Lipid-rich Necrotic Core Research Articles

Imaging signs of carotid plaque vulnerability predict subclinical neurological events in asymptomatic patients: the carotid artery multi-modality imaging prognostic study

Abstract Background Carotid artery plaques should be considered for invasive treatment if diameter stenoses is ≥60%, in the presence of clinical and/or imaging characteristics associated with an increased risk of ipsilateral stroke, such as intraplaque haemorrhage (IPH) or lipid-rich necrotic core (LRNC). However, little is known about plaque’s characteristics in patients with <60% stenoses. Purpose To evaluate the prevalence and significance of imaging signs of plaque vulnerability in patients with asymptomatic <60% carotid artery stenoses. Methods In the Carotid Artery Multi-modality imaging Prognostic (CAMP) study (granted by Bando Ricerca Salute 2018 - Regione Toscana) we prospectively enrolled 200 patients with asymptomatic, mild/moderate (40-60%) carotid artery stenoses, as assessed at Doppler ultrasound (DUS). All patients were evaluated with multimodality imaging, including computed tomography angiography (CTA), magnetic resonance angiography (MRA) and brain magnetic resonance imaging (MRI), whenever not contraindicated. A subgroup of 75 patients underwent also a 18[F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). A thorough clinical, biochemical, cardiological and neurological evaluation was performed in all patients. Results Imaging signs of plaque vulnerability were frequent (IPH and/or LRNC at MRA were found in 26.3% patients, plaque ulceration at CTA was found in 36.7% of patients). No difference in the prevalence of cardiovascular risk factors was noted in those with and without signs of vulnerability. Subclinical embolic brain infarctions at brain MRI were found in 8.8% of patients at enrollment. These patients had more frequently a LRNC at MRA than patients without subclinical embolic brain infarctions (50% vs 17%, p<0.05), lower estimated glomerular filtration rate (55±8 vs 73±23 mL/min/1.73mq, p<0.001), higher troponin HS values (16±4 vs 12±8 ng/ml, p<0.05). Presence of LRNC at MRA was the only predictor of embolic lesions at MRI (odds ratio 4.86, 95% confidence interval 1.08-21.8, p<0.05). Conclusions Imaging signs of vulnerability are highly prevalent in patients with asymptomatic intermediate carotid artery stenosis. Presence of a LRNC at MRA is associated with subclinical embolic brain infarcts. The use of non-invasive multi-imaging can better characterize carotid plaques, independent of the degree of stenosis, and help identifying a subgroup of patients at higher risk of events.

High physical activity relates to higher risk of incident carotid plaque components

Abstract Background The rupture of carotid atherosclerotic plaque, primarily driven by plaque components, is among the leading causes of ischemic stroke. Although physical activity (PA) stands as a major modifiable target for prevention of atherosclerotic diseases, recent studies suggested a potential adverse impact of high-volume PA on atherosclerotic plaque burden in athletes. Data remains scarce from the community-dwelling population regarding to the impact of PA on the longitudinal change of carotid plaque components. Objectives To assess the association between PA and the incidence of carotid plaque components and explore whether the association of PA with stroke and all-cause mortality differs by the presence of plaque components. Methods Between 2007 and 2012, in a community- dwelling cohort in Netherlands, 1327 stroke-free persons (mean ± standard deviation age 72 ± 9 years, 45% women) with carotid atherosclerosis (carotid intima-media thickness > 2.5 mm) were invited for magnetic resonance imaging (MRI) to assess carotid plaque components. From these, 696 persons (1267 carotid arteries) underwent a follow-up MRI between 2014 and 2017 (median between-scan interval 6 years). Carotid plaque components included calcification, intraplaque hemorrhage (IPH), and lipid-rich necrotic core (LRNC). The volume of moderate, vigorous and total PA (unit: metabolic equivalent task hour, MET-h) was assessed using LASA Physical Activity Questionnaires around the time of the first MRI scan. Participants were followed for the occurrence of stroke or all-cause mortality until December 31, 2019. Generalized estimation equation and Cox regression models were used in the analyses, with adjustments for plaque size and other cardiovascular risk factors. Results Compared to lowest quintile PA group, participants in the highest quintile total PA group had a higher risk of new onset of plaque components, odds ratio (95%CI) 2.69 (1.21; 5.94) for calcification, 1.35 (0.82; 2.24) for LRNC and 1.93 (1.12; 3.34) for IPH (Figure 1). Similar associations were observed for vigorous PA but not for moderate PA. Over a median follow-up of 9.5 years, 118 persons suffered a stroke and 298 died. As shown in table 1, baseline IPH, rather than LRNC or calcification, modulated the associations of PA with stroke and all-cause mortality (P-interaction <0.05): higher total PA was associated with a lower risk of stroke among IPH-free persons, with the hazard ratio (95% CI) of 0.929 (0.867; 0.996) per 10 MET-h/week increase; no associations between PA and stroke were found among those with IPH. Similar associations were found between vigorous PA and all-cause mortality. Conclusions Among the middle-aged and elderly with subclinical atherosclerosis, high level PA, especially high vigorous PA, may lead to an unstable carotid plaque. The beneficial effect of PA on stroke and all-cause mortality is only among persons with a stable carotid plaque profile, especially without IPH.

The evolution of carotid atherosclerotic plaque composition: a prospective study

Abstract Background The rupture of carotid atherosclerotic plaque is one of the major causes of ischemic stroke, and largely determined by the composition of the plaque. To date, most studies on carotid plaque composition focused on individual plaque components, whilst the interplay between different components within the same plaque may be a critical driving force for plaque evolution and rupture. Objectives To determine the interplay between carotid plaque components over time and describe the dynamics of plaque composition with a specific focus on age- and sex-specific changes in a population-based setting. Methods From a population-based cohort in Netherlands, 802 participants (mean age ± SD 68 ± 8 years, 43% women) with subclinical carotid atherosclerosis underwent repeat magnetic resonance imaging (MRI) of carotid plaque (first scan between 2007 and 2012, second scan between 2014 to 2017). We evaluated carotid plaque composition, including calcification, lipid-rich necrotic core (LRNC) and intraplaque hemorrhage (IPH). To assess the relationship between the incidence of one specific component and baseline plaque composition, plaques with this specific component present at the baseline were excluded. Generalized estimation equation models were used with adjustments for baseline plaque size and cardiovascular risk factors. We demonstrated the evolution of plaque composition along age and by sex. Results Baseline presence of calcification in carotid plaque is independently associated with a higher incidence of IPH (adjusted odds ratio: 2.25; 95% confidence interval: 1.40 to 3.63). No associations were found between baseline plaque composition and the new onset of calcification or LRNC. The proportion of complex plaques with multiple components significantly increased at follow-up (Figure 1a). The plaque composition dramatically evolved over time and the proportion of plaques with two or more components started with 10% around 55 years and increased to over 50% after 70 years of age (Figure 1b). Although the age distribution was comparable between men and women, men were more likely to have and develop plaques with multiple vulnerable plaque components such as IPH (Figure 2). Conclusions A higher incidence of IPH was found in plaques with baseline calcification. The pre-existing plaque composition strongly determines how the plaque will evolve over time. Given the interplay between individual components, the overall plaque composition exhibits significant age- and sex- specific characteristics.

Symptomatic Nonstenotic Carotids: A Topical Review.

Historically, the management of carotid artery disease has primarily focused on the degree of stenosis as the main indicator for assessing stroke etiology, risk, and need for intervention. However, accumulating evidence suggests that structural and biological features within the arterial wall, such as intraplaque hemorrhage, may have superior diagnostic, prognostic, and therapeutic values. Under current guidelines, unless an atheroma results in ≥50% stenosis, it is not considered the cause of a cerebrovascular event. This results in extensive and often unproductive diagnostic workup, prescription of ineffective medical therapy, and preclusion of patients from receiving revascularization procedures that have been shown to prevent recurrent cerebrovascular events in cases of ≥50% stenosis. A subset of embolic strokes of undetermined source, which account for up to 25% of all ischemic cerebrovascular events, are thought to be due to thromboembolic phenomena from undiagnosed plaque disruptions in nonstenotic arteries (<50% stenosis). Recently, it has been proposed to reclassify this subgroup of patients as symptomatic nonstenotic carotid if the carotid plaque ipsilateral to the cerebrovascular event presents with high-risk features including intraplaque hemorrhage, lipid-rich necrotic core, thinning/rupture of the fibrous cap, and ulceration. In this review, we first provide a historical overview of the chain of events and circumstances that resulted in the present management of carotid artery disease. Second, we embed the contemporary biomarkers of plaque vulnerability in a modern mechanistic paradigm of carotid plaque disruption and thromboembolization. Third, we review the clinically available imaging tools to detect these biomarkers, and how their use has started to shed light on the prevalence and natural history of this underdiagnosed condition. Fourth, we review recent clinical studies employing a contemporary definition of symptomatic nonstenotic carotid and discuss targeted treatments for this condition. Finally, we make a case to generate the much-needed high-level evidence to align the clinical management of patients with symptomatic nonstenotic carotid with a contemporary understanding of plaque disruption and thromboembolization.

Histological Validation of 3D Variable Flip Angle TSE Multi-Contrast Magnetic Resonance Vessel Wall Imaging in Characterizing Carotid Vulnerable Atherosclerotic Plaques

BackgroundAccurate assessment of the vulnerability of carotid atherosclerotic plaques is crucial for stroke prevention. The three-dimensional (3D) magnetic resonance (MR) vessel wall imaging (VWI) has been increasingly employed to evaluate carotid plaques due to its extensive coverage and isotropic high spatial resolution. However, the accuracy of such technique lacks validation by histology. ObjectiveThis study aims to validate the accuracy of 3D multi-contrast MR VWI used variable-flip-angle (VFA) and turbo spin echo (TSE) readout in identifying vulnerable carotid plaques, using histological analysis as a reference. MethodsTwenty-one male patients (mean age: 64.4 ± 7.2 years) scheduled for carotid endarterectomy (CEA) were recruited for this study. All patients underwent carotid multi-contrast MR VWI, including 3D T1- and T2-weighted variable flip angle-based turbo spin echo (VFA-TSE) sequences, as well as 3D time of flight (TOF) MR angiography (MRA), using a 3.0T MR system. Histological processing was performed for carotid plaque specimens. The presence or absence, along with the area measurements, of lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), and calcifications (CA) were independently evaluated on both MR images and histological sections. Cohen’s kappa (κ) analysis was utilized to determine the agreement between 3D multi-contrast MR VWI and histology in identifying carotid plaque compositions before and after excluding compositions bellow certain size threshold. Spearman’s correlation analysis was also conducted to assess the agreement in quantifying plaque compositions. ResultsA total of 81 slices of MR images were successfully matched with histological sections. Moderate to almost perfect agreements were observed between 3D MR VWI and histology in the identification of LRNC (κ: 0.85 and 0.89), IPH (κ: 0.65 and 0.69), and CA (κ: 0.46 and 0.62) before and after excluding compositions smaller than 0.79 mm2. Strong to very strong correlations were found in the quantification of plaque compositions including LRNC (r=0.88), IPH (r=0.80), and CA (r=0.74) between MR imaging and histology. ConclusionThe 3D VFA-TSE multi-contrast MR VWI is capable of accurately characterizing vulnerable carotid atherosclerotic plaques.

Diagnostic accuracy of carotid plaque magnetic resonance imaging compared to histopathology in symptomatic carotid artery stenosis

IntroductionVulnerable plaques have been shown to predict ipsilateral cerebral ischemic events and identifying them leads to appropriate secondary stroke prevention strategies. We evaluated the diagnostic accuracy of MR carotid plaque imaging in identifying plaque vulnerability when compared with histopathological findings in patients with symptomatic carotid stenosis who underwent carotid endarterectomy (CEA). MethodsA prospective cohort of forty-five consecutive patients with moderate to severe symptomatic carotid stenosis who underwent CEA at a tertiary Indian hospital had 3 T MRI plaque imaging with multi-parametric protocol between November 2021 and December 2022. Images were analyzed by a vascular radiologist blinded to histopathological data. High-risk plaque characteristics such as lipid rich necrotic core (LRNC), intraplaque hemorrhage (IPH), thin fibrous cap and ulceration were assessed and correlated with histopathological findings as per American Heart Association (AHA) classification using Cohen’s kappa statistics to obtain diagnostic accuracies. ResultsOf the 45 patients, 38(84 %) were males. The mean age was 65 ± 7.7 years and mean duration to CEA from the most recent event was 57 days (57 ± 46 days). A significant correlation between MR plaque imaging and histopathology was noted for IPH (sensitivity-91 %, specificity-86 %, κ = 0.774, p < 0.001), LRNC (sensitivity-92.1 %, specificity-85.7 %, κ = 0.697, p < 0.001), and plaque ulceration (sensitivity-84.6 %, specificity-78.1 %, κ = 0.563, p < 0.001). MRI had an overall sensitivity and specificity of 92.3 % and 84.2 % respectively (κ = 0.77, p < 0.001) in discriminating high risk plaques. ConclusionMR plaque imaging shows a very good correlation with histopathology and can identify unstable high-risk plaques with high accuracy. This may have implication in selection of patients for carotid revascularization in symptomatic carotid stenosis.

Comparison of the diagnostic performance of contrast-enhanced ultrasound and high-resolution magnetic resonance imaging in the evaluation of histologically defined vulnerable carotid plaque: a systematic review and meta-analysis.

Vulnerable carotid plaque is closely associated with ischemic stroke. Contrast-enhanced ultrasound (CEUS) and high-resolution magnetic resonance imaging (HR-MRI) are two imaging modalities capable of assessing the vulnerability of carotid plaques. This systematic review aimed to compare the diagnostic performance of CEUS and HR-MRI in the evaluation of histologically defined vulnerable carotid plaques. A systematic literature search with predefined search terms was performed on PubMed, the Cochrane library, Embase, and Web of Science from January 2001 to December 2023. Studies that evaluated the diagnostic accuracy of vulnerable carotid plaques confirmed by histology with CEUS and/or HR-MRI were included. The pooled values were calculated using a random-effects meta-analysis to determine diagnostic power. This analysis included a total of 839 patients from 20 studies comprising 1,357 HR-MRI plaques and CEUS 504 plaques. With the reference to histological results, all nine CEUS studies focused on the detection of intraplaque neovascularization (IPN), and three studies also examined morphological changes or ulcerated plaques; meanwhile, among the HR-MRI studies, seven predominantly focused on identifying intraplaque hemorrhage (IPH) and three mainly examined lipid-rich necrotic cores (LRNCs). The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the area under the curve (AUC) for CEUS studies were 0.85 [95% confidence interval (CI): 0.81-0.89], 0.76 (95% CI: 0.69-0.83), 3.41 (95% CI: 1.68-6.94), 0.14 (95% CI: 0.05-0.38), 27.68 (95% CI: 5.78-132.62), and 0.89 [standard error (SE) 0.06], respectively; for HR-MRI, these values were 0.88 (95% CI: 0.85-0.90), 0.89 (95% CI: 0.86-0.92), 7.49 (95% CI: 3.28-17.09), 0.17 (95% CI: 0.12-0.24), 49.13 (95% CI: 23.87-101.11), and 0.94 (SE 0.01), respectively. The difference in AUC between the two modalities was not statistically significant (Z=0.82; P=0.68). CEUS and HR-MRI are valuable noninvasive diagnostic tools for identifying histologically confirmed vulnerable carotid plaques and demonstrate similar diagnostic performance. CEUS is more capable of detecting IPN and morphological changes, while HR-MRI is more suited to classifying IPH and LRNCs.

Efficacy, safety and mechanism of Simiaoyongan decoction in the treatment of carotid atherosclerotic plaque: a randomized, double-blind, placebo-controlled clinical trial protocol

IntroductionChronic inflammation is the major pathological feature of Atherosclerosis(As). Inflammation may accelerate plaque to develop, which is a key factor resulting in the thinning of the fibrous cap and the vulnerable rupture of plaque. Presently, clinical treatments are still lacking. It is necessary to find a safe and effective treatment for As inflammation. Simiaoyongan Decoction (SMYA) has potential anti-inflammatory and plaque protection effects. This protocol aims to evaluate the efficacy, safety, and mechanism of SMYA for patients with carotid atherosclerotic plaque.Methods/designThe assessment of SMYA clinical trial is designed as a randomized, double-blind, placebo-controlled study. The sample size is 86 cases in total, with 43 participants in the intervention group and the control group respectively. The intervention group takes SMYA, while the control group takes SMYA placebo. The medication lasts for 14 days every 10 weeks, with a total of 50 weeks. We will use carotid artery high resolution magnetic resonance imaging (HR-MRI) to measure plaque. The plaque minimum fiber cap thickness (PMFCT) is adopted as the primary outcome. The secondary outcomes include plaque fiber cap volume, volume percentage of fiber cap, lipid-rich necrotic core (LRNC) volume, volume percentage of LRNC, internal bleeding volume of plaque, internal bleeding volume percentage of plaque, plaque calcification volume, volume percentage of plaque calcification, lumen stenosis rate, average and a maximum of vessel wall thickness, vessel wall volume, total vessel wall load, carotid atherosclerosis score, hs-CRP, IL-1β and IL-6, the level of lipid profiles and blood glucose, blood pressure, and body weight.DiscussionWe anticipate that patients with As plaque will be improved from SMYA by inhibiting inflammation to enhance plaque stability. This study analyzes plaque by using HR-MRI to evaluate the clinical efficacy and safety of SMYA. Moreover, we conduct transcriptome analysis, proteomic analysis, and metagenomic analysis of blood and stool of participants to study the mechanism of SMYA against As plaque. This is the first prospective TCM trial to observe and treat As plaque by inhibiting inflammatory reaction directly. If successful, the finding will be valuable in the treatment of As plaque and drug development, especially in the “statin era”.Trial registration numberThis trial is registered on Chinese Clinical Trials.gov with number ChiCTR2000039062 on October 15, 2020 (http://www.chictr.org.cn).

30-Day Risk Score for Mortality and Stroke in Patients with Carotid Artery Stenosis Using Artificial Intelligence Based Carotid Plaque Morphology

The gold standard for determining carotid artery stenosis intervention is based on a combination of percent stenosis and symptomatic status. Few studies have assessed plaque morphology as an additive tool for stroke prediction. Our goal was to create a predictive model and risk score for 30-day stroke and death inclusive of plaque morphology. Patients with a computed tomographic angiography head/neck between 2010 and 2021 at a single institution and a diagnosis of carotid artery stenosis were included in our analysis. Each computed tomography was used to create a three-dimensional image of carotid plaque based off image recognition software. A stepwise backward regression was used to select variables for inclusion in our prediction models. Model discrimination was assessed with area under the receiver operating characteristic curves (AUCs). Additionally, calibration was performed and the model with the least Akaike Information Criterion (AIC) was selected. The risk score was modeled from the Framingham Study. Primary outcome was mortality/stroke. We created 3 models to predict mortality/stroke from 366 patients: model A using only clinical variables, model B using only plaque morphology and model C using both clinical and plaque morphology variables. Model A used age, sex, peripheral arterial disease, hyperlipidemia, body mass index (BMI), chronic obstructive pulmonary disease (COPD), and history of transient ischemia attack (TIA)/stroke and had an AUC of 0.737 and AIC of 285.4. Model B used perivascular adipose tissue (PVAT) volume, lumen area, calcified volume, and target lesion length and had an AUC of 0.644 and AIC of 304.8. Finally, model C combined both clinical and software variables of age, sex, matrix volume, history of TIA/stroke, BMI, PVAT, lipid rich necrotic core, COPD and hyperlipidemia and had an AUC of 0.759 and an AIC of 277.6. Model C was the most predictive because it had the highest AUC and lowest AIC. Our study demonstrates that combining both clinical factors and plaque morphology creates the best predication of a patient's risk for all-cause mortality or stroke from carotid artery stenosis. Additionally, we found that for patients with even 3 points in our risk score model has a 20% chance of stroke/death. Further prospective studies are needed to validate our findings.

Diagnostics Accuracy of Magnetic Resonance Imaging in Detection of Atherosclerotic Plaque Characteristics in Carotid Arteries Compared to Histology: A Systematic Review.

Carotid plaque composition represents one of the main risk factors of future ischemic stroke. MRI provides excellent soft tissue contrast that can distinguish plaque characteristics. Our objective was to analyze the diagnostic accuracy of MRI imaging in the detection of carotid plaque characteristics compared to histology in patients with symptomatic and asymptomatic carotid atherosclerosis through a systematic review. After prospective registration in PROSPERO (ID CRD42022329690), Medline Ovid, Embase.com, Cochrane Library, and Web of Science Core were searched without any search limitation up to May 27, 2022 to identify eligible articles. Of the 8168 studies, 53 (37 × 1.5 T MRI, 17 × 3 T MRI) evaluated MRI accuracy in the detection of 13 specific carotid plaque characteristics in 169 comparisons. MRI demonstrated high diagnostic accuracy for detection of calcification (3 T MRI: mean sensitivity 92%/mean specificity 90%; 1.5 T MRI: mean sensitivity 81%/mean specificity 91%), fibrous cap (1.5 T: 89%/87%), unstable plaque (1.5 T: 89%/87%), intraplaque hemorrhage (1.5 T: 86%/88%), and lipid-rich necrotic core (1.5 T: 89%/79%). MRI also proved to have a high level of tissue discrimination for the carotid plaque characteristics investigated, allowing potentially for a better risk assessment and follow-up of patients who may benefit from more aggressive treatments. These results emphasize the role of MRI as the first-line imaging modality for comprehensive assessment of carotid plaque morphology, particularly for unstable plaque. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Association between Pericarotid Fat Density and Positive Remodeling in Patients with Carotid Artery Stenosis.

Background/Objectives: The underlying mechanism of the potential involvement of inflammatory crosstalk between pericarotid fat and vascular layers in atherosclerosis pathogenesis is unclear. We investigated the association between pericarotid fat density and positive remodeling and inflammatory markers in carotid stenosis. We hypothesized that pericarotid fat density might serve as a marker of plaque inflammation in a clinical setting. Methods: We evaluated the stenosis degree and pericarotid fat density in 258 patients with carotid plaques. Plaque composition was examined, and the correlation between pericarotid fat density and expansive remodeling was investigated. Pearson's product-moment correlation coefficient was used to examine the relationship between pericarotid fat density and the expansive remodeling ratio. We also evaluated the relationship of pericarotid fat density with plaque composition, degree of stenosis, and macrophage and microvessel counts by. The subgroup analysis compared these factors between symptomatic mild carotid stenosis. Results: The pericarotid fat density was -63.0 ± 11.1 HU. The carotid fat densities were -56.8 ± 10.4 HU in symptomatic and -69.2 ± 11.4 HU in asymptomatic lesions. The pericarotid fat density values in intraplaque hemorrhage, lipid-rich necrotic core, and fibrous plaque were -51.6 ± 10.4, -59.4 ± 12.8, and -74.2 ± 8.4 HU, respectively. Therefore, the expansive remodeling ratio was 1.64 ± 0.4. Carotid fat density and expansive remodeling ratio were correlated. Immunohistochemistry showed high macrophage and microvessel levels (143.5 ± 61.3/field and 121.2 ± 27.7/field, respectively). In symptomatic mild carotid stenosis, pericarotid fat density was correlated with other inflammatory factors. The pericarotid fat density and expansive remodeling ratio (2.08 ± 0.21) were high in mild stenosis (-50.1 ± 8.4 HU). Conclusions: Pericarotid fat and intraplaque components were well correlated. Carotid fat density may be a marker of plaque inflammation in carotid plaques.

Effect of evolocumab on carotid plaque composition in asymptomatic carotid artery stenosis (EVOCAR-1) using magnetic resonance imaging

Background and AimsTo determine the effect of evolocumab treatment in patients with asymptomatic carotid artery stenosis ≥50 % on carotid plaque morphology and composition, as determined by magnetic resonance imaging. MethodsWe conducted a double-blind randomized controlled trial in patients with asymptomatic carotid artery plaque with ≥50 % stenosis and low-density lipoprotein-associated cholesterol (LDL-C) ≥1.8 mmol/L, despite standard lipid-lowering therapy, with 12 months of evolocumab or placebo injection every two weeks. The primary endpoint was the between group difference in the absolute change from baseline in carotid plaque lipid-rich necrotic core (LRNC), assessed by carotid magnetic resonance. ResultsDue to interrupted recruitment during the COVID-19 pandemic, 33 patients (36 % female) were randomised, which was less than the target of 52. Mean age was 68.7 years (SD, 8.5) and baseline LDL-C 2.4 mmol/L(SD, 0.7). LDL-C was reduced with evolocumab to 0.8 mmol/L (SD, 0.5) vs 2.2 mmol/L (SD, 0.7) with placebo at 3 months (between group absolute difference -1.3 mmol/L [95 % CI, -1.7 to -0.9], p < 0.001). Evolocumab treatment was associated with a favourable change in LRNC at 12 months of -16 mm3 (SD, 54) whereas the placebo group showed -4 mm3 (SD, 44). Between group differences did not show statistically significance with a placebo-adjusted LRNC change of -17 mm3 ([95 % CI, -45 to 12], p = 0.25). Percentage carotid plaque LRNC also numerically reduced at 12 months, however this did not reach statistical significance (-2.4 % vessel wall volume [95 % CI, -5.7 to 0.9], p = 0.16). ConclusionIntensive LDL-C lowering with the addition of evolocumab to maximally tolerated lipid-lowering therapy did not lead to a statistically significant change in vulnerable plaque phenotype characteristics in patients with asymptomatic carotid artery stenosis, but the study was underpowered due to under-recruitment in the context of the COVID-19 pandemic.

Development and Validation of a Fusion Model Based on Carotid Plaques and White Matter Lesion Burden Imaging Characteristics to Evaluate Ischemic Stroke Severity in Symptomatic Patients.

The diagnostic value of carotid plaque characteristics based on higher-resolution vessel wall MRI (HRVW-MRI) combined with white matter lesion (WML) burden for the risk of ischemic stroke is unclear. To combine carotid plaque features and WML burden to construct a hybrid model for evaluating ischemic stroke severity and prognosis in patients with symptomatic carotid artery stenosis. Retrospective. One hundred and ninty-three patients with least one confirmed carotid atherosclerotic stenosis ≥30% and cerebrovascular symptoms within the last 2 weeks (136 in the training cohort and 57 in the test cohort). 3.0T, T2-weighted fluid attenuated inversion recovery (T2-FLAIR) and diffusion-weighted imaging (DWI); HRVW-MRI: 3D T1-weighted variable flip angle fast spin-echo sequences (VISTA), T2-weighted VISTA, simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP), and contrast-enhanced T1-VISTA. The following features of the plaques or vessel wall were assessed by three MRI readers independently: calcification (CA), intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), ulceration, plaque enhancement (PE), maximum vessel diameter (Max VD), maximum wall thickness (Max WT), total vessel area (TVA), lumen area (LA), plaque volume, and lumen stenosis. WMLs were graded visually and categorized as absent-to-mild WMLs (Fazekas score 0-2) or moderate-severe WMLs (Fazekas score 3-6). WML volumes were quantified using a semiautomated volumetric analysis program. Modified Rankin scores (mRS) were assessed at 90 days, following an outpatient interview, or by telephone. LASSO-logistic regression analysis was performed to construct a model. The performance of the model was evaluated using receiver operating characteristic (ROC) curve analyses, calibration curves, decision curve analyses, and clinical imaging curves. Conditional logistic regression analysis was used to explore the associations between the hybrid model-derived score and the modified Rankin Scale (mRS) score at 90 days. The model was constructed using five selected features, including IPH, plaque enhancement, ulceration, NWI, and total Fazekas score in deep WMLs (DWMLs). The hybrid model yielded an area under the curve of 0.92 (95% confidence interval [CI] 0.87-0.97) in the training cohort and 0.88 (0.80-0.96) in the test cohort. Furthermore, the hybrid model-derived score (odds ratio = 1.28; 95% CI 1.06-1.53) was independently associated with the mRS score 90 days after stroke. The hybrid model constructed using MRI plaque characteristics and WML burden has potential to be an effective noninvasive method of assessing ischemic stroke severity. The model-derived score has promising utility in judging neurological function recovery. Stage 2.

Abstract 1155: Symptomatic Low- And High-degree Carotid Stenoses Exhibit Similar Features Of Plaque Instability

Background: Carotid endarterectomy (CEA) for symptomatic carotid stenosis is recommended for patients with the &gt;70% (NASCET) stenosis but not for those with &lt;50%. Since low-degree stenoses may still cause strokes, refined risk stratification is necessary, which could be improved by incorporating biological features of plaque instability. In order to challenge risk-stratification by the degree of stenosis, we compared biological features of carotid plaques from symptomatic patients with &lt;50% stenosis vs. &gt;70% and explored mechanisms behind plaque instability in low-degree stenoses. Methods: CEA specimens were retrieved from symptomatic patients with &gt;70% (n=204) and &lt;50% stenosis (n=34), all part of the Biobank of Karolinska Endarterectomies (BiKE). Patient demographics, plaque morphology from image analyses of preoperative computed tomography angiography (CTA), and RNA-seq analyses of lesions were used for comparisons. Plaque biology was assessed by transcriptomics using principal component analyses (PCA), differential gene expression (DGE)- and gene-set enrichment analyses (GSEA). Immunohistochemistry (IHC) was used to study proteins corresponding to upregulated genes. Results: The demographics of the two groups were statistically similar. They also showed similar plaque morphology with respect to intraplaque hemorrhage (IPH), plaque burden and fibrous cap thickness, whereas calcification was higher in the &lt;50% group and lipid-rich necrotic core higher in the &gt;70% group. PCA analysis indicated poor clustering, while DGE and GSEA identified enrichment of genes and pathways related to tissue hypoxia and angiogenesis in &lt;50% lesions. Corresponding proteins were detected by IHC in neo-vascularized plaque regions. Conclusions: Plaques from symptomatic patients with &lt;50% carotid stenoses exhibit largely similar morphological and biological features as those from &gt;70% stenoses, emphasizing the need for improved stratification of patients for CEA of symptomatic carotid stenosis. However, pathways associating plaque burden, hypoxia and angiogenesis were particularly enriched in low-grade stenosis lesions suggesting mechanisms behind plaque instability and symptoms in patients with both low- and high-degree stenosis.

Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.

The concept of vulnerable carotid plaques is pivotal in understanding the pathophysiology of ischemic stroke secondary to large-artery atherosclerosis. In macroscopic evaluation, vulnerable plaques are characterized by one or more of the following features: microcalcification; neovascularization; lipid-rich necrotic cores (LRNCs); intraplaque hemorrhage (IPH); thin fibrous caps; plaque surface ulceration; huge dimensions, suggesting stenosis; and plaque rupture. Recognizing these macroscopic characteristics is crucial for estimating the risk of cerebrovascular events, also in the case of non-significant (less than 50%) stenosis. Inflammatory biomarkers, such as cytokines and adhesion molecules, lipid-related markers like oxidized low-density lipoprotein (LDL), and proteolytic enzymes capable of degrading extracellular matrix components are among the key molecules that are scrutinized for their associative roles in plaque instability. Through their quantification and evaluation, these biomarkers reveal intricate molecular cross-talk governing plaque inflammation, rupture potential, and thrombogenicity. The current evidence demonstrates that plaque vulnerability phenotypes are multiple and heterogeneous and are associated with many highly complex molecular pathways that determine the activation of an immune-mediated cascade that culminates in thromboinflammation. This narrative review provides a comprehensive analysis of the current knowledge on molecular biomarkers expressed by symptomatic carotid plaques. It explores the association of these biomarkers with the structural and compositional attributes that characterize vulnerable plaques.

Abstract WP116: Plaque Features and Infarct Pattern in Ischemic Stroke With Bilateral Carotid Artery Atherosclerosis

Objective: to compare the carotid artery plaque characteristics between ipsilateral and contralateral infarct in ischemic stroke with bilateral carotid artery atherosclerosis, and explore the association between plaque characteristics and infarct pattern. Methods: a total of 186 ischemic stroke patients with bilateral carotid artery atherosclerosis were included, carotid artery plaque burden (the degree of stenosis, maximum wall thickness, lumen area, wall area, normalized wall index (NWI=wall area/[lumen area+ wall area]), and eccentricity index), and vulnerability (intraplaque hemorrhage [IPH], calcification, irregular surface, thin or ruptured fibrous cap[TRFC], and lipid-rich necrotic core[LRNC]) were obtained by MR vessel wall imaging, infarct pattern was divided as single and multiple/recurrent infarcts in infarct ipsilateral carotid artery. Ipsilateral and contralateral carotid artery plaque features were compared, then the carotid artery plaque characteristics on the infarct side were correlated with the infarct pattern. Results: the mean age of subjects included was 68 years old, 79.6% of them were male. Compared with contralateral carotid artery plaque, plaque burden at the ipsilateral carotid artery was much heavy, presented with a higher degree of stenosis, smaller lumen area (0.22±0.15 vs. 0.28±0.15), larger wall area (0.50±0.19 vs.0.42±0.17), and higher eccentricity index (0.67±0.13 vs. 0.58±0.23), all p values&lt;0.05. The vulnerable plaques were also more prevalent at ipsilateral infarct, with a high percentage of IPH (47.8% vs. 19.8%), irregular surface (36.3% vs. 17.5%), TRFC (38.5% vs.12.3%), and LRNC (38.1% vs. 15.9%), all p values were &lt;0.05. After adjusting for covariates, the degree of stenosis (OR=1.590, 95% CI 1.048-2.410) and LRNC (OR=0.259, 95% CI 0.087-0.769) were associated with multiple or recurrent infarcts independently. Conclusion: in ischemic stroke with bilateral carotid atherosclerosis, the atherosclerotic plaque burden at ipsilateral infarct was much heavier and more vulnerable. Both lumen stenosis and plaque components were correlated with multiple or recurrent infarcts in this population.

Findings of Angiography and Carotid Vessel Wall Imaging Associated with Post-Procedural Clinical Events after Carotid Artery Stenting.

Vessel wall imaging (VWI) for carotid plaque is better for detecting unstable carotid plaque such as intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), and thin/ruptured fibrous cap. However, the role of VWI before carotid artery stenting (CAS) is unclear. Thus, this study aimed to determine the findings of symptomatic carotid stenosis before CAS on angiography and carotid VWI and to evaluate the imaging findings associated with post-procedural clinical events after CAS. This retrospective study included 173 consecutive patients who underwent carotid VWI, CAS, and post-procedural diffusion-weighted imaging (DWI) after CAS. Findings of unstable plaque on carotid VWI and unstable findings on angiography were analyzed. We also analyzed the incidence of post-procedural clinical events, any stroke, myocardial infarction (MI), and death within 30 days of CAS. Of 173 patients, 101 (58.4%) had initial ischemic symptoms and positive findings on DWI. Symptomatic patients were significantly higher in patients with IPH than in patients without IPH (62.4% vs. 45.8%, P=0.031). Degree of stenosis, thrombus of the stenotic lesion, flow delay of internal carotid artery, and flow arrest by filter thrombus had significantly higher prevalence in the symptomatic group. Twenty patients (11.6%) had post-procedural clinical events such as any stroke, clinical symptoms, and/or MI. Hyperlipidemia and intraluminal thrombus on angiography were identified as significant factors influencing post-procedural events after CAS. An intraluminal thrombus on angiography was identified as a significant factor influencing post-procedural clinical events after CAS.

Carotid plaque characteristics in the CREST-2 trial

BackgroundThe modest stroke prevention from surgery for asymptomatic carotid disease has prompted a search for predictors that may improve risk stratification beyond luminal stenosis. Plaque disruption and atheroembolization are associated with unique anatomical and histological changes. The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) collects information on duplex ultrasound (DUS) plaque biomarkers with the goal of evaluating their relationship to the periprocedural and long-term risks of stroke. In this study, we examine the reliability with which carotid plaque features can be measured from DUS images, and report baseline carotid DUS-derived stenosis and plaque features using semiautomated digital image analysis of patients enrolled in CREST-2. MethodsWe studied the first 503 patients in CREST-2. Patients underwent standardized carotid DUS evaluation pre-enrollment. B-Mode images were scaled linearly to normalize brightness. Plaques were outlined manually. Dedicated software automatically measured the longitudinal sectional area (mm2), grayscale median (GSM), Gray-Weale classification, and tissue composition (mm2) of intraplaque hemorrhage (IPH), lipid, fibrous tissue, muscle, and calcium. We present the mean, standard deviation, median, interquartile range, minimum and maximum range, and proportions of carotid peak systolic velocities (PSVs) and plaque morphological features. We tested for autocorrelation among plaque features and computed the proportion of potentially unstable plaques in the cohort. Reliability of the image analysis techniques was tested in 100 patients using Bland-Altman plots and intraclass and interclass correlation coefficients. ResultsMost patients were male (58.4%), older (mean age of 69.3 years), White (87.5%), and had a PSV of ≥230 cm/s (98.6%); the 1.4% with a PSV of <230 cm/s were enrolled based on catheter angiography. Plaques in this study were large; the mean longitudinal sectional area was 62 ± 37 mm2 (range, 6.2–256.5 mm2). The mean GSM was 58 ± 30 (unitless) (range, 0–168) and Gray-Weale classification was 3.5 ± 0.9 (range, 1–5). The mean areas of tissue types were IPH 5.3 ± 8.9 mm2, lipid 9.3 ± 8.6 mm2, fibrous tissue 10 ± 10 mm2, muscle 17 ± 12 mm2, and calcium 1.6 ± 4.1 mm2. The PSV of patients showed poor correlation with plaque features. The proportion of plaques with a GSM of ≤35 was 22.8%, IPH of ≥5 mm2 was 30.0%, and a lipid-rich necrotic core of ≥40% was 3.0% of the cohort. Plaque measurements could be performed with high reliability with good interobserver and intraobserver correlations. ConclusionsSite-generated, core laboratory-interpreted ultrasound examination provides a reliable way of characterizing carotid plaque morphological features across studies performed at many CREST-2 sites. The initial cohort of patients randomized in CREST-2 had heterogeneity of plaque features despite causing high-grade stenosis. Completion of the trial will provide an opportunity to assess whether plaque heterogeneity interacts with response to revascularization and medical management.

Carotid artery perivascular adipose tissue on magnetic resonance imaging: a potential indicator for carotid vulnerable atherosclerotic plaque.

Magnetic resonance imaging (MRI) has the potential in assessing the inflammation of perivascular adipose tissue (PVAT) due to its excellent soft tissue contrast. However, evidence is lacking for the association between carotid PVAT measured by MRI and carotid vulnerable atherosclerotic plaques. This study aimed to investigate the association between signal intensity of PVAT and vulnerable plaques in carotid arteries using multi-contrast magnetic resonance (MR) vessel wall imaging. In this cross-sectional study, a total of 104 patients (mean age, 64.9±7.0 years; 86 men) with unilateral moderate-to-severe atherosclerotic stenosis referred to carotid endarterectomy (CEA) were recruited from April 2018 to December 2020 at Department of Neurosurgery of Peking University Third Hospital. All patients underwent multi-contrast MR vessel wall imaging including time-of-flight (ToF) MR angiography, black-blood T1-weighted (T1w) and T2-weighted (T2w) and simultaneous non-contrast angiography and intraplaque hemorrhage (IPH) imaging sequences. Patients with contraindications to endarterectomy or MRI examinations were excluded. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of PVAT were measured on ToF images and vulnerable plaque characteristics including IPH, large lipid-rich necrotic core (LRNC), and fibrous cap rupture (FCR) were identified. The SNR and CNR of PVAT were compared between slices with and without vulnerable plaque features using Mann-Whitney U test and their associations were analyzed using the generalized linear mixed model (GLMM). Carotid artery slices with IPH (30.93±14.56 vs. 27.34±10.02; P<0.001), FCR (30.35±13.82 vs. 27.53±10.37; P=0.006), and vulnerable plaque (29.15±12.52 vs. 27.32±10.05; P=0.016) had significantly higher value of SNR of PVAT compared to those without. After adjusting for clinical confounders, the SNR of PVAT was significantly associated with presence of IPH [odds ratio (OR) =0.627, 95% confidence interval (CI): 0.465-0.847, Puncorr=0.002, PFDR=0.016] and vulnerable plaque (OR =0.762, 95% CI: 0.629-0.924, Puncorr=0.006, PFDR=0.020). However, no significant association was found between the CNR of PVAT and presence of vulnerable plaque features (all P>0.05). The SNR of carotid artery PVAT measured by ToF MR angiography is independently associated with vulnerable atherosclerotic plaque features, suggesting that the signal intensity of PVAT might be an effective indicator for vulnerable plaque.

Investigating the Association of Carotid Atherosclerotic Plaque MRI Features and Silent Stroke After Carotid Endarterectomy.

The predictive value of carotid plaque characteristics for silent stroke (SS) after carotid endarterectomy (CEA) is unclear. To investigate the associations between carotid plaque characteristics and postoperative SS in patients undergoing CEA. Prospective. One hundred fifty-three patients (mean age: 65.4 ± 7.9 years; 126 males) with unilateral moderate-to-severe carotid stenosis (evaluated by CT angiography) referred for CEA. 3 T, brain-MRI:T2-PROPELLER, T1-/T2-FLAIR, diffusion weighted imaging (DWI) and T2*, carotid-MRI:black-blood T1-/T2W, 3D TOF, Simultaneous Non-contrast Angiography intraplaque hemorrhage. Patients underwent carotid-MRI within 1-week before CEA, and brain-MRI within 48-hours pre-/post-CEA. The presence and size (volume, maximum-area-percentage) of carotid lipid-rich necrotic core (LRNC), intraplaque hemorrhage (Type-I/Type-II IPH) and calcification were evaluated on carotid-MR images. Postoperative SS was assessed from pre-/post-CEA brain DWI. Patients were divided into moderate-carotid-stenosis (50%-69%) and severe-carotid-stenosis (70%-99%) groups and the associations between carotid plaque characteristics and SS were analyzed. Independent t test, Mann-Whitney U-test, chi-square test and logistic regressions (OR: odds ratio, CI: confidence interval). P value <0.05 was considered statistically significant. SS was found in 8 (16.3%) of the 49 patients with moderate-carotid-stenosis and 21 (20.2%) of the 104 patients with severe-carotid-stenosis. In patients with severe-carotid-stenosis, those with SS had significantly higher IPH (66.7% vs. 39.8%) and Type-I IPH (66.7% vs. 38.6%) than those without. The presence of IPH (OR 3.030, 95% CI 1.106-8.305) and Type-I IPH (OR 3.187, 95% CI 1.162-8.745) was significantly associated with SS. After adjustment, the associations of SS with presence of IPH (OR 3.294, 95% CI 1.122-9.669) and Type-I IPH (OR 3.633, 95% CI 1.216-10.859) remained significant. Moreover, the volume of Type-II IPH (OR 1.014, 95% CI 1.001-1.028), and maximum-area-percentage of Type-II IPH (OR 1.070, 95% CI 1.002-1.142) and LRNC (OR 1.030, 95% CI 1.000-1.061) were significantly associated with SS after adjustment. No significant (P range: 0.203-0.980) associations were found between carotid plaque characteristics and SS in patients with moderate-carotid-stenosis. In patients with unilateral severe-carotid-stenosis, carotid vulnerable plaque MR features, particularly presence and size of IPH, might be effective predictors for SS after CEA. 2 TECHNICAL EFFICACY: Stage 2.