Risk assessment in patients with unstable angina/non-ST-elevation myocardial infarction and normal N-terminal pro-brain natriuretic peptide levels by N-terminal pro-atrial natriuretic peptide.
ABSTRACT To compare the accuracy of the N-terminal fragment of its pro-hormone (Nt-proBNP) and N-terminal pro-atrial natriuretic peptide (Nt-proANP) in the prediction of the 2 year mortality and to investigate whether additional measurement of Nt-proANP to troponin I (TnI) could improve risk assessment in the subgroups of patients with unstable coronary artery disease (UCAD) and normal Nt-proBNP.
Plasma levels of the TnI, Nt-proANP, and Nt-proBNP were determined in 120 consecutive patients with UCAD without ST-segment elevations and normal left ventricular function. In multivariable logistic regression analysis, TnI and Nt-proBNP were independent predictors of mortality (P=0.01 and P=0.02, respectively). However, in the group of patients with normal Nt-proBNP levels, only Nt-proANP and TnI were independently associated with mortality (P=0.007 and P=0.03, respectively). Accordingly, patients with elevated Nt-proANP levels in this group of patients had significantly higher mortality rate than patients with normal Nt-proANP levels (P=0.003).
Our results suggest that determination of Nt-proANP might improve risk assessment in patients with UCAD, especially when Nt-proBNP is in the normal range.
- SourceAvailable from: eurheartj.oxfordjournals.org[show abstract] [hide abstract]
ABSTRACT: To evaluate the level of plasma brain natriuretic peptide as a predictor of morbidity and mortality in patients with asymptomatic or minimally symptomatic left ventricular dysfunction. We measured plasma levels of atrial natriuretic peptide, brain natriuretic peptide, norepinephrine, angiotensin II, and endothelin-1 and monitored haemodynamic parameters in 290 consecutive patients with asymptomatic or minimally and newly symptomatic left ventricular dysfunction (functional classes I-II, mean left ventricular ejection fraction=37%). All patients were followed up for a median period of 812 days. The Cox proportional hazards model was used to assess the association of variables with mortality and morbidity. At the end of the follow-up, 24 patients had suffered cardiac death and 25 had been hospitalized for worsening heart failure during the follow-up period. Among 21 variables such as clinical characteristics, treatment, haemodynamics, and neurohumoral factors, high levels of plasma brain natriuretic peptide (P<0.0001), norepinephrine (P=0.042), left ventricular end-diastolic volume index (P=0.0035), and left ventricular end-diastolic pressure (P=0.033) were shown to be independent predictors of mortality and morbidity by stepwise multivariate analysis. Moreover, only a high level of plasma brain natriuretic peptide (P<0.0001) was shown to be an independent predictor of mortality in these patients. These results indicate that a high plasma brain natriuretic peptide level provides information about mortality and morbidity in patients with asymptomatic or minimally symptomatic left ventricular dysfunction.European Heart Journal 12/1999; 20(24):1799-807. · 14.10 Impact Factor
- ACC Current Journal Review 01/2002; 11(2):13.
- ACC Current Journal Review 01/2002; 11(5):16.
Risk assessment in patients with unstable
angina/non-ST-elevation myocardial infarction
and normal N-terminal pro-brain natriuretic peptide
levels by N-terminal pro-atrial natriuretic peptide
Rudolf Jarai1,2, Nelly Iordanova1, Robert Jarai3, Annamaria Raffetseder4,
Wolfgang Woloszczuk4, Mariann Gyo ¨ngyo ¨si2, Georg Geyer4, Johann Wojta2,
and Kurt Huber1,2*
1Third Department of Medicine (Cardiology and Emergency Medicine), Wilhelminen Hospital Vienna,
Montleartstrasse 37, A-1171 Vienna, Austria
2Department of Cardiology, University of Vienna, Vienna, Austria
3Department of Psychology, University of Pecs, Pecs, Hungary
4Ludwig-Boltzmann Institute of Experimental Endocrinology, Vienna, Austria
Received 21 November 2003; revised 15 September 2004; accepted 5 October 2004; online publish-ahead-of-print 20 December 2004
Aims To compare the accuracy of the N-terminal fragment of its pro-hormone
(Nt-proBNP) and N-terminal pro-atrial natriuretic peptide (Nt-proANP) in the predic-
tion of the 2 year mortality and to investigate whether additional measurement of
Nt-proANP to troponin I (TnI) could improve risk assessment in the subgroups of
patients with unstable coronary artery disease (UCAD) and normal Nt-proBNP.
Methods and results Plasma levels of the TnI, Nt-proANP, and Nt-proBNP were deter-
mined in 120 consecutive patients with UCAD without ST-segment elevations and
normal left ventricular function. In multivariable logistic regression analysis, TnI
and Nt-proBNP were independent predictors of mortality (P ¼ 0.01 and P ¼ 0.02,
respectively). However, in the group of patients with normal Nt-proBNP levels, only
Nt-proANP and TnI were independently associated with mortality (P ¼ 0.007 and
P ¼ 0.03, respectively). Accordingly, patients with elevated Nt-proANP levels in this
group of patients had significantly higher mortality rate than patients with normal
Nt-proANP levels (P ¼ 0.003).
Conclusion Our results suggest that determination of Nt-proANP might improve risk
assessment in patients with UCAD, especially when Nt-proBNP is in the normal range.
Atrial natriuretic peptide;
Brain natriuretic peptide;
Acute coronary syndromes;
Elevation of plasma levels of brain natriuretic peptide
(BNP) and the N-terminal fragment of its pro-hormone
(Nt-proBNP) is associated with increased mortality in
patients with congestive heart failure, left ventricular
systolic dysfunction, after acute myocardial infarction
(AMI),1–8and in patients with unstable coronary artery
disease (UCAD).9Nt-proBNP exhibits an exponential rela-
tionship with mortality in UCAD. Accordingly, highest
mortality rate has been observed in the small group of
patients within the highest Nt-proBNP quartile. In con-
trast, lower Nt-proBNP levels possess limited prognostic
European Heart Journal vol. 26 no. 3 & The European Society of Cardiology 2004; all rights reserved.
*Corresponding author. Tel: þ43 1 49150 2301; fax: þ43 1 49150 2309.
E-mail address: firstname.lastname@example.org
European Heart Journal (2005) 26, 250–256
by guest on May 31, 2013
value. Positive troponin I or T (TnI; TnT) levels in patients
with UCAD have been shown to be strong predictors of
mortality irrespective of Nt-proBNP levels.10,11The com-
bination of both BNP/Nt-proBNP and TnI significantly
improved risk assessment in patients with UCAD.10–12
Plasma levels of atrial natriuretic peptide (ANP) and
N-terminal pro-atrial natriuretic peptide (Nt-proANP)
levels are also elevated in congestive heart failure and
after AMI.13–16Recently, it has also been shown that
Nt-proANP is a strong predictor of mortality in patients
with UCAD independent of TnT and other risk factors of
coronary artery disease.17ANP and BNP exhibit similar
hormonal effects,18and the secretion of both peptides
is stimulated by myocardial stretch and ischaemia.19–21
However at the level of gene expression, ANP and BNP
are regulated differentially.19,22–24Accordingly, eleva-
tions of Nt-proANP and Nt-proBNP in UCAD might reflect
distinct pathological processes in accordance with myo-
cardial ischaemia. Therefore, simultaneous determi-
nation of these peptides might improve the risk
assessment of patients with UCAD.
The aim of the present study was to compare the accu-
racy of Nt-proBNP and Nt-proANP in the prediction of the
2-year mortality and to investigate whether additional
measurement of Nt-proANP to TnI could improve risk
assessment in the subgroup of patients with UCAD and
Patients and methods
One hundred and fifty-two consecutive patients, who were
admitted to our chest pain unit with normal left ventricular
function as determined by echocardiography at presentation
(ejection fraction ?52%), were included in the study. We
included men and women older than 20 years with typical
angina within the last 24 h with signs of myocardial ischaemia
in the 12 lead ECG: patients with either ST-depression of
0.1 mV in two continuous leads, T-wave inversion or both with
concomitantly elevated TnI (?0.15 ng/mL) levels were diag-
nosed as non-ST-elevation myocardial infarction (NSTEMI),
whereas patients without TnI elevations were diagnosed as
unstable angina (UA). Exclusion criteria were signs of acute
ST-elevation myocardial infarction, reduced global ventricular
function or signs of heart failure at admission, pacemaker
ECGs, suspected myocarditis or pericarditis, as well as disorders
known to influence plasma Nt-proBNP and Nt-proANP levels (e.g.
renal and hepatic disorders).
The endpoint of the study was cardiovascular death within 2
years. Follow-up information of the patients was collected at
24 months after inclusion in the study.
Blood sampling and analyses
Venous blood samples were obtained immediately at presen-
tation of the patients at the chest pain unit. In case of normal
troponin levels on admission, a second blood sample was
obtained after 4–6 h. Cardiac TnI levels were analysed by use
of the OPUS plus Immunoassay System (Behrings Diagnostic
Inc., Vienna, Austria) and accepted as pathological if the first
or the second determination exhibited a concentration of
Cardiac natriuretic peptides were measured in plasma samples
by immunoassays (Biomedica, Vienna, Austria). Nt-proANP was
measured by a non-competitive sandwich-type immunoassay
with a detection limit of 50 pmol/L and normal plasma level
lower than 1.9 nmol/L. Nt-proBNP 8–29 was measured by a com-
petitive enzyme immunoassay using a sheep antibody specific for
proBNP 8–29 and the synthetic peptide as a standard. Detection
limit of this assay is 5 pmol/L.
The Mann–Whitney U test was performed to compare plasma
levels of Nt-proBNP, Nt-proANP, and TnI between patients with
or without clinical events during the follow-up period. Spearman
rank correlation was performed to detect linear correlation
between the respective biomarkers. The predictive capacity
of TnI, Nt-proBNP, and Nt-proANP was assessed by receiver-
operating characteristic (ROC) curves, and the comparison of
the predictive values of these markers was achieved by
pair-wise comparison of the area under the ROC-curves accord-
ing to Hanley and McNeil.38Stepwise multivariable logistic
regression analysis with backward selection method was used
Nt-proANP, and TnI levels and mortality after 2 years. The logis-
tic model included age, diabetes mellitus, hypertension,
smoking, familial history of coronary artery disease, and creati-
nine kinase MB levels. Using Box–Tidwell transformation, we
proved the linear relationship between the logit of the endpoint
and the explanatory variables. Variables with significance levels
of P . 0.1 were excluded from the multivariable model. Prog-
nostic significance of TnI, Nt-proBNP, and Nt-proANP were
tested as continuous as well as dichotomized variables in two
independent logistic regression models. For cut-off values we
used the upper limit of normal range for all three markers:
0.33 nmol/L for Nt-proBNP, 1.94 nmol/L for Nt-proANP (accord-
ing to the product instruction manual of Nt-proANP and
Nt-proBNP) and 0.15 ng/mL for TnI. To test whether the logistic
regression models provide reliable data at a sample size of 120
patients, we performed power analysis according to Tosteson
et al.25The analyses showed that each of the models exhibited
a power of .80%. According to statistical guidelines,26these
results confirmed the reliability of our tests. In the group of
patients with normal Nt-proBNP, mortality rates of patients
with or without elevated Nt-proANP levels were compared
using the x2test. All significance tests were two-sided and stat-
istical significance was considered present if P , 0.05. To avoid
inflation of type I error by multiple testing, Bonferroni adjust-
ments were performed. All statistical analyses were assessed
using the Software Package for Social Sciences for Windows
(SPSS for Windows, SPSS Inc., IL, USA).
One hundred and twenty patients had echocardiography,
TnI, Nt-proBNP, and Nt-proANP values available at admis-
sion and 2-year outcome. The baseline characteristics of
our study population, including left ventricular ejection
fraction at admission, are depicted in Table 1. Patients
who died during the follow-up were significantly older,
hypercholesterolaemic, and showed significantly higher
TnI, Nt-proANP, and Nt-proBNP levels, respectively.
Risk assessment by natriuretic peptides251
by guest on May 31, 2013
Thirty-six percent of the patients had NSTEMI and 64%
had UA. Fiftypercent of
Nt-proANP levels and 24% of the patients had elevated
Nt-proBNP levels at admission.
In the whole study population, Nt-proANP and Nt-proBNP
levels correlated significantly (r ¼ 0.63; P , 0.0001). The
correlation was very strong in the group of patients with
elevated Nt-proBNP (r ¼ 0.74; P , 0.0001) but weak and
P ¼ 0.06). TnI concentrations showed no significant cor-
relation with Nt-proANP or Nt-proBNP levels (r ¼ 0.03;
P ¼ 0.679 and r ¼ 0.10; P ¼ 0.246), respectively.
cut-offpoint(r ¼ 0.16;
ROC-curves of TnI, Nt-proBNP, and Nt-proANP and the
respective area under the ROC-curves for discriminating
patients who died, from those who survived the study
period are depicted in Figure 1. The areas under the
ROC-curves indicated good predictive performance of
all markers. There were no significant differences
among the area under the ROC-curves. ROC analysis in
the group of patients with low Nt-proBNP levels
Nt-proANP had significant predictive values in detecting
patients whodied during
Nt-proBNP possessed no predictive capacity (Figure 2).
Stepwise multivariable logistic regression
Logistic regression analysis, adjusted for age, diabetes
mellitus, hypertension, hypercholesterolaemia, previous
myocardial infarction, smoking, familial history of coron-
ary artery disease, and creatinine kinase MB levels,
revealed an independent
Nt-proBNP levels with 2 years mortality and no indepen-
(Table 1). Similar results were obtained after dichotomi-
zation of TnI, Nt-proBNP, and Nt-proANP levels (data not
association of TnIand
In the group of patients with normal Nt-proBNP levels,
however, only TnI and Nt-proANP levels were significantly
associated with mortality, whereas Nt-proBNP provided
no significant prognostic information (Table 2) beyond
that of TnI or Nt-proANP.
Accordingly, elevated levels of Nt-proANP, in the pre-
sence of Nt-proBNP levels within the normal range,
were associated with a significantly higher mortality
rate compared with patients with normal Nt-proANP and
Nt-proBNP levels (Figure 3).
To our knowledge, this is the first prospective study inves-
tigating the prognostic significance of Nt-proANP in
addition to Nt-proBNP in patients with UCAD with pre-
served left ventricular function. Our results suggest that
Nt-proBNP levels are the strongest predictor for 2-year
mortality in these patients and that the measurement of
Nt-proANP might provide additional important prognostic
information beyond that of TnI when Nt-proBNP levels
are within the normal range.
Our results are in accordance with results of recent
reports, which confirm the long-term prognostic signifi-
cance of the B-type natriuretic peptide family in
UCAD.3,27,28From these studies it also became clear
that this strong prognostic significance is independent
of other known risk factors for coronary artery disease
in patients with or without clinical signs of heart failure
or left ventricular dysfunction, as well as in patients
with different index diagnoses (STEMI, NSTEMI, UA).28
Simultaneous determination of BNP and other coronary
risk factors, like C-reactive protein and troponins, has
been shown to significantly improve risk assessment of
patients with UCAD.12Furthermore, we could show that
a risk score, which includes clinical as well as biochemi-
cal variables, extended by Nt-proBNP levels performs sig-
nificantly better in predicting outcome after an acute
The prognostic significance of the ANP family in UCAD
has been less extensively investigated in the past
although studies have shown that elevated ANP and/or
Nt-proANP levels have strong prognostic significance
All (n ¼ 120)
Survived (n ¼ 105)
Non-survivors (n ¼ 15)
Previous myocardial infarction
TnI ng/mL (+SD)
Nt-proANP nmol/L (+SD)
Nt-proBNP nmol/L (+SD)
Unless depicted otherwise, values are given in n (%). LVEF, left ventricular ejection fraction measured by echocardiography at admission.
252R. Jarai et al.
by guest on May 31, 2013
in patients with UCAD independent of age, diabetes
mellitus, history of AMI, ST-changes, congestive heart
failure, troponin I or T, creatinine, and treatment
respectively. It is also known that
ANP/Nt-proANP secretion is induced by myocardial
ischaemia and hypoxia. However, it could also be shown
that when both ANP and BNP were included in the multi-
variable regression analysis, only BNP/Nt-proBNP remains
an independent predictor of outcome after AMI.7In
accordance with these results, Nt-proANP had no inde-
pendent relationship with mortality when Nt-proBNP
was included in the multivariable analysis of our study.
On the other hand, the strong predictive power of
Nt-proBNP was apparent only among patients with
highest Nt-proBNP levels; lower values of Nt-proBNP
had no prognostic significance. These results are in
agreement with recently published data showing that
BNP and/or Nt-proBNP elevations are exponentially
associated with mortality, exhibiting highest rate of
deathamong the highest
levels.10,11Moreover, similar to our results, it could be
shown that mortality increases significantly only above
the 80th percentile of the BNP levels.10
Interestingly, in the group of patients with normal
Nt-proBNP levels, Nt-proANP had important prognostic
significance independent of TnI levels and might there-
fore help to improve risk stratification of these patients.
The different relationships of Nt-proANP and Nt-proBNP
to long-term mortality, seen in the present study, might be
explained by the fact that despite similar receptor affinity
and hormonal effects, the functional roles of these pep-
tides are substantially different in physiological as well
found no significant correlation between Nt-proANP and
Nt-proBNP when the levels of the latter were within the
normal range, which suggests, and is in agreement with
ROC-curves of TnI, Nt-proBNP, and Nt-proANP for predicting mortality after 2 years. SE, standard error; Asympt.Sig., asymptotic significance.
Risk assessment by natriuretic peptides 253
by guest on May 31, 2013
other studies, that the secretion of these peptides is
regulated differentially by myocardial ischaemia.24,33–37
Unfortunately, based on our study, we cannot explain
why patients with elevated natriuretic peptide levels
have quite a high incidence of death in the subsequent
2 years, despite well preserved ventricular function and
reperfusion therapy. However, our findings are in agree-
ment with results of clinical trials and studies with a
larger sample size. In the global utilization of strategies
to open occluded arteries IV (GUSTO IV) trial, more
than 50% of all deaths occurred above the 80th
Nt-proBNP percentile. The fast assessment in thoracic
pain (FAST) study revealed an almost 70% mortality rate
of patients with NSTEMI and 40% mortality rate among
those with UA with Nt-proBNP levels above the 75th per-
centile. In our study, 60% of patients died with Nt-proBNP
levels above the 75th percentile. In the fragmin and
fast revascularization during instability in coronary
artery disease (FRISC II) trial, association of Nt-proBNP
elevations to mortality was not influenced by the pre-
sence or absence of reduced left ventricular function and
Nt-proBNP was a strong predictor of outcome in the group
SE, standard error; Asymp.Sig., asymptotic significance.
ROC-curves of TnI, Nt-proBNP, and Nt-proANP for predicting mortality after 2 years in the group of patients with normal Nt-proBNP levels.
Multivariate logistic regression analysis
B SEExp. B
? 0.33 nmol/L
B, beta coefficient; SE, standard error; Exp. B, adjusted odds ratio.
254R. Jarai et al.
by guest on May 31, 2013
of patients undergoing revascularization within 7 days
after the index event as well as among those patients
randomized to conservative management.
According to the results of the present study and
recent investigations, it could be assumed that a risk
score, consisting of clinical variables such as age, sex,
risk factors and ECG-changes as well as biochemical
markers of myocardial necrosis and ischaemia, inflamma-
tory processes, renal, and ventricular function, would
optimize estimation of patients’ risk and our manage-
ment of UCAD as well.
The main limitation of this report is the relatively
small number of patients included. According to the
power analysis of our logistic regression model and to
the fact that distribution of Nt-proANP and Nt-proBNP
levels and their associations with long-term mortality
are similar to studies with larger sample size, we
believe, that our results might provide important
In conclusion, the present study suggests that elevated
plasma levels of Nt-proANP and Nt-proBNP are related
to different pathological processes, which might influ-
ence the clinical outcome at different clinical stages of
acute coronary syndromes. For a better accuracy of risk
prediction in patients with UCAD, determination of
Nt-proANP seems to be of special interest when
Nt-proBNP is within the normal range.
The Association for the Promotion of Research in Arterio-
sclerosis, Thrombosis and Vascular Biology supported this
work. R.J. was a recipient of a scholarship from the
Austrian Cardiology Society. The excellent analytical
work of Mrs A. Raffetseder is gratefully acknowledged.
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by guest on May 31, 2013