Enzymatic evidence of impaired reperfusion in diabetic patients after thrombolytic therapy for acute myocardial infarction: a role for plasminogen activator inhibitor?

OBJECTIVE--To compare the activity of plasminogen activator inhibitor (PAI-1) in diabetic and non-diabetic patients admitted with acute myocardial infarction and to determine whether PAI-1 activity influences reperfusion after thrombolytic therapy. DESIGN--Prospective study of patients admitted with acute myocardial infarction. SETTING--District general hospital. MAIN OUTCOME MEASURES--Reperfusion assessed by time to peak release of creatine kinase-MB isoenzyme. RESULTS--Baseline PAI-1 activity and antigen concentrations were significantly higher in diabetic patients (n = 45) than in non-diabetic patients (n = 110) (24.6 (6.9) v 18.6 (7.9) AU/ml (AU = arbitrary units) (p = 0.0001) and 58.8 (13.1-328.8) v 41.0 (10.9-125.4) ng/ml (p = 0.004). Time to peak release of creatine kinase-MB was calculated in 123 (80%) patients. In 98 who received thrombolytic therapy the median time to peak enzyme release was 15.5 h (7.5-24 h) in diabetic patients (n = 26) and 12 h (5-26 h) in non-diabetic patients (n = 72) (p = 0.005). In those with a time to peak release of < or = 12 h, indicating likely successful reperfusion, PAI-1 activity was 17.5 (7.8) AU/ml compared with 22.8 (7.7) AU/ml in those with a time to peak release of > 12 h (p = 0.001). In multiple regression analysis both diabetes (p = 0.0001) and PAI-1 activity at admission (p = 0.029) were independently related to successful reperfusion. In 13 patients with evidence of reinfarction in hospital PAI-1 activity on day 3 was 26.7 (6.4) AU/ml compared with 21.7 (6.3) AU/ml in those without evidence of reinfarction (p = 0.032). CONCLUSION--Both raised PAI-1 activity on admission and diabetes were associated with a reduced likelihood of enzymatic evidence of reperfusion after thrombolytic therapy. Increased PAI-1 activity on day 3 was associated with an increased risk of reinfarction. Diabetic patients had higher PAI-1 activity on admission. This may partly explain their reduced likelihood of reperfusion.     

Effects of captopril therapy on endogenous fibrinolysis in men with recent,uncomplicated myocardial infarction

Objectives. This study investigated the effects of captopril therapy on endogenous fibrinolysis in men with recent, uncomplicated myocardial infarction.Background. Angiotensin-converting enzyme inhibitors reduce the incidence of acute coronary syndromes in patients with mild left ventricular dysfunction after myocardial infarction. Abnormal endogenous fibrinolysis, reflected in increased levels of endogenous tissue-type plasminogen activator (t-PA) antigen and plasminogen activator inhibitor type 1 activity, is associated with an increased risk of myocardial infarction in patients with ischemic heart disease.Methods. In a randomized, double-blind crossover study beginning 8 weeks after uncomplicated myocardial infarction, patients received 4 weeks of placebo and 4 weeks of captopril (75 mg daily) therapy. At the end of each treatment period, we measured t-PA antigen and plasminogen activator inhibitor type 1 antigen and activity.Results. Median values in the 15 patients after placebo and in 12 normal men matched for age and body mass index were, respectively, t-PA antigen 16.0 versus 9.5 ng/ml (p = 0.001), plasminogen activator inhibitor type 1 antigen 17.3 versus 8.6 ng/ml (p = 0.29) and plasminogen activator inhibitor type 1 activity 13.2 versus 6.3 AU/ml (p = 0.04). After 4 weeks of treatment with captopril in the 15 patients, the estimated (95% confidence interval) median reduction in t-PA antigen was 7.3 ng/ml (−4.6 to −10.3 ng/ml, p = 0.001), in plasminogen activator inhibitor type 1 antigen 3.1 ng/ml (+1.5 to −8.4 ng/ml, p = 0.17) and in plasminogen activator inhibitor type 1 activity −2.2 AU/ml (−1.0 to −4.3 AU/ml, p = 0.02).Conclusions. Treatment with captopril after uncomplicated myocardial infarction is associated with a significant decrease in elevated levels of t-PA antigen and plasminogen activator inhibitor type 1 activity. This may help to explain the reduction in risk of coronary thrombosis associated with the use of angiotensin-converting enzyme inhibitors.     

Management and short-term outcome of diabetic patients hospitalized for acute myocardial infarction: results of a nationwide French survey

OBJECTIVES: To compare management and short-term outcome of diabetic and non-diabetic patients hospitalized for acute myocardial infarction. METHODS: This was a prospective epidemiological survey. All patients admitted in coronary care units in France in November 2000 for confirmed acute myocardial infarction were eligible to enter the study. RESULTS: Of the 2320 patients recruited from 369 centers, 487 were diabetic (21%). Compared to non-diabetic patients, diabetic patients were 5 years older, more often female, obese and hypertensive; they had more often a history of cardiovascular disease; they had a lower ejection fraction and worse Killip class. Reperfusion therapy was less frequent among diabetic patients (39% versus 51%; p=0.0001), as was the use of beta-blockers (61% versus 72%; p=0.0001), aspirin (83% versus 89%; p=0.0001) and statins (52% versus 60%; p=0.001) during hospitalization. Conversely, the use of ACE-inhibitors was more frequent (54% versus 44%; p=0.0001). 58% of diabetic patients received insulin during hospitalization. Twenty-eight-day mortality was 13.1% in diabetic patients and 7.0% in non-diabetic patients (risk ratio: 1.87; p=0.001). Diabetes remained associated with increased mortality after adjustment for relevant risk factors including age and ejection fraction (risk ratio: 1.51; p=0.07). In patients treated with antidiabetic drugs (chiefly sulfonylureas) before admission, 28-day mortality was 10.4% compared with 19.9% in diabetic patients on diet alone or untreated (p=0.005). CONCLUSION: Despite higher cardiovascular risk and worse prognosis, in-hospital management of diabetic patients with acute myocardial infarction remains sub-optimal. Patients previously treated with antidiabetic drugs including sulfonylureas had a better prognosis than untreated diabetic patients.     

Early coronary reperfusion blunts the procoagulant response of plasminogen activator inhibitor-1 and von Willebrand factor in acute myocardial infarction

The effects of early coronary recanalization on the plasma levels of two procoagulant acute phase proteins, the fastacting plasminogen activator inhibitor and von Willebrand factor, were investigated in 24 patients with myocardial infarction receiving intravenous recombinant tissue-type plasminogen activator (rt-PA) within 6 h of the onset of symptoms. Coronary angiography was performed before and 90 min after the start of rt-PA infusion. Continuous electrocardiographic recordings and 4 h plasma creatine kinase MB isoenzyme (CK MB) were performed over the first 24 h. Plasma plasminogen activator inhibitor activity, von Willebrand factor and C-reactive protein were measured before rt-PA infusion, daily for the first 3 days and after 90 days. In the entire group, plasminogen activator inhibitor activity peaked at 24 h (day 1), representing a significant increase over values at all other times (p = 0.03). von Willebrand factor was higher in the first 2 days of infarction compared with after 90 days (p = 0.001). C-reactive protein peaked on day 2, with an eightfold increase over values on admission (p = 0.001). In the 16 patients with a patent infarct-related artery at 90 min, infarct size estimated by integrated 24 h CK MB, time for ST segment elevation to decrease to half-maximum and peak C-reactive protein were reduced significantly by more than twofold compared with values in the 8 patients with an occluded artery at 90 min. The patients with early recanalization also had lower plasminogen activator inhibitor activity on day 2 (p = 0.05) and day 3 (p = 0.02) and lower 0 to 72 h averaged von Willebrand factor (p = 0.01). Thus, early coronary recanalization curtails the response of plasminogen activator inhibitor activity and von Willebrand factor to myocardial infarction, most likely by reducing the extent of ischemia and necrosis and the consequent acute phase reaction. By blunting the early postinfarction procoagulant state, prompt recanalization may reduce the risk of thromboembolic complications in the first days after myocardial infarction.     

Importance of thrombosis and thrombolysis in silent ischaemia: comparison of patients with acute myocardial infarction and unstable angina.

OBJECTIVE--To investigate whether plaque rupture and thrombosis have a role in silent ischaemia as well as in unstable angina. DESIGN--Prospective analysis of the results of haemostatic diagnostic tests at the moment of developing silent ischaemia at rest. SETTING--Coronary care unit. PATIENTS--22 patients with acute myocardial infarction, 12 patients with symptomatic angina (unstable angina), and 10 normal volunteers (control group). INTERVENTIONS--Continuous cardiac monitoring detected 15 asymptomatic episodes (silent ischaemia) in 6 patients with unstable angina. Blood samples were obtained at admission and when an asymptomatic alteration was detected and 10 minutes later. MAIN OUTCOME MEASURES--Comparisons of concentrations of tissue plasminogen activator, urokinase type plasminogen activator, tissue plasminogen activator inhibitor-1, cross-linked fibrin degradation products, von Willebrand factor, and thrombin-antithrombin III complexes in patients and controls at admission; same comparisons in patients with silent ischaemia at the start of an episode and 10 minutes later. RESULTS--Tissue plasminogen activator concentrations were raised at admission in patients with acute myocardial infarction (mean (SD) 14.2 (6) ng/ml) and in patients with unstable angina (10.1 (2.5) ng/ml) in comparison with controls (5.1 (2.7) ng/ml, p < 0.01 and < 0.05 respectively). There was no differences between the two groups of patients, however. Similar results were observed at the start of a silent ischaemic episode (9.8 (1.9) ng/ml) and 10 minutes later (10.5 (2.9) ng/ml) compared with controls (p < 0.05). Tissue plasminogen activator inhibitor-1 concentrations were raised in patients with acute myocardial infarction (45.1 (15) ng/ml) compared with volunteers (20.6 (16) ng/ml, p < 0.01). In patients with silent ischaemia tissue plasminogen activator inhibitor-1 concentrations were slightly but not significantly increased. Concentrations of cross-linked fibrin degradation products (D dimer) increased during unstable angina (2150 (350) ng/ml) and silent ischaemia (2270 (450) ng/ml) compared with the concentrations in volunteers (340 (80) ng/ml) and patients with acute myocardial infarction (310 (120) ng/ml; p < 0.01). CONCLUSIONS--The results suggest that thrombosis mediates the pathophysiological mechanisms of silent ischaemia and unstable angina.     

Hospital outcome of acute myocardial infarction in patients with and without diabetes mellitus.

AIMS: To assess hospital mortality and morbidity in diabetic and non-diabetic patients with acute myocardial infarction and to compare the results between the two groups. METHODS: All patients admitted in 1999 to the intensive care unit of the Schwabing City Hospital with diagnosis of acute myocardial infarction were assessed for hospital mortality and co-morbidity. RESULTS: Three hundred and thirty patients with acute myocardial infarction were admitted. Of those, 126 (38%) were diabetic and 204 (62%) were non-diabetic patients. Mortality within 24 h after admission was 13.5% in diabetic patients and 5.4% in non-diabetic patients (P<0.01). Mortality during entire hospitalization was higher in diabetic than in non-diabetic patients (29.4% vs. 16.2%; P=0.004). Diabetic patients were resuscitated more frequently than non-diabetic patients (24% vs. 11%, P<0.01). In diabetic patients, heart rate at admission was increased (91 +/- 27 vs. 82 +/- 23/min; P<0.01) and presence of angina pectoris was reported less frequently (59% (n=72) vs. 82% (n=167); P<0.001). Preceding myocardial infarction, microalbuminuria, peripheral artery disease and arterial hypertension were more frequent in diabetic than in non-diabetic patients. Diabetic patients demonstrated higher C-reactive protein (CRP) levels than non-diabetic patients (91.4 +/- 78.2 mg/l vs. 45.2 +/- 62.4 mg/l; P<0.001). CONCLUSIONS: In diabetic patients with acute myocardial infarction, early hospital mortality is increased and signs of cardiac autonomic dysfunction and microangiopathy are detected more frequently than in non-diabetic patients. The need for advanced treatment strategies early in the course of diabetic patients with myocardial infarction is emphasized.     

A depression of active tissue plasminogen activator in plasma characterizes patients with unstable angina pectoris who develop myocardial infarction

The balance between the coagulation system generating fibrin and its subsequent removal by the fibrinolytic system determines the fate of fibrin deposited in the vascular system. In a prospective study, selected haemostatic variables assessing this balance were determined in plasma samples from 20 consecutive patients admitted with unstable angina pectoris. Over a follow-up period of 6 years, eight patients developed myocardial infarction, whereas 12 patients did not. There was no significant difference between the two groups in the median plasma concentrations of thrombin-antithrombin III complexes reflecting the coagulant activity. The infarction group was characterized by a significantly lower median activity of tissue plasminogen activator in plasma euglobulins (P less than 0.05), a higher median concentration of tissue plasminogen activator antigen in plasma (P less than 0.05) and a tendency to higher plasma levels of antigenic and functional plasminogen activator inhibition. In all patients, the activities of tissue plasminogen activator inhibitor and of tissue plasminogen activator were significantly associated (rs = -0.4811, P less than 0.05). We conclude that a depressed fibrinolytic capacity attributable to a low tissue plasminogen activator activity is of pathogenetic importance for the development of myocardial infarction in patients with unstable angina pectoris.     

Endothelial Tissue-Type Plasminogen Activator Release in Coronary Heart Disease: Transient Reduction in Endothelial Fibrinolytic Reserve in Patients With Unstable Angina Pectoris or Acute Myocardial Infarction

Objectives. We sought to examine whether the disturbed fibrinolytic system in patients with an acute coronary syndrome is associated with a reduced endothelial fibrinolytic capacity.Background. Intracoronary thrombus formation is a frequent finding in acute coronary syndromes. Systemic alterations of coagulation and fibrinolysis are known to occur, but possible disturbances of endothelial fibrinolytic function have not been investigated.Methods. We compared 42 patients with an acute coronary syndrome (acute myocardial infarction in 11 and unstable angina pectoris in 31) with 25 patients with stable angina. Venous blood was sampled serially for determination of markers of the fibrinolytic system and of hypercoagulability from admission to day 10. An occlusion test to determine the maximal endothelial tissue-type plasminogen activator (t-PA) release was also performed.Results. Both on day 0 and day 10, patients with an acute coronary syndrome had a marked elevation of t-PA mass concentration (mean value ± SEM 14.4 ± 1.6 [day 0], 18.9 ± 2.5 ng/ml [day 10]) and of plasminogen activator inhibitor (PAI) (9.4 ± 2.2 [day 0], 11.3 ± 2.6 AU/liter [day 10], p < 0.05 vs. patients with stable angina). There was also a hypercoagulative state with elevated thrombin activity and increased D-dimers (p < 0.05 vs. patients with stable angina). Maximal endothelial t-PA release was initially reduced (p < 0.05 vs. patients with stable angina) to 2.3 ± 0.9 ng/ml, but levels recovered during follow-up to 4.4 ± 1.4 ng/ml (vs. 5.7 ± 1.5 ng/ml in patients with stable angina).Conclusions. Despite the known prolonged systemic alteration of fibrinolysis in acute coronary syndromes, endothelial fibrinolytic capacity is reduced only during the acute phase and becomes normalized during follow-up, and thus is linked more to intravascular thrombus formation than to steady state levels of markers of the fibrinolytic system.     

Risk factors for thromboembolic events in renal failure

OBJECTIVES: To determine whether prior thromboembolic events (TE) influence current measures of hemostasis, inflammation and oxidative stress in a population at high cardiovascular risk. BACKGROUND: Renal failure patients demonstrate a remarkably elevated incidence of TE. METHODS: Relationships between plasma test results and prior TE history were studied in 78 diabetic and 23 non-diabetic patients with renal failure. TE were defined as myocardial infarction, stroke or vascular surgery. RESULTS: Markers for inflammation (interleukin (IL)-6, C reactive protein (CRP)), thrombosis (fibrinogen, low molecular weight (LMW) fibrinogen, factor VII, viscosity), fibrinolysis (fibrinolytic activity, plasminogen activator inhibitor (PAI)), endothelial/platelet activity (P-selectin, von Willebrand factor (vWf)) and oxidative stress (antibody to oxidized low-density lipoprotein (LDL), advanced glycated end products) were significantly different from a healthy control population. Dialysis patients with diabetes were twice as likely to have sustained a TE (58 vs. 30%, p = 0.032). Those patients in the total group with levels above the median for IL-6 (p = 0.045), and CRP (p < 0.017) were more likely to have sustained a TE than those with levels below the median. Those diabetic patients with levels above the median for CRP were more likely to have a prior history of TE (p < 0.021). For non-diabetic patients, levels above the median of IL-6 were associated with a prior history of TE (p = 0.027). Multiple correlations for factors of inflammation, hemostasis and oxidative stress indicate that these mechanisms are not independent of one another. CONCLUSION: Prior TE was associated with markers of inflammation a relationship that may influence the interpretation of these tests which are strongly interrelated in patients at high cardiovascular risk.     

Myocardial infarct size and mortality in patients with non-insulin-dependent diabetes mellitus

Abstract. Objectives. To study the infarct size and mortality in patients with non-insulin-dependent diabetes mellitus (NIDDM) and in non-diabetic subjects with their first acute myocardial infarction. Design. Seven year follow-up study of large representative cohorts of patients with non-insulin-dependent diabetes mellitus and non-diabetic subjects (study 1) and the FINMONICA acute myocardial infarction register study in 1988-89 (study 2). Setting. Populations of the districts of the Kuopio University Hospital and Turku University Central Hospital (study 1). Populations of Kuopio and North Karelia provinces and Turku/Loimaa area (study 2). Subjects. Study 1: 1059 patients with non-insulin dependent diabetes mellitus and 1373 non-diabetic subjects aged 45–64 years at baseline; during the follow-up 166 patients with non-insulin-dependent diabetes mellitus (91 men and 75 women) and 30 non-diabetic subjects (25 men and five women) were hospitalized for their first acute myocardial infarction. Study 2: 1622 patients aged 25–64 years hospitalized for their first acute myocardial infarction; 144 patients (90 men and 54 women) had non-insulin-dependent diabetes mellitus and 1153 (890 men and 263 women) were non-diabetic. Main outcome measures. The infarct size was assessed on the basis of maximum levels of serum cardiac enzymes (studies 1 and 2) and QRS-score (study 1). Results. No differences were found in maximum levels of serum cardiac enzymes between diabetic and non-diabetic patients. Similarly QRS-score gave no suggestion of a difference in infarct size between diabetic and non-diabetic patients. In both studies mortality before hospital admission was similar in diabetic and non-diabetic patients, but mortality within 28 days from hospital admission was twice as high in diabetic patients as in non-diabetic patients. Cardiac failure was the main cause of death significantly more often in diabetic patients than in non-diabetic patients (study 2). Conclusions. Poorer prognosis of acute myocardial infarction in diabetic patients appears not to be explained by a larger infarct size but probably by adverse effects of the diabetic state itself on myocardial function.     

The Prognostic Value of Blood Glucose in Diabetic Patients with Acute Myocardial Infarction

The aim of the study was to investigate prospectively the prognostic value of blood glucose on admission in diabetic and non-diabetic patients with an acute myocardial infarction. Three hundred and thirty-three diabetic and 565 non-diabetic patients were admitted with acute myocardial infarction during the study period of 3.5 years. There was a significant association between mortality and blood glucose on admission in diabetic patients (regression coefficient, r=0.92, 0.5<p<0.02) but not in non-diabetic individuals (r=0.69, 0.2<p<0.5). Age- and sex-standardized mortality was higher in the diabetic group (12.2% vs 7.4%, p<0.03), but was identical if standardized also for blood glucose on admission. We conclude that a high blood glucose on admission is a bad prognostic indicator in a diabetic patient with an acute myocardial infarction. The excess mortality in diabetic patients with acute myocardial infarction can be attributed to the higher proportion with hyperglycaemia.     

Long-term outcome after primary angioplasty: report from the primary angioplasty in myocardial infarction (PAMI-I) trial

OBJECTIVES: This study sought to compare the two-year outcome after primary percutaneous coronary angioplasty or thrombolytic therapy for acute myocardial infarction. BACKGROUND: Primary angioplasty, that is, angioplasty without antecedent thrombolytic therapy, has been shown to be an effective reperfusion modality for patients suffering an acute myocardial infarction. This report reviews the two-year clinical outcome of patients randomized in the Primary Angioplasty in Myocardial Infarction trial. METHODS: At 12 clinical centers, 395 patients who presented within 12 h of the onset of myocardial infarction were randomized to undergo primary angioplasty (195 patients) or to receive tissue-type plasminogen activator (t-PA) (200 patients) followed by conservative care. Patients were followed by physician visits, phone call, letter and review of hospital records for any hospital admission at one month, six months, one year and two years. RESULTS: At two years, patients undergoing primary angioplasty had less recurrent ischemia (36.4% vs. 48% for t-PA, p = 0.026), lower reintervention rates (27.2% vs. 46.5% for t-PA, p < 0.0001) and reduced hospital readmission rates (58.5% vs. 69.0% for t-PA, p = 0.035). The combined end point of death or reinfarction was 14.9% for angioplasty versus 23% for t-PA, p = 0.034. Multivariate analysis found angioplasty to be independently predictive of a reduction in death, reinfarction or target vessel revascularization (p = 0.0001). CONCLUSIONS: The initial benefit of primary angioplasty performed by experienced operators is maintained over a two-year follow-up period with improved infarct-free survival and reduced rate of reintervention.     

Influence of an antidiabetic treatment with sulfonylurea drugs on long-term survival after acute myocardial infarction in patients with type 2 diabetes. The LAngendreer Myocardial infarction and Blood glucose in Diabetic patients Assessment (LAMBDA).

INTRODUCTION: Patients with type 2 diabetes show a significantly higher mortality after acute myocardial infarction than non-diabetic patients. The influence of sulfonylureas on the survival after acute myocardial infarction is still under debate. PATIENTS AND METHODS: Survival of 562 patients, consecutively admitted to an intensive care unit with the diagnosis acute myocardial infarction, was prospectively assessed for > 3 years. At the time of hospital admission, patients were grouped as (a) non-diabetic patients; (b) patients with newly diagnosed type 2 diabetes; (c) patients with known type 2 diabetes not treated with sulfonylureas and (d) patients with known type 2 diabetes treated with sulfonylureas. Survival-analysis was performed according to Kaplan-Meier. RESULTS: 324 patients were non-diabetics, in 86 cases type 2 diabetes was newly diagnosed at the time of hospital admission, 77 patients with known diabetes had taken sulfonylureas (glibenclamide in all cases) prior to the acute myocardial infarction, 75 patients were on any other antidiabetic treatment. Long-term-survival was significantly shorter in patients with type 2 diabetes compared to the non-diabetic patients (p < 0.0001). However, no significant differences were observed between the patients with type 2 diabetes treated with sulfonylurea-drugs and those receiving any other antidiabetic treatment (p = 0.53) CONCLUSIONS: An antidiabetic treatment with sulfonylurea-drugs prior to acute myocardial infarction does not have negative effects on the long-term survival. Larger prospective studies will be necessary to finally clarify this question.     

Augmentation of plasminogen activator inhibitor type 1 activity in plasma by thrombosis and by thrombolysis

Both activation of platelets and elevation of plasminogen activator inhibitor type 1 (PAI-1) activity in plasma have been associated with acute myocardial infarction. Growth factors from platelet alpha-granules have been shown to increase PAI-1 synthesis in liver and endothelial cells in culture. The present study was designed to determine whether activation of platelets in vivo increases PAI-1 activity in plasma, thereby potentially attenuating thrombolysis. Carotid arteries in rabbits were stimulated with transluminal anodal current to initiate thrombosis manifested initially by cyclic flow variations known to reflect platelet activation. Flow was monitored with Doppler flow probes. Plasma PAI-1 activity (mean +/- SEM) assayed spectrophotometrically increased from 6.8 +/- 0.8 arbitrary units (AU)/ml to a peak of 19.1 +/- 2.9 AU/ml (n = 15) 4.8 +/- 0.6 h after the onset of cyclic flow variations. The magnitude of peak PAI-1 values correlated closely with the frequency and duration of antecedent cyclic flow variations. Complete thrombotic occlusion did not elevate PAI-1 beyond that seen with severe, repetitive partial occlusions (18.7 +/- 4.6 vs. 19.6 +/- 3.8 AU/ml). However, when recanalization of completely occluded vessels was induced with tissue-type plasminogen activator (t-PA), plasma PAI-1 increased more markedly (from 5.6 +/- 0.7 to 112.8 +/- 22.3 AU/ml, n = 11), exceeding the increase after corresponding intervals in animals in which t-PA failed to induce recanalization (from 5.2 +/- 1.1 to 28.3 +/- 6.1 AU/ml, n = 6). Thus, activation of platelets accompanying thrombosis or thrombolysis, or both, markedly increases PAI-1 activity in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Basal glucometabolic status has an impact on long-term prognosis following an acute myocardial infarction in non-diabetic patients

OBJECTIVES: Patients with diabetes are known to have a worse prognosis after an acute myocardial infarction (AMI) compared with non-diabetic patients. The primary aim of this study was to investigate the effect of glucometabolic status on long-term prognosis in non-diabetic patients with an AMI. The second aim was to evaluate the extent to which blood glucose levels at admission depended on acute stress, assessed as serum cortisol, previous glucometabolic status, measured as haemoglobin A1c (HbA1c), or both. DESIGN: In a prospective study of patients with an AMI, blood glucose, HbA1c and cortisol were measured at admission. Fasting blood glucose was determined before discharge and also afterwards, if necessary, for classification. Patients were followed-up for 5.5 years. SUBJECTS: Of the 305 consecutive patients 24% were diagnosed as diabetic and 76% as non-diabetic. MAIN OUTCOME MEASURES: Death or non-fatal myocardial re-infarction. RESULTS: In non-diabetic patients, a Cox regression model was used. With death or re-infarction as endpoint, the following prognostic factors had an impact on event-free survival: age (P<0.001), HbA1c (P=0.002), cortisol (P<0.001) and thrombolytic treatment (P=0.001). There was a correlation between cortisol and blood glucose at admission (r=0.44, P<0.001). Fasting blood glucose day 5 showed no association with event-free survival. CONCLUSIONS: In non-diabetic patients with AMI, admission HbA1c and cortisol were predictors for 5.5-year survival without recurrent non-fatal myocardial infarction. The glucometabolic status of importance for prognosis was detected by HbA1c but not by fasting blood glucose or admission blood glucose, of which the latter was influenced by cortisol.     

Hyperfibrinolysis increases the risk of gastrointestinal hemorrhage in patients with advanced cirrhosis.

Sixty-one patients with different degrees of liver failure, 23 with Child-Pugh class B and 38 with Child-Pugh class C, were studied and observed for 3 yr. Coagulation index analysis showed significantly lower values of prothrombin activity, more prolonged activated partial thromboplastin time, higher bilirubin and fibrinogen degradation products values in class C patients. Among all patients, 28 had fibrinogen degradation products values greater than 10 micrograms/ml, and in these patients a hyperfibrinolytic state was confirmed by higher values of circulating plasminogen activator antigen (17.3 +/- 8.7 ng/ml vs. 5.41 +/- 1.9 ng/ml; p less than 0.0001) and activity (6.6 +/- 2.1 IU/ml vs. 1.92 +/- 1.12 IU/ml; p less than 0.0001) and significantly lower plasminogen activator inhibitor antigen (6.4 +/- 3.5 ng/ml vs. 15.8 +/- 5.6 ng/ml; p less than 0.0001) and activity (3.6 +/- 2.2 IU/ml vs. 8.5 +/- 3.9 IU/ml; p less than 0.0001). Patients with positive fibrinogen degradation products had higher serum bilirubin (6 +/- 4 mg/dl vs. 2 +/- 2 mg/dl; p less than 0.0001) and lower fibrinogen (156 +/- 52 mg/dl vs. 194 +/- 62 mg/dl; p less than 0.02) than patients without hyperfibrinolysis. During the follow-up period, 41 patients died, 22 from fatal gastrointestinal hemorrhage and 19 from liver failure. Thirty patients experienced fatal (22 patients) and nonfatal (8 patients) gastrointestinal hemorrhage. Patients with positive fibrinogen degradation products or class C had a higher risk of gastrointestinal bleeding than patients with negative fibrinogen degradation products (odds ratio = 8) or class B (odds ratio = 3.5), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial infarction in diabetic vs non-diabetic subjects. Survival and infarct size following therapy with sulfonylureas (glibenclamide)

AIMS: Sulfonylureas may interfere with 'ischaemic preconditioning' and worsen the prognosis in diabetic patients with acute myocardial infarction. METHODS AND RESULTS: Three hundred and fifty-seven non-diabetic patients admitted with acute myocardial infarction to one hospital over 6.5 years (72 deaths, in-hospital mortality 20.2%) were compared to 245 Type 2 diabetic patients categorized as having taken sulfonylureas (glibenclamide 7+/-3 mg x day(-1); n = 76, 25 deaths = 32.9%;P = 0.025), not having taken sulfonylureas (n = 89, 29 deaths = 33.0%;P = 0.012), and newly diagnosed as having diabetes (n = 80, 20 deaths = 25.0%). Survival was significantly different (log-rank test: P = 0.03). Increments in creatine kinase and creatine kinase(MB)activity were higher in non-diabetic patients (P<0.01). CONCLUSIONS: In-hospital mortality in Type 2 diabetic patients is higher than in non-diabetic patients suffering acute myocardial infarction regardless of whether or not they had been treated with sulfonylureas. Glibenclamide does not enlarge myocardial necroses.     

The role of strict metabolic control by insulin infusion on fibrinolytic profile during an acute coronary event in diabetic patients

BACKGROUND: Many clinical and laboratory observations give support to the hypothesis that strict metabolic control by insulin infusion during acute coronary events may improve the ischemic damage and prognosis. HYPOTHESIS: We investigated the impact of intensive insulin treatment on fibrinolytic parameters during an acute ischemic myocardial event (unstable angina or acute myocardial infarction) in patients with type 2 diabetes mellitus. METHODS: The study group consisted of 48 type 2 diabetic patients, of whom 24 were randomized to conventional therapy plus intensive insulin treatment (Group 1) and 24 to conventional therapy only (Group 2). The two groups were comparable according to gender, age, body mass index, waist:hip ratio, duration of diabetes, previous antidiabetic treatment, type of ischemic events, concomitant therapy, and the classic risk factors for coronary disease. Insulin-treated patients were excluded from the study. Plasma levels of fibrinogen, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) were measured on admission and discharge. Fibrinogen (fibr) was measured using the photometric method. PAI-1 and t-PA were measured by enzyme-linked immunosorbent assays. RESULTS: T-PA increased in both groups during hospitalization (t-PA(admission) vs. t-PA(discharge): Group 1: 15.42 +/- 4.4 ng x ml(-1) vs. 21.2 +/- 5.74 ng x ml(-1), p = 0.000037; Group 2: 14.47 +/- 6.31 ng x ml(-1) vs. 19.18 +/- 6.88 ng x ml(-1), p = 0.001). On the other hand, fibr and PAI-1 levels increased remarkably in controls (Group 2, fibr(admission) vs. fibr(discharge): 2.98 +/- 1.04 g x l(-1) vs. 3.59 +/- 1.01 g x l(-1), p = 0.002, and PAI-1admission vs. PAI-1 discharge: 30.6 +/- 17.34 ng x ml(-1) vs. 40.62 +/- 23.48 ng x ml(-1), p = 0.003). This finding was not observed in the intensive insulin treatment group (Group 1, fibr(admission) vs. fibr(discharge): 2.87 +/- 0.73 g x l(-1) vs. 2.67 +/- 0.72 g x l(-1), p = 0.101, and PAI-1 admission vs. PAI-1 discharge: 30.75 +/- 15.81 ng x ml(-1) vs. 27.75 +/- 6.43 ng x ml(-1), p = 0.484). CONCLUSION: Intensive insulin treatment during an acute coronary event improves fibrinolytic profile in patients with diabetes mellitus. This is a possible mechanism for the reduced short- and long-term mortality in diabetic patients treated with intensive insulin treatment protocol.     

Circadian variation of tissue plasminogen activator and its inhibitor, von Willebrand factor antigen, and prostacyclin stimulating factor in men with ischaemic heart disease.

OBJECTIVES--To determine whether plasma concentrations of tissue plasminogen activator antigen, von Willebrand factor antigen, and prostacyclin stimulating factor and plasminogen activator inhibitor activity show circadian variation in men with ischaemic heart disease. DESIGN--Blood samples were obtained every four hours for 24 hours from 10 men with ischaemic heart disease. The men were ambulant from 08:10 until 00:00 when they went to bed and they remained in bed until 08:00 the following morning. PATIENTS--Ten men with positive diagnostic exercise tolerance tests with no significant past history, who were not regularly taking any medical treatment except for glyceryl trinitrate. RESULTS--There was significant circadian variation in plasminogen activator inhibitor activity (p = 0.001) (peak value 04:00 and trough value 20:00), but not in plasma concentrations of tissue plasminogen activator antigen, von Willebrand factor, or prostacyclin stimulating factor. CONCLUSION--Men with ischaemic heart disease showed a significant circadian variation in fibrinolysis. The combination of peak values of plasminogen activator inhibitor activity and failure of plasma concentrations of tissue plasminogen activator antigen to increase in the early morning must predispose to thrombosis at this time. The circadian variation in fibrinolysis may contribute to the increased incidence of myocardial infarction in the morning.     

Interrelationship between coagulant activity and tissue-type plasminogen activator (t-PA) system in acute ischaemic heart disease. Possible role of the endothelium.

Patients with unstable angina pectoris (UAP; n = 20) and acute myocardial infarction (AMI; n = 34) were studied in the acute phase of ischaemic heart disease. We found significantly higher levels of thrombin-antithrombin-III (TAT) complexes, lower levels of systemic tissue plasminogen activator (t-PA) activity, and higher levels of plasminogen activator inhibitor (PAI) activity in the AMI patients compared to the UAP patients. In contrast to these specific changes, general acute phase reactants such as C-reactive protein, fibrinogen and von Willebrand factor did not differ significantly between the two groups. Studies of the relationship between coagulation (TAT-complexes) and fibrinolysis data revealed a significant positive correlation between plasma antigen concentrations of TAT-complexes and t-PA (P less than 0.02), and between TAT-complexes and PAI-I (P less than 0.002). These observations indicate a common pathophysiological mechanism underlying the changes in coagulation and fibrinolysis, suggesting that coagulation activity and t-PA-related fibrinolysis are interrelated processes in vivo, and probably take place at the level of the endothelial cell.