Intraplaque Hemorrhage Volume Research Articles

Intraplaque hemorrhage volume in patients with carotid atherosclerosis: How informative is it?

Background and purposeIntraplaque hemorrhage (IPH) of carotid atherosclerosis is an important feature in complex lesions preceding acute stroke events. The current study aimed to determine the role played by IPH volume compared to that of carotid stenosis or maximal wall thickness in patients with carotid IPH. Materials and methodsThis retrospective study included 233 patients who presented with carotid IPH on vessel wall imaging (VWI). We divided the patients into symptomatic or asymptomatic groups based on territorial acute focal infarction. The IPH volume, degree of stenosis, and maximal wall thickness on VWI were analyzed. ResultsOf the 233 included patients with carotid IPH, 51 (21.9%) patients showed initial clinical symptoms and positive territorial findings on diffusion-weighted imaging (DWI). Moreover, 154 (66.1%) patients had low-grade stenosis below 50% (n = 19: symptomatic groups). Overall, carotid IPH volume, degree of stenosis, and maximal wall thickness were all significantly higher in the symptomatic groups (p = 0.001). The degree of stenosis, in all patients and especially in those with high-grade stenosis above 50%, was significantly correlated with territorial acute focal infarction on multivariate analysis (p < 0.01). In patients with low-grade stenosis below 50%, maximal wall thickness was associated with territorial acute focal infarction (p = 0.48). ConclusionCarotid IPH volume was a risk factor for territorial acute focal infarction. However, in patients with high-grade stenosis, the degree of stenosis was significantly linked to acute stroke. By contrast, in patients with low-grade stenosis, maximal wall thickness exhibited a significant association with acute stroke.

Machine Learning Detects Symptomatic Plaques in Patients With Carotid Atherosclerosis on CT Angiography.

This study aimed to develop and validate a computed tomography angiography based machine learning model that uses plaque composition data and degree of carotid stenosis to detect symptomatic carotid plaques in patients with carotid atherosclerosis. The machine learning based model was trained using degree of stenosis and the volumes of 13 computed tomography angiography derived intracarotid plaque subcomponents (eg, lipid, intraplaque hemorrhage, calcium) to identify plaques associated with cerebrovascular events. The model was internally validated through repeated 10-fold cross-validation and tested on a dedicated testing cohort according to discrimination and calibration. This retrospective, single-center study evaluated computed tomography angiography scans of 268 patients with both symptomatic and asymptomatic carotid atherosclerosis (163 for the derivation set and 106 for the testing set) performed between March 2013 and October 2019. The area-under-receiver-operating characteristics curve by machine learning on the testing cohort (0.89) was significantly higher than the areas under the curve of traditional logit analysis based on the degree of stenosis (0.51, P<0.001), presence of intraplaque hemorrhage (0.69, P<0.001), and plaque composition (0.78, P<0.001), respectively. Comparable performance was obtained on internal validation. The identified plaque components and associated cutoff values that were significantly associated with a higher likelihood of symptomatic status after adjustment were the ratio of intraplaque hemorrhage to lipid volume (≥50%, 38.5 [10.1-205.1]; odds ratio, 95% CI) and percentage of intraplaque hemorrhage volume (≥10%, 18.5 [5.7-69.4]; odds ratio, 95% CI). This study presented an interpretable machine learning model that accurately identifies symptomatic carotid plaques using computed tomography angiography derived plaque composition features, aiding clinical decision-making.

The value of coordinated analysis of multimodal atherosclerotic plaque imaging in the assessment of cardiovascular and cerebrovascular events

BackgroundAlthough atherosclerosis (AS) can affect multiple vascular beds, previous studies have focused on the analysis of single-site AS plaques.ObjectiveThe aim of this study is to explore the differences or similarities in the characteristics of atherosclerotic plaque found in the internal carotid artery, cerebral artery, and coronary artery between patients with atherosclerotic cardiovascular disease (ASCVD) and those without events.MethodsPatients aged ≥ 18 years who underwent both high-resolution vessel wall imaging (HR-VWI) and coronary computed tomography angiography (CCTA) were retrospectively collected and categorized into the ASCVD group and the non-event group. The plaques were then categorized into culprit plaques, non-culprit plaques, and non-event plaques. Plaque morphological data such as stenosis, stenosis grades, plaque length (PL), plaque volume (PV), minimal lumen area (MLA), enhancement grade, and plaque composition data such as calcified plaque volume (CPV), fibrotic plaque volume (FPV), fibro-lipid plaque volume (FLPV), lipid plaque volume (LPV), calcified plaque volume ratio (CPR), fibrotic plaque volume ratio (FPR), fibro-lipid plaque ratio (FLPR), lipid plaque volume ratio (LPR), intraplaque hemorrhage volume (IPHV), and intraplaque hemorrhage volume ratio (IPHR)were recorded and analyzed.ResultsA total of 44 patients (mean age 66 years, SD 9 years, 28 men) were included. In cervicocephalic plaques, the ASCVD group had more severe stenosis grades (p = 0.030) and demonstrated significant differences in LPV, LPR, and CPV (p = 0.044, 0.030, 0.020) compared with the non-event group. In coronary plaques, the ASCVD group had plaques with greater stenosis (p &amp;lt; 0.001), more severe stenosis grades (p &amp;lt; 0.001), larger volumes (p = 0.001), longer length (p = 0.008), larger FLPV (p = 0.012), larger FPV (p = 0.002), and higher FPR (p = 0.043) compared with the non-event group. There were significant differences observed in stenosis (HR-VWI, CCTA: p &amp;lt; 0.001, p &amp;lt; 0.001), stenosis grades (HR-VWI, CCTA: p &amp;lt; 0.001, p &amp;lt; 0.001), plaque length (HR-VWI, CCTA: p = 0.028, p &amp;lt; 0.001), and plaque volume (HR-VWI, CCTA: p = 0.013, p = 0.018) between the non-event plaque, non-culprit plaque, and culprit plaque. In the image analysis of HR-VWI, there were differences observed between IPHR (p &amp;lt; 0.001), LPR (p = 0.001), FPV (p = 0.011), and CPV (p = 0.015) among the three groups of plaques. FLPV and FPV were significantly different among the three different plaque types from the coronary artery (p = 0.043, p = 0.022).ConclusionThere is a consistent pattern of change in plaque characteristics between the cervicocephalic and coronary arteries in the same patient.

Signal intensity and volume of carotid intraplaque hemorrhage on magnetic resonance imaging and the risk of ipsilateral cerebrovascular events: The Plaque At RISK (PARISK) study

BackgroundThe Plaque at RISK (PARISK) study demonstrated that patients with a carotid plaque with intraplaque hemorrhage (IPH) have an increased risk of recurrent ipsilateral ischemic cerebrovascular events. It was previously reported that symptomatic carotid plaques with IPH showed higher IPH signal intensity ratios (SIR) and larger IPH volumes than asymptomatic plaques. We explored whether IPH SIR and IPH volume are associated with future ipsilateral ischemic cerebrovascular events beyond the presence of IPH. MethodsTIA and ischemic stroke patients with mild-to-moderate carotid stenosis and an ipsilateral IPH-positive carotid plaque (n=89) from the PARISK study were included. The clinical endpoint was a new ipsilateral ischemic cerebrovascular event during 5 years of follow-up, while the imaging-based endpoint was a new ipsilateral brain infarct on brain MRI after 2 years (n=69). Trained observers delineated IPH, a hyperintense region compared to surrounding muscle tissue on hyper T1-weighted MR images. The IPH SIR was the maximal signal intensity in the IPH region divided by the mean signal intensity of adjacent muscle tissue. The associations between IPH SIR or volume and the clinical and imaging-based endpoint were investigated using Cox-proportional hazard models and logistic regression, respectively. ResultsDuring 5.1 (interquartile range (IQR): 3.1-5.6) years of follow-up, 21 ipsilateral cerebrovascular ischemic events were identified. Twelve new ipsilateral brain infarcts were identified on the 2-year neuro MRI. There was no association for IPH SIR or IPH volume with the clinical endpoint (HR: 0.89 [95% CI: 0.67-1.10] and HR: 0.91 [0.69-1.19] per 100µl increase, respectively) nor with the imaging-based endpoint (OR: 1.04 [0.75-1.45] and OR: 1.21 [0.87-1.68] per 100µl increase, respectively). ConclusionsIPH SIR and IPH volume were not associated with future ipsilateral ischemic cerebrovascular events. Therefore, quantitative assessment of IPH does not seem to provide additional value beyond the presence of IPH for stroke risk assessment.Trial registrationThe PARISK study was registered on ClinicalTrials.gov with ID NCT01208025 on 21 September 2010 (https://clinicaltrials.gov/study/NCT01208025).

Association between Antiplatelet Therapy and Changes in Intraplaque Hemorrhage in Patients with Mild to Moderate Symptomatic Carotid Stenosis: A Longitudinal MRI Study

Plain Language SummaryCarotid artery narrowing due to an atherosclerotic plaque is responsible for around 20% of stroke. Intraplaque hemorrhage (IPH) predicts stroke. Antiplatelet agents are often given to patients who have had a stroke to prevent further cardiovascular events. A previous study found an association between previous antiplatelet use and IPH at a specific point in time. In this study, researchers investigated whether starting antiplatelet therapy after a stroke or continuing to use antiplatelets had any effect on IPH over a 2-year period.The study included patients with <70% carotid narrowing who had a carotid plaque MRI at the baseline and after 2 years to determine the presence and volume of IPH. Patients were categorized into new users (starting antiplatelet therapy following the stroke) and continued users (already using antiplatelet therapy before the stroke). The presence and the volume change of IPH over 2 years were investigated in each group. The study found that IPH was more present at the baseline when patients used antiplatelet agents before the stroke. However, new antiplatelet use after the stroke did not lead to new IPH or an increase in IPH volume over the subsequent 2 years. There were no significant associations between the new antiplatelet use and newly developed IPH or IPH volume progression. Therefore, while the baseline association between IPH and previous antiplatelet therapy was confirmed in this larger cohort, starting antiplatelet therapy after a stroke did not increase the risk of new IPH or progression of IPH volume over the subsequent 2 years.

The Relation of the Iron Metabolism Index to the Vulnerability Index of Carotid Plaque with Different Degrees of Stenosis.

To investigate the differences in serum iron index and iron metabolizing protein expression in plaques in patients with different degrees of carotid artery stenosis and the relationship with plaque traits. A total of 100 patients eligible for carotid endarterectomy (CEA) from August 2021 to February 2022 were included. Patients completed a computed tomography (CTA) scan for patient grouping and a magnetic resonance imaging (MRI) for precise quantification of carotid plaque traits within 1 week prior to surgery. Clinical indicators associated with the progression of carotid stenosis to occlusion were analyzed using ordered logistic regression. Twenty carotid plaques were analyzed immunohistochemically to investigate the relationship between plaque traits and the iron metabolism indexes. No significant correlation between high serum ferritin (SF), unsaturated iron binding capacity (UIBC) and progression of carotid stenosis (OR 1.100, 95% CI 0.004-0.165, p = 0.039; OR 1.050, 95% CI 0.005-0.094, p = 0.031). SF and serum transferrin receptor (sTfR) were correlated with normalized wall index (NWI) (R = 0.470, p = 0.036; R = 0.449, p = 0.046), and the results of multiple linear regression suggested that SF and sTfR remained associated with NWI (R = 0.630, R2 = 0.397, Adjusted R2 = 0.326, p = 0.014). In plaques, H-type ferritin (H-FT) was correlated with NWI and lipid-rich necrotic core (LRNC) volume (R = 0.502, p = 0.028; R = 0.468, p = 0.043). Transferrin receptor 1 (TfR1) was correlated with LRNC volume and intraplaque hemorrhage (IPH) volume (R = 0.538, p = 0.017; R = 0.707, p = 0.001). There were statistical differences in the expression of iron metabolism proteins in carotid plaques with different degrees of stenosis. Serum iron metabolism index (SF and sTfR) and expression of iron metabolizing proteins (H-FT and TfR1) in plaques were positively correlated with carotid plaque vulnerability index (NWI, LRNC volume).

Carotid Artery Tortuosity and Internal Carotid Artery Plaque Composition.

Little is known about the association between carotid artery tortuosity and internal carotid artery atherosclerosis. This study sought to evaluate the associations between various types of arterial tortuosity and vulnerable plaque components on magnetic resonance angiography (MRA). Aretrospective review was completed of 102patients who had undergone MRA neck imaging, with intraplaque hemorrhage (IPH) present in one or both cervical internal carotid arteries (ICA). Each ICA was assessed for two categories of tortuosity: variant arterial pathway(s) (retrojugular and/or retropharyngeal) and abnormal curvature (kinks, loops, and/or coils). All ICA plaques were assessed for the presence or absence of intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), ulceration, and enhancement, as well as the volume of IPH and degree of luminal stenosis. The mean age of included patients was 73.5years (SD = 9.0 years) and 88 (86.3%) subjects were male. The left carotid plaque was significantly more likely to have IPH (68.6% vs. 47.1%; p = 0.02). The left ICA was more likely to have aretrojugular course (22% vs. 9.9%; p = 0.002) and any variant arterial course (26.5% versus 14.67%, p = 0.01). On the right there was an association between the presence of aLRNC and retropharyngeal and/or retrojugular arterial pathway (p = 0.03). On the left there was an association between the presence of any abnormal arterial curvature and IPH volume (p = 0.03). Neither association met the adjusted statistical threshold after Bonferroni correction, with alpha set at 0.0028. ICA tortuosity is not associated with carotid artery plaque composition, and likely does not play arole in the development of high-risk plaques.

Prediction of new cerebral ischemic lesion after carotid artery stenting: a high-resolution vessel wall MRI-based radiomics analysis.

Carotid artery stenting (CAS) is an established treatment for local stenosis. The most common complication is new ipsilateral ischemic lesions (NIILs). This study aimed to develop models considering lesion morphological and compositional features, and radiomics to predict NIILs. One hundred and forty-six patients who underwent brain MRI and high-resolution vessel wall MR imaging (hrVWI) before and after CAS were retrospectively recruited. Lumen and outer wall boundaries were segmented on hrVWI as well as atherosclerotic components. A traditional model was constructed with patient clinical information, and lesion morphological and compositional features. Least absolute shrinkage and selection operator algorithm was performed to determine key radiomics features for reconstructing a radiomics model. The model in predicting NIILs was trained and its performance was tested. Sixty-one patients were NIIL-positive and eighty-five negative. Volume percentage of intraplaque hemorrhage (IPH) and patients' clinical presentation (symptomatic/asymptomatic) were risk factors of NIILs. The traditional model considering these two features achieved an area under the curve (AUC) of 0.778 and 0.777 in the training and test cohorts, respectively. Twenty-two key radiomics features were identified and the model based on these features achieved an AUC of 0.885 and 0.801 in the two cohorts. The AUCs of the combined model considering IPH volume percentage, clinical presentation, and radiomics features were 0.893 and 0.842 in the training and test cohort respectively. Compared with traditional features (clinical and compositional features), the combination of traditional and radiomics features improved the power in predicting NIILs after CAS. • Volume percentage of IPH and symptomatic events were independent risk factors of new ipsilateral ischemic lesions (NIILs). • Radiomics features derived from carotid artery high-resolution vessel wall imaging had great potential in predicting NIILs after CAS. • The combination model with radiomics and traditional features further improved the diagnostic performance than traditional features alone.

Predictors of Progression in Intraplaque Hemorrhage Volume in Patients With Carotid Atherosclerosis: A Serial Magnetic Resonance Imaging Study.

Background and PurposeThis study aimed to investigate the arterial disease risk factors for the progression of intraplaque hemorrhage (IPH) in patients with carotid atherosclerosis using serial high-resolution magnetic resonance (MR) imaging.MethodsConsecutive symptomatic patients who had MRI evidence of intraplaque hemorrhage present in the ipsilateral carotid artery with respect to the side of the brain affected by stroke or TIA were recruited in the study. All the patients underwent follow-up MR imaging at least 6 months after baseline. The annual change in IPH and other carotid plaque morphology was calculated, and a tertile method was used to classify the plaques as progressed or not with respect to IPH volume using the software CASCADE. Logistic regression and receiver operating characteristic (ROC) curve were conducted to evaluate the risk factors for the progression of IPH.ResultsA total of thirty-four symptomatic patients (mean age: 67.1 years, standard deviation [SD]: 9.8 years, 27 men) were eligible for the final analysis, and contralateral plaques containing IPH were seen in 11 of these patients (making 45 plaques with IPH in total). During mean 16.6-month (SD: 11.0 months) follow-up, the overall annual change in IPH volume in 45 plaques with IPH was mean −10.9 mm3 (SD: 49.1 mm3). Carotid plaques were significantly more likely to be classified in progressed IPH group if the patient was taking antiplatelet agent at baseline (OR: 9.76; 95%CI: 1.05 to 90.56; p = 0.045), had a baseline history of current or past smoking (OR: 9.28; 95%CI: 1.26 to 68.31; p = 0.029), or had a larger baseline carotid plaque-containing vessel wall volume (OR: 1.36 per 10 mm3; 95%CI: 1.02 to 1.81; p = 0.032) after adjustments for confounding factors. ROC analysis indicated that the combination of these three risk factors in the final model produced good discriminatory value for the progressed IPH group (area under the curve: 0.887).ConclusionsTaking an antiplatelet agent at baseline, a baseline history of current or past smoking and larger baseline carotid plaque-containing vessel wall volume were independently predictive of plaques being in the progressed IPH group. Our findings indicate that awareness and management of such risk factors may reduce the risk of intraplaque hemorrhage progression.

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)

Assessment of carotid atherosclerotic plaque using 3D motion-sensitized driven-equilibrium prepared rapid gradient echo: a comparative study.

3D motion-sensitized driven-equilibrium prepared rapid gradient echo (MERGE) can characterize carotid atherosclerotic plaque morphology and composition. The present study aimed to evaluate its performance by comparing it with reference images and assessing the inter-reader agreement. Eighty-four patients were prospectively recruited and scanned with 3D MERGE. Two trained magnetic resonance imaging (MRI) readers measured and calculated the maximum wall thickness (WT), maximum vessel diameter, total vessel area, lumen area, wall area, normalized wall index, plaque volume, intraplaque hemorrhage (IPH) volume, and calcification volume independently. IPH, calcification, mixed calcification, and ulceration were identified. The intraclass correlation coefficient (ICC) with 95% confidence interval (CI) was used to assess the inter-reader agreement. MERGE performance was assessed in terms of sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, kappa value (κ), and the results of the Bland-Altman analysis and compared with reference images. MERGE showed excellent inter-reader agreement (All ICCs >0.90). MERGE and simultaneous non-contrast angiography and intraplaque hemorrhage (SNAP) showed excellent agreement in detecting IPH (κ=0.938) and measuring IPH volume (ICC =0.995; 95% CI: 0.991-0.997). MERGE and computed tomography angiography (CTA) showed strong consistency in detecting calcification (κ=0.814) and mixed calcification (κ=0.972), and in measuring calcification volume (ICC =0.996; 95% CI: 0.993-0.997). MERGE and digital subtraction angiography (DSA) showed relatively strong consistency in identifying ulceration (κ=0.737). MERGE showed excellent performance in identifying and measuring IPH and calcification in carotid atherosclerotic plaques. Therefore, MERGE can be a promising imaging approach in atherosclerotic-vulnerable plaque.

Comparing Symptomatic and Asymptomatic Carotid Artery Atherosclerosis in Patients With Bilateral Carotid Vulnerable Plaques Using Magnetic Resonance Imaging.

We compared plaque characteristics between symptomatic and asymptomatic sides in patients with bilateral carotid vulnerable plaques using magnetic resonance imaging (MRI). Participants (n = 67; mean age: 65.8 ± 7.7 years, 61 males) with bilateral carotid vulnerable plaques were included. Vulnerable plaques were characterized by intraplaque hemorrhage (IPH), large lipid-rich necrotic core (LRNC), or fibrous cap rupture (FCR) on MRI. Symptomatic vulnerable plaques showed greater plaque burden, LRNC volume (median: 221.4 vs 134.8 mm3, P = .003), IPH volume (median: 32.2 vs 22.5 mm3, P = .030), maximum percentage (Max%) LRNC (median: 51.3% vs 41.8%, P = .002), Max%IPH (median: 13.4% vs 9.5%, P = .022), cumulative slices of LRNC (median: 10 vs 8, P = .005), and more juxtaluminal IPH and/or thrombus (29.9% vs 6.0%, P = .001) and FCR (37.3% vs 16.4%, P = .007) than asymptomatic ones. After adjusting for plaque burden, differences in juxtaluminal IPH and/or thrombus (odds ratio [OR]: 5.49, 95% CI: 1.61-18.75, P = .007) and FCR (OR: 2.90, 95% CI: 1.16-7.24, P = .022) between bilateral sides remained statistically significant. For patients with bilateral carotid vulnerable plaques, symptomatic plaques had greater burden, more juxtaluminal IPH and/or thrombus, and FCR compared with asymptomatic ones. The differences in juxtaluminal IPH and/or thrombus and FCR between bilateral sides were independent of plaque burden.

Oral microbiota and atherothrombotic carotid plaque vulnerability in periodontitis patients. A cross-sectional study.

An increased risk of atherothrombotic vascular events has been reported in periodontitis patients. Periodontitis is associated with dysbiotic subgingival biofilms and bacteremia. We hypothesized (a) that the oral microbiome is associated with the carotid microbiome and (b) that periodontitis could contribute to plaque vulnerability. The aim of this study was to determine the associations between periodontitis, the carotid microbiome, and the local innate immune response in carotid atherothrombotic plaques vulnerable to rupture. In this cross-sectional study, 45 patients admitted for carotid endarterectomy underwent a preoperative periodontal examination. The volume of intraplaque hemorrhage reflected by the hemoglobin level released in carotid-conditioned media was considered as a criterion of carotid plaque vulnerability. Levels of antibodies against periodontal bacteria were determined in sera. The signature of the oral microbiota was assessed by microbial whole-genome sequencing, nested PCR, and immunostaining in carotid plaque samples. Markers of neutrophil recruitment (leukotriene B4), neutrophil activation (myeloperoxidase, defensins), and cytokines were measured in carotid-conditioned media and/or plasma. All patients exhibited periodontitis. One hundred and forty-four bacterial genera were detected in the carotid microbiome. While Streptococcus was found in 84% of the carotid samples, periodontitis-associated genera were detected in 21%. P.gingivalis DNA and gingipains were also identified in carotid samples. There were significant inverse correlations between periodontal attachment loss/serum anti-P.gingivalis Immunoglobulin A and cytokine inhibiting neutrophils (all P<.01). There were also significant positive correlations between lipopolysaccharides, myeloperoxidase/human neutrophil peptides1-3, and hemoglobin levels (all P<.01). In patients at risk of stroke, the carotid plaque microbiome was highly diverse and compatible with an oral origin. Periodontitis was significantly associated with neutrophil activation markers and plaque vulnerability to rupture.

Plaque Composition as a Predictor of Plaque Ulceration in Carotid Artery Atherosclerosis: The Plaque At RISK Study.

Plaque ulceration is a marker of previous plaque rupture. We studied the association between atherosclerotic plaque composition at baseline and plaque ulceration at baseline and follow-up. We included symptomatic patients with a carotid stenosis of <70% who underwent MDCTA and MR imaging at baseline (n = 180). MDCTA was repeated at 2 years (n = 73). We assessed the presence of ulceration using MDCTA. Baseline MR imaging was used to assess the vessel wall volume and the presence and volume of plaque components (intraplaque hemorrhage, lipid-rich necrotic core, and calcifications) and the fibrous cap status. Associations at baseline were evaluated with binary logistic regression and reported with an OR and its 95% CI. Simple statistical testing was performed in the follow-up analysis. At baseline, the prevalence of plaque ulceration was 27% (49/180). Increased wall volume (OR = 12.1; 95% CI, 3.5-42.0), higher relative lipid-rich necrotic core (OR = 1.7; 95% CI, 1.3-2.2), higher relative intraplaque hemorrhage volume (OR = 1.7; 95% CI, 1.3-2.2), and a thin-or-ruptured fibrous cap (OR = 3.4; 95% CI, 1.7-6.7) were associated with the presence of ulcerations at baseline. In 8% (6/73) of the patients, a new ulcer developed. Plaques with a new ulceration at follow-up had at baseline a larger wall volume (1.04 cm3 [IQR, 0.97-1.16 cm3] versus 0.86 cm3 [IQR, 0.73-1.00 cm3]; P = .029), a larger relative lipid-rich necrotic core volume (23% [IQR, 13-31%] versus 2% [IQR, 0-14%]; P = .002), and a larger relative intraplaque hemorrhage volume (14% [IQR, 8-24%] versus 0% [IQR, 0-5%]; P < .001). Large atherosclerotic plaques and plaques with intraplaque hemorrhage and lipid-rich necrotic cores were associated with plaque ulcerations at baseline and follow-up.

MR imaging of vulnerable carotid plaque.

Current risk stratification for stroke is still based upon percentage of carotid stenosis, despite this measure providing minimal patient-specific information on the actual risk of stroke for both symptomatic individuals without significant carotid artery stenosis as well as asymptomatic carotid stenosis patients. A continuously growing body of literature suggests that the identification and quantification of certain carotid plaque characteristics, including lipid-rich necrotic core (LRNC), thin/ruptured fibrous cap (FC), and intraplaque hemorrhage (IPH), provide a superior means of predicting future stroke. These characteristics are identifiable via magnetic resonance imaging (MRI), with most features detectable using commercially available coils and sequences utilized in routine clinical practice in as little as 4 minutes. The presence of LRNC, a thin/ruptured FC, and IPH is associated with increased risk of future stroke or TIA. Plaques with greater than 40% LRNC with a thin overlying FC are prone to rupture. LRNC is T2 hypointense and lacks enhancement on contrast enhanced T1 weighted images. Increasing LRNC size is associated with the development of new ulceration, FC rupture, increasing plaque burden, as well as fatal and nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome (ACS), and symptom-driven revascularization, allowing for MR biomarkers of carotid plaque vulnerability to be utilized for systemic athero-thrombotic risk and not just stroke/TIA. LRNC typically shrinks with appropriate statin therapy, with PCSK9 inhibitors possibly playing a role in patients with inadequate response. Carotid plaques with IPH represent a more advanced stage of atherosclerotic disease. IPH is detectable with field strengths of both 3.0 T and 1.5 T and will demonstrate high signal on all T1 weighted imaging sequences. The presence of IPH increases the risk of future stroke in both symptomatic and asymptomatic patients, with multivariate analysis identifying IPH as a predictor of stroke, independent of percent stenosis, with no statistical difference in men vs. women, demonstrating that simple carotid stenosis measurements and traditional risk factor analysis may be inadequate in identifying patients at the highest risk for adverse cerebrovascular events. In the evaluation for recurrent stroke in recently symptomatic patients with >50% carotid stenosis, the estimated annual stroke risk is 23.2% in IPH+ patients and only 0.6% in IPH- patients, calling into question the current risk-benefit assessment for CEA. Additionally, a recent meta-analysis suggests that IPH+ plaque in patients with symptomatic <50% stenosis may be the etiology of embolic strokes previously labeled as "embolic stroke of undetermined source" (ESUS). There are no prospective drug trials testing the ability of any lipid-lowering therapies to decrease IPH and/or total plaque volume (TPV). Given the continuously increasing evidence of IPH as a significant predictor of carotid plaque progression and future adverse vascular events, trials aimed at targeted therapy for IPH represents a significant need.

Quantification of Carotid Intraplaque Hemorrhage: Comparison between Manual Segmentation and Semi-Automatic Segmentation on Magnetization-Prepared Rapid Acquisition with Gradient-Echo Sequences.

Purpose: Carotid intraplaque hemorrhage (IPH) increases risk of territorial cerebral ischemic events, but different sequences or criteria have been used to diagnose or quantify carotid IPH. The purpose of this study was to compare manual segmentation and semi-automatic segmentation for quantification of carotid IPH on magnetization-prepared rapid acquisition with gradient-echo (MPRAGE) sequences. Methods: Forty patients with 16–79% carotid stenosis and IPH on MPRAGE sequences were reviewed by two trained radiologists with more than five years of specialized experience in carotid plaque characterization with carotid plaque MRI. Initially, the radiologists manually viewed the IPH based on the MPRAGE sequence. IPH volume was then measured by three different semi-automatic methods, with high signal intensity 150%, 175%, and 200%, respectively, above that of adjacent muscle on the MPRAGE sequence. Agreement on measurements between manual segmentation and semi-automatic segmentation was assessed using the intraclass correlation coefficient (ICC). Results: There was near-perfect agreement between manual segmentation and the 150% and 175% criteria for semi-automatic segmentation in quantification of IPH volume. The ICC of each semi-automatic segmentation were as follows: 150% criteria: 0.861, 175% criteria: 0.809, 200% criteria: 0.491. The ICC value of manual vs. 150% criteria and manual vs. 175% criteria were significantly better than the manual vs. 200% criteria (p < 0.001). Conclusions: The ICC of 150% and 175% criteria for semi-automatic segmentation are more reliable for quantification of IPH volume. Semi-automatic classification tools may be beneficial in large-scale multicenter studies by reducing image analysis time and avoiding bias between human reviewers.

Carotid Intraplaque-Hemorrhage Volume and Its Association with Cerebrovascular Events.

Our aim was to assess the relationship between volume and percentage of intraplaque hemorrhage measured using CT and the occurrence of cerebrovascular events at the time of CT. One-hundred-twenty-three consecutive subjects (246 carotid arteries) with a mean age of 69 years who underwent CTA were included in this retrospective study. Plaque volume of components and subcomponents (including intraplaque hemorrhage volume) was quantified with dedicated software. Forty-six arteries were excluded because no plaque was identified. In the remaining 200 carotid arteries, a statistically significant difference was found between presentation with cerebrovascular events and lipid volume (P = .002), intraplaque hemorrhage volume (P = .002), percentage of lipid (P = .002), percentage of calcium (P = .001), percentage of intraplaque hemorrhage (P = .001), percentage of lipid-intraplaque hemorrhage (P = .001), and intraplaque hemorrhage/lipid ratio (P = .001). The highest receiver operating characteristic area under the curve was obtained with the intraplaque hemorrhage volume with a value of 0.793 (P = .001), percentage of intraplaque hemorrhage with an area under the curve of 0.812 (P = .001), and the intraplaque hemorrhage/lipid ratio with an area under the curve value of 0.811 (P = .001). Results of our study suggest that Hounsfield unit values <25 have a statistically significant association with the presence of cerebrovascular events and that the ratio intraplaque hemorrhage/lipid volume represents a strong parameter for the association of cerebrovascular events.

Carotid Plaque CTA Analysis in Symptomatic Subjects with Bilateral Intraparenchymal Hemorrhage: A Preliminary Analysis.

The presence of IPH is considered the most dangerous feature because it is significantly associated with clinical ipsilateral cerebrovascular events. Our aim was to explore the characterization of plaque with CT in symptomatic subjects with bilateral intraplaque hemorrhage. Three-hundred-forty-three consecutive patients with recent anterior circulation ischemic events (<2 weeks) and CT of the carotid arteries (performed within 14 days of the cerebrovascular event) evaluated between June 2012 and September 2017 were analyzed for plaque volume composition to identify all subjects with bilateral intraplaque hemorrhage. Plaque volume was semiautomatically measured, and tissue components were classified according to the attenuation values such as the following: calcified (for values of ≥130 HU), mixed (for values of ≥60 and <130 HU), lipid (for values of ≥25 and <60 HU), and intraplaque hemorrhage (for values of <25 HU). Twenty-one subjects (15 men; mean age, 70 ± 11 years; range, 44-87 years) had bilateral intraplaque hemorrhage and were included in the analysis. Volume measurement revealed significantly larger plaques on the symptomatic side compared with the asymptomatic one (mean, 28 ± 9 versus 22 ± 8 mm, P = .007). Intraplaque hemorrhage volume and percentage were also significantly higher in the plaque ipsilateral to the cerebrovascular event (P < .001 and < .001, respectively). The volume of other plaque components did not show a statically significant association except for lipid and lipid + intraplaque hemorrhage percentages (23% versus 18% and 11% versus 15%), which were significantly different between the symptomatic and the asymptomatic sides (.016 and .011, respectively). The intraplaque hemorrhage/lipid ratio was higher on the symptomatic side (0.596 versus 0.171, P = .001). In patients with bilateral intraplaque hemorrhage and recent ischemic symptoms, the plaque ipsilateral to the symptomatic side has significantly larger volume and a higher percentage of intraplaque hemorrhage compared with the contralateral, asymptomatic side.

Semiautomatic carotid intraplaque hemorrhage volume measurement using 3D carotid MRI.

Presence of intraplaque hemorrhage (IPH) is a known risk factor for stroke and plaque progression. Accurate and reproducible measurement of IPH volume are required for further risk stratification. To develop a semiautomatic method to measure carotid IPH volume. Retrospective. Patients scheduled for carotid endarterectomy and patients with 16-79% asymptomatic carotid stenosis by ultrasound. 3T. Simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP) MRI. A semiautomated volumetric measurement of IPH using signal intensity thresholding of 3D SNAP volume was implemented. Fourteen carotid endarterectomy patients were enrolled to determine the signal intensity threshold of IPH using histology. Thirty-three patients with 16-79% asymptomatic stenosis were scanned twice within 1 month to evaluate reproducibility. The normalized SNAP intensity with the highest Youden index for predicting IPH on histology was used for thresholding. Scan-rescan reproducibility of IPH measurement was assessed using the intraclass correlation coefficient (ICC) and coefficient of variation (CV). Receiver operating characteristic curve, area under the curve, Cohen's kappa, intraclass correlation coefficient, coefficient of variance (CV), and paired t-test. IPH detection by the algorithm had substantial agreement with manual review (kappa: 0.92; 95% confidence interval [CI]: 0.83, 1.00) and moderate agreement with histology (kappa: 0.55; 95% CI: 0.34, 0.68). IPH volume measurements by the algorithm were strongly correlated with histology (Spearman's rho = 0.76, P = 0.002). IPH measurements were also reproducible, with ICCs of 0.86 (95% CI: 0.57, 0.96), 0.77 (95% CI: 0.32, 0.94), and 0.99 (95% CI: 0.93, 1.00) for maximum/mean normalized intensity and IPH volume, respectively. The corresponding CVs were 10.6%, 5.2%, and 11.8%. IPH volume measurements on SNAP MRI are highly reproducible using semiautomatic measurement. Level of Evidence 2 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2019;50:1055-1062.

Association between fibrinogen and fibrinogen γ’ and atherosclerotic plaque morphology and composition in symptomatic carotid artery stenosis: Plaque-At-RISK study

IntroductionVon Willebrand Factor (VWF), ADAMTS13, fibrinogen and fibrinogen γ’ are associated with an increased risk of ischemic stroke. Carotid atherosclerosis is an important risk factor for ischemic stroke. Characteristics of the vulnerable plaque; intraplaque hemorrhage (IPH), plaque ulceration and lipid-rich necrotic core (LRNC) can be visualized with imaging techniques. Since atherosclerosis might attribute to the association between coagulation factors and ischemic stroke risk, the aim of this study is to investigate the association between coagulation factors and atherosclerotic plaque characteristics in more detail. Materials and methodsIn 182 patients of the Plaque-At-RISK study (prospective multicenter cohort study) with a recent transient ischemic attack (TIA) or ischemic stroke and a symptomatic mild-to-moderate carotid artery stenosis, we measured VWF antigen (VWF:Ag), ADAMTS13 activity, fibrinogen (Clauss), and fibrinogen γ’. Presence of plaque ulceration, IPH volume and LRNC volume were determined by Multidetector-Row Computed Tomography (MDCTA, n = 160) and Magnetic Resonance Imaging (MRI, n = 172). Linear regression analysis was used to assess the association between imaging biomarkers and coagulation factors. ResultsVWF:Ag or ADAMTS13 levels were not significantly associated with plaque ulceration, IPH and LRNC. We found an inverse association between fibrinogen and fibrinogen γ’ and IPH volume (B = −23.40 mm3/g/L, p = 0.01 and B = −161.73 mm3/g/L, p = 0.01) and between fibrinogen and fibrinogen γ’ and LRNC volume (B = −38.89 mm3 g/L, p < 0.01 and B = −227.06 mm3 g/L, p = 0.01). Additional adjustments for C-reactive protein (CRP) did not change the results. ConclusionsFibrinogen and fibrinogen γ’ are inversely associated with IPH volume and LRNC volume, independent of inflammation.Clinical Trial Registration: clinicaltrials.govNCT01208025