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

Gerd Heusch

10.1002/cphy.c140075

Source: Volume 5, Issue 3, July 2015

Published online: June 2015

Full Article on Wiley Online Library



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; G s/G i/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; G s/G i/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.
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Article Title: Treatment of Myocardial Ischemia/Reperfusion Injury by Ischemic and Pharmacological Postconditioning
 

How to Cite

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