Myocardial Ischemia/Reperfusion injury: novel strategies for an old problem

Main Article Content

Claudia Kusmic Serena L'Abbate


Ischemic heart disease remains the leading cause of death and disability in Europe and worldwide. Thrombolytic therapy and angioplasty, by allowing the recovery of coronary blood flow (reperfusion) after ischemia, greatly improved clinical outcomes and reduced the infarct size in patients.  Reperfusion per se, however, can cause serious and fatal cardiac dysfunctions, mainly due to the sudden entry of oxygen, ionic and metabolic disorders that, by overwhelming the endogenous cellular defences, can lead to the death of cardiomyocytes and trigger myocardial injury and dysfunction. Preclinical animal studies have identified and characterized many endogenous pathways that have the potential to protect cardiomyocytes and reduce the infarct size if activated before the ischemic event or early after the onset of reperfusion. However, the improvement in our knowledge and the implementation of adjuvant strategies to provide cardioprotection against short– and long–term ischemia‑reperfusion (I/R) induced damage are of great importance and remain a major unmet clinical need. The present review summarizes our current comprehension on the pathophysiology of I/R injury and analyze recent progress in pharmacological and non-pharmacological strategies of cardioprotection. Future perspectives of preclinical research on this field and its role in addressing important open questions, improving translation into the clinical setting included, are also presented.

Article Details

How to Cite
KUSMIC, Claudia; L'ABBATE, Serena. Myocardial Ischemia/Reperfusion injury: novel strategies for an old problem. Medical Research Archives, [S.l.], v. 8, n. 7, july 2020. ISSN 2375-1924. Available at: <>. Date accessed: 08 aug. 2020. doi:
Review Articles


1. Yellon DM , Hausenloy DJ . Myocardial reperfusion injury. N Engl J Med. 2007;357(11):1121–35.
2. Heusch G. The regional myocardial flow-function relationship: a framework for an understanding of acute ischemia, hibernation, stunning and coronary microembolization. 1980. Circ Res. 2013;112(12):1535-7.
3. Nesto RW, Kowalchuk GJ. The ischemic cascade: Temporal sequence of hemodynamic, electrocardiographic and symptomatic expressions of ischemia. Am J Cardiol 1987;59(7):23C–30C.
4. L'Abbate A. Recanalization versus reperfusion for myocardial survival and preservation of ventricular geometry. Am Heart J. 1999;138:S89-95.
5. Heusch G. Coronary microvascular obstruction: the new frontier in cardioprotection. Basic Res Cardiol. 2019;114(6):45.
6. Reimer KA, Jennings RB. The “wavefront phenomenon” of myocardial ischemic cell death. II. Transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest. 1979;40(6):633–44.
7. 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.
8. Jennings RB, Ganote CE. Structural changes in myocardium during acute ischemia. Circ Res. 1974;35(3):156-72.
9. Ganote CE. Contraction band necrosis and irreversible myocardial injury. J Mol Cell Cardiol. 1983;15(2):67–73.
10. Jennings RB. Historical perspective on the pathology of myocardial Ischemia/Reperfusion injury. Circ Res. 2013;113(4):428-38.
11. Tibaut M, Mekis D, Petrovic D. Pathophysiology of myocardial infarction and acute management strategies. Cardiovasc Hematol Agents Med Chem. 2017;14(3):150-9.
12. Bugger H, Pfeil K. Mitochondrial ROS in myocardial ischemia reperfusion and remodeling. Biochim Biophys Acta Mol Basis Dis. 2020;1866(7):165768.
13. Davidson SM, Adameová A, Barile L, Cabrera-Fuentes HA, Lazou A, Pagliaro P, Stensløkken KO, Garcia-Dorado D; EU-CARDIOPROTECTION COST Action (CA16225). Mitochondrial and mitochondrial-independent pathways of myocardial cell death during ischaemia and reperfusion injury. J Cell Mol Med. 2020;24(7):3795-806.
14. Kulek AR, Anzell A, Wider JM, Sanderson TH, Przyklenk K. Mitochondrial Quality Control: Role in Cardiac Models of Lethal Ischemia-Reperfusion Injury. Cells. 2020;9(1):E214.
15. Piquereau J, Caffin F, Novotova M, Lemaire C, Veksler V, Garnier A, Ventura-Clapier R, Joubert F. Mitochondrial dynamics in the adult cardiomyocytes: which roles for a highly specialized cell? Front Physiol. 2013;4:102.
16. Sulkin MS, Boukens BJ, Tetlow M, Gutbrod SR, Ng FS, Efimov IR. Mitochondrial depolarization and electrophysiological changes during ischemia in the rabbit and human heart. Am J Physiol Heart Circ Physiol. 2014;307(8): H1178–86.
17. 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. Mediators Inflamm. 2017;2017:7018393.
18. Thompson-Gorman SL, Zweier JL. Evaluation of the role of xanthine oxidase in myocardial reperfusion injury. J Biol Chem. 1990;265(12):6656-6663.
19. Matsushima S, Tsutsui H, Sadoshima J. Physiological and pathological functions of NADPH oxidases during myocardial ischemia-reperfusion. Trends Cardiovasc Med. 2014;24(5):202-205.
20. Sharma HS, Das DK. Role of cytokines in myocardial ischemia and reperfusion. Mediators Inflamm. 1997;6:175–183.
21. Kloner RA, Ganote CE, Whalen DA Jr, Jennings RB. Effect of a transient period of ischemia on myocardial cells. II. Fine structure during the first few minutes of reflow. Am J Pathol. 1974;74(3):399-422.
22. Niccoli G, Burzotta F, Galiuto L, Crea F. Myocardial no-reflow in humans. J Am Coll Cardiol. 2009;54(4):281-292.
23. Bekkers SC, Yazdani SK, Virmani R, Waltenberger J. Microvascular obstruction: underlying pathophysiology and clinical diagnosis. J Am Coll Cardiol. 2010;55(16):1649-1660.
24. Manciet LH, Poole DC, McDonagh PF, Copeland JG, Mathieu-Costello O. Microvascular compression during myocardial ischemia: mechanistic basis for no-reflow phenomenon. Am J Physiol. 1994;266(4):H1541-1550.
25. Kleinbongard P, Schleiger A, Heusch G. Characterization of vasomotor responses in different vascular territories of C57BL/6J mice. Exp Biol Med. 2013;238(10):1180-1191.
26. Zhao ZQ, Nakamura M, Wang NP, Velez DA, Hewan-Lowe KO, Guyton RA,Vinten-Johansen J. Dynamic progression of contractile and endothelial dysfunctionand infarct extension in the late phase of reperfusion. J Surg Res. 2000;94:133–144.
27. Jonassen AK, Sack MN, Mjos OD, Yellon DM. Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ Res. 2001;89:1191–1198.
28. Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res. 2003;60:617–625.
29. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124-1136.
30. Schott RJ, Rohmann S, Braun ER, Schaper W. Ischemic preconditioning reduces infarct size in swine myocardium. Circ Res. 1990;66(4):1133-1142.
31. Thornton J1, Striplin S, Liu GS, Swafford A, Stanley AW, Van Winkle DM, Downey JM. Inhibition of protein synthesis does not block myocardial protection afforded by preconditioning. Am J Physiol. 1990;259(6):H1822-1825.
32. Yellon DM, Alkhulaifi AM, Browne EE, Pugsley WB. Ischaemic preconditioning limits infarct size in the rat heart. Cardiovasc Res. 1992;26(10):983-7.
33. Burns PG1, Krunkenkamp IB, Calderone CA, Kirvaitis RJ, Gaudette GR, Levitsky S. Is the preconditioning response conserved in senescent myocardium? Ann Thorac Surg. 1996;61(3):925-929.
34. Sumeray MS, Yellon DM. Ischaemic preconditioning reduces infarct size following global ischaemia in the murine myocardium. Basic Res Cardiol. 1998;93(5):384-390.
35. 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):893-899.
36. Tomai F. Warm up phenomenon and preconditioning in clinical practice. Heart. 2002;87(2):99-100.
37. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003;285(2):H579-588.
38. Vinten-Johansen J, Shi W. The science and clinical translation of remote postconditioning. J Cardiovasc Med. 2013;14(3):206-213.
39. Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res. 2004;61(3):448-460.
40. Lecour S. Multiple protective pathways against reperfusion injury: a SAFE path without Aktion? J Mol Cell Cardiol. 2009;46(5):607-609.
41. Lecour S. Activation of the protective Survivor Activating Factor Enhancement (SAFE) pathway against reperfusion injury: Does it go beyond the RISK pathway? J Mol Cell Cardiol. 2009;47(1):32-40.
42. Lacerda L, Somers S, Opie LH, Lecour S. Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway. Cardiovasc Res. 2009;84(2):201-208.
43. Linseman DA, Butts BD, Precht TA, Phelps RA, Le SS, Laessig, TA, Bouchard RJ, Florez-McClure ML, Heidenreich KA. Glycogen synthase kinase-3β phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci. 2004; 24(44):9993–10002.
44. Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, Wang S, Ytrehus K, Antos CL, Olson EN, Sollot SJ. Glycogen synthase kinase-3β mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Investig. 2004;113(11):1535–1549.
45. Gomez L, Paillard M, Thibault H, Derumeaux G, Ovize M. Inhibition of GSK3β by postconditioning is required to prevent opening of the mitochondrial permeability transition pore during reperfusion. Circulation 2008;117(21):2761–2768.
46. Somers SJ, Frias M, Lacerda L, Opie LH, Lecour S. Interplay between SAFE and RISK pathways in sphingosine-1-phosphate-induced cardioprotection. Cardiovasc Drugs Ther. 2012;26(3):227-237.
47. Yu L, Li B, Zhang M, Jin Z, Duan W, Zhao G, Yang Y, Liu Z, Chen W, Wang S, Yang J, Yi D, Liu J, Yu S. Melatonin reduces PERK–eIF2alpha–ATF4-mediated endoplasmic reticulum stress during myocardial ischemia–reperfusion injury: role of RISK and SAFE pathways interaction. Apoptosis 2016;21:809–824.
48. Parratt, J.R. Possibilities for the pharmacological exploitation of ischaemic preconditioning. J Mol Cell Cardiol. 1995;27(4):991–1000.
49. Bulluck H, Yellon DM, Hausenloy,DJ. Reducing myocardial infarct size: Challenges and future opportunities. Heart 2016;102(5):341–348.
50. Jovanović A. Cardioprotective signalling: Past, present and future. Eur J Pharmacol. 2018;833:314-319.
51. Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent advances in pharmacological and non-pharmacological strategies of cardioprotection. Int J Mol Sci. 2019;20(16): E4002.
52. Salloum FN, Chau VQ, Hoke NN, Abbate A, Varma A, Ockaili RA, Toldo S, Kukreja RC. Phosphodiesterase-5 inhibitor, tadalafil, protects against myocardial ischemia/reperfusion through protein-kinase g-dependent generation of hydrogen sulfide. Circulation 2009;120(11 Suppl):S31-36.
53. Di Lisa F, Carpi A, Giorgio V, Bernardi P. The mitochondrial permeability transition pore and cyclophilin D in cardioprotection. Biochim Biophys Acta 2011;1813(7):1316-1322.
54. Hausenloy DJ, Boston-Griffiths EA, Yellon DM. Cyclosporin A and cardioprotection: from investigative tool to therapeutic agent. Br J Pharmacol. 2012;165(5):1235-1245.
55. Heusch G. Critical Issues for the Translation of Cardioprotection. Circ Res. 2017;120(9):1477-1486.
56. De Hert SG ,ten Broecke PW, Mertens E,Van Sommeren EW, DeBlier I G, Stockman BA, Rodrigus IE. Sevoflurane but not propofol preserves myocardial function in coronary surgery patients. Anesthesiology 2002;97(1):42–49.
57. Zaugg M, Lucchinetti E, Spahn DR, Pasch T, Schaub MC. Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial K(ATP) channels via multiple signaling pathways. Anesthesiology 2002;97(1):4–14.
58. Zaugg M, Lucchinetti E, Uecker M, Pasch T, Schaub MC. Anaesthetics and cardiac preconditioning. Part I .Signalling and cytoprotective mechanisms. Br J Anaesth. 2003:91(4):551–565.
59. Tanaka K, Ludwig LM, Kersten JR, Pagel PS, Warltier DC. Mechanisms of cardioprotection by volatile anesthetics. Anesthesiology 2004;100(3):707–721.
60. Riess ML, Stowe DF, Warltier DC. Cardiac pharmacological preconditioning with volatile anesthetics: from bench to bedside? Am J Physiol Heart Circ Physiol. 2004;286(5):H1603–H1607.
61. Van Allen NR, Krafft PR, Leitzke AS, Applegate RL 2nd, Tang J, Zhang JH. The role of volatile anesthetics in cardioprotection: a systematic review. Med Gas Res. 2012;2(1):22.
62. Agarwal B, Stowe DF, Dash RK, Bosnjak ZJ, Camara AK. Mitochondrial targets for volatile anesthetics against cardiac ischemia-reperfusion injury. Front Physiol. 2014;5:341.
63. Li H, Lang X–E. Protein kinase C signaling pathway involvement in cardioprotection during isoflurane pretreatment. Mol Med Reports 2015;11:2683–2688.
64. Chiari PC, Bienengraeber MW, Pagel PS, Krolikowski JG, Kersten JR, Warltier DC. Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol- 3-kinase signal transduction: evidence for anesthetic-induced postconditioning in rabbits. Anesthesiology 2005;102(1):102-109.
65. Lotz C, Kehl F. Volatile anesthetic-induced cardiac protection: molecular mechanisms, clinical aspects, and interactions with nonvolatile agents. J Cardiothorac Vasc Anesth. 2015;29(3):749-760.
66. Duncker DJ, Klassen CL, Ishibashi Y, Herrlinger SH, Pavek TJ, Bache RJ. Effect of temperature on myocardial infarction in swine. Am J Physiol. 1996;270(4):H1189—99.
67. Hale SL, Dave RH, Kloner RA. Regional hypothermia reduces myocardial necrosis even when instituted after the onset of ischemia. Basic Res Cardiol. 1997;92(5):351–357.
68. Hale SL, Kloner RA. Myocardial temperature in acute myocar-dial infarction: protection with mild regional hypothermia. AmJ Physiol. 1997;273(1):H220—227.
69. Miki T, Liu GS, Cohen MV, Downey JM. Mild hypothermia reduces infarct size in the beating rabbit heart: a practical intervention for acute myocardial infarction? Basic Res Cardiol. 1998;93(5):372–383.
70. Dae MW, Gao DW, Sessler DI, Chair K, Stillson CA. Effect of endovascular cooling on myocardial temperature, infarct size, and cardiac output in human-sized pigs. Am J Physiol Heart Circ Physiol. 2002;282(5):H1584–H1591.
71. Hale SL, Kloner RA. Mild hypothermia as a cardioprotective approach for acute myocardial infarction: laboratory to clinical application. J Cardiovasc Pharmacol Ther. 2011; 16(2):131–139.
72. Chien GL, Wolff RA, Davis RF, van Winkle DM. ‘Normothermic range’ temperature affects myocardial infarct size. Cardiovasc Res 1994;28(7):1014–1017.
73. Schwartz LM, Verbinski SG, Vander Heide RS, Reimer KA. Epicardial temperature is a major predictor of myocardial infarct size in dogs. J Mol Cell Cardiol. 1997;29(6):1577–1583.
74. Hamamoto H, Sakamoto H, Leshnower BG, Parish LM, Kanemoto S, Hinmon R, Plappert T, Miyamoto S, St John–Sutton MG, Gorman JH 3rd, Gorman RC. Very mild hypothermia during ischemia and reperfusion improves post infarction ventricular remodeling. Ann Thorac Surg. 2009;87(1):172–177.
75. Tissier R, Chenoune M, Ghaleh B, Cohen MV, Downey JM, Berdeaux A. The small chill: mild hypothermia for cardioprotection? Cardiovasc Res. 2010;88(3):406–414.
76. Knoop B, Naguib D, Dannenberg L, Helten C, Zako S, Jung C, Levkau B, Grandoch M, Kelm M, Zeus T, Polzin A. Cardioprotection by very mild hypothermia in mice. Cardiovasc Diagn Ther. 2019;9(1):64-67.
77. Hale SL, Dae MW, Kloner RA. Hypothermia during reperfusion limits ‘no-reflow’ injury in a rabbit model of acute myocardial infarction. Cardiovasc Res. 2003;59(3):715–722.
78. Gotberg M, Olivecrona GK, Engblom H, Ugander M, van der Pals J, ARheden H, Erlinge D. Rapid short-duration hypothermia with cold saline and endovascular cooling before reperfusion reduces microvascular obstruction and myocardial infarct size. BMC Cardiovasc Disord. 2008;8:7.
79. Chenoune M, Lidouren F, Ghaleh B, Couvreur N, Dubois-Rande J-L, Berdeaux A, Tissier R. Rapid cooling of the heart with total liquid ventilation prevents transmural myocardial infarction following prolonged ischemia in rabbits. Resuscitation 2010;81(3):359–362.
80. Tissier R, Ghaleh B, Cohen MV, Downey JM, Berdeaux A. Myocardial protection with mild hypothermia. Cardiovasc Res. 2012 May 1;94(2):217-25.
81. Voorhees 3rd WD, Abendschein DR, Tacker Jr WA. Effect of whole-body hypothermia on myocardial blood flow and infarct salvage during coronary artery occlusion in dogs. Am Heart J. 1984;107(5):945–949.
82. Schwartz DS, Bremner RM, Baker CJ, Uppal KM, Barr ML, Cohen RG, Starnes VA. Regional topical hypothermia of the beating heart: preservation of function and tissue. Ann Thorac Surg. 2001;72(3):804–809.
83. Maeng M, Mortensen UM, Kristensen J, Kristiansen SB, Andersen HR. Hypothermia during reperfusion does not reduce myocardial infarct size in pigs. Basic Res Cardiol. 2006;101(1):61–68.
84. Hale SL, Herring MJ, Kloner RA. Delayed treatment with hypothermia protects against the no-reflow phenomenon despite failure to reduce infarct size. J Am Heart Assoc. 2013;2:e004234.
85. Shao ZH, Chang WT, Chan KC, Wojcik KR, Hsu CW, Li CQ, Li J, Anderson T, Qin Y, Becker LB, Hamann KJ, Vanden Hoek TL. Hypothermia-induced cardioprotection using extended ischemia and early reperfusion cooling. Am J Physiol Heart Circ Physiol. 2007;292(4):H1995-2003.
86. Ichihara K, Robishaw JD, Vary TC, Neely JR. Protection of ischemic myocardium from metabolic products. Acta Med Scand Suppl. 1981;651:13–18.
87. Simkhovich BZ, Hale SL, Kloner RA. Metabolic mechanism by which mild regional hypothermia preserves ischemic tissue. J Cardiovasc Pharmacol Ther. 2004;9(2):83–90.
88. Ning X-H, Chen S-H, Xu C-S, Hyyti OM, Qian K, Krueger JJ, Portman MA. Hypothermia preserves myocardial function and mitochondrial protein gene expression during hypoxia. Am J Physiol Heart Circ Physiol. 2003;285(1):H212–H219.
89. Khaliulin I, Clarke SJ, Lin H, Parker J, Suleiman M-S, Halestrap AP. Temperature preconditioning of isolated rat hearts – a potent cardioprotective mechanism involving a reduction in oxidative stress and inhibition of the mitochondrial permeability transition pore. J Physiol. 2007;581:1147–1161.
90. Mochizuki T, Yu S, Katoh T, Aoki K, Sato S. Cardioprotective effect of therapeutic hypothermia at 34°C against ischaemia/reperfusion injury mediated by PI3K and nitric oxide in a rat isolated heart model. Resuscitation 2012;83(2):238-42.
91. Tissier R, Couvreur N, Ghaleh B, Bruneval P, Lidouren F, Morin D, Zini R, Bize A, Chenoune M, Belair MF, Mandet C, Douheret M, Dubois–Rande JL, Parker JC, Cohen MV, Downey JM, Berdeaux A . Rapid cooling preserves the ischaemic myocardium against mitochondrial damage and left ventricular dysfunction. Cardiovasc Res. 2009;83(2):345–353.
92. Curran J, Burkhoff D, Kloner RA. Beyond reperfusion: Acute ventricular unloading and cardioprotection during myocardial infarction. J Cardiovasc Transl Res. 2019;12(2):95-106.
93. Meyns B, Stolinski J, Leunens V, Verbeken E, Flameng W. Left ventricular support by catheter mounted axial flow pump reduces infarct size. J Am Coll Cardiol. 2003;41(7):1087–1095.
94. Yoshitake I, Hata M, Sezai A, Unosawa S, Wakui S, Kimura H, Nakata K, Hata H, Shiono M. The effect of combined treatment with Impella® and landiolol in a swine model of acute myocardial infarction. J Artif Organs 2012;15(3):231–239.
95. Kapur NK, Qiao X, Paruchuri V, Morine KJ, Syed W, Dow S, Shah N, Pandian N, Karas RH. Mechanical pre-conditioning with acute circulatory support before reperfusion limits infarct size in acute myocardial infarction. J Am Coll Cardiol HF. 2015;3(11):873–882.
96. Sun X, Li J, Zhao W, Lu S, Guo C, Lai H, Wang C. Early assistance with left ventricular assist device limits left ventricular remodeling after acute myocardial infarction in a swine model. Artif Organs 2016;40(3):243–251.
97. Esposito ML, Zhang Y, Qiao X, Reyelt L, Paruchuri V, Schnitzler GR, Morine KJ, Annamalai SK, Bogins C, Natov PS, Pedicini R, Breton C, Mullin A, Mackey EE, Patel A, Rowin E, Jaffe IZ, Karas RH, Kapur NK. Left ventricular unloading before reperfusion promotes functional recovery after acute myocardial infarction. J Am Coll Cardiol. 2018;72(5):501–514.
98. Hu X, Dai S, Wu WJ, Tan W, Zhu X, Mu J, Guo Y, Bolli R, Rokosh G. Stromal cell derived factor-1 alphaconfers protection against myocardial ischemia/reperfusion injury: role of the cardiac stromal cell derived factor-1 alpha CXCR4 axis. Circulation 2007;116(6):654–663.
99. Bromage DI, Davidson SM, Yellon DM. Stromal derived factor 1alpha: a chemokine that delivers a two-pronged defence of the myocardium. Pharmacol Ther. 2014;143(3):305–315.
100. Ding YF, Zhang MM, He RR. Role of renal nerve in cardioprotection provided by renal ischemic preconditioning in anesthetized rabbits. Acta Physiol Sin (Sheng Li Xue Bao) 2001;53(1):7-12.
101. Dong JH, Liu YX, Ji ES, He RR. Limb ischemic preconditioning reduces infarct size following myocardial ischemia– reperfusion in rats. Acta Physiol Sin (Sheng Li Xue Bao) 2004;56(1):41–46.
102. Steensrud T, Li J, Dai X, Manlhiot C, Kharbanda RK, Tropak M, Redington A. Pretreatment with the nitric oxide donor SNAP or nerve transection blocks humoral preconditioning by remote limb ischemia or intra-arterial adenosine. Am J Physiol Heart Circ Physiol. 2010;299(5):H1598–H1603.
103. Redington KL, Disenhouse T, Strantzas SC, Gladstone R, Wei C, Tropak MB, Dai X, Manlhiot C, Li J, Redington AN. Remote cardioprotection by direct peripheral nerve stimulation and topical capsaicin is mediated by circulating humoral factors. Basic Res Cardiol. 2012;107(2):241.
104. Jones WK, Fan GC, Liao S, Zhang JM, Wang Y, Weintraub NL, Kranias EG, Schultz JE, Lorenz J, Ren X. Peripheral nociception associated with surgical incision elicits remote non ischemic cardioprotection via neurogenic activation of protein kinase C signaling. Circulation 2009;120(11 Suppl):S1–9.
105. Katare RG, Ando M, Kakinuma Y, Arikawa M, Handa T. Yamasaki F, Sato T. Vagal nerve stimulation prevents reperfusion injury through inhibition of opening of mitochondrial permeability transition pore independent of the bradycardiac effect. J Thorac Cardiovasc Surg. 2009;137(1):223–231.
106. Kong SS, Liu JJ, Yu XJ, Lu Y, Zang WJ. Protection against ischemia induced oxidative stress conferred by vagal stimulation in the rat heart: Involvement of the AMPK-PKC pathway. Int J Mol Sci. 2012;13(11):14311–14325.
107. Cheng YF, Chang YT, Chen WH, Shih HC, Chen YH, Shyu BC, Chen CC. Cardioprotection induced in a mouse model of neuropathic pain via anterior nucleus of paraventricular thalamus. Nat Commun. 2017;8(1):826.
108. Merlocco AC, Redington KL, Disenhouse T, Strantzas SC, Gladstone R, Wei C, Tropak MB, Manlhiot C, Li J, Redington AN. Transcutaneous electrical nerve stimulation as a novel method of remote preconditioning: in vitro validation in an animal model and first human observations. Basic Res Cardiol. 2014;109(3):406.
109. Meerson FZ, Radzievskiĭ CA, Vovk VI, Vorontsova EIa, Shneider AB, Ustinova EE, Golubeva LIu. Adaptive stabilization of myocardium under the influence of electroacupuncture and cardiac protection. Kardiologiia 1991;31(10):72–77.
110. Gao J, Fu W, Jin Z, Yu X. Acupuncture pretreatment protects heart from injury in rats with myocardial ischemia and reperfusion via inhibition of the 𝛽1-adrenoceptor signalling pathway. Life Sciences 2007;80(16):1484–1489.
111. Huang Y, Lu SF, Hu CJ, Fu SP, Shen WX, Liu WX, Li Q, Wang N, He SY, Liang FR, Zhu BM. Electro-acupuncture at Neiguan pretreatment alters genome-wide gene expressions and protects rat myocardium against ischemia-reperfusion. Molecules 2014;19(10):16158–16178.
112. Lu SF, Huang Y, Wang N, Shen WX, Fu SP, Li Q, Yu ML, Liu WX, Chen X, Jing XY, Zhu BM. Cardioprotective effect of electroacupuncture pretreatment on myocardial ischemia/reperfusion injury via antiapoptotic signaling. Evid Based Complement Alternat Med. 2016;2016:4609784.
113. Ye X, Li J, Du C. Effect of eletroacupuncture at Zusanli (ST36) on vagal electrical activity in the rat. Acupuncture Res. 2006;31(5):290–293.
114. Shi L, Fang J, Zhao J, Liu G, Zhao Q, Zhang J, Zhang J, Zhu B, Liang F, Rong P. Comparison of the therapeutic effects of acupuncture at PC6 and ST36 for chronic myocardial ischemia. Evid Based Complement Alternat Med. 2017;2017:7358059.
115. Zhang H, Liu L, Huang G, Zhou L, Wu W, Zhang T, Huang H. Protective effect of electroacupuncture at the Neiguan point in a rabbit model of myocardial ischemia–reperfusion injury. Can J Cardiol. 2009;25(6):359–363.
116. Yang L, Yang J, Wang Q, Chen M, Lu Z, Xiong L. Cardioprotective effects of electroacupuncture pretreatment on patients undergoing heart valve replacement surgery: a randomized controlled trial. Ann Thorac Surg. 2010;89(3):781–786.
117. Wang Q, Liang D, F. Wang, Li W, Han Y, Zhang W, Xie Y, Xin W, Zhou B, Sun D, Cao F, Xiong L. Efficacy of electroacupuncture pretreatment for myocardial injury in patients undergoing percutaneous coronary intervention: a randomized clinical trial with a 2-year follow-up. Int J Cardiol. 2015;194:28–35.
118. Zhou W, Ko Y, Benharash P, Yamakawa K, Patel S, Ajijola OA, Mahajan A. Cardioprotection of electroacupuncture against myocardial ischemia–reperfusion injury by modulation of cardiac norepinephrine release. Am J Physiol Heart Circ Physiol. 2012;302(9):H1818–H1825.
119. Redington KL, Disenhouse T, Li J, Wei C, Dai X, Gladstone R, Manlhiot C, Redington AN. Electroacupuncture reduces myocardial infarct size and improves post-ischemic recovery by invoking release of humoral, dialyzable, cardioprotective factors. J Physiol Sci. 2013;63(3):219-223.
120. Matsumura K, Jeremy RW, Schaper J, Becker LC. Progression of myocardial necrosis during reperfusion of ischemic myocardium. Circulation 1998;97(8):795–804.
121. Rochitte CE, Lima JA, Bluemke DA, Reeder SB, McVeigh ER, Furuta T, Becker LC, Melin JA. Magnitude and time course of microvascular obstruction and tissue injury after acute myocardial infarction. Circulation 1998;98(10):1006–1014.
122. Zhao ZQ, Nakamura M, Wang NP, Velez DA, Hewan-Lowe KO, Guyton RA, Vinten-Johansen J. Dynamic progression of contractile and endothelial dysfunction and infarct extension in the late phase of reperfusion. J Surg Res. 2000 Dec;94(2):133-144.
123. Pfeffer MA. Left ventricular remodeling after acute myocardial infarction. Annu Rev Med. 1995; 46:455–466.
124. Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of thyroid hormone on cardiac function: the relative importance of heart rate, loading conditions, and myocardial contractility in the regulation of cardiac performance in human hyperthyroidism. J Clin Endocrinol Metab. 2002;87(3):968–974.
125. Kahaly GJ, Dillmann WH. Thyroid hormone action in the heart. Endocrine Rev. 2005;26(5):704–728.
126. Klein I, Danzi S. Thyroid disease and the heart. Circulation. 2007;116(15):1725–1735.
127. Friberg L, Werner S, Eggertsen G, Ahnve S. Rapid down-regulation of thyroid hormones in acute myocardial infarction: is it cardioprotective in patients with angina? Arch Intern Med. 2002;162(12):1388–1394.
128. Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, L’Abbate A, Donato L. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 2003;107(5):708–713.
129. Olivares EL, Marassi MP, Fortunato RS, da Silva AC, Costa-e-Sousa RH, Araújo IG, Mattos EC, Masuda MO, Mulcahey MA, Huang SA, Bianco AC, Carvalho DP. Thyroid function disturbance and type 3 iodothyronine deiodinase induction after myocardial infarction in rats a time course study. Endocrinology 2007;148(10):4786–4792.
130. Forini F, Kusmic C, Nicolini G, Mariani L, Zucchi R, Matteucci M, Iervasi G, Pitto L. Triiodothyronine prevents cardiac ischemia/reperfusion mitochondrial impairment and cell loss by regulating miR30a/p53 axis. Endocrinology 2014;155(11):4581-4590.
131. Klein I, Ojamaa K. Mechanisms of disease: Thyroid hormone and the cardiovascular system. N Engl J Med. 2001;344(7):501-509.
132. Iervasi G, Molinaro S, Landi P, Taddei MC, Galli E, Mariani F, L'Abbate A, Pingitore A. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med. 2007;167(14):1526-1532.
133. Song Y, Li J, S. Bian, Qin Z, Song Y, Jin J, Zhao X, Song M, Chen J, Huang L. Association between low free triiodothyronine levels and poor prognosis in patients with acute ST elevation myocardial infarction. Biomed. Res. Int. 2018;2018:9803851.
134. Pingitore A, Iervasi G, Barison A, Prontera C, Pratali L, Emdin M, Giannessi D, Neglia D. Early activation of an altered thyroid hormone profile in asymptomatic or mildly symptomatic idiopathic left ventricular dysfunction. J Card Fail. 2006;12(7):520–526.
135. Pingitore A, Galli E, Barison A, Iervasi A, Scarlattini M, Nucci D, L’Abbate A, Mariotti R, Iervasi G. Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low- T3 syndrome: a randomized, placebo-controlled study. J Clin Endocrinol Metab. 2008;93(4):1351–1358.
136. Gerdes AM, Iervasi G. Thyroid replacement therapy and heart failure. Circulation. 2010;122(4):385–393.
137. Nicolini G, Forini F, Kusmic C, Pitto L, Mariani L, Iervasi G. Early and short-term triiodothyronine supplementation prevents adverse postischemic cardiac remodeling: Role of transforming growth factor-β1 and antifibrotic miRNA signaling. Mol Med. 2016;21(1):900-911.
138. Goldenthal MJ, Ananthakrishnan R, Marín-García J. Nuclear-mitochondrial cross-talk in cardiomyocyte T3 signaling: A time-course analysis. J Mol Cell Cardiol. 2005;39(2):319–326.
139. Marín-García J. Thyroid hormone and myocardial mitochondrial biogenesis. Vascul Pharmacol. 2010;52(3–4):120–130.
140. Forini F, Nicolini G, Kusmic C, D'Aurizio R, Rizzo M, Baumgart M, Groth M, Doccini S, Iervasi G, Pitto L. Integrative analysis of differentially expressed genes and miRNAs predicts complex T3-mediated protective circuits in a rat model of cardiac ischemia reperfusion. Sci Rep. 2018;8(1):13870.
141. Kusmic C, L’Abbate S. TH metabolism in the ischemia/reperfusion models. In: Thyroid and Heart, Eds: Iervasi G, Pingitore A, Gerdes AM & Razvi S, Springer, pp. 71–83. doi: 10.1007/978-3-030-36871-5_6, 2020.
142. Madonna R, Cadeddu C, Deidda M, Giricz Z, Madeddu C, Mele D, Monte I, Novo G, Pagliaro P, Pepe A, Spallarossa P, Tocchetti CG, Varga ZV, Zito C, Geng YJ, Mercuro G, Ferdinandy P. Cardioprotection by gene therapy: A review paper on behalf of the Working Group on Drug Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology. Int J Cardiol. 2015;191:203-210.
143. Lin HH, Chen YH, Chang PF, Lee YT, Yet SF, Chau LY. Heme oxygenase-1 promotes neovascularization in ischemic heart by coinduction of VEGF and SDF-1. J Mol Cell Cardiol 2008; 45(1):44–55.
144. Kusmic C, Barsanti C, Matteucci M, Vesentini N, Pelosi G, Abraham NG, L'Abbate A. Up-regulation of heme oxygenase-1 after infarct initiation reduces mortality, infarct size and left ventricular remodeling: experimental evidence and proof of concept. J Transl Med. 2014;12:89.
145. Yin C, Salloum FN, and Kukreja RC. A novel role of microRNA in late preconditioning: upregulation of endothelial nitric oxide synthase and heat shock protein 70. Circ Res. 2009;104:572–575.
146. Madonna R, Van Laake LW, Botker HE, Davidson SM, De Caterina R, Engel FB, Eschenhagen T, Fernandez-Aviles F, Hausenloy DJ, Hulot JS, Lecour S, Leor J, Menasché P, Pesce M, Perrino C, Prunier F, Van Linthout S, Ytrehus K, Zimmermann WH, Ferdinandy P, Sluijter JPG. ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure. Cardiovasc Res. 2019;115(3):488-500.
147. Maring JA, Lodder K, Mol E, Verhage V, Wiesmeijer KC, Dingenouts CKE, Moerkamp AT, Deddens JC, Vader P, Smits AM, Sluijter JPG, Goumans MJ. Cardiac progenitor cell-derived extracellular vesicles reduce infarct size and associate with increased cardiovascular cell proliferation. J Cardiovasc Transl Res. 2019;12(1):5-17.
148. Kukreja RC, Yin C, Salloum FN. MicroRNAs: new players in cardiac injury and protection. Mol Pharmacol. 2011;80(4):558-564.
149. Vegter EL, van der Meer P, de Windt LJ, Pinto YM, Voors AA. MicroRNAs in heart failure: from biomarker to target for therapy. Eur J Heart Fail. 2016;18(5):457-68.
150. Zhang Y, Hu YW, Zheng L, Wang Q. Characteristics and roles of exosomes in cardiovascular disease. DNA Cell Biol. 2017; 36(3):202–211.
151. Das A, Samidurai A, Salloum FN. Deciphering non-coding RNAs in cardiovascular health and disease. Front Cardiovasc Med. 2018;5:73.
152. Gabisonia K, Prosdocimo G, Aquaro GD, Carlucci L, Zentilin L, Secco I, Ali H, Braga L, Gorgodze N, Bernini F, Burchielli S, Collesi C, Zandonà L, Sinagra G, Piacenti M, Zacchigna S, Bussani R, Recchia FA, Giacca M. MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs. Nature 2019;569(7756):418-422.
153. Przyklenk K. Ischaemic conditioning: pitfalls on the path to clinical translation. Br J Pharmacol. 2015;172(8):1961-1973.
154. Vander Heide RS, Steenbergen C. Cardioprotection and myocardial reperfusion: pitfalls to clinical application. Circ Res. 2013;113(4):464-477.

Most read articles by the same author(s)

Obs.: This plugin requires at least one statistics/report plugin to be enabled. If your statistics plugins provide more than one metric then please also select a main metric on the admin's site settings page and/or on the journal manager's settings pages.