High-risk Carotid Plaque Research Articles

Factors Associated with High-Risk Plaque Characteristics Among Patients with Medium to Severe Carotid Artery Stenosis

ObjectiveThere has been a large discussion in literature regarding the proper management of asymptomatic patients with significant carotid artery stenosis (CAS). This study aims to identify potential risk factors associated with high-risk carotid plaques. MethodsThis is a retrospective study based on a prospective database. Eligible patients had medium to severe symptomatic or asymptomatic carotid stenosis (≥50%, NASCET criteria). This study will analyze patients recruited by our institution as part of the multicenter TAXINOMISIS project (NCT03495830). According to protocol, all patients underwent a colored Duplex ultrasound examination and a magnetic resonance angiography (MRA) at baseline. Carotid plaques were classified according to Gray-Weale ultrasonographic criteria (Types I-V). Main outcomes included the occurrence of symptoms, the high/low echogenicity of the plaque, the existence of intraplaque hemorrhage (IPH) and the existence of lipidic/necrotic core. Secondary, risk factors associated with the aforementioned outcomes were evaluated. ResultsA total of 62 patients (mean age: 68.7+/-9.3 years, 66.1% males, 24.2% symptomatic) were recruited by our department. Mean carotid stenosis was 70.81%±13.53%. In multivariate regression analysis, CRP > 2mg/l was strongly associated with symptomatic stenosis (OR=9.92 [1.12-88.178]; P=0.039), and low HDL levels (<1200mmol/l) were associated with lipidic/necrotic plaque core (OR=16.88 [1.10-259.30]; P=0.043). Low HDL levels (OR=7.22 [1.00-51.95], P=0.049) and HbA1c >7% (OR=0.08 [0.01-0.93], P=0.044) were associated with type III/IV plaques whereas HgAbc1 >7% (OR=14.26 [1.21-168.34], P=0.035) was associated with Type V plaques. ConclusionsThis preliminary study has revealed some potential risk factors associated with unstable carotid plaques. This data could help the future development of prognostic models in order to early detect patients that could benefit from further intervention.

High-risk carotid artery plaque: the histological images and a review of the literature

High-risk carotid artery plaque: the histological images and a review of the literature

Clinical risk factors and features on computed tomography angiography in high-risk carotid artery plaque in patients with type 2 diabetes.

High-risk carotid artery plaque (HPR) is associated with a markedly increased risk of ischemic stroke. The aims of this study were: 1) to examine the prevalence of HRP in a cohort of asymptomatic adults with type 2 diabetes (T2D); 2) to investigate the relationship between HRP, established cardiovascular risk factors and computed tomography angiography (CTA) profile; and 3) to assess whether the presence of HRP is associated with an increased risk of major adverse cardiovascular events (MACE). This was a retrospective cohort study of T2D asymptomatic patients who underwent carotid endarterectomy (CEA) from January 2018 to July 2021. The carotid atherosclerotic plaque (CAP) was assessed for the presence of ulceration, the presence of lipids, fibrosis, thrombotic deposits, hemorrhage, neovascularization, and inflammation. A CAP presenting at least five of these histological features was defined as a HRP (Group A); in all other cases it was defined as a mild to moderate heterogeneous plaque and no-HRP (Group B). CTA features included the presence of rim sign consisting of thin peripheral adventitial calcification (<2 mm) and internal soft plaque (≥2 mm), NASCET percent diameter stenosis, maximum plaque thickness, ulceration, calcification, and intraluminal thrombus were recorded. Binary logistic regression with Uni- and Multivariate was used to evaluate possible predictors for HRP while multivariable Cox Proportional Hazards was used to assess independent predictors for MACE. One hundred eighty-five asymptomatic patients (mean age 73±8 years, 131 men), undergoing carotid endarterectomy, were included. Of these, 124 (67%) had HRP, and the 61 (33%) did not. Diabetic complications (OR 2.4, 95% CI: 1.1-5.1, P=0.01), NASCET stenosis ≥75% (OR 2.4, 95% CI: 1.2-3.7, P=0.02) and carotid RIM sign (OR 4.3, 95% CI: 3.9-7.3, P<0.001) were independently associated with HRP. However, HRP was not associated with a higher risk of MACE (freedom from MACE at 5 years: HRP 83.4% vs. non HRP 87.8%, P=0.72) or a reduction of survival (5-year survival estimates: HRP 96.4% vs. non HRP: 94.6%, P=0.76). A high prevalence of HRP (67%) was observed in asymptomatic and elderly T2D patients. Independent predictors of HRP were diabetic complications, NASCET stenosis ≥75% and carotid RIM sign (OR 4.3, 95% CI: 3.9-7.3, P<0.001). HRP was not associated with an increased risk of MACE during a mean follow-up of 39±24 years.

Abstract 42: Validation of a New Plaque-RADS Classification System to a Cohort of Embolic Stroke of Undetermined Source Patients

Introduction: A new Plaque-RADS classification (I-IV) is proposed to categorize the degree of carotid plaque instability and risk of embolic ischemic stroke. We tested the Plaque-RADS classification in a cohort of patients with embolic stroke of undetermined source (ESUS) and imaged with neck CTAs. Methods: Patients with unilateral anterior circulation ischemic stroke due to ESUS and neck CTAs showing &lt;50% carotid stenosis were retrospectively identified. Carotid total plaque thickness and ulceration were scored by a neuroradiologist blinded to stroke side. A semiautomated segmentation software measured intraplaque hemorrhage (IPH) volumes. The Plaque-RADS classification is defined as: I: no plaque; II: plaque thickness &lt;3mm ; III: plaque thickness ≥ 3mm or ulcerated; and IV: plaque with IPH&gt;50mL irrespective of thickness. Prevalence of Plaque-RADS subtypes was analyzed ipsilateral versus contralateral to stroke side. The proportion of low (subtypes I/II) versus high-risk (III/IV) carotid plaques on the ipsilateral versus contralateral stroke-side was tested using a McNemar’s test. Results: Ninety-four patients (N=52 female, mean age 65.4; N=188 plaques) met criteria. Plaque-RADS distribution was classified as: Plaque-RADS I: 18.1%; II: 44.7%; III: 36.7% (III ulc : 1.6%); IV: 0.5%. High-risk Plaque-RADS subtypes were significantly more prevalent on the ipsilateral (42.6%) compared to the contralateral side of stroke (31.9%, p=0.008). Conclusions: Carotid plaque ipsilateral to stroke side showed a higher proportion of Plaque-RADS III/IV subtypes. The Plaque-RADS classification may be used to risk-stratify carotid plaque phenotypes in patients with ESUS.

Increased incidence of napkin-ring sign plaques on cervicocerebral computed tomography angiography associated with the risk of acute ischemic stroke occurrence.

Carotid atherosclerosis plays an essential role in the occurrence of ischemic stroke. This study aimed to investigate whether a larger burden of napkin-ring sign (NRS) plaques on cervicocerebral computed tomography angiography (CTA) increased the risk of acute ischemic stroke (AIS). This retrospective, single-center, cross-sectional study enrolled patients with NRS plaques identified in the subclavian arteries, brachiocephalic trunk, carotid arterial system, and vertebrobasilar circulation on contrast-enhanced cervicocerebral CTA. Patients were divided into AIS and non-AIS groups based on imaging within 12h of symptom onset. Univariate and multivariate logistic regression analyses were performed to determine the risk factor of AIS occurrence. A total of 202 patients (66.72years ± 8.97, 157 men) were evaluated. Plaques with NRS in each subject of the AIS group (N = 98) were significantly more prevalent than that in the control group (N = 104) (1.96 ± 1.17 vs 1.41 ± 0.62). In the AIS group, there were substantially more NRS plaques on the ipsilateral sidethan contralateral side (1.55 ± 0.90 vs. 0.41 ± 0.66). NRS located on the ipsilateral side of the AIS showed an area under the receiver curve (AUC) of 0.86 to identify ischemic stroke. NRS plaque amounts were an independent risk factor for AIS occurrence (odds ratio, 1.86) after adjusting for other factors. Increased incidence of napkin-ring sign plaques on cervicocerebral CTA was positively associated with AIS occurrence, which could aid in detecting asymptomatic atherosclerotic patients at high risk of AIS in routine screening or emergency settings. Napkin-ring sign plaque provides an important imaging target for estimating acute ischemic stroke risk and identifying high-risk patients in routine screening or emergency settings, so that timely anti-atherosclerotic therapy can be used for prevention. • This cross-sectional study investigated the association between high-risk carotid artery plaques and acute ischemic stroke. • Increased incidence of napkin-ring sign plaques on cervicocerebral computed tomography angiography is positively associated with acute ischemic stroke occurrence. • Napkin-ring signs help identify risky patients prone to acute ischemic stroke to facilitate prevention.

Computed tomography angiography-based radiomics model to identify high-risk carotid plaques.

Extracranial atherosclerosis is one of the major causes of stroke. Carotid computed tomography angiography (CTA) is a widely used imaging modality that allows detailed assessments of plaque characteristics. This study aimed to develop and test radiomics models of carotid plaques and perivascular adipose tissue (PVAT) to distinguish symptomatic from asymptomatic plaques and compare the diagnostic value between radiomics models and traditional CTA model. A total of 144 patients with carotid plaques were divided into symptomatic and asymptomatic groups. The traditional CTA model was built by the traditional radiological features of carotid plaques measured on CTA images which were screened by univariate analysis and multivariable logistic regression. We extracted and screened radiomics features from carotid plaques and PVAT. Then, a support vector machine was used for building plaque and PVAT radiomics models, as well as a combined model using traditional CTA features and radiomics features. The diagnostic value between radiomics models and traditional CTA model was compared in identifying symptomatic carotid plaques by Delong method. The area under curve (AUC) values of traditional CTA model were 0.624 and 0.624 for the training and validation groups, respectively. The plaque radiomics model and PVAT radiomics model achieved AUC values of 0.766, 0.740 and 0.759, 0.618 in the two groups, respectively. Meanwhile, the combined model of plaque and PVAT radiomics features and traditional CTA features had AUC values of 0.883 and 0.840 for the training and validation groups, respectively, and the receiver operating characteristic curves of combined model were significantly better than those of traditional CTA model in the training group (P<0.001) and validation group (P=0.029). The combined model of the radiomics features of carotid plaques and PVAT and the traditional CTA features significantly contributes to identifying high-risk carotid plaques compared with traditional CTA model.

Identification of vulnerable carotid plaque with CT-based radiomics nomogram

To develop and validate a radiomics nomogram for identifying high-risk carotid plaques on computed tomography (CT) angiography (CTA). A total of 280 patients with symptomatic (n=131) and asymptomatic (n=139) carotid plaques were divided into a training set (n=135), validation set (n=58), and external test set (n=87). Radiomic features were extracted from CTA images. A radiomics model was constructed based on selected features and a radiomics score (rad-score) was calculated. A clinical factor model was constructed by demographics and CT findings. A radiomics nomogram combining independent clinical factors and the rad-score was constructed. The diagnostic performance of three models was evaluated and validated by region of characteristic curves. Calcification and maximum plaque thickness were the independent clinical factors. Twenty-four features were used to build the radiomics signature. In the validation set, the nomogram (area under the curve [AUC], 0.977; 95% CI, 0.899-0.999) performed better (p=0.017 and p=0.031) than the clinical factor model (AUC, 0.862; 95% CI, 0.746-0.938) and radiomics signature (AUC, 0.944; 95% CI, 0.850-0.987). In external test set, the nomogram (AUC, 0.952; 95% CI, 0.884-0.987) and radiomics signature (AUC, 0.932; 95% CI, 0.857-0.975) showed better discrimination capability (p=0.002 and p=0.037) than clinical factor model (AUC, 0.818; 95% CI, 0.721-0.892). The CT-based nomogram showed satisfactory performance in identification of high-risk plaques in carotid arteries, and it may serve as a potential non-invasive tool to identify carotid plaque vulnerability and risk stratification.

Radiomics and artificial neural networks modelling for identification of high-risk carotid plaques.

In this study, we aimed to investigate the classification of symptomatic plaques by evaluating the models generated via two different approaches, a radiomics-based machine learning (ML) approach, and an end-to-end learning approach which utilized deep learning (DL) techniques with several representative model frameworks. We collected high-resolution magnetic resonance imaging (HRMRI) data from 104 patients with carotid artery stenosis, who were diagnosed with either symptomatic plaques (SPs) or asymptomatic plaques (ASPs), in two medical centers. 74 patients were diagnosed with SPs and 30 patients were ASPs. Sampling Perfection with Application-optimized Contrasts (SPACE) by using different flip angle Evolutions was used for MRI imaging. Repeated stratified five-fold cross-validation was used to evaluate the accuracy and receiver operating characteristic (ROC) of the trained classifier. The two proposed approaches were investigated to train the models separately. The difference in the model performance of the two proposed methods was quantitatively evaluated to find a better model to differentiate between SPs and ASPs. 3D-SE-Densenet-121 model showed the best performance among all prediction models (AUC, accuracy, precision, sensitivity, and F1-score of 0.9300, 0.9308, 0.9008, 0.8588, and 0.8614, respectively), which were 0.0689, 0.1119, 0.1043, 0.0805, and 0.1089 higher than the best radiomics-based ML model (MLP). Decision curve analysis showed that the 3D-SE-Densenet-121 model delivered more net benefit than the best radiomics-based ML model (MLP) with a wider threshold probability. The DL models were able to accurately differentiate between symptomatic and asymptomatic carotid plaques with limited data, which outperformed radiomics-based ML models in identifying symptomatic plaques.

High-risk carotid plaques and incident ischemic stroke in patients with atrial fibrillation in the Cardiovascular Health Study.

Whether carotid artery disease could improve stroke risk stratification tools in patients with atrial fibrillation (AF) remains uncertain. This study was undertaken to investigate the risk of ischemic stroke associated with occlusive and nonocclusive carotid atheroscleroticdisease in patients with AF in the prospective population-based Cardiovascular Health Study. We included participants aged ≥65 years with AF. We used multivariable Cox regression analysis to explore the risk of ischemic stroke associated with the percentage of carotid stenosis, plaque irregularity, echogenicity, and vulnerability (markedly irregular, ulcerated, or hypoechoic plaques). A total of 1398 participants were included (55.2% female, 61.7% aged 65-74 years). The maximum carotid stenosis was <50%, 50%-99%, and 100% in 94.5%, 5%, and 0.5% of participants, respectively. High-risk plaques based on echogenicity and plaque irregularity were found in 25.6% and 8.9% of participants, respectively. After a median follow-up of 10.9 years (interquartile range = 7.5-15.6), 298 ischemic strokes were recorded. There was no difference in the incidence of ischemic stroke according to the degree of carotid artery stenosis (p = 0.44), plaque echogenicity (low vs. high risk, p = 0.68), plaque irregularity (low vs. high risk, p = 0.55), and plaque vulnerability (p = 0.86). The CHA₂DS₂-VASc score was associated with an increased risk of ischemic stroke (adjusted hazard ratio = 1.28, 95% confidence interval = 1.18-1.40, p < 0.001). Both maximum grade of stenosis and plaque vulnerability were not associated with incident ischemic stroke (all p > 0.05). Neither the degree of carotid stenosis nor the presence of vulnerable plaques was associated with incident ischemic stroke in this cohortof individuals with AF. This suggests that carotid disease was probably not a significant contributor to ischemic stroke in this population.

Intolerance to occlusion during carotid artery stenting with proximal protection: causes, mechanisms, treatment and prevention.

Periprocedural cerebral microembolization is the most important complication of carotid artery stenting. Among several variables that play a role to reduce this risk, brain protection (proximal vs. distal) plays a pivot role. Data are accumulating in favor of a better performance of proximal vs. distal especially in symptomatic patients and high-risk carotid plaques. A prerequisite for the technique to be safe and effective is the presence of a valid intracranial collateral circulation to compensate for the target vessel hemisphere avoiding patient intolerance. This complication may occur either soon after the common carotid balloon occlusion or slowly developing during the procedure peaking at the stent post-dilation step. While Willis' circle anatomic variants are the most frequent cause of acute intolerance, a mix of anatomic, hemodynamic and patient cerebral condition play a role for the late developing form. Prevention is the best treatment of intolerance through a pre- and procedural imaging with different techniques (CT angiography, NMR angiography, transcranial Doppler assessment, digital subtraction angiography and back pressure monitoring).

Translational Molecular Imaging Tool of Vulnerable Carotid Plaque: Evaluate Effects of Statin Therapy on Plaque Inflammation and American Heart Association–Defined Risk Levels in Cuff-Implanted Apolipoprotein E–Deficient Mice

Identification of high-risk carotid plaques in asymptomatic patients remains a challenging but crucial step in stroke prevention. The challenge is to accurately monitor the development of high-risk carotid plaques and promptly identify patients, who are unresponsive to best medical therapy, and hence targeted for carotid surgical interventions to prevent stroke. Inflammation is a key operator in destabilisation of plaques prior to clinical sequelae. Currently, there is a lack of imaging tool in routine clinical practice, which allows assessment of inflammatory activity within the atherosclerotic plaque. Herein, we have used a periarterial cuff to generate a progressive carotid atherosclerosis model in apolipoprotein E–deficient mice. This model produced clinically relevant plaques with different levels of risk, fulfilling American Heart Association (AHA) classification, at specific timepoints and locations, along the same carotid artery. Exploiting this platform, we have developed smart molecular magnetic resonance imaging (MRI) probes consisting of dual-targeted microparticles of iron oxide (DT-MPIO) against VCAM-1 and P-selectin, to evaluate the anti-inflammatory effect of statin therapy on progressive carotid atherosclerosis. We demonstrated that in vivo DT-MPIO-enhanced MRI can (i) quantitatively track plaque inflammation from early to advanced stage; (ii) identify and characterise high-risk inflamed, vulnerable plaques; and (iii) monitor the response to statin therapy longitudinally. Moreover, this molecular imaging–defined therapeutic response was validated using AHA classification of human plaques, a clinically relevant parameter, approximating the clinical translation of this tool. Further development and translation of this molecular imaging tool into the clinical arena may potentially facilitate more accurate risk stratification, permitting timely identification of the high-risk patients for prophylactic carotid intervention, affording early opportunities for stroke prevention in the future.

Non-HDL-C/HDL-C ratio is associated with carotid plaque stability in general population: A cross-sectional study.

BackgroundCarotid atherosclerosis, especially the rupture of unstable plaques, plays an important role in the development of stroke. A novel lipid ratio, the non-high-density lipoprotein cholesterol (non-HDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio, contains both atherogenic and anti-atherogenic particle information, and has been shown to be associated with carotid atherosclerosis. However, there is no data on evaluating the association between non-HDL-C/HDL-C ratio and carotid plaque stability.MethodsThis study was carried out on 27,436 urban workers aged 20 years or older who participated in a comprehensive health screening between January 2016 and December 2017. Carotid plaque stability was assessed using ultrasonography. Multinomial logistic regression models were used to explore the relationship between the non-HDL-C/HDL-C ratio and carotid plaque stability by odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were performed to verify the robustness of the results.ResultsCarotid plaque was detected in 7,161 (26.1%) participants, with stable and unstable plaque accounting for 3,277 (11.9%) and 3,884 (14.2%), respectively. The prevalence of stable carotid plaque substantially increased with increasing non-HDL-C/HDL-C ratio quartile levels (p for trend < 0.001) and with a similar association for unstable carotid plaque (p for trend < 0.001). The mean non-HDL-C/HDL-C ratios (mean ± SD) of non-carotid plaque (2.9 ± 1.1), stable carotid plaque (3.2 ± 1.2), and unstable carotid plaque (3.4 ± 1.4) gradually increased (p < 0.001). In multinomial logistic regression, ORs (95% CIs) for the highest vs. lowest quartile of the non-HDL-C/HDL-C ratio were 1.70 (1.48–1.95) between stable carotid plaques and no carotid plaque, 2.34 (2.06–2.67) between unstable carotid plaques and no carotid plaque, and 1.38 (1.18–1.61) between unstable carotid plaques and stable carotid plaque, after adjusting for common cardiovascular risk factors. The results of subgroup analysis and sensitivity analysis were similar.ConclusionOur findings suggested that the non-HDL-C/HDL-C ratio was significantly associated with carotid plaque stability and might be a useful indicator for the early identification of high-risk carotid plaque.

525 Should We Look For High-Risk Carotid Plaques In Patients With Coronary Artery Calcium?

Introduction: Coronary artery calcium scores (CACs) are being increasingly used for primary prevention of cardiovascular disease. CACs allow for personalized and precise information on the presence and quantity of coronary atherosclerosis. Atherosclerosis is however a systemic disease, and the increasing ubiquity of cardiac CT potentially allows the opportunity to look for high-risk carotid plaque in patients with CAC as a means of detecting patients also at a high-risk of stroke. We therefore studied an institutional sample of patients that underwent both CT for CAC and carotid MRI.

Evaluation of non-stenotic carotid atherosclerotic plaques with combined FDG-PET imaging and CT angiography in patients with ischemic stroke of unknown origin

ObjectivesNon-stenotic plaques are an underestimated cause of ischemic stroke. Imaging aspects of high-risk carotid plaques can be identified on CT angiography (CTA) and 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET) imaging. We evaluated in patients with cryptogenic ischemic stroke the usefulness of FDG-PET-CTA. Methods44 patients imaged with CTA and FDG-PET were identified retrospectively. Morphological features were identified on CTA. Intensity of FDG uptake in carotid arteries was quantified on PET. ResultsPatients were imaged 7 ± 8 days after stroke. 44 non-stenotic plaques with increased 18F-FDG uptake were identified in the carotid artery ipsilateral to stroke and 7 contralateral. Most-diseased-segment TBR on FDG-PET was higher in artery ipsilateral vs. contralateral to stroke (2.24 ± 0.80 vs. 1.84 ± 0.50; p < .05). In the carotid region with high FDG uptake, prevalence of hypodense plaques and extent of hypodensity on CTA were higher in artery ipsilateral vs. contralateral to stroke (41% vs. 11%; 0.72 ± 1.2 mm2 vs. 0.13 ± 0.43 mm2; p < .05). ConclusionsIn patients with ischemic stroke of unknown origin and non-stenotic plaques, we found an increased prevalence of high-risk plaques features ipsilateral vs. contralateral to stroke on FDG-PET-CTA imaging suggesting a causal role for these plaques.

Identification of high-risk carotid plaque by using carotid perivascular fat density on computed tomography angiography

BackgroundPerivascular fat attenuation index is considered a sensitive biomarker of vulnerable coronary plaques. However, its application in studying the carotid artery are unknown. PurposeThis study aimed to explore the association between cerebrovascular symptoms and carotid attenuation density of perivascular adipose tissue (PVAT) on computed tomography angiography (CTA). MethodsA total of 206 participants (mean age, 63.9 ± 7.9 years, 145 men) who underwent CTA were retrospectively analyzed. Perivascular fat density (PFD) was evaluated via CTA. The association between PFD and the occurrence of cerebrovascular symptoms was examined via generalized estimating equations and receiver operating characteristic analysis. ResultsAmong the 206 subjects, 49.5% (plaques were observed in 102 patients) presented cerebrovascular symptoms. Plaques with symptoms (−55.0 ± 10.0 Hounsfield units [HU]) had a higher PFD than those without symptoms (−68.0 ± 10.3 HU) (p < 0.001). After adjusting for hyperlipidemia, statin use, antiplatelet use, calcification, degree of luminal stenosis, maximum plaque thickness, and ulceration, PFD was found to be strongly associated with cerebrovascular symptoms (OR, 1.13; 95% CI, 1.07–1.19; p < 0.001). Receiver operating characteristic analysis revealed an area under the curve of 0.81 by using PFD measurements to discriminate between symptomatic and asymptomatic plaques with a sensitivity of 87.3% and a specificity of 60.6%. ConclusionsAn increase in attenuation density of PVAT on CTA was found to be related to an increase in the risks of cerebrovascular symptoms. PFD might serve as an imaging marker of symptomatic carotid plaques.

A Radiomics Approach to Assess High Risk Carotid Plaques: A Non-invasive Imaging Biomarker, Retrospective Study.

ObjectiveThis study aimed to construct a radiomics-based MRI sequence from high-resolution magnetic resonance imaging (HRMRI), combined with clinical high-risk factors for non-invasive differentiation of the plaque of symptomatic patients from asyptomatic patients.MethodsA total of 115 patients were retrospectively recruited. HRMRI was performed, and patients were diagnosed with symptomatic plaques (SPs) and asymptomatic plaques (ASPs). Patients were randomly divided into training and test groups in the ratio of 7:3. T2WI was used for segmentation and extraction of the texture features. Max-Relevance and Min-Redundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) were employed for the optimized model. Radscore was applied to construct a diagnostic model considering the T2WI texture features and patient demography to assess the power in differentiating SPs and ASPs.ResultsSPs and ASPs were seen in 75 and 40 patients, respectively. Thirty texture features were selected by mRMR, and LASSO identified a radscore of 16 radiomics features as being related to plaque vulnerability. The radscore, consisting of eight texture features, showed a better diagnostic performance than clinical information, both in the training (area under the curve [AUC], 0.923 vs. 0.713) and test groups (AUC, 0.989 vs. 0.735). The combination model of texture and clinical information had the best performance in assessing lesion vulnerability in both the training (AUC, 0.926) and test groups (AUC, 0.898).ConclusionThis study demonstrated that HRMRI texture features provide incremental value for carotid atherosclerotic risk assessment.

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

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. 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. We found significant difference in total plaque volume between men and women (β=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]). 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.

Expression of miRNAs Targeting ATP Binding Cassette Transporter 1 (ABCA1) among Patients with Significant Carotid Artery Stenosis.

Background: Carotid artery stenosis is a dynamic process associated with an increased risk of cardiovascular events. However, knowledge of biomarkers useful for identifying and quantifying high-risk carotid plaques associated with the increased incidence of cerebrovascular events is insufficient. Therefore, the objectives of this study were to evaluate the expression of ATP binding cassette transporter 1 (ABCA1) and validate its target microRNA (miRNA) candidates in human carotid stenosis arteries to identify its potential as a biomarker. Methods: In human carotid stenosis arterial tissues and plasma, the expression of ABCA1 and its target miRNAs (miRNA-33a-5p, 33b-5p, and 148a-3p) were evaluated by quantitative real time-polymerase chain reaction (qRT-PCR), immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). Results: The expression of ABCA1 was significantly decreased in the plasma of stenosis patients, but its expression was not different in arterial tissues (p < 0.05). However, significantly more target miRNAs were secreted by stenosis patients than normal patients (p < 0.05). Interestingly, lipotoxicity induced by the oleic and palmitic acid (OAPA) or lipopolysaccharide (LPS) treatment of human umbilical vein endothelial cells (HUVECs) dramatically enhanced the gene expression of adipogenic and inflammatory factors, whereas ABCA1 expression was significantly decreased. Conclusions: Therefore, miRNA-33a-5p, 33b-5p, and 148a-3p represent possible biomarkers of carotid artery stenosis by directly targeting ABCA1.

Development of Molecular Magnetic Resonance Imaging Tools for Risk Stratification of Carotid Atherosclerotic Disease Using Dual-Targeted Microparticles of Iron Oxide

Identification of patients with high-risk asymptomatic carotid plaques remains a challenging but crucial step in stroke prevention. Inflammation is the key factor that drives plaque instability. Currently, there is no imaging tool in routine clinical practice to assess the inflammatory status within atherosclerotic plaques. We have developed a molecular magnetic resonance imaging (MRI) tool to quantitatively report the inflammatory activity in atherosclerosis using dual-targeted microparticles of iron oxide (DT-MPIO) against P-selectin and VCAM-1 as a smart MRI probe. A periarterial cuff was used to generate plaques with varying degree of phenotypes, inflammation and risk levels at specific locations along the same single carotid artery in an Apolipoprotein-E-deficient mouse model. Using this platform, we demonstrated that in vivo DT-MPIO-enhanced MRI can (i) target high-risk vulnerable plaques, (ii) differentiate the heterogeneity (i.e. high vs intermediate vs low-risk plaques) within the asymptomatic plaque population and (iii) quantitatively report the inflammatory activity of local plaques in carotid artery. This novel molecular MRI tool may allow characterisation of plaque vulnerability and quantitative reporting of inflammatory status in atherosclerosis. This would permit accurate risk stratification by identifying high-risk asymptomatic individual patients for prophylactic carotid intervention, expediting early stroke prevention and paving the way for personalised management of carotid atherosclerotic disease.

Integrative multiomics analysis of human atherosclerosis reveals a serum response factor-driven network associated with intraplaque hemorrhage.

BackgroundWhile single‐omics analyses on human atherosclerotic plaque have been very useful to map stage‐ or disease‐related differences in expression, they only partly capture the array of changes in this tissue and suffer from scale‐intrinsic limitations. In order to better identify processes associated with intraplaque hemorrhage and plaque instability, we therefore combined multiple omics into an integrated model.MethodsIn this study, we compared protein and gene makeup of low‐ versus high‐risk atherosclerotic lesion segments from carotid endarterectomy patients, as judged from the absence or presence of intraplaque hemorrhage, respectively. Transcriptomic, proteomic, and peptidomic data of this plaque cohort were aggregated and analyzed by DIABLO, an integrative multivariate classification and feature selection method.ResultsWe identified a protein‐gene associated multiomics model able to segregate stable, nonhemorrhaged from vulnerable, hemorrhaged lesions at high predictive performance (AUC >0.95). The dominant component of this model correlated with αSMA−PDGFRα+ fibroblast‐like cell content (p = 2.4E‐05) and Arg1+ macrophage content (p = 2.2E‐04) and was driven by serum response factor (SRF), possibly in a megakaryoblastic leukemia‐1/2 (MKL1/2) dependent manner. Gene set overrepresentation analysis on the selected key features of this model pointed to a clear cardiovascular disease signature, with overrepresentation of extracellular matrix synthesis and organization, focal adhesion, and cholesterol metabolism terms, suggestive of the model's relevance for the plaque vulnerability. Finally, we were able to corroborate the predictive power of the selected features in several independent mRNA and proteomic plaque cohorts.ConclusionsIn conclusion, our integrative omics study has identified an intraplaque hemorrhage‐associated cardiovascular signature that provides excellent stratification of low‐ from high‐risk carotid artery plaques in several independent cohorts. Further study revealed suppression of an SRF‐regulated disease network, controlling lesion stability, in vulnerable plaque, which can serve as a scaffold for the design of targeted intervention in plaque destabilization.