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Inflammation in Heart Failure: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Ruxandra Florentina Ionescu.

Chronic heart failure is a terminal point of a vast majority of cardiac or extracardiac causes

affecting around 1–2% of the global population and more than 10% of the people above the age

of 65. Inflammation is persistently associated with chronic diseases, contributing in many cases to the

progression of disease. Even in a low inflammatory state, past studies raised the question of whether

inflammation is a constant condition, or if it is, rather, triggered in different amounts, according

to the phenotype of heart failure. By evaluating the results of clinical studies which focused on

the proinflammatory cytokines, this review aims to identify the ones that are independent risk factors

for heart failure decompensation or cardiovascular death. This review assessed the current evidence

concerning the inflammatorenoty activation cascade, but also future possible targets for inflammatory

responsee of modulation, which can further impact the course of heareart failure. 

  • heart failure
  • inflammation
  • proinflammatory cytokines
  • TNF-α
  • CRP
  • fibrinogen
  • IL-1
  • IL-6
  • iNOS
  • myeloperoxidase

1. TNF-α

TNF-α, a pivotal proinflammatory cytokine, is the most studied one in HF, since it can be produced by many types of cells: cardiomyocytes, macrophages, vascular cells and mast cells [34][1]. After binding to the cell membrane specific receptors (TNFR1 and TNFR2), TNF-α has a negative inotropic effect on cardiomyocytes, by reducing the cytosolic level of Ca2+ [35][2]. At the same time, TNF-α induces synthesis of other proinflammatory cytokines (inducible NO synthase, reactive oxygen species with mitochondrial DNA damage), apoptosis and extracellular matrix alteration and promotes interaction between endothelial cells and leukocytes at the site of microcirculation [34][1]. Also, high levels of TNF-α enhance protein synthesis and hypertrophy of cardiomyocytes by the production of reactive species of oxygen, which further decrease the contractility of the heart [36][3].
The sympathetic nervous system, one of the neurohormonal pathways which leads to cardiac remodelling, has its function impaired by TNF-α, resulting in β receptor dysfunction [37][4]. This triggers, in response, an excessive release of catecholamines, which produces a positive feedback increase in the levels of seric TNF-α, creating a perpetual cycle [38][5].
The proinflammatory TNF-α has significant interactions with the sympathetic system, its interaction with β receptors leading to a negative inotropic effect, both in vitro and in vivo [39,40][6][7].
In heart failure patients, the sympathetic overdrive and high levels of proinflammatory cytokines are in a vicious circle, representing, however, a hallmark of this disease [41,42][8][9].
Although this cytokine has been proven to take part in the inflammatory infiltrate of both HFrEF and HFpEF patients [43][10], efforts from clinical trials to inhibit it have been without evident success [17,44][11][12]. This can be explained by the fact that in other experimental studies, in ischemia-reperfusion injury scenarios, a small quantity of TNF-α had a protective cardiac effect, while only high levels of TNF-α had negative effect on cardiac function and remodelling [45,46][13][14].
The trials which tried to see the effect of the soluble receptor of TNF-α (etanercept) in chronic heart failure patients (RENEWAL and RECOVER), were stopped early in the process because of the negative results, in comparison to the placebo arm [17][11]. The same worsened prognosis was also observed in the case of the TNF-α monoclonal antibodies (infliximab) trial ATTACH [44][12]. There is a well-established direct relationship between the circulating levels of TNF-α and mortality in the patients which suffer from heart failure [41,47][8][15]. Since TNF-α is associated with a serious decrease in survival, it can be considered for risk assessment in HF patients with both HFpEF and HFrEF [47][15].

2. IL-1

IL-1 is one of the most important cytokines in the initiation of inflammation in HF [48][16]. The elevated levels of IL-1 are seen in patients with chronic HF, irrespective of etiology (ischemia, arterial hypertension, valvular disease, cardiomyopathy, arrhythmia) [49][17]. It represents a family with 11 members including IL-1α, IL-1β, IL-18 and IL-33 [50][18]. If IL-1α or IL-1β bind to the IL-1R1 (IL-1 type 1 receptor), this initiates the inflammatory process, while binding to IL-1R2 (IL-1 type 2 receptor) stops the triggering of the inflammatory response [51][19]. The synthesis of the active form of IL-1β is directly dependent on the caspase-1 enzyme, which is also at the expense of NLRP3 inflammasome (an intracellular sensor activated in the onset of danger-associated signals) [52,53][20][21]. NLRP3 gets activated in the cardiac fibroblasts and cardiomyocytes when there is a myocardial injury and this can also explain the proinflammatory response that appears post-myocardial infarction that further inflicts cardiac injury [54][22]. IL-1 also generates cardiac impairment and remodelling by reducing the capacity of the LTCC (Ca2+ channels type L) to respond to the sympathetic nervous system (β1 adrenergic) stimulus [48][16]. This cytokine, which can be produced by cardiomyocytes, immune cells, endothelial cells and fibroblasts, also reduces the expression of genes that promote calcium homeostasis and induces cardiomyocyte apoptosis, activation of endothelial cells and leukocytes, leading to cardiac fibrosis, micro arterial stiffness and inflammation [50][18]. One of the cytokines related to IL-1 is CRP, which is an independent predictor for cardiac decompensation in acute or chronic heart failure [55][23]. IL-1β can also disrupt mitochondrial energy production, which translates as dysfunctional myocardial inotropism [48,56][16][24].
This energetic “outage” produced by IL-1 is generated in part through an increase in nitric oxide synthase activity in the cardiac cells with a consequence of reduced myocardial contraction [57][25]. In the animal model trials, the mice that were injected with plasma rich in IL-1, from acute decompensated heart failure patients, had systolic and diastolic dysfunction with a decrease in contractile reserve [58][26]. However, the mice that were previously treated with the IL-1 human antagonist (anakinra) prior to plasma injection, were protected against cardiac impairment, leading to the conclusion that IL-1, and more specifically IL-1β, acts as a cardiodepressant agent [59][27]. The same antagonist of IL-1 was studied in the D-HART trial in a total of 12 chronic heart failure patients which were assigned to anakinra or placebo [48][16]. The primary endpoint of peak oxygen consumption was measured initially, at 14 and 28 days, showing a significant increase in peak oxygen consumption in patients receiving anakinra correlated with a statistically significant decrease in C-reactive protein seric levels [60][28].
It is known that IL-1 is a mediator in HF by diminishing cardiac contractility and promoting cardiomyocyte hypertrophy and apoptosis. However, there is also evidence that IL-1 is involved in atherothrombosis, by stimulating the development of atheromatous lesions, it promotes vascular inflammation and favours plaque vulnerability. In acute scenarios, after myocardial infarction, IL-1 is involved in the inflammatory response and adverse cardiac remodelling through amplifying matrix metalloproteinase expression [61][29].

3. IL-6

IL-6 is an important inflammation mediator, which can be regarded as a possible future biomarker for the development of HFpEF. In HF, oxidative stress is a strong inducer for the production of IL-6 [62][30]. Ischemia and hypoxia lead to IL-6 auto or paracrine binding to its receptor (receptor-coupled protein gp130), then following the JAK/STAT3 signalling pathway, leading to abnormal endothelium-dependent vasodilatation and muscular atrophy [63][31].
In HF, various cells can produce inflammatory mediators, such as IL-6, which can have several effects: systolic dysfunction, diastolic dysfunction, ventricular dilatation, cardiomyocyte hypertrophy, apoptosis [49][17] and lower coronary flow reserve [63][31]. IL-6 influences the inflammatory process, favouring ventricular remodelling, which is responsible for the debut, but also for the aggravation, of HF symptoms [64][32].
IL-6 has a multitude of effects on cardiac cells, some of which can lead to a myocardial phenotype very similar to that of the hypertensive heart (hypertrophy, fibrosis, diastolic dysfunction, further favouring HFpEF) [65,66][33][34].
The interest in anti-IL-6 drug development is increasing, since higher levels of IL-6 were statistically significantly associated with a higher risk of HFpEF development [67][35]. On the other hand, de Boer and colleagues indicated that IL-6 was associated with new-onset HF, IL-6 being evocative for HFrEF [68][36]. However, these differences between correlation with HFrEF and HFpEF may come from the dissimilarity between cohorts.
In the BIOSTAT-CHF cohort, HFpEF was an independent predictor of high IL-6 concentrations. In more than half of the patients involved, high IL-6 concentrations were associated with lower EF, iron deficiency and atrial fibrillation [69][37].
In patients with decompensated HFpEF, IL-6 was a predictor of all-cause mortality, cardiovascular mortality and HF hospitalization, according to Mooney et al. [70][38].
By downregulating SERCA2 gene expression, IL-6 and TNF-α can cause diastolic dysfunction by diminishing diastolic calcium reuptake, further leading to myocardial contractility impairment [71][39].
There is evidence that high concentrations of IL-6 can be found in patients with LV dysfunction, even when there is no clinical syndrome of HF. IL-6 may play a role in the evolution from asymptomatic LV dysfunction to symptomatic LV dysfunction, representing a promising biomarker for patients at risk of developing clinical HF, especially HFpEF [67][35].
IL-6 exerts negative effects on renal function by acting on the distal tubule (epithelial sodium channels), altering the process of natriuresis [72][40]. It is important to underline that another renal repercussion of IL-6 action can be diuretic resistance [73][41].
Hemodynamic worsening of the evolution of advanced HF patients was associated, according to Gabriele et al., with high levels of IL-6 and IL-6R mRNA [74][42].

4. IL-8

IL-8 (or CXCL8) can be produced mostly by macrophages and monocytes, but also by neutrophils, epithelial cells, fibroblasts, smooth muscle cells and endothelial cells, when triggers such as ischemia, hypoxia or shear stress are present [75][43].
IL-8 recruits, through chemotactic effect, monocytes and neutrophils, the main constituents of the acute inflammatory response. Besides recruitment, IL-8 also favours the activation of monocytes and neutrophils [76][44].
A special characteristic of IL-8 is its longevity, since it is produced in the first steps of the inflammatory response, but stays active for days, even weeks. It is resistant to temperature and proteolytic enzymes and relatively resistant to acidic environments, making it very useful in places of acute inflammation. IL-8 is very sensitive to oxidants, therefore antioxidants can significantly lower IL-8 gene expression [77][45].
IL-8 is involved in atherosclerosis. It can be found in high amounts in atherosclerotic lesion macrophages, in vascular injury sites and in fibrous plaques [76][44].
It was reported that angiotensin II increased IL-8 production, while fluvastatin diminished both basal and angiotensin II-induced IL-8 production in human vascular smooth muscle cells [78][46].
IL-8 is also involved in the pathogenesis of hypertension, being expressed in high concentrations in aortic tissue and vascular smooth muscle cells of hypertensive animal model [79][47].
Simonini et al. indicated that IL-8 is a significant mediator of angiogenesis in human coronary atherosclerosis, which may contribute to atherosclerotic plaque formation through its angiogenic properties [80][48].
A report of the potential role of IL-8 as a biomarker for chronic HF was highlighted in the results from the CORONA study, which evaluated patients aged over 60 years, with chronic HF of ischemic cause, with II-IV NYHA functional class and LVEF under 40%. The primary outcomes were a composite of CV mortality, non-fatal myocardial infarction and non-fatal stroke, and secondary outcomes were any coronary event, sudden cardiac death, ventricular defibrillation by implantable cardioverter-defibrillator, resuscitation after cardiac arrest, hospitalization for unstable angina pectoris, all-cause mortality, CV mortality and a composite endpoint of worsening HF hospitalization or CV mortality [81][49].
There was a statistical association between IL-8 and outcomes. However, IL-8 added information independent of hsCRP, which further underlines that they may represent different inflammatory pathways in chronic HF. NTproBNP and IL-8 were significantly associated with both cardiac and non-cardiac deaths. IL-8 was a consistently independent and significant predictor of outcomes after statistical adjustment for NTproBNP [81][49].
IL-8 is found in high concentrations in CHF and is associated with adverse outcomes [81[49][50],82], and it is a predictor of the development of HF in patients with myocardial infarction and percutaneous intervention [83][51].

5. IL-10

IL-10 is a major anti-inflammatory cytokine. Inflammation has essential roles in the development of cardiac hypertrophy and evolution to HF. IL-10 can be expressed in the cardiac tissue and may have an essential role in cardiac remodelling. For this reason, signalling modulated by IL-10 could become a promising target for controlling pathological cardiac hypertrophy [84][52].
Supporting the impact of IL-10 on cardiac remodelling is the work of Jung M. et al., which concludes that in vivo infusion of IL-10 after MI can improve the LV microenvironment, decrease inflammation and favour cardiac wound healing by stimulating M2 macrophage polarization and fibroblast activation [85][53].
Verma and colleagues showed that IL-10 treatment could be a potential therapeutic target in limiting the evolution of cardiac remodelling induced by pressure overload [86][54].
IL-10 can suppress inflammation, improve LV function and attenuate LV remodelling after MI by reducing fibrosis through inhibition of HuR (cytokine mRNA stabilizing protein) and activation of signal transducer and activator of transcription 3 (STAT-3), by increasing capillary density [87][55].
The antiatherosclerotic effect of IL-10 was intensely discussed. IL-10 can have effects on macrophages and T cells, modulating several cellular processes, which may interfere with the formation, evolution and stability of the atherosclerotic plaque. IL-10 was associated with low signs of inflammation, but was also a protective factor against environmental pathogens which can promote atherosclerosis in animal subjects [88][56].
In the case of ischemia-reperfusion injury, TNF-α is increased, which further initiates and sustains inflammation as well as cardiac injury. IL-10, being an anti-inflammatory cytokine, inhibits signalling pathways which participate in the pathogenesis of HF controlled by TNF-α [89][57].
Diminished seric concentrations of IL-10 were identified in patients with advanced CHF [90][58].
In special populations, such as patients suffering from chronic kidney disease (CKD), IL-10 was observed to increase along with the reduction of kidney function. Elevated IL-10 concentrations were associated with the risk of CV events [91][59].
Barcelos and colleagues evaluated the association between IL-10 and coronary artery disease in patients suffering from metabolic syndrome. In this category of patients, high IL-10 concentrations were associated with a lower incidence of severe coronary artery disease. This suggests a protective effect given by the anti-inflammatory activity even when there are significantly high concentrations of proinflammatory cytokines [92][60].
IL-10 proved to be cardioprotective in diabetic MI through the upregulation of heme clearance pathways. IL-10 lowered the myocardial infarct size and improved cardiac function in diabetic animal subjects, improved capillary density and lowered apoptosis rate and inflammation in the marginal zone of the infarct [93][61].

6. IL-18

IL-18, also named interferon gamma (IFN-γ) inducing factor, is a proinflammatory cytokine, belonging to the IL-1 cytokine superfamily. It has effects on immunity and the infectious and inflammatory response of the host, due to the production of IFN-γ. However, it also possesses other effects, independent of IFN-γ. IL-18 can be produced, as a response to injury, by infiltrated neutrophils, macrophages, endothelial cells, smooth muscle cells and cardiomyocytes. It is produced in an inactive form (pro-IL-18), being converted into the active form by caspase 1 (IL-1beta converting enzyme) [94][62].
High concentrations of IL-18 have been detected in myocardial tissue and circulation after MI and in sepsis [94][62].
IL-18, being a proinflammatory cytokine, is also involved in atherosclerosis. Jia et al. concluded that both IL-6 and IL-18 were associated with global CV disease and death [95][63].
Plausible molecular mechanisms regarding IL-18-induced myocardial injury can be represented by the promotion of inflammation, enhanced apoptosis, hypertrophic effect on cardiomyocytes, effects on mitogen activated protein kinase activation and alterations of the intracellular calcium transport and concentrations [94][62].
In patients with congestive HF, a high secretion of IL-18 is induced and is correlated with the severity of myocardial damage and dysfunction, according to Seta et al. [96][64].
O’Brien and colleagues evaluated IL-18 as a potential therapeutic target in acute MI and HF. In animal subjects, it is known that IL-18 influences cardiomyocyte hypertrophy and favours contractile dysfunction and extracellular matrix remodelling in cases of acute MI or pressure overload. In human subjects, elevated IL-18 levels were correlated with a higher risk of appearance and progression of HF and with a worse prognosis in patients with already established CVD [97][65].
Inhibition of IL-18 alters not only the pathological, but also the physiological hypertrophy response in cases of high pressure, which can result in improper remodelling [96][64].
Genetic deletion or neutralization in animal subjects of IL-18 lowered the rate of myocardial hypertrophy in cases of pressure overload [97,98][65][66].
IL-18 displays effects on both systolic and diastolic functions of the heart. The rapid negative inotropic effect of IL-18 implies that blocking IL-18 may represent an important treatment for acute decompensated HF or chronic, symptomatic HF [97,99][65][67].
Inflammatory cytokines are involved in the progression of HFpEF, considering that in this phenotype significant fibrosis and hypertrophy can be found [60][28]. IL-18 could be a possible treatment target for HFpEF since it has pro-hypertrophic and profibrotic effects [97,100,101][65][68][69].
There is evidence suggesting that plasma IL-18 concentrations are associated with coronary events [102,103][70][71].

7. Fibrinogen

Fibrinogen, a major acute phase protein, is widely recognized as a strong contributor to cardiovascular risk, high concentrations being associated with coronary heart disease, incident stroke, development of peripheral artery disease and total mortality. In inflammation, the abundance of cytokines elevates plasmatic concentrations of fibrinogen. Fibrinogen has several roles, such as influencing endothelial function, favouring smooth muscle cell proliferation and migration, modulating the interaction between plasmin and the corresponding receptor, creating the substrate for thrombin, constituting the final step in the coagulation process and being involved in platelet aggregation [104,105][72][73]. In over 2000 subjects from the Framingham Offspring Population (cycle 5), fibrinogen was associated with traditional cardiovascular risk factors, levels of fibrinogen being higher among individuals with known cardiovascular disease, compared to those without cardiac afflictions [106][74].

8. C-Reactive Protein

Continuous, but low-grade inflammation is present in the context of HF. One can aim to discuss the role of CRP, as an inflammatory marker, in the pathogenesis and development of HF. CRP has several roles in the mechanism of atherogenesis, such as increasing LDL uptake and oxidation, inhibition of NO production, upregulation of the expression of adhesion molecules, inhibition of fibrinolysis (by amplifying the expression of PAI-1), inducing complement activation and favouring monocyte infiltration into the vascular wall [109][75]. In patients with acute coronary syndromes, high CRP levels at admission are associated with poorer short- and long-term prognosis. CRP value on admission shows the baseline inflammatory status of the subject, elevated CRP concentrations in patients with acute coronary syndromes being linked to more cardiovascular complications during follow-up [109][75]. The more elevated the CRP levels, the greater the chances for severe acute coronary syndrome, ventricular remodelling, lower EF, cardiac rupture, HF and cardiac death. It is interesting to note that in STEMI patients, peak CRP levels were higher when compared to NSTEMI patients, drawing attention to the possible role of CRP in risk stratification after myocardial infarction [110][76].

9. iNOS (Inducible Nitric Oxide Synthase)

Nitric oxide (NO) is a diffusible free radical gas with a very short half-life. It is synthesized from l-arginine through the catalytic reaction of nitric oxide synthases (the neuronal type 1 isoform—nNOS or NOS1; the inducible type 2 isoform—iNOS or NOS2; and the endothelial, type 3 isoform—eNOS or NOS3). The activity of nNOS and eNOS is triggered, therefore it is transient. On the other hand, iNOS activity is sustained, as it does not depend on stimulating agonists and calcium [124][77]. nNOS is found in nerve endings (neurotransmission of norepinephrine) and eNOS in endothelial cells, endocardial cells and cardiomyocytes [124][77]. The effects of NO in the human heart include the inhibition of the positive inotropic effect as a result of beta-adrenergic stimulation in cases of LV dysfunction or severe HF [125,126][78][79]. The inducible nitric oxide synthase (iNOS or NOS2) is normally expressed in low concentrations in myocardial tissue. In specific cases, such as inflammation or ischemia, significant amounts of NO are generated, after the activation of iNOS [127][80].

10. Myeloperoxidase (MPO)

Myeloperoxidase (MPO) is a leukocyte-derived enzyme, a heme peroxidase, mainly expressed by neutrophils, which belongs to the innate immune response. MPO-derived oxidants are responsible for tissue destruction in inflammatory scenarios [140,141][81][82]. MPO has the ability to generate reactive species, with important roles in the innate host immunity and therefore antimicrobial activity. High circulatory levels of MPO are associated with inflammation, increased oxidative stress, poor prognosis and high risk of CVD-related mortality [140][81]. MPO can be regarded as an important target for cardiovascular protection. Circulating MPO can be regarded as an indicator of high risk in patients with acute coronary syndromes, atherosclerosis, heart failure, hypertension or stroke [140][81]. The role of MPO in atherosclerosis can be suggested by the MPO catalysed reactions, with pro-atherogenic effects, transforming MPO and its inflammatory pathways into potential therapeutic targets for the prophylaxis of atherosclerosis [141][82]. In chronic HF patients, MPO plasmatic levels were a predictor of adverse clinical outcomes, being also associated with the severity of HF, according to Tang et al. [142][83].

References

  1. Urschel, K.; Cicha, I. TNF-α in the Cardiovascular System: From Physiology to Therapy. Int. J. Interferon Cytokine Mediat. Res. 2015, 7, 9–25.
  2. Bartekova, M.; Radosinska, J.; Jelemensky, M.; Dhalla, N.S. Role of Cytokines and Inflammation in Heart Function during Health and Disease. Heart Fail. Rev. 2018, 23, 733–758.
  3. Higuchi, Y.; Otsu, K.; Nishida, K.; Hirotani, S.; Nakayama, H.; Yamaguchi, O.; Matsumura, Y.; Ueno, H.; Tada, M.; Hori, M. Involvement of Reactive Oxygen Species-Mediated NF-Kappa B Activation in TNF-Alpha-Induced Cardiomyocyte Hypertrophy. J. Mol. Cell Cardiol. 2002, 34, 233–240.
  4. Prabhu, S.D.; Frangogiannis, N.G. The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis. Circ. Res. 2016, 119, 91–112.
  5. Hotamisligil, G.S. The Role of TNFalpha and TNF Receptors in Obesity and Insulin Resistance. J. Intern. Med. 1999, 245, 621–625.
  6. Gulick, T.; Chung, M.K.; Pieper, S.J.; Lange, L.G.; Schreiner, G.F. Interleukin 1 and Tumor Necrosis Factor Inhibit Cardiac Myocyte Beta-Adrenergic Responsiveness. Proc. Natl. Acad. Sci. USA 1989, 86, 6753–6757.
  7. Müller-Werdan, U.; Schumann, H.; Fuchs, R.; Reithmann, C.; Loppnow, H.; Koch, S.; Zimny-Arndt, U.; He, C.; Darmer, D.; Jungblut, P.; et al. Tumor Necrosis Factor Alpha (TNF Alpha) Is Cardiodepressant in Pathophysiologically Relevant Concentrations without Inducing Inducible Nitric Oxide-(NO)-Synthase (INOS) or Triggering Serious Cytotoxicity. J. Mol. Cell Cardiol. 1997, 29, 2915–2923.
  8. Mann, D.L. Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future. Circ. Res. 2002, 91, 988–998.
  9. Schumacher, S.M.; Naga Prasad, S.V. Tumor Necrosis Factor-α in Heart Failure: An Updated Review. Curr. Cardiol. Rep. 2018, 20, 117.
  10. Pugliese, N.R.; Fabiani, I.; Conte, L.; Nesti, L.; Masi, S.; Natali, A.; Colombo, P.C.; Pedrinelli, R.; DIni, F.L. Persistent Congestion, Renal Dysfunction and Inflammatory Cytokines in Acute Heart Failure: A Prognosis Study. J. Cardiovasc. Med. (Hagerstown) 2020, 21, 494–502.
  11. Mann, D.L.; McMurray, J.J.V.; Packer, M.; Swedberg, K.; Borer, J.S.; Colucci, W.S.; Djian, J.; Drexler, H.; Feldman, A.; Kober, L.; et al. Targeted Anticytokine Therapy in Patients with Chronic Heart Failure: Results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004, 109, 1594–1602.
  12. Chung, E.S.; Packer, M.; Lo, K.H.; Fasanmade, A.A.; Willerson, J.T. 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, 3133–3140.
  13. Rathi, S.S.; Xu, Y.J.; Dhalla, N.S. Mechanism of Cardioprotective Action of TNF-α in the Isolated Rat Heart. Exp. Clin. Cardiol. 2002, 7, 146.
  14. Saini MPharm, H.K.; Xu, Y.-J.; Zhang, M.; Liu, P.P.; Kirshenbaum, L.A.; Dhalla DSc, N.S.; Dhalla, N.S.; Saini, H.; Xu, Y.; Zhang, M.; et al. Role of Tumour Necrosis Factor-Alpha and Other Cytokines in Ischemia-Reperfusion-Induced Injury in the Heart. Exp. Clin. Cardiol. 2005, 10, 213.
  15. Dunlay, S.M.; Weston, S.A.; Redfield, M.M.; Killian, J.M.; Roger, V.L. Tumor Necrosis Factor-Alpha and Mortality in Heart Failure: A Community Study. Circulation 2008, 118, 625–631.
  16. Szekely, Y.; Arbel, Y. A Review of Interleukin-1 in Heart Disease: Where Do We Stand Today? Cardiol. Ther. 2018, 7, 25–44.
  17. Yndestad, A.; Damås, J.K.; Øie, E.; Ueland, T.; Gullestad, L.; Aukrust, P. Systemic Inflammation in Heart Failure--the Whys and Wherefores. Heart Fail. Rev. 2006, 11, 83–92.
  18. Hanna, A.; Frangogiannis, N.G. Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure. Cardiovasc. Drugs Ther. 2020, 34, 849–863.
  19. Kaneko, N.; Kurata, M.; Yamamoto, T.; Morikawa, S.; Masumoto, J. The Role of Interleukin-1 in General Pathology. Inflamm. Regen. 2019, 39, 12.
  20. Frangogiannis, N. Interleukin-1 in Cardiac Injury, Repair, and Remodeling: Pathophysiologic and Translational Concepts. Discoveries (Craiova) 2015, 3, e41.
  21. Abbate, A.; Toldo, S.; Marchetti, C.; Kron, J.; Van Tassell, B.W.; Dinarello, C.A. Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease. Circ. Res. 2020, 126, 1260–1280.
  22. Segiet, O.A.; Piecuch, A.; Mielańczyk, Ł.; Michalski, M.; Nowalany-Kozielska, E. Role of Interleukins in Heart Failure with Reduced Ejection Fraction. Anatol. J. Cardiol. 2019, 22, 287–299.
  23. Braunwald, E. Biomarkers in Heart Failure. N. Engl. J. Med. 2008, 358, 2148–2159.
  24. Zell, R.; Geck, P.; Werdan, K.; Boekstegers, P. TNF-Alpha and IL-1 Alpha Inhibit Both Pyruvate Dehydrogenase Activity and Mitochondrial Function in Cardiomyocytes: Evidence for Primary Impairment of Mitochondrial Function. Mol. Cell Biochem. 1997, 177, 61–67.
  25. Tatsumi, T.; Matoba, S.; Kawahara, A.; Keira, N.; Shiraishi, J.; Akashi, K.; Kobara, M.; Tanaka, T.; Katamura, M.; Nakagawa, C.; et al. Cytokine-Induced Nitric Oxide Production Inhibits Mitochondrial Energy Production and Impairs Contractile Function in Rat Cardiac Myocytes. J. Am. Coll. Cardiol. 2000, 35, 1338–1346.
  26. van Tassell, B.W.; Arena, R.A.; Toldo, S.; Mezzaroma, E.; Azam, T.; Seropian, I.M.; Shah, K.; Canada, J.; Voelkel, N.F.; Dinarello, C.A.; et al. Enhanced Interleukin-1 Activity Contributes to Exercise Intolerance in Patients with Systolic Heart Failure. PLoS ONE 2012, 7.
  27. Kumar, A.; Thota, V.; Dee, L.; Olson, J.; Uretz, E.; Parrillo, J.E. Tumor Necrosis Factor Alpha and Interleukin 1beta Are Responsible for in Vitro Myocardial Cell Depression Induced by Human Septic Shock Serum. J. Exp. Med. 1996, 183, 949–958.
  28. Van Tassell, B.W.; Arena, R.; Biondi-Zoccai, G.; McNair Canada, J.; Oddi, C.; Abouzaki, N.A.; Jahangiri, A.; Falcao, R.A.; Kontos, M.C.; Shah, K.B.; 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, 321–327.
  29. Bujak, M.; Frangogiannis, N.G. The Role of IL-1 in the Pathogenesis of Heart Disease. Arch. Immunol. Ther. Exp. (Warsz) 2009, 57, 165–176.
  30. Ozova, E.; Kiiakbaev, G.K.; Kobalava, Z. . Kardiologiia 2007, 47, 52–64.
  31. Su, J.H.; Luo, M.Y.; Liang, N.; Gong, S.X.; Chen, W.; Huang, W.Q.; Tian, Y.; Wang, A.P. Interleukin-6: A Novel Target for Cardio-Cerebrovascular Diseases. Front. Pharmacol. 2021, 12, 745061.
  32. Huang, M.; Yang, D.; Xiang, M.; Wang, J. Role of Interleukin-6 in Regulation of Immune Responses to Remodeling after Myocardial Infarction. Heart Fail. Rev. 2015, 20, 25–38.
  33. Meléndez, G.C.; McLarty, J.L.; Levick, S.P.; Du, Y.; Janicki, J.S.; Brower, G.L. Interleukin 6 Mediates Myocardial Fibrosis, Concentric Hypertrophy, and Diastolic Dysfunction in Rats. Hypertension 2010, 56, 225–231.
  34. Hirota, H.; Yoshida, K.; Kishimoto, T.; Taga, T. Continuous Activation of Gp130, a Signal-Transducing Receptor Component for Interleukin 6-Related Cytokines, Causes Myocardial Hypertrophy in Mice. Proc. Natl. Acad. Sci. USA 1995, 92, 4862–4866.
  35. Chia, Y.C.; Kieneker, L.M.; van Hassel, G.; Binnenmars, S.H.; Nolte, I.M.; van Zanden, J.J.; van der Meer, P.; Navis, G.; Voors, A.A.; Bakker, S.J.L.; et al. Interleukin 6 and Development of Heart Failure with Preserved Ejection Fraction in the General Population. J. Am. Heart Assoc. 2021, 10, 18549.
  36. De Boer, R.A.; Nayor, M.; DeFilippi, C.R.; Enserro, D.; Bhambhani, V.; Kizer, J.R.; Blaha, M.J.; Brouwers, F.P.; Cushman, M.; Lima, J.A.C.; et al. Association of Cardiovascular Biomarkers With Incident Heart Failure With Preserved and Reduced Ejection Fraction. JAMA Cardiol. 2018, 3, 215–224.
  37. Markousis-Mavrogenis, G.; Tromp, J.; Ouwerkerk, W.; Devalaraja, M.; Anker, S.D.; Cleland, J.G.; Dickstein, K.; Filippatos, G.S.; van der Harst, P.; Lang, C.C.; et al. The Clinical Significance of Interleukin-6 in Heart Failure: Results from the BIOSTAT-CHF Study. Eur. J. Heart Fail. 2019, 21, 965–973.
  38. Mooney, L.; Jackson, C.E.; Adamson, C.; McConnachie, A.; Welsh, P.; Myles, R.C.; McMurray, J.J.V.; Jhund, P.S.; Petrie, M.C.; Lang, N.N. Adverse Outcomes Associated with Interleukin-6 in Patients Recently Hospitalized for Heart Failure with Preserved Ejection Fraction. Circ. Heart Fail. 2023, 16, E010051.
  39. Wu, C.K.; Lee, J.K.; Chiang, F.T.; Yang, C.H.; Huang, S.W.; Hwang, J.J.; Lin, J.L.; Tseng, C.D.; Chen, J.J.; Tsai, C.T. Plasma Levels of Tumor Necrosis Factor-α and Interleukin-6 Are Associated with Diastolic Heart Failure through Downregulation of Sarcoplasmic Reticulum Ca2+ ATPase. Crit. Care Med. 2011, 39, 984–992.
  40. Li, Y.Y.; Feng, Y.Q.; Kadokami, T.; McTiernan, C.F.; Draviam, R.; Watkins, S.C.; Feldman, A.M. Myocardial Extracellular Matrix Remodeling in Transgenic Mice Overexpressing Tumor Necrosis Factor Alpha Can Be Modulated by Anti-Tumor Necrosis Factor Alpha Therapy. Proc. Natl. Acad. Sci. USA 2000, 97, 12746–12751.
  41. Koprululu Kucuk, G.; Guney, A.I.; Sunbul, M.; Guctekin, T.; Koç, G.; Kirac, D. Il-6 and UGT1A1 Variations May Related to Furosemide Resistance in Heart Failure Patients. IUBMB Life 2023, 75, 830–843.
  42. Gabriele, P.; Zhi Fang, S.; Tonny D.T., T.; Carsten, K.; Hideo A., B.; Michael, E.; Markus, F.; Thomas, W.; Hans H., S.; Mario C., D. Activation of the Cardiac Interleukin-6 System in Advanced Heart Failure. Eur. J. Heart Fail. 2001, 3, 415–421.
  43. Reina-Couto, M.; Pereira-Terra, P.; Quelhas-Santos, J.; Silva-Pereira, C.; Albino-Teixeira, A.; Sousa, T. Inflammation in Human Heart Failure: Major Mediators and Therapeutic Targets. Front. Physiol. 2021, 12, 746494.
  44. Apostolakis, S.; Vogiatzi, K.; Amanatidou, V.; Spandidos, D.A. Interleukin 8 and Cardiovascular Disease. Cardiovasc. Res. 2009, 84, 353–360.
  45. DeForge, L.E.; Fantone, J.C.; Kenney, J.S.; Remick, D.G. Oxygen Radical Scavengers Selectively Inhibit Interleukin 8 Production in Human Whole Blood. J. Clin. Invest. 1992, 90, 2123–2129.
  46. Ito, T.; Ikeda, U.; Yamamoto, K.; Shimada, K. Regulation of Interleukin-8 Expression by HMG-CoA Reductase Inhibitors in Human Vascular Smooth Muscle Cells. Atherosclerosis 2002, 165, 51–55.
  47. Kim, H.Y.; Kang, Y.J.; Song, I.H.; Choi, H.C.; Kim, H.S. Upregulation of Interleukin-8/CXCL8 in Vascular Smooth Muscle Cells from Spontaneously Hypertensive Rats. Hypertens. Res. 2008, 31, 515–523.
  48. Simonini, A.; Moscucci, M.; Muller, D.W.M.; Bates, E.R.; Pagani, F.D.; Burdick, M.D.; Strieter, R.M. IL-8 Is an Angiogenic Factor in Human Coronary Atherectomy Tissue. Circulation 2000, 101, 1519–1526.
  49. Nymo, S.H.; Hulthe, J.; Ueland, T.; McMurray, J.; Wikstrand, J.; Askevold, E.T.; Yndestad, A.; Gullestad, L.; Aukrust, P. Inflammatory Cytokines in Chronic Heart Failure: Interleukin-8 Is Associated with Adverse Outcome. Results from CORONA. Eur. J. Heart Fail. 2014, 16, 68–75.
  50. Damås, J.K.; Gullestad, L.; Ueland, T.; Solum, N.O.; Simonsen, S.; Frøland, S.S.; Aukrust, P. CXC-Chemokines, a New Group of Cytokines in Congestive Heart Failure--Possible Role of Platelets and Monocytes. Cardiovasc. Res. 2000, 45, 428–436.
  51. Dominguez-Rodriguez, A.; Abreu-Gonzalez, P.; Garcia-Gonzalez, M.; Ferrer, J. Prognostic Value of Interleukin-8 as a Predictor of Heart Failure in Patients with Myocardial Infarction and Percutaneous Intervention. Int. J. Cardiol. 2006, 111, 158–160.
  52. Stafford, N.; Assrafally, F.; Prehar, S.; Zi, M.; De Morais, A.M.; Maqsood, A.; Cartwright, E.J.; Mueller, W.; Oceandy, D. Signaling via the Interleukin-10 Receptor Attenuates Cardiac Hypertrophy in Mice During Pressure Overload, but Not Isoproterenol Infusion. Front. Pharmacol. 2020, 11, 559220.
  53. Jung, M.; Ma, Y.; Iyer, R.P.; DeLeon-Pennell, K.Y.; Yabluchanskiy, A.; Garrett, M.R.; Lindsey, M.L. IL-10 Improves Cardiac Remodeling after Myocardial Infarction by Stimulating M2 Macrophage Polarization and Fibroblast Activation. Basic. Res. Cardiol. 2017, 112, 33.
  54. Verma, S.K.; Krishnamurthy, P.; Barefield, D.; Singh, N.; Gupta, R.; Lambers, E.; Thal, M.; MacKie, A.; Hoxha, E.; Ramirez, V.; et al. Interleukin-10 Treatment Attenuates Pressure Overload-Induced Hypertrophic Remodeling and Improves Heart Function via Signal Transducers and Activators of Transcription 3-Dependent Inhibition of Nuclear Factor-ΚB. Circulation 2012, 126, 418–429.
  55. Krishnamurthy, P.; Rajasingh, J.; Lambers, E.; Qin, G.; Losordo, D.W.; Kishore, R. IL-10 Inhibits Inflammation and Attenuates Left Ventricular Remodeling after Myocardial Infarction via Activation of STAT-3 and Suppression of HuR. Circ. Res. 2009, 104, e9.
  56. Mallat, Z.; Besnard, S.; Duriez, M.; Deleuze, V.; Emmanuel, F.; Bureau, M.F.; Soubrier, F.; Esposito, B.; Duez, H.; Fievet, C.; et al. Protective Role of Interleukin-10 in Atherosclerosis. Circ. Res. 1999, 85.
  57. Bagchi, A.K.; Malik, A.; Akolkar, G.; Belló-Klein, A.; Khaper, N.; Singal, P.K. IL-10: A Key Molecule in the Mitigation of Heart Failure. In Biomedical Translational Research: From Disease Diagnosis to Treatment; Springer Nature Singapore: Singapore, 2022; pp. 257–271.
  58. Stumpf, C.; Lehner, C.; Yilmaz, A.; Daniel, W.G.; Garlichs, C.D. Decrease of Serum Levels of the Anti-Inflammatory Cytokine Interleukin-10 in Patients with Advanced Chronic Heart Failure. Clin. Sci. (Lond.) 2003, 105, 45–50.
  59. Yilmaz, M.I.; Solak, Y.; Saglam, M.; Cayci, T.; Acikel, C.; Unal, H.U.; Eyileten, T.; Oguz, Y.; Sari, S.; Carrero, J.J.; et al. The Relationship between IL-10 Levels and Cardiovascular Events in Patients with CKD. Clin. J. Am. Soc. Nephrol. 2014, 9, 1207–1216.
  60. Barcelos, A.L.V.; de Oliveira, E.A.; Haute, G.V.; Costa, B.P.; Pedrazza, L.; Donadio, M.V.F.; de Oliveira, J.R.; Bodanese, L.C. Association of IL-10 to Coronary Disease Severity in Patients with Metabolic Syndrome. Clin. Chim. Acta 2019, 495, 394–398.
  61. Gupta, R.; Liu, L.; Zhang, X.; Fan, X.; Krishnamurthy, P.; Verma, S.; Tongers, J.; Misener, S.; Ashcherkin, N.; Sun, H.; et al. IL-10 Provides Cardioprotection in Diabetic Myocardial Infarction via Upregulation of Heme Clearance Pathways. JCI Insight 2020, 5.
  62. Wang, M.; Markel, T.A.; Meldrum, D.R. Interleukin 18 in the Heart. Shock. 2008, 30, 3–10.
  63. Jia, X.; Buckley, L.; Sun, C.; Al Rifai, M.; Yu, B.; Nambi, V.; Virani, S.S.; Selvin, E.; Matsushita, K.; Hoogeveen, R.C.; et al. Association of Interleukin-6 and Interleukin-18 with Cardiovascular Disease in Older Adults: Atherosclerosis Risk in Communities Study. Eur. J. Prev. Cardiol. 2023, zwad197.
  64. Seta, Y.; Kanda, T.; Tanaka, T.; Arai, M.; Sekiguchi, K.; Yokoyama, T.; Kurimoto, M.; Tamura, J.; Kurabayashi, M. Interleukin 18 in Acute Myocardial Infarction. Heart 2000, 84, 668.
  65. O’Brien, L.C.; Mezzaroma, E.; Van Tassell, B.W.; Marchetti, C.; Carbone, S.; Abbate, A.; Toldo, S. Interleukin-18 as a Therapeutic Target in Acute Myocardial Infarction and Heart Failure. Mol. Med. 2014, 20, 221–229.
  66. Colston, J.T.; Boylston, W.H.; Feldman, M.D.; Jenkinson, C.P.; de la Rosa, S.D.; Barton, A.; Trevino, R.J.; Freeman, G.L.; Chandrasekar, B. Interleukin-18 Knockout Mice Display Maladaptive Cardiac Hypertrophy in Response to Pressure Overload. Biochem. Biophys. Res. Commun. 2007, 354, 552–558.
  67. Mallat, Z.; Heymes, C.; Corbaz, A.; Logeart, D.; Alouani, S.; Cohen-Solal, A.; Seidler, T.; Hasenfuss, G.; Chvatchko, Y.; Shah, A.M.; et al. Evidence for Altered Interleukin 18 (IL)-18 Pathway in Human Heart Failure. FASEB J. 2004, 18, 1752–1754.
  68. Chandrasekar, B.; Mummidi, S.; Claycomb, W.C.; Mestril, R.; Nemer, M. Interleukin-18 Is a pro-Hypertrophic Cytokine That Acts through a Phosphatidylinositol 3-Kinase-Phosphoinositide-Dependent Kinase-1-Akt-GATA4 Signaling Pathway in Cardiomyocytes. J. Biol. Chem. 2005, 280, 4553–4567.
  69. Fix, C.; Bingham, K.; Carver, W. Effects of Interleukin-18 on Cardiac Fibroblast Function and Gene Expression. Cytokine 2011, 53, 19–28.
  70. Blankenberg, S.; Luc, G.; Ducimetière, P.; Arveiler, D.; Ferrières, J.; Amouyel, P.; Evans, A.; Cambien, F.; Tiret, L. Interleukin-18 and the Risk of Coronary Heart Disease in European Men: The Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation 2003, 108, 2453–2459.
  71. Kaptoge, S.; Seshasai, S.R.K.; Gao, P.; Freitag, D.F.; Butterworth, A.S.; Borglykke, A.; Di Angelantonio, E.; Gudnason, V.; Rumley, A.; Lowe, G.D.O.; et al. Inflammatory Cytokines and Risk of Coronary Heart Disease: New Prospective Study and Updated Meta-Analysis. Eur. Heart J. 2014, 35.
  72. Fibrin(Ogen) in Cardiovascular Disease: An Update. Available online: https://pubmed.ncbi.nlm.nih.gov/12669113/ (accessed on 5 November 2023).
  73. Kannel, W.B.; Bell, J. Influence of Fibrinogen on Cardiovascular Disease. Drugs 1997, 54 Suppl. 3, 32–40.
  74. Stec, J.J.; Silbershatz, H.; Tofler, G.H.; Matheney, T.H.; Sutherland, P.; Lipinska, I.; Massaro, J.M.; Wilson, P.F.W.; Muller, J.E.; D’Agostino, R.B. Association of Fibrinogen with Cardiovascular Risk Factors and Cardiovascular Disease in the Framingham Offspring Population. Circulation 2000, 102, 1634–1638.
  75. Shrivastava, A.K.; Singh, H.V.; Raizada, A.; Singh, S.K. C-Reactive Protein, Inflammation and Coronary Heart Disease. Egypt. Heart J. 2015, 67, 89–97.
  76. Habib, S.S.; Kurdi, M.I.; Al Aseri, Z.; Suriya, M.O. CRP Levels Are Higher in Patients with ST Elevation than Non-ST Elevation Acute Coronary Syndrome. Arq. Bras. Cardiol. 2011, 96, 13–17.
  77. Drexler, H. Nitric Oxide Synthases in the Failing Human Heart. Circulation 1999, 99, 2972–2975.
  78. Hare, J.M.; Givertz, M.M.; Creager, M.A.; Colucci, W.S. Increased Sensitivity to Nitric Oxide Synthase Inhibition in Patients with Heart Failure: Potentiation of Beta-Adrenergic Inotropic Responsiveness. Circulation 1998, 97, 161–166.
  79. Drexler, H.; Kästner, S.; Strobel, A.; Studer, R.; Brodde, O.E.; Hasenfuß, G. Expression, Activity and Functional Significance of Inducible Nitric Oxide Synthase in the Failing Human Heart. J. Am. Coll. Cardiol. 1998, 32, 955–963.
  80. Pérez-Torres, I.; Manzano-Pech, L.; Rubio-Ruíz, M.E.; Soto, M.E.; Guarner-Lans, V. Nitrosative Stress and Its Association with Cardiometabolic Disorders. Molecules 2020, 25.
  81. Ramachandra, C.J.A.; Ja, K.P.M.M.; Chua, J.; Cong, S.; Shim, W.; Hausenloy, D.J. Myeloperoxidase As a Multifaceted Target for Cardiovascular Protection. Antioxid. Redox Signal 2020, 32, 1135–1149.
  82. Nicholls, S.J.; Hazen, S.L. Myeloperoxidase and Cardiovascular Disease. Arterioscler. Thromb. Vasc. Biol. 2005, 25, 1102–1111.
  83. Tang, W.H.W.; Tong, W.; Troughton, R.W.; Martin, M.G.; Shrestha, K.; Borowski, A.; Jasper, S.; Hazen, S.L.; Klein, A.L. Prognostic Value and Echocardiographic Determinants of Plasma Myeloperoxidase Levels in Chronic Heart Failure. J. Am. Coll. Cardiol. 2007, 49, 2364–2370.
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