Cardiovascular effects of tumour necrosis factor α antagonism in patients with acute myocardial infarction: a first in human study.

OBJECTIVE: The inflammatory cytokine, tumour necrosis factor α (TNF-α), exerts deleterious cardiovascular effects. We wished to determine the effects of TNF-α antagonism on endothelial function and platelet activation in patients with acute myocardial infarction. DESIGN AND SETTING AND PATIENTS: A double-blind, parallel group, randomised controlled trial performed in a tertiary referral cardiac centre. 26 patients presenting with acute myocardial infarction randomised to receive an intravenous infusion of etanercept (10 mg) or saline placebo. MAIN OUTCOME MEASURES: Leucocyte count, plasma cytokine concentrations, flow cytometric measures of platelet activation and peripheral vasomotor and fibrinolytic function were determined before and 24 h after study intervention. RESULTS: Consistent with effective conjugation of circulating TNF-α, plasma TNF-α concentrations increased in all patients following etanercept (254 ± 15 vs 0.12 ± 0.02 pg/ml; p < 0.0001), but not saline infusion. Etanercept treatment reduced neutrophil (7.4 ± 0.6 vs 8.8 ± 0.6 × 10(9) cells/l; p = 0.03) and plasma interleukin-6 concentrations (5.8 ± 2.0 vs 10.6 ± 4.0 pg/ml; p = 0.012) at 24 h but increased platelet-monocyte aggregation (30 ± 5 vs 20 ± 3%; p = 0.02). Vasodilatation in response to substance P, acetylcholine and sodium nitroprusside, and acute tissue plasminogen activator release were unaffected by either treatment (p > 0.1 for all). CONCLUSIONS: Following acute myocardial infarction, etanercept reduces systemic inflammation but increases platelet activation without affecting peripheral vasomotor or fibrinolytic function. We conclude that TNF-α antagonism is unlikely to be a beneficial therapeutic strategy in patients with acute myocardial infarction.