Cardiac surgery patients are now more risky in terms of age, comorbidities, and the need for complex procedures. It brings about reperfusion injury, which leads to dysfunction and/or loss of part of the myocardium. These groups of patients have a higher incidence of postoperative complications and mortality. One way of augmenting intraoperative myocardial protection is the phenomenon of myocardial conditioning, elicited with brief nonlethal episodes of ischaemia-reperfusion. In addition, drugs are being tested that mimic ischaemic conditioning. Such cardioprotective techniques are mainly focused on reperfusion injury, a complex response of the organism to the restoration of coronary blood flow in ischaemic tissue, which can lead to cell death. Extensive research over the last three decades has revealed the basic mechanisms of reperfusion injury and myocardial conditioning, suggesting its therapeutic potential. But despite the enormous efforts that have been expended in preclinical studies, almost all cardioprotective therapies have failed in the third phase of clinical trials. One reason is that evolutionary young cellular mechanisms of protection against oxygen handling are not very robust. Ischaemic conditioning, which is among these, is also limited by this. At present, the prevailing belief is that such options of treatment exist, but their full employment will not occur until subquestions and methodological issues with the transfer into clinical practice have been resolved.

Department of Anesthesiology and Critical Care Medicine Mie University School of Medicine 1577 Kurimamachiya cho Tsu City Mie Prefecture 514 8507 Japan ; Department of Clinical Engineering Suzuka University of Medical Science 1001 1 Kishiokacho Suzuka Mie Prefecture 510 0226 Japan

Department of Cardiovascular Anesthesiology Centre of Cardiovascular and Transplant Surgery Pekarska 53 656 91 Brno Czech Republic ; Department of Cardiovascular Diseases International Clinical Research Center St Anne's University Hospital and Masaryk University Pekarska 53 656 91 Brno Czech Republic

Department of Cardiovascular Diseases International Clinical Research Center St Anne's University Hospital and Masaryk University Pekarska 53 656 91 Brno Czech Republic

Department of Cardiovascular Diseases International Clinical Research Center St Anne's University Hospital and Masaryk University Pekarska 53 656 91 Brno Czech Republic ; Department of Cardiovascular Surgery Centre of Cardiovascular and Transplant Surgery Pekarska 53 656 91 Brno Czech Republic

Institute of Experimental Cardiology Russian Cardiology and Research Complex 3rd Cherepkovskaya 15 A 12552 Moscow Russia

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Taggart DP, Kaul S, Boden WE, et al. Revascularization for unprotected left main stem coronary artery stenosis, stenting or surgery. Journal of the American College of Cardiology. 2008;51(9):885–892. PubMed

Lima ML, Fiorelli AI, Vassallo DV, Pinheiro BB, Stolf NAG, Gomes OM. Comparative experimental study of myocardial protection with crystalloid solutions for heart transplantation. Brazilian Journal of Cardiovascular Surgery. 2012;27(1):110–116. PubMed

Flack JE, III, Cook JR, May SJ, et al. Does cardioplegia type affect outcome and survival in patients with advanced left ventricular dysfunction? Results from the CABG Patch Trial. Circulation. 2000;102(19):III84–III89. PubMed

Beyersdorf F. Ischemia-Reperfusion Injury in Cardiac Surgery. Austin, Tex, USA: Eurekah.com/Landes Bioscience; 2001.

Costa MA, Carere RG, Lichtenstein SV, et al. Incidence, predictors, and significance of abnormal cardiac enzyme rise in patients treated with bypass surgery in the arterial revascularization therapies study (ARTS) Circulation. 2001;104(22):2689–2693. PubMed

Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Circulation. 2007;116(22):2634–2653. PubMed

Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD. Third universal definition of myocardial infarction. Journal of the American College of Cardiology. 2012;60(16):1581–1598. PubMed

Hausenloy DJ, Boston-Griffiths E, Yellon DM. Cardioprotection during cardiac surgery. Cardiovascular Research. 2012;94(2):253–265. PubMed PMC

Domanski MJ, Mahaffey K, Hasselblad V, et al. Association of myocardial enzyme elevation and survival following coronary artery bypass graft surgery. Journal of the American Medical Association. 2011;305(6):585–591. PubMed

Buscberg GD. Myocardial protection: an overview. Seminars in Thoracic and Cardiovascular Surgery. 1993;5:98–106. PubMed

Chambers DJ, Hearse DJ. Cardioplegia and surgical ischemia. In: Sperelakis N, Kurachi Z, Terzic A, Cohen MV, editors. Heart Physiology and Pathophysiology. San Diego, Calif, USA: Academic Press; 2001.

Chambers A, Fallouh H, Kentish CJ, Chambers DJ. Cardioplegia by polarised arrest: experimental studies with potential for clinical application. European Journal of Heart Failure. Supplement. 2009;8(2):p. 256.

Chambers DJ, Fallouh HB. Cardioplegia and cardiac surgery: pharmacological arrest and cardioprotection during global ischemia and reperfusion. Pharmacology and Therapeutics. 2010;127(1):41–52. PubMed

Jennings RB, Sommers HB, Smyth GA, Flack HA, Linn H. Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Archives of Pathology. 1960;70:68–78. PubMed

Monassier JP, Gressin V, Louvard Y, Hanssen M, Levy J, Katz O. The myocardial reperfusion syndrome. Archives des Maladies du Coeur et des Vaisseaux. 1992;85(5):743–750. PubMed

Jennings RB, Murry CE, Steenbergen C, Jr., Reimer KA. Development of cell injury in sustained acute ischemia. Circulation. 1990;82(3, supplement):II2–II12. PubMed

Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation. 1977;56(5):786–794. PubMed

Naka Y, Stern DM, Pinski DJ. The pathophysiology and biochemistry of myocardial ischemia, necrosis, and reperfusion. In: Fuster V, Ross R, Topol EJ, editors. Atherosclerosis and Coronary Artery Disease. Philadelphia, Pa , USA: Lippincot -Raven; 1996. pp. 807–814.

Krug A, Du Mesnil DR, Korb G. Blood supply of the myocardium after temporary coronary occlusion. Circulation Research. 1966;19(1):57–62. PubMed

Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? Journal of Clinical Investigation. 1985;76(5):1713–1719. PubMed PMC

Manning AS, Herse DJ. Reperfusion-induced arrhythmias: mechanism and prevention. Journal of Molecular and Cellular Cardiology. 1984;16:497–418. PubMed

Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation. 1982;66(6):1146–1149. PubMed

Bolli R, Marbán E. Molecular and cellular mechanisms of myocardial stunning. Physiological Reviews. 1999;79(2):609–634. PubMed

Weman SM, Karhunen PJ, Penttilä A, Järvinen AA, Salminen U-S. Reperfusion injury associated with one-fourth of deaths after coronary artery bypass grafting. The Annals of Thoracic Surgery. 2000;70(3):807–812. PubMed

Fröhlich GM, Meier P, White SK, Yellon DM, Hausenloy DJ. Myocardial reperfusion injury: looking beyond primary PCI. European Heart Journal. 2013;34(23):1714–1724. PubMed

Kloner RA. Does reperfusion injury exist in humans? Journal of the American College of Cardiology. 1993;21(2):537–545. PubMed

Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. The New England Journal of Medicine. 2007;357(11):1074–1135. PubMed

Hori M, Kitakaze M, Sato H, et al. Staged reperfusion attenuates myocardial stunning in dogs. Role of transient acidosis during early reperfusion. Circulation. 1991;84(5):2135–2145. PubMed

Heusch G. Postconditioning: old wine in a new bottle? Journal of the American College of Cardiology. 2004;44(5):1111–1112. PubMed

Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation. 2005;112(14):2143–2148. PubMed

Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. Journal of Clinical Investigation. 2005;115(5):500–508. PubMed PMC

Davies KJ. Oxidative stress: the paradox of aerobic life. Biochemical Society Symposium. 1995;61:1–31. PubMed

Allen DG, Orchard CH. Myocardial contractile function during ischemia and hypoxia. Circulation Research. 1987;60(2):153–168. PubMed

Hearse DJ, Humphrey SM, Chain EB. Abrupt reoxygenation of the anoxic potassium arrested perfused rat heart: a study of myocardial enzyme release. Journal of Molecular and Cellular Cardiology. 1973;5(4):395–407. PubMed

Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. The New England Journal of Medicine. 2007;357(11):1121–1135. PubMed

Gustafsson ÅB, Gottlieb RA. Heart mitochondria: gates of life and death. Cardiovascular Research. 2008;77(2):334–343. PubMed

Sanada S, Komuro I, Kitakaze M. Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures. American Journal of Physiology: Heart and Circulatory Physiology. 2011;301(5):H1723–H1741. PubMed

Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124–1136. PubMed

Shibi K, Heares DJ. Preconditioning of ischemic myocardium: reperfusion-induced arrhythmias. The American Journal of Physiology. 1987;253:H1470–H1476. PubMed

Asimakis GK, Inners-McBride K, Medellin G, Conti VR. Ischemic preconditioning attenuates acidosis and postischemic dysfunction in isolated rat heart. The American Journal of Physiology—Heart and Circulatory Physiology. 1992;263(3):H887–H894. PubMed

Jaffe MD, Quinn NK. Warm-up phenomenon in angina pectoris. The Lancet. 1980;2(8201):934–936. PubMed

Marber MS, Latchman DS, Walker JM, Yellon DM. Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation. 1993;88(3):1264–1272. PubMed

Keusch G, Boengler K, Schulz R. Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation. 2008;118(19):1915–1919. PubMed

Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM. Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning? Cardiovascular Research. 2002;55(3):534–543. PubMed

Bolli R. The late phase of preconditioning. Circulation Research. 2000;87(11):972–983. PubMed

West MB, Rokosh G, Obal D, et al. Cardiac myocyte-specific expression of inducible nitric oxide synthase protects against ischemia/reperfusion injury by preventing mitochondrial permeability transition. Circulation. 2008;118(19):1970–1978. PubMed PMC

Yamashita N, Nishida M, Hoshida S, et al. Induction of manganese superoxide dismutase in rat cardiac myocytes increases tolerance to hypoxia 24 hours after preconditioning. Journal of Clinical Investigation. 1994;94(6):2193–2199. PubMed PMC

Shinmura K, Bolli R, Liu SQ, et al. Aldose reductase is an obligatory mediator of the late phase of ischemic preconditioning. Circulation Research. 2002;91(3):240–246. PubMed

Zhou J, Pei J, Wang G, et al. Inducible HSP70 mediates delayed cardioprotection via U-50488H pretreatment in rat ventricular myocytes. American Journal of Physiology-Heart and Circulatory Physiology. 2001;281(1):H40–H47. PubMed

Patel HH, Hsu AK, Gross GJ. COX-2 and iNOS in opioid-induced delayed cardioprotection in the intact rat. Life Sciences. 2004;75(2):129–140. PubMed

Zhao Z, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. The American Journal of Physiology—Heart and Circulatory Physiology. 2003;285(2):H579–H588. PubMed

Skyschally A, van Caster P, Iliodromitis EK, Schulz R, Kremastinos DT, Heusch G. Ischemic postconditioning: experimental models and protocol algorithms. Basic Research in Cardiology. 2009;104(5):469–483. PubMed

Whittaker P, Przyklenk K. Reduction of infarct size in vivo with ischemic preconditioning: mathematical evidence for protection via non-ischemic tissue. Basic Research in Cardiology. 1994;89(1):6–15. PubMed

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. PubMed

Kharbanda RK, Mortensen UM, White PA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation. 2002;106(23):2881–2883. PubMed

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. The Lancet. 2010;375(9716):727–734. PubMed

Andreka G, Vertesaljai M, Szantho G, et al. Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs. Heart. 2007;93(6):749–752. PubMed PMC

Breivik L, Helgeland E, Aarnes EK, Mrdalj J, Jonassen AK. Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3K/Akt-dependent cell-survival signaling at reperfusion. Basic Research in Cardiology. 2011;106(1):135–145. PubMed PMC

Shimizu M, Tropak M, Diaz RJ, et al. Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clinical Science. 2009;117(5):191–200. PubMed

Steensrud T, Li J, Dai X, et al. Pretreatment with the nitric oxide donor SNAP or nerve transection blocks humoral preconditioning by remote limb ischemia or intra-arterial adenosine. American Journal of Physiology—Heart and Circulatory Physiology. 2010;299(5):H1598–H1603. PubMed

Mastitskaya S, Marina N, Gourine A, et al. Cardioprotection evoked by remote ischaemic preconditioning is critically dependent on the activity of vagal pre-ganglionic neurones. Cardiovascular Research. 2012;95(4):487–494. PubMed PMC

Lim SY, Yellon DM, Hausenloy DJ. The neural and humoral pathways in remote limb ischemic preconditioning. Basic Research in Cardiology. 2010;105(5):651–655. PubMed

Hausenloy DJ, Mwamure PK, Venugopal V, et al. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. The Lancet. 2007;370(9587):575–579. PubMed

Ali N, Rizwi F, Iqbal A, Rashid A. Induced remote ischemic pre-conditioning on ischemia-reperfusion injury in patients undergoing coronary artery bypass. Journal of the College of Physicians and Surgeons Pakistan. 2010;20(7):427–431. PubMed

Hong DM, Min JJ, Kim JH, et al. The effect of remote ischaemic preconditioning on myocardial injury in patients undergoing off-pump coronary artery bypass graft surgery. Anaesthesia and Intensive Care. 2010;38(5):924–929. PubMed

Wagner R, Piler P, Bedanova H, Adamek P, Grodecka L, Freiberger T. Myocardial injury is decreased by late remote ischaemic preconditioning and aggravated by tramadol in patients undergoing cardiac surgery: a randomised controlled trial. Interactive Cardiovascular and Thoracic Surgery. 2010;11(6):758–762. PubMed

Wu Q, Gui P, Wu J, et al. Effect of limb ischemic preconditioning on myocardial injury in patients undergoing mitral valve replacement surgery: a randomized controlled trial. Circulation Journal. 2011;75(8):1885–1889. PubMed

Xie JJ, Liao XL, Chen WG, et al. Remote ischaemic preconditioning reduces myocardial injury in patients undergoing heart valve surgery: randomised controlled trial. Heart. 2012;98(5):384–388. PubMed

Hoole SP, Heck PM, Sharples L, et al. Cardiac remote ischemic preconditioning in coronary stenting (CRISP stent) study: a prospective, randomized control trial. Circulation. 2009;119(6):820–827. PubMed

Munk K, Andersen NH, Schmidt MR, et al. Remote ischemic conditioning in patients with myocardial infarction treated with primary angioplasty: impact on left ventricular function assessed by comprehensive echocardiography and gated single-photon emission CT. Circulation: Cardiovascular Imaging. 2010;3(6):656–662. PubMed

Rentoukas I, Giannopoulos G, Kaoukis A, et al. Cardioprotective role of remote ischemic periconditioning in primary percutaneous coronary intervention. JACC: Cardiovascular Interventions. 2010;3(1):49–55. PubMed

Rahman IA, Mascaro JG, Steeds RP, et al. Remote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment? Circulation. 2010;122(11):S53–S59. PubMed

Lucchinetti E, Bestmann L, Feng J, et al. Remote ischemic preconditioning applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass graft surgery: lack of synergy or evidence of antagonism in cardioprotection? Anesthesiology. 2012;116(2):296–310. PubMed

Young PJ, Dalley P, Garden A, et al. A pilot study investigating the effects of remote ischemic preconditioning in high-risk cardiac surgery using a randomized controlled double-blind protocol. Basic Research in Cardiology. 2012;107(3, article 0256) PubMed

Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. The Lancet. 1993;342(8866):276–277. PubMed

Jenkins DP, Pugsley WB, Alkhulaifi AM, Kemp M, Hooper J, Yellon DM. Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery. Heart. 1997;77(4):314–318. PubMed PMC

Walsh SR, Tang TY, Kullar P, Jenkins DP, Dutka DP, Gaunt ME. Ischaemic preconditioning during cardiac surgery: systematic review and meta-analysis of perioperative outcomes in randomised clinical trials. European Journal of Cardio-thoracic Surgery. 2008;34(5):985–994. PubMed

Cheung MMH, Kharbanda RK, Konstantinov IE, et al. Randomized controlled trial of the effects of remove ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. Journal of the American College of Cardiology. 2006;47(11):2277–2282. PubMed

Thielmann M, Kottenberg E, Boengler K, et al. Remote ischemic preconditioning reduces myocardial injury after coronary artery bypass surgery with crystalloid cardioplegic arrest. Basic Research in Cardiology. 2010;105(5):657–664. PubMed

Karuppasamy P, Chaubey S, Dew T, et al. Remote intermittent ischemia before coronary artery bypass graft surgery: a strategy to reduce injury and inflammation? Basic Research in Cardiology. 2011;106(4):511–519. PubMed

D'Ascenzo F, Cavallero E, Moretti C, et al. Remote ischaemic preconditioning in coronary artery bypass surgery: a meta-analysis. Heart. 2012;98(17):1267–1271. PubMed

Hausenloy DJ, Candilio L, Laing C, et al. Effect of remote ischemic preconditioning on clinical outcomes in patients undergoing coronary artery bypass graft surgery (ERICCA): rationale and study design of a multi-centre randomized double-blinded controlled clinical trial. Clinical Research in Cardiology. 2012;101(5):339–348. PubMed

Luo W, Li B, Lin G, Huang R. Postconditioning in cardiac surgery for tetralogy of Fallot. The Journal of Thoracic and Cardiovascular Surgery. 2007;133(5):1373–1374. PubMed

Luo W, Li B, Chen R, Huang R, Lin G. Effect of ischemic postconditioning in adult valve replacement. European Journal of Cardio-thoracic Surgery. 2008;33(2):203–208. PubMed

Zhong H, Gao Z, Chen M, et al. Cardioprotective effect of remote ischemic postconditioning on children undergoing cardiac surgery: a randomized controlled trial. Paediatric Anaesthesia. 2013;23(8):726–733. PubMed

Hong DM, Lee E-H, Kim HJ, et al. Does remote ischaemic preconditioning with postconditioning improve clinical outcomes of patients undergoing cardiac surgery? Remote Ischaemic Preconditioning with Postconditioning Outcome Trial. European Heart Journal. 2013;35(3):176–183. PubMed

Kottenberg E, Thielmann M, Bergmann L, et al. Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol—a clinical trial. Acta Anaesthesiologica Scandinavica. 2012;56(1):30–38. PubMed

Burns PG, Krukenkamp IB, Caldarone CA, Gaudette GR, Bukhari EA, Levitsky S. Does cardiopulmonary bypass alone elicit myoprotective preconditioning? Circulation. 1995;92(9):II447–II451. PubMed

Pavione MA, Carmona F, De Castro M, Carlotti APCP. Late remote ischemic preconditioning in children undergoing cardiopulmonary bypass: a randomized controlled trial. Journal of Thoracic and Cardiovascular Surgery. 2012;144(1):178–e1. PubMed

Lee HT, LaFaro RJ, Reed GE. Pretreatment of human myocardium with adenosine during open heart surgery. Journal of Cardiac Surgery. 1995;10(6):665–676. PubMed

Mentzer RM, Jr., Rahko PS, Molina-Viamonte V, et al. Safety, tolerance, and efficacy of adenosine as an additive to blood cardioplegia in humans during corona, artery bypass surgery. American Journal of Cardiology. 1997;79(12):38–43. PubMed

Belhomme D, Peynet J, Florens E, Tibourtine O, Kitakaze M, Menasche P. Is adenosine preconditioning truly cardioprotective in coronary artery bypass surgery? The Annals of Thoracic Surgery. 2000;70:590–594. PubMed

Rinne T, Laurikka J, Penttilä I, Kaukinen S. Adenosine with cold blood cardioplegia during coronary revascularization. Journal of Cardiothoracic and Vascular Anesthesia. 2000;14(1):18–20. PubMed

Wei M, Wang X, Kuukasjärvi P, et al. Bradykinin preconditioning in coronary artery bypass grafting. Annals of Thoracic Surgery. 2004;78(2):492–497. PubMed

Nebigil CG, Etienne N, Messaddeq N, Maroteaoux L. Serotonin is a novel survival factor of cardiomyocytes: mitochondria as a target of 5-HT2B receptor signaling. The FASEB Journal. 2003;17:1373–1375. PubMed

Bilir A, Erkasap N, Koken T, et al. Effects of tramadol on myocardial ischaemia -reperfusion injury. Scandinavian Cardiovascular Journal. 2007;41:242–247. PubMed

Golino P, Piscione F, Willerson JT, et al. Divergent effects of serotonin on coronary-artery dimensions and blood flow in patients with coronary atherosclerosis and control patients. The New England Journal of Medicine. 1991;324:641–648. PubMed

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. The Lancet. 2007;370(9597):1483–1493. PubMed

Lønborg J, Vejlstrup N, Kelbæk H, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. European Heart Journal. 2012;33(12):1491–1499. PubMed

Symons JA, Myles PS. Myocardial protection with volatile anaesthetic agents during coronary artery bypass surgery: a meta-analysis. British Journal of Anaesthesia. 2006;97(2):127–136. PubMed

Kruzliak P, Pechanova O, Kara T. New perspectives of nitric oxide donors in cardiac arrest and cardiopulmonary resuscitation treatment. Heart Failure Reviews. 2014;19(3):383–390. PubMed PMC

Sun J, Morgan M, Shen RF, Steenbergen C, Murphy E. Preconditioning results in S-nitrosylation of proteins involved in regulation of mitochondrial energetics and calcium transport. Circulation Research. 2007;101(11):1155–1163. PubMed

Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. The New England Journal of Medicine. 2008;359(5):473–481. PubMed

Hausenloy DJ, Kunst G, Boston-Griffiths E, et al. The effect of cyclosporin-A on peri-operative myocardial injury in adult patients undergoing coronary artery bypass graft surgery: a randomised controlled clinical trial. Heart. 2014;100:544–549. PubMed PMC

Atar D, Abitbol JL, Arheden H, et al. Rationale and design of the “MITOCARE” Study: a phase II, multicenter, randomized, double-blind, placebo-controlled study to assess the safety and efficacy of TRO40303 for the reduction of reperfusion injury in patients undergoing percutaneous coronary intervention for acute myocardial infarction. Cardiology. 2012;123(4):201–207. PubMed

Chakrabarti AK, Feeney K, Abueg C, et al. Rationale and design of the EMBRACE STEMI study: a phase 2a, randomized, double-blind, placebo-controlled trial evaluate the safety, tolerability and on patients treated with standard therapy including stenting for elevation. American Heart Journal. 2013;165(4):509–514. PubMed

Clinical Trials gov. A service of the U.S. National Institutes of Health. Evaluation of the Safety and Efficacy of Using Insulin-like Growth Factor-1 in Patients With a Heart Attack (RESUS-AMI) NCT01438086, http://clinicaltrials.gov/show/NCT01438086.

Clinical Trials gov. A service of the U.S. National Institutes of Health. Mangafodipir as an Adjunct to Percutaneous Coronary Intervention (MANAMI) NCT00966563, http://clinicaltrials.gov/ct2/show/NCT00966563.

Clinical Trials gov. A service of the U.S. National Institutes of Health. The Melatonin Adjunct in the Acute Myocardial Infarction Treated With Angioplasty (MARIA) NCT00640094, http://clinicaltrials.gov/ct2/show/NCT00640094.

Clinical Trials gov. A service of the U.S. National Institutes of Health. Effects of Nitric Oxide for Inhalation in Myocardial Infarction Size (NOMI) NCT01398384, http://clinicaltrials.gov/show/NCT01398384.

Clinical Trials Government. A service of the U.S. National Institutes of Health. Nitrites in Acute Myocardial Infarction (NIAMI) NCT01388504, http://clinicaltrials.gov/ct2/show/NCT01388504.

Jones DA, Andiapen M, van-Eijl TJA, et al. The safety and efficacy of intracoronary nitrite infusion during acute myocardial infarction (NITRITE-AMI): study protocol of a randomised controlled trial. BMJ Open. 2013;3(4)e002813 PubMed PMC

Clinical Trials government. A service of the U.S. National Institutes of Health. A Study of the Safety and Efficacy of Injectable Thymosin Beta 4 for Treating Acute Myocardial Infarction. http://clinicaltrials.gov/ct2/show/NCT01311518?term=thymosin+4+beta&rank=1.

Clinical Trials gov. A service of the U.S. National Institutes of Health. Effect of METOprolol in CARDioproteCtioN During an Acute Myocardial InfarCtion. The METOCARD-CNIC Trial NCT01311700, http://clinicaltrials.gov/ct2/show/NCT01311700?term=metocard&rank=1.

Chaitman BR. A review of the GUARDIAN trial results: Clinical implications and the significance of elevated perioperative CK-MB on 6-month survival. Journal of Cardiac Surgery. 2003;18(1):13–20. PubMed

Mentzer RM, Jr., Bartels C, Bolli R, et al. Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study. Annals of Thoracic Surgery. 2008;85(4):1261–1270. PubMed

Newman MF, Ferguson TB, White JA, et al. Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial. Journal of the American Medical Association. 2012;308(2):157–164. PubMed

Smith PK, Shernan SK, Chen JC, et al. Effects of C5 complement inhibitor pexelizumab on outcome in high-risk coronary artery bypass grafting: combined results from the PRIMO-CABG i and II trials. Journal of Thoracic and Cardiovascular Surgery. 2011;142(1):89–98. PubMed

The Emip-FR Group. Effect of 48-h intravenous trimetazidine on short- and long-term outcomes of patients with acute myocardial infarction, with and without thrombolytic therapy; A double-blind, placebo-controlled, randomized trial. The EMIP-FR Group. European Myocardial Infarction Project—Free Radicals. European Heart Journal. 2000;21(18):1537–1546. PubMed

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. Journal of the American College of Cardiology. 2001;38(6):1644–1650. PubMed

Lincoff AM, Roe M, Aylward P, et al. Inhibition of delta-protein kinase C by delcasertib as an adjunct to primary percutaneous coronary intervention for acute anterior ST-segment elevation myocardial infarction: results of the PROTECTION AMI randomized controlled trial. European Heart Journal. 2014 PubMed

Eefting FD, Cramer MJ, Stella PRS, Rensing BJ, Doevendans PA. Rationale of the REPARATOR study: a randomised trial with serial cardiac MRI follow-up testing the ability of atorvastatin to reduce reperfusion damage after primary PCI for acute MI. Netherlands Heart Journal. 2006;14(3):95–98. PubMed PMC

Fatovich DM, Prentice DA, Dobb GJ. Magnesium in cardiac arrest (the magic trial ) Resuscitation. 1997;35:237–241. PubMed

Mehta SR, Yusuf S, Díaz R, et al. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the controlled trial. The Journal of the American Medical Association. 2005;293:437–446. PubMed

Najjar SS, Rao SV, Melloni C, et al. Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction: REVEAL: a randomized controlled trial. JAMA. 2011;305(18):1863–1872. PubMed PMC

Ott I, Schulz S, Mehilli J, et al. Erythropoietin in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomized, double-blind trial. Circulation: Cardiovascular Interventions. 2010;5:408–413. PubMed

Atar D, Petzelbauer P, Schwitter J, et al. Effect of intravenous FX06 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. results of the F.I.R.E. (efficacy of FX06 in the prevention of myocardial reperfusion injury) trial. Journal of the American College of Cardiology. 2009;53(8):720–729. PubMed

Heusch G. Cardioprotection: chances and challenges of its translation to the clinic. The Lancet. 2013;381(9861):166–175. PubMed

Takahama H, Minamino T, Asanuma H, et al. Prolonged targeting of ischemic/ reperfused myocardium by liposomal adenosine augments cardioprotection in rats. Journal of the American College of Cardiology. 2009;53(8):709–717. PubMed

Bolli R, Becker L, Gross G, Mentzer R, Jr., Balshaw D, Lathrop DA. Myocardial protection at a crossroads: the need for translation into clinical therapy. Circulation Research. 2004;95(2):125–134. PubMed

Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II) Journal of the American College of Cardiology. 2005;45(11):1775–1780. PubMed

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):1172–1179. PubMed PMC

Lefer DJ, Bolli R. Development of an NIH Consortium for preclinical assessment of cardio protective therapies (CAESAR): a paradigm shift in studies of infarct size limitation. Journal of Cardiovascular Pharmacology and Therapeutics. 2011;16(3-4):332–339. PubMed

Hausenloy DJ, Erik Botker 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. Cardiovascular Research. 2013;98(1):7–27. PubMed

The utility of biomarker risk prediction score in patients with chronic heart failure

Unbalanced upregulation of ryanodine receptor 2 plays a particular role in early development of daunorubicin cardiomyopathy