Version May 2024
INTRODUCTION — Myocardial injury in the setting of an acute myocardial infarction (MI) is the result of ischemic and reperfusion injury. Reperfusion therapies, including primary percutaneous coronary intervention and fibrinolytic therapy, promptly restore blood flow to ischemic myocardium and limit infarct size.
Paradoxically, however, the return of blood flow can result in additional cardiac damage and complications; this is referred to as reperfusion injury [1-3]. Effective therapies to reduce or prevent reperfusion injury have proven elusive. Despite an improved understanding of the pathophysiology of this process and encouraging preclinical trials of multiple agents, most of the clinical trials to prevent reperfusion injury have been disappointing [4-6]. Despite these problems, adjunctive therapies to limit reperfusion injury remain an active area of investigation.
This topic will discuss the pathophysiology and manifestations of reperfusion injury, as well as potential therapeutic strategies. The impact of the initial ischemic insult is discussed separately. (See "Approach to the patient with suspected angina pectoris", section on 'Pathophysiology'.)
General discussions of the use of reperfusion therapy in acute MI are presented separately. (See "Primary percutaneous coronary intervention in acute ST elevation myocardial infarction: Determinants of outcome" and "Acute ST-elevation myocardial infarction: The use of fibrinolytic therapy".)
DEFINITION — In the first stage of acute MI, myocardial cells are injured as the result of anoxia and the absence of new essential metabolic substrate. In the absence of reperfusion, and in the absence of an adequate collateral circulation, these injured cells die and scar tissue is formed.
In the presence of reperfusion, either spontaneous or consequent to reperfusion therapy, ischemic injury is halted but additional injury occurs as the result of reperfusion. Reperfusion injury is characterized by myocardial, vascular, or electrophysiological dysfunction that is induced by the restoration of blood flow to previously ischemic tissue.
PATHOPHYSIOLOGY — When blood flow to cardiac myocytes is disrupted by occlusion of a coronary artery, a series of events is set in motion that results in cellular injury and death (termed acute ischemic injury). These processes are related to energy production and utilization and include the following:
●Reduced energy production with a fall in intracellular adenosine triphosphate (ATP) levels
●A transition from aerobic to anaerobic energy utilization
●An accumulation of the products of anaerobic metabolism
●Sodium and calcium overload and reduced intracellular pH
These phenomena lead to dramatic distortions in myocyte physiology and architecture, including mitochondrial and sarcolemmal injury and alterations in intracellular calcium handling. Four important adverse intracellular events are opening of the mitochondrial permeability transition pore, rapid normalization of pH, intracellular calcium overload, and generation of reactive oxygen species [7-9].
Initially, the damage is reversible, and restoration of blood flow during this period will lead to recovery of normal structures and function. However, if ischemia persists for an extended period of time, this damage becomes irreversible and cell death occurs.
Prior to cell death there is a period during in which the ischemic myocyte is viable but vulnerable to further injury if blood flow is restored (ie, reperfusion injury). Restoration of blood flow is associated with three events that may further injure myocytes:
●Microvascular obstruction – Although reperfusion removes obstruction to flow in the epicardial circulation, distal flow may remain significantly impaired due to (microvascular) obstruction to flow in small arterial vessels; obstruction may be due to:
•Embolization of clot or plaque material from the original site of obstruction.
•Formation of new thrombus due to intravascular activation of platelets, complement, and circulating leukocytes.
•External compression of the small vessels due to interstitial edema consequent to a leaky endothelium (endothelial damage).
•Direct cellular toxicity.
•Vasoconstriction.
Preservation of the coronary microvasculature is essential to the ultimate recovery of myocardial function [10]. Microvascular dysfunction, or the "no reflow" phenomenon, refers to the impairment of resting blood flow within the postischemic vasculature. The clinical significance of microvascular dysfunction lies in its association with worse cardiovascular outcomes [11]. (See "Suboptimal reperfusion after primary percutaneous coronary intervention in acute ST-elevation myocardial infarction", section on 'No reflow'.)
●Damage due to local factors – Red blood cell deposits (hemorrhage) or local inflammation can further damage the microcirculation.
●Myocardial edema (intracellular and interstitial) occurs in a bimodal pattern after reperfusion. The first wave occurs soon after reperfusion and abates within days; the second wave that starts days later and is associated with healing [12].
Some of these factors act through mechanisms discussed below.
Myocyte hypercontracture — Restoration of blood flow to previously ischemic cells can result in myocyte hypercontracture and resultant contraction band necrosis [13]. Factors that contribute to hypercontracture include:
●Increased intracellular calcium – During an ischemic period, intracellular calcium increases due to impaired calcium cycling and sarcolemmal damage [14]. This process can be exacerbated with reperfusion. The restoration of a normal extracellular pH after reperfusion produces a hydrogen gradient across the cell membrane. The sodium/hydrogen (Na/H) exchanger is activated and causes a net influx of sodium into the cytosol. Under normal conditions, the resulting increase in intracellular sodium would be corrected by the sodium/potassium (Na/K) ATPase. However, this channel may not function normally after a period of ischemia due to a lack of energy and structural damage. In this setting, the sodium excess causes the sodium/calcium (Na/Ca) channel to run in reverse, producing an influx of calcium into the already calcium-overloaded cell.
●Reoxygenation and reenergization of the myocyte – Return of blood flow provides oxygen and energy that stimulates myofibrils, and, in the setting of increased calcium, contraction is uncontrolled and excessive.
●Restoration of normal acid-base status – Reduced cytosolic pH during ischemia inhibits myofibrillar contraction [15]. With restoration of blood flow, a normal pH is rapidly restored in the extracellular and then the intracellular space, removing the acidic inhibition to contraction.
Mechanisms by which hypercontracture can result in additional cardiac injury include the following [16]:
●Cytoskeletal elements can be significantly damaged, ultimately resulting in cell death.
●Myocytes tearing away from the tight intercellular junctions during hypercontracture can cause damage to the sarcolemma of adjacent cells.
Oxygen and other free radicals — Free radicals are produced within minutes of reperfusion and continue to be generated for hours after the restoration of blood flow to ischemic tissue [17]. These include:
●Superoxide anion (O2-)
●Hydrogen peroxide (H2O2)
●Hypochlorous acid (HOCl)
●Nitric oxide-derived peroxynitrite
●Hydroxyl radical (OH-)
Several mechanisms have been proposed for the development of these free radicals including xanthine oxidase, activated neutrophils, electron leakage from ischemic mitochondrion, catecholamine oxidation, as well as cyclooxygenase and lipoxygenase enzymes [18]. The relative importance of each of these pathways is not clear, but they are probably interrelated and may potentiate one another.
Free radicals damage myocytes directly by altering membrane proteins and phospholipids [19]. Because these membrane constituents play crucial roles as receptors, enzymes, and ion channels, free radical injury can lead to fatal metabolic and structural derangements. As an example, oxygen radicals injure the sarcolemma and may impair contractile function of the myocyte on this basis [18]. The role for free radicals as a source of significant myocardial damage is further supported by studies showing that free radical scavengers, such as superoxide dismutase, administered during thrombolytic therapy help preserve myocardial function [20]. Finally, reactive oxygen species stimulate leukocyte activation, chemotaxis, and leukocyte-endothelial adherence [19].
Reactive oxygen species may trigger the opening of the mitochondrial permeability transition pore. This is associated with uncoupling of oxidative phosphorylation and the release of pro-apoptotic molecules [21]. (See "Myocardial ischemic conditioning: Pathogenesis", section on 'Mediators'.)
Leukocyte aggregation — Multiple factors induced by ischemia and reperfusion trigger leukocyte aggregation and activation:
●Neutrophils are stimulated after plasma membrane phospholipase A2 is activated to form arachidonic acid, which is an important precursor in the inflammation pathway [19].
●Cytokines and complement are released from damaged myocardium [22-24].
●New expression of adhesion molecules, diminished release of nitric oxide (NO), and changes in the actin cytoskeleton allow greater vascular permeability, giving neutrophils access to vulnerable myocytes [25].
Neutrophil accumulation in nonperfused microvessels may contribute to the "no reflow" phenomenon [26]. Once in the extravascular space, leukocytes can release proteases and elastases that destroy the cell membrane and cause cell death [27,28]. However, the roles of the various inflammatory mediators are complex and incompletely understood. Although they play a role in reperfusion injury, some also appear to have cardioprotective effects [23,24].
Platelet activation — Circulating platelets become activated early during reperfusion, and their degree of activation is related to the duration of preceding ischemia [29]. Furthermore, the degree of platelet activation was related to the extent of reperfusion injury. These observations support the possibility of an important role for activated platelets in reperfusion injury.
Complement activation — Complement activation appears to play a role in the "no reflow" phenomenon and possibly reperfusion injury [30]. Terminal complement cascade species directly injure the endothelium, rendering it incapable of elaborating vasodilatory compounds such as NO. This perpetuates a cycle of vasoconstriction and reduction in microvascular perfusion, leading to apoptosis not only within the infarct area, but also in the border zone [31].
Apoptosis — Apoptosis, or programmed cell death, has a number of features that distinguish it from necrosis:
●Apoptosis can occur in response to limited molecular damage that is otherwise not sufficient to cause a fatal loss of cellular integrity.
●Apoptosis is an energy-dependent process.
●Apoptosis is an organized sequence of events triggered by specific signals.
While ischemic damage occurs principally through necrosis, reperfusion injury may also act through apoptosis [32-34]. In a rabbit model, markers of apoptosis found in reperfused tissue were not present in normal tissue or tissue injured solely by ischemia [33]. Others have reported the appearance of apoptotic cells in the perinecrotic zone during reperfusion [35] and suggested that understanding the different contributions of necrosis and apoptosis to reperfusion injury may help identify novel treatment strategies [36].
A link between reperfusion and apoptosis is supported by studies demonstrating the role of magnesium-dependent superoxide dismutase and oxygen radical formation in the activation of proapoptotic factors. An apoptosis repressor is capable of inhibiting this process and reducing the extent of MI [37,38].
CLINICAL CORRELATES — It has been suggested that reperfusion injury accounts for up to 50 percent of the final myocardial damage in the setting of acute MI [7]. Clinical manifestations of ischemic reperfusion injury include arrhythmias, microvascular dysfunction, myocardial stunning, and myocyte death.
Arrhythmias — Reperfusion-induced arrhythmias are common in patients treated with thrombolytic therapy, primary percutaneous coronary intervention, and cardiac surgery. The arrhythmia that is most commonly associated with reperfusion is an accelerated idioventricular rhythm. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features", section on 'Reperfusion arrhythmias'.)
Reperfusion arrhythmias may be mediated by mitochondrial dysfunction. Following prolonged ischemia, the mitochondrion may not be able to restore or maintain its inner membrane potential, thereby destabilizing the action potential and increasing susceptibility to arrhythmias [39]. (See 'Pathophysiology' above.)
Ventricular tachycardia and ventricular fibrillation can also occur after thrombolytic therapy; however, these arrhythmias are more likely to reflect persistent occlusion and infarction than a reperfused infarct-related artery [40]. The pathogenesis of reperfusion arrhythmias is discussed extensively elsewhere. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features".)
Myocardial stunning — Myocardial stunning refers to transient, myocardial dysfunction that occurs after reperfusion, as opposed to dysfunctional hibernating myocardium secondary to ongoing ischemia. It is thought to result from myocardial oxidative stress and calcium overload that continues after reperfusion [41]. Myocardial stunning is also associated with microvascular injury and better levels of regional and global myocardial function are seen when the microvasculature is structurally intact [10,42-44]. (See "Pathophysiology of stunned or hibernating myocardium".)
Because stunning can recover with time, inotropic agents can be used in the short term to improve cardiac function and organ perfusion. Several agents that may prevent its occurrence are being investigated. (See 'Potential therapies' below.)
Myocyte death — The most concerning consequence of reperfusion injury is myocyte death. If enough myocytes die, there may be manifestations of acute MI. (See "Diagnosis of acute myocardial infarction".)
Animal data suggest that up to 50 percent of an infarct size may be attributable to reperfusion injury [45,46]. This observation highlights the potential value of therapies that reduce or eliminate reperfusion injury. Despite an improved understanding of the processes associated with reperfusion injury, there is still uncertainty regarding the magnitude and significance of myocyte death associated with reperfusion.
Prolonged ischemia and subsequent reperfusion induce adverse cytosolic and mitochondrial changes, as discussed above. (See 'Pathophysiology' above.) Opening of the mitochondrial permeability transition pore and irreversible cardiomyocyte hypercontracture precede myocyte death [41].
POTENTIAL THERAPIES — Although the pathophysiology of reperfusion injury lends itself to potential therapeutic strategies, no treatment directed at reperfusion injury has been shown to lead to improvement in clinical outcomes. Potential reasons for the ultimate failure of agents that appeared promising in preclinical trials include the following:
●Multiple mechanisms contribute to the consequences of MI and reperfusion injury. Thus, the impact of a therapy targeted to a single component of the pathophysiology may be diluted in clinical practice.
●Some mechanisms, such as neutrophil stimulation, may be mediators of injury, but also play important roles in the healing process [22]. Targeting such mechanisms would have complex and unpredictable implications on outcomes. (See 'Leukocyte aggregation' above.)
●It may not be possible to administer a therapy at the optimal time in clinical practice (eg, some agents may perform best if patients are pretreated).
●The presence of comorbidities, such as diabetes, hypercholesterolemia, and age, may impact the efficacy of a new treatment.
Identification of patients at highest risk of reperfusion injury may be an important component of bringing therapies into clinical practice. As an example, myocardial blush grade has been used as a tool to evaluate myocardial level perfusion, and low blush grades correlate with myocardial dysfunction [47-49]. Such tools may also allow for better clinical assessment of therapeutic effectiveness of drugs tested in clinical trials. (See "Diagnosis and management of failed fibrinolysis or threatened reocclusion in acute ST-elevation myocardial infarction", section on 'Primary failure'.)
Ischemic conditioning — Ischemic pre- and postconditioning are discussed elsewhere. (See "Myocardial ischemic conditioning: Pathogenesis" and "Myocardial ischemic conditioning: Clinical implications".)
Glycoprotein IIb/IIIa inhibitors — Platelet activation contributes to microvascular injury and reperfusion injury in acute MI [29]. (See 'Platelet activation' above.) Glycoprotein IIb/IIIa inhibitors are potent inhibitors of platelet activity that improve outcomes in acute MI [50-53]. It is not known if part of the benefit of glycoprotein IIb/IIa inhibitors is due to a reduction in reperfusion injury. (See "Suboptimal reperfusion after primary percutaneous coronary intervention in acute ST-elevation myocardial infarction", section on 'No reflow'.)
In preclinical studies, P2Y12 inhibitors such as cangrelor significantly ameliorated infarct size when administered prior to the onset of reperfusion, and may have benefits beyond an impact on the rheology of blood. This would indicate pleiotropic effects of these agents beyond their ability to attenuate platelet thrombosis [54,55].
Adenosine — Adenosine has several properties that make it an attractive candidate to prevent reperfusion injury. These include:
●It is a substrate for adenosine triphosphate (ATP) replenishment
●Vasodilation
●Platelet and neutrophil inhibition
●Direct cardioprotective effect on the cardiomyocyte
Based upon these properties, adenosine has been tested in both preclinical and clinical studies. The demonstration of cardioprotective effects of adenosine in animal models [56-58] provided the rationale for randomized clinical trials. The following are representative studies that have shown mixed results:
●In the AMISTAD trial, 236 patients with an acute MI treated with fibrinolysis were randomly assigned to adenosine or placebo [59]. At a follow-up of six days, infarction size was significantly smaller in patients assigned to adenosine treatment, a benefit that was limited to those with anterior infarctions.
●AMISTAD 2 is the largest trial of intravenous adenosine as an adjunctive therapy during primary reperfusion for an acute MI [60,61]. This study included 2118 patients treated with primary percutaneous coronary intervention (PCI) or fibrinolytic therapy for anterior ST elevation MI (STEMI). Although infarct size was reduced with adenosine, there was no reduction in a combined clinical end point of heart failure or overall mortality at six months.
●In the PREVENT-ICARUS trial, 260 patients undergoing elective PCI were randomly assigned to either intracoronary adenosine or placebo [62]. There was no significant difference between the two groups in the primary end point of a periprocedural increase in troponin I >3 times the upper limit of normal.
In summary, the administration of either intravenous or intracoronary adenosine has not been established as an effective therapy to reduce the risk of clinical events after PCI in either stable patients or those with acute coronary syndromes. Adequately powered studies to evaluate whether intracoronary adenosine leads to improved clinical outcomes are unlikely to be performed.
Vasodilators — A number of vasodilators have been investigated as potential therapies for reperfusion injury.
●Human studies with papaverine have also demonstrated success in improving angiographically documented TIMI flow grades in epicardial arteries; however, its use is limited by occurrence of ventricular arrhythmias, especially with intracoronary administration [63].
●Several members of the sydnonimine class of nitric oxide (NO) donors have reduced infarct size in an animal model [64,65]. These compounds spontaneously decompose to form NO.
●Angiotensin converting enzyme (ACE) inhibitors may have several beneficial actions in reperfusion, including the scavenging of free radicals, vasodilation of the coronary bed, and elevation of prostacyclin and bradykinin levels [66]. In an animal model, ACE inhibitors enhanced coronary blood flow but failed to produce any improvement in regional ventricular function [67].
●Endothelin is a potent vasoconstrictor and possible mediator of the vasospastic component of reperfusion injury. Several studies have investigated the effects of inhibiting endothelin-1 synthesis or blocking its receptor [68-71]. Although conflicting results have been reported, further study is ongoing.
Ion channel modulation — Changes in intracellular and extracellular ion concentrations and pH play a role in some of the processes involved in reperfusion injury. Thus, ion channels are an attractive target for novel treatments of reperfusion injury. (See 'Pathophysiology' above and 'Myocyte hypercontracture' above.)
The potential role of ion channel modulation in the treatment of reperfusion injury is illustrated by the following observations:
●Sodium/hydrogen (Na/H) exchange inhibition – Na/H exchange is an important regulator of intracellular pH and calcium concentration. Blockade of this exchange reduces calcium uptake and helps to preserve cellular architecture [72]. Several in vitro and animal studies have suggested that inhibition of sodium/hydrogen exchange is effective in reducing reperfusion injury and infarct size [72-75]. However, in a two-stage randomized trial including a total of 1389 patients, the sodium/hydrogen exchange inhibitor eniporide did not improve infarct size or clinical outcome [76,77].
●Ranolazine – Ranolazine is effective in the treatment of chronic angina and may be effective in reperfusion injury and limit infarct size in acute MI [78]. Ranolazine is an inhibitor of the late sodium channel, and via this mechanism, it decreases sodium-dependent intracellular calcium overload during ischemia and reperfusion [79,80]. (See "New therapies for angina pectoris", section on 'Ranolazine'.)
●Potassium-ATP (K-ATP) channel openers – K-ATP channels are involved in ischemic preconditioning and microvascular vasodilation. In small clinical trials, K-ATP channel openers, such as nicorandil, resulted in better perfusion and left ventricular wall motion, as well as a reduction in adverse events [81,82]. Cardiac magnetic resonance imaging data suggest that nicorandil may improve microvascular obstruction [83].
Glucose-insulin-potassium solution — Glucose-insulin-potassium therapy has been tested as a potential way to stimulate anaerobic glycolysis, increase ATP levels, and decrease the free fatty acid release. Clinical trials have not demonstrated benefit. (See "Overview of the acute management of non-ST-elevation acute coronary syndromes", section on 'Intravenous glucose-insulin-potassium'.)
Antineutrophil and anticomplement therapy — Inhibition of the accumulation and activation of neutrophils has been correlated with a reduced infarct size in some studies, although other trials have failed to show a benefit [47,84-86]. Unfortunately, the prolonged time from the onset of infarction to the delivery of antineutrophil therapy such as anti-CD18 antibody may reduce the ability of these agents to mitigate neutrophil-mediated cell injury [47].
Similarly disappointing were results reported for the complement inhibitor pexelizumab [87-89]. This may be due to the complexity and the multiple steps of immune activation involved in reperfusion injury. Part of the success of the intracoronary glycoprotein IIb/IIIa inhibitor administration in PCI may be also due to its effect on leukocyte integrin receptors [90]. (See 'Glycoprotein IIb/IIIa inhibitors' above.)
Antioxidant therapy — The prominent role of oxygen radicals in the pathophysiology of reperfusion injury has prompted several studies to evaluate the efficacy of antioxidants in reducing the damage associated with reperfusion. (See 'Oxygen and other free radicals' above.)
The results have been mixed [91], and investigation remains focused at the animal level. Erythropoietin [24,92-95], estrogen [96,97], heme oxygenase1 [98], and hypoxia induced factor–1 [99] have all been shown to reduce reperfusion injury, and investigation is ongoing.
Magnesium — Intravenous magnesium has not been shown to improve outcomes in patients with acute MI. (See "Overview of the acute management of ST-elevation myocardial infarction", section on 'Therapies of unclear benefit'.)
Cyclosporine — Intravenous cyclosporine has not been shown to improve outcomes in patients with STEMI undergoing primary PCI, despite its ability to inhibit the opening of the mitochondrial permeability-transition pore [100,101]. An early study of 58 patients showed that a single intravenous bolus of cyclosporine administered before primary PCI results in a reduction of creatinine kinase by 44 percent, and in a subset of 27 patients, this translated into a 20 percent reduction in infarct size as measured by delayed enhancement cardiac magnetic resonance [102].
Despite the promise of benefit from cyclosporine, no benefit has been demonstrated in two clinical trials of STEMI patients undergoing primary PCI.
The CIRCUS trial randomly assigned 970 patients to an injection of intravenous cyclosporine or placebo before coronary recanalization [103]. There was no difference between the groups in the primary composite outcome of all-cause death, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at one year (defined as an increase of ≥15 percent in the left ventricular end-diastolic volume). Concerns have been raised that the formulation of cyclosporine used in the study may not have been the best available choice [104].
The CYCLE trial randomly assigned 410 patients to intravenous cyclosporine A or placebo prior to primary PCI [105]. There was no difference in the rates of the primary end point (≥70 percent ST-segment resolution 60 minutes after Thrombolysis In Myocardial Infarction flow grade 3) (table 1) or secondary end points of high-sensitivity cardiac troponin T on day four, measures of left ventricular function, or clinical events at six-month follow-up.
Intravenous MTP-131 — MTP-131 is a cell-permeable peptide that enhances mitochondrial energetics and improves myocyte survival during reperfusion [21]. (See 'Oxygen and other free radicals' above.)
Reduction in infarct size has been demonstrated with MTP-131 in animal STEMI models [106]. In a Phase 2 trial in which nearly 300 STEMI patients were randomly assigned to intravenous MTP-131 or placebo following successful PCI with stenting, there was no significant difference in infarct size between the two groups [21].
Intravenous sodium nitrite — In experimental models, sodium nitrite reduces ischemic reperfusion injury to the heart. In the NIAMI trial, 229 patients with acute STEMI were randomly assigned to either an intravenous infusion of sodium nitrite or placebo before primary PCI [107]. There was no difference in the two groups with regard to infarct size by cardiac magnetic resonance imaging at six to eight days or six months.
Losmapimod — p38 mitogen-activated protein kinase (MAPK) is a stress-activated kinase expressed in the myocardium and endothelial cells that regulates cellular responses, including contraction and death [108]. Losmapimod is an oral inhibitor of p38 MAPK that has been shown to reduce infarct size in preclinical models [109]. In the phase 2 SOLSTICE trial, 535 patients with non-ST elevation MI were randomly assigned to losmapimod or placebo given within 12 hours and continued for 12 weeks [110]. Losmapimod lowered the concentration of circulation inflammatory markers of high-sensitivity C-reactive protein and interleukin 6 within 72 hours and lowered concentrations of brain natriuretic peptide at 12 weeks. No significant difference was seen between the two groups in terms of serious adverse effects.
Inhibitors of delta-protein kinase C — Delcasertib is an inhibitor of the delta isoform of protein kinase C. Protein kinase C isoenzymes modulate myocardial protection. (See "Myocardial ischemic conditioning: Pathogenesis" and "Myocardial ischemic conditioning: Pathogenesis", section on 'Protein kinase C'.).
In the PROTECTION AMI trial, 1010 acute MI patients undergoing primary PCI were randomly assigned to one of three doses of delcasertib or placebo given intravenously [111]. There was no difference in infarct size between those who received delcasertib or placebo.
Endovascular cooling — Hypothermia induced before reperfusion in animal models of acute coronary occlusion reduces infarct size. The concept is that myocardial metabolism will be decreased at lower temperatures and thus some cardioprotection will be afforded, analogous to cold cardioplegia used by cardiac surgeons during coronary bypass grafting. Endovascular coils and external cooling blankets have been used to lower core temperature during PCI for acute MI [112-114]. However, the CHILL-MI trial, which used rapid infusion of cold saline and endovascular cooling prior to PCI, did not reduce the primary end point of infarct size [115].
SUMMARY
●Reperfusion injury is an important limitation to the efficacy of primary reperfusion therapies in acute myocardial infarction (MI). Reperfusion injury is characterized by myocardial, vascular, or electrophysiological dysfunction that is induced by the restoration of blood flow to previously ischemic tissue. (See 'Clinical correlates' above.)
●The pathophysiology of reperfusion injury is complex, involving abnormalities in energy production and utilization, disturbance of cellular architecture, and possibly leukocyte, platelet, and complement activation. (See 'Pathophysiology' above.)
●Reperfusion injury accounts for up to 50 percent of the final myocardial damage in the setting of acute MI. Clinical manifestations of ischemic reperfusion injury include arrhythmias, microvascular dysfunction, myocardial stunning, and myocyte death. (See 'Clinical correlates' above.)
●Despite ongoing improvements in the understanding of the underlying mechanisms of reperfusion injury, effective therapies remain elusive. (See 'Potential therapies' above.)
ACKNOWLEDGMENTS — The UpToDate staff acknowledges Bernard Gersh, MB, ChB, DPhil, FRCP, MACC, and Duane Pinto, MD, MPH, who contributed to earlier versions of this topic review.
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