Download The influence of iron deficiency on the functioning of skeletal

REVIEW
European Journal of Heart Failure (2016)
doi:10.1002/ejhf.467
The influence of iron deficiency on the
functioning of skeletal muscles: experimental
evidence and clinical implications
Magdalena Stugiewicz1, Michał Tkaczyszyn2,3, Monika Kasztura2,
Waldemar Banasiak3, Piotr Ponikowski3,4, and Ewa A. Jankowska2,3,*
1 Students’
Scientific Association, Laboratory for Applied Research on Cardiovascular System, Department of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland;
for Applied Research on Cardiovascular System, Department of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland; 3 Cardiology Department, Centre
for Heart Diseases, Military Hospital, Wroclaw, Poland; and 4 Department of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
2 Laboratory
Received 30 June 2015; revised 16 October 2015; accepted 22 October 2015
Skeletal and respiratory myopathy not only constitutes an important pathophysiological feature of heart failure and chronic obstructive
pulmonary disease, but also contributes to debilitating symptomatology and predicts worse outcomes in these patients. Accumulated
evidence from laboratory experiments, animal models, and interventional studies in sports medicine suggests that undisturbed systemic
iron homeostasis significantly contributes to the effective functioning of skeletal muscles. In this review, we discuss the role of iron status
for the functioning of skeletal muscle tissue, and highlight iron deficiency as an emerging therapeutic target in chronic diseases accompanied
by a marked muscle dysfunction.
..........................................................................................................
Iron deficiency • Skeletal muscles •
Exercise intolerance
Heart failure •
Introduction
Skeletal and respiratory muscle dysfunction constitutes an important pathophysiological feature of heart failure (HF) and chronic
obstructive pulmonary disease (COPD), highly prevalent chronic
diseases, which account for a significant health and socio-economic
burden in developed countries.1 – 6 As skeletal and respiratory
myopathy worsens symptoms and outcomes in patients with
HF and COPD,3 – 6 it is plausible to consider muscle tissue
abnormalities as a co-target in the therapeutic process.
Functional abnormalities of skeletal and respiratory muscle tissue in HF and COPD correlate with structural derangements,
which occur at both histological and molecular levels, and have all
been described.7 – 10 Since the vast majority of abnormalities impair
muscle energetics, it is presumed that there may be a common
denominator for those derangements.
................................................
Keywords
Chronic obstructive pulmonary disease •
There is evidence that iron plays a critical role in the optimal
functioning of skeletal muscle tissue. It is an essential micronutrient for oxidative energy metabolism as well as numerous cellular
processes.11 The particular importance of optimal iron status is
well reflected by the fact that both iron deficiency (ID) and iron
overload are detrimental to the cellular machinery involved in
energy generation.12 Iron overload represents one arm of the
U-shaped curve describing the relationship between cellular vitality, energy generation capacity, and iron status, and its potential
for excessive generation of reactive oxygen species (ROS) has
already been discussed.13,14 In this review, we aimed to summarize the evidence on the relationship between ID and skeletal
muscle dysfunction, from the subcellular to macroscopic levels.
Further, we discuss the possible pathophysiological links between
ID and myopathy in HF and COPD, along with potential clinical
implications.
*Corresponding author. Laboratory for Applied Research on Cardiovascular System, Department of Heart Diseases, Wroclaw Medical University, Centre for Heart Diseases,
Military Hospital, ul. Weigla 5, 50-981 Wroclaw, Poland. Tel:/Fax: +48 261 660 661, Email: [email protected]
© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology
2
Skeletal muscle plasticity for ATP
utilization
The efficient functioning of skeletal muscle is directly related to
its intact energy metabolism because of the extraordinarily high
energy demand in comparison with other body tissues, such as
smooth muscle, liver, or even brain.15 Therefore, skeletal muscle must be highly specialized in generating ATP as an immediate source of energy and must also provide adequate flexibility to meet the challenge of dynamic changes of ATP utilization. Indeed, the substantial increase (up to 300-fold) in energy
turnover from the resting to the fully activated state occurs in a
matter of milliseconds.16 In contrast, muscles have to deal with
long periods of moderately increased energy consumption. These
large fluctuations in energy demand require the complex network
of interacting pathways of fuel metabolism which result in ATP
production.17 – 19
Fibre types and their energetics
The quintessential attribute of skeletal muscles that significantly
contributes to their multitasking is the co-existence of different fibre types which allows the same muscle to be used for
various tasks from posture maintenance to explosive movements in response to an unexpected threat. The presently
dominating classification system for human skeletal muscle is
based on the myosin heavy chain (MHC) isoforms and determines three major fibre types: I, IIa, and IIx.6,19 – 21 The slow
type I fibres have highly oxidative properties, such as high mitochondrial content and high activity of iron-dependent enzymes,
and thus they are adapted to long-lasting repetitive activities
such as locomotion or respiration.6,20 – 24 The fast glycolytic
type IIx fibres exhibit a high glycolytic capacity (generate ATP
mostly via glycolysis), and thus are required for rapid and
generally powerful actions.6,20 – 24 The fast oxidative type IIa
fibres take advantage of both oxidative metabolism and the glycolytic pathway, and therefore their susceptibility to fatigue is
intermediate.6,20 – 24
Energy store in skeletal muscle
The immediate energy source during muscle contraction is a
phosphate–phosphate bond present in ATP.16 Skeletal muscle demonstrates a relatively poor reserve (∼80 g) of this
energy currency, which is sufficient only for 1–2 s of mechanical effort and must be continuously re-synthesized at the
same rate as its consumption.25,26 Hence, there is a need
for efficient ATP restoration, which occurs via three main
mechanisms: short-term phosphocreatine (PCr) hydrolysis,
medium-term anaerobic glycolysis, and long-term aerobic oxidative
phosphorylation.16
........................................................................................................................................................................
Skeletal muscle: highly specialized
tissue with an extraordinarily high
energy demand
M. Stugiewicz et al.
Energy metabolism during strenuous
activity
Upon the stimulus of exercise, the initial pathway of ATP restoration relies on the hydrolysis of a high-phosphate substrate, a reaction catalyzed by creatine kinase (CK) which provides 16% of
energy currency generated via anaerobic pathways.27 In turn, PCr
re-synthesis carried out by the mitochondrial isoform of CK occurs
when ATP is in abundance under resting conditions.16,28
The fuel for an increased turnover of ATP during strenuous
exercise is provided by carbohydrate catabolism, namely by
the conversion of intramuscular glycogen and blood glucose.29
After an initial consumption of the energetically more efficient glycogen store,30 the contribution of blood glucose
becomes more appreciable and constitutes up to 35% of
oxidative metabolism and nearly 100% of muscle carbohydrate
metabolism.29
Energy metabolism during long-term
activity
Carbohydrate substrates can be metabolized via two pathways, namely anaerobic glycolysis and aerobic oxidative
phosphorylation.16 The first process occurs in the cytoplasm
and permits the high performance of skeletal muscle when
oxidative metabolism alone is not sufficient. As soon as the
oxygen supply is plentiful, the catabolism of the same substrates
results in more efficient ATP synthesis which is then performed
within the mitochondrial respiratory chain in the oxidative
pathway.16
Besides carbohydrate substrates, the second main fuel for muscle oxidative metabolism is fat.31 Being released from their stores in
adipose tissue and muscle, and metabolized in mitochondria, fatty
acids are the preferred fuel used for a sustained contractile function
in oxidative skeletal muscle.32
Critical role of optimal iron
availability for effective cellular
energy metabolism in skeletal
muscle
Systemic vs. local iron metabolism
in skeletal muscle
Recently, there has been great interest in skeletal muscle in the
context of iron metabolism, as this tissue contains 10–15% of iron
in the body.33,34 Iron is fundamental to oxidative metabolism in
skeletal muscle, both for efficient oxygen storage in myoglobin and
for an optimal activity of mitochondrial enzymes. Therefore, iron is
present in a larger amount in slow, ‘red’ fibres, which are common
in, for example, dorsal muscles, lower extremity extensors, the
diaphragm, and intercostal muscles.35
In general, one should differentiate systemic iron metabolism
from local iron metabolism. On the whole, systemic iron homeostasis is maintained by the co-ordination of its absorption in the
© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology
3
duodenum, recycling of senescent erythrocytes, and a mobilization
of iron stored in the liver. The role of skeletal muscle as a tissue
utilizing and storing iron, and possibly in secreting molecules
modulating systemic iron metabolism (haemojuvelin; HJV) may
be hypothesized (see below),36,37 but has not been proven yet
(Figure 1).
All major processes within systemic iron metabolism are
controlled by hepatic hepcidin (HAMP), the key iron regulatory
hormone.38,39 HAMP down-regulates a membrane iron exporter,
ferroportin, thus inhibiting iron efflux from iron-storing and
iron-distributing cells into the circulation, where iron travels
bound to transferrin (Tf). Hepatic HAMP expression is regulated by: (i) body iron load [through bone morphogenetic
proteins (BMPs) together with HJV);39,40 (ii) inflammation,
through interleukin-6 (IL-6) and IL-22;39 and (iii) erythropoietic activity.39 Although HAMP is produced predominantly
by hepatocytes, it can be detected in other tissues, including
skeletal muscle, where it participates in local iron regulation,
which is different from systemic regulation and not clearly
understood.
Molecules involved in skeletal muscle
iron metabolism and their potential
participation in systemic iron regulation
There is a substantial gap in the understanding of muscle-specific
iron regulation. Only recently has local iron metabolism in skeletal
muscle started to be explored. For example, Polonifi et al. examined skeletal muscle iron metabolism and confirmed the expression
of several genes implicated in four pathways: iron import, export,
storage, and regulation (for a detailed review of iron metabolism
genes in skeletal muscle, see Polonifi et al.41 and Sekyere et al.42 )
As mentioned before, little has as yet been unravelled regarding the mechanisms that control local iron regulation in skeletal
muscle. Since the expression of two main regulatory peptides,
namely HAMP and HJV, has been confirmed in skeletal muscle,37,41
the existence of tissue-specific translational iron regulation can be
assumed. Although the production of HAMP in skeletal muscle
is negligible (in comparison with hepatic production), some preliminary results indicate its potential contribution to local iron
regulation and immune response.43 HJV, on the other hand, is
greatly expressed in skeletal muscle. Although a comprehensive
study on its biogenesis has been performed, the role of muscle HJV
in skeletal muscle remains undefined.36 Since muscle-derived HJV
accumulates in extracellular fluid, it was proposed to influence hepatic hepcidin expression,37 but there is a need for in-depth research
to support this hypothesis.
Involvement of iron in cellular energetics
in skeletal muscle
Iron in skeletal muscle is of a particular importance for oxygen
reducing systems in order to provide efficient ATP production.
Oxidative energy generation takes place in mitochondria via
the mitochondrial respiratory chain composed of four complex transmembrane iron-containing enzymes [haem proteins
........................................................................................................................................................................
Iron deficiency and skeletal muscles
© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology
(cytochromes) and iron–sulfur cluster (ISC) proteins].12,28 Haem
is a part of the cytochromes in complexes III and IV, whereas ISCs
are incorporated into respiratory complexes I, II, and III.12,28
Mechanisms aiming to preserve normal
intracellular iron status
Since iron-deficient conditions result in impairment of many cellular
processes and iron-containing enzymes, a single cell should be
in possession of mechanisms that minimize detrimental changes.
Mammalian cells employ iron-regulatory proteins 1/2 (IRP1/2) that
constitute central regulators of adaptive intracellular response
to ID (for a detailed review of IRP1/2, see Andeerson et al.44 ).
Importantly, the expression of IRP in rat skeletal muscle has been
reported by Guo et al., and the levels of IRP2 in myocardial and
skeletal muscle tissues were reported to be the highest of all
examined tissues.45
Recent studies have revealed the existence of another
iron-regulatory pathway in mammalian cells, which involves
the protein called tristetraprolin (TTP). TTP is induced by ID
within a cell, and its presence is critical for cell survival in
low-iron states,13 presumably by suppressing iron-consuming
cellular processes, such as haem synthesis, the Krebs cycle
(KC), or the mitochondrial electron transport chain (ETC).
The limitation of the aforementioned processes may not be
beneficial in the context of energy generation.46 Although the
expression of TTP in skeletal muscle has been neither investigated nor proven to date, this pathway could potentially
contribute to deranged skeletal muscle cell energetics in the
course of ID.
Molecular effects of depleted iron
on skeletal muscle energetics:
evidence from in vitro and animal
studies
Multifaceted detrimental effects of ID for the organism in the context of skeletal muscles involve decreased productivity and exercise
capacity, and several alterations within the muscle tissue (Figure 2).
Experimental data from in vitro and animal studies reveal that skeletal muscle energetics suffer from iron depletion at different levels, from shifts in energy substrate preferences to subcellular and
molecular derangements, which result mostly in a decrement of
oxidative capacity (Figure 3).47 – 50
Changes in fuel selection
Several studies have demonstrated that the intracellular iron status
influences the fuel selection for muscle energy metabolism. For
example, the activity of a lactate dehydrogenase isoenzyme in
muscle of iron-deficient rats was increased as compared with
healthy controls, which indicated a clear shift towards anaerobic
metabolism upon ID in order to maximize muscle capacity.50 – 54
It is hypothesized that these biochemical changes may also result
4
M. Stugiewicz et al.
Liver
Skeletal muscle
HEPATIC
HEPCIDIN
MUSCLE
HEMOJUVELIN
+?
FPN
–
+/– ?
–
Fe3+ –Tf
FPN
Fe
FPN
Macrophage
MUSCLE HEPCIDIN
- possible regulator
of local iron
metabolism
FPN
Duodeum
Myocyte
in alterations in skeletal muscle fibre composition, namely an
oxidative to glycolytic shift, which has been demonstrated in
different muscle pathologies associated with diminished oxidative
capacity.55
Derangements in mitochondrial
morphology
Intracellular iron depletion also affects the morphology of mitochondria. Cartier et al. provided electron micrographs of muscle
from iron-deficient rats, demonstrating an apparent decrease in the
density of cristae of the mitochondrial inner membrane.48 Since
these structures contain specific binding sites for mitochondrial
enzymes involved in oxidative energy metabolism (i.e. complexes
III and IV) and in ISC biogenesis, such a change should not persist
without an impact on the organelle efficacy.56
Impaired oxidative metabolism
Iron defiency severely affects the performance of respiratory
chain enzymes. The activities of mitochondrial complexes I, II,
and IV, and the activity of the machinery responsible for ISC
....................................................................
Figure 1 The contribution of skeletal muscles to systemic and local iron regulation. Fe, iron; FPN, ferroportin; Tf, transferrin.
protein maturation as well as the concentration of mitochondrial cytochromes were reported to be dramatically decreased
in skeletal muscle of non-anaemic iron-deficient rats.47,48,50,51,57 – 60
Importantly, ID is also accompanied by a diminished pool of
myoglobin, an oxygen-binding protein found in muscle tissue.61
The concentration of the aforementioned globin was decreased
in predominantly slow- and mixed-fibre skeletal muscle from
iron-deficient rats.58
Activation of a key regulator of cellular
energy homeostasis (5’-AMP-activated
protein kinase)
Since ID constitutes an energy challenge for the cell, it induces
an activation of a major sensor of cellular energetic insults, a
5’-AMP-activated protein kinase (AMPK).59,62 Indeed, the aforementioned kinase was proven to be chronically activated in
iron-deficient rats.59 Since the chronic activation of AMPK is
known to increase the expression of a glycolytic enzyme, i.e. hexokinase II,63,64 the described mechanism is suggested to contribute
to an oxidative to glycolytic shift which occurs in iron-deficient
skeletal muscle tissue.
© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology
5
Iron deficiency and skeletal muscles
Populational
effects
Organism
Economic productivity
Overall physical work capacity
Aerobic capacity
Endurance capacity
Aerobic & endurance adaptation
after training
Tissue level
Cellular level
− Altered muscle fiber composition
(oxidative glycolytic shift)
Muscle mass
− Deranged mitochondrial
morphology
Number of mitochondria
Myoglobin pool
− AMPK activation
Glycolytic activity
Mitochondria
Oxidative metabolism
Iron-sulfur clusters synthesis
Density of mitochondrial cristae
Figure 2 Detrimental effects of iron deficiency on economic productivity, exercise capacity, and the functioning of skeletal muscle tissue.
AMPK, 5’-AMP-activated protein kinase.
© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology
6
M. Stugiewicz et al.
OXPHOS
E
E
E
OXPHOS
Myoglobin
KC
XPHOS
XP
HOS
OXPHOS
E
E
OXPHOS
Pyruvate
Pyruva
Pyr
uvate
uva
te
E
KC
KC
Glycolysis
Glu
Glucos
cose
e E
Glucose
Myoglobin
SUFFICI
SUFFICIENT IRON STORES
- Undisturbed oxidative metabolism
- Efficient oxidative PHOSPHORYLATION (OXPHOS)
AMPK
Myoglobin
E
E
Pyruvate
Pyruva
Pyr
uvate
uva
te
E
E
KC
Glycolysis
Glucose
Glucos
Glu
cose
e
AMPK
A
E
AMPK
IRON DEFICIENCY
Density of mitochondrial cristae (inner membrane)
- Shift towards anaerobic metabolism
- AMPK activation
Myoglobin
Glycolysis
Possible mechanism of myocyte
derangements in the course of iron
deficiency
Taking together all the changes that occur at different levels in a
muscle cell in the course of ID it can be generally concluded that
................
Figure 3 Structural and functional alterations of human striated muscle tissue associated with iron deficiency. AMPK, 5’-AMP-activated
protein kinase; KC, Krebs cycle; E, energy.
in a low-iron state, a myocyte shifts its main pathway of energy
generation from mitochondrial respiration to glycolysis. The
mechanism that governs this energetically unfavourable process
might comprise a regulatory pathway of local iron metabolism
which is critical to cellular energetics. Presuming the presence of
the recently discovered iron conservation mechanism also in a
© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology
7
muscle cell (see above), we might hypothesize that ID forces the
myocyte to limit processes with high iron expenditure, including
mitochondrial respiration.
Links between iron deficiency,
decreased exercise capacity,
and impaired skeletal muscle
performance: data from
experimental animal models
and human studies
Decreased exercise performance
in iron-deficient animals with and
without concomitant anaemia
Tissue oxidative capacity of skeletal muscles depends on an efficient activity of the mitochondrial enzymatic machinery involved
in oxidative phosphorylation, and determines predominantly the
endurance capacity (the ability to perform prolonged submaximal exercises).51,65,66 Maximal physical efforts and aerobic exercise
depend on oxygen-carrying capacity, which reflects adequate oxygen supply provided by haemoglobin.51,65,66 There is evidence from
experimental models that animals with iron deficiency anaemia
(IDA) demonstrate decreased aerobic capacity.50,65 – 69 In turn,
endurance capacity is reduced across all successive stages of progressive ID, either with or without concomitant anaemia.50,65 – 68
More than four decades ago, Edgerton et al.68 demonstrated
that rats made anaemic with an iron-deficient diet presented with
decreased exercise performance, and the subsequent repletion
of iron improved functional capacity along with an increase in
haemoglobin.68 Indeed, in several animal studies, low haemoglobin
concentration (in the course of IDA) correlated with reduced aerobic capacity.65 Importantly, some studies showed that the relationship may be non-linear,66 and factors other than decreased
haemoglobin may play a role.67 Nevertheless, studies on iron repletion in experimental animals with IDA further confirm an association between haemoglobin concentration and maximal oxygen
consumption (VO2max ).51
Regarding ID without anaemia, the experiments of Finch et al.50
are of a particular relevance. The authors compared the running
ability in dietary iron-deficient and control rats.50 In the first
experiment, the exchange blood transfusion procedure lowered
the haemoglobin concentration to 6 g/dL, which resulted in a
reduction of the running time in animals both with and without
previously induced ID.50 In the next experiment, the exchange
blood transfusion increased the haemoglobin level to 10 g/dL,
which improved the running ability in animals without ID, whereas
in iron-deficient rodents the running time remained reduced.50
Importantly, impaired work capacity in iron-deficient animals with
a restored haemoglobin level was thereafter quickly corrected
with iron therapy.50
Furthermore, Davies et al.51 monitored the effects of dietary
iron repletion in rats with severe IDA. The authors demonstrated
that the normalization of haemoglobin occurred earlier and was
........................................................................................................................................................................
Iron deficiency and skeletal muscles
© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology
accompanied by an increase in VO2max , whereas an improvement
in muscle oxidative capacity and muscle mitochondrial content
was delayed, and was associated with an increase in endurance
capacity.51
Iron deficiency, global exercise capacity,
and skeletal muscle performance
in humans
Links between ID, IDA, and decreased global exercise capacity have
been the subject of interest in the field of sports medicine.70 Data
from studies focusing on the effects of physical training suggest that
ID even without anaemia can negatively affect physical performance
in humans, which can be reversed by iron therapy.71 Burden et al.72
performed a meta-analysis of 17 trials regarding iron therapy in
non-anaemic iron-deficient athletes and have shown that such
therapy improves both systemic iron parameters and VO2max .72
Importantly, although in experimental animals ID negatively
impacts skeletal muscle functioning, analogous data regarding
humans are limited, and particular studies have yielded inconsistent
results. With regard to interventional studies, it has been shown
that beneficial effects of iron repletion in both untrained subjects
and athletes with ID but without anaemia comprise increased
endurance capacity and improved energetic efficiency.73 – 76 Conversely, some observational studies on IDA in humans have failed
to confirm the associations between ID and muscle dysfunction. For example, Thompson et al. investigated skeletal muscle
bioenergetics in women with IDA using 31 P magnetic resonance
spectroscopy, and have not documented significant mitochondrial abnormality.77 Furthermore, Celsing et al. investigated the
biochemical properties of skeletal muscle samples obtained from
subjects with chronic moderate to severe IDA and controls, and
have demonstrated that the maximal activities of glycolytic and
oxidative enzymes in these two groups were similar.78 Importantly,
the aforementioned studies were observational only and the study
groups were relatively small. Therefore, these studies may not be
sufficiently powered to identify subtle differences in the skeletal
muscle energetics between subjects with and those without ID.
Iron status, symptoms,
and functional capacity in patients
with chronic diseases
accompanied by skeletal and
respiratory myopathy
Skeletal and respiratory myopathy in the
course of heart failure and chronic
obstructive pulmonary disease
Skeletal and respiratory muscle dysfunction constitutes a common and important pathophysiological feature of both HF and
COPD.3,5,79 – 82 It contributes to debilitating symptomatology of
these disease syndromes (exercise intolerance), poor quality of
Correction phase: 200 mg of iron Maximum 24
i.v. weekly until repletion dose
weeks
is achieved. Maintenance phase:
200 mg i.v. iron every 4 weeks.
Randomized,
LVEF ≤40% and
Hb, 9.5–13.5 g/dL ID, serum ferritin
double-blind,
NYHA class II;
<100 μg/L or
placebo-controlled, LVEF ≤45% and
100–299 μg/L
multicentre study
NYHA class III
with TSAT
<20%
Correction phase: 200 mg iron
i.v. weekly until ferritin ≥500
mg/L. Maintenance phase: 200
mg iron i.v. every 4 weeks
16 weeks
Randomized,
Ferritin <100 μg/L, –
NYHA class II–III, Hb <12.5 g/dL
(anaemic group)
open-label,
or ferritin
peakVO2 ≤ 18
mL/min/kg, LVEF
or Hb
observer-blinded,
100–300 μg/L
12.5–14.5 g/dL
placebo-controlled, ≤45%
with TSAT
(non-anaemic
double-centre
<20%
group)
study
FCM i.v. (n = 150) vs.
placebo (n = 151)
Correction phase: 500–2000 mg Maximum 36
(dosed at baseline and week 6).
weeks
Maintenance phase: 500 mg at
each of weeks 12, 24, and 36, if
ID was still present
Maximum 12
days
5 weeks
Prospective,
NYHA class II-III,
uncontrolled,
systolic HF
open-label,
single-centre study
Hb <12.0 g/dL
No specific criteria ↑ 6MWT distance
CrCl, creatinine clearance; FCM, ferric carboxymaltose, Hb, haemoglobin, HF, heart failure; ID, iron deficiency; ISC, iron sucrose; 6MWT, 6-min walking test; peakVO2 , peak oxygen consumption; TSAT, transferrin saturation.
All patients (n = 16)
200 mg iron i.v. on days 1, 3, 5,
treated with ISC i.v.
and additional 200 mg on days
(no placebo arm)
15 and 17 if serum ferritin
<400 ng/mL on day 12
6. Bolger et al.111
200 mg i.v. iron weekly
ISC i.v. (n = 20) vs.
placebo (n = 20)
5. Toblli et al.112
–
Randomized,
LVEF ≤35%,
Hb <12.5 g/dL for Ferritin <100
↑ 6MWT distance
–
double-blind,
NYHA II–IV,
men and <11.5
ng/mL or TSAT
placebo-controlled, CrCl ≤90
g/dL for women
<20%
single-centre study
mL/min
...................................................................................................................................................................................................................
4. Ponikowski
et al.114 ,
CONFIRM-HF
study
Randomized,
NYHA class II or Hb <15.0 g/dL
ID, serum ferritin All patients: ↑
–
double-blind,
III, LVEF ≤45%,
<100 ng/mL, or
6MWT distance
placebo-controlled, BNP >100
100–300 ng/mL
(primary
multicentre study
pg/mL and/or
if TSAT <20%
endpoint);
NT-proBNP
anaemic patients:
>400 pg/mL
↑ 6MWT distance
...................................................................................................................................................................................................................
ISC i.v. (n = 24) vs.
placebo (n = 11)
All patients: ↑ peakVO2
per kg body mass
(secondary endpoint);
anaemic patients: ↑
peakVO2 per kg body
mass, ↑ absolute
peakVO2
...................................................................................................................................................................................................................
3. Okonko
et al.115 ,
FERRIC-HF
study
ISC i.v. + placebo p.o. Group 1: ISC 200 mg i.v. once a Iron/placebo i.v., Randomized,
2. Beck-da-Silva
LVEF <40%,
Hb: ≥9.0 and
TSAT <20% and
–
↑ peakVO2 per kg body
mass
(group 1, n = 10) vs.
week (30 min infusions) for 5
et al.116 ,
5 weeks;
double-blind,
NYHA class
≤12.0 g/dL
ferritin <500
IRON-HF study
ferrous sulfate p.o.
weeks + oral placebo three
iron/placebo
placebo-controlled, II–IV
μg/L
+ placebo i.v. (group
times a day for 8 weeks.
p.o., 8 weeks
multicentre study
2, n = 7) vs. placebo Group 2: ferrous sulfate 200 mg
p.o. + placebo i.v.
p.o. three times a day for 8
(group 3, n = 6)
weeks + i.v. placebo once a
week for 5 weeks.
Group 3: oral placebo three times
a day for 8 weeks + i.v. placebo
once a week for 5 weeks.
...................................................................................................................................................................................................................
1. Anker et al.113 , FCM i.v. (n = 304) vs.
FAIR-HF study
placebo (n = 155)
(+ subanalysis,
Filippatos
et al.117 )
↑ 6MWT distance
–
(secondary
endpoint, also in
anaemic and
non-anaemic
subjects,
separately)
...................................................................................................................................................................................................................
Study details
Results: 6MWT
Results: peakVO2
Duration of
Study design
Inclusion criteria Inclusion criteria Inclusion
Intervention: study Iron dosing scheme
criteria
iron therapy
regarding clinical regarding
arms with numbers
regarding
characteristics haemoglobin
of patients,
iron status
concentration
iron compound
...................................................................................................................................................................................................................
Table 1 Summary of studies investigating the effects of intravenous iron therapy without erythropoiesis-stimulating agents on indices of exercise capacity in
patients with heart failure
8
M. Stugiewicz et al.
© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology
9
life, and predicts worse outcomes.3,5,79,80,82 Skeletal muscle mass
and volume assessed in different body regions are decreased
in patients with HF,81,83 and muscles demonstrate increased
exertional fatigability.84,85 In histopathological evaluation, skeletal muscle tissue in HF demonstrates fatty infiltration, diminished capillary length density, fibre atrophy, and a shift regarding
fibre type distribution (from type I slow aerobic fatigue-resistant
fibres to type IIx fast glycolytic fibres vulnerable to fatigue; in a
diaphragm, the direction is opposite, i.e. IIx→I).6,80,86 – 88 Skeletal muscle tissue in HF is characterized by altered cellular fuel
homeostasis, namely a switch towards earlier glycolysis.7,89,90 Skeletal myocytes in HF also present with decreased size and number
of mitochondria, a diminished surface density of mitochondrial
cristae,83,86,91,92 a decreased oxidative capacity, an altered turnover
of high-energy phosphates,7,87,89,90,93,94 and decreased expression
of enzymes involved in different metabolic pathways.87,93
Similar abnormalities within skeletal muscles have been demonstrated in patients with COPD. COPD is characterized not only
by a generalized fat-free mass loss, but also by a decrease in
cross-sectional area of skeletal muscles.5,79,80,95,96 Histopathological examination of skeletal muscle tissue in COPD reveals
fibre atrophy79 and a fiber type distribution shift analogous to
that observed in HF.79,82,97 Mitochondrial abnormalities include
a decreased number and decreased fractional area of these
organelles,79 respiratory chain dysfunction, less efficient regeneration of high-energy phosphates, early exertional acidification,
and diminished oxidative metabolism of glucose along with an
enhanced glycolysis.5,77,79,98 – 100
Importantly, the precise pathomechanisms underlying skeletal
and respiratory myopathy in HF and COPD are not fully explained,
and striated muscle dysfunction is probably multifactorial, with
several overlapping factors.6,80,82 Recently, particular attention
has been paid to metabolic and hormonal derangements, which
favour catabolic–anabolic imbalance and are followed by marked
impairment of cellular energy metabolism.6,80,82,101 Additional
potential causes of skeletal myopathy developing in HF and COPD
include: local hypoxia and/or hypoperfusion, oxidative stress,
low-grade systemic inflammation, muscle disuse, a sedentary
lifestyle, administered medications, and nutritional deficits, to
name but a few.6,80,82 Importantly, one of the potential pathomechanisms contributing to muscle dysfunction in the course of chronic
diseases such as HF is ID.102
Iron deficiency as a potential cause
of skeletal and respiratory myopathy
in heart failure and chronic obstructive
pulmonary disease
Iron deficiency constitutes a frequent co-morbid condition in
patients with HF and affects 30–60% of them.103 – 105 In an international pooled cohort of >1500 European patients with HF, ID
affected 50% of subjects.104,106 Regarding COPD, only a few analogous data are available. Among 107 consecutive patients admitted to hospital due to an acute exacerbation of COPD, all 18
anaemic patients who had their systemic iron status assessed met
........................................................................................................................................................................................................................
Iron deficiency and skeletal muscles
© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology
the aforementioned criteria of ID.107 Further, in the second parallel part of the study, the authors assessed iron parameters in 12
ambulatory anaemic patients with COPD and diagnosed ID in 11
of them.107
Iron deficiency correlates with impaired functional capacity
in patients with HF, as assessed using peak oxygen consumption (VO2peak ) and ventilatory response to exercise (VE–VCO2
slope).108,109 In patients with systolic HF and concomitant ID,
intravenous110 iron therapy improves functional capacity as
assessed using distance in a 6-min walking test (6MWT)111 – 114
and VO2peak 115,116 (Table 1). Importantly, beneficial effects of
iron supplementation are reported irrespective of the presence
of anaemia.113 – 115,117 In two large randomized, double blind,
placebo-controlled clinical trials on intravenous ferric carboxymaltose in patients with HF and ID (FAIR-HF and CONFIRM-HF
trials113,114,117 – 119 ), iron therapy improved 6MWT distance in both
anaemic and non-anaemic subjects. Regarding COPD, the effects of
iron therapy on physical performance have not been investigated.
Skeletal and respiratory muscle dysfunction due to ID102 constitutes a potential pathophysiological link between impaired iron
status and decreased exercise capacity in patients with HF and
COPD. Nevertheless, there are no direct experimental or clinical data confirming that the clinical correlation between ID and
decreased exercise capacity in HF or COPD results from muscle
dysfunction caused by impaired iron homeostasis. Further studies are needed to establish pathophysiologial links between ID and
skeletal muscle dysfunction in these disease syndromes.
Conclusions
Accumulated evidence from physiological experiments in animals
and interventional studies in the field of sports medicine suggest that undisturbed systemic iron homeostasis significantly contributes to the effective functioning of skeletal muscles. Although
ID constitutes a frequent co-morbid condition in debilitating
chronic diseases such as HF, the hypothesis of whether disordered iron homeostasis favours or aggravates skeletal and respiratory muscle dysfunction has not yet been verified. Further studies
investigating pathophysiological links between ID and myopathy in
chronic diseases are therefore warranted.
Funding
This research was financially supported by the National Science
Centre (Kraków, Poland) grant allocated on the basis of decision
number DEC-2012/05/E/NZ5/00590.
Conflict of interest: Wroclaw Medical University received an
unrestricted grant from Vifor Pharma. E.A.J. reports grants and
personal fees from Vifor Pharma. P.P. reports grants and personal
fees from Vifor Pharma, and personal fees from AMGEN. All other
authors report no conflict of interest.
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© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology