Role of hepcidin in assessing the prognosis of elderly and senile patients with heart failure and anemia

Aim. To study the role of hepcidin in assessing the prognosis of elderly and senile patients with heart failure (HF) and anemia.

Material and methods. The study included 105 patients aged 65 to 90 years with NYHA class II‑IV HF of ischemic origin with anemia. Patients were tested for hepcidin and N‑terminal pro‑brain natriuretic peptide (NT‑proBNP) levels once upon admission. Patients were followed up until the primary endpoint of cardiovascular and non‑cardiovascular death for up to 24 months. To assess the effect of hepcidin levels on the risk of death, patients were stratified by quartiles (Q) of hepcidin levels. In each quartile, patients were divided into 2 following groups: with absolute and functional iron deficiency. Cox proportional hazards regression analysis was used to assess the effect of hepcidin levels on the death risk.

Results. In patients with HF and anemia, hepcidin levels differed significantly between Q1 and Q4 (p<0,001). Severity of absolute iron deficiency decreased from Q1 to Q4, while the severity of the systemic inflammatory response, on the contrary, increased from Q1 to Q4. During the first 6 months of follow‑up, the highest mortality was found in patients in Q1 (40%), and during 24 months — in patients in Q4 (77%). Regression analysis revealed a significant effect on the death risk of low hepcidin levels (3,0510,33 ng/ml) in patients of Q1 in model 1 (odds ratio (OR) 1,661 (95% confidence interval (CI): 1,198‑2,303), p=0,002), in model 2 (OR 1,911 (95% CI: 1,350‑2,705), p<0,001). There was also a tendency towards a significant effect of elevated hepcidin levels on the death risk (25,81‑70,71 ng/ml) in Q4 patients in model 1 (OR 1,044 (95% CI: 0,997‑1,099), p=0,070), while in model 2, no significant effects on the death risk were found (OR 1,036 (95% CI: 0,989‑1,086), p=0,135). The relationship between hepcidin and the death risk had a U‑shaped curve in both models.

Conclusion. To assess the prognosis in elderly and senile patients with HF and anemia, taking into account the identified effect of both low and elevated hepcidin levels on the death risk, hepcidin levels should be determined in addition to NT‑proBNP.

1. Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276(11):7806‑10. doi:10.1074/jbc.M008922200.

2. Nemeth E, Rivera S, Gabayan V, et al. IL‑6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113(9):1271‑6. doi:10.1172/JCI20945.

3. Nemeth E, Valore EV, Territo M, et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute‑phase protein. Blood. 2003;101(7):2461‑3. doi:10.1182/blood2002‑10‑3235.

4. Lanser L, Fuchs D, Kurz K, et al. Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis‑Mechanistic Insights into Anemia of Inflammation and Its Treatment. Nutrients. 2021;13(11):3732. doi:10.3390/nu13113732.

5. Solomakhina NI, Lishuta AS, Dementieva AV. Hepcidin as a regulator of iron metabolism and mediator of inflammation in patients with chronic heart failure and anemia of chronic diseases of the elderly and senile age. Rational Pharmacotherapy in Cardiology. 2022;18(5): 553‑63. (In Russ.) doi:10.20996/1819‑6446‑2022‑09‑03.

6. Nemeth E, Ganz T. Hepcidin and Iron in Health and Disease. Annu Rev Med. 2023;74:26177. doi:10.1146/annurev‑med‑043021‑032816.

7. Blindar VN, Zubrikhina GN, Matveeva II. The main metabolites of ferrokinetics in differentiated diagnostic of anemic syndrome. Klin Lab Diagn. 2016;61(4):219‑23. (In Russ.) doi:10.18821/0869‑2084‑2016‑61‑4219‑223.

8. Ellingsen TS, Lappegård J, Ueland T, et al. Plasma hepcidin is associated with future risk of venous thromboembolism. Blood Adv. 2018;2(11):1191‑7. doi:10.1182/bloodadvances.2018018465.

9. Li X, Ding D, Zhang Y, et al. Associations of plasma hepcidin with mortality risk in patients with coronary artery disease. Oncotarget. 2017;8(65):109497‑508. doi:10.18632/oncotarget.22722.

10. Grammer TB, Scharnagl H, Dressel A, et al. Iron Metabolism, Hepcidin, and Mortality (the Ludwigshafen Risk and Cardiovascular Health Study). Clin Chem. 2019;65(7):849‑61. doi:10.1373/clinchem.2018.297242.

11. Zeller T, Altay A, Waldeyer C, et al. Prognostic Value of Iron‑Homeostasis Regulating Peptide Hepcidin in Coronary Heart Disease‑Evidence from the Large AtheroGene Study. Biomolecules. 2018;8(3):43. doi:10.3390/biom8030043.

12. Ruhe J, Waldeyer C, Ojeda F, et al. Intrinsic Iron Release Is Associated with Lower Mortality in Patients with Stable Coronary Artery Disease‑First Report on the Prospective Relevance of Intrinsic Iron Release. Biomolecules. 2018;8(3):72. doi:10.3390/biom8030072.

13. Jankowska EA, Kasztura M, Sokolski M, et al. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure. Eur Heart J. 2014;35(36):2468‑76. doi:10.1093/eurheartj/ehu235.

14. Alnuwaysir RIS, Grote Beverborg N, Hoes MF, et al. Additional burden of iron deficiency in heart failure patients beyond the cardio‑renal anaemia syndrome: findings from the BIOSTAT‑CHF study. Eur J Heart Fail. 2022;24(1):192‑204. doi:10.1002/ejhf.2393.

15. 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):301‑6. doi:10.1253/circj.cj‑09‑0663.

16. Podzolkov VI, Dragomiretskaya NA, Stolbova SK, et al. Associations of NT‑proBNP and hepcidin levels with clinical and laboratory parameters in patients with heart failure with various severity of left ventricular systolic dysfunction. Cardiovascular Therapy and Prevention. 2020;19(4):2587. (In Russ.) doi:10.15829/1728‑8800‑2020‑2587.

17. Girelli D, Marchi G, Camaschella C. Anemia in the Elderly. Hemasphere. 2018;2(3):40. doi:10.1097/HS9.0000000000000040.

18. Bulgakova SV, Zakharova NO, Treneva EV, et al. Current understanding of anemic syndrome in older age groups (literature review). Current problems of health care and medical statistics. 2020;(2);45‑68. (In Russ.) doi:10.24411/2312‑2935‑2020‑10031.

19. Merchant AA, Roy CN. Not so benign haematology: anaemia of the elderly. Br J Haematol. 2012;156(2):173‑85. doi:10.1111/j.1365‑2141.2011.08920.x.

20. 2020 Clinical practice guidelines for Chronic heart failure. Russian Society of Cardiology (RSC). Russian Journal of Cardiology. 2020;25(11):4083. (In Russ.) doi:10. 15829/1560‑4071‑2020‑4083.

21. Mareev VY, Fomin IV, Ageev FT, 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. Kardiologiia. 2018;58(6S):8‑158. (In Russ.) doi:10.18087/cardio.2475.

22. Ponikowska B, Suchocki T, Paleczny B, et al. Iron status and survival in diabetic patients with coronary artery disease. Diabetes Care. 2013;36(12):4147‑56. doi:10.2337/dc13‑0528.

23. Alnuwaysir RIS, Hoes MF, van Veldhuisen DJ, et al. Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology. J Clin Med. 2021;11(1):125. doi:10.3390/jcm11010125.

24. Nemeth E, Ganz T. Hepcidin‑Ferroportin Interaction Controls Systemic Iron Homeostasis. Int J Mol Sci. 2021;22(12):6493. doi:10.3390/ijms22126493.

25. Singh B, Bajaj N, Singh P, et al. Iron deficiency in patients of heart failure with reduced ejection fraction. Med J Armed Forces India. 2022;78(4):463‑8. doi:10.1016/j.mjafi.2022.04.013.

26. Zubrikhina GN, Blindar VN, Matveeva II. Differential diagnosis of anemia in true and functional iron deficiency in patients with chronic diseases (malignant tumors). Ter Arkh. 2016;88(4):61‑7. (In Russ.) doi:10.17116/terarkh201688461‑67.

27. Vorobyeva NM, Tkacheva ON. Safety issues of antiplatelet and anticoagulant therapy in cardiological practice. Pharmateca. 2020;27(13). (In Russ.) doi:10.18565/pharmateca. 2020.13.

28. Arutyunov GP, Kafarskaya LI, Bylova NA, et al. Qualitative and quantitative indicators of the microflora of the large intestine in various functional classes of chronic heart failure. Journal of Heart Failure. 2005;4(5):176‑81. (In Russ.)

29. Smirnova EA, Sedykh EV, Yakushin SS, et al. Prevalence and clinical significance of iron deficiency in patients with acute decompensated heart failure. Russian Journal of Cardiology. 2023;28(8):5413. (In Russ.) doi:10.15829/1560‑4071‑2023‑5413.

30. Köseoğlu FD, Özlek B. Anemia and Iron Deficiency Predict All‑Cause Mortality in Patients with Heart Failure and Preserved Ejection Fraction: 6‑Year Follow‑Up Study. Diagnostics (Basel). 2024;14(2):209. doi:10.3390/diagnostics14020209.

31. Klip IT, Voors AA, Swinkels DW, et al. Serum ferritin and risk for new‑onset heart failure and cardiovascular events in the community. Eur J Heart Fail. 2017;19(3):348‑56. doi:10.1002/ejhf.622.

32. Docherty KF, Welsh P, Verma S, et al. DAPA‑HF Investigators and Committees. Iron Deficiency in Heart Failure and Effect of Dapagliflozin: Findings From DAPA‑HF. Circulation. 2022;146(13):980‑94. doi:10.1161/CIRCULATIONAHA.122.060511.

33. de Almeida AJPO, de Almeida Rezende MS, Dantas SH, et al. Unveiling the Role of Inflammation and Oxidative Stress on Age‑Related Cardiovascular Diseases. Oxid Med Cell Longev. 2020;2020:1954398. doi:10.1155/2020/1954398.

34. Kuster N, Huet F, Dupuy AM, et al. Multimarker approach including CRP, sST2 and GDF‑15 for prognostic stratification in stable heart failure. ESC Heart Fail. 2020;7(5):2230‑9. doi:10.1002/ehf2.12680.