Microplastics and Nanoplastics in Atheromas and Cardiovascular Events.

BACKGROUND: Microplastics and nanoplastics (MNPs) are emerging as a potential risk factor for cardiovascular disease in preclinical studies. Direct evidence that this risk extends to humans is lacking. METHODS: We conducted a prospective, multicenter, observational study involving patients who were undergoing carotid endarterectomy for asymptomatic carotid artery disease. The excised carotid plaque specimens were analyzed for the presence of MNPs with the use of pyrolysis-gas chromatography-mass spectrometry, stable isotope analysis, and electron microscopy. Inflammatory biomarkers were assessed with enzyme-linked immunosorbent assay and immunohistochemical assay. The primary end point was a composite of myocardial infarction, stroke, or death from any cause among patients who had evidence of MNPs in plaque as compared with patients with plaque that showed no evidence of MNPs. RESULTS: A total of 304 patients were enrolled in the study, and 257 completed a mean (±SD) follow-up of 33.7±6.9 months. Polyethylene was detected in carotid artery plaque of 150 patients (58.4%), with a mean level of 21.7±24.5 µg per milligram of plaque; 31 patients (12.1%) also had measurable amounts of polyvinyl chloride, with a mean level of 5.2±2.4 µg per milligram of plaque. Electron microscopy revealed visible, jagged-edged foreign particles among plaque macrophages and scattered in the external debris. Radiographic examination showed that some of these particles included chlorine. Patients in whom MNPs were detected within the atheroma were at higher risk for a primary end-point event than those in whom these substances were not detected (hazard ratio, 4.53; 95% confidence interval, 2.00 to 10.27; P<0.001). CONCLUSIONS: In this study, patients with carotid artery plaque in which MNPs were detected had a higher risk of a composite of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than those in whom MNPs were not detected. (Funded by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale and others; ClinicalTrials.gov number, NCT05900947.).

Altered Callosal Morphology and Connectivity in Asymptomatic Carotid Stenosis.

BACKGROUND: Carotid stenosis, even in the clinically asymptomatic stage, causes cognitive impairment, silent lesions, and hemispheric changes. The corpus callosum (CC) is crucial for hemispheric cortical integration and specialization. PURPOSE: To examine if CC morphology and connectivity relate to cognitive decline and lesion burden in asymptomatic carotid stenosis (ACS). STUDY TYPE: Retrospective, cross-sectional. POPULATION: 33 patients with unilaterally severe (70%) ACS and 28 demographically and comorbidity-matched controls. A publicly available healthy adult lifespan (ages between 18 and 80; n = 483) MRI dataset was also included. FIELD STRENGTH/SEQUENCE: A 3.0 T; T1 MPRAGE and diffusion weighted gradient echo-planar imaging sequences. ASSESSMENT: Structural MRI and multidomain cognitive data were obtained. Midsagittal CC area, circularity, thickness, integrity, and probabilistic tractography were calculated and correlated with cognitive tests and white matter hyperintensity. Fractional anisotropy, mean diffusivity (MD), and radial diffusivity were determined from DTI. STATISTICAL TESTS: Independent two-sample t-tests, χ2 tests, Mann-Whitney U, locally weighted scatterplot smoothing (LOWESS) curve fit, and Pearson correlation. A P value < 0.05 was considered statistically significant. RESULTS: Patients with ACS demonstrated significant reductions in callosal area, circularity, and thickness compared to controls. The callosal atrophy was significantly correlated with white matter hyperintensity size (r = -0.629, P < 0.001). Voxel-wise analysis of diffusion measures in the volumetric CC showed that ACS patients exhibited significantly lower fractional anisotropy and higher MD and radial diffusivity in the genu and splenium of the CC than controls. Further lifespan trajectory analysis showed that although the midsagittal callosal area, circularity, and thickness exhibited age-related decreases, the values in the ACS patients were significantly lower in all age groups. DATA CONCLUSION: Midsagittal callosal atrophy and connectivity reflect the load of silent lesions and the severity of cognitive decline, respectively, suggesting that CC degeneration has potential to serve as an early marker in ACS. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Single-Cell Transcriptomics Reveals Crucial Cell Subsets and Functional Heterogeneity Associated With Carotid Atherosclerosis and Cerebrovascular Events.

BACKGROUND: Carotid atherosclerosis is a chronic inflammatory disorder and is responsible for the vast majority of ischemic strokes. Inappropriate innate and adaptive immune responses synergize with malfunctional vascular wall cells to cause atherosclerotic lesions. Yet, functional characteristics of specific immune and endothelial cell subsets associated with atherosclerosis and cerebrovascular events are poorly understood. METHODS: Here, using single-cell RNA sequencing, the unprecedentedly largest data set from 20 patients' carotid artery plaques and paired peripheral blood mononuclear cells was generated, with which an ultra-high-precision cellular landscape of the atherosclerotic microenvironment involving 372 070 cells was depicted. RESULTS: Compared with peripheral blood mononuclear cells, 3 plaque-specific T-cell subsets exhibiting proatherogenic features of both activation and exhaustion were identified. Strikingly, usually antiatherogenic, CD4+FOXP3+ regulatory T cells from plaques of patients with symptomatic disease acquired proinflammatory properties by probably converting to T helper 17 and T helper 9 cells, while CD4+NR4A1+/C0 and CD8+SLC4A10+ T cells related to cerebrovascular events possessed atherogenic attributes including proinflammation, polarization, and exhaustion. In addition, monocyte-macrophage dynamics dominated innate immune response. Two plaque-specific monocyte subsets performed diametrically opposed functions, EREG+ monocytes promoted cerebrovascular events while C3+ monocytes are anti-inflammatory. Similarly, IGF1+ and HS3ST2+ macrophages with classical proinflammatory M1 macrophage features were annotated and contributed to cerebrovascular events. Moreover, SULF1+ (sulfatase-1) endothelial cells were also found to participate in cerebrovascular events through affecting plaque vulnerability. CONCLUSIONS: This compendium of single-cell transcriptome data provides valuable insights into the cellular heterogeneity of the atherosclerotic microenvironment and the development of more precise cardiovascular immunotherapies.

Ethoxyquin, a Lipid Peroxidation Inhibitor, Has Protective Effects against White Matter Lesions in a Mouse Model of Chronic Cerebral Hypoperfusion.

White matter lesions induced by chronic cerebral hypoperfusion can cause vascular dementia; however, no appropriate treatments are currently available for these diseases. In this study, we investigated lipid peroxidation, which has recently been pointed out to be associated with cerebrovascular disease and vascular dementia, as a therapeutic target for chronic cerebral hypoperfusion. We used ethoxyquin, a lipid-soluble antioxidant, in a neuronal cell line and mouse model of the disease. The cytoprotective effect of ethoxyquin on glutamate-stimulated HT-22 cells, a mouse hippocampal cell line, was comparable to that of a ferroptosis inhibitor. In addition, the administration of ethoxyquin to bilateral common carotid artery stenosis model mice suppressed white matter lesions, blood-brain barrier disruption, and glial cell activation. Taken together, we propose that the inhibition of lipid peroxidation may be a useful therapeutic approach for chronic cerebrovascular disease and the resulting white matter lesions.

Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.

The concept of vulnerable carotid plaques is pivotal in understanding the pathophysiology of ischemic stroke secondary to large-artery atherosclerosis. In macroscopic evaluation, vulnerable plaques are characterized by one or more of the following features: microcalcification; neovascularization; lipid-rich necrotic cores (LRNCs); intraplaque hemorrhage (IPH); thin fibrous caps; plaque surface ulceration; huge dimensions, suggesting stenosis; and plaque rupture. Recognizing these macroscopic characteristics is crucial for estimating the risk of cerebrovascular events, also in the case of non-significant (less than 50%) stenosis. Inflammatory biomarkers, such as cytokines and adhesion molecules, lipid-related markers like oxidized low-density lipoprotein (LDL), and proteolytic enzymes capable of degrading extracellular matrix components are among the key molecules that are scrutinized for their associative roles in plaque instability. Through their quantification and evaluation, these biomarkers reveal intricate molecular cross-talk governing plaque inflammation, rupture potential, and thrombogenicity. The current evidence demonstrates that plaque vulnerability phenotypes are multiple and heterogeneous and are associated with many highly complex molecular pathways that determine the activation of an immune-mediated cascade that culminates in thromboinflammation. This narrative review provides a comprehensive analysis of the current knowledge on molecular biomarkers expressed by symptomatic carotid plaques. It explores the association of these biomarkers with the structural and compositional attributes that characterize vulnerable plaques.

Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia.

BACKGROUND: Chronic cerebral ischemia induces white matter injury (WMI) contributing to cognitive decline. Both astrocytes and microglia play vital roles in the demyelination and remyelination processes, but the underlying mechanism remains unclear. This study aimed to explore the influence of the chemokine CXCL5 on WMI and cognitive decline in chronic cerebral ischemia and the underlying mechanism. METHODS: Bilateral carotid artery stenosis (BCAS) model was constructed to mimic chronic cerebral ischemia in 7-10 weeks old male mice. Astrocytic Cxcl5 conditional knockout (cKO) mice were constructed and mice with Cxcl5 overexpressing in astrocytes were generated by stereotactic injection of adeno-associated virus (AAV). WMI was evaluated by magnetic resonance imaging (MRI), electron microscopy, histological staining and western blotting. Cognitive function was examined by a series of neurobehavioral tests. The proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), phagocytosis of microglia were analyzed via immunofluorescence staining, western blotting or flow cytometry. RESULTS: CXCL5 was significantly elevated in the corpus callosum (CC) and serum in BCAS model, mainly expressed in astrocytes, and Cxcl5 cKO mice displayed improved WMI and cognitive performance. Recombinant CXCL5 (rCXCL5) had no direct effect on the proliferation and differentiation of OPCs in vitro. Astrocytic specific Cxcl5 overexpression aggravated WMI and cognitive decline induced by chronic cerebral ischemia, while microglia depletion counteracted this effect. Recombinant CXCL5 remarkably hindered microglial phagocytosis of myelin debris, which was rescued by inhibition of CXCL5 receptor C-X-C motif chemokine receptor 2 (CXCR2). CONCLUSION: Our study revealed that astrocyte-derived CXCL5 aggravated WMI and cognitive decline by inhibiting microglial phagocytosis of myelin debris, suggesting a novel astrocyte-microglia circuit mediated by CXCL5-CXCR2 signaling in chronic cerebral ischemia.

Tortuosity and Proximal-Specific Hemodynamics Associated with Plaque Location in the Carotid Bulb Stenosis.

BACKGROUND: Atherosclerotic plaque locations in the carotid bulb increasingly have been found to be associated with patterns of ischemic lesions and plaque progression. However, the occurrence of carotid bulb plaque is a complex process. We aimed to investigate plaque characteristics and geometric and hemodynamic parameters among patients with body and apical plaques of the carotid bulb and to identify the mechanism of bulb plaque formation and location. METHODS: Consecutive patients with single carotid bulb stenosis (50-99%) were enrolled retrospectively. Patients were divided into body and apical plaque groups based on plaque location. Plaque location and characteristics were identified and measured on high-resolution vessel wall magnetic resonance imaging. Geometric parameters were derived from time-of-flight magnetic resonance imaging. Computational fluid dynamics simulations were performed to quantify wall shear stress (WSS) and four associated WSS-based metrics on the plaque side, on the non-plaque side, and in different parts of the lesion. Plaque characteristics and geometric and hemodynamic parameters were compared, and their associations with the plaque location were determined. RESULTS: Seventy patients were recruited (41 body plaques and 29 apical plaques). WSSplaque values were lower than WSSnon-plaque values for all plaques (median [interquartile range], 12.59 [9.83-22.14] vs. 17.27 [11.63-27.63] Pa, p = 0.001). In a multivariate binary logistic regression, the tortuosity of the stenosed region, the magnitudes of the mean relative residence time, and the minimum transverse WSS in the proximal part of the lesion were the key factors independently associated with plaque location (p = 0.022, 0.013, and 0.012, respectively). CONCLUSIONS: Plaque formation was associated with the local flow pattern, and the tortuosity and proximal-specific hemodynamics were significantly associated with plaque location in the carotid bulb.

Gut Microbiota, Plasma Metabolomic Profiles, and Carotid Artery Atherosclerosis in HIV Infection.

BACKGROUND: Alterations in gut microbiota and blood metabolomic profiles have been implicated in HIV infection and cardiovascular disease. However, it remains unclear whether alterations in gut microbiota may contribute to disrupted host blood metabolomic profiles in relation to atherosclerosis, especially in the context of HIV infection. METHODS: We analyzed cross-sectional associations between gut microbiota features and carotid artery plaque in 361 women with or at high risk of HIV (67% HIV+), and further integrated plaque-associated microbial features with plasma lipidomic/metabolomic profiles. Furthermore, in 737 women and men, we examined prospective associations of baseline gut bacteria-associated lipidomic and metabolomic profiles with incident carotid artery plaque over 7-year follow-up. RESULTS: We found 2 potentially pathogenic bacteria, Fusobacterium and Proteus, were associated with carotid artery plaque; while the beneficial butyrate producer Odoribacter was inversely associated with plaque. Fusobacterium and Proteus were associated with multiple lipids/metabolites which were clustered into 8 modules in network. A module comprised of 9 lysophosphatidylcholines and lysophosphatidylethanolamines and a module comprised of 9 diglycerides were associated with increased risk of carotid artery plaque (risk ratio [95% CI], 1.34 [1.09-1.64] and 1.24 [1.02-1.51] per SD increment, respectively). Functional analyses identified bacterial enzymes in lipid metabolism associated with these plasma lipids. In particular, phospholipase A1 and A2 are the key enzymes in the reactions producing lysophosphatidylcholines and lysophosphatidylethanolamines. CONCLUSIONS: Among individuals with or at high risk of HIV infection, we identified altered gut microbiota and related functional capacities in the lipid metabolism associated with disrupted plasma lipidomic profiles and carotid artery atherosclerosis.

Long-Term Results of Autologous Bifurcated Carotid Artery Reconstructions.

BACKGROUND: Carotid bifurcation revascularization using interposition grafts is rare. While internal carotid artery (ICA) revascularization is regarded as mandatory, the external carotid artery (ECA) is severed in most instances. Long-term results of an autologous bifurcated carotid artery reconstruction are discussed. METHODS: Single-center, retrospective analysis of a consecutive series of patients treated at an academic vascular surgery center. RESULTS: From December 2006 to November 2019, fifty-one patients underwent reconstruction of the carotid artery using an autologous bifurcated interposition graft (38 males, 75%; median age: 68.7 years; interquartile range [IQR]: 60.2-76.5). Thirty-eight patients were asymptomatic (74.5%). Indication for reconstruction was recurrent carotid stenosis unfavorable for endovascular treatment/redo patch plasty (n = 32, symptomatic: n = 7), carotid aneurysm (n = 11, symptomatic: n = 5), neck tumor with vascular involvement (n = 7), trauma (n = 1). Nonreversed valve depleted saphenous vein y-graft from the groin was used in 49 (94.2%) and reversed cubital vein bifurcation in 3 (5.8%) procedures. The median ICA cross-clamp time was 15 min (IQR: 13-20 min). In four procedures (7.7%), a shunt was inserted because of a significant decrease of cerebral perfusion. In one patient, additional intraoperative stent placement of a proximal common carotid artery (CCA) stenosis was performed. Six patients suffered from ischemic neurological deficits (11.5%), all but 1 recovered with no or moderate symptoms. After a median follow-up of 5.2 years (IQR: 1.1-8.7 years), 7 significant asymptomatic stenoses (13.5%) and 2 occlusions (3.8%, one symptomatic) of the ICA, two significant asymptomatic CCA stenoses (3.8%), five significant stenoses (9.6%) and 7 asymptomatic occlusions (13.5%) of the ECA were observed. This prompted 7 re-redo-interventions in 5 patients. Twenty-eight patients (54.9%) died after a median follow-up of 3.3 years (IQR: 0.5-5.6 years). Two of these patients died due to conditions related to the performed carotid artery reconstruction. CONCLUSIONS: Autologous bifurcated carotid artery interposition graft provides results comparable to other complex ICA revascularizations. Overall survival in this heterogeneous patient cohort is poor. Due to the high risk of stroke and poor long-term outcome, this procedure should be reserved for symptomatic patients with no other option for revascularization.

Pitfalls in Carotid Doppler Interpretation and How to Avoid Them.

Imaging pitfalls commonly occur in carotid Doppler ultrasound and may lead to false positive diagnosis of stenosis, missed diagnosis of stenosis, and errors in grading stenosis severity. These pitfalls may result from suboptimal technique and/or patient-specific factors including coexisting cardiovascular pathology, contralateral high-grade stenosis/occlusion, tortuous vessels, tandem lesions, long-segment stenosis, nearly occlusive stenosis, and heavily calcified plaque. Awareness of these pitfalls and careful assessment of the extent of plaque on grayscale and color Doppler as well as analysis of the spectral Doppler waveforms can help avoid misinterpretation of the carotid Doppler examination.

Anterior cerebral artery dilation to increase cerebral perfusion in a patient with chronic internal carotid artery occlusion.

Chronic internal carotid artery occlusions (CICAO) increase the risk of stroke recurrence and cognitive dysfunction. Here, we describe the case of an adult patient with ipsilateral CICAO who underwent endovascular treatment of anterior cerebral artery stenosis to improve cerebral perfusion. First, the patient presented ataxia and left facial palsy. Magnetic resonance imaging (MRI) showed right hemispherpe cerebral infarct, right CICAO, and sub-occlusive stenosis of the left bulbar internal carotid artery. Stenting of the left carotid artery was performed. One year later, she experienced acute walking imbalance and left hemiparesis. MRI showed new watershed and anterior cerebral artery infarctions, worsening of the right hemisphere hypoperfusion, and a new severe stenosis of the right anterior cerebral artery. Dilation of this stenosis was performed. Perfusion parameters, clinical deficit, and cognitive functions improved after the endovascular treatment, and the patient had no stroke recurrence.

Perceived Psychological Well-Being in Patients with Hemodynamically Insignificant Carotid Arteries Stenosis.

BACKGROUND: Analysis of the perception of the disease in borderline stenosis of the orifice of the internal carotid artery (ICA) (up to 69% in diameter) in asymptomatic patients. SUBJECTS AND METHODS: 48 patients (28 men and 20 women). Group 1: stenosis up to 49% - 23 people (13 men, 10 women), mean age 50.4±16.1 y.o. Group 2: stenosis 50-59% - 18 people (10 men, 8 women), mean age 57.3±16 y.o. Group 3: stenosis 60-69% - 7 people (5 men, 2 women), mean age 61±12.3 y.o. All patients underwent ultrasound Doppler of brachiocephalic arteries, examination with Brief Illness Perception Questionnaire E. Broadbent (Russian version). RESULTS: According to the results of examination of patients with ICA stenosis, patients with more pronounced lesions (60-69%) more often have a type of reaction "negative attitude to the consequences of the disease". CONCLUSIONS: The majority of patients (54.2%) have a "negative type of attitude towards the consequences of the disease". This type of attitude to the disease is most pronounced in women and patients with stenosis of the ICA 60-69%. It is necessary to perform the psychological work with patients with carotid stenosis in order to form in them more adaptive types of perception of the disease, understanding of the disease and a positive attitude towards treatment.

[Optical coherence tomography angiography in diagnosis of changes in macular capillary blood flow in chronic ischemic retinopathy]. / Opticheskaya kogerentnaya tomografiya-angiografiya v diagnostike izmenenii kapillyarnogo krovotoka makuly pri khronicheskoi ishemicheskoi retinopatii.

PURPOSE: Assessment of the indices of macular capillary blood flow and subfoveal choroidal thickness (SCT) using optical coherence tomography angiography in patients with retinal manifestations of ocular ischemic syndrome (RMOIS) associated with atherosclerotic internal carotid artery stenosis. MATERIAL AND METHODS: The study included 34 patients (68 eyes): 21 men, 13 women with RMOIS in one eye. All patients were divided into 2 groups depending on the severity of atherosclerotic internal carotid artery stenosis and ophthalmoscopic picture of the fundus. To obtain objective information we analyzed the degree of decrease in the main indices characterizing macular microcirculation and SCT depending on the severity of RMOIS. RESULTS AND DISCUSSION: Analysis of the results showed relationship between the severity of RMOIS and the deficit in macular microcirculation. The macula of the patients with mild RMOIS was characterized by a decrease in the density of superficial vascular plexus (SVP) and the density of deep capillary plexus (DCP) by 13.5% and 10.5% compared to the controls, respectively; in moderate RMOIS - by 19.7% and 14.6%; in severe RMOIS - by 35.9% and 28%, respectively. With an increase in the severity of RMOIS, the area of the foveal avascular zone increased too: in mild degree RMOIS - by 19%, in moderate - by 38.6%, in severe - by 51%. In proportion to the severity of RMOIS, SCT was reduced: in mild degree RMOIS - by only 8%, in moderate - by 22%, and in severe - by 29.8% of the control. CONCLUSION: The conducted research indicates that pathological changes in RMOIS extend to the entire capillary network of the macula and SCT. With increase in the degree of RMOIS, ischemic changes in all capillary layers of the central parts of the retina proportionally increase in comparison with the control group by 1.15 times in mild degree, by 1.24 times in moderate degree, and by 1.5 times in severe RMOIS.

Carotid Artery Plaque Calcifications: Lessons From Histopathology to Diagnostic Imaging.

The role of calcium in atherosclerosis is controversial and the relationship between vascular calcification and plaque vulnerability is not fully understood. Although calcifications are present in ≈50% to 60% of carotid plaques, their association with cerebrovascular ischemic events remains unclear. In this review, we summarize current understanding of carotid plaque calcification. We outline the role of calcium in atherosclerotic carotid disease by analyzing laboratory studies and histopathologic studies, as well as imaging findings to understand clinical implications of carotid artery calcifications. Differences in mechanism of calcium deposition express themselves into a wide range of calcification phenotypes in carotid plaques. Some patterns, such as rim calcification, are suggestive of plaques with inflammatory activity with leakage of the vasa vasourm and intraplaque hemorrhage. Other patterns such as dense, nodular calcifications may confer greater mechanical stability to the plaque and reduce the risk of embolization for a given degree of plaque size and luminal stenosis. Various distributions and patterns of carotid plaque calcification, often influenced by the underlying systemic pathological condition, have a different role in affecting plaque stability. Modern imaging techniques afford multiple approaches to assess geometry, pattern of distribution, size, and composition of carotid artery calcifications. Future investigations with these novel technologies will further improve our understanding of carotid artery calcification and will play an important role in understanding and minimizing stroke risk in patients with carotid plaques.

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

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: We found significant difference in total plaque volume between men and women (ß=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]). CONCLUSIONS: 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.

Pentoxifylline alleviates ischemic white matter injury through up-regulating Mertk-mediated myelin clearance.

BACKGROUND: Vascular dementia (VAD) is the second most common type of dementia lacking effective treatments. Pentoxifylline (PTX), a nonselective phosphodiesterase inhibitor, displays protective effects in multiple cerebral diseases. In this study, we aimed to investigate the therapeutic effects and potential mechanisms of PTX in VAD. METHODS: Bilateral common carotid artery stenosis (BCAS) mouse model was established to mimic VAD. Mouse behavior was tested by open field test, novel object recognition test, Y-maze and Morris water maze (MWM) tests. Histological staining, magnetic resonance imaging (MRI) and electron microscopy were used to define white matter integrity. The impact of PTX on microglia phagocytosis, peroxisome proliferator-activated receptors-γ (PPAR-γ) activation and Mer receptor tyrosine kinase (Mertk) expression was assessed by immunofluorescence, western blotting and flow cytometry with the application of microglia-specific Mertk knockout mice, Mertk inhibitor and PPAR-γ inhibitor. RESULTS: Here, we found that PTX treatment alleviated cognitive impairment in novel object recognition test, Y-maze and Morris water maze tests. Furthermore, PTX alleviated white matter injury in corpus callosum (CC) and internal capsule (IC) areas as shown by histological staining and MRI analysis. PTX-treatment group presented thicker myelin sheath than vehicle group by electron microscopy. Mechanistically, PTX facilitated microglial phagocytosis of myelin debris by up-regulating the expression of Mertk in BCAS model and primary cultured microglia. Importantly, microglia-specific Mertk knockout blocked the therapeutic effects of PTX in BCAS model. Moreover, Mertk expression was regulated by the nuclear translocation of PPAR-γ. Through modulating PPAR-γ, PTX enhanced Mertk expression. CONCLUSIONS: Collectively, our results demonstrated that PTX showed therapeutic potentials in VAD and alleviated ischemic white matter injury via modulating Mertk-mediated myelin clearance in microglia.

Near-Infrared Autofluorescence in Atherosclerosis Associates With Ceroid and Is Generated by Oxidized Lipid-Induced Oxidative Stress.

[Figure: see text].

Alternative Splicing of FN (Fibronectin) Regulates the Composition of the Arterial Wall Under Low Flow.

OBJECTIVE: Exposure of the arterial endothelium to low and disturbed flow is a risk factor for the erosion and rupture of atherosclerotic plaques and aneurysms. Circulating and locally produced proteins are known to contribute to an altered composition of the extracellular matrix at the site of lesions, and to contribute to inflammatory processes within the lesions. We have previously shown that alternative splicing of FN (fibronectin) protects against flow-induced hemorrhage. However, the impact of alternative splicing of FN on extracellular matrix composition remains unknown. Approach and Results: Here, we perform quantitative proteomic analysis of the matrisome of murine carotid arteries in mice deficient in the production of FN splice isoforms containing alternative exons EIIIA and EIIIB (FN-EIIIAB null) after exposure to low and disturbed flow in vivo. We also examine serum-derived and endothelial-cell contributions to the matrisome in a simplified in vitro system. We found flow-induced differences in the carotid artery matrisome that were impaired in FN-EIIIAB null mice. One of the most interesting differences was reduced recruitment of FBLN1 (fibulin-1), abundant in blood and not locally produced in the intima. This defect was validated in our in vitro assay, where FBLN1 recruitment from serum was impaired by the absence of these alternatively spliced segments. CONCLUSIONS: Our results reveal the extent of the dynamic alterations in the matrisome in the acute response to low and disturbed flow and show how changes in the splicing of FN, a common response in vascular inflammation and remodeling, can affect matrix composition.

H3K4 Methyltransferase Smyd3 Mediates Vascular Smooth Muscle Cell Proliferation, Migration, and Neointima Formation.

[Figure: see text].

Monocyte-Chemoattractant Protein-1 Levels in Human Atherosclerotic Lesions Associate With Plaque Vulnerability.

[Figure: see text].