Elevated Levels Of Plasminogen Activator Inhibitor Research Articles

Implications of Rosiglitazone and Pioglitazone on Cardiovascular Risk in Patients with Type 2 Diabetes Mellitus

Clinical data suggest that thiazolidinediones--specifically, rosiglitazone and pioglitazone--may improve cardiovascular risk factors through multiple mechanisms. Low insulin sensitivity has been described as an independent risk factor for coronary artery disease and cerebrovascular disease. Patients with insulin resistance often have several known risk factors, such as obesity, dyslipidemia, and hypertension. Other emerging risk factors may be prevalent in patients with insulin resistance, such as hyperinsulinemia, elevated C-reactive protein, elevated plasminogen activator inhibitor levels, and small, dense, low-density lipoproteins. The only available drug class that primarily targets insulin resistance is the thiazolidinediones. These drugs have shown efficacy in affecting surrogate markers of cardiovascular risk in patients with diabetes mellitus. Alterations in these risk factors are likely due to their effects on improving insulin sensitivity and/or glycemic control. Trials to assess whether thiazolidinediones actually reduce cardiovascular outcomes are continuing.

Elevated plasminogen activator inhibitor levels in cyclosporin-treated renal allograft recipients

Atherosclerosis and thrombosis, two major causes of morbidity and mortality in renal transplant recipients, share the same clinical risk factors including decreased fibrinolysis and lipid disturbances. In a cross-sectional study we have determined parameters of fibrinolysis in control subjects (n = 23) and stable renal allograft recipients without cyclosporin (CsA) (n = 10) and with CsA (n = 87) in their immunosuppressive treatment. In CsA-treated patients, tissue-type plasminogen activator was moderately increased compared to patients without CsA (8.4+/-3.3 vs 5.5+/-2.8 ng/ml). The plasminogen activator inhibitor (PAI) activity in plasma was clearly increased in CsA-treated patients: 14.5+/-8.8 vs 7.2+/-3.2 in normal controls and 8.5+/-2.4 AU/ml in patients without CsA. Total cholesterol and LDL cholesterol levels were higher in CsA-treated patients (256+/-62 and 169+/-60 mg/dl) than in patients without CsA (209+/-45 and 136+/-44 mg/dl). The two groups did not differ in HDL cholesterol, triglycerides, and lipoprotein(a). Hypercholesterolaemia, obesity, and steroid-induced diabetes could be identified as risk factors for elevated plasma PAI activity in CsA-treated patients. Hypofibrinolysis induced by elevated PAI levels and increased LDL cholesterol may contribute to the increased thrombogenicity and accelerated atherosclerosis observed in cyclosporin-treated patients.

Elevated plasminogen activator inhibitor levels in cyclosporin-treated renal allograft recipients

Elevated plasminogen activator inhibitor levels in cyclosporin-treated renal allograft recipients

Plasminogen activator inhibitor activity in various types of endogenous hypertriglyceridemia

In various groups of patients, plasminogen activator inhibitor (PAI), plasma insulin and triglyceride level are closely associated all together. To clarify this relationship we looked at PAI activity in patients with endogenous hypertriglyceridemia, 15 were obese (body mass index (BMI) higher than 27, mean: 36.2), 9 had a strictly normal weight (BMI lower than 25, mean: 22.8) and 11 had alcohol induced hypertriglyceridemia. They were compared to 20 control subjects of normal weight and with plasma triglyceride level lower than 1.7mmol/l and 11 hypercholesterolemic patients. Overall mean PAI levels in hypertriglyceridemic patients were higher than in controls and hypercholesterolemic subjects. Compared to controls (mean±SD PAI: 9.8±5AU/ml), both PAI activity (30±12U/ml p<0.05) and plasma insulin were elevated in obese hypertriglyceridemic patients but not different from normal in the normal weight hypertriglyceridemic patients (PAI activity 15.2±4.1 U/ml ns). In alcoholic hypertriglyceridemic patients, PAI activity was elevated (21±9.7U/ml p<0.05) but insulin was normal. In the whole series PAI activity was weekly correlated with triglyceride level (r=0.295 p<0.05), but in strong positive relationship with insulin levels (r=0.572 p<0.0001). These results suggest that in obese patients insulin resistance is the common cause of both hypertriglyceridemia and elevation of PAI activity. Other mechanisms have to be looked for in some conditions such as alcohol associated hypertriglyceridemia. Endogenous hypertriglyceridemia occurring in strictly normal weight subjects is not accompanied by elevated PAI levels.

Circulating proinsulinlike molecules

An improved understanding of the characteristics of proinsulin and its intermediate conversion products has resulted from the use of novel assays for distinguishing these molecules from insulin. Use of such assays may help clarify the role of insulin deficiency in non-insulin-dependent diabetes mellitus (NIDDM). Levels of proinsulinlike molecules are elevated in subjects who have NIDDM or impaired glucose tolerance. However, the observation that hyperproinsulinemia may occur in individuals without hyperglycemia suggests that elevated proinsulin levels may be a manifestation of β-cell dysfunction rather than of increased demand on the β cell. Although the metabolic effects of proinsulinlike molecules have yet to be elucidated, some studies indicate that the effect of these molecules on hepatocytes is greater than that on other insulin-sensitive cells. A potential therapeutic role of proinsulin in NIDDM thus has been envisioned, in that suppression of hepatic glucose output might reduce the risk of hypoglycemia caused by increased peripheral glucose uptake. Clinical study of proinsulin has been discontinued, however, owing to the finding of an association between use of human proinsulin and cardiovascular adverse events in one study. In NIDDM subjects, associations have been reported between elevated des 31,32 proinsulin concentrations and such cardiovascular risk factors as elevated blood pressure, increased serum triglyceride and total cholesterol values, and elevated plasminogen-activator inhibitor levels, suggesting a role of proinsulin in cardiovascular risk. Epidemiologic data, however, indicate that elevated levels of proinsulinlike molecules are related to low birth weight and that low birth weight is associated with increased risk of cardiovascular events, suggesting that inadequate intrauterine nutrition may be the common antecedent of augmented proinsulin levels and cardiovascular risk.

Correlation between Baseline Plasminogen Activator Inhibitor Levels and Clinical Outcome during Therapy with Tissue Plasminogen Activator for Acute Myocardial Infarction

Baseline plasminogen activator inhibitor (PAI) levels were examined for their influence on the responses to thrombolysis with recombinant tissue plasminogen activator (rt-PA) administered for acute myocardial infarction during the Thrombolysis and Myocardial Infarction (TAMI)-I study. Baseline PAI activity was 19 +/- 21 IU/ml (normal less than 5 IU/ml) and baseline PAI-1 antigen 54 +/- 53 ng/ml (normal 27 +/- 16 ng/ml), confirming previous findings of elevated PAI levels during acute myocardial infarction. Among clinical outcomes, lower PAI-1 antigen levels correlated weakly with greater patency at the 90 min angiogram. Thus, high baseline plasma PAI-1 levels may be detrimental to reperfusion with t-PA. There was no correlation with other major in-hospital clinical outcomes including reocclusion at the 7-10 day angiogram, survival to discharge, or bleeding. During the follow up period of 2.0 +/- 0.4 years, no relationship between baseline PAI levels and post-discharge reinfarction was observed.

Interleukin-1, endotoxin or tumor necrosis factor/cachectin enhance the level of plasminogen activator inhibitor messenger RNA in bovine aortic endothelial cells

It is known that either endotoxin (LPS) or interleukin-1 (IL-1) increase the activity of plasminogen activator inhibitor (PAI) in the culture media of human and bovine endothelial cells. We have confirmed these results in bovine aortic endothelial cells (BAEC). To determine if this effect was mediated by increases in the level of PAI messenger RNA (mRNA) we examined the effects of these cytokines on PAI mRNA levels in BAEC, using RNA blot analyses. Treatment of BAEC with either IL-1, LPS, or human recombinant tumor necrosis factor/cachectin (TNF) dramatically increased the level of PAI mRNA. Since elevated levels of PAI will decrease fibrinolytic potential, this mechanism is in concert with the known increase in in vivo procoagulant potential induced by these agents and could contribute to thromboembolic phenomena.

Reduction of elevated plasminogen activator inhibitor levels during modest weight loss

Plasma levels of tissue plasminogen activator inhibitor type 1(PAI-1) activity in 10 moderately obese subjects were measured at the start of and after 1 or 2 weeks of a diet experiment. During the experiment, the subjects' mean body weight dropped ( p < 0.05). The changes in body weight correlated with changes in PAI-1 activity ( p < 0.01). A correlation between body weight change and serum triglyceride changes ( p < 0.05) was also found, but not with changes in serum cholesterol or serum free fatty acids. Thus, PAI-1 activity levels appear to be particularly sensitive to variations in body weight. This result may have considerable clinical impact, since an elevated PAI-1 activity level is presently being established as a surrogate-end point for cardiovascular disease.

Circadian Fluctuations of Plasminogen Activator Inhibitor and Tissue Plasminogen Activator Levels in Plasma of Patients with Unstable Coronary Artery Disease and Acute Myocardial Infarction

A decrease in the fibrinolytic potential, mainly due to an elevation of plasminogen activator inhibitor (PAI), has been described in patients with stable coronary artery disease and a previous myocardial infarction. We investigated plasma levels of PAI and tissue plasminogen activator (t-PA) and their possible circadian variations in patients with unstable coronary artery disease (CAD). Sixty-three patients were studied for at least 2 consecutive days during their stay at the coronary care unit (CCU). Diurnal plasma fluctuations in PAI and t-PA and onset of further myocardial ischemic episodes were monitored. As controls we used 22 age-matched patients submitted to the clinic because of non cardiac chest pain or valvular disease who revealed no evidence of CAD. PAI levels were significantly elevated in patients with unstable CAD (p less than 0.0001) but were not influenced by the extent of underlying CAD, history of previous myocardial infarction, known risk factors for CAD, or by extent of myocardial damage. The circadian variation of PAI levels with peak values between midnight and 6 A.M. found in controls was still present in patients but at a higher level. Preservation of circadian pattern in PAI plasma levels despite myocardial ischemic attacks indicates that elevation of PAI is rather not caused by a reactive phenomenon. On the other hand, elevated PAI levels and episodes of severe myocardial ischemia exhibiting a median time of onset at 10 A.M. seem to be closely related.

Plasma fibrinolysis during and after normal childbirth

A detailed sequential study of plasma fibrinolytic components in 42 healthy women during and after childbirth showed that striking changes occurred within minutes of placental separation. Significant increases in overall fibrinolytic activity were detected 15 min after delivery. During this period statistically significant increases in tissue plasminogen activator levels were noted but were overshadowed by a dramatic decrease in the level of plasminogen activator inhibitor (PAI). A 10-fold fall in PAI was noted by days 3-5 post-partum, suggesting that the placenta is the major source of PAI detectable at the end of pregnancy and during labour. Persisting slightly elevated levels of PAI were detected for the first few days post partum. This may be due to increased production of normal 'endothelial' PAI in response to the vascular trauma incurred by placental separation, and in response to uterine vascular changes immediately post-partum.