Oxidant stress and aspirin-insensitive thromboxane biosynthesis in severe unstable angina

Abstract

Background - Unstable angina is associated with enhanced lipid peroxidation and reduced antioxidant defenses. We have previously reported aspirin failure in the suppression of enhanced thromboxane (TX) biosynthesis in a subset of episodes of platelet activation in this setting. We tested the hypothesis that the in vivo formation of the F2-isoprostane 8-iso-prostaglandin (PG)F(2α), a bioactive product of arachidonic acid peroxidation, is enhanced in unstable angina and contributes to aspirin-insensitive TX biosynthesis. Methods and Results - Urine samples were obtained from patients with unstable angina (n = 32), stable angina (n = 32), or variant angina (n = 4) and from 40 healthy subjects for the measurement of immunoreactive 8-iso-PGF2(α) and 11-dehydro-TXB2. 8-Iso-PGF(2α) excretion was significantly higher in patients with unstable angina (339±122 pg/mg creatinine) than in matched patients with stable angina (236±83 pg/mg creatinine, P = 0.001) and control subjects (192±71 pg/mg creatinine, P<0.0001). In patients with unstable angina, 8-iso-PGF(2α) was linearly correlated with 11-dehydro-TXB2 excretion (ρ=0.721, P<0.0001) and inversely correlated with plasma vitamin E (ρ=-0.710, P=0.004). Spontaneous myocardial ischemia in patients with variant angina or ischemia elicited by a stress test in patients with stable angina was not accompanied by any change in 8-iso-PGF(2α) excretion, thus excluding a role of ischemia per se in the induction of increased F2-isoprostane production. Conclusions - These findings establish a putative biochemical link between increased oxidant stress and aspirin-insensitive TX biosynthesis in patients with unstable angina and provide a rationale for dose-finding studies of antioxidants in this setting.