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The Ishemia Reperfusion Injury Challenge

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Myocardial Preservation
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Abstract

Ischemia reperfusion injury after early experimental description has entered the clinical setting with the advent of thrombolysis and primary angioplasty in the setting of acute myocardial infarction. It has four manifestations: Myocardial stunning, the no reflow phenomenon, arrhythmias, and cell death. It is caused by early overloading of cells- when reperfusion is established- with reactive oxygen species, rapid correction of acidosis, calcium overload and metabolic modulation. Apart from limiting the time of ischemia, main interventions to reverse its noxious effect are conditioning and use of various drugs, none of which has gained wide acceptance with beta- blockers and adenosine being still under consideration, while cyclosporine has disappointed. It is still a matter of intensive investigation.

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References

  1. Chazov EI, Matveeva LS, Mazaev AV, Sargin KE, Sadovskaia GV, Ruda MI. Intracoronary administration of fibrinolysin in acute myocardial infarct. Ter Arkh. 1976;48:8–192. Reatrop

    CAS  PubMed  Google Scholar 

  2. Rentrop P, Blanke H, Karsch KR, Kaiser H, Köstering H, Leitz K. Selective intracoronary thrombolysis in acute myocardial infarction and unstable angina pectoris. Circulation. 1981;63:307–17.

    Article  CAS  PubMed  Google Scholar 

  3. Goldberg S, Greenspon AJ, Urban PL, Muza B, Berger B, Walinsky P, et al. Reperfusion arrhythmia: a marker of restoration of antegrade flow during intracoronary thrombolysis for acute myocardial infarction. Am Heart J. 1983;105:26–32.

    Article  CAS  PubMed  Google Scholar 

  4. Tennant R, Wiggers CJ. The effect of coronary occlu- sion on myocardial contraction. Am J Phys. 1935;12:351–61.

    Article  Google Scholar 

  5. Grines CL, Browne KF, Marco J, Rothbaum D, Stone GW, O’Keefe J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. The Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med. 1993;328:673–9.

    Article  CAS  Google Scholar 

  6. Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? J Clin Invest. 1985;76:1713–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Grech ED, Jackson MJ, Ramsdale DR. Reperfusion injury after acute myocardial infarction. BMJ. 1995;310:477–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  9. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357:1121–35.

    Article  CAS  PubMed  Google Scholar 

  10. Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation. 1982;66:1146–9.

    Article  CAS  PubMed  Google Scholar 

  11. Ito H. No-reflow phenomenon and prognosis in patients with acute myocardial infarction. Nat Clin Pract Cardiovasc Med. 2006;3:499–506.

    Article  PubMed  Google Scholar 

  12. Monassier JP. Reperfusion injury in acute myocardial infarction: from bench to cath lab. Part I: Clinical issues and therapeutic options. Arch Cardiovasc Dis. 2008;101:565–75.

    Article  PubMed  Google Scholar 

  13. Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest. 2013;123:92–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vishwakarma VK, Upadhyay PK, Gupta PK, Yadav HN. Pathophysiologic role of ischemia reperfusion injury: a review. JICC. 2017;7(3):97–104. j.jicc.2017.06.017

    Google Scholar 

  15. Morishima I, Sone T, Okumura K, Tsuboi H, Kondo J, Mukawa H, et al. Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction. J Am Coll Cardiol. 2000;36:1202–9.

    Article  CAS  PubMed  Google Scholar 

  16. Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K, et al. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation. 1992;85:1699–705.

    Article  CAS  PubMed  Google Scholar 

  17. Schofer J, Montz R, Mathey DG. Scintigraphic evidence of the "no reflow" phenomenon in human beings after coronary thrombolysis. J Am Coll Cardiol. 1985;5:593–8.

    Article  CAS  PubMed  Google Scholar 

  18. van Kranenburg M, Magro M, Thiele H, de Waha S, Eitel I, Cochet A. Prognostic value of microvascular obstruction and infarct size, as measured by CMR in STEMI patients. JACC Cardiovasc Imaging. 2014;7:930–9.

    Article  PubMed  Google Scholar 

  19. Bulluck H, Hausenloy DJ. Microvascular obstruction: the bane of myocardial reperfusion. Rev Esp Cardiol. 2015;68:28–34.

    Article  Google Scholar 

  20. Rezkalla SH, Stankowski RV, Hanna J, Kloner RA. Management of no-reflow phenomenon in the catheterization laboratory. JACC Cardiovasc Interv. 2017;10:215–23. Esp Cardiol (Engl Ed). 2015;68:919–20

    Article  PubMed  Google Scholar 

  21. Mongeon FP, Bélisle P, Joseph L, Eisenberg MJ, Rinfret S. Adjunctive thrombectomy for acute myocardial infarction: a bayesian meta-analysis. Circ Cardiovasc Interv. 2010;3:6–16.

    Article  PubMed  Google Scholar 

  22. Mancini JG, Filion KB, Windle SB, Habib B, Eisenberg MJ. Meta-analysis of the long-term effect of routine aspiration thrombectomy in patients undergoing primary percutaneous coronary intervention. Am J Cardiol. 2016;118:23–31.

    Article  PubMed  Google Scholar 

  23. Garcia-Dorado D, Ruiz-Meana M, Piper HM. Lethal reperfusion injury in acute myocardial infarction: facts and unresolved issues. Cardiovasc Res. 2009;83:165–8.

    Article  CAS  PubMed  Google Scholar 

  24. Hearse DJ, Humphrey SM, Bullock GR. The oxygen paradox and the calcium paradox: two facets of the same problem? J Mol Cell Cardiol. 1978;10:641–68.

    Article  CAS  PubMed  Google Scholar 

  25. Downey JM. Free radicals and their involvement during long-term myocardial ischemia and reperfusion. Annu Rev Physiol. 1990;52:487–504.

    Article  CAS  PubMed  Google Scholar 

  26. Piper HM, García-Dorado D, Ovize M. A fresh look at reperfusion injury. Cardiovasc Res. 1998;38:291–300.

    Article  CAS  PubMed  Google Scholar 

  27. Jennings RB, Reimer KA. The cell biology of acute myocardial ischemia. Annu Rev Med. 1991;42:225–46.

    Article  CAS  PubMed  Google Scholar 

  28. Piper HM, García-Dorado D. Prime causes of rapid cardiomyocyte death during reperfusion. Ann Thorac Surg. 1999;68:1913–9.

    Article  CAS  PubMed  Google Scholar 

  29. Frank A, Bonney M, Bonney S, Weitzel L, Koeppen M, Eckle T. Myocardial ischemia reperfusion injury: from basic science to clinical bedside. Semin Cardiothorac Vasc Anesth. 2012;16:123–13230. Horowitz JD, Chirkov YY, Kennedy JA, Sverdlov AL. Modulation of myocardial metabolism: an emerging therapeutic principle. Curr Opin Cardiol. 2010;25:329–334.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Horowitz JD, Chirkov YY, Kennedy JA, Sverdlov AL. Modulation of myocardial metabolism: an emerging therapeutic principle. Curr Opin Cardiol. 2010;25:329–34.

    Article  PubMed  Google Scholar 

  31. Lemasters JJ, Bond JM, Chacon E, Harper IS, Kaplan SH, Ohata H, et al. The pH paradox in ischemia-reperfusion injury to cardiac myocytes. EXS. 1996;76:99–114.

    CAS  PubMed  Google Scholar 

  32. Qian T, Nieminen AL, Herman B, Lemasters JJ. Mitochondrial permeability transition in pH-dependent reperfusion injury to rat hepatocytes. Am J Phys. 1997;273(6 Pt 1):C1783–92.

    Article  CAS  Google Scholar 

  33. Klein HH, Pich S, Lindert S, Nebendahl K, Warneke G, Kreuzer H. Treatment of reperfusion injury with intracoronary calcium channel antagonists and reduced coronary free calcium concentration in regionally ischemic, reperfused porcine hearts. J Am Coll Cardiol. 1989;13:1395–401.

    Article  CAS  PubMed  Google Scholar 

  34. Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev. 2008;88:581–609.

    Article  CAS  PubMed  Google Scholar 

  35. Wu MY, Yiang GT, Liao WT, Tsai AP, Cheng YL, Cheng PW, et al. Current mechanistic concepts in ischemia and reperfusion injury. Cell Physiol Biochem. 2018;46:1650–67.

    Article  CAS  PubMed  Google Scholar 

  36. Neri M, Riezzo I, Pascale N, Pomara C, Turillazzi E. Ischemia/reperfusion injury following acute myocardial infarction: a critical issue for clinicians and forensic pathologists. Mediat Inflamm. 2017;2017:7018393.

    Article  CAS  Google Scholar 

  37. Thomas DD, Ridnour LA, Isenberg JS, Flores-Santana W, Switzer CH, Donzelli S, et al. The chemical biology of nitric oxide: implications in cellular signaling. Free Radic Biol Med. 2008;45:18–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33:829–37, 837a–837d.

    Article  PubMed  CAS  Google Scholar 

  39. Phillips L, Toledo AH, Lopez-Neblina F, Anaya-Prado R, Toledo-Pereyra LH. Nitric oxide mechanism of protection in ischemia and reperfusion injury. J Investig Surg. 2009;22:46–55.

    Article  Google Scholar 

  40. Schulz R, Kelm M, Heusch G. Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovasc Res. 2004;61:402–13.

    Article  CAS  PubMed  Google Scholar 

  41. Zweier JL, Fertmann J, Wei G. Nitric oxide and peroxynitrite in postischemic myocardium. Antioxid Redox Signal. 2001;3:11–22.

    Article  CAS  PubMed  Google Scholar 

  42. Radi R, Beckman JS, Bush KM, Freeman BA. Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys. 1991;288:481–7.

    Article  CAS  PubMed  Google Scholar 

  43. van der Vliet A, O’Neill CA, Halliwell B, Cross CE, Kaur H. Aromatic hydroxylation and nitration of phenylalanine and tyrosine by peroxynitrite. Evidence for hydroxyl radical production from peroxynitrite. FEBS Lett. 1994;339:89–92.

    Google Scholar 

  44. Menon B, Singh M, Singh K. Matrix metalloproteinases mediate beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes. Am J Physiol Cell Physiol. 2005;289:C168–76.

    Article  CAS  PubMed  Google Scholar 

  45. Zhou HZ, Ma X, Gray MO, Zhu BQ, Nguyen AP, Baker AJ, Simonis U, et al. Transgenic MMP-2 expression induces latent cardiac mitochondrial dysfunction. Biochem Biophys Res Commun. 2007;358:189–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sawicki G, Salas E, Murat J, Miszta-Lane H, Radomski MW. Release of gelatinase A during platelet activation mediates aggregation. Nature. 1997;386:616–9.

    Article  CAS  PubMed  Google Scholar 

  47. Fernandez-Patron C, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2 cleaves big endothelin-1 yielding a novel vasoconstrictor. Circ Res. 1999;85:906–11.

    Article  CAS  PubMed  Google Scholar 

  48. Fernandez-Patron C, Stewart KG, Zhang Y, Koivunen E, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2-dependent cleavage of calcitonin gene-related peptide promotes vasoconstriction. Circ Res. 2000;87:670–6.

    Article  CAS  PubMed  Google Scholar 

  49. Cheung PY, Sawicki G, Wozniak M, Wang W, Radomski MW, Schulz R. Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart. Circulation. 2000;101:1833–9.

    CAS  PubMed  Google Scholar 

  50. Gao WD, Atar D, Liu Y, Perez NG, Murphy AM, Marban E. Role of troponin I proteolysis in the pathogenesis of stunned myocardium. Circ Res. 1997;80:393–9.

    Article  CAS  PubMed  Google Scholar 

  51. Wang W, Schulze CJ, Suarez-Pinzon WL, Dyck JR, Sawicki G, Schulz R. Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury. Circulation. 2002;106:1543–9.

    Article  CAS  PubMed  Google Scholar 

  52. Pipikos T, Kapelouzou A, Tsilimigras DI, Fostinis Y, Pipikou M, Theodorakos A, et al. Stronger correlation with myocardial ischemia of high-sensitivity troponin T than other biomarkers. J Nucl Cardiol. 2018; https://doi.org/10.1007/s12350-018-1199-6.

  53. Lindsey M, Wedin K, Brown MD, Keller C, Evans AJ, Smolen J, et al. Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/reperfusion. Circulation. 2001;103:2181–7.

    Article  CAS  PubMed  Google Scholar 

  54. McMillan WD, Tamarina NA, Cipollone M, Johnson DA, Parker MA, Pearce WH. Size matters: the relationship between MMP-9 expression and aortic diameter. Circulation. 1997;96:2228–32.

    Article  CAS  PubMed  Google Scholar 

  55. Heymans S, Luttun A, Nuyens D, Theilmeier G, Creemers E, Moons L, et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med. 1999;5:1135–42.

    Article  CAS  PubMed  Google Scholar 

  56. Rohde LE, Ducharme A, Arroyo LH, Aikawa M, Sukhova GH, Lopez-Anaya A, et al. Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation. 1999;99:3063–70.

    Article  CAS  PubMed  Google Scholar 

  57. Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, et al. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest. 2000;106:55–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Vanhoutte D, Heymans S. TIMPs and cardiac remodeling: ‘Embracing the MMP-independent-side of the family’. J Mol Cell Cardiol. 2010;48:445–53.

    Article  CAS  PubMed  Google Scholar 

  59. Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res. 2004;61:481–97.

    Article  CAS  PubMed  Google Scholar 

  60. Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol. 2012;298:229–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang J, Frangogiannis NG Repair of the infarcted myocardium. Introduction to translational cardiovascular research. Cham: Springer 2015, p 279–97.

    Google Scholar 

  62. Dutta P, Nahrendorf M. Monocytes in myocardial infarction. Arterioscler Thromb Vasc Biol. 2015;35:1066–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Joshi NV, Toor I, Shah AS, Carruthers K, Vesey AT, Alam SR, et al. Systemic atherosclerotic inflammation following acute myocardial infarction: myocardial infarction begets myocardial infarction. J Am Heart Assoc. 2015;4:e001956.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Nahrendorf M, Swirski FK. Innate immune cells in ischaemic heart disease: does myocardial infarction beget myocardial infarction? Eur Heart J. 2016;37:868–72.

    Article  PubMed  Google Scholar 

  65. Shishido T, Nozaki N, Yamaguchi S, Shibata Y, Nitobe J, Miyamoto T, et al. Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation. 2003;108:2905–10.

    Article  CAS  PubMed  Google Scholar 

  66. Timmers L, Sluijter JP, van Keulen JK, Hoefer IE, Nederhoff MG, Goumans MJ, et al. Toll-like receptor 4 mediates maladaptive left ventricular remodeling and impairs cardiac function after myocardial infarction. Circ Res. 2008;102:257–64.

    Article  CAS  PubMed  Google Scholar 

  67. Lu C, Ren D, Wang X, Ha T, Liu L, Lee EJ, et al. Toll-like receptor 3 plays a role in myocardial infarction and ischemia/reperfusion injury. Biochim Biophys Acta. 1842;2014:22–31.

    Google Scholar 

  68. Dewald O, Zymek P, Winkelmann K, Koerting A, Ren G, Abou-Khamis T, et al. CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res. 2005;96:881–9.

    Article  CAS  PubMed  Google Scholar 

  69. Frangogiannis NG, Mendoza LH, Ren G, Akrivakis S, Jackson PL, Michael LH, et al. MCSF expression is induced in healing myocardial infarcts and may regulate monocyte and endothelial cell phenotype. Am J Physiol Heart Circ Physiol. 2003;285:H483–92.

    Article  CAS  PubMed  Google Scholar 

  70. Hofmann U, Frantz S. Role of T-cells in myocardial infarction. Eur Heart J. 2016;37:873–9.

    Article  CAS  PubMed  Google Scholar 

  71. Somasundaram P, Ren G, Nagar H, Kraemer D, Mendoza L, Michael LH, et al. Mast cell tryptase may modulate endothelial cell phenotype in healing myocardial infarcts. J Pathol. 2005;205:102–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bernal-Mizrachi L, Jy W, Jimenez JJ, Pastor J, Mauro LM, Horstman LL, et al. High levels of circulating endothelial microparticles in patients with acute coronary syndromes. Am Heart J. 2003;145:962–70.

    Article  PubMed  Google Scholar 

  73. Boulanger CM, Scoazec A, Ebrahimian T, Henry P, Mathieu E, Tedgui A, et al. Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation. 2001;104:2649–52.

    Article  CAS  PubMed  Google Scholar 

  74. Ozaki M, Kawashima S, Hirase T, Yamashita T, Namiki M, Inoue N, et al. Overexpression of endothelial nitric oxide synthase in endothelial cells is protective against ischemia-reperfusion injury in mouse skeletal muscle. Am J Pathol. 2002;160:1335–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Loscalzo J. Endothelial injury, vasoconstriction, and its prevention. Tex Heart Inst J. 1995;22:180–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Nieswandt B, Pleines I, Bender M. Platelet adhesion and activation mechanisms in arterial thrombosis and ischaemic stroke. J Thromb Haemost. 2011;9(Suppl 1):92–104.

    Article  CAS  PubMed  Google Scholar 

  77. Monassier JP. Reperfusion injury in acute myocardial infarction: from bench to cath lab. Part II: Clinical issues and therapeutic options. Arch Cardiovasc Dis. 2008;101:565–75.

    Article  PubMed  Google Scholar 

  78. Fröhlich GM, Meier P, White SK, Yellon DM, Hausenloy DJ. Myocardial reperfusion injury: looking beyond primary PCI. Eur Heart J. 2014;34:1714–22.

    Article  CAS  Google Scholar 

  79. Hausenloy DJ, Erik Bøtker H, Condorelli G, Ferdinandy P, Garcia-Dorado D, Heusch 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;98:7–27.

    Article  CAS  PubMed  Google Scholar 

  80. Hausenloy DJ, Garcia-Dorado D, Bøtker HE, Davidson SM, Downey J, Engel FB, et al. Novel targets and future strategies for acute cardioprotection: Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart. Cardiovasc Res. 2017;113:564–85.

    Article  CAS  PubMed  Google Scholar 

  81. Mahaffey KW, Puma JA, Barbagelata NA, DiCarli MF, Leesar MA, Browne KF, 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;34:1711–20.

    Article  CAS  PubMed  Google Scholar 

  82. 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;45:1775–80.

    Article  CAS  PubMed  Google Scholar 

  83. Quintana M, Hjemdahl P, Sollevi A, Kahan T, Edner M, Rehnqvist N, et al. Left ventricular function and cardiovascular events following adjuvant therapy with adenosine in acute myocardial infarction treated with thrombolysis, results of the ATTenuation by Adenosine of Cardiac Complications (ATTACC) study. Eur J Clin Pharmacol. 2003;59:1–9.

    Article  CAS  PubMed  Google Scholar 

  84. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Wu H, Ye M, Yang J, Ding J, Yang J, Dong W, et al. Nicorandil protects the heart from ischemia/reperfusion injury by attenuating endoplasmic reticulum response-induced apoptosis through PI3K/Akt signaling pathway. Cell Physiol Biochem. 2015;35:2320–32.

    Article  CAS  PubMed  Google Scholar 

  86. Campo G, Pavasini R, Morciano G, Lincoff MA, C Gibson M, Kitakaze M, et al. Data on administration of cyclosporine, nicorandil, metoprolol on reperfusion related outcomes in ST-segment Elevation Myocardial Infarction treated with percutaneous coronary intervention. Data Brief. 2017;14:197–205.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Mewton N, Croisille P, Gahide G, Rioufol G, Bonnefoy E, Sanchez I, et al. Effect of cyclosporine on left ventricular remodeling after reperfused myocardial infarction. J Am Coll Cardiol. 2010;55:1200–5.

    Article  CAS  PubMed  Google Scholar 

  88. Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, et al. Cyclosporine before PCI in Patients with Acute Myocardial infarction. N Engl J Med. 2015;373:1021–31.

    Article  CAS  PubMed  Google Scholar 

  89. Ottani F, Latini R, Staszewsky L, La Vecchia L, Locuratolo N, Sicuro M, et al. Cyclosporine A in reperfused myocardial infarction: the multicenter, controlled, open-label CYCLE trial. J Am Coll Cardiol. 2016;67:365–74.

    Article  CAS  PubMed  Google Scholar 

  90. Heusch G. Critical issues for the translation of cardioprotection. Circ Res. 2017;120:1477–86.

    Article  CAS  PubMed  Google Scholar 

  91. Ibanez B, Macaya C, Sánchez-Brunete V, Pizarro G, Fernández-Friera L, Mateos A, 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;128:1495–503.

    Article  CAS  PubMed  Google Scholar 

  92. Roolvink V, Ibáñez B, Ottervanger JP, Pizarro G, van Royen N, Mateos A, et al. Early intravenous beta-blockers in patients with ST-segment elevation myocardial infarction before primary percutaneous coronary intervention. J Am Coll Cardiol 2016;67:2705–2715.

    Google Scholar 

  93. Hausenloy DJ, Yellon DM. Combination therapy to target reperfusion injury after ST-segment-elevation myocardial infarction: a more effective approach to cardioprotection. Circulation. 2017;136:904–6.

    Article  PubMed  Google Scholar 

  94. Pasupathy S, Tavella R, Grover S, Raman B, NEK P, Du YT, et al. Early use of N-acetylcysteine with nitrate therapy in patients undergoing primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction reduces myocardial infarct size (the NACIAM trial [N-acetylcysteine in acute myocardial infarction]). Circulation. 2017;136:894–903.

    Article  CAS  PubMed  Google Scholar 

  95. Collard CD, Gelman S. Pathophysiology, clinical manifestations, and prevention of ischemia-reperfusion injury. Anesthesiology. 2001;94:1133–8.

    Article  CAS  PubMed  Google Scholar 

  96. Weisman HF, Bartow T, Leppo MK, Marsh HC Jr, Carson GR, Concino MF, et al. Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science. 1990;249:146–51.

    Article  CAS  PubMed  Google Scholar 

  97. Vakeva AP, Agah A, Rollins SA, Matis LA, Li L, Stahl GL. Myocardial infarction and apoptosis after myocardial ischemia and reperfusion: role of the terminal complement components and inhibition by anti-C5 therapy. Circulation. 1998;97:2259–67.

    Article  CAS  PubMed  Google Scholar 

  98. Boodram S, Evans E. Use of leukocyte-depleting filters during cardiac surgery with cardiopulmonary bypass: a review. J Extra Corpor Technol. 2008;40:27–42.

    PubMed  PubMed Central  Google Scholar 

  99. Chiang N, Gronert K, Clish CB, O’Brien JA, Freeman MW, Serhan CN. Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion. J Clin Invest. 1999;104:309–16.

    Article  CAS  PubMed Central  Google Scholar 

  100. Hausenloy DJ, Barrabes JA, Bøtker HE, Davidson SM, Di Lisa F, Downey J, et al. Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery. Basic Res Cardiol. 2016;111:70.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Cabrera-Fuentes HA, Alba-Alba C, Aragones J, Bernhagen J, Boisvert WA, Bøtker HE, et al. Meeting report from the 2nd International Symposium on New Frontiers in Cardiovascular Research. Protecting the cardiovascular system from ischemia: between bench and bedside. Basic Res Cardiol. 2016;111:7.

    Article  PubMed  Google Scholar 

  102. Cabrera-Fuentes HA, Aragones J, Bernhagen J, Boening A, Boisvert WA, Bøtker HE, et al. From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on "New frontiers in cardiovascular research". Basic Res Cardiol. 2016;111:69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Mentzer RM Jr. Myocardial protection in heart surgery. J Cardiovasc Pharmacol Ther. 2011;16:290–7.

    Article  CAS  PubMed  Google Scholar 

  104. Dianati Maleki N, Van de Werf F, Goldstein P, Adgey JA, Lambert Y, Sulimov V, et al. Aborted myocardial infarction in ST-elevation myocardial infarction: insights from the STrategic Reperfusion Early After Myocardial infarction trial. Heart. 2014;100:1543–9.

    Article  PubMed  Google Scholar 

  105. Musiolik J, van Caster P, Skyschally A, Boengler K, Gres P, Schulz R, Heusch G. Reduction of infarct size by gentle reperfusion without activation of reperfusion injury salvage kinases in pigs. Cardiovasc Res. 2010;85:110–7.

    Article  CAS  PubMed  Google Scholar 

  106. Beyersdorf F. The use of controlled reperfusion strategies in cardiac surgery to minimize ischaemia/reperfusion damage. Cardiovasc Res. 2009;83:262–8.

    Article  CAS  PubMed  Google Scholar 

  107. Pyda M, Grajek S, Oleśkowska-Florek F, Lesiak M, Siniawski S, Gwizdała A, et al. Aborted myocardial infarction in patients undergoing primary percutaneous coronary intervention. J Med Science. 2015;84:27–32.

    Google Scholar 

  108. Sluijter JP, Condorelli G, Davidson SM, Engel FB, Ferdinandy P, Hausenloy DJ, et al. Novel therapeutic strategies for cardioprotection. Pharmacol Ther. 2014;144:60–70.

    Article  CAS  PubMed  Google Scholar 

  109. Bostjancic E, Zidar N, Stajer D, Glavac D. MicroRNAs miR-1, miR-133a, miR-133b and miR-208 are dysregulated in human myocardial infarction. Cardiology. 2010;115:163–9.

    Article  CAS  PubMed  Google Scholar 

  110. Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, et al. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science. 2009;324:1710–3.

    Article  CAS  PubMed  Google Scholar 

  111. Boon RA, Iekushi K, Lechner S, Seeger T, Fischer A, Heydt S, et al. MicroRNA-34a regulates cardiac ageing and function. Nature. 2013;495:107–10.

    Article  CAS  PubMed  Google Scholar 

  112. Armstrong PW, Gershlick AH, Goldstein P, Wilcox R, Danays T, Lambert Y, et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. N Engl J Med. 2013;368:1379–87.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Dennis V. Cokkinos .

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Cokkinos, D.V. (2019). The Ishemia Reperfusion Injury Challenge. In: Cokkinos, D. (eds) Myocardial Preservation. Springer, Cham. https://doi.org/10.1007/978-3-319-98186-4_6

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