European Journal of Heart Failure

European Journal of Heart Failure 2003 5(5):599-606; doi:10.1016/S1388-9842(03)00108-9

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© 2003 European Society of Cardiology

Reference ranges for natriuretic peptides for diagnostic use are dependent on age, gender and heart rate

Ian Loke, Iain B. Squire^*, Joan E. Davies and Leong L. Ng

Department of Medicine and Therapeutics, Clinical Sciences Building, University of Leicester, Leicester Royal Infirmary Leicester LE2 7LX, UK

^* Corresponding author. Tel.: 44-116-252-3125; fax: 44-116-252-3108. E-mail address: is11{at}le.ac.uk

	Abstract

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

 
Background: Plasma natriuretic peptide levels may be useful in the diagnosis of heart failure. The available natriuretic peptide assays differ markedly in their performance characteristics. In addition, plasma levels are influenced by a number of factors including age and gender.

Aims: The aim of this study was to describe, in a healthy population, the influence of clinical and echocardiographic parameters on three natriuretic peptide moieties.

Methods: 1360 individuals were screened for the presence of left ventricular systolic dysfunction. We identified a cohort (n=720) of men aged 45–80 years (n=417) and women aged 55–80 years (n=303). None had history of cardiovascular disease or were taking any cardiovascular medication. All had normal echocardiographic and ECG findings. B-type (BNP), N-terminal pro-B-type (N-BNP) and N-terminal pro-Atrial (N-ANP) natriuretic peptides were assayed using in-house immunoluminometric assays.

Results: Of the considered clinical variables, only gender and heart rate (each P<0.005) were independently associated with levels of all three natriuretic peptides. Plasma levels of N-ANP (15%), BNP (25%) and N-BNP (75%) were higher in women compared to men. An increase in heart rate of 10 bpm corresponded to a reduction of 9% in N-ANP or BNP and a 15% reduction in N-BNP. Each 10 years of age was associated with 16% and 74% increase in ANP and N-BNP levels, respectively, but no increase in plasma BNP. Left ventricular ejection fraction could be assessed in 582 (81%) subjects and correlated positively with N-ANP (r_s=6.48x10^–3, P<0.001) and BNP (r_s=2.4x10^–2, P<0.001) but not N-BNP (P=0.405). No parameter of diastolic function was associated with any peptide level.

Conclusions: In this healthy population, plasma levels of N-ANP, BNP and N-BNP were variably influenced by clinical covariates. While all three peptides were higher in women, only N-ANP and N-BNP were influenced by age. Levels of all peptides were inversely correlated with heart rate. Using this immunoluminometric assay, plasma BNP is not influenced by age, in contrast to N-ANP and N-BNP. In constructing normal ranges for diagnostic use, covariates such as age and gender must be considered, in addition to the format of assay being used.

Key Words: Natriuretic peptides • Reference range

Received March 12, 2003; Accepted June 16, 2003

	1. Introduction

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

 
The extent of the problem of heart failure in industrialised societies, its impact on life expectancy, quality of life and health economics have led to suggestions for population screening for the condition [1]. Echocardiography represents the current ‘gold-standard’ for the diagnosis of left ventricular systolic dysfunction (LVSD). However, in many areas the cost of this investigation in large-scale screening may be prohibitive [2].

Alternative tools for screening for heart failure and asymptomatic LVSD include the natriuretic peptides. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are secreted from the cardiac atria and ventricles, respectively. Each is cleaved from the respective prohormone, a process producing a second, biologically inactive peptide, N-terminal proANP (N-ANP) or N-terminal proBNP (N-BNP). Several studies have demonstrated the utility of the natriuretic peptides, in particular BNP [2,3] and N-BNP [4], as tools in the identification of patients with heart failure and asymptomatic LVSD, both in a point of contact, emergency room setting [3] and in population screening programmes [2,4].

The clinical application of natriuretic peptide assays is complicated by a number of factors. To date no consensus has been reached as to which natriuretic peptide entity should be preferred for clinical use. Indeed few studies have compared the relative utility of natriuretic peptides in identifying LVSD. One large study concluded that BNP is superior to N-ANP as a marker of LVSD [2]. A second study concluded that the performance of both peptides is suboptimal and that these peptides are likely to be of limited usefulness in screening [5]. Normal ranges for these peptides, and factors influencing plasma natriuretic peptide levels in individuals without cardiovascular pathology, are poorly described. Plasma levels of BNP are higher in women than in men and increase with age [6,7]. Moreover, the performance characteristics of the currently commercially available assays for BNP vary markedly, necessitating the construction of age-, gender- and assay-specific normal ranges [6,7]. Clearly, the availability of an assay system, less subject to the influence of age and gender, may have important clinical implications for the use of these peptides. We developed competitive and non-competitive immunoluminometric assays for the natriuretic peptide moieties N-ANP, BNP and N-BNP. We then investigated the effect of age, gender, and other clinical variables on these three peptides in a normal healthy population without cardiovascular disease.

	2. Methods

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

 
2.1. Study population
From local general practices expressing an interest in the study, 21 were randomly selected and stratified by list size and deprivation index (Jarman score). The number of patients recruited at each was based on the practice list size. This study was conducted as part of a larger study investigating the relative utility of the natriuretic peptides N-ANP, BNP and N-BNP, together with clinical factors, in identifying previously undiagnosed heart failure in an unselected population. As such the invited population was restricted to men aged 45–80 and women aged 55–80 randomly selected from participating practices, younger individuals being expected to have a negligible prevalence of heart failure. Patients with previous hospitalisation for, or a prior, confirmed diagnosis of, heart failure were excluded, as were those for whom screening was considered inappropriate. From practice records we gathered information concerning past history of ischaemic heart disease (myocardial infarction or angina), hypertension, diabetes, smoking status, and prescribed medication. The study complies with the Declaration of Helsinki and was approved by the local ethics committee. All subjects gave written informed consent prior to undergoing physical examination, echocardiography and blood sampling.

For the purposes of this study, we excluded all participants with a history of heart disease, hypertension or diabetes, those identified as having LVSD, valvular disease or other pathology on echocardiography and those currently prescribed cardiovascular medication. Cases with major ECG abnormalities [8] were also excluded.

2.2. Laboratory methods
Twenty millilitres of peripheral venous blood was drawn into pre-chilled Na–EDTA (1.5 mg/ml blood) tubes containing 500 IU/ml aprotinin. After centrifugation at 3000 rpm at 4 °C for 15 min, plasma was separated and stored at –70 °C until assay. Assays for N-ANP and BNP were based on commercially available antibodies (Peninsular Laboratories Inc., Belmont, CA, USA) and Phoenix Pharmaceuticals Inc. (Belmont, CA, USA), respectively. Tracer peptides were biotinylated and purified on reverse phase C₁₈ HPLC. Competitive immunoluminometric assays were set up by preincubating 50 ng of the anti N-ANP or BNP IgG with standards or samples with subsequent addition of the appropriate tracers. Streptavidin labelled with methyl–acridinium ester was used to detect the bound tracer [9]. The lower limits of detection of N-ANP and BNP were 3.4 and 2.0 fmol/ml, respectively. Intra- and inter-assay coefficients of variation were 4.7 and 10.7% for N-ANP and 4.0 and 6.8% for BNP.

The non-competitive immunoluminometric assay for N-BNP has been described previously [10]. Streptavidin labelled with methyl–acridinium ester was used to detect bound biotinylated antibody. The lower limit of detection was 5.7 fmol/ml of unextracted plasma. Within and between assays, coefficients of variation were 2.3% and 4.8%, respectively. There was no cross reactivity between any of these assays or with CNP.

2.3. Echocardiography
Transthoracic Doppler echocardiography was performed in all participants by a single operator (IL). Images were obtained with subjects in the left lateral decubitus position using a Hewlett-Packard Sonos 5500 system and stored digitally. Left atrial and left ventricular internal diameter dimensions were obtained according to American Society of Echocardiography guidelines [11]. The transmitral e to a wave ratio was calculated by pulsed wave Doppler examination placed at the tips of the mitral valve leaflets. A 16-segment wall motion index (LVWMI) based on the American Society of Echocardiography model [12] was derived by scoring each LV segment (1=normal, 2=hypokinesis, 3=akinesis and 4=dyskinesis) and dividing the total score by the number of segments scored. Where feasible, left ventricular ejection fraction (LVEF) was calculated using the biplane method of discs formula [12] from data obtained from the apical 4 and apical 2 chamber views.

2.4. Statistical analyses
Univarate analysis was performed to investigate the relationship of clinical parameters with N-ANP, BNP and N-BNP. The considered parameters were age, gender, body surface area (BSA), body mass index, serum creatinine, heart rate and blood pressure. For each natriuretic peptide, factors associated in univariate analysis (P<0.1) were entered in logistic regression analysis for the prediction of each peptide. For multivariate analysis, a P-value of <0.05 was considered significant. BNP, N-BNP and N-ANP were log-normally distributed and analyses were performed after transformation of the data. Variables were entered in a hierarchical as well as a stepwise method and collinearity diagnostics, the Durbin–Watson calculation and casewise diagnostics to 3 S.D. were performed to check the regression model. A general linear model (univarate) was used to confirm the correlations. In order to check the results obtained, the study population was randomly split into two equal groups and the same statistical analyses were run in each. The results were very similar.

As expected, left ventricular ejection fraction (LVEF) could be calculated in only a proportion of the cases. Thus, multivariate analyses were repeated for this cohort of patients for whom both clinical and all echocardiographic parameters (LVEF, LA size, LV mass index, mitral A wave deceleration time and interventricular relaxation time) were available.

	3. Results

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

 
3.1. Population characteristics
Of 2392 patients approached, screening invitations were accepted by 1360 (57%; men 56%, women 58%, P=ns; inter-practice range 38–73%). In order to have a representative normal healthy group, subjects were excluded for the following reasons (not mutually exclusive): left ventricular systolic dysfunction, defined as an ejection fraction of <50% or left ventricular wall motion index score of >1 (n=114); previous myocardial infarction or angina (n=105); diabetes (n=64); history of hypertension (n=325); current use of diuretic (n=210), ACE inhibitor (n=118), calcium channel blocker (n=134) or nitrate (n=53); atrial fibrillation (n=18); significant valvular disease, defined as an echocardiographic quantification of any valvular disease (mitral or aortic regurgitation and mitral and aortic stenosis) graded as moderate and above (n=26); any other significant cardiac pathology on echocardiography such as right ventricular dilatation, elevated pulmonary artery pressure or congenital heart disease (n=3). Individuals with major ECG abnormalities including left bundle branch block (n=23), left ventricular hypertrophy (n=124) and pathological Q waves (n=47) were excluded. This left 720 healthy individuals without evidence of cardiovascular disease (Table 1).

View this table: [in this window] [in a new window]   Table 1 Demographic features of study population (n=720)

 
3.2. Predictors of plasma natriuretic peptide levels
3.2.1. Univariate analysis
A number of clinical variables were associated with plasma natriuretic peptide levels (Table 2). Levels of all three peptides were higher in females, increased with age and correlated negatively with heart rate and body surface area. Whilst the observed correlations with either systolic or diastolic blood pressure were weak, there was a consistent, positive correlation of pulse pressure for each peptide. In this healthy population the correlation of echo-cardiographic parameters with natriuretic peptide levels was weak. However, in the 582 individuals in whom LVEF could be measured, there was a weak but positive correlation of this parameter with plasma levels of each natriuretic peptide.

View this table: [in this window] [in a new window]   Table 2 Results of univariate analysis of correlation (rs, Spearman's Rho) of clinical and echocardiographic variables with plasma natriuretic peptides

 
3.2.2. Multivariate analysis—clinical parameters
The results of multivariate regression analysis are shown in Table 3 and, for the cohort of 582 in whom LVEF was measurable, in Table 4. As can be seen from the tables, the factors retaining independent predictive value for each natriuretic peptide differed. Only gender (levels higher in females) and heart rate (inversely correlated with plasma natriuretic peptide levels) were independently predictive of all three peptides. Age remained predictive of plasma N-ANP and N-BNP but not BNP.

View this table: [in this window] [in a new window]   Table 3 Results of multiple linear regression analysis. Correlation coefficients for the correlation of clinical variables with plasma N-ANP, BNP and N-BNP (n=720)

 

View this table: [in this window] [in a new window]   Table 4 Results of multiple linear regression analysis. Correlation coefficients for the correlation of clinical and echocardiographic variables with plasma N-ANP, BNP and N-BNP (n=582)

 
The median values, together with the 5–95% predictor intervals for plasma levels of each of the natriuretic peptide levels, plotted against age, are shown in Fig. 1. The observed relationships indicate a 16% increase in ANP levels and 74% increase in N-BNP levels for each 10 years of age, but no statistically significant increase in BNP. With regard to heart rate, an increase of 10 bpm would correspond to a reduction of 9% in N-ANP or BNP and a 15% reduction in N-BNP.

View larger version (12K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Median (bold line) and 5–95% confidence intervals (dotted lines) for plasma concentration of N-ANP, BNP and N-BNP in 720 healthy individuals.

 
3.2.3. Multivariate analysis—clinical and echocardiographic parameters
Echocardiographic estimation of LVEF was possible in 582 (81%) of the 720 subjects. For this cohort LVEF was included as a covariate in multivariate analysis. LVEF correlated positively with both N-ANP and BNP, but not N-BNP (Table 4). Indeed LVEF displaced gender as an independent predictor of plasma BNP. Age and gender remained predictive of plasma N-ANP and N-BNP. LA size, pulse pressure and LV mass had no significant influence on plasma natriuretic peptide levels in the models.

Only 6.3% and 4% of the variation in N-ANP and BNP, respectively, was explained by the considered variables compared to 16.5% of the variation in N-BNP.

3.2.4. Parameters of diastolic dysfunction
The measured parameters of diastolic function, IVRT [13] and E wave deceleration time (DT) [14], did not correlate with any of the natriuretic peptides. Because the effect of diastolic dysfunction on e/a ratio is biphasic [15], we considered e/a ratios in three ranges: e/a<0.75, e/a between 0.75 and 1.5, and e/a>1.5. There was no independent effect of e/a ratio on any of the three peptides in any of these groups

	4. Discussion

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

 
Few studies have examined the determinants of plasma natriuretic peptide levels in the healthy population and such studies to date have examined a single peptide moiety. Using novel, immunoluminometric assays, we observed potentially important differences in the determinants of individual natriuretic peptides.

The current study adds to the available information on age- and gender-related differences in plasma natriuretic peptide levels in the absence of cardiovascular disease. Our study confirms previous reports, in similar healthy populations, of higher BNP levels in women [6,7] and extends this finding to N-ANP and N-BNP. Indeed we found female gender to be the strongest independent predictor of natriuretic peptide levels in healthy individuals, plasma levels of BNP being approximately 25% higher in females. This compares to the 32 and 80% higher levels reported previously with alternative assay systems [6]. Higher BNP levels in women taking HRT [16], and higher ANP in premenopausal women [17], suggest an influence of oestrogen. The consistent finding of higher BNP levels in females confirms the need for gender-specific reference ranges for BNP.

We observed a lack of effect of age on plasma BNP, contrasting with a clear effect on levels of N-ANP and N-BNP. Previous reports indicated a positive correlation of age and plasma BNP [6,7]. There are a number of possible reasons for the differences between studies. Differences in the age-range of study populations may be relevant, as may the considered covariates. We found heart rate, not previously considered as a covariate [6,7], to predict levels of all three peptides. Interestingly, in this healthy population the correlation is of lower natriuretic peptide levels with higher heart rate, an increase in heart rate of 10 bpm corresponding to a reduction of 15% in N-BNP and 9% in N-ANP or BNP. The consistency of the observed relationship between heart rate and all three natriuretic peptides suggests that the association is real.

We are not aware of prior reports of an association between heart rate and plasma BNP. We may speculate that, at least in the healthy individual, synthesis or secretion of natriuretic peptides may be dependent upon diastolic duration or filling pressure. This would be of relevance only if alterations in heart rate resulted in significant intra-individual fluctuations in plasma natriuretic peptide levels. Our study in patients free of cardiovascular pathology does not inform us as to the relationship between heart rate and peptide level in pathological conditions. Plasma levels of both ANP and BNP increase in response to exercise in patients with coronary artery disease and normal LV function [18,19], and in patients with LVH [20]. Other reports have indicated little change [21] or significant increase [22] in plasma BNP levels during exercise in patients with heart failure. Further studies to determine the relationship between plasma natriuretic peptide and heart rate are required, both in healthy populations and in cohorts in whom the assay of BNP may be clinically applicable. In contrast to a previous study [6], we observed a weak correlation of both systolic blood pressure and pulse pressure with at least some natriuretic peptide moieties (Table 3). Once again the intra-individual influence of changes in blood pressure on natriuretic peptide levels has not been explored.

Previous studies of BNP in the identification of patients with LVSD reported the sensitivity and specificity of partition values [2,4] without reference to age or gender. Redfield observed increasing plasma BNP levels with age using both the Shionogi and Biosite BNP assays [6] and concluded, justifiably, that the use of either assay in clinical practice requires age- and gender-specific reference ranges. Our study suggests that correction for both age and gender may not be necessary, depending on the assay system used. Our assays, developed largely in-house, are not point of care tests but are well suited to batch testing of large numbers of samples, as would be required in screening programmes. It remains to be established if second generation natriuretic peptide assays are less influenced by age and gender.

As with heart rate, LVEF does not appear to have been considered as a potential cofactor influencing plasma natriuretic peptide levels in healthy populations [6,7]. We observed an independent, though weak, association of LVEF with plasma levels of two of the peptides, namely N-ANP and BNP. In both cases the correlation was positive, i.e. higher peptide levels with higher ejection fraction, the converse of the situation in LVSD and heart failure. To our knowledge this is a novel finding. In contrast to previous studies [6,7] we found no correlation between echocardiographic parameters and plasma natriuretic peptide levels. It may be relevant that in our study, unlike some others [6], all scans and analyses were performed by a single operator.

The physician will use natriuretic peptide levels to identify individuals who may have cardiovascular pathology, and thus merit further investigation. It may be suggested that information on the influence of LVEF on peptide levels in normal populations is clinically irrelevant. Similar comments may be made with regard to correlations with echocardiographic parameters of both systolic and diastolic function. Redfield excluded from analysis healthy individuals with a mitral e/a ratio of under 0.75, considering this group of subjects as having diastolic dysfunction [6]. In our view there is no reason to infer diastolic dysfunction in a group of healthy individuals without a history of hypertension, or any evidence of LV hypertrophy. As such, we did not exclude subjects with low e/a ratio from our analysis. The lack of association of natriuretic peptide levels with any parameter of diastolic dysfunction for any e/a ratio cohort supports this approach.

Differing associations between natriuretic peptide levels and echocardiographic parameters in healthy populations as opposed to cohorts with cardiac pathology may, however, be important in the understanding of mechanisms of control of the natriuretic peptide systems in health and in disease. The associations of natriuretic peptide levels with higher LVEF and lower heart rate in our healthy population, the converse of the situation in heart failure, suggests profound differences in the mechanisms of control of these peptide systems in health and disease.

Perhaps the most important conclusions from this study relate to the way in which natriuretic peptide reference ranges are constructed. Our study has many findings in common with previous reports [6] in terms of the observed associations of natriuretic peptide levels and clinical parameters. There are also a number of potentially important differences, which may relate, at least in part, to the choice of considered covariates in multivariate analyses. Similarly, findings may be related to the assay systems used in each study. These points emphasise the need for standardisation of the use of the natriuretic peptides in clinical practice, in particular with regard to reference ranges but perhaps also with regard to the preferred peptide moiety and the assay systems used.

4.1. Study limitations
We studied only white Caucasian patients and the findings cannot be applied with confidence to ethnic minority groups. Similarly our results can be considered appropriate to the studied population, men 45–80 years and aged and women aged 55–80 years.

	5. Conclusions

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

 
In this population of 720 apparently healthy individuals, higher natriuretic peptide levels are associated with higher LVEF (for N-ANP and BNP) and lower heart rate (for N-ANP, BNP and N-BNP). Plasma levels of BNP, N-BNP and N-ANP are higher in females. While levels of the N-terminal peptides N-BNP and N-ANP increase with age, those of BNP do not. These findings may have implications for the use of natriuretic peptide assays in clinical practice.

	References

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

 

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