osteoprotegerin and Carotid-Artery-Diseases

Stroke is one of the most common causes of disability and lack of independence in activities of daily living in adults. One of the most important factors predisposing to stroke, besides hypertension and atrial fibrillation, is carotid atherosclerosis. Rupture of unstable plaque with formation of a platelet plug is the cause of about 20-25% of ischemic strokes. Osteoprotegerin (OPG) is an important regulator of bone remodeling under physiological and disease conditions, as well as the regulator of osteoclast differentiation. Elevated plasma OPG level is associated with increased risk of ischemic stroke and heart diseases, including atrial fibrillation, and is observed in patients with symptomatic carotid artery stenosis and atherosclerotic vulnerable plaques. Furthermore, the occurrence of certain genotypes of OPG is 10 times more common in people with unstable atherosclerotic plaque, making them an independent risk predictor of plaque instability. This article summarizes the current state of knowledge on the potential role of OPG as a biomarker and prognostic indicator of stroke.

Topics: Atherosclerosis; Biomarkers; Carotid Artery Diseases; Genotype; Humans; Osteoprotegerin; Plaque, Amyloid; Plaque, Atherosclerotic; Risk Assessment; Stroke

Osteoprotegerin (OPG) is considered an important biomarker in cardiovascular (CV) disease. CV disease is the most common cause of mortality in patients with rheumatoid arthritis (RA), a consequence of accelerated atherosclerosis. The present study aimed to evaluate the relationship of serum OPG levels to arterial stiffness, carotid intima-media thickness (CIMT), and clinical and laboratory indices in RA patients.. Included in the study were 68 RA patients with no history or signs of CV disease and 48 healthy subjects Disease activity was assessed by the 28-joint disease activity score (DAS28) in RA patients. Serum OPG level was measured using enzyme-linked immunosorbent assay (ELISA). Carotid femoral pulse wave velocity (PWV) was measured as an index of arterial stiffness and CIMT was evaluated by carotid ultrasonography.. The mean serum OPG level was significantly higher in RA patients than controls (p < 0.001). Mean PWV and CIMT were also significantly increased in RA patients compared to controls (both p < 0.001). In RA patients, serum OPG level was significantly correlated with PWV and CIMT, as well as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody; but not with DAS28, high-sensitivity C-reactive protein (hsCRP), or erythrocyte sedimentation rate.. Serum OPG levels were increased and correlated with CIMT and PWV in RA patients. In addition to PWV and CIMT, OPG may be a useful biomarker for CV risk management in RA patients.

Topics: Arthritis, Rheumatoid; Carotid Artery Diseases; Carotid Intima-Media Thickness; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Osteoprotegerin; Pulse Wave Analysis; Reproducibility of Results; Sensitivity and Specificity; Statistics as Topic; Vascular Stiffness

Osteoporosis and atherosclerosis share common risk factors. Aim of this study was to test if FRAX (which is an algorithm that can identify subjects at risk of fracture), without or with BMD values, also adjusted for trabecular bone score (TBS) was able to identify subclinical atherosclerosis, evaluated by measurement of carotid intima media thickness (cIMT ≥ 0.9 mm) as compared to DXA values.. Ninety postmenopausal women underwent DXA measurement and cIMT evaluation. For each patient, the FRAX algorithm for major osteoporotic fracture (M) and for hip fracture (H) without BMD was computed, together with FRAX with BMD and TBS-adjusted FRAX. Serum levels of osteoprotegerin, sRANKL, and interleukin-6 were also measured.. There were no differences in anthropometric parameters and cardiovascular risk factors between subjects with cIMT ≥ 0.9 mm (35% of subjects, group A) compared to those with cIMT < 0.9 mm (group B). The prevalence of osteoporosis and FRAX BMD, TBS-adjusted FRAX both for M and H were higher in group A compared to group B. The best ROC curves to identify subjects with a cIMT ≥ 0.9 mm were: lumbar spine T-score, with a threshold of - 2.5 SD (area under the curve, AUC 0.64; p = 0.02) with a sensibility of 50% and a specificity of 76%; TBS-adjusted FRAX H with a sensibility of 50% and a specificity of 72% (AUC 0.64; p = 0.01 with a threshold of 3%). Interleukin-6 positively correlated with FRAX BMD H and M.. FRAX without BMD does not identify subclinical carotid atherosclerosis, while lumbar spine T-score and TBS-adjusted FRAX H similarly detected it with higher specificity for T-score.

Topics: Absorptiometry, Photon; Aged; Aged, 80 and over; Bone Density; Carotid Artery Diseases; Carotid Intima-Media Thickness; Female; Hip Fractures; Humans; Lumbar Vertebrae; Middle Aged; Osteoporotic Fractures; Osteoprotegerin; Postmenopause; Prevalence; RANK Ligand; Risk Assessment; ROC Curve; Spinal Fractures; Trabecular Meshwork

To assess the relation of high serum OPG level and carotid atherosclerosis in maintenance hemodialysis (MHD) patients using low-flux reused dialyzer.. We examined 209 MHD patients with and without carotid atherosclerosis (83 patients and 126 patients) to establish the relation between OPG and atherosclerosis.. The proportion of carotid atherosclerosis was 39.7%. The median serum OPG level was 45.3 pmol/L. Serum OPG had a good predicting value for atherosclerosis in MHD patients using low-flux reused dialyzer (AUC = 0.934, p < 0.001, cutoff value = 43.35 pmol/L, Se = 81.3%, Sp = 90.9%).. In this study, serum OPG had a good predicting value for atherosclerosis in MHD patients using low-flux reused dialyzer.

Topics: Adult; Atherosclerosis; Carotid Artery Diseases; Female; Humans; Logistic Models; Male; Middle Aged; Osteoprotegerin; Renal Dialysis

The OPG/RANKL/RANK (osteoprotegerin/receptor-activator of nuclear factor κB ligand/receptor-activator of nuclear factor κB) axis has been recently linked to the development of atherosclerosis and plaque destabilization. We have investigated whether polymorphism rs2073618 of the OPG gene is associated with subclinical markers of carotid atherosclerosis in subjects with type 2 diabetes mellitus (T2DM).. 595 subjects with T2DM were enrolled in the cross-sectional study. Subclinical markers of carotid atherosclerosis (carotid intima media thickness, plaque thickness, and plaques presence) were assessed with ultrasound at the time of recruitment. Genotyping for rs2073618 (a missense variant located in exon I of the OPG gene) was performed, and OPG serum levels were determined by ELISA.. Compared to the GG genotype, the CC genotype of the rs2073618 polymorphism had a significantly increased risk for the presence of carotid plaque (OR = 2.54, 95 % CI = 1.22-5.28, p = 0.01). No statistically significant difference could be detected (p = 0.68) upon comparing median values of serum OPG levels among studied genotype groups in subjects with T2DM. Multivariable linear regression analyses in T2DM subjects demonstrated that GC and CC genotypes (p = 0.03 and p = 0.003), together with statin therapy (p = 0.009), were independent predictors of the number of carotid segments with plaques.. Despite the fact that OPG rs2073618 genotypes failed to predict the serum OPG levels as there was no statistical difference among compared genotypes, our results demonstrate that the rs2073618 polymorphism could be a possible genetic marker for the prediction of increased risk for carotid plaque burden as a measure of advanced subclinical atherosclerosis in T2DM subjects.

Topics: Aged; Asymptomatic Diseases; Carotid Artery Diseases; Carotid Intima-Media Thickness; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Osteoprotegerin; Phenotype; Polymorphism, Single Nucleotide; Risk Assessment; Risk Factors; Slovenia; White People

Osteoprotegerin (OPG) is a soluble glycoprotein belonging to the tumor necrosis factor receptor superfamily and is linked to vascular atherosclerosis and calcification. The carotid intima-media thickness (CIMT) correlates with carotid atherosclerosis and is a significant predictor of cardiovascular events. The OPG levels are associated with the CIMT in coronary artery disease (CAD) patients. However, the pathophysiological mechanisms underlying this pathway remain unclear. We investigated 114 CAD patients (89 men, 25 women; mean age: 68.7 ± 10.3 years) and measured the Gensini score (a marker of the extent of coronary atherosclerosis), the mean CIMT and the plasma levels of OPG and asymmetric dimethylarginine (ADMA; a marker of endothelial function). Early carotid atherosclerosis was defined as a mean CIMT > 1.0 mm. Only 33 of the 114 patients (28.9%) had early carotid atherosclerosis. Patients with early carotid atherosclerosis had higher OPG levels than those without. The OPG levels were found to be significantly associated with ADMA (r = 0.191, P = 0.046) and the mean CIMT (r = 0.319, P = 0.001), but not with the Gensini score. A receiver operating curve analysis revealed the optimal cut-off value of the OPG levels for predicting early carotid atherosclerosis to be 100 pmol/L. A multivariate logistic regression analysis showed OPG ≥ 100 pmol/L to be significantly and independently associated with early carotid atherosclerosis (odds ratio: 2.98, 95% confidence interval: 1.22-7.20, P = 0.017). These data indicate that OPG is significantly associated with endothelial function and predicts early carotid atherosclerosis in patients with CAD.

Topics: Aged; Arginine; Biomarkers; Carotid Artery Diseases; Carotid Intima-Media Thickness; Coronary Angiography; Coronary Artery Disease; Early Diagnosis; Endothelium, Vascular; Female; Humans; Japan; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Risk Assessment; Risk Factors; Severity of Illness Index

We studied the impact of hypertension along with traditional and new cardiovascular risk factors on the structural and functional properties of arteries in psoriatic arthritis (PsA) patients. We examined 42 PsA subjects (aged 51±9 years) stratified according to hypertensive status (19 normotensive, PsA-NT and 23 hypertensives, PsA-HT). Thirty-eight normotensive subjects (C-NT) and 23 hypertensives (C-HT) comparable by age and sex served as controls. Mean carotid intima-media thickness (mean-IMT) and mean of the maximum IMT (M-Max) were evaluated by ultrasound in carotid artery segment bilaterally. Post-occlusion flow-mediated dilation (FMD) of the brachial artery was evaluated by ultrasonography. These parameters were correlated with risk factors, markers of inflammation and disease activity. Values of mean-IMT were higher in both groups of PsA patients compared with C-NT (0.68 mm in PsA-NT and 0.75 mm in PsA-HT versus 0.61 mm in C-NT). PsA-HT displayed higher M-Max (0.95 mm) versus both C-HT (0.71 mm) and PsA-NT (0.79 mm). FMD was impaired in PsA subjects compared with C-NT (5.7% in PsA-NT and 6.0% PsA-HT versus 9.3% in C-NT), whereas there was no difference among PsA-HT, PsA-NT, and C-HT groups. Values of carotid IMT were directly related to tumor necrosis factor (TNF)-α, osteoprotegerin (OPG), blood pressure and lipid profile levels. FMD showed an inverse relationship with TNF-α and blood pressure, but no correlation with lipids. In conclusion, PsA per se implies a pro-atherogenic remodeling, which is enhanced by the hypertensive status. TNF-α and OPG may have an independent role in the development of such vascular damage.

Topics: Adult; Arthritis, Psoriatic; Biomarkers; Brachial Artery; Carotid Arteries; Carotid Artery Diseases; Carotid Intima-Media Thickness; Case-Control Studies; Female; Humans; Hypertension; Inflammation Mediators; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Risk Factors; Tumor Necrosis Factor-alpha; Vasodilation

Osteoprotegerin (OPG) may contribute to the link between systemic inflammation and increased cardiovascular risk. We investigated the relationship of OPG concentrations with endothelial activation and carotid atherosclerosis in rheumatoid arthritis (RA).. OPG concentrations and those of endothelial activation molecules were measured by using ELISA in 34 patients who were treated with infliximab (IFX), both immediately before and after an IFX infusion. Carotid intima-media thickness (CIMT) and plaque were determined by ultrasound in 27 of the study participants.. Median (interquartile range) OPG concentrations decreased from 4.8 pmol/l (2.8-6.5) to 4.4 pmol/l (2.9-6.1; p = 0.04) upon IFX infusion. Baseline OPG concentrations were inversely associated with those of total and low-density lipoprotein (LDL) cholesterol (partial R = -0.50, p = 0.004, and R = -0.48, p = 0.007, respectively). Prior to IFX administration, OPG concentrations were associated with those of intercellular adhesion molecule (ICAM)-1 (partial R = 0.34, p = 0.05), CIMT (partial R = 0.51 to 0.52, p < 0.009), and plaque (OR = 1.52, 95% CI 1.01-2.29 to OR = 1.61, 95% CI 1.03-2.51; p < 0.04), independent of conventional risk factors and C-reactive protein concentrations or disease activity. Except for the OPG concentrations-plaque association (p = 0.09), these relationships remained significant subsequent to IFX administration (p < 0.05). Reductions in OPG levels related to those in vascular cell adhesion molecule (VCAM)-1 concentrations (partial R = 0.35, p = 0.04) and had borderline significance (p = 0.09) with those in ICAM-1 (partial R = 0.29) concentrations.. OPG concentrations are independently associated with endothelial activation and carotid atherosclerosis in RA. Reductions in OPG concentrations upon IFX administration are associated with decreased endothelial activation. OPG may be involved in increased cardiovascular disease risk and may improve its stratification in patients with RA.

Topics: Aged; Arthritis, Rheumatoid; Atherosclerosis; Carotid Artery Diseases; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Osteoprotegerin

Patients with systemic lupus erythematosus (SLE) have increased risk for cardiovascular disease. Previous studies disclosed the association of serum osteoprotegerin (OPG) with the presence of symptomatic atherosclerosis in the general population and several disease conditions. We thus investigated the association between serum OPG levels and subclinical atherosclerosis in premenopausal SLE patients.. Serum OPG levels and carotid artery intima-media thickness (IMT) were measured in 181 premenopausal SLE patients and age-matched 85 control subjects. Traditional cardiovascular risk factors and SLE-related factors were analyzed.. Patients with SLE had significantly increased serum OPG levels (1086 versus 517 pg/ml, p < 0.001) and carotid IMT (0.63 versus 0.45 mm, p < 0.001) compared with control subjects. Carotid IMT significantly increased across the quartiles of OPG. Logistic regression analysis revealed that compared to the lowest OPG quartile, the odds ratio (OR, 95% confidence interval) for increased carotid IMT in quartile 2, 3, and 4 was 1.126 (1.013-1.801), 1.562 (1.268-2.799), and 4.460 (1.126-7.128), respectively, after multiple adjustments (p for trend across quartiles < 0.001). These associations remained significant after further adjustment for inflammatory parameters. Interestingly, serum monocyte chemotactic protein-1 (MCP-1) levels were positively correlated with serum OPG levels (γ = 0.332, p < 0.001). Parallel analysis showed that serum MCP-1 was also an independent predictor of carotid IMT incrassation, but this association was lost when serum OPG was included in the model.. Serum OPG levels were increased and correlated with serum MCP-1 levels in premenopausal SLE patients. Increased serum OPG was independently associated with subclinical atherosclerosis in these patients.

Topics: Adult; Asymptomatic Diseases; Biomarkers; Carotid Artery Diseases; Carotid Intima-Media Thickness; Case-Control Studies; Chemokine CCL2; Chi-Square Distribution; Female; Humans; Logistic Models; Lupus Erythematosus, Systemic; Odds Ratio; Osteoprotegerin; Predictive Value of Tests; Premenopause; Republic of Korea; Risk Factors; Up-Regulation

Acute clinical complications of atherosclerosis such as myocardial infarction (MI) and ischaemic stroke are usually caused by thrombus formation on the ruptured plaque surface. Collagen, the main structural protein of the fibrous cap, provides mechanical strength to the atherosclerotic plaque. The integrity of the fibrous cap depends on collagen fibre cross-linking, a process controlled by the enzyme lysyl oxidase (LOX).. We studied atherosclerotic plaques from human carotid endarterectomies. LOX was strongly expressed in atherosclerotic lesions and detected in the regions with ongoing fibrogenesis. Higher LOX levels were associated with a more stable phenotype of the plaque. In the studied population, LOX mRNA levels in carotid plaques predicted the risk for future MI. Within the lesion, LOX mRNA levels correlated positively with levels of osteoprotegerin (OPG) and negatively with markers of immune activation. The amount of LOX-mediated collagen cross-links in plaques correlated positively also with serum levels of OPG.. Lysyl oxidase may contribute to the healing of atherosclerotic lesions and to the prevention of its lethal complications. Mediators of inflammation may control LOX expression in plaques and hence plaque stability.

Topics: Aged; Aged, 80 and over; Atherosclerosis; Carotid Artery Diseases; Female; Humans; Male; Middle Aged; Myocardial Infarction; Osteoprotegerin; Plaque, Atherosclerotic; Protein-Lysine 6-Oxidase; Risk Factors; RNA, Messenger

Osteoprotegerin (OPG) is a bone metabolism regulator but it is also involved in vascular calcification. Its role in the development of atherosclerosis is still a subject of debate. Postmenopausal women seem to have an increased risk for cardiovascular disease. The aim of the study is to evaluate the relationship between serum OPG and asymptomatic carotid atherosclerosis in postmenopausal non-diabetic women.. Carotid artery examination was performed in 100 postmenopausal women without diabetes mellitus and overt cardiovascular disease, using B-mode ultrasonography to determine the carotid intima-media thickness (CIMT) and the presence of plaques. Serum OPG was measured in all study participants and its relationship with clinical, biochemical and vascular parameters was evaluated.. CIMT correlated with age (r=0.45, p<0.001), years since menopause (r=0.30, p=0.003), abdominal circumference (r=0.25, p=0.01) and OPG (r=0.23, p=0.02). Carotid plaques correlated with age (p<0.001), obesity (p=0.03), abdominal circumference (p=0.03) and CIMT (p<0.001), but not with serum OPG (p=0.86). In regression analyses the independent predictors for CIMT were age (β=0.717, p<0.001), OPG (β=0.214, p=0.02), and years since menopause (β=-0.334, p=0.04) and for the presence of carotid plaques were obesity (p=0.04, OR=3.90), CIMT (p<0.001, OR=6408.86) and smoking (p=0.02, OR=687.93).. OPG is associated with cardiovascular risk factors, CIMT, but not with the presence of asymptomatic carotid plaques in non diabetic postmenopausal women. OPG may be a marker of cardiovascular risk.

Topics: Aged; Aging; Biomarkers; Carotid Artery Diseases; Carotid Intima-Media Thickness; Cross-Sectional Studies; Early Diagnosis; Female; Humans; Middle Aged; Osteoprotegerin; Plaque, Atherosclerotic; Postmenopause; Risk Factors; Romania; Severity of Illness Index; Up-Regulation

The aim of this study was to evaluate in detail the histopathological characteristics of endarterectomized carotid atherosclerotic lesions in symptomatic versus asymptomatic patients. Twenty carotid lesions, 10 from asymptomatic and 10 from symptomatic patients who underwent carotid endarterectomy were classified according to histomorphological features. Samples were analyzed for intraplaque localization and for the expression of proteins associated with inflammation, such as CD68, interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), pentraxin-3 (PTX-3), nuclear factor-κB (NF-κB), C-reactive protein (CRP) and transforming growth factor-β (TGF-β), as well as for proteins associated with vascular remodelling, such as matrix-metalloproteinase-9 (MMP-9), glycophorin A (GYPA), osteoprotegerin (OPG), vascular cell adhesion molecule-1 (VCAM-1), endothelin-1 (ET-1), vascular endothelial growth factor (VEGF) and vascular smooth muscle cell actin (VSMA). Corresponding expression scores were compared between the symptomatic and asymptomatic patients and evaluated statistically. The expression of all 14 evaluated markers was significantly elevated in the border zone adjacent to the mixed plaque compared with the unaffected control area of the same sample (p<0,016). The expression scores of GYPA and OPG were significantly higher in the border zones around the calcified (GYPA, p=0.035; OPG, p=0.043) and mixed (GYPA, p<0.001; OPG, p=0.007) plaque zones of symptomatic patients compared to asymptomatic patients. No difference in expression scores was observed for any of the analyzed inflammatory marker proteins between the border zones of symptomatic and asymptomatic patients. In conclusion, the increased expression of GYPA, indicating intraplaque hemorrhage, and OPG, indicating the transdifferentiation of vascular cells, in carotid atherosclerotic lesions may be associated with an increased risk of plaque instability.

Topics: Aged; Aged, 80 and over; Asymptomatic Diseases; Atherosclerosis; Carotid Artery Diseases; Female; Gene Expression; Glycophorins; Humans; Male; Middle Aged; Osteoprotegerin; Plaque, Atherosclerotic; Risk Factors

Osteoprotegerin (OPG), a regulator of bone resorption, is involved in the pathogenesis of rheumatoid arthritis (RA) and atherosclerosis. OPG is elevated in patients with coronary artery disease, and high OPG levels are associated with cardiac disease severity and mortality in the general population. The purpose of this study was to investigate the relationship of serum OPG levels, traditional coronary risk factors, and RA-related factors to carotid atherosclerosis in RA patients.. Ninety-one RA patients were studied (85 % women, age 60 ± 10 years). Serum OPG levels were measured by an enzyme-linked immunosorbent assay. The prevalence of carotid plaque was assessed by ultrasonographic imaging in all patients. The relationship between various clinical characteristics, OPG, and carotid plaque was examined.. Serum OPG levels were significantly higher in patients with carotid plaque than in those without plaque (median level 1,397 vs. 887 pg/mL, respectively; P = 0.006). There were no significant differences between RA patients with and without carotid plaque with respect to sex, duration of RA, blood pressure, body mass index, smoking, low-density lipoprotein cholesterol, Disease Activity Score-28, van der Heijde-modified Sharp score, and prednisolone dose. After adjusting for age, sex, and C-reactive protein, elevated levels of OPG were still associated with a higher prevalence of carotid plaque in patients with RA (P = 0.038).. RA patients suffer from accelerated atherosclerosis and also have increased levels of OPG. The serum OPG level is independently associated with carotid plaque.

Topics: Adult; Aged; Arthritis, Rheumatoid; Atherosclerosis; Carotid Artery Diseases; Female; Humans; Male; Middle Aged; Osteoprotegerin; Plaque, Atherosclerotic; Risk Factors; Ultrasonography

Osteoprotegerin (OPG) is considered to be a crucial regulatory mediator of bone metabolism by acting as a decoy receptor of the receptor activator of nuclear factor κB ligand (RANKL). OPG and RANKL have further become the subject of intense interest for their potential role in cardiovascular disease. The present study aimed to assess the clinical implication of plasma OPG and RANKL levels in patients with advanced carotid atherosclerosis.. Plasma OPG and RANKL concentrations measured by solid-phase enzyme-linked immunosorbent assay (ELISA) were correlated with medical history, risk factors and medication intake in 131 patients who underwent carotid endarterectomy for vascular repair.. Plasma OPG concentrations were associated with patients' age (p=0.0258), homocysteine levels (p<0.00001), eGFR (p=0.0254), history of diabetes (p=0.0324), statins therapy (p=0.0044), hyperlipidemia (p=0.0407), smoking (p=0.0226) and CAD (p=0.0377). Plasma RANKL concentrations were associated with patients' age (p=0.0191), homocysteine levels (p<0.00001), history of smoking (p=0.0185) and statins therapy (p=0.0004). Diabetes, CAD, smoking status, statins therapy and homocysteine were identified as independent predictors of OPG concentrations (p=0.0157, p=0.0030, p=0.0249, p=0.0047 and p=0.0072, respectively), whereas smoking showed an independent effect for RANKL (p=0.0010).. The present data reinforce the clinical utility of OPG in carotid atherosclerosis, whereas the clinical implication of RANKL seems uncertain.

Topics: Aged; Carotid Artery Diseases; Female; Humans; Male; Middle Aged; Osteoprotegerin; RANK Ligand; Risk Factors

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

Apoptosis and inflammation are important features of atherosclerotic plaques. We investigated whether a common signal molecule can trigger these two apparently separate pathways. Hypoxia inducible factor (HIF-1α) is known to participate in atherosclerosis and to stimulate apoptosis signal-regulating kinase 1 (ASK-1), one of the mitogen-activated protein kinases, which is activated by various extracellular stimuli and involved in a variety of cellular function.. We tested carotid artery specimens from 50 subjects who underwent angioplasty and five age-matched controls for either Western blot or histologic analysis. The hypoxic status was investigated by means of HIF-1α expression in carotid specimens.. HIF-1α was significantly upregulated in carotid specimens with respect to controls (P < .05), ASK-1 was detected in plaques of any composition from lipidic to calcific, and this expression increased with the stage of the plaque and with the expression of inflammatory (p-ERK, RANK-L, OPG) and apoptotic molecules (caspase 9, p-p-38, and p-JNK).. Our data suggest that hypoxia is the key regulating factor that triggers inflammation as well as apoptosis in the human atherosclerotic plaque.

Topics: Angioplasty; Apoptosis; Biomarkers; Blotting, Western; Carotid Arteries; Carotid Artery Diseases; Case-Control Studies; Caspase 9; Cell Hypoxia; Extracellular Signal-Regulated MAP Kinases; Finland; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Inflammation Mediators; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase Kinase 5; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Osteoprotegerin; p38 Mitogen-Activated Protein Kinases; Phosphorylation; RANK Ligand; Up-Regulation

Topics: Carotid Artery Diseases; Cerebral Angiography; Child; Humans; Intracranial Aneurysm; Male; Osteitis Deformans; Osteoprotegerin

Patients with vascular calcifications often have low bone mineral density (BMD), but it is still uncertain if osteoporosis and peripheral vascular disease (VD) are interrelated and linked by a common pathomechanism. Moreover, data on bone turnover in patients with advanced atherosclerosis are lacking. We measured BMD by dual-energy X-ray absorptiometry (DXA) and quantitative bone ultrasound (QUS), as well as the serum levels of osteocalcin (OC), bone-specific alkaline phosphatase (BAP), osteoprotegerin (OPG) and its ligand RANKL, and the urinary concentration of the C-terminal telopeptides of type I collagen (CrossLaps), in 36 patient (20 male and 16 female) with serious atherosclerotic involvement of the carotid and/or femoral artery to investigate the underlying mechanism of vascular and osseous disorders. Thirty age-matched and gender matched healthy individuals served as controls. After adjustment for age, BMD was significantly reduced at the lumbar spine in 23/36 (63%) patients (mean T score -1.71+/-1.42) and at the proximal femur in 34/36 (93%) patients (neck mean T score -2.5+/-0.88). Ten patients (27%) had abnormal QUS parameters. Gender and diabetes had no effect on the relationship between vascular calcification and bone density at any site measured. VD subjects had OC and BAP serum levels lower than controls (13.3+/-3.1 vs 27.7+/-3.3 ng/ml, P<0.01, and 8.4+/-2.3 vs 12.5+/-1.4 microg/l, P<0.01, respectively). Urinary CrossLaps excretion was not significantly different in patients with VD and in controls (257.9+/-138.9 vs 272.2+/-79.4 micro g/mmol Cr, respectively). Serum OPG and RANKL levels were similar in patients and in controls (3.5+/-1.07 vs 3.4+/-1.05 pmol/l, and 0.37+/-0.07 vs 0.36+/-0.06 pmol/l, respectively). We proved high occurrence of osteoporosis in VD, with evidence of age and gender independence. Negative bone remodelling balance would be a consequence of reduced bone formation, with no apparent increased activation of the OPG-RANKL system.

Topics: Absorptiometry, Photon; Aged; Arteriosclerosis; Biomarkers; Bone Density; Bone Remodeling; Calcinosis; Carotid Artery Diseases; Collagen; Female; Femoral Artery; Glycoproteins; Humans; Male; Middle Aged; Osteocalcin; Osteoporosis; Osteoprotegerin; Peptide Fragments; Peripheral Vascular Diseases; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Ultrasonography

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