osteoprotegerin and Ventricular-Dysfunction--Left

Initially described as key regulators in metabolic bone disease osteoprotegerin (OPG), receptor activator of nuclear factor kappa B (RANK) and RANK ligand (RANKL) have also been discriminated as regulators in immunologic function. Cardiovascular diseases (CVD) develop over many years in life and are often triggered by inflammatory processes within the vessel wall that lead to vascular remodeling. Recently some study groups have described OPG as a prognostic parameter for mortality and morbidity in cardiovascular patients.

Topics: Adult; Age Factors; Aged; Arteriosclerosis; Bone Density; Bone Resorption; Cardiovascular Diseases; Coronary Disease; Female; Gonadal Steroid Hormones; Heart Failure; Humans; Male; Middle Aged; Osteoclasts; Osteoporosis; Osteoprotegerin; Prognosis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Sex Factors; Ventricular Dysfunction, Left; Young Adult

Osteoprotegerin (OPG) is a molecule which belongs to the tumor necrosis factor receptor superfamily. OPG concentration is elevated in patients with left ventricle hypertrophy, heart failure and acute myocardial infarction. OPG concentrations rise in chronic kidney disease (CKD). The aim of this study was to investigate the association between OPG concentrations and cardiovascular complications, such as left ventricle hypertrophy, systolic and diastolic dysfunction of left ventricle and dysfunction of right ventricle in chronic kidney disease patients not treated with dialysis. The relation between OPG and the amount of pericardial fluid was also examined.. One hundred and one men with CKD stage 3-5 not treated with dialysis were included in the study. Overhydration, body fat mass and lean body mass were measured using bioimpedance spectroscopy (BIS). Echocardiography was performed to evaluate the amount of pericardial fluid and to measure the thickness of the interventricular septum (IVS), systolic and diastolic function of left ventricle, as well as systolic function of right ventricle.. We observed a significant positive association between OPG and the thickness of the interventricular septum, the size of the left atrium (LA) and the presence of pericardial fluid. A negative relationship was observed between OPG and ejection fraction (EF).. Our results suggest that OPG can be an independent marker of left ventricular hypertrophy, systolic and diastolic dysfunction of left ventricle and the presence of pericardial fluid in chronic kidney disease patients.

Topics: Heart Failure; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Male; Osteoprotegerin; Pericardial Fluid; Renal Dialysis; Renal Insufficiency, Chronic; Ventricular Dysfunction, Left

S-amlodipine has been broadly used to treat hypertension, but its protective effects and underlying mechanism remain controversial. The purpose of our study was to investigate the mechanism by which S-amlodipine improves endothelial dysfunction. Specifically, we investigated if S-amlodipine regulates RANK/RANKL/OPG and micro-RNA 155 (miR-155) levels. Spontaneous hypertensive rats (SHR) were randomly divided into two groups: SHR (n = 12) and S-amlodipine (n = 12). We found that left ventricular ejection fraction (LVEF) increased significantly in the S-amlodipine group compared to the SHR group. After 10 weeks of S-amlodipine treatment, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were significantly lower and eNOS and NO production was significantly higher in the S-amlodipine group compared to the SHR group. In human umbilical vein endothelial cells (HUVECs), miR-155, RANK, and RANKL levels were significantly decreased, while OPG mRNA levels were significantly increased in the S-amlodipine group. HUVECs were transfected with miR-155 mimics or an inhibitor to determine the relationship between miR-155 and RANK/RANKL/OPG and NF-κB signaling. OPG mRNA levels following miR-155 inhibition were significantly higher compared to levels following treatment with miR-155 mimics. S-amlodipine significantly inhibited RANKL expression and NF-κB phosphorylation, and there were no significant differences in response to the NF-κB inhibitor (Bay110785). RANKL expression and NF-κB phosphorylation significantly decreased in the miR-155 inhibitor group. Furthermore, OPG protein expression significantly increased in response to miR-155 inhibition and S-amlodipine treatment (all p < 0.05). Our results indicate that S-amlodipine inhibits inflammation and protects against endothelial dysfunction, likely via regulating the RANK/RANKL/OPG pathway, which appears to be downstream of miR-155.

Topics: Amlodipine; Animals; Cell Line; Female; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; Interleukin-6; Male; MicroRNAs; NF-kappa B; Osteoprotegerin; RANK Ligand; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left

Biomechanical stress and inflammatory biomarkers relate to global contractility dysfunction; however, adding these biomarkers into a risk model constructed on clinical data does not improve its prediction value in chronic heart failure (CHF).. The aim of this study was to evaluate whether biomarkers predict declining of left ventricular global contractility function in diabetic patients with ischemia-induced CHF.. The study retrospectively evolved 54 diabetic patients who had systolic or diastolic ischemia-induced CHF that was defined as left-ventricular ejection fraction (LVEF) ≤45% or 46-55% respectively assessed by quantitative echocardiography and other conventional criteria according to current clinical guidelines. Two-dimensional transthoracic echocardiography and tissue Doppler imaging were performed according to a conventional method. Radial, longitudinal, and circumferential strain and strain rate values were obtained by speckle-tracking Imaging analysis of both LV short axis and long axis views. Serum adiponectin, NT-pro brain natriuretic peptide (BNP), osteoprotegerin, and hs- C-reactive protein (CRP) were determined at baseline by ELISA.. We found lower global longitudinal strain and strain rate in diabetic patients with LVEF <45% than these in diabetic patients that did not have LVEF (Р=0.001 for all cases). Multivariate logistic regression analysis showed that NT-proBNP (r=0.432; P=0.001 and r=0.402; P=0.001, respectively), osteoprotegerin (r=0.422; P=0.001 and r=0.401; P=0.001, respectively), hs-CRP (r=0.408; P=0.001 and r=0.404; P=0.001, respectively) were independently inversely associated with global longitudinal strain and strain rate in CHF patients.. We suggest that osteoprotegerin may be useful in improving the NT-proBNP based model as predictor of decreased global contractility function in diabetic patients with CHF.

Topics: Biomarkers; Diabetes Mellitus; Female; Heart Failure; Humans; Kidney Function Tests; Male; Middle Aged; Natriuretic Peptide, Brain; Osteoprotegerin; Peptide Fragments; Retrospective Studies; Risk Factors; Ventricular Dysfunction, Left

Recently, the role of osteoprotegerin (OPG) in the pathogenesis of heart failure through different mechanisms has received much attention. Subclinical changes in left ventricular (LV) function can be identified using quantification of myocardial strain, and global longitudinal strain (GLS) is a superior predictor of outcomes than ejection fraction. We hypothesized that increased OPG levels could predict subclinical LV systolic dysfunction in treated diabetic hypertensive patients with preserved LV ejection fraction.. The study was composed of 86 diabetic hypertensive and 30 nondiabetic hypertensive patients. All patients underwent echocardiography and venous blood samples were taken for determination of OPG. The relation between OPG levels and LV GLS was investigated using 2-dimensional speckle tracking echocardiography.. Diabetic hypertensive patients had higher diastolic peak early/early diastolic tissue velocity and lower systolic tissue velocity, GLS, GLS rate systolic, and GLS rate early diastolic than nondiabetic hypertensive patients (P = 0.009, P = 0.049, P < 0.001, P = 0.004, and P < 0.001, respectively). Diabetic hypertensive patients were divided into 2 groups according to median GLS value (> 18.5 and ≤ 18.5). The patients with GLS ≤ 18.5 had higher diastolic blood pressure (mm Hg; P = 0.048), OPG (pmol/L; P < 0.001), and hemoglobin A1c (%; P = 0.042) values than those with GLS > 18.5. In multivariate logistic regression analysis, OPG was found to be an independent predictor of impaired GLS (P = 0.001). Receiver operating characteristic curve analysis revealed that OPG values of > 6.45 (pmol/L) identified the patients with GLS ≤ 18.5.. Plasma OPG values could predict subclinical LV systolic dysfunction in diabetic hypertensive patients.

Topics: Aged; Cross-Sectional Studies; Diabetes Mellitus; Echocardiography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Osteoprotegerin; Prognosis; Retrospective Studies; Stroke Volume; Systole; Ventricular Dysfunction, Left; Ventricular Function, Left

Topics: Diabetes Mellitus; Echocardiography; Female; Humans; Male; Myocardial Infarction; Osteoprotegerin; Percutaneous Coronary Intervention; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

Fetuin-A and osteoprotegerin (OPG) are arterial calcification regulators, which are related to cardiovascular survival in hemodialysis patients. We hypothesized that a balance of these calcification regulators might mediate the progression of left ventricular (LV) diastolic dysfunction in hemodialysis patients. We recruited 63 hemodialysis patients and measured their serum fetuin-A, OPG, arterial stiffness, aortic calcification and echocardiographic parameters, including the transmitral early diastolic velocity/tissue Doppler mitral annular early diastolic velocity ratio (E/E'), and analyzed the relationships between these variables. Fetuin-A levels were significantly and negatively correlated with the ankle-brachial pulse wave velocity (baPWV), aortic calcification score (AOCS), left atrial volume index (LAVI), LV mass index (LVMI) and E/E'. OPG levels and the ratio of OPG to fetuin-A levels were significantly and positively correlated with the baPWV, AOCS, LAVI and E/E'. A stepwise multiple regression analysis revealed that E/E' was independently correlated with fetuin-A levels (β=-0.334, P=0.02), OPG levels (β=0.367, P=0.01) and the ratio of OPG to fetuin-A (β=0.295, P=0.04). Categorizing the patients according to their serum fetuin-A and OPG levels revealed that patients with low fetuin-A and high OPG levels had the highest LAVI, LVMI and E/E' values after adjusting for potential confounders. Serum fetuin-A levels negatively reflected, whereas OPG levels and the ratio of OPG to fetuin-A positively reflected an increase in vascular and ventricular stiffness, leading to the aggravation of diastolic dysfunction. Therefore, based on our results, the balance of the tissue calcification regulators fetuin-A and OPG could mediate the progression of LV diastolic dysfunction in hemodialysis patients.

Topics: Aged; alpha-2-HS-Glycoprotein; Ankle Brachial Index; Blood Flow Velocity; Diastole; Female; Humans; Male; Middle Aged; Osteoprotegerin; Renal Dialysis; Renal Insufficiency; Ventricular Dysfunction, Left

Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, is linked to cardiovascular disease. Negative associations exist between circulating OPG and cardiac function. The adipocytokine adiponectin (ADPN) is downregulated in type 2 diabetes mellitus (T2DM) and coronary artery disease and shows an inverse correlation with insulin sensitivity and cardiovascular disease risk. We assessed the relationship of plasma OPG and ADPN and arterial function, cardiac function and myocardial glucose metabolism in T2DM.. We included 78 asymptomatic men with uncomplicated, well-controlled T2DM, without inducible ischemia, assessed by dobutamine-stress echocardiography, and 14 age-matched controls. Cardiac function was measured by magnetic resonance imaging, myocardial glucose metabolism (MMRglu) by 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography. OPG and ADPN levels were measured in plasma.. T2DM patients vs. controls showed lower aortic distensibility, left ventricular (LV) volumes, impaired LV diastolic function and MMRglu (all P < 0.05). In T2DM men vs. controls, OPG levels were higher (P = 0.02), whereas ADPN concentrations were decreased (P = 0.04). OPG correlated inversely with aortic distensibility, LV volumes and E/A ratio (diastolic function), and positively with LV mass/volume ratio (all P < 0.05). Regression analyses showed the associations with aortic distensibility and LV mass/volume ratio to be independent of age-, blood pressure- and glycated hemoglobin (HbA1c). However, the associations with LV volumes and E/A ratio were dependent of these parameters. ADPN correlated positively with MMRglu (P < 0.05), which, in multiple regression analysis, was dependent of whole-body insulin sensitivity, HbA1c and waist.. OPG was inversely associated with aortic distensibility, LV volumes and LV diastolic function, while ADPN was positively associated with MMRglu. These findings indicate that in asymptomatic men with uncomplicated T2DM, OPG and ADPN may be markers of underlying mechanisms linking the diabetic state to cardiac abnormalities.. Current Controlled Trials ISRCTN53177482.

Topics: Adiponectin; Aorta; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glucose; Glycated Hemoglobin; Heart; Humans; Hypertrophy, Left Ventricular; Insulin Resistance; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Osteoprotegerin; Positron-Emission Tomography; Ventricular Dysfunction, Left

Persistent inflammation appears to play a role in the development of heart failure (HF). Osteoprotegerin (OPG), the receptor activator of nuclear factor-kappaB (RANK), and RANK ligand (RANKL) are newly discovered members of the tumor necrosis factor superfamily that are critical regulators in bone metabolism but appear also to be involved in immune responses. We hypothesized that the OPG/RANK/RANKL axis could be involved in the pathogenesis of heart failure (HF), and this hypothesis was investigated in both experimental and clinical studies.. Our main and novel findings were as follows: (1) In a rat model of postinfarction HF, we found persistently increased gene expression of OPG, RANK, and RANKL in the ischemic part of the left ventricle (LV) and, for OPG, in the nonischemic part that involved both noncardiomyocyte and in particular cardiomyocyte tissue. (2) Enhanced myocardial protein levels of OPG, RANK, and RANKL, in particular, were also seen in human HF, and using immunohistochemistry, we localized these mediators to cardiomyocytes within the LV in both experimental and clinical HF. (3) In human HF, we also found increased systemic expression of RANKL (T cells and serum) and OPG (serum), with increasing levels according to functional, hemodynamic, and neurohormonal disease severity. (4) RANKL increased total matrix metalloproteinase activity in human fibroblasts, which indicates a matrix-degrading net effect and suggests a potential mechanism by which enhanced RANKL expression in HF may contribute to LV dysfunction.. These findings suggest a potential role for known mediators of bone homeostasis in the pathogenesis of HF and possibly represents new targets for therapeutic intervention in this disorder.

Topics: Adult; Animals; Carrier Proteins; Case-Control Studies; Female; Gene Expression Regulation; Glycoproteins; Heart Failure; Heart Ventricles; Humans; Male; Membrane Glycoproteins; Middle Aged; Myocytes, Cardiac; Osteoprotegerin; RANK Ligand; Rats; Rats, Wistar; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Ventricular Dysfunction, Left

Apoptosis has been attributed an essential role in dilated cardiomyopathy (DCM) recently. We assessed expression of TNF-related apoptosis-inducing ligand (TRAIL) and its decoy receptor osteoprotegerin (OPG) in men with nonischemic DCM, who underwent coronary angiography and endomyocardial biopsy (EMB) after exclusion of coronary artery disease compared to control patients. TRAIL plasma concentrations were elevated in DCM (p=0.02 vs. controls), and were positively correlated with left ventricular enddiastolic diameter (r=0.15, p=0.04), whereas OPG plasma levels did not differ between both groups (p=0.96). In EMB of DCM patients, TRAIL and OPG protein were detected by immunohistochemistry but not in controls. Furthermore, gene expression in EMB or peripheral blood leukocytes (PBL) of DCM patients assessed by real-time PCR showed an increase of TRAIL mRNA in PBL (p=0.01 vs. controls), whereas OPG mRNA was upregulated in endomyocardial specimens (p<0.001 vs. controls). In conclusion, myocardial overexpression of antiapoptotic OPG in DCM patients may represent a compensatory mechanism to limit systemic activation of TRAIL in patients with congestive heart disease.

Topics: Adult; Apoptosis Regulatory Proteins; Biopsy; Cardiomyopathy, Dilated; Fetal Heart; Gene Expression Regulation; Glycoproteins; Humans; Male; Membrane Glycoproteins; Middle Aged; Myocardium; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha; Up-Regulation; Ventricular Dysfunction, Left