Risk factors for nonplatelet thromboxane generation after coronary artery bypass graft surgery

Nikolaos Kakouros, Susanna M. Nazarian, Patrizia B. Stadler, Thomas S. Kickler, Jeffrey J. Rade

Research output: Contribution to journalArticlepeer-review

Abstract

Background-Persistent thromboxane (TX) generation while receiving aspirin therapy is associated with an increased risk of cardiovascular events. The Reduction in Graft Occlusion Rates (RIGOR) study found that aspirin-insensitive TXA2 generation, indicated by elevated urine 11-dehydro-TXB2 (UTXB2) 6 months after coronary artery bypass graft surgery, was a potent risk factor for vein graft thrombosis and originated predominantly from nonplatelet sources. Our goal was to identify risks factors for nonplatelet TXA2 generation. Methods and Results-Multivariable modeling was performed by using clinical and laboratory variables obtained from 260 RIGOR subjects with verified aspirin-mediated inhibition of platelet TXA2 generation. The strongest variable associated with UTXB2 months after surgery, accounting for 47.2% of the modeled effect, was urine 8-iso-prostaglandin (PG)F, an arachidonic acid metabolite generated nonenzymatically by oxidative stress (standardized coefficient 0.442, P<0.001). Age, sex, race, lipid therapy, creatinine, left ventricular ejection fraction, and aspirin dose were also significantly associated with UTXB2 (P<0.03), although they accounted for only 4.8% to 10.2% of the modeled effect. Urine 8-iso-PGF2a correlated with risk of vein graft occlusion (odds ratio 1.67, P=0.001) but was not independent of UTXB2. In vitro studies revealed that endothelial cells generate TXA2 in response to oxidative stress and direct exposure to 8-iso-PGF. Conclusions-Oxidative stress-induced formation of 8-iso-PGF is strongly associated with nonplatelet thromboxane formation and early vein graft thrombosis after coronary artery bypass graft surgery. The endothelium is potentially an important source of oxidative stress-induced thromboxane generation. These findings suggest therapies that reduce oxidative stress could be useful in reducing cardiovascular risks associated with aspirin-insensitive thromboxane generation.

Original languageEnglish (US)
Article numbere002615
JournalJournal of the American Heart Association
Volume5
Issue number3
DOIs
StatePublished - 2015

Keywords

  • Aspirin
  • Isoprostane
  • Oxidative stress
  • Thrombosis
  • Thromboxane

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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