Abstract

Iron is a micronutrient essential for cellular energy and metabolism, necessary for maintaining body homoeostasis. Iron deficiency is an important co-morbidity in patients with heart failure (HF). A major factor in the pathogenesis of anaemia, it is also a separate condition with serious clinical consequences (e.g. impaired exercise capacity) and poor prognosis in HF patients. Experimental evidence suggests that iron therapy in iron-deficient animals may activate molecular pathways that can be cardio-protective. Clinical studies have demonstrated favourable effects of i.v. iron on the functional status, quality of life, and exercise capacity in HF patients. It is hypothesized that i.v. iron supplementation may become a novel therapy in HF patients with iron deficiency.

Introduction

Iron deficiency (ID) is the commonest nutritional deficiency worldwide, affecting more than one-third of the population.1–4 Although ID is traditionally linked to anaemia,2–4 ID is more prevalent and its economic consequences relevant, although not commonly acknowledged,1,2,5,6 ID adversely affects the function and limits the survival of living organisms at every complexity level1,3,6 (Figure 1).

Figure 1

Importance of iron for functioning and survival across all levels of complexity of living structures.

Figure 1

Importance of iron for functioning and survival across all levels of complexity of living structures.

Iron deficiency is a complication of chronic diseases (e.g. inflammatory bowel disease, Parkinson's disease, rheumatoid disease, chronic renal failure), irrespective of concomitant anaemia.1,7–11 The first reports on ID in cardiovascular disease were published >50 years ago.12,13 Iron deficiency coincided with sympathetic activation,14 left ventricular hypertrophy,14–16 dilatation,16,17 compromised haemodynamics and symptomatic heart failure (HF).12,13 These findings have been mainly forgotten over the years.

In the last decade, anaemia was recognized as an important co-morbidity in HF, a factor limiting physical activity, responsible for a poor quality of life, and a predictor of unfavourable outcomes.18–22 Iron deficiency generated interest as a cause of anaemia.23–25 Iron deficiency was hypothesized to be the cause of erythropoietin resistance in HF,26–28 which could be responsible for the unsatisfactory effects of erythropoietin therapy in HF.29–31

Physiological role of iron

Iron is a metabolically active micronutrient with unique biochemical features.1,3,32–35 Iron changes between two oxidative states, bivalent ferrous (Fe2+) and trivalent ferric (Fe3+) iron.1,32–36 Hence, it can be a cofactor for enzymes and the catalyst of biochemical reactions, an element of proteins with distinct cellular functions (as enzymes, and transport and structural proteins).1,32–36

Iron plays a crucial role in oxygen transport (haemoglobin component), oxygen storage (myoglobin component), cardiac and skeletal muscle metabolism (component of oxidative enzymes and respiratory chain proteins), synthesis, and degradation of proteins, lipids, ribonucleic acids (enzyme component),1,3,32–34,37,38 and mitochondrial function.38–40

Iron is required for optimal haematopoiesis.3,28,33,41 The majority portion of it is taken up by erythroblasts and reticulocytes for haemoglobin synthesis.3,28,33,41 Iron deficiency results in resistance to haematopoietic growth factors (e.g. erythropoietin), and impairs the differentiation and maturation of all types of haematopoietic cells.26,27,33,41,42

In spite of its unquestionable role for optimal haematopoiesis, iron is indispensable for the maintenance of cellular energy and metabolism of extra-haematopoietic tissues.1,3,32–34,37,38 Cells with a high mitogenic potential (neoplastic, haematopoietic, immune) and high-energy demand (hepatocytes, adipocytes, skeletal and cardiac myocytes, renal cells) are particularly sensitive to depleted iron supplies and/or abnormal iron utilization.1,3,32,35,37 This is important in HF, as abnormal energy generation and utilization in the myocardium and the peripheral tissues (e.g. skeletal muscles) contribute to HF pathophysiology.43–47

Iron excess accumulates in cells, and at higher concentrations generates oxidative stress48–53 and triggers cardiomyocyte necrosis,54 whereas at lower concentrations stimulates inducible nitric oxide synthase activity and through increased NO production induces signalling pathways promoting cell survival.54

Major pathways of iron turnover

Average iron intake is 10–20 mg/day, but only 10–20% of dietary iron is normally absorbed using specific transport systems, mainly by duodenal enterocytes.55–58 There is no pathway for iron excretion. Under normal conditions, the same iron amount is lost from skin desquamation, sloughing of epithelial cells, and bleeding.55–58

Dietary iron in two forms, inorganic (non-haem) and organic (haem), is absorbed using distinct transmembrane transport systems consisting of three elements: a specific transport protein complex, an enzyme changing the oxidative iron state, and regulatory proteins.55–58 In the body, intracellular iron exists in the ferrous form (Fe2+) and extracellular circulating iron in the ferric form (Fe3+).55–58

Inorganic dietary iron is absorbed by the apical surface of duodenal enterocytes via the divalent metal transporter 1 (DMT1) and accompanying membrane ferrireductases reduce ferric to ferrous iron.55–59 Haem iron is absorbed through a haem carrier protein, and an inducible haemoxigenase 1 reduces iron before entering the cytosol.55–58 Iron is transported from the cytosol to the circulation by the basolateral surface of enterocytes using ferroportin and an accompanying membrane hephaestin oxidizes ferrous into ferric iron, which is released into the circulation and bound to transferrin.55–59

There are two major pools of iron, utilized and stored (Figure 2). Utilized iron consists of circulating and intracellular iron.55–58 Circulating ferric iron is bound to transferrin, which serves as a reservoir of soluble iron, delivers iron to target cells, and neutralizes the free-radical-generating properties of iron.55–58 Iron bound to transferrin enters the target cells using transferrin receptor type 1 (TfR 1)-mediated endocytosis, the major pathway of iron import.55–59 The vast majority of intracellular iron is in erythrocyte haemoglobin and circulating reticulocytes.55–58 Other cells contribute to specific functions in iron turnover, e.g. enterocytes for dietary absorption, macrophages eliminate senescent erythrocytes, hepatocytes release proteins regulating iron metabolism (hepcidin).55–58

Figure 2

Major pools of utilized and stored iron in the body.

Figure 2

Major pools of utilized and stored iron in the body.

Stored iron is in liver, bone marrow, and spleen cells in a non-toxic form in ferritin shells, which is secreted to the extracellular compartment.55–61 In iron overload or inflammation, the tissue expression of ferritin increases.55–61 However, the precise functions of intracellular and extracellular ferritin and the source of circulating ferritin remain unclear.

Iron pools interact with each other, and iron can be transferred between these compartments using tightly regulated mechanisms.55–60

Within iron homoeostasis, one can distinguish conceptually two dimensions of iron traffic, i.e. one related with iron absorption and its transport between tissues in the whole organism (systemic iron metabolism), and the other related to iron transport between organelles within the cell (intracellular iron metabolism).57,60 Each has distinct regulatory mechanisms. Systemic iron metabolism is controlled by mechanisms involving hepcidin and its receptor (ferroportin), whereas intracellular iron metabolism is orchestrated by a complex of iron-regulatory proteins.57,60 Hepcidin, a small peptide hormone synthesized mainly by hepatocytes, is considered the major regulator of iron metabolism and a part of an innate immune response.62–67 Circulating hepcidin interacts with its specific transmembrane receptor (ferroportin) on target cells, which causes: (i) reduced expression of proteins involved in transmembrane iron import to enterocytes, (ii) internalization of ferroportin, the only protein able to export intracellular iron.57,62–67 Hence, hepcidin blocks intestinal absorption of iron, and diverts iron from the circulation into the reticuloendothelial system.66,67 Decreased intestinal iron absorption together with its accumulation in the reticuloendothelial stores reduces the availability of iron to target tissues.57,62–65 Hepcidin synthesis by hepatocytes is precisely regulated in order to optimize and synchronize iron metabolism, and to react to changing tissue demands for iron. Major stimuli decreasing hepcidin expression in the liver and its release into the circulation are: depleted iron stores, hypoxia, and ineffective erythropoiesis, whereas inflammation produces the opposite effect.57,60,62–65,68

Diagnosis and classification of iron deficiency

Two types of ID need to be distinguished: absolute, and functional ID3,57,69–71 (Figure 3).

Figure 3

The concept of absolute and functional iron deficiency.

Figure 3

The concept of absolute and functional iron deficiency.

Absolute ID reflects depleted iron stores, often with intact iron homoeostasis mechanisms and erythropoiesis.69,70 The commonest causes are: low-dietary iron, impaired gastrointestinal (GI) absorption and GI blood loss, menorrhagia (Figure 3). Functional ID reflects inadequate iron supply to meet the demand despite normal or abundant body iron stores, because iron is trapped inside cells of the reticuloendothelial system and is unavailable for cellular metabolism69,70 (Figure 3). It is believed to be mainly caused by pro-inflammatory activation with hepcidin overproduction (see above).62,64–67

Approximately 80% of the total body iron is in the erythron, being a component of haemoglobin.28,33,41 Reduced iron delivery to erythroblasts and reticulocytes limits erythropoiesis, and ID is the commonest cause of anaemia.3,28,41 Diagnostic algorithms have been developed to optimize the detection and classification of ID, and to monitor iron stores to provide adequate and optimal management of anaemia.69–75

The gold standard for evaluating iron stores in target tissues is a bone marrow biopsy.70,72–76 Recently, Phiri et al.77 proposed a histological grading by iron smear assessment with separate detection of iron in macrophages (stored iron) and erythroblasts (utilized iron), differentiating between a normal status, absolute ID, functional ID, and combined functional and absolute ID. The invasiveness of bone marrow biopsy limits its use and can be replaced by the measurement of several blood biomarkers to show iron status indirectly in most clinical scenarios69,70,72,73,78 (Figure 4).

Figure 4

Tissues utilizing and/or storing iron and related biomarkers which are secreted by these tissues and can be detected in peripheral blood.

Figure 4

Tissues utilizing and/or storing iron and related biomarkers which are secreted by these tissues and can be detected in peripheral blood.

Absolute ID reflects depleted iron stores, hence its diagnosis is based on the measurement of circulating ferritin, a reliable surrogate of stored iron quantity, which originates from iron-storing cells (mainly hepatocytes and reticuloendothelial cells)69,70,72,73,78 (Figure 3). There is a linear relationship between serum ferritin and ferritin expression in iron storage tissues. Currently, the generally accepted serum ferritin cut-off level to diagnose absolute ID is <30 µg/L,70,72,73 although stricter cut-off values were used previously (12–15 µg/L).79 Both intracellular iron accumulation and inflammation stimulate the tissue expression of ferritin and increase its blood level. In such cases, for the diagnosis of absolute ID, a higher serum ferritin cut-off value is used (e.g. 100 µg/L).69,72

Circulating iron bound to transferrin (TIBC, total iron binding capacity—by transferrin) reflects the amount of iron available for metabolizing target cells.69,70,72,78 Importantly, neither serum iron nor serum transferrin alone should be used as biomarkers of iron status. Instead, transferrin saturation (Tsat), the per cent of transferrin that has iron bound to it (ratio of serum iron and TIBC × 100), is recommended. Reduced Tsat (<20%) is considered a surrogate of insufficient iron available for metabolizing cells.69,70,72,78 With malnutrition accompanying chronic diseases, liver synthesis and blood transferrin levels may be low, which can artificially increase Tsat disproportionate to the iron content.69

When serum ferritin is between 100 and 300 µg/L (which is frequent in patients with chronic diseases with pro-inflammatory activation), the diagnosis of ID is more complex. Such values are usually associated with normal/slightly increased intracellular iron stores and the diagnosis of absolute ID cannot be made.69,70,72,78 If there is restricted iron delivery to target cells (reduced Tsat < 20%), functional ID can be diagnosed.69

Therefore, in chronic diseases, absolute ID is typically diagnosed with higher cut-off ferritin values (i.e. <100 μg/L) and distinguished from functional ID, diagnosed with normal serum ferritin (100–300 μg/L) and low Tsat (<20%).69 Such a definition of ID has been applied in HF syndrome, including clinical trials.80,81

Iron plays a critical role in erythropoiesis, being incorporated into erythroblasts and reticulocytes.28,33,41 Restricted delivery to the erythron can be detected in peripheral blood using indices of so-called iron-restricted erythropoiesis.33,69,70,73,78,82 Reticulocytes are the earliest erythrocytes released into circulating blood and are present for only 1–2 days. Reduced reticulocyte haemoglobin content (<28 pg) is an early indicator of iron-restricted erythropoiesis.69,70,78,82 Reticulocyte haemoglobin content is also an early indicator of the response to iron therapy, increasing within 2–4 days after i.v. iron therapy. Later indicators of iron-restricted erythropoiesis are: increased percentage (>2.5%) of hypochromic erythrocytes [red blood cells (RBCs)] and an increased RBC zinc protoporphyrin, a product of abnormal haem synthesis.69,70,78 Among the last parameters to change with iron-deficient erythropoiesis are the basic haematological indices: haemoglobin level, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration with the picture of microcytic hypochromic anaemia.28,33,41,70,73–75,78

The red cell distribution width (RDW) reflecting MCV heterogeneity (quantitative index of anisocytosis, i.e. the percentage coefficient of MCV variation) can be considered another parameter of ID.78,83,84 Increased RDW is, however, typical not only for anaemia due to ID, but also anaemia resulting from deficiencies in vitamin B12 and folic acid, of chronic diseases and sideroblastic anaemia.77,83,84 In HF patients, there are associations between high RDW, and reduced haemoglobin, low MCV, reduced Tsat,85 increased mortality and hospitalization rates.85–87

Owing to pathophysiological links and overlaps in regulatory mechanisms of erythropoietin and iron metabolism,26–28 subjects with ID frequently have increased circulating erythropoietin levels, which can be considered another index of iron-restricted erythropoiesis in HF patients, being related to poor outcomes.88,89

Increased soluble transferrin receptor (sTfR) is another sensitive indicator of ID.69,70,73,78,90–92 Soluble transferrin receptor is the truncated form of transmembrane protein, a receptor for iron–transferrin complex and the major system responsible for the intracellular iron import.56,57,73,90 It is present on virtually all cells, but a vast majority is localized on erythroid precursors.57,90 When iron delivery to target tissues is insufficient for metabolic requirements, the expression of the transferrin receptor increases in order to facilitate intracellular iron influx.56,57,70,73,90 Consequently, circulating sTfR (originating from all cells metabolizing iron) quantitatively reflects both the tissue iron demand (tissue iron balance) and the erythroid proliferation rate (total erythroblast mass), but not body iron stores.69,70,73,78,90 No study has used this biomarker to indicate and/or guide therapy, and so it should be regarded as a research tool.

Because serum ferritin is a surrogate of iron stores and serum sTfR reflects the tissue iron demand, there is evidence that the combination of these two parameters may describe the iron status more accurately.73,90,93

Absolute and functional iron deficiency in heart failure

A pathophysiology milieu in HF syndrome favours the development of absolute and functional ID.

The following mechanisms are presumed to be involved in the development of absolute ID in HF: (i) insufficient dietary iron supply,94,95 (ii) poor GI absorption, impaired duodenal iron transport,96 drug interactions (e.g. omeprazole), or food reducing absorption, and (iii) GI blood loss (Figure 3).

Some studies demonstrate suboptimal dietary iron supply, particularly in patients with advanced HF. Based on a 4-day food diary, Hughes et al.94 showed that 46% of patients with stable HF consumed less iron than the dietary reference value, and average daily iron intake was markedly reduced in patients in NYHA class III–IV when compared with NYHA class II. In another study, Lourenço et al.95 assessed the nutritional status using an interview by nutritionists in 125 outpatients with stable HF, and in 12–35% found an inadequate dietary iron intake.

In HF, reduced iron intake may also be a consequence of deranged transport systems in the enterocytes. Theoretically, reduced expression of membrane proteins importing iron from the intestinal lumen to the enterocyte cytosol and the subsequent iron export to the circulation may result from increased circulating hepcidin levels, analogous to a reported experimental model of chronic kidney disease.97,98 Recent experimental evidence demonstrates the existence of disrupted regulatory mechanisms of duodenal iron transportation systems in animals with induced HF and ID.96 Animals from both HF and ID groups developed ID (and anaemia) along with a reduced hepatic expression of hepcidin compared with controls.96 In animals with ID but without HF, there was up-regulation of the elements of the duodenal iron transportation system (duodenal cytochrome b, DMT-1, ferroportin), which was not seen in animals with ID and HF. More importantly, the intestinal expression of hypoxia-inducible factor-2α (the major regulator of the duodenal iron transportation system98) was up-regulated in iron-deficient animals without HF, but not in animals with HF.96 This suggested a lack of adaptive physiological mechanisms to counteract depleted iron stores and to augment iron absorption in the duodenum.96 These mechanisms have not been investigated in HF patients, and it remains unclear whether they would play any role in a clinical setting of HF.

Heart failure is a state characterized by generalized inflammation with an augmented immune response, overactive immune cells, high circulating levels of pro-inflammatory mediators, and the up-regulation of these molecules within the failing myocardium and peripheral tissues.99–101 Activation of pro-inflammatory pathways constitutes an important element of the pathophysiology of HF, which triggers and maintains phenomena such as weight loss, impaired exercise capacity, insulin resistance, etc.99,102–104 Hence, it is tempting to hypothesize that in HF, functional ID may be secondary to the inflammation, or due to inflammatory processes resulting from concomitant pathologies (e.g. renal failure, chronic infections). In this context, hepcidin can be expected to play an important role. Both in rodents105 and humans,106 acute myocardial ischaemia is accompanied by increased circulating hepcidin, which subsequently decreases during recovery. Simonis et al.105 observed the parallel overexpression of hepcidin within the ischaemic and remote myocardium in rats. The role of hepcidin produced locally is unknown. Interestingly, in clinical settings of HF, there was no association between pro-inflammatory activation (as evidenced by circulating IL-6) and hepcidin levels.107,108 Anaemic HF patients have reduced serum and urine hepcidin compared with non-anaemic and healthy subjects, which is accompanied by depleted total body iron.107–109

Incidence of iron deficiency in heart failure patients

Clinical evidence on the incidence of ID in HF patients is scarce. Most available studies have presented a traditional view linking ID with anaemia.23–25,110 Additionally, difficulties in their interpretation are due to a lack of prospectively validated definition of ID in HF.

Ezekowitz et al.23 provided the first evidence that ID frequently coexisted with anaemia in HF patients. In this study, anaemia was present in 17% of hospital discharges for HF, and ID was diagnosed in 21% cases of anaemia.23

Witte et al.111 investigated the iron status in ambulatory patients with chronic HF using only the serum ferritin level. Iron deficiency (ferritin <30 µg/L) was found in 13% of HF patients, regardless of LVEF (functional ID not reported).111

Opasich et al.25 examined 148 outpatients with systolic HF and concomitant anaemia, among whom 20% had microcytic anaemia that mainly reflected insufficient bone marrow iron utilization (absolute ID).25 However, the commonest form was anaemia of chronic disease (57% of patients), and in this group nearly all demonstrated defective iron supply for erythropoiesis (functional ID).25 The presence of ID was confirmed in 36% of all anaemic subjects and 64% of patients with anaemia of chronic disease.25

The only study assessing the iron status in HF patients based on the gold standard (bone marrow biopsy) was reported by Nanas et al.24 Iron deficiency was confirmed in 27 (73%) of 37 anaemic patients with advanced decompensated HF.24 Although, serum ferritin in ID subjects was lower compared with non-ID patients, the vast majority of ID patients had serum ferritin within the normal range,24 further confirming the difficulty of evaluating ID in HF on the basis of serum ferritin assessment.

So far, only two observational studies have reported the incidence of ID in the general HF population.110,112 Adlbrecht et al.110 found ID (serum ferritin <30 µg/L or Tsat <15%) in 26% of patients with chronic systolic HF, with an ID incidence of 16 and 54% in non-anaemic and anaemic subjects, respectively. We have demonstrated a 37% incidence of ID (serum ferritin <100 μg/L or serum ferritin 100–300 μg/L with Tsat <20%) among 546 patients with chronic systolic HF.112 The incidence of ID reached 32 and 57% in anaemic and non-anaemic patients, respectively.112 We identified four independent determinants for a higher incidence of ID: female gender, advanced NYHA class, high plasma N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), and high serum high-sensitivity C-reactive protein.112 As we studied relatively young HF patients, predominantly men, in real life, the prevalence of ID may be even higher as HF patients are older, more frequently females, and with co-morbidities. Further studies are warranted.

Clinical and prognostic consequences of iron deficiency in heart failure patients

Iron deficiency and exercise intolerance in heart failure

In patients with stable systolic HF, ID was associated with reduced peak oxygen consumption and a high ventilatory response to exercise, also after an adjustment for clinical co-variables.113 The difference in exercise capacity between iron-deficient and iron-replete subjects was seen separately in anaemics and non-anaemics.113

There is also indirect evidence linking correction of ID with an improvement in exercise capacity in a few interventional studies in HF patients, regardless of baseline anaemia.80,81,114,115

Iron deficiency and depression symptoms in heart failure

Iron deficiency carries also a risk of depression in men with systolic HF. Moderate depression by beck depression inventory (BDI) (≥16 points) was more prevalent (48 vs. 25%), and the lack of depression symptoms (BDI <10 points) less common (13 vs. 51%) in men with ID than those without ID (E.A. Jankowska et al., submitted for publication). Iron deficiency was associated with more severe depression symptoms, irrespective of HF severity, neurohormonal activation, haemoglobin, and inflammation (E.A. Jankowska et al., submitted for publication).

Iron deficiency and prognosis in heart failure

The prognostic impact of ID in HF patients was investigated in only two observational prospective studies.112,116 Varma et al.116 investigated 120 consecutive patients with systolic dysfunction (LVEF ≤45%) undergoing percutaneous coronary intervention with a median follow-up of 30 months. They demonstrated that anaemia accompanied by ID strongly predicted cardiac mortality (33 vs. 1% in non-anaemics), malignancy-associated anaemia was related to high-non-cardiac mortality (57 vs. 4% in non-anaemics), whereas anaemia of chronic disease predicted neither cardiac nor non-cardiac death.116 Among 546 patients with systolic HF we found that ID was a strong independent predictor of death and heart transplantation during a 3-year follow-up.112 The presence of ID increased the risk of a poor outcome by 60% during the 3-year follow-up (Figure 5).112

Figure 5

Kaplan–Meier curves reflecting 3-year event-free survival rates in 546 patients with systolic heart failure with vs. without iron deficiency.112

Figure 5

Kaplan–Meier curves reflecting 3-year event-free survival rates in 546 patients with systolic heart failure with vs. without iron deficiency.112

Iron deficiency and dysfunction of myocardium and skeletal muscle

Mechanisms underlying links between ID and poor clinical status, exercise intolerance, and an unfavourable outcome in HF remain unclear. Dysfunction of both the myocardium and skeletal muscles are at the centre of the pathophysiology of HF.99,117,118 These organs have high energy demands, and their function in dependent on intact iron metabolism.

Consequences of deranged iron metabolism for myocardium

Iron is an element of enzymes and structural proteins in cardiomyocytes, and is stored inside these cells. Molecular elements controlling iron metabolism are tracked within healthy, failing, ischaemic, and inflamed myocardium.105,119–123 Hypoxia up-regulates hepcidin expression in the ischaemic rat myocardium (in contrast to hepatic hepcidin expression).120 Rat cardiomyocytes from experimental myocarditis and myocardial infarction demonstrate increased hepcidin expression which normalizes 3 weeks after heart damage.105,123 However, in the diseased myocardium, neither pathophysiological consequences of these changes nor their relationship with iron metabolism is understood.

Most available evidence reporting myocardial molecular consequences of ID comes from the experimental model of ID-anaemia. Iron deficiency-anaemic rats develop sympathetic activation with increased cardiac output,14 left ventricular hypertrophy,14–17,124–127 and finally left ventricular dilatation.16,17 The myocardium from ID-anaemic rats is also characterized by the overexpression of ANP and BNP,16 remodelling of extracellular matrix16,128 and mitochondrial dysfunction.17 In male rats with ID-anaemia and renal insufficiency, impaired left ventricular function was related to hypoferraemia and an increased semi-quantitative myocardial staining for hepcidin.119 In this study, cardiomyocytes from hypertrophied hearts showed features of inflammation, hypoxia, apoptosis, and a local up-regulation of erythropoietin and hepcidin transcription when compared with tissues from sham-operated animals.119 It can be concluded that in experimental models, anaemia and ID are accompanied by unfavourable changes in the myocardium.

Recently, Maeder et al.120 demonstrated reduced iron content and reduced TfR 1 expression in failing human myocardium when compared with normal hearts. They provided experimental evidence that the myocardial expression of TfR 1 was regulated by β-adrenoceptor agonists and aldosterone.129

Consequences of deranged iron metabolism for skeletal muscle

Skeletal muscle accounts for 10–15% of the total body iron, and the system controlling iron metabolism is present there.130–132 Sports medicine provided the earliest evidence linking ID and skeletal muscle function.133–135 The optimal iron status in non-anaemic subjects was critical for the efficient increase in aerobic and endurance capacity with exercise training.136–138

The haemoglobin level and iron status are interlinked determinants of exercise capacity and physical fitness.6 There are two determinants of exercise capacity and physical performance, i.e. tissue oxidative capacity and oxygen carrying capacity.6 The former, which determines endurance, energy efficiency, and submaximal exercise effort, is mainly affected by the iron status. The tissue oxidative capacity is impaired proportionally across the whole spectrum of ID (also when haemoglobin is normal).6 In contrast, the oxygen-carrying capacity determines mainly the aerobic capacity and the maximal exercise effort. The oxygen capacity is limited only with the most severe ID, when erythropoiesis is compromized with reduced haemoglobin.6

In rodent studies, the distinctions between the effects of diminished oxygen transport and oxygen diffusion and decreased oxidative capacity (due to ID at the tissue level, not necessarily linked with anaemia) have been established both in resting and exercising skeletal muscles.133,134,139 Additionally, impaired bioenergetics and abnormal patterns of glucose and free-fatty acid utilization as fuel sources with earlier lactate accumulation in exercising muscles at submaximal exercise in ID animals have been described.140,141 Finch et al.142 investigated ID anaemic rats who received different combinations of blood transfusion and/or iron-rich diet in order to obtain a similar increase in the haemoglobin level at different levels of iron repletion. An improvement in exercise capacity was not directly related to an increase in haemoglobin, but exercise capacity increased only in animals who received iron supplementation.142 Iron administration in ID non-anaemic young subjects increased serum ferritin (but not haemoglobin) and improved the submaximal energy efficiency.143

Almost all available evidence linking the iron status with skeletal muscle function comes from physiological experiments and studies performed in healthy subjects. It remains unclear whether analogous mechanisms may explain the unfavourable effects of ID on exercise capacity in HF patients. Comprehensive studies are needed in this field.

Iron supplementation in patients with heart failure

The effects of i.v. iron supplementation in HF patients were reported in seven studies: three open-label uncontrolled studies,115,143,144 two randomized open-label studies,80,145 two randomized double-blind placebo-controlled trials.81,113 Among them only two included both anaemic and non-anaemic HF patients80,81 (details in Table 1).

Table 1

Summary of seven studies with intravenous iron therapy administered in patients with heart failure

Publication Studied groups
 
Iron therapy
 
Major results
 
 Inclusion criteria: clinical status Inclusion criteria: Hb and iron status Study design Iron preparation Dose Period Hb and iron status QoL, HF symptoms Exercise capacity CV events Others 
Bolger et al.115 n = 16, systolic HF, NYHA II–III Hb ≤12 g/dL
Ferritin ≤400 µg/L 
Open-label, uncontrolled, single-centre Iron sucrose Maximum 1000 mg iron i.v. during 17 days (200 mg i.v. iron on Days 1, 3, 5, and if ferritin <400 µg/L on Day 12, also 200 mg i.v. iron on Days 15, 17) 12–17 days of therapy and further follow-up up to 3 months ↑ Hb
↑ Ferritin, ↑ Tsat 
↑ QoL ↑ 6MWD  ↓ (trend) cystatin C 
Toblli et al.114 n = 40, LVEF ≤35%, NYHA II-IV, creatinine clearance ≤90 mL/min Hb <12.5 g/dL for men, Hb <11.5 g/dL for women
Ferritin <100 µg/L or Tsat ≤20% 
Radomized, double-blind, placebo-controlled, single-centre Iron sucrose vs. placebo (20 vs. 20) 200 mg iron i.v. weekly for 5 weeks
Total iron dose: 1000 mg 
5 weeks of therapy and follow-up up to 6 months ↑ Hb
↑ Ferritin, ↑ Tsat 
↑ QoL, ↓ NYHA class ↑ 6MWD ↓ Hospitalization rate ↑ Creatinine clearance, ↑ LVEF, ↓ plasma NT-pro-BNP, ↓ CRP, ↓ resting heart rate 
Okonko et al.80 (FERRIC-HF) n = 35, NYHA class II–III, peak VO2 ≤18 mL/min/kg, LVEF ≤45% Hb <12.5 g/dL (anaemic group) or Hb 12.5–14.5 g/dL (non-anaemic group)
Ferritin <100 µg/L, or ferritin 100–300 µg/L and Tsat <20% 
Randomized, open-label, observer-blinded, placebo-controlled, double centre Iron sucrose vs. placebo (24 vs. 11) Correction phase: 200 mg iron i.v. weekly until ferritin ≥500 µg/L
Maintenance phase: 200 mg iron i.v. every 4 weeks
Iron repletion total dose: estimated using Ganzoni formula 
16 weeks of therapy and final assessments after next 2 weeks All: ↑ ferritin, ↑ Tsat, ↑ Hb
Anaemics: ↑ ferritin, ↑ Tsat, ↔Hb
Non-anaemics: ↑ ferritin, ↑ Tsat, ↔ Hb 
All: ↑ PGA, ↓ NYHA class, ↑ QoL
Anaemics: ↓ NYHA class
Non-anaemics:↓ (trend) NYHA class, 
All: ↑ (trend) peak VO2 (mL/min), ↑ peak VO2 (mL/min/kg)
Anaemics: ↑ peak VO2 (mL/min), ↑ peak VO2 (mL/min/kg)
Non-anaemics: ↔ peak VO2 (mL/min), ↔ peak VO2 (mL/min/kg) 
  
Usmanov et al.146 n = 32, NYHA III–IV, moderate renal failure (mean serum creatinine: 2.3 mg/dL) Hb <11 g/dL
Ferritin not specified 
Open-label, uncontrolled, single-centre Iron sucrose Correction phase: 100 mg iron i.v. three times weekly for 3 weeks
Maintenance phase: 100 mg iron i.v. weekly for 23 weeks
Total iron dose: 3200 mg 
26 weeks NYHA III: ↑ Hb
NYHA IV: ↑ Hb 
NYHA III: ↓ NYHA class
NYHA IV: ↔ NYHA class 
  NYHA III: ↓ PWT, ↓ ST, ↓ LVEDD, ↓ LVEDV, ↓ LVESD, ↓ LVESV, ↓ LV mass index, ↑ LVEF
NYHA IV: ↓ PWT, ↔ ST, ↓ LVEDD, ↓ LVEDV, ↓ LVESD, ↓ LVESV,↓ LV mass index, ↔ LVEF 
Drakos et al.145 n = 16 Anaemia (+)
Iron deficiency (+) verified by bone marrow aspiration 
Randomized, open label, single-centre Iron sucrose vs. iron sucrose + darbapoietin α (8 vs. 8) IV iron (300 mg weekly) vs. IV iron (300 mg weekly + darbapoietin α (50 µg sc weekly) 6 weeks of therapy and further 6 weeks of follow-up ↑ Hb (in absolute units and in %, similar in both arms)     
Comín-Colet et al.144 n = 65, NYHA class III–IV
mild to moderate chronic kidney disease (stage II–IV) or serum creatinine <3 mg/dL 
Hb <13 g/dL for men, Hb <12 g/dL for women
Ferritin not specified 
Open-label, uncontrolled, single-centre Recombined human erythropoietin (rhuEPO) + iron sucrose vs. none (27 vs. 38) rhuEPO—sc 4000 U per week, doses adjusted according to target Hb 12.5–14.5 g/dL
IV iron 200 mg per week for 5–6 weeks, later 200 mg every 4–6 weeks (adjusted according to haematinics) 
15 ± 9 months ↑ Hb
↔ Ferritin,
↑ Tsat, 
  ↓ Number of CV admissions, ↓ days spent in hospital for CV causes, ↓ CV hospitalization rate, ↔ all-cause-mortality ↓ Plasma NT-pro-BNP, 
Anker et al.81 (FAIR-HF) n = 459, LVEF ≤40% and NYHA II, LVEF ≤45% and NYHA III Hb: 9.5–13.5 g/dL
Ferritin <100 µg/L or ferritin 100–300 µg/L and Tsat <20% 
Randomized (2:1), double blind, placebo controlled, multi-centre Ferric carboxymaltose vs. placebo (304 vs. 155) Correction phase: 200 mg i.v. iron week until repletion dose is achieved
Maintenance phase: 200 mg i.v. iron every 4 weeks
Iron repletion total dose: estimated using Ganzoni formula 
24 weeks ↑ Hb
↑ Ferritin,
↑ Tsat,
↑ MCV
(all patients, and separately: anaemics and non-anaemics) 
↑ PGA,
↓ NYHA class (all patients, and separately: anaemics and non-anaemics) 
↑ 6MWD ↓ (trend) CV hospitalization rate  
Publication Studied groups
 
Iron therapy
 
Major results
 
 Inclusion criteria: clinical status Inclusion criteria: Hb and iron status Study design Iron preparation Dose Period Hb and iron status QoL, HF symptoms Exercise capacity CV events Others 
Bolger et al.115 n = 16, systolic HF, NYHA II–III Hb ≤12 g/dL
Ferritin ≤400 µg/L 
Open-label, uncontrolled, single-centre Iron sucrose Maximum 1000 mg iron i.v. during 17 days (200 mg i.v. iron on Days 1, 3, 5, and if ferritin <400 µg/L on Day 12, also 200 mg i.v. iron on Days 15, 17) 12–17 days of therapy and further follow-up up to 3 months ↑ Hb
↑ Ferritin, ↑ Tsat 
↑ QoL ↑ 6MWD  ↓ (trend) cystatin C 
Toblli et al.114 n = 40, LVEF ≤35%, NYHA II-IV, creatinine clearance ≤90 mL/min Hb <12.5 g/dL for men, Hb <11.5 g/dL for women
Ferritin <100 µg/L or Tsat ≤20% 
Radomized, double-blind, placebo-controlled, single-centre Iron sucrose vs. placebo (20 vs. 20) 200 mg iron i.v. weekly for 5 weeks
Total iron dose: 1000 mg 
5 weeks of therapy and follow-up up to 6 months ↑ Hb
↑ Ferritin, ↑ Tsat 
↑ QoL, ↓ NYHA class ↑ 6MWD ↓ Hospitalization rate ↑ Creatinine clearance, ↑ LVEF, ↓ plasma NT-pro-BNP, ↓ CRP, ↓ resting heart rate 
Okonko et al.80 (FERRIC-HF) n = 35, NYHA class II–III, peak VO2 ≤18 mL/min/kg, LVEF ≤45% Hb <12.5 g/dL (anaemic group) or Hb 12.5–14.5 g/dL (non-anaemic group)
Ferritin <100 µg/L, or ferritin 100–300 µg/L and Tsat <20% 
Randomized, open-label, observer-blinded, placebo-controlled, double centre Iron sucrose vs. placebo (24 vs. 11) Correction phase: 200 mg iron i.v. weekly until ferritin ≥500 µg/L
Maintenance phase: 200 mg iron i.v. every 4 weeks
Iron repletion total dose: estimated using Ganzoni formula 
16 weeks of therapy and final assessments after next 2 weeks All: ↑ ferritin, ↑ Tsat, ↑ Hb
Anaemics: ↑ ferritin, ↑ Tsat, ↔Hb
Non-anaemics: ↑ ferritin, ↑ Tsat, ↔ Hb 
All: ↑ PGA, ↓ NYHA class, ↑ QoL
Anaemics: ↓ NYHA class
Non-anaemics:↓ (trend) NYHA class, 
All: ↑ (trend) peak VO2 (mL/min), ↑ peak VO2 (mL/min/kg)
Anaemics: ↑ peak VO2 (mL/min), ↑ peak VO2 (mL/min/kg)
Non-anaemics: ↔ peak VO2 (mL/min), ↔ peak VO2 (mL/min/kg) 
  
Usmanov et al.146 n = 32, NYHA III–IV, moderate renal failure (mean serum creatinine: 2.3 mg/dL) Hb <11 g/dL
Ferritin not specified 
Open-label, uncontrolled, single-centre Iron sucrose Correction phase: 100 mg iron i.v. three times weekly for 3 weeks
Maintenance phase: 100 mg iron i.v. weekly for 23 weeks
Total iron dose: 3200 mg 
26 weeks NYHA III: ↑ Hb
NYHA IV: ↑ Hb 
NYHA III: ↓ NYHA class
NYHA IV: ↔ NYHA class 
  NYHA III: ↓ PWT, ↓ ST, ↓ LVEDD, ↓ LVEDV, ↓ LVESD, ↓ LVESV, ↓ LV mass index, ↑ LVEF
NYHA IV: ↓ PWT, ↔ ST, ↓ LVEDD, ↓ LVEDV, ↓ LVESD, ↓ LVESV,↓ LV mass index, ↔ LVEF 
Drakos et al.145 n = 16 Anaemia (+)
Iron deficiency (+) verified by bone marrow aspiration 
Randomized, open label, single-centre Iron sucrose vs. iron sucrose + darbapoietin α (8 vs. 8) IV iron (300 mg weekly) vs. IV iron (300 mg weekly + darbapoietin α (50 µg sc weekly) 6 weeks of therapy and further 6 weeks of follow-up ↑ Hb (in absolute units and in %, similar in both arms)     
Comín-Colet et al.144 n = 65, NYHA class III–IV
mild to moderate chronic kidney disease (stage II–IV) or serum creatinine <3 mg/dL 
Hb <13 g/dL for men, Hb <12 g/dL for women
Ferritin not specified 
Open-label, uncontrolled, single-centre Recombined human erythropoietin (rhuEPO) + iron sucrose vs. none (27 vs. 38) rhuEPO—sc 4000 U per week, doses adjusted according to target Hb 12.5–14.5 g/dL
IV iron 200 mg per week for 5–6 weeks, later 200 mg every 4–6 weeks (adjusted according to haematinics) 
15 ± 9 months ↑ Hb
↔ Ferritin,
↑ Tsat, 
  ↓ Number of CV admissions, ↓ days spent in hospital for CV causes, ↓ CV hospitalization rate, ↔ all-cause-mortality ↓ Plasma NT-pro-BNP, 
Anker et al.81 (FAIR-HF) n = 459, LVEF ≤40% and NYHA II, LVEF ≤45% and NYHA III Hb: 9.5–13.5 g/dL
Ferritin <100 µg/L or ferritin 100–300 µg/L and Tsat <20% 
Randomized (2:1), double blind, placebo controlled, multi-centre Ferric carboxymaltose vs. placebo (304 vs. 155) Correction phase: 200 mg i.v. iron week until repletion dose is achieved
Maintenance phase: 200 mg i.v. iron every 4 weeks
Iron repletion total dose: estimated using Ganzoni formula 
24 weeks ↑ Hb
↑ Ferritin,
↑ Tsat,
↑ MCV
(all patients, and separately: anaemics and non-anaemics) 
↑ PGA,
↓ NYHA class (all patients, and separately: anaemics and non-anaemics) 
↑ 6MWD ↓ (trend) CV hospitalization rate  

Hb, haemoglobin; QoL, quality of life; HF, heart failure; CV, cardiovascular; NYHA, New York Heart Association; i.v., intravenous; Tsat, transferrin saturation; 6MWD, 6-minute walking distance; PWT, posterior wall thickness; ST, septal thickness; LV, left ventricular; LVEDD, left ventricular end diastolic diameter; LVEDV, left ventricular end diastolic volume; LVESD, left ventricular end systolic diameter; LVESV, left ventricular end systolic volume; LVEF, left ventricular ejection fraction; PGA, patient global assessment; VO2, oxygen consumption; FERRIC-HF, Ferric Iron Sucrose in Heart Failure; NT-pro-BNP, N-terminal pro-B-type natriuretic peptide; CRP, C-reactive protein; FAIR-HF, Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure; MCV, mean corpuscular volume.

The first study by Bolger et al.115 provided data on 16 cases that iron sucrose given i.v. for 5–17 days in anaemic ID HF patients was well tolerated, increased haemoglobin, and improved symptoms and exercise capacity over a 3-month follow-up period. Toblli et al.114 confirmed in the first controlled study that i.v. iron treatment in anaemic HF patients with impaired renal function improved the functional status, exercise capacity, and quality of life. They also reported other beneficial effects of iron therapy on LVEF, plasma NT-pro-BNP and CRP, and hospitalization rate,114 but the small numbers make these findings uncertain.

In the FERRIC-HF (FERRIC Iron Sucrose in Heart Failure) study,80 16 weeks of i.v. iron therapy was well tolerated, and improved exercise tolerance and symptoms. Interestingly, benefits were also observed in non-anaemic ID patients although to a lesser extent, and an increase in the peak oxygen consumption was not related to changes in haemoglobin, but to an increment in the Tsat.80

Usmanov et al.146 demonstrated that i.v. iron given for 26 weeks to patients with advanced HF, anaemia, and chronic renal insufficiency exerted favourable anti-remodelling effects on the myocardium assessed by echocardiography, and improved the functional class (only in NYHA class III patients). In the study by Drakos et al.145 i.v. iron supplementation with erythropoietin in HF patients with anaemia and ID, verified by bone marrow aspiration, increased haemoglobin to a similar extent to erythropoietin alone. Comín-Colet et al.144 reported that long-term therapy with i.v. iron and erythropoietin in elderly patients with advanced HF, renal dysfunction, and anaemia, and corrected haemoglobin and creatinine levels, improved symptoms and decreased plasma NT-pro-BNP. This therapy was also associated with an 80% reduction in the combined endpoint of all-cause mortality and cardiovascular hospitalizations.144

FAIR-HF (Ferinject®Assessment in patients with IRon deficiency and chronic Heart Failure) study was a randomized double-blind placebo-controlled multi-centre trial, which so far recruited the greatest number of patients with chronic systolic HF and ID (both anaemics and non-anaemics) (n = 459) who subsequently received a 24-week therapy of i.v. iron or placebo (2:1).81 Beneficial effects of i.v. iron therapy on the NYHA class and the patient's global assessment were seen across the whole clinical spectrum of HF (Figure 6) (regardless of the baseline NYHA class, haemoglobin, LVEF, HF aetiology, the presence of co-morbidities).81 There was no increased risk of side-effects in the treated vs. the non-treated group, but the observation was limited to 6 months.81 Although the FAIR-HF trial was not designed to test the effects of iron therapy on the outcome, the authors reported a trend towards a reduced rate for the first cardiovascular hospitalization in the treated vs. the non-treated group,81 which is similar to other reports.114,144 Undoubtedly, there is a need for more and longer-running, randomized, double-blind, placebo-controlled trials that could validate the findings of FAIR-HF and also investigate the impact of this novel treatment modality on the morbidity and mortality in HF patients with ID.

Figure 6

Self-reported Patient Global Assessment and NYHA functional class at week 24 (primary endpoints of FAIR-HF trial), according to assigned study treatment (intravenous iron vs. placebo).81

Figure 6

Self-reported Patient Global Assessment and NYHA functional class at week 24 (primary endpoints of FAIR-HF trial), according to assigned study treatment (intravenous iron vs. placebo).81

Conclusions

Iron is a micronutrient that stands at the centre of cellular metabolism and is critical for the maintenance of homoeostasis.

Iron deficiency constitutes a frequent co-morbidity in HF patients. Iron deficiency is gaining interest, not only as an aetiological factor leading to and/or aggravating anaemia in HF, but is considered a separate condition with unfavourable clinical and prognostic consequences. There is experimental evidence suggesting that iron supplementation in iron-deficient animals may activate molecular pathways protecting the heart and preventing myocardial remodelling. Only recently, clinical studies demonstrated that in HF patients with ID, i.v. iron repletion was well-tolerated, and improved functional status, quality of life, and exercise capacity.

There are the premises that HF patients may benefit from the correction of anaemia, ID, or both. It is emphasized that currently there is neither convincing nor unequivocal evidence on the most accurate intervention to be applied in the two conditions. This is partially due to the unclear pathophysiology of ID in HF as well as lack of a clinically applicable and prospectively verified definition of this condition, all of which justify a need for future mechanistic and interventional studies. Further studies will finally establish whether ID may become a novel therapeutic target in HF patients.

Funding

This research was financially supported by the Ministry of Science and Higher Education (Poland) grant no. 4022/B/T02/2008/34. This work was also supported by European Regional Development Fund and the Polish Government (Operational Programme—Innovative Economy) under the grant ‘WROVASC—Integrated Cardiovascular Centre’ which is being realized in the years 2007–2013. Funding to pay the Open Access publication charges for this article was provided by Vifor (International) AG.

Conflict of interest: E.A.J. reports receiving honoraria for lectures and participation in advisory boards from Vifro Pharma and related travel/accomodation expenses covered by Vifor Pharma. S.v.H. reports receiving speaker's honoraria and travel support from Vifor Pharma and BRAHMS GmbH and research support from BRAHMS GmbH. S.D.A. reports receiving consulting fees from Alere, Brahms GmbH, Abbott laboratories, Vifor Pharma, honoraria from Alere, BRAHMS GmbH, Vifor Pharma, and research support from BRAHMS GmbH. I.C.M. has received consultancy fees and lecture honoraria from Amgen, Ortho Biotech, Roche, Affymax, and Vifor Pharma. P.P. reports receiving consulting fees from Vifor Pharma and Amgen, Inc., and honoraria from Vifor Pharma, and travel/accommodation expenses covered by Vifor Pharma and Amgen, Inc.

References

1
Kell
DB
Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases
BMC Med Genomics
 , 
2009
, vol. 
8
 pg. 
2
 
2
Zimmermann
MB
Hurrell
RF
Nutritional iron deficiency
Lancet
 , 
2007
, vol. 
370
 (pg. 
511
-
520
)
3
Andrews
NC
Disorders of iron metabolism
N Engl J Med
 , 
1999
, vol. 
341
 (pg. 
1986
-
1995
)
4
Milman
N
Anemia—still a major health problem in many parts of the world!
Ann Hematol
 , 
2011
, vol. 
90
 (pg. 
369
-
377
)
5
Black
RE
Allen
LH
Bhutta
ZA
Caulfield
LE
de Onis
M
Ezzati
M
Mathers
C
Rivera
J
Maternal and Child Undernutrition Study Group
Maternal and child undernutrition: global and regional exposures and health consequences
Lancet
 , 
2008
, vol. 
371
 (pg. 
243
-
260
)
6
Haas
JD
Brownlie
T
IV
Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship
J Nutr
 , 
2001
, vol. 
131
 (pg. 
676S
-
690S
)
7
Baker
JF
Ghio
AJ
Iron homoeostasis in rheumatic disease
Rheumatology
 , 
2009
, vol. 
48
 (pg. 
1339
-
1344
)
8
Balla
J
Jeney
V
Varga
Z
Komódi
E
Nagy
E
Balla
G
Iron homeostasis in chronic inflammation
Acta Physiol Hung
 , 
2007
, vol. 
94
 (pg. 
95
-
106
)
9
Zafon
C
Lecube
A
Simó
R
Iron in obesity. An ancient micronutrient for a modern disease
Obes Rev
 , 
2010
, vol. 
11
 (pg. 
322
-
328
)
10
Gomollón
F
Gisbert
JP
Anemia and inflammatory bowel diseases
World J Gastroenterol
 , 
2009
, vol. 
15
 (pg. 
4659
-
4665
)
11
Weiss
G
Iron metabolism in the anemia of chronic disease
Biochim Biophys Acta
 , 
2009
, vol. 
1790
 (pg. 
682
-
693
)
12
Somers
K
Acute reversible heart failure in severe iron-deficiency anemia associated with hookworm infestation in Uganda Africans
Circulation
 , 
1959
, vol. 
19
 (pg. 
672
-
675
)
13
Duke
M
Abelmann
WH
The hemodynamic response to chronic anemia
Circulation
 , 
1969
, vol. 
39
 (pg. 
503
-
515
)
14
Turner
LR
Premo
DA
Gibbs
BJ
Hearthway
ML
Motsko
M
Sappington
A
Walker
L
Mullendore
ME
Chew
HG
Jr
Adaptations to iron deficiency: cardiac functional responsiveness to norepinephrine, arterial remodeling, and the effect of beta-blockade on cardiac hypertrophy
BMC Physiol
 , 
2002
, vol. 
2
 pg. 
1
 
15
Tanne
Z
Coleman
R
Nahir
M
Shomrat
D
Finberg
JP
Youdim
MB
Ultrastructural and cytochemical changes in the heart of iron-deficient rats
Biochem Pharmacol
 , 
1994
, vol. 
47
 (pg. 
1759
-
1766
)
16
Naito
Y
Tsujino
T
Matsumoto
M
Sakoda
T
Ohyanagi
M
Masuyama
T
Adaptive response of the heart to long-term anemia induced by iron deficiency
Am J Physiol Heart Circ Physiol
 , 
2009
, vol. 
296
 (pg. 
H585
-
H593
)
17
Dong
F
Zhang
X
Culver
B
Chew
HG
Jr
Kelley
RO
Ren
J
Dietary iron deficiency induces ventricular dilation, mitochondrial ultrastructural aberrations and cytochrome c release: involvement of nitric oxide synthase and protein tyrosine nitration
Clin Sci
 , 
2005
, vol. 
109
 (pg. 
277
-
286
)
18
Silverberg
DS
Wexler
D
Iaina
A
Schwartz
D
The role of correction of anaemia in patients with congestive heart failure: a short review
Eur J Heart Fail
 , 
2008
, vol. 
10
 (pg. 
819
-
823
)
19
Anand
IS
Kuskowski
MA
Rector
TS
Florea
VG
Glazer
RD
Hester
A
Chiang
YT
Aknay
N
Maggioni
AP
Opasich
C
Latini
R
Cohn
JN
Anemia and change in hemoglobin over time related to mortality and morbidity in patients with chronic heart failure: results fromVal–Heft
Circulation
 , 
2005
, vol. 
112
 (pg. 
1121
-
1127
)
20
Komajda
M
Anker
SD
Charlesworth
A
Okonko
D
Metra
M
Di Lenarda
A
Remme
W
Moullet
C
Swedberg
K
Cleland
JG
Poole-Wilson
PA
The impact of new onset anemia on morbidity and mortality in chronic heart failure: results from COMET
Eur Heart J
 , 
2006
, vol. 
27
 (pg. 
1441
-
1446
)
21
Szachniewicz
J
Petruk-Kowalczyk
J
Majda
J
Kaczmarek
A
Reczuch
K
Kalra
PR
Piepoli
MF
Anker
SD
Banasiak
W
Ponikowski
P
Anaemia is an independent predictor of poor outcome in patients with chronic heart failure
Int J Cardiol
 , 
2003
, vol. 
90
 (pg. 
303
-
308
)
22
Kalra
PR
Bolger
AP
Francis
DP
Genth-Zotz
S
Sharma
R
Ponikowski
PP
Poole-Wilson
PA
Coats
AJ
Anker
SD
Effect of anemia on exercise tolerance in chronic heart failure in men
Am J Cardiol
 , 
2003
, vol. 
91
 (pg. 
888
-
891
)
23
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
, vol. 
107
 (pg. 
223
-
225
)
24
Nanas
JN
Matsouka
C
Karageorgopoulos
D
Leonti
A
Tsolakis
E
Drakos
SG
Tsagalou
EP
Maroulidis
GD
Alexopoulos
GP
Kanakakis
JE
Anastasiou-Nana
MI
Etiology of anemia in patients with advanced heart failure
J Am Coll Cardiol
 , 
2006
, vol. 
48
 (pg. 
2485
-
2489
)
25
Opasich
C
Cazzola
M
Scelsi
L
De Feo
S
Bosimini
E
Lagioia
R
Febo
O
Ferrari
R
Fucili
A
Moratti
R
Tramarin
R
Tavazzi
L
Blunted erythropoietin production and defective iron supply for erythropoiesis as major causes of anaemia in patients with chronic heart failure
Eur Heart J
 , 
2005
, vol. 
26
 (pg. 
2232
-
2237
)
26
Elliott
J
Mishler
D
Agarwal
R
Hyporesponsiveness to erythropoietin: causes and management
Adv Chronic Kidney Dis
 , 
2009
, vol. 
16
 (pg. 
94
-
100
)
27
van der Putten
K
Braam
B
Jie
KE
Gaillard
CA
Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure
Nat Clin Pract Nephrol
 , 
2008
, vol. 
4
 (pg. 
47
-
57
)
28
Nemeth
E
Iron regulation and erythropoiesis
Curr Opin Hematol
 , 
2008
, vol. 
15
 (pg. 
169
-
175
)
29
Ghali
JK
Anand
IS
Abraham
WT
Fonarow
GC
Greenberg
B
Krum
H
Massie
BM
Wasserman
SM
Trotman
ML
Sun
Y
Knusel
B
Armstrong
P
Study of Anemia in Heart Failure Trial (STAMINA-HeFT) Group
Randomized double blind trial of darbepoetin alpha treatment in patients with symptomatic heart failure and anemia
Circulation
 , 
2008
, vol. 
117
 (pg. 
526
-
535
)
30
Van Veldhuisen
DJ
Dickstein
K
Cohen-Solal
A
Lok
DJ
Wasserman
SM
Baker
N
Rosser
D
Cleland
JG
Ponikowski
P
Randomized double blind placebo-controlled trial to evaluate the effect of two dosing regimens of darbepoetin alpha in patients with heart failure and anaemia
Eur Heart J
 , 
2007
, vol. 
28
 (pg. 
2208
-
2216
)
31
Ponikowski
P
Anker
SD
Szachniewicz
J
Okonko
D
Ledwidge
M
Zymlinski
R
Ryan
E
Wasserman
SM
Baker
N
Rosser
D
Rosen
SD
Poole-Wilson
PA
Banasiak
W
Coats
AJ
McDonald
K
Effect of darbepoetin alpha on exercise tolerance in anemic patients with symptomatic chronic heart failure
J Am Coll Cardiol
 , 
2007
, vol. 
49
 (pg. 
753
-
762
)
32
Hower
V
Mendes
P
Torti
FM
Laubenbacher
R
Akman
S
Shulaev
V
Torti
SV
A general map of iron metabolism and tissue-specific subnetworks
Mol Biosyst
 , 
2009
, vol. 
5
 (pg. 
422
-
443
)
33
Fairbanks
V
Beutler
E
Beutler
E
Iron deficiency
Williams Hematology
 , 
2001
6th ed
New York
McGraw-Hill
 
p295–304 and p447–50
34
Dunn
LL
Rahmanto
YS
Richardson
DR
Iron uptake and metabolism in the new millennium
Trends Cell Biol
 , 
2007
, vol. 
17
 (pg. 
93
-
100
)
35
Cairo
G
Bernuzzi
F
Recalcati
S
A precious metal: iron, an essential nutrient for all cells
Genes Nutr
 , 
2006
, vol. 
1
 (pg. 
25
-
39
)
36
Carrondo
MA
Ferritins, iron uptake and storage from the bacterioferritin viewpoint
EMBO J
 , 
2003
, vol. 
22
 (pg. 
1959
-
1968
)
37
Beard
JL
Iron biology in immune function, muscle metabolism and neuronal functioning
J Nutr
 , 
2001
, vol. 
131
 
Suppl 2)
(pg. 
568S
-
579S
)
38
Rouault
TA
Tong
WH
Iron-sulphur cluster biogenesis and mitochondrial iron homeostasis
Nat Rev Mol Cell Biol
 , 
2005
, vol. 
6
 (pg. 
345
-
351
)
39
Huang
ML
Lane
DJ
Richardson
DR
Mitochondrial mayhem: the mitochondrion as a modulator of iron metabolism and its role in disease
Antioxid Redox Signal
 , 
2011
, vol. 
15
 (pg. 
3003
-
3019
)
40
Galy
B
Ferring-Appel
D
Sauer
SW
Kaden
S
Lyoumi
S
Puy
H
Kölker
S
Gröne
HJ
Hentze
MW
Iron regulatory proteins secure mitochondrial iron sufficiency and function
Cell Metab
 , 
2010
, vol. 
12
 (pg. 
194
-
201
)
41
Camaschella
C
Pagani
A
Iron and erythropoiesis: a dual relationship
Int J Hematol
 , 
2011
, vol. 
93
 (pg. 
21
-
26
)
42
Alcantara
O
Boldt
DH
Iron deprivation blocks multilineage haematopoietic differentiation by inhibiting induction of p21(WAF1/CIP1)
Br J Haematol
 , 
2007
, vol. 
137
 (pg. 
252
-
261
)
43
Ingwall
JS
Energy metabolism in heart failure and remodelling
Cardiovasc Res
 , 
2009
, vol. 
81
 (pg. 
412
-
419
)
44
Ventura-Clapier
R
Exercise training, energy metabolism, and heart failure
Appl Physiol Nutr Metab
 , 
2009
, vol. 
34
 (pg. 
336
-
339
)
45
Jankowska
EA
Biel
B
Majda
J
Szklarska
A
Lopuszanska
M
Medras
M
Anker
SD
Banasiak
W
Poole-Wilson
PA
Ponikowski
P
Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival
Circulation
 , 
2006
, vol. 
114
 (pg. 
1829
-
1837
)
46
Rosca
MG
Hoppel
CL
Mitochondria in heart failure
Cardiovasc Res
 , 
2010
, vol. 
88
 (pg. 
40
-
50
)
47
Turer
AT
Malloy
CR
Newgard
CB
Podgoreanu
MV
Energetics and metabolism in the failing heart: important but poorly understood
Curr Opin Clin Nutr Metab Care
 , 
2010
, vol. 
13
 (pg. 
458
-
465
)
48
Kell
DB
Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology and others as examples
Arch Toxicol
 , 
2010
, vol. 
84
 (pg. 
825
-
889
)
49
Xu
J
Marzetti
E
Seo
AY
Kim
JS
Prolla
TA
Leeuwenburgh
C
The emerging role of iron dyshomeostasis in the mitochondrial decay of aging
Mech Ageing Dev
 , 
2010
, vol. 
131
 (pg. 
487
-
493
)
50
Papanikolaou
G
Pantopoulos
K
Iron metabolism and toxicity
Toxicol Appl Pharmacol
 , 
2005
, vol. 
202
 (pg. 
199
-
211
)
51
Wang
Y
Wu
M
Al-Rousan
R
Liu
H
Fannin
J
Paturi
S
Arvapalli
RK
Katta
A
Kakarla
SK
Rice
KM
Triest
WE
Blough
ER
Iron-induced cardiac damage: role of apoptosis and deferasirox intervention
J Pharmacol Exp Ther
 , 
2011
, vol. 
336
 (pg. 
56
-
63
)
52
Beutler
E
Hoffbrand
AV
Cook
JD
Iron deficiency and overload
Hematology Am Soc Hematol Educ Program
 , 
2003
, vol. 
1
 (pg. 
40
-
61
)
53
Pietrangelo
A
Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment
Gastroenterology
 , 
2010
, vol. 
139
 (pg. 
393
-
408
)
54
Munoz
JP
Chiong
M
García
L
Troncoso
R
Toro
B
Pedrozo
Z
Diaz-Elizondo
J
Salas
D
Parra
V
Núñez
MT
Hidalgo
C
Lavandero
S
Iron induces protection and necrosis in cultured cardiomyocytes: role of reactive oxygen species and nitric oxide
Free Radic Biol Med
 , 
2010
, vol. 
48
 (pg. 
526
-
534
)
55
Munoz
M
García-Erce
JA
Remacha
AF
Disorders of iron metabolism. Part 1: molecular basis of iron homoeostasis
J Clin Pathol
 , 
2011
, vol. 
64
 (pg. 
281
-
286
)
56
Zhang
AS
Enns
CA
Molecular mechanisms of normal iron homeostasis
Hematology Am Soc Hematol Educ Program
 , 
2009
, vol. 
1
 (pg. 
207
-
214
)
57
Hentze
MW
Muckenthaler
MU
Galy
B
Camaschella
C
Two to tango: regulation of Mammalian iron metabolism
Cell
 , 
2010
, vol. 
142
 (pg. 
24
-
38
)
58
Anderson
GJ
Frazer
DM
McLaren
GD
Iron absorption and metabolism
Curr Opin Gastroenterol
 , 
2009
, vol. 
25
 (pg. 
129
-
135
)
59
Anderson
GJ
Vulpe
CD
Mammalian iron transport
Cell Mol Life Sci
 , 
2009
, vol. 
66
 (pg. 
3241
-
3261
)
60
Wang
J
Pantopoulos
K
Regulation of cellular iron metabolism
Biochem J
 , 
2011
, vol. 
434
 (pg. 
365
-
381
)
61
Koorts
AM
Viljoen
M
Ferritin and ferritin isoforms I: structure-function relationships, synthesis, degradation and secretion
Arch Physiol Biochem
 , 
2007
, vol. 
113
 (pg. 
30
-
54
)
62
Babitt
JL
Lin
HY
Molecular mechanisms of hepcidin regulation: implications for the anemia of CKD
Am J Kidney Dis
 , 
2010
, vol. 
55
 (pg. 
726
-
741
)
63
Viatte
L
Vaulont
S
Hepcidin, the iron watcher
Biochimie
 , 
2009
, vol. 
91
 (pg. 
1223
-
1228
)
64
Franchini
M
Montagnana
M
Lippi
G
Hepcidin and iron metabolism: from laboratory to clinical implications
Clin Chim Acta
 , 
2010
, vol. 
411
 (pg. 
1565
-
1569
)
65
Nemeth
E
Ganz
T
The role of hepcidin in iron metabolism
Acta Haematol
 , 
2009
, vol. 
122
 (pg. 
78
-
86
)
66
Handelman
GJ
Levin
NW
Iron and anemia in human biology: a review of mechanisms
Heart Fail Rev
 , 
2008
, vol. 
13
 (pg. 
393
-
404
)
67
Kemna
EH
Tjalsma
H
Willems
HL
Swinkels
DW
Hepcidin: from discovery to differential diagnosis
Haematologica
 , 
2008
, vol. 
93
 (pg. 
90
-
97
)
68
Piperno
A
Galimberti
S
Mariani
R
Pelucchi
S
Ravasi
G
Lombardi
C
Bilo
G
Revera
M
Giuliano
A
Faini
A
Mainini
V
Westerman
M
Ganz
T
Valsecchi
MG
Mancia
G
Parati
G
HIGHCARE investigators
Modulation of hepcidin production during hypoxia-induced erythropoiesis in humans in vivo: data from the HIGHCARE project
Blood
 , 
2011
, vol. 
117
 (pg. 
2953
-
2959
)
69
Wish
JB
Assessing iron status: beyond serum ferritin and transferrin saturation
Clin J Am Soc Nephrol
 , 
2006
, vol. 
1
 
Suppl 1
(pg. 
S4
-
S8
)
70
Goodnough
LT
Nemeth
E
Ganz
T
Detection, evaluation, and management of iron-restricted erythropoiesis
Blood
 , 
2010
, vol. 
116
 (pg. 
4754
-
4761
)
71
Macdougall
IC
Iron supplementation in the non-dialysis chronic kidney disease (ND-CKD) patient: oral or intravenous?
Curr Med Res Opin
 , 
2010
, vol. 
26
 (pg. 
473
-
482
)
72
Pasricha
SR
Flecknoe-Brown
SC
Allen
KJ
Gibson
PR
McMahon
LP
Olynyk
JK
Roger
SD
Savoia
HF
Tampi
R
Thomson
AR
Wood
EM
Robinson
KL
Diagnosis and management of iron deficiency anaemia: a clinical update
Med J Aust
 , 
2010
, vol. 
193
 (pg. 
525
-
532
)
73
Koulaouzidis
A
Said
E
Cottier
R
Saeed
AA
Soluble transferrin receptors and iron deficiency, a step beyond ferritin. A systematic review
J Gastrointestin Liver Dis
 , 
2009
, vol. 
18
 (pg. 
345
-
352
)
74
Moreno Chulilla
JA
Romero Colás
MS
Gutiérrez Martín
M
Classification of anemia for gastroenterologists
World J Gastroenterol
 , 
2009
, vol. 
15
 (pg. 
4627
-
4637
)
75
Goddard
AF
James
MW
McIntyre
AS
Scott
BB
on behalf of the British Society of Gastroenterology
Guidelines for the management of iron deficiency anaemia
Gut
 , 
2011
, vol. 
60
 (pg. 
1309
-
1316
)
76
Gale
E
Torrance
J
Bothwell
T
The quantitative estimation of total iron stores in human bone marrow
J Clin Invest
 , 
1963
, vol. 
42
 (pg. 
1076
-
1082
)
77
Phiri
KS
Calis
JC
Kachala
D
Borgstein
E
Waluza
J
Bates
I
Brabin
B
van Hensbroek
MB
Improved method for assessing iron stores in the bone marrow
J Clin Pathol
 , 
2009
, vol. 
62
 (pg. 
685
-
689
)
78
Briggs
C
Quality counts: new parameters in blood cell counting
Int J Lab Hematol
 , 
2009
, vol. 
31
 (pg. 
277
-
297
)
79
Ali
MA
Luxton
AW
Walker
WH
Serum ferritin concentration and bone marrow iron stores: a prospective study
Can Med Assoc J
 , 
1978
, vol. 
118
 (pg. 
945
-
946
)
80
Okonko
DO
Grzeslo
A
Witkowski
T
Mandal
AK
Slater
RM
Roughton
M
Foldes
G
Thum
T
Majda
J
Banasiak
W
Missouris
CG
Poole-Wilson
PA
Anker
SD
Ponikowski
P
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
, vol. 
51
 (pg. 
103
-
112
)
81
Anker
SD
Colet
JC
Filippatos
G
Willenheimer
R
Dickstein
K
Drexler
H
Lüscher
TF
Bart
B
Banasiak
W
Niegowska
J
Kirwan
BA
Mori
C
von Eisenhart Rothe
B
Pocock
SJ
Poole-Wilson
PA
Ponikowski
P
for the FAIR-HF Trial Investigators
Ferric carboxymaltose in patients with heart failure and iron deficiency
N Engl J Med
 , 
2009
, vol. 
361
  
2436–2448
82
Piva
E
Brugnara
C
Chiandetti
L
Plebani
M
Automated reticulocyte counting: state of the art and clinical applications in the evaluation of erythropoiesis
Clin Chem Lab Med
 , 
2010
, vol. 
48
 (pg. 
1369
-
1380
)
83
Buttarello
M
Plebani
M
Automated blood cell counts: state of the art
Am J Clin Pathol
 , 
2008
, vol. 
130
 (pg. 
104
-
116
)
84
Zhu
A
Kaneshiro
M
Kaunitz
JD
Evaluation and treatment of iron deficiency anemia: a gastroenterological perspective
Dig Dis Sci
 , 
2010
, vol. 
55
 (pg. 
548
-
559
)
85
Allen
LA
Felker
GM
Mehra
MR
Chiong
JR
Dunlap
SH
Ghali
JK
Lenihan
DJ
Oren
RM
Wagoner
LE
Schwartz
TA
Adams
KF
Jr
Validation and potential mechanisms of red cell distribution width as a prognostic marker in heart failure
J Card Fail
 , 
2010
, vol. 
16
 (pg. 
230
-
238
)
86
Felker
GM
Allen
LA
Pocock
SJ
Shaw
LK
McMurray
JJ
Pfeffer
MA
Swedberg
K
Wang
D
Yusuf
S
Michelson
EL
Granger
CB
CHARM Investigators
Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank
J Am Coll Cardiol
 , 
2007
, vol. 
50
 (pg. 
40
-
47
)
87
van Kimmenade
RR
Mohammed
AA
Uthamalingam
S
van der Meer
P
Felker
GM
Januzzi
JL
Jr
Red blood cell distribution width and 1-year mortality in acute heart failure
Eur J Heart Fail
 , 
2010
, vol. 
12
 (pg. 
129
-
136
)
88
Belonje
AM
Voors
AA
van der Meer
P
van Gilst
WH
Jaarsma
T
van Veldhuisen
DJ
Endogenous erythropoietin and outcome in heart failure
Circulation
 , 
2010
, vol. 
121
 (pg. 
245
-
251
)
89
van der Meer
P
Lok
DJ
Januzzi
JL
de la Porte
PW
Lipsic
E
van Wijngaarden
J
Voors
AA
van Gilst
WH
van Veldhuisen
DJ
Adequacy of endogenous erythropoietin levels and mortality in anaemic heart failure patients
Eur Heart J
 , 
2008
, vol. 
29
 (pg. 
1510
-
1515
)
90
Skikne
BS
Serum transferrin receptor
Am J Hematol
 , 
2008
, vol. 
83
 (pg. 
872
-
875
)
91
Chang
J
Bird
R
Clague
A
Carter
AC
Clinical utility of serum soluble transferrin receptor levels and comparison with bone marrow iron stores as an index for iron-deficient erythropoiesis in a heterogeneous group of patients
Pathology
 , 
2007
, vol. 
39
 (pg. 
349
-
353
)
92
Chua
E
Clague
JE
Sharma
AK
Horan
MA
Lombard
M
Serum transferrin receptor assay in iron deficiency anaemia and anaemia of chronic disease in the elderly
QJM
 , 
1999
, vol. 
92
 (pg. 
587
-
594
)
93
Rimon
E
Levy
S
Sapir
A
Gelzer
G
Peled
R
Ergas
D
Sthoeger
ZM
Diagnosis of iron deficiency anemia in the elderly by transferrin receptor-ferritin index
Arch Intern Med
 , 
2002
, vol. 
162
 (pg. 
445
-
449
)
94
Hughes
CM
Woodside
JV
McGartland
C
Roberts
MJ
Nicholls
DP
McKeown
PP
Nutritional intake and oxidative stress in chronic heart failure
Nutr Metab Cardiovasc Dis
 , 
2012
, vol. 
22
 (pg. 
376
-
382
)
95
Lourenço
BH
Vieira
LP
Macedo
A
Nakasato
M
Marucci Mde
F
Bocchi
EA
Nutritional status and adequacy of energy and nutrient intakes among heart failure patients
Arq Bras Cardiol
 , 
2009
, vol. 
93
 (pg. 
541
-
548
)
96
Naito
Y
Tsujino
T
Fujimori
Y
Sawada
H
Akahori
H
Hirotani
S
Ohyanagi
M
Masuyama
T
Impaired expression of duodenal iron transporters in Dahl salt-sensitive heart failure rats
J Hypertens
 , 
2011
, vol. 
29
 (pg. 
741
-
748
)
97
Srai
SK
Chung
B
Marks
J
Pourvali
K
Solanky
N
Rapisarda
C
Chaston
TB
Hanif
R
Unwin
RJ
Debnam
ES
Sharp
PA
Erythropoietin regulates intestinal iron absorption in a rat model of chronic renal failure
Kidney Int
 , 
2010
, vol. 
78
 (pg. 
660
-
667
)
98
Simpson
RJ
McKie
AT
Regulation of intestinal iron absorption: the mucosa takes control?
Cell Metab
 , 
2009
, vol. 
10
 (pg. 
84
-
87
)
99
Jankowska
EA
Ponikowski
P
Piepoli
MF
Banasiak
W
Anker
SD
Poole-Wilson
PA
Autonomic imbalance and immune activation in chronic heart failure - pathophysiological links
Cardiovasc Res
 , 
2006
, vol. 
70
 (pg. 
434
-
445
)
100
Satoh
M
Minami
Y
Takahashi
Y
Nakamura
M
Immune modulation: role of the inflammatory cytokine cascade in the failing human heart
Curr Heart Fail Rep
 , 
2008
, vol. 
5
 (pg. 
69
-
74
)
101
El-Menyar
AA
Cytokines and myocardial dysfunction: state of the art
J Card Fail
 , 
2008
, vol. 
14
 (pg. 
61
-
74
)
102
von Haehling
S
Anker
SD
Cachexia as a major underestimated and unmet medical need: facts and numbers
J Cachexia Sarcopenia Muscle
 , 
2010
, vol. 
1
 (pg. 
1
-
5
)
103
von Haehling
S
Morley
JE
Anker
SD
An overview of sarcopenia: facts and numbers on prevalence and clinical impact
J Cachexia Sarcopenia Muscle
 , 
2010
, vol. 
1
 (pg. 
129
-
133
)
104
von Haehling
S
Jankowska
EA
Anker
SD
Tumour necrosis factor-alpha and the failing heart: pathophysiology and therapeutic implications
Basic Res Cardiol
 , 
2004
, vol. 
99
 (pg. 
18
-
28
)
105
Simonis
G
Mueller
K
Schwarz
P
Wiedemann
S
Adler
G
Strasser
RH
Kulaksiz
H
The iron-regulatory peptide hepcidin is upregulated in the ischemic and in the remote myocardium after myocardial infarction
Peptides
 , 
2010
, vol. 
31
 (pg. 
1786
-
1790
)
106
Suzuki
H
Toba
K
Kato
K
Ozawa
T
Tomosugi
N
Higuchi
M
Kusuyama
T
Iso
Y
Kobayashi
N
Yokoyama
S
Fukuda
N
Saitoh
H
Akazawa
K
Aizawa
Y
Serum hepcidin-20 is elevated during the acute phase of myocardial infarction
Tohoku J Exp Med
 , 
2009
, vol. 
218
 (pg. 
93
-
98
)
107
Matsumoto
M
Tsujino
T
Lee-Kawabata
M
Naito
Y
Akahori
H
Sakoda
T
Ohyanagi
M
Tomosugi
N
Masuyama
T
Iron regulatory hormone hepcidin decreases in chronic heart failure patients with anemia
Circ J
 , 
2010
, vol. 
74
 (pg. 
301
-
306
)
108
van der Putten
K
Jie
KE
van den Broek
D
Kraaijenhagen
RJ
Laarakkers
C
Swinkels
DW
Braam
B
Gaillard
CA
Hepcidin-25 is a marker of the response rather than resistance to exogenous erythropoietin in chronic kidney disease/chronic heart failure patients
Eur J Heart Fail
 , 
2010
, vol. 
12
 (pg. 
943
-
950
)
109
Divakaran
V
Mehta
S
Yao
D
Hassan
S
Simpson
S
Wiegerinck
E
Swinkels
DW
Mann
DL
Afshar-Kharghan
V
Hepcidin in anemia of chronic heart failure
Am J Hematol
 , 
2011
, vol. 
86
 (pg. 
107
-
109
)
110
Adlbrecht
C
Kommata
S
Hülsmann
M
Szekeres
T
Bieglmayer
C
Strunk
G
Karanikas
G
Berger
R
Mörtl
D
Kletter
K
Maurer
G
Lang
IM
Pacher
R
Chronic heart failure leads to an expanded plasma volume and pseudoanaemia, but does not lead to a reduction in the body's red cell volume
Eur Heart J
 , 
2008
, vol. 
29
 (pg. 
2343
-
2350
)
111
Witte
KK
Desilva
R
Chattopadhyay
S
Ghosh
J
Cleland
JG
Clark
AL
Are hematinic deficiencies the cause of anemia in chronic heart failure?
Am Heart J
 , 
2004
, vol. 
147
 (pg. 
924
-
930
)
112
Jankowska
EA
Rozentryt
P
Witkowska
A
Nowak
J
Hartmann
O
Ponikowska
B
Borodulin-Nadzieja
L
Banasiak
W
Polonski
L
Filippatos
G
McMurray
JJ
Anker
SD
Ponikowski
P
Iron deficiency: an ominous sign in patients with systolic chronic heart failure
Eur Heart J
 , 
2010
, vol. 
31
 (pg. 
1872
-
1880
)
113
Jankowska
EA
Rozentryt
P
Witkowska
A
Nowak
J
Hartmann
O
Ponikowska
B
Borodulin-Nadzieja
L
von Haehling
S
Doehner
W
Banasiak
W
Polonski
L
Filippatos
G
Anker
SD
Ponikowski
P
Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure
J Card Fail
 , 
2011
, vol. 
17
 (pg. 
899
-
906
)
114
Toblli
JE
Lombrana
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
, vol. 
50
 (pg. 
1657
-
1665
)
115
Bolger
AP
Bartlett
FR
Penston
HS
O'Leary
J
Pollock
N
Kaprielian
R
Chapman
CM
Intravenous iron alone for the treatment of anemia in patients with chronic heart failure
J Am Coll Cardiol
 , 
2006
, vol. 
48
 (pg. 
1225
-
1227
)
116
Varma
A
Appleton
DL
Nusca
A
Lipinski
MJ
Goudreau
E
Cowley
MJ
Wittkamp
M
Vetrovec
GW
Abbate
A
Iron deficiency anemia and cardiac mortality in patients with left ventricular systolic dysfunction undergoing coronary stenting
Minerva Cardioangiol
 , 
2010
, vol. 
58
 (pg. 
1
-
10
)
117
Middlekauff
HR
Making the case for skeletal myopathy as the major limitation of exercise capacity in heart failure
Circ Heart Fail
 , 
2010
, vol. 
3
 (pg. 
537
-
546
)
118
Clark
AL
Poole-Wilson
PA
Coats
AJ
Exercise limitation in chronic heart failure: central role of the periphery
J Am Coll Cardiol
 , 
1996
, vol. 
28
 (pg. 
1092
-
1102
)
119
Toblli
JE
Cao
G
Rivas
C
Kulaksiz
H
Heart and iron deficiency anaemia in rats with renal insufficiency: the role of hepcidin
Nephrology
 , 
2008
, vol. 
13
 (pg. 
636
-
645
)
120
Merle
U
Fein
E
Gehrke
SG
Stremmel
W
Kulaksiz
H
The iron regulatory peptide hepcidin is expressed in the heart and regulated by hypoxia and inflammation
Endocrinology
 , 
2007
, vol. 
148
 (pg. 
2663
-
2668
)
121
Ge
XH
Wang
Q
Qian
ZM
Zhu
L
Du
F
Yung
WH
Yang
L
Ke
Y
The iron regulatory hormone hepcidin reduces ferroportin 1 content and iron release in H9C2 cardiomyocytes
J Nutr Biochem
 , 
2009
, vol. 
20
 (pg. 
860
-
865
)
122
Qian
ZM
Chang
YZ
Leung
G
Du
JR
Zhu
L
Wang
Q
Niu
L
Xu
YJ
Yang
L
Ho
KP
Ke
Y
Expression of ferroportin1, hephaestin and ceruloplasmin in rat heart
Biochim Biophys Acta
 , 
2007
, vol. 
1772
 (pg. 
527
-
532
)
123
Isoda
M
Hanawa
H
Watanabe
R
Yoshida
T
Toba
K
Yoshida
K
Kojima
M
Otaki
K
Hao
K
Ding
L
Tanaka
K
Takayama
T
Kato
K
Okura
Y
Kodama
M
Ota
Y
Hayashi
J
Aizawa
Y
Expression of the peptide hormone hepcidin increases in cardiomyocytes under myocarditis and myocardial infarction
J Nutr Biochem
 , 
2010
, vol. 
21
 (pg. 
749
-
756
)
124
Rossi
MA
Carillo
SV
Electron microscopic study on the cardiac hypertrophy induced by iron deficiency anaemia in the rat
Br J Exp Pathol
 , 
1983
, vol. 
64
 (pg. 
373
-
387
)
125
Olivetti
G
Lagrasta
C
Quaini
F
Ricci
R
Moccia
G
Capasso
JM
Anversa
P
Capillary growth in anemia-induced ventricular wall remodeling in the rat heart
Circ Res
 , 
1989
, vol. 
65
 (pg. 
1182
-
1192
)
126
Olivetti
G
Quaini
F
Lagrasta
C
Ricci
R
Tiberti
G
Capasso
JM
Anversa
P
Myocyte cellular hypertrophy and hyperplasia contribute to ventricular wall remodeling in anemia-induced cardiac hypertrophy in rats
Am J Pathol
 , 
1992
, vol. 
141
 (pg. 
227
-
239
)
127
Medeiros
DM
Beard
JL
Dietary iron deficiency results in cardiac eccentric hypertrophy in rats
Proc Soc Exp Biol Med
 , 
1998
, vol. 
218
 (pg. 
370
-
375
)
128
Chvapil
M
Hurych
J
Ehrlichová
E
The effect of iron deficiency on the synthesis of collagenous and non-collagenous proteins in wound granulation tissue and in the heart of rats
Exp Med Surg
 , 
1968
, vol. 
26
 (pg. 
52
-
60
)
129
Maeder
MT
Khammy
O
dos Remedios
C
Kaye
DM
Myocardial and systemic iron depletion in heart failure implications for anemia accompanying heart failure
J Am Coll Cardiol
 , 
2011
, vol. 
58
 (pg. 
474
-
480
)
130
Boulton
FE
The myoglobin content of human skeletal muscle
Br J Haematol
 , 
1973
, vol. 
25
 pg. 
281
 
131
Polonifi
A
Politou
M
Kalotychou
V
Xiromeritis
K
Tsironi
M
Berdoukas
V
Vaiopoulos
G
Aessopos
A
Iron metabolism gene expression in human skeletal muscle
Blood Cells Mol Dis
 , 
2010
, vol. 
45
 (pg. 
233
-
237
)
132
Robach
P
Cairo
G
Gelfi
C
Bernuzzi
F
Pilegaard
H
Viganò
A
Santambrogio
P
Cerretelli
P
Calbet
JA
Moutereau
S
Lundby
C
Strong iron demand during hypoxia-induced erythropoiesis is associated with down-regulation of iron-related proteins and myoglobin in human skeletal muscle
Blood
 , 
2007
, vol. 
109
 (pg. 
4724
-
4731
)
133
Dallman
PR
Biochemical basis for the manifestations of iron deficiency
Annu Rev Nutr
 , 
1986
, vol. 
6
 (pg. 
13
-
40
)
134
Finch
CA
Huebers
H
Perspectives in iron metabolism
N Engl J Med
 , 
1982
, vol. 
306
 (pg. 
1520
-
1528
)
135
Brownlie
T
IV
Utermohlen
V
Hinton
PS
Haas
JD
Tissue iron deficiency without anemia impairs adaptation in endurance capacity after aerobic training in previously untrained women
Am J Clin Nutr
 , 
2004
, vol. 
79
 (pg. 
437
-
443
)
136
Brownlie
T
IV
Utermohlen
V
Hinton
PS
Giordano
C
Haas
JD
Marginal iron deficiency without anemia impairs aerobic adaptation among previously untrained women
Am J Clin Nutr
 , 
2002
, vol. 
75
 (pg. 
734
-
742
)
137
Hinton
PS
Giordano
C
Brownlie
T
Haas
JD
Iron supplementation improves endurance after training in iron-depleted, nonanemic women
J Appl Physiol
 , 
2000
, vol. 
88
 (pg. 
1103
-
1111
)
138
Brutsaert
TD
Hernandez-Cordero
S
Rivera
J
Viola
T
Hughes
G
Haas
JD
Iron supplementation improves progressive fatigue resistance during dynamic knee extensor exercise in iron-depleted, nonanemic women
Am J Clin Nutr
 , 
2003
, vol. 
77
 (pg. 
441
-
448
)
139
McLane
JA
Fell
RD
McKay
RH
Winder
WW
Brown
EB
Holloszy
JO
Physiological and biochemical effects of iron deficiency on rat skeletal muscle
Am J Physiol
 , 
1981
, vol. 
241
 (pg. 
C47
-
C54
)
140
Willis
WT
Brooks
GA
Henderson
SA
Dallman
PR
Effects of iron deficiency and training on mitochondrial enzymes in skeletal muscle
J Appl Physiol
 , 
1987
, vol. 
62
 (pg. 
2442
-
2446
)
141
Davies
KJ
Maguire
JJ
Brooks
GA
Dallman
PR
Packer
L
Muscle mitochondrial bioenergetics, oxygen supply, and work capacity during dietary iron deficiency and repletion
Am J Physiol
 , 
1982
, vol. 
242
 (pg. 
E418
-
E427
)
142
Finch
CA
Miller
LR
Inamdar
AR
Person
R
Seiler
K
Mackler
B
Iron deficiency in the rat. Physiological and biochemical studies of muscle dysfunction
J Clin Invest
 , 
1976
, vol. 
58
 (pg. 
447
-
453
)
143
Hinton
PS
Sinclair
LM
Iron supplementation maintains ventilatory threshold and improves energetic efficiency in iron-deficient nonanemic athletes
Eur J Clin Nutr
 , 
2007
, vol. 
61
 (pg. 
30
-
39
)
144
Comín-Colet
J
Ruiz
S
Cladellas
M
Rizzo
M
Torres
A
Bruguera
J
A pilot evaluation of the long-term effect of combined therapy with intravenous iron sucrose and erythropoietin in elderly patients with advanced chronic heart failure and cardio-renal anemia syndrome: influence on neurohormonal activation and clinical outcomes
J Card Fail
 , 
2009
, vol. 
15
 (pg. 
727
-
735
)
145
Drakos
SG
Anastasiou-Nana
MI
Malliaras
KG
Nanas
JN
Anemia in chronic heart failure
Congest Heart Fail
 , 
2009
, vol. 
15
 (pg. 
87
-
92
)
146
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
, vol. 
21
 (pg. 
236
-
242
)
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