ABSTRACT
BACKGROUND: Haemophilic arthropathy (HA) is a major complication in haemophilia. Collagens IV, XV and XVIII are responsible for maintaining the integrity of the vessel wall in the joint. Following joint remodelling and damage, the short isoform of collagen type XVIII (COL-18N) is degraded, releasing measurable fragments. Our goal was to quantify the specific isoform COL-18N in haemophilia A patients and to assess its relation to the clinical and radiological data as well as haemophilia joint health score (HJHS), functional independence score for haemophilia (FISH), and haemophilia quality of life (Haemo-Qol). METHODS: This cross-sectional study included 50 haemophilia A patients recruited from the Paediatric Haematology and Oncology unit, Ain Shams University, Cairo, Egypt. Quantification of COL-18N was done by ELISA. Assessment of joint state clinically using FISH and HJH scores and radiologically by X-rays and ultrasound. RESULTS: Haemophilia A patients had significantly higher median COL-18N levels compared to the control group. Inhibitor positive and negative haemophilia A patients as well as those on non-steroidal anti-inflammatory drug and those not had comparable COL-18N levels. Patients with ≥2 target joints had significantly higher COL-18N level compared to those with one or those without target joints. There were significant positive correlations between COL-18N level and the total HJHS, Haemo-Qol, the HEAD-US score and annual bleeding rate. CONCLUSION: Our results demonstrated a high level of COL-18N in haemophilia A patients and argued its benefit as a potential marker for monitoring the development of haemophilic arthropathy and tailoring the optimal treatment to prevent further joint damage.
Subject(s)
Collagen Type XVIII , Hemarthrosis , Hemophilia A , Vascular Diseases , Adolescent , Blood Vessels/physiopathology , Child , Collagen Type XVIII/blood , Cross-Sectional Studies , Female , Hemarthrosis/blood , Hemarthrosis/etiology , Hemophilia A/blood , Hemophilia A/complications , Humans , Male , Protein Isoforms/blood , Quality of Life , Vascular Diseases/blood , Vascular Diseases/etiologyABSTRACT
BACKGROUND: The identification of abdominal aortic aneurysm (AAA) biomarker offers a perspective to determine disease progress and rupture risk. The aim of our study was to evaluate the association between selected circulating biomarkers and diameter of abdominal aorta. METHODS: One hundred and two patients (88 men and 14 women) with mean age 70.0±8.7 years were included in a single center cross-sectional study conducted between February 2016 and October, 2018. AAA was defined as subrenal aortic dilatation ≥3 cm. Serum biomarker concentrations (insulin-like growth factor-1, peroxiredoxin-1, collagen IV, collagen XVIII) were measured by an enzyme-linked immunosorbent assay (ELISA). Adjustments including variables with different baseline distribution at univariate level with P<0.1 (age, body mass index, coronary artery disease, fibrinogen) were performed in multivariate models. RESULTS: Higher collagen XVIII was found in AAA patients in comparison with the control group of patients (39.5 vs. 25.0 ng/mL; P=0.002). Diameter of abdominal aorta was positively associated with collagen XVIII levels in univariate (B=0.16; P=0.004), and in multivariate analysis (B=0.14; P=0.027), i.e. increase in collagen XVIII by 1 ng/mL corresponded to an increase in abdominal aortic diameter by 0.14 mm. Patients with serum collagen XVIII levels in the third tertile (Ë47 ng/mL) had 4.23 times higher risk of AAA compared to patients with collagen XVIII levels in the first and second tertiles (OR 4.23; 95% CI 1.42-11.6; P=0.020). No association was found between other examined biomarkers and abdominal aortic diameter. CONCLUSIONS: Diameter of abdominal aorta was positively associated with serum collagen XVIII level.
Subject(s)
Aorta, Abdominal/anatomy & histology , Aortic Aneurysm, Abdominal/blood , Collagen Type XVIII/blood , Aged , Aorta, Abdominal/diagnostic imaging , Aorta, Abdominal/pathology , Aortic Aneurysm, Abdominal/diagnostic imaging , Aortic Aneurysm, Abdominal/pathology , Biomarkers/blood , Cross-Sectional Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Multivariate Analysis , Risk Factors , UltrasonographyABSTRACT
OBJECTIVE: Abdominal aortic aneurysm (AAA) is characterised by enhanced proteolytic activity, and extracellular matrix (ECM) remodelling in the vascular wall. Type IV and XVIII collagen/endostatin are structural proteins in vascular basement membrane (VBM), a specialised ECM structure. Here the association between plasma levels of these collagens with the aortic diameter and expansion rate is studied, and their expression in aortic tissue characterised. METHODS: This was a retrospective population based cohort study. Type IV and XVIII collagen/endostatin were analysed in plasma by ELISA assay in 615 men, divided into three groups based on the aortic diameter: 1) normal aorta ≤ 25 mm, 2) sub-aneurysmal aorta (SAA) 26-29 mm, and 3) AAA ≥ 30 mm. Follow up data were available for 159 men. The association between collagen levels and aortic diameter at baseline, and with the expansion rate at follow up were analysed in ordinal logistic regression and linear regression models, controlling for common confounding factors. Tissue expression of the collagens was analysed in normal aorta (n = 6) and AAA (n = 6) by immunofluorescence. RESULTS: Plasma levels of type XVIII collagen/endostatin (136 ng/mL [SD 29] in individuals with a normal aorta diameter, 154 ng/ml [SD 45] in SAA, and 162 ng/ml [SD 46] in AAA; p = .001) and type IV collagen (105 ng/mL [SD 42] normal aorta, 124 ng/ml [SD 46] SAA, and 127 ng/ml [SD 47] AAA; p = .037) were associated with a larger aortic diameter. A significant association was found between the baseline levels of type XVIII/endostatin and the aortic expansion rate (p = .035), but in the multivariable model, only the initial aortic diameter remained significantly associated with expansion (p = .005). Altered expression patterns of both collagens were observed in AAA tissue. CONCLUSION: Plasma levels of circulating type IV and XVIII collagen/endostatin increase with AAA diameter. The expression pattern of VBM proteins is altered in the aneurysm wall.
Subject(s)
Aorta, Abdominal/chemistry , Aortic Aneurysm, Abdominal/blood , Basement Membrane/chemistry , Collagen Type IV/blood , Collagen Type XVIII/blood , Aged , Aged, 80 and over , Aorta, Abdominal/diagnostic imaging , Aorta, Abdominal/pathology , Aortic Aneurysm, Abdominal/diagnostic imaging , Aortic Aneurysm, Abdominal/pathology , Biomarkers/blood , Dilatation, Pathologic , Disease Progression , Endostatins/blood , Enzyme-Linked Immunosorbent Assay , Female , Fluorescent Antibody Technique , Humans , Linear Models , Logistic Models , Male , Middle Aged , Multivariate Analysis , Retrospective Studies , Vascular RemodelingABSTRACT
RATIONALE: Pulmonary arterial hypertension (PAH) is a medically incurable disease resulting in death from right ventricular (RV) failure. Both pulmonary vascular and RV remodeling are linked to dynamic changes in the microvasculature. Therefore, we hypothesized that circulating angiostatic factors could be linked to outcomes and represent novel biomarkers of disease severity in PAH. OBJECTIVES: We sought to determine the relationship of a potent angiostatic factor, endostatin (ES), with disease severity and mortality in PAH. Furthermore, we assessed genetic predictors of ES expression and/or function and their association with outcomes in PAH. METHODS: We measured levels of serum ES in two independent cohorts of patients with PAH. Contemporaneous clinical data included New York Heart Association functional class, 6-minute-walk distance, invasive hemodynamics, and laboratory chemistries. MEASUREMENTS AND MAIN RESULTS: Serum ES correlated with poor functional status, decreased exercise tolerance, and invasive hemodynamics variables. Furthermore, serum ES was a strong predictor of mortality. A loss-of-function, missense variant in the gene encoding ES, Col18a1, was linked to lower circulating protein and was independently associated with reduced mortality. CONCLUSIONS: Our data link increased expression of ES to disease severity in PAH and demonstrate a significant relationship with adverse outcomes. Circulating ES levels can be genetically influenced, implicating ES as a genetically determined modifier of disease severity impacting on survival. These observations support serum ES as a potential biomarker in PAH with the capacity to predict poor outcomes. More importantly, this study implicates Col18a1/ES as a potential new therapeutic target in PAH.
Subject(s)
Collagen Type XVIII/blood , Endostatins/blood , Hypertension, Pulmonary/blood , Ventricular Dysfunction, Right/physiopathology , Biomarkers/blood , Collagen Type XVIII/genetics , Endostatins/genetics , Exercise Test , Female , Follow-Up Studies , Humans , Hypertension, Pulmonary/classification , Hypertension, Pulmonary/genetics , Hypertension, Pulmonary/mortality , Kaplan-Meier Estimate , Male , Middle Aged , Polymorphism, Single Nucleotide , Predictive Value of Tests , Prognosis , Proportional Hazards Models , ROC Curve , Severity of Illness IndexABSTRACT
Pulmonary arteriovenous malformations (PAVMs) are a common source of morbidity after bidirectional superior cavopulmonary anastomosis (Glenn). The diversion of hepatic venous effluent away from the pulmonary circulation after Glenn appears to play a significant role in the pathogenesis of PAVMs. Although the liver is known to produce factors that regulate vascular development, specific hepatic inhibitors of angiogenesis have not been described in the post-Glenn population. Endostatin, produced from its precursor collagen XVIII, is a potent inhibitor of angiogenesis produced by the liver. This study aimed to investigate the hypothesis that endostatin levels decrease in patients after Glenn. Levels of endostatin and its precursor, long-type collagen XVIII, were determined by enzyme-linked immunoassay and immunoprecipitation, respectively, for serum samples from 38 patients undergoing Glenn, total cavopulmonary anastomosis (Fontan), or biventricular repair of cardiac defects. Samples were obtained before surgery and 24 h afterward. In patients undergoing a bidirectional Glenn procedure, endostatin levels decreased after surgery (n = 17; 4.42 vs 3.34 ng/ml; p < 0.001), and long type-collagen XVIII levels increased by 200 % (n = 10; p = 0.0001). However, endostatin levels did not change after surgery in patients undergoing Fontan (n = 13) or biventricular repair (n = 8). In patients undergoing Fontan, long-type collagen XVIII increased by 18 % (p < 0.01), whereas in control subjects, the levels were unchanged. These data suggest that the diversion of hepatic blood flow away from the pulmonary circulation in patients after the Glenn procedure inhibits endostatin production from collagen XVIII, resulting in decreased circulating serum endostatin levels. A decrease in endostatin may promote angiogenesis. The mechanism whereby the pulmonary circulation processes endostatin and its potential role in the pathogenesis of PAVMs warrant further study.
Subject(s)
Arteriovenous Fistula/blood , Endostatins/biosynthesis , Fontan Procedure/adverse effects , Heart Bypass, Right/adverse effects , Heart Defects, Congenital/surgery , Neovascularization, Pathologic/blood , Arteriovenous Fistula/epidemiology , Arteriovenous Fistula/etiology , Biomarkers/blood , Blotting, Western , Child, Preschool , Collagen Type XVIII/blood , Endostatins/blood , Enzyme-Linked Immunosorbent Assay , Female , Fontan Procedure/methods , Fontan Procedure/mortality , Heart Bypass, Right/mortality , Heart Defects, Congenital/mortality , Humans , Immunoprecipitation , Infant , Male , Morbidity/trends , Neovascularization, Pathologic/epidemiology , Neovascularization, Pathologic/etiology , Postoperative Complications , Pulmonary Artery/abnormalities , Pulmonary Veins/abnormalities , Survival Rate/trends , United States/epidemiologySubject(s)
Aortic Aneurysm, Abdominal/diagnosis , Collagen Type IV/blood , Collagen Type XVIII/blood , Female , Humans , MaleABSTRACT
AIM: The decision for abdominal aortic aneurysm (AAA) repair is based on aneurysm size. However, smaller aneurysms can rupture, while larger ones can remain stable. New variables and markers are needed to better select patients at high rupture risk. The study was done to analyse if AAA patients have increased levels of circulating basement-membrane (BM) fragments. DESIGN: Circulating levels of BM components type IV and XVIII collagen were measured by enzyme-linked immunosorbent assay (ELISA) in 10 patients with AAA, nine patients with peripheral artery disease (PAD) and 10 healthy controls (CON). RESULTS: AAA patients had significantly increased levels of type IV and XVIII collagen compared with CON (134.0 ± 24.8 ng ml(-1) vs. 104.5 ± 16.4 ng ml(-1); p = 0.005 and 149.0 ± 56.9 ng ml(-1) vs. 59.6 ± 8.7 ng ml(-1); p < 0.001, respectively). The PAD patients did not have significantly increased levels of these fragments when compared with CON. In addition, the AAA patients had significantly increased level of type XVIII collagen (149.0 ± 56.9 ng ml(-1) vs. 58.3 ± 25.4 ng/ml(-1); p < 0.01) when compared with the PAD group. CONCLUSION: Based on this preliminary analysis of a small number of subjects, patients with AAA had significantly increased levels of circulating BM components. BM fragments should be studied further to establish their potential role as biomarkers for AAA.
Subject(s)
Aortic Aneurysm, Abdominal/diagnosis , Collagen Type IV/blood , Collagen Type XVIII/blood , Aged , Aged, 80 and over , Aorta/metabolism , Aortic Aneurysm, Abdominal/blood , Aortic Rupture/diagnosis , Basement Membrane/metabolism , Biomarkers/blood , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Peripheral Arterial Disease/blood , Pilot ProjectsABSTRACT
BACKGROUND: Lipoprotein lipase (Lpl) acts on triglyceride-rich lipoproteins in the peripheral circulation, liberating free fatty acids for energy metabolism or storage. This essential enzyme is synthesized in parenchymal cells of adipose tissue, heart, and skeletal muscle and migrates to the luminal side of the vascular endothelium where it acts upon circulating lipoproteins. Prior studies suggested that Lpl is immobilized by way of heparan sulfate proteoglycans on the endothelium, but genetically altering endothelial cell heparan sulfate had no effect on Lpl localization or lipolysis. The objective of this study was to determine if extracellular matrix proteoglycans affect Lpl distribution and triglyceride metabolism. METHODS AND FINDINGS: We examined mutant mice defective in collagen XVIII (Col18), a heparan sulfate proteoglycan present in vascular basement membranes. Loss of Col18 reduces plasma levels of Lpl enzyme and activity, which results in mild fasting hypertriglyceridemia and diet-induced hyperchylomicronemia. Humans with Knobloch Syndrome caused by a null mutation in the vascular form of Col18 also present lower than normal plasma Lpl mass and activity and exhibit fasting hypertriglyceridemia. CONCLUSIONS: This is the first report demonstrating that Lpl presentation on the lumenal side of the endothelium depends on a basement membrane proteoglycan and demonstrates a previously unrecognized phenotype in patients lacking Col18.