Simultaneous integrin alphavbeta3 and glycoprotein IIb/IIIa inhibition causes reduction in infarct size in a model of acute coronary thrombosis and primary angioplasty.
OBJECTIVE
We tested the hypothesis that simultaneous inhibition of the endothelial integrin alpha(v)beta(3) 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 alpha(v)beta(3).


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 (99m)Tc-DMP444 autoradiography that reflects in vivo IIb/IIIa receptor activity. In vivo imaging using echistatin-conjugated and leukocyte-targeted microbubbles revealed significant alpha(v)beta(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.


CONCLUSIONS
Simultaneous inhibition of IIb/IIIa and alpha(v)beta(3) 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.
Sakuma
Tadamichi
T
Cardiovascular Division, Medical Center, University of Virginia, Charlottesville, 22908-0158, USA.
Sari
Ibrahim
I
Goodman
Craig N
CN
Lindner
Jonathan R
JR
Klibanov
Alexander L
AL
Kaul
Sanjiv
S
D000208:Acute Disease; D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D003328:Coronary Thrombosis / Q000188:drug therapy* / Q000628:therapy; D004285:Dogs; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008297:Male; D023421:Models, Animal; D009203:Myocardial Infarction / Q000517:prevention & control; D010880:Piperidines / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use*; D011897:Random Allocation; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000627:therapeutic use
C506519:CP-4715; D039302:Integrin alphaVbeta3; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011743:Pyrimidines; D014443:Tyrosine; D000077466:Tirofiban