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- Acute myocardial infarction
- left ventricular remodelling
- cellular immune response
- cardiac remodelling
- coronary collateral circulation
- myocardial ischaemia and infarction (IHD)
- acute coronary syndrome
After a myocardial infarction (MI), the damaged myocardial tissue is repaired and eventually replaced by scar tissue. In a substantial proportion of MI patients, the repair mechanisms induce profound structural and functional changes not only in the infarct zone, but also in the non-infarcted area. These patients show myocardial thinning and expansion of the infarct zone in the early phase after MI, and pathologic cardiomyocyte hypertrophy, apoptosis and extracellular matrix remodelling in the remote zone, a process that may continue for months. These underlying mechanisms induce alterations of the left ventricular (LV) shape, mass, volume, and function, which is also referred to as adverse LV remodelling (figure 1). Although some of these changes may be adaptive and physiological as short term compensation for the sudden loss of contractile function in the infarcted area, it may lead over time to heart failure and cardiac death.w1
Important determinants of adverse remodelling following MI include the extent of infarction and LV loading conditions. So far, most efforts have focused on reducing infarct size by timely restoration of myocardial perfusion using mechanical and/or pharmacological interventions,w2–w4 and by unloading of the left ventricle using drugs that target the renin―angiotensin―aldosterone system and the sympathetic nervous system.w5 w6 However, post-MI adverse remodelling depends on a complex myocardial healing process, which is mediated by immune cells.
This article summarises the role of immune cells in post-MI healing and adverse remodelling, and discusses the potential of different pharmacological and cell based therapies.
Key points 1: post-myocardial infarction adverse remodelling
Post-myocardial infarction (MI) adverse remodelling is characterised by changes in the left ventricular (LV) shape, mass, volume, and function and is associated with heart failure and cardiac death.
Mechanisms that underlie adverse remodelling involve myocardial thinning and infarct expansion in the infarct zone, and pathologic cardiomyocyte hypertrophy, cardiomyocyte apoptosis, and extracellular matrix remodelling in the remote zone.
Determinants of post-MI adverse remodelling include the extent of infarction, the LV loading conditions, and the post-MI healing process.
The link between infarct healing and adverse remodelling
The myocardial healing response can be divided into three sequential overlapping phases: (1) the inflammatory phase; (2) the proliferative phase; and (3) the maturation phase (figure 2). Upon acute MI, the ischaemic myocardium immediately triggers an intense inflammatory reaction. Neutrophils and monocytes, which are attracted to the infarcted area by CC chemokine ligand (CCL)-2, complement factors, and other mediators,w7 w8 remove dead cells and promote extracellular matrix degradation by activated matrix metalloproteinases (MMP). After clearing debris in the infarcted area, monocytes/macrophages produce cytokines and growth factors—for example, interleukin 10 (IL10) and transforming growth factor β (TGFβ)—that repress inflammatory signals and regulate the formation of granulation tissue during the proliferative phase. In this phase, new blood vessels are formed and fibroblasts produce new extracellular matrix. Finally, in the maturation phase, extracellular matrix is remodelled, fibroblasts and vascular cells undergo apoptosis, and a mature collagen based scar is formed.1
Accumulating evidence indicates that an exaggerated inflammatory reaction in the early phase after acute MI may evoke adverse remodelling and directly affect prognosis in patients with acute MI. Clinical studies have shown that elevated concentrations of circulating neutrophils and monocytes following acute MI are associated with adverse remodelling and development of heart failure.2 ,3 It has been suggested that massive infiltration of neutrophils and monocytes and excessive breakdown of extracellular matrix early after acute MI contribute to infarct expansion, and thus may lead to LV dilation, aneurysm formation or even cardiac rupture. Furthermore, enhanced fibrosis during the proliferative and maturation phase may stiffen the left ventricle and reduce LV compliance. Accordingly, modulation of the myocardial healing process by targeting immune cells may be an interesting therapeutic concept for patients with acute MI.
Key points 2: infarct healing and adverse remodelling
Immune cells are critical mediators of different phases of infarct healing.
In the inflammatory phase, neutrophils and monocytes/macrophages remove dead cells and degrade extracellular matrix. In the proliferative phase, monocytes/macrophages promote angiogenesis and modulate extracellular matrix deposition. In the maturation phase, a mature collagen based scar is formed.
Excessive extracellular matrix degradation in the inflammatory phase after acute myocardial infarction, as well as enhanced fibrosis during subsequent phases of infarct healing, may evoke adverse left ventricular remodelling.
Role of immune cells in post-MI healing and adverse remodelling
Activation of the innate immune system is essential for the healing process to take place. Hence, the role of mast cells, neutrophils and monocytes/macrophages in the complex healing process has been extensively studied. In contrast to the innate immune system, which provides immediate defence against tissue injury in a non-specific manner, the adaptive immune system provides the ability to react to a specific antigen. In the setting of infarct healing in patients, the role of the adaptive immune system is probably of minor importance. Nevertheless, involvement of the adaptive immune system cannot be excluded, considering the presence of T cells in the remote zone. Furthermore, progenitor cells and stem cells have drawn special attention, not only because of their capability of generating and sustaining fully differentiated cells, but also because of their paracrine effects.
Mast cells are tissue resident cells that can rapidly secrete a wide variety of preformed and newly synthesised immunomodulatory, angiogenic, and profibrotic factors. Frangogiannis et al showed that the number of cardiac mast cells dramatically increases after acute myocardial ischaemia and reperfusion in dogs.w9 A few hours after reperfusion, cardiac mast cells are a dominant source of tumour necrosis factor α (TNFα), which initiates cytokine cascades and promotes the influx of other immune cells.w10 In the proliferative phase, mast cells profoundly accumulate in areas of angiogenesis and collagen depositions.w9
Because of their location and their capability to regulate immune cell recruitment, fibroblast function and extracellular matrix metabolism, mast cells have been implicated as playing a role in post-MI adverse remodelling.w11 The degranulation of mast cells before ischaemia and reperfusion as well as blockage of mast cell degranulation has reduced infarct size in rats.w12 However, the significance of mast cells in adverse remodelling is still unclear, as results from experimental studies are contradictory.w11 w13
Upon MI, neutrophils are recruited by various chemoattractants such as IL8, and complement factors,w8 and are the first to arrive at the site of injury. The number of neutrophils peaks in the inflammatory phase after non-reperfused MI in mice.w14 Once in the infarcted area, neutrophils ingest dead cells and produce large amounts of MMPs that degrade extracellular matrix. Clearance of the infarct is a crucial step for the resolution of inflammation and initiation of the proliferative phase; however, neutrophils also have a potential downside. Excessive extravasation of neutrophils may cause microvascular plugging and may impair perfusion of the already injured myocardium. In addition, neutrophils can aggravate myocardial injury through the release of oxygen free radicals and various inflammatory mediators and proteolytic enzymes. Furthermore, it has been speculated that enhanced degradation of collagen and extracellular matrix components may compromise tissue integrity and lead to infarct expansion propagating adverse remodelling.w15 Neutrophils are abundantly present throughout the inflammatory phase of infarct healing and then undergo apoptosis, thereby contributing to the initiation of the proliferation phase. Whether neutrophils also play an important role in the proliferative phase and the maturation phase of infarct healing remains to be elucidated.
In patients with acute MI, high concentrations of circulating neutrophils at admission are predictive of adverse LV remodelling and poor prognosis.3 Because of their potential harmful effects, a variety of strategies, including complement inhibition and blockage of neutrophil extravasation, have been tested for their effect on infarct size.
It is well known that complement activation plays an important role in the recruitment of neutrophils and monocytes. After experimental studies demonstrated that inhibition of the C5 component of complement decreased infarct size in experimental models, Granger et al investigated treatment with pexelizumab, an antibody that binds to the C5 component of complement, in patients with acute MI in the COMMA (COMplement inhibition in Myocardial infarction treated with Angioplasty) trial. Although no effect on infarct size was found, the authors reported decreased mortality at 90 days of follow-up in the patient group that was treated with pexelizumab as a bolus and infusion.4 In contrast, pexelizumab (bolus and infusion) failed to increase survival in the subsequent APEX-AMI (Assessment of Pexelizumab in Acute Myocardial Infarction) trial.w16 Therefore, the potential of this drug remains uncertain.
Neutrophil extravasation depends on rolling, adhesion, and transmigration. For neutrophils, L-selectin is important for rolling, whereas integrin CD11/CD18 is involved in firm adhesion of the rolling neutrophils to the endothelium. Antibodies that block L-selectin or the integrin CD11/CD18 have been shown to effectively decrease neutrophil infiltration and to reduce infarct size in several experimental models of myocardial ischaemia and reperfusion injury.w15 However, in a patient study, treatment with a humanised antibody that blocked the integrin CD11/CD18 receptor did not show any beneficial effect with regard to infarct size or 30 day mortality.5 Further studies investigating not only the therapeutic effects on infarct size and mortality, but also the long term effects on post-MI remodelling, are needed.
Monocytes circulate in the blood and travel to the injured myocardium where they differentiate, and contribute to various parts of the healing process. After differentiation, monocytes/macrophages clear the infarcted myocardium from dead cells and debris, promote matrix breakdown, and phagocytose apoptotic neutrophils. In the proliferative phase, monocytes/macrophages secrete a wide variety of growth factors and cytokines that repress inflammation and stimulate fibroblast growth and angiogenesis. Moreover, monocytes/macrophages participate in the regulation of extracellular matrix remodelling through the production of MMPs and their inhibitors.w15
In blood, monocytes are a heterogeneous pool of cells, containing classical, intermediate, and non-classical monocytes. Monocyte subsets display different chemokine receptor repertoires and therefore respond to different attractants, allowing selective mobilisation.w17 Nahrendorf et al have shown, in a murine model of non-reperfused MI, that classical monocytes accumulate primarily in the inflammatory phase and promote inflammation and removal of dead cells and debris by producing TNFα and MMPs. In contrast, non-classical monocytes produce IL10 and the profibrotic factor transforming growth factor β (TGFβ) and are recruited in the proliferation phase to attenuate inflammation and to promote tissue repair.6
In patients, monocytosis following acute MI predicts adverse LV remodelling.2 Tsuijoka et al measured the blood concentrations of classical and non-classical monocytes in 36 patients with acute MI and showed that classical monocytes peak at day 3 whereas non-classical monocytes peak on day 5 after acute MI,7 in line with the biphasic monocyte response observed in mice. Importantly, van der Laan et al showed that an increased concentration of circulating classical monocytes following MI in patients is associated with impaired functional outcome.8 Consequently, classical monocytes have drawn considerable attention as a potential therapeutic target.
Monocyte/macrophage depletion following MI in mice dramatically affects the LV remodelling process, underscoring the critical role of monocytes/macrophages.w18 How specific monocyte/macrophage functions can be selectively influenced to prevent adverse remodelling has become the subject of intensive research. The discovery that monocytes/macrophages differ in phenotype and function has significantly raised the potential for strategies targeting a specific monocyte subset and/or function.
CCL-2 is a potent attractant for monocytes, especially for the classical subset, as these cells display high membrane expression of its receptor, the CC chemokine receptor 2 (CCR-2). Dewald et al investigated infarct healing in CCL-2 deficient mice and demonstrated decreased and delayed infiltration of monocytes/macrophages after myocardial ischaemia and reperfusion. Even though these CCL-2 deficient mice showed delayed formation of granulation tissue, adverse remodelling was attenuated.9 Similar results were found by Kaikita et al using CCR-2 deficient mice.10 Furthermore, silencing of the chemokine receptor CCR-2 with a short interfering RNA reduced the recruitment of classical monocytes to ischaemic myocardium, a strategy that also promises to curb excessive infarct inflammation.11 Taken together, targeting CCL-2/CCR-2 seems a worthwhile strategy, and the development of novel compounds or antigens/antibodies that can be tested in preclinical studies are mandatory.
Lymphocytes are the cornerstone of the adaptive immune system and include several types of T cells, such as helper T cells (Th) and cytotoxic T cells (Tc). After non-reperfused MI in mice, lymphocytes start to infiltrate in the inflammatory phase, and are abundantly present in the proliferation phase.w14
In post-MI patients, a low Th/Tc cell ratio has been associated with poor LV ejection fraction 1 week after the event.12 Tc cells are capable of inducing apoptosis of cells. Consequently, these cells are believed to contribute to adverse remodelling by promoting cardiomyocyte apoptosis. Th cells comprise several subsets that are characterised by distinct cytokine expression profiles. For example, Th1 cells produce cytokines, including interferon γ and TNFα, that enhance inflammation. Th2 cells, on the other hand, can suppress inflammation through the release of IL10. Cheng et al demonstrated an association between a Th1/Th2 imbalance and adverse LV remodelling in patients, suggesting involvement of Th cells in the remodelling process following MI.13 How T cells are involved in this process is incompletely understood and warrants further study.
Progenitor cells and stem cells
Normally, progenitor cells and stem cells circulate in the peripheral blood in low numbers. However, the blood concentrations of these cells transiently increase in patients with an acute MI.14 Bone marrow contains several populations of progenitor cells and stem cells, including endothelial progenitor cells, haematopoietic stem cells and mesenchymal stem cells, which are known for their capability of generating and sustaining fully differentiated cells. It has been suggested that mobilisation of these cells from the bone marrow to the infarcted area may be an important reparative mechanism.
In 2001, Orlic et al showed that intramyocardial injections of bone marrow cells resulted in partial restoration of the infarcted myocardial tissue in a murine model of non-reperfused MI.15 Additional evidence for involvement of circulating cells in the preservation of myocardial tissue came from a postmortem study of Quaini et al, demonstrating migration of precursor cells from the recipient to the donor sex-mismatched transplanted hearts.16 Since then, circulating progenitor cells and stem cells derived from the bone marrow were thought to contribute to infarct healing, attenuating adverse remodelling either through paracrine effects or regeneration of myocardium. In the last decades, multiple clinical trials have been initiated to investigate the effect of bone marrow cell therapy on outcome following acute MI. In 2006, the large randomised REPAIR-AMI (Reinfusion of Enriched Progenitor Cells and Infarct Remodelling in Acute Myocardial Infarction) study, which included 204 patients, reported a significant improvement in LV function following intracoronary bone marrow cell therapy.17 The results of subsequent trials varied considerably.w19–w21 A meta-analysis of these trials showed promising results at least in terms of LV function and LV volumes.18
The stimulation of progenitor cell and stem cell mobilisation using cytokines, such as granulocyte colony stimulating factor (G-CSF), stromal derived factor 1, stem cell factor, and erythropoietin, seems a less complex and attractive alternative to raise the concentrations of these cells in blood. Although adverse remodelling after MI can be influenced by G-CSF administration in experimental models, results of clinical trials have been disappointing.18 Increased understanding and knowledge of the intrinsic reparative mechanisms in MI patients is necessary for the development of cytokine or cell based therapies that effectively promote tissue repair.
Immune cells in the remote zone
There is no doubt that immune cells play important roles in the healing process following MI. Less is known, however, about their role in remodelling of areas remote from the infarct. It is believed that most aspects of the remodelling process in the remote zone, such as cardiomyocyte hypertrophy, apoptosis, matrix remodelling, and fibrosis, are primarily driven by the increase in LV wall stress and work load.
Nonetheless, it has been unequivocally demonstrated that monocytes/macrophages accumulate in the remote zone after MI in patients, suggesting an inflammatory response in the remote myocardium.19 Also, the study of Abbate et al showed the presence of active T cells in areas remote from the infarcted area in patients who died after MI.20 Additional studies are warranted to investigate whether inflammation, mediated by immune cells, directly contributes to the remodelling process in the remote zone.
Key points 3: role of immune cells in the healing process
Neutrophils are recruited in the inflammatory phase to ingest dead cells and to degrade extracellular matrix. An increased concentration of neutrophils in the peripheral blood upon acute myocardial infarction (MI) is associated with adverse left ventricular (LV) remodelling. Clinical studies, investigating blockage of neutrophil recruitment using an inhibitor of the C5 component of complement (pexelizumab) or an integrin CD11/CD18 receptor blocker in patients with acute MI, showed no beneficial effect on infarct size. Effects on post-MI remodelling are currently unknown.
Monocytes consist of several subsets, with distinct functions in the post-MI healing process. In patients a high concentration of classical monocytes in the peripheral blood is associated with poor functional outcome. Recent evidence from experimental studies indicates that targeting classical monocytes might be a promising approach to attenuate post-MI adverse remodelling.
Stem cells and progenitor cells from the bone marrow are thought to contribute beneficially to the post-MI healing process. A meta-analysis of clinical trials investigating bone marrow cell therapy showed at least modest beneficial effects in terms of LV function and LV volumes.
Although controversial, recent evidence indicates that immune cells also accumulate in areas remote from the infarcted myocardium, suggesting that inflammation may contribute to the remodelling process in the remote zone.
Future directions and therapies
Over the past decades, no immunomodulatory therapies have been translated into clinical practice. The European Society of Cardiology guidelines (published in 2008) for the management of patients with ST elevation MI recommend primary percutaneous coronary intervention, antiplatelet therapy, antithrombin therapy, β-blockade, and angiotensin converting enzyme inhibition in the early phase of acute MI.w22 Although the clinical significance of these therapies was initially attributed to their beneficial effects on infarct size and LV loading conditions, strong evidence from both clinical as well as basic studies suggests that these treatment modes also influence immune cells.w23 w24 Accordingly, one has to take into account that part of the standard MI therapy's success might be mediated through its effects on the post-MI healing process.
Experimental models of acute MI have been crucial in providing insight into the role of immune cells in infarct healing following MI; however, the role of each cell subset is complex. Many immune cells act in concert and crosstalk with resident and recruited cells. Furthermore, considerable differences exist between the healing response in experimental models and in patients, not to mention the effects of ageing and comorbidities (eg, dyslipidaemia and diabetes mellitus) which are complex to implement in experimental models. Therefore, a better understanding of the role of immune cells in the post-MI healing process in patients is needed for the development of effective immunomodulatory therapies.
Reliable, clinically applicable, non-invasive imaging modalities may increase knowledge on the dynamics of cell populations and molecular mechanisms associated with infarct healing in patients, and provide a template for assessing new immunomodulatory therapies. Moreover, these techniques may also be useful for the identification of patients at risk for adverse LV remodelling. Interestingly, the possibilities of new molecular imaging techniques, using positron emission tomography/CT and cardiovascular MRI, are currently being explored.w25
The future challenge will be the development of a novel immunomodulatory strategy that targets the early inflammatory response, without impairing reparative responses, and that has an acceptable safety profile. Timely resolution of the inflammation and prevention of massive infiltration of neutrophils and monocytes, and excessive extracellular matrix degradation early after acute MI, could maintain structural integrity of the injured myocardium and arrest infarct expansion and LV dilation that offset adverse LV remodelling. Promising therapeutic strategies include blockage of classical monocyte and neutrophil accumulation in the early stage of infarct healing. Of interest, numerous experimental studies have shown that broad inhibition of MMPs as well as selective MMP inhibitors can favourably influence LV remodelling by preventing excessive matrix breakdown. Although promising, future studies on timing and dosage are necessary before translation into clinical research can be pursued.w26
Furthermore, late blockage of the profibrotic factor TGFβ1, secreted by various immune cells, seems an effective approach to prevent fibrosis in the infarct zone as well as the non-infarct zone and to preserve LV compliance and function. Interestingly, several compounds are already at various stages of development.
Finally, cell therapy for the patient with acute MI still holds promise. Results from clinical trials suggest that a modest improvement over conventional therapy can be achieved.18 Additional data on optimal delivery strategy, timing, dosage, and cell type are required to assess the efficacy of this mode of therapy further.
Key points 4: future directions
A better understanding of the role of immune cells in post-myocardial infarction healing in patients is needed for the development of effective immunomodulatory therapies that attenuate adverse left ventricular remodelling.
Promising immunomodulatory therapies include blockage of classical monocyte and neutrophil accumulation, matrix metalloproteinase inhibition, blockage of the profibrotic factor TGFβ1, and bone marrow cell therapy.
The high incidence of adverse LV remodelling following acute MI justifies the search for therapeutic strategies to attenuate this process. The link between infarct healing and adverse remodelling has been recognised for years. Accumulating evidence indicates that an excessive inflammatory reaction in the early phase after acute MI, as well as an aberrant reparative response in subsequent phases of infarct healing, may evoke this adverse outcome.
So far, clinical studies have primarily focused on the enhancement of the reparative responses using cell based therapeutic strategies, with only modest success. Very few studies, on the other hand, have dealt with the inflammatory reaction early after acute MI, which is critically mediated by immune cells. The future challenge will be the development of an immunomodulatory treatment targeting the early inflammatory reaction, without impairing tissue repair. A number of promising immunomodulatory strategies are currently being evaluated in experimental studies, and results are eagerly awaited before their clinical evaluation.
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- ↵ Excellent review providing a detailed overview of the molecular and cellular mechanisms involved in infarct healing.
- ↵ Clinical study demonstrating an important association between the peak monocyte count and adverse LV remodelling following reperfused acute MI.
- ↵ Randomised clinical trial showing no beneficial effect of adjuvant treatment with the C5 complement inhibitor pexelizumab on infarct size in patients undergoing primary percutaneous coronary intervention.
- ↵ Randomised clinical trial demonstrating no reduction of infarct size after treatment with an antibody to the CD11/CD18 integrin receptor, Hu23F2G, in patients undergoing primary percutaneous coronary intervention.
- ↵ First experimental study showing that monocyte subsets are sequentially mobilised following acute MI in mice and that these subsets have different functions.
- ↵ Clinical study demonstrating for the first time an association between the peak level of classical monocytes in blood and myocardial salvage in patients with acute MI, treated with primary percutaneous coronary intervention.
- ↵ Clinical study showing that a high concentration of classical monocytes in blood is associated with impaired functional outcome following primary percutaneous coronary intervention.
- ↵ This experimental study is one of the first to show that bone marrow cell therapy ameliorates outcome after acute MI in mice.
- ↵ One of the largest randomised clinical trials investigating bone marrow cell therapy in patients with acute MI, treated with primary percutaneous coronary intervention, reporting a beneficial effect regarding functional outcome.
- ↵ One of the first studies unequivocally demonstrating the presence of macrophages in the remote zone after acute MI.
This is a reprint of a paper that first appeared in Heart, 2012, Volume 98, pages 1384–90.
Funding This work was supported by a grant by the Graduate School for Medical Sciences of the Academic Medical Centre, Amsterdam, The Netherlands to AML, and a grant from the National Institutes of Health (R01HL096576) to MN.
Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. The authors have no competing interests. JJP is member of the medical advisory board of Abbott Vascular and consultant for Miracor.
Provenance and peer review Commissioned; externally peer reviewed.
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