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9th Hatter Biannual Meeting: position document on ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection.

Bell RM, Bøtker HE, Carr RD, Davidson SM, Downey JM, Dutka DP, Heusch G, Ibanez B, Macallister R, Stoppe C, Ovize M, Redington A, Walker JM, Yellon DM - Basic Res. Cardiol. (2016)

Bottom Line: In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality.Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide.The need for effective cardioprotective strategies has never been so pressing.

View Article: PubMed Central - PubMed

Affiliation: The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.

ABSTRACT
In the 30 years since the original description of ischaemic preconditioning, understanding of the pathophysiology of ischaemia/reperfusion injury and concepts of cardioprotection have been revolutionised. In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality. Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide. The need for effective cardioprotective strategies has never been so pressing. However, despite unequivocal evidence of the existence of ischaemia/reperfusion in animal models providing a robust rationale for study in man, recent phase 3 clinical trials studying a variety of cardioprotective strategies in cardiac surgery and acute ST-elevation myocardial infarction have provided mixed results. The investigators meeting at the Hatter Cardiovascular Institute workshop describe the challenge of translating strong pre-clinical data into effective clinical intervention strategies in patients in whom effective medical therapy is already altering the pathophysiology of ischaemia/reperfusion injury-and lay out a clearly defined framework for future basic and clinical research to improve the chances of successful translation of strong pre-clinical interventions in man.

No MeSH data available.


Related in: MedlinePlus

Cartoon of injurious ischaemia/reperfusion injury and the different forms of cell death. Necrosis is the prototypical form of cell death resulting from prolonged ischaemia. Through high-energy phosphate depletion, the cells cease to maintain electro-chemical gradients and the cells and the intracellular organelles swell. Histologically, the cytoplasmic membranes become progressively more lucent, before rupturing leading to the dispersal of cellular contents into the extracellular space (although the nuclei may persist). The cellular contents, including both nucleic and mitochondrial DNA, form damage associated molecular patterns (DAMPs); signals that are also released into the extracellular space by necroptosis. Sharing features with necrosis and programmed cell death, apoptosis, necroptosis involves the recruitment of cellular pathways (typically through receptor-interacting protein kinase (RIPK)), that may be activated through the dissipation of DAMPS from neighbouring necrosed cells. Like necrosis, but unlike apoptosis, the cell membrane does not remain intact, and may lead to the release of further DAMPS. The ensuing inflammatory reaction can then lead to pryoptosis—inflammatory cytokine mediated injury. The consequence of the spreading wave of dying cells, like toppling dominos, is likely responsible for the formation of the characteristic confluent myocardial infarct. Apoptosis, in contrast, is the ordered process of cell death, through the successful completion of an ordered cellular shut-down and compartmentalisation of potentially injurious cellular contents that prevents unintended injury to neighbouring cells. Autophagy plays a role in the house keeping of healthy cells, removing senescent proteins and organelles, such as mitochondria (mitophagy). During ischemia/reperfusion injury, autophagy may be a double-edged sword: while autophagy may remove terminally injured and dangerous organelles and oxidised proteins, contributing to energy recovery in reperfusion, excess autophagy may be linked to apoptosis and excessive substrate degradation
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Fig1: Cartoon of injurious ischaemia/reperfusion injury and the different forms of cell death. Necrosis is the prototypical form of cell death resulting from prolonged ischaemia. Through high-energy phosphate depletion, the cells cease to maintain electro-chemical gradients and the cells and the intracellular organelles swell. Histologically, the cytoplasmic membranes become progressively more lucent, before rupturing leading to the dispersal of cellular contents into the extracellular space (although the nuclei may persist). The cellular contents, including both nucleic and mitochondrial DNA, form damage associated molecular patterns (DAMPs); signals that are also released into the extracellular space by necroptosis. Sharing features with necrosis and programmed cell death, apoptosis, necroptosis involves the recruitment of cellular pathways (typically through receptor-interacting protein kinase (RIPK)), that may be activated through the dissipation of DAMPS from neighbouring necrosed cells. Like necrosis, but unlike apoptosis, the cell membrane does not remain intact, and may lead to the release of further DAMPS. The ensuing inflammatory reaction can then lead to pryoptosis—inflammatory cytokine mediated injury. The consequence of the spreading wave of dying cells, like toppling dominos, is likely responsible for the formation of the characteristic confluent myocardial infarct. Apoptosis, in contrast, is the ordered process of cell death, through the successful completion of an ordered cellular shut-down and compartmentalisation of potentially injurious cellular contents that prevents unintended injury to neighbouring cells. Autophagy plays a role in the house keeping of healthy cells, removing senescent proteins and organelles, such as mitochondria (mitophagy). During ischemia/reperfusion injury, autophagy may be a double-edged sword: while autophagy may remove terminally injured and dangerous organelles and oxidised proteins, contributing to energy recovery in reperfusion, excess autophagy may be linked to apoptosis and excessive substrate degradation

Mentions: Since the original description of ischaemic conditioning by Murry, Jennings and Reimer in 1986 [56], the understanding of the mechanisms of cell death arising from injurious ischaemia and reperfusion injury has been transformed: no longer a purely necrotic model, it is now recognised as a complex, multifaceted pathophysiological process [37], involving not only necrosis, but also cellular signalling, apoptosis, necroptosis [16] and the complex interaction of autophagy [15] through to inflammatory injury and pyroptosis [78] (Fig. 1). In parallel, identification of numerous pharmacological targets, both in modifying cell death pathways and in up-regulating canonical conditioning signalling Reperfusion Injury Salvage Kinase (RISK) [30] and Survivor Activating Factor Enhancement (SAFE) [48] pathways that culminate in the inhibition of the mitochondrial transition pore (mPTP, Fig. 2) have provided irrefutable proof of the existence of reperfusion injury following injurious ischaemia in animal models [32]. Moreover, the evolution of remote ischaemic conditioning the phenomenon whereby transient ischaemic stress of one organ can lead to protection of another, remote organ such as the heart against injurious ischaemia/reperfusion injury [33, 47] as a putative therapeutic intervention that can be applied prior to or immediately upon onset of reperfusion has supported the existence of ischaemia/reperfusion injury in man—both in proof-of-concept and meta-analysis of phase 2 clinical trials [46].Fig. 1


9th Hatter Biannual Meeting: position document on ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection.

Bell RM, Bøtker HE, Carr RD, Davidson SM, Downey JM, Dutka DP, Heusch G, Ibanez B, Macallister R, Stoppe C, Ovize M, Redington A, Walker JM, Yellon DM - Basic Res. Cardiol. (2016)

Cartoon of injurious ischaemia/reperfusion injury and the different forms of cell death. Necrosis is the prototypical form of cell death resulting from prolonged ischaemia. Through high-energy phosphate depletion, the cells cease to maintain electro-chemical gradients and the cells and the intracellular organelles swell. Histologically, the cytoplasmic membranes become progressively more lucent, before rupturing leading to the dispersal of cellular contents into the extracellular space (although the nuclei may persist). The cellular contents, including both nucleic and mitochondrial DNA, form damage associated molecular patterns (DAMPs); signals that are also released into the extracellular space by necroptosis. Sharing features with necrosis and programmed cell death, apoptosis, necroptosis involves the recruitment of cellular pathways (typically through receptor-interacting protein kinase (RIPK)), that may be activated through the dissipation of DAMPS from neighbouring necrosed cells. Like necrosis, but unlike apoptosis, the cell membrane does not remain intact, and may lead to the release of further DAMPS. The ensuing inflammatory reaction can then lead to pryoptosis—inflammatory cytokine mediated injury. The consequence of the spreading wave of dying cells, like toppling dominos, is likely responsible for the formation of the characteristic confluent myocardial infarct. Apoptosis, in contrast, is the ordered process of cell death, through the successful completion of an ordered cellular shut-down and compartmentalisation of potentially injurious cellular contents that prevents unintended injury to neighbouring cells. Autophagy plays a role in the house keeping of healthy cells, removing senescent proteins and organelles, such as mitochondria (mitophagy). During ischemia/reperfusion injury, autophagy may be a double-edged sword: while autophagy may remove terminally injured and dangerous organelles and oxidised proteins, contributing to energy recovery in reperfusion, excess autophagy may be linked to apoptosis and excessive substrate degradation
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4863033&req=5

Fig1: Cartoon of injurious ischaemia/reperfusion injury and the different forms of cell death. Necrosis is the prototypical form of cell death resulting from prolonged ischaemia. Through high-energy phosphate depletion, the cells cease to maintain electro-chemical gradients and the cells and the intracellular organelles swell. Histologically, the cytoplasmic membranes become progressively more lucent, before rupturing leading to the dispersal of cellular contents into the extracellular space (although the nuclei may persist). The cellular contents, including both nucleic and mitochondrial DNA, form damage associated molecular patterns (DAMPs); signals that are also released into the extracellular space by necroptosis. Sharing features with necrosis and programmed cell death, apoptosis, necroptosis involves the recruitment of cellular pathways (typically through receptor-interacting protein kinase (RIPK)), that may be activated through the dissipation of DAMPS from neighbouring necrosed cells. Like necrosis, but unlike apoptosis, the cell membrane does not remain intact, and may lead to the release of further DAMPS. The ensuing inflammatory reaction can then lead to pryoptosis—inflammatory cytokine mediated injury. The consequence of the spreading wave of dying cells, like toppling dominos, is likely responsible for the formation of the characteristic confluent myocardial infarct. Apoptosis, in contrast, is the ordered process of cell death, through the successful completion of an ordered cellular shut-down and compartmentalisation of potentially injurious cellular contents that prevents unintended injury to neighbouring cells. Autophagy plays a role in the house keeping of healthy cells, removing senescent proteins and organelles, such as mitochondria (mitophagy). During ischemia/reperfusion injury, autophagy may be a double-edged sword: while autophagy may remove terminally injured and dangerous organelles and oxidised proteins, contributing to energy recovery in reperfusion, excess autophagy may be linked to apoptosis and excessive substrate degradation
Mentions: Since the original description of ischaemic conditioning by Murry, Jennings and Reimer in 1986 [56], the understanding of the mechanisms of cell death arising from injurious ischaemia and reperfusion injury has been transformed: no longer a purely necrotic model, it is now recognised as a complex, multifaceted pathophysiological process [37], involving not only necrosis, but also cellular signalling, apoptosis, necroptosis [16] and the complex interaction of autophagy [15] through to inflammatory injury and pyroptosis [78] (Fig. 1). In parallel, identification of numerous pharmacological targets, both in modifying cell death pathways and in up-regulating canonical conditioning signalling Reperfusion Injury Salvage Kinase (RISK) [30] and Survivor Activating Factor Enhancement (SAFE) [48] pathways that culminate in the inhibition of the mitochondrial transition pore (mPTP, Fig. 2) have provided irrefutable proof of the existence of reperfusion injury following injurious ischaemia in animal models [32]. Moreover, the evolution of remote ischaemic conditioning the phenomenon whereby transient ischaemic stress of one organ can lead to protection of another, remote organ such as the heart against injurious ischaemia/reperfusion injury [33, 47] as a putative therapeutic intervention that can be applied prior to or immediately upon onset of reperfusion has supported the existence of ischaemia/reperfusion injury in man—both in proof-of-concept and meta-analysis of phase 2 clinical trials [46].Fig. 1

Bottom Line: In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality.Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide.The need for effective cardioprotective strategies has never been so pressing.

View Article: PubMed Central - PubMed

Affiliation: The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.

ABSTRACT
In the 30 years since the original description of ischaemic preconditioning, understanding of the pathophysiology of ischaemia/reperfusion injury and concepts of cardioprotection have been revolutionised. In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality. Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide. The need for effective cardioprotective strategies has never been so pressing. However, despite unequivocal evidence of the existence of ischaemia/reperfusion in animal models providing a robust rationale for study in man, recent phase 3 clinical trials studying a variety of cardioprotective strategies in cardiac surgery and acute ST-elevation myocardial infarction have provided mixed results. The investigators meeting at the Hatter Cardiovascular Institute workshop describe the challenge of translating strong pre-clinical data into effective clinical intervention strategies in patients in whom effective medical therapy is already altering the pathophysiology of ischaemia/reperfusion injury-and lay out a clearly defined framework for future basic and clinical research to improve the chances of successful translation of strong pre-clinical interventions in man.

No MeSH data available.


Related in: MedlinePlus