nature reviews cardiology https://doi.org/10.

1038/s41569-024-00988-1

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Iron deficiency and

supplementation in heart failure
Samira Lakhal-Littleton 1
& John G. F. Cleland 2

Abstract Sections

Non-anaemic iron deficiency (NAID) is a strategic target in cardiovascular Introduction

medicine because of its association with a range of adverse effects Iron and its markers
in various conditions. Endeavours to tackle NAID in heart failure Relationship between iron
have yielded mixed results, exposing knowledge gaps in how best to status and HF
define ‘iron deficiency’ and the handling of iron therapies by the body. Iron supplementation in HF
To address these gaps, we harness the latest understanding of the
Opportunities in the
mechanisms of iron homeostasis outside the erythron and integrate management of ID in HF
clinical and preclinical lines of evidence. The emerging picture is that Conclusions
current definitions of iron deficiency do not assimilate the multiple
influences at play in patients with heart failure and, consequently, fail
to identify those with a truly unmet need for iron. Additionally, current
iron supplementation therapies benefit only certain patients with
heart failure, reflecting differences in the nature of the unmet need
for iron and the modifying effects of anaemia and inflammation on
the handling of iron therapies by the body. Building on these insights,
we identify untapped opportunities in the management of NAID,
including the refinement of current approaches and the development
of novel strategies. Lessons learned from NAID in cardiovascular
disease could ultimately translate into benefits for patients with other
chronic conditions such as chronic kidney disease, chronic obstructive
pulmonary disease and cancer.

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. 2British Heart Foundation
1

Centre of Research Excellence, School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK.
e-mail: samira.lakhal-littleton@dpag.ox.ac.uk

Nature Reviews Cardiology

Review article
Key points
•• Non-anaemic iron deficiency (NAID) is a strategic target in
cardiovascular medicine because of its high prevalence, adverse
effects on a range of outcomes and its role as a precursor to anaemia.
•• In patients with heart failure (HF), variation in iron markers reflects
the demographic factors that influence them in the general population
as well as the modifying effects of common comorbidities and
certain medications.
•• Mechanisms underlying the adverse effects of NAID in HF could
include the unmet needs for iron by the myocardium, skeletal muscle
or pulmonary vasculature and the role of iron dysregulation in
comorbidities.
•• The benefits of oral iron therapies should be re-examined in light
of the latest developments in dosing regimens and slow-release
formulations.
•• Although intravenous iron therapy benefits some patients with HF,
the fate of iron in the body and the long-term safety of repeated dosing
remain unknown.
•• Identifying markers of the unmet need for iron by tissues and
targeting the iron homeostatic pathways in the body hold the potential
to transform the management of NAID.
Introduction
The haemoglobin-centric view has long dominated our understand-
ing of the adverse health effects of iron deficiency (ID). In patients
with cardiovascular disease (CVD), the haemoglobin level is often
measured as a proxy for iron status1–3. However, haemoglobin is only
one of many life-sustaining proteins whose function depends on iron4,5
(Fig. 1). Impairment of haemoglobin synthesis is a late consequence
of ID, with anaemia manifesting in only one-third of iron-deficient
individuals6. Non-anaemic ID (NAID) has long been overlooked but
is now recognized as a strategic clinical target in patients with heart
failure (HF) because of its high prevalence, its adverse effects on
multiple outcomes and its role as a precursor to the comorbidity of
anaemia3,7–14 (Table 1).
Recognition of NAID as a strategic clinical target has coincided
with a paradigm shift in approaches to iron replacement, from incre-
mental oral therapies to bolus intravenous therapies. Cardiovascular
medicine has been at the leading edge of these developments, both in
adopting intravenous iron therapies and in recognizing the potential
gains of treating NAID in patients with CVD. However, endeavours to
unlock that potential have been met with challenges, exposing the
substantial limitations of current approaches to the diagnosis and
management of ID.
In this Review, we harness the latest understanding of iron home-
ostasis to evaluate existing and emerging markers of iron status,
interrogate the reciprocal relationship between iron status and HF,
and mechanistically examine the benefits of oral and intravenous
iron replacement therapies. We conclude by highlighting a range
of untapped opportunities to improve the management of NAID in
patients with HF.
Nature Reviews Cardiology
Iron and its markers
Iron regulation in the body
Iron is an essential trace element found in all living organisms. The aver-
age amount of iron in the human body starts at ~0.2 g at birth, increasing
throughout childhood to ~3.0 g, then plateauing in adulthood at ~3.5 g
in women and ~4.0 g in men15–18. Iron fluxes between oxidative states,
complexing ligands and functional pools are shown in Fig. 2.
Iron can exist in various oxidation states in the body, most fre-
quently as ferrous (Fe2+) or ferric (Fe3+) iron19,20. In the gut lumen, Fe3+ is
reduced to Fe2+ by plasma membrane ascorbate-dependent reductase
CYBRD1 (also known as duodenal cytochrome b) to allow uptake by the
divalent metal transporter 1 (DMT1)21. The iron exporter solute carrier
family 40 member 1 (also known as ferroportin) exports Fe2+ from duo-
denal enterocytes, hepatocytes or splenic macrophages, which are the
cells involved in iron absorption, storage and recycling, respectively.
Fe2+ is then oxidized back to Fe3+ by hephaestin or ceruloplasmin, before
being loaded onto the plasma iron chaperone transferrin22.
Iron forms complexes with various ligands. In the circulation, iron
can be tightly bound to its chaperone transferrin in the Fe3+ form22,23
and can also be found as non-transferrin-bound iron (NTBI), typically
as citrate-bound Fe3+ or albumin-bound Fe2+ or Fe3+ (ref. 19). Inside
cells, ~40–50% of iron is bound to the cellular storage protein ferritin
as Fe3+, and ~40–50% is contained within prosthetic groups such as
haem (as Fe2+) or iron–sulfur groups (as Fe2+or Fe3+) mostly in mito-
chondrial enzymes4,5,15,24,25. In cardiac and skeletal muscle cells, iron
is also contained in the haem group of the oxygen storage protein
myoglobin26. Only a small proportion of cellular iron, typically <5%,
is labile (termed the labile iron pool (LIP)), where iron is either ligand
free, bound to reduced glutathione or coordinated by iron chaperones
such as poly(rC)-binding proteins19,20,22.
Iron also participates in various ‘functional’ pools. The largest,
accounting for around two-thirds of total iron in the body, is the eryth-
roid pool in which the primary function of iron is to bind oxygen to the
haem prosthetic group of haemoglobin for oxygen transport around
the body27. Pro-erythroblasts and erythroblasts take up ~80% of circu-
lating iron daily via transferrin receptor protein 1 (TFR1), then shed any
remaining receptors into the circulation in soluble form (sTFR)28. The
erythroid pool accounts for most of the daily iron demand and there-
fore exerts dominant control over systemic iron homeostasis29,30. Iron is
recycled from the erythroid pool by reticuloendothelial macrophages
in the spleen following the breakdown of senescent red blood cells27.
Hepatocytes contain the second largest functional pool, in which
iron is stored in an inert form in ferritin shells (each of which can hold
up to 4,500 atoms) but can be readily mobilized to meet the demands
of the erythron, growth or pregnancy24. The iron content of the liver
at birth is in the order of ~30 mg, rising in adulthood to ~1,000 mg
in men and ~300 mg in women31,32. When the rate of iron entry into
the plasma exceeds the rate of its clearance by the liver, NTBI levels
increase and iron is deposited in secondary storage organs, such as the
heart and pancreas, owing to their high expression of NTBI transport-
ers, including DMT1, zinc transporters 8 and 14, and L-type calcium
channels20,33,34.
The third largest functional pool is the intracellular pool in
non-erythroid tissues, where the primary function of iron is to activate
oxygen for a wide range of cellular chemistries. For example, iron in
haem and iron–sulfur groups catalyses the activation of oxygen for oxi-
dative phosphorylation, and unbound iron in the LIP activates oxygen
via cytoplasmic dioxygenases4,5,22. The cellular LIP is controlled at the
point of uptake (TFR1) and storage (cellular ferritin) and, in some cells
Review article

DNA replication and repair Myelin biosynthesis

XPD Stearoyl-CoA ∆9-desaturase MUFAs
Polα/δ/ε Palmitoyl-CoA

Polα/δ/ε Trimethyl lysine TMLH GBBH Carnitine

NTHL1
Lanosterol CYP51A1 Cholesterol
Cellular respiration
Neurotransmitter release
CI CII CIII CIV
Phenylalanine PAH Tyrosine TH Dopamine
CytoC
Tryptophan TPH Serotonin
NADH FAD
NAD+ FADH2 Oxygen storage
SD

Krebs O2
H

cycle
Deoxymyoglobin Oxymyoglobin
CO
A

1 FH O2

Oxygen sensing Vitamin D metabolism

PHD1/2/3 Degradation Calcitoic
HIF1/2α Vitamin D CYP2R1 25(OH)D CYP27B1 1,25(OH)2D CYP24A1 acid
FIH Inactivation

Oxygen transport
Collagen synthesis
4 × O2
Р4Н
Procollagen Mature collagen Deoxyhaemoglobin Oxyhaemoglobin
LH 4 × O2

Fe Haem Fe Fe–S cluster

Fig. 1 | Vital iron-dependent proteins and their signalling pathways.
Proteins requiring free iron are shown in yellow. Proteins requiring iron within
a haem functional group are shown in red. Proteins requiring iron within an
Fe–S functional group are shown in blue. Only iron-dependent steps are shown.
1,25(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; ACO1,
aconitate hydratase 1; CI, complex I; CII, complex II; CIII, complex III; CIV,
complex IV; CYP2R1, vitamin D 25-hydroxylase; CYP24A1, 1,25-dihydroxyvitamin
D3 24-hydroxylase, mitochondrial; CYP27B1, 25-hydroxyvitamin D-1α
hydroxylase, mitochondrial; CYP51A1, lanosterol 14α demethylase; CytoC,
cytochrome c; FH, fumarate hydratase; FIH, hypoxia-inducible factor 1α inhibitor
(also known as factor inhibiting HIF1α); GBBH, γ-butyrobetaine dioxygenase; HIF,
hypoxia-inducible factor; LH, lysyl hydroxylase; MUFA, monounsaturated fatty
acid; NTHL1, endonuclease III-like protein 1 (also known as DNA glycosylase);
P4H, prolyl 4-hydroxylase; PAH, phenylalanine-4-hydroxylase; PHD1, prolyl
hydroxylase 1; Polα, polymerase subunit-α; SDH, succinate dehydrogenase;
TH, tyrosine 3-monooxygenase (also known as tyrosine hydroxylase); TPH,
tryptophan hydroxylase; TMLH, trimethyllysine dioxygenase; XPD, helicase
subunit of transcription factor IIH.

(such as cardiomyocytes and vascular smooth muscle cells), addi-
tionally via ferroportin-mediated export23,35–38. Despite constituting
<5% of intracellular iron, the LIP is important as the substrate that is
sensed by iron regulatory proteins (IRPs) that ultimately orchestrate
cellular uptake, usage and storage, as an obligatory intermediate in the
exchange of iron between ligands, and as the cause of tissue damage
when in excess19,32,35,39–41.
Another functional pool is the circulating iron pool, in which ~3 mg
of iron is bound to transferrin, with NTBI becoming detectable when
transferrin saturation (Tsat) exceeds 70%22,32,42. Although ferritin mole­
cules are abundant in the circulation, they are iron-poor and derive
primarily from macrophages rather than hepatocytes43–45. Iron enters
the circulating pool following ferroportin-mediated export from gut
enterocytes, reticuloendothelial macrophages and hepatocytes46,47.
Ferroportin at these sites is subject to post-translational control by
the iron homeostatic hormone hepcidin, which causes its internaliza-
tion and degradation46,47. The circulating iron pool is important as
the substrate of iron sensing that sets hepcidin levels, an obligatory
intermediate in the influx of dietary and parenteral iron and in the
exchange of iron between functional pools as well as being the primary
site of sampling in the clinical assessment of iron status.
No active processes exist for iron excretion from the body because
all the iron that is filtered through the kidneys is reabsorbed48,49. A small
amount of iron (~1–2 mg daily) is lost through the sloughing of skin
and mucosal cells46,47. In menstruating women, up to 50 mg of iron is
lost per cycle50,51 and, in pregnancy, >500 mg of maternal iron is irre-
versibly ‘lost’ to fetal development52,53. The typical 100 mg oral iron
dose results in about 10 mg being absorbed into the circulation54,55.
Transfusion delivers ~200 mg of iron per unit of blood into the eryth-
roid pool56. Intravenous iron formulations release some iron directly
into the circulating pool as NTBI and some indirectly following
macrophage-dependent release of iron from the carbohydrate shell,
with the proportion of iron released as NTBI ranging between 10% and
40% depending on the formulation57,58.
Circulating iron markers
Circulating iron markers reflect the iron homeostatic pathways that
govern them and, in disease, they also indicate the influence of inflamma-
tion and hypoxia. The profound effects of inflammation on iron markers
originated in the evolutionary ‘arms race’ between host and pathogens
for access to iron, meaning that the signals that accompany infection
(and sterile inflammation) also influence iron handling in the body59,60.

Nature Reviews Cardiology

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Table 1 | Prevalence and outcomes of NAID in studies of patients with HF

Patients Number Definition of NAID Prevalence of Clinical outcomes associated with NAID Ref.
NAID (%)

HFpEF (LVEF ≥50%); HFmrEF 15,197 Ferritin <100 μg/l or ferritin HFpEF 61.0, HFmrEF Increased incidence of recurrent hospitalization for 3
(LVEF 40–49%); HFrEF (LVEF <40%) 100–299 μg/l with Tsat <20% 51.0, HFrEF 54.0 HF and cardiovascular death (HR 1.63)a
CHF with LVEF ≤45% 1,198 Ferritin <100 µg/l or ferritin 42.5 Reduced maximum exercise capacityb 7
100–299 µg/l with Tsat <20%
HFpEF (LVEF >45%) or HFrEF 1,506 Ferritin <100 µg/l or ferritin 50.0 All-cause mortality (HR 1.42)c 8
(LVEF ≤45%) 100–299 µg/l with Tsat <20%
AHF (discharged from hospital) 626 Ferritin <100 µg/l 48.2 Increased risk of 30-day hospital readmission 9
(HR 1.72)d
Ferritin 100–299 µg/l with 25.7 No effect on risk of 30-day hospital readmission
Tsat <20%
HFpEF (LVEF >50%); HFmrEF 1,197 Ferritin <100 µg/l or ferritin HFpEF 64.0, HFmrEF Reduced VO2e; freedom from all-cause death and 10
(LVEF 40–50%); HFrEF (LVEF <40%) 100–299 µg/l with Tsat <20% 61.0, HFrEF 50.0 heart failure hospitalizatione; progression from
NAID to IDA
Stable systolic CHF (LVEF 26 ± 7%) 546 Ferritin <100 µg/l or ferritin 37.0 Increased risk of death or heart transplantation 11
100–299 µg/l with Tsat <20% (HR 1.58)f
DHF 1,701 Ferritin <100 μg/l or ferritin 73.3 Increase in composite of 30-day death or hospital 12
100–299 μg/l with Tsat <20% readmission for DHF (HR 1.75; lower quartile Tsat
versus upper quartile Tsat)g
AHF, acute heart failure; CHF, chronic heart failure; DHF, decompensated heart failure; HF, heart failure; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with
preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; hsCRP, C-reactive protein level measured by high-sensitivity assay; IDA, iron deficiency anaemia; LVEF, left
ventricular ejection fraction; NAID, non-anaemic iron deficiency; Tsat, transferrin saturation; VO2, peak oxygen consumption. aAdjusted for centre, age, sex, BMI, CHF aetiology, NYHA class,
LVEF, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, serum sodium level, serum hsCRP level, renal function assessed using estimated glomerular filtration rate, presence
of diabetes mellitus and presence of anaemia. bAdjusted for age, sex, BMI, diabetes status, NYHA functional class, LVEF, renal function, levels of hsCRP and NT-proBNP, treatment with
angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins or loop diuretics, and presence of anaemia. cAdjusted for prior admission to hospital for AHF, presence of
hypertension or dyslipidaemia, length of hospital stay, interaction between LVEF ≤50% and diastolic blood pressure, and NT-proBNP and troponin T (high-sensitivity assay) levels. dAdjusted for
age, sex, anaemia, LVEF, and levels of serum creatinine, CRP and natriuretic peptides. eAdjusted for age, sex, implantable cardioverter–defibrillator use, cardiac resynchronization therapy use,
ischaemic aetiology of HF, use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers or mineralocorticoid receptor antagonists, NYHA functional class, loop
diuretic use, and baseline LVEF. fAdjusted for age, sex, last NYHA functional class III/IV under stable conditions, prior admission for DHF, presence of dyslipidaemia, Charlson comorbidity index,
systolic blood pressure, heart rate, atrial fibrillation, LVEF, left atrial diameter, haemoglobin, estimated glomerular filtration rate and NT-proBNP levels. gAdjusted for sociodemographic and
clinical factors, comorbidities, treatment variables, and anaemia.

The influence of hypoxia (anaemic hypoxia and hypoxaemia of severe
chronic obstructive pulmonary disease (COPD)) is underpinned by
the extensive crosstalk between iron-sensing and oxygen-sensing
pathways4,5,61. Because inflammation and hypoxia are common denomi-
nators in CVD, correct interpretation of circulating iron markers requires
a firm understanding of these influences (Fig. 3 and Table 2).
Ferritin. Ferritin is both an iron-storage protein and a positive acute-
phase protein. In comparison with intracellular ferritin, serum ferritin
is iron-poor, has a high ratio of light-to-heavy-chain subunits and is
frequently glycosylated, with evidence that the level of glycosylation
is increased by inflammation45,62,63. Serum ferritin is primarily derived
from macrophages rather than hepatocytes, although hepatocyte
ferritin can leak into the circulation as a result of liver injury43,44,64,65.
In macrophages, tumour necrosis factor (TNF) regulates the expression
of the ferritin heavy chain, whereas IRPs regulate the expression of both
heavy and light chains23,66–68. High serum ferritin levels are associated
with high mortality in a broad range of underlying pathologies, includ-
ing myocardial infarction and HF69–74. Therefore, serum ferritin levels
reflect the interaction between inflammation and iron in macrophages
as well as the extent of liver injury in patients with liver disease.
Transferrin. Transferrin is both a serum iron chaperone and a negative
acute-phase protein22,42. The importance of transferrin is demonstrated
by the genetic disorder atransferrinaemia, which is characterized by
both microcytic hypochromic anaemia and excess iron deposition in
tissues75. Transferrin serum levels depend on the rates of biosynthesis in
the liver, consumption for erythropoiesis and clearance by the kidneys42.
Transferrin biosynthesis in the liver is increased by ID anaemia, hypoxia,
or when liver iron stores are depleted (such as during pregnancy) and
is decreased when liver iron stores are excessive or as a result of liver
injury42,76–80. Serum transferrin levels can also be reduced due to urinary
loss in patients with renal disease81,82. In acute settings, TNF suppresses
transferrin biosynthesis, and serum transferrin levels can drop mark-
edly (for example, by ~30% after myocardial infarction)83–87. Raised
transferrin levels can therefore denote the depletion of liver iron stores;
however, this rise would be masked by the opposing effects of inflamma-
tion, liver injury, nephrosis and excessive erythropoiesis (for example,
ineffective erythropoiesis and erythroid anaemia).
Serum iron. The serum iron measured in standard clinical tests consti-
tutes the sum of transferrin-bound iron and NTBI. Serum iron levels are
determined by the rates of export from supply tissues and uptake by
demand tissues19,47,76,80. The levels are also subject to diurnal variation,
changing by as much as 30% during the course of the day88. A reduced
serum iron level can denote low iron stores in the body, increased
demand during growth or for erythropoiesis, or increased sequestra-
tion due to infection or inflammation (due to hepcidin elevation).
By contrast, elevated serum iron levels can denote excess iron stor-
age, an acute response to hypoxia, reduced iron consumption by the
bone marrow (such as with cytotoxic therapies) or failure to produce
sufficient transferrin due to liver injury89–93.

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Transferrin saturation. Tsat represents the proportion of iron-binding
sites in transferrin molecules that are occupied by iron and is often
calculated using serum iron and total iron-binding capacity, which
reflects serum transferrin concentration94. Therefore, the interpreta-
tion of changes in Tsat should consider both the factors that influence
serum iron levels and those that influence serum transferrin levels.
Soluble TFR. sTFR derives primarily from the shedding of TFR1 from
erythroblasts95–97. IRPs upregulate TFR1 expression in iron-hungry
erythroblasts and, therefore, sTFR levels reflect not only the size of
the erythroblast pool but also its demand for iron. Indeed, the sTFR
level is increased in β-thalassaemia and in response to erythropoietin
dose, and is reduced by bone marrow suppression (such as with chemo-
therapy)98–100. sTFR levels have not been reported to be influenced by
inflammation; consequently, sTFR and the sTFR/log ferritin index have
been proposed as superior diagnostic markers for ID anaemia101–103.
Hepcidin. Serum hepcidin is the master hormone of systemic iron
homeostasis and derives primarily from hepatocytes46,91. Some cells
(including cardiomyocytes) also express hepcidin although, in this
context, hepcidin acts in an autocrine or paracrine manner to regulate
the cellular LIP rather than systemic iron levels35–38. Hepatic hepcidin
expression is controlled by bone morphogenetic protein 2 (BMP2)
and BMP6, signalling via a BMP receptor complex that involves several
accessory receptors, including homeostatic iron regulator protein,
haemojuvelin and TFR2 (ref. 91). Raised serum levels of hepcidin can
reflect increased hepatic expression due to high Tsat, inflammation
(specifically IL-6 and IL-1β), liver injury and hyperlactataemia. Altera-
tively, they can reflect impaired renal clearance of the hepcidin pep-
tide due to reduced glomerular filtration rate (GFR) such as in patients
with kidney disease90,104–115. Conversely, reduced serum levels of hep-
cidin can be caused by hypoxia, low Tsat and the endocrine action of
erythroferrone, all of which suppress hepcidin expression90,91,104–115.
Erythroferrone is released by erythroblasts under the influence
of erythropoietin108–110. Overstimulation of the erythropoietin–
erythroferrone axis accounts for profound hepcidin suppression and
results in non-transfusional iron overload in disorders of ineffective
erythropoiesis108–110. Erythroferrone-mediated suppression of hepci-
din seems to overcome the stimulatory effects of IL-6, accounting for
recovery from anaemia of inflammation (also known as anaemia of
chronic disease (ACD))30,111. Therefore, in the absence of inflammation,
serum hepcidin levels reflect Tsat, hypoxia and erythropoietic activity.
In inflammatory settings, hepcidin levels are increased (causing Tsat
to decline), but subsequent onset of anaemia can break the associa-
tion between inflammation and hepcidin if erythroferrone levels are
sufficiently raised.
Erythropoietin. Erythropoietin influences iron homeostasis both by
stimulating the erythropoietic demand for iron and by suppressing
hepcidin (via erythroferrone) to meet that demand108,116. Erythropoi-
etin is primarily produced by renal interstitial fibroblasts under the
transcriptional control of hypoxia-inducible factor 2 (HIF2) in response
to hypoxia resulting from altitude, anaemia or pulmonary disease
hypoxaemia117,118. Erythropoietin production is acutely upregulated
by iron chelation because the degradation of HIF2 by prolyl hydroxy-
lases requires iron as a cofactor119. Conversely, sustained ID blunts
erythropoietin production owing to translational repression of HIF2 by
IRP1 — a feedback mechanism that tethers erythropoietin production
to iron availability120. Indeed, mice lacking Irp1 and patients with IRP1
Nature Reviews Cardiology
somatic mutations have HIF2 accumulation, excess erythropoietin
production, stress erythropoiesis, polycythaemia and suppressed
hepcidin levels121,122. TNF decreases renal erythropoietin production
and suppresses differentiation of erythroid progenitors in the bone
marrow, whereas IFNγ reduces the lifespan of red blood cells, speed-
ing up their turnover123,124. Under these conditions, the body resorts to
stress erythropoiesis in the spleen driven by growth/differentiation
factor 15 (ref. 125). Therefore, ACD is not solely the consequence of
hepcidin-driven iron sequestration but also the direct influence
of inflammation on erythropoietin. Furthermore, sampling the bone
marrow in inflammatory settings might not produce a complete picture
of erythroid iron demand, because of stress erythropoiesis.
Definition and diagnosis of ID
The management of ID faces two challenges. First, guidelines for the
management of ID126–131 are still intertwined with those for anaemia,
meaning that NAID is often not screened for and iron markers are inves-
tigated only when anaemia is suspected based on full blood count or
haemoglobin measurements. For instance, in patients with HF, iron
markers are most likely to be checked when haemoglobin is at least
2 g/dl below the WHO threshold for anaemia2,3. Second, even when
iron markers are investigated, often only ferritin is tested2. Even the
combination of ferritin and Tsat has limitations because these markers
reflect the convergence of the multiple influences outlined above, they
vary according to sex, age, ethnicity and smoking status, are subject to
diurnal variation, and are confounded by the presence of conditions
such as haemoglobinopathy or blood loss through the gastrointestinal
tract or menstruation132–136. The lack of a clear, evidence-based defini-
tion of ID risks both undertreating patients who have a true unmet need
for iron and overdosing patients who do not need supplementary iron.
The past decade has seen efforts to reach a consensus definition of ID
in the general population and in specific patient groups126–131 (Table 3).
In patients with HF, the diagnosis of ID is further confounded by
common comorbidities, such as diabetes mellitus, obesity, COPD
and chronic kidney disease (CKD), and certain medications such as
β-blockers and sodium–glucose cotransporter 2 inhibitors137–142. Dapa-
gliflozin, for example, was shown to reduce Tsat, ferritin and hepcidin
levels and to raise total iron-binding capacity and sTFR in patients with
HF with reduced ejection fraction (HFrEF)142 through as-yet unknown
mechanisms. The ESC guidelines129 define ID as a ferritin concentration
of <100 μg/l, or <300 μg/l with Tsat <20%, and they advocate testing
all patients with HF and supplementing those meeting this definition.
The rationale for this definition is to encompass both individuals with
absolute ID, in whom iron stores are truly depleted, and those with func-
tional ID, in whom iron stores are not mobilizable due to elevated hep-
cidin levels. However, a prospective study published in 2022 indicated
that this definition does not adequately identify patients who are at
highest risk of adverse events or those most likely to benefit from
intravenous iron therapy137. Therefore, there is a disconnect between
the current interpretation of iron markers and the true nature of the
pathophysiology that they reflect or contribute to.
Relationship between iron status and HF
Changes in iron markers during HF
Following acute cardiovascular events, the serum level of ferri-
tin increases and that of transferrin decreases rapidly, as both are
acute-phase proteins regulated by TNF42,85. Transient decreases in
plasma iron levels and Tsat as well as a temporary elevation of the
hepcidin level also occur after myocardial infarction, probably driven
Review article

Diet: Fe2+
Haem: Fe2+
Fetus and Tablets: Fe2+
placenta
~500 mg Storage
~1.5 mg daily ~1,000 mg
Gut
Fe3+ Fe2+ 15

Fe3+ Fe2+ 14 Fe2+ Fe3+ Degradation 13

Mobilization as
per demand

18 16 17 11 Fe2+ Fe3+ 12 Ferritin (Fe3+)

10 Fe3+ 12

Uptake when
Tf(Fe3+)2 in excess
~3 mg
Non-erythroid pool
4 9 Degradation Ferritin (Fe3+) ~500 mg

As needed for 21
24 Fe 3+ 7
growth, renewal Mitochrondrion Sloughing
LIP Fe–S (Fe2+) ~1.5 mg daily
and function
NTBI Fe2+ 6 ETC
Intravenous Albumin:
iron Fe3+ Fe3+ 23 5 Haem (Fe2+) 8 Myoglobin (Fe2+)
Fe2+, Fe3+
~1,500 mg Citrate: Fe3+
Erythroid pool
Ferritin Ferritin Reticuloendothelial macrophages
16 17 ~600 mg
(?Fe3+) (?Fe3+)
~25 mg daily
Fe2+ HO-1
Fe3+ Fe2+ 2

22 Degradation

3
20
RBCs
~1,800 mg Transfusion
~200 mg
Free haem (Fe2+), Haemolysis
per unit
Cell-free haemoglobin
Haemoglobin (Fe2+)
(Fe2+) Menstruation
~1–50 mg per cycle
19

~25 mg daily Bone marrow

1 Fe3+ Fe2+ Haem (Fe2+) ~300 mg
Circulating pool

by IL-6 (refs. 85,86,143,144). Concomitantly, myocardial iron content
increases as a result of intramyocardial haemorrhage145. Therefore,
caution must be used when inferring the iron status of a patient from
snapshot measurements of iron markers in the hours after an acute
cardiovascular event.
In chronic HF (CHF), most of the available evidence derives from
populations with ischaemic HF or HFrEF and shows that iron markers
change gradually as disease progresses146–150 (Box 1). Hepcidin levels
are elevated in the early stages of HF owing to the active inflammatory
processes of ischaemic heart disease, infarct scarring and cardiac
remodelling144,148. Indeed, the association between hepcidin and IL-6
is strongest in patients with NYHA class I HF148. An elevated hepcidin
level reduces serum iron availability, which begins to restrict erythro-
poiesis, eventually resulting in anaemia. Indeed, there is a progressive
reduction in serum iron and Tsat and a gradual increase in sTFR with
advancing NYHA class148. The role of iron restriction as a precursor to
anaemia in CHF is supported by the finding that low serum iron and
low Tsat, and not low ferritin, are the strongest predictors of the risk
of anaemia as HF progresses149. Furthermore, only a serum iron level of
≤13 μmol/l or Tsat of ≤19.8% (not the ESC definition of ID) predict bone
marrow ID in patients with HFrEF149.
Progression towards anaemia stimulates erythropoietin pro-
duction, which overcomes the inflammatory stimulus on hepcidin,
probably via erythroferrone. Indeed, hepcidin declines as patients
progress through NYHA classes, and this decline is strongly corre-
lated with the increase in sTFR level148. In advanced HF, the association
between hepcidin and IL-6 is broken, and hepcidin levels are lower than
in earlier NYHA classes despite IL-6 levels being higher148. A gradual
increase in erythropoietin level occurs over the course of HF pro-
gression, and its role in hepcidin suppression is supported by the
observation that plasma hepcidin levels are lower in patients with
CHF and anaemia than in healthy controls and correlate negatively
with erythropoietin levels147,150. Despite the suppression of hepcidin in
advanced HF, circulating iron availability continues to decline, which is

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Review article
Fig. 2 | The oxidative states, binding ligands and functional pools of
iron in the body. The various functional iron pools in the body are depicted
in different colours. Iron fluxes into and out of the body are shown in red
boxes around the edge. Most iron in the body is present in the erythroid pool
(green area), either within reticuloendothelial macrophages, red blood cells
(RBCs) or the bone marrow. Haemoglobin synthesis in the bone marrow
requires the uptake of ~25 mg of iron daily from the circulating pool (grey area)
in the form of transferrin (Fe3+) (1). This uptake is balanced by recycling of
senescent RBCs by reticuloendothelial macrophages in the spleen, resulting
in ~25 mg of iron being released back into the circulation via ferroportin on the
surface of macrophages (2). These macrophages also recycle iron from free
haem or cell-free haemoglobin resulting from haemolysis (3). In non-erythroid
tissues (blue area), transferrin-bound iron Tf(Fe3+)2 is taken up by transferrin
receptor (TFR)-mediated endocytosis (4), and some tissues additionally
take up non-transferrin-bound iron (NTBI) via NTBI transporters (5). When
inside the cells, iron joins the labile iron pool (LIP), before being used for
the synthesis of functional groups (6), such as those used in mitochondrial
enzymes, or stored in ferritin (7). In cardiac and skeletal muscle, iron is also
used for the synthesis of haem in myoglobin (8). Iron uptake via TFR-mediated
endocytosis can be increased (4) and iron from ferritin released (9) to meet
cellular iron needs. Hepatocytes (yellow area) can buffer plasma iron levels by
likely to reflect continued funnelling of iron towards the bone marrow
(under the influence of erythropoietin) and, in some patients, truly
depleted iron stores148. Notably, CKD (a common comorbidity) is an
important confounder of iron status in patients with HF owing to the
impairment of erythropoietin production (renal anaemia) and reduced
urinary clearance of hepcidin151.
ID as a comorbidity in HF
Neither preclinical nor clinical studies have detected an increased risk
of CVD in the setting of iron overload (such as in patients with thalas-
saemia or haemochromatosis), challenging the long-standing notion
that iron is atherogenic152–155. By contrast, most prospective studies
indicate that low serum iron availability, denoted specifically by low
serum iron, Tsat or hepcidin (but not ferritin), predicts an increased risk
of CVD events such as myocardial infarction and related adverse out-
comes, and worse long-term outcomes in patients with HF8,14,137,148,156–164
(Table 4). Several potential mechanisms underpin the role of ID in HF
(Fig. 4), which are discussed in detail below.
Myocardial iron depletion. Whether myocardial iron depletion occurs
in HF and whether it has disease-modifying effects remain subject to
debate. Myocardial iron levels have been assessed in patients with HF
using magnetic resonance imaging (MRI) relaxometry parameters,
such as T1, R1 and T2*, and by direct quantification from myocardial
biopsy samples. However, MRI studies have either not detected an
association between serum iron and myocardial iron levels or have
detected only a trend towards reduced iron levels in myocardial and
skeletal muscle in patients with HF165,166. Taken together, myocardial
biopsy studies support the notion that, in the early stages of HF, the
myocardium maintains normal iron levels (despite reduced serum
iron availability) by increasing the expression of TFR1 and decreasing
ferroportin locally. Subsequently, a decrease in TFR1 expression and
an increase in ferroportin levels are associated with myocardial iron
depletion with advancing HF167–171.
The importance of myocardial ferroportin and TFR1 for the main-
tenance of normal myocardial iron levels has been demonstrated in
preclinical models35,36. Mice lacking cardiomyocyte ferroportin show
Nature Reviews Cardiology
taking up both Tf(Fe3+)2 via TFR-mediated endocytosis (10) and NTBI via NTBI
transporters (11). This iron is primarily stored in ferritin cages (12); it can be
released from ferritin (13) and exported via ferroportin into the circulation to
meet extrahepatic demands (14). Iron taken up from the gut is also released into
the circulation via ferroportin (15). Iron released into the circulation as Fe2+ via
ferroportin at the sites of recycling, storage and absorption is oxidized to Fe3+
for loading onto transferrin (16). Some iron also joins the circulating NTBI pool,
being bound to albumin or citrate (17). During pregnancy, the mother can lose
up to 500 mg of iron to the fetus owing to the high expression of TFR on the
maternal side of the placenta (18). In women of reproductive age, up to 50 mg of
iron is lost in each menstrual cycle (19). Every unit of blood transfusion delivers
200 mg of iron in RBCs (20), which eventually joins the circulating iron pool
when transfused RBCs have been recycled. Some iron (~1.5 mg) is lost daily due
to sloughing of cells from the skin and mucosal surfaces (21) and is replenished
by dietary iron uptake. Intravenous iron therapies can deliver up to 1,500 mg
of iron into the circulation. Most of this iron is enclosed in a carbohydrate shell
and is released into the circulation only following breakdown and ferroportin-
mediated export by reticuloendothelial macrophages (22). However, 10–40%
of the iron is released directly into the circulation to join the NTBI pool (23) or
loaded onto transferrin (24). Values shown are for an average, iron-replete adult.
ETC, electron transport chain.
rapid myocardial iron accumulation in the absence of any change in
serum iron availability35. Conversely, mice lacking cardiac hepcidin
or harbouring a cardiac-specific substitution of ferroportin with a
hepcidin-resistant ferroportin develop myocardial iron depletion
despite normal circulating iron levels36. Mice lacking cardiac TFR1
show early and fatal myocardial iron depletion172. These preclinical
studies also provide proof of concept that myocardial iron depletion
is sufficient to compromise the contractile function of the heart35,36,172.
However, studies examining the relationship between myocar-
dial iron levels and echocardiographic measures of heart function in
patients have yielded inconsistent results169,173,174. An important impli-
cation of the roles of hepcidin, ferroportin and TFR1 in myocardial
iron control is that myocardial iron depletion would be more likely
in individuals with absolute ID (in whom both serum iron availability
and hepcidin are reduced) than in patients with functional ID (in whom
serum iron availability is reduced but hepcidin is elevated). Consistent
with this theory, in biopsy samples obtained during coronary artery
bypass graft (CABG) surgery, myocardial TFR1 expression (indicative of
an IRP-driven response to cellular ID) was higher in patients with abso-
lute ID (ferritin <100 μg/l) than in those with functional ID (Tsat <20%
and ferritin 100–299 μg/l)171.
Several mechanisms through which myocardial iron depletion
could impair cardiac contractile function have been proposed such as
a reduction in the activity of iron-dependent complexes in the electron
transport chain as well as a reduction in mitochondrial oxygen respira-
tion and a shift from oxidative phosphorylation to glycolysis36,167–180.
Impairments in respiration were shown to persist in vitro in isolated
myocardial mitochondria, suggesting an intrinsic decline in oxygen
utilization rather than simply reduced oxygen delivery175. By contrast,
the only published study of myocardial energetics in living patients,
using cardiovascular hyperpolarized MRI and phosphorus-31 magnetic
resonance spectroscopy, showed that patients with non-ischaemic HF
had preserved myocardial energetics176. As alluded to above, another
proposed mechanism involves the upregulation of glycolysis in a man-
ner that phenocopies HIF-driven responses, probably because iron
is a cofactor for the prolyl hydroxylases that regulate HIF stability,
and indeed cellular ID can stabilize HIF and induce its transcriptional
Review article

DMT1 Lactic acid

Duodenal
5 enterocyte 8
IL-6 Hepatocyte
O2 HIF Injury
1 6 HIF 10 O2

FPN
Ferroportin 9
Fe Hepcidin 4 Hepcidin 7

Erythrophagolysosome 14 TNF TFR

Fe
12 Transferrin 13 Fe Transferrin
Hb 21
Ferroportin Ferroportin
Fe 2 Fe Fe Fe 3
Ferritin
Transferrin
IRP 22 Ferritin 24 Ferritin 25 Injury
Kidney
23 Haemoglobin
Injury 11
TNF sTFR TNF
Splenic macrophage Consumption
27
Circulation Fe
18 15 Renal
EPO 19 HIF clearance
Transferrin O2
Senescence 26 IFNγ Fe Interstitial fibroblast
26
TFR 17

Senescence Haemoglobin IRP

Fe

Haemoglobin EPO 16 16 EPO Bone

marrow
20 RBC
Erythroblast Erythroblast
Gas exchange

Erythroferrone
Injury Lungs

Fig. 3 | Multifactorial influences on serum iron markers in health
and disease. Circulating markers of iron status are shown in the centre.
Arrows leading into the centre depict the tissue sources of each marker.
Regulatory influences in each tissue are also shown. Circulating iron levels are
dependent on ferroportin-mediated iron export from duodenal enterocytes
(1), splenic reticuloendothelial macrophages (2) and hepatocytes (3).
Ferroportin-mediated iron export from all three cell types is controlled by
plasma hepcidin, which is primarily derived from hepatocytes (4). In duodenal
enterocytes, iron absorption at the luminal side is dependent on several
transporters, including divalent metal transporter 1 (DMT1) (5). Iron absorption
is inhibited by injury (such as malabsorptive disorders) due to downregulation
of DMT1 at the luminal side (5) and ferroportin at the apical side (1), and is
upregulated by hypoxia owing to the regulatory effects of hypoxia-inducible
factor (HIF) on duodenal DMT1 and ferroportin gene transcription. Hepcidin
production in hepatocytes is upregulated by inflammation (IL-6) (6),
hepatocyte iron content (7) and anaerobic metabolism (lactic acid) (8),
and downregulated by the endocrine action of erythroferrone derived from
the bone marrow (9) and the local action of hypoxia via HIF (10). Circulating
hepcidin levels can also become elevated in chronic kidney disease due to
impaired renal clearance (11). Serum transferrin is produced by hepatocytes
(12) in a manner that is downregulated by liver iron content (13) and
inflammation (tumour necrosis factor; TNF) (14). When in the circulation and
loaded with iron, transferrin is consumed via transferrin receptor (TFR)-
mediated endocytosis in tissues, most notably developing erythroblasts in
the bone marrow (15). This rate of consumption is dependent on the erythroid
drive, which is stimulated by renal-derived erythropoietin (EPO) (16). Greater
erythroid demand is accompanied by greater erythroferrone production,
aimed at suppressing hepcidin (9) and increasing iron availability in the
circulation. In erythroblasts, cellular iron demand for haemoglobin synthesis
is met via iron regulatory protein (IRP)-dependent upregulation of TFR (17).
When haemoglobin synthesis is complete, TFR is shed into the circulation in
its soluble form (sTFR) (18). Therefore, sTFR levels reflect both the size of the
erythroblast pool and its requirement for iron. Production of haemoglobin sets
the oxygen-carrying capacity of the blood. Low haemoglobin production
(anaemia) can result in hypoxaemia with consequences for iron absorption
in the gut (1 and 5), hepcidin expression in hepatocytes (10) and erythropoietin
production in renal interstitial fibroblasts (19). Impaired lung gas exchange
(for example, due to chronic obstructive pulmonary disease) can also result
in hypoxaemia (20). Senescent red blood cells (RBCs) are engulfed by splenic
macrophages (21), and recycled iron is subsequently released via ferroportin (2).
Inside these macrophages, ferritin expression is upregulated both by iron
availability (via IRP inhibition) (22) and by inflammation (via TNF) (23). Serum
ferritin derives from splenic macrophages (24), reflecting the interaction
between iron and inflammation in these cells. Serum ferritin levels can also be
augmented by leakage from hepatocytes due to liver injury (25). Inflammation
can cause anaemia through iron-independent mechanisms. For example,
IFNγ speeds up RBC senescence (26), whereas TNF and renal injury suppress
erythropoietin production in interstitial fibroblasts (27). Iron-dependent
mechanisms are also involved due to the elevation of hepcidin levels (8), which
reduces iron flux into the circulation.

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Table 2 | Factors that affect levels of circulating iron markers

Circulating Direction of Factors affecting change Mechanisms of change Refs.

iron marker change

Serum ferritin Increase Iron supplementation (intravenous or oral) Iron in macrophages inhibits IRP2, allowing translation of 23,43,44
ferritin heavy and light chains
Iron overload (for example, haemochromatosis, 23,43,44
iron-loading anaemias)
Inflammation (for example, acute cardiovascular events, TNF stimulates transcription of ferritin heavy chain in 66,68
chronic inflammation, infection) macrophages
Liver damage (for example, alcoholic or non-alcoholic Leakage from hepatocytes 64,65
liver disease)
Decrease Iron depletion (for example, absolute ID, iron chelation) Low iron in macrophages activates IRP2, inhibiting 23,43,44
translation of ferritin heavy and light chains
Serum Increase Depletion of liver stores (for example, pregnancy, Increased biosynthesis in the liver 42,76
transferrin absolute ID)
Hypoxia (for example, at altitude, hypoxaemia of Induction of transferrin gene expression by HIF1α 77
pulmonary disease)
Decrease Acute inflammation (for example, acute cardiovascular TNF inhibits transferrin biosynthesis in the liver and 84–87
events, infection) promotes transferrin uptake by macrophages
Repletion of liver iron stores (for example, intravenous Decreased biosynthesis in the liver 42,78
iron, haemochromatosis, thalassaemia)
Liver damage (for example, alcoholic or non-alcoholic 79,80
liver disease)
Erythropoietic expansion (for example, response Expansion of the erythroid pool accompanied by increased 42,116
to erythropoietin, ineffective erythropoiesis (as in transferrin uptake via TFR1 on erythroblasts
β-thalassaemia) and erythroid anaemia due to vitamin
B12 deficiency)
Nephrosis Excess renal clearance 42,81,82
Serum iron Increase Iron supplementation (intravenous or oral) Increased iron release from gut enterocytes (oral iron), 54,55,
direct iron release into the circulation (intravenous iron) 57,58
Hypoxia (for example, at altitude, hypoxaemia of HIF stimulates expression of DMT1 for iron uptake at the 92,93
pulmonary disease) lumen side and ferroportin for iron export at the basolateral
side of gut enterocytes
Liver injury (for example, alcoholic or non-alcoholic liver Decreased serum transferrin increases NTBI 79,80
disease)
Decrease Inflammation (for example, acute cardiovascular events, Increased iron uptake into macrophages via DMT1; increased 46,90,91
infection, chronic disease) levels of endogenous chelators (for example, lactoferrins and
lipocalin 2); decreased levels of ferroportin in gut enterocytes
and splenic macrophages due to hepcidin elevation
Erythropoietic expansion (for example, response to Expansion of the erythroid pool increases transferrin (Fe3+) 27,116
erythropoietin) turnover
Increase or Time of day (a.m. = increase; p.m. = decrease) Reflects variation in hepcidin level 88
decrease
Transferrin Increase Acute inflammation (for example, acute cardiovascular Decreased serum transferrin 83–85
saturation events, infection)
Liver injury (for example, alcoholic or non-alcoholic liver 79,80
disease)
Iron supplementation (intravenous or oral) Increased serum iron 54,55,
57,58
Decrease Inflammation (for example, chronic disease, infection) Decreased serum iron 46,90,91
Iron chelation, phlebotomy 212
Increase or Time of day (a.m. = increase; p.m. = decrease) Reflects variation in serum iron level 87
decrease
sTFR Increase Unmet erythroid iron demand (for example, ID) Reduced LIP in erythroblasts activates IRP to increase surface 97
expression of TFR1, which is subsequently shed as sTFR
Erythropoietic expansion (for example, erythropoietin Expansion of erythroblast pool leads to more TFR1 being 98,99
response, haemolytic or sickle cell anaemia, ineffective shed into the circulation as sTFR
erythropoiesis)

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Table 2 (continued) | Factors that affect levels of circulating iron markers

Circulating Direction of Factors affecting change Mechanisms of change Refs.

iron marker change

sTFR Decrease Suppressed erythropoiesis (for example, following Contraction of the erythroblast pool leads to less TFR1 being 100,101
(continued) chemotherapy, impaired erythropoietin production in shed into the circulation as sTFR
renal disease)
Hepcidin Increase Iron supplementation (intravenous or oral) Tsat elevation stimulates hepcidin transcription by 36,57
increasing BMPR2 signalling on hepatocytes
Inflammation (for example, chronic disease, infection, IL-6 signals at IL-6 receptor on hepatocytes to stimulate 90,91,
acute cardiovascular events) hepcidin transcription via a STAT3 binding site in hepcidin 105,111
promoter; IL-1β increases C/EBPδ expression in hepatocytes,
which activates hepcidin transcription
Liver injury (for example, alcoholic or non-alcoholic Endoplasmic reticulum stress in hepatocytes activates 106
liver disease) DDIT3, which increases C/EBPα activity and hepcidin
transcription
Hyperlactataemia (for example, in athletes, Lactate interaction with soluble adenylyl cyclase raises 114
some cancers) cAMP levels, which activates SMAD1/5/8 signalling and
increases hepcidin transcription in hepatocytes
Renal disease with reduced eGFR Impaired hepcidin clearance from circulation 115
Decrease Erythropoietic expansion (for example, anaemia, Differentiating erythroblasts release the hormone 30,108–111
response to erythropoietin, ineffective erythropoiesis erythroferrone, which inhibits BMPR2 signalling in
(as in β-thalassaemia) and erythroid anaemia due to hepatocytes to suppress hepcidin transcription
vitamin B12 deficiency)
Hypoxia (for example, at altitude, hypoxaemia of HIF stimulates the expression of furin and matriptase 2, 112,113
pulmonary disease) proteases that cleave the BMP co-receptor haemojuvelin
from the surface of hepatocytes, reducing hepcidin
transcription
Erythropoietin Increase Anaemia Reduced oxygen delivery to interstitial fibroblasts inhibits 108,117,118
HIF prolyl hydroxylases; HIF2 is stabilized and drives
transcription of the erythropoietin gene
Hypoxia (for example, at altitude, hypoxaemia of Local hypoxia in interstitial fibroblast inhibits HIF prolyl 117,121
pulmonary disease) hydroxylases; HIF2 is stabilized and drives transcription of
the erythropoietin gene
Iron chelation Removal of intracellular iron from interstitial fibroblast 119
inhibits HIF prolyl hydroxylases (they require iron as a
cofactor); HIF2 is stabilized and drives transcription of the
erythropoietin gene
Decrease Iron deficiency with low Tsat Reduced iron delivery to interstitial fibroblasts activates 119–121
IRP1, which causes translational inhibition of HIF2, thereby
reducing erythropoietin transcription
Inflammation (for example, chronic disease, infection, TNF decreases renal erythropoietin production 124,125
acute cardiovascular events)
BMP, bone morphogenetic protein; BMPR2, bone morphogenetic protein receptor type 2; C/EBP, CCAAT/enhancer-binding protein; DDIT3, DNA damage-inducible transcript 3 protein
(also known as CAAT/enhancer-binding protein homologous protein, CHOP); DMT1, divalent metal transporter 1; eGFR, estimated glomerular filtration rate; HIF, hypoxia-inducible factor;
ID, iron deficiency; IRP, iron regulatory protein; LIP, labile iron pool; NTBI, non-transferrin-bound iron; SMAD, mothers against decapentaplegic homologue; STAT3, signal transducer and
activator of transcription 3; sTFR, soluble transferrin receptor; TFR, transferrin receptor; TNF, tumour necrosis factor; Tsat, transferrin saturation.

targets, even in normoxia61,179. Disruption of calcium signalling genes
has also been proposed, involving the downregulation of ryanodine
receptor 2 and a reduction in sarcoplasmic/endoplasmic reticulum Ca2+
ATPase activity in the myocardium180. Impaired oxygen storage due to
reduced myoglobin synthesis has also been suggested as a potential
mechanism, although this phenomenon has been observed only in
skeletal muscle and not in the myocardium181,182.
Skeletal muscle iron depletion. Exercise capacity is often reduced
in patients with HF and universally predicts worse outcomes173,183. In
HF, ID is also associated with reduced exercise capacity and increased
muscle wasting184,185. The observation that ID reduces myoglobin in skel-
etal muscle provides a potential mechanism for this association181,182.
In COPD, ID and low circulating hepcidin levels are associated with
increased skeletal muscle IRPs (consistent with intracellular ID) and
with reduced exercise capacity186. The effects of ID on skeletal muscle
function and physical activity have long been recognized and are not
unique to patients with HF26,187–189.
Pulmonary disease. COPD is one of the major comorbidities in HF,
affecting 10–40% of patients190,191. ID is common in COPD and is para-
doxically accompanied by iron accumulation in lung parenchyma,
a phenomenon that has been confirmed in preclinical models192–194.
Lung epithelial cells and alveolar macrophages express ferroportin, and
elevated hepcidin levels seen in advanced COPD have been suggested
to promote both serum ID and iron accumulation in the lungs, which

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Review article

is an important driver of fibrosis and hypoxaemia194,195. Patients with
COPD and ID were found to be more hypoxaemic than their iron-replete
counterparts and intravenous iron therapy improved exercise capacity
without improving hypoxaemia192,196. Therefore, in patients with HF
and COPD, the presence of functional ID could contribute to worse
HF outcomes by compounding iron accumulation in lung parenchyma,
worsening fibrosis and hypoxaemia. Furthermore, interpretation of
iron markers in patients with HF and severe COPD could be confounded
by the presence of hypoxaemia-driven polycythaemia141,197,198.
Haemodynamic stress on the right heart. Pulmonary hyperten-
sion affects an estimated 36–83% of patients with HFpEF and is also
a frequent complication of COPD199–202. Pulmonary hypertension is
characterized by remodelling of the pulmonary circulation, leading to
chronically raised pulmonary arterial pressure (PAP), haemodynamic
stress on the right ventricle and ultimately right HF203. ID is common
in pulmonary hypertension and is associated with increased PAP and
NYHA functional class, poor survival, and elevated markers of car-
diovascular dysfunction204–208. In healthy individuals, the pulmonary
vascular response to hypoxia is potentiated by clinical ID or pharma-
cological iron chelation and is attenuated by repleted iron stores or
iron supplementation209–213. The speed by which iron chelation or sup-
plementation modifies the pulmonary vascular response to hypoxia
indicates a haemoglobin-independent mechanism, probably relating to
iron levels in pulmonary vascular cells212,213. Consistent with this theory,
preclinical studies have shown that ID in pulmonary arterial smooth
muscle cells is sufficient to cause pulmonary hypertension and right
HF by stimulating the production of the vasoconstrictor endothelin 1
in a manner that could be prevented, yet only partially reversed,
by intravenous iron therapy38.
In patients with pulmonary vascular disease, the definition of
ID as Tsat <21% (but not the ESC definition) identified patients with
reduced peak oxygen consumption (VO2) or worse performance in
the 6-min walking test207. Patients with ID had similar left ventricular
function and structure to those without but had more right ventricular
remodelling, including larger right ventricular volume and mass and
lower right ventricular ejection fraction207. Trials of iron supplementa-
tion in pulmonary hypertension have not shown reproducible effects
on functional parameters despite improvements in haematological
parameters214. These findings potentially reflect a level of pulmonary
vascular remodelling that is irreversible as seen in preclinical models38.
Therefore, absolute ID can promote or exacerbate pulmonary hyper-
tension, and these effects could contribute to worsening outcomes in
patients with HFpEF or COPD.
(PharmaNutra), have been suggested to have greater fractional absorp-
tion potentially because the slow release of iron blunts the subsequent
rise in hepcidin218–221. Fractional absorption is enhanced by alternate-day
dosing, which avoids sustained hepcidin elevation, and by dosing in
the early morning or in the evening when hepcidin levels are low222–224.
Malabsorptive disorders, such as coeliac disease and Crohn’s disease,
reduce fractional absorption, rendering patients refractory to oral iron
therapy225,226. The notion that inflammation blocks the absorption of
iron from oral iron supplementation by raising hepcidin levels provided
the rationale for the move towards intravenous iron therapies. However,
some evidence exists that this paradigm might not apply to individuals
with ID anaemia. Indeed, influenza and diphtheria–pertussis–tetanus
vaccinations were shown to raise hepcidin levels and decrease frac-
tional iron absorption from a 57Fe-labelled test meal in women without
anaemia but the vaccines had no effects on women with ID anaemia111.
These findings echo previous observations that anaemia breaks the
association between inflammation and hepcidin30,109.
In patients with HF, oral iron therapy often improves haemato-
logical and circulating iron parameters but its effects on functional
and clinical outcomes have not been consistent227–234. The conflict-
ing findings are likely to reflect differences between studies in the
total dose of iron delivered to the circulation that, in turn, depends
on whether the formulation has fast or slow release, the frequency of
dosing, and the presence and severity of inflammation and anaemia30,111.
Oral iron therapy seems to be less effective for preventing or treat-
ing acute blood loss anaemia, for example, in the setting of CABG
surgery234,235, than for chronic anaemia.
One underexplored question is the extent to which oral iron therapy
influences myocardial iron levels. In a mouse model of iron-refractory
ID anaemia (harbouring a deletion of the Tmprss6 gene, which encodes
transmembrane serine protease 6, causing excessive hepcidin produc-
tion), administration of sucrosomial iron corrected ID and restored
liver iron stores but did not increase myocardial iron levels220. By
contrast, in neonatal piglets with anaemia, oral administration of
ferrous glycine chelate increased myocardial iron levels by ~50%236.
Table 3 | Current definitions of iron deficiency
Population Ferritin Transferrin Refs.
(µg/l) saturation (%)
Healthy individuals
Adults (aged >20 years) <15 No cut-off 126
Children and adolescents (aged 5–20 years) <15 No cut-off 126

Iron supplementation in HF Infants (aged 0–5 years) <12 No cut-off 126

The balance between the benefits and harms of iron supplementation Pregnant women <15 <16 126,127
depends on whether therapies are given to individuals with a truly
Individuals with infection or inflammation
unmet need for iron and whether they meet that need in a timely and
safe manner. In this section, we examine findings from key clinical trials Adults (aged >20 years) <70 No cut-off 126

of oral and intravenous iron therapies in patients with HF (Table 5). Children and adolescents (aged 5–20 years) <70 No cut-off 126
Infants (aged 0–5 years) <30 No cut-off 126
Oral iron therapy
Individuals with kidney disease
Oral formulations differ according to the complexing ligand and the
amount of elemental iron they contain. However, these agents typically All individuals <500 <30 128
deliver ~100 mg of ferrous iron into the gut lumen, where uptake is Individuals with heart failure
dependent on DMT1, and fractional absorption of iron to the basolateral All individuals <100 No cut-off 129
side is 10–22%21,215,216. Tsat and serum hepcidin subsequently rise within
<300 <20
4 h and 8 h, respectively54,217. Novel formulations, such sucrosomial iron

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Box 1
Evolution of serum iron markers in chronic HF
The model is based on observational and longitudinal cohort studies
of patients with chronic heart failure (HF). The mechanisms at play
and the levels of serum iron markers change with disease progression
(see the figure).
NYHA class I
Adverse cardiac remodelling triggers inflammation (IL-6), which
increases hepcidin production. Serum ferritin levels are raised,
reflecting tumour necrosis factor (TNF) signalling and translational
de-repression of the ferritin transcript iron regulatory proteins (IRPs)
(caused by iron retention in macrophages).
NYHA class II
Adverse cardiac remodelling and worsening comorbidities sustain
inflammation and continue to stimulate hepcidin production.
However, a hepcidin-mediated drop in transferrin saturation
(Tsat) begins to exert negative feedback on hepcidin expression.
Consequently, iron retention in macrophages is partially relieved,
activating IRPs and causing translational repression of ferritin,
resulting in a relative decrease in serum ferritin levels.
NYHA class III
The now sustained lowering of Tsat restricts erythropoiesis
(as indicated by an increase in the soluble transferrin receptor
(sTFR) level), and the haemoglobin level begins to fall. Anaemia
stimulates the synthesis of erythropoietin and erythropoiesis in the
bone marrow, thus releasing erythroferrone. This hormone exerts
a dominant inhibitory effect on hepcidin, overcoming the IL-6
signal. The serum ferritin level drops, reflecting the shift from TNF
An important difference between the mouse and piglet studies is that
hepcidin was elevated in the mouse model (owing to the loss of trans-
membrane serine protease 6) and was probably suppressed in the piglet
model due to the dominant inhibitory effect of anaemia. This factor
raises the intriguing possibility that hepcidin not only modifies the
fractional absorption of oral iron but also its subsequent retention in
ferroportin-expressing tissues such as the myocardium.
Intravenous iron therapy
Clinically approved intravenous iron formulations deliver iron inside
a carbohydrate shell — disaccharide in iron sucrose, branched poly-
saccharide in iron dextran and ferric carboxymaltose (FCM), or linear
oligosaccharide in ferric derisomaltose (also known as iron isomalto-
side)237. Unlike oral iron, which delivers incremental increases in serum
iron levels, a single bolus dose of intravenous iron can deliver up to
1,500 mg of iron directly into the circulation. For example, FCM infu-
sion increases serum iron levels within 30 min, with Tsat subsequently
exceeding 90%57. Some intravenous iron formulations release iron in
two stages: first rapidly and directly into the circulation as NTBI and
then indirectly following breakdown and release by macrophages57,58.
The ESC guidelines advocate the use of intravenous iron therapy
in all patients with HF who meet its definition of ID129. Over the past
Nature Reviews Cardiology
stimulation to IRP-mediated translational repression of the ferritin
transcript in macrophages.
NYHA class IV
Worsening disease and comorbidities heighten inflammation, but
hepcidin is now dominantly suppressed by bone marrow-derived
erythroferrone and low Tsat. These circumstances enable iron to
be mobilized from the macrophages, resulting in IRP-mediated
translational repression of ferritin and a further drop in serum
ferritin level. Despite the low hepcidin concentration, Tsat
and serum iron remain low due to increased iron utilization by
the bone marrow, which is required to recover haemoglobin
synthesis.
Serum iron marker level
I II III IV
Worsening HF (NYHA class)
Heathy levels IL-6 and CRP Haemoglobin
sTFR Ferritin
Hepcidin Serum iron and Tsat
decade, the percentage of patients with HF and ID receiving intravenous
iron has grown to 19% in Sweden, 33% in Spain, 39% in France and 49% in
the UK232–242. Several trials have shown that intravenous iron administra-
tion reduces the risk of recurrent hospitalization for HF or cardiovas-
cular death and/or improves functional capacity (typically measured
by the 6-min walking test or peak VO2)243–255. However, some of these
benefits were not reproduced in other trials. In the placebo-controlled
HEART-FID trial255 of intravenous iron therapy (FCM) in patients with
HFrEF, a significance level of P = 0.01 was set to enable an assessment of
efficacy based on a single randomized trial. No sufficiently significant
improvements were identified in the hierarchical composite outcome
of death, hospitalization for HF or change in 6-min walking distance
with the use of intravenous iron (P = 0.02)255. The IRONMAN study252
of iron isomaltoside in patients with HFrEF did not identify signifi-
cant improvements in functional capacity despite reducing the risk of
hospital admissions for HF and cardiovascular death.
The divergent findings from these trials are likely to reflect the
collective effects of differences in the definition of ID, minimum hae-
moglobin concentration cut-off, the type and dose of iron formula-
tion, and the HF phenotype of the participants. In most trials, the ESC
definition of ID was used and, therefore, probably captured a mix
of patients with functional or absolute ID. In the IRONMAN trial252,
Review article
a ferritin cut-off of 400 µg/l was used and probably captured a greater
proportion of patients with functional ID, whereas Toblli et al. defined
ID as Tsat <20% and ferritin <100 ng/ml, which probably enriched
their study with patients who had absolute ID243,252. The type of ID is
relevant because it can influence HF prognosis. Indeed, low Tsat alone
or the combination of anaemia with high ferritin have been shown to
predict poor prognosis in HF256,257. Trials have also used various intra-
venous iron formulations known to have differing pharmacokinetic
properties. For instance, NTBI is low with iron isomaltoside, moderate
and more acute with iron sucrose, and high and more sustained with
FCM. This variation results in an area under the curve for NTBI that is
sevenfold greater for FCM than for the other two formulations57,58. The
distinct pharmacokinetics of these iron formulations have been dem-
onstrated in otherwise healthy volunteers with anaemia (absolute ID)
but have yet to be compared in the contexts of HF or functional ID57,58.
A minimum haemoglobin concentration cut-off (typically 8–9 g/dl)
was set in some trials but not others, meaning that the proportions
of patients with moderate or severe anaemia varied between studies.
These patients with severe anaemia typically have worse prognoses but
derive greater benefit from haemoglobin correction than those with
mild anaemia. The HF phenotype of participants also differed between
trials according to left ventricular ejection fraction threshold, use of
plasma markers and NHYA functional class243–255. Although seemingly
subtle, these variations would have resulted in different proportions
of patients with HFrEF and those with HFpEF, with correspondingly
distinct aetiologies and comorbidities.
Overall, the body of evidence indicates that some but not all
patients with HF derive benefits from intravenous iron therapy.
Responder analyses have identified low Tsat, diabetes mellitus,
impaired renal function, ischaemic heart disease and anaemia as pre-
dictors of those who will derive the greatest benefits from intravenous
iron therapy in terms of reducing recurrent hospitalization from HF and
cardiovascular death254. In patients who had undergone heart trans-
plantation within 1 year before study enrolment, those with ferritin
<30 μg/l or sTFR above the reference value had the greatest improve-
ment in peak oxygen uptake following intravenous iron therapy, and
this group also had significantly reduced hepcidin levels, consistent
with absolute ID258,259. One interpretation of responder analyses is that
different patient subgroups derive benefits through different path-
ways. For example, among patients with anaemia, the benefit is likely
to be mediated through haemoglobin correction, whereas in patients
without anaemia, fulfilment of an unmet need outside the erythron is
the probable mechanism. Conversely, the lack of a response to intra-
venous iron therapy in some patients suggests that their diagnosis of
ID does not reflect an unmet need for iron or that the unmet need is
not being adequately fulfilled by intravenous iron therapy. Future tri-
als need to be sufficiently powered to resolve differences in response
between absolute and functional ID as well as the modifying effects of
anaemia, inflammation and HF phenotype.
Mechanisms of benefit for intravenous iron
Improved myocardial energetics. Improvement in echocardiographic
parameters of heart function has been reported in some trials of intra-
venous iron therapy in HF260–262. In preclinical models, intravenous iron
therapy prevented the energetic impairment and contractile dysfunc-
tion caused by global or myocardial ID36,170. Improvements in energetics
could be the result of either increased oxygen delivery to the myocar-
dium due to improved haemoglobin concentration or increased oxygen
utilization following myocardial iron repletion165,166,263. Cardiovascular
Nature Reviews Cardiology
hyperpolarized MRI and phosphorus-31 magnetic resonance spectros-
copy should help to determine the effects of intravenous iron therapy
on myocardial energetics, including whether these effects manifest
before or after improvement in haemoglobin concentration.
Improved skeletal muscle energetics. Among patients with chronic
HFrEF (NYHA class ≥II) and ID, iron isomaltoside versus placebo was
found to improve phosphocreatine and ADP recovery half-times, rest-
ing respiratory rate and post-exercise Borg dyspnoea score at 12 weeks
after infusion264. FCM was also found to improve peak VO2 in a similar
timeframe, which was related to the extent of change in haemoglobin
level, and skeletal muscle iron content did not change166. Together,
these data suggest that the improvement in exercise capacity might
be driven by improved oxygen delivery rather than by iron repletion
to the skeletal muscle.
Improved respiratory and ventilatory functions. In patients with HFrEF,
anaemia and ID, FCM improved the hypercapnic ventilatory response
and sleep-disordered breathing within 2 weeks, with subsequent
Table 4 | Cardiovascular risk and related adverse outcomes
associated with ID
Population Findings Ref.
Risk of cardiovascular events
Oldera individuals Low serum iron predicts an increased risk of 156
first CVD in women only
Low serum iron predicts an increased risk of 158
acute MI and stroke
Individuals with high Low serum iron (but not Tsat or TIBC) predicts 159
cardiovascular risk an increased risk of MI in women only
Healthy individuals Lowest quintiles for serum iron and Tsat 160
predict highest risk of MI in the short term
Mixedb Serum iron and Tsat inversely related to the 161
risk of CHD; haem iron positively related to
the risk of CHD; ferritin shows borderline
positive association with the risk of CHD
Adverse outcomes after cardiovascular events
Patients discharged Absolute ID but not functional ID predicts an 9
from hospital after AHF increased risk of 30-day hospital readmission
Patients with STEMI Low serum iron predicts the risk of 14
developing HF regardless of ferritin or
haemoglobin
Patients with AHF Combination of low hepcidin and high sTFR 163
(excluding ACS) predicts the risk of death
Healthy individuals Lowest quartile for Tsat or serum iron 164
predicts the highest risk of death from IHD
Adverse outcomes in patients with CHF
Patients with HF Tsat <20% and serum iron ≤13 μmol/l predict 137
increased all-cause mortality over 5 years
Patients with systolic HF Low Tsat and low hepcidin (but not ferritin) 148
predict increased risk of 3-year mortality
ACS, acute coronary syndrome; AHF, acute heart failure; CHD, coronary heart disease;
CHF, chronic heart failure; CVD, cardiovascular disease; HF, heart failure; ID, iron deficiency;
IHD, ischaemic heart disease; MI, myocardial infarction; STEMI, ST-segment elevation
myocardial infarction; sTRF, soluble transferrin receptor; TIBC, total iron-binding capacity;
Tsat, transferrinsaturation. aMen aged 55–80 years, women aged 60–80 years. bMeta-analysis
of 21 prospective cohort studies.
Review article

Absolute ID Reduced serum Functional ID

• Depleted iron stores iron availability • Inflammation
• Increased iron demand (chronic disease,
• Blood loss infection)

Bone Kidney Lung epithelium

marrow
Iron accumulation
↓ Cellular iron uptake ↓ Haemoglobin ↓ Erythropoietin

Fibrosis

Impaired gas
exchange

↓ Oxygen delivery

Cellular iron Cellular hypoxia

depletion

Chronic activation Pulmonary

Endothelin 1 vasculature
of HIF signalling

Skeletal muscle Myocardium Pulmonary

Impaired ETC activity Impaired Glycolytic Impaired Ca2+ hypertension
myoglobin metabolism signalling
synthesis
Reduced oxidative
phosphorylation
Energetic
insufficiency

Reduced exercise Reduced cardiac ↑ Haemodynamic stress

capacity contractility

↑ HF hospitalization and mortality

Fig. 4 | Potential mechanisms linking ID with poor outcomes in HF. Interconnections between functional and absolute iron deficiency (ID), and the mechanisms
involving haemoglobin-dependent and haemoglobin-independent pathways. ETC, electron transport chain; HF, heart failure; HIF, hypoxia-inducible factor.

improvements in oxygen delivery to muscles and patient-reported
outcomes, particularly fatigue, when compared with placebo265.
In iron-deficient but otherwise healthy volunteers, FCM reduces PAP
and blunts the pulmonary vascular responses to hypoxia associated
with inhibition of the vasoconstrictor endothelin 1 (refs. 38,213). There-
fore, some patients with HF (such as those with pulmonary hyperten-
sion or COPD) might derive benefits from intravenous iron therapy via
improved respiratory and ventilatory functions.
Decongestion. Fluid congestion is common in CHF and is an independ-
ent predictor of prognosis. In the placebo-controlled FAIR-HF trial266
of 459 patients with CHF and ID, FCM reduced body weight and plasma
volume status (a novel index of congestion), which was associated with
improvements in 6-min walking distance and NYHA class. Plausible
mechanisms through which iron supplementation reduces plasma
volume status include improved renal function or a reduction in the
level of catecholamines that normally activate the pro-congestive
renin–angiotensin–aldosterone pathway.
Improved renal function. In some trials of intravenous iron therapy,
up to 40% of patients with HF had an estimated GFR (eGFR) consistent
with stage 3a CKD245,247. Patients with low eGFR were found to derive
greater benefits from intravenous iron therapy in terms of change in
6-min walking distance than those with normal eGFR. Furthermore,
in a subgroup analysis of the FAIR-HF trial245,246, FCM improved eGFR
after week 24. Therefore, in some patients, improved HF outcomes
might relate to improved renal function. Given the high prevalence
of CKD in patients with HF, more studies are needed to specifically
examine the interaction between CKD and HF in terms of intravenous
iron therapy outcomes.
Unresolved questions
The fate of intravenous iron. Intravenous therapies deliver a supra-
physiological dose of iron rapidly and directly into the circulation.
In healthy volunteers, MRI T1 values of the myocardium, liver, spleen
and skeletal muscle were all shortened (indicating a greater tissue
concentration of iron) within 60 min of FCM infusion267. In rats, the
MRI R2 relaxometry parameter increased (indicating a greater tissue
concentration of iron) in the liver, spleen and kidneys within 10–20 min
of iron sucrose infusion, only decreasing over 24 h in the kidneys,
probably reflecting renal iron reabsorption268. Importantly, there
were no changes in bone marrow or muscle R2 signals over this time
course268. The rapid increase in iron levels in some non-erythroid tis-
sues suggests direct circulatory uptake of the NTBI released from the
carbohydrate shell57,58. Evidence for the physiological consequences of
this process exists; in healthy volunteers, the hypoxia-induced rise in
PAP was blunted within 60 min of FCM infusion before any detectable
rise in haemoglobin level213.

Nature Reviews Cardiology

Review article
Table 5 | Effects of oral and intravenous iron therapies in HF
Study Formulation and dose
Oral iron
Crosby et al. Elemental iron 50 mg or
200 mg daily for 2 months
vs placebo
Clevenger Various oral iron formulations
et al. (meta-analysisa)
IRONOUT Oral iron polysaccharide
150 mg twice daily for 16 weeks or ferritin of 101–299 µg/l with
vs placebo
Zdravkovic Ferrous fumarate 115 mg twice
et al. daily for 6 months or ferric
hydroxide polymaltose 100 mg
twice daily for 6 months
Karavidas et al. Sucrosomial iron 28 mg daily
for 3 months vs no treatment
Suryani et al. Oral ferrous sulfate, 200 mg
three times per day for
12 weeks vs placebo
Oral vs intravenous iron
IRON-HF Intravenous iron sucrose
200 mg once per week for
5 weeks or oral ferrous sulfate
200 mg three times per day for
8 weeks vs placebo
Garrido-Martin Intravenous iron(III)-hydroxide
et al. sucrose complex three
doses of 100 mg per day
during preoperative and
postoperative hospitalization
or oral ferrous fumarate
iron 105 mg (one pill) per
day preoperatively and
postoperatively and for
1 month after hospital
discharge
Intravenous iron
Toblli et al. Iron sucrose 200 mg weekly for LVEF ≤35%, Tsat <20%, ferritin
5 weeks vs placebo
FERRIC-HF Iron sucrose 200 mg weekly
until ferritin >500 µg/l, 200 mg ferritin <100 μg/l or 100–300 μg/l
monthly thereafter for 16 weeks with Tsat <20%
vs no treatment
Nature Reviews Cardiology
Population
Patients undergoing CABG surgery 59 days
Adults with anaemia and without
CKD, including a subgroup with HF
HFrEF with ID (ferritin 15–100 µg/l
Tsat <20%)
Chronic DHF with ID (ferritin
<100 µg/l with Tsat <20%)
HFrEF with ID (ferritin <100 ng/ml
or ferritin 100–299 ng/ml with Tsat
<20%)
Patients with HFrEF and ID anaemia 12 weeks
(ferritin <100 µg/l or 100–300 µg/l
with Tsat <20%)
Patients with HF and anaemia
(ferritin <500 µg/l with Tsat <20%)
Patients undergoing CABG surgery 1 month
<100 µg/l
HF NYHA class II/III, LVEF ≤45%,
Follow-up Parameters improved Parameters not Ref.
duration improved
None Red blood cell 227
mass, ferritin
1 yeara ∆Haemoglobin (0.91 g/dl vs Mortality 229
1.04 g/dl (for parenteral iron));
requirement for blood transfusion
(RR 0.66 vs RR 0.84 (for parenteral
iron)) compared with inactive
control
16 weeks ∆Serum iron (effect of treatment Exercise 230
11 µg/dl); ∆Tsat (effect of capacity
treatment +3.3%); ∆sTFR
(effect of treatment –0.3 mg/ml)
6 months ∆Haemoglobin (10.45 g/l vs None 232
4.56 g/l); ∆Tsat (21.0% vs 23.4%);
∆6MWD (62.07 m vs 35.38 m);
NYHA class
3 months ∆Haemoglobin (0.37 ± 0.55 g/dl None 233
vs –0.21 ± 0.47 g/dl); ∆serum
iron (17.58 ± 11.73 mg/dl vs
−1.36 ± 8.68 mg/dl); ∆ferritin
(28.34 ± 31.39 ng/ml vs
−0.05 ± 6.97 ng/ml); ∆6MWD
(9.50 ± 15.83 m vs −3.00 ± 8.81 m);
∆KCCQ (4 ± 5 vs –1 ± 3)
∆Haemoglobin (1.0 g/dl vs –0.1 g/dl); None 234
∆ferritin (86 ng/ml vs 2 ng/ml);
∆Tsat (12.4% vs 3.0%), ∆6MWD
(46.23 ± 35.00 m vs –13.70 ± 46.00 m)
3 months ∆Haemoglobin (1.04 g/dl oral Peak VO2 228
vs 1.69 g/dl intravenous iron (oral iron)
vs 1.1 g/dl placebo); ∆ferritin
(126 µg/l oral vs 103 µg/l intravenous
iron vs –42 µg/l placebo); ∆peak
VO2 (3.5 ml/kg/min; intravenous
iron only)
Ferritin levels at hospital discharge Anaemia status, 235
(1,321 ± 495 ng/ml vs 541 ± 471 ng/ml transfusion
(intravenous iron only)) requirement
6 months LVEF (35.7 ± 4.7% vs 28.8 ± 2.4%); None 243
NYHA functional class (2.0 ± 0.2
vs 3.3 ± 0.6); 6MWD (240.1 ± 51.2 m
vs 184.5 ± 58.5 m); MLHFQ score
(41 ± 7 vs 59 ± 8)
16 weeks Ferritin (treatment effect 273 ng/ml); Haemoglobin 244
peak VO2 (treatment effect
2.2 ml/kg/min); NYHA functional
class (treatment effect –0.6)
Review article

Table 5 (continued) | Effects of oral and intravenous iron therapies in HF

Study Formulation and dose Population Follow-up Parameters improved Parameters not Ref.
duration improved

Intravenous iron (continued)

FAIR-HF Ferric carboxymaltose weekly
until repletion, then every
2 weeks during maintenance
phase vs placebo
CONFIRM-HF Ferric carboxymaltose
2–5 doses over 36 weeks
vs placebo
EFFECT-HF Ferric carboxymaltose up
to 3 doses over 12 weeks vs
standard of care
Dhoot et al. Ferric carboxymaltose single
dose vs placebo
AFFIRM-AHF Ferric carboxymaltose
2–4 doses over 24 weeks
vs placebo
IRONMAN Isomaltoside 1–9 doses over
20 months vs usual care
Mollace et al. Ferric carboxymaltose 500 mg
at 0 and 4 weeks vs placebo
HEART-FID Ferric carboxymaltose
2,316 ± 1,366 mg cumulative
dose over 3 years vs placebo
6MWD, 6-minute walking distance; CABG, coronary artery bypass graft; CHF, chronic heart failure; CKD, chronic kidney disease; DHF, decompensated heart failure; EQ-5D, European Quality
of Life – Five Dimensions; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; ID, iron deficiency; KCCQ, Kansas City
Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; MLHFQ, Minnesota Living with Heart Failure Questionnaire; NA, not available; sTFR, soluble transferrin receptor;
Tsat, transferrin saturation; VO2, peak oxygen consumption. aMeta-analysis examined outcomes at 1 year from 64 randomized controlled trials with various follow-up times.
CHF (NYHA class II/III), LVEF 24 weeks Haemoglobin (130 ± 1 g/l vs None 245
≤40%; minimum haemoglobin 125 ± 1 g/l); ferritin (323 ± 13 μg/l vs
cut-off 9.5 g/dl 74 ± 8 μg/l); Tsat (29 ± 1% vs 19 ± 1%);
6MWD (treatment effect 35 ± 8 m)
and quality-of-life assessments
(KCCQ and EQ-5D: OR 2.51 for
improvement)
CHF (NYHA class II/III), LVEF ≤45% 52 weeks ∆Haemoglobin (treatment effect None 247
and elevated natriuretic peptide 1.0 ± 0.2 g/dl); ∆ferritin (treatment
levels effect 200 ± 19 ng/ml); ∆Tsat
(treatment effect 5.7 ± 1.2%);
risk of recurrent hospitalization for
HF (HR 0.71); ∆6MWD (treatment
effect 36 m)
HF (NYHA class II/III), LVEF ≤45%, 24 weeks Haemoglobin (13.9 ± 1.3 g/dl vs None 248
elevated natriuretic peptide 13.2 ± 1.4 g/dl); ferritin (283 ± 150 ng/ml
levels, decreased exercise vs 79 ng/ml); Tsat (27 ± 8% vs
capacity, ferritin <100 μg/l or 20.2%); ∆peak VO2 (–0.16 ± 0.387
100–300 μg/l with Tsat <20% vs 1.19 ± 0.389 ml/min/kg); NYHA
class, patient global assessment
Symptomatic with CHF (NYHA 12 weeks Peak VO2 (14.9 ± 3.4 vs 12.9 ± LVEF 250
class II/III), ferritin <100 μg/l or 3.2 ml/min/kg); NYHA class (class I:
100–300 μg/l with Tsat <20%, 74.3% vs 48.6%, class II: 25.7%
minimum haemoglobin cut-off vs 51.4%); 6MWD (502.1 ± 70 m vs
8 g/dl 455.5 ± 52.3 m); MLHFQ (46.9 ± 15.7
vs 47.9 ± 15.1)
Patients hospitalized for acute HF 52 weeks ∆Haemoglobin (0.8 g/dl vs None 251
with LVEF <50%, ferritin <100 μg/l 0.3 g/dl); ferritin and Tsat (not
or 100–299 μg/l with Tsat <20%, reported numerically); risk of
minimum haemoglobin cut-off recurrent hospitalization for HF
8 g/l or cardiovascular death (RR 0.8)
New or established HF, LVEF 2.7 years Risk of recurrent hospitalization 6MWD 252
≤45% in preceding 24 months, (median for HF or cardiovascular death
ferritin <100 μg/l or Tsat <20% with follow-up) (RR 0.76)
minimum haemoglobin cut-off
9 g/dl
HFpEF with ID (ferritin <100 μg/l 8 weeks Group 1 only: ferritin (129.1 ± None 253
or 100–300 μg/l with Tsat <20%), 13.9 ng/ml vs 62.3 ± 12.4 ng/ml);
three groups according to degree 6MWD (354.4 ± 23.7 m vs
of diastolic function: group 1: E/e′ 294.7 ± 20.7 m)
ratio ≥15, group 2: E/e′ ratio 9–14,
group 3: E/e′ ratio ≤8
LVEF ≤40% and either 12 months NA Hierarchical 255
hospitalization for HF within the outcome that
previous 12 months or elevated included death,
natriuretic peptide levels, ferritin hospitalizations
<100 μg/l or 100–300 μg/l for HF and
with Tsat <20%, minimum 6MWD
haemoglobin cut-off 9 g/l in
women only

Regarding the long-term fate of iron, MRI studies in patients
undergoing dialysis showed that the iron concentration in the liver
(estimated by magnetic resonance T1 and T2*) was increased by iron
sucrose administration but not by FCM or iron isomaltoside administra-
tion, whereas the iron concentration in the spleen (estimated by R2*
relaxometry) was most increased by iron sucrose and iron isomaltoside
administration269. In patients with systolic CHF and ID, the MRI T2*
signal indicated that the iron concentration is increased in the heart,
liver and spleen but not in the skeletal muscle at 3 months after FCM
infusion166. In another study of patients with CHF and ID, MRI T2* val-
ues indicated an increase in cardiac iron concentration at 7 days that
persisted at 30 days, whereas T1 mapping showed an increase at 7 days

Nature Reviews Cardiology

Review article
that was lost at 30 days after FCM infusion263. The discrepant results of
these studies indicate that different MRI parameters reflect different
cellular iron pools, with T1 reflecting the labile cellular iron level that
rises early as a result of NTBI uptake, and T2* reflecting the totality of
cellular iron or that which is integrated in cellular ferritin stores or in
the mitochondria. Notwithstanding these technical considerations, the
short-term and long-term fates of various intravenous iron formula-
tions in non-erythroid tissues, where iron turnover is far slower than in
the erythroid tissue, warrant further investigation. This research will aid
our understanding of the basis and time course of any observed ben-
efits and identify dosing intervals that safeguard against cumulative
iron loading into non-erythroid tissues.
Inflammation and the response to intravenous iron. One of the reasons
for using intravenous rather than oral iron formulations in patients with
HF is to bypass the inhibitory effect of hepcidin on absorption in the
gut. However, hepcidin also controls iron efflux from macrophages,
which are responsible for the breakdown and release of most of the
iron from the carbohydrate shell. Consequently, elevation of serum
hepcidin levels would result in iron eventually becoming trapped in
macrophages (Fig. 5). This trapping could be compounded by the fact
that the intravenous iron itself induces a rapid and marked increase in
hepcidin level36,57. A study in which the homing of supplemented iron
was compared between rat models of ID anaemia and ACD supports this
idea270. In the absence of treatment, the liver and spleen of rats with ID
anaemia were iron depleted, whereas those of rats with ACD showed iron
retention in Kupffer cells in the liver and splenic macrophages. In rats
with ID anaemia, intravenous iron therapy reversed anaemia and resulted
in the appearance of iron in Kupffer cells and hepatocytes. By contrast,
intravenous iron therapy did not correct anaemia in rats with ACD and
resulted in iron retention in Kupffer cells but not in hepatocytes270.
One implication of these findings is that, in some patients, the rise
in ferritin levels after intravenous iron infusion reflects the extent of
iron trapping in macrophages (which are the primary source of serum
ferritin) rather than repletion of liver iron stores. Another concern
relates to the trapping of iron in lung epithelial cells and macrophages,
which has the potential to exacerbate lung fibrosis in patients with
both HF and COPD. Comparing macrophage iron trapping after intra-
venous iron therapy between patients with absolute ID and those with
functional ID will help to determine the extent to which macrophage
iron trapping relates to the recovery of haematological parameters
and the improvement in functional outcomes.
Safety of repeated intravenous iron dosing. Repeated dosing
with intravenous iron is increasingly being used to maintain ferritin
and/or haemoglobin levels in the normal range. In iron therapy trials
of patients with HF, the maximum cumulative dose of intravenous iron
resulting from repeated infusion ranges from 2 g to 13 g, equivalent
to between one and four times the total amount of iron in the body of
healthy individuals245,247,251–253. One pertinent question is why such a
large dose of iron is needed to maintain haemoglobin or ferritin levels in
the normal range in the absence of substantial blood loss. One possibil-
ity is that patients requiring repeated dosing are those in whom iron is
trapped in macrophages, potentially owing to a high hepcidin level, as
discussed previously270. Evidence from patients receiving dialysis sug-
gests that intravenous iron dosing regimens of ≥300 mg per month are
associated with increased mortality271,272. In patients with HF, repeated
iron dosing seems to be well tolerated in the timescale of the trials
(typically 6–20 months) but its long-term safety remains unexplored.
Nature Reviews Cardiology
One potential pathway for harm is cumulative myocardial iron
loading given that iron delivered to the myocardium persists there
for at least 3 months166. Redosing at shorter intervals could result in
prolonged myocardial exposure to NTBI that, in conditions such as
haemochromatosis and β-thalassaemia, underpins the development
of iron overload cardiomyopathy273,274. The interaction between intra-
venous iron and phosphate homeostasis is another important safety
consideration in the context of repeated dosing because of the risk
of sustained hypophosphataemia, subsequent hypophosphataemic
osteomalacia and its sequelae, including fractures275. Long-term moni-
toring of NTBI levels, phosphate levels and myocardial iron concentra-
tion should form part of future trials of intravenous iron therapy that
use repeated dosing regimens.
When intravenous iron should be avoided. Some evidence suggests
that intravenous iron therapy should not be used in the setting of
myocardial reperfusion (after myocardial infarction, percutaneous
coronary intervention or CABG surgery). In this setting, preclinical
models provide proof of concept that iron therapy promotes myo-
cardial ischaemia–reperfusion injury276,277. Moreover, in patients with
ST-segment elevation myocardial infarction, ID was found to be cou-
pled with smaller areas of myocardial ischaemia–reperfusion injury
and better in-hospital outcomes, whereas NTBI levels correlated with
markers of cardiac injury, particularly in patients with evidence of
microvascular obstruction and haemorrhage278,279. In CABG surgery,
iron chelation with desferroxamine was found to ameliorate lipid per-
oxidation and protect the myocardium against ischaemia–reperfusion
injury280. Accordingly, clinical and preclinical data support the notion
that pre-emptive or delayed iron supplementation might be safer than
acute supplementation281–287.
Another setting in which intravenous iron therapy might be det-
rimental is arrhythmias, including atrial fibrillation. Polymorphisms
associated with raised serum levels of iron, Tsat and ferritin are also asso-
ciated with an increased risk of atrial fibrillation288. Furthermore,
raised serum ferritin concentrations are associated with atrial fibril-
lation risk in the general population73. In patients with haemophilia A,
serial phlebotomy resulted in remission from symptomatic atrial
fibrillation289. Furthermore, arrythmias affect ~16% of patients with
haemochromatosis290,291. The mechanistic links between increased iron
levels and arrythmias seem to relate to abnormal calcium handling,
specifically the effects of iron on L-type calcium channels292–294. The
ongoing IRON-AF trial295 of intravenous iron therapy in patients with
atrial fibrillation and ID should provide insights as to whether iron
supplementation is beneficial or harmful in this setting. Finally, in
patients with HF and COPD, the potential for intravenous iron therapy
to compound lung iron loading and fibrosis should be considered.
Cost-effectiveness of intravenous iron. In the setting of CHF, analyses
in which the reduced risk of hospitalization and recurrent HF have been
considered suggest that intravenous iron therapy is cost-effective241,284.
However, no cost-effectiveness analyses have been performed on the
comparison between intravenous and oral iron therapy or factor-
ing in the financial cost and potential harm of repeated intravenous
iron dosing.
Opportunities in the management of ID in HF
Our understanding of iron homeostasis has grown rapidly since the
turn of the century, providing a mechanistic basis for the behaviour of
various iron markers, the physiological role of iron outside the erythron
Review article

Fig. 5 | The effects of inflammation

a No inflammation NTBI
on the fate of intravenous iron
Fe
supplementation. Comparison of
iron handling after intravenous iron
infusion between non-inflammatory
Spleen Liver Lung and inflammatory states. a, In non-
Alveolar
Splenic Kupffer inflammatory states, when hepcidin
Hepatocyte macrophage
macrophage cell is not elevated, iron delivered to
Lung
Fe Fe epithelium macrophages is readily mobilized
Fe ↑Fe
Fe into the circulation to meet demands
of the erythroid compartment as well
as those of the skeletal muscle and
myocardium, and any excess iron
Mobilization Mobilization Mobilization Storage Mobilization can become stored in hepatocytes,
where it is also readily mobilizable
when needed. b, In inflammatory
↑↑ Tf(Fe3+)
states, elevated hepcidin levels
prevent the mobilization of iron from
macrophages, causing iron trapping.
Ferroportin Iron can also become trapped in
↑Fe ↑Fe alveolar macrophages. At the same
Fe Transferrin
time, any iron stored in hepatocytes is
↑↑ Haemoglobin Myotubule Cardiomyocyte not mobilizable. Overall, iron trapping
TFR
in inflammatory states reduces the
Erythroblast Intravenous
Bone marrow Skeletal muscle Myocardium uptake of iron into the erythroid
iron drug
compartment, myocardial and skeletal
NTBI transporter
muscles, resulting in a poor response
Flux reduced in
to intravenous iron therapy. NTBI,
inflammation
b Inflammation NTBI non-transferrin-bound iron; Tf(Fe3+),
Fe transferrin-bound iron; TFR, transferrin
receptor.

Spleen Liver Lung

Alveolar
Splenic Kupffer Hepatocyte macrophage
macrophage cell
Lung
↑Fe ↑Fe epithelium
↑Fe
↑Fe

Hepcidin

No
No mobilization No mobilization mobilization No storage No mobilization

↑ Tf(Fe3+)

↑Fe ↑Fe

↑ Haemoglobin Myotubule Cardiomyocyte

Erythroblast
Bone marrow Skeletal muscle Myocardium

and the handling of exogenous iron in the body. This growing body of
knowledge presents various untapped opportunities to improve the
management of ID in patients with HF.
Improve interpretation of existing iron markers
In HF, the current ESC definition of ID does not predict worse prog-
nosis or a favourable response to iron supplementation137. Ferritin
in particular has proved to be a problematic iron marker due to its
inability to resolve true repletion of iron stores from macrophage iron
trapping255–257. Existing ferritin thresholds should be re-evaluated; for
instance, the ferritin values below which absorption increases can be
determined with isotopic iron tracing. Using this approach, Galetti et al.
found that a ferritin cut-off of 50 μg/l denoted “physiological iron defi-
ciency” in young women296. A similar strategy could be used to refine

Nature Reviews Cardiology

Review article
ferritin thresholds for individuals with varying degrees of inflammation.
Analysis of the ferritin light-to-heavy-chain ratio and its glycosylation
status could also improve the resolving power of ferritin62,63. Changes
in Tsat should be interpreted in the context of changes in both serum
iron and serum transferrin levels. The presence of liver injury, which
can cause both ferritin leakage and impairment of transferrin biosyn-
thesis, should also be considered64,79,80. Finally, as a shared regulator
of ferritin, transferrin and erythropoietin, TNF could prove useful in
distinguishing ACD from ID anaemia66,68,83,84.
Develop biomarkers of unmet iron need
sTFR is emerging as a promising marker of the unmet need for iron by
the erythron because it is derived from the shedding of TFR1 from the
surface of erythroblasts, where TFR1 expression is directly regulated
by IRP1 according to intracellular iron availability95,103,297. There are no
established biomarkers of the unmet need for iron outside the erythron.
The regulation of endothelin 1 by the iron status of pulmonary arterial
smooth muscle cells suggests that endothelin 1 should be explored
further as a candidate ID marker for the pulmonary circulation38,213.
Metabolomic and proteomic studies are warranted to identify circu-
lating biomarkers of the unmet need for iron in the myocardium and
skeletal muscle. In the meantime, iron quantification techniques based
on cardiac magnetic resonance T1, T2 and T2* (traditionally used for the
detection of iron overload) should be optimized to detect myocardial
iron depletion. This approach could be used to identify patients with a
truly unmet need for iron in the myocardium, guide dosing regimens
and safeguard against excess iron loading.
Re-evaluate oral and intravenous iron therapies
The benefits of oral iron therapies should be re-evaluated in the
light of updated guidelines on alternate-day dosing and the advent
of new slow-release formulations, such as sucrosomial iron, which
seem to be less sensitive than earlier formulations to the effects
of inflammation218,219. Intravenous iron therapies should also be
re-evaluated in the context of evidence for differential iron handling
in patients with absolute ID and those with functional ID as well as the
potential for macrophage iron trapping in the latter setting.
Develop alternatives to iron supplementation
An alternative approach to supplementing iron is to target the homeo-
static pathways that control iron levels and distribution in the body.
Normalizing hepcidin in functional ID would restore the ability of the
gut to absorb iron, unlock the iron that is trapped in macrophages and
hepatocytes, and allow tissues that express ferroportin (such as the
myocardium and pulmonary vasculature) to maintain normal homeo-
static control of the LIP35–38. Hepcidin levels can be normalized with the
use of some anti-inflammatory drugs; for example, those against IL-1 or
IL-6. The IL-1β inhibitor canakinumab has been shown to both reverse
and prevent anaemia in patients with previous myocardial infarction and
elevated CRP level. These effects were associated with a dose-dependent
reduction in hospitalization for HF and HF-related mortality298,299. Hep-
cidin was one of the most downregulated proteins in the active group
of a trial involving the IL-6 receptor antagonist tocilizumab in patients
with non-ST-segment elevation myocardial infarction143.
As an alternative to anti-inflammatory drugs, hepcidin could be
normalized by leveraging the dominant inhibitory effects of erythro-
poietin and erythroferrone. In healthy volunteers, microdosing with
recombinant human erythropoietin is sufficient to increase erythro-
ferrone levels and suppress hepcidin300,301. Erythropoietin could be
Nature Reviews Cardiology
used in conjunction with oral or intravenous iron supplementation
to meet the concomitant increase in erythroid iron demand, and this
combinatorial approach has been shown to be superior to iron therapy
alone in patients with HF and anaemia302,303. However, recombinant
erythropoietin has been linked with an increased risk of recurrent HF
and death304. Therefore, one alternative is to stimulate endogenous
erythropoietin production with HIF prolyl hydroxylase inhibitors
developed to treat anaemia. Indeed, molidustat has already been shown
to suppress hepcidin in patients with anaemia associated with CKD305.
Recombinant erythroferrone itself could be developed to normalize
hepcidin levels in functional ID, with the advantage that erythroferrone,
unlike erythropoietin, does not place additional erythroid demand on
iron resources and does not adversely affect HF outcomes. In preclini-
cal models, recombinant erythroferrone inhibits hepcidin, prevents its
induction by BMP6 and IL-6, and contributes to recovery from ACD29,30.
Finally, hepcidin could be targeted directly. One hepcidin antagonist
(PRS-080#22) has been tested in phase I trial in healthy volunteers and
in patients with CKD undergoing dialysis, with promising effects on iron
parameters306. In a primate model, this antagonist achieved sustained
hepcidin suppression and elevation of plasma iron markers307.
Conclusions
Having an unmet need for iron is detrimental in a broad range of cardio-
vascular conditions, particularly in HF. Although the unmet need for
iron by the erythron is readily diagnosed through measurement of hae-
moglobin and sTFR concentrations, diagnosis of the unmet needs for
iron by non-erythroid tissues remains extremely challenging. Current
circulating iron markers, although useful in the general population, are
much harder to interpret in patients with HF, because of the confound-
ing effects of inflammation and hypoxia, hepatic, renal and respiratory
comorbidities, and the use of certain medications. The shortcomings
of these markers in identifying those with a truly unmet need for iron
have probably limited the success of oral and intravenous iron thera-
pies in patients with HF and other cardiovascular conditions. Dissect-
ing, at a more fundamental level, the mechanisms and importance of
tissue-level iron control can help to identify biomarkers of an unmet
need for iron outside the erythron. These biomarkers would transform
the management of iron status, from a one-size-fits-all approach to
personalized strategies, tailored quantitatively and qualitatively to the
specific needs of each patient.
Until novel biomarkers are identified, existing iron therapies
should be re-evaluated in light of new data on the physiological han-
dling of iron supplements, including the effects of the type of formu-
lation and the speed of iron release on hepcidin, and the modifying
effects of anaemia and inflammation. This re-evaluation should also
consider the possibility that pathways of benefit differ between patients
according to the specific nature of their unmet need for iron. Equally
important is the identification of predictors of poor response to iron
supplementation to minimize repeated dosing of poor responders, for
which the availability of long-term safety data is limited. In functional
ID, greater attention should be given to approaches that can un-trap
iron such as targeting the inflammatory pathways that induce hepcidin
or leveraging the ability of the erythroferrone axis to overcome the
effect of inflammation on hepcidin. Cardiovascular medicine has led
the way both in the recognition of NAID as an important clinical target
and in embracing novel iron therapies and is therefore well placed to
tackle these future challenges and realize the untapped opportunities.
Published online: xx xx xxxx
Review article
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Acknowledgements
S.L.-L. is funded by MR/V009567/1/ from the Medical Research Council, UK, and by HSR00031
from the British Heart Foundation, UK.
Author contributions
S.L.-L. researched data for the article and wrote the manuscript. Both authors reviewed/edited
the manuscript before submission.
Competing interests
S.L.-L. reports receipt of previous research funding from Vifor Pharma, personal honoraria for
a lecture from Pharmacosmos, and consultancy fees from Disc Medicine and ScholarRock.
J.G.F.C. reports personal honoraria for lectures and advisory boards from Amgen,
AstraZeneca, Bayer, Novartis, Pharmacosmos, Servier and Vifor Pharma.
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Peer review information Nature Reviews Cardiology thanks Gavin Oudit, Gianluigi Savarese
and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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