Decreased fibrin network permeability and impaired fibrinolysis in the acute and convalescent phase of ischemic stroke.

INTRODUCTION: We investigated fibrin network permeability and fibrinolysis in the acute and convalescent phase of ischemic stroke. METHODS: 20 patients with a mean age of 74 years were studied in the acute (day 1) and convalescent phase (day 60) of ischemic stroke. 23 healthy individuals (controls) were also investigated. Fibrin formation in the samples was triggered by addition of tissue factor (1 pmol/L) and washed frozen-thawed platelets obtained from a healthy donor. The permeability constant (K(s)), which reflects fibrin network permeability, was then calculated from liquid flow measurements. A global assay newly developed in our group was also employed to determine the balance between fibrin formation ("Coagulation profile"; Cp) and fibrin degradation ("Fibrinolysis profile"; Fp) in the same samples. We also measured PAI-1 antigen and fibrinogen concentrations in plasma. RESULTS: As compared to controls, the stroke patients had lower Ks (lower fibrin network permeability) both on day 1 and on day 60 (p < 0.01 and p < 0.05, respectively). Fibrinolysis, assessed by Fp, was reduced on both day 1 and day 60 (p < 0.001, compared to controls), and PAI-1 concentrations were increased (p < 0.01 for both, compared to controls). Fibrin formation capacity in plasma (i.e. Cp) was increased in the acute phase (p < 0.05) but not in the convalescence, as compared to controls. CONCLUSION: The combination of a proneness to form a tighter fibrin network and impaired fibrinolysis is a feature of ischemic stroke that is present in both the acute and convalescent phase of the disease.

Angiotensin II infusion in man is proinflammatory but has no short-term effects on thrombin generation in vivo.

BACKGROUND: Angiotensin (Ang) II may be involved in the development of cardiovascular disease. We examined the potential proinflammatory and prothrombotic effects of Ang II in 16 healthy subjects and in 16 subjects with familial combined hyperlipidemia (FCHL), a condition associated with an increased risk of cardiovascular complications. METHODS: We studied the effects of a three hour intravenous infusion of Ang II (10 ng/kg/min) on plasma concentrations of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), circulating leukocyte count, tissue plasminogen activator/plasminogen activator inhibitor-1 (t-PA/PAI-1) complexes, prothrombin fragment 1+2 (F1+2), and thrombin-antithrombin (TAT) complexes. Blood was collected before, during and 1 h after Ang II infusion. RESULTS: IL-6 was higher in subjects with FCHL at rest (P < 0.05) and increased (P < 0.001) similarly in both groups by Ang II infusion. Also leukocyte count was higher in subjects with FCHL at rest (P < 0.001) and increased (P < 0.001) similarly in both groups by Ang II infusion. T-PA/PAI-1 complexes were higher in subjects with FCHL at rest (P < 0.001) and decreased (P < 0.001) similarly in both groups during Ang II infusion. TNF-alpha, F1+2 and TAT complexes were similar in the two groups at rest and did not change during or after the Ang II infusion. CONCLUSIONS: A three hour Ang II infusion increases inflammation and may enhance fibrinolysis but does not affect short term thrombin generation. Subjects with FCHL have signs of increased inflammation and impaired fibrinolysis.

Effects of an expanded cardiac rehabilitation programme in patients treated for an acute myocardial infarction or a coronary artery by-pass graft operation.

OBJECTIVE: To investigate the effects of expanded cardiac rehabilitation with multifactorial interventions on metabolic and inflammatory markers, exercise performance and on established cardiovascular risk factors. DESIGN: Single-centre prospective randomized controlled trial. SETTING: A university hospital. SUBJECTS: Two hundred and twenty-four patients with an acute myocardial infarction or patients undergoing coronary artery by-pass grafting. INTERVENTION: Patients were randomized to expanded cardiac rehabilitation including stress management, increased physical training, staying at a 'patient hotel' and cooking sessions, or to usual cardiac rehabilitation. MAIN MEASURES: Biochemical risk markers and exercise performance; follow-up was one year. RESULTS: There were no significant differences between the two treatment groups in the changes of biochemical risk markers or in exercise performance. Thus, low-density lipoprotein (LDL)-cholesterol levels decreased from 3.00 (0.97) to 2.54 (0.66) mmol/L in the intervention group and from 3.20 (0.85) to 2.54 (0.63) mmol/L in the control group, fibrinogen levels decreased from 5.30 (2.00) to 4.25 (1.01) g/L in the intervention group and from 5.29 (1.89) to 4.33 (0.83) g/L in the control group and C-reactive protein (CRP) levels decreased from 3.04 (2.79) to 2.09 (2.13) mg/L in the intervention group and from 4.01 (3.49) to 2.39 (2.49) mg/L in the control group. Total workload (W) improved from 118 (35) to 136 (34) in the intervention group and from 117 (36) to 133 (39) in the control group. CONCLUSION: There was no further significant benefit in biochemical risk markers or in exercise performance among patients undergoing the expanded rehabilitation as compared to the control group which received usual cardiac rehabilitation.

Meal-induced platelet activation in Type 2 diabetes mellitus: effects of treatment with repaglinide and glibenclamide.

AIMS: To compare the effects of treatment with repaglinide and glibenclamide on platelet function and endothelial markers in patients with Type 2 diabetes mellitus, before and after a standardized meal. METHODS: Fifteen patients with Type 2 diabetes were investigated on three occasions: at baseline without oral hypoglycaemic drug treatment, and after 6 weeks' treatment with repaglinide or glibenclamide, respectively, in an open randomized cross-over study. Agonist-induced platelet P-selectin expression and platelet aggregation, urinary thromboxane, soluble P-selectin, von Willebrand factor (VWF), soluble E-selectin, intercellular adhesion molecule (ICAM-1) and C-reactive protein (CRP) were measured. In addition, pre-meal data were compared with non-diabetic control subjects (n = 15), matched for sex, age and BMI. RESULTS: Adenosine diphosphate (ADP)-induced platelet P-selectin expression increased post-meal in Type 2 diabetic patients both at baseline and after treatment with repaglinide and glibenclamide (P < 0.01 for all; repeated measures anova). Repaglinide treatment reduced fasting ADP-induced P-selectin expression compared with baseline (P = 0.01), but did not influence meal-induced platelet hyper-reactivity (P = 0.32). No significant anti-platelet effects of glibenclamide treatment were found. Plasma concentrations of VWF and ICAM-1 were elevated in patients with Type 2 diabetes compared with control subjects (P < 0.05 for both) and were reduced during treatment with repaglinide (P < 0.01 for both) but did not change during glibenclamide treatment. CONCLUSIONS: The post-meal state is associated with enhanced platelet reactivity in patients with Type 2 diabetes mellitus. Pre-meal treatment with repaglinide or glibenclamide does not inhibit postprandial platelet activation, but repaglinide treatment is associated with attenuated platelet and endothelial activity in the fasting state.

Circulating markers of inflammation are related to carotid artery atherosclerosis.

AIM: The role of inflammation in atherothrombotic disorders is becoming increasingly recognized. The present study prospectively investigates relationships between inflammatory markers and hemostatic variables, and non-invasive measures of carotid artery atherosclerosis. METHODS: Markers of hemostasis (sP-selectin and fibrinogen), cytokines (IL-6, IL-8, TNF-a and MCP-1), inflammatory variables (hsCRP, SAA and calprotectin) and cell adhesion molecules (ICAM-1 and VCAM-1) as well as ultrasonography of the carotid arteries were assessed in 111 consecutive outpatients with manifest or suspected coronary artery disease (CAD). RESULTS: Thirty-eight patients with manifest cardiovascular disease had higher IL-6 (P < 0.01) but not hsCRP levels. Higher levels of IL-6, calprotectin and VCAM-1 (all P < 0.05) were found in 35 patients with carotid plaques. In the whole study population (n = 109) an increased common carotid artery lumen diameter (LD) and cross sectional intima-media area (CIMA) was related to higher IL-6, IL-8 and MCP-1 levels (all P < 0.05), and increased LD also to higher hsCRP, calprotectin (both P < 0.05), sP-selectin and fibrinogen levels (both P < 0.01). Both LD and CIMA were related to VCAM-1 (both P < 0.01), but not to ICAM-1 levels. The intima-media thickness of the carotid artery was only positively related to MCP-1 levels (P < 0.05). Only the relation between IL-6 and LD remained significant after adjustment for age, gender, body mass index, smoking status or present lipid-lowering treatment. CONCLUSIONS: Several biomarkers of inflammation are related to ultrasonographic measures of carotid artery atherosclerosis in patients with moderate to high prevalence of CAD. IL-6 seems to be an independent and useful biomarker of atherosclerosis in this group of patients.

Prothrombotic responses to exercise are little influenced by clopidogrel treatment.

AIMS: Adenosine diphosphate (ADP) is involved in shear-induced platelet activation, which may be important for platelet responses to stress. We therefore tested the hypothesis that ADP receptor antagonism by clopidogrel treatment would attenuate exercise-induced platelet activation. METHODS AND RESULTS: Fifteen healthy volunteers performed exhaustive exercise without and with clopidogrel pretreatment (75 mg/day; 7 days) in a randomised crossover study. Filtragometry readings (reflecting platelet aggregability in vivo) and 11-dehydro-thromboxane B(2) (TxM) in plasma were determined before and after exercise. Platelet and leukocyte activity, platelet-platelet (PPA), and platelet-leukocyte aggregates (PLAs) in vivo and their responsiveness to agonist stimulation in vitro were assessed by flow cytometry. Clopidogrel treatment inhibited ADP-induced platelet P-selectin expression by 72% (54-85%). Exercise increased platelet aggregation (filtragometry and PPAs), elevated plasma TxM, increased single platelet P-selectin expression, elevated circulating PLAs, and enhanced ADP and thrombin-stimulated P-selectin expression. Clopidogrel prolonged filtragometry readings and attenuated agonist stimulated P-selectin expression at rest, but did not influence TxM in plasma or urine or attenuate platelet or leukocyte responses to exercise. Clopidogrel treatment did not influence plasma CD40L (ligand) at rest or after exercise. CONCLUSION: Clopidogrel treatment attenuates platelet activity in vivo at rest, but exercise counteracts the platelet stabilizing effects of clopidogrel. The hypothesis that ADP is involved in stress-induced platelet activation was not supported.

Enhanced P-selectin expression and increased soluble CD40 Ligand in patients with Type 1 diabetes mellitus and microangiopathy: evidence for platelet hyperactivity and chronic inflammation.

AIMS/HYPOTHESIS: Platelet activation, endothelial dysfunction and inflammation may be involved in early stages of diabetic microangiopathy. We therefore investigated patients with Type 1 diabetes mellitus, without ( n=19) and with ( n=20) microangiopathy, matched for glycaemic control and duration of disease, and matched with healthy control subjects ( n=27). METHODS: Platelet activation was measured as platelet P-selectin expression using whole blood flow cytometry and as soluble P-selectin by immunoassay. Von Willebrand factor antigen in plasma, serum soluble E-selectin, CD40 ligand (sCD40L) and C-reactive protein (CRP) served as markers for endothelial function and inflammation. RESULTS: Thrombin-induced platelet P-selectin expression was enhanced, and soluble P-selectin and sCD40L concentrations were increased in patients with microangiopathy compared with the control subjects ( p<0.01 for both) and with patients without microangiopathy ( p<0.05 for P-selectin expression and sP-selectin), whereas all three parameters were similar in patients without microangiopathy and in the control subjects. CRP and soluble E-selectin were increased in patients with microangiopathy, compared with the control subjects ( p<0.01 and p<0.05), whereas von Willebrand factor did not differ between the groups. CONCLUSIONS/INTERPRETATION: Microangiopathy in Type 1 diabetes is associated with platelet hyperactivity, endothelial dysfunction and low-grade inflammation, indicating an increased risk for cardiovascular disease.

Enhanced leukocyte-platelet cross-talk in Type 1 diabetes mellitus: relationship to microangiopathy.

BACKGROUND: Platelets and leukocytes may influence each others' function, i.e. platelet-leukocyte cross-talk. Diabetes mellitus (DM) is associated with platelet and leukocyte dysfunction. OBJECTIVE: To evaluate platelet-leukocyte cross-talk, and if this might contribute to platelet and leukocyte dysfunction and microangiopathy in DM patients. PATIENTS AND METHODS: We evaluated platelet and leukocyte function, and cross-talk between these cells in Type 1 DM patients without (n = 19) and with (n = 20) microangiopathy, and healthy subjects (n = 27), using whole blood flow cytometry. Platelet-leukocyte cross-talk was studied in hirudinized whole blood incubated at 37 degrees C with stirring. RESULTS: Basal single platelet P-selectin and leukocyte CD11b expression were similar in DM patients and healthy subjects, whilst circulating platelet-leukocyte aggregates and plasma elastase levels were elevated in DM patients. The thromboxane A2 analog U46619 (3 x 10(-7) m) induced more marked increases of platelet P-selectin expression and platelet-leukocyte aggregation in DM patients than in healthy subjects. The leukocyte-specific agonist N-formyl-methionyl-leucyl-phenylalanine (fMLP) (10(-7) m) induced more marked CD11b expression in DM patients with microangiopathy, compared with healthy subjects. Platelet-leukocyte cross-talk induced by U46619 (10(-6) m) showed no difference between DM patients and healthy subjects. fMLP (10(-6) m) evoked marked leukocyte activation, which subsequently caused mild platelet P-selectin expression. This leukocyte-platelet cross-talk was more pronounced in DM patients than in healthy subjects. Furthermore, enhanced leukocyte-platelet cross-talk was correlated to platelet hyperreactivity among DM patients with microangiopathy only. CONCLUSIONS: Type 1 DM is associated with platelet and leukocyte hyperactivity, and enhanced leukocyte-platelet cross-talk, which may contribute to platelet hyperactivity and the microvascular complications seen in Type 1 DM.

Increased plasma fibrin gel porosity in patients with Type I diabetes during continuous subcutaneous insulin infusion.

BACKGROUND: Patients with Type 1 diabetes have a tighter plasma fibrin gel structure, to which impaired glycemic control might contribute. Improved glycemic control can be achieved with continuous subcutaneous insulin infusion (CSII). OBJECTIVES: The aim of the present study was to investigate the effect of CSII on plasma fibrin gel properties and circulating markers of inflammatory activity in patients with Type 1 diabetes. PATIENTS AND METHODS: Twenty-eight patients were investigated before and after 4-6 months' treatment with CSII. Fibrin gel structure formed in vitro from plasma samples was investigated by liquid permeation of hydrated fibrin gel networks. P-fibrinogen was analyzed by a syneresis method. Comparisons were made between patients with improved (> 0.5%) and unchanged (< 0.5%) glucosylated hemoglobin (HbA1c) during CSII. RESULTS: Eighteen patients showed improved and 10 patients unchanged HbA1c during CSII. P-fibrinogen, high sensitive C-reactive protein and serum amyloid A-antigen were not significantly changed, while fibrin gel permeability (Ks) and fiber mass-length ratio ( micro ) increased in both groups (P < 0.02). P-insulin and triglycerides decreased (P < 0.05) in both groups, while reductions of total cholesterol and intercellular adhesion molecule-1 were seen only in patients with improved HbA(1c) (P < 0.05). Absolute changes in Ks were inversely correlated to changes in plasma fibrinogen (r = 0.50; P < 0.01) and in LDL-cholesterol (r = 0.46; P < 0.05). CONCLUSIONS: Treatment with CSII in patients with Type 1 diabetes is associated with increased plasma fibrin gel porosity. Slight attenuation of the inflammatory activity was also observed. The changes in fibrin gel porosity seem to be mainly mediated by changes in plasma fibrinogen and blood lipids, and are probably secondary to improved insulin sensitivity.

Insulin enhances platelet activation in vitro.

Diabetes mellitus is associated with an increased risk of atherothrombotic complications. There is accumulating evidence of platelet hyperreactivity in diabetes, which may be of importance in the pathogenesis of diabetic vascular complications. Platelets possess insulin receptors, but their physiological relevance is not clear, and data on insulin effects on platelet function in the literature are less than consistent. We therefore investigated the influence of insulin on platelet activation in vitro. Fasting blood samples were collected in 20 healthy males, using citrate or hirudin as anticoagulants. Platelet activation was measured as platelet P-selectin expression and fibrinogen binding using whole blood flow cytometry in unstimulated and adenosine diphosphate (ADP) stimulated samples, incubated with 0-10000 microU/ml insulin for 20 min. The effect of insulin (30 or 300 microU/ml, incubated for 3 min) on platelet aggregation was studied using Born aggregometry in platelet-rich plasma (PRP). Insulin enhanced platelet fibrinogen binding more than P-selectin expression in unstimulated and ADP stimulated samples (P<.001 by analysis of variance [ANOVA]; n=20). Insulin (30 or 300 microU/ml) also enhanced ADP-induced platelet aggregation in PRP (P<.01 or P<.001; n=14). The platelet activating effect of insulin was verified in hirudinized samples (n=12), indicating that it was not dependent on unphysiologically low extracellular calcium concentrations. Thus, insulin enhances platelet activation in vitro, independently of extracellular calcium concentrations. Beneficial effects of insulin treatment on platelet function in vivo are probably related to improved metabolic control, rather than to direct platelet stabilizing effects.

Feedback on prescribing rate combined with problem-oriented pharmacotherapy education as a model to improve prescribing behaviour among general practitioners.

OBJECTIVE: To develop a working model with which prescribing behaviour among general practitioners might be influenced. DESIGN: Intervention based on feedback on prescribing rates and problem-oriented educational outreach visits, using educational material and local opinion leaders. Randomised study with three parallel intervention groups of general practitioners, which also served as controls for each other. The pharmacotherapeutic fields chosen were hypertension, peptic ulcer/dyspepsia and depression. Prescription data were retrieved from the electronic patient records for periods of 1 year before and after the intervention. SETTING: Six health care centres and three continuing medical education groups in Stockholm. SUBJECTS: Forty general practitioners. MAIN OUTCOME MEASURES: Drug prescribing rates and patterns before and after the intervention. RESULTS: In the hypertension field, desired trends in fractional prescribing (favouring diuretics and beta blocking agents) were recorded, with a significant (P < 0.05) effect on prescriptions for agents acting on the renin-angiotensin system, despite a pre-existing prescribing behaviour already much in line with the goals. In the peptic ulcer/dyspepsia field, desired trends were recorded for both types of therapies addressed. The fractional prescribing rates for proton-pump inhibitors decreased from 61.0% to 52.6% in the intervention arm and increased from 68.1% to 76.0% in the control arm (not significant due to low power). The depression group focused on better general attention to the disease and only minor changes were registered. CONCLUSION: Feedback of individual prescribing rates, combined with problem-oriented educational outreach visits, is a promising model for the improvement of prescribing behaviour. Data from the electronic patient record were feasible for feedback on prescribing rates.

Acute hyperglycemia increases soluble P-selectin in male patients with mild diabetes mellitus.

The aim of this study was to examine if acute hyperglycemia (an oral glucose tolerance test) activates platelet function, endothelial cells or thrombin generation in diabetic patients and healthy controls. Eleven males with mild type II diabetes mellitus and 11 healthy male volunteers, matched for age and body mass index, were investigated before and after the glucose load. Soluble P-selectin, von Willebrand factor antigen and markers of thrombin generation in plasma were determined by immunoassays, and platelet P-selectin expression (unstimulated and agonist-stimulated) by flow cytometry in whole blood. Acute hyperglycemia elevated plasma soluble P-selectin from 32.5 to 50.9 ng/ml in the diabetic group (P = 0.05) but not in the controls (from 27.3 to 28.8 ng/ml; P = 0.6). Also, soluble P-selectin levels were higher in patients with diabetes than in healthy controls during hyperglycemia, but not in the fasting state. Adenosine diphosphate- and thrombin-induced platelet P-selectin expression was slightly, but significantly, decreased by the glucose load, whereas platelet P-selectin expression in unstimulated samples was not affected. Plasma levels of von Willebrand factor and thrombin generation were similar in patients and controls, and were not altered by hyperglycemia. In conclusion, we found that acute hyperglycemia elevates soluble P-selectin in plasma in males with mild type II diabetes mellitus. Our observation of unaltered plasma levels of the endothelial marker von Willebrand factor is in agreement with platelets being the main source of P-selectin released into plasma following hyperglycemia. Thus, platelets in individuals with type II diabetes may be more susceptible to hyperglycemia than platelets in non-diabetic individuals.

Platelet activation during angiotensin II infusion in healthy volunteers.

The present study was undertaken to evaluate the effects of an intravenous infusion of angiotensin II (10 ng/kg per min) on platelet function and coagulation in vivo in 18 healthy males. The infusion increased mean arterial pressure by 23+/-2 mm Hg. Plasma beta-thromboglobulin levels, reflecting platelet secretion, increased by 66+/-24% during the infusion, as did also platelet surface expression of P-selectin as measured by flow cytometry. Platelet fibrinogen binding increased, whereas platelet aggregability, assessed by ex vivo filtragometry, was unaltered. Angiotensin II caused mild activation of the coagulation cascade with increases in plasma levels of thrombin-antithrombin complex and prothrombin fragment F1 + 2. In conclusion, angiotensin II has mild platelet-activating effects in vivo and also enhances coagulation. Markers of platelet secretion are significantly increased, whereas markers of platelet aggregability are less affected. The clinical relevance of these findings remains to be clarified.

Inhaled nitric oxide does not influence bleeding time or platelet function in healthy volunteers.

BACKGROUND: Bleeding time has been reported to increase during gaseous nitric oxide (NO) inhalation in healthy volunteers and patients, and it has been speculated that inhaled NO inhibits platelet function. However, results have not been unanimous, and we have been unable to document any effects of inhaled NO on circulating platelets. MATERIALS AND METHODS: We performed a double-blind, placebo controlled cross-over study in which healthy volunteers (n = 15) inhaled NO (30 ppm, 30 min) or control gas. Aspirin (640 mg x 1 orally) was used as positive control on the third occasion (n = 14). Bleeding time was measured, and platelet function was determined flow cytometrically by measuring the expression of P-selectin on circulating platelets and locally activated platelets in wound blood. Skin perfusion close to the site for bleeding time incisions was assessed by laser Doppler flowmetry. RESULTS: Bleeding time was unaffected by NO, as there were slight increases during both NO and control inhalation (+20% and +14% respectively, P = 0.9). Similarly, NO inhalation had no effect on platelet P-selectin expression in either systemic or wound blood, or on skin perfusion. Aspirin pretreatment, on the other hand, prolonged bleeding time (P < 0.001) and decreased P-selectin expression of platelets in wound blood (P = 0.03). CONCLUSIONS: This first placebo-controlled study indicates that inhaled NO does not influence either bleeding time, platelet activity or skin perfusion. Thus, it is unlikely that treatment of critically ill patients with inhaled NO will aggravate haemostatic disturbances, which has previously been feared, by influencing platelet function.

Evidence for prothrombotic effects of exercise and limited protection by aspirin.

BACKGROUND: Exercise may activate platelets and leukocytes and promote thrombosis. The effects of aspirin treatment on the prothrombotic effects of exercise have not been established. METHODS AND RESULTS: A total of 15 healthy men performed exhaustive exercise without and with 1 week of pretreatment with aspirin (500 mg/day). Before and immediately after exercise, platelet aggregability ex vivo was measured by filtragometry, and venous blood samples were obtained. Whole-blood flow cytometry was used to determine platelet and leukocyte activation and platelet-leukocyte aggregates. Exercise increased platelet P-selectin expression, CD11b expression in neutrophils and lymphocytes, and platelet and leukocyte responses to thrombin, ADP, platelet activating factor, and N-formyl-methionyl-leucyl-phenylalanine (fMLP) in vitro. Consistent with enhanced platelet and leukocyte activation, more circulating platelet-platelet and platelet-leukocyte aggregates were detected after exercise (P<0.001 for both). Filtragometry readings were shortened, and plasma soluble P-selectin and prothrombin fragment 1+2 were elevated. Aspirin markedly reduced the urinary excretion of 11-dehydrothromboxane B(2), decreased P-selectin expression in single platelets at rest (P<0.05), and inhibited fMLP-induced neutrophil CD11b expression, but it did not attenuate exercise-induced increases in platelet aggregability, platelet P-selectin expression, leukocyte CD11b expression, platelet-leukocyte aggregate formation, soluble P-selectin, or prothrombin fragment 1+2. CONCLUSIONS: Exercise induced platelet and leukocyte activation and platelet-leukocyte aggregation in vivo, and it increased platelet and leukocyte responsiveness to in vitro stimulation. Aspirin treatment attenuated certain signs of platelet activity in vivo at rest and fMLP-induced neutrophil activation in vitro, but it did not attenuate the prothrombotic effects of exercise.

Elevated serum intercellular adhesion molecule-1 and vascular adhesion molecule-1 among patients with stable angina pectoris who suffer cardiovascular death or non-fatal myocardial infarction.

AIMS: Inflammatory mechanisms have been implicated in the pathogenesis of atherosclerosis. Cell adhesion molecules, expressed on endothelial cells and leukocytes, mediate transendothelial migration of leukocytes into the vessel wall, but also circulate in soluble forms. In the present study we related soluble cell adhesion molecules to the risk of suffering a cardiovascular death or a non-fatal myocardial infarction (cardiovascular death/myocardial infarction) in a substudy to the Angina Prognosis Study in Stockholm (APSIS). METHODS AND RESULTS: Soluble intercellular adhesion molecule-1, vascular adhesion molecule-1 and E-selectin were measured in serum collected on inclusion in the APSIS study. During follow-up, seven patients suffered non-fatal myocardial infarction or cardiovascular death, whereas 86 patients were event-free. Cardiovascular death/myocardial infarction was associated with elevated intercellular adhesion molecule-1 (354+/-142 vs 282+/-62ng x ml-1;P<0.01) and vascular adhesion molecule-1 (538+/-138 vs 433+/-135ng x ml-1;P =0.05), and E-selectin levels tended to be higher (72+/-54 vs 49+/-20ng x ml-1). Clinical risk factors (history of hypertension, previous myocardial infarction, diabetes and smoking) were more abundant in the event group. Subgroup analyses showed that hypertension, smoking or male sex were associated with elevated intercellular adhesion molecule-1, whereas previous myocardial infarction or male sex were associated with elevated vascular adhesion molecule-1. CONCLUSION: Patients with stable angina pectoris who developed cardiovascular death/myocardial infarction had elevated serum levels of soluble cell adhesion molecules, indicating increased inflammatory activity. The value of soluble cell adhesion molecules as prognostic markers in patients with stable ischaemic heart disease merits further study.

Activation of haemostasis by exercise, mental stress and adrenaline: effects on platelet sensitivity to thrombin and thrombin generation.

Stress-induced activation of haemostasis may be involved in the triggering of acute coronary syndromes. We compared the effects of mental stress, dynamic exercise and adrenaline infusion on platelet sensitivity to thrombin using flow-cytometric analysis of platelet fibrinogen binding in whole blood, and platelet aggregability using filtragometry ex vivo, in healthy volunteers. Furthermore, we assessed thrombin generation [prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complexes in plasma] and thrombin activity (fibrinopeptide A in plasma). Exercise (bicycle ergometry) enhanced thrombin-induced platelet fibrinogen binding (P<0.05) and platelet aggregability (P<0.01), and elevated F1+2, thrombin-antithrombin complexes and fibrinopeptide A (P<0.05 for all three). Adrenaline infusion enhanced thrombin-induced platelet fibrinogen binding and platelet aggregability (P<0.05), and elevated thrombin-antithrombin complexes (P<0.05), whereas F1+2 and fibrinopeptide A levels were not significantly affected. Mental stress increased platelet sensitivity to high concentrations of thrombin only, and produced small increases in levels of thrombin-antithrombin complexes. Time control experiments showed no important changes with repeated measurements during rest. Platelet responses to exercise and adrenaline were reversible, with recovery 60 min later. Thus, heavy exercise and high levels of adrenaline reversibly increased platelet aggregability and platelet sensitivity to thrombin, and enhanced thrombin formation; the effects were most pronounced during exercise. Mental stress only weakly affected these parameters.

Acute effects of angiotensin II on fibrinolysis in healthy volunteers.

Recent studies have suggested that angiotensin II may inhibit fibrinolysis. In order to further test this hypothesis, we investigated the acute effects of angiotensin II (intravenous infusion of 10 ng/kg per min over 15-20 min) on fibrinolytic function in 18 healthy men. Time-controls (n=11) and control experiments with a placebo infusion (n = 13) were also performed. The activities of plasmin activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA), as well as t-PA antigen levels, were determined in plasma before, during and 60 min after the infusion of angiotensin II. Angiotensin II caused a clear-cut elevation in blood pressure; heart rate and plasma noradrenaline levels tended to decrease during the infusion but increased afterwards, indicating reflexogenic adjustments. Plasma t-PA activity and antigen levels increased by 81+/-11 and 14+/-3%, respectively, during angiotensin II infusion (both P < 0.001), whereas t-PA activity was unchanged and t-PA antigen decreased (P < 0.05) in placebo experiments. PAI-1 activity decreased similarly in time-controls and during angiotensin infusion (P < 0.001). Thus, short-term infusion of angiotensin II enhances fibrinolysis by elevating plasma t-PA. It is not clear whether this is a direct angiotensin-receptor-mediated effect or if it is related to the hemodynamic effects of the infusion.