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N-terminal pro-B-type natriuretic peptide is an independent predictor of cardiovascular morbidity and mortality in the general population

Gerard C.M. Linssen, Stephan J.L. Bakker, Adriaan A. Voors, Ron T. Gansevoort, Hans L. Hillege, Paul E. de Jong, Dirk J. van Veldhuisen, Rijk O.B. Gans, Dick de Zeeuw
DOI: http://dx.doi.org/10.1093/eurheartj/ehp420 120-127 First published online: 23 October 2009

Abstract

Aims Natriuretic peptides including N-terminal pro-B-type natriuretic peptide (NT-proBNP) are established biomarkers in heart failure. However, their prognostic value in the general population is less well established. The purpose of our study was to investigate the prognostic properties of NT-proBNP for death and cardiovascular (CV) events in the general population.

Methods and results In the population-based Prevention of Renal and Vascular End-stage Disease (PREVEND) study, 8383 subjects were prospectively followed for a median period of 7.5 years. There were 4181 (49.9%) males and 4202 (50.1%) females, mean age was 49.3 ± 12.7 years (range 28–75). Median NT-proBNP at baseline was 37.7 pg/mL (IQR 16.8–73.8). All-cause death occurred in 437 (5.2%) subjects and there were 557 (6.6%) CV events. Higher levels of plasma NT-proBNP were related to higher event rates. When adjusted for age, gender, and other relevant covariates, each doubling of NT-proBNP remained significantly associated with a 22% increased risk for all-cause mortality (P < 0.001) and a 16% increased risk of CV events (P < 0.001).

Conclusion In this large community-based cohort, plasma NT-proBNP was a strong predictor of death and a wide range of CV events.

  • Cardiovascular diseases
  • Epidemiology
  • Natriuretic peptides
  • Population
  • Prognosis

Introduction

Natriuretic peptides including brain-type natriuretic peptide (BNP) and its equimolarly secreted N-terminal fragment (NT-proBNP) are established biomarkers for diagnosis, prognosis, and management, in particular in patients with established cardiovascular (CV) disease and heart failure.18

In the general population, however, the prognostic value of these peptides is less well established. Wang et al.9 were the first to describe the prognostic value of BNP in participants of the Framingham Offspring Study. In another community-based cohort from Olmsted County, both BNP and NT-proBNP were shown to predict mortality.10 Three European groups reported on the predictive value of NT-proBNP in small samples of the general population.1113

In the present study, we investigated the independent prognostic value of NT-proBNP in so far the largest sample of the general population, consisting of 8383 subjects. Our cohort is also characterized by a wider age-range of adult subjects (28–75 years) and a long follow-up with a substantially higher number of CV events compared with the previous studies.

Methods

This study was performed in subjects participating in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study. This project was designed to prospectively investigate the natural course of increased levels of urinary albumin excretion (UAE) and its relation to renal and CV disease in a large cohort drawn from the general population. Details of this protocol have been described elsewhere.14,15 In summary, in the period 1997–1998, all inhabitants of the city of Groningen, The Netherlands, aged 28–75 years, were sent a one-page postal questionnaire and a vial to collect an early morning urinary sample (n = 85 421). Of these subjects, 40 856 responded (47.8%) and sent a vial to a central laboratory where urinary albumin and creatinine concentrations were measured. After exclusion of subjects with type 1 diabetes mellitus (defined as the use of insulin) and pregnant women, all subjects with a UAE of ≥10 mg/L (n = 6000) and a randomly selected control group with UAE < 10 mg/L (n = 2592) were further investigated in an outpatient clinic and asked to collect two consecutive 24 h urines. These 8592 subjects form the PREVEND cohort. In 8383 subjects plasma levels of NT-proBNP were measured. They comprise the current study population.

All subjects gave written informed consent. The PREVEND study was approved by the local medical Ethical Committee, and is conducted in accordance with the guidelines of the Declaration of Helsinki.

Analytical methods

N-terminal pro-B-type natriuretic peptide measurements were performed in plasma on an Elecsys™ 2010 analyser, a commercially available electrochemiluminescent sandwich immunoassay (Elecsys proBNP, Roche Diagnostics, Mannheim, Germany). The intra- and interassay coefficient of variation were 1.2–1.5 and 4.4–5.0%, respectively, with an analytical range of 5–35 000 pg/mL.16 Conversion of NT-proBNP levels: 100 pg/mL equates to 11.82 pmol/L. Urinary albumin excretion was determined by nephelometry, with a threshold of 2.3 mg/L and intra- and interassay coefficients variation of 2.2 and 2.6%, respectively (BNII, Dade Behring Diagnostica, Marburg, Germany). High-sensitive C-reactive protein was also determined by nephelometry with a threshold of 0.175 mg/L and intra- and inter-assay coefficients of less than 4.4 and 5.7%, respectively.

Definitions and calculations

Systolic and diastolic blood pressures were calculated as the mean of the last two measurements of the two visits. Hypertension was defined as having a systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg and/or use of anti-hypertensive medication. Body mass index (BMI) was calculated as the ratio of weight and height (kg/m2). Type 2 diabetes was defined as a fasting glucose level of ≥7.0 mmol/L (126 mg/dL) or a non-fasting glucose level of ≥11.1 mmol/L (200 mg/dL) or the use of anti-diabetic drugs. Hypercholesterolaemia was defined as a serum cholesterol ≥6.5 mmol/L (251 mg/dL) or a serum cholesterol ≥5.0 mmol/L (193 mg/dL) if a history of myocardial infarction (MI) was present or when lipid-lowering medication was used. Smoking was defined as current smoking or stopped smoking within the previous year. Histories of MI or cerebrovascular disease were considered present if a participant reported having been hospitalized for at least 3 days because of these conditions. An elevated C-reactive protein was defined as a level >3 mg/L. Urinary albumin excretion was calculated as the average UAE in the two consecutive 24 h urine collections. An estimate of the glomerular filtration rate (eGFR) was calculated using the simplified Modification of Diet in Renal Disease (sMDRD) formula.17,18

Electrocardiography

Standard 12-lead electrocardiograms were recorded with Cardio Perfect equipment (Cardio Control, Rijswijk, the Netherlands), stored digitally using the computer program MEANS (Modular Electrocardiogram Analysis System). Left ventricular hypertrophy (LVH) was identified using Cornell voltage–duration product, which was calculated as follows: RaVL+SV3 (with 6 mm added in women) times QRS duration. A threshold of 2440 mm ms was used to identify LVH.19,20

Cardiovascular events

For CV outcome, we used the combined incidence of CV morbidity and mortality after the baseline screening. Data on mortality were received through the municipal register. Cause of death was obtained by linking the number of the death certificate to the primary cause of death as coded by the Dutch Central Bureau of Statistics. Information on hospitalization for CV morbidity was obtained from PRISMANT, the Dutch national registry of hospital discharge diagnoses. All data were coded according to the International classification of diseases, 9th revision and the classification of interventions. For this study, CV events were defined as the following; acute MI (ICD-code 410), acute and subacute ischaemic heart disease (411), subarachnoid hemorrhage (430), intracerebral haemorrhage (431), other intracranial haemorrhage (432), occlusion or stenosis of the precerebral (433) or cerebral arteries (434), coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA), and other vascular interventions as percutaneous transluminal angioplasty (PTA) or bypass grafting of aorta and peripheral vessels. Survival time was defined as the period from the date of urine collection of the participant to the date of first CV event or 31 December 2005. In case a person had moved to an unknown destination, the date on which the person was removed from the municipal registry was used as census date.

Statistical analyses

Continuous variables with a normal distribution are expressed as means with standard deviation (SD). Variables with a skewed distribution, such as UAE, C-reactive protein, and NT-proBNP, are given as medians with interquartile range (IQR). Differences in proportions were tested using χ2 analysis and Fisher's exact test. Differences in continuous variables between quintiles of NT-proBNP levels were tested using weighted ANOVA. For the screening of the PREVEND study, we overselected subjects with an elevated UAE to acquire sufficient subjects with microalbuminuria. It should be clear that this is not a simple random sample from an infinite population, where all sampling elementary units have an equal probability of being sampled. Within this context, statistical formulas to calculate population parameter estimates should take into account the probability of selection. To overcome this oversampling of subjects with elevated UAE, a design-based analysis was performed. Due to this statistical weighting method, our conclusions can be generalized to the general population. The design-based Cox proportional-hazards regression models evaluating the prognostic properties of NT-proBNP to the risk of death or CV events were built with STATA (Statistical Software release 10.0, StataCorp LP, College Station, TX, USA). The multivariable model was adjusted for all confounders: age, gender, smoking, medical history, waist-hip ratio, BMI, systolic and diastolic blood pressure, serum cholesterol, serum HDL-cholesterol, serum glucose, eGFR, mean 24 h UAE, C-reactive protein, and LVH (Table 1).

View this table:
Table 1

Baseline characteristics according to the plasma N-terminal-pro-B-type natriuretic peptide levels (total population, n = 8383)

CharacteristicTotalQuintiles of NT-proBNP (pg/mL)P-value
Quintile12345
NT-proBNP, min–max5.0–13.313.3–28.228.2–48.848.8–87.587.5–35,000
Mean7.420.737.865.1336.5
n838316771677167616771676
Age, years49.3 ± 12.744.1 ± 9.946.2 ± 11.248.1 ± 11.950.7 ± 12.757.4 ± 13.1<0.001
Female gender (%)4202 (50.1)348 (20.7)705 (42.0)986 (58.9)1123 (67.0)1040 (62.1)<0.001
Smoking, n (%)3160 (37.8)645 (38.6)664 (39.8)647 (38.7)614 (36.7)590 (35.3)0.058
Medical history
Diabetes, n (%)310 (3.8)64 (3.9)52 (3.2)47 (2.8)51 (3.1)96 (5.8)<0.001
Myocardial infarction, n (%)513 (6.2)47 (2.9)57 (3.5)62 (3.8)86 (5.2)261 (15.9)<0.001
Hypertension, n (%)2642 (32.0)396 (24.1)390 (23.6)434 (26.2)560 (33.9)862 (52.2)<0.001
Hypercholesterolaemia, n (%)2179 (26.4)456 (27.6)390 (23.7)396 (24.1)421 (25.5)516 (31.3)<0.001
Stroke, n (%)78 (1.0)6 (0.4)11 (0.7)14 (0.9)18 (1.1)29 (1.8)0.001
Waist-hip ratio0.88 ± 0.100.91 ± 0.080.88 ± 0.090.87 ± 0.100.88 ± 0.100.88 ± 0.10<0.001
BMI, kg/m226.1 ± 4.226.5 ± 3.926.0 ± 4.325.8 ± 4.226.0 ± 4.426.3 ± 4.30.18
Systolic BP, mmHg129.1 ± 20.3128.1 ± 14.8126.1 ± 17.7125.4 ± 18.6128.3 ± 20.8137.6 ± 25.7<0.001
Diastolic BP, mmHg74.0 ± 9.874.8 ± 8.473.4 ± 9.372.6 ± 9.573.3 ± 10.075.9 ± 11.10.006
Serum cholesterol, mmol/L5.6 ± 1.15.8 ± 1.15.6 ± 1.25.6 ± 1.15.6 ± 1.15.7 ± 1.10.001
Serum HDL-cholesterol, mmol/L1.3 ± 0.41.2 ± 0.31.3 ± 0.41.4 ± 0.41.4 ± 0.41.4 ± 0.4<0.001
Serum glucose, mmol/L4.9 ± 1.25.0 ± 1.34.9 ± 1.24.8 + 1.04.8 ± 1.05.0 ± 1.30.20
eGFR, mL/min/1.73 m280.7 ± 14.785.4 ± 13.783.2 ± 13.780.7 ± 13.779.4 ± 14.574.7 ± 15.4<0.001
Mean 24 h UAE, mg/24 ha9.5 (6.3–17.9)9.2 (6.5–16.3)9.0 (6.3–15,6)8.7 (6.0–15.1)9.4 (6.1–17.2)11.7 (6.8–29.8)<0.001
C-reactive protein, mg/La1.3 (0.6–3.0)1.1 (0.5–2.4)1.1 (0.5–2.6)1.2 (0.5–2.8)1.4 (0.6–3.1)2.0 (0.9–4.4)<0.001
LVH, n (%)420 (5.0)57 (3.4)59 (3.5)69 (4.1)69 (4.1)166 (9.9)<0.001
  • BP, blood pressure; BMI, body mass index; UAE, urinary albumin excretion; eGFR, estimated glomerular filtration rate by simplified Modification of Diet in Renal Disease (sMDRD) formula; LVH, left-ventricular hypertrophy was identified on standard 12-lead electrocardiogram. Conversion of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels: 100 pg/mL equates to 11.82 pmol/L. All continuous variables are presented as mean ± SD.

  • aContinuous variable is presented as median value (25–75th percentiles).

Results are summarized by hazard (risk) ratios (HR) with 95% confidence intervals (CI). N-terminal pro-B-type natriuretic peptide showed a log-linear functional shape with the response variable and was transformed to a 2-log scale. This means that risk estimates should be interpreted as the relative risk if values of NT-proBNP were doubled (e.g. 10–20 pg/mL). All reported probability values are two-tailed and P < 0.05 was considered statistically significant. The independent contribution or NT-proBNP was explored crude, age and sex adjusted and by modelling in a mutually adjusted model. In addition, we calculated the incremental value of NT-proBNP beyond C-reactive protein by means of Harrel's C concordance statistics. Analyses were performed using the Statistical Package for Social Sciences software (SPSS version 14.0.1 for Windows, SPSS Inc., Chicago, IL, USA) and STATA software (STATA version 10.0, College Station, TX, USA).

Results

A total of 8383 subjects were followed for a median of 7.5 years (IQR 7.3–7.9). The median NT-proBNP level at baseline was 37.7 pg/mL (IQR 16.8–73.8). Figure 1 shows the frequency distribution of plasma levels of NT-proBNP. The majority of subjects (83.4%) had a level below 100 pg/mL (11.8 pmol/L). Baseline characteristics of the participants according to quintiles of plasma NT-proBNP are presented in Table 1. The population consisted of 4181 (49.9%) males and 4202 (50.1%) females. Mean age was 49.3 ± 12.7 years (28–75). Individuals in the highest quintile of NT-proBNP levels were generally older, more often female, and more often had a history of hypertension and/or MI, hypercholesterolaemia and stroke. Furthermore, subjects in the highest quintile had higher BP, serum cholesterol, UAE, and C-reactive protein levels, while they had lower values of eGFR and more often LVH on the ECG at baseline in comparison to subjects in the lower four quintiles (P-value for all <0.001).

Figure 1

Frequency distribution of plasma levels of N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP) and multivariable adjusted hazard ratios on the risk of cardiovascular events and all-cause mortality. Values below the detection limit are reported as 5 pg/mL.

All-cause mortality and cardiovascular events

A total of 437 (5.2%) subjects died and 557 (6.6%) had a CV event during follow-up. Table 2 shows the numbers of all pre-specified endpoints according to quintiles of NT-proBNP levels. In the fifth quintile of NT-proBNP, about half of the total number of events occurred. In Figure 2 Kaplan–Meier curves are plotted for CV events by quintiles of NT-proBNP extrapolated to the original screening sample numbers. CV outcome of subjects in the highest quintile of NT-proBNP [>87.5 pg/mL (10.3 pmol/L)] was worse in comparison to the lower four quintiles. However, there were no statistically significant differences with regard to CV outcome between the first four quintiles. The majority of CV events were of cardiac origin (4.9%). Cerebral and peripheral events occurred in 1.4 and 0.3%, respectively.

Figure 2

Kaplan–Meier plot for cardiovascular events by quintiles (Q) of N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP).

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Table 2

Events according to quintiles of the N-terminal pro-B-type natriuretic peptide level

EventNumber of events (% of total cohort)Quintiles of NT-proBNP (pg/mL)
Quintile12345
NT-proBNP, min–max5.0–13.313.3–28.228.2–48.848.8–87.587.5–35,000
All-cause death437 (5.2)25555771229
Cardiovascular events557 (6.6)62628299252
Cardiac morbidity385 (4.6)52475469163
 Myocardial infarction147 (1.8)2523212157
 Ischaemic heart disease111 (1.3)811152354
 PTCA78 (0.9)119111631
 CABG49 (0.6)847921
Cardiac mortality24 (0.3)023019
Cerebral morbiditya116 (1.4)109192652
Cerebral mortality4 (0.05)01003
Peripheral morbidityb28 (0.3)036415
  • aCerebral morbidity is defined as CVA and arterial disease, carotid desobstruction, and cerebral (subarachnoid or intracerebral or other intracranial) haemorrhage.

  • bPeripheral morbidity is defined as peripheral arterial or aorta surgery, and percutaneous transluminal angioplasty.

Five year incidences of CV morbidity/mortality were 3.50% (95% CI 3.10–3.97), with cerebral and cardiac event rates of 0.77% (95% CI 0.60–1.00) and 2.73% (95% CI 2.38–3.16), respectively.

Doubling of NT-proBNP was univariably associated with a 1.56-fold increased risk of all-cause mortality (P < 0.001; Table 3), a 1.37-fold increased risk of CV events (P < 0.001; Table 3), and a 1.38 increased risk of non-CV death (P < 0.001; Table 3).

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Table 3

Hazard ratios for all-cause mortality, cardiovascular events, and non-cardiovascular mortality according to doubling of N-terminal pro-B-type natriuretic peptide

Hazard ratioT95% CIP-value
For all-cause mortality
 Unadjusted model1.5610.071.43–1.70<0.001
 Model 11.274.881.16–1.41<0.001
 Model 21.223.891.10–1.35<0.001
For cardiovascular events
 Unadjusted model1.376.851.25–1.50<0.001
 Model 11.224.191.11–1.33<0.001
 Model 21.162.781.05–1.29<0.005
For non-cardiovascular mortality
 Unadjusted model1.384.771.20–1.57<0.001
 Model 11.111.410.95–1.280.16
 Model 21.070.760.90–1.270.45
  • Model 1: age and gender adjusted model.

  • Model 2: multivariate model adjusted for all characteristics as presented in Table 1.

When adjusted for age, gender, and all other baseline characteristics listed in Table 1, doubling of NT-proBNP was still significantly associated with a 1.22-fold increased risk of all-cause mortality (P < 0.001; Table 3) and a 1.16-fold increased risk of CV events (P < 0.001; Table 3). However, doubling of NT-proBNP was not associated with non-CV death (HR 1.07; P = 0.45; Table 3).

Multivariable HR on the risk of CV events and all-cause death are presented in Figure 1. For reference, an NT-proBNP concentration of 40 pg/mL, which is approximately the median value, was defined as an HR of 1.0. Figure 3 shows that at a similar level of NT-proBNP male subjects are at higher risk for mortality and CV events than female subjects. There was however no significant influence of gender on the relationship between NT-proBNP and prognosis. Finally, only marginal model improvements in the fully adjusted model were observed in Harrel's C concordance statistics regarding C-reactive protein alone vs. C-reactive protein and NT-proBNP: 0.838 vs. 0.841, respectively (P = NS).

Figure 3

Multivariable adjusted hazard ratios on the risk of all-cause mortality in female and male subjects according to the level of N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP).

Discussion

The main finding of the present study is that plasma NT-proBNP independently predicted all-cause mortality and CV events in the general population. Our large PREVEND cohort is characterized by a wide age-range (28–75 years) and more than 60 000 subject-years of follow-up, which is considerably more than any other comparable study to date.

Particularly in the highest quintile of NT-proBNP [plasma level >87.5 pg/mL (10.3 pmol/L)] markedly higher event rates during follow-up were found in comparison to the lower four quintiles. Kaplan–Meier survival curves indicated that the risk of mortality and CV events was particularly increased in patients with NT-proBNP levels of >87.5 pg/mL. This might suggest a cut-off level. However, it should be noted that the fifth quintile showed a less favourable CV risk profile including a substantial higher mean NT-proBNP concentration when compared with the other quintiles. The adjusted models demonstrated a gradual increased risk of mortality and CV events with increasing levels of NT-proBNP, without a clear cut-off.

Each doubling of NT-proBNP was associated with a 56% increase in all-cause mortality and a 37% increase in CV events. After adjustment for age, gender, and other relevant covariates, the increased risks remained significant, 22 and 16%, respectively. Interestingly, neither C-reactive protein nor eGFR and mean 24 h UAE influenced the prognostic value of NT-proBNP.

In three studies of the general population, NT-proBNP was found to be predictive for CV events and mortality.1113 First, in a population-based study of 626 participants aged 50–89 years free of heart or renal failure from a community in Copenhagen, the adjusted HR for mortality during 5 years of follow-up for values above the 80th percentile of NT-proBNP was 1.96 (95% CI 1.21–3.19) and for first major CV event 3.24 (95% CI 1.80–5.79), respectively.11 In another study Laukkanen et al.12 reported on the predictive power of NT-ANP and NT-proBNP with respect to CV events and mortality in a sample of 905 men (age 46–65 years) from eastern Finland. The third study was a community-based sample of 2656 individuals (41, 51, 61, or 71 years of age) from Denmark, where CV risk prediction improved by using NT-proBNP.13 In the Olmsted County study in 1991 subjects from the general population, aged ≥45 years, both NT-proBNP and BNP were evaluated as biomarkers for predicting mortality.10 In their multivariable model the HR per 1-SD increase in Log Variable of NT-proBNP for all-cause mortality during 7 years of follow-up was 1.44 (CI 1.08–1.94, P = 0.014). In the Framingham Offspring Study, in which 3346 subjects participated, the level of BNP independently predicted death, heart failure, atrial fibrillation, and stroke during a mean follow-up period of 5.2 years.9

In selected populations with an increased risk, (NT-pro)BNP can be applied for further risk stratification.2124 In the previous community-based studies the rates of all-cause mortality ranged from 0.6 to 3% per year.912 The highest mortality rate was found in the study from Copenhagen in which subjects where older (mean age of 68 years).11 In our PREVEND study all-cause death occurred in 0.7% of subjects per year during a median follow-up period of 7.5 years. Taken both the wider age range (28–75 years) and the lower mean age of the participants of our study also into consideration, our cohort comprises a representative sample of the community.

In the reported studies, different natriuretic peptide assays and antibodies were used. These differences in precision and performance of analytical methods may have influenced the predictive value of those peptides. Furthermore, the magnitude of the effects of NT-proBNP on mortality and CV outcome differs between studies. We analysed the effects of doubling of NT-proBNP, while in previous studies several other methods were used.1113

Although NT-proBNP was associated with both CV and non-CV mortality, in multivariable analysis, NT-proBNP was only associated with CV mortality. Therefore, increased NT-proBNP in the general population seems to be associated with an increased risk of predominantly CV disease, and might therefore reflect underlying silent or overt CV disease. Slight elevations of NT-proBNP may represent subtle cardiac remodelling. Elevated natriuretic peptides reflect increased atrial or ventricular stretch from pressure or volume overload. An increased left-ventricular filling pressure in the setting of diastolic dysfunction may be the underlying mechanism of the association between elevated natriuretic peptides and mortality in the general population.2125 Additional mechanisms, in which natriuretic peptides play a role in vascular function and remodelling, may also be important. Besides myocardial stretch and ischaemia, other factors including endothelin, angiotensin II, and tumour necrosis factor α have been found to stimulate secretion of BNP in vitro.26,27 Both cardiac myocytes and fibroblasts secrete BNP which leads to fibrosis through induction of matrix metalloproteinases.28 The increased vascular reactivity and myocardial alterations enhanced by local and circulating factors may progress to CV disease.29 Subclinical myocardial ischaemia, hypertrophy, and fibrosis induce elevated cardiac filling pressures which result in increased myocardial stretch enhancing synthesis and release of B-type natriuretic peptides. Furthermore, ischaemic or injured myocardial tissue releases additional BNP irrespective of haemodynamic factors.30,31

Risk stratification using biomarkers will help to identify those subjects in the community who may benefit most from advanced diagnostic testing and therapeutic intervention. However, whether specific preventive strategies or treatment may be of benefit for subjects with increased NT-proBNP remain to be addressed before this biomarker can be applied for routine screening purposes.3234

Limitations

The present study has several limitations. We measured NT-proBNP only once and without correction for potential variability in concentrations. The PREVEND cohort is predominantly white, and our findings may not be representative for non-whites. However, the finding that the percentage of all deaths in the present study that is classified as being due to CV disease is in line with previous prospective studies of subjects of the general population. Echocardiography was not part of our study design. It may have provided additional information in the early detection of CV disease.

Conclusions

In our large community-based cohort, plasma NT-proBNP was a strong predictor of the risk of death and a wide range of CV events. Higher values might reflect subclinical CV disease such as LVH, diastolic dysfunction, or even asymptomatic LV systolic dysfunction.

Funding

The PREVEND study was financially supported by grant E.013 of the Netherlands Kidney Foundation. D.J.v.V. and A.A.V. are Clinical Established Investigators of the Netherlands Heart Foundation (grant D97.017 and grant 2006T037).

Conflict of interest: none declared.

Acknowledgements

The authors acknowledge the Trial Coordination Center, Groningen, the Netherlands. We are grateful to Dade Behring Diagnostica, Marburg, Germany; and Roche Diagnostics, Mannheim, Germany for providing tests, assay kits, and technical support.

References

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