INCREASED PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-1 IN CORONARY-ARTERY ATHERECTOMY SPECIMENS FROM TYPE-2 DIABETIC COMPARED WITH NONDIABETIC PATIENTS - A POTENTIAL FACTOR PREDISPOSING TO THROMBOSIS AND ITS PERSISTENCE

Background-Inhibition of fibrinolysis attributable to elevated concent rations of plasminogen activator inhibitor type 1 (PAI-1) in blood is associated with insulin resistance, hyperinsulinemia, and type 2 diabe tes mellitus. Because we have shown that insulin can stimulate PAI-1 s ynthesis in vivo and because accelerated vascular disease is common in such patients as well, we hypothesized that increased PAI-1, potentia lly predisposing to thrombosis, acute occlusion, and accelerating athe rosclerosis because of thrombus-associated mitogens, would be present in excess in atheroma from type 2 diabetic subjects. Methods and Resul ts-Samples acquired by directional coronary atherectomy from 25 patien ts with type 2 diabetes and 18 patients without diabetes were characte rized qualitatively histologically for cellularity and by immunohistoc hemistry visually and qualitatively and by quantitative image analysis for assessment of urokinase-type plasminogen activator (u-PA) and PAI -1, Patients with and without diabetes were similar with respect to de mographic features and the distribution and severity of coronary arter y disease, Substantially more PAI-1 and substantially less u-PA were p resent in the atherectomy samples from subjects with diabetes. Conclus ions-The disproportionate elevation of PAI-1 compared with u-PA observ ed in atheromatous material extracted from vessels of diabetic subject s is consistent with increased gene expression of PAI-1 in vessels as well as the known increase of PAI-1 in blood, presumably reflecting in creased synthesis. The increased PAI-1 detected in the atheroma may co ntribute in vivo to accelerated or persistent thrombosis underlying ac ute occlusion and to vasculopathy exacerbated by clot-associated mitog ens in the vessel wall. Because the changes were observed to be associ ated with insulin resistance and type 2 diabetes mellitus, they may be modifiable by reduction of insulin resistance with insulin sensitizer s and stringent control of hyperglycemia.