Two Classes of Anti-Platelet Drugs Reduce Anatomical Infarct Size in Monkey Hearts
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Recent studies in rabbits have demonstrated that platelet P2Y12 receptor antagonists are cardioprotective, and that the mechanism is surprisingly not related to blockade of platelet aggregation but rather to triggering of the same signal transduction pathway seen in pre- and postconditioning. We wanted to determine whether this same cardioprotection could be documented in a primate model and whether the protection was limited to P2Y12 receptor antagonists or was a class effect.
Thirty-one macaque monkeys underwent 90-min LAD occlusion/4-h reperfusion.
The platelet P2Y12 receptor blocker cangrelor started just prior to reperfusion significantly decreased infarction by an amount equivalent to that seen with ischemic postconditioning (p < 0.001). For any size of risk zone, infarct size in treated hearts was significantly smaller than that in control hearts. OM2, an investigational murine antibody against the primate collagen receptor glycoprotein (GP) VI, produced similar protection (p < 0.01) suggesting a class effect. Both cangrelor and OM2 were quite effective at blocking platelet aggregation (94 % and 97 %, respectively).
Thus in a primate model in which infarct size could be determined directly platelet anti-aggregatory agents are cardioprotective. The important implication of these investigations is that patients with acute myocardial infarction who are treated with platelet anti-aggregatory agents prior to revascularization may already be in a postconditioned state. This hypothesis may explain why in recent clinical trials postconditioning-mimetic interventions which were so protective in animal models had at best only a modest effect.
KeywordsCangrelor Monkey Myocardial infarction OM2 Platelet Postconditioning
This study was supported in part by grant HL-20648 from the Heart, Lung and Blood Institute of the National Institutes of Health and by funds supplied by Otsuka Maryland Medicinal Labs., Inc., Rockville, MD. Cangrelor was synthesized by a private firm.
Monkey studies were funded by a contract with Otsuka Maryland Medicinal Labs, Rockville, MD.
- 6.Yang X-M, Liu Y, Cui L, Yang X, Liu Y, Tandon N, et al. Platelet P2Y12 blockers confer direct postconditioning-like protection in reperfused rabbit hearts. J Cardiovasc Pharmacol Ther. 2013 (in press).Google Scholar
- 8.Patti G, Bárczi G, Orlic D, Mangiacapra F, Colonna G, Pasceri V, et al. Outcome comparison of 600- and 300-mg loading doses of clopidogrel in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: results from the ARMYDA-6 MI (Antiplatelet therapy for Reducton of MYocardial Damage during Angioplasty-Myocardial Infarction) randomized study. J Am Coll Cardiol. 2011;58:1592–9.PubMedCrossRefGoogle Scholar
- 10.National Research Council. Guide for the care and use of laboratory animals. 7th ed. Washington, D.C: National Academy Press; 1996.Google Scholar
- 15.Takaya N, Katoh Y, Iwabuchi K, Hayashi I, Konishi H, Itoh S, et al. Platelets activated by collagen through the immunoreceptor tyrosine-based activation motif in the Fc receptor γ-chain play a pivotal role in the development of myocardial ischemia-reperfusion injury. J Mol Cell Cardiol. 2005;39:856–64.PubMedCrossRefGoogle Scholar
- 16.Li H, Takizawa H, Gong X, Concepcion A, Kambayashi J, Tandon N, et al. Platelet glycoprotein VI (GPVI) deletion reduces myocardial infarction in mice. Circulation. 2007;116(Suppl II):II–200.Google Scholar
- 20.Tarantini G, Favaretto E, Marra MP, Frigo AC, Napodano M, Cacciavillani L, et al. Postconditioning during coronary angioplasty in acute myocardial infarction: the POST-AMI trial. Int J Cardiol. 2012;162:33–8.Google Scholar
- 27.Barrabés JA, Garcia-Dorado D, Mirabet M, Lidón R-M, Soriano B, Ruiz-Meana M, et al. Lack of effect of glycoprotein IIb/IIIa blockade on myocardial platelet or polymorphonuclear leukocyte accumulation and on infarct size after transient coronary occlusion in pigs. J Am Coll Cardiol. 2002;39:157–65.PubMedCrossRefGoogle Scholar