Presence Of Intraplaque Hemorrhage Research Articles

Association between Vascular Calcification and Intraplaque Hemorrhage in Coronary Atherosclerosis from Autopsy: The Hisayama Study.

Vascular calcification is observed in advanced atherosclerotic lesions. Vascular calcification is considered to increase the risk of intraplaque hemorrhage and subsequent plaque destabilization; however, there is limited pathohistoological evidence of the association between vascular calcification and intraplaque hemorrhage. The aim of this study was to investigate the association between vascular calcification and intraplaque hemorrhage in the coronary arteries. We examined 374 coronary arteries obtained from the autopsy samples of 126 deceased individuals. The vascular calcification levels of each artery were categorized into no calcification and quintiles of calcification area size among the arteries with calcification. Macrophage infiltration and neovascularization were also evaluated. The association of the calcification area, macrophage area, or number of vessels with the presence of intraplaque hemorrhage in the coronary arteries was estimated using a logistic regression analysis. Calcification lesions were observed in 149 coronary arteries. Arteries in the fourth quintile of calcification area size had a significantly greater likelihood of intraplaque hemorrhage than the arteries without calcification, after adjusting for confounders: odds ratio 13.13 (95% confidence interval: 2.97-58.16). After evaluating the influence of macrophage infiltration, the highest odds ratio of intraplaque hemorrhage was associated with the combination of large macrophage area and moderately sized calicification areas. The odds ratio of intraplaque hemorrhage additively increased with the combination of calcification and the number of vessels. The present findings suggest that vascular calcification is significantly associated with intraplaque hemorrhage. The association between vascular calcification and intraplaque hemorrhage may decrease above a certain size of the calcification area.

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.

Inflammatory activity of vulnerable plaques in asymptomatic, non-hemodynamically significant carotid artery stenoses: preliminary results of the carotid artery multi-modality imaging prognostic study

Abstract Background [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a valid technique to quantify carotid plaque inflammation and can improve identification of patients at high risk for stroke. There are few data on the inflammatory plaque activity in asymptomatic patients and of its association with other characteristics of plaque vulnerability. Purpose To assess the inflammatory carotid plaque activity and its correlations with patient characteristics and features of plaque vulnerability detected by other imaging techniques in a population of patients with asymptomatic mild/moderate degree of stenosis. Methods Seventy-five asymptomatic patients with 40-60% unilateral carotid stenosis at Doppler ultrasound (DUS) were prospectively evaluated with [18F]FDG-PET, computed tomography angiography (CTA), and magnetic resonance angiography (MRA). Regions of interests were drawn using fused PET/CT slices on the most diseased segment (MDS), defined as the single hottest slice of [18F]FDG uptake. Background blood pool activity was obtained from regions of interests placed in the lumen of the jugular vein. The target-to-background ratio (TBR) was calculated by dividing maximum standardized uptake value (SUVmax) of the MDS to SUVmax of ipsilateral blood pool activity. Plaque vulnerability was defined as the presence of an echolucent plaque at DUS, plaque ulceration at CTA, intraplaque hemorrhage, and lipid-rich necrotic core at MRA. Results Patients with a TBR ≥median (1.75), compared with those below the median, were significantly more frequently male and on statin therapy, had higher prevalence of ulcerated plaque at CTA (61% vs 35%, p=0.03) and intraplaque hemorrhage at MRA (33% vs 10%, p=0.03), while the prevalence of a lipid-rich necrotic core at MRA was not significantly different (p=0.16). TBR and SUVmax of the MDS were similar in those with or without a ≥50% stenosis, and peak velocities indices at DUS were not significantly correlated with TBR or SUVmax. Log(TBR) was significantly higher in ulcerated, rather than non-ulcerated, plaque (0.27 vs 0.21, p=0.03) and numerically higher in plaques with an intraplaque hemorrhage (0.22 vs 0.30, p=0.06). Log(TBR) and Log(SUVmax) were similar in plaques with and without a lipid-rich necrotic core (p=0.86 for both). Conclusions Higher TBR or SUVmax, indicating a high inflammatory activity, are associated with an ulcerated plaque and the presence of intraplaque hemorrhage but not with either the degree of stenosis or the presence of a lipid-rich necrotic core.

Imaging signs of vulnerability, neurological events and cognitive impairment in asymptomatic carotid artery stenosis: results from the Carotid Artery Multi-modality imaging Prognostic (CAMP) study

Abstract Background Carotid artery plaques with imaging signs of vulnerability, such as ulceration, intraplaque haemorrhage (IPH) or a lipid-rich necrotic core (LRNC), are associated with a high risk of ischemic stroke, and are reported to be considered for invasive treatment if % diameter stenoses ≥60. Little is known about their fate in patients with &amp;lt;60% stenoses. Purpose To evaluate the prevalence of ulceration, IPH and LRNC and their characteristics in patients with asymptomatic, non-significant (&amp;lt;60%) carotid artery stenoses. Methods One hundred and twenty-one patients with asymptomatic, unilateral, mild/moderate (40-60%) carotid artery stenoses at Doppler ultrasound (DUS), were prospectively evaluated with computed tomography angiography (CTA), magnetic resonance angiography (MRA) and brain magnetic resonance imaging (MRI). IPH and LRNC were defined at MRA, while ulceration was defined at CTA. Verbal and memory skills were tested by the Fifteen Reye’s Words and other standardized tests. Results At least one sign of vulnerability (IPH, LRNC or ulceration) was detected in 51.6% patients. Signs of vulnerability were more frequent in patients with ≥50% stenoses compared with those with &amp;lt;50% at DUS (62.5% vs 27.6%, p=0.002). No difference in the prevalence of cardiovascular risk factors was present in those with and without signs of vulnerability (Table). An ulceration at CTA was significantly associated with presence of IPH or LRNC even after adjustment for the degree of stenosis (OR 4.2, 95% CI 1.3-13.2; OR 4.0, 95% CI 1.4-11.2). Subclinical embolic brain infarctions were found in 10% of patients. A higher prevalence of LRNC was found in patients with brain infarctions (50% vs 17%, p&amp;lt;0.05). Patients with either IPH or LRNC performed worse at standardized tests of cognitive impairment (score 1.6±1.1 vs 2.2±1.4, p&amp;lt;0.05). Conclusions Imaging signs of vulnerability are highly prevalent in patients with asymptomatic intermediate carotid artery stenosis, and can be detected in more than one fourth of patients with a non-significant plaque in terms of degree of stenosis. Plaque ulceration at CTA is independently associated with LRNC and IPH at MRA, independent of the degree of stenosis. Plaques with LRNC are associated with subclinical embolic brain infarcts and a worse cognitive performance.TableFigure

Abstract 19141: Carotid Artery Plaque Rim Sign on Computed Tomography Angiography is Associated With Intraplaque Hemorrhage and Inflammatory Microenvironment

Introduction: The carotid artery rim sign on CTA is characterized by soft-plaque components surrounded by a rind of thin, adventitial calcification and its role in plaque instability is not established yet. Intraplaque hemorrhage (IPH) and the inflammatory microenvironment in carotid atheroma are considered features of atherosclerotic plaque vulnerability leading to cerebrovascular events. Hypothesis: The association between rim sign on CTA and carotid IPH and inflammation remains scantly investigated. In this study, we aimed to determine whether rim sign is associated with IPH on MRA and with the extent of IPH and inflammation on histology. We hypothesized that rim sign may be a radiological predictor of carotid IPH and inflammation. Methods: We retrospectively enrolled 100 consecutive patients who underwent carotid endarterectomy (CEA) and neck CTA before CEA. On CTA, the ipsilateral rim sign was defined as the presence of adventitial calcifications with internal soft-tissue plaque of ≥2 mm in maximum thickness. Of the included patients, 25 had MRA with 3D magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequence. Carotid plaque specimens were collected and stained with H&amp;E to quantify IPH (%). Histologically, we defined IPH as an area of carotid plaque with blood elements, and inflammatory microenvironment as the presence of lymphocytes and plasma cells (chronic inflammation) and foam cells. Results: The rim sign on CTA was present in 56 (56%) of patients. IPH on MRA was present in 11 (44%) patients. The rim sign was significantly associated with the presence of IPH on MRA [9 (81.8%) vs 2 (14.3%); p=0.003]. On histology, the rim sign was associated with a higher extent of IPH [5.0 % (IQR 2.0-25.0) vs 5.0% (IQR 0.0-10.0); p=0.017], with chronic inflammation [44 (78.6%) vs 12 (21.4%); p=0.003], and foam cells [51 (91.1%) vs 5 (8.9%); p&lt;0.001]. Conclusions: These findings suggest that rim sign on CTA may be proposed as a potential imaging marker of IPH as well as a histologic predictor of IPH extent and carotid plaque inflammatory microenvironment.

The accumulation of erythrocytes quantified and visualized by Glycophorin C in carotid atherosclerotic plaque reflects intraplaque hemorrhage and pre-procedural neurological symptoms

The accumulation of erythrocyte membranes within an atherosclerotic plaque may contribute to the deposition of free cholesterol and thereby the enlargement of the necrotic core. Erythrocyte membranes can be visualized and quantified in the plaque by immunostaining for the erythrocyte marker glycophorin C. Hence, we theorized that the accumulation of erythrocytes quantified by glycophorin C could function as a marker for plaque vulnerability, possibly reflecting intraplaque hemorrhage (IPH), and offering predictive value for pre-procedural neurological symptoms. We employed the CellProfiler-integrated slideToolKit workflow to visualize and quantify glycophorin C, defined as the total plaque area that is positive for glycophorin C, in single slides of culprit lesions obtained from the Athero-Express Biobank of 1819 consecutive asymptomatic and symptomatic patients who underwent carotid endarterectomy. Our assessment included the evaluation of various parameters such as lipid core, calcifications, collagen content, SMC content, and macrophage burden. These parameters were evaluated using a semi-quantitative scoring method, and the resulting data was dichotomized as predefined criteria into categories of no/minor or moderate/heavy staining. In addition, the presence or absence of IPH was also scored. The prevalence of IPH and pre-procedural neurological symptoms were 62.4% and 87.1%, respectively. The amount of glycophorin staining was significantly higher in samples from men compared to samples of women (median 7.15 (IQR:3.37, 13.41) versus median 4.06 (IQR:1.98, 8.32), p < 0.001). Glycophorin C was associated with IPH adjusted for clinical confounders (OR 1.90; 95% CI 1.63, 2.21; p = < 0.001). Glycophorin C was significantly associated with ipsilateral pre-procedural neurological symptoms (OR:1.27, 95%CI:1.06–1.41, p = 0.005). Sex-stratified analysis, showed that this was also the case for men (OR 1.37; 95%CI 1.12, 1.69; p = 0.003), but not for women (OR 1.15; 95%CI 0.77, 1.73; p = 0.27). Glycophorin C was associated with classical features of a vulnerable plaque, such as a larger lipid core, a higher macrophage burden, less calcifications, a lower collagen and SMC content. There were marked sex differences, in men, glycophorin C was associated with calcifications and collagen while these associations were not found in women. To conclude, the accumulation of erythrocytes in atherosclerotic plaque quantified and visualized by glycophorin C was independently associated with the presence of IPH, preprocedural symptoms in men, and with a more vulnerable plaque composition in both men and women. These results strengthen the notion that the accumulation of erythrocytes quantified by glycophorin C can be used as a marker for plaque vulnerability.

Systematic Review on Magnetic Resonance Angiography with Vessel Wall Imaging for the Characterization of Symptomatic Carotid Artery Plaque

To perform a systematic literature review to assess the usefulness of performing magnetic resonance angiography (MRA) with vessel wall imaging (VWI) sequences for the assessment of symptomatic carotid artery plaques and the identification of risky plaque features predisposing for stroke. We performed a systematic review of the literature pertaining to MRA with VWI techniques in patients with carotid artery disease, focusing on symptomatic patients' plaque features and morphology. Independent reviewers screened and analyzed data extracted from eligible studies, and a modified Newcastle-Ottawa Scale was used to appraise the quality of the design and content of the selected manuscripts to achieve an accurate interpretation. This review included nineteen peer-reviewed manuscripts, all of them including MRA and VWI assessments of the symptomatic carotid artery plaque. We focused on patients' comorbidities and reviewed plaque features, including intraplaque hemorrhage, a lipid-rich necrotic core, a ruptured fibrous cap, and plaque ulceration. MRA with VWI is a useful tool in the evaluation of carotid artery plaques. This imaging technique allows clinicians to identify plaques at risk of causing a neurovascular event. The presence of intraplaque hemorrhage, plaque ulceration, a ruptured fibrous cap, and a lipid-rich necrotic core are associated with neurovascular symptoms. The timely identification of these features could have a positive impact on neurovascular event prevention.

Destabilization of Atherosclerotic Plaque by Bilirubin Deficiency.

The rupture of atherosclerotic plaque contributes significantly to cardiovascular disease. Plasma concentrations of bilirubin-a byproduct of heme catabolism-inversely associate with risk of cardiovascular disease, although the link between bilirubin and atherosclerosis remains unclear. To assess the role of bilirubin in atherosclerotic plaque stability, we crossed Bvra-/- with Apoe-/- mice and used the tandem stenosis model of plaque instability. Human coronary arteries were obtained from heart transplant recipients. Analysis of bile pigments, heme metabolism, and proteomics were performed by liquid chromatography tandem mass spectrometry. MPO (myeloperoxidase) activity was determined by in vivo molecular magnetic resonance imaging, liquid chromatography tandem mass spectrometry analysis, and immunohistochemical determination of chlorotyrosine. Systemic oxidative stress was evaluated by plasma concentrations of lipid hydroperoxides and the redox status of circulating Prx2 (peroxiredoxin 2), whereas arterial function was assessed by wire myography. Atherosclerosis and arterial remodeling were quantified by morphometry and plaque stability by fibrous cap thickness, lipid accumulation, infiltration of inflammatory cells, and the presence of intraplaque hemorrhage. Compared with Bvra+/+Apoe-/- tandem stenosis littermates, Bvra-/-Apoe-/- tandem stenosis mice were deficient in bilirubin, showed signs of increased systemic oxidative stress, endothelial dysfunction, as well as hyperlipidemia, and had a higher atherosclerotic plaque burden. Heme metabolism was increased in unstable compared with stable plaque of both Bvra+/+Apoe-/- and Bvra-/-Apoe-/- tandem stenosis mice and in human coronary plaques. In mice, Bvra deletion selectively destabilized unstable plaque, characterized by positive arterial remodeling and increased cap thinning, intraplaque hemorrhage, infiltration of neutrophils, and MPO activity. Proteomic analysis confirmed Bvra deletion enhanced extracellular matrix degradation, recruitment and activation of neutrophils, and associated oxidative stress in unstable plaque. Bilirubin deficiency, resulting from global Bvra deletion, generates a proatherogenic phenotype and selectively enhances neutrophil-mediated inflammation and destabilization of unstable plaque, thereby providing a link between bilirubin and cardiovascular disease risk.

Higher Leukocyte Count Is Associated with Lower Presence of Carotid Lipid-Rich Necrotic Core: A Sub-Study in the Plaque at RISK (PARISK) Study.

Increasing evidence suggests that inflammation inside the vessel wall has a prominent role in atherosclerosis. In carotid atherosclerosis in particular, vulnerable plaque characteristics are strongly linked to an increased stroke risk. An association between leukocytes and plaque characteristics has not been investigated before and could help with gaining knowledge on the role of inflammation in plaque vulnerability, which could contribute to a new target for intervention. In this study, we investigated the association of the leukocyte count with carotid vulnerable plaque characteristics. All patients from the Plaque At RISK (PARISK) study whom had complete data on their leukocyte count and CTA- and MRI-based plaque characteristics were included. Univariable logistic regression was used to detect associations of the leukocyte count with the separate plaque characteristics (intra-plaque haemorrhage (IPH), lipid-rich-necrotic core (LRNC), thin or ruptured fibrous cap (TRFC), plaque ulceration and plaque calcifications). Subsequently, other known risk factors for stroke were included as covariates in a multivariable logistic regression model. 161 patients were eligible for inclusion in this study. Forty-six (28.6%) of these patients were female with a mean age of 70 [IQR 64-74]. An association was found between a higher leukocyte count and lower prevalence of LRNC (OR 0.818 (95% CI 0.687-0.975)) while adjusting for covariates. No associations were found between the leucocyte count and the presence of IPH, TRFC, plaque ulceration or calcifications. The leukocyte count is inversely associated with the presence of LRNC in the atherosclerotic carotid plaque in patients with a recently symptomatic carotid stenosis. The exact role of leukocytes and inflammation in plaque vulnerability deserves further attention.

Slice-based and time-specific hemodynamic measurements discriminate carotid artery vulnerable atherosclerotic plaques

Background and objectiveHemodynamic patterns play key roles in progression of carotid vulnerable plaques. However, most of previous studies utilized maximum or averaged value of hemodynamic measurements which is not an ideal representative of hemodynamic patterns. This study aimed to investigate the association of slice-based and time-specific hemodynamic measurements with carotid vulnerable plaque using magnetic resonance (MR) vessel wall imaging and histology. MethodsThirty-two patients (mean age: 63.9±8.1 years; 25 males) with carotid atherosclerotic stenosis (≥50% stenosis) referred to carotid endarterectomy were recruited and underwent MR vessel wall imaging. Carotid plaque burden was evaluated on MR images and vulnerable plaque features including calcification, lipid-rich necrotic core, and intra-plaque hemorrhage (IPH) were identified by histology. The slice-based and time-specific hemodynamic measurements were extracted from computational fluid dynamics simulation of 3D carotid arterial model. Correlation coefficients between hemodynamic measurements and carotid plaque features were calculated and the logistic regressions with generalized estimating equation (GEE) were conducted. The value in discriminating carotid vulnerable plaque features was determined by receiver-operating-characteristic analysis. ResultsOf 102 MR-histology matched slices from 32 patients, time-averaged wall shear stress (TAWSS) (r=0.263, p=0.008), oscillatory shear index (OSI) (r=-0.374, p<0.001), and peakWSS (r=0.232, p=0.019) were significantly associated with carotid IPH. The logistic regression with GEE revealed that peakWSS (OR, 1.206; 95% CI, 1.026-1.418; p, 0.023) and TAWSS (OR, 0.364, 95% CI, 0.138-0.959; p, 0.041) were significantly associated with presence of IPH after adjusting for age and BMI. In discriminating carotid IPH, the AUC of TAWSS, OSI, combined TAWSS with maximum wall thickness (MWT) and combined OSI with MWT was 0.656, 0.722, 0.761, and 0.764, respectively. ConclusionsSlice-based and time-specific hemodynamic characteristics could effectively discriminate carotid IPH. Combination of hemodynamic measurements with carotid plaque burden might be a stronger indicator for carotid vulnerable plaque features than each measurement alone.

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

BackgroundPatients 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. ObjectivesThe PARISK (Plaque At RISK) study aimed to improve the identification of patients at increased risk of recurrent ischemic stroke using multimodality carotid imaging. MethodsThe 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. ResultsDuring 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). ConclusionsIPH 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)

Carotid Plaque Composition and Prediction of Incident Atherosclerotic Cardiovascular Disease.

Whether information on carotid plaque composition contributes to prediction of incident atherosclerotic cardiovascular disease (ASCVD) remains to be investigated. We determined the sex-specific added value of carotid plaque components for predicting incident ASCVD events, beyond traditional cardiovascular risk factors. Between 2007 and 2012, participants from the population-based Rotterdam Study with asymptomatic carotid wall thickening >2.5 mm on ultrasonography were invited for carotid magnetic resonance imaging. Among 1349 participants (mean age: 72 years [SD±9.3], 49.5% women) without cardiovascular disease, we assessed plaque thickness, luminal stenosis (>30%), presence of intraplaque hemorrhage, lipid-rich necrotic core, and calcification. Follow-up for ASCVD was complete until January 1, 2015. Using Cox proportional hazards models, we fitted sex-specific prediction models including traditional cardiovascular risk factors (base model). We extended the base model by single and simultaneous additions of plaque characteristics and calculated improvement of model performance by the C statistics. During a median follow-up of 4.8 years, 60 men and 48 women developed ASCVD. In women, presence of intraplaque hemorrhage was associated with incident ASCVD (adjusted hazard ratio, 3.37 [95% CI, 1.81-6.25]). The C statistic (95% CI) improved from 0.73 (0.66-0.79) to 0.76 (0.70-0.83) after single addition of intraplaque hemorrhage to the base model. Simultaneous addition of plaque components, plaque thickness, and stenosis did not change the results. In men, only carotid stenosis was statistically significantly associated with incident ASCVD (adjusted hazard ratio, 1.75 [95% CI, 1.00-3.08]); yet, the association diminished after the addition of other plaque characteristics, and no improvements were observed in C statistics. Presence of intraplaque hemorrhage contributes to the prediction of incident ASCVD in women, beyond traditional cardiovascular risk factors, other plaque components, plaque size, and stenosis.

Reassessing the Carotid Artery Plaque "Rim Sign" on CTA: A New Analysis with Histopathologic Confirmation.

The CTA "rim sign" has been proposed as an imaging marker of intraplaque hemorrhage in carotid plaques. This study sought to investigate such findings using histopathologic confirmation. Included patients had CTA neck imaging <1 year before carotid endarterectomy. On imaging, luminal stenosis and the presence of adventitial (<2-mm peripheral) and "bulky" (≥2-mm) calcifications, total plaque thickness, soft-tissue plaque thickness, calcification thickness, and the presence of ulcerations were assessed. The rim sign was defined as the presence of adventitial calcifications with internal soft-tissue plaque of ≥2 mm in maximum thickness. Carotid endarterectomy specimens were assessed for both the presence and the proportional makeup of lipid material, intraplaque hemorrhage, and calcification. Sixty-seven patients were included. Twenty-three (34.3%) were women; the average age was 70.4 years. Thirty-eight (57.7%) plaques had a rim sign on imaging, with strong interobserver agreement (κ = 0.85). A lipid core was present in 64 (95.5%) plaques (average, 22.2% proportion of plaque composition); intraplaque hemorrhage was present in 52 (77.6%), making up, on average, 13.7% of the plaque composition. The rim sign was not associated with the presence of intraplaque hemorrhage (P = .11); however, it was associated with a greater proportion of intraplaque hemorrhage in a plaque (P = .049). The sensitivity and specificity of the rim sign for intraplaque hemorrhage were 61.5% and 60.0%, respectively. The rim sign is not associated with the presence of intraplaque hemorrhage on histology. However, it is associated with a higher proportion of hemorrhage within a plaque and therefore may be a biomarker of more severe intraplaque hemorrhage, if present.

Comparison of symptomatic vertebrobasilar plaques between patients with and without Diabetes Mellitus using computed tomographic angiography and vessel wall magnetic resonance imaging.

ObjectivesDiabetes mellitus is significantly associated with posterior circulation ischemic stroke. We aimed to compare the characteristics of vertebrobasilar plaques in symptomatic patients with and without diabetes using high-resolution vessel wall magnetic resonance imaging and computed tomographic angiography.MethodsFrom April 2017 to May 2021, cases from patients with transient ischemic attack or stroke in the posterior circulation territory who underwent high-resolution vessel wall magnetic resonance imaging and computed tomographic angiography were reviewed. Characteristics of culprit vertebrobasilar plaques were compared between patients with and without diabetes. Multivariate regression analysis was performed to assess the correlation between culprit plaque characteristics and diabetes.ResultsA total of 148 patients were included and 75 patients were diagnosed with diabetes mellitus. Patients with diabetes had more intraplaque hemorrhage, calcification, spotty calcification presence, and higher calcification volume (all p < 0.05) compared with those without diabetes. Multivariate analysis demonstrated differences in the presence of intraplaque hemorrhage (p = 0.045) and number of spotty calcifications (p = 0.047) were statistically significant after adjusting for baseline characteristics.ConclusionsSymptomatic patients with diabetes have a higher incidence of intraplaque hemorrhage and larger calcification burden than those without diabetes, indicating the association of diabetes with more advanced plaque features in the posterior circulation.

Association Between Carotid Artery Perivascular Fat Density and Intraplaque Hemorrhage.

Objectives: Perivascular adipose tissue plays a key role in atherosclerosis, but its effects on the composition of carotid atherosclerotic plaques are unknown. This study aimed to investigate the association between inflammatory carotid artery and intraplaque hemorrhage (IPH) in the carotid artery.Methods: This is a single-center retrospective study. Carotid inflammation was assessed by perivascular fat density (PFD) in 72 participants (mean age, 65.1 years; 56 men) who underwent both computed tomography angiography (CTA) and magnetic resonance imaging (MRI) within 2 weeks. The presence of IPH was assessed with MRI. Carotid stenosis, maximum plaque thickness, calcification, and ulceration were evaluated through CTA. The association between PFD and the occurrence of IPH was studied using generalized estimating equations analysis.Results: Of 156 plaques, 72 plaques (46.2%) had IPH. Plaques with IPH showed higher PFD than those without [−41.4 ± 3.9 vs. −55.8 ± 6.5 Hounsfield unit (HU); p < 0.001]. After age, calcification, degree of stenosis, maximum plaque thickness, and ulceration were adjusted for, PFD (OR, 1.96; 95% CI, 1.41–2.73; p < 0.001) was found to be strongly associated with the presence of IPH.Conclusions: A higher PFD is associated with the presence of IPH in the carotid artery. These findings may provide a novel marker to identify carotid IPH and risk stratification.

Evaluation of Plaque Vulnerability via Combination of Hemodynamic Analysis and Simultaneous Non-Contrast Angiography and Intraplaque Hemorrhage (SNAP) Sequence for Carotid Intraplaque Hemorrhage.

The purpose of this study was to assess the vulnerability of plaque using a combination of simultaneous non-contrast angiography, intraplaque hemorrhage (SNAP) sequence, and local hemodynamic analysis in an intraplaque hemorrhage (IPH), and to evaluate the association between morphological and hemodynamic factors and IPH by comparing the IPH (presence of IPH) and non-IPH (plaque with absence of IPH) groups. In total, 27 IPH patients and 27 non-IPH patients were involved in this study, and baseline characteristics were collected. For morphological factors, diameters, and areas of the internal carotid artery (ICA), external carotid artery, and common carotid artery were measured, and bifurcation angle (α) and ICA angle (β) were also measured for comparison between the IPH group and non-IPH group. For hemodynamic factors, time-averaged wall shear stress (WSS), minimum WSS, maximum WSS, and oscillatory shear index were calculated using computational fluid dynamics (CFD) simulations. For the qualitative analysis, cross-sectional images with analyzed WSS and SNAP sequences were combined to precisely assess local hemodynamics. Bifurcation angle (α) was significantly different between the IPH and non-IPH groups (39.47 degrees vs. 47.60 degrees, p = 0.041). Significantly higher time-averaged WSS, minimum WSS, and maximum WSS were observed in the IPH group compared to the non-IPH group. In the IPH group, when using the combined analysis with SNAP sequences and WSS, the WSS of the region with IPH was significantly higher than the region without IPH (2.32 vs. 1.21 Pa, p = 0.005). A smaller bifurcation angle (α) and higher time-averaged WSS, minimum WSS, and maximum WSS were associated with IPH. The combined analysis of SNAP sequences and WSS might help to evaluate the risk of carotid IPH.

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

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

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.

Identification, risk stratification and prognostication of stroke by detection of intra-carotid plaque hemorrhage

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Atherosclerotic stenosis of the internal carotid artery is present in 1% to 2% of the adult population and is the cause of 10% to 15% of ischemic strokes. Intra-plaque hemorrhage (IPH) in carotid stenosis increases the risk of cerebrovascular events. Magnetic resonance imaging can be used to detect pathologies like IPH and necrosis in carotid stenosis. Purpose : This study sought to compare the risk of stroke between patients with carotid artery disease with and without the presence of intraplaque hemorrhage (IPH) on magnetic resonance imaging. Methods : In this meta-analysis we gathered the data from 10 original cohort studies including 631 patients with symptomatic carotid stenosis and 157 patients with asymptomatic carotid stenosis. Primary outcome was the hazards of ipsilateral ischemic stroke which were compared between patients with and without IPH. Results : IPH was present in 57.1% of patients with symptomatic carotid stenosis and 24.7% of patients with asymptomatic carotid stenosis. During 1,334 observed person-years, 74 ipsilateral strokes occurred. Presence of IPH at baseline increased the risk of ipsilateral stroke both in symptomatic (hazard ratio [HR]: 11.7; 95% confidence interval [CI]: 4.7 to 22.8) and asymptomatic (HR: 6.8; 95% CI: 0.9 to 45.4) patients. Multivariate analysis identified IPH (HR: 11.7; 95% CI: 5.3 to 26.4) and severe degree of stenosis (HR: 3.8; 95% CI: 02 to 8.2) as independent predictors of ipsilateral stroke. Conclusion : Our study concludes that IPH is common in patients with carotid artery stenosis and is a stronger predictor of stroke. Magnetic resonance imaging is the modality that can help in identification of patients with carotid disease who would benefit from revascularization.

Carotid Intraplaque Hemorrhage and Stenosis: At What Stage of Plaque Progression Does Intraplaque Hemorrhage Occur, and When is It Most Likely to Be Associated with Symptoms?

The relationship between carotid intraplaque hemorrhage and luminal stenosis severity is not well-established. We sought to determine whether intraplaque hemorrhage is related to carotid stenosis and at what degree of stenosis intraplaque hemorrhage most likely contributes to ischemic symptoms. Consecutive patients who underwent MR carotid plaque imaging with MPRAGE sequences to identify intraplaque hemorrhage were retrospectively reviewed. Degrees of stenoses were categorized as minimal (<30%), moderate (30%-69%), and severe (>70%). Arteries were categorized into 2 groups: symptomatic (ipsilateral to a cerebral ischemic event) and asymptomatic (from a patient without an ischemic event). Multiple regression analyses were used to determine independent associations between the degree of stenosis and intraplaque hemorrhage and the presence of intraplaque hemorrhage with symptoms among categories of stenosis. We included 449 patients with 449 carotid arteries: Two hundred twenty-five (50.1%) were symptomatic, and 224 (49.9%) were asymptomatic. An increasing degree of stenosis was independently associated with the presence of intraplaque hemorrhage (OR = 1.02; 95% confidence interval, 1.01-1.03). Intraplaque hemorrhage was independently associated with ischemic events in arteries with <30% stenosis (OR = 5.68; 95% CI, 1.49-21.69). No such association was observed in arteries with >30% stenosis. Of symptomatic arteries with minimal stenosis, 8.7% had intraplaque hemorrhage versus 1.7% of asymptomatic arteries (P = .02). No differences in intraplaque hemorrhage prevalence were found between symptomatic and asymptomatic groups with moderate (P = .18) and severe stenoses (P = .99). The presence of intraplaque hemorrhage on high-resolution plaque imaging is likely most useful in identifying symptomatic plaques in cases of minimal stenosis.