LVEF indicates left ventricular ejection fraction. To convert serum
creatinine to μmol/L, multiply by 88.4.
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.
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(13):1609-1616. doi:10.1001/jama.293.13.1609
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.
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.
Risk stratification in the general population is receiving increasing
interest.1- 3 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.13- 15 In
nonhospitalized individuals, a limited number of studies haveevaluated the
prognostic information of the B-type natriuretic peptides.16- 18 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,
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).
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.
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.
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.
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.4,19,25- 27 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.
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).
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.
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).
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
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.
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),
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).
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
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.33- 35 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 (firstname.lastname@example.org).
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,
Acquisition of data: Kistorp, Raymond, Pedersen,
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.