Levels of soluble tumor necrosis factor receptor 1 and 2 are associated with survival after ST segment elevation myocardial infarction.

The soluble tumor necrosis factor receptors (sTNFR1 and sTNFR2) are suggested to play dual roles on physiological and pathophysiological actions of TNF-α. The aim of this study was to investigate the dynamic changes of these biomarkers in patients with ST-segment elevation myocardial infarction (STEMI). Blood was collected from 165 STEMI patients at admission, 1-3 days and 3 months after percutaneous coronary intervention (PCI) and from 40 healthy blood donors. sTNFR1 and sTNFR2 were measured with ELISA. The plasma levels of both sTNFR1 and sTNFR2 were significantly higher than in healthy donors at all three time points. We found no significant differences in sTNFR1 or sTNFR2 when comparing patients with patent versus occluded culprit vessels, or between patients having a thrombus aspiration or not. Survival analysis was performed comparing patients with levels of biomarkers above and below the median values at that time point. We found significant differences in survival for sTNFR2 in acute samples (p = 0.0151) and for both sTNFR1 and sTNFR2 in samples 1-3 days after PCI (p = 0.0054 and p = 0.0003, respectively). Survival analyses suggest that sTNFR1 or sTNFR2 could be promising markers to predict mortality in STEMI patients after PCI.

Dynamic Changes in Pentraxin-3 and Neprilysin in ST Segment Elevation Myocardial Infarction.

Pentraxin-3 (PTX3) and neprilysin have been associated with increased morbidity and mortality in chronic inflammatory disease and heart failure, but these biomarkers have been studied less in patients with ST segment elevation myocardial infarction (STEMI). We investigated the dynamic changes in these biomarkers, as well as the well-known C-reactive protein (CRP), in STEMI patients. PTX3, neprilysin and CRP were measured in samples from 165 STEMI patients, collected at the acute stage, 1-3 days after and 3 months after percutaneous coronary intervention (PCI), and from 40 healthy donors. Patient survival was followed for approximately 8 years after the PCI. As compared with samples from healthy donors, plasma levels of CRP and PTX3 were significantly increased in the acute samples and 1-3 days after PCI, but not at 3 months. CRP levels peaked at 1-3 days, while PTX3 was similarly high in both acute and 1-3 days samples. For neprilysin, no significant differences were observed at the group level. We found no significant differences when comparing patients with patent versus occluded culprit vessels or between patients having a thrombus aspiration or not. However, we found a significant reduction in survival for individuals with PTX3 above the median, both for samples collected at the acute stage and 1-3 days after PCI (p = 0.0001 and p = 0.0008, respectively). For CRP, no significant differences were observed using this approach, but patients above the reference range for healthy donors in the acute samples showed significantly lower survival (p = 0.0476). Conclusions: Survival analysis suggests that PTX3 might be a promising marker to predict mortality in this patient population.

Evidence of contact activation in patients suffering from ST-elevation myocardial infarction.

INTRODUCTION: Factor (F) XIIa is an attractive target for anticoagulation in arterial thrombosis. The aim of this study is to investigate the degree of involvement of the contact system in cardiac infarctions. METHODS AND PATIENTS: 165 patients suffering from ST-elevation myocardial infarction (STEMI) and 100 healthy controls were included in the study. Samples were drawn at admission before percutaneous intervention (PCI), 1-3days post-percutaneous intervention (PCI) and, in one-third of the patients, 3months after PCI. In order to investigate the degree of Factor XII (FXII) activation, changes in FXIIa/AT and FXIIa/C1INH complex levels were quantified by ELISA. RESULTS: FXIIa/AT levels at admission (0.89±0.50; p<0.01) were significantly higher than those in normal individuals (0.39±0.28), but the levels after 1-3days (0.33±0.33; p<0.05) were essentially normalized. In contrast, the FXII/C1INH levels at admission (1.40±0.72; p<0.001) and after 1-3days (0.83±0.59; p<0.001) were both significantly higher than those in normal individuals (0.40±0.30). FXIIa/AT and FXIIa/C1INH complexes at admission (p<0.001; p<0.001) and after 1-3days (p<0.02; p<0.001) were significantly different from those at 3months. No significant differences were observed when the data were stratified for patency (open/closed culprit lesions). CONCLUSION: Both FXIIa/AT and FXIIa/C1INH complexes were significantly increased and reflected the activation of FXII in STEMI patients at admission. In particular, FXIIa/AT complex elevations support the hypothesis that clot propagation-mediated FXII activation had occurred, and this activation may be a target for anticoagulation in patients with cardiac infarction. Based on previous studies, the FXIIa/C1INH complex levels were primarily interpreted to reflex endothelial cell activation.

Left bundle branch block and suspected myocardial infarction: does chronicity of the branch block matter?

BACKGROUND: Our aim was to investigate if patients with suspected myocardial infarction (MI) and a new or presumed new left bundle branch block (nLBBB) were treated according to the ESC reperfusion guidelines and to compare them with patients having a previously known LBBB (oLBBB). Furthermore, we investigated the prevalence of ST-segment concordance in this population. METHODS: Retrospective data was collected from the Swedeheart registry for patients admitted to the cardiac care unit at Örebro University Hospital with LBBB and suspected MI during 2009 and 2010. The patients were divided in two age groups; <80 or ≥80 years and analysed for LBBB chronicity (nLBBB or oLBBB), MI, and reperfusion treatment. We also compared our data with the national Swedeheart database for 2009. RESULTS: A total of 99 patients fulfilled the inclusion criteria. A diagnosis of MI was significantly more common in the group ≥80 years compared to the group <80 years (53.8 vs. 25%, p=0.007). The rate of MI was similar in the groups with nLBBB and oLBBB (33 and 37% respectively, p=0.912). Of the 36 patients with a final diagnosis of MI, only eight (22%) had nLBBB. Reperfusion treatment, defined as an acute coronary angiography with or without intervention, was significantly more often performed in patients with nLBBB compared to patients with oLBBB (42 vs. 8%, p<0.001). The rate of MI and reperfusion treatment did not differ between our institution and the Swedish national data. ST-concordance was present in only two cases, one of which did not suffer an MI. CONCLUSIONS: The proportion of patients receiving reperfusion treatment was low, but higher in nLBBB, reflecting a partial adherence to the guidelines. We found no correlation between LBBB chronicity and MI. Furthermore, only a minority of the MIs occurred in patients with nLBBB. ST-concordance was found in only one of 36 MI cases, indicating lack of sensitivity for this test.

Downregulation of platelet activation markers during long-term immobilization.

Immobilization and sedentary lifestyle are risk factors for venous thromboembolism and cardiovascular disease, yet little is known about platelet function during long-term physical inactivity. Our aim was to investigate platelet activation markers and their coupling to standardized immobilization: platelet-derived growth factor (PDGF-BB) and P-selectin. We studied 15 healthy females participating in the Women International Space simulation for Exploration study. Following a 20-day ambulatory control period, the subjects underwent 60 days of bed rest in head-down tilt position (-6°) 24 hours a day, finalized by 20 days of recovery. The subjects were randomized into two groups during bed rest: a control group (n = 8) that remained physically inactive and an exercise group (n = 7) that participated in both supine resistance and aerobic exercise training. Blood samples for the analysis of platelet activation markers were collected at baseline (5 days before bed rest), after 44 days of bed rest and 8 days into the recovery period. Compared to baseline, the levels of P-selectin and PDGF-BB decreased after bed rest (by 55%, p = 0.01 and 73%, p < 0.03, respectively) and remained decreased in the recovery period (by 76%, p < 0.001 and 78%, p < 0.02, respectively, compared to baseline). Platelet count (baseline value for the exercise group 260 000/µl ± 34 000 and baseline value for the control group 210 000/µl ± 30 000) did not change during the bed rest study (two-way repeated measurements ANOVA, p = ns). There were no statistical differences between the physically inactive and the exercise group. During long-term immobilization, a known risk factor for thrombosis, the levels of P-selectin and PDGF-BB decreased. Our findings indicate downregulation of platelet activation during immobilization.

Effect of prolonged standardized bed rest on cystatin C and other markers of cardiovascular risk.

BACKGROUND: Sedentary lifestyle is associated with coronary artery disease but even shorter periods of physical inactivity may increase cardiovascular risk. Cystatin C is independently associated with cardiovascular disease and our objective was to investigate the relation between this novel biomarker and standardized bed rest. Research of immobilization physiology in humans is challenging because good biological models are in short supply. From the Women International Space simulation for Exploration study (WISE) we studied markers of atherosclerosis and kidney function, including cystatin C, in a standardized bed rest study on healthy volunteers. Fifteen healthy female volunteers participated in a 20-day ambulatory control period followed by 60 days of bed rest in head-down tilt position (-6°) 24 h a day, finalized by 20 days of recovery. The subjects were randomized into two groups during bed rest: a control group (n = 8) that remained physically inactive and an exercise group (n = 7) that participated in both supine resistance and aerobic exercise training. RESULTS: Compared to baseline values there was a statistically significant increase in cystatin C in both groups after bed rest (P < 0.001). Glomerular filtration rate (GFR), calculated by both cystatin C and Cockcroft-Gault equation, decreased after bed rest while there were no differences in creatinine or creatine kinase levels. CRP did not change during bed rest in the exercise group, but there was an increase of CRP in the control group during recovery compared to both the baseline and the bed rest periods. The apo-B/apo-Ai ratio increased during bed rest and decreased again in the recovery period. Subjects experienced a small but statistically significant reduction in weight during bed rest and compared to baseline weights remained lower at day 8 of recovery. CONCLUSION: During and following prolonged standardized bed rest the concentrations of several clinically relevant cardiovascular risk markers change.

Platelet function in brown bear (Ursus arctos) compared to man.

BACKGROUND: Information on hemostasis and platelet function in brown bear (Ursus arctos) is of importance for understanding the physiological, protective changes during hibernation. OBJECTIVE: The study objective was to document platelet activity values in brown bears shortly after leaving the den and compare them to platelet function in healthy humans. METHODS: Blood was drawn from immobilized wild brown bears 7-10 days after leaving the den in mid April. Blood samples from healthy human adults before and after clopidogrel and acetylsalicylic acid administration served as control. We analyzed blood samples by standard blood testing and platelet aggregation was quantified after stimulation with various agonists using multiple electrode aggregometry within 3 hours of sampling. RESULTS: Blood samples were collected from 6 bears (3 females) between 1 and 16 years old and from 10 healthy humans. Results of adenosine diphosphate, aspirin, and thrombin receptor activating peptide tests in bears were all half or less of those in humans. Platelet and white blood cell counts did not differ between species but brown bears had more and smaller red blood cells compared with humans. CONCLUSION: Using three different tests, we conclude that platelet function is lower in brown bears compared to humans. Our findings represent the first descriptive study on platelet function in brown bears and may contribute to explain how bears can endure denning without obvious thrombus building. However, the possibility that our findings reflect test-dependent and not true biological variations in platelet reactivity needs further studies.

Effects on blood compatibility in vitro by combining a direct P2Y12 receptor inhibitor and heparin coating of stents.

The effect of the direct platelet P2Y12 receptor inhibitor, AR-C69931MX, on activation of blood induced by stents with and without heparin coating was investigated using a whole blood Chandler loop model in vitro. Stents were deployed in Chandler loops. Fresh human blood with heparin and AR-C69931MX was rotated for 1 h at 37 degrees C and used for measurements of platelets, microparticles, thrombin-antithrombin complex (TAT), fibrinogen binding to platelets, P-selectin expression by platelets, CD11b, Prothrombin Fragment F1+2, FXIa-AT, FXIIa-AT, C3a, sC5b-9 and stent score. In the first experiment there were four study groups with unmodified stents: 1a, no AR-C69931MX; 1b, 250 nmol/L; 1c, 750 nmol/L; 1d, 2250 nmol/L of AR-C69931MX. In the second experiment the concentration of AR-C69931MX was 500 nmol/L: 2a; tubings without stent; 2b; tubings with heparin-coated stent; 2c; tubings with unmodified stents. Heparin-coated stents were used in the third experiment: 3a; no AR-C69931MX; 3b; 500 nmol/L of AR-C69931MX. In the first experiment there were significant differences in all parameters analysed except for C3a, and stent score when the group with no AR-C69931MX was compared to all the groups with AR-C69931MX. In the second experiment there were significant differences in platelet count, TAT, FXIa-AT, FXIIa-AT and stent score when unmodified stents were compared to loops with no stents and partly to loops with heparin-coated stents. In the third experiment there was a significant reduction in generation of TAT, stent score and better preservation of platelet number by combining the platelet inhibitor and heparin-coated stents as compared to heparin-coated stents alone. The conclusion is that the direct P2Y12 receptor inhibitor AR-C69931MX reduced the different aspects of activation of blood induced by both unmodified and heparin-coated stents.

Improved blood compatibility of a stent graft by combining heparin coating and abciximab.

UNLABELLED: The aim of this study was to assess the combined effect of heparin coating of a stent graft and administration of abciximab, on platelet and coagulation activity in vitro. METHODS: Stent grafts with an expanded polytetrafluoroethylene (ePTFE) membrane interfoliated between two stents were deployed in tubings to form Chandler loops. Fresh human blood with a low concentration of heparin and various doses of abciximab was rotated for 1 h, then collected and used for measurements of platelets, thrombin-antithrombin complex (TAT), CD11b, complement and contact activation of coagulation. In the first set of experiments, all stent grafts were heparin coated. There were three study groups: Group 1a (no abciximab, n=5); Group1b (abciximab in a concentration of 3.3 microg/ml, n=5); Group 1c (abciximab in a concentration of 8.3 microg/ml, n=5). In the second set of experiments, the concentration of abciximab was 3.3 microg/ml. There were three study groups: Group 2a (untreated stent grafts, n=4); Group 2b (heparin-coated stent grafts, n=4); Group 2c (heparin-coated PVC tubings with no stent grafts, n=4). RESULTS: In the first set of experiments, there was a significant reduction in platelet count in Group 1c compared to Group 1a and Group 1b. There was a significant reduction in TAT in Group 1b and Group 1c as compared to Group 1a. In the second set of experiments, TAT was reduced in Group 2b and Group 2c compared to Group 2a. Contact activation was lowered in Group 1b and Group 1c as compared to Group 1a for both FXIa-AT (0.088 and 0.088 vs. 0.115) and FXIIa-AT (0.12 and 0.12 vs. 0.19). CONCLUSION: Heparin coating of a stent graft was shown to improve blood compatibility and this was further enhanced by addition of abciximab.

Pharmaceutical thrombosis prevention in cardiovascular disease.

Cardiovascular diseases are a leading cause of morbidity and mortality in modern society. As a result of this, great efforts have been made to establish regimens for prophylaxis and treatment of such disorders. Pharmacological intervention is also a prerequisite for the success of other therapeutic approaches, e.g. coronary angioplasty. Prevention of platelet aggregation is a goal that can be achieved by counteracting various receptors on the platelet surface. The main attentions for such interventions are focused on inhibiting the glycoprotein IIb/IIIa receptor. So far, they are limited to intravenous usage. Adenosine diphosphate receptor inhibitors are available for intravenous and oral usage. Their effect is, at least partly, also exerted via the counteraction of adenosine diphosphate-mediated activation of the glycoprotein IIb/IIIa complex. An oral direct thrombin inhibitor is under clinical evaluation. This review focuses on atherothrombotic disorders, but recent advances within new fields of anticoagulation (i.e., treatment of severe septic shock and a novel approach to prevent thromboembolic disorder during surgery) should not be overlooked.