THE ROLE OF IRON IN HEART FAILURE: A LITERATURE REVIEW

Iron has a key role in the energy generation of the cell. Different organs utilize iron for their diverse needs. The heart is an organ that demands high energy. Nearly one-third of stable heart failure patients and half of the hospitalized patients, regardless of their heart failure status, have anemia. The potential cause of anemia in heart failure patients is found to be multifactorial. Iron deficiency anemia is associated with the reduced number of red blood cells, which transport oxygen into the tissues of the human body. Therefore, in iron deficiency, mitochondria produce less energy. Since iron deficiency has a very important role in the prognosis of heart failure, since the beginning of the 2000s, researchers have conducted several studies and trials, investigating the effect of correcting iron deficiency on the clinical and symptomatic outcomes of heart failure. The most recent results of those studies and trials suggest that intravenous iron therapy in heart failure with reduced ejection fraction patients is associated with improved exercise capability, quality of life, and New York Heart Association class. Ongoing trials such as Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure 2 are aimed more into investigating hospitalization and mortality rates of patients on intravenous iron therapy.

Keywords:

iron anemia, heart failure,

PDF

___

1.Shahar E, Lee S, Kim J et al. Hospitalized heart failure: rates and long-term mor- tality. J Card Fail 2004;10(5):374-9.
2. Klip IT, Comin-Colet J, Voors AA et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J 2013;165(4):575-82.e3.
3. Anand IS, Gupta P. Anemia and iron deficiency in heart failure: current concepts and emerging therapies. Circulation 2018;138(1):80-98.
4. Anderson GJ, Frazer DM. Current understanding of iron homeostasis. Am J Clin Nutr 2017;106(6):1559-66.
5. Wallace DF. The regulation of iron absorption and homeostasis. Clin Biochem Rev 2016;37(2):51-62.
6. Saito H. Metabolism of iron stores. Nagoya J Med Sci 2014;76(3-4):235-54.
7. Umbreit JN, Conrad ME, Moore EG et al. Iron absorption and cellular transport: the mobilferrin/paraferritin paradigm. Semin Hematol 1998;35(1):13-26.
8. Beck KL. Anemia: prevention and dietary strategies. In: Caballero B, editor. Ency- clopedia of Food and Health. Oxford: Academic Press; 2016.p.164-8.
9. Maitra D, Byun J, Andreana PR et al. Reaction of hemoglobin with HOCl: mechanism of heme destruction and free iron release. Free Radic Biol Med 2011;51(2):374-86.
10. Enculescu M, Metzendorf C, Sparla R et al. Modelling systemic iron regulation during dietary iron overload and acute inflammation: role of hepcidin-indepen- dent mechanisms. PLoS Comput Biol 2017;13(1):e1005322.
11. Rassow J, Hauser K, Netzker R et al. Duale Reihe Biochemie. Thieme; 2016.p.324.
12. Gulec S, Anderson GJ, Collins JF. Mechanistic and regulatory aspects of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol 2014;307(4):397-409.
13. Loreal O, Cavey T, Bardou-Jacquet E et al. Iron, hepcidin, and the metal connec- tion. Front Pharmacol 2014;5:128.
14. Ganz T. Systemic iron homeostasis. Physiol Rev 2013;93(4):1721-41.
15. MacKenzie EL, Iwasaki K, Tsuji Y. Intracellular iron transport and storage: from molecular mechanisms to health implications. Antioxid Redox Signal 2008;10(6):997-1030.
16. Wilkinson N, Pantopoulos K. The IRP/IRE system in vivo: insights from mouse models. Front Pharmacol 2014;5:176.
17. Mastrogiannaki M, Matak P, Peyssonnaux C. The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions. Blood 2013;122(6):885-92.
18. Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nat Chem Biol 2014;10(1):9-17.
19. Orino K, Lehman L, Tsuji Y et al. Ferritin and the response to oxidative stress. Biochem J 2001;357(1):241-7.
20. Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis: dis- tinct control mechanisms in erythroid cells. Blood 1997;89(1):1-25.
21. Severance S, Hamza I. Trafficking of heme and porphyrins in metazoa. Chem Rev 2009;109(10):4596-616.
22. Kumari A. Heme synthesis. In: Kumari A, editor. Sweet Biochemistry: Academic Press; 2018.p.33-6.
23. Ferreira GC, Franco R, Lloyd SG et al. Structure and function of ferrochelatase. J Bioenerg Biomembr 1995;27(2):221-9.
24. Haq RU, Wereley JP, Chitambar CR. Induction of apoptosis by iron deprivation in human leukemic CCRF-CEM cells. Exp Hematol 1995;23(5):428-32.
25. Ghafourian K, Shapiro JS, Goodman L et al. Iron and heart failure: diagnosis, therapies, and future directions. JACC Basic Transl Sci 2020;5(3):300-13.
26. Comin-Colet J, Enjuanes C, Gonzalez G et al. Iron deficiency is a key determinant of health-related quality of life in patients with chronic heart failure regardless of anaemia status. Eur J Heart Fail 2013;15(10):1164-72.
27. Kuo KL, Hung SC, Lee TS et al. Iron sucrose accelerates early atherogenesis by increasing superoxide production and upregulating adhesion molecules in CKD. J Am Soc Nephrol 2014;25(11):2596-606.
28. Kautz L, Gabayan V, Wang X et al. Testing the iron hypothesis in a mouse model of atherosclerosis. Cell Rep 2013;5(5):1436-42.
29. Anand IS, Kuskowski MA, Rector TS 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.
30. Anand I, McMurray JJ, Whitmore J et al. Anemia and its relationship to clinical outcome in heart failure. Circulation 2004;110(2):149-54.
31. Opasich C, Cazzola M, Scelsi L et al. Blunted erythropoietin production and de- fective iron supply for erythropoiesis as major causes of anaemia in patients with chronic heart failure. Eur Heart J 2005;26(21):2232-7.
32. Al-Ahmad A, Rand WM, Manjunath G et al. Reduced kidney function and ane- mia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol 2001;38(4):955-62.
33.Horwich TB, Fonarow GC, Hamilton MA et al. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant in- crease in mortality in patients with advanced heart failure. J Am Coll Cardiol 2002;39(11):1780-6.
34. Anand IS. Anemia and chronic heart failure. Journal of the American College of Cardiology 2008;52(7):501-11.
35. Witte KK, Desilva R, Chattopadhyay S et al. Are hematinic deficiencies the cause of anemia in chronic heart failure? Am Heart J 2004;147(5):924-30.
36. Bauer C, Kurtz A. Oxygen sensing in the kidney and its relation to erythropoietin production. Annu Rev Physiol 1989;51:845-56.
37. Volpe M, Tritto C, Testa U et al. Blood levels of erythropoietin in congestive heart failure and correlation with clinical, hemodynamic, and hormonal profiles. Am J Cardiol 1994;74(5):468-73.
38. van der Meer P, Lipsic E, Westenbrink BD et al. Levels of hematopoiesis inhibitor N-acetyl-seryl-aspartyl-lysyl-proline partially explain the occurrence of anemia in heart failure. Circulation 2005;112(12):1743-7.
39. Androne AS, Katz SD, Lund L et al. Hemodilution is common in patients with advanced heart failure. Circulation 2003;107(2):226-9.
40. Montero D, Lundby C, Ruschitzka F et al. True anemia-red blood cell volume deficit-in heart failure: a systematic review. Circ Heart Fail 2017;10(5):e003610.
41. Jelkmann W. Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res 1998;18(8):555-9.
42. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352(10):1011-23.
43. McMahon LP, Mason K, Skinner SL et al. Effects of haemoglobin normaliza- tion on quality of life and cardiovascular parameters in end-stage renal failure. Nephrol Dial Transplant 2000;15(9):1425-30.
44. O'Meara E, Clayton T, McEntegart MB et al. Clinical correlates and consequences of anemia in a broad spectrum of patients with heart failure: results of the Can- desartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program. Circulation 2006;113(7):986-94.
45. Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12 065 patients with new-onset heart failure. Circulation 2003;107(2):223-5.
46. Groenveld HF, Januzzi JL, Damman K et al. Anemia and mortality in heart failure patients a systematic review and meta-analysis. J Am Coll Cardiol 2008;52(10):818-27.
47. Komajda M, Anker SD, Charlesworth 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.
48. Sharma R, Francis DP, Pitt B et al. Haemoglobin predicts survival in pa- tients with chronic heart failure: a substudy of the ELITE II trial. Eur Heart J 2004;25(12):1021-8.
49. Gagnon DR, Zhang TJ, Brand FN et al. Hematocrit and the risk of cardio- vascular disease--the Framingham study: a 34-year follow-up. Am Heart J 1994;127(3):674-82.
50. Sabatine MS, Morrow DA, Giugliano RP et al. Association of hemoglo- bin levels with clinical outcomes in acute coronary syndromes. Circulation 2005;111(16):2042-9.
51. Brown DW, Giles WH, Croft JB. Hematocrit and the risk of coronary heart disease mortality. Am Heart J 2001;142(4):657-63.
52. Datta BN, Silver MD. Cardiomegaly in chronic anaemia in rats; gross and histo- logic features. Indian J Med Res 1976;64(3):447-58.
53. Ponikowski P, Voors AA, Anker SD et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagno- sis 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. European Heart Journal 2016;37(27):2129-200.
54. Grote Beverborg N, Klip IT, Meijers WC 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.
55. Swedberg K, Young JB, Anand IS et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med 2013;368(13):1210-9.
56. Kotecha D, Ngo K, Walters JA et al. Erythropoietin as a treatment of anemia in heart failure: systematic review of randomized trials. Am Heart J 2011;161(5):822- 31.e2.
57. McMurray JJ, Anand IS, Diaz R et al. Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF). Eur J Heart Fail 2013;15(3):334-41.
58. Silverberg DS, Wexler D, Blum M et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant conges- tive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol 2000;35(7):1737-44.
59. Lewis GD, Semigran MJ, Givertz MM et al. Oral iron therapy for heart failure with reduced ejection fraction: design and rationale for oral iron repletion effects on oxygen uptake in heart failure. Circ Heart Fail 2016;9(5):e000345.
60. Lewis GD, Malhotra R, Hernandez AF et al. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection frac- tion and iron deficiency: the IRONOUT HF randomized clinical trial. JAMA 2017;317(19):1958-66.
61. Anker SD, Kirwan BA, van Veldhuisen DJ et al. Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis. Eur J Heart Fail 2018;20(1):125-33.
62. Anker SD, Comin-Colet J, Filippatos G et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361(25):2436-48.
63. Anker SD, Comin-Colet J, Filippatos G et al. Rationale and design of Ferinject assessment in patients with IRon deficiency and chronic Heart Failure (FAIR-HF) study: a randomized, placebo-controlled study of intravenous iron supplementa- tion in patients with and without anaemia. Eur J Heart Fail 2009;11(11):1084-91.
64. Ponikowski P, van Veldhuisen DJ, Comin-Colet J et al. Beneficial effects of long- term intravenous iron therapy with ferric carboxymaltose in patients with symp- tomatic heart failure and iron deficiencydagger. Eur Heart J 2015;36(11):657-68.
65. Ponikowski P, van Veldhuisen DJ, Comin-Colet J et al. Rationale and design of the CONFIRM-HF study: a double-blind, randomized, placebo-controlled study to assess the effects of intravenous ferric carboxymaltose on functional capac- ity in patients with chronic heart failure and iron deficiency. ESC Heart Fail 2014;1(1):52-8.
66. van Veldhuisen DJ, Ponikowski P, van der Meer P et al. Effect of ferric carboxy- maltose on exercise capacity in patients with chronic heart failure and iron defi- ciency. Circulation 2017;136(15):1374-83.
67.Ponikowski P, Kirwan B-A, Anker SD et al. Ferric carboxymaltose for iron de- ficiency at discharge after acute heart failure: a multicentre, double-blind, ran- domised, controlled trial. The Lancet 2020;396(10266):1895-904.
68. Ponikowski P, Kirwan BA, Anker SD et al. Rationale and design of the AF- FIRM-AHF trial: a randomised, double-blind, placebo-controlled trial compar- ing the effect of intravenous ferric carboxymaltose on hospitalisations and mor- tality in iron-deficient patients admitted for acute heart failure. Eur J Heart Fail 2019;21(12):1651-8.
69. Khan MS, Usman MS, von Haehling S et al. Ferric carboxymaltose for the treat- ment of iron-deficient heart failure patients: a systematic review and meta-analy- sis. ESC Heart Fail 2020;7(6):3392-400.
70. Intravenous Iron in Patients with Systolic Heart Failure and Iron Deficiency to Improve Morbidity & Mortality (FAIR-HF2) (serial online) (cited 2021 May 24) Available from: URL:https://clinicaltrials.gov/ct2/show/NCT03036462?term=- FAIR-HF2&draw=2&rank=1.