The vascular endothelium plays a vital role in the control of blood flow, haemostasis,
fibrinolysis and inflammation. Impairment of endothelial vasomotor and fibrinolytic
function is implicated in the pathogenesis of ischaemic heart disease. Atherosclerosis
is now widely recognised to be an inflammatory disease process, but the mechanistic
links between inflammation, endothelial dysfunction and endogenous fibrinolysis
remain poorly understood.In a series of studies, we explored the effects of inflammation on endothelial
vasomotion and fibrinolytic capacity using an in vivo forearm model of systemic and
local inflammation. Systemic inflammation stimulated by typhoid vaccination had no
major effect on vasomotor tone. However, tumour necrosis factor-a induced local
vascular inflammation was associated with impaired resistance vessel endotheliumdependent vasodilatation, possibly through the development of acute arterial injury.
Both systemic and local inflammation were found to augment the acute release of
endothelial tissue plasminogen activator. In addition, intra-arterial tumour necrosis
factor-a administration resulted in a unique profile of substantial and sustained local
increase in endogenous tissue plasminogen activator.We extended these investigations and assessed the role of endogenous fibrinolysis
and endothelial dysfunction in the pathogenesis of prothrombotic conditions such as
hyperhomocysteinaemia and coronary stent thrombosis or in-stent restenosis using
this forearm model of endothelial function assessment. In patients with recent
myocardial infarction, elevation of plasma homocysteine concentration was
associated with impaired endothelium-dependent vasodilatation but not endogenous
fibrinolysis. This vasomotor dysfunction was not rectified by vitamin
supplementation. We also assessed three critical aspects of vascular function in
patients who have undergone percutaneous coronary intervention and found no
evidence that endothelial vasomotor, fibrinolytic or platelet function play a major
role in the pathogenesis of acute stent thrombosis or in-stent restenosis.We conclude that there is complex interaction between inflammation, endothelial
function and endogenous fibrinolysis. We have identified the unique role of systemic
inflammation and specifically, tumour necrosis factor-a. Furthermore, our studies
indicated that there were no significant associations between fibrinolysis and
hyperhomocysteinaemia or coronary stent complications. Therefore modulating
cytokine actions and their interaction with fibrinolysis may be critical in the
prevention of thrombotic coronary occlusion and myocardial ischaemia as well as in
the future development of anti-thrombotic therapies
