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Michael P. Robich1, Louis M. Chu1, Jun Feng1, Cesario Bianchi1, Roger J. Laham2, Michael A. Coady3, Frank W. Sellke3 1 Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; 2 Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; 3 Surgery, Warren Alpert Medical School, Brown University, Boston, MA Objective: Selective cyclooxygenase-2 (COX-2) inhibitors have been purported to increase the risk of myocardial infarction and death. We sought to explore the effects of nonselective cyclooxygenase (COX) and selective COX-2 inhibition on collateral development in a model of chronic myocardial ischemia. We hypothesized that COX-2 inhibitors will negatively effect angiogenesis and pro-angiogenic pathways. Methods: The hearts of Yorkshire swine were made chronically ischemic by placing an ameroid constrictor on the left circumflex coronary artery (LCx). Swine were divided into three groups and given no drug (control, n=7), a nonselective COX inhibitor (naproxen 400 mg PO daily, NSAID, n=7), or a selective COX-2 inhibitor (celecoxib 200 mg PO daily, COX-2, n=7). After 7 weeks, coronary angiography was performed and images graded for TIMI flow scores of collateral formation. Myocardial function and perfusion and microvascular reactivity were assessed. Serum prostacyclin (PGI2) levels and immunoblotting for protein markers of angiogenesis were examined. Results: The COX-2 group demonstrated significantly increased mean arterial pressure (MAP) when compared to the control and NSAID groups. Animals in the COX-2 group had similar TIMI score vs. control, but the NSAID group had a trend toward increased TIMI flow. Myocardial perfusion in the COX-2 group was similar to that in the control, but less than that in the NSAID group. Coronary microvascular relaxation in the collateral dependent territory was diminished in the COX-2 group vs. NSAID or control groups. The COX group had a trend toward decreased serum PGI2. Protein expression of angiogenic markers showed decreased levels of VEGF and phospho-eNOS (ser1177) in both the COX-2 and NSAID groups, though only significantly in the COX-2 group. The NSAID group had decreased expression of endostatin, an anti-angiogenic protein. (Table 1) Conclusion: COX-2 inhibitors resulted in increased MAP and endothelial microvascular dysfunction, but similar collateral formation and myocardial perfusion vs. control. NSAID was associated with an increase in collateral formation and perfusion vs. control. Thus, selective COX-2 inhibition in this model is not associated with impairment in collateral formation, but is associated with decreased circulating levels of PGI2 and tissue levels of phospho-eNOS and VEGF. Table 1
Summary of results. PGI2- prostacyclin I2, VEGF- vascular endothelial growth factor, eNOS- endothelial nitric oxide synthase. Statistics performed using 1 way ANOVA with Newman-Keuls multiple comparison test (NSAID vs. COX-2) Back to 2010 Annual Meeting Back to Program Outline Back to Main Program |
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