osteoprotegerin and Hypertension

Osteoprotegerin (OPG) is a member of the tumour necrosis factor receptor superfamily of cytokines which, in spite of being initially described as a strong anti-resorptive factor, has lately been considered as a possible link between bone and vascular disease. In the last few years, several studies have evidenced its close relationship with the development of diabetes. In this review, we analyse the role of OPG in diabetic patients and its links with the most relevant associated diseases such as atherosclerosis, hypertension, endothelial dysfunction and diabetic nephropathy, as well as its connection with related pathologies as fibrosis, obesity and metabolic syndrome.

Topics: Atherosclerosis; Diabetes Complications; Diabetic Nephropathies; Fibrosis; Humans; Hypertension; Metabolic Syndrome; Obesity; Osteoprotegerin

Patients with end-stage renal disease have greatly elevated risks of atherosclerotic disease. Vascular calcification in advanced atherosclerosis is a common feature in ESRD patients. Risk factors of atherosclerosis in ESRD patients are coronary risk factors such as hypertension, diabetes and hyperlipidemia and hyperphosphatemia. Bone associated proteins including osteopontin, matrix Gla protein and osteoprotegerin may be involved in the progression of atherosclerosis.

Topics: Arteriosclerosis; Calcium-Binding Proteins; Diabetes Complications; Diabetes Mellitus; Extracellular Matrix Proteins; Glycoproteins; Humans; Hyperlipidemias; Hypertension; Kidney Failure, Chronic; Matrix Gla Protein; Osteopontin; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; Sialoglycoproteins

The renin-angiotensin-aldosterone system (RAAS) has recently been considered as a possible link between bone and vascular disease. The present study was designed to determine the effect of the angiotensin II receptor blocker candesartan on circulating osteoprotegerin (OPG) in hypertensive patients with multiple cardiovascular risk factors.. A total of 69 hypertensive patients were randomized to two groups: Group 1 included patients treated with oral candesartan in doses of 16 mg to 32 mg per day in addition to routine standard of care (routine care + ARB), and Group 2 included patients who received routine standard of care other than ARBs or ACEIs, with no change to their treatment (routine care). Patients were evaluated for lipid profile, HbA1C, insulin, C-peptide, CRP, aldosterone, renin, homeostasis model assessment-insulin resistance (HOMA-IR) and OPG.. Baseline OPG levels did not differ significantly by treatment group. Post-treatment serum OPG levels were marginally lower in Group1 compared with Group 2; however, this decrease did not reach statistical significance (p = 0.077).. In the present study, treatment with the ARB candesartan had no significant effect on circulating OPG levels in hypertensive patients with multiple cardiovascular risk factors. To the best of our knowledge, the present study is the first to estimate an effect of candesartan on bone remodeling marker such as OPG.

Topics: Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Biphenyl Compounds; Bone and Bones; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Osteoprotegerin; Renin-Angiotensin System; Tetrazoles

Vascular calcification is a potent predictor of plaque instability and cardiac events. Osteoprotegerin (OPG), well-known vascular calcification mediator, is a signaling molecule involved in bone remodeling, which has been implicated in the regulation of vascular calcification and atherogenesis. The purpose of this study was to compare the combination treatments of olmesartan/azelnidipine and olmesartan/diuretics on serum bone-related markers in patients with essential hypertension.. A total of 48 patients with hypertension treated with 20 mg olmesartan were randomized to receive combination treatment with 16 mg azelnidipine (O/A group) or diuretics (1 mg indapamide; O/D group) for 12 months. Osteoprotegerin, matrix metalloproteinase 2 (MMP-2), and high-sensitive CRP (hs-CRP) were measured after 3 and 12 months of treatment. Cardio-ankle vascular index (CAVI) was measured as the arterial stiffness using a VaSera CAVI instrument at the same time points. In both groups, the systolic and diastolic blood pressure reduction is similar. Serum OPG, MMP-2, and hs-CRP were significantly decreased at 12 months in the O/A group (P < .05), while there were no significant reductions in the O/D group. CAVI was significantly improved at 12 months in both the treatment groups. The improvement in CAVI was significantly greater in the O/A group than in the O/D group.. Azelnidipine, but not indapamide, combined with olmesartan, improved arterial stiffness and were associated with significant decrease in OPG, MMP-2, and hs-CRP concentrations. These results suggest that the beneficial effects of the combination treatments of olmesartan/azelnidipine on arterial stiffness are mediated by alteration in bone-remodeling and inflammatory markers.

Topics: Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Azetidinecarboxylic Acid; Biomarkers; Blood Pressure; C-Reactive Protein; Calcium Channel Blockers; Dihydropyridines; Diuretics; Drug Therapy, Combination; Essential Hypertension; Female; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Male; Matrix Metalloproteinase 2; Middle Aged; Osteoprotegerin; Prospective Studies; Tetrazoles

The biomarker Osteoprotegerin (OPG) is associated with coronary artery disease (CAD). The main purpose of this study was to evaluate the diagnostic value of OPG in healthy subjects and in patients with suspected angina pectoris (AP).. A total of 1805 persons were enrolled: 1152 healthy subjects and 493 patients with suspected AP. For comparison 160 patients with acute myocardial infarction (MI) were included. To uncover subclinical coronary atherosclerosis, a non-contrast cardiac-CT scan was performed in healthy subjects; while in patients with suspected AP a contrast coronary angiography was used to detect significant stenosis. OPG concentrations were analyzed and compared between groups. ROC-analyses were performed to estimate OPG cut-off values.. OPG concentrations increased according to disease severity with the highest levels found in patients with acute MI. No significant difference (p = 0.97) in OPG concentrations was observed between subgroups of healthy subjects according to severity of coronary calcifications. A significant difference (p < 0.0001) in OPG concentrations was found between subgroups of patients with suspected stable AP according to severity of CAD. ROC-analysis showed an AUC of 0.62 (95% CI: 0.57-0.67). The optimal cut-off value of OPG (<2.29 ng/mL) had a sensitivity of 56.2% (95% CI: 49.2-63.0%) and a specificity of 62.9% (95% CI: 57.3-68.2%).. OPG cannot be used to differentiate between healthy subjects with low versus high levels of coronary calcifications. In patients with suspected AP a single OPG measurement is of limited use in the diagnosis of CAD.

Topics: Angina Pectoris; Area Under Curve; Biomarkers; Calcinosis; Calcium; Comorbidity; Coronary Angiography; Coronary Artery Disease; Coronary Disease; Diabetes Mellitus; Female; Humans; Hyperlipidemias; Hypertension; Male; Middle Aged; Myocardial Infarction; Osteoprotegerin; ROC Curve; Sampling Studies; Severity of Illness Index; Smoking; Tomography, X-Ray Computed

Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor receptor family, and in previous studies has been shown to regulate osteoclast activity and differentiation. Ablation of the OPG gene in mice results in calcification of the aorta and renal arteries. We have previously reported an association between a single nucleotide polymorphism in the promoter region of OPG and vascular morphology and function in healthy humans. The objective with this study was to confirm our previous results in a larger population, and in addition, to study subjects with hypertension. The OPG genotype was determined by restriction fragment length and the intima-media thickness (IMT) of the common carotid artery was measured by ultrasound in 100 patients with hypertension and left ventricular hypertrophy, and 75 healthy normotensive control subjects. In the hypertensive group subjects with the CC genotype (n=24) showed a significantly increased IMT compared to those with the TC (n=52, p=0.007) and TT (n=24, p=0.009) genotype, in the hypertensive group only (mean +/- SD for TT=0.88 +/- 0.21 mm, TC=0.90 +/- 0.16 mm, CC=1.05 +/- 0.31 mm). The allele distribution did not differ between hypertensive and control individuals. The present study confirms our previous finding and shows that polymorphism in the promoter region of OPG is associated with vascular morphology in hypertensive subjects.

Topics: Adrenergic beta-Antagonists; Adult; Atenolol; Carotid Arteries; Female; Genotype; Glycoproteins; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Osteoprotegerin; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sweden

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

Topics: Atherosclerosis; Biomarkers; Humans; Hypertension; Linear Models; Osteoprotegerin; Regression Analysis

Background The biological mechanism of action for osteoprotegerin, a soluble decoy receptor for the receptor activator of nuclear factor-kappa B ligand in the vascular structure, has not been elucidated. The study aim was to determine if osteoprotegerin affects aortic structural integrity in angiotensin II (Ang II)-induced hypertension. Methods and Results Mortality was higher (

Topics: Angiotensin II; Animals; Aortic Dissection; Aortic Rupture; Disease Models, Animal; Elastin; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoprotegerin; RANK Ligand

The aim of the study was to determine the relationship between the serum selenium concentration (Se-S) and the blood concentrations of osteoprotegerin (OPG), receptor activator of nuclear factor kappa-Β ligand (RANKL) and the OPG/RANKL ratio in patients with arterial hypertension. The study group comprised 138 patients with arterial hypertension (age: 56.04 ± 11.59 years). Se-S was determined in all the subjects. Based on the Se-S, the following subgroups were distinguished: a subgroup of patients with a lower Se-S ("low-Se", Se-S < median) and a subgroup of patients with a higher Se-S ("high-Se", Se-S ≥ median). Moreover, the blood concentrations of the parameters of bone metabolism and extraskeletal calcification were assessed: OPG and RANKL. The OPG/RANKL ratio was calculated. In the "low-Se" subgroup, the RANKL concentration was statistically significantly lower, and the OPG/RANKL ratio was statistically significantly higher than in the patients in the "high-Se" subgroup. The correlation analysis showed the negative linear relationships between Se-S and OPG (r = - 0.25, p < 0.05) and between Se-S and OPG/RANKL (r = - 0.47, p < 0.05). Moreover, Se-S positively correlated with RANKL (r = 0.33, p < 0.05). In regression analysis, higher body mass index (BMI), smoking and lower Se-S were independently associated with a higher OPG/RANKL ratio, while lower BMI, use of diuretics, β-blockers and ACE inhibitors and lower OPG/RANKL ratio with effective blood pressure control. In summary, in the group of patients with arterial hypertension, lower Se-S is associated with an unfavourable prognostic panel of parameters of bone metabolism and extraskeletal calcification. Lower Se-S is an independent risk factor for a higher OPG/RANKL ratio, which is an independent prediction factor of ineffective blood pressure control in patients with hypertension.

Topics: Adult; Aged; Humans; Hypertension; Middle Aged; NF-kappa B; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Selenium

Decreased baroreflex sensitivity (BRS) has been shown to be a marker of cardiovascular (CV) risk. In the present study, the difference in CV risk biomarkers in type 2 diabetes (T2D) patients receiving oral antidiabetic drugs (OAD) with and without hypertension has been assessed.. Ninety-two T2D patients on OAD without hypertension (control group) and eighty-eight diabetic patients with hypertension on OAD and antihypertensive drugs (test group) matched for age, gender, body mass index, serum glucose, glycated haemoglobin, and duration of the disease were recruited for the study. Their blood pressure (BP) variability including BRS, heart rate variability (HRV), insulin, lipid profile, osteoprotegerin (OPG), and tumor necrosis factor-α (TNF-α) were estimated. The association of various factors with BRS was assessed by Spearman correlation and multiple regression analysis.. BRS was decreased (13.90 ± 5.27 vs 6.76 ± 4.58), HRV sympathetic indices [LFnu, LF-HF ratio (1.30 ± 0.49 vs 1.93 ± 0.62)], HOMA-IR, atherogenic index of plasma (AIP), OPG (223.08 ± 103.86 vs 287.60 ± 121.36) and TNF-α were increased, and parasympathetic indices [TP (1012.90 ± 316.18 vs 625.88 ± 229.84), RMSSD, SDNN, NN50, pNN50] were decreased in the test group compared to control group. In control group, parasympathetic indices, AIP, OPG, and TNF-α had a significant correlation and OPG had an independent association (β - 0.344; p 0.004) with BRS. In test group, BP, LF-HF ratio, parasympathetic indices, AIP, OPG, and TNF-α had significant correlation, and TNF-α alone (β - 0.297; p 0.022) had an independent contribution to decreased BRS.. Despite antidiabetic and antihypertensive treatments, T2D patients with hypertension had more cardiometabolic risks in comparison to normotensive T2D patients. Inflammation could be the inciting factor for rise in BP and decrease in BRS (CV risk) in hypertensive T2D patients. Hypertension in diabetes could attenuate the link of OPG to the reduction in BRS. Reduction in BRS could be a physiological marker of CV risk in T2D patients treated with OAD.

Topics: Antihypertensive Agents; Baroreflex; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Humans; Hypertension; Hypoglycemic Agents; Osteoprotegerin; Tumor Necrosis Factor-alpha

Osteoprotegerin (OPG), a well-known protein that inhibits osteoclast formation and activity, might also be a potential marker for identifying patients with high cardiovascular risk. This study aimed to compare OPG levels, FMD, and CIMT measurements in subjects with vs. without diabetes and investigate the association of serum osteoprotegerin level with the early atherosclerotic markers, endothelial function, and carotid intima-media thickness (CIMT) in patients with type 2 diabetes mellitus (DM2).. Forty-nine patients with DM2 (F/M: 26/23, 49.3 ± 10.0 years) and 45 healthy volunteers (F/M: 26/19, 48.3 ± 7.5 years) were included in this cross-sectional study. Serum OPG levels were measured by solid-phase enzyme-linked immunosorbent assay (ELISA). Fasting plasma glucose (FPG) and HbA1c levels were measured. CIMT was measured by B-mode ultrasound, and endothelial function was evaluated via flow-mediated dilation (FMD) of the brachial artery with Doppler ultrasonography.. Serum OPG levels were significantly higher in patients with DM2 (617.0 ± 111.0 pg/mL) compared to controls (481.0 ± 96.0 pg/mL, p < 0.001). While CIMT in diabetic patients (0.65 + 0.13 mm) was higher than controls (0.54 ± 0.10 mm, p = 0.009), FMD measurement was lower in DM2 group (4.2% ± 3.1 mm vs. 7.6% ± 4.1 mm, p = 0.01). Univariate analysis showed that OPG was associated with the presence of diabetes (OR: 6.999, p = 0.001, R. Osteoprotegerin and CIMT levels were increased, and FMD measurements were decreased in patients with DM2. No association between CIMT, FMD, and OPG measurements was observed. The presence of DM and hypertension were associated with circulating OPG levels.

Topics: Adult; Biomarkers; Blood Glucose; Brachial Artery; Carotid Intima-Media Thickness; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Glycated Hemoglobin; Humans; Hypertension; Male; Middle Aged; Osteoprotegerin; Ultrasonography

Previous studies showed that subclinical abnormal left atrial (LA) function could be diagnosed with LA speckle tracking evaluation long before chamber enlargement. Osteoprotegerin (OPG) is a member of the tumor necrosis factor (TNF) receptor superfamily and was recently found to be an indicator for adverse cardiovascular outcomes and a risk factor for new onset atrial fibrillation. The authors hypothesized that OPG values could predict LA mechanical dysfunction and LA remodeling assessed by two-dimensional speckle tracking echocardiography (2D-STE) in patients with hypertension (HT) and diabetes mellitus (DM).. A single center study was conducted including consecutive patients presenting to the authors' outpatient clinic. Enrolled patients needed to have been treated for HT and DM for at least 1 year.. The study included 80 patients (mean age, 57.5 ± 8.3 years). Patients in the impaired LA strain group were older (p = 0.035), had lower low density lipoprotein (LDL) cholesterol (mg/dl) (p = 0.021), and higher OPG (pmol/l) (p = 0.004) values than patients in the normal LA strain group. Univariate logistic regression analysis demonstrated that age (p = 0.039), LDL cholesterol (mg/dl) (p = 0.025), and OPG (pmol/l) (p = 0.008) values were associated with impaired LA strain. Backward multivariate logistic regression analysis showed that LDL cholesterol (mg/dl) (OR: 0.982, CI 95% 0.964-0.999, p = 0.049) and OPG (pmol/l) (OR: 1.438, CI 95% 1.043-1.983, p = 0.027) were independently associated with impaired LA strain.. In hypertensive and diabetic patients, higher OPG values were associated with impaired LA function assessed by 2D-STE. In this high-risk patient group, serum OPG can be used as a risk predictor for LA mechanical dysfunction.. ZIELSETZUNG: Frühere Studien belegen, dass eine subklinisch gestörte linksatriale (LA) Funktion mithilfe der linksatrialen Speckle-tracking-Analyse lange vor einer Kammervergrößerung diagnostiziert werden kann. Osteoprotegerin (OPG) gehört zur Familie der Tumor-Nekrose-Faktor(TNF)-Rezeptor-Superfamilie und wurde vor Kurzem als Indikator eines ungünstigen kardiovaskulären Verlaufs und als Risikofaktor für neu auftretendes Vorhofflimmern identifiziert. Es wird postuliert, dass die OPG-Werte bei Patienten mit Hypertonie (HT) und Diabetes mellitus (DM) ein Prädiktor für mechanische LA-Dysfunktion und LA-Remodeling in der zweidimensionalen Speckle-tracking-Echokardiographie (2D-STE) sind.. In eine Single-Center-Studie wurden konsekutiv Patienten eingeschlossen, die sich in der Klinik der Autoren ambulant vorstellten. Voraussetzung für den Einschluss war eine mindestens 1‑jährige Behandlung wegen HT und DM.. Insgesamt 80 Patienten wurden in die Studie eingeschlossen (Durchschnittsalter 57,5 ± 8,3 Jahre). Die Patienten in der Gruppe mit gestörtem LA-Strain waren älter (p = 0,035), hatten einen niedrigeren Low-density-Lipoprotein(LDL)-Cholesterin-Spiegel (mg/dl; p = 0,021) und höhere OPG-Spiegel (pmol/l; p = 0,004) als Patienten in der Gruppe mit normalem LA-Strain. Eine univariate logistische Regressionsanalyse ergab, dass das Alter (p = 0,039), LDL-Cholesterin (mg/dl; p = 0,025) und OPG (pmol/l; p = 0,008) mit einem gestörten LA-Strain assoziiert waren. In einer rückwärts gerichteten multivariaten logistischen Regressionsanalyse waren LDL-Cholesterin (mg/dl; OR 0,982, 95%-Konfidenzintervall [KI] 0,964–0,999, p = 0,049) und OPG (pmol/l; OR 1,438, 95%-KI 1,043–1,983, p = 0,027) unabhängig mit einem gestörten LA-Strain assoziiert.. Bei Patienten mit Hypertonie und Diabetes waren höhere OPG-Werte mit einer gestörten LA-Funktion in der 2D-STE assoziiert. In dieser Hochrisikogruppe kann der Serum-OPG-Spiegel als Risikoprädiktor der mechanischen LA-Dysfunktion genutzt werden.

Topics: Aged; Atrial Function, Left; Atrial Remodeling; Diabetes Mellitus; Heart Atria; Humans; Hypertension; Middle Aged; Osteoprotegerin

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

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

Pre-eclampsia is a known risk factor for long-term cardiovascular complications. Osteoprotegerin (OPG) and the receptor activator of nuclear factor κB ligand (RANKL) have been implicated in the pathogenesis of cardiovascular disease. The OPG-RANKL axis function is also altered in pregnant women with pre-eclampsia, but there is lack of data regarding OPG and RANKL concentrations in their neonates.. To examine the effects of early-onset pre-eclampsia on OPG and RANKL serum concentrations at birth, taking into account the influence of various perinatal factors.. OPG and RANKL serum concentrations were measured in 28 premature newborns of mothers with early onset pre-eclampsia, and in 28 preterm and 28 full-term neonates of normotensive mothers (control groups).. Neonates of pre-eclamptic mothers had higher OPG and lower RANKL levels compared to both control groups (Kruskal-Wallis P < 0.0001 and P = 0.014, respectively). Regression analysis showed that pre-eclampsia (P < 0.0001), birth weight z-score (P = 0.048) and antenatal steroid administration (P = 0.034) were significant determinants of OPG levels. Multivariable regression analysis also showed that pre-eclampsia was an independent predictor of increased diastolic and mean blood pressure in these neonates.. Early-onset pre-eclampsia affects OPG concentrations at birth and is an independent predictor of increased blood pressure in the offspring. Our findings suggest that altered OPG-RANKL axis function may be one of the mechanisms of cardiovascular 'programming' in fetuses exposed to pre-eclampsia.

Topics: Adult; Biomarkers; Blood Pressure; Female; Humans; Hypertension; Infant, Newborn; Male; Osteoprotegerin; Pre-Eclampsia; Pregnancy; Prenatal Exposure Delayed Effects; RANK Ligand

Osteoprotegerin (OPG) is a glycoprotein that plays an important regulatory role in the skeletal, vascular, and immune system. It has been shown that OPG predicts chronic kidney disease (CKD) in diabetic patients. We hypothesized that OPG could be a risk marker of CKD development also in non-diabetic hypertensive patients.. A case-control study was carried out to measure circulating OPG levels in 42 hypertensive patients with CKD and in 141 hypertensive patients without CKD. A potential relationship between OPG and the presence of CKD was investigated and a receiver-operating characteristic (ROC) curve was designed thereafter to identify a cut-off value of OPG that best explained the presence of CKD. Secondly, to evaluate whether OPG increase could affect the kidney, 18 C57BL/6J mice were randomized to be treated with saline or recombinant OPG every 3 weeks for 12 weeks.. Circulating OPG levels were significantly higher in hypertensive patients with CKD, and there was a significant inverse association between OPG and renal function, that was independent from other variables. ROC analysis showed that OPG levels had a high statistically predictive value on CKD in hypertensive patients, which was greater than that of hypertension. The OPG best cut-off value associated with CKD was 1109.19 ng/L. In the experimental study, OPG delivery significantly increased the gene expression of pro-inflammatory and pro-fibrotic mediators, as well as the glomerular nitrosylation of proteins.. This study shows that OPG is associated with CKD in hypertensive patients, where it might have a higher predictive value than that of hypertension for CKD development. Secondly, we found that OPG delivery significantly increased the expression of molecular pathways involved in kidney damage. Further longitudinal studies are needed not only to evaluate whether OPG predicts CKD development but also to clarify whether OPG should be considered a risk factor for CKD.

Topics: Aged; Animals; Biomarkers; Case-Control Studies; Female; Follow-Up Studies; Humans; Hypertension; Male; Mice; Mice, Inbred C57BL; Middle Aged; Osteoprotegerin; Random Allocation; Renal Insufficiency, Chronic

Osteoprotegerin (OPG) is associated with a poor prognosis in patients with heart failure with preserved ejection fraction (HFpEF). OPG has also been associated with fibrosis and collagen cross-linking, which increase arterial and left ventricle (LV) myocardial stiffness. Little is known about the relation of OPG and LV structure and function in African-Americans who are disproportionately affected by HFpEF.. Our analysis included 1172 participants with preserved LV ejection fraction (>50%) from the African-American cohort in the Genetic Epidemiology Network of Arteriopathy Study (mean age 63 years, 72% female). We used diastolic wall strain indicator measured by echocardiography to assess LV myocardial stiffness. Diastolic wall strain was calculated as (LV posterior thickness at end-systole - LV posterior thickness at end-diastole)/LV posterior thickness at end-systole. Associations between OPG levels and indices of arterial and LV structure and function were evaluated by using generalized linear mixed models and adjusted for possible confounders. OPG levels were correlated with age, female sex, presence of hypertension and diabetes, and lower estimated glomerular filtration rate (P < 0.05 for all). Multivariable analysis revealed that higher OPG levels were associated with greater LV mass index, increased LV myocardial stiffness, and higher N-terminal prohormone brain natriuretic peptide levels (P < 0.05 for all).. In African-Americans, higher OPG levels were associated with characteristics common in patients with HFpEF and were significantly associated with known precursors to HFpEF. These findings indicate a potential role for OPG in the pathophysiology of HFpEF in African-Americans.

Topics: Aged; Black or African American; Diabetes Complications; Echocardiography; Female; Heart Failure; Heart Ventricles; Humans; Hypertension; Linear Models; Male; Middle Aged; Mississippi; Multivariate Analysis; Myocardium; Osteoprotegerin; Stroke Volume; Vascular Stiffness; Ventricular Function, Left

The present study aims to study the role of receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin (RANKL/RANK/OPG) system in cardiac hypertrophy in a spontaneous hypertension rat (SHR) model and the effects of amlodipine and atorvastatin intervention. Thirty-six-week-old male SHRs were randomly divided into four groups: 1) SHR control group; 2) amlodipine alone (10 mg/kg/d) group, 3) atorvastatin alone (10 mg/kg/d) group, 4) combination of amlodinpine and atorvastatin (10 mg/kg/d for each) group. Same gender, weight, and age of Wistar-Kyoto (WKY) rats with normal blood pressure were used as normal control. Drugs were administered by oral gavage over 12 weeks. The thicknesses of left ventricle walls, left ventricle weight, and cardiac function were measured by transthoracic echocardiography. Left ventricular pressure and function were assessed by hemodynamic examination. Cardiomyocyte hypertrophy and collagen accumulation in cardiac tissue were measured by hematoxylin and eosin (HE) and Masson staining, respectively. The hydroxyproline content of cardiac tissue was examined by biochemistry technique. RANKL, RANK and OPG mRNA, protein expression and tissue localization were studied by RT-PCR, Immunohistochemistry and Western blot. Treatment with amlodipine or atorvastatin alone significantly decreased left ventricular mass index, cardiomyocyte cross-sectional area and interstitial fibrosis in SHR (each P < 0.05). Moreover, combined amlodipine and atorvastatin treatment induced significant reversal of left ventricular hypertrophy and decreased cardiomyocyte cross-sectional area and interstitial fibrosis in SHR to a greater extent than each agent alone (P < 0.05). Compared with WKY rats, the myocardial expression of RANKL, RANK, and OPG was increased. Both amlodipine and atorvastatin reduced RANKL, RANK, and OPG expression, with the best effects seen with the combination. Based on our results, activation of the RANKL/RANK/OPG system may be an important factor leading to ventricular remodeling in SHR rats. Amlodipine and atorvastatin could improve ventricular remodeling in SHR rats through intervention with the RANKL/RANK/OPG system.

Topics: Administration, Oral; Amlodipine; Animals; Antihypertensive Agents; Atorvastatin; Cardiomegaly; Cross-Sectional Studies; Disease Models, Animal; Gene Expression Profiling; Hydroxyproline; Hypertension; Immunohistochemistry; Male; Myocardium; NF-kappa B; Osteoprotegerin; RANK Ligand; Rats, Inbred SHR; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Treatment Outcome; Ventricular Function, Left

Wnt/β-catenin signaling pathway is thought to be implicated in the development of arterial stiffness and vascular calcification. As a Wnt signaling pathway inhibitor, it is interesting to investigate whether sclerostin or dickkopf-1 (DKK1) level is correlated with arterial stiffness in renal transplant (RT) recipients. Fasting blood samples were obtained for biochemical data, sclerostin, DKK1, and osteoprotegerin (OPG) determinations. In this study, we applied automatic pulse wave analyzer (VaSera VS-1000) to measure brachial-ankle pulse wave velocity and either sides of brachial-ankle pulse wave velocity value, which greater than 14.0 m/s was determined as high arterial stiffness. Among 68 RT recipients, 30 patients (44.1%) were in the high arterial stiffness group. Compared with patients in the low arterial stiffness group, patients in the high arterial stiffness group had higher prevalence of hypertension (P = 0.002), diabetes (P < 0.001), metabolic syndrome (P = 0.025), longer posttransplant duration (P = 0.005), higher systolic blood pressure (P < 0.001) and diastolic blood pressure (P = 0.018), and higher fasting glucose (P = 0.004), total cholesterol (P = 0.042), blood urea nitrogen (P = 0.020), phosphorus (P = 0.042), and sclerostin levels (P = 0.001). According to our multivariable forward stepwise linear regression analysis, age (β = 0.272, P = 0.014), phosphorus (β = 0.308, P = 0.007), and logarithmically-transformed OPG (log-OPG; β = 0.222, P = 0.046) were positively associated with sclerostin levels, and multivariate logistic regression analysis, sclerostin (odds ratio 1.052, 95% confidence interval 1.007-1.099, P = 0.024), and posttransplant duration (odds ratio 1.024, 95% confidence interval 1.004-1.045, P = 0.019) were the independent predictors of peripheral arterial stiffness in RT recipients. In this study, serum sclerostin level, but not DKK1, was proved to be involved in the pathogenetic process of peripheral arterial stiffness in RT recipients.

Topics: Adaptor Proteins, Signal Transducing; Adult; Ankle Brachial Index; Biomarkers; Bone Morphogenetic Proteins; Cross-Sectional Studies; Female; Genetic Markers; Humans; Hypertension; Intercellular Signaling Peptides and Proteins; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Osteoprotegerin; Postoperative Complications; Prospective Studies; Pulse Wave Analysis; Statistics as Topic; Taiwan; Vascular Calcification; Vascular Stiffness

Arterial stiffness is recognized to be an independent risk factor for cardiovascular morbidity and mortality. Recent studies have found that osteoprotegerin (OPG) is associated with increased pulse wave velocity and may reflect endothelial dysfunction. The aim of this study was to evaluate the relationship between the serum OPG level and arterial stiffness in hypertensive patients using the cardio-ankle vascular index (CAVI).. Fasting blood samples were obtained from 115 hypertensive patients and 52 healthy participants. The CAVI value was derived using the waveform device (CAVI-VaSera VS-1000). The serum OPG levels were measured using a commercially available enzyme-linked immunosorbent assay. A CAVI value of ≥9 defined the high arterial stiffness group.. Sixty-five hypertensive patients (56.5%) were included in the high arterial stiffness group. Diabetes (p=0.032), smoking (p=0.044), age (p < 0.001), systolic blood pressure (p=0.001), diastolic blood pressure (p=0.024), pulse pressure (p=0.046) and the creatinine (p=0.013) and serum OPG (p < 0.001) levels were higher in the high arterial stiffness group than in the low arterial stiffness group, while the glomerular filtration rate (p=0.003) was lower in the high arterial stiffness group than in the low arterial stiffness group among the hypertensive patients. The results of the Spearman's rank correlation coefficient test also indicated a strong positive correlation between the OPG and CAVI values (r=0.484, p < 0.001) in the hypertensive patients. In addition, a multivariate logistic regression analysis showed that age (odds ratio: 1.162, 95% confidence interval (CI): 1.070-1.263, p < 0.001), diastolic blood pressure (odds ratio: 1.109, 95% CI: 1.033-1.190, p=0.004), and serum OPG level (odds ratio: 1.275, 95% CI: 1.030-1.580, p=0.026) were independent predictors of arterial stiffness in hypertensive patients.. The serum OPG level is positively associated with arterial stiffness in hypertensive patients.

Topics: Aged; Ankle; Case-Control Studies; Humans; Hypertension; Middle Aged; Osteoprotegerin; Vascular Stiffness

We evaluated the structural/functional characteristics of the arterial wall in a cohort of hypertensives with well-controlled blood pressure (BP) levels. We studied 40 hypertensives with well-controlled BP. We assessed by B-mode ultrasound the mean intima-media thickness (mean-IMT) and maximum-IMT (M-MAX) of carotid artery (common, bulb, internal) bilaterally. Endothelial function was evaluated by post-occlusion flow-mediated dilation (FMD) of the brachial artery. Along with traditional risk factors, we studied the impact of serum high-sensitivity C-reactive protein (hs-CRP) and osteoprotegerin (OPG). Forty normotensive subjects served as controls. In the hypertensives, the BP levels were well controlled (office BP: 129/79 mm Hg, ambulatory BP monitoring: 121/75 mm Hg). Compared with controls, higher BP levels and body mass index were present in hypertensives, whereas age and metabolic parameters were similar. In hypertensives, the IMT (mean-IMT 0.68 mm, M-MAX 0.81 mm) was significantly higher than in controls (mean-IMT 0.60 mm, M-MAX 0.71 mm). FMD was impaired in hypertensives (5.9%) compared with controls (9.2%). In multivariate analyses, it turned out that in hypertensives IMT parameters were related to age, hs-CRP and OPG. Low-density lipoprotein (LDL) cholesterol was the only factor related to FMD. IMT and FMD had no relationship with BP levels. In conclusion, in hypertensives with well-controlled BP, the pro-atherogenic remodelling (IMT) is mainly dependent on age and the inflammatory cytokines, OPG in particular. The functional impairment of the arterial wall (FMD) was related to the levels of LDL cholesterol. Under these conditions, when the impact of BP is minimized, the role of inflammatory cytokines and lipids on structural/functional remodelling becomes predominant.

Topics: Adult; Antihypertensive Agents; Biomarkers; Blood Pressure; Brachial Artery; C-Reactive Protein; Carotid Artery, Common; Carotid Intima-Media Thickness; Case-Control Studies; Cholesterol, LDL; Female; Humans; Hypertension; Inflammation Mediators; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Prospective Studies; Treatment Outcome; Vascular Remodeling; Vasodilation

Topics: Ankle; Humans; Hypertension; Osteoprotegerin

Recent studies have revealed that the receptor activator of nuclear factor-kappa B ligand/RANK/osteoprotegerin (RANKL/RANK/OPG) system has an important role in vascular calcification, which is contributory to various cardiovascular diseases and intimately linked to the regulation of blood pressure. Therefore, we performed a case-control study to investigate the associations of 21 single-nucleotide polymorphisms (SNPs) in the TNFSF11, TNFRSF11A and TNFRSF11B genes in the RANKL/RANK/OPG system with hypertension and blood pressure in post-menopausal Chinese women. In this study, 503 hypertensive patients and 509 normal controls were recruited. Genotyping was performed using the high-throughput Sequenom genotyping platform. The results showed that two SNPs (rs6567270 and rs4603673) in the TNFRSF11A were associated with hypertension (P=0.010 and P=0.013, respectively) and systolic blood pressure (P=0.024 and P=0.023, respectively). One SNP (rs9646629) in the TNFRSF11A showed significant association with diastolic blood pressure (P=0.031). The results of this study suggest that TNFRSF11A but not TNFSF11 and TNFRSF11B genetic variation is associated with hypertension and blood pressure in Chinese women. The findings provide additional support for the genetic role of RANKL/RANK/OPG system in hypertension and blood pressure regulation.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Blood Pressure; Case-Control Studies; Female; Haplotypes; Humans; Hypertension; Middle Aged; Osteoprotegerin; Polymorphism, Single Nucleotide; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Growing evidence suggests the presence of a complex interplay between hypertension as well as type 2 diabetes mellitus (DM) and osteoporosis. The present study was designed to investigate a possible effect of type 2 DM on bone remodelling markers such as osteoprotegerin and N-terminal propeptide of type 1 collagen (P1NP) in hypertensive patients.. The 100 study participants were divided into three groups according to the presence of DM and hypertension: group one included diabetic hypertensive subjects, group 2 included hypertensive subjects without diabetes and group 3 included subjects without hypertension and without DM (controls). Blood sampling for metabolic parameters, including osteoprotegerin, P1NP, adiponectin, fasting glucose, HbA1c , CRP, homeostasis model assessment-insulin resistance, homeostasis model assessment-beta function was performed.. Circulating P1NP increased from group 1 to group 3 in a continuous fashion. P1NP was significantly lower in hypertensive subjects with DM (group 1), than in groups 2 and 3 (p < 0.0001). P1NP, was marginally lower in diabetic hypertensive subjects as compared with nondiabetic subjects with hypertension (p = 0.079). Circulating osteoprotegerin did not differ significantly between groups (p = 0.593).. In the present study, bone formation marker, P1NP, was significantly lower in diabetic hypertensive subjects as compared with nondiabetic subjects with and without hypertension. P1NP was inversely associated with parameters of glucose homeostasis such as fasting glucose, HbA1c and positively with homeostasis model assessment-beta cell function. Type 2 DM was associated with an adverse effect on bone formation independently of age, sex and exposure to anti-diabetic drugs.

Topics: Adiponectin; Aged; Biomarkers; Blood Glucose; Bone and Bones; Bone Remodeling; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Osteoporosis; Osteoprotegerin; Peptide Fragments; Procollagen

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) has been implicated in the process of vascular stiffness. The aim of this study was to evaluate the relationship between fasting serum OPG concentration and carotid-femoral pulse wave velocity (c-f PWV) in hypertensive patients. Fasting blood samples were obtained from 184 participants with or without hypertension. c-f PWV were performed by SphygmoCor system. Serum OPG levels were measured using a commercially available enzyme-linked immunosorbent assay. Hypertensive patients who had diabetes had higher c-f PWV levels than those without diabetes (P=.031). The univariable linear regression analysis showed that age (P<.001), systolic blood pressure (P=.003), pulse pressure (r=0.287; P=.003), log-BUN (P=.011), Cre (P<.001), and log-OPG concentration (P<.001) were positively correlated with c-f PWV levels, while the glomerular filtration rate (P=.005) and HDL-C level (P=.024) was negatively correlated with c-f PWV levels among the hypertensive patients. Multivariable forward stepwise linear regression analysis of the significant variables also showed that log-OPG (β=0.312, regression coefficient: 1.736; 95% confidence interval, 0.809-2.663; P<.001) was still an independent predictor of c-f PWV levels in hypertensive patients. Serum OPG levels positively associated with c-f PWV levels in hypertensive patients.

Topics: Age Factors; Aged; Blood Pressure; Carotid Arteries; Case-Control Studies; Cholesterol, HDL; Cross-Sectional Studies; Female; Femoral Artery; Glomerular Filtration Rate; Humans; Hypertension; Linear Models; Male; Middle Aged; Multivariate Analysis; Osteoprotegerin; Pulse Wave Analysis

to compare blood serum levels of osteoprotegerin (OPG) and soluble receptor activator of nuclear factor B ligand (sRANKL) in patients with different morphological variants of stenosis.. We included in this study 57 patients with aortic stenosis: 29 with bicuspid aortic valve (BAV) and 28 with tricuspid aortic valve (TAV). Subjects without heart diseases (n=32) were also examined. In all patients we determined lipid profile and measured serum levels of C-reactive protein, OPG and sRANKL.. OPG levels were evaluated in all patients with aortic stenosis while evaluated sRANKL was found only in patients with BAV. Age and arterial hypertension were key risk factors for OPG/RANKL/RANK system activation.. Despite differences in pathogenesis of aortic stenosis in patients with BAV and TAV processes of calcification may have common mechanisms. The data obtained correspond to the conception of importance of OPG/RANKL/RANK system activation for development and progression of degenerative aortic stenosis.

Topics: Aortic Valve; Aortic Valve Stenosis; Biomarkers; C-Reactive Protein; Calcinosis; Echocardiography; Female; Humans; Hypertension; Lipids; Male; Middle Aged; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Risk Factors; Severity of Illness Index; Statistics as Topic

The aim of the study was to investigate the role of osteoprotegerin (OPG) in left ventricular hypertrophy (LVH) development in patients with essential hypertension (EH). A total of 1092 patients diagnosed with EH were recruited. The LVHs were determined and OPG gene polymorphisms were genotyped. Patients with LVH had a significantly higher mean serum OPG level than those without LVH. The 1181CC genotype carriers had significantly lower risk for LVH compared with GC and GG genotype carriers. The serum OPG level and OPG 1181 G>C polymorphism were found to be independent risk factors for the occurrence of LVH in hypertensive patients. In vitro study shows that OPG overexpression upregulates cell surface size, protein synthesis per cell, and hypertrophy- and fibrosis-related proteins in both cardiomyocytes and cardiac fibroblasts, whereas OPG inhibition can abolish the above-mentioned changes. Consistent with the in vitro data, our in vivo study revealed that the OPG administration induced the LVH in hypertensive rats. This study is the first to report the close association between OPG and LVH development in EH patients and the regulatory effect of OPG on cardiomyocytes and cardiac fibroblasts.

Topics: Animals; Animals, Newborn; Atrial Natriuretic Factor; Case-Control Studies; Cells, Cultured; Female; Fibroblasts; Gene Frequency; Genotype; Heart Ventricles; Heterozygote; Humans; Hypertension; Hypertrophy, Left Ventricular; Logistic Models; Male; Middle Aged; Myocytes, Cardiac; Osteoprotegerin; Polymorphism, Genetic; Rats, Sprague-Dawley; Risk Factors; RNA, Small Interfering; Troponin I; Ventricular Myosins

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

Atherosclerosis is the main cause of cardiovascular disease, but the extent of atherosclerosis in individual patients is difficult to estimate. A biomarker of the atherosclerotic burden would be very valuable. The aim of the present study was to evaluate the association of plasma osteoprotegerin (OPG) to clinical and subclinical atherosclerotic disease in a large community-based, cross-sectional population study. In the Copenhagen City Heart Study, OPG concentrations were measured in 5,863 men and women. A total of 494 participants had been hospitalized for ischemic heart disease or ischemic stroke, and compared to controls, this group with clinical atherosclerosis had higher mean OPG (1,773 vs 1,337 ng/L, p <0.001) and high-sensitivity C-reactive protein (2.3 vs 1.6 mg/L, p <0.001). In a multivariate model with age, gender, body mass index, hypertension, diabetes, hypercholesterolemia, smoking status, estimated glomerular filtration rate, high-sensitivity C-reactive protein, and OPG, OPG remained significantly associated with clinical atherosclerosis (p <0.01); high-sensitivity C-reactive protein, in contrast, did not (p = 0.74). In the control group without clinical atherosclerosis, OPG was independently associated with hypertension, diabetes, hypercholesterolemia, smoking, and subclinical peripheral atherosclerosis as measured by ankle brachial index. For each doubling of the plasma OPG concentration, the risk for subclinical peripheral atherosclerosis increased by 50% (p <0.001) after multivariate adjustment. In conclusion, OPG appears to be a promising biomarker of atherosclerosis that is independently associated with traditional risk factors of atherosclerosis, subclinical peripheral atherosclerosis, and clinical atherosclerotic disease such as ischemic heart disease and ischemic stroke.

Topics: Adult; Aged; Aged, 80 and over; Ankle Brachial Index; Atherosclerosis; Biomarkers; C-Reactive Protein; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Multivariate Analysis; Osteoprotegerin; Risk Factors; Smoking; Young Adult

We conducted a cross-sectional observation study that included 500 asymptomatic subjects to investigate the relationship between bone metabolism and coronary artery calcification (CAC) in hypertensive conditions. Osteoprotegerin (OPG) and osteopontin (OPN) levels and their associations with hypertension were analyzed to predict CAC in 316 subjects. Multislice computed tomography was used to quantify CAC. Multivariate analysis of variance was used to test the non-interactive effects of hypertension, CAC severity and biomarker levels, and the logistic regression model was applied to predict the risk of CAC. OPG and OPN concentrations were significantly higher in the hypertensive than the normotensive subjects, at 3.0 (2.3-4.0) pmol l(-1) and 51 (21-136) ng ml(-1) vs. 2.4 (2.0-3.0) pmol l(-1) and 41 (13-63) ng ml(-1), respectively. The OPG level, but not OPN level, increased with age (r = 0.29; P = 0.0001). Zero or minimal CAC (<10 Agatston units (AU)) was observed in 63% of the subjects, mild (11-100 AU) in 17%, moderate (101-400 AU) in 12% and severe (401-1000 AU)-to-extensive (>1000 AU) in 8%. In hypertensive subjects, only glomerular filtration rate (GFR) (β = -0.67) and gender (β = 0.52) were significant predictors for CAC (R = 0.68). In normotensive patients, GFR (β = -0.81), gender (β = 0.48) and log-transformed OPG levels (β = 0.15) were significant predictors for CAC. OPG levels were associated with an increased risk of CAC in normotensive subjects only (odds ratio: 3.37; 95% confidence interval (1.63-6.57); P = 0.0002). OPG predicted a premature state of vascular calcification in asymptomatic normotensive individuals, and renal function significantly contributed to this process in both hypertensive and normotensive subjects.

Topics: Age Factors; Aged; Cross-Sectional Studies; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Multidetector Computed Tomography; Osteopontin; Osteoprotegerin; Predictive Value of Tests; Severity of Illness Index; Sex Factors; Vascular Calcification

Osteoprotegerin (OPG) and osteopontin (OPN) are bone metabolism biomarkers which are involved in the regulation of vascular calcification processes and prediction of future adverse cardiac events.. OPG, OPN levels and classic risk factors were determined in 130 asymptomatic and hypertensive subjects. Receiver operator characteristic (ROC) analysis was performed and the area under the curve (AUC) was calculated.. The hypertensive subjects had elevated OPG, OPN, fibrinogen, CRP and fasting glucose levels in comparison to the normotensive ones. There were significant correlations between age, CRP and OPG. Multiple regression analysis showed that as well as inflammation (CRP), age and hypertension were predictors of increased OPG levels. OPN increase was correlated with CRP and glucose levels. The AUCs were similar for OPG and OPG biomarkers.. Plasma OPG and OPN levels were significantly associated with inflammation and arterial hypertension. They might be useful as additional biomarkers for monitoring endothelial dysfunction and prognosis of cardiovascular diseases.

Topics: Biomarkers; Bone Remodeling; Demography; Female; Humans; Hypertension; Male; Osteopontin; Osteoprotegerin; Poland; Risk Factors; ROC Curve; Sex Characteristics

Topics: Adult; Arginine; Biomarkers; Blood Pressure; Exercise; Exercise Test; Humans; Hypertension; Male; Middle Aged; Osteoprotegerin

To investigate the inter-relationships of osteoprotegerin (OPG) with albumin to creatinine ratio (ACR) and asymmetric dimethylargine (ADMA) in hypertensive patients.. In 198 untreated non-diabetic hypertensive patients [130 males, mean age=51.5 years, office blood pressure (BP)=152/98 mmHg] ACR values and OPG and ADMA levels were determined.. Based on the median value of OPG distribution (5.03 pmol/l) patients with high (n=101) compared with those with low OPG values (n=97) had greater 24-h systolic BP (152±5 versus 137±7 mmHg, p<0.0001), ACR [25.3 (5-190) versus 17.3 (5-92) mg/g, p=0.003) and ADMA [0.62 (0.58-0.68) versus 0.57 (0.48-0.62) μmol/l, p=0.001), independently of confounding factors. Multiple regression analyses revealed that ADMA (b=0.388, p<0.0001), 24-h systolic BP (b=0.228, p=0.01) and ACR (b=0.470, p<0.0001) were independent predictors of OPG (R2=0.398, p<0.0001).. In hypertensive patients, high OPG levels are accompanied by pronounced albuminuria and endothelial dysfunction, as reflected by raised ADMA levels. Furthermore, the independent associations of OPG with ACR and ADMA, suggests a link between OPG and the progression of diffuse hypertensive vascular damage.

Topics: Adult; Albuminuria; Arginine; Blood Pressure; Cross-Sectional Studies; Echocardiography; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Osteoprotegerin

African-Americans with hypertension are susceptible to left ventricular hypertrophy (LVH). Serum osteoprotegerin level has been reported to be associated with LVH. We investigated the association of osteoprotegerin with LV mass (LVM) in 898 African-Americans with hypertension (mean age 65 years, 71% women).. Osteoprotegerin levels were measured in serum by an immunoassay and log-transformed for analyses. LVM index (LVMi; LVM/height(2.7)) was estimated using M-mode echocardiography. Linear regression analyses using generalized estimating equations were used to assess the association of osteoprotegerin with LVMi.. Serum osteoprotegerin was correlated with LVMi (r = 0.21; P < 0.0001), an estimated increase in LVMi of 5.05 (95% confidence interval 2.93, 7.17) g/m(2.7) in the highest compared to the lowest osteoprotegerin quartile. This association remained statistically significant after adjustment for conventional cardiovascular risk factors (age, sex, body mass index (BMI), history of smoking, diabetes, systolic blood pressure (BP), total and high-density lipoprotein cholesterol), estimated renal function, history of myocardial infarction and stroke, lifestyle factors (physical activity score, years of education, amount of alcohol consumption), medications (aspirin, antihypertensives, statins, estrogens), and C-reactive protein (CRP) (P = 0.02). Additionally, osteoprotegerin was correlated with early/atrial (E/A) ratio (r = -0.16; P < 0.0001), LV mean wall thickness (r = 0.17; P < 0.0001) and relative wall thickness (r = 0.14; P < 0.0001) but not ejection fraction (r = 0.04; P = 0.24) or internal end-diastolic dimension (r = 0.02; P = 0.60).. In African-Americans with hypertension, a higher serum osteoprotegerin level is weakly but independently associated with a higher LVM.

Topics: Aged; Biomarkers; Black or African American; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Organ Size; Osteoprotegerin

This study evaluates the ligature-induced bone loss (BL) and quality of tooth-supporting alveolar bone in spontaneously hypertensive rats (SHRs) by histometric, histochemical, and immunohistochemical analyses and assesses the effects of lercanidipine on these parameters.. Wistar rats and SHRs were assigned to one of the following groups: normotensive rats (n = 15), untreated SHRs (n = 15), and treated SHRs (n = 15). The latter group was treated daily with lercanidipine for 45 days. Two weeks after the beginning of drug administration, the first right mandibular molar received a cotton ligature, whereas the contralateral tooth was left unligated. The following parameters were analyzed in the furcation area of decalcified histologic sections: BL, bone density (BD), number of positive cells for tartrate-resistant acid phosphatase (TRAP+), and expression of receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG).. In ligated teeth, no significant differences among groups were found regarding BL, TRAP+ cells, and the ratio of RANKL/OPG+ cells (P >0.05), although the expression of RANKL was decreased in the treated SHR group (P <0.05). Increased BL and decreased BD were observed around unligated teeth of the untreated and treated SHR groups (P <0.05). In the furcation area of the unligated teeth, the untreated SHR group presented a higher number of TRAP+ cells and higher ratio of RANKL/OPG+ cells compared to the other groups.. SHRs present harmful alterations in the quality of tooth-supporting bone, independently of inflammation. In addition, the administration of lercanidipine for 45 days decreased the expression of bone-resorption markers.

Topics: Acid Phosphatase; Alveolar Bone Loss; Alveolar Process; Animals; Antihypertensive Agents; Biomarkers; Bone Density; Dihydropyridines; Hypertension; Immunohistochemistry; Isoenzymes; Male; Molar; Osteoprotegerin; RANK Ligand; Rats; Rats, Inbred SHR; Rats, Wistar; Tartrate-Resistant Acid Phosphatase; Tooth Root

Osteoprotegerin (OPG), a member of tumor necrosis factor receptor superfamily, has been implicated in vascular disease. We investigated the association of serum OPG with the ankle-brachial index (ABI) and urine albumin:creatinine ratio (UACR), in a bi-ethnic cohort of 1324 African-Americans (mean age 64 years, 71% women) and 1237 non-Hispanic whites (mean age 59 years, 57% women) belonging to hypertensive sibships. Serum levels of OPG were measured by solid phase sandwich immunoassay. ABI was measured using a standard protocol and peripheral arterial disease (PAD) defined as ABI<0.90. UACR was expressed as mg albumin/gm creatinine. Multivariable regression analysis using generalized estimating equations (GEE) were performed to assess whether serum OPG levels were associated with ABI and UACR. After adjustment for conventional risk factors (age, sex, diabetes, waist circumference, history of smoking, total and HDL cholesterol, hypertension), prior history of myocardial infarction or stroke, and medication (renin-angiotensin-aldosterone system inhibitors, statins, aspirin, estrogen) use, higher OPG levels were significantly associated with lower ABI and higher UACR in African-Americans (P=0.001 and P<0.0001, respectively) and non-Hispanic whites (P=0.017 and P=0.002, respectively); the association remained significant after further adjustment for plasma C-reactive protein (CRP) in both ethnic groups. In multivariable logistic regression analysis, higher OPG levels were associated with PAD in African-Americans, independent of the covariates listed above (P=0.026); the association remained significant after additional adjustment for plasma CRP (P=0.047). In non-Hispanic whites, the association of higher OPG levels with PAD was of borderline significance after adjustment for the relevant covariates (P=0.106). We conclude that higher OPG levels are associated with lower ABI and higher UACR, independent of conventional risk factors and plasma CRP.

Topics: Aged; Albuminuria; Ankle Brachial Index; Black or African American; C-Reactive Protein; Cohort Studies; Creatinine; Female; Humans; Hypertension; Male; Middle Aged; Osteoprotegerin; Regression Analysis; White People

Osteoprotegerin (OPG) has been associated with cardiovascular events but currently the mechanisms underlying this association are unknown. OPG is thought to play a role in controlling artery calcification and small studies have suggested that it may influence artery structure. We examined the association between single nucleotide polymorphisms (SNPs) in the gene encoding OPG (tumor necrosis factor receptor superfamily, member 11b, TNFRSF11B), with blood pressure in a large cohort of elderly men.. 21 tagging SNPs in the region encoded by TNFRSF11B were examined in 1,071 men recruited in a population-based study of elderly men. Genotyping was carried out using the Illumina Golden Gate assay. SNPs were investigated for their association with resting systolic and diastolic blood pressure after adjusting for other variables using linear regression. The association of SNPs in the region encoded by TNFRSF11B with plasma OPG was assessed in a random subset of 467 men.. One SNP, rs11573901, was significantly associated with diastolic blood pressure, after adjusting for other risk factors and multiple testing (coefficient -4.36, P = 0.001). Men with the TC genotype had lower diastolic blood pressure than those with the common cc variation. this snp was not associated with plasma opg in the 467 men in which this was examined.. This study suggests that a SNP within the region encoded by TNFRSF11B, which is believed to code for OPG, is associated with blood pressure. The mechanism underlying this observed association is currently unclear.

Topics: Aged; Aged, 80 and over; Blood Pressure; Cholesterol; Creatine; DNA Fingerprinting; Humans; Hypertension; Lipoproteins, HDL; Lipoproteins, LDL; Male; Osteoprotegerin; Polymorphism, Single Nucleotide

Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor family, is involved in the process of bone turnover and also in the pathogenesis of osteoporosis and premature calcification of the vascular system. In the present study on patients with peripheral artery disease (PAD), we correlated plasma OPG concentrations with severity of disease and the presence of cardiovascular risk factors.. Sixty-seven consecutive inpatients (26 females; mean age 70 years (S.D.: 12), undergoing percutaneous transluminal angioplasty (PTA) because of advanced symptomatic PAD of the lower extremities were studied. Severity grade of disease (clinical stage after "Fontaine", functional measurements in terms of the ankle brachial index (ABI) and "Bollinger score" of angiographies), biochemical parameters and a detailed cardiovascular risk profile were documented. Fasting plasma concentrations of OPG were measured by a commercial sandwich enzyme immunoassay.. The mean plasma concentrations of OPG were 5.3 pmol/l (S.D.: 3.3). Plasma OPG concentrations in subjects with PAD, clinical stages III-IV (n=15) were 7.9 pmol/l (S.D.: 5.3) and were significantly higher than in patients without ischemic ulcerations (n=52; 4.6 pmol/l; S.D.: 2.0; p<0.01). The mean value of Bollinger score was 29.1 (S.D.: 19.8). OPG was positively correlated with Bollinger score of disease (r=0.31; p<0.02), age (r=0.58; p<0.01) and creatinine-values (r=0.32; p<0.01) and negatively correlated with ABI (r=-0.39; p<0.03).. In patients with PAD, plasma OPG concentrations were significantly higher in subjects with ischemic ulcerations than in those without and were positively correlated with higher severity grade of disease, age and creatinine-values. Further studies are required to analyze the role of OPG as a diagnostic marker for severity of atherosclerotic disease and to assess a possible therapeutic potential as "vasculoprotegerin".

Topics: Aged; Aged, 80 and over; Biomarkers; Female; Glycoproteins; Humans; Hypertension; Male; Middle Aged; Osteoprotegerin; Peripheral Vascular Diseases; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; Severity of Illness Index

We examined the association between serum osteoprotegerin (OPG) levels, systemic inflammation and arterial stiffness in normal and diabetic patients.. The study subjects comprised 49 newly diagnosed diabetic patients and 72 age- and sex-matched normal glucose controls. Anthropometric parameters, blood pressure, fasting blood glucose (FBG), lipid profiles, serum OPG, high-sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6) and brachial-ankle pulse wave velocity (baPWV) were measured.. Serum OPG levels (6.1 +/- 1.4 vs. 5.4 +/- 1.3 pmol/l, P = 0.011) and baPWV (1562 +/- 354 vs. 1399 +/- 257 cm/s, P = 0.004) were significantly higher in the diabetic group than in the normal glucose group. Serum OPG levels in normal and diabetic patients correlated significantly with systolic blood pressure (r = 0.20, P = 0.035), FBG (r = 0.30, P = 0.002), right baPWV (r = 0.22, P = 0.021), left baPWV (r = 0.26, P = 0.006), homeostasis model assessment insulin resistance (HOMA-IR) (r = 0.19, P = 0.045), IL-6 (r = 0.32, P = 0.001) and hsCRP (r = 0.21, P = 0.027) after adjusting for age and sex. Multiple regression analysis showed that serum OPG level was significantly associated with age, FBG, IL-6, systolic blood pressure, triglyceride and hsCRP (R(2) = 0.299).. In summary, serum OPG and baPWV levels are elevated in diabetic patients and serum OPG levels are significantly associated with inflammation and arterial stiffness.

Topics: Biomarkers; Blood Glucose; Brachial Artery; C-Reactive Protein; Case-Control Studies; Diabetes Mellitus; Female; Glycoproteins; Humans; Hypertension; Inflammation; Insulin Resistance; Interleukin-6; Lipids; Male; Middle Aged; Osteoprotegerin; Pulsatile Flow; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Regression Analysis; Signal Processing, Computer-Assisted; Systole; Triglycerides