Interleukin 6 Signalling in Heart Failure With Preserved and Reduced Ejection Fraction

Aim. Identification of interleukin-6 (IL-6) signaling pathways in patients with chronic heart failure (CHF).

Material and methods. The diversity of IL-6 effects is due to the presence of classical signaling and trans-signaling pathways. The study included 164 patients with CHF hospitalized for acute decompensated heart failure (ADHF), of which 129 had reduced left ventricular ejection fraction (HFrEF), and 35 had preserved ejection fraction (HFpEF). Blood concentrations of IL-6, soluble IL-6 receptor (sIL-6R), soluble transducer protein gp130 (sgp130), and high-sensitivity C-reactive protein (hsCRP) were measured.

Results. Patients with HFpEF had lower concentrations of IL-6 (6.15 [2.78, 10.65] pg/ml) and hsCRP (11.27 [5.84, 24.40] mg/ml) than patients with HFrEF (9.20 [4.70; 15.62] pg/ml and 17.23 [8.70; 34.51 mg/ml], respectively). In contrast, concentrations of rIL-6R were higher in HFpEF (59.06 [40.00; 75.85] ng/ml) than in HFrEF (49.15 [38.20; 64.89] ng/ml). Concentrations of sgp130 were not significantly different. In patients with HFrEF, positive correlations were found between the concentrations of IL-6 and hsCRP, IL-6 and rIL-6R, and IL-6 and sgp130, while in patients with HFpEF, there was a correlation only between IL-6 and hsCRP, which appeared stronger than in patients with HFrEF (r=0.698; p<0.001 and r=0.297; p<0.05, respectively).

Conclusion. Classical IL-6 signaling and trans-signaling are expressed to different degrees in patients with HFrEF and HFpEF in ADHF. The results of the study supplement the existing knowledge about the pathogenesis of inflammation in CHF and may contribute to the development of new methods and approaches to the treatment of the disease.

1. Tereshchenko S.N., Galyavich A.S., Uskach T.M., Ageev F.T., Arutyunov G.P., Begrambekova Yu.L. et al. 2020 Clinical practice guidelines for Chronic heart failure. Russian Journal of Cardiology. 2020;25(11):311–74. DOI: 10.15829/1560-4071-2020-4083

2. Polyakov D.S., Fomin I.V., Belenkov Yu.N., Mareev V.Yu., Ageev F.T., Artemjeva E.G. et al. Chronic heart failure in the Russian Federation: what has changed over 20 years of follow-up? Results of the EPOCH-CHF study. Kardiologiia. 2021;61(4):4–14. DOI: 10.18087/cardio.2021.4.n1628

3. Kittleson MM, Panjrath GS, Amancherla K, Davis LL, Deswal A, Dixon DL et al. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. Journal of the American College of Cardiology. 2023;81(18):1835–78. DOI: 10.1016/j.jacc.2023.03.393

4. Akhilgova Z.M., Kurkina M.V., Dzhioeva Z.R., Puhaeva A.A., Avtandilov A.G. Diagnosis and the debatable issues of the treatment of heart failure with preserved ejection fraction. CardioSomatics. 2018;9(4):32–7. DOI: 10.26442/22217185.2018.4.000013

5. Ngkelo A, Richart A, Kirk JA, Bonnin P, Vilar J, Lemitre M et al. Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction. Journal of Experimental Medicine. 2016;213(7):1353–74. DOI: 10.1084/jem.20160081

6. Borlaug BA, Olson TP, Lam CSP, Flood KS, Lerman A, Johnson BD et al. Global Cardiovascular Reserve Dysfunction in Heart Failure With Preserved Ejection Fraction. Journal of the American College of Cardiology. 2010;56(11):845–54. DOI: 10.1016/j.jacc.2010.03.077

7. Gavryushina S.V., Ageev F.T. Heart failure with preserved left ventricular ejection fraction: epidemiology, patient “portrait”, clinic and diagnostics. Kardiologiia. 2018;58(S4):55–64. DOI: 10.18087/cardio.2467

8. Murphy SP, Kakkar R, McCarthy CP, Januzzi JL. Inflammation in Heart Failure. Journal of the American College of Cardiology. 2020;75(11):1324–40. DOI: 10.1016/j.jacc.2020.01.014

9. Tokmachev R.E., Budnevsky A.V., Kravchenko A.Ya. The role of inflammation in the pathogenesis of chronic heart failure. Therapeutic Archive. 2016;88(9):106–10. DOI: 10.17116/terarkh2016889106-110

10. Soehnlein O, Libby P. Targeting inflammation in atherosclerosis — from experimental insights to the clinic. Nature Reviews Drug Discovery. 2021;20(8):589–610. DOI: 10.1038/s41573-021-00198-1

11. Georgakis MK, Malik R, Richardson TG, Howson JMM, Anderson CD, Burgess S et al. Associations of genetically predicted IL-6 signaling with cardiovascular disease risk across population subgroups. BMC Medicine. 2022;20(1):245. DOI: 10.1186/s12916-022-02446-6

12. Matsuda T. The Physiological and Pathophysiological Role of IL-6/STAT3-Mediated Signal Transduction and STAT3 Binding Partners in Therapeutic Applications. Biological and Pharmaceutical Bulletin. 2023;46(3):364–78. DOI: 10.1248/bpb.b22-00887

13. Markousis-Mavrogenis G, Tromp J, Ouwerkerk W, Devalaraja M, Anker SD, Cleland JG et al. The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study. European Journal of Heart Failure. 2019;21(8):965–73. DOI: 10.1002/ejhf.1482

14. Korotaeva A.A., Samoilova E.V., Mindzaev D.R., Nasonova S.N., Zhirov I.V., Tereschenko S.N. Pro-inflammatory cytokines in chronic cardiac failure: state of problem. Therapeutic Archive. 2021;93(11):1389–94. DOI: 10.26442/00403660.2021.11.201170

15. Fontes JA, Rose NR, Čiháková D. The varying faces of IL-6: From cardiac protection to cardiac failure. Cytokine. 2015;74(1):62–8. DOI: 10.1016/j.cyto.2014.12.024

16. Ziegler L, Gajulapuri A, Frumento P, Bonomi A, Wallén H, De Faire U et al. Interleukin 6 trans-signalling and risk of future cardiovascular events. Cardiovascular Research. 2019;115(1):213–21. DOI: 10.1093/cvr/cvy191

17. Baran P, Hansen S, Waetzig GH, Akbarzadeh M, Lamertz L, Huber HJ et al. The balance of interleukin (IL)-6, IL-6·soluble IL-6 receptor (sIL-6R), and IL-6·sIL-6R·sgp130 complexes allows simultaneous classic and trans-signaling. Journal of Biological Chemistry. 2018;293(18):6762–75. DOI: 10.1074/jbc.RA117.001163

18. Peters M, Odenthal M, Schirmacher P, Blessing M, Fattori E, Ciliberto G et al. Soluble IL-6 receptor leads to a paracrine modulation of the IL-6-induced hepatic acute phase response in double transgenic mice. Journal of Immunology. 1997;159(3):1474–81. PMID: 9233646

19. Rose-John S, Waetzig GH, Scheller J, Grötzinger J, Seegert D. The IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert Opinion on Therapeutic Targets. 2007;11(5):613–24. DOI: 10.1517/14728222.11.5.613

20. George MJ, Jasmin NH, Cummings VT, Richard-Loendt A, Launchbury F, Woollard K et al. Selective Interleukin-6 Trans-Signaling Blockade Is More Effective Than Panantagonism in Reperfused Myocardial Infarction. JACC: Basic to Translational Science. 2021;6(5):431–43. DOI: 10.1016/j.jacbts.2021.01.013

21. Chen B, Zhang S, Wang B, Chen H, Li Y, Cao Q et al. Efficacy and safety of the IL-6 trans-signalling inhibitor olamkicept: a phase 2 randomized, placebo-controlled trial in moderately to severely active Ulcerative Colitis. Journal of Crohn’s and Colitis. 2021;15(Suppl 1):S041–2. DOI: 10.1093/ecco-jcc/jjab073.040

22. Schulte DM, Waetzig GH, Schuett H, Marx M, Schulte B, Garbers C et al. Case Report: Arterial Wall Inflammation in Atherosclerotic Cardiovascular Disease is Reduced by Olamkicept (sgp-130Fc). Frontiers in Pharmacology. 2022;13:758233. DOI: 10.3389/fphar.2022.758233

23. Rose-John S, Jenkins BJ, Garbers C, Moll JM, Scheller J. Targeting IL-6 trans-signalling: past, present and future prospects. Nature Reviews Immunology. 2023;23(10):666–81. DOI: 10.1038/s41577-023-00856-y