Heart Fail Rev (2008) 13:379386

DOI 10.1007/s10741-008-9088-8

Heart failure and anemia: mechanisms and pathophysiology

Inder S. Anand

Published online: 31 January 2008

Springer Science+Business Media, LLC 2008

Abstract Anemia is a common comorbidity in patients

with heart failure and affects up to 50% of patients,
depending on the definition of anemia used and on the
population studied. Presence of anemia and lower hemoglobin (Hgb) concentrations are powerful independent
predictors of adverse outcomes in heart failure. Even small
reductions in Hgb are associated with worse outcomes.
Correction of anemia may be useful in improving heart
failure outcomes. However, the causes of anemia in heart
failure are not entirely clear. Specific causes of anemia
such as hematinic abnormalities are seen only in a minority
of subjects. Renal dysfunction and neurohormonal and
proinflammatory cytokine activation appear to contribute
to anemia of chronic disease in the majority of the patients,
resulting in inappropriate erythropoietin production and
defective iron utilization. Under normal conditions,
reduced tissue oxygenation due to chronic anemia results in
non-hemodynamic and hemodynamic compensatory
responses to enhance oxygen carrying capacity. Erythropoiesis is the predominant non-hemodynamic response to
hypoxia, but because erythropoiesis is defective in heart
failure, hemodynamic mechanisms predominate. Hemodynamic responses are complex and involve a vasodilationmediated high-output state with neurohormonal activation.
The high-output state initially helps to increase oxygen
transport. However, the hemodynamic and neurohormonal
alterations could potentially have deleterious long-term
consequences and could contribute to anemias role as an
independent risk factor for adverse outcomes.

I. S. Anand (&)
Department of Medicine, University of Minnesota Medical
School, VA Medical Center 111C, Minneapolis,
MN 55417, USA
e-mail: anand001@umn.edu

Keywords Anemia
Heart failure
Erythropoietin

High output heart failure
Chronic kidney disease

Introduction
Although significant morbidity and mortality benefits have
been achieved in patients with chronic heart failure with the
introduction of beta-blockers and renin-angiotensin-aldosterone antagonists, heart failure remains a challenging
disease with an increasing incidence and a poor prognosis [1,
2]. Patients with heart failure often have large number of
comorbid conditions that contribute to worse long-term
outcomes. Identifying and treating these may help to further
reduce the burden of heart failure. Presence of anemia has
been recognized as an important and treatable comorbidity
that is common in patients with heart failure [311] and is
associated with adverse outcomes [411]. Early studies have
shown beneficial effects of empirically treating anemia in
heart failure patients with recombinant erythropoietin and
intravenous iron [1214]. However, little is know about the
pathogenesis of anemia in heart failure and the mechanisms
by which it may worsen heart failure.
In this review, the magnitude of the problem of anemia
in heart failure will be briefly discussed, factors that are
associated with the development and worsening of anemia
in heart failure will be reviewed, and the possible mechanisms that may worsen heart failure in patients with anemia
will be examined.
Clinical characteristics of anemic patients with heart
failure
As compared to heart failure patients who do not have
anemia, the anemic patients are more likely to be older,

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have diabetes, and chronic renal failure. These patients are

also more likely to have worse heart failure as indicated by
higher NYHA class, lower exercise capacity, worse quality
of life scores, greater peripheral edema, lower blood
pressure, higher use of diuretics and other cardiovascular
medications, worse neurohormonal profile and higher
inflammatory markers such as cytokines and C-reactive
protein (CRP) [3, 811, 1517]. In Val-HeFT, renal dysfunction, diabetes, peripheral edema, high BNP and CRP,
low serum albumen, low weight, and low diastolic blood
pressure were found to be independently associated with
the likelihood of anemia. Importantly, hemoglobin (Hgb)
was inversely related to ejection fraction in the few studies
where LV function was measured; patients with lower Hgb
had higher ejection fraction [7, 11, 18]. Moreover, spontaneous increase in Hgb over time in the Val-HeFT patients
was associated with a decrease in LV ejection fraction and
increase in LV size [11].

Causes of anemia in heart failure

Although the mechanisms for the development of anemia
in patients with heart failure are not entirely clear, several
factors may be involved.

Hematinic abnormalities
Abnormal serum levels of hematinics like vitamin B12 and
folic acid are seen in only a minority of anemic patients
with heart failure [15, 1921]. Intestinal function is often
abnormal in heart failure patients [22] and can lead to
malabsorption causing iron and other nutritional deficiencies [23]. Aspirin-induced gastro-intestinal bleeding could
also cause iron deficiency. Detailed investigations of iron
homeostasis in anemic HF patients are not available.
Because no standard criteria [i.e., transferrin saturation
(Tsat), soluble transferrin receptor (sTFR) or ferritin cut off
levels] were used, the reported prevalence of iron deficiency has varied in different studies. However, most
studies have found iron deficiency in only 5 to 21% percent
of patients [15, 1921, 24]. Recently, De Silva and colleagues reported that 43% of their anemic patients with HF
had either low serum iron (\ 8 lmol/L) or ferritin (\ 30
lg/L), but microcytic anemia was only seen in 6% patients
[25]. In contrast, in a small study on 37 severely ill patients
hospitalized for acute decompensated heart failure, Nanas
et al. [26] found depleted iron stores in the bone marrow of
73% patients, despite normal serum iron and ferritin. The
mean corpuscular volume was at the lower limit of normal
in these patients with a wide standard deviation suggesting
that microcytic anemia was not seen in all these patients.

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Heart Fail Rev (2008) 13:379386

Whether iron deficiency was the cause of anemia in these

patients is unclear. Moreover, these patients did not have
high serum erythropoietin or low ferritin as might be
expected with iron deficiency. As will be discussed later,
some of these findings could be explained by dysregulation
of iron homeostasis that diverts iron from the circulation to
the reticuloendothelial system so that serum iron and ferritin may be normal or increased but are not available for
erythropoiesis. This is a classical feature of anemia of
chronic disease [27]. Taken together, these studies suggest
either absolute or relative iron deficiency may be more
common than previously thought in anemic patients with
heart failure.

Renal dysfunction and impaired erythropoietin

production
Erythropoietin is a glycoprotein hormone that regulates
erythroid cell proliferation in the bone marrow in response
to tissue hypoxia. Erythropoietin is produced primarily in
the kidney by specialized peritubular fibroblasts that are
situated within the cortex and outer medulla [2830]. The
primary stimulus for erythropoietin production is reduced
oxygen tension at the level of the peritubular fibroblasts
where oxygen sensing is considered to occur. Low oxygen
tension activates hypoxia-inducible factor-1, which in turn
induces the transcription of the erythropoietin gene [31].
The kidney is very susceptible to hypoxia despite the fact
that it receives nearly 25% of the cardiac output and uses
less than 10% of the oxygen delivered. This is because
oxygen tension is remarkably inhomogeneous across the
renal parenchyma. In order to maintain the osmotic gradient
generated by the loop of Henle, the arterial and venous
blood vessels supplying it run countercurrent and in close
contact. This leads to shunt diffusion of oxygen between the
arterial and venous circulations, causing an oxygen gradient
across the renal parenchyma [29]. Consequently, oxygen
tension decreases with increasing distance from the surface
of the kidney, reaching around 10 mmHg at the tips of the
cortical pyramids where the oxygen sensing and erythropoietin producing cells are located. This remarkable design
makes this area very sensitive to small changes in the
oxygen tension resulting from the imbalance between
oxygen delivery and utilization. Oxygen delivery to this
region is determined by renal blood flow, hematocrit, and
the P50 of the Hgb oxygen-dissociation curve. Conversely,
oxygen consumption is determined by proximal tubular
sodium reabsorption, which is largely dependent on the
glomerular filtration rate (GFR).
Although there is extensive evidence for inadequate
erythropoietin production in chronic kidney disease (CKD),
the mechanisms remain unclear. Tubulointerstitial fibrosis,

Heart Fail Rev (2008) 13:379386

381

tubular loss, and vascular obliteration are probably the most

important factors that contribute to a decrease in erythropoietin producing cells [32]. In heart failure, the renal blood
flow is decreased [33], and approximately 50% of heart
failure patients have some renal dysfunction [3436]. These
findings lead to the suggestion that decreased renal erythropoietin production was the cause of anemia in heart
failure. In fact, erythropoietin levels are not low and are
often increased, in proportion to the severity of heart failure
but lower than expected for the degree of anemia, suggesting a blunted erythropoietin response [15, 3739]. Only
a few studies have examined the relation between renal
blood flow and erythropoietin in patients with heart failure.
Two studies, on a small number of patients, did find that
renal blood flow was an independent determinant of
erythropoietin secretion [40, 41]. More recently, however,
Westenbrink et al. [21] could not confirm this in a larger
subset of heart failure patients. The relation between renal
blood flow and erythropoietin production may be more
complex because many other factors affect erythropoietin
production in heart failure (Fig. 1). High levels of angiotensin II (AII) seen in heart failure reduce the oxygen supply
by decreasing renal blood flow. At the same time, AIIinduced decrease in GFR causes an increase in proximal
tubular sodium reabsorption that increases oxygen demand.
Hence, AII activation in heart failure stimulates erythropoietin production by reducing oxygen delivery at the level
of the erythropoietin producing cells. Several factors might
explain the finding that erythropoietin levels are inappropriate to the degree of anemia in heart failure. Perhaps the
most important factor is the role played by inflammation.
Tumor necrosis factor-a (TNF-a), its soluble receptors
(sTNF-R1 and sTNF-R2), interleukin-6 (IL-6), and several
other pro-inflammatory cytokines [15, 42], and circulating

neutrophils and CRP are increased in heart failure patients

[43] and are inversely related to Hgb [16, 44]. IL-6 and
TNF-a inhibit erythropoietin production in the kidney by
activating GATA-2 and NF-jB [45]. These cytokines also
directly inhibit the differentiation and proliferation of erythroid progenitor cells in the bone marrow [46, 47].
Moreover, IL-6 stimulates the production of the acute phase
protein hepcidin from the liver that inhibits the duodenal
absorption of iron [22]. Furthermore, IL-6 downregulates
the expression of ferroportin, preventing the release of iron
from body stores [48]. Thus, proinflammatory cytokines
may contribute to the development of anemia by several
mechanisms. However, whereas TNF-a, sTNF-R1, sTNFR2, and IL-6 were elevated in the anemic patients randomized in the Vesnarinone Heart Failure Trial, these
cytokines could explain only 5% of the variability in Hgb
seen in those patients [16].
Anemia and renin-angiotensin blockade
As discussed above, AII stimulates erythropoietin production in the kidney by decreasing oxygen tension. AII has
also been shown to directly stimulate the proliferation of the
erythroid progenitor cells in the bone marrow [49]. Use of
the angiotensin converting enzyme inhibitor (ACE-I)
enalapril was shown to cause a progressive decrease in
erythropoietin over a 48-week period in a clinical study
[50]. This may explain, in part, the modest reduction in Hgb
associated with the use of ACE-I and angiotensin receptor
blockers in heart failure [11, 51]. In addition, ACE-I prevent
the breakdown of the naturally occurring hematopoiesis
inhibitor N-acetyl-seryl-aspartyl-lysyl-proline [52] that
could also contribute to the development of anemia.
Therefore, the renin-angiotensin system appears to be closely involved in the control of erythropoiesis (Fig. 1).

Chronic Heart Failure

Neurohormonal Activation

Hemodilution
Renal blood flow GFR

PO2 peritubular fibroblasts

+ve
Proinflammatory
Cytokines

GATA-2/NF-B

-ve

EPO

Angiotensin II

-ve

+ve
Hepcidin

-ve

Bone marrow
erythroid progenitor cells

ACE-I/ARB

-ve

-ve
Iron Stores

AcSDKP

Anemia may be a consequence of hemodilution from an

increase in plasma volume [21, 53]. Androne et al. [53]
found that nearly half the patients referred for cardiac
transplant, who were clinically euvolemic, had hemodilution-induced pseudoanemia. However, others have
found that patients who are clinically euvolemic have
normal plasma volume [54, 55]. In any case, it is questionable whether pseudoanemia should or could be treated.

RBC mass

Fig. 1 Role of neurohormonal and proinflammatory activation in the

pathogenesis of anemia in heart failure

Anemia of chronic diseases

The above discussion suggests that although multiple
mechanisms could cause anemia in patients with heart

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failure, a treatable cause of anemia is often not identified in

the majority of the patients. In a large cohort of community-dwelling patients with anemia and heart failure, 58%
patients were reported to have anemia of chronic disease,
on the basis of ICD-9 (285.9) codes alone [24]. However,
evidence supporting the presence of anemia of chronic
disease was not available. Recently, Opasich et al. [15]
have provided conclusive evidence of the existence of
anemia of chronic disease in heart failure. These authors
studied 148 well-characterized patients with stable heart
failure and anemia. A specific cause of anemia including
CKD, iron, folic acid, vitamin B12 deficiency, and bthalassemia could be identified in only 43% cases. In the
vast majority of the remaining 57% patients, they found
proinflammatory cytokine activation, inadequate erythropoietin production, and/or defective iron utilization despite
adequate iron stores, suggesting anemia of chronic disease
[27]. Therefore, anemia of chronic disease appears to be
the most frequent cause of anemia in heart failure and a
rational approach to its correction may involve the use of
erythropoiesis stimulating agents.

Heart Fail Rev (2008) 13:379386

(2,3-DPG) shift the Hgboxygen dissociation curve to the

right, which increases the P50, decreases the affinity of Hgb
for oxygen, and improves oxygen delivery to the tissues. In
chronic anemia, the red blood cell (RBC) concentration of
2,3-DPG is increased and the Hgboxygen dissociation
curve is shifted to the right [58, 59]. A right-shifted curve is
the least energy-consuming mechanism to support
increased oxygen delivery to the tissues without a significant increase in cardiac output. 2,3-DPG is a metabolic
intermediate of RBC glycolysis and is quantitatively the
most important organic phosphate regulating oxygen
affinity in erythrocytes [60]. The activity of many RBC
glycolytic enzymes and therefore the concentrations of 2,3DPG and ATP are largely dependent on the age of the
erythrocyte. Enzyme activity is especially high in young
RBCs and decreases with increasing cell age. Consequently, young erythrocytes have a right-shifted oxygen
dissociation curve and a steeper curve slope, which further
adds to the effectiveness of oxygen unloading [61].

Hemodynamic mechanisms to maintain oxygen delivery

in anemia
Compensatory mechanisms and pathophysiological
consequences of anemia
Reduced tissue oxygenation due to chronic anemia results
in non-hemodynamic and hemodynamic compensatory
responses. Non-hemodynamic responses to hypoxia
include increase in erythropoiesis to enhance oxygen carrying capacity, as well as changes in the Hgboxygen
dissociation curve, which decreases the affinity of Hgb for
greater oxygen delivery to the peripheral tissues. Hemodynamic responses are more complex and involve a
vasodilation-mediated high-output state with neurohormonal activation [56]. The high-output state initially helps
to increase oxygen transport [57]. However, the hemodynamic and neurohormonal alterations could potentially
have deleterious long-term consequences and contribute to
anemias role as an independent risk factor for adverse
outcomes [411].

Non-hemodynamic mechanisms to maintain oxygen

delivery in anemia
Hgboxygen dissociation curve
A change in the affinity of Hgb for oxygen is a rapid and
reversible process allowing for immediate adjustments of
oxygen binding and oxygen release at the periphery. Hgb
oxygen dissociation is influenced by several factors. A low
pH and high concentrations of 2,3-diphosphoglycerate

123

The initial hemodynamic response to anemia is a fall in

systemic vascular resistance [56, 62], which is partly due to
the decrease in blood viscosity and in part, the result of
enhanced nitric oxide-mediated vasodilation [62, 63]. The
decrease in systemic vascular resistance reduces blood
pressure and causes a baroreceptor-mediated neurohormonal activation [56], identical to that seen in patients with
severe low output heart failure [33, 64]. The increased
sympathetic and renin-angiotensin-aldosterone activity
cause peripheral vasoconstriction and decrease in renal
blood flow and GFR. The kidneys start to retain salt and
water resulting in an expansion of the extracellular and
plasma volume. The combined effects of volume expansion
and vasodilation lead to a significant increase in cardiac
output [56]. While these may be useful short-term compensatory responses, over time pulmonary and systemic
venous congestion occur, resulting in the clinical syndrome
of heart failure. In animal models of anemia, increased
hemodynamic load and chronic elevation of catecholamines and AII have been shown to cause LV hypertrophy,
increase in LV mass and LV dilation [6567]. Correction
of anemia in patients with normal LV function causes a
rapid and complete regression of the syndrome of high
output heart failure [56, 62]. However, correction of anemia in patients with depressed LV function is unlikely to
improve LV ejection fraction given the inverse relationship
between Hgb and LV ejection fraction. The possible
sequence of events in the pathogenesis of heart failure in
patients with anemia is shown in Fig. 2.

Heart Fail Rev (2008) 13:379386

383

Pathophysiology of Fluid Retention in

Chronic Severe Anemia
C h ro n i c S e v er e A n e m ia
Worsening
Heart Failure

Peripheral vasodilation

Blood pressure
Work load
LV Mass
LV Remodeling
LV Dysfunction

Extracellular volume
Plasma volume

Neurohormones
SNS
RAAS
Natriuretic peptides
AVP
Renal blood flow
GFR
Salt and Water Retention

Fig. 2 The possible sequence of events in the pathogenesis of anemia

and heart failure [56]

Why is anemia associated with poor outcomes

Anemia and low Hgb have consistently been shown to be
independently associated with the increased risk of mortality in acutely decompensated and chronic heart failure
patients with both impaired [4, 5, 711, 24, 68, 69] and
preserved LV function [7, 6972]. Anemia increased the
risk of death in these studies by 2050%. The mechanisms
linking anemia to increased mortality and morbidity are not
entirely clear but are likely to be complex and multifactorial. Increased myocardial workload to compensate for
reduced tissue oxygen delivery and volume overload can
lead to unfavorable LV remodeling with LV hypertrophy
and dilation that may contribute to adverse outcomes [73].
Whereas LV hypertrophy is consistently seen in CKD
patients with anemia [74], it is unclear whether it is related
to anemia or the associated hypertension [75]. Treatment of
anemia with erythropoiesis stimulating agents has, however, not shown to reverse LV hypertrophy in several
clinical trials [7678]. This may be related to the development of irreversible myocardial fibrosis [79]. There are no
clinical data linking LV hypertrophy and anemia in heart
failure, and it is not known whether correction of anemia
reverses LV hypertrophy. However, in a substudy on heart
failure patients enrolled in the RENIASSIANCE trial, a 1 g/
dl spontaneous increase in Hgb over a period of 24 weeks
was associated with a 4.1 g/m2 decrease in LV mass [10].
As mentioned before, patients with lower Hgb tend to have
a higher LV ejection fraction [7, 11, 18]. Moreover, whereas
BNP, a marker of LV dysfunction is related to anemia and
change in Hgb over time, anemia remains an independent
predictor of adverse outcome in the presence of BNP,
suggesting that these variables may have their effect
through different mechanisms [11]. Taken together, these
findings suggest that LV dysfunction may not be directly
involved in the pathogenesis of worse outcomes in anemia.

Chronic kidney disease is a common comorbidity in

heart failure, and anemic patients are more likely to have
CKD [9, 35, 80]. A number of studies have shown that
anemia and renal dysfunction remain independent predictors of outcomes in multivariate models. [7, 9, 11]. The
relative risk of death at 2 years was increased by a factor of
1.6 in anemic patients with heart failure who also had CKD
in a large Medicare database [81]. In addition, anemia is
often a marker of poor nutritional status and is associated
with low albumin [7, 11] and cardiac cachexia [82], both of
which are related to worse outcomes. Finally, anemic
patients are more likely to have worse neurohormonal and
proinflammatory cytokine profile that may also contribute
to worse outcomes [16, 44]. Thus, anemia may be related
to a worse prognosis through multiple mechanisms.
In conclusion, anemia is a common comorbidity in
patients with heart failure and is associated with worse
long-term outcomes. Although the mechanisms involved in
the genesis of anemia in heart failure are not clear, the
weight of evidence suggests that renal dysfunction, and
neurohormonal and proinflammatory cytokine activation in
heart failure favors the development of anemia of chronic
disease. Similarly, the mechanisms by which anemia
worsens heart failure outcomes are also unknown.
Increased myocardial workload associated with anemia can
lead to LV hypertrophy and LV dilation. In patients with
normal LV function, severe anemia leads to a vasodilationmediated high-output state with fluid retention that rapidly
reverses with the correction of anemia. Because increase in
Hgb is associated with an elevation in the systemic vascular resistance, it is unlikely that correction of anemia will
improve impaired LV function, and there are no data to
show the LV hypertrophy regresses on increasing Hgb in
heart failure patients. However, uncontrolled studies have
shown beneficial effects of treating anemia in patients with
heart failure [12, 13, 83]. Further studies are therefore
required to understand the basis of the remarkable association of anemia with heart failure mortality and morbidity,
to prospectively assess the potential benefit of correcting
anemia, and to evaluate the ideal threshold at which therapy should be initiated and the extent of correction
considered safe and desirable in the individual patient with
heart failure. In one such study, darbepoetin alfa is being
tested in Reduction of Events with Darbepoetin alfa in
Heart Failure (RED-HF) trial, a large-scale, phase III
morbidity and mortality trial [84].

References
1. Disease Statistics (2005) NHLBI FY 2005 Fact Book: 3756
2. Rosamond W, Flegal K, Friday G et al (2007) Heart disease and
stroke statistics2007 update: a report from the American Heart

123

384

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

Heart Fail Rev (2008) 13:379386

Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 115(5):e69e171
Komajda M (2004) Prevalence of anemia in patients with chronic
heart failure and their clinical characteristics. J Card Fail 10(1
Suppl):S1S4
Kosiborod M, Smith GL, Radford MJ et al (2003) The prognostic
importance of anemia in patients with heart failure. Am J Med
114(2):112119
Mozaffarian D, Nye R, Levy WC (2003) Anemia predicts mortality in severe heart failure: the prospective randomized
amlodipine survival evaluation (PRAISE) J Am Coll Cardiol
41(11):19331939
Tang YD, Katz SD (2006) Anemia in chronic heart failure:
prevalence, etiology, clinical correlates, and treatment options.
Circulation 113(20):24542461
OMeara E, Clayton T, McEntegart MB et al (2006) Clinical
correlates and consequences of anemia in a broad spectrum of
patients with heart failure: results of the candesartan in heart
failure: assessment of reduction in mortality and morbidity
(CHARM) program. Circulation 113(7):986994
Horwich TB, Fonarow GC, Hamilton MA et al (2002) Anemia is
associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients
with advanced heart failure. J Am Coll Cardiol 39(11):1780
1786
Al-Ahmad A, Rand WM, Manjunath G et al (2001) Reduced
kidney function and anemia as risk factors for mortality in
patients with left ventricular dysfunction. J Am Coll Cardiol
38(4):955962
Anand I, McMurray JJ, Whitmore J et al (2004) Anemia and its
relationship to clinical outcome in heart failure. Circulation
110(2):149154
Anand IS, Kuskowski MA, Rector TS et al (2005) Anemia and
change in hemoglobin over time related to mortality and morbidity in patients with chronic heart failure: results from ValHeFT. Circulation 112(8):11211127
Mancini DM, Katz SD, Lang CC et al (2003) Effect of erythropoietin on exercise capacity in patients with moderate to severe
chronic heart failure. Circulation 107(2):294299
Silverberg DS, Wexler D, Blum M et al (2000) The use of subcutaneous erythropoietin and intravenous iron for the treatment of
the anemia of severe, resistant congestive heart failure improves
cardiac and renal function and functional cardiac class, and
markedly reduces hospitalizations. J Am Coll Cardiol
35(7):17371744
Silverberg DS, Wexler D, Sheps D et al (2001) The effect of
correction of mild anemia in severe, resistant congestive heart
failure using subcutaneous erythropoietin and intravenous iron: a
randomized controlled study. J Am Coll Cardiol 37(7):17751780
Opasich C, Cazzola M, Scelsi L et al (2005) Blunted erythropoietin production and defective iron supply for erythropoiesis as
major causes of anaemia in patients with chronic heart failure.
Eur Heart J 26(21):22322237
Anand IS, Rector T, Deswal A et al (2006) Relationship between
proinflammatory cytokines and anemia in heart failure. Eur Heart
J 27(Suppl 1):485
Maggioni AP, Opasich C, Anand I et al (2005) Anemia in
patients with heart failure: prevalence and prognostic role in a
controlled trial and in clinical practice. J Card Fail 11(2):9198
Philipp S, Ollmann H, Schink T et al (2005) The impact of
anaemia and kidney function in congestive heart failure and
preserved systolic function. Nephrol Dial Transplant 20(5):915
919
Witte KK, Desilva R, Chattopadhyay S et al (2004) Are hematinic deficiencies the cause of anemia in chronic heart failure?
Am Heart J 147(5):924930

123

20. Cromie N, Lee C, Struthers AD (2002) Anaemia in chronic heart

failure: what is its frequency in the UK and its underlying causes?
Heart 87(4):377378
21. Westenbrink BD, Visser FW, Voors AA et al (2007) Anaemia in
chronic heart failure is not only related to impaired renal perfusion and blunted erythropoietin production, but to fluid retention
as well Eur Heart J 28(2):166171
22. Sandek A, Bauditz J, Swidsinski A et al (2007) Altered intestinal
function in patients with chronic heart failure. J Am Coll Cardiol
50(16):15611569
23. Anker SD, Chua TP, Ponikowski P et al (1997) Hormonal
changes and catabolic/anabolic imbalance in chronic heart failure
and their importance for cardiac cachexia. Circulation 96(2):526
534
24. Ezekowitz JA, McAlister FA, Armstrong PW (2003) Anemia is
common in heart failure and is associated with poor outcomes:
insights from a cohort of 12 065 patients with new-onset heart
failure. Circulation 107(2):223225
25. de Silva R, Rigby AS, Witte KK, et al (2006) Anemia, renal
dysfunction, and their interaction in patients with chronic heart
failure. Am J Cardiol 98(3):391398
26. Nanas JN, Matsouka C, Karageorgopoulos D et al (2006) Etiology of anemia in patients with advanced heart failure. J Am Coll
Cardiol 48(12):24852489
27. Weiss G, Goodnough LT (2005) Anemia of chronic disease. N
Engl J Med 352(10):10111023
28. Eckardt KU, Koury ST, Tan CC et al (1993) Distribution of
erythropoietin producing cells in rat kidneys during hypoxic
hypoxia. Kidney Int 43(4):815823
29. Bauer C, Kurtz A (1989) Oxygen sensing in the kidney and its
relation to erythropoietin production. Annu Rev Physiol 51:845
856
30. Bachmann S, Le Hir M, Eckardt KU (1993) Co-localization of
erythropoietin mRNA and ecto-5-nucleotidase immunoreactivity
in peritubular cells of rat renal cortex indicates that fibroblasts
produce erythropoietin. J Histochem Cytochem 41(3):335341
31. Mole DR, Ratcliffe PJ (2007) Cellular oxygen sensing in health
and disease. Pediatr Nephrol, published online, October 23.
32. Nangaku M (2006) Chronic hypoxia and tubulointerstitial injury:
a final common pathway to end-stage renal failure. J Am Soc
Nephrol 17(1):1725
33. Anand IS, Ferrari R, Kalra GS et al (1989) Edema of cardiac
origin. Studies of body water and sodium, renal function,
hemodynamic indexes, and plasma hormones in untreated congestive cardiac failure. Circulation 80(2):299305
34. McCullough PA, Lepor NE (2005) Piecing together the evidence
on anemia: the link between chronic kidney disease and cardiovascular disease. Rev Cardiovasc Med 6(Suppl 3):S4S12
35. Anand IS (2005) Pathogenesis of anemia in cardiorenal disease.
Rev Cardiovasc Med 6(Suppl 3):S13S21
36. McClellan WM, Flanders WD, Langston RD et al (2002) Anemia
and renal insufficiency are independent risk factors for death
among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol
13(7):19281936
37. Volpe M, Tritto C, Testa U et al (1994) Blood levels of erythropoietin in congestive heart failure and correlation with clinical,
hemodynamic, and hormonal profiles. Am J Cardiol 74(5):468
473
38. George J, Patal S, Wexler D et al (2005) Circulating erythropoietin levels and prognosis in patients with congestive heart
failure: comparison with neurohormonal and inflammatory
markers. Arch Intern Med 165(11):13041309
39. van der Meer P, Voors AA, Lipsic E et al (2004) Prognostic value
of plasma erythropoietin on mortality in patients with chronic
heart failure. J Am Coll Cardiol 44(1):6367

Heart Fail Rev (2008) 13:379386

40. Jensen JD, Eiskjaer H, Bagger JP et al (1993) Elevated level of
erythropoietin in congestive heart failure relationship to renal
perfusion and plasma renin. J Intern Med 233(2):125130
41. Pham I, Andrivet P, Sediame S et al (2001) Increased erythropoietin synthesis in patients with COLD or left heart failure is
related to alterations in renal haemodynamics. Eur J Clin Invest
31(2):103109
42. Deswal A, Petersen NJ, Feldman AM et al (2001) Cytokines and
cytokine receptors in advanced heart failure: an analysis of the
cytokine database from the Vesnarinone trial (VEST). Circulation
103(16):20552059
43. Anand IS, Latini R, Florea VG et al (2005) C-reactive protein in
heart failure: prognostic value and the effect of valsartan. Circulation 112(10):14281434
44. Rauchhaus M, Koloczek V, Volk H et al (2000) Inflammatory
cytokines and the possible immunological role for lipoproteins in
chronic heart failure. Int J Cardiol 76(23):125133
45. Jelkmann W (1998) Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res 18(8):555559
46. Means RT Jr (2003) Recent developments in the anemia of
chronic disease. Curr Hematol Rep 2(2):116121
47. Macdougall IC, Cooper AC (2002) Erythropoietin resistance: the
role of inflammation and pro-inflammatory cytokines. Nephrol
Dial Transplant 17(Suppl 11):3943
48. Nemeth E, Rivera S, Gabayan V et al (2004) IL-6 mediates
hypoferremia of inflammation by inducing the synthesis of the
iron regulatory hormone hepcidin. J Clin Invest 113(9):1271
1276
49. Mrug M, Stopka T, Julian BA et al (1997) Angiotensin II stimulates proliferation of normal early erythroid progenitors. J Clin
Invest 100(9):23102314
50. Fyhrquist F, Karppinen K, Honkanen T et al (1989) High serum
erythropoietin levels are normalized during treatment of congestive heart failure with enalapril. J Intern Med 226(4):257
260
51. Albitar S, Genin R, Fen-Chong M et al (1998) High dose enalapril impairs the response to erythropoietin treatment in
haemodialysis patients. Nephrol Dial Transplant 13(5):1206
1210
52. van der Meer P, Lipsic E, Westenbrink BD et al (2005) Levels of
hematopoiesis inhibitor N-acetyl-seryl-aspartyl-lysyl-proline
partially explain the occurrence of anemia in heart failure. Circulation 112(12):17431747
53. Androne AS, Katz SD, Lund L et al (2003) Hemodilution is
common in patients with advanced heart failure. Circulation
107(2):226229
54. Anand IS, Veall N, Kalra GS et al (1989) Treatment of heart
failure with diuretics: body compartments, renal function and
plasma hormones. Eur Heart J 10(5):445450
55. Kalra PR, Anagnostopoulos C, Bolger AP et al (2002) The regulation and measurement of plasma volume in heart failure. J Am
Coll Cardiol 39(12):19011908
56. Anand IS, Chandrashekhar Y, Ferrari R et al (1993) Pathogenesis
of oedema in chronic severe anaemia: studies of body water and
sodium, renal function, haemodynamic variables, and plasma
hormones. Br Heart J 70(4):357362
57. Varat MA, Adolph RJ, Fowler NO (1972) Cardiovascular effects
of anemia. Am Heart J 83(3):415426
58. Oski FA, Marshall BE, Cohen PJ et al (1971) The role of the leftshifted or right-shifted oxygen-hemoglobin equilibrium curve
Ann Intern Med 74(1):4446
59. Metivier F, Marchais SJ, Guerin AP et al (2000) Pathophysiology
of anaemia: focus on the heart and blood vessels. Nephrol Dial
Transplant 15(Suppl 3):1418
60. Brewer GJ (1974) 2,3-DPG and erythrocyte oxygen affinity.
Annu Rev Med 25:2938

385
61. Schmidt W, Boning D, Braumann KM (1987) Red cell age effects
on metabolism and oxygen affinity in humans. Respir Physiol
68(2):215225
62. Anand IS, Chandrashekhar Y, Wander GS et al (1995) Endothelium-derived relaxing factor is important in mediating the high
output state in chronic severe anemia. J Am Coll Cardiol
25(6):14021407
63. Ni Z, Morcos S, Vaziri ND (1997) Up-regulation of renal and
vascular nitric oxide synthase in iron-deficiency anemia. Kidney
Int 52(1):195201
64. Anand IS, Ferrari R, Kalra GS et al (1991) Pathogenesis of
edema in constrictive pericarditis. Studies of body water and
sodium, renal function, hemodynamics, and plasma hormones
before and after pericardiectomy. Circulation 83(6):18801887
65. Datta BN, Silver MD (1975) Cardiomegaly in chronic anemia in
rats and man experimental study including ultrastructural, histometric, and stereologic observations. Lab Invest 32(4):503514
66. Olivetti G, Quaini F, Lagrasta C et al (1992) Myocyte cellular
hypertrophy and hyperplasia contribute to ventricular wall
remodeling in anemia-induced cardiac hypertrophy in rats. Am J
Pathol 141(1):227239
67. Rakusan K, Cicutti N, Kolar F (2001) Effect of anemia on cardiac
function, microvascular structure, and capillary hematocrit in rat
hearts. Am J Physiol Heart Circ Physiol 280(3):H1407H1414
68. Ishani A, Weinhandl E, Zhao Z et al (2005) Angiotensin-converting enzyme inhibitor as a risk factor for the development of
anemia, and the impact of incident anemia on mortality in
patients with left ventricular dysfunction. J Am Coll Cardiol
45(3):391399
69. Go AS, Yang J, Ackerson LM et al (2006) Hemoglobin level,
chronic kidney disease, and the risks of death and hospitalization
in adults with chronic heart failure: the Anemia in Chronic Heart
Failure: Outcomes and Resource Utilization (ANCHOR) Study
Circulation 113(23):27132723
70. Berry C, Norrie J, Hogg K et al (2006) The prevalence, nature,
and importance of hematologic abnormalities in heart failure. Am
Heart J 151(6):13131321
71. Felker GM, Shaw LK, Stough WG et al (2006) Anemia in
patients with heart failure and preserved systolic function. Am
Heart J 151(2):457462
72. Brucks S, Little WC, Chao T et al (2004) Relation of anemia to
diastolic heart failure and the effect on outcome. Am J Cardiol
93(8):10551057
73. Lauer MS, Evans JC, Levy D (1992) Prognostic implications of
subclinical left ventricular dilatation and systolic dysfunction in
men free of overt cardiovascular disease (the Framingham Heart
Study). Am J Cardiol 70(13):11801184
74. Levin A (2001) Prevalence of cardiovascular damage in early
renal disease. Nephrol Dial Transplant 16(Suppl 2):711
75. Levin A (2002) Anemia and left ventricular hypertrophy in
chronic kidney disease populations: a review of the current state
of knowledge Kidney Int Suppl 80:3538
76. Parfrey PS, Foley RN, Wittreich BH et al (2005) Double-blind
comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc
Nephrol 16(7):21802189
77. Roger SD, McMahon LP, Clarkson A et al (2004) Effects of early
and late intervention with epoetin alpha on left ventricular mass
among patients with chronic kidney disease (stage 3 or 4): results
of a randomized clinical trial. J Am Soc Nephrol 15(1):148156
78. Levin A (2007) The treatment of anemia in chronic kidney disease: understandings in 2006. Curr Opin Nephrol Hypertens
16(3):267271
79. Mall G, Huther W, Schneider J et al (1990) Diffuse intermyocardiocytic fibrosis in uraemic patients. Nephrol Dial Transplant
5(1):3944

123

386
80. McCullough PA, Lepor NE (2005) The deadly triangle of anemia,
renal insufficiency, and cardiovascular disease: implications for
prognosis and treatment. Rev Cardiovasc Med 6(1):110
81. Collins AJ (2003) The hemoglobin link to adverse outcomes. Adv
Stud Med 3(3C):S194S197
82. Anker SD, Coats AJ (1999) Cardiac cachexia: a syndrome with
impaired survival and immune and neuroendocrine activation.
Chest 115(3):836847
83. Silverberg DS, Wexler D, Blum M et al (2003) The effect of
correction of anaemia in diabetics and non-diabetics with severe

123

Heart Fail Rev (2008) 13:379386

resistant congestive heart failure and chronic renal failure by
subcutaneous erythropoietin and intravenous iron. Nephrol Dial
Transplant 18(1):141146
84. van Veldhuisen DJ, McMurray JJ (2007) Are erythropoietin
stimulating proteins safe and efficacious in heart failure? Why we
need an adequately powered randomised outcome trial. Eur J
Heart Fail 9(2):110112