Yonago Acta medica 1997;40:1–11

Release of Brain Natriuretic Peptide during the Perioperative Period of
Cardiac Surgery
Keisuke Morimoto, Shingo Ishiguro and Hiroaki Kuroda
Second Department of Surgery, Faculty of Medicine, Tottori University, Yonago 683, Japan
Brain natriuretic peptide (BNP) is well known as a cardiac hormone. To examine therelease of BNP in patients undergoing cardiac surgery with cardiopulmonary bypass
and to investigate the relationships between plasma BNP concentrations and various
clinical parameters, we measured the arterial plasma BNP level in 17 consecutive adultpatients during the perioperative period, and compared it with the level from anothercardiac hormone, atrial natriuretic peptide (ANP). The mean preoperative plasma
BNP level (baseline) was 63.8 ± 34.4 pg/mL (mean ± SD). A slight decrease in the mean
plasma BNP level was observed during cardiopulmonary bypass (CPB) surgery. Afterthe cessation of CPB, however, the mean plasma BNP level gradually increased, and asignificant increase was observed 12, 24 and 48 h after the cessation of CPB (mean ±SD; 149.5 ± 43.0 pg/mL, 175.2 ± 93.6 pg/mL and 146.2 ± 59.4 pg/mL, respectively; P < 0.01,
P < 0.01 and P < 0.01, respectively). The mean value 3 weeks after the operation was
similar to that before the operation. The plasma ANP levels did not significantly change
during the same time course. The plasma BNP as opposed to the ANP concentration 12
h after CPB significantly correlated with the cardiac index (r = –0.52, P < 0.05), current
injection rate of dopamine hydrochloride (r = 0.51, P < 0.05), aortic crossclamp time (r =0.55, P < 0.05) and peak postoperative serum creatine phosphokinase level (r = 0.82, P< 0.01). We conclude that plasma levels of BNP are markedly elevated in the acutephase after cardiac surgery requiring bypass and reflect the left ventricular function at
the same time. Furthermore, myocardial damage due to ischemia may participate in
the mechanism of synthesis and secretion of BNP.
Key words: atrial natriuretic peptide; brain natriuretic peptide; cardiac surgery; cardiopulmonary
bypass

The heart does not only play the role of a pump,
but also as an important endocrine organ that
secretes 2 natriuretic peptides. One of these
peptides is atrial natriuretic peptide (ANP),
which is primarily derived from the atrium(Arai et al., 1988; Ogawa et al., 1991). The
other is brain natriuretic peptide (BNP), which
was originally isolated from the porcine brain(Sudoh et al., 1988), and subsequently found in
the heart (Kambayashi et al., 1990). A higher
concentration of BNP is present in the heartrather than in the brain (Ogawa et al., 1990),
and BNP is known as a novel cardiac hormonethat is mainly synthesized in, and secreted from,the ventricle (Mukoyama et al., 1991). These 2
cardiac hormones perform biologic actions
including natriuresis, diuresis, vasorelaxationand inhibition of renin and aldosterone secretion (Nakao et al., 1992). Although the physiologic plasma level of BNP is lower than that of
ANP, it markedly increases along with theseverity of congestive heart failure (CHF) and

Abbreviations: ANP, atrial natriuretic peptide; AP; angina pectoris; AR, aortic valve regurgitation; AS, aortic valve
stenosis; ASD, atrial septal defect; AXCl, aortic crossclamp; BNP, brain natriuretic peptide; CHF, congestive heart
failure; CPB, cardiopulmonary bypass; CPK, creatine phosphokinase; LA, left atrial; MR, mitral valve
regurgitation; mRNA, messenger RNA; MS, mitral valve stenosis; TR, tricuspid valve regurgitation

1

K. Morimoto et al.

Table 1. Clinical variables and patient demographics
Patient Age Gender
No. (year)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17

42
73
51
58
52
69
58
76
63
66
52
52
60
59
51
54
73

Diagnosis

ProcedureTime (min)AXCl CPB

Male
FemaleMale
FemaleFemaleFemaleMale
FemaleFemaleMale
Male
FemaleFemale
Male
Male
Male
Female

MS
MVR
64
105
MS, atrial fibrillation
MVR
61
100
MS, atrial fibrillation
MVR
57
88
MR, TR
MVR, tricuspid annuloplasty
148
231
MR, atrial fibrillation
MVR, maze operation
151
217
MR
MVR
90
203
AP
Coronary artery bypass grafting
74
118
AS, AP
AVR, coronary artery bypass grafting
169
202
Ebstein’s anomaly
ASD repair, tricuspid annuloplasty
72
106
AR
AVR
75
110
AP
Coronary artery bypass grafting
111
197
ASD
ASD repair
30
48
AR
AVR
68
91
MR, atrial fibrillation
MVR, maze operation
117
216
AS
AVR
86
114
AP
Coronary artery bypass grafting
117
186
LA myxoma,
Resection
80
185
atrial fibrillation
AP, angina pectoris; AR, aortic valve regurgitation; AS, aortic valve stenosis; ASD, atrial septal defect; AVR, aortic
valve replacement; AXCl, aortic crossclamp; CPB, cardiopulmonary bypass; LA, left atrial; MR, mitral valve
regurgitation; MS, mitral valve stenosis; MVR, mitral valve replacement; TR, tricuspid valve regurgitation.

years (mean ± SD; 59.4 ± 9.5 years). The
preoperative diagnosis included mitral valve
regurgitation (MR) in 3 patients, mitral valve
stenosis (MS) in 3, angina pectoris (AP) in 3,
aortic valve regurgitation (AR) in 2, aortic
valve stenosis (AS) in 1, MR and tricuspid
valve regurgitation (TR) in 1, AS and AP in 1,
atrial septal defect (ASD) in 1, Ebstein’s anomaly in 1 and a left atrial (LA) myxoma in 1. The
surgical procedure and length of aortic crossclamp (AXCl) and CPB are summarized inTable 1. There were no patients with metabolic
diseases or primary lung diseases. Preoperative
routine biochemical examinations for liver andrenal function revealed no abnormalities in any
patients.
Intraoperative anesthetic management was
uniform for all patients, and the operation was
performed through median sternotomy. The
superior and inferior vena cava and ascending
aorta were cannulated separately to institute thebypass circuit. The circuit was primed with 800
mL of Ringer’s lactate solution, 1000 mL ofhydroxyethylated starch and 20% D-mannitol(4 mL/kg body weight). Mannitol also was

exceeds the plasma ANP concentration insevere cases (Mukoyama et al., 1990, 1991;
Yoshida et al., 1991). Previous studies haveshown changes in plasma ANP concentrations
associated with cardiac surgery (Greeley et al.,
1986; Hedner et al., 1986; Nicklas et al., 1986).
However, changes in plasma BNP in adultpatients undergoing cardiac surgery withcardiopulmonary bypass (CPB) have not been
identified. In this study, we investigated thechanges in plasma BNP during the perioperative period of cardiac surgery and the relationships between plasma BNP concentrations andvarious clinical parameters.

Subjects and Methods

Patients
After approval by the local ethics committee, 17
consecutive adult patients (8 males and 9 females) (Table 1) who were undergoing cardiac
surgery with CPB were prospectively selected
for the study. Their ages ranged from 42 to 76
2

Release of BNP in cardiac surgery

added to the circuit (2 mL/h/kg body weight)
during the CPB. Heparin (2.5 mg/kg bodyweight) was administered to maintain an activated clotting time of more than 400 s during
CPB. The CPB flow used during AXCl was
generated with a roller pump, motor control(model 6501) (PEMCO Inc., Cleveland, OH) ata pump flow rate of 2.2 L/min per square meterof body surface area. In addition to moderate
systemic hypothermia, a cold blood cardioplegic solution was administered continuously
via the aortic root or coronary sinus. Oxygenation was provided by a membrane oxygenatorin all cases. Protamine sulfate was administered at a ratio of 1:1 to the total heparin dose toneutralize the effects of heparin following termination of CPB.
Plasma electrolytes were maintained within
the normal range during the study. Serum
creatine phosphokinase (CPK) was measured
by an autoanalyzer immediately at the end of
the operation, and then 6, 12, 24, 36, 48 and 72
h after the operation by the autoanalyzer. After
weaning the patient from CPB, dopaminehydrochloride was administered as needed toachieve a systolic arterial pressure greater than
90 mmHg.

Kohden) and thermal array recorder (model
WS-180G) (Nihon Kohden). Cardiac output
was measured by the thermodilution method.
All hemodynamic measurements were done at
the following times: i) before the operation; ii)
30 min after AXCl (during CPB); iii) 1 h after;iv) 6 h after; v) 12 h after; vi) 24 h after and vii)
48 h after cessation of CPB; and viii) 3 weeks
after the operation. Other hemodynamic parameters were calculated using standard formulas. Preoperative left ventriculography was
performed to determine the left ventricular enddiastolic and end-systolic volumes and left
ventricular ejection fraction.

Blood sampling and measurements ofplasma BNP and ANP concentrations
At the same time as the hemodynamic measurements were taken, arterial blood samples formeasurements of plasma BNP concentration
were drawn from a peripheral artery. For
measurements of plasma ANP concentrations,peripheral arterial blood samples were drawn at
the following times: i) before the operation; ii)
30 min after AXCl (during CPB); iii) 12 h after
cessation of CPB and iv) 3 weeks after the operation. Furthermore, we examined plasma concentrations of BNP following the induction ofanesthesia and the systemic administration of
heparin and protamine sulfate in 5 of 17 patientsin this study. The plasma BNP concentrations
15 min after the induction of general anesthesia
and 5 min following the administration of
heparin and protamine were measured. The
samples were immediately placed into prechilled tubes containing EDTA sodium (5 mmol/L)and aprotinin (0.15 mmol/L), and centrifuged at
3000 rpm (4˚C) for 10 min. The plasma samples were then stored at –20˚C until assays
could be performed. Plasma concentrations of
ANP and BNP were determined using immunoradiometric assay kits, SHIONORIA ANP and
SHIONORIA BNP (Shionogi, Osaka, Japan).
Both kits include 2 kinds of monoclonal
antibodies. One monoclonal antibody, coatedon beads, recognizes the carboxyl terminus of
the natriuretic peptide. The other antibody,labeled with iodine 125, recognizes the ring

Hemodynamic measurements
Hemodynamic measurements included theheart rate, systemic arterial blood pressure,
central venous pressure, pulmonary arteryblood pressure, pulmonary capillary wedge
pressure and cardiac output. A balloon-tipped
thermodilution catheter, Swan-Ganz thermodilution catheter (model 93A-171H-7F or
746H-8F) (Baxter, Irvine, CA) was inserted via
the jugular vein or the femoral vein and was
positioned in the pulmonary artery, and acannula was placed in the radial artery or the
femoral artery. Heart rate was monitored
throughout the examination by standard electrocardiographic leads, and blood pressures were
measured by a transducer (model JH-180H)(Nihon Kohden, Tokyo, Japan), color memory
scope (model VM-185G) (Nihon Kohden), controller (model RMC-1200M) (Nihon Kohden),bedside monitor (model BSM-8500) (Nihon
3

K. Morimoto et al.

portion of the natriuretic peptide. One hundred
microliters of plasma were incubated with the 2
antibodies at 4˚C for 24 h. After washing,radioactivity in the beads was measured with a γ
scintillation counter. The recovery of BNP during extraction was 104% as assessed by calculating the recovery of known quantities ofstandard BNP added to plasma. The antibody
used in this study exhibited cross-reactivity of
100% with human BNP (4-32, 7-32, 10-32),
and did not cross-react with human BNP (1026) without the carboxyl terminus or human
BNP (27-32) without the ring portion. The
antibody did not cross-react with α- and βhuman ANP, human endothelin, human angiotensin I, vasopressin and human vasoactive
intestinal peptide. The intraassay and interassay coefficients of variation were 8.6 and
6.4%, respectively. The effect of hemodilution
during CPB on plasma BNP concentration wascorrected by the formula: corrected BNP concentration = measured BNP concentration
during CPB × (hematocrit before the operation/
hematocrit during CPB).

relations between natriuertic peptide concentrations and clinical or hemodynamic parameters were assessed by linear regression analysis. Significance was accepted at a P value lessthan 0.05.

Results
The total CPB time ranged from 48 to 231 min(mean: 148.1 ± 57.9 min) and the AXCl time
ranged from 30 to 169 min (mean: 92.4 ± 37.7
min). The minimum hematocrit during CPB
ranged from 18.0 to 24.2% (mean: 20.8 ±2.0%) and the minimum rectal temperature
ranged from 27.7 to 33.2˚C (mean: 29.2 ±1.4˚C). All patients recovered without incident
and had no significant postoperative complications.

Changes in BNP and ANP
The mean corrected preoperative plasma BNPlevel (baseline) was 63.8 ± 34.4 pg/mL. A
slight decrease in the mean plasma BNP and
ANP levels (Table 2, Fig. 1) was observed 30
min after AXCl during CPB. After the cessation of CPB, however, the mean plasma BNPlevel gradually increased, and a significant
increase (in the mean plasma BNP levels) was
observed 12, 24 and 48 h after the cessation of

Statistical analysis
Results were expressed as mean ± SD. Comparisons of plasma natriuretic peptide levels at
different times were performed by an analysis
of variance with Scheffe’s F correction. Cor-

Table 2. Perioperative changes in BNP and ANP levels
Plasma level corrected for hemodilution
BNP (pg/mL)
ANP (pg/mL)
Range Mean ± SD
Range
Mean ± SD

BNP/ANP ratio
Range
Mean ± SD

Before operation
15–14063.8 ± 34.4
15–28079.4 ± 85.1
0.2–2.3
1.2 ± 0.7
30 min after AXCl
4–270
55.8 ± 58.1
19–20352.2 ± 45.4
0.1–2.9
1.3 ± 0.7
1 h after CPB cessation
11–36579.4 ± 80.1
ND
ND
ND
ND
6 h after CPB cessation
36–20089.5 ± 42.8
ND
ND
ND
ND
12 h after CPB cessation 117–272 149.5 ± 43.0** 17–248
67.6 ± 63.5
0.5–11.3 4.1 ± 3.1**
24 h after CPB cessation
75–498 175.2 ± 93.6**
ND
ND
ND
ND
48 h after CPB cessation
65–263 146.2 ± 59.4**
ND
ND
ND
ND
3 weeks after operation
41–22083.5 ± 45.1
22–33
75.0 ± 78.3
0.6–3.5
1.3 ± 0.8
ANP, plasma level of atrial natriuretic peptide corrected for hemodilution;AXCl, aortic crossclamping;
BNP, plasma level of brain natriuretic peptide corrected for hemodilution; CPB, cardiopulmonary bypass;
ND, not determined.
**P < 0.01 versus preoperative value.

4

Release of BNP in cardiac surgery(pg/mL)A

Plasma BNP level

300

**

250

**

**

200

a: before operationb: 30 min after aortic crossclamp
c: 1 h after cessation of CPB
d: 6 h after cessation of CPB
e: 12 h after cessation of CPB
f: 24 h after cessation of CPB
g: 48 h after cessation of CPB
h: 3 weeks after operation

150

100
50

0

a

c

d

e

B

f

g

h

C

8

**

150

BNP/ANP ratio

Plasma ANP level(pg/mL)

b

100

50

0

6

Fig. 1. Changes in plasma levels of (A)BNP, (B) ANP and (C) BNP/ANP ratio
during the perioperative period in 17
patients undergoing CPB. Results are
expressed as mean ± SD. **P < 0.01
versus preoperative value.

4

2

0

a

b

e

h

a

b

e

CPB (149.5 ± 43.0 pg/mL, 175.2 ± 93.6 pg/mL
and 146.2 ± 59.4 pg/mL; P < 0.01, P < 0.01 and
P < 0.01, respectively). The mean value 3
weeks after the operation was similar to that
before the operation. The corrected preoperative plasma level of ANP was 79.4 ± 85.1 pg/
mL and there were no significant changes in themean plasma ANP levels 12 h after CPB or 3
weeks after the operation. The mean preoperative BNP/ANP ratio was 1.2 ± 0.7 and did not
significantly change during CPB. However, themean ratio 12 h after the cessation of CPB (4.1
± 3.1) was significantly higher than the mean
preoperative ratio (P < 0.01). The mean ratio 3
weeks after the operation was not significantly
above the mean preoperative ratio. Thesechanges in the BNP/ANP ratio were similar to
those in the BNP level.
Furthermore, we examined the plasma
levels of BNP following the induction of anesthesia and the systemic administration of
heparin and protamine sulfate in 5 of the 17
patients in this study. The corrected plasmah

BNP level 15 min after the induction of generalanesthesia ranged from 13 to 58 pg/mL (mean:
45.3 ± 23.7 pg/mL), and did not significantly
change (as opposed to the preoperative level).
The plasma BNP levels 5 min after the administration of heparin and protamine were 11 to 58
pg/mL (mean: 39.2 ± 17.6 pg/mL) and 13 to 66
pg/mL (mean: 33.4 ± 24.2 pg/mL), respectively, and did not significantly differ from thelevels 15 min after the induction of anesthesia
or 30 min after AXCl (during CPB), respectively.

Correlations between plasma natriuretic
peptide concentrations and hemodynamic or clinical data
Preoperatively, the plasma BNP concentration
correlated significantly with the left ventricularejection fraction (r = –0.727; P = 0.017); however, there was no significant correlation
between the plasma BNP concentration or any
other hemodynamic parameter assessed (Table3). The preoperative plasma ANP concen5

K. Morimoto et al.

Table 3. Correlations between plasma natriuretic peptide concentrations and preoperative
hemodynamic parameters
Hemodynamic parameter

BNP

Variable

Value

Heart rate
(beats/min)
70 ± 13
Mean systemic arterial pressure(mmHg)
93 ± 21
Central venous pressure(mmHg)
6 ±4
Mean pulmonary arterial pressure(mmHg)
23 ± 12
Pulmonary capillary wedge pressure(mmHg)
13 ± 7
Left ventricular end-diastolic pressure(mmHg)
14 ± 8
Cardiac index(L/min/m 2)
2.8± 0.4
Stroke volume index(mL/m 2)46 ± 21
Systemic vascular resistance(dyne •s/cm 5) 1730 ± 590
Pulmonary vascular resistance(dyne•s/cm 5) 168 ± 128
Left ventricular end-systolic volume index (mL)
31 ± 16
Left ventricular end-diastolic volume index (mL)
78 ± 39
Left ventricular ejection fraction(%)
60 ± 13
ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide.
All values are expressed as mean ± SD.
* P < 0.05.

tration correlated significantly with cardiac
index (r = –0.606; P = 0.013), but did not
significantly correlate with other parameters(Table 3).

ANP

r

P

r

P

0.064
0.165
0.179
0.041
0.143
–0.154–0.1250.077
0.074–0.0270.596
0.258–0.727

0.808
0.540
0.507
0.877
0.596
0.634
0.646
0.777
0.803
0.928
0.069
0.472
0.017*

0.150
0.037
0.165
0.386
0.362
0.064
–0.606–0.2460.449
0.015–0.021–0.262–0.468

0.566
0.893
0.541
0.126
0.168
0.843
0.013*
0.359
0.107
0.959
0.954
0.464
0.172

The plasma BNP concentration 12 h after
the cessation of CPB correlated significantlywith the cardiac index at this time (r = –0.520; P= 0.032), the injection rate of dopamine hydro-

Table 4. Correlations between plasma natriuretic peptide concentrations and hemodynamic
or clinical data 12 h after cessation of CPB
Hemodynamic or clinical data
Variable
Value

BNP
r

ANP
P

r

P

Heart rate
(beats/min)
92 ± 10–0.4190.106–0.222
0.428
Mean systemic arterial pressure(mmHg)
77 ± 13–0.3970.128–0.450
0.092
Central venous pressure(mmHg)
11 ± 3–0.3150.235–0.1480.599
Mean pulmonary artery pressure(mmHg)
21 ± 5–0.146
0.589
0.336
0.222
Pulmonary capillary wedge pressure (mmHg)
11 ± 4
0.053
0.845
0.370
0.175
Cardiac index(L/min/m2 )3.0± 0.9–0.5200.032*
0.017
0.949
Stroke volume index(mL/m2 )33 ± 9–0.325
0.219
0.004
0.988
Systemic vascular resistance(dynes• s/cm5 ) 1330 ± 656
0.397
0.128
0.044
0.876
Pulmonary vascular resistance (dynes• s/cm5 )195 ± 89
0.204
0.449
0.192
0.494
Injection rate of DA(µg/min/kg)
5.6± 1.8
0.510
0.036*
0.412
0.113
AXCl time(min)
92 ± 38
0.547
0.023* –0.106
0.696
Cardiopulmonary bypass time(min)
148 ± 58
0.204
0.432
–0.2770.300
Operation time(min)
423 ± 109
0.223
0.390
0.067
0.805
Bleeding volume during operation(mL)
924 ± 604
0.061
0.817
0.121
0.655
Peak CPK concentration(mg/dL) 1035 ± 756
0.824 < 0.0001** 0.477
0.062
ANP, atrial natriuretic peptide; AXCl, aortic crossclamp; BNP, brain natriuretic peptide; CPK, creatine
phosphokinase; DA, dopamine hydrochloride.
All values are expressed as mean ± SD.
* P < 0.05.
** P < 0.01.

6

Release of BNP in cardiac surgery

chloride at this time (r = 0.510; P = 0.036), the
AXCl time (r = 0.547; P = 0.023), and the peak
postoperative serum creatine phosphokinase(CPK) level (r = 0.824; P < 0.0001) (Table 4,
Fig. 2). However, there was no significant correlation between the plasma ANP concentrationr = –0.520
P < 0.05(pg/mL)J

r = 0.017
NSJ(pg/mL)

200

ANP

150

BNP

A

or any of these parameters (Table 4, Fig. 2).
The plasma BNP concentration 12 h after CPB
also correlated significantly with the preoperative plasma BNP concentration (r = 0.563; P =0.019) (Fig. 3).

J
J

150

J

J

J
J
50

J

J J
J

J

J
J

2

4

5
(L/min/m2 )

1

3

2

B

(pg/mL)J

5(L/min/m2)

r = 0.412
NS

J

ANP

BNP

150

J
J

J

150

J

J
J
J

100

J

J

J
J J

J J
J
J
J
J
J

J

J
J

0

4

2

J
J

50

J
J
J J J
J

J

100

6

8

10
(µg/min/kg)

Injection rate of DA

2

4

6

8

10
(µg/min/kg)

Injection rate of DA(pg/mL)(pg/mL)r = 0.547
P < 0.05

200

J

r = –0.106
NS

J

ANP

150

BNP

C

4

Cardiac index

r = 0.510
P < 0.05

200

J

J

0

3

Cardiac index(pg/mL)

J J
J

J
J

J

J JJ

100
1

J
100

J
J
J
J

J

J

J
J

150

J
J
100

J

J J

J
50

JJ
J J

J

JJ
J

JJ

J

J

100

J

J

J

J
J
JJ

J
J

JJ

0
50

100

50

150

150

100

(min)

(min)

AXCl time(pg/mL)(pg/mL)r = 0.824
P < 0.0001

200J

r = 0.477
NS

J

ANP

150

BNP

D

AXCl time

J
J

J
J

100

150

J
J
J
JJ
J
J
J J
JJ J
J

J
J
J JJ
J J
J
JJ J J
J J

J

100
0

1000

50

0
2000

Peak CPK

3000

4000

0

(pg/mL)

1000

2000

Peak CPK

3000

4000
(pg/mL)

Fig. 2. Correlations between the plasma natriuretic peptide concentration at 12 post-CPB h and (A) the
cardiac index (L/min/m 2) at this time; (B) the injection rate of dopamine hydrochloride (DA) at this time (µg/min/kg); (C) the aortic crossclamp (AXCl) time (min) and (D) the peak creatine phosphokinase (CPK)
concentration (mg/dL). NS, not significant.

7

K. Morimoto et al.

of CPB alters ANP levels. Others have shownthat there is a specific influence of temperature
on ANP release, and that a reduction in temperature produces a marked decrease in ANP
release in vitro (Bilder et al., 1986). In ourstudy, the nonsignificant change in BNP and
ANP levels during CPB may be due in part to a
reduction in both synthesis-secretion and theclearance of these 2 natriuretic peptides becauseof cooling of the heart, cardiac arrest and generalized hypothermia during CPB. In addition, it
has been reported that anesthesia has no significant effects on plasma ANP levels during
CPB (Curello et al., 1991). In the present study,
we also found that general anesthesia did not
significantly affect plasma BNP levels. Furthermore, the peptide level during CPB was notchanged by intraoperative surgical stress. It is
possible that the suitable control of hemodynamics by anesthesia and use of vasoactive
drugs may indirectly affect hormone levels,
although systemic heparinization with subsequent neutralization did not significantly change
plasma BNP levels in this study. Kharasch andcoworkers (1989) have reported that systemic
heparinization prior to CPB and neutralizationof heparin following CPB also does not affectcirculating ANP levels. In the present study,
the plasma BNP levels expressed reflect a correction for hemodilution. Thus, we think thatsystemic heparinization and neutralization of
heparin in cardiac surgery with CPB do notmarkedly affect the release of BNP.
The present study revealed that the plasma
levels of BNP were significantly elevated 12,24, and 48 h after the cessation of CPB, but thatthe plasma levels of ANP did not show any significant change. This difference in characteristic between BNP and ANP may have been
produced by the differences in the mechanismsof synthesis and secretion or the difference inproduction between the 2 natriuretic peptides.
For example, it has been reported that BNP
messenger RNA (mRNA) is degraded more
rapidly than ANP mRNA, and that BNP gene
expression is regulated differently from ANP
gene expression, while BNP gene expression
may be turned on and off more rapidly than
ANP gene expression (Nakao et al., 1992). In(pg/mL)r = 0.563
P < 0.05

BNP 12 h after CPB

220

J

200
180
J
160

J

140

J
JJ

120

J
J

J

J

JJ

J

100
0

20

J

J
J
J

40

60

80

100

120

BNP before operation

140

160
(pg/mL)

Fig. 3. Correlation of plasma BNP concentration
between 12 h after CPB and before the operation.

Discussion
Preoperatively, plasma BNP and ANP concentrations negatively correlated significantly withthe left ventricular ejection fraction and cardiac
index, respectively. These results indicate thatplasma BNP and ANP concentrations reflect
cardiac function, and are consistent with findings in previous reports (Yoshimura et al., 1993;
Yasue et al., 1994; Kohno et al., 1995; Matsumoto
et al., 1995).
In vitro and in vivo, BNP and ANP are rapidly
synthesized in, and secreted from, cardiac myocytes by acute stimulation, such as volume expansion (Wambach and Koch, 1995), atrial
stretch (Bilder et al., 1986), vasoactive agents(Hu et al., 1988; Suzuki et al., 1992), cardiac
pacing (Naruse et al., 1994), percutaneous
balloon mitral valvuloplasty (Waldman et al.,1988) and exercise (Tanaka et al., 1986). These
2 hormones disappear rapidly from plasma
because of their short half lives (Nakao et al.,
1987; McGregor et al., 1990; Yoshimura et al.,
1991; Kohno et al., 1992; Hashimoto et al.,1994). Therefore, plasma levels of BNP and
ANP can be influenced by some stimuli. In thisstudy, a slight decrease in the mean plasma
BNP and ANP levels was observed 30 min after
AXCl (during CPB). Flezzani and coworkers(1988) have reported that CPB does not appear
to have an appreciable effect on ANP levels,and mentioned that neither hemodilution nor
unloading of the atria caused by the institution
8

Release of BNP in cardiac surgery

addition, BNP is secreted predominantly fromthe ventricle in contrast to ANP, which is mainly derived from the atrium.
In this study, furthermore, the plasma BNP
as opposed to the ANP concentration 12 h after
the cessation of CPB correlated significantlywith the cardiac index and injection rate of
dopamine hydrochloride. We used the cardiac
index and injection rate of dopamine hydrochloride as indices of postoperative cardiac
function, that is, we considered a low cardiac
index and a high injection rate of dopaminehydrochloride as indicating a state of heart
failure. These findings indicate that the plasma
level of BNP is markedly elevated in the acutephase after open heart surgery performed with
CPB, which reflects the left ventricular function
more appropriately than does the ANP concentration. In previous studies, it has been documented that the plasma BNP concentration
markedly increases along with the severity of
CHF, exceeding the plasma ANP concentrationin severe cases (Mukoyama et al., 1990, 1991;
Yoshida et al., 1993; Matsumoto et al., 1995).
We suggest that the measurement of plasma
BNP concentration is valuable for the estimation of postoperative cardiac functions in patients treated with open heart surgery.
It was also demonstrated that plasma ANP
concentrations correlate with atrial pressures(Bates et al., 1986; Raine et al., 1986; Richards
et al., 1986; Rodeheffer et al., 1986; Hirata etal., 1987), and that the most significant physiologic stimulus for the secretion of ANP is theatrial stretch (Dietz, 1984; Lang et al., 1985).
Concerning BNP, it was reported that the plasma
concentration is elevated in patients with hypertension, ventricular hypertrophy (Kohno et al.,
1994, 1995), CHF (Yoshimura et al., 1993;
Yasue et al., 1994; Matsumoto et al., 1995) andvarious cardiovascular diseases (Richards et al.,
1993; Naruse et al., 1994). Very recently, it has
been reported that exercise-induced increases in
BNP and ANP are observed in patients withCHF (Matsumoto et al., 1995). Previous reports have shown that the plasma BNP level ismore prominently elevated than the ANP levelin patients with acute myocardial infarction(Mukoyama et al., 1991). This raises the possi-

bility that the synthesis and secretion of BNP
could be stimulated by myocardial necrosis
and/or local mechanical stress on ventricularcardiomyocytes. Current studies reveal that theplasma BNP and not the ANP level is significantly elevated in the acute phase after cardiac
surgery undergoing CPB, and that the elevated
BNP concentration correlates significantly with
the AXCl time and peak postoperative CPKlevel. The elevated BNP concentration did not
significantly correlate with other parameters,such as duration of the CPB, duration of theoperation, and bleeding volume during the operation. It is also well-known that the duration of
AXCl and peak CPK level following cardiac
surgery are indices of myocardial damage due
to ischemia in patients treated with cardiac
surgery. In the present study, there were nopatients suffering from perioperative myocardial infarction. These facts suggest that BNP
may be synthesized and secreted by the stimulus of myocardial damage due to ischemia
during AXCl.
As mentioned above, the plasma BNP levelreflects left ventricular dysfunction. In thepresent study, the plasma BNP concentration in
the acute postoperative phase correlates withthe preoperative plasma BNP concentration.
This finding suggests that the severity of heart
failure in the acute phase after cardiac surgery
can be predicted by the preoperative plasma
BNP concentration. Preoperative high plasma
BNP concentration may be a risk factor for
open heart surgery. A more definite conclusion
about the estimation of prognosis after cardiac
surgery will require further studies.
In conclusion, the present study has revealed that the plasma BNP level is markedly elevatedin the acute phase following open heart surgery
with CPB in adults, and that plasma BNP concentrations reflect current left ventricularfunctioning more appropriately than ANP concentrations. We hypothesize that injury of cardiomyocytes due to ischemia may participate inmechanisms of the synthesis and secretion of
BNP.

9K. Morimoto et al.

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Acknowledgments: The authors wish to express theirsincere gratitude to Prof. Toru Mori, Second Dept. ofSurgery, Faculty of Medicine, Tottori Univ., for his
helpful suggestions and reading of the manuscript,
and would like to thank very much Prof. Nobuaki
Kaibara, First Dept. of Surgery, Faculty of Medicine, Tottori Univ. and Prof. Chiaki Shigemasa, First
Dept. of Internal Medicine, Faculty of Medicine,
Tottori Univ., for many helpful discussions. We also
thank Dr. Akihiko Suyama, Dept. of Hygiene, Faculty of Medicine, Tottori Univ., for advice in statisticalanalysis.
The abstract of this paper was presented at the26th Annual Meeting of the Japanese Society for
Cardiovascular Surgery held in 1996.
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