Gerrit L. ten Kate

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.

Noninvasive Imaging of the Vulnerable Atherosclerotic Plaque

Atherosclerosis is an inflammatory disease, complicated by progressively increasing atherosclerotic plaques that eventually may rupture. Plaque rupture is a major cause of cardiovascular events, such as unstable angina, myocardial infarction, and stroke. A number of noninvasive imaging techniques have been developed to evaluate the vascular wall in an attempt to identify so-called vulnerable atherosclerotic plaques that are prone to rupture. The purpose of the present review is to systematically investigate the accuracy of noninvasive imaging techniques in the identification of plaque components and morphologic characteristics associated with plaque vulnerability, assessing their clinical and diagnostic value.

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.

Molecular imaging of inflammation and intraplaque vasa vasorum: A step forward to identification of vulnerable plaques?

Current developments in cardiovascular biology and imaging enable the noninvasive molecular evaluation of atherosclerotic vascular disease. Intraplaque neovascularization sprouting from the adventitial vasa vasorum has been identified as an independent predictor of intraplaque hemorrhage and plaque rupture. These intraplaque vasa vasorum result from angiogenesis, most likely under influence of hypoxic and inflammatory stimuli. Several molecular imaging techniques are currently available. Most experience has been obtained with molecular imaging using positron emission tomography and single photon emission computed tomography. Recently, the development of targeted contrast agents has allowed molecular imaging with magnetic resonance imaging, ultrasound and computed tomography. The present review discusses the use of these molecular imaging techniques to identify inflammation and intraplaque vasa vasorum to identify vulnerable atherosclerotic plaques at risk of rupture and thrombosis. The available literature on molecular imaging techniques and molecular targets associated with inflammation and angiogenesis is discussed, and the clinical applications of molecular cardiovascular imaging and the use of molecular techniques for local drug delivery are addressed.

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.

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.

Prognostic significance of QRS duration in patients with suspected coronary artery disease referred for noninvasive evaluation of myocardial ischemia.

The purpose of this study was to evaluate the prognostic significance of QRS duration in patients with suspected coronary artery disease (CAD) referred for noninvasive evaluation of myocardial ischemia by dobutamine stress echocardiography. QRS duration is a prognostic marker in patients with previous myocardial infarction and/or heart failure. The relation between QRS duration and outcome of patients without known heart disease has not been evaluated. A total of 1,227 patients (707 men, mean age 61 +/- 14 years) with suspected CAD underwent dobutamine stress echocardiography for evaluation of myocardial ischemia. Patients were followed to determine predictors of cardiac events and to assess the incremental significance of QRS duration compared to clinical and dobutamine stress echocardiographic data. During a mean follow-up of 4.2 +/- 2.4 years, 280 patients (23%) died (129 cardiac deaths), and 60 (5%) had a nonfatal infarction. Annualized cardiac death rates were 2.0% in patients with QRS duration <120 ms and 4.4% in patients with QRS duration >or=120 ms, respectively (p <0.0001). Annualized event rates for cardiac death/nonfatal infarction were 2.8% in patients with QRS duration <120 ms and 4.8% in patients with QRS duration >or=120 ms (p = 0.0001). Multivariate models identified age, male gender, smoking, QRS duration >or=120 ms, and an abnormal dobutamine stress echocardiogram as independent predictors of cardiac death and the combined end point cardiac death/nonfatal infarction. In conclusion, QRS duration is an independent predictor of cardiac death and cardiac death/nonfatal infarction in patients with suspected CAD. This risk is persistent after adjustment for clinical variables, left ventricular function, and myocardial ischemia.

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.

Assessment of subclinical atherosclerosis using contrast-enhanced ultrasound

AIMS The sensitivity of standard carotid ultrasound and colour Doppler for the detection of subclinical atherosclerotic plaques is suboptimal. The aim of this study is to assess whether contrast-enhanced ultrasound (CEUS) added to standard carotid ultrasound improves the detection of subclinical atherosclerosis. METHODS AND RESULTS Carotid intima-media thickness (CIMT) measurement, standard carotid ultrasound including colour Doppler imaging, and CEUS were performed in 100 asymptomatic patients with one or more risk factors for atherosclerosis. CEUS was performed using intravenous administration of SonoVue™ contrast agent (Bracco S.p.A., Milan, Italy). CIMT, standard ultrasound, colour Doppler, and CEUS were reviewed by two independent observers. Standard ultrasound, colour Doppler, and CEUS were scored for the presence of atherosclerotic plaques. Subclinical atherosclerosis was diagnosed if patients had a CIMT above their age-corrected threshold value or if atherosclerotic plaques were present on standard carotid ultrasound clips or CEUS clips. McNemars test was performed to compare between groups. Twenty-one patients (21%) had a thickened CIMT value and were considered to have subclinical atherosclerosis. Standard carotid ultrasound including colour Doppler demonstrated atherosclerotic plaques in 77 patients (77%). The addition of CEUS to the standard ultrasound protocol demonstrated atherosclerotic plaques in 88 patients (88%). The incorporation of CEUS into the standard carotid ultrasound protocol resulted in a significantly improved detection of patients with subclinical atherosclerosis (P < 0.01). CONCLUSION CEUS has an incremental value for the detection of subclinical atherosclerosis in the carotid arteries. Atherosclerotic plaques which were only detected with CEUS and not with standard carotid ultrasound and colour Doppler imaging were predominantly hypoechoic.