the therapeutic potential of ischemic conditioning: an update

NATURE REVIEWS | CARDIOLOGY VOLUME 8 | NOVEMBER 2011 | 619

The Hatter Cardiovascular Institute, University College London Hospital, 67 Chenies Mews, London WC1E 6HX, UK (D. J. Hausenloy, D. M. Yellon).

Correspondence to: D. M. Yellon [email protected]

The therapeutic potential of ischemic conditioning: an updateDerek J. Hausenloy and Derek M. Yellon

Abstract | Novel approaches are required to improve clinical outcomes in patients with coronary heart disease (CHD). Ischemic conditioning—the practice of applying brief episodes of nonlethal ischemia and reperfusion to confer protection against a sustained episode of lethal ischemia and reperfusion injury—is one potential therapeutic strategy. Importantly, the protective stimulus can be applied before (ischemic preconditioning) or after (ischemic perconditioning) onset of the sustained episode of lethal ischemia, or even at the onset of myocardial reperfusion (ischemic postconditioning). Furthermore, the protective stimulus can be applied noninvasively by placing a blood-pressure cuff on an upper or lower limb to induce brief episodes of nonlethal ischemia and reperfusion (remote ischemic conditioning), a finding that has greatly facilitated the translation of ischemic conditioning to various clinical settings. In addition to mechanical approaches, elucidation of the signal-transduction pathways underlying ischemic conditioning has identified several novel targets for pharmacological conditioning. This Review highlights findings from proof-of-concept clinical studies conducted in the past 5–6 years, in which the therapeutic potential of ischemic and pharmacological conditioning has been realized. Large, randomized, controlled trials are now required to determine whether pharmacological and ischemic conditioning improve clinical end points and outcomes in patients with CHD.

Hausenloy, D. J. & Yellon, D. M. Nat. Rev. Cardiol. 8, 619–629 (2011); published online 21 June 2010; doi:10.1038/nrcardio.2011.85

IntroductionCardiovascular disease is the leading cause of death and disability worldwide, and one of its major manifestations is coronary heart disease (CHD). Although reperfusion is essential to salvage viable myocardium following a period of sustained ischemia caused by CHD, the actual process of reperfusing ischemic myocardium can itself para doxically induce injury—a process termed myocardial reperfusion injury—and such damage attenuates the benefits of myocardial reperfusion.1,2 The heart can be protected against acute myocardial ischemia–reperfusion injury by cardioprotective strategies that target both the ischemic and reperfusion components of myocardial injury. Novel therapeutic strategies for acute ischemia–reperfusion injury are required to reduce the risk of cardiac failure and improve health outcomes in patients with CHD.

In this regard, ischemic conditioning is an innovative method of protecting the heart from both these forms of myocardial injury. Ischemic conditioning is the blanket term given to the intriguing finding that brief episodes of nonlethal ischemia and reperfusion applied to an organ or tissue confer powerful protection against a subsequent episode of sustained, lethal ischemia–reperfusion injury. This unique phenomenon was originally discovered in 1986, in a landmark experimental study by Murry et al., and termed ‘ischemic preconditioning’.3 These researchers made the surprising observation that subjecting the canine myocardium to four 5 min cycles of nonlethal

ischemia and reperfusion (induced by alternate occlusion and reper fusion of the circumflex coronary artery) immediately before a sustained episode of lethal myocardial ischemia (40 min of circumflex coronary artery occlusion) and reperfusion for 4 days, paradoxically reduced the size of the resultant myocardial infarction (MI) to 25% of that observed in untreated control hearts.3 Since the publication of this seminal experimental study, the two major research objectives have been elucidation of the mechanisms underlying ischemic preconditioning and translation of this treatment into the clinical setting for the benefit of patients. Progress towards the latter objective has been remarkably slow (Figure 1), but has been facilitated by important new experimental observations that have broadened the initial concept of ischemic preconditioning to include remote ischemic conditioning, ischemic perconditioning, and ischemic post conditioning. Furthermore, elucidation of the signaltransduction pathways underlying ischemic conditioning has resulted in the identification of mediators amenable to pharmacological manipulation.4–7 These efforts enable drugs to be used to mimic the cardioprotective effects of the various forms of ischemic conditioning (Figure 2).

This Review includes an overview of ischemic and pharmacological conditioning. The authors’ main focus, however, is the clinical application of these techniques in patients with CHD. This Review comprises an update of the therapeutic potential of ischemic conditioning in the light of the important new developments of the past 5 years. The complex signaling mechanisms that

Competing interestsThe authors declare no competing interests.

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underlie this cardioprotective effect are only touched upon in this article, as they have been comprehensively reviewed elsewhere.4,6–12

Ischemic conditioningThe discovery that ischemic precon ditioning has a protective effect against arrhythmias was first reported in 1977,13 several years before the original description of the protective effects of ischemic precon ditioning against MI, in 1986.3 Accordingly, 2011 marks the 25th year since the discovery of ischemic precon ditioning. Despite intensive investigation (>6,000 experimental studies) the actual mechanisms at the heart of ischemic preconditioning remain undiscovered, although many of the signal transduction pathways underlying ischemic precon ditioning have been unraveled.4,6–12 To greatly simplify these pathways, the ischemic stimulus initially results in production of autacoids from the cardio myocyte. These autacoids then initiate a variety of complex intra cellular signal transduction pathways, many of which converge on the mitochondria,5,9 resulting in the first of two periods of cardioprotection. The first window of protection begins immediately following the stimulus and lasts for 2–3 h, after which cardio protection wanes (acute or classic ischemic preconditioning).3 The second window of protection begins 12–24 h after the stimulus and lasts 48–72 h (delayed or late ischemic preconditioning).14,15 The delayed cardio protective effect in the second window of protection is believed to result from the transcription of specific mediators that enable the effects of the ischemic conditioning stimulus to persist into the following 2–3 days (Figure 2).12

Despite these promising findings, ischemic preconditioning has not yet been successfully translated into benefi cial treatments for patients in the clinical setting. The failure to take advantage of this powerful cardioprotective strategy can be attributed to two major factors. Firstly, the requirement to implement the ischemic preconditioning stimulus before a sustained episode of acute, lethal ischemia– reperfusion injury has restricted its clinical

Key points

■ Ischemic conditioning describes an endogenous phenomenon, in which one or more brief episodes of nonlethal ischemia and reperfusion confer protection against a sustained lethal episode of ischemia and reperfusion

■ The conditioning stimulus can be applied before (ischemic preconditioning) or after the onset of (ischemic perconditioning) ischemia, or at the transition from sustained ischemia to reperfusion (ischemic postconditioning)

■ The conditioning stimulus can, moreover, be applied either directly to the heart or to a distant organ or tissue, such as a limb (remote ischemic conditioning)

■ Elucidation of the mechanistic pathways underlying ischemic conditioning has identified potential pharmacological cardioprotective strategies (pharmacological conditioning), which have been largely unsuccessful in the clinical setting

■ Proof-of-concept studies reported benefits with ischemic perconditioning, postconditioning, and remote ischemic conditioning in patients with acute myocardial infarction, and those undergoing cardiac surgery or percutaneous coronary intervention

■ Large, multicenter, randomized, placebo-controlled, clinical trials are now required to determine whether ischemic conditioning can improve clinical outcomes in patients with coronary heart disease

application to settings in which such events can be readily anticipated (Figure 2), such as planned CABG surgery and percutaneous coronary intervention (PCI). Secondly, classic ischemic preconditioning requires an intervention to be applied directly to the heart, which is not possible outside the setting of cardiac surgery. This latter obstacle was overcome by the discovery that the standard ischemic preconditioning stimulus of brief nonlethal ischemia and reperfusion was still effective when applied to an organ or tissue away from the heart.16,17 In a landmark experi mental study published in 1993, Przyklenk and coworkers demonstrated that applying four 5 min cycles of occlusion and reperfusion to the circumflex coronary artery reduced the size of MI subsequently generated in a different coronary artery territory by 70%.16 Subsequent experimental studies have demonstrated that the heart can be remotely protected against MI by applying the ischemic pre conditioning stimulus to an organ (such as the kidney, liver, or intestine)17 or tissue (upper or lower limb skeletal muscle)18 remote from the heart.11

The discovery that the conditioning stimulus could be applied to an organ or tissue away from the heart was pivotal in facilitating the translation of this cardioprotective strate gy into the clinical setting of acute ischemia– reperfusion injury. In 2002, Kharbanda et al.19 described a non invasive remote ischemic conditioning protocol in human volunteers, which comprised the inflation and deflation of a blood pressure cuff placed on the upper arm to apply three 5 min cycles of alternating ischemia and reperfusion to skeletal muscle of the forearm.19 The success of this approach has greatly facilitated the translation of remote ischemic conditioning into a variety of clinical settings of acute ischemia–reperfusion injury in the past 4–5 years. Furthermore, the remote ischemic conditioning stimulus can also be applied before (remote ischemic precondi tioning) or during (remote ischemic perconditioning) the index myocardial ischemia,20 or even at the onset of myocardial reper fusion (remote ischemic postcondi tioning).21 This flexibility enables the application of ischemic conditioning to a wide variety of clinical settings of ischemia–reperfusion injury (Figure 2).11 Despite intensive investigation, the mechanism linking the preconditioned organ or tissue to the cardioprotective effect remains unknown, but has been attributed to a neurohormonal pathway.11,19,23

The latest form of ischemic conditioning to be described is ischemic postconditioning. Interestingly, the term ischemic postconditioning was first used in 1996 by Na and coworkers,24 who demonstrated that intermittent reperfusion driven by premature ventricular contractions could reduce reperfusioninduced ventricular fibrillation following myocardial ischemia in feline hearts. In 2003, Zhao et al. reported that cardioprotection could also be induced in canine hearts by interrupting the reperfusion of previously ischemic myocardium by 3–6 shortlived episodes (of 30–60 s each) of coronary artery reocclusion (Figure 2).25 These pioneering researchers demonstrated that this technique resulted in a 43% reduction in MI size following 60 min of left anterior descending artery occlusion.25 Importantly, the reduction in MI size was associated with decreased myocardial edema, reduced neutrophil

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accumulation, attenuation of apoptotic cell death, and improved endothelial function, factors associated with myocardial reperfusion injury.25

In common with ischemic preconditioning, the signaltransduction pathway recruited in ischemic postconditioning seems to originate with the activation of cell surface receptors that, in turn, drive a number of signal ing pathways. Many of these pathways seem to involve mitochondria and result in prevention of cardiomyocyte hypercontracture and inhibition of opening of the mitochondrial permeability transition pore.7 The discovery that this intervention could be applied at the onset of myocardial reperfusion to reduce myocardial injury also provided crucial, solid evidence for the existence of lethal myo cardial reperfusion injury.8,26 The major breakthrough of this therapeutic stra tegy was that it could be applied at the onset of myocardial reperfusion, allowing its rapid application in patients with STsegment elevation MI (STEMI) under going primary PCI,27 and incidentally confirming the existence of lethal myocardial reperfusion injury in humans.26

The choice of conditioning strategyPatients with CHD are subjected to acute myo cardial ischemia–reperfusion injury in a variety of different clinical settings, and the appropriate ischemic conditioning strategy should be applied to the specific clinical scenario concerned.

STEMIThe most obvious clinical setting of acuteonset myocardial ischemia–reperfusion injury occurs in patients with STEMI who present with myocardial ischemia as a result of an acute complete thrombotic occlusion of a coronary artery. These patients are treated by primary PCI, CABG, or thrombolytic therapy and, therefore, undergo acute myocardial reperfusion injury. In these patients, the cardio protective strategy has to be applied after the onset

of myocardial ischemia, but before the onset of myocardial reperfusion. As such, the ischemic conditioning strategies that could be of benefit in this group of patients include remote ischemic percondi tioning, ischemic perconditioning, and ischemic postconditioning (Figure 2). The efficacy of the conditioning strategy can be assessed by measuring MI size and myocardial salvage (using serum cardiac enzyme levels, singlephoton emission computed tomography [SPECT] or cardiac MRI), left ventricular systolic function or clinical outcomes.

The patients most likely to benefit from an intervention administered as an adjunct to myocardial reperfusion are highrisk patients who present with complete occlusion of the proximal left anterior descending artery, in whom the area at risk is substantial and coronary collateralization is absent. In comparison, lowrisk patients who present with incomplete occlusion in a relatively small coronary artery (resulting in a limited area at risk of MI), and in whom coronary collateralization is evident, might not accrue any benefit from adjunctive reperfusion therapy. This suggestion is supported by observations from several clinical studies, in which myocardial salvage from the ischemic condi tioning strategy was greatest in patients who presented with complete coronary occlusion in the proximal left anterior descending artery.28–30 This information should be used to guide the design of future studies of the cardioprotective effects of ischemic conditioning, by restricting selection of participants to the groups most likely to benefit.

Ischemic postconditioning: STEMIOnly 2 years after the initial discovery of ischemic postconditioning in 2003,25 this technique was successfully applied in the clinical setting to 30 patients with STEMI undergoing primary PCI.27 The participants were randomly allocated to receive (or not receive) ischemic postconditioning comprising six 30 s inflations and deflations of the coronary angioplasty balloon following stent

Figure 1 | Timeline showing the slow translation of the results of animal studies of ischemic conditioning to the clinic. Notable developments in ischemic conditioning have occurred in the past 5 years.

1977 1986 1992 1994 1996 2002 2004 2006 2008 2010 2012

Ischemic preconditioningin animals (arrhythmia)

First window of protection:Ischemic preconditioning

in animals(myocardial infarction)

Ischemic postconditioningin animals (arrhythmia)

Remote ischemicpreconditioning in patients

(endothelial function)

First evidence in patients of long-term cardioprotection with

ischemic postconditioning(myocardial infarction)

Pharmacological postconditioningusing ciclosporin

(myocardial infarction)

First clinical outcomestudy begins investigating ischemic postconditioning

in patients(myocardial infarction)

First clinical outcome studiesbegin investigating remoteischemic preconditioning

in patients (CABG surgery)

Second window of protection:Ischemic preconditioning

in animals(myocardial infarction)

Ischemic postconditioningin patients


Remoteischemic

perconditioningin patients(myocardialinfarction)Ischemic

preconditioning in patients(CABG surgery)

Remote ischemicpreconditioning in animals


Ischemic postconditioningin animals


Remote ischemicpreconditioning in adultpatients (CABG surgery)

Ischemic postconditioningin patients (pediatric

cardiac surgery)

Pharmacologicalpostconditioning using

atrial natriuretic peptide(myocardial infarction)

Remote ischemicpreconditioning in patients (pediatric cardiac surgery)

2003 2005 2007 2009 2011

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deployment in the infarctrelated coronary artery. Ischemic postconditioning resulted in a 36% reduction in the 72 h area under the curve for total creatine kinase.27 Several clinical studies subsequently confirmed that ischemic postconditioning has longterm cardioprotective effects in this setting, with sustained reductions in MI size at 6 months and preserved left ventricular ejection fraction at 1 year (Table 1).31 Overall, most of the evidence suggests that ischemic postcondition ing is beneficial and does limit MI size in patients with STEMI undergoing primary PCI. Clinical trials in which the effect of ischemic postconditioning is being investigated are ongoing (the POSTEMI32 and POSTAMI33 studies). Whether ischemic postconditioning can improve clinical outcomes in this group of patients is currently being investigated (Figure 1).

Remote ischemic perconditioning: STEMITwo clinical studies have evaluated the effect of remote ischemic perconditioning in patients with STEMI who were treated with primary PCI.28,34 Botker and coworkers28 demonstrated that 251 such patients who were randomly allocated to receive remote ischemic perconditioning (four 5 min arm cuff inflations and deflations, applied by paramedics to the patient in the ambulance) had improved myocardial salvage as assessed by SPECT, compared with control patients who did not receive remote ischemic perconditioning.28 Importantly, the benefits of remote ischemic perconditioning were greatest in the subgroup of patients who presented with occlusion of the left anterior descending artery and a complete obstruction in the infarctrelated coronary artery.28 Another clinical study of patients with STEMI undergoing primary PCI has confirmed the beneficial effects of remote ischemic perconditioning (three 4 min cycles of arm cuff inflations and deflations) on MI size as estimated by serum levels of troponin T.34 Interestingly, concomitant administration of morphine

seemed to increase the protective effect of remote ischemic perconditioning.34 However, whether the reduced MI size associated with remote ischemic perconditioning in this setting translates into improved clinical outcomes after treatment with primary PCI remains to be determined in a large, multicenter, randomized, clinical trial.

CABG and other heart surgeryPatients with stable CHD undergoing coronary revascularization by CABG surgery experience substantial perioperative myocardial injury despite cardioplegic cardioprotection. The severity of this form of myocardial injury can be measured by serum levels of cardiac enzymes, such as creatine kinase MB (CKMB), troponin T, or troponin I, and can be detected by late gadolinium enhancement cardiac MRI as discrete areas of myonecrosis.35 The presence of this form of myocardial injury is associated with poor postsurgical clinical outcomes.36–39 Acute global myocardial ischemia– reperfusion injury, inflammation, manual handling of the heart, and coronary microembolization are the major factors that contribute to this form of myocardial injury at the time of surgery.40,41 The number of highrisk patients undergoing CABG surgery is increasing as a result of several factors, including ageing of the population; elderly patients have an increased prevalence of concomitant valve disease and comorbidities (such as hypertension and dia betes mellitus). Given the low rates of morbidity and mortal ity associated with routine CABG surgery in lowrisk patients, such individuals might not be the ideal population to investigate the cardioprotective effects of ischemic conditioning, as a statistically significant effect on these end points would be hard to demonstrate. Highrisk patients might actually accrue more benefit from an ischemic conditioning strategy than lowrisk patients. For the clinical setting of planned cardiac surgery, in which the timing of the index lethal episode of ischemia–reperfusion injury can be readily

Figure 2 | The timing of ischemic conditioning in relation to ischemia–reperfusion injury. In both ischemic preconditioning and pharmacological preconditioning, transient nonlethal myocardial ischemia and reperfusion or drug treatment is applied 0–3 h (first window of protection) or 12–24 h (second window of protection) before the index ischemic episode. In ischemic postconditioning, transient myocardial ischemia is applied at the onset of reperfusion. Remote ischemic conditioning, in which transient nonlethal ischemia and reperfusion is applied to a limb, can be administered before (remote ischemic preconditioning) during (remote ischemic perconditioning) or after (remote ischemic postconditioning) the index myocardial ischemia. Clinical studies indicate beneficial roles for ischemic preconditioning, remote ischemic preconditioning, ischemic perconditioning and remote ischemic postconditioning in patients undergoing CABG surgery. Remote ischemic preconditioning has been successful in patients undergoing elective PCI, and remote ischemic perconditioning and remote ischemic postconditioning are beneficial in patients with STEMI undergoing primary PCI. Other settings, in which ischemic conditioning might have therapeutic potential in the future, include cardiac transplantation, cardiac arrest, unstable angina and NSTEMI treated with PCI. Abbreviations: PCI, percutaneous coronary intervention; NSTEMI; non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

Preconditioning

Two windows of protectionbefore index ischemic event:

Perconditioning Postconditioning

<1 min0–3 h12–24 h

Heart ischemia

Conditioning

Reperfusion

CABG surgeryElective PCI

NSTEMI with PCICardiac transplantation

Clinical proof-of-concept studies:

Potential futureapplications:

CABG surgerySTEMI

Cardiac transplantationCardiac arrest

CABG surgerySTEMI

Cardiac transplantationCardiac arrest

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anticipated, a variety of ischemic conditioning strategies, detailed below, can be implemented either before or during the index myocardial ischemia caused by crossclamping of the aorta, or at the onset of myocardial reperfusion with unclamping of the aorta (Figure 2).

Ischemic preconditioningIschemic preconditioning was the first ischemic conditioning strategy to be used in the clinical setting. Our research group demonstrated in 1993 that ischemic pre conditioning could be reproduced in patients undergoing CABG surgery by alternately clamping and unclamping the aorta for periods of 2 min each to induce brief episodes of nonlethal global myocardial ischemia and reperfusion prior to the sustained global myocardial ischemia arising from the aortic clamping required for CABG surgery.42 Patients randomly allocated to receive ischemic precondition ing at the time of CABG surgery had preserved ATP levels in ventricular biopsies43 and reduced perioperative myocardial injury, as demonstrated by decreased serum levels of troponin T.43 In the time since these initial findings were published, a number of clinical studies have investigated ischemic preconditioning in the setting of CABG surgery. The results of 22 of these studies (which collectively

involved 933 patients) were summarized in a meta analysis published in 2008, which concluded that ischemic preconditioning was associated with a reduced incidence of ventricular arrhythmias, reduced inotrope requirements, and a decreased duration of stay in the intensive care unit.44 Owing to the invasive nature of the ischemic preconditioning protocol and the risk of arterial thromboembolism from clamping and unclamping the aorta, however, performing a large, prospective, clinical study to determine definitively whether ischemic preconditioning can improve clinical outcomes in patients undergoing CABG surgery will be difficult to justify.

Remote ischemic preconditioningThe first successful clinical application of remote ischemic preconditioning was reported in 2006, in children under going corrective cardiac surgery for congenital heart disease.45 In this small, proofofconcept study, 37 children were randomly allocated to receive either remote ischemic preconditioning (four 5 min inflations and deflations of a blood pressure cuff placed on the thigh, to 15 mmHg above systolic blood pressure) or control treatment (a deflated blood pressure cuff placed on the thigh for 40 min) 5–10 min before going on bypass. Children who received remote

Table 1 | Clinical studies of ischemic postconditioning in patients with STEMI

Study Ischemic postconditioning protocol (min)

n, time elapsed since STEMI (h)

Outcome

Staat et al. (2005)27,*

4 × 1 (inflation and deflation)

30, 6 72 h AUC for total CK (by 36%)

Laskey et al. (2005)78

2 × 1.5 inflation and 4–5 deflation

17, 12 Coronary blood flow and ST-segment resolution

Ma et al. (2006)79

3 × 0.5 (inflation and deflation)

94, 12 Peak levels of total CK (by 28%); CK-MB (by 32%); serum levels of malondialdehyde; myocardial perfusion; endothelial function; WMSI at 8 weeks

Yang et al. (2007)80


41, 12 72 h AUC for total CK and MI size at 7 days by SPECT (both 27%)

Laskey et al. (2008)81

2 × 1.5 inflation and 4–5 deflation

24, 12‡ Peak total CK level (by 19%); improved coronary flow velocity reserve; ST-segment resolution

Thibault et al. (2008)31,§

4 × 1 (inflation and deflation)

38, 6 72 h AUC for total CK (by 40%); CK-MB (by 41%); MI size at 6 months on SPECT (by 39%); EF at 7 years (by 7%)

Zhao et al. (2009)82

3 × 0.5 or 3 × 1 (inflation and deflation)

75, 12 Plasma apoptotic marker soluble Fas, particularly with 3 × 1 min protocol

Xue et al. (2010)83


43, 12 ST-segment resolution; 72 h AUC for CK-MB (by 26%); MI size at 7 days on SPECT (by 46%); hsCRP value (by 10%); EF after PPCI

Lin et al. (2010)84

3 × 0.5 or 3 × 1 (inflation and deflation)

74, 12 EF and WMSI at 1 year (3 × 1 min > 3 × 0.5 min); TNF levels

Lønborg et al. (2010)85,||


118, 12 No difference in troponin T or EF; MI size at 3 months by cardiac MRI (by 18%)

Sörensson et al. (2010)29,¶


76, 6 No difference in 48 h AUCs for CK-MB and troponin T; no difference in overall myocardial salvage by cardiac MRI at 7–9 days; however, significantly myocardial salvage in patients with large areas at risk

Garcia et al. (2010)86


43, 12 Peak levels of total CK (by 11%); CK-MB (by 20%); myocardial blush grade; EF after PPCI (by 9%)

Fan et al. (2011)87


50, NR iNOS activity in white blood cells; plasma nitrotyrosine; cardiac function

*First clinical application of ischemic postconditioning. ‡Anterior STEMI. §First demonstration that ischemic postconditioning offers long-term cardioprotection. ||First clinical application of cardiac MRI to assess MI size in patients treated with ischemic postconditioning. ¶First study to assess the effect of ischemic postconditioning on myocardial salvage. Abbreviations: AUC, area under the receiver operating characteristic curve; CK, creatine kinase; CK-MB, creatine kinase MB; EF, ejection fraction; hsCRP, high-sensitivity C-reactive protein; iNOS, inducible nitric oxide synthase; MI, myocardial infarct; n, number of patients; NR, not reported; PPCI, primary percutaneous coronary intervention; SPECT, single-photon-emission computed tomography; STEMI, ST-segment elevation MI; WMSI, wall motion score index.

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ischemic preconditioning had a lower inotrope score, lower airway pressures, and less perioperative myocardial injury (measured by 24 h area under the curve for troponin I levels) than children who received the control treatment. The first trial of remote ischemic preconditioning in patients undergoing CABG surgery was a small pilot study published in 2000.46 Eight patients were randomly allocated to receive remote ischemic preconditioning (a bloodpressure cuff placed on the upper arm was inflated to 300 mmHg for 3 min and deflated for 2 min, a cycle which was repeated three times in total) before CABG surgery. No difference in CKMB levels was detected in the two groups at 5 min after unclamping of the aorta, although at this time point lactate dehydrogenase levels were higher in the group treated with remote ischemic preconditioning. However, given the small size of the study, and the failure to examine levels of serum cardiac enzymes beyond 5 min of aortic unclamping, these results are difficult to interpret. Our research group was the first to successfully apply remote ischemic preconditioning to adults undergoing planned CABG surgery with or without valve surgery.47 The 57 patients were randomly allocated to receive remote ischemic preconditioning (three

5 min inflations to 200 mmHg and deflations of a blood pressure cuff placed on the upper arm) or control treatment (a deflated blood pressure cuff placed on the upper arm for 30 min) after induction of anesthesia but before surgery. Perioperative myocardial injury, as measured by the 72 h area under the curve for serum levels of troponin T, was reduced by 43% in patients treated with remote ischemic preconditioning versus values in the control group. Subsequently, various clinical studies performed by other research groups have demonstrated the concept of the second window of protection (also termed delayed remote ischemic preconditioning) and remote ischemic per conditioning in patients under going CABG surgery, although not all the findings have been positive (Table 2).48 The reasons for the contradictory findings are unclear, but could be related to a number of factors, such as differences in the remote ischemic preconditioning protocol used; the possibility that the remote ischemic pre conditioning stimulus might have been submaximal or incorrectly applied; intraoperative use of medications, such as inhaled anesthetics or glyceryl trinitrate, which protect the heart against ischemia–reperfusion injury during cardiac bypass surgery;

Table 2 | Clinical studies of remote ischemic conditioning in patients undergoing cardiac surgery

Study RIC protocol (min), (site)

Patients Procedure durations in control vs RIC groups

Outcome Notes

AXC (min) CPB (min)

Günaydin et al. (2000)46

3 × 3 or 3 × 2 (leg)

8 adults undergoing CABG surgery ± valvoplasty

29 vs 38 NR LDH 5 min after aortic unclamping

CardioplegiaFirst investigation of RIC in CABG surgery

Cheung et al. (2006)45

4 × 5 (leg) 37 children (aged 1–2 years)

55 vs 59 80 vs 88 24 h AUC troponin I, inotrope, airway pressures

CardioplegiaFirst clinical application of RIC

Hausenloy et al. (2007)47

3 × 5 (arm) 57 adults undergoing CABG surgery ± valvoplasty

45 vs 36 80 vs 75 72 h AUC troponin T (by 43%)

Cardioplegia and crossclamp fibrillationFirst clinical application of RIC in CABG surgery

Venugopal et al. (2009)70

3 × 5 (arm) 45 adults undergoing CABG surgery ± valvoplasty

65 vs 53 97 vs 86 72 h AUC troponin T (by 42%)

CardioplegiaNo patients with diabetes

Wenwu et al. (2010)73

3 × 5 (arm) 60 children (aged <7 years)

24 vs 24 34 vs 35 2 h, 4 h, 12 h, 24 h CK-MB and troponin T

Cardioplegia

Thielmann et al. (2010)74

3 × 5 (arm) 53 adults undergoing CABG surgery

76 vs 71 110 vs 109 48 h AUC troponin I (by 35%)

Cold crystalloid cardioplegiaNo patients with diabetes

Rahman et al. (2010)48

3 × 5 (arm) 162 adults undergoing elective or urgent CABG surgery

71 vs 76 96 vs 100 No difference in 48 h troponin T or LVEF

CardioplegiaMost patients received intravenous glyceryl trinitrate, enflurane or sevoflurane

Wagner et al. (2010)75

3 × 5 (arm)* 101 adults undergoing CABG surgery ± valvoplasty

51 vs 45 87 vs 80 8 h troponin I (by 27%)

Cold crystalloid cardioplegiaFirst clinical application of delayed RIC

Hong et al. (2010)76

4 × 5 (arm) 130 patients undergoing off pump CABG surgery

NA NA 72 h troponin T (by 26%, not significant)

NR

Ali et al. (2010)77

3 × 5 (arm) 100 adults undergoing elective CABG surgery

NA NA 6 h, 24 h, 48 h CK-MB and troponin T

NR

*18 h before surgery. Abbreviations: AUC, area under the receiver operating characteristic curve; AXC, aortic crossclamp time; CK-MB, creatine kinase MB; CPB, cardiac bypass time; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; NA, not applicable; NR, not reported; RIC, remote ischemic conditioning.

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and selection of patients. Whether patientrelated factors (such as age or the presence of diabetes, hypercholestero lemia, or hypertension) can influence the efficacy of cardioprotection by remote ischemic preconditioning, and whether highrisk patients are more or less amenable to remote ischemic preconditioning is unclear. Moreover, the effects of the surgery itself—that is, whether the duration of aortic crossclamping or cardiac bypass time affect the efficacy of remote ischemic pre conditioning—are also unclear. In addition, whether remote ischemic preconditioning can improve clinical outcomes in patients undergoing CABG surgery is also unknown; this factor is currently being investigated in two ongoing multicenter clinical trials.49,50

Ischemic postconditioningIschemic postconditioning has also been used in patients undergoing CABG surgery, with beneficial effects. The conditioning stimulus is applied at the time of declamping the aorta, which subjects the heart to global reper fusion. Luo and coworkers were the first to demonstrate the benefi cial effect of ischemic postconditioning in the setting of cardiac surgery.51 These investigators randomly allocated 24 children undergoing cardiac surgery for tetralogy of Fallot to receive ischemic postconditioning, which comprised two cycles of unclamping the aorta for 30 s and then reclamping it for 30 s. This treatment resulted in decreased 2 h levels of CKMB and troponin T.51 Clearly, however, the risk of clamping the aorta in young patients with little or no athero sclerosis is not as great as it would be in adult patients undergoing CABG surgery with or without valve surgery. A number of subsequent clinical studies have confirmed the cardioprotective effects of ischemic postconditioning in the setting of cardiac surgery for tetralogy of Fallot52 and aortic valve replacement,53 and have reported beneficial effects on perioperative myocardial injury, inotrope requirements, the duration of intensive care unit stay, and ventilation time. Again, whether this invasive cardioprotective strategy can improve clinical outcomes in patients undergoing CABG surgery remains to be determined.

Percutaneous coronary interventionUp to 30% of patients undergoing coronary revascularization by PCI for stable CHD experience substantial periprocedural myocardial injury, as measured by the release of serum cardiac enzymes (such as CKMB, troponin T, and troponin I), and detected on late gadolinium enhancement cardiac MRI as a discrete area of myonecrosis.54,55 This form of myocardial injury is particularly prominent in patients with unstable CHD and those undergoing complex PCI, and has been attributed to several factors, including distal branch occlusions and coronary micro embolization.42,56 As PCI does not result in a defined episode of sustained ischemia–reperfusion injury, the choice of ischemic condition ing strategy is restricted to those types that can be instigated before the procedure as a means of reducing periprocedural myocardial injury (Figure 2).

The cardioprotective mechanisms underlying remote ischemic preconditioning have been explored in several studies. Although initial benefits of remote ischemic preconditioning on coronary blood flow and microvascular

resistance were observed,57,58 these findings were not reproduced in a subsequent study.59 Whether remote ischemic preconditioning using brief upper limb ischemia and reper fusion can reduce periprocedural myocardial injury in patients with stable CHD undergoing elective PCI was investigated in a small study published in 2006.60 In 41 patients undergoing planned PCI, remote ischemic preconditioning (blood pressure cuffs placed on both upper arms and inflated to 200 mmHg) paradoxically increased myocardial injury, as indicated by increased 48 h areas under the receiver operating characteristic curve for CKMB and troponin T.60 However, in a subsequent clinical study comprising 202 patients undergoing elective PCI,61 remote ischemic preconditioning using three cycles of 5 min inflations and deflations of a blood pressure cuff placed on the patient’s upper arm was associated with reduced numbers of patients experiencing chest pain, lessened STsegment deviation, and reduced numbers of patients experiencing substantial periprocedural myocardial injury, as measured by serum levels of troponin T. Further studies are required to investigate whether remote ischemic preconditioning can improve clinical outcomes in patients undergoing elective PCI. However, these studies might need to be conducted in highrisk patients (for whom clinical end points remain important), such as those with unstable CHD, nonST segment elevation MI (NSTEMI) treated with PCI, or individuals undergoing complex interventions, such as rotational atherectomy and multivessel PCI.

Pharmacological conditioningIntensive investigation of the mechanisms underlying ischemic conditioning has identified a number of signal transduction pathways that might be amenable to pharmaco logical manipulation.4,5,7 These studies have resulted in a number of pharmacological agents being investigated as potential preconditioning, per conditioning, and postconditioning therapeutic strategies in a variety of clinical settings, including cardiac surgery, PCI, and STEMI. However, the results of these proofofconcept clinical studies have been overwhelmingly disappointing, and in this clinical update Review we have only focused on studies conducted in the past 5 years that have investigated pharmacological postconditioning strategies in patients with STEMI undergoing primary PCI. Reasons for the disappointing results are many and are briefly described in the next section.

Proofofconcept clinical studies investigating the effects of pharmacological agents that target known mediators of ischemic conditioning, administered as adjuncts to reperfusion, have produced mixed results in patients with STEMI (Table 3). The most promising avenue of research seems to be targeting of the mitochondrial permeability transition pore. Opening of these pores, which occurs at the onset of myocardial reperfusion, is a critical mediator of myo cardial reperfusion injury: a single intravenous bolus dose of ciclosporin, administered as a pharmacological postconditioning agent, limits the size of MI in patients with STEMI who are undergoing primary PCI (Table 3).62,63 Further studies are required to confirm the beneficial effects of mitochondrial permeability transition

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pore inhibition in this clinical setting and to identify novel inhibitors that are both safe and efficacious.

Obstacles to clinical translationThe reasons for the failure to translate the cardio protective effects of ischemic and pharmacological conditioning strate gies observed in preclinical studies into clinical

practice have been discussed in a number of publications, as well as in workshops of the Hatter Cardiovascular Institute30 and National Heart, Lung, and Blood Institute (NHLBI).64–67 Briefly, this failure can be attributed to a number of factors: the failure to first demonstrate conclusive cardioprotection in the preclinical setting before clinical testing; the inadequacy of the available animal models

Table 3 | Pharmacological conditioning in patients with STEMI undergoing PPCI

Study n, Time after STEMI (h)

Therapeutic strategy Results

Nikolaides et al. (2004)94

22 (LVEF <40%), <6

Intravenous infusion of glucagon-like peptide 1,* 1.5 pmol/kg/min for 72 h, started 2 h after PPCI

Improved LVEF and regional wall motion at 6–12 h

Lipsic et al. (2006)89

22, <6 Intravenous darbepoetin alfa 300 μg (long-acting erythropoietin‡) before PPCI

No effect on LVEF at 4 months

Kitakaze et al. (2007)95 J-WIND

569, <12 Intravenous carperitide§ infusion, 0.025 μg/kg per min for 3 days, started after PPCI

14.7% reduction in MI size (AUC for total CK); 2.5% increase in LVEF at 6–12 months

Kitakaze et al. (2007)95 J-WIND

545||, <12 Intravenous bolus nicorandil,¶ 0.067 mg/kg, followed by infusion of 1.67 μg/kg/min for 24 h for 3 days, started after PPCI

No difference in MI size or LVEF

Bates et al. (2008)96 DELTA-MI

154||, <6 Intracoronary delcasertib# 0.05 mg, 0.5 mg, 1.25 mg, or 5.0 mg; divided into two doses given before and after PPCI

Safe; efficacy not primary end point but nonsignificant reductions in MI size on CK-MB and SPECT

Ferrario et al. (2009)98

30, <6 Intravenous erythropoietin 33,000 IU before PPCI, repeated after 24 h and 48 h

30% reduction in 120 h AUC for CK-MB; no difference in MI size on cardiac MRI at 3 days or at 6 months

Piot et al. (2008)62 Mewton et al. (2010)63

58, <12 Intravenous ciclosporin,** 2.5 mg/kg, before PPCI 44% reduction in MI size (72 h AUC total CK); 20% reduction in MI size on cardiac MRI (subset of 27 patients); nonsignificant 13% reduction in MI size (72 h troponin I); 28% reduction in MI size and reduced LVEF on cardiac MRI at 6 months

Kim et al. (2010)97 STATIN STEMI

171, <12 Atorvastatin‡‡ 80 mg versus atorvastatin 10 mg prior to PPCI

No effect on primary end point (death, MI, revascularization); no difference in MI size (CK-MBmax); improved myocardial perfusion (blush grade, ST-segment resolution)

Suh et al. (2010)99

57||, <12 Intravenous recombinant human erythropoietin 50 U/kg before PPCI

No beneficial effects on MI size (assessed by CK-MB and cardiac MRI at 4 days)

Ozawa et al. (2010)90 EPO-AMI-1

36, <24 Intravenous erythropoietin (epoetin β) 12,000 IU within 24 h after PPCI

No difference in MI size or LVEF at 6 months

Voors et al. (2010)88 HEBE-III

529, <12 Intravenous erythropoietin (epoetin α) 60,000 IU within 3 h after PPCI

No difference in LVEF at 6 weeks (primary end point); no difference in MI size (AUCs for CK-MB and troponin T); improved MACE (secondary end point)

Tanaguichi et al. (2010)91

35, <12 Intravenous erythropoietin (epoetin α) 6,000 IU within 3 h after PPCI, repeated after 24 h and 48 h

No difference in LVEF at 4 days or at 6 months on SPECT

Ott et al. (2010)92 REVIVAL-3

222, <8 Intravenous erythropoietin (epoetin β) 33,000 IU within 4 h after PPCI, repeated after 24 h and 48 h

No difference in LVEF at 6 months (primary end point) or MI size at 5 days and 6 months on cardiac MRI; trend towards increased MACE (death, recurrent MI, stroke or target vessel revascularization) at 6 months, and increased MI size in patients aged >70 years

Najjar et al. (2011)REVEAL93

138, <8 Intravenous erythropoietin (epoetin β) 60,000 IU immediately after PPCI, repeated after 24 h and 48 h

No difference in MI size on cardiac MRI within 6 days and 3 months; trend towards increased MACE in patients aged >70 years

Lincoff et al. (2011) PROTECTION-AMI100

908||, 150§§, <6

Intravenous delcasertib 50 mg/h, 150 mg/h or 450 mg/h, each administered as 2.5 h infusion started before PPCI

No difference in MI size as assessed by CK-MB (primary end point)

Ludman et al. (in press)

52, <12 Intravenous erythropoietin (epoetin β) 50,000 IU before PPCI, repeated 24 h after PPCI

No difference in LVEF at 6 months on cardiac MRI (primary end point); no difference in MI size at 3 days (cardiac MRI or troponin T); doubling of incidence of microvascular obstruction and acutely increased cardiac volumes and mass; no difference at 4 months in any variables on cardiac MRI

*Insulin incretin. ‡Hematopoietic cytokine. §Natriuretic peptide. ||Anterior STEMI. ¶Angina drug that activates mitochondrial KATP channels and induces release of nitric oxide. #Inhibitor of proapoptotic protein kinase Cδ. **Immunosuppressive agent that inhibits opening of mitochondrial permeability transition pores. ‡‡Pleiotropic effects, including direct intracellular activation of the RISK pathway. Erythropoietins, glucagon-like peptide 1 and nicorandil also induce direct intracellular activation of the RISK pathway, which limits MI size. §§Inferior STEMI. Abbreviations: AUC, area under the curve; CK, creatine kinase; CK-MB, creatine kinase-MB; LVEF, left ventricular ejection fraction; MACE, major adverse cardiac events; MI, myocardial infarction; n, number of patients; PPCI, primary percutaneous coronary intervention; RISK, reperfusion injury signaling kinase; SPECT, single-photon-emission computed tomography; STEMI, ST-segment elevation MI.

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of ischemia–reperfusion injury with regard to representing the wide spectrum of comorbidities in patients with CHD (such as diabetes, hypertension, hyperlipidemia, and preexisting coronary artery disease) as well as other coexisting factors (such as advanced age and other medical therapy); and poorly designed clinical studies, which have failed to take into account the results from experimental studies.68 As a way forward, the NHLBI has proposed formation of the multicenter Consortium for Preclinical Assessment of Cardioprotective Therapies (CAESAR) to first demonstrate using a multicenter, random ized, placebocontrolled trial approach that a proposed novel cardioprotective strategy is beneficial in the preclinical setting, before taking the strategy into the clinical arena for testing. In addition, guidelines for the future design of both basic science and clinical studies have been proposed.30

Potential future clinical applicationsRemote ischemic conditioningThe potential clinical applications for remote ischemic conditioning in particular are numerous and extend far beyond protection from STEMI or NSTEMI treated with PCI, owing to the noninvasive nature of the remote ischemic conditioning stimulus and its capacity to protect organs other than the heart against acute ischemia–reperfusion injury. Proofofconcept clinical studies have demonstrated that remote ischemic conditioning (from upper or lower limb ischemia and reperfusion) protects both the heart and kidney during elective surgery for abdominal aortic aneurysm,69 the kidney during CABG surgery,70 and the brain during surgery for cervical decompression.71 Intriguingly, remote ischemic conditioning (four 5 min cycles of upper limb ischemia and reperfusion) also improves maximal performance in highly trained swimmers.72

Cardiac transplantationDuring cardiac transplantation, the donor heart is subjected to an acute episode of global lethal myocardial ischemia as the heart is explanted from the donor and transported from the donor to the recipient. Implantation of the donor heart into the recipient then subjects the myocardium to acute myocardial reperfusion injury. This clinical scenario provides opportunities to apply a remote ischemic preconditioning protocol to the donor directly before harvesting the heart, followed by the application of a remote ischemic preconditioning protocol to the recipient prior to implantation. Furthermore, at the time of cardiac implantation, ischemic postconditioning could be applied when unclamping the aorta (Figure 2).

Cardiac arrestPatients who survive a cardiac arrest are first subjected to acute global myocardial ischemia and then to acute myocardial reperfusion injury upon the return of spontaneous circulation following a cardiac arrest. As such, an opportunity to apply a remote ischemic perconditioning protocol exists following a cardiac arrest, to protect the heart from the detrimental effects of acute global ischemia– reperfusion injury on cardiac function, and to facilitate the patient’s recovery (Figure 2).

ConclusionsDespite the original discovery of ischemic pre conditioning taking place in 1986, its therapeutic potential is only now being realized. In the past 5–6 years, ischemic and pharmaco logical conditioning has been used in an increasing number of proofofconcept clinical studies to protect the heart against acute ischemia–reperfusion injury in a variety of clinical settings. The beneficial effects of ischemic preconditioning in patients undergoing CABG surgery were first demonstrated in 1993.43 However, owing to the invasive nature of ischemic preconditioning, the full therapeutic potential of this cardioprotective strategy has yet to be realized. The discovery of remote ischemic conditioning has gone some way towards applying ischemic conditioning in the clinical setting. For patients undergoing planned procedures (such as PCI and CABG surgery, in which the acute ischemia–reperfusion injury event can be readily anticipated) remote ischemic preconditioning using noninvasive blood pressure cuff inflation on the upper or lower limb has therapeutic potential. Remote ischemic preconditioning has already been demonstrated to reduce myocardial injury in patients undergoing these procedures. Whether this technique can also improve clinical outcomes in patients undergoing CABG surgery will be determined in the ongoing multicenter, randomized, controlled ERICCA50 and RIPHeart51 trials. For patients who present with STEMI and are treated with primary PCI, both remote ischemic perconditioning and ischemic postconditioning have been reported to limit MI size and have therapeutic potential. Adequately powered, multicenter, randomized, controlled trials are now required to determine whether these two techniques can improve clinical outcomes in this group of patients. A number of pharmaco logical conditioning strategies reported to be beneficial in the preclinical setting have been investigated in clinical trials, with mixed results; this approach might prove to be more successful with improved study design and the use of combination therapy.

Other, as yet unexplored, clinical settings in which ischemic and pharmacological conditioning also have therapeutic potential, include cardiac transplantation, cardiac arrest, and NSTEMI treated with PCI. In most settings, however, adequately powered, large, multi center, clinical studies are now required to determine whether mechanical and pharmacological ischemic conditioning can improve clinical outcomes of patients at risk of ischemia–reperfusion injury.

Review criteria

We searched for original articles focusing on the therapeutic potential of ischemic conditioning in MEDLINE and PubMed, published between 1986 and 2011. The search terms we used were “ischemic preconditioning”, “ischemic perconditioning”, “ischemic postconditioning” and “remote”, alone and in combination. We also searched the NIH clinical trials registry for planned and ongoing clinical trials of ischemic conditioning. All papers identified were English-language, full-text papers. We also searched the reference lists of identified articles for further relevant papers.

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AcknowledgmentsD. J. Hausenloy’s research is funded by the British Heart Foundation (FS/10/039/28270). His work was undertaken at University College London Hospital/University College London, which received a portion of funding from the UK Department of Health’s NIH Research Biomedical Research Center’s funding scheme.

Author contributionsBoth authors contributed equally to all aspects of the manuscript, including researching data for the article, discussions of the content, writing the article, and review and/or editing of the manuscript before submission.

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