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European Heart Journal Advance Access originally published online on November 21, 2006
European Heart Journal 2006 27(24):3004-3010; doi:10.1093/eurheartj/ehl406
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Plasma pro-B-type natriuretic peptide in the general population: screening for left ventricular hypertrophy and systolic dysfunction

Jens Peter Goetze1,3,*, Rasmus Mogelvang1,2, Lars Maage1, Henrik Scharling1, Peter Schnohr1, Peter Sogaard2, Jens F. Rehfeld3 and Jan Skov Jensen1,2

1 The Copenhagen City Heart Study, Epidemiological Research Unit, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
2 Department of Cardiology Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
3 Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark

Received 3 April 2006; revised 30 October 2006; accepted 10 November 2006; online publish-ahead-of-print 21 November 2006.

* Corresponding author. Tel: +45 3545 5509; fax: +45 3545 4640. E-mail address: jpg{at}dadlnet.dk


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims B-type natriuretic peptide (BNP) measurement in screening for left ventricular hypertrophy (LVH) and left ventricular systolic dysfunction (LVSD) has been evaluated in the general population, but corresponding information on proBNP and the N-terminal proBNP fragment is still limited. We therefore examined whether proBNP measurement is useful for LVH and LVSD screening in the general population.

Methods and results In the 4th Copenhagen City Heart Study, 3497 participants underwent echocardiography with assessment of left ventricular ejection fraction (LVEF) and mass. The impact of gender and age was determined and the diagnostic performance of the plasma proBNP concentration was evaluated using receiver operating characteristic (ROC) curves. Of 1502 men and 1995 women, 4.1 and 2.6% had LVSD defined as an LVEF<60% whereas only 0.4% displayed LVEF<40%. The proBNP concentration was 1.7-fold higher in women compared with men (P<0.0001) and related to age in both genders. The mean proBNP plasma concentration was two-fold higher in subjects with LVSD than without LVSD (P<0.0001). Likewise, LVH imposed a 1.9-fold increase in the proBNP concentration (P<0.0001): Both differences persisted after adjusting for ischaemic heart disease, hypertension, diabetes, gender, and age. The diagnostic performance of proBNP in detecting LVEF<40% was high with an area under the ROC curves of 0.92 (95% CI 0.79–1.00) in women and 0.85 (95% CI 0.74–0.96) in men.

Conclusion We have established the impact of age and gender on the proBNP concentration in a large, community-based cohort. The diagnostic performance for proBNP measurement in screening for LVH and LVSD in the general population parallels the reported data for BNP.

Key Words: BNP • Heart failure • Left ventricular systolic function • Left ventricular hypertrophy • ProBNP


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Left ventricular hypertrophy (LVH) and left ventricular systolic dysfunction (LVSD) are common conditions in today's world. Both conditions can precede overt heart failure, which still is a grave disease associated with high morbidity and mortality.1–3 In heart failure, echocardiography has become the gold standard examination providing information on LV anatomy and function. Echocardiographic testing, however, is most often performed in patients when cardiac disease is already suspected. Clinicians in general practice consequently often make critical decisions based on diffuse and unspecific symptoms. Moreover, patients with mild to moderate LVH and LVSD may not present signs or even acknowledge their symptoms.4 Thus, there is a need for simple tools to facilitate identification of LVH and LVSD in the general population.5,6

Plasma concentrations of cardiac-derived natriuretic peptides have been firmly associated with cardiac function.7,8 In particular, increased concentrations of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), as well as the N-terminal fragments of their biosynthetic precursors (N-terminal proANP and proBNP), are hallmarks of congestive heart failure. Accordingly, the European Society of Cardiology has suggested that measurement of the cardiac-derived peptides may be helpful in diagnosing chronic heart failure.9 Automated assays for measurement of BNP and the N-terminal proBNP fragment 1–76 in plasma have now become available and may facilitate routine measurement.10

Most studies so far have focused on patients consulting either a physician or an emergency ward, which indicates a sudden change in their clinical status. In contrast, measurement of natriuretic peptides as a tool for community screening is not well elucidated.11 Although some of the first studies on BNP as marker for severe LVSD were highly promising,12,13 plasma BNP and N-terminal proANP measurement has also been reported to be suboptimal for LVH and LVSD screening in the general population.14,15 Other reports suggest that measurement of the N-terminal proBNP peptides increases the diagnostic usefulness in primary care16 and may even be used for LVSD community screening.17,18 Recently, a population-based study compared BNP with N-terminal proBNP as heart failure markers and suggested that the N-terminal proBNP fragment (NT-proBNP) is ‘at least equivalent’ to BNP in detecting LVSD.19

Although different BNP assays have been used in the clinical studies, one automated assay has predominantly been employed to examine the clinical usefulness of N-terminal proBNP measurement.20 A noteworthy discrepancy, however, persists in head-to-head comparisons of the few available N-terminal proBNP assays.21,22 Moreover, BNP and N-terminal proBNP concentrations are not always related, which has led to the suggestion that the two markers may have different diagnostic performances depending on the clinical situation.23 Importantly, the discrepancies may not solely be due to analytical variation between the different assays but could also be caused by changes in the molecular heterogeneity of the peptides in plasma.24 In the present study, we, therefore, evaluated plasma measurement of intact proBNP together with its N-terminal fragment using a processing-independent assay (PIA). Plasma proBNP concentrations were determined in a large, community-based population in relation to age and gender, and the diagnostic performance in detecting LVH and LVSD was assessed.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Study population
The study was performed as a substudy of the 4th Copenhagen City Heart Study, a longitudinal cohort study of cardiovascular disease and risk factors.25,26 At the first examination in 1976–78, a random sample of 19 329 citizens living within a defined area of inner Copenhagen city boundary was drawn from the Copenhagen Population Register and invited to take part in the study. The sample was stratified by gender and age (5-year strata from the age of 20 years) so that nearly equal numbers within each stratum were invited. At the fourth examination, which took place in 2001–03, a total of 12 600 persons were invited in a random order. This study population consisted of participants from the previous examinations who were still alive (n=11 600) supplemented by a random sample of persons from the younger age strata (n=1000). Out of these, 6238 (49.5%) participated and 3497 (56.1%) randomly selected participants underwent an echocardiographic examination, thus constituting the population included in the present report. Whether a participant underwent echocardiography or not was completely independent of health status and other risk factors. All subjects gave informed consent to participate, and the study was performed in accordance with the 2nd Helsinki Declaration and was approved by the regional ethics committee.

Health examination
Blood pressure was measured in the sitting position after a 5 min rest with a London School of Hygiene sphygmomanometer with an appropriately sized cuff on the left upper arm. Hypertension was defined as systolic blood pressure>130 mmHg or diastolic blood pressure>80 mmHg. Non-fasting blood samples were obtained for measurement of plasma glucose and creatinine by enzymatic methods. Blood samples for measurement of plasma proBNP were collected in EDTA-containing vacutainers, immediately centrifuged at 3000 rpm for 10 min, and the plasma was stored at –70°C until analysis. Height and weight were measured without shoes and heavy clothing, and the body mass index (BMI) defined as weight/height2 (kg/m2). Body surface area was calculated by the formula: 0.007184xweight0.425xheight0.725 (m2). Anamnestic information was obtained regarding ischaemic heart disease, diabetes mellitus, and present medication. Ischaemic heart disease was defined as either a history of hospital admission due to acute coronary artery occlusion, percutaneous coronary intervention or coronary artery bypass grafting, or major ischaemic alterations on the electrocardiogram as defined by the Minnesota codes 1.1–3. Diabetes mellitus was defined as a non-fasting plasma glucose concentration ≥11.1 mmol/L or use of antidiabetic medicine or self-reported disease.

Echocardiography
All the echocardiograms were performed by three experienced echo technicians using GE Vingmed Ultrasound's Vivid Five ultrasound machine with a 2.5 MHz probe (Horten, Norway). The collected data were stored on magneto-optical discs and in an external FireWire hard drive and analysed off-line by one expert with the EchoPAC program version 6.4.3f1. All subjects were examined with two-dimensional and M-mode echocardiography while lying down on their left side. All images were recorded in second harmonic imaging and at the time of end-expiration. One loop of the apical four-chamber, two-chamber, and long-axis projections were recorded, more if atrial fibrillation was present. The 16 standard segments model as suggested by the American Society of Echocardiography27 was used for evaluation of regional function. The wall motion index was estimated and used for calculation of the left ventricular ejection fraction (LVEF).28–30 LVSD was defined as LVEF<60%, unless otherwise stated. One loop was recorded of the parasternal long axis and one M-mode still frame in correct 90° angle between the tips of the mitral leaflets and the tips of the papillary muscles. If the correct angle could not be obtained, two-dimensional images were used instead to quantify the myocardial thickness and the dimensions of the left ventricle. The LV mass index (LVMI) was calculated by the formula: [0.8x(1.04((IVS+LVDd+LVPW)3–LVDd3))+0.6]/body surface area,31, where IVS and LVPW are the thickness of the interventricular septum and the posterior wall of the left ventricle in diastole and LVDd is the diameter of the left ventricle in diastole. LVH was defined as LVMI≥104 g/m2 for women and ≥116 g/m2 for men.32

Plasma proBNP measurement
The plasma proBNP concentration was measured using a PIA.33 Plasma was incubated with the endoprotease trypsin (Worthington Cooperation). Trypsin cleaves intact proBNP and its N-terminal fragments at an arginyl residue in position 21, which releases a uniform fragment (proBNP 1–21) from each molecule. The enzymatic reaction was terminated by boiling the mixture, and the proBNP 1–21 fragment was quantitated with a radioimmunoassay specific for the N-terminal decapeptide. The analytical validation of this PIA has been reported elsewhere.34 The present inter-assay coefficients of variation were 23% at 38 pmol/L, 11% at 76 pmol/L, and 7% at 152 pmol/L (n=62). Overall, the molar measurements using this PIA proBNP assay are highly comparable with those of, for instance, the NT-proBNP assay on the Elecsys platform from Roche with a negligible systematic bias (manuscript in preparation).

Statistical analyses
The plasma proBNP concentrations in the population were positively skewed and therefore logarithmically transformed (ln) prior to further statistical analysis. Comparisons between groups were performed by Student's t-test, {chi}2 test, and test for trend by linear regression. Associations were tested by univariate and multivariable linear regression analyses. The parameters included in the multivariable analyses were chosen from the existing information on medical conditions that can affect the proBNP concentration (ischaemic heart disease, hypertension, diabetes, gender, and age). The diagnostic performance of proBNP for detection of LVSD and LVH was evaluated by receiver operating characteristic (ROC) curves with calculation of areas under the curves (AUC) of sensitivity plotted vs. 1-specificity for each possible cut-off proBNP concentration. Cut-off values for proBNP concentrations ruling out LVSD or LVH were then estimated from the curves assuring 100% sensitivity with the highest possible specificity. Cut-off values for proBNP concentrations diagnosing LVEF<40% assuring 95% specificity were also found with corresponding estimates of the positive predictive values. Confidence intervals (CIs) for these estimates were calculated using Bootstrap estimation (10 000 replications) with the 2.5th and 97.5th percentiles. P<0.05 on two-sided tests were considered significant. Values in brackets are 95% CIs, unless otherwise stated. All analyses were performed by SAS (SAS System for Windows, release 8.02, SAS Institute Inc., Cary, NC, USA) and Stata software (release 8.2 College Station, Stata Corporation, TX, USA).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
The characteristics of the study cohort are listed in Table 1. There was no difference in mean age between men and women. Of the 1502 men, 62 (4.1%) had LVSD defined as an LVEF<60% on echocardiography, whereas 52 of the 1995 women (2.6%) had LVEF<60%. As expected, the prevalence of ischaemic heart disease and LVH was higher in men, whereas the geometric mean plasma proBNP concentration was 1.7-fold higher in women compared with men [16.4 (15.5–17.4) vs. 9.8 (9.0–10.6) pmol/L, P<0.0001]. LVEF<50% was present in 37 subjects (1.0%; 13 females and 24 males), and only 14 subjects (0.4%; five females and nine males) displayed severely reduced LVEF<40%. In addition, subjects in medical treatment for hypertension displayed a 1.9-fold higher proBNP concentration compared with subjects not in treatment [22.7 (20.3–25.4) vs. 11.8 (11.1–12.4) pmol/L, P<0.001].


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  		Table 1 Population demographics

 
To assess the distribution of LVSD and LVH according to the proBNP concentrations, we divided the population into inter-quartile intervals of proBNP (Table 2). Both LVSD and LVH were more common in men with proBNP concentrations in the highest inter-quartile interval, which underscores the association between the plasma proBNP concentration and LV function and anatomy. Overall, the mean proBNP concentration was two-fold higher in subjects with LVSD than in subjects without [25.4 (19.1–33.8) vs. 12.8 (12.2–13.5) pmol/L, P<0.0001]. In a multivariable analysis including ischaemic heart disease, hypertension, diabetes, gender, and age, this increase remained unaffected (P<0.01). In parallel, the presence of LVH imposed a 1.9-fold increase in plasma proBNP concentrations [21.6 (18.8–24.8) vs. 11.4 (10.8–12.1) pmol/L], which persisted after adjusting for ischaemic heart disease, hypertension, diabetes, gender, and age (P<0.0001).


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  		Table 2 Distribution of LVSD (LVEF<60%) and LVH according to inter-quartile proBNP intervals

 
Both gender and age have been shown to influence the BNP concentrations in plasma.35 To examine the possible impact of these parameters on plasma proBNP concentrations, we stratified the population according to gender and age (Table 3). In subjects without LVSD and LVH, the impact of increasing age was more than three-fold between subjects <50 years compared with subjects >70 years for both men (4.3-fold, P<0.0001) and women (3.3-fold, P<0.0001). This difference was further pronounced in men with LVSD (8.6-fold in men, P<0.0001; 3.3-fold in women, P<0.0001) and in subjects with LVH (10.9-fold in men, P<0.0001; 5.3-fold in women, P<0.0001). Thus, the proBNP concentration not only depends on gender and age, but our results indicate that the pathophysiological response reflected by the proBNP concentration could also differ between women and men. Combined LVSD and LVH was present in 17 women [<50 years: n=0; 50–70 years: n=5, mean proBNP=34.9 (14.0–87.3) pmol/L; >70 years: n=12, mean proBNP= 74.9 (47.2–118.8) pmol/L] and 29 men [<50 years: n=2, mean proBNP=2.4 pmol/L; 50–70 years: n=9, mean proBNP=36.5 (18.9–70.1) pmol/L; >70 years: n=18, mean proBNP=72.2 (43.4–118.9) pmol/L].


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  		Table 3 Plasma proBNP concentrations in age groups with or without LVSD or LVH

 
Several earlier reports have examined BNP or proBNP as markers of LVSD defined as an LVEF<50%. When using this lower echocardiographic limit, only 24 males (1.6%) and 13 females (1.1%) were identified in the present population. This is in striking contrast to an earlier report from the same town.17 However, the participants in this study were recruited from general practitioners, which clearly is a selected group from the general population. As expected, the lower threshold for LVSD (LVEF<50%) did not have a clear impact on the proBNP concentrations in subjects without LVSD, but the concentrations were generally higher in subjects with LVEF<50% compared with LVEF<60%: Men <50 years (n=1): mean proBNP 30 pmol/L; 50–70 years (n=9): 22.7 (10.8–47.7) pmol/L; >70 years (n=14): 44.6 (27.5–72.2) pmol/L and women <50 years: n=0, 50–70 years (n=5): 42.0 (11.5–153.7)  pmol/l,>70 years (n=8): 94.2 (47.7–186.2) pmol/L.

The diagnostic performance of proBNP measurement in detecting LVSD and LVH was assessed using ROC curves that combine sensitivity and specificity (Table 4). The AUC values disclosed the best performance for severe LVSD (LVEF<40%) with AUC values of 0.92 (0.79–1.00) and 0.85 (0.74–0.96) for women and men, respectively. However, the AUC values for detecting LVEF<60% were markedly lower, which parallels earlier findings from plasma BNP as screening marker.14 The diagnostic performance in detecting LVH was 0.70 (0.66–0.74) and 0.63 (0.59–0.68) for women and men, respectively (Table 4). The cut-off values for proBNP concentrations assuring 100% sensitivity in ruling out LVEF<40% was found to be<17 (17–55) pmol/L with a corresponding specificity of 56% (54–59) and positive predictive value of 1.4% (0.6–2.3) in men and <30 (30–173) pmol/L with a specificity of 66% (64–68) and a positive predictive value of 0.7% (0.2–1.5) in women. Conversely, proBNP cut-off concentrations for diagnosing LVEF<40% was 74 (66–88) pmol/L for men and 77 (72–83) pmol/L for women. At these cut-off values, the specificity was 95% with sensitivities and positive predictive values of 33% (0–67) and 3.9% (0.0–8.8) in men and 60% (0–100) and 3.0% (0.0–6.7) in women, respectively.


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  		Table 4 ROC of plasma proBNP in detecting LVSD and LVH (n=3497)

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
The present study reports on the plasma proBNP concentrations in subjects from a large community-based population. Using a PIA for proBNP and its N-terminal fragments in plasma, our results sustain the connotation that plasma concentrations are influenced by both gender and age. Additionally, echocardiography of the 3497 subjects established that increased proBNP concentrations are independently related to echocardiographic findings of LVSD and LVH in the general population. The overall diagnostic performance, expressed as AUC values from ROC curves, was comparable to the previously reported diagnostic performance of plasma BNP in a large population.14 Thus, neither proBNP nor BNP measurement seem to be optimal for diagnostic LVSD and LVH screening, but should possibly be introduced in primary health care combined with other clinical or biochemical markers of heart failure.

The present findings of gender and age-specific differences in plasma proBNP concentrations compare well with the reported differences in BNP concentrations.35 In this key study by Redfield et al., plasma BNP concentrations were not only related to gender and age, but the differences also proved assay-dependent when comparing two commercial BNP assays. In contrast, the existing data on proBNP concentrations has been dominated by one single assay.36 As BNP data from previous studies have shown assay-specific effects, it is important to also examine proBNP measurement in plasma using different methodologies. Notably, the few head-to-head comparisons of proBNP methods have indicated some hitherto unexplained concentration-dependent differences.21,22 In this context, it should be recapitulated that different assays are based on recognition of different epitopes within the precursor molecule (for review, see Goetze37), which in turn will be affected differently by changes in post-translational processing as well as enzymatic degradation in circulation. Nevertheless, the present findings of a 4.3-fold (men) and 3.3-fold (women) increase in proBNP concentrations between the chosen age groups seem to compare reasonably well with a smaller recent study that examined 397 normal subjects using an automated method for the N-terminal proBNP fragment.38 We therefore suspect that assay-related differences in gender and age-specific concentrations may be less pronounced in normal subjects. In contrast, we found a marked effect of gender and age in subjects with LVSD or LVH (Table 3). This may reflect differences in the underlying pathology leading to LVSD and LVH in the gender and age-specific groups, which may further obscure the search for a uniform reference interval.

In this study, LVSD was defined as an LVEF<60%. Earlier studies used a lower limit for LVSD.12,13 Today, LVSD is often defined as LVEF<50%. In this population-based study, only 37 of the 3497 participants had LVEF<50%, which severely reduced the possibility of further subdividing these subjects. A recent study from the same town recruited participants from general practitioners, and as much as 11% of the participants had LVEF<50%.17 This large difference is likely to reflect that subjects recruited from general practitioners represent a select group from the general population. Results from truly population-based studies like the present one should therefore not readily be compared with studies that examine subjects already selected by, for instance, an established contact to a doctor. In this respect, our findings are in line with another population-based study.39 The diagnostic performance of proBNP measurement in detecting LVSD was also assessed using ROC curves (Table 4). As expected, the performance increased in a step-wise manner with more severe LVSD (LVEF<40%) harbouring the highest AUC values of 0.92 and 0.85 in women and men, respectively. An earlier population-based study that evaluated plasma BNP as screening marker found AUC values of 0.85 (women) and 0.79 (men) in detecting moderate to severe LVSD.14 Our results using proBNP as a screening marker, therefore, seem to parallel or even supercede these findings. Importantly, both the previous Framingham report and our present study did not include measurement of diastolic dysfunction, which in turn could influence the diagnostic performance.

A recent report has suggested that proBNP measurement may at least be equivalent to BNP measurement in a head-to-head study.19 In this study, the AUC values for detecting LVEF≤50 or 40% were reported higher for N-terminal proBNP compared with BNP in men (but not in women). Unfortunately, it is not possible to directly compare those results with our findings. Whether the differences are statistically significant or not, it still seems reasonable to address the actual main question of whether BNP and/or proBNP measurement are to be considered for population screening inspite of small differences in ROC analyses. For instance, the AUC values for screening for prostate cancer in men using prostate-specific antigen measurement was recently reported as low as 0.69 for men younger than 70 years.40 In that respect, the World Health Organization has proposed a set of criteria which should be considered for any given screening marker. Essentially, the condition to screen for should be of public health importance and detectable in a pre-clinical stage. Also, the screening method should be safe and the condition should have an effective treatment. Finally, the screening and intervention should be economically reasonable. Several of these criteria are in fact fulfilled by BNP or proBNP measurement including the medical importance of LVSD and LVH and an established treatment for the conditions. However, the impact of mild LVSD on morbidity and mortality is still not well documented, and perhaps most unclear is still the potential impact of such screening on the health care economy, although a few studies already have addressed this issue.41 Clearly, many subjects will undergo echocardiography without having LVSD or LVH, but whether early identification of a few patients could counteract this expense in the long-term is still unknown.

In population screening, there is a particular demand for high diagnostic sensitivity. In our study, we identified separate threshold values for men (<17 pmol/L) and women (<31 pmol/L), which completely could exclude a diagnosis of LVEF<40%. Thus, the data not only support a role for proBNP measurement in ruling out severe LVEF but also show that the number of subjects with increased proBNP concentrations without LVSD is high. In heart failure diagnostics, proBNP and BNP measurement has generally been hampered by low specificity, which has prompted the rational suggestion of using these markers primarily as ‘rule out’ markers.42 Increased proBNP and BNP concentrations can be caused by other medical conditions including changes in peripheral elimination such as renal impairment.43 In addition, increased plasma concentrations may be due to augmented cardiac expression caused by mechanisms not detected by standard echocardiographic assessment. For instance, stable coronary artery disease in the absence of LVSD is associated with increased plasma concentrations.44–46 Another stimulus for increased cardiac BNP gene expression can be proinflammatory cytokines in vitro, which also may be involved in vivo during sepsis.47 In this respect, precipitation of acute dyspnoea has been shown to represent a useful clinical threshold at hospital admission,45,46 and that both plasma proBNP and BNP measurements seem to be useful as biochemical markers.48–50 We therefore propose that the future search for new markers may be related to conditions other than LVSD that may precede acute dyspnoea as, for instance, pulmonary function tests.

In conclusion, the present study has demonstrated that measurement of proBNP in plasma parallels earlier findings of BNP as screening marker for LVH and LVSD in the general population. Using a PIA for proBNP measurement, our results consolidate the impact of gender and age on proBNP concentrations in subjects with and without LVSD and LVH. LVSD is uncommon in the general population and not obvious to screen for, but proBNP measurement can be used to rule out severe LVSD. Identification of other markers that can increase the diagnostic specificity is warranted.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
We are grateful for the expert technical assistance from Lone Olsen. The study was supported by grants from the Lundbeck Foundation, the Novo Nordisk Foundation, the Ellab Foundation, the Eva and Robert Voss Hansen Foundation, and the Danish Heart Foundation.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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