Studies into endogenous fibrinolysis in the peripheral and coronary vascular beds of man

BACKGROUND: Acute myocardial infarction is caused by thrombotic occlusion of a coronary artery compromised by atheromatous plaque. The interplay between acute plaque rupture or erosion and the local haemostatic and fibrinolytic activities are critical determinants in the initiation and resolution of the thrombotic complications of coronary atheroma. This is exemplified by the high rate of spontaneous reperfusion in the infarct related artery after acute myocardial infarction.OBJECTIVES: The aims of the thesis were: first, to establish a selective, specific and reproducible model for assessing endothelial function and acute endogenous fibrinolytic capacity in vivo in the peripheral circulation of man; second, to characterise the underlying mechanisms of the fibrinolytic response in this model; third, to compare the acute endogenous fibrinolytic capacity in health and disease; fourth, to examine the influence of therapeutic intervention on the fibrinolytic response; and finally, fifth, to apply this model to the coronary circulation in order to determine the acute coronary fibrinolytic response and assess its relationship with the extent of coronary atheroma.METHODS: Peripheral circulation. Blood flow and plasma fibrinolytic parameters were determined in both forearms using venous occlusion plethysmography and blood samples withdrawn from the antecubital fossae. The brachial artery of the nondominant forearm was cannulated and intra-artenal drugs administered. Plasma fibrinolytic parameters were determined using enzyme linked immunosorbant and photometric methods. The mechanisms of substance P action were explored using neurokinin type 1 receptor antagonism, nitric oxide synthase inhibition and the nitric oxide donor, sodium nitroprusside. The acute fibrinolytic response was examined in habitual cigarette smokers and patients with hypercholesterolaemia: the latter were also assessed following 6 weeks of lipid lowering therapy. Coronary circulation. Following diagnostic coronary angiography, the proximal coronary artery plaque volume was determined using computerised three dimensional reconstruction of intravascular ultrasound images. Blood flow and fibrinolytic responses to selective left anterior descending coronary artery infusion were assessed using intracoronary ultrasound and Doppler, and coronary sinus and arterial blood sampling.RESULTS: Intrabrachial substance P infusion was well tolerated and produced reproducible increases in forearm blood flow and tissue plasminogen activator release without affecting plasminogen activator inhibitor type 1 and von Willebrand factor concentrations. In contrast, endothelin-1 and L-monomethyl arginine infusion did not cause acute tissue plasminogen activator release. The response to substance P infusion appears to be dependent on the endothelial cell neurokinin type 1 receptor, and is, in part, mediated by the L-arginine:nitric oxide pathway. Whilst endothelium-dependent vasomotion was impaired in both cigarette smokers and patients with hypercholesterolaemia, tissue plasminogen activator release was diminished only in cigarette smokers and was unaffected by hypercholesterolaemia or lipid lowering therapy. Coronary fibrinolytic activity, but not endothelium-dependent coronary vasodilatation, inversely correlated with the volume of coronary artery atheroma.CONCLUSIONS: A model to assess the acute endogenous fibrinolytic capacity has been developed and characterised which was well tolerated and reproducible. Cigarette smoking, but not hypercholesterolaemia, is associated with an impairment of the acute tissue plasminogen activator release which may, in part, explain the increased propensity of smokers to sustain an acute myocardial infarction as well as to respond more favourably to thrombolytic therapy. The apparently normal fibrinolytic response in patients with hypercholesterolaemia indicates that endothelial dysfunction can be manifest in separate distinct pathways depending upon the nature of the insult. Finally, the demonstration of an association between the extent of coronary atheroma and the local endogenous fibrinolytic response provides a potentially important mechanism through which endothelial dysfunction can directly contribute to the thrombotic consequences of coronary artery disease