UMMS Affiliation

Department of Medicine, Division of Cardiovascular Medicine

Date

3-15-2016

Document Type

Article

Disciplines

Cardiology | Cardiovascular Diseases

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 6 months after surgery, accounting for 47.2% of the modeled effect, was urine 8-iso-prostaglandin (PG)F2alpha, 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-PGF2alpha 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-PGF2alpha.

CONCLUSIONS: Oxidative stress-induced formation of 8-iso-PGF2alpha 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.

Rights and Permissions

Citation: J Am Heart Assoc. 2016 Mar 15;5(3):e002615. doi: 10.1161/JAHA.115.002615. Link to article on publisher's site

DOI of Published Version

10.1161/JAHA.115.002615

Related Resources

Link to Article in PubMed

Keywords

aspirin, isoprostane, oxidative stress, thrombosis, thromboxane

Journal Title

Journal of the American Heart Association

PubMed ID

27068626

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

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