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“… it will not be long before pharmacological therapy, based upon our understanding of the mechanisms of “conditioning”, can be used to protect patients from the consequences of severe acute myocardial ischaemia–reperfusion injury”
See article on page 749
Over 35 years ago1 the factors which determine infarct size following an acute coronary occlusion were first documented, with the duration of myocardial ischaemia being the major determinant. Shortly thereafter the same laboratory described the powerful cardioprotective potential of myocardial reperfusion using an in situ canine model of myocardial ischaemia–reperfusion injury. In this seminal study, restoring coronary artery flow after 3 h of acute coronary occlusion reduced myocardial infarct size to 10% from 64% in non‐reperfused hearts.2 This pivotal finding made at the laboratory “bench” has been successfully translated into the myocardial reperfusion strategies of thrombolytic treatment and primary percutaneous coronary intervention (PCI) presently used at the patient “bedside”; these remain the most powerful interventional strategies for reducing myocardial infarct size, and have succeeded in dramatically improving clinical outcomes following an acute myocardial infarction (AMI).
However, although early effective myocardial reperfusion is clearly a prerequisite for myocardial salvage, it comes at a price. As well as restoring coronary blood flow to ischaemic myocardium, the “double‐edged sword” of myocardial reperfusion is capable of inflicting myocardial injury of which the reversible forms of myocardial stunning, no‐reflow phenomenon and reperfusion arrhythmias are easily dealt with.3 Crucially, however, the irreversible form of myocardial reperfusion injury is capable of causing the death of cardiomyocytes which were immediately viable pre‐reperfusion, thereby mitigating the benefits mediated by myocardial reperfusion in terms of infarct‐size reduction—a phenomenon termed “lethal reperfusion injury”. The existence of this covert form of cardiomyocyte death induced by myocardial reperfusion may in part explain the mortality rate associated with AMI, which, despite early and successful myocardial reperfusion, remains at close to 10%.4 As such, reducing the cardiomyocyte death mediated by lethal reperfusion injury presents an important target for cardioprotection for AMI patients undergoing myocardial reperfusion. It should be emphasised that in spite of optimal myocardial reperfusion in conjunction with antithrombotic and antiplatelet treatment, there is still a requirement to protect the muscle from the injury associated with the reperfusion itself.
In 1986, the concept of “conditioning” the myocardium to protect it against ischaemia–reperfusion injury was first introduced by Murry et al.5 These investigators made the critical observation that deliberately inducing short bouts of myocardial ischaemia and reperfusion by intermittent occlusion of the coronary artery rendered the myocardium resistant to a subsequent more prolonged episode of myocardial ischaemia, such that the resultant infarct size was notably reduced—a phenomenon they termed “ischaemic preconditioning” (IPC). This ubiquitous endogenous form of cardioprotection has been observed in all species tested, including man; is capable of limiting ischaemia–reperfusion in non‐cardiac organs such as the brain, liver, gut, bladder and skin; and has the capacity to protect both isolated cells and mitochondria against simulated ischaemia–reperfusion injury.6
The cardioprotective effect elicited by the IPC stimulus is biphasic with the first window of cardioprotection (termed “classical IPC”) lasting 3–4 h,6 following which the cardioprotective effect disappears. Studies from our laboratory first revealed that cardioprotection actually reappears 24 h later when it can persist for up to 72 h (termed the second window of protection (SWOP) or delayed/late preconditioning).7 Elucidation of the major signal transduction pathways underlying preconditioning have identified “triggers” (generated during the preconditioning stimulus) which activate “mediators” such as protein kinases which recruit effector mechanisms in the case of classical IPC; however, in the case of delayed preconditioning these protein kinases mediate the transcription of distal mediators and effectors 24–72 h later, which manifest the delayed protective effect.
The phenomenon of IPC has been described in patients using surrogate models of myocardial ischaemia–reperfusion injury such as in the settings of pre‐infarct angina, the warm‐up phenomenon and percutaneous coronary angioplasty.8 Our laboratory was the first to demonstrate the cardioprotective potential of IPC in patients undergoing acute myocardial ischaemia–reperfusion injury. In a clinical study we demonstrated the attenuation of myocardial injury in patients undergoing coronary artery bypass graft (CABG) surgery, using an IPC protocol comprising cross‐clamping of the aorta.9,10 However, this particular preconditioning intervention was both invasive and impractical to apply, and a more amenable and less invasive approach to cardioprotection may be realised by “conditioning” the heart remotely, using the phenomenon of remote ischaemic preconditioning (RIPC), in which brief ischaemia in one tissue or organ protects distant tissue or organs from a sustained episode of ischaemia. This phenomenon was first described by Przyklenk and colleagues in 1993.11 Using a canine model of myocardial ischemia–reperfusion injury, they showed that brief episodes of circumflex artery occlusion could reduce the myocardial infarct size induced in the left anterior descending artery territory by acute occlusion of that artery. This concept was further advanced in studies reporting that brief episodes of ischaemia remote from the myocardium, in organs such as the kidney,12 the intestine,13 or skeletal muscle,14 were capable of protecting the heart against a subsequent myocardial infarction, the mechanism of which has been attributed to a hormonal mediator12,15,16 or the recruitment of a neural pathway.13,17 MacAllister's laboratory17,18 characterised and pioneered the use of transient limb ischaemia as an RIPC stimulus in human volunteers, demonstrating endothelial protection in the contralateral arm and modification of myocardial gene expression with upregulation of cytoprotective genes and suppression of pro‐inflammatory genes potentially involved in the pathogenesis of ischaemia–reperfusion injury.19,20 This RIPC has been used to attenuate myocardial injury in a porcine model of CABG surgery.21 We have taken this concept to the clinical setting in that we have recently shown that RIPC attenuates myocardial injury in patients undergoing elective CABG surgery.22
After myocardial reperfusion, preconditioning remains the most powerful intervention for reducing myocardial infarct size, but its clinical application has been hampered by the requirement to intervene before the onset of acute myocardial ischaemia, which in the setting of an AMI is clearly not possible.
However, in order to circumvent this problem, the concept of ‘conditioning' has recently evolved into ischaemic postconditioning (IPost), which was originally introduced in 2003 by Zhao et al.23 IPost describes the cardioprotection elicited by interrupting normal myocardial reperfusion with 3–6 short‐lived episodes (each lasting 10–60 s) of myocardial ischaemia using a canine model of ischaemia–reperfusion injury. As an intervention which can be applied at the time of myocardial reperfusion, the clinical application of this strategy has already been demonstrated in several small clinical studies of AMI patients undergoing primary PCI.24,25,26 These pioneering studies showed that by applying a series of low pressure inflations/deflations of the coronary angioplasty balloon immediately following the direct stenting of the infarct‐related coronary artery, in order to interrupt the normal myocardial reperfusion process, it was possible to reduce myocardial infarct size, as measured by cardiac enzymes and nuclear scanning, and improve myocardial reperfusion.24,25,26 Therein lies the major limitation of this cardioprotective strategy—it relies on an invasive protocol which can only be utilised in AMI patients undergoing PCI.
This brings us to the exciting study by Andreka et al27 in this issue of Heart in which the “conditioning” concept evolves still further into the phenomenon of remote ischaemic postconditioning (RIPost), in which short‐lived episodes of ischaemia–reperfusion, in an organ or tissue remote from the heart, are applied at the end of an episode of sustained myocardial ischaemia.28 In the original remote postconditioning study, Kerendi et al28 demonstrated that applying transient episodes of renal ischaemia–reperfusion at the end of a sustained myocardial ischaemic period reduced the resultant myocardial infarct size, an effect which appeared dependent on adenosine. Andreka et al27 reproduced RIPost using an in situ porcine model of myocardial ischaemia–reperfusion injury, a model closely related to the human AMI model, but utilising a far less invasive preconditioning stimulus comprising transient hindlimb ischaemia. This RIPost protocol reduced myocardial infarct size 72 h later as measured by cardiac enzyme release, tetrazolium staining and gadolinium‐late enhancement on cardiac magnetic resonance imaging.27
Clearly the next crucial step is to translate these findings into clinical practice. With reference to RIPC, Cheung et al29 have reported that transient limb ischaemia is cardioprotective in children undergoing corrective cardiac surgery for congenital heart disease. As alluded to above, a preliminary study by our group has demonstrated in a small proof‐of‐concept clinical study that RIPC using transient limb ischaemia attenuated myocardial injury sustained by adult patients undergoing elective CABG surgery.22 Whether RIPost has the capacity to cardioprotect AMI patients undergoing primary PCI or thrombolytic treatment is currently being examined by our group, and will hopefully establish whether RIPost has any place in clinical practice.
However, in the 35 years since the concept of cardioprotection was first proposed, we believe we have now reached the stage where we are able to translate basic research into clinical reality. In this regard we predict that it will not be long before pharmacological therapy, based upon our understanding of the mechanisms of “conditioning”, can be used to protect patients from the consequences of severe acute myocardial ischaemia–reperfusion injury.injury.
AMI - acute myocardial infarction
CABG - coronary artery bypass graft
IPC - ischaemic preconditioning
IPost - ischaemic postconditioning
PCI - percutaneous coronary intervention
RIPC - remote ischaemic preconditioning
RIPost - remote ischaemic postconditioning
SWOP - second window of protection
Conflict of interest: none declared.