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Circulation. Author manuscript; available in PMC 2011 Jun 8.
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Monocytes: protagonists of infarct inflammation and repair

Introduction

Myocardial infarction (MI) is the most frequent cause of heart failure, which is an incapacitating disease with high prevalence and broad socioeconomic impact. In 2008 in the United States, 5.7 million people suffered from heart failure, and more than 287,000 people died.1 Timely revascularisation of ischemic myocardium reduces acute infarct mortality, and current standard therapy with beta-blockers and ACE inhibitors curbs development of post-MI heart failure. For example, ACE inhibitor treatment reduced mortality from 25 to 20% in the SAVE trial.2 While this is a major advance, long-term mortality remains high. The combination of reduced acute infarct mortality due to efficient acute care and insufficient options to treat infarct survivors chronically has contributed to an increased heart failure prevalence (Fig. 1).3

Figure 1
Disease statistics.

The need to understand and treat heart failure better has motivated clinicians and basic scientists to explore new therapeutic strategies to repair the failing heart, for instance with stem cells.4, 5 Augmentation of intrinsic wound healing that occurs during the first 1–2 weeks post MI is a prospective approach with the potential to prevent heart failure. During this period, the infarct is highly active biologically.68 Delicate granulation tissue undergoes rapid turnover of cells and of structural components such as the extracellular matrix. Pre-existing collagen is digested and new matrix is laid down. During these extensive changes of tissue architecture the vulnerable wound is exposed to the mechanical stress of cycling intraventricular pressure and myocardial contraction, and the heart can undergo profound and deleterious changes in ventricular geometry and function. In the short-term (days, weeks), poor healing can lead to infarct expansion and left ventricular dilatation, and in some cases to infarct rupture and death. In the long-term (months, years), filling pressure, wall stress and left ventricular volume can increase and propagate adverse remodeling, leading to heart failure and a poor prognosis.7, 9, 10 Conversely, “sufficient” healing preserves left ventricular geometry and prevents heart failure. In this review we propose that the quality of infarct healing shortly after injury determines the fate of the patient for years to come.

Clinicians are well aware of the adverse impact of diabetes, atherosclerosis and immunosuppression on tissue repair in leg ulcers, diabetic retinopathy or surgical wounds. However, the wound in the ischemic heart, possibly because it is concealed beneath the skin, has only recently drawn attention as a potential therapeutic target. Consequently, the impact of co-morbidities on healing processes in the heart is poorly understood. This review focuses on the role of monocytes, immune cells that dominate healing of the injured myocardium within the first 2 weeks after MI. We will discuss recruitment and function of monocyte subsets, and their dual role as key inflammatory components of atherosclerotic disease and as central regulators in infarct healing.

Monocyte subset phenotypes and their specific functions

The immune system’s central function is response to injury and infection. The innate immune system, which is typically the first to respond, consists of cells of the myeloid lineage that include neutrophils and monocytes. During injury, these cells accumulate quickly so as to eliminate dead or dying tissue. The response is massive but “blunt” as it lacks the specificity emblematic of adaptive immunity. Studies continue to demonstrate, however, that innate immunity is nuanced and regulated by a plethora of signals; while responses can be “blunt” from the perspective of antigen recognition, they are remarkably specific spatiotemporally and quantitatively. One line of investigation that is particularly demonstrative of this has focused on monocytes and their subsets.

Monocytes belong to the mononuclear phagocyte system, a categorization that encompasses multiple cell types of shared ontogeny at various stages of differentiation with essential roles in development, inflammation and host defense.11, 12 Mononuclear phagocytes have been discovered by Elie Metchnikoff a century ago. Monocytes are produced in the bone marrow from macrophage and dendritic cell progenitors (MDP)13, 14 and, upon maturation, enter the circulation in a process that depends on the chemokine receptor CCR2.15, 16 Monocytes circulate freely17 or patrol18 blood vessels for several days19 but differentiate irreversibly to either macrophages or dendritic cells (DC) upon tissue infiltration (the spleen is a notable exception and is discussed below). In recent years, many investigators have focused on delineating the relationships between monocytes and DC. Convincing data now indicate that in the steady state a dedicated common dendritic cell precursor (CDP) gives rise to pre-dendritic cells (preDC), classical DC (cDC) and another kind of type I interferon-producing DC, called a plasmacytoid DC (pDC) without monocyte intermediates.2024 These cells are important to the homeostasis of the organism. They reside in lymphoid tissues such as the lymph nodes or spleen and play important roles in orchestrating adaptive immunity. However, during inflammation (e.g., after MI), monocytes can give rise to inflammatory DC or macrophages that accumulate in large numbers in target sites.25, 26, 2630

The ability of monocytes to differentiate to various cell phenotypes suggests remarkable “plasticity” in response to the environment. The prevailing belief is that circulating monocytes are relatively uncommitted, and that their eventual phenotype depends entirely on the tissue environment. In 1989 Loems Ziegler-Heitbrock and colleagues reported that human monocytes can be divided into two subsets according to expression of CD16 and CD14.31 The dominant subset represents ~85% of the monocyte pool and expresses CD14 at high levels and is low or negative for CD16 (CD16) whereas the minor subset is low for CD14 but high for CD16 (CD16+).32, 33 CD16+ monocytes produce TNFα in vitro34 and increase in the circulation in certain inflammatory conditions.3537 Accumulating evidence suggests, however, that CD16 monocytes are inflammatory; for example they express high levels of CCR2, a receptor for an inflammatory chemokine MCP-1, and can release myeloperoxidase.11, 38 It is possible that both subsets play a role in inflammation, but differ according to the stimuli they encounter.

The existence of monocyte subsets in the mouse was first suggested by Ulrich von Andrian and colleagues in 200139 and their phenotypic and functional characterization was conducted in 2003 by Frederic Geissman et al.40 As in the human, mouse monocytes can be divided into two subsets. One subset expresses Ly-6C (or Gr-1) at high levels (Ly-6Chigh) and represents ~50–60% of the monocyte pool in the steady state whereas the other expresses Ly-6C at low levels (Ly-6Clow). Based on the expression of the chemokine receptors CCR2 and CX3CR1, mouse Ly-6Chigh (CCR2highCX3CR1+) monocytes resemble human CD16 monocytes, while mouse Ly-6Clow (CCR2+CX3CR1high) cells resemble human CD16+ cells, although some discrepancy between the subsets has been documented. 41 This finding ushered in renewed interest in monocytes because now it was possible to study the functional consequence of phenotypic heterogeneity in mouse models. Monocyte subtypes mediate distinct biological functions: in the mouse, Ly-6Chigh monocytes are potent inflammatory mediators,40, 4246 while Ly-6Clow monocytes, initially termed “resident” because of the capacity to accumulate regardless of inflammation11, 40, and later shown to exhibit “patrolling” behavior18 may be important in the resolution of inflammation.30

Monocyte/macrophage response after MI

Neutrophils accumulate in the infarcted myocardium in the first hours after onset of ischemia, and peak after one day, in a process that depends on the chemokines IL-8 (CXCL8) and CXCL1 and the adhesion molecules L- and P-selectin and ICAM-1 (reviewed in 68, 47). Thereafter, monocytes and their lineage descendant macrophages dominate the cellular infiltrate. The presence, time course, and importance of these phagocytes have been investigated in rodent and large animal models.30, 4852 The studies confirm that monocytes/macrophages dominate the cellular infiltrate for the first 2 weeks after MI and participate in infarct wound healing. Germ-line deletion of MCP-153 or its receptor CCR254 point to a central role of this chemokine/chemokine receptor pair in the recruitment of monocytes to the infarct. In addition, some adhesion molecules such as VCAM-1 are upregulated in the infarct30, 55 and may contribute to monocyte recruitment through binding the integrin VLA-4 on their cell surface.

In ischemia-reperfusion injury, any inflammation is likely harmful. Neutrophils and monocytes/macrophages release proteolytic enzymes and reactive oxygen species, and exacerbate the injury by harming myocytes that survived the ischemic period. Preclinical studies have shown that anti-inflammatory treatment can be beneficial because it decreases the infarct size-to-area-at-risk ratio after ischemia-reperfusion injury (recently reviewed in5658). However, none of these strategies have been translated into the clinic and it is unknown whether reparative monocytes play a role in this type of injury.

In unreperfused MI, experimental data report both negative54, 59, 60 and positive30, 6164 correlations between monocyte/macrophage numbers and healing/left ventricular remodeling. To reconcile these seemingly conflicting results, we argue that adequate wound healing after death of a large number of myocytes requires a monocyte/macrophage response that balances inflammatory and reparative functions. Indeed, in contrast to ischemia-reperfusion injury, unreperfused MI requires that a large portion of the necrotic myocardium is replaced with scar tissue, a process that requires monocytes. However, either broad suppression of inflammation or unbridled inflammatory activity may stall the reparative functions mediated by these cells.

Monocytes/macrophages have similar functions in skin wounds65 and myocardial infarcts68, 66: The cells a) release inflammatory mediators such as iNOS, reactive oxygen species, IFN-γ, TNF-α, IL-1, IL-6, and MIP1-α; b) phagocytose apoptotic and necrotic myocytes and neutrophils and other debris; c) release proteases such as metalloproteinases (MMP-2, 9 and 13), u-PA and cathepsins which digest the preexisting collagen network and facilitate cell movement; d) promote angiogenesis through VEGF and fibroblast growth factor (FGF) secretion; e) transport reparative enzymes and pro-survival factors such as transglutaminases; and f) stimulate collagen synthesis and deposition by myofibroblasts through release of TGF-β and FGF.

The sum of these functions positions monocytes and their tissue descendants as key regulators of infarct healing. However, the antagonistic nature of these functions presents a conundrum: how can a cell be destructive and reparative at the same time? The existence of monocyte and macrophage subsets11 provides a possible resolution to this tension. A study in a murine model of coronary ligation found that the monocyte response in the myocardium is temporally biphasic.30 Pro-inflammatory Ly-6Chigh monocytes dominate on days 1–4 (phase 1) and promote digestion of infarcted tissue and removal of necrotic debris, whereas reparative Ly-6Clow monocytes dominate during the resolution of inflammation (phase 2) and propagate repair (Fig. 2). Monocyte subsets express different chemokine receptors and thus respond differentially to chemokines released from the cardiac wound. MCP-1 (also known as CCL2) is released during phase 1 and recruits Ly-6Chigh (CCR2+ CX3CR1low) monocytes preferentially. In the absence of CX3CR1, Ly-6Clow monocytes do not accumulate during phase 2. Concomitantly, fractalkine expression is decreased in phase 1 but increases in phase 2, suggesting that it recruits Ly-6Clow (CCR2 CX3CR1high) monocytes during phase 2. Once recruited, monocyte subsets mediate distinct biologic activities: Ly-6Chigh monocytes express TNF-α, IL-1b, myeloperoxidase, MMPs, cathepsins, and plasminogen activator urokinase, and are therefore potently inflammatory, whereas Ly-6Clow monocytes express IL-10, TGF-β and the pro-angiogenic factor VEGF, and are therefore reparative. The biological properties of monocyte subsets and their sequential recruitment to infarcts correlate well with the time course of tissue healing: the early inflammatory and digestive phase 1 is followed by active resolution of inflammation and tissue repair in phase 2. A well-coordinated biphasic monocyte response is necessary for proper healing. Abrogation of phase 1 impairs the removal of dead cardiac myocytes and debris, whereas abrogation of phase 2 decreases the generation of microvessels and the deposition of collagen.30

Figure 2
Biphasic monocyte response after myocardial infarction in the mouse. Time course of monocyte subset recruitment and their function depicted in the lower panel are adapted from Nahrendorf/Swirski et al. J Exp Med 2007.30 PMN: neutrophil, Mφ: macrophage, ...

Patients with acute MI show a similar biphasic monocyte response.67 A longitudinal study of a cohort of 36 patients over two weeks after MI identified that circulating inflammatory CD16 monocytes expanded first (peak on day 2.6), followed by CD16+ monocytes (peak on day 4.8). These findings are in line with studies in mice, which showed that the equivalent Ly-6Chigh and Ly-6Clow monocytes peak at similar times in the infarct (on day 3 and 5–7, respectively).30 Similar prognostic value of blood monocyte levels has been described in patients with stroke.68 Because the clinical studies evaluated monocytes in blood only, additional investigations are needed to determine how the monocyte responses in blood and tissue are related.

The paradigm shift from a monophasic to biphasic monocyte response after MI offers new therapeutic strategies. For instance, it could be beneficial to modulate the timing of recruitment or the ratio of subsets to emphasize tissue repair. The distinct recruitment mechanisms of monocyte subsets (MCP-1–dependent for Ly-6Chigh cells, but fractalkine-dependent for Ly-6Clow cells) offer reasonable targets to control monocytic phases and the number of inflammatory monocytes in the infarct.

Atherosclerosis induces chronic monocytosis

Myocardial infarction triggers an acute inflammatory response whereas atherosclerosis is considered a chronic inflammatory disease. Despite their frequent concurrence, the interconnection between the chronic and acute inflammatory conditions is mostly neglected. Below we review briefly the role of monocytes/macrophages in atherosclerosis, and then discuss the impact of atherosclerosis on infarct healing.

Multiple studies indicate that atherosclerosis is a multifactorial disease that mobilizes metabolic and inflammatory pathways.69, 70 It has been known for a long time that atherosclerotic lesions in humans and mice contain macrophages. Lesional macrophages ingest oxidized lipoproteins and, upon prolonged residence in atheromata, acquire morphological characteristics of foam cells. Recent reports in mouse models of atherosclerosis have also revealed the presence of dendritic cells, either in the steady state aorta71 or within tertiary lymphoid structures that develop adjacent to the adventitia.72 Direct involvement of monocytes in initiation and progression of atherosclerosis was demonstrated in mice with decreased M-CSF receptor expression.73 These studies indicate that monocytes and their tissue descendants are active participants in disease progression rather than passive responders of ongoing inflammation. The conclusions are consistent with the view, championed by Peter Libby,69 Russel Ross74 and others, that atherosclerosis is an inflammatory disease.

Appreciation of monocytes and macrophages in atherosclerosis raised many questions about their trafficking and function. Multiple studies have now demonstrated that chemokines and their cognate receptors drive monocyte infiltration to the growing atheroma.7579 The best-described chemokine/receptor pairing is MCP-1/CCR2, but fractalkine/CX3CR1 and MIP-1α/CCR5 are also important. Fate-mapping experiments designed to explore the dynamics of monocyte recruitment have revealed their continuous accumulation in the growing lesion.80, 81 Macrophages in the progressive lesion produce proteases, cathepsins, myeloperoxidase, and other inflammatory mediators70 that typically associate with so-called unstable plaques, a designation relevant to human, if less so to mouse, atherosclerosis.82, 83

The discovery of monocyte and macrophage heterogeneity necessitated the evaluation of subsets in the context of atherosclerosis. Studies have shown that hypercholesterolemic mice gradually accumulate Ly-6Chigh (CCR2high) monocytes in the circulation and the growing lesions (Fig. 3).84, 85 Although Ly-6Clow monocytes increase less severely, they ingest oxidized LDL and likely differentiate to dendritic cells upon tissue infiltration.86, 87 Upon accumulation, Ly-6Chigh monocytes differentiate to macrophages and contribute to inflammation.84, 8890 However, Ly-6Chigh monocytes can also differentiate to dendritic cells during inflammation while Ly-6Clow monocytes are known to differentiate to macrophages (for a recent review discussing the ontogeny of monocytes, macrophages, and dendritic cells, refer to reference14). The designation of macrophages as either M1 or M2, the former denoting cells that are activated through so-called classical triggers such as LPS or IFNγ, while the latter referring to alternative activation through IL-4 or IL-13, has led to the idea that Ly-6Chigh monocytes preferentially become M1 macrophages while Ly-6Clow monocyte can become M2 macrophages; further study is required to determine the strength of this relationship.91 It is possible that the eventual subsets’ phenotype combines environmentally-dependent (arguing for plasticity of monocytes) and environmentally-independent (arguing for determinism of monocytes) signals. Future studies will need to show more precisely the differential participation of subsets in atherosclerosis and whether the cells can be manipulated to influence the course of disease. Monocyte heterogeneity, then, links atherosclerosis and its complications, especially because monocytosis that occurs in atherosclerosis generates a pool of inflammatory cells that are capable of infiltrating the injured myocardium.

Figure 3
The repertoire of circulating inflammatory monocytes (inset shows a sorted Ly-6Chigh monocyte) expands over time in mice with hyperlipidemia. Adapted from Swirski et al., JCI 2007.84

Impact of atherosclerosis-related blood monocytosis on infarct healing

The vast majority of myocardial infarcts are caused by occlusion of a coronary artery following the rupture of an inflamed atherosclerotic plaque. Yet, until recently, most data on myocardial infarction and heart failure have been generated in animals that lack the heightened inflammatory state of atherosclerosis and associated chronic monocytosis. A recent study of MI in hypercholesterolemic apoE−/− mice with preexisting atherosclerosis and systemic monocytosis may recapitulate the clinical situation more faithfully.92 The study found that hypercholesterolemic mice recruit more Ly-6Chigh monocytes in infarcts and that these monocytes persist longer (prolonged phase 1). The compromised monocyte response associates with impaired infarct healing and accelerated left ventricular remodeling. Serial cardiac MRI showed that the hypercholesterolemic mice exhibit enhanced left ventricular dilatation and an increased propensity to develop heart failure. The study also showed that blood monocytosis by itself (i.e., in the absence of atherosclerosis or hypercholesterolemia, but induced by LPS injections), is sufficient to recapitulate the prolonged and heightened Ly-6Chigh monocyte–associated inflammation in the infarct, the acceleration of left ventricular dilatation, and the development of heart failure. Thus, these animal studies indicate that high blood monocyte counts and increased recruitment of the cells into the infarct adversely affect healing and promote left ventricular dilatation (Fig. 4).

Figure 4
Atherosclerosis is associated with an increased number of inflammatory monocytes, cells that are also centrally involved in the wound healing response after MI. The cartoon illustrates how increased recruitment of Ly-6Chigh monocytes impairs healing and ...

The experimental data mentioned above are in line with clinical studies that investigated monocyte blood levels at the time of infarction and chronic left ventricular remodeling.93, 94 Specifically, Takashi Akasaka et al. correlated the blood level of the inflammatory CD16 monocyte subset during acute MI with MRI-derived ejection fraction 6 months later, and found that patients with increased blood levels of inflammatory monocytes at the time of MI were more prone to develop heart failure.67 Taken together, these observations indicate that CD16 monocytes represent prospective therapeutic targets after MI.

Splenic reservoir monocytes and infarct healing

It has long been thought that circulating blood monocytes differentiate irreversibly into dendritic cells or macrophages upon tissue entry.11, 12 Recent findings, however, indicate that bona fide undifferentiated monocytes can be stored in large amounts in the splenic red-pulp. In case of an emergency, these monocytes are quickly released into blood and thus represent an important resource that the body uses to regulate inflammation.64 In the steady state, splenic monocytes are found in large numbers in the cords of the subcapsular red pulp; they organize in clusters of 20–50 cells around the entire organ (Fig. 5A). The cells are distinct from previously described iron-recycling red-pulp macrophages and from marginal zone macrophages and dendritic cells.95 Splenic and blood monocytes exhibit the same morphology, do not differ in their gene-expression profile, are comparably phagocytic, and can differentiate into macrophages or dendritic cells in vitro. However, splenic monocytes are virtually immotile, and vastly outnumber their equivalents in circulation.

Figure 5
Fig. 5A: The spleen stores large numbers of monocytes clustered in the subcapsular red pulp. Intravital microscopy of monocytes obtained in a mouse that expresses GFP under the CX3CR1 promoter.

In response to ischemic myocardial injury, splenic monocytes enter the blood stream and relocate to the infarct (Fig. 5B, C). The studies, performed in mouse and rat models, indicate that the spleen can contribute 40–75% monocytes to the ischemic myocardium.64 The deployment of splenic monocytes involves Angiotensin II (Ang II), the levels of which increase after MI. The angiotensin type 1 receptor (AT1), expressed by splenic monocytes, dimerizes upon interaction with the hormone. This event induces a variety of effector programs within the cell,96 including cytoskeletal rearrangement and chemotaxis-induced migration.97 Time-lapse in vivo studies have revealed that the splenic monocytes that respond to Ang II increase their motility, encounter neighboring venous sinuses or collecting veins, enter the blood stream (Fig. 5B), and become available for redistribution in the ischemic myocardium.

A 1977 study following 740 American servicemen who had been splenectomized because of trauma sustained during World War II revealed an increased mortality from ischemic heart disease when compared to a similar size sample of veterans who had not been splenectomized.98 These results suggest that reservoir splenic monocytes also play a significant role in humans. Decisive testing of this hypothesis requires further investigation.

Efficient healing after MI depends on a coordinated mobilization of monocytes to the ischemic myocardium. Therefore, it will be important to explore the molecular mechanisms that orchestrate the release of splenic monocytes. The findings could lead to new therapeutic options that promote or prevent the mobilization and activation of monocytes (or their subsets), and therefore inflammation. Patients with monocytosis-associated inflammatory disorders (e.g., atherosclerosis), and who develop MI, are likely to mount an exaggerated inflammatory monocyte response in the infarct. Thus, decreasing the availability of monocytes immediately after MI could be favorable to these patients. Because monocyte deployment from the spleen at least in part depends on Ang II,64 it should be tested whether targeting of the hormone (e.g., with ACE inhibitors) or its receptors (e.g., with AT1 receptor antagonists) controls the biodistribution of monocytes. ACE inhibitors are already part of the standard therapy for heart failure, and patients usually receive these drugs within days after ischemia, but their specific impact on monocyte trafficking is unknown.

Monocyte recruitment and healing outcome - a parabolic relationship?

Healing necessitates a balanced inflammatory response. On the one hand, monocytes and macrophages are needed to remove necrotic tissue, trigger angiogenesis, and initiate collagen synthesis by myofibroblasts; on the other, these cells can secrete proteases and oxygen radicals in abundance and can therefore compromise tissue integrity. The cells’ prolonged presence or exaggerated number hampers swift resolution of inflammation and prevents formation of a durable extracellular matrix. Through extrapolation of experimental and clinical data, we propose that the outcome after non-perfused MI is related to the number of monocytes that accumulate within the first two weeks (Fig. 6). The relationship is parabolic: if the infarct recruits insufficient numbers of monocytes, wound healing is delayed because debris is neither cleared nor replaced with granulation tissue and collagen matrix (blue stars in Fig. 6). If inflammatory monocytes persist too long, the reparative functions of Ly-6Clow monocytes, myofibroblasts and endothelial cells are impaired (red stars in Fig. 6). The scenario represented by red stars in Fig. 6 is relevant to patients with atherosclerosis who suffer from a high inflammatory burden. However, as data depicted by blue stars suggest, indiscriminate depletion of monocytes will also be detrimental. A therapeutic goal to prevent heart failure, then, is to shift the monocyte response to a hypothetical vertex that denotes “optimal” healing (green star in Fig. 6). Thus, the inflammation in the healing heart should be a) monitored with monocyte imaging100 to identify patients in need of therapeutic intervention, and b) targeted by tailored therapy to modulate the recruitment of monocyte subsets. Additionally, future studies should explore how already established therapeutics affect monocyte biology; for example, statins lower blood monocyte levels in experimental atherosclerosis84 whereas ACE inhibitors may interfere with monocyte exit from the splenic reservoir.64 A more nuanced understanding of these drugs’ actions may allow to refine their dosage and timing of administration. The nature of the inflammatory response during infarct healing deserves our attention as it may provide a key to prophylactic treatment options for patients with coronary artery disease.

Figure 6
Hypothetical relationship of monocyte numbers in the infarct and the healing outcome. We propose that insufficient as well as exaggerated monocyte presence is associated with impaired healing. Stars represent data from the following studies: 1. Swirski/Nahrendorf ...

Acknowledgments

We gratefully acknowledge Drs. Ralph Weissleder and Georg Ertl for fruitful discussions.

Funding Sources

This work was funded in part by grants from NIH (R01HL095629 and R01HL096576) and American Heart Association (SDG0835623D) to Matthias Nahrendorf, and Filip Swirski (R01HL095612).

Footnotes

Conflict of Interest Disclosures

None.

References

1. AHA. Cardiovascular Disease Statistics. 2008. www.americanheart.org.
2. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau J, Rutherford J, Wertheimer JH, Hawkins M. on behalf of the SAVE investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med. 1992;327:669–677. [PubMed]
3. NHLBI. NHLBI Financial Year 2008 Fact Book. 2008. http://wwwnhlbinihgov/about/factbook/tochtm.
4. Anversa P, Kajstura J, Leri A, Bolli R. Life and death of cardiac stem cells: a paradigm shift in cardiac biology. Circulation. 2006;113:1451–1463. [PubMed]
5. Chien KR, Domian IJ, Parker KK. Cardiogenesis and the complex biology of regenerative cardiovascular medicine. Science. 2008;322:1494–1497. [PubMed]
6. Cleutjens JP, Blankesteijn WM, Daemen MJ, Smits JF. The infarcted myocardium: simply dead tissue, or a lively target for therapeutic interventions. Cardiovasc Res. 1999;44:232–241. [PubMed]
7. Ertl G, Frantz S. Healing after myocardial infarction. Cardiovasc Res. 2005;66:22–32. [PubMed]
8. Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res. 2002;53:31–47. [PubMed]
9. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990;81:1161–1172. [PubMed]
10. Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000;101:2981–2988. [PubMed]
11. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–964. [PubMed]
12. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–969. [PMC free article] [PubMed]
13. Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol. 2009;27:669–692. [PubMed]
14. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science. 2010;327:656–661. [PMC free article] [PubMed]
15. Serbina NV, Pamer EG. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol. 2006;7:311–317. [PubMed]
16. Tsou CL, Peters W, Si Y, Slaymaker S, Aslanian AM, Weisberg SP, Mack M, Charo IF. Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Invest. 2007;117:902–909. [PMC free article] [PubMed]
17. van Furth R, Cohn ZA. The origin and kinetics of mononuclear phagocytes. J Exp Med. 1968;128:415–435. [PMC free article] [PubMed]
18. Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, Sarnacki S, Cumano A, Lauvau G, Geissmann F. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science. 2007;317:666–670. [PubMed]
19. Liu K, Waskow C, Liu X, Yao K, Hoh J, Nussenzweig M. Origin of dendritic cells in peripheral lymphoid organs of mice. Nat Immunol. 2007;8:578–583. [PubMed]
20. Auffray C, Fogg DK, Narni-Mancinelli E, Senechal B, Trouillet C, Saederup N, Leemput J, Bigot K, Campisi L, Abitbol M, Molina T, Charo I, Hume DA, Cumano A, Lauvau G, Geissmann F. CX3CR1+ CD115+ CD135+ common macrophage/DC precursors and the role of CX3CR1 in their response to inflammation. J Exp Med. 2009;206:595–606. [PMC free article] [PubMed]
21. Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, Cumano A, Geissmann F. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science. 2006;311:83–87. [PubMed]
22. Liu K, Victora GD, Schwickert TA, Guermonprez P, Meredith MM, Yao K, Chu FF, Randolph GJ, Rudensky AY, Nussenzweig M. In vivo analysis of dendritic cell development and homeostasis. Science. 2009;324:392–397. [PMC free article] [PubMed]
23. Naik SH, Sathe P, Park HY, Metcalf D, Proietto AI, Dakic A, Carotta S, O’Keeffe M, Bahlo M, Papenfuss A, Kwak JY, Wu L, Shortman K. Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nat Immunol. 2007;8:1217–1226. [PubMed]
24. Onai N, Obata-Onai A, Schmid MA, Ohteki T, Jarrossay D, Manz MG. Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nat Immunol. 2007;8:1207–1216. [PubMed]
25. Landsman L, Varol C, Jung S. Distinct differentiation potential of blood monocyte subsets in the lung. J Immunol. 2007;178:2000–2007. [PubMed]
26. Serbina NV, Salazar-Mather TP, Biron CA, Kuziel WA, Pamer EG. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity. 2003;19:59–70. [PubMed]
27. Tacke F, Ginhoux F, Jakubzick C, van Rooijen N, Merad M, Randolph GJ. Immature monocytes acquire antigens from other cells in the bone marrow and present them to T cells after maturing in the periphery. J Exp Med. 2006;203:583–597. [PMC free article] [PubMed]
28. Varol C, Landsman L, Fogg DK, Greenshtein L, Gildor B, Margalit R, Kalchenko V, Geissmann F, Jung S. Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J Exp Med. 2007;204:171–180. [PMC free article] [PubMed]
29. Varol C, Vallon-Eberhard A, Elinav E, Aychek T, Shapira Y, Luche H, Fehling HJ, Hardt WD, Shakhar G, Jung S. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity. 2009;31:502–512. [PubMed]
30. Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, Pittet MJ. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007;204:3037–3047. [PMC free article] [PubMed]
31. Passlick B, Flieger D, Ziegler-Heitbrock HW. Identification and characterization of a novel monocyte subpopulation in human peripheral blood. Blood. 1989;74:2527–2534. [PubMed]
32. Draude G, von Hundelshausen P, Frankenberger M, Ziegler-Heitbrock HW, Weber C. Distinct scavenger receptor expression and function in the human CD14(+)/CD16(+) monocyte subset. Am J Physiol. 1999;276:H1144–9. [PubMed]
33. Ziegler-Heitbrock L. The CD14+ CD16+ blood monocytes: their role in infection and inflammation. J Leukoc Biol. 2007;81:584–592. [PubMed]
34. Belge KU, Dayyani F, Horelt A, Siedlar M, Frankenberger M, Frankenberger B, Espevik T, Ziegler-Heitbrock L. The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J Immunol. 2002;168:3536–3542. [PubMed]
35. Fingerle-Rowson G, Auers J, Kreuzer E, Fraunberger P, Blumenstein M, Ziegler-Heitbrock LH. Expansion of CD14+CD16+ monocytes in critically ill cardiac surgery patients. Inflammation. 1998;22:367–379. [PubMed]
36. Hanai H, Iida T, Takeuchi K, Watanabe F, Yamada M, Kikuyama M, Maruyama Y, Iwaoka Y, Hirayama K, Nagata S, Takai K. Adsorptive depletion of elevated proinflammatory CD14+CD16+DR++ monocytes in patients with inflammatory bowel disease. Am J Gastroenterol. 2008;103:1210–1216. [PubMed]
37. Horelt A, Belge KU, Steppich B, Prinz J, Ziegler-Heitbrock L. The CD14+CD16+ monocytes in erysipelas are expanded and show reduced cytokine production. Eur J Immunol. 2002;32:1319–1327. [PubMed]
38. Wildgruber M, Lee H, Chudnovskiy A, Yoon TJ, Etzrodt M, Pittet MJ, Nahrendorf M, Croce K, Libby P, Weissleder R, Swirski FK. Monocyte subset dynamics in human atherosclerosis can be profiled with magnetic nano-sensors. PLoS One. 2009;4:e5663. [PMC free article] [PubMed]
39. Palframan RT, Jung S, Cheng G, Weninger W, Luo Y, Dorf M, Littman DR, Rollins BJ, Zweerink H, Rot A, von Andrian UH. Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J Exp Med. 2001;194:1361–1373. [PMC free article] [PubMed]
40. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19:71–82. [PubMed]
41. Ingersoll MA, Spanbroek R, Lottaz C, Gautier EL, Frankenberger M, Hoffmann R, Lang R, Haniffa M, Collin M, Tacke F, Habenicht AJ, Ziegler-Heitbrock L, Randolph GJ. Comparison of gene expression profiles between human and mouse monocyte subsets. Blood. 2010;115:e10–9. [PMC free article] [PubMed]
42. An G, Wang H, Tang R, Yago T, McDaniel JM, McGee S, Huo Y, Xia L. P-selectin glycoprotein ligand-1 is highly expressed on Ly-6Chi monocytes and a major determinant for Ly-6Chi monocyte recruitment to sites of atherosclerosis in mice. Circulation. 2008;117:3227–3237. [PMC free article] [PubMed]
43. Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Bruck W, Priller J, Prinz M. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci. 2007;10:1544–1553. [PubMed]
44. Noel JG, Osterburg A, Wang Q, Guo X, Byrum D, Schwemberger S, Goetzman H, Caldwell CC, Ogle CK. Thermal injury elevates the inflammatory monocyte subpopulation in multiple compartments. Shock. 2007;28:684–693. [PubMed]
45. Robben PM, LaRegina M, Kuziel WA, Sibley LD. Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis. J Exp Med. 2005;201:1761–1769. [PMC free article] [PubMed]
46. Sunderkotter C, Nikolic T, Dillon MJ, Van Rooijen N, Stehling M, Drevets DA, Leenen PJ. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol. 2004;172:4410–4417. [PubMed]
47. Frangogiannis NG, Entman ML. Targeting the chemokines in myocardial inflammation. Circulation. 2004;110:1341–1342. [PubMed]
48. Weihrauch D, Zimmermann R, Arras M, Schaper J. Expression of extracellular matrix proteins and the role of fibroblasts and macrophages in repair processes in ischemic porcine myocardium. Cell Mol Biol Res. 1994;40:105–116. [PubMed]
49. Sun Y, Weber KT. Cells expressing angiotensin II receptors in fibrous tissue of rat heart. Cardiovasc Res. 1996;31:518–525. [PubMed]
50. Yang F, Liu YH, Yang XP, Xu J, Kapke A, Carretero OA. Myocardial infarction and cardiac remodelling in mice. Exp Physiol. 2002;87:547–555. [PubMed]
51. Frangogiannis NG, Mendoza LH, Ren G, Akrivakis S, Jackson PL, Michael LH, Smith CW, Entman ML. MCSF expression is induced in healing myocardial infarcts and may regulate monocyte and endothelial cell phenotype. Am J Physiol Heart Circ Physiol. 2003;285:H483–92. [PubMed]
52. Dewald O, Ren G, Duerr GD, Zoerlein M, Klemm C, Gersch C, Tincey S, Michael LH, Entman ML, Frangogiannis NG. Of mice and dogs: species-specific differences in the inflammatory response following myocardial infarction. Am J Pathol. 2004;164:665–677. [PMC free article] [PubMed]
53. Dewald O, Zymek P, Winkelmann K, Koerting A, Ren G, Abou-Khamis T, Michael LH, Rollins BJ, Entman ML, Frangogiannis NG. CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res. 2005;96:881–889. [PubMed]
54. Kaikita K, Hayasaki T, Okuma T, Kuziel WA, Ogawa H, Takeya M. Targeted deletion of CC chemokine receptor 2 attenuates left ventricular remodeling after experimental myocardial infarction. Am J Pathol. 2004;165:439–447. [PMC free article] [PubMed]
55. Nahrendorf M, Keliher E, Panizzi P, Zhang H, Hembrador S, Figueiredo JL, Aikawa E, Kelly K, Libby P, Weissleder R. 18F-4V for PET-CT imaging of VCAM-1 expression in atherosclerosis. JACC Cardiovasc Imaging. 2009;2:1213–1222. [PMC free article] [PubMed]
56. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357:1121–1135. [PubMed]
57. Prasad A, Stone GW, Holmes DR, Gersh B. Reperfusion injury, microvascular dysfunction, and cardioprotection: the "dark side" of reperfusion. Circulation. 2009;120:2105–2112. [PubMed]
58. Steffens S, Montecucco F, Mach F. The inflammatory response as a target to reduce myocardial ischaemia and reperfusion injury. Thromb Haemost. 2009;102:240–247. [PubMed]
59. Hayashidani S, Tsutsui H, Shiomi T, Ikeuchi M, Matsusaka H, Suematsu N, Wen J, Egashira K, Takeshita A. Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation. 2003;108:2134–2140. [PubMed]
60. Maekawa Y, Anzai T, Yoshikawa T, Sugano Y, Mahara K, Kohno T, Takahashi T, Ogawa S. Effect of granulocyte-macrophage colony-stimulating factor inducer on left ventricular remodeling after acute myocardial infarction. J Am Coll Cardiol. 2004;44:1510–1520. [PubMed]
61. Leor J, Rozen L, Zuloff-Shani A, Feinberg MS, Amsalem Y, Barbash IM, Kachel E, Holbova R, Mardor Y, Daniels D, Ocherashvilli A, Orenstein A, Danon D. Ex vivo activated human macrophages improve healing, remodeling, and function of the infarcted heart. Circulation. 2006;114:I94–100. [PubMed]
62. Morimoto H, Takahashi M, Izawa A, Ise H, Hongo M, Kolattukudy PE, Ikeda U. Cardiac Overexpression of Monocyte Chemoattractant Protein-1 in Transgenic Mice Prevents Cardiac Dysfunction and Remodeling After Myocardial Infarction. Circ Res. 2006 [PubMed]
63. van Amerongen MJ, Harmsen MC, van Rooijen N, Petersen AH, van Luyn MJ. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am J Pathol. 2007;170:818–829. [PMC free article] [PubMed]
64. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325:612–616. [PMC free article] [PubMed]
65. Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341:738–746. [PubMed]
66. Frantz S, Bauersachs J, Ertl G. Post-infarct remodelling: contribution of wound healing and inflammation. Cardiovasc Res. 2009;81:474–481. [PMC free article] [PubMed]
67. Tsujioka H, Imanishi T, Ikejima H, Kuroi A, Takarada S, Tanimoto T, Kitabata H, Okochi K, Arita Y, Ishibashi K, Komukai K, Kataiwa H, Nakamura N, Hirata K, Tanaka A, Akasaka T. Impact of heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary acute myocardial infarction. J Am Coll Cardiol. 2009;54:130–138. [PubMed]
68. Urra X, Villamor N, Amaro S, Gomez-Choco M, Obach V, Oleaga L, Planas AM, Chamorro A. Monocyte subtypes predict clinical course and prognosis in human stroke. J Cereb Blood Flow Metab. 2009;29:994–1002. [PubMed]
69. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–874. [PubMed]
70. Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol. 2008;8:802–815. [PubMed]
71. Choi JH, Do Y, Cheong C, Koh H, Boscardin SB, Oh YS, Bozzacco L, Trumpfheller C, Park CG, Steinman RM. Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves. J Exp Med. 2009;206:497–505. [PMC free article] [PubMed]
72. Grabner R, Lotzer K, Dopping S, Hildner M, Radke D, Beer M, Spanbroek R, Lippert B, Reardon CA, Getz GS, Fu YX, Hehlgans T, Mebius RE, van der Wall M, Kruspe D, Englert C, Lovas A, Hu D, Randolph GJ, Weih F, Habenicht AJ. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE−/− mice. J Exp Med. 2009;206:233–248. [PMC free article] [PubMed]
73. Rajavashisth T, Qiao JH, Tripathi S, Tripathi J, Mishra N, Hua M, Wang XP, Loussararian A, Clinton S, Libby P, Lusis A. Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor- deficient mice. J Clin Invest. 1998;101:2702–2710. [PMC free article] [PubMed]
74. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999;340:115–126. [PubMed]
75. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2−/−mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998;394:894–897. [PubMed]
76. Combadiere C, Potteaux S, Rodero M, Simon T, Pezard A, Esposito B, Merval R, Proudfoot A, Tedgui A, Mallat Z. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation. 2008;117:1649–1657. [PubMed]
77. Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 1998;2:275–281. [PubMed]
78. Lesnik P, Haskell CA, Charo IF. Decreased atherosclerosis in CX3CR1−/− mice reveals a role for fractalkine in atherogenesis. J Clin Invest. 2003;111:333–340. [PMC free article] [PubMed]
79. Saederup N, Chan L, Lira SA, Charo IF. Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2−/− mice: evidence for independent chemokine functions in atherogenesis. Circulation. 2008;117:1642–1648. [PMC free article] [PubMed]
80. Kim CJ, Khoo JC, Gillotte-Taylor K, Li A, Palinski W, Glass CK, Steinberg D. Polymerase chain reaction-based method for quantifying recruitment of monocytes to mouse atherosclerotic lesions in vivo: enhancement by tumor necrosis factor-alpha and interleukin-1 beta. Arterioscler Thromb Vasc Biol. 2000;20:1976–1982. [PubMed]
81. Swirski FK, Pittet MJ, Kircher MF, Aikawa E, Jaffer FA, Libby P, Weissleder R. Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc Natl Acad Sci U S A. 2006;103:10340–10345. [PMC free article] [PubMed]
82. Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Juhani Airaksinen KE, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull WJ, Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation. 2003;108:1664–1672. [PubMed]
83. Schwartz SM, Galis ZS, Rosenfeld ME, Falk E. Plaque rupture in humans and mice. Arterioscler Thromb Vasc Biol. 2007;27:705–713. [PubMed]
84. Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest. 2007;117:195–205. [PMC free article] [PubMed]
85. Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, van Rooijen N, Lira SA, Habenicht AJ, Randolph GJ. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest. 2007;117:185–194. [PMC free article] [PubMed]
86. Tacke F, Randolph GJ. Migratory fate and differentiation of blood monocyte subsets. Immunobiology. 2006;211:609–618. [PubMed]
87. Wu H, Gower RM, Wang H, Perrard XY, Ma R, Bullard DC, Burns AR, Paul A, Smith CW, Simon SI, Ballantyne CM. Functional role of CD11c+ monocytes in atherogenesis associated with hypercholesterolemia. Circulation. 2009;119:2708–2717. [PMC free article] [PubMed]
88. Gautier EL, Jakubzick C, Randolph GJ. Regulation of the migration and survival of monocyte subsets by chemokine receptors and its relevance to atherosclerosis. Arterioscler Thromb Vasc Biol. 2009;29:1412–1418. [PMC free article] [PubMed]
89. Swirski FK, Weissleder R, Pittet MJ. Heterogeneous in vivo behavior of monocyte subsets in atherosclerosis. Arterioscler Thromb Vasc Biol. 2009;29:1424–1432. [PMC free article] [PubMed]
90. Woollard KJ, Geissmann F. Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol. 2010;7:77–86. [PMC free article] [PubMed]
91. Mantovani A, Garlanda C, Locati M. Macrophage diversity and polarization in atherosclerosis: a question of balance. Arterioscler Thromb Vasc Biol. 2009;29:1419–1423. [PubMed]
92. Panizzi P, Swirski FK, Figueiredo JL, Waterman P, Sosnovik D, Aikawa E, Libby P, Pittet M, Weissleder R, Nahrendorf M. Impaired infarct healing in atherosclerotic mice with Ly-6Chi monocytosis. J Am Coll Cardiol. 2010;55:1629–38. [PMC free article] [PubMed]
93. Maekawa Y, Anzai T, Yoshikawa T, Asakura Y, Takahashi T, Ishikawa S, Mitamura H, Ogawa S. Prognostic significance of peripheral monocytosis after reperfused acute myocardial infarction:a possible role for left ventricular remodeling. J Am Coll Cardiol. 2002;39:241–246. [PubMed]
94. Mariani M, Fetiveau R, Rossetti E, Poli A, Poletti F, Vandoni P, D’Urbano M, Cafiero F, Mariani G, Klersy C, De Servi S. Significance of total and differential leucocyte count in patients with acute myocardial infarction treated with primary coronary angioplasty. Eur Heart J. 2006;27:2511–2515. [PubMed]
95. Mebius RE, Kraal G. Structure and function of the spleen. Nat Rev Immunol. 2005;5:606–616. [PubMed]
96. AbdAlla S, Lother H, Langer A, el Faramawy Y, Quitterer U. Factor XIIIA transglutaminase crosslinks AT1 receptor dimers of monocytes at the onset of atherosclerosis. Cell. 2004;119:343–354. [PubMed]
97. Kintscher U, Wakino S, Kim S, Fleck E, Hsueh WA, Law RE. Angiotensin II induces migration and Pyk2/paxillin phosphorylation of human monocytes. Hypertension. 2001;37:587–593. [PubMed]
98. Robinette CD, Fraumeni JFJ. Splenectomy and subsequent mortality in veterans of the 1939–45 war. Lancet. 1977;2:127–129. [PubMed]
99. Roberts R, DeMello V, Sobel BE. Deleterious effects of methylprednisolone in patients with myocardial infarction. Circulation. 1976;53:I204–6. [PubMed]
100. Nahrendorf M, Sosnovik DE, French BA, Swirski FK, Bengel F, Sadeghi MM, Lindner JR, Wu JC, Kraitchman DL, Fayad ZA, Sinusas AJ. Multimodality cardiovascular molecular imaging, Part II. Circ Cardiovasc Imaging. 2009;2:56–70. [PMC free article] [PubMed]
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