Iron Deficiency in Heart Failure: Characteristics and Treatment
Tóm tắt
Iron deficiency in heart failure has been associated with impaired functional capacity and quality of life. The purpose of this paper is to review mechanisms of iron homeostasis and current clinical data exploring mechanisms of iron repletion in heart failure. Multiple international societies now advise iron repletion for symptomatic heart failure patients with iron deficiency. Due to the chronic inflammation in heart failure, iron deficiency in heart failure is classically defined as ferritin < 100 µg/L or ferritin 100–300 µg/L and transferrin saturation < 20%. Multiple randomized clinical trials have demonstrated benefit from intravenous iron repletion, though studies have predominantly focused on functional capacity and quality of life. A recent study, AFFIRM-AHF, supports the treatment of iron deficiency identified during acute heart failure admissions, noting a reduction in future heart failure hospitalizations. Studies examining iron repletion in patients with heart failure with preserved ejection fraction are currently in process. Iron homeostasis is maintained predominantly through the regulation of iron absorption, keeping iron levels tightly controlled in the normal state regardless of iron intake. In chronic heart failure however, iron homeostasis becomes dysregulated with resulting iron deficiency in many patients, with and without associated anemia. Iron is a critical element not only for erythropoiesis and oxygen carrying, but also for energy production at the level of the mitochondria and in other cell processes. We thus propose a standardized approach be utilized to screen and treat heart failure patients with iron deficiency.
Tài liệu tham khảo
Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, et al. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation. 2021;143(8):e254–743. https://doi.org/10.1161/CIR.0000000000000950.
Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B, et al. Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure. J Card Fail. 2011;17(11):899–906. https://doi.org/10.1016/j.cardfail.2011.08.003.
Okonko DO, Grzeslo A, Witkowski T, Mandal AK, Slater RM, Roughton M, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J Am Coll Cardiol. 2008;51(2):103–12. https://doi.org/10.1016/j.jacc.2007.09.036.
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017;70(6):776–803. https://doi.org/10.1016/j.jacc.2017.04.025.
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, 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 Heart J. 2016;37(27):2129–200. https://doi.org/10.1093/eurheartj/ehw128.
Ghafourian K, Shapiro JS, Goodman L, Ardehali H. Iron and Heart Failure: Diagnosis, Therapies, and Future Directions. JACC Basic Transl Sci. 2020;5(3):300–13. https://doi.org/10.1016/j.jacbts.2019.08.009.
Nikolaou M, Chrysohoou C, Georgilas TA, Giamouzis G, Giannakoulas G, Karavidas A, et al. Management of iron deficiency in chronic heart failure: Practical considerations for clinical use and future directions. Eur J Intern Med. 2019;65:17–25. https://doi.org/10.1016/j.ejim.2019.05.011.
Winterbourn CC. Toxicity of iron and hydrogen peroxide: the Fenton reaction. Toxicol Lett. 1995;82–83:969–74. https://doi.org/10.1016/0378-4274(95)03532-x.
Ganz T. Systemic iron homeostasis. Physiol Rev. 2013;93(4):1721–41. https://doi.org/10.1152/physrev.00008.2013.
Paterek A, Mackiewicz U, Maczewski M. Iron and the heart: A paradigm shift from systemic to cardiomyocyte abnormalities. J Cell Physiol. 2019;234(12):21613–29. https://doi.org/10.1002/jcp.28820.
Beaumont C, Delaby C. Recycling iron in normal and pathological states. Semin Hematol. 2009;46(4):328–38. https://doi.org/10.1053/j.seminhematol.2009.06.004.
• Cappellini MD, Comin-Colet J, de Francisco A, Dignass A, Doehner W, Lam CS et al. Iron deficiency across chronic inflammatory conditions: International expert opinion on definition, diagnosis, and management. Am J Hematol. 2017;92(10):1068–78. https://doi.org/10.1002/ajh.24820. This expert panel defines iron deficiency in chronic inflammatory conditions such as heart failure and propose a screening approach to heart failure patients.
Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B, et al. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J. 2010;31(15):1872–80. https://doi.org/10.1093/eurheartj/ehq158.
Klip IT, Comin-Colet J, Voors AA, Ponikowski P, Enjuanes C, Banasiak W, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J. 2013;165(4):575–82 e3. https://doi.org/10.1016/j.ahj.2013.01.017.
Jankowska EA, von Haehling S, Anker SD, Macdougall IC, Ponikowski P. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J. 2013;34(11):816–29. https://doi.org/10.1093/eurheartj/ehs224.
Divakaran V, Mehta S, Yao D, Hassan S, Simpson S, Wiegerinck E, et al. Hepcidin in anemia of chronic heart failure. Am J Hematol. 2011;86(1):107–9. https://doi.org/10.1002/ajh.21902.
Jankowska EA, Kasztura M, Sokolski M, Bronisz M, Nawrocka S, Oleskowska-Florek W, 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. https://doi.org/10.1093/eurheartj/ehu235.
Toblli JE, Lombrana A, Duarte P, Di Gennaro F. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol. 2007;50(17):1657–65. https://doi.org/10.1016/j.jacc.2007.07.029.
Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015;36(11):657–68. https://doi.org/10.1093/eurheartj/ehu385.
Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2017;14(10):591–602. https://doi.org/10.1038/nrcardio.2017.65.
Alcaide-Aldeano A, Garay A, Alcoberro L, Jimenez-Marrero S, Yun S, Tajes M, et al. Iron Deficiency: Impact on Functional Capacity and Quality of Life in Heart Failure with Preserved Ejection Fraction. J Clin Med. 2020;9(4). https://doi.org/10.3390/jcm9041199.
Injectafer (Ferric Carboxymaltos) [Package Insert]. Switzerland. Vifor International, Inc. 2021.
Venofer (Iron Sucrose) [Package Insert]. Switzerland. Vifor International, Inc. 2020.
Lewis GD, Malhotra R, Hernandez AF, McNulty SE, Smith A, Felker GM, et al. Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial. JAMA. 2017;317(19):1958–66. https://doi.org/10.1001/jama.2017.5427.
Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436–48. https://doi.org/10.1056/NEJMoa0908355.
van Veldhuisen DJ, Ponikowski P, van der Meer P, Metra M, Bohm M, Doletsky A, et al. Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency. Circulation. 2017;136(15):1374–83. https://doi.org/10.1161/CIRCULATIONAHA.117.027497.
• Ponikowski P, Kirwan BA, Anker SD, McDonagh T, Dorobantu M, Drozdz J, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020;396(10266):1895–904. https://doi.org/10.1016/S0140-6736(20)32339-4. The only randomized control trial to assess benefit of iron repletion on acute decompensated heart failure. Technically a negative study, but with a clinically important reduction in HF hospitalizations on secondary analysis. Trial results impacted in part by COVID-19 pandemic.
Anker SD, Kirwan BA, van Veldhuisen DJ, Filippatos G, Comin-Colet J, Ruschitzka F, 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. https://doi.org/10.1002/ejhf.823.
Jankowska EA, Tkaczyszyn M, Suchocki T, Drozd M, von Haehling S, Doehner W, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Fail. 2016;18(7):786–95. https://doi.org/10.1002/ejhf.473.
Jankowska EA, Kirwan BA, Kosiborod M, Butler J, Anker SD, McDonagh T, et al. The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study. Eur Heart J. 2021. https://doi.org/10.1093/eurheartj/ehab234.
Anker SD, Colet JC, Filippatos G, Willenheimer R, Dickstein K, Drexler H, 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 supplementation in patients with and without anaemia. Eur J Heart Fail. 2009;11(11):1084–91. https://doi.org/10.1093/eurjhf/hfp140.
Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, 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 capacity in patients with chronic heart failure and iron deficiency. ESC Heart Fail. 2014;1(1):52–8. https://doi.org/10.1002/ehf2.12006.
Lewis GD, Semigran MJ, Givertz MM, Malhotra R, Anstrom KJ, Hernandez AF, 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). https://doi.org/10.1161/CIRCHEARTFAILURE.115.000345.
• P Ponikowski BA Kirwan SD Anker M Dorobantu J Drozdz V Fabien et al 2019 Rationale and design of the AFFIRM-AHF trial: a randomised, double-blind, placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalisations and mortality in iron-deficient patients admitted for acute heart failure Eur J Heart Fail 21 12 1651 1658 https://doi.org/10.1002/ejhf.1710. Details an iron repletion regimen that can be implemented in clinical practice.