osteoprotegerin and Heart-Failure

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

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

The pathophysiological role of tumor necrosis factor (TNF) in myocardial failure has been extensively examined in experimental and clinical studies. Recent studies suggest that other members of the TNF/TNF receptor superfamily (TNFSF/TNFRSF) also may play a pathogenic role in chronic HF. TNF ligands, and in particular members of the TNFRSF, are expressed by a wide variety of cells, including myocardial cells. By activating the nuclear factor-κB (NF-κB) and death-related pathways, TNF ligands can induce a variety of effects within the myocardium, including apoptosis, hypertrophy, inflammation, and extracellular matrix remodeling. Among several TNFSF members that have been shown activated in HF, the OPG/RANK/RANKL (osteoprotegerin/receptor activator of NF-κB/RANK ligand) axis may be of importance in the pathogenesis of this disorder through different mechanisms. In this paper, we revisited the role of TNFSF/TNFRSF in the pathophysiology of HF, possibly representing new targets for therapy as well as new biomarkers in this disorder.

Topics: Apoptosis; Biomarkers; Extracellular Matrix; Heart Failure; Humans; Ligands; Osteoprotegerin; Prognosis; Receptors, Tumor Necrosis Factor; Signal Transduction; Tumor Necrosis Factor-alpha

The mortality of end-stage renal disease (ESRD) patients, including those receiving long-term peritoneal dialysis (PD), has remained unacceptably high owing to the prevalence of cardiovascular disease. It is well recognized that both traditional Framingham risk factors and kidney disease-related risk factors may contribute to the high prevalence of cardiovascular disease in these patients. Of the different risk factors, chronic inflammation frequently is observed in long-term PD patients. The causes of inflammation are usually complex and multifactorial, involving both dialysis-related and dialysis-unrelated factors. Inflammation is strongly associated with cardiovascular disease and malnutrition, and has been shown consistently to be a powerful predictor of mortality and adverse cardiovascular outcomes in PD patients. In this article we review the prevalence and potential causes of chronic inflammation in PD patients. More importantly, we provide emerging evidence that shows the serious consequences of chronic systemic inflammation in PD patients and the important contribution of inflammation to adverse clinical outcomes.

Topics: C-Reactive Protein; Cachexia; Calcinosis; Cardiomegaly; Chronic Disease; Heart Failure; Humans; Inflammation; Insulin Resistance; Kidney Failure, Chronic; Osteoprotegerin; Peritoneal Dialysis; Prevalence

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

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

Our aim was to explore potential use of temporal profiles of seven emerging cardio-renal and two pulmonary candidate biomarkers for predicting future adverse clinical outcome in stable patients with chronic heart failure (CHF).. In 263 CHF patients, we determined the risk of a composite endpoint of HF-hospitalization, cardiac death, LVAD-placement and heart transplantation in relation to repeatedly assessed (567 samples in total) blood biomarker levels, and slopes of their temporal trajectories (i.e., rate of biomarker change per year). In each patient, we estimated biomarker trajectories using repeatedly measured osteopontin (OPN), osteoprotegerin (OPG), epidermal growth factor receptor (EGFR), heparin-binding protein (HBP), trefoil factor-3 (TFF3), kallikrein-6 (KLK-6), matrix extracellular phosphoglycoprotein (MEPE), pulmonary surfactant-associated protein-D (PSP-D), and secretoglobulin family 3A-member-2 (SCGB3A2).. During 2.2 years of follow-up, OPN, OPG, and HBP levels predicted the composite endpoint (univariable hazard ratio [95% confidence interval] per 1SD increase: 2.31 [1.76-3.15], 2.23 [1.69-3.00], and 1.36[1.09-1.70]). Independently of the biomarkers' levels, the slopes of OPG, TFF-3, PSP-D trajectories were also strong clinical predictors (per 0.1SD increase: 1.24 [1.14-1.38], 1.31 [1.17-1.49], and 1.32 [1.21-1.47]). All associations persisted after multivariable adjustment for baseline characteristics, and repeatedly assessed CHF pharmacological treatment and cardiac biomarkers NT-proBNP and troponin T.. Repeatedly-measured levels of OPN, OPG, and HBP, and slopes of OPG, TFF-3, and PSP-D strongly predict clinical outcome. These candidate biomarkers may be clinically relevant as they could further define a patient's risk and provide additional pathophysiological insights into CHF.

Topics: Aged; Aged, 80 and over; Biomarkers; Chronic Disease; Cohort Studies; ErbB Receptors; Female; Follow-Up Studies; Heart Failure; Heart Transplantation; Humans; Kidney; Lung; Male; Middle Aged; Natriuretic Peptide, Brain; Netherlands; Osteoprotegerin; Peptide Fragments; Prospective Studies; Time Factors

High circulating levels of osteoprotegerin (OPG) carry prognostic impact in cohorts with various cardiovascular diagnoses. With the present study, we aim to investigate the role of OPG within the scale of myocardial damage.. This study includes 219 consecutive patients with acute ST-elevation myocardial infarction randomized to primary percutaneous coronary intervention (pPCI) or pPCI and remote ischemic per-conditioning. Salvage index via myocardial single-photon emission CT assessment (data available in 61% of the patients) was performed, and derived from Day 1 (myocardial area at risk) and Day 30 (final infarct size). Plasma OPG levels were measured using an in-house immunoassay. A combined end-point of all-mortality, myocardial infarction, stroke, readmission for heart failure and ischemic stroke/transient ischemic attack (Major Adverse Cardiac and Cerebrovascular Events [MACCE]) was used for follow-up; 45 (38-48 months).. High OPG levels were associated with the severity of cardiovascular disease. During follow-up, OPG was a predictor of MACCE (unadjusted, HR: 2.1, 95% CI: 1.14-3.85, P = 0.017). Adjustments for age, gender, and body mass index preserved the independent predictive power of OPG. However, OPG levels were neither associated with salvage index nor with the final infarct size. Remote ischemic per-conditioning had no effect on OPG levels.. Despite absent association between OPG levels and the scale of myocardial damage, high OPG levels predict a significantly increased risk of MACCE.

Topics: Aged; Biomarkers; Brain Ischemia; Denmark; Female; Heart Failure; Humans; Immunoassay; Ischemic Attack, Transient; Ischemic Preconditioning; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Osteoprotegerin; Patient Readmission; Percutaneous Coronary Intervention; Predictive Value of Tests; Proportional Hazards Models; Recurrence; Risk Factors; Stroke; Time Factors; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Up-Regulation; Upper Extremity

Osteoprotegerin (OPG) may be implicated in the pathogenesis of heart failure (HF), and circulating levels predict survival in patients with postinfarction HF. Our primary goal was to determine whether OPG provided independent prognostic information in patients with chronic HF, and to examine its potential interactions with statin therapy.. OPG as a risk factor for the primary end point (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke; n=318), all-cause mortality (n=329), and all-cause mortality/hospitalization for worsening of heart failure (WHF; n=475) was investigated in 1464 patients (≥60 years, New York Heart Association class II to IV, ischemic systolic HF, optimal pharmacological therapy) in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) population, randomly assigned to 10 mg rosuvastatin or placebo. In multivariate analyses, OPG (continuous variable) added no significant predictive information for risk estimation of the primary end point (adjusting for left ventricular ejection fraction, New York Heart Association class, age, body mass index, diabetes, sex, intermittent claudication, heart rate, serum creatinine, apoA1, and N-terminal pro-B-type natriuretic peptide). However, OPG added independent predictive information for WHF hospitalization (hazard ratio [HR] 1.10 [1.04 to 1.16], P<0.001) and all-cause mortality/WHF hospitalization (HR 1.06 [1.01 to 1.11]). The HR indicated a reduced risk for all-cause mortality in the rosuvastatin group in those with lowest OPG values (tertile 1, HR=0.66 unadjusted [P=0.025]; HR=0.71 Cox adjusted [P=0.025]; interaction by treatment effect for the tertiles P=0.086).. OPG added no predictive information for the primary end point, but independently predicted WHF hospitalization in older patients with advanced chronic systolic HF of ischemic etiology. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

Topics: Aged; Aged, 80 and over; Biomarkers; Chronic Disease; Europe; Female; Fluorobenzenes; Heart Failure; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kaplan-Meier Estimate; Lipids; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Proportional Hazards Models; Pyrimidines; Risk Assessment; Risk Factors; Rosuvastatin Calcium; Sulfonamides; Time Factors; Treatment Outcome

Circulating levels of osteoprotegerin (OPG), a member of the tumor necrosis factor receptor superfamily, is predictive of death and hospitalization for heart failure after acute coronary syndrome. The association between OPG and outcome in patients with chronic heart failure (CHF) is unknown.. Plasma OPG levels at baseline were assessed in 1,229 patients with CHF recruited from 51 clinical centers and included in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Heart Failure (GISSI-HF) trial. Patients were randomized to n-3 polyunsaturated fatty acids (1 g/d) or rosuvastatin (10 mg/d) versus placebo. Osteoprotegerin was analyzed by enzyme-linked immunosorbent assay. The association between OPG and outcome was assessed by Cox proportional hazards regression models.. During a median follow-up time of 3.9 years, 332 patients died; and 791 patients died or were hospitalized because of cardiovascular causes. By univariate analysis, baseline OPG levels were strongly associated with the incidence of death (hazard ratio {HR} [95% CI] 1.53 [1.40-1.67] per 1-SD increase in log OPG). After adjustment for conventional risk markers, OPG remained a significant predictor of death (HR [95% CI] 1.20 [1.06-1.35], P < .001). Similar findings were observed for the composite end point (HR [95% CI] 1.34 [1.07-1.69], P = .012).. In patients with CHF, OPG is associated with the incidence of death independently of conventional cardiovascular risk factors.

Topics: Aged; Female; Fluorobenzenes; Fluoroimmunoassay; Heart Failure; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Italy; Male; Middle Aged; Osteoprotegerin; Prognosis; Proportional Hazards Models; Pyrimidines; Rosuvastatin Calcium; Sulfonamides

Chronic heart failure causes osteoporosis, but the mechanism remains unclear. The sympathetic nerve plays an important role in both bone metabolism and cardiovascular function.. Thirty-six adult male SD rats were randomly divided into the following four groups: sham surgery (Sham) group, guanethidine (GD) group, abdominal transverse aorta coarctation-induced heart failure + normal saline (TAC) group, and TAC + guanethidine (TAC + GD) group. Normal saline (0.9 % NaCl) or guanethidine (40 mg/kg/ml) was intraperitoneally injected daily for 5 weeks. Then, DXA, micro-CT, ELISA and RT-PCR analyses were performed 12 weeks after treatment.. The bone loss in rats subjected to TAC-induced chronic heart failure and chemical sympathectomy with guanethidine was increased. Serum norepinephrine levels were increased in rats with TAC-induced heart failure but were decreased in TAC-induced heart failure rats treated with guanethidine. The expression of α2A adrenergic receptor, α2C adrenergic receptor, osteoprotegerin (OPG), and osteocalcin in the tibia decreased in the TAC-induced heart failure group, and the expression of β1 adrenergic receptor, β2 adrenergic receptor, receptor activator of nuclear factor-κ B ligand (RANKL), and RANKL/OPG in the tibia increased in the heart failure group. In addition, these changes in gene expression levels were rescued by chemical sympathectomy with guanethidine.. TAC-induced chronic heart failure is associated with bone mass loss, and the sympathetic nerve plays a significant role in heart failure-related bone mass loss.. The present study supports the hypothesis that heart failure is related to bone loss, and the excessive activation of sympathetic nerves participates in this pathophysiological process. The present study suggests a potential pathological mechanism of osteoporosis associated with heart failure and new perspectives for developing strategies for heart failure-related bone loss.

Topics: Animals; Guanethidine; Heart Failure; Male; Osteoporosis; Osteoprotegerin; RANK Ligand; Rats; Rats, Sprague-Dawley; Saline Solution

To assess bone status expressed as hip bone mineral density (BMD) in men with heart failure (HF).. Patients with HF lose BMD over time. Markers of bone turnover can help in identifying patients at risk with osteocalcin being an independent marker of lower hip BMD and osteoprotegerin an independent predictor of death. HF patients with increased osteocalcin and osteoprotegerin may benefit from BMD assessment as manifest osteoporosis seems to be too late for clinically meaningful intervention in HF.

Topics: Absorptiometry, Photon; Bone Density; Heart Failure; Humans; Male; Morbidity; Osteocalcin; Osteoprotegerin

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

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

Topics: Angiotensin-Converting Enzyme 2; Biomarkers; Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Echocardiography, Doppler; Heart Failure; Humans; Microcirculation; Microvessels; Osteoprotegerin; Peptidyl-Dipeptidase A; Protein Interaction Maps; Regression Analysis; Ventricular Function, Left

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 aim of the study was to assess the role of serum osteoprotegerin (OPG) as a biomarker in patients with aortic valve stenosis (AS) in relation to heart failure and symptomatic status. This was a case control study, which included 51 patients with AS and 39 control subjects. At the time of study enrolment, detailed medical history was obtained and all subjects underwent physical examination, chest x-ray and echocardiography. OPG levels were measured in all subjects, and serum N-terminal of the pro b-type natriuretic peptide (NT pro BNP) levels were determined in patients with AS. Serum OPG levels were elevated in patients with AS compared to control subjects (p=0.001). Patients with heart failure due to AS had elevated serum OPG levels in comparison to patients without heart failure (p=0.001). A significant correlation between OPG and symptomatic status was observed in all patients with AS (p<0.001), however, it was not the case in patients without heart failure (p=0.425). There was a positive correlation between OPG and NT pro BNP concentrations with objective signs of heart failure on chest x-ray (p<0.001). Negative correlation of OPG concentrations with aortic valve area was present (p<0.040), as well as with left ventricular ejection fraction (p<0.001). Serum OPG could be a valuable biomarker in the evaluation of severity of calcified AS and serve as an additional indicator besides clinical presentation and echocardiography in the assessment of surgical treatment or aortic valve replacement.

Topics: Aortic Valve; Aortic Valve Stenosis; Biomarkers; Case-Control Studies; Heart Failure; Humans; Osteoprotegerin

Heart failure (HF) is a disabling condition involving complex vascular, neurohormonal and immune systems' interactions. Osteoprotegerin (OPG), a bone-regulatory cytokine, has been suggested to play a key role in skeletal, vascular, and immune biology, with elevated levels observed in both experimental and clinical HF. In the present study we aimed to identify clinical OPG correlates and investigated whether elevated OPG, as a marker of HF vascular and immune activation, may interact with N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of HF neurohormonal activation, thus synergistically increasing HF risk. We used a case-cohort study, nested within the European Prospective Investigation into Cancer and Nutrition-Potsdam, comprising 2647 participants including 252 incident HF cases identified during a mean follow-up of 8.2 ± 1.6 years. In both men and women significant positive associations were observed between OPG and age, smoking, prevalent diabetes, C-reactive protein, sex hormone-binding globulin, and additionally prevalent coronary heart disease and uric acid in men only. In women, OPG was furthermore positively related to hypertension and fetuin-A. After multivariable adjustment each doubling of OPG was associated with a 3.01-fold increased HF risk (95 % CI 1.49-6.06) in men. A significant interaction was observed between OPG and NT-proBNP. In men, a combination of high levels of both OPG and NT-proBNP, compared to a combination of low levels, was associated with an approximately fivefold increased HF risk. In women, no associations were observed. These findings suggest that, in men, the activation of different immune, neurohormonal, and vascular pathophysiological pathways may confer increased HF risk.

Topics: Biomarkers; Cohort Studies; Female; Heart Failure; Humans; Male; Middle Aged; Osteoprotegerin; Prospective Studies; Risk Factors

Circulating osteoprotegerin (OPG) levels are increased in patients with chronic heart failure (HF). The diagnostic and prognostic merit of OPG measurement in patients admitted with acute dyspnoea is unknown.. To evaluate the diagnostic and prognostic value of measuring OPG in patients admitted to hospital with acute dyspnoea.. OPG was analysed by ELISA in 308 patients admitted due to acute dyspnoea. Investigators blinded to OPG results adjudicated the diagnosis for the index hospitalization. Clinical outcomes were obtained from hospital records.. In total, 139 patients (45%) were hospitalized with acute HF. OPG levels on hospital admission were higher in patients with acute HF vs. no acute HF, 7.8 (5.5-10.4) vs. 5.4 (3.8-7.2) pmol/L, p<0.001. The area under the receiver operator characteristic curve (ROC AUC) of OPG to discriminate between HF vs. non-HF was 0.695 [95% CI 0.636-0.754]. OPG did not provide incremental information to the ED physician's prediction or N-terminal pro-B-type natriuretic peptide regarding the diagnosis of acute HF. OPG levels (log transformed) were associated with mortality in crude analysis (HR (95% CI) 1.87 (1.34 to 2.61), p<0.001), but this association was attenuated and no longer significant after including established cardiac biomarkers into the model.. In patients admitted to hospital with acute dyspnoea, OPG levels are higher in patients with acute HF than in those with dyspnoea from other causes. However, OPG does not provide incremental information beyond ED physician assessment for the diagnosis of acute HF or beyond clinical risk variables and established cardiac biomarkers concerning prognosis.

Topics: Aged; Biomarkers; Female; Heart Failure; Humans; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests

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

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

Osteoprotegerin (OPG) is promising as a predictor of adverse prognosis in patients with acute coronary syndromes and chronic heart failure. Its prognostic value in acute heart failure (AHF) is unknown. The aim of this study was to assess the prognostic value provided by serum OPG levels at discharge after an admission for AHF.. In a prospective study, we enrolled 338 patients consecutively admitted with AHF to the internal medicine department of a tertiary care university hospital in Porto, Portugal between March 2009 and December 2010. OPG was measured using a commercial enzyme-linked immunosorbent assay and was both analyzed as a continuous variable and categorized by quartiles. Patients were followed for up to 6 months after discharge to ascertain the occurrence of all-cause death or hospital readmission resulting from AHF.. During follow-up, 119 patients died or were readmitted for AHF. A graded increase in the risk of the combined end point was observed across quartiles of OPG. At 6 months, the cumulative risk of the end point was 25% for the first quartile and 50% for the fourth quartile. The multivariable adjusted risk of death or hospitalization for AHF increased progressively across categories of OPG up to a statistically significant 2.44-fold increase in risk in the highest category (P for linear trend = 0.002, ie, by 5% per 10 pg/mL increase in OPG).. Serum OPG was directly associated with a higher probability of death or readmission for AHF within 6 months, irrespective of other known prognostic markers. This was true both when the ejection fraction was preserved and when it was reduced.

Topics: Acute Disease; Aged; Biomarkers; Cohort Studies; Female; Heart Failure; Humans; Male; Middle Aged; Osteoprotegerin; Outcome Assessment, Health Care; Patient Readmission; Portugal; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Assessment; Risk Factors; Survival Analysis

Osteoprotegerin (OPG) is a member of the tumor necrosis factor superfamily.Recent evidence supports a relationship between serum OPG level and atherosclerosis. The aim of this study was to evaluate the possible association of OPG with the presence of coronary artery disease (CAD), its severity and prognosis in patients with chest pain and suspected coronary stenosis.. In this cross-sectional analytic study, 180 candidates of elective coronary artery angiography were recruited. Serum level of OPG was measured by ELISA method in all patients and its relation with presence and severity of CAD based on a coronary atherosclerosis score (CAS) was assessed. Patients were followed for a mean period of about 24 ± 3.2 months and the relationship between OPG levels and future cardiac events were evaluated.. The mean serum level of OPG was 1637 ± 226 pg/mL in those with CAD and 1295 ± 185 pg/mL (nonparametric p = 0.001) in those without it. There was a significant direct correlation between the level of serum OPG and CAS (rho = 0.225, p = 0.002). The optimalcut-off point for predicting a significant coronary artery obstruction was a serum level of≥ 1412 pg/mL with a sensitivity and specificity of 60% and 57.8%, respectively. Major adversecardiac events (MACE) including cardiovascular death, admission with acute coronary syndrome,or heart failure, was significantly higher in those with higher OPG levels (22 [34.3%]vs. 15 [16%], p = 0.012).. There was a direct and significant correlation between the serum level of OPG and CAS. MACE occurred more commonly in those with higher baseline OPG levels.

Topics: Acute Coronary Syndrome; Adult; Aged; Angina Pectoris; Biomarkers; Coronary Angiography; Coronary Artery Disease; Coronary Stenosis; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Prognosis; Risk Factors; Severity of Illness Index; Time Factors; Up-Regulation

Osteoprotegerin (OPG) upregulates endothelial cell adhesion molecule response to TNF-α by upregulating angiopoietin-2 (Ang-2). The aim of this study was to investigate the association between admission plasma levels of OPG, Ang-2 and TNF-α in patients with acute ST-segment elevation myocardial infarction (STEMI) and no-reflow after primary angioplasty and subsequent left ventricular remodeling (LVR).. Ninety-two patients with first STEMIs, reperfused within 12 h of symptom onset, were included. LVR was defined as a >20% increase in LV end-diastolic volume at 6-month follow-up assessed using echocardiography.. The incidences of angiographic no-reflow and electrocardiographic no-reflow were 40.2% and 55.4%, respectively. Thirty-six percent of patients subsequently developed LVR. OPG levels were significantly higher in patients who developed angiographic no-reflow (173 pg/ml, interquartile range [IQR] 83-416 vs 104 pg/ml, IQR 57-235; p=0.04), electrocardiographic no-reflow (160 pg/ml, IQR 81-315 vs 102 pg/ml, IQR 47-230; p=0.025) and LVR (174 pg/ml, IQR 120-342 vs 97 pg/ml, IQR 51-219; p=0.004). In multivariable logistic regression, OPG level was an independent predictor of angiographic (OR 1.05: 95% CI 1.01-1.08 [per 10 pg/ml increase]; p=0.005) and electrocardiographic (OR 1.04: 95% CI 1.00-1.07 [per 10 pg/ml increase]; p=0.04) no-reflow. ROC analysis showed an area under the curve of 0.69 for OPG and LVR. Plasma OPG≥132 pg/ml showed a sensitivity of 72% and a specificity of 61% for predicting LVR (OR 4.05: 95% CI 1.06-15.38; p=0.04).. High OPG level on admission is significantly associated with no-reflow after primary angioplasty and subsequent LVR at follow-up in patients with STEMI.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Angiopoietin-2; Biomarkers; Coronary Angiography; Echocardiography; Electrocardiography; Female; Heart Failure; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; No-Reflow Phenomenon; Odds Ratio; Osteoprotegerin; Patient Admission; Predictive Value of Tests; Prospective Studies; Risk Assessment; Risk Factors; ROC Curve; Sensitivity and Specificity; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Turkey; Up-Regulation; Ventricular Remodeling

Chronic heart failure (CHF) is associated with a 4-fold increased risk for osteoporotic fractures. Therefore, we sought to identify the pathophysiological link between chronic heart failure and catabolic bone remodeling.. In a total cohort of 153 subjects (123 patients with CHF, 30 patients with coronary artery disease and preserved cardiac function) as well as mice with heart failure, bone marrow (BM) plasma levels of the catabolic receptor activator of NF-κB ligand (RANKL), and its antagonist, osteoprotegerin were measured. The osteoclast inducing activity of BM plasma was tested in cell culture. BM plasma levels of RANKL and of the ratio RANKL/osteoprotegerin were significantly elevated in patients with CHF. On multivariate regression analysis, parameters of severity and duration of heart failure were independent determinants of elevated BM plasma RANKL levels. BM plasma levels of RANKL were directly correlated with the systemic marker of bone turnover C-telopeptide of type 1 collagen (r=0.6; P<0.001). Alterations in BM plasma levels of RANKL/osteoprotegerin were confirmed in a mouse model of postinfarction heart failure. Stimulation of human mesenchymal cells with BM plasma obtained from CHF patients increased the formation of osteoclasts, and this effect was blocked by the RANKL inhibition.. CHF is associated with a profound and selective elevation of the bone resorption stimulating RANKL within the BM microenvironment. These data for the first time disclose a direct pathophysiological pathway linking CHF with catabolic bone remodeling associated with an increased osteoporotic fracture risk.. URL: http://www.clinicaltrials.gov. Unique identifiers: NCT 00289822, NCT 00284713, NCT 00326989, NCT 00962364.

Topics: Aged; Animals; Biomarkers; Bone Marrow; Bone Remodeling; Case-Control Studies; Cell Differentiation; Cells, Cultured; Chronic Disease; Cohort Studies; Collagen Type I; Comorbidity; Coronary Artery Disease; Disease Models, Animal; Female; Heart Failure; Humans; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Middle Aged; Osteoclasts; Osteoporosis; Osteoprotegerin; Peptides; RANK Ligand; Regression Analysis

Heart failure (HF) had been reported with increased risk of hip fractures. However, the relationship between circulating biomarkers and bone mineral density (BMD) in chronic HF remained unclear.. This is a cross-sectional study which recruited stable chronic HF from registry of the Heart Failure Center of National Taiwan University Hospital. Patients underwent dual-energy x-ray absorptiometry (DEXA) measurements at hip and lumbar spines and biochemical assessments including B-type natriuretic peptide (BNP-32), myostatin, follistatin and osteoprotegerin (OPG).. A total of 115 stable chronic HF individuals with left ventricular ejection fraction (EF) <45% (74% of male, mean age at 59) were recruited with 24 patients in NYHA class I, 73 patients in NYHA class II and 18 patients in NYHA class III. Results of BMD showed that Z scores of hip in NYHA III group (-0.12 ± 1.15) was significantly lower than who were NYHA II (0.58 ± 1.04). Serum OPG was significantly higher in subjects of NYHA III (9.3 ± 4.6 pmol/l) than NYHA II (7.4 ± 2.8 pmol/l) or NYHA I (6.8 ± 3.6 pmol/l) groups. There's a significant negative association between log transformed serum OPG and trochanteric BMD (R = -0.299, P = 0.001), which remained significant after multivariate analysis.. Our study demonstrated an inverse association between serum OPG and trochanteric BMD in patients with HF. OPG may be a predictor of BMD and an alternative to DEXA for identifying at risk HF patients for osteoporosis.

Topics: Absorptiometry, Photon; Adult; Aged; Biomarkers; Bone Density; Chronic Disease; Cross-Sectional Studies; Female; Femur; Heart Failure; Humans; Lumbar Vertebrae; Male; Middle Aged; Multivariate Analysis; Osteoporosis; Osteoprotegerin

Osteoprotegerin (OPG) is a glycoprotein with a regulatory role in immune, skeletal and vascular systems. Data suggest that high circulating OPG levels are associated with an increased risk of cardiovascular disease. We analyzed the association between OPG and long-term outcome in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI).. We included 716 consecutive STEMI patients admitted to a single high-volume invasive heart center from September 2006 to December 2008. Endpoints were all-cause mortality, repeat myocardial infarction, admission due to heart failure and combinations thereof. Median follow-up lasted 27 months (interquartile range: 22-33).. OPG levels exhibited a non-Gaussian distribution and were therefore divided into quartiles. High levels of OPG were significantly associated with a worse outcome. After adjustment for conventional risk factors (e.g. C-reactive protein, estimated glomerular filtration rate, symptom-to-balloon time and troponin I) using Cox regression, OPG remained a significantly independent predictor of death (HR per increase in OPG quartile: 1.28; CI: 1.03-1.59; p = 0.03), repeat myocardial infarction (HR: 1.30; CI: 1.00-1.68; p = 0.05) and admission with heart failure (HR: 1.50; CI: 1.18-1.90; p = 0.001).. This study shows that OPG independently predicts long-term outcome in STEMI patients treated with pPCI. Eventually, this knowledge could improve risk stratification and overall outcome.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Osteoprotegerin; Percutaneous Coronary Intervention; Prognosis; Risk Assessment; Risk Factors; Survival Analysis; Treatment Outcome

Topics: Female; Heart Failure; Humans; Male; Myocardial Infarction; Osteoprotegerin; Percutaneous Coronary Intervention

CXCL16 and osteoprotegerin (OPG) both predict mortality in acute coronary syndromes. We hypothesized that a combination of CXCL16 and OPG concentrations would add prognostic information to the Global Registry of Acute Coronary Events (GRACE) score in patients hospitalized for acute coronary syndromes.. We assessed the associations between circulating OPG and soluble CXCL16 levels, obtained within 24 hours of admission (day 1) and after 3 months, and mortality, heart failure and reinfarction in 1322 patients admitted with acute coronary syndromes. After adjustment for the GRACE score, medication, diabetes mellitus and sex, the combination of high values (fourth quartile) for OPG and CXCL16 at baseline was associated with increased short-term (3 months) cardiovascular mortality (hazard ratio, 3.28; 95% CI, 1.84-5.82; P<0.0001). The combined high values were also significantly associated with the long-term (median 91 months) prognosis after adjustment, with hazard ratios 2.18 for cardiovascular mortality (95% CI, 1.62-2.92; P<0.0001), and 2.22 for heart failure (95% CI, 1.67-2.96; P<0.0001). These long-term associations remained significant after further adjustment for left ventricular ejection fraction, C-reactive protein, and pro B-type natriuretic peptide. For 635 patients with blood samples within 24 hours and at 3 months, the combination of high CXCL16 and OPG values (fourth quartile) in the early or stable phase was of a similar order associated with mortality and morbidity beyond 3 months.. Circulating CXCL16 and OPG are independent predictors of long-term mortality and heart failure development in acute coronary syndromes patients, even after extensive adjustments. Their combination gives more information than either marker alone.

Topics: Acute Coronary Syndrome; Aged; Biomarkers; Chemokine CXCL16; Chemokines, CXC; Female; Heart Failure; Humans; Longitudinal Studies; Male; Middle Aged; Osteoprotegerin; Prognosis; Prospective Studies; Receptors, Scavenger; Registries; Retrospective Studies; Risk Assessment; Survival Rate

High PTH levels have been reported in patients with chronic heart failure (CHF). Similarly, its levels increase with aging and are related to impaired survival in elderly adults. However, its relationship with neuroendocrine activation and endothelial dysfunction in CHF has not been previously studied. Seventy-three CHF males with New York Heart Association (NYHA) classes II and III and 20 control subjects aged ≥ 55 yr were recruited. PTH, 25-hydroxyvitamin D [25(OH)D], N-terminal pro-brain natriuretic peptide (NT-pro-BNP), adiponectin, and osteoprotegerin were measured. Endothelial function (brachial flow mediated dilation), echocardiography, physical performance, and quality of life were assessed, as well. CHF patients had markedly increased serum PTH (77 ± 33 vs 40 ± 11 pg/ml, p<0.0001), NT-pro-BNP [1809 (2742) vs 67 (74) pg/ml, p<0.0001], adiponectin (17 ± 9 vs 10 ± 2 μg/ml, p<0.0001), osteoprotegerin, whereas 25(OH)D levels were decreased compared to controls. Increased PTH is positively correlated with NTpro- BNP (r=0.399, p<0.0001), adiponectin (r=0.398, p<0.0001), and osteoprotegerin, whereas negatively with 25(OH)D in CHF patients. Additionally, increased serum PTH was associated with endothelial dysfunction, echocardiographic variables of heart failure progression, impaired physical performance, and deteriorated quality of life. In a multivariate linear regression analysis, increased serum PTH was independently associated with neuroendocrine activation (NT-pro-BNP, adiponectin) and endothelial dysfunction in elderly CHF men (R2=0.455). Additionally, demonstrated relations with other well-established variables of heart failure severity suggest the potential role of serum PTH in the pathogenesis and non-invasive monitoring of heart failure progression. Future studies are needed to evaluate the predictive value of serum PTH for clinical outcomes as well as beneficial potential of PTH suppression in CHF patients.

Topics: Adiponectin; Aged; Chronic Disease; Endothelium, Vascular; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neurosecretory Systems; Osteoprotegerin; Parathyroid Hormone; Peptide Fragments; ROC Curve; Vascular Diseases; Vitamin D

This study was designed to evaluate the biological significance of simultaneous changes in the circulating levels of osteoprotegerin (OPG) and TNF-related apoptosis inducing ligand (TRAIL) in patients with coronary artery disease (CAD), and, in particular, with acute myocardial infarction (AMI).. Total levels of OPG and TRAIL were measured by ELISA in patients with AMI (n=113), unstable angina (UA, n=21) and healthy controls (n=120).. Since OPG was elevated during the acute phase (first 12-24-48h) after AMI and in patients with UA with respect to healthy controls, while TRAIL was decreased in acute AMI patients, CAD patients were characterized by an increased OPG/TRAIL ratio. Moreover, the OPG/TRAIL ratio was significantly (p<0.05) higher in the acute AMI patients who developed heart failure (HF) than in those who did not develop HF in the follow-up.. An impaired OPG/TRAIL ratio after AMI is related to a higher risk of HF.

Topics: Angina, Unstable; Coronary Disease; Enzyme-Linked Immunosorbent Assay; Female; Heart Failure; Humans; Male; Myocardial Infarction; Osteoprotegerin; TNF-Related Apoptosis-Inducing Ligand

The main cytokines regulating bone remodeling are the receptor activator of nuclear factor-κB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG). Recent data have linked RANKL and OPG to cardiovascular disease as well. NT-pro-BNP and adiponectin are well-established biomarkers of heart failure reflecting neuroendocrine activation in this multi-complex disorder. The objective of this article was to investigate whether RANKL is associated with neuroendocrine activation in 75 elderly males with mild to moderate congestive heart failure (CHF) and left ventricular ejection fraction <40%. The control group consisted of 20 healthy male volunteers with matching age and body mass index (BMI). Serum RANKL (sRANKL), OPG, NT-pro-BNP, adiponectin, leptin, clinical, and echocardiography parameters were evaluated. In comparison to the control group, the CHF patients showed significantly increased sRANKL levels [126.8 (122.6) vs. 47.8 (44.4) pg/ml, P < 0.0001]. There was a significant relative risk of systolic CHF in elderly males associated with increased sRANKL above the calculated cut-off of 83 pg/ml [OR = 10.286 (95%CI 3.079-34.356), P < 0.0001; RR = 3.600 (95%CI = 1.482-8.747)]. In the CHF patients, the log-transformed values of sRANKL levels correlated positively with the log-transformed values of the serum NT-pro-BNP and adiponectin levels (P = 0.004, r = 0.326 and P = 0.037, r = 0. 241, respectively), while inversely correlated with the BMI and creatinine clearance (P = 0.015, r = -0.281 and P = 0.042, r = -0.236, respectively). In multivariate regression model, sRANKL was a significant determinant of NT-pro-BNP independent of age, BMI and creatinine clearance (P = 0.002, R (2) = 0.546). In conclusion, our study suggests that in elderly males with systolic heart failure sRANKL was significantly associated with parameters of neuroendocrine activation such as NT-pro-BNP and adiponectin. Further studies are needed to elucidate the potential role of sRANKL in the complex pathogenesis of heart failure.

Topics: Adiponectin; Aged; Biomarkers; Body Mass Index; Cross-Sectional Studies; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neurosecretory Systems; Osteoprotegerin; Peptide Fragments; RANK Ligand; Statistics as Topic

This study was designed to investigate whether IL-17 can regulate the expression of the MMP/TIMP system, the OPG/RANK/RANKL system, or type-I and type-III collagen fibers in a rat model of isoproterenol-induced heart failure (HF). We also investigated the effect of IL-17 on myocardial fibrosis in this model.. HF was induced in Wistar-Kyoto rats by hypodermic injection of isoproterenol (ISO) twice every 24 h. After 2 months, the surviving rats were divided into three groups: monoclonal Anti-IL-17 Ab (100 microg/day), IgG (100 microg/day) or PBS were injected five times every 48 h (i.p.). One day after the last injection, all of the rats were sacrificed. H&E and Masson staining were used to evaluate myocardial fibrosis, and immunohistochemistry was used to measure the levels of MMP-1, TIMP-1, TIMP-4, OPG, RANKL, type-I and type-III collagen fibers. We also treated adult rat cardiac fibroblasts with IL-17 (10 ng/ml), IL-17 (10 ng/ml)+OPG (10 ng/ml), IL-17 (10 ng/ml)+anti-RANKL Ab (100 ng/ml), or PBS for 24 h, realtime RT-PCR was used to measure the expressions of MMP-1.. The expressions of MMP-1, RANKL, and type-I and -III collagen fibers decreased, and the expressions of TIMP-1, TIMP-4, and OPG increased in the Anti-IL-17 group compared to controls. H&E and Masson staining revealed that blockade of IL-17 can improve myocardial fibrosis in HF. IL-17 increased the expression of MMP-1 in cardiac fibroblasts, and OPG and anti-IL-17 Ab could inhibit this function partly. Thus, IL-17 was dependent on the RANKL/OPG system to induce MMP-1 partly.. Our study demonstrates the contribution of IL-17 to myocardial fibrosis in isoproterenol-induced HF. IL-17 can regulate the RANKL/OPG and MMP/TIMP systems in this model. The RANKL/OPG system is one of intermediaries between IL-17 and MMP-1 in cardiac fibroblasts. As a harmful cytokine, anti-IL-17 treatment is a potential therapeutic strategy in HF.

Topics: Animals; Disease Models, Animal; Fibrosis; Heart Failure; Interleukin-17; Isoproterenol; Male; Matrix Metalloproteinases; Myocardium; Osteoprotegerin; RANK Ligand; Rats; Rats, Wistar; Signal Transduction; Tissue Inhibitor of Metalloproteinases

The pathophysiology of heart failure is complex, and the list of biomarkers representing distinct pathophysiologic pathways is growing rapidly. This article focuses on some promising newer biomarkers that have contributed to a better understanding of pathophysiologic mechanisms involved in heart failure but for which less data are currently available: osteoprotegerin, galectin-3, cystatin C, chromogranin A, and the adipokines adiponectin, leptin, and resistin. Despite the intriguing early information from these newer markers, none is ready for routine clinical use. Much additional study is needed to determine how these biomarkers will fit into diagnostic and treatment algorithms for patients who have heart failure.

Topics: Adipokines; Biomarkers; Cystatin C; Galectin 3; Heart Failure; Humans; Osteoprotegerin

Osteoprotegerin (OPG) and the receptor activator of nuclear factor-kappaB ligand (RANKL), two cytokines regulating bone remodeling, have recently been raised as potential pathogenetic factors in cardiovascular diseases. We have studied circulating and myocardial OPG and RANKL in patients having severe aortic stenosis (AS) with or without heart failure (HF).. We studied 131 adults with AS. Blood was sampled from the aortic root, coronary sinus, and femoral vein at cardiac catheterization. LV myocardial biopsies were taken at surgery. Plasma OPG and soluble (s)RANKL were analyzed by ELISA, and myocardial OPG and RANKL by RT-PCR and immunohistochemistry.. Circulating OPG was elevated in AS patients with HF, the association being independent of age, sex, and presence of coronary artery disease (beta=0.17, p=0.033). Elevated plasma OPG decreased after valve replacement in patients with preoperative HF (p=0.0005). Relative to its concentration in the aortic root, plasma OPG was reduced in the coronary sinus (p<0.05) and in the femoral vein (p<0.001), these arteriovenous gradients being accentuated in HF (p=0.003).. HF due to LV pressure overload in AS increases circulating OPG and augments OPG extraction by the heart and peripheral tissues. OPG may be involved in the pathogenesis of HF and could serve as a useful biomarker in HF due to LV pressure overload.

Topics: Aged; Aortic Valve Stenosis; Biomarkers; Cytokines; Female; Heart Failure; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Immunoenzyme Techniques; Male; Myocardium; Osteoprotegerin; Pilot Projects; Receptor Activator of Nuclear Factor-kappa B; Risk Factors

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

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