Nikolaos G. Frangogiannis
Abstract | Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair,
but which is also implicated in the pathogenesis of postinfarction remodelling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited to the infarcted area, remove dead cells and matrix debris by phagocytosis, while preparing the area for scar formation. Timely repression of the inflammatory response is critical for effective healing, and is followed by activation of myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor β family are critically involved in suppression of inflammation and activation of a profibrotic programme. Translation of these concepts to the clinic requires an understanding of the pathophysiological complexity and heterogeneity of postinfarction remodelling in patients with myocardial infarction. Individuals with an overactive and prolonged postinfarction inflammatory response might exhibit left ventricular dilatation and systolic dysfunction and might benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with an exaggerated fibrogenic reaction can develop heart failure with preserved ejection fraction and might require inhibition of the Smad3 (mothers against decapentaplegic homolog 3) cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies.
Frangogiannis, N. G. Nat. Rev. Cardiol.11, 255–265 (2014); published online 25 March 2014; doi:10.1038/nrcardio.2014.28 Introduction
More than 70 years ago, cardiac pathologists noted that
myocardial infarction triggers an intense inflammatory
reaction characterized by infiltration of leukocytes into the
infarcted heart.1 In the following decades, recognition of
the injurious properties of leukocytes and their close asso-
ciation with cardiomyocytes in the viable border zone of
an infarct suggested that subpopulations of blood-derived
cells can adhere to viable cardiomyocytes and might exert
cytotoxic effects extending ischaemic injury (Figure 1).2
In the 1980s and 1990s, experimental studies demon-
strated that targeting leukocyte-mediated inflammation
in reperfused myocardial infarction markedly reduced the
size of the infarct, and thereby prevented an extension of
ischaemic cardiomyocyte injury.3–6 Approaches targeting
molecules involved in leukocyte activation, adhesion, and
extravasation (such as integrins, selectins, and components
of the complement cascade) were successful in animal
studies in attenuating ischaemic injury, leading to con-
siderable enthusiasm for their potential use in humans.3–5
Unfortunately, despite promising data from animal studies,
translation of leukocyte-focused treatment into therapy
for human populations with myocardial infarction was
un s uccessful, and several anti-inflammatory approaches
failed to reduce infarct size in clinical investigations.6
The disappointment from these early negative clinical
results had lasting consequences in the field. Considering
the critical role of the inflammatory cascade in response
to cardiac injury, and the involvement of inflammatory
mediators in repair and remodelling of the infarcted heart,
the reduced interest in this therapeutic direction was
unfortunate. The pathogenesis of heart failure after myo-
cardial infarction is intricately linked with the develop-
ment of postinfarction ventricular remodelling. Structural,
functional, and geometric alterations that involve both the
infarcted and noninfarcted myo c ardial segments and lead
to chamber dilatation, increase spher i city of the ventricle
and cardiac dysfunction.7 Cardiac remodelling is asso-
ciated with the progression of heart failure, increased
incidence of arrhythmias, and poor prognosis in patients
surviving a myocardial infarction.8 The extent of post-
infarction remodelling is dependent on the infarct size
and quality of cardiac repair.9 Experimental studies have
called into question the notion that inflammatory signals
can extend ischaemic injury,10,11 but inflammatory path-
ways are undoubtedly critically involved in dilative and
fibrotic remodelling of the infarcted heart and, therefore,
drive key events in the pathogenesis of postinfarction
heart failure.
In this Review, I discuss the role of inflammatory signals
in regulating repair and remodelling of the infarcted heart,
and the attempts to identify therapeutic targets. From
advances in the understanding of pathophysiology of
cardiac remodelling, I will attempt to provide a guide for
development of anti-inflammatory treatments for patients
who survive a myocardial infarction.
Competing interests
The author declares no competing interests.
REVIEWS
Postinfarction inflammatory response
The adult mammalian heart has little regenerative capa-city, therefore, healing of the infarcted myo c ardium is dependent on an orchestrated sequence of cellular events that lead to the formation of a collagen-based scar. Repair of the infarcted myocardium can be described in three overlapping phases: the inflam m atory phase, the proliferative phase, and the maturation phase.12 Acute sudden death of cardiomyocytes in the infarcted heart rapidly activates innate immune pathways that trigger an intense, but transient, inflammatory reaction. This response clears the infarcted area of dead cells and extracellular matrix debris, and is then actively repressed to prepare the infarct for the proliferative phase of healing. During the proliferative phase, mononuclear cell and macrophage subpopulations secrete growth factors that recruit and activate mesenchymal repara-tive cells—predominantly myofibroblasts and vascular
cells. The myofibroblasts secrete large amounts of extra-cellular matrix proteins, thereby preserving the structural integrity of the left ventricle. Apoptosis of the majority of reparative cells marks the end of the proliferative phase, as the infarct matures and a scar comprised of cr o ss-linked collagen is formed.12
Necrosis and innate immune signals
Tissue injury generates endogenous signals that acti-vate the innate immune system; these molecules belong to a large family of mediators that warn the body of injury and are known as danger-associated molecular patterns (DAMPs).13,14 The term ‘alarmins’ describes a group of structurally diverse endogenous signals that, when released after tissue necrosis, promote activation of innate immune cells by binding to pattern recogni-tion receptors.15 The best characterized alarmin—high mobility group protein B1 (HMGB1)—is a key initiator of inflammatory injury following myocardial ischaemia through actions that might involve toll-like receptors (TLRs), a family of transmembrane receptors that activate downstream proinflammatory cascades, and the recep-tor for advanced glycation end products (RAGE).16,17 Considering the fundamental role of alarmin-mediated signalling in inflammation and repair, the fact that both detrimental 16,17 and beneficial 18 effects of HMGB1 have been reported in the infarcted m y ocardium is not surprising.
Other intracellular constituents released by necrotic cells, such as heat shock proteins and ATP , might also activate an immune response in the infarcted heart.13,19–21 The damaged extracellular matrix might also transduce key signals for activation of innate immune cells in the infarcted heart. Low molecular weight hyaluronan and fibronectin fragments can activate TLRs and function as important initiators of proinflammatory signalling.22,23
a
c
Figure 1 inflammatory reaction and infiltration of the infarct with abundant leukocytes. a | Canine infarct (1 h coronary occlusion/24 h reperfusion) stained with MAC387 (red), a marker for newly recruited myeloid cells (neutrophils and monocytes), and an antimacrophage antibody (black). Abundant, newly recruited leukocytes closely associated with viable cardiomyocytes. b | The same canine infarct after 7 days of reperfusion. The density of MAC387 positive cells is markedly reduced. However, mature macrophages are still abundant (black) reflecting repression of the acute inflammatory reaction. c | The close spatial association between leukocytes and viable cardiomyocytes in the border zone and the injurious potential of subsets of blood-derived cells generated the concept of leukocyte-mediated cardiomyocyte injury. Neutrophils interact with endothelial cells, roll along the endothelial surface, decelerate to a firm arrest, transmigrate across the vascular wall, infiltrate the infarct, and adhere to viable cardiomyocytes exerting cytotoxic effects and extending ischaemic injury. Infiltrating leukocytes are also important for infarct repair by releasing proteases and ROS, thereby clearing the wound from dead cells and debris. Abbreviation: ROS, reactive oxygen species.
Chemokines and cytokines
Activation of alarmin-mediated signalling induces a molecular programme that leads to the recruitment of inflammatory cells in the healing infarct. Induction of proinflammatory chemokines in the infarcted heart generates chemotactic gradients that recruit leukocyte subpopulations via interactions with the corresponding chemokine receptors. Upregulation of proinflammatory cytokines (such as tumor necrosis factor [TNF], IL-1β and members of the IL-6 family) induce endothelial cell adhe-sion molecule synthesis and activate leukocyte integrins, mediating strong adhesive interactions that ultimately lead to extravasation of inflammatory cells into the infarct.9
The role of chemokines
Expression of both major chemokine subfamilies (the CC and CXC chemokines) is increased in the infarcted heart and mediates recruitment of inflammatory leuko-cytes.31 CXC chemokines containing the tripeptide sequence Glu–Leu–Arg (known as the ELR motif, and also found in IL-8 in placental or eutherian mammals and the cor r esponding CXCR2 ligands in mice),32 are rapidly induced in the infarcted myocardium and mediate recruit-ment of neutrophils.33 Trafficking of mononuclear cell subsets involves CC chemokine signalling; distinct inter-actions between chemokines and their receptors might be respon s ible for recruitment of different sub p opulations of mononuclear cells. CC motif chemokine 2 (also known as monocyte chemoattractant protein 1 [MCP-1]) is rapidly upregulated in the infarcted myocardium and mediates recruitment of proinflammatory phagocytotic monocytes that clear the area of dead cells and matrix debris.34 Chemokines might also recruit inhibitory and reparative mononuclear cell subsets into the infarct; however, the specific chemokine–chemokine-receptor pairs mediating these cellular events remain poorly under-stood. Interactions involving the CC chemokine receptor type 5 might be involved in recruitment of mononuclear cell subpopulations with anti-inflammatory proper-ties, such as inhibitory monocyte subsets and regulatory T cells.35 Systematic characterization of monocyte subsets infiltrating the infarcted myocardium and understand-ing of the mechanisms mediating their recruitment has important therapeutic implications.
The role of proinflammatory cytokines Expression of the proinflammatory cytokines TNF, IL-1β, and IL-6 is markedly and consistently increased in experimental models of myocardial infarction.36,37 However, the pleiotropic properties of these cytokines and their multi f unctional effects on all cell types involved in cardiac injury and repair have hampered our under-standing of their functional roles in the infarcted and remodelling heart. TNF is released following myocardial infarction,38 and can promote inflammatory injury indu-cing chemokine and adhesion molecule synthesis in the infarcted myocardium.39 As a highly pleiotropic mediator, TNF can also protect cardiomyocytes from apop t osis.40 Divergent effects transduced through TNF receptors 1 and 2 might regulate remodelling of the infarcted heart.41 The failure of anti-TNF strategies in patients with chronic heart failure42 might reflect the pleio t ropic actions of the cytokine, and has discouraged the design of approaches targeting the pathway in myocardial infarction. IL-1β is also markedly induced in the infarct and mediates inflammatory leukocyte recruitment and activation,43,44 while delaying myofibroblast activation.44 No protective effects of IL-1 on cardiomyocytes have been reported, and because IL-1 neutralization can attenuate cardio-myocyte apoptosis in vitro and in vivo,45 inhibition of IL-1 following myocardial i n farction might have no major d etrimental consequences.46
IL-6 is also upregulated in the infarcted myocardium, and might modulate the inflammatory and reparative response signalling through IL-6 receptor subunit beta and activating the JAK/STAT (janus tyrosine kinase/ sig n al transducer and activator of transcription) cascade.47 Blocking IL-6 function has been effective in the treat-ment of rheumatic disorders.48 However, the pleiotropic effects of IL-6 in the healing infarct and the induction of other IL-6 receptor family members that might compen-sate for the loss of this cytokine, raise concerns about its potential role as a therapeutic target in patients with myo-cardial infarction. Experimental studies in IL-6-knockout mice demonstrated that the loss of IL-6 does not affect cardiac function and remodelling in a model of non-reperfused infarction.49 Other IL-6 family cytokines might compensate for the loss of IL-6 by activating JAK/STAT signalling and maintaining STAT3 phosphorylation. Conversely, treatment with an anti-IL-6 receptor anti-body attenuated adverse remodelling in a mouse model of nonreperfused infarction.50 Timely down r egulation of the IL-6 response might be important for infarct healing. In a mouse model of myocardial infarction, impaired sup-pression of IL-6 receptor/STAT3 signalling was associated with prolonged and enhanced inflammation increasing the incidence of cardiac rupture.51
Effectors of postinfarct inflammation
The inflammatory response in the infarcted myo-cardium involves cells that are normally found in the
REVIEWSheart and newly recruited cells (Figure 2); however, the relative contribution of the different cell types remains unclear. In the absence of injury, the adult mammalian myocardium contains relatively small populations of macrophages, mast cells,52 and dendritic cells.53 Cardiac resident mast cells contain preformed proinflammatory cytokines, and can be rapidly activated following myo-cardial ischaemia releasing their granular content and triggering the inflammatory cascade.38 ROS generation, adenosine, and complement factor C5a might stimu-late mast cell degranulation.54–56 The function of TLR ligands in this context is less convincingly established. In the early hours after myocardial infarction, leukocytes (neutrophils and mononuclear cells) rapidly infiltrate the infarct. Circulating neutrophils are recruited through acti-vation of both chemokine-dependent28 and chemokine-independent pathways.57,58 Monocyte subpopulations infiltrate the myocardium s e quentially—first by pro-inflammatory monocytes that are rapidly mobilized from the bone marrow and the splenic r e servoir.59 Recruitment of inflammatory monocytes into the infarcted heart is the result of marked upregulation of the MCP-1.34 Experiments in a mouse model of non r eperfused infarc-tion suggested that B lymphocytes might mediate chemokine-driven mobilization of proinflammatory monocytes in the infarct.60 Reparative monocytes follow the proinflammatory cells, but the signals involved their recruitment remain poorly understood. Macrophage subsets with proinflammatory properties also infiltrate the infarct and might sustain a proinflammatory environ-ment in the infarcted myocardium.61 The concept sug-gesting recruitment of two polarized populations of monocytes or macrophages in the infarct represents an oversimplification, because several subpopulations of cells with distinct functional properties (and perhaps also with varying potential for differentiation and activation) are probably recruited in the infarcted myocardium.
As the most abundant noncardiomyocyte population in the mammalian heart, fibroblasts might also contrib-ute to the initiation of the inflammatory reaction in the infarcted myocardium. Activation of the inflammasome cascade (the molecular platform that triggers activation of inflammatory caspases and processes pro-IL-1β) has been demonstrated in infarct fibroblasts,62 which might reflect an important role for these versatile cells in pro-inflammatory signalling. During the early stages of the postinfarction response, fibroblasts acquire a proinflam-matory and matrix-degrading phenotype; local release of
Figure 2 | The postinfarction inflammatory response. In the infarcted myocardium, dying cardiomyocytes and damaged matrix release DAMPs that activate TLR signalling in myocardial cells, triggering an inflammatory reaction. Activation of the complement cascade and ROS generation also help initiate the inflammatory reaction. Dying and surviving cardiomyocytes, endothelial cells, resident cardiac fibroblasts, resident mast cells and newly recruited neutrophils monocytes and platelets participate in the post-infarction inflammatory response. However, their relative contributions remain unclear. Leukocytes are recruited through activation of a multistep adhesion cascade.57 Capture (1) of circulating leukocytes by activated endothelial cells is followed by rolling (2), mediated through interactions involving the selectins. Rolling leukocytes are activated (3) by chemokines bound to PG on the endothelial surface. Activated leukocytes express integrins and adhere to endothelial cells (4). Strengthening of the adhesive interaction (5) between leukocytes and endothelial cells is followed by transmigration of the cells into the infarcted area (6). Abbreviations: C5a, complement factor 5a; DAMP, danger-associated molecular pattern; PG, proteoglycan; ROS, reactive oxygen species; TLR, Toll-like receptor.IL-1 might inhibit their conversion into matrix-synthetic myofibroblasts44 until the infarct microenvironment is cleared from dead cells and matrix debris and can support deposition of a new collagen-based matrix. The heart is abundant with blood vessels, endothelial cells might, therefore, be important in the synthesis and release of proinflammatory cytokines and chemokines.31 Descriptive studies in canine models have identifie d venular endothelial cells as an important source of chemo-kines in the infarcted myocardium.63, ROS generation and activation of TLR signalling by alarmins released by dying cells and matrix debris might mediate inflam-matory activation of the infarct endothelium. Platelets also accumulate within the infarcted myo c ardium and might be important for the inflammatory reaction, both through direct release of cytokines and chemokines and by m odulating phenotype of other cell types.65
Dying cardiomyocytes are crucial for triggering inflam-matory pathway activation through release of DAMPs; however, the potential role of viable border zone cardio-myocytes as a source of inflammatory mediators remains unclear. In a canine model of reperfused myocardial infarc-tion, border zone cardiomyocytes have been identified as a source of IL-6.66 However, noncardiomyocytes (includ-ing leukocytes, vascular cells, and fibroblasts) can produce large amounts of cytokines and chemokines;38,,67 there-fore, the relative importance of c a rdiomyocyte-derived inflammatory mediators is unknown.
Effective repair and inflammation
Repair of injured tissues is dependent on timely suppres-sion and containment of inflammation. This process is accompanied by activation of mesenchymal cells that restore tissue integrity. Extensive experimental work suggests that repression of proinflammatory signalling is not a passive process, but requires induction of inhibi-tory molecules and activation of suppressive pathways.68 In injured tissues, overactive, prolonged, or spatially expanded inflammatory reactions lead to accentu-ated damage and dysfunction. Myocardial function is intricately linked with preservation of structural integ-rity, impaired suppression or defective containment of inflammation in the injured heart can, therefore, have catastrophic consequences. Prolonging inflammatory signalling in the infarcted heart might have many con-sequences, including loss of cardiomyocytes, suppres-sion of systolic function, enhanced matrix-degrading processes leading to chamber dilation, increased tissue breakdown causing loss of ventricular wall integrity and cardiac rupture, and extended fibrotic changes beyond the initial infarct. Extensive experimental evidence, derived from mouse models with impaired repression or resolution of the inflammatory response, suggests that overactive inflammatory signalling leads to increased left ventricular dilatation following myocardial infarc-tion.11,35,69,70 Whether such defects lead to dilative remod-elling in humans has not been established. However, evidence from clinical studies suggests that patients with persistent elevation of serum inflammatory biomark-ers (such as MCP-1) 1 month after an acute coronary syndrome have increased mortality in the absence of an increase in new coronary events.71 Adverse prognosis in these patients might reflect increased remodelling and accentuated injury in individuals with defective a c tivation of anti-inflammatory pathways.72
Anti-inflammatory signalling
All cell types involved in cardiac repair likely participate in repression and resolution of the postinfarction inflam-matory reaction; however, the key cellular effectors that drive inhibition of inflammation remain unknown. Through their unique cytokine expression profile, and their potential for regulated recruitment and activation in response to local stimuli, inhibitory subsets of monocytes and lymphocytes and anti-inflammatory macro p hages are ideally suited to suppress inflammation in the infarcted heart. Experimental studies have demonstrated dynamic changes in macrophage phenotype in the infarcted heart, which suggests a transition from early infiltration with proinflammatory M1 cells to the late predominance of reparative M2 macrophages.73 The signals leading to these phenotypic changes of infarct macrophages remain poorly understood, and two questions remain: are macrophage subsets derived from distinct monocyte subpopulations, and do dynamic changes in the infarct microenvironment mediate acquisition of an inhibitory profile? Evidence suggests that the phagocytotic activity of macrophages can be important for modulating their phenotype and in repression of the inflammatory reac-tion. Efficient clearance of apoptotic cells by phagocytes (known as efferocytosis) activates proresolving signals that might aid the transition from inflammation to repair. The induction of tyrosine-protein kinase Mer in macro-phages seems to be important for cardiomyocyte effero-cytosis and subsequent suppression of the post-infarction inflammatory reaction.74 Inhibitory lympho c yte sub-populations, such as regulatory T cells, can participate in suppression of the postinfarction inflammatory response.35 Moreover, fibroblasts and vascular cells are abundant in the healing infarct and might also contribute to suppression of inflammatory signalling. Acquisition of a pericyte coat by angiogenic vessels in the infarcted heart might suppress inflammatory activity s t abilizing the microvasculature and preventing prolonged recruitment of leukocytes.75
Molecular stop signals
Negative regulation of proinflammatory signalling pathways is essential to maintain tissue homeostasis and activate the reparative response after the clearance of dead cells. Both intracellular molecules and soluble mediators have been implicated in the inhibition of the inflam m atory reaction following myocardial infarc-tion. In our own work, we have identified IL-1 receptor-associated kinase 3 (IRAK-3; also known as IRAK-M), a member of the IRAK family. IRAK-3 does not activate inflammation, but functions as an inhibitor of innate immune signalling76 and as an essential intracellular molecule for repression of macrophage-driven inflam-mation and fibroblast-mediate d matrix degradation
REVIEWS
following myocardial infarction.11 IRAK-3 is expressed in fibroblasts and a subset of infarct macrophages, and promotes an anti-inflammatory phenotype that inhibits cytokine expression. In addition to induction of intra-cellular signals that make cells less responsive to proin-flammatory activation, expression of decoy cytokine and chemokine receptors, and release of soluble inhibitory mediators might be important additional mechanisms involved in suppression of the inflammatory reaction. Members of the transforming growth factor β (TGF-β) family,77–79 IL-10,80 and p r oinflammatory-resolving lipid mediators 81 have been identified as secreted media-tors that might act as i n hibitors of the postinfarction i n flammatory reaction.
From inflammation to fibrosis
Repression of inflammation in the infarcted heart is associated with activation of mesenchymal cells that deposit extracellular matrix proteins, thereby preserv-ing the structural integrity of the infarcted heart. The adult mam m alian heart contains an abundant popula-tion of interstitial and perivascular fibroblasts;82,83 these cells can trans d ifferentiate into myofibroblasts, cells that express contractile proteins (such as α-smooth muscle actin) and are key for repair of the infarcted myocar-dium by secreting matrix proteins.84–86 In addition to the resident cardiac fibroblasts, bone marrow-derived fibroblast progenitors, endothelial cells undergoing transdifferentiation into m e senchymal cells, smooth muscle cells, and pericytes might contribute to the infarct myofibroblast population.87–91 Conversion of fibroblasts into myofibroblasts requires the co-operation of several microenvironmental factors: activation of TGF-β, a key mediator in induction of contractile pro-teins in mesenchymal cells; expression and deposition of specialized matrix proteins, such as ED-A fibronectin and matricellular proteins;92 increased mechanical stress trig-gered by the disruption of the normal matrix network; and removal of proinflammatory mediators (such as IL-1β) that inhibit myofibroblast conversion.
Transforming growth factor β
Activation of TGF-β signalling cascades is a key molecular link between the inflammatory and reparative response (Figure 3). Latent TGF-β is stored in the myocardium and can be rapidly activated following injury. Generation of ROS, induction of matricellular proteins (such as thrombo s pondin-1), and activation of proteases contribute to activation of preformed TGF-β in the infarcted area.92,93 Moreover, platelets, leukocytes and fibroblasts infiltrat-ing the infarcted heart synthesize and release de novo TGF-β, further increasing its levels.67 TGF-β bio a ctivity is increased during the early hours after infarction;94 however, the abundance of proinflammatory medi a tors at this stage might reduce cellular responsiveness to TGF-β, delaying myofibroblast transdifferentiation and matrix deposition until the infarct is cleared from dead cells and matrix debris.44 As proinflammatory signalling is repressed, TGF-β signalling promotes myofibroblast transdifferentiation and activates a matrix-preserving molecular programme, inducing expression of collagens and fibronectin, while upregulating synthesis of protease inhibitors (such as metalloproteinase inhibitor 1).95 TGF-β signals through activation of intracellular effectors, the Smads, and through Smad-independent pathways (such as, mitogen-activated protein kinases). Experimental evidence suggests that the profibrotic, matrix-preserving actions of TGF-β in fibroblasts are predominantly medi-ated through activation of Smad3 signalling;95,96 the poten-tial involvement of smad-independent cascades remains poorly understood. The TGF-β signalling cascade inter-acts with several other important pathways that regulate the fibrogenic response in the remodelling myocardium. Neurohumoral mediators, such as angiotensin II 97 and aldosterone 98 are important for fibroblast activation; their effects might be mediated in part through activa-tion of TGF-β signalling.99 Moreover, the Notch path-way—a signalling cascade critically involved in cardiac fibrotic responses—negatively regulates the TGF-β/Smad response.100,101 In addition to the critical effects of angio-tensin II and of the TGF-β/Smad cascade, other fibrogenic growth factors (such as platelet-derived growth factors) might modulate fibroblast phenotype regulating their p r oliferation, synthetic profile, and migratory activity.
Targeting the infarcted heart
Lessons from the past
Unfortunately, translation of early evidence that anti-inflammatory strategies might reduce infarct size into a clinical context has been disappointing. Although anti-CD11/CD18 integrin approaches were very effective at reducing infarct size in experimental models,102–104 three small clinical trials targeting β2 integrins in patients with myocardial infarction did not demonstrate beneficial effects.105–107 A large clinical trial targeting the comple-ment system, a pathway critical in activation of the post-infarction inflammatory reaction, also showed no benefit in patients undergoing percutaneous inter v entions
for acute myocardial infarction.108
These failures had a lasting influence and reduced enthusiasm for the poten-tial clinical usefulness of anti-inflammatory approaches
macrophage
Figure 3 | TGF-β is a key mediator in postinfarction remodelling. TGF-β exerts anti-inflammatory actions, inducing a regulatory macrophage phenotype, promoting regulatory T reg cell activation and reducing adhesion molecule synthesis by endothelial cells. TGF-β is also critically involved in fibroblast to myofibroblast conversion by activating a profibrotic signalling cascade. Abbreviations: TGF-β, transforming growth factor β; T reg , regulatory T cell.
in patients with myocardial infarction. Moreover, such failures question the usefulness of animal models in pre-dicting the success of therapeutic approaches.109 What is the reason for the apparent disconnect between findings in animals and clinical investigations? Why is translating promising approaches to the clinical context so difficult, despite abundant evidence in experimental models? The academic community and public are often overly optimistic about new and promising therapeutic strat-egies. Studies with impressive positive results generate great enthusiasm and are more likely to be published. Laboratories reporting these observations are more likely to attract funding and have a better chance of completing their work. During the early stages after the introduction of a new concept, therefore, the literature often reflects a publication bias that favours positive findings and results in overly optimistic appraisal of the therapeutic potential of a strategy. Only after a concept is established in the scientific community does the publication of negative studies becomes attractive; by which time the published work might better reflect the collective experience of the scientific community. In the field of cardiac injury and repair,the abundant early reports suggesting that infarct size could be reduced using anti-inflammatory strategies were later challenged by studies in genetically targeted animals showing that postinfarction inflammation does not extend ischaemic cardiomyocyte injury.10,34,43 Animal models are great tools for dissection of patho-physiological concepts. However, these results cannot directly predict effectiveness in a clinical context, owing to limitations of the animal model itself and the complex pathophysiology of human diseases. Animal models of myocardial infarction cannot, therefore, fully recapitu-late the clinical outcome observed in humans. In clini-cal trials, mortality is the most important end point; by contrast, mortality data in animal investigations are often difficult to interpret and do not always provide evidence that can be easily translated to humans. Cardiac rupture is the most-common cause of death in mouse models of nonreperfused myocardial infarction,49,69 but is uncom-mon in humans and its incidence has declined over the past 30 years, owing to the introduction of reperfusion strategies and advances in medical care.110 Conversely, ventricular arrhythmias are a common causes of death in patients with acute myocardial infarction, but in mouse models the incidence of fatal arrhythmias is low and the mechanisms of arrhythmogenesis might differ owing to the small size of the mouse heart and its rapid beating rate. Moreover, animal models of surgical coronary occlusion do not provide information on the incidence of recurrent coronary events, and the severity of post-infarction heart failure as a clinical syndrome cannot be reliably assessed in mice. Conclusions about outcomes in animal models of myocardial infarction are often based on extrapolation from data reflecting specific functional end points. Although these conclusions might provide important and accurate pathophysiological insights, direct relevance to clinical outcome is limited. Perhaps the most-important reason for the challenges in translating experimental findings into clinically relevant information for myocardial infarction, specifi-cally, is the pathophysiological complexity and hetero-geneity of the condition in humans. Optimally executed investigations in animal models are designed to eliminate variability, test a hypothesis, and provide insights into a molecular pathway or cellular process. In a typical loss-of-function study to examine a specific mediator, the goal is to compare responses of age-matched and sex-matched animals with identical genetic backgrounds that only differ in the presence or absence of the mediator of interest. This strategy is optimal for understanding the pathophysiology of disease, but unfortunately limits our ability to make translational predictions. Patients with myocardial infarction differ in a wide range of factors that affect outcome. Genetic profile, age, sex, the pres-ence of comorbid conditions (such as hypertension, hyperlipidaemia and diabetes mellitus), treatment with pharmacological agents, and the pattern of the disease, are some of the important clinical variables that can profoundly affect the response to myocardial infarction. Considering the complexity of the human pathophysiol-ogy, attempts to introduce these variables and generate an animal model of high predictive value are imprac t ical. An illustration of the profound effects of one of these factors on the postinfarction inflammatory and repara-tive response is provided by our experience in senescent animals. In a model of reperfused myocardial infarction, aging was associated with a marked suppression (and modest prolongation) of the inflammatory reaction fol-lowing reperfused myocardial infarction.111 On the basis of these observations, one reason that explains the lack of effectiveness of targeted anti-inflammatory strategies in humans might be the advanced age of many patients with myocardial infarction. Y oung animals have been used in all studies showing beneficial effects of anti-inflammatory strategies after myocardial infarction. The failure of these therapies in humans might, therefore, reflect a less robust inflammatory reaction in older individuals. The dysregu-lated immune responses associated with senescence com-plicate efforts to design therapeutic strategies targeting the postinfarction inflammatory reaction.
The future: modulating inflammation Successful clinical translation requires both pathophysio-logical insights and an understanding of the clinical context. Implementation of this simple principle is of paramount importance in myocardial infarction. Over the past 30 years, experimental studies have revealed important mechanisms in the reparative and remodel-ling responses that occur after myocardial infarction. Experiments using animal models have highlighted the complexity of inflammatory pathways—cytokines and growth factors are highly pleiotropic mediators that exert multiple effects on all cell types involved in cardiac injury and repair. Understanding the temporal and spatial regulation of inflammatory signals is criti-cal to the design effective therapies. For example, early activation of cytokine and chemokine pathways might be important in clearing the infarct of dead cells and debris, and for stimulation of downstream reparative cascades.
However, prolonged or excessive induction of proinflam-matory signalling is associated with accentuated injury and increased adverse remodelling. Spatial containment of inflammatory cascades is equally important—effective repair is dependent on signals that prevent extension of the inflammatory response into the viable myocardium, therefore, limiting fibrosis to the infarcted region.
Proinflammatory mediators, such as TNF, often exert both detrimental and protective responses on the same cell type mediated through distinct receptors—dissection of the pathways involved in these effects might lead to more specific and effective therapeutic strategies. The growing interest in cardiac regeneration through cell therapy 112–114 has added a new perspec-tive to the potential role of inflammatory signals in cardiac repair, stressing the role of selected chemokines (such as stromal cell-derived factor 1 [also known as CXC motif chemokine 12])115 cytokines, and growth factors,116,117 in regulating trafficking, activation, dif-ferentiation, and survival of progenitor cells. The effect of inflam m atory signalling in extending ischaemic cardio m yocyte injury remains controversial; however, the involvement of inflammatory and fibrogenic signals in cardiac remodelling and in the development of post-infarction heart failure is already well-established. In the infarcted myocardium, left ventricular geometry and
function are dependent on the balance between matrix-degradin g and matrix-preserving signals. Overactive matrix-degrading processes caused by local activation of matrix metalloproteases by proinflammatory media-tors, such as IL-1β and MCP-1, are generally associated with decreased tensile strength, leading to left ventricular dilatation and systolic dysfunction. Degradation of the inter s titial matrix is also associated with cardiomyocyte slippage and might lead to cardiomyocyte death owing to deprivation of key prosurvival signals transduced by the matrix.23 Conversely, overactive matrix-preserving responses, possibly associated with accentuated TGF-β signalling cascades, promote fibrosis and might cause diastolic dysfunction. Patients with myocardial infarc-tion exhibit very different remodelling responses, which are at least in part independent of the size of the infarct. The molecular determinants of geometric remodel-ling in patients with myocardial infarction remain unknown; however, one could speculate that exagger-ated left ventricular dilatation might reflect overactive proinflammatory signalling in individuals with defective downregulation of acute inflammation. The association between increased mortality and persistent elevation of proinflammatory chemokines in the serum of patients with acute coronary syndromes might reflect the adverse consequences of prolonged inflammation on the remod-elling myocardium.71 However, certain subpopulations of patient, such as those with diabetes, have post i nfarction heart failure in the absence of clinically relevant dilata-tion.118 In patients with diabetes, postinfarction heart failure is often linked with diastolic dysfunction,119 and might reflect excessive activation of the profibrotic TGF-β/Smad axis.120 Different therapeutic strategies are, therefore, needed for these pathophysiologically distinct patient subpopulations.
The development of strategies to identify subgroups of patients with distinct pathophysiological alterations represents an important step towards implementation of effective therapy targeting the inflammatory and fibrotic response in myocardial infarction. Biomarker-based strategies are needed to identify individuals with over-active inflammatory responses and patients with exces-sive fibrosis (Figure 4). Serum levels of inflammatory cytokines and chemokines might provide useful infor-mation on the underlying pathophysiology. However, such markers are influenced by a wide range of clini-cal and pathological conditions, such as the extent of atherosclerotic disease, diabetes, obesity, and meta-bolic dysfunction, and might not reflect alterations in the myocardial inflammatory and reparative process. Molecular imaging modalities can reveal structural, cel-lular, and molecular alterations in the infarcted heart, and might be particularly promising for identification of patients with overactive inflammatory responses. Patients with such a response might benefit from targeted anti-inflammator y approaches, such as pharmacological interventions to inhibit MCP-1 or IL-1. The crucial role of the IL-1 system in postinfarction inflammation,43 the availability of effective IL-1 inhibitors and neutralizing antibodies,121 the safety of IL-1 antagonists in patients
Dilatation,systolic dysfunction
Fibrosis,diastolic dysfunction
Figure 4 | Biomarker-based approaches to target the inflammatory response in patients with acute myocardial infarction. Patients surviving a myocardial
infarction exhibit pathophysiologically heterogeneous responses, which are partly independent of the size of the infarct. Distinct pathophysiological responses might be related to differences in genetic background and to the presence of conditions, such as diabetes mellitus or hypertension, which affect inflammatory and fibrogenic pathways. After myocardial infarction, some patients develop progressive dilatation and systolic dysfunction, whereas others develop diastolic dysfunction.
Dilatation might reflect excessive inflammatory activity causing matrix degradation. Conversely, diastolic dysfunction might indicate overactive profibrotic signalling. We propose the measurement of inflammatory biomarkers, such as serum cytokine and chemokine levels, and of profibrotic markers, including indicators of matrix synthesis and remodelling, to stratify patients into subpopulations based on the predominant pathophysiology. Patients with overactive inflammation might benefit from targeted inhibition of inflammatory signals (anti-IL-1 or anti-MCP-1 strategies), whereas patients with profibrotic responses might benefit from inhibition of the TGF-β/smad cascade. Abbreviation: MCP-1, monocyte chemoattractant protein 1 (also known as CC motif chemokine 2).
Conclusions
Inflammatory pathways are critically involved in the repair and adverse remodelling of the infarcted heart. Therapeutic approaches targeting specific components of the inflammatory response are promising for patients with myocardial infarction. However, the complexity of the pathophysiological process in humans is a major challenge for clinical translation. Biomarker and i m aging-based strategies identifying patient subpopulations with overactive proinflammatory or fibrogenic signalling might contribute to rational implementation of therapies
to prevent postinfarction heart failure.
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Acknowledgements
Dr Frangogiannis’ laboratory is funded by NIH grants
R01 HL76246 and R01 HL85440 and by the Wilf
Family Cardiovascular Research Institute, Albert
Einstein College of Medicine, New York, USA.下载本文
