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Inflammation in Human Heart Failure: Major Mediators and Therapeutic Targets

Marta Reina-Couto, Patrícia Pereira-Terra, Janete Quelhas-Santos and 3 more

Frontiers in Physiology · 2021 · Review · CC BY

doi:10.3389/fphys.2021.746494

Abstract

Inflammation has been recognized as a major pathophysiological contributor to the entire spectrum of human heart failure (HF), including HF with reduced ejection fraction, HF with preserved ejection fraction, acute HF and cardiogenic shock. Nevertheless, the results of several trials attempting anti-inflammatory strategies in HF patients have not been consistent or motivating and the clinical implementation of anti-inflammatory treatments for HF still requires larger and longer trials, as well as novel and/or more specific drugs. The present work reviews the different inflammatory mechanisms contributing to each type of HF, the major inflammatory mediators involved, namely tumor necrosis factor alpha, the interleukins 1, 6, 8, 10, 18, and 33, C-reactive protein and the enzymes myeloperoxidase and inducible nitric oxide synthase, and their effects on heart function. Furthermore, several trials targeting these mediators or involving other anti-inflammatory treatments in human HF are also described and analyzed. Future therapeutic advances will likely involve tailored anti-inflammatory treatments according to the patient’s inflammatory profile, as well as the development of resolution pharmacology aimed at stimulating resolution of inflammation pathways in HF.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 25, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Heart failure (HF) is a complex clinical syndrome caused by structural and/or functional cardiac abnormalities which result in the impairment of ventricular filling and/or ejection. Although hemodynamic and neurohormonal counterregulatory responses are activated in order to maintain adequate tissue perfusion, their perpetuation contributes to structural and functional damage at medium and long term. Chronic HF (CHF) is currently divided in three categories based on left ventricular ejection fraction (LVEF), namely reduced (HFrEF), preserved (HFpEF) or mid-range (HFmrEF). This last category (HFmrEF), recently individualized in European guidelines, represents an intermediate range of LVEF that has been less rigorously studied, with clinical characteristics that resemble those of the HFpEF group but with a higher prevalence of coronary artery disease, and so a similar response to the treatment of HFrEF patients.

Despite therapeutic advances, CHF inexorably progresses with acute episodes, requiring recurrently urgent hospitalization and medical support. Although acute heart failure (AHF) frequently refers to this acute decompensation of CHF, it may also correspond to the new-onset form (“de novo HF”) caused by direct ischemic, infectious/inflammatory or toxic insults to the myocardium, or indirectly by mechanical development of acute valve insufficiency or cardiac tamponade. Cardiogenic shock (CS), the severest form of these AHF syndromes, evolve as a continuum from those underlying precipitants until the subsequent state of low cardiac output, organ failure and death. Therefore, there is an urgent need to explore new pathophysiological pathways and therapeutic strategies for HF.

Inflammation is accepted as an important pathophysiological factor in both AHF and CHF, predicting poor prognosis independently of LVEF, although it appears to contribute in different ways to each type of HF.

In HFpEF, where a more evident association with inflammatory markers is reported, underlying comorbidities, such as obesity, arterial hypertension, diabetes, chronic obstructive pulmonary disease, chronic kidney disease and also aging, trigger a systemic inflammatory state which cause microvascular endothelial cell inflammation associated with increased reactive oxygen species (ROS) production and decreased nitric oxide (NO) bioavailability. Chronic inflammation also favors the infiltration of monocytes into the myocardium and further differentiation into proinflammatory macrophages (M1). These events promote adverse left ventricle remodeling and relaxation impairment.

In HFrEF, myocardial injury is the main trigger for the inflammatory responses mediated by the innate and adaptive immune systems. These are characterized by an initial increase in proinflammatory cytokines and chemokines, along with the infiltration of neutrophils and monocytes into the injured myocardium. Subsequently, in the resolution and repair phase (also termed “proliferative”), there is the phagocytosis of apoptotic and necrotic cells, the influx of adaptive immune cells (T-and B-cells), the activation of collagen-synthesizing myofibroblasts and the production of anti-inflammatory and proresolving molecules (e.g., transforming growth factor beta, lipoxins, IL-10). The maturation phase is marked by the apoptosis of reparative cells and scar maturation. The maintenance of a chronic inflammatory status may result from sustained myocardial injury and continuous activation of proinflammatory cascades. Importantly, activation of classic neurohormonal systems, such as the sympathetic nervous system and the renin-angiotensin-aldosterone system and hemodynamic overload can also trigger sustained myocardial inflammatory responses – termed as para-inflammation – even in the absence of tissue injury. The persistence of inflammation may also be caused by a failure in the resolution of inflammation mechanisms. Of note, we and others have observed that CHF is associated with impaired resolution of inflammation, namely decreased plasma and urinary lipoxins in CHF patients with severe New York Heart Association (NYHA) functional classes compared to CHF patients with mild-to-moderate NYHA classes, and significantly lower plasma concentration of resolvin D1 in patients with CHF compared to healthy age-matched controls. However, so far, targeting of resolution of inflammation pathways has only been attempted in experimental HF models.

In AHF, the inflammatory response may arise from antigenic stimulation during infection (e.g., viral myocarditis) or as a result of hemodynamic stress. Systemic congestion and/or peripheral hypoperfusion cause neurohormonal activation, inflammation and oxidative stress which damage endothelial glycocalix and consequently impair endothelial function and fluid homeostasis. Inflammatory activation also promotes a prothrombotic and proapoptotic environment. Noteworthy, neurohormonal and inflammatory activation seem to persist beyond the acute event and may contribute to the high rehospitalization rates of this syndrome. In CS, low cardiac output leads to systemic hypoperfusion caused by or followed by a systemic inflammatory response syndrome and end-organ injury that, if not promptly treated or supported, leads to death. Very early after CS onset, an inflammatory environment seen in 40% of the CS patients can contribute to the CS hallmark vasodilation, with concentrations of various interleukins being associated with mortality. This marked inflammatory activation may be due to direct myocardial necrosis and tissue ischemia, inducing the release of damage-associated molecular patterns (DAMPs), mostly recognized by Toll-like receptor 4, highly expressed in the heart, that contributes to myocardial inflammation that occurs in HF. Also indirect but early secondary hypoperfusion leading to intestinal ischemia may promote the translocation of bacteria and pathogen-associated molecular patterns (PAMPs) and, alongside with the release of inflammatory mediators by the spleen or adipose tissue and the para-inflammation generated by the comorbidities and endothelial dysfunction, contribute to cardiac deterioration. The intensity of this inflammatory response in CS patients is associated with CS severity.

Tumor Necrosis Factor Alpha

Tumor necrosis factor alpha (TNF-α) is the most studied proinflammatory cytokine in HF. In the heart, it can be produced by different types of cells such as activated macrophages, cardiomyocytes, vascular cells and mast cells. TNF-α exists in membrane-bound or cytosolic forms and exerts its actions by binding to cell membrane TNFR1 or TNFR2 receptors. TNF-α has been shown to mediate several adverse effects on heart function and structure, namely negative inotropic actions due to the disruption of calcium homeostasis, upregulation of other inflammatory molecules, including induction of inducible NO synthase, enhancement of oxidative stress and consequent mitochondrial DNA damage, promotion of apoptosis and extracellular matrix degradation and increase of microvascular endothelial permeability and activation, enhancing endothelial-leukocyte interactions. Increased TNF-α concentrations have been detected in patients with HFrEF, HFpEF, patients with AHF and CS. Despite large evidence of the protective effects of TNF-α inhibition or deletion in experimental models of HF, studies in HF patients have been disappointing. It has been suggested that TNF-α may exert not only deleterious, but also protective effects, which may be compromised under high intensity TNF-α blockade. Of note, in experimental cardiac ischemia-reperfusion injury, low doses of TNF-α were shown to be cardioprotective, while higher doses had deleterious cardiac effects. Dose-dependent effects of TNF-α may difficult patient treatment since an optimal amount of this cytokine may be required to counteract excessive remodeling and preserve cardiac function.

Interleukin 1

Interleukin 1 (IL-1) seems to be a major mediator of inflammation in heart diseases. Among the 11 ligands of the IL-1 family, the best known members acting on the cardiovascular system are IL-1α, IL-1β, IL-18, and IL-33. Binding of IL-1α or IL-1β to the IL-1 type 1 receptor (IL-1R1) initiates inflammatory responses, while the IL-1 receptor type 2 (IL-1R2) functions as a decoy receptor and does not initiate signal transduction. The IL-1 receptor type 3 (IL-1R3) acts as a co-receptor for IL-1R1, being responsible for signaling after the binding of IL-1α or IL-1β to IL-1R1. The generation of the active form of IL-1β from its precursor protein is primarily dependent on the enzymatic activity of caspase-1, which in turn is activated by the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, a macromolecular structure containing the intracellular sensing protein NLRP3 that responds to danger-associated signals. The activation of the NRLP3 inflammasome in cardiac fibroblasts and cardiomyocytes is induced by myocardial injury and may contribute to the post-infarction inflammatory process that aggravates cardiac injury.

In HF, IL-1 can be produced by immune cells, cardiomyocytes, vascular cells and fibroblasts. IL-1 contributes to cardiac dysfunction and remodeling by reducing beta-adrenergic responsiveness of L-type calcium channels and the expression of genes involved in the regulation of calcium homeostasis, by stimulating apoptosis in cardiomyocytes, by inducing the activation of leukocytes and endothelial cells, thus promoting their interaction and increasing the recruitment of inflammatory cells to the myocardium, by favoring fibrosis and by promoting arterial stiffness and microvascular inflammation. IL-1β also decreases energy production and myocardial contractility by directly damaging mitochondria.

Interleukin 6

The proinflammatory cytokine interleukin 6 (IL-6) is an important player in the acute phase response of inflammation, being a stimulus for C-reactive protein production by the liver, but also appears to contribute to the transition from acute to chronic inflammation by favoring the change from neutrophil to monocyte recruitment. IL-6 is produced by several cell types like macrophages, T-lymphocytes, endothelial cells, cardiomyocytes and fibroblasts. Although both proinflammatory and anti-inflammatory effects have been described for this cytokine, its effects in HF appear to be mostly proinflammatory.

IL-6 signaling classically involves cytokine binding to the cell surface IL-6 receptor and further association of the cytokine-receptor complex with gp130, dimerization and signaling initiation. However, IL-6 receptor can be cleaved by proteases, originating a soluble form that can bind IL-6 and initiate signaling in cells that do not express this receptor, thus increasing the complexity of IL-6 cellular effects. Regarding the heart, IL-6 has been shown to exert negative inotropic effects and to promote hypertrophy and fibrosis, contributing to increased myocardial stiffness. The impairment of myocardial contractility appears to be related with the upregulation of myocardial NO synthase and downregulation of the sarcoplasmic reticulum Ca2+ ATPase (SERCA2). IL-6 has also a negative impact on renal function since it activates the epithelial sodium channel (ENaC) in the distal tubule, impairing natriuresis. Of note, high values of IL-6 are associated with diuretic resistance in HF patients.

Higher IL-6 concentrations have been associated with worse clinical status in CHF patients, being an independent predictor of mortality. In AHF, IL-6 values at 48–72 h were found to be independently associated with 30-day mortality, but not with 180-day mortality. CS patients also exhibit an early rise of IL-6 which correlates with the severity of circulatory failure.

Interleukin-8

Interleukin-8 (IL-8), also termed CXCL8, is a chemokine produced by monocytes, macrophages, neutrophils, epithelial cells, fibroblasts, smooth muscle cells, and endothelial cells, being induced by diverse stimuli such as shear stress, ischemia and hypoxia. It is highly expressed in atherosclerotic lesion macrophages. IL-8 induces the firm adhesion of monocytes in the initial stages of atherogenesis. In the heart after infarction, it appears to mediate neutrophil activation and chemotaxis, as well as angiogenesis. IL-8 is increased in CHF, being related with worse outcomes. It also appears to predict HF development after myocardial infarction. Increased IL-8 values have also been observed in AHF and CS patients. An important feature of IL-8 is its relative longevity in acute inflammatory conditions, remaining active for a prolonged period, in contrast to other inflammatory cytokines. It is not clear whether IL-8 contributes to cardiac injury or is cardioprotective in the post-infarcted heart through its angiogenic effects.

Interleukin 10

The anti-inflammatory cytokine interleukin 10 (IL-10) is produced by several cell types, such as monocytes, macrophages, activated T and B cells, eosinophils, mast cells, dendritic cells, epithelial cells and also tumor cells. It exerts its actions by binding to a specific receptor complex, that consists of two IL-10 receptor-1 (IL-10R1) proteins and two IL-10 receptor-2 (IL-10R2) proteins. Major effects of IL-10 include the inhibition of proinflammatory cytokines secretion, reduction of NO generation and inhibition of ROS production and TNF-α-mediated oxidative stress. It also appears to counteract TNF-α-induced cardiomyocyte apoptosis. In CHF patients, IL-10 values were shown to be either increased when compared to healthy controls and positively correlated with NYHA class, or unchanged. Of note, although β-adrenergic receptor stimulation has been shown to increase IL-10 production, this anti-inflammatory response appears to be reduced in moderate and severe CHF patients.

Among patients with AHF, IL-10 values did not differ when compared to healthy controls or when patients were stratified according to the presence of renal dysfunction and/or congestion. However, IL-10 values have been shown to be significantly increased and to predict outcomes in CS patients.

Interleukin 18

The proinflammatory cytokine interleukin 18 (IL-18) is a member of the IL-1 superfamily, being activated similarly to IL-1β by caspase-1 after inflammasome formation. IL-18 exists mostly as a soluble cytokine, although a membrane-bound form can also be found in a subset of macrophages, which can release soluble IL-18 upon stimulation with lipopolysaccharide. The receptor for IL-18 (IL-18R) is a dimer formed by the IL-18Rα chain, which is the low-affinity binding site for mature IL-18, and the IL-18R β chain, which binds the IL-18/IL-18Rα complex, thus forming a high-affinity complex that initiates signaling. These receptor subunits are members of the IL-1R family. Of note, the activation of the IL-18R requires higher amounts of IL-18 (10–20 ng/mL or higher) than the activation of IL-1R by IL-1α or IL1β (frequently activated in the pg/mL range). The activity of IL-18 is negatively regulated by IL-18 binding protein (IL-18BP), which is constitutively secreted and binds IL-18 with extremely high affinity. Since IL-18BP neutralizes the circulating IL-18, the concentration of the free form of IL-18 is lower than the total circulating IL-18 amount. Moreover, the values of free IL-18 appear to have a better correlation with disease activity than total IL-18 concentration.

In the heart, IL-18 induces an inflammatory response by increasing IFN-γ production by infiltrated neutrophils, resident macrophages and endothelial cells and by stimulating IL-1β and TNF-α generation by endothelial cells. IL-18 also increases the expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) in endothelial cells and cardiomyocytes, thus increasing leukocyte recruitment into the injured myocardium and amplifying cardiac inflammation. IL-18 has also been shown to induce cardiac hypertrophy and fibrosis, apoptosis, contractile dysfunction and decreased β-adrenergic receptor responsiveness. Some of these effects appear to be mediated, at least in part, by the induction of other cytokines and chemokines, such as IL-1β, TNF-α, and IFN-γ.

The precursor form of IL-18 is constitutively expressed in several cell types such as monocytes, macrophages, epithelial cells, endothelial cells and cardiomyocytes. Following acute MI, the activation of the inflammasome in leukocytes, fibroblasts and cardiomyocytes in the ischemic myocardial tissue increases the local production of IL-18. In the human failing ischemic myocardium, IL-18 was detected in endothelial cells, macrophages and cardiomyocytes. Both the active and the precursor form of IL-18 protein were also shown to be highly expressed in human atherosclerotic plaque macrophages. Furthermore, IL-18 mRNA expression was higher in unstable than in asymptomatic plaques.

Patients with acute MI also have raised systemic IL-18 concentrations which correlate with increased values of atrial natriuretic peptide (ANP), suggesting a role for IL-18 in ANP induction. Of note, higher IL-18 concentrations are associated with the development of congestive HF and acute MI in patients with acute coronary syndromes and with increased mortality in elderly patients with HF.

Interleukin 33

Interleukin 33 (IL-33) is a member of IL-1 cytokine family and was found to be the ligand for the ST2 receptor which belongs to the IL-1 receptor superfamily. The ST2 receptor exists as a functionally active transmembrane form (ST2L) and as a soluble “decoy” receptor form (sST2). sST2 is a mechanically induced cardiomyocyte protein that counteracts the anti-hypertrophic action of IL-33 and other IL-33/ST2L-mediated effects. There is considerable evidence that sST2 concentration may be used as an indicator of cardiac stress and remodeling in several cardiovascular diseases such as HF, cardiomyopathies, arterial hypertension and aortic stenosis. There have been more studies evaluating sST2 than IL-33 because of its higher concentrations and stability.

IL-33 is constitutively expressed in endothelial cells of both small and large vessels, but not of brain or glomeruli microvessels. Epithelial cells, smooth muscle cells, fibroblasts and keratinocytes also constitutively express IL-33. Adipose tissue and endothelial cells of human atherosclerotic plaque also express IL-33. In the heart, it is predominantly expressed in vascular endothelial cells, but it is also present in fibroblasts and cardiomyocytes, having a fivefold higher expression in fibroblasts than in cardiomyocytes. Of note, endothelial cells appear to be important to translate myocardial pressure overload into a systemic inflammatory response via IL-33 secretion. Mechanical strain is the main stimulus for the induction of IL-33 expression in the heart, although proinflammatory cytokines such as TNF-α, IL-1β, and IFN-γ also increase its production. IL-33 is also released during cell necrosis. Angiotensin II (Ang II) also induces IL-33, with both mediators exerting compensatory effects in response to increased cardiac stretch.

In contrast to other members of the IL-1 family such as IL-1α, IL-1β and IL-18, IL-33 has predominantly an anti-inflammatory action since it is associated with T-helper type 2 (Th2) immune responses. IL-33 exerts cardioprotective effects by reducing cardiomyocyte hypertrophy, cardiomyocyte loss by apoptosis, infarct size, cardiac remodeling and fibrosis. IL-33 also inhibits the formation of atherosclerotic plaque and reduces angiotensin II-induced ROS and lipid peroxidation products in human cardiomyocytes, an effect that may be attenuated by increased sST2 concentrations. However, IL-33 has also been shown to induce proinflammatory cytokines and adhesion molecules in endothelial cells, promoting vascular permeability and angiogenesis and contributing to the early endothelial dysfunction events involved in the development of atherosclerotic lesions.

Some studies have shown that IL-33 concentrations are increased, positively correlated with TNF-α and N-terminal-pro-B-type-natriuretic peptide (NT-proBNP) and negatively correlated with LVEF in CHF patients. These effects might be due to a reduction of IL-33 bioactivity caused by the increase of sST2 in these patients. Of note, sST2 concentrations are higher in HFrEF than in HFpEF, being a predictor of adverse outcomes in both HF populations. In patients with acute worsening of HF, higher sST2 values were also shown to be useful to identify those patients at high-risk of in-hospital death. sST2 concentrations rapidly decreased after hospital admission in AHF patients with uncomplicated short-term follow-up, while AHF patients that died within 6 months showed a significant increase of sST2 values after admission. Furthermore, higher sST2 concentrations appear to be associated with lower diuretic efficiency in patients with AHF and concomitant renal dysfunction.

In contrast to the studies describing an increase of IL-33 in human HF, a recent study showed reduced IL-33 concentrations in HFrEF patients when compared to healthy controls, with patients with HF of ischemic etiology presenting lower values than those with non-ischemic etiology. More studies are needed to clarify whether IL-33 is cardioprotective or contributes to chronic inflammation, aggravating the disease.

Myeloperoxidase

Myeloperoxidase (MPO) is a haem-containing enzyme mainly secreted by neutrophils and monocytes, under inflammatory conditions, but has also been detected in other cell types such as macrophages (e.g., infiltrating macrophages in atherosclerotic lesions, peritoneal macrophages), CD4+ and CD8+ lymphocytes, endothelial cells and platelets. MPO activity in macrophages probably results from neutrophils endocytosis or MPO internalization, while in endothelial cells, MPO may be endogenously expressed or originate from external sources. MPO uses H2O2 derived from leukocyte or vascular NADPH oxidases to produce several oxidizing molecules such as hypochlorous acid (HClO), chloramines, tyrosyl radicals and nitrogen dioxides. These MPO-derived ROS and reactive nitrogen species (RNS) exert not only bactericidal effects, but also tissue damaging actions in the cardiovascular and renal systems and in the brain. MPO significantly affects vascular tone, endothelial NO availability, being involved in atherogenesis and cardiovascular disease. MPO also contributes to myocardial dysfunction. Experimental studies using MPO knockout mice or an oral MPO inhibitor showed significant less left ventricle dilation and improved left ventricular function in models of myocardial infarction, evidencing a pathophysiological role of MPO in the development of CHF. In humans, CHF patients exhibit higher systemic MPO values, which appear to be associated with worse outcomes. Patients with AHF and CS also show markedly increased circulating MPO values. In acutely decompensated CHF, MPO concentration was also associated with an increased risk for 1-year mortality.

Inducible Nitric Oxide Synthase

NO is a free radical involved in several physiological processes relevant for cardiovascular regulation, including vasodilation, regulation of cardiac contractility, modulation of sympathetic outflow, smooth muscle cell proliferation, regulation of renal renin release, natriuresis and immune response. It is generated by the oxidation of L-arginine to L-citrulline by NO synthases (NOS), a family of enzymes composed of 2 constitutive isoforms, namely neuronal NOS (nNOS or NOS1) and endothelial NOS (eNOS or NOS3), and one inducible isoform (inducible NO synthase, iNOS or NOS2). iNOS is not normally produced in most cells, being only expressed after induction or stimulation, generally by proinflammatory cytokines (e.g., TNF-α; IL-1β; interferon gamma, IFN-γ) and lipopolysaccharide. After induction, iNOS generates high amounts of NO (100- to 1000-fold more NO than that produced by eNOS). This production persists for many hours until the enzyme is degraded. Although these significant amounts of NO are important for the immune response, they can also contribute to toxic effects and to several human diseases, including HF.

iNOS was originally discovered in macrophages but has been shown to be expressed in several cell types, including smooth muscle cells, endothelial cells, cardiomyocytes, hepatocytes, neurons, glial cell and astrocytes. Regarding cardiac function, high concentrations of NO have been shown to exert negative inotropic and chronotropic effects and to reduce the response to β-adrenergic stimulation. Importantly, under inflammatory conditions, the reaction of NO with ROS is favored, originating RNS such as peroxynitrite. Both excess NO and peroxynitrite can cause deleterious effects in the heart, namely cell apoptosis, contractile dysfunction, irreversible reduction of myocardial oxygen consumption and dysregulation of heart rate and rhythm. The overexpression of iNOS also appears to contribute to myocardial fibrosis and ventricular hypertrophy. iNOS has been detected in the hearts of CHF patients (NYHA classes III-IV), regardless of the etiology. Furthermore, it was shown to be uniformly distributed in the left and right ventricles and was primarily located in endothelial and vascular smooth muscle cells of the myocardial vasculature of these patients, being also found, although to a lesser extent, in the cardiomyocyte membrane. Infiltrating macrophages also account for iNOS expression in the post-ischemic failing heart. Additionally, the activation of iNOS in peripheral vessels of CHF patients (NYHA classes II and III) was shown to be positively associated with systemic BNP concentration and appears to be an independent predictor for worsening HF. Patients with decompensated CHF were also shown to have increased iNOS expression in peripheral mononuclear cells which was also positively correlated with plasma BNP values. As previously mentioned, CS induces a systemic inflammatory response, iNOS activation and excessive production of NO which reduces myocardial contractility, suppresses mitochondrial respiration, attenuates the β-adrenergic inotropic response and induces inadequate systemic vasodilation, leading to systemic hypoperfusion. The overproduction of peroxynitrite also aggravates myocardial contractile dysfunction.

C-Reactive Protein

C-reactive protein (CRP) is the best studied acute-phase protein. Its synthesis occurs mainly in the liver, being induced by raised IL-6 concentrations under conditions of infection, trauma and other inflammatory states. In humans, CRP values markedly increase in the first 72 h after tissue damage, being a sensitive yet non-specific biomarker of inflammation. CRP is primarily present as a pentamer of five similar polypeptide subunits but can also dissociate into monomers. It is still under debate whether these pentameric and monomeric forms exert different functions. While circulating CRP is pentameric, local deposition of monomeric CRP has been detected in infarcted myocardial tissue, in brain tissue of stroke patients and in the kidney of diabetic patients with severe chronic kidney disease.

CRP is a strong chemotaxin/opsonin for macrophages. It binds to phosphorylcholine groups in pathogens and also in non-healthy human cells (e.g., apoptotic, necrotic, energy-depleted, ischemic/hypoxic cells), marking these cells and consequently inducing their phagocytosis through complement activation. The phagocytosis of ischemic/hypoxic cells in the setting of acute myocardial infarction activates IL-6 production, which further induces more CRP, amplifying the immune response. Thus, CRP exacerbates tissue injury and scarring after a cardiovascular event. CRP is also present in the myocardium of patients with non-ischemic HF, where it may contribute to myocardial damage through complement system activation and chemotaxis of macrophages.

CRP can also be produced outside the liver, namely in vascular smooth muscle cells from human coronary arteries, respiratory epithelium, renal cortical tubular cells, neuronal cells, adipocytes and leukocytes. Noteworthy, CRP appears to be preferentially expressed in diseased vessels, with its mRNA expression being 7–10-fold higher within atherosclerotic plaque compared to the values found in the liver and normal blood vessels. CRP seems to promote vascular injury by upregulating endothelial adhesion molecules, monocyte chemoattractant protein-1 (MCP-1), endothelin-1 and endothelial plasminogen activator inhibitor 1 (PAI-1), by contributing to the impairment of endothelial NO bioactivity, by increasing low density lipoprotein (LDL) cholesterol uptake by macrophages and triggering LDL cholesterol oxidation and by inducing complement activation.

CRP is an established independent cardiovascular risk factor, with higher CRP values being associated with major cardiovascular events and mortality and showing prognostic significance for risk stratification. Since traditional assays of CRP do not effectively detect basal CRP values, assays for the quantification of high-sensitivity CRP (hsCRP) were developed in order to improve risk stratification, with values below 1 mg/L, from 1 to 3 mg/L and higher than 3 mg/L corresponding to low-, moderate- and high-risk groups.

Increased CRP values appear to be a predictor for HF development in high-risk populations. CRP values higher than 3.23 mg/L are associated with higher HF severity evidenced by lower LVEF, higher NYHA functional classes, higher heart rate and increased prevalence of atrial fibrillation. In AHF, CRP values are increased by fivefold at admission when compared to the concentrations found in CHF patients. Elevated CRP is also related with worse prognosis in ADHF patients and CRP values above 12 mg/L are associated with increased risk of death and HF readmissions within 3 months.

The major effects of these inflammatory mediators with relevance for HF pathophysiology are summarized in Figures 1, 2.

Anti-Inflammatory Strategies in Human Heart Failure

Several direct or indirect anti-inflammatory therapies have been tested in HF patients. Direct therapies include anti-cytokines therapies, prednisone or colchicine, while indirect strategies repurposed drugs that were previously evidenced to exert pleiotropic anti-inflammatory/immunomodulatory effects.

Anti-cytokine Therapies

Direct anti-inflammatory therapies have yielded conflicting results. Both anti-TNF-α drugs, namely etanercept and infliximab are now well accepted to be contraindicated in HF, at least in these high-intensity schemes. The contradictory results between preclinical, observational, preliminary data and the bigger randomized trial might be due to the abolishment of cardioprotective effect of NF-κB, a downstream effector of TNF-α, as well as to the demonstrated infliximab apoptotic and lytic properties. On the other hand, anti-IL-1 strategy seems more promising. First, anakinra, an IL-1 receptor antagonist, was shown to improve exercise capacity in both small trials in HFrEF and HFpEF but in longer courses in AHF it decreased the composite of death or hospitalization for HF; second, canakinumab, a recombinant human monoclonal antibody that targets IL-1β, when added to optimal statin therapy, reduced the risk of the composite end point of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death compared with placebo. It showed greater benefit in a dose and hsCRP-dependent fashion, a surrogate biomarker of IL-1 activity, confirming the concept of personalized treatment in HF. Nevertheless, although the neutralization of IL-1β or the blockade of IL-1R1 were shown to be protective in human CHF and AHF, circulating IL-1β values are frequently below detection limits, being very difficult to establish a correlation between IL-1β concentration and disease severity.

For anti-IL-6 therapy, we still have to wait for major HF trials, with preliminary data in rheumatoid arthritis and in NSTEMI patients showing encouraging results, as well as for the anti-IL-12/-23 therapy where treatment with ustekinumab in patients with psoriasis was associated with improved echocardiographic measures, lower IL-6 and NT-proBNP.

Anti-IL-8 treatment has not been evaluated yet in HF patients, although an antibody targeting IL-8 (BMS-986253) is being tested in clinical trials involving patients with malignant tumors or patients with COVID-19. Of note, since IL-8 expression is redox regulated, antioxidants may be useful to therapeutically modulate IL-8 concentrations.

Regarding IL-10 therapy, although its administration was shown to exert cardioprotective effects in animal models, it has not been tested yet in HF patients.

Therapies targeting IL-18 have been tested in other clinical conditions, but not in HF patients. In patients with type 2 diabetes mellitus or in patients undergoing renal transplantation, trials with a IL-18 neutralizing antibody (GSK1070806) did not show evidence of clinical benefits. More recently, a clinical trial with a recombinant human IL-18 BP (tadekinig alfa), as well as a short report of a prolonged treatment with this therapy, showed signs of efficacy in patients with a rare systemic autoinflammatory disease. With respect to IL-33, it remains to clarify whether it is mainly cardioprotective or contribute to endothelial inflammation, aggravating cardiovascular diseases. Trials with anti-IL-33 antibodies (etokimab and SAR440340) have been conducted in asthma and atopic dermatitis patients, showing disease improvement with these treatments. Astegolimab, an anti-ST2 antibody that selectively inhibits the IL-33 receptor, was also tested in asthmatics, being able to reduce asthma exacerbation rate. So far, therapies targeting the IL-33/ST2L/sST2 axis have not been tested in human cardiovascular diseases.

Nitric Oxide Synthases Inhibitors

The role of nitrates and NOS is not unanimous in HF. While in HFrEF, direct donors of NO have its place, at least in patients with optimized treatment or in those not tolerating first line options or in ischemic or black patients, in AHF, the GALACTIC study failed to demonstrate the improvement in all-cause mortality and re-hospitalization with the early intensive and sustained treatment with nitrates.

On the contrary, adjunctive use of NOS inhibition in the setting of CS, based on the theory of overproduction of NO by activated iNOS secondary to systemic inflammatory response, was enthusiastic once again in small single-center trials with L-NMMA (NG-monomethyl L-arginine), a competitive non-specific NOS inhibitor. However, this was not confirmed in the randomized multi-centre trial SHOCK-2 nor in TRIUMPH trial, which tested another pan-NOS inhibitor. This lack of clinical benefit might have been caused by the inhibition of constitutive NOS isoforms, which contribute to protective effects on vascular tone and microcirculation, promote ventricular relaxation and prevent platelet adhesion and aggregation. Furthermore, the peroxynitrite-mediated effects are not readily reversible by the acute treatment with NOS inhibitors. Nevertheless, newer strategies focusing on the specific inhibition of iNOS or on drugs targeting nitrosative stress should also be tested.

Other Anti-inflammatory Therapies

The results of indirect anti-inflammatory therapies have as well to be considered. Statins possess pleiotropic properties, namely antioxidant, angiogenic, immunomodulatory, and also anti-inflammatory effects evidenced by the reduction of CRP concentrations independently of lipid reduction. Again, the observational and post hoc analyses data derived from TNT and PROVE-IT studies and the randomized trials UNIVERSE, CORONA and GISSI-HF showed neutral effects. Nevertheless, the individualized use of these drugs in patients with atherosclerosis and high LDL-cholesterol could magnify beneficial effects against detrimental inhibition of CoQ10 synthesis that intensifies hypertrophy, especially with high doses of statins in patients with long-term HF.

In CHF patients, CRP concentration has also been shown to be reduced by other drugs such as β-blockers (carvedilol) and angiotensin II receptor antagonists (valsartan), but not by the combination of valsartan with angiotensin converting enzyme inhibitors. In addition, in AHF patients, significantly decreased hsCRP concentrations were observed at 30 days after short-term inotropic support. However, the putative effect of hsCRP reduction on mortality could not be demonstrated due to the small sample size. In acute settings, CRP values need to be rapidly lowered and this cannot be achieved by using CRP-lowering drugs that take several days to influence CRP concentrations. This problem can be solved by CRP apheresis, which removes CRP from the blood plasma after myocardial infarction, significantly reducing the infarct area and improving LVEF.

Noteworthy, the GISSI-HF study opened new possibilities as the first large scale clinical trial testing omega-3 fatty acids, that when adding 1 g daily to the best medical treatment offered a modest but significant reduction on all-cause mortality and CV hospitalization and proved to be a safe option. In a subsequent trial, the reduction seen in inflammatory markers, like IL-6 and TNF-α, in the high dose of 4g/d regimen, accompanied by a dose-dependent increase of LVEF and improvement of endothelial function, could justify the outcome benefits. Recent trials, like MESA cohort, showed a significant independent inverse correlation between circulating levels of omega-3 fatty acids, specifically eicosapentaenoic acid (EPA), and the occurrence of HF over a long median follow-up period of 13 years, as well as the ability of plasma EPA concentrations to predict the occurrence of HF in all ethnicities. Also, in the REDUCE-IT trial, very high plasma values of omega-3 fatty acids were associated with a reduction of major CV events and in the OMEGA REMODEL trial, a 6-month treatment with 4 g daily of omega-3 fatty acids on top of the current guideline-based standard of care was associated with a reduction of adverse left ventricular remodeling, myocardial fibrosis and serum biomarkers of systemic inflammation, namely MPO and ST2. Interestingly, EPA is also the precursor of resolvin E1 (RvE1), one of the specialized proresolving mediators actively contributing to resolution of inflammation. Experimental studies have already shown that RvE1, through its receptor ChemR23, exerts a direct protective effect on cardiomyocytes against ischemia-reperfusion injury and limits infarct size when administered intravenously before reperfusion. Preliminary studies of our group, conducted in patients with AHF and CS, also demonstrated that RvE1 is increased in AHF and CS and correlated with CRP and MPO.

Despite several lines of evidence indicating an association between increased MPO concentrations and HF pathogenesis and severity, the clinical benefit of MPO inhibition in HF patients remains unknown. A clinical trial is currently evaluating the hemodynamic effects of an oral MPO inhibitor, AZD4831, following baseline, resting and exercise testing in HFpEF patients during right heart catheterization.

Serum uric acid (UA) is widely recognized as a biomarker of oxidative stress in several cardiovascular diseases, including HF. After cellular damage, increased amounts of available xanthine and hypoxanthine can be converted into UA by xanthine oxidase (XO), upregulated itself in cardiovascular disease. Since XO uses oxygen as an electron acceptor, ROS are also generated, contributing to oxidative stress. Although several studies and meta-analyses have identified elevations of serum UA as an independent marker of poor prognosis in HF patients and pre-clinical and case-control studies, as well as the later OPT-HF study, showed that XO inhibition was associated with improved survival in HF, the EXACT-HF trial failed to demonstrate a clinical benefit of high-dose allopurinol in HFrEF patients with increased UA concentrations. This lack of benefit might have resulted from the short duration of this study. The authors also suggested that serum UA might be just a marker of disease severity and prognosis and not a target for therapy, even though there was trend toward lower hospitalizations in the allopurinol group of this study. Other possible explanation is that other metabolic pathways, not targeted by the selective inhibition of XO, may be responsible for the nitroso-redox imbalance, as suggested by the unchanged concentrations of MPO in these patients.

Immunomodulators

Other strategies based not only on classic anti-inflammatory schemes, but in a new concept of modulation of inflammation, as shown by the small trials with intravenous immunoglobulin (IVIg), pentoxifylline and thalidomide or the recent repurposed colchicine, could have a role in HF management. IVIg preparations are known to have anti-infectious, anti-inflammatory, and immunomodulatory properties, but recent prospective, randomized, double-blind, placebo-controlled trial to evaluate the effect of IVIg on systolic cardiac function in adult patients with idiopathic chronic dilated cardiomyopathy (DCM) and parvovirus cardiac B19V persistence did not demonstrate improvement of cardiac systolic function or functional capacity beyond standard medical therapy. Importantly, nor even, could confirm the IVIg protective effects, years later after their study in 2001, in ischemic patients. This treatment is nowadays reserved as an alternative therapy to myocarditis and inflammatory cardiomyopathy in combination with immunoadsorption, which still needs validation in multi-center, double blind studies. The same author,, trying the same rationale of beneficial effects of immunomodulation in HF patients, also tested thalidomide. While immunoregulatory (anti-TNF drug, inhibition of neutrophils), as well as matrix stabilizing and antifibrotic properties could contribute to the beneficial effects of thalidomide in HF, a potential risk of harmful effects on the myocardium should also be considered. Our knowledge of its mechanisms of action in chronic HF is limited, awaiting further elucidation in forthcoming studies, as well as the test of newer thalidomide analogs such as lenalidomide, which are more potent and have a more favorable toxicity profile. Interestingly, a meta-analysis of trials with pentoxifylline, a medication with a larger therapeutic index and multiple uses, like limb ischemia or alcoholic hepatitis, seems to suggest a significant nearly fourfold decrease in all-cause mortality in human HF, even though small trials did not show reduction of mortality. Thus, this xanthinic base with vasodilatatory, anti-inflammatory, antiapoptotic, and rheological properties deserves further exploration in HF. Treatment with colchicine, a well-known alkaloid with potent anti-inflammatory properties, has demonstrated promising results for the secondary prevention of CVD, although it did not provide a benefit in death or HF hospitalization, despite a reduction in inflammatory markers. Thus, the Colchicine in STEMI Patients Study (COVERT-MI), an ongoing confirmative prospective, multicenter, randomized, double-blind trial, is testing whether a short course oral treatment with colchicine versus placebo decreases myocardial injury in patients presenting with STEMI, since add-on treatment of coronary artery disease patients already proved to reduce inflammatory biomarkers. The anti-inflammatory effects of methotrexate seem to depend on adenosine receptor stimulation by endogenously generated adenosine. Adenosine is a potent immunomodulatory agent and its receptors activation also induces vasodilation, inhibition of sympathetic neurotransmitter release and induction of ischemic preconditioning, independently of adenosine immunomodulatory effects. This could explain why preliminary studies demonstrated cardioprotective effects of raised adenosine concentrations in HF patients. However, once again, there is still no sufficient data yet to generalize the prevention of incidence of cardiovascular events, demonstrated for rheumatoid arthritis patients, in order to treat patients with coronary heart disease. Glucocorticoid administration is not recommended routinely in the international guidelines in patients with HF because of its related sodium and fluid retention caused by the stimulation of sodium reabsorption at the level of renal tubules. On the other hand, few studies have demonstrated that glucocorticoids can enhance natriuresis in HF patients, probably by causing vasodilation of the afferent and efferent arterioles and consequently increasing renal blood flow mediated by NO and prostaglandins restricted to kidney bed, as well as by up-regulating ANP synthesis and receptors. So, larger randomized clinical trials must assure safety and clinical results of COPE-ADHF with enough evidence to promote re-discussion of the main consensus.

Major trials targeting important inflammatory mediators of HF or involving other anti-inflammatory/immunomodulatory strategies in HF are summarized in Tables 1, 2. Most of them were conducted in HFrEF patients, except for the ongoing study with MPO and DHART trials which were specifically designed for HFpEF patients. Contrary to HFrEF, to date, no treatment has been shown to reduce morbidity and mortality in patients with HFpEF. Although candesartan and sacubitril/valsartan appear to reduce hospitalizations in patients with LVEF > 40 or 45%, respectively, no randomized clinical trial convincingly reached its primary endpoint. Treating hypervolemia and the mineralocorticoid antagonist spironolactone seemed to produce similar results, with no effect on mortality. On the other hand, nebivolol in SENIORS trial showed promising effects on reduction of cardiovascular mortality but the group of HFpEF considered had LVEF > 35%, including only 15% with a LVEF > 50%. Therefore, the effect of NO-GMPc pathway was also explored but also failed to improve exercise capacity and quality of life. Recently, novel evidence emerged strengthening the inflammatory paradigm and reinforcing research for anti-cytokine biological therapy in HFpEF. For example, higher IL-6 levels were demonstrated to be associated with an increased risk of developing HFpEF and circulating levels of TNF-α receptor 2 were shown to be increased in association with the degree of diastolic dysfunction in patients with HFpEF but not HFrEF. Also, (anti-inflammatory) high density lipoprotein cholesterol/(inflammatory) CRP ratio was shown to be a useful marker for prognostication and correlated with echocardiographic parameters in HFpEF patients. Moreover, a recent report suggested that the deletion of resolution sensor ALX/FPR2 is associated with the development of diastolic dysfunction related with obesity in mice with HFpEF, supporting the concept of non-resolving inflammation in HFpEF. Besides all this, until now, anti-inflammatory therapies in HFpEF were negative, including D-HART2 which failed to improve exercise capacity demonstrated in the pilot study despite lowering CRP and NT-pro-BNP in these patients.

Conclusion

Since the recognition by of elevated TNF-α in CHF patients, there has been a growing body of evidence on the association of a myriad of cytokines and chemokines with HFrEF but more recently this has also been demonstrated in the entire clinical spectrum of HF like HFpEF and even in AHF and CS. The progression of HF was believed to be due, along with neurohormonal activation, to a sustained inflammatory signaling – chronic para-inflammation – a theory that became collectively known as the “cytokine hypothesis”. Major inflammatory players in HF include TNF-α, IL-1, IL-6, IL-8, IL-10, MPO, iNOS, and CRP, to which experimental and clinical attempts have been directed to target or modulate them. However, the optimal approach seems far to be completed, underscoring the complexity of anti-inflammatory strategies. Although disappointing, negative results do not necessarily argue against the cytokine hypothesis. If, in one hand, isolated high intensity anti-TNF-α strategies seem to be rejected, anti-IL-1 and anti-IL-6 therapeutics remain to be explored and individualized. While a new therapeutic strategy such as MPO inhibition is currently being tested, immunomodulators like pentoxyfilline, thalidomide, n-3-PUFAs, glucocorticoids or colchicine, already evaluated in preliminary studies, also deserve further larger research. Trials based on serum CRP and UA have underpinned them as biomarkers and probably not as therapeutic targets. In fact, one of the main conclusions we can get from this cytokine hypothesis history is that probably the future will be to tailor the therapeutics according to an inflammatory profile which will require a better knowledge of the players acting on HF immunopathogenesis in order to improve immunomodulatory treatment, or alternatively to promote the resolution of inflammation which remains scarcely studied in human HF.

Author Contributions

MR-C and TS conceived and wrote the manuscript. PP-T, JQ-S, and CS-P wrote the manuscript. TS and AA-T supervised and reviewed the manuscript. All the authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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