Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking - Direct link between endothelial dysfunction and atherothrombosis

Background-The aim of the study was to establish the influence of proximal coronary artery atheroma and smoking habit on the stimulated release of tis sue plasminogen activator (tPA) from the heart. Methods and Results-After diagnostic coronary angiography in 25 patients, t he left anterior descending coronary artery (LAD) was instrumented, and the proximal LAD plaque volume was determined by use of intravascular ultrasou nd (IVUS). Blood flow and fibrinolytic responses to selective LAD infusion of saline, substance P (10 to 40 pmol/min; endothelium-dependent), and sodi um nitroprusside (5 to 20 mug/min; endothelium-independent) were measured b y intracoronary IVUS and Doppler, combined with arterial and coronary sinus blood sampling. Mean plaque burden was 5.5 +/-0.8 mm(3)/mm vessel (range 0 .6 to 13.7 mm(3)/mm vessel). LAD blood flow increased with both substance P and sodium nitroprusside (P<0.001), although coronary sinus plasma tPA ant igen and activity concentrations increased only during substance P infusion (P<0.006 for both). There was a strong inverse correlation between the LAD plaque burden and release of active tPA (r= -0.61, P=0.003). Cigarette smo king was associated with impaired coronary release of active tPA (current s mokers, 31 +/- 23 IU/min; ex-smokers, 50 +/- 33 IU/min; nonsmokers 202 +/- 73 IU/min; P<0.05). Conclusions-We found that both the coronary atheromatous plaque burden and smoking habit are associated with a reduced acute local fibrinolytic capaci ty of the heart. These important findings provide evidence of a direct link between endogenous fibrinolysis, endothelial dysfunction, and atherothromb osis in the coronary circulation and may explain the greater efficacy of th rombolytic therapy for myocardial infarction in cigarette smokers.