Cardiovascular Drugs and Therapy

, Volume 31, Issue 1, pp 53–61 | Cite as

Cardioprotection: Where to from here?

  • Robert A. Kloner
  • Sharon L. Hale
  • Wangde Dai
  • Jianru Shi


The size of the myocardial infarction remains an important therapeutic target, because heart attack size correlates with mortality and heart failure. In this era, myocardial infarct size is reduced primarily by timely reperfusion of the infarct related coronary artery. Whereas numerous pre-clinical studies have shown that certain pharmacologic agents and therapeutic maneuvers reduce myocardial infarction size greater than reperfusion alone, very few of these therapies have translated to successful clinical trials or standard clinical use. In this review we discuss both the recent successes as well as recent disappointments, and describe some of the newer potential therapies from the preclinical literature that have not yet been tested in clinical trials.


Acute myocardial infarction ST elevation myocardial infarction Myocardial infarct size reduction Beta blockade Adenosine Hypothermia 


  1. 1.
    Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics: 2015 update: a report from the American Heart Association. Circulation. 2016;133(4):e38–360.CrossRefPubMedGoogle Scholar
  2. 2.
    Boden H, Ahmed TA, Velders MA, et al. Peak and fixed-time high-sensitive troponin for prediction of infarct size, impaired left ventricular function, and adverse outcomes in patients with first ST-segment elevation myocardial infarction receiving percutaneous coronary intervention. Am J Cardiol. 2013;111(10):1387–93.CrossRefPubMedGoogle Scholar
  3. 3.
    Turer AT, Mahaffey KW, Gallup D, et al. Enzyme estimates of infarct size correlate with functional and clinical outcomes in the setting of ST-segment elevation myocardial infarction. Curr Control Trials Cardiovasc Med. 2005;6:12.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Menees DS, Peterson ED, Wang Y, et al. Door-to-balloon time and mortality among patients undergoing primary PCI. N Engl J Med. 2013;369(10):901–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Schwartz Longacre L, Kloner RA, Arai AE, et al. New horizons in cardioprotection: recommendations from the 2010 National Heart, Lung, and Blood Institute workshop. Circulation. 2011;124(10):1172–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Heusch G. Cardioprotection: chances and challenges of its translation to the clinic. Lancet. 2013;381(9861):166–75.CrossRefPubMedGoogle Scholar
  7. 7.
    Hausenloy DJ, Bøtker HE, Condorelli G, et al. Translating cardioprotection for patient benefit: position paper from the working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res. 2013;98(1):7–27.Google Scholar
  8. 8.
    Lecour S, Bøtker HE, Condorelli G, et al. ESC working group cellular biology of the heart: position paper: improving the preclinical assessment of novel cardioprotective therapies. Cardiovasc Res. 2014;104(3):399–411.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ibáñez B, Heusch G, Ovize M, Van de Werf F. Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol. 2015;65(14):1454–71.CrossRefPubMedGoogle Scholar
  10. 10.
    Heusch G, Gersh BJ. The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J 2016;pii:ehw224.Google Scholar
  11. 11.
    Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357(11):1121–35.CrossRefPubMedGoogle Scholar
  12. 12.
    Gerczuk PZ, Kloner RA. An update on cardioprotection: a review of the latest adjunctive therapies to limit myocardial infarction size in clinical trials. J Am Coll Cardiol. 2012;59(11):969–78.CrossRefPubMedGoogle Scholar
  13. 13.
    Roubille F, Mewton N, Elbaz M, et al. No post-conditioning in the human heart with thrombolysis in myocardial infarction flow 2-3 on admission. Eur Heart J. 2014;35(25):1675–82.CrossRefPubMedGoogle Scholar
  14. 14.
    Freixa X, Bellera N, Ortiz-Pérez JT, et al. Ischaemic postconditioning revisited: lack of effects on infarct size following primary percutaneous coronary intervention. Eur Heart J. 2012;33(1):103–12.CrossRefPubMedGoogle Scholar
  15. 15.
    Hahn JY, Song YB, Kim EK, et al. Ischemic postconditioning during primary percutaneous coronary intervention: the effects of postconditioning on myocardial reperfusion in patients with ST-segment elevation myocardial infarction (POST) randomized trial. Circulation. 2013;128(17):1889–96.CrossRefPubMedGoogle Scholar
  16. 16.
    Cung TT, Morel O, Cayla G, et al. Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med. 2015;373(11):1021–31.CrossRefPubMedGoogle Scholar
  17. 17.
    Ottani F, Latini R, Staszewsky L, et al. Cyclosporine a in reperfused myocardial infarction: the multicenter, controlled, open-label CYCLE trial. J Am Coll Cardiol. 2016;67(4):365–74.CrossRefPubMedGoogle Scholar
  18. 18.
    Kumbhani, DH. The Third DANish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction: Ischemic Postconditioning During Primary PCI - DANAMI 3-iPOST - See:
  19. 19.
    Gibson CM, Giugliano RP, Kloner RA, et al. EMBRACE STEMI study: a phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention. Eur Heart J. 2016;37(16):1296–303.CrossRefPubMedGoogle Scholar
  20. 20.
    Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R. Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev. 2014;66(4):1142–74.CrossRefPubMedGoogle Scholar
  21. 21.
    Mahaffey KW, Puma JA, Barbagelata NA, et al. 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. 1999;34(6):1711–20.Google Scholar
  22. 22.
    Ross AM, Gibbons RJ, Stone GW, Kloner RA. Alexander RW; AMISTAD-II investigators. 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. 2005;45(11):1775–80.CrossRefPubMedGoogle Scholar
  23. 23.
    Kloner RA, Forman MB, Gibbons RJ, Ross AM, Alexander RW, Stone GW. Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial. Eur Heart J. 2006;27(20):2400–5.CrossRefPubMedGoogle Scholar
  24. 24.
    Garcia-Dorado D, García-del-Blanco B, Otaegui I, et al. Intracoronary injection of adenosine before reperfusion in patients with ST-segment elevation myocardial infarction: a randomized controlled clinical trial. Int J Cardiol. 2014;177(3):935–41.CrossRefPubMedGoogle Scholar
  25. 25.
    Desmet W, Bogaert J, Dubois C, et al. High-dose intracoronary adenosine for myocardial salvage in patients with acute ST-segment elevation myocardial infarction. Eur Heart J. 2011;32:867–77.CrossRefPubMedGoogle Scholar
  26. 26.
    Tian F, Chen YD, Lü SZ, et al. Intracoronary adenosine improves myocardial perfusion in late reperfused myocardial infarction. Chin Med J. 2008;121:195–9.PubMedGoogle Scholar
  27. 27.
    De Luca G, Iorio S, Venegoni L, Marino P. Evaluation of intracoronary adenosine to prevent periprocedural myonecrosis in elective percutaneous coronary intervention (from the PREVENT-ICARUS trial). Am J Cardiol. 2012;109:202–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Bulluck H, Sirker A, Loke YK, Garcia-Dorado D, Hausenloy DJ. Clinical benefit of adenosine as an adjunct to reperfusion in ST-elevation myocardial infarction patients: an updated meta-analysis of randomized controlled trials. Int J Cardiol. 2016;202:228–37.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993;87(3):893–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD. Myocardial protection by brief ischemia in noncardiac tissue. Circulation. 1996;94:2193–200.CrossRefPubMedGoogle Scholar
  31. 31.
    Birnbaum Y, Hale SL, Kloner RA. Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation. 1997;96(5):1641–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Bøtker HE, Kharbanda R, Schmidt MR, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010;375(9716):727–34.CrossRefPubMedGoogle Scholar
  33. 33.
    Sloth AD, Schmidt MR, Munk K, et al. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J. 2014;35(3):168–75.CrossRefPubMedGoogle Scholar
  34. 34.
    Yellon DM, Ackbarkhan AK, Balgobin V, et al. Remote ischemic conditioning reduces myocardial infarct size in STEMI patients treated by thrombolysis. J Am Coll Cardiol. 2015;65(25):2764–5.CrossRefPubMedGoogle Scholar
  35. 35.
    Prunier F, Angoulvant D, Saint Etienne C, et al. The RIPOST-MI study, assessing remote ischemic perconditioning alone or in combination with local ischemic postconditioning in ST-segment elevation myocardial infarction. Basic Res Cardiol. 2014;109(2):400.CrossRefPubMedGoogle Scholar
  36. 36.
    Crimi G, Pica S, Raineri C, et al. Remote ischemic post-conditioning of the lower limb during primary percutaneous coronary intervention safely reduces enzymatic infarct size in anterior myocardial infarction: a randomized controlled trial. JACC Cardiovasc Interv. 2013;6(10):1055–63.CrossRefPubMedGoogle Scholar
  37. 37.
    Sharma V, Marsh R, Cunniffe B, Cardinale M, Yellon DM, Davidson SM. From protecting the heart to improving athletic performance - the benefits of local and remote ischaemic preconditioning. Cardiovasc Drugs Ther. 2015;29:573–88.CrossRefPubMedCentralGoogle Scholar
  38. 38.
    Yamanaka T, Kawai Y, Miyoshi T, et al. Remote ischemic preconditioning reduces contrast-induced acute kidney injury in patients with ST-elevation myocardial infarction: a randomized controlled trial. Int J Cardiol. 2015;178:136–41.CrossRefPubMedGoogle Scholar
  39. 39.
    Zuo B, Wang F, Song Z, Xu M, Wang G. Using remote ischemic conditioning to reduce acute kidney injury in patients undergoing percutaneous coronary intervention: a meta-analysis. Curr Med Res Opin. 2015;31(9):1677–85.CrossRefPubMedGoogle Scholar
  40. 40.
    Yetgin T, Manintveld OC, Boersma E, et al. Remote ischemic conditioning in percutaneous coronary intervention and coronary artery bypass grafting. Circ J. 2012;76(10):2392–404.CrossRefPubMedGoogle Scholar
  41. 41.
    Le Page S, Bejan-Angoulvant T, Angoulvant D, Prunier F. Remote ischemic conditioning and cardioprotection: a systematic review and meta-analysis of randomized clinical trials. Basic Res Cardiol. 2015;110(2):11.CrossRefPubMedGoogle Scholar
  42. 42.
    Hausenloy DJ, Candilio L, Evans R, et al. Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med. 2015;373:1408–17.CrossRefPubMedGoogle Scholar
  43. 43.
    Meybohm P, Bein B, Brosteanu O, et al. A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med. 2015;373:1397–407.CrossRefPubMedGoogle Scholar
  44. 44.
    Hale SL, Kloner RA. Ischemic preconditioning and myocardial hypothermia in rabbits with prolonged coronary artery occlusion. Am J Phys. 1999;276(6 Pt 2):H2029–34.Google Scholar
  45. 45.
    Gho BC, van den Doel MA, Duncker DJ, Schoemaker RG, Verdouw PD. Myocardial infarct size limiting effect of low body temperature in rats depends on the duration of coronary artery occlusion. Circulation. 1997;96:1064.PubMedGoogle Scholar
  46. 46.
    Herring MJ, Dai W, Hale SL, Kloner RA. Rapid induction of hypothermia by the ThermoSuit system profoundly reduces infarct size and anatomic zone of no reflow following ischemia-reperfusion in rabbit and rat hearts. J Cardiovasc Pharmacol Ther. 2015;20(2):193–202.CrossRefPubMedGoogle Scholar
  47. 47.
    Götberg M, Olivecrona GK, Koul S, et al. A pilot study of rapid cooling by cold saline and endovascular cooling before reperfusion in patients with ST-elevation myocardial infarction. Circ Cardiovasc Interv. 2010;3(5):400–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Erlinge D, Götberg M, Lang I, et al. Rapid endovascular catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction. The CHILL-MI trial: a randomized controlled study of the use of central venous catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction. J Am Coll Cardiol. 2014;63(18):1857–65.CrossRefPubMedGoogle Scholar
  49. 49.
    Erlinge D, Götberg M, Noc M, et al. Therapeutic hypothermia for the treatment of acute myocardial infarction-combined analysis of the RAPID MI-ICE and the CHILL-MI trials. Ther Hypothermia Temp Manag. 2015;5(2):77–84.CrossRefPubMedGoogle Scholar
  50. 50.
    Nichol G, Strickland W, Shavelle D, et al. Prospective, multicenter, randomized, controlled pilot trial of peritoneal hypothermia in patients with ST-segment- elevation myocardial infarction. Circ Cardiovasc Interv. 2015;8(3):e001965.CrossRefPubMedGoogle Scholar
  51. 51.
    Maroko PR, Kjekshus JK, Sobel B, et al. Factors influencing infarct size following experimental coronary artery occlusions. Circulation. 1971;43:67–82.CrossRefPubMedGoogle Scholar
  52. 52.
    Rasmussen MM, Reimer KA, Kloner RA, et al. Infarct size reduction by propranolol before and after coronary ligation in dogs. Circulation. 1977;56:794–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Kloner RA, Fishbein MC, Braunwald E, et al. Effect of propranolol on mitochondrial morphology during acute myocardial ischemia. Am J Cardiol. 1978;41:880–6.CrossRefPubMedGoogle Scholar
  54. 54.
    Ibanez B, Macaya C, Sánchez-Brunete V, et al. Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the effect of metoprolol in cardioprotection during an acute myocardial infarction (METOCARD-CNIC) trial. Circulation. 2013;128(14):1495–503.CrossRefPubMedGoogle Scholar
  55. 55.
    García-Ruiz JM, Fernández-Jiménez R, García-Alvarez A, et al. Impact of the timing of metoprolol administration during STEMI on infarct size and ventricular function. J Am Coll Cardiol. 2016;67(18):2093–104.CrossRefPubMedGoogle Scholar
  56. 56.
    Kloner RA, Braunwald E. Intravenous Beta-blockade for limiting myocardial infarct size: rejuvenation of a concept. J Am Coll Cardiol. 2016;67(18):2105–7.CrossRefPubMedGoogle Scholar
  57. 57.
    Roolvink V, Ibanez J, Ottervanger J-P, et al. Early intravenous beta-blocker in patients with ST-segment elevation myocardial infarction before primary percutaneous coronary intervention. J Am Coll Cardiol. 2016;67:2705–15.Google Scholar
  58. 58.
    Newby LK. Intravenous beta-blockers for cardioprotection in STEMI. The Saga Continues J Am Coll Cardiol. 2016;67:2716–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Stone GW, Martin JL, de Boer MJ, et al. Effect of supersaturated oxygen delivery on infarct size after percutaneous coronary intervention in acute myocardial infarction. Circ Cardiovasc Interv. 2009;2(5):366–75.CrossRefPubMedGoogle Scholar
  60. 60.
    Kitakaze M, Asakura M, Kim J, 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(9597):1483–93.Google Scholar
  61. 61.
    Lønborg J, Vejlstrup N, Kelbæk H, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2012;33(12):1491–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Lønborg J, Kelbæk H, Vejlstrup N, et al. Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia. Circ Cardiovasc Interv. 2012;5(2):288–95.CrossRefPubMedGoogle Scholar
  63. 63.
    Kloner RA. Current state of clinical translation of cardioprotective agents for acute myocardial infarction. Circ Res. 2013;113(4):451–63.CrossRefPubMedGoogle Scholar
  64. 64.
    Hausenloy DJ, Botker HE, Engstrom T, et al. Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations. Eur Heart J 2016;pii:ehw 145.Google Scholar
  65. 65.
    Kleinbongard P, Heusch G. Extracellular signalling molecules in the ischaemic/reperfused heart - druggable and translatable for cardioprotection? Br J Pharmacol. 2015;172:2010–25.CrossRefPubMedGoogle Scholar
  66. 66.
    Jones SP, Tang XL, Guo Y, et al. 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. 2015;116:572–86.Google Scholar
  67. 67.
    Ong SB, Samangouei P, Kalkhoran SB, Hausenloy DJ. The mitochondrial permeability transition pore and its role in myocardial ischemia reperfusion injury. J Mol Cell Cardiol. 2015;78:23–34.CrossRefPubMedGoogle Scholar
  68. 68.
    Pell VR, Chouchani ET, Murphy MP, Brookes PS, Krieg T. Moving forwards by blocking back-flow: the Yin and Yang of MI therapy. Circ Res. 2016;118(5):898–906.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Shen Z, Ye C, McCain K, Greenberg ML. The role of cardiolipin in cardiovascular health. Biomed Res Int. 2015;2015:891707.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Zhang J, Nadtochiy SM, Urciuoli WR, Brookes PS. The cardioprotective compound cloxyquin uncouples mitochondria and induces autophagy. Am J Physiol Heart Circ Physiol. 2016;310(1):H29–38.CrossRefPubMedGoogle Scholar
  71. 71.
    Badalzadeh R, Yousefi B, Tajaddini A, Ahmadian N. Diosgenin-induced protection against myocardial ischaemia-reperfusion injury is mediated by mitochondrial KATP channels in a rat model. Perfusion. 2015;30(7):565–71.CrossRefPubMedGoogle Scholar
  72. 72.
    Meng G, Wang J, Xiao Y, et al. GYY4137 protects against myocardial ischemia and reperfusion injury by attenuating oxidative stress and apoptosis in rats. J Biol Res. 2015;29(3):203–13.Google Scholar
  73. 73.
    Zhao Y, Yang C, Organ C, et al. Design, synthesis, and cardioprotective effects of N-mercapto-based hydrogen sulfide donors. J Med Chem. 2015;58(18):7501–11.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Stratmann B, Tschoepe D. Heart in diabetes: not only a macrovascular disease. Diabetes Care. 2011;34(Suppl 2):S138–44.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Bhamra GS, Hausenloy DJ, Davidson SM. Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening. Basic Res Cardiol. 2008;103:274–84.CrossRefPubMedGoogle Scholar
  76. 76.
    Oidor-Chan VH, Hong E, Pérez-Severiano F, et al. Fenofibrate plus metformin produces cardioprotection in a type 2 diabetes and acute myocardial infarction model. PPAR Res. 2016;2016:8237264.Google Scholar
  77. 77.
    Lexis CP, van der Horst IC, Lipsic E. Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. JAMA. 2014;311:1526–35.CrossRefPubMedGoogle Scholar
  78. 78.
    Kloner RA, Rezkalla SH. Cardiac protection during acute myocardial infarction: where do we stand in 2004? J Am Coll Cardiol. 2004;44(2):276–86.CrossRefPubMedGoogle Scholar
  79. 79.
    Miura T, Miki T. Limitation of myocardial infarct size in the clinical setting: current status and challenges in translating animal experiments into clinical therapy. Basic Res Cardiol. 2008;103(6):501–13.CrossRefPubMedGoogle Scholar
  80. 80.
    Cohen MV, Downey JM. Status of P2Y12 treatment must be considered in evaluation of myocardial ischaemia/reperfusion injury. Cardiovasc Res. 2015;106(1):8.Google Scholar
  81. 81.
    Kloner RA, Schwartz LL. State of the science of cardioprotection: challenges and opportunities: proceedings of the 2010 NHLBI workshop on cardioprotection. J Cardiovasc Pharmacol Ther. 2011;16(3–4):223–32.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Cardiovascular Research InstituteHuntington Medical Research InstitutesPasadenaUSA
  2. 2.Division of Cardiovascular Medicine, Department of MedicineKeck School of Medicine at University of Southern CaliforniaLos AngelesUSA

Personalised recommendations