Plasma N-terminal pro-brain natriuretic peptide concentration predicts coronary events in men at work: a report from the BELSTRESS study

Johan De Sutter1,*, Dirk De Bacquer2, Sofie Cuypers1, Joris Delanghe3, Mark De Buyzere1, Marcel Kornitzer4 and Guy De Backer2

1Department of Cardiology 8K12 IE, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium
2Department of Public Health, Ghent University, Belgium
3Department of Clinical Biology, Ghent University, Belgium
4School of Public Health, Université Libre de Bruxelles, Belgium

Received 7 March 2005; revised 24 August 2005; accepted 2 September 2005; online publish-ahead-of-print 4 October 2005.

* Corresponding author. Tel: +32 9 240 34 76; fax: +32 9 240 58 26. E-mail address: johan.desutter{at}ugent.be

See page 2603 for the editorial comment on this article (doi:10.1093/eurheartj/ehi614)


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusions
 Acknowledgements
 References
 
Aims Increased levels of neurohormonal markers, including the N-terminal fragment of pro-brain natriuretic peptide (NT-pro-BNP), have been shown to be of prognostic significance in patients with heart failure or coronary heart disease (CHD). The aim of this study was to study the predictive value of NT-pro-BNP for coronary events in a middle-aged population of men at work.

Methods and results A nested case–control study was performed in a large cohort of over 10 000 men at work (aged 35–59) after a median follow-up of 2.66 years. In total, 66 individuals who developed coronary events were matched on a 3-to-1 basis to 198 controls free of coronary events during follow-up. Besides clinical characteristics and conventional cardiac risk factors, NT-pro-BNP (electrochemiluminiscence assay, Roche diagnostics) and serum creatinine levels were determined. In univariable analysis, cases were more frequently current smokers and diabetics, had more frequently a history of CHD, and had higher levels of total cholesterol and systolic blood pressure (SBP), and lower levels of HDL cholesterol. A highly significant difference (P<0.0001) was noted for NT-pro-BNP levels between cases (median 48.5 pg/mL, interquartile range 26.4–116.6 pg/mL) and controls (30.0 pg/mL, 19.5–47.6 pg/mL). In multivariable conditional logistic regression analysis, NT-pro-BNP remained strongly associated with risk for coronary events [third vs. first tertile, odds ratio (95% CI) 3.24 (1.18–8.85)], independent of body mass index, smoking, diabetes, SBP, total and HDL cholesterol, creatinine, and previous CHD.

Conclusion NT-pro-BNP is a strong predictor of coronary events in men at work after a relatively short period, even after adjustment for conventional risk factors.

Key Words: Natriuretic peptide • Cardiac risk factors • Cardiac events • General population


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusions
 Acknowledgements
 References
 
Increased levels of neurohormonal markers, including brain natriuretic peptide (BNP) and the inactive N-terminal pro-BNP (NT-pro-BNP), have been shown to be of prognostic significance in patients with heart failure or coronary heart disease (CHD).16 In addition, in the general population, it has been shown that levels of BNP and NT-pro-BNP are predictive for cardiac events, although most of these studies have focused on elderly subjects.710 Recently, data from the Framingham Heart Study showed that BNP levels were strong predictors of cardiac morbidity and mortality even after adjustment for conventional cardiac risk factors and even when BNP levels were below the threshold used to identify patients with heart failure.11 In addition, Kistorp et al.12 reported that NT-pro-BNP provided prognostic information on mortality and first major cardiovascular events beyond traditional risk factors in a population-based prospective study of 626 participants aged 50–89. The prognostic value of NT-pro-BNP in younger populations, especially in middle-aged individuals at work, is, however, unknown.

BNP and NT-pro-BNP are predominantly released from ventricular myocardium as a response to ventricular dilatation and pressure overload.13,14 It has, however, also been suggested that levels of BNP and NT-pro-BNP may not only reflect increased left ventricular wall stress but also result directly from myocardial ischaemia.1517 The relationship between NT-pro-BNP levels and subsequent coronary events in the general population has, however, not been studied in detail.

Therefore, we aimed to investigate the relationship between NT-pro-BNP levels and the occurrence of coronary events in a middle-aged population of men at work. We used a nested case–control study design in a large cohort of over 10 000 men at work (aged 35–59) who were included in the Belgian Job Stress Project (BELSTRESS).18


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusions
 Acknowledgements
 References
 
BELSTRESS study cohort
The BELSTRESS is a multi-disciplinary large-scale study focusing on the independent association of perceived job stress with health18 and is part of the international JACE study (Job stress, Absenteeism and Coronary heart disease-European co-operative prospective study).19 For a detailed description of the study protocol and study participants, we refer to previous publications.1821 In brief, the sample consists of middle-aged men and women at work in 25 large industries or administrations across Belgium. All 44 530 employees aged 35–59 received a personal invitation letter including a reply form and a return envelope. Invitation letters were distributed internally under the supervision of the occupational health service. The self-administered questionnaires were then distributed among the interested participants together with a personal invitation for the medical screening at the workplace. Participants were asked to complete questionnaires at home and bring them to the medical examination which took place at least a week later. There were no formal exclusion criteria. A total of 21 419 participants (16 329 men and 5090 women) complied with the study (participation rate 48%). Data collection was conducted in the period between 1994 and 1998.

Clinical examination and laboratory analysis
The clinical examination took place in the medical office at the workplace and was done in accordance with a manual of operations by centrally trained paramedics either from the occupational health service or from the research centre. Blood pressure was calculated as the average of two readings obtained by sphygmomanometry in a sitting position with a 5-min interval. Current smoking was considered as the current consumption of cigarettes, cigars, or pipes. Body mass index (BMI) was calculated as weight (in kilograms) divided by the squared height (in metres). Prevalent CHD at the clinical examination was defined as a history of myocardial infarction or angina pectoris according to the Rose questionnaire or a previous hospitalization for coronary angioplasty or bypass surgery or ischaemic-like abnormalities on the resting ECG [consisting of Q/QS patterns (Minnesota codes I1–3) or ST segment depression (codes IV1–3) or T-wave inversion (codes V1–3) or complete left bundle branch block (code VII1)].22 Apart from the ECG information, all this information was self-reported in the medical history questionnaire but verified with the paramedics during clinical examination.

A non-fasting blood sample was taken at the worksite at the time of initial clinical examination and shipped to a central laboratory. Total cholesterol was determined using the CHOD-PAP High Performance Method (Boehringer) on a Hitachi 747 analyser, whereas HDL cholesterol was determined using the heparin– manganese precipitation method.20,21 After initial lipid determinations, blood samples were frozen at –80°C for future analysis.

Follow-up of the BELSTRESS cohort
Regarding the low number of events expected among women, female employees did not participate in this short-term prospective study. The male subcohort was followed up until 31 December 1999 for incident clinical manifest coronary events. Because of organizational reasons, follow-up information was not gathered in seven of the smaller companies resulting in 14 987 male employees for inclusion for follow-up. Incident coronary events were defined as the occurrence of an acute myocardial infarction (AMI), unstable angina, and hospitalizations for coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA). The incidence of CHD was carefully monitored according to the following procedure. For sickness absence spells of at least 3 weeks reported to the human resources department, the occupational health service in close collaboration with the co-ordinating research centre contacted the person's treating physician or hospital to check for a possible CHD diagnosis. In the case of a suspect coronary event, maximum efforts were put in accurately ascertaining the clinical diagnosis by following a formal diagnostic algorithm of gathering information on cardiac enzymes, electrocardiographic findings, and necropsy findings. After a median follow-up of 2.66 years, 82 subjects had developed coronary events. For 66 of these subjects, blood samples, taken at the initial visit, were still available to determine NT-pro-BNP and creatinine levels. These 66 subjects formed the cases and they were matched on a 3-to-1 basis to 198 controls free of coronary events during follow-up. Because controls were selected as subjects not having experienced a CHD event at the end of the study period, by default, controls were matched to cases for follow-up because at the time a case experienced an event, the control was free of an event. Cases and controls were matched for age. An exact match in age (within 1 year) was required. If more than three matches were found, the eligible controls were selected randomly. Given the large data pool of eligible controls, matched controls were found for all the cases. Because all studied individuals were men, no gender matching was performed.

The exclusion of 16 patients with missing blood samples probably did not introduce significant bias because the data availability was a random process which was caused by loss of blood samples that was not dependent on the status or progression of CHD. Furthermore, median age was comparable between the included cases and the missing cases (50 vs. 49 years, P=0.37) as well as the prevalence of CHD (31.8 vs. 21.4%, P=0.75). NT-pro-BNP levels were determined with an electrochemiluminiscence assay on a Modular E analyser (Roche diagnostics) and serum creatinine was determined using a rate-blanked compensated Jaffé method. The lower limit of detection was 5 pg/mL for the assay of NT-pro-BNP with an average interassay coefficient of variation of 3%. For data analysis, tertile cut points were pre-specified and were based on the distribution of NT-pro-BNP in the combined sample of cases and controls. Given the number of events, quartile or quintile analysis was expected to be inappropriate.

Statistical methods
Data are presented as median (interquartile range) or percentage (total number). Comparison of the characteristics between cases and matched controls was done by the Kruskal–Wallis test or Fisher's exact test. Spearman rank correlation coefficients were used to evaluate the association between NT-pro-BNP levels and quantitative characteristics among control subjects. NT-pro-BNP levels were compared between levels of categorical variables after age-adjustment according to analysis of covariance. To meet the model assumptions, NT-pro-BNP levels were logarithmically transformed in the latter analysis. Conditional logistic regression for matched sets was used for the multivariable analysis of the association between NT-pro-BNP and coronary events. Potential confounders chosen as covariates in multivariable modelling were smoking, diabetes, systolic blood pressure (SBP), total and HDL cholesterol, serum creatinine, prevalent CHD, and BMI all being established coronary risk factors which were indeed less favourable in our case series compared with the control subjects (Table 1). For continuous variables, the assumption of linearity was a priori checked by visual analysis of CHD odds after categorization according to their tertiles. An additional multivariable analysis was performed using NT-pro-BNP as a continuous variable to further strengthen the results and to rule out inflation of the type I error. All statistical analyses were performed using SAS software (The SAS system, release 6.12, Cary, NC, USA: SAS Institute Inc.). A two-sided P-value less than 0.05 was considered as indicating statistical significance.


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Table 1 Characteristics of the cases and matched controls
 

    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusions
 Acknowledgements
 References
 
Baseline characteristics
Median follow-up was 2.66 years (interquartile 2.12–3.69 years). During this follow-up period, 66 coronary events were registered including 36 cases of AMI (13 fatal cases), 22 cases of unstable angina, seven cases of PTCA, and one case of CABG. These 66 cases were matched on a 3-to-1 basis to 198 controls free of coronary events during follow-up.

Table 1 provides the baseline characteristics of the cases and controls. In total, 30 individuals had evidence for existing CHD at baseline: previous history of myocardial infarction (n=17), previous coronary angioplasty or bypass surgery (n=1), angina pectoris according tot the Rose questionnaire (n=2), or ischaemic-like abnormalities on the resting ECG (n=10). The prevalence of CHD at baseline was higher in the cases than in the controls. Regarding risk factors, cases were more frequently diabetics and had a higher blood pressure and total cholesterol levels as well as lower HDL cholesterol levels. Use of antihypertensive and lipid-lowering drugs was similar in both groups.

Association between NT-pro-BNP levels and other quantitative characteristics among control subjects
In 198 control subjects, NT-pro-BNP was only significantly correlated to age (r=0.14, P=0.04) but not to BMI, SBP or diastolic blood pressure, heart rate, or lipid levels. In addition, there was no significant correlation with serum creatinine (r=–0.04). Table 2 shows the levels of NT-pro-BNP and serum creatinine according to smoking status, physical activity, diabetes, and treatment with antihypertensive or lipid lowering drugs. No significant differences were noted for NT-pro-BNP levels after age-adjustment.


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Table 2 Association between NT-pro-BNP and serum creatinine levels and qualitative characteristics among control subjects
 
Association between NT-pro-BNP levels and coronary events
As can be noted from Table 1, cases had significantly higher levels of NT-pro-BNP compared with controls, whereas serum creatinine levels were comparable. Table 3 shows the association between NT-pro-BNP levels, divided into tertiles, and coronary events. The highest tertile (NT-pro-BNP levels >45.6 pg/mL) was associated with a significantly elevated matched odds ratio of 3.77 (95% CI 1.74–8.20). Table 4 shows the results of the multivariable conditional logistic regression analysis for the association between NT-pro-BNP levels and coronary events. In this analysis, NT-pro-BNP remained associated with the risk for coronary events [third vs. first tertile odds ratio (95% CI) 3.24 (1.18–8.85)], independent of BMI, smoking, diabetes, SBP, total and HDL cholesterol, creatinine, and prevalent CHD. Additional analysis modelling NT-pro-BNP as a continuous variable (after log transformation of NT-pro-BNP) further confirmed the strength of the positive association between NT-pro-BNP and coronary events (matched OR 2.49, 95% CI 1.43–4.33, P=0.001).


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Table 3 Association between NT-pro-BNP levels and coronary events
 

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Table 4 Multivariable analysis of the association between NT-pro-BNP and coronary events: results of conditional logistic regression
 
When the analysis was restricted to subjects with no prevalent CHD at baseline, the matched odds ratio for the highest tertile of NT-pro-BNP vs. the lowest tertile remained similar (OR=3.15, 95% CI 0.94–10.48, P=0.07) in multivariable analysis.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusions
 Acknowledgements
 References
 
The main finding of this study is that NT-pro-BNP levels are strong predictors of coronary events in men at work, even after adjustment for conventional risk factors and the presence of CHD. NT-pro-BNP levels have shown to have a prognostic value in patients with acute coronary syndromes,1,2 heart failure,3,4 and even in stable coronary artery disease patients who are at ‘intermediate’ risk.5,6 In the general population, NT-pro-BNP levels are also related to cardiovascular morbidity and mortality, but studies have mainly been restricted to elderly patients.10,12 Recently, Kistorp et al.12 reported that NT-pro-BNP predicted mortality and first major cardiovascular events in a population-based prospective study of individuals aged 50–89 from a community in Copenhagen, Denmark. Importantly, NT-pro-BNP remained a prognostic risk factor after adjustment for cardiovascular risk factors and was a stronger risk biomarker for cardiovascular disease and death than C-reactive protein. Similar to NT-pro-BNP, the prognostic value of BNP has also been documented in several clinical entities.79 In the general population, Wang et al.11 reported that BNP was a strong predictor of morbidity and mortality even when BNP levels were below the threshold of 100 pg/mL normally used to identify patients with heart failure. Similar to our study, the prognostic value of BNP levels remained after adjusted analyses for age, sex, the presence or absence of hypertension and diabetes, the ratio of total to HDL cholesterol, the BMI, the serum creatinine level, and smoking status. An important distinction between the present study and the studies by Kistorp et al.12 and Wang et al.11 is its focus on CHD events. We report a significant association between NT-pro-BNP levels and coronary events, whereas the other studies in the general population have not documented this association. This could be due to differences in study populations (focused on younger men in the present study), length of follow-up (shorter for the present study), choice of peptide (NT-pro-BNP in the present study), or other factors. For instance, the study by Kistorp et al.12 only had 12 CHD events, leaving it underpowered to assess this specific outcome.

Several possibilities could explain our findings. First, levels of BNP and NT-pro-BNP are related to increased ventricular strain due to an increase of filling pressure and ventricular volume.2325 Although we did not perform echocardiography in this epidemiological study, the contribution of overt increases of ventricular strain was probably of minor importance in our population because all individuals were at work and the prognostic value of NT-pro-BNP levels remained after adjustment for prevalent coronary artery disease or restriction of the analysis to individuals without prevalent coronary artery disease. More subtle increases of ventricular strain due to increases of left ventricular mass could, however, have contributed to the elevated NT-pro-BNP levels because echocardiographic estimated left ventricular mass correlates with natriuretic peptide levels, even after adjustment for other cardiovascular risk factors.26 Therefore, increases of ventricular strain and filling pressures could have contributed to higher myocardial oxygen demand and subsequent coronary events in our study population. Clearly, more studies incorporating echocardiography are needed to unravel the contribution of subtle abnormal loading conditions (including pressure and volume overload) to NT-pro-BNP levels in the younger, general population.

A second possible explanation could be that higher NT-pro-BNP levels are an indicator of ongoing myocardial ischaemia. Already in 1995, Hama et al.27 showed a rapid induction of ventricular BNP gene expression in rats with AMI. Importantly, the BNP concentrations and BNP mRNA were increased in the non-infarcted region as well as in the infarcted region of the left ventricle. Goetze et al.16 showed that myocardial ischaemia per se can cause an increase in plasma BNP and NT-pro-BNP concentrations in patients with coronary artery disease without overt heart failure. This mechanism most likely reflects an increased cardiac BNP gene expression in the ischaemic left ventricle, because plasma BNP and NT-pro-BNP concentrations were closely associated with ventricular BNP mRNA expression measured in biopsies from coronary artery disease patients undergoing CABG. Other studies in humans showed that circulating BNP and NT-pro-BNP increase after percutaneous coronary intervention, even when the intraventricular filling pressures remain unchanged28 and that BNP levels increase after exercise in patients with known angina with a relationship between the degree of BNP elevation and the size of the ischaemic territory.15 More recently, Bibbins-Domingo et al.17 reported that in outpatients with stable coronary artery disease, elevated levels of BNP were associated with inducible ischaemia even after adjustment for measures of systolic and diastolic dysfunction. This association suggests not only a potential explanation for the increased risk of future coronary events associated with BNP elevations after acute coronary syndromes, but may also be part of the explanation of the association we found between elevated NT-pro-BNP levels and future coronary events in our study. Interestingly, in a recent study by Kragelund et al.5 in patients with stable CHD, the increased risk of death associated with elevated NT-pro-BNP was independent of both left ventricular ejection fraction and left ventricular end-diastolic pressure, thus providing further evidence in support of the hypothesis that ischaemia directly promotes the release of NT-pro-BNP, in a manner that is independent of left ventricular wall stress.

Finally, the natriuretic peptides have a fundamental role in cardiovascular functioning and remodelling with varying documented effects ranging from endothelial regeneration,29 increase of the effects of nitric oxide,30 inhibition of oxidized LDL-induced migration of human coronary artery smooth muscle cells,31 and augmentation of the parasympathetic tone.32 Therefore, elevated NT-pro-BNP levels in patients without coronary artery disease could reflect an up-regulation of the natriuretic peptide axis in the setting of subclinical vascular disease and could therefore explain the increased risk for coronary events.

Our study potentially widens the spectrum of clinical usefulness of NT-pro-BNP as a prognostic marker because we studied a younger population of men at work. We report odds ratios of 3.15–3.77 which are comparable to those reported in other studies on older individuals in the general population. For instance, Kistorp et al.12 reported adjusted hazard ratios for NT-pro-BNP levels of 1.96 for mortality and 3.24 for first major cardiovascular events. Similarly, Wang et al.11 reported adjusted hazard ratios for BNP levels of 1.62 for mortality and 1.76 for first major cardiovascular events in the Framingham Offspring Study. However, in order to be useful for daily clinical work, further studies will be needed in larger populations of young individuals to define clinical useful cut-off values.


    Study limitations
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusions
 Acknowledgements
 References
 
The lack of echocardiographic data made matching or adjustment for left ventricular systolic dysfunction or left ventricular mass impossible. However, most of our study individuals had no previous cardiac history and NT-pro-BNP levels remained predictive of coronary events after adjustment for prevalent CHD. In addition, in the previously mentioned study by Kistorp et al.,12 measurements of NT-pro-BNP provided prognostic information on mortality and first major cardiovascular events after adjustment for left ventricular systolic dysfunction (left ventricular ejection fraction <50%) and left ventricular hypertrophy. Of note, the NT-pro-BNP levels in that study (lowest tertile <181.7 pg/mL, highest tertile >411.1 pg/mL) were higher when compared with the values in the present study (median value for the cases 48.5 pg/mL and median value for the controls 30 pg/mL). We studied only men during a relatively short follow-up period. Clearly, further studies are needed in the general population to confirm our findings, especially in women and during a longer-term follow-up. Finally, our study was not designed or powered to evaluate a threshold effect. Again, larger studies with longer-term follow-up are therefore needed.


    Conclusions
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusions
 Acknowledgements
 References
 
This prospective study indicates that NT-pro-BNP levels are predictive of coronary events in men at work, even after adjustment for conventional risk factors. Therefore, this parameter may aid in the early detection of cardiovascular disease. However, additional studies are needed to confirm our results and to determine the value of natriuretic peptides when compared with other biomarkers (e.g. C-reactive protein) or measurements of atherosclerosis burden (e.g. intima-media thickness measurements) to risk stratify asymptomatic persons.


    Acknowledgements
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusions
 Acknowledgements
 References
 
J.D.S. is a senior clinical investigator of the Fund for Scientific Research—Flanders (Belgium) (FWO-Vlaanderen). The BELSTRESS study was supported by grants from the Federal Office for Scientific, Technical, and Cultural Affairs (ST/02/007), the FWO- Vlaanderen, and the FNRS. Roche Diagnostics provided the assay kits but had no other role in the study.

Conflict of interest: none declared.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusions
 Acknowledgements
 References
 

  1. de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatini MS, McCabe CH, Hall C, Cannon CP, Braunwald E. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014–1021.[Abstract/Free Full Text]
  2. Omland T, de Lemos JA, Morrow DA, Antman EM, Cannon CP, Hall C, Braunwald E. Prognostic value of N-terminal pro-atrial and pro-brain natriuretic peptide in patients with acute coronary syndromes. Am J Cardiol 2002;89:463–465.[CrossRef][ISI][Medline]
  3. Richards AM, Nicholls MG, Yanddle TG, Framptom C, Espiner EA, Turner TG, Buttimore RC, Lainchbury JG, Elliott JM, Ikram H, Crozieri G, Smyth DW. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation 1998;97:1921–1929.[Abstract/Free Full Text]
  4. Gardner RS, Ozalp F, Murday AJ, Robb SD, McDonagh TA. N-terminal pro-brain natriuretic peptide: a new gold standard in predicting mortality in patients with advanced heart failure. Eur Heart J 2003;24:1735–1743.[Abstract/Free Full Text]
  5. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med 2005;352:666–675.[Abstract/Free Full Text]
  6. Schnabel R, Rupprecht HJ, Lackner KJ, Lubos E, Bickel C, Meyer J, Munzel T, Cambien F, Tiret L, Blankenberg S for the AtheroGene Investigators. Analysis of N-terminal-pro-brain natriuretic peptide and C-reactive protein for risk stratification in stable and unstable coronary artery disease: results from the AtheroGene study. Eur Heart J 2005;26:241–249.[Abstract/Free Full Text]
  7. Wallen T, Landahl S, Hedner T, Nakao K, Saito Y. Brain natriuretic peptide predicts mortality in the elderly. Heart 1997;77:264–267.[Abstract]
  8. Ueda R, Yokouchi M, Suzuki T, Otomo E, Katagiri T. Prognostic value of high plasma brain natriuretic peptide concentrations in very elderly persons. Am J Med 2003;114:266–270.[CrossRef][ISI][Medline]
  9. McDonagh TA, Cunningham AD, Morrison CE, McMurray JJ, Ford I, Morton JJ, Dargie HJ. Left ventricular dysfunction, natriuretic peptides, and mortality in an urban population. Heart 2001;86:21–26.[Abstract/Free Full Text]
  10. Groenning BA, Raymond I, Hildebrandt PR, Nilsson JC, Baumann M, Pedersen F. Diagnostic and prognostic evaluation of left ventricular systolic heart failure by plasma N-terminal pro-brain natriuretic peptide concentrations in a large sample of the general population. Heart 2004;90:297–303.[Abstract/Free Full Text]
  11. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, Wolf PA, Vasan RS. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004;350:655–663.[Abstract/Free Full Text]
  12. Kistorp C, Raymond I, Pedersen F, Gustafsson F, Faber J, Hildebrandt P. N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. JAMA 2005; 293:1609–1616.[Abstract/Free Full Text]
  13. Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998;339:321–328.[Free Full Text]
  14. Boomsma F, Van der Meiracker AH. Plasma A-and B-type natriuretic peptides: physiology, methodology, and clinical use. Cardiovasc Res 2001;51:442–449.[CrossRef][ISI][Medline]
  15. Marumoto K, Hamada M, Hiwada K. Increased secretion of atrial and brain natriuretic peptide during acute myocardial ischaemia induced by dynamic exercise in patients with angina pectoris. Clin Sci (Lond.) 1995;88:551–556.[ISI][Medline]
  16. Goetze JP, Christoffersen C, Perko M, Arendrup H, Rehfeld JF, Kastrup J, Nielsen LB. Increased cardiac BNP expression associated with myocardial ischemia. FASEB J 2003;17:1105–1107.[Abstract/Free Full Text]
  17. Bibbins-Domingo K, Ansari M, Schiller NB, Massie B, Whooley MA. B-type natriuretic peptide and ischemia in patients with stable coronary disease. Data from the Heart and Soul Study. Circulation 2003;108:2987–2992.[Abstract/Free Full Text]
  18. Coetsier P, De Backer G, De Corte W, Kornitzer M. Belgian job stress study (BELSTRESS): overview of the study model and research methods. Revue de Psychologie et de Psychométrie 1996;17:17–35.
  19. Houtman I, Kornitzer M, De Smet P, De Backer G. Job stress, absenteeism and coronary heart disease European cooperative study. Design of a multicenter prospective study. Eur J Public Health 1999;9:52–57.[Abstract]
  20. Kittel F, Leynen F, Stam M, Dramaix M, De Smet P, Kornitzer M, De Backer G. Job conditions and fibrinogen in 14226 Belgian workers: the Belstress study. Eur Heart J 2002;23:1841–1848.[Abstract/Free Full Text]
  21. De Bacquer D, Pelfrene E, Clays E, Mak R, Moreau M, De Smet P, Kornitzer M, De Backer G. Perceived job stress and incidence of coronary events: 3-year follow-up of the Belgian Job Stress Project cohort. Am J Epidemiol 2005;161:434–441.[Abstract/Free Full Text]
  22. Rose GA. The diagnosis of ischaemic heart pain and intermittent claudicatio in field surveys. Bull World Health Organ 1962;27:645–658.[ISI][Medline]
  23. Nakagawa O, Ogawa Y, Itoh H, Suga S, Komatsu Y, Kishimoto I, Nishino K, Yoshimasa T, Nakao K. Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiomyocyte hypertrophy. J Clin Invest 1995;96:1280–1287.[ISI][Medline]
  24. Yamamoto K, Burnett JC Jr, Jougasaki M, Nishimura RA, Bailey KR, Saito Y, Nakao K, Redfield MM. Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension 1996;28:988–994.[Abstract/Free Full Text]
  25. Maeda K, Tsutamoto T, Wada A, Hisanaga T, Kinoshita M. Plasma brain natriuretic peptide as a biochemical marker of high left ventricular end-diastolic pressure in patients with left ventricular dysfunction. Am Heart J 1998;135:825–832.[ISI][Medline]
  26. Schirmer H, Omland T. Circulating N-terminal pro-atrial natriuretic peptide is an independent predictor of left ventricular hypertrophy in the general population: the Tromso Study. Eur Heart J 1999;20:755–763 (erratum, Eur Heart J 1999;20:1439).[Abstract/Free Full Text]
  27. Hama N, Itoh H, Shirakami G, Nakagawa O, Suga S, Ogawa Y, Masuda I, Nakanishi K, Yoshimasa T, Hashimoto Y, Yamaguchi M, Hori R, Yasue H, Nakao K. Rapid ventricular induction of brain natriuretic peptide gene expression in experimental acute myocardial infarction. Circulation 1995;92:1558–1564.[Abstract/Free Full Text]
  28. Tateishi J, Masutani M, Ohyanagi M, Iwasaki T. Transient increase in plasma brain (B-type) natriuretic peptide after percutaneous transluminal coronary angioplasty. Clin Cardiol 2000;23:776–780.[ISI][Medline]
  29. Kook H, Itoh H, Choi BS, Sawada N, Doi K, Hwang TJ, Kim KK, Arai H, Baik YH, Nakao K. Physiological concentration of atrial natriuretic peptide induces endothelial regeneration in vitro. Am J Physiol Heart Circ Physiol 2003;284:H1388–H1397.
  30. Brunner F, Wolkart G. Relaxant effect of C-type natriuretic peptide involves endothelium and nitric oxide-cGMP system in rat coronary microvasculature. Cardiovasc Res 2001;51:577–584.[CrossRef][ISI][Medline]
  31. Kohno M, Yokokawa K, Yasunari K, Kano H, Minami M, Veda M, Yoshikana J. Effect of natriuretic peptide family on the oxidized LDL-induced migration of human coronary artery smooth muscle cells. Circ Res 1997;81:585–590.[Abstract/Free Full Text]
  32. Herring N, Zaman JA, Paterson DJ. Natriuretic peptides like NO facilitate cardiac vagal neurotransmission and bradycardia via a cGMP pathway. Am J Physiol Heart Circ Physiol 2001;281:H2318–H2327.

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