osteoprotegerin and Aortic-Valve-Stenosis

Left ventricular myocardial fibrosis in patients with aortic stenosis (AS) confers worse prognosis. Plasma osteoprotegerin (OPG), a cytokine from the TNF receptor family, correlates with the degree of valve calcification in AS, reflecting the activity of the tissue RANKL/RANK/OPG (receptor activator of nuclear factor κΒ ligand/RANK/osteoprotegerin) axis, and is associated with poorer outcomes in AS. Its association with myocardial fibrosis is unknown. We hypothesised that OPG levels would reflect the extent of myocardial fibrosis in AS. We included 110 consecutive patients with AS who had undergone late-gadolinium contrast enhanced cardiovascular magnetic resonance (LGE-CMR). Patients were characterised according to pattern of fibrosis (no fibrosis, midwall fibrosis, or chronic myocardial infarction fibrosis). Serum OPG was measured with ELISA and compared between groups defined by valve stenosis severity. Some 36 patients had no fibrosis, 38 had midwall fibrosis, and 36 had chronic infarction. Patients with midwall fibrosis did not have higher levels of OPG compared to those without fibrosis (6.78 vs. 5.25 pmol/L, p = 0.12). There was no difference between those with midwall or chronic myocardial infarction fibrosis (6.78 vs. 6.97 pmol/L, p = 0.27). However, OPG levels in patients with chronic myocardial infarction fibrosis were significantly higher than those without fibrosis (p = 0.005).

Topics: Aged; Aged, 80 and over; Aortic Valve Stenosis; Female; Fibrosis; Heart Ventricles; Humans; Male; Middle Aged; Myocardial Infarction; Myocardium; Osteoprotegerin

Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor superfamily and is known to be among the mediators of the calcification process that has been shown to increase in patients with aortic stenosis (AS). The aim of this study was to characterize the association of OPG with left ventricular (LV) function and remodeling and to evaluate the significance of preoperative OPG on long-term outcome in terms of survival and symptomatic improvement in 124 patients with severe AS scheduled for aortic valve replacement (AVR). Patients were divided according to tertiles of preoperative OPG. Preoperative OPG was associated with age, EuroSCORE, and preoperative functional capacity. Despite similar ejection fraction and diastolic function among groups, longitudinal LV systolic function consistently decreased and markers of filling pressure increased across groups. During median follow-up of 4 years, 41 patients died of a presumed cardiovascular cause or remained in New York Heart Association functional class III or IV. The risk of a poor postoperative outcome after AVR increased with increasing OPG tertiles (15% vs 33% vs 51%, p = 0.002). In a multivariate model containing age, ejection fraction, N-terminal pro-brain natriuretic peptide and left atrial volume index, OPG was still significantly associated with postoperative outcome. In addition, OPG levels associated with cardiovascular mortality during follow-up. In conclusion, OPG is associated with LV and left atrial remodeling in patients with symptomatic severe AS undergoing AVR. Moreover, plasma OPG is associated with long-term postoperative outcome and may identify patients with poor symptomatic improvement after surgery.

Topics: Aged; Aortic Valve Stenosis; Female; Follow-Up Studies; Heart Valve Prosthesis; Humans; Male; Osteoprotegerin; Postoperative Period; Prospective Studies; Severity of Illness Index; Time Factors; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling

Following the SEAS and SALTIRE studies in moderate-to-severe aortic stenosis (AS), it was postulated that the statin treatment had been initiated far too late during the disease course. Thus, the study aim was to assess the effect of four-week atorvastatin treatment (20 mg/day) on levels of calcification biomarkers in patients with early-stage disease (i.e., aortic sclerosis or mild AS).. In total, 33 patients (18 males, 15 females; mean age 70 +/- 8 years) with aortic sclerosis or mild AS, who had never received statin treatment, were enrolled into the study. According to their baseline lipid levels, 17 patients were hypercholesterolemic and 16 normocholesterolemic. Hence, rather than apply randomization, all patients were administered atorvastatin at a moderate dose level. Plasma levels of three biomarkers of calcification were measured, namely osteoprotegerin (OPG), osteopontin (OPN), and soluble receptor activator of nuclear factor (NF)-kappaB ligand (sRANKL).. Plasma levels of all three biomarkers were decreased after atorvastatin treatment. OPG levels fell from 13.23 +/- 5.33 to 10.92 +/- 5.34 pmol/l (p < 0.05), sRANKL from 105.36 +/- 69.47 to 86.74 +/- 71.36 ng/ml (p < 0.05), and OPN from 31.60 +/- 20.29 to 28.45 +/- 15.98 ng/ml (p = NS). When comparing patients with no/mild valvular calcification to those with moderate valvular calcification, only the OPG level before atorvastatin was statistically higher in patients from the latter group: 11.44 +/- 4.51 versus 16.09 +/- 5.67 pmol/l (p < 0.05).. Atorvastatin, at a dose level of 20 mg per day, reduced the plasma levels of calcification biomarkers in patients with aortic sclerosis and mild AS. The pre-atorvastatin OPG level was significantly higher when the aortic valve was moderately calcified, despite a persistent low transvalvular gradient.

Topics: Aged; Aortic Valve Stenosis; Atorvastatin; Biomarkers; Calcinosis; Down-Regulation; Drug Administration Schedule; Echocardiography, Doppler; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Osteopontin; Osteoprotegerin; Poland; Pyrroles; RANK Ligand; Sclerosis; Severity of Illness Index; Time Factors; Treatment Outcome

Aortic valve sclerosis is a highly prevalent, poorly characterized asymptomatic manifestation of calcific aortic valve disease and may represent a therapeutic target for disease mitigation. Human aortic valve cusps and blood were obtained from 333 patients undergoing cardiac surgery (

Topics: Aged; Aortic Valve; Aortic Valve Stenosis; Base Sequence; Biomarkers; Calcinosis; Case-Control Studies; Cell-Free Nucleic Acids; Extracellular Matrix; Female; Humans; Male; Middle Aged; Osteopontin; Osteoprotegerin; RNA-Seq; RNA, Messenger; Transcriptome

The mechanism of valve calcification that is the main cause of aortic stenosis formation and progression is not yet clear. In recent years, the role of the OPG/RANKL/RANK system is considered as one of possible variants of pathogenesis of valve calcification. In presented work the differences in OPG and sRANKL levels involved in the calcification processes in tissues of patients with severe aortic stenosis have been examined. The study was performed using three groups of patients: group 1 - patients with aortic stenosis, group 2 - patients with aortic aneurysm, and group 3 - patients with aortic stenosis and aortic dilatation. In patients with aortic stenosis, the level of RANKL was significantly higher, and the level of RANKL was higher in valve than in tissue. The negative correlation between aortic dilatation and RANKL level indicated the lack of RANKL influence on pathogenesis of aortic dilatation. The obtained data confirm the increased expression of RANKL in patients with aortic valve calcification. The results of this study confirm importance of the OPG/RANKL/RANK system in calcification in patients with aortic stenosis. Athough patients of all groups had comparable values of OPG (including patients with aortic dilatation), the RANKL level increased only in patients with aortic stenosis. This suggest involvement of some additional mechanisms influencing the increase of RANKL expression.. Mekhanizm kal'tsifikatsii klapana, iavliaiushchiĭsia osnovnoĭ prichinoĭ formirovaniia i posleduiushchego progressirovaniia aortal'nogo stenoza (AS), poka ne iasen. V poslednie gody odnim iz vozmozhnykh variantov patogeneza kal'tsifikatsii aortal'nogo klapana rassmatrivaiut rol' sistemy OPG/RANKL/RANK. V predstavlennoĭ rabote provedeno izuchenie razlichiĭ v urovniakh OPG i sRANKL, uchastvuiushchikh v protsessakh kal'tsifikatsii v tkaniakh patsientov s tiazhelym AS. Dannoe issledovanie provedeno kak u patsientov s AS, tak i u patsientov s dilatatsieĭ aorty i sochetaniem étikh dvukh zabolevaniĭ. Povyshennaia ékspressiia RANKL byla vyiavlena u patsientov s AS; pri étom ona byla vyshe v klapane, chem v tkani aorty. U patsientov s dilatatsieĭ aorty byla vyiavlena otritsatel'naia korreliatsionnaia sviaz' mezhdu dilatatsieĭ aorty i RANKL. Rezul'taty nastoiashchego issledovaniia podtverzhdaiut znachenie sistemy OPG/RANKL/RANK v kal'tsifikatsii u patsientov s AS. Odnako na fone sopostavimykh znacheniĭ OPG v sravnivaemykh podgruppakh, v tom chisle u patsientov s dilatatsieĭ aorty, povyshenie RANKL otmechalos' tol'ko u patsientov s AS, chto ukazyvaet na sushchestvovanie dopolnitel'nykh mekhanizmov, vliiaiushchikh na uvelichenie ékspressii RANKL.

Topics: Aortic Valve; Aortic Valve Stenosis; Calcinosis; Humans; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Comparative in vitro study examined the osteogenic potential of interstitial cells of aortic valve obtained from the patients with aortic stenosis and from control recipients of orthotopic heart transplantation with intact aortic valve. The osteogenic inductors augmented mineralization of aortic valve interstitial cells (AVIC) in patients with aortic stenosis in comparison with the control level. Native AVIC culture of aortic stenosis patients demonstrated overexpression of osteopontin gene (OPN) and underexpression of osteoprotegerin gene (OPG) in comparison with control levels. In both groups, AVIC differentiation was associated with overexpression of RUNX2 and SPRY1 genes. In AVIC of aortic stenosis patients, expression of BMP2 gene was significantly greater than the control level. The study revealed an enhanced sensitivity of AVIC to osteogenic inductors in aortic stenosis patients, which indicates probable implication of OPN, OPG, and BMP2 genes in pathogenesis of aortic valve calcification.

Topics: Aged; Aortic Valve; Aortic Valve Stenosis; Ascorbic Acid; Bone Morphogenetic Protein 2; Calcinosis; Cell Differentiation; Core Binding Factor Alpha 1 Subunit; Dexamethasone; Female; Gene Expression Regulation; Glycerophosphates; Heart Transplantation; Humans; Male; Membrane Proteins; Middle Aged; Osteoblasts; Osteogenesis; Osteopontin; Osteoprotegerin; Phosphoproteins; Primary Cell Culture; Stromal Cells; Tricuspid Valve

Previous studies suggest a relationship of the epicardial adipose tissue (EAT) with progression and calcification of the atherosclerotic plaque; however, it is unknown if this tissue expresses genes that may participate on these processes and if the expression of these genes is regulated by high-density lipoprotein (HDL) subclasses.. To explore this possibility, we determined the mRNA expression by qPCR of a pro-calcifying gene (osteopontin (OPN)), and two anti-calcifying genes (osteoprotegerin (OPG) and osteonectin (ON)), in biopsies of EAT obtained from 15 patients with coronary artery disease (CAD) determined by angiography, and 15 patients with diagnostic of aortic valve stenosis but without CAD as control group. We determined the distribution and composition of HDL subclasses by electrophoresis and their statistical relationship with the gene expression in EAT.. EAT from CAD patients showed a higher expression level of OPN and OPG than control group, whereas ON expression was similar between groups. Large HDL subclasses were cholesterol-poor in CAD patients as estimated by the cholesterol-to-phospholipid ratio. A linear regression model showed an independent association of OPN expression with HDL3a-cholesterol, and OPG expression with the relative proportion of HDL3b protein. Logistic analysis determined that OPN expression was positively associated with the presence of atherosclerotic plaque CONCLUSION: OPN, ON, and OPG genes are transcribed in EAT; to the exception of ON, the level of expression was different in CAD patients and control group, and correlated with some HDL subclasses, suggesting a new role of these lipoproteins.

Topics: Adipose Tissue; Aged; Aortic Valve Stenosis; Case-Control Studies; Cholesterol, HDL; Coronary Artery Disease; Female; Gene Expression Regulation; Humans; Lipoproteins, HDL3; Male; Middle Aged; Osteonectin; Osteopontin; Osteoprotegerin; Pericardium; Plaque, Atherosclerotic; RNA, Messenger; Severity of Illness Index

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

Calcific aortic valve disease is associated with inflammation and calcification, thus the osteoprotegerin (OPG), receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) system involved in osteoclastogenesis and inflammation may play a significant role in valve degeneration.. The aim of this study was to assess whether circulating OPG, sRANKL, and other bone metabolism markers can predict the presence of osteoclasts in stenotic valves and to evaluate their impact on the mode of degeneration.. The study involved 60 patients with aortic stenosis who underwent valve replacement surgery and subsequently were divided into 2 groups: osteoclastic (n = 12) and nonosteoclastic (n = 48), according to the presence or absence of intravalvular osteoclasts. Before the surgery, we measured serum levels of OPG, sRANKL, osteocalcin, osteopontin, tumor necrosis factor α (TNF-α), interleukin (IL) 1β, and IL-6. Immunohistochemistry and morphometry were used to determine the extent of valve calcification, lipid accumulation, neovascularization, and the number and phenotype of macrophages.. Compared with the nonosteoclastic group, patients with intravalvular osteoclasts had lower levels of OPG (P = 0.0006) and TNF-α (P = 0.02) and less frequently had diabetes (P = 0.04). Their valves showed higher incidence of ossification (P = 0.002), higher total (P = 0.008) and M2 macrophage counts (P = 0.0002), increased neovascularization (P = 0.003), and lower accumulation of lipids (P = 0.04). They also showed a negative correlation between valve calcification and age (r = -0.79, P = 0.002), which was not observed in patients without osteoclasts. In a multivariate analysis, low circulating OPG levels and the absence of diabetes were predictors of intravalvular osteoclastic differentiation.. The presence of osteoclasts in stenotic valves associated with low circulating OPG levels and an enhanced proportion of M2 macrophages can represent a variant of calcific aortic valve disease with a specifically regulated calcification process.

Topics: Aged; Aortic Valve; Aortic Valve Stenosis; Calcinosis; Cytokines; Female; Humans; Male; Middle Aged; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

The aim of the present study was to evaluate value of osteoprotegerin (OPG) in patients with degenerative aortic stenosis and preserved left-ventricular ejection fraction.. We have prospectively followed 70 patients with aortic stenosis (mean aortic gradient ≥15 mmHg) and preserved left-ventricular ejection fraction for 1 year. In all patients, echocardiography and blood tests (OPG, lipids, high-sensitivity C-reactive protein) were performed at baseline and after 1 year of follow-up. Detailed medical history including atherosclerotic risk factors was obtained. The control group consisted of 20 healthy individuals with normal echocardiographic findings. Rapid progression of aortic stenosis was defined as more than 7 mmHg increase in mean aortic gradient per year.. Osteoprotegerin concentrations were significantly higher in patients with aortic stenosis (P < 0.0001) and correlated with the degree of aortic stenosis. In multivariable regression model analysis, age (β = 0.015, P < 0.0001), mean aortic gradient (β = 0.04, P = 0.0078) and presence of coronary artery disease (β = 0.111, P = 0.0408) were the only independent determinants of plasma OPG concentrations. There was no association between OPG concentrations and coronary artery disease risk factors: male sex, smoking, hypertension and hypercholesterolemia. Concentrations of high-sensitivity C-reactive protein correlated positively with OPG levels only in nonsurgical patients (with lower degree of stenosis) (r = 0.34, P = 0.01). Aortic stenosis progression was related to body mass, diabetes, triglyceride concentrations, metabolic syndrome and left-ventricular systolic volume. In multivariate analysis, only metabolic syndrome was an independent predictor of aortic stenosis progression.. Osteoprotegerin concentrations are linked to the presence and severity of aortic stenosis. Metabolic syndrome was the only independent predictor of degenerative aortic stenosis progression.

Topics: Aged; Aortic Valve Stenosis; Biomarkers; C-Reactive Protein; Disease Progression; Female; Follow-Up Studies; Heart Valve Prosthesis Implantation; Humans; Male; Metabolic Syndrome; Middle Aged; Osteoprotegerin; Prognosis; Prospective Studies; Severity of Illness Index; Stroke Volume; Ventricular Function, Left

To clarify the potential mechanisms by which oxidized low-density lipoprotein (oxLDL) could contribute to the progression of aortic valve stenosis (AVS).. We investigated a total of 46 stenotic and 20 control human aortic valves. The mRNA expression levels of scavenger receptor class A type 1 (SR-A1), CD36, Lectin-like oxidized LDL receptor-1 (LOX-1), and scavenger receptor class B type 1 (SR-B1) were studied using qPCR. Their cellular distribution in the valves was assessed by immunohistochemistry, and the potential effects of oxLDL were studied in cultured myofibroblasts isolated from the aortic valves.. In AVS, the proinflammatory SR-A1 and the angiogenic LOX-1 were upregulated (p = 0.003 and p = 0.002), whereas the antiangiogenic CD36 was downregulated (p = 0.02). The expression of the atheroprotective SR-B1 remained unchanged. Immunohistochemistry revealed that SR-A1 was expressed by macrophages, whereas the expression of CD36 and LOX-1 was confined to myofibroblasts and endothelial cells in the diseased valves. In cultured valvular myofibroblasts, mast cell-derived components and TNF-α induced LOX-1 expression (p = 0.05 and p < 0.001), whereas oxLDL promoted the expression of proinflammatory cytokines. Furthermore, the expression of osteoprotegerin, an inhibitor of valvular calcification, decreased in response to oxLDL. Finally, myofibroblasts derived from stenotic valves accumulated more DiI-labeled oxLDL than myofibroblasts derived from macroscopically healthy valves (p = 0.035), so revealing enhanced foam cell-forming potential of myofibroblasts in the diseased valves.. This study unveils the presence of SR-A1, CD36, and LOX-1 in aortic valves and suggests potential mechanisms by which they may contribute to the pathological angiogenesis, inflammation, calcification, and lipid accumulation in AVS.

Topics: Aortic Valve Stenosis; CD36 Antigens; Cells, Cultured; Disease Progression; Down-Regulation; Endothelial Cells; Humans; Lipoproteins, LDL; Myofibroblasts; Osteoprotegerin; Scavenger Receptors, Class A; Scavenger Receptors, Class E; Up-Regulation

Calcific aortic valve stenosis (CAVS) is an actively regulated process that involves mechanisms of bone development, including the receptor activator of nuclear factor κB, its ligand, and osteoprotegerin (RANK/RANKL/OPG) regulatory system. The aim of this study was to investigate whether the levels of circulating OPG and RANKL can be correlated with some histopathological features of the stenotic valves. Serum levels of osteoprotegerin (OPG) and soluble RANKL (sRANKL) were assessed in 27 patients with CAVS prior to valve replacement surgery and in 12 control subjects. The removed valves were examined macroscopically and microscopically. Valve sections were stained with hematoxylin and eosin for general morphology, with Oil Red O for lipids and immunostained with antibodies against markers visualizing osteoclastic cells (tartrate-resistant acid phosphatase, TRAP), macrophages (CD68) and blood vessels (CD34). Patients with CAVS had elevated levels of OPG as compared to the control group (p=0.005). Within the CAVS group, patients with osteoclastic TRAP-positive cells in their valves had significantly lower serum levels of OPG (p=0.009) and lipid content (p=0.03) than those without such cells. Moreover, osteogenic metaplasia was observed exclusively in the valves containing TRAP-positive cells. Results of this study suggest that the circulating OPG can influence the processes occurring in the calcifying valves by inhibiting osteoclastic differentiation of cells involved in calcification and by preventing osteogenic metaplasia.

Topics: Aged; Aortic Valve Stenosis; Cell Differentiation; Female; Humans; Male; Osteoclasts; Osteoprotegerin; RANK Ligand

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

There are no rigorously confirmed effective medical therapies for calcific aortic stenosis. Hypercholesterolemic Ldlr (-/-) Apob (100/100) mice develop calcific aortic stenosis and valvular cardiomyopathy in old age. Osteoprotegerin (OPG) modulates calcification in bone and blood vessels, but its effect on valve calcification and valve function is not known.. To determine the impact of pharmacologic treatment with OPG upon aortic valve calcification and valve function in aortic stenosis-prone hypercholesterolemic Ldlr (-/-) Apob (100/100) mice.. Young Ldlr (-/-) Apob (100/100) mice (age 2 months) were fed a Western diet and received exogenous OPG or vehicle (N = 12 each) 3 times per week, until age 8 months. After echocardiographic evaluation of valve function, the aortic valve was evaluated histologically. Older Ldlr (-/-) Apob (100/100) mice were fed a Western diet beginning at age 2 months. OPG or vehicle (N = 12 each) was administered from 6 to 12 months of age, followed by echocardiographic evaluation of valve function, followed by histologic evaluation.. In Young Ldlr (-/-) Apob (100/100) mice, OPG significantly attenuated osteogenic transformation in the aortic valve, but did not affect lipid accumulation. In Older Ldlr (-/-) Apob (100/100) mice, OPG attenuated accumulation of the osteoblast-specific matrix protein osteocalcin by ∼80%, and attenuated aortic valve calcification by ∼ 70%. OPG also attenuated impairment of aortic valve function.. OPG attenuates pro-calcific processes in the aortic valve, and protects against impairment of aortic valve function in hypercholesterolemic aortic stenosis-prone Ldlr (-/-) Apob (100/100) mice.

Topics: Age Factors; Animals; Aortic Valve; Aortic Valve Stenosis; Apolipoprotein B-100; Calcinosis; Disease Models, Animal; Female; Hypercholesterolemia; Injections; Male; Mice; Mice, Transgenic; Osteogenesis; Osteoprotegerin; Receptors, LDL; Ultrasonography

There is an ongoing debate regarding aortic valve degenerative processes. Some markers of calcification and atherosclerosis may be potentially useful in establishing their etiology.. The aim of the study was to assess the biochemical markers of calcification and atherosclerosis in patients with degenerative aortic stenosis (AS) in relation to the aortic valve calcium score (AVCS) and concomitant coronary artery disease (CAD).. The study involved 88 patients: 68 patients with degenerative AS (group A), including 44 patients with severe AS (A1; 25 patients with CAD) and 24 patients with moderate AS (A2; 13 patients with CAD) and 20 matched subjects as controls (18 patients with CAD). In all patients, clinical data were assessed, laboratory tests were done (including the analysis of serum interleukin4 [IL-4], osteoprotegerin [OPG], and fetuin-A levels), coronary angiography was performed, and the AVCS was measured.. Study groups and subgroups had comparable serum IL-4, OPG, and fetuin-A levels. There were significant differences in the AVCS between patients with severe AS, moderate AS, and controls (3605 ± 2542 Agatston units [AU], 1390 ± 1143 AU, 100 ± 194 AU, respectively; P <0.001). There were no significant correlations between the AVCS and serum IL-4, OPG, or fetuin-A levels. In moderate AS, serum OPG levels were higher in subjects with concomitant CAD (5.84 ± 1.4 vs. 4.03 ± 1.3 pmol/l, P = 0.036). In severe AS, the mean AVCS was similar in patients with and without CAD. Higher AVCS was observed only in patients with moderate AS and coexisting CAD compared with patients without CAD (1644 ± 1285 vs. 902 ± 789 AU, P = 0.038).. There were no significant differences between patients with and without degenerative AS in selected biochemical markers. The presence of CAD in moderate AS was associated with increased AVCS and serum OPG levels suggesting the effect of atherosclerosis on early valve calcification. In patients with severe AS, there were no correlations between calcification and atherosclerotic markers.

Topics: Aged; alpha-2-HS-Glycoprotein; Aortic Valve Stenosis; Case-Control Studies; Comorbidity; Coronary Artery Disease; Female; Humans; Interleukin-4; Male; Middle Aged; Osteoprotegerin; Plaque, Atherosclerotic; Poland; Severity of Illness Index

Topics: Aged; Aged, 80 and over; Aortic Valve Stenosis; Biomarkers; Cardiac Catheterization; Female; Follow-Up Studies; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Humans; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Osteoprotegerin

To examine the prognostic value of osteoprotegerin (OPG) levels in relation to all-cause mortality in patients with symptomatic severe aortic stenosis (AS).. We measured plasma OPG levels in 136 patients with symptomatic severe AS and investigated associations with transvalvular gradients, valve area, valve calcification (using ultrasonic backscatter analysis as an estimate) and measures of heart failure. Then, we assessed the prognostic value of elevated plasma OPG in determining all-cause mortality (n = 29) in these patients.. Elevated OPG was poorly correlated with the degree of AS but was associated with increased backscatter measurements and impaired cardiac function. Furthermore, OPG was associated with all-cause mortality in patients with symptomatic AS, even after adjustment for conventional risk markers. The strongest association was obtained by using a combination of high levels of both OPG and N-terminal pro-brain natriuretic peptide (NT-proBNP), suggesting that these markers may reflect distinct pathways in the development and progression of AS.. The level of circulating OPG is significantly associated with all-cause mortality alone and in combination with NT-proBNP in patients with severe symptomatic AS.

Topics: Aged; Aged, 80 and over; Aortic Valve Stenosis; Biomarkers; Female; Humans; Logistic Models; Male; Middle Aged; Natriuretic Peptide, Brain; Norway; Osteoprotegerin; Peptide Fragments; Predictive Value of Tests

To determine whether differences exist in valvular high density lipoprotein (HDL) content between non-stenotic and stenotic aortic valves, and whether HDL could retard valvular calcification locally.. Stenotic aortic valves were obtained from valve replacement surgery and non-stenotic control valves from cardiac transplantations or at autopsy. The valvular localization and concentration of apolipoproteinA-I (apoA-I) were analyzed by immunohistochemistry and ELISA. The effects of HDL on the secretion of calcifying mediators and proinflammatory cytokines by cultured aortic valve myofibroblasts were assessed by ELISA and real-time PCR.. The concentration of apoA-I was higher in control than in stenotic valves (p < 0.05). ApoA-I surrounded the calcific deposits in stenotic valves, co-localizing with apoB, apoE, and osteoprotegerin (OPG). Incubation of cultured valve myofibroblasts with HDL increased their secretion of OPG (p < 0.001). Furthermore, incubation of myofibroblasts with HDL led to decreased mRNA expression of tumor necrosis factor alpha (TNF-α) (p < 0.05).. The amount of valvular HDL is reduced in aortic valve stenosis. HDL both induces the secretion of OPG and reduces the expression of TNF-α in vitro. Since OPG is known to inhibit and TNF-α to promote aortic valve calcification, HDL may have an anti-calcifying effect in human aortic valves.

Topics: Aortic Valve; Aortic Valve Stenosis; Apolipoprotein A-I; Apolipoproteins B; Apolipoproteins E; Autopsy; Calcinosis; Case-Control Studies; Cells, Cultured; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Finland; Heart Valve Prosthesis Implantation; Humans; Immunohistochemistry; Inflammation Mediators; Lipoproteins, HDL; Myofibroblasts; Osteoprotegerin; Real-Time Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index; Time Factors; Tumor Necrosis Factor-alpha

Data suggest a link of aortic stenosis (AS) with calcium and bone metabolism. To further investigate this, the following parameters were analyzed in 38 patients with severe AS and in 38 age- and gender-matched controls, without obstructive coronary artery disease and with preserved renal function: calcium, phosphate, 1,25(OH(2))-vitamin D(3), intact parathyroid hormone (iPTH), and osteoprotegerin. Patients with AS had significantly higher serum levels of calcium (2.63 +/- 0.28 vs 2.48 +/- 0.23 mmol/L, p <0.01) and phosphate (1.56 +/- 0.33 vs 1.38 +/- 0.26 mmol/L, p <0.01) and increased calcium-phosphorus products (4.16 +/- 1.13 vs 3.44 +/- 0.89 mmol/L(2), p = 0.003). Notably, the iPTH concentration in the AS group was lower, and significantly more patients in the AS group had levels less than the study median of 60 ng/L. Osteoprotegerin was elevated in patients with AS, confirming reports in other populations (9.94 +/- 5.96 vs 6.73 +/- 4.28 pmol/L, p = 0.009). The relations of several parameters to iPTH were also altered (AS vs controls): calcium and iPTH, 0.071 +/- 0.034 versus 0.046 +/- 0.023, p <0.0001; phosphate and iPTH, 0.042 +/- 0.020 versus 0.025 +/- 0.013, p <0.0001; vitamin D and iPTH, 0.99 +/- 0.61 versus 0.63 +/- 0.46, p = 0.006; and osteoprotegerin and iPTH, 0.24 +/- 0.15 versus 0.12 +/- 0.09, p <0.0001. In conclusion, these data support a hypothesis connecting (severe) AS to altered calcium and bone homeostasis.

Topics: Aged; Aortic Valve Stenosis; Calcium; Cholecalciferol; Creatinine; Female; Humans; Kidney Function Tests; Male; Osteoprotegerin; Parathyroid Hormone; Phosphates

Topics: Animals; Aortic Valve Stenosis; Aortitis; Calcinosis; Humans; Osteoprotegerin; RANK Ligand; Thromboplastin; von Willebrand Diseases

Although degenerative calcific aortic valve stenosis is the most common valvular disease among the elderly, neither the etiology underlying the condition nor degeneration of the bioprostheses is yet fully understood. The study aim was to assess the expression profile of those OPG/RANKL/RANK-system determinants known to act as key regulators of bone metabolism and the immune system in calcific aortic valve stenosis and porcine aortic bioprostheses.. Valve probes from a total of 69 patients (41 with end-stage aortic stenosis, 11 with mild-to-moderate aortic sclerosis, 17 with degenerative porcine aortic bioprostheses) were explanted either during surgery or at autopsy. The presence and localization of OPG, RANKL, RANK and NF-kappaB were analyzed by immunostaining and morphometry.. The majority of stenotic and sclerotic valves exhibited cell-bound signals of OPG, RANKL, RANK and NF-kappaB, while bioprostheses showed only sparse signaling. As key findings, the percentage of cells labeled by OPG, RANK and NF-kappaB was increased in sclerotic valves compared with stenotic valves (each p < 0.001), whereas the frequency of RANKL was higher in stenotic compared to sclerotic valves (p < 0.001). As a consequence, the OPG/RANKL ratio was decreased in stenotic (0.83) compared to sclerotic valves (20.2).. The differential expression profile of specific members of the OPG/RANKL/RANK axis suggests an involvement of their determinants in native valve calcification, but not in the degeneration of porcine bioprostheses. Thus, these mediators of bone homeostasis may represent new targets for a more specified prevention and/or therapy of native aortic stenosis.

Topics: Aged; Aortic Valve Stenosis; Bioprosthesis; Calcinosis; Female; Heart Valve Prosthesis; Humans; Immunohistochemistry; Male; Middle Aged; NF-kappa B; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Retrospective Studies

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

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

Topics: Aortic Valve; Aortic Valve Stenosis; Carrier Proteins; Glycoproteins; Humans; Membrane Glycoproteins; Osteogenesis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sclerosis; Signal Transduction

- Recent studies have suggested that valvular calcification in calcific aortic stenosis (AS) may be actively regulated. "Receptor Activator of Nuclear factor kappaB Ligand" (RANKL) and osteoprotegerin (OPG) are members of a cytokine system involved in bone turnover and vascular calcification. Their role in calcific AS is not known.. - By immunohistochemistry using human aortic valves, RANKL was not expressed at relevant levels in controls but detectable in AS. OPG expression was marked in controls but significantly lower in AS. Areas containing focal calcification exhibited significantly less OPG-positive cells as compared to non-calcified regions. Stimulation with RANKL lead to a significant rise in matrix calcification, nodule formation, alkaline phosphatase activity, expression of the bone-type isoenzyme of alkaline phosphatase, and expression of osteocalcin in cultured human aortic valve myofibroblasts. Moreover, RANKL increased DNA binding of the essential osteoblast transcription factor cbfa-1.. - RANKL and OPG are differentially expressed in calcific AS. In cultured human aortic valve myofibroblasts, RANKL promotes matrix calcification and induces the expression of osteoblast-associated genes, indicating a transition towards an osteogenic phenotype. These results suggest that the RANKL-OPG pathway may regulate valvular calcification in calcific AS?

Topics: Aortic Valve; Aortic Valve Stenosis; Calcinosis; Carrier Proteins; DNA; Fibroblasts; Glycoproteins; Humans; Immunohistochemistry; Membrane Glycoproteins; Neoplasm Proteins; Osteogenesis; Osteoprotegerin; Protein Binding; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sclerosis; Transcription Factors