Differences In Plaque Composition Research Articles

Coronary atherosclerotic plaque burden and characterization by spectral computed tomography scan in patients with high lipoprotein a and non-hemodynamically significant stenosis

Abstract Introduction Atherosclerotic coronary disease increases morbidity and mortality worldwide. Lipoprotein A (LpA) has emerged as a cardiovascular risk marker, but little is known of its direct influence in plaque volume and composition. Spectral computed tomography (CT) technology allows to characterize coronary plaques with new promising tools. Purpose To evaluate the association of LpA with the extent and composition of non-significant coronary plaques producing stenosis <50%. Methods We prospectively recruited 109 patients referred for noninvasive CT angiography (November 2023-January 2024) with suspected coronary artery disease. 20 had totally/partially non-calcified, non-significant coronary plaques. Plaques were segmented and volume was measured. Their composition was stablished as calcified (>200 UH), lipidic (<60 UH) and fibrous (60-200 UH). Spectral data-based plaque parameters were analyzed, including radiological attenuation on polyenergetic images (CTPI), on virtual low/high monoenergetic images (CT40KeV and CT140KeV, respectively), variation in attenuation across monoenergetic levels (slope40-140 KeV) and Z-effective value. CT scan images were acquired with a 128 detectors dual-layer spectral scan with prospective-retrospective/synchronization. Intravascular iodine-based contrast was administered. LpA was stablished as high (≥25 mg/dL) or low (<25 mg/dL). Results Mean age was 60 ± 11. Cardiovascular risk factor were equally distributed between groups. We analyzed 33 plaques. Total plaque volume was significantly higher in high LpA patients (125.9 mm3 vs 62.1 mm3). There were no differences in plaque composition by LpA (Table). Additionally, spectral data showed significantly higher plaque attenuation on CT140KeV images in high LpA patients (36.07 vs 21.32 HU; p = 0.05). There were no differences for the rest of spectral parameters. Conclusions Plaque volume was higher in patients with non-significant atherosclerotic disease and high LpA, but these plaques showed similar composition in high and low LpA patients. These patients might, therefore, respond to the same conventional treatment event though there is not specific treatment for high LpA yet. Additionally, spectral CT140KeV images could add more precision differentiating these plaques since radiological attenuation in these reconstructions is higher in patients with high LpA.TableFigure

Circulating Sex-Specific Markers of Plaque Instability in Women and Men With Severe Carotid Atherosclerosis.

Sex-specific differences in plaque composition and instability underscore the need to explore circulating markers for better prediction of high-risk plaques. This cross-sectional study aims to (1) investigate differences in lipid, immune, and adipokine circulating profiles between men and women with stable versus unstable plaques and (2) identify circulating markers that can better classify men and women according to plaque instability. Preoperative blood samples and plaque specimens were collected from consecutive men and women with carotid artery stenosis ≥50% and who underwent a carotid endarterectomy between 2009 and 2018. Adipokine, lipid, and immune profiling was conducted. Plaque stability was determined by gold-standard histological classifications. Statistical analyses, including χ2, ANOVA, Kruskal-Wallis, and logistic regression, assessed differences in plaque features and blood parameters between men and women with stable and unstable plaques. Of 470 recruited patients (aged 70.8±9.2 years), the final study analyses included 317 men and 143 women (aged 71.0±9.0 years). Men exhibited more unstable plaques (P<0.001), characterized by increased plaque hemorrhage, larger lipid core, and inflammation (P<0.001), along with less favorable circulating profiles. Antagonistic interactions between sex and white blood cell (WBC) counts, basophil-to-WBC ratio, and platelet counts influenced plaque instability. In men, low WBC counts, high monocyte-to-WBC ratio, low basophil-to-WBC ratio, and high LDL-C (low-density lipoprotein cholesterol) levels were associated with greater plaque instability (odds ratio, 0.827 [95% CI, 0.713-0.926], 1.158 [95% CI, 1.027-1.305], 0.495 [95% CI, 0.281-0.871], and 1.564 [95% CI, 1.001-2.443], respectively) and more unstable features (ie, inflammation, foam cells, and neovascularization). In women, a high basophil-to-WBC ratio was associated with greater plaque instability (3.142 [95% CI, 1.220-8.093]), hemorrhage, and thrombosis, while a high molecular weight-to-total adiponectin ratio was associated with decreased instability (0.014 [95% CI, 0.000-0.646]) and inflammation. Our findings demonstrated sex-specific differences, with women displaying more stable plaque phenotypes and favorable circulating profiles compared with men. This proof-of-concept study was also designed as the key first step in exploring novel sex-specific associations between circulating lipid, immune, and adipokine profiles and carotid plaque instability.

Sex-specific associations of cardiovascular risk factors and coronary plaque composition for hemodynamically significant coronary artery stenosis: a coronary computed tomography angiography study

BackgroundIt has been reported that there are sex differences in plaque composition and hemodynamically significant stenosis. This study aimed to explore the impact of sex on cardiovascular risk factors for specific plaque compositions and hemodynamically significant stenosis.MethodsData regarding demographics and cardiovascular risk factors were collected. Hemodynamically significant stenosis was identified by a computed tomography-derived fractional flow reserve of ≤ 0.8. Associations among cardiovascular risk factors, plaque composition, and hemodynamically significant stenosis were assessed using a multivariate binary logistic regression analysis across sexes. The discriminating capacity of diverse plaque components for hemodynamically significant stenosis was assessed by area under the receiver-operating characteristics curve with 95% confidence intervals.ResultsA total of 1164 patients (489 men and 675 women) were included. For men, hyperlipidemia and cigarette smoking were risk factors for each plaque component (all P < 0.05), and diabetes mellitus also predicted fibrotic components (P < 0.05). For women, risk factors for each plaque component were hypertension and diabetes mellitus (all P < 0.01). Nonetheless, hyperlipidemia (P < 0.05) was a specific risk factor for non-calcified components. Calcified components combined with fibrotic components showed superior discrimination of hemodynamically significant stenosis in men and calcified components alone in women (all P < 0.01). Hypertension (P < 0.01) was a risk factor for hemodynamically significant stenosis in women. In contrast, diabetes, hyperlipidemia, and cigarette smoking were risk factors for hemodynamically significant stenosis in men (all P < 0.05).ConclusionsIn men, hemodynamically significant stenosis was predicted by a combination of calcified and fibrotic components with multiple risk factors. In women, hemodynamically significant stenosis was predicted by calcified components caused by a single risk factor. It might be a key point to improve prognosis by more precise risk management between men and women, which needs to be proved by further prospective trials.

Relation of Gender to Atherosclerotic Plaque Characteristics by Differing Angiographic Stenosis Severity

It is unknown whether gender influences the atherosclerotic plaque characteristics (APCs) of lesions of varying angiographic stenosis severity. This study evaluated the imaging data of 303 symptomatic patients from the derivation arm of the CREDENCE (Computed TomogRaphic Evaluation of Atherosclerotic Determinants of Myocardial IsChEmia) trial, all of whom underwent coronary computed tomographic angiography and clinically indicated nonemergent invasive coronary angiography upon study enrollment. Index tests were interpreted by 2 blinded core laboratories, one of which performed quantitative coronary computed tomographic angiography using an artificial intelligence application to characterize and quantify APCs, including percent atheroma volume (PAV), low-density noncalcified plaque (LD-NCP), noncalcified plaque (NCP), calcified plaque (CP), lesion length, positive arterial remodeling, and high-risk plaque (a combination of LD-NCP and positive remodeling ≥1.10); the other classified lesions as obstructive (≥50% diameter stenosis) or nonobstructive (<50% diameter stenosis) based on quantitative invasive coronary angiography. The relation between APCs and angiographic stenosis was further examined by gender. The mean age of the study cohort was 64.4±10.2years (29.0% female). In patients with obstructive disease, men had more LD-NCP PAV (0.5±0.4 vs 0.3±0.8, p=0.03) and women had more CP PAV (11.7±1.6 vs 8.0±0.8, p=0.04). Obstructive lesions had more NCP PAV compared with their nonobstructive lesions in both genders, however, obstructive lesions in women also demonstrated greater LD-NCP PAV (0.4±0.5 vs 1.0±1.8, p=0.03), and CP PAV (17.4±16.5 vs 25.9±18.7, p=0.03) than nonobstructive lesions. Comparing the composition of obstructive lesions by gender, women had more CP PAV (26.3±3.4 vs 15.8±1.5, p=0.005) whereas men had more NCP PAV (33.0±1.6 vs 26.7±2.5, p=0.04). Men had more LD-NCP PAV in nonobstructive lesions compared with women (1.2±0.2 vs 0.6±0.2, p=0.02). In conclusion, there are gender-specific differences in plaque composition based on stenosis severity.

B cell-specific knockout of AID protects against atherosclerosis

Antigen-naive IgM-producing B cells are atheroprotective, whereas mature B cells producing class-switched antibodies promote atherosclerosis. Activation-induced cytidine deaminase (AID), which mediates class switch recombination (CSR), would thus be expected to foster atherosclerosis. Yet, AID also plays a major role in the establishment of B cell tolerance. We sought to define whether AID affects atherosclerotic plaque formation. We generated Ldlr-/- chimeras transplanted with bone marrow from Aicda-/- or wild-type (WT) mice, fed a HFD for 14 weeks. Decreased B cell maturation in Ldlr-/-Aicda-/- mice was demonstrated by 50% reduction in splenic and aortic BAFFR expression, a key signaling component of B2 cell maturation. This was associated with increased plasma IgM in Ldlr–/-Aicda-/- compared with Ldlr-/-WT animals. Importantly, Ldlr-/-Aicda-/- mice had reduced atherosclerotic lesion area (0.20 ± 0.03mm2) compared with Ldlr-/-WT (0.30 ± 0.04mm2, P < 0.05), although no differences in plaque composition were noted between groups. In addition, immunofluorescence analysis revealed increased splenic B and T cell areas independent of cell number. AID depletion directly inhibits atherosclerotic plaque formation.

Wall shear stress and its role in atherosclerosis.

Atherosclerosis (AS) is the major form of cardiovascular disease and the leading cause of morbidity and mortality in countries around the world. Atherosclerosis combines the interactions of systemic risk factors, haemodynamic factors, and biological factors, in which biomechanical and biochemical cues strongly regulate the process of atherosclerosis. The development of atherosclerosis is directly related to hemodynamic disorders and is the most important parameter in the biomechanics of atherosclerosis. The complex blood flow in arteries forms rich WSS vectorial features, including the newly proposed WSS topological skeleton to identify and classify the WSS fixed points and manifolds in complex vascular geometries. The onset of plaque usually occurs in the low WSS area, and the plaque development alters the local WSS topography. low WSS promotes atherosclerosis, while high WSS prevents atherosclerosis. Upon further progression of plaques, high WSS is associated with the formation of vulnerable plaque phenotype. Different types of shear stress can lead to focal differences in plaque composition and to spatial variations in the susceptibility to plaque rupture, atherosclerosis progression and thrombus formation. WSS can potentially gain insight into the initial lesions of AS and the vulnerable phenotype that gradually develops over time. The characteristics of WSS are studied through computational fluid dynamics (CFD) modeling. With the continuous improvement of computer performance-cost ratio, WSS as one of the effective parameters for early diagnosis of atherosclerosis has become a reality and will be worth actively promoting in clinical practice. The research on the pathogenesis of atherosclerosis based on WSS is gradually an academic consensus. This article will comprehensively review the systemic risk factors, hemodynamics and biological factors involved in the formation of atherosclerosis, and combine the application of CFD in hemodynamics, focusing on the mechanism of WSS and the complex interactions between WSS and plaque biological factors. It is expected to lay a foundation for revealing the pathophysiological mechanisms related to abnormal WSS in the progression and transformation of human atherosclerotic plaques.

Additive effects of ezetimibe, evolocumab, and alirocumab on plaque burden and lipid content as assessed by intravascular ultrasound: A PRISMA-compliant meta-analysis.

Background:The additive effects of ezetimibe, evolocumab or alirocumab on lipid level, plaque volume, and plaque composition using intravascular ultrasound (IVUS) remain unclear.Methods:According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement, we performed a systematic review and meta-analysis of trials assessing the effects of ezetimibe, evolocumab, and alirocumab on coronary atherosclerosis using IVUS. The primary outcome was change in total atheroma volume (TAV), and the secondary outcomes were changes and differences in plaque composition and lipid content.Results:Data were collected from 9 trials, involving 917 patients who received ezetimibe, evolocumab or alirocumab in addition to a statin and 919 patients who received statins alone. The pooled estimate demonstrated a significant reduction in TAV with the addition of ezetimibe and favorable effects of evolocumab and alirocumab on TAV. Subgroup analysis also supported favorable effects of evolocumab and alirocumab on TAV, according to baseline TAV, gender, type 2 diabetes mellitus, and prior stain use. Addition of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to statin therapy resulted in significant reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG), but not in high-density lipoprotein cholesterol (HDL-C). The pooled estimate also showed significant favorable effects of ezetimibe on LDL-C, TC, and TG, but an insignificant effect on HDL-C. Patients who received ezetimibe showed similar changes in the necrotic core, fibro-fatty plaque, fibrous plaque, and dense calcification compared with patients not treated with ezetimibe.Conclusions:The addition of ezetimibe to statin therapy may further reduce plaque and lipid burdens but may not modify plaque composition. Although current evidence supports a similar impact from the addition of PCSK9 inhibitors to statin therapy, more evidence is needed to confirm such an effect.

C47 CORO–CT PLAQUE ANALYSIS IN ASSESSMENT OF CARDIOVASCULAR RISK

Abstract Background Computed tomographic (CT) coronary angiography represents a non–invasive approach to assess plaque characteristics that provides information to change treatment of coronary artery disease (CAD) and to asses risk stratification. Purpose Analyze the differences in plaque composition between patients with different plaque features: soft unstable plaques, hard stable plaques and no plaques; identify whether there is a relationship between the plaque density and the pericoronary fat attenuation index (pFAI). Materials and methods: 372 patients retrospectively analyzed who underwent CTCA for exclusion of CAD. They were divided into three groups: 37 (10%) patients with high attenuated plaques (&amp;gt; 60HU), 137 (37%)with low attenuated plaques (&amp;lt;29 HU and a volume of at least 15 mm3 and/or 30–59 HU with a volume greater than 52 mm3) and 198 (53%) patients without significant CAD. For each patients we collected clinical, radiological and follow–up data. Results and Discussion Low–attenuated plaques are significantly associated with older age, male sex, dyslipidemia and diabetes mellitus (p &amp;lt; 0.001). Higher values of pFAI were more present in patients with soft plaques than in those with stable plaques and without plaques (p = 0.005). It was also found that soft plaques were present in more CA segments compared to stable plaques. Overall volume of soft plaque appears greater than hard plaques and mainly localized in the anterior descendant coronary artery with higher stenosis values (p &amp;lt; 0.001). Presence of plaques with soft or high–risk features predisposes significantly and independently (p &amp;lt; 0.001) to a composite outcome (death, in–hospital admissions for percutaneous angioplasty or by–pass procedures) at the follow up. Conclusions Coronary plaque analysis showed a good correlation between high–risk plaques and pFAI, supporting the hypothesis that the presence of high–risk plaques can be correlated to inflammatory burden. Furthermore, the presence of high risk plaques predispose to death or hospitalization for coronary intervention.

The Effects of Exercise on Plaque Volume and Composition in a Mouse Model of Early and Late Life Atherosclerosis.

BackgroundExercise is associated with a less atherogenic lipid profile; however, there is limited research on the effect of exercise on atherosclerotic plaque composition and markers of plaque stability.MethodsA total of 110 apolipoprotein (apo)E−/− mice were placed on a chow diet and randomly assigned to control or exercise for a period of 10 weeks, commencing either at 12 weeks of age (the early-stage atherosclerosis, EA group) or at 40 weeks of age (the late-stage atherosclerosis, LA group). At the end of the exercise period, blood was assayed for lipids. Histologic analysis of the aortic sinus was undertaken to assess plaque size and composition that includes macrophage content, monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase-2 (MMP-2), and tissue inhibitors of metalloproteinase 1 and 2 (TIMP-1 and 2).ResultsA total of 103 mice (38 EA, 65 LA) completed the protocol. In the EA group, exercise reduced plasma total cholesterol (TC) (−16%), free cholesterol (−13%), triglyceride (TG) (−35%), and phospholipid (−27%) levels, when compared to sedentary control mice (p < 0.01). In the EA group, exercise also significantly reduced plaque stenosis (−25%, p < 0.01), and there were higher levels of elastin (3-fold increase, p < 0.0001) and collagen (11-fold increase, p < 0.0001) in plaques, compared to control mice. There was an increase in plaque MMP-2 content in the exercise group (13% increase, p < 0.05) but no significant difference in macrophage or MCP-1 content. In the LA group, exercise reduced plaque stenosis (−18%, p < 0.05), but there was no significant difference in plaque composition. There was no difference in macrophage, MCP-1, or MMP-2 content in the LA groups. TIMP-1 was lower with exercise in both the EA and LA groups (−59%, p < 0.01 and −51%, p < 0.01 respectively); however, there was no difference in TIMP-2 levels.ConclusionA 10-week exercise period reduces atherosclerotic plaque stenosis when commenced at both early- and late-stage atherosclerosis. Intervening earlier with exercise had a greater beneficial effect on lipids and plaque composition than when starting exercise at a later disease stage.

Sex Differences in Plaque Composition and Morphology Among Symptomatic Patients With Mild-to-Moderate Carotid Artery Stenosis.

Incidence of ischemic stroke differs between men and women, with substantially higher rates in men. The underlying mechanism of this difference remains poorly understood but may be because of differences in carotid atherosclerosis. Using an in-depth imaging-based approach, we investigated differences between carotid plaque composition and morphology in male and female patients with stroke, taking into account differences in total plaque burden. Additionally, we investigated all possible within-artery combinations of plaque characteristics to explore differences between various plaque phenotypes. We included 156 men and 68 women from the PARISK (Plaque At Risk) study, a prospective cohort study of patients with recent ischemic cerebrovascular symptoms and <70% ipsilateral carotid stenosis. Plaque characteristics (intraplaque hemorrhage [IPH], lipid-rich necrotic core [LRNC], calcifications, thin-or-ruptured fibrous cap, ulcerations, total plaque volume) were assessed with magnetic resonance imaging and multidetector-row computed tomography angiography. We used multivariable logistic and linear regression analyses to assess sex differences in plaque characteristics. We found significant difference in total plaque volume between men and women (β=22.9 mm3 [95% CI, 15.4-30.5]; mean volume in men 1399±425 mm3, in women 1011±242 mm3). Additionally, men were more likely to have IPH (odds ratio [OR]=2.8 [95% CI, 1.3-6.3]; IPH proportion in men 49%, in women 16%) and LRNC (OR=2.4 [95% CI, 1.2-4.7]; LRNC proportion in men 73%, in women 41%) even after adjustment for total plaque volume. We found no sex-specific differences in plaque volume-corrected volumes of IPH, LRNC, and calcifications. In terms of coexistence of plaque characteristics, we found that men had more often a plaque with coexistence of calcifications, LRNC, and IPH (OR=2.7 [95% CI, 1.2-7.0]), with coexistence of thin-or-ruptured fibrous cap/ulcerations, LRNC, and IPH (OR=2.4 [95% CI, 1.1-5.9]), and with coexistence of all plaque characteristics (OR=3.0 [95% CI, 1.2-8.6]). In symptomatic patients with mild-to-moderate carotid stenosis, men are more likely to have a high-risk carotid plaque with IPH and LRNC than women, regardless of total plaque burden. Men also have more often a plaque with multiple vulnerable plaque components, which could comprise an even higher stroke risk. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01208025.

Lower levels of low-density lipoprotein cholesterol are associated with lower prevalence of thin-cap fibroatheroma in statin-treated patients with coronary artery disease

Abstract Background Lowering low-density lipoprotein cholesterol (LDL-C) with statins slows progression of atherosclerotic plaques and reduces cardiovascular events. The 2019 European Society of Cardiology guideline for the management of dyslipidaemias recommends the absolute LDL-C treatment target as &amp;lt;55mg/dL for very high-risk patients, &amp;lt;70 mg/dL for high-risk patients and &amp;lt;100 mg/dL for moderate-risk patients. However, the difference in plaque composition of coronary lesions according to these LDL-C levels remains to be elucidated. Purpose To investigate plaque morphologies according to LDL-C levels in statin-treated patients with coronary artery disease (CAD). Methods A total of 685 consecutive statin-treated patients with CAD, who underwent optical coherence tomography (OCT) imaging of culprit lesions were enrolled. The prevalence of vulnerable compositions in culprit plaques evaluated by OCT was compared among the groups of patients classified by LDL-C levels (&amp;lt;55, 55–70, 70–100, ≥100 mg/dL). Results LDL-C levels &amp;lt;55 mg/dL, &amp;lt;70 mg/dL and &amp;lt;100 mg/dL were observed in 6.3%, 21.8% and 63.9% of patients, respectively. The prevalence of thin-cap fibroatheroma was significantly different among the groups (P=0.014, Figure) with a trend toward lower prevalence in the lower two LDL-C groups than in the higher two LDL-C groups. A gradient with lower prevalence of thrombus in lower LDL-C groups was observed, although the statistical significance was not demonstrated (Figure). There was no significant difference in the prevalence of macrophage or cholesterol crystal among the groups. Conclusions Lower LDL-C level was associated with a trend toward lower prevalence of thin-cap fibroatheroma and thrombus in statin-treated patients with CAD. Funding Acknowledgement Type of funding source: None

Sex differences in the natural history of plaque progression by serial coronary computed tomography angiography

Abstract Background Sex related differences exist for coronary artery disease (CAD). Women tend to be older when presenting with CAD and have lower rates of obstructive disease. Invasive intravascular ultrasound studies have shown differences in plaque composition between males and females. However, these studies were performed in a high risk population needing invasive imaging. Coronary computed tomography angiography (CTA) allows for a fast and non-invasive quantification of CAD in low risk patients. Sex differences and quantitative analysis of plaque progression and changes in plaque composition have not been studied intensively. Purpose To evaluate the role of sex on long term plaque progression and on the change of plaque composition in a population with low-intermediate risk. Methods Patients that received a coronary CTA were prospectively included in the SMARTool study to receive a follow-up coronary CTA. In total, 275 patients from 5 European countries were recruited in 7 centers. Baseline and follow-up coronary CTA were quantitative analyzed on a per-lesion basis using dedicated software package. Patients without coronary plaques at follow-up or with uninterpretable coronary CTA results were excluded. Total plaque volume and compositional volumes, calcified or non-calcified (defined as fibrous, fibro-fatty or necrotic core), were normalized using the vessel volume to calculate a percentage atheroma volume (PAV). Lesions between males and females were compared using linear mixed models. We further classified patients into age groups &amp;lt;55 and ≥55 years to evaluate the influence of menopause on plaque progression. Results In total, 211 patients were included in this analysis, 146 (69%) were male and 65 (31%) were female. Mean interscan period was 6.2±1.4 years. Females were older (64±7 vs 61±8 years; p&amp;lt;0.001), had higher HDL levels (56±15 vs 49±15 mg/dL; p=0.003) and presented more often with atypical chest pain (62 vs 38%; p=0.017). Males had 434 plaque sites and females 156. On a per-lesion analysis females had less fibro-fatty PAV compared to males (β −1.3±0.4%; p&amp;lt;0.001), no other differences were seen (p&amp;gt;0.05). When stratifying the patients in above and below 55 years old, females still had less fibro-fatty PAV compared to males in both age groups (p&amp;lt;0.05). However, females in the age group &amp;lt;55 years showed more regression of fibrous PAV compared to males (β −0.8±0.3% per year; p=0.002) and non-calcified plaque PAV (β −0.7±0.3% per year; p=0.027) (Figure). Conclusions Males have larger fibro-fatty PAV compared to females, however the rate of change did not differ. Younger women showed more regression of fibrous PAV and non-calcified PAV compared to males. No differences in the rate of plaque progression or plaque composition changes were seen between males and females in the older age group. Figure plaque progression and sex diff Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): EU H2020 research and innovation program

C-reactive protein levels and plaque regression with evolocumab: Insights from GLAGOV

ObjectiveOn-treatment levels of high sensitivity C-reactive protein (hsCRP) in statin-treated patients predict plaque progression and the prospective risk of atherosclerotic cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors produce additional LDL-C lowering, reduce plaque burden and improve cardiovascular outcomes in statin-treated patients. It is unknown whether residual systemic inflammation attenuates their favorable effects on plaque burden. MethodsGLAGOV compared the effects of treatment for 78 weeks with evolocumab or placebo on progression of coronary atherosclerosis in statin-treated patients with coronary artery disease.Clinical demographics, biochemistry and changes in both the burden (percentage atheroma volume (PAV), total atheroma volume (TAV), n ​= ​413) and composition (n ​= ​162) of coronary plaque were evaluated in evolocumab-treated patients according to baseline hsCRP strata (<1, 1–3, >3 ​mg/L). ResultsThe study cohort comprised 413 evolocumab-treated patients (32% low [<1 ​mg/L], 41% intermediate [1–3 ​mg/L] and 27% high [>3 ​mg/L] baseline hsCRP levels). Patients in the highest hsCRP stratum were more likely to be female and had a higher prevalence of diabetes, hypertension, and the metabolic syndrome. LDL-C levels were similar across the groups, however participants with higher hsCRP levels had higher triglyceride and lower HDL-C levels at baseline. At follow-up, the change in PAV from baseline (−0.87% [low] vs. −0.84% [intermediate] vs. −1.22% [high], p ​= ​0.46) and the proportion of patients experiencing any degree of regression (65.9% vs. 63.5% vs. 63.1%, p ​= ​0.88) was similar across hsCRP strata and when evaluated by levels of achieved LDL-C. There were no serial differences in plaque composition by hsCRP strata. ConclusionThe ability of evolocumab to induce regression in statin-treated patients is not attenuated by the presence of enhanced systemic inflammation. This underscores the potential benefits of intensive lipid lowering, even in the presence of heightened inflammatory states.

Sex Differences in Coronary Artery Calcium and Long-term CV Mortality.

To summarize differences in plaque depositions, coronary artery calcium (CAC) scoring, and the role of CAC in predicting atherosclerotic cardiovascular disease (ASCVD) mortality in men and women. Women have coronary plaque that is more lipid-rich, dense, and less calcified than their male counterparts. CAC scoring has emerged as a useful tool to quantify ASCVD burden. However, recent evidence favors the use of sex-adjusted CAC cutoffs for women to account for the relatively lower overall CAC burden and therefore risk stratify women appropriately. Several studies have identified CAC distribution patterns in women associated with increased CV mortality, particularly the number of lesions involved, CAC volume, and size. Multiple studies have shown that the pathophysiology and associated risks of ASCVD are different in women when compared with men. CAC scoring is a tool that is widely being used for ASCVD risk stratification. Recent studies have shown that although men have higher CAC burdens, women are more likely to develop plaque erosions with non-calcified plaque that carries a greater risk for cardiovascular events. Providers should be aware of sex-specific CAC patterns carrying increased mortality risk for women, particularly increasing lesion size and number. Given the differences in plaque composition and distribution, revised sex-adjusted CAC scoring is suggested to better risk stratify patients, especially those deemed intermediate risk, and decrease CV mortality.

P360 Site specific phenotype of atherosclerotic lesions according to plaque location within the coronary tree, a CCTA based study

Abstract Funding Acknowledgements Research grant PlaqueImage, contract number 26/01.09.2016, SMIS code 103544, Project funded by the European Union and the Government of Romania Background The coronary CT angiography (CCTA)-based differences in composition, morphology and vulnerability of coronary plaques (CPs), according to their location within the coronary tree, have not been investigated so far. Purpose We sought to perform a comparative analysis between plaques located at different levels within the coronary tree, to identify the differences in plaque composition, morphology, and vulnerability between the three major coronary branches. Methods We conducted a cross-sectional, observational study on 75 patients with stable coronary artery disease who underwent CCTA for assessment of coronary lesions that exhibited at least one vulnerable plaque (VP) in the coronary tree. After image acquisition, coronary plaque analysis was performed with the use of the Syngo.via Frontier (Siemens) software. Plaque analysis also included evaluation of presence of VM: low attenuation plaque – LAP; napkin ring sign – NRS; spotty calcifications – SC; positive remodeling – PR. VP were defined as lesions that presented at least 1 vulnerability marker (VM). In total, 90 coronary VPs located at the level of the left anterior descending (LAD; n = 30), circumflex (CXA; n = 30) and right coronary artery respectively (RCA; n = 30) were identified and analyzed. Results Lesions located in the RCA presented a significantly higher length (LAD - 18.67± 5.49 vs. CXA - 15.48 ±3.73 vs. RCA - 20.47 ± 5.97 mm, p = 0.001), a higher degree of stenosis (LAD - 57.77 ± 8.62 vs. CXA - 54.50 ± 11.25 vs. RCA - 59.63 ± 10.42 mm, p = 0.022), and were more voluminous (LAD - 187.9 ± 86.03 vs. CXA - 146.9 ± 102.4 vs. RCA - 248.1 ± 11.4 mm3, p = 0.0007) compared to those located in the LAD and CXA, but no difference was observed regarding the remodeling (p = 0.180) or eccentricity indexes (p = 0.423). Plaque composition was also significantly different according to plaque location: calcified volume (LAD - 44.07 ± 63.90 vs. CXA - 12.40 ± 19.65 vs. RCA - 33.69 ± 34.38 mm3, p = 0.002), non-calcified volume (LAD - 143.8 ± 76.02 vs. CXA - 134.5 ± 102.2 vs. RCA - 214.4 ± 99.67 mm3, p = 0.002), lipid rich volume (LAD - 14.95 ± 22.69 vs. CXA - 6.44 ± 13.42 vs. RCA -16.07 ± 15.74 mm3, p = 0.0005), fibrotic volume (LAD - 128.9 ± 66.10 vs. CXA - 128.1 ± 91.56 vs. RCA - 198.3 ± 92.34 mm3, p = 0.003). The highest number of VM per plaque was present in the LAD (LAD - 2.2 ± 0.8 vs. CXA - 1.6 ± 0.7 vs. RCA - 1.8 ± 0.6, p = 0.01), as well as highest rate of VPs (LAD – 80%, CXA – 46.6%, RCA – 70%, p = 0.01). No difference was registered between coronary arteries on the presence of SCs (p = 0.670), NRS (p = 0.455), PR (p = 0.833), but LAPs were more frequently located in the LAD (p = 0.0009). Conclusions Coronary plaques located in the RCA were more voluminous and exhibited a higher volume of lipid rich and non-calcified atheroma. However, compared to the RCA and CXA, the left anterior descending artery presented CPs with a more expressed degree of vulnerability, a higher number of vulnerability markers per plaque, and a higher incidence of LAP.

3039Vulnerability of carotid atherosclerosis: relationship with plaque location, plaque eccentricity and vessel remodeling patterns. Insight from the the MAGNETIC observational study

Abstract Carotid atherosclerosis is a cause of brain ischemic events. Cardiovascular magnetic resonance (CMR) can assess plaque vulnerability. We investigated atherosclerosis vulnerability in relation to plaque location, eccentricity and vessel remodeling. Methods-Baseline CMR evaluations of the MAGNETIC observational study, were analyzed. We quantitated with MRI-Plaque View™, vessel lumen/wall and vulnerable plaque components of a 32-mm segment of common carotid artery (12 mm), bulb (8 mm) and internal carotid artery (12 mm). Lipid-rich necrotic core [LRNC], fibrous cap [CAP] and intraplaque hemorrhage [IPH] were expressed as percent of wall area. Results-A data-set of 8080 sections of adequate quality in 260 patients (198 male [76%], median age 71 years [65–76]), were analyzed. Patients were on therapy with antiplatelet, ACE-inhibitors/ARB and statins (196–229 out of 260 [75–88%]). We found significant differences in plaque composition according to longitudinal and circumferential location, eccentricity and vessel remodeling (table). At multivariate regression analysis, including classical RF and atherosclerotic burden, we found an independent association of: LRNC and IPH with longitudinal location, eccentricity and positive remodeling, and of CAP with eccentricity (p&lt;0.001 for all). Lipid-rich necrotic core Fibrous cap Intraplaque hemorrhage Longitudinal distribution Common carotid artery 4% [1–10] p&lt;0.001 6% [4–11] p&lt;0.001 0% [0–3] p&lt;0.001 Carotid bulb 7% [3–13] 9% [5–13] 1% [0–4] Internal carotid artery 3% [0–10] 7% [4–11] 0% [0–1] Circunferenzial location Antero-medial 4% [0–11] p&lt;0.001 7% [4–12] p=0.07 0% [0–2] p&lt;0.001 Antero-lateral 6% [1–12] 8% [5–12] 1% [0–4] Postero-lateral 5% [0–11] 7% [4–12] 0% [0–3] Postero-medial 5% [0–11] 7% [4–12] 0% [0–1] Plaque eccentricity Concentric 3% [0–9] p&lt;0.001 7% [4–11] p&lt;0.001 0% [0–2] p&lt;0.001 Eccentric 9% [4–15] 9% [5–13] 1% [0–4] Remodelling pattern Negative 4% [0–10] p&lt;0.001 7% [4–11] p&lt;0.001 0% [0–2] p&lt;0.001 Positive 7% [3–13] 8% [5–13] 1% [0–4] Plaque eccentricity was defined as eccentricity index (EI = [maximum wall thickness − minimum wall thickness]/maximum wall thickness) in the highest quartile. Positive remodeling was defined as remodeling index (= [vessel cross-sectional area − reference area]/cross-sectional area) in the highest quartile. Conclusions Carotid atherosclerotic plaque vulnerability seems to be independently associated with longitudinal location, plaque eccentricity and vessel positive remodeling. Acknowledgement/Funding Bayer AG, Leverkusen, Germany

A cross-sectional survey of coronary plaque composition in individuals on non-statin lipid lowering drug therapies and undergoing coronary computed tomography angiography

IntroductionNon-statin therapy (NST) is used as second-line treatment when statin monotherapy is inadequate or poorly tolerated. ObjectiveTo determine the association of NST with plaque composition, alone or in combination with statins, in patients undergoing coronary computed tomography angiography (coronary CTA). MethodsFrom the multicenter CONFIRM registry, we analyzed individuals who underwent coronary CTA with known lipid-lowering therapy status and without prior coronary artery disease at baseline. We created a propensity score for being on NST, followed by stepwise multivariate linear regression, adjusting for the propensity score as well as risk factors, to determine the association between NST and the number of coronary artery segments with each plaque type (non-calcified (NCP), partially calcified (PCP) or calcified (CP)) and segment stenosis score (SSS). ResultsOf the 27,125 subjects in CONFIRM, 4,945 met the inclusion criteria; 371 (7.5%) took NST. At baseline, patients on NST had more prevalent risk factors and were more likely to be on concomitant cardiac medications. After multivariate and propensity score adjustment, NST was not associated with plaque composition: NCP (0.07 increase, 95% CI: −0.05, 0.20; p = 0.26), PCP (0.10 increase, 95% CI: −0.10, 0.31; p = 0.33), CP (0.18 increase, 95% CI: −0.10, 0.46; p = 0.21) or SSS (0.45 increase, 95% CI: −0.02,0.93; p = 0.06). The absence of an effect of NST on plaque type was not modified by statin use (p for interaction > 0.05 for all). ConclusionIn this cross-sectional study, non-statin therapy was not associated with differences in plaque composition as assessed by coronary CTA.

Relationship between patient presentation and morphology of coronary atherosclerosis by quantitative multidetector computed tomography.

Quantitative computed tomography (QCT) allows assessment of morphological features of coronary atherosclerosis. We aimed to test the hypothesis that clinical patient presentation is associated with distinct morphological features of coronary atherosclerosis. A total of 1652 participants, representing a spectrum of clinical risk profiles [787 asymptomatic individuals from the general population, 468 patients with acute chest pain without acute coronary syndrome (ACS), and 397 patients with acute chest pain and ACS], underwent multidetector computed tomography. Of these, 274 asymptomatic individuals, 254 patients with acute chest pain without ACS, and 327 patients with acute chest pain and ACS underwent QCT to assess coronary plaque volumes and proportions of dense calcium (DC), fibrous, fibro fatty (FF), and necrotic core (NC) tissue. Furthermore, the presence of vulnerable plaques, defined by plaque volume and tissue composition, was examined. Coronary plaque volume increased significantly with worsening clinical risk profile [geometric mean (95% confidence interval): 148 (129-166) mm3, 257 (224-295) mm3, and 407 (363-457) mm3, respectively, P < 0.001]. Plaque composition differed significantly across cohorts, P < 0.0001. The proportion of DC decreased, whereas FF and NC increased with worsening clinical risk profile (mean proportions DC: 33%, 23%, 23%; FF: 50%, 61%, 57%; and NC: 17%, 17%, 20%, respectively). Significant differences in plaque composition persisted after multivariable adjustment for age, gender, body surface area, hypertension, statin use at baseline, diabetes, smoking, family history of ischaemic heart disease, total plaque volume, and tube voltage, P < 0.01. Coronary atherosclerotic plaque volume and composition are strongly associated to clinical presentation.

CT ANGIOGRAPHIC PLAQUE CHARACTERISTICS AND PREDICTION OF MACE ACCORDING TO PRESENCE OF DIABETES: THE CONFIRM REGISTRY

We examined the differences in plaque composition and prognosis assessed by coronary CT angiography (CCTA) in patients with and without diabetes (DM). We studied 2918 subjects from the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry without

Cortical iron regulation and inflammatory response in Alzheimer's disease and APPSWE/PS1ΔE9 mice: a histological perspective.

Disruption of iron homeostasis and increased glial response are known to occur in brains afflicted by Alzheimer's disease (AD). While the APP/PS1 transgenic mouse model recapitulates the hallmark amyloid-beta plaque pathology of AD, it does so in a different neuronal mileu than humans. Understanding the iron characteristics and glial response of the APP/PS1 model is important when testing new treatment procedures and translating these results. Brain tissue from AD patients, APP/PS1 mice, and controls were stained for iron, H- and L-ferritin, microglia, astrocytes, Aβ40∕42, and degenerating neurons. The histological data demonstrate differences in ferritin, iron distribution, gliosis, and Aβ plaque composition between APP/PS1 and AD tissue. Specifically, an association between focal iron deposition and Aβ plaques is found ubiquitously throughout the AD tissue and is not observed in the APP/PS1 mouse model. Ferritin, microglia, and astrocyte staining show differential response patterns to amyloid plaques in AD and the APP/PS1 tissue. Aβ 40 and 42 antibody and thioflavin staining demonstrate morphological differences in plaque composition. The histological data support the hypothesis that iron distribution, iron management, and glial response histologically differ between the APP/PS1 and AD brain. Acknowledging the caveat that there are distinct plaque, iron, and glial contrasts between the AD brain and the APP/PS1 mouse is crucial when utilizing this model.