Official reprint from UpToDate®
www.uptodate.com ©2015 UpToDate®

Reperfusion injury of the heart

Duane S Pinto, MD, MPH
C Michael Gibson, MS, MD
Section Editors
Derek M Yellon, PhD, DSc, Hon FRCP, FACC, FESC
Derek J Hausenloy, MD, PhD, FRCP, FACC, FESC
Deputy Editor
Gordon M Saperia, MD, FACC


Myocardial injury in the setting of an acute myocardial infarction is the result of ischemic and reperfusion injury. Reperfusion therapies, including primary percutaneous coronary intervention and fibrinolytic therapy, promptly restore blood flow to ischemic myocardium and limit infarct size.

Paradoxically, however, the return of blood flow can result in additional cardiac damage and complications; this is referred to as reperfusion injury [1-3]. Effective therapies to reduce or prevent reperfusion injury have proven elusive. Despite an improved understanding of the pathophysiology of this process and encouraging preclinical trials of multiple agents, most of the clinical trials to prevent reperfusion injury have been disappointing [4-6]. Despite these problems, adjunctive therapies to limit reperfusion injury remain an active area of investigation.

This topic will discuss the pathophysiology and manifestations of reperfusion injury, as well as potential therapeutic strategies. The impact of the initial ischemic insult is discussed separately. (See "Angina pectoris: Chest pain caused by myocardial ischemia", section on 'Pathophysiology of myocardial ischemia'.)

General discussions of the use of reperfusion therapy in acute myocardial infarction are presented separately. (See "Primary percutaneous coronary intervention in acute ST elevation myocardial infarction: Determinants of outcome" and "Fibrinolytic therapy in acute ST elevation myocardial infarction: Initiation of therapy".)


In the first stage of acute myocardial infarction, myocardial cells are injured as the result of anoxia and the absence of new essential metabolic substrate. In the absence of reperfusion, and in the absence of an adequate collateral circulation, these injured cells die and scar tissue is formed.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Oct 2015. | This topic last updated: Nov 18, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2015 UpToDate, Inc.
  1. Simoons ML, Serruys PW, van den Brand M, et al. Early thrombolysis in acute myocardial infarction: limitation of infarct size and improved survival. J Am Coll Cardiol 1986; 7:717.
  2. White HD, Norris RM, Brown MA, et al. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med 1987; 317:850.
  3. Sheehan FH, Doerr R, Schmidt WG, et al. Early recovery of left ventricular function after thrombolytic therapy for acute myocardial infarction: an important determinant of survival. J Am Coll Cardiol 1988; 12:289.
  4. Bolli R, Becker L, Gross G, et al. Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res 2004; 95:125.
  5. Cannon RO 3rd. Mechanisms, management and future directions for reperfusion injury after acute myocardial infarction. Nat Clin Pract Cardiovasc Med 2005; 2:88.
  6. Ibáñez B, Heusch G, Ovize M, Van de Werf F. Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol 2015; 65:1454.
  7. Hausenloy DJ, Erik Bøtker H, 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; 98:7.
  8. Lønborg JT. Targeting reperfusion injury in the era of primary percutaneous coronary intervention: hope or hype? Heart 2015; 101:1612.
  9. Bell RM, Yellon DM. There is more to life than revascularization: therapeutic targeting of myocardial ischemia/reperfusion injury. Cardiovasc Ther 2011; 29:e67.
  10. Iliceto S, Galiuto L, Marchese A, et al. Analysis of microvascular integrity, contractile reserve, and myocardial viability after acute myocardial infarction by dobutamine echocardiography and myocardial contrast echocardiography. Am J Cardiol 1996; 77:441.
  11. Hoffmann R, Haager P, Lepper W, et al. Relation of coronary flow pattern to myocardial blush grade in patients with first acute myocardial infarction. Heart 2003; 89:1147.
  12. Fernández-Jiménez R, García-Prieto J, Sánchez-González J, et al. Pathophysiology Underlying the Bimodal Edema Phenomenon After Myocardial Ischemia/Reperfusion. J Am Coll Cardiol 2015; 66:816.
  13. Ladilov YV, Siegmund B, Balser C, Piper HM. Simulated ischemia increases the susceptibility of rat cardiomyocytes to hypercontracture. Circ Res 1997; 80:69.
  14. Meissner A, Morgan JP. Contractile dysfunction and abnormal Ca2+ modulation during postischemic reperfusion in rat heart. Am J Physiol 1995; 268:H100.
  15. Ladilov YV, Siegmund B, Piper HM. Protection of reoxygenated cardiomyocytes against hypercontracture by inhibition of Na+/H+ exchange. Am J Physiol 1995; 268:H1531.
  16. Piper HM, García-Dorado D, Ovize M. A fresh look at reperfusion injury. Cardiovasc Res 1998; 38:291.
  17. Bolli R, Jeroudi MO, Patel BS, et al. Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog. Proc Natl Acad Sci U S A 1989; 86:4695.
  18. Verma S, Fedak PW, Weisel RD, et al. Fundamentals of reperfusion injury for the clinical cardiologist. Circulation 2002; 105:2332.
  19. Toyokuni S. Reactive oxygen species-induced molecular damage and its application in pathology. Pathol Int 1999; 49:91.
  20. Salvemini D, Cuzzocrea S. Superoxide, superoxide dismutase and ischemic injury. Curr Opin Investig Drugs 2002; 3:886.
  21. Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res 2004; 61:481.
  22. Kempf T, Eden M, Strelau J, et al. The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res 2006; 98:351.
  23. Namiuchi S, Kagaya Y, Ohta J, et al. High serum erythropoietin level is associated with smaller infarct size in patients with acute myocardial infarction who undergo successful primary percutaneous coronary intervention. J Am Coll Cardiol 2005; 45:1406.
  24. Becker LC. Myocardial Reperfusion Injury. J Thromb Thrombolysis 1997; 4:43.
  25. Engler RL, Schmid-Schönbein GW, Pavelec RS. Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog. Am J Pathol 1983; 111:98.
  26. Carden DL, Granger DN. Pathophysiology of ischaemia-reperfusion injury. J Pathol 2000; 190:255.
  27. Panés J, Perry M, Granger DN. Leukocyte-endothelial cell adhesion: avenues for therapeutic intervention. Br J Pharmacol 1999; 126:537.
  28. Xu Y, Huo Y, Toufektsian MC, et al. Activated platelets contribute importantly to myocardial reperfusion injury. Am J Physiol Heart Circ Physiol 2006; 290:H692.
  29. Rezkalla SH, Kloner RA. No-reflow phenomenon. Circulation 2002; 105:656.
  30. Saraste A, Pulkki K, Kallajoki M, et al. Apoptosis in human acute myocardial infarction. Circulation 1997; 95:320.
  31. Umansky SR, Cuenco GM, Khutzian SS, et al. Post-ischemic apoptotic death of rat neonatal cardiomyocytes. Cell Death Differ 1995; 2:235.
  32. Gottlieb RA, Burleson KO, Kloner RA, et al. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 1994; 94:1621.
  33. Piot CA, Wolfe CL. Apoptosis: A New Mechanism of Lethal Myocardial "Reperfusion Injury"? J Thromb Thrombolysis 1997; 4:67.
  34. Zhao ZQ, Velez DA, Wang NP, et al. Progressively developed myocardial apoptotic cell death during late phase of reperfusion. Apoptosis 2001; 6:279.
  35. Zhao ZQ, Vinten-Johansen J. Myocardial apoptosis and ischemic preconditioning. Cardiovasc Res 2002; 55:438.
  36. Zhang YQ, Herman B. ARC protects rat cardiomyocytes against oxidative stress through inhibition of caspase-2 mediated mitochondrial pathway. J Cell Biochem 2006; 99:575.
  37. Donath S, Li P, Willenbockel C, et al. Apoptosis repressor with caspase recruitment domain is required for cardioprotection in response to biomechanical and ischemic stress. Circulation 2006; 113:1203.
  38. Akar FG, Aon MA, Tomaselli GF, O'Rourke B. The mitochondrial origin of postischemic arrhythmias. J Clin Invest 2005; 115:3527.
  39. Berger PB, Ruocco NA, Ryan TJ, et al. Incidence and significance of ventricular tachycardia and fibrillation in the absence of hypotension or heart failure in acute myocardial infarction treated with recombinant tissue-type plasminogen activator: results from the Thrombolysis in Myocardial Infarction (TIMI) Phase II trial. J Am Coll Cardiol 1993; 22:1773.
  40. Bulluck H, Hausenloy DJ. Ischaemic conditioning: are we there yet? Heart 2015; 101:1067.
  41. Iliceto S, Galiuto L, Marchese A, et al. Functional role of microvascular integrity in patients with infarct-related artery patency after acute myocardial infarction. Eur Heart J 1997; 18:618.
  42. Ito H, Maruyama A, Iwakura K, et al. Clinical implications of the 'no reflow' phenomenon. A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation 1996; 93:223.
  43. Sabia PJ, Powers ER, Ragosta M, et al. An association between collateral blood flow and myocardial viability in patients with recent myocardial infarction. N Engl J Med 1992; 327:1825.
  44. Matsumura K, Jeremy RW, Schaper J, Becker LC. Progression of myocardial necrosis during reperfusion of ischemic myocardium. Circulation 1998; 97:795.
  45. Arai M, Lefer DJ, So T, et al. An anti-CD18 antibody limits infarct size and preserves left ventricular function in dogs with ischemia and 48-hour reperfusion. J Am Coll Cardiol 1996; 27:1278.
  46. Baran KW, Nguyen M, McKendall GR, et al. Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study. Circulation 2001; 104:2778.
  47. Hoffmann R, Haager P, Arning J, et al. Usefulness of myocardial blush grade early and late after primary coronary angioplasty for acute myocardial infarction in predicting left ventricular function. Am J Cardiol 2003; 92:1015.
  48. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation 2000; 101:125.
  49. Montalescot G, Barragan P, Wittenberg O, et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001; 344:1895.
  50. Neumann FJ, Blasini R, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation 1998; 98:2695.
  51. de Lemos JA, Antman EM, Gibson CM, et al. Abciximab improves both epicardial flow and myocardial reperfusion in ST-elevation myocardial infarction. Observations from the TIMI 14 trial. Circulation 2000; 101:239.
  52. Antoniucci D, Rodriguez A, Hempel A, et al. A randomized trial comparing primary infarct artery stenting with or without abciximab in acute myocardial infarction. J Am Coll Cardiol 2003; 42:1879.
  53. Yang XM, Liu Y, Cui L, et al. Two classes of anti-platelet drugs reduce anatomical infarct size in monkey hearts. Cardiovasc Drugs Ther 2013; 27:109.
  54. Bell RM, Sivaraman V, Kunuthur SP, et al. Cardioprotective Properties of the Platelet P2Y12 Receptor Inhibitor, Cangrelor: Protective in Diabetics and Reliant Upon the Presence of Blood. Cardiovasc Drugs Ther 2015; 29:415.
  55. Ely SW, Berne RM. Protective effects of adenosine in myocardial ischemia. Circulation 1992; 85:893.
  56. Headrick JP, Hack B, Ashton KJ. Acute adenosinergic cardioprotection in ischemic-reperfused hearts. Am J Physiol Heart Circ Physiol 2003; 285:H1797.
  57. Morrison RR, Teng B, Oldenburg PJ, et al. Effects of targeted deletion of A1 adenosine receptors on postischemic cardiac function and expression of adenosine receptor subtypes. Am J Physiol Heart Circ Physiol 2006; 291:H1875.
  58. 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; 34:1711.
  59. Ross AM, Gibbons RJ, Stone GW, et al. 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; 45:1775.
  60. Kloner RA, Forman MB, Gibbons RJ, et al. 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; 27:2400.
  61. 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.
  62. Ishihara M, Sato H, Tateishi H, et al. Attenuation of the no-reflow phenomenon after coronary angioplasty for acute myocardial infarction with intracoronary papaverine. Am Heart J 1996; 132:959.
  63. Siegfried MR, Erhardt J, Rider T, et al. Cardioprotection and attenuation of endothelial dysfunction by organic nitric oxide donors in myocardial ischemia-reperfusion. J Pharmacol Exp Ther 1992; 260:668.
  64. Schlüter KD, Weber M, Schraven E, Piper HM. NO donor SIN-1 protects against reoxygenation-induced cardiomyocyte injury by a dual action. Am J Physiol 1994; 267:H1461.
  65. Van Gilst, WH, Kingma, JH. Protection of the myocardium against postischemic reperfusion damage: possible role of angiotensin-converting enzyme inhibitors. J Cardiovasc Pharmacol 1992; 19:S13.
  66. Piana RN, Wang SY, Friedman M, Sellke FW. Angiotensin-converting enzyme inhibition preserves endothelium-dependent coronary microvascular responses during short-term ischemia-reperfusion. Circulation 1996; 93:544.
  67. Wang QD, Li XS, Lundberg JM, Pernow J. Protective effects of non-peptide endothelin receptor antagonist bosentan on myocardial ischaemic and reperfusion injury in the pig. Cardiovasc Res 1995; 29:805.
  68. Grover GJ, Dzwonczyk S, Parham CS. The endothelin-1 receptor antagonist BQ-123 reduces infarct size in a canine model of coronary occlusion and reperfusion. Cardiovasc Res 1993; 27:1613.
  69. Pernow J, Wang QD. Endothelin in myocardial ischaemia and reperfusion. Cardiovasc Res 1997; 33:518.
  70. Galiuto, L, DeMaria, AN, del Balzo, U, et al. Endothelin A-antagonist reduces no-reflow and infarct size in dogs. J Am Coll Cardiol 1999; Special Issue (Suppl): 382A.
  71. Klein HH, Pich S, Bohle RM, et al. Myocardial protection by Na(+)-H+ exchange inhibition in ischemic, reperfused porcine hearts. Circulation 1995; 92:912.
  72. Meng HP, Maddaford TG, Pierce GN. Effect of amiloride and selected analogues on postischemic recovery of cardiac contractile function. Am J Physiol 1993; 264:H1831.
  73. Hendrikx M, Mubagwa K, Verdonck F, et al. New Na(+)-H+ exchange inhibitor HOE 694 improves postischemic function and high-energy phosphate resynthesis and reduces Ca2+ overload in isolated perfused rabbit heart. Circulation 1994; 89:2787.
  74. Rohmann S, Weygandt H, Minck KO. Preischaemic as well as postischaemic application of a Na+/H+ exchange inhibitor reduces infarct size in pigs. Cardiovasc Res 1995; 30:945.
  75. Coletta AP, Cleland JG. Clinical trials update: highlights of the scientific sessions of the XXIII Congress of the European Society of Cardiology--WARIS II, ESCAMI, PAFAC, RITZ-1 and TIME. Eur J Heart Fail 2001; 3:747.
  76. Zeymer U, Suryapranata H, Monassier JP, et al. 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 2001; 38:1644.
  77. Hale SL, Leeka JA, Kloner RA. Improved left ventricular function and reduced necrosis after myocardial ischemia/reperfusion in rabbits treated with ranolazine, an inhibitor of the late sodium channel. J Pharmacol Exp Ther 2006; 318:418.
  78. Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation 2004; 110:904.
  79. Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart 2006; 92 Suppl 4:iv6.
  80. Sakata Y, Kodama K, Ishikura F, et al. Disappearance of the 'no-reflow' phenomenon after adjunctive intracoronary administration of nicorandil in a patient with acute myocardial infarction. Jpn Circ J 1997; 61:455.
  81. Ito H, Taniyama Y, Iwakura K, et al. Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction. J Am Coll Cardiol 1999; 33:654.
  82. Krombach GA, Higgins CB, Chujo M, Saeed M. Gadomer-enhanced MR imaging in the detection of microvascular obstruction: alleviation with nicorandil therapy. Radiology 2005; 236:510.
  83. Gonon AT, Gourine AV, Middelveld RJ, et al. Limitation of infarct size and attenuation of myeloperoxidase activity by an endothelin A receptor antagonist following ischaemia and reperfusion. Basic Res Cardiol 2001; 96:454.
  84. Harlan JM, Winn RK. Leukocyte-endothelial interactions: clinical trials of anti-adhesion therapy. Crit Care Med 2002; 30:S214.
  85. Faxon DP, Gibbons RJ, Chronos NA, et al. The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty: the results of the HALT-MI study. J Am Coll Cardiol 2002; 40:1199.
  86. Mahaffey KW, Granger CB, Nicolau JC, et al. 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 2003; 108:1176.
  87. Granger CB, Mahaffey KW, Weaver WD, et al. Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction: the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial. Circulation 2003; 108:1184.
  88. APEX AMI Investigators, Armstrong PW, Granger CB, et al. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial. JAMA 2007; 297:43.
  89. Simon DI, Xu H, Ortlepp S, et al. 7E3 monoclonal antibody directed against the platelet glycoprotein IIb/IIIa cross-reacts with the leukocyte integrin Mac-1 and blocks adhesion to fibrinogen and ICAM-1. Arterioscler Thromb Vasc Biol 1997; 17:528.
  90. Przyklenk K. Pharmacologic treatment of the stunned myocardium: the concepts and the challenges. Coron Artery Dis 2001; 12:363.
  91. Hanlon PR, Fu P, Wright GL, et al. Mechanisms of erythropoietin-mediated cardioprotection during ischemia-reperfusion injury: role of protein kinase C and phosphatidylinositol 3-kinase signaling. FASEB J 2005; 19:1323.
  92. Bullard AJ, Govewalla P, Yellon DM. Erythropoietin protects the myocardium against reperfusion injury in vitro and in vivo. Basic Res Cardiol 2005; 100:397.
  93. Xu B, Dong GH, Liu H, et al. Recombinant human erythropoietin pretreatment attenuates myocardial infarct size: a possible mechanism involves heat shock Protein 70 and attenuation of nuclear factor-kappaB. Ann Clin Lab Sci 2005; 35:161.
  94. Hirata A, Minamino T, Asanuma H, et al. Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphatidylinositol-3 kinase-dependent pathway in canine hearts. Cardiovasc Drugs Ther 2005; 19:33.
  95. Jeanes HL, Wanikiat P, Sharif I, Gray GA. Medroxyprogesterone acetate inhibits the cardioprotective effect of estrogen in experimental ischemia-reperfusion injury. Menopause 2006; 13:80.
  96. Sbarouni E, Iliodromitis EK, Bofilis E, et al. Estrogen alone or combined with medroxyprogesterone but not raloxifene reduce myocardial infarct size. Eur J Pharmacol 2003; 467:163.
  97. Liu X, Pachori AS, Ward CA, et al. Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function. FASEB J 2006; 20:207.
  98. Jung F, Palmer LA, Zhou N, Johns RA. Hypoxic regulation of inducible nitric oxide synthase via hypoxia inducible factor-1 in cardiac myocytes. Circ Res 2000; 86:319.
  99. Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res 2003; 60:617.
  100. 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.
  101. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008; 359:473.
  102. Cung TT, Morel O, Cayla G, et al. Cyclosporine before PCI in Patients with Acute Myocardial Infarction. N Engl J Med 2015; 373:1021.
  103. Hausenloy DJ, Yellon DM. Targeting Myocardial Reperfusion Injury--The Search Continues. N Engl J Med 2015; 373:1073.
  104. Siddiqi N, Neil C, Bruce M, et al. Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI). Eur Heart J 2014; 35:1255.
  105. Marber MS, Rose B, Wang Y. The p38 mitogen-activated protein kinase pathway--a potential target for intervention in infarction, hypertrophy, and heart failure. J Mol Cell Cardiol 2011; 51:485.
  106. Ma XL, Kumar S, Gao F, et al. Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion. Circulation 1999; 99:1685.
  107. Newby LK, Marber MS, Melloni C, et al. Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial. Lancet 2014; 384:1187.
  108. Direct Inhibition of delta-Protein Kinase C Enzyme to Limit Total Infarct Size in Acute Myocardial Infarction (DELTA MI) Investigators, Bates E, Bode C, et al. Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Circulation 2008; 117:886.
  109. Dixon SR, Whitbourn RJ, Dae MW, et al. Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. J Am Coll Cardiol 2002; 40:1928.
  110. Ly HQ, Denault A, Dupuis J, et al. A pilot study: the Noninvasive Surface Cooling Thermoregulatory System for Mild Hypothermia Induction in Acute Myocardial Infarction (the NICAMI Study). Am Heart J 2005; 150:933.
  111. Kandzari DE, Chu A, Brodie BR, et al. Feasibility of endovascular cooling as an adjunct to primary percutaneous coronary intervention (results of the LOWTEMP pilot study). Am J Cardiol 2004; 93:636.
  112. 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; 63:1857.