Oxidant Stress and Aspirin-Insensitive Thromboxane Biosynthesis in Severe Unstable Angina

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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)F2α, 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-PGF2α and 11-dehydro-TXB2. 8-Iso-PGF2α 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, P2α was linearly correlated with 11-dehydro-TXB2 excretion (ρ=0.721, PP=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-PGF2α 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.