Why is Iron Deficiency Recognised as an Important Comorbidity in Heart Failure?

Login or register to view PDF.
Creative Commons Licence
 
Abstract

There is an increasing awareness of the prevalence of iron deficiency in patients with heart failure (HF), and its contributory role in the morbidity and mortality of HF. Iron is a trace element necessary for cells due to its capacity to transport oxygen and electrons. The prevalence of iron deficiency increases with the severity of HF. For a long time the influence of iron deficiency was underestimated, especially in terms of worsening of cardiovascular diseases and developing anaemia. In recent years, studies with intravenous iron agents in patients with iron deficiency and HF showed new insights into the improvement of iron therapy. Additionally, experimental studies supporting the understanding of iron metabolism and the resulting pathophysiological pathways of iron have been carried out. The aim of this mini review is to highlight why iron deficiency is recognised as an important comorbidity in HF.

Disclosure
The authors have no conflicts of interest to declare.
Correspondence
Nicole Ebner, University Medical Centre Goettingen, Department of Cardiology and Pneumology, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. E: nicole.ebner@med.uni-goettingen.de
Received date
18 March 2019
Accepted date
21 May 2019
Citation
Cardiac Failure Review 2019;5(3):ePub: 15 September 2019.
DOI
https://doi.org/10.15420/cfr.2019.9.2
Open access
This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Iron is an essential trace element that is present in a number of molecular systems, and it is increasingly recognised as an important cofactor for a variety of cell systems.1 It has been acknowledged that iron plays an important role in oxygen transport, as well as in cell growth and proliferation. In recent years, more insight has been gained into iron physiology and the regulation of cellular iron homeostasis.2 Iron deficiency occurs, for example, when the dietary intake is inadequate, during times of digestive blood loss or menstrual periods or during states that excessively increase iron requirements, particularly during childhood growth or pregnancy.2,3 However, in patients with chronic illnesses, iron may become unable to be immobilised as a consequence of chronic inflammation, thus leading to functional iron deficiency. Many studies have shown that iron deficiency is very common in patients with heart failure (HF), and its prevalence increases with increasing New York Heart Association class.4–8

Prevalence and Prognostic Factors of Iron Deficiency

A large meta-analysis of major HF trials showed that the prevalence of iron deficiency is nearly 50% in all patients with HF, and that iron deficiency has important prognostic and quality of life implications, irrespective of the presence of anaemia.9–14 However, iron deficiency, whether absolute or functional, is a frequent finding in HF patients also presenting with anaemia, affecting up to 80% of these individuals.15 In humans, intracellular iron is stored as ferritin and reflects body iron stores. However, ferritin is also an acute-phase reactant whose levels may increase during inflammatory processes. Transferrin saturation reflects the relative amount of transferrin that is loaded with iron. In contrast to ferritin, transferrin is a negative acute-phase reactant. Importantly, neither serum iron nor serum transferrin alone should be used as indicators of iron status.2 In addition, it is important to understand that different cut-off values indicate iron deficiency in healthy individuals and in patients with chronic illness.

Approximately half of all patients with HF have either absolute iron deficiency or functional iron deficiency defined as transferrin saturation <20% and serum ferritin 100–300 μg/L, and this finding is only partly associated with the presence of anaemia.2,16,17 Indeed, many HF patients present with iron deficiency, many with anaemia and some of these with both.

Mechanism of Iron Deficiency

It is important to understand the mechanisms of iron absorption and distribution. There are two different pathways of iron absorption, one for haem iron across a haem transporter, and another for iron in its ferrous form, across the divalent metal transporter.2,3 Iron absorption across the gut wall is only possible in the ferrous form, and ferric iron that is found in vegetables needs to be reduced before absorption. The cytosolic protein that accumulates iron is ferritin. Ferritin protects cells from iron toxicity and prevents iron from reacting with other cellular constituents.2 Under normal conditions, nearly the total amount of circulating iron is transported by transferrin.13 The amount of iron transported in ferritin is low compared with transferrin-iron.

Cohen et al. suggested that serum ferritin is not a major pathway of systemic iron transport, but locally secreted ferritin may play such a role in selected tissues.18 Despite there being some insight, the detailed pathways that enable iron trafficking from the endosome to the mitochondria and to other cellular sites are not well understood.19 Generally, a large number of proteins need iron as a cofactor, and the two major elements that require iron are haem and iron–sulphur (Fe-S) clusters.20 Under iron replete conditions, iron regulatory protein 1 binds Fe-S clusters and acts as an aconitase when Fe-S cluster synthesis is normal. The presence of Fe-S clusters determines the function of the aconitase.

Aconitase is an essential enzyme in the citrate cycle that catalyses the reaction from citrate into aconitate, and requires Fe-S clusters as cofactors. When cellular iron levels are low, iron regulatory protein loses aconitase activity, and there is a corresponding reduction in Fe-S cluster synthesis.19 Mitochondrial function requires iron, since iron is a cofactor for haem proteins that are involved in electron transfer, and in adenosine triphosphate and energy production in the cells. The reason why iron may have an effect on HF irrespective of anaemia and haemoglobin values is that iron is an essential constituent of myoglobin, which is found in the cytoplasm, and avidly binds and releases oxygen.20

The absence of iron in the blood of patients with HF may also be reflected as reduced iron load in the bone marrow and in the myocardium.21,22 Interestingly, a subset of patients in whom myocardial transferrin receptor expression was measured showed upregulation of the receptor. Such upregulation hints at iron deficiency inside the myocardium. In addition, left ventricular stiffness was correlated with peak oxygen uptake, but not with the ferritin level or transferrin saturation.23 The symptoms and signs of iron deficiency are partially explained by the presence of anaemia, but experimental evidence suggests that iron itself improves muscle function and exercise capacity in animals without changes in haemoglobin levels.2,24–26

Iron Deficiency and Exercise Capacity

Iron deficiency independently relates to exercise intolerance expressed as reduced peak oxygen uptake and augmented ventilatory response to exercise in patients with chronic HF.27,28 This finding emphasises the role of iron as a cofactor in skeletal and cardiac muscle function. A recent study showed that iron is important for muscle function.29 In recent years, different therapeutic possibilities embrace iron replacement by oral or IV routes.9,12,17 The IV route is more effective than the oral route, mostly as a consequence of the limited absorption capacity in the duodenum and due to the side-effects of oral iron therapy that are encountered in up to 20% of all patients treated with oral iron.30

The Iron Repletion Effects on Oxygen Uptake in Heart Failure (IRONOUT-HF) trial previously demonstrated that oral iron supplementation minimally increased iron stores and did not improve exercise capacity in patients with HF with a reduced ejection fraction and iron deficiency.31

Current guidelines of the European Society of Cardiology for the diagnosis and treatment of HF state that all patients should be screened for iron deficiency and anaemia, a class I recommendation based on meta-analysis (level of evidence: A, because two large trials, Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure [FAIR-HF] and Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure [CONFIRM-HF], published positive results). Patients who remain symptomatic in New York Heart Association classes II–IV benefit from iron supplementation, preferably via the IV route.32 However, it has to be taken into account that the definition of iron deficiency used by the European Society of Cardiology in the current version of the HF guideline has been validated in clinical trials only in patients with HF with reduced ejection fraction. As no validations exists for HF with preserved ejection fraction, it should be regarded with caution in this population.

Ongoing Studies

Several studies with intravenous iron are ongoing; for example, the Iron or Placebo for Anaemia in Intensive Care (IRONMAN study) (NCT03037931, NCT03833336, NCT02937454, NCT03218384, NCT02642562). That study will address whether the additional use of IV iron (iron isomaltoside) on top of standard care will improve the outlook for patients with HF and iron deficiency.

Other studies are the FAIR trials. The purpose of the FAIR HF2 study is to determine whether intravenous iron supplementation (ferric carboxymaltose) reduces hospitalisation and mortality in patients with iron deficiency and HF (NCT03036462). The FAIR HFpEF study addresses whether treatment with IV iron (ferric carboxymaltose) for patients with HF with preserved ejection fraction and iron deficiency can improve exercise capacity and symptoms while being safe (NCT03074591).

Future Developments

In addition to the ongoing studies with the known IV iron treatments, some new IV iron drugs are being tested. For example, ferric bepectate, a new iron drug, was studied in 33 iron‐depleted anaemic patients who had undergone cardiac surgery.33 They were treated with either 200, 500 or 1500 mg ferric bepectate compared with 500 mg ferric carboxymaltose. They showed that with ferric bepectate, the iron excretion in urine was reduced compared with ferric carboxymaltose.

Recent results of the FERRIC iron in Heart Failure (FERRIC HF II) trial showed that iron isomaltose was safe and well tolerated in patients with chronic HF and iron deficiency.34 Moreover, they showed that iron isomaltoside was associated with faster skeletal muscle energy measured in the form of adenosine triphosphate and phosphocreatine after 2 weeks, implying better mitochondrial function. Additionally, these results showed that iron per se is an obligate component of mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine. Augmented skeletal muscle energetics might be an important mechanism by which iron repletion confers benefits in chronic HF. The exact mechanisms by which chronic heart failure patients develop iron deficiency are still not completely understood.

Moliner et al. recently showed an interplay between raised sympathetic nervous system activity and systemic iron deficiency in patients with chronic HF and, particularly, with those biomarkers that suggest impaired iron transport (transferrin saturation <20%) and increased iron demand (raised soluble transferrin receptor levels).35 This impressively supports the hypothesis that iron deficiency might not just be a comorbidity, but may also be a key element in the pathophysiological sequence leading to, and promoting the progression of, chronic HF. However, many questions remain and require further research. We look forward to future research to answer important questions about the use of iron agents in HF.

References
  1. Jelani QU, Katz SD. Treatment of anemia in heart failure: potential risks and benefits of intravenous iron therapy in cardiovascular disease. Cardiol Rev 2010;18:240–50.
    Crossref | PubMed
  2. Ebner N, von Haehling S. Iron deficiency in heart failure: a practical guide. Nutrients 2013;5:3730–9.
    Crossref | PubMed
  3. Toblli JE, Silverberg DS, Di Gennaro F, et al. Iron metabolism. In: Cardio-Renal Anaemia Syndrome CRAS. Basics and Clinical Aspects. 1st ed. Buenos Aires, Argentina: Publicaciones Latinoamericans, 2008;55–68.
  4. Okonko DO, Mandal AK, Missouris CG, Poole-Wilson PA. Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival. J Am Coll Cardiol 2011;58:1241–51.
    Crossref | PubMed
  5. Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: An international pooled analysis. Am Heart J 2013;165:575–82.e3.
    Crossref | PubMed
  6. Jankowska EA, von Haehling S, Anker SD, et al. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J 2013; 34: 816–29.
    Crossref | PubMed
  7. González-Costello J, Comín-Colet J, Lupón J, et al. Importance of iron deficiency in patients with chronic heart failure as a predictor of mortality and hospitalizations: insights from an observational cohort study. BMC Cardiovasc Disord 2018;18:206.
    Crossref | PubMed
  8. McDonagh T, Damy T, Doehner W, et al. Screening, diagnosis and treatment of iron deficiency in chronic heart failure: putting the 2016 European Society of Cardiology heart failure guidelines into clinical practice. Eur J Heart Fail 2018;20:1664–72.
    Crossref | PubMed
  9. Jankowska EA, Tkaczyszyn M, Suchocki T, 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;18:786–95.
    Crossref | PubMed
  10. Zhang S, Zhang F, Du M, et al. Efficacy and safety of iron supplementation in patients with heart failure and iron deficiency: a meta-analysis. Br J Nutr 2019;20:1–23.
    Crossref | PubMed
  11. Qian C, Wei B, Ding J, et al. The Efficacy and safety of iron supplementation in patients with heart failure and iron deficiency: a systematic review and meta-analysis. Can J Cardiol 2016;32:151–9.
    Crossref | PubMed
  12. Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J 2013;165:575–82.e3.
    Crossref | PubMed
  13. von Haehling S, Ebner N, Evertz R, et al. Iron deficiency in heart failure: an overview. JACC Heart Fail 2019;7:36–46.
    Crossref | PubMed
  14. 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;20:125–33.
    Crossref | PubMed
  15. 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;107:223–5.
    Crossref | PubMed
  16. von Haehling S, Anker SD. Iron deficiency in health and disease. In: Anker SD, von Haehling S (eds). Anaemia in chronic heart failure. 2nd ed. Bremen, Germany: UNI-MED Verlag AG, 2009;34–7.
  17. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361:2436–48.
    Crossref | PubMed
  18. Cohen LA, Gutierrez L, Weiss A, et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood 2010;116:1574–84.
    Crossref | PubMed
  19. Anderson GJ, Vulpe CD. Mammalian iron transport. Cell Mol Life Sci 2009;66:3241–61.
    Crossref | PubMed
  20. Ye H, Rouault TA. Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease. Biochemistry 2010;49:4945–56.
    Crossref | PubMed
  21. Punnonen K, Irjala K, Rajamäki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood 1997;89:1052–57.
    PubMed
  22. Leszek P, Sochanowicz B, Szperl M, et al. Myocardial iron homeostasis in advanced chronic heart failure patients. Int J Cardiol 2012;159:47–52.
    Crossref | PubMed
  23. Kasner M, Aleksandrov AS, Westermann D, et al. Functional iron deficiency and diastolic function in heart failure with preserved ejection fraction. Int J Cardiol 2013;168:4652–7.
    Crossref | PubMed
  24. Willis WT, Gohil K, Brooks GA, Dallman PR. Iron deficiency: improved exercise performance within 15 h of iron treatment in rats. J Nutr 1990;120:909–16.
    Crossref | PubMed
  25. Tobin BW, Beard JL. Interactions of iron deficiency and exercise training relative to tissue norepinephrine turnover, triiodothyronine production and metabolic rate in rats. J Nutr 1990;120:900–8.
    Crossref | PubMed
  26. Blayney L, Bailey-Wood R, Jacobs, A et al. The effects of iron deficiency on the respiratory function and cytochrome content of rat heart mitochondria. Circ Res 1976;39:744–748.
    Crossref | PubMed
  27. Ebner N, Jankowska EA, Ponikowski P. The impact of iron deficiency and anaemia on exercise capacity and outcomes in patients with chronic heart failure. Results from the Studies Investigating Co-morbidities Aggravating Heart Failure. Int J Cardiol 2016;205:6–12.
    Crossref | PubMed
  28. Bekfani T, Pellicori P, Morris D, et al. Iron deficiency in patients with heart failure with preserved ejection fraction and its association with reduced exercise capacity, muscle strength and quality of life. Clin Res Cardiol 2019;108:203–11.
    Crossref | PubMed
  29. Dziegala M, Josiak K, Kasztura M, et al. Iron deficiency as energetic insult to skeletal muscle in chronic diseases. J Cachexia Sarcopenia Muscle 2018;9:802–815.
    Crossref | PubMed
  30. Altman NL, Patel A. Intravenous iron therapy in heart failure. Heart Fail Clin 2018;14:537–43.
    Crossref | PubMed
  31. Lewis GD, Malhotra R, Hernandez AF, 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;317:1958–66.
    Crossref | PubMed
  32. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Rev Esp Cardiol (Engl Ed) 2016;69:1167.
    Crossref | PubMed
  33. Muñoz M, Olsen PS, Petersen TS, et al. Pharmacokinetics of ferric bepectate – a new intravenous iron drug for treating iron deficiency. Basic Clin Pharmacol Toxicol 2019; epub ahead of press.
    Crossref | PubMed
  34. Charles-Edwards G, Amaral N, et al. Effect of iron isomaltoside on skeletal muscle energetics in patients with chronic heart failure and iron deficiency: the FERRIC-HF II randomized mechanistic trial. Circulation 2019;139:2386–98.
    Crossref | PubMed
  35. Moliner P, Enjuanes C, Tajes M, 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:e010887.
    Crossref | PubMed
  36. Pollock RF, Muduma G. A systematic literature review and indirect comparison of iron isomaltoside and ferric carboxymaltose in iron deficiency anemia after failure or intolerance of oral iron treatment. Expert Rev Hematol 2019;12:129–36.
    Crossref | PubMed