Simultaneous integrin αvβ3 and glycoprotein IIb/IIIa inhibition causes reduction in infarct size in a model of acute coronary thrombosis and primary angioplasty

Tadamichi Sakuma, Ibrahim Sari, Craig N. Goodman, Jonathan R. Lindner, Alexander L. Klibanov, Sanjiv Kaul

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    Abstract

    Objective: We tested the hypothesis that simultaneous inhibition of the endothelial integrin αvβ3 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 αvβ3. 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 αvβ 3 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 αvβ3 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.

    Original languageEnglish (US)
    Pages (from-to)552-561
    Number of pages10
    JournalCardiovascular research
    Volume66
    Issue number3
    DOIs
    StatePublished - Jun 1 2005

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    Keywords

    • Echocardiography
    • Infarction
    • Inflammation
    • Microcirculation
    • Reperfusion

    ASJC Scopus subject areas

    • Physiology
    • Cardiology and Cardiovascular Medicine
    • Physiology (medical)

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