The association between antiplatelet therapy and changes in intraplaque hemorrhage in patients with mild to moderate symptomatic carotid stenosis: a longitudinal MRI study.

INTRODUCTION: Carotid atherosclerotic intraplaque hemorrhage (IPH) predicts stroke. Patients with a history of stroke are treated with antiplatelet agents to prevent secondary cardiovascular events. A positive association between previous antiplatelet use and IPH was reported in a cross-sectional analysis. We investigated changes in IPH over two years in patients who recently started versus those with continued antiplatelet use. METHODS: In the Plaque at Risk (PARISK) study, symptomatic patients with <70% ipsilateral carotid stenosis underwent carotid plaque MRI at baseline and after two years to determine IPH presence and volume. Participants were categorized into new users (starting antiplatelet therapy following the index event) and continued users (previous use of antiplatelet therapy before the index event). The association between previous antiplatelet therapy and the presence of IPH at baseline MRI was investigated using multivariable logistic regression analysis. IPH volume change over a period of two years, defined as the difference in volume between follow-up and baseline, was investigated in each group with a Wilcoxon signed-rank test. The IPH volume change was categorized as progression, regression, or no change. Using multivariable logistic regression, we investigated the association between new antiplatelet use and 1) newly developed ipsilateral or contralateral IPH and 2) IPH volume progression. RESULTS: A total of 108 patients underwent carotid MRI at baseline and follow-up. At baseline, previous antiplatelet therapy was associated with any IPH (OR=5.6, 95% CI: 1.3-23.1; p=0.02). Ipsilateral IPH volume did not change significantly during the two years in patients who continued receiving antiplatelet agents (86.4 mm3 [18.2-235.9] vs. 59.3 mm3 [11.4-260.3]; p=0.6) nor in the new antiplatelet users (n=31) (61.5 mm3 [0.0-166.9] vs. 27.7 mm3 [9.5-106.4]; p=0.4). Similar results of a nonsignificant change in contralateral IPH volume during those two years were observed in both groups (p>0.05). No significant associations were found between new antiplatelet use and newly developed IPH at two years (odds ratio (OR)=1.0, 95% CI:0.1-7.4) or the progression of IPH (ipsilateral: OR=2.4, 95% CI:0.3-19.1; contralateral: OR=0.3, 95% CI:0.01-8.5). CONCLUSION: Although the baseline association between IPH and previous antiplatelet therapy was confirmed in this larger cohort, the new onset of antiplatelet therapy after TIA/stroke was not associated with newly developed IPH or progression of IPH volume over the subsequent two years.

Carotid Plaque Characteristics Predict Recurrent Ischemic Stroke and TIA: The PARISK (Plaque At RISK) Study.

BACKGROUND: Patients with symptomatic carotid stenosis are at high risk for recurrent stroke. The decision for carotid endarterectomy currently mainly relies on degree of stenosis (cutoff value >50% or 70%). Nevertheless, also, patients with mild-to-moderate stenosis still have a considerable recurrent stroke risk. Increasing evidence suggests that carotid plaque composition rather than degree of stenosis determines plaque vulnerability; however, it remains unclear whether this also provides additional information to improve clinical decision making. OBJECTIVES: The PARISK (Plaque At RISK) study aimed to improve the identification of patients at increased risk of recurrent ischemic stroke using multimodality carotid imaging. METHODS: The authors included 244 patients (71% men; mean age, 68 years) with a recent symptomatic mild-to-moderate carotid stenosis in a prospective multicenter cohort study. Magnetic resonance imaging (carotid and brain) and computed tomography angiography (carotid) were performed at baseline and after 2 years. The clinical endpoint was a recurrent ipsilateral ischemic stroke or transient ischemic attack (TIA). Cox proportional hazards models were used to assess whether intraplaque hemorrhage (IPH), ulceration, proportion of calcifications, and total plaque volume in ipsilateral carotid plaques were associated with the endpoint. Next, the authors investigated the predictive performance of these imaging biomarkers by adding these markers (separately and simultaneously) to the ECST (European Carotid Surgery Trial) risk score. RESULTS: During 5.1 years follow-up, 37 patients reached the clinical endpoint. IPH presence and total plaque volume were associated with recurrent ipsilateral ischemic stroke or TIA (HR: 2.12 [95% CI: 1.02-4.44] for IPH; HR: 1.07 [95% CI: 1.00-1.15] for total plaque volume per 100 µL increase). Ulcerations and proportion of calcifications were not statistically significant determinants. Addition of IPH and total plaque volume to the ECST risk score improved the model performance (C-statistics increased from 0.67 to 0.75-0.78). CONCLUSIONS: IPH and total plaque volume are independent risk factors for recurrent ipsilateral ischemic stroke or TIA in patients with mild-to-moderate carotid stenosis. These plaque characteristics improve current decision making. Validation studies to implement plaque characteristics in clinical scoring tools are needed. (PARISK: Validation of Imaging Techniques [PARISK]; NCT01208025).

Sex Differences in Plaque Composition and Morphology Among Symptomatic Patients With Mild-to-Moderate Carotid Artery Stenosis.

BACKGROUND AND PURPOSE: Incidence of ischemic stroke differs between men and women, with substantially higher rates in men. The underlying mechanism of this difference remains poorly understood but may be because of differences in carotid atherosclerosis. Using an in-depth imaging-based approach, we investigated differences between carotid plaque composition and morphology in male and female patients with stroke, taking into account differences in total plaque burden. Additionally, we investigated all possible within-artery combinations of plaque characteristics to explore differences between various plaque phenotypes. METHODS: We included 156 men and 68 women from the PARISK (Plaque At Risk) study, a prospective cohort study of patients with recent ischemic cerebrovascular symptoms and <70% ipsilateral carotid stenosis. Plaque characteristics (intraplaque hemorrhage [IPH], lipid-rich necrotic core [LRNC], calcifications, thin-or-ruptured fibrous cap, ulcerations, total plaque volume) were assessed with magnetic resonance imaging and multidetector-row computed tomography angiography. We used multivariable logistic and linear regression analyses to assess sex differences in plaque characteristics. RESULTS: We found significant difference in total plaque volume between men and women (ß=22.9 mm3 [95% CI, 15.4-30.5]; mean volume in men 1399±425 mm3, in women 1011±242 mm3). Additionally, men were more likely to have IPH (odds ratio [OR]=2.8 [95% CI, 1.3-6.3]; IPH proportion in men 49%, in women 16%) and LRNC (OR=2.4 [95% CI, 1.2-4.7]; LRNC proportion in men 73%, in women 41%) even after adjustment for total plaque volume. We found no sex-specific differences in plaque volume-corrected volumes of IPH, LRNC, and calcifications. In terms of coexistence of plaque characteristics, we found that men had more often a plaque with coexistence of calcifications, LRNC, and IPH (OR=2.7 [95% CI, 1.2-7.0]), with coexistence of thin-or-ruptured fibrous cap/ulcerations, LRNC, and IPH (OR=2.4 [95% CI, 1.1-5.9]), and with coexistence of all plaque characteristics (OR=3.0 [95% CI, 1.2-8.6]). CONCLUSIONS: In symptomatic patients with mild-to-moderate carotid stenosis, men are more likely to have a high-risk carotid plaque with IPH and LRNC than women, regardless of total plaque burden. Men also have more often a plaque with multiple vulnerable plaque components, which could comprise an even higher stroke risk. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01208025.

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.

Investigations of Carotid Stenosis to Identify Vulnerable Atherosclerotic Plaque and Determine Individual Stroke Risk.

Selection of patients with atherosclerotic carotid stenosis for revascularization is mainly based on the degree of luminal narrowing of the carotid artery. However, identification of other features of plaque apart from the degree of stenosis could enable better selection for intervention if they are also associated with the occurrence of stroke. Before these risk factors can possibly play a role in treatment decisions, their prognostic value needs to be proven. The purpose of this narrative review is to summarize current knowledge regarding the risk factors for stroke in patients with carotid stenosis, how they can be determined, and to what extent they predict stroke, based on recent literature. References for this review were identified by searches of PubMed between 1995 and October, 2016 and references from relevant articles. For each topic in this review different relevant search terms were used. The main search terms were 'carotid stenosis', 'atherosclerosis', 'stroke risk', and 'vulnerable plaque'. Language was restricted to English. The final reference list was generated on the basis of relevance to the topics covered in this review.

Three-dimensional quantitative T1 and T2 mapping of the carotid artery: Sequence design and in vivo feasibility.

PURPOSE: A novel three-dimensional (3D) T1 and T2 mapping protocol for the carotid artery is presented. METHODS: A 3D black-blood imaging sequence was adapted allowing carotid T1 and T2 mapping using multiple flip angles and echo time (TE) preparation times. B1 mapping was performed to correct for spatially varying deviations from the nominal flip angle. The protocol was optimized using simulations and phantom experiments. In vivo scans were performed on six healthy volunteers in two sessions, and in a patient with advanced atherosclerosis. Compensation for patient motion was achieved by 3D registration of the inter/intrasession scans. Subsequently, T1 and T2 maps were obtained by maximum likelihood estimation. RESULTS: Simulations and phantom experiments showed that the bias in T1 and T2 estimation was < 10% within the range of physiological values. In vivo T1 and T2 values for carotid vessel wall were 844 ± 96 and 39 ± 5 ms, with good repeatability across scans. Patient data revealed altered T1 and T2 values in regions of atherosclerotic plaque. CONCLUSION: The 3D T1 and T2 mapping of the carotid artery is feasible using variable flip angle and variable TE preparation acquisitions. We foresee application of this technique for plaque characterization and monitoring plaque progression in atherosclerotic patients.

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.

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.