osteoprotegerin and Cardiovascular-Diseases

Osteoprotegerin (OPG) is a glycoprotein involved in the regulation of bone remodelling. OPG regulates osteoclast activity by blocking the interaction between the receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL). More and more studies confirm the relationship between OPG and cardiovascular diseases. Numerous studies have confirmed that a high plasma concentration of OPG and a low concentration of tumour necrosis factor-related apoptosis inducing ligand (TRAIL) together with a high OPG/TRAIL ratio are predictors of poor prognosis in patients with myocardial infarction. A high plasma OPG concentration and a high ratio of OPG/TRAIL in the acute myocardial infarction are a prognostic indicator of adverse left ventricular remodelling and of the development of heart failure. Ever more data indicates the participation of OPG in the regulation of the function of vascular endothelial cells and the initiation of the atherosclerotic process in the arteries. Additionally, it has been shown that TRAIL has a protective effect on blood vessels and exerts an anti-atherosclerotic effect. The mechanisms of action of both OPG and TRAIL within the cells of the vascular wall are complex and remain largely unclear. However, these mechanisms of action as well as their interaction in the local vascular environment are of great interest to researchers. This article presents the current state of knowledge on the mechanisms of action of OPG and TRAIL in the circulatory system and their role in cardiovascular diseases. Understanding these mechanisms may allow their use as a therapeutic target in cardiovascular diseases in the future.

Topics: Atherosclerosis; Cardiovascular Diseases; Endothelial Cells; Heart Failure; Humans; Ligands; Myocardial Infarction; Osteoprotegerin; Receptor Activator of Nuclear Factor-kappa B; TNF-Related Apoptosis-Inducing Ligand

Beyond being epiphenomenon of shared epidemiological factors, the integration of Osteoporosis (OP) with Cardiovascular Disease (CVD) - termed "calcification paradox" - reflects a continuum of aberrant cardiometabolic status. The present review provides background knowledge on "calcification paradox", focusing on the endocrine aspect of vasculature orchestrated by the osteoblastic molecular fingerprint of vascular cells, acquired via imbalance among established modulators of mineralization. Osteoprotegerin (OPG), the well-established osteoprotective cytokine, has recently been shown to exert a vessel-modifying role. Prompted by this notion, the present review interrogates OPG as the potential missing link between OP and CVD. However, so far, the confirmation of this hypothesis is hindered by the equivocal role of OPG in CVD, being both proatherosclerotic and antiatherosclerotic. Further research is needed to illuminate whether OPG could be a biomarker of the "calcification paradox". Moreover, the present review brings into prominence the dual role of statins - cardioprotective and osteoprotective - as a potential illustration of the integration of CVD with OP. Considering that the statins-induced modulation of OPG is central to the statins-driven osteoprotective signalling, statins could be suggested as an illustration of the role of OPG in the bone/vessels crosstalk, if further studies consolidate the contribution of OPG to the cardioprotective role of statins. Another outstanding issue that merits further evaluation is the inconsistency of the osteoprotective role of statins. Further understanding of the varying bone-modifying role of statins, likely attributed to the unique profile of different classes of statins defined by distinct physicochemical characteristics, may yield tangible benefits for treating simultaneously OP and CVD.

Topics: Bone and Bones; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Osteoporosis; Osteoprotegerin

Experimental and clinical studies aimed at investigating the mechanism(s) underlying vascular complications of diabetes indicate that a great number of molecules are involved in the pathogenesis of these complications. Most of these molecules are inflammatory mediators or markers generated by immune or adipose tissue. Some of them, i.e. resistin and sortilin, have been shown to be involved in the cross talk between adipocytes and inflammatory cells. This interaction is an attractive area of research, particularly in type 2 diabetes and obesity. Other proteins, such as adiponectin and visfatin, appear to be more promising as possible vascular markers. In addition, some molecules involved in calcium/phosphorus metabolism, such as klotho and FGF23, have an involvement in the pathogenesis of diabetic vasculopathy, which appears to be dependent on the degree of vascular impairment. Inflammatory markers are a promising tool for treatment decisions while measuring plasma levels of adipokines, sortilin, Klotho and FGF23 in adequately sized longitudinal studies is expected to allow a more precise characterization of diabetic vascular disease and the optimal use of personalized treatment strategies.

Topics: Adaptor Proteins, Vesicular Transport; Adipokines; Adipose Tissue; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exosomes; Fibroblast Growth Factor-23; Glucuronidase; HMGB Proteins; Humans; Immune System; Interleukin-1; Klotho Proteins; Osteoprotegerin; Prevalence; Serum Amyloid P-Component; Signal Transduction; Tumor Necrosis Factor-alpha

Studies have shown inconsistent results regarding the association between osteoprotegerin (OPG) concentration and cardiovascular mortality in patients with chronic kidney disease (CKD). This systematic review and meta-analysis aims to investigate the association between OPG concentration and cardiovascular mortality in patients with CKD.. Between January 1970 and February 2020, the PubMed, EMBASE, and Cochrane Library databases were searched for eligible studies investigating the association between OPG concentration and cardiovascular mortality in patients with CKD. Pooled hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were calculated using random effects models.. In total, 10 studies comprising 2,120 patients (including 1,723 receiving dialysis) with CKD were included. The included studies were considered to be of fair to high quality. Patients in the highest OPG concentration group had a significantly higher risk of cardiovascular mortality (4 studies; adjusted HR, 2.05; 95% CI, 1.39-3.00) than patients in the low OPG concentration group. An increase of 1 pmol/L in OPG concentration was associated with a 4% increased risk of cardiovascular mortality (6 studies; adjusted HR, 1.04; 95% CI, 1.02-1.07).. Elevated OPG concentrations are associated with an increased risk of cardiovascular death in patients with CKD.

Topics: Cardiovascular Diseases; Humans; Osteoprotegerin; Prognosis; Renal Insufficiency, Chronic; Risk Factors

Patients with chronic kidney disease (CKD) are at increased risk of osteoporosis and vascular calcification. Bone demineralization and vascular mineralization go often hand in hand in CKD, similar to as in the general population. This contradictory association is independent of aging and is commonly referred to as the "calcification paradox" or the bone-vascular axis. Various common risk factors and mechanisms have been identified. Alternatively, calcifying vessels may release circulating factors that affect bone metabolism, while bone disease may infer conditions that favor vascular calcification. The present review focuses on emerging concepts and major mechanisms involved in the bone-vascular axis in the setting of CKD. A better understanding of these concepts and mechanisms may identify therapeutics able to target and exert beneficial effects on bone and vasculature simultaneously.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cardiovascular Diseases; Glucuronidase; Humans; Inflammation; Klotho Proteins; Osteoporosis; Osteoprotegerin; Parathyroid Hormone; Renal Insufficiency, Chronic; Signal Transduction; Vascular Calcification; Vitamin K

Cardiovascular disease (CVD) is an overall term that comprises a number of related pathologies, these include peripheral arterial disease, cerebrovascular disease, coronary heart disease (CHD), venous thromboembolism, and rheumatic and congenital heart diseases. Fatty acids in the diet have been reported to affect CVD. The OPG/RANKL/RANK system appears to have a role in CVD outcomes. However, there have been few studies on the impact of diet-gene interaction for effects of fatty acids consumption on the OPG/RANKL/RANK system in CVD. This review focuses on the effects of fatty acids on OPG/RANKL/RANK in CVD.

Topics: Cardiovascular Diseases; Diet; Fatty Acids; Humans; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Osteoporosis (OP) and cardiovascular diseases (CVD) are both important causes of mortality and morbidity in aging patients. There are common mechanisms underlying the regulation of bone remodeling and the development of smooth muscle calcification; a temporal relationship exists between osteoporosis and the imbalance of mineral metabolism in the vessels. Vascular calcification appears regulated by mechanisms that include both inductive and inhibitory processes. Multiple factors are implicated in both bone and vascular metabolism. Among these factors, the superfamily of tumor necrosis factor (TNF) receptors including osteoprotegerin (OPG) and its ligands has been established. OPG is a soluble decoy receptor for receptor activator of nuclear factor-kB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG binds to RANKL and TRAIL, and inhibits the association with their receptors, which have been labeled as the receptor activator of NF-kB (RANK). Sustained release of OPG from vascular endothelial cells (ECs) has been demonstrated in response to inflammatory proteins and cytokines, suggesting that OPG/RANKL/RANK system plays a modulatory role in vascular injury and inflammation. For the development of potential therapeutic strategies targeting vascular calcification, critical consideration of the implications for bone metabolism must be taken into account to prevent potentially detrimental effects to bone metabolism.

Topics: Animals; Bone and Bones; Bone Remodeling; Cardiovascular Diseases; Humans; Osteoporosis; Osteoprotegerin; Signal Transduction; Therapies, Investigational; Vascular Calcification

Cardiovascular events make up the primary cause of death in hemodialysis patients, and the risk for cardiovascular mortality is significantly increased by vascular calcification, a condition observed frequently in this patient population. The mechanisms underlying the pathogenesis of vascular calcification are complex, and many factors facilitate or hinder the development of calcification. In this review, we first summarize the main factors contributing to the pathogenesis of vascular calcification in patients with end-stage renal disease. We then explore the role of calcification inhibitors in the calcification process, as well as their effect on vascular dysfunction and mortality in hemodialysis patients.

Topics: alpha-2-HS-Glycoprotein; Cardiotonic Agents; Cardiovascular Diseases; Cause of Death; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Osteopontin; Osteoprotegerin; Renal Dialysis; Risk Assessment; Survival Analysis; Treatment Outcome; Vascular Calcification

Among the numerous molecules that are being studied for their potential utility as biomarkers of cardiovascular diseases, much interest has been shown in the superfamily of tumor necrosis factor (TNF) receptors. Members of this family include osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor κB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). These signals may be expressed and regulated, and their functions could be involved in several physiological and pathological processes. The relationship between bone regulatory proteins and vascular biology has attracted attention, and it has been suggested that OPG may mediate vascular calcification and cardiometabolic diseases. OPG is steadily released from vascular endothelial cells in response to inflammatory stimuli, suggesting that it plays a modulatory role in vascular injury, inflammation, and atherosclerosis. Vascular calcification, a hallmark of atherosclerosis, is similar to bone remodeling. It is an actively regulated mechanism that includes both inductive and inhibitory processes. There is a temporal link between the development of osteoporosis and vascular calcification, which is particularly marked in post-menopausal women and the elderly. The precise nature of the link between bone metabolism, vascular calcification and cardiovascular disease is largely unknown but increasing evidence suggests that the triad of RANK/RANKL/OPG may be important in the initiation of various diseases. An increased release of OPG is associated with increased cardiovascular risk and it is suggested that increased OPG levels resulting from vascular damage correspond to a protective mechanism. Circulating OPG levels could be used as independent biomarkers of cardiovascular disease in patients with acute or chronic cardiometabolic disease and thus an improved prognosis.

Topics: Bone Remodeling; Cardiovascular Diseases; Humans; Osteoprotegerin; Vascular Calcification

Cardiovascular disease is one of the most frequent causes of mortality and morbidity worldwide. Several variables have been identified as risk factors for cardiovascular disease. Recently, the role of receptor activator of nuclear factor kappa B, receptor activator of nuclear factor kappa B ligand, and the osteoprotegerin system has been recognized as more important in the pathogenesis of cardiovascular disease. Besides their roles in the regulation of bone resorption, these molecules have been reported to be associated with the pathophysiology of cardiovascular disease. There are conflicting data regarding the impact of osteoprotegerin, a glycoprotein with a regulatory role in the cardiovascular system. The aim of this review is to discuss the current knowledge and the role of osteoprotegerin in cardiovascular disease.

Topics: Biomarkers; Bone Resorption; Cardiovascular Diseases; Humans; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Background Osteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease ( CVD ) in the general population, its relevance as a biomarker among populations at high CVD risk is less clear. Methods and Results Three independent reviewers systematically searched PubMed, EMBASE , and Web of Science to identify prospective studies that had recruited participants on the basis of having conditions related to high CVD risk. A total of 19 studies were eligible for inclusion, reporting on 27 450 patients with diabetes mellitus (2 studies), kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow-up of 4.2 years, 4066 CVD events were recorded. In a random-effects meta-analysis, the pooled risk ratio for CVD events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 (95% confidence interval, 1.12-1.50; P<0.001; I

Topics: Acute Coronary Syndrome; Angina Pectoris; Biomarkers; Cardiovascular Diseases; Comorbidity; Diabetes Mellitus; Heart Diseases; Humans; Kidney Diseases; Myocardial Infarction; Myocardial Revascularization; Osteoprotegerin; Risk; Stroke

Recent experimental and epidemiological studies have suggested that osteoprotegerin, a key regulator in bone metabolism, may be involved in vascular calcification and atherosclerosis. Our aim was to reliably quantify the associations of osteoprotegerin concentration and incidence of first-ever cardiovascular disease outcomes in the general population.. Using the electronic databases MEDLINE, EMBASE and Web of Science (January 1975 and April 2017, no language restrictions), nine relevant studies were identified involving a total of 26,442 participants recruited from the general population. Over a mean follow-up of 8.5 years, 2,160 cardiovascular disease, 2,123 coronary heart disease, and 1,102 stroke outcomes were recorded. Study-specific risk ratios were combined with random-effects meta-analysis.. When comparing individuals in the top with those in the bottom third of osteoprotegerin concentration, the combined risk ratio was 1.83 (95% confidence interval: 1.46, 2.30; P<0.001; I2 = 76.8%) for cardiovascular disease, 1.72 for coronary heart disease (1.26, 2.37; P = 0.001; I2 = 83.5%), and 1.58 for stroke (1.18, 2.12; P = 0.002; I2 = 65.2%). Associations appeared stronger at younger age (P = 0.018 for cardiovascular disease), in studies that did not employ statistical adjustment (P = 0.023 for cardiovascular disease and 0.018 for coronary heart disease), and potentially in studies that measured osteoprotegerin in plasma rather than in serum (P = 0.005 for cardiovascular disease and 0.018 for coronary heart disease). Magnitudes of associations did not differ according to the proportion of males, geographical region, or osteoprotegerin assay manufacturer. There was no evidence for publication bias for any of the outcomes assessed (all P>0.05).. Elevated osteoprotegerin concentration is associated with an increased risk of incident cardiovascular disease in the general population. The mechanisms underlying this observation deserve further investigation.

Topics: Cardiovascular Diseases; Humans; Incidence; Osteoprotegerin; Risk Factors

BACKGROUND The aim of this meta-analysis was to determine whether genetic polymorphisms in the osteoprotegerin (OPG) gene contribute to increased risk of cardiovascular disease (CVD). MATERIAL AND METHODS Electronic databases were searched carefully without any language restriction. Analyses of data were conducted using STATA software. Odds ratios (OR) and 95% confidence intervals (95%CI) were also calculated. RESULTS Seven clinical case-control studies that enrolled 1170 CVD patients and 1194 healthy subjects were included. The results indicated that OPG gene polymorphism might be closely associated with susceptibility to CVD, especially for rs2073617 T>C and rs2073618 G>C polymorphisms. Ethnicity-stratified analysis indicated that genetic polymorphism in the OPG were closely related with the pathogenesis of CVD among Asians (all P<0.001), but no obvious relationship was found among Caucasians (all P>0.05). CONCLUSIONS Our meta-analysis provided quantitative evidence that OPG gene polymorphism may be closely related to an increased risk of CVD, especially for rs2073617 T>C and rs2073618 G>C polymorphisms.

Topics: Asian People; Cardiovascular Diseases; Case-Control Studies; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Humans; Odds Ratio; Osteoprotegerin; Polymorphism, Genetic; Risk Factors; White People

Cardiovascular diseases (CVD) remain the major cause of death and premature disability in Western societies. Assessing the risk of CVD is an important aspect in clinical decision-making. Among the growing number of molecules that are studied for their potential utility as CVD biomarkers, a lot of attention has been focused on osteoprotegerin (OPG) and its ligands, which are receptor activator of nuclear factor κB ligand (RANKL) and TNF-related apoptosis-inducing ligand. Based on the existing literature and on our experience in this field, here we review what the possible roles of OPG and TRAIL in CVD are and their potential utility as CVD biomarkers.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Humans; Osteoprotegerin; RANK Ligand; Risk; TNF-Related Apoptosis-Inducing Ligand

Vascular calcification is a risk factor for cerebral and cardiovascular events and has a high prevalence among elderly. To finding ways of prevent or cure vascular calcification may leads to not only a healthy longevity but also medical expenditure reduction. However, the molecular mechanism underlying this pathogenic process is still obscure. To clarify the mechanism of vascular calcification, the development of animal models that exhibit extensive and robust vascular calcification is an important issue for research in vascular biology.

Topics: Aging; Animals; Bone Morphogenetic Protein 2; Calmodulin-Binding Proteins; Cardiovascular Diseases; Cell Differentiation; Cerebrovascular Disorders; Core Binding Factor Alpha 1 Subunit; Disease Models, Animal; Humans; Mice; Muscle, Smooth, Vascular; Osteoblasts; Osteoprotegerin; RANK Ligand; Risk Factors; Vascular Calcification

The OPG/RANK/RANKL axis is now recognized as a master regulator of bone remodeling, controlling osteoclast's maturation and extracellular matrix calcification. Nevertheless, a number of clinical and basic science studies conducted in the last few years demonstrated that the triad could be also involved in several physiological and pathological processes outside the bone tissue. In particular, evidences have been collected showing an active participation of OPG and RANKL in vascular pathology, including atherogenesis and arterial calcification. A series of epidemiological studies also showed that increased circulating levels of OPG are associated with significant, independent predictive value for future cardiovascular mortality/morbidity. However, the human studies did not unravel whether OPG should be considered as a promoter, a protective mechanism or is instead neutral with regard of vascular disease progression. Main objective of the present review is to summarize findings from both in vivo and in vitro investigations on the role played by OPG in vascular disease progression and to delineate a plausible scenario on the actual involvement of the OPG/RANK/RANKL triad and TRAIL in cardiovascular pathology.

Topics: Cardiovascular Diseases; Humans; Osteoprotegerin

Kidney transplantation is the treatment of choice for chronic kidney disease (CKD), but in kidney transplant recipients (KTRs) cardiovascular events are the first cause of death with a functioning graft, ranging from 36 to 55%. The impact of vascular calcification (VC) on morbidity and mortality of KTRs is not appreciated enough nowadays.. This review summarizes 13 important studies on VC in KTRs, comparing the results with CKD and dialysis populations. We focused on VC evaluation and use of coronary artery calcification (CAC) and aorta calcification (AoC) scores. We also evaluated the influence of traditional and non-traditional progression risk factors.. VC strongly predicts cardiovascular events and all-cause mortality in KTRs. VC assessment is important in KTRs and based essentially on multislice computed tomography or electron beam computed tomography recognition of lesions. Quantitative measurement of CAC and AoC scores is essential for a correct definition of the calcium burden before and after kidney transplant. Progression of CAC slows down but does not halt after kidney transplant. A variable association of both traditional and non-traditional risk factors is shown. There is a strong association between baseline CAC score and CAC progression. A significant improvement in secondary hyperparathyroidism after transplantation favorably affects the progression of CAC. Low 25(OH)D3 levels are an independent determinant of CAC progression. Diabetes is a risk factor for the presence of CAC in KTRs, but has not been independently associated with CAC progression. The data published on the use of immunosuppressive drugs as progression factors are few and inconclusive.

Topics: alpha-2-HS-Glycoprotein; Aorta; Calcifediol; Calcium-Binding Proteins; Cardiovascular Diseases; Coronary Vessels; Diabetes Mellitus; Disease Progression; Extracellular Matrix Proteins; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Transplantation; Matrix Gla Protein; Osteoprotegerin; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors; Vascular Calcification

A narrow serum calcium level which is essential for many metabolic processes is regulated by the calcium-sensing receptor which regulates parathyroid hormone (PTH) release. Primary hyperparathyroidism is supposed to be the third most common endocrine disorder. Besides nephrolithiasis and an increased incidence of cardiovascular symptoms it is associated with bone loss and an increased risk of fracture. Several different classical bone turnover markers have been shown to be increased. However, there are many uncertainties in pathophysiology of PHPT. Hardly any conclusive data exist on the RANK (receptor activator of nuclear factor-kB)/RANKL (receptor activator of nuclear factor-kB ligand)/OPG (osteoprotegerin) system, cathepsin K, sclerostin, FGF-23 (Fibroblast growth factor-23), Klotho, and DKK 1 (Dickkopf 1) in patients suffering from PHPT.

Topics: Adaptor Proteins, Signal Transducing; Biomarkers; Bone Morphogenetic Proteins; Bone Remodeling; Calcium; Cardiovascular Diseases; Cathepsin K; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Genetic Markers; Glucuronidase; Homeostasis; Humans; Hyperparathyroidism; Intercellular Signaling Peptides and Proteins; Kidney Calculi; Klotho Proteins; Osteoprotegerin; Parathyroid Glands; Parathyroid Hormone; Receptor Activator of Nuclear Factor-kappa B; Receptors, Calcium-Sensing

Chronic obstructive pulmonary disease (COPD) can no longer be considered as a disease affecting only the lungs. Increasing evidence supports the presence of a systemic inflammatory component which is thought to provide the link between COPD and the co-morbidities commonly associated with this disease. These include cardiovascular disorders, skeletal muscle dysfunction, diabetes, and osteoporosis. The majority of current therapies for COPD have been developed to improve airway obstruction or to target airway inflammation, leaving an unmet medical need with respect to the systemic inflammatory component of COPD and its extra-pulmonary manifestations. This review describes systemic biomarkers in COPD and their relationship with both the local lung and systemic manifestations of the disease. A summary is provided of the most promising biomarkers that have been investigated in COPD and its co-morbidities. Such biomarkers may be used to assess and manage the systemic effects of COPD, and may guide future development of novel therapeutic interventions to provide a more holistic approach to treating this multi-faceted disease.

Topics: Adiponectin; Aging; Airway Remodeling; Biomarkers; C-Reactive Protein; Cachexia; Cardiovascular Diseases; CD40 Ligand; Chemokines, CC; Cytokines; Desmosine; Fibrinogen; Humans; Inflammation; Intercellular Adhesion Molecule-1; Isodesmosine; Lung Neoplasms; Matrix Metalloproteinases; Natriuretic Peptide, Brain; Osteoprotegerin; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactant-Associated Protein D; Serum Amyloid A Protein; Severity of Illness Index; Telomere; Uteroglobin

Osteoprotegerin (OPG) is a 401 amino acid N-glycosylated protein, which is highly expressed in a large number of tissues. OPG mainly binds to two ligands, i.e. RANKL (receptor activator of nuclear factor κB ligand) and TRAIL (tumor necrosis factor- related apoptosis-inducing ligand). Upon binding to the former ligand, OPG inhibits the activation of osteoclasts and promotes apoptosis of osteoclasts, whereas the binding of OPG with TRAIL prevents apoptosis of tumor cells. There is now emerging evidence that OPG participates in the pathogenesis of atherosclerosis and cardiovascular diseases by amplifying the adverse effects of inflammation and several traditional risk factors such as hyperlipidemia, endothelial dysfunction, diabetes mellitus, and hypertension. Some epidemiological studies also showed a positive association between OPG levels and cardiovascular morbidity and mortality. The aim of this article is to provide an overview of the main biochemical, physiological, and pathological aspects of OPG biology in cardiovascular disease.

Topics: Aging; Aortic Diseases; Atherosclerosis; Blood Flow Velocity; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus; Endothelium, Vascular; Gene Expression; Humans; Inflammation; Lipids; Obesity; Osteoprotegerin; Polymorphism, Genetic; Prognosis; Vascular Calcification

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

Studies on bones metabolism regulation mechanisms leaded to discovery of RANKL/OPG/RANK signal system (receptor activator of nuclear factor kappaB ligand/osteoprotegerin/receptor activator of nuclear factor kappaB). It was found that beyond bone metabolism regulation Osteoprotegerin (OPG) is involved in some other processes: apoptosis, regulation of immunological system. Data from numerous studies performed in the last years indicate potential association between OPG and cardiovascular pathology. OPG was identified as atherosclerosis marker. Molecular mechanism by which OPG exerts its atherogenic effect is not fully elucidated.

Topics: Animals; Apoptosis; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Disease Models, Animal; Humans; Osteoprotegerin

Coronary artery disease (CAD) represents the most relevant cause of death and morbidity in the adult population of developed and developing countries. During the last decades, a strong research effort has been performed to identify more selective markers and better assess the cardiovascular risk in both primary and secondary prevention.. This review updates current knowledge regarding the pathophysiological relevance as possible markers of coronary calcification of the receptor activator of nuclear factor-kappa ligand (RANKL)/osteoprotegerin (OPG) system. Furthermore, the potential clinical use of both RANKL/OPG and coronary calcium score (CAC) to assess cardiovascular vulnerability has been discussed.. Emerging evidence indicates that atherosclerotic plaque calcification is positively correlated with vulnerability. Several inflammatory mediators have been shown to modulate arterial calcification, thus increasing the risk of plaque rupture. Among these factors, RANKL/OPG axis might be of particular interest as a promising biomarker of plaque vulnerability in subjects with diffuse coronary calcification.. Together with clinical parameters of coronary calcification (such as CAC), circulating RANKL/OPG levels could contribute to better assess and predict cardiac events.

Topics: Biomarkers; Calcinosis; Cardiovascular Diseases; Coronary Artery Disease; Humans; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Risk Factors

 Previous studies have reported conflicting results on the relation between serum osteoprotegerin (OPG) concentration and carotid intima media thickness (CIMT)..  The present study was conducted to investigate the relations between OPG, risk factors for cardiovascular diseases (CVD) and carotid intima media thickness (CIMT) in a large cross-sectional study including 6516 subjects aged 25-85years who participated in a population-based health survey..  CIMT increased significantly across tertiles of OPG after adjustment for traditional cardiovascular risk factors such as age, gender, smoking, total cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index (BMI), systolic blood pressure, CVD and diabetes mellitus (P<0.0001). There was a significant interaction between age and OPG (P=0.026). The risk of being in the uppermost quartile of CIMT was reduced (OR 0.52, 95% CI 0.30-0.88) with each standard deviation (SD) higher level of OPG in subjects <45years (n=444), whereas subjects ≥55years of age (n=4884) had an increased risk of being in the uppermost quartile of CIMT (OR 1.19, 95% CI 1.10-1.29) after adjustment for traditional CVD risk factors.. Age has a differential impact on the association between OPG and CIMT in a general population. The present findings may suggest that increased serum OPG does not promote early atherosclerosis in younger subjects.

Topics: Adult; Aged; Aged, 80 and over; Atherosclerosis; Blood Pressure; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Norway; Osteoprotegerin; Risk Factors; Tunica Intima; Tunica Media

Osteoprotegerin (OPG) strongly inhibits bone resorption and may also serve as a vascular calcification inhibitor. However, recent studies have indicated that high plasma OPG is a strong predictor of cardiovascular disease (CVD) and mortality. To evaluate this capability, the data concerning OPG as a CVD predictor was gathered through a systematic literature review.. Studies investigating OPG as a predictor of CVD or mortality were extracted from Medline and the Cochrane Library, retrieving 187 articles. Non-relevant articles were excluded, resulting in a total of 45 articles. After thorough evaluation of the abstracts, only eight prospective studies containing a follow-up period with a clinical emphasis on CVD were eligible for the literature review.. All studies except one confirmed that OPG measurement adds important prognostic information to the existing markers of CVD and mortality in high-risk populations. Hazard ratios emphasized the significant correlation between plasma OPG concentration and mortality. Due to methodological problems (e.g., population investigated, measurement principle, and statistics performed), meta-analysis could not be performed. As only one study was conducted in a healthy cohort, the results cannot per se be extrapolated to the general population.. The combined results support plasma OPG as an independent predictor of CVD and mortality in high-risk populations. However, more longitudinal studies in general cohorts are needed before the use of plasma OPG can be evaluated in this regard.

Topics: Cardiovascular Diseases; Humans; Osteoprotegerin; Predictive Value of Tests; Risk Factors

Experimental and clinical trials in the field of bone biology helped to clarify the role of receptors, which belong to the tumor necrosis factor family, such as osteoprotegerin and receptor activator of nuclear factor kappaB (RANK), in the regulation of bone remodeling. The ligand of the receptor activator of nuclear factor kappaB (RANKL) is a stimulator of bone resorption, while osteoprotegerin is the soluble "decoy" receptor to RANKL, protecting thereby bone from resorption. Pathological states of bone remodeling (like osteoporosis) are associated with imbalance in the activity of osteoprotegerin and the receptor activator of nuclear factor kappaB. Recent studies, however, also indicate that the osteoprotegerin/RANKL/RANK system has important roles in the regulation of the immune and vascular system as well. In this review we summarize the function and regulation of osteoprotegerin, its role in pathological states--primarily in cardiovascular diseases--and its relevance as a marker of cardiovascular risk. Finally, we present our prospective trial performed among the chronic dialyzed patients, where we examined the association between the cardiovascular mortality, osteoprotegerin levels and the arterial stiffness.

Topics: Aged; Analysis of Variance; Animals; Biomarkers; Blood Flow Velocity; Bone Diseases; Bone Remodeling; Calcinosis; Cardiovascular Diseases; Carotid Arteries; Female; Femoral Artery; Heart Rate; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Osteoprotegerin; Prospective Studies; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Renal Dialysis; Risk Assessment; Risk Factors; Time Factors; Vascular Diseases; Vascular Resistance; Vasodilation

The mortality rate is extremely high in chronic kidney disease (CKD), primarily due to the high prevalence of cardiovascular disease (CVD) in this patient group. Apart from traditional Framingham risk factors, evidences suggest that nontraditional risk factors, such as inflammation, oxidative stress, endothelial dysfunction, and vascular calcification also contribute to this extremely high risk of CVD. Disturbance in the mineral metabolism, especially in the ions of Ca and PO4, are linked to enhanced calcification of blood vessels. Although the mechanism(s) of this enhanced calcification process are not fully understood, current knowledge suggests that a large number (and an imbalance between them) of circulating promoters and inhibitors of the calcification process, that is, fetuin-A (or alpha 2-Heremans-Schmid glycoprotein, AHSG), matrix-Gla protein (MGP), osteoprotegerin (OPG), osteopontin (OPN), bone morphogenetic proteins (BMPs), and inorganic pyrophosphate (PPi), are involved in the deterioration of vascular tissue. Thus, an imbalance in these factors may contribute to the high prevalence of vascular complications in CKD patients. Among these mediators, studies on fetuin-A deserve further attention as clinical studies consistently show that fetuin-A deficiency is associated with vascular calcification, all-cause and cardiovascular mortality in CKD patients. Both chronic inflammation and the uremic milieu per se may contribute to fetuin-A depletion, as well as specific mutations in the AHSG gene. Recent experimental and clinical studies also suggest an intriguing link between fetuin-A, insulin resistance, and the metabolic syndrome.

Topics: alpha-2-HS-Glycoprotein; Blood Proteins; Bone Morphogenetic Protein 7; Calcinosis; Calcium-Binding Proteins; Cardiovascular Diseases; Chronic Disease; Extracellular Matrix Proteins; Humans; Inflammation; Kidney Diseases; Matrix Gla Protein; Metabolic Syndrome; Osteopontin; Osteoprotegerin; Vascular Diseases

Topics: Anorexia Nervosa; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Female; Glycoproteins; Humans; Kidney Diseases; Male; Multiple Myeloma; Osteitis Deformans; Osteoprotegerin; Prostatic Neoplasms; Reagent Kits, Diagnostic; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reference Values; Specimen Handling; Urinary Bladder Neoplasms

The discovery of the signalling system consisting of receptor activator of nuclear factor-KB ligand (RANKL), its receptor RANKL and its decoy receptor osteoprotegerin (OPG) has been a key step in the understanding of pathophysiology of the bone microenvironment and has provided pharmacological targets for new anti-resorptive drugs. The system is central to the interactions among bone, vascular and immune cells. OPG and a soluble form of RANKL (sRANKL) are present in the blood stream. The measurement of their concentrations offers insights into the regulatory mechanisms of the system and the possibility of using new markers in a number of diseases. Besides bone metabolic disorders, the list includes malignancies, rheumatic and cardiovascular diseases. However, apparent discrepancies in the outcome of studies point to a number of caveats: lack of control of pre-analytical and analytical variables; paucity of data on the metabolic removal of the molecules; the cross sectional design of most studies comparing patients with healthy subjects. Finally, circulating OPG and sRANKL derive from several sources, and their concentrations may be alterated by different coexisting pathological processes. In the absence of tissue-specific isoforms, diagnostic or prognostic significance may be suggested from data obtained in large cohorts, but is still of limited usefulness in single patients.

Topics: Biomarkers; Bone and Bones; Bone Diseases, Metabolic; Bone Neoplasms; Cardiovascular Diseases; Carrier Proteins; Cohort Studies; Glycoproteins; Humans; Membrane Glycoproteins; Multiple Myeloma; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; Signal Transduction

Osteoporosis and cardiovascular disease have numerous epidemiologic changes, health economic consequences, and molecular mechanisms in common, which are highlighted in this short review.. The incidence of osteoporosis and cardiovascular disease is increasing in western societies, and genetic background, nutrition and psychologic factors play important roles in the pathogenesis of both diseases. The presence of a decreased bone mass or osteoporotic vertebral fractures are associated with an increased cardiovascular mortality. Calcaneal bone loss of 1 SD (standard deviation) as measured by osteodensitometry is associated with a 1.31 times increased risk for the occurrence of stroke.. The observed increase in interleukin-6 and tumor necrosis factor serum concentrations during the menopause contributes to osteoporotic bone loss and is associated with arteriosclerosis. Furthermore, the presence of hydroxyapatite in arteriosclerotic plaques supports the notion of common pathogenetic mechanisms for both, osteoporosis and arteriosclerosis. Osteopontin, bone GLA protein and bone morphogenetic protein-2, which have first been isolated from the organic bone matrix, are also present in arteriosclerotic plaques. 1,25-dihydroxycholecalciferol potently stimulates bone matrix mineralization and is also a negative regulator of the renin-angiotensin system; therefore vitamin D(3) deficiency in addition to bone metabolism also affects blood pressure. Osteoporosis and arteriosclerosis develop in mice lacking the osteoprotegerin gene and also in klotho gene knockout mice.. Diagnosis of osteopenia, osteoporosis and osteoporotic vertebral or hip fractures indicates the presence of an increased cardiovascular risk which needs to be addressed by the physician who cares for patients with osteoporosis. The experimental finding of an osteoanabolic effect of statins supports the possibility of common pathogenetic disturbances which may be responsible for the simultaneous and frequent manifestation of osteoporosis and arteriosclerosis in elderly patients.

Topics: Animals; Cardiovascular Diseases; Causality; Cholecalciferol; Comorbidity; Fractures, Spontaneous; Glucuronidase; Glycoproteins; Humans; Klotho Proteins; Membrane Proteins; Mice; Mice, Knockout; Osteoporosis; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk; Spinal Fractures

Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Osteoprotegerin (OPG), known to regulate bone mass by inhibiting osteoclast differentiation and activation, might also play a role in vascular calcification. Increased circulating OPG levels in patients with CKD are associated with aortic calcification and increased mortality. We assessed the predictive role of OPG for all-cause and cardiovascular mortality in patients with CKD stages 3-5 over a 5-year follow-up period. We evaluated the relationship between OPG and all-cause and cardiovascular mortality in 145 CKD patients (stages 3-5) in a prospective observational follow-up study. Inflammation markers, including high-sensitivity C-reactive protein, standard echocardiography, and estimation of intima-media thickness in the common carotid artery, were assessed at baseline, and correlations with OPG levels were determined. The cutoff values for OPG were defined using ROC curves for cardiovascular mortality. Survival was assessed during follow up lasting for up to 5.5 years using Fine and Gray model. A total of 145 (89 men; age 58.9 ± 15.0 years) were followed up. The cutoff value for OPG determined using ROC was 10 pmol/L for general causes mortality and 10.08 pmol/L for CV causes mortality. Patients with higher serum OPG levels presented with higher mortality rates compared to patients with lower levels. Aalen-Johansen cumulative incidence curve analysis demonstrated significantly worse survival rates in individuals with higher baseline OPG levels for all-cause and cardiovascular mortality (p < 0.001). In multivariate analysis, OPG was a marker of general and cardiovascular mortality independent of sex, age, CVD, diabetes, and CRP levels. When CKD stages were included in the multivariate analysis, OPG was an independent marker of all-cause mortality but not cardiovascular mortality. Elevated serum OPG levels were associated with higher all-cause and cardiovascular mortality risk, independent of age, CVD, diabetes, and inflammatory markers, in patients with CKD.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Female; Follow-Up Studies; Humans; Male; Middle Aged; Osteoprotegerin; Prospective Studies; Renal Insufficiency, Chronic

Arterial stiffness and vascular calcification significantly contribute to coronary atherosclerosis progression. The prognostic value of increased arterial stiffness and vascular calcification in subjects with stable coronary artery disease (CAD) after percutaneous coronary intervention(PCI) is currently under question.. We randomly enrolled 262 patients with stable CAD 1 month after successful PCI. Carotid-femoral pulse wave velocity (PWV) was measured as a well-established index of central aortic stiffness. Osteoprotegerin (OPG) plasma levels were measured as a biomarker of vascular calcification. Patients were followed up prospectively up to 52 months. The primary endpoint was the composite of death from cardiovascular causes, myocardial infarction, stroke or hospitalization for cardiovascular causes.. During the follow-up period, 48 patients presented the primary composite endpoint. Subjects who presented the primary endpoint, compared to subjects free of cardiovascular events, had significantly increased PWV (9.45 ± 2.19 m/s vs 8.73 ± 2.07 m/s, P = .04) and OPG levels (4.21 ± 2.19 pmol/L vs 3.18 ± 1.74 pmol/L, P = .003). Survival analysis indicated that PWV predicted adverse cardiac events MACE (Hazard ratio = 1.29 95%CI: 1.07-1.57, P = .008) independently from confounders such as age, sex, smoking habits, ejection fraction, extent of coronary artery disease, hypertension and diabetes mellitus. Interestingly, for every increase in pulse wave velocity by 1 m/s, there is an anticipated increase in the risk of major adverse cardiovascular event (MACE) by 29%.. These findings extend the current knowledge concerning the role of arterial stiffness as powerful biomarkers in cardiovascular disease. Measurement of PWV might have a role in ascertaining prognosis and managing treatment in patients with stable CAD after PCI.

Topics: Biomarkers; Cardiovascular Diseases; Coronary Artery Disease; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Osteoprotegerin; Prognosis; Risk Factors; Vascular Stiffness

Osteoprotegerin (OPG), a member of the tumour necrosis factor receptor (TNFR) superfamily of proteins known to be involved in a large number of biological systems, plays a pivotal role in bone remodelling. In addition to the roles of OPG in bone metabolism, it has been reported to be associated with a high cardiovascular risk in patients with metabolic syndrome. In most cases, the exact functions of OPG remain to be established; however, the widespread expression of OPG suggests that this molecule may have multiple biological activities, mainly in the cardiometabolic environment. The aim of this study was to evaluate the value of OPG as a predictive marker for cardiovascular and metabolic risk in osteoporotic patients. The study group comprised patients with osteoporosis, in order to evaluate the association between OPG serum levels and cardiovascular pathology. Our results revealed significant correlations between classical biochemical bone and metabolic parameters, such as osteocalcin and parathyroid hormone with lipid and glucose biomarkers, sustaining the crosstalk between calcium and bone parameters and cardiovascular risk. The OPG serum level proved to have a significant and independent predictive value for metabolic syndrome (MetS) as a cardiovascular risk standard in osteoporotic patients. The OPG serum levels were increased in patients with MetS as a protective response against the atherosclerotic lesions. The serum levels of 25‑hydroxy vitamin D had significant and independent predictive value for cardiovascular and metabolic risk in our subjects, sustaining the active role of vitamin D beyond the area of bone metabolism.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Bone Remodeling; Cardiovascular Diseases; Female; Glucose; Humans; Lipids; Metabolic Syndrome; Middle Aged; Osteocalcin; Osteoporosis; Osteoprotegerin; Parathyroid Hormone; Risk Assessment; Risk Factors; Vitamin D; Young Adult

Although ferritin has been considered as a possible link between accelerated bone loss and atherosclerosis, the long-term impact of therapeutic agents widely used to treat osteoporosis, such as bisphosphonates, on ferritin levels has not been investigated. The present study investigated the effects of risedronate on serum ferritin levels in postmenopausal women with osteoporosis.. In an open-label, prospective, uncontrolled study, 68 postmenopausal women with osteoporosis were evaluated. Study participants received risedronate orally at a dose of 35 mg/week during a 6-month treatment period. Blood sampling for lipid profile, hemoglobin A1c, insulin, fibrinogen, C-reactive protein, osteoprotegerin, and ferritin was performed at baseline and after 6 months of treatment. Pulse-wave velocity and augmentation index at baseline were determined using SphygmoCor version 7.1 (AtCor Medical, Sydney, Australia).. Mean (SD) serum ferritin decreased significantly from 62.1 (44.8) to 46.7 (29.4) μg/dL (P < 0.0001) during the treatment period. On multiple linear regression analysis, the significant predictors of Δferritin were pulse-wave velocity (P = 0.04; effect size, 0.188), C-reactive protein (P = 0.021; effect size, 0.043), insulin (P = 0.011; effect size, 0.100), and high-density lipoprotein cholesterol (P = 0.046; effect size, 0.132) at baseline.. Risedronate treatment is associated with significantly decreased serum ferritin levels in postmenopausal women with osteoporosis and cardiovascular risk factors.

Topics: Aged; Bone Density Conservation Agents; C-Reactive Protein; Cardiovascular Diseases; Female; Ferritins; Fibrinogen; Glycated Hemoglobin; Humans; Insulin; Linear Models; Lipids; Lipoproteins, HDL; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Postmenopause; Prospective Studies; Pulse Wave Analysis; Research Design; Risedronic Acid; Risk Factors; Time Factors

Excess dietary salt is strongly correlated with cardiovascular disease, morbidity, and mortality. Conversely, potassium likely elicits favorable effects on cardiovascular disorders. In epidemiological studies, increased plasma osteoprotegerin (OPG) concentrations are associated with atherosclerosis and vascular deaths. Our study was designed to examine the effects of salt intake and potassium supplementation on plasma OPG levels in normotensive subjects.Methods and Results:The 18 normotensive subjects were selected from a rural community in China. They were sequentially maintained on low-salt diet for 7 days (3 g/day, NaCl), high-salt diet for 7 days (18 g/day), and high-salt diet with potassium supplementation for 7 days (18 g/day of NaCl+4.5 g/day of KCl). High-salt intake enhanced plasma OPG levels (252.7±13.9 vs. 293.4±16.1 pg/mL). This phenomenon was abolished through potassium supplementation (293.4±16.1 vs. 235.1±11.3 pg/mL). Further analyses revealed that the OPG concentration positively correlated with 24-h urinary sodium excretion (r=0.497, P<0.01). By contrast, OPG concentration negatively correlated with 24-h urinary potassium excretion (r=0.594, P<0.01).. Salt loading can enhance the production of circulating OPG. Potassium supplementation can reverse the effects of excessive OPG. Our study results may improve our understanding of the roles of salt and potassium in the risk of cardiovascular disorders.

Topics: Cardiovascular Diseases; Dietary Supplements; Female; Humans; Male; Middle Aged; Osteoprotegerin; Potassium; Risk Factors; Rural Population; Sodium Chloride, Dietary

Data on the predictive role of estimated glomerular filtration rate (eGFR) and osteoprotegerin (OPG) for cardiovascular (CVD) and all-cause mortality risk have been presented by our group and others. We now present data on the interactions between OPG with stage I to III chronic kidney disease (CKD) for all-cause and CVD mortality.. The setting was a 15-year study of 1,292 women over 70 years of age initially randomized to a 5-year controlled trial of 1.2 g of calcium daily. Serum OPG and creatinine levels with complete mortality records obtained from the Western Australian Data Linkage System were available. Interactions were detected between OPG levels and eGFR for both CVD and all-cause mortality (P < 0.05). Compared to participants with eGFR ≥60 ml/min/1.73 m2 and low OPG, participants with eGFR of <60 ml/min/1.73 m2 and elevated OPG had a 61% and 75% increased risk of all-cause and CVD mortality respectively (multivariate-adjusted HR, 1.61; 95% CI, 1.27-2.05; P < 0.001 and HR, 1.75; 95% CI, 1.22-2.55; P = 0.003). This relationship with mortality was independent of decline in renal function (P<0.05). Specific causes of death in individuals with elevated OPG and stage III CKD highlighted an excess of coronary heart disease, renal failure and chronic obstructive pulmonary disease deaths (P < 0.05).. The association between elevated OPG levels with CVD and all-cause mortality was more evident in elderly women with poorer renal function. Assessment of OPG in the context of renal function may be important in studies investigating its relationship with all-cause and CVD mortality.

Topics: Aged; Australia; Biomarkers; Cardiovascular Diseases; Cardiovascular System; Creatinine; Female; Glomerular Filtration Rate; Humans; Osteoprotegerin; Prospective Studies; Renal Insufficiency; Renal Insufficiency, Chronic; Risk Factors

Patients treated with hemodialysis (HD) have an increased mortality, mainly caused by cardiovascular disease (CVD). Osteoprotegerin (OPG) is a glycoprotein involved in the regulation of the vascular calcification process. Previous studies have demonstrated that OPG is a prognostic marker of mortality. The aim of this study was to investigate if OPG was a prognostic marker of all-cause mortality in high-risk patients with end-stage renal disease and CVD.. We prospectively followed 206 HD patients with CVD. OPG was measured at baseline and the patients were followed for 2 years or until reaching the primary endpoint, i.e., all-cause mortality.. All-cause mortality during follow-up was 44% (90/206). High OPG was associated with increased mortality, using the first tertile as reference, with an unadjusted HR of 1.70 (CI 1.00 - 2.88) for the second tertile and HR of 1.63 (CI 0.96 - 2.78) for the third tertile. In a multivariate Cox-regression analysis age, CRP and OPG in both the second and third tertile were significantly associated with increased mortality In the unadjusted survival analysis, a test for trend of OPG yielded a p-value of 0.08; in the adjusted analyses, the p-value for trend was 0.03.. In a high-risk population of hemodialysis patients with previously documented cardiovascular disease, a high level of OPG was an independent risk marker of all-cause mortality.

Topics: Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Chi-Square Distribution; Denmark; Double-Blind Method; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Osteoprotegerin; Proportional Hazards Models; Prospective Studies; Renal Dialysis; Risk Assessment; Risk Factors; Secondary Prevention; Time Factors; Treatment Outcome; Up-Regulation

In patients with chronic kidney disease, vascular calcification contributes to increased cardiovascular (CV) morbidity and mortality. CV risk remains high after successful renal transplantation. Osteoprotegerin (OPG) is a glycoprotein, involved in the regulation of the vascular calcification process. Previous studies have shown that elevated OPG is predictive of mortality in high-risk populations. The aim of this study was to investigate the prognostic value of OPG for graft function, CV events and all-cause death, in a large transplant cohort.. OPG was measured at baseline in renal transplant recipients enrolled in the Assessment of Lescol in Renal Transplantation (ALERT) study, a randomized placebo-controlled intervention study comparing fluvastatin and placebo. Patients were followed for 6.7 years with evaluation of pre-specified end points, graft loss, graft function, CV events and death.. OPG was analysed in 1889 renal transplant recipients, with a mean value of 4.69 ± 1.85 pg/L. The number of renal and CV events increased by quartiles of OPG. In the multivariate analysis, OPG in the fourth as compared to first quartile was an independent predictor of graft failure or doubling of serum creatinine [hazard ratio (HR) 2.20 (1.56-3.11), P < 0.001], major CV events [HR 2.40 (1.58-3.64), P < 0.001], cardiac mortality [HR 2.80 (1.32-5.94), P = 0.007] and all-cause mortality [HR 2.31 (1.53-3.49), P < 0.001].. In a large cohort of kidney transplant patients with long-term follow-up, OPG was independently associated with renal events, CV events and mortality.

Topics: Adult; Aged; Anticholesteremic Agents; Biomarkers; Cardiovascular Diseases; Creatinine; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Graft Rejection; Humans; Indoles; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Osteoprotegerin; Prognosis; Risk Factors; Survival Rate; Vascular Calcification

Cardiovascular disease is the leading cause of death in patients with type 2 diabetes mellitus (T2DM). We suggested that plasma osteoprotegerin (OPG), a strong, independent predictor of cardiovascular disease, could discriminate between anti-diabetic treatments depending on their benefits regarding cardiovascular disease. The South Danish Diabetes Study, an investigator-driven, randomized, controlled clinical trial lasting 2 years, was used to test this hypothesis in patient groups with different medication strategies (insulin aspart or NPH insulin, added either metformin/placebo or rosiglitazone/placebo). A total of 371 individuals were eligible for the study. Basic variables were analysed along with measurement of plasma OPG and HbA(1c) at the beginning and end of the study. Only rosiglitazone treatment caused a significant decrease in plasma OPG concentrations (p = 0.003), while no significant change was seen in the other treatment groups. The effect of rosiglitazone on plasma OPG remained significant in a univariate analysis adjusted for change in HbA(1c) (p = 0.013). Of note, the change in plasma OPG significantly correlated with HbA(1c) improvement in rosiglitazone-treated patients (R = 0.29, p = 0.0002), while this correlation was poor in those not receiving rosiglitazone (R = 0.06, p =0.48). Treatment with rosiglitazone among patients with T2DM reduces the concentration of plasma OPG. This is not seen with metformin despite similar reductions in HbA(1c) . Alteration in the OPG/RANKL pathway by glitazones may have implications for the understanding of both cardiovascular effects and bone side effects of the drug.

Topics: Adult; Aged; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Osteoprotegerin; Rosiglitazone; Thiazolidinediones; Treatment Outcome

Recent evidence suggests that genistein aglycone may act beneficially on surrogate cardiovascular risk markers in postmenopausal women. We assessed the effects of genistein aglycone on some cardiovascular risk factors and homocysteine levels after 3-years of continued therapy in a cohort of osteopenic, postmenopausal women.. The parent study was a randomized, double-blind, placebo-controlled trial involving 389 postmenopausal women with low bone mass for 24 months. Subsequently, a subcohort (138 patients) continued therapy for an additional year. Participants received 54mg of genistein aglycone (n=71) or placebo (n=67), daily. Both arms received calcium and vitamin D(3) in therapeutic doses. Moreover, 4 weeks before randomization procedures and during our follow-up study, all patients received dietary instructions in an isocaloric fat-restricted diet. Blood lipid profiles, fasting glucose and insulin, insulin resistance (HOMA-IR), fibrinogen, osteoprotegerin (OPG) and homocysteine at baseline and after 24 and 36 months of treatment were measured. Compared to placebo, genistein significantly decreased fasting glucose and insulin, HOMA-IR, fibrinogen and homocysteine after 24 and 36 months of treatment. By contrast, isoflavone administration did not affect high-density lipoprotein cholesterol and triglycerides though serum OPG was higher in the genistein recipients. There were no differences in adverse events or discomfort between groups. Results on routine biochemical, liver function, and hematologic testing did not change over time in placebo or genistein group.. After 3-years of treatment, genistein aglycone plus calcium, vitamin D(3) and a healthy diet showed positive effects on some cardiovascular risk factors and homocysteine levels in a cohort of postmenopausal women with low bone mass.

Topics: Calcium Carbonate; Cardiovascular Diseases; Cholecalciferol; Female; Follow-Up Studies; Genistein; Homocysteine; Humans; Insulin Resistance; Lipids; Middle Aged; Osteoprotegerin; Postmenopause; Research Design; Risk Factors

Genistein, a soy isoflavone, has received wide attention over the last few years because of its potential preventive role for cardiovascular disease.. Our objective was to assess the effects of genistein administration (54 mg/d) on some predictors of cardiovascular risk in osteopenic, postmenopausal women.. We conducted a randomized, double-blind, placebo-controlled trial at three Italian university medical centers.. After a 4-wk stabilization on a standard isocaloric, fat-reduced diet, participants were randomly assigned to receive genistein (n = 198) or placebo (n = 191) daily for 24 months. Both intervention and placebo contained calcium and vitamin D(3).. Blood lipid profiles, fasting glucose and insulin, homeostasis model assessment for insulin resistance, fibrinogen, soluble intercellular adhesion molecule-1, soluble vascular cellular adhesion molecule-1, F2-isoprostanes, and osteoprotegerin at baseline and after 12 and 24 months of treatment were measured.. Compared with placebo, genistein significantly reduced fasting glucose and insulin as well as homeostasis model assessment for insulin resistance after both 12 and 24 months of treatment. By contrast, genistein administration did not affect blood lipid levels although fibrinogen, F2-isoprostanes, soluble intercellular adhesion molecule-1, and soluble vascular cellular adhesion molecule-1 decreased significantly compared with placebo after 24 months. Serum osteoprotegerin was higher in the genistein group compared with placebo. At 24 months, the genistein group showed no change in endometrial thickness compared with placebo. Most treatment-related adverse events were moderate and composed of gastrointestinal side effects [genistein, n = 37 (19%); placebo, n = 15 (8%)].. These results suggest that 54 mg genistein plus calcium, vitamin D(3), and a healthy diet was associated with favorable effects on both glycemic control and some cardiovascular risk markers in a cohort of osteopenic, postmenopausal women.

Topics: Aged; Biomarkers; Blood Glucose; Bone Density; Bone Diseases, Metabolic; Cardiovascular Diseases; Diet; Double-Blind Method; Female; Fibrinogen; Genistein; Humans; Insulin; Intercellular Adhesion Molecule-1; Isoprostanes; Lipids; Middle Aged; Osteoprotegerin; Postmenopause; Risk Factors; Treatment Outcome; Ultrasonography; Uterus; Vascular Cell Adhesion Molecule-1

The phytoestrogen genistein has been shown to be the most efficacious in clinical and experimental studies. We studied whether genistein treatment affects some cardiovascular risk markers in postmenopausal women.. Sixty healthy postmenopausal women, who were 52 to 60 years of age, were enrolled in a 6-month double-blind, placebo-controlled, randomized study. After a 4-week stabilization on a standard fat-reduced diet, participants were randomly assigned to receive either genistein (n = 30; 54 mg/d) or placebo (n = 30). At baseline and after a 6-month treatment, we measured fasting glucose, insulin, insulin resistance (HOMA-IR), osteoprotegerin (OPG), fibrinogen, and sex hormone-binding globulin (SHBG).. By comparison with placebo, genistein treatment decreased significantly fasting glucose (genistein = -8.7 +/- 2.3%; placebo = 3.2 +/- 2.3%; P < 0.001), fasting insulin (genistein = -12 +/- 3.33%; placebo = 36 +/- 3.29%; P < 0.001), and HOMA-IR (genistein = -14 +/- 5.8%; placebo = 42 +/- 0.6%; P < 0.001). After genistein-treatment, fibrinogen decreased (genistein = 3.18 +/- 0.12 g/L; placebo = 3.83 +/- 0.04 g/L; P < 0.001) with respect to placebo. In the genistein group, serum OPG was lower (-2 +/- 0.3%) than in placebo (9 +/- 1.5%; P < 0.001), and serum SHBG was higher (63 +/- 3.8 nmol/L) compared with placebo (53 +/- 2.9 nmol/L; P < 0.05).. Our study suggests that genistein may have a favorable effect on some cardiovascular markers.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Double-Blind Method; Estrogen Replacement Therapy; Female; Fibrinogen; Genistein; Glycoproteins; Humans; Insulin; Middle Aged; Osteoprotegerin; Phytoestrogens; Phytotherapy; Postmenopause; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sex Hormone-Binding Globulin; Treatment Outcome

The relationship between circulating osteoprotegerin (OPG) levels and the risk of cardiovascular diseases (CVDs) has been the subject of conflicting results in previous observational and experimental studies. To assess the causal effect of genetically predicted OPG levels on the risk of a wide range of CVDs, we used the Mendelian randomization design.. We initially extracted information of genetic variants on OPG levels and their corresponding effect values from the summary data based on the European ancestry genome-wide association study. Subsequently, we performed two-sample Mendelian randomization analyses to assess the causal effect of genetically predicted OPG levels on CVDs by using inverse variance weighting (IVW), MR-Egger, weighted median, and MR-PRESSO methods. We also conducted sensitivity analyzes as well as complementary analyses with a more relaxed threshold for the exposure genetic instrumental variable (P < 5 × 10. Our results indicated that genetically predicted OPG levels causally reduce the risk of atrial fibrillation (IVW OR = 0.84; 95% CI = 0.72-0.98; P = 0.0241), myocardial infarction(IVW OR = 0.89; 95% CI = 0.80-0.98; P = 0.0173) and coronary heart disease (IVW: OR = 0.90; 95% CI = 0.82-0.99; P = 0.0286). Further complementary analyses also confirmed the above results remain robust and we also identified a potential causal association of OPG levels with a reduced risk of hypertensive diseases(IVW OR = 0.94;95% CI = 0.88-1.00; P = 0.0394).. This study provides compelling evidence for a causal relationship between genetically predicted OPG levels and risk reduction of coronary heart disease, myocardial infarction, and atrial fibrillation, indicating that OPG could potentially serve as a cardiovascular risk marker in clinical practice.

Topics: Atrial Fibrillation; Cardiovascular Diseases; Genome-Wide Association Study; Humans; Mendelian Randomization Analysis; Myocardial Infarction; Osteoprotegerin

There are reports of link of osteoprotegerin (OPG) gene polymorphism to type-2 diabetes (T2D) and hypertension (HTN). The objective of the study was to assess the allele frequency of OPG (rs2073618) gene polymorphism and its association with heart rate variability (HRV) and blood pressure variability profile as CVD risks in diabetes mellitus patients with hypertension undergoing treatment. T2D patients on treatment without hypertension (n = 172), with hypertension (n = 177) and 191 healthy volunteers were recruited for the study. Their blood pressure variability including baroreflex sensitivity (BRS), heart rate variability (HRV), OPG, insulin, lipid profile, receptor-activator for NFkB (RANK), receptor-activator for NFkB-Ligand (RANKL), and tumor necrosis factor-α (TNF-α) were estimated. Allele frequency of OPG (rs2073618) gene polymorphism was assessed from the DNA samples. BRS and HRV indices were decreased, and RANKL/OPG and TNF-α were increased in T2D and T2D + HTN groups, respectively compared to healthy control group. The reduction in BRS was contributed by increased inflammation and reduced SDNN of HRV in GG genotype in T2D + HTN. In GG + GC subgroup, it was additionally contributed by rise in RANKL/OPG level (β - 0.219; p 0.008). Presence of mutant GG genotype contributed to the risk of hypertension among T2D patients (OR 3.004) as well as in general population (OR 2.79). It was concluded that CV risks are more in T2D patients with HTN expressing OPG rs2073618 gene polymorphism.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Disease Risk Factors; Humans; Hypertension; Osteoprotegerin; Polymorphism, Single Nucleotide; RANK Ligand; Risk Factors; Tumor Necrosis Factor-alpha

The purpose of this study was to compare vascular calcification (VC), serum osteoprotegerin (OPG) levels, and other biochemical markers to determine their value as available predictors of all-cause and cardiovascular (CV) mortality in patients on peritoneal dialysis (PD). A total of 197 patients were recruited from seven dialysis centers in Mexico City. VC was assessed with multi-slice computed tomography, measured using the calcification score (CaSc). OPG, albumin, calcium, hsC-reactive protein, phosphorous, osteocalcin, total alkaline phosphatase, and intact parathormone were also analyzed. Follow-up and mortality analyses were assessed using the Cox regression model. The mean age was 43.9 ± 12.9 years, 64% were males, and 53% were diabetics. The median OPG was 11.28 (IQR: 7.6−17.4 pmol/L), and 42% of cases had cardiovascular calcifications. The median VC was 424 (IQR:101−886). During follow-up (23 ± 7 months), there were 34 deaths, and 44% were cardiovascular in origin. In multivariable analysis, OPG was a significant predictor for all-cause (HR 1.08; p < 0.002) and CV mortality (HR 1.09; p < 0.013), and performed better than VC (HR 1.00; p < 0.62 for all-cause mortality and HR 1.00; p < 0.16 for CV mortality). For each mg/dL of albumin-corrected calcium, there was an increased risk for CV mortality, and each g/dL of albumin decreased the risk factor for all-cause mortality. OPG levels above 14.37 and 13.57 pmol/L showed the highest predictive value for all-cause and CV mortality in incident PD patients and performed better than VC.

Topics: Adult; Albumins; Biomarkers; Calcium; Cardiovascular Diseases; Female; Humans; Male; Middle Aged; Osteoprotegerin; Peritoneal Dialysis; Risk Factors; Vascular Calcification

Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Epidemiological studies suggest serum Osteoprotegrin (OPG)/Tumour-necrosis-factor-related-apoptosis-inducing- ligand (TRAIL) ratio may be a useful marker of cardiovascular risk. This study aimed to compare serum levels of TRAIL, OPG and OPG/TRAIL ratio in people with T2DM, with and without a history of CVD, and controls; and to determine which of these indices, if any, predict cardiovascular risk.. In this single centre observational study of 133 participants, people with T2DM, with and without a history of a cardiovascular event in the last 5 years, were recruited along with a control cohort without T2DM or CVD. Demographic information and anthropometric measurements were recorded. Blood samples were taken and OPG and TRAIL were measured using ELISA.. People with T2DM and CVD had higher OPG/TRAIL ratios compared to controls or those with a new diagnosis of T2DM. After adjustment for potential confounding factors, OPG/TRAIL ratio was significantly associated with the presence of CVD in people with T2DM and an OPG/TRAIL ratio cut-off > 38.6 predicted the presence of CVD in this cohort with a sensitivity of 80% and specificity of 82%.. This study suggests that OPG/TRAIL ratio may have a role as a biomarker of CVD in people with T2DM.

Topics: Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Osteoprotegerin; TNF-Related Apoptosis-Inducing Ligand

Disturbances in bone mineral metabolism are associated with increased mortality and cardiovascular events (CVEs). However, the association between bone-associated protein biomarkers, mortality and CVEs independent of cytokine activation remains unknown. This study aimed to investigate bone-associated protein biomarkers and the association with inflammatory cytokines and cardiovascular (CV) outcomes.. This prospective study enrolled haemodialysis patients in Denmark between December 2010 and March 2011. Using a proximity extension proteomics assay, nine bone-associated proteins were examined: cathepsin D (CTSD), cathepsin L1 (CTSL1), dickkopf-related protein 1, fibroblast growth factor 23, leptin, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-Β ligand, TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor 2 (TRAIL-R2). The importance of the bone-associated protein markers was evaluated by a random forest (RF) algorithm. The association between bone-associated proteins with all-cause death, CV death and CVEs was analysed in multivariable Cox models adjusted for age, gender, comorbidities, laboratory data and dialysis duration.. We enrolled 331 patients [63.7% men; mean age, 65 years (standard deviation 14.6)] in a prospective cohort study with 5 years of follow-up. When adjusting for confounders, CTSL1 remained associated with all-cause death and four biomarkers were associated with CVEs. However, the association between bone markers and the outcomes was attenuated after adjusting for inflammatory proteins and only OPG remained associated with CVEs in the adjusted model. Evaluating the importance of bone markers by RF, OPG was the most important marker related to CVEs. OPG also improved the prediction of CVEs in integrated discrimination improvement and net reclassification improvement analyses.. OPG, a well-known bone biomarker, was associated with CVEs independent of cytokine activity. In contrast, the association between CVEs and the remaining three bone-associated proteins (TRAIL-R2, CTSD and CTSL1) was affected by cytokine inflammation activity.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Cytokines; Female; Humans; Male; Osteoprotegerin; Prospective Studies; Receptors, TNF-Related Apoptosis-Inducing Ligand; Renal Dialysis; TNF-Related Apoptosis-Inducing Ligand

Epidemiology and pathogenesis of cardiovascular diseases (CVD) and osteoporosis are strikingly overlapping. This study presents matrix metalloproteinase-9 (MMP-9), as a simple molecular link more consistently associated with the pathophysiology of both osteoporosis and CVD risk factors. 40 adult female rats were randomly distributed into 4 groups [control sham-operated, untreated osteoporosis, carvedilol-treated osteoporosis and alendronate-treated osteoporosis]. After 8 weeks, blood samples were collected to estimate Lipid profile (Total cholesterol, HDL, Triglycerides), inflammatory markers (IL-6, TNF alpha, CRP and NO), and Bone turnover markers (BTM) (Alkaline phosphatase, osteocalcin and pyridinoline). The tibias were dissected to estimate MMP-9 and NF-kB gene expression, OPG, RANKL levels and for histological examination. Induction of osteoporosis resulted in a significant elevation in BTM, inflammatory markers and dyslipidemia. MMP-9 was significantly elevated and positively correlated with BTM, inflammation and dyslipidemia markers. Carvedilol and alendronate exerted a bone preservative role and attenuated dyslipidaemia and inflammation in accordance with their respective effect on MMP-9.

Topics: Alkaline Phosphatase; Amino Acids; Animals; Bone Remodeling; Cardiovascular Diseases; Cholesterol; Cortical Bone; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Inflammation; Lipoproteins, HDL; Matrix Metalloproteinase 9; NF-kappa B; Osteocalcin; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; RANK Ligand; Rats; Risk Factors; Tibia; Triglycerides

Basic and clinical research have demonstrated that osteoprotegerin (OPG) plays an important role in the development and progression of cardiovascular diseases. The aim of this study was to evaluate the association of four polymorphic sites (rs2073618, rs3134069, rs3134070, and rs3102735) of

Topics: Aged; Cardiovascular Diseases; Coronary Artery Disease; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Genotype; Haplotypes; Humans; Male; Mexico; Middle Aged; Osteoprotegerin; Polymorphism, Single Nucleotide; Risk Factors

Background The incidence and clinical manifestations of cardiovascular disease (CVD) differ between blacks and whites. Biomarkers that reflect important pathophysiological pathways may provide a window to allow deeper understanding of racial differences in CVD. Methods and Results The study included 2635 white and black participants from the Dallas Heart Study who were free from existing CVD. Cross-sectional associations between race and 32 biomarkers were evaluated using multivariable linear regression adjusting for age, traditional CVD risk factors, imaging measures of body composition, renal function, insulin resistance, left ventricular mass, and socioeconomic factors. In fully adjusted models, black women had higher lipoprotein(a), leptin, d-dimer, osteoprotegerin, antinuclear antibody, homoarginine, suppression of tumorigenicity-2, and urinary microalbumin, and lower adiponectin, soluble receptor for advanced glycation end products and N-terminal pro-B-type natriuretic peptide versus white women. Black men had higher lipoprotein(a), leptin, d-dimer, high-sensitivity C-reactive protein, antinuclear antibody, symmetrical dimethylarginine, homoarginine, high-sensitivity cardiac troponin T, suppression of tumorigenicity-2, and lower adiponectin, soluble receptor for advanced glycation end products, and N-terminal pro-B-type natriuretic peptide versus white men. Adjustment for biomarkers that were associated with higher CVD risk, and that differed between blacks and whites, attenuated the risk for CVD events in black women (unadjusted hazard ratio 2.05, 95% CI 1.32, 3.17 and adjusted hazard ratio 1.15, 95% CI 0.69, 1.92) and black men (unadjusted hazard ratio 2.39, 95% CI 1.64, 3.46, and adjusted hazard ratio 1.21, 95% CI 0.76, 1.95). Conclusions Significant racial differences were seen in biomarkers reflecting lipids, adipokines, and biomarkers of endothelial function, inflammation, myocyte injury, and neurohormonal stress, which may contribute to racial differences in the development and complications of CVD.

Topics: Adiponectin; Adult; Albuminuria; Antibodies, Antinuclear; Arginine; Biomarkers; Black or African American; C-Reactive Protein; Cardiovascular Diseases; Cross-Sectional Studies; Female; Fibrin Fibrinogen Degradation Products; Homoarginine; Humans; Interleukin-1 Receptor-Like 1 Protein; Leptin; Linear Models; Lipoprotein(a); Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Osteoprotegerin; Peptide Fragments; Proportional Hazards Models; Receptor for Advanced Glycation End Products; Troponin T; White People

Osteopontin (OPN), osteoprotegerin (OPG) and osteocalcin (OC) are matrix glycoproteins which mediate bone mineralization; moreover, their effects on glucose/insulin homeostasis have recently been demonstrated. Higher circulating OPN and OPG levels have been associated with the presence of insulin resistance, atherosclerosis and coronary heart disease. No data are available on contextual changes of these markers in type 2 diabetes mellitus (T2DM). Therefore, aims of this study were to evaluate serum OPN, OPG and OC levels in T2DM patients and their clinical correlates.. We recruited 83 consecutive T2DM patients referring to our diabetes outpatient clinics at Sapienza, University of Rome, and 71 non-diabetic sex and age-comparable subjects as a control group. Study population underwent metabolic characterization and carotid ultrasound for intima-media thickness measurement. Plasma OPN, OPG and OC were measured by MILLIPLEX Multiplex Assays Luminex.. T2DM patients had significantly higher circulating OPN and OPG levels than controls (14.3 ± 13.6 vs 10.6 ± 13.7 ng/ml p < 0.001, 0.70 ± 0.60 vs 0.54 ± 4.1 ng/ml, p = 0.02) while OC levels were similar in the two cohorts (6.35 ± 5.8 vs 7.80 ± 7.0 ng/ml, p = n.s). OPN and OPG positively correlated with greater systolic blood pressure (SBP) values, HOMA-IR and HOMA-β, and with the presence of dyslipidemia and carotid atherosclerosis. The association between greater OPN and OPG levels and SBP was independent from possible confounders (both p = 0.01).. Circulating OPN and OPG levels are increased in T2DM patients and identify a particularly unfavourable metabolic profile, mostly expressed by higher SBP. Bone peptides may represent novel markers of vascular stress and accelerated atherosclerosis in diabetes, constituting a possible tool for cardiovascular risk stratification in diabetes.

Topics: Adult; Aged; Biomarkers; Cardiovascular Diseases; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Male; Metabolic Syndrome; Metabolome; Middle Aged; Osteocalcin; Osteopontin; Osteoprotegerin; Prognosis; Risk Factors

To investigate the correlation between elevated serum sclerostin levels and chronic kidney disease outcomes for patients receiving peritoneal dialysis (PD).. We performed a prospective observational study in stable PD patients. Serum sclerostin levels were determined via enzyme immunoassay, and median levels of sclerostin were used to divide patients into high and low sclerostin groups. New-onset cardiovascular events (CVEs) and cardiovascular mortality were evaluated during a 6-year follow-up period.. Ninety-eight patients [mean age 52.5 ± 10.9 years, 49% males, 21.4% diabetic, median dialysis vintage 40.7 (range 17.9-72.2) months] were recruited. Compared with those in the low sclerostin group, patients in the high sclerostin group demonstrated higher levels of total-cholesterol, NT-proBNP, and osteoprotegerin (all P < 0.05). During the 6-year study period, 25 CVEs and 17 cardiovascular deaths occurred in the high sclerostin group, whereas 11 CVEs and four cardiovascular deaths occurred in the low sclerostin group. A Cox regression analysis determined that high sclerostin levels significantly increased the risk for CVEs (HR 2.475, 95% CI 1.116-5.489, P = 0.026) and cardiovascular death (HR 3.484, 95% CI1.134-10.706, P = 0.029), after multiple adjustments were made.. Our data suggest that high sclerostin levels may predict the onset of CVEs and cardiovascular mortality among PD patients.

Topics: Adaptor Proteins, Signal Transducing; Adult; Bone Morphogenetic Proteins; Cardiovascular Diseases; Cholesterol; Female; Follow-Up Studies; Genetic Markers; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Osteoprotegerin; Peptide Fragments; Peritoneal Dialysis; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors

Vascular calcification (VC) and atherosclerosis are associated with an increased cardiovascular morbimortality in chronic kidney disease (CKD). Osteoprotegerin (OPG) and osteopontin (OPN) are involved in both VC and CKD. Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) has been related to cardiovascular disease. We hypothesized that OPG, OPN and sTWEAK levels may be associated with a higher prevalence of cardiovascular outcomes in patients with CKD.. The presence of calcified or non-calcified atherosclerotic plaques was assessed in 1043 stage 3 to 5D CKD patients from The NEFRONA Study. Biochemical measurements and OPG, OPN and sTWEAK serum levels were analyzed. Patients were followed for cardiovascular outcomes (41 ± 16 months).. At recruitment, 26% of CKD patients had VC. The adjusted odds ratios for having VC were 2.22 (1.32-3.75); p=.003 for OPG, and 0.45 (0.24-0.84); p=.01 for sTWEAK concentrations. After follow-up, 95 CV events occurred. In a Cox model, patients with OPG or OPN above and sTWEAK below their optimal cut-off points had an adjusted higher risk of cardiovascular events [HR: 2.10 (1.49-3.90); p=.02; 1.65 (1.02-2.65); p=.04; 2.05 (1.28-3.29), p=.003; respectively]. When CKD patients were grouped according to the number of biomarkers above (OPG and OPN) or below (sTWEAK) their cut-off points, the combination of these biomarkers showed the highest risk for cardiovascular events [HR: 9.46 (3.80-23.5) p < .001]. A composite score of these three biomarkers increased the C-statistic and net reclassification index beyond conventional risk factors and VC.. The combination of OPG, OPN and sTWEAK increased the predictability of cardiovascular outcomes.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Cytokine TWEAK; Female; Humans; Male; Middle Aged; Osteopontin; Osteoprotegerin; Predictive Value of Tests; Prevalence; Prognosis; Prospective Studies; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Spain; Time Factors; Vascular Calcification

We studied the correlations between circulating osteoprotegerin (OPG) level and radial artery calcification (RAC) assessed histologically and carotid artery intima-media thickness (CCA-IMT). Moreover, we studied the relationship between OPG levels and all-cause and cardiovascular (CV) mortality during a 5-year observation period. The study comprised 59 CKD patients (36 hemodialyzed (HD), 23 predialysis). The biochemical parameters included: creatinine, calcium, phosphate, intact parathormone, C-reactive protein, interleukin-6, tumor necrosis factor receptor II (TNFRII), transforming growth factor-β, hepatocyte growth factor, fibroblast growth factor 23, osteonectin (ON), osteopontin, osteoprotegerin, and osteocalcin. CCA-IMT and the presence of atherosclerotic plaques was assessed by ultrasound. Fragments of radial artery obtained during creation of HD access were prepared for microscopy and stained for calcifications with alizarin red. RAC was detected in 34 patients (58%). In multiple regression adjusted for dialysis status, TNFRII, ON and Framingham risk score (FRS) were identified as the independent predictors of OPG. Serum OPG above the median value of 7.55 pmol/L significantly predicted the presence of RAC in simple logistic regression (OR 5.33; 95%CI 1.39-20.4; P = 0.012) and in multiple logistic regression adjusted for FRS, dialysis status and CCA-IMT values (OR 6.56; 95%CI 1.06-40.6; P = 0.036). OPG levels above the median were associated with higher CCA-IMT values (1.02 ± 0.10 vs. 0.86 ± 0.13; P < 0.001) and predicted the presence of atherosclerotic plaques in carotid artery (OR 14.4; 95%CI 2.84-72.9; P < 0.001), independently of FRS, dialysis status and RAC. In this study, elevated serum OPG levels correlated with higher CCA-IMT, the presence of atherosclerotic plaques and the severity of the RAC independently of each other. During follow-up, 25 patients (42%) died, including 21 due to CV causes. In multiple Cox regression, OPG above the median predicted overall survival independently of dialysis status, Framingham risk score, CCA-IMT above the median value, and the presence of atherosclerotic plaques in CCA, but not independently of RAC. We postulate that circulating OPG may play a dual role as a marker for both medial arterial calcification and atherosclerosis, hence it seems to be a valuable tool for assessing CV risk in patients with CKD. OPG might be an early indicator of all-cause mortality in CKD patients with advanced medial arterial ca

Topics: Adult; Aged; Biomarkers; Cardiovascular Diseases; Carotid Intima-Media Thickness; Female; Follow-Up Studies; Humans; Logistic Models; Male; Middle Aged; Osteoprotegerin; Plaque, Atherosclerotic; Radial Artery; Renal Dialysis; Renal Insufficiency, Chronic; Severity of Illness Index; Survival Rate; Vascular Calcification

Osteoprotegerin (OPG) plays protective roles against the development of vascular calcification (VC) which greatly contributes to the increased cardiovascular events in patients with chronic kidney disease (CKD). The present study aimed to find the non-traditional, kidney-related cardiovascular risk factors correlated to serum OPG and the effect of serum OPG on the arterial stiffness measured by brachial ankle pulse wave velocity (baPWV) in patients with the pre-dialysis CKD.. We cross-sectionally analyzed the data from the patients in whom baPWV and the serum OPG were measured at the time of enrollment in a prospective pre-dialysis CKD cohort study in Korea.. Along with traditional cardiovascular risk factors such as age, diabetes mellitus, pulse pressure, and baPWV, non-traditional, kidney-related factors such as albuminuria, plasma level of hemoglobin, total CO. Non-traditional, kidney-related cardiovascular risk factors in addition to traditional cardiovascular risk factors were related to serum level of OPG in CKD. Serum OPG level was significantly related to baPWV. Our study suggests that kidney-related factors involved in CKD-specific pathways for VC play a role in the increased secretion of OPG into circulation in patients with CKD.. ClinicalTrials.gov Identifier: NCT01630486.

Topics: Adult; Aged; Blood Pressure; Cardiovascular Diseases; Creatinine; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Linear Models; Male; Middle Aged; Osteoprotegerin; Pulse Wave Analysis; Renal Insufficiency, Chronic; Risk Factors; Vascular Stiffness

Fragility fractures and cardiovascular diseases often coincide. However, data on shared risk factors and markers are scarce. Our aim was to assess the independent associations of serum osteoprotegerin (OPG) levels with the risk of fracture and cardiovascular outcomes (acute coronary syndrome, cardiac death) in older men. A cohort of 819 home-dwelling men aged 60 to 87 years was followed prospectively for 8 years. Serum OPG was measured at baseline by ELISA. Bone mineral density (BMD) at femoral neck and Trabecular Bone Score (TBS) were assessed by DXA. Clinical risk factors and Fracture Risk Assessment Tool (FRAX) were assessed. The incident events (self-reported peripheral fractures and acute coronary syndrome, cardiac death reported by a proxy) confirmed by a health professional were retained for the statistical analysis. Incident vertebral fractures were assessed on lateral DXA scans after 4 and 8 years. Hazard risk (HR) was assessed using the Cox model. After adjustment for FRAX corrected for femoral neck BMD and TBS, diabetes mellitus, ischemic heart disease, and prior falls, the risk of fracture was twofold higher in the highest versus the lowest OPG quartile (HR 2.35; 95% CI, 1.35 to 4.10). The risk of vertebral and nonvertebral fracture was higher in the highest versus the lowest OPG quartile (OR 2.76 [95% CI, 1.08 to 7.05] and HR 2.46 [95% CI, 1.23 to 4.92]). The risk of major osteoporotic fracture was higher in the fourth versus the first OPG quartile (HR 2.43; 95% CI, 1.16 to 5.10). The risk of cardiovascular outcome (adjusted for confounders) was higher in the highest versus the lowest OPG quartile (HR 3.93; 95% CI, 1.54 to 10.04). The risk of fracture and cardiovascular outcome was higher in the highest OPG quartile versus the lower quartiles combined (HR 2.06 [95% CI, 1.35 to 3.14] and HR 2.98 [95% CI, 1.60 to 5.54], respectively). In conclusion, in older men, higher serum OPG levels represent an independent risk factor for cardiovascular and fracture risk. © 2017 American Society for Bone and Mineral Research.

Topics: Aged; Aged, 80 and over; Cardiovascular Diseases; Disease-Free Survival; Fractures, Bone; Humans; Male; Osteoprotegerin; Prospective Studies; Risk Factors

To assess whether serum osteoprotegerin (OPG) and/or fetuin-A predict mortality and cardiovascular (CV) morbidity and mortality in hemodialysis patients.. Multicenter, observational, prospective study that included 220 hemodialysis patients followed up for up to 6 years. Serum OPG and fetuin-A levels were measured at baseline and their possible association with clinical characteristics, CV risk biomarkers, carotid ultrasonographic findings, as well as their association with overall and CV mortality and CV events were assessed.. During a mean follow-up of 3.22 ± 1.91 years, there were 74 deaths (33.6%) and 86 new cardiovascular events. In the Kaplan-Meier survival analysis, the highest tertile of OPG levels was associated with higher overall mortality (p = 0.005), as well as a higher, although non-significant, incidence of CV events and CV mortality. In contrast, fetuin-A levels did not predict any of these events. OPG levels were directly associated with age, the Charlson comorbidity index (CCI), prevalent cardiovascular disease, carotid intima-media thickness, adiponectin, troponin-I and brain natriuretic peptide (BNP). OPG showed a negative correlation with left ventricular ejection fraction (LVEF) and phosphate levels. In the multivariate Cox proportional hazard analysis, all-cause mortality was associated with the highest tertile of OPG (HR:1.957, p = 0.018), age (HR:1.031, p = 0.036), smoking history (HR:2.122, p = 0.005), the CCI (HR:1.254, p = 0.004), troponin-I (HR:3.894, p = 0.042), IL-18 (HR:1.061, p < 0.001) and albumin levels (HR:0.886, p < 0.001). In the bootstrapping Cox regression analysis, the best cut-off value of OPG associated with mortality was 17.69 pmol/L (95%CI: 5.1-18.02).. OPG, but not fetuin-A levels, are independently associated with overall mortality, as well as clinical and subclinical atherosclerosis and cardiac function, in prevalent hemodialysis patients.

Topics: Aged; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Middle Aged; Mortality; Osteoprotegerin; Prospective Studies; Renal Dialysis

Patients with type I diabetes mellitus (T1DM) have increased incidence of atherosclerosis and cardiovascular disease. Although these complications are unusual in children with T1DM, prevention, and early intervention could decrease morbidity and mortality. Osteoprotegerin (OPG), asymmetric dimethylarginine (ADMA), and Fetuin-A have been associated with increased cardiovascular risk (CVR). Increased OPG and ADMA, and decreased or increased Fetuin-A serum levels have been associated with increased CVR.. Because patients with T1DM have higher CVR we investigated OPG, ADMA, and Fetuin-A, in children with T1DM.. We determined the serum levels of OPG, receptor activator of nuclear factor-κB ligand (RANKL), ADMA, and Fetuin-A by enzyme-linked immunosorbent assay (ELISA) in 56 children with T1DM aged 12.1 ± 3.4 yr and in 46 normal control children, (C) aged 11.3 ± 3.0 yr.. Serum OPG levels were significantly increased in patients with T1DM (3.352 ± 0.73 pmol/L) compared with C (2.75 ± 0.67 pmol/L, p < 0.0001) but RANKL did not change. ADMA was significantly decreased in T1DM compared with C (0.68 ± 0.13 µmol/L versus 0.82 ± 0.18 µmol/L, p < 0.0001). Fetuin-A was similar in T1DM (0.551 ± 0.13 g/L) and C (0.540 ± 0.11 g/L) subjects. OPG was positively associated with glycosylated hemoglobin A1c (p < 0.001) and negatively associated with BMI (p < 0.01). ADMA and Fetuin-A were not associated with A1c and ADMA was only negatively associated with age (p < 0.05).. OPG is increased, ADMA is decreased, but RANKL and Fetuin-A are unchanged in T1DM children. Whereas increased OPG has been firmly related to increased CVR, more studies, especially longitudinal studies, are needed to delineate the role and clinical significance of decreased ADMA and if Fetuin-A has any role in T1DM.

Topics: Adolescent; alpha-2-HS-Glycoprotein; Arginine; Biomarkers; Cardiovascular Diseases; Child; Cohort Studies; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Cardiomyopathies; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Greece; Humans; Male; Osteoprotegerin; RANK Ligand; Reproducibility of Results

Elevated osteoprotegerin (OPG) levels have been reported in patients with diabetes complications. We investigated whether plasma OPG levels can be used as a marker of cardiovascular risk in children and adolescents with type 1 diabetes (T1D).. Plasma blood samples were obtained from 243 subjects (143 children and adolescents with T1D and 100 healthy controls). OPG concentrations were measured by enzyme-linked immunosorbent assay (ELISA) method. All data were analyzed by using PASW statistics 18.. A significant higher plasma OPG level was found in children with T1D compared to controls (p < 0.001). A significant increase of OPG levels has been related to the glucose level ≥ 7 mmol/L (2.44 [0.01-6.22] vs. 2.16 [0.13-6.22] pmol/L, p = 0.019), microalbuminuria ≥ 30 mg/24 h (3.71 [0.160-6.03] vs. 2.26 [0.01-6.22] pmol/L, p < 0.001), and cystatin-C ≥ 0.789 mg/L (2.64 [0.37-6.22] vs. 2.11 [0.01-5.82] pmol/L, p < 0.001). We noted a significant higher frequency of children with increased cystatin-C levels in the group with elevated plasma level of OPG compared with those with normal levels (49 vs. 18%, respectively) with an odds ratio (OR) = 4.42 [1.41-13.84] (p = 0.006). We showed a significant increase of OPG levels when the number of cardiovascular risk factors exceeds 3 (p = 0.001).. OPG may be a potential biomarker of cardiovascular risk in T1D. Implementation of OPG determination in the clinical laboratory setting would be useful in order to better stratify patients and to assess the most adequate treatment.

Topics: Adolescent; Biomarkers; Blood Glucose; Cardiovascular Diseases; Case-Control Studies; Child; Child, Preschool; Comorbidity; Cystatin C; Diabetes Mellitus, Type 1; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Humans; Male; Osteoprotegerin; Reproducibility of Results; Risk Factors; Tunisia; Up-Regulation

HIV-infected patients appear to have a significantly greater risk of non-AIDS comorbidities such as osteoporosis and atherosclerosis. Subjects with osteoporosis are at a higher risk of developing cardiovascular disease than those with normal bone mass, therefore a possible relation between these two conditions can be hypothesized. In the setting of HIV infection, several factors might contribute to bone disease and endothelial dysfunction. The aim of our study was to evaluate the relationship between bone and cardiovascular disease and to investigate the role of traditional factors, T-cell phenotype and osteoprotegerin in HIV positive subjects on effective antiretroviral therapy. We included 94 HIV positive subjects on antiretroviral therapy with virological suppression and 41 healthy subjects matched for age and gender as a control group. Carotid-Intima Media Thickness (c-IMT) and bone mineral density (BMD) were performed by ultrasound and DEXA, respectively. CD4+/CD8+ T-cell activation, senescence and osteoprotegerin plasma levels were measured by flow-cytometry and ELISA, respectively. Among HIV positive patients, 56.4% had osteopenia/osteoporosis and 45.7% had pathological c-IMT (>0.9 mm). Subjects with pathological c-IMT and BMD exhibited higher CD4+ and CD8+ activated, CD8+ senescent and osteoprotegerin than subjects with normal c-IMT and BMD. HIV positive subjects with osteopenia/osteoporosis had higher c-IMT than subjects with normal BMD, and linear regression analysis showed a negative correlation between BMD and c-IMT. Several factors are implicated in the pathogenesis of non-AIDS comorbidities in HIV positive patients. Osteoprotegerin together with inflammation and immunosenescence in HIV positive patients could affect bone and vascular system and could be considered as a possible common link between these two diseases.

Topics: Anti-HIV Agents; Biomarkers; Bone Diseases; Cardiovascular Diseases; Carotid Intima-Media Thickness; Comorbidity; Female; HIV Infections; Humans; Immunosenescence; Male; Middle Aged; Osteoprotegerin; Phenotype; T-Lymphocytes

To evaluate osteoprotegerin (OPG) levels in relation to cardiovascular (CV) risk factors in patients with chronic kidney disease (CKD) on different regimens of renal replacement therapy.. A total of 143 patients with CKD and 30 healthy controls were included in this study and divided into five categories, including predialysis patients with chronic renal failure (preD; n = 36), chronic peritoneal dialysis patients (PD; n = 36), hemodialysis patients (HD; n = 35), renal transplant patients (RT; n = 36), and controls (n = 30). Data on demographics, concomitant diseases and CV risk factors, serum OPG levels, and correlates of serum OPG levels were determined.. Serum OPG (pmol/l) levels were significantly higher in HD (P <0.001 for each), PD (P <0.001 for each), and preD (P <0.01 vs. control, P <0.05 vs. RT) groups than RT and control groups. Diabetics than nondiabetics in HD (P = 0.008), PD (P = 0.024), and RT (P = 0.004) groups and males than females in PD group (P = 0.021) had higher OPG levels. Serum OPG levels were associated positively with age in HD (P <0.001), PD (P = 0.001), and in overall population (P <0.001).. Our findings revealed increased serum levels of OPG in dialysis and preD patients compared to RT and controls. In the patient groups receiving two dialysis treatment, the levels were worse, indicating a more pronounced vascular injury. Age, C-reactive protein (CRP), high-density lipoprotein cholesterol (HDL-C), and cystatin C (CysC) in CKD patients, CRP and PTH in the control subjects, and age and BMI in the overall population were the significant correlates of serum OPG levels.

Topics: Adult; Aged; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Cystatin C; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lipoproteins, HDL; Male; Middle Aged; Osteoprotegerin; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors

Vascular injury and dysfunction contribute to cardiovascular disease, the leading cause of death in patients with chronic kidney disease (CKD). Osteoprotegerin (OPG) is a soluble member of the tumor necrosis factor receptor superfamily that has been linked to atherogenesis and endothelial dysfunction. Elevated circulating OPG levels predict future cardiovascular events (CVE). Our aim was to evaluate the determinants of circulating OPG levels, to investigate the relationship between OPG and markers of vascular damage and to test whether OPG improves risk stratification for future CVE beyond traditional and renal-specific risk factors in a CKD population. 291 patients with CKD stage 1-5 not on dialysis were included in the study. In the multivariate analysis, OPG was a significant predictor for flow-mediated dilatation, but not for carotid intima media thickness levels. During follow-up (median 36 months, IQR = 32-42 months), 87 patients had CVE. In the Cox survival analysis, OPG levels were independently associated with CVE even after adjustment for traditional and renal-specific cardiovascular risk factors. The addition of OPG to a model based on commonly used cardiovascular factors significantly improved the reclassification abilities of the model for predicting CVE. We show for the first time that OPG improves risk stratification for CVE in a non-dialysis CKD population, above and beyond a model with established traditional and renal-specific cardiovascular risk factors, including estimated glomerular filtration rate and fibroblast growth factor 23.

Topics: Adult; Aged; Atherosclerosis; Cardiovascular Diseases; Carotid Intima-Media Thickness; Female; Glomerular Filtration Rate; Humans; Inflammation; Male; Middle Aged; Osteoprotegerin; Renal Insufficiency, Chronic; Risk Factors

The high prevalence of cardiovascular morbidity and mortality among patients with chronic kidney disease (CKD) is observed especially in those undergoing dialysis. Osteoprotegerin (OPG) and its ligands, receptor activator of nuclear factor kappa-B ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have been associated with cardiovascular complications. Our aim was to study their role as cardiovascular risk factors in stage 5 CKD patients.. OPG, RANKL and TRAIL concentrations were measured in 69 hemodialyzed CKD patients and 35 healthy volunteers. In CKD patients, cardiovascular dysfunction was assessed with aortic pulse wave velocity (AoPWV), carotid artery intima-media thickness (CCA-IMT), coronary artery calcium score (CACS) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) serum concentrations. Cardiovascular and overall mortality data were collected during a 7-years follow-up.. OPG plasma concentrations were higher in CKD patients comparing to controls. Total soluble RANKL was lower and OPG/RANKL ratio higher in patients. Soluble TRAIL concentrations did not differ between the groups and OPG/TRAIL ratio was higher in CKD patients. OPG and OPG/TRAIL positively predicted long-term mortality (all-cause and cardiovascular) in CKD patients. OPG positively correlated with AoPWV, CCA-IMT and NT-proBNP whereas OPG/TRAIL with AoPWV and NT-proBNP. Described relationships were independent of classical and non-classical cardiovascular risk factors, with exception of age.. Our study confirmed the role of OPG as a biomarker of cardiovascular dysfunction and a predictor of mortality in stage 5 CKD. OPG/TRAIL ratio can be proposed as a predictor of cardiovascular dysfunction and mortality.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Case-Control Studies; Female; Humans; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; Natriuretic Peptide, Brain; Osteoprotegerin; Proportional Hazards Models; RANK Ligand; Renal Insufficiency; Solubility; TNF-Related Apoptosis-Inducing Ligand

Numerous biomarkers have been shown to associate with clinical endpoints in chronic kidney disease (CKD). There is limited evidence whether biomarkers improve risk prediction in relation to clinical outcomes. Our study investigates whether a small suite of key chronic kidney disease-mineral and bone disorder biomarkers could be used to enhance risk assessment in CKD.. Fetuin-A, fibroblast growth factor-23 and osteoprotegerin were measured on baseline plasma samples from 463 patients recruited to the Chronic Renal Insufficiency Standards Implementation Study. The biomarkers were analysed in relation to progression to end stage kidney disease, death and major cardiovascular events.. Over a median follow up of 46 months (interquartile range 21-69), fibroblast growth factor-23 was associated with risk for renal replacement therapy (hazard ratio (HR) 1.35, P = 0.05, 95% confidence interval (CI) 1.001-1.820), cardiovascular events (HR 1.74 P < 0.001, 95% CI 1.303-1.305) and death (HR 1.4 P = 0.005, 95% CI 1.109-1.767). Osteoprotegerin was associated with risk for death (HR 1.06, P = 0.03, 95% CI 1.006-1.117). There was no clear association between Fetuin-A and any of the clinical endpoints. The addition of biomarkers to risk models led to marginal improvement in model discrimination and reclassification.. Biomarkers are often associated with clinical endpoints, and we observed such associations in our study of patients with advanced CKD. However, the markers analysed in our study were of limited benefit in improving the prediction of these outcomes. Any extra information biomarkers may provide to improve risk prediction in clinical practice needs to be carefully balanced against the potential cost of these tools.

Topics: Aged; alpha-2-HS-Glycoprotein; Area Under Curve; Biomarkers; Cardiovascular Diseases; Disease Progression; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Osteoprotegerin; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; ROC Curve; Time Factors

Nutritional strategies can be effective for the prevention of menopause-related diseases, such as osteoporosis and cardiovascular disease. Our aim was to evaluate the effects of a dairy product enriched in polyunsaturated fatty acids, calcium, oleic acid, and vitamins on cardiovascular markers and bone metabolism in postmenopausal women with moderate cardiovascular risk.. One hundred seventeen healthy postmenopausal women (aged 45 ± 7.7 years) were allocated to 2 groups: the intervention group (IG; n = 63), who consumed 0.5 L/day of a low-lactose skimmed milk enriched with 40 mg/100 mL of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), 0.54 g/100 mL oleic acid, and vitamins, and the control group (CG; n = 54), who consumed 0.5 L/day of semiskimmed milk 0.5 L/day enriched with vitamins A and D.. After 12 months, in the IG there was an improvement in lipid profile: a -5.78% decrease in total cholesterol (p = 0.010), -9.79% (p = 0.004) in low-density lipoprotein (LDL) cholesterol, -9.56% (p < 0.001) in total cholesterol (TC)/high-density lipoprotein (HDL) ratio, and -3.38% in LDL/HDL ratio (p < 0.001). No changes were observed in the CG. In the IG we observed a decrease of -28.20% in high-sensitivity C-reactive protein (hs-CRP; p = 0.012). There was no effect on bone turnover markers or serum osteoprotegerin (OPG) in either of the study groups. In the IG, receptor activator of nuclear factor κB ligand (RANKL) was reduced -17.64% (p = 0.003), with no effect in the CG.. In postmenopausal women with moderate cardiovascular risk, dietary supplementation with a dairy drink enriched with fatty acids (EPA+DHA), oleic acid, minerals, and vitamins induces a positive effect on cardiovascular risk and parameters of bone metabolism. Its regular consumption may be a useful nutritional support for postmenopausal women.

Topics: Adult; Animals; Biomarkers; Bone and Bones; Bone Remodeling; C-Reactive Protein; Calcium, Dietary; Cardiovascular Diseases; Fatty Acids, Omega-3; Female; Food, Fortified; Humans; Lipids; Middle Aged; Milk; Oleic Acid; Osteoprotegerin; Postmenopause; Risk Factors

Cardiovascular disease is a cardinal trait of Turner syndrome (TS), causing half of the threefold excess mortality. As osteoprotegerin (OPG) is a potential biomarker of cardiovascular disease, this cross-sectional and prospective study aimed at elucidating OPG levels in TS and its relationship to aortic diameter as well as validated cardiovascular risk markers.. Adult women with TS (n = 99) were examined thrice (mean follow-up 4·7 ± 0·5 years), and 68 age-matched healthy female controls were examined once. Aortic diameter was assessed by cardiovascular magnetic resonance. Twenty-four-hours blood pressure monitoring and biochemical assessments were also performed.. Osteoprotegerin levels (median with range) were lower in TS (777 [326-10 569] ng/l) compared with controls (979 [398-1987] ng/l; P < 0·05) and did not change during follow-up. The OPG concentration was higher among women with TS older than 50 years of age (996 [542-4996] vs 756 [326-10 569] ng/l; P < 0·05) with a trend towards a higher OPG in TS who were on antihypertensive medication (938 [490-2638] vs 752 [326-10 569] ng/l; P = 0·09). Contrary to controls, OPG levels correlated with BSA-indexed aortic diameter (r = 0·31-0·45; P < 0·05), age (r = 0·29; P < 0·05) and high-sensitivity C-reactive protein (r = 0·23; P = 0·02) and inversely with BSA (r = -0·20; P < 0·05), weight (r = -0·23; P < 0·05) and plasma oestradiol levels (r = -0·34; P < 0·05).. Levels of OPG are lower in TS and correlate with aortic diameter, age, BSA, weight and oestradiol in TS, but not controls. Future studies are needed to assess whether OPG may serve as a biomarker of aortic or cardiovascular disease in TS.

Topics: Adolescent; Adult; Anthropometry; Blood Pressure; Cardiovascular Diseases; Cross-Sectional Studies; Estradiol; Female; Humans; Karyotype; Magnetic Resonance Imaging; Male; Osteoprotegerin; Prospective Studies; Risk Factors; Turner Syndrome; Young Adult

To investigate the relationships of osteoprotegerin (OPG) concentrations to brachial artery flow-mediated vasodilation (FMD) and the carotid artery intima media thickness (CIMT) in polycystic ovary syndrome (PCOS).. Thirty-seven women with PCOS and 41 controls matched for body mass index (BMI) and age were included in study. The serum OPG concentrations, hormonal and metabolic profiles were measured in women with PCOS and in control group. The CIMT and brachial artery FMD were evaluated in both groups.. The mean serum concentrations of all hormones were comparable, except LH, which was higher in women with PCOS. Lipid parameters were similar between groups. There were no differences between groups with respect to fasting glucose, 2-h glucose, fasting insulin, HbA1c and HOMA-IR. The mean osteoprotogerin concentrations were higher in PCOS group (11.39 ± 2.29 vs. 10.22 ± 2.25 pmol/L, P = 0.026). The mean CIMT was higher in PCOS group than control group (0.52 ± 0.058 vs. 0.45 ± 0.059 mm, P < 0.01). The mean brachial artery FMD was lower in PCOS group (0.068 ± 0.022 vs. 0.055 ± 0.029, P = 0.017).. We found high osteoprotogerin concentrations, increased CIMT and decreased FMD, in women with PCOS. However, there was no correlation between osteoprotegerin and cardiovascular risk markers.

Topics: Adult; Body Mass Index; Brachial Artery; Cardiovascular Diseases; Carotid Intima-Media Thickness; Case-Control Studies; Cross-Sectional Studies; Endothelium, Vascular; Female; Humans; Lipids; Obesity; Osteoprotegerin; Polycystic Ovary Syndrome; Risk Factors; Vasodilation

We determined whether osteoprotegerin (OPG) concentrations are associated with established cardiovascular disease (CVD) among patients with rheumatoid arthritis (RA).. OPG concentrations were measured by ELISA in 151 patients with RA (54 with CVD) and 62 age-matched control subjects without CVD. Established CVD was composed of documented ischemic heart disease, cerebrovascular disease, and peripheral artery disease.. In patients with RA, age, body mass index (BMI), rheumatoid factor (RF) positivity, anticyclic citrullinated peptide (anti-CCP) antibody positivity, and joint erosion status were associated with OPG concentrations [partial R (p) = 0.175 (0.03), -0.277 (0.0009), 0.323 (< 0.0001), 0.217 (0.008), and 0.159 (0.05), respectively]. Median (interquartile range) OPG concentrations increased from 6.38 (3.46-9.31) to 7.07 (5.04-10.65) and 8.64 (6.00-11.52) ng/ml in controls and patients with RA who had CVD and those who did not, respectively (p = 0.0002). Upon adjustment for age, sex, traditional risk factors, and BMI in mixed regression models, OPG concentrations remained lower in controls compared to patients with RA without CVD (p = 0.05) and in the latter compared to those with CVD (p = 0.03); the association of OPG concentrations with CVD among patients with RA also persisted after additional adjustment for RF and anti-CCP antibody positivity, and erosion status (p = 0.04).. OPG concentrations are associated with disease severity and CVD prevalence in patients with RA. Whether consideration of OPG concentrations can improve CVD risk stratification in RA merits future longitudinal investigation.

Topics: Aged; Aged, 80 and over; Arthritis, Rheumatoid; Cardiovascular Diseases; Female; Humans; Male; Middle Aged; Osteoprotegerin; Risk Factors; Severity of Illness Index

To assess the osteoprotegerin (OPG) relationship with cardiovascular complications in hemodialysis (HD) patients.. The study included 87 HD patients. Clinical characteristics, ankle-arm index (AAI), OPG and mineral markers levels were recorded. Arterial intimal calcification (AIC) and arterial medial calcification (AMC) were registered.. OPG levels were increased in HD patients. Patients with AIC (p = 0.006)/ AMC (p = 0.01) had higher OPG levels. OPG did not have any relation with cardiovascular diseases. OPG correlated positively with age, increased HD vintage and inversely with albumin and AAI. OPG has not been a risk factor for VC or cardiovascular disease.. OPG rising could be a reaction in defense to vascular aggression, because OPG was associated with VC, but not with vascular disease.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Biomarkers; Blood Pressure; Calcinosis; Cardiovascular Diseases; Cross-Sectional Studies; Female; Humans; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Osteoprotegerin; Prospective Studies; Renal Dialysis; Risk Factors; Tunica Intima; Tunica Media; Young Adult

Chronic kidney disease-mineral and bone disorder (CKD-MBD) ranks among clinically and pathogenetically significant complications in patients with CKD. Numerous factors are involved in its development, and histomorphometric analysis of the bone tissue is still necessary for accurate diagnosis.. The open, pilot, prospective study aimed at performing a comprehensive histomorphometric bone analysis in 26 dialysis patients and assessing the relationships of different types of CKD-MBD to selected parameters of calcium and phosphate metabolism, densitometry, activity of parathyroid glands, presence of diabetes mellitus, and duration of dialysis treatment.. Comparison of the histomorphometric characteristics demonstrated statistically significant correlations between the volume of bone trabeculae and s-procollagen 1 (.754) as well as s-calcitonin (.856). Similarly, there was a positive correlation between the size of tetracycline lines and volume of bone trabeculae (.705) and a strong negative correlation with the thickness of trabeculae (-.442). When assessing the serum levels of s-osteoprotegerin and serum RANKL, there was a correlation with osteoid thickness and bone trabeculae thickness. In case of s-osteoprotegerin, a statistical power was demonstrated in relation to osteoid thickness (.880); in case of s-RANKL, a statistical power was demonstrated in relation to the thickness of trabeculae (.830). When assessing the influence of dialysis duration, relationships to the volume of trabecular bone (.665) and volume of bone trabeculae (.949) were demonstrated. Finally, a relationship between s-1,25-hydroxyvitamin D and s-osteoprotegerin was observed (.739); also the relationships demonstrated were significantly lower volume of bone trabeculae in men (p = 0.067) and lower values of s-osteocalcin and s-procollagen 1 in diabetic patients (p = 0.014).. The results provide new noninvasive possibilities of CKD-MBD detection that are based on selected serum parameters of bone metabolism. Presented are possibilities of noninvasive assessment of different types of CKD-MBD using serum osteomarkers in relation to comprehensive CKD-MBD histomorphometry.

Topics: Aged; Biomarkers; Bone and Bones; Bone Density; Calcitriol; Calcium; Cardiovascular Diseases; Chronic Kidney Disease-Mineral and Bone Disorder; Czech Republic; Female; Humans; Kidney; Male; Osteocalcin; Osteoprotegerin; Parathyroid Hormone; Pilot Projects; Prospective Studies; RANK Ligand; Renal Dialysis; Renal Insufficiency, Chronic; Reproducibility of Results; Risk Factors

The objective of the study was to determine the relationship between common carotid artery intima-media thickness (CCA-IMT) and histologically assessed calcification of radial artery in relation to clinical features and laboratory markers of bone and mineral metabolism, inflammation, and oxidative stress in patients with stage 5 chronic kidney disease (CKD).. The study comprised 59 patients (36 hemodialyzed, 23 predialysis). CCA-IMT was measured by ultrasonography; the biochemical parameters examined were assessed using routine laboratory methods, ELISA micro-plate immunoassays and spectrophotometry. Fragments of radial artery obtained during creation of hemodialysis access were cryosectioned and stained for calcifications using von Kossa method and alizarin red.. Glucose, osteoprotegerin, pentraxin 3 and Framingham risk score significantly correlated with CCA-IMT. In multiple regression analysis, OPG positively predicted CCA-IMT. Radial artery calcifications were found in 34 patients who showed higher CCA-IMT (0.98 ± 0.13 vs 0.86 ± 0.14 mm; P = 0.006). Higher CCA-IMT values were also associated with more advanced calcifications. CCA-IMT and the presence of plaques in common carotid artery were positive predictors of radial artery calcifications, independent of dialysis status, Framingham risk score, CRP and Ca x Pi [OR for calcifications 2.19 (1.08-4.45) per 0.1 mm increase in CCA-IMT]. The presence of radial artery calcifications was a significant predictor of mortality, independent of dialysis status and Framingham risk score [HR 3.16 (1.03-9.64)].. In CKD patients, CCA-IMT examination can be used as a surrogate measure to assess the incidence and severity of arterial medial calcification which is associated with poor clinical outcome in these patients.

Topics: Adult; Aged; Aged, 80 and over; alpha-2-HS-Glycoprotein; Blood Glucose; C-Reactive Protein; Cardiovascular Diseases; Carotid Artery, Common; Carotid Intima-Media Thickness; Cohort Studies; Coronary Artery Disease; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Incidence; Inflammation; Insulin Resistance; Interleukin-6; Kidney Failure, Chronic; Logistic Models; Middle Aged; Multivariate Analysis; Osteocalcin; Osteopontin; Osteoprotegerin; Oxidative Stress; Radial Artery; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Serum Amyloid P-Component; Severity of Illness Index; Tunica Media; Vascular Calcification

Abdominal aortic calcification (AC) has been reported to be associated with cardiovascular disease (CVD) in hemodialysis patients but is rarely discussed in peritoneal dialysis (PD) patients. We examined the independent predictors and predictive power for survival of AC in prevalent PD patients.. AC was detected by computed tomography (CT) and represented as the percentage of the total aortic cross-section area affected by AC (%AC). The predictors of %AC ≥ 15 were examined by multiple logistic regression analysis. Cox proportional hazard analysis was used to determine the hazard ratios associated with high %AC. A total of 183 PD patients were recruited to receive CT scans and divided into group 1 (%AC < 15, n = 97), group 2 (%AC ≥ 15, n = 41), and group 3 (diabetic patients, n = 45). Group 1 patients had lower osteoprotegerin (OPG) levels than group 2 patients (798 ± 378 vs. 1308 ± 1350 pg/mL, p < 0.05). The independent predictors for %AC ≥ 15 included the atherogenic index, OPG, and C-reactive protein (CRP). The age-adjusted hazard ratios associated with %AC ≥ 15 were 3.46 (p = 0.043) for mortality and 1.90 (p = 0.007) for hospitalization.. %AC can predict mortality and morbidity in non-diabetic PD patients, and 15% is a good cut-off value for such predictions. There are complex associations among mineral metabolism, inflammation, and dyslipidemia in the pathogenesis of AC.

Topics: Adult; Aged; Aorta, Abdominal; Biomarkers; C-Reactive Protein; Calcinosis; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus; Dyslipidemias; Female; Follow-Up Studies; Humans; Inflammation; Male; Middle Aged; Osteoprotegerin; Peritoneal Dialysis; Prospective Studies; Taiwan; Tomography, X-Ray Computed

Topics: Age Factors; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Data Collection; Humans; Male; Middle Aged; Osteoprotegerin; Population Surveillance; Risk Factors

Osteoprotegerin (OPG), an osteoclastogenesis inhibitor implicated in bone remodelling, has emerged as a potential biomarker for cardiovascular disease. In order to implement OPG determination in the clinical laboratory, it is crucial to identify the most appropriate specimen type, preparation and measurement conditions. The present study focuses on identifying the pre-analytical variables that may influence OPG measurements.. Serum and plasma (in EDTA, heparin and citrate) were collected from 45 healthy volunteers (men (n=21, 46.7%), women (n=24, 53.3%)). OPG was analysed by ELISA. The influence of the centrifugation speed, the number of freeze-thaw cycles, delay in sample processing, thermo-stability and endogenous interfering agents (haemolysis, triglycerides, bilirubin, cholesterol and RANKL) were studied.. OPG concentrations were significantly lower (p<0.0001) in serum (1015±357 pg/mL) than in all plasma samples (1314±448 pg/mL in EDTA, 1209±417 pg/mL in heparin and 1260±498 pg/mL in citrate). Increasing centrifugation speed (200 g to 3000 g) did not change serum OPG concentration (p=0.88). However, OPG concentration significantly increased when centrifuged serum samples were stored at 48 h at room temperature (p<0.0001). Repeated freeze-thaw cycles did not modify OPG levels until 4 cycles (p<0.0001). Increasing time before processing the samples (2 h and 6 h) raised OPG concentrations both at room temperature (p<0.0001) or 4°C (p<0.001). Positive concentration-dependent interference of triglycerides was found in the analysed pooled samples; however, OPG concentrations were falsely diminished with haemoglobin interference. Bilirubin, cholesterol and RANKL did not interfere with OPG measurements.

Topics: Adult; Bilirubin; Biomarkers; Cardiovascular Diseases; Cholesterol; Female; Humans; Male; Osteoprotegerin; Plasma; RANK Ligand; Serum; Triglycerides

Osteoprotegerin (OPG), a soluble member of tumor necrosis factor receptor superfamily that inhibits bone resorption, has been suggested as a cardiovascular risk factor in humans. In this study, we aim to investigate the potential relationship between OPG and MetS (MetS) in a sub-Saharan African population.. Four hundred and eleven volunteers (152 men, 259 women) aged ≥18 years recruited from the general population in Douala and Edea, Cameroon participated in this study. Anthropometric parameters measured and blood samples were collected for glucose, serum lipids and OPG concentrations measurements. Mean differences of the variables in different groups were compared using Students' t test. We performed logistic regressions to analyze the impact of independent factors on the relation between OPG and MetS outcome. MetS was defined using the Joint Interim Statement 2009.. OPG levels did not vary significantly between both men and women with and without MetS (both P>0.05). However, with high fasting blood glucose (≥5.6 mmol/L) had a significantly higher OPG level than those with lower glucose level (P=0.014). In multiple logistic regression analysis, MetS did not show any significant association with serum OPG levels in men and women after adjusting for age, physical activity, alcohol consumption and menopausal status in women (P=0.720 and P=0.930 respectively).. This study failed to demonstrate any relationship between OPG and MetS. Nevertheless, the positive association between blood glucose and OPG levels reveals that OPG might be involved in cardiovascular risk development in this sub-Saharan African population.

Topics: Adult; Africa South of the Sahara; Aged; Aging; Alcohol Drinking; Blood Glucose; Cardiovascular Diseases; Exercise; Fasting; Female; Humans; Logistic Models; Male; Menopause; Metabolic Syndrome; Middle Aged; Osteoprotegerin; Risk Factors; Sex Factors

To study the role of the bone mineral metabolic mediators osteoprotegerin (OPG) and fibroblast growth factor 23 (FGF-23) in the mechanisms of cardiovascular events (CVEs) in chronic kidney disease (CKD).. Sixty-eight patients (30 men and 38 women) aged 38 to 64 years (mean age 49 +/- 6.3 years) with Stages III-VD CKD were examined. The stages of CKD were determined in accordance with the NKF-K/DOQI guidelines; glomerular filtration rate was calculated using the CKD-EPI formula. Serum OPG and FGF-23 were examined in all the patients, by applying commercial enzyme immunoassay kits. Doppler echocardiography was performed to evaluate the morphofunctional state of the left ventricle (LV).. As renal failure progressed from Stage III to Stage VD CKD, the examined patients had higher serum OPG and FGF-23 concentrations. The levels of OPG and FGF-23 and the morphofunctional indicators of LV lesion, blood pressure, and anemia showed a strong direct correlation that preserved its significance in analyzing the factors in question in relation to the function of the kidneys and the pattern of cardiovascular system lesion.. The morphogenetic proteins OPG and FGF-23 seem to play a significant role not only in bone remodeling processes, but also in the development of CVEs in CKD.

Topics: Adult; Cardiovascular Diseases; Disease Progression; Echocardiography, Doppler; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Male; Middle Aged; Osteoprotegerin; Renal Insufficiency, Chronic; Severity of Illness Index

Traditional clinical risk factors are associated with inflammation cross-sectionally, but associations of longitudinal variation in inflammatory biomarkers with corresponding changes in clinical risk factors are incompletely described. We sought to analyze clinical factors associated with change in inflammation in the community.. We studied 3013 Framingham Offspring (n = 2735) and Omni Cohort (n = 278) participants (mean age 59 years, 55% women, 9% ethnic/racial minority) who attended two consecutive examination cycles (mean 6.7 years apart). We selected ten inflammatory biomarkers representing distinctive biological functions: C-reactive protein (CRP), intercellular adhesion molecule-1, interleukin-6, isoprostanes, lipoprotein-associated phospholipase-2 (Lp-PLA2) activity, Lp-PLA2-mass, monocyte chemoattractant protein-1, osteoprotegerin, P-selectin, and tumor necrosis factor receptor II (TNFRII). We constructed multivariable-adjusted regression models to assess the relations of baseline, follow-up and change in clinical risk factors with change in biomarker concentrations over time.. Baseline, follow-up and change in clinical risk factors explain a moderate amount of the variation in biomarker concentrations across 2 consecutive examinations (ranging from r(2) = 0.28 [TNFRII] up to 0.52 [Lp-PLA2-mass]). In multivariable models, increasing body-mass index, smoking initiation, worsening lipid profile, and increasing waist size were associated with increasing concentrations of several biomarkers. Conversely, hypercholesterolemia therapy and hormone replacement cessation were associated with decreasing concentrations of biomarkers such as CRP, Lp-PLA2-mass and activity.. Cardiovascular risk factors have different patterns of association with longitudinal change in inflammatory biomarkers and explain modest amounts of variability in biomarker concentrations. Nevertheless, a substantial proportion of longitudinal change in inflammatory markers is not explained by traditional risk factors.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Chemokine CCL2; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Isoprostanes; Longitudinal Studies; Male; Massachusetts; Middle Aged; Osteoprotegerin; P-Selectin; Receptors, Tumor Necrosis Factor, Type II; Risk Factors; Vasculitis

Von Willebrand factor (VWF) is pivotal in arterial thrombosis, and osteoprotegerin (OPG) is besides being a bone protein also related to cardiovascular diseases. OPG can bind VWF, but the significance of this interaction is not known.. The aim was to develop an assay for measurement of von Willebrand factor-osteoprotegerin complex (VWF:OPG) in human plasma. Furthermore, the significance of VWF:OPG complex as a marker of cardiovascular disease (CVD) was evaluated.. A sandwich ELISA for quantification of VWF:OPG was developed using a polyclonal rabbit anti-human VWF capturing antibody and a monoclonal anti-human OPG detecting antibody. Samples were quantified relative to a standard curve obtained from dilutions of a plasma pool from healthy individuals. The assay was evaluated in two groups of patients with CVD and two groups of asymptomatic individuals with and without documented coronary calcification (total n=118).. The assay detected VWF:OPG complexes in human plasma, while no significant signal was observed when testing solutions containing VWF or recombinant OPG alone. Importantly, the ELISA assay was able to detect in vitro formed complexes between human VWF and recombinant OPG in a dose-dependent manner. There was a large inter-individual variation in plasma VWF:OPG levels, but we found no significant differences in the level of VWF:OPG complexes between the four groups. Thus, we conclude that increasing OPG plasma levels in atherosclerotic CVD are not derived from increased levels of complexed form of VWF and OPG, but are more likely due to increased amounts of OPG secreted into the circulation.

Topics: Aged; Cardiovascular Diseases; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Osteoprotegerin; von Willebrand Diseases; von Willebrand Factor

Arterial thickening contributes to elevated cardiovascular risk in patients on maintenance renal replacement therapy. The common carotid artery intima-media thickness (CCA-IMT) is an early atherosclerotic marker and may be used to assess the stratification of atherosclerotic advancement and resultant arterial calcification.. The aim of the study was to evaluate the associations between atherosclerotic changes in the common carotid arteries expressed as the CCA-IMT and the body mass index (BMI), serum lipid levels, C‑reactive protein (CRP), and selected bone metabolism parameters including phosphorus, calcium, intact parathormone (iPTH), alkaline phosphatase, osteopontin, osteoprotegerin, osteocalcin, fetuin A, and fibroblast growth factor‑23 (FGF‑23) in patients treated with peritoneal dialysis.. The study included 67 patients with chronic kidney disease (36 men and 31 women) aged 53 ±13 years (range, 19-75 years) treated with peritoneal dialysis for 30 ±24 months. The CCA‑IMT was assessed by ultrasonography using Acuson 128/10 XP. The BMI was calculated using the Quetelet formula. Serum lipid levels, phosphorus, calcium, iPTH, alkaline phosphatase, and CRP were measured using standard laboratory methods, while fetuin A, osteocalcin, osteoprotegerin, osteopontin, and FGF‑23 using commercial enzyme‑linked immunosorbent assay kits.. Positive correlations were observed between CCA-IMT and age (r = 0.54, P <0.0001), BMI (r = 0.39, P = 0.003), and osteoprotegerin (r = 0.38, P = 0.004). In a multiple regression analysis, age (r = 0.41, P = 0.01), osteocalcin (r = 0.34, P = 0.04), and log‑transformed osteoprotegerin values (r = 0.38, P = 0.02) remained independently associated with the CCA-IMT. The highest CCA‑IMT values (0.85 ±0.21) were observed in patients with osteoprotegerin concentrations in the upper tertile. Osteoprotegerin concentrations strongly and positively correlated with the duration of dialysis treatment (r = 0.55, P <0.0001).. The CCA‑IMT has been shown to be a reliable noninvasive measure of subclinical atherosclerosis and, therefore, of associated increased vascular risk. Elevated serum osteoprotegerin levels may be useful as a prognostic marker of cardiovascular risk in dialyzed patients.

Topics: Adult; Aged; Atherosclerosis; Biomarkers; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Carotid Artery, Common; Carotid Intima-Media Thickness; Female; Fibroblast Growth Factor-23; Humans; Lipids; Male; Middle Aged; Osteoprotegerin; Peritoneal Dialysis; Prognosis; Renal Insufficiency, Chronic; Risk Factors

Osteoprotegerin (OPG) is involved in the process of vascular calcification. We investigated whether OPG is associated with the development and progression of diabetes complications in adults with type 1 diabetes (T1D).. Serum OPG was measured in 1,939 adults with T1D participating in the Finnish Diabetic Nephropathy (FinnDiane) Study. Patients with end-stage renal disease (dialysis or transplantation) at baseline were excluded from analysis. Data on cardiovascular (CV) events and mortality during follow-up were verified from hospital discharge registries (ICD codes) and the Finnish National Death Registry, respectively. The follow-up time was 10.4 ± 2.0 (mean ± SD) years.. Only patients with macroalbuminuria and/or renal impairment had elevated OPG concentrations, when compared with participants without overt kidney disease. Patients with retinopathy or CV disease also had higher OPG concentrations, but this was attributable to their higher frequency of chronic kidney disease. OPG predicted an incident CV event (hazard ratio 1.21 [95% CI 1.01-1.45]; P = 0.035) and peripheral vascular disease/amputation events (1.46 [1.13-1.88]; P = 0.004) during follow-up.. We showed that serum OPG is an independent predictor of CV complications. OPG may be directly involved in extraosseous calcification, resulting in stiffening of the arteries and subsequent vascular insufficiency in patients with T1D.

Topics: Adult; Albuminuria; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Female; Finland; Humans; Male; Osteoprotegerin

Osteoprotegerin (OPG), osteopontin (OPN) and matrix Gla protein (MGP) are markers of bone metabolism but they are also involved in vascular calcification. However, their precise role is not completely understood. Arterial stiffness is considered an independent predictor of cardiovascular events and it may be one of the causes of the increased cardiovascular risk associated with postmenopausal status. Medial and intimal calcification may increase arterial stiffness. The aim of our study was to assess the relationship of OPG, OPN and MGP with aortic pulse wave velocity (aPWV) as a marker of arterial stiffness in postmenopausal women.. Circulating OPG, OPN and serum total MGP were measured in 144 postmenopausal women using the enzyme-linked immunosorbent assay method. Aortic PWV was determined by an oscillometric method.. Osteoprotegerin correlated with age (p<0.001, r=0.27), aPWV (p<0.001, r=0.32) and hypersensitive C reactive protein (hsCRP) (p<0.001, r=0.37), OPN correlated directly with hsCRP (p<0.001, r=0.39) and inversely with high density lipoprotein cholesterol (p=0.02, r=-0.02). No significant association was found between total MGP and clinical, biochemical and vascular parameters. The correlation between OPG and aPWV persisted even after the adjustment for various potential confounders (p=0.02, r=0.19). In multiple regression analysis in the whole study population the most important predictors of aPWV were OPG (β=0.230, p=0.006), hsCRP (β=0.212, p=0.01) and systolic blood pressure (β=0.163, p=0.04). After exclusion of patients treated with statins the independent predictors were hsCRP (β=0.275, p=0.005) and OPG (β=0.199, p=0.04).. Circulating OPG, but not OPN and total MGP, is associated with aPWV and may be a marker of the increased arterial stiffness and cardiovascular risk in postmenopausal women.

Topics: Aged; Bone and Bones; Calcium-Binding Proteins; Cardiovascular Diseases; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix Proteins; Female; Humans; Linear Models; Matrix Gla Protein; Middle Aged; Osteopontin; Osteoprotegerin; Pulse Wave Analysis; Vascular Stiffness

Topics: Cardiovascular Diseases; Female; Humans; Male; Osteoprotegerin; Renal Dialysis; Renal Insufficiency, Chronic; Vascular Stiffness

Osteoprotegerin (OPG) and fetuin-A are vascular calcification regulators that may be related to high cardiovascular (CV) mortality in hemodialysis (HD) patients. We evaluated the relationship between OPG, fetuin-A, and pulse wave velocity (PWV), a marker of vascular stiffness, and determined whether OPG and fetuin-A were independent predictors of CV events in HD patients.. We conducted a prospective observational study in 97 HD patients. OPG and fetuin-A were measured at baseline and arterial stiffness was evaluated by PWV. All patients were stratified into tertiles according to serum OPG levels.. A significant trend was observed across increasing serum OPG concentration tertiles for age, HD duration, systolic blood pressure, cholesterol, triglycerides, and PWV. Multiple linear regression analysis revealed that diabetes (β = 0.430, p = 0.000) and OPG levels (β = 0.308, p = 0.003) were independently associated with PWV. The frequency of new CV events was significantly higher in the upper OPG tertiles compared with those in the lower OPG tertiles. In Cox proportional hazards analysis, upper tertiles of OPG levels were significantly associated with CV events (hazard ratio = 4.536, p = 0.011).. Serum OPG, but not fetuin-A, levels were closely associated with increased vascular stiffness, and higher OPG levels may be independent predictors of new CV events in HD patients.

Topics: Adult; Aged; alpha-2-HS-Glycoprotein; Biomarkers; Cardiovascular Diseases; Female; Humans; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; Multivariate Analysis; Osteoprotegerin; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Pulse Wave Analysis; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors; Up-Regulation; Vascular Stiffness

Microfibrillar-associated protein 4 (MFAP4) is located in the extracellular matrix (ECM). We sought to identify tissues with high levels of MFAP4 mRNA and MFAP4 protein expression. Moreover, we aimed to evaluate the significance of MFAP4 as a marker of cardiovascular disease (CVD) and to correlate MFAP4 with other known ECM markers, such as fibulin-1, osteoprotegerin (OPG), and osteopontin (OPN). Quantitative real-time PCR demonstrated that MFAP4 mRNA was more highly expressed in the heart, lung, and intestine than in other elastic tissues. Immunohistochemical studies demonstrated high levels of MFAP4 protein mainly at sites rich in elastic fibers and within blood vessels in all tissues investigated. The AlphaLISA technique was used to determine serum MFAP4 levels in a clinical cohort of 172 patients consisting of 5 matched groups with varying degrees of CVD: 1: patients with ST elevation myocardial infarction (STEMI), 2: patients with non-STEMI, 3: patients destined for vascular surgery because of various atherosclerotic diseases (stable atherosclerotic disease), 4: apparently healthy individuals with documented coronary artery calcification (CAC-positive), and 5: apparently healthy individuals without signs of coronary artery calcification (CAC-negative). Serum MFAP4 levels were significantly lower in patients with stable atherosclerotic disease than CAC-negative individuals (p<0.05). Furthermore, lower serum MFAP4 levels were present in patients with stable atherosclerotic disease compared with STEMI and non-STEMI patients (p<0.05). In patients with stable atherosclerotic disease, positive correlations between MFAP4 and both fibulin-1 (ρ = 0.50; p = 0.0244) and OPG (ρ = 0.62; p = 0.0014) were found. Together, these results indicate that MFAP4 is mainly located in elastic fibers and is highly expressed in blood vessels. The present study suggests that serum MFAP4 varies in groups of patients with different cardiovascular conditions. Further studies are warranted to describe the role of serum MFAP4 as a biomarker of stable atherosclerotic disease.

Topics: Aged; Animals; Cardiovascular Diseases; Carrier Proteins; Demography; Elastic Tissue; Extracellular Matrix Proteins; Female; Gene Expression Profiling; Gene Expression Regulation; Glycoproteins; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Middle Aged; Myocardial Infarction; Organ Specificity; Osteopontin; Osteoprotegerin; Protein Transport; Real-Time Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric

The role of osteoprotegerin (OPG) as a marker of cardiovascular disease (CVD) in Type 2 diabetes (T2DM) is not well established. Moreover, the relationship between OPG, osteoporosis, and vertebral fractures in T2DM remains to be elucidated.. To determine the role of serum OPG in the prediction of CVD and bone disease in T2DM males.. Cross-sectional study with 68 males, 43 with T2DM and 25 subjects without diabetes. We measured: serum OPG by inmunoassay, the presence of CVD (coronary heart disease, cerebrovascular and peripheral artery disease), surrogate markers of CVD [intima- media thickness (IMT) and aortic calcification] and bone disease (bone mineral density and prevalent vertebral fractures).. OPG serum levels (in pmol/l) were significantly higher in T2DM males with abnormal IMT (5.12 ± 1.59 vs 3.76 ± 1.98), carotid plaque (5.46 ± 1.67 vs 4.20 ± 1.81), aortic calcification (5.91 ± 1.39 vs 4.07 ± 1.76), hypertension (5.11 ± 1.86 vs 3.81 ± 1.47), and peripheral artery disease (6.24 ± 1.64 vs 4.21 ± 1.63, p < 0.05 for all comparisons). In the logistic regression analysis (after adjustment for age and main cardiovascular risk factors), serum OPG (per 1 pmol/l increase in OPG) was associated with increased risk of abnormal IMT [odds ratio (OR) 1.84, confidence interval (CI) 1.21-2.79, p = 0.004), carotid plaque (OR 1.71, CI 1.13-2.58, p = 0.012), aortic calcification (OR 2.21, CI 1.27-3.84, p = 0.05) and peripheral artery disease (OR 4.02, CI 1.65-9.8 p = 0.002). However, OPG were not related to bone mass or vertebral fractures.. Our results suggest that in T2DM males OPG serum concentrations constitute a marker of CVD, but not a marker of bone disease.

Topics: Absorptiometry, Photon; Biomarkers; Blood Pressure Determination; Bone Density; Bone Diseases; Cardiovascular Diseases; Carotid Intima-Media Thickness; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Osteoprotegerin; Prognosis; Risk Factors

The increased vascular calcification, cardiovascular morbidity, and mortality in chronic kidney disease (CKD) patients has been associated with disturbances in mineral-bone metabolism. In order to determine markers of the vascular calcification frequently observed in these patients, blood samples of elderly male and female hemodialysis CKD patients were used to measure serum levels of: osteoprotegerin (OPG), total soluble receptor activator of nuclear factor-κB ligand (sRANKL), and fetuin-A by enzyme immunoassay; tartrate-resistant acid phosphatase (TRACP-5b), and bone-specific alkaline phosphatase (BAP) by immunoenzymometric assay; osteocalcin (OC) by ELISA; iPTH by immunoradiometric assay; 25(OH)D(3) and 1,25(OH)(2)D(3), by I(125) radioimmunoassay; and calcium and phosphorus by photometric assay. Serum OPG, BAP, iPTH, phosphorus, and OC levels were higher and serum 25(OH)D(3), 1,25(OH)(2)D(3), and fetuin-A levels lower in both male and female CKD patients than in their respective controls. Our results indicate that the bone formation and resorption parameters are altered in elderly male and female hemodialysis CKD patients. These changes may lead to vascular calcifications and cardiovascular complications, given that elevated OPG and OC levels and reduced fetuin-A levels are associated with cardiovascular events.

Topics: Acid Phosphatase; Aged; Alkaline Phosphatase; alpha-2-HS-Glycoprotein; Biomarkers; Cardiovascular Diseases; Female; Humans; Isoenzymes; Male; Middle Aged; Osteoprotegerin; RANK Ligand; Renal Dialysis; Renal Insufficiency, Chronic; Tartrate-Resistant Acid Phosphatase; Vascular Calcification

To evaluate the association of plasma osteoprotegerin (OPG) to hospitalisation for ischaemic heart disease (IHD), ischaemic stroke and all-cause mortality, and the effect of combining plasma OPG and high-sensitivity C-reactive protein (hsCRP).. OPG and hsCRP concentrations were measured at baseline in a large Danish prospective community-based population study.. The 4th Copenhagen City Heart Study.. 5863 men and women aged 20-95 were recruited from the general population.. Combined end-point of IHD, ischaemic stroke or all-cause mortality.. During a median follow-up of 7.8 years (IQR 7.3-8.3), 1270 subjects (21.7%) reached the combined end-point. A twofold increase in plasma OPG was a significant predictor of the combined end-point (univariable HR 1.85, 95% CI 1.75 to 1.96; p<0.001). In a multivariable Cox-regression model containing age, male sex, hypertension, diabetes, hypercholesterolaemia, present or former smoking, glomerular filtration rate, prior IHD, prior ischaemic stroke, hsCRP and plasma OPG, high concentrations of hsCRP and plasma OPG were independent predictors of the combined end-point. The two biomarkers interacted statistically (p<0.001). Compared to low hsCRP and low OPG (n=1927), either high hsCRP or high OPG (univariable HR 2.38, 95% CI 2.02 to 2.80, p<0.001; n=2816), or both high hsCRP and high OPG (univariable HR 5.13, 95% CI 4.29 to 6.13, p<0.001; n=775) conferred increased risk of the combined end-point.. OPG is an independent predictor of the combined end-point of hospitalisation of IHD, ischaemic stroke and all-cause mortality. The combination of plasma OPG and hsCRP provides more prognostic information than the individual effect of the two biomarkers.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Cause of Death; Early Diagnosis; Female; Follow-Up Studies; Humans; Male; Middle Aged; Osteoprotegerin; Population Surveillance; Predictive Value of Tests; Prevalence; Proportional Hazards Models; Prospective Studies; Risk Factors; Survival Rate; Time Factors; Young Adult

Cardiovascular disease and osteoporosis are important causes of morbi-mortality in the elderly and may be mutually related. Low bone mineral density (BMD) may be associated with increased risk of cardiovascular events. We investigated the prevalence of low bone mass and fractures in metabolic syndrome patients with acute coronary events. A case-control study was conducted with 150 individuals (30-80years-old) with metabolic syndrome. Seventy-one patients had had an acute coronary syndrome episode in the last 6months (cases) and the remaining 79 had no coronary event (controls). Cases and controls were matched for gender, BMI and age. DXA measurements and body composition were performed while spine radiographs surveyed for vertebral fractures and vascular calcification. Biochemical bone and metabolic parameters were measured in all patients. No statistically significant difference in BMD and the prevalence of osteopenia, osteoporosis and non-vertebral fractures was observed between cases and controls. The prevalence of vertebral fractures and all fractures was higher in the cases (14.1 versus 1.3%, p=0.003 and 22.5versus7.6%, p=0.010, respectively). Male gender (OR=0.22 95% CI 0.58 to 0.83, p=0.026) and daily intake of more than 3 portions of dairy products (OR=0.19 95% CI 0.49 to 0.75, p=0.017) were associated with lower prevalence of fractures. Cases had higher risk for fractures (OR=4.97, 95% CI 1.17 to 30.30, p=0.031). Bone mass and body composition parameters were not associated with cardiovascular risk factors or bone mineral metabolism. Patients with fragility fractures had higher OPG serum levels than those without fractures (p<0.001). Our findings demonstrated that patients with recent coronary events have a higher prevalence of vertebral fractures independently of BMD.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Body Composition; Bone Density; Brazil; Cardiovascular Diseases; Female; Humans; Lipids; Logistic Models; Lumbar Vertebrae; Male; Metabolic Syndrome; Middle Aged; Osteoporosis; Osteoprotegerin; Prevalence; Spinal Fractures

Extra-skeletal calcification and disordered phosphate metabolism are hallmarks of chronic kidney disease-mineral bone disorder (CKD-MBD). Osteoprotegerin (OPG) and fibroblast growth factor 23 (FGF-23) are increased in chronic kidney disease (CKD) and have been associated with arterial and cardiac dysfunction and reduced survival. Troponin T (cTnT) is released from cardiac myocytes under conditions of stress and is predictive of mortality across a range of renal functions. However, the utility of this biomarker was formerly limited by the lower limit of assay detection. The introduction of a high-sensitivity assay has enabled more detailed study of myocyte stress below the previous limit of detection. We studied the association of mediators of CKD-MBD with arterial stiffness and also of these mediators and arterial stiffness with myocardial damage in patients with CKD stages 3-4.. OPG and FGF-23 were measured in 200 CKD stages 3-4 patients. cTnT was measured using a high-sensitivity assay. Aortic stiffness was assessed using aortic pulse wave velocity (APWV).. Mean age was 69 ± 11 years, mean systolic and diastolic blood pressure was 151 ± 22/81 ± 11 mmHg and renal function was 33 ± 11 mL/min/1.73 m(2). OPG, FGF-23, high-sensitivity troponin T (hs-cTnT) and APWV all correlated with renal function. After multivariate analysis, OPG and age remained independently associated with aortic stiffness. OPG and FGF-23 were independently associated with hs-cTnT in addition to other non-traditional risk factors (Model R(2) = 0.596).. We have shown that changes in bone mediators and phosphate metabolism induced by CKD are independently associated with vascular and cardiomyocyte dysfunction. Our findings suggest that cardiac dysfunction may be specifically associated with such abnormalities in addition to recognized increases in vascular stiffness.

Topics: Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Biomarkers; Bone Density; Bone Diseases; Cardiomyopathies; Cardiovascular Diseases; Cohort Studies; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Prognosis; Regression Analysis; Risk Assessment; Severity of Illness Index; Sex Factors; Survival Rate; Troponin T; Vascular Resistance

Osteoprotegerin (OPG), a secreted member of the tumour necrosis factor receptor superfamily of cytokines, has been associated with endothelial dysfunction. We studied in type 2 diabetic and/or hypertensive patients the relationship between serum OPG and vascular alterations associated with these pathologies.. We analysed 191 consecutive patients (52 with type 2 diabetes and 139 hypertensive nondiabetic patients) and 54 healthy controls. We assessed the relationship of OPG serum levels measured by ELISA with basal glycaemia, glycosylated haemoglobin, blood pressure, endothelial dysfunction (assessed by pulse wave velocity), retinopathy (by Keith-Wagener classification), left ventricular hypertrophy (by Cornell index), cardiovascular risk and target organs (heart, vascular, kidney) damage.. Serum OPG levels were higher in either hypertensive or diabetic patients and in patients with non-dipper and riser circadian blood pressure patterns. We found significant correlations between OPG levels and age, height, glycaemia, systolic, diastolic and pulse blood pressure, pulse wave velocity and left ventricular hypertrophy in both hypertensive and diabetic patients. OPG levels were also higher in hypertensive patients with retinopathy, patients with high probability of 10-year cardiovascular risk, patients with three or more damaged target organs (heart, vessels, kidneys) and patients with previous episodes of ischaemic cardiopathy or hypercholesterolaemia.. Osteoprotegerin is an indicator of diabetes- and hypertension-associated vascular pathologies as endothelial dysfunction and cardiovascular risk.

Topics: Adult; Aged; Biomarkers; Blood Pressure; Cardiovascular Diseases; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension; Male; Middle Aged; Osteoprotegerin; Risk Factors; Time Factors

Cardiovascular disease (CVD) and osteoporosis share some common risk factors such as old age, smoking, alcoholic drinking, hypertension, diabetes mellitus, and hyperlipidemia. Although previous studies have investigated the association of bone mineral density (BMD) with CVD, the results were conflicting. There are limited studies on the association of BMD loss rate with CVD. We therefore conducted a 5-year prospective study to examine the relation among BMD, bone loss, and risk of CVD in a Chinese cohort. Of 9,657 community residents 30 to 75 years old, 6,092 were enrolled in the study and followed annually for 5 years. At baseline demographic data, BMD, smoking and drinking statuses, medical history, and blood samples were collected. Cox proportional hazards analysis was used to evaluate the association of BMD and incidence of CVD. Over the 5-year follow-up period, CVD developed in 118 subjects. Baseline BMD, bone loss rate, current smoking, daily alcoholic ingestion, and higher osteoprotegerin and leptin levels were independently associated with increased risk of CVD, whereas higher baseline adiponectin level was associated with decreased risk of CVD in women and men. In conclusion, uncovering the relation linking osteoporosis and CVD is important for understanding the pathogenesis of these 2 common disorders.

Topics: Absorptiometry, Photon; Adiponectin; Adult; Aged; Alcohol Drinking; Biomarkers; Bone Density; Cardiovascular Diseases; China; Female; Humans; Incidence; Leptin; Male; Middle Aged; Osteoporosis; Osteoprotegerin; Proportional Hazards Models; Prospective Studies; Risk; Risk Factors; Smoking; Statistics, Nonparametric

Biomarkers of cardiovascular (CV) risk are tests that predict a patient's risk of future CV events. Recently, two proteins involved in vascular calcification; serum levels of osteoprotegerin (OPG) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) have emerged as potentially useful biomarkers. OPG levels are positively correlated with CV risk, whereas TRAIL levels show a negative correlation. Exercise training is known to reduce risk factors for CV disease by improving metabolism, vascular biology and blood flow. This study examined the effects of a 6-month exercise training programme on levels of OPG and TRAIL. Pulse wave velocity (PWV) and high-sensitivity C-reactive protein (hsCRP) were measured for comparative purposes.. Overweight and obese patients undertook a 6-month exercise programme. Patients participated in 4 h of primarily aerobic exercise per week of which 2 h were supervised. At the beginning and end of the programme, anthropometric measurements, PWV and serum levels of OPG, TRAIL and hsCRP were measured.. A total of 21 patients (17 men) aged 55.2 ± 10 years completed the programme. Mean body mass index decreased from 34.1 ± 5.8 to 32.6 ± 5.4 kg/m(2) (P<0.05), while waist circumference decreased from 111.8 ± 12.4 to 109.6 ± 12.8 cm (P<0.05). PWV decreased from 9.2 to 8.5 m/s (P<0.02). OPG, TRAIL and hsCRP levels did not change significantly.. Exercise training reduced PWV but not OPG, TRAIL or hsCRP in this population. These data suggest that while an intervention of this nature improves vascular tone, it does not exert significant effects on serum biomarkers related to atherosclerotic inflammation and calcification.

Topics: Biomarkers; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Exercise; Female; Humans; Male; Middle Aged; Obesity; Osteoprotegerin; Pulse Wave Analysis; Risk Factors; TNF-Related Apoptosis-Inducing Ligand; Waist Circumference

Severe mental disorder and cardiovascular disease (CVD) are often associated, and inflammation is implicated in both disorders. We investigated whether there is a relationship between CVD risk factors and inflammation in schizophrenia or bipolar disorder, and if second generation antipsychotics (SGA) interact.. We included 361 patients in a naturalistic cross-sectional study, 235 subjects on current SGA treatment and 126 subjects not treated with SGA as controls. Cardiovascular parameters were measured and current medication recorded. Fasting plasma levels of the following cytokines were measured: high sensitivity CRP (hsCRP), soluble tumor necrosis factor receptor 1 (sTNF-R1), osteoprotegerin (OPG), soluble CD40 ligand (sCD40L), interleukin-1 receptor antagonist (IL-1Ra), von Willebrand factor (vWf) and interleukin-6 (IL-6).. In this relatively young sample of patients with a mean age of 33.3years, the following CVD risk factors were associated with elevated inflammation markers after adjusting for confounders: BMI, triglycerides and glucose with hsCRP (p=0.041-0.001), HDL-cholesterol and triglycerides with sTNF-R1 (p=0.009-0.001) and triglycerides with vWf (p=0.004). In patients treated with SGA, elevated hsCRP was significantly associated with high BMI (p=0.012), and with high glucose levels (p=0.003).. Several CVD risk factors are associated with elevated levels of inflammation markers in young patients with severe mental illness. The interaction between SGA and CVD risk factors on hsCRP levels might indicate a specific inflammatory activation related to SGA induced overweight and hyperglycemia. This suggests that hsCRP could be a valuable marker for future cardiovascular events, particularly in patients treated with SGA.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Bipolar Disorder; Blood Glucose; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Cross-Sectional Studies; Cytokines; Female; Humans; Male; Middle Aged; Osteoprotegerin; Psychiatric Status Rating Scales; Receptors, Tumor Necrosis Factor; Risk Factors; Schizophrenia; Triglycerides; von Willebrand Factor; Young Adult

Subtle changes in hypothalamic- pituitary-adrenal (HPA) axis of subjects with nonfunctioning adrenal adenoma may be associated with endothelial alterations. We sought to investigate endothelial function, visceral adiposity and osteoprotegerin (OPG) and interleukin- 18 (IL-18) levels in subjects with non-functioning adrenal adenomas.. The adenoma group included 40 subjects without clinical and subclinical findings of hypercortisolism or other adrenal gland disorders. Twenty-two body mass index-matched controls were also enroled. The patients and control subjects underwent hormonal evaluation and assessment of anthropometric and metabolic parameters. Endothelial function was assessed with flowmediated dilatation (FMD) of the brachial artery and intima media thickness (IMT) of common carotid arteries. Visceral adipose tissue area was measured by computed tomography. Plasma OPG and serum IL-18 levels were also measured.. When compared with healthy controls, the adenoma group had elevated systolic blood pressure, post-dexamethasone suppression test cortisol and reduced DHEAS. Visceral adipose tissue area and IMT of common carotid arteries were comparable. In the adenoma group, FMD of the brachial artery was significantly impaired and IL-18 level was significantly elevated. Visceral adipose tissue area was independently related with FMD. Homeostasis model assessment (HOMA) was the independent factor associated with visceral adipose tissue area. Cortisol, DHEAS and visceral adipose tissue area were independently associated with HOMA.. We achieved evidence that could be attributable to endothelial alterations in subjects with non-functioning adrenal adenomas. Impaired FMD appeared to be a consequence of subtle changes in HPA axis in terms of elevated cortisol and reduced DHEAS as these conditions were known to disturb endothelial-dependent vasodilatation.

Topics: Adenoma; Adiposity; Adrenal Gland Neoplasms; Adrenocortical Adenoma; Adult; Cardiovascular Diseases; Endothelium; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Interleukin-18; Intra-Abdominal Fat; Male; Middle Aged; Osteoprotegerin; Pituitary-Adrenal System

A high circulating osteoprotegerin (OPG) level may be a risk factor for vascular calcification and mortality in hemodialysis patients. OPG and pulse wave velocity (PWV) were measured at baseline in 151 normoalbuminemic, long-term (>3 years) Japanese hemodialysis patients who were prospectively followed for 6 years. In long-term normoalbuminemic Japanese hemodialysis patients, OPG levels were strongly linked with both arterial stiffness and worse outcome.. A high circulating OPG level is reported to be a risk factor for vascular calcification and mortality in Western chronic kidney disease (CKD) patients but it is not known if this is true for Japanese CKD patients, where a different risk profile may operate.. OPG and PWV were measured at baseline in 151 normoalbuminemic, long-term (>3 years) Japanese hemodialysis patients (median age 62 years) who were prospectively followed for 6 years.. OPG levels were associated in multivariate analysis with age, dialysis vintage, history of cardiovascular disease (CVD) and parathyroid hormone levels. C-reactive protein levels did not correlate with OPG. Patients with clinical history of CVD had significantly higher OPG levels and OPG levels were positively correlated to PWV, an index of arterial stiffness. These associations were independent of age, sex, dialysis vintage, and diabetes. During the follow-up period, 40 deaths, including 25 cardiovascular deaths, were recorded. In crude analysis, each unit of increase in OPG was associated with increased all-cause (hazard ratios 1.14, 95% confidence interval 1.08-1.20) and CVD mortality (1.14 [1.07-1.21]), which persisted after adjustment for age, sex, dialysis vintage, diabetes, and baseline CVD (1.12 [1.05-1.19] and 1.11 [1.02-1.19], all-cause and CVD mortality, respectively).. In long-term normoalbuminemic Japanese hemodialysis patients, with low prevalence of inflammation, OPG levels were strongly linked with both arterial stiffness and worse outcome.

Topics: Aged; Biomarkers; Blood Flow Velocity; Brachial Artery; Cardiovascular Diseases; Epidemiologic Methods; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Prognosis; Renal Dialysis; Serum Albumin; Vascular Stiffness

Osteoprotegerin (OPG), a novel soluble member of tumour necrosis factor receptor superfamily, has been shown to link cardiovascular disorders. The aim of this study is to investigate the potential relationship between serum OPG levels, cardiovascular risk factors and metabolic syndrome in a relatively large group of women with previous GDM. In this cross-sectional case-control study, 128 women with previous GDM and 67 age-matched controls were enrolled. Subjects were evaluated for the diagnosis of metabolic syndrome according to the criteria of the American Heart Association (AHA). Fasting glucose, insulin, serum lipids, CRP and OPG were assayed. HOMA score was calculated. Carotid intima media thickness (IMT) was measured. There was no significant increase in OPG levels in women with previous GDM when compared to controls. On the other hand, women with previous GDM developing metabolic syndrome had higher OPG levels than those without metabolic syndrome and healthy controls. Serum OPG levels were associated with obesity, insulin resistance, serum CRP and carotid IMT. Serum OPG is related to cardiovascular risk factors and metabolic syndrome, and might be involved in the development of cardiovascular disorders in women with previous GDM.

Topics: Adult; Atherosclerosis; C-Reactive Protein; Cardiovascular Diseases; Carotid Arteries; Case-Control Studies; Cross-Sectional Studies; Diabetes, Gestational; Female; Humans; Insulin Resistance; Metabolic Syndrome; Obesity; Osteoprotegerin; Pregnancy; Risk Factors; Tunica Intima; Tunica Media; Turkey; Ultrasonography

Osteoprotegerin (OPG) concentration in serum is associated with the presence and severity of atherosclerosis.. To investigate the association between serum osteoprotegerin and the risk of a future myocardial infarction, ischemic stroke and mortality in a general population.. OPG was measured in serum collected from 6265 subjects recruited from a general population without a prior myocardial infarction and ischemic stroke (the Tromsø Study). Incident myocardial infarction, ischemic stroke and mortality were registered during follow-up. Cox regression models were used to estimate crude and adjusted hazard ratios and 95% confidence intervals (HR; 95% CI).. There were 575 myocardial infarctions, 284 ischemic strokes and 824 deaths (146 deaths as a result of ischemic heart disease, 78 deaths because of stroke and 600 deaths due to other causes) in the cohort during a median of 10.6 years of follow-up. Serum OPG (per SD [1.13 ng mL(-1)] increase in OPG) was associated with an increased risk of a myocardial infarction (1.20; 1.11-1.31), ischemic stroke (1.32; 1.18-1.47), total mortality (1.34; 1.26-1.42), death because of ischemic heart disease, (1.35; 1.18-1.54), stroke (1.44; 1.19-1.75) and non-vascular causes (1.31; 1.22-1.41) after adjustment for age, gender, current smoking, systolic blood pressure, body mass index, high density lipoprotein cholesterol, total cholesterol, creatinine, high sensitivity C-reactive protein (CRP) and diabetes mellitus or HbA1c > 6.1%. No association was detected between OPG and incident hemorrhagic stroke (1.02; 0.73-1.43).. Serum OPG was associated with future risk of myocardial infarction, ischemic stroke, total mortality, mortality of ischemic heart disease, stroke and of non-vascular causes independent of traditional cardiovascular risk factors.

Topics: Aged; Aged, 80 and over; Cardiovascular Diseases; Humans; Incidence; Middle Aged; Norway; Osteoprotegerin

Osteoprotegerin (OPG), a cytokine that regulates bone resorption, has been implicated in the process of vascular calcification and stiffness.. Serum OPG was measured in 351 participants with chronic kidney disease (CKD) from one site of the Chronic Renal Insufficiency Cohort Study. Cortical bone mineral content (BMC) was measured by quantitative computed tomography in the tibia. Multivariable linear regression was used to test the association between serum OPG and traditional cardiovascular risk factors, measures of abnormal bone and mineral metabolism, and pulse wave velocity.. Higher serum OPG levels were associated with older age, female gender, greater systolic BP, lower estimated GFR, and lower serum albumin. OPG was not associated with measures of abnormal bone or mineral metabolism including serum phosphorus, albumin-corrected serum calcium, intact parathyroid hormone, bone-specific alkaline phosphatase, or cortical BMC. Among 226 participants with concurrent aortic pulse wave velocity measurements, increasing tertiles of serum OPG were associated with higher aortic pulse wave velocity after adjustment for demographics, traditional vascular risk factors, and nontraditional risk factors such as estimated GFR, albuminuria, serum phosphate, corrected serum calcium, presence of secondary hyperparathyroidism, serum albumin, and C-reactive protein or after additional adjustment for cortical BMC in a subset (n = 161).. These data support a strong relationship between serum OPG and arterial stiffness independent of many potential confounders including traditional cardiovascular risk factors, abnormal bone and mineral metabolism, and inflammation.

Topics: Aged; Analysis of Variance; Aorta; Biomarkers; Bone Density; Cardiovascular Diseases; Chi-Square Distribution; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Female; Humans; Kidney Diseases; Linear Models; Male; Middle Aged; Osteoprotegerin; Pulsatile Flow; Regional Blood Flow; Risk Assessment; Risk Factors; Tibia; Tomography, X-Ray Computed; United States; Up-Regulation

Osteoprotegerin (OPG) is known to regulate bone mineral metabolism and to be also associated with inflammation, cardiovascular disease (CVD) and mortality. Malnutrition-inflammation-atherosclerosis (MIA) syndrome is commonly found and closely linked to mortality in dialysis patients. The aim of this study was to investigate the associations between OPG and MIA syndrome in prevalent peritoneal dialysis (PD) patients.. Prevalent PD patients for more than 6 months were prospectively followed up from March 2005 to May 2010. At baseline, OPG, hs-CRP, albumin, and %lean body mass (LBM) by creatinine kinetics were checked, and subjective global assessment (SGA) was performed. New-onset cardiovascular events were evaluated during the study period. Based on the median level of OPG, patients were classified as lower OPG (LO) group (n = 88) and higher OPG (HO) group (n = 88).. A total of 176 patients (age 52.0 ± 11.8 years, male 50.6%, duration of PD 105.3 ± 67.2 months) were recruited and followed. In HO group, age, hs-CRP level and Charlson's comorbidity indices were higher, whereas serum albumin level, %LBM and SGA score were significantly lower than LO group. OPG levels were positively correlated with inflammatory markers, whereas negatively correlated with nutritional status. Cardiovascular events occurred in 51 patients during the study period. Newly developed cardiovascular events were significantly common in HO group (n = 36, 40.9%) than LO group (n = 15, 17%, p = 0.002). Cox regression analysis revealed that higher OPG level (per 1-SD increase in OPG, HR: 1.44; 95% CI: 1.03-2.00; p = 0.034) was a significant risk factor for cardiovascular events even after adjustments for demographic and biochemical parameters.. OPG was significantly correlated with markers of systemic inflammation and malnutrition and was a significant predictor of CVD in PD patients. These findings suggest OPG might be a prognostic indicator of MIA syndrome in prevalent PD patients.

Topics: Adult; Biomarkers; Body Composition; C-Reactive Protein; Cardiovascular Diseases; Comorbidity; Creatinine; Female; Humans; Inflammation; Inflammation Mediators; Kaplan-Meier Estimate; Male; Malnutrition; Middle Aged; Osteoprotegerin; Peritoneal Dialysis; Prognosis; Proportional Hazards Models; Prospective Studies; Republic of Korea; Risk Assessment; Risk Factors; Serum Albumin; Time Factors; Up-Regulation

Experimental evidence identified the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappaB (RANK)/RANK ligand (RANKL) pathway as a candidate system modulating vascular remodeling and cardiovascular disease (CVD).. Serum concentrations of OPG and RANKL were measured in 3250 Framingham Study participants (54% women, 61+/-9 years). During a mean follow-up of 4.6 years, 143 (of 3084 free of CVD at baseline) participants developed a first CVD event, and 235 died. In multivariable models, OPG was associated with increased hazards for incident CVD and mortality (hazard ratio, 1.27; 95% CI, 1.04 to 1.54; and hazard ratio, 1.25; 95% CI, 1.07 to 1.47, per 1-SD increment in log-OPG, respectively). Log-OPG was positively related to multiple CVD risk factors, including age, smoking, diabetes, systolic blood pressure, and prevalent CVD. In a subsample (n=1264), the prevalence of coronary artery calcification, measured by computed tomography, increased nonsignificantly with OPG quartiles. RANKL concentrations displayed inverse associations with multiple CVD risk factors, including smoking, diabetes, and antihypertensive treatment, and were not related to coronary artery calcification or incident CVD or mortality.. Our prospective data reinforce OPG as marker for CVD risk factor burden and predictor for CVD and mortality in the community.

Topics: Aged; Biomarkers; Calcinosis; Cardiovascular Diseases; Coronary Artery Disease; Female; Humans; Incidence; Logistic Models; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; RANK Ligand; Risk Assessment; Risk Factors; Time Factors; Tomography, X-Ray Computed

Osteoprotegerin (OPG) is a member of the tumor necrosis factor superfamily with pleiotropic effects on bone metabolism, endocrine function and the immune system. Circulating OPG levels are elevated in cardiovascular disease (CVD). We assessed serum OPG as predictor of long-term prognosis in patients with suspected stable angina pectoris (SAP) undergoing elective coronary angiography.. Samples were obtained from 1025 patients (median [25th, 75th percentile] age 62 [54, 70] years, 71.9% men). At inclusion, 43.2% of patients had single or double vessel disease, whereas 34.3% had triple vessel disease.. During a median follow-up of 73 months, 11.0% of patients died, 5.9% died from CVD and 10.0% experienced an acute myocardial infarction (MI). In univariable analyses, strong associations were observed between OPG concentrations and all-cause mortality, CVD mortality and the incidence of MI (fatal or nonfatal). However, adjustment for conventional risk factors attenuated the risk estimates which were no longer significant, except for the subgroup with levels above the 90th percentile. For decile 10 versus deciles 1-9 of serum OPG, the following multivariable hazard ratios (95% confidence intervals) were observed: All-cause mortality: 1.94 (1.18, 3.18), p=0.01; CVD mortality: 2.29 (1.16, 4.49), p=0.02; and MI: 1.76 (1.02, 3.06), p=0.04.. In patients with SAP, elevated serum OPG is associated with increased risk of all-cause mortality, CVD mortality and MI, but independent effects are mainly confined to levels above the 90th percentile.

Topics: Aged; Angina Pectoris; Angiography; Cardiovascular Diseases; Coronary Angiography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Osteoprotegerin; Prognosis; Risk Factors

Topics: Biomarkers; Calcinosis; Cardiovascular Diseases; Coronary Artery Disease; Humans; Incidence; Osteoprotegerin; Predictive Value of Tests; RANK Ligand; Risk Assessment; Risk Factors; Time Factors

Patients on hemodialysis (HD) frequently experience cardiovascular events associated with vascular calcification. We investigated the involvement of osteoprotegerin (OPG), an inhibitor of vascular calcification, in the incidence of cardiovascular events and mortality among new HD patients.. We conducted a prospective cohort study of the association of serum OPG levels with morbidity and mortality in subjects who became new HD patients between June 2000 and May 2006.. A total of 99 patients (age 58.9 +/- 14.6 years, 65 male, 34 female) were prospectively followed up for 41.5 +/- 20.2 months. During this period, 27 patients developed cardiovascular events and 12 died of causes related to cardiovascular disease. When divided into 2 groups according to OPG levels, the high OPG group showed a higher prevalence of cardiovascular morbidity and mortality compared with the low OPG group. Cox's proportional hazards analysis associated the new onset of cardiovascular events with the high OPG group (HR 2.88, 95% CI 1.09-7.62, p = 0.033). Furthermore, the high OPG group at the start of HD was significantly associated with older age, male gender and a high aortic calcification index.. Elevated levels of serum OPG in new HD patients may predict subsequent cardiovascular events.

Topics: Adult; Aged; Aged, 80 and over; Calcinosis; Cardiovascular Diseases; Cohort Studies; Female; Humans; Japan; Kaplan-Meier Estimate; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Osteoprotegerin; Proportional Hazards Models; Renal Dialysis; Young Adult

Topics: Bone Resorption; Cardiovascular Diseases; Diabetes, Gestational; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Osteoprotegerin; Pregnancy; Pregnancy Complications

Osteoprotegerin (OPG) is a soluble tumour necrosis factor-receptor-like molecule present in connective tissues, especially bone and vasculature. It is known to accumulate in the arterial wall in diabetes. As its synthesis in vascular cells is decreased by insulin, we wanted to elucidate the acute effects of insulin on plasma OPG concentrations in individuals with type 2 diabetes and obese individuals compared with lean controls.. The study population consisted of ten type 2 diabetic, ten obese subjects, and ten lean subjects with no family history of diabetes.. All subjects underwent a 4-h euglycemic-hyperinsulinemic clamp. Plasma OPG, insulin, lactate, HbA1c, cholesterol, triglycerides, free fatty acids (FFA), and glucose disposal rate were measured before and at the end of the clamp.. Baseline OPG concentrations did not differ significantly between groups. Insulin infusion decreased plasma OPG concentrations in all groups (P<0.01); however, the fall in OPG was 50% less in obese and type 2 diabetic individuals (P=0.007). Baseline OPG correlated with fasting insulin, baseline lactate, and low density lipoprotein cholesterol in the diabetic group, and with baseline FFA in the lean group. The relative change of OPG in response to insulin correlated inversely with HbA1c and baseline FFA in the lean group.. Acute hyperinsulinemia decreases plasma OPG, but with diminished effect in individuals with type 2 diabetes and obesity. Increased levels of OPG in arteries and plasma in diabetes together with the capability of plasma OPG as a cardiovascular risk predictor may be related to the described effects of insulin.

Topics: Acute Disease; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Obesity; Osteoprotegerin; Risk Factors

To investigate the role of serum osteoprotegerin (OPG) and OPG gene polymorphisms in relation to cardiovascular (CV) and all-cause mortality in elderly women.. The OPG/RANK/RANKL plays a vital role in bone cell biology. It has also been detected in myocardial tissue and atherosclerotic plaques. In some population studies, OPG and OPG gene polymorphisms have been associated with CV disease risk.. In an 8.5-year cohort population study of 1333 postmenopausal women mean age 75.2 ± 2.7 years, serum OPG concentrations above the median were associated with an increased risk of all-cause [odds ratio (OR) 1.39 (1.04-1.85)], and in particular CV mortality [OR 1.83 (1.10-3.05)], before and after adjusting for age, BMI, treated hypertension, diabetes, hypercholesterolemia, previous HRT use, calcium supplementation and smoking. Genotyping the OPG gene did not provide further information on the association between OPG and CV risk or mortality events.. Raised osteoprotegerin appears to be an independent risk factor for total and CV death and thus has potential as a useful biomarker of risk as well as a potential target for therapeutic intervention.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Female; Humans; Osteoprotegerin; Polymorphism, Genetic; Risk Factors

.Microvascular damage is an early pathogenetic event in systemic sclerosis (SSc). The receptor activator of nuclear factor-kappaB ligand (RANKL)/RANK/osteoprotegerin (OPG) system is involved in vascular biology. Our aim was to assess OPG and soluble RANKL (sRANKL) serum levels in patients with SSc and healthy controls.. Sixty patients with SSc (median age 58, range 31-72 yrs) and 60 healthy subjects matched for age, sex, and menopausal status were recruited. Serum OPG, sRANKL, soluble vascular cell adhesion molecule (sVCAM; marker of endothelial activation/injury), and bone turnover markers were measured. Bone mineral density in patients was assessed and cardiovascular/coronary risk was estimated.. OPG was similar in the 2 groups, while sRANKL and sRANKL/OPG ratio was higher in patients (p = 0.01 for both). sVCAM was markedly higher in patients (p < 0.001). OPG levels correlated positively with age in both patients (Spearman R = 0.50, p < 0.001) and controls (R = 0.56, p < 0.001). In patients, OPG was lower in men and higher in those with active ulcers or calcinosis. sRANKL levels were higher in patients treated with platelet aggregation inhibitors, and correlated negatively with densitometric measures. 25-hydroxyvitamin D levels were significantly lower in patients (p < 0.001). In patients, OPG levels correlated positively with cardiovascular and coronary risk (R = 0.28, p = 0.05 and R = 0.34, p < 0.01, respectively) and were higher in patients with hypertension and left ventricular hypertrophy. sVCAM levels correlated positively with cardiovascular and coronary risk (R = 0.27, p = 0.06, and R = 0.38, p < 0.01, respectively).. Higher sRANKL levels and sRANKL/OPG ratio in patients with SSc are likely to be a consequence of altered bone microenvironment. We show a dissociation between the well established marker of endothelial activation/injury, sVCAM, and the alleged marker of vascular damage, OPG, in patients with SSc. Further studies are needed to better ascertain the relationships of the RANKL/RANK/OPG system with the progression of macro- and microvascular damage.

Topics: Adult; Aged; Biomarkers; Bone and Bones; Bone Density; Cardiovascular Diseases; Female; Humans; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; RANK Ligand; Risk Factors; Scleroderma, Systemic; Solubility; Vascular Cell Adhesion Molecule-1

We analyzed the relation of osteoprotegerin (OPG) with insulin sensitivity, lipid profile, serum glutamic pyruvic transaminase (SGPT), adipocytokines, and C-reactive protein (CRP) in obese and non-obese subjects.. In the study, 170 subjects (106 obese and 64 non-obese, sex ratio female/male=2.03) were included. Thirty-two obese subjects were reevaluated 6 months after the weight loss induced by bariatric surgery.. OPG did not differ between obese and non-obese subjects (respective mean values 5.17 and 4.96 pmol/l) or according to gender, but was positively correlated with age (P<0.0001 for both groups). OPG was statistically higher in 18 obese diabetic subjects compared with non-diabetics (P=0.03). After adjustment for age, no significant correlation was found between OPG and body mass index (BMI), waist, systolic and diastolic blood pressure, cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, leptin, and adiponectin in both the obese and non-obese subjects. However, OPG was positively correlated with homeostasis model assessment (HOMA) index and SGPT levels in obese subjects at baseline (r=0.295, r=0.20, P<0.05) and after adjustment for age (r=0.28, r=0.20, P<0.05). OPG was also significantly correlated with CRP; this correlation persisted after adjustment for age in obese subjects (r=0.30, P<0.01). In a multivariate analysis in the obese group, HOMA index and CRP were independent predictors of OPG while SGPT was not. Six months post-surgery, OPG did not change, despite a significant reduction in glucose, SGPT, cholesterol, triglycerides, CRP, and leptin values (P=0.02, P=0.006, P=0.007, P<0.001, P<0.001, P<0.001 respectively) and a significant increase in adiponectin and HDL values (P<0.001 for both variables).. Our results show that in obese subjects, OPG is not related to BMI. However, we describe new relationships between OPG and both HOMA index and CRP.

Topics: Adipokines; Adult; Alanine Transaminase; Bariatric Surgery; Body Weight; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Homeostasis; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Osteoprotegerin; Regression Analysis; Risk Factors; Triglycerides; Weight Loss

Osteoprotegerin (OPG) is a marker and regulator of arterial calcification, and it is related to cardiovascular survival in haemodialysis patients. The link between OPG and aortic stiffening--a consequence of arterial calcification--has not been previously evaluated in this population, and it is not known whether OPG-related mortality risk is mediated by arterial stiffening.. At baseline, OPG and aortic pulse wave velocity (PWV) were measured in 98 chronic haemodialysis patients who were followed for a median of 24 months. The relationship between OPG and PWV was assessed by multivariate linear regression. The role of PWV in mediating OPG related cardiovascular mortality was evaluated by including both OPG and PWV in the same survival model.. At baseline mean (standard deviation) PWV was 11.2 (3.3) m/s and median OPG (interquartile range) was 11.1 (7.5-15.9) pmol/L. There was a strong, positive, linear relationship between PWV and lnOPG (P = 0.009, model R(2) = 0.540) independent of covariates. During follow-up 23 patients died of cardiovascular causes. In separate univariate survival models both PWV and lnOPG were related to cardiovascular mortality [hazard ratios 1.31 (1.14-1.50) and 8.96 (3.07-26.16), respectively]. When both PWV and lnOPG were entered into the same model, only lnOPG remained significantly associated with cardiovascular mortality [hazard ratio 1.11 (0.93-1.33) and 7.18 (1.89-27.25), respectively).. In haemodialysis patients OPG is strongly related to PWV and OPG related cardiovascular mortality risk is, in part, mediated by increased PWV.

Topics: Aged; Blood Flow Velocity; Calcinosis; Cardiovascular Diseases; Carotid Arteries; Cohort Studies; Female; Femoral Artery; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Models, Cardiovascular; Multivariate Analysis; Osteoprotegerin; Prospective Studies; Regional Blood Flow; Renal Dialysis; Risk Factors

Vascular calcification occurs in the majority of patients with chronic kidney disease, but a subset of patients does not develop calcification despite exposure to a similar uraemic environment. Physiological inhibitors of calcification, fetuin-A, osteoprotegerin (OPG) and undercarboxylated-matrix Gla protein (uc-MGP) may play a role in preventing the development and progression of ectopic calcification, but there are scarce and conflicting data from clinical studies.. We measured fetuin-A, OPG and uc-MGP in 61 children on dialysis and studied their associations with clinical, biochemical and vascular measures.. Fetuin-A and OPG were higher and uc-MGP lower in dialysis patients than controls. In controls, fetuin-A and OPG increased with age. Fetuin-A showed an inverse correlation with dialysis vintage (P = 0.0013), time-averaged serum phosphate (P = 0.03) and hs-CRP (P = 0.001). Aortic pulse wave velocity (PWV) and augmentation index showed a negative correlation with fetuin-A while a positive correlation was seen with PWV and OPG. Patients with calcification had lower fetuin-A and higher OPG than those without calcification. On multiple linear regression analysis Fetuin-A independently predicted aortic PWV (P = 0.004, beta = -0.45, model R(2) = 48%) and fetuin-A and OPG predicted cardiac calcification (P = 0.02, beta = -0.29 and P = 0.014, ss = 0.33, respectively, model R(2) = 32%).. This is the first study to define normal levels of the calcification inhibitors in children and show that fetuin-A and OPG are associated with increased vascular stiffness and calcification in children on dialysis. Higher levels of fetuin-A in children suggest a possible protective upregulation of fetuin-A in the early stages of exposure to the pro-calcific and pro-inflammatory uraemic environment.

Topics: Adolescent; alpha-2-HS-Glycoprotein; Blood Flow Velocity; Blood Proteins; Blood Vessels; Calcinosis; Calcium-Binding Proteins; Cardiovascular Diseases; Case-Control Studies; Child; Child, Preschool; Extracellular Matrix Proteins; Female; Humans; Kidney Failure, Chronic; Male; Matrix Gla Protein; Osteoprotegerin; Renal Dialysis

Patients with Cushing's syndrome (CS) have a mortality rate four times higher than age- and sex-matched subjects, mainly due to cardiovascular events. Serum osteoprotegerin (OPG) levels are increased in patients with cardiovascular disease and/or excess bone resorption.. The aim of the study was to assess serum OPG and soluble receptor activator of nuclear factor-kappaB ligand (sRANKL) levels in CS and their possible relationship with coronary risk profile.. We conducted a cross-sectional study at a tertiary referral center.. We studied 48 adult patients with CS and 48 age- and sex-matched controls. Twenty-six patients had pituitary-dependent CS; five patients had CS caused by ectopic ACTH secretion; and 17 patients had adrenal-dependent CS, accounted for by cortisol-secreting adenoma (n = 9), ACTH-independent macronodular bilateral adrenal hyperplasia (n = 4), or World Health Organization stage II cortisol-secreting carcinoma (n = 4). Patients underwent assessment of the absolute coronary risk and measurement of bone mineral density by dual-energy x-ray absorptiometry. Serum OPG and total sRANKL were measured by ELISA.. Serum OPG (but not sRANKL) levels were significantly higher in CS patients than in controls (P < 0.01). In patients, serum OPG showed a positive correlation with age (r = 0.36; P = 0.01). OPG levels were higher in patients with the metabolic syndrome [median, 1262 (range, 199-2306) pg/ml vs. 867 (412-2479) pg/ml; P = 0.03], and showed a positive correlation with the absolute coronary risk (r = 0.36; P = 0.01). Serum OPG levels were higher in patients with pituitary-dependent CS in comparison with adrenal-dependent CS.. In patients with CS, serum OPG levels are increased and appear to be associated with coronary risk.

Topics: Absorptiometry, Photon; Adrenal Glands; Adrenocorticotropic Hormone; Adult; Aged; Cardiovascular Diseases; Cross-Sectional Studies; Cushing Syndrome; Female; Humans; Hydrocortisone; Male; Metabolic Syndrome; Middle Aged; Osteoprotegerin; Pituitary Function Tests; Pituitary Gland; Receptor Activator of Nuclear Factor-kappa B; Risk

Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i.e., white matter hyperintensities [WMH]) and AD (i.e., total brain volume [TCB]).. MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 +/- 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNFalpha), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures.. In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNFalpha was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals.. Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age.

Topics: Adult; Age Distribution; Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Brain; Brain Ischemia; Cardiovascular Diseases; Cross-Sectional Studies; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Magnetic Resonance Imaging; Male; Middle Aged; Osteoprotegerin; Sex Distribution; Tumor Necrosis Factor-alpha

Enhanced osteoclastogenesis, increased bone resorption, and osteoporosis have been reported in osteoprotegerin-deficient (OPG (-/-)) mice. OPG (-/-) mice available in Japan usually do not show vascular calcification. We have found that arterial calcification can be quickly induced by a simple procedure in OPG (-/-) mice.. Male OPG (-/-), OPG (+/-), and OPG (+/+) mice were fed a high phosphate diet from 6 to 10 weeks after birth, and then 1alpha,25-dihydroxyvitamin D3 (calcitriol) was injected for 3 days. We found that severe calcification developed in the media of the aorta in OPG (-/-) mice. Under electron microscopy, calcium deposits were observed in the cytoplasm and extracellular matrix of vascular smooth muscle cells (VSMCs). Neither apoptosis of VSMCs nor infiltration of macrophages was observed. Alkaline phosphatase (ALP) activity of aortic tissue correlated with the calcified lesion area. Mouse aorta and bone extracts revealed an identical pattern by ALP electrophoresis.. Our results demonstrated that OPG had anticalcification activity in the aorta, probably through the downregulation of ALP activity. Because the time course of arterial calcification after the injection of calcitriol is accurate and reproducible, this mouse model will be useful for further investigation of vascular calcification.

Topics: Alkaline Phosphatase; Animals; Aorta; Calcinosis; Calcitriol; Calcium; Cardiovascular Diseases; Disease Models, Animal; Down-Regulation; Male; Mice; Mice, Knockout; Osteoprotegerin; Vitamins

Patients on hemodialysis exhibit a drastically increased cardiovascular mortality. Inflammation, hyperphosphatemia and lack of calcification inhibitors are uremia-associated risk factors for vascular calcification. Functional and morphological vascular parameters are used to assess cardiovascular risk. The aim of our study was to analyse the relation between pulse wave velocity (PWV) and intima-media-thickness (IMT) with calcification inhibitors.. A cohort of 97 hemodialysis patients was consecutively selected and investigated (age 56 +/- 9 years). Carotid-femoral PWV, carotid IMT, left ventricular ejection fraction and septum thickness were determined. These parameters were correlated with serum levels of CRP and calcification inhibitors (fetuin-A and osteoprotegerin [OPG]).. Both PWV and IMT showed a positive correlation with age and systolic blood pressure and a negative correlation with Kt/V (dialysis efficiency). Additionally, fetuin-A was negatively associated with CRP and positively with cholesterol and triglycerides. Serum levels of the calcification inhibitors fetuin-A and OPG were not correlated to PWV or IMT.. The lack of correlation of calcification inhibitors with PWV and IMT means that functional and morphological measurements of vascular properties can not necessarily be replaced by analysing "biomarkers".

Topics: Aging; alpha-2-HS-Glycoprotein; Arteriosclerosis; Blood Pressure; Blood Proteins; C-Reactive Protein; Cardiovascular Diseases; Cholesterol; Female; Humans; Male; Middle Aged; Osteoprotegerin; Pulse; Renal Dialysis; Triglycerides; Tunica Intima; Tunica Media

The bone-related peptide osteoprotegerin (OPG) has recently been found in increased amounts in the vasculature in diabetes. It is produced by vascular smooth muscle and endothelial cells, and may be implicated in the development of vascular calcifications. OPG is present in the circulation, where increased amounts have been observed in patients with diabetes. In this study, we examined whether plasma OPG is associated with the glycaemic and vascular status of patients with type 1 diabetes.. Two gender-, age- and duration-comparable groups of type 1 diabetic patients either with (n = 199) or without (n = 192) signs of diabetic nephropathy were studied. Plasma OPG was determined by an ELISA.. The plasma OPG concentration was significantly higher in patients with nephropathy than those without (3.11 (2.49-3.99) vs 2.57 (2.19-3.21) (median (interquartiles), ng/ml), P < 0.001). Plasma OPG correlated with haemoglobin A1c (HbA1c), systolic blood pressure and age in both groups and, in addition, with kidney function in the nephropathic group. These correlations remained significant in multivariate models. In addition, we found that plasma OPG concentrations were increased among patients with cardiovascular diseases (CVD), both in the normoalbuminuric and the nephropathic groups. The differences between nephropathic and normoalbuminuric, as well as subgroups with and without CVD, could largely be ascribed to changes in HbA1c, age, systolic blood pressure and creatinine.. OPG is associated with glycaemic control and CVD in patients with type 1 diabetes, compatible with the hypothesis that OPG is associated with the development of diabetic vascular complications.

Topics: Adult; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glycated Hemoglobin; Glycoproteins; Humans; Male; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

This study sought to prospectively evaluate the relationship between plasma osteoprotegerin (OPG), inflammatory biomarkers (high-sensitivity C-reactive protein [hs-CRP], interleukin-6 [IL-6], coronary artery calcification (CAC), and cardiovascular events in patients with type 2 diabetes.. Arterial calcification is a prominent feature of atherosclerosis and is associated with an increased risk of cardiovascular events. Osteoprotegerin is a cytokine that has recently been implicated in the regulation of vascular calcification.. A total of 510 type 2 diabetic patients (53 +/- 8 years; 61% male) free of symptoms of cardiovascular disease were evaluated by CAC imaging. Risk factors, hs-CRP, IL-6, and OPG levels were measured. Patients were followed up for cardiovascular events (cardiac death, myocardial infarction, acute coronary syndrome, late revascularization, and nonhemorrhagic stroke).. Significant CAC (>10 Agatston units) was seen in 236 patients (46.3%); OPG was significantly elevated in patients with increased CAC. In multivariable analyses, OPG retained a strong association with elevated CAC scores after adjustment for age, gender, and other risk factors (odds ratio = 2.84, 95% confidence interval 2.2 to 3.67; p < 0.01). Sixteen cardiovascular events occurred during a mean follow-up of 18 +/- 5 months. The waist-to-hip ratio, United Kingdom Prospective Diabetes Study (UKPDS) risk score, OPG level, and CAC score were significant predictors of time to cardiovascular events in a univariate Cox proportional hazards model. In the multivariate model, the CAC score was the only independent predictor of adverse events. Levels of hs-CRP and IL-6 were related to neither the extent of CAC nor short-term events.. A high proportion of asymptomatic diabetic patients have significant subclinical atherosclerosis. Of the biomarkers studied, only OPG predicted both subclinical disease and near-term cardiovascular events. Therefore, measurement of OPG merits further investigation as a simple test for identifying high-risk type 2 diabetic patients.

Topics: Biomarkers; C-Reactive Protein; Calcinosis; Cardiovascular Diseases; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Glycoproteins; Humans; Interleukin-6; Male; Middle Aged; Osteoprotegerin; Prognosis; Proportional Hazards Models; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; Sensitivity and Specificity; Survival Rate

The primary objectives of this analysis were to examine the effects of early posttransplantation (10 wk) serum levels of osteoprotegerin (OPG), mannose-binding lectin (MBL), and MBL-associated serine proteases (MASP; MASP-2 and MASP-3) on long-term (8-yr) patient survival, graft survival, and cardiovascular (CV) death. During a period of 16 mo (1995 to 1996), a total of 173 consecutive renal transplant recipients without diabetes before transplantation were included in a prospective study that was designed to address the impact of metabolic CV risk factors on survival and CV end points. Baseline sera from 172 patients were available for analysis. Follow-up data until January 1, 2004, were obtained from a national renal registry. Patients with high (fourth quartile) serum levels of OPG had significantly higher all-cause mortality (hazard ratio [HR] 6.3; 95% confidence interval [CI] 3.3 to 11.8; P<0.001) and CV death (HR 10.8; 95% CI 3.8 to 30.4; P<0.001) than patients with lower OPG concentrations. After multiple Cox regression analysis, high serum levels of OPG remained an independent predictor of all-cause mortality (HR 6.0; 95% CI 3.1 to 11.6, P<0.001) and CV death (HR 8.2; 95% CI 2.5 to 26.4; P<0.001). Multiple linear regression analysis revealed that age, creatinine clearance, and high-sensitivity C-reactive protein all were independently associated with OPG (R2=0.42). No significant association between OPG and death-censored graft loss was revealed. Serum levels of MBL, MASP-2, and MASP-3 were not significantly associated with patient survival, CV death, or graft loss. Early measured posttransplantation serum OPG is a highly significant independent predictor of death from any cause or CV death in white renal transplant recipients.

Topics: Adult; Cardiovascular Diseases; Female; Graft Survival; Humans; Kidney Transplantation; Linear Models; Male; Middle Aged; Osteoprotegerin; Prognosis; Proportional Hazards Models; Registries; Time Factors; Treatment Outcome

Osteoprotegerin (OPG) is a recently identified cytokine that acts as a decoy receptor for the receptor activator of nuclear factor I masculine B ligand. Osteoprotegerin has been shown to be an important inhibitor of osteoclastogenesis and arterial calcification in animal models. Recently, OPG has been proposed as a link molecule between osteoporosis and arterial calcification, but the relationship between circulating OPG levels and cardiovascular disease in human populations is unclear. Thus, the aim of this study was to investigate the relationship between circulating OPG levels and cardiovascular risk factors in healthy Korean women. The subjects were 286 women aged 37 to 73 (mean +/- SD, 51.5 +/- 6.9 years). We examined blood pressure, body mass index, and waist-to-hip ratio. Serum concentrations of OPG were determined by enzyme-linked immunosorbent assay. Fasting plasma glucose levels, serum lipid profiles, insulin levels, and serum follicle-stimulating hormone (FSH) levels were determined by standard methods and homeostasis model assessment of insulin resistance was calculated. We observed a significant association between serum OPG levels and age, waist-to-hip ratio, total cholesterol, low-density lipoprotein cholesterol, and FSH levels (P < .05). Among the metabolic components, the older, obese, and hypercholsterolemic subjects had higher serum OPG levels (P < .05). However, no significant relationship was found between serum OPG levels and blood pressure and fasting plasma glucose levels. We found that mean serum OPG levels were about 11% greater in postmenopausal women (mean +/- SD, 1358.5 +/- 380.0 pg/mL) than in premenopausal women (mean +/- SD, 1228.8 +/- 407.7 pg/mL, P < .001). In multiple regression analysis with OPG as the dependent variable, serum FSH and low-density lipoprotein cholesterol levels were the significant predictor for serum OPG level (R(2) = 0.051, P < .05). In conclusion, our results show that circulating OPG levels are partly associated with cardiovascular risk factors and menopausal status in healthy Korean women. Out findings suggest that OPG may be an important paracrine factor of cardiovascular disease in the female population.

Topics: Adult; Age Factors; Aged; Cardiovascular Diseases; Carrier Proteins; Cholesterol; Cholesterol, LDL; Female; Glycoproteins; Humans; Insulin Resistance; Membrane Glycoproteins; Middle Aged; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; Waist-Hip Ratio

Osteoprotegerin is a novel member of the tumor necrosis factor receptor superfamily and a soluble decoy receptor of the receptor activator of nuclear factor-kappaB ligand. Recent experimental research has implicated osteoprotegerin in atherogenesis, but epidemiological confirmation of this concept is sparse.. As part of the prospective, population-based Bruneck Study, severity, initiation, and progression of atherosclerosis were assessed in carotid arteries. Cases of incident cardiovascular disease and vascular mortality were carefully recorded over a 10-year period (1990 to 2000). Osteoprotegerin levels were measured in samples obtained at baseline and during follow-up. Serum osteoprotegerin showed a strong association with numerous vascular risk factors, including age, diabetes, markers of systemic inflammation, chronic infection, and smoking. In multivariate analyses, osteoprotegerin was significantly related to severity and 10-year progression of carotid atherosclerosis. Furthermore, a high level of osteoprotegerin was an independent risk factor for incident cardiovascular disease (adjusted relative risk for the top versus bottom tertile group for osteoprotegerin 2.2 [1.3 to 3.8]; P=0.001) and vascular mortality (adjusted relative risk for the top versus bottom tertile group for osteoprotegerin 3.1 [1.2 to 8.2]; P=0.010) but not for mortality due to nonvascular causes.. Osteoprotegerin is an independent risk factor for the progression of atherosclerosis and onset of cardiovascular disease.

Topics: Aged; Aged, 80 and over; Apoptosis; Biomarkers; Calcinosis; Cardiovascular Diseases; Carotid Artery Diseases; Cohort Studies; Comorbidity; Disease Progression; Female; Follow-Up Studies; Glycoproteins; Humans; Incidence; Italy; Male; Middle Aged; Odds Ratio; Osteoprotegerin; Prospective Studies; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk; Risk Factors; Sampling Studies; Ultrasonography; Vascular Diseases

Osteoprotegerin (OPG) and its ligand are cytokines that regulate osteoclastogenesis and that may be involved in the regulation of vascular calcification. We examined whether serum OPG levels were associated with stroke, mortality, and cardiovascular risk factors, including diabetes, as well as with bone mineral density and fractures in a sample of 490 participants in a prospective cohort of white women, at least 65 yr of age. We found that OPG levels, assayed blinded from serum obtained at baseline, were about 30% greater in women with diabetes (mean +/- SD, 0.30 +/- 0.17 ng/mL) than in those without diabetes (0.23 +/- 0.10 ng/mL; P = 0.0001). OPG levels were associated with all-cause mortality [age-adjusted odds ratio, 1.4/SD (0.11 ng/mL) increase in serum OPG level; 95% confidence interval, 1.2--1.8] and cardiovascular mortality (odds ratio, 1.4; 95% confidence interval, 1.1--1.8); these effects were not confounded by diabetes. OPG levels were not associated with baseline bone mineral density or with subsequent strokes or fractures. The association of serum OPG levels with diabetes and with cardiovascular mortality raises the possibility that OPG may be a cause of or a marker for vascular calcification.

Topics: Aged; Biomarkers; Blood Pressure; Bone Density; Cardiovascular Diseases; Cause of Death; Cohort Studies; Confidence Intervals; Diabetes Mellitus; Estrogen Replacement Therapy; Female; Fractures, Bone; Glycoproteins; Humans; Mortality; Observer Variation; Odds Ratio; Osteoprotegerin; Prospective Studies; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; San Francisco; Smoking; Stroke; White People