Cardiac diseases are the leading cause of mortality and morbidity worldwide, especially in the elderly. The primary function of the heart is to pump the blood that supplies oxygen and nutrients to the entire body. This association between inflammation and adverse cardiac events is well-acknowledged. Immune response participates in several heart conditions and diseases, including myocardial infarction (MI), myocarditis, endocarditis, myocardial fibrosis (MF) and arrhythmia. Many cardiac diseases have been recognized as inflammatory conditions characterized by the infiltration of monocytes and macrophage differentiation to promote localized inflammation.

The Origin and Phenotypes of Macrophages

Dysregulation of macrophages is important in cardiac diseases. The resident macrophages in cardiac derive from the yolk sac and liver in embryonic and maintain renewal in the heart. These populations self-renew without input from monocytes after birth. In cardiac diseases, the majority of the macrophages are recruited to the ischemic area from the differentiation of peripheral blood monocytes, which stem from 2 sources: bone marrow and spleen. In the diseased area, the renewal of resident macrophages is trivial. Macrophages perform an adaptation of the phenotypes and functions according to the surrounding microenvironment. M1-polarized macrophages can secrete more pro-inflammatory cytokines, immune activators, and chemokines, all resulting in acute pro-inflammatory and immune polarization reactions. The healthy heart contains a low number of M2-like macrophages, which are often considered protective and increase myocardial tissue repair in cardiac diseases.

Fig.1 Functions and phenotype of macrophages during infection and tissue repair.¹

Macrophage and Cardiac Diseases

Macrophages contribute to the outcome of various types of cardiac diseases. MI is a serious cardiovascular disorder that frequently results in death. After MI, macrophages are recruited to the site of injury, resulting in substantial inflammation and leading to adverse cardiac remodeling and dysfunction, thereby inhibiting cardiac function. MF is a cardiovascular disease mainly resulting from abnormal accumulation of extracellular matrix (ECM) proteins such as collagen, elastins, fibronectin, and laminins. Pathological macrophage polarization may be closely related to atrial and ventricular arrhythmias, providing a new hypothetical concept for the possible diagnosis of arrhythmias. Myocarditis is an inflammatory disease of the muscular portion of the heart. Massive infiltration of immune cells, particularly macrophages, is a typical feature in acute and chronic myocarditis. The rate of viral myocarditis (VM) is closely related to various cardiac viral infections. Macrophage polarization was stated to be closely related to VM pathogenesis. B cells can promote chemotaxis, monocyte recruitment, and chemokine receptor 2 (CCR2) macrophage infiltration to myocardial tissue which exacerbates the myocardial injury.

Fig.2 Potential mechanism underlying the regulation of macrophages in cardiovascular disease. (Nasser, 2020)

Strategies of Targeting Macrophages in Cardiac Diseases

• Blockade of macrophage recruitment by inhibition of blocking toll-like receptor 4 (TLR4), clodronate, chemokine receptors (the anti-CCR2 antibody, siRNA for CCR2). Inhibition of monocyte and macrophage accumulation is a primary treatment approach for cardiac tissue healing after MI and MF.
• Reprogramming macrophages from M1 phenotype to the M2. For cardiac diseases including myocarditis, MI, and MF, increased accumulation of M1 macrophages is a common feature. miR-155 in macrophages results in cardiac inflammation. miR-155 inhibition has been shown to decrease M1 polarization. miR-21 is another nucleic acid that can modulate the polarization of macrophages.
• Depletion of macrophages. Clodronate can combat circulating monocytes that infiltrate the myocardia and contribute to MF.
• Regulation of pro-inflammatory factors. Downregulation of macrophage-secreted factors, including matrix metalloproteinases (MMPs), transforming growth factor β (TGFβ), tumor necrosis factor (TNFα), interleukin 10 (IL-10), IL-13, IL-4, and IL-1, facilitates the suppression of myocarditis. Curcumin is an approved drug to combat inflammation by inhibiting NF-ĸB and TLR4, thus suppressing the production of pro-inflammatory cytokines like TNF-α and IL-1β.
• Modulation of ECM degradation. Hyaluronic acid-based micro-rods with anti-inflammatory properties decrease ECM deposition, attenuate myocardial wall thinning, and improve left ventricle function.

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References

1. Chen, Ganyi, et al. "Macrophage, a potential targeted therapeutic immune cell for cardiomyopathy." Frontiers in Cell and Developmental Biology 10 (2022): 908790.
2. Nasser, M. I., et al. "Macrophages: First guards in the prevention of cardiovascular diseases." Life Sciences 250 (2020): 117559.