Increased Plaque Vulnerability Research Articles

The association of cholesterol crystals and non-culprit plaque characteristics in AMI patients: an OCT study

Objective: To analyze plaque characteristics of non-culprit coronary lesions with cholesterol crystals in patients with acute myocardial infarction(AMI) by using optical coherence tomography(OCT). We also investigated the potential association between cholesterol crystals with plaque rupture and healed plaque at non-culprit segment. Methods: This study was a retrospective cohort study. Between January 2017 and December 2017, patients with AMI who underwent 3-vessel OCT imaging were included in this study. Patients were divided into two groups according to the presence or absence of cholesterol crystals at the non-culprit lesions. All patients underwent coronary angiography and OCT examination, and non-culprit plaque characteristics were compared between the two groups. The generalized estimating equation log-binomial multirariate regression model was used to assess the relationship between non-culprit lesions with cholesterol crystals and plaque rupture and plaque healing. The follow-up data collection ended in October 2023. Kaplan-Meier survival curves were plotted, and log-rank tests were used to compare the cumulative incidence of major adverse cardiovascular events between the two groups. Results: A total of 173 AMI patients were included (aged (56.8±11.6) years; 124 men (71.7%)). Among 710 non-culprit lesions identified by OCT, there were 102 (14.4%) in cholesterol crystals group and 608 (85.6%) in non-cholesterol crystals group. Compared with non-culprit lesions without cholesterol crystals, those with cholesterol crystals had smaller minimum lumen diameter, severer diameter stenosis, and longer lesion length (all P<0.01). The prevalence of plaque rupture (17.6% (18/102) vs. 4.9% (30/608), P=0.001) and thin-cap fibroatheroma (31.4% (32/102) vs. 11.5% (70/608), P<0.01) was higher in the cholesterol crystals groups than in the non-cholesterol crystals group. In addition, vulnerable plaque characteristics such as (44.1% (45/102) vs. 25.8% (157/608), P<0.01), macrophages were more frequently observed in non-culprit lesions with cholesterol crystals. The generalized estimating equation log-binomial multivariate regression analyses showed that non-culprit cholesterol crystals were positively correlated with healed plaque (OR=1.583, 95%CI: 1.004-2.495, P=0.048). Conversely, cholesterol crystals were not associated with plaque rupture (OR=1.632, 95%CI: 0.745-3.576, P=0.221). The follow-up time was 2 142 (1 880, 2 198) days. Non-culprit cholesterol crystals were not related to the major adverse cardiovascular events in patients with AMI (log-rank P=0.558). Conclusions: Among AMI patients, non-culprit lesions with cholesterol crystals presented with severer luminal stenosis and increased plaque vulnerability. The presence of non-culprit cholesterol crystals was associated with rather than plaque rupture.

Higher Noncalcified Plaque Volume Is Associated With Increased Plaque Vulnerability and Vascular Inflammation.

Recently, it was reported that noncalcified plaque (NCP) volume was an independent predictor for cardiac events. Pericoronary adipose tissue (PCAT) attenuation is a marker of vascular inflammation and has been associated with increased cardiac mortality. The aim of this study was to evaluate the relationships between NCP volume, plaque vulnerability, and PCAT attenuation. Patients who underwent preintervention coronary computed tomography angiography and optical coherence tomography were enrolled. Plaque volume was measured by computed tomography angiography, plaque vulnerability by optical coherence tomography, and the level of coronary inflammation by PCAT attenuation. The plaques were divided into 2 groups of high or low NCP volume based on the median NCP volume. Among 704 plaques in 454 patients, the group with high NCP volume had a higher prevalence of lipid-rich plaque (87.2% versus 75.9%; P<0.001), thin-cap fibroatheroma (38.1% versus 20.7%; P<0.001), macrophage (77.8% versus 63.4%; P<0.001), microvessel (58.2% versus 42.9%; P<0.001), and cholesterol crystal (42.0% versus 26.7%; P<0.001) than the group with low NCP plaque volume. The group with high NCP volume also had higher PCAT attenuation than the group with low NCP volume (-69.6±10.0 versus -73.5±10.6 Hounsfield unit; P<0.001). In multivariable analysis, NCP volume was significantly associated with thin-cap fibroatheroma and high PCAT attenuation. In the analysis of the combination of PCAT attenuation and NCP volume, the prevalence of thin-cap fibroatheroma was the highest in the high PCAT attenuation and high NCP volume group and the lowest in the low PCAT attenuation and low NCP volume group. Higher NCP volume was associated with higher plaque vulnerability and vascular inflammation. The combination of PCAT attenuation and NCP volume may help identify plaque vulnerability noninvasively. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04523194.

Coronary artery calcification and plaque stability： an optical coherence tomography study

BackgroundCoronary artery calcification (CAC), a surrogate of atherosclerosis, is related to stent underexpansion and adverse cardiac events. However, the effect of CAC on plaque stability is still controversial and the morphological significance of CAC has yet to be elucidated. MethodsA retrospective series of 419 patients with acute coronary syndrome (ACS) who underwent optical coherence tomography (OCT) were enrolled. Patients were classified into three groups based on the calcification size in culprit plaques and the features of the culprit and non-culprit plaques among these groups were compared. Logistic regression was used to analyze independent risk factors for culprit plaque rupture and the nonlinear relationship between calcification parameters and culprit plaque rupture. Furthermore, we compared the detailed calcification parameters of different kinds of plaques. ResultsA total of 419 culprit plaques and 364 non-culprit plaques were identified. The incidence of calcification was 53.9 % in culprit plaques and 50.3 % in non-culprit plaques. Compared with culprit plaques without calcification, plaque rupture, macrophages and cholesterol crystals were more frequently observed in the spotty calcification group, and the lipid length was longer; the incidence of macrophages and cholesterol crystals was higher in the macrocalcification group. Calcification tended to be smaller in ruptured plaques than in non-ruptured plaques. Moreover, the arc and length of calcification were greater in culprit plaques than in non-culprit plaques. ConclusionsVulnerable features were more frequently observed in culprit plaques with spotty calcification, whereas the presence of macrocalcification calcifications did not significantly increase plaque vulnerability. Calcification tends to be larger in culprit plaques than in non-culprit plaques.

Long-term pulmonary iron oxide nanoparticles exposure disrupts hepatic iron-lipid homeostasis and increases plaque vulnerability in ApoE−/− mice

Iron oxide nanoparticles (Fe3O4 NPs) have attracted great attention due to their extensive applications, which warranted their environmental concerns. Although recent advances have proposed the relevance of Fe3O4 NPs to cardiovascular disease, the intrinsic mechanisms underlying the effects of NPs remain indistinct. ApoE−/− mice were chosen as a long-term exposure model to explore the immanent association between respiratory exposure to Fe3O4 NPs and the development of cardiovascular diseases. Pulmonary exposure to 20 nm and 200 nm Fe3O4 NPS resulted in significant lung injury, and pulmonary histopathological examination displayed inflammatory cell infiltration, septal thickening and alveolar congestion. Intriguingly, liver iron deposition and variations in the hepatic lipid homeostasis were found in Fe3O4 NPs-exposed mice, eventually leading to dyslipidemia, hinting the potential cardiovascular toxicity of Fe3O4 NPs. In addition, we not only found that Fe3O4 NPs exposure increased aortic plaque area, but also increased M1 macrophages in the plaque, which yielding plaque vulnerability in ApoE−/− mice Of note, 20 nm Fe3O4 NPs showed enhanced capability on the progression of atherosclerosis than 200 nm Fe3O4 NPs. This study may propose the potential mechanism for adverse cardiovascular disease induced by Fe3O4 NPs and provide convincing evidence for the safety evaluation of Fe3O4 NPs.

Lipoprotein(a) Is Associated With the Progression and Vulnerability of New-Onset Carotid Atherosclerotic Plaque.

Although important progress has been made in understanding Lp(a) (lipoprotein[a])-mediated stroke risk, the contribution of Lp(a) to the progression of vulnerable plaque features associated with stroke risk remains unclear. This study aims to evaluate whether Lp(a) is associated with carotid plaque progression, new-onset plaque features, and plaque vulnerability in a prospective community-based cohort study. Baseline Lp(a) levels were measured using latex-enhanced turbidimetric immunoassay among 804 participants aged 45 to 74 years and free of cardiovascular disease in the Chinese Multi-provincial Cohort Study-Beijing project. Carotid atherosclerosis was measured twice by B-mode ultrasonography over a 10-year interval during the 2002 and 2012 surveys to assess the progression of total, vulnerable and stable plaques, and plaque vulnerability. The total plaque area and plaque vulnerability score were calculated. The median baseline Lp(a) level was 10.20 mg/dL (interquartile range, 6.20 to 17.18 mg/dL). Modified Poisson regression analysis showed that Lp(a) ≥50 mg/dL was significantly associated with 10-year progression of total carotid plaque (relative risk [RR], 1.41 [95% CI, 1.21-1.64]; E-value=2.17), vulnerable plaque (RR, 1.93 [95% CI, 1.54-2.41]), and stable plaque (RR, 1.51 [95% CI, 1.11-2.07]) compared with Lp(a) <50 mg/dL. Moreover, among participants without plaque at baseline, Lp(a) ≥50 mg/dL was related to an increased total plaque area (β=0.36 [95% CI, 0.06-0.65]; P=0.018) and increased plaque vulnerability score (β=0.30 [95% CI, 0.01-0.60]; P=0.045) in multivariable linear regression. Elevated Lp(a) levels were associated with 10-year carotid plaque progression and plaque vulnerability, providing a basis for Lp(a) as a treatment target for stroke prevention.

Oxidized Low-density Lipoproteins and Lipopolysaccharides Augment Carotid Artery Plaque Vulnerability in Hypercholesterolemic Microswine.

Atherosclerosis is a chronic inflammatory disease and hypercholesterolemia is a risk factor. This study aims to compare the potency of lipopolysaccharide (LPS) and oxidized low-density lipoproteins (oxLDL) to induce plaque formation and increase plaque vulnerability in the carotid artery of hypercholesterolemic Yucatan microswine. Atherosclerotic lesions at the common carotid artery junction and ascending pharyngeal artery were induced in hypercholesterolemic Yucatan microswine at 5-6 months of age with balloon angioplasty. LPS or oxLDL were administered intraluminally at the site of injury after occluding the arterial flow temporarily. Pre-intervention ultrasound (US), angiography, and optical coherence tomography (OCT) were done at baseline and just before euthanasia to assess post-op parameters. The images from the US, OCT, and angiography in the LPS and the oxLDL-treated group showed increased plaque formation with features suggestive of unstable plaque, including necrotic core, thin fibrous caps, and a signal poor region more with oxLDL compared to LPS. Histomorphology of the carotid artery tissue near the injury corroborated the presence of severe lesions in both LPS and oxLDL-treated pigs but more in the oxLDL group. Vascular smooth muscle and endothelial cells treated with LPS and oxLDL showed increased folds changes in mRNA transcripts of the biomarkers of inflammation and plaque vulnerability compared to untreated cells. Collectively, the results suggest that angioplasty-mediated intimal injury of the carotid arteries in atherosclerotic swine with local administration of LPS or ox-LDL induces vulnerable plaques compared to angioplasty alone and oxLDL is relatively more potent than LPS in inducing vulnerable plaque.

Intravascular molecular imaging: translating pathophysiology of atherosclerosis into human disease conditions.

Progression of atherosclerotic plaque in coronary arteries is characterized by complex cellular and non-cellular molecular interactions. Within recent years, atherosclerosis has been recognized as inflammation-driven disease condition, where progressive stages are characterized by morphological changes in plaque composition but also relevant molecular processes resulting in increased plaque vulnerability. While existing intravascular imaging modalities are able to resolve key morphological features during plaque progression, they lack capability to characterize the molecular profile of advanced atherosclerotic plaque. Because hybrid imaging modalities may provide incremental information related to plaque biology, they are expected to provide synergistic effects in detecting high risk patients and lesions. The aim of this article is to review existing literature on intravascular molecular imaging approaches, and to provide clinically oriented proposals of their application. In addition, we assembled an overview of future developments in this field geared towards detection of patients at risk for cardiovascular events.

Abstract 525: Uncovering Mechanisms Between Oligosaccharide Galactose-alpha 1,3-galactose (alpha-gal) Sensitization And Atherosclerosis

Recent work by our group and others have shown individuals with IgE to the oligosaccharide allergen present in mammalian products (α-gal) have increased atheroma burden with increased necrosis and calcification compared to those without α -gal specific IgE. These data suggest α -gal specific IgE increase plaque severity and vulnerability, yet the mechanisms that promote production of IgE to α -gal are unknown. Previous work from our group utilized multi-omics single cell analysis of circulating PBMCs from subjects with coronary angiography at UVA and showed subjects with IgE α -gal sensitization had a higher frequency of CCR6hi switched memory (SWM) B cells and that the CCR6 ligand, CCL20, increased class switching to IgE. To determine mechanisms whereby CCR6 may mediated class switching to IgE, we enriched total B cells from healthy donor peripheral blood mononuclear cells and stimulated with 20ng/ml human IL-4 and 10μg/ml agnostic anti-human CD40 with or without 20ng/ml CCL20 for 3 days. After 3 days of treatment, cells were collected and stained with a 15-color panel and analyzed via flow cytometry. Cells were analyzed for surface expression of CD20 and CD3 to gate total B cells. Gated B cells were further separated into CD27+/IgM-/IgD- to define SWM B cell population. CCL20 treatment did not increase the total percent of SWM B cells; however, there was a 2-3-fold increase in CCR6+ SWM B cells compared to CCR6- SWM B cells. CCL20 treated CCR6+ SWM B cells have an average of 7% increase of phosphorylated mTOR in total SWM B cells compared to nonCCL20 treated CCR6+ SWM B cells. These results suggest CCL20 stimulation induces mTOR phosphorylation and activation. Thus, mTOR activation and downstream mediators may be necessary for α -gal induced B cell class switching. From these preliminary studies, we conclude that CCL20 stimulation increases the percent pmTOR+ SWM B cells. We will continue to investigate downstream mTOR mediators in regard to B cell class switching after CCL20 stimulation and how α-gal sensitization augments B cell IgE class switching and increases atherosclerosis with our novel α -gal-/- Apoe-/- mouse.

Increased Vulnerability and Distinct Layered Phenotype at Culprit and Nonculprit Lesions in STEMI Versus NSTEMI

ObjectivesThis study aimed to investigate the pancoronary plaque vulnerability (including culprit and nonculprit lesions) and layered phenotype in patients with ST-segment elevation myocardial infarction (STEMI) vs non-STEMI (NSTEMI). BackgroundPancoronary vulnerability should account for distinct clinical manifestations of acute myocardial infarction (AMI). Layered plaque is indicative of previous coronary destabilization and thrombosis. MethodsA total of 464 patients with AMI who underwent 3-vessel optical coherence tomography imaging were consecutively studied and divided into a STEMI group (318 patients; 318 culprit and 1,187 nonculprit plaques) and a NSTEMI group (146 patients; 146 culprit and 560 nonculprit plaques). Patients were followed up for a median period of 2 years. ResultsCompared with NSTEMI, culprit lesions in STEMI had more plaque rupture, thrombus, thin-cap fibroatheroma (TCFA), calcification, macrophage accumulation, and microvessels. The prevalence of plaque rupture (8.2% vs 4.8%; P = 0.018), microvessels (57.5% vs 45.2%; P < 0.001), and calcification (40.7% vs 30.2%; P = 0.003) at nonculprit lesions was higher in STEMI than NSTEMI. The layer area and thickness at the culprit and nonculprit lesions were significantly larger in STEMI than in NSTEMI. Multivariate analyses showed that culprit layer area (odds ratio: 1.443; 95% CI: 1.138-1.830; P = 0.002) was predictive of STEMI (vs NSTEMI), in addition to culprit TCFA, culprit thrombus, and non–left circumflex artery location of the culprit lesion. Although the type of AMI was not related to clinical outcomes, high-sensitivity C-reactive protein, culprit calcified nodule, and nonculprit TCFA predicted the 2-year major adverse cardiovascular events in patients with AMI. ConclusionsPatients with STEMI had increased plaque vulnerability (ie, more plaque rupture and microvessels) and distinct layered phenotype at the culprit and nonculprit lesions compared with patients with NSTEMI. Culprit lesion features of large layer area, TCFA, thrombus, and non–left circumflex artery location predicted the clinical presentation of STEMI.

Plaque Longitudinal Heterogeneity in Morphology, Property, and Mechanobiology

Background and Purpose: The hemodynamic environment of an atherosclerotic plaque varies along the longitudinal direction. Investigating the changes in plaque morphology and its biomechanical environment along the longitudinal direction and their correlations will enhance our understanding of plaque progression and arterial remodeling. Methods: Six male patients with carotid stenosis >70% were recruited. Multisequence high-resolution MRI was performed at the carotid bifurcation. Carotid endarterectomy was performed following MRI, and the plaque tissue was collected for histological and mechanical testing. Patient-specific biomechanical modeling and simulations were conducted to calculate the mechanical stresses (wall shear stress [WSS] and von Mises stress [VMS]). Changes in plaque cross-sectional morphology, WSS, and VMS as well as their correlations were evaluated. Results: Positive correlations were found between % stenosis and % inflammation (MA) (p = 0.019), % lipid area and % MA (p = 0.026), and % calcification area and VMS (p = 0.007). Negative correlations were found between VMS and % stenosis (p = 0.028) and VMS and average WSS (p = 0.034). Moreover, the peak stresses and neovessels were found to be in the shoulder regions. High-stress concentrations were found in the interface regions of the calcification and surrounding tissue, thereby increasing plaque vulnerability. Conclusions: Correlations between the morphology and stresses suggest that arterial remodeling is a dynamic interaction between mechanical environment and plaque progression resulting in plaque heterogeneity. Our finding indicates that plaque heterogeneity is associated with plaque progression and can be combined with mechanical stresses for identifying high-risk plaques.

Common Variants Associated With OSMR Expression Contribute to Carotid Plaque Vulnerability, but Not to Cardiovascular Disease in Humans.

Background and Aims: Oncostatin M (OSM) signaling is implicated in atherosclerosis, however the mechanism remains unclear. We investigated the impact of common genetic variants in OSM and its receptors, OSMR and LIFR, on overall plaque vulnerability, plaque phenotype, intraplaque OSMR and LIFR expression, coronary artery calcification burden and cardiovascular disease susceptibility.Methods and Results: We queried Genotype-Tissue Expression data and found that rs13168867 (C allele) was associated with decreased OSMR expression and that rs10491509 (A allele) was associated with increased LIFR expression in arterial tissues. No variant was significantly associated with OSM expression.We associated these two variants with plaque characteristics from 1,443 genotyped carotid endarterectomy patients in the Athero-Express Biobank Study. After correction for multiple testing, rs13168867 was significantly associated with an increased overall plaque vulnerability (β = 0.118 ± s.e. = 0.040, p = 3.00 × 10−3, C allele). Looking at individual plaque characteristics, rs13168867 showed strongest associations with intraplaque fat (β = 0.248 ± s.e. = 0.088, p = 4.66 × 10−3, C allele) and collagen content (β = −0.259 ± s.e. = 0.095, p = 6.22 × 10−3, C allele), but these associations were not significant after correction for multiple testing. rs13168867 was not associated with intraplaque OSMR expression. Neither was intraplaque OSMR expression associated with plaque vulnerability and no known OSMR eQTLs were associated with coronary artery calcification burden, or cardiovascular disease susceptibility. No associations were found for rs10491509 in the LIFR locus.Conclusions: Our study suggests that rs1316887 in the OSMR locus is associated with increased plaque vulnerability, but not with coronary calcification or cardiovascular disease risk. It remains unclear through which precise biological mechanisms OSM signaling exerts its effects on plaque morphology. However, the OSM-OSMR/LIFR pathway is unlikely to be causally involved in lifetime cardiovascular disease susceptibility.

Abstract P572: Cerebral Hemodynamics Underlying Artery-To-Artery Embolism in Symptomatic Intracranial Atherosclerotic Disease

Background: Artery-to-artery embolism (AAE) is a common stroke mechanism in patients with symptomatic intracranial atherosclerotic disease (ICAD), which might be associated with a higher risk of recurrent stroke than other stroke mechanisms. We aimed to investigate cerebral hemodynamic features associated with AAE in symptomatic ICAD patients. Methods: Patients with acute, anterior-circulation ischemic stroke attributed to ICAD (50-99% stenosis) confirmed in CT angiography (CTA) were recruited from two teaching hospitals. We classified probable stroke mechanisms as isolated parent artery atherosclerosis occluding penetrating artery (PAO), AAE, hypoperfusion, and mixed mechanisms, based on infarct topography in MRI and ICAD lesion features. CTA-based computational fluid dynamics (CFD) models were built to simulate blood flow across culprit ICAD lesions. Translesional pressure ratio (PR=Pressure post-stenotic /Pressure pre-stenotic ) and translesional wall shear stress ratio (WSSR=WSS stenotic-throat /WSS pre-stenotic ) were calculated, to reflect the relative change of the two hemodynamic metrics across an ICAD lesion. PR ≤ median was defined as low PR, indicating a larger pressure gradient across the lesion; and WSSR ≥ 4 th quartile as high WSSR, indicating elevated WSS upon the lesion. We associated PR and WSSR with presence of AAE as a probable stroke mechanism. Results: Among 99 symptomatic ICAD patients, 44 had AAE as a probable stroke mechanism, 13 with AAE alone and 31 with coexisting hypoperfusion; the remaining patients respectively had isolated PAO (n=18) and isolated hypoperfusion (n=37) as the probable stroke mechanisms. High WSSR was independently associated with AAE (adjusted OR 4.21; 95% CI 1.33-13.26; p=0.014). The significant, positive relationship between high WSSR and higher risk of AAE remained in those with a low PR (adjusted OR 4.01; 95% CI 1.03-15.46; p=0.044), but not in those with a normal PR (p=0.621). Conclusions: High WSS upon ICAD lesions may increase plaque vulnerability and lead to distal embolism, while sustained antegrade flow across the ICAD lesion (normal PR) may help clear the emboli. In secondary prevention of symptomatic ICAD with AAE, impaired cerebral perfusion may be a therapeutic target.

Vascular smooth muscle cells in atherosclerosis: time for a re-assessment.

Vascular smooth muscle cells (VSMCs) are key participants in both early and late-stage atherosclerosis. VSMCs invade the early atherosclerotic lesion from the media, expanding lesions, but also forming a protective fibrous cap rich in extracellular matrix to cover the 'necrotic' core. Hence, VSMCs have been viewed as plaque-stabilizing, and decreased VSMC plaque content-often measured by expression of contractile markers-associated with increased plaque vulnerability. However, the emergence of lineage-tracing and transcriptomic studies has demonstrated that VSMCs comprise a much larger proportion of atherosclerotic plaques than originally thought, demonstrate multiple different phenotypes in vivo, and have roles that might be detrimental. VSMCs down-regulate contractile markers during atherosclerosis whilst adopting alternative phenotypes, including macrophage-like, foam cell-like, osteochondrogenic-like, myofibroblast-like, and mesenchymal stem cell-like. VSMC phenotypic switching can be studied in tissue culture, but also now in the media, fibrous cap and deep-core region, and markedly affects plaque formation and markers of stability. In this review, we describe the different VSMC plaque phenotypes and their presumed cellular and paracrine functions, the regulatory mechanisms that control VSMC plasticity, and their impact on atherogenesis and plaque stability.

High Dietary Inflammatory Index Is Associated With Increased Plaque Vulnerability of Carotid in Patients With Ischemic Stroke.

Long-term dietary patterns can influence the intensity of systemic inflammation and, therefore, the development of atherosclerosis. This study aimed to evaluate the association between dietary inflammatory index (DII) and vulnerability characteristics of carotid atherosclerotic plaques in patients with ischemic stroke. Patients with ischemic stroke within 7 days of onset were enrolled. DII was calculated from 32 food components with the help of a food frequency questionnaire. Vulnerable plaque was defined as presence of artery positive remodeling (remodeling index >1.1) and low CT attenuation plaques (<35 HU) on carotid arteries by computed tomography angiography. Of the 398 enrolled patients, 144 (36.2%) were detected with vulnerable plaque. Their DII ranged from -4.58 to 4.18. Patients with vulnerable plaques consumed less nutrients with anti-inflammatory properties, less fruits and vegetables (85.6±64.3 versus 94.6±74.4 g/d, P=0.027), and less nuts (5.66±7.14 versus 8.84±15.9 g/d, P=0.024) than patients without vulnerable plaques. Patients with vulnerable plaque had higher DII than patients without vulnerable plaque (-0.26±1.54 versus -0.64±1.53, P=0.018). Logistic regression analysis revealed that DII was associated with vulnerable plaques after adjusted for major confounding factors (odds ratio=1.307; 95% CI, 1.113-1.533). DII is associated with the vulnerability of carotid plaques in patients with ischemic stroke. Considering a possible causal relationship, the mechanisms underlying the association between diet and atherosclerosis warrant further study.

CD163+ macrophages are associated with a vulnerable plaque phenotype in human carotid plaques

Macrophages are a functionally heterogeneous group of immune cells abundant in atherosclerotic plaques. Macrophages expressing CD163 are associated with intraplaque hemorrhage and have previously been considered atheroprotective. However, in a recent study CD163-deficient atherosclerotic ApoE−/− mice exhibited smaller and less complex plaques, suggesting a proatherogenic role of CD163. Previous smaller studies on CD163+ macrophages and plaque stability in humans have yielded diverging results. Here we assessed the association of CD163+ cells to plaque vulnerability in a large cohort of human carotid plaques. CD163 protein expression was analyzed by immunohistochemistry in 200 human carotid plaques removed by endarterectomy from 103 patients with and 93 patients without cerebrovascular symptoms. Furthermore, CD163 mRNA expression was analyzed in 66 of the plaques. Both protein and mRNA expression of CD163 was higher in plaques from symptomatic patients and in plaques with high vulnerability index. CD163+ macrophages were primarily found in shoulder regions and in the center of the plaques. The present data show that CD163 is associated with increased plaque vulnerability in human carotid plaques, supporting the notion that CD163+ macrophages could contribute to clinical events.

Human cytomegalovirus infection is correlated with atherosclerotic plaque vulnerability in carotid artery.

Several studies have suggested that human cytomegalovirus (CMV) infection is closely related to the pathogenesis of atherosclerosis. The present study aimed to investigate the association between human CMV infection and carotid atherosclerotic plaque vulnerability in a Chinese population. In total, 42 patients with carotid atherosclerosis (observation group) and 30 healthy volunteers (control group) were recruited in our study from October 2016 to January 2018. Statistical analysis was carried out to calculate the infection rate of CMV in subjects. Spearman's rank analysis was performed to evaluate the correlation between CMV infection and atherosclerotic plaque vulnerability. The positive rate of CMV was significantly higher in the observation group compared to the control group, and matrix metalloproteinase 9 (MMP-9), tumor necrosis factor-α (TNF-α) and lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) expression levels were also elevated in the observation group compared to those in the control group. In carotid atherosclerotic patients, the detection rate of unstable plaques and the Crouse scores in vulnerable plaque were significantly higher in the CMV-positive group compared to those in the CMV-negative group. As revealed by correlation analysis, CMV infection was significantly positively correlated with plaque vulnerability and expression levels of MMP-9, TNF-α and LOX-1 in carotid atherosclerotic patients. Human CMV infection might be a potential risk factor for increased plaque vulnerability in patients with carotid atherosclerosis.

Ambient air pollution, traffic proximity and coronary atherosclerotic phenotype in China

BackgroundExposure to ambient air pollution is associated with cardiovascular risk, potentially via atherosclerosis promotion. The disease mechanisms underlying these associations remain uncertain. ObjectivesWe aim to investigate the relationship of air pollution and traffic proximity with subclinical atherosclerosis, using coronary plaque phenotypes to gain insight into potential mechanisms. MethodsCoronary plaque total and component volumes, high-risk plaque (HRP) appearance, and luminal stenosis were characterized by coronary computed tomography angiography in 2279 patients with atherosclerosis at baseline between 2014 and 2017. Annual average exposure to air pollutants including fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) was estimated by air pollution models for individual participants. Multiple linear regression models were used to assess the association of each exposure with plaque phenotypes and coronary stenosis, controlling for potential confounders. Multiple logistic regression models were used to estimate associations with plaque vulnerability. ResultsThe studied population was 60.2±9.2 years old. PM2.5 and NO2 concentrations were significantly associated with a 5.0% (95%CI: 0.3, 9.9%, per 15 μg/m3 increase for PM2.5), 12.0% (95%CI: 2.5, 22.5% per 20 μg/m3 for NO2) larger volume of non-calcified plaque, respectively. Increase in O3 concentration was associated with a 12.2% (95%CI: 2.2, 23.2%, per 5 μg/m3 O3) larger volume of calcified plaque and a 12.8% (95%CI: 0.9, 26.2%) greater lumen narrowing. Increased PM2.5 and NO2, was also associated with increase in HRP, determined by the napkin ring sign (odds ratio: 1.41 [95%CI: 1.10, 1.80] for PM2.5 and 1.78 [95%CI: 1.20, 2.63] for NO2) and positive remodeling index (OR: 1.11 [95%CI: 1.01, 1.21] for PM2.5 and 1.20 [95%CI: 1.02, 1.42] for NO2), respectively, indicating increased plaque vulnerability. ConclusionLong-term exposures to air pollution were associated with greater plaque volume and luminal stenosis, and increased plaque vulnerability with attendant risk of plaque rupture and erosion.

The impact of hyperglycaemia on PKM2-mediated NLRP3 inflammasome/stress granule signalling in macrophages and its correlation with plaque vulnerability: an in vivo and in vitro study

BackgroundThe mechanism of pyruvate kinase M2 (PKM2)-mediated inflammatory signalling in macrophages when plaques rupture and the impact of hyperglycaemia on the signalling are unclear. The present study aimed to explore the impact of hyperglycaemia on PKM2-mediated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome/stress granule signalling in macrophages and its correlation with plaque vulnerability in vivo and in vitro. MethodsFrom July to December 2019, 80 patients with coronary heart disease (CHD) were divided into acute ST-segment elevation myocardial infarction (STEMI) (n = 57) (DM-STEMI, n = 21; non-DM-STEMI, n = 36) and stable CHD (SCHD) groups (n = 23). Circulating mononuclear cells were isolated. The value of peak troponin I (TnI), the Global Registry of Acute Coronary Events (GRACE) risk score, and the expression levels of the related markers were quantified and compared. In vitro studies on the THP-1 cells were also performed. ResultsThe DM-STEMI group had a higher value of peak TnI and a higher GRACE risk score than the non-DM-STEMI group (p < 0.05). The highest expression levels of PKM2, NLRP3, interleukin (IL)-1β, and IL-18 and the lowest expression level of GTPase activating protein (SH3 domain)-binding protein 1 (G3BP1) (a stress granule marker protein) were observed in the DM-STEMI group, and they were followed by the non-DM-STEMI group and the SCHD group (p < 0.05). In vitro studies showed similar results and that TEPP-46 (a PKM2 activator) and 2-deoxy-d-glucose (a toxic glucose analogue) reversed the hyperglycaemia-induced increase in the NLRP3 inflammasome and decrease in G3BP1 expression. ConclusionHyperglycaemia might increase the activation of PKM2-mediated NLRP3 inflammasome/stress granule signalling and increase plaque vulnerability, associating it with worse prognosis. PKM2 may be a novel prognostic indicator and a new target for the treatment of patients with CHD and DM.

Abstract WP169: Symptomatic Intracranial Atherosclerotic Stenosis: The Associations Between Cerebral Hemodynamics and the Stroke Mechanisms

Background: Intracranial atherosclerotic stenosis (ICAS) may cause ischemic stroke by various mechanisms; artery-to-artery (AA) embolism and hypoperfusion often co-exist and bear a high risk of recurrent stroke despite optimal medical treatment. Little is known regarding how ICAS lesions cause ischemic strokes via different mechanisms, while the hemodynamic features of ICAS lesions may play an important role. Methods: Patients with acute ischemic stroke attributed to 50-99% ICAS in the anterior circulation confirmed in CT angiography (CTA) were recruited from two teaching hospitals. We classified probable stroke mechanisms as parent artery atherosclerosis occluding penetrating artery (PAO), AA embolism, hypoperfusion, and mixed mechanisms, based on infarct topography and ICAS lesion features. Computational fluid dynamics (CFD) models were built based on CTA to simulate blood flow across culprit ICAS lesions. We calculated translesional pressure ratio (PR), the ratio of pressures distal and proximal to the lesion; and translesional wall shear stress ratio (WSSR), the ratio of WSS at the stenosis throat and at proximal normal vessel segment. We defined PR ≤ median as low PR, indicating larger pressure gradient across the lesion, hence restricted downstream perfusion; and WSSR ≥ 4 th quartile as high WSSR, indicating higher WSS upon the lesion. We associated PR and WSSR with probable stroke mechanisms. Results: Among 99 patients, 44 had AA embolism as a probable stroke mechanism, 13 with AA embolism alone and 31 with coexisting hypoperfusion; 18 and 37 respectively had isolated PAO and isolated hypoperfusion as the probable stroke mechanisms. High WSSR was independently associated with AA embolism (adjusted OR 4.86; p = 0.008). The significant, positive relationship between high WSSR and higher risk of AA embolism remained in those with a low PR (adjusted OR 4.01; p = 0.044), but not in those with a normal PR (p = 0.621). Conclusions: High WSS upon ICAS lesions may increase plaque vulnerability, but it may only cause distal arterial embolism when there is impaired cerebral perfusion. Therefore, in secondary prevention of ischemic stroke in ICAS via AA embolism, impaired cerebral perfusion may be an important therapeutic target.

Carotid Plaque Morphology is Similar in Patients with Reduced and Normal Renal Function.

Background:Chronic Kidney Disease (CKD) is associated with an increased risk for cardiovascular events such as stroke. However, it is still unclear if decreased kidney function is associated with a vulnerable atherosclerotic plaque phenotype. To explore if renal function was associated with carotid plaque vulnerability we analyzed carotid plaques obtained at surgery from the Carotid Plaque Imaging Project (CPIP).Methods:Patients were enrolled through the CPIP cohort. The indication for surgery was plaques with stenosis >70%, associated with ipsilateral symptoms or plaques with stenosis >80% not associated with symptoms. Transversal sections from the most stenotic plaque region were analyzed for connective tissue, calcium, lipids, macrophages, intraplaque hemorrhage, and smooth muscle cells. Homogenates were analyzed for collagen and elastin.Results:Carotid endarterectomy specimens from 379 patients were obtained. The median GFR was 73 ml/min/1.73 m2. Plaque characteristics showed no significant association with eGFR, neither when eGFR was divided in CKD groups nor when eGFR was handled as a continuous variable and adjusting for other known risk factors (ie, age, diabetes, hypertension, and smoking).Conclusions:The higher risk of cardiovascular disease such as stroke in CKD is not associated with increased plaque vulnerability and other factors have to be sought.