Treatment of Iron Deficiency in Heart Failure

Iron deficiency (ID) is defined as insufficient levels of iron to meet physiological demands. ID is increasingly recognised as an important phenomenon in heart failure (HF). There is a high prevalence of ID among HF patients, which can impact upon both symptoms and quality of life. Consequently, recognising and treating ID has been shown to be beneficial for patients.

Our understanding of the pathophysiology and treatment of ID in HF is based on the overarching clinical HF phenotype rather than on specific HF aetiologies. This review summarises contemporary evidence for the measurement and treatment of ID in HF and the available evidence for the management of ID in specific HF aetiologies.

Iron is obtained from our diet and absorbed in the gut. There are two major forms: haem iron, a chelated form of ferrous iron (Fe²⁺) which is derived from haemoglobin and myoglobin and is typically from animal sources, and non-haem iron, or ferric iron (Fe³⁺), that typically originates from plants. Haem iron is absorbed into the enterocyte through several transporters but three in particular have been shown to be particularly important in haem homeostasis: haem carrier protein 1 (HCP1), haem responsive gene 1 (HRG-1), and feline leukaemia virus subgroup C receptor 2 (FLVCR2) [1]. It is then reduced to unchelated ferrous iron [2]. Non-haem iron first undergoes reduction in the gut, as it cannot be directly absorbed, into ferrous iron, before being transported into the enterocyte via divalent metal transporter 1 (DMT1) which is highly expressed in the duodenum in iron deficiency (Fig. 1) [2, 3]. Ferrous iron is toxic within cells and so either needs to be stored in the non-toxic form of ferritin or exported out of the cell via ferroportin. In the circulation, the ferrous iron is oxidised into the ferric form and bound by transferrin as free iron can be harmful outside cells due to its pro-oxidant effect [4]. It then either remains as an iron reservoir or is delivered to target cells [5].

Iron plays a vital role in cellular homeostasis. Some of its pleiotropic roles include being a component of haemoglobin and myoglobin contributing to the transportation and storage of oxygen, acting as an important cofactor for enzymes and proteins involved in oxidative metabolic processes, a role in microRNA biogenesis, contributing to the function of the central nervous and immune systems, and involvement in the synthesis and degradation of proteins, lipids, carbohydrates, DNA, and RNA [6]. As a result, iron is in constant use by high-energy demanding cells in the body.

ID is independent of anaemia and can manifest itself as either low iron store concentrations, called absolute iron deficiency, or insufficient iron supply to meet physiological demands, which is known as functional iron deficiency [7]. Absolute iron deficiency is usually defined as a serum ferritin concentration of < 30 μg/L as ferritin is directly proportional to iron stores [8]. However, given that ferritin is also an acute phase protein, in inflammatory conditions such as HF, it is arbitrarily defined as < 100 μg/L. Transferrin saturation indicates the percentage of transferrin that is iron-bound and acts as a biomarker for available iron. Functional iron deficiency is defined as a ferritin concentration of 100–299 μg/L with a transferrin saturation < 20% [9].

These definitions are based on the FAIR-HF trial that used higher parameters of ID with reference to chronic kidney disease (CKD) patients due to the artificial increases in ferritin seen in chronic inflammatory and oxidative stress, commonly seen in HF as well [7, 10]. As a result, ferritin can become an unreliable marker in advanced disease and acute heart failure (AHF) when stress levels are high. In these states, other markers of ID such as soluble transferrin receptor, which increases in ID and is not affected by inflammation, may be more sensitive, but its use as a tool to guide iron replacement has not yet been proven [11‐15]. However, CKD has a different pathophysiology to HF, such as associated uraemia-mediated inflammation and decreased production of erythropoietin, and so, it is still not fully clear whether these definitions, based on serum ferritin and transferrin saturation marker levels, are accurate enough to diagnose ID in HF populations [16].

ID is one of the most prevalent comorbidities in chronic heart failure (CHF) [7]. Up to 50% of patients with heart failure and reduced ejection fraction (HFrEF) suffer from lD with the prevalence being higher in patients with NYHA Class III and IV than those with NYHA Class I and II [9, 17]. This figure can be even higher in patients with AHF [18]. Interestingly, in these pooled cohorts, the mean age was relatively low, and elderly patients may also have a higher prevalence [5]. Higher levels of inflammatory markers and NT-proBNP have also been associated with higher prevalence of ID [17, 19]. Other risk factors for ID in HF patients include female sex and advanced HF [20]. ID has also been reported in heart failure with preserved ejection fraction (HFpEF) cohorts with a meta-analysis showing a prevalence of up to 59% [21].

There are many potential mechanisms for ID in HF. Mucosal oedema from fluid overload and reduced intestinal blood flow can result in impaired absorption of iron from the intestine [22]. The chronic inflammatory process in HF can also impair the metabolism of available iron [18]. It has also been shown that HF patients, particularly those with advanced disease, have a reduced nutritional intake, including iron [23].

There can also be disrupted iron uptake due to increased degradation of luminal iron transporters, ferroportin, by hepcidin, an acute phase protein [7]. Hepcidin can also cause sequestration of iron by inhibiting ferroportin-mediated transport of iron out of enterocytes and macrophages [24]. Hepcidin is upregulated by proinflammatory cytokines, high levels of which are seen in patients with HF. Early stages of systolic HF have been associated with high levels of hepcidin but as the clinical severity developed, hepcidin levels decreased [25]. This paradox remains unexplained but, overall, HF patients typically have elevated levels of hepcidin [25]. As a regulator of iron homeostasis, hepcidin levels might be the most immediate indicator of iron deficiency [26]. However, due to questions over analytical validity as well as cost and confounding factors, it is not currently used as a biomarker for iron status [26]. Iron can also be lost through proteinuria from concomitant chronic kidney disease [27]. In addition, antiplatelet use in underlying ischaemic heart disease can predispose HF patients to gastritis and intestinal ulceration that can lead to iron loss through bleeding [27].

Iron has a central role in erythropoiesis, and when iron supplies are low, it can result in anaemia. Anaemia is independently associated with increased mortality and hospitalisation in both HFrEF and HFpEF, with higher risk with more severe anaemia [28]. This is likely to relate to reduced oxygen delivery to the myocardium resulting in increased workload and remodelling [29]. Anaemia is also associated with comorbidities such as kidney disease, which can further worsen outcomes [30].

However, iron also plays an important role in other cellular activities as a co-factor in both haem and non-haem proteins. As a component of myoglobin, iron is involved in oxygen storage, and, via oxidative enzymes and mitochondrial chain proteins, iron is used in the generation of energy for skeletal and cardiac myocytes [7]. It is also used in the synthesis and degradation of carbohydrates, lipids, and nucleic acids [31].

As a result of the wide range of cellular functionals of iron, its deficiency can present clinically in a variety of ways such as fatigue, generalised weakness, or pallor. It can also manifest as dyspnoea, palpitations, or chest pain, especially on exertion, headaches, and lethargy [32]. Hypoxaemia can result in reduced intestinal blood flow causing nausea, abdominal pain, and more critically, malabsorption [32]. Chronic iron deficiency can also result in brittle nails and hair loss.

In HF patients, not only are there low systemic iron levels but also low myocardial concentrations, which likely contribute to the deterioration of cellular function [33]. Multiple observational studies have suggested a strong association of ID with mortality, after adjusting for confounding factors and regardless of anaemia, which further demonstrates the importance of iron on myocardial function and survival [9, 17, 19, 34, 35]. In a prospective observational cohort study of 546 stable systolic HF patients, 3-year survival was 71% in those without ID compared to 59% with ID [17].

Low iron levels have also been associated with exercise intolerance in HF patients due to its impact on cardiac and skeletal muscle. A prospective study of 155 patients with stable HF and an average left ventricular ejection fraction (LVEF) of 26% showed that patients with adequate iron levels had better exercise tolerance than those without, even after the results were adjusted for demographic and clinical variables [36].

Furthermore, low iron levels have also been associated with lower quality of life, irrespective of anaemia status, than those with adequate iron storage supplies in an analysis of > 500 CHF patients [37]. ID is also associated with frailty and is an independent predictor of worse functional capacity [25].

This evidence is predominantly derived from studies of HFrEF. On the contrary, the role of iron and importance of correcting ID in HFpEF is not yet fully understood. An observational study of 751 HF patients found that functional iron deficiency occurred at the same rate in those with and without preserved systolic function [38]. However, less is known about the impact of iron supply on myocardial function, morbidity, and mortality in this group of patients. A multicentre study of 1278 HF patients demonstrated a negative impact on health-related quality of life in those with ID, regardless of whether the LVEF was preserved or reduced [39]. In another small, but well-designed, study of 26 patients with HFpEF, there was no association between cardiac dysfunction and exercise performance with functional iron deficiency [40]. However, a more recent cross-sectional study of 447 HFpEF patients showed that those with ID performed significantly worse in a 6-min walk test than those without and had a worse quality of life [41]. More data is needed in this important group of patients to fully understand the impact of ID.

The association of ID in HF with worse exercise tolerance, hospitalisation, and mortality have resulted in increasing interest in its role in the treatment of HF patients [42], and several therapeutic preparations are available.

As well as improving cardiac myocyte health, one of the proposed methods by which iron repletion improves functional status and exercise tolerance could be its beneficial impact on ventricular remodelling and improving systolic function [80]. The RIDE-CRT study showed that ID was a negative predictor of effective cardiac resynchronization therapy (CRT) due to reverse cardiac remodelling [81]. The recent randomised, double-blind IRON-CRT trial showed that patients with ID that had persistently reduced LVEF < 45% 6 months after CRT implant benefitted from IV FCM as measured by increased LVEF, functional capacity and cardiac force-frequency relationship, and a decrease in LVESV at 3 months [82]. Interestingly, treatment with FCM also improved right ventricular function and contractile reserve [83].

The focus of IV iron therapy has been on HFrEF patients as no formal randomised controlled trials have yet evaluated IV iron in patients with HFpEF and ID. However, a retrospective single-centre study showed there was an increase in ferritin, TSAT, and haemoglobin in stable HFrEF and HFpEF patients who were given IV FCM as well as an improvement of functional status between the two groups [84]. Large, randomised trials in this patient population are required to ascertain the benefit of IV iron as a treatment for ID. The FAIR-HF-HFpEF study [75] is looking at the impact on exercise tolerance of FCM vs. placebo in ID patients with LVEF > 45%, and PREFER-HF [76] is looking at the effect of both oral and intravenous iron on symptoms and functional class.

ID is a common comorbidity in HF patients, irrespective of anaemia status, and can result in reduced exercise tolerance, recurrent decompensation of HF, and increased cardiovascular and all-cause mortality [85, 86]. The 2021 European Society of Cardiology (ESC) Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure states that all HF patients should be regularly screened for anaemia and ID, and detection of either should prompt investigation and treatment [18]. Based on the available data, it also recommends that IV iron supplementation with FCM should be considered to alleviate HF symptoms and improve exercise tolerance or quality of life in patients with ID, defined as above, and symptomatic HF with LVEF < 45% or LVEF < 50% with a recent HF hospitalisation [18]. The American guidelines, published in 2022, recommended that all HF patients should have iron studies as part of their initial assessment and suggested that IV iron replacement in patients with HFrEF and ID is reasonable to improve functional status and quality of life as a class IIa recommendation, but gave no recommendation on a specific formulation [87]. A summary of the diagnosis and treatment of ID in HFrEF based on guidelines and evidence presented can be found in Fig. 2.

Patients should be made aware of the common side effects that include headache, dizziness, and injection site reactions [5]. Anaphylaxis is rare with 3rd-generation IV iron preparations, but it should always be administered in a clinical setting with access to a resuscitation team. It should also be avoided in patients with active bacteraemia [5]. Oral iron is not recommended in the treatment of ID in systolic HF patients as it has neither been shown to be affective in iron repletion nor to improve exercise tolerance or health status [47]. However, oral Sucrosomial iron, which has shown similar efficacy to IV iron in some conditions associated with ID, could be a promising area in the future [51].

McDonagh et al. suggested an algorithm for the treatment of ID in HF patients that advises either weekly 200 mg FCM to correct ID followed by 4-weekly maintenance 200 mg doses based on FAIR-HF trial or a single 500–1000 mg dose of FCM and 500 mg maintenance dose thereafter to maintain iron level targets based on CONFIRM-HF [7]. Large trials using other formulations of IV iron are ongoing in HFrEF and AHF populations, which will help guide us on the best management options available.

It is not known if there are important differences in the pathophysiology, treatment, and outcomes of ID in different aetiologies of HF as the available studies, described in this review, are not adequately powered to answer this question. It has been shown that ID in both non-ischaemic dilated cardiomyopathy (DCM) and ischaemic cardiomyopathy (ICM) end-stage HF patients resulted in dysfunctional mitochondria and increased oxidative stress in the left ventricle which then drove pathological remodelling of the heart and worsening of LVEF and NYHA classification [88], but no comparison to other aetiologies was performed. However, in AFFIRM-HF, patients with non-ischaemic HF aetiologies did not benefit from IV iron in relation to the primary endpoint of recurrent HF hospitalisations and cardiovascular death compared to ischaemic aetiologies (RR 1.11 vs. 0.6) [71••], which is a hypothesis-generating finding. No other trials have distinguished between aetiologies. Furthermore, most trials of IV iron excluded patients with recent acute coronary syndrome or cardiac surgery and those with uncorrected significant valvular heart disease, which means the impact of IV iron in these HF subgroups remains unclear. Possible differential effects of iron therapy in different HF aetiologies remains unanswered and is an interesting area for further research.

ID is a common comorbidity in HF patients and has an increasingly understood role in its morbidity and mortality. The mechanism of ID in HF patients varies from reduced absorption, impaired uptake, metabolism, and transportation of available iron as well as loss. Multiple studies have investigated IV iron in HF patients, mainly focusing on HFrEF. To date, large randomised controlled trials have shown a clear benefit in correcting ID, irrespective of anaemia status, in chronic HF patients with IV iron, with 3rd-generation preparations such as FCM, with respect to improving symptoms, functional status, exercise tolerance, reducing hospitalisations, and quality of life. However, discernible impact on mortality has not yet been demonstrated, and long-term data on safety is required. More trials using different iron preparations, including newer oral formulations, in varying clinical settings such as HFpEF and AHF are awaited. More research is required in other key areas. We need more data on whether the beneficial impact of IV iron is linked to certain aetiologies of HF. Furthermore, the definition of ID in HF is still debatable and newer biomarkers such as hepcidin, and soluble transferring receptor may hold the key for more accurate diagnosis of ID. We also need a better understanding of the long-term potential damaging consequences of IV iron, particularly relating to oxidative stress and endothelial function. With ID becoming much more topical, we will gain a more robust appreciation of its impact and how we can best treat it in HF.