Macrophages of the heart: Homeostasis and disease

Abstract

Cardiac macrophages (CMs) are the most abundant immune cell type in the heart. They are critical for maintaining cardiac homeostasis and in the orchestration of immune responses to ischemic and non-ischemic cardiomyopathies. Their functions are highly heterogeneous and regulated by their tissue microenvironment. CMs have high plasticity, which allows them to perform various functions in the myocardium to bring about homeostasis within the cardiovascular system (CVS). CMs also play critical roles in coronary development and angiogenesis, tissue repair and remodeling, cardiac conduction and in the clearance of necrotic and apoptotic cells. However, there is a paucity of studies on the biology of cardiac macrophages in both steady state and disease, especially in humans. In this review, we discuss the multifaceted roles of CMs in the heart, focusing on their ontogeny, homeostatic functions and immunological responses during inflammation and reparative processes post-injury. We highlight the heterogeneity of CMs in their ontogeny, phenotypes and functions as well as their roles in the pathogenesis of pathological conditions such as myocarditis, myocardial fibrosis and heart failure. Understanding the unique characteristics of cardiac macrophages in the cardiac milieu is critical for the development of macrophage-specific therapeutic interventions to alleviate the global burden of cardiovascular disease (CVD). Therefore, future studies should focus on further improving the understanding of the biology of cardiac macrophages to harness their potential as therapeutic targets for cardiovascular disorders.

Graphical abstract

Highlights

• •Cardiac macrophages (CMs) are the most abundant immune cell type in the heart.
• •They are heterogenous cells that orchestrate immune responses to ischemic and non-ischemic cardiomyopathies.
• •They have critical functions in homeostasis, angiogenesis, tissue repair, cardiac conduction and immune tolerance.

1. Introduction

Macrophages are heterogeneous cells with crucial physiological and pathological functions within the cardiovascular system (CVS) [1,2]. The CVS is made-up of the heart, blood and blood vessels that work in synergy to transport oxygen, carbon dioxide and nutrients [3,4], and to regulate body temperature [5]. Macrophages are a major component of the innate immune system, where they serve in the first line of defense against invading pathogens, in tissue homeostasis, and inflammation [6,7]. Cardiac macrophages (CMs) are a major component of cardiac immune cells in the adult myocardium where their phenotype and functions are regulated by their microenvironment and may be altered by pathophysiological conditions of the CVS [8]. CMs play various critical roles in the normal functioning of the CVS. They contribute to homeostatic functions such as the regulation of extracellular matrix (ECM) protein turnover rate within the heart muscle [9], the regulation of angiogenesis and electrical conduction of the heart [10], and the phagocytosis of necrotic and apoptotic cells and immune surveillance [9,10].

Although there is strong evidence supporting the importance of cardiac macrophages in homeostatic functions within the CVS, there is a lack of consensus in literature that describes cardiac macrophage phenotypic markers in human and mice [10,11]. This is partly due to challenges in studying this population of cells in humans. Various groups that use contemporary models to study tissue-resident macrophages are in unison regarding the complexity and heterogeneity of macrophage populations in different tissues. It is now widely accepted that CMs, for instance, exist in a continuum that is highly regulated by changes in their microenvironment [12,13]. The phenotype of macrophages is strongly associated with their metabolic profile and functions [14], however, there is a paucity of studies on the metabolic and spatial transcriptomic differences between the various subsets of CMs [15,16]. Although studies in humans remain cumbersome, studies in mice and non-human primates (NHPs) are crucial to provide valuable insights into the ontogeny, phenotypes, functions and transcriptional profile of these abundant cells in the heart during steady-state and in ischemic and non-ischemic pathologies. There is a need for studies on the biology of CMs in different species in both steady state and disease that could provide valuable targets for therapeutic interventions. In this review, we discuss the heterogeneity of CMs with regards to their ontogeny, phenotype and functions as well as their roles in the pathogenesis of pathological conditions such as acute myocarditis, and myocardial fibrosis and heart failure. Furthermore, we highlight the therapeutic potential of CMs in the fight against cardiovascular disease (CVDs).

2. Ontogeny of cardiac macrophages

Cardiac macrophages (CMs) are a highly heterogeneous population of immune cells within the heart. Evidence suggests that a majority of these cells have embryonic origin and localized to the heart before birth [17] [18]. However, a combination of omics, bioimaging and fate mapping technologies have identified various clusters of cardiac macrophage sub-populations in a healthy and diseased heart [8]. Therefore, there is phenotypic and functional diversity in CMs that seeded to the heart before birth. Advances in gene expression profiling technologies and immune profiling studies have identified four subsets of cardiac macrophages in mice [16]. Interestingly, all four identified subsets expressed a combination of surface markers CD45⁺F4/80⁺CD11b⁺CD64⁺MERTK⁺ but differed in their expression of MHC class II molecules, CC-chemokine receptor 2 (CCR2) and lymphocyte antigen 6C (Ly6C) [[19], [20], [21]]. Furthermore, others have reported that these cells express canonical macrophage markers such as CD14, CD64 and Lpar6 allowing them to recognize and respond to a variety of damage-associated molecular patterns (DAMPs), while their gene expression profile was closely associated with alternatively activated macrophages expressing markers such as MRC1, CD163, and Lyve-1 [22,23]. Lineage tracing studies suggest that the differences between these subsets are strongly associated with their ontogeny [19,24,25]. Functionally, in mice the embryonic-derived CMs are pivotal in cardiac development and homeostasis while the blood-derived, CCR2+ CMs are critical in orchestrating the immune response to injury and wound healing [26]. Embryonic-derived CMs that are CD64⁺, MERTK+ and CX3CR1^high are pro-angiogenic and myogenic and are also crucial for coronary development and remodeling while the TIMD4+, LYVE1+ and IGF-1+ are mainly involved in the regulation of homeostasis [27]. Overall, CMs are highly heterogeneous in their ontogeny, phenotypes, gene expression profiles and functions during homeostasis and disease.

Moreover, these resident macrophages exhibit unique functions, including regulating inflammation and promoting tissue repair by modulating ECM dynamics and facilitating fibroblast trans-differentiation into myofibroblasts [28,29]. As the heart matures, these embryonic-derived macrophages are gradually replaced by monocyte-derived counterparts, particularly during inflammatory responses or after myocardial injury [9,30]. The embryonic-derived macrophages through surveillance of the myocardium can recognize invading pathogens or tissue injury by pattern recognition receptor (PRRs) and release cytokines such as CCL2, a chemoattractant of inflammatory cells to the site and therefore initiating an inflammatory response [Fig. 1]. The recruited inflammatory cells, such as CCR2+ monocytes work synergistically with the tissue-resident cells to regulate the inflammatory response leading immune resolution and healing. Therefore, the CMs of embryonic origin that populate the heart during early development are essential for processes such as coronary maturation, angiogenesis, and the clearance of cellular debris following injury [31]. They are also crucial in setting the balance between inflammation and homeostasis.

Fig. 1.

CCR2- tissue-resident cardiac macrophages regulate the inflammatory response to biochemical insults within the myocardium. (1) Upon biochemical insults to the myocardium, tissue-resident CCR2^- cardiac macrophages get activated through interaction with cardiomyocytes, leading to (2) secretion CCL2 which recruits inflammatory CCR2⁺ blood monocytes to the site of injury or fibrotic tissue area (3). Polarization (4) of the blood-derived CCR2⁺ macrophages is tightly regulated by the tissue-resident cardiac macrophages leading to a restoration of a homeostatic environment in the myocardium. Figure created using BioRender.

Lineage-tracing markers revealed that a high number of CMs in the myocardium following myocardial injury are derived from blood monocytes expressing the chemokine receptor type 2 (CCR2) [32]. CCR2-expression has been reported as a major distinguishing feature between CMs of adult monocytes versus embryonic origin [20]. While monocyte-derived macrophages are instrumental in acute wound healing and orchestrating inflammatory responses, tissue-resident macrophages are vital for long-term homeostasis and regeneration, highlighting their complementary roles in cardiac health [33]. Following myocardial injury detected by the embryonic-derived MHC-II^HICCR2^- CMs, chemoattractant proteins and cytokines are released by these macrophages leading to an influx of MHC-II^LOCCR2⁺ blood monocyte-derived macrophages to the site of injury [Fig. 2], these cells collaborate with fibroblasts and other myocardial cells to regulate the inflammatory and reparative response.

Fig. 2.

Developmental origins and homeostatic functions of cardiac macrophages. A majority of the tissue-resident CCR2^- cardiac macrophages (MHC-II^hi) originate from the yolk sac during embryonic development while the CCR2+ (MHC-II^lo) macrophages are derived from circulating monocytes and recruited to the myocardium at tissue-specific turnover rate. Both monocyte-derived and tissue-resident macrophages work in collaboration with tissue cells such as endothelial cells and fibroblasts to bring about homeostasis in the myocardium. Figure created using BioRender.

3. The role of cardiac macrophages in homeostasis

In a steady-state, CMs are essential for maintaining cardiac homeostasis through their diverse functions which include phagocytosis, electrical conduction, regulation of inflammation, metabolic support, and tissue remodeling [26]. CMs maintain cardiac tissue homeostasis through immune surveillance against invading pathogens, and phagocytosis of apoptotic cells and cellular debris [31,34]. These cells guard against infection, regulate angiogenesis, and coordinate matrix turnover rate [35]. Immune surveillance involves lymphocyte function-associated antigen-1 (LFA-1) and CX3CR1 receptors which allow for endothelial translocation and detection of necrotic and apoptotic cells which are then eliminated by phagocytosis [5]. CMs are crucial in the electrical conduction of the heart. Hulsmans et al. reported an abundance of tissue-resident macrophages in the human atrioventricular (AV) node, an important component of the heart's electrical conduction system [36]. Moreover, they reported that these macrophages modulate the electrical activity of cardiomyocytes through Connexin 43, a protein that forms gap junctions to allow cell-to-cell communication [36,37]. Aberrations within these macrophages trigger AV a blockage in conduction resulting in conduction abnormalities such as atrial fibrillation, ischemia-induced ventricular arrhythmias or arrhythmias associated with various inflammatory responses [38,39].

Transcriptional and functional data revealed that the CCR2⁺ monocyte-derived cardiac macrophages are crucial in the coordinating cardiac inflammation while the embryonic-derived CCR2⁻ cardiac macrophages coordinate the inflammatory response to bring about homeostasis, wound healing and regeneration of tissue integrity [11,20,31]. Therefore, homeostatic roles of the embryonic-derived MHC-II^HI CCR2⁻ CMs are diverse and include immune surveillance, phagocytosis of apoptotic cells and damaged mitochondria [[40], [41], [42]], the orchestration of electrical conduction through interaction with cardiomyocytes [36,39], which is not unique to the embryonic-derived cardiac macrophages as blood recruited macrophages have been reported to elicit atrial fibrillation [43] and lastly, the regulation of extracellular matrix turnover rate and angiogenesis in coordination with surrounding fibroblasts and endothelial cells [Fig. 3]. Both embryonic and monocyte-derived tissue-resident cardiac macrophages form an intrinsic component of a healthy functioning myocardium, they work in synergy with the fibroblasts and endothelial cells to maintain a homeostatic environment that is crucial for optimum heart function [34].

Fig. 3.

A summary of various functions of CCR2^- tissue-resident cardiac macrophages in the maintenance of homeostasis in the myocardium.

4. Cardiac macrophages and acute myocarditis

Myocarditis is defined as an inflammation of the myocardium with necrosis, or degeneration of cardiomyocytes and other cell types [44]. It is characterized by the infiltration of inflammatory cells to the myocardium, resulting in inflammatory cardiomyopathy, tissue-damage and fibrosis [45]. Myocarditis can result from infectious and non-infectious agents [Table 1]. Here, we discuss the role of cardiac macrophages in the pathogenesis of virus-induced myocarditis, the most common type of myocarditis [[45], [46], [47], [48]]. The pathogenesis of viral myocarditis has three stages: the acute stage, beginning with viral entrance and replication; the subacute stage, marked by inflammatory cell infiltration; and the chronic stage, characterized by cardiac remodeling and regeneration [49]. CMs play crucial roles in all three stages [50]. Both myocardium-resident macrophages and myocardium infiltrating blood leukocytes express surface markers that facilitate virus entry, the first step of infection. The recent global pandemic of Coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was linked to the development of viral myocarditis [51,52]. SARS-CoV-2 infection of epithelial cells in the upper respiratory tract activates inflammatory pathways leading to activation of various cell types within the CVS [53,54]. Activation of tissue-resident macrophages in response to viral antigens results in the release of pro-inflammatory cytokines such as TNF-α and IL-1β, which exacerbate cardiac injury and promote fibroblast activation through pathways involving transforming growth factor-beta (TGF-β) and the renin-angiotensin-aldosterone system (RAAS) [55,56]. The subsequent recruitment of peripheral monocytes to the heart further enhances this inflammatory response; these monocytes develop into macrophages that can adopt either M1 or M2 phenotypes. M1 macrophages are associated with pro-inflammatory responses that increase tissue damage and fibrosis, whereas M2 macrophages are involved in tissue repair but can potentially promote fibrogenesis if their activation is prolonged [57]. The inflammatory response to direct and indirect SARS-CoV-2 infection is tightly orchestrated by the tissue-resident, MHC-C^IIHICCR2^- macrophages of embryonic origins. These cells regulate the recruitment and polarization of inflammatory immune cells from the blood, local myofibroblast proliferation and tissue repair. Therefore, both tissue-resident and monocyte-derived cardiac macrophages play crucial roles in the pathogenesis of virus-induced myocarditis. However, more studies in this niche are required to fully elucidate the immune mechanisms involved.

Table 1.

Potential causes of infectious and non-infectious acute myocarditis.

Infectious		Non-infectious
Virus	Coxsackie virus, echovirus, HIV, adenovirus, hepatitis B and C, parvovirus B19, poliovirus, Epstein-Barr virus	Cardiotoxic drugs	Anthracyclines, alkylating agents, antimetabolites, monoclonal antibodies, taxanes, antiretroviral agents, antidiabetic agents, illicit drugs
Bacteria	Legionella, Staphylococcus, Salmonella, Shigella, Streptococci, Clostridium, Mycobacterium tuberculosis	Systemic diseases	Sarcoidosis, inflammatory bowel disease, giant cell arteritis, acute rheumatic fever
Parasites	Trichinella genus, Schistosoma	Chemical exposure	Hydrocarbons
Protozoa	Trypanosoma cruzi, Toxoplasmosis gondii	Anticancer drugs	Immune checkpoint inhibitors
Spirochetes	Borrelia burgdorferi	Collagen vascular diseases	Systemic lupus erythematosus, polymyositis, dermatomyositis

Acute myocarditis may also be due to non-infectious agents such as chemicals, systemic autoimmune diseases and drug metabolites [46]. Drug-induced myocarditis warrants particular attention in cases linked to immune checkpoint inhibitors (ICI), specifically, Programmed Cell Death Protein-1 (PD-1) inhibitors (e.g., nivolumab), Programmed Cell Death-Ligand 1 (PD-L1) inhibitors, and Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) inhibitors [58]. Previous research reported an increased infiltration of immune cells, macrophages and T cells during in PD-1-induced lymphocytic myocarditis [59]. However, the immune mechanisms associated with cardiac macrophages in the pathogenesis of immune checkpoint inhibitors (ICIs)-related myocarditis remain poorly understood. Autoimmune myocarditis occurs due to the aberrant activation of the immune system that may be caused by inborn errors of metabolism [60]. Certain autoimmune disorders, such as systemic lupus erythematosus can lead to myocarditis [61]. Animal models have been established to replicate autoimmune myocarditis, known as experimental autoimmune myocarditis (EAM) [18]. In the EAM model, several studies have reported that monocytes and macrophages account for approximately three-quarters of the infiltrating cells in the damaged myocardium [62]. There is a paucity of data on the role of cardiac macrophages in the pathogenesis of myocarditis induced by non-infectious agents, therefore, more studies are required to fill this gap in knowledge.

5. Roles of cardiac macrophages ischemic and non-ischemic cardiomyopathies

Ischemic cardiomyopathy (ICM) describes a condition characterized by weakening of the myocardium due to inadequate blood supply, caused by coronary artery disease (CAD), leading to impaired cardiac function [63]. ICMs include CAD, post-myocardial infarction (MI) cardiomyopathy, myocardial stunning, and myocardial hibernation. Non-ischemic cardiomyopathy (NICM) is linked to genetic predispositions, infections, immunological illnesses, and metabolic abnormalities rather than diminished heart blood flow [64]. Primary causes of NICM include infiltrating cardiomyopathy, Takotsubo cardiomyopathy, dilated cardiomyopathy, hypertrophic and restrictive cardiomyopathies, while secondary causes include sarcoidosis, amyloidosis, endocrine disorders and toxins [65].

Following ischemic injury, macrophages initiate an inflammatory response [10]. This inflammatory response involves crosstalk with other cells through the release of different mediators which affects the chemotaxis and functions of other immune cells to suppress the generation of vascular endothelial cells (ECs) and regulation of fibrosis by directly facilitating the activation and proliferation of fibroblasts and promoting their differentiation into myofibroblasts [66]. In chronic ischemic cardiomyopathy, M1 macrophages secrete pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which exacerbate inflammation and contribute to myocardial injury, whereas M2 macrophages exhibit anti-inflammatory properties and promote tissue repair by secreting factors like TGF-β and VEGF that facilitate cardiac healing and angiogenesis [67]. Evaluating the role of macrophages in a non-ischemic cardiomyopathy, genetic fate mapping confirmed the existence of the TIMD4^hiMHC^hi macrophage subset and showed that they were resident macrophages with minimal input from peripheral monocytes, suggesting that macrophage-specific loss of Retnla facilitated heart failure (HF) progression [66]. Below, we highlight the role of macrophages in pathogenesis of common ICMs and NICMs [Table 2].

Table 2.

Roles of Cardiac macrophages in the pathogenesis of cardiomyopathies.

Disease types	Macrophage	Species	Function	Reference
Ischemic cardiomyopathy
Myocardial stunning	-	-	clearing necrotic cells and cellular debris	-
Myocardial hibernation	-	-	angiogenesis	-
Myocardial infarction	CCR2-	Mice	Promote cardiac repair Reparative (Timd4, Lyve1, Folr2, Igf1), pro-inflammatory and pathogenic (II1b, NIrp3, Tlr2); Interferon stimulation: Irf3, Ifnb1, Isg15, Irf7, Cxcl10; and Anti-inflammatory function: Trem2, pro-fibrotic and reparative function: Spp1, Gdf15, Prdx1	[10,68]
	TLF+
	MHC+
	ISG+
	Trem2+
Chronic ischemic cardiomyopathy	TIMD4hiMHChi	Mice	Facilitate heart failure progression; anti-inflammatory and tissue repair	[69,70]
	M2 macrophages
Non-ischemic cardiomyopathy
Dilated cardiomyopathy	CD11+	Mice	Expressing pro-angiogenic growth factors, inducing adaptive cardiac remodeling, promotion of fibrosis, preventing fibroblast proliferation, promoting inflammation, M2-like macrophages attenuate doxorubicin-induced myocardial fibrosis by transferring mitochondria from macrophages into injured cardiomyocytes	[71,[72], [73], [74], [75]]
	CCR2-
	F4/80+
	CCR2+
	CD206+
Hypertrophic cardiomyopathy	CCR2-	Human	Promote fibroblast proliferation	[76]
Arrhythmogenic right ventricular cardiomyopathy (ARVC)	IL-32	Human Mice	promoting fibrofatty replacement of cardiac muscle; alleviation of ARVC features	[23]
	CCR2
Takotsubo Cardiomyopathy	CCR2	Mice	Blocked macrophage infiltration	[65]

6. Cardiac macrophages and myocardial infarction and fibrosis

Myocardial infarction (MI), commonly referred to as heart attack, is a cardiovascular condition characterized by low supply of oxygen to the myocardium or myocardial ischemia leading to irreversible necrosis of the heart muscle [77]. The most common cause of MI is coronary atherosclerotic rupture, which is due to thrombus formation in the coronary artery, leading to the obstruction of blood supply to the heart and subsequently, hypoxia, cardiomyocytes death and myocardial damage [78]. The immune resolution process following MI typically occurs in three phases, namely, inflammatory, proliferative and maturation phases [79,80]. The inflammatory phase forms the foundation of the immune response to MI and is characterized by immune cell infiltration [81]. Briefly, following MI, tissue-resident CCR2^- cardiac macrophages and cardiac fibroblasts of the myocardium secrete cytokines, and chemokines such as CCL2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), which recruit inflammatory CCR2⁺ blood monocytes to the site of injury [32,[71], [82], [83]]. The blood-derived CCR2⁺ monocytes differentiate into monocyte-derived macrophages [32]. Upon interactions with the tissue-resident cardiac macrophages, these monocyte-derived macrophages shift towards anti-inflammatory or immune regulatory phenotype that is characterized by elevated levels of IL-10 and expression of scavenger receptor, CD163 and mannose-receptor CD206 [[69], [70], [72], [84]]. The alternative activation of macrophages is crucial to cardiac tissue repair and regeneration [9,69,73]. Alternative activation of monocyte-derived macrophages leads to the resolution of inflammation, and proliferation of myofibroblasts, a characteristic of the proliferative phase, which is followed by scar formation and neovascularization, the maturation phase [24,31,35,55,81,74] [Fig. 4]. However, aberrations of immune inflammatory pathways lead to failure to resolve inflammation, prolonged tissue damage, poor wound healing and adverse cardiovascular outcomes. Therefore, the inflammatory response cascade presents a potential target for therapeutic interventions.

Fig. 4.

Cardiac macrophages regulate the three phases of immune resolution after myocardial fibrosis. Tissue-resident CCR2-cardiac macrophages and cardiac fibroblasts secrete CCL2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), which recruit inflammatory CCR2+ blood monocytes to the site of injury. The blood-derived CCR2+ monocytes differentiate into monocyte-derived macrophages which then shift towards anti-inflammatory phenotype. Activation of monocyte-derived macrophages leads to the resolution of inflammation, and proliferation of myofibroblasts, followed by scar formation and neovascularization. Figure created using BioRender.

Macrophages have key roles in setting the balance between matrix synthesis and degradation in the myocardium [75]. The abnormal accumulation of ECM, a hallmark of myocardial fibrosis (MF), leads to aberrant myocardial function and subsequently, heart failure [85] [86]. Macrophages play a crucial role in the pathogenesis of MF [87,68]. Revelo et al., reported that that resident CCR2⁻ macrophages play a role in inhibiting cardiac fibrosis, while the inflammatory monocyte-derived CCR2⁺ macrophages that are recruited to the infarct promote cardiac fibrosis [88]. The immune processes involved in the resolution of MF further highlight the importance of cardiac macrophages in orchestrating the immune response to both MI and MF [76]. To bring about immune resolution following fibrosis, macrophages and fibroblasts engage in complex interactions through various molecular pathways [55,89,90]. Briefly, fibroblasts attract macrophages to fibrotic sites by releasing cytokines like colony-stimulating factor 1 (CSF1) and the CCL2, which promote macrophage proliferation, activation, and differentiation [91]. The interaction between CSF1 and its receptor CSF1R is considered a critical factor maintaining the link between fibroblasts and macrophages in different contexts. Activated macrophages, in turn, release TGF-β, IL-6, and AREG, which drive fibroblast proliferation and activation [91]. Homeostasis within the myocardium depends on the crosstalk between cells, such as that between macrophages and fibroblasts [92]. Manipulating the inflammatory responses of CMs following acute MI and myocardial fibrosis, as well as targeting specific macrophage subsets during fibroblast activation, may serve as therapeutic targets for minimizing cardiac injury and preventing heart failure [[93], [94], [95]].

7. Therapeutic potential of macrophages in cardiovascular disease

As highlighted in several sections above, CMs are heterogeneous in ontogeny, phenotype and functions. They play a central role in facilitating and orchestrating the inflammatory response, tissue remodeling, wound healing and homeostasis following cardiac impairment. The heterogeneous etiology of cardiovascular conditions presents challenges for the discovery and development of new therapies to improve health outcomes of cardiovascular disease. However, the role of CMs in both homeostasis and immune response present opportunities for various therapeutic approaches [96]. Targeting the inhibition of macrophage recruitment presents a promising therapeutic approach for cardiovascular diseases. The origin, plasticity, and function of macrophages in a specific context are crucial therapeutically because they influence how macrophages respond to different stimuli and contribute to disease progression. More studies on the distinct roles of tissue-resident macrophages in their interactions with other tissue-resident cells and immune cells in systemic circulation can enhance the specificity of targeted therapies [97,98]. In conditions such as atherosclerosis and myocardial infarction, manipulations of blood monocytes can impact the behaviour of monocyte-derived macrophages at inflammatory sites. Nanoparticles and liposomes are effective delivery systems that can target myeloid cell phenotypes [99]. Liposomes enriched with phosphatidylserine (PS) mimic the recognition of apoptotic cells, inducing anti-inflammatory responses in macrophages [99]. These PS-containing liposomes have shown therapeutic potential, particularly in MI, where they facilitate improved infarct healing [98,99]. Although these studies highlight the potential therapeutic benefits of targeting macrophages, such therapies are still not available in clinical practice.

8. Conclusions

Tissue-resident macrophages are crucial in the regulation of homeostasis in both the steady state and disease. CMs, the most abundant immune cell type in heart, are crucial in setting the balance between inflammation, tissue remodeling and wound healing. These cells play a central and dynamic role in normal heart functions and in the pathogenesis of cardiovascular diseases. In low- and middle-income countries, the burden of infectious diseases is exacerbated by underlying non-communicable diseases such as cardiovascular disease. Infectious disease pandemics can also lead to the dysregulation of immune inflammatory pathways affecting CMs, leading to uncontrolled inflammation and poor wound healing. Therefore, CMs represents a potential target for therapeutic interventions to alleviate cardiovascular conditions of known and unknown etiology. However, there is a paucity of research investigating the intersection between these conditions, especially in the most affected populations. Specifically, there is a need for more studies to investigate the effect of infectious disease, and chronic medication on the pathogenesis of cardiovascular diseases.

Statement of ethics

The authors adhered to the highest ethical standards by accurately representing the findings of original research, citing sources appropriately, and avoiding any form of bias or selective reporting.

Disclosure statement

The authors have no ethical conflicts to disclose.

Disclosure statement

M.Z.Z. conceived the review; M.Z.Z.; K.C.M., P.L., O.A., wrote the review.

Funding source

K.C.M. is funded by the Mastercard Foundation MSc Scholarship. M.Z.Z. is supported by the South African Medical Research Council (SAMRC) Early Investigator Programme award through its Division of Research Capacity Development under the Research Capacity Development Initiative from funding received from the South African National Treasury. The content and findings reported / illustrated are the sole deduction, view and responsibility of the researcher and do not reflect the official position and sentiments of the SAMRC.