Simultaneous integrin ?? and glycoprotein IIb/IIIa inhibition causes reduction in infarct size in a model of acute coronary thrombosis and primary angioplasty

Abstract

Objective: We tested the hypothesis that simultaneous inhibition of the endothelial integrin α_vβ₃ and the platelet glycoprotein IIb/IIIa receptor will substantially reduce infarct size in a model of acute coronary thrombosis and primary angioplasty. Methods: Dogs were subjected to thrombus formation in the left anterior descending coronary artery followed by primary angioplasty. Prior to angioplasty, they were randomized into 3 treatment groups. Group 1 (n=7) received saline; Group 2 (n=9) received MK-383 that inhibits only IIb/IIIa; and Group 3 (n=9) received CP-4715, that inhibits both IIb/IIIa and α_vβ₃. Results: There was a 59% reduction in infarct size in dogs receiving CP-4715 compared to controls (p=0.002) and a 37% reduction compared to the dogs receiving MK-383 (p=0.04). Myocardium microthrombi were seen to be reduced similarly with both drugs on post-mortem ^99mTc-DMP444 autoradiography that reflects in vivo IIb/IIIa receptor activity. In vivo imaging using echistatin-conjugated and leukocyte-targeted microbubbles revealed significant α_vβ₃ inhibition and reduction in active leukocyte recruitment only in Group 3 dogs. Myocardial blood flow and regional function after reperfusion were also significantly better in this group. Conclusion: Simultaneous inhibition of IIb/IIIa and α_vβ₃ causes a marked reduction in infarct size in a model of acute coronary thrombosis and primary PTCA that is associated with reduced myocardial microthrombi and inflammation, as well as improved myocardial blood flow and regional function. These results may have important implications in the treatment of acute coronary syndromes.