Implications for neutrophils in cardiac arrhythmias

Abstract

Cardiac arrhythmias commonly occur as a result of aberrant electrical impulse formation or conduction in the myocardium. Frequently discussed triggers include underlying heart diseases such as myocardial ischemia, electrolyte imbalances, or genetic anomalies of ion channels involved in the tightly regulated cardiac action potential. Recently, the role of innate immune cells in the onset of arrhythmic events has been highlighted in numerous studies, correlating leukocyte expansion in the myocardium to increased arrhythmic burden. Here, we aim to call attention to the role of neutrophils in the pathogenesis of cardiac arrhythmias and their expansion during myocardial ischemia and infectious disease manifestation. In addition, we will elucidate molecular mechanisms associated with neutrophil activation and discuss their involvement as direct mediators of arrhythmogenicity.

Keywords: arrhythmia; immune system; mechanisms; molecular; neutrophils.

Figure 1.

Conditions sharing neutrophil expansion and arrhythmia incidence. The occurrence of arrhythmias has been demonstrated in various different pathologies. A: myocardial infarction. Neutrophil spread in myocardial infarction is mediated by recognition of damage-associated molecular patterns (DAMPs) via Toll-like receptors 2 (TLR2) and 4 (TLR4), triggering neutrophil recruitment from the bone marrow to the site of cardiac injury. B: sepsis. Neutrophil proliferation in sepsis is driven by the presence of pathogens in the bloodstream that affects multiple organs, especially heart and lungs, causing upregulation of CXCL1 and downregulation of CXCL12, which ultimately promotes the recruitment of neutrophils from the bone marrow. C: myocarditis. Neutrophil expansion in myocarditis involves midkine-mediated promotion of neutrophil transport and NETosis in myocarditis, which is achieved through activation of lipoprotein receptor-related protein 1 on the surface of neutrophils, ultimately leading to increased cardiac inflammation and neutrophil recruitment from the bone marrow. D: COVID-19. Neutrophil expansion in COVID-19 is driven by COVID-19 pathogens in the bloodstream and lungs, resulting in increased levels of IL-6, IL-8, and TNF-α, which interact with their respective receptors on the neutrophil surface, including CXCR4, CXCR2, TNFR1, TNFR2, and IL-6R, promoting neutrophil activation and recruitment from the bone marrow to the site of infection. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 2.

Interactions of cardiomyocytes with (myo-)fibroblast, immune cells, and mast cells. Major cytokines involved in paracrine signaling are summarized. (Myo-)fibroblasts and cardiomyocytes can interact through secretion of transforming growth factor β (TGFβ), fibroblast growth factor (FGF), tumor necrosis factor α (TNFα), and IL-1β. Immune cells can affect the other cell types by secreting TNFα, IL-1β, macrophage migration inhibitory factor (MIF), and osteopontin. Lastly, cardiomyocytes and (myo-)fibroblasts can modulate the activity of immune cells by secreting TNFα and IL-1β. In addition, cardiomyocytes can form gap junctions with noncardiomyocytes, allowing these cells to passively affect action potential propagation. *Gap junction formation between (myo-)fibroblasts and immune cells such as macrophages has not been shown but might enable a direct interaction. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 3.

Neutrophil involvement in the onset of cardiac arrhythmias. Arrhythmias have been linked to a number of neutrophil-mediated host defense mechanisms that are explained in the following. A: cardiac heterocellularity. Neutrophils invade the myocardium in great numbers and are thought to significantly contribute to increased heterocellularity that likely impairs proper cardiac conduction. ECM, extracellular matrix. B: neutrophil-mediated modulation of the inflammatory response by degranulation. Neutrophils are producers of a wide range of pro- and anti-inflammatory mediators [among them tumor necrosis factor (TNF) superfamily members, granulocyte colony-stimulating factor (GCSF), macrophage inhibitory peptide (MIP), MPO, as well as a ladder of pro- and anti-inflammatory interleukins (ILs)]. C: oxidative stress. Neutrophil activation leads to assembly of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) complex consisting of the catalytic core (gp91^phox and p22^phox), its subunits (p47^phox, p40^phox, p67^phox), as well as Rac2 in its GTP-bound form. Upon NADPH binding, it cleaves the hydrogen and transports it to the extracellular space where a superoxide anion radical (O₂^•−) is generated. The superoxide dismutase (SOD) then generates hydrogen peroxide (H₂O₂), which subsequently is a substrate for myeloperoxidase (MPO)-mediated hypochlorous acid (HOCl) synthesis. D: neutrophil extracellular trap (NET) formation. As part of the neutrophil-mediated host defense, neutrophils evert nuclear and mitochondrial DNA fragments armored with antimicrobial proteins such as MPO, neutrophil elastase (NE), or protein arginine deiminase 4 (PAD4) to “trap” and neutralize invading pathogens. This process can either go along with neutrophil death, termed NETosis, or occur as vital NET-formation. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.