Is there still a need to reduce myocardial infarct size in patients with ST-segment elevation myocardial infarction? Ischaemic heart disease (IHD) remains the leading cause of death and disability in Europe and worldwide. A major cause of morbidity and mortality in IHD patients is an acute ST-segment elevation myocardial infarction (STEMI), which despite prompt reperfusion by primary percutaneous coronary intervention (PPCI) has significant mortality (7% death at 1 year) and morbidity (22% prolonged or new hospitalization for heart failure at 1 year) in patients with large infarcts. 1 When high-risk STEMI patients presenting with cardiogenic shock are not excluded, mortality at 1 year is even higher, at 12% after 1 year. 2 As such, there remains an urgent need to discover novel therapies which can be given prior to or at the time of PPCI to reduce myocardial infarct (MI) size in order to preserve left ventricular (LV) systolic function, prevent the onset of heart failure, and improve survival in reperfused STEMI patients. In patients presenting with STEMI, rapid access to the emergency medical services and timely reperfusion by PPCI minimize the total ischaemic time, a major determinant of MI size. Although myocardial reperfusion is essential to salvage myocardium following a STEMI, the process of restoring coronary blood flow to the ischaemic tissue can, in itself, induce myocardial injury and cardiomyocyte death, a phenomenon which is known as ‘myocardial reperfusion injury’. 3,4 Crucially, there is currently no effective therapy for reducing myocardial reperfusion injury in STEMI patients, and therefore, it remains a valid target for cardioprotection. However, the search for an effective therapy capable of targeting myocardial reperfusion injury and reducing MI size has been quite challenging, with a large number of failures to translate novel cardioprotective therapies into the clinical setting. 5,6 In this consensus article, we highlight the importance of myocardial reperfusion injury as a viable target for cardioprotection and discuss the potential reasons underlying the neutral results of recent clinical cardioprotection trials and explore the future possibilities for reducing MI size and improving clinical outcomes in patients with IHD. Why has it been so difficult to prevent myocardial reperfusion injury in patients with ST-segment elevation myocardial infarction? One major factor is an incomplete understanding of the mechanisms underlying myocardial reperfusion injury, with variable reperfusion times, multiple pathophysiological factors (calcium overload, oxidative stress, inflammation, and mitochondrial dysfunction), and multiple players (cardiomyocytes, microvasculature, inflammatory cells, and platelets), making it a complex phenomenon to target effectively. 4,7,8 There is general agreement that a large part of the cell death caused by myocardial reperfusion injury occurs during the first few minutes of reperfusion, and that early treatment is required to prevent it. 4,7 The most important aspect of reperfusion injury is cardiomyocyte cell death, which depends mainly on phenomena occurring within cardiomyocytes themselves, as it is possible to recapitulate reperfusion injury and demonstrate cardioprotection in isolated cardiomyocytes 9 (Figure 1 ). However, other cells can also contribute to cardiomyocyte cell death during reperfusion injury. This is particularly clear in the case of platelets, the activation and adhesion of which increase cell death independently of aggregation and of any effects on myocardial flow. 10 Activated resident cardiac fibroblasts may also exacerbate the local inflammatory reaction and aggravate reperfusion damage to cardiomyocytes. 11,12 Microvascular injury and microvascular obstruction may prevent the restoration of myocardial blood flow despite restoration of coronary artery patency in patients with STEMI, and its extent is associated with larger MI size, adverse LV remodelling, 13 and worse prognosis, 14,15 but up to what a point it is a cause or consequence of the existence of large infarcts needs to be clarified—and it may depend on the circumstances. Furthermore, increased endothelial permeability and subsequent recruitment of inflammatory cells into the site of infarction may also contribute to acute ischaemia/reperfusion injury—a number of clinical studies that have investigated anti-inflammatory therapies administered at the time of reperfusion to reduce MI size have had neutral results. 16,17 Figure 1 Main mechanisms of cardiomyocyte cell death during myocardial reperfusion and their inter-relations. The mitochondrial permeability transition pore (MPTP) is an important mediator of myocardial reperfusion injury, 18 yet several aspects of its role remain obscure. It is not well understood how opening of the MPTP causes sarcolemmal rupture within the first few minutes of reperfusion. A potential link could be the development of hypercontracture, caused by high and oscillating Ca2+ in the presence of ATP. 19 Calpain activation occurring upon normalization of intracellular pH in cells with Ca2+ has been demonstrated to contribute to cardiomyocyte death. 20 Reactive oxygen species may induce MPTP opening, and interventions attenuating mitochondrial ROS production can prevent MPTP opening and reduce MI size, 21 but they also have extra-mitochondrial targets, the importance of which needs to be clarified. A potentially important target of ROS is the tetrahydrobiopterin–eNOS complex, which may be dissociated by oxidation, resulting in peroxynitrite formation and reduced NO availability. 22 Recent studies have proposed that RIP3-mediated programmed cell necrosis may play a role in myocardial reperfusion injury through CaMKII and the MPTP. 23 A number of mechanical and pharmacological interventions have been investigated in clinical cardioprotection studies to target myocardial reperfusion injury in reperfused STEMI patients over the last few years—these are discussed in the following sections (Table 1 ; Figures 1 and 2 ). Table 1 Summary of the data available for several therapeutic interventions for targeting myocardial reperfusion injury and reducing myocardial infarct size Ischaemic conditioning NO/cGMP pathway Mitochondria and MPTP Multiple targets IPost RIC ANP GIK Exenatide Nitric oxide and nitrite MTP-131 CsA TRO40303 PKC-δ inhibition Hypothermia Metoprolol Adenosine Mechanism of cardioprotection known + + + + + + + + +/− +/− + + + Pre-clinical data shows consistent cardioprotection + + + + + +/− + +/− +/− +/− + + + Potential issues over safety − − − − − − − − +/− − +/− +/− − Clinical MI studies ++ ++ + +/− + +/− − +/− − − − + +/− Meta-analysis data + + +/− + Clinical outcome studies * * − * Mechanism of cardioprotection known: +, known; +/−, not clear. Pre-clinical data shows consistent cardioprotection: +, consistent cardioprotection; +/−, inconsistent cardioprotection. Potential issues over safety: −, no known safety issues; +/−, potential safety issues. Clinical MI studies: ++, several positive MI studies; +, only one positive MI study; +/−, inconsistent MI studies; −, neutral MI studies. Meta-analysis data: +, positive data; +/−, inconsistent data. Clinical outcome studies: *, outcome study ongoing; −, neutral outcome study data. Figure 2 Various time-windows for applying therapeutic strategies for reducing myocardial infarct size in STEMI patients undergoing PPCI. Ischaemic post-conditioning Zhao et al. first reported that brief episodes of ischaemia and reperfusion performed immediately after reflow can limit MI size in the dog heart. 24 This novel finding was later confirmed in different experimental models. 25,26 Staat et al. and Thibault et al. first demonstrated that comparable cardioprotection could be obtained in STEMI patients with four 1-min cycles alternating inflations and deflations of the angioplasty balloon applied immediately after reopening the culprit coronary artery as evidenced by a reduction in MI size, measured by cardiac enzyme release, SPECT, and cardiac magnetic resonance imaging (MRI). 27,28 Several, but not all, Phase II trials have confirmed that ischaemic post-conditioning (IPost) is cardioprotective in STEMI patients admitted with a full coronary artery occlusion. 29–32 Reasons for failure of some trials might be related to the absence of direct stenting and delivery of the IPost protocol within the stent with the incumbent risk of coronary micro-embolization. 31–33 Specific questions remain as to whether all patients may benefit from IPost given the potential influence of risk factors (e.g. diabetes, age) and concurrent treatments (e.g. anti-platelet agents, statins). 34–38 Although none of these studies have reported safety concerns, it remains uncertain whether IPost can improve clinical outcomes in STEMI patients. In this regard, the DANAMI-3 Phase III trial has completed recruitment, and the results are expected this year (NCT01435408). 39 Remote ischaemic conditioning The application of cycles of brief ischaemia and reperfusion to an organ or tissue remote from the heart has been demonstrated to reduce MI size following an episode of acute ischaemia/reperfusion injury, a phenomenon which has been termed remote ischaemic conditioning (RIC). 40–44 The ability to recapitulate this cardioprotective effect by simply inflating a blood pressure cuff placed on the upper arm or thigh to induce cycles of brief ischaemia and reperfusion in the upper or lower limb, has facilitated the translation of RIC into the clinical setting, where it has been shown to reduce perioperative myocardial injury but to not improve clinical outcomes in patients undergoing coronary artery bypass graft surgery. 45–49 Several clinical studies have found that RIC using transient arm or leg ischaemia/reperfusion reduced MI size by 20–30% (assessed by cardiac enzymes, SPECT or cardiac MRI) in STEMI patients reperfused by either PPCI 50–54 or thrombolysis. 55 Furthermore, RIC has been reported to improve LV systolic function at four weeks in a subgroup of anterior STEMI patients 56 and reduce major adverse cardiac and cerebral events in a follow-up study of 251 STEMI patients. 57 It has been shown to be a cost-effective intervention within the first 2 years following PPCI, an effect which was mainly driven by a reduction in hospital re-admissions for heart failure (unpublished data). Finally, post hoc analysis failed to find any major confounding effects of co-morbidities or concomitant medication on the cardioprotective efficacy of RIC in reperfused STEMI patients. 58 In summary, RIC using transient limb ischaemia/reperfusion holds promise as an adjunct to PPCI in STEMI patients for reducing MI size. Whether it can improve long-term clinical outcomes is not known and is currently being investigated in the 4300 STEMI patient CONDI-2/ERIC-PPCI clinical study. 59 Therapies which target the nitric oxide/cyclic guanosine monophosphate signalling pathway There is extensive and consistent experimental evidence that nitric oxide/cyclic guanosine monophosphate (NO/cGMP) is reduced in reperfused myocardium, and pharmacological activation of this pathway at the time of reperfusion has been shown to reduce MI size. 60 However, there is only one published trial testing the effect of stimulating cGMP synthesis by particulate guanylate cyclase with atrial natriuretic peptide in STEMI—it showed a modest reduction in enzymatic MI size. 61 A number of other clinical trials have investigated other therapies which target the NO/cGMP signalling pathway. These include insulin, as part of glucose–insulin–potassium (GIK) therapy which has had mixed results in clinical studies, although the IMMEDIATE trial found that GIK administered in the ambulance reduced MI size in a subset of STEMI patients, 62 and other insulin-mimetics such as exenatide. Exenatide The anti-diabetic, glucagon-like peptide-1 (GLP-1), has been demonstrated in experimental animal studies to reduce MI size when administered at the onset of reperfusion by mechanisms independent of increased insulin levels. 63 As a therapeutic strategy, the GLP-1 analogue, exenatide, has also been shown to protect against myocardial reperfusion injury in small and large animal MI models. 64,65 In the clinical setting, an intravenous infusion of exenatide initiated prior to PPCI has been shown to reduce MI size in patients presenting with an acute STEMI, especially in those patients presenting with short ischaemic times from symptom onset ( 30–40% of LV) 129 such as anterior STEMI Fully occluded coronary artery prior to PPCI (TIMI flow <1) 29 No significant coronary collaterals Dosing the intervention A failure to ascertain the most efficacious dose of the cardioprotective intervention, whether it be a mechanical or pharmacological one, may have contributed to the failure to translate cardioprotection in some of the clinical STEMI studies. Timing the intervention The intervention is more likely to be effective at targeting myocardial reperfusion injury in the following circumstances: There is consistent pre-clinical evidence that the intervention can reduce MI size when administered prior or at the onset of reperfusion, and it has achieved sufficient concentrations in the blood in the first few minutes of reperfusion. It is important to note that those cardioprotective interventions that are effective only when present during the ischaemic period may act by reducing acute myocardial ischaemic injury. 62,123 Limiting ischaemic injury is a very effective strategy to limit MI size, but it may be difficult to apply in STEMI because it requires very early administration, and in patients with a completely occluded artery, the treatment may not be able to reach the ischaemic myocardium. Even when drugs are administered before reperfusion, they may not reach a sufficient concentration in time to protect against the cell death, which occurs in the first few minutes of reflow. Combination therapy for reducing myocardial infarct size Using combination reperfusion therapy to target either the different pro-survival signalling pathways within the cardiomyocyte or different proponents of myocardial reperfusion injury (cardiomyocyte, platelets, inflammation, and microvasculature) may provide more effective cardioprotection against myocardial reperfusion injury than a single targeted approach. Alburquerque-Béjar et al. 130 found an additional 26% reduction in MI size when combining RIC with insulin-like therapies (such as GIK and exenatide) in a porcine acute MI model. The COMBinAtion Therapy in Myocardial Infarction (COMBAT-MI) study (NCT02404376) will investigate the potential benefits of combined reperfusion therapy using RIC with exenatide on MI size reduction in STEMI patients treated by PPCI. Although an initial clinical study of 54 patients in reperfused STEMI patients failed to show an additive cardioprotective effect with RIC and IPost administered in combination, 52 the recently published LIPSIA study of 696 patients reported increased myocardial salvage in those patients administered RIC in combination with IPost when compared with control. 54 Future perspectives Translating cardioprotective therapies for targeting myocardial reperfusion injury from experimental studies into the clinical setting for patient benefit has been extremely challenging. The failure to find an effective agent for preventing myocardial reperfusion injury thus far, however, does not question the existence of myocardial reperfusion injury as a valid target for cardioprotection. Rather it underscores the need to better understand the mechanisms underlying myocardial reperfusion injury. As such experimental studies in this area should continue, as this will allow us to better define effective therapeutic strategies for targeting reperfusion injury to reduce MI size. Currently, an incomplete understanding and lack of appreciation of the complexities of myocardial reperfusion injury has contributed, in part, to the failure to effectively target myocardial reperfusion injury in the clinical setting for patient benefit. Clinical research in this area should also continue. However, lessons should be learned from recent clinical trials: (i) future clinical trials should be restricted to interventions with consistent experimental data and the latter should include studies in large animals; (ii) clinical study design is crucial when testing novel cardioprotective therapies in STEMI patients; and (iii) only interventions consistently found to be effective at limiting MI size in Phase II clinical trials should be investigated in large clinical outcome trials. Therapeutic strategies that have potential to improve clinical outcomes in reperfused STEMI patients include remote ischaemic conditioning, exenatide, and metoprolol, and clinical studies are underway to test their efficacy in this regard. New approaches for limiting MI size should include combination therapy to (i) target different cardioprotective signalling pathways within the cardiomyocyte in order to provide additive cardioprotection and (ii) target the different players involved in myocardial reperfusion injury (cardiomyocyte, microvasculature, inflammatory cells, and platelets). These experimental and clinical studies are currently underway and should allow more effective targeting of myocardial reperfusion injury, thereby reducing MI size in reperfused STEMI and preventing the onset of heart failure. Funding D.J.H. and D.M.Y. are funded by the British Heart Foundation and the Rosetrees Trust, and are supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre of which D.M.Y. is a senior investigator. D.G.-D. is funded by the Cardiovascular Research Network of the Spanish Institute of Health Instituto de Salud Carlos III (ISCiii RETICS-RIC, RD12/0042/0021). G.H. is supported by the German Research Foundation (He 1320/18-3; SFB 1116 B8). B.I. is funded by the Carlos III Institute of Health and European Regional Development Fund (ERDF/FEDER) (PI13/01979), and the ISCiii Cardiovascular Research Network (RD12/0042/0054). Funding to pay the Open Access publication charges for this article was provided by Red de Investigación Cardiovascular del Instituto de Salud Carlos III, grupo Hospital Universitari Vall d'Hebron (RETICS 2012 RD12/0042/0021). Conflict of interest: H.E.B. is shareholder of CellAegis Inc. M.O. was a consultant for Neurovive Pharmaceuticals. D.E. has received speaker fees from Zoll. G.H. served as a consultant to Servier. D.G.-D. served as a consultant to Neurovive Pharmaceuticals. R.A.K. serves as a consultant and receives research support from Stealth BioTherapeutics; he is a consultant to Servier, IC Therapeutics/Endothelix, Pfizer, Gilead, Neurovive; he is on the speaker bureau for AMGEN.
