Indexes of pro-inflammatory cytokines and hepsidin in case of anemia in chronic heart failure patients


DOI: https://dx.doi.org/10.18565/therapy.2021.2.56-65

Tkachenko E.I., Borovkova N.Yu., Borovkov N.N., Bakka T.E.

1) Privolzhsky Research Medical University of the Ministry of Healthcare of Russia, Nizhny Novgorod; 2) N.A. Semashko Nizhegorodsky Regional Clinical Hospital, Nizhny Novgorod
Abstract. The aim of the study was to examine the indexes of proinflammatory cytokines (interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor (TNF-α)) and hepcidin in anemia pathogenetically associated with chronic heart failure (CHF).
Material and methods. The data of 873 patients with CHF were prospectively studied. Anemia was verified in 191 (22%) patients, in 96 of them (50,3%) it was pathogenetically associated with CHF (the main group). The control group consisted of patients with CHF without anemia (n=35), comparable in gender, age, and left ventricular ejection fraction (LVEF). The data of the study participants on the severity of CHF, chronic kidney disease (CKD), anemia were analyzed, the indicators of iron metabolism, erythropoietin, the concentration of IL-1β, IL-6, TNF-α and hepcidin in blood serum were determined.
Results. Anemia associated with CHF has been associated with CKD presence. In 42% of cases, it was accompanied by iron deficiency; in 58% of patients, iron deficiency was not found. It was revealed that in CHF anemia patients, pro-inflammatory cytokines and hepcidin are activated. High levels of IL-6, TNF-α, and hepcidin were associated with functional iron deficiency formation. An inverse correlation of cytokines and hepcidin with hemoglobin level was determined. The obtained results are confirming the importance of immune inflammation in the genesis of anemia in CHF patients.
Conclusion. Proinflammatory cytokines activation and hepcidin increase affect the anemia formation in CHF patients.
Keywords: chronic heart failure, anemia of chronic diseases, proinflammatory cytokines, interleukin-1β, interleukin-6, tumor necrosis factor-α, hepcidin, chronic kidney disease
Read entire article

Literature


  1. Соломахина Н.И., Находнова Е.С., Беленков Ю.Н. Анемия хронических заболеваний и железодефицитная анемия: сравнительная характеристика показателей феррокинетики и их связь с воспалением у больных ХСН в пожилом и старческом возрасте. Кардиология. 2018; S8: 58–64. [Solomakhina N.I., Nakhodnova E.S., Belenkov Y.N. Anemia of chronic disease and iron deficiency anemia: Comparative characteristics of ferrokinetic parameters and their relationship with inflammation in late middle-aged and elderly patients with CHF. Kardiologiya = Cardiology. 2018; S8: 58–64 (In Russ.)]. doi: https://dx.doi.org/10.18087/cardio.2472.

  2. Соломахина Н.И., Находнова Е.С., Гитель Е.П., Ю.Н. Беленков. Гепсидин и его связь с воспалением у больных с анемией хронических заболеваний на фоне ХСН в пожилом и старческом возрасте. Кардиология. 2018; S2: 4–11. [Solomakhina N.I., Nakhodnova E.S., Gitel E.P., Belenkov Y.N. Hepcidin and its relationship with inflammation in old and older patients with anemia of chronic disease associated with CHF. Kardiologiya = Cardiology. 2018; S2: 4–11 (In Russ.)]. doi: https://dx.doi.org/10.18087/cardio.2457.

  3. Ларина В.Н. Анемия в практике врача-терапевта: новый взгляд на старую проблему. РМЖ. 2019; 12: 44–50. [Larina V.N. Anemia in the practice of a general practitioner: a new look at an old problem. Russkiy meditsinskiy zhurnal = Russian medical journal. 2019; 12: 44–50 (In Russ.)].

  4. Packer M., Fowler M.B., Roecker E.B. et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure. Circulation. 2002; 106(17): 2194–99. doi: 10.1161/01.cir.0000035653.72855.bf.

  5. Pozzo J., Fournier P., Delmas C. et al. Absolute iron deficiency without anemia in patients with chronic systolic heart failure is associated with poorer functional capacity. Arch Cardiovasc Dis. 2017; 110(2): 99–105. doi: 10.1016/j.acvd.2016.06.003.

  6. Wienbergen H., Pfister O., Hochadel M. et al. Long-term effects of iron deficiency in patients with heart failure with or without anemia: the RAID-HF follow-up study. Clin Res Cardiol. 2019; 108(1): 93–100. doi: 10.1007/s00392-018-1327-y.

  7. Karla P.R., Collier Т., Cowie M.R. et al. Haemoglobin concentration and prognosis in new cases of heart failure. Lancet. 2003; 362(9379): 211–12. 10.1016/S0140-6736(03)13912-8.

  8. Enjuanes C., Bruguera J., Grau M. et al. Iron status in chronic heart failure: impact on symptoms, functional class and submaximal exercise capacity. Rev Esp Cardiol. 2016; 69(3): 247–55. doi: 10.1016/j.rec.2015.08.018.

  9. Стуклов Н.И. Дефицит железа и анемия у больных хронической сердечной недостаточностью. Рациональная фармакотерапия в кардиологии. 2017; 5: 651–660. [Stuklov N.I. Iron deficiency and anemia in patients with chronic heart failure. Ratsional'naya farmakoterapiya v kardiologii = Rational pharmacotherapy in cardiology. 2017; 5: 651–660 (In Russ.)]. doi: https://dx.doi.org/10.20996/1819-6446-2017-13-5-651-660.

  10. Hoes M.F., Grote Beverborg N., Kijlstra J.D. et al. Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function: Impaired contractility in iron-deficient cardiomyocytes. Eur J Heart Fail. 2018; 20(5): 910–19. doi: 10.1002/ejhf.1154.

  11. Резник Е.В., Никитин И.Г. Кардиоренальный синдром у больных с сердечной недостаточностью как этап кардиоренального континуума (часть I): определение, классификация, патогенез, диагностика, эпидемиология (обзор литературы). Архивъ внутренней медицины. 2019; 1: 5–22. [Reznik E.V., Nikitin I.G. Cardiorenal syndrome in patients with chronic heart failure as a stage of the cardiorenal continuum (part I): definition, classification, pathogenesis, diagnosis, epidemiology. Arkhiv vnutrenney meditsiny = Archive of internal medicine. 2019; 1: 5–22 (In Russ.)]. doi: https://doi.org/10.20514/2226-6704-2019-9-1-5-22.

  12. Боровкова Н.Ю., М.В. Буянова, В.В. Терехова с соавт. Особенности аспирин-индуцированных поражений желудочно-кишечного тракта у больных хронической ишемической болезнью сердца и возможные пути их коррекции. Кардиоваскулярная терапия и профилактика. 2020; 2: 42–48. [Borovkova N.Yu., Buyanova M.V., Terekhova V.V. et. al. Aspirin-induced gastrointestinal lesions in patients with chronic coronary artery disease: special aspects and therapeutic options. Kardiovasculyarnaya terapiya i profilaktika = Cardiovascular therapy and prevention. 2020; 2: 42–48 (In Russ.)]. doi: https://doi.org/10.15829/1728-8800-2020-2-2463.

  13. Мареев В.Ю., Гиляревский С.Р., Мареев Ю.В. с соавт. Согласованное мнение экспертов по поводу роли дефицита железа у больных с хронической сердечной недостаточностью, а также о современных подходах к его коррекции. Кардиология. 2020; 1: 99–106. [Mareev V.Yu., Gilyarevskiy S.R., Mareev Y.V. et. al. Position Paper. The role of iron deficiency in patients with chronic heart failure and current corrective approaches. Kardiologiya = Cardiology. 2020; 1: 99–106 (In Russ.)]. doi: https://doi.org/10.18087/cardio.2020.1.n961.

  14. Atkinson M.A., Furth S.L. Anemia in children with chronic kidney disease. Nat Rev Nephrol. 2011; 7(11): 635–41. doi: 10.1038/nrneph.2011.115.

  15. Lipsic E., van der Meer P. Erithropoietin, iron, or both in heart failure: FAIR-HF in perspective. Eur J Heart Fail. 2010; 12(2): 104–05. doi: 10.1093/eurjhf/hfp196.

  16. Androne A.S., Katz S.D., Lund L. Hemodilution is common in patients with advanced heart failure. Circulation. 2003; 107(2): 226–29. doi: 10.1161/01.cir.0000052623.16194.80.

  17. shani A., Weinhandl E., Zhao Z. et. al. Angiotensin-converting enzyme inhibitor as a risk factor for the development of anemia, and the impact of incident anemia on mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2005; 45(3): 391–99. doi: 10.1016/j.jacc.2004.10.038.

  18. Montero, D., Haider T., Flam A.J. Erythropoietin response to anaemia in heart failure. Eur J Prev Cardiol. 2019; 26(1): 7–17. doi: 10.1177/2047487318790823.

  19. Perticone M., Zito R., Miceli S. et al. Immunity, inflammation and Heart Failure: their role on cardiac function and iron status. Front. Immunol. 2019; 10: 2315. doi:10.3389/fimmu.2019.02315

  20. Adamo L., Rocha-Resende C., Prabhu S.D. Reappraising the role of inflammation in heart failure. Nat Rev Cardiol. 2020; 17(5): 269–85. doi:10.1038/s41569-019-0315-x

  21. Ridker P.M., Libby P., MacFadyen J. G. et. al. Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J. 2018; 39(38): 3499–507. doi: 10.1093/eurheartj/ehy310.

  22. Захидова К.Х. Выбор оптимальной терапии при коррекции анемического синдрома у больных с хронической сердечной недостаточностью. Кардиология. 2018; 1: 25–31. [Zakhidova K.Kh. The choice of optimal therapy for the correction of anemic syndrome in patients with chronic heart failure. Kardiologiya = Cardiology. 2018; 1: 25–31 (In Russ.)]. doi: https://doi.org/10.18087/cardio.2018.1.10076.

  23. Fraenkel P.G. Anemia of inflammation: A review. Med Clin North Am. 2017; 101(2): 285–96. doi: 10.1016/j.mcna.2016.09.005.

  24. Gardenghi S., Renaud T. M., Meloni A. et al. Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus. Blood. 2014; 123(8): 1137–45. doi: 10.1182/blood-2013-08-521625.

  25. Katsarou A., Pantopoulos K. Hepcidin therapeutics. Pharmaceuticals (Basel). 2018; 11(4): 127. doi: 10.3390/ph11040127.

  26. Matsumoto M., Tsujino T., Lee-Kawabata M. et.al. Iron regulatory hormone hepcidin decreases in chronic heart failure patients with anemia. Circ J. 2010; 74(2): 301–06. doi: 10.1253/circj.cj-09-0663.

  27. Divakaran V., Mehta S., Yao D. et al. Hepcidin in anemia of chronic heart failure. Am J Hematol. 2011; 86(1): 107–09. doi: 10.1002/ajh.21902.

  28. van der Puten K., Jie K.E., van den Broek D. et al. Hepcidin-25 is a marker of the response rather than resistance to exogenous erythropoietin in chronic kidney disease/chronic heart failure patients. Eur J Heart Fail. 2010; 12(9): 943–50. doi: 10.1093/eurjhf/hfq099.

  29. Ginzburg Y.Z. Hepcidin-ferroportin axis in health and disease. Vitam Horm. 2019; 110: 17–45. doi: 10.1016/bs.vh.2019.01.002.

  30. Arezes J., Foy N., McHugh K. et al. Erythroferrone inhibits the induction of hepcidin by BMP6. Blood. 2018; 132(14): 1473–77. doi: 10.1182/blood-2018-06-857995.

  31. Ponikowski P., Voors A.A., Anker S.D. et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2016: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur Heart J. 2016; 37(27): 2129–200. doi: 10.1093/eurheartj/ehw128.

  32. Мареев В.Ю., Фомин И.В., Агеев Ф.Т. с соавт. Клинические рекомендации ОССН – РКО – РНМОТ. Сердечная недостаточность: хроническая (ХСН) и острая декомпенсированная (ОДСН). Диагностика, профилактика и лечение. Кардиология. 2018; S6: 8–158. [Mareev V.Yu., Fomin I.V., Ageev F.T. et al. Russian Heart Failure Society, Russian Society of Cardiology. Russian Scientific Medical Society of Internal Medicine guidelines for heart failure: Chronic (CHF) and acute decompensated (ADHF). Diagnosis, prevention and treatment. Kardiologiya = Cardiology. 2018; S6: 8–158 (In Russ.)]. doi: https://doi.org/10.18087/cardio.2475.

  33. Всемирная организация здравоохранения. Концентрации гемоглобина для диагностики анемии и оценки ее тяжести. (WHO/NMH/NHD/MNM/11.1). 2011. Доступ: https://www.who.int/vmnis/indicators/haemoglobin_ru.pdf (дата обращения – 01.02.2021). [World Health Organization. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. (WHO/NMH/NHD/MNM/11.1). 2011. Available at: https://www.who.int/vmnis/indicators/haemoglobin_ru.pdf (date of access – 01.02.2021) (In Russ.)].

  34. World Health Organization. Serum ferritin concentrations for the assessment of iron status and iron deficiency in populations. (WHO/NMH/NHD/MNM/11.2). 2011. Available at: https://apps.who.int/iris/bitstream/handle/10665/85843/WHO_NMH_NHD_MNM_11.2_eng.pdf?ua=1 (date of access – 01.02.2021).

  35. Wagner J., Knaier R., Infanger D. et al. Functional aging in health and heart failure: the COmPLETE Study. BMC Cardiovasc Disord. 2019; 19(1): 180. doi: 10.1186/s12872-019-1164-6.

  36. Minamisawa M., Miura T., Motoki H. et al. Prognostic impact of сardio-renal-anemia syndrome in patients at risk for heart failure. Circulation. 2017; 136: A14876.

  37. Nagai T., Nishimura K., Honma T. et al. Prognostic significance of endogenous erythropoietin in long-term outcome of patients with acute decompensated heart failure: Endogenous erythropoietin in acute heart failure. Eur J Heart Fail. 2016; 18(7): 803–13. doi: 10.1002/ejhf.537.

  38. Затонский С.А. Патогенетическое значение цитокинов при хронической сердечной недостаточности ишемического генеза и влияние кардиоваскулярной терапии на иммунологические показатели. Современные проблемы науки и образования. 2013; 6: 607–616. [Zatonsky S.A., Kastanyan A.A. The pathogenetic significance of cytokines in chronic heart failure of ischemic genesis and the effect of cardiovascular therapy on immunological parameters. Sovremennye problemy nauki i obrazovaniya = Modern problems of science and education. 2013; 6: 607–616 (In Russ.)].

  39. Nicolas G., Chauvet C., Viatte L. et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002; 110(7): 1037–44. doi: 10.1172/JCI15686.


About the Autors

Ekaterina I. Tkachenko, postgraduate student of the Department of hospital therapy and general medical practice named after V.G. Vogralik, Privolzhsky Research Medical University of the Ministry of Healthcare of Russia. Address: 603005, Nizhny Novgorod, 10/1 Minin and Pozharsky Sq. Tel.: +7 (915) 944-00-68. E-mail: etkachenko.doc@gmail.com. ORCID: 0000-0003-4767-4945
Natalia Yu. Borovkova, MD, associate professor, professor of the Department of hospital therapy and general medical practice named after V.G. Vogralik, Privolzhsky Research Medical University of the Ministry of Healthcare of Russia. Address: 603005, Nizhny Novgorod, 10/1 Minin and Pozharsky Sq. Tel.: +7 (910) 382-20-73. E-mail: borovkov-nn@mail.ru
Nikolay N. Borovkov, MD, professor, professor of the Department of hospital therapy and general medical practice named after V.G. Vogralik, Privolzhsky Research Medical University of the Ministry of Healthcare of Russia. Address: 603005, Nizhny Novgorod, 10/1 Minin and Pozharsky Sq. Tel.: +7 (910) 382-20-72. E-mail: borovkov-nn@mail.ru
Tatiana E. Bakka, acting head of the cardiology Department, N.A. Semashko Nizhegorodsky Regional Clinical Hospital. Address: 603126, Nizhny Novgorod, 190 Rodionova Str. Тел.: +7 (987) 399-53-86. E-mail: medic.89@list.ru

Back to Content

Бионика Медиа