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European Journal of Heart Failure 2004 6(7):891-900; doi:10.1016/j.ejheart.2004.03.005
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© 2004 European Society of Cardiology

Is plasma N-BNP a good indicator of the functional reserve of failing hearts? The FRESH-BNP study

Simon G. Williamsa, Leong L. Ngb, Russell J. O'Brienb, Steve Taylorc, D. Jay Wrighta and Lip-Bun Tana,*

a Academic Unit of Molecular Vascular Medicine, University of Leeds, Martin Wing, Leeds General Infirmary Leeds LS1 3EX, UK
b Department of Medicine and Therapeutics, University of Leicester Leicester, UK
c Department of Mathematical Sciences, University of Liverpool Liverpool, UK

* Corresponding author. Tel.: +44-113-392-5401; Fax: +44-113-392-5395


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Aims: Whether plasma N-terminal brain natriuretic peptide (N-BNP) is useful in the diagnosis of heart failure (HF) depends traditionally on whether it is as good as the putative ‘gold-standard’, left ventricular ejection fraction (LVEF), in indicating cardiac dysfunction. However, since HF is primarily an impairment of function of the cardiac pump, we explored the relationship between N-BNP and direct and indirect indicators of cardiac pump dysfunction.

Methods and Results: Eighty-six HF patients (mean age 56 years) with a range of LVEF's (mean 36.9±15.2%, range 15–66%) and 10 age-matched healthy controls were recruited into the study and had resting N-BNP measured. Cardiopulmonary exercise testing was performed to assess peak oxygen consumption (VO2). A subgroup of 23 subjects underwent further exercise haemodynamic assessment to evaluate peak cardiac power output (CPO). The CHF group had significantly higher N-BNP (median [interquartile range]) levels (299 [705] fmol/ml) than the control group (7 [51] fmol/ml, P<0.005). Significant correlations between N-BNP and peak VO2, and N-BNP and peak CPO were observed (R≥0.5, P<0.005). Although significant correlation was observed between N-BNP and LVEF (R=0.34, P=0.01), the correlations between LVEF and peak VO2 or peak CPO (all R<0.3, P>0.3) were not significant. Multivariate analysis identified plasma N-BNP and NYHA class, but not LVEF, as independent predictors of peak VO2.

Conclusions: We have found that N-BNP was surprisingly good as a simple indicator of cardiac pump dysfunction. Since heart failure is an inadequacy of function, these results strongly support the notion that N-BNP is a useful blood test in estimating the extent of cardiac pump dysfunction and helpful in establishing positive diagnosis of heart failure.

Key Words: Chronic heart failure • Brain natriuretic peptide • Peak oxygen consumption • Cardiac power output • Left ventricular ejection fraction • Cardiac pump function

Received December 17, 2003; Revised February 16, 2004; Accepted March 13, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
In recent years there have been much research directed towards finding a clinically useful circulating marker so that physicians can employ a blood test to diagnose and monitor heart failure [1,2]. The initial interest in the 1980s with noradrenaline as a marker [3] stimulated interest in other markers, angiotensin II and aldosterone, [4,5] through to the recent interest on cardiac peptides, cytokines and troponins. Emerging as a leading candidate is brain natriuretic peptide (BNP) [6–9]. It has been found to be predictive of prognosis, [10–12] apparently even better than left ventricular ejection fraction (LVEF) [13,14]. Recently, there has been a growing interest in the 76 amino acid residue amino terminal portion of pro-brain natriuretic peptide, N-BNP, which circulates in plasma at higher concentrations than BNP in patients with symptomatic heart failure [15] and in asymptomatic left ventricular dysfunction [16]. Richards et al. [17] showed plasma N-BNP to independently predict radionuclide LVEF and 2-year survival following an acute myocardial infarction. Talwar et al. [18] showed N-BNP to provide a strong correlation with reduced left ventricular wall motion index (LVWMI), measured by echocardiography, and 2-year survival following myocardial infarction [19].

Based on these and other results, plasma BNP level is increasingly being considered as a potential tool to aid the diagnosis of heart failure, [6–9,20,21] but how good it is often depends on how well it compares to the hitherto ‘gold standard’ test, the LVEF in defining LV ‘dysfunction’ [17,22–26]. There has been some disquiet about adopting LVEF as the ‘gold standard’ largely because it is a rather poor indicator of cardiac pump function, mainly because LVEF shows virtually no correlation with exercise capacity or peak cardiac pumping performance [27–32]. This lack of correlation appears to be puzzling in view of the fact that low LVEF is a hallmark of ventricular dilatation and systolic impairment and a well-known prognostic indicator [33].

An outstanding question is therefore whether plasma BNP is more than just a good indicator of left ventricular dilative impairment, and emerges to be also an indicator of cardiac pump function or dysfunction. It is now established that the reserve function of failing heart pump is best measured during peak cardiac stimulation (e.g. maximal exercise, pharmacological stimulation), and represented directly by peak cardiac power output, which has been shown to be a powerful predictor of prognosis [34–37], or indirectly by peak oxygen consumption or NYHA (New York Heart Association) functional class [38]. We therefore investigated whether plasma N-BNP actually correlates with these measures of the functional reserve of failing hearts (FRESH-BNP Study). Since N-BNP is considered to be a hormone released through a mechanism related to ventricular dilatation or augmented wall stress [39–42], it is likely to correlate with LVEF and not with cardiac pump reserve function. The current study was therefore undertaken to test the hypothesis that there is no consistent relationship between plasma N-BNP taken at rest and various peak exercise indicators of cardiac pump function represented indirectly and directly by peak oxygen consumption and peak exercise cardiac power output, respectively, in patients with chronic heart failure and in healthy controls.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patient population and study design
Eighty-six consecutive patients with stable chronic heart failure of New York Heart Association functional class I–IV and echocardiographic evidence of left ventricular systolic impairment were recruited from those patients undergoing routine cardiopulmonary exercise testing for evaluation of their condition at the General Infirmary in Leeds. Ten healthy age- and sex-matched volunteers were recruited as controls. Healthy volunteers who were free from any known cardiovascular diseases were either spouses or partners of patients or staff at the hospital. None of these volunteers were taking any prescribed medication. All patients received a written information sheet and were formally consented for the study. The study was approved by the local ethics committee and carried out in accordance with the Declaration of Helsinki (1989) of the World Medical Association. Exclusion criteria included inability to perform a familiarisation test, reduced exercise tolerance due to severe myocardial ischaemia or non-cardiac factors, or a myocardial infarction or revascularisation procedure in the preceding 3 months.

2.2. Cardiopulmonary exercise testing and estimation of cardiac power output
Exercise testing was conducted on a Marquette 2000 treadmill (Marquette Electronics, Milwaukee, USA) using the modified Bruce protocol. A preliminary familiarisation procedure identified patients not able to exercise for reasons other than cardiac limitation – these patients were excluded. The same supervisor (SGW) conducted the tests throughout the study. All patients performed symptom limited exercise tests unless termination was indicated for safety reasons. Patients were exercised after a 4-h postprandial period and were asked not to consume alcohol or caffeine in the preceding 12 h. The room in which the tests were carried out was maintained at a constant temperature between 21 and 23 °C using an air conditioning system controlled by a thermostat. Beta-blockers were stopped for 48 h before the exercise test.

The first stage consisted of an incremental exercise test. Electrocardiogram (ECG) and blood pressure were monitored throughout. Rates of oxygen consumption (VO2), carbon dioxide production (VCO2), end tidal partial pressure of carbon dioxide (ETpCO2), tidal volume (Vt), and respiratory rate were recorded breath-by-breath using the Medgraphics CardiO2 analytic system (Medgraphics, Minnesota, USA). Respiratory exchange ratio (RER=VCO2/VO2), minute ventilation (VE=Vt x respiratory rate), and VO2/kg were calculated from the above variables. The V-slope method [43] was used to calculate anaerobic threshold (AT). Peak circulatory power [44] was calculated as the product of peak VO2 and peak systolic blood pressure (SBP).

An unselected subgroup of 22 patients and 1 healthy volunteer performed a second exercise test following 45–60 min of recovery. Resting cardiac output was measured using the equilibrium CO2 re-breathing technique of Collier [45] and calculated using the indirect Fick method. At least three measurements of cardiac output were taken in order to calculate an average. The patient then performed a constant maximum workload exercise test for at least 4 min to a VO2 of at least 95% of the maximum level obtained during the incremental test. Peak cardiac output was measured in duplicate using the exponential CO2 re-breathing technique of Defares [47]. Validation and reproducibility of non-invasive cardiac power output measurements have previously been reported from our laboratory [46]. Cardiac power output, in Watts, was calculated from the equation: CPO=(COxMBP)xK, where MBP is the mean arterial pressure in mm Hg, CO is the cardiac output in l/min and K the conversion factor 2.22x10–3. Mean arterial pressure was calculated from the equation: MBP=(systolic pressure+2xdiastolic pressure)/3 [48]. Cardiac reserve [35] was calculated as the difference between peak exercise and resting CPO.

2.3. Measurement of N terminal pro brain natriuretic peptide
Samples of venous blood were taken after 20–30 min rest in a supine position before exercise testing and transferred immediately to ice-cold tubes containing EDTA (final concentration 1.5 mg/ml) and Trasylol (final concentration 500 IU/ml). The sample was then centrifuged and plasma stored in a –70 °C freezer until analysis.

Analysis of N-BNP was performed by the Department of Cardiovascular Sciences at Leicester Royal Infirmary using an in-house non-competitive assay [49]. Rabbit antibodies were raised to the N- and C-terminals of human N-BNP. The C-terminal directed IgG coated onto ELISA plates served as the capture antibody. The N-terminal IgG was affinity purified and biotinylated. Plasma samples (20 µl) or N-BNP standards were incubated in coated plates with the biotinylated antibody for 24 h at 4 °C. Detection was with methyl-acridinium ester (MAE) labelled streptavidin read on a Dynex MLX luminometer. The lower limit of detection was 5.7 fmol/ml. Within- and between-assay coefficients of variation were 2.3% and 4.8%, respectively. There was no cross-reactivity with ANP, BNP or CNP.

All samples were determined blind to patient data and assayed in duplicate and the average of the two measurements was reported.

2.4. Echocardiographic assessment of left ventricular function
Standard echocardiography was performed using Hewlett Packard Sonos 5500 and Acuson Sequoia 256 imaging systems. Left ventricular function was assessed using a simple grading system [50] as mild, moderate or severe. Left ventricular dimensions were assessed using Hewlett Packard software and LVEF was calculated using Simpson's method.

2.5. Statistical analysis
Continuous data are expressed as mean±standard deviation (S.D.). Absolute levels of N-BNP were expressed as median (interquartile range, IQR). The Mann–Whitney U test for unpaired samples was performed to assess differences in N-BNP levels between patients with CHF and healthy control subjects.

Values of N-BNP were normalised by logarithmic transformation (log N-BNP) prior to correlation with exercise parameters using Pearson's correlation methods. Non-parametric data (echocardiographic data) were correlated with the logarithmic transformation of N-BNP using Spearman's rank correlation methods.

Univariate analysis of variance (One way ANOVA) was used to compare log N-BNP overall between NYHA classes in all subjects (both healthy controls and CHF patients). Differences between N-BNP levels in each NYHA class (and compared with controls) were assessed using the Mann–Whitney U test.

Multiple regressions were used to assess the predictive abilities of a number of variables on the outcome peak oxygen consumption. Variables were initially assessed individually for predictive significance. Those with a significant effect were considered for inclusion in a multiple regression. Other variables were included in the regression because of their clinical relevance, whether significant or not in single variable analyses. Predictors chosen for inclusion in the stepwise regression were: grade of left ventricular function (mild, moderate, severe), LVEF, left ventricular internal end-diastolic dimension (LVEDD), age, NYHA functional class, aetiology of CHF (ischaemic or non-ischaemic), peak MBP, peak SBP and (log) N-BNP. Continuous variables were assessed by means of their correlation with the outcomes. Both size and significance of correlation was used as an assessment of predictive ability. Categorical variables were assessed for association with the outcomes using the t-test for those with two categories, or one-way ANOVA for those with more than two categories.

The SPSS General Linear Model (GLM) procedure was used to fit the regression models. Factors were assessed for their predictive significance using the F statistic. Model fit was assessed using the adjusted R2 statistics. A P value <0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Baseline clinical characteristics of study populations
Baseline characteristics are shown in Table 1. The study patients had an average age of (mean±S.D.) 55.7±12.0 (range: 20–78) years and there was a majority of males. Fifty-nine (69%) patients were taking diuretics, 62 (72%) patients were on angiotensin converting enzyme (ACE) inhibitors and 37 (43%) were taking beta-blockers. Thirty (35%) patients had previously undergone bypass grafting (CABG), 45 (52%) had a previous history of a myocardial infarction (MI) and 8 (9%) patients were diabetic. Twenty patients (23%) had a history of hypertension and six (7%) were in atrial fibrillation at the time of the exercise test.


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  		Table 1 Baseline clinical characteristics of study population

 
Left ventricular dysfunction was classified as echocardiographically mild in 17 (20%) patients, moderate in 34 (39%) patients, and severe in 35 (41%) patients. Mean (±S.D.) left ventricular ejection fraction (LVEF) was 36.9±15.2 (range: 15–66)% with a mean left ventricular end diastolic dimension (LVEDD) of 65.1±10.0 mm.

3.2. N-BNP and cardiopulmonary exercise data in CHF and healthy subjects
The CHF patient and healthy control groups were well matched for age (55.7±12.0 years in patients vs. 51.8±11.9 years in controls, P=0.33) and sex (84% male in study population vs. 90% male in control group). Significantly, higher N-BNP levels were found in the CHF group (299.3 [704.8] fmol/ml, median [IQR]) compared with the healthy control group (7.2 [51.2] fmol/ml), P<0.0001. The contrasting N-BNP levels are mirrored by the markedly different exercise parameters. In the CHF patient population, mean (±S.D.) peak VO2 was 19.8±5.9 (range: 9.19–45.24) mls/kg/min (Table 2). In contrast, the 10 healthy volunteers had a significantly higher peak VO2 (31.8±6.6 mls/kg/min, P<0.00001). RER values at peak exercise were not significantly different (1.08±0.09 in the CHF cohort, 1.13±0.06 in healthy controls, P=0.09). Resting HR was significantly lower in the healthy control group (74.5±9.1 min–1 vs. 85.6±15.5, P=0.003) but the reverse was true with peak exercise HR, being higher in the controls at 171.2±16.5 min–1 than 141.7±26.0 min–1 in the patients (P=0.005). Mean BP at rest was not significantly different, but the values at peak exercise were significantly higher in the healthy controls (127.2±13.3 mmHg vs. 108.3±16.5 mmHg, P=0.0007). Peak circulatory power was significantly higher in the healthy control group at 5.84±2.0 than the 3.13±1.3 units (=10–3.torr.mls/kg/min) in CHF patients (P<0.00001). In the subgroup of subjects (n=23) who underwent direct non-invasive measurements of haemodynamic data, mean resting CO was 4.5±1.0 l/min rising to a peak of 11.1±3.0 l/min during maximal exercise. Mean resting CPO was 0.99±0.27 W, increasing to 2.82±1.03 W at peak exercise, giving a cardiac functional reserve of 1.83±0.89 W.


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  		Table 2 Differences in cardiopulmonary and exercise data between study population and healthy controls

 
3.3. Correlates of plasma N-BNP
Circulating N-BNP was found to correlate well with peak exercise oxygen consumption in the CHF cohort (R=0.50, P<0.001, Fig. 1a). The correlation was surprisingly also significant in the much smaller cohort of 10 healthy volunteers (R=0.78, P<0.01, Fig. 1b). It also correlated well with circulatory power [44], a surrogate measure of cardiac power output, in the CHF cohort (R=0.53, P<0.001, Fig. 1c). In the subgroup (n=23) that underwent the extended exercise testing, there was also significant correlation with the directly measured peak exercise cardiac power output (R=0.64, P<0.001, Fig. 1d).


Figure 1
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  		Fig. 1 Graphs showing good correlation between plasma N-BNP and (a) peak oxygen consumption (Peak VO2) in heart failure patients, (b) peak oxygen consumption in the cohort of healthy controls, (c) peak exercise ‘circulatory power’ in heart failure patients, (d) peak exercise cardiac power output, (e) exercise duration in heart failure patients and (f) exercise duration in healthy controls.

 
The N-BNP levels were further analysed according to exercise duration and the data are shown in Fig. 1e,f. Similar to the N-BNP correlation with peak oxygen consumption, there was a good correlation between plasma N-BNP and exercise duration in the CHF cohort (R=0.35, P=0.001, Fig. 1e), and the correlation was also good in the much smaller cohort of healthy volunteers R=0.72, P<0.01, Fig. 1f). There was a significant difference in N-BNP levels according to NYHA class over the whole of the study population (both healthy controls and CHF patients), F=6.077, P=0.001.

Further analysis was performed to assess the correlation between N-BNP levels with LVEF (R=0.34, P=0.01, Fig. 2a) and LV end-diastolic dimension (LVEDD, R=0.33, P=0.015, Fig. 2b). In contrast to the correlation between N-BNP and peak VO2 and exercise duration, the correlations between LVEF and peak VO2 (R=0.0788, P=0.33) and exercise duration (R=0.0034, P=0.39) were not statistically significant. Similar poor correlation was found between LVEF and CPO (R=0.0143, P=0.44).


Figure 2
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  		Fig. 2 Graphs showing significant correlation between N-BNP and (a) LV ejection fraction (LVEF) and (b) LV end-diastolic dimension (LVEDD).

 
Having established the correlations between N-BNP and measures of cardiac performance and their significance, a related crucial issue was to consider the relative clinical relevance of these correlations. Table 3 illustrates the proportional changes in N-BNP levels relative to unit changes in clinically important variables that correlated well with N-BNP levels. The impact of unit changes on N-BNP levels appeared to be greater for variables such as peak CPO and peak VO2, or their related variables.


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  		Table 3 Changes in (log) N-BNP levels according to unit changes in clinically important variables

 
3.4. Multivariate analysis for determinants of aerobic exercise capacity
From univariate analyses we found a number of significant predictor variables for inclusion into a multiple regression analysis to find independent determinants of aerobic exercise capacity (represented by peak oxygen consumption). Variables with a significant effect and other clinically important variables were entered into a multiple regression model. This showed that log N-BNP (F=17.56, P<0.0001), New York Heart Association functional class (F=13.67, P<0.0001) and aetiology of heart failure (F=4.82, P=0.03) were the only independent predictors of peak oxygen consumption (Table 4). Diagnostic checks and plots of the residuals showed that the model gave a good fit to the data (adjusted R2=0.53).


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  		Table 4 Multivariate analysis: predictors of peak oxygen consumption in the patient cohort with heart failure

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
The study shows N terminal pro brain natriuretic peptide (N-BNP) levels to be significantly elevated in patients with chronic heart failure (CHF) compared with healthy subjects, confirming previous work [15–18,51]. We also found significant correlation between N-BNP and LVEF, in line with previous reports [17,22–26]. However, the main findings from this study do not support our stated hypothesis of no consistent relationship between N-BNP, measured at rest, and direct or indirect indicators of cardiac pump function measured during peak exercise. Instead, the results showed that in the heart failure cohort, there were indeed good correlations between circulating N-BNP with peak exercise cardiac power output, oxygen consumption and with the duration of symptom-limited maximal exercise testing (Fig. 1). Previous relationships have been demonstrated between BNP levels and peak VO2 [52–55] in patients with CHF. Significantly, the multivariate analysis also identified plasma N-BNP and NYHA class as strong and independent predictors of peak oxygen consumption. In our study, the NYHA functional classification was found to be a remarkably good independent predictor of peak VO2. To our knowledge, these findings have not been previously reported suggesting that N-BNP may be a simple and readily available indicator of functional cardiac capacity.

In the subgroup of subjects who underwent a second single-stage exercise test enabling the non-invasive measurement of peak exercise cardiac power output (CPO), which is a direct indicator of cardiac (dys) function [18,46,56,57], there was good correlation between resting circulating N-BNP and peak CPO. Despite a smaller number of subjects participating in this extra test, the correlation coefficient and significance level were remarkably good. There was also a good correlation between N-BNP and circulatory power, a surrogate representation of CPO [44,58]. The correlations were not only statistically significant, but also clinically relevant with sizeable changes in N-BNP levels for unit changes in peak cardiac power output and circulatory power (Table 3), suggesting that improvement in peak cardiac power output may be associated with a reduction in N-BNP. In practice, this opens the possibility that monitoring serial BNP levels may be a readily available surrogate indicator of changes in cardiac function in heart failure patients [59]. This attractive concept warrants further investigations.

These observations are consistent with recent insight that exercise duration, peak exercise oxygen consumption, circulatory power are indirect indicators of cardiac (dys) function which can be directly represented by peak exercise cardiac power output [38,57]. Remarkably, plasma N-BNP levels were found to correlate well with each of these parameters. By virtue of the fact that plasma N-BNP correlates consistently with these different true indicators of cardiac pump function and dysfunction, it may now be considered to be not only an investigative tool for diagnosing the presence or absence of heart failure, but also provide information about the extent of functional impairment. Unexpectedly, we also found good correlation between N-BNP and aerobic exercise capacity and exercise duration in the cohort of 10 healthy control subjects. However, because of the small number of healthy subjects involved, this observation requires further testing in a larger study cohort.

We found a significant relationship between N-BNP and various echocardiographic parameters reflecting left ventricular remodelling despite the heterogeneity of the study population, also in line with other reports [22–26]. A significant (negative) linear relationship was demonstrated between plasma N-BNP and left ventricular ejection fraction (LVEF), confirming a previous study by Richards and colleagues [17]. N-BNP was also observed to significantly correlate with left ventricular end diastolic dimension (LVEDD), which together with its three-dimensional counterpart, the LVEDV (end-diastolic volume), provide purely structural information – that of how dilated the LV chamber is. In contrast, simultaneous with the above findings, LVEF was found to have no significant correlation with peak oxygen consumption, exercise duration or cardiac power output, consistent with previous reports [27–32]. A previous study also reported no correlation between LV dimensions with peak VO2 [60].

There are profound implications of these results. The commonest method of measuring LVEF in practice is echocardiography. Various more easily measured echocardiographic approximations of LVEF have also been proposed and employed [61]. Consequently, almost all major guidelines for heart failure management advocate that all patients with suspected heart failure should have an echocardiographic examination [62–64]. Some would even advocate that primary care physicians should have direct access to an echocardiography service [65], so that all new patients presenting with a history suggestive of heart failure should have a first-line echocardiographic examination. Programs are being established to make available portable echocardiographic equipment (usually devoid of recording facility) and qualified technicians for such purposes. This has major resource implications. An alternative first-line investigation is a blood test for plasma N-BNP, not only because of its powerful negative predictive value [21,66,67], but also because it is a strong independent determinant of aerobic exercise capacity (Table 4), an indirect indicator of cardiac (dys) function [38,57], and is strongly correlated with peak cardiac power output, a direct measure of cardiac function [11,34,35,46,56]. A blood test is significantly less demanding of resources than properly conducted echocardiograms, especially when all the logistical problems of conducting the tests are also taken into consideration. The fact that this study showed N-BNP is consistently correlated to various direct and indirect measures of cardiac (dys) function, whereas LVEF is devoid of such a property, suggests that a more rational first-line investigation in primary care is plasma N-BNP estimation, while echocardiography can be reserved as a complementary investigation to establish the aetiology.

4.1. Study limitations and future investigations
The study population was recruited from patients on the waiting lists for cardiopulmonary exercise testing in hospital, and, therefore may not be representative of all heart failure populations in the community or primary care. Future studies should investigate whether the same results are obtained from unselected patients referred from the community with suspected unconfirmed heart failure. There were insufficient numbers of CHF patients in the study with preserved LV systolic function (LVEF>50%) to allow any conclusion to be drawn about whether N-BNP is helpful in the diagnosis of diastolic heart failure. A future study should recruit larger numbers of patients with diastolic heart failure and compare these results with those with systolic heart failure. It would also be useful to directly measure peak cardiac output and cardiac power output if possible in all subjects in future studies.

The findings in the normal cohort in this study were novel and intriguing. Despite the small number (n=10), the P values of <0.01 exceeded the stated statistical requirement of P<0.05. A larger study is warranted to confirm these observations, and to investigate the effects of age, sex, body size, and physical conditioning on the relationship between N-BNP levels and exercise capacity. This may even provide some insight into the mechanisms of BNP release and the physiological and pathophysiological roles of this hormone in normal subjects and patients.

Brain natriuretic peptide (BNP), cytokines and other humoral markers of CHF were not measured. The study did not address the relationship between pharmacological treatments (especially angiotensin converting enzyme inhibitors), renal function and neurohormonal levels, and the multivariate analysis did not take into account the influence of concomitant drug therapy or serum creatinine levels. Plasma levels of N-BNP are raised in chronic renal failure [68] and creatinine concentration has previously been shown to be a univariate predictor of left ventricular impairment, although this was not significant on multivariate analysis [18].


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
This study has shown that plasma level of N-BNP may be the best available simple indicator of various aspects of chronic heart failure, including peak exercise oxygen consumption and cardiac power output, exercise duration, NYHA functional class, LV ejection fraction and end-diastolic dimension. Like peak VO2 [69] and peak cardiac power output [46,70], it reflects exercise capacity and symptoms of heart failure and has been shown to predict prognosis in previous work [10–12,17]. The fact that LVEF showed no correlation with indicators of cardiac pump (dys) function suggests that it should no longer be regarded as the ‘gold standard’ measure against which other simple indirect tests such as plasma N-BNP are judged. The results strongly support the proposal that plasma N-BNP is a useful simple blood test applicable in not only the negative but also the positive diagnosis of chronic heart failure and in categorising the extent of impairment of cardiac pump function.


   Acknowledgements
 
The authors would like to express sincere thanks to Mr Jonathan Diesch and Mrs Gill Wharton for the technical assistance in performing exercise tests and echocardiography.


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

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