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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:357.)
© 2003 American Heart Association, Inc.

Thrombosis

Blockade of the Platelet P2Y₁₂ Receptor by AR-C69931MX Sustains Coronary Artery Recanalization and Improves the Myocardial Tissue Perfusion in a Canine Thrombosis Model

Kai Wang; Xiaorong Zhou; Zhongmin Zhou; Khaldoun Tarakji; Marcelo Carneiro; Marc S. Penn; Daniel Murray; Allan Klein; Robert G. Humphries; Jonathan Turner; James D. Thomas; Eric J. Topol; A. Michael Lincoff

From the Department of Cardiovascular Medicine (K.W., X.Z., Z.Z., K.T., M.C., M.S.P., D.M., A.K., J.D.T., E.J.T., A.M.L.), The Cleveland Clinic Foundation, Cleveland, Ohio, and Astra-Zeneca (R.G.H., J.T.), R & D, Charnwood, England.

Correspondence to Kai Wang, MD, PhD, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, 9500 Euclid Ave, F25, Cleveland, OH 44195. E-mail wangk{at}ccf.org

Objective— Reperfusion therapy for myocardial infarction is limited by a significant reocclusion rate and less optimal myocardial tissue perfusion due to excessive platelet accumulation and recruitment at the sites of vascular injury. We assessed the influence of a selective P2Y₁₂-receptor antagonist (AR-C69931MX), in conjunction with thrombolytic therapy, on the prevention of platelet aggregation and thrombus formation.

Methods and Results— A canine coronary electrolytic injury thrombosis model was used. Tissue-type plasminogen activator (t-PA; 1 mg/kg in phase I, 0.5 mg/kg in phase II in the AR-C69931MX group, and 1 mg/kg in the placebo group in phase I and II) was administered 30 minutes after thrombus formation; either saline or AR-C69931MX (4 µg · kg^-1 · min^-1) was given to all animals intravenously 10 minutes before t-PA administration for a total of 2 hours. All animals received heparin (80 U/kg) as an intravenous bolus followed by a continuous infusion of 17 U · kg^-1 · h^-1. Myocardial tissue perfusion was evaluated by use of the colored microsphere technique and real-time myocardial contrast echocardiography. The incidences of reocclusion and cyclic flow variation were significantly decreased in the AR-C69931MX group (P<0.05). Myocardial tissue flow with AR-C69931MX treatment improved significantly at 20 and 120 minutes after reflow, whereas tissue flow with placebo remained at a level similar to that during occlusion (P<0.05).

Conclusions— The adjunctive administration of AR-C69931MX blocked ADP-mediated platelet aggregation and recruitment and prevented platelet-mediated thrombosis, resulting in prolongation of reperfusion time and a decrease in reocclusion and cyclic flow variations. Importantly, myocardial tissue perfusion was significantly improved in the P2Y₁₂ antagonist group.

Key Words: P2Y₁₂ receptor • thrombosis • myocardial tissue perfusion • myocardial contrast echocardiography

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