Clinical Physiology of Circulation

Chief Editor

Leo A. Bockeria, MD, PhD, DSc, Professor, Academician of Russian Academy of Sciences, Director of Bakoulev National Medical Research Center for Cardiovascular Surgery

Anemia associated with heart failure: epidemiology, pathogenesis, and prognosis

Authors: A.A. Kupryashov, M.I. Rivnyak

Bakoulev National Medical Research Center for Cardiovascular Surgery, Moscow, 121552, Russian Federation

E-mail: Сведения доступны для зарегистрированных пользователей.


UDC: 616.12-008.46:616.15

Link: Clinical Physiology of Blood Circulaiton. 2020; 17 (3): 172-182

Quote as: Kupryashov A.A., Rivnyak M.I. Anemia associated with heart failure: epidemiology, pathogenesis, and prognosis. Clinical Physiology of Circulation. 2020; 17 (3): 172–82 (in Russ.). DOI: 10.24022/1814-6910-2020-17-3-172-182

Received / Accepted:  19.06.2020/22.06.2020

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Anemia are important and common comorbidities that often coexist in patients with heart failure, with a prevalence of 12 to 76.7%, depending on the study population. Both diseases, together or independently, are associated with an increase in mortality, the number of hospitalizations and a decrease in exercise tolerance, quality of life and an increase costs. The causes of heart failure associated anemia are various. The main pathophysiological mechanisms involved in its development are iron deficiency, inflammation, insufficient secretion of erythropoietin, hemodilution and bone marrow dysfunction, pharmacological effects. In clinical practice, the etiology of anemia requires careful to determine the optimal method for its correction. In this context, further studies should be carried out in order to understand the basis of the complex pathophysiology of the association of anemia with a decrease in exercise tolerance, to prospectively identify the contribution of each of the factors, to evaluate the ideal threshold at which therapy should be started.


  1. Ponikowski P., Voors A.A., Anker S.D., Bueno H., Cleland J.G., Coats A.J. et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. J. Heart Fail. 2016; 18: 891–975. DOI: 10.1002/ejhf.592 
  2. Munting K.E., Klein A.A. Optimisation of pre-operative anaemia in patients before elective major surgery – why, who, when and how? Anaesthesia. 2019; 74 (1): 49–57. DOI: 10.1111/anae.14466 
  3. Mozaffarian D., Nye R., Levy W.C. Anemia predicts mortality in severe heart failure: the prospective randomized amlodipine survival evaluation (PRAISE). J. Am. Coll. Cardiol. 2003; 41 (11): 1933–9. DOI: 10.1016/ s0735-1097(03)00425-x 
  4. Anker S., Coats A.J.S., Roecker E.B., Mohacsi P., Packer M. Hemoglobin level is associated with mortality and hospitalization in patients with severe chronic heart failure: results from the COPERNICUS study (abstr). J. Am. Coll. Cardiol. 2004; 43 (Suppl. A): 216A. DOI: 10.1016/S0735-1097(04)90919-9 
  5. Anand I., McMurray J.J., Whitmore J., Warren M., Pham A., McCamish M.A. et al. Anemia and its relationship to clinical outcome in heart failure. Circulation. 2004; 110 (2): 149–54. DOI: 10.1161/01.CIR. 0000134279.79571.73 
  6. Anand I.S., Kuskowski M.A., Rector T.S., Florea V.G., Glazer R.D., Hester A. et al. Anemia and change in hemoglobin over time related to mortality and morbidity in patients with chronic heart failure: results from Val-HeFT. Circulation. 2005; 112 (8): 1121–7. DOI: 10.1161/CIRCULATIONAHA.104.512988 
  7. Komajda M., Anker S.D., Charlesworth A., Okonko D., Metra M., Di Lenarda A. et al. The impact of new onset anaemia on morbidity and mortality in chronic heart failure: results from COMET. Eur. Heart J. 2006; 27 (12): 1440–6. DOI: 10.1093/eurheartj/ehl012
  8. O'Meara E., Clayton T., McEntegart M.B., McMurray J.J., Lang C.C., Roger S.D. et al. Clinical correlates and consequences of anemia in a broad spectrum of patients with heart failure: results of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program. Circulation. 2006; 113 (7): 986–94. DOI: 10.1161/CIRCULATIONAHA. 105.582577
  9. Nanas J.N., Matsouka C., Karageorgopoulos D., Leonti A., Tsolakis E., Drakos S.G. et al. Etiology of anemia in patients with advanced heart failure. J. Am. Coll. Cardiol. 2006; 48 (12): 2485–9. DOI: 10.1016/ j.jacc.2006.08.034 
  10. Dunlay S.M., Weston S.A., Redfield M.M., Killian J.M., Roger V.L. Anemia and heart failure: a community study. Am. J. Med.2008; 121 (8): 726–32. DOI: 10.1016/ j.amjmed.2008.03.039 
  11. Cardoso J., Brito M.I., Ochiai M.E., Novaes M., Berganin F., Thicon T. et al. Anemia in patients with advanced heart failure. Arq. Bras. Cardiol. 2010; 95 (4): 524–8. DOI: 10.1590/s0066-782x2010005000118 
  12. Berry C., Poppe K.K., Gamble G.D., Earle N.J., Ezekowitz J.A., Squire I.B. et al. Prognostic significance of anaemia in patients with heart failure with preserved and reduced ejection fraction: results from the MAGGIC individual patient data meta-analysis. QJM. 2015; 109 (6): 377–82. DOI: 10.1093/qjmed/hcv087 
  13. Yamauchi T., Sakata Y., Takada T., Nochioka K., Miura M., Tadaki S. et al. Prognostic impact of anemia in patients with chronic heart failure – with special reference to clinical background: Report from the CHART-2 Study. Circ. J. 2015; 79 (9): 1984–93. DOI: 10.1253/circj.CJ-15-0174 
  14. Ebner N., Jankowska E.A., Ponikowski P., Lainscak M., Elsner S., Sliziuk V. et al. The impact of iron deficiency and anaemia on exercise capacity and outcomes in patients with chronic heart failure. Results from the Studies Investigating сo-morbidities Aggravating Heart Failure. Int. J. Cardiol. 2016; 205: 6–12. DOI: 10.1016/ j.ijcard.2015.11.178 
  15. Cleland J.G., Zhang J., Pellicori P., Dicken B., Dierckx R., Shoaib A. et al. Prevalence and outcomes of anemia and hematinic deficiencies in patients with chronic heart failure. JAMA Cardiol. 2016; 1 (5): 539–47. DOI: 10.1001/jamacardio.2016.1161 
  16. Frigy A., Fogarasi Z., Kocsis I., MáthéL., Nagy E. The prevalence and clinical significance of anemia in patients hospitalized with acute heart failure. F1000Res. 2016; 5: 1006. DOI: 10.12688/f1000research.7872.2 
  17. Son Y.J., Kim B.H. Prevalence of anemia and its influence on hospital readmissions and emergency department visits in outpatients with heart failure. Eur. J. Cardiovasc. Nurs. 2017; 16 (8): 687–95. DOI: 10.1177/ 1474515117710154 
  18.  Arora H., Sawhney J.P.S., Mehta A., Mohanty A. Anemia profile in patients with congestive heart failure a hospital based observational study. Indian Heart J. 2018; 70 (Suppl 3): S101–4. DOI: 10.1016/j.ihj.2018. 06.017 
  19. Jankowska E.A., Malyszko J., Ardehali H., Koc-Zorawska E., Banasiak W., von Haehling S. et al. Iron status in patients with chronic heart failure. Eur. Heart J. 2013; 34 (11): 827–34. DOI: 10.1093/eurheartj/ehs377 
  20. Weiss G., Goodnough L.T. Anemia of chronic disease. N. Engl. J. Med.2005; 352 (10): 1011–23. DOI: 10.1056/ NEJMra041809 
  21. Silverberg D.S., Wexler D., Schartz D. Is correction of iron deficiency a new addition to the treatment of the heart failure? Int. J. Mol. Sci. 2015; 16 (6): 14056–74. DOI: 10.3390/ijms160614056 
  22. Witte K.K., Clark A.L., Cleland J.G. Chronic heart failure and micronutrients. J. Am. Coll. Cardiol. 2001; 37 (7): 1765–74. DOI: 10.1016/s0735-1097 (01)01227-x 
  23. Westenbrink B.D., Voors A.A., de Boer R.A., Schuringa J.J., Klinkenberg T. van der Harst P. et al. Bone marrow dysfunction in chronic heart failure patients. Eur. J. Heart Fail. 2010; 12 (7): 676–84. DOI: 10.1093/ eurjhf/hfq061 
  24. Mahmud H., Ruifrok W.P, Westenbrink B.D., Cannon M.V., Vreeswijk-Baudoin I., van Gilst W.H. et al. Suicidal erythrocyte death, eryptosis, as a novel mechanism in heart failure-associated anaemia. Cardiovasc. Res. 2013; 98 (1): 37–46. DOI: 10.1093/cvr/cvt010 
  25. Adlbrecht C., Kommata S., Hülsmann M., Szekeres T., Bieglmayer C., Strunk G. et al. Chronic heart failure leads to an expanded plasma volume and pseudoanaemia, but does not lead to a reduction in the body's red cell volume. Eur. Heart J. 2008; 29 (19): 2343–50. DOI: 10.1093/eurheartj/ehn359 
  26. Caramelo C., Gil P. Insuficiencia combinada cardiorrenal: una clave evolutiva y terapéutica en el fallo cardíaco. Rev. Esp. Cardiol. 2006; 59: 87–90. DOI: 10.1157/13084633 
  27. Van der Meer P., Lipsic E., Westenbrink B.D., van de Wal R.M., Schoemaker R.G., Vellenga E. et al. Levels of hematopoiesis inhibitor N-acetyl-seryl-aspartyllysyl-proline partially explain the occurrence of anemia in heart failure. Circulation. 2005; 112 (12): 1743–7. DOI: 10.1161/CIRCULATIONAHA.105.549121 
  28. Eggold J.T., Rankin E.B. Erythropoiesis, EPO, macrophages, and bone. Bone. 2019; 119: 36–41. DOI: 10.1016/ j.bone.2018.03.014 
  29. RuifrokW.P., Qian C., SilljéH.H., van Goor H., van Veldhuisen D.J., van Gilst W.H. et al. Heart failure-associated anemia: bone marrow dysfunction and response to erythropoietin. J. Mol. Med (Berl). 2011; 89 (4): 377–87. DOI: 10.1007/s00109-010-0710-6 
  30. Iversen P.O., Woldbaek P.R., Tønnessen T., Christensen G. Decreased hematopoiesis in bone marrow of mice with congestive heart failure. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2002; 282 (1): R166–72. DOI: 10.1152/ajpregu.2002.282.1.R166 
  31. Zhang H., Trivedi A., Lee J.U., Lohela M., Lee S.M., Fandel T.M. et al. Matrix metalloproteinase-9 and stromal cell-derived factor-1 act synergistically to support migration of blood-borne monocytes into the injured spinal cord. J. Neurosci. 2011; 31 (44): 15894–903. DOI: 10.1523/JNEUROSCI.3943-11.2011 
  32. Miller E.S., Loftus T.J., Kannan K.B., Plazas J.M., Efron P.A., Mohr A.M. Systemic regulation of bone marrow stromal cytokines after severe trauma. J. Surg. Res. 2019; 243: 220–8. DOI: 10.1016/j.jss.2019.05.033 
  33. Chow A., Huggins M., Ahmed J., Hashimoto D., Lucas D., Kunisaki Y. et al. CD169+ macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nat. Med. 2013; 19 (4): 429–36. DOI: 10.1038/nm.3057 
  34. Gossmann J., Burkhardt R., Harder S., Lenz T., Sedlmeyer A., Klinkhardt U. et al. Angiotensin II infusion increases plasma erythropoietin levels via an angiotensin II type 1 receptor-dependent pathway. Kidney Int. 2001; 60 (1): 83–6. DOI: 10.1046/j.15231755.2001.00773.x 
  35. Montero D., Haider T., Flammer A.J. Erythropoietin response to anaemia in heart failure. Eur. J. Prev. Cardiol. 2019; 26 (1): 7–17. DOI: 10.1177/ 2047487318790823 
  36. Wilkinson N., Pantopoulos K. IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2α mRNA translation. Blood. 2013; 122 (9): 1658–68. DOI: 10.1182/blood-2013-03-492454 
  37. Paul B.T., Manz D.H., Torti F.M., Torti S.V. Mitochondria and iron: current questions. Expert Rev. Hematol. 2017; 10 (1): 65–79. DOI: 10.1080/17474086. 2016.1268047 
  38.  Hashimoto T., Shibasaki F. Hypoxia-inducible factor as an angiogenic master switch. Front. Pediatr. 2015; 3: 33. DOI: 10.3389/fped.2015.00033 
  39. Dziegala M., Kobak K.A., Kasztura M., Bania J., Josiak K., Banasiak W. et al. Iron depletion affects genes encoding mitochondrial electron transport chain and genes of non-oxidative metabolism, pyruvate kinase and lactate dehydrogenase, in primary human cardiac myocytes cultured upon mechanical stretch. Cells. 2018; 7 (10). DOI: 10.3390/cells7100175 
  40. Rineau E., Gaillard T., Gueguen N., Procaccio V., Henrion D., Prunier F. et al. Iron deficiency without anemia is responsible for decreased left ventricular function and reduced mitochondrial complex I activity in a mouse model. Int. J. Cardiol. 2018; 266: 206–12. DOI: 10.1016/j.ijcard.2018.02.021 
  41. Pozzo J., Fournier P., Delmas C., Vervueren P.L., Roncalli J., Elbaz M. et al. Absolute iron deficiency without anaemia 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 
  42. Moliner P., Enjuanes C., Tajes M., Cainzos-Achirica M., Lupón J., Garay A. et al. Association between norepinephrine levels and abnormal iron status in patients with chronic heart failure: is iron deficiency more than a comorbidity? J. Am. Heart Assoc. 2019; 8 (4): e010887. DOI: 10.1161/JAHA.118.010887 
  43. Peyrin-Biroulet L., Wiliet N., Cacoub P. Guidelines on the diagnosis and treatment of iron deficiency across indications: a systematic review. Am. J. Clin. Nutr. 2015; 102 (6): 1585–94. DOI: 10.3945/ajcn.114.103366 
  44. Grote Beverborg N., Klip I.T., Meijers W.C., Voors A.A., Vegter E.L., van der Wal H.H. et al. Definition of iron deficiency based on the gold standard of bone marrow iron staining in heart failure patients. Circ. Heart Fail. 2018; 11 (2): e004519. DOI: 10.1161/ CIRCHEARTFAILURE.117.004519 
  45. Petzer V., Theurl I., Weiss G. Established and emerging concepts to treat imbalances of iron homeostasis in inflammatory diseases. Pharmaceuticals (Basel). 2018; 11 (4). pii: E135. DOI: 10.3390/ph11040135 
  46. Buck I., Morceau F., Cristofanon S., Reuter S., Dicato M., Diederich M. The inhibitory effect of the proinflammatory cytokine TNFalpha on erythroid differentiation involves erythroid transcription factor modulation. Int. J. Oncol. 2009; 34 (3): 853–60. DOI: 10.3892/ijo_00000212 
  47. Соломахина Н.И., Находнова Е.С., Ершов В.И., Беленков Ю.Н. Роль гепсидина в формировании анемии хронических заболеваний и железодефицитной анемии убольных схронической сердечной недостаточностью в пожилом и старческом возрасте. Кардиология. 2018; 58 (3): 20–7. DOI: 10.18087/ cardio.2018.3.10094 [Solomakhina N.I., Nakhodnova E.S., Ershov V.I., Belenkov Yu.N. The role of hepcidin in formation of anemia of chronic disease and iron deficiency anemia in elderly and old patients with chronic heart failure. Kardiologiia.2018; 58 (3): 20–7 (in Russ.). DOI: 10.18087/ cardio.2018.3.10094] 
  48. Markousis-Mavrogenis G., Tromp J., Ouwerkerk W., Devalaraja M., Anker S.D., Cleland J.G. et al. The clinical significance of interleukin-6 in heart failure: results fromthe BIOSTAT-CHF study. Eur. J. Heart Fail. 2019; 21 (8): 965–73. DOI: 10.1002/ejhf.1482
  49. Оtto J.M., Plumb J.O.M., Clissold E., Kumar S.B., Wakeham D.J., Schmidt W. et al. Hemoglobin concentration, total hemoglobin mass and plasma volume in patients: implications for anemia. Haematologica. 2017; 102 (9):1477–85. DOI: 10.3324/haematol.2017.169680 
  50. Montero D., Lundby C., Ruschitzka F., Flammer A.J. True anemia–red blood cell volume deficit–in heart failure: a systematic review. Circ. Heart Fail. 2017; 10 (5). pii: e003610. DOI: 10.1161/CIRCHEARTFAILURE. 116.003610 
  51. Nijst P., Verbrugge F.H., Bertrand P.B., Martens P., Dupont M., Drieskens O. et al. Plasma volume is normal but heterogeneously distributed, and true anemia is highly prevalent in patients with stable heart failure. J. Card. Fail. 2017; 23 (2): 138–44. DOI: 10.1016/ j.cardfail.2016.08.008 
  52. Strobeck J.E., Feldschuh J., Miller W.L. Heart failure outcomes with volume-guided management. JACC Heart Fail. 2018; 6 (11): 940–8. DOI: 10.1016/j.jchf. 2018.06.017 
  53. Ishani A., Weinhandl E., Zhao Z., Gilbertson D.T., Collins A.J., Yusuf S. 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): 391–9. DOI: 10.1016/j.jacc. 2004.10.038 
  54. Kaiafa G., Kanellos I., Savopoulos C., Kakaletsis N., Gannakoulas G., Hatzitolios A.I. Is anemia a new car diovascular risk factor? Int. J. Cardiol. 2015; 186: 117–24. DOI: 10.1016/j.ijcard.2015.03.159 
  55. Golden J.S., Fallick C.C., Josephson S.R. et al. Baseline hematocrit predicts clinical outcomes in heart failure. Circulation. 2002; 106 (Suppl): 3358A. 
  56. . Polanczyk C.A., Newton C., Dec G.W., Di Salvo T.G. Quality of care and hospital readmission in congestive heart failure: an explicit review process. J. Card. Fail. 2001; 7 (4): 289–98. DOI: 10.1054/jcaf.2001.28931 
  57. Felker G.M., Gattis W.A., Leimberger J.D., Adams K.F., Cuffe M.S., Gheorghiade M. et al. Usefulness of anemia as a predictor of death and rehospitalization in patients with decompensated heart failure. Am. J. Cardiol. 2003; 92: 625–8. DOI: 10.1016/s0002-9149 (03)00740-9 
  58.  Al-Ahmad A., Rand W.M., Manjunath G., Konstam M.A., Salem D.N., Levey A.S. et al. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J. Am. Coll. Cardiol. 2001; 38: 955–62. DOI: 10.1016/s0735-1097 (01)01470-x
  59.  Kalra P.R., Bolger A.P., Francis D.P., Genth-Zotz S., Sharma R., Ponikowski P.P. et al. Effect of anemia on exercise tolerance in chronic heart failure in men. Am. J. Cardiol. 2003; 91 (7): 888–91. DOI: 10.1016/s00029149 (03)00030-4 
  60. Allen L.A., Anstrom K.J., Horton J.R., Shaw L.K., Eisenstein E.L., Felker G.M. Relationship between anemia and health care costs in heart failure. J. Card. Fail. 2009; 15 (10): 843–9. DOI: 10.1016/j.cardfail. 2009.06.435

About Authors

  • Aleksey A. Kupryashov, Dr. Med. Sc., Head of Department of Clinical and Industrial Transfusiology and Diagnostic Laboratory; 
  • Marina I. Rivnyak, Cardiologist;

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