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Triple Therapy Greatly Increases Myocardial Salvage During Ischemia/Reperfusion in the in situ Rat Heart

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Abstract

Background

Cangrelor, a P2Y12 receptor blocker, administered just prior to reperfusion reduced but did not eliminate myocardial infarction in rabbits. Combining cangrelor with ischemic postconditioning offered no additional protection suggesting they protected by a similar mechanism. To determine if cangrelor’s protection might be additive to other cardioprotective interventions we tested cangrelor in combination with ischemic preconditioning, cariporide, a sodium-hydrogen exchange blocker, and mild hypothermia.

Methods

Open-chest rats underwent 30-min coronary occlusion/2-h reperfusion.

Results

Cangrelor, administered as a bolus (60 μg/kg) 10 min before reperfusion and continued as an infusion (6 μg/kg/min) for the duration of the experiment, decreased infarction from 45.3 % of risk zone in control hearts to 25.0 %. Combining cangrelor and ischemic preconditioning offered no additional protection. Mild hypothermia (32–33 °C) instituted by peritoneal lavage with cold saline just prior to coronary occlusion resulted in 25.2 % infarction, and combining cangrelor and hypothermia nearly halved infarction to 14.1 % of risk zone. Cariporide (0.5 mg/kg) just prior to occlusion resulted in 27.2 % infarction and 15.8 % when combined with cangrelor. Combining cangrelor, hypothermia and cariporide further halved infarction to only 6.3 %. We also tested another P2Y12 inhibitor ticagrelor which is chemically similar to cangrelor. Ticagrelor (20 mg/kg) fed 1 h prior to surgery reduced infarct size by an amount similar to that obtained with cangrelor (25.6 % infarction), and this protective effect was abolished by chelerythrine and wortmannin, thus implicating participation of PKC and PI3-kinase, resp., in signaling.

Conclusions

Cardioprotection from a P2Y12 receptor antagonist can be combined with at least 2 other strategies to magnify the protection. Combining multiple interventions that use different cardioprotective mechanisms could provide powerful protection against infarction in patients with acute coronary thrombosis.

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References

  1. Kitakaze M, Asakura M, Kim J, Shintani Y, Asanuma H, Hamasaki T, et al. Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials. Lancet. 2007;370:1483–93.

    Article  PubMed  CAS  Google Scholar 

  2. Mochly-Rosen D, Grimes KV. Myocardial salvage in acute myocardial infarction–challenges in clinical translation. J Mol Cell Cardiol. 2011;51:451–3.

    Article  PubMed  CAS  Google Scholar 

  3. Heusch G. Cardioprotection: chances and challenges of its translation to the clinic. Lancet. 2013;381:166–75.

    Article  PubMed  Google Scholar 

  4. Cohen MV, Downey JM. Is it time to translate ischemic preconditioning’s mechanism of cardioprotection into clinical practice? J Cardiovasc Pharmacol Ther. 2011;16:273–80.

    Article  PubMed  CAS  Google Scholar 

  5. 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.

    Article  PubMed  CAS  Google Scholar 

  6. Roubille F, Lairez O, Mewton N, Rioufol G, Ranc S, Sanchez I, et al. Cardioprotection by clopidogrel in acute ST-elevated myocardial infarction patients: a retrospective analysis. Basic Res Cardiol. 2012;107:275.

    Article  PubMed  Google Scholar 

  7. 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;18:251–62.

    Article  PubMed  CAS  Google Scholar 

  8. Yang X-M, Liu Y, Cui L, Yang X, Liu Y, Tandon N, et al. Two classes of anti-platelet drugs reduce anatomical infarct size in monkey hearts. Cardiovasc Drugs Ther. 2013;27:109–15.

    Article  PubMed  CAS  Google Scholar 

  9. Xu Z, Jiao Z, Cohen MV, Downey JM. Protection from AMP 579 can be added to that from either cariporide or ischemic preconditioning in ischemic rabbit heart. J Cardiovasc Pharmacol. 2002;40:510–8.

    Article  PubMed  CAS  Google Scholar 

  10. Kristo G, Yoshimura Y, Ferraris SP, Jahania SA, Mentzer Jr RM, Lasley RD. The preischemic combination of the sodium-hydrogen exchanger inhibitor cariporide and the adenosine agonist AMP579 acts additively to reduce porcine myocardial infarct size. J Am Coll Surg. 2004;199:586–94.

    Article  PubMed  Google Scholar 

  11. Miki T, Liu GS, Cohen MV, Downey JM. Mild hypothermia reduces infarct size in the beating rabbit heart: a practical intervention for acute myocardial infarction? Basic Res Cardiol. 1998;93:372–83.

    Article  PubMed  CAS  Google Scholar 

  12. Hausenloy DJ, Wynne AM, Yellon DM. Ischemic preconditioning targets the reperfusion phase. Basic Res Cardiol. 2007;102:445–52.

    Article  PubMed  CAS  Google Scholar 

  13. National Research Council. Guide for the Care and Use of Laboratory Animals. 7th ed. Washington, DC: National Academy Press; 1996.

    Google Scholar 

  14. Yang X-M, Liu Y, Liu Y, Tandon N, Kambayashi J, Downey JM, et al. Attenuation of infarction in cynomolgus monkeys: preconditioning and postconditioning. Basic Res Cardiol. 2010;105:119–28.

    Article  PubMed  Google Scholar 

  15. Sugidachi A, Asai F, Ogawa T, Inoue T, Koike H. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol. 2000;129:1439–46.

    Article  PubMed  CAS  Google Scholar 

  16. Ytrehus K, Liu Y, Tsuchida A, Miura T, Liu GS, Yang X-M, et al. Rat and rabbit heart infarction: effects of anesthesia, perfusate, risk zone, and method of infarct sizing. Am J Physiol. 1994;267:H2383–90.

    PubMed  CAS  Google Scholar 

  17. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L’Huillier I, et al. Postconditioning the human heart. Circulation. 2005;112:2143–8.

    Article  PubMed  Google Scholar 

  18. Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, McCabe CH, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009;373:723–31.

    Article  PubMed  CAS  Google Scholar 

  19. Kohli P, Wallentin L, Reyes E, Horrow J, Husted S, Angiolillo DJ, et al. Reduction in first and recurrent cardiovascular events with ticagrelor compared with clopidogrel in the PLATO study. Circulation. 2013;127:673–80.

    Google Scholar 

  20. Tissier R, Hamanaka K, Kuno A, Parker JC, Cohen MV, Downey JM. Total liquid ventilation provides ultra-fast cardioprotective cooling. J Am Coll Cardiol. 2007;49:601–5.

    Article  PubMed  Google Scholar 

  21. Yang X, Liu Y, Yang X-M, Hu F, Cui L, Swingle MR, et al. Cardioprotection by mild hypothermia during ischemia involves preservation of ERK activity. Basic Res Cardiol. 2011;106:421–30.

    Article  PubMed  CAS  Google Scholar 

  22. Liu GS, Thornton J, Van Winkle DM, Stanley AWH, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation. 1991;84:350–6.

    Article  PubMed  CAS  Google Scholar 

  23. Sibbing D, Bernlochner I, Schulz S, Massberg S, Schömig A, Mehilli J, et al. Prognostic value of a high on-clopidogrel treatment platelet reactivity in bivalirudin versus abciximab treated non-ST-segment elevation myocardial infarction patients: ISAR-REACT 4 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment-4) platelet substudy. J Am Coll Cardiol. 2012;60:369–77.

    Article  PubMed  CAS  Google Scholar 

  24. Parodi G, Valenti R, Bellandi B, Migliorini A, Marcucci R, Comito V, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol. 2013;61:1601–6.

    Article  PubMed  CAS  Google Scholar 

  25. Mentzer Jr RM, Bartels C, Bolli R, Boyce S, Buckberg GD, Chaitman B, et al. Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study. Ann Thorac Surg. 2008;85:1261–70.

    Article  PubMed  Google Scholar 

  26. Shao Z-H, Sharp WW, Wojcik KR, Li C-Q, Han M, Chang W-T, et al. Therapeutic hypothermia cardioprotection via Akt- and nitric oxide-mediated attenuation of mitochondrial oxidants. Am J Physiol. 2010;298:H2164–73.

    CAS  Google Scholar 

  27. Miura T, Ogawa T, Suzuki K, Goto M, Shimamoto K. Infarct size limitation by a new Na+-H+ exchange inhibitor, Hoe 642: difference from preconditioning in the role of protein kinase C. J Am Coll Cardiol. 1997;29:693–701.

    Article  PubMed  CAS  Google Scholar 

  28. Miura T, Liu Y, Goto M, Tsuchida A, Miki T, Nakano A, et al. Mitochondrial ATP-sensitive K+ channels play a role in cardioprotection by Na+-H+ exchange inhibition against ischemia/reperfusion injury. J Am Coll Cardiol. 2001;37:957–63.

    Article  PubMed  CAS  Google Scholar 

  29. Toda T, Kadono T, Hoshiai M, Eguchi Y, Nakazawa S, Nakazawa H, et al. Na+/H+ exchanger inhibitor cariporide attenuates the mitochondrial Ca2+ overload and PTP opening. Am J Physiol. 2007;293:H3517–23.

    CAS  Google Scholar 

  30. Chien GL, Wolff RA, Davis RF, VanWinkle DM. “Normothermic range“ temperature affects myocardial infarct size. Cardiovasc Res. 1994;28:1014–7.

    Article  PubMed  CAS  Google Scholar 

  31. Tissier R, Cohen MV, Downey JM. Protecting the acutely ischemic myocardium beyond reperfusion therapies: are we any closer to realizing the dream of infarct size elimination? Arch Mal Coeur Vaiss. 2007;100:794–802.

    PubMed  CAS  Google Scholar 

  32. Karmazyn M. NHE-1: still a viable therapeutic target. J Mol Cell Cardiol. 2013 in press

  33. Avkiran M, Marber MS. Na+/H+ exchange inhibitors for cardioprotective therapy: progress, problems and prospects. J Am Coll Cardiol. 2002;39:747–53.

    Article  PubMed  CAS  Google Scholar 

  34. Kunichika H, Ben-Yehuda O, Lafitte S, Kunichika N, Peters B, DeMaria AN. Effects of glycoprotein IIb/IIIa inhibition on microvascular flow after coronary reperfusion. A quantitative myocardial contrast echocardiography study J Am Coll Cardiol. 2004;43:276–83.

    Article  CAS  Google Scholar 

  35. Lefer AM, Campbell B, Scalia R, Lefer DJ. Synergism between platelets and neutrophils in provoking cardiac dysfunction after ischemia and reperfusion: role of selectins. Circulation. 1998;98:1322–8.

    Article  PubMed  CAS  Google Scholar 

  36. Campbell B, Chuhran CM, Lefer DJ, Lefer AM. Cardioprotective effects of abciximab (ReoPro) in an isolated perfused rat heart model of ischemia and reperfusion. Methods Find Exp Clin Pharmacol. 1999;21:529–34.

    Article  PubMed  CAS  Google Scholar 

  37. Freixa X, Bellera N, Ortiz-Pérez JT, Jiménez M, Paré C, Bosch X, et al. Ischaemic postconditioning revisited: lack of effects on infarct size following primary percutaneous coronary intervention. Eur Heart J. 2012;33:103–12.

    Article  PubMed  Google Scholar 

  38. 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.

    Article  PubMed  Google Scholar 

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Acknowledgments

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 kindly supplied by The Medicines Company, Parsippany, NJ.

Conflict of Interest

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Authors and Affiliations

  1. Department of Physiology, University of South Alabama, College of Medicine, Mobile, AL, 36688, USA

    Xi-Ming Yang, Lin Cui, James M. Downey & Michael V. Cohen

  2. Department of Medicine, University of South Alabama, College of Medicine, Mobile, AL, USA

    Ahmad Alhammouri & Michael V. Cohen

Authors
  1. Xi-Ming Yang
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  2. Lin Cui
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Correspondence to Michael V. Cohen.

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Yang, XM., Cui, L., Alhammouri, A. et al. Triple Therapy Greatly Increases Myocardial Salvage During Ischemia/Reperfusion in the in situ Rat Heart. Cardiovasc Drugs Ther 27, 403–412 (2013). https://doi.org/10.1007/s10557-013-6474-9

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