Iron deficiency (ID) has been increasingly recognized
as an important co-morbidity associated with heart failure (HF). Irrespective
of anemic status, ID significantly impairs exercise tolerance and is an
independent predictor of poor outcomes in patients with HF. Routine screening
of ID is necessary in HF patients, and intravenous iron repletion has been
recommended by the American Heart Association HF treatment guidelines to
improve patient symptoms. Patients treated with intravenous iron show
improvement in quality of life, N-terminal pro-B-type natriuretic peptide levels,
6-minute walk test and New York Heart Association functional class. The effect
of iron therapy on HF re-hospitalization and mortality rate remains unclear. Large
dose oral iron treatment is found to be ineffective in improving HF patient
symptoms. This review summarizes the current knowledge on prevalence, clinical relevance,
and molecular mechanism of ID in patients with chronic HF and available
evidence for parenteral iron therapy.

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Heart failure

Iron deficiency



Iron therapy




Heart failure (HF) is a global epidemic with approximately 6
million adults being affected in United States alone (at a cost of about $20
billion per year). Despite the availability of new treatment strategies, the
incidence, hospitalizations and mortality associated with HF remains a big
health burden.1 In addition to increasing age,
the factors that contribute to poor prognosis in HF are the co-morbidities
associated with the disease. Iron deficiency (ID) has been increasingly
recognized as the important co-morbidity that contributes to increased
incidence, re-hospitalization and poor survival in patients with HF.2 Anemia is the ultimate
consequence of ID, but both these diseases represent distinct clinical
scenarios. Identification of ID in chronic diseases such as HF is of importance
as iron repletion has shown to improve patient symptoms irrespective of anemic



Iron is an essential micronutrient in all types of
cells, more importantly, in energy demanding cells such as cardiomyocytes.3
Iron acts as a co-factor for several enzymes involved in oxidative
phosphorylation and plays a key role in oxygen transport through
erythropoiesis. The etiology of ID in HF is not clearly understood – it could
possibly be due to multiple factors including poor iron absorption due to
edematous gastrointestinal tract, low bioavailability of iron, and chronic
inflammatory state present in HF.4  At the molecular level, one possible
mechanism of ID is related to hepcidin, an iron regulatory hormone, whose
synthesis is stimulated when iron stores or the cytokine, interlukin-6 (IL-6) levels
are elevated. In chronic inflammatory conditions, hepcidin levels are increased
owing to increased IL-6 and/or fluctuating iron levels. Elevated hepcidin results
in removal of ferroportin from the duodenal surfaces, a protein that increases iron
efflux into the bloodstream.5
However, in HF, a reverse mechanism exists: initially hepcidin level increases,
however, as HF progresses, hepcidin is downregulated maintaining ferroportin
levels thereby increasing iron efflux.6
The reason for this is still not clearly understood. Importantly, lower
hepcidin was associated with poor outcomes in HF patients. Another mechanism of
ID in HF is thought to be due to liver congestion7
that leads to increased hemosiderin laden macrophages. This results in
inappropriate stimulation of hepcidin which then increases iron stores
systematically. Importantly, cardiomyocytes have a high-energy demand and hence
are susceptible to ID. In patients referred to cardiac transplantation,
myocardial iron stores were lower compared to non-HF heart.8
HF patients also showed reduced myocardial oxygen respiration and reduction in
mitochondrial respiratory enzymes.9
In experimental models, the left ventricular cardiomyocytes with IRP (iron-regulatory
protein that maintains intracellular iron availability) depletion showed
reduced mitochondrial complex I activity and the mice were unable to increase ventricular
systolic function in response to dobutamine stress.10
Despite different possibilities for the mechanism underlying ID in HF disease,
it is quite not clear what is the exact underlying pathophysiology.



The prevalence of ID has been widely studied in
patients with chronic HF with reduced ejection fraction (HFrEF) and ranges
between 36 to 69% among different races.18
There were no differences between the percentages of anemic and non-anemic
subjects highlighting the fact that ID is prevalent independent of anemic
status. In patients presenting with acute decompensated HF (ADHF), the
prevalence of ID was much higher than chronic HF.15
A gender difference in the prevalence of ID in ADHF was shown by a study in
about 66% of men and 75% of women had ID. Independent correlates of ID in HF
include increased age, higher New York Heart Association (NYHA) functional
class, female gender, elevated N-terminal pro-B-type natriuretic peptide
(NT-proBNP), and high sensitivity C-reactive protein.2
The prevalence of ID in HFpEF is still unknown.



Heart failure with reduced ejection
fraction (HFrEF)

In patients with HFrEF, ID greatly decreases the
quality of life irrespective of the presence of anemia. Patients with
concurrent ID and HFrEF had lower peak oxygen consumption (peak VO2)
and increased ventilator response to exercise (VE-VCO2 slope) compared
to those without concurrent ID, both reflecting poor exercise capacity.11
Quality of life was significantly affected in HF patients irrespective of
diagnostic criteria: European Quality of Life-5D, Kansas City Cardiomyopathy or
the Minnesota Living with Heart Failure questionnaires.12
Short-term 6-month follow-up showed higher odds of death in patients with HF
and ID compared to patients with HF and no ID (8.7 vs 3.6% respectively, P