Matrix Remodeling In Patients Research Articles

Association of Epicardial Adipose Tissue Adipocytes Hypertrophy with Biomarkers of Low-Grade Inflammation and Extracellular Matrix Remodeling in Patients with Coronary Artery Disease

The aim of the study was to compare the morphological features of epicardial adipose tissue (EAT) adipocyte with the circulating inflammatory biomarkers and parameters of extracellular matrix remodeling in patients with coronary artery disease (CAD). We recruited 42 patients with CAD (m/f 28/14) who were scheduled for coronary artery bypass graft surgery (CABG). EAT adipocytes were obtained by the enzymatic method from intraoperative adipose tissue samples. Concentrations of secreted and lipoprotein-associated phospholipase A2 (sPLA2 and LpPLA2), TNF-α, IL-1β, IL-6, IL-10, high-sensitive C-reactive protein (hsCRP), metalloproteinase-9 (MMP-9), MMP-2, C-terminal cross-linking telopeptide of type I collagen (CTX-I), and tissue inhibitor of metalloproteinase 1 (TIMP-1) were measured in blood serum. Patients were divided into two groups: group 1-with mean EAT adipocytes' size ≤ 87.32 μm; group 2-with mean EAT adipocytes' size > 87.32 μm. Patients of group 2 had higher concentrations of triglycerides, hsCRP, TNF-α, and sPLA2 and a lower concentration of CTX-I. A multiple logistic regression model was created (RN2 = 0.43, p = 0.0013). Concentrations of TNF-α, sPLA2 and CTX-I appeared to be independent determinants of the EAT adipocyte hypertrophy. ROC analysis revealed the 78% accuracy, 71% sensitivity, and 85% specificity of the model, AUC = 0.82. According to our results, chronic low-grade inflammation and extracellular matrix remodeling are closely associated with the development of hypertrophy of EAT adipocytes, with serum concentrations of TNF-α, sPLA2 and CTX-I being the key predictors, describing the variability of epicardial adipocytes' size.

Markers of extracellular matrix remodeling and systemic inflammation in patients with heritable thoracic aortic diseases.

In approximately 20% of patients with thoracic aortic aneurysms or dissections a heritable thoracic aortic disease (HTAD) is suspected. Several monogenic connective tissue diseases imply high risk of aortic disease, including both non-syndromic and syndromic forms. There are some studies assessing inflammation and extracellular matrix remodeling in patients with non-hereditary aortic disease, but such studies in patients with hereditary diseases are scarce. To quantify markers of extracellular matrix (ECM) and inflammation in patients with vascular connective tissue diseases versus healthy controls. Patients with Loeys-Dietz syndrome (LDS, n = 12), Marfan syndrome (MFS, n = 11), and familial thoracic aortic aneurysm 6 (FTAA6, n = 9), i.e., actin alpha 2 (ACTA2) pathogenic variants, were recruited. Exome or genome sequencing was performed for genetic diagnosis. Several markers of inflammation and ECM remodeling were measured in plasma by enzyme immunoassays. Flow cytometry of T-cell subpopulations was performed on a subgroup of patients. For comparison, blood samples were drawn from 14 healthy controls. (i) All groups of HTAD patients had increased levels matrix metalloproteinase-9 (MMP-9) as compared with healthy controls, also in adjusted analyses, reflecting altered ECM remodeling. (ii) LDS patients had increased levels of pentraxin 3 (PTX3), reflecting systemic inflammation. (iii) LDS patients have increased levels of soluble CD25, a marker of T-cell activation. Our data suggest that upregulated MMP-9, a matrix degrading enzyme, is a common feature of several subgroups of HTAD. In addition, LDS patients have increased levels of PTX3 reflecting systemic and in particular vascular inflammation.

Effect of positive airway pressure therapy of obstructive sleep apnea on circulating Angiopoietin-2

BackgroundObstructive sleep apnea (OSA) has been identified as a possible contributor to interstitial lung disease. While positive airway pressure (PAP) is effective therapy for OSA, it causes large increases in lung volumes during the night that are potentially deleterious, analogous to ventilator-induced lung injury, although this has not been previously studied. The goal of this study was to assess the impact of PAP therapy on four biomarkers of alveolar epithelial and endothelial injury and extracellular matrix remodeling in patients with OSA. MethodsIn 82 patients with moderate to severe OSA who were adherent to PAP therapy, surfactant protein D, osteopontin, angiopoietin-2, and matrix metalloprotease-7 were measured by ELISA in serum samples collected before and 3- to 6-months after initiation of PAP therapy. ResultsAn increase in angiopoietin-2 level of 0.28 ng/mL following PAP therapy was observed (p = 0.007). This finding was replicated in an independent sample of OSA patients. No significant change was detected in surfactant protein D, osteopontin, or matrix metalloprotease-7. ConclusionsThis finding raises concern for a possible adverse impact of PAP therapy on vascular endothelium.

Serum biomarkers of fibrosis and extracellular matrix remodeling in patients with nonalcoholic fatty liver disease: association with liver histology.

We sought to explore the interplay of multiple serum biomarkers of fibrosis and extracellular matrix remodeling with the results of liver histology in patients with nonalcoholic fatty liver disease (NAFLD). Venous blood samples were collected from 80 patients with biopsy-proven NAFLD and 59 age-matched and sex-matched healthy controls. Serum levels of transforming growth factor (TGF)-β1, TGF-β2, matrix metalloproteinases (MMP)-1, MMP-2, MMP-7, MMP-9, MMP-10, tissue inhibitors of metalloproteinase (TIMP)-1, and TIMP-2 were determined by using the Luminex MagPix technology on a MAGPIX analyzer. We documented significant differences in the levels of TGF-β1, TGF-β2, MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-2 between NAFLD patients and controls. However, none of these biomarkers was able to distinguish between nonalcoholic steatohepatitis and nonalcoholic fatty liver. TIMP-1 levels were significantly higher in patients with significant fibrosis (fibrosis stage ≥2; 2624±1261 pg/ml) than in those without (fibrosis stage 0-1; 2096±906 pg/ml; P=0.03). Moreover, serum levels of TIMP-1 were identified as the only independent predictor of histological fibrosis (β=0.298, t=2.7, P=0.007). Our study provides insights into the association of multiple serum biomarkers of fibrosis and extracellular matrix remodeling with NAFLD histology. Notably, serum levels of TIMP-1 were identified as a clinically useful marker for distinguishing NAFLD patients with and without significant fibrosis.

Serological markers of extracellular matrix remodeling predict transplant-free survival in primary sclerosing cholangitis.

Primary sclerosing cholangitis is a progressive liver disease with a remarkably variable course. Biomarkers of disease activity or prognostic models predicting outcome at an individual level are currently not established. To evaluate the prognostic utility of four biomarkers of basement membrane and interstitial extracellular matrix remodeling in patients with primary sclerosing cholangitis. Serum samples were available from 138 large-duct primary sclerosing cholangitis patients (of which 102 [74%] with IBD) recruited 2008-2012 and 52 ulcerative colitis patients (controls). The median follow-up time was 2.2 (range 0-4.3) years. Specific biomarkers of type III and V collagen formation (PRO-C3 and PRO-C5, respectively) and type III and IV collagen degradation (C3M and C4M, respectively) were assessed. The Enhanced Liver Fibrosis test, including procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinase-1 and hyaluronic acid was assessed for comparison. All markers were elevated in primary sclerosing cholangitis compared to ulcerative colitis patients (P<0.001). PRO-C3 showed the largest difference between the two groups with a threefold increase in primary sclerosing cholangitis compared to ulcerative colitis patients. Patients with high baseline serum levels of all markers, except C3M, had shorter survival compared to patients with low baseline serum levels (P<0.001). Combining PRO-C3 and PRO-C5 the odds ratio for predicting transplant-free survival was 47 compared to the Enhanced Liver Fibrosis test's odds ratio of 11. Extracellular matrix remodeling is elevated in primary sclerosing cholangitis patients compared to ulcerative colitis patients. Furthermore, the interstitial matrix marker PRO-C3 was identified as a potent prognostic marker and an independent predictor of transplant-free survival in primary sclerosing cholangitis.

Tissue inhibitor of matrix metalloproteinase-1 role in left atrium matrix remodeling in patients with atrial febrillation

Tissue inhibitor of matrix metalloproteinase-1 role in left atrium matrix remodeling in patients with atrial febrillation

Aberrant Epicardial Adipose Tissue Extracellular Matrix Remodeling in Patients with Severe Ischemic Cardiomyopathy: Insight from Comparative Quantitative Proteomics

There is ample evidence indicating that epicardial adipose tissue (EAT) volume and thickness is positively associated with coronary artery disease (CAD). However, the exact pathological changes in the human EAT after myocardial ischemia remains largely unclear. In the current study, we applied a comparative quantitative proteomics to elucidate the altered biological processes in the EAT of ischemic cardiomyopathy (ICM) patients. A total of 1649 proteins were successfully quantified in our study, among which 165 proteins were significantly changed (ratio <0.8 or >1.2 fold and p < 0.05 in both repetitions) in EAT of ICM individuals. Gene ontology (GO) enrichment analysis revealed that cardiac structure and cellular metabolism were over-represented among these regulated proteins. The hypertrophic cardiomyopathy, adrenergic signaling in cardiomyocytes, extracellular matrix (ECM)-receptor interaction, phagosome, Glycolysis/Gluconeogenesis, and PPAR signaling pathway were highlighted by the KEGG PATHWAY analysis. More importantly, we found that the proteins responsible for extracellular matrix organization were dramatically increased in EAT of ICM patients. In addition, the picrosirius red (PSR) staining results showed that the collagen fiber content was prominently increased, which indicated the EAT of ICM individuals underwent extracellular matrix remodeling and ERK1/2 activation maybe responsible for these pathological changes partially.

A novel serological type III collagen a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) degradation marker for assessment of the extracellular matrix remodeling in patients with osteoarthritis

A novel serological type III collagen a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) degradation marker for assessment of the extracellular matrix remodeling in patients with osteoarthritis

Extracellular matrix remodeling in patients with ischemic chronic heart failure with preserved ejection fraction

З метою виявлення особливостей, взаємозв’язків між параметрами екстрацелюлярного матриксу та ниркової функції у 110 хворих на хронічну серцеву недостатність ішемічного генезу за допомогою імуноферментного аналізу й ехокардіографії вивчили активність маркерів колагенового обміну (ММП-9, ТІМП-1, РІСР), цистатину С, структурно-функціональні параметри серця. Встановили, що при хронічній серцевій недостатності ішемічного генезу зі збереженою фракцією викиду лівого шлуночка дисбаланс у системі ММП/ТІМП призводить до порушення структурної повноцінності екстрацелюлярного матриксу міокарда, посилює його функціональну неспроможність та асоціюється з порушенням ниркової функції. Протягом кореляційного аналізу встановили значущі взаємозв’язки між параметрами системи ММП/ТІМП і ШКФ, цистатином С, що свідчить про роль порушення балансу екстрацелюлярного матриксу в розвитку дисфункції нирок у пацієнтів із хронічною серцевою недостатністю ішемічного генезу.

Heart diastolic dysfunction in patients with systemic sclerosis.

IntroductionThere are limited data on left (LV) and right ventricular (RV) diastolic function in systemic sclerosis (SSc) patients especially in relation to biomarkers of matrix remodeling. The aim of the study was to analyze LV and RV myocardial diastolic function in SSc patients at baseline and after at least 1 year of follow-up and its relation to serum tissue inhibitors of metalloproteinase 1 (TIMP-1) level.Material and methodsWe prospectively studied 111 SSc patients (101 female, 10 male, age 54.2 ±13.8 years) and 21 age-matched controls (18 female, 3 male, age 49.3 ±10.5 years). After at least 1 year of observation (3.0 ±1.1 years) we reevaluated 69 of the SSc patients. Transthoracic echocardiography (Philips, iE33) for assessment of LV and RV diastolic function was performed and TIMP-1 serum level was measured.ResultsImpaired LV relaxation was observed in 38 (34%) SSc patients and in 1 (5%) of the controls (p < 0.001). The mean E/A ratio was lower in patients with SSc than in controls (p = 0.002) and significantly decreased after the follow-up period (p = 0.02). Impaired RV relaxation was detected in 25 (22.5%) SSc patients and in 1 (5%) control subject (p < 0.001) but did not deteriorate after follow-up. Mean serum level of TIMP-1 was significantly elevated in the follow-up group compared to baseline examination (p = 0.0001). Serum TIMP-1 level correlated positively with E/E’, both septal and lateral (r = 0.4, p = 0.002 and r = 0.32, p = 0.01).ConclusionsThe LV and RV relaxation is impaired in SSc patients. Moreover, left ventricular diastolic function deteriorated after the follow-up period. The TIMP-1 serum levels correlate with echocardiographic parameters, providing a potent link for LV diastolic function and matrix remodeling in patients with SSc.

Exposure to Uremic Serum Induces a Procalcific Phenotype in Human Mesenchymal Stem Cells

Medial artery calcification in patients with chronic kidney disease proceeds through intramembranous ossification resulting from osteoblast-induced calcification of the collagen extracellular matrix. The current study is based on the hypothesis that mesenchymal stem cells (MSC) constitute critical cells for procalcific extracellular matrix remodeling in patients with chronic kidney disease. Human MSC were cultured in media supplemented with pooled sera from either healthy or uremic patients (20%). Exposure to uremic serum enhanced the proliferation of MSC (cell counting, BrdU incorporation) whereas apoptosis and necrosis were not affected (annexin V and 7-amino-actinomycin staining). Uremic serum-exposed MSC recapitulated osteogenesis by matrix calcification and expression of bone-related genes (bone morphogenetic protein [BMP]-2 receptor, alkaline phosphatase, osteopontin, and Runx2) in 35 days. The uremic serum-induced osteogenesis was completely blocked by a BMP-2/4 neutralizing antibody or the natural antagonist NOGGIN. Calcification and matrix remodeling were further analyzed in a collagen-embedded osteogenesis model recapitulating the vascular collagen I/III environment. The uremic serum-induced calcification was shown to occur along collagen fibers as shown by scanning electron microscopy, energy-dispersive X-ray spectroscopy, and von Kossa staining and was accompanied by extensive matrix remodeling. Uremic serum induced in a BMP-2/4-dependent manner an osteoblast-like phenotype in MSC accompanied by matrix remodeling and calcification.

183: The Role of Cathepsin K in Extra Cellular Matrix Remodeling in Patients with End Stage Heart Failure

183: The Role of Cathepsin K in Extra Cellular Matrix Remodeling in Patients with End Stage Heart Failure

Nephrogenic systemic fibrosis with a spectrum of clinical and histopathological presentation: a disorder of aberrant dermal remodeling

Nephrogenic fibrosing dermopathy (NFD) has emerged as a clinicopathologic entity since 1997 and recently renamed as nephrogenic systemic fibrosis (NSF). The etiology and pathogenesis remain uncertain. Characteristic clinical presentation is described as diffuse thickening and hardening of the skin occurring in patients with renal insufficiency. Typical histological features include proliferation of CD34 positive fibrocytes, increased thick collagen bundles and mucin deposition, without significant inflammatory infiltrate. Variations in clinical presentations have been reported, including papular and plaque-like skin lesions, focal lesion only, as well as systemic involvement. Histological changes can be subtle and non-specific, overlapping with other disease processes and harboring features including calcification and osteoclast-like giant cells with osseous metaplasia. We reviewed patients with NSF that presented to our dermatology clinic by chart review, clinical examination and histological examination. Skin biopsy specimens were obtained from all cases. Histopathology evaluations were carried out by three dermatopathologists (AD, BS and GK) independently and the features were compared among all the cases. Special stains and immunohistochemistry study were also performed to highlight the histological features. Seven cases of NSF presented with a spectrum of clinical manifestations, from classic diffuse hardening of the skin to localized linear plaques. On histological examination, proliferation of CD34-positive fibrocytes ranged from sparse to dense, collagen bundles ranged from thin to thick, and the interstitial dermal mucin accumulation ranged from scant-patchy to abundant. In addition, the lesion displayed various degrees of vascular proliferation, inflammatory infiltrates and intensities of CD68 and Factor XIIIa staining. Two cases showed extensive dermal calcification and ossification. NSF may present with a spectrum of clinical abnormalities, and exhibit overlapping histopathological features resembling cicatrix and other dermal reparative/regenerative processes. NSF may in fact to be a disorder of aberrant extracellular matrix remodeling in patients with renal insufficiency.

Correlation of Biomarkers of Endothelium Dysfunction and Matrix Remodeling in Patients with Systemic Sclerosis

Systemic sclerosis (SSc) is a multisystem disease characterized by microvascular dysfunction and excessive fibrosis. However, the relationship between these 2 features remains unclear. Endothelial dysfunction can be assessed by quantifying plasma asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase. Matrix remodeling can be assessed by quantifying serum tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Both biomarkers are elevated in patients with SSc. Our objective was to test whether plasma ADMA is correlated with serum TIMP-1. We enrolled 91 subjects, 39 patients with SSc, 28 patients with primary Raynaud's phenomenon (RP), and 24 healthy volunteers. Plasma ADMA concentrations were measured by liquid chromatography-tandem mass spectrometry. Serum TIMP-1 concentrations were determined by ELISA. Mean ADMA concentrations were higher in patients with SSc (0.68 microM +/- 0.12) than in patients with primary RP or healthy volunteers (respectively, 0.56 microM +/- 0.14 and 0.62 microM +/- 0.12; p = 0.002). Median serum TIMP-1 concentrations were increased in patients with SSc compared to primary RP and healthy volunteers [12 (9-15), 11 (8-13), and 10 (7-13) nM, respectively; p = 0.05]. In the SSc group, we observed a statistically significant correlation between plasma ADMA and serum TIMP-1 (r = 0.34, p = 0.035). These data are consistent with our hypothesis of an association of endothelial dysfunction and matrix remodeling in scleroderma spectrum disorders.

Localized nephrogenic fibrosing dermopathy: Aberrant dermal repairing?

Nephrogenic fibrosing dermopathy (NFD) has emerged as a clinicopathologic entity since 2000 and was recently renamed nephrogenic systemic fibrosis. The cause and pathogenesis remain uncertain. The classic clinical presentation is diffuse thickening and hardening of the skin that occurs in patients with renal insufficiency, with or without systemic involvement. We report a patient with renal failure who presented to our dermatology clinic with a localized plaque on the left forearm along the vein that was traumatized during the infusion of erythropoietin. Histologic examination revealed a dermal proliferation of CD34(+) fibrocytes with collagen fibers and interstitial mucin accumulation, features characteristic for NFD. We conclude that NFD may present as a localized, scarlike plaque after trauma and exhibit overlapping histopathologic features resembling cicatrix and other dermal reparative/regenerative processes. NFD may, in fact, be a disorder of aberrant extracellular matrix remodeling in patients with renal insufficiency. This is a single case observation with discussion of literature and attempted hypothesis on pathogenesis. No experimental evidence is provided.

Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation

BackgroundPatients with bicuspid aortic valve malformations are at an increased risk of aortic dilatation, aneurysm formation, and dissection. Vascular tissues with deficient fibrillin-1 microfibrils release matrix metalloproteinases, enzymes that weaken the vessel wall by degrading elastic matrix components. In bicuspid aortic valve disease a deficiency of fibrillin-1 and increased matrix metalloproteinase matrix degradation might result in aortic degeneration and dilatation. MethodsSamples of the pulmonary artery and aorta were obtained from surgical patients with bicuspid aortic valves (n = 21) and tricuspid aortic valves (n = 16). ResultsFibrillin-1 content was reduced in bicuspid aortic valve aortas compared with that seen in tricuspid aortic valve aortas (P = .001), whereas the associated matrix components, elastin and collagen, were unchanged (P = .51 and P = .21). Reductions of aortic fibrillin-1 content were independent of valve function and patient age. Compared with tricuspid aortic valve aorta, matrix metalloproteinase 2 activity was increased more than 2-fold in bicuspid aortic valve aortas (P = .04) and correlated positively with aortic diameter (r = 0.74, P = .05). Matrix metalloproteinase 9 activity was not significantly different. Fibrillin-1 content was also reduced in the pulmonary arteries of patients with bicuspid aortic valves (P = .06), suggesting a systemic deficiency of fibrillin-1. Promatrix metalloproteinase 2 was increased (P = .04), reflecting an increased production of matrix metalloproteinase 2 in these fibrillin-1–deficient tissues, whereas active matrix metalloproteinase 2 and matrix metalloproteinase 9 species were unchanged, and correspondingly, the pulmonary arteries were not dilated. ConclusionsDeficient fibrillin-1 content in the vasculature of patients with bicuspid aortic valves might trigger matrix metalloproteinase production, leading to matrix disruption and dilatation. This process of vascular matrix remodeling in patients with bicuspid aortic valves offers novel therapeutic targets to prevent the aortic degeneration and dilatation characteristic of this disease.