Inflammation and Heart Failure: History
Please note this is an old version of this entry, which may differ significantly from the current revision.
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Inflammation is defined as the response of the immune system to a variety of stimuli that might be infectious or tissue harmful. Regardless of the initial insult, there is a series of programmed sequelae depending on the ability of the immune system to eliminate the ‘enemy’ and restore the tissues’ normal structure and function. The inflammatory process can be divided, without clearly defined and therefore overlapping borders, into three sequential phases, including the acute phase, the intermediate and the restore/repair phase. The pivotal role of inflammation in the pathophysiology of heart-failure (HF) development and progression has long been recognized. High blood levels of pro-inflammatory and inflammatory markers are present and associated with adverse outcomes in patients with HF. 

  • heart failure
  • inflammation
  • homeostasis

1. Following a Self-Catastrophic Path—Missing the Balance

Following an acute index event, the body, as a whole, tries to retain its homeostatic status. If the cause is of minimal aggressiveness, then the homeostatic status remains within normality by using low adaptation mechanisms. However, in the case of a major index event, the body tries to maintain homeostatic status by any means in order to limit the cause, to heal, resolve and ultimately to repair the tissues’ structure and function. In this respect, when a severe disturbance of homeostasis occurs, then the inflammatory process is activated as the acute-intermediaterestore phase, followed, in case of failure of the above-described sequence, by the chronic phase. Regardless of the cause of a sterile inflammation, there is tissue damage and consequently a release of intracellular (nuclear and/or cytosolic proteins, etc.) and extracellular (hyaluronic acid, fibronectin, etc.) products. The release of these proteins activates a series of injury-associated molecular pathways through cardiac receptor signaling. At the beginning, release of inflammatory cytokines, neutrophil aggregation and activation, release of proteases and ROS production occur. Failure of this initial reaction to restore tissue integrity activates a forward step of inflammation, in which the toll and nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs) are involved with further accumulation and activation of pro-inflammatory mediators. At this crucial phase, it is very important to maintain equilibrium between protein degradation (cysteine-protease system, ubiquitin proteasome, autophagy, etc.) and protein synthesis. If this equilibrium fails, apoptogenic mediators, misfolded proteins and damaged mitochondria lead to the phase of chronic inflammation (Figure 1). The NLRs, joined by caspase-activity complexes, form the inflammasome that further stimulates the production of IL-1b and IL-18 that affect left ventricular systolic function, alter mitochondrial function and decrease sympathetic activity [1][2].
Figure 1. Deranged homeostasis leading to heart failure.
The role of NLRP3 inflammasome (NLR family, pyrin domain-containing 3) in heart failure is well documented [3][4][5]. NLRP3 inflammasome sets off the maturation of proinflammatory cytokines (IL-1β and IL-18) to initiate the inflammatory response and plays a key role in modulating chronic inflammation, altering the physiological adaptation of cardiomyocyte and leading to heart failure progression [3]. Recent data showed that two other inflammasomes seem to be involved in the inflammatory process in failing hearts. Inflammasome protein absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) have been found to be over-expressed and activated in human-heart tissues as well in vivo animal models. These two other inflammasomes may contribute to the chronic inflammation in heart failure and also a therapeutic target [4]. The inflammasome also defines the interplay between innate and adaptive responses, paving the way toward the development of heart failure. Furthermore, the involvement of the immune process (effect of T and B cells) promotes chronicity according to the self-antigen hypothesis, the production of autoantibodies and tissue fibrosis, suggesting a role for autoimmune mechanisms [6][7]. This self-protection/elimination process integrates the endogenous inducers, cell-, tissue-, plasma- and extracellular matrixderived signals and might develop in an uncontrolled manner. Any injured myocardial cells can maintain a basal, stressed, apoptotic or necrotic state. If the amount of injured tissue is enormous and overpasses the homeostatic capacity to restore cell-tissue normality, then the detrimental chronic inflammatory phase develops [8]. On the other hand, the successful restoration of homeostasis prevents the harmful effect of chronic inflammation [9][10].

2. Homeostatic Mechanisms

To achieve homeostasis, a balanced activity between protein synthesis-degradation and organelle capacity to eliminate apoptogenic proteins and damaged mitochondria should be activated and well-functioning. If this is not the case, then the cardiomyocyte death along with extra-cellular cardiac matrix dysregulation, lead to myocardial cellular dysfunction and ultimately to heart failure (Figure 1). In other words, the body tries to protect itself from itself. Indeed, when mitochondrial morphology and function are disturbed (lack of fission, fusion and hence mitophagy), mitochondrial DNA is released into cytosol, and along with the misfolded proteins and the activation of the mitochondria-associated endoplasmic reticulum membranes (MAMs), promotes the enhancement of a self-destruction process, that might involve the entire body [11][12]. In case of a cardiac harmful event, there is an activation of danger-associated molecular patterns (DAMP) released by the nucleus (e.g., DNA, RNA), the mitochondria (e.g., DNA) and the cytosol (e.g., RNA). In this respect, regardless of the initial triggering event (pressure overload, volume overload, myocardial infarction, etc.), there is an activation of an inflammatory process associated with the harmful release of cell proteins along with the activation of the aforementioned self-elimination/protection mechanism. Thus, if there is an imbalance of this sequel, then the chronic inflammation is switched on, and in case of an uncontrolled process, heart failure develops. In other words, it seems that if the homeostatic mechanism (degradation system, autophagy, etc.) is successful, inflammation is limited. On the other hand, if the homeostatic protective mechanism cannot control and limit the harmful events, the self-catastrophic pathway promotes cardiomyocyte death and hence heart failure. The inevitable question that arises is whether the cause of heart failure is inflammation per se or the incapacity of the homeostatic protective mechanisms.
Damaged and un-repaired mitochondria are the source of reactive oxygen species, and along with mitochondrial DNA release, generate proinflammatory cytokines and the activation of inflammasome, promoting inflammation chronicity. This leads to an increase of the rate and amount of myocardial cell death and hence to the development of heart failure. Although the role of inflammasome (and its subfamilies) is not very well understood, it appears that its formation and activation have dual contradictory roles. The first one is to eliminate the ‘enemy’ and restore the normal anatomy and function of the tissue, while the second one, under certain circumstances, could be harmful by distorting the normal activity, which is to avoid chronic inflammation and to promote the protective mechanisms of homeostasis; in other words, to recognize the released material as foreign and to attack these unrecognized substances in order to ‘protect’ the cell and consequently the normal anatomy and function of the tissue [13][14].
It should be stressed that cardiomyocyte homeostasis as described above is different from heart (organ) and body homeostasis. The heart as an organ tries to adapt to stressors and noxious agents mediated by inflammation and redox disorders with an effort to maintain its function in the human body.

3. Organelle Communication

The normal function of a cell depends mainly on the structural functional integrity of its constituents, the organelles. The endoplasmic reticulum (ER) is an organelle that regulates important intracellular function, including protein synthesis, calcium transportation, etc. In the case of an index event, the ER is stressed and tries to maintain normality through homeostasis. In fact, ER-associated degradation, the unfolded protein response, reticulophagy, proteostasis, autophagy, etc., are activated in order to maintain normality [15][16][17]. In addition, there is communication with the other organelles, lysosomes, mitochondria, plasma membrane, etc., thus facilitating the normal functions of the cell, including lipid metabolism [18], calcium homeostasis [15][19], ion exchange [18], etc. However, if the index event surpasses the capacity of the cell to retain homeostasis or if ER homeostatic properties are impaired, then the cell-defending mechanisms fail, thus leading to a possible harmful path [20][21][22].
Although there is vast communication among the organelles, it seems that the most important one is between the ER and mitochondria [23][24]. Indeed, these two organelles form the ER-mitochondria contacts (ERMCs) [25], constituted by both lipid and protein complexes [26]. Studies have demonstrated that ERMCs are involved in the progression of several cardiovascular diseases [18][27][28][29][30][31], because they are involved in several biological processes, such as calcium homeostasis, apoptosis, autophagy, protein synthesis and folding, inflammation etc. [32][33][34][35][36][37][38][39]. After an index event, misfolded proteins are accumulated in the ER promoting the activation of the unfolded protein response in order to maintain proteostasis. In the case of failure of the misfolded protein repair, or of a large amount of accumulated unfolded proteins, a vicious circle begins [40][41]. This vicious circle is characterized by the loss of homeostatic capacity, promoting apoptosis. However, ER activation facilitates steroid synthesis, ER stress, phospholipid metabolism in mitochondria, autophagy and apoptosis [41], and under certain circumstances can increase transcription-factor expression (ATF) 6 and 4 and promote apoptosis either alone or in cooperation with mitochondria [42][43][44]. A self-catastrophic sequence thus begins. Indeed, when the collaboration between these two organelles is impaired, a progression to advanced heart failure may occur [45][46]. In fact, it has been stated that uncontrolled ER stress provokes distortion of myocardial architecture, alteration of mitochondrial metabolism and function, leading to an energy deficiency, along with a reduction of calcium transfer and consequently impairment of cardiac contractility and relaxation, hence heart failure [47][48].

4. Targeting Inflammation, Oxidative Stress and Mitochondrial Dysfunction

Regardless of whether the inflammation is the cause or the consequence of heart failure, it remains an important factor and a potential therapeutic target [49]. Although, several studies have been conducted in order to investigate the role of anti-inflammatory therapies, the results have hitherto been poor or controversial [50]. Notably, anti-cytokine therapies were tested in the ATTACH and RENEWAL studies with poor results [51][52]. On the other hand, the CANTOS trial has shown that the inhibition of IL-1b with canakinumab was followed by a significant trend for a dose-dependent reduction in the incidence of the composite endpoint of hospitalization for heart failure and heart failure-related mortality [53]. However, this was not the case in other studies, showing that after IL-1b inhibition with canakinumab, substantial residual inflammatory risk remained, related to both IL-18 and IL-6 [54]. Other studies based on anti-inflammatory therapies have been published [55][56][57], among which those using either immunomodulation [58] or anti-inflammatory drugs [59][60][61], showing overall poor results. The same was true when N-terminal pro-B-type natriuretic peptide (NT-pro BNP) or high-sensitivity C-reactive protein (hs-CRP) were used as endpoints [62][63].
These data support the need for a better understanding of the inflammatory process. As it has been pointed out, important inflammatory mediators are released after the activation of the inflammasome, suggesting that the inflammasome could be a therapeutic target. Since the inflammasome is part of homeostatic mechanism, one could speculate that homeostatic controlled response is the master key to investigate and target.

This entry is adapted from the peer-reviewed paper 10.3390/jcdd10010019

References

  1. DeLuca, G.; Cavalli, G.; Campochiaro, C.; Tresoldi, M.; Dagna, L. Myocarditis: An interleukin-1-mediated disease? Front. Immunol. 2018, 9, 1335.
  2. Toldo, S.; Kannan, H.; Bussani, R.; Anzini, M.; Sonnino, C.; Sinagra, G.; Merlo, M.; Mezzaroma, E.; De-Giorgio, F.; Silvestri, F.; et al. Formation of the inflammasome in acute myocarditis. Int. J. Cardiol. 2014, 171, e119–e121.
  3. Butts, B.; Gary, R.A.; Dunbar, S.B.; Butler, J. The importance of NLRP3 inflammasome in heart failure. J. Card. Fail. 2015, 21, 586–593.
  4. Onódi, Z.; Ruppert, M.; Kucsera, D.; Sayour, A.A.; Tóth, V.E.; Koncsos, G.; Novák, J.; Brenner, G.B.; Makkos, A.; Baranyai, T.; et al. AIM2-driven inflammasome activation in heart failure. Cardiovasc. Res. 2021, 117, 2639–2651.
  5. Wu, J.; Dong, E.; Zhang, Y.; Xiao, H. The role of the inflammasome in heart failure. Front. Physiol. 2021, 12, 709703.
  6. Youker, K.A.; Assad-Kottner, C.; Cordero-Reyes, A.M.; Trevino, A.R.; Flores-Arredondo, J.H.; Barrios, R.; Fernandez-Sada, E.; Estep, J.D.; Bhimaraj, A.; Torre-Amione, G. High proportion of patients with end-stage heart failure regardless of aetiology demonstrates anti-cardiac antibody deposition in failing myocardium: Humoral activation, a potential contributor of disease progression. Eur. Heart J. 2014, 35, 1061–1068.
  7. Adamo, L.; Rocha-Resende, C.; Lin, C.-Y.; Evans, S.; Williams, J.; Dun, H.; Li, W.; Mpoy, C.; Andhey, P.S.; Rogers, B.E.; et al. Myocardial B cells are a subset of circulating lymphocytes with delayed transit through the heart. JCI Insight 2020, 5, e134700.
  8. Medzhitov, R. Origin and physiological roles of inflammation. Nature 2008, 454, 428–435.
  9. Kologrivova, I.; Shtatolkina, M.; Suslova, T.; Ryabov, V. Cells of the immune system in cardiac remodeling: Main players in resolution of inflammation and repair after myocardial infarction. Front. Immunol. 2021, 12, 664457.
  10. Isobe, Y.; Kato, T.; Arita, M. Emerging roles of eosinophils and eosinophil-derived lipid mediators in the resolution of inflammation. Front. Immunol. 2012, 3, 270.
  11. Heineke, J.; Molkentin, J.D. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat. Rev. Mol. Cell Biol. 2006, 7, 589–600.
  12. Stachowski, M.J.; Holewinski, R.J.; Grote, E.; Venkatraman, V.; Van Eyk, J.E.; Kirk, J.A. Phospho-Proteomic Analysis of Cardiac Dyssynchrony and Resynchronization Therapy. Proteomics 2018, 18, e1800079.
  13. Henao-Mejia, J.; Elinav, E.; Strowig, T.; Flavell, R.A. Inflammasomes: Far beyond inflammation. Nat. Immunol. 2012, 13, 321–324.
  14. Missiroli, S.; Patergnani, S.; Caroccia, N.; Pedriali, G.; Perrone, M.; Previati, M.; Wieckowski, M.R.; Giorgi, C. Mitochondria-associated membranes (MAMs) and inflammation. Cell Death Dis. 2018, 9, 329.
  15. Chen, Y.-J.; Quintanilla, C.G.; Liou, J. Recent insights into mammalian ER–PM junctions. Curr. Opin. Cell Biol. 2019, 57, 99–105.
  16. Hwang, J.; Qi, L. Quality control in the endoplasmic reticulum: Crosstalk between ERAD and UPR pathways. Trends Biochem. Sci. 2018, 43, 593–605.
  17. Loi, M.; Molinari, M. Mechanistic insights in recov-ER-phagy: Micro-ER-phagy to recover from stress. Autophagy 2020, 16, 385–386.
  18. Zhou, H.; Wang, S.; Hu, S.; Chen, Y.; Ren, J. ER–mitochondria microdomains in cardiac ischemia–reperfusion injury: A fresh perspective. Front. Physiol. 2018, 9, 755.
  19. Guido, D.; Demaurex, N.; Nunes, P. Junctate boosts phagocytosis by recruiting endoplasmic reticulum Ca2+ stores near phagosomes. J. Cell Sci. 2015, 128, 4074–4082.
  20. Ren, J.; Bi, Y.; Sowers, J.R.; Hetz, C.; Zhang, Y. Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases. Nat. Rev. Cardiol. 2021, 18, 499–521.
  21. Pastor-Cantizano, N.; Ko, D.K.; Angelos, E.; Pu, Y.; Brandizzi, F. Functional diversification of ER stress responses in Arabidopsis. Trends Biochem. Sci. 2020, 45, 123–136.
  22. Lebeaupin, C.; Vallée, D.; Hazari, Y.; Hetz, C.; Chevet, E.; Bailly-Maitre, B. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 2018, 69, 927–947.
  23. Nunnari, J.; Suomalainen, A. Mitochondria: In sickness and in health. Cell 2012, 148, 1145–1159.
  24. Reddish, F.N.; Miller, C.L.; Gorkhali, R.; Yang, J.J. Calcium dynamics mediated by the endoplasmic/sarcoplasmic reticulum and related diseases. Int. J. Mol. Sci. 2017, 18, 1024.
  25. Szymański, J.; Janikiewicz, J.; Michalska, B.; Patalas-Krawczyk, P.; Perrone, M.; Ziółkowski, W.; Duszyński, J.; Pinton, P.; Dobrzyń, A.; Więckowski, M.R. Interaction of mitochondria with the endoplasmic reticulum and plasma membrane in calcium homeostasis, lipid trafficking and mitochondrial structure. Int. J. Mol. Sci. 2017, 18, 1576.
  26. Annunziata, I.; Sano, R.; d’Azzo, A. Mitochondria-associated ER membranes (MAMs) and lysosomal storage diseases. Cell Death Dis. 2018, 9, 328.
  27. Gao, P.; Yan, Z.; Zhu, Z. Mitochondria-associated endoplasmic reticulum membranes in cardiovascular diseases. Front. Cell Dev. Biol. 2020, 8, 604240.
  28. Silva-Palacios, A.; Zazueta, C.; Pedraza-Chaverri, J. ER membranes associated with mitochondria: Possible therapeutic targets in heart-associated diseases. Pharmacol. Res. 2020, 156, 104758.
  29. Yang, M.; Li, C.; Yang, S.; Xiao, Y.; Xiong, X.; Chen, W.; Zhao, H.; Zhang, Q.; Han, Y.; Sun, L. Mitochondria-associated ER membranes–the origin site of autophagy. Front. Cell Dev. Biol. 2020, 8, 595.
  30. Gomez-Suaga, P.; Paillusson, S.; Stoica, R.; Noble, W.; Hanger, D.P.; Miller, C.C.J. The ER-mitochondria tethering complex VAPB-PTPIP51 regulates autophagy. Curr. Biol. 2017, 27, 371–385.
  31. Kornmann, B. The molecular hug between the ER and the mitochondria. Curr. Opin. Cell Biol. 2013, 25, 443–448.
  32. Lee, S.; Min, K.-T. The interface between ER and mitochondria: Molecular compositions and functions. Mol. Cells 2018, 41, 1000–1007.
  33. Kho, C.; Lee, A.; Hajjar, R.J. Altered sarcoplasmic reticulum calcium cycling—Targets for heart failure therapy. Nat. Rev. Cardiol. 2012, 9, 717–733.
  34. Chan, D.C. Mitochondrial dynamics and its involvement in disease. Annu. Rev. Pathol. Mech. Dis. 2020, 15, 235–259.
  35. Guerriero, C.J.; Brodsky, J.L. The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. Physiol. Rev. 2012, 92, 537–576.
  36. Bagur, R.; Hajnóczky, G. Intracellular Ca2+ sensing: Its role in calcium homeostasis and signaling. Mol. Cell 2017, 66, 780–788.
  37. Klecker, T.; Böckler, S.; Westermann, B. Making connections: Interorganelle contacts orchestrate mitochondrial behavior. Trends Cell Biol. 2014, 24, 537–545.
  38. Senft, D.; Ronai, Z.A. UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem. Sci. 2015, 40, 141–148.
  39. Rosati, E.; Sabatini, R.; Rampino, G.; DeFalco, F.; DiIanni, M.; Falzetti, F.; Fettucciari, K.; Bartoli, A.; Screpanti, I.; Marconi, P. Novel targets for endoplasmic reticulum stress-induced apoptosis in B-CLL. Blood 2010, 116, 2713–2723.
  40. Oakes, S.A.; Papa, F.R. The role of endoplasmic reticulum stress in human pathology. Annu. Rev. Pathol. 2015, 10, 173–194.
  41. Wang, Y.; Zhang, X.; Wen, Y.; Li, S.; Lu, X.; Xu, R.; Li, C. Endoplasmic reticulum-mitochondria contacts: A potential therapy target for cardiovascular remodeling-associated diseases. Front. Cell Dev. Biol. 2021, 9, 774989.
  42. Burkewitz, K.; Feng, G.; Dutta, S.; Kelley, C.A.; Steinbaugh, M.; Cram, E.J.; Mair, W.B. Atf-6 regulates lifespan through ER-mitochondrial calcium homeostasis. Cell Rep. 2020, 32, 108125.
  43. Verfaillie, T.; Rubio, N.; Garg, A.D.; Bultynck, G.; Rizzuto, R.; Decuypere, J.-P.; Piette, J.; Linehan, C.; Gupta, S.; Samali, A.; et al. PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ. 2012, 19, 1880–1891.
  44. Rozpedek, W.; Pytel, D.; Mucha, B.; Leszczynska, H.; Diehl, J.A.; Majsterek, I. The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr. Mol. Med. 2016, 16, 533–544.
  45. Chaanine, A.H.; Gordon, R.E.; Kohlbrenner, E.; Benard, L.; Jeong, D.; Hajjar, R.J. Potential role of BNIP3 in cardiac remodeling, myocardial stiffness, and endoplasmic reticulum: Mitochondrial calcium homeostasis in diastolic and systolic heart failure. Circ. Heart Fail. 2013, 6, 572–583.
  46. Ma, M.; Chen, W.; Hua, Y.; Jia, H.; Song, Y.; Wang, Y. Aerobic exercise ameliorates cardiac hypertrophy by regulating mitochondrial quality control and endoplasmic reticulum stress through M2AChR. J. Cell. Physiol. 2021, 236, 6581–6596.
  47. Prola, A.; Nichtova, Z.; Pires Da Silva, J.; Piquereau, J.; Monceaux, K.; Guilbert, A.; Gressette, M.; Ventura-Clapier, R.; Garnier, A.; Zahradnik, I.; et al. Endoplasmic reticulum stress induces cardiac dysfunction through architectural modifications and alteration of mitochondrial function in cardiomyocytes. Cardiovasc. Res. 2019, 115, 328–342.
  48. Eisner, V.; Csordás, G.; Hajnóczky, G. Interactions between sarco-endoplasmic reticulum and mitochondria in cardiac and skeletal muscle–pivotal roles in Ca2+ and reactive oxygen species signaling. J. Cell Sci. 2013, 126, 2965–2978.
  49. Szabo, T.M.; Frigy, A.; Nagy, E.E. Targeting Mediators of Inflammation in Heart Failure: A Short Synthesis of Experimental and Clinical Results. Int. J. Mol. Sci. 2021, 22, 13053.
  50. Champs, B.; Degboé, Y.; Barnetche, T.; Cantagrel, A.; Ruyssen-Witrand, A.; Constantin, A. Short-term risk of major adverse cardiovascular events or congestive heart failure in patients with psoriatic arthritis or psoriasis initiating a biological therapy: A meta–analysis of randomised controlled trials. RMD Open 2019, 5, e000763.
  51. Chung, E.S.; Packer, M.; Lo, K.H.; Fasanmade, A.A.; Willerson, J.T.; 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-α, 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.
  52. 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.
  53. Everett, B.M.; Cornel, J.H.; Lainscak, M.; Anker, S.D.; Abbate, A.; Thuren, T.; Libby, P.; Glynn, R.J.; Ridker, P.M. Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation 2019, 139, 1289–1299.
  54. Ridker, P.M.; MacFadyen, J.G.; Thuren, T.; Libby, P. Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: Further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis. Eur. Heart J. 2020, 41, 2153–2163.
  55. Kjekshus, J.; Apetrei, E.; Barrios, V.; Böhm, M.; Cleland, J.G.F.; Cornel, J.H.; Dunselman, P.; Fonseca, C.; Goudev, A.; Grande, P.; et al. Rosuvastatin in older patients with systolic heart failure. N. Engl. J. Med. 2007, 357, 2248–2261.
  56. Tavazzi, L.; Maggioni, A.P.; Marchioli, R.; Barlera, S.; Franzosi, M.G.; Latini, R.; Lucci, D.; Nicolosi, G.L.; Porcu, M.; Tognoni, G.; 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, 1231–1239.
  57. Hare, J.M.; Mangal, B.; Brown, J.; Fisher, C.; Freudenberger, R.; Colucci, W.S.; Mann, D.L.; Liu, P.; Givertz, M.M.; Schwarz, R.P.; et al. Impact of oxypurinol in patients with symptomatic heart failure: Results of the OPT-CHF study. J. Am. Coll. Cardiol. 2008, 51, 2301–2309.
  58. Torre-Amione, G.; Anker, S.D.; Bourge, R.C.; Colucci, W.S.; Greenberg, B.H.; Hildebrandt, P.; Keren, A.; Motro, M.; Moyé, L.A.; Otterstad, J.E.; et al. Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy Investigators. Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): A placebo-controlled randomised trial. Lancet 2008, 371, 228–236.
  59. Moreira, D.M.; Vieira, J.L.; Gottschall, C.A.M. 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, 828–834.
  60. Deftereos, S.; Giannopoulos, G.; Panagopoulou, V.; Bouras, G.; Raisakis, K.; Kossyvakis, C.; Karageorgiou, S.; Papadimitriou, C.; Vastaki, M.; Kaoukis, A.; et al. Anti-inflammatory treatment with colchicine in stable chronic heart failure: A prospective, randomized study. JACC Heart Fail. 2014, 2, 131–137.
  61. Givertz, M.M.; Anstrom, K.J.; Redfield, M.M.; Deswal, A.; Haddad, H.; Butler, J.; Tang, W.H.W.; Dunlap, M.E.; Le Winter, M.M.; Mann, D.L.; 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, 1763–1771.
  62. Yokoe, I.; Kobayashi, H.; Kobayashi, Y.; Giles, J.T.; Yoneyama, K.; Kitamura, N.; Takei, M. Impact of tocilizumab on N-terminal pro-brain natriuretic peptide levels in patients with active rheumatoid arthritis without cardiac symptoms. Scand. J. Rheumatol. 2018, 47, 364–370.
  63. Kleveland, O.; Kunszt, G.; Bratlie, M.; Ueland, T.; Broch, K.; Holte, E.; Michelsen, A.E.; Bendz, B.; Amundsen, B.H.; Espevik, T.; et al. Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: A double-blind, randomized, placebo-controlled phase 2 trial. Eur. Heart J. 2016, 37, 2406–2413.
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