Monitoring Iron Therapy in Chronic Heart Failure (2013)

This editorial refers to ‘The effect of intravenous ferric carboxymaltose on red cell distribution width: a subanalysis of the FAIR-HF study,’ by E.M. Van Craenenbroeck et al., published in this issue on pages 756–762. Iron deficiency has recently been identified as an important pathogenic factor affecting the severity and progression of chronic heart failure (CHF).1,2 Iron deficiency in CHF patients can result due to different reasons. First, chronic bleeding mostly on the basis of occult gastrointestinal blood loss results in true iron deficiency and frequent development of iron deficiency anaemia (IDA). This type of anaemia is mostly microcytic and hypochromic, paralleled by low serum concentrations of iron and of the iron storage protein ferritin. True iron deficiency is mostly a consequence of epithelial or ulcerative lesions in the upper gastrointestinal tract partly arising from side effects of medications taken by CHF patients, such as non-steroidal antirheumatic drugs, and further aggravated by treatment with anticoagulants.1,2 However, lower gastrointestinal bleeding as well as an impaired dietary iron absorption, the latter being a consequence of right heart insufficiency or Helicobacter pylori infections, should also be taken into account.3 Importantly, more advanced CHF is accompanied by increased circulating levels of proinflammatory cytokines such as tumour necrosis factor-α (TNF-α) or interleukin-6 (IL-6).4 These cytokines as well as the IL-6-inducible master regulator of iron homeostasis hepcidin induce a diversion of iron traffic which results in iron retention within macrophages and incorporation of the metal into ferritin which impairs the availability of the essential metal iron for erythropoiesis.3 This so-called inflammatory or functional iron deficiency can lead to the development of the normochromic and normocytic anaemia of chronic disease (ACD) or anaemia of chronic inflammation, which is characterized by low serum iron levels paralleled by normal or increased circulating ferritin concentrations.5 Importantly, the majority of anaemic patients with CHF suffer from ACD, followed by IDA, and a combination of both.2,6 Thus, in CHF patients, a careful work-up of the pathology underlying iron deficiency should be mandatory. The importance of iron deficiency for CHF has been impressively highlighted by large, well-designed, randomized clinical trials demonstrating that treatment of CHF patients with i.v. iron resulted in a significant improvement of CHF severity as reflected by a reduction in the NHYA class in patients receiving iron as compared with placebo, along with a significant improvement of cardiac performance as reflected, for example, by an increasing distance covered in the 6 min walk test (6MWT).7 Importantly, further subanalyses revealed that not only anaemic but also non-anaemic patients benefited from iron supplementation therapy. However, the mechanisms underlying the beneficial effects of iron in this latter setting remained elusive.6 While iron therapy may compensate iron deficiency, it may also improve mitochondrial respiration and oxidative phosphorylation.8 The latter notion is based on the observation that CHF patients have an impaired mitochondrial functionality which progresses with more advanced disease,9 and that iron deficiency negatively affects citric acid cycle activity and mitochondrial function. This is due to the fact that iron controls the expression of the central citric acid cycle enzyme aconitase and because the metal is a central component in mitochondrial respiration complexes where it catalyses the transfer of electrons in oxidation–reduction processes.8 Moreover, while application of iron may cause a transient increase in oxidative stress, its long-term use is associated with a sustained anti-inflammatory effect as reflected by a reduction of circulating TNF-α levels.10 This is based on an inhibitory effect of iron on the activity of key T-helper cell cytokines such as interferon-γ, whereas iron increased the expression of anti-inflammatory cytokines and modulates T-helper cell (CD4+) differentiation towards the anti-inflammatory T-helper cell type-2 phenotype.3,10 By this action iron reduces proinflammatory immune effector functions which may also improve CHF because the severity of CHF has been shown to be directly correlated with the increased expression of cytokines such as IL-6 and TNF-α. However, although a comparison of CHF patients receiving i.v. iron, given as iron-carboxymaltose, revealed a significant improvement of cardiac performance in those subjects as compared with patients receiving placebo, a certain percentage of patients did not respond to iron therapy with an amelioration of symptoms.7 As i.v. iron therapy also carries some risks, a careful selection of those patients who may benefit from therapy is mandatory.5,6 These risks include intravascular generation of toxic hydroxyl radicals and dose-related accumulation of iron in tissues, with subsequent promotion of radical formation which may be more prominent in association with inflammation as found in CHF. In addition, iron loading may increase the risk of infection, which is specifically relevant in high endemic regions, and modulate immune effector pathways; however, most of these concerns arise from observational and/or retrospective studies, whereas data from high quality prospective clinical trials are rare.10 The identification of patients with true iron deficiency who will obviously need iron therapy is quite easy in the absence of inflammation because low ferritin levels with characteristic changes of erythrocyte haemoglobin content are diagnostic.2,3,5 However, the identification of true iron deficiency becomes more complicated in association with chronic inflammation as found in advanced CHF because serum ferritin levels are not only affected by tissue iron loading but are also induced by various cytokines which increase circulating ferritin levels independently of iron loading.3,6 Thus, several other parameters including soluble transferrin receptor (sTfR), the sTfR/log ferritin ratio, the percentage of hypochromic red blood cells, reticulocyte haemoglobin content, or zinc-protoporphyrin, as well as combinations of these parameters have been used to identify patients suffering from true iron deficiency in the context of chronic inflammatory diseases.3,11 However, the sensitivity and specificity of these assays vary greatly depending on the patient population investigated and have not resulted in the definition of a gold standard assays which may help clinicians to identify those subjects who may potentially benefit from iron therapy. In this issue of the journal Van Craenenbroeck and co-workers12 evaluated a new parameter which may be helpful in making this important clinical decision. They investigated the utility of red cell distribution width (RDW) to indicate iron deficiency in patients with CHF. RDW is a measurement of the size of variation of erythrocyte volume.13 It is determined automatically by most haematology analysers and calculated by dividing the standard deviation of erythrocyte volume [mean corpuscular volume (MCV)] by the mean of MCV.13,14 Normal reference values for RDW are considered to be between 11% and 14%, and a greater RDW indicates variations in erythrocyte size and composition, which is defined as anisocytosis.14 It is proposed that a normal RDW would distinguish iron deficiencies from ACD; however, several limitations have been annotated regarding the sensitivity and specificity of this simplified approach.13,14 Nonetheless, RDW has been identified as a significant predictor of cardiovascular morbidity and mortality in patients with CHF, and an increased RDW was associated with a poor prognosis.15 Van Craenenbroeck et al.12 investigated the clinical usefulness of RDW to predict the response to i.v. iron therapy and to monitor its therapeutic success. They analysed the data from CHF patients who were included in the FAIR-HF trial in order to compare the therapeutic efficacy of iron-isocarboxymaltose with placebo.7 They found that an increased RDW was associated with iron deficiency. Interestingly, RDW increased following i.v. iron treatment but then declined and subsequently became significantly lower 24 weeks after the study initiation in iron-treated patients as compared with the placebo group. Of note, the authors found a significant relationship between changes in RDW and parameters of cardiac performance such as the 6MWT distance or LVEF. In addition, they observed a close relationship between circulating iron parameters and RDW even in the presence of inflammation, as determined by measurement of C-reactive protein levels. This indicated that RDW is a promising parameter to indicate treatable iron deficiency in patients with CHF and that follow-up determination of RDW provides useful information on the response to iron therapy. These interesting results will likewise initiate subsequent prospective clinical studies which will examine the true diagnostic and clinical potential of RDW for decision-making at the bedside, for evaluating the usefulness of RDW to identify those patients who will benefit from iron supplementation, and for predicting the response to iron therapy. Conflict of interest: none declared.