Monocyte recruitment and fate specification after myocardial infarction

Abstract

Monocytes are critical mediators of the inflammatory response following myocardial infarction (MI) and ischemia-reperfusion injury. They are involved in both initiation and resolution of inflammation and play an integral role in cardiac repair. The antagonistic nature of their function is dependent on their subset heterogeneity and biphasic response following injury. New advancements in single-cell transcriptomics and mass cytometry have allowed us to identify smaller, transcriptionally distinct clusters that may have functional relevance in disease and homeostasis. Additionally, recent insights into the spatiotemporal dynamics of monocytes following ischemic injury and their subsequent interactions with the endothelium and other immune cells reveal a complex interplay between monocytes and the cardiac milieu. In this review, we highlight recent findings on monocyte functional heterogeneity, present new mechanistic insight into monocyte recruitment and fate specification following MI, and discuss promising therapeutic avenues targeting monocytes for the treatment of ischemic heart disease.

INTRODUCTION

Prolonged myocardial ischemia, caused by an imbalance between oxygen supply and demand, together with myocardial injury, manifested by a rising and/or falling pattern of cardiac troponin (cTn), define an acute myocardial infarction (MI) (89). MI continues to be the leading cause of death and disability in developed nations, despite advancements in reperfusion and pharmacotherapy. A clinically significant MI causes significant cardiomyocyte cell death by necrosis, apoptosis, and dysregulated autophagy, leading to myocardial degeneration and adverse remodeling (20, 21). A coordinated response by the innate immune system is crucial to cardiac repair following ischemia. Monocytes comprise a small percentage of blood leukocytes but play a major role in removing debris and facilitating repair via a carefully orchestrated biphasic response dependent on the release of cytokines from cardiac resident immune and vascular cells. Understanding the interplay between monocytes and the cardiac milieu following MI is critical in the development of effective interventions to minimize cardiac damage from ischemia and reperfusion. To this end, we present the most recent findings on monocyte subtype classification, interaction with the endothelium, and recruitment following myocardial injury and highlight emerging therapeutic strategies targeting the monocyte response in MI and heart failure.

ORIGINS AND FUNCTIONAL CHARACTERIZATION OF MONOCYTE SUBTYPES

Monocytes are part of the mononuclear phagocyte system and arise from granulocyte-monocyte progenitors (GMPs) and monocyte-dendritic cell progenitors (MDPs) derived from hematopoietic stem cells (HSCs) in the bone marrow (36, 101). The differentiation of HSCs to monocyte precursors is tightly regulated by expression of specific transcription factors such as PU.1 (48, 72) and NR4A1 (35) at key time points in their development. Upon maturation, monocytes enter the bloodstream in a process dependent on monocyte chemotactic protein (MCP)-1/3 (also referred to as CCL2) and CCR2 (the receptor to MCP-1/CCL2) (92). At steady state, they comprise 4–10% of leukocytes in circulation and vastly higher quantities in the spleen, where they exist in an undifferentiated state in reservoirs within the subcapsular red pulp (26, 84). With the exception of the spleen, once monocytes enter the tissue they differentiate into dendritic cells or macrophages. In the heart, genetic fate mapping has revealed that the majority of tissue-resident macrophages arise in the yolk sac during early embryogenesis (27). Following MI, blood monocytes are recruited to the heart, where they replace established resident macrophage populations, coordinate cardiac inflammation as activated “M1” inflammatory macrophages, and contribute to efferocytosis and tissue remodeling as reparative “M2” macrophages (27). While it is well established that macrophages are highly plastic and exist on a spectrum of activation states, controversy remains over the mechanisms regulating their M1 to M2 switch (43). Our understanding is still evolving as to whether M1 and M2 macrophages are phenotypically and functionally distinct subpopulations arising from different monocyte subtypes (Ly6C^high to M1 and Ly6C^high to M2) (6, 66) or whether the same cells shift between M1 and M2 functional phenotypes in response to cues from their microenvironment (4, 18).

Historically, human monocytes have been broadly categorized into three distinct subsets based on their surface expression of CD14 and CD16 (73): 1) classical CD14^highCD16⁻ monocytes, 2) intermediate CD14^highCD16^low monocytes, and 3) nonclassical CD14^lowCD16^high monocytes (Fig. 1). Recent studies using human in vivo deuterium labeling and fate mapping into humanized mice suggest that classical monocytes give rise to intermediate and nonclassical monocytes by sequential transition (74). Classical monocytes represent the most prevalent monocyte population in the blood. They express high levels of scavenger receptor CD36 (57), CD64, and CCR2 along with other chemokine receptors such as CCR1, CCR5, CXCR1, and CXCR5. Classical monocytes are associated with several diseases hallmarked by inflammation and play an important role in the initiation and progression of the inflammatory response (10, 54, 80). Nonclassical monocytes, in contrast, are dependent on NR4A1 for development (88), express high levels of CX3CR1 (the receptor to CX3CL1 or fractalkine) and low levels of chemokine receptors, and play a role in the resolution of inflammation. Intermediate monocytes are characterized by high expression of CCR5 and HLA-DR molecules. Their role in immunity appears to be mixed with studies highlighting both pro- (77, 78) and anti-inflammatory (7, 94) roles. In mice, functional adaptive transfer studies identified two main monocyte subsets in the blood that appear to functionally overlap with classical and nonclassical human monocytes, respectively, a short-lived population positive for CCR2 with low expression of CX3CR1 that migrates to the tissue during inflammation (Ly6C^highTREML4⁻CD43⁻), and a CCR2⁻CX3CR1⁺ subset that patrols the vasculature and is recruited to normal tissue via a CX3CR1-dependent mechanism (Ly6C^lowTREML4⁺CD43⁺) (Fig. 1) (30).

Fig. 1.

Monocyte subtypes in human and mouse. A: human monocytes are broadly categorized into three distinct subsets (classical, intermediate, and nonclassical) based on their surface expression of CD14 and CD16, as illustrated by flow cytometry on human peripheral blood monocytes. B: these subsets differ with respect to their chemokine receptor-mediated chemotaxis, surface marker expression, and cytokine secretion. Mouse monocyte subtypes are broadly conserved with human subsets but differ in expression of certain surface markers. CCR, C-C chemokine receptor; CD, cluster of differentiation; CXCL, CCL, C-C chemokine ligand; iNOS, inducible nitric oxide synthase; Ly6, lymphocyte antigen 6; SLAN, 6-sulfo LacNAc; TLR, Toll-like receptor. [Data for this image was derived from Wacleche et al. (97).]

Recent research has highlighted heterogeneity within classical and nonclassical human monocytes, challenging the current three subset paradigm (33). Using mass cytometry (CyTOF), Roussel et al. (78a) increased the phenotypical resolution of nonclassical monocytes, separating CD14^lowCD16^high monocytes into two groups by 6-sulfo LacNAc (SLAN)^+/− expression. Pairing high dimensional mass cytometry with a FlowSOM clustering algorithm, Hamers et al. (34) identified eight human monocyte subsets in healthy individuals based on surface marker phenotype. Their work also highlighted the heterogeneity of SLAN expression within nonclassical monocytes. They defined a SLAN⁺CXCR5⁺ nonclassical subset with enhanced capacity for efferocytosis and migration toward CXCL16, establishing it as a potential regulator of vascular homeostasis in late atherogenesis (34). While they identified four subsets within CD14^high classical monocytes (varying by expression levels of IgE, CD61, CD9, CD93, and CD11a), they found no difference in proliferation or LDL/oxidized LDL (oxLDL) update between groups. Additional studies focusing on the functional relevance of these subsets are needed to clarify their role in health and disease. Furthermore, even though human and mouse monocyte subtypes appear broadly conserved between species (which has allowed mouse models to serve as surrogates for the study of human monocyte behavior), differences do exist between comparable species subsets (i.e., expression of MHC class II, CD11c, CD36, CD9, TREM-1, and PPARγ) (30, 42). As advancements in single-cell transcriptomics and mass cytometry permit us to identify smaller, transcriptionally distinct clusters, it will be important to continue to elucidate the functional significance in vivo of divergent expression patterns between intra- and interspecies monocyte subtypes.

SPATIOTEMPORAL DYNAMICS OF MONOCYTES POST-MI

Following a myocardial infarction, widespread cell death and damaged extracellular matrix triggers a robust inflammatory response from the innate immune system (40). Monocytes, enabled by their heterogeneity and plasticity, play a crucial role in infarct wound healing. In the first phase of the post-MI inflammatory response, necrotic cells and damaged matrix release “danger signal” molecules called (DAMPs), which bind to pattern recognition receptors (PRPs) on immune and vascular cells (5, 96, 105), activating the transcription and release of proinflammatory cytokines and chemokines (5, 96, 105). Resident immune cells (macrophages and mast cells) and vascular cells release chemokines of the CC, CXC, and CXC3 subtypes that play distinct roles in mobilizing leucocytes to the heart (15, 68, 75). CC chemokines are strong attractants of monocytes; the most potent are CCL2 (MCP-1) and CCL7 (MCP-7), which mediate CCR2-dependent monocyte mobilization along a chemotactic gradient post-MI. CXC chemokines attract neutrophils, and CXC3 chemokines attract both monocytes and lymphocytes (15). The release of DAMPs also activates inflammasomes, such as NLRP3 (85), which recognize danger signals and activate caspase-1, inducing release of IL-1β (25). In addition, recent studies have elucidated a separate endogenous exosome-mediated signaling mechanism by the ischemic myocardium that suppresses CXCR4 in BM-progenitor cells and mediates their mobilization into the circulation (16).

The second phase of the post-MI inflammatory response is heralded by leukocyte mobilization (Fig. 2). In response to chemoattractants, leukocytes migrate toward endothelial cells (ECs) in the injured region. EC-leukocyte adhesive interactions occur in postcapillary venules, where the wall shear stress is lower than in arterioles and capillaries, allowing for leukocytes to flow at reduced velocities near the vessel wall. Extravasation of leukocytes from the circulation requires reactive oxygen species (ROS)-mediated activation of the proinflammatory EC transcription factor nuclear factor (NF)-κB, followed by upregulation of CCL2 expression and endothelial cell adhesion molecules (CAMs), and resultant adhesive interactions between flowing leukocytes and ECs (49, 50, 102). P-selectin, the only endothelial CAM that does not require transcriptional activation, is rapidly mobilized from Weibel-Palade bodies and expressed within minutes on the EC surface (59). In general, EC P- and E-selectin binding to their respective O-glycosylated carbohydrate ligands on leukocytes and leukocyte L-selectin binding to its carbohydrate ligand on ECs mediate the rolling of leukocytes along the venular endothelium (59). Transition to arrest is facilitated by leukocyte activation, chemokine signaling, and binding of leukocyte integrins to their corresponding immunoglobulin receptors on activated ECs (14, 50, 61). Crawling and transmigration of adherent leukocytes is both integrin and chemokine dependent, with transmigration facilitated by increased monolayer permeability during MI and post-MI (102). Paracellular leukocyte diapedesis depends on functional alterations of VE-cadherin that resides at adherens junctions between neighboring ECs as well as on other junctional proteins at the EC borders, such as PECAM-1 and the family of junctional cell adhesion molecules (JAMs) (31, 71). Once in the extravascular space, leukocytes travel in response to chemokine gradients by crawling on pericytes and squeezing through areas of low extracellular matrix protein density until they reach the infarcted region (71).

Fig. 2.

The leukocyte/monocyte adhesion cascade. A: endothelial activation triggers the selectin-mediated capture and rolling of monocytes along the endothelial luminal surface. Chemokines presented on the EC surface activate leukocyte integrins, allowing for integrin-mediated firm adhesion and subsequent crawling. Leukocyte transmigration is facilitated by different receptor pairs on neighboring endothelial cells (ECs; only paracellular migration is shown), as described in more detail in the text. B: specific adhesion molecules and ligands involved in monocyte adhesion and transmigration. CAG, glycosaminoglycan; CD, cluster of differentiation; CAR, chimeric antigen receptor; CCR, C-C chemokine receptor; DNAM-1, DNAX accessory molecule-1; EC, endothelial cell; ICAM, intercellular adhesion molecule; JAM, junctional cell adhesion molecule; LFA, lymphocyte function-associated antigen; Mac-1, macrophage-1; MCAM, melanoma cell adhesion molecule; PECAM, platelet endothelial cell adhesion molecule; PILR, paired Ig-like type 2 receptor; PSGL-1, P-selectin glycoprotein ligand-1; TIGIT, T cell immunoreceptor with Ig and ITIM domains; VCAM, vascular cell adhesion molecule; VE, vascular endothelium; VLA, very late antigen. [Data for this image was derived from Gerhardt and Ley (31).]

Neutrophils rapidly accumulate in the infarcted tissue, peaking in density at 24 h post-MI. While previously thought to be the first cells recruited to the ischemic myocardium, a recent study using intravital microscopy and a CX3CR1^gfp/+ mouse model of acute MI showed monocyte recruitment outpaced that of neutrophils following MI (45). Jung et al. (45) discovered a robust population of CX3CR1⁺ patrolling monocytes in the normal heart that rapidly transitioned from rolling to flow status following ischemia and comprised the first pool of monocytes to infiltrate the infarct immediately after the onset of MI. This population may play an early role in attracting neutrophils to the infarct and amplifying the initial inflammatory signal, similar to what has recently been described in models of lung inflammation (47). Tissue-resident CCR2⁺ macrophages also influence neutrophil response post-MI, promoting neutrophil extravasation into ischemic myocardium through TLR9/MyD88-mediated production of CXCL2 and CXCL5 (53). Once they arrive at the infarct site, neutrophils play a role in clearing cellular debris, degrading extracellular matrix (ECM), propagating inflammation through production of ROS, recruiting monocytes, and modulating macrophage polarization (29, 39, 83, 87).

Monocytes, released from the bone marrow and spleen, follow the initial neutrophil influx and predominate in the heart for 2 weeks post-MI. In addition to functioning as a monocyte reservoir in the first 24 h post-MI, the spleen also meets the sustained need for newly formed monocytes by IL-1β-regulated extramedullary monocytopoiesis (52). Monocyte recruitment to the ischemic myocardium follows a biphasic response. Both phases are essential for infarct healing in mice and also occur in humans (37, 66, 93, 95). Ly6C^high monocytes migrate to the infarct within the first 24 h post-MI and peak at 3 days. Their mobilization is CCR2 dependent (51, 66, 104) and mediated by release of CCL2 (MCP-1) and CCL7 (MCP-3) from macrophages, endothelial cells, and B cells (Fig. 3) (104). Recent studies also implicate endogenous cardiac extracellular vesicles in modulating the CCL2/CCR2 axis (55). Loyer et al. (55) demonstrated that endogenous cardiac extracellular vesicles (EVs) released from cardiomyocytes and ECs following myocardial infarction are taken up by Ly6C^high cardiac monocytes and increase their release of IL-6, CCL2, and CCL7. During their adhesion to activated ECs and transmigration, classical monocytes also undergo transcriptional changes that result in CCL2 upregulation, which facilitates recruitment of additional monocytes. Along with the release of CCL2, Ly6C^high monocytes release proteolytic enzymes, secrete proinflammatory cytokines, present antigens to T cells, and secrete matrix metalloproteinases (MMPs), which contribute to further degradation of the ECM. In the ischemic myocardium, Ly6C^high monocytes differentiate to M1 CCR2⁺ inflammatory macrophages that express IL-1β and TNF-α (44).

Fig. 3.

Modulation of the CCL2/CCR2 axis following cardiac injury (1). Following myocardial infarction, CCL2/MCP-1 is released by B cells, CCR2⁺ resident cardiac macrophages, and endothelial cells within the ischemic myocardium (2). CLL2/MCP-1 mediates CCR2-dependent mobilization of classical monocytes (also defined as cluster of differentiation (CD)14^highCD16⁻ in human and Ly6C^highCCR2⁺ in mice) from the bone marrow and spleen (3) and recruitment of classical monocytes to the infarct (4). Patients with a heightened or prolonged inflammatory response are susceptible to developing adverse remodeling which further potentiates an inflammatory cardiac environment (5). Modulating the CLL2/CCR2 axis via delivery of CCL2 antibodies or CCR2 antagonists has shown efficacy in reducing adverse remodeling following myocardial infarct (MI) in preclinical studies and may represent a promising therapy for clinical translation (6). CCL2, C-C chemokine ligand 2; CCR2, C-C chemokine receptor 2; MCP-1, monocyte chemoattractant protein-1.

In the later stages (3–5 days) following acute MI, the Ly-6C^lowCCR2⁻CX3CR1⁺ monocyte/M2 macrophage phenotypes become the predominant subtype. They have a reparative function and release anti-inflammatory cytokines (IL-10) and growth factors (VEGF, TGF-β) to stimulate cell proliferation, angiogenesis, and ECM production (37, 66, 67). In addition, they also produce specialized pro-resolving lipid mediators that may facilitate recruitment of additional monocytes, tissue repair, and return to homeostasis (81). Prior studies in other tissues outside the heart provide evidence for two dichotomous paradigms: 1) that M2 Ly6C^low macrophages arise from Ly6C^highCCR2⁺ circulating monocytes (18) and 2) that CCR2-expressing proinflammatory monocytes transition into Ly6C^lowCX3CR1^high monocytes at the site of injury without macrophage differentiation (19). Further studies are needed to elucidate the predominant conversion that occurs post-MI in the heart.

A large MI that has not undergone reperfusion therapy will inevitably lead to deleterious post-MI remodeling and chronic heart failure. During this time, macrophages continue to play a role in the remodeling of nonischemic remote myocardium, where they increase in number by threefold through a combination of local macrophage proliferation and monocyte recruitment (79). This is mediated by increased sympathetic output through the β₃-adrenergic receptor (which expands medullary and extramedullary hematopoiesis), increased mechanical strain (which promotes local macrophage proliferation via activation of the MAPK pathway), and increased myocardial expression of CAMs (which enhance leukocyte extravasation and recruitment to the heart (Fig. 2) (79).

Current treatment strategies to salvage ischemic myocardium hinge on prompt reperfusion by primary percutaneous intervention (PCI) to restore coronary blood flow. However, reperfusion itself can cause further irreversible cell death in a paradoxical phenomenon known as ischemia-reperfusion (I/R) injury secondary to an abrupt reintroduction of O₂, leading to a burst in cellular production of ROS and activation of the complement cascade (32, 64, 90, 106). This results in dysfunction of the vascular endothelium (11, 82) and a second wave of cardiomyocyte cell death (20, 21). Recent studies suggest the temporal dynamics of the innate immune response to injury differ between persistent total occlusion of the infarct artery and timely reperfusion (100). Using flow cytometry to characterize leukocyte rich fractions of the heart, Yan et al. (100) showed that reperfusion temporally shifted the innate immune response dynamics to an earlier time point, with macrophages accumulating at the I/R injury site 4 days earlier than a non-reperfused infarct. Unlike a nonreperfused injury, which requires a robust population of monocytes to convert necrotic tissue to scar, any additional inflammation in I/R injury is likely detrimental (65). In I/R injury, recruited monocytes release proteolytic enzymes and ROS that harm cardiomyocytes that survived the first ischemic event, further exacerbating injury (65). Monocytes subjected to ischemia-reperfusion have also been shown to inhibit endothelial cell migration and angiogenesis in vitro, two processes necessary for wound healing (41). In animal models of I/R, neutrophils expressing high levels of ICAM-1 and low levels of CXCR1 have been observed to re-enter the circulation via the endothelium in a process known as reverse transendothelial migration (rTEM) (12). In I/R injury, neutrophil rTEM appears to play a role in disseminating inflammation (13). Monocytes have also been observed to undergo rTEM and differentiate into dendritic cells that can prime and activate naïve T cells (76).

THERAPEUTIC STRATEGIES TARGETING THE MONOCYTE RESPONSE

The biphasic monocyte response is essential for cardiac repair and remodeling post-MI. Disruption of either monocyte subtype can result in deleterious effects on myocardial healing. For example, while an increase in the absolute number of classical monocytes is associated with major adverse cardiac events in patients (38), depletion of circulating Ly6C^high monocytes with clodronate-loaded liposomes results in larger areas of debris and necrotic tissue in the infarcted heart (66). Similarly, depletion of circulating Ly6C^low monocytes decreases angiogenesis and granulation tissue formation (66), hampering myocardial healing.

Attempts at fine-tuning the monocyte immune response may be more efficacious in promoting myocardial repair and attenuating adverse post-infarction remodeling. Two pilot studies examining the effect of IL-1 blockade in ST elevation myocardial infarction (STEMI) demonstrated improved cardiac remodeling, suppression of the acute inflammatory response, and lower incidence of heart failure in patients treated with the FDA-approved IL-1 receptor antagonist anakinra (1, 2). Acute MI studies using azithromycin, a macrolide antibiotic, reduced expression of CCR7 and inflammatory cytokines and enhanced levels of Ly6C^low monocytes in the peri-infarct border of the injured heart. Shifting the monocyte/macrophage response toward a more reparative phenotype resulted in a preservation of cardiac function, reduction in scar size and adverse remodeling, and improved survival post-MI (3). Toor et al. (91) directly compared the post-MI healing response of C57BL/6 mice, which have a proinflammatory type 1 immune response, to BALB/c mice, which have a more anti-inflammatory type 2 immune response. C57BL/6 mice had increased classical monocyte infiltration, prolonged monocyte-derived macrophage accumulation, and delayed transition of proinflammatory macrophages to anti-inflammatory macrophages. Prolonged inflammation resulted in impaired infarct healing in C57BL/6 mice and increased susceptibility to cardiac rupture when compared with BALB/c mice (91). Exogenous stem cell-derived exosomes have also shown efficacy in shifting inflammatory monocytes/macrophages toward a more reparative phenotype (60) and modulating cellular postconditioning (22). In another recent discovery, mononuclear cells have been shown to retain memory or trained immunity of prior activation (9, 17, 46, 62). Targeted immunotherapy to dampen monocyte-trained immunity may regulate inflammation post-MI (63). Prior to its translation as a feasible cardioprotective therapy, however, additional studies are needed to comprehensively characterize the trained immune cell epigenetic signature in patients with cardiovascular disease (70).

Numerous recent pre-clinical studies have also focused on targeting the CCL2/CCR2 axis to modify the monocyte response and promote cardiac repair (Fig. 3) (69). In addition to the role of CCL2/MCP-1 in recruiting inflammatory monocytes to the ischemic myocardium post-MI, human genetic evidence from the Framingham Heart Study has linked CCL2 polymorphisms with serum MCP-1 levels and the pathogenesis of human atherosclerosis and MI (58). This is further supported by a number of clinical studies that have demonstrated a correlation between increased levels of CCL2/MCP-1 and worse outcomes following cardiac injury (8, 23, 103). Experimental studies have also shown promising results for MCP-1 inhibition and targeted CCR2 deletion. MCP-1 deficiency as well as MCP-1 antibody inhibition both resulted in attenuated left ventricular remodeling (with no change in infarct size), despite reduced clearance of dead cardiomyocytes, when compared with wild-type animals (24). siRNA-mediated silencing of CCR2 in an apolipoprotein E-deficient (apoE^−/−) mouse model of MI decreased recruitment of inflammatory monocytes to the ischemic myocardium (56). Additionally, siCCR2-treated apoE^−/− mice were found to have decreased levels of inflammation and improved cardiac function by PET/MRI imaging (56). In another recent study, CCR2 targeted micelles loaded with a CCR2 antagonist significantly decreased the number of Ly6C^high inflammatory cells in the spleen and heart and significantly reduced infarct size following MI (98). Inhibition of CCR2 has also been shown to module atherogenesis in vivo (99). Winter et al. (99) found that circadian rhythm influences the biology of atherosclerosis with diurnal myeloid cell recruitment feeding chronic inflammation of large vessels. By utilizing chrono-pharmacological inhibition of CCR2 in apoE^−/− mice fed a high-fat diet for 4 weeks, they were able to reduce early atherosclerosis development, suggesting there may be an optimal time for atherosclerosis-directed CCR2-targeted pharmacotherapy. Because underlying atherosclerosis heightens leukocyte inflammation in I/R, this has the potential of dampening myocardial injury following reperfusion. Finally, inhibiting CCL2/CCR2 has also shown promise in limiting cardiac fibrosis in the chronic phase (∼4 weeks after injury). Administration of a mid-to-high dose of puerarin in mice following MI inhibited monocyte and macrophage recruitment to the heart, decreased MCP-1 levels, and attenuated cardiac fibrosis 4 weeks after injury (86).

Ultimate success in optimizing functional recovery following myocardial infarction and I/R injury will involve a directed and measured strategy to modulate the innate immune system and target the biphasic monocyte response. Patients exhibiting an accentuated, prolonged, or dysregulated immune response to acute MI may stand to benefit the most from implementation of such an approach (Fig. 3) (28). Additional research is needed to elucidate the functional significance of newly defined monocyte subtypes and ensure selection of robust preclinical models that best translate to human disease. The development of new therapeutic strategies modulating the monocyte response post-MI with translatable pharmacological interventions may present a crucial step toward patient-specific therapy for modifying inflammation in acute MI and chronic heart failure.

GRANTS

This work was supported by grants from the NIH (National Heart, Lung, and Blood Institute Grants K08HL130594 to J.K.L. and R01HL142673 to B.R.A.) and US Department of Veterans Affairs (IK2BX004097 to J.K.L.).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

K.I.M., A.P., and J.K.L. prepared figures; K.I.M., L.M.E., B.R.A., and J.K.L. drafted manuscript; K.I.M., L.M.E., B.R.A., and J.K.L. edited and revised manuscript; K.I.M., L.M.E., A.P., B.R.A., and J.K.L. approved final version of manuscript.