osteoprotegerin and Cardiomyopathies

Extra-skeletal calcification and disordered phosphate metabolism are hallmarks of chronic kidney disease-mineral bone disorder (CKD-MBD). Osteoprotegerin (OPG) and fibroblast growth factor 23 (FGF-23) are increased in chronic kidney disease (CKD) and have been associated with arterial and cardiac dysfunction and reduced survival. Troponin T (cTnT) is released from cardiac myocytes under conditions of stress and is predictive of mortality across a range of renal functions. However, the utility of this biomarker was formerly limited by the lower limit of assay detection. The introduction of a high-sensitivity assay has enabled more detailed study of myocyte stress below the previous limit of detection. We studied the association of mediators of CKD-MBD with arterial stiffness and also of these mediators and arterial stiffness with myocardial damage in patients with CKD stages 3-4.. OPG and FGF-23 were measured in 200 CKD stages 3-4 patients. cTnT was measured using a high-sensitivity assay. Aortic stiffness was assessed using aortic pulse wave velocity (APWV).. Mean age was 69 ± 11 years, mean systolic and diastolic blood pressure was 151 ± 22/81 ± 11 mmHg and renal function was 33 ± 11 mL/min/1.73 m(2). OPG, FGF-23, high-sensitivity troponin T (hs-cTnT) and APWV all correlated with renal function. After multivariate analysis, OPG and age remained independently associated with aortic stiffness. OPG and FGF-23 were independently associated with hs-cTnT in addition to other non-traditional risk factors (Model R(2) = 0.596).. We have shown that changes in bone mediators and phosphate metabolism induced by CKD are independently associated with vascular and cardiomyocyte dysfunction. Our findings suggest that cardiac dysfunction may be specifically associated with such abnormalities in addition to recognized increases in vascular stiffness.

Topics: Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Biomarkers; Bone Density; Bone Diseases; Cardiomyopathies; Cardiovascular Diseases; Cohort Studies; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Prognosis; Regression Analysis; Risk Assessment; Severity of Illness Index; Sex Factors; Survival Rate; Troponin T; Vascular Resistance

The aim of the study was to assess the factors potentially involved in coronary artery calcifications (CAC) in end-stage renal disease patients. 253 hemodialysis (HD) patients (92 females, 161 males), aged 62.5 +/- 13.5, who had been on HD treatment for at least 6 months, were enrolled in a cross-sectional study. Calcium-phosphate product (Ca x P), body mass index (BMI), fetuin-A, osteoprotegerin (OPG), osteopontin, transforming growth factor-beta1 (TGF-beta1), fibroblast growth factor-23 (FGF-23) and matrix Gla protein (MGP) were considered. CAC was assessed using multislice spiral computed tomography and calcium score was quantified by means of the Agatston score. The median calcium score was 364 Agatston (range 0-7,336). CAC was detected in 228/253 patients (90.1%). Multivariate regression analysis, adjusted for age and for dialysis vintage, showed that TGF-beta1, OPG and days with Ca x P >55 mg/dl are independent predictors of CAC, while MGP was shown to be a protective factor. Surprisingly, results showed that BMI was a protective factor too: the interpolation with cubic spline function revealed a significant reduction in calcium score in patients with a high BMI (>28). However, when diabetes was considered in the regression analysis, only OPG emerged as a predictor of a high CAC score. The interpolation with spline function continued to show a significant reduction in CAC score in nondiabetic and in diabetic patients with the highest BMI quartile. The protective effect of a high BMI on CAC might represent another example of inverse biology in dialysis patients but it needs to be further addressed in larger longitudinal studies.

Topics: Adult; Aged; Body Mass Index; Calcinosis; Calcium; Cardiomyopathies; Cross-Sectional Studies; Diabetes Mellitus; Female; Fibroblast Growth Factor-23; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Transforming Growth Factor beta1

Clinically, calcific aortic valve disease is a progressive continuum from obstructive fibro(sclero)tic valve thickening to aortic stenosis. Recent evidence suggests that, in addition to nonbone miscellaneous mineralization, calcified valves present distinct signs of active bone remodeling; and in this context, noncollagenous bone-associated proteins are assumed to have a critical role. The expression of 5 bone matrix proteins-bone morphogenetic protein-2 and -4, bone sialoprotein II, osteopontin, and osteoprotegerin-was examined by reverse transcriptase polymerase chain reaction (n = 31) and immunolabeling (n = 83) in the clinical continuum from healthy pliable valves to heavily calcified ones. As a known structural pathologic sign, the extent of neovascularization was also examined. We observed progressive increase in the gene expression of osteopontin (7.4-fold elevation, P < .001) and bone sialoprotein II (5.8-fold elevation, P < .05), and also 1.7-fold elevation (P < .05) in osteoprotegerin gene expression during the disease course. These findings were congruent with that of immunohistochemical analysis. Surprisingly, bone morphogenetic protein-2 and -4 showed a comparable significant decrease in messenger RNA levels in calcified valves (P < .01 and P < .05, respectively). Our results support the view that aortic valve calcification is an actively regulated process. Furthermore, the results suggest that the expression of pro- and anticalcific noncollagenous bone-associated matrix proteins is altered during the disease continuum and that this imbalance may contribute to the pathology of calcific aortic valve disease.

Topics: Adult; Aged; Aged, 80 and over; Aortic Valve; Aortic Valve Stenosis; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins; Calcinosis; Cardiomyopathies; Female; Gene Expression Regulation; Humans; Immunohistochemistry; Integrin-Binding Sialoprotein; Male; Middle Aged; Neovascularization, Pathologic; Osteopontin; Osteoprotegerin; Sialoglycoproteins

Coronary artery calcification may play a significant role in the pathophysiology of plaque progression and healing. We hypothesized that osteoprotegerin, an inhibitor of osteoclastogenesis, may participate in the calcification of coronary plaques or the response to injury after coronary stenting. A prospective registry was performed in 2004. Blood samples from 100 patients undergoing percutaneous coronary intervention (PCI) were obtained before PCI and 24 h after PCI. The concentrations of osteoprotegerin (OPG), C-reactive protein, interleukin-6, and soluble CD40 ligand (sCD40L) were determined by ELISA. Quantitative coronary angiography was performed to define the presence of culprit lesion calcification (CLC). Comparisons among markers of inflammation and tertiles of OPG were stratified with respect to CLC. Patients with CLC (n = 28) compared with no CLC (n = 71) were older (P < 0.01), had lower creatinine clearance (P < 0.01), lower hemoglobin (P = 0.02), and were less likely to smoke (P = 0.04). Patients without CLC were over twice as likely to present with a marker-positive acute coronary syndrome. CLC was associated with less pre-PCI platelet-mediated inflammation as measured by sCD40L (4.65 vs. 7.15 pg/ml, P = 0.05), but not with lower levels of OPG. Inflammatory cytokines increased significantly after PCI for patients with and without CLC. For patients in the highest tertile of OPG at baseline, there was a reduction in OPG after PCI. Systemic osteoprotegerin levels are not associated with angiographic calcification of culprit plaques. For patients with elevated levels of OPG prior to PCI, there is a significant reduction after PCI consistent with a counterregulatory role for OPG.. Both calcified and non-calcified culprit plaques exhibited a similar inflammatory response to stent-mediated injury. After PCI, osteoprotegerin decreased while proinflammatory cytokines increased, which may be consistent with a counterregulatory role for osteoprotegerin.

Topics: Aged; Angioplasty, Balloon, Coronary; Calcinosis; Cardiomyopathies; Coronary Angiography; Coronary Vessels; Cytokines; Female; Humans; Inflammation; Male; Middle Aged; Osteoprotegerin; Prospective Studies; Stents