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Clinical Science (2004) 106, 135–139 (Printed in Great Britain)
Vigorous response in plasma N-terminal
pro-brain natriuretic peptide (NT-BNP) to
acute myocardial infarction
Denzil GILL, Timothy SEIDLER, Richard W. TROUGHTON, Timothy G. YANDLE,
Christopher M. FRAMPTON, Mark RICHARDS, John G. LAINCHBURY
and Gary NICHOLLS
Christchurch Cardioendocrine Research Group, Department of Medicine, Christchurch School of Medicine and Health Sciences,
P.O. Box 4356, Christchurch 8001, New Zealand
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Acute myocardial infarction (MI) results in activation of neurohormonal systems and increased
plasma concentrations of myocardial enzymes and structural proteins. We hypothesized
that plasma levels of N-terminal pro-brain natriuretic peptide (NT-BNP) would respond more
vigorously after MI than those of other natriuretic peptides. We also sought to compare this
response with that of the established myocardial injury markers troponin T (TnT), myoglobin
and creatine kinase MB (CK-MB). We obtained multiple blood samples for measurement of atrial
natriuretic peptide (ANP), N-terminal pro-ANP, brain natriuretic peptide (BNP) and NT-BNP
along with CK-MB, TnT and myoglobin in 24 patients presenting to the Coronary Care Unit
within 6 h of onset of MI. Multiple samples were obtained in the first 24 h, then at 72 h, 1 week,
6 weeks and 12 weeks. NT-BNP increased rapidly to peak at 24 h and exhibited greater (P < 0.001)
absolute increments from baseline compared with BNP and ANP, whereas NT-ANP did not change
from baseline. Proportional increments in NT-BNP were also greater than those for the other
natriuretic peptides (P < 0.05). Natriuretic peptide levels reached their peak around 24 h, later
than peak TnT, CK-MB and myoglobin (peak between 1–10 h), and NT-BNP and ANP remained
elevated on average for 12 weeks. Our present results, with detailed sampling of a cohort of acute
MI patients, demonstrate greater absolute and proportional increments in NT-BNP than ANP or
BNP with sustained elevation of these peptides at 12 weeks.
INTRODUCTION
It is well known that acute myocardial infarction (MI)
is associated with activation of neurohormonal systems
and increased circulating levels of myocardial enzymes and structural proteins. These have turned out, in
some cases, to have diagnostic and prognostic use and also
therapeutic implications. It is now clear that plasma levels
of atrial natriuretic peptide (ANP) and brain natriuretic
peptide (BNP), both produced within myocardiocytes,
also are elevated soon after acute MI [1–7]. Furthermore,
reports [8–19] suggest that the level of ANP, N-terminal
pro-ANP (NT-ANP) or BNP measured soon after
infarction might provide a simple useful biochemical
reflection of left ventricular function and/or a prognostic
index for subsequent cardiac function and prognosis.
Since the N-terminal fragment of pro-BNP (NT-BNP)
circulates at similar levels to BNP in healthy volunteers
yet increases more steeply as cardiac function deteriorates
[20,21], we hypothesized that NT-BNP would exhibit a
Key words: creatine kinase, hormone, myocardial infarction, myoglobin, natriuretic peptide, troponin.
Abbreviations: ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CK-MB, creatine kinase MB; NT-ANP, N-terminal
pro-ANP; NT-BNP, N-terminal pro-BNP; TnT, troponin T.
Correspondence: Dr J. G. Lainchbury (e-mail [email protected]).
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D. Gill and others
more vigorous response after acute MI than BNP, ANP
or NT-ANP. If indeed this was so, NT-BNP, assays for
which will soon be widely available, might provide a
relatively simple, rapid and cheap diagnostic test for, and
prognostic index after, acute MI. Detailed comparisons
of the response to acute MI of the natriuretic peptides,
including NT-BNP, along with the myocardial injury
markers troponin T (TnT), myoglobin and creatine kinase
MB (CK-MB), have not been carried out previously.
METHODS
The study protocol was approved by the Ethics Committee of the Canterbury District Health Board and
patients gave informed consent.
We studied 24 consecutive patients presenting to the
Coronary Care Unit at Christchurch Hospital within
6 h of the onset of chest pain and clear evidence of STelevation acute MI, together with a rise then fall in plasma
TnT. Patients with cardiogenic shock were excluded.
An 18-gauge intravenous cannula was inserted into a
forearm vein for blood sampling. Venous samples (10 ml)
were drawn on admission to the Coronary Care Unit
(time 0) and thereafter at 0.5, 1, 4, 8, 12, 24 and 72 h as inpatients, and at 1, 6 and 12 weeks as out-patients. Samples
were taken into tubes on ice and centrifuged at + 4 ◦ C at
2700 g for 5 min and the plasma stored at − 80 ◦ C until
analysed. Plasma samples were assayed for TnT, CK-MB
and myoglobin using heterogeneous immunoassays on
an Elecsys 2010 using ruthenium-labelled biotinylated
antibodies. Reagents, consumables and instrumentation
were supplied by Roche Diagnostics.
ANP, NT-ANP, BNP and NT-BNP were measured
by our well-established and validated RIAs using plasma
extracted on C18 Sep Pak cartridges [20,22,23]. All
measurements for each analyte were carried out in a
single assay to avoid inter-assay variability. Intra-assay
variability (coefficient of variation) for the hormone
measurements was between 4 and 9 %. Cross-reactivity
between the individual assays and the other natriuretic
peptides was < 0.007 % for all assays, except the ANP
assay, which had a cross-reactivity with BNP of 0.05 %.
Comparisons between plasma concentrations and
changes in concentrations were made using paired
Student’s t tests. Correlations were assessed using
Pearson’s correlation coefficients. Statistical significance was taken as P < 0.05. Data are presented as
means +
− S.E.M.
RESULTS
Twenty-four patients, 19 males, ages 37–82 (mean 65.2)
years were studied. Twelve patients had previously documented hyperlipidaemia, nine had hypertension, three
had an earlier MI, three were being treated for cardiac
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2004 The Biochemical Society
failure and four had diabetes mellitus. Medications on
admission were diuretics (five patients), angiotensinconverting enzyme inhibitors (six patients), aspirin
(15 patients), β-blockers (five patients), calcium channel
blockers (two patients) and nitrates (two patients). Three
patients had primary percutaneous transluminal coronary
angioplasty (PTCA; two with anterior MI and one with
anterolateral MI), 21 patients received thrombolysis,
two patients subsequently had coronary artery bypass
grafting during the admission, and two patients developed
left ventricular failure. One patient died from myocardial
rupture on the fourth day after admission. One patient
developed atrial fibrillation. Seventeen patients had an
ECG during the hospital stay, and the average ejection
fraction was 54 % (range, 24–75 %). Average hospital stay
for the 23 patients discharged alive was 6.6 days (range,
3–15 days). The time between the onset of chest pain
and drawing of the baseline (time 0) venous sample was
3.9 +
− 0.3 h.
Baseline NT-BNP (43 +
− 6 pmol/l) levels were higher
(P < 0.0001) than both concurrent BNP (10 +
− 1.5 pmol/l)
and ANP (19.5 +
3.5
pmol/l)
levels,
but
were
lower than
−
NT-ANP levels (0.94 +
0.13
nmol/l;
Table
1).
Plasma
−
levels of NT-BNP increased rapidly to peak at 12–24 h
(Table 1), and exhibited a greater (P < 0.001) absolute
increment from baseline than BNP and ANP (123 +
− 15
+
compared with 19 +
2
and
27
3
pmol/l
respectively).
−
−
Furthermore, NT-BNP showed a greater proportional
rise than either plasma BNP or ANP (5.6 +
− 0.9-fold
compared with 3.4 +
− 0.6- and 2.4 +
− 0.3-fold respectively;
P < 0.05; Figure 1, upper panel). NT-ANP levels were,
on average, towards the upper limit of normal at baseline
and did not change significantly thereafter (Table 1, and
Figure 1, upper panel).
At time 0, the percentage of patients with elevated BNP,
NT-BNP, ANP or NT-ANP was identical (29 %). The
percentage of patients with plasma NT-BNP levels above
the upper limit of normal at 8, 12 and 24 h was 95 %, 96 %
and 96 % respectively. These percentages were similar
for plasma levels of BNP (95 %, 92 % and 95 %), but
were considerably higher than for ANP (74 %, 79 %
and 74 %) and, particularly, NT-ANP (22 %, 29 % and
17 %).
The temporal pattern of change for NT-BNP, BNP
and ANP contrasted sharply with those for plasma levels
of TnT, CK-MB and myoglobin (Figure 1, lower panel).
Whereas peak levels for NT-BNP, BNP and ANP were
achieved generally around 24 h (Figure 1, upper panel),
maximum levels of TnT, CK-MB and myoglobin were
reached at between 1 and 10 h (Figure 1, lower panel).
Furthermore, the elevation in the natriuretic peptide
levels was considerably more sustained than TnT, CKMB or myoglobin, as the latter had normalized by
6 weeks and, in the case of CK-MB and myoglobin had,
in general, normalized by 70 h (Figure 1, lower panel,
and Table 1), whereas NT-BNP, BNP and ANP remained
Natriuretic peptides in myocardial infarction
Table 1 Levels of natriuretic peptides and myocardial markers in 24 patients after acute myocardial infarction
Values are means +
− S.E.M. Time 0 is on average 3.9 +
− 0.3 h after the onset of chest pain.
Natriuretic peptides
Normal range
Time (h)
0
0.5
1
4
8
12
24
72
Time (weeks)
1
6
12
Myocardial markers
ANP (pmol/l)
NT-ANP (nmol/l)
BNP (pmol/l)
NT-BNP (pmol/l)
TnT (µg/l)
CK-MB (µg/l)
Myoglobin (µg/l)
4–19
0.13–0.91
2–12
2–50
< 0.03
0–5
0–116
19.5 +
− 3.5
17 +
−2
16.5 +
−2
23 +
− 2.5
25 +
−3
26.5 +
− 2.5
28.5 +
−3
35.5 +
−5
0.94 +
− 0.13
1.01 +
− 0.11
0.96 +
− 0.10
0.78 +
− 0.07
0.67 +
− 0.07
0.67 +
− 0.06
0.64 +
− 0.07
0.76 +
− 0.08
10 +
− 1.5
10 +
−1
11 +
− 1.5
14.5 +
− 1.5
19 +
− 1.5
21.5 +
− 1.5
24 +
−2
21.5 +
−2
43 +
−6
46 +
− 6.5
49.5 +
−7
72 +
−9
100.5 +
− 10.5
124.5 +
− 11.5
143 +
− 15.5
109 +
− 15
0.16 +
− 0.06
0.79 +
− 0.51
1.05 +
− 0.63
2.35 +
− 0.60
4.52 +
− 0.96
4.53 +
− 0.98
3.08 +
− 0.69
2.23 +
− 0.44
24.9 +
− 7.0
62.5 +
− 24.3
84.0 +
− 31.0
191.1 +
− 40.4
248.3 +
− 47.6
203.5 +
− 36.3
92.3 +
− 21.2
5.7 +
− 1.1
543 +
− 136
786 +
− 196
840 +
− 214
731 +
− 153
377 +
− 82
241 +
− 52
157 +
− 35
58 +
−5
28 +
− 3.5
35 +
−4
28.5 +
−4
0.76 +
− 0.09
0.93 +
− 0.13
0.60 +
− 0.05
22.5 +
− 2.5
21 +
−3
14 +
− 1.5
102 +
− 14
94.5 +
− 15.5
49 +
− 6.5
2.7 +
− 0.5
2.9 +
− 0.3
3.6 +
− 0.7
47 +
−3
56 +
−3
61 +
−7
0.68 +
− 0.16
0.01 +
− < 0.01
0.01 +
− < 0.01
DISCUSSION
Figure 1 Proportional change from baseline (time 0) in
plasma levels of natriuretic peptides (upper panel) and
myocardial markers (lower panel)
Values are means. AMI, acute MI.
elevated, on average, at 12 weeks (Figure 1, upper panel,
and Table 1).
There was a modest, but statistically significant, correlation between maximum NT-BNP and maximum CKMB (r = 0.435, P = 0.038). There were no other significant
correlations between maximum natriuretic peptide levels
and maximum TnT, CK-MB and myoglobin.
Various biomarkers have been used for the diagnosis
of acute MI and as a guide to subsequent prognosis
[24–27]. Considerable enthusiasm and experience exists,
particularly for the cardiac troponins and, to a lesser
extent with, CK-MB and myoglobin. As noted by
Hamm [24], the search for new markers will continue,
particularly in regard to risk stratification.
It has been known for more than a decade that ANP
and BNP are released from cardiac muscle during acute
MI [8–19]. The magnitude of the response in ANP
and/or BNP has been shown by some authors [8–19]
to be predictive of subsequent ventricular dysfunction,
morbidity or mortality. As NT-BNP circulates at similar
levels to the bioactive BNP itself in healthy volunteers
yet shows a proportionally greater rise as ventricular
dysfunction deteriorates in patients with heart failure
[20,21], we surmized that this 1–76 amino acid peptide
might show an exaggerated rise following acute MI
compared with ANP or BNP. If so, there might be
potential usefulness in measuring this peptide soon after
a MI, both from a diagnostic and prognostic viewpoint.
The present study, in a small cohort of patients,
demonstrates that NT-BNP exhibits a greater absolute
and proportional rise after acute MI than ANP or
BNP. Peak levels of the three peptides were observed
at approx. 24 h and, in general, remained elevated even at
12 weeks. This pattern of response contrasts with the
more standard cardiac biomarkers TnT, CK-MB and
myoglobin, whose peak levels were reached between 1
and 10 h and normalizing more rapidly.
In regard to NT-ANP, we found the levels to be
elevated in only a minority of our patients after MI with
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D. Gill and others
little pattern of change thereafter. Accordingly, our results
do not raise enthusiasm for measurements of this peptide
in diagnosis of acute MI and suggest it may convey
less prognostic information than the measurement of
NT-BNP.
The mechanisms behind the increase in natriuretic
peptides are likely to be numerous and complex, but
could involve myocardial hypoxia, intracellular acidosis,
stimulation of the renin–angiotensin system and the
sympathetic nervous system and, in addition, MIassociated stress of the left ventricle and possibly left
atrium [28–32]. As for the differences between the peptide
patterns, the plasma half-lives differ, the distribution
of ANP and BNP differs in at least some chambers of
the human heart and with stretch or hypertrophy gene
expression of the peptides differs temporally, at least
under experimental circumstances [33–35]. Our present
study was not designed to examine this question, and
further investigation is required to determine which of
these and other factors dictates the patterns observed.
Whether the level of NT-BNP achieved after MI will
prove superior as a prognostic indicator to ANP or BNP,
or the more standard markers, especially the cardiac
troponins, remains to be determined in larger studies.
The few studies [36–39] reported previously support the
possibility that NT-BNP might prove clinically useful.
We observed NT-BNP, measured post-MI, to be
predictive of left ventricular function and prognosis
[36]. Talwar et al. [37] reported a strong correlation of
NT-BNP with left ventricular wall motion index soon
after and remote from acute MI. In that study [37],
NT-BNP and previous MI were independent predictors
of poor outcome [37]. Jernberg and co-workers [38]
reported that a combination of NT-BNP, clinical factors,
ECG and TnT levels provided a discerning tool for
risk stratification from a study of 755 patients admitted
with chest pain, but no ST-segment elevation on
ECG. Omland and co-workers [39], in a nested casecontrol study, suggested that NT-BNP measured 12–24 h
following hospitalization for non-ST-segment elevation
acute coronary syndromes was predictive of early death,
although not of non-fatal recurrent acute MI.
Utilization of NT-BNP as a diagnostic marker of acute
MI requires further exploration. It appears most unlikely
that it will replace current cardiac biomarkers in the few
hours subsequent to the onset of MI. It might, however,
find a place when further time has elapsed, particularly
beyond 70 h, when CK-MB and myoglobin levels have,
by and large, returned to normal. However, it is more
likely that NT-BNP might find a place as a prognostic
index for subsequent ventricular function or for cardiac
morbidity or mortality following acute MI. Whether it
will prove more or less successful in this regard than
the bioactive peptides ANP or BNP or indeed the more
classical biomarkers, particularly TnT, remains to be
determined.
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2004 The Biochemical Society
ACKNOWLEDGMENTS
This study was supported by the Health Research
Council of New Zealand, and the National Heart
Foundation of New Zealand. Secretarial assistance was
provided by Barbara Griffin.
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Received 11 April 2003/3 July 2003; accepted 15 September 2003
Published as Immediate Publication 15 September 2003, DOI 10.1042/CS20030131
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