Article

Iron Deficiency, a Common Neglected Burden in Heart Failure

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Abstract

A satellite symposium at the 2014 European Society of Cardiology (ESC) congress discussed the importance of iron deficiency (ID) in heart failure (HF). ID is the main cause of anaemia and is observed in almost 50 % of HF patients in Europe and up to 80 % of patients in Asia. ID is an independent factor associated with reduced exercise capacity, reduced quality of life (QoL) and poor outcomes in HF. The importance of ID in HF is reflected in the fact that the current ESC Guidelines for HF recognise ID as a co-morbidity in HF for the first time, and recommend routine diagnosis and monitoring for ID based on iron parameters. Intravenous (i.v) administration of ferric carboxymaltose (FCM) was considered as a possible treatment option according to the findings of the Ferric Carboxymaltose Assessment in Patients With IRon Deficiency and Chronic Heart Failure (FAIR-HF) clinical study, which showed that treatment with FCM in HF patients with ID improves symptoms, exercise capacity and QoL. These findings were confirmed by the recent Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure (CONFIRM-HF) study, which demonstrated that, in symptomatic patients with chronic HF and ID treatment with i.v. FCM over one year resulted in sustainable improvements in exercise capacity, symptoms and QoL, and was associated with a reduced risk of hospitalisations due to worsening HF.

Disclosure:Josep Comin-Colet has received consulting fees from Vifor Pharma and was a member of the FAIR-HF and CONFIRM-HF steering committees. Stefan Anker has received honoraria for consultancy, lectures, clinical trial committee work and/or trial adjudication work as well as he received research grants from Vifor Pharma. Carolyn SP Lam has received unrestricted research grants and honoraria from Vifor Pharma. Piotr Ponikowski has received honoraria from Vifor Pharma as a member of the FAIR-HF and CONFIRM-HF steering committees; consultancy and speakers bureau from Vifor Pharma and Amgen Inc; and a research grant from Vifor Pharma.

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Dr Carolyn Lam began by discussing data from the recent prevalence study of ID in HF,3 for which the study cohort was from European countries only. A study of ID in Asian patients with HF (n=751) found a higher prevalence of ID (61 %).8 The prevalence was particularly high in women (71 % versus 59 % in men) and in South Asian Indian populations (a prevalence of 82 %).8 South Asians tend to be vegetarian and also drink black tea, which has been shown to decrease iron absorption by 80 % when taken with food.9

Genetic factors are also important in determining ID; a number of studies have investigated TMPRSS6, which encodes a transmembrane serine protease produced by the liver that regulates the expression of the systemic iron-regulatory hormone hepcidin. Germline mutations in TMPRSS6 have been found in extended families where more than one member had ID.10 Variants in TMPRSS6 have also been found to be risk factors for ID and iron deficiency anaemia (IDA) in 2,139 unrelated elderly Chinese women.11

In order to evaluate the impact of ID in HF, it is important to understand iron metabolism. Dietary iron is utilised not only in circulating erythrocytes, but also in muscle myoglobin and other iron containing enzymes.12 Patients with HF may be iron deficient as a result of reduced iron storage (absolute ID), which may be caused by malnutrition, malabsorption and gastrointestinal (GI) oedema and blood losses (due to use of anticoagulants, non-steroidal anti-inflammatory drugs [NSAIDs] and loss of mucosal integrity).13 Another important cause of ID in HF is impaired iron mobilisation (functional ID), resulting from the inflammatory processes that characterise chronic HF. Activation of pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF-α) causes over-expression of hepcidin by the liver. This blocks the intestinal absorption of iron and diverts iron from the circulation into the reticuloendothelial system (RES), causing reticuloendothelial block, as well as blunting responses to erythropoietin (EPO) and causing apoptosis of erythroid progenitors.13–15 At the cellular level, ID reduces the delivery of oxygen to the mitochondria but also directly decreases the activity of key enzymes of the citric acid cycle and of the respiratory chain of the mitochondria, resulting in reduced oxygen utilisation (which is, in the clinical setting, observed as reduced peak oxygen consumption [pVO2]).16

Association Between Iron Deficiency and Mortality in Heart Failure

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Suggested Algorithm for Diagnosis of Iron Deficiency in Heart Failure

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ID reduces work capacity and energy efficiency in HF17,18 and iron status correlates to NYHA status.3 The fact that ID but not anaemia is associated with reduced exercise capacity in HF4 can be explained by the non-haematopoietic effects of iron, including its role in mitochondrial function in cells with high energy requirements, such as cardiomyocytes and skeletal myocytes. In patients with chronic HF, ID but not anaemia has also been associated with reduced QoL (assessed using the Minnesota Living with Heart Failure [MLWHF] questionnaire), mostly due to physical factors.5,6 Furthermore, ID is a stronger negative prognostic indicator for all-cause mortality than anaemia (see Figure 2).3 A recent study in Singapore assessed the impact of ID in Asian patients with HF. Functional ID was found in the majority (64 %) of patients with HF. Patients with ID were more symptomatic with higher NYHA class and MLWHF score, regardless of ejection fraction (EF).19 Patients with concurrent ID and anaemia had the poorest prognosis regardless of EF.

In the 2012 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure, the ESC recommended ID testing in HF patients based on the assessments of ferritin and TSAT.2,7 This raises the question of which iron indices are the most useful. Two are currently used: ferritin (a measure of stored iron) and TSAT (a measure of circulating iron for functional utilisation). However, ferritin is also an acute phase protein and can be falsely elevated if inflammation or subclinical infection is present, but a low ferritin level is a clear indication of ID (absolute). If ferritin is increased TSAT (<20 %) can be used for the diagnosis of ID (functional). The only limitation of TSAT is the circadian differences since the calculated value is dependent on the serum iron. Due to their intrinsic limitations, the combination of thresholds of these two parameters is suggested, as for the FAIR-HF study (ferritin <100 ng/mL or ferritin 100–300 ng/mL if TSAT <20 %). The ideal marker would probably be the soluble transferrin receptor (sTfR); however, this is not widely available or used in clinical practice.13 Based on the ESC recommendations and data from the FAIR-HF clinical trial, a suggested algorithm for diagnosis on ID in HF is proposed (see Figure 3). Recommendations worldwide are being changed to incorporate the need to assess and treat ID in
patients with chronic HF.20

In conclusion, ID is present in half of all HF patients in Europe and in up to 80 % of Asian patients. While it is the main cause of anaemia in HF, ID occurs in over 45 % of non-anaemic patients and is independently associated with reduced exercise capacity, reduced QoL and poor outcomes

References

  1. Lesman-Leegte I, Jaarsma T, Coyne JC, et al., Quality of life and depressive symptoms in the elderly: a comparison between patients with heart failure and age- and gender-matched community controls, J Card Fail, 2009;15:17–23.
    Crossref | Pubmed
  2. McMurray JJ, Adamopoulos S, Anker SD, et al., ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC, Eur Heart J, 2012;33:1787–847.
    Crossref | Pubmed
  3. 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
  4. Jankowska EA, Rozentryt P, Witkowska A, et al., Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure, J Card Fail, 2011;17:899–906.
    Crossref | Pubmed
  5. Comin-Colet J, Enjuanes C, González 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;15:1164–72.
    Crossref | Pubmed
  6. Enjuanes C, Klip IT, Bruguera J, et al., Iron deficiency and health-related quality of life in chronic heart failure: results from a multicenter European study, Int J Cardiol, 2014;174:268–75.
    Crossref | Pubmed
  7. McMurray JJ, Adamopoulos S, Anker SD, et al., ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC, Eur J Heart Fail, 2012;14:803–69.
    Crossref | Pubmed
  8. Yeo TJ, Yeo PS, Ching-Chiew Wong R, et al., Iron deficiency in a multi-ethnic Asian population with and without heart failure: prevalence, clinical correlates, functional significance and prognosis, Eur J Heart Fail, 2014;16:1125–32.
    Crossref | Pubmed
  9. Zijp IM, Korver O, Tijburg LB, Effect of tea and other dietary factors on iron absorption, Crit Rev Food Sci Nutr, 2000;40:371–98.
    Crossref | Pubmed
  10. Finberg KE, Heeney MM, Campagna DR, et al., Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA), Nat Genet, 2008;40:569–71.
    Crossref | Pubmed
  11. An P, Wu Q, Wang H, et al., TMPRSS6, but not TF, TFR2 or BMP2 variants are associated with increased risk of iron-deficiency anemia, Hum Mol Genet, 2012;21:2124–31.
    Crossref | Pubmed
  12. Andrews NC, Disorders of iron metabolism, N Engl J Med, 1999;341:1986–95.
    Crossref | Pubmed
  13. 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
  14. Ganz T, Hepcidin and its role in regulating systemic iron metabolism, Hematology Am Soc Hematol Educ Program, 2006;29–35, 507.
    Crossref | Pubmed
  15. Zhang AS, Enns CA, Molecular mechanisms of normal iron homeostasis, Hematology Am Soc Hematol Educ Program, 2009;207–14.
    Crossref | Pubmed
  16. Oexle H, Gnaiger E, Weiss G, Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation, Biochim Biophys Acta, 1999;1413:99–107.
    Crossref | Pubmed
  17. Haas JD, Brownlie T 4th, Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship, J Nutr, 2001;131:676S–88S; discussion 688S–90S.
    Pubmed
  18. Dallman PR, Iron deficiency: does it matter?, J Intern Med, 1989;226:367–72.
    Crossref | Pubmed
  19. Yeo TJ, Yeo PS, Sim DKL, et al., Functional iron deficiency in heart failure with preserved versus reduced ejection fraction, J Am Coll Cardiol, 2014;63(12 S):A778.
    Crossref
  20. Krum H, Jelinek MV, Stewart S, et al., 2011 update to National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand Guidelines for the prevention, detection and management of chronic heart failure in Australia, 2006, Med J Aust, 2011;194:405–9.
    Pubmed
  21. 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;35:2468–76.
    Crossref | Pubmed
  22. 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
  23. Kao DP, Kreso E, Fonarow GC, Krantz MJ, Characteristics and outcomes among heart failure patients with anemia and renal insufficiency with and without blood transfusions (public discharge data from California 2000-2006), Am J Cardiol, 2011;107:69–73.
    Crossref | Pubmed
  24. Swedberg K, Young JB, Anand IS, et al., Treatment of anemia with darbepoetin alfa in systolic heart failure, N Engl J Med, 2013;368:1210–9.
    Crossref | Pubmed
  25. Ghali JK, Anand IS, Abraham WT, et al., Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia, Circulation, 2008;117:526–35.
    Crossref | Pubmed
  26. Parissis JT, Kourea K, Panou F, et al., Effects of darbepoetin alpha on right and left ventricular systolic and diastolic function in anemic patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy, Am Heart J, 2008;155:751 e1–7.
    Crossref | Pubmed
  27. van Veldhuisen DJ, Dickstein K, Cohen-Solal A, et al., Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia, Eur Heart J, 2007;28:2208–16.
    Crossref | Pubmed
  28. Kourea K, Parissis JT, Farmakis D, et al., Effects of darbepoetin-alpha on quality of life and emotional stress in anemic patients with chronic heart failure, Eur J Cardiovasc Prev Rehabil, 2008;15:365–9.
    Crossref | Pubmed
  29. Palazzuoli A, Silverberg DS, Iovine F, et al., Effects of beta-erythropoietin treatment on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels in patients with the cardiorenal anemia syndrome, Am Heart J, 2007;154:645 e9–15.
    Crossref | Pubmed
  30. Beck-da-Silva L, Piardi D, Soder S, et al., IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia, Int J Cardiol, 2013;168:3439–42.
    Crossref | Pubmed
  31. Bolger AP, Bartlett FR, Penston HS, et al., Intravenous iron alone for the treatment of anemia in patients with chronic heart failure, J Am Coll Cardiol, 2006;48:1225–7.
    Crossref | Pubmed
  32. Toblli JE, Lombraña 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;50:1657–65.
    Crossref | Pubmed
  33. Okonko DO, Grzeslo A, Witkowski T, 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;51:103–12.
    Crossref | Pubmed
  34. Usmanov RI, Zueva EB, Silverberg DS, Shaked M, Intravenous iron without erythropoietin for the treatment of iron deficiency anemia in patients with moderate to severe congestive heart failure and chronic kidney insufficiency, J Nephrol, 2008;21:236–42.
    Pubmed
  35. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, 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, 2014 [Epub ahead of print].
    Crossref | Pubmed
  36. Iron in Congestive Heart Failure (iCHF). Available at: http://clinicaltrials.gov/ct2/show/NCT01837082?term=iCHF&rank=1 (accessed 17 September 2014).
  37. EFfect of Ferric carboxymaltose on Exercise Capacity in PaTients with iron deficiency and chronic Heart Failure (EFFECT-HF). Available at: http://clinicaltrials.gov/show/NCT01394562 (accessed 3 September 2014).