Colchicine exerts anti-atherosclerotic and -plaque-stabilizing effects targeting foam cell formation.

Colchicine is a broad-acting anti-inflammatory agent that has attracted interest for repurposing in atherosclerotic cardiovascular disease. Here, we studied its ability at a human equivalent dose of 0.5 mg/day to modify plaque formation and composition in murine atherosclerosis and investigated its actions on macrophage responses to atherogenic stimuli in vitro. In atherosclerosis induced by high-cholesterol diet, Apoe-/- mice treated with colchicine had 50% reduction in aortic oil Red O+ plaque area compared to saline control (p = .001) and lower oil Red O+ staining of aortic sinus lesions (p = .03). In vitro, addition of 10 nM colchicine inhibited foam cell formation from murine and human macrophages after treatment with oxidized LDL (ox-LDL). Mechanistically, colchicine downregulated glycosylation and surface expression of the ox-LDL uptake receptor, CD36, and reduced CD36+ staining in aortic sinus plaques. It also decreased macrophage uptake of cholesterol crystals, resulting in lower intracellular lysosomal activity, inhibition of the NLRP3 inflammasome, and reduced secretion of IL-1ß and IL-18. Colchicine's anti-atherosclerotic actions were accentuated in a mouse model of unstable plaque induced by carotid artery tandem stenosis surgery, where it decreased lesion size by 48% (p = .01), reduced lipid (p = .006) and necrotic core area (p = .007), increased collagen content and cap-to-necrotic core ratio (p = .05), and attenuated plaque neutrophil extracellular traps (p < .001). At low dose, colchicine's effects were not accompanied by the evidence of microtubule depolymerization. Together, these results show that colchicine exerts anti-atherosclerotic and plaque-stabilizing effects at low dose by inhibiting foam cell formation and cholesterol crystal-induced inflammation. This provides a new framework to support its repurposing for atherosclerotic cardiovascular disease.

Role of sirtuins in attenuating plaque vulnerability in atherosclerosis.

Atherosclerosis is characterized by the development of intimal plaque, thrombosis, and stenosis of the vessel lumen causing decreased blood flow and hypoxia precipitating angina. Chronic inflammation in the stable plaque renders it unstable and rupture of unstable plaques results in the formation of emboli leading to hypoxia/ischemia to the organs by occluding the terminal branches and precipitate myocardial infarction and stroke. Such delibitating events could be controlled by the strategies that prevent plaque development or plaque stabilization. Despite the use of statins to stabilize plaques, there is a need for novel targets due to continuously increasing cases of cardiovascular events. Sirtuins (SIRTs), a family of signaling proteins, are involved in sustaining genome integrity, DNA damage response and repair, modulating oxidative stress, aging, inflammation, and energy metabolism. SIRTs play a critical role in modulating inflammation and involves in the development and progression of atherosclerosis. The role of SIRTs in relation to atherosclerosis and plaque vulnerability is scarcely discussed in the literature. Since SIRTs regulate oxidative stress, inflammation, and aging, they may also regulate plaque progression and vulnerability as these molecular mechanisms underlie the pathogenesis of plaque development, progression, and vulnerability. This review critically discusses the role of SIRTs in plaque progression and vulnerability and the possibility of targeting SIRTs to attenuate plaque rupture, focusing on the highlights in genomics, molecular pathways, and cell types involved in the underlying pathophysiology.

What Is the Added Value of Carotid CEUS in the Characterization of Atherosclerotic Plaque?

Background and Objectives: Unstable atherosclerotic plaque in the arteries is one of the main risk factors for cerebral ischemia. Duplex ultrasound is a frequently used diagnostic method, but it has some limitations for microvascularization and neovascularization evaluation. The aim of this review was to evaluate the role of the new multiparametric US method-contrast-enhanced ultrasound (CEUS)-in atherosclerotic plaque instability verification. Materials and Methods: Original studies, reviews, and meta-analyses were included in this article. A total of 53 studies were retrieved; 29 were included in this study. Results: Carotid artery CEUS as a part of the multiparametric ultrasound method shows promising results and provides additional characteristics of soft- and high-risk atherosclerotic plaques; it can be advised in clinical practice for patients with carotid artery soft- and high-risk plaques. However, there are some limitations, such as extensive calcinosis with important acoustic shadows in carotid atherosclerotic plaque neovascularization diagnostics by CEUS. The added value of CEUS in the characterization of atherosclerotic plaque is that it indicates regions with high neovascularization and visualizes ulcerations on plaque surfaces, suggestive of increased instability risk.

Residual risks and evolving atherosclerotic plaques.

Atherosclerotic disease of the coronary and carotid arteries is the primary global cause of significant mortality and morbidity. The chronic occlusive diseases have changed the epidemiological landscape of health problems both in developed and the developing countries. Despite the enormous benefit of advanced revascularization techniques, use of statins, and successful attempts of targeting modifiable risk factors, like smoking and exercise in the last four decades, there is still a definite "residual risk" in the population, as evidenced by many prevalent and new cases every year. Here, we highlight the burden of the atherosclerotic diseases and provide substantial clinical evidence of the residual risks in these diseases despite advanced management settings, with emphasis on strokes and cardiovascular risks. We critically discussed the concepts and potential underlying mechanisms of the evolving atherosclerotic plaques in the coronary and carotid arteries. This has changed our understanding of the plaque biology, the progression of unstable vs stable plaques, and the evolution of plaque prior to the occurrence of a major adverse atherothrombotic event. This has been facilitated using intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy in the clinical settings to achieve surrogate end points. These techniques are now providing exquisite information on plaque size, composition, lipid volume, fibrous cap thickness and other features that were previously not possible with conventional angiography.

Immunohistochemical analysis of MMP-9 and COX-2 expression in carotid atherosclerotic plaques among patients undergoing carotid endarterectomy: A prospective study.

BACKGROUND: Matrix metalloproteinase-9 protein (MMP-9) and cyclooxygenase-2 (COX-2) proteins may have a role in remodelling of atherosclerotic plaques. We analysed and compared the radiological, histological and immunohistochemical characteristics of carotid atherosclerotic plaques between symptomatic and asymptomatic patients who underwent carotid endarterectomy (CEA). METHODS: This prospective single-blinded study included 31 patients (70 [64-75] years, 58% males, 42% symptomatic) who underwent CEA and a total of 155 carotid plaque sections that were analysed. Preoperative assessment and multimodality diagnostic imaging with magnetic resonance imaging (MRI) or computed tomography angiography (CTA), histological and immunohistochemical analyses of carotid plaques including the expression of MMP-9 and COX-2 proteins were performed. RESULTS: Symptomatic and asymptomatic patients did not significantly differ in respect to preoperative characteristics. Unstable plaques were detected in 12/13 (92.3%, p = 0.020) symptomatic patients using MRI or CTA. There was no perioperative mortality and perioperative outcomes were comparable in both groups. A significantly higher expression of MMP-9 in macrophages was observed among symptomatic patients (p = 0.020). ROC curve analysis showed statistically significant associations of both the higher intensity of COX-2 staining in CD68 PG-M1 positive macrophages (area under the curve [AUC]=0.701, p = 0.014) and higher MVD (AUC=0.821, p < 0.001) within the plaque with cerebrovascular symptoms. The expression of COX-2 and the intensity of COX-2 staining in macrophages within the unstable carotid plaques detected by preoperative MRI or CTA were significantly higher (76.1% vs. 40.0%, p = 0.038; 76.2% vs. 30.0%, p = 0.01, respectively). CONCLUSIONS: Advanced non-invasive multimodality diagnostic imaging including MRI or CTA is reliable in differentiating unstable from stable carotid plaques. High expression of MMP-9 and COX-2 in macrophages within the symptomatic plaque is associated with increased risk of cerebrovascular complications. TRIAL REGISTRATION: This study has been registered at the ISRCTN registry (ID ISRCTN46536832), isrctn.org Identifier: https://www.isrctn.com/ISRCTN46536832.

Implication of miR-155-5p and miR-143-3p in the Vascular Insulin Resistance and Instability of Human and Experimental Atherosclerotic Plaque.

(1) Background: Cardiovascular diseases (CVDs) are the main cause of death in developed countries, being atherosclerosis, a recurring process underlying their apparition. MicroRNAs (miRNAs) modulate the expression of their targets and have emerged as key players in CVDs; (2) Methods: 18 miRNAs were selected (Pubmed and GEO database) for their possible role in promoting atherosclerosis and were analysed by RT-qPCR in the aorta from apolipoprotein E-deficient (ApoE-/-) mice. Afterwards, the altered miRNAs in the aorta from 18 weeks-ApoE-/- mice were studied in human aortic and carotid samples; (3) Results: miR-155-5p was overexpressed and miR-143-3p was downregulated in mouse and human atherosclerotic lesions. In addition, a significant decrease in protein kinase B (AKT), target of miR-155-5p, and an increase in insulin-like growth factor type II receptor (IGF-IIR), target of miR-143-3p, were noted in aortic roots from ApoE-/- mice and in carotid plaques from patients with advanced carotid atherosclerosis (ACA). Finally, the overexpression of miR-155-5p reduced AKT levels and its phosphorylation in vascular smooth muscle cells, while miR-143-3p overexpression decreased IGF-IIR reducing apoptosis in vascular cells; (4) Conclusions: Our results suggest that miR-155-5p and miR-143-3p may be implicated in insulin resistance and plaque instability by the modulation of their targets AKT and IGF-IIR, contributing to the progression of atherosclerosis.

The role of magnetic resonance imaging and the expression of MMP-9 protein in the analysis of carotid atherosclerotic plaques in patients undergoing carotid endarterectomy: a prospective pilot study.

Components of carotid atherosclerotic plaque can be analysed preoperatively by non-invasive advanced imaging modalities such as magnetic resonance imaging (MRI). The expression of matrix metalloproteinase-9 protein (MMP-9), which has a potential role in remodelling of atherosclerotic plaques, can be analysed immunohistochemically. The aim of the present prospective pilot study is to analyse histological characteristics and expression of MMP-9 in carotid plaques of patients undergoing carotid endarterectomy (CEA) and to investigate the correlation with preoperative clinical symptoms and MRI features. Preoperative clinical assessment, MRI imaging, postoperative histological and immunohistochemical analyses were performed. Fifteen patients with symptomatic (7/15; 47%) and asymptomatic carotid artery stenosis undergoing CEA were included. Among symptomatic patients, 5 (71%) had recent stroke and 2 (29%) had recent transient ischaemic attack with a median timing of 6 weeks (IQR: 1, 18) before the surgery. Both groups did not significantly differ in respect to preoperative characteristics. Prevalence of unstable plaque was higher in symptomatic than asymptomatic patients, although it was not significant (63% vs. 37%, p = 0.077). The expression of MMP-9 in CD68 cells within the plaque by semiquantitative analysis was found to be significantly higher in symptomatic as compared to asymptomatic patients (86% vs. 25% with the highest expression, p = 0.014). The average microvascular density was found to be higher and lipid core area larger among both symptomatic patients and unstable carotid plaque specimens, although this did not reach statistical significance (p = 0.064 and p = 0.132, p = 0.360 and p = 0.569, respectively). Our results demonstrate that MRI is reliable in classifying carotid lesions and differentiating unstable from stable plaques. We have also shown that the expression of MMP-9 is significantly higher among symptomatic patients undergoing CEA.

MicroRNA-205-5p Promotes Unstable Atherosclerotic Plaque Formation In Vivo.

PURPOSE: Atherosclerosis is a narrowing of the arteries caused by plaque buildup. MicroRNAs (miRNAs) have been proposed to participate in the pathogenesis of atherosclerosis. Here, we aimed to investigate miR-205-5p's role in promoting atherosclerotic progression. METHODS: Knock-in (KI) mice with human/murine miR-205-5p within the murine host gene for miR-205 (MIR205HG) were crossed with apolipoprotein E knockout (Apoe-/-) mice. This miR-205KI Apoe-/- murine model was employed to study the impact of miR-205-5p in Apoe-/- mice susceptible to atherosclerotic plaque formation. RESULTS: miR-205KI Apoe-/-mice developed larger, more unstable plaques relative to their Apoe-/- counterparts (0.45 vs. 0.26 mm2, P < 0.001). miR-205KI Apoe-/- mice exhibited lower serum levels of high-density lipoprotein cholesterol (HDL-C) (5.18 vs. 19.31 mg/dL, P < 0.001) and triglycerides (32.79 vs. 156.76 mg/dL, P < 0.001) with system-wide reversal of cholesterol transport. Macrophages derived from miR-205KI Apoe-/- mice exhibited ~ 20% lowered cholesterol efflux capability with enhanced pro-inflammatory gene expression through lipid raft formation. Bone marrow transplantation demonstrated that bone marrow (BM) donor cells with miR-205-5pKI simulated plaque formation independent of the recipients' miR-205-5p status. CONCLUSIONS: miR-205-5p encourages unstable atherogenesis in vivo. miR-205-5p also adversely influences lipid metabolism and promotes a pro-inflammatory macrophage phenotype. Our findings advocate miR-205-5p as a potential therapeutic target for combating unstable atherogenesis.

Early identification of carotid vulnerable plaque in asymptomatic patients.

BACKGROUND: This study was to explore the influencing factors of atherosclerotic plaque formation and stability in patients with asymptomatic carotid atherosclerotic plaques, so as to identify the vulnerable plaques at early stage, and then find high-risk group of cardio-cerebrovascular events for early clinical intervention to reduce related mortality and disability. METHODS: A total of 302 enrolled patients with asymptomatic carotid atherosclerotic plaques were divided into 3 groups based on the results of carotid artery color Doppler ultrasound: atherosclerotic unstable plaque (UP) group, atherosclerotic stable plaque (SP) group, and control group without plaques. Serum markers were measured by ELISA. χ2 test, t test, Pearson correlation analysis, and Logistic multivariate regression analysis were used in the analysis, and P < 0.05 was considered statistically significant. RESULTS: It revealed that high MMP-9, LOX-1and YKL-40 were independent risk factors for unstable plaque formation. The area under the curve (AUC) of serum markers combined with MMP-9, LOX-1 and YKL-40 was 0.850, with sensitivity 87.67%, specificity 81.13%, and diagnostic accuracy 84.92%, which was significantly better than the individual diagnostic efficacy of other three factors. The accuracy rate of Crouse Plaque Score (CPS) in the diagnosis of vulnerable plaques was 61.90%, the 10-year ICVD diagnosis accuracy rate was 56.75%, and the diagnostic accuracy of serum markers was significantly better than CPS and 10-year ICVD. CONCLUSION: Noninvasive cervical color Doppler ultrasound combined with serum markers MMP-9, LOX-1 and YKL-40 have significant early recognition effect on asymptomatic carotid vulnerable plaque patients.

A model to predict unstable carotid plaques in population with high risk of stroke.

BACKGROUND: Several models have been developed to predict asymptomatic carotid stenosis (ACS), however these models did not pay much attention to people with lower level of stenosis (<50% or carotid plaques, especially instable carotid plaques) who might benefit from early interventions. Here, we developed a new model to predict unstable carotid plaques through systematic screening in population with high risk of stroke. METHODS: Community residents who participated the China National Stroke Screening and Prevention Project (CNSSPP) were screened for their stroke risks. A total of 2841 individuals with high risk of stroke were enrolled in this study, 266 (9.4%) of them were found unstable carotid plaques. A total of 19 risk factors were included in this study. Subjects were randomly distributed into Derivation Set group or Validation Set group. According to their carotid ultrasonography records, subjects in derivation set group were further categorized into unstable plaque group or stable plaque group. RESULTS: 174 cases and 1720 cases from Derivation Set group were categorized into unstable plaque group and stable plaque group respectively. The independent risk factors for carotid unstable plaque were: male (OR 1.966, 95%CI 1.406-2.749), older age (50-59, OR 6.012, 95%CI 1.410-25.629; 60-69, OR 13.915, 95%CI 3.381-57.267;≥70, OR 31.267, 95%CI 7.472-130.83), married(OR 1.780, 95%CI 1.186-2.672), LDL-C(OR 2.015, 95%CI 1.443-2.814), and HDL-C(OR 2.130, 95%CI 1.360-3.338). A predictive scoring system was generated, ranging from 0 to 10. The cut-off value of this predictive scoring system is 6.5. The AUC value for derivation and validation set group were 0.738 and 0.737 respectively. CONCLUSIONS: For those individuals with high risk of stroke, we developed a new model which could identify those who have a higher chance to have unstable carotid plaques. When an individual's predictive model score exceeds 6.5, the probability of having carotid unstable plaques is high, and carotid ultrasonography should be conducted accordingly. This model could be helpful in the primary prevention of stroke.

High-intensity vessel sign on fluid-attenuated inversion recovery imaging: a novel imaging marker of high-risk carotid stenosis-a MRI and SPECT study.

BACKGROUND: Measurement of luminal stenosis and determination of plaque instability using MR plaque imaging are effective strategies for evaluating high-risk carotid stenosis. Nevertheless, new methods are required to identify patients with carotid stenosis at risk of future stroke. We aimed to clarify the mechanisms and clinical implications of the hyperintense vessel sign (HVS) as a marker of high-risk carotid stenosis. METHODS: We included 148 patients who underwent carotid stent (CAS) or carotid endarterectomy (CEA). MRI FLAIR was performed to detect HVS prior to and within 7 days after CAS/CEA. MR plaque imaging and 123I-iodoamphetamine SPECT was performed prior to CEA/CAS. Detailed characteristics of HVS were categorized in terms of symptomatic status, hemodynamic state, plaque composition, and HVS on time series. RESULTS: Forty-six of 80 symptomatic hemispheres (57.5%) and 5 of 68 asymptomatic hemispheres (7.4%) presented HVS (P < 0.01). Of the 46 symptomatic hemispheres with HVS, 19 (41.3%) presented with hemodynamic impairment and 27 (58.7%) presented without hemodynamic impairment. Of 19 hemispheres with hemodynamic impairment, 12 subjects (63.2%) showed high intensity and 7 (36.8%) showed iso-intensity plaques on T1WI. All 27 hemispheres without hemodynamic impairment showed high-intensity plaques. Of the five asymptomatic and HVS-positive hemispheres, one showed hemodynamic impairment; MR plaque imaging revealed T1 iso-intensity. The other four hemispheres that did not show hemodynamic impairment showed T1WI high-intensity plaques. CONCLUSION: There are two possible mechanisms of HVS, hemodynamic impairment due to severe carotid stenosis and micro-embolism from unstable plaques. HVS could be a radiological marker for high-risk carotid stenosis.

[Predictors of acute coronary syndrome in patients with ischaemic heart disease]. / Prediktory ostrogo koronarnogo sindroma u patsientov s ishemicheskoi bolezn'iu serdtsa.

Acute coronary syndrome has for a long time been giving no way of decreasing mortality related to ischaemic heart disease. The primary cause of acute coronary syndrome in the majority of cases is rupture of an unstable atherosclerotic plaque in the coronary artery followed by thrombosis thereof. The main missions of modern cardiology include: assessment of the risk of acute coronary syndrome, identification of predictors of adverse events, and working-out of measures aimed at prevention and optimal management of patients with ischaemic heart disease. This article deals with clinical and morphological factors associated with destabilization of coronary plaques, their rupture, and the development of an acute coronary event.

Carotid Artery Stenting Using a Closed-Cell Stent-in-Stent Technique for Unstable Plaque.

Purpose: To examine whether carotid artery stenting (CAS) of stenoses with unstable plaque using a closed-cell stent-in-stent technique prevents plaque protrusion. Materials and Methods: Between December 2014 and August 2018, 35 consecutive patients (mean age 75.8 years; 29 men) with carotid artery stenosis (20 symptomatic) and unstable plaque diagnosed by magnetic resonance imaging were prospectively analyzed. Mean diameter stenosis was 83.5%. All CAS procedures were performed with stent-in-stent placement of Carotid Wallstents using an embolic protection device and conservative postdilation. The technical success rate, incidence of plaque protrusion, ischemic stroke rate within 30 days, and new ipsilateral ischemic lesions on diffusion-weighted imaging (DWI) within 48 hours after CAS were prospectively assessed. Follow-up outcomes included the incidences of ipsilateral stroke and restenosis. Results: The technical success rate was 100%. No plaque protrusion or stroke occurred in any patient. New ischemic lesions were observed on DWI in 10 (29%) patients. During the mean 11.6-month follow-up, no ipsilateral strokes occurred. Two (6%) patients developed asymptomatic restenosis recorded as 53% lumen narrowing and occlusion, respectively. Conclusion: CAS using a closed-cell stent-in-stent technique for unstable plaque may be useful for preventing plaque protrusion and ischemic complications.

Correlation between of small dense low-density lipoprotein cholesterol with acute cerebral infarction and carotid atherosclerotic plaque stability.

BACKGROUND: Acute cerebral infarction (ACI) is seriously harmful to human health worldwide. However, at present, the risk of disease onset is still not accurately predicted for some people. METHODS: Five hundred and nineteen patients with ACI and 300 healthy controls were included in this study. We divided the patients into three groups according to the results of cervical artery contrast-enhanced ultrasound. Ninety-five patients were in the CAS without plaque group, 108 patients were in the stable plaque group, and 316 patients were in the unstable plaque group. TC, TG, HDL-C, LDL-C, and sdLDL-C were measured in all subjects. RESULTS: The level of small dense low-density lipoprotein cholesterol (sdLDL-C) in the ACI group was significantly higher than that in the control group (P < 0.001). Logistic regression analysis showed that sdLDL-C was an independent risk factor for ACI (OR = 1.067, 95% CI: 1.041-1.093, P < 0.001); serum sdLDL-C was significantly higher in the unstable plaque group than in the stable plaque group and plaque-free group (P < 0.05, P < 0.001); serum sdLDL-C was also higher in the stable plaque group than the plaque-free group (P < 0.001). Logistic regression analysis showed that sdLDL-C was an independent risk factor for unstable carotid plaques (OR = 1.053, 95% CI: 1.038-1.068, P < 0.001); Spearman correlation analysis showed that sdLDL-C test results were positively correlated with carotid plaque stability (r = 0.363, P < 0.001). CONCLUSION: Small dense low-density lipoprotein cholesterol is an independent risk factor for the onset of ACI and may be an early serum marker for this disease.

Unstable Carotid Plaque is Associated With Coagulation Function and Platelet Activity Evaluated by Thrombelastography.

BACKGROUND: Rupture of unstable carotid plaque and consequently occlusive thrombus formation for the most part cause ischemic cerebral vascular event. Many researchers have been studying on the risk predictors of carotid plaque formation. But the risk factors for unstable carotid plaque have not been researched for so much. In the current study, we aimed to evaluate the association of coagulation function and carotid plaque especially unstable plaque by thrombelastography (TEG). METHODS: This was a cross-sectional study. Consecutive eligible patients with acute ischemic stroke were included and their TEG data were collected. Carotid plaque was evaluated by carotid ultrasound. Echolucent plaque and heterogeneous echo plaque in ultrasound were classified as unstable carotid plaque. Patients were classified according to being with carotid plaque or unstable plaque for comparison. RESULTS: Four hundred and seven patients were enrolled. Compared to those without carotid plaques, patients with carotid plaques had higher ages, higher incidence of hypertension and diabetes mellitus, lower k (P = .017) and higher angle (P = .021) on TEG. In the comparison between groups with unstable plaque and stable plaque, no significant difference was found in baseline characteristics; higher serum fibrinogen and higher maximum amplitude on TEG were significantly correlated to unstable carotid plaques (P = .051, P = .009). Multivariate logistic analysis revealed that age, hypertension, and smoking were independent risk factors of carotid plaques formation; higher serum fibrinogen was an independent risk factor of unstable plaques formation. CONCLUSIONS: This study demonstrates that carotid plaques formation in ischemic stroke patients has a link to abnormal coagulation function, while high platelet activity has an additional contribution to unstable plaque formation.

Study of the Inflammatory Mechanisms in Hyperhomocysteinemia on Large-Artery Atherosclerosis Based on Hypersensitive C-Reactive Protein-A Study from Southern China.

OBJECTIVE: To study the inflammatory mechanism of hyperhomocysteinemia on large-artery atherosclerosis based on hypersensitive C-reactive protein in patients. METHODS: In all, 153 inpatients and 1357 physical examinees were selected. The levels of homocysteine were compared between the carotid/intracranial artery stenosis group and the nonstenosis group, between the carotid artery unstable plaque group and the nonplaque group, and between the intima-media thickness (IMT) greater than or equal to 1 group and the normal IMT group. The hypersensitive C-reactive protein levels were compared between the lacunar infarction (LI) group and the nonstroke control group and between the unstable plaque group and the nonplaque group. RESULTS: Homocysteine level was significantly higher in the carotid/intracranial artery stenosis group than in the nonstenosis group, in the LI group than in the inpatient nonstroke group, and in the IMT greater than or equal to 1 group than in the normal IMT group. The hypersensitive C-reactive protein level was significantly higher in the LI group than in the nonstroke group and in the unstable plaque group than in the nonplaque group. CONCLUSIONS: Hyperhomocysteinemia may aggravate the development of IMT, carotid atherosclerotic plaque instability, and carotid/intracranial artery stenosis by increasing inflammation, ultimately leading to the occurrence of LI. Hyperhomocysteinemia-induced inflammation mechanism warrants further study.

Stabilization of symptomatic carotid atherosclerotic plaques by statins: a clinico-pathological analysis.

Human and animal studies have revealed a stabilization of atherosclerotic plaques by statins. However, the stabilization of human carotid plaques has not been thoroughly described pathologically. This analysis explored the relationship between statin therapy and plaque stability in carotid endarterectomy (CEA) specimens. We analyzed specimens harvested between May 2015 and February 2017, from 79 consecutive patients presenting with > 70% carotid artery stenoses, of whom 66 were untreated (group 1) and 13 treated (group 2) with a statin. Immunohistochemistry was performed, using an endothelial specific antibody to CD31, CD34 and platelet derived growth factor receptor-ß. The prevalence of plaque ruptures (P = 0.009), lumen thrombi (P = 0.009), inflammatory cells (P = 0.008), intraplaque hemorrhages (P = 0.030) and intraplaque microvessels (P < 0.001) was significantly lower in group 2 than in group 1. Among 66 patients presenting with strokes and infarct sizes > 1.0 cm3 on magnetic resonance imaging, the mean infarct volume was significantly smaller (P = 0.031) in group 2 (4.2 ± 2.5 cm3) than in group 1 (8.2 ± 7.1 cm3). The difference in mean concentration of low-density lipoprotein cholesterol between group 1 (121 ± 32 mg/dl) and group 2 (105 ± 37 mg/dl) was non-significant (P = 0.118). This analysis of plaques harvested from patients undergoing CEA suggests that statin therapy mitigates the plaque instability, which, in patients presenting with strokes, might decrease infarct volume.

Intravascular Photothermal Strain Imaging for Lipid Detection.

Cardiovascular disease (CVD) is one of the major threats to humanity, accounting for one-third of the world's deaths. For patients with high-risk CVD, plaque rupture can lead to critical condition. It is therefore important to determine the stability of the plaque and classify the patient's risk level. Lipid content is an important determinant of plaque stability. However, conventional intravascular imaging methods have limitations in finding lipids. Therefore, new intravascular imaging techniques for plaque risk assessment are urgently needed. In this study, a novel photothermal strain imaging (pTSI) was applied to an intravascular imaging system for detecting lipids in plaques. As a combination of thermal strain imaging and laser-induced heating, pTSI differentiates lipids from other tissues based on changes in ultrasound (US) velocity with temperature change. We designed an optical pathway to an intravascular ultrasound catheter to deliver 1210-nm laser and US simultaneously. To establish the feasibility of the intravascular pTSI system, we experimented with a tissue-mimicking phantom made of fat and gelatin. Due to the difference in the strain during laser heating, we can clearly distinguish fat and gelatin in the phantom. The result demonstrates that pTSI could be used with conventional intravascular imaging methods to detect the plaque lipid.

Immunohistochemical Features of Different Types of Unstable Atherosclerotic Plaques of Coronary Arteries.

We performed a complex morphological study of samples of different types of unstable atherosclerotic plaques obtained from 33 men with occlusive coronary atherosclerosis, who underwent coronary artery endarterectomy during coronary artery bypass surgery. In the samples, expression of MMP-2 and MMP-9, collagen IV, CD31, CD34, factor VIII, and actin of smooth muscle cells was evaluated by morphometric and immunohistochemical methods. The maximum expression of MMP-9 was found in unstable plaques of the lipid type, where it 1.4- and 1.24-fold surpassed the corresponding levels in plaques of the inflammatory-erosive and degenerative-necrotic types. Unstable plaques of the degenerative-necrotic type are characterized by the most intensive expression of collagen IV in comparison with plaques of the inflammatory-erosive and lipid types (by 2.8 and 2.2 times, respectively). The maximum neovascularization was detected in inflammatory-erosive plaques, which was confirmed by enhanced expression of CD31 and CD34 markers in comparison with plaques of the lipid (by 7.6 and 18.95 times, respectively) and degenerative-necrotic (by 31.1 and 39.8 times) types.

Pathological Quantification of Carotid Artery Plaque Instability in Patients Undergoing Carotid Endarterectomy.

BACKGROUND: Unstable atherosclerotic carotid plaques cause cerebral thromboemboli and ischemic events. However, this instability has not been pathologically quantified, so we sought to quantify it in patients undergoing carotid endarterectomy (CEA).Methods and Results:Carotid plaques were collected during CEA from 67 symptomatic and 15 asymptomatic patients between May 2015 and August 2016. The specimens were stained with hematoxylin-eosin and elastica-Masson. Immunohistochemistry was performed using an endothelial-specific antibody to CD31, CD34 and PDGFRß. The histopathological characteristics of the plaques were studied. By multiple-variable logistic regression analysis, plaque instability correlated with the presence of plaque rupture [odds ratio (OR), 9.75; P=0.013], minimum fibrous cap thickness (OR per 10 µm 0.70; P=0.025), presence of microcalcifications in the fibrous cap (OR 7.82; P=0.022) and intraplaque microvessels (OR 1.91; P=0.043). Receiver-operating characteristics analyses showed that these factors combined into a single score diagnosed symptomatic carotid plaques in patients with carotid artery stenosis with a high level of accuracy (area under the curve 0.92; 95% confidence interval 0.85-0.99 vs. asymptomatic). CONCLUSIONS: This analysis of carotid plaque instability strongly suggested that the diagnostic scoring of carotid plaque instability improves the understanding and treatment of carotid artery disease in patients undergoing CEA.