17%), and high in 11 patients (11%). A total of 21 patients (21%) had abnormal carotid intima-media thickness, 77% had plaques on conventional carotid ultrasound, and 88% had plaques on standard carotid ultrasound combined with CEUS. Detection of atherosclerosis led to the reclassification of 79 patients (79%) to high cardiovascular risk (p <0.001). In conclusion, CEUS changes the risk category as estimated by a traditional risk stratification model in most asymptomatic patients. CEUS may thus be an additional method for cardiovascular risk prediction in patient groups with co-morbidities.

Motion compensation method using dynamic programming for quantification of neovascularization in carotid atherosclerotic plaques with contrast enhanced ultrasound (CEUS)

Intraplaque neovascularization (IPN) has been linked with progressive atherosclerotic disease and plaque instability in several studies. Quantification of IPN may allow early detection of vulnerable plaques. A dedicated motion compensation method with normalized-cross-correlation (NCC) block matching combined with multidimensional (2D+time) dynamic programming (MDP) was developed for quantification of IPN in small plaques (<30% diameter stenosis). The method was compared to NCC block matching without MDP (forward tracking (FT)) and showed to improve motion tracking. Side-by-side CEUS and B-mode ultrasound images of carotid arteries were acquired by a Philips iU22 system with a L9-3 linear array probe. The motion pattern for the plaque region was obtained from the Bmode images with MDP. MDP results were evaluated in-vitro by a phantom and in-vivo by comparing to manual tracking of three experts for multibeat-image-sequences (MIS) of 11 plaques. In the in-vivo images, the absolute error was 72±55μm (mean±SD) for X (longitudinal) and 34±23μm for Y (radial). The methods success rate was visually assessed on 67 MIS. The tracking was considered failed if it deviated >2 pixels (~200μm) from true motion in any frame. Tracking was scored as fully successful in 63 MIS (94%) for MDP vs. 52(78%) for FT. The range of displacement over these 63 was 1045±471μm (X) and 395±216μm (Y). The tracking sporadically failed in 4 MIS (6%) due to poor image quality, jugular vein proximity and out-of-plane motion. Motion compensation showed improved lumen-plaque contrast separation. In conclusion, the proposed method is sufficiently accurate and successful for in vivo application.