Torbjörn K. Nilsson

High Plasminogen Activator Inhibitor and Tissue Plasminogen Activator Levels in Plasma Precede a First Acute Myocardial Infarction in Both Men and Women Evidence for the Fibrinolytic System as an Independent Primary Risk Factor

BACKGROUND In patients with established ischemic heart disease, prospective cohort studies have indicated that plasminogen activator inhibitor (PAI-1), the inhibitor of the fibrinolytic system, may predict cardiovascular events. So far, there have been no primary prospective studies of PAI-1. METHODS AND RESULTS The aim of the present study was to test whether plasma levels of PAI-1, tissue-type plasminogen activator (tPA), von Willebrand factor (vWF), and thrombomodulin (TM) could predict the occurrence of a first acute myocardial infarction (AMI) in a population with high prevalence of coronary heart disease by use of a prospective nested case-control design. Mass concentrations of PAI-1 and tPA were significantly higher for the 78 subjects who developed a first AMI compared with the 156 references matched for age, sex, and sampling time; for tPA, this increase was independent of smoking habits, body mass index, hypertension, diabetes, cholesterol, and apolipoprotein A-I. The ratio of quartile 4 to 1 for tPA was 5.9 for a patient to develop a first AMI. The association between tPA and AMI was seen in both men and women. Increased levels of vWF were associated with AMI in a univariate analysis. High levels of TM were associated with AMI in women but not in men. CONCLUSIONS The plasma levels of PAI-1, tPA, and vWF are associated with subsequent development of a first AMI; for PAI-1 and tPA, this relation was found in both men and women. For tPA but not for PAI-1 and vWF, this association is independent of established risk factors.

Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease. A 7-year follow-up.

BackgroundThe fibrinolytic system is part of the defense against thrombotic and cardiovascular events, but so far no study has shown that clinical measurements of fibrinolytic key components such as tissue plasminogen activator (t-PA) or plasminogen activator inhibitor type 1 (PAI-1) have any predictive value beyond 3 years. Methods and ResultsIn 1983 through 1985, 213 consecutive patients with angina pectoris and angiographically verified coronary artery disease were sampled, and the mass concentration of t-PA and the activity of PAI-1 were measured in citrated plasma samples. At a mean follow-up time of 7 years, the all-cause mortality was checked. No patient was lost to follow-up. The data were analyzed by Cox regression, and t-PA mass concentration was found to be the only laboratory risk factor significantly related to mortality in all patients (P<.022) and also in the major subgroup (78% of all patients) subjected to coronary bypass surgery (P<.027). In the latter subgroup, body mass index was also related to mortality. ConclusionsAn increased mass concentration of t-PA is a new risk factor of long-term mortality in patients with angina pectoris and coronary artery stenosis. This paradoxical effect probably reflects increased t-PA levels attributable to enzyme inhibitor complex formation in subjects with increased plasma levels of t-PA inhibitors.

Enzymatic properties of the one-and two-chain form of tissue plasminogen activator

Abstract The properties of the one-chain and two-chain forms of the porcine tissue plasminogen activator have been compared with respect to their amidolytic activities against a low molecular weight synthetic substrate, and their inhibition by diisopropylphosphofluoridate, α2-antiplasmin and C1-esterase inhibitor. The two-chain form is the more efficient catalyst, and is more rapidly inhibited by diisopropylphosphofluoridate and α2-antiplasmin. Physiological implications are discussed.

DNA methylome profiling of human tissues identifies global and tissue-specific methylation patterns

BackgroundDNA epigenetic modifications, such as methylation, are important regulators of tissue differentiation, contributing to processes of both development and cancer. Profiling the tissue-specific DNA methylome patterns will provide novel insights into normal and pathogenic mechanisms, as well as help in future epigenetic therapies. In this study, 17 somatic tissues from four autopsied humans were subjected to functional genome analysis using the Illumina Infinium HumanMethylation450 BeadChip, covering 486 428 CpG sites.ResultsOnly 2% of the CpGs analyzed are hypermethylated in all 17 tissue specimens; these permanently methylated CpG sites are located predominantly in gene-body regions. In contrast, 15% of the CpGs are hypomethylated in all specimens and are primarily located in regions proximal to transcription start sites. A vast number of tissue-specific differentially methylated regions are identified and considered likely mediators of tissue-specific gene regulatory mechanisms since the hypomethylated regions are closely related to known functions of the corresponding tissue. Finally, a clear inverse correlation is observed between promoter methylation within CpG islands and gene expression data obtained from publicly available databases.ConclusionsThis genome-wide methylation profiling study identified tissue-specific differentially methylated regions in 17 human somatic tissues. Many of the genes corresponding to these differentially methylated regions contribute to tissue-specific functions. Future studies may use these data as a reference to identify markers of perturbed differentiation and disease-related pathogenic mechanisms.

Interrelationships between plasma levels of plasminogen activator inhibitor, tissue plasminogen activator, lipoprotein (a), and established cardiovascular risk factors in a north Swedish population.

Serum lipids, lipoprotein (a), plasminogen activator inhibitor and tissue plasminogen activator levels were measured in 260 subjects, constituting a cross-section sample of 30-60-year-old men and women. For Lp(a), there were positive correlations with age and cholesterol, but not with any of other measured parameters. Triglyceride, cholesterol, and HDL-cholesterol (inversely) levels were associated with waist-to-hip girth circumference ratio: this variable remained significant in a multiple regression model. PAI-1 activity and tPA antigen levels were positively associated with triglycerides and inversely associated with HDL-cholesterol. Moreover, tPA antigen was positively related to total cholesterol level. In multiple regression analysis, however, only triglycerides were found to contribute significantly to the variance of tPA antigen and PAI-1 activity levels, when BMI (in men) and abdominal skinfold thickness (in women) were entered into the model. Insulin or glucose postload responses to an OGTT were not independently related to any lipid or fibrinolytic variable. These data demonstrate the importance of anthropometric variables both for fibrinolytic variables and traditional lipid risk factors. Only Lp(a) was found to be largely unrelated to the endocrine-metabolic and anthropometric variables.

Diagnostic accuracy of plasma biomarkers for intestinal ischaemia

Objective. Intestinal ischaemia is a life‐threatening condition with high mortality, and the lack of accurate and readily available diagnostic methods often results in delay in diagnosis and treatment. The aim of this study was to investigate the accuracy of different plasma biomarkers in diagnosing intestinal ischaemia. Material and methods. Prospective inclusion of patients older than 50 years with acute abdomen admitted to hospital in Karlskrona, Sweden, between 2001 and 2003. Venous blood was sampled prior to any surgery and within 24 h from onset of pain. D‐lactate, alpha glutathione S‐transferase, intestinal fatty acid binding protein, creatine kinase B, isoenzymes of lactate dehydrogenase (LD) and alkaline liver phosphatase (ALP) were analysed. D‐dimer was analysed using four different commercially available test kits. Results. In‐hospital mortalities among patients with (n = 10) and without (n = 61) intestinal ischaemia were 40 % and 3 %, respectively (p = 0.003). D‐dimer was associated with intestinal ischaemia (p = 0.001) independently of which assay was used. No patient presenting with a normal D‐dimer had intestinal ischaemia. D‐dimer >0.9 mg/L had a specificity, sensitivity and accuracy of 82 %, 60 % and 79 %, respectively. Total LD, isoenzymes of LD 1–4 and liver isoenzyme of ALP (ALP liver) were significantly higher in patients with intestinal ischaemia, and accuracies for LD 2 (cut‐off 2.3 µkat/L) and ALP liver (cut‐off 0.7 µkat/L) were 69 % and 66 %, respectively. Conclusions. D‐dimer may be used as an exclusion test for intestinal ischaemia, but lacks specificity. The other plasma biomarkers studied had insufficient accuracy for this group of patients. Further studies are needed.

The extrinsic fibrinolytic system in survivors of myocardial infarction

The extrinsic fibrinolytic system was assessed among 124 consecutive survivors of acute myocardial infarction below 70 years of age. In samples drawn 3 months after discharge from hospital, the PAI-1 levels were higher and the tPA activities were lower than among elderly healthy controls. In contrast, the AMI survivors had higher tPA antigen levels at rest and after venous occlusion, and higher tPA activities after venous occlusion. Among patients having PAI-1 levels greater than 10 IU/ml, there was a positive correlation between PAI-1 and serum triglycerides, and a negative correlation between PAI-1 and age; this group was also significantly younger than the subgroup having less than or equal to 10 IU/ml of PAI-1. There were thus multiple disturbances of the extrinsic fibrinolytic system among these patients. As cardiovascular risk factors, these disturbances appear to be relatively more important the younger the patients are.

Fibrinolytic variables are related to age, sex, blood pressure, and body build measurements: a cross-sectional study in Norsjö, Sweden.

Levels of the fibrinolytic variables, tissue plasminogen activator (tPA) antigen concentration and plasminogen activator inhibitor (PAI-1) activity, were measured in a cross sectional sample of 260 subjects aged 30, 40, 50, or 60 years. There was a significant increase of tPA with age in both sexes, but PAI-1 increased only in women. Linear regression analysis was used to assess relations between tPA or PAI-1 and the anthropometric data. In men, tPA levels were related to body mass index and waist-to-hip ratio, whereas in women, it was also related to systolic and diastolic blood pressures and with abdominal or triceps skinfold thicknesses. PAI-1 levels were related to body mass index and waist-to-hip ratio in men, and in women it was in addition related to systolic and diastolic blood pressures and to abdominal and triceps skinfold thicknesses. These data offer new insight into pathophysiological mechanisms whereby age, sex, blood pressure, and body composition variables such as body mass index or waist-to-hip ratio, might act as cardiovascular risk factors.

D-dimer testing in patients with suspected acute thromboembolic occlusion of the superior mesenteric artery

There is no accurate non‐invasive method available for the diagnosis of acute thromboembolic occlusion of the superior mesenteric artery (SMA). The aim of this study was to assess the diagnostic properties of the fibrinolytic marker D‐dimer.

Low and high circulating cortisol levels predict mortality and cognitive dysfunction early after stroke

Objective.  Elevated cortisol levels are associated with confusion and poor outcome after stroke. Dehydroepiandrosterone sulphate (DS), the most abundant adrenal androgen may act as an anti‐glucocorticoid. An altered regulation of these steroids may affect numerous brain functions, including neuronal survival. The purpose of this study was to investigate serum cortisol and DS levels and the cortisol/DS ratio early after stroke and relate our findings to the presence of disorientation and mortality.