Lipid-rich Necrotic Core Volume Research Articles

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

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

Vulnerable carotid plaque characteristics on magnetic resonance vessel wall imaging: potential predictors for hemodynamic instability during carotid artery stenting.

This cross-sectional study sought to explore the possible risk factors assessed with magnetic resonance (MR) vessel wall imaging for hemodynamic instability (HI) during carotid artery stenting (CAS). Patients with carotid stenosis who were referred for CAS from January 2017 to December 2019 were recruited and underwent carotid MR vessel wall imaging. The vulnerable plaque features, including lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), fibrous cap rupture, and plaque morphology, were evaluated. The HI was defined as a drop of systolic blood pressure (SBP) of ≥30 mmHg or the lowest SBP measurement of <90 mmHg after stent implantation. The carotid plaque characteristics were compared between the HI and non-HI groups. The association between carotid plaque characteristics and HI was analyzed. A total of 56 participants (mean age 68.7±8.3 years; 44 males) were recruited. Patients in the HI group (n=26, 46%) had a significantly greater wall area [median 43.2 (IQR, 34.9-50.5) vs. 35.9 (IQR, 32.3-39.4) mm2; P=0.008], total vessel area (79.7±17.2 vs. 69.9±17.3 mm2; P=0.03), prevalence of IPH (62% vs. 30%; P=0.02), prevalence of vulnerable plaque (77% vs. 43%; P=0.01), and volume of LRNC [median 344.7 (IQR, 155.1-665.7) vs. 103.1 (IQR, 53.9-162.9) mm3; P=0.001] in carotid plaque compared to those in non-HI group (n=30, 54%). Carotid LRNC volume (OR =1.005, 95% CI: 1.001-1.009; P=0.01) and presence of vulnerable plaque (OR =4.038, 95% CI: 0.955-17.070; P=0.06) were significantly and marginally associated with HI, respectively. Carotid plaque burden and vulnerable plaque features, particularly a larger LRNC, might be effective predictors for HI during the CAS procedure.

Association of Circulating Neutrophils with Relative Volume of Lipid-Rich Necrotic Core of Coronary Plaques in Stable Patients: A Substudy of SMARTool European Project

Coronary atherosclerosis is a chronic non-resolving inflammatory process wherein the interaction of innate immune cells and platelets plays a major role. Circulating neutrophils, in particular, adhere to the activated endothelium and migrate into the vascular wall, promoting monocyte recruitment and influencing plaque phenotype and stability at all stages of its evolution. We aimed to evaluate, by flow cytometry, if blood neutrophil number and phenotype-including their phenotypic relationships with platelets, monocytes and lymphocytes-have an association with lipid-rich necrotic core volume (LRNCV), a generic index of coronary plaque vulnerability, in a group of stable patients with chronic coronary syndrome (CCS). In 55 patients, (68.53 ± 1.07 years of age, mean ± SEM; 71% male), the total LRNCV in each subject was assessed by a quantitative analysis of all coronary plaques detected by computed tomography coronary angiography (CTCA) and was normalized to the total plaque volume. The expression of CD14, CD16, CD18, CD11b, HLA-DR, CD163, CCR2, CCR5, CX3CR1, CXCR4 and CD41a cell surface markers was quantified by flow cytometry. Adhesion molecules, cytokines and chemokines, as well as MMP9 plasma levels, were measured by ELISA. On a per-patient basis, LRNCV values were positively associated, by a multiple regression analysis, with the neutrophil count (n°/µL) (p = 0.02), neutrophil/lymphocyte ratio (p = 0.007), neutrophil/platelet ratio (p = 0.01), neutrophil RFI CD11b expression (p = 0.02) and neutrophil-platelet adhesion index (p = 0.01). Significantly positive multiple regression associations of LRNCV values with phenotypic ratios between neutrophil RFI CD11b expression and several lymphocyte and monocyte surface markers were also observed. In the bivariate correlation analysis, a significantly positive association was found between RFI values of neutrophil-CD41a+ complexes and neutrophil RFI CD11b expression (p < 0.0001). These preliminary findings suggest that a sustained increase in circulating neutrophils, together with the up-regulation of the integrin/activation membrane neutrophil marker CD11b may contribute, through the progressive intra-plaque accumulation of necrotic/apoptotic cells exceeding the efferocytosis/anti-inflammatory capacity of infiltrating macrophages and lymphocytes, to the relative enlargement of the lipid-rich necrotic core volume of coronary plaques in stable CAD patients, thus increasing their individual risk of acute complication.

Differences in left and right carotid plaque vulnerability in patients with bilateral carotid plaques: a CARE-II study

Background and purposeAtherosclerosis 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...

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

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

Effects of alirocumab on carotid plaque lipid content and inflammation: a time course study using serial vessel wall imaging

Abstract Background PCSK9 inhibition has emerged as a potent pharmaceutical approach to lowering LDL cholesterol (LDL-C). Monoclonal anti-PCSK9 antibodies have been shown in recent clinical trials to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease, but the underlying mechanisms are not fully understood. Meanwhile, circulatory inflammation markers were not reduced with PCSK9 inhibitors, thus their effects on plaque inflammation remain elusive. Vessel wall imaging with magnetic resonance (VW-MRI) has enabled serial monitoring of changes in carotid plaque lipid content and inflammation noninvasively that correlates with coronary and carotid vascular events. Purpose Using serial VW-MRI, we studied the effects and time course of PCSK9 inhibition with alirocumab on carotid plaque lipid content and inflammation. Methods Patients with LDL-C ≥70 mg/dl on ≤70 mg per week atorvastatin or an equivalent (due to statin intolerance or treating-physician discretion) and soft carotid plaque(s) identified on ultrasound underwent carotid VW-MRI. Those with confirmed lipid-rich plaque(s) on VW-MRI received alirocumab (150 mg subcutaneously every other week) and were re-scanned at 3, 6, and 12 months after treatment. Carotid VW-MRI included pre- and post-contrast images for measuring percent lipid-rich necrotic core volume (%LRNC) and dynamic contrast-enhanced images for measuring the extravasation rate of gadolinium contrast (Ktrans, reflecting tissue blood flow, endothelial surface area, and microvessel permeability), a marker of plaque inflammation. The co-primary endpoints were changes in %LRNC and Ktrans at 12 months from baseline. Results Of 31 patients enrolled, 27 completed the study (mean age: 69±9; male: 67%; on statins and/or ezetimibe: 41%; median LDL-C: 120 mg/dl [interquartile range: 99, 158]). Alirocumab induced a 59% reduction in LDL-C (p&amp;lt;0.001) on average at 3 months to a median of 54 mg/dl (interquartile range: 29, 69), which was maintained at later time points. From 9.8% at baseline, %LRNC was progressively reduced to 8.4% at 3 months, 7.5% at 6 months, and 7.2% at 12 months, representing a rapid 14% reduction (p=0.032) at 3 months and a total reduction of 20% (p=0.019) at 12 months. From 0.07±0.02 min-1 at baseline, Ktrans was not reduced at 3 or 6 months but was significantly reduced by 17% (p=0.029) at 12 months to 0.06±0.02 min-1. No significant changes in lumen or wall area were observed during the study period. Conclusions Serial VW-MRI documented plaque-stabilizing effects of PCSK9 inhibition with alirocumab, including plaque delipidation and attenuation of plaque inflammation. The reduction in plaque lipid content was apparent as early as 3 months. The reduction in Ktrans was not seen until 12 months of treatment and may indicate a later effect on microvascular structure and/or function. This observation represents the earliest time course of plaque morphology modification by non-statin therapy reported to date. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): The study was funded by an investigator-initiated grant from Regeneron and Sanofi.

Automated plaque analysis for the prognostication of major adverse cardiac events

ObjectiveThe purpose of this study is to assess the value of an automated model-based plaque characterization tool for the prediction of major adverse cardiac events (MACE). MethodsWe retrospectively included 45 patients with suspected coronary artery disease of which 16 (33%) experienced MACE within 12 months. Commercially available plaque quantification software was used to automatically extract quantitative plaque morphology: lumen area, wall area, stenosis percentage, wall thickness, plaque burden, remodeling ratio, calcified area, lipid rich necrotic core (LRNC) area and matrix area. The measurements were performed at all cross sections, spaced at 0.5 mm, based on fully 3D segmentations of lumen, wall, and each tissue type. Discriminatory power of these markers and traditional risk factors for predicting MACE were assessed. ResultsRegression analysis using clinical risk factors only resulted in a prognostic accuracy of 63% with a corresponding area under the curve (AUC) of 0.587. Based on our plaque morphology analysis, minimal cap thickness, lesion length, LRNC volume, maximal wall area/thickness, the remodeling ratio, and the calcium volume were included into our prognostic model as parameters. The use of morphologic features alone resulted in an increased accuracy of 77% with an AUC of 0.94. Combining both clinical risk factors and morphological features in a multivariate logistic regression analysis increased the accuracy to 87% with a similar AUC of 0.924. ConclusionAn automated model based algorithm to evaluate CCTA-derived plaque features and quantify morphological features of atherosclerotic plaque increases the ability for MACE prognostication significantly compared to the use of clinical risk factors alone.

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

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

Size of carotid artery intraplaque hemorrhage and acute ischemic stroke: a cardiovascular magnetic resonance Chinese atherosclerosis risk evaluation study

BackgroundTo determine the usefulness of the size of carotid artery intraplaque hemorrhage (IPH) in discriminating the risk of acute ischemic stroke using cardiovascular magnetic resonance (CMR) vessel wall imaging.MethodsSymptomatic patients with carotid atherosclerotic plaque who participated in a cross-sectional, multicenter study of CARE-II (NCT02017756) were included. All patients underwent carotid and brain CMR imaging. Carotid plaque burden and the size of plaque compositions including calcification, lipid-rich necrotic core (LRNC), and IPH were measured. Presence of acute cerebral infarct (ACI) in ipsilateral hemisphere of carotid plaque was determined. The relationship between carotid plaque features and presence of ipsilateral ACI was then analyzed.ResultsOf 687 recruited patients (62.7 ± 10.1 years; 69.4% males) with carotid plaque, 28.5% had ACI in ipsilateral hemispheres. Logistic regression revealed that carotid plaque burden was significantly associated with the presence of ACI before and after adjusted for clinical confounding factors. The volume of LRNC, %LRNC volume, volume of IPH, and %IPH volume were significantly associated with ACI before (volume of LRNC: OR = 1.297, p = 0.005; %LRNC volume: OR = 1.119, p = 0.018; volume of IPH: OR = 2.514, p = 0.003; %IPH volume: OR = 2.202, p = 0.003) and after (volume of LRNC: OR = 1.312, p = 0.006; %LRNC volume: OR = 1.90, p = 0.034; volume of IPH: OR = 2.907, p = 0.007; % IPH volume: OR = 2.374, p = 0.004) adjusted for clinical confounding factors. The association between volume of IPH and ACI remained statistically significant after further adjusted for plaque volume (OR = 2.813, p = 0.016) or both plaque volume and volume of LRNC (OR = 4.044, p = 0.024).ConclusionsIn symptomatic patients with carotid atherosclerotic plaques, the size of IPH is independently associated with ipsilateral ACI, suggesting the size of IPH might be a useful indicator for the risk of ACI.Trial registrationClinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique Identifier: NCT02017756.

Abstract 17054: Sex-Related Differences in Atherosclerosis Burden and Composition Evaluated by Magnetic Resonance: A Complex Interaction Between Visceral Adiposity and Atherogenic Lipoproteins

Introduction: Visceral adiposity increases the level of atherogenic lipoproteins and is linked to sex-related differences in cardiovascular risk. Hypothesis. Atherogenic lipoproteins could mediate the relationship between visceral fat and sex-related differences in atherosclerosis burden and composition, including the lipid-rich necrotic core (LRNC). Methods: This study included 294 women (39.4 ± 15.0 years) and 324 men (39.5 ± 13.8 years), matched for age and risk factors (hypertension, dyslipidemia, obesity, diabetes, smoking). Carotid atherosclerosis, visceral abdominal fat (VAT) and cardiac fat (CAT) were studied by magnetic resonance imaging. Results: For similar age and risk profile, women had less VAT ( p &lt;0.001) and CAT ( p &lt;0.001) than men. Carotid atherosclerosis prevalence ( p &lt;0.001) and carotid wall volume ( p &lt;0.001) were higher in men. Although LRNC prevalence was similar in women and men ( p =0.23), men had a greater LRNC volume ( p &lt;0.001). An interaction was observed between waist-to-hip ratio (WHR) and sex on LRNC volume ( p =0.025). There was also an interaction between sex, VAT, and total cholesterol/high-density lipoprotein cholesterol ratio (TC/HDL-C) on LRNC volume ( p =0.012), beyond age and risk factors ( p =0.011). Only 8.6% of men and none of the women were classified at high risk (presence of LRNC) by the Framingham Risk Score while 35.4% of men and 14.0% of women were classified at high risk by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) risk score (risk of advanced atherosclerosis). Elevated TC/HDL-C (≥3) and/or WHR (≥0.8 in women, ≥0.9 in men) were superior to the PDAY risk score, identifying 62.2% of women (Net Reclassification Improvement [NRI]=1.85, p &lt;0.001) and 79.3% of men (NRI=0.26, p &lt;0.001) with LRNC. Conclusions: Women had less visceral adiposity, carotid atherosclerosis burden and LRNC volume, independently of age and risk profile. Carotid LRNC volume varied with sex, VAT, and atherogenic lipoproteins. WHR and TC/HDL-C improved the identification of high-risk carotid atherosclerosis features in women as well as men. This evidence supports the clinical potential of the atherogenic lipoprotein profile and of adiposity distribution in atherosclerosis risk evaluation of both women and men.

Hypertriglyceridemic Waist: A Simple Marker of High-Risk Atherosclerosis Features Associated With Excess Visceral Adiposity/Ectopic Fat.

BackgroundSubclinical atherosclerosis identification remains challenging; abdominal visceral adiposity may improve risk stratification beyond traditional cardiovascular risk factors. Hypertriglyceridemic waist, a visceral adiposity marker combining elevated triglycerides (≥2 mmol/L) and waist circumference (≥90 cm), has been related to carotid atherosclerosis, although associations with high‐risk features, including lipid‐rich necrotic core (LRNC), remain unknown. We tested the hypothesis that hypertriglyceridemic waist is an independent marker of high‐risk atherosclerosis features.Methods and ResultsIn this cross‐sectional study including 467 white men (mean age, 45.9±14.8 years; range 19.4–77.6 years), carotid atherosclerosis characteristics were examined by magnetic resonance imaging and associations with hypertriglyceridemic waist and benefits beyond Framingham Risk Score (FRS) and Pathobiological Determinants of Atherosclerosis in Youth (PDAY) were determined. Subclinical carotid atherosclerosis was present in 61.9% of participants, whereas 50.1% had LRNC. Hypertriglyceridemic waist was associated with carotid maximum wall thickness (P=0.014), wall volume (P=0.025), normalized wall index (P=0.004), and Carotid Atherosclerosis Score (derived from wall thickness and LRNC; P=0.049). Hypertriglyceridemic waist was associated with carotid LRNC volume beyond FRS (P=0.037) or PDAY (P=0.015), contrary to waist circumference alone (both P>0.05). Although 69.7% and 62.0% of participants with carotid atherosclerosis and/or LRNC were not high‐risk by FRS or PDAY, respectively, hypertriglyceridemic waist correctly reclassified 9.7% and 4.5% of them, respectively. Combining hypertriglyceridemic waist with FRS (net reclassification improvement=0.17; P<0.001) or PDAY (net reclassification improvement=0.05; P=0.003) was superior to each score alone in identifying individuals with carotid atherosclerosis and/or LRNC.ConclusionsHypertriglyceridemic waist is an independent marker of carotid high‐risk atherosclerosis features in men, improving on FRS and PDAY risk score.

Abstract 65: Magnetic Resonance Plaque Imaging Before Carotid Artery Stenting (MR-CAS) Study: Initial Results

Background: Carotid artery stenting (CAS) has recently emerged as a potential alternative to carotid endarterectomy. A major disadvantage of CAS is the high incidence of periprocrdural cerebral embolization. Previous studies suggested carotid plaque composition as lesion-specific risk factors for cerebral embolization during CAS, yet prospective studies are lacking. Magnetic resonance imaging (MRI) is a validated, noninvasive technique that affords quantitative analysis of carotid plaque tissue composition. MR-CAS is a prospective multicenter observational study to test the hypothesis that carotid plaque characteristics evaluated by pre-surgical MRI predict ischemic complications after CAS. Materials and Methods: We enrolled 128 arteries which underwent CAS. Multicontrast MRI was performed prior to CAS. Quantitative analysis of carotid plaque composition was done blinded to clinical information, including measures of intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), and calcification. Pre- and post-CAS diffusion weighted (DW) MRI were performed to detect new cerebral infarction after CAS. New ischemic symptoms within 30 days after CAS were also recorded. Associations between quantitative measures of plaque composition and new ischemic lesions on DW-MRI and new ischemic symptoms were evaluated. Results: Fifty arteries (39%) had new DW-MRI positive lesions in the ipsilateral carotid territory after CAS. Five patients (3.9%) developed new ischemic symptoms within 30 days after CAS. There were no significant differences in IPH volume or LRNC volume between the groups with and without ipsilateral DW-MRI positive lesions (IPH: 42 mm 3 [95%CI: 0-1140] vs. 20 mm 3 [0-804] p=0.55, LRNC: 240 mm 3 [0-1606] vs. 312 mm 3 [0-1374] p=0.76). However, IPH and LRNC volume were significantly larger in the patients with new ischemic symptoms after CAS than those without (IPH: 323 mm 3 [95%CI: 18-478] vs. 22 mm 3 [0-1140] p=0.009, LRNC: 501 mm 3 [392-1185] vs. 261 mm 3 [0-1606] p=0.013). Conclusions: Quantitative measures of carotid plaque composition predicted new ischemic symptoms after CAS but not new DW-MRI.

What We Have Learned from the Recent Meta-analyses on Diagnostic Methods for Atherosclerotic Plaque Regression.

Atherosclerosis has major morbidity and mortality implications globally. While it has often been considered an irreversible degenerative process, recent evidence provides compelling proof that atherosclerosis can be reversed. Plaque regression is however difficult to appraise and quantify, with competing diagnostic methods available. Given the potential of evidence synthesis to provide clinical guidance, we aimed to review recent meta-analyses on diagnostic methods for atherosclerotic plaque regression. We identified 8 meta-analyses published between 2015 and 2017, including 79 studies and 14,442 patients, followed for a median of 12months. They reported on atherosclerotic plaque regression appraised with carotid duplex ultrasound, coronary computed tomography, carotid magnetic resonance, coronary intravascular ultrasound, and coronary optical coherence tomography. Overall, all meta-analyses showed significant atherosclerotic plaque regression with lipid-lowering therapy, with the most notable effects on echogenicity, lipid-rich necrotic core volume, wall/plaque volume, dense calcium volume, and fibrous cap thickness. Significant interactions were found with concomitant changes in low density lipoprotein cholesterol, high density lipoprotein cholesterol, and C-reactive protein levels, and with ethnicity. Atherosclerotic plaque regression and conversion to a stable phenotype is possible with intensive medical therapy and can be demonstrated in patients using a variety of non-invasive and invasive imaging modalities.

The effects of statin therapy on carotid plaque composition and volume: A systematic review and meta-analysis

Background and purposePrior studies have demonstrated that statin use stabilizes and diminishes atherosclerotic lesions. The main objective of this systematic review and meta-analysis was to study the effects of statin therapy on carotid plaque composition as seen on serial high-resolution carotid plaque MRI. We hypothesized that statin therapy would result in significant improvements in lipid-rich-necrotic-core (LRNC) volumes, wall volumes and lumen volumes. Materials and methodsProspective studies using serial high-resolution carotid plaque MRI (1.5 or 3T only) in patients on statin therapy to document changes in carotid plaque composition were included. All studies had a minimum of 10 patients and minimum follow-up duration of 3 months. Outcomes included change in LRNC volume, wall volume, and lumen volume at: (1) 1–6 months; (2) 7–12 months; (3) >12 months following initiation of statin therapy; and (4) at last follow-up. Meta-analysis was performed using the random effects model. Results were reported as weighted mean differences (WMD) and 95% confidence interval (CI). ResultSeven studies including 361 patients were included. There was no significant change in carotid wall volume or lumen volume at any time points. While there was no significant difference in LRNC at 1–6 months and at 7–12 months following initiation of statin therapy; at >12 months, there was significant decrease in LRNC volume (WMD=−9.9mm3, 95% CI=−8.9, −2.3). ConclusionsOur study suggests statin therapy is associated with significant reductions in LRNC at 1-year of statin therapy on serial carotid MRI. However, no significant reduction in carotid wall volume was seen.

Changes in carotid plaque tissue composition in subjects who continued and discontinued statin therapy

Changes in plaque tissue components such as lipid-rich necrotic core (LRNC) and fibrous tissue with long-term statin treatment or discontinuation have not been studied. LRNC and fibrous tissue by magnetic resonance imaging were evaluated in subjects who continued and discontinued statin therapy for 2years after a prospective study. The Rosuvastatin Evaluation of Atherosclerotic Chinese Patients study in 32 lipid treatment naïve subjects showed a significant reduction in LRNC during 24months of rosuvastatin therapy. After Rosuvastatin Evaluation of Atherosclerotic Chinese Patients was completed, 15 subjects continued taking statins and 17 discontinued despite receiving an instruction to continue statin therapy. LRNC and fibrous tissue were compared between 24 and 48months within each group and between the 2 groups. At 48months, LRNC volume and composition decreased significantly compared with that at 24months in the statin-continued group (101±76 vs 76±65mm(3); P=.001 and 17.3±11.9% vs 12.6±7.6%; P=.04), whereas fibrous tissue increased significantly in both volume (337±160 vs 357±169mm(3); P<.001) and composition (76.3±10.5% vs 83.1±10.1%, P=.002). Such changes were not seen in subjects who discontinued statin. Furthermore, the changes in LRNC volume and composition and fibrous tissue composition from 24 to 48months were significantly different between the statin-continued and -discontinued groups (-25±18 vs 9±14mm(3); P<.001) and (-4.6±8.2% vs 1.3±2.8%; P=.009) and (6.9±6.8% vs 1.3±5.4%, P=.018). Continued statin therapy leads to continued decrease in LRNC and increase in fibrous tissue, which indicates improved plaque stability and supports long-term statin therapy.

Abstract 366: Gender Differences Exist in Carotid Arterial Plaque Composition Among Men and Women with Carotid or Coronary Artery Disease and Elevated ApoB Levels

Introduction: Postmortem coronary artery histopathology and post-surgical carotid endarterectomy studies demonstrate that women have less calcification and inflammatory cells, but more smooth muscle cells than men. Gender differences in atherosclerotic plaque composition are not well known. Yet, the age-adjusted incidence of stroke and myocardial infarction are higher in men than women. Hypothesis: We hypothesized that gender differences exist in carotid plaque composition (CPC), % lipid rich necrotic core (LRNC) and % wall volume (PWV), comparing living women and men. Methods: The CPC study is a prospective, randomized study evaluating the effect of 1) atorvastatin + placebo + placebo vs 2) atorvastatin + niacin ER + placebo 3) atorvastatin + niacin ER + colsevelam on CPC. Participants had coronary or carotid artery disease and ApoB levels ≥120 mg/dL. CPC was evaluated using MRI. Baseline PWV [(wall volume/total vessel volume) х 100%], a measure of plaque burden that adjusts for variation in artery size, and % LRNC volume (among slices with LRNC present) were evaluated. Statistical analysis used Wilcoxon rank sum test, chi-square, and multivariate linear regression. Results: There were 82 women and 118 men. Women vs. men were older, mean±SD age 58±8 vs. 55±8 yrs. (p=0.008), had higher HDL-C, 48±13 vs. 40±10 mg/dL (p&lt;0.001), higher ApoA1 147±24 vs. 126±19 mg/dL (p&lt;0.001), higher ApoE 5.5±3.4 vs. 4.5±1.6 mg/dL (p=0.04), lower % of prior myocardial infarction 22% vs. 52% (p=0.02) and higher % of metabolic syndrome 48% vs. 46% (p=0.01). There were no significant differences in ApoB levels, 123±32 vs. 120±29 (p=0.4). After adjusting for age, HDL-C (strongly correlated with ApoA1, r=0.89), ApoE, prevalence of myocardial infarction and metabolic syndrome, the men-women difference in PWV was small and statistically non-significant ([[Unable to Display Character: &amp;#8710;]] 0.0%, 95% CI -2.5 to 2.6%, p=1.0). However, among participants with LRNC, men had more % LRNC than women ([[Unable to Display Character: &amp;#8710;]] 5.9%, 95% CI 1.4 to 10.3%, p=0.01) after the same adjustments. Conclusions: Gender differences exist in CPC in that there is a higher volume of LRNC in men compared to women. Further studies are needed which delineate the mechanisms underlying the differences in prevalence of LRNC comparing men to women.

Clinical Factors Associated With High-Risk Carotid Plaque Features as Assessed by Magnetic Resonance Imaging in Patients With Established Vascular Disease (from the AIM-HIGH Study)

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 5years 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.

Association between coronary artery calcium score and carotid atherosclerotic disease

The aim of the present study was to evaluate the association between coronary calcification and carotid atherosclerosis. Briefly, 123 patients with suspected coronary artery disease were recruited. The coronary artery calcium score (CACS) was measured and multi‑contrast carotid magnetic resonance imaging (MRI) was performed. Parameters of the carotid morphological measurements were determined and the presence or absence of carotid plaque tissue compositions was recorded for each subject, as well as plaque surface disruption. Two reviewers blind to CACS status interpreted the MRIs. All the subjects were divided into two groups, high‑ and low‑CACS and the carotid morphological measurements in the CACS groups and categories were compared using independent t‑tests and one way ANOVA, respectively. CACS was found to exhibit a moderate correlation with carotid wall area (WA; r=0.521) and mean wall thickness (MWT; r=0.556) and a weak correlation with total vessel area (TVA; r=0.215) and normalized wall index (r=0.377). No significant correlation between CACS and carotid lumen area was identified. Compared with low‑CACS, the high‑CACS group revealed increased carotid WA, TVA and MWT. In the entire cohort, carotid plaque burden revealed an increasing trend with an increasing CACS. CACS and presence of carotid calcification and lipid‑rich necrotic core (LRNC) demonstrated a significant correlation. No significant correlation was observed between CACS with carotid intraplaque hemorrhage (IPH) and surface disruption. CACS was found to moderately correlate with carotid calcification and LRNC volume and weakly correlate with carotid IPH volume. Results of the present study indicated that CACS significantly correlates with carotid atherosclerotic plaque burden and the presence of tissue compositions.

Subclinical Carotid Atherosclerosis: Short-term Natural History of Lipid-rich Necrotic Core—A Multicenter Study with MR Imaging

To use magnetic resonance (MR) imaging to examine the short-term (6 months) natural history of the lipid-rich necrotic core (LRNC) in carotid artery plaques by examining the placebo group of a multicenter clinical trial. Study procedures and consent forms were approved by the institutional review board for this HIPAA-compliant study. Written informed consent was obtained for all enrolled subjects. Subjects in the placebo group of a multicenter clinical trial who showed LRNC at screening MR imaging had a follow-up MR imaging examination after 6 months. Lumen and wall volumes and LRNC volume and percentage were measured on images from both examinations by readers who were blinded to the time sequence. Plaque progression was calculated as annualized change in common coverage by using the carotid artery bifurcation as a landmark. Associations of clinical and imaging variables with LRNC progression were examined by using linear regression analysis. Fifty-nine of 73 (81%) subjects completed the study, with a mean interval ± standard deviation of 6.9 months ± 1.0. The mean progression rates per year ± standard deviation of LRNC volume and percentage were -5.2 mm(3) ± 34.3 (P = .249) and -1.74% ± 6.27% (P = .038), respectively. Of the clinical and imaging variables examined, presence of intraplaque hemorrhage (IPH) was significantly associated with LRNC progression (P = .001). Plaques with IPH had increased LRNC volume per year (62.9 mm(3) ± 46.2 vs -8.8 mm(3) ± 29.9, P < .001) and percentage per year (3.67% ± 1.85% vs -2.03% ± 6.30%, P = .126) compared with those without IPH. Spearman correlation analysis showed that change in LRNC positively correlated with change in wall volume (ρ = 0.60, P < .001), but not with change in lumen volume (ρ = -0.17, P = .201). Serial MR imaging of the carotid artery allowed observation of changes in LRNC over a short follow-up period and demonstrated the complexity of plaque progression patterns related to tissue composition. LRNC progression may be influenced not only by clinical characteristics, but also and to a large extent by plaque characteristics such as IPH.

High intensity signal on MIP images from routine TOF-MRA of carotid atherosclerotic plaque indicates higher volume of intraplaque hemorrhage and lipid rich necrotic core

Background Carotid intraplaque haemorrhage (IPH) and lipid rich necrotic core (LRNC) have been associated with accelerated plaque growth, luminal narrowing, future surface disruption and development of symptomatic events. It has also been reported that unstable plaque which contains LRNC or IPH is associated with an increased number of emboli after carotid artery stenting. Therefore, a simple screening method to detect these components in the plaque is needed. Maximum intensity projection (MIP) images from time-of-flight MR angiography (TOF-MRA) are widely and routinely used for screening carotid artery stenosis. This study examined whether high-intensity signal (HIS) in the plaque on MIP images from routine TOF-MRA could quantify IPH. Methods Seventy six patients with a diagnosis of carotid artery stenosis underwent carotid MR imaging. Two experienced reviewers first assessed the presence of HIS in the plaque on MIP images from TOF-MRA and then, blinded to the results, assessed plaque component volumes (IPH, LRNC, Fibrous tissue and Calcification volume) on multicontrast cross sectional MRI using a specialized software suite for plaque analysis. Results Eight carotid plaques produced HIS in the plaque on MIP images from TOF-MRA. In the HIS-positive plaque group (P group; n=8), IPH volume and LRNC volume were significantly higher than those in the HIS negative group (N group; n=68) (IPH; 142.8±97.7mm3 vs 13.4 ±36.1 mm3, P<0.001. LRNC; 379.8±203.4 mm3 vs 106.4 ±122.1 mm3, p<0.001). There were no differences in the fibrous tissue and calcification volume between the P and N groups. Conclusions Our results strongly suggest an association between the presence of carotid LRNC with IPH and HIS on MIP images from TOF-MRA. TOF-MRA is routinely used in atherosclerosis screening and the validation of high signal on MIP images has created a valuable tool in the assessment of carotid plaque vulnerability. Funding None.