European Heart Journal (2008) 29, 1510–1515 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehn205 Heart failure/cardiomyopathy

Adequacy of endogenous erythropoietin levels

and mortality in anaemic heart failure patients
Peter van der Meer1,2*, Dirk J. Lok 3, James L. Januzzi 2,
Pieta W. Bruggink-Andre de la Porte 3, Erik Lipsic3, Jan van Wijngaarden 3,
Adriaan A. Voors 1, Wiek H. van Gilst1, and Dirk J. van Veldhuisen 1
1
Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; 2Division of Cardiology and Cardiovascular Research Center, Department of
Medicine, Massachusetts General Hospital, Harvard Medical School, Charles River Plaza, 185 Cambridgestreet, Simches Building, 3rd Floor, Boston, MA 02114, USA; and
3
Department of Cardiology, Deventer Hospital, Deventer, The Netherlands

Downloaded from eurheartj.oxfordjournals.org by guest on November 21, 2010

Received 19 November 2007; revised 26 March 2008; accepted 24 April 2008; online publish-ahead-of-print 21 May 2008

See page 1481 for the editorial comment on this article (doi:10.1093/eurheartj/ehn229)

Aims We examined the adequacy of endogenous erythropoietin (EPO) levels for the degree of anaemia in patients with
chronic heart failure (CHF) and its relation to prognosis.
.....................................................................................................................................................................................
Methods We studied 74 anaemic CHF patients from a cohort of 240 patients. The adequacy of endogenous EPO levels was
and results assessed by derived observed/predicted (O/P) ratio. A ratio value ,0.92 indicates EPO levels lower than expected,
whereas a value .1.09 indicates EPO levels higher than expected. The primary endpoint was mortality. During a
median follow up of 4.9 years, 35 of the 74 (47.3%) anaemic patients died. EPO levels lower than expected were
observed in 29 patients (39%), whereas EPO levels higher than expected were present in 22 anaemic patients
(29%). The Kaplan–Meier analysis revealed that anaemic patients with EPO levels higher than expected had a signifi-
cantly higher mortality rate compared to patients with EPO levels as expected or EPO levels lower than expected
(log-rank: P ¼ 0.024). A higher O/P ratio was an independent predictor of increased mortality risk adjusted for
variables including age, sex, haemoglobin, NT-proBNP, and renal function; hazard ratio (HR): 1.020 95%CI
(1.004– 1.036), P ¼ 0.012.
.....................................................................................................................................................................................
Conclusion EPO levels higher than expected, suggesting resistance to the hormone, are common in CHF patients and are
associated with a higher mortality.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Heart failure † Anaemia † Erythropoietin † Prognosis

important cause of anaemia in patients with chronic diseases

Introduction
Anaemia is commonly observed in patients with chronic heart
failure (CHF). The prevalence of anaemia depends both on the
severity of heart failure and the diagnostic criteria, but may be as
high as 55%.1,2 In addition, among patients with CHF, anaemia is
associated with an impaired prognosis and more severe symp-
toms.3 However, while it is both common and relevant from a
prognostic perspective, anaemia in such patients may be due to a
wide range of aetiologies.4,5 One aetiology yet studied among
anaemic patients with CHF is the phenomenon of bone marrow
resistance to endogenous effects of erythropoietin (EPO), an
other than CHF.6,7
Previously, we and others have shown that elevated endogenous
EPO levels are observed in CHF patients and are associated
with an impaired survival, independent of haemoglobin levels.8,9
However, among these subjects, for a given haemoglobin concen-
tration, we observed large variations in endogenous EPO levels
with a subgroup of patients demonstrating high endogenous EPO
levels and only marginally low haemoglobin levels. Considering
the possible mechanisms to explain this observation, those with
higher than expected EPO levels, might theoretically be character-
ized as those resistant to endogenous EPO, while others with

* Corresponding author. Tel: þ1 617 643 3441, Email: pvandermeer@partners.org or p_van_der_meer@hotmail.com

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.
Adequacy of EPO in CHF
either low or more appropriate levels of EPO relative to their
anaemia could be characterized as having normal or elevated sen-
sitivity to endogenous EPO in the bone marrow; given this possible
scenario.
We, therefore, aimed to study the relation between endogenous
EPO levels and haemoglobin levels in anaemic CHF patients and
related this to outcome. Our hypothesis was that EPO resistance
would be common among patients with CHF and in those CHF
patients with a phenotype of EPO resistance we would observe
a higher rate or mortality.
Methods
Patients
All patients in the present study were recruited into a prospective mul-
ticentre CHF study evaluating the influence of protocolized interven-
tion by clinician and cardiovascular nurse, as previously described.10
Referral of patients to our clinic was by general practitioners, cardiol-
ogists of other local hospitals, or other units of the hospital. Patients,
either hospitalized or visiting the outpatient clinic, with New York
Heart Association (NYHA) III or IV were eligible for the study. In all
patients, CHF was diagnosed on the basis of standard criteria, and
the presence of left ventricular enlargement or systolic functional
impairment by radionuclide ventriculography or echocardiography,
according to the European Society of Cardiology guidelines.11 Exclu-
sion criteria were: dementia, psychiatric illness, discharge, or stay in
nursing home, diseases other than CHF with a life expectancy less
than 1 year, ongoing or planned hospitalization and kidney function
replacement. All subjects gave informed consent for the protocol,
which was approved by the local Medical Ethics Committee. The
total cohort consisted of 240 CHF patients, of which 77 were
anaemic (32%). In the present analysis, we included 74 anaemic
patients with complete datasets of plasma EPO, NT-proBNP, renal
function, biometric measurements, and medication use.
Study endpoints
Patients were recruited between March 2000 and April 2003 and fol-
lowed until 15 September 2006. Mortality was assessed by review of
the medical record or contacting the general practitioner or the
heart failure clinic. There was no loss-to follow-up. The primary end-
point was all-cause mortality.
Renal function, haemoglobin level,
and ferritin
The glomerular filtration rate (GFR) is a standard indicator of renal
function. Under steady-state conditions, GFR is estimated from
serum creatinine using a formula that accounts for the influence of
age on creatinine production [simplified modification of diet in renal
disease (sMDRD)] GFR:Male: 186.3  (serum creatinine)– 1.154 
(age)– 0.203; black male: sMDRD  1.212; female: sMDRD  0.742;
black female: sMDRD  1.212  0.742, which has been validated in
CHF patients.12 Anaemia was defined as a haemoglobin level
,13.0 g/dL for men and postmenopausal women and ,12.0 g/dL
for premenopausal women, as previously described.13 Ferritin levels
were measured in stored plasma. According to Thomas and
Thomas,14 the cut-off values for ferritin deficiency were dependent
on the acute-phase response. Ferritin deficiency was defined as
,20.8 ug/L in patients with high sensitive (hs)-C-reactive protein
levels 5 mg/L, and,61.7 ug/L in patients with hs-C-reactive protein
levels .5 mg/L.
1511
Erythropoietin
Plasma EPO levels were measured using the IMMULITEw EPO assay
(DPC, Los Angeles, CA, USA), which has been described before.8
The adequacy of endogenous EPO levels is assessed by the
observed/predicted (O/P) ratio, as previously described.15,16 A value
below 1 suggests that endogenous EPO production is lower than
expected, whereas a value above 1 suggests that endogenous EPO pro-
duction is higher than expected. To define EPO levels appropriate or
inappropriate for a given degree of anaemia, we obtained a reference
sample of anaemic patients without cardiac and renal disease and
hs-C-reactive protein levels ,5 mg/L. In total, 143 patients were
screened for the reference sample. In ten patients, EPO levels could
not be measured due to insufficient blood collection. Of the remaining
133 patients, 23 were considered anaemic. Two patients were
excluded due to renal failure and one was excluded due to elevated
hs-C-reactive protein levels. Eventually, the 20 remaining patients
were included in the reference sample. By using the haemoglobin
and EPO levels, a regression equation was constructed: log(EPO)
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¼4.6402(0.274  Hb), which is well comparable to a previous
study in CHF patients.17 This equation was used to predict the EPO
levels based on the haemoglobin level: predicted log(EPO) levels.
The actual observed log(EPO) levels in our CHF patients was
divided by the predicted log(EPO) values to create an O/P ratio.
The mean O/P ratio for the reference subjects was 1.003 [95% confi-
dence interval (CI) 0.916– 1.087]. Lower than expected was defined as
an O/P , 0.916, while EPO level higher than expected was defined as
an O/P . 1.087, based on the 95% CI of the reference population.
Statistics
Data are given as mean+SD when normally distributed, as median and
interquartile range (IQR) when skewed, and as frequencies for categ-
orical variables. We compared differences between groups with the
Mann– Whitney U test, Kruskall – Wallis test, student t-test, ANOVA
with Bonferroni post hoc testing, and Pearson x2 test when appropriate.
Kaplan –Meier method was used to study the influence of the O/P
ratio of EPO levels on survival, with log-rank testing. Furthermore,
we used the Cox proportional hazard analysis to assess the association
between O/P ratio of EPO levels and mortality. Regarding the limited
sample size, in the multivariable model, we corrected for five risk
factors known to be important predictors of mortality in CHF patients
including: age, sex, nt-proBNP, renal function, and haemoglobin.
Hazard ratios (HRs) with 95% CIs demonstrated the risk of death.
The validity of the proportional hazard assumption was checked
using the Schoenfeld residuals. The proportional hazard assumption
was tested for each covariate in the multivariable analysis. Plots of
Schoenfeld residuals against the time were made. No violations were
found. Spearman correlation coefficients were calculated to determine
the correlations between O/P ratio of EPO levels and hs-C-reactive
protein. All reported probability values were two-tailed, and a
P-value ,0.05 was considered statistically significant. For all statistical
analysis, SPSS version 13.0 was used.
Results
The average age of the anaemic patients was 73 + 8 years, 68%
were male, and the average left ventricular ejection fractionwas
30 + 8%. The majority of patients were in NYHA class III (92%).
Of the 74 anaemic patients, 35 patients (47.3%) died after 26
days to 5.9 years. Median follow-up period of the 39 survivors
was 4.9 years (IQR 4.3 –5.9).
1512
Adequacy of erythropoietin production
Median endogenous EPO levels were 23.4 U/L (IQR 14.0–45.1);
(range: 7.70–276). The average haemoglobin level in the anaemic
cohort was 11.7 + 1.0 g/dL. The majority of the patients included
in the current study had an ischaemic aetiology (76%). We only
found a non-significant difference in EPO levels between patients
with ischaemic CHF and non-ischaemic CHF; 25.7 U/L (15.2–
52.5) and 17.4 U/L (11.2–36.9), respectively. The O/P ratios
were divided in three groups, as described in the methods
section: lower than predicted EPO levels (39%; n ¼ 29), higher
than predicted EPO levels (29%, n ¼ 22), and EPO levels as pre-
dicted (31%, n ¼ 23). The baseline characteristics of the anaemic
patients are depicted in Table 1. The mean O/P ratio was 1.01 +
0.26. As expected, cGFR was significantly lower in patients with
EPO levels lower than expected (P ¼ 0.004). Haemoglobin levels
were slightly higher in patients with unexpectedly high EPO
levels (P ¼ 0.01). Also C-reactive protein levels were higher in
patients with EPO levels higher than expected, although this did
not reach statistical significance. We observed a positive corre-
lation between C-reactive protein and O/P ratio (r ¼ 0.277, P ¼
0.017). Ferritin deficiency was mostly observed in patients with
EPO levels as expected (P ¼ 0.04).
Adequacy of erythropoietin production
and survival
Higher than expected EPO levels were associated with a higher
mortality rate compared to patients with EPO levels as expected
or those with lower than expected EPO levels. Kaplan–Meier sur-
vival curves for the three groups showed an increased mortality
over time in patients with higher than expected EPO levels (log
rank: P ¼ 0.024; Figure 1). The multivariate regression analysis
revealed that a higher O/P ratio, suggesting EPO resistance, was
an independent predictor of increased mortality risk in Cox-
regression analyses adjusted for variables including age, sex, hae-
moglobin, NT-proBNP, and cGFR; HR: 1.020 95% CI (1.004–
1.036), P ¼ 0.012 (Table 2).
Discussion
The main and novel finding of the present study is that higher than
expected EPO levels in anaemic heart failure patients are fre-
quently present and are strongly associated with a higher mortality
compared to anaemic CHF patients with (lower than) expected
EPO levels. Mechanistically, anaemic CHF patients with higher
than expected EPO levels are obviously capable of producing
endogenous EPO, but their bone marrow might be resistant to
the hormone. These patients should be distinguished from
anaemic CHF patients with lower than expected EPO levels, in
which the primary problem probably reflects renal dysfunction,
but who have a normal or even increased sensitivity to EPO.
This is supported by our observation that renal dysfunction was
more frequent amongst the group of patients with lower than
expected EPO levels.
Few studies have been performed on the role of endogenous
EPO levels in CHF. It has been observed that endogenous EPO
levels in CHF patients are generally elevated; proportional to the
P. van der Meer et al
severity of symptoms.18,19 In a relatively small study, we previously
showed that the plasma EPO and haemoglobin levels were inde-
pendent predictors of survival.8 These findings were recently con-
firmed by others in a slightly larger CHF population.9 We
additionally demonstrated only a mild inverse correlation
between EPO and haemoglobin levels in CHF patients, whereas
the control group showed a clear significant inverse correlation,
as expected. These findings already suggested large variations in
EPO levels for given haemoglobin levels in CHF patients. In the
present study, we focused on O/P ratios of EPO in CHF patients
to further explore the adequacy of endogenous EPO levels in
anaemic CHF patients.
With respect to adequacy of the endogenous EPO level relative
to the severity of anaemia, we suggest that proposed O/P ratio
allows for a better mechanistic understanding of the cause of
anaemia. Indeed, while the observation that the effects of EPO
may be affected in patients with CHF has been made, the expla-
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nation for this finding or the prognostic relationships between
this finding remained less clear. Higher than expected EPO levels
have been observed as a primary response in patients after
intense chemotherapy, although mechanistically it remains
unclear why this may be and how it might be related to our sub-
jects with CHF.20 The association between EPO levels and inflam-
mation in those with possible EPO resistance has been described
previously.6,21,22 In addition, in vitro data have shown that greater
amounts of EPO are needed to restore proliferation of bone
marrow-derived cells when inflammatory cytokines are
present,23 and indeed in our analysis, higher than expected EPO
levels correlated with C-reactive protein concentrations in sub-
jects so afflicted. The effects of inflammation in CHF are numer-
ous,24,25 although to our knowledge a unifying theory for
inflammation, anaemia, and CHF has not been previously pro-
posed. Another theory may be that a circulating inhibitor to hae-
matopoiesis may be present in those with higher than expected
EPO concentrations. Previous studies from our group showed
that serum of CHF patients inhibits the proliferation of bone
marrow derived erythropoietic cells from healthy volunteers, indi-
cating that serum factors induce insensitivity to endogenous
EPO.26 We established that serum levels of Ac-SDKP, a strong hae-
matopoiesis inhibitor, were significantly higher in these anaemic
CHF patients. Since ACE is the principle enzyme metabolizing
Ac-SDKP, the ramification for those anaemic patients treated
with ACE-inhibitors is clear.
We acknowledge that the mechanisms of anaemia in CHF are
many. Indeed, lower than expected EPO values were also fre-
quently seen in our cohort. Chronic kidney disease (CKD) is
likely to be a significant contributory factor in the anaemia
observed in CHF patients. In many patients with end-stage renal
disease, anaemia is a common feature. In turn, CHF can cause
CKD due to decreased cardiac output and relative renal vasocon-
striction, leading to chronic renal ischaemia, CKD, and ultimately
anaemia. The links between CKD, CHF, and anaemia have been
called the Cardio-Renal-Anaemia syndrome.27 The current study
supports the concept that anaemia develops due to the inability
of the kidney to produce sufficient levels of EPO to stimulate
the bone marrow adequately. Lastly, adequate EPO levels for the
degree of anaemia are mostly observed in patients with low ferritin
Adequacy of EPO in CHF 1513

Table 1 Baseline characteristics

Variable EPO levels lower than EPO levels as EPO levels higher than P-value
expected (n 5 29) expected (n 5 23) expected (n 5 22)
...............................................................................................................................................................................
Age (years) 72.7 + 8.1 72.6 + 9.4 72.3 + 6.1 0.98
Sex (n/% male) 16 (55.2) 15 (65.2) 19 (86.4) 0.06
Ischaemic aetiology (n/%) 21 (72.4) 18 (78.3) 17 (77.3) 0.31
NYHA class III (n/%) 26 (89.7) 21 (91.3) 21 (95.5) 0.75
Systolic blood pressure (mmHg) 122 + 29.2 121 + 19.0 122 + 19.7 0.98
LVEF (%) 32 + 7.8 30 + 9.0 28 + 9.0 0.36
NT-proBNP (pmol/L) 265 (109– 862) 367 (200–614) 533 (435– 904) 0.48
O/P (%) 0.77 + 0.08 1.00 + 0.05 1.32 + 0.19 –
Haemoglobin (g/dL) 11.4 + 1.0 11.6 + 0.9 12.2 + 0.7§ 0.007
Mean corpuscular volume (fL) 88.9 + 5.2 90.1 + 7.0 90.4 + 7.4 0.69
Erythropoietin (U/L) 13.0 (10.7– 16.6) 24.1 (16.6– 47.7) 43.7 (26.2–77.4)†§ 0.001
hs-C-reactive protein (mg/L) 13 (4.5–27) 6 (2–22) 14 (4– 37.5) 0.15

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cGFR (mL/min/1.73 m2) 41.4 + 10.8† 54.1 + 16.5 46.3 + 16.4 0.01
Ferritin deficiency (%) 4 (13.8)* 10 (43.5) 5 (22.7)* 0.04
Medication (n/% use)
ACE-inhibitor 26 (89.7) 20 (87.0) 18 (81.0) 0.68
Angiotensin receptor blocker 3 (10.3) 5 (21.7) 2 (9.5) 0.40
Diuretics 28 (96.6) 23 (100) 22 (100) 0.47
Digoxin 8 (27.6) 5 (21.7) 8 (38.1) 0.49
Beta blocker 20 (69.0) 17 (73.9) 18 (81.0) 0.84

LVEF, left ventricular ejection fraction; O/P, observed/predicted; cGFR, calculated glomerular filtration rate.
*P , 0.05 vs. adequate EPO response.
†
P , 0.01 vs. adequate EPO response.
‡
P , 0.05 vs. inadequate low EPO response.
§
P , 0.01 vs. inadequate low EPO response.

Figure 1 Kaplan – Meier survival curve for all cause mortality for the three different groups. EPO levels lower than expected (n ¼ 29), EPO
levels as expected (n ¼ 23), and EPO levels higher than expected (n ¼ 22).

levels.21 Our study confirms these findings since almost 50% of
the anaemic patients with adequate EPO levels had low ferritin
values.
Several limitations of the present study have to be acknowl-
edged. The analysis of the anaemic subgroup was based on a rela-
tively small sample size, although the mortality rate was almost
50%. We did not measure cytokine levels nor Ac-SDKP levels
which may play an important role in the resistance of the bone
marrow for endogenous EPO in CHF. Because of these limitations,
we regard our study mainly as a hypothesis-generating study.
Nevertheless, our findings suggest that resistance to endogen-
ous EPO is common in anaemic CHF patients and relates to an
1514
Table 2 Multivariable predictors of all-cause mortality
in the anaemic cohort (n 5 74)
Variable Multivariable
............................................
HR CI
................................................................................
O/P ratio (%) 1.020 1.004–1.036
Sex (male) 2.541 1.089–5.805
cGFR (mL/min/1.73 m2) 0.958 0.931–0.985
Age (10 years) 1.335 0.817–2.182
ntproBNP (10 pmol/L) 1.001 0.996–1.005
Haemoglobin (g/dL) 0.748 0.367–1.521
HR, hazard ratio; CI, 95% confidence intervals; O/P, observed predicted ratio;
cGFR, calculated glomerular filtration rate.
impaired prognosis. This may help to understand the pathophysiol-
ogy of anaemia in CHF and the relation between elevated
endogenous EPO levels and mortality. Furthermore, it would be
interesting to evaluate whether (anaemic) CHF patients with
EPO resistance are also resistant to exogenous EPO, and
whether such patients have comparable or worse prognosis to
those without such resistance. Currently, a large randomized
placebo-controlled trial is being conducted to investigate the
role of exogenous EPO in anaemic CHF patients.28
Conflict of interest: none declared.
Funding
Netherlands Organisation for Scientific Research (AGIKO grant
920-03-219 and Rubicon grant 825-07-011 to P.v.d.M.), the Novartis
Foundation for Cardiovascular Excellence grant (to P.v.d.M.) and the
Netherlands Heart Foundation (grant D97-017 to D.J.v.V. and grant
2006T37 to A.A.V.).
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doi:10.1093/eurheartj/ehm623
CLINICAL VIGNETTE Online publish-ahead-of-print 5 January 2008
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Thoracic mycotic pseudoaneurysm from Candida albicans infection

Stefan Brunner†*, Markus G. Engelmann†, and Michael Näbauer
Medical Department I – Cardiology, Ludwig-Maximilians University, Klinikum Grosshadern Munich, Marchioninistr. 15, D – 81377 Munich, Germany
* Corresponding author. Tel: þ49 89 7095 6074, Fax: þ49 89 7095 6100, Email: stefan.brunner@med.uni-muenchen.de
†
Both S.B. and M.G.E. contributed equally to this work.

A 33-year-old man was admitted to the emergency

department with fever, chills since 3 weeks and an
elevated C-reactive protein. Two years ago, he had
undergone an aortic valve reconstruction and mitral
valve replacement owing to endocarditis. Three months
prior to admission, he suffered from sternal osteomyelitis
caused by infected cerclages with a smear positive for
Candida albicans. Both artificial valves did not present
signs of endocarditis. Blood cultures were tested negative.
Serology was tested positive for C. albicans. CT scans
demonstrated a localized mycotic pseudoaneurysm of
the ascending aorta and retrosternal hemorrhage (Panel
A). Histology of the felt-like aortic tissue demonstrated
amorphous material with an inflammatory edge in the
H&E staining (Panel B). The Grokott staining, specific for
fungal structures, was strongly positive and demonstrated
multiple black layers of Candida sp. (Panels C and D). The
defect was closed with a patch and the patient recovered
completely after long-term antimycotic treatment.
Panel A: The Multidetector-Row CT scan (64-slice CT)
of the chest demonstrates a localized pseudoaneurysm of
the ascending aorta with retrosternal hemorrhage.
Panel B: Micrograph of the surgical specimen from the
aortic wall showing amorphous material with an inflammatory edge (Hematoxylin & eosin stain, original magnification 200).
Panel C: Micrograph demonstrates multiple black layers of fungus (Grokott stain, original magnification 100).
Panel D: Higher magnification detected round fungus spores with longish hyphae indicating Candida sp. (Grokott stain, original
magnification 400).

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.