Clinical perspectives on reperfusion injury in acute myocardial infarction Kevin R. Bainey, MD, MSc, and Paul W. Armstrong, MD Alberta, Canada
Prompt reperfusion therapy in acute myocardial infarction enhances clinical outcome. However, reperfusion itself may contribute to myocardial cell death. The current review outlines the multifocal mechanisms of reperfusion injury and focuses on understanding the potential role of each element and its contribution to the injury pattern inflicted upon the myocardium. We evaluate the spectrum of contemporary therapies that have been tested in an attempt to reduce myocardial injury. Finally, we explore promising innovative strategies targeting novel reperfusion injury pathways to protect ischemic myocardium during reperfusion. (Am Heart J 2014;0:1-9.)
Although prompt reperfusion therapy has been shown to reduce mortality, infarct size, and improve left ventricular function in ST-elevation myocardial infarction (STEMI), residual morbidity and mortality still exist. Despite the progress achieved through reperfusion therapy, it is also recognized that restoration of blood flow is associated with adverse events. This phenomenon, termed reperfusion injury, leads to lethal cell death and has been estimated to account for up to half of the ultimate infarct size. 1 Our aim is to provide insight into the concept of reperfusion injury and outline the various mechanisms contributing to the injury pattern inflicted upon the myocardium. We also review contemporary therapies and novel future strategies aimed to protect ischemic myocardium during reperfusion.
Historical perspective In 1960, Jennings et al 2 induced myocardial necrosis and reperfusion in the canine model and showed histologic features of “explosive” cell swelling along with contracture of myofibrils. Significant disruption of the sarcolemma was noted with an abundant appearance of intramitochondrial calcium phosphate particles. Similar findings were reported in 1977 when Bulkely and Hutchins 3 reported a “paradox of myocardial necrosis” in humans after successful revascularization with coro-
From the Mazankowski Alberta Heart Institute, Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada. Submitted September 25, 2013; accepted January 24, 2014. Reprint requests: Kevin R. Bainey MD, MSc, FRCPC, Mazankowski Alberta Heart Institute University of Alberta Hospital 2C2 Walter C Mackenzie Edmonton, Alberta, Canada T6G 2B7. E-mail: [email protected] 0002-8703/$ - see front matter © 2014, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.01.015
nary artery bypass grafting surgery and speculated that this was related to calcium overloading and subsequent myocardial cellular edema distal to the patent bypass grafts. In 1985, Braunwald and Kloner 4 characterized reperfusion as a “double-edged sword” recognizing the multifactorial mechanisms involved with reperfusion in myocardial infarction (MI).
No-reflow phenomenon Described by Kloner et al, 5 no reflow occurs when the release of vascular occlusion does not translate toward restoration of coronary blood flow. It refers to the impedance of microvascular blood flow encountered despite patency of the epicardial infarct-related artery. The clinical significance of suboptimal coronary blood flow is of particular importance given its association with poor inhospital major adverse cardiac events (MACE) and 1-year mortality. 6 The presence of Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 (normal epicardial flow) after reperfusion is a strong predictor of survival. 7 However, even with epicardial TIMI flow grade 3, suboptimal perfusion of the myocardium may occur (angiographic myocardial perfusion grade ≤2) resulting in reduced 30-day survival. 8 Complete STsegment resolution after reperfusion appears well aligned with overall myocardial perfusion and provides robust prognostic information regarding clinical outcomes. 9 As seen in Figure 1, the optimal clinical outcome and standard of care in STEMI is to achieve both epicardial patency (assessed by angiography) and myocardial perfusion (assessed for example by electrocardiogram). 10
Reperfusion injury During reperfusion, the inflammatory cascade facilitates white blood cells to release inflammatory mediators such as interleukins and activating complement leading
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Figure 1
Thirty-day clinical outcomes according to metrics of epicardial patency in STEMI patients undergoing primary percutaneous coronary intervention (n = 585). Modified from Bainey et al 10 with permission from the journal.
to myocardial injury. 11 Reperfusion is a prothrombotic environment in which platelets become activated resulting in “platelet plugging” of the microvasculature. 12 This distal occlusive phenomenon is further exacerbated by atheromatous debris disrupted during the course of mechanical intervention. Reintroduction of oxygen potentiates formation of reactive oxygen species and accumulation of intracellular calcium, which damages cellular proteins, organelles, and plasma membranes. 13 Activation of proapoptotic signaling cascades potentiates further myocyte injury. 14 Because of inner cell membrane instability, ventricular fibrillation can occur resulting in sudden death after reperfusion of the infarct-related artery. As seen in Figure 2, the molecular mechanisms of reperfusion injury appear to be multifactorial with various consequences to cellular function.
Modulators of reperfusion injury The mediators of lethal reperfusion injury have continued to elude clinicians despite ongoing research efforts to attenuate cardiac myocyte injury. Figure 3 outlines the various pharmacologic therapies tested in clinical trials of which the details are summarized below.
Glycoprotein IIb/IIIa inhibitors Upon reperfusion, distal embolization of platelet-rich thrombus occurs, which obstructs the microvasculature resulting in impaired myocardial perfusion and altered clinical outcomes. Glycoprotein (GP) IIb/IIIa inhibitors prevent the aggregation of platelets and formation of occlusive thrombus. Reduced emboli in the microvasculature inhibit the release of proinflammatory/vasoactive particles. When administered at presentation in STEMI patients undergoing percutaneous coronary intervention
(PCI), GP IIb/IIIa inhibitors enhance clinical outcome 15; however, their particular role in the treatment of reperfusion injury remains less defined.
Free radical antagonists Molecular enzymes become supercharged with reintroduction of oxygen during reperfusion generating potent free radicals from ischemic myocardium, which are known to compromise cell membrane structure leading to myocardial necrosis. A multicenter, randomized, placebo-controlled, randomized trial evaluating the efficacy of superoxide dismutase (a scavenger of oxygen-free radicals) in patients undergoing angioplasty for acute MI enrolled 120 patients and found no improvement in global left ventricular function when superoxide dismutase was given as an intravenous bolus followed by a 60-minute infusion before angioplasty (50.9% + 14.0% versus 50.1% ± 16.7%, P = not significant). 16 Allopurinol, a potent inhibitor of xanthine oxidase, was tested in a 38-patient, single-center, randomized, placebocontrolled trial with oral allopurinol (400 mg) versus placebo given before primary percutaneous transluminal coronary angioplasty in acute MI. Improvement in free radical inhibition and recovery of left ventricular function at 6 months was found with allopurinol (urinary 8-epi-prostaglandin F2 as a surrogate for free radical production 15% ± 8% versus 111% ± 15%, P b .01; left ventricular ejection fraction (LVEF) 57% ± 2% versus 49% ± 2%, P = .04). 17 This small single-centered trial requires confirmation in a larger more definitive study. Edaravone, another free radical scavenger, was evaluated in a single-center, randomized, placebo-controlled study involving 104 patients with an acute MI and undergoing primary PCI. Infarct size and reperfusion
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Figure 2
Pathophysiologic mechanisms contributing to lethal reperfusion injury after reperfusion of an occlusive coronary thrombus.
arrhythmias were significantly reduced with a 30 mg intravenous bolus of edaravone before reperfusion (peak creatine kinase [CK] 2,246 ± 221 versus 3,037 ± 290 IU/L; P = .035) (ventricular tachycardia or ventricular fibrillation in 1 patient versus 8 patients; P = .031). Long-term MACE was lower in the edaravone group as well (2.0% versus 15.7%; P = .045). Still, this trial was not powered for long-term clinical outcomes and thus deserves further investigation. 18
Inhibitors of intracellular calcium overload During myocardial reperfusion, abrupt surges of intracellular calcium occur due to altered calcium cycling and sarcolemmal damage, which induces hypercontracture of cardiac cells. As a result, cardiomyocyte death occurs from damage to cytoskeletal elements. Intracoronary verapamil acts directly on the sarcolemmal membrane altering calcium flux, which enhances intracellular calcium homeostasis and provides myocardial protection to injured cardiomyocytes. Complementary effects include vasodilation of the microvasculature. However, limited randomized studies have been performed to test the true effects of intracoronary verapamil. In a recent meta-analysis involving 7 small trials (539 patients), verapamil decreased the incidence of no reflow (relative risk (RR) 0.33; 95% CI 0.23-0.50) and improved TIMI myocardial perfusion grade (RR 0.43; 95% CI 0.290.64) in acute coronary syndrome patients. Moreover,
inhospital MACE was reduced with verapamil (RR 0.37; 95% CI 0.17-0.80). 19 However, the studies selected for this meta-analysis are of inadequate size and require harder clinical end points and longer follow-up before they can be considered definitive. A large-scale, prospective, randomized trial with longer follow-up is required to assess the true safety and efficacy of intracoronary verapamil in STEMI. Caldaret (5-methyl-2-[piperazine-1-yl] benzenesulfonic acid monohydrate inhibits intracellular calcium overload induced by ischemia and reperfusion. The multicenter, randomized CASTEMI study compared 2 different dose of caldaret (low dose 57.5 mg or higher dose 172.5 mg) or placebo infusion over 48 hours started before PCI in 387 STEMI patients. No effect was observed with low dose or higher dose of caldaret on single-photon emission computed tomography (SPECT) infarct size or ejection fraction at day 7 or day 30. 20
Inhibitors of inflammation—neutrophil injury After myocardial reperfusion, release of chemoattractants draw neutrophils to the infarct zone via celladhesion molecules. Neutrophils cause vascular plugging and release degradative enzymes with reactive oxygen species resulting in myocardial cell death. The HALT-MI study examined the effect of the Hu23F2G (LeukoArrest) antibody on myocardial infarct size measured with SPECT scan 5 to 8 days later in 425
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Figure 3
Modulators of reperfusion injury tested in clinical trials.
patients. No difference in myocardial infarct size was noted (16.2% versus 17.2% versus 16.6%; P = .796). 21 In the recombinant P-selectin GP ligand–immunoglobulin (P-selectin antagonist) as an adjunct to thrombolysis in acute MI, the PSALM randomized trial, recombinant Pselectin GP ligand–immunoglobulin was evaluated for efficacy in STEMI. This multicenter European study was stopped prematurely for a lack of efficacy in measuring myocardial tissue perfusion or recovery of function using positive emission tomography. 22 Complement activation in acute MI has been shown to be an important modulator of inflammation during reperfusion. In a small phase II study, pexelizumab, an anti-C5 complement antibody, showed a significant reduction in mortality in STEMI undergoing primary PCI. 23 As a result, the APEX-AMI phase III trial was performed, which enrolled 5,745 patients who presented with STEMI and underwent primary PCI. There was no difference in the primary end point of all-cause mortality to day 30 between pexelizumab (2 mg/kg bolus just before PCI followed by a 0.05 mg/kg-perhour infusion for 24 hours) and placebo treatment groups (4.1% versus 3.9%, P = .78). 24 Complement activation occurs early in STEMI, and perhaps, late administration of pexelizumab impeded cardiomyocyte protection. 25 Adenosine, a known inhibitor of neutrophil migration and a potent agent for adenosine triphosphate repletion, was tested in a randomized, double-blinded, placebocontrolled multicenter trial of adenosine as an adjunct to
reperfusion in the treatment of acute MI, the AMISTAD-II study. In the largest adenosine trial to date (n = 2118), there was no difference in the primary end point of congestive heart failure, rehospitalization for heart failure, or all-cause death at 6 months between placebo versus intravenous adenosine (17.9% versus 16.3% , P = .43). However, a reduction in myocardial infarct size with a higher dose of adenosine (70 μg/kg per minute) was noted with anterior STEMI. 26 Although promising, adenosine needs to be studied in an adequately powered clinical trial enrolling large territory infarcts to assess clinical benefit.
Inhibitors of free fatty acids After myocardial reperfusion, production of harmful free fatty acids occurs leading to myocardial uptake and necrosis. Glucose-insulin-potassium (GIK) therapy suppresses plasma free fatty acids and myocardial uptake in acute MI. The effect of GIK infusion on mortality in patients with acute MI was tested in the CREATE-ECLA international multicenter trial, which randomized 20,201 STEMI patients to a 24-hour GIK intravenous infusion versus usual care before reperfusion with either primary PCI or thrombolytic therapy. At 30 days, there was no difference in the primary composite of mortality, cardiac arrest, cardiogenic shock, and reinfarction (10.0% versus 9.7%, P = .45). 27 Our group has demonstrated higher baseline glucose levels that are associated with reduced ST-segment resolution and worse clinical outcome in
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Table. Summary of alternative ischemic and pharmacologic therapies targeting other reperfusion injury pathways Clinical trial Noninvasive ischemic conditioning Botker et al 33 Invasive ischemic conditioning Staat et al 35 Laskey 36 Thibault et al 37 Tarantini et al 38 Freixa et al 39 Supersaturated oxygen O’Neill et al 40 Stone et al 41 Cyclosporine Piot et al 42 Exenatide Lonborg et al 46 Bernink et al 47 Endovascular cooling Dixon et al 48 O’Neill 49
No. of patients
333 30 17 38 78 79 269 301 58
Outcomes
Improved myocardial salvage Improved infarct size and myocardial blush grade Greater ST-segment resolution and improved coronary flow Improvements in left ventricular function No benefit in infarct size No benefit in infarct size or left ventricular function No difference in infarct size, ST-segment resolution, or regional wall motion score Reduction in infarct size Reduction in infarct size with cyclosporine
172 23
Improved myocardial salvage and reduction in infarct size No difference in infarct size or left ventricular function
42 357
No difference in MACE or infarct size No difference in MACE or infarct size
STEMI. 28 Yet, modulation of baseline glucose levels with intensive insulin therapy has shown no clinical benefit. 29
Alternative methods to reduce reperfusion injury The limited success with prior studies of cardioprotective agents to treat reperfusion injury has engendered continuing exploration of additional therapies. The table provides a brief summary of key clinical studies using new techniques and pharmacology using novel physiologic pathways to provide myocardial protection.
Ischemic conditioning Release of endogenous protective factors against reperfusion injury can be triggered with mechanical vessel stimulation. This was first demonstrated by Murry et al, 30 where brief episodes of coronary occlusion before reperfusion resulted in a reduction in histologic myocardial infarct size. It was presumed the benefit was due to reduced adenosine triphosphate depletion and/or reduced catabolite accumulation in the distal myocardium before reperfusion. Noninvasive ischemic conditioning Development of this concept was extended noninvasively using mechanical compression of an external limb to induce episodes of ischemia. Termed remote ischemic conditioning, reductions in ischemic myocardial cell necrosis have been demonstrated. Hoole et al 31 tested this concept in the CRISP Stent randomized study by inducing upper limb ischemia with blood pressure cuff compression (3× 5-minute blood pressure cuff inflations to 200 mm Hg followed by 5 minutes of reperfusion). Limb ischemia induced before arrival to the cardiac
catheterization laboratory for PCI resulted in a decrease in postprocedural troponin elevation (0.06 versus 0.16; P = .04) and improved 6-month major adverse cardiac and cerebral event–free survival (4 versus 13 events; P = .018) in a stable population with symptomatic angina (242 patients). Follow-up results from the CRISP Stent trial found continued major adverse cardiac and cerebral event–free survival at 6 years. 32 Botker et al 33 evaluated this concept in patients with acute MI undergoing primary PCI with 4 cycles of 5-minute inflation and 5minute deflation of a blood pressure cuff to induce intermittent arm ischemia. This study attempted to enroll 333 patients, but 82 patients were excluded on arrival to hospital due to failure to meet inclusion criterion, 32 were lost to follow-up, and 72 did not complete follow-up for the myocardial salvage index using gated SPECT at 30 days (primary end point). Despite these limitations, improvements in myocardial salvage were demonstrated with remote ischemic preconditioning (median salvage index was 0.75 [interquartile range {IQR} 0.50-0.93] in the remote conditioning group versus 0.55 [IQR 0.350.88] in the control group; P = .033). These findings are provocative and are potentially aligned with the improved outcomes seen in STEMI patients who have preinfarction angina before STEMI presentation. 34 Albeit impressive, remote ischemic conditioning needs to be confirmed in a larger study focused on meaningful clinical end points.
Invasive ischemic conditioning The impact of ischemic conditioning has also been demonstrated with coronary invasive therapy using repeated balloon inflations in the infarct-related artery after reperfusion. Termed ischemic postconditioning, the angioplasty balloon is inflated 4 times for 1 minute
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with low pressure (4 to 6 atmospheres), each separated by 1 minute of reflow. In a small, 30-patient study, patients with MI were randomized to a postconditioning or control group. Ischemic postconditioning reduced infarct size by 36% (area under the curve for CK release 208,984 ± 26,576 versus 326,095 ± 8,779 arbitrary units; P b .05) and improved myocardial blush grade (2.44 ± 0.17 versus 1.95 ± 0.27; P b .05). 35 In a small, randomized pilot study (17 patients), greater ST-segment resolution and improved coronary flow were observed with repetitive balloon occlusions in STEMI. 36 Improvements in LVEF have also been noted out to 1 year in a small, randomized study of 38 patients (56 ± 8% versus 49 ± 13%; P = .04). 37 More recently, the POST-AMI trial evaluated the efficacy of 4 cycles of 1-minute inflation and 1-minute deflation of the angioplasty balloon after reperfusion with a direct stent technique in 78 patients with STEMI. Surprisingly, the investigators found a trend toward a larger infarct size with ischemic postconditioning as measured using cardiac magnetic resonance imaging assessed at 30 days after primary PCI (20 ± 12% versus 14 ± 10%, P = .054). 38 A similar study of 79 patients found no improvement in cardiac magnetic resonance measured infarct size or LVEF at 1 week or 6 months with ischemic postconditioning (1 week: 27.5% ± 17.2% versus 22.1% ± 10.2%, P = .11; 43.6% ± 13.1% versus 46.7% ± 8.6%; P = .22, respectively) (6 months: 21.8% ± 13.2% versus 18.7% ± 10.6%, P = .37; 47.5% ± 12.8% versus 50.3% ± 9.9%; P = .44, respectively). 39 Thus, true equipoise exists, and clinical end points remain to be studied.
Supersaturated oxygen Hyperoxemic reperfusion therapy in acute MI has been studied as a novel approach for reducing reperfusion injury. Delivery of supersaturated oxygen into the infarctrelated artery can reduce capillary endothelial swelling and improve nitric oxide function. However, in the 269-patient AMIHOT-I trial, no difference was seen in the primary end points of infarct size (11% versus 13%; P = .30), ST-segment resolution (P = .25), or regional wall motion score (−0.62 ± 0.53 versus −0.57 ± 0.48; P = .24) between the supersaturated oxygen and control group. 40 Although the primary end point was neutral, a post hoc subgroup analysis of the anterior infarcts found a statistical reduction in infarct size in favor of supersaturated oxygen (9% versus 23%; P = .04). 40 As a result, AMIHOT II randomized 301 patients with large anterior infarcts reperfused within 6 hours to catheterization-delivered supersaturated oxygen (PaO2 700-1,000 mm Hg) for 90 minutes or standard treatment after primary PCI. A greater reduction in infarct size (primary end point) was noted with supersaturated oxygen in the 281 patients with infarct assessment as measured by technicium Tc 99m sestamibi SPECT performed at 14 days (20.0% versus 26.5%; adjusted P = .03). Still, there was no difference in 30-day MACE (5.4%
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versus 3.8%; P = .77) with a numerically higher number of deaths with supersaturated oxygen (4 versus 0 patients; P = .58). 41 It is clear that this trial is underpowered to detect a difference in clinical outcomes and requires a larger trial to assess true safety and efficacy of this investigative therapy.
Mitochondria-targeted therapy During the reperfusion phase accompanied by calcium overload, mitochondrial permeability transition pore proteins open, thereby allowing large molecules to enter the mitochondrial matrix with resultant membrane instability and osmotically mediated apoptosis. Cyclosporine is a potent inhibitor of mitochondrial permeability transition pore opening, which attenuates mitochondrial overload and subsequent cell death. Several laboratory and physiologic experimental studies report improvement in reperfusion injury with cyclosporine. More recently, the effects of cyclosporine was tested in a study of 58 patients with acute STEMI undergoing primary PCI and found a 40% relative reduction in myocardial infarct size as measured by area under the curve for CK release (median 138,053 [IQR 114,008-283,461] arbitrary units versus 247,930 [IQR 145,639- 404,349] arbitrary units; P = .04). In a subset of 27 patients who underwent delayed enhancement cardiac magnetic resonance imaging, a 20% relative reduction in the mass of the area of hyperenhancement was seen (median of 37 [IQR 21-51 g] versus 46 [IQR 2065 g]; P = .04). No adverse effects were noted with an intravenous 2.5 mg/kg bolus dose of cyclosporine. 42 Although the treatment effect is impressive, this was a small pilot trial underpowered to detect clinical outcomes. Both the CIRCUS and CYCLE phase III clinical trials are currently underway designed to address the utility of cyclosporine in STEMI undergoing reperfusion therapy on clinical outcomes. 43,44 Bendavia, an intravenously administered mitochondrialtargeting peptide, is currently being tested in EMBRACE STEMI. Bendavia localizes to the mitochondrial inner membrane and reduces reactive oxygen species through modulation of the electron transport chain during oxidative stress after reperfusion. The primary end point is infarct size measured by the area under the CKMB enzyme curve. 45 Glucagon-like peptide 1 receptor agonists Glucagon-like peptide 1 (GLP-1) is an incretin hormone, which regulates serum glucose and is used in the treatment of diabetes. Glucagon-like peptide 1 receptors have also been found in the myocardium, and expression with GLP-1 or its analogues appear to attenuate reperfusion-induced apoptotic cell death. Exenatide is a synthetic analog of GLP-1 available for commercial use and has been tested in a proof-of-concept trial administered intravenously 15 minutes before reperfusion and
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continued 6 hours after restoration of coronary blood flow in STEMI undergoing primary PCI. In this 172-patient study, myocardial infarct size was reduced with exenatide (30% ± 0.15% versus 39% ± 0.15%; P = .003), and myocardial salvage index (measured by cardiac magnetic resonance) was greater with exenatide versus placebo (0.71 ± 0.13 versus 0.62 ± 0.16; P = .003). 46 Recently, the EXAMI trial studied 23 patients and found no difference in left ventricular function or infarct size but a trend toward a lower infarct size to area at risk ratio in STEMI patients treated with exenatide (intravenous bolus over 30 minutes followed by an infusion for 72 hours) (0.35 ± 0.14 versus. 0.47 ± 017; P = .09). 47 It is apparent that larger studies are required to evaluate myocardial salvage and clinical outcome.
Endovascular cooling Systemic hypothermia is known to reduce myocardial necrosis by decreasing myocardial metabolism. This was tested in a small multicenter study of 42 patients with acute MI randomized to either endovascular cooling (target core temperature 33°C) for 3 hours after reperfusion or standard of care. No difference in MACE at 30 days (primary end point) was seen (0% versus 10%; P N .05). As well, no difference in myocardial infarct size measured with SPECT imaging at 30 days was noted (2% versus 8%, P N .05). 48 The COOL MI was a larger trial including 357 patients and found no difference in the primary end point of myocardial infarct size measured with SPECT imaging at 30 days (14.1% versus 13.8%; P = .45). As well, there was no difference in MACE (6.2% versus 3.9%; P = .45) or mortality (3.4% versus 2.2%; P = .71). However, in patients with an anterior MI cooled to b35°C, a borderline reduction in myocardial infarct size was demonstrated (9.3% versus 18.2%; P = .05). 49 This validity of this result remains unclear given the limited number of patients and awaits publication. These investigators proceeded to evaluate the subgroup of patients with anterior MI in the COOL MI II trial. This was stopped prematurely, however, due to loss of funding after 255 patients with anterior MI were randomized in the study and as yet is unpublished. 50 A new trial named CHILL-MI is designed to evaluate the utility of administering 1 to 2 L of cold saline using a central venous catheterization before PCI for STEMI. The primary end point is myocardial infarct size as measured by cardiac magnetic resonance imaging at 4 ± 2 days after acute MI. The study has now completed enrollment of 120 patients, and results are expected this year. 51
Temporal relationship between reperfusion and cardioprotection The duration of symptoms before presentation is a key modulator of outcomes with reperfusion. As seen in Figure 4, a temporal relationship also exists with
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Figure 4
Hypothetical temporal relationship between reperfusion and cardioprotection in STEMI.
cardioprotection: reperfusion initiated early, during symptom presentation of STEMI, can minimize or even abort myocardial necrosis and reduce the likelihood of reperfusion injury. 52 However, between 2 and 6 hours, an abrupt decline of salvaged myocardium occurs, and after 12 hours, recovery of viable myocardium is minimal with reperfusion. 53 Accordingly, cardioprotection may be of limited benefit during the early phase of STEMI given the short ischemic time limiting the emergence of endogenous cytotoxins and other injurious factors. However, when symptom onset to reperfusion is delayed, reperfusion injury is more likely to occur. Thus, an opportunity for modulation by cytoprotective therapy emerges in the context of still viable myocardium. Hence, future clinical trials investigating novel cardioprotective agents should account for specific symptom duration intervals and other metrics of total ischemic time to capture a potential “sweet spot” of cardioprotection.
Summary Prompt recanalization of the infarct-related artery in STEMI is paramount to improve clinical outcome, but despite enormous advances in trying to accomplish this objective, it is rarely achieved. Moreover, despite the conventional focus on establishing epicardial coronary patency, this metric does not necessarily align with myocardial perfusion. Known as the Achilles heel of reperfusion, research efforts have increasingly focused on strategies to reduce myocardial injury. With the discovery of new mechanisms, the search for therapies to overcome reperfusion injury has been reinvigorated. Cyclosporine shows potential as a cardioprotective pharmacologic agent with 2 major phase III trials underway. Remote ischemic conditioning holds promise as a safe and efficacious therapy for myocardial protection but needs to be confirmed in a large, well-designed
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clinical trial powered for clinical outcomes. Further studies must take into consideration the crucial temporal relationship between reperfusion and cardioprotection to enhance the efficacy of tested therapy. Given rapid advances in the field, we should remain optimistic about the emergence of definitive therapies to treat reperfusion injury.
Disclosures No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this review, the drafting and editing of the manuscript, and its final contents.
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myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005;26:650-61. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74:1124-36. Hoole SP, Heck PM, Sharples L, et al. Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) study: a prospective, randomized control trial. Circulation 2009;119:820-7. Davies WR, Brown AJ, Watson W, et al. Remote ischemic preconditioning improves outcome at 6 years after elective percutaneous coronary intervention: the CRISP Stent trial long-term follow-up. Circ Cardiovasc Interv 2013;6:246-51. Botker HE, Kharbanda R, Schmidt MR, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 2010;375:727-34. Kloner RA, Shook T, Przyklenk K, et al. Previous angina alters inhospital outcome in TIMI 4. A clinical correlate to preconditioning? Circulation 1995;91:37-45. Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation 2005;112:2143-8. Laskey WK. Brief repetitive balloon occlusions enhance reperfusion during percutaneous coronary intervention for acute myocardial infarction: a pilot study. Catheter Cardiovasc Interv 2005;65:361-7. Thibault H, Piot C, Staat P, et al. Long-term benefit of postconditioning. Circulation 2008;117:1037-44. Tarantini G, Favaretto E, Marra MP, et al. Postconditioning during coronary angioplasty in acute myocardial infarction: the POST-AMI trial. Int J Cardiol 2012;162:33-8. Freixa X, Bellera N, Ortiz-Perez JT, et al. Ischaemic postconditioning revisited: lack of effects on infarct size following primary percutaneous coronary intervention. Eur Heart J 2012;33:103-12. O'Neill WW, Martin JL, Dixon SR, et al. Acute Myocardial Infarction with Hyperoxemic Therapy (AMIHOT): a prospective, randomized trial of intracoronary hyperoxemic reperfusion after percutaneous coronary intervention. J Am Coll Cardiol 2007;50:397-405. Stone GW, Martin JL, de Boer MJ, et al. Effect of supersaturated oxygen delivery on infarct size after percutaneous coronary intervention in acute myocardial infarction. Circ Cardiovasc Interv 2009;2:366-75. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359: 473-81.
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43. Ovize M. Does Cyclosporine ImpRove Clinical oUtcome in ST Elevation Myocardial Infarction Patients. , ClinicalTrials.gov identifier: NCT01502774. 44. Latini R. CYCLosporinE A in Reperfused Acute Myocardial Infarction Prospective, Controlled, Randomized, Multicentre Trial to Examine Whether a Single i.v. Bolus of Cyclosporine A Before PCI Can Reduce Myocardial Reperfusion Injury in Patients With STEMI. , ClinicalTrials. gov identifier: NCT01650662. 45. Chakrabarti AK, Feeney K, Abueg C, et al. Rationale and design of the EMBRACE STEMI study: a phase 2a, randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability and efficacy of intravenous Bendavia on reperfusion injury in patients treated with standard therapy including primary percutaneous coronary intervention and stenting for ST-segment elevation myocardial infarction. Am Heart J 2013;165:509-14. 46. Lonborg J, Vejlstrup N, Kelbaek H, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 2012;33:1491-9. 47. Bernink FJ, Timmers L, Diamant M, et al. Effect of additional treatment with EXenatide in patients with an Acute Myocardial Infarction: the EXAMI study. Int J Cardiol 2013;167:289-90. 48. Dixon SR, Whitbourn RJ, Dae MW, et al. Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. J Am Coll Cardiol 2002;40:1928-34. 49. O'Neill WW. A randomized trial of mild hypothermia during PCI treatment of ST elevation MI. Presented at Transcatheter Cardiovascular Therapeutics; 2003. 50. Carrozza J.P. COOL MI II: Cooling as an adjunctive therapy to percutaneous intervention in patients with acute myocardial infarction. , ClinicalTrials.gov: NCT00248196. 51. Erlinge D. Efficacy of Endovascular Catheter Cooling Combined With Cold Saline for the Treatment of Acute Myocardial Infarction (CHILLMI). , ClinicalTrials.gov Identifier: NCT01379261. 52. Taher T, Fu Y, Wagner GS, et al. Aborted myocardial infarction in patients with ST-segment elevation: insights from the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen-3 Trial Electrocardiographic Substudy. J Am Coll Cardiol 2004;44:38-43. 53. Francone M, Bucciarelli-Ducci C, Carbone I, et al. Impact of primary coronary angioplasty delay on myocardial salvage, infarct size, and microvascular damage in patients with ST-segment elevation myocardial infarction: insight from cardiovascular magnetic resonance. J Am Coll Cardiol 2009;54:2145-53.
Prompt reperfusion therapy in acute myocardial infarction enhances clinical outcome. However, reperfusion itself may contribute to myocardial cell death. The current review outlines the multifocal mechanisms of reperfusion injury and focuses on understanding the potential role of each element and its contribution to the injury pattern inflicted upon the myocardium. We evaluate the spectrum of contemporary therapies that have been tested in an attempt to reduce myocardial injury. Finally, we explore promising innovative strategies targeting novel reperfusion injury pathways to protect ischemic myocardium during reperfusion. (Am Heart J 2014;0:1-9.)
Although prompt reperfusion therapy has been shown to reduce mortality, infarct size, and improve left ventricular function in ST-elevation myocardial infarction (STEMI), residual morbidity and mortality still exist. Despite the progress achieved through reperfusion therapy, it is also recognized that restoration of blood flow is associated with adverse events. This phenomenon, termed reperfusion injury, leads to lethal cell death and has been estimated to account for up to half of the ultimate infarct size. 1 Our aim is to provide insight into the concept of reperfusion injury and outline the various mechanisms contributing to the injury pattern inflicted upon the myocardium. We also review contemporary therapies and novel future strategies aimed to protect ischemic myocardium during reperfusion.
Historical perspective In 1960, Jennings et al 2 induced myocardial necrosis and reperfusion in the canine model and showed histologic features of “explosive” cell swelling along with contracture of myofibrils. Significant disruption of the sarcolemma was noted with an abundant appearance of intramitochondrial calcium phosphate particles. Similar findings were reported in 1977 when Bulkely and Hutchins 3 reported a “paradox of myocardial necrosis” in humans after successful revascularization with coro-
From the Mazankowski Alberta Heart Institute, Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada. Submitted September 25, 2013; accepted January 24, 2014. Reprint requests: Kevin R. Bainey MD, MSc, FRCPC, Mazankowski Alberta Heart Institute University of Alberta Hospital 2C2 Walter C Mackenzie Edmonton, Alberta, Canada T6G 2B7. E-mail: [email protected] 0002-8703/$ - see front matter © 2014, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.01.015
nary artery bypass grafting surgery and speculated that this was related to calcium overloading and subsequent myocardial cellular edema distal to the patent bypass grafts. In 1985, Braunwald and Kloner 4 characterized reperfusion as a “double-edged sword” recognizing the multifactorial mechanisms involved with reperfusion in myocardial infarction (MI).
No-reflow phenomenon Described by Kloner et al, 5 no reflow occurs when the release of vascular occlusion does not translate toward restoration of coronary blood flow. It refers to the impedance of microvascular blood flow encountered despite patency of the epicardial infarct-related artery. The clinical significance of suboptimal coronary blood flow is of particular importance given its association with poor inhospital major adverse cardiac events (MACE) and 1-year mortality. 6 The presence of Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 (normal epicardial flow) after reperfusion is a strong predictor of survival. 7 However, even with epicardial TIMI flow grade 3, suboptimal perfusion of the myocardium may occur (angiographic myocardial perfusion grade ≤2) resulting in reduced 30-day survival. 8 Complete STsegment resolution after reperfusion appears well aligned with overall myocardial perfusion and provides robust prognostic information regarding clinical outcomes. 9 As seen in Figure 1, the optimal clinical outcome and standard of care in STEMI is to achieve both epicardial patency (assessed by angiography) and myocardial perfusion (assessed for example by electrocardiogram). 10
Reperfusion injury During reperfusion, the inflammatory cascade facilitates white blood cells to release inflammatory mediators such as interleukins and activating complement leading
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Figure 1
Thirty-day clinical outcomes according to metrics of epicardial patency in STEMI patients undergoing primary percutaneous coronary intervention (n = 585). Modified from Bainey et al 10 with permission from the journal.
to myocardial injury. 11 Reperfusion is a prothrombotic environment in which platelets become activated resulting in “platelet plugging” of the microvasculature. 12 This distal occlusive phenomenon is further exacerbated by atheromatous debris disrupted during the course of mechanical intervention. Reintroduction of oxygen potentiates formation of reactive oxygen species and accumulation of intracellular calcium, which damages cellular proteins, organelles, and plasma membranes. 13 Activation of proapoptotic signaling cascades potentiates further myocyte injury. 14 Because of inner cell membrane instability, ventricular fibrillation can occur resulting in sudden death after reperfusion of the infarct-related artery. As seen in Figure 2, the molecular mechanisms of reperfusion injury appear to be multifactorial with various consequences to cellular function.
Modulators of reperfusion injury The mediators of lethal reperfusion injury have continued to elude clinicians despite ongoing research efforts to attenuate cardiac myocyte injury. Figure 3 outlines the various pharmacologic therapies tested in clinical trials of which the details are summarized below.
Glycoprotein IIb/IIIa inhibitors Upon reperfusion, distal embolization of platelet-rich thrombus occurs, which obstructs the microvasculature resulting in impaired myocardial perfusion and altered clinical outcomes. Glycoprotein (GP) IIb/IIIa inhibitors prevent the aggregation of platelets and formation of occlusive thrombus. Reduced emboli in the microvasculature inhibit the release of proinflammatory/vasoactive particles. When administered at presentation in STEMI patients undergoing percutaneous coronary intervention
(PCI), GP IIb/IIIa inhibitors enhance clinical outcome 15; however, their particular role in the treatment of reperfusion injury remains less defined.
Free radical antagonists Molecular enzymes become supercharged with reintroduction of oxygen during reperfusion generating potent free radicals from ischemic myocardium, which are known to compromise cell membrane structure leading to myocardial necrosis. A multicenter, randomized, placebo-controlled, randomized trial evaluating the efficacy of superoxide dismutase (a scavenger of oxygen-free radicals) in patients undergoing angioplasty for acute MI enrolled 120 patients and found no improvement in global left ventricular function when superoxide dismutase was given as an intravenous bolus followed by a 60-minute infusion before angioplasty (50.9% + 14.0% versus 50.1% ± 16.7%, P = not significant). 16 Allopurinol, a potent inhibitor of xanthine oxidase, was tested in a 38-patient, single-center, randomized, placebocontrolled trial with oral allopurinol (400 mg) versus placebo given before primary percutaneous transluminal coronary angioplasty in acute MI. Improvement in free radical inhibition and recovery of left ventricular function at 6 months was found with allopurinol (urinary 8-epi-prostaglandin F2 as a surrogate for free radical production 15% ± 8% versus 111% ± 15%, P b .01; left ventricular ejection fraction (LVEF) 57% ± 2% versus 49% ± 2%, P = .04). 17 This small single-centered trial requires confirmation in a larger more definitive study. Edaravone, another free radical scavenger, was evaluated in a single-center, randomized, placebo-controlled study involving 104 patients with an acute MI and undergoing primary PCI. Infarct size and reperfusion
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Figure 2
Pathophysiologic mechanisms contributing to lethal reperfusion injury after reperfusion of an occlusive coronary thrombus.
arrhythmias were significantly reduced with a 30 mg intravenous bolus of edaravone before reperfusion (peak creatine kinase [CK] 2,246 ± 221 versus 3,037 ± 290 IU/L; P = .035) (ventricular tachycardia or ventricular fibrillation in 1 patient versus 8 patients; P = .031). Long-term MACE was lower in the edaravone group as well (2.0% versus 15.7%; P = .045). Still, this trial was not powered for long-term clinical outcomes and thus deserves further investigation. 18
Inhibitors of intracellular calcium overload During myocardial reperfusion, abrupt surges of intracellular calcium occur due to altered calcium cycling and sarcolemmal damage, which induces hypercontracture of cardiac cells. As a result, cardiomyocyte death occurs from damage to cytoskeletal elements. Intracoronary verapamil acts directly on the sarcolemmal membrane altering calcium flux, which enhances intracellular calcium homeostasis and provides myocardial protection to injured cardiomyocytes. Complementary effects include vasodilation of the microvasculature. However, limited randomized studies have been performed to test the true effects of intracoronary verapamil. In a recent meta-analysis involving 7 small trials (539 patients), verapamil decreased the incidence of no reflow (relative risk (RR) 0.33; 95% CI 0.23-0.50) and improved TIMI myocardial perfusion grade (RR 0.43; 95% CI 0.290.64) in acute coronary syndrome patients. Moreover,
inhospital MACE was reduced with verapamil (RR 0.37; 95% CI 0.17-0.80). 19 However, the studies selected for this meta-analysis are of inadequate size and require harder clinical end points and longer follow-up before they can be considered definitive. A large-scale, prospective, randomized trial with longer follow-up is required to assess the true safety and efficacy of intracoronary verapamil in STEMI. Caldaret (5-methyl-2-[piperazine-1-yl] benzenesulfonic acid monohydrate inhibits intracellular calcium overload induced by ischemia and reperfusion. The multicenter, randomized CASTEMI study compared 2 different dose of caldaret (low dose 57.5 mg or higher dose 172.5 mg) or placebo infusion over 48 hours started before PCI in 387 STEMI patients. No effect was observed with low dose or higher dose of caldaret on single-photon emission computed tomography (SPECT) infarct size or ejection fraction at day 7 or day 30. 20
Inhibitors of inflammation—neutrophil injury After myocardial reperfusion, release of chemoattractants draw neutrophils to the infarct zone via celladhesion molecules. Neutrophils cause vascular plugging and release degradative enzymes with reactive oxygen species resulting in myocardial cell death. The HALT-MI study examined the effect of the Hu23F2G (LeukoArrest) antibody on myocardial infarct size measured with SPECT scan 5 to 8 days later in 425
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Figure 3
Modulators of reperfusion injury tested in clinical trials.
patients. No difference in myocardial infarct size was noted (16.2% versus 17.2% versus 16.6%; P = .796). 21 In the recombinant P-selectin GP ligand–immunoglobulin (P-selectin antagonist) as an adjunct to thrombolysis in acute MI, the PSALM randomized trial, recombinant Pselectin GP ligand–immunoglobulin was evaluated for efficacy in STEMI. This multicenter European study was stopped prematurely for a lack of efficacy in measuring myocardial tissue perfusion or recovery of function using positive emission tomography. 22 Complement activation in acute MI has been shown to be an important modulator of inflammation during reperfusion. In a small phase II study, pexelizumab, an anti-C5 complement antibody, showed a significant reduction in mortality in STEMI undergoing primary PCI. 23 As a result, the APEX-AMI phase III trial was performed, which enrolled 5,745 patients who presented with STEMI and underwent primary PCI. There was no difference in the primary end point of all-cause mortality to day 30 between pexelizumab (2 mg/kg bolus just before PCI followed by a 0.05 mg/kg-perhour infusion for 24 hours) and placebo treatment groups (4.1% versus 3.9%, P = .78). 24 Complement activation occurs early in STEMI, and perhaps, late administration of pexelizumab impeded cardiomyocyte protection. 25 Adenosine, a known inhibitor of neutrophil migration and a potent agent for adenosine triphosphate repletion, was tested in a randomized, double-blinded, placebocontrolled multicenter trial of adenosine as an adjunct to
reperfusion in the treatment of acute MI, the AMISTAD-II study. In the largest adenosine trial to date (n = 2118), there was no difference in the primary end point of congestive heart failure, rehospitalization for heart failure, or all-cause death at 6 months between placebo versus intravenous adenosine (17.9% versus 16.3% , P = .43). However, a reduction in myocardial infarct size with a higher dose of adenosine (70 μg/kg per minute) was noted with anterior STEMI. 26 Although promising, adenosine needs to be studied in an adequately powered clinical trial enrolling large territory infarcts to assess clinical benefit.
Inhibitors of free fatty acids After myocardial reperfusion, production of harmful free fatty acids occurs leading to myocardial uptake and necrosis. Glucose-insulin-potassium (GIK) therapy suppresses plasma free fatty acids and myocardial uptake in acute MI. The effect of GIK infusion on mortality in patients with acute MI was tested in the CREATE-ECLA international multicenter trial, which randomized 20,201 STEMI patients to a 24-hour GIK intravenous infusion versus usual care before reperfusion with either primary PCI or thrombolytic therapy. At 30 days, there was no difference in the primary composite of mortality, cardiac arrest, cardiogenic shock, and reinfarction (10.0% versus 9.7%, P = .45). 27 Our group has demonstrated higher baseline glucose levels that are associated with reduced ST-segment resolution and worse clinical outcome in
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Table. Summary of alternative ischemic and pharmacologic therapies targeting other reperfusion injury pathways Clinical trial Noninvasive ischemic conditioning Botker et al 33 Invasive ischemic conditioning Staat et al 35 Laskey 36 Thibault et al 37 Tarantini et al 38 Freixa et al 39 Supersaturated oxygen O’Neill et al 40 Stone et al 41 Cyclosporine Piot et al 42 Exenatide Lonborg et al 46 Bernink et al 47 Endovascular cooling Dixon et al 48 O’Neill 49
No. of patients
333 30 17 38 78 79 269 301 58
Outcomes
Improved myocardial salvage Improved infarct size and myocardial blush grade Greater ST-segment resolution and improved coronary flow Improvements in left ventricular function No benefit in infarct size No benefit in infarct size or left ventricular function No difference in infarct size, ST-segment resolution, or regional wall motion score Reduction in infarct size Reduction in infarct size with cyclosporine
172 23
Improved myocardial salvage and reduction in infarct size No difference in infarct size or left ventricular function
42 357
No difference in MACE or infarct size No difference in MACE or infarct size
STEMI. 28 Yet, modulation of baseline glucose levels with intensive insulin therapy has shown no clinical benefit. 29
Alternative methods to reduce reperfusion injury The limited success with prior studies of cardioprotective agents to treat reperfusion injury has engendered continuing exploration of additional therapies. The table provides a brief summary of key clinical studies using new techniques and pharmacology using novel physiologic pathways to provide myocardial protection.
Ischemic conditioning Release of endogenous protective factors against reperfusion injury can be triggered with mechanical vessel stimulation. This was first demonstrated by Murry et al, 30 where brief episodes of coronary occlusion before reperfusion resulted in a reduction in histologic myocardial infarct size. It was presumed the benefit was due to reduced adenosine triphosphate depletion and/or reduced catabolite accumulation in the distal myocardium before reperfusion. Noninvasive ischemic conditioning Development of this concept was extended noninvasively using mechanical compression of an external limb to induce episodes of ischemia. Termed remote ischemic conditioning, reductions in ischemic myocardial cell necrosis have been demonstrated. Hoole et al 31 tested this concept in the CRISP Stent randomized study by inducing upper limb ischemia with blood pressure cuff compression (3× 5-minute blood pressure cuff inflations to 200 mm Hg followed by 5 minutes of reperfusion). Limb ischemia induced before arrival to the cardiac
catheterization laboratory for PCI resulted in a decrease in postprocedural troponin elevation (0.06 versus 0.16; P = .04) and improved 6-month major adverse cardiac and cerebral event–free survival (4 versus 13 events; P = .018) in a stable population with symptomatic angina (242 patients). Follow-up results from the CRISP Stent trial found continued major adverse cardiac and cerebral event–free survival at 6 years. 32 Botker et al 33 evaluated this concept in patients with acute MI undergoing primary PCI with 4 cycles of 5-minute inflation and 5minute deflation of a blood pressure cuff to induce intermittent arm ischemia. This study attempted to enroll 333 patients, but 82 patients were excluded on arrival to hospital due to failure to meet inclusion criterion, 32 were lost to follow-up, and 72 did not complete follow-up for the myocardial salvage index using gated SPECT at 30 days (primary end point). Despite these limitations, improvements in myocardial salvage were demonstrated with remote ischemic preconditioning (median salvage index was 0.75 [interquartile range {IQR} 0.50-0.93] in the remote conditioning group versus 0.55 [IQR 0.350.88] in the control group; P = .033). These findings are provocative and are potentially aligned with the improved outcomes seen in STEMI patients who have preinfarction angina before STEMI presentation. 34 Albeit impressive, remote ischemic conditioning needs to be confirmed in a larger study focused on meaningful clinical end points.
Invasive ischemic conditioning The impact of ischemic conditioning has also been demonstrated with coronary invasive therapy using repeated balloon inflations in the infarct-related artery after reperfusion. Termed ischemic postconditioning, the angioplasty balloon is inflated 4 times for 1 minute
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with low pressure (4 to 6 atmospheres), each separated by 1 minute of reflow. In a small, 30-patient study, patients with MI were randomized to a postconditioning or control group. Ischemic postconditioning reduced infarct size by 36% (area under the curve for CK release 208,984 ± 26,576 versus 326,095 ± 8,779 arbitrary units; P b .05) and improved myocardial blush grade (2.44 ± 0.17 versus 1.95 ± 0.27; P b .05). 35 In a small, randomized pilot study (17 patients), greater ST-segment resolution and improved coronary flow were observed with repetitive balloon occlusions in STEMI. 36 Improvements in LVEF have also been noted out to 1 year in a small, randomized study of 38 patients (56 ± 8% versus 49 ± 13%; P = .04). 37 More recently, the POST-AMI trial evaluated the efficacy of 4 cycles of 1-minute inflation and 1-minute deflation of the angioplasty balloon after reperfusion with a direct stent technique in 78 patients with STEMI. Surprisingly, the investigators found a trend toward a larger infarct size with ischemic postconditioning as measured using cardiac magnetic resonance imaging assessed at 30 days after primary PCI (20 ± 12% versus 14 ± 10%, P = .054). 38 A similar study of 79 patients found no improvement in cardiac magnetic resonance measured infarct size or LVEF at 1 week or 6 months with ischemic postconditioning (1 week: 27.5% ± 17.2% versus 22.1% ± 10.2%, P = .11; 43.6% ± 13.1% versus 46.7% ± 8.6%; P = .22, respectively) (6 months: 21.8% ± 13.2% versus 18.7% ± 10.6%, P = .37; 47.5% ± 12.8% versus 50.3% ± 9.9%; P = .44, respectively). 39 Thus, true equipoise exists, and clinical end points remain to be studied.
Supersaturated oxygen Hyperoxemic reperfusion therapy in acute MI has been studied as a novel approach for reducing reperfusion injury. Delivery of supersaturated oxygen into the infarctrelated artery can reduce capillary endothelial swelling and improve nitric oxide function. However, in the 269-patient AMIHOT-I trial, no difference was seen in the primary end points of infarct size (11% versus 13%; P = .30), ST-segment resolution (P = .25), or regional wall motion score (−0.62 ± 0.53 versus −0.57 ± 0.48; P = .24) between the supersaturated oxygen and control group. 40 Although the primary end point was neutral, a post hoc subgroup analysis of the anterior infarcts found a statistical reduction in infarct size in favor of supersaturated oxygen (9% versus 23%; P = .04). 40 As a result, AMIHOT II randomized 301 patients with large anterior infarcts reperfused within 6 hours to catheterization-delivered supersaturated oxygen (PaO2 700-1,000 mm Hg) for 90 minutes or standard treatment after primary PCI. A greater reduction in infarct size (primary end point) was noted with supersaturated oxygen in the 281 patients with infarct assessment as measured by technicium Tc 99m sestamibi SPECT performed at 14 days (20.0% versus 26.5%; adjusted P = .03). Still, there was no difference in 30-day MACE (5.4%
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versus 3.8%; P = .77) with a numerically higher number of deaths with supersaturated oxygen (4 versus 0 patients; P = .58). 41 It is clear that this trial is underpowered to detect a difference in clinical outcomes and requires a larger trial to assess true safety and efficacy of this investigative therapy.
Mitochondria-targeted therapy During the reperfusion phase accompanied by calcium overload, mitochondrial permeability transition pore proteins open, thereby allowing large molecules to enter the mitochondrial matrix with resultant membrane instability and osmotically mediated apoptosis. Cyclosporine is a potent inhibitor of mitochondrial permeability transition pore opening, which attenuates mitochondrial overload and subsequent cell death. Several laboratory and physiologic experimental studies report improvement in reperfusion injury with cyclosporine. More recently, the effects of cyclosporine was tested in a study of 58 patients with acute STEMI undergoing primary PCI and found a 40% relative reduction in myocardial infarct size as measured by area under the curve for CK release (median 138,053 [IQR 114,008-283,461] arbitrary units versus 247,930 [IQR 145,639- 404,349] arbitrary units; P = .04). In a subset of 27 patients who underwent delayed enhancement cardiac magnetic resonance imaging, a 20% relative reduction in the mass of the area of hyperenhancement was seen (median of 37 [IQR 21-51 g] versus 46 [IQR 2065 g]; P = .04). No adverse effects were noted with an intravenous 2.5 mg/kg bolus dose of cyclosporine. 42 Although the treatment effect is impressive, this was a small pilot trial underpowered to detect clinical outcomes. Both the CIRCUS and CYCLE phase III clinical trials are currently underway designed to address the utility of cyclosporine in STEMI undergoing reperfusion therapy on clinical outcomes. 43,44 Bendavia, an intravenously administered mitochondrialtargeting peptide, is currently being tested in EMBRACE STEMI. Bendavia localizes to the mitochondrial inner membrane and reduces reactive oxygen species through modulation of the electron transport chain during oxidative stress after reperfusion. The primary end point is infarct size measured by the area under the CKMB enzyme curve. 45 Glucagon-like peptide 1 receptor agonists Glucagon-like peptide 1 (GLP-1) is an incretin hormone, which regulates serum glucose and is used in the treatment of diabetes. Glucagon-like peptide 1 receptors have also been found in the myocardium, and expression with GLP-1 or its analogues appear to attenuate reperfusion-induced apoptotic cell death. Exenatide is a synthetic analog of GLP-1 available for commercial use and has been tested in a proof-of-concept trial administered intravenously 15 minutes before reperfusion and
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continued 6 hours after restoration of coronary blood flow in STEMI undergoing primary PCI. In this 172-patient study, myocardial infarct size was reduced with exenatide (30% ± 0.15% versus 39% ± 0.15%; P = .003), and myocardial salvage index (measured by cardiac magnetic resonance) was greater with exenatide versus placebo (0.71 ± 0.13 versus 0.62 ± 0.16; P = .003). 46 Recently, the EXAMI trial studied 23 patients and found no difference in left ventricular function or infarct size but a trend toward a lower infarct size to area at risk ratio in STEMI patients treated with exenatide (intravenous bolus over 30 minutes followed by an infusion for 72 hours) (0.35 ± 0.14 versus. 0.47 ± 017; P = .09). 47 It is apparent that larger studies are required to evaluate myocardial salvage and clinical outcome.
Endovascular cooling Systemic hypothermia is known to reduce myocardial necrosis by decreasing myocardial metabolism. This was tested in a small multicenter study of 42 patients with acute MI randomized to either endovascular cooling (target core temperature 33°C) for 3 hours after reperfusion or standard of care. No difference in MACE at 30 days (primary end point) was seen (0% versus 10%; P N .05). As well, no difference in myocardial infarct size measured with SPECT imaging at 30 days was noted (2% versus 8%, P N .05). 48 The COOL MI was a larger trial including 357 patients and found no difference in the primary end point of myocardial infarct size measured with SPECT imaging at 30 days (14.1% versus 13.8%; P = .45). As well, there was no difference in MACE (6.2% versus 3.9%; P = .45) or mortality (3.4% versus 2.2%; P = .71). However, in patients with an anterior MI cooled to b35°C, a borderline reduction in myocardial infarct size was demonstrated (9.3% versus 18.2%; P = .05). 49 This validity of this result remains unclear given the limited number of patients and awaits publication. These investigators proceeded to evaluate the subgroup of patients with anterior MI in the COOL MI II trial. This was stopped prematurely, however, due to loss of funding after 255 patients with anterior MI were randomized in the study and as yet is unpublished. 50 A new trial named CHILL-MI is designed to evaluate the utility of administering 1 to 2 L of cold saline using a central venous catheterization before PCI for STEMI. The primary end point is myocardial infarct size as measured by cardiac magnetic resonance imaging at 4 ± 2 days after acute MI. The study has now completed enrollment of 120 patients, and results are expected this year. 51
Temporal relationship between reperfusion and cardioprotection The duration of symptoms before presentation is a key modulator of outcomes with reperfusion. As seen in Figure 4, a temporal relationship also exists with
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Figure 4
Hypothetical temporal relationship between reperfusion and cardioprotection in STEMI.
cardioprotection: reperfusion initiated early, during symptom presentation of STEMI, can minimize or even abort myocardial necrosis and reduce the likelihood of reperfusion injury. 52 However, between 2 and 6 hours, an abrupt decline of salvaged myocardium occurs, and after 12 hours, recovery of viable myocardium is minimal with reperfusion. 53 Accordingly, cardioprotection may be of limited benefit during the early phase of STEMI given the short ischemic time limiting the emergence of endogenous cytotoxins and other injurious factors. However, when symptom onset to reperfusion is delayed, reperfusion injury is more likely to occur. Thus, an opportunity for modulation by cytoprotective therapy emerges in the context of still viable myocardium. Hence, future clinical trials investigating novel cardioprotective agents should account for specific symptom duration intervals and other metrics of total ischemic time to capture a potential “sweet spot” of cardioprotection.
Summary Prompt recanalization of the infarct-related artery in STEMI is paramount to improve clinical outcome, but despite enormous advances in trying to accomplish this objective, it is rarely achieved. Moreover, despite the conventional focus on establishing epicardial coronary patency, this metric does not necessarily align with myocardial perfusion. Known as the Achilles heel of reperfusion, research efforts have increasingly focused on strategies to reduce myocardial injury. With the discovery of new mechanisms, the search for therapies to overcome reperfusion injury has been reinvigorated. Cyclosporine shows potential as a cardioprotective pharmacologic agent with 2 major phase III trials underway. Remote ischemic conditioning holds promise as a safe and efficacious therapy for myocardial protection but needs to be confirmed in a large, well-designed
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clinical trial powered for clinical outcomes. Further studies must take into consideration the crucial temporal relationship between reperfusion and cardioprotection to enhance the efficacy of tested therapy. Given rapid advances in the field, we should remain optimistic about the emergence of definitive therapies to treat reperfusion injury.
Disclosures No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this review, the drafting and editing of the manuscript, and its final contents.
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