Association between Intraplaque Hemorrhage and Vascular Remodeling in Carotid Arteries: The Plaque at RISK (PARISK) Study.

INTRODUCTION: Vascular remodeling is a compensatory enlargement of the vessel wall in response to atherosclerotic plaque growth. We aimed to investigate the association between intraplaque hemorrhage (IPH), vascular remodeling, and luminal dimensions in recently symptomatic patients with mild to moderate carotid artery stenosis in which the differences in plaque size were taken into account. MATERIALS AND METHODS: We assessed vessel dimensions on MRI of the symptomatic carotid artery in 164 patients from the Plaque At RISK study. This study included patients with recent ischemic neurological event and ipsilateral carotid artery stenosis <70%. The cross section with the largest wall area (WA) in the internal carotid artery (ICA) was selected for analysis. On this cross section, the following parameters were determined: WA, total vessel area (TVA), and lumen area (LA). Vascular remodeling was quantified as the remodeling ratio (RR) and was calculated as TVA at this position divided by the TVA in an unaffected distal portion of the ipsilateral ICA. Adjustment for WA was performed to correct for plaque size. RESULTS: Plaques with IPH had a larger WA (0.56 vs. 0.46 cm2; p < 0.001), a smaller LA (0.17 vs. 0.22 cm2; p = 0.03), and a higher RR (2.0 vs. 1.9; p = 0.03) than plaques without IPH. After adjustment for WA, plaques containing IPH had a smaller LA (B = -0.052, p = 0.01) than plaques without IPH, but the RR was not different. CONCLUSION: After correcting for plaque size, plaques containing IPH had a smaller LA than plaques without IPH. However, RR was not different.

High Spatial Inhomogeneity in the Intima-Media Thickness of the Common Carotid Artery is Associated with a Larger Degree of Stenosis in the Internal Carotid Artery: The PARISK Study.

Purpose Inhomogeneity of arterial wall thickness may be indicative of distal plaques. This study investigates the intra-subject association between relative spatial intima-media thickness (IMT) inhomogeneity of the common carotid artery (CCA) and the degree of stenosis of plaques in the internal carotid artery (ICA). Materials and Methods We included 240 patients with a recent ischemic stroke or transient ischemic attack and mild-to-moderate stenosis in the ipsilateral ICA. IMT inhomogeneity was extracted from B-mode ultrasound recordings. The degree of ICA stenosis was assessed on CT angiography according to the European Carotid Surgery Trial method. Patients were divided into groups with a low (≤ 2 %) and a high (> 2 %) IMT inhomogeneity scaled with respect to the local end-diastolic diameter. Results 182 patients had suitable CT and ultrasound measurements. Relative CCA-IMT inhomogeneity was similar for the symptomatic and asymptomatic side (difference: 0.02 %, p = 0.85). High relative IMT inhomogeneity was associated with a larger IMT (difference: 235 µm, p < 0.001) and larger degree of ICA stenosis (difference: 5 %, p = 0.023) which remained significant (p = 0.016) after adjustment for common risk factors. Conclusion Regardless of common risk factors, high relative CCA-IMT inhomogeneity is associated with a greater degree of ICA stenosis and is therefore indicative of atherosclerotic disease. The predictive value of CCA-IMT inhomogeneity for plaque progression and recurrence of cerebrovascular symptoms will be determined in the follow-up phase of PARISK.

Heritability and Genome-Wide Association Analyses of Intracranial Carotid Artery Calcification: The Rotterdam Study.

BACKGROUND AND PURPOSE: Intracranial carotid artery calcification (ICAC) is one of the most important risk factors for stroke. Although several environmental risk factors for ICAC have been identified, its genetic background remains unclear. METHODS: Between 2003 and 2006, 2034 participants from the prospective population-based Rotterdam study (mean age: 69.6±6.8 years; 51.7% female) underwent computed tomography to quantify vascular calcification in the intracranial internal carotid artery. Blood samples were drawn for genotyping. Genotypes of the participants were imputed to the 1000 Genomes reference panel to generate genetic relationship matrices for the estimation of the heritability of ICAC volume. Adjustments were made for age and sex. Subsequently, genome-wide association analyses were performed to identify specific variants. RESULTS: The age- and sex-adjusted heritability (h(2)) of ICAC was 47% [standard error (SE): 19%; P=0.009]. Genome-wide association analyses identified a variant on chromosome 9p21.3 (rs1537372; N=2034; P=4.75×10(-9)) and 1 variant on chromosome 11p11.2 (rs11038042, N=2034; P=3.27×10(-8)) that were significantly associated with ICAC volume. Rs1537372 replicated in an independent sample of 716 stroke patients (Pcombined=1.38×10(-10)). CONCLUSIONS: ICAC volume is a heritable trait, which is partly explained by common genetic variation. We identified specific genetic variants associated with ICAC, which given the importance of ICAC in stroke risk, needs replication in larger-scale studies to further elucidate its genetic basis.

Use of Antiplatelet Agents Is Associated With Intraplaque Hemorrhage on Carotid Magnetic Resonance Imaging: The Plaque at Risk Study.

BACKGROUND AND PURPOSE: Intraplaque hemorrhage (IPH), visualized by magnetic resonance imaging, has shown to be associated with the risk of stroke in patients with carotid artery stenosis. The mechanisms of IPH development are poorly understood. In this study, we investigated the association between clinical patient characteristics and carotid IPH on high-resolution magnetic resonance imaging. METHODS: Patients participate in the Plaque at Risk (PARISK) study. This prospective, multicenter cohort study included patients with recent amaurosis fugax, hemispheric transient ischemic attack, or nondisabling stroke in the internal carotid artery territory and an ipsilateral carotid stenosis of <70%, who were not scheduled for carotid revascularization procedure. One hundred patients, recruited between 2010 and 2012, underwent a 3-T high-resolution carotid magnetic resonance imaging. We documented clinical patient characteristics and performed multivariable logistic regression analysis to investigate their association with IPH. RESULTS: IPH was observed in 45 patients (45%) in 1 or both carotid arteries. Male sex and the use of antiplatelet agents before the index event were associated with IPH in univariable analysis. In a multivariable analysis, only previous use of antiplatelet agents was significantly associated with IPH (odds ratio, 2.71; 95% confidence interval, 1.12-6.61). Risk factors of atherosclerotic arterial disease, including a history of symptomatic arterial diseases, were not associated with IPH. CONCLUSIONS: In this cohort of 100 patients with recently symptomatic carotid stenosis, the previous use of antiplatelet agents is associated with carotid IPH on magnetic resonance imaging. Antiplatelet therapy may increase the risk of IPH, but our findings need to be confirmed in larger patient cohorts. The implications for risk stratification remain to be determined.

Plaque components in symptomatic moderately stenosed carotid arteries related to cerebral infarcts: the plaque at RISK study.

BACKGROUND AND PURPOSE: Carotid plaque composition is a major determinant of cerebrovascular events. In the present analysis, we evaluated the relationship between intraplaque hemorrhage (IPH) and a thin/ruptured fibrous cap (TRFC) in moderately stenosed carotid arteries and cerebral infarcts on MRI in the ipsilateral hemisphere. METHODS: A total of 101 patients with a symptomatic 30% to 69% carotid artery stenosis underwent MRI of the carotid arteries and the brain, within a median time of 45 days from onset of symptoms. The presence of ipsilateral infarcts in patients with and without IPH and TRFC was evaluated. RESULTS: IPH was seen in 40 of 101 plaques. TRFC was seen in 49 of 86 plaques (postcontrast series were not obtained in 15 patients). In total, 51 infarcts in the flow territory of the symptomatic carotid artery were found in 47 patients. Twenty nine of these infarcts, found in 24 patients, were cortical infarcts. No significant relationship was found between IPH or TRFC and the presence of ipsilateral infarcts. CONCLUSIONS: MRI detected IPH and TRFC are not related to the presence of old and recent cortical and subcortical infarcts ipsilateral to a symptomatic carotid artery stenosis of 30% to 69%. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01208025.

Association between arterial calcifications and nonlacunar and lacunar ischemic strokes.

BACKGROUND AND PURPOSE: Nonlacunar cerebral infarcts are presumed to be caused by thromboembolism from the heart or extracranial arteries, whereas lacunar infarcts are thought to be caused by small vessel disease. We investigated to what extent arterial calcifications differ between nonlacunar and lacunar ischemic strokes. METHODS: We studied 820 consecutive patients with transient ischemic attack or ischemic stroke in the anterior circulation who underwent multidetector computed tomography angiography and had no rare cause of stroke. The presence of likely cardioembolic pathogenesis was determined according to the Trial of Org 10172 in Acute Stroke Treatment criteria. The remaining 708 patients were categorized as nonlacunar or lacunar strokes, either transient ischemic attacks or strokes, based on clinical symptoms corrected by brain imaging results. We measured volume of calcifications in the aortic arch, symptomatic extracranial and intracranial carotid artery using multidetector computed tomography angiography. The difference in calcifications between nonlacunar and lacunar strokes was assessed with a multivariable logistic regression analysis. We adjusted for degree of symptomatic carotid artery stenosis and cardiovascular risk factors. RESULTS: We found an independent association between volume of aortic arch calcifications and nonlacunar ischemic strokes (adjusted odds ratio [95% confidence interval], 1.11 [1.02-1.21]). No independent associations between extracranial and intracranial carotid artery calcifications and nonlacunar strokes were present. CONCLUSIONS: The only difference we found between nonlacunar and lacunar strokes was a higher calcification volume in the aortic arch in nonlacunar strokes. Our findings only partially confirm the notion of distinct etiologies and suggest that the potential role of other plaque components, plaque morphology, and aortic arch calcifications in ischemic stroke subtypes awaits further evaluation.

Intraplaque hemorrhage, fibrous cap status, and microembolic signals in symptomatic patients with mild to moderate carotid artery stenosis: the Plaque at RISK study.

BACKGROUND AND PURPOSE: In patients with mild to moderate symptomatic carotid artery stenosis, intraplaque hemorrhage (IPH) and a thin/ruptured fibrous cap (FC) as evaluated with MRI, and the presence of microembolic signals (MESs) as detected with transcranial Doppler, are associated with an increased risk of a (recurrent) stroke. The objective of the present study is to determine whether the prevalence of MES differs in patients with and without IPH and thin/ruptured FC, and patients with only a thin/ruptured FC without IPH. METHODS: In this multicenter, diagnostic cohort study, patients with recent transient ischemic attack or minor stroke in the carotid territory and an ipsilateral mild to moderate carotid artery plaque were included. IPH and FC status were dichotomously scored. Analysis of transcranial Doppler data was done blinded for the MRI results. Differences between groups were analyzed with Fisher exact test. RESULTS: A total of 113 patients were included. Transcranial Doppler measurements were feasible in 105 patients (average recording time, 219 minutes). A total of 26 MESs were detected in 8 of 105 patients. In 44 of 105 plaques IPH was present. In 92 of 105 plaques FC status was assessable, 36 of these had a thin/ruptured FC. No significant difference in the prevalence of MES between patients with and without IPH (P=0.46) or with thick versus thin/ruptured FC (P=0.48) was found. CONCLUSIONS: In patients with a symptomatic mild to moderate carotid artery stenosis, IPH and FC status are not associated with MES. This suggests that MRI and transcranial Doppler provide different information on plaque vulnerability. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01709045.

Lipoprotein(a) levels and atherosclerotic plaque characteristics in the carotid artery: The Plaque at RISK (PARISK) study.

BACKGROUND AND AIMS: Lipoprotein(a) is an independent risk factor for cardiovascular disease and recurrent ischemic stroke. Lipoprotein(a) levels are known to be associated with carotid artery stenosis, but the relation of lipoprotein(a) levels to carotid atherosclerotic plaque composition and morphology is less known. We hypothesize that higher lipoprotein(a) levels and lipoprotein(a)-related SNPs are associated with a more vulnerable carotid plaque and that this effect is sex-specific. METHODS: In 182 patients of the Plaque At RISK study we determined lipoprotein(a) concentrations, apo(a) KIV-2 repeats and LPA SNPs. Imaging characteristics of carotid atherosclerosis were determined by MDCTA (n = 161) and/or MRI (n = 171). Regressions analyses were used to investigate sex-stratified associations between lipoprotein(a) levels, apo(a) KIV-2 repeats, and LPA SNPs and imaging characteristics. RESULTS: Lipoprotein(a) was associated with presence of lipid-rich necrotic core (LRNC) (aOR = 1.07, 95% CI: 1.00; 1.15), thin-or-ruptured fibrous cap (TRFC) (aOR = 1.07, 95% CI: 1.01; 1.14), and degree of stenosis (ß = 0.44, 95% CI: 0.00; 0.88). In women, lipoprotein(a) was associated with presence of intraplaque hemorrhage (IPH) (aOR = 1.25, 95% CI: 1.06; 1.61). In men, lipoprotein(a) was associated with degree of stenosis (ß = 0.58, 95% CI: 0.04; 1.12). Rs10455872 was significantly associated with increased calcification volume (ß = 1.07, 95% CI: 0.25; 1.89) and absence of plaque ulceration (aOR = 0.25, 95% CI: 0.04; 0.93). T3888P was associated with absence of LRNC (aOR = 0.36, 95% CI: 0.16; 0.78) and smaller maximum vessel wall area (ß = -10.24, 95%CI: -19.03; -1.44). CONCLUSIONS: In patients with symptomatic carotid artery stenosis, increased lipoprotein(a) levels were associated with degree of stenosis, and IPH, LRNC, and TRFC, known as vulnerable plaque characteristics, in the carotid artery. T3888P was associated with lower LRNC prevalence and smaller maximum vessel wall area. Further research in larger study populations is needed to confirm these results.

No independent association found between von Willebrand factor and plaque ulceration in carotid artery atherosclerosis.

Angiography Computerized Tomography (CT) Cerebrovascular disease/stroke Ischemic stroke Atherosclerosis Stenosis Thrombosis.

No Association between Thrombin Generation and Intra-Plaque Haemorrhage in Symptomatic Carotid Atherosclerotic Plaques: The Plaque at RISK (PARISK) Study.

BACKGROUND: Carotid atherosclerosis is an important cause of stroke. Intra-plaque haemorrhage (IPH) on magnetic resonance imaging (MRI) increases stroke risk. Development of IPH is only partly understood. Thrombin is an essential enzyme in haemostasis. Experimental animal studies have shown conflicting results on the relation between thrombin and plaque vulnerability. We hypothesize that decreased thrombin generation (TG) is associated with IPH and plaque vulnerability. OBJECTIVE: This article investigates whether TG is associated with IPH and other features of plaque vulnerability in stroke patients. METHODS: Recently symptomatic stroke patients underwent carotid MRI and blood sampling. MRI plaque features include plaque burden, presence of IPH, amount of lipid-rich necrotic core (LRNC), calcified tissue and fibrous tissue (% of total wall volume). TG was assessed in platelet-poor plasma and expressed as: peak height (PH) and endogenous thrombin potential (ETP). MR images could be analysed in 224 patients. Blood samples were available in 161 of 224 patients. Binary multivariate logistic and linear regression were used to investigate the association between TG and MRI plaque features. RESULTS: IPH and LRNC were present in 65 (40%) and 102 (63%) of plaques. There were no significant associations between TG and IPH; PH odds ratio (OR) = 1, 95% confidence interval (CI): 0.76 to 1.45 and ETP OR = 1, 95% CI: 0.73 to 1.37. After correction for age, sex and hypercholesterolaemia, the association was weak but non-significant; PH: OR = 0.76, 95% CI: 0.52 to 1.10 and ETP: OR = 0.73, 95% CI: 0.53 to 1.37. CONCLUSION: Features of carotid plaque on MRI show no significant association with TG in stroke patients. Systemic TG does not seem to be an important factor in IPH development.

Multi-Center MRI Carotid Plaque Component Segmentation Using Feature Normalization and Transfer Learning.

Automated segmentation of plaque components in carotid artery magnetic resonance imaging (MRI) is important to enable large studies on plaque vulnerability, and for incorporating plaque composition as an imaging biomarker in clinical practice. Especially supervised classification techniques, which learn from labeled examples, have shown good performance. However, a disadvantage of supervised methods is their reduced performance on data different from the training data, for example on images acquired with different scanners. Reducing the amount of manual annotations required for each new dataset will facilitate widespread implementation of supervised methods. In this paper we segment carotid plaque components of clinical interest (fibrous tissue, lipid tissue, calcification and intraplaque hemorrhage) in a multi-center MRI study. We perform voxelwise tissue classification by traditional same-center training, and compare results with two approaches that use little or no annotated same-center data. These approaches additionally use an annotated set of different-center data. We evaluate 1) a nonlinear feature normalization approach, and 2) two transfer-learning algorithms that use same and different-center data with different weights. Results showed that the best results were obtained for a combination of feature normalization and transfer learning. While for the other approaches significant differences in voxelwise or mean volume errors were found compared with the reference same-center training, the proposed approach did not yield significant differences from that reference. We conclude that both extensive feature normalization and transfer learning can be valuable for the development of supervised methods that perform well on different types of datasets.

Joint intensity-and-point based registration of free-hand B-mode ultrasound and MRI of the carotid artery.

PURPOSE: To introduce a semiautomatic algorithm to perform the registration of free-hand B-Mode ultrasound (US) and magnetic resonance imaging (MRI) of the carotid artery. METHODS: The authors' approach combines geometrical features and intensity information. The only user interaction consists of placing three seed points in US and MRI. First, the lumen centerlines are used as landmarks for point based registration. Subsequently, in a joint optimization the distance between centerlines and the dissimilarity of the image intensities is minimized. Evaluation is performed in left and right carotids from six healthy volunteers and five patients with atherosclerosis. For the validation, the authors measure the Dice similarity coefficient (DSC) and the mean surface distance (MSD) between carotid lumen segmentations in US and MRI after registration. The effect of several design parameters on the registration accuracy is investigated by an exhaustive search on a training set of five volunteers and three patients. The optimum configuration is validated on the remaining images of one volunteer and two patients. RESULTS: On the training set, the authors achieve an average DSC of 0.74 and a MSD of 0.66 mm on volunteer data. For the patient data, the authors obtain a DSC of 0.77 and a MSD of 0.69 mm. In the independent set composed of patient and volunteer data, the DSC is 0.69 and the MSD is 0.87 mm. The experiments with different design parameters show that nonrigid registration outperforms rigid registration, and that the combination of intensity and point information is superior to approaches that use intensity or points only. CONCLUSIONS: The proposed method achieves an accurate registration of US and MRI, and may thus enable multimodal analysis of the carotid plaque.

Carotid artery lumen segmentation in 3D free-hand ultrasound images using surface graph cuts.

We present a new approach for automated segmentation of the carotid lumen bifurcation from 3D free-hand ultrasound using a 3D surface graph cut method. The method requires only the manual selection of single seed points in the internal, external, and common carotid arteries. Subsequently, the centerline between these points is automatically traced, and the optimal lumen surface is found around the centerline using graph cuts. To refine the result, the latter process was iterated. The method was tested on twelve carotid arteries from six subjects including three patients with a moderate carotid artery stenosis. Our method successfully segmented the lumen in all cases. We obtained an average dice overlap with respect to a manual segmentation of 84% for healthy volunteers. For the patient data, we obtained a dice overlap of 66.7%.

Usefulness of contrast-enhanced ultrasound for detection of carotid plaque ulceration in patients with symptomatic carotid atherosclerosis.

Previous data have indicated that carotid plaque ulceration is a strong predictor of cerebrovascular events. Standard ultrasound and color Doppler ultrasound (CDUS) scans have poor diagnostic accuracy for the detection of carotid plaque ulceration. The aim of the present prospective study was to assess the value of contrast-enhanced ultrasound (CEUS) scans for the detection of carotid plaque ulceration. The Institutional Ethics Committee approved the study protocol, and all patients provided informed consent. The patients had symptomatic stenosis of the internal carotid artery and underwent carotid computed tomographic angiography as part of their clinical evaluation. All patients underwent a CDUS examination in conjunction with CEUS. Carotid plaque ulceration was defined as the presence of ≥1 disruptions in the plaque-lumen border ≥1 × 1 mm. Carotid computed tomographic angiography was used as reference technique. The study population consisted of 20 patients (mean age 64 ± 9 years, 80% men), and 39 carotid arteries were included in the present analysis. Computed tomographic angiography demonstrated that the plaque surface was smooth in 15 (38%), irregular in 7 (18%) and ulcerated in 17 (44%) carotid arteries. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of CDUS for the detection of ulceration was 29%, 73%, 54%, 46%, and 57%, respectively. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of CEUS for the detection of ulceration was 88%, 59%, 72%, 63%, and 87%, respectively. CEUS had superior sensitivity and diagnostic accuracy for the assessment of carotid plaque ulceration compared with CDUS. CEUS improved the intrareader and inter-reader variability for the assessment of carotid plaque ulceration compared with CDUS. In conclusion, CEUS could be an additional method for the detection of carotid plaque ulceration. The role of CDUS for the assessment of carotid plaque ulceration seems limited.

Relationship of Von Willebrand Factor with carotid artery and aortic arch calcification in ischemic stroke patients.

BACKGROUND: Large population studies have revealed that increased von Willebrand Factor (VWF) levels are associated with an increased risk of ischemic stroke. In previous studies VWF was associated with atherosclerosis in healthy individuals. However, it is yet unknown what the association is between atherosclerosis and VWF levels in patients with ischemic stroke. OBJECTIVES: The aim of our study was to determine the association of atherosclerosis, measured with recent developed techniques, and VWF levels in a large, well characterized, cohort of ischemic stroke patients and to determine the prognostic value. METHODS: We included 925 consecutive patients with transient ischemic attack (TIA) or ischemic stroke. Calcification volumes (mm(3)) were scored in the aortic arch and both carotid arteries using multidetector computed tomography (CT) angiography. VWF antigen (VWF:Ag) levels were measured using ELISA. RESULTS: Mean VWF:Ag levels were significantly higher in the presence of calcification in either the aortic arch (1.47 vs. 1.37 IU/ml [P = 0.039]) or the carotid arteries (1.49 vs. 1.34 IU/ml [P = 0.001]). Patients with a large artery atherosclerosis ischemic stroke had significantly higher VWF:Ag levels then the other TOAST subtypes (P < 0.0001). High VWF:Ag levels were associated with an unfavorable outcome (modified Rankin Scale >2 vs. ≤2; 1.64 vs. 1.41 IU/ml, [P < 0.0001]). CONCLUSION: Our study showed a strong association between the extent of atherosclerosis in both the aortic arch and the carotid arteries and VWF levels in patients with TIA or ischemic stroke. Higher VWF levels are found in large artery atherosclerosis and are associated with a poor outcome.