Environmental, genetic and inflammatory factors modifying endothelial function in patients with coronary heart disease

BACKGROUND The endothelium plays a vital role in the regulation of blood flow and haemostasis as well as mediating the response to tissue injury and inflammation. Disruption to these pathways is a critical factor in the development of coronary heart disease (CHD) and clinical syndromes such as acute myocardial infarction (MI). Endothelial dysfunction may be demonstrated in patients with CHD and its risk factors such as cigarette smoking with a decrease in the synthesis and release of endothelial-derived factors including the endogenous fibrinolytic factor tissue plasminogen activator (t-PA) and nitric oxide (NO) as well as impaired regulation of vascular tone.OBJECTIVES (1) Although a reduction in endogenous fibrinolytic capacity may be associated with a greater risk of arterial thrombosis, the relationship between acute t-PA release and future atherothrombotic events was unknown. (2) Previous work in healthy subjects had suggested that genetic variation within the t-PA gene may be important in determining inter-individual differences in t-PA release and the risk of future MI; we therefore assessed the effect of t-PA genetic polymorphisms on t-PA release in patients with CHD. (3) Although unable to prove causation, previous studies indicated a relationship between inflammatory markers, plasma t-PA concentrations and the risk of future cardiovascular events. However the direct effect of local arterial inflammation in patients with CHD was unknown. (4) As impaired NO bioavailability may contribute to the development of atherosclerosis, we postulated that prolonging the effect of NO with a highly selective phosphodiesterase type 5 inhibitor (sildenafil citrate) may improve vascular function.OUTCOME Measures In a well characterised cohort of patients with stable CHD: atherothrombotic events during follow-up (death from a cardiovascular cause, MI, ischaemic stroke (CVA), hospitalisation for myocardial ischaemia); t-PA genotype; inflammatory cytokines; acute t-PA release and forearm blood flow (FBF) during intra-brachial infusion of vaso-agonists.RESULTS (1) Net t-PA release was 44% lower in the patients who experienced death, MI, CVA or hospitalisation for myocardial ischaemia (p<0.02) over a median follow-up of 34 months. This novel finding validates the application of the forearm model to studying the pathophysiological changes observed in CHD and suggests that the acute endogenous fibrinolytic capacity is important in determining future cardiovascular risk. (2) Despite confirming previous reports of impaired t-PA release and reduced FBF responses in cigarette smokers (p<0.05), we found no effect of a number of t-PA genetic polymorphisms on acute t-PA release. In subjects with established CHD, inter-individual differences in t-PA release appear to predominantly reflect the presence of environment factors such as cigarette smoking. (3) Intra-brachial infusion of tumour necrosis factor-a impaired NO-dependent vasodilatation (p<0.001), increased basal t-PA concentrations and doubled bradykinininduced t-PA release (p=0.006). This suggests a pathophysiological mechanism whereby circulating levels of inflammatory cytokines are directly related to plasma t-PA concentrations and the risk of future cardiovascular events. Pharmacological interventions with anti-cytokine therapies may have a therapeutic role in subjects at risk of acute coronary syndromes. (4) Despite augmenting the effects of basal NO release and a direct NO donor (p