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To recognise that acute myocardial ischaemia/reperfusion injury is a neglected therapeutic target for cardioprotection that is responsible for the ongoing morbidity and mortality of patients with ischaemic heart disease.
To be aware that cardiac bypass surgery and ST segment elevation myocardial infarction are the major clinical settings in which the heart is subjected to acute ischaemia/reperfusion injury.
To be familiar with the concept of ‘ischaemic conditioning’, in which the heart is protected against acute ischaemia/reperfusion injury by subjecting it to cycles of brief ischaemia and reperfusion, a therapeutic strategy which has been demonstrated in proof-of-concept studies to be beneficial in patients with ischaemic heart disease.
Introduction—the need for cardioprotection
Ischaemic heart disease (IHD) is the leading cause of death and disability worldwide. Despite current therapies, patients still experience significant morbidity and mortality when undergoing cardiac bypass surgery or when presenting with an ST segment elevation myocardial infarction (STEMI). This is partly attributed to the detrimental effects of acute ischaemia/reperfusion injury (IRI) on the heart, which in combination mediate cardiomyocyte death, resulting in impaired LV systolic function and increased risk of heart failure. Although a number of strategies exist for reducing the ischaemic component of acute IRI injury in cardiac bypass surgery (such as cardioplegia and hypothermia) and STEMI (such as prompt reperfusion with primary percutaneous intervention—PPCI), paradoxically, reperfusing previously ischaemic myocardium leads to further cardiomyocyte death—termed ‘myocardial reperfusion injury’ and for which there is currently no effective therapy. Therefore, novel therapeutic interventions are required to protect the heart from acute IRI in these clinical settings in order to improve clinical outcomes. In this regard, ‘ischaemic conditioning’, in which the heart is rendered tolerant to acute IRI by subjecting it to cycles of brief ischaemia and reperfusion, provides an endogenous form of cardioprotection. In this article, we review the role for ischaemic conditioning as a therapeutic strategy for attenuating cardiomyocyte death, preserving myocardial function, and improving clinical outcomes in patients subjected to acute myocardial IRI.
Myocardial reperfusion injury—a neglected therapeutic target
Although myocardial reperfusion is essential to salvage viable myocardium following the onset of acute myocardial ischaemia, the restoration of coronary blood flow comes at a price, paradoxically inducing myocardial injury and cardiomyocyte death—termed ‘myocardial reperfusion injury’. Four types of myocardial reperfusion injuries have been described:
Reperfusion-induced arrhythmias: These occur on reperfusing previously ischaemic myocardium and comprise idioventricular rhythm and ventricular arrhythmias, the majority of which are self-terminating or are easily treated.
Myocardial stunning: This refers to the reversible contractile dysfunction that occurs on reperfusing acute ischaemic myocardium and is believed to be due to myocardial oxidative stress and intracellular calcium overload.
Coronary no-reflow and microvascular obstruction (MVO): Coronary no-reflow is indicative of underlying MVO—defined as the ‘inability to reperfuse a previously ischaemic region’.1 MVO is present on cardiovascular MRI (CMR) in 40–60% of primary percutaneous intervention (PPCI) patients, despite the presence of normal coronary flow (thrombolysis in myocardial infarction (TIMI) 3) within the infarct-related artery post-PPCI.2 ,3 The presence of MVO is associated with adverse LV remodelling and worse clinical outcomes post-PPCI.
Lethal myocardial reperfusion injury: Ischaemia/reperfusion induces cytosolic and mitochondrial calcium overload, oxidative stress, rapid restoration in intracellular pH, which on a background of relative ATP depletion, culminates in the opening of the mitochondrial permeability transition pore and irreversible cardiomyocyte hypercontracture—the hallmark of lethal myocardial reperfusion injury. Cardiomyocytes that were still viable at the end of the index ischaemic insult undergo necrosis and this accounts for up to 50% of the final myocardial infarct (MI) size, thereby mitigating the benefits of reperfusion, and making lethal myocardial reperfusion injury a therapeutic target for cardioprotection (figure 1).
Crucially, there is currently no effective therapy for reducing either MVO or lethal myocardial reperfusion injury. In the following sections we review the therapeutic potential of ischaemic conditioning, a collective term given to the different forms of endogenous cardioprotection, which have been described, and these include ischaemic preconditioning (IPC), ischaemic postconditioning (IPost) and remote ischaemic conditioning (RIC).
Ischaemic preconditioning—limited clinical application
In 1986, Murry et al4 made the intriguing observation that following an acute coronary artery occlusion the resultant MI size could be significantly reduced by ‘preconditioning’ the heart with brief episodes of ischaemia and reperfusion. In that landmark experimental study, four cycles of 5-min alternating left anterior descending (LAD) coronary artery occlusion and reflow applied immediately prior to a 90-min LAD occlusion and a 3-day reperfusion period, led to a 25% reduction in MI size in the canine heart.4 This endogenous form of cardioprotection, which was termed IPC, has been shown to be ubiquitous in several other organs and all species tested (reviewed in refs. 5 and 6). The IPC stimulus is known to elicit two windows of cardioprotection, the first one occurring immediately and lasting 2–3 h, and the second one appearing 12–24 h later, and lasting up to 72 h. In several clinical scenarios the heart is able to protect itself by IPC—for example, (1) ‘Warm-up angina’ refers to the phenomenon in which a patient with stable IHD is able to exercise more following an episode of angina followed by a period of rest;7 (2) ‘Preinfarct angina’ refers to the cardioprotective effects of an episode of angina immediately prior to an MI resulting in smaller MI size and better clinical outcomes.8 As a cardioprotective strategy for protecting the heart against acute IRI, its clinical application has been limited by the need to apply the IPC stimulus directly to the heart, and prior to the index ischaemia, which cannot be predicted in patients with acute MI. In this regard, the discovery of IPost has provided a cardioprotective strategy which can be applied at the time of reperfusion to protect the heart against acute IRI.
Ischaemic postconditioning—protection at the time of reperfusion
In 2003, Zhao et al9 discovered that by interrupting myocardial reperfusion with several short-lived episodes of myocardial ischaemia could reduce MI size to a similar extent as IPC—a phenomenon which has been termed ‘IPost’.6 ,10 They9 found that applying three cycles of 30-s LAD coronary artery occlusion and reflow at the onset of myocardial reperfusion could reduce MI size by 44% in the canine heart.9 The idea of modifying reperfusion as a strategy to limit MI size was first proposed in the 1980s and 1990s using gentle11 and gradual12 reperfusion instead of sudden reperfusion. The discovery of IPost as a therapeutic strategy which could be applied at the onset of myocardial reperfusion has rekindled interest in lethal myocardial reperfusion injury as a target for cardioprotection, and was rapidly translated into the clinical setting within 2 years of discovery.13 It has also provided confirmatory evidence for the existence of lethal myocardial reperfusion injury in man. However, IPC and IPost require an intervention applied to the heart directly, which may not always be feasible depending on the clinical situation, and therefore, the strategy of RIC, in which the cardioprotective stimulus is applied to an organ or tissue away from the heart is vastly more attractive as a clinical application.
Remote ischaemic conditioning—cardioprotection made easy
In 1993, Przyklenk et al14 made the interesting observation that the cardioprotective effect of IPC was not restricted to one particular coronary artery territory as it could be transferred to another coronary artery territory. This gave rise to the concept of ‘RIC’, the term given to the cardioprotection induced by applying cycles of brief ischaemia and reperfusion to an organ or tissue away from the heart. Using the canine heart, these authors found that brief occlusions and reflow in the circumflex coronary artery were able to reduce MI size by 63% following LAD coronary artery occlusion.14 This idea was soon extended beyond the heart with the demonstration that the RIC stimulus (cycles of brief ischaemia and reperfusion) could be applied to the kidney to limit MI size, giving rise to the concept of interorgan protection against acute IRI.15 Two key properties of RIC have facilitated its translation into the clinical setting:
Feasibility: The discovery in an experimental animal MI model that the RIC stimulus could be applied to the hind limb to protect the heart against acute IRI,16 ,17 and the finding that the RIC stimulus could be delivered non-invasively in human volunteers by simply inflating a blood pressure cuff on the upper arm to induce cycles of brief ischaemia and reperfusion,18 has greatly increased its feasibility in the clinical setting.
Flexibility: The application of IPC and IPost are restricted in terms of their ‘timings’ (as the protective stimulus has to be applied either prior to ischaemia or at the onset of reperfusion, respectively) and ‘target’ (the protective stimulus has to be applied to the heart directly), whereas RIC can be applied at any time (either prior to, after the onset of or at the end of ischaemia) and to an organ or tissue away from the heart, thereby making it much more flexible as a cardioprotective strategy (figure 2).
Therefore, most clinical studies applying RIC as a cardioprotective strategy have used cycles of brief ischaemia and reperfusion in the upper or lower limb (henceforth referred to as limb RIC).
Overview of mechanisms underlying ischaemic conditioning
The mechanisms underlying ischaemic conditioning are rather complex and have been the subject of intensive investigation over the last 20–30 years (for comprehensive reviews please see refs. 5, 6, 19 and 20). With respect to IPC and IPost, the current paradigm proposes that the cycles of brief ischaemia and reperfusion, which make up the protective stimulus, generate autacoids in the interstitium which then activate a number of signal transduction pathways by binding to their respective receptors on the cardiomyocyte plasma membrane. This in turn results in the recruitment of a number of prosurvival protein kinase pathways (such as the Reperfusion Injury Salvage Kinase,21 ,22 Survivor Activator Factor Enhancement23 and cyclic guanosine monophosphate-PKG pathways24), which converge on and protect mitochondria from dysfunction induced by acute IRI. However, it is important to appreciate that there are some differences between IPC and IPost in terms of signalling components. With IPC there is an additional signalling pathway responsible for the ‘memory’ effect of classical IPC (the activation of protein kinases such as protein kinase C) and of the second window of protection (the transcription of new proteins such as cyclooxygenase-2, inducible nitric oxide synthase and so on).6 ,20 The mechanisms underlying RIC are even more complex given the added dimension of having to convey the cardioprotective signal from the remote organ or tissue to the heart. Once at the heart, the signalling pathways alluded to above for IPC and IPost are also recruited by RIC. The details of the pathway linking the remote organ or tissue to the heart remain unresolved, but are believed to involve the release of local autacoids stimulating the sensory afferent neural pathway in the remote organ or tissue leading to the production of a circulating transferrable bloodborne factor(s), which is able to confer cross-species cardioprotection. The identity of the cardioprotective factor(s) remains unknown, but is probably a peptide <30 kilodaltons in size (reviewed in refs 25 and 26).
Clinical application of ischaemic conditioning
Ischaemic conditioning has been investigated in several clinical settings in which the heart is subjected to acute myocardial IRI including cardiac bypass surgery, elective percutaneous coronary intervention (PCI) and PPCI (figure 2).
7.1. Cardiac bypass surgery as a clinical setting for cardioprotection
In patients undergoing cardiac bypass surgery the heart is subjected to global ischaemic injury (when the aorta is clamped and the heart is put onto cardiopulmonary bypass) followed by global reperfusion injury (when the aorta is unclamped and the heart is taken off cardiopulmonary bypass).27 However, acute IRI is not the only cause of myocardial injury during cardiac bypass surgery as direct handling of the heart, coronary embolisation and the inflammatory response to cardiopulmonary bypass can all contribute. The perioperative myocardial injury (PMI) which occurs during cardiac bypass surgery can be quantified by measuring serum cardiac enzymes (Creatine Kinase MB isoenzyme, Troponin T and I),28 ,29 and can be detected as late gadolinium enhancement on CMR.30 Given that the presence of PMI has been associated with worse clinical outcomes post cardiac surgery,28 ,29 the measurement of serum cardiac enzymes has been used as a surrogate end point to assess the cardioprotective efficacy of novel therapies in patients undergoing cardiac bypass surgery.
IPC and IPost in cardiac bypass surgery
IPC was the first cardioprotective strategy to be investigated in the setting of cardiac bypass surgery. In 1993, Yellon's group31 first demonstrated that brief episodes of global ischaemia induced by clamping and declamping the aorta prior to cardiopulmonary bypass preserved myocardial ATP levels in patients with IHD. Since then a number of studies have investigated the role of IPC as a cardioprotective strategy in cardiopulmonary bypass surgery. In a recent meta-analysis it was shown that IPC significantly reduced ventricular arrhythmias, decreased inotrope requirements and shortened the intensive care unit stay.32 However, despite these potential beneficial effects, the need to intervene on the heart directly and the risk of embolisation arising from clamping an atherosclerotic aorta have prevented IPC from being adopted in this clinical setting.
Using a similar approach to cardioprotection at the time of aorta unclamping it has been reported that IPost induced by reclamping and declamping the aorta to stutter global myocardial reperfusion attenuated PMI in terms of serum cardiac enzyme release.33 There is the potential to apply this cardioprotective strategy to children (in whom the aorta is not yet atherosclerotic) undergoing cardiopulmonary bypass surgery to correct congenital cardiac defects.34
Limb RIC in cardiac bypass surgery
Limb RIC was first demonstrated to show benefit in the clinical setting of cardiac bypass surgery in 2006 by Cheung et al35 in children undergoing corrective cardiac surgery for congenital heart defects. Subsequent studies have reported beneficial effects of RIC in adult patients undergoing coronary artery bypass graft surgery (CABG) and/or valve surgery in terms of attenuated PMI as evidenced by decreased serum cardiac enzyme release (table 1). However, there have been several neutral studies36–38 including at least one very large study.39 The reasons for this discrepancy are not clear but may relate to the following factors: patient selection (CABG vs valve surgery, patients with stable vs unstable IHD); timing of the limb RIC protocol (prior to vs after surgical incision); blinding of the RIC protocol (proper vs limited blinding); the intensity of the RIC protocol (three vs four cycles of limb RIC and inflation of cuff to 200 mm Hg vs 15 mm Hg above systolic blood pressure); and the presence of confounding factors (table 5). The results of several recent meta-analyses have confirmed the cardioprotective effects of RIC in this clinical setting in terms of attenuating PMI.40 ,41 The ongoing RIPHeart42 and ERICCA43 multicentre clinical trials, which are currently investigating the effect of RIC on clinical outcomes post cardiac bypass surgery (table 1), should hopefully provide definitive evidence of the cardioprotective effects of RIC in this clinical setting.
7.2. Elective PCI as a clinical setting for cardioprotection
Ischaemic conditioning has been investigated as a cardioprotective strategy for protecting the heart against periprocedural myocardial injury in patients undergoing elective PCI. It is important to appreciate that PCI-related injury, which occurs in about 20–30% of patients undergoing elective PCI and measured by the release of serum cardiac enzymes, is not due to acute IRI, but mainly by acute ischaemic injury (distal branch occlusions and coronary embolisation)—complications which are more frequent following multivessel and complex PCI.44 Limb RIC administered prior to elective PCI has been reported to be beneficial in patients with IHD, in terms of reducing serum levels of cardiac enzymes (table 2), although there have been a number of neutral studies45 ,46 and one negative study.47 The reasons for this discrepancy are not clear but may relate to the following factors: the setting itself (acute IRI is not a major component of myocardial injury during elective PCI); patient selection (patients with stable vs unstable IHD); the timing of RIC in relation to the PCI procedure (prior to vs after) and the PCI procedure itself (simple vs multivessel or complex PCI). A recent meta-analysis has suggested that limb RIC may be beneficial if lower limb RIC is used in the setting of multivessel or complex PCI.48
7.3. PPCI as a clinical setting for cardioprotection
For patients presenting with STEMI, the most effective therapy for limiting MI size and preserving LV systolic function is myocardial reperfusion by PPCI. However, the restoration of coronary blood flow in the infarct-related artery induces myocardial reperfusion injury, thereby providing a target for cardioprotection for ischaemic conditioning strategies such as IPost and RIC.
IPost in patients with STEMI
IPost was rapidly translated into the clinical setting by Staat et al in 200513 only 2 years after its discovery in the original animal experimental study. They demonstrated in a small proof-of-concept study of 30 patients that IPost could reduce enzymatic MI size by 36% (table 3). The IPost protocol was applied following direct stenting of the infarct-related artery by inflation of the angioplasty balloon to low pressure upstream of the stent to interrupt coronary flow for 1 min followed by deflation of the angioplasty balloon for 1 min to allow coronary reflow and was repeated four times in total. A number of clinical studies have gone on to confirm the cardioprotective effect of IPost using echocardiographic, myocardial single-photon emission CT and CMR end points (table 3). However, not all the studies have been positive,49 ,50 and the reasons for this are not clear but may be due to a number of factors including: patient selection (only patients with complete occlusion of the infarct-related artery and no coronary collateralisation should be included), the stenting technique (most benefit seen with direct stenting), the IPost protocol itself (which should not be delivered within the stent); the end points used to assess cardioprotection (ST segment resolution vs MI size). The results of recent meta-analyses of IPost in PPCI patients have also produced mixed results.51–54 Whether IPost can actually improve clinical outcomes following PPCI is currently being investigated in the DANAMI-3 trial (ClinicalTrials.gov Identifier: NCT01435408) (table 3).
Limb RIC in patients with STEMI
Several proof-of-concept studies have reported cardioprotective effects with limb RIC in patients with STEMI treated by PPCI (table 3). It appears to be effective when given in the ambulance by paramedics,55 on arrival at the hospital prior to PPCI56 ,57 and even at the onset of reperfusion at the time of PPCI.58 Whether limb RIC can improve clinical outcomes in PPCI patients is currently being investigated in the ERIC-PPCI and CONDI2 trials (ClinicalTrials.gov Identifier: NCT01857414), which are investigating, in collaboration, whether RIC can reduce the rates of cardiac death and hospitalisation for heart failure at 12 months.
Pharmacological conditioning—mimicking ischaemic conditioning
The elucidation of the signal transduction pathways underlying ischaemic conditioning have resulted in the identification of new targets for cardioprotection, some of which can be modulated by pharmacological agents (reviewed in refs 59 and 60). In this regard, the most promising of these pharmacological conditioning strategies include atrial natriuretic peptide,61 ciclosporin-A,62 exenatide63 and metoprolol,64 all of which have been reported in proof-of-concept clinical studies to reduce MI size and preserve LV systolic function (table 4). Whether ciclosporin-A therapy can improve clinical outcomes post PPCI is currently being tested in two clinical outcome studies (the CYCLosporinE A in Reperfused Acute Myocardial Infarction (CYCLE) (ClinicalTrials.gov NCT01650662) and Cyclosporine and Prognosis in Acute Myocardial Infarction Patients (CIRCUS) (ClinicalTrials.gov NCT01502774) multicentre randomised clinical trials).
New avenues for ischaemic conditioning
Other clinical settings of acute myocardial IRI
There are other clinical settings in which acute myocardial IRI is a critical determinant of outcome. In patients having a cardiac arrest the whole body including the heart is subjected to acute global ischaemia, and in those patients which are successfully resuscitated, the whole body is then subjected to acute global reperfusion injury. Whether limb RIC is a therapeutic option in patients who are successfully resuscitated following a cardiac arrest remains to be tested. The added benefit of limb RIC in this setting is multiorgan protection against acute IRI.
For patients undergoing cardiac transplantation acute IRI is a major determinant of graft dysfunction post transplantation. In this setting, the heart is subjected to global ischaemic injury as it is removed from the donor, followed by global reperfusion injury as it is transplanted into the recipient. In this setting there is the opportunity to perform limb RIC to the donor prior to organ harvesting and to the recipient prior to transplantation, but whether this approach is beneficial remains to be tested.
Limb RIC and cardiac function
A number of clinical studies are investigating the cardioprotective effects of limb RIC on cardiac function. Limb RIC has been reported to attenuate ST segment depression and prevent myocardial stunning in patients with chronic renal failure undergoing haemodialysis during which the heart is subjected to repeated bouts of acute myocardial ischaemia resulting in myocardial stunning and chronic LV systolic impairment.65
Whether repeated episodes of limb RIC, applied as a daily therapy, is beneficial in the clinical setting is not known. One experimental study demonstrated that repeating limb RIC daily for 28 days prevented adverse post-MI LV remodelling in the rat heart.66 There are currently two clinical studies investigating the effect of daily RIC continued for 4 weeks on post-MI LV remodelling (Daily REmote Ischaemic Conditioning following Acute Myocardial Infarction (DREAM, ClinicalTrials.gov Identifier: NCT01664611) and the Chronic Remote Ischaemic Conditioning to Modify Post-MI Remodelling (CRIC-RCT; ClinicalTrials.gov Identifier:NCT01817114) trials). The CONDI-heart failure study (ClinicalTrials.gov Identifier: NCT02248441) is currently investigating the effect of daily RIC on LVEF in patients with chronic heart failure.
Increasing exercise performance by limb RIC
Interestingly, limb RIC has been reported to improve exercise performance in elite swimmers,67 presumably by rendering skeletal muscle more tolerant to acute ischaemia, although the actual mechanism is not clear. In the setting of heart failure however, limb RIC failed to improve exercise capacity and oxygen consumption, with the suggestion that patients with heart failure were already chronically preconditioned, as plasma dialysate obtained from sham and patients with RIC reduced murine MI size compared with plasma dialysate from historical healthy controls.68
Limb RIC protection of other organs
The key advantage of limb RIC as a therapeutic strategy is that it offers multiorgan protection against acute IRI. As such limb RIC has been shown to be beneficial in a number of non-cardiac organs including the brain (against acute ischaemic stroke69), the kidney (protection against acute kidney injury induced by cardiac bypass surgery,38 ,70 ,71 and induced by contrast following coronary angiography72) and the liver (during acute liver resection (ClinicalTrials.gov Identifier: NCT007965880) and liver transplantation (Remote Ischaemic PreCOnditioning in Liver Transplant or RIPCOLT)). The recently completed REnal Protection Against Ischaemia-Reperfusion in transplantation (REPAIR) trial (ISRCTN30083294) has found that limb RIC of the donor and recipient preserved estimated glomerular filtration rate of the transplanted kidney at 6 months in recipient patients undergoing live-donor related renal transplantation, suggesting limb RIC to be a potential therapeutic strategy for preserving renal graft function post transplantation.
Optimising the translation of cardioprotection
The field of cardioprotection has a chequered history with a disappointingly large number of neutral clinical studies in which a novel cardioprotective therapy has failed to improve clinical outcomes in patients with IHD subjected to acute IRI. The failure to translate the large number of cardioprotective therapies discovered in laboratory studies into patient benefit has been the subject of several recent articles73–76—the major issues are highlighted in table 5.
Summary and conclusions
Ischaemic conditioning is an endogenous form of cardioprotection which can be elicited by cycles of brief ischaemia and reperfusion to the heart directly or to an organ or tissue away from the heart. A number of proof-of-concept clinical studies have shown beneficial effects with ischaemic conditioning in the settings of cardiac bypass surgery, elective PCI and PPCI, with reduced myocardial injury and preservation of cardiac function. Whether ischaemic conditioning can actually improve clinical outcomes in CABG and PPCI patients is currently being investigated in several large multicentre randomised clinical trials. As a result, in the next couple of years we should know whether ischaemic conditioning could benefit patients with IHD in terms of reducing morbidity and mortality and potentially change clinical practice.
‘Ischaemic conditioning’ has the therapeutic potential to protect the heart against acute ischaemia/reperfusion injury (IRI) and improve clinical outcomes in patients with ischaemic heart disease, the leading cause of death and disability worldwide.
Ischaemic conditioning is mediated by applying cycles of brief ischaemia and reperfusion to either the heart itself or to an organ/tissue remote from the heart—it can be reproduced by certain pharmacological agents (termed ‘pharmacological conditioning’).
Ischaemic and pharmacological conditioning have been reported in proof-of-concept studies to be beneficial in three major clinical settings in which the heart is subjected to acute IRI: patients with cardiac bypass surgery, elective percutaneous coronary intervention (PCI) and ST segment elevation myocardial infarction treated by primary PCI.
Whether this therapeutic strategy can improve patient outcomes in these clinical settings should be known in the next few years with the availability of results from several large multicentre clinical trials.
The translation of promising cardioprotective therapies discovered in the research laboratory into the clinic has been hampered by the use of inadequate animal models and poorly designed clinical studies—this can be overcome by increased interaction between basic scientists and clinicians, thereby facilitating the translation of novel cardioprotective therapies into the clinical setting for patient benefit.
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Contributors HB and DJH conceived and drafted and critically reviewed the manuscript.
Funding DJH is funded by the British Heart Foundation (grant number FS/10/039/28270), the Rosetrees Trust, and is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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