Nephrol Dial Transplant (2005) 20 [Suppl 7]: vii7vii10

doi:10.1093/ndt/gfh1100

Anaemia and heart failure: aetiology and treatment

Marc W. Klutstein and Dan Tzivoni
Department of Cardiology, Jesselson Heart Center, Shaare Zedek Medical Center, Jerusalem, Israel

Keywords: anaemia; heart failure; prognosis;

renal failure; treatment

Leviticus 17:11: For the life of the esh is in the blood

Heart failure (HF) is a common and costly clinical
condition, associated with grave outcome. It is
estimated that the 1-year mortality rates for patients
with New York Heart Association (NYHA) class II, III
and IV are 10, 20 and 40%, respectively. Ischaemic
heart disease (IHD) and hypertension account for

Correspondence and offprint requests to: Dan Tzivoni, MD,

Professor of Medicine/Cardiology, Director, Department of
Cardiology, Shaare Zedek Medical Center, 12 Hans Beyth Street,
POB 3235, Jerusalem 91031, Israel. Email: cardio@szmc.org.il

most cases of HF in developed countries. HF is the

most common cause for hospitalization in patients
>65 years old, and its frequency increases with
increased age [1]. Several clinical and laboratory
markers identify patients with HF with worse outcome;
amongst them are advanced age, reduced ejection
fraction, presence of IHD, elevated lling pressure,
reduced exercise capacity [2] and elevated levels of
several inammatory cytokines such as tumour
necrosis factor (TNF)-a, C-reavtive protein (CRP),
interleukin-6 [3], naturietic peptides [4,5] and neurohormones [6]. In recent years, the presence of anaemia
has emerged as one of the important predictors of poor
outcome in HF patients. Anaemia is one of the most
common causes of increased cardiac output and, when
extremely severe, may result in HF due to a high output
state even in the absence of intrinsic heart disease.
Normally, 1 g of haemoglobin (Hb) binds 1.34 ml of O2.
When the Hb level is 15 g/dl, 100 ml of arterial blood
contains 20 ml of O2, while during mild to moderate
anaemia of 10 g/dl, the O2 content of 100 ml of blood
falls to 13.3 ml. A physiological compensation can be
achieved by an increase in cardiac output, enhanced
oxygen unloading from the Hb by a shift to the
right of the HbO2 dissociation curve, or by increased
erythropoietin production [7]. In the presence of
anaemia, when the need for greater cardiac output is
combined with decreased systolic and/or diastolic
performance, the clinical state of congestive HF may
develop or become aggravated.
The World Health Organizations denition of
anaemia is Hb <13 g/dl in men and <12 g/dl in women.
Horwich et al. [8] studied 1061 patients with advanced
HF (functional capacity III or IV) and left ventricular
ejection fraction (LVEF) <40%. The patients were
divided into four quartiles according to their Hb
levels <12.3, 12.313.6, 13.714.8 and >14.8 g/dl. Even
a small decrease in the Hb level was associated with
worsening of prognosis, with a 1-year survival of 55.6,
63.9, 71.4 and 74.4% in the different Hb quartiles. On
multivariate analysis, adjusting for known HF prognostic factors, low Hb proved to be an independent
predictor of mortality with a relative risk of 1.13 for
each decrease of 1 g/dl in Hb. It seems, therefore, that

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Abstract
Heart failure (HF) is a common disease associated
with poor prognosis. Anaemia is commonly associated
with HF due to bone marrow depression, reduced
availability of iron and haemodilution, and is sometimes aggravated by too frequent blood testing. Low
haemoglobin is very detrimental to the haemodynamic
state of the patient with decreased cardiac output as
it further diminishes the oxygen supply to the tissues.
When anaemia is associated with HF. and renal
failure, the patient enters a vicious cycle called cardio
renal anaemia syndrome. The prognosis of patients
with HF is worse as the haemoglobin is lower and
even mild anaemia is associated with <1 year survival.
Aggressive correction of the anaemia by subcutaneous
injections of erythropoeitin and intravenous iron has
been shown to improve the functional capacity and
quality of life of patients with cardio renal anaemia
syndrome and to reduce the need for hospitalization.
However, intravenous iron can be detrimental because
of increased formation of free radicals, oxidative stress
and risk of infection. The level of haemoglobin needed
to be achieved is not clear, but it seems indicated to
maintain it above 12 g%.

vii8

that anaemia is related to increased inammatory

activity.
Wexler et al. (this supplement), who performed
several pioneering studies on the frequency and
signicance of anaemia in HF patients, found that
anaemia is present in 40% of HF patients. This is
in concordance with the ndings of Lewis et al. [this
supplement], who reported an incidence of almost
50% of anaemia (dened as Hb<12 g/dl) in HF
patients. In the European Heart Failure Survey [16],
an Hb of <11 g/dl was found in 23% of the women
and 18% of the men. These authors suggest that in
HF patients, the main cause of the anaemia is the
renal damage caused by the reduced cardiac output.
Several other reports have demonstrated reduced
renal function in anaemic HF patients [3,17,18].
Ezekowitz et al. [18] analysed the data from a large
cohort of 12 065 patients hospitalized in Alberta,
Canada with new onset HF. Seventeen percent of
these patients were found to be anaemic, 58% of whom
had anaemia of chronic disease, 21% of iron deciency
and 8% of other causes. Anaemia was more common
in older patients, females, hypertensive or chronic
renal failure patients. The hazard ratio for mortality
was 1.34 in anaemic patients.
A major advance was made by Silverberg et al.
[1922] who corrected the anaemia of HF patients by
subcutaneous (s.c.) erythropoietin and intravenous
(i.v.) iron. In their rst and second reports, which
included 26 patients [19] and 179 patients [20],
respectively, the functional capacity improved by 34%
and the hospitalization numbers dropped dramatically
by 96%. In their randomized trial [21], which included
only 16 treated and 16 control patients, the improvement in exercise capacity, quality of life and renal
function was nevertheless remarkable. The functional
class improved by 42% in the treated patients and
worsened by 11% in the control group. In the rst
26 treated patients [22], an increase in LVEF from 27.7
to 35.4% was observed. The majority of these patients
had advanced renal failure with a mean serum
creatinine of 2.59 mg%.
Wexler et al. (this supplement) suggest that treatment
of anaemia in the HF patient can break the vicious
cycle of the cardio renal anaemia syndrome [14]
which in their opinion is crucial to the improvement
in response to the treatment of HF. If the anaemia is
not corrected, the extent of improvement, even with
an optimal treatment of HF, is limited. The benecial
effect of the correction of anaemia is probably
not related to protection from ischaemia, as silent
ischaemia was as common in 15 haemodialysis
patients treated with erythropoietin and normalized
Hb compared wih 16 control haemodialysis
patients [23].
Slotki, in an extensive review in the current supplement, discussed the risk of iron supplementation
in patients with HF and renal failure. The clinical
studies reported [2426] included only patients on
haemodialysis and it is not clear whether the risk of the
iron toxicity, namely free radical formation, oxidative

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even an Hb of 1213.6 g/dl should be considered

abnormal in patients with reduced cardiac function.
The aetiology of anaemia in HF is multifactorial,
including bone marrow depression and reduced availability of iron and heamodilution secondary to
sodium and water retention. As discussed by Lewis
et al. and Wexler et al. in the current supplement, HF
is accompanied by bone marrow depression, probably
due to chronic inammation with production of
proinammatory cytokines and induced erythropoietin
resistance [9]. The low iron level, due to reduced
content of iron in the diet and also reduced iron
absorption, is often present in patients with HF [10,11].
Witte et al. [12] explored the relationship between
levels of iron, B12 and folic acid levels. They measured
the Hb levels and exercise tolerance in 173 patients
with systolic dysfunction, 123 patients with diastolic
HF and 58 control patients. Thirty-ve percent of the
patients with systolic dysfunction, 33% of the patients
with diastolic dysfunction and four control patients
were anaemic. Exercise tolerance and peak oxygen
consumption during effort correlated with Hb levels.
There was no difference in the levels of iron, B12 and
folic acid among the different groups of patients.
Altogether, 6% had vitamin B12 deciency, 13% had
iron deciency and 8% folate deciency.
Anaemia can be also iatrogenic due to repeated
blood testing. Smoller et al. [13] studied 50 HF patients
who were hospitalized in intensive care units and found
that a volume of 762 ml of blood was withdrawn
during their hospitalization. It is clear that every blood
test should be ordered only if necessary and not only
by routine!
IHD is the most common cause of HF. Zeidman et al.
[14] compared 317 anaemic IHD patients with 50
anaemic patients without IHD and 50 IHD patients
without anaemia (control). Patients with combined
IHD and anaemia had more severe clinical presentations, with 44% presenting with acute coronary
syndrome and 36% with acute myocardial infarction,
compared with 26 and 20% in the group of IHD
patients with normal Hb levels. HF was more common
in IHD patients with anaemia compared with IHD
patients without anaemia (31 vs 18%). Mortality was
also signicantly higher in IHD patients with anaemia
(13 vs 4%). In their discussion, the authors raise the
possibility that the more severe clinical manifestation
is due to more severe chronic inammation, leading
both to anaemia and to more advanced atherosclerosis.
Recently, Iversen et al. [15] demonstrated a decreased
haematopoiesis in the bone marrow of mice with HF.
The HF mice had a 60% reduction in the amount of
progenitor cells compared with control mice. A 3-fold
increase in apoptosis was probably the reason for
the paucity in progenitor cells. As measured in vitro,
the proliferative capacity of progenitor cells in mice
with HF was only 50% of the control. The authors also
found that the expression of TNF-a was markedly
increased in bone marrow natural killer cells and T cells
and these lymphocytes exhibited increased cytolytic
activity against progenitor cells in vitro, indicating

M. W. Klutstein and D. Tzivoni

Anaemia and heart failure: aetiology and treatment

Conict of interest statement. None declared.

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stress and infection, can be applied to patients not on

haemodialysis.
Kurishev et al. [27] examined a model of iron
overload in Mongolian gerbils given repeated injections
of iron dextran. They noticed important electrophysiological changes: (i) the iron content of gerbil
ventricular myocytes was increased to amounts similar
to those found in patients with iron-induced cardiomyopathy; (ii) the overshoot and duration of the
cardiac action potential were decreased; and (iii)
sodium current was reduced and transient, outward
potassium current was increased. Schwartz et al. [28]
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Yang et al. [29], using the Mongolian gerbil model,
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left ventricular dp/dt were signicantly greater than
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concentric hypertrophy developed and cardiac output
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failure similar to patients with transfusional iron
overload. It is possible that treatment with erythropoietin by itself can be detrimental by worsening
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Topuzovic [30], while systolic function at rest and
during exercise remain unchanged.
In summary, anaemia is very common in HF
patients. It is frequently associated with renal failure
and, when present, it affects prognosis of these patients,
their quality of life and their response to treatment.
Aggressive correction of the anaemia with s.c. erythropoietin and i.v. or p.o. iron can improve the Hb levels
of these patients, their quality of life, their response
to medical therapy and, hopefully, though not yet
demonstrated, improve their prognosis. While the
level to which the anaemia should be corrected is not
clear, Hb probably should exceed 12 g/dl.

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