Improving myocardial injury, infarct size, and myocardial salvage in the era of primary PCI for STEMI.

Review in depth 341

Improving myocardial injury, infarct size, and myocardial salvage in the era of primary PCI for STEMI Gjin Ndrepepa ST-segment elevation myocardial infarction (STEMI) is a major cause of mortality and disability worldwide. Reperfusion therapy by thrombolysis or primary percutaneous coronary intervention (PPCI) improves survival and quality of life in patients with STEMI. Despite the proven efficacy of timely reperfusion, mortality from STEMI remains high, particularly among patients with suboptimal reperfusion. Reperfusion injury following opening of occluded coronary arteries mitigates the efficacy of PPCI by further accentuating ischemic damage and increasing infarct size (IS). On the basis of experimental studies, it is assumed that nearly 50% of the final IS is because of the reperfusion injury. IS is a marker of ischemic damage and adequacy of reperfusion that is strongly related to mortality in reperfused patients with STEMI. Many therapeutic strategies including pharmacological and conditioning agents have been proven effective in reducing reperfusion injury and IS in preclinical research. Mechanistically, these agents act either by inhibiting reperfusion injury cascades or by activating cellular prosurvival pathways. Although most of these agents/ strategies are at the experimental stage, some of them

Abundant evidence gathered over the last three decades bears witness to the life-saving effect of reperfusion therapy by thrombolysis or percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). Timely reperfusion results in myocardial salvage, increased electrical stability, and reduced incidence of fatal ventricular arrhythmias in the acute phase as well as preservation of left ventricular function and improvement in short-term and long-term survival. Primary PCI (PPCI) has become the mainstay of reperfusion therapy in patients with STEMI in the USA and Europe. Over the years, considerable efforts have been made to improve the therapy of patients with STEMI by working in four directions: (a) the increase in the number of centers capable of providing reperfusion by PPCI; (b) building and application of the triage and transfer systems of care to reduce ischemia time and provide timely access to reperfusion; (c) refinement of the PPCI equipment and adjunct pharmacologic therapy by developing new generations of coronary stents and antithrombotic/ anticoagulant drugs; and (d) optimization of PPCI by testing various therapies to promote myocardial salvage by reducing distal embolization, providing hemodynamic support, alleviating microvascular obstruction, and reducing reperfusion injury (Fig. 1). 0954-6928 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

have been tested clinically in patients with STEMI. This review provides an update on key pharmacological agents and postconditioning used in the setting of PPCI to reduce reperfusion injury and IS. Despite intensive research, no strategy or intervention has been shown to prevent reperfusion injury or enhance myocardial salvage in a consistent manner in a clinical setting. A number of novel therapeutic strategies to reduce reperfusion injury in the setting of PPCI in patients with STEMI are currently under investigation. They will lead to a better understanding of reperfusion injury and to more efficient strategies for its prevention. Coron Artery Dis 26:341–355 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Coronary Artery Disease 2015, 26:341–355 Keywords: infarct size, myocardial salvage, primary percutaneous coronary intervention, reperfusion injury, ST-segment elevation myocardial infarction German Heart Center Munich, Technical University, Munich, Germany Correspondence to Gjin Ndrepepa, MD, Deutsches Herzzentrum, Lazarettstrasse 36, 80636 München, Germany Tel: + 49 89 12181535; fax: + 49 89 12184053; e-mail: [email protected]

Strategies to promote myocardial salvage or reduce infarct size (IS) during PPCI comprise mechanical devices (or approaches), pharmacological agents, conditioning, or their combination. Mechanical strategies are supposed to promote myocardial salvage by reducing distal embolization (direct stenting, thrombectomy and distal protection devices, mesh-covered stents, or deferred stenting) or by providing hemodynamic support (intra-aortic balloon pumping) during PPCI procedures. The primary focus of this review was to summarize the results of the recent clinical research on pharmacological therapeutic strategies used to promote myocardial salvage and reduce IS mostly by reducing reperfusion injury. Studies involving the use of mechanical devices or approaches, antithrombotic drugs (unless their primary objective was to assess their impact on myocardial salvage or IS during PPCI), or cell therapy during PPCI procedures were not covered.

IS as a marker of ischemic damage and adequacy of reperfusion Mortality from STEMI depends on the patient’s characteristics such as age, comorbidities (diabetes, congestive heart failure, renal disease, and bystander multivessel disease), time-to-reperfusion interval, and DOI: 10.1097/MCA.0000000000000220

Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.

342 Coronary Artery Disease 2015, Vol 26 No 4

Fig. 1

Availability of PPCI centers - Increased number of centers - Increased expertise

Reduction of ischemia time - Regional systems of care - Door-to-balloon time reduction

Increased myocardial salvage

Reduced infarct size

New technology - Newer generation of stents - New antiaggregant drugs - New anticoagulant drugs - New adjunct devices

Strategies to optimize PPCI - Reduce distal embolization - Provide hemodynamic support - Improve microvascular function - Prevent reperfusion injury

Main strategies to improve the therapy of patients with ST-segment elevation myocardial infarction by primary percutaneous coronary intervention (PPCI).

type of reperfusion therapy. However, IS is strongly related to mortality after reperfusion in patients with STEMI [1]. One study showed that for each 5% of the left ventricular mass increase in the IS in patients with STEMI treated by PPCI, the adjusted risk of 5-year mortality increased by 9% [2]. Moreover, the amount of myocardium salvaged by reperfusion per se was found to be an independent correlate of survival in reperfused patients with STEMI [3]. Therefore, it is evident that measures to optimize myocardial salvage and reduce IS at the time of PPCI are of paramount clinical importance. The IS can be assessed accurately by histologic techniques in an experimental setting. In the clinical setting, IS can be assessed by circulating biomarkers and imaging techniques. Among circulating biomarkers, creatine kinase myocardial band (CK-MB) and cardiac troponins (either as peak values or preferably as areas under the curve obtained from serial testing) are mostly used for the quantification of myocardial necrosis. CK-MB predicts prognosis after STEMI and may be used to estimate IS [4]. Although single point measurements of troponin have been shown to estimate IS effectively [5], concerns have been raised that the troponin concentration in myocardium differs between patients and that reperfusion may impact on the kinetics of troponin release and degradation [6]. Imaging techniques offer an anatomic estimation of the myocardial area at risk, IS, and myocardial salvage. Single photon emission computed tomography (SPECT) and cardiac magnetic resonance (CMR) are most frequently used imaging techniques to quantify myocardial necrosis in the clinical setting. Paired SPECT studies

(by repeating the test 7–14 days after reperfusion) allow predicting the initial area at risk (first imaging test), IS (second imaging test), and myocardial salvage (initial area at risk minus IS). The use of the radionuclide tracer in the emergency room (or catheterization laboratory), the risk posed by radiation especially during repeat tests, and the low resolution of the scans are considered as limitations of this imaging technique. CMR represents another validated imaging technique that is used to estimate the initial area at risk (derived from T2-weighted scans), IS, myocardial salvage, and extent of microvascular obstruction in patients with STEMI. At present, CMR is considered the most accurate tool to assess IS and myocardial salvage in the clinical setting [7]. CMR imaging is increasingly being used in studies to assess various strategies aiming to reduce IS in patients with STEMI after reperfusion. ST-segment resolution is used widely as a surrogate marker of myocardial salvage and as a marker of reperfusion in patients with STEMI. ST-segment resolution on ECG correlated closely with myocardial salvage in SPECT imaging in patients with STEMI after reperfusion [8].

Brief description of ischemic and reperfusion injury Acute coronary artery occlusion results in a marked reduction of the coronary blood flow and myocardial ischemia that gradually progresses to necrosis, which is typically complete about 6 h after the onset of occlusion. A rapid phase of cell death mostly in the subendocardial region follows the coronary occlusion and about half of


Infarct size reduction during PPCI Ndrepepa 343

the ischemic myocardium that is necrotic at 24 h has already died at 40 min after coronary occlusion. A second phase of cell death occurs more slowly in the midepicardial and subepicardial myocardium. This phase of myocardial necrosis is mostly completed within 6 h of coronary occlusion and about one-third of ischemic myocardium is salvageable at 3 h [9]. Cellular mechanisms of acute myocardial reperfusion injury have been reviewed recently [10–12]. In the absence of oxygen in the myocardium supplied by the occluded coronary vessel, the use of fatty acids as an energetic fuel, aerobic respiration, oxidative phosphorylation, and production of ATP are almost halted. To counteract stimuli leading to mitochondrial inner membrane depolarization, the F1F0–ATPase complex (located in the mitochondrial inner membrane and activated by protons to produce ATP according to the chemiosmotic theory) functions in the reverse direction, leading to hydrolysis of ATP available, further reducing ATP concentration [12]. In the absence of oxygen, glucose breakdown continues by anaerobic glycolysis with two results: first, anaerobic glycolysis produces a limited amount of ATP that may be crucial for membrane integrity and pump and ionic channel functioning; and second, it increases the concentration of lactic acid and consequently the concentration of protons, leading to cellular acidosis. Increased concentration of protons activates Na+/H+ ion exchanger, leading to increased concentration of intracellular Na+ ions. This mechanism and inactivation of ATP-dependent Na+/K+ ATPase increase the intracytoplastic concentration of Na+. In response to Na+ overload, mechanisms to extrude Na+ from the cell are activated. In particular, the activation of 2Na+/Ca2 + exchanger leads to increased concentrations of intracellular calcium. Of note, in the presence of increased concentrations of protons and calcium, the mitochondrial permeability transition pore (MPTP) remains closed [12]. According to the current paradigm, the MPTP (located in the mitochondrial inner membrane) is a downstream element in the signaling pathways involved in reperfusion injury and an important therapeutic target of therapies aimed at preventing it (Fig. 2a). Upon restoration of the blood flow to ischemic myocardium, a rapid washout of the protons and lactic acid from the extracellular place occurs. Rapid restoration of extracellular pH stimulates Na+/H+ exchange, which leads to rapid normalization of intracellular pH, a massive Na+ influx, and intracellular Ca2 + overload (because of reverse mode activation of the Na+/Ca2 + exchanger and other mechanisms). However, prompt restoration of oxygen and substrates enables aerobic metabolism, electron transfer in the mitochondrial respiratory chain, and oxidative phosphorylation, increasing the production of ATP. Increased availability of ATP in the presence of

Ca2 + overload and restored intracellular pH leads to hypercontracture of cardiomyocytes. Sudden activation of aerobic metabolism leads to a surge in the production of reactive oxygen species (ROS), from, at least, three sources: mitochondrial respiratory chain, xanthine oxidase from the endothelial cells, and NADPH oxidase from neutrophils supplied after blood flow restoration. ROS are important mediators of reperfusion injury. They attack membranes by causing lipid peroxidation (including sarcoplasmic reticulum membranes exacerbating the Ca2 + overload), activate neutrophils, inactivate various enzymes, and damage DNA. Withdrawal of the inhibitory effects of low pH, ROS, and Ca2 + overload lead to opening of MPTP in the inner mitochondrial membrane. MPTP opening is also facilitated by increased Ca2 + in the mitochondrial matrix (upon restoration of the mitochondrial membrane potential, Ca2 + is pumped into the matrix) [11,12]. MPTP opening in the setting of reperfusion injury has devastating effects for the mitochondria and the cell in general by causing rapid loss of mitochondrial inner membrane potential, uncoupling of oxidative phosphorylation and ATP depletion, release of apoptotic factors, and cell death (Fig. 2b). According to the current paradigm, in patients with STEMI undergoing spontaneous or therapeutic reperfusion, the damage responsible for cell death has two components: ischemic damage and reperfusion injury damage. Although the relative contribution of these components may be interrelated and multifactorial, it is assumed that almost 50% of the final IS is because of the reperfusion injury [12].

Pharmacological strategies to prevent (reduce) reperfusion injury Apart from identification of mediators and signaling pathways involved in the myocardial damage, research in the field of reperfusion injury has identified various prosurvival pathways that represent inherent defensive mechanisms adopted by the cells to protect from reperfusion injury. Various strategies (pharmacological agents and conditioning) have been used to target responsible mediators or activate prosurvival pathways to prevent reperfusion injury and reduce IS in patients with STEMI (Table 1).

Antithrombotic/anticoagulant drugs Apart from antithrombotic effects, antithrombotic drugs may impact on reperfusion injury and IS. A higher dose of clopidogrel (600 mg) reduced enzymatic IS (estimated by area under curve of CK-MB) compared with a lower dose (300 mg) used before PPCI (median: 2070 vs. 3049 ng/ml; P = 0.0001) [54]. In the Bavarian Reperfusion AlternatiVes Evaluation 3 trial that included 800 patients undergoing PPCI, intravenous abciximab did not reduce IS measured with SPECT compared with placebo



Fig. 2

Ischemia

(a)

Glucose

Oxygen deficiency Inhibition of aerobic respiration

(b)

Oxygen delivery

Glucose

Anaerobic glycolysis

Inhibition of oxidative phosphorylation

Proton washout

ATP

Xanthine oxidase

ATP depletion +

3Na H+

NAD+ Cellular acidosis

Activated neutrophils

LDH

H++Lactate

2Na

Reperfusion

Ca2+

Ca2+ overload

Aerobic respiration

2Na+

Oxidative phosphorylation

Rapid pH restoration

Na+

ATP

SR

Ca2+

Ca2+ +

2K

3Na+

Ca +

Na+

Ca2+

2+

2+

Na+

H+

ROS

Ca

Na+

Oxygen

Ca2+

Pyruvate

Ca2+ 2K+

Oxygen

Reperfusion

Lactate washout

Ca2+

SR

Massive Ca2+ overload

MPTP (opening)

ATP

Ca2+

Contractile Apparatus

> 20% of coronary blood flow Respiratory chain

Reverse F1F0-ATPase

MPTP (closed)

Hypercontracture Rapid loss of inner membrane potential Cell death

Ischemia

ATP depletion

Blood vessel

Main metabolic events developing during ischemia (a) and reperfusion (b) in cardiomyocytes. During ischemia, anaerobic glycolysis leads to the generation of pyruvic acid, which, in the absence of aerobic respiration, is converted into lactic acid (lactate) by enzyme lactate dehydrogenase (LDH). The conversion of pyruvate into lactate is crucial for continuation of anaerobic glycolysis for two reasons: first, it generates nicotinamide adenine dinucleotide (NAD+), which is needed in a previous glycolytic reaction (by the enzyme glyceraldehyde-3-phosphate dehydrogenase), and second, it generates lactate, which leaves the cell and is washed out if coronary blood flow is > 20% of the normal value. Pyruvate does not exit the cell and in the absence of LDH reaction under conditions of ischemia, it accumulates and inhibits the glycolysis. During the reperfusion, oxygen and substrate delivery and rapid washout of the protons set into operation a series of events leading to rapid pH restoration, generation of oxygen free species, massive calcium overload, MPTP opening, hypercontracture, and cell death (see text for further explanation). Dashed arrows show ATP-dependent ionic pumps. MPTP, mitochondrial permeability transition pore; ROS, reactive oxygen species; SR, sarcoplasmic reticulum.

[mean: 15.7 vs. 16.6% of the left ventricle (LV); P = 0.47] [13]. In a small study of 39 patients with STEMI, upstream high-dose tirofiban did not reduce IS measured with CMR compared with conventional PPCI (mean: 22.1 vs. 25.2% of the LV; P = 0.44), although tirofiban improved pre-PCI thrombolysis in myocardial infarction (TIMI) flow grade 2–3 [55]. The impact of bivalirudin on IS compared with unfractionated heparin plus abciximab was investigated in the CMR substudy of the Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction trial. IS was not significantly different after treatment with bivalirudin compared with heparin plus abciximab either within 7 days (median: 9.3 vs. 20.0% of the LV; P = 0.28) or at 6 months (6.7 vs. 8.2%; P = 0.73) [56].

Intracoronary use of glycoprotein IIb/IIIa inhibitors A direct intracoronary injection of the glycoprotein IIb/IIIa inhibitors has been tested as a strategy to improve tissue reperfusion during PPCI. The Comparison of Intracoronary Versus Intravenous Abciximab Administration During Emergency Reperfusion of ST-Segment Elevation Myocardial Infarction (CICERO) trial randomized 534 patients with STEMI to intravenous or intracoronary abciximab. Intracoronary abciximab did not improve myocardial reperfusion as assessed by ST-segment resolution (64 vs. 62%; P = 0.562); however, it improved myocardial reperfusion as assessed by myocardial blush grade 2/3 (76 vs. 67%; P = 0.022) and reduced the enzymatic IS (peak CK-MB median: 154 vs. 232 U/l; P = 0.003)



Table 1

Pharmacologic agents used to reduce infarct size and proposed mechanism of action

References [13–16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31,32] [33] [34] [35] [36] [37] [38] [39] [40] [41,42] [38] [43–46] [37,47,48] [49] [50] [51] [52,53]

Agent

Proposed mechanism of action

Abciximab Statins RAS inhibitors Anisodamine/ diltiazem Metoprolol Recombinant human SOD Desferoxamine Edaravone Allopurinol Hu23F2G (LeukArrest) Pexelizumab FX06 Exenatide Pioglitazone Metformin GIK Trimetazidine

Inhibits platelet aggregation and leukocyte adhesion; improves microcirculation Conditioning promoting (by opening of mitochondrial ATP-sensitive channels) and anti-inflammatory effects Reduce angiotensin II levels; reduce Ca2 + overload Diltiazem: causes endothelium-mediated vasodilatation; reduces metabolic demand by negative inotropic and chronotropic effects; anisodamine: anticholinergic and α1-adrenergic receptor antagonist Reduces myocardial oxygen consumption Free radical scavenger

Cyclosporine TRO40303 Sodium nitrite Nitroprusside Nicorandil Cariporide Eniporide Caldaret Atrial natriuretic peptide Erythropoietin Adenosine BQ-123 Delcasertib Hypothermia Supersaturated oxygen

Iron chelator Free radical scavenger Inhibitor of xanthine oxidase Blocks CD11/CD18 integrin receptor; inhibits neutrophils Inhibits complement factors C5b-9b Prevents leukocyte migration; anti-inflammatory effects Stimulates glucose metabolism; activates prosurvival kinases; inhibits apoptosis Insulin sensitizer with anti-inflammatory effects Enhanced phosphorylation of AMP-activated protein kinase; increased formation of adenosine; prevention of MPTP opening Improves myocardial metabolism; membrane-polarizing effects Inhibits β-oxidation of fatty acids; promotes glucose metabolism; decreases platelet aggregation and leukocyte influx into the infarct size; scavenger of oxygen free radicals Inhibits MPTP opening Inhibits MPTP opening Nitric oxide donor; arteriolar vasodilatation, platelet inhibition, and anti-inflammatory actions Nitric oxide donor Stimulates guanylate cyclase; K+ATP channel agonist Inhibits Na+/H+ exchanger Inhibits Na+/H+ exchanger Inhibits Na+/Ca2 + exchanger Suppresses renin–angiotensin–aldosterone system and endothelin-1; vasodilatation effects Anti-inflammatory, antihypoxic, and antiapoptotic effects Potent vasodilator of arterioles; inhibits neutrophils Endothelin-1 receptor inhibitor Selective inhibitor of delta-protein kinase C Reduces metabolic demand, inflammatory response, and platelet aggregation Reduces the formation of lipid peroxide radicals; alters nitric oxide synthase expression; inhibits leukocyte adhesion

GIK, glucose-insulin-potassium; MPTP, mitochondrial permeability transition pore; SOD, superoxide dismutase.

compared with intravenous administration [14]. The Abciximab Intracoronary versus intravenous Drug Application in ST-Elevation Myocardial Infarction (AIDA STEMI) trial randomized 2065 patients to intracoronary or intravenous abciximab. The trial did not find any significant difference in clinical outcomes in mortality or reinfarction within 90 days of randomization. However, fewer patients in the intracoronary abciximab group had new congestive heart failure (2.4 vs. 4.1%; P = 0.04) [57]. The CMR substudy of the AIDA STEMI trial included 795 patients who completed CMR imaging within 1 week after STEMI. The area at risk (median: 35.0 vs. 35.0% of the LV; P = 0.97), final IS (median: 16 vs. 17% of the LV; P = 0.52), myocardial salvage index (median: 52 vs. 50%; P = 0.25), and microvascular obstruction (47 vs. 52% of the patients, P = 0.19 or median: 0 vs. 0.2% of the LV; P = 0.22) did not differ significantly between the intracoronary or the intravenous abciximab strategies [15]. The Intracoronary Abciximab and Aspiration Thrombectomy in Patients With Large Anterior Myocardial Infarction (INFUSE-AMI) trial randomized 452 patients with anterior wall STEMI to bolus intracoronary abciximab delivered locally at the infarct lesion site versus no abciximab and to manual

aspiration thrombectomy versus no thrombectomy (2 × 2 factorial design). IS was assessed with CMR. Patients randomized to abciximab showed a significant reduction in the 30-day IS (median: 15.1 vs. 17.9% of the LV; P = 0.03) and absolute infarct mass (median: 18.7 vs. 24.0 g, P = 0.03). Conversely, patients randomized to aspiration thrombectomy versus no aspiration thrombectomy showed no significant difference in IS at 30 days (median: 17.0 vs. 17.3% of the LV; P = 0.51) or absolute infarct mass (median: 20.3 vs. 21.0 g; P = 0.36) [16]. These studies showed that the use of glycoprotein IIb/IIIa inhibitors in the current practice of PPCI to improve tissue reperfusion may be reduced because of the availability of potent antiplatelet inhibitors.

Statins Statins exert multiple protective vascular (endothelial), plaque-stabilizing, and conditioning-promoting (by opening of mitochondrial ATP-sensitive channels) effects. Concerns, however, have been raised that they may also have deleterious effects by interfering with the reperfusion injury signaling pathways, leading to loss of endogenous cardioprotection especially after long-term


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therapy [58]. Nevertheless, evidence on the use of statins in the setting of PPCI remains limited. In a recent study, 173 patients with STEMI undergoing PPCI within 12 h were randomized to atorvastation 80 mg before and for 5 days after PPCI or atorvastatin 10 mg. IS was measured with SPECT at 5–14 days. IS did not differ significantly between the 80 mg and the 10 mg atrovastation groups (mean: 22.6 vs. 21.6% of the LV; P = 0.79). Myocardial blush grade 2/3 or ST-segment resolution at 60 min after PPCI was also similar in groups that received 80 or 10 mg of atorvastatin [17].

tartrate 2 min apart) reduces IS in 270 patients with anterior wall STEMI presenting within 6 h. The primary outcome was IS measured with CMR. IS calculated in grams of infarcted tissue (mean: 25.6 vs. 32.0 g; P = 0.013) or as a percentage of the LV (mean: 21.2 vs. 25.1%; P = 0.029) was reduced significantly by metoprolol. Of note, 34.9% of the initial myocardial area at risk was salvaged in the metoprolol group compared with 27.7% in the control group (P = 0.028). The left ventricular ejection fraction (LVEF) was slightly, but significantly higher in the metoprolol group [20].

Angiotensin-converting enzyme inhibitors, calcium channel antagonists, and β-blocking agents

Antioxidant drugs

These commonly used cardiovascular drugs were also studied for their effect on IS during PPCI. Experimental studies have shown that angiotensin-converting enzyme inhibitors reduce IS and prevent infarct expansion. A retrospective analysis of 511 patients with STEMI showed that compared with patients not taking renin–angiotensin system inhibitors, those who were taking these agents had a lower peak troponin I level after reperfusion (79 vs. 120 ng/dl; P = 0.016). The beneficial effects remained after adjustment for the concomitant use of aspirin and statins [18]. On the basis of the central role of calcium in ischemia/ reperfusion injury, calcium channel antagonists have been used as adjuncts to reperfusion. Two randomized studies yielded conflicting results with respect to the impact of intravenous diltiazem on enzymatic IS in patients with STEMI receiving reperfusion with fibrinolytic therapy [59,60]. A recent study of 108 patients with STEMI undergoing PPCI showed that a combination of intracoronary anisodipine (1 mg/5 ml) and diltiazem (2 mg/5 ml) reduced the rate of no-reflow/slow flow compared with diltiazem (2 mg/5 ml) alone [19]. A recent meta-analysis of seven randomized trials (539 patients with acute coronary syndromes undergoing PCI) showed that verapamil reduced the incidence of no-reflow, TIMI frame count, TIMI myocardial perfusion grade, and the 30-day wall motion index [61]. However, evidence on the use of these agents in the setting of PPCI remains limited. β-Blocking agents have long been a component of care in patients with STEMI because of their ability to reduce myocardial oxygen consumption by reducing heart rate and myocardial contractility. Experimental studies have shown that β-blockers reduce IS particularly when they are administered before coronary artery ligation. The impact of peri-PPCI β-blockade on IS was investigated on a randomized basis in the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial. The trial investigated whether early prereperfusion intravenous β-blocker therapy (up to three 5 mg intravenous boluses of metoprolol

On the basis of the crucial role of ROS in reperfusion injury, various antioxidant drugs have been used to reduce IS during PPCI. In one study, recombinant human superoxide dismutase was used intravenously (a bolus of 10 mg/kg, followed by a 60 min infusion of 0.2 mg/kg/min) on a randomized basis in 120 patients with STEMI undergoing percutaneous transluminal coronary angioplasty. The agent did not impact on left ventricular function measured on contrast or radionuclide ventriculograms [21]. Iron chelator desferoxamine was tested on a randomized basis in 60 patients with STEMI undergoing PPCI. The drug (used as an intravenous bolus of 500 mg) failed to reduce IS measured with CMR compared with placebo (mean: 17.4 vs. 18.6% of the LV; P = 0.73). Myocardial salvage was also not affected by the drug [22]. Edaravone – a free radical scavenger – was tested in 101 patients with STEMI undergoing PPCI. Edaravone reduced IS (estimated by CK-MB) compared with placebo (mean: 146 vs. 192 U/l; P = 0.048) [23]. In a small (n = 38), randomized, placebo-controlled trial, allopurinol – an inhibitor of xanthine oxidase – at a dose of 400 mg administered orally ∼ 60 min before reperfusion improved left ventricular recovery at 6 months after PPCI (mean LVEF: 57 vs. 49%; P = 0.04) [24].

Neutrophil and complement system inhibitors Neutrophils and complement system play an important role in the pathophysiology of reperfusion injury and cell death related to this syndrome. The Hu23F2G (LeukArrest) – a humanized antibody against CD11/ CD18 integrin receptor – was tested (vs. placebo) in 492 patients with STEMI undergoing PPCI. IS measured with SPECT did not differ significantly among patients who received the study drug or placebo (mean IS: 16, 17.2, and 16.6% of the LV for placebo, 0.3 and 1 mg/kg of drug, respectively; P = 0.796) [25]. Pexelizumab, a humanized monoclonal antibody that binds the C5 component of complement, was tested in 5745 patients with STEMI (within 6 h) undergoing PPCI in the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial. Patients were assigned to receive pexelizumab (2 mg/kg intravenous bolus before PCI, followed by 0.05 mg/kg/h infusion over the



subsequent 24 h) or placebo. No difference was observed in the 30-day rate of all-cause mortality (4.06 vs. 3.92%; P = 0.78) or in the composite end point of death, cardiogenic shock, or congestive heart failure at 30 days (8.99 vs. 9.19%; P = 0.81) or 90 days (10.24 vs. 10.16%; P = 0.91) between pexelizimab and placebo groups [62]. In a subgroup of patients (n = 97), IS was measured at 30 and 90 days by CMR. IS was smaller with pexelizumab than placebo at 30 days (mean: 10.5 vs. 16.2% of the LV; P = 0.022) and 90 days (mean: 5.9 vs. 12.4% of the LV; P = 0.015) [26]. The impact of intravenous FX06 (a naturally occurring peptide derived from human fibrin with antiinflammatory properties) on IS was investigated in 234 patients with STEMI undergoing PPCI. IS was assessed at 5 days and 4 months after randomization. IS did not differ between groups assigned to FX06 or placebo at 5 days (median: 21.7 vs. 27.3 g; P = 0.207) or 4 months (15.4 vs. 19.3 g; P = 0.363). The necrotic core, however, was reduced by FX06 compared with placebo (median: 1.77 vs. 4.20 g; P = 0.025) [27].

Antidiabetic drugs Exenatide – a glucagon-like peptide 1 receptor agonist – is suggested to protect from reperfusion injury by activating prosurvival pathways. A recent study randomized patients with STEMI and pre-PPCI TIMI flow 0/1 to intravenous exenatide (initiated 15 min before intervention and maintained for 6 h after the procedure) or a continuous infusion of placebo. Area at risk, IS, and myocardial salvage were measured with CMR. Patients were stratified according to the median system delay (132 min). Among patients with a system delay up to 132 min (n = 74), exenatide reduced IS (median: 9 vs. 13 g; P = 0.008 or 8 vs. 11% of the LV; P = 0.015). Myocardial salvage index was greater among patients assigned to exenatide than placebo (median: 0.75 vs. 0.66; P = 0.012). In patients with system delay greater than 132 min (n = 74), no difference was observed in IS expressed in grams (P = 0.49) or percentage (P = 0.46) or the myocardial salvage index (0.84). There was a significant interaction between system delay and treatment allocation in terms of IS (P = 0.018) [28]. The study was important in showing that therapies against reperfusion injury may be time dependent. A recent trial (n = 23) did not find differences in the left ventricular function or IS with exenatide [63]. Pioglitazone – an insulin sensitizer with antiinflammatory properties – was tested in 319 diabetic patients with STEMI undergoing PPCI presenting within 24 h. Patients treated with pioglitazone (n = 26) showed a higher incidence of blush grade of at least 2 (71 vs. 38%; P = 0.04), complete ST-segment resolution (71 vs. 44%; P = 0.04), and trends toward smaller IS (peak CK: 2041 vs. 3207; P = 0.06) and improved LVEF (48 vs. 41%; P = 0.10). The study was not randomized and the

number of patients in the pioglitazone group was small [29]. In nondiabetic patients with STEMI undergoing PPCI, metformin did not improve LVEF assessed with CMR at 4 months compared with placebo (median: 53.1 vs. 54.8%; P = 0.10) [30].

Glucose–insulin–potassium infusion The impact of therapy with glucose–insulin–potassium (GIK) on IS and myocardial salvage was investigated in the Reevaluation of Intensified Venous Metabolic Support for Acute Infarct Size Limitation (REVIVAL) trial, which included 312 patients with STEMI undergoing PPCI. IS and myocardial salvage were measured with SPECT at 7–14 days. The final IS (median: 9.0 vs. 8.5% of the LV; P = 0.67) or the myocardial salvage index (median: 0.50 vs. 0.48; P = 0.96) was not different among patients assigned to GIK therapy or placebo. Subgroup analysis showed that GIK therapy was associated with increased salvage index only among diabetic patients (mean difference, 0.19; P for interaction between diabetes and GIK therapy efficacy = 0.037 in multivariable analysis) [31]. Another study of 940 patients with STEMI undergoing PPCI also showed no impact of GIK therapy on IS (mean: peak CK-MB 249 U/l in the GIK group vs. 240 U/l in the control group; P = NS) or LVEF at hospital discharge (43.7 vs. 42.4%; P = 0.12) [32].

Trimetazidine Trimetazidine – an anti-ischemic agent – inhibits β-oxidation of fatty acids (by blocking the enzyme 3-ketoacylCoA thiolase) and enhances glucose utilization. By promoting glucose metabolism, trimetazidine may prevent a decrease in the intracellular ATP levels, thereby maintaining energy metabolism, which is crucial for the functioning of ionic pumps and preservation of transmembrane potential during ischemia [64]. However, limited clinical studies so far have not reported a promising view of the use of this agent to protect from reperfusion injury. A randomized, double-blind, placebocontrolled pilot study of 94 patients with STEMI undergoing primary angioplasty did not show an impact of trimetazidine (40 mg bolus, followed by 60 mg/day intravenously for 48 h) on IS estimated by the total mass of myoglobin released (P = 0.099) compared with placebo [33].

Inhibitors of MPTP opening Because of its position as a downstream element in reperfusion injury signaling cascades, the MPTP is considered an important therapeutic target in the therapy of reperfusion injury. Cyclosporine A – an inhibitor of MPTP opening – was tested in 58 patients with STEMI, randomized to receive an intravenous bolus of 2.5 mg/kg of weight of cyclosporine or normal saline. The release of CK was significantly reduced in the cyclosporine group


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compared with the control group (P = 0.04). On day 5, the absolute mass of the area of hyperenhancement (i.e. infarcted tissue) on CMR was significantly reduced in the cyclosporine group compared with placebo (median: 37 vs. 46 g; P = 0.04) [34]. Nevertheless, the study was small and differences were of borderline statistical significance. A meta-analysis of 20 experimental studies showed that cyclosporine A reduced IS, but there was considerable heterogeneity of effect across the studies. The lack of effect in porcine hearts raised concerns about the cardioprotective effects of cyclosporine in humans [65]. The recently published MITOCARE trial tested the efficacy of TRO40303 – another agent that inhibits MPTP opening – in 167 patients with STEMI undergoing PPCI within 6 h from the symptom onset. IS was measured with CMR. There was no significant difference in the CMR-assessed myocardial salvage index (mean: 52 vs. 58%), IS (mean: 21.9 vs. 20.0 g, or 17 vs. 15% of the LV mass), or LVEF (46 vs. 48%), or 30-day echocardiographic LVEF (51.5 vs. 52.2%) between TRO40303 and placebo [35]. Another MPTP opening inhibitor, bendavia, is being investigated.

Nitric oxide donors Nitric oxide donors have been used in patients with STEMI undergoing PPCI to reduce the incidence of noreflow and IS. Sodium nitrite – a selective nitric oxide donor – has multiple vascular functions including arteriolar vasodilatation, platelet inhibition, and anti-inflammatory actions. Sodium nitrite was shown to markedly reduce IS in the experimental setting and the agent is under investigation as a protective agent against reperfusion injury in the clinical setting. However, the recently published Nitrites in Acute Myocardial Infarction (NIAMI) trial – a randomized placebo-controlled study – did not report a benefit of sodium nitrate (intravenous infusion of 70 mmol, 5 min before PCI procedure) versus placebo among 229 patients with STEMI undergoing PPCI. IS (measured with CMR) did not differ between patients assigned to sodium nitrite or placebo at 6–8 days (mean: 22.9 vs. 23.1% of the LV; P = NS) or 6 months (13.3 vs. 15.0% of the LV; P = NS) [36]. In another recent study of 240 patients with STEMI with pre-PCI TIMI flow grade 0/1 undergoing PPCI and thrombus aspiration and randomized to receive adenosine, nitroprusside, or saline, STsegment resolution greater than 70% was observed in 71% of patients assigned to adenosine, 54% of patients assigned to nitroprusside, and 51% of patients assigned to saline (P = 0.009 and 0.75 for adenosine versus saline and nitroprusside vs. saline, respectively) [37]. Nicorandil – a combined nitrate and K+ATP channel agonist – has proven beneficial in reducing IS in animal models, but this effect was not confirmed in randomized studies. A randomized placebo-controlled trial of 545

patients with acute MI undergoing mechanical reperfusion showed that intravenous nicorandil did not reduce IS compared with placebo (median area under curve of CK: 70 520.5 vs. 70 852.7 IU/l/h; P = 0.941) or improve LVEF at 6–12 months (42.5 vs. 43.2%; P = 0.460) [38]. In the same study, intravenous atrial natriuretic peptide modestly reduced IS compared with placebo (see below). A recent meta-analysis showed that nicorandil treatment reduced the incidence of TIMI flow grade up to 2, exerted no effect on the peak CK value, and improved LVEF [66]. However, the studies were small and the data were not sufficient to enable a firm recommendation on the use of ATP-sensitive potassium channel openers in PPCI.

Na+/H+ ion exchanger inhibitors

Na+/H+ ion exchanger is implicated in the genesis of calcium overload in the cardiomyocytes during the ischemia/reperfusion cycles (Fig. 2). In one randomized, placebo-controlled study, 100 patients with STEMI undergoing PPCI were randomized to Na+/H+ ion exchanger cariporide (40 mg intravenous bolus over 10 min) or placebo. The area under the curve for CK-MB was significantly lower in the cariporide group than in the placebo group (P = 0.047). The LVEF at follow-up (21 days) was higher in the cariporide-treated patients (50 vs. 40%; P < 0.05) [39]. The Evaluation of the Safety and Cardioprotective Effects of Eniporide in AMI (ESCAMI) trial assessed eniporide (another Na+/H+ ion exchanger inhibitor) in patients with STEMI undergoing thrombolysis or PPCI. In patients undergoing PPCI (n = 363), there was no significant difference in the IS (assessed by the area under curve of α-hydroxybutyrate dehydrogenase) between patients assigned to placebo, 100, or 150 mg eniporide (mean: 42.3, 45.7, or 44.4 U/ml/h; P = NS). There was no effect of eniporide on clinical outcome (death, cardiogenic shock, heart failure, or life-threatening arrhythmias) [40].

Na+/Ca2 + ion exchanger inhibitors

Na+/Ca2 + ion exchanger is directly involved in the calcium overload in the setting of ischemia/reperfusion in cardiomyocytes (Fig. 2). In the CAldaret in patients undergoing a primary percutaneous coronary intervention for ST-Elevation Myocardial Infarction (CASTEMI) trial, 387 patients with STEMI within 6 h were randomized to caldaret (an agent purported to reduce intracellular calcium by inhibiting Na/Ca exchanger and enhancing calcium reuptake by the sarcoplasmic reticulum) or placebo. Patients were randomized to caldaret 57.5 mg (low dose), caldaret 172.5 mg (high dose), or placebo as a 45 min loading infusion (40 ml/h) started before PCI, followed by a maintenance infusion (4.2 ml/h) for 24–48 h. IS was measured with SPECT. Caldaret was not associated with a reduction in IS (arithmetic mean in patients with pre-PCI TIMI flow 0/1: 19.5, 22.1, 20.0% of the LV at 7 days and 16.8, 19.5, and 16.1% of the LV at


Infarct size reduction during PPCI Ndrepepa

30 days; P = NS) or improvement in LVEF measured by gated SPECT [41]. A subsequent publication from the same trial reported that 1 month after infarction, there was a significant decrease in the incidence of left ventricular dysfunction (LVEF ≤ 30%) in patients receiving low and high doses of caldaret versus placebo (8.0, 6.9 vs. 17.5%; P < 0.05 for both comparisons) [67]. The evaluation of MCC-135 for left ventricular salvage in acute myocardial infarction (EVOLVE) study found no benefits of caldaret on preservation of LVEF or reduction of IS on day 5 in patients with STEMI undergoing PPCI [42].

Atrial natriuretic peptides Atrial natriuretic peptides have reduced IS in experimental studies. Atrial natriuretic peptide was used (as an infusion of 0.025 μg/kg/min for 3 days) in 569 patients with STEMI undergoing PCI in the setting of the Japan working group studies on acute myocardial infarction for the reduction of necrotic damage (J-WIND) trial. The IS measured by area under the curve of CK was significantly lower (median: 66 459.9 vs. 77 878.9 UI/l/h; P = 0.016) and LVEF at 6–12 months was significantly higher (median: 44.7 vs. 42.5%; P = 0.024) among patients assigned to atrial natriuretic peptide than among patients assigned to placebo [38].

Erythropoietin Erythropoietin exerts anti-inflammatory, antihypoxic, and antiapoptotic effects. Because of these effects, erythropoietin was used in clinical trials of patients with STEMI. The effects of erythropoietin (60 000 U epoietin-α administered within 4 h of reperfusion) on IS (measured with CMR at 2–6 days and 12 ± 2 weeks) was assessed in the Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial that included 222 patients with STEMI undergoing primary or rescue PCI. In the efficacy cohort (n = 136), the IS did not differ between groups on either the first CMR scan (15.8% in the epoietin group vs. 15.0% of the LV in the placebo group, P = 0.67; n = 136 patients) or the second CMR scan (10.6 vs. 10.4% of the LV; P = 0.89; n = 124 patients). The subgroup analysis showed that in patients older than 70 years of age, IS in the first CMR scan was higher in the epoietin group (19.9 vs. 11.7% of the LV; P = 0.03; n = 21 patients) [43]. Other recent randomized studies [44–46] and a meta-analysis [68] did not show a reduction in IS by erythropoietin. Although the effects of erythropoietin on IS are still under investigation, on the basis of the available results, this agent does not play a clear role as a protective agent during PPCI.

Adenosine In experimental studies, adenosine – a potent vasodilator of arterioles – reduced reperfusion injury and IS and improved left ventricular function. Intracoronary or intravenous adenosine has been tested as an adjunctive

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therapy to PPCI in patients with STEMI. However, most of the recent research on the use of adenosine as an adjunctive to PPCI was disappointing [47,48]. In one recent, double-blind, placebo-controlled study, adenosine was selectively administered distal to the occlusion site of the culprit lesion (4 mg in 5 ml of 0.9% NaCl) in 112 patients with STEMI undergoing PPCI. IS and the myocardial salvage index were measured with CMR at 2–3 days. IS (median: 18.1 vs. 16.1% of the LV; P = 0.13) or the myocardial salvage index (median: 41.3 vs. 47.8%; P = 0.52) did not differ significantly among patients assigned to adenosine or placebo [47]. A recent metaanalysis of randomized controlled trials showed no reduction in the IS with intracoronary adenosine [69]. On the basis of these results, there is no clear benefit of adenosine as an adjunctive to PPCI in patients with STEMI.

Endothelin receptor inhibitors Endothelin exerts powerful vasoconstrictor effects and evidence from experimental studies suggests the involvement of this peptide in reperfusion injury by enhancing neutrophil adhesion and activation, ROS generation, fibroblast proliferation, and apoptosis of cardiac cells. Evidence on the benefits of endothelin receptor inhibitors in reducing reperfusion injury in patients with STEMI is limited. In a small proof-of-concept, randomized, double-blind, placebo-controlled trial, 57 patients with posterior wall ST-elevation acute coronary syndromes were assigned randomly to receive intravenous BQ-123 (an endothelin receptor blocker) at 400 nmol/min or placebo over 60 min starting at the onset of PCI. IS was measured with CMR at 6 days and 6 months after PPCI. BQ-123 reduced biomarker-assessed IS (maximal CK median: 1365 vs. 2132 U/l; P = 0.014). However, IS (median: 18.4 vs. 20.4% of the LV; P = 0.571) or the salvage index (median: 21.6 vs. 18.1%; P = 0.183) measured with CMR at day 6 was not different among patients assigned to endothelin receptor blocker or placebo. At 6 months, LVEF was better in the endothelin receptor inhibitor group (median: 63 vs. 59%; P = 0.047) [49].

Protein kinase inhibitors Protein kinase plays a key role in the signal transduction pathways involved in the reperfusion injury. Delcasertib – a selective inhibitor of delta-protein kinase C – was shown to reduce IS during ischemia/reperfusion in animal models. The Inhibition of delta-PROTEin kinase C for the reducTION of IS in Acute Myocardial Infarction (PROTECTION AMI) trial investigated whether this agent reduces IS in patients with anterior wall STEMI undergoing PPCI. Patients were randomized to placebo or one of three doses of delcasertib (50, 150, or 450 mg/h). There were no differences in the IS (measured by CKMB area under the curve) among patients assigned to placebo or delcasertib 50, 150, or 450 mg/h (5156, 5043,



4419, or 5253 ng/h/ml; P = 0.43). Delcasertib also did not affect the rates of adjudicated clinical endpoints (death, heart failure, or serious ventricular arrhythmias) [50].

Hypothermia Hypothermia during ischemia may reduce metabolic demand, inflammatory response, and platelet aggregation [10]. Experimental studies have shown a reduction in IS by hypothermia if applied at the beginning or during ischemia, but not during or after the reperfusion. A pooled analysis of two small randomized trials showed that hypothermia was associated with a 24% relative reduction in the IS estimated by SPECT or CMR (mean: 10.7 vs. 14.1% of the LV; P = 0.049) [70]. However, the Rapid Endovascular Catheter Core Cooling combined with cold saline as an Adjunct to Percutaneous Coronary Intervention For the Treatment of Acute Myocardial Infarction (CHILL-MI) trial did not show a significant reduction in the IS (as a percent of myocardium at risk) assessed by CMR at 4 ± 2 days. The trial randomized 120 patients with STEMI (within 6 h) scheduled to undergo PPCI to hypothermia induced by the rapid infusion of 600–2000 ml cold saline and endovascular cooling or standard of care. Hypothermia was initiated before PCI and continued for 1 h after reperfusion. The median IS/myocardium at risk was 40.5% in patients assigned to hypothermia versus 46.6% in the control group (P = 0.15). The incidence of heart failure was lower with hypothermia at 45 ± 15 days (3 vs. 14%; P < 0.05). Exploratory analysis of early anterior infarctions (0–4 h) found a reduction in IS/myocardium at risk end point of 33% (P < 0.05) [51].

Hyperoxemia It is suggested that hyperoxemia may reduce IS by reducing the formation of lipid peroxide radicals, altering nitric oxide synthase expression, and inhibiting leukocyte adherence and plugging in microcirculation [10]. Delivery of hyperbaric oxygen has been tested as a strategy to reduce IS during PPCI procedures. However, the evidence is limited and the data are inconsistent. The Acute Myocardial Infarction with Hyperoxemic Therapy (AMIHOT) trial randomized patients with acute MI within 24 h after primary stenting to intracoronary hyperoxemic reperfusion with aqueous oxygen or control. Although the hyperoxemic reperfusion was safe and well tolerated, it did not show benefit in the improvement of ST-segment resolution or regional wall motion by serial echocardiography or reduction of IS measured with SPECT at 14 days compared with the control (median: 11 vs. 13% of the LV; P = 0.30). In post-hoc analysis, patients with anterior MI reperfused within 6 h showed a greater improvement in regional wall motion and smaller IS (9.0 vs. 23% of the LV; P = 0.03) with hyperoxemic reperfusion. At 30 days, the incidence of major adverse cardiac events was similar between the control and the aqueous oxygen groups (5.2 vs. 6.7%; P = 0.62) [52]. The

AMIHOT-II trial, which included 301 patients with STEMI of the anterior wall, showed that an intracoronary delivery of supersaturated oxygen reduced scintigraphic IS (20 vs. 26.5%; adjusted P = 0.03), with noninferior rates of major adverse cardiac events at 30 days compared with placebo [53].

Ischemic postconditioning Ischemic postconditioning (transient episodes of deliberate ischemia/reperfusion caused by repetitive inflation/ deflation of an occluding balloon in the infarct-related artery) has been shown to reduce IS by 44% in a canine model [71]. Mechanistically, it is believed that postconditioning activates cellular prosurvival pathways by various mediators (adenosine, bradykinin, opioids, nitric oxide, or hypothetic peptides), leading to protection from reperfusion injury. In small randomized human studies, the impact of postconditioning on IS has been controversial. A small randomized study of 50 patients with STEMI showed that postconditioning reduced IS and myocardial edema estimated with CMR (mean: 13 g/m2 in the postconditioning group vs. 21 g/m2 in the control group; P = 0.01) [72]. Conversely, another recent study that randomized 76 STEMI patients to standard PCI or postconditioning did not show a reduction in the IS estimated with CMR at 6–9 days (median IS as a percentage of the area at risk: 47% in the postconditioning group vs. 44% in the control group, P = NS). However, IS was significantly reduced by postconditioning in patients with large initial areas at risk (P < 0.001) [73]. The recently published POstconditioning in ST-Elevation Myocardial Infarction (POSTEMI) trial randomized 272 patients with STEMI within 6 h to ischemic postconditioning (four cycles of 1-min reocclusion starting 1 min after opening, followed by stenting) or control. The IS measured with CMR at 4 months did not differ in the postconditioning or control groups (median: 14.4 vs. 13.5% of the LV; P = 0.18) [74]. Meta-analyses of postconditioning studies have yielded conflicting results with respect to the impact of postconditioning on IS, ventricular function, and clinical outcome of patients with STEMI after PPCI. One recent meta-analysis of 19 trials with 1844 patients showed a reduction in IS (expressed as the standardized mean deference) quantified by circulating cardiac enzymes or imaging as well as an improvement in the LVEF by ischemic postconditioning [75]. Another meta-analysis of 15 trials with 1545 patients did not show an impact of ischemic postconditioning on ST-segment resolution (P = 0.75) or IS (P = 0.17). The meta-analysis showed a marginal improvement in the LVEF (P = 0.04), but no impact on clinical outcome including mortality, recurrent MI, stent thrombosis, or composite major adverse cardiac events by postconditioning [76]. Another recent meta-analysis showed an overall reduction in IS by postconditioning in patients with STEMI undergoing



PPCI. However, restricting the analysis to trials that used CMR imaging to measure IS (six randomized trials with 448 patients) led to the disappearance of the benefit of postconditioning on IS [77]. Remote ischemic conditioning (repetitive cycles of ischemia in a tissue remote from the heart) has also been shown to significantly increase myocardial salvage when performed in 333 patients with STEMI in the ambulance en route to the PPCI center. The remote postconditioning protocol consisted of intermittent arm ischemia through four cycles of 5 min inflation and 5 min deflation of a blood-pressure cuff. The primary outcome was the myocardial salvage index (proportion of initial area at risk salvaged) estimated by SPECT at 30 days. The median myocardial salvage index was 0.75 in the remote conditioning group and 0.55 in the control group (P = 0.033) [78]. A recent publication of this study showed a beneficial effect of remote postconditioning on the long-term clinical outcome. After a median of 3.8 years of follow-up, the rate of major adverse events – composite of all-cause mortality, myocardial infarction, readmission for heart failure, and ischemic stroke/transient ischemic attack – was 13.5% in the postconditioning group and 25.6% in the control group (P = 0.018) [79]. Despite these results, the clinical benefit of remote postconditioning remains largely unexplored. Although preconditioning was found to exert powerful effects against reperfusion injury and reduce IS, this approach is not practical in the setting of PPCI.

Appraisal of the strategies to reduce reperfusion injury in STEMI Despite intensive research over the last 30 years into strategies to reduce reperfusion injury and IS in patients with STEMI, no strategy or intervention has been shown to prevent reperfusion injury or enhance myocardial salvage in a consistent manner in the clinical setting (Table 2). The degree of discrepancy between experimental studies in animal models of acute myocardial infarction showing almost consistently reduced IS by a myriad of strategies and human studies not reproducing the benefits observed in experimental setting is so obvious that the very existence of reperfusion injury in humans has been questioned [35]. Although direct proof on the existence of reperfusion injury in humans is still missing [10], there is no evolutionary basis to negate the existence of reperfusion injury in humans. The research in the field of reperfusion injury has been consistent in the sense that fundamental pathophysiological mechanisms of reperfusion injury remained solid over the last 30 years. Thus, although improved understanding of the pathophysiology of reperfusion injury may enable identification of novel therapeutic strategies, any new research that will lead to a paradigm shift in the pathophysiology of reperfusion injury is not expected. Although reasons for failure to replicate the benefits of

strategies to reduce IS by preventing reperfusion injury as observed in experimental studies in the clinical setting remain unclear, some putative explanations may be offered. First, there are considerable differences between acute myocardial infarction in the experimental setting and spontaneously occurring STEMI in humans. Acute myocardial infarction in the experimental setting is mostly produced by ligation of normal coronary arteries. Moreover, there is considerable flexibility in the timing of application of strategies against ischemia/reperfusion injury, that is before ligation, during ischemia, or at exact time points during reperfusion. In spontaneously occurring STEMI, coronary occlusion is mostly because of acute thrombosis in already diseased coronary arteries, which may dislodge and impair microcirculation at the time of reperfusion, leading to resistance to therapies and worse outcomes. Of note, flexibility of application of reperfusion strategies in terms of timing and dosing is markedly reduced in human studies compared with experimental studies. Second, experimental models of myocardial infarction involve young animals, whereas spontaneous STEMI occurs mostly in aged individuals. In this respect, two factors, the presence of cardiovascular risk factors and the possibility of diminution of activity of prosurvival pathways with aging in humans, may underlie the limited efficacy of strategies to prevent reperfusion injury in humans. Almost all known cardiovascular risk factors seem to reduce the efficacy of strategies to reduce reperfusion injury when present in patients with STEMI [80]. Third, cyclic oscillations (occlusion/reopening) in the coronary blood flow in the infarct-related artery at the time of coronary occlusion (stuttering course) or spontaneous reopening may lead to spontaneously occurring preconditioning (or postconditioning) in patients with STEMI. These factors as well as the effects of peri-PPCI pharmacologic therapy may reduce the efficacy of deliberate use of pharmacological or conditioning strategies in patients with STEMI. Fourth, inadequacies in the applications protocols of pharmacologic agents to prevent reperfusion injury may also account for their reduced efficacy in STEMI studies. At least, bolus application of intracoronary adenosine [47] has been criticized for being less effective in reducing reperfusion injury compared with more prolonged application [81]. Fifth, the existence of multiple signaling pathways involved in the reperfusion injury may imply that inhibition of one pathway, as is the case with most pharmacological strategies, may be not enough to prevent reperfusion injury. Sixth, late application of therapeutic strategies to prevent reperfusion injury may reduce their efficacy. Experimental studies have shown that reperfusion injury is maximal within a few minutes following restoration of coronary blood flow [10]. In at least one study, drug application after a longer interval of ischemia did not reduce IS [28]. Seventh, myocardial tissue undergoing ischemia/reperfusion cycles may be not a good substrate for pharmacologic agents. These agents may not enter


i.v. abciximab i.c. vs. i.v. abciximab i.c. vs. i.v. abciximab i.c. abciximab 80 vs. 10 mg atorvastatin RAS inhibitors (yes; no)b i.v. anisodamine/diltiazem vs. diltiazem/saline i.v. metoprolol i.v. recombinant human SOD i.v. desferoxamine i.v. edaravone Oral allopurinol i.v. Hu23F2G (LeukArrest) i.v. pexelizumab i.v. FX06 i.v. exenatide Oral metformin i.v. GIK i.v. GIK i.v. trimetazidine i.v. cyclosporine i.v. TRO40303 i.v. sodium nitrite i.c. adenosine or nitropusside i.v. nicorandil i.v. cariporide i.v. eniporide i.v. caldaret i.v. caldaret i.v. atrial natriuretic peptide i.v. epoietin-alfa i.v. rhEPO-beta i.v. epoietin-beta i.v. epoietin i.c. high-dose adenosine i.c. adenosine i.v. BQ-123 i.v. delcasertib i.v. cold saline i.c. supersaturated oxygen i.c. supersaturated oxygen

RCT RT RT RT RT RA RT RT RCT RCT RCT RT RCT RCT RCT RCT RCT RT RT RCT RT RCT RCT RCT RCT RCT RCT RCT RCT RCT RCT RCT RCT RT RCT RCT RCT RCT RT RCT RT

Type of study 800 534 795a 452 218 511 108 270 120 60 101 38 420 97a 234 387 380 312 940 94 58 167 229 240 545 100 363a 387 468 569 222 51 138 529 112 448 57 1100 120 269 301

Number of patients

Endpoints IS by SPECT at 4–6 days ST-Res > 70%; IS by peak CK-MB IS by CMR at 1 week IS by CMR at 30 days IS by SPECT at 5–14 days IS by peak TnI after reperfusion No/slow reflow; IS by peak CK-MB IS by CMR at 5–7 days; IS by 72 h AUC of CK LVEF at 24 h and 4–6 weeks after PTCA IS (CMR at 3 ± 1 days after PPCI) IS (peak CK-MB and CK) LVEF at 6 months IS (SPECT at 5–9 days after PPCI) IS (CMR at 30 and 90 days after PPCI) IS (CMR at 5 days and 4 months) IS by CMR at 3 months LVEF by CMR at 4 months Salvage index by paired SPECT IS by AUC of CK-MB; LVEF before discharge ST-Res; IS (total mass of myoglobin) IS by AUC of CK or CMR at 5 days IS by AUC of CK or TnI; IS by CMR at 3–5 days IS by AUC of CK or TnI; IS by CMR at 6–8 days ST-Res > 70%; MVO (TIMI ≤ 2 with blush < 2) IS by CK; LVEF at 6–12 months IS (AUC of CK-MB); LVEF at 21 days IS (AUC of α-hydroxybutyrate dehydrogenase) IS by SPECT at 7 and 30 days LVEF on day 5; IS by SPECT on day 5 and 30 IS by CK; LVEF at 6–12 months IS by CMR at 2–6 days and 12 ± 2 weeks IS by AUC of TnT or 2-day and 4-month CMR IS by CMR at 6 days; LVEF at 6 months IS (AUC of CK-MB); LVEF at 6 months IS by CMR at 2–3 days ST-Res; IS by peak CK or CK-MB IS by peak CK-MB; IS by CMR at day 6 IS by AUC of CK-MB; LVEF at 3 months IS/myocardium at risk by CMR at 4 ± 2 days IS by SPECT at 14 days IS by SPECT at 14 days

Outcome IS not reduced ST-Res not improved; IS reduced IS not reduced; SI and MVO not improved IS not reduced by abciximab IS not reduced IS reduced in patients on RAS inhibitors No/slow reflow improved; IS not reduced CMR IS reduced; enzymatic IS reduced LVEF not improved IS not reduced IS reduced by 24%; P = 0.048 LVEF improved 8%; P = 0.04 IS not reduced IS reduced at 30-day and 90-day scans IS not reduced at 5-day and 4-month scans IS reduced if treatment delay ≤ 132 min LVEF not improved SI not improved IS not reduced; LVEF ≤ 30% improved Improved ST-Res; IS not reduced IS reduced by AUC of CK or CMR IS not reduced by CK, TnI, or CMR IS not reduced by CK, TnI, or CMR ST-Res improved by adenosine only IS not reduced; LVEF not improved IS reduced; LVEF improved IS not reduced IS not reduced LVEF not improved; IS not reduced IS reduced by 14.7%; LVEF improved IS not reduced; IS increased in elderly IS not reduced; increased rate of MVO IS not reduced; LVEF not improved IS not reduced; LVEF not improved IS not reduced; MVO worsened (P = 0.07) SR-Res not improved; IS not reduced Enzymatic IS reduced IS not reduced; LVEF not improved IS/myocardium at risk not reduced IS not reduced; IS reduced in anterior MI IS reduced (patients with anterior STEMI)

Trial abbreviations: AIDA STEMI, Abciximab Intracoronary versus intravenous Drug Application in ST-Elevation Myocardial Infarction trial; AMIHOT, Acute Myocardial Infarction with Hyperoxemic Therapy; APEX-AMI, Assessment of Pexelizumab in Acute Myocardial Infarction; BRAVE-3, Bavarian Reperfusion AlternatiVes Evaluation; CASTEMI, CAldaret in patients undergoing primary percutaneous coronary intervention for ST-Elevation Myocardial Infarction; CHILL-MI, Rapid Endovascular Catheter Core Cooling combined with cold saline as an Adjunct to Percutaneous Coronary Intervention For the Treatment of Acute Myocardial Infarction; CICERO, Comparison of Intracoronary Versus Intravenous Abciximab Administration During Emergency Reperfusion of ST-Segment Elevation Myocardial Infarction; ESCAMI, Evaluation of the Safety and Cardioprotective Effects of Eniporide in Acute Myocardial Infarction; EVOLVE, Evaluation of MCC-135 for left ventricular salvage in acute myocardial infarction; F.I.R.E., Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury; GIPS III, Glycometabolic Intervention as Adjunct to Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction; INFUSE-AMI, The Intracoronary Abciximab and Aspiration Thrombectomy in Patients With Large Anterior Myocardial Infarction; J-WIND, Japan working group studies on acute myocardial infarction for the reduction of necrotic damage; LIST, Limitation of Infarct Size with Trimetazidine; METOCARD-CNIC, the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction; NIAMI, Nitrites in Acute Myocardial Infarction; PROTECTION AMI, The Inhibition of delta-PROTEin kinase C for the reducTION of IS in Acute Myocardial Infarction; REOPEN-AMI, (Intracoronary Nitroprusside Versus Adenosine in Acute Myocardial Infarction); REVEAL, Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction; REVIVAL, Reevaluation of Intensified Venous Metabolic Support for Acute Infarct Size Limitation; REVIVAL-3, Efficacy Study of Erythropoietin After Revascularization in Myocardial Infarction. Other abbreviations: AUC, area under curve; CK-MB, creatine kinase myocardial band; CMR, cardiac magnetic resonance; GIK, glucose–insulin–potassium; i.c., intracoronary; IS, infarct size; i.v., intravenous; LVEF, left ventricular ejection fraction; MPTP, mitochondrial permeability transition pore; MVO, microvascular obstruction; PPCI, primary percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; RA, retrospective analysis; RAS, renin–angiotensin system; RCT, randomized controlled trial; rhEPO, recombinant human erythropoietin; RT, randomized trial; SOD, superoxide dismutase; SPECT, single photon emission tomography; STEMI, ST-segment elevation myocardial infarction; ST-Res, ST-segment resolution; TIMI, thrombolysis in myocardial infarction; TnI, troponin I; TnT, troponin T. a Only patients who underwent IS assessment are included. b Retrospective analysis of patients with or without RAS inhibitors at the time of intervention.

BRAVE-3/Mehilli et al. [13] CICERO/Gu et al. [14] AIDA STEMI/Eitel et al. [15] INFUSE-AMI/Stone et al. [16] Hahn et al. [17] Shariff et al. [18] Peng et al. [19] METOCARD-CNIC/Ibanez et al. [20] Flaherty et al. [21] Chan et al. [22] Tsujita et al. [23] Guan et al. [24] HALT-MI/Faxon et al. [25] APEX-AMI/Patel et al. [26] F.I.R.E./Atar et al. [27] Lonborg et al. [28] GIPS III/Lexis et al. [30] REVIVAL/Pache et al. [31] Van der Horst et al. [32] LIST/Steg et al. [33] Piot et al. [34] MITOCARE/Atar et al. [35] NIAMI/Siddiqi et al. [36] REOPEN-AMI/Niccoli et al. [37] J-WIND/Kitakaze et al. [38] Rupprecht et al. [39] ESCAMI/Zeyman et al. [40] CASTEMI/Bar et al. [41] EVOLVE/Jang et al. [42] J-WIND/Kitakaze et al. [38] REVEAL/Najjar et al. [43] Ludman et al. [44] REVIVAL-3/Ott et al. [45] HEBE III/Voors et al. [46] Desmet et al. [47] Fokkema et al. [48] Adlbrecht et al. [49] PROTECTION AMI/Lincoff et al. [50] CHILL-MI/Erlinge et al. [51] AMIHOT/O’Neill et al. [52] AMIHOT-II/Stone et al. [53]

Route/Agent

Outcomes of trials of agents used to reduce infarct size during PPCI

Trial/References

Table 2




the cells or even may not survive structurally to exert their actions because of the destructive actions of ROS, cellular acidosis, and other noxious agents present in the myocardium undergoing ischemia/reperfusion cycles.

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Conclusion and future directions

Despite the life-saving effect of PPCI in patients with STEMI, reperfusion injury occurring during the course of reperfusion by this strategy mitigates its efficacy in promoting myocardial salvage and reducing IS. Of note, there are currently no effective strategies to prevent reperfusion injury in STEMI patients. A huge number of randomized studies are being carried out to investigate the efficacy of various strategies to enhance myocardial salvage by preventing distal embolization, reperfusion injury, or microvascular obstruction after PPCI procedures. The improvement in the understanding of pathophysiology of reperfusion injury may lead to novel therapeutic agents. Hypothetically, novel agents (or combinations) that lead to sequential inhibition within a given signaling cascade or to inhibition of more than one signaling transduction cascade may lead to more extensive (or deeper) inhibition of these cascades and reduction of reperfusion injury. A combination of mechanical strategies (i.e. thrombus aspiration) and pharmacological agents against thrombus embolization, reperfusion injury, or microvascular obstruction may optimize myocardial salvage during PPCI and improve clinical outcome. Finally, investigation of the most appropriate time interval for the application of therapeutic strategies against reperfusion injury relative to ischemia or reperfusion onset remains to be assessed in future studies.

Acknowledgements

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Conflicts of interest

There are no conflicts of interest.

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Impact of sleep-disordered breathing on myocardial salvage and infarct size in patients with acute myocardial infarction.

Poor R-wave progression and myocardial infarct size after anterior myocardial infarction in the coronary intervention era.

Hyaluronidase-induced reductions in myocardial infarct size.

Smoking and infarct size among STEMI patients undergoing primary angioplasty.

Myocardial infarct size: clinicopathologic agreement and discordance.

Impact of acute hyperglycemia on myocardial infarct size, area at risk, and salvage in patients with STEMI and the association with exenatide treatment: results from a randomized study.

Effects of Ticagrelor on Myocardial Infarct Size.

Left Ventricular Hypertrophy Is Associated With Increased Infarct Size and Decreased Myocardial Salvage in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

The measurement and control of myocardial infarct size.

Impact of manual thrombectomy on myocardial reperfusion as assessed by ST-segment resolution in STEMI patients treated by primary PCI.

[Myocardial rupture after myocardial infarct].

Ventricular fibrillation threshold in acute myocardial infarction and its relation to myocardial infarct size.

Chronic cardiac denervation, infarct size, and myocardial blood flow.

Reducing myocardial infarct size: challenges and future opportunities.

Relationship between myocardial reperfusion, infarct size, and mortality.

Impact of hypertension on infarct size in ST elevation myocardial infarction patients undergoing primary angioplasty.

Insular infarct size but not levosimendan influenced myocardial injury triggered by cerebral ischemia in rats.

Leucocyte expression of complement C5a receptors exacerbates infarct size after myocardial reperfusion injury.

Myocardial infarct size measurement using geometric angle calculation.

Multiscale Characterization of Impact of Infarct Size on Myocardial Remodeling in an Ovine Infarct Model.

Hyperoxemic reperfusion does not increase myocardial infarct size.

Stroke after acute myocardial infarction: relation to infarct size.

Intra-myocardial hemorrhage in STEMI reperfusion: An alternative explanation for failures from "augmented" fibrinolysis regimes and fibrinolysis-facilitated PCI?

[Myocardial infarct and ovulation inhibitors].