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European Journal of Heart Failure 2003 5(2):155-160; doi:10.1016/S1388-9842(02)00247-7
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© 2002 European Society of Cardiology

Bedside B-type natriuretic peptide and functional capacity in chronic heart failure

P. Jourdaina,*, F. Funcka, M. Bellorinia, N. Guillarda, J. Loireta, B. Thebaulta, M. Desnosb and D. Dubocc

a Service de Cardiologie Centre Hospitalier René Dubos 6 avenue d'Ile de France 95300 Pontoise, France
b Service de Cardiologie, Hôpital Européen G. Pompidou Avenue Leblanc 75015 Paris, France
c Service de Cardiologie Hôpital Cochin 24 Bd Saint Jacques 75014 Paris, France

* Corresponding author. Tel.: +33-1-30-75-41-86; fax: +33-1-30-75-44-28 E-mail address: patrickjourdain{at}hotmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Objectives: To determine if B-type natriuretic peptide (BNP) measurement could be useful in determination of functional capacity in patients suffering from chronic heart failure.

Background: Evaluating functional capacity is a crucial factor in the follow-up of patients with chronic heart failure. There are numerous methods for measuring functional capacity and their relative merits remain under discussion. Clinical classifications are very subjective and other methods are difficult to use in clinical practice.

Methods: We evaluated functional capacity in 151 consecutive patients using the 6-min walk test. All patients were clinically classified using the New York Heart Association (NYHA) classification. We measured BNP plasma levels using a bedside BNP test.

Results: Six minute walk test performance decreased through NYHA classes 1 to 4 (469±87, 411±82, 325±83 and 196±63 m, respectively, P<0.01) and BNP levels increased through NYHA classes 1 to 4 (26.3±7.2, 73±13, 401±74 and 924±84 pg/ml, respectively, P<0.001). There was a significant correlation between 6-min walk test performance and BNP plasma levels (R=0.69 P<0.001) and a weaker correlation between BNP and left ventricular ejection fraction (R=0.45 P<0.04). In some patients there was a mismatch between NYHA classification and 6-min walk test performance. In all cases BNP could correct the clinical estimation of functional capacity. When we divided the patients into three sub-groups within each NYHA class, we showed that using BNP could better define functional capacity in patients suffering from chronic heart failure in NYHA classes I to III.

Conclusion: The measurement of BNP levels thus usefully supplements the clinical examination. The existence of bedside BNP testing methods facilitates its use in routine clinical practice. It also permits easier follow-up of patients with chronic heart failure.

Key Words: B-type natriuretic peptide • Functional capacity • Chronic heart failure • Six minute walk test

Received September 26, 2001; Revised February 21, 2002; Accepted May 1, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Chronic heart failure is a major health problem whose importance has progressively increased over recent years [1–3]. The reduction of functional capacity in patients suffering from this disease is one of the key factors in diagnosis. Evaluating the limitations of functional capacity on physical effort makes it possible to confirm the diagnosis, to estimate prognosis and to measure the effectiveness of therapy. Evaluating functional capacity is thus a crucial element in the follow-up of patients suffering from chronic heart failure. That being known, there are numerous methods of measuring functional capacity and their relative merits remain under discussion. Two methods for determining functional capacity are currently used in clinical practice. One is the determination of New York Heart Association (NYHA) class [4] and the second involves the 6-min walk test [5,6]. Since these two methods are simple to undertake and do not require any specialised equipment, they can be performed routinely by all cardiologists. However, the NYHA classification system is sometimes difficult to use and does not always allow correct estimation of the severity of the disease among certain patients [7]. The measurement of B-type natriuretic peptide (BNP) is a recognized prognostic marker in chronic heart failure [8]. The aim of this study was to identify the relationship between this objective biological marker, NYHA classification and 6-min walk test performance, in order to assess the value of BNP in the determination of functional capacity in patients suffering from chronic heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
We included 151 consecutive patients aged between 18 and 80 years, sent to our hospital for chronic heart failure assessment between November 2000 and April 2001. All patients had been suffering from heart failure for more than 2 months and had been admitted to hospital at least once for documented heart failure. We excluded patients presenting with kidney failure (defined as plasma creatinine >250 µmol/ml) and patients presenting with known respiratory insufficiency (defined as a forced expiratory volume <1 l). In order to be included in the study, patients presenting with ischaemic cardiomyopathy must not have presented with acute coronary syndrome for at least 1 month. In the same way, we excluded patients presenting with an infirmity preventing them from carrying out a 6-min walk test.

The investigation conformed with the principles outlined in the declaration of Helsinki.

2.1. NYHA class determination
Patients were examined by two experienced independent clinicians and classified into one of the four functional classes defined by the NYHA [4]. In the event of disparity between the two clinicians, a third clinician was asked to arbitrate.

The 6-min walk test was carried out by an independent investigator. The test was performed on flat ground, previously measured with reference marks every 2 m. The patient was asked to walk the longest distance possible during the 6-min test. The patient was supervised by the investigator who encouraged him throughout the 6-min walk test [6]. The patient could decide to stop or slow down during the test if required, according to his state.

Echocardiography was performed using an Agilent Technologies 5500 device equipped with ‘second harmonic’ function. Left ventricular ejection fraction was measured by an independent operator according to the Simpson's biplane method measured by apical way as recommended by the American Society of Echocardiography (ASE) [9]. In the event of poor echogeneicity, measurement could be performed through the left para sternal large axis, using the Teilchoz method to calculate the left ventricular ejection fraction.

In order to measure BNP we took 5 ml [3] of whole blood via a peripheral venous catheter as part of the usual check-up of these patients after 15 min of dorsal decubitus. Blood was collected in tubes containing potassium ethylenediaminetetraacetic acid EDTA (1 mg/ml). 2.5 mm [3] of whole blood were immediately taken and measured using the triage BNP test (Biosite diagnostics Inc. San Diego CA). The triage test is a fluorescence immunoassay for the quantitative determination of BNP in whole blood and plasma specimens and was recently approved by the FDA. A murine recombinant polyclonal antibody is bound to the fluorescent label and a murine monoclonal antibody against the disulfide bond mediated ring structure of BNP 32 is bound to the solid phase. The concentration of BNP is proportional to the fluorescence bound to the detection lane. The results of BNP measurement were available in 15 min. The average confidence limit of the analytical sensitivity is less than 5 pg/ml (95% confidence interval 0.2–4.8 pg/ml) [10].

2.2. Follow-up
The patients were followed for 6±1.2 months. No patient was lost at the end of the follow-up.

The events which were analysed were mortality and hospitalisations for worsening heart failure. The diagnosis was confirmed by an independent clinician on the basis of the data collected at patient admission. To be validated, it had to last more than 24 h and the patient had to present with congestive signs, which required the use of intra venous diuretics during the hospitalisation.

The BNP level was not known by the clinicians in charge of the patient, therefore, the BNP level did not influence the patient's treatment.

2.3. Statistical analysis
The statistical data are expressed as mean±standard deviation. The proportions were compared by the intermediary of a {chi}2-test, the parametric data using a Student's t-test and the non-parametric data by a Mann–Whitney test. The results were regarded as statistically significant for a P-value <0.05. The multivariate analyses and all other statistical tests were carried out on Sigmastat 2.5 (SPSS) and Statview 5.0 software.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
The characteristics of patients included in this study conformed with the usual data for patients treated in our medical department. The main data are included in Table 1. It was noted that patients were relatively young with an average age of 57.1±12 years. The percentage of patients with ischaemic cardiomyopathy was high (>60%), this is probably related to the importance of the angiographic activity of our hospital and its influence on the recruitment of the patients. The average LVEF was 37±8%, which is usual in this type of study.


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  		Table 1 Population characteristics

 
The mean daily dose of diuretics was 31±23 mg of furosemide per day, which is a usual amount. Most of our patients were treated with carvedilol, which conforms with recommended treatment guidelines, but can differ somewhat from the practice in other hospitals in France and abroad. The mean therapeutic dose of carvedilol was 21.5±3.8 mg which corresponds to our usual practice. Ninety-five percent of our patients were treated with an ACEI. The therapeutic dose employed was 14±7.8 mg of lisinopril, which is the ACEI used in our medical centre. Only a few patients were treated with spironolactone (15%) despite the results of the RALES study.

The average plasma level of BNP was 305±45 pg/ml, which is a relatively high level, classically found when this type of method is used in patients suffering from chronic heart failure.

The plasma BNP level appeared to be strongly correlated with 6-min walk test performance (R=0.69 P<0.001) (Fig. 1). On the other hand, the correlation between BNP and LVEF was weaker (R=0.45 P=0.04). We did not find any significant correlation between BNP and 6-min walk test in patients in NYHA class 1.


Figure 1
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  		Fig. 1 B-type natriuretic peptide, 6-min walk test and NYHA classification.

 
3.1. Results according to NYHA classification
When compared with other groups, patients in NYHA class 1 were relatively younger, with a lower incidence of ischaemic cardiomyopathy and higher haemodynamic parameters (systolic arterial pressure and heart rate). Mean LVEF was approximately 40% and BNP levels could be described as subnormal (26.3±7 pg/ml) which conforms with the strictly asymptomatic characteristics of these patients. The 6-min walk test performances were also excellent in this group, with an average distance of approximately 469±87 m. With regard to medication, the prescribed doses of ACEI and beta-blockers were higher in this group than in any other, however the doses of diuretics used were lower (17.8±13; 29.3±18; 45±25; 80±20 mg, respectively, from NYHA class 1 to NYHA class 4). It was also noticed that the average doses of ACEI and beta-blockers decreased as NYHA class increased (Table 1). It is nevertheless unclear whether the variations in treatment (more diuretics and less ‘long term’ treatments in the most symptomatic patients) is responsible for the symptomatic character of heart failure.

The level of events indexed during the follow-up conforms with data found in the literature. In ROC curves, BNP plasma levels higher than 400 pg/ml seem to be the best threshold for predicting events during follow-up.

3.2. Sub-group analysis
In order to study what the measurement of BNP could bring to the clinical analysis reflected by NYHA classification, we decided to carry out a sub-group analysis. Within each NYHA class we created 3 sub-groups.

Sub-group A included the quarter of patients with the lowest 6-min walk test performance within the NYHA class, representing the ‘most severe’ patients in the NYHA class under consideration. Sub-group C included the quarter of patients with the highest 6-min walk test performance within the NYHA class, representing the ‘least severe’ patients in the NYHA class under consideration. Sub-group B included patients with an average 6-min walk test performance within the NYHA class (i.e. 50% of the patients from that NYHA class). We divided each NYHA functional class into sub-groups in the same way.

In Table 2 and Fig. 2 it can be seen that the plasma BNP levels are very different within each NYHA class, depending on the sub-group A, B or C. The levels are as high in the most severe sub-group (i.e. sub-group A) of a given NYHA class as in the less severe sub-group of the upper NYHA class. The most severe patients (sub-group A) within one NYHA class had significantly higher BNP levels than patients in sub-group B, who had plasma BNP levels superior to those with the best 6-min walk test performance (sub-group C).


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  		Table 2 NYHA sub-groups 6-min walk test performance and BNP levels

 


Figure 2
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  		Fig. 2 BNP plasma levels and NYHA sub-groups.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
BNP thus allows evaluation of patients suffering from chronic heart disease in a finer way than NYHA classification. In patients for whom NYHA classification is not in agreement with the BNP level, the 6-min walk test performance proves the neurohormonal measurement to be right. The number of patients ‘wrongly’ classified by means of the NYHA classification is moreover relatively weak.

All in all, the plasma level of BNP increases when NYHA class increases which is in agreement with data found in Refs. [8,11]. That being known, there are large differences in terms of BNP levels within the same NYHA class. These differences cannot be completely explained by reference to a disparity of LVEF. In our population, indeed, the correlation between the BNP level and LVEF is very average. It thus seems that the traditional factors alone (NYHA, LVEF) cannot give an account of the BNP level. This tends to agree with the assumptions put forth by certain authors such as Maeda et al. [12] for whom BNP correlated much more with LVEDP than with LVEF in patients with chronic heart failure. In the same way, Omland et al., found that the plasma BNP level was correlated less with LVEF than with LVEDP [13] and for Richards, BNP was correlated to the left ventricular filling pressures [14]. Currently, even if the mechanism of decrease of BNP remains unclear, the assumption most commonly put forward is that BNP levels are modulated directly or indirectly by the stretching of the ventricular myocardial fibres [15]. Even if NYHA class is correlated overall to LVEDP, it seems that there exists, as for the BNP large differences within the same class [8,11].

The correlation between the 6-min walk test and BNP is to be brought closer to the correlation between VO2 kinetics and the BNP level measured by radio immunological methodology [16].

The separation of patients within NYHA classes into three sub-groups according to their walk test performance is rather artificial. It, however, allows a finer analysis of the functional capacity of these patients. It was noticed that there was a significant overlapping between the distances covered during the walk test in the different NYHA classes. This is in agreement with the work of Lipkin et al. [17] and Riley et al. [18]. Both have shown that walk test performance remained correlated with NYHA classification. In Bittner et al. [19] which related to 833 patients from the SOLVD register compared to 40 control subjects, the overlap in 6-min walk test performance between different NYHA classes was particularly clear for patients in class 2, but occurred in all the NYHA classes. In this study, there was a negative connection between the distance covered and mortality, the only independent elements predicting mortality being LVEF and 6-min walk test performance. BNP levels are very different within one NYHA class. In our study, these differences can be explained by the existence of very different BNP levels according to sub-groups within the same NYHA class. These differences are also correlated to the 6-min walk test performance.

For patients with severe heart failure (NYHA class IV) the distinction between more or less serious patients according to the BNP level and the 6-min walk test is less convincing. This is possibly related to the poor walk test performances among these very severe patients. Lucas [20] showed similar results in patients awaiting transplantation. That being known, the prognostic value of the 6-min walk test among patients in NYHA class II and III has been shown in many studies [19,21]. It thus seems that BNP permits finer analysis of functional capacity than NYHA classification in patients suffering from chronic heart failure. It also permits freedom from the subjective character of NYHA classification.

4.1. Study limitations
Our population characteristics were relatively unusual, patients were younger with less depressed left ventricular ejection fraction. It could be a bias of recruitment in our centre, linked to a younger population around our medical hospital. It will be interesting to perform a large multicentre study to include more typical patients.

Our analysis of the 6-min walk test performance in the three sub-groups within each NYHA class prevented us, given the small number of patients in the different groups, from carrying out an analysis of mortality or morbidity. A larger study on many more patients is thus necessary in order to be able to confirm our analysis.

The measurement of maximum oxygen consumption could have been coupled with the 6-min walk test in order to refine the data concerning the functional capacity of the patients included. At the time of the protocol, it seemed more relevant to us to study what BNP could bring in routine clinical practice and thus to privilege the 6-min walk test.

In our study, concomitant treatments differed according to the NYHA class. In particular, the amount of prescribed ACEI decreased as NYHA class increased. However, as van Veldhuisen et al. [22] showed, BNP depends on the amount of ACEI prescribed independently of the effect on ACE plasma activity. However, the variation of the plasma BNP level is relatively weak in this study, (~10% of the initial BNP level under the highest dose of ACEI) this minimises the importance of this potential skew.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
BNP makes it possible to evaluate in a finer way the functional capacity of patients suffering from chronic heart failure by means of NYHA classification. The measurement of BNP thus usefully supplements the clinical examination. The existence of a bedside type analysis method allows its use in routine clinical practice. BNP measurement makes it possible to be freed from the subjective, patient and operator dependent, NYHA classification. It also allows easier follow-up of patients suffering from chronic heart failure.


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

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  9. American Society of Echocardiography Committee on Standards, Sub Committee on Quantification of Two Dimensional Echocardiograms. Recommendations for quantification of the left ventricle by two dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358–67.
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