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)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. CONCLUSIONS: 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.
Subject(s)
Coronary Artery Bypass/adverse effects , Graft Occlusion, Vascular/urine , Human Umbilical Vein Endothelial Cells/metabolism , Saphenous Vein/metabolism , Saphenous Vein/transplantation , Thromboxane B2/analogs & derivatives , Aged , Biomarkers/urine , Cells, Cultured , Dinoprost/analogs & derivatives , Dinoprost/urine , Female , Graft Occlusion, Vascular/diagnosis , Graft Occlusion, Vascular/etiology , Graft Occlusion, Vascular/physiopathology , Graft Occlusion, Vascular/prevention & control , Humans , Male , Middle Aged , Multivariate Analysis , Oxidative Stress , Platelet Aggregation Inhibitors/therapeutic use , Risk Assessment , Risk Factors , Saphenous Vein/physiopathology , Thromboxane B2/urine , Time Factors , Treatment Outcome , United States , Vascular PatencyABSTRACT
Type 1 diabetic patients have increased risk of developing in-stent restenosis following endovascular stenting. Underlying pathogenetic mechanisms are not fully understood partly due to the lack of a relevant animal model to study the effect(s) of long-term autoimmune diabetes on development of in-stent restenosis. We here describe the development of in-stent restenosis in long-term (~7 months) spontaneously diabetic and age-matched, thymectomized, nondiabetic Diabetes Prone BioBreeding (BBDP) rats (n = 6-7 in each group). Diabetes was suboptimally treated with insulin and was characterized by significant hyperglycaemia, polyuria, proteinuria, and increased HbA(1c) levels. Stented abdominal aortas were harvested 28 days after stenting. Computerized morphometric analysis revealed significantly increased neointima formation in long-term diabetic rats compared with nondiabetic controls. In conclusion, long-term autoimmune diabetes in BBDP rats enhances in-stent restenosis. This model can be used to study the underlying pathogenetic mechanisms of diabetes-enhanced in-stent restenosis as well as to test new therapeutic modalities.
Subject(s)
Diabetes Mellitus, Type 1/physiopathology , Disease Models, Animal , Graft Occlusion, Vascular/physiopathology , Animals , Aorta, Abdominal/surgery , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/urine , Glucose/metabolism , Glycated Hemoglobin/metabolism , Graft Occlusion, Vascular/blood , Graft Occlusion, Vascular/urine , Kidney/physiopathology , Polyuria/physiopathology , Proteinuria/physiopathology , RatsABSTRACT
We aimed to analyze periprocedural creatinine phosphokinase (CPK)-MB elevation in patients treated with intracoronary radiation therapy (IRT) for in-stent restenosis (ISR) to risk stratify these patients. The clinical significance of periprocedural CPK-MB elevation after IRT for ISR is unknown. An elevated CPK-MB has been associated with increased mortality after conventional angioplasty. We evaluated 1,326 patients who were enrolled in radiation trials for ISR at the Washington Hospital Center using gamma- and beta-emitters. Patients were analyzed according to degree of CPK-MB increase within 24 hours of the index IRT procedure (normal CPK-MB, CPK-MB 1 to 3 times the upper limit of normal, or CPK-MB >3 times the upper limit of normal). Patients with CPK-MB >3 times the upper limit of normal were older (64 +/- 12 years, p = 0.04), more likely to be smokers (64%, p = 0.04), hypertensive (85%, p <0.01), and diabetic (49%, p = 0.04). The cohort with the highest CPK-MB release (CPK-MB >3 times the upper limit of normal) had significantly higher rates of adverse clinical events at 12 months (major adverse cardiac events 40%, p <0.01), including death (9.3%, p <0.01) and late thrombosis (6.3%, p <0.01). Periprocedural CPK-MB elevation is of prognostic importance in patients treated with IRT for ISR, and its analysis appears to be mandatory to risk stratify these patients. The impact of glycoprotein IIb/IIIa antagonists in reducing periprocedural CPK-MB release awaits evaluation.
