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More than 50 years ago, Jennings et al127 first suggested that reperfusion may actually hasten the necrotic process of myocytes irreversibly injured during ischemia, with the concept that reperfusion could induce the death of reversibly injured cardiomyocytes.8,9 Currently, despite inducing additional damage to the myocardium,128 reperfusion is the mainstay treatment for patients with acute ST-segment elevation myocardial infarction (STEMI). Therefore, any therapy able to reduce the size of infarction must do so in conjunction with reperfusion (either mechanically [primary angioplasty] or pharmacologically [thrombolytics]). Despite significant data demonstrating that reperfusion-induced injury significantly contributes to final infarct size (reviewed earlier in this chapter), at present, there is still no effective therapy in routine clinical use for reducing lethal myocardial reperfusion injury in reperfused STEMI or cardiac surgery patients.129 Therefore, reperfusion injury is still a neglected therapeutic target.1,31 In the following sections, we review the strategies potentially available to attenuate IRI and for protecting the heart against acute myocardial infarction and myocardial reperfusion injury.
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Ischemic Conditioning
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The possibility of “preparing” the myocardium for a subsequent ischemic insult is termed conditioning in the context of this chapter. The execution of brief episodes of ischemia and reperfusion is known as ischemic conditioning if these brief episodes of ischemia occur before the index episode (eg, brief coronary occlusion/reperfusion before prolonged coronary occlusion–myocardial infarction) or after the index episode (eg, brief episodes of coronary occlusion/reperfusion at the end of a prolonged coronary occlusion–myocardial infarction). This conditioning can be local (ie, the brief episodes of ischemia occur at the same organ) or remote (ie, the brief episodes of ischemia occur at a different distant organ) (Fig. 38–6).130 The existence of “natural” local IPC has been known for several decades; for example, patients suffering preinfarction anginal episodes (representing brief episodes of spontaneous occlusion/reperfusion [eg, thrombosis-spontaneous lysis] of the coronary artery preceding STEMI) have smaller infarctions and better prognoses than patients without preinfarction angina (ie, straight coronary occlusion).131 In the following sections, we describe different forms of ischemic conditioning as well as their clinical applications.
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Ischemic Preconditioning
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For patients suffering a STEMI or undergoing cardiac surgery (a paradigmatic “model” of planned myocardial IRI), the phenomenon known as ischemic conditioning provides an endogenous strategy that is capable of protecting the heart from the detrimental effects of acute IRI and that has the therapeutic potential to improve clinical outcomes in patients with ischemic heart disease.
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This remarkable cardioprotective strategy is the term given to a number of related endogenous cardioprotective procedures, which are all based on rendering the heart tolerant to acute IRI by “conditioning” it with one or more brief cycles of ischemia and reperfusion. Discovered by Murry, Jennings, and Reimer in 1986,20,132 it remains the most consistent and powerful form of cardioprotection at our disposal to date. What makes it so important is that it can be seen in all species examined, including man, and can be readily applied to other organs and tissues (reviewed in Yellon and Downey133 and Bulluck and Hausenloy134). Other than direct reperfusion of a blocked coronary artery, IPC remains the most powerful intervention for reducing myocardial infarction size in the ischemic heart.
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IPC has been shown to induce two distinct windows of cardioprotection. The first, usually referred to as classic preconditioning, occurs immediately after the IPC stimulus and lasts 2 to 3 hours followed by a disappearing of the effect. This is followed by a second window of protection or delayed effect appearing 12 to 24 hours later and lasting 48 to 72 hours.135,136 Despite intensive investigation, the actual mechanisms that mediate the cardioprotective effect induced by IPC are not fully understood. Importantly a large number of signaling pathways have been identified, which are briefly mentioned below (for more comprehensive review, see Yellon and Downey133 and Heusch137). In brief, the sublethal cycles of short bursts of ischemia and reperfusion, which make up the IPC stimulus, produce a number of endogenous biological factors (ie, autacoids) from the myocyte, including adenosine, bradykinin, endothelin, acetylcholine, and opioids, which can bind to their respective receptors on the plasma membrane. This will direct the appropriate cardioprotective communication pathway that will convey the protective signal to the mitochondria. It is believed that, within the cell, a signaling ROS is produced that activates protein kinases, such as Akt, Erk1/2, tyrosine kinase, and protein kinase C, that provide the “memory” for the cardioprotective effect such that the effect lasts up to 2 to 3 hours (for classical or acute IPC); the role of protein kinase C in such memory is somewhat controversial.138 In the second window of protection or delayed conditioning, these protein kinases activate transcription factors (such as STAT1/3, NFκB, AP-1, Nrf2, and HIF-1α), which mediate the synthesis of distal mediators (such as inducible nitric oxide synthase, heat shock protein, and cyclooxygenase-2), which then induce the cardioprotective effect 12 to 24 hours following the IPC stimulus.139 In terms of preventing myocardial IRI, IPC has been shown to recruit prosurvival signaling pathways at the onset of reperfusion, including the reperfusion injury salvage kinase (RISK) pathway, first identified by Yellon’s group in 2002 and comprising Akt and Erk1/2,140,141 and the survivor activator factor enhancement (SAFE) pathway, comprising TNF-α and JAK-STAT3 and identified by Lecour’s group in 2008.141,142,143
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Although the end effectors of cardioprotection in classical and delayed IPC remain unclear, it has been suggested that preservation of mitochondrial function with less calcium overload, attenuated ROS production, and MPTP inhibition all contribute to the protective effect.133,144,145 It is hoped that functional genomics of myocardial tissue may provide further insights into the potential mechanisms underlying IPC strategies.146
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Clinical Application of Ischemic Preconditioning
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The first clinical study to apply an IPC stimulus in patients was by Yellon’s group in 1993 in the setting of coronary artery bypass grafting (CABG) surgery.147 They found that intermittent clamping and declamping of the aorta of patients undergoing CABG surgery preserved myocardial ATP levels in a similar manner to that seen by Murry and colleagues in their seminal preconditioning paper. Since then, a number of small studies148 have confirmed the cardioprotective effect of IPC, as measured by serum cardiac enzymes, in terms of reducing the extent of perimyocardial injury in patients undergoing CABG surgery; a recent meta-analysis of 22 trials of 933 patients found that IPC reduced ventricular arrhythmias, decreased inotrope requirements, and shortened the intensive care unit stay.149 Despite these potential beneficial effects, the need to intervene on the heart directly and the inherent risk of thromboembolization arising from clamping an atherosclerotic aorta have prevented IPC from being adopted in this clinical setting.150
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Interestingly it has been suggested that the phenomenon of IPC can be observed in a number of clinical scenarios in which the heart is able to protect itself with brief episodes of ischemia (eg, in the setting of “warm-up angina,” which refers to the occurrence in which a patient with stable ischemic heart disease is able to increase his or her exercise tolerance following an episode of angina followed by a period of rest).151 In addition, antecedent angina prior to an acute myocardial infarction, or preinfarct angina, has also been suggested to account for the cardioprotective effects of smaller myocardial infarction size and improved clinical outcomes.131
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Ischemic Postconditioning
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The major disadvantage of IPC as a cardioprotective strategy is the requirement to intervene prior to the index ischemic event, which in the case of an acute myocardial infarction is not possible. However, in 2003, Zhao et al6 made the exciting discovery that the heart could be protected against acute myocardial infarction by interrupting myocardial reperfusion with several short-lived episodes of myocardial ischemia; they termed this phenomenon IPost.152 These authors found that applying three cycles of 30-second left anterior descending coronary artery reocclusion and reflow within 1 minute of myocardial reperfusion could reduce myocardial infarction size by 44% in the canine heart.6 In addition, IPost was found to confer a myriad of protective effects with preserved endothelial function and reduced levels of myocardial edema, oxidative stress, and polymorphonuclear neutrophil accumulation, findings that were consistent with there being less myocardial reperfusion injury in postconditioned hearts.6
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Interestingly, the concept of modifying reperfusion as a strategy to limit myocardial infarction size had already been introduced in the 1980s with the strategies of gentle5 and gradual153 reperfusion.7 Indeed, in 1996, Na et al154 had already coined the term postconditioning when they described the phenomenon by which intermittent reperfusion, induced by ventricular premature beats, prevented reperfusion-induced ventricular fibrillation in ischemic feline hearts. However, the concept of IPost has captured the imagination and restored efforts to target myocardial reperfusion injury as a therapeutic strategy for reducing myocardial infarction size. Importantly, this phenomenon has been shown to reduce myocardial infarction size in rodents, rabbits, pigs, and other species, including man, although the cardioprotective effect of IPost does not appear to be as robust as IPC.137,155
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IPost appears to share many of the same signaling mechanisms recruited at the time of reperfusion by IPC,134,137 which include the activation of cell-surface receptors on the cardiomyocyte (such as adenosine, bradykinin, opioids) and the recruitment of prosurvival signaling pathways (such as the RISK, SAFE, and cyclic guanosine monophosphate pathways)156 that converge on mitochondria and mediate cardioprotection by preserving mitochondrial function (less calcium overload, attenuated oxidative stress, and inhibited MPTP opening).
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Ischemic Postconditioning in ST-Segment Elevation Myocardial Infarction
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The ability to apply the therapeutic intervention at the onset of reperfusion in STEMI patients has greatly facilitated the translation of IPost into the clinical setting,73,157 where it was shown that following direct stenting, IPost, performed within 1 minute of reflow by four episodes of 1-minute inflation and 1-minute deflation of an angioplasty balloon positioned upstream of the stent, reduced enzymatic myocardial infarction size (total creatine kinase) by 36% and improved myocardial perfusion (assessed by myocardial blush grade).157 This study provided the first evidence that confirmed the existence of myocardial reperfusion injury in man,158 as it clearly demonstrated that intervening at the onset of reperfusion was able to reduce myocardial infarction size.
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A number of small studies have confirmed the myocardial infarction–limiting effects of IPost using serum troponin release,159 myocardial single-photon emission computed tomography,160,161 and cardiac magnetic resonance imaging,162 with apparent long-term benefits on cardiac function.161 However, a number of recent studies have also failed to show any beneficial effects with IPost,163 and there are even some studies reporting possible detrimental effects with IPost.164,165 Although recent meta-analyses have confirmed the myocardial infarction–limiting effects of IPost in STEMI patients,166,167,168 the largest clinical study of more than 700 STEMI patients failed to find any benefits with IPost in terms of ST-segment resolution, peak creatine kinase myocardial band levels, myocardial blush grade, or major adverse cardiovascular event at 30 days.169 The reasons for these discrepancies are not fully understood but may have a variety of explanations.28,170,171
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Remote Ischemic Conditioning
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The major disadvantage of IPC and IPost is that they both require an intervention to be applied to the heart directly; therefore, with the discovery of the phenomenon of remote preconditioning by Przyklenk and colleagues,172 the idea that conditioning may indeed have a practical role to play in protecting the heart from IRI has been realized. Remote ischemic conditioning (RIC) is the phenomenon whereby the application of one or more brief cycles of nonlethal ischemia and reperfusion to an organ or tissue protects the heart against a lethal episode of acute IRI.
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The actual mechanism through which an episode of brief ischemia and reperfusion in an organ or tissue away from the heart exerts protection against a subsequent sustained insult of acute myocardial IRI injury is currently unclear.173,174,175 It has been suggested that the underlying mechanistic pathways and signaling cascades activated within the protected organ may be similar to those recruited in the setting of IPC and IPost (Fig. 38–7).137,173 What remains uncertain is the mechanistic pathway responsible for conveying the cardioprotective signal from the remote preconditioned organ or tissue to the heart. The current paradigm suggests a neurohormonal pathway is central to the protective effect underlying RIC. In this regard, it has been shown that a substance or humoral factor generated by the preconditioning ischemia is transported to the heart to elicit protection. It has been shown that blood taken from a rabbit that has been preconditioned reduced myocardial infarction size when transfused into a naïve rabbit,176 suggesting the transfer of one or more humoral cardioprotective factors. Furthermore hexamethonium (a ganglion blocker),177 resection of the neural innervation of the limb,178,179 genetic inhibition of preganglionic vagal neurons in the brainstem,180 and resection of the vagal nerve supply to the heart181 have all been shown to abrogate the myocardial infarction–limiting effects of limb RIC, suggesting the requirement for an intact neural pathway for RIC cardioprotection. The exact details of the neural pathway have not been completely elucidated. The stimulation of the neural pathway in the RIC-treated organ or tissue appears to be a result of the local production of autacoids such as adenosine182,183 and bradykinin.184 Furthermore, proteomic analysis of plasma harvested from RIC-treated animals has failed to identify the cardioprotective factor(s), although the evidence suggests that the factor(s) is thermolabile and hydrophobic and is in the range of 3 to 8.5 kDa in size.182,183,184,185,186 Recent studies have provided experimental evidence implicating calcitonin gene-related peptide,187 stromal derived factor-1α,188 nitrite,189 and microRNA-144190 as possible mediators of RIC cardioprotection, although conclusive evidence for their role as the bloodborne transferrable cardioprotective factors in RIC is lacking.
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Furthermore, the generation of this cardioprotective factor has been shown to be dependent on an intact neural pathway to the RIC-treated limb,191 with neural stimulation of the limb using direct nerve stimulation,192 electroacupuncture,193 topical capsaicin,192 or transcutaneous electrode stimulation194 generating a bloodborne transferrable cardioprotective factor and reducing myocardial infarction size in animal models. Finally, Jensen et al195 have confirmed the need for an intact neural pathway to the limb by showing that the bloodborne transferrable cardioprotective factor was not produced by limb RIC in diabetic patients with a sensory neuropathy of the limb. In the myocardium, RIC activates both the RISK and the SAFE pathways, and their activation is species dependent196; in humans, RIC activates STAT5 in the myocardium.197
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Studies are required to tease out the exact interplay between the neuronal and hormonal pathways underlying RIC and to identify the bloodborne cardioprotective factor(s) that mediate RIC cardioprotection.
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Clinical Application of Remote Ischemic Conditioning
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The discovery by Kharbanda et al198 that cardioprotection could be achieved noninvasively by simply inflating and deflating a blood pressure cuff placed on the upper arm or thigh has facilitated a simple means of translating this phenomenon into the clinical setting. With the rush to clinical trial, the RIC stimulus to the limb itself has not been properly characterized and appears to be taken from experimental animal models most often using 5 to 15 minutes. However, the most effective limb RIC stimulus is still not known. Importantly, however, RIC can be delivered at different time points with respect to the ischemia/reperfusion insult, including 24 hours prior to the index ischemia (delayed remote IPC), immediately prior to the index ischemia (remote IPC), after the onset of index ischemia but prior to reperfusion (remote ischemic perconditioning),199 at the onset of reperfusion (remote IPost),200,201 and even 15 to 30 minutes into reperfusion (delayed remote IPost),202 allowing its application in a wide variety of clinical settings of acute IRI.
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Remote Ischemic Conditioning in Cardiac Surgery
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RIC using limb ischemia was first investigated by Guanydin et al in 2000203 in a small eight-patient study, although perioperative myocardial injury was not assessed. In 2006, Cheung et al204 were the first to demonstrate a cardioprotective effect with limb RIC in children undergoing cardiac surgery for congenital heart disease. They used four 5-minute cycles of lower limb ischemia and reperfusion induced by inflating and deflating a blood pressure cuff on the thigh and demonstrated reduced perioperative myocardial injury (less troponin I), reduced inotrope requirements, and decreased airway pressure. Yellon’s group went on to report beneficial effects in terms of a 43% reduction in perioperative myocardial injury (72-hour area under the curve troponin T)205 in adults undergoing CABG surgery.
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Although recent meta-analyses appeared to confirm the cardioprotective effect of limb RIC in terms of reducing perioperative myocardial injury, the fundamental question was whether such a supposed benefit could be seen in terms of clinical outcome.206,207,208,209 Most important in this regard are the recently reported large prospective multicenter randomized clinical trials (adequately powered to detect major adverse cardiovascular events) that confirm that limb RIC has no beneficial effects on major clinical outcomes in patients undergoing cardiac surgery.210,211,212
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There have been many proposed reasons why RIC has not been observed in the setting of CABG, and this is the subject of much debate.213,214,215,216
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Remote Ischemic Conditioning in Planned Percutaneous Coronary Intervention
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The setting of planned percutaneous coronary intervention (PCI) has also been used to examine the potential cardioprotective effects of RIC. It is known that injury occurs in about 30% of stable patients and up to 80% of unstable patients undergoing urgent PCI. The injury is measured by the release of serum cardiac enzymes. However, the etiology of this form of injury is not a result of acute IRI per se, but is mainly caused by acute ischemic injury (arising from distal branch occlusions and coronary embolization), which are complications that are more frequent following multivessel and complex PCI.217 In 2006, Iliodromitis et al218 were the first to investigate limb RIC in this clinical setting and found that in 41 patients RIC using bilateral upper arm cuff inflations/deflations actually exacerbated myocardial injury. In 2010, in a much larger study, Hoole et al219 found that this intervention reduced the magnitude of PCI-related myocardial injury. The reasons for this discrepancy are not clear, but a recent meta-analyses found benefit in patients undergoing elective coronary intervention.220
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Remote Ischemic Conditioning in ST-Segment Elevation Myocardial Infarction
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Compared to the above settings of CABG and PCI, the clinical setting of STEMI provides the most promising setting to investigate any cardioprotective therapy that targets myocardial IRI. To date, a number of proof-of-concept studies have reported cardioprotective effects with limb RIC in STEMI patients treated by primary angioplasty. This form of treatment is effective when given by paramedics in the ambulance,221 as well as on arrival at the hospital prior to primary angioplasty222,223 and at the onset of reperfusion at the time of primary angioplasty.224 Importantly, as with the setting of CABG mentioned earlier, outcome studies will inform us as to whether RIC can indeed find a place in cardiovascular medicine, and this is now being jointly investigated in the CONDI2 and ERIC-PPCI trials (ClinicalTrials.gov Identifier: NCT01857414). The aim of these studies is to demonstrate whether RIC can reduce the rates of cardiac death and hospitalization for heart failure at 12 months.
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Pharmacologic Cardioprotection
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Finding appropriate pharmacologic therapy to protect against IRI has been ongoing for many years. It was with the improved understanding of the pathophysiology of ischemia/reperfusion, as well as the advent of the mechanisms associated with preconditioning, that the identification of a number of molecular targets amenable to pharmacologic manipulation became apparent.132,133,136,139,140,141,218
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The history of pharmacologic cardioprotection has been hugely disappointing, with antioxidants, magnesium, calcium channel blockers, anti-inflammatory agents, erythropoietin, and atorvastatin all failing to reduce myocardial infarction size and/or improve clinical outcomes.225 A number of pharmacologic cardioprotective strategies, such as adenosine226 and glucose-insulin-potassium therapy,227 have had mixed results, with cardioprotective efficacy depending on study design. A more targeted pharmacologic approach has also failed to limit myocardial infarction size or improve clinical outcomes in recent clinical studies that investigated the cardioprotective effects of therapeutic hypothermia,228,229 mitochondria-targeted agents (eg, MTO-131),230 cyclosporine A (CsA), and modulation of nitric oxide signaling using nitrite or inhaled nitric oxide.231,232 Although CsA was shown to reduce myocardial infarction size in an initial proof-of-concept clinical study,233 it failed to improve clinical outcomes in a subsequent large multicenter clinical trial (the CIRCUS trial),234 illustrating the challenge of translating cardioprotection into clinical benefit. The reason for the failure of CsA to reduce myocardial infarction size and improve clinical outcomes in STEMI patients is not completely understood. A number of factors to consider include the inconclusive preclinical data, with some experimental studies failing to show a cardioprotective effect with CsA administered at reperfusion; the limited clinical data with only one positive clinical study with CsA in STEMI; the use of the CicloMulsion formulation of CsA; and the potential failure of CsA to reach its molecular target in time.235,236
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On a more optimistic note, there are a number of pharmacologic strategies that have shown promise. An interesting example of this is metoprolol. Early β-blocker therapy in reperfused STEMI patients is controversial and had largely been investigated in the pre-reperfusion era. However, recently, Ibanez and colleagues demonstrated that intravenous (IV) metoprolol administered prior to reperfusion in a porcine model reduced myocardial infarction size.237 They followed this by undertaking a clinical trial (METOCARD-CNIC trial) demonstrating that IV metoprolol administered in the ambulance prior to primary angioplasty reduced myocardial infarction size and improved clinical outcomes (as a secondary end point) in anterior STEMI patients presenting early (< 6 hours from symptom onset).18,125 More importantly, in the METOCARD-CNIC trial, not only did patients receiving pre-reperfusion IV metoprolol have CMR-evaluated smaller infarctions18,238 and better long-term LVEF,125 but also the incidence of left ventricular severe systolic dysfunction was significantly reduced.125 Recently, the results of the EARLY BAMI trial have been reported. This trial recruited 600 STEMI patients (any location) presenting within 12 hours from symptom onset. Patients were randomized to IV metoprolol (10 mg) or placebo.239 The primary end point was myocardial infarction size as assessed by CMR 1 month after infarction. The trial was neutral, and infarct size was not smaller in patients allocated to IV metoprolol. There were no signs of adverse effects in patients receiving IV metoprolol, and the incidence of ventricular fibrillation was significantly lower in metoprolol-treated patients. These data support the safety of this strategy in Killip I-II STEMI patients.
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There are important differences between the METOCARD-CNIC and EARLY BAMI trials. Dose and timing of IV metoprolol administration were different between trials. In contrast to the METOCARD-CNIC trial, in the EARLY BAMI trial, patients received only one 5-mg dose at recruitment, and per protocol, the second dose was given in the catheter lab immediately before PCI. In fact, the first dose of metoprolol did not have any effect on blood pressure or heart rate, suggesting an underdosing effect. In this regard, a recent subanalysis from the METOCARD-CNIC trial demonstrated that the longer the “onboard” metoprolol time at the time of reperfusion, the higher the infarct-reduction effect.240 In fact, patients receiving IV metoprolol close to reperfusion had a mild protective effect, whereas those with a long time between the metoprolol 15-mg bolus and reperfusion had the largest reduction in infarct size and greatest improvement in long-term LVEF. These differences in dose and timing of metoprolol administration might explain the different conclusions from both trials. Given the clear safety profile and the low cost of this therapy (< $2.00), it is worth continuing the clinical research and performing a definite large end-point–powered trial. In the near future, the MOVE ON! trial (Ibanez and Fuster, principal investigators) will be initiated, and more than 1200 anterior STEMI patients will be recruited and randomized to IV metoprolol (15 mg immediately after diagnosis is made in the out-of-hospital setting) or placebo. The primary end point will be the composite of cardiovascular death, heart failure, implantable cardioverter-defibrillator insertion, or severe left ventricular dysfunction.
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As we know, optimal medical management of acute coronary syndromes at the time of initial presentation consists of many facets that include analgesia, supportive therapies where required (eg, inotropes, mechanical intra-aortic balloon pump), and dual antiplatelet therapy consisting of both the cyclooxygenase inhibitor aspirin and an adenosine diphosphate P2Y12 receptor antagonist (clopidogrel, prasugrel, or ticagrelor). These latter antiplatelet interventions are orally loaded at the time of presentation in an attempt to reduce platelet aggregation and optimize postinterventional outcomes and coronary flow in the culprit vessel(s). Of great interest is the unanticipated significant mortality benefit of the P2Y12 inhibitor ticagrelor in the PLATO study.241 However, the benefits of this drug may not be fully explained by a pure antiplatelet effect. In this regard, ticagrelor has been shown to increase the levels of extracellular adenosine,242 a mediator known to exert a wide range of benefits, including vasodilation, inhibition of platelet aggregation, and leukocyte adherence to the vessel wall. In addition, it has recently been shown that cangrelor is significantly cardioprotective in mice,243 rats,244 rabbits,170 and primates.245 Interestingly, the protection conferred by cangrelor is dependent upon the presence of blood, with no evidence of protection ex vivo in crystalloid-perfused Langendorff heart.170,244 Downey’s group has shown that this protection is mediated through pathways typically recruited by ischemic conditioning, suggesting that P2Y12 inhibition, via a blood component, leads to conditioning-like protection.170,244 Therefore, IV P2Y12 inhibition may thus have the dual advantage of optimizing both platelet inhibition and offering cardioprotection. Consequently, although the protective potential of these agents in the clinical arena has yet to be fully realized, given the strength of preclinical data and plausible mechanism, there is clear potential for harnessing and optimizing P2Y12 inhibition at the time of reperfusion with the exciting prospect for further improving clinical outcomes.
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Other Promising Agents
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Another pharmacologic approach that has shown promise is that of exenatide, a synthetic version of exendin-4 (a peptide isolated from the saliva of the Gila lizard). Exenatide is an analogue of glucagon-like peptide-1 (GLP-1), a hormone that lowers blood glucose by stimulating insulin secretion.246 Interestingly, GLP-1 and its analogues, such as exenatide, have been reported in experimental animal studies to reduce myocardial infarction size through the activation of prosurvival intracellular signaling pathways when administered prior to reperfusion.247,248 Clinical studies have found that administering exenatide prior to primary angioplasty increased salvage index in STEMI patients,248,249,250,251 with most benefit observed in patients presenting with shorter ischemic times (< 132 minutes).250 Whether this effect of exenatide translates to improved clinical outcomes in reperfused STEMI patients is not known and remains to be determined in a large randomized clinical trial.
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Atrial natriuretic peptide given prior to myocardial reperfusion has also been shown to reduce myocardial infarction size in experimental animal studies. This is believed to occur via the activation of known prosurvival signaling pathways.252 Kitakaze et al253 translated this therapeutic approach in a large clinical study comprising 569 STEMI patients, in which administering carperitide (an atrial natriuretic peptide analogue) at the time of primary PCI was associated with a modest reduction in myocardial infarction size. Further studies are required to confirm these findings and investigate whether this therapeutic approach can improve clinical outcomes in reperfused STEMI patients.
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Combination Reperfusion Therapy: A Novel Therapeutic Strategy
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As detailed earlier, most attempts to reduce myocardial infarction size in STEMI patients have relied on using a single agent to target one single component of myocardial reperfusion injury. As detailed in Figure 38–2, myocardial IRI is the result of several mechanisms, and thus targeting on individual phenomenon will unlikely reduce infarct size. The possibility of targeting several mechanisms simultaneously (either with one agent targeting different layers or by several agents administered simultaneously) is attractive, although not widely undertaken. The use of combination reperfusion therapy is still in its infancy, but because of the complex pathophysiology associated with IRI, this could be considered an important option. Interestingly, the RISK and SAFE signaling pathways have been shown to interact in remote limb perconditioning in combination with local IPost.254 Alburquerque-Béjar et al255 recently combined RIC with glucose-insulin-potassium and exenatide in a porcine acute myocardial infarction model and demonstrated an additive benefit in terms of myocardial infarction size reduction. The Combination Therapy in Myocardial Infarction (COMBAT-MI) study (ClinicalTrials.gov identifier: NCT02404376) is set to investigate the potential benefits of using RIC with exenatide on myocardial infarction size reduction in STEMI patients treated by primary PCI. Although an initial small clinical study failed to show an additive cardioprotective effect with RIC and IPost administered in combination in reperfused STEMI patients,256 a recently published large study found increased myocardial salvage in patients given RIC and IPost in combination when compared with patients given IPost alone.257