osteoprotegerin and Atrial-Fibrillation

Atrial structural remodeling is increasingly emphasized in initiation and perpetuation of atrial fibrillation (AF). Osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) axis, a key regulatory system in bone homeostasis, was recently linked to some cardiovascular disorders for its regulatory functions to myocardial remodeling. It was hypothesized that OPG/RANK/RANKL axis is involved in the development and progression of AF by regulating atrial structural remodeling.. Clinical data, and biopsies of right atrial appendage were collected from sex- and age-matched subjects: 24 persistent AF patients, 24 paroxysmal AF patients, 24 sinus rhythm patients undergoing isolated mitral valve surgery and 24 healthy heart donors. AF groups had higher atrial gene expression of OPG/RANK/RANKL axis and RANKL/OPG ratio, particularly in paroxysmal AF. This upregulated expression and activity were positively correlated with higher regulatory indicators of atrial structural remodeling as reflected by higher transcripts of tumor necrosis factor (TNF)-related apoptosis-inducing ligand, matrix metalloproteinase (MMP)-2 and MMP-9, pro-inflammatory factors TNF-α and interleukin-6, and higher ratios of MMP-9/tissue inhibitor of metalloproteinase (TIMP)-1 and MMP-2/TIMP-2 in AF.. The present findings suggest a potential role for known mediators of bone metabolism in the development and progression of AF and possibly represent new targets for therapeutic intervention in this disorder.

Topics: Adult; Atrial Fibrillation; Disease Progression; Female; Gene Expression Regulation; Heart Atria; Humans; Interleukin-6; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tumor Necrosis Factor-alpha

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

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

There is a growing amount of evidence that inflammatory processes are involved in the development of atrial fibrillation (AF) and its complications. We decided to investigate the behavior of osteoprotegerin (OPG) and TNF-related apoptosis inducing ligand (TRAIL) in terms of acute onset of AF.. We included 60 patients with acute onset of AF, candidates for pharmacological cardioversion. The presence of cardiovascular comorbidities was connected with higher concentration of OPG and lower level of TRAIL right from the first hours of AF paroxysm. The initial TRAIL level correlated also positively with left ventricle ejection fraction and negatively with left atrium diameter. We found subsequent increase of OPG in subgroups selected on the basis of CHA2DS2-VASc scoring. Although basal concentrations of studied markers did not allow prediction of the restoration of sinus rhythm, we observed important increase of TRAIL concentration in subgroup with sinus rhythm maintenance (94.11 ± 29.46 versus 111.39 ± 30.23 pg/mL; p = 0.002).. OPG and TRAIL are associated with the underlying cardiovascular damage in AF, but their balance is modulated by the fact of sinus rhythm restoration. Determining the suitability of OPG and TRAIL as predictive markers in AF requires further prospective studies.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Biomarkers; C-Reactive Protein; Cholesterol; Electric Countershock; Female; Humans; Male; Middle Aged; Osteoprotegerin; Prospective Studies; TNF-Related Apoptosis-Inducing Ligand; Treatment Outcome

The osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) axis may play an important role in the stabilization of restored sinus rhythm (SR) after mitral valve (MV) surgery by stimulating atrial fibrillation (AF)-related atrial remodeling in AF patients. Herein, we investigated the association between preoperative serum soluble RANKL (sRANKL)/OPG and the stabilization of restored SR after MV surgery.. Persistent AF patients who had spontaneously restored SR after MV replacement were enrolled (n = 203). Comparison was made between patients without AF recurrence (n = 71) and patients experiencing recurrence (n = 132).. Patients experiencing recurrence had higher serum levels of sRANKL, OPG and sRANKL/OPG ratio than patients without recurrence. Multivariate survival regression analysis showed that clinical factors such as duration of AF, left atrial diameter and left atrial thrombosis, as well as serum sRANKL level and the sRANKL/OPG ratio, were independent predictors of AF recurrence. Receiver operating characteristic curve analysis showed that the best diagnostic values of the serum sRANKL level and the sRANKL/OPG ratio for predicting recurrence were 3.44 pmol/l and 0.53, respectively.. Patients who had a low preoperative serum sRANKL level and sRANKL/OPG ratio are likely to have a stable spontaneously restored SR postoperatively. Thus, we suggest that patients at high risk of early AF recurrence should be considered for concomitant surgical cardioversion during MV surgery.

Topics: Atrial Fibrillation; Biomarkers; Chronic Disease; Female; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Mitral Valve Stenosis; Osteoprotegerin; Preoperative Care; Receptor Activator of Nuclear Factor-kappa B; Secondary Prevention

Topics: Atrial Fibrillation; Female; Heart Atria; Humans; Male; Mitral Valve; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Topics: Atrial Fibrillation; Heart Atria; Humans; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Postoperative atrial fibrillation (POAF), a frequent complication after cardiac surgery, causes morbidity and prolongs hospitalization. A significant association between circulating osteoprotegerin concentration and atrial fibrillation incidence had been identified. Osteoprotegerin/receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand (RANKL) axis may also contribute to the development and progression of AF. Herein we sought to determine whether preoperative serum soluble RANKL and osteoprotegerin and soluble RANKL/osteoprotegerin ratio are associated with the incidence of POAF in cardiac surgery patients.. We enrolled 154 patients with preoperative sinus rhythm undergoing isolated cardiac valve surgery. Preoperative venous blood samples were obtained for measurement of serum soluble RANKL and osteoprotegerin. The POAF was defined as the characteristic arrhythmia lasting for at least 30 seconds before discharge. Comparison was made between patients without episode of POAF (sinus rhythm group, n=93) and patients experiencing POAF (atrial fibrillation group, n=61).. Serum levels of soluble RANKL and osteoprotegerin and soluble RANKL/osteoprotegerin ratio were significantly higher in the atrial fibrillation group than the sinus rhythm group. In multivariate survival regression, C-reactive protein, ejection fraction, left and right atrial diameters, preoperative use of beta-blocker, duration of ventilation, particularly serum soluble RANKL level, and soluble RANKL/osteoprotegerin ratio independently predicted POAF. According to receiver operating characteristic curve analysis, the best threshold values of serum soluble RANKL level and soluble RANKL/osteoprotegerin ratio for predicting POAF were 3.62 pmol/L and 0.51, respectively.. Elevated preoperative serum soluble RANKL level and soluble RANKL/osteoprotegerin ratio are independent predictors for POAF in patients undergoing cardiac valve surgery. These findings have important implications for identifying patients at higher risk of POAF who could be considered for prophylactic therapy.

Topics: Adult; Analysis of Variance; Atrial Fibrillation; Biomarkers; Cohort Studies; Female; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Humans; Male; Middle Aged; Osteoprotegerin; Postoperative Complications; Predictive Value of Tests; Preoperative Care; Proportional Hazards Models; Receptor Activator of Nuclear Factor-kappa B; Regression Analysis; Retrospective Studies; Risk Assessment; Solubility; Statistics, Nonparametric; Survival Rate; Treatment Outcome

Topics: Atrial Fibrillation; Female; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Humans; Male; Osteoprotegerin; Receptor Activator of Nuclear Factor-kappa B

Atrial remodeling is considered as the structural basis for the development and sustaining of atrial fibrillation (AF). Osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) axis, a key regulatory system in bone metabolism, was recently identified in some cardiovascular disorders for its regulation to myocardial remodeling. We hypothesized that the OPG/RANK/RANKL axis is involved in development and perpetuation of AF by regulating atrial remodeling.. Biopsies of right atrial appendage and clinical data were collected from sex- and age-matched 24 persistent AF, 24 paroxysmal AF, 24 sinus rhythm (SR) patients undergoing isolated mitral valve surgery and 24 healthy heart donors (normal controls).. A significantly increasing gradient of atrial expression of OPG, RANKL, RANK and RANKL/OPG ratio was identified in normal controls, SR and AF groups. RANKL/OPG ratio was also found significantly higher in paroxysmal AF than persistent AF. Furthermore, atrial expression and activity of the axis was statistically correlated with collagen III/I levels and ratio and the degree of interstitial fibrosis reflected by collagen volume fraction in right atrial appendages.. The present findings suggest a potential role for known mediators of bone homeostasis in the pathogenesis of AF and possibly represent new targets for therapeutic intervention in AF.

Topics: Adult; Atrial Fibrillation; Atrial Remodeling; Biomarkers; Female; Humans; Male; Middle Aged; Mitral Valve; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

To investigate the expression of the osteoprotegerin (OPG)/receptor activator of nuclear factor-ĸB (RANK)/RANK ligand (RANKL) axis in the stabilization of spontaneously restored sinus rhythm (SR) in permanent atrial fibrillation (AF) patients after mitral valve (MV) surgery and study its clinical significance.. Clinical data, biopsies of right atrial appendages were collected from 135 permanent AF patients who spontaneously restored SR after conventional isolated MV replacement. A comparison was made between patients who had recurrence of AF within 7 days and patients with persistent SR for more than 7 days.. AF patients had an increased expression of RANK, RANKL, and the RANKL/OPG ratio compared to SR patients, and the degree of fibrosis was lower in SR compared to AF in the atria. Moreover, the expressions of RANK, RANKL, and the RANKL/OPG ratio were positively correlated with the degree of fibrosis.. These findings suggest that the OPG/RANK/RANKL axis plays important roles in the stabilization of restored SR after MV surgery by stimulating AF-related atrial remodeling in AF patients.

Topics: Atrial Fibrillation; Female; Heart Atria; Humans; Male; Middle Aged; Mitral Valve; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Topics: Atrial Fibrillation; Female; Heart Atria; Humans; Male; Mitral Valve; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Inflammatory biomarkers are reported as risk factors for atrial fibrillation (AF), but their impact is uncertain.. We investigated the associations between inflammatory biomarkers and future AF in a large general cohort.. Available markers were white blood cells (WBCs) with subgroups, fibrinogen, high-sensitivity C-reactive protein (hs-CRP), and osteoprotegerin (OPG). A total of 6315 men and women from a population survey in Tromsø, Norway in 1994 to 1995 were followed for a mean of 10.9 years. Mean age at baseline was 60 years. Measurements of height, weight, blood pressure, heart rate, total cholesterol, high-density lipoprotein (HDL) cholesterol, WBC count, and information on diabetes, angina, myocardial infarction, and antihypertensive treatment, were obtained at baseline. Fibrinogen, hs-CRP, and OPG were obtained at a follow-up visit. The outcome measure was first-ever AF, documented on an electrocardiogram. The Cox proportional hazards regression model was used to estimate hazard ratios of AF.. In the multivariable analysis, adjusted for traditional cardiovascular risk factors and other inflammatory biomarkers, hs-CRP was associated with AF in men only (hazard ratio = 1.14 for a 1 SD increase; 95% CI, 1.02-1.28). There was a significant increase in AF across quartiles of WBCs in men (P = 0.007) and in the total study population (P = 0.004). OPG was associated with AF in patients free of coronary heart disease at baseline. Fibrinogen and subgroups of WBCs showed no significant association with AF.. This population-based cohort study showed that hs-CRP was independently associated with AF in men, but apparently not in women, and that patients with WBCs in the upper quartile had increased risk of AF.

Topics: Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Biomarkers; C-Reactive Protein; Coronary Disease; Electrocardiography; Female; Fibrinogen; Humans; Inflammation; Leukocyte Count; Male; Middle Aged; Multivariate Analysis; Norway; Osteoprotegerin; Proportional Hazards Models; Prospective Studies; Risk Factors; Sex Factors

Basic and clinical studies have suggested that inflammation predisposes to atrial fibrillation (AF). We assessed the association of 12 circulating inflammatory biomarkers (i.e., C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, osteoprotegerin, P-selectin, and tumor necrosis factor receptor II) with incident AF in 2863 Framingham Offspring Study participants (mean age 60.7 years, SD = 9.4, 55% women). During follow-up (median 6 years), 148 participants (43% women) developed incident AF. In the multivariable proportional hazards models, the inflammatory biomarker panel was associated with incident AF (p = 0.03). With stepwise selection (p <0.01 for entry and retention), log-transformed osteoprotegerin was associated with incident AF (hazard ratio per SD 1.30, 95% confidence interval 1.08 to 1.56, p = 0.006). Adjusting for interim myocardial infarction or heart failure attenuated the association between osteoprotegerin and incident AF (hazard ratio 1.18, 95% confidence interval 0.98 to 1.43, p = 0.09). In conclusion, circulating osteoprotegerin concentration was significantly associated with incident AF in our community-based sample, possibly mediated by interim cardiovascular events.

Topics: Atrial Fibrillation; Biomarkers; C-Reactive Protein; Confidence Intervals; Female; Germany; Humans; Incidence; Inflammation; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Osteoprotegerin; Prospective Studies; Risk Factors; Survival Analysis