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European Journal of Heart Failure 2005 7(1):69-74; doi:10.1016/j.ejheart.2004.04.012
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© 2004 European Society of Cardiology

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 and Jens Kastrupa

a Cardiac Catheterization Laboratory Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
b Department of Clinical Biochemistry section 3014, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100, Copenhagen, Denmark

* Corresponding author. Tel.: +45-3545-8323; fax: +45-3545-4640. E-mail address: jpg{at}dadlnet.dk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
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.

Key Words: B-type natriuretic peptide • Cardiac secretion • Heart failure • Natriuretic peptide • proBNP

Received November 26, 2003; Revised March 3, 2004; Accepted April 26, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
A hallmark of the endocrine heart is augmented synthesis and secretion of natriuretic peptides during cardiac dysfunction. Accordingly, an increased plasma concentration 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 fragment 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 cardiac BNP 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 maturation [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.

The cardiac secretion of BNP-32 has been well documented 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 analytical bias. Secondly, proBNP circulates as oligomeric complexes comprising three to four proBNP (or proANP) molecules [21,22], which further complicates antibody binding 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
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
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 creatinine, and left ventricular ejection fraction was estimated by ventriculography. Only patients with minor mitral regurgitation 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 fraction: 60%, range 50–60%), and normal renal function (median serum creatinine: 89 µmol/l, range 68–130 µmol/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).


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  		Table 1 Patient characteristics and hemodynamics (n=21)

 
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 °C.

2.3. BNP-32 and proBNP analyses
The BNP-32 concentrations were measured with a commercial 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 concentration in plasma was measured with a processing-independent 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. Furthermore, the troublesome precursor oligomerization is eliminated [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 cardiac disease is 15 pmol/l (97.5th percentile; 95% confidence 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
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Patient characteristics including hemodynamic findings at catheterization are listed in Table 1. All heart failure patients had severely reduced left ventricular ejection fraction 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 approximately 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).


Figure 1
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  		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.

 
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 concentrations were highly correlated both for BNP-32 (Fig. 2a) and for proBNP (Fig. 2b). However, the BNP-32 concentration 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 coronary sinus and the inferior caval vein was 1.8-fold higher for BNP-32 than for proBNP (P=0.009, Fig. 3b).


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  		Table 2 Regional plasma BNP-32 and proBNP concentrations in heart failure patients

 


Figure 2
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  		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.

 


Figure 3
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  		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.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
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 concentrations 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 ventricular—but not atrial—BNP gene expression in patients with chronic ischemic heart disease [27]. It therefore seems reasonable to assume that the present findings predominantly 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 proBNP and its N-terminal fragment with different potencies. The molar relation of BNP-32 and proBNP concentrations in venous blood from failing hearts has, therefore not yet been resolved. Our results show that the total proBNP concentration measured with a processing independent analysis is closely associated to the BNP-32 concentrations (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 immunoreactivity 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 difference 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].


   Acknowledgements
 
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
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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S. J. Nielsen, J. F. Rehfeld, F. Pedersen, J. Kastrup, R. Videbaek, and J. P. Goetze
Measurement of Pro-C-Type Natriuretic Peptide in Plasma
Clin. Chem., November 1, 2005; 51(11): 2173 - 2176.
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