dinoprost and Graft-Occlusion--Vascular

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.. 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)F2α, 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-PGF2α 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-PGF2α.. Oxidative stress-induced formation of 8-iso-PGF2α 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.

Topics: Aged; Biomarkers; Cells, Cultured; Coronary Artery Bypass; Dinoprost; Female; Graft Occlusion, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Male; Middle Aged; Multivariate Analysis; Oxidative Stress; Platelet Aggregation Inhibitors; Risk Assessment; Risk Factors; Saphenous Vein; Thromboxane B2; Time Factors; Treatment Outcome; United States; Vascular Patency

Prostaglandin formation is enhanced in vascular disease, in part through induction of cyclooxygenase (COX-2) in vascular smooth muscle cells. Because COX regulates cell growth and migration, we examined whether the COX expression plays a role in the development of intimal hyperplasia after vascular injury. Rats undergoing balloon angioplasty of the carotid artery were randomized to receive a selective COX-2 inhibitor (SC-236), a selective COX-1 inhibitor (SC-560) or a combination of the two. Normal, uninjured vessels showed COX-1, but no COX-2 expression. Fourteen days after balloon injury, both COX-1 and COX-2 were expressed in the neointima. Balloon angioplasty resulted in a marked increase in the urinary excretion of prostaglandin (PG) E(2,) PGF(2alpha), and thromboxane (TX) B(2). Both the COX-1 inhibitor SC-560 and the COX-2 inhibitor SC-236 suppressed the generation of PGE(2) and PGF(2alpha), particularly when combined, suggesting a role for both isozymes in the generation of prostaglandins in this model. In contrast, TXA(2) was markedly suppressed by the COX-1 inhibitor SC-560. COX-2 inhibition with SC-236 had no effect on intimal hyperplasia at day 14 (0 versus 8.5%; n = 7 in controls). In contrast, intimal hyperplasia was reduced by SC-560 when administered alone (by 42%; n = 7, p < 0.05) or in combination with SC-236 (by 40%; n = 7, p < 0.05). COX-1 may play a role in the development of intimal hyperplasia, potentially through the inhibition of platelet TXA(2). Despite being expressed in the neointima, COX-2 does not play a role in the development of intimal hyperplasia after vascular injury.

Topics: Angioplasty, Balloon; Animals; Carotid Arteries; Cyclooxygenase 1; Dinoprost; DNA Primers; Eicosanoids; Graft Occlusion, Vascular; Hyperplasia; Immunohistochemistry; Isoenzymes; Male; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Thromboxane B2; Tunica Intima

This animal study was designed to compare a collagen coated heparin bonded vascular graft (CHG) versus a collagen coated vascular graft (CG) regarding intraoperative blood loss and healing process. 24 polyester vascular grafts (12 CHG and 12 CG) of 6 mm in diameter and 5 mm in length were implanted between the common iliac and external iliac artery in 12 adult dogs. The grafts were explanted between the first and the sixth months which followed the implantations. The healing process was observed by gross examination, microscopic and scanning electron microscopic examination. Prostaglandin PGE2, TXB2, 6 keto PGF1 alpha and PGF2 alpha were measured by radioimmunologic assay from samples retrieved from the medium part of the graft. During implantation, there was no notable difference in blood loss through the graft. At the time of explantation, 20 grafts were patent (10 CHG, 10 CG). In both grafts, the healing process developed progressively between 2 and 6 months and 90% of the internal surface of the grafts were covered with endothelial like cells. At 6 months, the internal layer was thinner in heparinized graft. PGI2 secretion was found with the two types of grafts. In conclusion, the present study showed no difference in the blood loss or healing characteristic of CHG and CG except for a potentially thinner internal layer with CHG. Comparative studies in humans are necessary to evaluate the potential benefit of heparin bonded graft in clinical practice.

Topics: 6-Ketoprostaglandin F1 alpha; Anastomosis, Surgical; Animals; Blood Loss, Surgical; Blood Vessel Prosthesis; Collagen; Dinoprost; Dinoprostone; Dogs; Epoprostenol; Graft Occlusion, Vascular; Heparin; Iliac Artery; Microscopy, Electron, Scanning; Polyesters; Radioimmunoassay; Thrombosis; Thromboxane B2; Vascular Patency

Many vasoconstrictors (spasmogens) may cause arterial graft spasm; however, there is lack of an overview of the nature of vasoconstriction in grafts. This study was designed to investigate the response of three major arterial grafts currently used for coronary artery bypass grafting to various vasoconstrictor substances. Segments of three arterial grafts (gastroepiploic [GEA], n = 28; internal mammary [IMA], n = 213; inferior epigastric [IEA], n = 24) taken from patients undergoing coronary artery bypass grafting were studied in organ baths under a physiologic pressure. Cumulative concentration-contraction curves were established for the following vasoconstrictor substances: endothelin-1, U46619, prostaglandin F2 alpha, norepinephrine, methoxamine, phenylephrine, 5-hydroxytryptamine, and potassium chloride (K+). In IMA, the highest contraction force was induced by U46619 (5.69 +/- 0.48 g), endothelin-1 (4.43 +/- 0.4 g), PGF2 alpha (6.29 +/- 1.42 g), and K+ (4.58 +/- 0.5 g). Internal mammary artery is highly sensitive to endothelin-1 (EC50, -8.13 +/- 0.08 log M) and U46619 (EC50, -8.21 +/- 0.21 log M) (lower than any other vasoconstrictors, p < 0.001). Next sensitive vasoconstrictors were PGF2 alpha and norepinephrine. 5-Hydroxytryptamine induced significantly higher contraction force in the IMA without endothelium (2.8 +/- 0.64 g versus 1.4 +/- 0.23 g, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Abdominal Muscles; Adrenergic alpha-Agonists; Arteries; Coronary Artery Bypass; Dinoprost; Endothelins; Endothelium, Vascular; Graft Occlusion, Vascular; Humans; Mammary Arteries; Potassium Chloride; Prostaglandin Endoperoxides, Synthetic; Serotonin; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents