International Journal of Cardiology 167 (2013) 14121416

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International Journal of Cardiology

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Relation between changes in red cell distribution width and clinical outcomes in
acute decompensated heart failure
Badira F. Makhoul a, d, Amal Khourieh d, Marielle Kaplan b, d, Fadel Bahouth c,
Doron Aronson c, d, e, Zaher S. Azzam a, d, e,
a
Department of Internal Medicine B, Rambam Health Care Campus, Haifa, Israel
b
The Laboratory of Clinical Biochemistry, Rambam Health Care Campus, Haifa, Israel
c
Heart Institute, Rambam Health Care Campus, Haifa, Israel
d
Ruth & Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
e
The Rappaport Family, Institute for Research in the Medical Sciences, Technion, Israel Institute of Technology, Haifa, Israel

a r t i c l e i n f o a b s t r a c t

Article history: Background: Increased red blood cell distribution (RDW) has been associated with adverse outcomes in
Received 17 September 2011 patients with heart failure. We studied the association between baseline RDW and changes in RDW during
Received in revised form 29 March 2012 hospital course with clinical outcomes in acute decompensated heart failure (ADHF) patients.
Accepted 8 April 2012 Methods and results: We prospectively studied 614 patients with ADHF. Baseline RDW and RDW change
Available online 2 May 2012
during hospital course were determined. The relationship between RDW and clinical outcomes after hospital
discharge was tested using Cox regression models, adjusting for clinical characteristics, echocardiographic
Keywords:
Anemia
ndings and brain natriuretic peptide levels. During follow up (1 year), 286 patients (46.6%) died and 84
Heart failure were readmitted for ADHF (13.7%). Median RDW was signicantly higher among patients who died com-
Red cell distribution width pared to patients who survived (15.6% interquartile range [14.5 to 17.1] vs. 14.9% mg/L interquartile range
[14.1 to 16.1], P b 0.0001). Compared with patients in the 1st RDW quartile, the adjusted hazard ratio [HR]
for death or rehospitalization was 1.9 [95% CI 1.32.6] in patients in the 4th quartile. Changes in RDW during
hospitalization were strongly associated with changes in mortality risk. Compared with patients with persis-
tent normal RDW (b 14.5%), the adjusted HR for mortality was 1.9 [95% CI 1.13.1] for patients in whom RDW
increased above 14.5% during hospital course, similar to patients with persistent elevation of RDW (HR was
1.7, 95% CI 1.22.3).
Conclusion: In patients hospitalized with ADHF, RDW is a strong independent predictor of greater morbidity
and mortality. An increase in RDW during hospitalization also portends adverse clinical outcome.
2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction the relationship between RDW and clinical outcomes of HF patients

Heart failure (HF) is the leading cause for hospitalization among
patients older than 65 years of age [1]. Clinical trials and observation-
al studies have identied multiple prognostic factors in patients
admitted with acute decompensated heart failure, including renal
function, hyponatremia, brain natriuretic peptide (BNP) and cardiac
troponins [2]. Red blood cell distribution width (RDW) is a measure
of the variability in the size of circulating erythrocytes, that can be
used in the classication of anemia and in the detection of early
iron and folate deciency [3].
Recently, RDW has been shown to be among the strongest predic-
tors of both mortality and HF hospitalizations in patients with either
stable or decompensated heart failure (HF) [48]. Previous studies on
Corresponding author at: Dept. of Internal Medicine B, Rambam Health Care
Campus, P.O. Box 9602, Haifa, 31096, Israel. Tel.: + 972 4 8542676; fax: + 972 4
8543252.
E-mail address: z_azzam@rambam.health.gov.il (Z.S. Azzam).
have used a single RDW measurement. However, RDW may be a
dynamic variable, with rapid changes in acute disease states [9]. In the
present study we explore the possibility that changes in RDW during
hospital stay for acute decompensated heart failure (ADHF) may
provide prognostic information beyond a single RDW value.
2. Methods
Between January 2008 and April 2010, we prospectively studied all patients admit-
ted to the Rambam Medical Center, Haifa, Israel with the primary diagnosis of ADHF
and survived the index hospitalization. Eligible patients were those hospitalized as
with new-onset or worsening preexisting heart failure as primary cause of admission
or those with signicant heart failure symptoms that developed during the hospitaliza-
tion where heart failure was the primary discharge diagnosis [10]. ADHF was diag-
nosed according to the European Society of Cardiology criteria including a brain
natriuretic peptide (BNP) level >400 pg/mL [11]. The study was conducted in accor-
dance with the principles of the Declaration of Helsinki and approved by the institu-
tional review committee on human research.
Hemoglobin levels, mean corpuscular volume (MCV) and RDW were measured on
admission and prior to hospital discharge, using the Advia 120 Hematology Analyzer

0167-5273/$ see front matter 2012 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2012.04.065
 B.F. Makhoul et al. / International Journal of Cardiology 167 (2013) 14121416 1413

RDW in our laboratory is 11.5 to 14.5%. The correctness of this normal range was con-
rmed by analyzing RDW data in 17293 ambulatory subjects who attended the
Rambam Center for Preventive Medicine for a medical examination and health
counseling. In this group, mean RDW was 13.1% (median 13.0%) with 95% condence
interval of RDW of 12.0 to 14.4%. Patient BNP levels were measured with the AxSYM
BNP microparticle enzyme immunoassay (Abbott Laboratories, Abbott Park, IL, USA).

2.1. Study endpoints

All patients were followed for 12 months after hospital discharge. The primary end
point of the study was all-cause mortality [13] or readmission for the management of
HF. Readmission for HF was dened if the main reason for a new admission was new
symptoms of dyspnea with pulmonary venous congestion on X-ray with interstitial
or alveolar edema and BNP > 400 pg/mL. Following hospital discharge, clinical endpoint
information was acquired by reviewing the national death registry and by contacting
each patient individually and independently reviewing the hospital course for major
clinical events if the patient had been re-hospitalized.

2.2. Statistical analysis

Continuous variables are presented as mean (SD) or medians (with interquartile

Fig. 1. Frequency distribution (expressed as percentage of the entire population; vertical
axis) of RDW in normal subjects and in the study population. The red line shows the me-
dian value. P = 0.003 for the comparison between admission and hospital course data.
(Siemens Healthcare Diagnostics). When more than 2 RDW measurements were avail-
able, the second RDW measurement was taken as the last RDW measurement during
hospitalization. Data on RBC transfusions was collected in each patient. Anemia was
dened as hemoglobin levels lower than 13 g/dL in men and 12 g/dL in women, in
accordance with the World Health Organization (WHO) criteria [12]. RDW is reported
as coefcient of variation (in percent) of red blood cell volume. The normal range for
ranges), and categorical variables as numbers and percentages. The baseline character-
istics of the groups were compared using analysis of variance for continuous variables
and by 2 statistic for categorical variables. Changes in RDW at different time points
were evaluated by using a nonparametric approach to paired measures (Wilcoxon
signed-ranks test).
The distribution of RDW was skewed. Therefore, logarithmically transformed
values of RDW (ln RDW) were used. The strength of the association between RDW
and clinical and biochemical variables was assessed by univariable linear regression
of ln RDW on each variable separately followed by multiple linear regression with
backward selection. In addition to age and gender (which were forced into the
model) baseline variables considered for inclusion in the multivariable model includ-
ed: history of hypertension, history of diabetes, atrial brillation, estimated GFR,
BUN, serum sodium, baseline hemoglobin, MCV, BNP, cardiac troponin I and left ven-
tricular ejection fraction and medications.
To avoid assuming linearity, RDW was categorized according to quartiles of the
distribution, with the lowest quartile serving as the reference group. Survival curves
were constructed using the KaplanMeier method, and comparisons were made
using the logrank test. Stepwise Cox proportional hazards models with backward
selection were used to calculate hazard ratios (HRs) and 95% condence intervals
(CI) for RDW categories. The Cox models were adjusted for age, gender, history of
diabetes, hypertension, smoking status, estimated glomerular ltration rate (eGFR),
blood urea nitrogen (BUN), serum sodium, atrial brillation, elevated cardiac troponin

Table 1
Baseline clinical characteristics according to quartiles of baseline RDW.

RDW quartile

Characteristic 14.3 14.415.2 15.316.5 16.6 P value

(n = 156) (n = 158) (n = 148) (n = 152)

Age (years) 78 12 77 10 77 10 75 13 0.12

Male gender 64 (41) 67 (52) 79 (53) 72 (47) 0.13
Coronary artery disease 96 (62) 103 (65) 90 (61) 94 (62) 0.84
History of hypertension 127 (84) 126 (86) 133 (84) 17 (76) 0.09
Diabetes mellitus 81 (53) 72 (49) 78 (50) 74 (48) 0.78
Creatinine (mg/dL) 1.4 0.6 1.6 1.1 1.7 1.1 1.7 0.9 0.02
eGFR (mlmin 1/1.73 m 2) 52 24 50 24 46 21 47 24 0.09
BUN (mg/dl) 30 15 31 17 35 22 38 25 0.001
Serum sodium (mmole/l) 137 5 137 6 137 5 137 5 0.61
Baseline hemoglobin (g/dl) 12.2 1.8 11.9 1.8 11.4 1.6 10.7 2.0 b 0.0001
Anemia (WHO) 84 (54) 97 (61) 106 (72) 123 (81) b 0.0001
Mean corpuscular volume (m3) 90 5 89 6 86 7 84 8 b 0.0001
Intravenous iron 5 (3) 2 (1) 7 (5) 13 (9) 0.02
Erythropoietin 0 (0) 1 (1) 1 (1) 5 (3) 0.03
Blood transfusion 1 (1) 0 (0) 2 (1) 11 (7) b 0.0001
BNP (pg/ml) 1227 930 1343 103 1544 1102 1550 1061 0.01
cTn I elevation (%) 19 (12) 24 (15) 22 (15) 16 (11) 0.57
Left ventricular ejection fraction (%) 47 18 42 18 42 18 42 20 0.30
Medications
Beta blockers 96 (62) 108 (68) 97 (66) 107 (70) 0.38
ACE inhibitors/ARBs 102 (65) 104 (66) 90 (61) 88 (58) 0.42
Loop diuretics 131 (86) 130 (88) 125 (79) 110 (71) b 0.0001
Spironolactone 25 (16) 26 (18) 24 (15) 21 (14) 0.78
Digoxin 13 (9) 15 (10) 7 (4) 9 (6) 0.20
Days hospitalized 7 [511,12,13] 7 [411] 7 [411,12] 8 [511,12,13] 0.33

Values are expressed as number (%) of patients, mean value SD, or Median [Interquartile Range].
ACE = angiotensin converting enzyme; ARB = Angiotensin receptor blockers.
1414 B.F. Makhoul et al. / International Journal of Cardiology 167 (2013) 14121416

Table 2 I, BNP levels and medical therapy (beta blockers, angiotensin converting-enzyme in-
Multiple linear regression analysis with Ln RDW as the dependent variable. hibitors, loop diuretics, spironolactone and digoxin). The Cox models were also adjusted
for baseline hemoglobin and for left ventricular ejection fraction (LVEF). Similar adjust-
Unadjusted Adjusted ments were used to model changes in RDW with additional adjustments for length of
Independent variable Regression P value Regression P value hospital stay in days, intravenous iron therapy, erythropoietin therapy and blood
coefcient (SE) coefcient (SE) transfusion.
The relation between changes in RDW during hospital course and the primary end-
Age (per 10 years) 0.009 (0.001) 0.004 0.009 (0.003) 0.001 point was also analyzed by categorizing the patients according to RDW at baseline and
Atrial brillation 0.02 (0.01) 0.007 0.03 (0.01) 0.002 follow-up values. Differences were considered statistically signicant at the 2-sided
Beta blockers 0.02 (0.01) 0.02 P b 0.05 level. Statistical analyses were performed using the SPSS statistical software
Loop diuretic at 0.04 (0.01) b 0.0001 0.02 (0.001) 0.046 version 16.0 (Chicago, IL) and STATA version 11.0 (College station, TX).
presentation
Estimated GFR 0.004 (0.002) 0.04
(per 10 ml/min 3. Results
increase)
Blood urea nitrogen 0.01 (0.002) b 0.0001 0.01 (0.002) b0.0001
(per 10 mg/ml
During the study period, 614 patients who met the inclusion cri-
increase) teria were recruited. The median time between the baseline and in-
Ln BNP 0.02 (0.007) 0.0007 0.01 (0.006) 0.02 hospital RDW measurements was 5 days (interquartile range 2 to
Hemoglobin (g/dL) 0.02 (0.002) b 0.0001 0.01 (0.002) b0.0001 11 days). The distribution for RDW in normal subjects and the study
MCV () 0.005 (0.001) b 0.0001 0.004 (0.001) b0.0001
HF patients is shown in Fig. 1. The RDW distribution curve is shifted
to the right in HF patients with marked increase in RDW values.
The clinical characteristics of patients according to quartiles of
baseline RDW are shown in Table 1. Patients with higher RDW values
had reduced renal function, lower baseline hemoglobin and MCV, and
presented with higher BNP levels. They were more likely to be on
loop diuretics. Intravenous iron, erythropoietin and blood transfusion
were more likely to be used in the highest RDW quartile.
Table 2 depicts clinical and laboratory parameters that were inde-
pendently associated with RDW. Of the measures of renal function,
RDW was more strongly associated with BUN than with eGFR. There
was a poor correlation between RDW and BNP in both patients with
(r = 0.11, P = 0.14) and without anemia (r = 0.12, P = 0.003). Of
note, there was no association between RDW and left ventricular
ejection fraction. The nal model explained only 22% of the variability
in RDW.

3.1. Baseline RDW and survival

During the follow up period, 286 patients died (46.6%) and 84

Fig. 2. KaplanMeier plot showing the crude cumulative incidence of death according
to quartiles of baseline RDW. P b 0.0001 by the log rank test for the overall comparison
among the groups.
were readmitted for ADHF (13.7%). Median RDW was signicantly
higher among patients who died than among patients who survived
(15.6% interquartile range [14.5 to 17.1] vs. 14.9% mg/L interquartile
range [14.1 to 16.1], P b 0.0001). KaplanMeier analysis showed a
graded increased probability of death during follow up with increas-
ing quartile of RDW (Fig. 2). The 1-year mortality or readmission

Table 3
Unadjusted and adjusted Cox's proportional hazards model for all-cause mortality according to quartile of RDW.

Model Unadjusted Adjusted*

HR (95% CI) P value P trend HR (95% CI) P value P trend

Baseline RDW
1st Quartile 1.0 b0.0001 1.0 b 0.0001
2nd Quartile 0.9 (0.61.3) 0.45 0.9 (0.61.3) 0.63
3rd Quartile 1.3 (0.91.8) 0.15 1.2 (0.81.7) 0.28
4th Quartile 1.8 (1.32.5) 0.0002 1.9 (1.32.6) b0.0001
BNP
1st Quartile 1.0 b0.0001 1.0 0.08 0.01
2nd Quartile 1.4 (0.05) 0.05 1.4 (1.02.9) 0.13
3rd Quartile 1.5 (1.12.2) 0.02 1.3 (0.91.9) 0.01
4th Quartile 2.1 (1.52.9) b0.0001 1.6 (1.12.4)
Age (per 10 years 1.3 (1.11.4) b0.0001 1.2 (1.11.4) b0.0001
increase)
Bun (per 10 mg/dL 1.2 (1.101.3) b0.0001 1.1 (1.01.2) 0.001
increase)
Elevated cTnI 1.6 (1.22.2) 0.002 1.5 (1.12.1) 0.02
LVEF b 50% 1.8 (1.42.4) b0.0001 1.6 (1.22.1) 0.004
Beta blocker 0.8 (0.61.0) 0.03 0.7 (0.60.9) 0.02

* The Cox models were adjusted for age, gender, history of diabetes, hypertension, smoking status, estimated glomerular ltration rate (eGFR), blood urea nitrogen (BUN), serum
sodium, atrial brillation, elevated cardiac troponin I, BNP levels and medical therapy (beta blockers, angiotensin converting-enzyme inhibitors, loop diuretics, spironolactone and
digoxin), baseline hemoglobin and for left ventricular ejection fraction.
 B.F. Makhoul et al. / International Journal of Cardiology 167 (2013) 14121416 1415

rates were 44.9%, 43.0%, 54.7% and 67.8% in the rst, second, third and
fourth RDW quartile respectively.
The results of a multivariable Cox model are shown in Table 3. Both
RDW and BNP levels remained independent predictors of 1-year mor-
tality or rehospitalization for HF together with age, reduced LVEF,
elevated BUN, elevated cTnI and use of beta-blockers. The most pro-
nounced increase in mortality occurred from the third to the forth
RDW quartile. Using RDW as a continuous rather than categorical vari-
able in the same model, the adjusted HR for 1% increase in RDW during
hospital course was 1.15 (95% CI 1.081.21, P b 0.0001).

3.2. Changes in RDW during hospital course

The distribution of RDW change during hospital course is shown

in Fig. 3. We categorized the patients into 4 groups based on whether
RDW was within the normal range at both the rst and second mea-
surements (n = 392 [63.8%]), elevated at the rst but normal at the
second (n = 34 [5.5%]), normal at the rst and elevated at the second
(n = 43 [7.0%]), or elevated at both time points (n = 145 [23.6%]).
The relationship between changes in RDW during hospital course
and the primary endpoint is shown in Fig. 4A. Patients with normal
RDW at both time points had the best outcome. There was a marked
increase in mortality and rehospitalization among patients in whom
RDW became elevated during hospital course. Similar results were
obtained after multivariable adjustments in a Cox model (Fig. 4B).
However, the outcome of patients with a reduction of RDW into the
normal range was similar to that of patients with normal RDW at
both timepoints. After forcing length of hospital days, intravenous
iron therapy, erythropoietin therapy and blood transfusion in the
model, compared with patients with persistent normal RDW, the ad-
justed HR for the primary endpoint was 1.9 [95% CI 1.23.1] for pa-
tients in whom RDW increased above 14.5% during hospital course,
0.5 [0.21.1] in patients with elevated RDW at baseline but normal
RDW at the second measurement and 1.7 (95% CI 1.22.3) in patients
with persistent elevation of RDW. Using RDW change as a continuous
variable, the adjusted HR for 1% increase in RDW during hospital
course was 1.23 (95% CI 1.091.38, P = 0.001). Fig. 4. (A) Cumulative incidence of subsequent death according to changes in RDW during
hospital course. Each group is labeled by the RDW at baseline and follow-up. For example,
4. Discussion the group with elevated RDW at both timepoints is labeled as elevated-elevated and
the group with normal baseline RDW and elevated RDW at follow-up is labeled as
normal-elevated. (B) Adjusted hazard ratios and 95% condence intervals are shown
The results of the present study add signicantly to the available for each RDW category, using the Normal-Normal category as reference.
data regarding the clinical signicance of elevated RDW in HF
patients. As in previous studies, there was a positive graded associa-
tion between baseline RDW and risk of readmission for HF or death. However, the present study demonstrates that RDW is a dynamic vari-
able that may rapidly change during hospital course. Importantly, an in-
crease in RDW during hospitalization was a strong independent
predictor of greater morbidity and mortality. This association remained
independent after adjustment for a multiple risk factors including renal
function, BNP levels and LVEF.
An important and unique nding in our analysis was the strong prog-
nostic value of changes in RDW levels during hospital course. There was
a marked increase in mortality and rehospitalizations among patients
with normal RDW values at admission in whom RDW became elevated
during hospital course. Thus, elevations of RDW occurring during hospi-
tal course shifted patients to a substantially higher risk. On the other
hand normalization of an elevated RDW value on admission was associ-
ated with better outcome. These results suggest that changes in RDW
during hospitalization provides a simple and sensitive measure that re-
ects individual changes in risk and can be used by clinicians to quickly
reclassify patient risk.
Red blood cell distribution width reects the variability in size of
circulating red blood cells and, when elevated, denes the state of
Fig. 3. Frequency distribution (expressed as percentage of the entire population) of anisocytosis. RDW is dened as the standard deviation of erythrocyte
RDW change during hospital course in the study population. The upper panel is a
box-and whisker plot of the RDW change. The line within the box denotes the median
size divided by the mean corpuscular volume (MCV) [14]. MCV and
and the box spans the interquartile range (25th to 75th percentiles). Whiskers extend RDW together can help to differentiate between several etiologies of
from the 5th to 95th percentiles. anemia. RDW is increased in iron deciency, B12 or folate deciency,
1416 B.F. Makhoul et al. / International Journal of Cardiology 167 (2013) 14121416
hemoglobinopathies, hemolysis and after blood transfusion [1517].
Felker et al. were the rst to report the excess mortality and morbid-
ity in patients with chronic heart failure and elevated RDW [18].
Other studies have conrmed this nding in patients with stable HF
[7] as well as in the decompensated state [4,5].
The mechanisms underlying the association between RDW and
outcome of heart failure are not fully understood. Several studies sug-
gested that RDW may be related to the degree of inammation, inad-
equate production of erythropoietin and nutritional status [19,20].
The inammatory mechanism is believed to be mediated by the re-
lease of pro-inammatory cytokines which in turn block the activity
of erythropoietin and cause the production of ineffective RBC and el-
evated RDW [2123]. Lippi et al. found a correlation between high
RDW and elevated indices of inammation, such as elevated erythro-
cyte sedimentation rate and C-reactive protein [23]. This correlation
was independent of concomitant diseases, and was demonstrated
even when anemic patients were excluded from the analysis [23].
Malnutrition markers, including total cholesterol, are believed to be
signicantly related with RDW [7]. In addition, renal function which is a
factor linked with malnutrition and inammation in heart failure, is as-
sociated with RDW values [24]. Therefore, it is reasonable to assume
that RDW is a good integrative marker of this complex malnutrition-
inammation syndrome in patients with heart failure. However,
markers of inammation, renal function and nutritional deciencies ex-
plain only a small fraction of the variability in RDW values. The present
study demonstrates that rapid changes in RDW may occur in ADHF,
suggesting that the increased inammatory and oxidative stress that
characterized HF exacerbations and impact on patient outcome [25],
may also lead to an acute increase in RDW values. In these patients, in-
tervening events such as the development of excessive neurohormonal
activation may also contribute to RDW change. By contrast, the poor
correlation between RDW and BNP levels suggest that hemodynamic
factors have little inuence or RDW values.
4.1. Study limitations
Our study has some limitations that merit emphasis. The time of
the repeated blood counts were determined according to the discre-
tion of the treating physician. Thus, it is possible that some patients
were misclassied because repeated RDW values were obtained too
early with respect to peak values.
Our study does not provide a mechanism for the association be-
tween rapid changes in RDW and adverse outcome in ADHF. There
was no data about important factors that may explain elevated
RDW such as reticulocyte count, erythropoietin levels, measures of
haemolysis, or measurements of folate, vitamin B12, and iron. Addi-
tional studies are needed to determine the underlying factors that af-
fect RDW variation in HF patients.
4.2. Conclusion
In patients with ADHF, baseline RDW levels on admission are fre-
quently elevated and are positively associated with rates of mortality
and readmission rates. RDW is a dynamic variable that may rapidly
change in ADHF. An increase in RDW portends higher mortality and
rehospitalization after hospital discharge.
Acknowledgement
The authors of this manuscript have certied that they comply
with the Principles of Ethical Publishing in the International Journal
of Cardiology.
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