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The natriuretic peptide present in cardiac tissue, initially patients with left ventricular dysfunction and heart failure.
discovered in the porcine brain,1 is termed B-type Recently, the clinical usefulness of BNP in the diagnosis
natriuretic peptide (BNP). Seventy-seven percent of the of heart failure in patients with acute dyspnea in an
BNP messenger RNA (mRNA) is found in the cardiac emergency-care setting has been established.9-11 Also,
ventricles2; BNP is secreted mainly in the left ventricles.3 plasma BNP concentrations have significant prognostic
In response to wall stretching or ventricular tension. value in patients with acute coronary syndromes.12-15 NT-
BNP is synthesized as prohormone proBNP (amino proBNP has also been demonstrated to be useful in the
acid, [aa] 108), and in the bloodstream is cleaved into an clinical assessment of left ventricular dysfunction,16,17 heart
inactive N-terminal fragment, NT-proBNP (aa 1-76), and failure,4,18 and risk stratification of patients with acute
the bioactive C-terminal fragment, BNP (aa 77-108).4,5 coronary syndromes.19-21
Numerous studies3,6-8 have shown elevated BNP levels in
Although BNP and NT-proBNP primarily are biomarkers for
the diagnosis of heart failure, their levels could be elevated
in other ischemic diseases.22 The present study was
DOI: 10.1309/LMPEAZF6UYU8FG4H initiated to explore the diagnostic values of NT-proBNP
and BNP in chronic heart failure, cerebral infarction,
Abbreviations cerebral hemorrhage, and acute cerebral infarction
BNP, brain natriuretic peptide; aa, amino acid(s); mRNA, messenger complicated with heart failure.
RNA; ACCF, American College of Cardiology Foundation; GFR, glomeru-
lar filtration rate; EDTA, ethylenediaminetetraacetic acid; CNS, central
nervous system
1
Department of Laboratory Diagnosis, Zhongshan Hospital, Sun Yat-Sen
University, Zhongshan, 2Nanfang Hospital, Guangzhou, China
Materials and Methods
*To whom correspondence should be addressed. A total of 303 patients aged 33 to 80 years with
E-mail: xuelangchichao@yahoo.com.cn chronic heart failure, acute cerebral infarction, cerebral
Table 1. Demographic and Clinical Characteristics of the Patients and the Healthy Control
hemorrhage, or acute cerebral infarction complicated for this study only and the study was approved by the
with heart failure were recruited in a university hospital institutional review board [IRB] at the university hospital).
in Zhongshan city of China. Their heart failure stages I The demographic and clinical characteristics of the cohort
to III (equivalent to NYHA grades II to IV) were classified are shown in Table 1.
according to American College of Cardiology Foundation
(ACCF)/American Heart Association (AHA) guidelines The concentrations of BNP and NT-proBNP in 363 serum
for the diagnosis and management of heart failure in and ethylenediaminetetraacetic acid (EDTA) plasma
adults.23 Patients with NYHA grade I heart failure were not samples were determined by ADVIA Centaur (Siemens AG,
included in the study because it is difficult to determine Munich, Germany) and cobas E601 (F. Hoffman–La Roche,
this classification accurately and because of the large Ltd, Basel, Switzerland) analyzers, respectively. The
variability seen in laboratory data from patients within this analytical performance of instruments had been verified
classification. by standard documents issued by Clinical and Laboratory
Standards Institute (CLSI).
Among the tested volunteers, 100 patients had chronic
heart failure, 65 had acute cerebral infarction, 35 had
cerebral hemorrhage, and 103 had acute cerebral infarction
complicated with heart failure. To determine the correct Results
diagnosis for patients, 2 cardiologists and 2 neurologists
masked to NT-proBNP and BNP concentrations and the The mean NT-proBNP and BNP concentrations in the
clinical diagnosis reviewed all medical records pertaining patients with acute cerebral infarction or heart failure were
to the patients and classified their conditions as follows: significantly higher than those of controls. At the time of
cerebral infarction, cerebral hemorrhage, and heart admission, mean (SD) NT-proBNP levels were 1132.27
failure. The conditions of patients with heart failure were (106.54) ng/L in patients with acute cerebral infarction
subclassified into heart failure only and acute cerebral and 3217.12 (369.19) ng/L in patients with heart failure,
infarction complicated with heart failure groups. Patients compared with a mean (SD) of 93.57 (9.18) ng/L in controls
with renal failure were evaluated according to glomerular (P <.01). However, the levels of BNP (Figure 1, part A)
filtration rate (GFR). BNP and NT-proBNP concentrations and NT-proBNP (Figure 1, part B) were not statistically
in patients with GFR of greater than 60 ml/minute did not different between the cerebral hemorrhage and control
seem to be influenced by renal disease.24 The grades of groups (P > .05).
heart failure were determined by the ACCF/AHA guidelines
previously mentioned. The diagnosis was established on Further, the NT-proBNP and BNP levels in patients
the basis of clinical data sheets and additional information with chronic heart failure and acute cerebral infarction
that became available during hospitalization, including complicated with heart failure were significantly higher
results of echocardiography, spirometric testing, and brain than in the control group and increased according to
serial quantitative computed tomographic scans. Also, increasing heart-failure stage. However, higher levels of
60 individuals of similar ages who underwent a physical NT-proBNP were observed in the group with cerebral
examination were selected as controls (all the individuals infarction complicated with heart failure compared to the
were assured that all serum samples would be used group with chronic heart failure alone at an equivalent
A
B
1,200
10,000 BNP
NT-proBNP
1,000
1,000
800
100
(ng/L)
600
10
400
1
200
0.1 0
Control Cerebral Cerebral Heart Control Cerebral Cerebral Heart
Hemorrhage Infarction Failure Hemorrhage Infarction Failure
Figure 1
Levels of brain natriuretic peptide (BNP) (A) and NT-proBNP (B) between the cerebral hemorrhage and control groups (P > .05).
A
B
12,000 1,600
Simple heart failure Simple heart failure
Cerebral infarction Cerebral infarction
complicated with
Concentration (pg/ml)
complicated with
Concentration (pg/ml)
6,000 800
3,000 400
0 0
Normal Stage I Stage II Stage III Normal Stage I Stage II Stage III
A
B
4,000 y=0.0866x + 33.876 2,500 y=0.0325x + 224.11
R2=0.9928 R2=0.3454
3,200 2,000
BNP (pg/ml)
BNP (pg/ml)
2,400 1,500
800 500
0 0
0 12,500 25,000 37,500 50,000 0 12,500 25,000 37,500 50,000
elevated after cerebral infarction. Regardless of whether however, because of their different patterns of metabolism,
the ischemia-hypoxia of the central nervous system the activation of the endocrine system controlled by CNS
(CNS) stimulates the release of NT-proBNP and BNP or degrade BNP more than NT-proBNP, resulting in a relative
the change of blood kinetics promotes the release of NT- increase of NT-proBNP. Last, following the deterioration
proBNP by ventricle cardiomyocytes, these observations that occurs due to heart failure, organisms begin to
prompted us to reposition NT-proBNP as a marker of heart mobilize activity factors that collaborate with the rennin-
failure. Our results indicated that BNP and NT-proBNP angiotensin-aldosterone system to induce a diastolic
are linearly correlated with each other and increase state in blood vessels. Together with the synergic effect
following the deterioration that occurs due to heart failure. of the endocrine system, this mobilization promotes the
Monitoring BNP or NT-proBNP could reflect the progress secretion and release of BNP as a vasodilatory activity
of heart failure. factor, resulting in a significant increase of BNP in stage III
cerebral infarction complicated with heart failure. Also, the
It has been reported25 that NT-proBNP and BNP are be International Expert Consensus27 regarding BNP clearly
elevated in patients with acute cerebral infarction; however, points out that cardiomyocytes can release truncated and
this elevation was not observed in cerebral hemorrhage. untruncated BNPs, which may not exist in a 1:1 ratio; this
Moreover, in acute cerebral infarction complicated with supports the possibility that NT-proBNP and BNP may not
heart failure, the NT-proBNP level, unlike the BNP level, was be proportional under particular conditions.
significantly higher. However, BNP was not observed to have
significantly increased until stage III heart failure occurred. During the subsequent monitoring of 14 patients with acute
cerebral infarction complicated with heart failure, who had
Although NT-proBNP and BNP are derived from the higher levels of NT-proBNP, we found that after treatment
same precursor protein, their concentrations in blood of their infarction, NT-proBNP decreased quickly whereas
are notynchronous. There are 3 possible mechanisms BNP increased slowly. Also, the relative deviation was
to explain these observations. First, damage to central close to the maintained ratio in patients with chronic heart
blood vessels promotes massive release of NT-proBNP failure (data not shown). Therefore, continuously monitoring
from the CNS to the blood, resulting in an absolute the NT-proBNP level in patients with acute cerebral
increase of NT-proBNP. Second, NT-proBNP and BNP infarction complicated with heart failure may be more
concentrations derived from the same precursor protein helpful in determining the correct diagnosis. The BNP level
increase simultaneously when cerebral infarction occurs; is not notably different between patients with stage I and II
acute cerebral infarction complicated with heart failure and 12. Arakawa N, Nakamura M, Aoki H, Hiramori K. Plasma brain
natriuretic peptide concentrations predict survival after acute
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less than those of NT-proBNP. Therefore, we propose that 13. Omland T, Asbjorn A, Bonarjee V, et al. Plasma brain natriuretic
BNP levels reflect the actual condition of heart failure in peptide as an indicator of left ventricular systolic function and
long-term survival after acute myocardial infarction. Circulation.
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1996;93:1963-1969.
failure better than levels of NT-proBNP. LM 14. De Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of
B-type natriuretic peptide in patients with acute coronary syndromes.
Xiuming Zhang and Weija Wang, as co-first authors, 15. Morrow D, Lemos J, Sabatine M, et al. Evaluation of B-type
natriuretic peptide for risk assessment in unstable Angina/Non-
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supported by Zhongshan Science Fund, No. 20102A018, prognosis in TACTICS-TIMI 18. J Am Coll Cardiol. 2003;41:1264-1272.
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the QR code, http://labmed. Puschendorf B, Mair J. Head-to-head comparison of N-terminal pro-
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