. Ueland T, Gullestad L, Dahl CP, Aukrust P, Aakhus S, Solberg OG, Vermeer C, Schurgers LJ (Research Institute for Internal Medicine, University of Oslo, Oslo; University of Oslo, Oslo, Norway; and ...VitaK & Cardiovascular Research Institute CARIM (CV, LS), Maastricht University, Maastricht, The Netherlands) Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis. J Intern Med 2010; 268: 483–492.
Objective. Matrix Gla protein (MGP) is a calcification inhibitor and alterations in circulating MGP have been observed in different populations characterized by vascular calcification. We hypothesized that patients with calcific valvular aortic stenosis (AS) would have dysregulated circulating MGP levels.
Design and subjects. We examined plasma levels of nonphosphorylated carboxylated and undercarboxylated MGP (dp‐cMGP and dp‐ucMGP, respectively) in 147 patients with symptomatic severe AS and in matched healthy controls.
Main outcome measures. We further investigated the relationship between MGP levels and aortic pressure gradients and valve area by echocardiography and measures of heart failure. Finally, we assessed the prognostic value of elevated plasma dp‐ucMGP level in relation to all‐cause mortality in patients with AS.
Results. We found markedly enhanced plasma levels of dp‐cMGP and in particular of dp‐ucMGP in patients with symptomatic AS. Although only weak correlations were found with the degree of AS, circulating dp‐ucMGP was associated with cardiac function and long‐term mortality in multivariate analysis.
Conclusions. A dysregulated MGP system may have a role in the development of left ventricular dysfunction in patients with symptomatic AS.
Introduction
Osteoprotegerin (OPG) is a member of the tumor necrosis factor (TNF) receptor family. It has recently been demonstrated that OPG is produced by a variety of tissues, including the ...cardiovascular system (heart, arteries, veins), lung, kidney, immune tissues, and bone. The OPG-RANKL signaling pathway is strongly related to vascular calcification. We determined the association of this biomarker with subclinical atherosclerosis in systemic lupus erythematous (SLE).
Methods
We measured OPG and markers of subclinical atherosclerosis (coronary artery calcium (CAC), carotid intima-media thickness (cIMT) carotid plaque) in 166 SLE patients (91% female, 64% Caucasian, 31% African American, 5% others, mean age 45 years). Subgroups of patients with different levels of OPG level were compared with respect to average levels of CAC, cIMT, and with respect to presence of carotid plaque. Age was adjusted for using multiple regression.
Results
OPG was highly correlated with age (p < 0.0001). Individuals with higher levels of OPG tended to have higher measures of CAC, cIMT, and more carotid plaque. However, after adjustment for age, these associations, while still positive, were no longer statistically significant.
Conclusion
In our study much of the association observed was due to confounding by age, and after adjusting for age, our findings do not rule out the possibility of a null association.
Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect ...of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12‐month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7–11 weeks after HTx or standard cyclosporine immunosuppression. Ninety‐five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm3 and 13.8 ± 28.0 mm3 all p‐values ≤ 0.01). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor‐1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus‐based CNI‐free can potentially be considered in suitable de novo HTx recipients.
This randomized, open‐label, multicenter Scandinavian trial utilizing intravascular ultrasound in de novo heart transplant recipients shows that everolimus combined with reduced‐exposure cyclosporine withdrawn at 7–11 weeks significantly reduces the development of cardiac allograft vasculopathy at 12 months versus standard‐exposure cyclosporine.
Abstract Objective CXCL16 is a chemokine involved in atherosclerosis by promoting inflammation, lipid accumulation and matrix degradation. The level of circulating CXCL16 has been proposed as a ...predictor of long-term mortality in acute coronary syndromes. We studied plasma CXCL16 in acute ischemic stroke and examined associations with long-term mortality following the acute event. Methods CXCL16 samples were obtained from 244 patients with acute ischemic stroke (age: 69 ± 13 years) daily from presentation to day 5 and at half a year after the stroke. Patients with overt ischemic heart disease and atrial fibrillation were excluded. The patients were followed for 47 months, with all-cause and cardiovascular (CV) mortality as end-points. Results At follow-up, 72 patients had died with 43 due to CV causes. Plasma CXCL16 was stably elevated in the first days after the acute event followed by a marked decrease after 6 months. In patients who subsequently suffered an adverse outcome, CXCL16 levels at 4 days after the initial event were elevated and were moderately associated with mortality. The increase in CXCL16 from day 1 to 4 was a predictor for all-cause and, in particular, CV mortality even after adjustment in the multivariate analysis for established risk factors such as age, the presence of heart/renal failure, troponin, C-reactive protein and stroke severity. Conclusions An increase in plasma CXCL16 during the first days after the initial event is associated with an adverse outcome in patients with acute ischemic stroke, supporting the potential pathogenic role of CXCL16 in atherosclerosis and vascular remodelling as well as their major clinical consequences.
Background
Natriuretic peptides are currently used to predict mortality in patients with heart failure (HF). However, novel independent biomarkers are needed to improve risk stratification in these ...patients. We hypothesized that annexin A5 (anxA5) would be highly expressed by organs which are generally affected by HF and that circulating anxA5 levels would predict mortality in HF patients.
Methods
We prospectively determined the diagnostic value of anxA5, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), C‐reactive protein (CRP) and estimated glomerular filtration rate (eGFR) to predict mortality in 180 HF patients during a median follow‐up of 3.6 years. Studies were conducted with anxA5−/− mice to investigate the underlying mechanisms.
Results
AnxA5 levels were significantly elevated in HF patients compared to healthy control subjects. Cox regression analysis demonstrated that anxA5, NT‐proBNP and eGFR all predict mortality independently. AnxA5 significantly improved the diagnostic efficiency of NT‐proBNP alone (improvement of c‐statistic from 0.662 to 0.705, P < 0.001) and also combined with eGFR and CRP (improvement of c‐statistic from 0.675 to 0.738, P < 0.001) to predict mortality in the Cox regression model. Receiver operating characteristic curve analysis showed that anxA5 predicted 3‐year survival (area under curve 0.708) with an optimal cut‐off value of 2.24 ng mL−1. Using anxA5−/− mice, we demonstrated that anxA5 is highly expressed in organs that are often affected by HF including lung, kidney, liver and spleen. Lysis of these organs in vitro resulted in a marked and significant increase in anxA5 concentrations.
Conclusion
AnxA5 improves the diagnostic efficiency of conventional biomarkers to predict mortality in HF patients. Whereas natriuretic peptides originate from the myocardium, high circulating anxA5 levels in patients with HF are likely to reflect peripheral organ damage secondary to HF.
Objective
We evaluated if plasma levels of inflammatory markers are persistently altered in severe mental disorders with psychotic symptoms or associated with state characteristics in a longitudinal ...study.
Methods
Soluble tumor necrosis factor receptor 1 (sTNF‐R1), interleukin‐1 receptor antagonist (IL‐1Ra), von Willebrand factor (VWF), and osteoprotegerin (OPG) were measured in schizophrenia (n = 69) and affective (n = 55) spectrum patients at baseline and at one‐year follow‐up, and compared to healthy controls (HC) (n = 92) with analysis of covariance. Association between change in symptoms and inflammatory markers was analyzed with mixed‐effects models.
Results
sTNF‐R1 was higher in the schizophrenia (P < 0.0001) and affective disorders (P = 0.02) compared to HC, while IL‐1Ra was higher in schizophrenia (P = 0.01) compared to HC at one year follow‐up. There were no significant differences between schizophrenia and affective groups; however, levels in the affective group were in between schizophrenia and HC for sTNF‐R1 and IL‐1Ra. There were no significant associations between change in symptoms and inflammatory markers.
Conclusion
Persistently increased sTNF‐R1 and IL‐1Ra after one year in patients with severe mental disorders primarily reflecting data from the schizophrenia group may suggest that inflammation is a trait phenomenon, and not only the result of stress‐related mechanisms associated with acute episodes.
. Jensen JK, Ueland T, Atar D, Gullestad L, Mickley H, Aukrust P, Januzzi JL (Odense University Hospital, Denmark; Rikshospitalet, Oslo, Norway; Massachusetts General Hospital, USA). Osteoprotegerin ...concentrations and prognosis in acute ischaemic stroke. J Intern Med 2010; 267: 410–417.
Aim. Concentrations of osteoprotegerin (OPG) have been associated with the presence of vascular and cardiovascular diseases, but the knowledge of this marker in the setting of ischaemic stroke is limited.
Methods and results. In 244 patients with acute ischaemic stroke (age: 69 ± 13 years), samples of OPG were obtained serially from presentation to day 5. Patients with overt ischaemic heart disease and atrial fibrillation were excluded. The patients were followed for 47 months, with all‐cause mortality as the sole end‐point. Multivariable predictors of OPG values at presentation included haemoglobin (T = −2.82; P = 0.005), creatinine (T = 4.56; P < 0.001), age (T = 9.66; P < 0.001), active smoking (T = 2.25; P = 0.025) and pulse rate (T = 3.23; P = 0.001). At follow‐up 72 patients (29%) had died. Patients with OPG ≤2945 pg mL−1 at baseline had a significantly improved survival rate on univariate analysis (P < 0.0001); other time‐points did not add further prognostic information. In multivariate analysis, after adjustment for age, stroke severity, C‐reactive protein levels, troponin T levels, heart and renal failure concentrations of OPG independently predicted long‐term mortality after stroke (adjusted hazard ratio, 2.3; 95% CI: 1.1 to 4.9; P = 0.024).
Conclusion. Osteoprotegerin concentrations measured at admission of acute ischaemic stroke are associated with long‐term mortality.
Objectives
Experimental studies have shown involvement of Wnt signalling in heart failure (HF). We hypothesized that secreted frizzled‐related protein 3 (sFRP3), a modulator of Wnt signalling, is ...related to the progression of HF.
Design
Circulating sFRP3 was measured in 153 HF patients and compared with 25 healthy controls. The association of sFRP3 with mortality was evaluated in 1202 patients (GISSI‐HF trial). sFRP3 mRNA expression was assessed in failing human and murine left ventricles (LV), and cellular localization was determined after fractioning of myocardial tissue. In vitro studies were carried out in cardiac fibroblasts subjected to cyclic mechanical stretch.
Results
(i) Heart failure patients had significantly raised serum sFRP3 levels compared with controls, (ii) during a median follow‐up of 47 months, 315 patients died in the GISSI‐HF substudy. In univariable Cox regression, tertiles of baseline sFRP3 concentration were significantly associated with all‐cause and cardiovascular mortality. After adjustment for demographic and clinical variables, but not for CRP and NT‐proBNP, the associations with mortality remained significant for the third tertile (all‐cause, HR 1.45, P = 0.011; cardiovascular, HR 1.66, P = 0.003), (iii) sFRP3 mRNA expression was increased in failing human LV, with a decline following LV assist device therapy. LV from post‐MI mice showed an increased sFRP3 mRNA level, particularly in cardiac fibroblasts, and (iv) mechanical stretch enhanced sFRP3 expression and release in myocardial fibroblasts.
Conclusion
There is an association between increased sFRP3 expression and adverse outcome in HF, suggesting that the failing myocardium itself contributes to an increase in circulating sFRP3.
Background
Acute clinical complications of atherosclerosis such as myocardial infarction (MI) and ischaemic stroke are usually caused by thrombus formation on the ruptured plaque surface. Collagen, ...the main structural protein of the fibrous cap, provides mechanical strength to the atherosclerotic plaque. The integrity of the fibrous cap depends on collagen fibre cross‐linking, a process controlled by the enzyme lysyl oxidase (LOX).
Methods and results
We studied atherosclerotic plaques from human carotid endarterectomies. LOX was strongly expressed in atherosclerotic lesions and detected in the regions with ongoing fibrogenesis. Higher LOX levels were associated with a more stable phenotype of the plaque. In the studied population, LOX mRNA levels in carotid plaques predicted the risk for future MI. Within the lesion, LOX mRNA levels correlated positively with levels of osteoprotegerin (OPG) and negatively with markers of immune activation. The amount of LOX‐mediated collagen cross‐links in plaques correlated positively also with serum levels of OPG.
Conclusions
Lysyl oxidase may contribute to the healing of atherosclerotic lesions and to the prevention of its lethal complications. Mediators of inflammation may control LOX expression in plaques and hence plaque stability.
C‐reactive protein (CRP) increases after strenuous exercise. It has been a concern that prolonged strenuous exercise may be harmful and induce a deleterious inflammatory response. The purpose of this ...study was to (a) assess and quantify the magnitude of CRP response following an endurance cycling competition in healthy middle‐aged recreational cyclists. (b) Identify important determinants of this response. (c) Identify the relationship between CRP, myocardial damage (cardiac Troponin I (cTnI)), and myocardial strain (B‐type natriuretic peptide BNP). (d) Identify the relationship between CRP and clinical events, defined as utilization of healthcare services or self‐reported unusual discomfort. Race time was used as a measure of physical fitness. A total of 97 individuals (43±10 years of age, 74 76% males) were assessed prior to and 0, 3, and 24 hours following the 91‐km mountain bike race “Nordsjørittet” (Sandnes, Norway, June 2013). There was a highly significant increase in CRP from baseline to 24 hours (0.9 (0.5‐1.8) mg/L vs. 11.6 (6.0‐17.5) mg/L (medianIQR), P<.001), with no correlation of CRP to cTnI and BNP at any time‐point. CRP was strongly correlated to race time at baseline (r=.38, P<.001) and at 24 hours following the race (r=.43, P<.001), In multivariate models, race time was an independent predictor of CRP both at baseline and at 24 hours (P<.01). There was no relationship between CRP levels and clinical events. In conclusion, high physical fitness was associated with reduction in both basal‐ and exercise‐induced CRP. No adverse relationship was found between high intensity physical exercise, CRP levels, and outcomes.
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