Atherosclerotic Carotid Plaque Composition and Incident Stroke and Coronary Events.

BACKGROUND: Increasing evidence suggests that atherosclerotic plaque composition rather than plaque size is linked to ischemic cardiovascular events, yet largescale population-based data in asymptomatic individuals remain scarce. OBJECTIVES: This study sought to investigate carotid plaque composition in relation to incident stroke and coronary heart disease (CHD) in a population-based setting. METHODS: Between 2007 and 2012, 1,349 persons (mean age 72 years, 49.5% women) from the population-based Rotterdam Study who were free from a history of stroke or CHD, in whom carotid ultrasonography showed subclinical atherosclerosis, and who underwent high-resolution magnetic resonance imaging of the carotid arteries to assess plaque characteristics. These included the presence of specific plaque components (intraplaque hemorrhage [IPH], lipid-rich necrotic core, and calcification), and measures of plaque size (maximum plaque thickness and presence of stenosis of more than 30%). Individuals were continuously followed for the occurrence of stroke or CHD until January 1, 2015. The authors used Cox regression models to assess the association of the plaque characteristics with the incidence of stroke and CHD, with adjustments for age, sex, and cardiovascular risk factors. RESULTS: During a median of 5.1 years' follow-up for stroke and 4.8 years for CHD, 51 individuals had a stroke and 83 developed CHD. Independent of maximum plaque thickness and cardiovascular risk factors, the presence of IPH was associated with incident stroke and CHD (fully adjusted hazard ratio: 2.42 [95% confidence interval: 1.30 to 4.50], and 1.95 [95% confidence interval: 1.20 to 3.14]). Presence of a lipid-rich necrotic core and calcification were not associated with stroke or CHD. CONCLUSIONS: The presence of IPH in the carotid atherosclerotic plaque is an independent risk factor for stroke and CHD. These findings indicate the promise of IPH as a marker of plaque vulnerability in healthy persons with subclinical atherosclerosis.

Change in Carotid Intraplaque Hemorrhage in Community-dwelling Subjects: A Follow-up Study Using Serial MR Imaging.

Purpose To investigate intraplaque hemorrhage (IPH) development and change over time. Materials and Methods Institutional review board approval and written informed consent from all participants were obtained. From a population-based study on subclinical atherosclerosis, 40 participants with IPH at baseline magnetic resonance (MR) imaging (53 carotids with IPH) were randomly selected and were matched with 27 control subjects (53 carotids without IPH) to undergo a second MR examination (mean interval, 17 months ± 4 [standard deviation]) to assess IPH change. IPH volume change was evaluated by using both a visual rating scale and an automated volumetric segmentation tool. Cardiovascular risk factors for IPH volume change were investigated with linear regression analyses. Results IPH remained present in 50 (94%) of the 53 carotids with IPH at baseline, and it developed in five (7%) of the 40 carotids without IPH at baseline. Visual progression of IPH volume was present in 14 (26%) of the 53 carotids with IPH at baseline, and regression was present in 16 (30%). Mean quantitative change in IPH volume was -13.7 mm3 ± 62.6 per year of follow-up. Male sex (men vs women, 37.7 mm3; 95% confidence interval [CI]: 11.0, 64.4; P = .006), smoking (smokers vs nonsmokers, 45.2 mm3; 95% CI: 7.1, 83.4; P = .020), and hypertension (subjects with hypertension vs those without hypertension, 32.5 mm3; 95% CI: 7.7, 57.2; P = .010) were associated with IPH volume change. Conclusion During 17 months of follow-up, both visual progression and regression of IPH volume occurs, whereas quantitatively IPH volume decreases. This suggests that IPH is a dynamic process with potential for either growth or resolution over time. © RSNA, 2016 Online supplemental material is available for this article.

Coexistence of Calcification, Intraplaque Hemorrhage and Lipid Core within the Asymptomatic Atherosclerotic Carotid Plaque: The Rotterdam Study.

BACKGROUND: There is a growing amount of evidence suggesting that the composition of carotid atherosclerotic plaques may be of clinical relevance. Yet, little is known on the coexistence of potentially vulnerable and stabilizing components within asymptomatic plaques. Therefore, in this study we set out to investigate the coexistence of intraplaque calcification, hemorrhage and lipid core within the carotid artery using a multi-modality imaging approach. METHODS: In 329 subjects from the population-based Rotterdam Study, all with ultrasound-confirmed carotid wall thickening, we performed a multi-detector CT and a high-resolution MRI of the carotid artery bifurcation at both sides. On the CT examinations, we quantified the volume of intraplaque calcification, and using the MRI examinations we rated the presence of intraplaque hemorrhage and of lipid core. In total, we investigated 611 carotid arteries with plaques. With logistic regression models we investigated the relationship of calcification volume - as a potential stabilizing component - with the presence of potential vulnerable components (intraplaque hemorrhage and lipid core) within each carotid plaque. We adjusted all analyses for age, sex and maximal plaque thickness. Next, we stratified on degree of stenosis (≤ or >30%) to evaluate effect modification by atherosclerotic burden. RESULTS: We found that a larger calcification volume was associated with a higher prevalence of intraplaque hemorrhage, and a lower prevalence of lipid core (fully-adjusted odds ratio (OR) per standard deviation (SD) increase in calcification volume: 2.04 (95% confidence intervals (CI): 1.49; 2.78) and 0.72 (95% CI: 0.58; 0.90), respectively). Stratification on the degree of stenosis showed no difference in the association between calcification volume and hemorrhage over strata, while the relationship between a larger calcification volume and a lower prevalence of lipid seemed more pronounced in persons with a high degree of stenosis. CONCLUSIONS: In this population-based setting, we found that there is a complex relationship between calcification, intraplaque hemorrhage and lipid core within the carotid atherosclerotic plaque. Plaques with a higher load of calcification contain more often hemorrhagic components, but less often lipid core. Our results suggest that both in small and large plaques, intraplaque calcification may not be a stabilizing factor per se. These findings create an urge for conducting prospective studies investigating the interrelation of these different plaque components with regard to future cerebrovascular events.

Chronic obstructive pulmonary disease and lipid core carotid artery plaques in the elderly: the Rotterdam Study.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is an independent risk factor for ischemic stroke and the risk increases with severity of airflow limitation. Even though vulnerable carotid artery plaque components, such as intraplaque hemorrhage and lipid core, place persons at high risk for ischemic events, the plaque composition in patients with COPD has never been explored. OBJECTIVES: To investigate the prevalence of carotid wall thickening, the different carotid artery plaque components, and their relationship with severity of airflow limitation in elderly patients with COPD. METHODS: This cross-sectional analysis was part of the Rotterdam Study, a prospective population-based cohort study performed in subjects aged 55 years and older. Diagnosis of COPD was confirmed by spirometry. Participants with carotid wall intima-media thickness greater than or equal to 2.5 mm on ultrasonography underwent high-resolution magnetic resonance imaging for characterization of carotid plaques. Data were analyzed using logistic regression. MEASUREMENTS AND MAIN RESULTS: COPD cases (n = 253) had a twofold increased risk (odds ratio, 2.0; 95% confidence interval, 1.44-2.85; P < 0.0001) of presentation with carotid wall thickening on ultrasonography compared with control subjects with a normal lung function (n = 920). Moreover, the risk increased significantly with severity of airflow limitation. On magnetic resonance imaging, vulnerable lipid core plaques were more frequent in COPD cases than in control subjects (odds ratio, 2.1; 95% confidence interval, 1.25-3.69; P = 0.0058). CONCLUSIONS: Carotid artery wall thickening is more prevalent in patients with COPD than in control subjects. In elderly subjects with carotid wall thickening, COPD is an independent predictor for the presence of a lipid core, and therefore of vulnerable plaques.

Blood pressure parameters and carotid intraplaque hemorrhage as measured by magnetic resonance imaging: The Rotterdam Study.

Intraplaque hemorrhage (IPH) is a characteristic of the vulnerable atherosclerotic plaque that has been associated with ischemic stroke. Not much is known about determinants of IPH. We studied whether blood pressure parameters are associated with presence of IPH. Within the framework of a prospective population-based cohort study, The Rotterdam Study, the carotid arteries of 1006 healthy participants ≥45 years and with intima-media thickening (≥2.5 mm) on ultrasound were imaged with a 1.5-T magnetic resonance imaging scanner. IPH was defined as a hyperintense signal on a 3D-T1w-GRE magnetic resonance sequence. Generalized estimation equation analysis, adjusted for age, sex, carotid wall thickness, and cardiovascular risk factors, was used to assess the association between blood pressure parameters and IPH. Magnetic resonance imaging of the carotid arteries revealed presence of IPH in 444 of 1860 plaques (24%). Systolic blood pressure and pulse pressure (PP) were significantly associated with IPH after adjustment for age and sex. In multivariate analysis, PP yielded the strongest association, with an odds ratio per SD increase in PP of 1.22 (95% CI, 1.07-1.40). The odds ratio per SD for systolic blood pressure was 1.13 (0.99-1.28). Only PP remained significant after additional adjustment for other blood pressure components. The combination of smoking and isolated systolic hypertension was associated with 2.5 times increased risk of IPH (1.2-5.2). In conclusion, PP was the strongest determinant of IPH independent of cardiovascular risk factors and other blood pressure components. The association between pulsatile flow and IPH may provide novel insights in the development of the vulnerable plaque.

Semiautomatic carotid lumen segmentation for quantification of lumen geometry in multispectral MRI.

Quantitative information about the geometry of the carotid artery bifurcation is relevant for investigating the onset and progression of atherosclerotic disease. This paper proposes an automatic approach for quantifying the carotid bifurcation angle, carotid area ratio, carotid bulb size and the vessel tortuosity from multispectral MRI. First, the internal and external carotid centerlines are determined by finding a minimum cost path between user-defined seed points where the local costs are based on medialness and intensity. The minimum cost path algorithm is iteratively applied after curved multi-planar reformatting to refine the centerline. Second, the carotid lumen is segmented using a topology preserving geodesic active contour which is initialized by the extracted centerlines and steered by the MR intensities. Third, the bifurcation angle and vessel tortuosity are automatically extracted from the segmented lumen. The methods for centerline tracking and lumen segmentation are evaluated by comparing their accuracy to the inter- and intra-observer variability on 48 datasets (96 carotid arteries) acquired as part of a longitudinal population study. The evaluation reveals that 94 of 96 carotid arteries are segmented successfully. The distance between the tracked centerlines and the reference standard (0.33 mm) is similar to the inter-observer variation (0.32 mm). The lumen segmentation accuracy (average DSC=0.89, average mean absolute surface distance=0.31 mm) is close to the inter-observer variation (average dice=0.92, average mean surface distance=0.23 mm). The correlation coefficient of manually and automaticly derived bifurcation angle, carotid proximal area ratio, carotid proximal bulb size and vessel totuosity quantifications are close to the correlation of these measures between observers. This demonstrates that the automated method can be used for replacing manual centerline annotation and manual contour drawing for lumen segmentation in MRIs data prior to quantifying the carotid bifurcation geometry.

Determinants of magnetic resonance imaging detected carotid plaque components: the Rotterdam Study.

AIMS: Components of carotid atherosclerotic plaque such as intraplaque haemorrhage and lipid core are important determinants of plaque progression and destabilization. The association between plaque components and risk factors for cardiovascular disease is not well studied. METHODS AND RESULTS: Participants from the population-based Rotterdam Study with carotid wall thickening on ultrasound (n = 1006) underwent high-resolution magnetic resonance imaging for carotid plaque characterization. Maximum wall thickening, the degree of stenosis, and the presence of intraplaque haemorrhage, lipid core, and calcification were assessed in both carotid arteries and their associations with cardiovascular risk factors were investigated. Intraplaque haemorrhage and lipid core were present in almost 25% of plaques, respectively, and occurred simultaneously in 9% of plaques. In men, intraplaque haemorrhage and lipid core were more prevalent compared with women (28.8 vs. 18.3 and 28.9 vs. 21.7%, respectively). Intraplaque haemorrhage occurred more frequently at older age [odds ratio (OR) per 10 years 1.8, 95% confidence interval 1.6-2.1], in men (OR 2.2, 1.7-2.9), in persons with hypertension (multivariate adjusted OR 1.4, 1.1-1.8), and in current smokers (multivariate adjusted OR 1.6, 1.2-2.3). Men (OR 1.5, 1.2-1.9) and subjects with hypercholesterolaemia (multivariate adjusted OR 1.4, 1.1-1.7) more often exhibited a lipid core. CONCLUSION: In subjects from the general population with carotid wall thickening, intraplaque haemorrhage and lipid core-both considered indicators of unstable plaque-are highly frequent and more prevalent in men compared with women. Furthermore, different risk factors are associated with these plaque components: hypertension and current smoking were risk factors for the presence of intraplaque haemorrhage, and hypercholesterolaemia was the only risk factor for lipid core presence.

Association between carotid artery plaque ulceration and plaque composition evaluated with multidetector CT angiography.

BACKGROUND AND PURPOSE: Symptomatic carotid artery plaque ulceration is associated with distinct plaque components such as a large lipid-rich necrotic core (LR-NC) in ischemic stroke patients with a ≥50% carotid stenosis. We evaluated the associations between carotid artery plaque ulceration and plaque characteristics in ischemic stroke patients with ≥50% stenosis, as well as in those with a low degree of stenosis (0% to 49%). METHODS: Consecutive patients (n=346) with symptoms in the anterior circulation were evaluated with multidetector CT angiography (MDCTA) for the presence of atherosclerotic plaque, degree of stenosis, and plaque ulceration in the symptomatic carotid artery. Plaque volume and plaque component proportions of LR-NC, fibrous tissue, and calcification were measured. The associations between plaque ulceration and plaque characteristics were analyzed using logistic regression. RESULTS: Atherosclerotic plaque was present in 185 patients. Plaque ulcerations were present in 38 (21%) patients, of which half had a low degree stenosis (0% to 49%). Plaque volume was significantly larger in ulcerated plaques. After adjustment for age, sex, and degree of stenosis, LR-NC proportion was strongly associated with plaque ulceration (odds ratio, 2.21; 95% CI, 1.49 to 3.27), whereas calcification proportion was inversely associated with plaque ulceration (odds ratio, 0.60; 95% CI, 0.40 to 0.89). These associations remained significant in patients with a low degree stenosis (0% to 49%). CONCLUSIONS: Plaque volume, degree of stenosis, and LR-NC proportion evaluated noninvasively with MDCTA are associated with carotid artery plaque ulceration, even in patients with a low degree stenosis (0% to 49%). Plaque volume and composition analysis with MDCTA may identify rupture prone plaques and improve risk stratification in ischemic stroke patients.

A semi-automatic method for segmentation of the carotid bifurcation and bifurcation angle quantification on black blood MRA.

Quantitative information about the geometry of the carotid artery bifurcation may help in predicting the development of atherosclerosis. A geodesic active contours based segmentation method combining both gradient and intensity information was developed for semi-automatic, accurate and robust quantification of the carotid bifurcation angle in Black Blood MRA data. The segmentation method was evaluated by comparing its accuracy to inter and intra observer variability on a large dataset that has been acquired as part of a longitudinal population study which investigates the natural progression of carotid atherosclerosis. Furthermore, the method is shown to be robust to initialization differences. The bifurcation angle obtained from the segmented lumen corresponds well with the angle derived from the manual lumen segmentation, which demonstrates that the method has large potential to replace manual segmentations for extracting the carotid bifurcation angle from Black Blood MRA data.

MRI-based quantification of outflow boundary conditions for computational fluid dynamics of stenosed human carotid arteries.

Accurate assessment of wall shear stress (WSS) is vital for studies on the pathogenesis of atherosclerosis. WSS distributions can be obtained by computational fluid dynamics (CFD) using patient-specific geometries and flow measurements. If patient-specific flow measurements are unavailable, in- and outflow have to be estimated, for instance by using Murray's Law. It is currently unknown to what extent this law holds for carotid bifurcations, especially in cases where stenoses are involved. We performed flow measurements in the carotid bifurcation using phase-contrast MRI in patients with varying degrees of stenosis. An empirical relation between outflow and degree of area stenosis was determined and the outflow measurements were compared to estimations based on Murray's Law. Furthermore, the influence of outflow conditions on the WSS distribution was studied. For bifurcations with an area stenosis smaller than 65%, the outflow ratio of the internal carotid artery (ICA) to the common carotid artery (CCA) was 0.62+/-0.12 while the outflow ratio of the external carotid artery (ECA) was 0.35+/-0.13. If the area stenosis was larger than 65%, the flow to the ICA decreased linearly to zero at 100% area stenosis. The empirical relation fitted the flow data well (R(2)=0.69), whereas Murray's Law overestimated the flow to the ICA substantially for larger stenosis, resulting in an overestimation of the WSS. If patient-specific flow measurements of the carotid bifurcation are unavailable, estimation of the outflow ratio by the presented empirical relation will result in a good approximation of calculated WSS using CFD.