Abstract 690: Acute Endothelial Tissue Plasminogen Activator Release Predicts Future Adverse Cardiovascular Events in Patients with Stable Coronary Heart Disease
Background The fibrinolytic factor tissue plasminogen activator (t-PA) is rapidly released from the endothelium and is a major determinant of vessel patency and clinical sequelae following acute coronary plaque rupture. We assessed whether acute t-PA release predicts future atherothrombotic events in patients with stable coronary heart disease (CHD).
Methods Plasma t-PA and plasminogen activator inhibitor (PAI-1) antigen concentrations and net release of t-PA were determined in response to intra-arterial substance P infusion (2– 8 pmol/min) in 97 patients with proven CHD (stable anginal symptoms for ≥3 months). Forearm blood flow was measured during infusion of substance P and sodium nitroprusside (2– 8 μg/min). Cardiovascular events, including death from cardiovascular causes, myocardial infarction (MI), ischemic stroke (CVA) and hospitalization for myocardial ischemia, were determined through a validated national database.
Results Patients experiencing cardiovascular events (n = 20; median follow-up, 34 months) had similar baseline characteristics to those free of events (P = ns for all). Substance P caused a dose-dependent increase in plasma t-PA antigen (P < 0.001, ANOVA) but not PAI-1 (P = ns) concentrations. Net release of t-PA was reduced by 91% in patients with death/MI/CVA, and 44% for those with Death/MI/CVA/hospitalization for myocardial ischemia (p ≤ 0.02; ANOVA for both). Major adverse cardiovascular events increased with decreasing t-PA release (P = 0.04, log rank) with the lowest quartile having the highest rate of adverse events (P = 0.02, versus upper 3 quartiles). Endothelium-dependent and -independent vasodilatation did not differ between the groups.
Conclusion For the first time, we have demonstrated that acute endothelial t-PA release predicts the future risk of adverse cardiovascular events in patients with stable coronary disease. The endogenous fibrinolytic capacity may be more closely allied to the future risk of atherothrombotic events than stimulated vasodilatation. Further studies of the factors modifying the endogenous fibrinolytic capacity have the potential to provide major new insights into the pathophysiology of coronary heart disease and to shape future therapeutic interventions.