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Aims: Transforming growth factor-beta (TGF-β) exists in three isoforms TGF-β1, -β2, and -β3. TGF-β1 has been suggested to be important for maintaining plaque stability, yet the role of TGF-β2 and -β3 in atherosclerosis remains to be investigated.This study explores the association of the three isoforms of TGF-β with plaque stability in the human atherosclerotic disease., Methods and Results: TGF-β1, -β2, and -β3 proteins were quantified in 223 human carotid plaques by immunoassays. Indications for the endarterectomy were: symptomatic carotid plaque with stenosis >70% or without symptoms and >80% stenosis. Plaque mRNA levels were assessed by RNA sequencing. Plaque components and extracellular matrix were measured histologically and biochemically. Matrix metalloproteinases and monocyte chemoattractant protein-1 (MCP-1) was measured with immunoassays. The effect of TGF-β2 on inflammation and protease activity was investigated in vitro using THP-1 and RAW264.7 macrophages. Patients were followed longitudinally for cardiovascular (CV) events.TGF-β2 was the most abundant isoform and was increased at both protein and mRNA levels in asymptomatic plaques. TGF-β2 was the main determinant separating asymptomatic plaques in an Orthogonal Projections to Latent Structures Discriminant Analysis. TGF-β2 correlated positively to features of plaque stability and inversely to markers of plaque vulnerability. TGF-β2 was the only isoform inversely correlated to the matrix-degrading matrix metalloproteinase-9 and inflammation in the plaque tissue. In vitro, TGF-β2 pre-treatment reduced MCP-1 gene and protein levels as well as matrix metalloproteinase-9 gene levels and activity. Patients with plaques with high TGF-β2 levels had a lower risk to suffer from future CV events., Conclusions: TGF-β2 is the most abundant TGF-β isoform in human plaques and may maintain plaque stability by decreasing inflammation and matrix degradation., Competing Interests: Conflict of interest: P.V. is now employed at Data Science and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca and M.C. is employed at GUBRA. The remaining authors have nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Extracellular matrix (ECM) remodeling is one of the key components in the formation of vulnerable atherosclerotic plaques and cardiovascular events. We recently showed that the full-length ECM-proteoglycan osteoglycin was associated with plaque vulnerability and future cardiovascular events. In the present study, we aimed to investigate the association of cleaved osteoglycin with plaque phenotype., Methods: Two-hundred human carotid plaques were analyzed by immunohistochemistry. Cleaved osteoglycin and active caspase-3 were assessed by ELISA. ECM components (collagen, elastin and glycosaminoglycans) were assessed by colorimetric assays in plaque tissue homogenates. Matrix metalloproteinases (MMPs) were assessed using Milliplex. MMP-cleavage of osteoglycin and its effect on apoptosis were studied in vitro. Cardiovascular events were recorded during follow-up using national registries., Results: Plaque levels of cleaved osteoglycin were significantly higher in asymptomatic plaques and correlated to α-actin plaque area, collagen, elastin and inversely to lipids, active. caspase-3 and a histological vulnerability index. Cleaved osteoglycin correlated to several MMPs, especially MMP-12, which was also shown to cleave osteoglycin in vitro. In vitro cleavage of osteoglycin was also associated with less smooth muscle cell apoptosis. Patients with high plaque levels of cleaved osteoglycin had a significantly lower risk to suffer from future cardiovascular events., Conclusions: The current study shows that cleaved osteoglycin is associated with a stable plaque phenotype and lower risk for future cardiovascular events. Potentially due to reduced cell apoptosis and ability to retain LDL. These results indicate that targeting the cleavage of osteoglycin may be a potential therapeutic strategy to stabilize plaques., (Copyright © 2022. Published by Elsevier B.V.)

Background: Type 2 diabetes (T2D) patients are at a greater risk of cardiovascular events due to aggravated atherosclerosis. Oxidized LDL (oxLDL) has been shown to be increased in T2D plaques and suggested to contribute to plaque ruptures. Despite intensified statin treatment during the last decade the higher risk for events remains. Here, we explored if intensified statin treatment was associated with reduced oxLDL in T2D plaques and if oxLDL predicts cardiovascular events, to elucidate whether further plaque oxLDL reduction would be a promising therapeutic target., Methods: Carotid plaque OxLDL levels and plasma lipoproteins were assessed in 200 patients. Plaque oxLDL was located by immunohistochemistry. Plaque cytokines, cells and scavenger receptor gene expression were quantified by Luminex, immunohistochemistry and RNA sequencing, respectively. Clinical information and events during follow-up were obtained from national registers., Results: Plaque oxLDL levels correlated with markers of inflammatory activity, endothelial activation and plasma LDL cholesterol (r = 0.22-0.32 and p ≤ 0.01 for all). T2D individuals exhibited lower plaque levels of oxLDL, sLOX-1(a marker of endothelial activation) and plasma LDL cholesterol (p = 0.001, p = 0.006 and p = 0.009). No increased gene expression of scavenger receptors was identified in T2D plaques. The lower oxLDL content in T2D plaques was associated with a greater statin usage (p = 0.026). Supporting this, a linear regression model showed that statin treatment was the factor with the strongest association to plaque oxLDL and plasma LDL cholesterol (p < 0.001 for both). However, patients with T2D more frequently suffered from symptoms and yet plaque levels of oxLDL did not predict cardiovascular events in T2D (findings are summarized in Fig. 1a)., Conclusions: This study points out the importance of statin treatment in affecting plaque biology in T2D. It also implies that other biological components, beyond oxLDL, need to be identified and targeted to further reduce the risk of events among T2D patients receiving statin treatment.

Background The balance between stabilizing and destabilizing atherosclerotic plaque components is used in experimental studies and in imaging studies to identify rupture prone plaques. However, we lack the evidence that this balance predicts future cardiovascular events. Here we explore whether a calculated histological ratio, referred to as vulnerability index (VI), can predict patients at higher risk to suffer from future cardiovascular events. Methods and Results Carotid plaques and clinical information from 194 patients were studied. Tissue sections were used for histological analysis to calculate the VI (CD68 [cluster of differentiation 68], alpha-actin, Oil red O, Movat pentachrome, and glycophorin A). Postoperative cardiovascular events were identified through the Swedish National Inpatient Health Register (2005-2013). During the follow-up (60 months) 45 postoperative cardiovascular events were registered. Patients with a plaque VI in the fourth quartile compared with the first to third quartiles had significantly higher risk to suffer from a future cardiovascular event ( P =0.0002). The VI was an independent predictor and none of the 5 histological variables analyzed separately predicted events. In the 13 patients who underwent bilateral carotid endarterectomy, the VI of the right plaque correlated with the VI of the left plaque and vice versa ( r =0.7, P =0.01). Conclusions Our findings demonstrate that subjects with a high plaque VI have an increased risk of future cardiovascular events, independently of symptoms and other known cardiovascular risk factors . This strongly supports that techniques which image such plaques can facilitate risk stratification for subjects in need of more intense treatment.

Objective: Atherosclerosis is characterized by accumulation of lipids, cells and extracellular matrix (ECM) proteins in the arterial wall. Collagen type I (COL1), a component of the arterial ECM, is cleaved by matrix metalloproteinases (MMPs) and known to be remodelled in atherosclerosis. We explored whether the MMP-mediated COL1 biomarker, C1M, was associated with cardiovascular events, cardiovascular mortality and all-cause mortality in a large prospective cohort of patients with known atherosclerosis.Methods: Serum from 787 patients who underwent a carotid endarterectomy was included. Circulating levels of C1M were measured in serum. A total of 473 patients were followed for 6 years after surgery. Associations between C1M and incidence of cardiovascular events, cardiovascular mortality and all-cause mortality were assessed by Kaplan-Meier curves and Cox regression analysis.Results: A total of 101 (21.4%) patients suffered from nonfatal cardiovascular events during the follow-up period, and 64 (13.5%) patients died. Of these, 39 (60.9%) died from cardiovascular diseases. Patients with C1M levels above the median were significantly associated with cardiovascular events, cardiovascular mortality and all-cause mortality (P < 0.001, P = 0.004 and P < 0.001, respectively). C1M was included in the final model for prediction of cardiovascular events (HR 2.15, 95% CI 1.40-3.32, P = 0.001), cardiovascular mortality (HR 2.20, 95% CI 1.07-4.51, P = 0.031) and all-cause mortality (HR 2.98 95% CI 1.67-5.33, P = < 0.001).Conclusions: In patients with atherosclerotic carotid lesions, high levels of C1M predicted cardiovascular events, cardiovascular mortality and all-cause mortality. These findings emphasize the importance of remodelling mechanisms in atherosclerosis that are now becoming more and more explored. [ABSTRACT FROM AUTHOR]

Placental growth factor (PlGF) is a mitogen for endothelial cells, but it can also act as a proinflammatory cytokine. Because it promotes early stages of plaque formation in experimental models of atherosclerosis and was implicated in epidemiological associations with risk of cardiovascular disease (CVD), PlGF has been attributed a pro-atherogenic role. Here, we investigated whether PlGF has a protective role in CVD and whether elevated PlGF reflects activation of repair processes in response to vascular stress. In a population cohort of 4742 individuals with 20 years of follow-up, high baseline plasma PlGF was associated with increased risk of cardiovascular death, myocardial infarction, and stroke, but these associations were lost or weakened when adjusting for cardiovascular risk factors known to cause vascular stress. Exposure of cultured endothelial cells to high glucose, oxidized low-density lipoprotein (LDL) or an inducer of apoptosis enhanced the release of PlGF. Smooth muscle cells and endothelial cells treated with PlGF small interference RNA demonstrated that autocrine PlGF stimulation plays an important role in vascular repair responses. High expression of PlGF in human carotid plaques removed at surgery was associated with a more stable plaque phenotype and a lower risk of future cardiovascular events. When adjusting associations of PlGF with cardiovascular risk in the population cohort for plasma soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2, a biomarker of cellular stress, a high PlGF/TRAIL receptor-2 ratio was associated with a lower risk. Our findings provide evidence for a protective role of PlGF in CVD., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background and Aims: A vulnerable plaque is an atherosclerotic plaque that is rupture-prone with a higher risk to cause cardiovascular symptoms such as myocardial infarction or stroke. Mimecan or osteoglycin is a small leucine-rich proteoglycan, important for collagen fibrillogenesis, that has been implicated in atherosclerotic disease, yet the role of mimecan in human atherosclerotic disease remains unknown., Methods: 196 human atherosclerotic carotid plaques were immunostained for mimecan. Smooth muscle cells, macrophages and intraplaque haemorrhage were also measured with immunohistochemistry. Neutral lipids were stained with Oil Red O and calcium deposits were quantified. Plaque homogenate levels of MCP-1, IL-6 and MIP-1β were measured using a Proximity Extension Assay and MMP-9 levels were measured using Mesoscale. Glycosaminoglycans, collagen and elastin were assessed by colorimetric assays and TGF-β1, β2 and β3 were measured using a multiplex assay. Mimecan gene expression in THP-1 derived macrophages was quantified by qPCR and protein expression in vitro was visualized with immunofluorescence. Cardiovascular events were registered using medical charts and national registers during follow-up., Results: Mimecan correlated positively with plaque area of lipids, macrophages, intraplaque haemorrhage and inversely with smooth muscle cell staining. Mimecan also correlated positively with plaque levels of MMP-9 and MCP-1. Mimecan was upregulated in THP-1 derived macrophages upon stimulation with MCP-1. Patients with high levels of mimecan (above median) had higher risk for cardiovascular death., Conclusions: This study indicates that mimecan is associated with a vulnerable plaque phenotype, possibly regulated by plaque inflammation. In line, plaque levels of mimecan independently predict future cardiovascular death., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 m 2 . 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., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Objective: CD4 + CD28 null T cells have been shown to be associated with recurrent coronary events and suggested as potential biomarker and therapeutic target. It is unknown whether CD4 + CD28 null T cells associate with first-time cardiovascular events. We examined CD4 + CD28 null T cells in a prospective population-based cohort and in patients with advanced atherosclerosis. Approach and Results: CD4 + CD28 null T cells were quantified in 272 individuals experiencing a first-time coronary event during up to 17 years of follow-up and 272 age- and sex-matched controls in a case-control study, nested within the population-based Malmö Diet and Cancer study. The highest tertile of CD4 + CD28 null T cells was associated with a lower incidence of first-time coronary events compared with the lowest tertile (odds ratio, 0.48 [95% CI, 0.29-0.79], P =0.004) when adjusting for Framingham risk factors. This association remained significant for events recorded after >9 years of follow-up, when most coronary events occurred, but not during the first 9 years of follow-up, despite similar odds ratio. Additionally, we analyzed CD4 + CD28 null T cells in 201 patients with advanced atherosclerosis undergoing carotid endarterectomy. The adjusted hazard ratio for cardiovascular events in patients with advanced atherosclerosis was 2.11 (95% CI, 1.10-4.05, P =0.024), comparing the highest with the lowest CD4 + CD28 null T-cell tertile., Conclusions: Our findings reveal complex associations between CD4 + CD28 null T cells and cardiovascular disease. Although we confirm the reported positive associations with an adverse prognosis in patients with already established disease, the opposite associations with first-time coronary events in the population-based cohort may limit the clinical use of CD4 + CD28 null T cells.

Background and Purpose- Cellular apoptosis is an important feature in atherosclerosis, contributing to necrotic core formation, and plaque vulnerability. Activation of the death receptor TRAIL-R2 (TNF [tumor necrosis factor]-related apoptosis-inducing ligand receptor 2) through its ligand tumor necrosis factor-relate apoptosis-inducing ligand (TRAIL), induces apoptosis in cells in vitro. sTRAIL-R2 (soluble TRAIL-R2) was recently shown to predict cardiovascular events in healthy individuals. In the present study, we explored if plaque levels of sTRAIL-R2 and sTRAIL reflect plaque apoptosis and vulnerability and if plasma levels of these markers predict future events in subjects with advanced atherosclerosis. Methods- Plasma from 558 patients and 202 carotid plaques from the Carotid Plaque Imaging Project biobank were used. sTRAIL-R2, sTRAIL, and caspase-8 levels were assessed using a Proseek Multiplex CVD 96×96 assay. Active caspase-3 was measured using ELISA to assess plaque apoptosis. Plaque morphology was studied by immunohistochemistry. Inflammatory cytokines were assessed by Luminex. mRNA levels were quantified by RNA sequencing. Monocytes, T cells, B cells, and human coronary artery smooth muscle cells were used to study sTRAIL-R2 and sTRAIL release on cell apoptosis and inflammatory stimuli in vitro. Results- Plaque levels of sTRAIL-R2 and sTRAIL correlated to markers of extrinsic induced apoptosis (caspase-3 and -8). sTRAIL-R2 and sTRAIL protein expression were increased in symptomatic carotid plaques and patients with higher plasma levels of sTRAIL-R2 had a higher risk of future cardiovascular events. sTRAIL-R2 and sTRAIL were released upon activation of the extrinsic apoptosis pathway in vitro. sTRAIL-R2 and sTRAIL correlated with inflammatory cytokines, to CD68 expression and inversely to α-actin in the plaque tissue. Conclusions- The present study shows that sTRAIL-R2 and sTRAIL are associated to human plaque cell apoptosis, plaque inflammatory activity, and with symptomatic carotid plaques. Furthermore, high plasma levels of sTRAIL-R2 in plasma predict, independently, future cardiovascular events in individuals with manifest atherosclerotic disease.

Background Patients with atherosclerosis have a high risk of cardiovascular events and death. Atherosclerosis is characterized by accumulation of lipids, cells and extracellular matrix proteins in the intima. We hypothesized that dysregulated remodeling of the basement membrane proteins may be associated with clinical outcomes in patients with atherosclerosis. Methods and Results Neoepitope fragments of collagen type IV (C4M) and laminin ( LG 1M) were assessed by ELISA s in serum from 787 endarterectomy patients. Matrix metalloproteinase s were measured using proximity extension assay and correlated to C4M and LG 1M levels using Spearman correlations. A total of 473 patients were followed up for 6 years using national registers, medical charts, and telephone interviews. The incidence of cardiovascular events, cardiovascular mortality, and all-cause mortality were associated to levels of C4M and LG 1M using Kaplan-Meier curves and Cox regression analyses. A total of 101 patients had cardiovascular events, 39 died of cardiovascular mortality, and 64 patients died from all-cause mortality. C4M levels were increased in patients with symptomatic carotid atherosclerotic disease before surgery ( P=0.048). High C4M and LG 1M levels were associated with increased risk of all-cause mortality ( P=0.020 and 0.031, respectively) and predicted all-cause death together with glomerular filtration rate and diabetes mellitus. Conclusions High LG 1M and C4M levels were associated with all-cause mortality, together with glomerular filtration rate and diabetes mellitus. These novel biomarkers need further evaluation but might be tools to identify high-risk patients.

Dystrophin of the dystrophin-glycoprotein complex connects the actin cytoskeleton to basement membranes and loss of dystrophin results in Duchenne muscular dystrophy. We have previously shown injury-induced neointima formation of the carotid artery in mice with the mdx mutation (causing dystrophin deficiency) to be increased. To investigate the role of dystrophin in intimal recruitment of smooth muscle cells (SMCs) that maintains plaque stability in atherosclerosis we applied a shear stress-modifying cast around the carotid artery of apolipoprotein E (ApoE)-null mice with and without the mdx mutation. The cast induces formation of atherosclerotic plaques of inflammatory and SMC-rich/fibrous phenotypes in regions of low and oscillatory shear stress, respectively. Unexpectedly, presence of the mdx mutation markedly reduced the development of the inflammatory low shear stress plaques. Further characterization of the low shear stress plaques in ApoE-null mdx mice demonstrated reduced infiltration of CD3(+) T cells, less laminin and a higher SMC content. ApoE-null mdx mice were also found to have a reduced fraction of CD3(+) T cells in the spleen and lower levels of cytokines and monocytes in the circulation. The present study is the first to demonstrate a role for dystrophin in atherosclerosis and unexpectedly shows that this primarily involves immune cells.

Aims: The small leucine-rich proteoglycans fibromodulin and lumican are functionally related extracellular matrix proteins involved in the regulation of collagen fiber formation. Fibromodulin-deficient apolipoprotein E-null mice have decreased vascular retention of lipids and reduced development of atherosclerosis suggesting that fibromodulin may influence the disease process. The aim of the present study was to investigate if fibromodulin and lumican are expressed in human carotid plaques and to determine if their expression is associated with the occurrence of preoperative symptoms and with risk for postoperative cardiovascular events., Methods and Results: 153 plaques (51% symptomatic) obtained by carotid endarterectomy were included in this study. Plaque content was analyzed by immunohistochemistry and plaque cytokine content by multiplex technology. Fibromodulin and lumican were widely expressed in plaques and fibromodulin expression was significantly higher in symptomatic plaques. Expression of fibromodulin was significantly higher in plaques obtained from patients with diabetes and a high fibromodulin expression was associated with a higher incidence of post-operative cerebrovascular events, whereas no such associations were seen for lumican. Fibromodulin expression also correlated with plaque lipids and several pro-inflammatory cytokines. In addition, fibromodulin expression correlated with low levels of smooth muscle cells and the anti-inflammatory cytokine IL-10., Conclusions: These observations support previous experimental findings in mice for a role of fibromodulin in atherosclerosis and provide clinical evidence of the involvement of fibromodulin in the inflammatory processes that characterize atherosclerotic plaque vulnerability. They also suggest that this is of particular importance in diabetes., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

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Aims: Cardiovascular disease remains a major global health concern, with atherosclerosis (AS) being a significant contributor. Vulnerable plaques play a critical role in acute cardiovascular events. Syndecan-1 (SDC-1), a vital membrane proteoglycan in the vascular endothelial glycocalyx, is believed to be associated with plaque progression. However, its precise relationship with severity and vulnerability of atherosclerotic plaque remains unclear. This study aimed to investigate SDC-1 expression and its potential correlation with plaque vulnerability in ApoE-/- atherosclerosis mouse model. Methods and results: Eight-week-old mice were induced into the AS model using a high-fat diet (HFD) and/or partial ligation of the left common carotid artery (PLCA), with a chow diet (CD) control group. After 16 weeks, plaques in the aortic root showed the following order: HFD + PLCA group > HFD group > CD + PLCA group > CD group. Immunohistochemistry revealed heightened accumulation of lipid/foam cells and CD68-labeled macrophages in the plaques, elevated vascular endothelial growth factor (VEGF), and matrix Metalloproteinase-9 (MMP-9) in the HFD + PLCA group's plaques, along with reduced collagen and α-SMA-labeled smooth muscle cells, resulting in the highest vulnerability index value. Immunohistofluorescence analysis of frozen plaque sections showed significantly higher SDC-1 expression in the AS mice group compared to the CD group, both positively correlated with plaque vulnerability. Serum analysis demonstrated elevated levels of SDC1, sphingosine 1-phosphate (S1P), and VEGF-A in the AS mice, all positively correlated with plaque vulnerability. Multivariate analysis identified SDC1 as an independent predictor of plaque vulnerability. Conclusion: This study enhances our understanding of plaque vulnerability mechanisms and presents SDC1 as a potential biomarker for atherosclerosis. These findings underscore the importance of addressing modifiable risk factors, such as diet and hemodynamics and suggest the utility of serum SDC1 as a valuable clinical marker. Ultimately, these insights may lead to more effective strategies in combating cardiovascular diseases and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Stroke is the second leading cause of death and a major cause of disability around the world, and the development of atherosclerotic plaques in the carotid arteries is generally considered the leading cause of severe cerebrovascular events. In recent years, new reports have reinforced the role of an accurate histopathological analysis of carotid plaques to perform the stratification of affected patients and proceed to the correct prevention of complications. This work proposes applying an unsupervised learning approach to analyze complex whole-slide images (WSIs) of atherosclerotic carotid plaques to allow a simple and fast examination of their most relevant features. All the code developed for the present analysis is freely available. The proposed method offers qualitative and quantitative tools to assist pathologists in examining the complexity of whole-slide images of carotid atherosclerotic plaques more effectively. Nevertheless, future studies using supervised methods should provide evidence of the correspondence between the clusters estimated using the proposed textural-based approach and the regions manually annotated by expert pathologists. [ABSTRACT FROM AUTHOR]

Background: We studied the potential of human bone marrow–derived mesenchymal stem cell conditioned media (hBMSC CM) in protecting endothelial cell properties (viability, proliferation, and migrations) from the deleterious effects produced by the inflammatory environment of H2O2. Additionally, we investigated their impact on the endothelial cells' gene expression of some inflammatory‐related genes, namely, TGF‐β1, FOS, ATF3, RAF‐1, and SMAD3. Methods: Human umbilical vein endothelial cells (HUVECs) were cultured individually under three conditions: alone, with varying concentrations of H2O2, or with varying concentrations of H2O2 and hBMSC CM. HUVEC adhesion, proliferation, and migration were evaluated using the xCELLigence system. The HUVECs' gene expressions were evaluated by real‐time polymerase chain reaction (RT–PCR). Results: Generally, we observed enhanced HUVEC viability, proliferation, and migration when cultured in media supplemented with H2O2 and hBMSC CM. Furthermore, the CM modulated the expressions of the studied inflammatory‐related genes in HUVECs, promoting a more robust cellular response. Conclusion: This study has illuminated the protective role of hBMSC CM in mitigating the damaging effects of H2O2 on endothelial cell function. Our data demonstrate that hBMSC CM enhances the viability, proliferation, and migration of HUVECs even under oxidative stress conditions. Additionally, the conditioned medium was found to modulate the gene expression of pivotal markers related to inflammation, suggesting a favorable influence on cellular response mechanisms. [ABSTRACT FROM AUTHOR]

Objective: This study is aimed at investigating diagnostic biomarkers associated with lipotoxicity and the molecular mechanisms underlying diabetic nephropathy (DN). Methods: The GSE96804 dataset from the Gene Expression Omnibus (GEO) database was utilized to identify differentially expressed genes (DEGs) in DN patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the DEGs. A protein–protein interaction (PPI) network was established to identify key genes linked to lipotoxicity in DN. Immune infiltration analysis was employed to identify immune cells with differential expression in DN and to assess the correlation between these immune cells and lipotoxicity-related hub genes. The findings were validated using the external dataset GSE104954. ROC analysis was performed to assess the diagnostic performance of the hub genes. The Gene set enrichment analysis (GSEA) enrichment method was utilized to analyze the key genes associated with lipotoxicity as mentioned above. Result: In this study, a total of 544 DEGs were identified. Among them, extracellular matrix (ECM), fatty acid metabolism, AGE-RAGE, and PI3K-Akt signaling pathways were significantly enriched. Combining the PPI network and lipotoxicity-related genes (LRGS), LUM and ALB were identified as lipotoxicity-related diagnostic biomarkers for DN. ROC analysis showed that the AUC values for LUM and ALB were 0.882 and 0.885, respectively. The AUC values for LUM and ALB validated in external datasets were 0.98 and 0.82, respectively. Immune infiltration analysis revealed significant changes in various immune cells during disease progression. Macrophages M2, mast cells activated, and neutrophils were significantly associated with all lipotoxicity-related hub genes. These key genes were enriched in fatty acid metabolism and extracellular matrix-related pathways. Conclusion: The identified lipotoxicity-related hub genes provide a deeper understanding of the development mechanisms of DN, potentially offering new theoretical foundations for the development of diagnostic biomarkers and therapeutic targets related to lipotoxicity in DN. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) are epigenetic modifying enzyme that is closely related to chromatin structure and gene transcription, and numerous studies have found that HDACs play an important regulatory role in atherosclerosis disease. Apoptosis, autophagy and programmed necrosis as the three typical programmed cell death modalities that can lead to cell loss and are closely related to the developmental process of atherosclerosis. In recent years, accumulating evidence has shown that the programmed cell death mediated by HDACs is increasingly important in the pathophysiology of atherosclerosis. This paper first gives a brief overview of HDACs, the mechanism of programmed cell death, and their role in atherosclerosis, and then further elaborates on the role and mechanism of HDACs in regulating apoptosis, autophagy, and programmed necrosis in atherosclerosis, respectively, to provide new effective measures and theoretical basis for the prevention and treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Objective: Carotid intraplaque neovascularization (IPN) detected by contrast-enhanced ultrasound (CEUS) is a risk factor for recurrent ischemic stroke. However, it is still unclear whether IPN can be used to accurately identify patients with recurrent ischemic stroke in clinical practice. Herein, we investigated the clinical predictive value of IPN for recurrent ischemic stroke in a real-world setting., Methods: We enrolled 200 patients with ischemic stroke and atherosclerotic carotid stenosis who were followed up for 2 years. The endpoint was recurrent ischemic stroke. Cox regression and subgroup analyses were employed to assess whether treatment affected the relationship between IPN and recurrent ischemic stroke. The net classification index (NRI) and integrated discriminant improvement index (IDI) were used to validate the additional clinical value of IPN in identifying recurrent ischemic stroke., Results: During the 2-year follow-up, 36 patients experienced recurrent ischemic stroke. Cox regression analyses showed that IPN (grade 2), hypoechoic plaque, high homocysteine levels, and smoking were independent risk factors for recurrent ischemic stroke. Additional IPN evaluation may increase the NRI (0.512; 95% confidence interval [CI]: 0.083-0.624) and IDI (0.151; 95% CI: 0.010-0.213) for identifying high-risk patients with recurrent ischemic stroke. In addition, in the subgroup undergoing revascularization, the proportion of IPN (grade 2) was significantly higher in patients with recurrent ischemic stroke than in patients with nonrecurrent ischemic stroke (p = 0.001)., Interpretation: In clinical settings, IPN, assessed by CEUS, may provide additional clinical value for predicting recurrent ischemic stroke, helping to identify patients with ischemic stroke who require close follow-up., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Psoriasis is a skin disease with a complicated pathophysiology that includes an extensive inflammatory cytokine network. Nevertheless, the relationship between psoriasis severity, cytokine levels, and coronary artery atherosclerosis remains poorly understood. Our aim was to find serum markers as potential candidates for cardiovascular disease (CVD) risk monitoring in patients with psoriasis. Therefore, we examined coronary artery atherosclerosis via coronary computed tomography angiography (CCTA), serum cytokine levels via multiple immunoassays, and the patients' psoriasis state. Our findings reveal for the first time that the mainstream psoriasis cytokines interleukin 17A (IL-17A), IL-19, and IL-36 in the sera of Japanese patients with psoriasis showed a linear regression association with the Psoriasis Area and Severity Index score. Furthermore, the serum level of IL-19 was remarkably correlated to T h2 -related serum cytokines such as IL-4 and IL-17E. When we investigated potential markers to monitor CVD in patients with psoriasis, circulating cluster of differentiation 31 (CD31) and resistin, but not psoriasis-related cytokines, were expressed differently at each stage of coronary atherosclerosis by CCTA. CD31 and resistin levels rose dramatically in individuals with psoriasis vulgaris (PV) and noncalcified atherosclerosis. In contrast, CD31 was negatively correlated with the coronary artery calcification score (CACS) in patients with PV, whereas resistin was inversely correlated with CACS in patients with psoriatic arthritis. In conclusion, the axis of IL-17A, IL-19, and IL-36 remains associated with the severity of psoriasis during the chronic phase of the disease, regardless of the application of topical or systemic treatment. Monitoring the levels of these cytokines can accurately determine the severity of skin inflammation. Resistin and CD31 are linked to coronary artery lesions and might be good candidates for tracking the progression of coronary atherosclerosis in patients with psoriasis., (© 2024 Japanese Dermatological Association.)

Background: Diabetic nephropathy (DN) and atherosclerosis (AS) are prevalent and severe complications associated with diabetes, exhibiting lesions in the basement membrane, an essential component found within the glomerulus, tubules, and arteries. These lesions contribute significantly to the progression of both diseases, however, the precise underlying mechanisms, as well as any potential shared pathogenic processes between them, remain elusive. Methods: Our study analyzed transcriptomic profiles from DN and AS patients, sourced from the Gene Expression Omnibus database. A combination of integrated bioinformatics approaches and machine learning models were deployed to identify crucial genes connected to basement membrane lesions in both conditions. The role of integrin subunit alpha M (ITGAM) was further explored using immune infiltration analysis and genetic correlation studies. Single-cell sequencing analysis was employed to delineate the expression of ITGAM across different cell types within DN and AS tissues. Results: Our analyses identified ITGAM as a key gene involved in basement membrane alterations and revealed its primary expression within macrophages in both DN and AS. ITGAM was significantly correlated with tissue immune infiltration within these diseases. Furthermore, the expression of genes encoding core components of the basement membrane was influenced by the expression level of ITGAM. Conclusion: Our findings suggest that macrophages may contribute to basement membrane lesions in DN and AS through the action of ITGAM. Moreover, therapeutic strategies that target ITGAM may offer potential avenues to mitigate basement membrane lesions in these two diabetes-related complications. [ABSTRACT FROM AUTHOR]

The effect of oxidised lipoproteins on the endothelium, monocytes, platelets, and macrophages is a key factor in the initiation and development of atherosclerosis. Antioxidant action, lipoprotein metabolism, and chronic inflammation are the fields of research interest for better understanding the development of the disease. All the fields are related to inflammation and hence to the secretion of cytokines, which are being investigated as potential diagnostic markers for the onset of atherosclerosis. Pathways of vascular damage are crucial for the development of new laboratory readouts. The very early detection of endothelial cell damage associated with the onset of atherosclerosis, allowing the initiation of therapy, remains a major research goal. This article summarises the latest results on the relationship of tumour growth factor beta (TGF-β) isoforms and growth differentiation factor 15 (GDF-15) to the pathogenesis of atherosclerosis: which cells involved in atherosclerosis produce them, which effectors stimulate their synthesis and secretion, how they influence atherosclerosis development, and the relationship between the levels of TGF-β and GDF-15 in the blood and the development and extent of atherosclerosis. [ABSTRACT FROM AUTHOR]

Mechanical properties of living cells play a crucial role in a wide range of biological functions and pathologies, including atherosclerosis. We used low-stress Scanning Ion-Conductance Microscopy (SICM) correlated with confocal imaging and demonstrated the topographical changes and mechanical properties alterations in EA.hy926 and THP-1 exposed to LDL extracted from CVD patients' blood samples. We show that the cells stiffened in the presence of LDL, which also triggered caveolae formation. Endothelial cells accumulated less cholesterol in the form of lipid droplets in comparison to THP-1 cells based on fluorescence intensity data and biochemical analysis; however, the effect on Young's modulus is higher. The cell stiffness is closely connected to the distribution of lipid droplets along the z-axis. In conclusion, we show that the sensitivity of endothelial cells to LDL is higher compared to that of THP-1, triggering changes in the cytoskeleton and membrane stiffness which may result in the increased permeability of the intima layer due to loss of intercellular connections and adhesion. [ABSTRACT FROM AUTHOR]

Background: Concomitant cerebrovascular diseases (CeVD) have been identified as an important determinant of Alzheimer's disease (AD) progression. Development of robust blood-based biomarkers will provide critical tools to evaluate prognosis and potential interventional strategies for AD with CeVD. Objective: This study investigated circulating placental growth factor (PlGF), a potent pro-angiogenic factor related to endothelial dysfunction and vascular inflammation, in an Asian memory clinic cohort of non-demented individuals as well as AD, including its associations with neuroimaging markers of CeVD. Methods: 109 patients with AD, 76 cognitively impaired with no dementia (CIND), and 56 non-cognitively impaired (NCI) were included in this cross-sectional study. All subjects underwent 3T brain magnetic resonance imaging to assess white matter hyperintensities (WMH), lacunes, cortical infarcts, and cerebral microbleeds (CMBs). Serum PlGF concentrations were measured by electrochemiluminescence immunoassays. Results: Serum PlGF was elevated in AD, but not CIND, compared to the NCI controls. Adjusted concentrations of PlGF were associated with AD only in the presence of significant CeVD. Elevated PlGF was significantly associated with higher burden of WMH and with CMBs in AD patients. Conclusions: Serum PlGF has potential utility as a biomarker for the presence of CeVD, specifically WMH and CMBs, in AD. Further studies are needed to elucidate the underlying pathophysiological mechanisms linking PlGF to CeVD, as well as to further assess PlGF's clinical utility. [ABSTRACT FROM AUTHOR]

Background: To identify subjects with rupture-prone atherosclerotic plaques before thrombotic events occur is an unmet clinical need. Thus, this proof-of-concept study aims to determine which rupture-prone plaque features can be detected using clinically available photon-counting computed tomography (PCCT). Methods: In this retrospective study, advanced atherosclerotic plaques (ex vivo, paraffin-embedded) from the Carotid Plaque Imaging Project were scanned by PCCT with reconstructed energy levels (45, 70, 120, 190 keV). Density in HU was measured in 97 regions of interest (ROIs) representing rupture-prone plaque features as demonstrated by histopathology (thrombus, lipid core, necrosis, fibrosis, intraplaque haemorrhage, calcium). The relationship between HU and energy was then assessed using a mixed-effects model for each plaque feature. Results: Plaques from five men (age 79 ± 8 [mean ± standard deviation]) were included in the study. Comparing differences in coefficients (b1diff) of matched ROIs on plaque images obtained by PCCT and histology confirmed that calcium was distinguishable from all other analysed features. Of greater novelty, additional rupture-prone plaque features proved discernible from each other, particularly when comparing haemorrhage with fibrous cap (p = 0.017), lipids (p = 0.003) and necrosis (p = 0.004) and thrombus compared to fibrosis (p = 0.048), fibrous cap (p = 0.028), lipids (p = 0.015) and necrosis (p = 0.017). Conclusions: Clinically available PCCT detects not only calcification, but also other rupture-prone features of human carotid plaques ex vivo. Relevance statement: Improved atherosclerotic plaque characterisation by photon-counting CT provides the ability to distinguish not only calcium, but also rupture-prone plaque features such as haemorrhage and thrombus. This may potentially improve monitoring and risk stratification of atherosclerotic patients in order to prevent strokes. Key points: • CT of atherosclerotic plaques mainly detects calcium. • Many components, such as intra-plaque haemorrhage and lipids, determine increased plaque rupture risk. • Ex vivo carotid plaque photon-counting CT distinguishes haemorrhage and thrombus. • Improved plaque photon-counting CT evaluation may refine risk stratification accuracy to prevent strokes. [ABSTRACT FROM AUTHOR]

Atherosclerosis and one of its most serious consequences, coronary artery disease, are important sources of morbidity and mortality globally, necessitating early detection and treatment. Considering their complex pathophysiology, including several harmful processes, a comprehensive approach to diagnosis, prognosis, and therapy is very desirable. Extracellular matrix remodeling is a major component of this dangerous cascade, including the cleavage of constituents (collagen, elastin, proteoglycans) and the propagation or exacerbation of the inflammatory response. Several extracellular matrix degradation indicators have been hypothesized to correlate with the existence, severity, and prognosis of coronary artery disease. The potency of matrix metalloproteinases, notably collagenases and gelatinases, has been the most thoroughly investigated in clinical studies. Stromelysins, matrilysins, transmembrane matrix metalloproteinases, collagen and laminin turnover indicators, as well as fibronectin, have also been studied to a lesser level. Among the most well-studied markers, MMP-1, MMP-2, MMP-8, and MMP-9 have been found increased in patients with cardiovascular risk factors such as metabolic syndrome, its components (obesity, dyslipidemia, diabetes mellitus), and smoking. Increasing concentrations are detected in acute coronary syndromes compared to stable angina pectoris and healthy control groups. It should also be stressed that those extracellular matrix biomarkers may also be detected in high concentrations in other vascular pathologies such as peripheral artery disease, carotid artery disease, aortic aneurysms, and dissections. Despite the advances gained, future research should focus on their importance and, more crucially, their added utility as biomarkers in identifying persons at risk of developing overt coronary artery disease. At the same time, determining the prognosis of coronary artery disease patients using such biomarkers may be important for their adequate care., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Adipokines are substances secreted by adipose tissue that are receiving increasing attention. The approach to adipose tissue has changed in recent years, and it is no longer looked at as just a storage organ but its secretion and how it influences systems in the human body are also looked at. The role of adipokine seems crucial in developing future therapies for pathologies of selected systems. In this study, we look at selected adipokines, leptin, adiponectin, chemerin, resistin, omentin-1, nesfatin, irisin-1, visfatin, apelin, vaspin, heparin-binding EGF-like growth factor (HB-EGF), and TGF-β2, and how they affect systems in the human body related to physical activity such as the musculoskeletal and cardiovascular systems. [ABSTRACT FROM AUTHOR]

The objective of our study was to evaluate the concentrations of pro-inflammatory biomarkers in patients with acute myocardial infarction with non-obstructive coronary arteries (MINOCA) compared to patients with acute myocardial infarction with obstructive coronary arteries (MI-CAD) in the early post-infarction period and after 1 year and to perform a comparative analysis of the relationship between laboratory biomarkers and atherosclerosis progression in patients with MINOCA and MI-CAD. Methods: Samples of peripheral venous blood were collected upon admission and on days 2, 4, and 7 of hospitalization and after 1 year. An extended multiplex analysis was performed in blood serum. Multidetector-computed tomography coronary angiography was performed on day 7 and 1 year after acute myocardial infarction to assess the progression of atherosclerosis. Results: The level of high-sensitive C-reactive protein (hsCRP) was elevated upon admission in MINOCA patients compared to MI-CAD patients (p = 0.05), but it was comparable in two groups at other time points and did not exceed the reference range after 1 year. Despite comparable levels of cytokines CXCL-6, LIGHT, CCL-8, and endocan-1 in patients in both groups, MINOCA patients had a greater increase in pro-inflammatory cytokines PlGF, oncostatin M, IL-20, and CCL-15 sVCAM-1 in the early post-infarction period and in CCL-21, sVCAM-1, oncostatin M, and PlGF after 1 year. We observed significant differences in the dynamics of the following biomarkers between patients with MI-CAD and MINOCA: the dynamics of concentrations of CCL21 (p = 0.002), LIGHT (p = 0.03), and endocan-1 (p = 0.03) after 1 year compared to day 1 in MI-CAD and MINOCA patients was opposite, while the dynamics of CXCL6 (p = 0.04) and endocan-1 (p = 0.02) differed between groups when evaluated after 1 year compared to day 7 of the early post-infarction period. In the MINOCA group, factors associated with atherosclerosis progression were concentrations of sVCAM-1 and CCL-21, while in the MI-CAD group, concentrations of CCL-8 and CXCL6 were the main determinants of atherosclerosis progression. Conclusions: This small study showed that MINOCA and MI-CAD patients exhibited differences in a pro-inflammatory biomarker profile in the early post-infarction period and after 1-year follow-up, which implies distinct inflammatory pathways involved in atherogenesis during MINOCA. The key factors that were associated with atherosclerosis progression in MINOCA patients are sVCAM-1 and CCL-21, which may suggest a complex genesis of atherosclerosis progression due to structurally altered plaques and changes in the microcirculatory bed. In MI-CAD patients, CCL-8 and CXCL-6 were the key biomarkers associated with atherosclerosis progression. Further large-scale studies are required to confirm our data. [ABSTRACT FROM AUTHOR]

Transforming growth factor-beta 2 (TGF-β2), an important member of the TGF-β family, is a secreted protein that is involved in many biological processes, such as cell growth, proliferation, migration, and differentiation. TGF-β2 had been thought to be functionally identical to TGF-β1; however, an increasing number of recent studies uncovered the distinctive features of TGF-β2 in terms of its expression, activation, and biological functions. Mice deficient in TGF-β2 showed remarkable developmental abnormalities in multiple organs, especially the cardiovascular system. Dysregulation of TGF-β2 signalling was associated with tumorigenesis, eye diseases, cardiovascular diseases, immune disorders, as well as motor system diseases. Here, we provide a comprehensive review of the research progress in TGF-β2 to support further research on TGF-β2. [ABSTRACT FROM AUTHOR]

Aims: Invariant natural killer T (iNKT) cells, a T cell subset that is CD1d-restricted and expresses a semi-invariant T cell receptor, have been proposed to contribute to dyslipidaemia-driven cardiovascular disease due to their ability to specifically recognize lipid antigens. Studies in mice have attributed pro-atherogenic properties to iNKT cells, but studies in humans investigating associations of iNKT cells with incident coronary events (CE) are lacking. Methods and results: Here, we used flow cytometry to enumerate circulating iNKT cells (CD3+ CD1d-PBS57-Tetramer+) in a case-control cohort nested within the prospective population-based Malmö Diet and Cancer Study (n = 416) to explore associations with incident first-time CE during a median follow-up of 14 years. We found a significant inverse association between CD4− and CD8− double negative (DN) iNKT cells and incident CE, with an odds ratio of 0.62 [95% confidence interval (CI) 0.38–0.99; P = 0.046] comparing the highest vs. the lowest tertile of DN iNKT cells. The association remained significant after adjustment for cardiovascular risk factors with an odds ratio of 0.57 (95% CI 0.33–0.99; P = 0.046). In contrast, total iNKT cells were not significantly associated with incident CE after adjustment, with an odds ratio of 0.74 (95% CI 0.43–1.27; P = 0.276). Conclusion: Our findings indicate that animal studies suggesting an atherosclerosis-promoting role for iNKT cells may not translate to human cardiovascular disease as our data show an association between high circulating numbers of DN iNKT cells and decreased risk of incident CE. Graphical abstract [ABSTRACT FROM AUTHOR]

Osteoglycin, a fundamental proteoglycan within the vascular extracellular matrix, is expressed in vascular smooth muscle cells (VSMCs). Type 2 diabetes (T2D) is associated with cardiovascular disease (CVD) but the role of osteoglycin in the development of CVD is controversial to date. Therefore, our aims are to determine and compare the level of osteoglycin in T2D patients with/ without CVD versus control subjects both at serum and vascular tissue and to analyze in vitro role of osteoglycin in VSMCs under calcified conditions. For this, serum osteoglycin levels were determined by enzyme-linked immunosorbent assay (ELISA) in 117 controls and 129 patients with T2D (46 with CVD and 83 without CVD), revealing a significant increase in patients with T2D compared with controls. Osteoglycin level was not an estimator of CVD but correlated with markers of insulin resistance (triglycerides and triglycerides/high-density lipoprotein cholesterol index) in patients with T2D. At the vascular level, osteoglycin expression was assessed by RT-qPCR and immunohistochemistry, and no significant differences were observed between calcified arteries from patients with T2D and noncalcified arteries from controls. In vitro experiments using VSMCs (mock and overexpressing osteoglycin) under calcifying conditions were performed to analyze the osteoglycin function. The overexpression of osteoglycin in VMSCs under calcifying conditions revealed an increase of cell proliferation without effect on apoptosis and an upregulation of the expression of autotaxin (ATX) involved in inflammatory processes. In conclusion, osteoglycin could play a role in glycemic homeostasis, being a potential biomarker of insulin resistance in patients with T2D. Furthermore, osteoglycin could indirectly participate in the development of atherosclerosis through its regulatory effect on ATX and by proliferating VSMCs. [ABSTRACT FROM AUTHOR]

Thin endometrium, defined as an endometrial thickness of less than 7 mm during the late follicular phase, is a common cause of frequent cancelation of embryo transfers or recurrent implantation failure during assisted reproductive treatment. Small proteoglycans regulate intracellular signaling cascades by bridging other matrix molecules and tissue elements, affecting cell proliferation, adhesion, migration, and cytokine concentration. The aim of the study is to investigate the role of small leucine-rich proteoglycans in the pathogenesis of thin and thick human endometrium and their differences from normal endometrium in terms of fine structure properties. Normal, thin, and thick endometrial samples were collected, and small leucine-rich proteoglycans (SLRPs), decorin, lumican, biglycan, and fibromodulin immunoreactivities were comparatively analyzed immunohistochemically. The data were compared statistically. Moreover, ultrastructural differences among the groups were evaluated by transmission electron microscopy. The immunoreactivities of decorin, lumican, and biglycan were higher in the thin endometrial glandular epithelium and stroma compared to the normal and thick endometrium (p < .001). Fibromodulin immunoreactivity was also higher in the thin endometrial glandular epithelium than in the normal and thick endometrium (p < .001). However, there was no statistical difference in the stroma among the groups. Ultrastructural features were not profoundly different among cases. Telocytes, however, were not seen in the thin endometrium in contrast to normal and thin endometrial tissues. These findings suggest a possible role of changes in proteoglycan levels in the pathogenesis of thin endometrium. [ABSTRACT FROM AUTHOR]