Skip to main content
Log in

The impact of irreproducibility and competing protection from P2Y12 antagonists on the discovery of cardioprotective interventions

  • Invited Review
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Scientists and clinicians have been concerned by the lack of a clinically suitable strategy for cardioprotection in patients with acute myocardial infarction despite decades of intensive pre-clinical investigations and a surprising number of clinical trials based on those observations which have uniformly been disappointing. However, it would be a mistake to abandon this search. Rather it would be useful to examine these past efforts and determine reasons for the multiple failures. It appears that earlier clinical trials were often based on results from a single experimental laboratory, thus minimizing the importance of establishing reproducibility in multiple laboratories by multiple scientists and in multiple models. Clinical trials should be discouraged unless robust protection is demonstrated in pre-clinical testing. After approximately 2005 a loading dose of a platelet P2Y12 receptor antagonist became increasingly widespread in patients with acute myocardial infarction prior to revascularization and quickly became standard-of-care. These agents are now thought to be a cause of failure of recent clinical trials since these pleiotropic drugs also happen to be potent postconditioning mimetics. Thus, introduction of an additional cardioprotective strategy such as ischemic postconditioning which uses the same signaling pathway as these P2Y12 antagonists would be redundant and doomed to failure. Additive cardioprotection could be achieved only if the second intervention had a different mechanism of cardioprotection. This concept has been demonstrated in experimental animals. So lack of reproducibility of earlier studies and failure to examine interventions in experimental animals also treated with anti-platelet agents could well explain past failures. These realizations should clear the way for development of interventions which can be translated into successful clinical treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Reproduced with permission from Yang et al. [78]

Fig. 2

Modified from Yang et al. [75, 78]

Fig. 3

Reproduced with permission from Yang et al. [75]

Fig. 4

Modified from Yang et al. [76]

Similar content being viewed by others

References

  1. Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M (2005) Postconditioning inhibits mitochondrial permeability transition. Circulation 111:194–197. doi:10.1161/01.CIR.0000151290.04952.3B

    Article  CAS  PubMed  Google Scholar 

  2. Armstrong D, Summers C, Ewart L, Nylander S, Sidaway JE, van Giezen JJJ (2014) Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. J Cardiovasc Pharmacol Ther 19:209–219. doi:10.1177/1074248413511693

    Article  CAS  PubMed  Google Scholar 

  3. Bãr FW, Tzivoni D, Dirksen MT, Fernández-Ortiz A, Heyndrickx GR, Brachmann J, Reiber JHC, Avasthy N, Tatsuno J, Davies M, Hibberd MG, Krucoff MW (2006) Results of the first clinical study of adjunctive CAldaret (MCC-135) in patients undergoing primary percutaneous coronary intervention for ST-Elevation Myocardial Infarction: the randomized multicentre CASTEMI study. Eur Heart J 27:2516–2523. doi:10.1093/eurheartj/ehl304

    Article  PubMed  Google Scholar 

  4. Bell RM, Sivaraman V, Kunuthur SP, Cohen MV, Downey JM, Yellon DM (2015) Cardioprotective properties of the platelet P2Y12 receptor inhibitor, cangrelor: protective in diabetics and reliant upon the presence of blood. Cardiovasc Drugs Ther 29:415–418. doi:10.1007/s10557-015-6609-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, Price MJ, Leonardi S, Gallup D, Bramucci E, Radke PW, Widimský P, Tousek F, Tauth J, Spriggs D, McLaurin BT, Angiolillo DJ, Généreux P, Liu T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA (2013) Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 368:1303–1313. doi:10.1056/NEJMoa1300815

    Article  CAS  PubMed  Google Scholar 

  6. Birnbaum Y, Birnbaum GD, Birnbaum I, Nylander S, Ye Y (2016) Ticagrelor and rosuvastatin have additive cardioprotective effects via adenosine. Cardiovasc Drugs Ther 30:539–550. doi:10.1007/s10557-016-6701-2

    Article  CAS  PubMed  Google Scholar 

  7. Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, Jakubowski JA, Naganuma H, Winters KJ (2007) A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 153:66.e9–66.e16. doi:10.1016/j.ahj.2006.10.010

    Article  Google Scholar 

  8. Braunwald E, Kloner RA (1985) Myocardial reperfusion: a double-edged sword? J Clin Invest 76:1713–1719. doi:10.1172/JCI112160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cohen MV, Audia JP, Yang X-M, Crockett ES, Housley N, O’Donnell K, Ul Haq E, Downey JM, Alvarez DF (2017) Blocking caspase-1 at reperfusion adds to cardioprotection from platelet P2Y12 receptor antagonists. (Abst) Circulation 136 (in press)

  10. Cohen MV, Downey JM (2015) Signalling pathways and mechanisms of protection in pre- and postconditioning: historical perspective and lessons for the future. Br J Pharmacol 172:1913–1932. doi:10.1111/bph.12903

    Article  CAS  PubMed  Google Scholar 

  11. Cohen MV, Yang X-M, White J, Yellon DM, Bell RM, Downey JM (2016) Cangrelor-mediated cardioprotection requires platelets and sphingosine phosphorylation. Cardiovasc Drugs Ther 30:229–232. doi:10.1007/s10557-015-6633-2

    Article  CAS  PubMed  Google Scholar 

  12. Cung T-T, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, Bonnefoy-Cudraz E, Guérin P, Elbaz M, Delarche N, Coste P, Vanzetto G, Metge M, Aupetit J-F, Jouve B, Motreff P, Tron C, Labeque J-N, Steg PG, Cottin Y, Range G, Clerc J, Claeys MJ, Coussement P, Prunier F, Moulin F, Roth O, Belle L, Dubois P, Barragan P, Gilard M, Piot C, Colin P, De Poli F, Morice M-C, Ider O, Dubois-Randé J-L, Unterseeh T, Le Breton H, Béard T, Blanchard D, Grollier G, Malquarti V, Staat P, Sudre A, Elmer E, Hansson MJ, Bergerot C, Boussaha I, Jossan C, Derumeaux G, Mewton N, Ovize M (2015) Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med 373:1021–1031. doi:10.1056/NEJMoa1505489

    Article  CAS  PubMed  Google Scholar 

  13. Dangas G, Mehran R, Guagliumi G, Caixeta A, Witzenbichler B, Aoki J, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Rabbani LE, Parise H, Stone GW (2009) Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction) trial. J Am Coll Cardiol 54:1438–1446. doi:10.1016/j.jacc.2009.06.021

    Article  CAS  PubMed  Google Scholar 

  14. DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT (1980) Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 303:897–902. doi:10.1056/NEJM198010163031601

    Article  CAS  PubMed  Google Scholar 

  15. Downey JM, Cohen MV (2017) Letter by Downey and Cohen regarding article, “Protective effects of ticagrelor on myocardial injury after infarction”. Circulation 135:e1000–e1001. doi:10.1161/CIRCULATIONAHA.117.027207

    Article  PubMed  Google Scholar 

  16. Dwyer NB, Mikami Y, Hilland D, Aljizeeri A, Friedrich MG, Traboulsi M, Anderson TJ (2013) No cardioprotective benefit of ischemic postconditioning in patients with ST-segment elevation myocardial infarction. J Interv Cardiol 26:482–490. doi:10.1111/joic.12064

    Article  PubMed  Google Scholar 

  17. EMIP-FR group (2000) Effect of 48-h intravenous trimetazidine on short- and long-term outcomes of patients with acute myocardial infarction, with and without thrombolytic therapy: a double-blind, placebo-controlled, randomized trial. Eur Heart J 21:1537–1546. doi:10.1053/euhj.1999.2071

    Article  Google Scholar 

  18. Engstrøm T, Kelbæk H, Helqvist S, Høfsten DE, Kløvgaard L, Clemmensen P, Holmvang L, Jørgensen E, Pedersen F, Saunamaki K, Ravkilde J, Tilsted H-H, Villadsen A, Aarøe J, Jensen SE, Raungaard B, Bøtker HE, Terkelsen CJ, Maeng M, Kaltoft A, Krusell LR, Jensen LO, Velen KT, Kofoed KF, Torp-Pedersen C, Kyhl K, Nepper-Christensen L, Treiman M, Vejlstrup N, Ahtarovski K, Lønborg J, Køber L (2017) Effect of ischemic postconditioning during primary percutaneous coronary intervention for patients with ST-segment elevation myocardial infarction: a randomized clinical trial. JAMA Cardiol 2:490–497. doi:10.1001/jamacardio.2017.0022

    Article  PubMed  Google Scholar 

  19. ESPRIM Group (1994) The ESPRIM trial: short-term treatment of acute myocardial infarction with molsidomine. European Study of PRevention of Infarct with Molsidomine (ESPRIM) Group. Lancet 344:91–97. doi:10.1016/S0140-6736(94)91282-3

    Google Scholar 

  20. Favaretto E, Roffi M, Frigo AC, Lee MS, Marra MP, Napodano M, Tarantini G (2014) Meta-analysis of randomized trials of postconditioning in ST-elevation myocardial infarction. Am J Cardiol 114:946–952. doi:10.1016/j.amjcard.2014.06.026

    Article  PubMed  Google Scholar 

  21. Flaherty JT, Pitt B, Gruber JW, Heuser RR, Rothbaum DA, Burwell LR, George BS, Kereiakes DJ, Deitchman D, Gustafson N, Brinker JA, Becker LC, Mancini GBJ, Topol E, Werns SW (1994) Recombinant human superoxide dismutase (h-SOD) fails to improve recovery of ventricular function in patients undergoing angioplasty for acute myocardial infarction. Circulation 89:1982–1991. doi:10.1161/01.CIR.89.5.1982

    Article  CAS  PubMed  Google Scholar 

  22. Freixa X, Bellera N, Ortiz-Pérez JT, Jiménez M, Paré C, Bosch X, De Caralt TM, Betriu A, Masotti M (2012) Ischaemic postconditioning revisited: lack of effects on infarct size following primary percutaneous coronary intervention. Eur Heart J 33:103–112. doi:10.1093/eurheartj/ehr297

    Article  PubMed  Google Scholar 

  23. Goldbourt U, Behar S, Reicher-Reiss H, Zion M, Mandelzweig L, Kaplinsky E (1993) Early administration of nifedipine in suspected acute myocardial infarction. The Secondary Prevention Reinfarction Israel Nifedipine Trial 2 Study. Arch Intern Med 153:345–353. doi:10.1001/archinte.1993.00410030053008

    Article  CAS  PubMed  Google Scholar 

  24. Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R, Antonino MJ, Patil SB, Karunakaran A, Kereiakes DJ, Parris C, Purdy D, Wilson V, Ledley GS, Storey RF (2009) Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 120:2577–2585. doi:10.1161/CIRCULATIONAHA.109.912550

    Article  CAS  PubMed  Google Scholar 

  25. Hausenloy DJ, Barrabes JA, Bøtker HE, Davidson SM, Di Lisa F, Downey J, Engstrom T, Ferdinandy P, Carbrera-Fuentes HA, Heusch G, Ibanez B, Iliodromitis EK, Inserte J, Jennings R, Kalia N, Kharbanda R, Lecour S, Marber M, Miura T, Ovize M, Perez-Pinzon MA, Piper HM, Przyklenk K, Schmidt MR, Redington A, Ruiz-Meana M, Vilahur G, Vinten-Johansen J, Yellon DM, Garcia-Dorado D (2016) Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery. Basic Res Cardiol 111:70. doi:10.1007/s00395-016-0588-8

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hausenloy DJ, Botker HE, Engstrom T, Erlinge D, Heusch G, Ibanez B, Kloner RA, Ovize M, Yellon DM, Garcia-Dorado D (2017) Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations. Eur Heart J 38:935–941. doi:10.1093/eurheartj/ehw145

    PubMed  Google Scholar 

  27. Heusch G (2017) Critical issues for the translation of cardioprotection. Circ Res 120:1477–1486. doi:10.1161/CIRCRESAHA.117.310820

    Article  CAS  PubMed  Google Scholar 

  28. Heusch G (2015) Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 116:674–699. doi:10.1161/CIRCRESAHA.116.305348

    Article  CAS  PubMed  Google Scholar 

  29. Heusch G, Gersh BJ (2017) The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J 38:774–784. doi:10.1093/eurheartj/ehw224

    PubMed  Google Scholar 

  30. Heusch G, Rassaf T (2016) Time to give up on cardioprotection? A critical appraisal of clinical studies on ischemic pre-, post-, and remote conditioning. Circ Res 119:676–695. doi:10.1161/CIRCRESAHA.116.308736

    Article  CAS  PubMed  Google Scholar 

  31. Jennings RB, Sommers HM, Smyth GA, Flack HA, Linn H (1960) Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Arch Pathol 70:68–78

    CAS  PubMed  Google Scholar 

  32. Jones SP, Tang X-L, Guo Y, Steenbergen C, Lefer DJ, Kukreja RC, Kong M, Li Q, Bhushan S, Zhu X, Du J, Nong Y, Stowers HL, Kondo K, Hunt GN, Goodchild TT, Orr A, Chang CC, Ockaili R, Salloum FN, Bolli R (2015) The NHLBI-sponsored Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR). A new paradigm for rigorous, accurate, and reproducible evaluation of putative infarct-sparing interventions in mice, rabbits, and pigs. Circ Res 116:572–586. doi:10.1161/CIRCRESAHA.116.305462

    Article  CAS  PubMed  Google Scholar 

  33. Kitakaze M, Asakura M, Kim J, Shintani Y, Asanuma H, Hamasaki T, Seguchi O, Myoishi M, Minamino T, Ohara T, Nagai Y, Nanto S, Watanabe K, Fukuzawa S, Hirayama A, Nakamura N, Kimura K, Fujii K, Ishihara M, Saito Y, Tomoike H, Kitamura S (2007) Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials. Lancet 370:1483–1493. doi:10.1016/S0140-6736(07)61634-1

    Article  CAS  PubMed  Google Scholar 

  34. Klein HH, Bohle RM, Pich S, Lindert-Heimberg S, Wollenweber J, Schade-Brittinger C, Nebendahl K (1998) Time-dependent protection by Na+/H+ exchange inhibition in a regionally ischemic, reperfused porcine heart preparation with low residual blood flow. J Mol Cell Cardiol 30:795–801. doi:10.1006/jmcc.1998.0644

    Article  CAS  PubMed  Google Scholar 

  35. Klein HH, Pich S, Bohle RM, Wollenweber J, Nebendahl K (1995) Myocardial protection by Na+–H+ exchange inhibition in ischemic, reperfused porcine hearts. Circulation 92:912–917. doi:10.1161/01.CIR.92.4.912

    Article  CAS  PubMed  Google Scholar 

  36. Kloner RA, Forman MB, Gibbons RJ, Ross AM, Alexander RW, Stone GW (2006) Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial. Eur Heart J 27:2400–2405. doi:10.1093/eurheartj/ehl094

    Article  CAS  PubMed  Google Scholar 

  37. Kohli P, Wallentin L, Reyes E, Horrow J, Husted S, Angiolillo DJ, Ardissino D, Maurer G, Morais J, Nicolau JC, Oto A, Storey RF, James SK, Cannon CP (2013) Reduction in first and recurrent cardiovascular events with ticagrelor compared with clopidogrel in the PLATO study. Circulation 127:673–680. doi:10.1161/CIRCULATIONAHA.112.124248

    Article  CAS  PubMed  Google Scholar 

  38. Koul S, Smith JG, Scherstén F, James S, Lagerqvist B, Erlinge D (2011) Effect of upstream clopidogrel treatment in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Eur Heart J 32:2989–2997. doi:10.1093/eurheartj/ehr202

    Article  CAS  PubMed  Google Scholar 

  39. Kuno A, Critz SD, Cui L, Solodushko V, Yang X-M, Krahn T, Albrecht B, Philipp S, Cohen MV, Downey JM (2007) Protein kinase C protects preconditioned rabbit hearts by increasing sensitivity of adenosine A2b-dependent signaling during early reperfusion. J Mol Cell Cardiol 43:262–271. doi:10.1016/j.yjmcc.2007.05.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lefer DJ, Marbán E (2017) Is cardioprotection dead? Circulation 136:98–109. doi:10.1161/CIRCULATIONAHA.116.027039

    Article  PubMed  Google Scholar 

  41. Lewis BS, Mehta SR, Fox KAA, Halon DA, Zhao F, Peters RJG, Keltai M, Budaj A, Yusuf S (2005) Benefit of clopidogrel according to timing of percutaneous coronary intervention in patients with acute coronary syndromes: further results from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Am Heart J 150:1177–1184. doi:10.1016/j.ahj.2005.01.044

    Article  CAS  PubMed  Google Scholar 

  42. Lim SY, Davidson SM, Hausenloy DJ, Yellon DM (2007) Preconditioning and postconditioning: the essential role of the mitochondrial permeability transition pore. Cardiovasc Res 75:530–535. doi:10.1016/j.cardiores.2007.04.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Limalanathan S, Andersen GØ, Kløw N-E, Abdelnoor M, Hoffmann P, Eritsland J (2014) Effect of ischemic postconditioning on infarct size in patients with ST-elevation myocardial infarction treated by primary PCI: results of the POSTEMI (POstconditioning in ST-Elevation Myocardial Infarction) randomized trial. J Am Heart Assoc 3:e000679. doi:10.1161/JAHA.113.000679

    Article  PubMed  PubMed Central  Google Scholar 

  44. Lønborg J, Kelbæk H, Vejlstrup N, Jørgensen E, Helqvist S, Saunamäki K, Clemmensen P, Holmvang L, Treiman M, Jensen JS, Engstrøm T (2010) Cardioprotective effects of ischemic postconditioning in patients treated with primary percutaneous coronary intervention, evaluated by magnetic resonance. Circ Cardiovasc Interv 3:34–41. doi:10.1161/CIRCINTERVENTIONS.109.905521

    Article  PubMed  Google Scholar 

  45. Mahaffey KW, Granger CB, Nicolau JC, Ruzyllo W, Weaver WD, Theroux P, Hochman JS, Filloon TG, Mojcik CF, Todaro TG, Armstrong PW (2003) Effect of pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to fibrinolysis in acute myocardial infarction: the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) trial. Circulation 108:1176–1183. doi:10.1161/01.CIR.0000087404.53661.F8

    Article  CAS  PubMed  Google Scholar 

  46. Mahaffey KW, Puma JA, Barbagelata NA, DiCarli MF, Leesar MA, Browne KF, Eisenberg PR, Bolli R, Casas AC, Molina-Viamonte V, Orlandi C, Blevins R, Gibbons RJ, Califf RM, Granger CB (1999) Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction. Results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial. J Am Coll Cardiol 34:1711–1720. doi:10.1016/S0735-1097(99)00418-0

    Article  CAS  PubMed  Google Scholar 

  47. Maroko PR, Kjekshus JK, Sobel BE, Watanabe T, Covell JW, Ross J Jr, Braunwald E (1971) Factors influencing infarct size following experimental coronary artery occlusions. Circulation 43:67–82. doi:10.1161/01.CIR.43.1.67

    Article  CAS  PubMed  Google Scholar 

  48. Maroko PR, Libby P, Bloor CM, Sobel BE, Braunwald E (1972) Reduction by hyaluronidase of myocardial necrosis following coronary artery occlusion. Circulation 46:430–437. doi:10.1161/01.CIR.46.3.430

    Article  CAS  PubMed  Google Scholar 

  49. Mehta SR, Yusuf S, Peters RJG, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H-J, Zhao F, Chrolavicius S, Copland I, Fox KAA (2001) Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 358:527–533. doi:10.1016/S0140-6736(01)05701-4

    Article  CAS  PubMed  Google Scholar 

  50. Miki T, Liu GS, Cohen MV, Downey JM (1998) Mild hypothermia reduces infarct size in the beating rabbit heart: a practical intervention for acute myocardial infarction? Basic Res Cardiol 93:372–383. doi:10.1007/s003950050105

    Article  CAS  PubMed  Google Scholar 

  51. Mirabet M, Garcia-Dorado D, Inserte J, Barrabés JA, Lidón R-M, Soriano B, Azevedo M, Padilla F, Agulló L, Ruiz-Meana M, Massaguer A, Pizcueta P, Soler-Soler J (2002) Platelets activated by transient coronary occlusion exacerbate ischemia-reperfusion injury in rat hearts. Am J Physiol 283:H1134–H1141. doi:10.1152/ajpheart.00065.2002

    CAS  Google Scholar 

  52. Miura T, Downey JM, Ooiwa H, Ogawa S, Adachi T, Noto T, Shizukuda Y, Iimura O (1989) Progression of myocardial infarction in a collateral flow deficient species. Jpn Heart J 30:695–708. doi:10.1536/ihj.30.695

    Article  CAS  PubMed  Google Scholar 

  53. Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, McCabe CH, Antman EM (2009) Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 373:723–731. doi:10.1016/S0140-6736(09)60441-4

    Article  CAS  PubMed  Google Scholar 

  54. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136. doi:10.1161/01.CIR.74.5.1124

    Article  CAS  PubMed  Google Scholar 

  55. Ottani F, Latini R, Staszewsky L, La Vecchia L, Locuratolo N, Sicuro M, Masson S, Barlera S, Milani V, Lombardi M, Costalunga A, Mollichelli N, Santarelli A, De Cesare N, Sganzerla P, Boi A, Maggioni AP, Limbruno U (2016) Cyclosporine A in reperfused myocardial infarction: the multicenter, controlled, open-label CYCLE trial. J Am Coll Cardiol 67:365–374. doi:10.1016/j.jacc.2015.10.081

    Article  CAS  PubMed  Google Scholar 

  56. Patti G, Bárczi G, Orlic D, Mangiacapra F, Colonna G, Pasceri V, Barbato E, Merkely B, Édes I, Ostojic M, Wijns W, Di Sciascio G (2011) 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 Reduction of MYocardial Damage during Angioplasty-Myocardial Infarction) randomized study. J Am Coll Cardiol 58:1592–1599. doi:10.1016/j.jacc.2011.06.044

    Article  CAS  PubMed  Google Scholar 

  57. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, André-Fouët X, Revel D, Kirkorian G, Monassier J-P, Derumeaux G, Ovize M (2008) Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 359:473–481. doi:10.1056/NEJMoa071142

    Article  CAS  PubMed  Google Scholar 

  58. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW (2005) A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J Am Coll Cardiol 45:1775–1780. doi:10.1016/j.jacc.2005.02.061

    Article  CAS  PubMed  Google Scholar 

  59. Roubille F, Lairez O, Mewton N, Rioufol G, Ranc S, Sanchez I, Cung TT, Elbaz M, Piot C, Ovize M (2012) Cardioprotection by clopidogrel in acute ST-elevated myocardial infarction patients: a retrospective analysis. Basic Res Cardiol 107:275. doi:10.1007/s00395-012-0275-3

    Article  PubMed  Google Scholar 

  60. Rusnak JM, Kopecky SL, Clements IP, Gibbons RJ, Holland AE, Peterman HS, Martin JS, Saoud JB, Feldman RL, Breisblatt WM, Simons M, Gessler CJ Jr, Yu AS (2001) An anti-CD11/CD18 monoclonal antibody in patients with acute myocardial infarction having percutaneous transluminal coronary angioplasty (the FESTIVAL study). Am J Cardiol 88:482–487. doi:10.1016/S0002-9149(01)01723-4

    Article  CAS  PubMed  Google Scholar 

  61. Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Lewis BS, Murphy SA, McCabe CH, Braunwald E (2005) Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 294:1224–1232. doi:10.1001/jama.294.10.1224

    Article  CAS  PubMed  Google Scholar 

  62. Skyschally A, Schulz R, Heusch G (2010) Cyclosporine A at reperfusion reduces infarct size in pigs. Cardiovasc Drugs Ther 24:85–87. doi:10.1007/s10557-010-6219-y

    Article  PubMed  PubMed Central  Google Scholar 

  63. Sörensson P, Saleh N, Bouvier F, Böhm F, Settergren M, Caidahl K, Tornvall P, Arheden H, Rydén L, Pernow J (2010) Effect of postconditioning on infarct size in patients with ST elevation myocardial infarction. Heart 96:1710–1715. doi:10.1136/hrt.2010.199430

    Article  PubMed  Google Scholar 

  64. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L’Huillier I, Aupetit J-F, Bonnefoy E, Finet G, André-Fouët X, Ovize M (2005) Postconditioning the human heart. Circulation 112:2143–2148. doi:10.1161/CIRCULATIONAHA.105.558122

    Article  PubMed  Google Scholar 

  65. Sugidachi A, Ogawa T, Kurihara A, Hagihara K, Jakubowski JA, Hashimoto M, Niitsu Y, Asai F (2007) The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel’s active metabolite. J Thromb Haemost 5:1545–1551. doi:10.1111/j.1538-7836.2007.02598.x

    Article  CAS  PubMed  Google Scholar 

  66. Tarantini G, Favaretto E, Marra MP, Frigo AC, Napodano M, Cacciavillani L, Giovagnoni A, Renda P, De Biasio V, Plebani M, Mion M, Zaninotto M, Isabella G, Bilato C, Iliceto S (2012) Postconditioning during coronary angioplasty in acute myocardial infarction: the POST-AMI trial. Int J Cardiol 162:33–38. doi:10.1016/j.ijcard.2012.03.136

    Article  PubMed  Google Scholar 

  67. Thibault H, Piot C, Staat P, Bontemps L, Sportouch C, Rioufol G, Cung TT, Bonnefoy E, Angoulvant D, Aupetit J-F, Finet G, André-Fouët X, Macia JC, Raczka F, Rossi R, Itti R, Kirkorian G, Derumeaux G, Ovize M (2008) Long-term benefit of postconditioning. Circulation 117:1037–1044. doi:10.1161/CIRCULATIONAHA.107.729780

    Article  CAS  PubMed  Google Scholar 

  68. Thuny F, Lairez O, Roubille F, Mewton N, Rioufol G, Sportouch C, Sanchez I, Bergerot C, Thibault H, Cung TT, Finet G, Argaud L, Revel D, Derumeaux G, Bonnefoy-Cudraz E, Elbaz M, Piot C, Ovize M, Croisille P (2012) Post-conditioning reduces infarct size and edema in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 59:2175–2181. doi:10.1016/j.jacc.2012.03.026

    Article  PubMed  Google Scholar 

  69. Tissier R, Hamanaka K, Kuno A, Parker JC, Cohen MV, Downey JM (2007) Total liquid ventilation provides ultra-fast cardioprotective cooling. J Am Coll Cardiol 49:601–605. doi:10.1016/j.jacc.2006.09.041

    Article  PubMed  Google Scholar 

  70. Vilahur G, Gutiérrez M, Casani L, Varela L, Capdevila A, Pons-Lladó G, Carreras F, Carlsson L, Hidalgo A, Badimon L (2016) Protective effects of ticagrelor on myocardial injury after infarction. Circulation 134:1708–1719. doi:10.1161/CIRCULATIONAHA.116.024014

    Article  CAS  PubMed  Google Scholar 

  71. Wall TC, Califf RM, Blankenship J, Talley JD, Tannenbaum M, Schwaiger M, Gacioch G, Cohen MD, Sanz M, Leimberger JD, Topol EJ (1994) Intravenous Fluosol in the treatment of acute myocardial infarction: results of the Thrombolysis and Angioplasty in Myocardial Infarction 9 trial. Circulation 90:114–120. doi:10.1161/01.CIR.90.1.114

    Article  CAS  PubMed  Google Scholar 

  72. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057. doi:10.1056/NEJMoa0904327

    Article  CAS  PubMed  Google Scholar 

  73. Witkowski A, Maciejewski P, Wąsek W, Malek ŁA, Niewada M, Kamiński B, Drzewiecki J, Kośmider M, Kubica J, Rużyłło W, Peruga JZ, Dudek D, Opolski G, Dobrzycki S, Gil RJ (2009) Influence of different antiplatelet treatment regimens for primary percutaneous coronary intervention on all-cause mortality. Eur Heart J 30:1736–1743. doi:10.1093/eurheartj/ehp114

    Article  CAS  PubMed  Google Scholar 

  74. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann F-J, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015. doi:10.1056/NEJMoa0706482

    Article  CAS  PubMed  Google Scholar 

  75. Yang X-M, Cui L, Alhammouri A, Downey JM, Cohen MV (2013) Triple therapy greatly increases myocardial salvage during ischemia/reperfusion in the in situ rat heart. Cardiovasc Drugs Ther 27:403–412. doi:10.1007/s10557-013-6474-9

    Article  CAS  PubMed  Google Scholar 

  76. Yang X-M, Cui L, White J, Kuck J, Ruchko MV, Wilson GL, Alexeyev M, Gillespie MN, Downey JM, Cohen MV (2015) Mitochondrially targeted Endonuclease III has a powerful anti-infarct effect in an in vivo rat model of myocardial ischemia/reperfusion. Basic Res Cardiol 110:3. doi:10.1007/s00395-014-0459-0

    Article  PubMed  PubMed Central  Google Scholar 

  77. Yang X-M, Downey JM, Cohen MV, Housley NA, Alvarez DF, Audia JP (2017) The highly selective caspase-1 inhibitor VX-765 provides additive protection against myocardial infarction in rat hearts when combined with a platelet inhibitor. J Cardiovasc Pharmacol Ther. doi:10.1177/1074248417702890

    PubMed  Google Scholar 

  78. Yang X-M, Liu Y, Cui L, Yang X, Liu Y, Tandon N, Kambayashi J, Downey JM, Cohen MV (2013) Platelet P2Y12 blockers confer direct postconditioning-like protection in reperfused rabbit hearts. J Cardiovasc Pharmacol Ther 18:251–262. doi:10.1177/1074248412467692

    Article  CAS  PubMed  Google Scholar 

  79. Yang X-M, Liu Y, Cui L, Yang X, Liu Y, Tandon N, Kambayashi J, Downey JM, Cohen MV (2013) Two classes of anti-platelet drugs reduce anatomical infarct size in monkey hearts. Cardiovasc Drugs Ther 27:109–115. doi:10.1007/s10557-012-6436-7

    Article  CAS  PubMed  Google Scholar 

  80. Yang X-M, Proctor JB, Cui L, Krieg T, Downey JM, Cohen MV (2004) Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. J Am Coll Cardiol 44:1103–1110. doi:10.1016/j.jacc.2004.05.060

    Article  PubMed  Google Scholar 

  81. Ye Y, Birnbaum GD, Perez-Polo JR, Nanhwan MK, Nylander S, Birnbaum Y (2015) Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction. Arterioscler Thromb Vasc Biol 35:1805–1814. doi:10.1161/ATVBAHA.115.305655

    Article  CAS  PubMed  Google Scholar 

  82. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494–502. doi:10.1056/NEJMoa010746

    Article  CAS  PubMed  Google Scholar 

  83. Zeymer U, Arntz H-R, Mark B, Fichtlscherer S, Werner G, Schöller R, Zahn R, Diller F, Darius H, Dill T, Huber K (2012) Efficacy and safety of a high loading dose of clopidogrel administered prehospitally to improve primary percutaneous coronary intervention in acute myocardial infarction: the randomized CIPAMI trial. Clin Res Cardiol 101:305–312. doi:10.1007/s00392-011-0393-1

    Article  CAS  PubMed  Google Scholar 

  84. Zeymer U, Suryapranata H, Monassier JP, Opolski G, Davies J, Rasmanis G, Linssen G, Tebbe U, Schröder R, Tiemann R, Machnig T, Neuhaus K-L (2001) The Na+/H+ exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction. Results of the Evaluation of the Safety and Cardioprotective effects of eniporide in Acute Myocardial Infarction (ESCAMI) trial. J Am Coll Cardiol 38:1644–1650i. doi:10.1016/S0735-1097(01)01608-4

    Article  CAS  PubMed  Google Scholar 

  85. Zhao Z-Q, Corvera JS, Halkos ME, Kerendi F, Wang N-P, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol 285:H579–H588. doi:10.1152/ajpheart.01064.2002

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael V. Cohen.

Ethics declarations

Conflict of interest

There are no conflicts of interest.

Study involving human and/or animal participants

The manuscript does not contain patient data or description of new clinical studies. No new animal studies are described.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cohen, M.V., Downey, J.M. The impact of irreproducibility and competing protection from P2Y12 antagonists on the discovery of cardioprotective interventions. Basic Res Cardiol 112, 64 (2017). https://doi.org/10.1007/s00395-017-0653-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-017-0653-y

Keywords

Navigation