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Treatment of Myocardial Ischemia/Reperfusion Injury by Ischemic and Pharmacological Postconditioning

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ABSTRACT

Timely reperfusion is the only way to salvage ischemic myocardium from impending infarction. However, reperfusion also adds a further component to myocardial injury such that the ultimate infarct size is the result of both ischemia‐ and reperfusion‐induced injury. Modification of reperfusion can attenuate reperfusion injury and thus reduce infarct size. Ischemic postconditioning is a maneuver of repeated brief interruption of reperfusion by short‐lasting coronary occlusions which results in reduced infarct size. Cardioprotection by ischemic postconditioning is mediated through delayed reversal of acidosis and the activation of a complex signal transduction cascade, including triggers such as adenosine, bradykinin, and opioids, mediators such as protein kinases and, notably, mitochondrial function as effector. Inhibition of the mitochondrial permeability transition pore appears to be a final signaling step of ischemic postconditioning. Several drugs which recruit in part such signaling steps of ischemic postconditioning can induce cardioprotection, even when the drug is only administered at reperfusion, that is, there is also pharmacological postconditioning.

Ischemic and pharmacological postconditioning have been translated to patients with acute myocardial infarction in proof‐of‐concept studies, but further mechanistic insight is needed to optimize the conditions and algorithms of cardioprotection by postconditioning. © 2015 American Physiological Society. Compr Physiol 5:1123‐1145, 2015.

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Figure 1. Figure 1. Infarct size results from a combination of ischemia‐induced and reperfusion‐induced injury. Ischemia‐induced injury depends on the duration of ischemia and on the amount of residual blood flow. Reperfusion‐induced injury depends also on the duration and severity of the preceding ischemia. The greater the ischemia‐induced injury, the less myocardium is salvaged but also potentially damaged by reperfusion.
Figure 2. Figure 2. A typical no‐reflow area within infarcted pig myocardium is shown in contrast‐enhanced magnetic resonance imaging (A) and in histochemical staining by triphenyl tetrazolium chloride (B). Histology of the no‐reflow area (C) and the surrounding, hyperenhanced area (D, scale bar 40 μm) with signs of edema and contraction‐band necrosis. Typical erythrocyte plugging in a capillary (E, scale bar 10 μm). Adapted from (39) with permission.
Figure 3. Figure 3. Schematic diagram of coronary microembolization after spontaneous or interventional atherosclerotic plaque rupture. Microinfarcts with an inflammatory response are associated with arrhythmias, contractile dysfunction and impaired coronary reserve. Proinflammatory and vasomotor substances contribute to contractile dysfunction and impaired coronary reserve. Adapted from (81) with permission.
Figure 4. Figure 4. After persistent ischemia secondary to coronary occlusion in dogs for 24 h myocardial tissue creatine kinase is depleted, and the magnitude of this depletion is related to the severity of ischemia, as reflected by the magnitude of ST segment elevation on the ECG at 15 min ischemia. With reperfusion after 3 h coronary occlusion, the creatine kinase depletion is largely attenuated. Adapted from (136) with permission.
Figure 5. Figure 5. Ischemic preconditioning by four cycles of 5 min coronary occlusion and 5 min reperfusion before sustained 40 min coronary occlusion reduces infarct size markedly. Adapted from (149) with permission.
Figure 6. Figure 6. Ischemic postconditioning by three cycles of 30 s reperfusion and 30 s reocclusion following sustained 60 min coronary occlusion reduces infarct size markedly. Adapted from (247) with permission.
Figure 7. Figure 7. Gentle reperfusion by restoration of baseline coronary blood flow over 30 min reperfusion following 90 min ischemia reduces infarct size. Data adapted, with permission, from (150). The difference to the infarct size following an ischemic postconditioning protocol of six cycles of 20 s reperfusion and 20 s reocclusion is small. Data adapted, with permission, from (209).
Figure 8. Figure 8. Simplified scheme of cardioprotective signal transduction. Please note, this scheme does not entail the dimension of time and details of mitochondrial signaling are displayed in Figure 10. Abbreviations: Akt protein kinase B; cAMP cyclic adenosine monophosphate; cGMP cyclic guanosine monophosphate; DAG diacylglycerol; ERK extracellular regulated kinase; Gs/Gi/q stimulatory/inhibitory G protein; GPCR G protein‐coupled receptor; gp130 glycoprotein 130; GSK3β glycogen synthase kinase 3 β; IP3 inositoltrisphosphate; JAK Janus kinase; KATP ATP‐dependent potassium channel; Na+/H+ sodium/proton‐exchanger; NO nitric oxide; eNOS endothelial nitric oxide synthase; PDK phosphoinositide‐dependent kinase; PI3K phosphatidylinositol (4,5)‐bisphosphate 3‐kinase; PIP3 phosphatidylinositoltrisphosphate; PKC protein kinase C; PKG protein kinase G; PLC phospholipase C; ROS reactive oxygen species; sGC soluble guanylate cyclase; SR sarcoplasmic reticulum; STAT signal transducer and activator of transcription; TNFα tumor necrosis factor α. The NO/PKG‐pathway is displayed in green, the RISK‐pathway in yellow, the SAFE‐pathway in red.
Figure 9. Figure 9. Blockade of the RISK pathway by combined wortmannin and UO 126 during reperfusion does not abrogate the infarct size reduction by ischemic postconditioning with six cycles of 20 s reperfusion and 20 s reocclusion following 90 min ischemia in pigs. Data adapted, with permission, from (209).
Figure 10. Figure 10. Ischemic postconditioning reduces infarct size in pigs [(A) Triphenyl tetrazolium chloride (TTC) staining, (B) mean ± SEM]. Infarct size reduction is abrogated by inhibition of signal transducer and activator of transcription 3 (STAT 3) (C). Original Western blot (D) and averaged data (E) of increased mitochondrial STAT 3 phosphorylation at tyrosine 705 after ischemic postconditioning. Isolated mitochondria (F) have increased ADP‐stimulated respiration after ischemic postconditioning (G). Data adapted from (85) and modified figure from (75) with permission.
Figure 11. Figure 11. Simplified scheme of cardioprotective signaling at the mitochondria. Abbreviations: I, II, III, and IV respiratory chain complexes I, II, III, and IV; CypD, cyclophilin D; ER/SR, endoplasmic/sarcoplasmic reticulum; F, F‐ATPase; GSK3β, glycogen synthase kinase 3 β; KATP, ATP‐dependent potassium channel; MPTP, mitochondrial permeability transition pore; NO, nitric oxide; NOS, nitric oxide synthase; PKC, protein kinase C; PKG, protein kinase G; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription.
Figure 12. Figure 12. Ischemic postconditioning by 4 cycles of 1 min reperfusion and 1 min reocclusion of the culprit coronary artery by intracoronary balloon inflation in patients with acute ST segment elevation myocardial infarction reduces the release of creatine kinase, whereas duration of ischemia and area at risk are not different by comparison to patients without ischemic postconditioning. Adapted from (215) with permission. Infarct size by single photon emission computer tomography (SPECT) remains reduced at 6 months. Adapted from (220) with permission.
Figure 13. Figure 13. Forest plot of clinical trials with ischemic postconditioning and pharmacological postconditioning in patients with acute myocardial infarction. Ischemic postconditioning reduced infarct size in most studies, whereas pharmacological postconditioning reduced infarct size only when using atrial natriuretic peptide (ANP), exenatide, cyclosporine or metoprolol. CK, creatine kinase; CK‐MB, creatine kinase‐myocardial band; MRI, magnetic resonance imaging; PLA, placebo; PoC, ischemic postconditioning; SPECT, single photon emission computer tomography; TnI, troponin I.
Figure 14. Figure 14. Coronary microembolization during early reperfusion increases infarct size, and the combination of ischemic postconditioning with coronary microembolization results in only a small infarct size reduction by comparison to plain full reperfusion. Adapted from (211) with permission.
Figure 15. Figure 15. Confounding variables which reduce infarct size in the placebo group and increase infarct size in the conditioning group tend to diminish the difference between groups and make identification of cardioprotection more difficult. Adapted from (74) with permission.
Figure 16. Figure 16. Cyclosporine A when given just before reperfusion reduces infarct size in mice and pigs. Adapted from (14) and (208) with permission. Cyclosporine A when given just before reperfusion also reduces infarct size, as reflected by creatine kinase release, in patients with acute myocardial infarction. CK, creatine kinase. Adapted from (170) with permission.


Figure 1. Infarct size results from a combination of ischemia‐induced and reperfusion‐induced injury. Ischemia‐induced injury depends on the duration of ischemia and on the amount of residual blood flow. Reperfusion‐induced injury depends also on the duration and severity of the preceding ischemia. The greater the ischemia‐induced injury, the less myocardium is salvaged but also potentially damaged by reperfusion.


Figure 2. A typical no‐reflow area within infarcted pig myocardium is shown in contrast‐enhanced magnetic resonance imaging (A) and in histochemical staining by triphenyl tetrazolium chloride (B). Histology of the no‐reflow area (C) and the surrounding, hyperenhanced area (D, scale bar 40 μm) with signs of edema and contraction‐band necrosis. Typical erythrocyte plugging in a capillary (E, scale bar 10 μm). Adapted from (39) with permission.


Figure 3. Schematic diagram of coronary microembolization after spontaneous or interventional atherosclerotic plaque rupture. Microinfarcts with an inflammatory response are associated with arrhythmias, contractile dysfunction and impaired coronary reserve. Proinflammatory and vasomotor substances contribute to contractile dysfunction and impaired coronary reserve. Adapted from (81) with permission.


Figure 4. After persistent ischemia secondary to coronary occlusion in dogs for 24 h myocardial tissue creatine kinase is depleted, and the magnitude of this depletion is related to the severity of ischemia, as reflected by the magnitude of ST segment elevation on the ECG at 15 min ischemia. With reperfusion after 3 h coronary occlusion, the creatine kinase depletion is largely attenuated. Adapted from (136) with permission.


Figure 5. Ischemic preconditioning by four cycles of 5 min coronary occlusion and 5 min reperfusion before sustained 40 min coronary occlusion reduces infarct size markedly. Adapted from (149) with permission.


Figure 6. Ischemic postconditioning by three cycles of 30 s reperfusion and 30 s reocclusion following sustained 60 min coronary occlusion reduces infarct size markedly. Adapted from (247) with permission.


Figure 7. Gentle reperfusion by restoration of baseline coronary blood flow over 30 min reperfusion following 90 min ischemia reduces infarct size. Data adapted, with permission, from (150). The difference to the infarct size following an ischemic postconditioning protocol of six cycles of 20 s reperfusion and 20 s reocclusion is small. Data adapted, with permission, from (209).


Figure 8. Simplified scheme of cardioprotective signal transduction. Please note, this scheme does not entail the dimension of time and details of mitochondrial signaling are displayed in Figure 10. Abbreviations: Akt protein kinase B; cAMP cyclic adenosine monophosphate; cGMP cyclic guanosine monophosphate; DAG diacylglycerol; ERK extracellular regulated kinase; Gs/Gi/q stimulatory/inhibitory G protein; GPCR G protein‐coupled receptor; gp130 glycoprotein 130; GSK3β glycogen synthase kinase 3 β; IP3 inositoltrisphosphate; JAK Janus kinase; KATP ATP‐dependent potassium channel; Na+/H+ sodium/proton‐exchanger; NO nitric oxide; eNOS endothelial nitric oxide synthase; PDK phosphoinositide‐dependent kinase; PI3K phosphatidylinositol (4,5)‐bisphosphate 3‐kinase; PIP3 phosphatidylinositoltrisphosphate; PKC protein kinase C; PKG protein kinase G; PLC phospholipase C; ROS reactive oxygen species; sGC soluble guanylate cyclase; SR sarcoplasmic reticulum; STAT signal transducer and activator of transcription; TNFα tumor necrosis factor α. The NO/PKG‐pathway is displayed in green, the RISK‐pathway in yellow, the SAFE‐pathway in red.


Figure 9. Blockade of the RISK pathway by combined wortmannin and UO 126 during reperfusion does not abrogate the infarct size reduction by ischemic postconditioning with six cycles of 20 s reperfusion and 20 s reocclusion following 90 min ischemia in pigs. Data adapted, with permission, from (209).


Figure 10. Ischemic postconditioning reduces infarct size in pigs [(A) Triphenyl tetrazolium chloride (TTC) staining, (B) mean ± SEM]. Infarct size reduction is abrogated by inhibition of signal transducer and activator of transcription 3 (STAT 3) (C). Original Western blot (D) and averaged data (E) of increased mitochondrial STAT 3 phosphorylation at tyrosine 705 after ischemic postconditioning. Isolated mitochondria (F) have increased ADP‐stimulated respiration after ischemic postconditioning (G). Data adapted from (85) and modified figure from (75) with permission.


Figure 11. Simplified scheme of cardioprotective signaling at the mitochondria. Abbreviations: I, II, III, and IV respiratory chain complexes I, II, III, and IV; CypD, cyclophilin D; ER/SR, endoplasmic/sarcoplasmic reticulum; F, F‐ATPase; GSK3β, glycogen synthase kinase 3 β; KATP, ATP‐dependent potassium channel; MPTP, mitochondrial permeability transition pore; NO, nitric oxide; NOS, nitric oxide synthase; PKC, protein kinase C; PKG, protein kinase G; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription.


Figure 12. Ischemic postconditioning by 4 cycles of 1 min reperfusion and 1 min reocclusion of the culprit coronary artery by intracoronary balloon inflation in patients with acute ST segment elevation myocardial infarction reduces the release of creatine kinase, whereas duration of ischemia and area at risk are not different by comparison to patients without ischemic postconditioning. Adapted from (215) with permission. Infarct size by single photon emission computer tomography (SPECT) remains reduced at 6 months. Adapted from (220) with permission.


Figure 13. Forest plot of clinical trials with ischemic postconditioning and pharmacological postconditioning in patients with acute myocardial infarction. Ischemic postconditioning reduced infarct size in most studies, whereas pharmacological postconditioning reduced infarct size only when using atrial natriuretic peptide (ANP), exenatide, cyclosporine or metoprolol. CK, creatine kinase; CK‐MB, creatine kinase‐myocardial band; MRI, magnetic resonance imaging; PLA, placebo; PoC, ischemic postconditioning; SPECT, single photon emission computer tomography; TnI, troponin I.


Figure 14. Coronary microembolization during early reperfusion increases infarct size, and the combination of ischemic postconditioning with coronary microembolization results in only a small infarct size reduction by comparison to plain full reperfusion. Adapted from (211) with permission.


Figure 15. Confounding variables which reduce infarct size in the placebo group and increase infarct size in the conditioning group tend to diminish the difference between groups and make identification of cardioprotection more difficult. Adapted from (74) with permission.


Figure 16. Cyclosporine A when given just before reperfusion reduces infarct size in mice and pigs. Adapted from (14) and (208) with permission. Cyclosporine A when given just before reperfusion also reduces infarct size, as reflected by creatine kinase release, in patients with acute myocardial infarction. CK, creatine kinase. Adapted from (170) with permission.
References
 1. Ambrosio G , Weisman HF , Mannisi JA , Becker LC . Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow. Circulation 80: 1846‐1861, 1989. doi: 10.1161/01.CIR.80.6.1846
 2. Andreka G , Vertesaljai M , Szantho G , Font G , Piroth Z , Fontos G , Juhasz ED , Szekely L , Szelid Z , Turner MS , Ashrafian H , Frenneaux MP , Andreka P . Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs. Heart 93: 749‐752, 2007. doi: 10.1136/hrt.2006.114504
 3. Andrukhiv A , Costa AD , West IC , Garlid KD . Opening mitoKATP increases superoxide generation from complex I of the electron transport chain. Am J Physiol Heart Circ Physiol 291: H2067‐H2074, 2006. doi: 10.1152/ajpheart.00272.2006
 4. Araszkiewicz A , Grygier M , Pyda M , Rajewska J , Michalak M , Lesiak M , Grajek S . Postconditioning reduces enzymatic infarct size and improves microvascular reperfusion in patients with ST‐segment elevation myocardial infarction. Cardiology 129: 250‐257, 2014.
 5. Argaud L , Gateau‐Roesch O , Raisky O , Loufouat J , Robert D , Ovize M . Postconditioning inhibits mitochondrial permeability transition. Circulation 111: 194‐197, 2005. doi: 10.1161/01.CIR.0000151290.04952.3B
 6. Atar D , Arheden H , Berdeaux A , Bonnet JL , Carlsson M , Clemmensen P , Cuvier V , Danchin N , Dubois‐Rande JL , Engblom H , Erlinge D , Firat H , Halvorsen S , Hansen HS , Hauke W , Heiberg E , Koul S , Larsen AI , Le CP , Nordrehaug JE , Paganelli F , Pruss RM , Rousseau H , Schaller S , Sonou G , Tuseth V , Veys J , Vicaut E , Jensen SE . Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST‐elevation myocardial infarction: MITOCARE study results. Eur Heart J 2014 [Epub ahead of print]: doi: http://dx.doi.org/10.1093/eurheartj/ehu331
 7. Baars T , Skyschally A , Klein‐Hitpass L , Cario E , Erbel R , Heusch G , Kleinbongard P . microRNA expression and its potential role in cardioprotection by ischemic postconditioning in pigs. Pflügers Arch ‐ Eur J Physiol 466: 1953‐1961, 2014. doi: 10.1007/s00424‐013‐1429‐3
 8. Barrabes JA , Inserte J , Agullo L , Alonso A , Mirabet M , Garcia‐Dorado D . Microvascular thrombosis: An exciting but elusive therapeutic target in reperfused acute myocardial infarction. Cardiovasc Hematol Disord Drug Targets 10: 273‐283, 2010. doi: 10.2174/187152910793743797
 9. Barsukevich V , Basalay M , Sanchez J , Mrochek A , Whittle J , Ackland GL , Gourine AV , Gourine A . Distinct cardioprotective mechanisms of immediate, early and delayed ischaemic postconditioning. Basic Res Cardiol 110: 452, 2015.
 10. Baxter GF , Hale SL , Miki T , Kloner RA , Cohen MV , Downey JM , Yellon DM . Adenosine A1 agonist at reperfusion trial (AART): Results of a three‐center, blinded, randomized, controlled experimental infarct study. Cardiovasc Drugs Ther 14: 607‐614, 2000. doi: 10.1023/A:1007850527878.
 11. Bekkers SC , Yazdani SK , Virmani R , Waltenberger J . Microvascular obstruction: Underlying pathophysiology and clinical diagnosis. J Am Coll Cardiol 55: 1649‐1660, 2010. doi: 10.1016/j.jacc.2009.12.037
 12. Bernardi P , Di Lisa F . The mitochondrial permeability transition pore: Molecular nature and role as a target in cardioprotection. J Mol Cell Cardiol 2014, in press: doi: 10.1016/j.yjmcc.2014.09.023
 13. Boengler K , Buechert A , Heinen Y , Roeskes C , Hilfiker‐Kleiner D , Heusch G , Schulz R . Cardioprotection by ischemic postconditioning is lost in aged and STAT3‐deficient mice. Circ Res 102: 131‐135, 2008. doi: 10.1161/CIRCRESAHA.107.164699
 14. Boengler K , Hilfiker‐Kleiner D , Heusch G , Schulz R . Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion. Basic Res Cardiol 105: 771‐785, 2010. doi: 10.1007/s00395‐010‐0124‐1
 15. Boengler K , Schulz R , Heusch G . Loss of cardioprotection with ageing. Cardiovasc Res 83: 247‐261, 2009. doi: 10.1093/cvr/cvp033
 16. Boengler K , Stahlhofen S , van de SA , Gres P , Ruiz‐Meana M , Garcia‐Dorado D , Heusch G , Schulz R . Presence of connexin 43 in subsarcolemmal, but not in interfibrillar cardiomyocyte mitochondria. Basic Res Cardiol 104: 141‐147, 2009. doi: 10.1007/s00395‐009‐0007‐5
 17. Boengler K , Ungefug E , Heusch G , Schulz R . The STAT3 inhibitor stattic impairs cardiomyocyte mitochondrial function through increased reactive oxygen species formation. Curr Pharm Des 19: 6890‐6895, 2013. doi: 10.2174/138161281939131127115940
 18. Bose AK , Mocanu MM , Carr RD , Yellon DM . Glucagon like peptide‐1 protective against myocardial ischemia/reperfusion injury when given either as a preconditioning mimetic or at reperfusion in an isolated rat heart model. Cardiovasc Drugs Ther 19: 9‐11, 2005. doi: 10.1007/s10557‐005‐6892‐4
 19. 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 Res Cardiol 106: 135‐145, 2011.doi: 10.1007/s00395‐010‐0133‐0
 20. Bullard AJ , Govewalla P , Yellon DM . Erythropoietin protects the myocardium against reperfusion injury in vitro and in vivo. Basic Res Cardiol 100: 397‐403, 2005. doi: 10.1007/s00395‐005‐0537‐4
 21. Burley DS , Baxter GF . B‐type natriuretic peptide at early reperfusion limits infarct size in the rat isolated heart. Basic Res Cardiol 102: 529‐541, 2007. doi: 10.1007/s00395‐007‐0672‐1
 22. Burns RJ , Gibbons RJ , Yi Q , Roberts RS , Miller TD , Schaer GL , Anderson JL , Yusuf S . The relationships of left ventricular ejection fraction, end‐systolic volume index and infarct size to six‐month mortality after hospital discharge following myocardial infarction treated by thrombolysis. J Am Coll Cardiol 39: 30‐36, 2002. doi: 10.1016/S0735‐1097(01)01711‐9
 23. Calvert JW , Jha S , Gundewar S , Elrod JW , Ramachandran A , Pattillo CB , Kevil CG , Lefer DJ . Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res 105: 365‐374, 2009. doi: 10.1161/CIRCRESAHA.109.199919
 24. Cohen MV , Downey JM . Cardioprotection: Spotlight on PKG. Br J Pharmacol 152: 833‐834, 2007. doi: 10.1038/sj.bjp.0707453
 25. Cohen MV , Downey JM . Combined cardioprotectant and antithrombotic actions of platelet P2Y12 receptor antagonists in acute coronary syndrome: Just what the doctor ordered. J Cardiovasc Pharmacol Ther 19: 179‐190, 2014. doi: 10.1177/1074248413508465
 26. Cohen MV , Yang XM , Downey JM . The pH hypothesis of postconditioning: Staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 115: 1895‐1903, 2007. doi: 10.1161/CIRCULATIONAHA.106.675710
 27. Cohen MV , Yang XM , Downey JM . Acidosis, oxygen, and interference with mitochondrial permeability transition pore formation in the early minutes of reperfusion are critical to postconditioning's success. Basic Res Cardiol 103: 464‐471, 2008. doi: 10.1007/s00395‐008‐0737‐9
 28. Cohen MV , Yang XM , Liu Y , Solenkova NV , Downey JM . Cardioprotective PKG‐independent NO signaling at reperfusion. Am J Physiol Heart Circ Physiol 299: H2028‐H2036, 2010. doi: 10.1152/ajpheart.00527.2010
 29. Costa AD , Garlid KD . Intramitochondrial signaling ‐ interactions among mitoKATP, PKCe, ROS, and MPT. Am J Physiol Heart Circ Physiol 295: H874‐H882, 2008. doi: 10.1152/ajpheart.01189.2007
 30. Costa AD , Pierre SV , Cohen MV , Downey JM , Garlid KD . cGMP signalling in pre‐ and post‐conditioning: The role of mitochondria. Cardiovasc Res 77: 344‐352, 2008. doi: 10.1093/cvr/cvm050
 31. Costa ADT , Garlid KD , West IC , Lincoln TM , Downey JM , Cohen MV , Critz SD . Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria. Circ Res 97: 329‐336, 2005. doi: 10.1161/01.RES.0000178451.08719.5b
 32. Costa ADT , Jakob R , Costa CL , Andrukhiv K , West IC , Garlid KD . The mechanism by which the mitochondrial ATP‐sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition. J Biol Chem 281: 20801‐20808, 2006. doi: 10.1074/jbc.M600959200
 33. Degterev A , Zhou W , Maki JL , Yuan J . Assays for necroptosis and activity of RIP kinases. Methods Enzymol 545: 1‐33, 2014. doi: 10.1016/B978‐0‐12‐801430‐1.00001‐9
 34. Desmet W , Bogaert J , Dubois C , Sinnaeve P , Adriaenssens T , Pappas C , Ganame J , Dymarkowski S , Janssens S , Belmans A , Van de WF . High‐dose intracoronary adenosine for myocardial salvage in patients with acute ST‐segment elevation myocardial infarction. Eur Heart J 32: 867‐877, 2011. doi: 10.1093/eurheartj/ehq492
 35. Dong Y , Undyala VV , Gottlieb RA , Mentzer RM, Jr , Przyklenk K . Autophagy: Definition, molecular machinery, and potential role in myocardial ischemia‐reperfusion injury. J Cardiovasc Pharmacol Ther 15: 220‐230, 2010. doi: 10.1177/1074248410370327
 36. Downey JM , Cohen MV . We think we see a pattern emerging here. Circulation 111: 120‐121, 2005. doi: 10.1161/01.CIR.0000153622.49496.10
 37. Downey JM , Cohen MV . A really radical observation. Basic Res Cardiol 101: 190‐191, 2006. doi: 10.1007/s00395‐006‐0586‐3
 38. Downey JM , Davis AM , Cohen MV . Signaling pathways in ischemic preconditioning. Heart Fail Rev 12: 181‐188, 2007. doi: 10.1007/s10741‐007‐9025‐2
 39. Driesen RB , Zalewski J , Driessche NV , Vermeulen K , Bogaert J , Sipido KR , Van de WF , Claus P . Histological correlate of a cardiac magnetic resonance imaged microvascular obstruction in a porcine model of ischemia‐reperfusion. Cardiovasc Pathol 21: 129‐131, 2011. doi: 10.1016/j.carpath.2011.07.008
 40. Duan X , Ji B , Wang X , Liu J , Zheng Z , Long C , Tang Y , Hu S . Expression of microRNA‐1 and microRNA‐21 in different protocols of ischemic conditioning in an isolated rat heart model. Cardiology 122: 36‐43, 2012. doi: 10.1159/000338149
 41. Duncker DJ , Klassen CL , Ishibashi Y , Herrlinger SH , Pavek TJ , Bache RJ . Effect of temperature on myocardial infarction in swine. Am J Physiol 270: H1189‐H1199, 1996.
 42. Ferdinandy P , Hausenloy DJ , Heusch G , Baxter GF , Schulz R . Interaction of risk factors, comorbidities and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev 66: 1142‐1174, 2014. doi: 10.1124/pr.113.008300
 43. Fishbein MC , Meerbaum S , Rit J , Lando U , Kanmatsuse K , Mercier JC , Corday E , Ganz W . Early phase acute myocardial infarct size quantification: Validation of the triphenyl tetrazolium chloride tissue enzyme staining technique. Am Heart J 101: 593‐600, 1981.
 44. Fokkema ML , Vlaar PJ , Vogelzang M , Gu YL , Kampinga MA , de Smet BJ , Jessurun GA , Anthonio RL , van den Heuvel AF , Tan ES , Zijlstra F . Effect of high‐dose intracoronary adenosine administration during primary percutaneous coronary intervention in acute myocardial infarction: A randomized controlled trial. Circ Cardiovasc Interv 2: 323‐329, 2009. doi: 10.1161/CIRCINTERVENTIONS.109.858977.109.858977
 45. Foster DB , Ho AS , Rucker J , Garlid AO , Chen L , Sidor A , Garlid KD , O'Rourke B . Mitochondrial ROMK channel is a molecular component of mitoKATP. Circ Res 111: 446‐454, 2012. doi: 10.1161/CIRCRESAHA.112.266445
 46. Garcia‐Dorado D , Garcia‐Del‐Blanco B , Otaegui I , Rodriguez‐Palomares J , Pineda V , Gimeno F , Ruiz‐Salmeron R , Elizaga J , Evangelista A , Fernandez‐Aviles F , San‐Roman A , Ferreira‐Gonzalez I . Intracoronary injection of adenosine before reperfusion in patients with ST‐segment elevation myocardial infarction: A randomized controlled clinical trial. Int J Cardiol 177: 935‐941, 2014. doi: 10.1016/j.ijcard.2014.09.203
 47. Garcia‐Dorado D , Oliveras J . Myocardial edema: A preventable cause of reperfusion injury. Cardiovasc Res 27: 1555‐1563, 1993.
 48. Gateau‐Roesch O , Argaud L , OPvize M . Mitochondrial permeability transition pore and postconditioning. Cardiovasc Res 70: 264‐273, 2006. doi: 10.1016/j.cardiores.2006.02.024
 49. Ginks WR , Sybers HD , Maroko PR , Covell JW , Sobel BE , Ross J, Jr . Coronary artery reperfusion. II. Reduction of myocardial infarct size at 1 week after the coronary occlusion. J Clin Invest 51: 2717‐2723, 1972.
 50. Gomez L , Paillard M , Thibault H , Derumeaux G , Ovize M . Inhibition of GSK3beta by postconditioning is required to prevent opening of the mitochondrial permeability transition pore during reperfusion. Circulation 117: 2761‐2768, 2008. doi: 10.1161/CIRCULATIONAHA.107.755066
 51. Grall S , Prunier‐Mirebeau D , Tamareille S , Mateus V , Lamon D , Furber A , Prunier F . Endoplasmic reticulum stress pathway involvement in local and remote myocardial ischemic conditioning. Shock 39: 433‐439, 2013. doi: 10.1097/SHK.0b013e31828e4f80
 52. Granato JE , Watson DD , Flanagan TL , Beller GA . Myocardial thallium‐201 kinetics and regional flow alterations with 3 hours of coronary occlusion and either rapid reperfusion through a totally patent vessel or slow reperfusion through a critical stenosis. J Am Coll Cardiol 9: 109‐118, 1987.
 53. Gritsopoulos G , Iliodromitis EK , Zoga A , Farmakis D , Demerouti E , Papalois A , Paraskevaidis IA , Kremastinos DT . Remote postconditioning is more potent than classic postconditioning in reducing the infarct size in anesthetized rabbits. Cardiovasc Drugs Ther 23: 193‐198, 2009. doi: 10.1007/s10557‐009‐6168‐5
 54. Gross ER , Hsu AK , Gross GJ . Acute methadone treatment reduces myocardial infarct size via the delta‐opioid receptor in rats during reperfusion. Anesth Analg 109: 1395‐1402, 2009. doi: 10.1213/ANE.0b013e3181b92201
 55. Gross GJ , Gauthier KM , Moore J , Campbell WB , Falck JR , Nithipatikom K . Evidence for role of epoxyeicosatrienoic acids in mediating ischemic preconditioning and postconditioning in dog. Am J Physiol Heart Circ Physiol 297: H47‐H52, 2009. doi: 10.1152/ajpheart.01084.2008
 56. Hahn JY , Song YB , Kim EK , Yu CW , Bae JW , Chung WY , Choi SH , Choi JH , Bae JH , An KJ , Park JS , Oh JH , Kim SW , Hwang JY , Ryu JK , Park HS , Lim DS , Gwon HC . Ischemic postconditioning during primary percutaneous coronary intervention: The POST Randomized Trial. Circulation 128: 1889‐1896, 2013. doi: 10.1161/CIRCULATIONAHA.113.001690
 57. Hamid SA , Baxter GF . Adrenomedullin limits reperfusion injury in experimental myocardial infarction. Basic Res Cardiol 100: 387‐396, 2005. doi: 10.1007/s00395‐005‐0538‐3
 58. Hausenloy DJ , Ong SB , Yellon DM . The mitochondrial permeability transition pore as a target for preconditioning and postconditioning. Basic Res Cardiol 104: 189‐202, 2009. doi: 10.1007/s00395‐009‐0010‐x
 59. Hausenloy DJ , Tsang A , Yellon DM . The reperfusion injury salvage kinase pathway: A common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med 15: 69‐75, 2005. doi: 10.1016/j.tcm.2005.03.001
 60. Hausenloy DJ , Wynne AM , Yellon DM . Ischemic preconditioning targets the reperfusion phase. Basic Res Cardiol 102: 445‐452, 2007. doi: 10.1007/s00395‐007‐0656‐1
 61. Hausenloy DJ , Yellon DM . New directions for protecting the heart against ischaemia‐reperfusion injury: Targeting the reperfusion injury salvage kinase (RISK)‐pathway. Cardiovasc Res 61: 448‐460, 2004. doi: 10.1016/j.cardiores.2003.09.024
 62. He B , Xiao J , Ren AJ , Zhang YF , Zhang H , Chen M , Xie B , Gao XG , Wang YW . Role of miR‐1 and miR‐133a in myocardial ischemic postconditioning. J Biomed Sci 18: 22, 2011. doi: 10.1186/1423‐0127‐18‐22
 63. Headrick JP , Ashton KJ , Rose'Meyer RB , Peart JN . Cardiovascular adenosine receptors: Expression, actions and interactions. Pharmacol Ther 140: 92‐111, 2013. doi: 10.1007/s00395‐013‐0337‐1
 64. Hedstrom E , Engblom H , Frogner F , Astroem‐Olsson K , Ohlin H , Jovinge S , Arheden H . Infarct evolution in man studied in patients with first‐time coronary occlusion in comparison to different species ‐ implications for assessment of myocardial salvage. J Cardiovasc Magn Reson 11: 38, 2009. doi: 10.1186/1532‐429X‐11‐38
 65. Heinzel FR , Luo Y , Li X , Boengler K , Buechert A , García‐Dorado D , Di Lisa F , Schulz R , Heusch G . Impairment of diazoxide‐induced formation of reactive oxygen species and loss of cardioprotection in connexin 43 deficient mice. Circ Res 97: 583‐586, 2005. doi: 10.1161/01.RES.0000181171.65293.65
 66. Herrett E , Bhaskaran K , Timmis A , Denaxas S , Hemingway H , Smeeth L . Association between clinical presentations before myocardial infarction and coronary mortality: A prospective population‐based study using linked electronic records. Eur Heart J 35: 2363‐2371, 2014. doi: 10.1093/eurheartj/ehu286
 67. Heusch G . Hibernating myocardium. Physiol Rev 78: 1055‐1085, 1998.
 68. Heusch G . Nitroglycerin and delayed preconditioning in humans. Yet another new mechanism for an old drug? Circulation 103: 2876‐2878, 2001. doi: 10.1161/01.CIR.103.24.2876
 69. Heusch G . Postconditioning. Old wine in a new bottle? J Am Coll Cardiol 44: 1111‐1112, 2004. doi: 10.1016/j.jacc.2004.06.013
 70. Heusch G . Obesity–a risk factor or a RISK factor for myocardial infarction? Br J Pharmacol 149: 1‐3, 2006. doi: 10.1038/sj.bjp.0706833
 71. Heusch G . Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: Benefit from selective bradycardic agents. Br J Pharmacol 153: 1589‐1601, 2008. doi: 10.1038/sj.bjp.0707673
 72. Heusch G . Pleiotropic action(s) of the bradycardic agent ivabradine: Cardiovascular protection beyond heart rate reduction. Br J Pharmacol 155: 970‐971, 2008. doi: 10.1038/bjp.2008.347
 73. Heusch G . Adenosine and maximum coronary vasodilation in humans: Myth and misconceptions in the assessment of coronary reserve. Basic Res Cardiol 105: 1‐5, 2010. doi: 10.1007/s00395‐009‐0074‐7
 74. Heusch G . Reduction of infarct size by ischaemic post‐conditioning in humans: Fact or fiction? Eur Heart J 33: 13‐15, 2012. doi: 10.1093/eurheartj/ehr341
 75. Heusch G . Cardioprotection: Chances and challenges of its translation to the clinic. Lancet 381: 166‐175, 2013. doi: 10.1016/S0140‐6736(12)60916‐7
 76. Heusch G . The molecular basis of cardioprotection: Signal transduction in ischemic pre‐, post‐ and remote conditioning. Circ Res 2015, in press
 77. Heusch G , Boengler K , Schulz R . Cardioprotection: Nitric oxide, protein kinases, and mitochondria. Circulation 118: 1915‐1919, 2008. doi: 10.1161/CIRCULATIONAHA.108.805242
 78. Heusch G , Boengler K , Schulz R . Inhibition of mitochondrial permeability transition pore opening: The holy grail of cardioprotection. Basic Res Cardiol 105: 151‐154, 2010. doi: 10.1007/s00395‐009‐0080‐9
 79. Heusch G , Botker HE , Przyklenk K , Redington A , Yellon DM . Remote ischemic conditioning. J Am Coll Cardiol 65: 177‐195, 2015. doi: 10.1016/j.jacc.2014.10.031
 80. Heusch G , Büchert A , Feldhaus S , Schulz R . No loss of cardioprotection by postconditioning in connexin 43‐deficient mice. Basic Res Cardiol 101: 354‐356, 2006. doi: 10.1007/s00395‐006‐0589‐0
 81. Heusch G , Kleinbongard P , Boese D , Levkau B , Haude M , Schulz R , Erbel R . Coronary microembolization: From bedside to bench and back to bedside. Circulation 120: 1822‐1836, 2009. doi: 10.1161/CIRCULATIONAHA.109.888784
 82. Heusch G , Kleinbongard P , Skyschally A . Myocardial infarction and coronary microvascular obstruction: An intimate, but complicated relationship. Basic Res Cardiol 108: 380, 2013. doi: 10.1007/s00395‐013‐0380‐y
 83. Heusch G , Kleinbongard P , Skyschally A , Levkau B , Schulz R , Erbel R . The coronary circulation in cardioprotection: More than just one confounder. Cardiovasc Res 94: 237‐245, 2012. doi: 10.1093/cvr/cvr271
 84. Heusch G , Libby P , Gersh B , Yellon D , Böhm M , Lopaschuk G , Opie L . Cardiovascular remodeling in coronary artery disease and heart failure. Lancet 383: 1933‐1943, 2014. doi: 10.1016/S0140‐6736(14)60107‐0
 85. Heusch G , Musiolik J , Gedik N , Skyschally A . Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ Res 109: 1302‐1308, 2011. doi: 10.1161/CIRCRESAHA.111.255604
 86. Heusch G , Schulz R , Rahimtoola SH . Myocardial hibernation: A delicate balance. Am J Physiol Heart Circ Physiol 288: H984‐H999, 2005. doi: 10.1152/ajpheart.01109.2004
 87. Heusch G , Skyschally A , Gres P , van Caster P , Schilawa D , Schulz R . Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: Protection beyond heart rate reduction. Eur Heart J 29: 2265‐2275, 2008. doi: 10.1093/eurheartj/ehn337
 88. Heusch G , Yoshimoto N . Effects of heart rate and perfusion pressure on segmental coronary resistances and collateral perfusion. Pflügers Arch 397: 284‐289, 1983.
 89. Hirata A , Minamino T , Asanuma H , Sanada S , Fujita M , Tsukamoto O , Wakeno M , Myoishi M , Okada K , Koyama H , Komamura K , Takashima S , Shinozaki Y , Mori H , Tomoike H , Hori M , Kitakaze M . Erythropoietin just before reperfusion reduces both lethal arrythmias and infarct size via the phosphatidylinositol‐3 kinase‐dependent pathway in canine hearts. Cardiovasc Drugs Ther 19: 33‐40, 2005. doi: 10.1007/s10557‐005‐6895‐1
 90. Horneffer PJ , Healy B , Gott VL , Gardner TJ . The rapid evolution of a myocardial infarction in an end‐artery coronary preparation. Circulation 76: V39‐V42, 1987.
 91. Huang YE , Tang ZH , Xie W , Shen XT , Liu MH , Peng XP , Zhao ZZ , Nie DB , Liu LS , Jiang ZS . Endogenous hydrogen sulfide mediates the cardioprotection induced by ischemic postconditioning in the early reperfusion phase. Exp Ther Med 4: 1117‐1123, 2012. doi: 10.3892/etm.2012.733
 92. Ibanez B , Macaya C , Sanchez‐Brunete V , Pizarro G , Fernandez‐Friera L , Mateos A , Fernandez‐Ortiz A , Garcia‐Ruiz JM , Garcia‐Alvarez A , Iniguez A , Jimenez‐Borreguero J , Lopez‐Romero P , Fernandez‐Jimenez R , Goicolea J , Ruiz‐Mateos B , Bastante T , Arias M , Iglesias‐Vazquez JA , Rodriguez MD , Escalera N , Acebal C , Cabrera JA , Valenciano J , Perez de PA , Fernandez‐Campos MJ , Casado I , Garcia‐Rubira JC , Garcia‐Prieto J , Sanz‐Rosa D , Cuellas C , Hernandez‐Antolin R , Albarran A , Fernandez‐Vazquez F , de la Torre‐Hernandez JM , Pocock S , Sanz G , Fuster V . 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 128: 1495‐1503, 2013. doi: 10.1161/CIRCULATIONAHA.113.003653
 93. Inagaki K , Chen L , Ikeno F , Lee FH , Imahashi K , Bouley DM , Rezaee M , Yock PG , Murphy E , Mochly‐Rosen D . Inhibiiton of d‐protein kinase C protects against reperfusion injury of the ischemic heart in vivo. Circulation 108: 2304‐2307, 2003. doi: 10.1161/01.CIR.0000101682.24138.36
 94. Inserte J , Barba I , Hernando V , Abellan A , Ruiz‐Meana M , Rodriguez‐Sinovas A , Garcia‐Dorado D . Effect of acidic reperfusion on prolongation of intracellular acidosis and myocardial salvage. Cardiovasc Res 77: 782‐790, 2008. doi: 10.1093/cvr/cvm082
 95. Inserte J , Barba I , Hernando V , Garcia‐Dorado D . Delayed recovery of intracellular acidosis during reperfusion prevents calpain activation and determines protection in postconditioned myocardium. Cardiovasc Res 81: 116‐122, 2009. doi: 10.1093/cvr/cvn260
 96. Inserte J , Barba I , Poncelas‐Nozal M , Hernando V , Agullo L , Ruiz‐Meana M , Garcia‐Dorado D . cGMP/PKG pathway mediates myocardial postconditioning protection in rat hearts by delaying normalization of intracellular acidosis during reperfusion. J Mol Cell Cardiol 50: 903‐909, 2011. doi: 10.1016/j.yjmcc.2011.02.013
 97. Inserte J , Garcia‐Dorado D , Agullo L , Paniagua A , Soler‐Soler J . Urodilatin limits acute reperfusion injury in the isolated rat heart. Cardiovasc Res 45: 351‐359, 2000. http://dx.doi.org/10.1016/S0008‐6363(99)00371‐5
 98. Inserte J , Hernando V , Garcia‐Dorado D . Contribution of calpains to myocardial ischaemia/reperfusion injury. Cardiovasc Res 96: 23‐31, 2012. doi: 10.1093/cvr/cvs232
 99. Inserte J , Hernando V , Ruiz‐Meana M , Poncelas‐Nozal M , Fernandez C , Agullo L , Sartorio C , Vilardosa U , Garcia‐Dorado D . Delayed phospholamban phosphorylation in post‐conditioned heart favours Ca2+ normalization and contributes to protection. Cardiovasc Res 103: 542‐553, 2014. doi: 10.1093/cvr/cvu163
 100. Jang Y , Xi J , Wang H , Mueller RA , Norfleet EA , Xu Z . Postconditioning prevents reperfusion injury by activating delta‐opioid receptors. Anesthesiology 108: 243‐250, 2008. doi: 10.1097/01.anes.0000299437.93898.4a
 101. Jin ZQ , Karliner JS , Vessey DA . Ischaemic postconditioning protects isolated mouse hearts against ischaemia/reperfusion injury via sphingosine kinase isoform‐1 activation. Cardiovasc Res 79: 134‐140, 2008. doi: 10.1093/cvr/cvn065
 102. Jolly SS , Bertrand OF . Another chapter in the story of thrombectomy in ST‐elevation myocardial infarction: A story not yet finished. Eur Heart J 34: 1024‐1026, 2013. doi: 10.1093/eurheartj/eht029
 103. Jones DA , Pellaton C , Velmurugan S , Andiapen M , Antoniou S , Van ES , Webb AJ , Westwood M , Parmar M , Mathur A , Ahluwalia A . Randomized phase 2 trial of intra‐coronary nitrite during acute myocardial infarction. Circ Res 2015, doi: 10.1161/CIRCRESAHA.116.305082
 104. Jones SP , Tang XL , Guo Y , Steenbergen C , Lefer DJ , Kukreja RC , Kong M , Li Q , Bhushan S , Zhu X , Du J , Nong Y , Stowers HL , Kondo K , Hunt GN , Goodchild TT , Orr A , Chang CC , Ockaili R , Salloum FN , Bolli R . The NHLBI‐sponsored consortium for preclinicAL assESsment of cARdioprotective therapies (CAESAR): A new paradgm for rigorous, accurate, and reproducible evaluation of putative infarct‐sparing interventions in mice, rabbits, and pigs. Circ Res 2014 [Epub ahead of print]. doi: 10.1161/CIRCRESAHA.116.305462
 105. Juhaszova M , Zorov DB , Kim S‐H , Pepe S , Fu Q , Fishbein KW , Ziman BD , Wang S , Ytrehus K , Antos CL , Olson EN , Sollott SJ . Glycogen synthase kinase‐3ß mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 113: 1535‐1549, 2004. doi: 10.1172/JCI200419906
 106. Juhaszova M , Zorov DB , Yaniv Y , Nuss HB , Wang S , Sollott SJ . Role of glycogen synthase kinase‐3beta in cardioprotection. Circ Res 104: 1240‐1252, 2009. doi: 10.1161/CIRCRESAHA.109.197996
 107. Kerendi F , Kin H , Halkos ME , Jiang R , Zhao Z‐Q , Guyton RA , Vinten‐Johansen J . Remote postconditioning. Brief renal ischemia and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. Basic Res Cardiol 100: 404‐412, 2005. doi: 10.1007/s00395‐005‐0539‐2
 108. Kitakaze M , Asakura M , Kim J , Shintani Y , Asanuma H , Hamasaki T , Seguchi O , Myoishi M , Minamino T , Ohara T , Nagai Y , Nanto S , Watanabe K , Fukuzawa S , Hirayama A , Nakamura N , Kimura K , Fujii K , Ishihara M , Saito Y , Tomoike H , Kitamura S . Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J‐WIND): Two randomised trials. Lancet 370: 1483‐1493, 2007. doi: 10.1016/S0140‐6736(07)61634‐1
 109. Klein HH , Puschmann S , Schaper J , Schaper W . The mechanism of the tetrazolium reaction in identifying experimental myocardial infarction. Virchows Arch 393: 287‐297, 1981.
 110. Kleinbongard P , Baars T , Mohlenkamp S , Kahlert P , Erbel R , Heusch G . Aspirate from human stented native coronary arteries vs. saphenous vein grafts: More endothelin but less particulate debris. Am J Physiol Heart Circ Physiol 305: H1222‐H1229, 2013. doi: 10.1152/ajpheart.00358.2013
 111. Kleinbongard P , Boese D , Baars T , Moehlenkamp S , Konorza T , Schoener S , Elter‐Schulz M , Eggebrecht H , Degen H , Haude M , Levkau B , Schulz R , Erbel R , Heusch G . Vasoconstrictor potential of coronary aspirate from patients undergoing stenting of saphenous vein aortocoronary bypass grafts and its pharmacological attenuation. Circ Res 108: 344‐352, 2011. doi: 10.1161/CIRCRESAHA.110.235713
 112. Kleinbongard P , Heusch G . Extracellular signalling molecules in the ischaemic/reperfused heart ‐ druggable and translatable for cardioprotection? Br J Pharmacol 2014, doi: 10.1111/bph.12902
 113. Klionsky DJ , for the Working Group Guidelines for Monitoring Autophagy. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8: 445‐544, 2012. doi: 10.4161/auto.19496
 114. Kloner RA , Ellis SG , Lange R , Braunwald E . Studies of experimental coronary artery reperfusion. Effects on infarct size, myocardial function, biochemistry, ultrastructure and microvascular damage. Circulation 68(Suppl. I): I‐8‐I‐15, 1983.
 115. Kloner RA , Ganote CE , Jennings RB . The “no‐reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest 54: 1496‐1508, 1974.
 116. Kloner RA , Rude RE , Carlson N , Maroko PR , DeBoer LWV , Braunwald E . Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion: Which comes first? Circulation 62: 945‐952, 1980. doi: 10.1161/01.CIR.62.5.945
 117. Korichneva I , Hoyos B , Chua R , Levi E , Hammerling U . Zinc release from protein kinase C as the common event during activation by lipid second messenger or reactive oxygen. J Biol Chem 277: 44327‐44331, 2002. doi: 10.1074/jbc.M205634200
 118. Kuno A , Critz SD , Cui L , Solodushko V , Yang XM , Krahn T , Albrecht B , Philipp S , Cohen MV , Downey JM . Protein kinase C protects preconditioned rabbit hearts by increasing sensitivity of adenosine A(2b)‐dependent signaling during early reperfusion. J Mol Cell Cardiol 43: 262‐271, 2007. doi: 10.1016/j.yjmcc.2007.05.016
 119. Lacerda L , Somers S , Opie LH , Lecour S . Ischemic postconditioning protects against reperfusion injury via the SAFE pathway. Cardiovasc Res 84: 201‐208, 2009. doi: 10.1093/cvr/cvp274
 120. Ladilov YV , Siegmund B , Piper HM . Protection of reoxygenated cardiomyocytes against hypercontracture by inhibition of Na+/H+ exchange. Am J Physiol 268: H1531‐H1539, 1995.
 121. Lecour S . Multiple protective pathways against reperfusion injury: A SAFE path without aktion? J Mol Cell Cardiol 46: 607‐609, 2009. doi: 10.1016/j.yjmcc.2009.01.003
 122. Lecour S , Suleman N , Deuchar GA , Somers S , Lacerda L , Huisamen B , Opie LH . Pharmacological preconditioning with tumor necrosis factor‐a activates signal transducer and activator of transcription‐3 at reperfusion without involving classic prosurvival kinases (Akt and extracellular signal‐regulated kinase). Circulation 112: 3911‐3918, 2005. doi: 10.1161/CIRCULATIONAHA.105.581058
 123. Leineweber K , Boese D , Vogelsang M , Haude M , Erbel R , Heusch G . Intense vasoconstriction in response to aspirate from stented saphenous vein aortocoronary bypass grafts. J Am Coll Cardiol 47: 981‐986, 2006. doi: 10.1016/j.jacc.2005.10.053
 124. Lim SY , Davidson SM , Hausenloy DJ , Yellon DM . Preconditioning and postconditioning: The essential role of the mitochondrial permeability transition pore. Cardiovasc Res 75: 530‐535, 2007. doi: 10.1016/j.cardiores.2007.04.022
 125. Lincoff AM , Roe M , Aylward P , Galla J , Rynkiewicz A , Guetta V , Zelizko M , Kleiman N , White H , McErlean E , Erlinge D , Laine M , Dos Santos Ferreira JM , Goodman S , Mehta S , Atar D , Suryapranata H , Jensen SE , Forster T , Fernandez‐Ortiz A , Schoors D , Radke P , Belli G , Brennan D , Bell G , Krucoff M . 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. Eur Heart J 35: 2516‐2523, 2014. doi: 10.1093/eurheartj/ehu177
 126. Liu Y , Sato T , O'Rourke B , Marban E . Mitochondrial ATP‐dependent potassium channels. Novel effectors of cardioprotection? Circulation 97: 2463‐2469, 1998. doi: 10.1161/01.CIR.97.24.2463
 127. Lonborg J , Kelbaek H , Helqvist S , Holmvang L , Jorgensen E , Saunamaki K , Klovgaard L , Kaltoft A , Bøtker HE , Lassen JF , Thuesen L , Terkelsen CJ , Kofoed KF , Clemmensen P , Kober L , Engstrom T . The impact of distal embolization and distal protection on long‐term outcome in patients with ST elevation myocardial infarction randomized to primary percutaneous coronary intervention ‐ results from a randomized study. Eur Heart J Acute Cardiovasc Care 2014. doi: 10.1177/2048872614543780: doi: 10.1177/2048872614543780
 128. Lonborg J , Kelbaek H , Vejlstrup N , Bøtker HE , Kim WY , Holmvang L , Jorgensen E , Helqvist S , Saunamaki K , Terkelsen CJ , Schoos MM , Kober L , Clemmensen P , Treiman M , Engstrom T . Exenatide reduces final infarct size in patients with ST‐segment‐elevation myocardial infarction and short‐duration of ischemia. Circ Cardiovasc Interv 5: 288‐295, 2012. doi: 10.1161/CIRCINTERVENTIONS.112.968388
 129. Lonborg J , Vejlstrup N , Kelbaek H , Holmvang L , Jorgensen E , Helqvist S , Saunamaki K , Ahtarovski KA , Bøtker HE , Kim WY , Clemmensen P , Engstrom T . Final infarct size measured by cardiovascular magnetic resonance in patients with ST elevation myocardial infarction predicts long‐term clinical outcome: An observational study. Eur Heart J Cardiovasc Imaging 14: 387‐395, 2013. doi: 10.1093/ehjci/jes271
 130. Loubeyre C , Morice MC , Lefevre T , Piechaud JF , Louvard Y , Dumas P . A randomized comparison of direct stenting with conventional stent implantation in selected patients with acute myocardial infarction. J Am Coll Cardiol 39: 15‐21, 2002. doi: 10.1016/S0735‐1097(01)01701‐6
 131. Lowe JE , Reimer KA , Jennings RB . Experimental infarct size as a function of the amount of myocardium at risk. Am J Pathol 90: 363‐377, 1978.
 132. Luan HF , Zhao ZB , Zhao QH , Zhu P , Xiu MY , Ji Y . Hydrogen sulfide postconditioning protects isolated rat hearts against ischemia and reperfusion injury mediated by the JAK2/STAT3 survival pathway. Braz J Med Biol Res 45: 898‐905, 2012.
 133. Mahaffey KW , Puma JA , Barbagelata A , DiCarli MF , Leesar MA , Browne KF , Eisenberg PR , Bolli R , Casas C , Molina‐Viamonte V , Orlandi C , Blevins R , Gibbons RJ , Califf RM , Granger CB . Adenosine as an adjunct thrombolytic therapy for acute myocardial infarction. J Am Coll Cardiol 34: 1711‐1720, 1999.
 134. 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 266: H1541‐H1550, 1994.
 135. Manintveld OC , Te Lintel HM , van den Bos EJ , Suurenbroek GM , Dekkers DH , Verdouw PD , Lamers JM , Duncker DJ . Cardiac effects of postconditioning depend critically on the duration of index ischemia. Am J Physiol Heart Circ Physiol 292: H1551‐H1560, 2007. doi: 10.1152/ajpheart.00151.2006
 136. Maroko PR , Libby P , Ginks WR , Bloor CM , Shell WE , Sobel BE , Ross J, Jr . Coronary artery reperfusion. I. Early effects on local myocardial function and the extent of myocardial necrosis. J Clin Invest 51: 2710‐2716, 1972.
 137. Martin C , Schulz R , Post H , Boengler K , Kelm M , Kleinbongard P , Gres P , Skyschally A , Konietzka I , Heusch G . Microdialysis‐based analysis of interstitial NO in situ: NO synthase‐independent NO formation during myocardial ischemia. Cardiovasc Res 74: 46‐55, 2007. doi. org/10.1016/j.cardiores.2006.12.020
 138. Maxwell MP , Hearse DJ , Yellon DM . Species variation in the coronary collateral circulation during regional myocardial ischaemia: A critical determinants of the rate of evolution and extent of myocardial infarction. Cardiovasc Res 21: 737‐746, 1987.
 139. Menees DS , Peterson ED , Wang Y , Curtis JP , Messenger JC , Rumsfeld JS , Gurm HS . Door‐to‐balloon time and mortality among patients undergoing primary PCI. N Engl J Med 369: 901‐909, 2013. doi: 10.1056/NEJMoa1208200
 140. Methner C , Lukowski R , Grube K , Loga F , Smith RA , Murphy MP , Hofmann F , Krieg T . Protection through postconditioning or a mitochondria‐targeted S‐nitrosothiol is unaffected by cardiomyocyte‐selective ablation of protein kinase G. Basic Res Cardiol 108: 337, 2013. doi: 10.1007/s00395‐013‐0337‐1
 141. Methner C , Schmidt K , Cohen MV , Downey JM , Krieg T . Both A2a and A2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts. Am J Physiol Heart Circ Physiol 299: H1262‐H1264, 2010. doi: 10.1152/ajpheart.00181.2010
 142. Mewton N , Rapacchi S , Augeul L , Ferrera R , Loufouat J , Boussel L , Micolich A , Rioufol G , Revel D , Ovize M , Croisille P . Determination of the myocardial area at risk with pre‐ versus post‐reperfusion imaging techniques in the pig model. Basic Res Cardiol 106: 1247‐1257, 2011. doi: 10.1007/s00395‐011‐0214‐8
 143. Mewton N , Thibault H , Roubille F , Lairez O , Rioufol G , Sportouch C , Sanchez I , Bergerot C , Cung TT , Finet G , Angoulvant D , Revel D , Bonnefoy‐Cudraz E , Elbaz M , Piot C , Sahraoui I , Croisille P , Ovize M . Postconditioning attenuates no‐reflow in STEMI patients. Basic Res Cardiol 108: 383, 2013. doi: 10.1007/s00395‐013‐0383‐8
 144. Michael LH , Entman ML , Hartley CJ , Youker KA , Zhu J , Hall SR , Hawkins HK , Berens K , Ballantyne CM . Myocardial ischemia and reperfusion: A murine model. Am J Physiol 269: H2147‐H2154, 1995.
 145. Miura T , Yellon DM , Hearse DJ , Downey JM . Determinants of infarct size during permanent occlusion of a coronary artery in the closed chest dog. J Am Coll Cardiol 9: 647‐654, 1987.
 146. Moran AE , Forouzanfar MH , Roth GA , Mensah GA , Ezzati M , Flaxman A , Murray CJ , Naghavi M . The global burden of ischemic heart disease in 1990 and 2010: the global burden of disease 2010 study. Circulation 129: 1493‐1501, 2014. doi: 10.1161/CIRCULATIONAHA.113.004046
 147. Mudalagiri NR , Mocanu MM , Di SC , Kolvekar S , Hayward M , Yap J , Keogh B , Yellon DM . Erythropoietin protects the human myocardium against hypoxia/reoxygenation injury via phosphatidylinositol‐3 kinase and ERK1/2 activation. Br J Pharmacol 153: 50‐56, 2008. doi: 10.1038/sj.bjp.0707461
 148. Murray CJ , Vos T , Lozano R , Naghavi M , Flaxman AD , Michaud C , Ezzati M , Shibuya K , Salomon JA , AbdAlla S , Aboyans V , Abraham J , Ackerman I , Aggarwal R , Ahn SY , Ali MK , Alvarado M , Anderson HR , Anderson LM , Andrews KG , Atkinson C , Baddour LM , Bahalim AN , Barker‐Collo S , Barrero LH , Bartels DH , Basanez MG , Baxter A , Bell ML , Benjamin EJ , Bennett D , Bernabe E , Bhalla K , Bhandari B , Bikbov B , Bin AA , Birbeck G , Black JA , Blencowe H , Blore JD , Blyth F , Bolliger I , Bonaventure A , Boufous S , Bourne R , Boussinesq M , Braithwaite T , Brayne C , Bridgett L , Brooker S , Brooks P , Brugha TS , Bryan‐Hancock C , Bucello C , Buchbinder R , Buckle G , Budke CM , Burch M , Burney P , Burstein R , Calabria B , Campbell B , Canter CE , Carabin H , Carapetis J , Carmona L , Cella C , Charlson F , Chen H , Cheng AT , Chou D , Chugh SS , Coffeng LE , Colan SD , Colquhoun S , Colson KE , Condon J , Connor MD , Cooper LT , Corriere M , Cortinovis M , de Vaccaro KC , Couser W , Cowie BC , Criqui MH , Cross M , Dabhadkar KC , Dahiya M , Dahodwala N , msere‐Derry J , Danaei G , Davis A , De LD , Degenhardt L , Dellavalle R , Delossantos A , Denenberg J , Derrett S , Des J . Disability‐adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990‐2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380: 2197‐2223, 2012. doi: 10.1016/S0140‐6736(12)61689‐4
 149. Murry CE , Jennings RB , Reimer KA . Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 74: 1124‐1136, 1986. doi: 10.1161/01.CIR.74.5.1124
 150. 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 85: 110‐117, 2010. doi: 10.1093/cvr/cvp271
 151. Niccoli G , Burzotta F , Galiuto L , Crea F . Myocardial no‐reflow in humans. J Am Coll Cardiol 54: 281‐292, 2009. doi: 10.1016/j.jacc.2009.03.054
 152. Nishida K , Kyoi S , Yamaguchi O , Sadoshima J , Otsu K . The role of autophagy in the heart. Cell Death Differ 16: 31‐38, 2009. doi: 10.1038/cdd.2008.163
 153. Nishino Y , Webb IG , Davidson SM , Ahmed AI , Clark JE , Jacquet S , Shah AM , Miura T , Yellon DM , Avkiran M , Marber MS . Glycogen synthase kinase‐3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse. Circ Res 103: 307‐314, 2008. doi: 10.1161/CIRCRESAHA.107.169953
 154. Nithipatikom K , Moore JM , Isbell MA , Falck JR , Gross GJ . Epoxyeicosatrienoic acids in cardioprotection: Ischemic versus reperfusion injury. Am J Physiol Heart Circ Physiol 291: H537‐H542, 2006. doi: 10.1152/ajpheart.00071.2006
 155. O'Rourke B . Evidence for mitochondrial K+ channels and their role in cardioprotection. Circ Res 94: 420‐432, 2004. doi: 10.1161/01.RES.0000117583.66950.43
 156. Oerlemans MI , Koudstaal S , Chamuleau SA , de Kleijn DP , Doevendans PA , Sluijter JP . Targeting cell death in the reperfused heart: Pharmacological approaches for cardioprotection. Int J Cardiol 165: 410‐422, 2013. doi: 10.1016/j.ijcard.2012.03.055
 157. Oerlemans MI , Liu J , Arslan F , den OK , van Middelaar BJ , Doevendans PA , Sluijter JP . Inhibition of RIP1‐dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia‐reperfusion in vivo. Basic Res Cardiol 107: 270, 2012. doi: 10.1007/s00395‐012‐0270‐8
 158. Okamoto F , Allen BS , Buckberg GD , Bugyi H , Leaf J . Studies of controlled reperfusion after ischemia. XIV. Reperfusion conditions: Importance of ensuring gentle versus sudden reperfusion during relief of coronary occlusion. J Thorac Cardiovasc Surg 92: 613‐620, 1986.
 159. Ovize M , Baxter GF , Di Lisa F , Ferdinandy P , Garcia‐Dorado D , Hausenloy DJ , Heusch G , Vinten‐Johansen J , Yellon DM , Schulz R . Postconditioning and protection from reperfusion injury: Where do we stand? Cardiovasc Res 87: 406‐423, 2010. doi: 10.1093/cvr/cvq129
 160. Paillard M , Gomez L , Augeul L , Loufouat J , Lesnefsky EJ , Ovize M . Postconditioning inhibits mPTP opening independent of oxidative phosphorylation and membrane potential. J Mol Cell Cardiol 46: 902‐909, 2009. doi: 10.1016/j.yjmcc.2009.02.017
 161. Pain T , Yang X‐M , Critz SD , Yue Y , Nakano A , Liu GS , Heusch G , Cohen MV , Downey JM . Opening of mitochondrial KATP channels triggers the preconditioned state by generating free radicals. Circ Res 87: 460‐466, 2000. doi: 10.1161/01.RES.87.6.460
 162. Penna C , Cappello S , Mancardi D , Raimondo S , Rastaldo R , Gattullo D , Losano G , Pagliario P . Post‐conditioning reduces infarct size in the isolated rat heart: Role of coronary flow and pressure and the nitric oxide/cGMP pathway. Basic Res Cardiol 101: 168‐179, 2006. doi: 10.1007/s00395‐005‐0543‐6
 163. Penna C , Mancardi D , Rastaldo R , Losano G , Pagliaro P . Intermittent activation of bradykinin B(2) receptors and mitochondrial K(ATP) channels trigger cardiac postconditioning through redox signaling. Cardiovasc Res 75: 168‐177, 2007. doi: 10.1016/j.cardiores.2007.03.001
 164. Penna C , Mancardi D , Rastaldo R , Losano G , Pagliaro P . Intermittent activation of bradykinin B(2) receptors and mitochondrial K(ATP) channels trigger cardiac postconditioning through redox signaling. Cardiovasc Res 75: 168‐177, 2007. doi: 10.1016/j.cardiores.2007.03.001
 165. Penna C , Mancardi D , Tullio F , Pagliaro P . Postconditioning and intermittent bradykinin induced cardioprotection require cyclooxygenase activation and prostacyclin release during reperfusion. Basic Res Cardiol 103: 368‐377, 2008. doi: 10.1007/s00395‐007‐0695‐7
 166. Penna C , Mancardi D , Tullio F , Pagliaro P . Intermittent adenosine at the beginning of reperfusion does not trigger cardioprotection. J Surg Res 153: 231‐238, 2009. doi: 10.1016/j.jss.2008.02.070
 167. Penna C , Pasqua T , Perrelli MG , Pagliaro P , Cerra MC , Angelone T . Postconditioning with glucagon like peptide‐2 reduces ischemia/reperfusion injury in isolated rat hearts: Role of survival kinases and mitochondrial KATP channels. Basic Res Cardiol 107: 272, 2012. doi: 10.1007/s00395‐012‐0272‐6
 168. Penna C , Rastaldo R , Mancardi D , Raimondo S , Cappello S , Gattullo D , Losano G , Pagliario P . Post‐conditioning induced cardioprotection requires signaling through a redox‐sensitive mechanism, mitochondrial ATP‐sensitive K+ channel and protein kinase C activation. Basic Res Cardiol 101: 180‐189, 2006. doi: 10.1007/s00395‐006‐0584‐5
 169. Pich S , Klein HH , Lindert S , Nebendahl K , Kreuzer H . Cell death in ischemic, reperfused porcine hearts: A histochemical and functional study. Basic Res Cardiol 83: 550‐559, 1988.
 170. Piot C , Croisille P , Staat P , Thibault H , Rioufol G , Mewton N , Elbelghiti R , Cung TT , Bonnefoy E , Angoulvant D , Macia C , Raczka F , Sportouch C , Gahide G , Finet G , Andre‐Fouet X , Revel D , Kirkorian G , Monassier J‐P , Derumeaux G , Ovize M . Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 359: 473‐481, 2008. doi: 10.1056/NEJMoa071142
 171. Piper HM , Abdallah Y , Schäfer C . The first minutes of reperfusion: A window of opportunity for cardioprotection. Cardiovasc Res 61: 365‐371, 2004. doi: http://dx.doi.org/10.1016/j.cardiores.2003.12.012
 172. Pizarro G , Fernandez‐Friera L , Fuster V , Fernandez‐Jimenez R , Garcia‐Ruiz JM , Garcia‐Alvarez A , Mateos A , Barreiro MV , Escalera N , Rodriguez MD , de MA , Garcia‐Lunar I , Parra‐Fuertes JJ , Sanchez‐Gonzalez J , Pardillos L , Nieto B , Jimenez A , Abejon R , Bastante T , Martínez de Vega V , Cabrera JA , Lopez‐Melgar B , Guzman G , Garcia‐Prieto J , Mirelis JG , Zamorano JL , Albarran A , Goicolea J , Escaned J , Pocock S , Iniguez A , Fernandez‐Ortiz A , Sanchez‐Brunete V , Macaya C , Ibanez B . Long term benefit of early pre‐reperfusion metoprolol administration in patients with acute myocardial infarction: Results from the METOCARD‐CNIC trial. J Am Coll Cardiol 63: 2356‐2362, 2014. doi: 10.1016/j.jacc.2014.03.014
 173. Prasad A , Stone GW , Holmes DR , Gersh B . Reperfusion injury, microvascular dysfunction, and cardioprotection: The “dark side” of reperfusion. Circulation 120: 2105‐2112, 2009. doi: 10.1161/CIRCULATIONAHA.108.814640
 174. Prunier F , Angoulvant D , Saint Etienne C , Vermes E , Gilard M , Piot C , Roubille F , Elbaz M , Ovize M , Biere L , Jeanneteau J , Delepine S , Benard T , bi‐Khalil W , Furber A . The RIPOST‐MI study, assessing remote ischemic perconditioning alone or in combination with local ischemic postconditioning in ST‐segment elevation myocardial infarction. Basic Res Cardiol 109: 400, 2014. doi: 10.1007/s00395‐013‐0400‐y
 175. Przyklenk K . Lethal myocardial “reperfusion injury”: The opinions of good men. J Thromb Thrombolysis 4: 5‐6, 1997.
 176. Przyklenk K , Undyala VV , Wider J , Sala‐Mercado JA , Gottlieb RA , Mentzer RM, Jr . Acute induction of autophagy as a novel strategy for cardioprotection: Getting to the heart of the matter. Autophagy 7: 432‐433, 2011. doi: 10.4161/auto.7.4.14395
 177. Rassaf T , Totzeck M , Hendgen‐Cotta UB , Shiva S , Heusch G , Kelm M . Circulating nitrite contributes to cardioprotection by remote ischemic preconditioning. Circ Res 114: 1601‐1610, 2014. doi: 10.1161/CIRCRESAHA.114.303822
 178. Redel A , Jazbutyte V , Smul TM , Lange M , Eckle T , Eltzschig H , Roewer N , Kehl F . Impact of ischemia and reperfusion times on myocardial infarct size in mice in vivo. Exp Biol Med (Maywood) 233: 84‐93, 2008. doi: 10.3181/0612‐RM‐308
 179. Reffelmann T , Kloner RA . Microvascular reperfusion injury: Rapid expansion of anatomic no reflow during reperfusion in the rabbit. Am J Physiol Heart Circ Physiol 283: H1099‐H1107, 2002. doi: 10.1152/ajpheart.00270.2002
 180. 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 40: 633‐644, 1979.
 181. Reimer KA , Jennings RB , Cobb FR , Murdock RH , Greenfield, JC Jr , Becker LC , Bulkley BH , Hutchins GM , Schwartz, RP Jr , Bailey KR , Passamani ER . Animal models for protecting ischemic myocardium: Results of the NHLBI cooperative study. Comparison of unconscious and conscious dog models. Circ Res 56: 651‐665, 1985. doi: 10.1161/01.RES.56.5.651
 182. 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 56: 786‐794, 1977. doi: 10.1161/01.CIR.56.5.786
 183. Roberts CS , Schoen FJ , Kloner RA . Effect of coronary reperfusion on myocardial hemorrhage and infarct healing. Am J Cardiol 52: 610‐614, 1983.
 184. Rochitte CE , Lima JAC , 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 98: 1006‐1014, 1998. doi: 10.1161/01.CIR.98.10.1006
 185. Rodriguez‐Sinovas A , Cabestrero A , Garcia Del BB , Inserte J , Garcia A , Garcia‐Dorado D . Intracoronary acid infusion as an alternative to ischemic postconditioning in pigs. Basic Res Cardiol 104: 761‐771, 2009. doi: 10.1007/s00395‐009‐0032‐4
 186. Ross A , 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). J Am Coll Cardiol 45: 1775‐1780, 2005. doi: 10.1016/j.jacc.2005.02.061
 187. Roubille F , Franck‐Miclo A , Covinhes A , Lafont C , Cransac F , Combes S , Vincent A , Fontanaud P , Sportouch‐Dukhan C , Redt‐Clouet C , Nargeot J , Piot C , Barrere‐Lemaire S . Delayed postconditioning in the mouse heart In vivo. Circulation 124: 1330‐1336, 2011. doi: 10.1161/CIRCULATIONAHA.111.031864
 188. Roubille F , Lairez O , Mewton N , Rioufol G , Ranc S , Sanchez I , Cung TT , Elbaz M , Piot C , Ovize M . Cardioprotection by clopidogrel in acute ST‐elevated myocardial infarction patients: A retrospective analysis. Basic Res Cardiol 107: 275, 2012. doi: 10.1007/s00395‐012‐0275‐3
 189. Roubille F , Mewton N , Elbaz M , Roth O , Prunier F , Cung TT , Piot C , Roncalli J , Rioufol G , Bonnefoy‐Cudraz E , Wiedemann JY , Furber A , Jacquemin L , Willoteaux S , bi‐Khallil W , Sanchez I , Finet G , Sibellas F , Ranc S , Boussaha I , Croisille P , Ovize M . No post‐conditioning in the human heart with thrombolysis in myocardial infarction flow 2‐3 on admission. Eur Heart J 35: 1675‐1682, 2014. doi: 10.1093/eurheartj/ehu054
 190. Sala‐Mercado JA , Wider J , Undyala VV , Jahania S , Yoo W , Mentzer RM Jr , Gottlieb RA , Przyklenk K . Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia‐reperfusion injury. Circulation 122: S179‐S184, 2010. doi: 10.1161/CIRCULATIONAHA.109.928242
 191. Samavati L , Monick MM , Sanlioglu S , Buettner GR , Oberley LW , Hunninghake GW . Mitochondrial K(ATP) channel openers activate the ERK kinase by an oxidant‐dependent mechanism. Am J Physiol Cell Physiol 283: C273‐C281, 2002. doi: 10.1152/ajpcell.00514.2001
 192. Sasaki N , Sato T , Ohler A , O'Rourke B , Marban E . Activation of mitochondrial ATP‐dependent potassium channels by nitric oxide. Circulation 101: 439‐445, 2000. doi: 10.1161/01.CIR.101.4.439
 193. Sato H , Jordan JE , Zhao Z‐Q , Sarvotham SS , Vinten‐Johansen J . Gradual reperfusion reduces infarct size and endothelial injury but augments neutrophil accumulation. Ann Thorac Surg 64: 1099‐1107, 1997.
 194. Sato T , O'Rourke B , Marban E . Modulation of mitochondrial ATP‐dependent K+ channels by protein kinase C. Circ Res 83: 110‐114, 1998. doi: 10.1161/01.RES.83.1.110
 195. Schaper W , Görge G , Winkler B , Schaper J . The collateral circulation of the heart. Prog Cardiovasc Dis 31: 57‐77, 1988.
 196. Schlüter KD , Jakob G , Ruiz‐Meana GJM , Garcia‐Dorado D , Piper HM . Protection of reoxygenated cardiomyocytes against osmotic fragility by nitric oxide donors. Am J Physiol 271: H428‐H434, 1996.
 197. Schömig A , Mehilli J , Antoniucci D , Ndrepepa G , Markwardt C , Di Pede F , Nekolla SG , Schlotterbeck K , Schühlen H , Pache J , Seyfarth M , Martinoff S , Benzer W , Schmitt C , Dirschinger J , Schwaiger M , Kastrati A . Mechanical reperfusion in patients with acute myocardial infarction presenting more than 12 hours from symptom onset. A randomized controlled trial. JAMA 293: 2865‐2872, 2005. doi: 10.1001/jama.293.23.2865
 198. Schulman D , Latchman DS , Yellon DM . Urocortin protects the heart from reperfusion injury via upregulaiton of p42/p44 MAPK signaling pathway. Am J Physiol Heart Circ Physiol 283: H1481‐H1488, 2002. doi: 10.1152/ajpheart.01089.2001
 199. Schulz R . A new paradigm: Cross talk of protein kinases during reperfusion saves life! Am J Physiol Heart Circ Physiol 288: H1‐H2, 2005. doi: 10.1152/ajpheart.00886.2004
 200. Schulz R , Ferdinandy P . Does nitric oxide signaling differ in pre‐ and post‐conditioning? Importance of S‐nitrosylation vs. protein kinase G activation. Free Radic Biol Med 54: 113‐115, 2013. doi: 10.1016/j.freeradbiomed.2012.10.547
 201. Schulz R , Post H , Vahlhaus C , Heusch G . Ischemic preconditioning in pigs: A graded phenomenon. Its relation to adenosine and bradykinin. Circulation 98: 1022‐1029, 1998. doi: 10.1161/01.CIR.98.10.1022
 202. Schwanke U , Konietzka I , Duschin A , Li X , Schulz R , Heusch G . No ischemic preconditioning in heterozygous connexin43‐deficient mice. Am J Physiol Heart Circ Physiol 283: H1740‐H1742, 2002. doi: 10.1152/ajpheart.00442.2002
 203. Seiler C , Stoller M , Pitt B , Meier P . The human coronary collateral circulation: Development and clinical importance. Eur Heart J 34: 2674‐2682, 2013. doi: 10.1093/eurheartj/eht195
 204. Shen Y‐T , Fallon JT , Iwase M , Vatner SF . Innate protection of baboon myocardium: Effects of coronary artery occlusion and reperfusion. Am J Physiol 270: H1812‐H1818, 1996.
 205. Siddiqi N , Neil C , Bruce M , Maclennan G , Cotton S , Papadopoulou S , Feelisch M , Bunce N , Lim PO , Hildick‐Smith D , Horowitz J , Madhani M , Boon N , Dawson D , Kaski JC , Frenneaux M . Intravenous sodium nitrite in acute ST‐elevation myocardial infarction: A randomized controlled trial (NIAMI). Eur Heart J 35: 1255‐1262, 2014. doi: 10.1093/eurheartj/ehu096
 206. Sivaraman V , Mudalgiri NR , Di SC , Kolvekar S , Hayward M , Yap J , Keogh B , Hausenloy DJ , Yellon DM . Postconditioning protects human atrial muscle through the activation of the RISK pathway. Basic Res Cardiol 102: 453‐459, 2007. doi: 10.1007/s00395‐007‐0664‐1
 207. Skyschally A , Schulz R , Heusch G . Pathophysiology of myocardial infarction: Protection by ischemic pre‐ and postconditioning. Herz 33: 88‐100, 2008. doi: 10.1007/s00059‐008‐3101‐9
 208. Skyschally A , Schulz R , Heusch G . Cyclosporine A at reperfusion reduces infarct size in pigs. Cardiovasc Drugs Ther 24: 85‐87, 2010. doi: 10.1007/s10557‐010‐6219‐y
 209. Skyschally A , van Caster P , Boengler K , Gres P , Musiolik J , Schilawa D , Schulz R , Heusch G . Ischemic postconditioning in pigs: No causal role for RISK activation. Circ Res 104: 15‐18, 2009. doi: 10.1161/CIRCRESAHA.108.186429
 210. Skyschally A , van Caster P , Iliodromitis EK , Schulz R , Kremastinos DT , Heusch G . Ischemic postconditioning ‐ experimental models and protocol algorithms. Basic Res Cardiol 104: 469‐483, 2009. doi: 10.1016/S0140‐6736(12)60916‐7
 211. Skyschally A , Walter B , Heusch G . Coronary microembolization during early reperfusion ‐ infarct extension, but protection by ischemic postconditioning. Eur Heart J 34: 3314‐3321, 2013. doi: 10.1093/eurheartj/ehs434
 212. Smith CC , Dixon RA , Wynne AM , Theodorou L , Ong SG , Subrayan S , Davidson SM , Hausenloy DJ , Yellon DM . Leptin‐induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore. Am J Physiol Heart Circ Physiol 299: H1265‐H1270, 2010. doi: 10.1152/ajpheart.00092.2010
 213. 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 26: 227‐237, 2012. doi: 10.1007/s10557‐012‐6376‐2
 214. Speechly‐Dick ME , Grover GJ , Yellon DM . Does ischemic preconditioning in the human involve protein kinase C and the ATP‐dependent K+ channel? Studies of contractile function after simulated ischemia in an atrial in vitro model. Circ Res 77: 1030‐1035, 1995. doi: 10.1161/01.RES.77.5.1030
 215. Staat P , Rioufol G , Piot C , Cottin Y , Cung TT , L'Huillier I , Aupetit J‐F , Bonnefoy E , Finet G , Andre‐Fouet X , Ovize M . Postconditioning the human heart. Circulation 112: 2143‐2148, 2005. doi: 10.1161/CIRCULATIONAHA.105.558122
 216. Szczepanek K , Chen Q , Derecka M , Salloum FN , Zhang Q , Szelag M , Cichy J , Kukreja RC , Dulak J , Lesnefsky EJ , Larner AC . Mitochondrial‐targeted signal transducer and activator of transcription (STAT3) protects against ischemia‐induced changes in the electron transport chain and the generation of reactive oxygen species. J Biol Chem 286: 29610‐29620, 2011. doi: 10.1074/jbc.M111.226209
 217. Tang XL , Sato H , Tiwari S , Dawn B , Bi Q , Li Q , Shirk G , Bolli R . Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions <45 min. Am J Physiol Heart Circ Physiol 291: H2308‐H2317, 2006. doi: 10.1152/ajpheart.00479.2006
 218. Tani M , Neely JR . Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Circ Res 65: 1045‐1056, 1989. doi: 10.1161/01.RES.65.4.1045
 219. Thibault H , Gomez L , Donal E , Pontier G , Scherrer‐Crosbie M , Ovize M , Derumeaux G . Acute myocardial infarction in mice: Assessment of transmurality by strain rate imaging. Am J Physiol Heart Circ Physiol 293: H496‐H502, 2007. doi: 10.1152/ajpheart.00087.2007
 220. Thibault H , Piot C , Staat P , Bontemps L , Sportouch C , Rioufol G , Cung TT , Bonnefoy E , Angoulvant D , Aupetit JF , Finet G , Andre‐Fouet X , Macia JC , Raczka F , Rossi R , Itti R , Kirkorian G , Derumeaux G , Ovize M . Long‐term benefit of postconditioning. Circulation 117: 1037‐1044, 2008. doi: 10.1161/CIRCULATIONAHA.107.729780
 221. Thuny F , Lairez O , Roubille F , Mewton N , Rioufol G , Sportouch C , Sanchez I , Bergerot C , Thibault H , Cung TT , Finet G , Argaud L , Revel D , Derumeaux G , Bonnefoy‐Cudraz E , Elbaz M , Piot C , Ovize M , Croisille P . Post‐conditioning reduces infarct size and edema in patients with ST‐segment elevation myocardial infarction. J Am Coll Cardiol 59: 2175‐2181, 2012. doi: 10.1016/j.jacc.2012.03.026
 222. Tong G , Aponte AM , Kohr MJ , Steenbergen C , Murphy E , Sun J . Postconditioning leads to an increase in protein S‐nitrosylation. Am J Physiol Heart Circ Physiol 306: H825‐H832, 2014. doi: 10.1152/ajpheart.00660.2013
 223. Touboul C , Angoulvant D , Mewton N , Ivanes F , Muntean D , Prunier F , Ovize M , Bejan‐Angoulvant T . Ischaemic postconditioning reduces infarct size: Systematic review and meta‐analysis of randomized controlled trials. Arch Cardiovasc Dis 2014. doi: 10.1016/j.acvd.2014.08.004
 224. Tsang A , Hausenloy DJ , Mocanu MM , Yellon DM . Postconditioning: A form of “Modified Reperfusion” protects the myocardium by activating the phosphatidylinositol 3‐kinase‐Akt pathway. Circ Res 95: 230‐232, 2004. doi: 10.1161/01.RES.0000138303.76488.fe
 225. Tu Y , Wan L , Fan Y , WAng K , Bu L , Huang T , Cheng Z , Shen B . Ischemic postconditioning‐mediated miRNA‐21 protects against cardiac ischemia/reperfusion injury via PTEN/Akt pathway. PLoS One 8: e75872, 2013. doi: 10.1371/journal.pone.0075872
 226. Tullio F , Angotti C , Perrelli MG , Penna C , Pagliaro P . Redox balance and cardioprotection. Basic Res Cardiol 108: 392, 2013. doi: 10.1007/s00395‐013‐0392‐7
 227. van de Werf F . The history of coronary reperfusion. Eur Heart J 2014. doi: 10.1093/eurheartj/ehu268
 228. Varga ZV , Zvara A , Farago N , Kocsis GF , Pipicz M , Gaspar R , Bencsik P , Gorbe A , Csonka C , Puskas LG , Thum T , Csont T , Ferdinandy P . MicroRNAs associated with ischemia‐reperfusion injury and cardioprotection by ischemic pre‐ and postconditioning: ProtectomiRs. Am J Physiol Heart Circ Physiol 307: H216‐H227, 2014. doi: 10.1152/ajpheart.00812.2013
 229. Vessey DA , Li L , Honbo N , Karliner JS . Sphingosine 1‐phosphate is an important endogenous cardioprotectant released by ischemic pre‐ and postconditioning. Am J Physiol Heart Circ Physiol 297: H1429‐H1435, 2009. doi: 10.1152/ajpheart.00358
 230. Vessey DA , Li L , Kelley M , Zhang J , Karliner JS . Sphingosine can pre‐ and post‐condition heart and utilizes a different mechanism from sphingosine 1‐phosphate. J Biochem Mol Toxicol 22: 113‐118, 2008. doi: 10.1002/jbt.20227
 231. Wegrzyn J , Potla R , Chwae YJ , Sepuri NB , Zhang Q , Koeck T , Derecka M , Szczepanek K , Szelag M , Gornicka A , Moh A , Moghaddas S , Chen Q , Bobbili S , Cichy J , Dulak J , Baker DP , Wolfman A , Stuehr D , Hassan MO , Fu XY , Avadhani N , Drake JI , Fawcett P , Lesnefsky EJ , Larner AC . Function of mitochondrial Stat3 in cellular respiration. Science 323: 793‐797, 2009. doi: 10.1126/science.1164551
 232. Wei C , Li H , Han L , Zhang L , Yang X . Activation of autophagy in ischemic postconditioning contributes to cardioprotective effects against ischemia/reperfusion injury in rat hearts. J Cardiovasc Pharmacol 61: 416‐422, 2013. doi: 10.1097/FJC.0b013e318287d501
 233. Wei M , Xin P , Li S , Tao J , Li Y , Li J , Liu M , Li J , Zhu W , Redington AN . Repeated remote ischemic postconditioning protects against adverse left ventricular remodeling and improves survival in a rat model of myocardial infarction. Circ Res 108: 1220‐1225, 2011.
 234. Wong GT , Li R , Jiang LL , Irwin MG . Remifentanil post‐conditioning attenuates cardiac ischemia‐reperfusion injury via kappa or delta opioid receptor activation. Acta Anaesthesiol Scand 54: 510‐518, 2010. doi: 10.1111/j.1399‐6576.2009.02145.x
 235. Woo JS , Kim W , Ha SJ , Kim JB , Kim SJ , Kim WS , Seon HJ , Kim KS . Cardioprotective effects of exenatide in patients with ST‐segment‐elevation myocardial infarction undergoing primary percutaneous coronary intervention: Results of exenatide myocardial protection in revascularization study. Arterioscler Thromb Vasc Biol 33: 2252‐2260, 2013. doi: 10.1161/ATVBAHA.113.301586
 236. Xia X‐H , Allen DG . Activity of the Na+/H+ exchanger is critical to reperfusion damage and preconditioning in the isolated rat heart. Cardiovasc Res 48: 244‐253, 2000. doi: http://dx.doi.org/10.1016/S0008‐6363(00)00166‐8
 237. Xu Z , Yang X‐M , Cohen MV , Neumann T , Heusch G , Downey JM . Limitation of infarct size in rabbit hearts by the novel adenosine receptor agonist 579 administerd at reperfusion. J Mol Cell Cardiol 32: 2339‐2347, 2000. doi: 10.1006/jmcc.2000.1264
 238. Yang XM , Liu Y , Liu Y , Tandon N , Kambayashi J , Downey JM , Cohen MV . Attenuation of infarction in cynomolgus monkeys: Preconditioning and postconditioning. Basic Res Cardiol 105: 119‐128, 2010. doi: 10.1007/s00395‐009‐0050‐2
 239. Yang X‐M , Philipp S , Downey JM , Cohen MV . Atrial natriuretic peptide administered just prior to reperfusion limits infarction in rabbit hearts. Basic Res Cardiol 101: 311‐318, 2006. doi: 10.1007/s00395‐006‐0587‐2
 240. Yang X‐M , Proctor JB , Cui L , Krieg T , Downey JM , Cohen MV . Multiple, brief coronary occlusions during early reperfusion protect hearts by targeting cell signaling pathways. J Am Coll Cardiol 44: 1103‐1110, 2004. doi: 10.1016/j.jacc.2004.05.060
 241. Yellon DM , Hausenloy DJ . Myocardial reperfusion injury. N Engl J Med 357: 1121‐1135, 2007. doi: 10.1056/NEJMra071667
 242. Yong QC , Lee SW , Foo CS , Neo KL , Chen X , Bian JS . Endogenous hydrogen sulphide mediates the cardioprotection induced by ischemic postconditioning. Am J Physiol Heart Circ Physiol 295: H1330‐H1340, 2008. doi: 10.1152/ajpheart.00244.2008
 243. Zatta AJ , Kin H , Lee G , Wang N , Jiang R , Lust R , Reeves JG , Mykytenko J , Guyton RA , Zhao ZQ , Vinten‐Johansen J . Infarct‐sparing effect of myocardial postconditioning is dependent on protein kinase C signalling. Cardiovasc Res 70: 315‐324, 2006. doi: http://dx.doi.org/10.1016/j.cardiores.2005.11.030
 244. Zatta AJ , Kin H , Yoshishige D , Jiang R , Wang N , Reeves JG , Mykytenko J , Guyton RA , Zhao ZQ , Caffrey JL , Vinten‐Johansen J . Evidence that cardioprotection by postconditioning involves preservation of myocardial opioid content and selective opioid receptor activation. Am J Physiol Heart Circ Physiol 294: H1444‐H1451, 2008.doi: 10.1152/ajpheart.01279.2006
 245. Zhang JH , Xu M . DNA fragmentation in apoptosis. Cell Res 10: 205‐211, 2000. doi: 10.1038/sj.cr.7290049
 246. Zhao Z‐Q , Corvera JS , Halkos ME , Kerendi F , Wang N‐P , Guyton RA , Vinten‐Johansen J . Inhibition of myocardial injury by ischemic postconditioning during reperfusion: Comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285: H579‐H588, 2003. doi: 10.1152/ajpheart.01069.2002
 247. Zhao ZQ , Nakamura M , Wang NP , Wilcox JN , Shearer S , Guyton RA , Vinten‐Johansen J . Administration of adenosine during reperfusion reduces injury of vascular endothelium and death of myocytes. Coron Artery Dis 10: 617‐628, 1999.
 248. Zhou W , Yuan J . SnapShot: Necroptosis. Cell 158: 464, 2014. doi: 10.1016/j.cell.2014.06.041
 249. Zhu M , Feng J , Lucchinetti E , Fischer G , Xu L , Pedrazzini T , Schaub MC , Zaugg M . Ischemic postconditioning protects remodeled myocardium via the PI3K‐PKB/Akt reperfusion injury salvage kinase pathway. Cardiovasc Res 72: 152‐162, 2006. doi: 10.1016/j.cardiores.2006.06.027
 250. Zhu SB , Liu Y , Zhu Y , Yin GL , Wang RP , Zhang Y , Zhu J , Jiang W . Remote preconditioning, perconditioning, and postconditioning: A comparative study of their cardio‐protective properties in rat models. Clinics (Sao Paulo) 68: 263‐268, 2013.

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Gerd Heusch. Treatment of Myocardial Ischemia/Reperfusion Injury by Ischemic and Pharmacological Postconditioning. Compr Physiol 2015, 5: 1123-1145. doi: 10.1002/cphy.c140075