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Purpose: Intraplaque haemorrhage (IPH) is a well-known risk factor for faster plaque progression (volume increase); however, its etiology is unclear. We aimed at determining what other local plaque- and systemic factors contribute to plaque progression and to the development and progression of IPH., Methods: We examined 98 asymptomatic participants with carotid plaque using serial multi-contrast magnetic resonance imaging. We measured the percent of wall volume (%WV=100 x [wall volume] / [total vessel volume]) and measured IPH and calcification volumes. We used generalized estimating equations-based regression to analyze predictors of %WV change and new IPH while accounting for covariates (sex, age and statin use), and multiple non-independent observations per participant., Results: Total follow-up was 1.8 ± 0.8 years on average. The presence of IPH (β: 0.6 %/y, p = 0.033) and calcification (β: 1.2 %/y, p = 0.028) were each associated with faster plaque progression. New IPH, detected on a subsequent scan in 4 % of arteries that did not initially have IPH, was associated with larger calcification (odds ratio [OR]: 2.6 per 1-SD increase, p = 0.038) and higher pulse pressure (OR: 2.3 per 1-SD increase, p = 0.016). Larger calcification was associated with greater increases in pulse pressure (β: 1.4 mm Hg/y per 1-SD increase, p = 0.040)., Conclusions: IPH and calcification are each independently associated with faster plaque progression. The association of carotid calcification to increased pulse pressure and new IPH development suggests a possible mechanism by which calcification drives IPH development and plaque progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

PCSK9 inhibitors lower low-density lipoprotein cholesterol (LDL-C) and reduce cardiovascular events. The clinical benefits presumably result from favorable effects on atherosclerotic plaques. Lipid-core and plaque inflammation have been recognized as main determinants of risk for plaque rupture and cardiovascular events. Both can be noninvasively assessed with carotid MRI. We studied if PCSK9 inhibition with alirocumab induces regression in lipid-core or plaque inflammation within 6 months as measured by MRI. Patients with non-calcified carotid plaque(s) and baseline LDL-C ≥ 70 mg/dl, who were statin-intolerant or taking a low-dose statin (≤ 10 mg per day of atorvastatin or an equivalent), received subcutaneous alirocumab 150 mg every 2 weeks. Carotid MRI was performed at baseline and 6 months after treatment, including pre- and post-contrast images for measuring percent lipid-core volume (%LC) and dynamic contrast-enhanced images for measuring microvessel leakiness (K trans ), a marker of inflammation. Twenty-eight patients completed the study (69 ± 9 years; 64% male). Alirocumab led to significant changes in LDL-C (p < 0.001) and high-density lipoprotein cholesterol (HDL-C) (p = 0.003). At 6 months, there was a significant reduction in %LC (mean: - 2.1% [- 3.5, - 0.7], p = 0.005; a 17% reduction from baseline of 9.9%) without significant changes in lumen/wall area or in the inflammatory index K trans . Carotid plaque lipid content was reduced by 17% after 6 months of PCSK9 inhibition with alirocumab. This was seen before observable changes in lumen or wall areas, which supports pursing plaque lipid content as a more sensitive marker of therapeutic response compared to lumen or wall areas in future technical developments and serial studies.

Background and Purpose: To investigate differences in the characteristics of carotid atherosclerotic plaques of symptomatic subjects in northern and southern China using MRI., Methods: Sixty-three subjects in northern China (mean age: 59.1±8.6 years, 45 men) and 56 subjects in southern China (mean age: 60.4±8.6 years, 38 men) were included. All subjects underwent carotid artery multicontrast vessel wall MRI. Plaque morphology, calcification, lipid-rich necrotic core, intraplaque haemorrhage, luminal surface disruption and high-risk plaque were measured and identified. All plaque characteristics were compared between subjects in northern and southern China using Mann-Whitney U test or χ 2 test., Results: Compared with subjects in southern China, those in northern China had significantly greater areas for lumen (57.7±14.9 mm 2 vs 50.4±18.3 mm 2 , p=0.009), wall (38.4±13.1 mm 2 vs 31.9±11.7 mm 2 , p<0.001) and total vessel (96.1±20.2 mm 2 vs 82.4±22.7 mm 2 , p=0.001) and mean wall thickness (1.25±0.43 mm vs 1.13±0.40 mm, p=0.019). χ 2 analysis showed that subjects in northern China tended to have a higher prevalence of intraplaque haemorrhage (14.3% vs 5.4%, p=0.106) and high-risk plaque (20.6% vs 10.7%, p=0.140) than those in southern China, although these differences were not statistically significant (all p>0.05)., Conclusion: Subjects in northern China have significantly larger vessel size and may have a higher prevalence of vulnerable plaques than those in southern China. Our findings provide additional perspective to optimise the management of cerebrovascular disease in individuals in different regions in China., Trial Registration Number: NCT02017756., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Carotid bifurcation geometry has been believed to be a risk factor for the initiation of atherosclerosis because of its influence on hemodynamics. However, the relationships between carotid bifurcation geometry and plaque vulnerability are not fully understood. This study aimed to determine the association between carotid bifurcation geometry and plaque vulnerability using magnetic resonance vessel wall imaging. Approach and Results: A total of 501 carotid arteries with nonstenotic atherosclerosis were included from the cross-sectional, multicenter CARE II study (Chinese Atherosclerosis Risk Evaluation). Four standardized carotid bifurcation geometric parameters (bifurcation angle, internal carotid artery planarity, luminal expansion FlareA, and tortuosity Tort2D) were derived from time-of-flight magnetic resonance angiography. Presence of vulnerable plaque, which was characterized by intraplaque hemorrhage, large lipid-rich necrotic core, or disrupted luminal surface, was determined based on multicontrast carotid magnetic resonance vessel wall images. Vulnerable plaques (N=43) were found to occur at more distal locations (ie, near the level of flow divider) than stable plaques (N=458). Multivariable logistic regression showed that the luminal expansion FlareA (odds ratio, 0.45 [95% CI, 0.25-0.81]; P =0.008) was associated with plaque vulnerability after adjustment for age, sex, maximum wall thickness, plaque location, and other geometric parameters., Conclusions: Smaller luminal expansion at carotid bifurcation is associated with vulnerable plaque. The finding needs to be verified with longitudinal studies and the underlying mechanism should be further explored with hemodynamics measurement in the future.

Background and Purpose- High-resolution magnetic resonance imaging is capable of characterizing carotid atherosclerotic plaque morphology and composition. Most reported carotid plaque imaging techniques are 2-dimensional (2D) based with limited longitudinal coverage of ≈30 mm, which may be insufficient for complete visualization of extracranial carotid atheroma. A 3D black-blood imaging technique, motion-sensitized driven equilibrium prepared rapid gradient echo technique (3D-MERGE) can provide larger coverage. We sought to use 3D-MERGE to investigate carotid atherosclerosis plaque distribution and to analyze their correlation with clinical information and stroke risk factors. Methods- From 5 hospitals in China, 97 subjects suspected of recent stroke or transient ischemic attack were imaged with 3D-MERGE within 2 weeks of symptoms using 3T magnetic resonance imaging. Images were analyzed by 2 reviewers. Plaque length was calculated and categorized as plaques within, partially outside, or completely outside of typical 2D magnetic resonance imaging coverage. Associations between plaque features and clinical information, stroke risk factors were assessed. Results- Ninety-seven subjects with 194 carotid arteries (70 men and 27 women, mean age 60 years) were analyzed. Of the 136 plaques identified, 68 (50%) were within, 46 (33.8%) were partially outside, and 22 (16.2%) were completely outside of 2D magnetic resonance imaging coverage. Total plaque length was significantly positively associated with male sex ( P <0.001), hypertension ( P =0.011), and history of smoking ( P <0.001). Hypertensive subjects were more likely to have at least one plaque completely outside the 2D magnetic resonance imaging coverage than nonhypertensive subjects ( P =0.007). Conclusions- The 3D-MERGE allows for the identification of substantially more carotid plaques than 2D black-blood techniques. The extent and distribution of plaque, identified by the larger coverage afforded by 3D-MERGE, were found to correlate significantly with male sex and risk factors that are common among patients with stroke, including hypertension and history of cigarette smoking.

Objectives: To investigate the differences in characteristics of carotid plaques between patients Xining at high altitude and Jinan at sea level using magnetic resonance (MR) imaging., Methods: Subjects were recruited from a cross-sectional, observational, multicenter imaging study of CARE-II study. Forty-nine (mean age 63.3 ± 12.0 years, 33 males) and 51 (mean age 64.5 ± 12.0 years, 34 males) patients were recruited from a site located in a high altitude region and a site located near sea level, respectively. All patients underwent multicontrast MR vessel wall imaging for carotid arteries on 3.0 T MR scanner. The carotid plaques features were compared between 2 patient groups., Results: Compared with patients at sea level, those at high altitude had significantly greater lumen area (58.5 ± 17.8 mm 2 versus 50.0 ± 19.6 mm 2 , P = .008), smaller maximum normalized wall index (48.6% ± 14.2% versus 57.8% ± 16.3%, P = .002), and smaller percentage volume of calcium (0.9% versus 5.6%, P < .001) in the symptomatic carotid artery. After adjustment for clinical risk factors including age, sex, systolic blood pressure, LDL-C, and statin use, these differences in plaque morphology and composition remained statistically significant. After further adjustment for normalized wall index as a measure of plaque burden, percentage volume of calcification was still significantly smaller in patients at high altitude area than that in patients at sea level area (P = .047)., Conclusion: Symptomatic subjects from a high altitude area have lower plaque burden and less calcification in the carotid artery compared to those from an area near sea level., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective- Diabetes mellitus is associated with high-risk atherosclerotic plaques. This study aimed to compare characteristics of carotid atherosclerotic plaques in symptomatic Chinese diabetic and nondiabetic patients using vessel wall magnetic resonance imaging. Approach and Results- Patients with cerebral ischemic symptoms in the anterior circulation and carotid atherosclerotic plaque determined by ultrasound were recruited from a cross-sectional, observational, multicenter study of CARE-II (Chinese Atherosclerosis Risk Evaluation). All patients underwent magnetic resonance imaging for carotid arteries. The morphological and compositional characteristics of carotid plaques were compared between diabetic and nondiabetic patients using linear (continuous variables) and logistic regression (binary variables). In a total of 584 recruited patients, 182 (31.2%) had diabetes mellitus. From the univariate analysis, diabetic patients had significantly greater mean wall area (33.7 versus 31.1 mm 2 ; P=0.002), maximum wall thickness (3.2 versus 2.8 mm; P<0.001), and mean normalized wall index (43.8% versus 41.0%; P<0.001) and had significantly higher prevalence of calcification (51.6% versus 36.6%; P=0.001), lipid-rich necrotic core (77.5% versus 58.5%; P<0.001), and high-risk plaque (29.7% versus 19.9%; P=0.011) than nondiabetic patients. After adjusting for clinical characteristics, the differences in presence of calcification ( P=0.018) and lipid-rich necrotic core ( P=0.001) remained statistically significant. Conclusions- Symptomatic Chinese diabetic patients are more likely to have carotid plaques with calcification and lipid-rich necrotic core than nondiabetic patients, suggesting that diabetic patients may develop more severe atherosclerotic disease that should be accounted for in their clinical management.

Objective: Early atherosclerosis is often undetected due in part to compensatory enlargement of the outer wall, termed positive remodeling. Variations in hemodynamic conditions and clinical factors influence the patterns of remodeling. The carotid artery provides an opportunity to examine these variations because of the unique geometry of the carotid bulb. This study aimed to determine differences in remodeling of the common, internal, and bifurcation segments of the carotid using magnetic resonance imaging., Approach and Results: Carotid arteries of 525 subjects without history of cardiovascular disease were imaged by magnetic resonance imaging. The carotid artery was divided into 3 segments: common carotid artery; bifurcation; and internal carotid artery. Remodeling patterns were characterized using linear regression analysis of lumen and total vessel areas (dependent variables) compared with maximum wall thickness (independent variable) for each segment, adjusted for age, sex, and height. The common carotid artery demonstrated a pattern consistent with positive remodeling, whereas the bifurcation demonstrated negative remodeling. The internal carotid artery demonstrated a mixed pattern of outer wall expansion and lumen constriction. Females and subjects with diabetes mellitus showed more positive remodeling, hypertension was associated with attenuated positive remodeling, and those with hypercholesterolemia showed more negative remodeling., Conclusions: In this cohort of 55- to 80-year-old individuals without history of cardiovascular disease, the pattern of early carotid artery remodeling was segment specific and appeared to be associated with sex and clinical characteristics. These findings provide the groundwork for longitudinal studies to define local and systemic factors such as hemodynamic and clinical conditions on carotid artery remodeling., (© 2018 American Heart Association, Inc.)

Objective: To assess whether Lp(a) (lipoprotein(a)) levels and other lipid levels were predictive of progression of atherosclerosis burden as assessed by carotid magnetic resonance imaging in subjects who have been treated with LDL-C (low-density lipoprotein cholesterol)-lowering therapy and participated in the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes)., Approach and Results: AIM-HIGH was a randomized, double-blind study of subjects with established vascular disease, elevated triglycerides, and low HDL-C (high-density lipoprotein cholesterol). One hundred fifty-two AIM-HIGH subjects underwent both baseline and 2-year follow-up carotid artery magnetic resonance imaging. Plaque burden was measured by the percent wall volume (%WV) of the carotid artery. Associations between annualized change in %WV with baseline and on-study (1 year) lipid variables were evaluated using multivariate linear regression and the Bonferroni correction to account for multiple comparisons. Average %WV at baseline was 41.6±6.8% and annualized change in %WV over 2 years ranged from -3.2% to 3.7% per year (mean: 0.2±1.1% per year; P =0.032). Increases in %WV were significantly associated with higher baseline Lp(a) (β=0.34 per 1-SD increase of Lp(a); 95% confidence interval, 0.15-0.52; P <0.001) after adjusting for clinical risk factors and other lipid levels. On-study Lp(a) had a similar positive association with %WV progression (β=0.33; 95% confidence interval, 0.15-0.52; P <0.001)., Conclusions: Despite intensive lipid therapy, aimed at aggressively lowering LDL-C to <70 mg/dL, carotid atherosclerosis continued to progress as assessed by carotid magnetic resonance imaging and that elevated Lp(a) levels were independent predictors of increases in atherosclerosis burden., (© 2018 American Heart Association, Inc.)

Background and Aims: Dynamic contrast-enhanced MR imaging (DCE-MRI) provides a noninvasive approach to the functional status of carotid adventitial vasa vasorum. Contrast extravasation rate, or K trans , derived from kinetic modeling of adventitial enhancement, has been correlated with plaque neovascularization and inflammation. This study sought to clarify the clinical implications of K trans by evaluating its relationship with documented cardiovascular events (CVE)., Methods: Seventy patients with carotid plaque at clinical ultrasound examination were recruited and imaged with a previously-described bright-blood DCE-MRI protocol (spatial resolution: 0.55 × 0.58 mm 2 ; time resolution: 18 s). Patients were classified by the presence of documented coronary and/or cerebrovascular events. Adventitial K trans was estimated via kinetic modeling of outer wall enhancement as captured by DCE-MRI., Results: After excluding six patients with insufficient image quality, 64 patients (66 ± 12 years, 51 male) had DCE-MRI measurements. Patients with documented CVE showed significantly higher adventitial K trans than those without (0.056 ± 0.024 versus 0.034 ± 0.008 min -1 , p < 0.001), whereas comparable measurements were seen among the subgroups with CVE (p > 0.05): 0.054 ± 0.027 min -1 in patients with coronary events alone, 0.056 ± 0.018 min -1 in patients with cerebrovascular events alone, and 0.069 ± 0.022 min -1 in patients with both. Carotid adventitial K trans was negatively correlated with time since clinical event (Spearman's rho = -0.40, p = 0.003)., Conclusions: Patients with documented CVE demonstrated increased rate of contrast extravasation from carotid adventitial vasa vasorum on DCE-MRI irrespective of the territory of events. Systemic factors implicated in the pathophysiology of acute atherothrombotic events may influence the functional status of adventitial vasa vasorum., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to investigate whether and what carotid plaque characteristics predict systemic cardiovascular outcomes in patients with clinically established atherosclerotic disease., Background: Advancements in atherosclerosis imaging have allowed assessment of various plaque characteristics, some of which are more directly linked to the pathogenesis of acute cardiovascular events compared to plaque burden., Methods: As part of the event-driven clinical trial AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes), subjects with clinically established atherosclerotic disease underwent multicontrast carotid magnetic resonance imaging (MRI) to detect plaque tissue composition and high-risk features. Prospective associations between MRI measurements and the AIM-HIGH primary endpoint (fatal and nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, and symptom-driven revascularization) were analyzed using Cox proportional hazards survival models., Results: Of the 232 subjects recruited, 214 (92.2%) with diagnostic image quality constituted the study population (82% male, mean age 61 ± 9 years, 94% statin use). During median follow-up of 35.1 months, 18 subjects (8.4%) reached the AIM-HIGH endpoint. High lipid content (hazard ratio [HR] per 1 SD increase in percent lipid core volume: 1.57; p = 0.002) and thin/ruptured fibrous cap (HR: 4.31; p = 0.003) in carotid plaques were strongly associated with the AIM-HIGH endpoint. Intraplaque hemorrhage had a low prevalence (8%) and was marginally associated with the AIM-HIGH endpoint (HR: 3.00; p = 0.053). High calcification content (HR per 1 SD increase in percent calcification volume: 0.66; p = 0.20), plaque burden metrics, and clinical risk factors were not significantly associated with the AIM-HIGH endpoint. The associations between carotid plaque characteristics and the AIM-HIGH endpoint changed little after adjusting for clinical risk factors, plaque burden, or AIM-HIGH randomized treatment assignment., Conclusions: Among patients with clinically established atherosclerotic disease, carotid plaque lipid content and fibrous cap status were strongly associated with systemic cardiovascular outcomes. Markers of carotid plaque vulnerability may serve as novel surrogate markers for systemic atherothrombotic risk., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Carotid atherosclerotic plaque is identified as one of the main sources of ischaemic stroke. However, the prevalence of carotid high-risk atherosclerotic plaque in Chinese patients with ischaemic cerebrovascular events has been inconsistently reported and needs to be investigated in a large population., Objectives: The primary objective of CARE II study was to determine the prevalence and characteristics of high-risk features of atherosclerotic plaques in the carotid arteries in Chinese patients with recent ischaemic stroke or transient ischaemia attack (TIA). The relationship between carotid plaque features and cerebral infarcts, the differences of carotid plaque patterns among different regions of China and the gender specific characteristics of carotid plaque will be also determined., Study Design: The CARE II study will enrol 1000 patients with recent ischaemic stroke or TIA and carotid plaque from 13 hospitals and medical centres across China. In this cross-sectional, non-randomised, observational, multicentre study, all patients will undergo carotid artery MRI of bilateral carotid arteries and routine brain MRI with standardised protocols. The MRI will be interpreted at core reading centres to evaluate the characteristics of morphology and compositions of carotid plaque., Conclusions: This is a cross-sectional, multicentre study to investigate the prevalence and characteristics of high-risk atherosclerotic carotid plaque in Chinese patients with stroke and TIA by using high-resolution MRI of vessel wall. This trial is sufficiently powered to demonstrate the prevalence of carotid high-risk plaque and to explore regional differences in Chinese patients who suffered stroke., Trial Registration Number: NCT02017756., Competing Interests: Competing interests: None declared.

Background and Aims: Plaque fissuring, a phenomenon morphologically distinct from the classical rupture of a thinned fibrous cap, has not been well characterized in carotid atherosclerosis. The aim of this study was to establish the prevalence of plaque fissures in advanced carotid plaques with an otherwise intact luminal surface, and to determine whether they might be a source of intraplaque hemorrhage (IPH)., Methods: We evaluated 244 surgically intact, 'en bloc' embedded, serially sectioned carotid endarterectomy specimens and included only those plaques with a grossly intact luminal surface., Results: Among the 67 plaques with grossly intact luminal surface, cap fissure was present in 39 (58%) plaques. A total of 60 individual fissures were present, and longitudinally mean fissure length was 1.3 mm. Most fissures were found distal to the bifurcation (63%), proximal to the stenosis (88%), and in the posterior (opposite the flow divider) or lateral quadrants (80%). 36% of the fissures remained in the superficial third of the plaque. 52% extended from the lumen surface to the middle third of the plaque and 12% reached the outer third of the plaque on cross section. Fissures often occurred between two tissue planes and were connected to IPH (fresh: 63%; any type: 92%) and calcifications (43%). No correlation was found with patient characteristics such as symptom status, carotid stenosis, hypertension, diabetes, smoking and medications (statins or antiplatelet agents)., Conclusions: Plaque fissures are common in advanced carotid plaques with an otherwise grossly intact luminal surface and are associated with fresh intraplaque hemorrhage. As they occur on the interface between plaque components with different mechanical properties, further biomechanical studies are needed to unravel the underlying failure mechanisms., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Intraplaque hemorrhage (IPH) is associated with atherosclerosis progression and subsequent cardiovascular events. We sought to develop a semi-automatic method with an optimized threshold for carotid IPH detection and quantification on MP-RAGE images using matched histology as the gold standard., Methods: Fourteen patients scheduled for carotid endarterectomy underwent 3D MP-RAGE cardiovascular magnetic resonance (CMR) preoperatively. Presence and area of IPH were recorded using histology. Presence and area of IPH were also recorded on CMR based on intensity thresholding using three references for intensity normalization: the sternocleidomastoid muscle (SCM), the adjacent muscle and the automatically generated local median value. The optimized intensity thresholds were obtained by maximizing the Youden's index for IPH detection. Using leave-one-out cross validation, the sensitivity and specificity for IPH detection based on our proposed semi-automatic method and the agreement with histology on IPH area quantification were evaluated., Results: The optimized intensity thresholds for IPH detection were 1.0 times the SCM intensity, 1.6 times the adjacent muscle intensity and 2.2 times the median intensity. Using the semi-automatic method with the optimized intensity threshold, the following IPH detection and quantification performance was obtained: sensitivities up to 59, 68 and 80 %; specificities up to 85, 74 and 79 %; Pearson's correlation coefficients (IPH area measurement) up to 0.76, 0.93 and 0.90, respectively, using SCM, the adjacent muscle and the local median value for intensity normalization, after heavily calcified and small IPH were excluded., Conclusions: A semi-automatic method with good performance on IPH detection and quantification can be obtained in MP-RAGE CMR, using an optimized intensity threshold comparing to the adjacent muscle. The automatically generated reference of local median value provides comparable performance and may be particularly useful for developing automatic classifiers. Use of the SCM intensity as reference is not recommended without coil sensitivity correction when surface coils are used.

Background and Purpose: Although studies have evaluated the differential imaging of moyamoya disease and atherosclerosis, none have investigated the added value of vessel wall magnetic resonance imaging (MRI). This study evaluates the added diagnostic value of vessel wall MRI in differentiating moyamoya disease, atherosclerotic-moyamoya syndrome (A-MMS), and vasculitic-MMS (V-MMS) with a multicontrast protocol., Methods: We retrospectively reviewed the carotid artery territories of patients with clinically defined vasculopathies (moyamoya disease, atherosclerosis, and vasculitis) and steno-occlusive intracranial carotid disease. Two neuroradiologists, blinded to clinical data reviewed the luminal imaging of each carotid, evaluating collateral extent and making a presumed diagnosis with diagnostic confidence. After 3 weeks, the 2 readers reviewed the luminal imaging+vessel wall MRI for the presence, pattern and intensity of postcontrast enhancement, T2 signal characteristics, pattern of involvement, and presumed diagnosis and confidence., Results: Ten A-MMS, 3 V-MMS, and 8 moyamoya disease cases with 38 affected carotid segments were included. There was significant improvement in diagnostic accuracy with luminal imaging+vessel wall MRI when compared with luminal imaging (87% versus 32%, P<0.001). The most common vessel wall MRI findings for moyamoya disease were nonenhancing, nonremodeling lesions without T2 heterogeneity; for A-MMS eccentric, remodeling, and T2 heterogeneous lesions with mild/moderate and homogeneous/heterogeneous enhancement; and for V-MMS concentric lesions with homogeneous, moderate enhancement. Inter-reader agreement was moderate to substantial for all vessel wall MRI characteristics (κ=0.46-0.86) and fair for collateral grading (κ=0.35). There was 11% inter-reader agreement for diagnosis on luminal imaging when compared with 82% for luminal imaging+vessel wall MRI (P<0.001)., Conclusions: Vessel wall MRI can significantly improve the differentiation of moyamoya vasculopathies when combined with traditional imaging techniques., (© 2016 American Heart Association, Inc.)

Objective: Plaque neovasculature is a major route for lipoprotein and leukocyte ingress into plaques, and has been identified as a risk factor for carotid plaque disruption. Vp, a variable derived from pharmacokinetic modeling of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), correlates with plaque neovasculature density. Because lipid-lowering therapy has been associated with regression of neovasculature in animal models, we sought to determine clinical correlates of carotid plaque neovasculature (as assessed by Vp) in participants on statin therapy for established cardiovascular disease., Methods: 98 participants from an AIM-HIGH sub-study underwent DCE-MRI of their carotid arteries. Expert readers who were blinded to all clinical variables analyzed the MR images to measure carotid plaque Vp in all participants. Associations between Vp and duration of statin therapy and other clinical risk factors were analyzed., Results: Prior duration of statin treatment at enrollment ranged from <1 year (21%) 1-5 years (40%) and >5 years (39%). In univariate analyses, shorter duration of statin therapy (P = 0.01), the presence of metabolic syndrome (P = 0.02), and higher body mass index (P = 0.01) and lipoprotein(a) (P = 0.01) were all significantly associated with higher baseline Vp values. In multivariate analyses, significant associations remained between shorter duration of statin therapy (P = 0.004) and lipoprotein(a) (P = 0.04)., Conclusions: These are the first human, in vivo findings suggesting a relationship between duration of statin therapy and regression of carotid plaque neovasculature. Future longitudinal studies are warranted both to confirm this finding and to address whether changes in neovasculature may translate into change in risk for plaque disruption. CLINICALTRIALS., Gov Identifiers: NCT00880178, NCT01178320 and NCT00120289., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

This study sought to discover which atherosclerotic plaque components co-localize with enhanced [(18)F]-fluorodeoxyglucose (FDG) uptake in carotid positron emission tomography (PET) images. Although in vivo PET currently lacks the resolution, high-resolution ex vivo FDG-microPET with histology validation of excised carotid plaque might accomplish this goal. Thirteen patients were injected with FDG before carotid endarterectomy. After excision, the plaque specimens were scanned by microPET and magnetic resonance imaging, and then serially sectioned for histological analysis. Two analyses were performed using generalized linear mixed models: (1) a PET-driven analysis which sampled high and low FDG uptake areas from PET images to identify their components in matched histology specimens; and (2) a histology-driven analysis where specific plaque components were selected and matched to corresponding PET images. In the PET-driven analysis, regions of high FDG uptake were more likely to contain inflammatory cells (p < 0.001) and neovasculature (p = 0.008) than regions of low FDG uptake. In the histology-driven analysis, regions with inflammatory cells (p = 0.001) and regions with loose extracellular matrix (p = 0.001) were associated with enhanced FDG uptake. Furthermore, areas of complex inflammatory cell infiltrate (co-localized macrophages, lymphocytes and foam cells) had the highest FDG uptake among inflammatory subgroups (p < 0.001). In conclusion, in carotid plaque, regions of inflammatory cell infiltrate, particularly complex one, co-localized with enhanced FDG uptake in high-resolution FDG-microPET images. Loose extracellular matrix and areas containing neovasculature also produced FDG signal. This study points to the potential ability of FDG-PET to detect the cellular components of the vulnerable plaque.

The purpose of this study was to evaluate differences of plaque composition and morphology within the same patient in different vascular beds using non-invasive MR-plaque imaging. 28 patients (67.8 ± 7.4 years, 8 females) with high Framingham general cardiovascular disease 10-year risk score and mild-to-moderate atherosclerosis were consecutively included in the study. All subjects underwent a dedicated MRI-plaque imaging protocol using TOF and T1w and T2w black-blood-sequences with fat suppression at 1.5 T. The scan was centered on the carotid bulb of the carotid arteries and on the most stenotic lesion of the ipsilateral femoral artery, respectively. Plaques were classified according to the American Heart Association (AHA) lesion type classification and area measurements of lumen, wall and the major plaque components, such as calcification, necrotic core and hemorrhage were determined in consensus by two blinded reviewers using dedicated software (Cascade, Seattle, USA). Plaque components were recorded as maximum percentages of the wall area. Carotid arteries had larger maximum wall and smaller minimum lumen areas (p < 0.001) than femoral arteries, whereas no significant difference was find with respect to the max. NWI (p = 0.87). Prevalence of lipid-rich AHA lesion type IV/V and complicated AHA lesion type VI with hemorrhage/thrombus/fibrous cap rupture was significantly higher in the carotid arteries compared to the femoral arteries. Plaque composition as percentage of the vessel wall differed significantly between carotid and femoral arteries: Max. %necrotic core and max. %hemorrhage were significantly higher in the carotid arteries compared to the femoral arteries (p = 0.001 and p = 0.02, respectively). Max. %calcification did not differ significantly. Average stenotic degree of carotid arteries at duplex was 49.7 ± 12.5 (%). Non-invasive MR plaque-imaging is able to visualize differences in plaque composition across the vascular tree. We observed significant differences in quantitative and qualitative plaque features between carotid and femoral arteries within the same patient, which in the future could help to improve risk stratification in patients with atherosclerosis.

Purpose: To assess fast three-dimensional (3D) black-blood (BB) magnetic resonance (MR) imaging as a noninvasive alternative to intraarterial digital subtraction angiography (DSA) at quantifying moderate to severe carotid artery atherosclerotic disease., Materials and Methods: Local ethics committee approval and written informed patient consent were obtained for this study. Sixty-five carotid arteries from 52 patients with at least 50% stenosis underwent 3D BB MR imaging and DSA. Quantitative measurements, including stenosis, lesion length, and the presence or absence of plaque ulceration, obtained with the two modalities were independently determined. Sensitivity and specificity, the intraclass correlation coefficient (ICC), Cohen κ, and Bland-Altman analysis were used to assess the agreement., Results: Excellent agreement in measuring luminal stenosis was found between 3D BB MR imaging and DSA (ICC, 0.96; 95% confidence interval [CI]: 0.93, 0.97). Three-dimensional BB MR imaging was also found to have high sensitivity (91.7%), specificity (96.2%), and agreement (Cohen κ, 0.85; 95% CI: 0.66, 0.99) with DSA for detection of ulcers. Good agreement was found between lesion length measured by using 3D BB MR imaging and DSA (ICC, 0.75; 95% CI: 0.51, 0.84). However, lesion length measurements by using 3D BB MR imaging were, on average, 4.0 mm longer than those measured by using DSA (P < .001)., Conclusion: Three-dimensional BB MR imaging is a noninvasive and accurate way to quantify moderate to severe carotid artery atherosclerotic disease. With fast acquisition and large coverage, 3D BB MR imaging has the potential to become an alternative imaging approach in evaluating the severity of atherosclerosis., (© RSNA, 2014.)

This study sought to determine the multicenter reproducibility of magnetic resonance imaging (MRI) and the compatibility of different scanner platforms in assessing carotid plaque morphology and composition. A standardized multi-contrast MRI protocol was implemented at 16 imaging sites (GE: 8; Philips: 8). Sixty-eight subjects (61 ± 8 years; 52 males) were dispersedly recruited and scanned twice within 2 weeks on the same magnet. Images were reviewed centrally using a streamlined semiautomatic approach. Quantitative volumetric measurements on plaque morphology (lumen, wall, and outer wall) and plaque tissue composition [lipid-rich necrotic core (LRNC), calcification, and fibrous tissue] were obtained. Inter-scan reproducibility was summarized using the within-subject standard deviation, coefficient of variation (CV) and intraclass correlation coefficient (ICC). Good to excellent reproducibility was observed for both morphological (ICC range 0.98-0.99) and compositional (ICC range 0.88-0.96) measurements. Measurement precision was related to the size of structures (CV range 2.5-4.9 % for morphology, 36-44 % for LRNC and calcification). Comparable measurement variability was found between the two platforms on both plaque morphology and tissue composition. In conclusion, good to excellent inter-scan reproducibility of carotid MRI can be achieved in multicenter settings with comparable measurement precision between platforms, which may facilitate future multicenter endeavors that use serial MRI to monitor atherosclerotic plaque progression.

Association between clinical factors and high-risk plaque features, such as, thin or ruptured cap, intraplaque hemorrhage, presence of lipid-rich necrotic core (LRNC), and increased LRNC volume as assessed by magnetic resonance imaging (MRI), was examined in patients with established vascular disease in the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides (AIM-HIGH) trial. A total of 214 subjects underwent carotid MRI and had acceptable image quality for assessment of plaque burden, tissue contents, and MRI-modified American Heart Association lesion type by a core laboratory. We found that 77% of subjects had carotid plaques, 52% had lipid-containing plaques, and 11% had advanced American Heart Association type-VI lesions with possible surface defect, intraplaque hemorrhage, or mural thrombus. Type-VI lesions were associated with older age (odds ratio [OR] = 2.6 per 5 years increase, p <0.001). After adjusting for age, these lesions were associated with history of cerebrovascular disease (OR = 4.1, p = 0.01), higher levels of lipoprotein(a) (OR = 2.0 per 1 SD increase, p = 0.02), and larger percent wall volume (PWV [OR = 4.6 per 1 SD increase, p <0.001]) but, were negatively associated with metabolic syndrome (OR = 0.2, p = 0.02). Presence of LRNC was associated with the male gender (OR = 3.2, p = 0.02) and PWV (OR = 3.8 per 1 SD, p <0.001); however, it was negatively associated with diabetes (OR = 0.4, p = 0.02) and high-density lipoprotein cholesterol levels (OR = 0.7 per 1 SD, p = 0.02). Increased percent LRNC was associated with PWV (regression coefficient = 0.36, p <0.001) and negatively associated with ApoA1 levels (regression coefficient = -0.20, p = 0.03). In conclusion, older age, male gender, history of cerebrovascular disease, larger plaque burden, higher lipoprotein(a), and lower high-density lipoprotein cholesterol or ApoA1 level have statistically significant associations with high-risk plaque features. Metabolic syndrome and diabetes showed negative associations in this population., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The aim of this study is to investigate the inter-scan reproducibility of kinetic parameters in atherosclerotic plaque using dynamic contrast-enhanced (DCE) cardiovascular magnetic resonance (CMR) in a multi-center setting at 3T., Methods: Carotid arteries of 51 subjects from 15 sites were scanned twice within two weeks on 3T scanners using a previously described DCE-CMR protocol. Imaging data with protocol compliance and sufficient image quality were analyzed to generate kinetic parameters of vessel wall, expressed as transfer constant (K trans ) and plasma volume (v p ). The inter-scan reproducibility was evaluated using intra-class correlation coefficient (ICC) and coefficient of variation (CV). Power analysis was carried out to provide sample size estimations for future prospective study., Results: Ten (19.6%) subjects were found to suffer from protocol violation, and another 6 (11.8%) had poor image quality (n=6) in at least one scan. In the 35 (68.6%) subjects with complete data, the ICCs of K trans and v p were 0.65 and 0.28, respectively. The CVs were 25% and 62%, respectively. The ICC and CV for v p improved to 0.73 and 28% in larger lesions with analyzed area larger than 25 mm2. Power analysis based on the measured CV showed that 50 subjects per arm are sufficient to detect a 20% difference in change of K trans over time between treatment arms with 80% power without consideration of the dropout rate., Conclusion: The result of this study indicates that quantitative measurement from DCE-CMR is feasible to detect changes with a relatively modest sample size in a prospective multi-center study despite the limitations. The relative high dropout rate suggested the critical needs for intensive operator training, optimized imaging protocol, and strict quality control in future studies.

Background and Purpose: It remains unclear whether direct vessel wall imaging can identify carotid high-risk lesions in symptomatic subjects and whether carotid plaque characteristics are more effective indicators for cerebral infarct severity than stenosis. This study sought to determine the associations of carotid plaque characteristics by MR imaging with stenosis and acute cerebral infarct (ACI) sizes on diffusion weighted imaging (DWI)., Materials and Methods: One hundred and fourteen symptomatic patients underwent carotid and brain MRI. ACI volume was determined from symptomatic internal carotid artery territory on DWI images. Ipsilateral carotid plaque morphological and compositional characteristics, and stenosis were also determined. The relationships between carotid plaque characteristics, stenosis and ACIs size were then evaluated., Results: In carotid arteries with 30-49% stenosis, 86.7% and 26.7% were found to have lipid-rich necrotic core (LRNC) and intraplaque hemorrhage, respectively. Furthermore, 45.8% of carotid arteries with 0-29% stenosis developed LRNCs. Carotid morphological measurements, such as % wall volume, and the LRNC size were significantly associated with ipsilateral ACIs volume before and after adjustment for significant demographic factors (age and LDL) or stenosis in patients with carotid plaque (all p<0.05)., Conclusions: A substantial number of high-risk plaques characterized by vessel wall imaging exist in carotid arteries with lower grade stenosis. In addition, carotid plaque characteristics, particularly the % wall volume and LRNC size, are independently associated with cerebral infarction as measured by DWI lesions. Our findings indicate that characterizing atherosclerotic plaque by MR vessel wall imaging might be useful for stratification of plaque risk and infarction severity., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Arterial distensibility is a marker that can measure vessel wall functional and structural changes resulting from atherosclerosis with applications including estimation of mechanical properties of the wall. We sought to assess the feasibility of using magnetic resonance imaging (MRI) to include wall distensibility in the characterization of atherosclerotic carotid arteries and to analyze the relationship between distensibility and morphological and compositional plaque features., Methods: Five healthy volunteers were imaged with a multiple-slice CINE MR sequence twice, within 24 h, to determine the interscan reproducibility of distensibility measurements. Twenty-one subjects with >15% carotid stenosis and the five healthy volunteers were imaged using a multicontrast carotid MRI protocol to characterize arterial wall morphology and composition. Normalized wall index (wall area∕total vessel area), maximum wall thickness and, if present, percentages of wall area occupied by calcification and lipid-rich necrotic core were determined. A multiple-slice CINE MR sequence was added to the multicontrast protocol to measure the distensibility coefficient (DC) at several locations spanning the bifurcation. The intraclass correlation coefficient (ICC) and the coefficient of variation were used to assess the reproducibility of DC measurements made on the healthy subjects. The DC was compared between arterial segments and between the healthy and diseased groups. Furthermore, within the diseased group, DC was correlated to plaque morphology and composition at each location as well as that averaged over the plaque., Results: Distensibility measurements were highly reproducible: ICC (95% confidence interval) was 0.998 (0.96-1.0) for the common carotid segment and 0.990 (0.92-1.0) for the internal carotid segment. In healthy volunteers, we found significantly higher distensibility in the common segment of the carotid artery compared to the internal carotid segment (mean ± SD = 4.56 ± 1.02 versus 3.56 ± 1.32 × 10(-5)∕Pa; p < 0.05). However, no segmental differences were seen in the diseased group (3.25 ± 1.84 versus 3.26 ± 1.60 × 10(-5)∕Pa; p = 0.607). Location-to-location changes in DC were not found to correlate to changes in the local plaque morphology or composition nor were average DC found to be associated with aggregate plaque features., Conclusions: These results demonstrate the feasibility of MRI to measure distensibility in the carotid artery and to presumably detect changes in distensibility due to age and∕or disease. The results suggest that the effect of atherosclerosis on local distensibility may not strongly depend upon the specific underlying plaque features in mild to moderate stenotic carotid lesions though more diffuse or nonlocal changes in arterial distensibility could not be ruled out.

Background: Carotid atherosclerotic ulceration is a significant source of stroke. This study evaluates the efficacy of adding longitudinal black-blood (BB) cardiovascular magnetic resonance (CMR) angiography to cross-sectional CMR images in the identification of carotid atherosclerotic ulceration., Methods: Thirty-two subjects (30 males and two females with ages between 48 and 83 years) scheduled for carotid endarterectomy were imaged on a 1.5T GE Signa scanner using multisequence [3D time-of-flight, T1, proton density, T2, contrast enhanced T1], cross-sectional CMR images and longitudinal BB CMR angiography (0.625 x 0.625 mm/pixel). Two rounds of review (round 1: cross-sectional CMR images alone and round 2: cross-sectional CMR images plus longitudinal BB CMR angiography) were conducted for the presence and volume measurements of ulceration. Ulceration was defined as a distinct depression into the plaque containing blood flow signal on cross-sectional CMR and longitudinal BB CMR angiography., Results: Of the 32 plaques examined by histology, 17 contained 21 ulcers. Using the longitudinal BB CMR angiography sequence in addition to the cross-sectional CMR images in round 2, the sensitivity improved to 80% for ulcers of at least 6 mm3 in volume by histology and 52.4% for all ulcers, compared to 30% and 23.8% in round 1, respectively. There was a slight decline in specificity from 88.2% to 82.3%, though both the positive and negative predictive values increased modestly from 71.4% to 78.6% and from 48.4% to 58.3%, respectively., Conclusion: The addition of longitudinal BB CMR angiography to multisequence cross-sectional CMR images increases accuracy in the identification of carotid atherosclerotic ulceration.

Stroke is a leading cause of long-term disability and is the third most common cause of death in the U.S. and western countries. Twenty percent of strokes are thought to arise from the carotid artery. Histopathological studies have suggested that plaque disruption is a key factor in the etiology of carotid-related ischemic events. Features associated with plaque disruption include intraplaque hemorrhage, large necrotic cores with thin overlying fibrous caps, plaque neovasculature, and inflammatory cell infiltrate. In vivo high-spatial-resolution, multicontrast-weighted cardiac magnetic resonance (CMR) has been extensively evaluated using histology as the gold standard, and has documented reliability in the identification of these key carotid plaque features. This pictorial essay illustrates the capability of CMR for identifying features of disruption-prone and disrupted atherosclerotic carotid plaques.

Background: Carotid intraplaque hemorrhage (IPH) and lipid rich necrotic core (LRNC) have been associated with accelerated plaque growth, luminal narrowing, future surface disruption and development of symptomatic events. The aim of this study was to evaluate the quantitative relationships between high intensity signals (HIS) in the plaque on TOF-MRA and IPH or LRNC volumes as measured by multicontrast weighted CMR. Methods: Seventy six patients with a suspected carotid artery stenosis or carotid plaque by ultrasonography underwent multicontrast carotid CMR. HIS presence and volume were measured from TOF-MRA MIP images while IPH and LRNC volumes were separately measured from multicontrast CMR. Results: For detecting IPH, HIS on MIP images overall had high specificity (100.0%, 95% CI: 93.0 - 100.0%) but relatively low sensitivity (32%, 95% CI: 20.8 - 47.9%). However, the sensitivity had a significant increasing relationship with underlying IPH volume (p = 0.033) and degree of stenosis (p = 0.022). Mean IPH volume was 2.7 times larger in those with presence of HIS than in those without (142.8 ± 97.7 mm3 vs. 53.4 ± 56.3 mm3, p = 0.014). Similarly, mean LRNC volume was 3.4 times larger in those with HIS present (379.8 ± 203.4 mm3 vs. 111.3 ± 122.7 mm3, p = 0.001). There was a strong correlation between the volume of the HIS region and the IPH volume measured from multicontrast CMR (r = 0.96, p < 0.001). Conclusion: MIP images are easily reformatted from three minute, routine, clinical TOF sequences. High intensity signals in carotid plaque on TOF-MRA MIP images are associated with increased intraplaque hemorrhage and lipid-rich necrotic core volumes. The technique is most sensitive in patients with moderate to severe stenosis. [ABSTRACT FROM AUTHOR]