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Background and Purpose: Atherosclerosis is a very complex process influenced by various systemic and local factors. Therefore, in patients with bilateral carotid plaques (BCPs), there may be differences in carotid plaque vulnerability between the sides. We aimed to investigate the differences in BCP characteristics in patients with BCPs using magnetic resonance vessel wall imaging (MR-VWI)., Methods: Participants with BCPs were selected for subanalysis from a multicentre study of Chinese Atherosclerosis Risk Evaluation II. We measured carotid plaque burden, identified each plaque component and measured their volume or area bilaterally on MR-VWI. Paired comparisons of the burden and components of BCPs were performed., Results: In all, 540 patients with BCPs were eligible for analysis. Compared with the right carotid artery (CA), larger mean lumen area (p<0.001), larger mean wall area (p=0.025), larger mean total vessel area (p<0.001) and smaller normalised wall index (p=0.006) were found in the left CA. Regarding plaque components, only the prevalence of lipid-rich necrotic core (LRNC) in the left CA was higher (p=0.026). For patients with a vulnerable plaque component coexisting on both sides, only the intraplaque haemorrhage (IPH) volume (p=0.011) was significantly greater in the left CA than in the right CA., Conclusions: There were asymmetries in plaque growth and evolution between BCPs. The left carotid plaques were more likely to have larger plaque burden, higher prevalence of LRNC and greater IPH volume, which may contribute to the lateralisation of ischaemic stroke in the cerebral hemispheres., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recent studies report that the rate of recurrent stroke is highest in the stages immediately following cerebral infarction and decreases over time in patients with atherosclerotic carotid stenosis. The purpose of this study was to identify temporal differences in early stage carotid plaque components from acute cerebrovascular ischemic events using carotid MRI. Carotid plaque images were obtained on 3 T MRI from 128 patients enrolled in MR-CAS. Among the 128 subjects, 53 were symptomatic and 75 asymptomatic. The symptomatic patients were classified into three groups based on interval from onset of symptoms to the date of the carotid MRI (Group <14 days; 15-30 days; and > 30 days). The volume of each plaque component was identified and quantified from MR images. The presence of juxtaluminal loose matrix/inflammation (LM/I) was identified as a possible indicator of inflammation on the luminal side. Plaque components were compared between groups using the Wilcoxon rank-sum or the Chi-square test. Patient characteristics and carotid plaque morphology were similar among all four groups. The median volume of LM/I in Group >30 days was significantly lower than in other groups (0 mm3 vs 12.3 mm3 and 18.1 mm3; p = 0.003). In addition, the prevalence of juxtaluminal LM/I decreased over time (ptrend = 0.002). There were no statistically significant differences in other plaque components between the symptomatic groups. The volume of LM/I was significantly smaller in Group >30 days and prevalence of juxtaluminal LM/I in the atherosclerotic carotid plaque was high in the early stages after events. This suggests that carotid plaques undergo rapid evolution after an acute cerebrovascular ischemic event., Competing Interests: Declaration of Competing Interest D.S. Hippe received research grants from GE Healthcare, Philips Healthcare, Toshiba America Medical Systems, and Siemens Medical Solutions. N. Balu received research grant from Philips Healthcare. T.S. Hatsukami received research grants from Philips Healthcare. C. Yuan received research grants from Philips Healthcare. All other authors have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Background: Intraplaque hemorrhage (IPH) is associated with plaque progression and ischemic events, and plaque lipid content (% lipid core) predicts the residual atherosclerotic cardiovascular disease risk. This study examined the impact of IPH on lipid content change in the setting of intensive lipid-lowering therapy., Methods: In total, 214 AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low High-Density Lipoprotein/High Triglycerides: Impact on Global Health Outcomes) participants with clinically established ASCVD and low high-density lipoprotein cholesterol received cartoid MRI at baseline and 2 years to assess changes in carotid morphology and composition. Patients were randomized to extended-release niacin or placebo, and all received simvastatin with optional ezetimibe as necessary to lower low-density lipoprotein cholesterol to 40 to 80 mg/dL. Changes in lipid content and carotid morphology were tested using the Wilcoxon signed-rank test. Differences between subjects with and without IPH and between subjects assigned extended-release niacin or placebo were tested using the Wilcoxon rank-sum test. Linear regression was used to test the association of IPH and lipid content changes after adjusting for clinical risk factors., Results: Among 156 patients (61±9 years; 81% men) with complete MRI, prior statin use: <1 year, 26%; 1 to 5 years, 37%; >5 years, 37%. Triglycerides and ApoB decreased significantly, whereas high-density lipoprotein cholesterol and ApoA1 increased significantly over time. Plaque lipid content was significantly reduced (-0.5±2.4 %/year, P = 0.017) without a significant difference between the 2 treatment groups. However, the lipid content increased in plaques with IPH but regressed in plaques without IPH (1.2±2.5 %/year versus -1.0±2.2, P = 0.006). Additionally, IPH was associated with a decrease in lumen area (-0.4±0.9 mm2/year versus 0.3±1.4, P = 0.033). IPH remained significantly associated with increase in lipid content in multivariable analysis (54.4%, 95% CI: 26.8, 88.0, P < 0.001)., Conclusions: Carotid plaques under continued intensive lipid-lowering therapy moved toward stabilization. However, plaques with IPH showed greater increases in lipid content and greater decreases in lumen area than plaques without IPH., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01178320.

Objectives: Non-stenotic plaques have been observed in intracranial arteries but are less understood compared to those in coronary and carotid arteries. We sought to compare plaque distribution and morphology between stenotic and non-stenotic intracranial plaques with MR vessel wall imaging (VWI) and quantitative image analysis., Materials and Methods: Twenty-four patients with intracranial arterial stenosis or luminal irregularity on clinical imaging were scanned with a multi-contrast VWI protocol. Plaques were detected as focal wall thickening on co-registered multiplanar reformats of multi-contrast VWI, with assessment of the location and morphology. TOF-MRA was independently reviewed for any appreciable stenosis using the WAISD criteria., Results: Across 504 arterial segments, a total of 80 plaques were detected, including 23 (29%) with stenosis on TOF-MRA, 56 (70%) without, and 1 (1%) not covered by TOF-MRA. Plaques involving the ICA were more likely to be non-stenotic than those involving other segments (80% versus 55%, p = 0.030) whereas the basilar artery (40%) and PCA (33%) had the lowest proportions of non-stenotic plaques. Maximum wall thickness, indicative of plaque burden, correlated poorly with degree of stenosis (p = 0.10) and overlapped substantially between stenotic and non-stenotic plaques (1.9 [1.5, 2.4] versus 2.0 [1.5, 2.2] mm, p = 0.074)., Conclusions: Intracranial plaques without appreciable stenosis on TOF-MRA represent a large proportion of lesions throughout arterial segments but disproportionately affect the ICA. Morphological characterization of plaques with and without stenosis shows that luminal stenosis is a poor indicator of the underlying burden of intracranial atherosclerosis., Competing Interests: Declarations of Competing Interest All authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce cardiovascular events, but their effects on atherosclerotic plaque remain elusive. Using serial magnetic resonance imaging (MRI), we studied changes in carotid plaque lipid content and neovasculature under PCSK9 inhibition with alirocumab., Methods: Among patients with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl but ineligible for high-dose statin therapy, those with lipid core on carotid MRI were identified to receive alirocumab 150 mg every 2 weeks. Follow-up MRI was performed at 3, 6, and 12 months after treatment. Pre- and post-contrast MRI were acquired to measure percent lipid core volume (% lipid core). Dynamic contrast-enhanced MRI was acquired to measure the extravasation rate of gadolinium contrast (K trans ), a marker of plaque neovasculature., Results: Of 31 patients enrolled, 27 completed the study (mean age: 69 ± 9; male: 67%). From 9.8% at baseline, % lipid core was progressively reduced to 8.4% at 3 months, 7.5% at 6 months, and 7.2% at 12 months (p = 0.014 for trend), which was accompanied by a progressive increase in % fibrous tissue (p = 0.009) but not % calcification (p = 0.35). K trans was not reduced until 12 months (from 0.069 ± 0.019 min -1 to 0.058 ± 0.020 min -1 ; p = 0.029). Lumen and wall areas did not change significantly during the study period., Conclusions: Regression in plaque composition and neovasculature were observed under PCSK9 inhibition on carotid MRI, which provides unique insight into the biological process of plaque stabilization with disease-modifying therapies., (Copyright © 2021 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: While extracranial carotid artery stenosis is more common among Caucasians and intracranial artery stenosis is more common among Asians, the differences in atherosclerotic plaque characteristics have not yet been extensively examined. We sought to investigate plaque location and characteristics within extracranial carotid and intracranial arteries in symptomatic Caucasians and Chinese using vessel wall MRI., Methods: Subjects with recent anterior circulation ischaemic stroke were recruited and imaged at two sites in the USA and China using similar protocols. Both extracranial carotid and intracranial arteries were reviewed to determine plaque location and characteristics., Results: The prevalence of extracranial carotid plaque in Caucasians and Chinese was 73.1% and 49.1%, respectively (p=0.055). Prevalence of intracranial plaque was 38.5% and 69.1% in Caucasians and Chinese, respectively (p=0.02). Furthermore, 42% of Caucasians and 16% of Chinese had high-risk plaque (HRP) features (intraplaque haemorrhage, luminal surface disruption) in the extracranial carotid artery (p=0.03). The prevalence of HRP features in intracranial arteries was not significantly different between the two cohorts (4% vs 11%; p=0.42)., Conclusions: Differences in the location and characteristics of cerebrovascular atherosclerosis were identified by vessel wall MRI in US Caucasian and Chinese subjects with recent anterior circulation ischaemic stroke. Extracranial carotid plaques with HRP features were more common in Caucasians. Intracranial plaques were more common in Chinese subjects, but no significant difference between the two cohorts in intracranial HRP prevalence was found. Larger studies using vessel wall imaging to investigate racial differences in cerebrovascular disease may inform underlying mechanisms of HRP development and may ultimately help guide appropriate therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine the bilaterally asymmetrical associations between extracranial carotid artery atherosclerosis and ipsilateral middle cerebral artery (MCA) stenosis in symptomatic patients using magnetic resonance vessel wall imaging. Approach and Results: Patients with symptomatic carotid artery atherosclerosis were recruited from the Chinese Atherosclerosis Risk Evaluation, a multicenter study. All subjects underwent intracranial magnetic resonance angiography and extracranial carotid artery magnetic resonance imaging. Severe stenosis (stenosis ≥50%) of MCA, carotid moderate-to-severe stenosis (stenosis ≥50%), plaque compositions, and high-risk plaque on symptomatic side were evaluated in all subjects. Associations between ipsilateral MCA stenosis and extracranial carotid plaque features were evaluated. A total of 363 patients (mean age: 61.2±10.4 years old; 254 males) were included. In the left symptomatic cerebrovascular group (n=186), carotid moderate-to-severe stenosis (odds ratio [OR], 3.00 [95% CI, 1.03-8.79]; P =0.045), intraplaque hemorrhage (OR, 3.68 [95% CI, 1.21-11.19]; P =0.021), fibrous cap rupture (OR, 5.70 [95% CI, 1.60-20.31]; P =0.007), and high-risk plaque (OR, 2.95 [95% CI, 1.19-7.35]; P =0.020) were significantly associated with ipsilateral severe MCA stenosis, after adjusting for confounding factors. In the right symptomatic cerebrovascular group (n=177), severe MCA stenosis was significantly associated with ipsilateral carotid moderate-to-severe stenosis (OR, 3.98 [95% CI, 1.54-10.32]; P =0.004) but not with other extracranial carotid plaque features (all P >0.05), after adjusting for confounding factors., Conclusions: In the symptomatic arteries, vulnerable plaque features are independently associated with ipsilateral severe MCA stenosis on the left side, but this association is not found on the right side, indicating the associations of atherosclerotic disease between intracranial and extracranial carotid arteries are asymmetrical.

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.)

Background: 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., Purpose: To develop a semiautomatic method to measure carotid IPH volume., Study Type: Retrospective., Population: Patients scheduled for carotid endarterectomy and patients with 16-79% asymptomatic carotid stenosis by ultrasound., Field Strength: 3T., Sequence: Simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP) MRI., Assessment: 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)., Statistical Tests: Receiver operating characteristic curve, area under the curve, Cohen's kappa, intraclass correlation coefficient, coefficient of variance (CV), and paired t-test., Results: 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%., Data Conclusion: 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., (© 2019 International Society for Magnetic Resonance in Medicine.)

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: 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.)

Little is known about the prognostic significance of specific characteristics of magnetic resonance imaging (MRI) measured plaque in the superficial femoral artery (SFA). Associations of MRI-measured plaque quantity, lumen area, and plaque composition in the SFA with subsequent mobility loss were studied in people with lower extremity peripheral artery disease (PAD). Participants with an ankle-brachial index (ABI) < 1.00 were identified from Chicago medical centers and underwent direct visualization of atherosclerotic plaque in the SFA using MRI. Participants were followed annually for up to 4 years. Mobility loss was defined as becoming unable to walk up and down a flight of stairs or walk one-quarter of a mile without assistance among participants without mobility impairment at baseline. Analyses adjusted for age, sex, race, comorbidities, ABI, physical activity, and other confounders. Of 308 PAD participants without baseline mobility impairment, 100 (32.5%) developed mobility loss during follow-up. Compared to the lowest mean plaque area tertile at baseline, participants in the highest (worst) plaque area tertile had a higher rate of mobility loss (hazard ratio (HR) = 2.08, 95% confidence interval (CI) = 1.14-3.79, p = 0.018). Compared to the highest mean lumen area tertile, the smallest (worst) mean lumen area tertile was associated with greater mobility loss (HR = 2.18, 95% CI = 1.20-3.96, p = 0.011). Neither lipid rich necrotic core nor calcium in the SFA were associated with mobility loss. In conclusion, greater plaque quantity and smaller lumen area in the proximal SFA, but not lipid rich necrotic core or calcium, were associated with higher mobility loss in people with PAD.

Objectives: The aim of this study was to describe associations of the presence of lipid-rich necrotic core (LRNC) in the proximal superficial femoral artery (SFA) with lower extremity peripheral artery disease (PAD) event rates and systemic cardiovascular event rates., Background: LRNC in the coronary and carotid arteries is associated with adverse outcomes but has not been studied previously in lower extremity arteries., Methods: Participants with ankle-brachial index (ABI) values <1.00 were identified from Chicago medical centers and followed annually. Magnetic resonance imaging was used to characterize SFA atherosclerotic plaque at baseline. Medical records for hospitalizations and procedures after baseline were adjudicated for lower extremity revascularization, amputation, and critical limb ischemia and also for new coronary events, ischemic stroke, and mortality., Results: Of 254 participants with PAD, 62 (24%) had LRNC and 149 (59%) had calcium in the SFA at baseline. Cox regression analyses were adjusted for age, sex, race, comorbidities, baseline ABI, and other confounders. SFA LRNC was associated with an increased incidence of the combined outcome of lower extremity amputation, critical limb ischemia, ABI decline >0.15, and revascularization at 47-month follow-up (hazard ratio: 2.18; 95% confidence interval: 1.27 to 3.75; p = 0.005). The association of SFA LRNC with PAD events was maintained even when this combined outcome excluded lower extremity revascularization (hazard ratio: 2.58; 95% confidence interval: 1.25 to 5.33; p = 0.01). LRNC in the SFA was not associated with all-cause mortality, acute coronary events, or stroke., Conclusions: Among patients with PAD, LRNC in the SFA was associated with higher rates of clinical PAD events, and this association was independent of ABI. Further study is needed to determine whether interventions that reduce SFA LRNC prevent PAD events., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Carotid atherosclerotic plaque rupture is an important source of ischemic stroke. However, the prevalence of high-risk plaque (HRP) defined as plaques with luminal surface disruption, a lipid-rich necrotic core occupying >40% of the wall, or intraplaque hemorrhage in Chinese population remains unclear. This study uses carotid magnetic resonance imaging (CMRI) to investigate HRP prevalence in carotid arteries of Chinese patients with cerebrovascular symptoms., Methods and Results: Patients with cerebral ischemic symptoms in the anterior circulation within 2 weeks and carotid plaque determined by ultrasound were recruited and underwent CMRI. The HRP features were identified and compared between symptomatic and asymptomatic arteries. Receiver-operating-characteristic analysis was used to calculate area-under-the-curve (AUC) of stenosis and maximum wall thickness for discriminating presence of HRP. In 1047 recruited subjects, HRP detected by CMRI was nearly 1.5 times more prevalent than severe stenosis (≥50%) in this cohort (28% versus 19%, P <0.0001). Approximately two thirds of HRPs were found in arteries with <50% stenosis. The prevalence of HRP in symptomatic carotid arteries was significantly higher than that of the contralateral asymptomatic carotid arteries (23.0% versus 16.4%, P =0.001). Maximum wall thickness was found to be a stronger discriminator than stenosis for HRP (AUC: 0.93 versus 0.81, P <0.0001)., Conclusions: There are significantly more high-risk carotid plaques than carotid arteries with ≥50% stenosis in symptomatic Chinese patients. A substantial number of HRPs were found in arteries with lower grade stenosis and maximum wall thickness was a stronger indicator for HRP than luminal stenosis., Clinical Trial Registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02017756., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

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: Prospective studies have shown a strong association between carotid intraplaque hemorrhage (IPH), detected by magnetic resonance imaging (MRI), and cerebrovascular ischemic events. However, IPH is also observed in a substantial number of asymptomatic patients. We hypothesized that there are differences in the characteristics of IPH+ plaques associated with recent symptoms, compared to IPH+ plaques not associated with recent symptoms., Methods: Patients with recent (≤2 weeks) anterior circulation ischemic events were scanned using a standardized multisequence protocol. Those showing IPH bilaterally were included and analyzed for differences in T1/T2 signals, plaque morphology, and coexisting plaque characteristics between the ipsilateral symptomatic and contralateral asymptomatic sides., Results: Thirty-one subjects (67 ± 9 years, 97% males) with bilateral IPH were studied. Despite comparable luminal stenosis (53 ± 42% vs. 53 ± 39%, p = 0.99), T1 signal of IPH measured as signal-intensity-ratio compared to muscle was stronger (SIR IPH-to-muscle : 5.8 ± 2.4 vs. 4.7 ± 1.8, p = 0.004) and tended to be more extensively distributed (IPH volume: 150 ± 199 vs. 88 ± 106 mm 3 , p = 0.071) on the symptomatic side. IPH+ plaques on the symptomatic side were longer (24 ± 6 vs. 21 ± 7 mm, p = 0.026) and associated with larger necrotic core volume (406 ± 354 vs. 291 ± 293 mm 3 , p = 0.039) than those on the asymptomatic side., Conclusions: In recently symptomatic patients with bilateral carotid IPH, the symptomatic side showed stronger T1 signals, larger necrotic cores, and longer plaque length than the asymptomatic side. Serial studies on the temporal relationship between these imaging features and clinical events will eventually establish their diagnostic and prognostic value beyond the mere presence of IPH., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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.

Objective: Effective prevention and management strategies of intraplaque hemorrhage (IPH) remain elusive because of our limited knowledge regarding its contributing factors. This hypothesis-generating study aimed to investigate associations between cardiovascular risk factors and IPH for improved understanding of the pathogenesis of IPH., Approach and Results: Asymptomatic subjects with 16% to 79% stenosis on ultrasound underwent carotid magnetic resonance imaging using a large-coverage, 3-dimensional magnetic resonance imaging protocol. Individual plaques (maximum thickness >1.5 mm) in bilateral carotid arteries were identified, and presence of IPH was determined. From 80 subjects, 176 de novo plaques were measured, of which 38 (21.6%) contained IPH. Blood pressure (BP), primarily low diastolic BP, was associated with IPH in multivariate analysis adjusted for age, sex, and plaque size (odds ratio with 95% confidence interval per 10-mm Hg increase: 0.51 [0.30-0.88]), which was little changed after adjusting for antihypertensive use and systemic atherosclerosis. Antiplatelet use was associated with IPH in age and sex-adjusted models (P=0.018), for which a trend remained after considering plaque size and past medical history (odds ratio for aspirin alone versus none: 3.1 [0.66-14.8]; odds ratio for clopidogrel or dual therapy versus none: 5.3 [0.80-35.0]; P=0.083)., Conclusions: Low diastolic BP was independently associated with IPH, which was not attributed to treatment difference or BP changes from systemic atherosclerosis. Hemodynamic changes from lowering diastolic BP may be the pathophysiological link. Prospective serial studies are needed to assess whether BP and antiplatelet use are associated with the development of new or repeated IPH., (© 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.

Automatic in vivo segmentation of multicontrast (multisequence) carotid magnetic resonance for plaque composition has been proposed as a substitute for manual review to save time and reduce inter-reader variability in large-scale or multicenter studies. Using serial images from a prospective longitudinal study, we sought to compare a semi-automatic approach versus expert human reading in analyzing carotid atherosclerosis progression. Baseline and 6-month follow-up multicontrast carotid images from 59 asymptomatic subjects with 16-79 % carotid stenosis were reviewed by both trained radiologists with 2-4 years of specialized experience in carotid plaque characterization with MRI and a previously reported automatic atherosclerotic plaque segmentation algorithm, referred to as morphology-enhanced probabilistic plaque segmentation (MEPPS). Agreement on measurements from individual time points, as well as on compositional changes, was assessed using the intraclass correlation coefficient (ICC). There was good agreement between manual and MEPPS reviews on individual time points for calcification (CA) (area: ICC; 0.85-0.91; volume: ICC; 0.92-0.95) and lipid-rich necrotic core (LRNC) (area: ICC; 0.78-0.82; volume: ICC; 0.84-0.86). For compositional changes, agreement was good for CA volume change (ICC; 0.78) and moderate for LRNC volume change (ICC; 0.49). Factors associated with LRNC progression as detected by MEPPS review included intraplaque hemorrhage (positive association) and reduction in low-density lipoprotein cholesterol (negative association), which were consistent with previous findings from manual review. Automatic classifier for plaque composition produced results similar to expert manual review in a prospective serial MRI study of carotid atherosclerosis progression. Such automatic classification tools may be beneficial in large-scale multicenter studies by reducing image analysis time and avoiding bias between human reviewers.

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.

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.

Objectives: The goal of this prospective study was to evaluate the carotid atherosclerosis score (CAS) for predicting the development of high-risk plaque features and plaque burden progression., Background: Previous studies have shown that carotid intraplaque hemorrhage (IPH) and a disrupted luminal surface (DLS), as identified by using magnetic resonance imaging, are associated with greater risk for cerebrovascular events. On the basis of data from a large cross-sectional study, a scoring system was developed to determine which plaque features are associated with the presence of IPH and DLS. However, the predictive value of CAS has not been previously tested in a prospective, longitudinal study., Methods: A total of 120 asymptomatic subjects with 50% to 79% carotid stenosis underwent carotid magnetic resonance imaging scans at baseline and 3 years thereafter. Presence of IPH and DLS, wall volume, maximum wall thickness, and maximum percent lipid-rich necrotic core area were measured at both time-points. Baseline CAS values were calculated on the basis of previously published criteria., Results: Of the 73 subjects without IPH or DLS at baseline, 9 (12%) developed 1 or both of these features during follow-up. There was a significant increasing trend between CAS and the development of new DLS (p < 0.001) and with plaque burden progression (p = 0.03) but not with the development of new IPH (p = 0.3). Percent carotid stenosis was not significantly associated with new DLS (p = 0.2), new IPH (p = 0.1), or plaque progression (p = 0.6)., Conclusions: CAS was found to have a significant increasing relationship with incident DLS and plaque progression in this prospective study. CAS can potentially provide improved risk stratification beyond luminal stenosis., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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 mm(3) vs. 53.4 ± 56.3 mm(3), p = 0.014). Similarly, mean LRNC volume was 3.4 times larger in those with HIS present (379.8 ± 203.4 mm(3) vs. 111.3 ± 122.7 mm(3), 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.

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.