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Cited by 7Cardiac Fibrosis and RemodelingCongenital heart defects researchAtherosclerosis and Cardiovascular Diseases

Cardiac Macrophages across Space and Time: Roles in Homeostasis, Disease, and Remodeling

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Shrestha, Seily, Dick, Sarah A.·2026·Canadian Journal of Cardiology
DOI 10.1016/j.cjca.2026.02.025
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Abstract

Cardiac macrophages are central regulators of heart homeostasis, injury response, and repair, exhibiting remarkable heterogeneity shaped by developmental origin, transcriptional state, and spatial localization. Recent advances in single-cell and spatial transcriptomics have revealed the complex organization of macrophage niches, raising a critical question: could targeting macrophages in a zone- and context-specific manner unlock more effective therapies for cardiac injury and remodeling? Tissue-resident macrophages (TRMs), derived from embryonic progenitors, and recruited CCR2 + macrophages from hematopoietic sources that occupy distinct niches within cardiac tissue, enabling precise crosstalk with cardiomyocytes, fibroblasts, endothelial cells, and pericytes. Following myocardial infarction, ischemia-reperfusion injury, myocarditis, or pressure-overload stress, macrophage subsets dynamically redistribute, promoting inflammation, fibrosis, and vascular remodeling in a zone-specific manner. Early-phase TRMs clear apoptotic debris, secrete reparative cytokines, and stimulate angiogenesis, whereas recruited monocyte-derived macrophages mediate pro-inflammatory signaling and ECM deposition, contributing to adverse remodeling. Spatial proximity to fibroblasts and endothelial cells underlies paracrine interactions that drive myofibroblast differentiation, angiogenesis, and scar formation, while macrophage-cardiomyocyte coupling via Cx43 and OSM-gp130 signaling regulates electrical conduction and regenerative responses. Aging alters macrophage composition, density, and spatial organization, leading to pro-fibrotic signaling and impaired repair. Understanding these spatially defined interactions provides a framework for precision immunomodulatory strategies, potentially improving cardiac repair while limiting pathological remodeling.

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  • Resident macrophage loss is immediately followed by a massive influx of pro-inflammatory, monocyte-derived macrophages (CCR2+) recruited from the circulation.

    “Their localized loss is immediately followed by a massive influx of pro-inflammatory, monocyte-derived macrophages (CCR2+) recruited from the circulation [8,9,10].”

    From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [10]

    Section 2 says injury recruits CCR2+ monocytes that become inflammatory macrophages. Section 3.2.1 reports both a roughly 70% loss of infarct-zone resident macrophages by day 2 and extensive macrophage infiltration. It does not establish that resident-cell loss is immediately followed by that influx: CCR2+ cells are reported as early as 4 hours after infarction, before the stated day-2 loss. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • During EAM, dysregulated macrophage-cardiomyocyte interactions impair contractility and exacerbate tissue damage.

    “However, during EAM, dysregulated macrophage–cardiomyocyte interactions impair contractility and exacerbate tissue damage [3,8,10].”

    From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [10]

    Section 3.3 (page unavailable) links acute autoimmune myocarditis to decreased contractile function and describes pro-inflammatory macrophage activity. It also describes macrophage-driven injury in viral myocarditis, but attributes that effect to interactions with fibroblasts. The copy does not establish that dysregulated macrophage–cardiomyocyte interactions cause impaired contractility or tissue damage during EAM. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The coexistence of pro-inflammatory (Mac-rMHCII, Mono-C) and potentially reparative (Mac-ResL, Mac-TLF) macrophage subsets suggests that broad immunosuppression may unintentionally impair resolution processes.

    “The coexistence of pro-inflammatory (Mac-rMHCII, Mono-C) and potentially reparative (Mac-ResL, Mac-TLF) macrophage subsets suggests that broad immunosuppression may unintentionally impair resolution processes [9,10,30].”

    From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [10]

    The Clinical Implications and Conclusion section (page unavailable) says that cardiac macrophages have beneficial and harmful functions and that broad immunosuppression risks disrupting reparative populations. The paper does not identify the four subsets by the names Mac-rMHCII, Mono-C, Mac-ResL, and Mac-TLF, so it supports the inference but not those specific classifications. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • IL-17A-driven inflammation synergizes with macrophage-derived signals to promote maladaptive remodelling.

    “This is consistent with previous findings demonstrating that IL-17A-driven inflammation synergizes with macrophage-derived signals to promote maladaptive remodelling [10,13].”

    From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [10]

    Section 3.3 (page not provided) reports that IL-17A promotes fibrosis in autoimmune myocarditis and shifts fibroblast signaling toward pro-inflammatory macrophages. It separately reports that SPP1-positive macrophages amplify injury in viral myocarditis. The passage does not demonstrate that IL-17A-driven inflammation synergizes with macrophage-derived signals; the two effects are described in different myocarditis settings. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • In response to acute injury, the primary resident macrophage population undergoes rapid depletion, declining by roughly 70% in the injury zone within the first few days.

    “In response to acute injury, this primary resident population undergoes rapid depletion, declining by roughly 70% in the injury zone within the first few days.”

    From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [10]

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Cited by

Sorted by citations

Authors
Shrestha, S., & Dick, S. A.
Affiliations
Queen's University (CA)
Corresponding author
Dick, Sarah A.
ORCID
Dick, Sarah A.
Venue
Canadian Journal of Cardiology
Publisher
Elsevier BV
Published
2026-08
Volume
42
Issue
8
Pages
1781-1797
ISSN
0828-282X (ISSN-L)
DOI
10.1016/j.cjca.2026.02.025
OpenAlex
W7130598326
Cited by
7
References
13
Citations by year
2026: 7
FWCI
9.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Canadian Journal of Cardiology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Canadian Institutes of Health Research (PJT-528485)
  • Faculty of Health Sciences, Queen's University
  • Natural Sciences and Engineering Research Council of Canada (RGPIN-03887)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Keywords
cardiac macrophages, tissue-resident macrophages, CCR2+ macrophages, macrophage heterogeneity, cardiac remodeling, myocardial infarction, myocarditis, pressure overload, myocardial fibrosis, angiogenesis, myofibroblast differentiation, connexin 43, cardiac aging, macrophage niche, spatial transcriptomics, cardiac repair, immunomodulation
MeSH terms
Animals, Homeostasis, Humans, Macrophages, Myocardium, Ventricular Remodeling, Myocytes, Cardiac

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