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Original Contribution |

N-Terminal Pro-Brain Natriuretic Peptide, C-Reactive Protein, and Urinary Albumin Levels as Predictors of Mortality and Cardiovascular Events in Older Adults FREE

Caroline Kistorp, MD; Ilan Raymond, MD, PhD; Frants Pedersen, MD; Finn Gustafsson, MD, PhD; Jens Faber, MD, DMSc; Per Hildebrandt, MD, DMSc
[+] Author Affiliations

Author Affiliations: Department of Cardiology and Endocrinology, Frederiksberg University Hospital, Copenhagen (Drs Kistorp, Raymond, Pedersen, and Hildebrandt); Department of Cardiology, Rigshospitalet, Copenhagen (Dr Gustafsson); and Department of Endocrinology, Herlev University Hospital, Herlev (Dr Faber), Denmark.

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JAMA. 2005;293(13):1609-1616. doi:10.1001/jama.293.13.1609.
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Published online

Context B-type natriuretic peptides have been shown to predict cardiovascular disease in apparently healthy individuals but their predictive ability for mortality and future cardiovascular events compared with C-reactive protein (CRP) and urinary albumin/creatinine ratio is unknown.

Objective To assess the prognostic value of the N-amino terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP) vs CRP and urinary albumin/creatinine ratio in an older adult population.

Design, Setting, and Participants A population-based prospective study of 764 participants aged 50 to 89 years from a community in Copenhagen, Denmark, in which 658 participants provided blood and urinary samples and were examined between September 1, 1998, and January 24, 2000. Of these participants, 626 without heart or renal failure were enrolled. A subgroup of 537 had no history of cardiovascular disease at baseline. During 5 years of follow-up (to December 31, 2003), 94 participants died and 65 developed a first major cardiovascular event.

Main Outcome Measures Risk of mortality and first major cardiovascular event by baseline levels of NT-proBNP, CRP, and urinary albumin/creatinine ratio levels.

Results After adjustment for the cardiovascular risk factors of age, sex, smoking, diabetes mellitus, hypertension or ischemic heart disease, total cholesterol, and serum creatinine, the hazard ratio (HR) of mortality for values above the 80th percentile of NT-proBNP was 1.96 (95% confidence interval [CI], 1.21-3.19); for CRP, 1.46 (95% CI, 0.89-2.24); and for urinary albumin/creatinine ratio, 1.88 (95% CI, 1.18-2.98). Additional adjustment for left ventricular systolic dysfunction did not markedly attenuate the predictive value of NT-proBNP (HR, 1.82; 95% CI, 1.11-2.98). The absolute unadjusted increase in mortality risk for participants with values above the 80th percentile vs equal to or below the 80th percentile was 24.5% for NT-proBNP, 7.8% for CRP, and 19.5% for urinary albumin/creatinine ratio. The NT-proBNP levels were associated with first major cardiovascular events (nonfatal myocardial infarction, fatal coronary heart disease, unstable angina, heart failure, stroke, and transient ischemic attack) with an adjusted HR of 3.24 (95% CI, 1.80-5.79) vs 1.02 (95% CI, 0.56-1.85) for CRP and 2.32 (95% CI, 1.33-4.05) for urinary albumin/creatinine ratio when comparing participants with values above the 80th percentile with those with values equal to or below the 80th percentile.

Conclusions Measurements of NT-proBNP provide prognostic information of mortality and first major cardiovascular events beyond traditional risk factors. NT-proBNP was a stronger risk biomarker for cardiovascular disease and death than CRP was in nonhospitalized individuals aged 50 to 89 years.

Figures in this Article

Risk stratification in the general population is receiving increasing interest.13 In particular, C-reactive protein (CRP) has emerged as a possible potent risk marker for cardiovascular disease.4,5 Measurements of CRP are now considered to improve risk stratification beyond traditional cardiovascular risk factors in the general population.6 The B-type natriuretic peptides have also received increasing interest as potential risk markers. Brain natriuretic peptide (BNP) and the N-amino terminal fragment of the prohormone BNP (NT-proBNP)7 are released predominantly from the ventricular myocardium in response to increased ventricular wall stress.8 Plasma levels of these peptides are substantially increased in conditions like chronic heart failure9,10 and during acute coronary syndromes.11

The prognostic value of BNPs has mainly been established in patients with heart failure12 and in populations covering the range of acute coronary syndromes.1315 In nonhospitalized individuals, a limited number of studies haveevaluated the prognostic information of the B-type natriuretic peptides.1618 However, one study only included older participants,18 and no studies have compared the predictive value of BNPs with established cardiovascular risk markers. These studies and data from the Framingham Heart study19 suggest that the B-type natriuretic peptides can provide important prognostic information beyond traditional cardiovascular risk factors in the general population.

The objective of our study was to investigate the prognostic value of plasma NT-proBNP compared with that of CRP and urinary albumin levels on overall mortality and cardiovascular events in older people from a community in Copenhagen, Denmark.

Study Population

The participants in this study were recruited from the general population in the municipality of Frederiksberg, in Copenhagen, Denmark. The study population has previously been demonstrated to be representative of the population in the urban community of Copenhagen.20,21 A random sample was collected of 1088 persons from the local community who were invited to participate in the study. As we were interested in analyzing a representative sample of high-risk individuals, enrollees had to be aged 50 to 89 years. Exclusion criteria were participants’ inability to cooperate and lack of response to 2 written invitations. A total of 764 individuals (70.2%) responded to the invitations.20 Cardiovascular event rates 1 year before and 1 year after baseline did not differ between those individuals who did not respond and those who did, with age- and sex-adjusted relative risks (RRs) of 1.07 (95% confidence interval [CI], 0.72-1.59; P=.75) and 1.20 (95% CI, 0.76-1.90; P=.43), respectively. However, individuals who did not respond had a higher 1-year mortality rate; those who responded had an age- and sex-adjusted RR of 0.32 (95% CI, 0.16-0.62; P<.001). The mortality of the total invited sample was higher than the background population, with an age- and sex-adjusted RR of 1.56 (95% CI, 1.10-2.23; P=.01). The 1-year mortality rate among those who responded was similar to the background population (RR, 0.98; 95% CI, 0.84-1.14; P=.78).20 Plasma NT-proBNP, CRP, and urinary albumin concentration were measured in 658 participants. Among these, 27 participants were excluded because of prevalent heart failure, 3 because of renal insufficiency (defined as serum creatinine of at least 2.26 mg/dL [≥200 μmol/L]), and 2 because of lack of follow-up data. A total of 626 individuals were finally included in the study (Figure 1).

Figure 1. Flow Diagram of the Study Population
Graphic Jump Location

LVEF indicates left ventricular ejection fraction. To convert serum creatinine to μmol/L, multiply by 88.4.

The population was examined between September 1, 1998, and January 24, 2000. All participants completed a questionnaire providing information on current symptoms and on demographic, behavioral, and lifestyle factors. An extensive medical and drug history was obtained by study physicians, including information on previous hospital admissions. Prevalent cardiovascular disease was defined as previous hospital admission for the primary diagnosis of myocardial infarction, unstable angina pectoris, stroke or transient ischemic attack, or current symptoms of angina pectoris. All participants underwent echocardiography assessing presence of left ventricular hypertrophy and left ventricular ejection fraction (LVEF), which was evaluated off-line in a blinded fashion by 2 experienced and independent observers. The participants were followed up until December 31, 2003, with respect to mortality status and development of cardiovascular events. The median (range) follow-up period was 5.0 (0.17-5.28) years. The study was approved by the central ethics committee of Copenhagen, and all participants provided written informed consent.

Laboratory Methods

Plasma concentration of NT-proBNP was measured using a highly sensitive and specific immunoassay based on double-antibody sandwich technique (Roche Diagnostics, Mannheim, Germany). The intra-assay and interassay coefficients of variation were 1.3% and 4.8%, respectively.22 C-reactive protein was measured with a highly sensitive, latex-particle–enhanced immunoassay (Roche Diagnostics), with a measuring range of 0.1 to 300 mg/L and a lower detection limit of 0.03 mg/L. The intra-assay and interassay coefficients of variation were 1.3% and 6.5%, respectively, for values less than 4 mg/L.23 Urine samples were collected as first morning–voided urine. Urinary albumin concentration was measured by immunoturbidimetry on a Cobas Bioanalyzer (Roche Products, Basel, Switzerland). Lower detection limit was 1 mg/L and the coefficient of variation was less than 4%. Urinary albumin excretion was determined as the urinary albumin/creatinine ratio; upper limit of normal range was 30 mg/g.

Main Outcome Measures

Participants were monitored with respect to mortality status and first major cardiovascular events on a regular basis after enrollment. Major cardiovascular events were recorded by the discharge registry of the Danish National Board of Health, which records all primary hospital discharge diagnoses in Denmark. The register has been described previously.24 All cardiovascular events required hospitalization to meet the outcome definition. The codes of diagnosis for the cardiovascular events were prespecified. Codes were assigned according to the International Classification of Diseases, 10th Revision (ICD-10). All deaths were confirmed by the Danish Personal Register, which records all deaths in Denmark within 2 weeks. Deaths from cardiovascular disease were ascertained from central registers in the Danish National Board of Health and verified by study physicians from death certificates. The members of the Danish National Board of Health and the study physicians were blinded with respect to data on the biomarkers. Major cardiovascular events were analyzed as a combined end point, including nonfatal myocardial infarction, fatal coronary heart disease (CHD), unstable angina pectoris, heart failure, stroke, and transient ischemic attack, defined as hospitalization with the following ICD-10 codes: I20.0-I22, I24, I42.0, I46, I50, I63, I65, and I66. The major cardiovascular events were subsequently analyzed individually as heart failure, stroke, or transient ischemic attack, and as CHD, which included myocardial infarction and unstable angina pectoris.

Statistical Analysis

The participants were divided into tertiles according to their baseline NT-proBNP levels. Comparisons between the groups were performed by 1-way analysis of variance or Kruskal-Wallis test for the continuous variables, according to whether distribution of variables was Gaussian. The χ2 test was used for categorical data. Baseline NT-proBNP, CRP, and urinary albumin/creatinine levels were highly skewed and therefore logarithmically transformed in all analyses. Levels of NT-proBNP, CRP, and urinary albumin/creatinine ratio were compared for individuals who died (n = 94) vs those who were alive at the time of follow-up (n = 532), using the Mann-Whitney test. Subsequently, the cumulative survival according to increasing tertiles of NT-proBNP, CRP, and urinary albumin/creatinine ratio was estimated by Kaplan-Meier curves, followed by a trend test. Using Cox proportional hazards regression models, hazard ratios (HRs) for NT-proBNP, CRP, and urinary albumin/creatinine ratio with each outcome were assessed. To evaluate the association between the biomarkers and outcomes, these were considered both as continuous (logarithmically transformed) and as categorical variables. We used the prespecified cut points corresponding to the 80th percentile of each biomarker in the categorical analysis. This cut point was used to facilitate comparisons with previous studies.4,19,2527 Analyses of first major cardiovascular event, stroke or transient ischemic attack, and CHD were restricted to participants without prevalent cardiovascular disease; 537 participants were included in these analyses. Analyses of development of heart failure were restricted to participants with LVEF of more than 50% at baseline, and this subpopulation comprised 598 individuals (Figure 1). Hazard ratios and 95% CIs were calculated in unadjusted analyses, after adjustment for age and sex, as well as in multivariable models with traditional cardiovascular risk factors (age, sex, smoking status, diabetes mellitus, hypertension, serum total cholesterol, and serum creatinine) and variables reflecting severity of cardiovascular disease. In the analyses of overall mortality, additional adjustment was made for presence of ischemic heart disease. In a second analysis, we further adjusted the mortality model for intervening cardiovascular events (incident nonfatal myocardial infarction, unstable angina pectoris, stroke, or transient ischemic attack) to determine whether NT-proBNP was predictive of mortality independent of increased risk for cardiovascular events. Secondary analyses of mortality included adjustments for baseline systolic blood pressure, heart rate, and cardiovascular medication instead of history of hypertension. Analyses of first major cardiovascular event and stroke also included adjustment for atrial fibrillation. Furthermore, all outcome measures were analyzed with additional adjustment for left ventricular systolic dysfunction (LVEF <50%) and left ventricular hypertrophy.

For the Cox proportional hazards regression model analyses, deviation from linearity was tested by comparing models with nonlinear transformations of the covariates (square root terms) with models containing linear terms of the covariates, using likelihood ratio test. The assumption of proportionality with regard to NT-proBNP, CRP, and urinary albumin/creatinine ratio was met. When testing specifically whether the association between NT-proBNP and mortality and first cardiovascular event varied according to age (>65 years), sex, renal function, hypertension, or LVEF, by entering interaction terms in the multivariable models, only interaction with age was found. Accordingly, interaction between age and log-transformed CRP was assessed. Inclusion of interaction terms with age did not significantly alter the results of the main multivariable models with NT-proBNP and CRP, respectively. All P values were 2-sided and P<.05 was considered statistically significant. The statistical software package SPSS version 11.5 (SPSS Inc, Chicago, Ill) was used for all analyses.

Baseline Characteristics

Mean (SD) age at baseline was 67.9 (10.6) years. Among the 626 participants, 361 (57.7%) were women, 72 (11.5%) had ischemic heart disease, 149 (23.8%) had a history of hypertension, and 36 (5.8%) had diabetes mellitus. Baseline clinical characteristics according to tertiles of baseline NT-proBNP levels are presented in Table 1. Participants in the highest tertiles were older, more often women, and more likely to have a history of hypertension. Higher levels of NT-proBNP were positively associated with urinary albumin/creatinine ratio (R = 0.33, P<.001) and with serum creatinine (R = 0.14, P<.001) and negatively associated with LVEF (R = −0.23, P<.001).

Table Graphic Jump LocationTable 1. Baseline Characteristics According to Tertiles of NT-proBNP Levels (N=626)*
Main Outcome Measures

During the 5 years of follow-up, 94 (15%) of 626 participants died from any cause. A total of 65 (12%) of 537 participants without cardiovascular disease at baseline had a first major cardiovascular event. Of these participants, 23 had a stroke or transient ischemic attack, 17 developed heart failure, 12 had a CHD event, and 32 died of cardiovascular disease. A total of 20 (3%) of 598 patients with normal left ventricular systolic function (LVEF ≥50%) at baseline developed heart failure.

Mortality

In individuals who died compared with those who were alive at follow-up, baseline median (interquartile range) plasma NT-proBNP was 505.5 (281.8-1138.3) vs 234.9 (134.9-461.5) pg/mL, respectively (P<.001); CRP was 2.98 (1.43-6.95) vs 2.24 (1.05-4.82) mg/L, respectively (P = .03); and urinary albumin/creatinine ratio was 14.0 (7.0-30.0) vs 6.0 (4.0-11.0) mg/g, respectively (P<.001). Mortality risk increased by increasing tertile of NT-proBNP (P for trend <.001) (Figure 2A), with an absolute increase in risk of 18.5% between the lowest and highest tertile. Mortality rates also increased by tertile of CRP (P for trend = .02) (Figure 2B), with an absolute increase in risk of 8.1% between the lowest and highest tertile. For urinary albumin/creatinine ratio, the absolute increase in risk between the lowest and highest tertile was 20.3% (Figure 2C).

Figure 2. Kaplan-Meier Curves of Unadjusted Cumulative Survival According to Tertiles of NT-proBNP, C-Reactive Protein, and Urinary Albumin/Creatinine Ratio
Graphic Jump Location

NT-proBNP indicates N-amino terminal fragment of the prohormone brain natriuretic peptide. The levels of the respective tertiles (tertile 1, 2, and 3) were less than 181.7 pg/mL, 181.7 to 411.0 pg/mL, and at least 411.1 pg/mL, respectively, for NT-proBNP (A); less than 1.42 mg/L, 1.42 to 3.90 mg/L, and at least 3.91 mg/L, respectively, for C-reactive protein (B); and less than 5.0 mg/g, 5.0 to 10.0 mg/g, and at least 10.1 mg/g, respectively, for urinary albumin/creatinine ratio (C). P for trend across the respective tertiles was P<.001 for NT-proBNP, P = .02 for C-reactive protein, and P<.001 for urinary albumin/creatinine ratio.

Increased levels of NT-proBNP predicted total mortality even after adjusting for cardiovascular risk factors. Participants with NT-proBNP values above the 80th percentile had a 2-fold increase in mortality (HR, 1.96; 95% CI, 1.21-3.19; P = .007) relative to those with values equal to or below, and a 24.5% absolute increase in unadjusted risk. When NT-proBNP was analyzed as a continuous variable, increasing NT-proBNP also was associated with increased mortality, the adjusted HR being 1.43 per 1-SD increase in log-transformed peptide values (95% CI, 1.10-1.86; P = .008) (Table 2). Additional adjustment for left ventricular systolic dysfunction and left ventricular hypertrophy only moderately attenuated the association between NT-proBNP and death; the HR was 1.82 (95% CI, 1.11-2.98; P = .02) for values above the 80th percentile. After adjusting for intervening incident major cardiovascular events, high levels of NT-proBNP continued to predict mortality (HR, 1.69; 95% CI, 1.05-2.76; P = .03) for individuals with NT-proBNP levels above the 80th percentile.

Table Graphic Jump LocationTable 2. Hazard Ratios for Mortality During 5 Years of Follow-up According to Baseline NT-proBNP, C-Reactive Protein, and Urinary Albumin/Creatinine Ratio Levels (N = 626)

In secondary analyses, systolic blood pressure, heart rate, and the use of cardiovascular medication were included in the model instead of the presence of hypertension. These analyses yielded results similar to those of the main model (HR, 2.65; 95% CI, 1.34-3.70; P<.001) for values above the 80th percentile.

Urinary albumin/creatinine ratio levels were independently associated with an increased risk of death, with an adjusted HR of 1.88 (95% CI, 1.18-2.98; P = .008) for values above the 80th percentile (Table 2). The absolute increase in unadjusted mortality risk was 19.5%. In contrast, increasing levels of CRP were significantly associated with an increased mortality risk only in the unadjusted model, and had an absolute unadjusted increase in mortality risk of 7.8% for values above the 80th percentile vs those equal to or below the 80th percentile. Thus, high levels of CRP did not significantly predict mortality after adjusting for cardiovascular risk factors; adjusted HR was 1.46 (95% CI, 0.89-2.24; P = .14) for values above the 80th percentile. When the biomarker was analyzed as a continuous variable, the results also were not significant (HR, 1.17; 95% CI, 0.95-1.43; P = .12).

A multivariable model including both NT-proBNP and urinary albumin/creatinine ratio and the clinical baseline variables of age, sex, diabetes mellitus, hypertension, ischemic heart disease, current smoking, serum cholesterol, and creatinine demonstrated that both markers were still independent predictors of mortality. Adjusted HRs for levels above the 80th percentile of NT-proBNP and urinary albumin/creatinine ratio were 1.98 (95% CI, 1.22-3.22; P = .006) and 1.90 (95% CI, 1.22-2.96; P = .004), respectively.

Cardiovascular Events

Table 3 shows the HRs for a first major cardiovascular event according to baseline levels of all 3 biomarkers. Plasma NT-proBNP and urinary albumin/creatinine ratio levels were significantly associated with the risk of a first major cardiovascular event. Participants with values of NT-proBNP above the 80th percentile had a 3.2-fold (95% CI, 1.80-5.79; P<.001) increase in risk; while for urinary albumin/creatinine ratio, the increase in risk was 2.3-fold (95% CI, 1.33-4.05; P = .003), after adjustment for cardiovascular risk factors, left ventricular systolic dysfunction, and left ventricular hypertrophy. Conversely, CRP levels did not predict an increased risk of a major cardiovascular event, independent of the covariables in the model. Plasma NT-proBNP and urinary albumin/creatinine ratio were still independent predictors of a first cardiovascular event when entered into the same multivariable model, with HRs for values of NT-proBNP and urinary albumin/creatinine ratio above the 80th percentile of 2.63 (95% CI, 1.60-4.32; P<.001) and 1.67 (95% CI, 1.05-2.65; P = .03), respectively.

Table Graphic Jump LocationTable 3. Hazard Ratios for First Major Cardiovascular Event During 5 Years of Follow-up According to Baseline NT-proBNP, C-Reactive Protein, and Urinary Albumin/Creatinine Ratio Levels (n = 537)

Plasma levels of NT-proBNP predicted the risk of stroke or transient ischemic attack, with a 3.63-fold (95% CI, 1.15-11.45; P = .03) increased risk of stroke for participants with values above the 80th percentile vs those with values equal to or below the 80th percentile. Urinary albumin levels were also associated with increased risk of stroke, although after complete adjustment this relationship was no longer significant (HR, 2.63; 95% CI, 0.98-7.07; P = .06 for urinary albumin/creatinine ratio levels above the 80th percentile). No association between levels of CRP and ischemic stroke was found (Table 4).

Table Graphic Jump LocationTable 4. Hazard Ratios for First Ischemic Stroke During 5 Years of Follow-up According to Baseline NT-proBNP, C-Reactive Protein, and Urinary Albumin/Creatinine Ratio Levels (n = 537)

In the 598 participants with normal left ventricular systolic function at baseline, plasma NT-proBNP levels predicted the development of heart failure (n = 19, missing covariate in 1 participant). The adjusted HR was 2.29 (95% CI, 1.29-3.98; P = .004) per 1-SD increment in log NT-proBNP value; the HR for values above the 80th percentile was 3.21 (95% CI, 1.13-9.08; P = .03). In contrast, there were no associations between CRP or urinary albumin/creatinine ratio and heart failure. In age- and sex-adjusted analyses, HRs were 1.24 (95% CI, 0.81-1.87; P = .33) and 1.38 (95% CI, 0.98-1.98; P = .06), respectively, per 1-SD increase in log CRP and log urinary albumin/creatinine ratio.

Only 12 major CHD events were recorded among those individuals initially free of cardiovascular disease, and none of the 3 biomarkers were significantly associated with an increased risk of a first CHD event. After adjustment for age and sex, individuals with NT-proBNP values above the 80th percentile had a nonsignificant trend toward higher risk of CHD event (HR, 2.66; 95% CI, 0.74-9.57; P = .13; n = 12, also in the multivariate models), whereas there was no association between CHD events and high levels of CRP (HR, 1.04; 95% CI, 0.29-3.67; P = .95) and urinary albumin/creatinine ratio (HR, 1.05; 95% CI, 0.29-3.72; P = .94) for values above the 80th percentile of the 2 respective biomarkers.

This is the first study to our knowledge to examine the prognostic value of the cardiac peptide NT-proBNP compared with the established cardiovascular risk markers, CRP, and urinary albumin/creatinine ratio in nonhospitalized individuals. In our study, plasma NT-proBNP levels independently predicted mortality and first major cardiovascular events. The prognostic information of NT-proBNP was independent of traditional cardiovascular risk factors, prevalent cardiovascular disease, as well as left ventricular dysfunction and renal function. NT-proBNP was a better predictor than both CRP and urinary albumin with respect to all of the outcomes, and CRP did not provide prognostic information beyond traditional risk factors.

Our study suggests that CRP levels are not independently associated with mortality or first cardiovascular event in older individuals. Increasing age seems to attenuate the association between plasma CRP levels and the risk of cardiovascular disease. In accordance with our observations, several studies have demonstrated that high CRP levels did not predict mortality or cardiovascular risk beyond traditional risk factors in older persons,28,29 although other studies have found an independent relationship between CRP levels and cardiovascular risk.30 The majority of the previous studies that have found an independent association between plasma levels of CRP and cardiovascular outcome or mortality only enrolled middle-aged populations.4,27,31 Both NT-proBNP and CRP had significant interactions with age, but NT-proBNP continued to be a significant predictor after controlling for age. Furthermore, improving risk stratification beyond traditional risk factors with measurements of CRP has proven difficult.28,31 This lack of improved predictive ability was further emphasized in a recent meta-analysis of CRP and prediction of coronary heart disease.32

In contrast to previous studies on the prognostic value of the B-type natriuretic peptides and CRP, measurements of urinary albumin excretion were included in our study. High urinary albumin excretion rate is a well-known risk marker of overall mortality and cardiovascular disease, both in individuals with and without diabetes mellitus.3335 This was supported in our study, as NT-proBNP and urinary albumin/creatinine ratio both emerged as independent predictors of death and a first major cardiovascular event, even when entered into the same model.

The only biomarker that was able to predict an increased risk of stroke was NT-proBNP. This association was remarkably strong, as values above the 80th percentile were associated with a 3.63-fold increase in risk of ischemic stroke in individuals without known cardiovascular disease, even after accounting for known risk factors. This observation supports similar recent data from the Framingham population.19 The mechanism behind this interesting relationship remains to be elucidated. However, an association between the gene for atrial natriuretic peptide and the risk of stroke has recently been found in humans.36

High NT-proBNP levels were also markedly and independently associated with increasing risk of heart failure, even after exclusion of individuals with impaired left ventricular systolic dysfunction at baseline. Several mechanisms apart from possible undetected diastolic dysfunction at baseline may account for this observation.37,38 The B-type natriuretic peptides are released in response to increased ventricular wall stress.39 However, the results of our study suggest that plasma NT-proBNP levels independently predict future mortality and major cardiovascular events, even after adjustment for echocardiographic variables related to left ventricular dysfunction. This observation could reflect the relatively weak association that has been observed between left ventricular systolic dysfunction and increased levels of BNPs in individuals without any symptoms.40,41 However, other mechanisms may be important and, interestingly, myocardial ischemia could also be a key stimulus for BNP and NT-proBNP release.42 Furthermore, both circulating BNP and NT-proBNP increase after percutaneous coronary intervention, even when the intraventricular filling pressures remain unchanged.43,44 Thus, these peptides could be indicators of generalized early cardiac impairment, including asymptomatic myocardial ischemia. A possible reason for no observed significant association between NT-proBNP and a first CHD event could be the limited number of CHD events in our study.

Plasma NT-proBNP values were associated with an increased 2- to 3.5-fold risk at levels found in the upper fifth of the population, which is consistent with the recent study of the predictive value of BNP on mortality and cardiovascular events in the younger Framingham population.19 Our study extends these findings using BNP with the use of NT-proBNP and adds to the applicability of the test by including a broad range of older individuals. We have previously reported on the short-term prognostic value of NT-proBNP in the present cohort, which suggested that NT-proBNP is a strong predictor of mortality. Unlike our current investigation, this study included individuals with known heart failure and the follow-up period was only 2.2 years.17 Previous population studies measured BNP and demonstrated the predictive ability of this peptide in younger as well as in older individuals.16,18 Thus, measurement of both BNP and NT-proBNP are promising risk biomarkers in apparently healthy individuals. To our knowledge, no studies have compared the prognostic value of BNP and NT-proBNP in the same cohort; hence, whether one of these peptides may be better as a risk marker is unknown.

There are several limitations to our study. Given the sampling procedure, the current cohort included only individuals aged 50 to 89 years; thus, the main results should not be extrapolated to younger groups, especially as CRP seems to be a stronger risk marker among those groups. Furthermore, as in the Framingham cohort,19 our population is homogeneous and almost exclusively white, which may limit the generalizability to other ethnic groups. We did not include lifestyle factors, such as body mass index, diet, and exercise, in the survival analyses because these data were not available. However, given the strength of the results, we consider it unlikely that further adjustment for these factors would change the main results of our study. The small number of individual cardiovascular events requires caution when interpreting our results. Hence, the cut points used in this population may not be applicable in other community cohorts. Future large-scale population studies may provide clinically useful information regarding prognostic cut points for various high-risk populations. Finally, being the first population study examining the predictive ability of NT-proBNP, our findings should be confirmed in other populations from the community.

In conclusion, our results demonstrate that increased plasma NT-proBNP was independently associated with increased mortality and first cardiovascular events even after controlling for traditional cardiovascular risk factors. Urinary albumin/creatinine ratio was also predictive but plasma CRP did not contribute to the risk stratification in older nonhospitalized individuals.

Corresponding Author: Caroline Kistorp, MD, Department of Cardiology and Endocrinology, Frederiksberg University Hospital, 57 Nordre Fasanvej, DK-2000 Copenhagen, Denmark (cnkistorp@dadlnet.dk).

Author Contributions: Dr Kistorp had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kistorp, Raymond, Hildebrandt.

Acquisition of data: Kistorp, Raymond, Pedersen, Faber.

Analysis and interpretation of data: Kistorp, Raymond, Gustafsson, Faber, Hildebrandt.

Drafting of the manuscript: Kistorp, Faber.

Critical revision of the manuscript for important intellectual content: Raymond, Pedersen, Gustafsson, Faber, Hildebrandt.

Statistical analysis: Kistorp, Gustafsson.

Obtained funding: Kistorp, Raymond.

Administrative, technical, or material support: Raymond, Pedersen, Faber, Hildebrandt.

Study supervision: Raymond, Faber, Hildebrandt.

Financial Disclosures: Dr Hildebrandt receives honoraria for being on the advisory board and lectures from Roche Diagnostics. No other authors reported financial disclosures.

Funding/Support: This study was supported by grant 10/02S from the Copenhagen Hospital Corporation, Copenhagen, Denmark (Dr Kistorp). Roche Diagnostics, Mannheim, Germany, provided the measurements of plasma NT-proBNP and C-reactive protein for the study.

Role of the Sponsor: The Copenhagen Hospital Corporation and Roche Diagnostics had no role in the design or conduct of the study, no involvement in the management, analysis, and interpretation of the data, and did not review or approve the manuscript.

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Pearson TA, Bazzarre TL, Daniels SR.  et al.  American Heart Association guide for improving cardiovascular health at the community level: a statement for public health practitioners, healthcare providers, and health policy makers from the American Heart Association Expert Panel on Population and Prevention Science.  Circulation. 2003;107:645-651
PubMed   |  Link to Article
Hunt PJ, Yandle TG, Nicholls MG.  et al.  The amino-terminal portion of pro-brain natriuretic peptide (Pro-BNP) circulates in human plasma.  Biochem Biophys Res Commun. 1995;214:1175-1183
PubMed   |  Link to Article
Wiese S, Breyer T, Dragu A.  et al.  Gene expression of brain natriuretic peptide in isolated atrial and ventricular human myocardium.  Circulation. 2000;102:3074-3079
PubMed   |  Link to Article
Gustafsson F, Badskjær J, Hansen FS.  et al.  Value of N-terminal proBNP in the diagnosis of left ventricular systoic dysfunction in primary care patients referred for echocardiography.  Heart Drug. 2003;3:141-146
Link to Article
Omland T, Aakvaag A, Vik-Mo H. Plasma cardiac natriuretic peptide determination as a screening test for the detection of patients with mild left ventricular impairment.  Heart. 1996;76:232-237
PubMed   |  Link to Article
Omland T, Aakvaag A, Bonarjee VV.  et al.  Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction.  Circulation. 1996;93:1963-1969
PubMed   |  Link to Article
Tsutamoto T, Wada A, Maeda K.  et al.  Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure.  Circulation. 1997;96:509-516
PubMed   |  Link to Article
Richards AM, Nicholls MG, Espiner EA.  et al.  B-type natriuretic peptides and ejection fraction for prognosis after myocardial infarction.  Circulation. 2003;107:2786-2792
PubMed   |  Link to Article
Omland T, Persson A, Ng L.  et al.  N-terminal pro-B-type natriuretic peptide and long-term mortality in acute coronary syndromes.  Circulation. 2002;106:2913-2918
PubMed   |  Link to Article
de Lemos JA, Morrow DA, Bentley JH.  et al.  The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes.  N Engl J Med. 2001;345:1014-1021
PubMed   |  Link to Article
McDonagh TA, Cunningham AD, Morrison CE.  et al.  Left ventricular dysfunction, natriuretic peptides, and mortality in an urban population.  Heart. 2001;86:21-26
PubMed   |  Link to Article
Groenning BA, Raymond I, Hildebrandt PR.  et al.  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
PubMed   |  Link to Article
Wallen T, Landahl S, Hedner T.  et al.  Brain natriuretic peptide predicts mortality in the elderly.  Heart. 1997;77:264-267
PubMed   |  Link to Article
Wang TJ, Larson MG, Levy D.  et al.  Plasma natriuretic peptide levels and the risk of cardiovascular events and death.  N Engl J Med. 2004;350:655-663
PubMed   |  Link to Article
Raymond I, Pedersen F, Sørensen MS.  et al.  The Frederiksberg Heart Failure Study: rationale, design and methodology, with special emphasis on the sampling procedure for the study population and its comparison to the background population.  Heart Drug. 2002;2:167-174
Link to Article
Raymond I, Groenning BA, Hildebrandt PR.  et al.  The influence of age, sex and other variables on the plasma level of N-terminal pro brain natriuretic peptide in a large sample of the general population.  Heart. 2003;89:745-751
PubMed   |  Link to Article
Karl J, Borgya A, Gallusser A.  et al.  Development of a novel, N-terminal-proBNP (NT-proBNP) assay with a low detection limit.  Scand J Clin Lab Invest Suppl. 1999;230:177-181
PubMed
Eda S, Kaufmann J, Roos W.  et al.  Development of a new microparticle-enhanced turbidimetric assay for C-reactive protein with superior features in analytical sensitivity and dynamic range.  J Clin Lab Anal. 1998;12:137-144
PubMed   |  Link to Article
Andersen TF, Madsen M, Jorgensen J.  et al.  The Danish National Hospital Register: a valuable source of data for modern health sciences.  Dan Med Bull. 1999;46:263-268
PubMed
Berger R, Huelsman M, Strecker K.  et al.  B-type natriuretic peptide predicts sudden death in patients with chronic heart failure.  Circulation. 2002;105:2392-2397
PubMed   |  Link to Article
Mendall MA, Strachan DP, Butland BK.  et al.  C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men.  Eur Heart J. 2000;21:1584-1590
PubMed   |  Link to Article
Folsom AR, Aleksic N, Catellier D.  et al.  C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study.  Am Heart J. 2002;144:233-238
PubMed   |  Link to Article
van der Meer IM, de Maat MP, Kiliaan AJ.  et al.  The value of C-reactive protein in cardiovascular risk prediction.  Arch Intern Med. 2003;163:1323-1328
PubMed   |  Link to Article
Tracy RP, Lemaitre RN, Psaty BM.  et al.  Relationship of C-reactive protein to risk of cardiovascular disease in the elderly.  Arterioscler Thromb Vasc Biol. 1997;17:1121-1127
PubMed   |  Link to Article
Pradhan AD, Manson JE, Rossouw JE.  et al.  Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women's Health Initiative observational study.  JAMA. 2002;288:980-987
PubMed   |  Link to Article
Koenig W, Sund M, Frohlich M.  et al.  C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men.  Circulation. 1999;99:237-242
PubMed   |  Link to Article
Danesh J, Wheeler JG, Hirschfield GM.  et al.  C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease.  N Engl J Med. 2004;350:1387-1397
PubMed   |  Link to Article
Rossing P, Hougaard P, Borch-Johnsen K.  et al.  Predictors of mortality in insulin dependent diabetes: 10 year observational follow up study.  BMJ. 1996;313:779-784
PubMed   |  Link to Article
Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S.  et al.  Urinary albumin excretion: an independent predictor of ischemic heart disease.  Arterioscler Thromb Vasc Biol. 1999;19:1992-1997
PubMed   |  Link to Article
Damsgaard EM, Froland A, Jorgensen OD.  et al.  Microalbuminuria as predictor of increased mortality in elderly people.  BMJ. 1990;300:297-300
PubMed   |  Link to Article
Rubattu S, Stanzione R, Di Angelantonio E.  et al.  Atrial natriuretic peptide gene polymorphisms and risk of ischemic stroke in humans.  Stroke. 2004;35:814-818
PubMed   |  Link to Article
Troughton RW, Prior DL, Pereira JJ.  et al.  Plasma B-type natriuretic peptide levels in systolic heart failure: importance of left ventricular diastolic function and right ventricular systolic function.  J Am Coll Cardiol. 2004;43:416-422
PubMed   |  Link to Article
Lubien E, DeMaria A, Krishnaswamy P.  et al.  Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings.  Circulation. 2002;105:595-601
PubMed   |  Link to Article
Mizuno Y, Yoshimura M, Harada E.  et al.  Plasma levels.  Am J Cardiol. 2000;86:1036-1040, A11
PubMed   |  Link to Article
Vasan RS, Benjamin EJ, Larson MG.  et al.  Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the Framingham heart study.  JAMA. 2002;288:1252-1259
PubMed   |  Link to Article
McClure SJ, Caruana L, Davie AP.  et al.  Cohort study of plasma natriuretic peptides for identifying left ventricular systolic dysfunction in primary care.  BMJ. 1998;317:516-519
PubMed   |  Link to Article
Hama N, Itoh H, Shirakami G.  et al.  Rapid ventricular induction of brain natriuretic peptide gene expression in experimental acute myocardial infarction.  Circulation. 1995;92:1558-1564
PubMed   |  Link to Article
Tateishi J, Masutani M, Ohyanagi M.  et al.  Transient increase in plasma brain (B-type) natriuretic peptide after percutaneous transluminal coronary angioplasty.  Clin Cardiol. 2000;23:776-780
PubMed   |  Link to Article
Goetze JP, Yongzhong W, Rehfeld JF.  et al.  Coronary angiography transiently increases plasma pro-B-type natriuretic peptide.  Eur Heart J. 2004;25:759-764
PubMed   |  Link to Article

Figures

Figure 1. Flow Diagram of the Study Population
Graphic Jump Location

LVEF indicates left ventricular ejection fraction. To convert serum creatinine to μmol/L, multiply by 88.4.

Figure 2. Kaplan-Meier Curves of Unadjusted Cumulative Survival According to Tertiles of NT-proBNP, C-Reactive Protein, and Urinary Albumin/Creatinine Ratio
Graphic Jump Location

NT-proBNP indicates N-amino terminal fragment of the prohormone brain natriuretic peptide. The levels of the respective tertiles (tertile 1, 2, and 3) were less than 181.7 pg/mL, 181.7 to 411.0 pg/mL, and at least 411.1 pg/mL, respectively, for NT-proBNP (A); less than 1.42 mg/L, 1.42 to 3.90 mg/L, and at least 3.91 mg/L, respectively, for C-reactive protein (B); and less than 5.0 mg/g, 5.0 to 10.0 mg/g, and at least 10.1 mg/g, respectively, for urinary albumin/creatinine ratio (C). P for trend across the respective tertiles was P<.001 for NT-proBNP, P = .02 for C-reactive protein, and P<.001 for urinary albumin/creatinine ratio.

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics According to Tertiles of NT-proBNP Levels (N=626)*
Table Graphic Jump LocationTable 2. Hazard Ratios for Mortality During 5 Years of Follow-up According to Baseline NT-proBNP, C-Reactive Protein, and Urinary Albumin/Creatinine Ratio Levels (N = 626)
Table Graphic Jump LocationTable 3. Hazard Ratios for First Major Cardiovascular Event During 5 Years of Follow-up According to Baseline NT-proBNP, C-Reactive Protein, and Urinary Albumin/Creatinine Ratio Levels (n = 537)
Table Graphic Jump LocationTable 4. Hazard Ratios for First Ischemic Stroke During 5 Years of Follow-up According to Baseline NT-proBNP, C-Reactive Protein, and Urinary Albumin/Creatinine Ratio Levels (n = 537)

References

Blake GJ, Ridker PM. Inflammatory bio-markers and cardiovascular risk prediction.  J Intern Med. 2002;252:283-294
PubMed   |  Link to Article
Ridker PM, Hennekens CH, Buring JE.  et al.  C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.  N Engl J Med. 2000;342:836-843
PubMed   |  Link to Article
Vasan RS, Sullivan LM, Roubenoff R.  et al.  Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study.  Circulation. 2003;107:1486-1491
PubMed   |  Link to Article
Ridker PM, Rifai N, Rose L.  et al.  Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events.  N Engl J Med. 2002;347:1557-1565
PubMed   |  Link to Article
Haverkate F, Thompson SG, Pyke SD.  et al.  Production of C-reactive protein and risk of coronary events in stable and unstable angina.  Lancet. 1997;349:462-466
PubMed   |  Link to Article
Pearson TA, Bazzarre TL, Daniels SR.  et al.  American Heart Association guide for improving cardiovascular health at the community level: a statement for public health practitioners, healthcare providers, and health policy makers from the American Heart Association Expert Panel on Population and Prevention Science.  Circulation. 2003;107:645-651
PubMed   |  Link to Article
Hunt PJ, Yandle TG, Nicholls MG.  et al.  The amino-terminal portion of pro-brain natriuretic peptide (Pro-BNP) circulates in human plasma.  Biochem Biophys Res Commun. 1995;214:1175-1183
PubMed   |  Link to Article
Wiese S, Breyer T, Dragu A.  et al.  Gene expression of brain natriuretic peptide in isolated atrial and ventricular human myocardium.  Circulation. 2000;102:3074-3079
PubMed   |  Link to Article
Gustafsson F, Badskjær J, Hansen FS.  et al.  Value of N-terminal proBNP in the diagnosis of left ventricular systoic dysfunction in primary care patients referred for echocardiography.  Heart Drug. 2003;3:141-146
Link to Article
Omland T, Aakvaag A, Vik-Mo H. Plasma cardiac natriuretic peptide determination as a screening test for the detection of patients with mild left ventricular impairment.  Heart. 1996;76:232-237
PubMed   |  Link to Article
Omland T, Aakvaag A, Bonarjee VV.  et al.  Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction.  Circulation. 1996;93:1963-1969
PubMed   |  Link to Article
Tsutamoto T, Wada A, Maeda K.  et al.  Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure.  Circulation. 1997;96:509-516
PubMed   |  Link to Article
Richards AM, Nicholls MG, Espiner EA.  et al.  B-type natriuretic peptides and ejection fraction for prognosis after myocardial infarction.  Circulation. 2003;107:2786-2792
PubMed   |  Link to Article
Omland T, Persson A, Ng L.  et al.  N-terminal pro-B-type natriuretic peptide and long-term mortality in acute coronary syndromes.  Circulation. 2002;106:2913-2918
PubMed   |  Link to Article
de Lemos JA, Morrow DA, Bentley JH.  et al.  The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes.  N Engl J Med. 2001;345:1014-1021
PubMed   |  Link to Article
McDonagh TA, Cunningham AD, Morrison CE.  et al.  Left ventricular dysfunction, natriuretic peptides, and mortality in an urban population.  Heart. 2001;86:21-26
PubMed   |  Link to Article
Groenning BA, Raymond I, Hildebrandt PR.  et al.  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
PubMed   |  Link to Article
Wallen T, Landahl S, Hedner T.  et al.  Brain natriuretic peptide predicts mortality in the elderly.  Heart. 1997;77:264-267
PubMed   |  Link to Article
Wang TJ, Larson MG, Levy D.  et al.  Plasma natriuretic peptide levels and the risk of cardiovascular events and death.  N Engl J Med. 2004;350:655-663
PubMed   |  Link to Article
Raymond I, Pedersen F, Sørensen MS.  et al.  The Frederiksberg Heart Failure Study: rationale, design and methodology, with special emphasis on the sampling procedure for the study population and its comparison to the background population.  Heart Drug. 2002;2:167-174
Link to Article
Raymond I, Groenning BA, Hildebrandt PR.  et al.  The influence of age, sex and other variables on the plasma level of N-terminal pro brain natriuretic peptide in a large sample of the general population.  Heart. 2003;89:745-751
PubMed   |  Link to Article
Karl J, Borgya A, Gallusser A.  et al.  Development of a novel, N-terminal-proBNP (NT-proBNP) assay with a low detection limit.  Scand J Clin Lab Invest Suppl. 1999;230:177-181
PubMed
Eda S, Kaufmann J, Roos W.  et al.  Development of a new microparticle-enhanced turbidimetric assay for C-reactive protein with superior features in analytical sensitivity and dynamic range.  J Clin Lab Anal. 1998;12:137-144
PubMed   |  Link to Article
Andersen TF, Madsen M, Jorgensen J.  et al.  The Danish National Hospital Register: a valuable source of data for modern health sciences.  Dan Med Bull. 1999;46:263-268
PubMed
Berger R, Huelsman M, Strecker K.  et al.  B-type natriuretic peptide predicts sudden death in patients with chronic heart failure.  Circulation. 2002;105:2392-2397
PubMed   |  Link to Article
Mendall MA, Strachan DP, Butland BK.  et al.  C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men.  Eur Heart J. 2000;21:1584-1590
PubMed   |  Link to Article
Folsom AR, Aleksic N, Catellier D.  et al.  C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study.  Am Heart J. 2002;144:233-238
PubMed   |  Link to Article
van der Meer IM, de Maat MP, Kiliaan AJ.  et al.  The value of C-reactive protein in cardiovascular risk prediction.  Arch Intern Med. 2003;163:1323-1328
PubMed   |  Link to Article
Tracy RP, Lemaitre RN, Psaty BM.  et al.  Relationship of C-reactive protein to risk of cardiovascular disease in the elderly.  Arterioscler Thromb Vasc Biol. 1997;17:1121-1127
PubMed   |  Link to Article
Pradhan AD, Manson JE, Rossouw JE.  et al.  Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women's Health Initiative observational study.  JAMA. 2002;288:980-987
PubMed   |  Link to Article
Koenig W, Sund M, Frohlich M.  et al.  C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men.  Circulation. 1999;99:237-242
PubMed   |  Link to Article
Danesh J, Wheeler JG, Hirschfield GM.  et al.  C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease.  N Engl J Med. 2004;350:1387-1397
PubMed   |  Link to Article
Rossing P, Hougaard P, Borch-Johnsen K.  et al.  Predictors of mortality in insulin dependent diabetes: 10 year observational follow up study.  BMJ. 1996;313:779-784
PubMed   |  Link to Article
Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S.  et al.  Urinary albumin excretion: an independent predictor of ischemic heart disease.  Arterioscler Thromb Vasc Biol. 1999;19:1992-1997
PubMed   |  Link to Article
Damsgaard EM, Froland A, Jorgensen OD.  et al.  Microalbuminuria as predictor of increased mortality in elderly people.  BMJ. 1990;300:297-300
PubMed   |  Link to Article
Rubattu S, Stanzione R, Di Angelantonio E.  et al.  Atrial natriuretic peptide gene polymorphisms and risk of ischemic stroke in humans.  Stroke. 2004;35:814-818
PubMed   |  Link to Article
Troughton RW, Prior DL, Pereira JJ.  et al.  Plasma B-type natriuretic peptide levels in systolic heart failure: importance of left ventricular diastolic function and right ventricular systolic function.  J Am Coll Cardiol. 2004;43:416-422
PubMed   |  Link to Article
Lubien E, DeMaria A, Krishnaswamy P.  et al.  Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings.  Circulation. 2002;105:595-601
PubMed   |  Link to Article
Mizuno Y, Yoshimura M, Harada E.  et al.  Plasma levels.  Am J Cardiol. 2000;86:1036-1040, A11
PubMed   |  Link to Article
Vasan RS, Benjamin EJ, Larson MG.  et al.  Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the Framingham heart study.  JAMA. 2002;288:1252-1259
PubMed   |  Link to Article
McClure SJ, Caruana L, Davie AP.  et al.  Cohort study of plasma natriuretic peptides for identifying left ventricular systolic dysfunction in primary care.  BMJ. 1998;317:516-519
PubMed   |  Link to Article
Hama N, Itoh H, Shirakami G.  et al.  Rapid ventricular induction of brain natriuretic peptide gene expression in experimental acute myocardial infarction.  Circulation. 1995;92:1558-1564
PubMed   |  Link to Article
Tateishi J, Masutani M, Ohyanagi M.  et al.  Transient increase in plasma brain (B-type) natriuretic peptide after percutaneous transluminal coronary angioplasty.  Clin Cardiol. 2000;23:776-780
PubMed   |  Link to Article
Goetze JP, Yongzhong W, Rehfeld JF.  et al.  Coronary angiography transiently increases plasma pro-B-type natriuretic peptide.  Eur Heart J. 2004;25:759-764
PubMed   |  Link to Article

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