Inflammation in Heart Failure: Mechanisms and Therapeutic Strategies

Abstract

Cardiovascular disease remains a leading cause of death and disability worldwide. Heart failure (HF) is the end stage of various cardiovascular diseases. Despite recent advancements in understanding of HF pathogenesis and treatment, the prognosis of patients with HF remains poor. Inflammation is a key player in the development of HF, and its role in the pathogenesis of HF has been extensively studied. Inflammation is associated with elevated HF risk and adverse prognosis. Targeting cardiac inflammation has been suggested as a promising treatment strategy for HF. However, almost all clinical trials on the anti-inflammatory treatment of HF have not indicated improved clinical outcomes, and some have reported deterioration of the condition, possibly because of limited understanding of the specific role of inflammation in HF. The summary of inflammatory mechanisms contributing to the pathogenesis of different HF types, current anti-inflammation therapies for HF, and the results of clinical trials could provide new perspectives for understanding and targeting the role of inflammation in HF through the development of effective clinical therapeutic strategies.

Main article text

Heart Failure Classification, Epidemiology, and Prognosis

Heart failure (HF), a clinical syndrome caused by a variety of disturbances in cardiac structure and/or function, leads to ventricular systolic and/or diastolic dysfunction and insufficient delivery of blood and oxygen to the surrounding tissues to fulfill their metabolic needs [1]. This complex clinical syndrome is characterized by pulmonary or systemic congestion. Currently, HF can be classified into four types according to left ventricular ejection fraction (LVEF): HF with decreased ejection fraction (HFrEF; LVEF ≤40%), HF with preserved ejection fraction (HFpEF, LVEF ≥50%), HF with mildly decreased EF (HFmrEF, LVEF 40–49%), and HF with improved EF (HFimpEF), with respect to a baseline LVEF of ≤40%, a ≥10% increase from baseline LVEF, and a second measurement of LVEF of >40% [2].

HF affects more than 64 million people worldwide [3]. The China Hypertension survey, enrolling 22,158 participants, has revealed a weighted prevalence of HF among the Chinese population ≥35 years of age of 1.3% (estimated 13.7 million) [4]. Of these, 1.4% of participants exhibited HFrEF, and 2.7% were classified as having moderate or severe diastolic dysfunction. In the United States, the prevalence of HF was 2.42% in 2012 and is expected to rise to 2.97% by 2030 [5]. In European countries, the prevalence of HF has been estimated to be 17.20 cases per 1000 people [6]. In Australia, the HF prevalence ranges between 1.0% and 2.0% [7]. Most reports on the epidemiology of HF have been conducted in developed countries, whereas reliable estimates of the prevalence of HF in middle- and low-income countries are lacking. However, HF is clearly the fastest-growing cardiovascular disease worldwide. The prevalence of HFpEF is increasing and currently exceeds that of HFrEF, whereas the prevalence of HFrEF appears to be stable or even declining. This trend may largely account for the primary prevention of cardiovascular disease and improved management of ischemic heart disease. In contrast, the risk factors for HFpEF, such as aging, obesity, diabetes, and hypertension, have markedly increased in this century [8].

In recent years, with medical developments, the 5-year HF survival rate in developed countries is substantially greater than that 20 years ago. A 2016 study of HF in the UK has indicated that the overall 1-year, 5-year, and 10-year survival rates of patients with HF increased by 6.6% (from 74.2% in 2000 to 80.8% in 2016), 7.2% (from 41.0% in 2001 to 48.2% in 2012), and 6.4% (from 19.8% in 2005 to 26.2% in 2007), respectively [9]. Similarly, the 5-year HF survival rate was 48% in Sweden [9]. The China Heart Failure Registration Research (China-HF) analysis of 13,687 patients with HF in 132 hospitals across the country from January 2012 to September 2015 has revealed a 4.1% fatality rate among hospitalized patients with HF [10]. According to the 2020 China Heart Failure Medical Quality Control Report, an analysis of 33,413 patients with HF admitted to 113 hospitals across the country between January 2017 and October 2020 has revealed an in-hospital mortality rate of 2.8% [11]. Despite notable advancements in the treatment and prevention of HF in recent decades, the 5-year HF survival rate has improved; however, the overall prognosis remains poor, and further research is required.

Inflammatory Biomarkers in Heart Failure

Systemic inflammation is intimately involved in the pathophysiology of HF [12]. In 1990, circulating levels of tumor necrosis factor were observed to be elevated in patients with HF, thus providing the earliest evidence of sustained inflammation in HF [13]. Subsequent experimental and clinical findings have highlighted that the activation of immune systems aggravates cardiac dysfunction, and targeting inflammatory responses is a potential therapeutic strategy for HF. Consequently, inflammatory biomarkers might serve as potential targets to regulate immune systems in HF (Figure 1).

Figure 1

The inflammatory biomarkers in HF.

The circulating levels of inflammatory biomarkers such as pro-inflammatory cytokines (TNFα, IL-1β, IL-6, et al), chemokines (MCP1, CCL5, CCL17, CCL24, et al.), soluble tumor suppressant factor-2 (sST2), growth differentiation factor-15 (GDF-15), high mobility group 1 (HMGB1), carbohydrate antigen 125 (CA125), C-reactive protein (CRP), and galectin-3 (Gal-3) have been shown to be significantly elevated in patients with HF. These inflammatory biomarkers play an important role in the development of HF via promoting leukocyte migration and infiltration, triggering endothelial dysfunction and apoptosis of cardiomyocyte, activating matrix metalloproteinases and degrading extracellular matrix, and eliciting cardiac hypertrophy and fibrosis.

Pro-Inflammatory Cytokines

Cytokines are low-molecular-weight bioactive proteins that regulate cell function in an autocrine or paracrine manner [14]. Elevated circulating pro-inflammatory cytokine concentrations in patients with HFrEF or HFpEF are a well-known characteristic associated with poorer clinical outcomes [15–17]. The most important pro-inflammatory cytokines involved in HF include tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6. Experimental models have shown that pro-inflammatory cytokines may produce negative inotropic effects [18], and induce activation of matrix metalloproteinases (MMPs) that disturb the structure of the myocardial extracellular matrix [19]; induce hypertrophy and promote cardiomyocyte apoptosis [20]; and stimulate a fibrogenic program, induce the production of fibroblast growth factors, and eventually lead to myocardial fibrosis [21]. Cardiac-specific overexpression of TNF in mice can activate MMPs, thus producing a classic spontaneous HF phenotype [19]. MMPs, a family of proteases, degrade extracellular matrix proteins and determine the interstitial architecture. An imbalance between the activity of MMPs and tissue inhibitor of MMPs (TIMPs) is associated with the progression of HF [22]. Moreover, an increase in the ratio of MMPs/TIMPs leads to degradation of the extracellular matrix, whereas a decrease in this ratio leads to progressive myocardial fibrosis [23]. Therefore, cytokines may also elicit a direct effect on the pathogenesis of HF by regulating the expression of both MMPs and TIMPs.

Chemokines

Chemokines are small glycoproteins that stimulate leukocyte migration and infiltration, and induce the production of pro-inflammatory cytokines and reactive oxygen species [24]. The four known chemokine subfamilies, distinguished by their primary amino acid sequences, are CXC, CC, C, and CX3C [25]. Patients with HF exhibit significantly higher plasma chemokine concentrations than healthy individuals, including CC-chemokine ligand 2 (CCL2; also known as MCP1) [26], CCL3 (also known as MIP1α) [27], CCL5 (also known as RANTES) [28], CCL17 [29], CCL21 [30], and CCL24 [31]. Animal experiments have revealed that anti-CCL5 mAb decreased leucocyte recruitment, infarct size, and improved the post-infarction HF [32]. CCL17 knockout or anti-CCL17 neutralizing antibody significantly repressed cardiac hypertrophy and fibrosis by reducing the T helper 17 (Th17)/regulatory T cell (Treg) ratio and promoting Th1-type polarization, in a mouse model of age-related and angiotensin II–induced HF [31]. Therefore, the level of circulating chemokines can be considered to indicate the severity and prognosis of HF, and may be a potential intervention target.

C-Reactive Protein

C-reactive protein (CRP), produced by the liver during inflammation, is widely used to assess systemic inflammation. A prospective cohort study has suggested that elevated CRP is an independent risk marker and is associated with poor prognosis for HF [33]. Similarly, a meta-analysis of 19 studies has revealed that CRP can serve as a biomarker to predict the development of HFpEF and long-term clinical outcomes in patients with HFpEF [34]. Notably, for every 1 mg/L increase in CRP, the risk of HF increases by 10%, and the risk of HFrEF and HFpEF increases by 9% and 12%, respectively [33]. Therefore, CRP might serve as an important inflammatory response marker reflecting HF severity and prognosis.

Growth Differentiation Factor-15

Growth differentiation factor-15 (GDF-15), an inflammatory stress marker, is a member of the transforming growth factor-beta superfamily. GDF-15 has a protective effect on the ischemic myocardium, and GDF-15 deficiency causes loss of anti-inflammatory mechanisms in mice that can lead to fatal cardiac rupture after myocardial infarction [35]. A clinical study has revealed that GDF-15 is associated with long-term mortality in patients with acute HF and can predict the prognosis of patients with acute HF independently of BNP [36]. Therefore, GDF-15 may serve as a new indicator for diagnosis and follow-up of patients with HF and may be used as an anti-inflammatory therapy target for HF in the future.

Other Inflammatory Biomarkers in Heart Failure

High mobility group box 1 (HMGB1), a non-histone DNA binding protein, is significantly elevated in the serum in patients with HF, and positively correlates with NT-proBNP and negatively correlates with LVEF [37]. Galectin-3 (Gal-3), a beta-galactoside-binding animal lectin, is a potential novel therapeutic target for inflammatory diseases [38]. The level of Gal-3 is elevated in the plasma in patients with HF and positively correlates with the risk of death and all-cause mortality [39]. Pharmacological inhibition of Gal-3 alleviates cardiac inflammation and fibrosis and ameliorates the HF phenotype in mouse models of HF [40]. Soluble suppression of tumorigenesis-2 (sST2), a biomarker associated with inflammation, has also been reported to be associated with the prognosis of HFrEF [41] and HFpEF [42]. In addition, carbohydrate antigen 125 (CA-125), a high molecular weight glycoprotein, is associated with increased pro-inflammatory cytokines in the serum in patients with chronic HF [43]. Notably, a recent clinical trial has indicated that CA-125 is prognostic for only HFrEF but is not associated with HFpEF [44]. These novel inflammatory markers, which have not been extensively studied in HF, may be potential targets for the inflammation in HF in the future.

Roles of Inflammation in Heart Failure

Elevated local and systemic inflammation is associated with deterioration in cardiac function in both HFrEF and HFpEF. HFmrEF and HFrEF are generally believed to be significantly associated with markers of myocardial traction, whereas HFpEF is more closely associated with biomarkers of inflammation. The clinical features and drug strategies for treating HFmrEF are similar to those for HFrEF [45]. Therefore, we focused on HFrEF and HFpEF (Figure 2).

Figure 2

The role of inflammation in HFrEF and HFpEF.

The etiologies of HFrEF and HFpEF are very different. HFrEF is mainly caused by local diseases such as coronary heart disease, hypertension driven stress load, and cardiomyopathy to induce myocardial damage, while HFpEF is more likely to be driven by systemic diseases such as obesity, hypertension, diabetes and aging, which are usually accompanied by systemic chronic inflammation. The myocardial injury in HFrEF appears to precede inflammation, whereas myocardial damages in HFpEF tend to follow inflammation. The pathogen-associated molecular models (PAMPs) and danger-associated molecular patterns (DAMPs) are involved in the inflammatory initiation of HFrEF, activating innate immunity by toll-like or NOD-like receptor. The activated leukocytes can secrete a large number of inflammatory cytokines and chemokines via intracellular myeloid differentiation factor 88 (MyD88), NF-κB signaling pathway or NLRP3 inflammasome, inducing local infiltration and migration, secreting matrix metalloproteinases (MMPs) and degrading myocardial extracellular matrix (ECM). Persistent, excessive inflammation can further damage cardiomyocyte, forming a vicious cycle, and eventually resulting in ventricular systolic dysfunction. The chronic systemic inflammation driven by multiple comorbidities in HFpEF triggers microvascular endothelial dysfunction, leukocyte infiltration, reactive oxygen species (ROS) production, and myocardial metabolic dysfunction, which further cause myocardial damage and resulting in ventricular diastolic dysfunction.

HFrEF

HFrEF is driven largely by inflammation-induced damage and volume overload. Cardiomyocyte damage and loss is the primary driver of HFrEF. The factors initiating a cardiac inflammatory response in HFrEF include pathogen-associated molecular models, such as virus or bacterial antigens, and danger-associated molecular patterns (DAMPs) such as ATP, mtDNA, and hyaluronic acid (released in myocardial ischemia or hemodynamic overload). In fact, most HFrEF-associated inflammation is aseptic, thus indicating activation of innate immunity [46]. Under such sterile conditions, the release of DAMPs triggers an inflammatory response by activating Toll-like receptor 2 (TLR2) or TLR4 on neutrophils and macrophages via intracellular myeloid differentiation factor 88 (MyD88), mitogen-activated protein kinases (MAPK), and NF-κB signaling in local heart tissue [40]. These DAMPS also activate NOD-like receptors on immune cells, such as NLRP3 inflammasomes, thus leading to the release and conversion of pro-IL-1β to IL-1β by caspase-1 [47]. In general, myocardial injury due to multiple causes can trigger a local immune response; lead to leukocyte recruitment and cytokine secretion; elicit cardiomyocyte death, myocardial extracellular matrix degradation, myocardial hypertrophy, or fibrosis; and eventually result in a major loss of contractile function.

HFpEF

The etiology of HFpEF is complex. Obesity, hypertension, diabetes, and aging are common comorbidities with HFpEF [48, 49] that usually precede HFpEF development. The visceral white adipose tissue in obese individuals induces infiltration of monocytes and macrophages, which secrete pro-inflammatory cytokines, adipokines, and immunoglobulins, thus resulting in a low-level chronic systemic inflammatory state [50, 51]. Bariatric surgery decreases systemic inflammation, thereby diminishing the risk of cardiovascular disease [52]. Similarly to obesity, hypertension and aging can also drive systemic microvascular inflammation [53, 54], which participates in the pathogenesis of HFpEF. The primary cardiac changes in HFpEF have been postulated to be coronary microvascular endothelial dysfunction, oxidative stress, and inflammation. Elevated peripheral blood inflammatory biomarkers are more pronounced in HFpEF than in HFrEF, thereby suggesting a more central role of inflammation in HFpEF than in HFrEF [55]. Further study is necessary to elucidate how systemic inflammation transforms into myocardium inflammation in HFpEF, and eventually triggers cardiac diastolic dysfunction.

Clinical Trials Targeting Inflammation Strategies in Heart Failure

Targeted Cytokine Therapies

Pro-inflammatory cytokines play important roles in the progression of chronic HF. Unfortunately, the net results of large-scale clinical trials targeting TNF-α have been disappointing. In 2003, data for the ATTACH trial, the first randomized controlled trial (RCT) of short-term TNF-α antagonism (infliximab), indicated that this treatment did not provide any beneficial effects, and high doses (10 mg/kg) adversely affected clinical condition in patients with moderate-to-severe chronic HFrEF [56]. In 2004, the RENEWAL trial also indicated that TNF-α antagonism (etanercept) did not yield clinically relevant benefits in terms of mortality and hospitalization rates due to chronic HFrEF [57]. The negative results of two large-scale TNF-α antagonism clinical trials were attributed primarily to the complex interactions in inflammatory cytokine networks; therefore, antagonizing individual cytokines alone is unlikely to provide benefit but may cause drug cytotoxicity. Further clinical studies, have evaluated the role of IL-1β inhibition in HF. In 2016, anakinra, an IL-1 receptor antagonist, was found to decrease CRP plasma levels in patients with acute decompensated HFrEF [58]. In 2017, the REDHART trial showed that administration of anakinra for 12 weeks improved exercise capacity patients with HFrEF [59]. In 2019, the CANTOS trial demonstrated that administration of canakinuma, an interleukin-1β inhibitor, decreased HF-associated hospitalizations and mortality among patients with HFrEF, in a dose-dependent manner [60]. The REDHART2 trial is currently assessing the effects of anakinra administration for 24 weeks on cardiorespiratory fitness and HF re-hospitalization in patients with recent hospitalization due to acute decompensated HFrEF [61]. Importantly, the main participants in clinical trials have been patients with HFrEF. As previously stated, chronic systemic inflammation plays a more important role in the development of HFpEF than HFrEF [55]. In 2014, the D-HART trial evaluated the clinical value of anakinra in HFpEF. Administration of anakinra for 14 days was found to improve aerobic exercise capacity in patients with HFpEF [62]. However, administration of anakinra for 12 weeks did not improve ventilation function in patients with HFpEF in the subsequent phase II trial (D-HART2) [63]. In summary, the clinical value of targeting pro-inflammatory cytokines in the treatment of HF must be further studied.

Colchicine

Colchicine, a lipophilic alkaloid extracted from colchicum liliaceae, effectively treats acute gout attacks and has been approved by the US Food and Drug Administration for anti-inflammatory cardiovascular therapy [64]. Multiple clinical trials (COLCOT [65], LoDoCo [66], and LoDoCo2 [67]) have demonstrated the efficacy and safety of low-dose colchicine in patients with acute or chronic coronary artery disease. However, for patients with stable chronic HFrEF, colchicine (0.5 mg bid) decreases inflammatory cytokine levels but has no effect on any clinical indices for HF [68]. Notably, that study was limited by a small sample size. At present, the COLICA trial is evaluating the efficacy and safety of colchicine in the treatment of acute HF, and is expected to provide further clinical evidence [69]. In addition, an animal study has indicated that colchicine alleviates inflammation and ameliorates cardiac diastolic dysfunction in a rat HFpEF model [70]. Currently, the COLpEF trial (NCT04857931), testing the efficacy and safety of colchicine in patients with HFpEF, is ongoing.

Statins

The beneficial effects of statins in cardiovascular diseases have been generally recognized to be independent of their lipid-lowering effects, and to potentially be associated with anti-inflammatory effects [71]. Data on the effects of statins in patients with HFrEF are controversial. In 2006, an RCT reported that atorvastatin decreases serum markers (high sensitivity CRP, IL-6, and TNF-α) of inflammation and ameliorates left ventricular systolic function in patients with HFrEF [72]. However, in 2007, the CORONA trial, the first large-scale, prospective clinical trial evaluating the anti-inflammatory effects of statins in patients with HFrEF, showed that rosuvastatin decreased levels of high-sensitivity CRP and the number of cardiovascular hospitalizations, but did not decrease coronary outcomes or death from cardiovascular causes [73]. Similarly, in 2008, the GISSI-HF trial showed that rosuvastatin did not improve the prognosis of patients with HFrEF [74]. In contrast, a recent meta-analysis has indicated decreased mortality after statin treatment in patients with HFrEF [75]. Current clinical guidelines do not recommend routine use of statins in patients with HFrEF. Many observational studies have consistently reported positive effects of statins on mortality in patients with HFpEF [76–80]. However, statin therapy for HFpEF has not been evaluated in randomized trials. Thus, challenges persist in using statins to treat HF.

SGLT2 Inhibitors

Sodium glucose cotransporter 2 (SGLT2) inhibitors are novel antihyperglycemic drugs demonstrated to be beneficial in cardiovascular disease. Cardiovascular protection by SGLT2 inhibitors has been partly attributed to anti-inflammatory effects [81]. SGLT2 inhibitors indirectly decrease systemic inflammation by modulating inflammatory pathways [81, 82]. SGLT2 inhibitors also exert direct anti-inflammatory effects by modulating immune cells [83]. A meta-analysis of 30 animal studies has suggested that SGLT2 inhibitors decrease inflammatory markers [84]. Two meta-analyses of RCTs have also provided strong evidence supporting the anti-inflammatory effects of SGLT2 inhibitors [85, 86]. The EMPA – REG OUTCOME trial (empagliflozin) [87], CANVAS (canagliflozin) [88], and DECLARE-TIMI 58 (dapagliflozin) [89] trials have consistently shown that SGLT-2 inhibitors significantly decrease severe new-onset HF in patients with type 2 diabetes. Furthermore, the DAPA-HF trial (dapagliflozin) [90] and EMPEROR-Reduced trial (empagliflozin) [91] have provided strong evidence that SGLT2 inhibitors decrease the risk of cardiovascular death and hospitalization among patients with HFrEF, regardless of the presence or absence of diabetes. Two RCTs, the EMPEROR-Preserved trial [92] and DELIVER trial [93], have shown that SGLT2 inhibitors decrease the risk of cardiovascular death and hospitalization among patients with HFmrEF or HFpEF, regardless of the presence or absence of diabetes. Current clinical guidelines strongly recommend the use of SGLT2 inhibitors in patients with HFrEF and HFpEF [94]. Overall, SGLT2 inhibitors have emerged as promising therapeutic agents for targeting inflammation in HF.

Glucagon-Like Peptide 1 Receptor Agonists

Glucagon-like peptide-1 (GLP-1) is released from gut enteroendocrine cells, promotes blood glucose homeostasis, slows gastric emptying, and decreases appetite; its receptor (GLP-1R) agonist has been approved for the treatment of type 2 diabetes and obesity. Accumulating evidence suggests that GLP1-R agonists also exert anti-inflammatory effects [95, 96]. Currently, although three important RCTs, the albiglutide trial [97], FIGHT trial [98], and LIVE trial [99], have shown that GLP1R agonists do not confer beneficial effects in patients with HFrEF, they have been found to decrease CRP concentrations and ameliorate symptoms, physical limitations, and exercise function in patients with HFpEF in STEP-HFpEF trial [100, 101].

Omega-3

Omega-3 fatty acids, found in fish oil, are essential polyunsaturated fatty acids that are considered potential anti-inflammatory agents. Fish oils have been found to decrease TNF-a production in patients with HF [102]. In the GISSI-HF trial [103, 104], a large-scale RCT, omega-3 supplementation significantly decreased all-cause mortality by 9%, and all-cause mortality or cardiovascular hospitalizations by 8%, over 3.9 years in patients with HFrEF. No clinical trials have evaluated the efficacy of omega-3 supplementation for HFpEF, but omega-3 serum levels are inversely associated with cardiometabolic risk factors in patients with HFpEF [105]. Current guidelines recommend omega-3 treatment for patients with NYHA II to IV HF, to decrease the risk of cardiovascular hospitalization and death [94]. Importantly, whether omega-3 fatty acids provide clinical benefit in cardiac disease remains controversial. In 2018, the REDUCE-IT trial [106] showed that omega-3 supplementation significantly decreased cardiovascular risk in patients with elevated triglyceride levels. In contrast, in 2020, the OMEMI trial [107] and STRENGTH trial [108] indicated that high-dose omega-3 did not confer significant cardiovascular risk benefits in patients with myocardial infarction or high cardiovascular risk. Subsequently, a meta-analysis indicated that omega-3 fatty acids decrease cardiovascular mortality and improve cardiovascular outcomes, but increase incident atrial fibrillation [109]. In addition, in the general population, regular use of fish oil supplements might increase risk of atrial fibrillation and stroke [110]. Therefore, further research is needed to evaluate the roles of this treatment in cardiovascular disease.

Vagus Nerve Stimulation

In the pathophysiology of HF, the activity of the vagus nerve is clearly inhibited, thus potentially leading to the release of many inflammatory factors and further aggravating HF. The anti-inflammatory effects of vagus nerve stimulation (VNS) have been well established. Preclinical studies have demonstrated that VNS markedly ameliorates the phenotype of HF through its anti-inflammatory effects in animal models of HFrEF [111, 112] and HFpEF [113]. De Ferrari et al. [114] first reported a clinical trial of VNS for HF, indicating that VNS safely improves quality of life and cardiac function in patients with HFrEF. The safety and efficacy of VNS in patients with HFrEF were further confirmed in the subsequent ANTHEM-HF trial [115]. These beneficial effects have been found to be sustained across multiple years during high-intensity VNS [116]. However, two RCT studies, the NECTAR-HF trial [117] and INOVATE-HF trial [118], have reported that VNS did not improve cardiac function, or decrease the rates of death or worsening of HF, in patients with HFrEF. Clinical studies on VNS in the treatment of HFrEF have yielded controversial findings. Differences in patient demographics, neurologic targets, technology platforms, and VNS mode and delivery might explain the differing results among clinical trials [119]. Recently, a proof-of-concept pilot study has demonstrated that low-level tragus stimulation (LLTS), a noninvasive VNS strategy, attenuates systemic inflammation and provides beneficial effects in patients with acute HF [120]. In addition, LLTS acutely ameliorates left ventricular global longitudinal strain in patients with HFpEF [121]. LLTS for 3 months decreases inflammatory cytokines and improves quality of life, but does not affect echocardiographic markers of diastolic dysfunction in patients with HFpEF [122]. Similarly, in the recent ANTHEM-HFpEF trial, VNS improved clinical symptoms and quality of life, but did not alter mechanical function measures in patients with HFpEF [123]. Importantly, the small sample sizes of those prior clinical studies limited their power to detect differences. Further large-scale randomized clinical trials are required to evaluate the long-term efficacy of VNS in terms of clinical outcomes in patients with HFpEF.

Historical Small-Scale Studied Targets

Methotrexate, a nonspecific anti-inflammatory drug for rheumatoid arthritis, has anti-inflammatory effects and improves NYHA scores, but does not alter LVEF and clinical outcomes in patient with HFrEF [124, 125]. Thalidomide, a drug with potential immunomodulating and matrix-stabilizing properties, ameliorates LVEF in patients with HFrEF [126]. However, positive results of thalidomide in HFrEF have not been found in a subsequent trial [127]. In addition, oxypurinol [128] and allopurinol [129], xanthine oxidase (XO) inhibitors, have not been observed to produce clinical improvements in patients with HFrEF. Despite numerous failed attempts, the search for anti-inflammatory strategies for HF continues. Because of the many available studies, several small clinical studies of anti-inflammation in HF are not discussed herein.

Summary and Future Prospects

Causal evidence has demonstrated that inflammation plays a major role in the development of HF. Targeting inflammation in HF is a topic of an ongoing research. Targeting inflammatory biomarkers in HF remains an important future research direction. Broad-spectrum anti-inflammatory strategies may achieve more significant clinical effects than inhibition of individual pro-inflammatory cytokines. Importantly, most early completed clinical trials assessing inflammation targeting therapies in HF have not yielded promising findings, but recent trials of anti-inflammatory treatment, such as anti-IL-1β therapy, have yielded encouraging preliminary findings. The relevant clinical trials are summarized in Table 1. Developing a specific anti-inflammatory therapy for HF has proven challenging. Well-designed and expensive clinical trials with long follow-up are required for identifying candidate anti-inflammatory therapies with clinical benefits in human HF. Current animal models cannot accurately recapitulate the pathophysiologic heterogeneity in HF, particularly HFpEF, thus challenging the successful translation of conclusions from animal experiments into clinical practice.

Table 1

Overview of Clinical Trials Targeting Inflammation in Patients with Heart Failure.

Study (year)	Therapy	Study type	Number of patients	Main HF category	Follow-up	Outcomes
ATTACH (2003) [56]	Infliximab (TNF)	RCT	150	HFrEF	7 months	Did not improve clinical outcomes
RENEWAL (2004) [57]	Etanercept (TNF)	RCT	2048	HFrEF	5.7/12.9 months	Did not improve clinical outcomes
Van Tassell et al. (2016) [58]	Anakinra (IL-1β)	RCT	30	ADHF (HFrEF)	14 days	Decreased CRP plasma levels
REDHART (2017) [59]	Anakinra (IL-1β)	RCT	60	HFrEF	3 months	Increased exercise capacity
CANTOS (2019) [60]	Canakinumab (IL-1β)	RCT	10,061	HFrEF	3.7 years	Decreased HF-associated hospitalizations and mortality in a dose-dependent manner
D-HART (2014) [62]	Anakinra (IL-1β)	RCT	12	HFpEF	14 days	Decreased systemic inflammatory response; improved aerobic exercise capacity
D-HART2 (2018) [63]	Anakinra (IL-1β)	RCT	31	HFpEF	3 months	Decreased plasma CRP levels; did not improve ventilation function
Deftereos et al. (2014) [68]	Colchicine	RCT	267	HFrEF	6 months	Decreased inflammatory cytokine levels; did not affect any clinical indices
Sola S et al. (2006) [72]	Atorvastatin	RCT	108	HFrEF	12 months	Decreased inflammatory cytokine levels; improved left ventricular systolic function
CORONA (2007) [73]	Rosuvastatin	RCT	5011	HFrEF	2.7 years	Decreased high-sensitivity CRP levels and the number of cardiovascular hospitalizations; did not decrease coronary events and cardiovascular death
GISSI-HF (2008) [74]	Rosuvastatin	RCT	4574	HFrEF	3.9 years	Did not improve clinical outcomes
Fukuta H et al. (2005) [76]	Statins	Observational study	137	HFpEF	21 ± 12 months	Improved survival
Roik et al. (2008) [78]	Statins	Observational study	146	HFpEF	1 year	Decreased mortality and rehospitalization rates
Tsujimoto and Kajio (2018) [80]	Statins	Observational study	3378	HFpEF	3.3 years	Decreased risk of all-cause and cardiovascular mortality
Nochioka et al. (2015) [79]	Statins	Observational study	3124	HFpEF	3.4 years	Improved mortality rates
DAPA-HF (2019) [90]	Dapagliflozin (SGLT2 inhibitors)	RCT	4744	HFrEF	18.2 months	Decreased risk of worsening HF or cardiovascular death
EMPEROR-Decreased (2020) [91]	Empagliflozin (SGLT2 inhibitors)	RCT	3730	HFrEF	16 months	Decreased risk of cardiovascular death or hospitalization for heart failure
EMPEROR-Preserved (2021) [92]	Empagliflozin (SGLT2 inhibitors)	RCT	5988	HFpEF	26.2 months	Decreased risk of cardiovascular death or hospitalization
DELIVER (2022) [93]	Dapagliflozin (SGLT2 inhibitors)	RCT	6263	HFpEF	2.3 years	Decreased risk of worsening heart failure or cardiovascular death
Lepore et al. (2016) [97]	Albiglutide (GLP-1R agonist)	RCT	82	HFrEF	12 weeks	Did not improve cardiac function
FIGHT (2016) [98]	Liraglutide (GLP-1R agonist)	RCT	300	HFrEF	180 days	Did not affect the primary endpoint
LIVE (2017) [99]	Liraglutide (GLP-1R agonist)	RCT	241	HFrEF	24 weeks	Did not affect left ventricular systolic function; increased risk of serious cardiac adverse events
STEP-HFpEF (2024) [100]	Semaglutide (GLP-1R agonist)	RCT	529	HFpEF	52 weeks	Decreased CRP plasma levels; ameliorated HF-related symptoms
GISSI-HF (2008) [103]	Omega-3	RCT	6975	HFrEF	3.9 years	Decreased all-cause mortality by 9% and all-cause mortality or cardiovascular hospitalization by 8%
De Ferrari et al. (2011) [114]	VNS	Open-label study	32	HFrEF	6 months	Improved quality of life and left ventricular function
ANTHEM-HF (2014) [115]	VNS	RCT	60	HFrEF	6 months	Indicated encouraging safety and efficacy measures
NECTAR-HF (2015) [117]	VNS	RCT	87	HFrEF	6 months	Did not significantly affect primary and secondary endpoints
INOVATE-HF (2016) [118]	VNS	RCT	707	HFrEF	16 months	Did not affect rate of death or HF events
Dasari et al. (2023) [120]	VNS	RCT	19	ADHF (HFrEF)	4 days	Attenuated systemic inflammation and provided beneficial effects
Tran et al. (2019) [121]	VNS	RCT	24	HFpEF	1 hours	Ameliorated left ventricular global longitudinal strain
Stavrakis et al. (2022) [122]	VNS	RCT	52	HFpEF	3 months	Decreased inflammatory cytokines and improved quality of life; did not affect echocardiographic markers of diastolic dysfunction
ANTHEM-HFpEF (2023) [123]	VNS	RCT	52	HFpEF	12 months	Improved heart failure symptoms; did not affect mechanical function measures
Gong et al. (2006) [124]	Methotrexate	RCT	62	HFrEF	4 months	Did not improve LVEF and adverse events; had anti-inflammatory effects; improved NYHA scores and quality of life
METIS (2009) [125]	Methotrexate	RCT	52	HFrEF	3 months	Did not improve inflammation and clinical outcome
Gullestad et al. (2005) [126]	Thalidomide	RCT	56	HFrEF	3 months	Improved LVEF
Orea-Tejeda et al. (2007) [127]	Thalidomide	RCT	80	HFrEF	6 months	Did not improve LVEF
OPT-CHF (2008) [128]	Oxypurinol (xanthine oxidase inhibitor)	RCT	405	HFrEF	6 months	Did not achieve clinical improvements in HF
EXACT-HF (2015) [129]	Allopurinol (xanthine oxidase inhibitor)	RCT	253	HFrEF	6 months	Did not improve clinical status, exercise capacity, quality of life, or LVEF

Note: RCT, randomized controlled trial; SGLT2, sodium glucose cotransporter 2; GLP1R, glucagon-like peptide 1 receptor; VNS, vagus nerve stimulation; HF, heart failure; HFrEF, heart failure with decreased ejection fraction; HFpEF, heart failure with preserved ejection fraction; ADHF, acutely decompensated heart failure; TNF, tumor necrosis factor; IL-1β, interleukin-1β; CRP, C-reactive protein; LVEF, left ventricular ejection fraction.

Clinical trials of anti-inflammatory treatment for HF remain ongoing (Table 2). The REDHART2 (NCT03797001) [61] and COLICA (NCT04705987) [69] trials are being conducted to evaluate the clinical efficacy of anakinra and colchicine for acute decompensated HFrEF, respectively. In addition, AZD4831 (NCT04986202), a myeloperoxidase inhibitor; ziltivekimab (NCT05636176), an IL-6 inhibitor; and colchicine (NCT04857931) are currently in clinical trials to assess their therapeutic value against HFpEF/HFmrEF [130, 131]. With refined understanding of the complex inflammatory networks within the heterogeneous syndrome of HF, as well as the cumulative lessons learned from previous clinical trials, the development of more intelligently targeted anti-inflammatory therapeutic strategies might be possible in the foreseeable future.

Table 2

Ongoing Clinical Trials of Anti-Inflammatory Therapies in Patients with Heart Failure.

Trial registration number	Therapy	Category of HF	Numbers of patients	Follow-up
NCT03797001	Anakinra (IL-1β receptor antagonist)	ADHF	102	6-month
NCT05636176	Ziltivekimab (IL-6 inhibitor)	HFpEF	5600	4-year
NCT04705987	Colchicine	ADHF	278	2-month
NCT04857931	Colchicine	HFpEF	No message	6-month
NCT04986202	AZD4831 (myeloperoxidase inhibitor)	HFpEF	1480	1-year

Note: HF, heart failure; ADHF, acutely decompensated heart failure; HFpEF, heart failure with preserved ejection fraction.

Conflict of Interest

The authors declare no conflicts of interest.

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References

1. KK Teo, T Rafiq. Cardiovascular risk factors and prevention: a perspective from developing countries. Can J Cardiol 2021;37(5):733–43.

2. B Bozkurt, AJS Coats, H Tsutsui, CM Abdelhamid, S Adamopoulos, N Albert, et al. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur J Heart Fail 2021;23(3):352–80.

3. G Savarese, PM Becher, LH Lund, P Seferovic, GMC Rosano, AJS Coats. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res 2023;118(17):3272–87.

4. G Hao, X Wang, Z Chen, L Zhang, Y Zhang, B Wei, et al. Prevalence of heart failure and left ventricular dysfunction in China: the China Hypertension Survey, 2012-2015. Eur J Heart Fail 2019;21(11):1329–37.

5. PA Heidenreich, NM Albert, LA Allen, DA Bluemke, J Butler, GC Fonarow, et al. Forecasting the impact of heart failure in the United States. Circ Heart Fail 2013;6(3):606–19.

6. PM Seferović, P Vardas, EA Jankowska, AP Maggioni, A Timmis, I Milinković, et al. The Heart Failure Association atlas: heart failure epidemiology and management statistics 2019. Eur J Heart Fail 2021;23(6):906–14.

7. BW Sahle, AJ Owen, MP Mutowo, H Krum, CM Reid. Prevalence of heart failure in Australia: a systematic review. BMC Cardiovasc Disord 2016;16:32.

8. BA Borlaug. Evaluation and management of heart failure with preserved ejection fraction. Nat Rev Cardiol 2020;17(9):559–73.

9. CJ Taylor, JM Ordóñez-Mena, AK Roalfe, S Lay-Flurrie, NR Jones, T Marshall, et al. Trends in survival after a diagnosis of heart failure in the United Kingdom 2000-2017: population based cohort study. Br Med J 2019;364:l223.

10. Y Zhang, J Zhang, J Butler, X Yang, P Xie, D Guo, et al. Contemporary epidemiology, management, and outcomes of patients hospitalized for heart failure in China: results from the China Heart Failure (China-HF) Registry. J Card Fail 2017;23(12):868–75.

11. Y Zhang, C Gao, SJ Greene, BH Greenberg, J Butler, J Yu, et al. Clinical performance and quality measures for heart failure management in China: the China-Heart Failure registry study. ESC Heart Fail 2023;10(1):342–52.

12. FJ Carrillo-Salinas, N Ngwenyama, M Anastasiou, K Kaur, P Alcaide. Heart inflammation: immune cell roles and roads to the heart. Am J Pathol 2019;189(8):1482–94.

13. B Levine, J Kalman, L Mayer, HM Fillit, M Packer. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990;323(4):236–41.

14. C Liu, D Chu, K Kalantar-Zadeh, J George, HA Young, G Liu. Cytokines: from clinical significance to quantification. Adv Sci (Weinh) 2021;8(15):e2004433.

15. A Hanna, NG Frangogiannis. Inflammatory cytokines and chemokines as therapeutic targets in heart failure. Cardiovasc Drugs Ther 2020;34(6):849–63.

16. A Alogna, KE Koepp, M Sabbah, JM Espindola Netto, MD Jensen, JL Kirkland. Interleukin-6 in patients with heart failure and preserved ejection fraction. JACC Heart Fail 2023;11(11):1549–61.

17. G Markousis-Mavrogenis, J Tromp, W Ouwerkerk, M Devalaraja, SD Anker, JG Cleland. The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study. Eur J Heart Fail 2019;21(8):965–73.

18. S Toldo, E Mezzaroma, L O’Brien, C Marchetti, IM Seropian, NF Voelkel. Interleukin-18 mediates interleukin-1-induced cardiac dysfunction. Am J Physiol Heart Circ Physiol 2014;306(7):H1025–31.

19. N Sivasubramanian, ML Coker, KM Kurrelmeyer, WR MacLellan, FJ DeMayo, FG Spinale, et al. Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor. Circulation 2001;104(7):826–31.

20. T Hamid, SZ Guo, JR Kingery, X Xiang, B Dawn, SD Prabhu. Cardiomyocyte NF-κB p65 promotes adverse remodelling, apoptosis, and endoplasmic reticulum stress in heart failure. Cardiovasc Res 2011;89(1):129–38.

21. W Zhang, AL Chancey, H-P Tzeng, Z Zhou, KJ Lavine, F Gao, et al. The development of myocardial fibrosis in transgenic mice with targeted overexpression of tumor necrosis factor requires mast cell-fibroblast interactions. Circulation 2011;124(19):2106–16.

22. S Mori, G Gibson, CF McTiernan. Differential expression of MMPs and TIMPs in moderate and severe heart failure in a transgenic model. J Card Fail 2006;12(4):314–25.

23. H Nagase, R Visse, G Murphy. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006;69(3):562–73.

24. H Noels, C Weber, RR Koenen. Chemokines as therapeutic targets in cardiovascular disease. Arterioscler Thromb Vasc Biol 2019;39(4):583–92.

25. A Zlotnik, O Yoshie. The chemokine superfamily revisited. Immunity 2012;36(5):705–16.

26. A Talvani, MOC Rocha, LS Barcelos, YM Gomes, AL Ribeiro, MM Teixeira. Elevated concentrations of CCL2 and tumor necrosis factor-alpha in chagasic cardiomyopathy. Clin Infect Dis 2004;38(7):943–50.

27. C-Y Li, C-S Tsai, P-C Hsu, CT Wu, CS Wong, ST Ho. Dobutamine modulates lipopolysaccharide-induced macrophage inflammatory protein-1alpha and interleukin-8 production in human monocytes. Anesth Analg 2003;97(1):210–5.

28. J Lipkova, J Parenica, K Duris, K Helanova, J Tomandl, L Kubkova, et al. Association of circulating levels of RANTES and -403G/A promoter polymorphism to acute heart failure after STEMI and to cardiogenic shock. Clin Exp Med 2015;15(3):405–14.

29. Y Zhang, Y Ye, X Tang, H Wang, T Tanaka, R Tian. CCL17 acts as a novel therapeutic target in pathological cardiac hypertrophy and heart failure. J Exp Med 2022;219(8):e20200418.

30. T Ueland, SH Nymo, R Latini, JJ McMurray, J Kjekshus, A Yndestad. CCL21 is associated with fatal outcomes in chronic heart failure: data from CORONA and GISSI-HF trials. Eur J Heart Fail 2013;15(7):747–55.

31. Z Wang, H Xu, M Chen, Y Lu, L Zheng, L Ma. CCL24/CCR3 axis plays a central role in angiotensin II-induced heart failure by stimulating M2 macrophage polarization and fibroblast activation. Cell Biol Toxicol 2023;39(4):1413–31.

32. F Montecucco, V Braunersreuther, S Lenglet, BM Delattre, G Pelli, V Buatois. CC chemokine CCL5 plays a central role impacting infarct size and post-infarction heart failure in mice. Eur Heart J 2012;33(15):1964–74.

33. PM Burger, S Koudstaal, A Mosterd, ATL Fiolet, M Teraa, MG van der Meer. C-reactive protein and risk of incident heart failure in patients with cardiovascular disease. J Am Coll Cardiol 2023;82(5):414–26.

34. I Lakhani, MV Wong, JKF Hung, M Gong, KB Waleed, Y Xia. Diagnostic and prognostic value of serum C-reactive protein in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Heart Fail Rev 2021;26(5):1141–50.

35. T Kempf, A Zarbock, C Widera, S Butz, A Stadtmann, J Rossaint. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med 2011;17(5):581–8.

36. P Bettencourt, J Ferreira-Coimbra, P Rodrigues, P Marques, H Moreira, MJ Pinto, et al. Towards a multi-marker prognostic strategy in acute heart failure: a role for GDF-15. ESC Heart Fail 2018;5(6):1017–22.

37. T Liu, D-Y Zhang, Y-H Zhou, QF Han, LH Wang, L Wu, et al. Increased serum HMGB1 level may predict the fatal outcomes in patients with chronic heart failure. Int J Cardiol 2015;184:318–20.

38. NC Henderson, T Sethi. The regulation of inflammation by galectin-3. Immunol Rev 2009;230(1):160–71.

39. F Edelmann, V Holzendorf, R Wachter, K Nolte, AG Schmidt, E Kraigher-Krainer, et al. Galectin-3 in patients with heart failure with preserved ejection fraction: results from the Aldo-DHF trial. Eur J Heart Fail 2015;17(2):214–23.

40. G-R Xu, C Zhang, H-X Yang, JH Sun, Y Zhang, TT Yao, et al. Modified citrus pectin ameliorates myocardial fibrosis and inflammation via suppressing galectin-3 and TLR4/MyD88/NF-κB signaling pathway. Biomed Pharmacother 2020;126:110071.

41. IS Anand, TS Rector, M Kuskowski, J Snider, JN Cohn. Prognostic value of soluble ST2 in the Valsartan Heart Failure Trial. Circ Heart Fail 2014;7(3):418–26.

42. KB Shah, WJ Kop, RH Christenson, DB Diercks, S Henderson, K Hanson, et al. Prognostic utility of ST2 in patients with acute dyspnea and preserved left ventricular ejection fraction. Clin Chem 2011;57(6):874–82.

43. AE Stanciu, MM Stanciu, RG Vatasescu. NT-proBNP and CA 125 levels are associated with increased pro-inflammatory cytokines in coronary sinus serum of patients with chronic heart failure. Cytokine 2018;111:13–9.

44. JP Ferreira, M Packer, N Sattar, J Butler, SJ Pocock, SD Anker, et al. Carbohydrate antigen 125 concentrations across the ejection fraction spectrum in chronic heart failure: the EMPEROR programme. Eur J Heart Fail 2024;26(4):788–802.

45. G Savarese, D Stolfo, G Sinagra, LH Lund. Heart failure with mid-range or mildly reduced ejection fraction. Nat Rev Cardiol 2022;19(2):100–16.

46. A Dutta, M Das, A Ghosh, S Rana. Molecular and cellular pathophysiology of circulating cardiomyocyte-specific cell free DNA (cfDNA): biomarkers of heart failure and potential therapeutic targets. Genes Dis 2023;10(3):948–59.

47. S Toldo, A Abbate. The role of the NLRP3 inflammasome and pyroptosis in cardiovascular diseases. Nat Rev Cardiol 2024;21(4):219–37.

48. GG Schiattarella, D Rodolico, JA Hill. Metabolic inflammation in heart failure with preserved ejection fraction. Cardiovasc Res 2021;117(2):423–34.

49. F Triposkiadis, A Xanthopoulos, RC Starling, E Iliodromitis. Obesity, inflammation, and heart failure: links and misconceptions. Heart Fail Rev 2022;27(2):407–18.

50. X Unamuno, J Gómez-Ambrosi, B Ramírez, A Rodríguez, S Becerril, V Valentí, et al. NLRP3 inflammasome blockade reduces adipose tissue inflammation and extracellular matrix remodeling. Cell Mol Immunol 2021;18(4):1045–57.

51. BC Cossins, I van den Munckhof, JHW Rutten, M van der Graaf, R Stienstra, LAB Joosten, et al. Sex-specific association between adipose tissue inflammation and vascular and metabolic complications of obesity. J Clin Endocrinol Metab 2023;108(10):2537–49.

52. WJ English, DB Williams. Metabolic and bariatric surgery: an effective treatment option for obesity and cardiovascular disease. Prog Cardiovasc Dis 2018;61(2):253–69.

53. C Engelmann, J Clària, G Szabo, J Bosch, M Bernardi. Pathophysiology of decompensated cirrhosis: portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction. J Hepatol 2021;75 Suppl 1:S49–66.

54. F Triposkiadis, A Xanthopoulos, J Butler. Cardiovascular aging and heart failure: JACC review topic of the week. J Am Coll Cardiol 2019;74(6):804–13.

55. A Kalogeropoulos, V Georgiopoulou, BM Psaty, N Rodondi, AL Smith, DG Harrison, et al. Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study. J Am Coll Cardiol 2010;55(19):2129–37.

56. ES Chung, M Packer, KH Lo, AA Fasanmade, JT Willerson; Anti-TNF Therapy Against Congestive Heart Failure Investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003;107(25):3133–40.

57. DL Mann, JJV McMurray, M Packer, K Swedberg, JS Borer, WS Colucci, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004;109(13):1594–602.

58. BW Van Tassell, NA Abouzaki, C Oddi Erdle, S Carbone, CR Trankle, RD Melchior, et al. Interleukin-1 blockade in acute decompensated heart failure: a randomized, double-blinded, placebo-controlled pilot study. J Cardiovasc Pharmacol 2016;67(6):544–51.

59. BW Van Tassell, J Canada, S Carbone, C Trankle, L Buckley, C Oddi Erdle, et al. Interleukin-1 blockade in recently decompensated systolic heart failure: results from REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). Circ Heart Fail 2017;10(11):e004373.

60. BM Everett, JH Cornel, M Lainscak, SD Anker, A Abbate, T Thuren, et al. Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation 2019;139(10):1289–99.

61. B Van Tassell, V Mihalick, G Thomas, A Marawan, AH Talasaz, J Lu, et al. Rationale and design of interleukin-1 blockade in recently decompensated heart failure (REDHART2): a randomized, double blind, placebo controlled, single center, phase 2 study. J Transl Med 2022;20(1):270.

62. BW Van Tassell, R Arena, G Biondi-Zoccai, JM Canada, C Oddi, NA Abouzaki, et al. Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study). Am J Cardiol 2014;113(2):321–7.

63. BW Van Tassell, CR Trankle, JM Canada, S Carbone, L Buckley, D Kadariya, et al. IL-1 blockade in patients with heart failure with preserved ejection fraction. Circ Heart Fail 2018;11(8):e005036.

64. A Bonaventura, A Abbate. Colchicine for cardiovascular prevention: the dawn of a new era has finally come. Eur Heart J 2023;44(35):3303–4.

65. N Bouabdallaoui, J-C Tardif, DD Waters, FJ Pinto, AP Maggioni, R Diaz, et al. Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). Eur Heart J 2020;41(42):4092–9.

66. SM Nidorf, ATL Fiolet, A Mosterd, JW Eikelboom, A Schut, TSJ Opstal, et al. Colchicine in patients with chronic coronary disease. N Engl J Med 2020;383(19):1838–47.

67. TSJ Opstal, A van Broekhoven, ATL Fiolet, A Mosterd, JW Eikelboom, SM Nidorf, et al. Long-term efficacy of colchicine in patients with chronic coronary disease: insights from LoDoCo2. Circulation 2022;145(8):626–8.

68. S Deftereos, G Giannopoulos, V Panagopoulou, G Bouras, K Raisakis, C Kossyvakis, et al. Anti-inflammatory treatment with colchicine in stable chronic heart failure: a prospective, randomized study. JACC Heart Fail 2014;2(2):131–7.

69. D Pascual-Figal, J Núñez Villota, MT Pérez-Martínez, JR González-Juanatey, M Taibo-Urquía, P Llàcer Iborra, et al. Colchicine in acute heart failure: rationale and design of a randomized double-blind placebo-controlled trial (COLICA). Eur J Heart Fail 2024.

70. S Shen, J Duan, J Hu, Y Qi, L Kang, K Wang, et al. Colchicine alleviates inflammation and improves diastolic dysfunction in heart failure rats with preserved ejection fraction. Eur J Pharmacol 2022;929:175126.

71. A Ovchinnikov, A Potekhina, T Arefieva, A Filatova, F Ageev, E Belyavskiy. Use of statins in heart failure with preserved ejection fraction: current evidence and perspectives. Int J Mol Sci 2024;25(9):4958.

72. S Sola, MQS Mir, S Lerakis, N Tandon, BV Khan. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J Am Coll Cardiol 2006;47(2):332–7.

73. J Kjekshus, E Apetrei, V Barrios, M Böhm, JG Cleland, JH Cornel, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357(22):2248–61.

74. L Tavazzi, AP Maggioni, R Marchioli, S Barlera, MG Franzosi, R Latini, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372(9645):1231–9.

75. A Bielecka-Dabrowa, I Bytyçi, S Von Haehling, S Anker, J Jozwiak, J Rysz, et al. Association of statin use and clinical outcomes in heart failure patients: a systematic review and meta-analysis. Lipids Health Dis 2019;18(1):188.

76. H Fukuta, DC Sane, S Brucks, WC Little. Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report. Circulation 2005;112(3):357–63.

77. H Kaneko, S Suzuki, J Yajima, Y Oikawa, K Sagara, T Otsuka, et al. Clinical characteristics and long-term clinical outcomes of Japanese heart failure patients with preserved versus reduced left ventricular ejection fraction: a prospective cohort of Shinken Database 2004-2011. J Cardiol 2013;62(2):102–9.

78. M Roik, MH Starczewska, Z Huczek, J Kochanowski, G Opolski. Statin therapy and mortality among patients hospitalized with heart failure and preserved left ventricular function--a preliminary report. Acta Cardiol 2008;63(6):683–92.

79. K Nochioka, Y Sakata, S Miyata, M Miura, T Takada, S Tadaki, et al. Prognostic impact of statin use in patients with heart failure and preserved ejection fraction. Circ J 2015;79(3):574–82.

80. T Tsujimoto, H Kajio. Favorable effects of statins in the treatment of heart failure with preserved ejection fraction in patients without ischemic heart disease. Int J Cardiol 2018;255:111–7.

81. A Elrakaybi, K Laubner, Q Zhou, MJ Hug, J Seufert. Cardiovascular protection by SGLT2 inhibitors - do anti-inflammatory mechanisms play a role? Mol Metab 2022;64:101549.

82. DD Wang, AV Naumova, D Isquith, J Sapp, KA Huynh, I Tucker, et al. Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure. Cardiovasc Diabetol 2024;23(1):197.

83. FR Alsereidi, Z Khashim, H Marzook, A Gupta, AM Al-Rawi, MM Ramadan, et al. Targeting inflammatory signaling pathways with SGLT2 inhibitors: insights into cardiovascular health and cardiac cell improvement. Curr Probl Cardiol 2024;49(5):102524.

84. P Theofilis, M Sagris, E Oikonomou, AS Antonopoulos, G Siasos, K Tsioufis, et al. The impact of SGLT2 inhibitors on inflammation: a systematic review and meta-analysis of studies in rodents. Int Immunopharmacol 2022;111:109080.

85. D Wang, J Liu, L Zhong, S Li, L Zhou, Q Zhang, et al. The effect of sodium-glucose cotransporter 2 inhibitors on biomarkers of inflammation: a systematic review and meta-analysis of randomized controlled trials. Front Pharmacol 2022;13:1045235.

86. L Buttice, M Ghani, J Suthakar, S Gnanalingham, E Carande, BWC Kennedy, et al. The effect of sodium-glucose cotransporter-2 inhibitors on inflammatory biomarkers: a meta-analysis of randomized controlled trials. Diabetes Obes Metab 2024;26(7):2706–21.

87. B Zinman, C Wanner, JM Lachin, D Fitchett, E Bluhmki, S Hantel, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373(22):2117–28.

88. B Neal, V Perkovic, KW Mahaffey, D de Zeeuw, G Fulcher, N Erondu, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377(7):644–57.

89. SD Wiviott, I Raz, MP Bonaca, O Mosenzon, ET Kato, A Cahn, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380(4):347–57.

90. JJV McMurray, SD Solomon, SE Inzucchi, L Køber, MN Kosiborod, FA Martinez, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381(21):1995–2008.

91. M Packer, SD Anker, J Butler, G Filippatos, SJ Pocock, P Carson, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383(15):1413–24.

92. SD Anker, J Butler, G Filippatos, JP Ferreira, E Bocchi, M Böhm, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;385(16):1451–61.

93. SD Solomon, JJV McMurray, B Claggett, RA de Boer, D DeMets, AF Hernandez, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 2022;387(12):1089–98.

94. PA Heidenreich, B Bozkurt, D Aguilar, LA Allen, JJ Byun, MM Colvin, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. J Am Coll Cardiol 2022;79(17):e263–421.

95. G Bendotti, L Montefusco, ME Lunati, V Usuelli, I Pastore, E Lazzaroni, et al. The anti-inflammatory and immunological properties of GLP-1 receptor agonists. Pharmacol Res 2022;182:106320.

96. CK Wong, BA McLean, LL Baggio, JA Koehler, R Hammoud, N Rittig, et al. Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation. Cell Metab 2024;36(1):130–43.e5.

97. JJ Lepore, E Olson, L Demopoulos, T Haws, Z Fang, AM Barbour, et al. Effects of the novel long-acting GLP-1 agonist, albiglutide, on cardiac function, cardiac metabolism, and exercise capacity in patients with chronic heart failure and reduced ejection fraction. JACC Heart Fail 2016;4(7):559–66.

98. KB Margulies, AF Hernandez, MM Redfield, MM Givertz, GH Oliveira, R Cole, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. J Am Med Assoc 2016;316(5):500–8.

99. A Jorsal, C Kistorp, P Holmager, RS Tougaard, R Nielsen, A Hänselmann, et al. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)-a multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail 2017;19(1):69–77.

100. MN Kosiborod, S Verma, BA Borlaug, J Butler, MJ Davies, T Jon Jensen, et al. Effects of semaglutide on symptoms, function, and quality of life in patients with heart failure with preserved ejection fraction and obesity: a prespecified analysis of the STEP-HFpEF trial. Circulation 2024;149(3):204–16.

101. J Butler, SJ Shah, MC Petrie, BA Borlaug, SZ Abildstrøm, MJ Davies, et al. Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials. Lancet 2024;403(10437):1635–48.

102. MR Mehra, CJ Lavie, HO Ventura, RV Milani. Fish oils produce anti-inflammatory effects and improve body weight in severe heart failure. J Heart Lung Transplant 2006;25(7):834–8.

103. L Tavazzi, AP Maggioni, R Marchioli, S Barlera, MG Franzosi, R Latini, et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372(9645):1223–30.

104. S Ghio, L Scelsi, R Latini, S Masson, E Eleuteri, M Palvarini, et al. Effects of n-3 polyunsaturated fatty acids and of rosuvastatin on left ventricular function in chronic heart failure: a substudy of GISSI-HF trial. Eur J Heart Fail 2010;12(12):1345–53.

105. K Lechner, J Scherr, E Lorenz, B Lechner, B Haller, A Krannich, et al. Omega-3 fatty acid blood levels are inversely associated with cardiometabolic risk factors in HFpEF patients: the Aldo-DHF randomized controlled trial. Clin Res Cardiol 2022;111(3):308–21.

106. DL Bhatt, PG Steg, M Miller, EA Brinton, TA Jacobson, SB Ketchum, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380(1):11–22.

107. AA Kalstad, PL Myhre, K Laake, SH Tveit, EB Schmidt, P Smith, et al. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized, controlled trial. Circulation 2021;143(6):528–39.

108. SJ Nicholls, AM Lincoff, M Garcia, D Bash, CM Ballantyne, PJ Barter, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. J Am Med Assoc 2020;324(22):2268–80.

109. SU Khan, AN Lone, MS Khan, SS Virani, RS Blumenthal, K Nasir, et al. Effect of omega-3 fatty acids on cardiovascular outcomes: a systematic review and meta-analysis. EClinicalMedicine 2021;38:100997.

110. G Chen, ZM Qian, J Zhang, S Zhang, Z Zhang, MG Vaughn, et al. Regular use of fish oil supplements and course of cardiovascular diseases: prospective cohort study. BMJ Med 2024;3(1):e000451.

111. M Li, C Zheng, T Sato, T Kawada, M Sugimachi, K Sunagawa. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation 2004;109(1):120–4.

112. Y Zhang, ZB Popovic, S Bibevski, I Fakhry, DA Sica, DR Van Wagoner, et al. Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model. Circ Heart Fail 2009;2(6):692–9.

113. K Elkholey, M Niewiadomska, L Morris, S Whyte, J Houser, MB Humphrey, et al. Transcutaneous vagus nerve stimulation ameliorates the phenotype of heart failure with preserved ejection fraction through its anti-inflammatory effects. Circ Heart Fail 2022;15(8):e009288.

114. GM De Ferrari, HJGM Crijns, M Borggrefe, G Milasinovic, J Smid, M Zabel, et al. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J 2011;32(7):847–55.

115. RK Premchand, K Sharma, S Mittal, R Monteiro, S Dixit, I Libbus, et al. Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial. J Card Fail 2014;20(11):808–16.

116. BD Nearing, I Libbus, GM Carlson, B Amurthur, BH KenKnight, RL Verrier. Chronic vagus nerve stimulation is associated with multi-year improvement in intrinsic heart rate recovery and left ventricular ejection fraction in ANTHEM-HF. Clin Auton Res 2021;31(3):453–62.

117. F Zannad, GM De Ferrari, AE Tuinenburg, D Wright, J Brugada, C Butter, et al. Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR heart failure (NECTAR-HF) randomized controlled trial. Eur Heart J 2015;36(7):425–33.

118. MR Gold, DJ Van Veldhuisen, PJ Hauptman, M Borggrefe, SH Kubo, RA Lieberman, et al. Vagus nerve stimulation for the treatment of heart failure: the INOVATE-HF trial. J Am Coll Cardiol 2016;68(2):149–58.

119. IS Anand, MA Konstam, HU Klein, DL Mann, JL Ardell, DD Gregory, et al. Comparison of symptomatic and functional responses to vagus nerve stimulation in ANTHEM-HF, INOVATE-HF, and NECTAR-HF. ESC Heart Fail 2020;7(1):75–83.

120. TW Dasari, P Chakraborty, P Mukli, K Akhtar, A Yabluchanskiy, MW Cunningham, et al. Noninvasive low-level tragus stimulation attenuates inflammation and oxidative stress in acute heart failure. Clin Auton Res 2023;33(6):767–75.

121. N Tran, Z Asad, K Elkholey, BJ Scherlag, SS Po, S Stavrakis. Autonomic neuromodulation acutely ameliorates left ventricular strain in humans. J Cardiovasc Transl Res 2019;12(3):221–30.

122. S Stavrakis, K Elkholey, L Morris, M Niewiadomska, ZUA Asad, MB Humphrey. Neuromodulation of inflammation to treat heart failure with preserved ejection fraction: a pilot randomized clinical trial. J Am Heart Assoc 2022;11(3):e023582.

123. HU Kumar, BD Nearing, S Mittal, RK Premchand, I Libbus, LA DiCarlo, et al. Autonomic regulation therapy in chronic heart failure with preserved/mildly reduced ejection fraction: ANTHEM-HFpEF study results. Int J Cardiol 2023;381:37–44.

124. K Gong, Z Zhang, X Sun, X Zhang, A Li, J Yan, et al. The nonspecific anti-inflammatory therapy with methotrexate for patients with chronic heart failure. Am Heart J 2006;151(1):62–8.

125. DM Moreira, JL Vieira, CAM Gottschall. The effects of METhotrexate therapy on the physical capacity of patients with ISchemic heart failure: a randomized double-blind, placebo-controlled trial (METIS trial). J Card Fail 2009;15(10):828–34.

126. L Gullestad, T Ueland, JG Fjeld, E Holt, T Gundersen, K Breivik, et al. Effect of thalidomide on cardiac remodeling in chronic heart failure: results of a double-blind, placebo-controlled study. Circulation 2005;112(22):3408–14.

127. A Orea-Tejeda, O Arrieta-Rodríguez, L Castillo-Martínez, T Rodríguez-Reyna, E Asensio-Lafuente, J Granados-Arriola, et al. Effects of thalidomide treatment in heart failure patients. Cardiology 2007;108(4):237–42.

128. JM Hare, B Mangal, J Brown, C Fisher Jr, R Freudenberger, WS Colucci, et al. Impact of oxypurinol in patients with symptomatic heart failure: results of the OPT-CHF study. J Am Coll Cardiol 2008;51(24):2301–9.

129. MM Givertz, KJ Anstrom, MM Redfield, A Deswal, H Haddad, J Butler, et al. Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the xanthine oxidase inhibition for hyperuricemic heart failure patients (EXACT-HF) study. Circulation 2015;131(20):1763–71.

130. CSP Lam, LH Lund, SJ Shah, AA Voors, D Erlinge, A Saraste, et al. Myeloperoxidase inhibition in heart failure with preserved or mildly reduced ejection fraction: SATELLITE trial results. J Card Fail 2024;30(1):104–10.

131. LH Lund, CSP Lam, PE Pizzato, A Gabrielsen, E Michaëlsson, K Nelander, et al. Rationale and design of ENDEAVOR: a sequential phase 2b-3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction. Eur J Heart Fail 2023;25(9):1696–707.