MOLECULAR MARKERS OF ENDOTHELIAL CELL DYSFUNCTION: OBSERVATIONS ON EXTRINSIC FIBRINOLYSIS IN SURVIVORS OF MYOCARDIAL INFARCTION AND IN TYPE-1 DIABETES MELLITUS

Abstract

We have studied the extrinsic fibrinolytic system in survivors, below 70 years, from myocardial infarction (AMI) treated in Umeci during 1983; in 43 type-1 diabetics; and in controls. Elderly controls underwent chest x-ray, ECG, EEG, brain CT scan to verify their health. Tissue plasminogen activator (tPA) activity was measured with a fibrin-stimulated rate assay, before and after a 10 min venous occlusion test (VO), tPA antigen (Ag) with an ELISA, and plasminogen activator inhibitor (PAI) by incubating samples with purified tPA and measuring remaining tPA with a polylysine-stimulated rate assay.In the diabetics, PAI and tPA:Ag were similar to the controls. tPA:Ag correlated with age (r=0.6). Diabetics had much higher specific activity of tPA (61,300 vs 21,900), and had also much higher tPA activity after VO (2.2 vs 1.2 U/ml). The tPA activities after VO correlated well with HbA1c (r=0.39). A significant effect of smoking was disclosed. Smoking diabetics had higher PAI and tPA antigen but also lower specific activity of tPA (60,600 vs 115,700 U/mg). Ex-smokers were very similar to smokers, not to the non-smokers. Retinopathy, nephropathy, or hypertension didn’t appear to affect fibrinolysis independently.In the AMI survivors (sampled 3 months after discharge from hospital), PAI was 6-fold higher than in elderly controls (p less than 0.0001). tPA activity after VO was much higher (3.2 vs 1.2 U/ml), as was tPA:Ag. tPA specific activity was lower. Among AMI patients with PAI over 10 U/ml, PAI correlated with triglycerides (r=0.4) and negatively with age (r=™0.4): these relations were not seen in the patients with PAI less than 10. The effects of smoking seen in diabetics were not observed among the AMI patients, von Willebrand factor was not increased among AMI nor diabetic patients, except for those with retinopathy.The results suggest that the tPA/PAI system is a more sensitive indicator than vWF of endothelial cell dysfunction. It relates to effects of age, atherosclerotic vascular disease, and among diabetics also to degree of metabolic control and to tobacco smoking habits.