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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)357-362
Number of pages6
JournalArteriosclerosis, thrombosis, and vascular biology
Volume23
Issue number2
DOIs
StatePublished - Feb 1 2003

Keywords

  • Myocardial contrast echocardiography
  • Myocardial tissue perfusion
  • P2Y receptor
  • Thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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