2016/04/26 by Derek J. Hausenloy, Hans Erik Bøtker, Thomas Engstrøm +7 · 2 citations
Medicine · Engineering · #Cardiac Ischemia and Reperfusion #Cardiac Arrest and Resuscitation #Mechanical Circulatory Support Devices #Medicine #Cardiogenic shock #Myocardial infarction #Cardiology #Internal medicine #Reperfusion therapy #Percutaneous coronary intervention #Cardioprotection #Heart failure
paper · pdf · doi:10.1093/eurheartj/ehw145
openalex publication_date 2016/04/26 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/05
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. 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 Summary of the data available for several therapeutic interventions for targeting myocardial reperfusion injury and reducing myocardial infarct size 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. Summary of the data available for several therapeutic interventions for targeting myocardial reperfusion injury and reducing myocardial infarct size 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. Various time-windows for applying therapeutic strategies for reducing myocardial infarct size in STEMI patients undergoing PPCI. 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 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 PPCI50–54 or thrombolysis.55 Furthermore, RIC has been reported to improve LV systolic function at four weeks in a subgroup of anterior STEMI patients56 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 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. 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 (<132 min).66–68 Another GLP-1 analogue, liraglutide, when administered prior to PPCI and continued for 7 days, has been shown in a study of 85 STEMI patients to improve LV systolic function.69 Further studies are now required to determine whether this therapeutic approach can improve clinical outcomes in reperfused STEMI patients. Nitric oxide is known to be an important mediator of cardioprotection in various forms of ischaemic conditioning,70 and circulatory nitrite has been demonstrated to be a potential humoral mediator of remote ischaemic preconditioning.71 Although, there have been experimental studies demonstrating cardioprotection with intravenous nitrite administered at the onset of reperfusion,72 the National Heart Lung and Blood Institute (NHLBI) Consortium for preclinicAl assESsment of cARdioprotective therapies (CESAR) Network failed to demonstrate MI size reduction with nitrite using a multi-centre approach in small and large animal MI models.73,74 Two recent clinical studies have failed to demonstrate a significant reduction in MI size with nitrite administered by either the intravenous75 or intracoronary76 routes in STEMI patients treated by PPCI. However, there was a borderline increase in myocardial salvage index and reduced MI size in a subgroup of patients presenting with a fully occluded coronary artery.76 The recent 250 patient NOMI study (NCT01398384) has investigated the role of inhaled nitric oxide (vasoKINOX 450) as an adjunct to PPCI to target myocardial reperfusion injury in STEMI patients. Although no beneficial effect on MI size (Day 3 cardiac MRI) was demonstrated, post hoc subgroup analysis revealed that there was a significant reduction in MI size in those patients who had not received nitrates in the ambulance. Since there were no adverse events in these trials, further studies on nitrite and nitric oxide appear worthwhile, to test whether this therapeutic approach may yield benefit in a selected patient group. As a potent inhibitor of MPTP opening, cyclosporin A (CsA) has been shown to significantly reduce MI size in a number of experimental studies,77–79 but not all.80,81 Some, but not all, Phase II clinical trials have suggested that CsA might also protect the heart and brain following a prolonged ischaemic insult.82–86 The recently completed CYCLE trial of 410 STEMI patients failed to demonstrate any benefit with CsA administered prior to PPCI in terms of ST-segment resolution and enzymatic MI size.87 Finally, in the CsA in Reperfused Acute Myocardial Infarction (CIRCUS) 970 patient trial, the administration of CsA immediately prior to PPCI failed to improve clinical outcomes at 1 year (all-cause death, heart failure hospitalization, and adverse LV remodelling) in anterior STEMI patients.1 Why these larger clinical trials failed to confirm the benefit of CsA in reducing MI size from initial Phase II trials is unclear.88,89 Apart from a classical type I error frequently observed in small-size clinical studies, several different causes may have attributed to the neutral results of the CIRCUS trial: (i) CsA is a non-specific inhibitor of cyclophilin D and its other actions (e.g. cyclophilin A and calcineurin inhibition) might have counteracted the benefit of inhibiting MPTP opening.90 (ii) Important changes in STEMI patients since the initial Phase II trial might have played a role, including a greater use of the new P2Y12 platelet inhibitors (prasugrel, ticagrelor), which are known to reduce MI size per se.91 (iii) The concentration of CsA required to inhibit MPTP opening in STEMI patients is not known. The blood concentration of CsA at 4 h after IV bolus administration averaged 533 ± 189 ng/mL in a subset of CIRCUS patients—this was comparable to that observed in the original positive Phase II trial.1,82 (iv) Whether it is enough to inhibit MPTP opening to prevent myocardial reperfusion injury in STEMI patients may be questioned. One may wonder whether much longer ischaemia times observed in humans (when compared with animal models) might alter the binding site or the function of cyclophilin D and render it inaccessible to CsA. This last point may be pertinent in the CIRCUS trial in which total ischaemic times were relatively prolonged at 4.5 h.1 In any case, the failure of CsA to improve clinical outcomes in STEMI patients by no means questions the concept of protection against myocardial reperfusion injury. The mitochondria-targeting peptide, MTP-131, optimizes mitochondrial energetics and attenuates the production of ROS by selectively targeting cardiolipin in the inner mitochondrial membrane. It has been reported in small and large animal experimental studies to reduce MI size when administered at the onset of reperfusion and prevent adverse LV remodelling following MI.92,93 However, in the 117 patient EMBRACE STEMI clinical trial,94 intravenous MTP-131 administered prior to PPCI failed to reduce enzymatic MI size in a carefully selected population of anterior STEMI patients with ischaemic time <4 h, no collaterals, and fully occluded coronary artery. The reasons for the neutral results of this study are not known, but may include reasons similar to those of other MPTP-targeted interventions (as discussed previously) as well as pharmacokinetic or pharmacodynamic difficulties to target mitochondria in STEMI patients. Clinical trials are currently underway to investigate whether this agent can benefit patients with chronic heart failure. The mitochondrial targeting drug, TRO40303, which binds to the translocator protein TSPO in the outer mitochondrial membrane and aims to inhibit MPTP opening by attenuating ROS production, has been reported in small animal experimental studies to reduce MI size when administered at time of reperfusion.95 However, in a clinically-relevant large animal MI model, it failed to reduce MI size in the porcine heart.96 In the 163 STEMI patient MITOCARE study,97 this agent failed to reduce MI size despite careful patient selection (completely occluded infarct-related artery, large area-at-risk). Prior experimental studies had revealed ambiguous cardioprotective capacity, and the formulation and dosage of in the clinical study from experimental studies, which may in part the neutral of the MITOCARE Finally, adverse events were reported in patients when compared with the the clinical application of this therapeutic et al. first protein to be a mediator of ischaemic the role of the in cardioprotection has been with some studies its or to be other studies finding it to be a mediator of ischaemic and initial clinical study had suggested that administered prior to PPCI may be cardioprotective in STEMI patients. 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The intervention is to be effective at targeting myocardial reperfusion injury in the following There is consistent evidence that the intervention can reduce MI size when administered prior or at the onset of and it has in the blood in the first few minutes of reperfusion. It is important to that those cardioprotective interventions that are effective only when during the ischaemic may by reducing acute myocardial ischaemic ischaemic injury is a effective to limit MI size, but it may be to in STEMI it and in patients with a occluded artery, the may not be to the ischaemic when are administered they may not a concentration in time to protect against the cell death, which in the first few minutes of reperfusion therapy to target either the different signalling within the cardiomyocyte or different of myocardial reperfusion injury and may effective cardioprotection against myocardial reperfusion injury a et found an reduction in MI size when RIC with therapies as GIK and in a porcine acute MI The in Myocardial Infarction study investigate the potential of reperfusion therapy using RIC with exenatide on MI size reduction in STEMI patients treated by PPCI. Although an initial clinical study of patients in reperfused STEMI patients failed to an cardioprotective effect with RIC and IPost administered in the recently published study of patients reported increased myocardial salvage in those patients administered RIC in with IPost when compared with cardioprotective therapies for targeting myocardial reperfusion injury from experimental studies into the clinical for patient benefit has been The failure to find an effective agent for myocardial reperfusion injury not the of myocardial reperfusion injury as a valid target for cardioprotection. it the need to the mechanisms underlying myocardial reperfusion injury. As such experimental studies in this as this to effective therapeutic strategies for targeting reperfusion injury to reduce MI size. an and of of the of myocardial reperfusion injury has in to the failure to target myocardial reperfusion injury in the clinical for patient Clinical in this also However, be from recent clinical (i) future clinical trials be to interventions with consistent experimental data and the include studies in large (ii) clinical study is when testing novel cardioprotective therapies in STEMI and (iii) only interventions found to be effective at MI size in Phase II clinical trials be investigated in large clinical outcome strategies that have potential to improve clinical outcomes in reperfused STEMI patients include remote ischaemic exenatide, and and clinical studies are underway to test their efficacy in this for MI size include therapy to (i) target different cardioprotective signalling within the cardiomyocyte in order to cardioprotection and (ii) target the different in myocardial reperfusion injury and These experimental and clinical studies are currently underway and effective targeting of myocardial reperfusion injury, reducing MI size in reperfused STEMI and the onset of heart failure. and are by the Heart and the and are by the National Institute for of which is a is by the Network of the Institute of III is by the is by the III Institute of and and the Network to the for this was by of is of was a for has received from as a to as a to as a and from is a to is on the for