Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges

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REVIEW ARTICLE Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges Q22

AMIT SAXENA, ILARIA RUSSO, and NIKOLAOS G. FRANGOGIANNIS BRONX, NY

In the infarcted myocardium, necrotic cardiomyocytes release danger signals, activating an intense inflammatory response. Inflammatory pathways play a crucial role in regulation of a wide range of cellular processes involved in injury, repair, and remodeling of the infarcted heart. Proinflammatory cytokines, such as tumor necrosis factor a and interleukin 1, are markedly upregulated in the infarcted myocardium and promote adhesive interactions between endothelial cells and leukocytes by stimulating chemokine and adhesion molecule expression. Distinct chemokine/ chemokine receptor pairs are implicated in recruitment of various leukocyte subpopulations in the infarcted myocardium. For more than the past 30 years, extensive experimental work has explored the role of inflammatory signals and the contributions of leukocyte subpopulations in myocardial infarction. Robust evidence derived from experimental models of myocardial infarction has identified inflammatory targets that may attenuate cardiomyocyte injury or protect from adverse remodeling. Unfortunately, attempts to translate the promising experimental findings to clinical therapy have failed. This review article discusses the biology of the inflammatory response after myocardial infarction, attempts to identify the causes for the translational failures of the past, and proposes promising new therapeutic directions. Because of their potential involvement in injurious, reparative, and regenerative responses, inflammatory cells may hold the key for design of new therapies in myocardial infarction. (Translational Research 2015;-:1–15)

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INTRODUCTION From the Department of Medicine (Cardiology), The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY. Submitted for publication April 2, 2015; revision submitted July 8, 2015; accepted for publication July 9, 2015. Reprint requests: Nikolaos G. Frangogiannis, Department of Medicine (Cardiology), The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer G46B, Bronx, NY 10461; e-mail: [email protected]. 1931-5244/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.trsl.2015.07.002

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n myocardial infarction, coronary artery occlusion causes ischemia of the territory subserved by the vessel, eventually leading to death of up to a billion cardiomyocytes.1 The adult mammalian heart has negligible regenerative capacity; thus, acute myocardial infarction is associated with loss of a large amount of myocardium that is replaced by a collagen-based scar. Necrosis of ischemic cardiomyocytes triggers an intense inflammatory reaction that serves to clear the wound from dead cells and matrix debris and contributes to formation of a collagen-based scar.2 Abundant leukocytes infiltrate the infarcted myocardium and are predominantly 1

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localized in the infarct border zone where they may interact with viable cardiomyocytes. In the 1980s and 1990s, a large body of experimental evidence suggested that inflammatory leukocytes may extend ischemic injury, exerting potent cytotoxic effects on border zone cardiomyocytes.3 These observations generated significant enthusiasm regarding the potential use of targeted anti-inflammatory strategies to reduce infarct size and to attenuate injury after myocardial infarction. Unfortunately, clinical trials inhibiting leukocyte integrins and the complement cascade to attenuate postinfarction inflammation were disappointing.4,5 The failures of the clinical studies markedly dampened enthusiasm regarding the translational potential of the field. This is unfortunate, because inflammatory signaling is implicated in repair and remodeling of the infarcted heart. Thus, targeting inflammatory mediators may exert beneficial actions by attenuating dilative remodeling of the infarcted heart. Moreover, recent observations suggesting cytoprotective and regenerative actions of inflammatory signals have (once again) fueled interest in the field. This review article deals with the potential role of the inflammatory cascade as a therapeutic target in myocardial infarction. After a brief overview of the cellular effectors and molecular signals implicated in the postinfarction inflammatory reaction, promising therapeutic approaches targeting the inflammatory response have been discussed. Dissection of the molecular signals regulating induction and resolution of postinfarction inflammation needs to be complemented by understanding of the pathophysiological complexity of the clinical context to design effective therapeutic approaches for patients with myocardial infarction. THE INFLAMMATORY RESPONSE IN MYOCARDIAL INFARCTION

Healing of the infarcted heart can be divided into 3 distinct but overlapping phases: the inflammatory phase, the proliferative phase, and the maturation phase.6 During the inflammatory phase, danger signals (alarmins) released from dying cardiomyocytes activate innate immune pathways inducing chemokine and cytokine synthesis, and stimulating adhesion molecule expression on vascular endothelial cells (Fig 1). Experimental studies have suggested that high mobility group box 1, heat shock proteins, adenosine, extracellular RNA, matrix fragments, and interleukin (IL)-1a released from necrotic cardiomyocytes may stimulate the innate immune response initiating the postinfarction inflammatory cascade.7-10 The relative role of specific cardiomyocyte-derived alarmins in activation of the postinfarction inflammatory response remains unknown. Alarmins released by necrotic cells activate

toll-like receptor and receptor for advanced glycation end-products–dependent pathways in vascular endothelial cells, immune cells, and fibroblasts inducing synthesis of chemokines and cytokines.11,12 Activation of the complement cascade is also prominent in the infarcted heart and stimulates downstream proinflammatory pathways.13-15 Proinflammatory cytokines, such as tumor necrosis factor (TNF)-a, IL-1b, and IL-6, released by leukocytes, fibroblasts, endothelial cells, and cardiomyocytes induce adhesion molecule and chemokine synthesis promoting recruitment of leukocytes into the infarcted area.16-18 IL-1 signaling plays a central role in activation of the postinfarction inflammatory reaction, stimulating chemokine expression by leukocytes and fibroblasts,19 whereas preventing premature conversion of the abundant cardiac fibroblasts into matrix-synthetic myofibroblasts.20 The inflammasome, a molecular platform that triggers caspase-1 activation and mediates subsequent cleavage of active pro–IL-1b into IL-1b, plays an important role in generation of bioactive IL-1 in the infarct. In vivo evidence has demonstrated that activation of the inflammasome is localized in both cardiomyocytes and interstitial cells in the infarcted heart.21,22 Chemokine upregulation is a hallmark of the postinfarction inflammatory response and mediates recruitment of proinflammatory leukocyte subsets in the infarcted heart.23 CXC chemokines containing the Glu-Leu-Arg sequence (the ELR motif), such as CXCL8/IL-8, are secreted in the infarct,24 and stimulate recruitment of neutrophils, whereas CC chemokines, such as monocyte chemoattractant protein (MCP)-1/ CCL2 and CCL7, mediate recruitment of proinflammatory monocytes.25-27 Infiltrating leukocytes phagocytose dead cells and matrix debris and set the stage for activation of reparative cells. Apoptosis of infiltrating neutrophils marks the end of the inflammatory phase. Professional phagocytes clear the infarct from apoptotic cells28,29; this process known as efferocytosis is associated with release of antiinflammatory cytokines, such as IL-10 and transforming growth factor (TGF)-b, and may play an important role in suppression of the postinfarction inflammatory response. In addition to the role of secreted anti-inflammatory mediators, activation of endogenous intracellular signals that restrain the immune response (such as IL receptor– associated kinase-M) suppresses proinflammatory cascades in the healing infarct.30 Suppression of inflammatory signaling and resolution of the inflammatory infiltrate are dependent on infiltration of the infarct with inhibitory leukocyte subsets, such as anti-inflammatory monocyte subpopulations31 and regulatory T cells.32,33 Moreover, modulation of cardiac macrophages toward an anti-inflammatory

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Fig 1. The postinfarction inflammatory reaction exerts both protective and detrimental actions on the infarcted heart. Necrotic cardiomyocytes release danger signals that activate innate immune responses leading to induction of cytokines and chemokines. CXC and CC chemokines bind to glycosaminoglycans on the endothelial surface and mediate recruitment of neutrophils and mononuclear cells in the infarcted area. Infiltrating leukocytes exert a wide range of protective and detrimental actions on the infarcted heart. It has been proposed that infiltrating neutrophils may extend ischemic injury exerting cytotoxic and proapoptotic actions on cardiomyocytes. Moreover, leukocyte-derived secretory products may have negative inotropic effects and proteases may increase matrix degradation causing adverse remodeling of the infarcted heart. Other actions of leukocytes may be protective. Thus, leukocyte subsets may phagocytose dead cells and matrix debris and may promote repair by activating endothelial cells and fibroblasts. Recent studies have suggested that subsets of myeloid cells may also exert prosurvival and regenerative actions on cardiomyocytes. eRNA, extracellular RNA; HMGB1, high mobility group box 1; HSP, heat shock proteins; IL-1a, interleukin 1a.

phenotype may contribute to suppression of inflammatory cytokine and chemokine expression.34,35 Surviving cardiomyocytes in the infarct border zone may also limit inflammation by secreting mediators with antiinflammatory properties.29,36 Because unrestrained activity, temporal prolongation, or spatial expansion of the inflammatory reaction result in accentuated cardiac remodeling and worse dysfunction, defective negative regulation of the postinfarction inflammatory response may be implicated in the pathogenesis of heart failure in patients surviving an acute myocardial infarction (Fig 2).37 As proinflammatory signaling is suppressed, activated myofibroblasts become the predominant cell type in the healing infarct. Infarct myofibroblasts are phenotypically modulated fibroblasts, primarily localized in the infarct border zone that express contractile proteins (such as a-smooth muscle actin and the embryonal isoform of smooth muscle myosin),38,39 but do not synthesize the SM1 and SM2 isoforms of smooth muscle myosin heavy chain.38 Their origin is debated: proliferation and activation of resident fibroblast populations, endothelial to mesenchymal transdifferentiation, recruitment of circulating and resident fibroblast

progenitors, and modulation of cardiac pericytes have been proposed as potential sources for the abundant myofibroblasts in the infarct border zone. Recent lineage-tracing studies have suggested that resident epicardium-derived fibroblasts may be the main source of myofibroblasts in healing myocardial scars.40 Infarct myofibroblasts secrete both structural and matricellular proteins in the healing infarct. Deposition of structural matrix proteins (such as collagens) preserves the integrity and geometry of the ventricle. On the other hand, incorporation of matricellular proteins into the matrix network plays an important role in transducing cytokine and growth factor-mediated signals from the cardiac interstitium to the cellular elements, thus contributing to the plasticity of the infarct environment.41-44 The renin-angiotensin-aldosterone system, TGF-b, plateletderived growth factor, and the mast cell–derived proteases tryptase and chymase play an important role in activating fibroblasts in the healing infarct.45-48 During the maturation phase, proliferative activity of the fibroblasts is suppressed and deposition of new matrix proteins is inhibited. Little is known regarding the pathways and inhibitory signals that terminate the fibrotic response in the infarct. During the inflammatory

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Fig 2. The consequences of excessive, prolonged, and expanded inflammatory responses on the remodeling infarcted heart. Overactive or prolonged inflammation may accentuate matrix degradation by stimulating protease activation. Increased cytokine expression may increase cardiomyocyte apoptosis and suppress contractility. Defects in spatial containment of the postinfarction inflammatory response may result in extension of inflammatory injury in the viable myocardial areas leading to expansion of fibrosis. Impaired negative regulation of postinfarction inflammation may cause adverse dilative remodeling and accentuate systolic dysfunction.

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and proliferative phase of infarct healing, the antifibrotic chemokine interferon-g–inducible protein 10/CXC L10 is upregulated in the infarcted area and inhibits fibroblast migration, preventing an overactive fibrotic response.49,50 Whether, inducible protein 10 or other antifibrotic mediators are involved in scar maturation remains unknown. As the scar matures, the collagenous matrix is cross-linked and reparative infarct myofibroblasts become quiescent or may undergo apoptosis. However, in large infarcts, interstitial cell activation persists in the infarct border zone and in remodeling noninfarcted myocardial segments, likely reflecting regional alterations of the cardiac mechanics because of loss of contractile myocardium and the effects of pressure and volume overload on the surviving myocardium. TARGETING INFLAMMATION IN MYOCARDIAL INFARCTION. LESSONS FROM PAST TRANSLATIONAL FAILURES The concept of cytotoxic inflammatory injury. Several observations fueled the notion that inflammation may

extend ischemic injury after myocardial infarction. First, the idea that the inflammatory reaction triggered to clear the infarcted heart from dead cells may be inherently overactive for the delicate requirements of the myocardium. Inflammatory cascades did not evolve to protect the injured heart. In most species, cardiovascular disease is an uncommon cause of death. In humans, heart disease is a major cause of morbidity and mortality; however, myocardial infarction occurs past the reproductive age and would not be expected to impose any evolutionary pressures on the inflammatory cascade. Thus, inflammatory processes evolved as a response to traumatic injury and as a protective shield from pathogenic organisms and may be excessive for the sterile environment of the infarcted heart.51 Second, in the infarcted myocardium, leukocytes infiltrate the viable border zone, where they may interact with surviving cardiomyocytes. Through the production of proteases, cytokines, and reactive oxygen species, neutrophils and proinflammatory monocytes may exert cytotoxic actions on viable cardiomyocytes extending ischemic injury. In a large

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animal model of reperfused myocardial infarction, neutrophil depletion was reported to reduce infarct size by more than 40% providing strong support for a leukocyte-driven mechanism responsible for extension of ischemic injury.52 The deleterious effects of neutrophils on cardiomyocytes were supported by in vitro evidence suggesting that activated neutrophils adhere to stimulated cardiomyocytes through integrin/ intercellular adhesion molecule 1 interactions and induce oxidative injury.3 It should be noted that experimental evidence did not consistently support the deleterious effects of the neutrophils in accentuating cardiomyocyte death after myocardial ischemia, as neutrophil depletion studies failed, in some cases, to reduce infarct size.53 Thus, the role of the neutrophils in extending ischemic myocardial injury has remained controversial.54 Broad-range anti-inflammatory strategies may have catastrophic consequences on repair of the infarcted heart. If inflammation extends ischemic injury,

broad inhibition of the inflammatory response with corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs) could confer significant protection to the infarcted myocardium. It should be noted that the therapeutic use of corticosteroids in acute myocardial infarction was proposed before the development of the inflammatory injury hypothesis based on experimental studies suggesting protective actions on cell survival and cardiomyocyte metabolism.55 Clinical studies on the use of corticosteroids in patients with myocardial infarction have produced conflicting results and, in some cases, raised significant concerns regarding the safety of this approach.56,57 In vivo experiments have suggested that corticosteroid treatment impairs clearance of the infarct from dead cells and may disrupt fibroblast function58; these effects would be expected to be detrimental in repair of the infarcted heart. NSAIDs also exert a broad range of anti-inflammatory actions mediated through inhibition of cyclooxygenase. In animal models of myocardial infarction, use of NSAIDs had both beneficial actions (on acute infarct size) and detrimental effects (on the reparative response). Treatment with ibuprofen reduced infarct size59; the protective effects were presumed because of attenuated leukocyte infiltration.60 However, observations in a canine model of nonreperfused infarction suggested that reduced inflammation in animals treated with NSAIDs is associated with marked thinning of the scar.61 Clinical investigations showed an association between the use of NSAIDs and adverse outcome after myocardial infarction, at least in part because of increased incidence of cardiac rupture.62 Thus, nonselective inhibition of the inflammatory cascade has potentially catastrophic consequences on the

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reparative response. On the basis of this concern, current guidelines recommend against the use of broad-range anti-inflammatory therapy (corticosteroids and NSAIDs) in patients with acute myocardial infarction.63 Selective

inhibition

of

inflammatory

signaling.

Advances in understanding of the biology of inflammation suggested that targeted inhibition of selected inflammatory pathways may afford protection to the infarcted heart without disturbing the reparative response. Extensive experimental evidence demonstrated that neutralization of specific inflammatory mediators (including leukocyte integrins, endothelial adhesion molecules, cytokines, and chemokines) has impressive beneficial effects in large animal models of reperfused myocardial infarction, markedly reducing the size of the infarct. Approaches targeting CD11/ CD18 integrins seemed particularly promising: the bulk of experimental evidence derived from a wide range of animal models, ranging from rats to primates, showed impressive reduction in infarct size on treatment with neutralizing antibodies.4,64-69 The protective actions were presumed because of reduced infiltration of the infarct with neutrophils65 and to attenuated neutrophil-induced cardiomyocyte injury. Unfortunately, the beneficial effects of anti-integrin targeting in animal models could not be reproduced in clinical studies. In 3 small clinical trials, anti-integrin approaches failed to reduce the size of the infarct in patients with myocardial infarction.5,70,71 Approaches targeting the complement system, an upstream activator of the innate immune response, were equally disappointing. In the Assessment of Pexelizumab in Acute Myocardial Infarction Clinical trial, 5745 patients with STEMI received the anti-C5 antibody pexelizumab as an intravenous bolus before percutaneous intervention followed by continuous infusion for more than the next 24 hours. Pexelizumab administration did not affect 30-day mortality and the composite end point of death, cardiogenic shock, and congestive heart failure.72 Moreover, administration of the P-selectin inhibitor inclacumab in patients with acute coronary syndromes reduced the release of enzymes associated with cardiomyocyte necrosis, but was associated with trends toward worse clinical outcome.73,74 Considering the great enthusiasm generated by the impressive results of the animal model studies, what are the possible causes of these translational failures? The anti-inflammatory strategies used in clinical trials may have been suboptimal. Translation of a therapeutic

approach from the animal model to the clinical context is not dependent solely on implementation of a sound pathophysiological concept, but also requires careful planning of the strategy to maximize the likelihood of

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success. Selection of an appropriate molecular target, identification of an effective therapeutic agent, correct timing, and optimal delivery of the agent in the infarcted area are all crucial for successful translation of the approach. Ultimately, understanding the basis for failure of anti-integrin and complement inhibition strategies requires assessment of the effectiveness of these strategies in inhibiting the myocardial inflammatory response. Unfortunately, such data are lacking. In a subgroup of patients enrolled in the Assessment of Pexelizumab in Acute Myocardial Infarction trial, assessment of circulating biomarkers suggested that pexelizumab was not successful in suppressing most indicators of inflammation.75 Although use of circulating biomarkers as a window to the myocardial inflammatory response is inherently problematic, ineffective suppression of inflammation may provide an explanation for the negative trial. Moreover, experimental studies suggested that the protective actions of integrin inhibition on the infarcted myocardium are variable and may be dependent on the specific characteristics of the antibody used.76 Protective actions could only partially be predicted by the extent of inhibition of neutrophil infiltration.76 Future strategies targeting postinfarction inflammation need to include systematic assessment of the effectiveness of the approach in attenuating several distinct aspects of the inflammatory response through a combination of in vivo imaging approaches and analysis of circulating biomarkers. Inflammation may not extend cardiomyocyte death after myocardial infarction. An alternative explanation

of the translational failure of anti-inflammatory approaches may be that, despite the abundant evidence in animal models of myocardial infarction, acute inflammatory cardiomyocyte injury may be of limited significance in human myocardial infarction. Considering the intense inflammatory reaction triggered after infarction in both human patients with STEMI and in animal models of infarction, the disconnect between the human clinical studies and the animal model investigations is unlikely to be explained only by species-specific effects, but may reflect the limitations of animal model experiments. First, enthusiasm regarding the effectiveness of antiinflammatory strategies in myocardial infarction derived by early inhibition experiments in large animal models may have been premature and somewhat misguided. In contrast to the impressive protective effects of antibody neutralization in large animal models, a more recent body of work in genetically targeted mice has challenged the notion that postinfarction inflammation extends ischemic cardiomyocyte injury. Mice lacking Pselectin and intercellular adhesion molecule 1,77

animals with defective IL-1 signaling,19 and MCP-1 knockouts25 had no significant reduction in infarct size, despite a marked attenuation of the postinfarction inflammatory response. Second, animal models cannot recapitulate the pathophysiological complexity and heterogeneity of the clinical context. Outcome in human patients with myocardial infarction is affected by a wide range of factors. Differences in gender, age, genetic profile, the pattern of coronary disease, comorbid conditions (including diabetes, obesity, hypertension, and hyperlipidemia), and treatment with various pharmacologic agents have profound effects on the pathophysiological response to myocardial infarction. In contrast, in a well-designed animal study, the goal is to eliminate variability to test a specific hypothesis. Experimental animals are healthy, matched for gender and age, and have an identical genetic profile so that the consequences of a very specific genetic or pharmacologic intervention can be studied. For this reason, animal model studies are optimally used to gain pathophysiological insights and not to predict effectiveness of a therapeutic approach. Experiments in senescent animals illustrate the impact of age on the inflammatory and reparative response after myocardial infarction. Senescent mice exhibited significantly suppressed (and somewhat prolonged) inflammatory activation after myocardial infarction, associated with defective activation of growth factor signaling and impaired collagen deposition.78 Considering that the conclusions on the effectiveness of anti-integrin approaches in myocardial infarction were derived from experimental studies performed in young mammals (known to exhibit very robust inflammatory reactions), the translational failure may reflect, at least in part, the suppressed inflammatory activation in aged human populations presenting with myocardial infarction. USE OF TARGETED ANTI-INFLAMMATORY STRATEGIES TO IMPROVE REPAIR AND TO REDUCE ADVERSE POSTINFARCTION REMODELING

The failures of anti-inflammatory strategies in myocardial infarction may reflect the limited role of inflammatory cardiomyocyte injury during the early stages of infarction. However, inflammation is critically involved in repair and remodeling of the infarcted heart. Inflammatory pathways have been implicated in recruitment of progenitor cells that may play a crucial role in infarct angiogenesis and cardiac repair.79 Chemokines (such as stromal cell–derived factor [SDF]-1/CXCL12 and MCP-3) mediate homing of progenitor cell subpopulations in the infarcted myocardium.80,81 Growth factors, such as stem cell factor, hepatocyte growth factor, and vascular endothelial growth factor are also

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upregulated in the infarcted myocardium82,83 and may be involved in recruitment and activation of stem cell subsets. On the other hand, prolonged or expanded proinflammatory signaling may accentuate adverse remodeling by activating proteases, transducing proapoptotic cascades in cardiomyocytes, and promoting matrix degradation. Extensive experimental work suggests that overactive, temporally prolonged,30 or spatially expanded42 inflammation may cause dilative remodeling after myocardial infarction. Highly selective approaches to inhibit inflammation-driven protease activation and to promote recruitment of reparative cells may exert beneficial actions on the infarcted heart by stimulating repair, reducing adverse remodeling, and preventing the development of postinfarction heart failure. Several inflammatory mediators have shown promise as therapeutic targets. THE CHEMOKINES

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The chemokines are a large family of small (8–14 kDa) chemotactic cytokines with a crucial role in regulating immune function and inflammatory responses.84 On a structural basis, chemokines are classified into 4 subfamilies according to the presence of one or more amino acids between the N-terminal cysteine residues region (CC, CXC, CX3C, and XC subfamilies). Most chemokines belong to CC and CXC subfamilies. The structural differences between the chemokines have important functional implications. CC chemokines are potent mononuclear cell chemoattractants, whereas CXC chemokines that contain the ELR motif preceding the first amino terminal cysteine mediate chemotactic recruitment of neutrophils.85 Experimental studies in animal models of myocardial infarction demonstrated that several members of the chemokine family are rapidly and consistently upregulated in the infarcted heart and may play an important role in regulation of the postinfarction inflammatory response.23 Certain members of the family, including MCP-1/CCL2 and SDF-1/CXCL12 have shown promise as potential therapeutic targets. The findings of experimental studies targeting chemokine family members in myocardial infarction are summarized in Table I. CC chemokines. The CC chemokine MCP-1/CCL2 is rapidly upregulated in the infarcted myocardium and is predominantly expressed in vascular endothelial cells.97 Genetic disruption of MCP-1 or its receptor CCR2 attenuated adverse remodeling after myocardial infarction, inhibiting recruitment of proinflammatory monocytes and decreasing cytokine expression in the infarct.25,98 In a model of nonreperfused infarction, anti–MCP-1 therapy exerted beneficial actions on the infarcted ventricle, reducing mortality, attenuating chamber dilation, and improving systolic function.86

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Thus, experimental observations suggest that MCP-1/ CCL2 may be a promising therapeutic target after myocardial infarction. However, a word of caution should be raised by observations suggesting that genetic disruption of MCP-1 results in impaired phagocytosis of dead cardiomyocytes and delayed formation of granulation tissue.99,100 These defects may reflect decreased recruitment of monocytes and impaired macrophage maturation.25 The clinical consequences of impaired clearance of the infarct from dead cells cannot be predicted. Persistence of nonphagocytosed necrotic cardiomyocytes in the infarcted region may have adverse consequences on cardiac function and may be associated with dysrhythmic events in human patients with infarction. A recent study suggested that inhibition of the CC chemokine CCL5/RANTES (regulated on activation, normal T cell expressed, and secreted) may exert cardioprotective actions.88 RANTES neutralization decreased the size of the infarct and improved cardiac function 3 weeks after infarction, reducing expression of matrix metalloproteinase 9. Whether RANTES mediates recruitment a specific subset of proinflammatory mononuclear cells or promotes a matrix-degrading phenotype in leukocytes infiltrating the infarct remains unknown. Although MCP-1 and RANTES may be promising therapeutic targets, broad inhibition of CC chemokines may have detrimental actions. In a mouse model of reperfused infarction, genetic disruption of the CC chemokine receptor 5 (CCR5) was associated with accentuated dilative remodeling, presumed because of impaired recruitment of inhibitory monocyte subsets and regulatory T cells.101 Thus, certain chemokine-chemokine receptor interactions may be important in repression and resolution of postinfarction inflammation through recruitment of anti-inflammatory leukocyte subpopulations. ELR1 CXC chemokines. Although ELR1 CXC chemokines are markedly upregulated in the healing infarct and mediate neutrophil infiltration,24,102 their potential therapeutic role has not been systematically studied. Early experiments suggested that IL-8/CXCL8 inhibition in rabbits undergoing ischemia/reperfusion protocols reduced infarct size; surprisingly, the beneficial effects were not associated with attenuated neutrophil infiltration.90 Enthusiasm about neutrophil chemoattractant chemokines as therapeutic targets in myocardial infarction was dampened by the translational failures of anti-integrin approaches. However, a recent investigation in a mouse model of myocardial ischemia/reperfusion suggested that treatment with evasin-3, a protein that binds and neutralizes neutrophil chemoattractant CXC chemokines, reduces infarct size by attenuating leukocyte recruitment.103

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Table I. Experimental studies targeting the chemokines in myocardial infarction: functional outcome and histopathologic consequences Target

Approach

Animal model

Timing of intervention/route

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MCP-1/CCL286

Gene transfection

Mouse (PO)

3 d before and 14 d after PO/IM

MCP-1/CCL287

Competitive inhibition

Mouse (I/R)

MCP-1/CCL218

Ab neutralization

Rat (I/R)

100 after I, 2 h after R, and daily up to 7 d/IP IV

RANTES/CCL588

Ab neutralization

Mouse (PO)

50 and 3 d after PO/IV

Fractalkine/ CX3CL189

Ab neutralization

Mouse (PO)

Daily from 7 to 14 d after PO/IP

IL-8/CXCL890 SDF-1/CXCR491

Ab neutralization Hydrogel delivery system Hydrogel delivery system

Rabbit (I/R) Rat (PO)

150 after R/IV At time of PO/into the border zone At time of PO/into the border zone

Hydrogel delivery system Administration of a small molecule CXCR4 antagonist Administration of a small molecule CXCR4 antagonist Administration of a small molecule CXCR4 antagonist

Mouse (PO)

SDF-1/CXCR492

SDF-1/CXCR493 SDF-1/CXCR494

SDF-1/CXCR495

SDF-1/CXCR496

Sheep (PO)

Mouse (I/R)

Rat (PO)

Mouse (PO)

Outcome

Improved survival, attenuated LV dilation, reduced contractile dysfunction, comparable infarct size Preserved LV function, reduced infarct size Reduced infarct size Smaller infarct size, improved survival and LV function Delayed progression of LV enlargement and improved LV function, smaller infarct size Reduced infarct size Preserved LV geometry, improved systolic function Preserved systolic LV function, reduced infarct size

Histopathologic/molecular consequences

Attenuated interstitial fibrosis, reduced macrophage recruitment, attenuated myocardial expression of TNF-a and TGF-b Reduced monocyte infiltration, reduced collagen and myofibroblast content in the infarcted area Q19 Decreased macrophage infiltration, reduced ICAM-1 mRNA expression Reduced neutrophil and macrophage infiltration, reduced cardiac MMP-9, lower collagen content Reduced ICAM-1 in vascular endothelium

Comparable neutrophil infiltration Improved angiogenesis Q20

Preserved cardiac function Smaller infarct size, improved LV function

IP injection or oral administration 24 h post-MI, for 6 d Acute treatment: single-dose, SC, 1 h after infarction Chronic treatment: infusion for more than 2 wk

Smaller scar size, improved LV systolic function

Attenuated atrial natriuretic peptide expression in remodelling myocardium

Acute: improved LV function and survival Chronic: increased adverse remodeling

Acute: enhanced angiogenesis, attenuated inflammation, reduced incorporation of endothelial progenitor cells Chronic: reduced capillary density

Abbreviations: I/R, ischemia/reperfusion; ICAM-1, intercellular adhesion molecule 1; IM, intramuscularly; IP, intraperitoneally; IV, intravenously; MCP, monocyte chemoattractant protein; MMP, matrix metalloproteinase; mRNA, messenger RNA; LV, left ventricular; PO, permanent occlusion; SC, subcutaneously; SDF-1, stromal cell–derived factor 1; TGF, transforming growth factor; TNF, Q2 tumor necrosis factor.

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At time of PO/into the border zone At reperfusion/SC

Reduced MMP-2 in the infarct border zone, increased levels of TIMP-1 and elastin in the infarct, increased capillary and arteriolar density Suppressed neutrophil infiltration, increased angiogenesis, reduced apoptosis Increased capillary density, mobilization of endothelial progenitors

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The ELR-negative CXC chemokine SDF-1/CXCL12 has potent angiogenic properties, activates prosurvival pathways in cardiomyocytes, and enhances the regenerative capacity of progenitor cells.104 Thus, it is not surprising that treatment with SDF-1 has been considered as a therapeutic strategy for patients with myocardial infarction. The effectiveness of SDF-1 therapy is supported by extensive experimental evidence. Treatment with SDF-1 reduced infarct size, promoting cardiomyocyte survival and accentuating angiogenesis in experimental models of myocardial infarction.105,106 Several protective mechanisms have been suggested. First, SDF-1–induced angiogenesis in the infarct and border zone may improve the quality of the scar attenuating systolic dysfunction. Second, SDF-1 may exert direct antiapoptotic actions on cardiomyocytes or may promote chemotaxis of a CXCR41 myeloid cell subset that secretes cytoprotective mediators.107 Third, SDF-1 may promote repair and regeneration through recruitment of progenitor cells. Extensive evidence suggests that SDF-1 is critically implicated in mobilization and trafficking of hematopoietic stem cells,108 and mediates homing of endothelial progenitor cells in ischemic tissues.80 In recent studies, novel synthetic analogs of SDF-1 in both rodent and large animal models of myocardial infarction have been tested. Injection of a biomimetic hydrogel containing a combination of SDF-1 and angiogenic peptides reduced the size of the infarct and improved angiogenesis in a rat model of myocardial infarction.109 In both rat and ovine models, administration of a bioengineered SDF-1 analog in the infarct border zone induced chemotaxis of endothelial progenitor cells and preserved ventricular function, improving left ventricular mechanics.91,92 Although these experimental studies are promising, it should be emphasized that SDF-1 may also exert proinflammatory actions. The pleiotropic, cell-specific, and contextdependent actions of SDF-1 are highlighted by the conflicting observations reported in SDF-1 antagonism studies. Some investigations showed that SDF-1 inhibition accentuated dysfunction (supporting the protective actions of the chemokine revealed by the gain-offunction approaches),110 whereas other studies suggested beneficial effects.95,96 Fractalkine/CX3CL1. The CX3C chemokine fractalkine exists in membrane-anchored and soluble forms and may regulate trafficking and function of immune cells. Its role in myocardial infarction remains poorly understood. In a mouse model of myocardial infarction, fractalkine expression was markedly increased in the viable remodeling myocardium111; fractalkine inhibition delayed progression of chamber dilation, attenuating Stromal cell–derived factor 1.

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proinflammatory and matrix-degrading pathways.89 Thus, fractalkine may hold promise as a therapeutic target to attenuate adverse postinfarction remodeling. THE CYTOKINES Targeting the IL-1 system. The prototypical proinflammatory cytokine IL-1 plays a crucial role in stimulation of the postinfarction inflammatory response and is involved in the pathogenesis of cardiac remodeling. Thus, targeting the IL-1 signaling cascade may be a promising therapeutic target for patients with myocardial infarction. In experimental models of myocardial infarction, IL-1a is released by dying cardiomyocytes,9 whereas IL-1b synthesis is markedly upregulated after infarction16 and is predominantly localized in leukocytes and vascular cells.112 Both genetic and pharmacologic strategies disrupting IL-1 signaling have been shown to protect the infarcted heart from adverse remodeling. Genetic loss of the type 1 IL1 receptor (IL-1R1) attenuates dilation of the infarcted heart, reducing adverse remodeling.19 Pharmacologic approaches targeting the IL-1 system have also been tested in models of myocardial infarction. The availability of safe and effective pharmacologic strategies to inhibit IL-1 signaling in human patients provides promising therapeutic tools. Anakinra, a nonglycosylated recombinant form of IL-1 receptor antagonist (IL-1Ra) binds to the IL-1R1 without activating a signaling response, thus functioning as a competitive inhibitor for both IL-1a and IL-1b. Anakinra has been approved for treatment of patients with rheumatoid arthritis who fail to respond to disease modifying agents. Anti–IL-1b antibodies (such as canakinumab) provide more selective options, specifically targeting IL-b signaling and have been approved for treatment of autoinflammatory diseases and certain forms of inflammatory arthritides. Treatment with anakinra reduced chamber dilation in a rat model of myocardial infarction113; administration of an anti–IL-1b antibody in a mouse model of nonreperfused infarction also exerted protective actions.114 The protective effects of IL-1 blockade may be only in part mediated through reduction in the size of the infarct. Attenuation of IL-1–driven protease activation in the cardiac interstitium may be implicated in protection from adverse remodeling. Small clinical trials have tested the effectiveness of IL-1 inhibition in patients with myocardial infarction. Pilot studies have suggested that anakinra can be safely administered as a 2-week course in patients with STEMI and may attenuate adverse remodeling, and at the same time protecting from the development of postinfarction heart failure.115-117 Because IL-1 has been implicated in

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the pathogenesis of the vulnerable plaque, a large clinical trial is currently underway to examine the effectiveness of IL-1b antibody inhibition in prevention of cardiovascular events in postmyocardial infarction patients with accentuated systemic inflammatory responses.118 Although both experimental and early clinical findings suggest that IL-1 inhibition may hold promise for treatment of patients with myocardial infarction, a word of caution should be raised regarding cytokine inhibition in patients with heart disease. Cytokines are notoriously pleiotropic and multifunctional and are known to exert a wide range of context-dependent actions on all cell types involved in cardiac injury and repair. In the infarcted and remodeling heart, cytokines may exert both beneficial and detrimental effects; thus, prediction of the consequences of cytokine inhibition in the clinical context is challenging. The failure of antiTNF strategies in patients with heart failure highlights the challenges in implementation of targeted anticytokine approaches in patients with cardiovascular disease. However, it should be noted that, in contrast to TNF-a, IL-1 is not known to exert protective actions on cardiomyocytes. Studies in patients with rheumatoid arthritis suggest protective actions of anakinra on myocardial function.119,120 Targeting the TGF-b cascade. Members of the TGF-b family are critically involved in regulation of inflammation and fibrosis in a wide range of pathophysiological conditions.121 It has been suggested that after myocardial infarction TGF-b may serve as the ‘‘master switch’’ that deactivates inflammatory macrophages, and at the same time promoting fibrosis.122 Clearly, this concept represents an oversimplification. TGF-b modulates phenotype and function of all cell types involved in cardiac repair, activating both Smaddependent and Smad-independent signaling.123,124 The effects of TGF-b inhibition may be dependent on timing: early neutralization of TGF-b may prolong inflammation and enhance the incidence of cardiac rupture; late suppression may attenuate profibrotic signaling improving diastolic function. Because TGF-b plays an important role in preservation of cardiovascular homeostasis, targeting the TGFb system in heart failure may carry significant risks, promoting aneurysmal rupture in vulnerable patients.125-127 Dissection of downstream signaling effectors and identification of specific TGF-b–activated pathways associated with postinfarction remodeling and dysfunction are needed to design safe and effective therapy for patients with myocardial infarction. Do inflammatory mediators transduce cytoprotective and regenerative signals? Identification of cytoprotective

and regenerative actions of leukocyte subsets contributes

an additional layer of complexity to the effects of inflammatory cells on the infarcted heart.128 Experiments in models of neonatal cardiac injury suggested that subpopulations of macrophages with unique phenotypic profiles may promote cardiomyocyte proliferation activating a regenerative program.129,130 The signals that may drive macrophages toward a regenerative phenotype remain unknown. In adult mice, a recent investigation identified myeloid-derived growth factor, as a novel mediator released by a subset of CXCR4expressing macrophages, that protects cardiomyocytes from ischemic death.107 These findings suggest that inflammatory cells recruited in the infarcted heart not only debride the wound and contribute to scar formation, but may also exert direct protective actions on cardiomyocytes and may hold the key to cardiac regeneration. CHALLENGES IN IMPLEMENTATION OF ANTIINFLAMMATORY STRATEGIES IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

Inflammatory mediators exert a wide range of diverse functions on the infarcted heart. The involvement of inflammatory cells and their secretory products in both injurious and protective effects complicates our efforts to design effective therapy for patients with myocardial infarction. Experimental studies in animal models of myocardial infarction have identified several promising therapeutic targets. However, the failures of the antiintegrin and complement inhibition approaches, despite strong experimental evidence supporting their effectiveness, have generated skepticism regarding our ability to translate promising animal findings into clinical applications. It should be emphasized that investigations using animal models are essential for dissection of the pathophysiological mechanisms, but have limited value in predicting success of a therapeutic intervention in the clinical context. As discussed in the previous section, the complexities of the clinical context cannot be simulated in an experimental model. In view of these challenges, how can we optimally use insights from animal models to design effective strategies targeting the inflammatory response in human patients with myocardial infarction? Considering the pathophysiological heterogeneity of STEMI patients that may explain differences in susceptibility to adverse remodeling, there is a need to identify patients with overactive postinfarction inflammatory responses that may benefit from targeted anti-inflammatory strategies.37,131 Certain patient subpopulations, such as diabetics and the elderly, may exhibit dysregulated inflammatory reactions after myocardial infarction that may be responsible for accentuated remodeling and worse

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dysfunction. For example, diabetics have an increased incidence of heart failure after myocardial infarction despite a smaller infarct size and comparable systolic dysfunction.132 Development of postinfarction heart failure in diabetics is associated with diastolic dysfunction.133 In mice, diabetes and obesity are associated with cardiac fibrosis, hypertrophy, and overactive myocardial TGF-b/Smad signaling.43,127,134 A link between diabetes-associated TGF-b activation and fibrotic remodeling of the infarcted heart is plausible; thus, in these patients targeting the TGF-b system may be a promising therapeutic strategy. On the other hand, persistently increased circulating levels of proinflammatory mediators (such as MCP-1/CCL2) are associated with worse prognosis in patients with acute coronary syndromes. Targeted inhibition of inflammation may be effective in patients with defective negative regulation of proinflammatory signaling that may exhibit evidence of prolonged inflammatory activation Biomarkers and imaging approaches may be used to obtain information on activation of inflammatory pathways in each patient to personalize treatment options. CONCLUDING REMARKS

Activation of inflammatory cascades in the infarcted heart stimulates a range of cellular responses that clear the wound from dead cells and promote repair, but may also extend injury and cause adverse remodeling of the ventricle. Progress in understanding the cellular effectors and molecular signals regulating postinfarction inflammation has not yet translated into effective therapy. Future research should dissect protective and detrimental inflammatory pathways in animal models, and at the same time expand our understanding of the human pathophysiology. Identification and validation of biomarkers that may reflect specific perturbations of the inflammatory response in human patients may provide much-needed pathophysiological guidance for implementation of personalized treatment approaches.

ACKNOWLEDGMENTS

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Conflicts of Interest: All authors have read the journal’s policy on disclosure of potential conflicts of interest and have none to declare. Dr Frangogiannis’ laboratory is supported by the National Institutes of Health grants R01 HL76246 and R01 HL85440. Ilaria Russo is supported by training grants from the Fondazione Cassa di Risparmio di Lucca and the Fondazione Banca del Monte di Lucca. All authors have reviewed and approved the manuscript and have read the journal’s authorship agreement.

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