osteoprotegerin and Myocardial-Ischemia

Increased circulating osteoprotegerin (OPG) levels have been associated with the prevalence and severity of coronary artery disease and the risk of cardiovascular death. OPG is a cytokine of the tumor necrosis factor receptor superfamily and is expressed in various cell types in the body, including osteoblasts, inflammatory cells, vascular smooth muscle cells/endothelial cells and cardiomyocytes. The main sources determining OPG levels in the circulation however, are not well understood, and whether reversible myocardial ischemia influences OPG levels are not known. Accordingly, OPG levels were measured in 198 patients referred for exercise stress testing and myocardial perfusion imaging (MPI). In addition OPG levels were measured in 8 healthy control subjects performing a maximal bicycle stress test. Plasma samples were collected before, immediately after, 1.5h and 4.5h after exercise stress testing with MPI. OPG levels at baseline were not different in patient with reversible myocardial ischemia (n=19) and patients without reversible ischemia (n=179) (4.7 [3.6-5.5]pmol/L vs. 4.3 [3.4-5.2]pmol/L, p=0.21), and there was an increase in OPG levels immediately after exercise regardless of whether or not the patient had reversible ischemia on MPI (absolute increase: 0.2 [0-0.55]pmol/L vs. 0.3 [0-0.5]pmol/L, p=0.72). OPG levels also increased immediately after stress in the 8 control subjects (3.5 (3.2-3.8)pmol/L at baseline to 3.8 (3.5-4.7), p=0.008). In conclusion, OPG levels increase acutely during exercise stress testing, but this increase is likely caused by mechanisms other than myocardial ischemia.

Topics: Adult; Coronary Artery Disease; Exercise Test; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Myocardial Perfusion Imaging; Osteoprotegerin

Atherosclerotic plaque stabilization is a promising strategy to prevent cerebrovascular events in patients with carotid atherosclerosis. Vascular calcification inhibitors, known osteopontin (OPN) and osteoprotegerin (OPG), have emerged as novel cardiovascular biomarkers. This open-label, prospective study aimed to examine whether aggressive lipid-lowering therapy with atorvastatin is more effective than moderate lipid-lowering in increasing carotid plaque echogenicity, assessed by Gray-Scale Median (GSM) score and suppressing serum OPN and OPG levels in patients with moderate carotid stenosis.. One hundred forty patients (64 males, 76 females), aged 50 to 75 years, with carotid stenosis (North American Symptomatic Carotid Endarterectomy Trial [NASCET]: 30%-60% for symptomatic and 30%-70% for asymptomatic), but without indications for surgical intervention, were enrolled. Patients with coronary heart disease, renal failure, hypothyroidism, osteoporosis, and ongoing use of statins were excluded. Patients were randomly assigned to: Group A (N = 70): Moderate lipid-lowering therapy with low-dose of atorvastatin (10 mg-20 mg) to target LDL-C <100 mg/dL. Group B (N = 70): Aggressive lipid-lowering therapy with high-dose of atorvastatin (80 mg) to target LDL-C <70 mg/dL. Blood pressure, lipid and glycemic indexes, hsCRP, serum OPN, and OPG were measured at baseline and after 12 months as well as the GSM score. Independent samples t test, paired samples t test, Pearson correlation, and multiple regression analysis were used (P < .05).. There were no significant differences between groups at baseline. Three patients in group A experienced either cerebrovascular or cardiac ischemic attacks, while two patients in group B underwent coronary angioplasty during follow-up. Group B showed a more pronounced improvement in total cholesterol and LDL-cholesterol compared with group A (P < .05). Moreover, atorvastatin treatment suppressed serum hsCRP, OPN, and OPG levels from baseline in both groups (P < .001). Notably, aggressive treatment decreased OPN (P = .012) and OPG (P = .025) levels to a greater degree compared with moderate treatment. Similarly, GSM score was remarkably increased in both groups, but that augmentation was greater in group B (from 66.39 +/- 23.66 to 100.4 +/- 25.31) than in group A (from 64.4 +/- 23.62 to 85.39 +/- 20.21) (P = .024). No change in the degree of carotid stenosis was noted in both treatment arms. Importantly, the aforementioned reduction in OPN (r = -0.517, P = .024) and OPG (r = -0.312, P = .008) levels was inversely associated with GSM score changes in univariate and standard multiple regression analysis (R(2) = 0.411, P = .021).. Among patients with moderate carotid stenosis, an aggressive atorvastatin regimen enhanced carotid plaque echogenicity and reduced serum OPN and OPG levels to a greater extent than respective moderate atorvastatin therapy. Most importantly, those atorvastatin-induced effects were associated with OPN and OPG suppression in a dose-dependent manner.

Topics: Aged; Atorvastatin; Biomarkers; C-Reactive Protein; Carotid Stenosis; Cerebrovascular Disorders; Cholesterol, LDL; Dose-Response Relationship, Drug; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Myocardial Ischemia; Osteopontin; Osteoprotegerin; Prospective Studies; Pyrroles; Severity of Illness Index; Time Factors; Treatment Outcome; Ultrasonography, Doppler

Osteoprotegerin (OPG), receptor activator of nuclear factor-ΚB ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have been involved in rheumatoid arthritis (RA) pathophysiology. In this study, we assessed messenger RNA (mRNA) expression of these molecules by qPCR in peripheral blood from 26 patients with RA (12 of them with ischemic heart disease -IHD) and 10 healthy controls. Correlation coefficients between OPG, RANKL and TRAIL expression levels in RA patients and their clinical and demographic characteristics were also evaluated. Whereas OPG and OPG/TRAIL ratio expression were significantly increased in RA patients compared to controls (fold change = 1.79, p = 0.013 and 2.07, p = 0.030, respectively), RANKL/OPG ratio was significantly decreased (fold change = 0.50, p = 0.020). No significant differences were found between patients and controls in RANKL and TRAIL expression. Interestingly, TRAIL expression was significantly higher in RA patients with IHD compared to those without IHD (fold change = 1.46, p = 0.033). Moreover, biologic disease-modifying antirheumatic drugs (DMARDs) significantly decreased RANKL expression in RA patients (p = 0.016). Our study supports an important role of OPG and TRAIL in RA. Furthermore, it highlights an effect of biologic DMARDs in the modulation of RANKL.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Female; Gene Expression Regulation; Humans; Male; Myocardial Ischemia; Osteoprotegerin; RANK Ligand; TNF-Related Apoptosis-Inducing Ligand

Diabetic patients often exhibit severe, asymptomatic coronary artery disease (CAD). The relationship between osteoprotegerin (OPG), inflammatory markers and silent myocardial ischemia remains to be elucidated.. We recruited 45 type 2 diabetic patients and 33 healthy controls and assessed them for silent myocardial ischemia (SMI) by myocardial perfusion imaging. Patient blood was tested for OPG, IL-6 and leptin concentrations.. OPG, leptin and IL-6 levels were found significantly elevated in diabetic patients (p < 0.001, p < 0.01, p < 0.05). Based on our classification of presence/absence of SMI in our diabetic group, we found that there was a significant association between SMI and the biomarkers IL-6 (p < 0.001), leptin (p < 0.001) and OPG (p < 0.05). In multivariate regression analyses, OPG was found to be significantly related to diabetes mellitus and to SMI. Age, sex and smoking increased the association between OPG and SMI.. High OPG, leptin and IL-6 levels are associated with the presence and severity of SMI in type 2 diabetic patients.

Topics: Adult; Biomarkers; Case-Control Studies; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exercise Test; Female; Humans; Interleukin-6; Leptin; Male; Middle Aged; Multivariate Analysis; Myocardial Ischemia; Myocardial Perfusion Imaging; Osteoprotegerin; Regression Analysis

The incidence of coronary artery disease (CAD) and osteoporosis increases with age, especially in the elderly. Many studies have shown that vessel calcification is associated with low bone mineral density (BMD) and an increased risk of bone fractures. Experimental studies have shown that osteoprotegerin (OPG) gene knockout mice have aortic calcification and osteoporosis at the same time.. To assess the frequency of OPG gene polymorphisms in patients with CAD and to analyse the relationship between the severity of CAD and BMD.. The study group comprised 31 postmenopausal women (mean age 65.6, range 39-82 years) undergoing elective coronary angiography for CAD symptoms. The BMD was measured at the hip by dual X-ray absorptiometry (DEXA). Clinical data were collected using a questionnaire developed by the authors which addressed CAD risk factors, treatment, previous diagnosis of osteoporosis and the risk factors of osteoporosis. The control group consisted of 30 postmenopausal women attending the osteoporosis clinic without the history of CAD (mean age 70.5, range 56-84 years). Written informed consent was obtained from all the patients. Genotyping of two polymorphisms 209, 245 in the promoter region and 1181 in the exon of the OPG gene was performed in both groups.. Coronary angiography in study group revealed normal coronary arteries in 35% (n = 11) of the women. The analysis of 209 C/T polymorphism showed no presence of TT homozygotes in either group. Also, no significant differences between the 209 C/T polymorphic variants, BMD and progression of atherosclerosis in coronary arteries were found. In both groups no CC homozygous variants for 245 A/C were revealed. However, a statistically significant relationship between 245 A/C polymorphism and BMD was shown. The AC carriers had osteoporosis more frequently (57%) than AA carriers (12%) of the OPG gene (p = 0.0382). There were no significant differences in the OPG gene 245 A/C polymorphisms and CAD progression. Homozygotes for CC 1181 were shown to have normal coronary arteries more frequently (60%) than heterozygotes for CG 1181 (29%; p = 0.0023). We failed to show significant differences between 1181 C/G polymorphism and BMD in both groups.. 1. This study revealed a significant association between homozygotes for AA 245 and normal BMD in study group. 2. The analysis of 209 C/T and 245 C/T C polymorphisms has shown no presence of homozygotes for TT 209 OPG or CC 245 OPG in both groups. 3. Carriers of the homozygous CC 1181 OPG gene were shown to have normal coronary arteries more frequently when compared to heterozygotes for CG or homozygotes for GG.

Topics: Adult; Aged; Aged, 80 and over; Bone Density; Case-Control Studies; Coronary Vessels; Female; Humans; Middle Aged; Myocardial Ischemia; Osteoprotegerin; Polymorphism, Genetic; Severity of Illness Index

Topics: Bone Density; Coronary Vessels; Female; Humans; Myocardial Ischemia; Osteoprotegerin; Polymorphism, Genetic

Cardiovascular disease (CVD) is frequent in type 2 diabetes mellitus patients due to accelerated atherosclerosis. Plasma osteoprotegerin (OPG) has evolved as a biomarker for CVD. We examined the relationship between plasma OPG levels and different CVD manifestations in type 2 diabetes.. Type 2 diabetes patients without known CVD referred consecutively to a diabetes clinic for the first time (n = 305, aged: 58.6 ± 11.3 years, diabetes duration: 4.5 ± 5.3 years) were screened for carotid arterial disease, peripheral arterial disease, and myocardial ischemia by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy (MPS). In addition, plasma OPG concentrations and other CVD-related markers were measured.. The prevalence of carotid arterial disease, peripheral arterial disease, and myocardial ischemia was 42%, 15%, and 30%, respectively. Plasma OPG was significantly increased in patients with carotid and peripheral arterial disease compared to patients without (p < 0.001, respectively), however, this was not the case for patients with myocardial ischemia versus those without (p = 0.71). When adjusted for age, HbA1c and U-albumin creatinine ratio in a multivariate logistic regression analysis, plasma OPG remained strongly associated with carotid arterial disease (adjusted OR: 2.12; 95% CI: 1.22-3.67; p = 0.008), but not with peripheral arterial disease or myocardial ischemia.. Increased plasma OPG concentration is associated with carotid and peripheral arterial disease in patients with type 2 diabetes, whereas no relation is observed with respect to myocardial ischemia on MPS. The reason for this discrepancy is unknown.

Topics: Adult; Aged; Biomarkers; Blood Pressure; Carotid Arteries; Carotid Artery Diseases; Diabetes Mellitus, Type 2; Female; Humans; Logistic Models; Male; Middle Aged; Myocardial Ischemia; Osteoprotegerin; Perfusion Imaging; Peripheral Arterial Disease; Prevalence; Retrospective Studies; Risk Factors; Ultrasonography

Topics: Age Factors; Aged; Blood Pressure; Body Mass Index; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Creatinine; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Myocardial Ischemia; Osteoprotegerin; Sex Factors; Thiazolidinediones; Triglycerides

Hypothyroidism is associated with an increased risk for cardiovascular disease. Exercise-induced silent myocardial ischaemia (SI) is an early stage of coronary artery disease. Recently, many studies have shown that endothelial dysfunction is an early physiological event in atherosclerosis, and osteoprotegerin (OPG) acts as an important regulatory molecule in the vasculature. The aim of this study was to investigate the alteration of endothelial function and its association with plasma OPG in hypothyroidism with SI.. Forty-eight female postmenopausal hypothyroid patients with normal rest electrocardiography (ECG) were selected. Of these, 19 cases had SI. Twenty healthy females without SI were selected as controls. High-resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperaemia and after sublingual glyceryltrinitrate (GTN). Plasma OPG concentration was measured in duplicate by a sandwich enzyme-linked immunosorbent assay (ELISA).. Flow-mediated arterial dilation (FMD) in the total hypothyroid group, the hypothyroidism with SI group and the hypothyroidism without SI group was 3.51 +/- 0.62%, 3.20 +/- 0.54% and 3.72 +/- 0.60%, respectively, significantly lower than that in the controls (5.08 +/- 0.61%) (P < 0.01). Compared with the hypothyroidism without SI group, FMD in the hypothyroidism with SI group was significantly lower (P < 0.05). Plasma OPG levels in the total hypothyroid group, patients with SI and patients without SI were significantly higher than in the control group (P < 0.05). Compared with patients without SI, OPG levels were significantly higher in patients with SI (P < 0.05). On multiple regression analysis, low density lipoprotein cholesterol (LDL-C), lipoprotein (a) [Lp(a)], C-reactive protein (CRP), OPG, TSH, free T3 (FT3) and thyroid peroxidase antibody (TPO-Ab) were found to be significant factors that were associated with FMD. Logistic analysis also showed that LDL-C, TSH, OPG, CRP and FMD were independently and significantly associated with SI in hypothyroidism.. Impaired endothelial function and increased levels of OPG exist in hypothyroid patients, especially those with SI. These findings support the growing concept that endothelial dysfunction may be associated with vascular disease, and subsequently elevated plasma OPG may have a role in the development of vascular dysfunction in hypothyroid patients.

Topics: Blood Pressure; Case-Control Studies; Endothelium, Vascular; Exercise; Female; Humans; Hypothyroidism; Lipids; Middle Aged; Myocardial Ischemia; Osteoprotegerin; Risk Factors

We sought to evaluate osteoprotegerin, an inhibitor of osteoclastogenesis involved in atherosclerosis, and other novel risk factors as predictive markers of silent myocardial ischemia (SMI).. A total of 465 consecutive diabetic patients with more than one additional risk factor were evaluated for SMI using stress myocardial perfusion imaging (MPI). We studied the association of SMI (positive stress electrocardiogram and/or abnormal MPI) with osteoprotegerin, other novel risk factors (lipoprotein[a], homocysteine, adiponectin, C-reactive protein, and fibrinogen), and conventional risk factors (total, LDL, and HDL cholesterol and triglycerides).. A total of 92 patients were diagnosed with SMI. Of the six novel markers, osteoprotegerin was the only one associated with SMI; the relative risk (RR) of SMI in patients with osteoprotegerin values above the 75th percentile was 3.19 (95% CI 1.99-5.18; P < 0.001) in comparison with those with osteoprotegerin below the 75th percentile. In univariate analyses, the other plasma markers significantly associated with SMI were higher triglycerides (P = 0.04) and lower HDL cholesterol (P = 0.02). The association of osteoprotegerin with SMI remained significant after correcting for other variables associated with SMI at P < 0.15 in univariate analysis (RR 3.95 [95% CI 2.21-7.06]; P < 0.0001). The association of osteoprotegerin with SMI was observed in male (P < 0.0001) and female (P = 0.03) patients, in type 1 (P = 0.002) and type 2 (P = 0.0004) diabetic patients, in patients with (P = 0.0004) or without (P = 0.03) nephropathy, and in patients without (P < 0.0001) but not with (P = 0.2) peripheral arterial disease.. Osteoprotegerin measurement, together with other conventional factors, can help to better define the diabetic population with an increased likelihood for SMI.

Topics: Aged; Biomarkers; Body Mass Index; Cross-Sectional Studies; Diabetic Angiopathies; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Myocardial Ischemia; Osteoprotegerin; Predictive Value of Tests; Risk; Risk Factors