|Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives.|
|Jump to Full Text|
|PMID: 23100285 Owner: NLM Status: Publisher|
|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.|
|Ewa A Jankowska; Stephan von Haehling; Stefan D Anker; Iain C Macdougall; Piotr Ponikowski|
Related Documents :
|10159775 - Catheter ablation in competitive athletes: indication.
18416595 - Cardiac troponin t release after prolonged strenuous exercise.
7591395 - Hypogonadism as a cause of recurrent muscle injury in a high level soccer player. a cas...
9395795 - Contribution of nitric oxide to exercise-induced changes in healthy volunteers: effects...
9494025 - Effects of moderate exercise training on thallium uptake and contractile response to lo...
20935605 - The effects of early aerobic exercise after single-level lumbar microdiscectomy: a pros...
|Type: JOURNAL ARTICLE Date: 2012-10-25|
|Title: European heart journal Volume: - ISSN: 1522-9645 ISO Abbreviation: Eur. Heart J. Publication Date: 2012 Oct|
|Created Date: 2012-10-26 Completed Date: - Revised Date: -|
Medline Journal Info:
|Nlm Unique ID: 8006263 Medline TA: Eur Heart J Country: -|
|Languages: ENG Pagination: - Citation Subset: -|
|Department of Heart Diseases, Wroclaw Medical University, ul. Weigla 5, 50-981 Wroclaw, Poland.|
|APA/MLA Format Download EndNote Download BibTex|
Journal ID (nlm-ta): Eur Heart J
Journal ID (iso-abbrev): Eur. Heart J
Journal ID (publisher-id): eurheartj
Journal ID (hwp): ehj
Publisher: Oxford University Press
© The Author 2012. Published by Oxford University Press on behalf of European Society of Cardiology.
Received Day: 30 Month: 5 Year: 2011
Revision Received Day: 21 Month: 10 Year: 2011
Accepted Day: 1 Month: 7 Year: 2012
Print publication date: Day: 14 Month: 3 Year: 2013
Electronic publication date: Day: 25 Month: 10 Year: 2012
pmc-release publication date: Day: 25 Month: 10 Year: 2012
Volume: 34 Issue: 11
First Page: 816 Last Page: 829
PubMed Id: 23100285
Publisher Id: ehs224
|Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives|
|Ewa A. Jankowska12*|
|Stephan von Haehling3|
|Stefan D. Anker34|
|Iain C. Macdougall5|
1Department of Heart Diseases, Wroclaw Medical University, ul. Weigla 5, 50-981 Wroclaw, Poland
2Centre for Heart Diseases, Military Hospital, Wroclaw, Poland
3Division of Applied Cachexia Research, Department of Cardiology, Charité Medical School, Berlin, Germany
4Centre for Clinical and Basic Research, IRCCS San Raffaele, Rome, Italy
5Department of Renal Medicine, King's College Hospital, London, UK
|*Corresponding author. Tel:+48 608553169, Fax: +48 717660250, Email: email@example.com
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).
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
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
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
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.
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
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).
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
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
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.
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
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).
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
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.
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
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.
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).
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.
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.
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.
|1.||Kell DB. Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseasesBMC Med GenomicsYear: 200982 doi:10.1038/ni1037. 19133145|
|2.||Zimmermann MB,Hurrell RF. Nutritional iron deficiencyLancetYear: 2007370511520 doi:10.1111/j.1600-0897.2007.00512.x. 17693180|
|3.||Andrews NC. Disorders of iron metabolismN Engl J MedYear: 19993411986199510607817|
|4.||Milman N. Anemia—still a major health problem in many parts of the world!Ann HematolYear: 20119036937721221586|
|5.||Black RE,Allen LH,Bhutta ZA,Caulfield LE,de Onis M,Ezzati M,Mathers C,Rivera J. Maternal and Child Undernutrition Study GroupMaternal and child undernutrition: global and regional exposures and health consequencesLancetYear: 2008371243260 doi:10.1016/j.molmed.2007.05.005. 18207566|
|6.||Haas JD,Brownlie T IV. Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationshipJ NutrYear: 2001131676S690S doi:10.1158/0008-5472.CAN-10-4157. 11160598|
|7.||Baker JF,Ghio AJ. Iron homoeostasis in rheumatic diseaseRheumatologyYear: 20094813391344 doi:10.1038/nm1680. 19628641|
|8.||Balla J,Jeney V,Varga Z,Komódi E,Nagy E,Balla G. Iron homeostasis in chronic inflammationActa Physiol HungYear: 2007949510617444278|
|9.||Zafon C,Lecube A,Simó R. Iron in obesity. An ancient micronutrient for a modern diseaseObes RevYear: 201011322328 doi:10.1016/j.placenta.2004.03.006. 19619262|
|10.||Gomollón F,Gisbert JP. Anemia and inflammatory bowel diseasesWorld J GastroenterolYear: 20091546594665 doi:10.4049/jimmunol.1103433. 19787829|
|11.||Weiss G. Iron metabolism in the anemia of chronic diseaseBiochim Biophys ActaYear: 20091790682693 doi:10.1182/blood-2011-12-396457. 18786614|
|12.||Somers K. Acute reversible heart failure in severe iron-deficiency anemia associated with hookworm infestation in Uganda AfricansCirculationYear: 195919672675 doi:10.1007/s00281-007-0069-0. 13652359|
|13.||Duke M,Abelmann WH. The hemodynamic response to chronic anemiaCirculationYear: 196939503515 doi:10.1159/000129639. 5778251|
|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 hypertrophyBMC PhysiolYear: 200221 doi:10.4049/jimmunol.0902245. 11818034|
|15.||Tanne Z,Coleman R,Nahir M,Shomrat D,Finberg JP,Youdim MB. Ultrastructural and cytochemical changes in the heart of iron-deficient ratsBiochem PharmacolYear: 19944717591766 doi:10.1016/j.jri.2010.12.007. 8204092|
|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 deficiencyAm J Physiol Heart Circ PhysiolYear: 2009296H585H593 doi:10.1093/molehr/gar053. 19136608|
|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 nitrationClin SciYear: 2005109277286 doi:10.1093/humrep/den344. 15877545|
|18.||Silverberg DS,Wexler D,Iaina A,Schwartz D. The role of correction of anaemia in patients with congestive heart failure: a short reviewEur J Heart FailYear: 200810819823 doi:10.1111/j.1476-5381.2008.00055.x. 18703380|
|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–HeftCirculationYear: 200511211211127 doi:10.1182/blood-2006-04-016451. 16103233|
|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 COMETEur Heart JYear: 20062714411446 doi:10.1046/j.1365-2249.2001.01512.x.|
|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 failureInt J CardiolYear: 200390303308 doi:10.1084/jem.20050019. 12957766|
|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 menAm J CardiolYear: 20039188889112667582|
|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 failureCirculationYear: 2003107223225 doi:10.1210/en.2012-1035. 12538418|
|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 failureJ Am Coll CardiolYear: 20064824852489 doi:10.1111/j.1600-065X.2008.00697.x. 17174186|
|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 failureEur Heart JYear: 20052622322237 doi:10.1046/j.1432-1327.1998.2520400.x. 15987710|
|26.||Elliott J,Mishler D,Agarwal R. Hyporesponsiveness to erythropoietin: causes and managementAdv Chronic Kidney DisYear: 20091694100 doi:10.1038/ni.1772. 19233068|
|27.||van der Putten K,Braam B,Jie KE,Gaillard CA. Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failureNat Clin Pract NephrolYear: 200844757 doi:10.1093/molehr/gal032. 18094727|
|28.||Nemeth E. Iron regulation and erythropoiesisCurr Opin HematolYear: 20081516917518391780|
|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) GroupRandomized double blind trial of darbepoetin alpha treatment in patients with symptomatic heart failure and anemiaCirculationYear: 2008117526535 doi:10.1073/pnas.0706017104. 18195176|
|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 anaemiaEur Heart JYear: 20072822082216 doi:10.1073/pnas.0604268104. 17681958|
|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 failureJ Am Coll CardiolYear: 20074975376217306703|
|32.||Hower V,Mendes P,Torti FM,Laubenbacher R,Akman S,Shulaev V,Torti SV. A general map of iron metabolism and tissue-specific subnetworksMol BiosystYear: 20095422443 doi:10.1371/journal.pone.0028514. 19381358|
|33.||Fairbanks V,Beutler E. Beutler EIron deficiencyWilliams HematologyYear: 20016th edNew YorkMcGraw-Hill p295–304 and p447–50doi:10.1084/jem.20030305.|
|34.||Dunn LL,Rahmanto YS,Richardson DR. Iron uptake and metabolism in the new millenniumTrends Cell BiolYear: 2007179310017194590|
|35.||Cairo G,Bernuzzi F,Recalcati S. A precious metal: iron, an essential nutrient for all cellsGenes NutrYear: 20061253918850218|
|36.||Carrondo MA. Ferritins, iron uptake and storage from the bacterioferritin viewpointEMBO JYear: 20032219591968 doi:10.4049/jimmunol.1002940. 12727864|
|37.||Beard JL. Iron biology in immune function, muscle metabolism and neuronal functioningJ NutrYear: 2001131Suppl 2)568S579S doi:10.1111/j.1447-0756.2009.01079.x. 11160590|
|38.||Rouault TA,Tong WH. Iron-sulphur cluster biogenesis and mitochondrial iron homeostasisNat Rev Mol Cell BiolYear: 20056345351 doi:10.1111/j.1600-0897.2010.00821.x. 15803140|
|39.||Huang ML,Lane DJ,Richardson DR. Mitochondrial mayhem: the mitochondrion as a modulator of iron metabolism and its role in diseaseAntioxid Redox SignalYear: 20111530033019 doi:10.1016/j.fertnstert.2003.06.007. 21545274|
|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 functionCell MetabYear: 201012194201 doi:10.1111/j.1749-6632.2012.06479.x. 20674864|
|41.||Camaschella C,Pagani A. Iron and erythropoiesis: a dual relationshipInt J HematolYear: 2011932126 doi:10.1095/biolreprod.105.049379. 21170616|
|42.||Alcantara O,Boldt DH. Iron deprivation blocks multilineage haematopoietic differentiation by inhibiting induction of p21(WAF1/CIP1)Br J HaematolYear: 2007137252261 doi:10.1016/S0143-4004(97)80044-6. 17408467|
|43.||Ingwall JS. Energy metabolism in heart failure and remodellingCardiovasc ResYear: 200981412419 doi:10.1016/j.clim.2010.12.018. 18987051|
|44.||Ventura-Clapier R. Exercise training, energy metabolism, and heart failureAppl Physiol Nutr MetabYear: 200934336339 doi:10.3109/03009740903013213. 19448695|
|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 survivalCirculationYear: 200611418291837 doi:10.1196/annals.1434.006. 17030678|
|46.||Rosca MG,Hoppel CL. Mitochondria in heart failureCardiovasc ResYear: 2010884050 doi:10.1111/j.1600-0897.2010.00836.x. 20668004|
|47.||Turer AT,Malloy CR,Newgard CB,Podgoreanu MV. Energetics and metabolism in the failing heart: important but poorly understoodCurr Opin Clin Nutr Metab CareYear: 201013458465 doi:10.1002/eji.200838295. 20453645|
|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 examplesArch ToxicolYear: 201084825889 doi:10.1096/fj.07-9268com. 20967426|
|49.||Xu J,Marzetti E,Seo AY,Kim JS,Prolla TA,Leeuwenburgh C. The emerging role of iron dyshomeostasis in the mitochondrial decay of agingMech Ageing DevYear: 2010131487493 doi:10.1046/j.1365-2249.2001.01461.x. 20434480|
|50.||Papanikolaou G,Pantopoulos K. Iron metabolism and toxicityToxicol Appl PharmacolYear: 200520219921115629195|
|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 interventionJ Pharmacol Exp TherYear: 20113365663 doi:10.1038/378736a0. 20947636|
|52.||Beutler E,Hoffbrand AV,Cook JD. Iron deficiency and overloadHematology Am Soc Hematol Educ ProgramYear: 200314061 doi:10.4049/jimmunol.0800839. 14633776|
|53.||Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatmentGastroenterologyYear: 2010139393408 doi:10.1095/biolreprod55.3.548. 20542038|
|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 oxideFree Radic Biol MedYear: 20104852653419969068|
|55.||Munoz M,García-Erce JA,Remacha AF. Disorders of iron metabolism. Part 1: molecular basis of iron homoeostasisJ Clin PatholYear: 20116428128621177266|
|56.||Zhang AS,Enns CA. Molecular mechanisms of normal iron homeostasisHematology Am Soc Hematol Educ ProgramYear: 20091207214 doi:10.1016/j.immuni.2012.03.004. 20008200|
|57.||Hentze MW,Muckenthaler MU,Galy B,Camaschella C. Two to tango: regulation of Mammalian iron metabolismCellYear: 20101422438 doi:10.1084/jem.190.3.385. 20603012|
|58.||Anderson GJ,Frazer DM,McLaren GD. Iron absorption and metabolismCurr Opin GastroenterolYear: 200925129135 doi:10.1038/sj.cdd.4401009. 19528880|
|59.||Anderson GJ,Vulpe CD. Mammalian iron transportCell Mol Life SciYear: 2009663241326119484405|
|60.||Wang J,Pantopoulos K. Regulation of cellular iron metabolismBiochem JYear: 2011434365381 doi:10.1111/j.1749-6632.2012.06492.x. 21348856|
|61.||Koorts AM,Viljoen M. Ferritin and ferritin isoforms I: structure-function relationships, synthesis, degradation and secretionArch Physiol BiochemYear: 20071133054 doi:10.4049/jimmunol.1103063. 17522983|
|62.||Babitt JL,Lin HY. Molecular mechanisms of hepcidin regulation: implications for the anemia of CKDAm J Kidney DisYear: 201055726741 doi:10.1167/iovs.05-1234. 20189278|
|63.||Viatte L,Vaulont S. Hepcidin, the iron watcherBiochimieYear: 20099112231228 doi:10.1016/S1535-6108(04)00024-8. 19555735|
|64.||Franchini M,Montagnana M,Lippi G. Hepcidin and iron metabolism: from laboratory to clinical implicationsClin Chim ActaYear: 201041115651569 doi:10.1111/j.1600-0897.2010.00852.x. 20620132|
|65.||Nemeth E,Ganz T. The role of hepcidin in iron metabolismActa HaematolYear: 2009122788619907144|
|66.||Handelman GJ,Levin NW. Iron and anemia in human biology: a review of mechanismsHeart Fail RevYear: 20081339340418363095|
|67.||Kemna EH,Tjalsma H,Willems HL,Swinkels DW. Hepcidin: from discovery to differential diagnosisHaematologicaYear: 2008939097 doi:10.1093/molehr/gaq079. 18166790|
|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 investigatorsModulation of hepcidin production during hypoxia-induced erythropoiesis in humans in vivo: data from the HIGHCARE projectBloodYear: 201111729532959 doi:10.1111/j.1600-0897.2007.00510.x. 21149632|
|69.||Wish JB. Assessing iron status: beyond serum ferritin and transferrin saturationClin J Am Soc NephrolYear: 20061Suppl 1S4S8 doi:10.1073/pnas.0807606105. 17699374|
|70.||Goodnough LT,Nemeth E,Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesisBloodYear: 201011647544761 doi:10.1016/j.tem.2011.09.003. 20826717|
|71.||Macdougall IC. Iron supplementation in the non-dialysis chronic kidney disease (ND-CKD) patient: oral or intravenous?Curr Med Res OpinYear: 201026473482 doi:10.1080/14767050802041961. 20014980|
|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 updateMed J AustYear: 2010193525532 doi:10.1073/pnas.0603883103. 21034387|
|73.||Koulaouzidis A,Said E,Cottier R,Saeed AA. Soluble transferrin receptors and iron deficiency, a step beyond ferritin. A systematic reviewJ Gastrointestin Liver DisYear: 200918345352 doi:10.1038/ni1482. 19795030|
|74.||Moreno Chulilla JA,Romero Colás MS,Gutiérrez Martín M. Classification of anemia for gastroenterologistsWorld J GastroenterolYear: 2009154627463719787825|
|75.||Goddard AF,James MW,McIntyre AS,Scott BB. on behalf of the British Society of GastroenterologyGuidelines for the management of iron deficiency anaemiaGutYear: 20116013091316 doi:10.1016/j.jri.2009.12.006. 21561874|
|76.||Gale E,Torrance J,Bothwell T. The quantitative estimation of total iron stores in human bone marrowJ Clin InvestYear: 19634210761082 doi:10.1038/ni1317. 13946227|
|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 marrowJ Clin PatholYear: 200962685689 doi:10.1016/j.molimm.2006.02.011. 19638538|
|78.||Briggs C. Quality counts: new parameters in blood cell countingInt J Lab HematolYear: 200931277297 doi:10.1210/jcem-69-6-1195. 19452619|
|79.||Ali MA,Luxton AW,Walker WH. Serum ferritin concentration and bone marrow iron stores: a prospective studyCan Med Assoc JYear: 1978118945946 doi:10.1007/978-1-4614-0106-3_2. 647567|
|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 trialJ Am Coll CardiolYear: 200851103112 doi:10.1093/molehr/gah144. 18191732|
|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 InvestigatorsFerric carboxymaltose in patients with heart failure and iron deficiencyN Engl J MedYear: 2009361 2436–2448doi:10.1016/S0002-9440(10)62302-4.|
|82.||Piva E,Brugnara C,Chiandetti L,Plebani M. Automated reticulocyte counting: state of the art and clinical applications in the evaluation of erythropoiesisClin Chem Lab MedYear: 2010481369138020666695|
|83.||Buttarello M,Plebani M. Automated blood cell counts: state of the artAm J Clin PatholYear: 200813010411618550479|
|84.||Zhu A,Kaneshiro M,Kaunitz JD. Evaluation and treatment of iron deficiency anemia: a gastroenterological perspectiveDig Dis SciYear: 20105554855920108038|
|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 failureJ Card FailYear: 20101623023820206898|
|86.||Felker GM,Allen LA,Pocock SJ,Shaw LK,McMurray JJ,Pfeffer MA,Swedberg K,Wang D,Yusuf S,Michelson EL,Granger CB. CHARM InvestigatorsRed cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke DatabankJ Am Coll CardiolYear: 200750404717601544|
|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 failureEur J Heart FailYear: 20101212913620026456|
|88.||Belonje AM,Voors AA,van der Meer P,van Gilst WH,Jaarsma T,van Veldhuisen DJ. Endogenous erythropoietin and outcome in heart failureCirculationYear: 201012124525120048213|
|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 patientsEur Heart JYear: 2008291510151518495690|
|90.||Skikne BS. Serum transferrin receptorAm J HematolYear: 20088387287518821709|
|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 patientsPathologyYear: 20073934935317558864|
|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 elderlyQJMYear: 19999258759410627880|
|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 indexArch Intern MedYear: 200216244544911863478|
|94.||Hughes CM,Woodside JV,McGartland C,Roberts MJ,Nicholls DP,McKeown PP. Nutritional intake and oxidative stress in chronic heart failureNutr Metab Cardiovasc DisYear: 20122237638221186107|
|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 patientsArq Bras CardiolYear: 20099354154820084317|
|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 ratsJ HypertensYear: 20112974174821191310|
|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 failureKidney IntYear: 20107866066720631677|
|98.||Simpson RJ,McKie AT. Regulation of intestinal iron absorption: the mucosa takes control?Cell MetabYear: 200910848719656486|
|99.||Jankowska EA,Ponikowski P,Piepoli MF,Banasiak W,Anker SD,Poole-Wilson PA. Autonomic imbalance and immune activation in chronic heart failure - pathophysiological linksCardiovasc ResYear: 20067043444516480965|
|100.||Satoh M,Minami Y,Takahashi Y,Nakamura M. Immune modulation: role of the inflammatory cytokine cascade in the failing human heartCurr Heart Fail RepYear: 20085697418765076|
|101.||El-Menyar AA. Cytokines and myocardial dysfunction: state of the artJ Card FailYear: 200814617418226775|
|102.||von Haehling S,Anker SD. Cachexia as a major underestimated and unmet medical need: facts and numbersJ Cachexia Sarcopenia MuscleYear: 201011521475699|
|103.||von Haehling S,Morley JE,Anker SD. An overview of sarcopenia: facts and numbers on prevalence and clinical impactJ Cachexia Sarcopenia MuscleYear: 2010112913321475695|
|104.||von Haehling S,Jankowska EA,Anker SD. Tumour necrosis factor-alpha and the failing heart: pathophysiology and therapeutic implicationsBasic Res CardiolYear: 200499182814685702|
|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 infarctionPeptidesYear: 2010311786179020553779|
|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 infarctionTohoku J Exp MedYear: 2009218939819478464|
|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 anemiaCirc JYear: 20107430130620019408|
|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 patientsEur J Heart FailYear: 20101294395020601671|
|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 failureAm J HematolYear: 20118610710921080339|
|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 volumeEur Heart JYear: 2008292343235018701467|
|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 JYear: 200414792493015131553|
|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 failureEur Heart JYear: 2010311872188020570952|
|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 failureJ Card FailYear: 20111789990622041326|
|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 insufficiencyJ Am Coll CardiolYear: 2007501657166517950147|
|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 failureJ Am Coll CardiolYear: 2006481225122716979010|
|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 stentingMinerva CardioangiolYear: 20105811020145590|
|117.||Middlekauff HR. Making the case for skeletal myopathy as the major limitation of exercise capacity in heart failureCirc Heart FailYear: 2010353754620647489|
|118.||Clark AL,Poole-Wilson PA,Coats AJ. Exercise limitation in chronic heart failure: central role of the peripheryJ Am Coll CardiolYear: 199628109211028890800|
|119.||Toblli JE,Cao G,Rivas C,Kulaksiz H. Heart and iron deficiency anaemia in rats with renal insufficiency: the role of hepcidinNephrologyYear: 20081363664518808386|
|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 inflammationEndocrinologyYear: 20071482663266817363462|
|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 cardiomyocytesJ Nutr BiochemYear: 20092086086519027283|
|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 heartBiochim Biophys ActaYear: 2007177252753217383861|
|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 infarctionJ Nutr BiochemYear: 20102174975619615879|
|124.||Rossi MA,Carillo SV. Electron microscopic study on the cardiac hypertrophy induced by iron deficiency anaemia in the ratBr J Exp PatholYear: 1983643733876225450|
|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 heartCirc ResYear: 198965118211922529998|
|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 ratsAm J PatholYear: 19921412272391385927|
|127.||Medeiros DM,Beard JL. Dietary iron deficiency results in cardiac eccentric hypertrophy in ratsProc Soc Exp Biol MedYear: 19982183703759714082|
|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 ratsExp Med SurgYear: 19682652605718756|
|129.||Maeder MT,Khammy O,dos Remedios C,Kaye DM. Myocardial and systemic iron depletion in heart failure implications for anemia accompanying heart failureJ Am Coll CardiolYear: 20115847448021777743|
|130.||Boulton FE. The myoglobin content of human skeletal muscleBr J HaematolYear: 1973252814726915|
|131.||Polonifi A,Politou M,Kalotychou V,Xiromeritis K,Tsironi M,Berdoukas V,Vaiopoulos G,Aessopos A. Iron metabolism gene expression in human skeletal muscleBlood Cells Mol DisYear: 20104523323720691620|
|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 muscleBloodYear: 20071094724473117311997|
|133.||Dallman PR. Biochemical basis for the manifestations of iron deficiencyAnnu Rev NutrYear: 1986613403524613|
|134.||Finch CA,Huebers H. Perspectives in iron metabolismN Engl J MedYear: 1982306152015287043270|
|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 womenAm J Clin NutrYear: 20047943744314985219|
|136.||Brownlie T IV,Utermohlen V,Hinton PS,Giordano C,Haas JD. Marginal iron deficiency without anemia impairs aerobic adaptation among previously untrained womenAm J Clin NutrYear: 20027573474211916761|
|137.||Hinton PS,Giordano C,Brownlie T,Haas JD. Iron supplementation improves endurance after training in iron-depleted, nonanemic womenJ Appl PhysiolYear: 2000881103111110710409|
|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 womenAm J Clin NutrYear: 20037744144812540406|
|139.||McLane JA,Fell RD,McKay RH,Winder WW,Brown EB,Holloszy JO. Physiological and biochemical effects of iron deficiency on rat skeletal muscleAm J PhysiolYear: 1981241C47C546264804|
|140.||Willis WT,Brooks GA,Henderson SA,Dallman PR. Effects of iron deficiency and training on mitochondrial enzymes in skeletal muscleJ Appl PhysiolYear: 198762244224463038829|
|141.||Davies KJ,Maguire JJ,Brooks GA,Dallman PR,Packer L. Muscle mitochondrial bioenergetics, oxygen supply, and work capacity during dietary iron deficiency and repletionAm J PhysiolYear: 1982242E418E4277091311|
|142.||Finch CA,Miller LR,Inamdar AR,Person R,Seiler K,Mackler B. Iron deficiency in the rat. Physiological and biochemical studies of muscle dysfunctionJ Clin InvestYear: 197658447453956378|
|143.||Hinton PS,Sinclair LM. Iron supplementation maintains ventilatory threshold and improves energetic efficiency in iron-deficient nonanemic athletesEur J Clin NutrYear: 200761303916835600|
|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 outcomesJ Card FailYear: 20091572773519879457|
|145.||Drakos SG,Anastasiou-Nana MI,Malliaras KG,Nanas JN. Anemia in chronic heart failureCongest Heart FailYear: 200915879219379455|
|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 insufficiencyJ NephrolYear: 20082123624218446719|
[Figure ID: EHS224F1]
Importance of iron for functioning and survival across all levels of complexity of living structures.
[Figure ID: EHS224F2]
Major pools of utilized and stored iron in the body.
[Figure ID: EHS224F3]
The concept of absolute and functional iron deficiency.
[Figure ID: EHS224F4]
Tissues utilizing and/or storing iron and related biomarkers which are secreted by these tissues and can be detected in peripheral blood.
[Figure ID: EHS224F5]
Kaplan–Meier curves reflecting 3-year event-free survival rates in 546 patients with systolic heart failure with vs. without iron deficiency.112
[Figure ID: EHS224F6]
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
Summary of seven studies with intravenous iron therapy administered in patients with heart failure
|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
|↓ 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
(all patients, and separately: anaemics and non-anaemics)
↓ 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.
Keywords: Heart failure, Iron deficiency, Soluble transferrin receptor, Hepcidin, Prognosis, Exercise capacity.
Previous Document: The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activ...
Next Document: Vasa vasorum and plaque progression, and their response to atorvastatin in a rabbit model of atheros...