ReviewIron Deficiency in Heart Failure: Looking Beyond Anaemia
Introduction
Chronic heart failure (CHF) is an increasingly common condition in Australia, with a prevalence of 1.3% and an incidence of 30,000 cases per year [1]. It is associated with significant mortality, with five-year survival ranging from 50-75% [2]. Chronic heart failure also causes significant morbidity with approximately 22,000 hospital admissions in one year [3]. The Australian Institute of Health and Welfare estimated that CHF led to healthcare costs of $411 million in 1993-1994 [4], while a more recent study concluded that current healthcare expenditure on CHF was closer to $1 billion per annum [3]. Over the last decade, iron deficiency (ID) has been increasingly recognised as both a poor prognostic marker and a potential therapeutic target in CHF patients. This review article aims to provide a summary of the current evidence that exists for the treatment of ID in CHF.
Section snippets
Overview of Iron Turnover
Dietary iron is reduced to Fe2+ by duodenal cytochrome B in the lumen of the duodenum and proximal jejunum, where it enters the enterocyte via the divalent metal transporter-1 (DMT-1). Iron is then exported into the circulation by ferroportin, which is located on the basolateral membrane of the enterocyte. Exported iron is subsequently oxidised to Fe3+ by hephaestin and bound to plasma transferrin. The transferrin-iron complex is eventually taken up by target cells expressing transferrin
Definition and Diagnosis of Iron Deficiency in Chronic Heart Failure
Iron deficiency can be classified as absolute or functional [11]. Absolute ID reflects depleted body stores caused by poor dietary intake, impaired gastrointestinal (GI) absorption, and chronic blood loss. Functional ID is thought to be caused by increased hepcidin production and subsequent inhibition of the iron exporter ferroportin, leading to impaired absorption and utilisation of iron [7], [8]. Chronic heart failure patients are susceptible to both forms of ID [8].
The diagnosis of ID in
Aetiology of Iron Deficiency in Chronic Heart Failure
The aetiology of ID in CHF is multifactorial and complex. Aside from reduced dietary intake [21] and chronic GI blood loss, it is believed that CHF causes an inflammatory state which leads to increased hepcidin levels and subsequent ID due to reduced iron absorption and enhanced reticuloendothelial block [8], [17], [22], [23]. However, multiple studies have provided conflicting evidence on the exact cause of ID in CHF. An experimental model found that rats with heart failure and anaemia had
Prevalence of Iron Deficiency in Chronic Heart Failure
Iron deficiency is common in CHF patients. However, the reported prevalence rates of ID in CHF patients vary widely, ranging from 37% to 61%, due to differences in the definitions of ID and the studies’ inclusion criteria (Table 1) [28], [29], [30], [31], [32]. It is also recognised that patients do not necessarily have to be anaemic for ID to be present [28]. Nanas et al. [15] showed that in a group of patients with advanced CHF (NYHA IV) and anaemia, ID (diagnosed on bone marrow aspiration)
Iron Deficiency, Cardiac Function, Exercise Capacity and Quality of Life
Aside from its well-recognised role in erythropoiesis, iron is also a critical component in many important cellular processes such as oxygen transport, electron transfer reactions, mitochondrial respiration, gene regulation, and cellular immunity [33], [34]. The maintenance of iron homeostasis is particularly important in cells with high energy demands such as skeletal and cardiac myocytes [35]. Willis et al. [36] found that rats with ID anaemia had a threefold improvement in exercise endurance
Iron Deficiency and Mortality in Chronic Heart Failure
Multiple observational studies have now shown that ID is associated with increased mortality in CHF. Jankowska et al. [28] found in a large cohort of patients with CHF that the presence of ID is a strong predictor for poor outcomes including hospitalisation and death, with three-year survival rates of 59% for patients with ID versus 71% for those without (p=0.0006). The authors also showed that ID alone led to an adverse prognosis that was independent of the presence of anaemia [28]. Okonko et
Clinical Trials of IV Iron Supplementation
Given the prevalence of ID and its associated negative impact in patients with CHF, there has been interest in treating ID in CHF with IV iron supplementation. To date, there have been nine published clinical trials using IV iron supplementation in patients with CHF. These consist of three open-labelled, uncontrolled studies [42], [43], [44]; one observer-blinded, randomised controlled study [45]; and five double-blinded, randomised, placebo-controlled studies [19], [46], [47], [48], [49].
Is Intravenous Iron Treatment Cost Effective and Can We Do More?
A cost effectiveness analysis in the UK found the use of IV FCM in CHF patients with ID to be cost effective, with an incremental cost effectiveness ratio of €4,414 per quality-adjusted-life-year (QALY). This was much lower than the National Institute for Health and Clinical Excellence threshold of €22,200 to €33,300 per QALY gained, with the result mainly due to improved symptoms and QoL [50]. Use of IV FCM in CHF patients has also been shown to be cost effective in other countries [51], [52],
Conclusion
Iron is an essential micronutrient and has many important physiological roles in the body beyond erythropoiesis. Iron deficiency is common in patients suffering from chronic heart failure regardless of the presence of anaemia, and is associated with worse clinical outcomes. Intravenous iron therapy is safe, cost effective, and improves exercise capacity and quality of life in patients with chronic heart failure. The impact of iron repletion on mortality in chronic heart failure remains
Acknowledgements
This work was financially supported by an unrestricted grant from Biotronik. However, the sponsor had no role in the writing of this article.
References (55)
- et al.
Uncovering a Hidden Epidemic: A Study of the Current Burden of Heart Failure in Australia
Heart, Lung, and Circ.
(2004) - et al.
Nutritional iron deficiency
Lancet.
(2007) - et al.
Detection, evaluation, and management of iron-restricted erythropoiesis
Blood.
(2010) - et al.
Etiology of Anemia in Patients With Advanced Heart Failure
J Am Coll Cardiol.
(2006) - et al.
Diagnosis and treatment of iron deficiency in patients with heart failure: Expert position paper from French cardiologists
Arch Cardiovasc Dis.
(2014) - et al.
Nutritional intake and oxidative stress in chronic heart failure
Nutr Metab Cardiovasc Dis.
(2012) - et al.
Inappropriate Expression of Hepcidin by Liver Congestion Contributes to Anemia and Relative Iron Deficiency
J Cardiac Fail.
(2014) - et al.
Disordered Iron Homeostasis in Chronic Heart Failure
JACC
(2011) - et al.
Functional iron deficiency and diastolic function in heart failure with preserved ejection fraction
Int J Cardiol.
(2013) - et al.
Molecular Changes in Myocardium in the Course of Anemia or Iron Deficiency
Heart Fail Clin.
(2010)
Iron Deficiency: Improved Exercise Performance Within 15 Hours of Iron Treatment in Rats
J Nutr.
Iron Deficiency Predicts Impaired Exercise Capacity in Patients With Systolic Chronic Heart Failure
J Cardiac Fail.
Iron deficiency and health-related quality of life in chronic heart failure: Results from a multicenter European study
Int J Cardiol.
Expansion of the red cell distribution width and evolving iron deficiency as predictors of poor outcome in chronic heart failure
Int J Cardiol.
Intravenous Iron Alone for the Treatment of Anemia in Patients With Chronic Heart Failure
J Am Coll Cardiol.
Effect of Intravenous Iron Sucrose on Exercise Tolerance in Anemic and Nonanemic Patients With Symptomatic Chronic Heart Failure and Iron Deficiency
J Am Coll Cardiol.
Intravenous Iron Reduces NT-Pro-Brain Natriuretic Peptide in Anemic Patients With Chronic Heart Failure and Renal Insufficiency
J Am Coll Cardiol.
IRON-HF study: A randomized trial to assess the effects of iron in heart failure patients with anemia
Int J Cardiol.
The missed opportunities to diagnose and treat iron deficiency in patients hospitalized with heart failure
Int J Cardiol.
Iron Deficiency in Heart Failure: A Practical Guide
Nutrients.
Disorders of iron metabolism. Part 1: molecular basis of iron homoeostasis
J Clin Pathol.
New insights into the regulation of iron homeostasis
Eur J Clin Invest.
Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives
Eur Heart J.
The Role of Hepcidin in Iron Metabolism
Acta Haematol.
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