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Estimates of the prevalence of anemia in patients with CHF evidence of a causal link, these observations suggest that
and low ejection fraction range widely from 4% to 61% several distinct mechanisms may commonly contribute to
(median 18%).115 Variability in estimated prevalence is anemia in patients with CHF. Several of the most important
partly attributable to use of inconsistent definitions of anemia potential causal pathways will be discussed briefly below and
in individual reports. The World Health Organization defini- are summarized in Figure 1.
tion of anemia (hemoglobin concentration 13.0 g/dL in men Chronic kidney disease is a common comorbidity in
and 12.0 g/dL in women) takes into account known gender patients with CHF and is a strong independent predictor of
differences in distribution of hemoglobin values,16 whereas increased risk of anemia in several studies. In chronic kidney
the National Kidney Foundation defines anemia as hemoglo- disease populations without heart failure, moderate to severe
bin 12 g/dL in men and postmenopausal women.17 These kidney disease (defined as glomerular filtration rate [GFR]
standard definitions of anemia are not based on well- 60 mL/min) is associated with diminished erythropoietin
established physiological or population norms. Published production and a progressive decrease in hemoglobin values
reports in CHF populations have used these and other that is linearly related to reduction in GFR.25 The estimated
study-specific definitions of anemia (including other arbitrary prevalence of at least moderate chronic kidney disease
or statistically defined hemoglobin and hematocrit categories (defined as GFR 60 mL/min) in CHF populations is 20% to
and administrative diagnostic codes from hospital records). 40%.4,9,26,27
Despite these inconsistencies in the definition of anemia Anemia is frequently associated with decreased body mass
cases, most studies indicate that the prevalence of anemia is index in published reports, a finding that suggests that
increased in CHF populations with comorbid kidney disease, patients with cachexia are at greater risk for anemia. Serum
advanced age, and more severe symptoms (range, 30% to levels of proinflammatory cytokines are increased in cachec-
61%) when compared with less symptomatic ambulatory tic patients with CHF and may contribute to development of
populations (range, 4% to 23%). In patients with CHF and anemia by several mechanisms. Proinflammatory cytokines
preserved ejection fraction, the few published reports indicate including tumor necrosis factor- (TNF-), interleukin-1,
that anemia is also highly prevalent in this group.18 20 and interleukin-6 have been shown to disrupt multiple aspects
of erythropoiesis, including reduction of renal erythropoietin
Underlying Cause of Anemia in CHF secretion, suppression of erythropoietin activity in red blood
Anemia occurs when there is a deficiency in new erythrocyte cell precursors in the bone marrow level, and reduction of
production relative to the rate of removal of aged erythro- bioavailability of iron stores for hemoglobin synthesis.28 31
cytes. Erythropoietin, a 30.4-kDa glycoprotein growth factor Proinflammatory cytokines also increase levels of the liver-
produced primarily by kidney, is the key component of the derived peptide hormone, hepcidin.32,33 Hepcidin interacts
homeostatic system for regulation of red blood cell mass and with ferroportin and other iron transport proteins in the
tissue oxygen delivery.2124 Erythropoietin prevents the pro- enterocyte to inhibit gut iron absorption and thereby reduces
grammed cell death of erythrocyte progenitor cells and iron bioavailability for hemoglobin synthesis.32,33 In a mouse
From the Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Conn.
Correspondence to Stuart D. Katz, MD, Yale Heart Failure and Transplant Center, Yale University School of Medicine, 135 College St, Suite 301, New
Haven, CT 06510. E-mail stuart.katz@yale.edu
(Circulation. 2006;113:2454-2461.)
2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.105.583666
2454
Tang and Katz Anemia in CHF 2455
Clinical Characteristics Associated With Increased Risk duced hemoglobin levels.12,39,40 ACE also catalyzes the
of Anemia breakdown of Ac-SDKP, a tetrapeptide inhibitor of erythro-
Increasing age poiesis. In ACE inhibitortreated anemic CHF subjects with
Female gender
low serum ACE activity, Ac-SDKP levels are increased when
compared with nonanemic CHF subjects.41 Serum taken from
Chronic kidney disease (increased serum creatinine or decreased GFR)
anemic patients with CHF with high levels of Ac-SDKP
Decreased body mass index
inhibited formation of erythroid precursors in culture when
Use of ACE inhibitors compared with serum from nonanemic CHF or healthy
Increased jugular venous pressure control subjects. The effects of ACE inhibition on hematocrit
Lower-extremity edema are complex as ACE inhibition may decrease red cell pro-
duction and also reduce plasma volume (see discussion on
hemodilution below). In clinical trials, pharmacological inhi-
model of heart failure induced by myocardial infarction, bition of the renin-angiotensin system is associated with
anemia was linked to activation of the TNF-/Fas signaling small but statistically significant reduction in hemoglobin
pathway.34 The number of bone marrow progenitor cells and levels.12,40,42
the proliferative capacity of these cells were reduced by 40% Anemia is frequently associated with clinical signs and
to 50% in heart failure mice when compared with control symptoms of congestion, a finding that suggests that plasma
animals. A 3-fold increase in apoptosis among progenitor volume expansion may contribute to anemia in CHF by a
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cells in heart failure mice was significantly correlated with process of hemodilution. In 37 ambulatory nonedematous
the increase of TNF-/Fas expression in bone marrow natural anemic patients with CHF, a radiolabeled albumin technique
killer and T cells.34 In patients with CHF, increased levels of for direct measurement of plasma volume demonstrated 46%
proinflammatory cytokines (TNF- and soluble TNF recep- of the patients with low hematocrit values had normal red
tors) or other blood markers of inflammation (C-reactive blood cell volume such that the anemia was entirely attribut-
protein) are inversely related to the hemoglobin level.35 able to expanded plasma volume and consequent hemodilu-
The renin-angiotensin system plays an integral role in the tion.3 Patients with hemodilution were clinically similar to
normal regulation of plasma volume and red blood cell patients with reduced red blood cell volume but were at
volume. Increased angiotensin II signaling in the kidney greater risk for mortality during follow-up. The impact of
alters peritubular oxygen tension, a key regulatory factor for hemodilution on treatment approaches in anemic patients
erythropoietin secretion.21,24 Reduced oxygen tension in the with CHF is uncertain. Administration of erythropoietic
peritubular fibroblasts of the renal cortex is associated with agents to increase red blood mass in hemodilution patients
increased intracellular concentrations of reactive oxygen could further increase total blood volume with possible
species, which, in turn, increases activation of hypoxia adverse clinical consequences. Alternatively, it is possible
inducible factor-1 (HIF-1) and erythropoietin gene expres- that more aggressive treatment with diuretics could reduce
sion.36 Angiotensin II increases erythropoietin secretion by plasma volume and effectively correct anemia in hemodilu-
reducing renal blood flow and increasing proximal tubular tion patients.
reabsorption.21 Angiotensin II may also have direct stimula-
tory effects on bone marrow erythrocyte precursors.37 Eryth- Pathophysiological Consequences of Anemia
ropoietin levels are modestly increased in patients with CHF Severe reduction in hemoglobin (to 4 to 5 g/dL) is associated
in proportion to measures of activation of the renin-angioten- with sodium and water retention, reduction of renal blood
sin system.38 Inhibition of the renin-angiotensin system with flow and glomerular filtration rate, and evidence of neuro-
either ACE inhibitors or angiotensin receptor blockers is hormonal activation in the absence of organic heart disease.43
associated with decreased erythropoietin production and re- These cardiorenal responses may be attributable to the effects
the growth and maturation of proerythroblasts and normo- with CHF and concomitant predialysis chronic kidney dis-
blasts. Subsequently, reticulocytosis occurs and hemoglobin ease.69 Mancini and colleagues70 conducted a single-blinded,
concentration rises. randomized, placebo-controlled trial of rHuEpo therapy in 26
There are 3 currently available erythropoietic agents for patients with advanced CHF and anemia (hematocrit 35%).
treatment of anemia: epoetin-, epoetin- (both of which are Patients received subcutaneous rHuEpo 5000 IU 3 times per
recombinant human erythropoietin [rHuEpo]), and week adjusted to raise hematocrit to 45% for up to 3 months
darbepoetin-.31 rHuEpo was first synthesized in 1985, 2 or a single subcutaneous injection of saline. Supplemental
years after the erythropoietin gene was cloned, and was oral iron and folate were also given to the patients who
approved by the US Food and Drug Administration for received rHuEpo therapy. Compared with the placebo group,
clinical use for treatment of anemia in end-stage chronic rHuEpo therapy was associated with significant increases in
kidney disease in 1988.63 Early studies in dialysis-dependent hemoglobin (11.00.5 to 14.31.0 g/dL, P0.05), peak
patients with chronic kidney disease showed that intravenous oxygen uptake (11.01.8 to 12.72.8 mL/min per kilogram,
or subcutaneous administration of 150 to 200 IU/kg per week P0.05), and treadmill exercise duration (590107 to
(in 1 to 3 divided doses) increased hemoglobin concentrations 657119 seconds, P0.004). The increases in hemoglobin
to 10 to 12 g/dL in 83% to 90% of anemic patients with levels were linearly associated with the increase in peak
chronic kidney disease.64 Plasma half-life of rHuEpo after oxygen uptake (r0.53, P0.02).70 Subjects with both he-
intravenous dosing is 6 to 8 hours. Approximately 25% of the modilution anemia and true anemia with reduced red blood
administered dose is absorbed after subcutaneous dosing, but cell volume appeared to derive comparable improvement in
the plasma half-life is increased to 24 hours.65 The amount
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patients with hemodialysis-dependent end-stage chronic kid- response to erythropoietic agents.17 Although intravenous
ney disease and comorbid heart disease. This study was iron sucrose and iron gluconate preparations are not associ-
terminated prematurely because of a trend toward increased ated with anaphylaxis and are generally well tolerated in
relative risk of death or nonfatal myocardial infarction in the chronic kidney disease populations, there are concerns that
group assigned to the normal hemoglobin target when com- excess iron stores may be associated with increased risk of
pared with group assigned to the target hematocrit of 30% infection and cardiovascular events.17,87,88 Additional work is
(relative risk, 1.3, 95% CI, 0.9 to 1.9). The mechanisms needed to determine the safety and efficacy of intravenous
underlying this observation are uncertain, as within each iron supplementation in anemic patients with CHF with
treatment group, higher hemoglobin values were associated functional iron deficiency.
with reduced risk. In a retrospective study of anemic patients
with cervical cancer, chronic rHuEpo therapy was associated Recommendations for Current Practice
with increased risk of deep vein thrombosis that was inde- There is little discussion of assessment and treatment options
pendent of hematocrit.80 rHuEPO therapy has also been for anemia in recent CHF clinical guidelines.89,90 On the basis
associated with increased risk of all-cause mortality in 2 of available data, we recommend serial measurement of
randomized, placebo-controlled trials of patients with breast hemoglobin in patients with CHF at 6-month intervals in
cancer and head and neck cancer.81,82 Thrombotic events order to identify the subset of patients with anemia who may
were not common causes of death in these studies. Although benefit from further assessment and treatment. In patients
the findings in chronic kidney disease and cancer populations with anemia (defined by World Health Organization criteria),
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may not be directly pertinent to patients with CHF, these further assessment including evaluation for iron or other
findings raise concerns and emphasize the need for additional nutritional deficiencies and estimation of glomerular filtration
trials to determine the long-term safety and efficacy of rate should be performed. For the subpopulation of patients
erythropoietic agents in the CHF population. In the small with CHF with moderate-to-severe anemia (hemoglobin 11
clinical trials of anemic patients with CHF summarized g/dL) and concomitant moderate to severe chronic kidney
above, no thrombotic events or other adverse effects of disease (estimated glomerular filtration rate 60 mL/min),
erythropoietic agents have been reported in approximately current guidelines of the National Kidney Foundation recom-
300 patients.1,68 70,72 Antiplatelet and anticoagulant medica- mend treatment with erythropoietic agents and supplemental
tions commonly prescribed in patients with CHF may miti- iron to a target hemoglobin of 12 g/dL.17,27 The primary goal
gate prothrombotic effects of erythropoietic agents. of treatment is to improve quality of life; there are no clinical
Chronic rHuEPO therapy is frequently associated with outcome trials in predialysis patients with chronic kidney
increased blood pressure.83,84 Increased blood pressure during disease that support use of erythropoietic agents. Given the
chronic erythropoietic therapy may be attributable to in- absence of data on long-term clinical outcomes in patients
creased blood viscosity due to increased red cell mass, altered with CHF and the concerns raised by the finding of increased
neurohormonal milieu, and direct effects on microvascular mortality rates in other anemic populations, treatment with
structure and function.84,85 In patients with chronic kidney erythropoietic agents in patients with CHF with less severe
disease, risk factors for hypertension include rapid increase in degrees of anemia and preserved renal function is not
hematocrit during therapy, a low baseline hematocrit before recommended until more data on safety and efficacy is
rHuEpo administration, high doses and intravenous route of available.91
rHuEPO administration, the presence of native kidneys, and a
genetic predisposition to hypertension.85 In the study of Future Directions
anemic subjects with CHF by Mancini and colleagues,70 treat- The erythropoietin receptor is present in a variety of cells not
ment with rHuEPO did not change blood pressure at rest or directly involved in erythropoiesis, including endothelial
during exercise and did not change forearm vascular resistance cells, vascular smooth muscle cells, neuronal cells, and
as measured with venous occlusion plethysmography. myocardium.92,93 Cytoprotective antiapoptotic effects of
Other rare serious side effects reported with rHuEPO erythropoietin have been reported in animal models of central
therapy include seizures and pure red cell aplasia caused by nervous system injury and in experimental models of myo-
antibody formation against erythropoietin. cardial hypoxia or ischemia-reperfusion injury.9396 Because
ongoing apoptosis has been postulated to be an important
Role of Iron Supplementation mechanism of myocyte loss in CHF, the antiapoptotic effects
Although frank iron deficiency is apparent in only a minority of rHuEpo in cardiovascular tissues suggest a potential
of anemic patients with CHF, functional iron deficiency, therapeutic role beyond the treatment of anemia.97 Certain
which is characterized by reduced availability of tissue iron derivatives of naturally occurring erythropoietin (carbamy-
stores for erythropoiesis, may be a common problem in the lated erythropoietin and erythropoietin mutants) do not bind
CHF population.86 Available small studies in anemic patients to the classical erythropoietin receptor nor promote erythro-
with CHF demonstrated significant increases in hemoglobin poiesis and yet have been shown to confer neuroprotection in
values in response to rHuEpo with intravenous or oral iron experimental models of stroke, spinal cord compression, and
supplementation.69,70 Current guidelines from the National diabetic neuropathy.98 These derivatives appear to mediate
Kidney Foundation recommend use of intravenous iron to cytoprotective effects via specific binding to a heterodimeric
maintain serum ferritin level of 100 to 800 ng/mL and a receptor complex consisting of the erythropoietin receptor
transferrin saturation 20% to 50% to optimize the clinical and common -receptor.99,100 Derivatives designed to target
Tang and Katz Anemia in CHF 2459
this heteroreceptor could potentially provide therapeutic cy- Anaemia is an independent predictor of poor outcome in patients with
toprotection without stimulating erythropoiesis in nonanemic chronic heart failure. Int J Cardiol. 2003;90:303308.
14. Wexler D, Silverberg D, Sheps D, Blum M, Keren G, Iaina A, Schwartz
CHF or other cardiovascular disease populations. D. Prevalence of anemia in patients admitted to hospital with a primary
diagnosis of congestive heart failure. Int J Cardiol. 2004;96:79 87.
Conclusions 15. Maggioni AP, Opasich C, Anand I, Barlera S, Carbonieri E, Gonzini L,
Tavazzi L, Latini R, Cohn J. Anemia in patients with heart failure:
Preliminary studies suggest potential beneficial effects of
prevalence and prognostic role in a controlled trial and in clinical
treatment of anemia with erythropoietic agents on exercise practice. J Card Fail. 2005;11:9198.
capacity and quality of life. Further studies are needed to 16. McCullough PA, Lepor NE Anemia: a modifiable risk factor for heart
determine the optimal threshold for initiation of treatment and disease. Introduction. Rev Cardiovasc Med. 2005;6(Suppl 3):S1S3.
17. IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic
target hemoglobin during therapy, optimum dosing regimen Kidney Disease: update 2000. Am J Kidney Dis. 2001;37:S182S238.
and choice of erythropoietic agent, the role of intravenous or 18. Berry C, Hogg K, Norrie J, Stevenson K, Brett M, McMurray J. Heart
oral iron supplementation, and long-term safety of erythro- failure with preserved left ventricular systolic function: a hospital cohort
poietic agents in anemic patients with CHF. study. Heart. 2005;91:907913.
19. Brucks S, Little WC, Chao T, Rideman RL, Upadhya B, Wesley-
Farrington D, Sane DC. Relation of anemia to diastolic heart failure and
Disclosures the effect on outcome. Am J Cardiol. 2004;93:10551057.
Dr Stuart Katz has received research support, consulting fees, and 20. Klapholz M, Maurer M, Lowe AM, Messineo F, Meisner JS, Mitchell J,
speaker honoraria from Amgen, Inc. Kalman J, Phillips RA, Steingart R, Brown EJ Jr, Berkowitz R,
Moskowitz R, Soni A, Mancini D, Bijou R, Sehhat K, Varshneya N,
Kukin M, Katz SD, Sleeper LA, Le Jemtel TH. Hospitalization for heart
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doi: 10.1161/CIRCULATIONAHA.105.583666
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Copyright 2006 American Heart Association, Inc. All rights reserved.
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