title: Vascular and fibrinolytic effects of intra-arterial tumour necrosis factor-alpha in patients with coronary heart disease.
abstract: Elevated plasma t-PA (tissue plasminogen activator) and serum CRP (C-reactive protein) concentrations are associated with an adverse cardiovascular risk. In the present study, we investigated whether acute local inflammation causes vascular dysfunction and influences t-PA release in patients with stable coronary heart disease. Serum CRP, plasma t-PA and PAI-1 (plasminogen activator inhibitor type 1) concentrations were determined in 95 patients with stable coronary heart disease. A representative subpopulation of 12 male patients received an intra-brachial infusion of TNF-alpha (tumour necrosis factor-alpha) and saline placebo using a randomized double-blind cross-over study design. Forearm blood flow and plasma fibrinolytic and inflammatory variables were measured. Serum CRP concentrations correlated with plasma t-PA concentrations (r=0.37, P<0.001) and t-PA/PAI-1 ratio (r=-0.21, P<0.05). Intra-arterial TNF-alpha caused a rise in t-PA concentrations (P<0.001) without affecting blood flow or PAI-1 concentrations. TNF-alpha pretreatment impaired acetylcholine- and sodium nitroprusside-induced vasodilatation (P<0.001 for both) whilst doubling bradykinin-induced t-PA release (P=0.006). In patients with stable coronary heart disease, plasma fibrinolytic factors correlate with a systemic inflammatory marker and local vascular inflammation directly impairs vasomotor function whilst enhancing endothelial t-PA release. We suggest that the adverse prognosis associated with elevated plasma t-PA concentrations relates to the underlying causative association with vascular inflammation and injury.
authors.affiliation: Centre for Cardiovascular Sciences, University of Edinburgh, Royal Infirmary of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, Scotland, U.K. simon.robinson@ed.ac.uk
authors.forename: Simon D
authors.initials: SD
authors.lastname: Robinson
authors.forename: Pamela
authors.initials: P
authors.lastname: Dawson
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ludlam
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Boon
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D002097:C-Reactive Protein / Q000378:metabolism; D003327:Coronary Disease / Q000097:blood* / Q000503:physiopathology; D018592:Cross-Over Studies; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects*; D005542:Forearm / Q000098:blood supply; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D012039:Regional Blood Flow; D010959:Tissue Plasminogen Activator / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014657:Vasculitis / Q000097:blood* / Q000139:chemically induced / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects; D014666:Vasomotor System / Q000187:drug effects / Q000503:physiopathology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D017395:Plasminogen Activator Inhibitor 1; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D010959:Tissue Plasminogen Activator