Specific changes in circulating cytokines and growth factors induced by exercise stress testing in asymptomatic aortic valve stenosis.

BACKGROUND: We evaluated exercise-induced changes in the profile of circulating cytokines and growth factors in patients with AS. METHODS: We studied 32 consecutive asymptomatic moderate-to-severe AS patients and 32 age and sex-matched controls. Plasma levels of interleukin (IL)-6, IL-10, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-ß were measured at 4 time points, i.e. at rest, at peak bicycle exercise, one hour and 24 hours after a symptom-limited exercise. RESULTS: Exercise increased all the 5 markers in both groups (all p<0.0001). The maximum levels of all tested cytokines were higher in the AS group (all p<0.05) compared with controls. In AS patients the highest levels of VEGF, IL-6, and IL-10 were observed one hour after exercise, while in the control group at peak exercise. In both groups maximum TGF- ß levels were observed one hour after exercise. HGF levels were higher at peak and one hour after test in the AS group (p = 0.0001), however the maximum value in AS was observed at peak while in controls after test. In both groups TGF-ß was the only marker that remained increased 24 hours after exercise compared with the value at rest (p = 0.0001). The cytokines and growth factors showed no association with heart rate and the workload. CONCLUSION: In asymptomatic patients with moderate-to-severe AS, exercise produces a different pattern of changes in circulating cytokines and growth factors, and maximum levels of all tested cytokines were significantly higher in AS patients compared with the control group.

Prolonged duration of type 2 diabetes is associated with increased thrombin generation, prothrombotic fibrin clot phenotype and impaired fibrinolysis.

It has been shown that type 2 diabetes (DM) is associated with enhanced thrombin generation and formation of denser fibrin clots of reduced lysability. We sought to investigate the impact of diabetes duration versus glycaemia control on fibrin clot phenotype and its determinants in type 2 diabetic patients. In 156 consecutive Caucasian patients with type 2 diabetes we investigated ex vivo thrombin generation, fibrinolytic proteins, along with plasma fibrin clot permeation (Ks), compaction, turbidity, and efficiency of tissue plasminogen activator (t-PA)-mediated fibrinolysis. Patients with longer diabetes duration (>5 years, median; n=68) had higher peak thrombin generation (+16.3%, p<0.001), plasminogen activator inhibitor-1 (PAI-1) antigen (+14.8%, p=0.001), t-PA antigen (+13.9%, p=0.002) compared with those with duration ≤5 years (n=88). No such differences were observed between patients with inadequate glycaemic control, defined as glycated haemoglobin (HbA1C) >6.5% (48 mmol/mol) (n=77), versus those with HbA1C≤6.5% (n=79). Fibrinogen, thrombin-activatable fibrinolysis inhibitor antigen, plasminogen and soluble thrombomodulin were unaffected by disease duration or glycaemia control. Lower clot permeability, longer clot lysis, and higher maximum D-dimer levels released from clots (all p<0.05 after adjustment for fibrinogen, age, body mass index, insulin, acetylsalicylic acid treatment, and HbA1c or diabetes duration) were also observed in patients with diabetes duration >5 years and those with HbA1C>6.5%. We conclude that prolonged duration of type 2 diabetes is associated with increased thrombin formation, hypofibrinolysis, and prothrombotic fibrin clot phenotype. The impact of disease duration on coagulation is different and stronger than that observed during inadequate glycaemia control.

Altered fibrin clot properties in patients with premature peripheral artery disease.

INTRODUCTION: It has been shown that formation of denser and poorly lysable fibrin clots is observed in elderly patients with peripheral artery disease (PAD). OBJECTIVES: The aim of the study was to test the hypothesis that premature PAD is associated with more prothrombotic fibrin clot phenotype. PATIENTS AND METHODS: Ex­vivo plasma fibrin clot permeability, turbidity, and susceptibility to lysis were evaluated in 31 premature PAD patients (median ankle brachial index [ABI], 0.75; interquartile range, 0.5-0.8) aged 55 or less and 32 PAD patients (ABI, 0.66; 0.56-0.76) aged over 55 years. Subjects without PAD matched for age and sex (n = 40) served as controls. RESULTS: Premature PAD patients were characterized by 32% lower clot permeability (Ks) (P <0.001), 7% longer clot lysis time (t50%) (P = 0.004), and 31% higher maximum D-dimer levels released from fibrin clots (D-Dmax) (P <0.001) compared with controls. These differences remained significant after adjustment for risk factors and medications. None of the fibrin clot parameters differed between premature and older PAD patients. There were correlations between fibrin clot parameters and CRP in premature PAD patients and with ABI in older PAD patients. In a multiple regression model, premature PAD and ABI were independent predictors of Ks, and premature PAD and plasma fibrinogen of the maximum absorbance of a fibrin gel. CONCLUSIONS: Plasma fibrin clots show similarly abnormal prothrombotic phenotype in premature and older PAD patients. However, different factors influence fibrin clot parameters in these patient groups. Premature PAD was an independent predictor of clot permeability and maximum absorbance of a fibrin gel.

Lipoprotein-associated phospholipase A2 is elevated in patients with severe aortic valve stenosis without clinically overt atherosclerosis.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory mediator involved in atherosclerosis. Since aortic valve stenosis (AVS) is regarded as an atherosclerosis-like inflammatory disease, we sought to investigate whether AVS is associated with elevated Lp-PLA2. METHODS: Plasma Lp-PLA2 levels were determined in 48 consecutive patients with severe AVS without atherosclerotic vascular disease and compared with the values obtained in 48 controls matched for age, sex and cardiovascular risk factors. RESULTS: Lp-PLA2 was higher in AVS than in controls (242.3±50.4 vs. 151.9±28.1 ng/mL, p<0.0001). Lp-PLA2 correlated inversely with aortic valve area (AVA) (r=-0.53; p=0.0001) and positively with mean pressure gradient (PG) (r=0.32; p=0.029). In multivariable analysis C-reactive protein (CRP) (OR=1.42; 95% CI 0.95-2.1; p=0.09) and AVA (OR=0.003; 95% CI 0.00004-0.23; p<0.01) were independently associated with Lp-PLA2 above a mean of 242 ng/mL. After adjustment for CRP, AVA was the only independent predictor of Lp-PLA2 in AVS patients (p<0.001). CONCLUSIONS: This study is the first to show that AVS is characterized by increased plasma Lp-PLA2 levels associated with the severity of AVS, which suggests active involvement of Lp-PLA2 in the pathogenesis of AVS.

Osteoprotegerin, but not osteopontin, as a potential predictor of vascular calcification in normotensive subjects.

We conducted a cross-sectional observation study that included 500 asymptomatic subjects to investigate the relationship between bone metabolism and coronary artery calcification (CAC) in hypertensive conditions. Osteoprotegerin (OPG) and osteopontin (OPN) levels and their associations with hypertension were analyzed to predict CAC in 316 subjects. Multislice computed tomography was used to quantify CAC. Multivariate analysis of variance was used to test the non-interactive effects of hypertension, CAC severity and biomarker levels, and the logistic regression model was applied to predict the risk of CAC. OPG and OPN concentrations were significantly higher in the hypertensive than the normotensive subjects, at 3.0 (2.3-4.0) pmol l(-1) and 51 (21-136) ng ml(-1) vs. 2.4 (2.0-3.0) pmol l(-1) and 41 (13-63) ng ml(-1), respectively. The OPG level, but not OPN level, increased with age (r = 0.29; P = 0.0001). Zero or minimal CAC (<10 Agatston units (AU)) was observed in 63% of the subjects, mild (11-100 AU) in 17%, moderate (101-400 AU) in 12% and severe (401-1000 AU)-to-extensive (>1000 AU) in 8%. In hypertensive subjects, only glomerular filtration rate (GFR) (ß = -0.67) and gender (ß = 0.52) were significant predictors for CAC (R = 0.68). In normotensive patients, GFR (ß = -0.81), gender (ß = 0.48) and log-transformed OPG levels (ß = 0.15) were significant predictors for CAC. OPG levels were associated with an increased risk of CAC in normotensive subjects only (odds ratio: 3.37; 95% confidence interval (1.63-6.57); P = 0.0002). OPG predicted a premature state of vascular calcification in asymptomatic normotensive individuals, and renal function significantly contributed to this process in both hypertensive and normotensive subjects.