Heart failure, inflammation and exercise

Abstract

Heart failure (HF) is a condition characterized by high morbidity, mortality, and a substantial healthcare burden, in which inflammation plays a pivotal role. This review provides a comprehensive overview of inflammation in HF progression, highlighting the dynamic alterations in immune cell populations-such as monocytes/macrophages and neutrophils-and regulatory mechanisms of key signaling pathways, including JAK and NLRP3. Furthermore, the clinical relevance of inflammatory biomarkers in predicting disease prognosis is also discussed. Emerging evidence indicates that exercise intervention can enhance cardiac function by promoting the expression of anti-inflammatory cytokines (e.g., IL-10) and mitigating myocardial fibrosis, oxidative stress, and apoptosis. Future studies should investigate how exercise modulates critical inflammatory pathways-such as TLR/MyD88/NF-κB and the NLRP3 inflammasome-and aim to establish personalized exercise protocols tailored to patients' inflammatory profiles and disease stages. Such insights may pave the way for innovative therapeutic strategies in HF management.

Keywords: exercise; heart failure; inflammation; signaling pathway.

Figure 1

Role of inflammation in heart failure. Figure 1 illustrates the central role of inflammation in the pathogenesis of heart failure. Myocardial injury due to various causes activates the innate immune system, leading to the expression of damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) by cardiomyocytes, endothelial cells, and resident immune cells in response to stimuli. Those patterns are recognized by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs). The activation of those receptors initiates a signaling cascade that promotes the gene expression of pro-inflammatory cytokines and chemokines, activating B cells and T cells, and promoting the recruitment of circulating neutrophils and monocytes/macrophages to the myocardium, thereby triggering adaptive immunity. The primary function of the inflammatory response is to resolve myocardial injury, allowing the heart to adapt to abnormal conditions in the short term and restore homeostasis and cardiovascular function in the long term. However, if the abnormal condition persists, a persistent inflammatory state in the tissue can have adverse effects on cardiomyocytes and the extracellular matrix, leading to progressive left ventricular remodeling and dysfunction, ultimately resulting in heart failure due to maladaptation. PAMPs, pathogen-associated molecular patterns; LPS, lipopolysaccharide; CpG, cytosine-phosphate-guanine; DAMPs, damage-associated molecular patterns; HSPs, heat-shock proteins; HMGB1, high mobility group box 1; MRPs, multidrug resistance proteins; LDL, low-density lipoprotein; NLRs, NOD-like receptors; TLRs, Toll-like receptors.

Figure 2

Role of monocytes/macrophages and neutrophils in heart failure. Figure 2 highlights the dynamic changes of monocytes/macrophages and neutrophils in the development of heart failure. As heart failure advances, circulating macrophages gradually replace resident cardiac macrophages. In addition, in the TAC model, treatments administered at 2-5 weeks, such as Dapagliflozin, TD139 and Arglabin, significantly preserved cardiac function and inhibited cardiac fibrosis at 5 and 8 weeks, whereas similar effects were observed at 0-2 weeks, indicating the effectiveness of specific targeting of macrophages in inhibiting pathological cardiac hypertrophy. Neutrophils, as key cells of the innate immune system, plays a significant role in the development of heart failure, being involved in the inflammatory response, cardiac remodeling, angiogenesis, and the repair process of cardiomyocytes, interacting with macrophages. CCL7, Chemokine (C-C motif) ligand 7; CCL2, Chemokine C-C motif ligand 2; IL-1β, Interleukin-1β; LGALS3, Galectin 3; LVEF, left ventricular ejection fraction; HCM, hypertrophic cardiomyopathy; CAD, coronary atherosclerotic heart disease; LVAD, left ventricular assist device; IL-10, Interleukin-10; MMP, matrix metalloproteinase; NET, neutrophil extracellular trap; FRP2, flavin reductase; NGAL, neutrophil gelatinase-associated lipocalin; CXCL1, C-X-C motif chemokine ligand 1; MERTK, mer tyrosine kinase.

Figure 3

Role of T cells and B cells in heart failure. Figure 3 depicts the role of T cells and B cells in heart failure. T cells, characterized by the expression of CD3, are divided into CD8⁺T cells and CD4⁺T cells. CD4⁺T cells further differentiate into various subtypes, including TH cells and Treg cells, which regulate the activity of B cells and other T cells, and suppress immune responses. In chronic heart failure, T cell populations expand and become activated in the heart. B cells play a role in myocarditis, heart transplant rejection, and chronic myocardial inflammation and heart failure. The figure shows the changes in B cells and T cells, their interactions, and the impact on cardiac remodeling and function. IFN-γ, immune interferon γ; TNF-α, tumor necrosis factor-α; IL-2, Interleukin-2; IL-1β, Interleukin-1β;IL-4, Interleukin-4; IL-5, Interleukin-5; IL-6, Interleukin-6; IL-13, Interleukin-13; IL-17A, Interleukin-17A; Il-17F, Interleukin-17F; IL-21, Interleukin-21; IL-22, Interleukin-22; IL-23, Interleukin-23; IL-10, Interleukin-10; TGF-β, transforming growth factor-β; MMP, matrix metalloproteinase; TIMP, tissue inhibitors of metalloproteinase; CCL7, Chemokine (C-C motif) ligand 7;TCR, T cell receptor; MHC I, the major histocompatibility complex I; MHC II, the major histocompatibility complex II.

Figure 4

Heart failure, inflammation and exercise. Figure 4 explores the relationship between heart failure, inflammation, and exercise. It demonstrates how exercise intervention may improve cardiac function in heart failure by modulating the inflammatory response. Exercise intervention may alleviate the inflammatory response by reducing the activity of pro-inflammatory cytokines, and improve cardiac function by reducing myocardial fibrosis, oxidative stress, and apoptosis. Gal-3, Galectin 3; TNF-α, tumor necrosis factor-α; MLR, monocyte-to-lymphocyte ratio; SUA, serum uric acid; NLRP3, pyrin domain-containing protein 3; LVED, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; IL-1β, Interleukin-1β; IL-17, Interleukin-17; sST2, soluble suppression of tumorigenesis-2; GDF-15, growth differentiation factor 15; CRP, C-reactive protein; IL-6, Interleukin-6; NYHA, New York Heart Association; 6MWD, the 6-minute-walk distance; VO₂peak, peak oxygen uptake; NPAR, neutrophil-to-albumin ratio; NLR, neutrophil-to-lymphocyte ratio; sTIPS, simplified thrombo-inflammatory score; IL-8, Interleukin-8; SIRI, systemic inflammation response index; SII, systemic immune inflammatory index.

Figure 5

Potential mechanisms of exercise in the intervention of inflammation in heart failure. Figure 5 illustrates the potential mechanisms by which exercise intervention may regulate the inflammatory response in heart failure. Exercise may reduce the symptoms and progression of heart failure by modulating inflammatory mediators in the heart and circulation. The figure outlines the complex anti-inflammatory mechanisms of exercise, involving multiple molecules, transcription factors, and non-coding RNAs, and the regulation of signaling pathways such as JAK, NLRP3 and PI3K. TGF-β, transforming growth factor-β; IL-6, Interleukin-6; JAK, Janus kinase; STAT, signal transducer and activator of transcription; NRF2, NF-E2-related factor 2; HO-1, heme oxygenase-1; NQO-1, an quinone oxidoreductase 1; GCLC, glutamate-cysteine ligase catalytic subunit; MALAT1, metastasis-associated lung adenocarcinoma transcript-1; PIK3, phosphatidylinositol 3-kinase; AKT, threonine-serine protein kinase; MMP2, matrix metalloproteinase 2; IL-1RN, Interleukin-1RN; VCAM1, vascular cell adhesion molecule 1; S100A9, S100 Calcium Binding Protein A9; ROS, reactive oxygen species; NLRP3, pyrin domain-containing protein 3.