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Science

BNP and NT-proBNP Assays for Heart-Failure


Diagnosis in Patients With Cerebral Infarction

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Xiuming Zhang, PhD,1 Weijia Wang, MD,1* Yuanlong Yu, MD,1 Qian Wang, MD,2 Youye Yang, PhD,1
Dongmei Wen, MT,1 Fei Li, PhD,1 Nengliang Ouyang, MT,1 Lijuan Kan, MD,1 Minghuan Suo, PhD,1
Haizhong Yan, PhD1

ABSTRACT Results: Mean NT-proBNP and BNP concentrations in the patients


with acute cerebral infarction or heart failure were significantly higher
Objective: To determine whether BNP or NT-proBNP levels more than those of the controls (mean [SD] NT-proBNP levels, 1132.27
strongly indicate or predict cardiac diseases in patients with chronic [106.54] ng/L in patients with acute cerebral infarction and 3217.12
heart failure, cerebral infarction, cerebral hemorrhage, and acute [369.19] ng/L in patients with heart failure). However, the levels of
cerebral infarction complicated with heart failure. BNP and NT-proBNP were not statistically different between the
cerebral hemorrhage and control groups (P> .05).
Methods: A total of 303 patients aged 33 to 80 years with chronic
heart failure, acute cerebral infarction, cerebral hemorrhage, or acute Conclusions: Continuous monitoring of NT-proBNP levels in patients
cerebral infarction complicated with heart failure were consecutively with acute cerebral infarction complicated with heart failure may be
recruited in a university hospital. Their heart failure stages I to III more helpful in determining correct diagnoses. Also, because BNP
(equivalent to grades II to IV) were classified according to American levels vary much less than those of NT-proBNP, the former better
College of Cardiology Foundation/American Heart Association reflect the actual condition of heart failure in acute cerebral infarction
guidelines for adults. complicated with heart failure compared with the latter.
Keywords: NT-proBNP, BNP, cerebral infarction, heart failure

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

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Table 1. Demographic and Clinical Characteristics of the Patients and the Healthy Control

Heart Failure Stages

Groups Number Male/Female Age I II III GFR

Healthy control 60 28 (46.7%)/32 (53.3%) 57.14 ± 12.69 — — — >60ml/min


Chronic heart failure 100 46 (46%)/54 (54%) 58.26 ± 14.84 30 37 33 >60ml/min

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Acute cerebral infarction 65 33 (50.8%)/32 (49.2%) 60.52 ± 10.53 — — — >60ml/min
Cerebral hemorrhage 35 20 (57.1%)/15 (42.9%) 51.39 ± 9.78 — — — >60ml/min
Acute cerebral infarction 103 44 (42.7%)/59 (57.3%) 59.17 ± 18.33 31 37 35 >60ml/min
  complicated with heart failure

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

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A   
B
1,200
10,000 BNP
NT-proBNP
1,000
1,000

800
100

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(ng/L)

(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)

9,000 1,200 heart failure


heart failure

6,000 800

3,000 400

0 0
Normal Stage I Stage II Stage III Normal Stage I Stage II Stage III

Heart Failure Heart Failure


Figure 2
Concentrations of NT-proBNP (A) and brain natriuretic peptide (BNP) (B) among healthy patients and those with stages I, II, and II heart failure.

stage (P = 0.003). BNP levels, by contrast, were not


statistically different between stages I and II heart failure
Discussion
(P = .37 > .05) but was much higher in cerebral infarction NT-proBNP and BNP have been widely used in
complicated with stage III heart failure than in chronic the diagnosis, monitoring, and evaluation of heart-
heart failure at stage III (P <.001). These results are shown failure. Giannakoulas et al25 found that the NT-proBNP
in Figure 2. The NT-proBNP levels correlated strongly levels in patients who have had a stroke but did not
with BNP in chronic heart failure (P <.001; Figure 3, part have heart failure was significantly higher than in the
A) but not in acute cerebral infarction complicated with healthy population; they proposed that the NT-proBNP
heart failure (P = .41 > .05, depending on the patient; concentration was a general marker of ischemia. Eguchi
Figure 3, part B). et al26 also reported that the BNP levels were significantly

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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

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1,600 1,000

800 500

0 0
0 12,500 25,000 37,500 50,000 0 12,500 25,000 37,500 50,000

NT–proBNP (pg/ml) NT–proBNP (pg/ml)


Figure 3
Correlation of NT-proBNP with brain natriuretic peptide (BNP) in patients with chronic heart failure (A) (P <.001) and those with acute
cerebral infarction complicated by heart failure (B) (P = .41 and P >.05, depending on the patient).

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

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