B-type natriuretic peptide and its precursor in cardiac venous blood

from failing hearts

Jens Peter Goetzea,b,*, Jens F. Rehfeldb, Regitze Videbaeka, Lennart Friis-Hansenb, Jens Kastrupa

aCardiac Catheterization Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, DenmarkbDepartment of Clinical Biochemistry, section 3014, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100, Copenhagen, Denmark

Received 26 November 2003; received in revised form 3 March 2004; accepted 26 April 2004

Available online 28 July 2004

Abstract

Background: Plasma concentrations of B-type natriuretic peptide (BNP-32) and its precursor (proBNP) are increased in chronic heart

failure. Accordingly, BNP-32 and proBNP are both being implemented as clinical markers. Aim: To determine the molar relation of BNP-32

and proBNP in different cardiovascular regions. Methods and results: Blood samples were obtained from different cardiovascular regions

during right heart catheterization in heart failure patients, and from normal subjects. Plasma BNP-32 and proBNP concentrations were

measured using sequence-specific radioimmunoassays. Patients with severe left ventricular dysfunction (n=21) displayed increased

peripheral plasma concentrations of both BNP-32 (four-fold, P=0.0008) and proBNP (seven-fold, P=0.0002) compared with normal subjects.

Moreover, the peripheral concentrations were highly correlated with the corresponding concentrations in the coronary sinus (BNP-32: r=0.97,

P<0.0001; proBNP: r=0.94, P<0.0001). Despite comparable peripheral concentrations of BNP-32 and proBNP, the BNP-32 concentration

was higher than the proBNP concentration in the coronary sinus (median 126 pmol/l (21–993) vs. 103 pmol/l (16–691), P=0.035).

Conclusions: The BNP-32 and proBNP concentrations are closely related in venous cardiac blood. The findings suggest an overall

constitutive secretion of processed proBNP, i.e. an N-terminal precursor fragment and BNP-32, in chronic heart failure.

D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Keywords: B-type natriuretic peptide; Cardiac secretion; Heart failure; Natriuretic peptide; proBNP

1. Introduction

A hallmark of the endocrine heart is augmented syn-

thesis and secretion of natriuretic peptides during cardiac

dysfunction. Accordingly, an increased plasma concentra-

tion of B-type natriuretic peptide (BNP-32) is a marker of

chronic heart failure [1]. The biosynthetic precursor,

proBNP, also circulates in plasma together with the

complementary N-terminal fragment to BNP-32 [2–4].

Plasma measurements of proBNP and its N-terminal frag-

ment are likewise useful in heart failure diagnosis and

therapy [5–8]. The N-terminal amino acid sequence of

proBNP seems more stable than BNP-32 in plasma and

may, therefore represent a practical marker in routine

handling and laboratory analysis [3,4,9,10]. In addition,

the metabolic half-live of N-terminal proBNP has been

suggested to be considerably longer than for BNP-32 [11],

which in turn also could favour proBNP and its N-

terminal fragment as the ‘markers of choice’ in chronic

heart failure.

Normal cardiacBNP expression is predominantly a feature

of atrial myocytes, which instantly respond to atrial distension

by secretion of natriuretic hormones [12]. Accordingly, atrial

myocytes possess a phenotype like other endocrine cells, i.e.

the presence of secretory granules and functional expression

of endoproteolytic enzymes essential for prohormone matu-

ration [13–15]. In contrast, normal ventricular myocytes do

not contain secretory granules for peptide storage, and they

predominantly express the BNP gene during disease like

ventricular dysfunction [16,17]. In this way, the source of

cardiac peptides shifts from the atrium to the ventricle in

chronic heart failure, and the molecular heterogeneity of the

secreted peptides may consequently also differ.

1388-9842/$ - see front matter D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.ejheart.2004.04.012

* Corresponding author. Tel.: +45-3545-8323; fax: +45-3545-4640.

E-mail address: jpg@dadlnet.dk (J.P. Goetze).

www.elsevier.com/locate/heafai

The European Journal of Heart Failure 7 (2005) 69–74

The cardiac secretion of BNP-32 has been well docu-

mented in chronic heart failure [18–20]. In contrast, cardiac

secretion of proBNP and its N-terminal fragment has so far

only been reported in seven patients [5]. Although a well-

validated radioimmunoanalysis for N-terminal proBNP was

used in that study, the molar concentrations may not be

exact. Firstly, antibody binding to intact proBNP and N-

terminal fragments may differ and thereby introduce ana-

lytical bias. Secondly, proBNP circulates as oligomeric

complexes comprising three to four proBNP (or proANP)

molecules [21,22], which further complicates antibody bind-

ing kinetics. To overcome these analytical problems, we

have developed a processing-independent analysis (PIA)

[4]. Using this type of analysis, proBNP and its N-terminal

fragment are measured with an equal affinity and the total

concentration of proBNP-derived products in plasma can be

accurately quantitated regardless of prohormone maturation

and oligomerization.

The aim of the present study was, therefore to determine

the molar relation between BNP-32 and proBNP in different

cardiovascular regions using sequence-specific assays,

including the proBNP PIA assay. Together, the results

suggest an overall constitutive secretion of processed

proBNP products, i.e. an N-terminal precursor fragment

and BNP-32, in chronic cardiac failure.

2. Methods

2.1. Patients

Blood samples were collected from 21 chronic heart

failure patients undergoing right heart catheterization for

evaluation prior to cardiac transplantation (Table 1). All

patients were on standard medical treatment for congestive

heart failure. Renal function was assessed by serum crea-

tinine, and left ventricular ejection fraction was estimated

by ventriculography. Only patients with minor mitral regur-

gitation were included in the present study. Coronary

angiography had disclosed coronary artery disease in five

of the 21 patients, and four patients suffered from chronic

atrial fibrillation. In addition, 12 subjects initially referred

for coronary angiography for suspected coronary artery

disease were included as controls (six females and six

males, median age 59 years, range 37–72 years). All

control subjects displayed normal findings on angiography

and ventriculography (median left ventricular ejection frac-

tion: 60%, range 50–60%), and normal renal function

(median serum creatinine: 89 Amol/l, range 68–130

Amol/l). All patients and control subjects gave informed

and written consent for participation in the study, and the

study protocol was approved by the local ethics committee

(KF 01-231/99).

2.2. Catheterization and blood sampling

Right heart catheterization was performed in the heart

failure patients with either an eight French Swann-Ganz

catheter or a six French multipurpose catheter. In both cases,

pressures were recorded in the right atrium, right ventricle

and the trunk of the pulmonary artery. Cardiac output was

determined by either Fick’s oxygen method or continuous

thermo-dilution. Cardiac index was calculated as cardiac

output/body surface area. Blood was collected in chilled 10

ml vacutainers containing Na2- EDTA (1.5 mg/ml) or Na2-

EDTA (1.5 mg/ml) with aprotinin (500 KIU/ml). Twenty

millilitres of blood was sampled from the inferior caval

vein, the right atrium and right ventricle, and the trunk of the

pulmonary artery. In 14 of the 21 patients, an additional

sample was obtained from the coronary sinus with the

position of the catheter tip verified by a small retrograde

infusion of contrast agent under fluoroscopic guidance. In

the control subjects, blood samples were obtained from the

aortic root prior to angiography and ventriculography. The

plasma was separated by centrifugation immediately after

the invasive procedure and stored at �80 jC.

2.3. BNP-32 and proBNP analyses

The BNP-32 concentrations were measured with a com-

mercial immunoradiometric assay (Shionoria BNP, Osaka,

Japan [23–25]). This assay detects BNP-32 with no cross-

reactivity to proBNP. Lowest level of detection is 0.6 pmol/l

(1 pmol/l equals 3.46 pg/ml) with an upper reference limit in

normal individuals of 5.3 pmol/l. The assay imprecision is

2.7% at 6.4 pmol/l and 2.0% at 149 pmol/l (within-runs)

according to the manufacturer. The total proBNP concen-

tration in plasma was measured with a processing-independ-

ent assay (PIA) [4]. This assay quantifies the total

concentration of prohormone products after a pre-analytical

enzymatic step [26]. Briefly, plasma is incubated with a

protease (trypsin) that cleaves proBNP after an amino acid

in position 21. In this way, intact proBNP and its N-terminal

fragment are both cleaved into the same analyte. Further-

more, the troublesome precursor oligomerization is elimi-

nated [4]. The released fragment is measured with a

conventional radioimmunoassay specific for the N-terminal

decapeptide. Assay imprecision within-runs is 12% at 13

pmol/l and 5% at 130 pmol/l. The assay sensitivity is 0.2

pmol/l, and the upper reference limit in individuals without

Table 1

Patient characteristics and hemodynamics (n=21)

Age in years 52 (26–62)

Male gender (% of total) 81

Patients in NYHA class III and IV (%) 76

Serum creatinine (Amol/l) 107 (71–162)

Left ventricular ejection fraction (%) 20 (10–35)

Mean right atrial pressure (mmHg) 9 (4–23)

Mean pulmonary artery pressure (mmHg) 30 (13–50)

Cardiac index (l/min m2) 2.4 (1.3–3.4)

Data are listed as medians with ranges. NYHA: New York Heart

Association heart failure classification system.

J.P. Goetze et al. / The European Journal of Heart Failure 7 (2005) 69–7470

cardiac disease is 15 pmol/l (97.5th percentile; 95% con-

fidence interval: 9–16 pmol).

2.4. Statistics

Results are listed as medians with ranges. The Mann–

Whitney test was used for comparison of data between heart

failure patients and control subjects, and the Wilcoxon

matched pairs test for comparison of data within groups.

Due to non-Gaussian distribution and small sample sizes,

data were logarithmically transformed (log 10) before

regression analyses, and P-values <0.05 were considered

statistically significant.

3. Results

Patient characteristics including hemodynamic findings

at catheterization are listed in Table 1. All heart failure

patients had severely reduced left ventricular ejection frac-

tion on ventriculography, and > 70% of the patients had a

mean pulmonary artery pressure greater than 25 mmHg at

rest. The BNP-32 concentration was increased approxi-

mately four-fold (50 pmol/l (5–705) vs. 14 pmol/l (0.1–

50), P=0.0008) in peripheral plasma from the heart failure

patients, and the proBNP concentration was increased

approximately seven-fold (70 pmol/l (3–500) vs. 12 pmol/

l (0–43), P=0.0002) compared with control subjects. There

were no differences between the BNP-32 and proBNP

concentrations in peripheral plasma from the heart failure

patients (Fig. 1) or in the control subjects. The peripheral

BNP-32 and proBNP concentrations were correlated both in

the heart failure patients (r=0.73, P=0.0002), and in the

control subjects (r=81, P=0.0014).

The BNP-32 and proBNP concentrations in different

cardiovascular regions are shown in Table 2. Only a minor

difference in the local BNP-32 concentration was found

between plasma from the inferior caval vein and the right

ventricle (P=0.015). In addition, a blood sample was

obtained from the coronary sinus in 14 of the patients. Both

the BNP-32 and the proBNP concentrations were increased

more than two-fold in the coronary sinus compared to the

inferior caval vein (BNP-32: 125 pmol/l (21–993) vs. 52

pmol/l (7–705), P<0.0001; proBNP: 103 pmol/l (16–691)

vs. 47 pmol/l (8–500), P<0.0001). The regional concen-

trations were highly correlated both for BNP-32 (Fig. 2a)

and for proBNP (Fig. 2b). However, the BNP-32 concen-

tration was 1.2-fold higher than the proBNP concentration

in plasma from the coronary sinus (Fig. 3a). Accordingly,

the regional difference in concentrations between the coro-

nary sinus and the inferior caval vein was 1.8-fold higher for

BNP-32 than for proBNP (P=0.009, Fig. 3b).

4. Discussion

The present study shows a close relation between BNP-

32 and N-terminal proBNP concentrations in different

cardiovascular regions. Plasma from the coronary sinus in

heart failure patients contain highly increased concentra-

tions of both BNP-32 and N-terminal proBNP compared

with peripheral plasma, and the BNP-32 concentration was

even higher than the corresponding N-terminal proBNP

concentration in the coronary sinus. Taken together, the

results suggest an overall constitutive secretion of processed

proBNP, i.e. an N-terminal precursor fragment and BNP-32,

in chronic cardiac failure.

Cardiac secretion of BNP-32 in heart failure has been

reported previously [5,18–20]. The principal source of

BNP-32 has been shown to be the failing left ventricle by

regional blood sampling from the anterior interventricular

vein [18]. In parallel, we recently reported that plasma BNP-

32 and proBNP concentrations are associated with ventric-

ular—but not atrial—BNP gene expression in patients with

chronic ischemic heart disease [27]. It therefore seems

reasonable to assume that the present findings predomi-

nantly reflect ventricular secretion. Cardiac secretion of

proBNP has so far only been reported in seven patients

[5]. However, the study utilized a radioimmunoassay that

measures the N-terminus of proBNP which may detect

Fig. 1. Peripheral plasma BNP-32 and proBNP concentrations in chronic

heart failure patients (n=21). The horizontal lines indicate median

concentrations and connected points represent data obtained from the same

patient.

Table 2

Regional plasma BNP-32 and proBNP concentrations in heart failure

patients

Cardiovascular region BNP-32 (pmol/l) proBNP (pmol/l)

Inferior caval vein 50 (5–705) 70 (3–500)

Right atrium 55 (7–689) 56 (4–387)

Right ventricle 56 (7–734)* 60 (5–429)

Pulmonary artery 46 (5–691) 60 (5–327)

Concentrations are listed as medians with ranges. Data were obtained from

regional blood sampling in the heart failure patients (n=21).* Only a difference in the local BNP-32 concentration between the

inferior caval vein and the right ventricle was found ( P=0.015).

J.P. Goetze et al. / The European Journal of Heart Failure 7 (2005) 69–74 71

proBNP and its N-terminal fragment with different poten-

cies. The molar relation of BNP-32 and proBNP concen-

trations in venous blood from failing hearts has, therefore

not yet been resolved. Our results show that the total

proBNP concentration measured with a processing inde-

pendent analysis is closely associated to the BNP-32 con-

centrations (Fig. 1), and that the BNP-32 concentration in

plasma from the coronary sinus is even higher than the

proBNP concentration (Fig. 3a). These results, therefore

suggest that the chronically failing heart predominantly

releases processed proBNP. This is in agreement with a

chromatographic evaluation of N-terminal proBNP immu-

noreactivity in coronary sinus plasma, where only one

molecular form was detected [5]. In addition, the peripheral

plasma concentrations of both BNP-32 and proBNP are

closely correlated to the concentrations in the coronary sinus

(Fig. 2). Thus, the peripheral concentrations of both peptides

reflect cardiac release in chronic heart failure patients with

normal renal function. Of note, it still remains to be clarified

whether the prohormone maturation is also efficient in acute

cardiac disease, where the BNP gene expression is rapidly

upregulated, i.e. acute ventricular failure and acute coronary

syndromes [28].

Cardiac secretion is determined as the difference in

concentration between arterial (aortic or femoral) plasma

and plasma from the coronary sinus. This technique can

demonstrate secretion into the cardiac veins but does not

account for endocardial secretion into the cardiac chambers.

Our study was based on right heart catheterization, and

concomitant samples from the femoral artery were only

obtained in four patients. However, the concentration differ-

Fig. 3. Panel (a) shows the BNP-32 and proBNP concentrations in plasma

from the coronary sinus. Panel (b) shows the regional difference between

the coronary sinus and the inferior caval vein concentrations. The horizontal

lines indicate median concentrations and points connected with a line

represent data obtained from the same patient.

Fig. 2. Panel (a) shows the association of the BNP-32 concentration in

plasma from the coronary sinus and plasma from the inferior caval vein,

and panel (b) shows the association of proBNP concentrations in the same

samples (n=14). Each point represents data obtained from individual

patients, and the data were logarithmically transformed prior to regression

analysis.

J.P. Goetze et al. / The European Journal of Heart Failure 7 (2005) 69–7472

ence between the femoral vein and the femoral artery was

negligible in these patients (0–10%, data not shown).

Furthermore, the previous report on proBNP secretion did

not describe a significant concentration gradient between

plasma from the femoral artery and the femoral vein [5]. In

parallel, we could not demonstrate a proBNP gradient

between plasma from the femoral artery and the femoral

vein in patients with right ventricular heart failure [29]. The

present proBNP measurements in peripheral and coronary

sinus plasma, therefore seem to represent an overall cardiac

secretion. In addition, previous studies on BNP-32 secretion

reported cardiac gradients ranging from 1.6-fold to 2.9-fold

[5,18–20]. Accordingly, the present findings of a 2.4-fold

difference in BNP-32 from the coronary sinus to the inferior

caval vein are in line with these results, although the

concentration in plasma from the inferior caval vein may

also reflect some peripheral elimination (Fig. 3b).

Interestingly, there was a significantly lower proBNP

compared to BNP-32 concentration in plasma from the

coronary sinus (Fig. 3a). This could suggest that the cardiac

secretion of proBNP is different from the BNP-32 secretion.

However, the difference could also be due to a selective

pulmonary clearance of proBNP. In fact, we recently found

that the local proBNP concentration is significantly higher

in the pulmonary artery than the aortic root in patients with

right ventricular failure [29]. The small difference in the

proBNP and BNP-32 concentrations in the coronary sinus

may, therefore reflect differences in clearance rather than

differences in secretion.

In conclusion, the molar relation of proBNP and BNP-32

is closely associated in venous cardiac blood. The findings,

therefore, suggest an overall constitutive cardiac secretion of

processed proBNP, i.e. an N-terminal precursor fragment

and BNP-32, in chronic heart failure, and provide an

expedient explanation for the strikingly similar performance

of BNP-32 and proBNP in clinical trials [30].

Acknowledgments

The expert technical assistance of Lone Olsen and Bo

Lindberg are most gratefully acknowledged. The study was

supported by grants from the Danish Heart Foundation and

the Yde Foundation.

References

[1] De Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide

in cardiovascular disease. Lancet 2003;362:316–22.

[2] Hunt PJ, Yandle TG, Nicholls MG, Richards AM, Espiner EA. The

amino-terminal portion of pro-brain natriuretic peptide (Pro-BNP)

circulates in human plasma. Biochem Biophys Res Commun 1995;

214:1175–83.

[3] Schulz H, Langvik TA, Lund SE, Smith J, Ahmadi N, Hall C. Radio-

immunoassay for N-terminal probrain natriuretic peptide in human

plasma. Scand J Clin Lab Invest 2001;61:33–42.

[4] Goetze JP, Kastrup J, Pedersen F, Rehfeld JF. Quantification of pro-B-

type natriuretic peptide and its products in human plasma by use of an

analysis independent of precursor processing. Clin Chem 2002;48:

1035–42.

[5] Hunt PJ, Richards AM, Nicholls MG, Yandle TG, Doughty RN,

Espiner EA. Immunoreactive amino-terminal pro-brain natriuretic

peptide (NT-PROBNP): a new marker of cardiac impairment. Clin

Endocrinol (Oxf) 1997;47:287–96.

[6] Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG,

Richards AM. Treatment of heart failure guided by plasma amino-

terminal brain natriuretic peptide (N-BNP) concentrations. Lancet

2000;355:1126–30.

[7] Bay M, Kirk V, Parner J, et al. NT-proBNP: a new diagnostic screen-

ing tool to differentiate between patients with normal and reduced left

ventricular systolic function. Heart 2003;89:150–4.

[8] Gardner RS, Ozalp F, Murday AJ, Robb SD, McDonagh TA.

N-terminal pro-brain natriuretic peptide. A new gold standard in pre-

dicting mortality in patients with advanced heart failure. Eur Heart J

2003;24:1735–43.

[9] Hunt PJ, Espiner EA, NichollsMG, Richards AM, Yandle TG. The role

of the circulation in processing pro-brain natriuretic peptide (proBNP)

to amino-terminal BNP and BNP-32. Peptides 1997;18:1475–81.

[10] Downie PF, Talwar S, Squire IB, Davies JE, Barnett DB, Ng LL.

Assessment of the stability of N-terminal pro-brain natriuretic peptide

in vitro: implications for assessment of left ventricular dysfunction.

Clin Sci (Lond) 1999;97:255–8.

[11] Pemberton CJ, Johnson ML, Yandle TG, Espiner EA. Deconvolution

analysis of cardiac natriuretic peptides during acute volume overload.

Hypertension 2000;36:355–9.

[12] de Bold AJ, Bruneau BG, Kuroski de Bold ML. Mechanical and

neuroendocrine regulation of the endocrine heart. Cardiovasc Res

1996;31:7–18.

[13] Christoffersen C, Goetze JP, Bartels ED, et al. Chamber-dependent

expression of brain natriuretic peptide and its mRNA in normal and

diabetic pig heart. Hypertension 2002;40:54–60.

[14] Wu F, Yan W, Pan J, Morser J, Wu Q. Processing of pro-atrial natriu-

retic peptide by corin in cardiac myocytes. J Biol Chem 2002;277:

16900–5.

[15] Yan W, Wu F, Morser J, Wu Q. Corin, a transmembrane cardiac serine

protease, acts as a pro-atrial natriuretic peptide-converting enzyme.

Proc Natl Acad Sci USA 2000;97:8525–9.

[16] Takemura G, Takatsu Y, Doyama K, et al. Expression of atrial and

brain natriuretic peptides and their genes in hearts of patients with

cardiac amyloidosis. J Am Coll Cardiol 1998;31:754–65.

[17] Wiese S, Breyer T, Dragu A, et al. Gene expression of brain natriu-

retic peptide in isolated atrial and ventricular human myocardium:

influence of angiotensin II and diastolic fiber length. Circulation

2000;102:3074–9.

[18] Mukoyama M, Nakao K, Hosoda K, et al. Brain natriuretic peptide as

a novel cardiac hormone in humans. Evidence for an exquisite dual

natriuretic peptide system, atrial natriuretic peptide and brain natriu-

retic peptide. J Clin Invest 1991;87:1402–12.

[19] Mizuno Y, Yoshimura M, Yasue H, et al. Aldosterone production is

activated in failing ventricle in humans. Circulation 2001;103:72–7.

[20] Kalra PR, Clague JR, Bolger AP, et al. Myocardial production of

C-type natriuretic peptide in chronic heart failure. Circulation 2003;

107:571–3.

[21] Seidler T, Pemberton C, Yandle T, Espiner E, Nicholls G, Richards M.

The amino terminal regions of proBNP and proANP oligomerise

through leucine zipper-like coiled-coil motifs. Biochem Biophys

Res Commun 1999;255:495–501.

[22] Shimizu H, Masuta K, Asada H, Sugita K, Sairenji T. Characterization

of molecular forms of probrain natriuretic peptide in human plasma.

Clin Chim Acta 2003;334:233–9.

[23] Nishikimi T, Yoshihara F, Morimoto A, et al. Relationship between

left ventricular geometry and natriuretic peptide levels in essential

hypertension. Hypertension 1996;28:22–30.

J.P. Goetze et al. / The European Journal of Heart Failure 7 (2005) 69–74 73

[24] Clerico A, Del Ry S, Maffei S, Prontera C, Emdin M, Gianessi D. The

circulating levels of cardiac natriuretic hormones in healthy adults:

effects of age and sex. Clin Chem Lab Med 2002;40:371–7.

[25] Redfield MM, Rodefelder RJ, Jacobsen SJ, Mahoney DW, Bailey KR,

Burnett Jr JC. Plasma brain natriuretic peptide concentration: Impact

of age and gender. J Am Coll Cardiol 2002;40:976–82.

[26] Rehfeld JF, Goetze JP. The posttranslational phase of gene expression:

new possibilities inmolecular diagnosis. CurrMolMed 2003;3:25–38.

[27] Goetze JP, Christoffersen C, Perko M, et al. Increased cardiac BNP

expression associated with myocardial ischemia. FASEB J 2003;

17:1105–7.

[28] Goetze JP, Kastrup J, Rehfeld JF. The paradox of increased natriuretic

hormones in congestive heart failure patients: does the endocrine

heart also fail in heart failure? Eur Heart J 2003;24:1471–2.

[29] Goetze JP, Videbaek R, Boesgaard S, Aldershvile J, Rehfeld JF,

Carlsen J. Pro-brain natriuretic peptide as marker of cardiovascular

or pulmonary causes of dyspnea in patients with terminal parenchy-

mal lung disease. J Heart Lung Transplant 2004;23:80–7.

[30] Richards AM, Nicholls MG, Espiner EA, et al. B-type natriuretic

peptides and ejection fraction for prognosis after myocardial infarc-

tion. Circulation 2003;107:2786–92.

J.P. Goetze et al. / The European Journal of Heart Failure 7 (2005) 69–7474

Copyright of European Journal of Heart Failure is the property of Oxford University Press / UK and its content

may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express

written permission. However, users may print, download, or email articles for individual use.