J C E M
O N L I N E
Hot Topics in Translational Endocrinology—Endocrine Research
Paradoxical Clearance of Natriuretic Peptide between
Pulmonary and Systemic Circulation: A Pulmonary
Mechanism of Maintaining Natriuretic Peptide Plasma
Concentration in Obese Individuals
Taro Date, Teiichi Yamane, Seigo Yamashita, Seiichiro Matsuo,
Masato Matsushima, Keiichi Inada, Ikuo Taniguchi, and Michihiro Yoshimura
Division of Cardiology, Department of Internal Medicine (T.D., T.Y., S.Y., S.M., K.I., I.T., M.Y.), and
Division of Clinical Epidemiology (M.M.), The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi,
Minato-ku, Tokyo 105-8461, Japan
Context: Although it has been reported that obese patients have low levels of natriuretic peptide,
the metabolism of natriuretic peptide in this population remains unclear.
Objectives: This study aimed to examine the effects of body mass index on the natriuretic peptide
clearance rate from the pulmonary and systemic circulation.
Design: We conducted a prospective observational cohort study.
Setting/Patients: Thirty patients with atrial fibrillation undergoing pulmonary vein isolation in
single center participated in the study.
Main Outcomes and Measures: We measured pulmonary and systemic atrial/brain natriuretic
peptide clearance and clinical parameters including body mass index and pulmonary oxygen levels.
Results: Significantly lower atrial natriuretic peptide levels were found in all pulmonary veins when
compared with the pulmonary artery. The pulmonary atrial natriuretic peptide clearance rate was
negatively correlated with body mass index. In contrast, the systemic atrial natriuretic peptide
clearance rate was positively correlated with the body mass index. A reciprocal relationship therefore exists between pulmonary and systemic atrial natriuretic peptide clearance. Regional pulmonary atrial natriuretic peptide clearances in the inferior lung were significantly negatively correlated to oxygen pressure in the inferior pulmonary veins. There was a similar tendency for brain
natriuretic peptide, but the differences between the pulmonary artery and each pulmonary vein
were not significant.
Conclusions: Overweight patients have higher systemic atrial natriuretic peptide clearance,
whereas they show a lower pulmonary atrial natriuretic peptide clearance, which might be related
to pulmonary tissue hypoxia. (J Clin Endocrinol Metab 97: E14 –E21, 2012)
A
-type or atrial natriuretic peptide (ANP) and B-type or
brain natriuretic peptide (BNP) have a wide range of
biological effects, including vasodilation, natriuretic action, inhibition of the renin-angiotension-aldosterone system, and inhibition of the sympathetic nervous system
(1– 4). It has recently been reported that obese subjects
have low circulating natriuretic peptide (NP) levels (5– 8).
Obesity is an underlying risk factor for hypertension and
other cardiovascular diseases (9), and therefore elucidating the NP metabolism is especially important in obese
subjects. There are two possible explanations for the low
NP levels in obese individuals: increased NP clearance,
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/jc.2011-2090 Received July 21, 2011. Accepted October 7, 2011.
First Published Online November 2, 2011
Abbreviations: AF, Atrial fibrillation; ANP, atrial NP; BMI, body mass index; BNP, brain NP;
FEV1.0%, forced expiratory volume in 1 sec; NP, natriuretic peptide; NPR, NP receptor;
PCO2, carbon dioxide pressure; PO2, oxygen pressure; PV, pulmonary vein.
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jcem.endojournals.org
J Clin Endocrinol Metab, January 2012, 97(1):E14 –E21
J Clin Endocrinol Metab, January 2012, 97(1):E14 –E21
and diminished myocardial NP release. The reason for low
NP levels in obese subjects, however, has not been elucidated. In this study, we determined the NP clearance from
the systemic and pulmonary circulation in humans and
examined the effects of body mass index (BMI) on the NP
clearance from each.
Patients and Methods
Patients
This study included 30 patients with atrial fibrillation (AF; 27
males and three females; mean age, 54 yr; AF type, 15 paroxysmal, 15 persistent) who underwent catheter ablation. All patients
were informed of the nature of catheter ablation and its possible
complications and gave their informed consent to participate in
the study protocol, which was approved by the Human Research
Committee at this institution. Two-dimensional echocardiography was performed in all patients in the left lateral decubitus
position, using an ultrasonic device equipped with a 2.5-MHz
transducer. The left ventricular diastolic and systolic dimensions
were measured in the parasternal long-axis view according to the
standard recommendations (10). Clinical parameters including
BMI (kilograms per square meter) were also examined.
Blood sampling before the electrophysiological
study
An electrophysiological study was performed as described
previously (11). The left atrium and pulmonary vein (PV) were
explored through either a patent foramen ovale or transseptal
catheterization with two catheters: one for circumferential PV
mapping, the other a quadripolar mapping/ablation catheter.
Before blood sampling from each patient, direct visualization of
all four PV was performed using selective venography, which
was performed during midexpiration by hand injection of contrast media in biplane views. The findings were displayed during
the procedure to show the venous anatomy and the location of
the left atrium-PV junction. After the venography was performed, a 5F NIH catheter was placed in the main trunk of the
pulmonary artery, the femoral vein, the left superior PV, the left
inferior PV, the right superior PV, the right inferior PV, the middle of left atrium, or the coronary sinus via either a subclavian or
femoral vein. Blood was sampled within 2 min at each location
before delivering any radiofrequency application in either sinus
rhythm (n ⫽ 13) or AF (n ⫽ 17). Arterial blood was also obtained
from a femoral artery. The blood samples of PV were obtained
from deep inside each PV to avoid contamination with the atrial
blood, as described previously (12). The oxygen pressure (PO2)
and carbon dioxide pressure (PCO2) values were measured
within approximately 10 min of their sampling by a blood gas
analyzer (ABL715; Radiometer, Copenhagen, Denmark). Twopoint and one-point calibrations were set up every 8 and 4 h,
respectively. Neither sedative-hypnotic agents nor oxygen was
given to the patients before taking all of the blood samples. None
of the studied subjects received any oxygen before or during the
blood sampling. Catheter intervention for AF was performed
after the blood sampling without cardioversion for AF.
jcem.endojournals.org
E15
Natriuretic hormone analysis
Blood samples were taken into plastic syringes and transferred to chilled siliconized disposable tubes with EDTA (1 mg/
ml), then immediately placed on ice and centrifuged at 4 C.
Plasma was extracted, aliquoted, and stored at ⫺80 C until analysis. The plasma ANP and BNP concentrations were measured
using a chemiluminescent enzyme immunoassay specific for each
human NP using a commercial kit (MI02 Shionogi ANP and
BNP; Shionogi Pharmaceutical Co., Tokyo, Japan), as we previously described (13). The mean interassay variance for determination of ANP and BNP was 4.5% (range, 4.1–5.3% for
plasma samples with a concentration of 30.8 to 434.8 pg/ml) and
8.2% (range, 5.6 –11.8% for plasma samples with a concentration of 23.3 to 759.4 pg/ml), respectively. The pulmonary and
systemic NP clearance rates were defined as (NPPA ⫺ NPLA)/
NPPA and (NPFA ⫺ NPFV)/NPFA, (where PA, LA, FA, and FV
represent pulmonary artery, left atrium, femoral artery, and femoral vein) respectively, as previously described, with some modifications (14). Each regional pulmonary ANP clearance was also
defined as (ANPPA ⫺ ANPPV)/ANPPA. The total body ANP clearance was defined as (ANPPA ⫺ ANPFV)/ANPPA.
Ventilation function test
Ventilation function tests (spirometry, CHESTAC-9800;
Chest Co., Tokyo, Japan) were performed in 12 of 30 patients
within a few days after the ablation procedure. The value of
forced expiratory volume in 1 sec (FEV1.0%) represents the ratio
of the measured FEV1.0 value/vital capacity. The reference value
(predicted value) of the vital capacity, corrected for height, sex,
and age, was calculated using Baldwin’s equation.
Statistical analysis
Quantitative data are expressed as means ⫾ SEM. The differences between 1) the BNP levels in the pulmonary artery and each
PV, and 2) the BNP level in the femoral vein and those in the
femoral artery, the coronary sinus, the pulmonary artery, and the
left atrium were tested with Wilcoxon’s signed-ranks test. A P
value ⬍ 0.0125 was considered significant after Bonferroni correction for multiple tests. The differences between pulmonary
regional ANP clearances were tested by paired Student’s t test,
and a P value ⬍ 0.05 was considered to be significant for it.
Pearson (linear) correlation tests were used for correlation analysis. A P value ⬍ 0.05 was considered to be significant for correlation analysis. A multiple linear regression analysis was used
to determine factors independently associated with the dependent variables (ANP clearance of inferior PV). Statistical analyses
were performed with the use of a statistical software program
(SPSS for Windows version 11.5; SPSS, Inc., Chicago, IL).
Results
Patient characteristics
The studied subjects included nine patients with hypertension and one patient with coronary spastic angina. The
mean left ventricular ejection fraction was 63.6%, and
none of the subjects had a less than 55% left ventricular
ejection fraction. The mean left atrial dimension was 38.2
mm. The mean BMI was 24.5 (19.2–29.8) kg/m2. Twelve
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Date et al.
Natriuretic Peptide and Lungs
J Clin Endocrinol Metab, January 2012, 97(1):E14 –E21
TABLE 1. Plasma ANP and BNP levels in the femoral
vein, coronary sinus, pulmonary artery, left atrium, and
femoral artery in the study subjects (n ⫽ 30)
Femoral vein
Coronary sinus
Pulmonary artery
Left atrium
Femoral artery
ANP (pg/ml)
61.1 ⫾ 6.0
901.1 ⫾ 197.1a
153.3 ⫾ 18.5a
133.6 ⫾ 17.3a
101.8 ⫾ 12.8a
a
P ⬍ 0.005 vs. femoral vein.
b
P ⫽ 0.03 vs. femoral vein.
BNP (pg/ml)
79.6 ⫾ 10.8
237.1 ⫾ 36.5a
84.0 ⫾ 11.1b
92.2 ⫾ 12.4a
90.8 ⫾ 12.1a
patients were treated with a ␤-blocker for rate control or
hypertension and two patients with an angiotensin II receptor blocker for hypertension. All drugs were withdrawn for 24 h before the ablation procedure.
Pulmonary and systemic ANP clearance
Table 1 shows that the ANP in the pulmonary artery
was significantly increased compared with the femoral
vein because of cardiac secretion of ANP, as indicated by
the higher levels of ANP in the coronary sinus (901.1 ⫾
197.1 pg/ml). In contrast, the BNP levels in pulmonary
artery were not significantly different from the femoral
vein, although higher levels of BNP were noted in the coronary sinus (237.1 ⫾ 36.5 pg/ml). An analysis of the overall pulmonary ANP clearance rate, which was obtained by
the difference in ANP levels between the pulmonary artery
and left atrium, demonstrated a significant negative correlation between pulmonary clearance and the BMI (Fig.
1A). We also examined the effect of BMI on the systemic
ANP clearance, which was represented by that in the lower
extremity calculated by the difference in ANP between the
femoral artery and the femoral vein. There was a positive
correlation between the systemic ANP clearance and the
BMI (Fig. 1B, P ⬍ 0.05). No significant relationship between total body ANP clearance and the BMI was observed (P ⫽ 0.427; R ⫽ ⫺0.151). Importantly, a reciprocal
relationship was noted between the pulmonary and systemic ANP clearance (Fig. 1C). Taken together, these data
indicate that the reduced ANP levels due to accelerated
systemic clearance were accompanied by decreased pulmonary ANP clearance in overweight or obese subjects.
Regional pulmonary ANP clearance, obesity, and
pulmonary hypoxia
We next compared the NP in each PV and pulmonary
artery to examine the relative contribution of pulmonary
natriuretic clearance. There were no significant differences in the BNP levels between the pulmonary artery and
each PV (mean value, 70.9 ⫾ 10.9, 80.1 ⫾ 10.3, 75.0 ⫾
11.4, and 82.5 ⫾ 10.7 pg/ml in the left superior, left inferior, right superior, and right inferior PV, respectively;
FIG. 1. Correlation between the systemic ANP clearance, the
pulmonary ANP clearance rate and the BMI (kg/m2) (n ⫽ 30). A, A
significant relationship between the pulmonary ANP clearance rate and
the BMI was observed (P ⫽ 0.008). B, A significant relationship
between the systemic ANP clearance rate and the BMI was noted (P ⫽
0.047). C, Correlation between the pulmonary and systemic ANP
clearance rates. A significant relationship was observed between the
rates (P ⫽ 0.019).
P ⫽ not significant vs. BNP level in pulmonary artery),
although approximately average 13 and 7% pulmonary
BNP clearance was observed in left superior and right inferior PV, respectively. In contrast, significantly lower
ANP levels were noted in all four PV when compared with
that in the pulmonary artery (P ⬍ 0.001; Fig. 2, A and B).
The ANP level in the left atrium was significantly higher
than that in each PV (P ⬍ 0.05). The regional pulmonary
ANP clearance rate was significantly higher in the left and
right superior PV compared with that in the left or right
inferior PV, respectively (Fig. 2C; P ⬍ 0.05).
J Clin Endocrinol Metab, January 2012, 97(1):E14 –E21
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independently correlated with the regional ANP clearance in the inferior
lungs (n ⫽ 46 inferior PV).
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from the inferior lungs. Finally, the pulFIG. 2. Simultaneous plasma ANP and BNP levels in the pulmonary artery and veins, and the
monary ANP clearance was recipropulmonary regional ANP clearance. Plasma ANP (A) and BNP (B) levels in the pulmonary artery
cally correlated with the systemic ANP
and veins (n ⫽ 30). *, P ⬍ 0.001 vs. PA. C, The pulmonary ANP clearance rate in the superior
clearance.
and inferior lung regions (n ⫽ 30). †, P ⬍ 0.05. Averaged data are presented as the mean ⫹
It has been known that obese paSEM. PA, Pulmonary artery; LS, left superior PV; LI, left inferior PV; RS, right superior PV; RI,
right inferior PV.
tients have low NP levels and also have
an impaired NP response (5), thus sugWe next examined the relationship between the re- gesting that the NP system, counter-regulators of sodium
gional pulmonary clearance of ANP and the clinical pa- retention and neurohormonal activation, might be imrameters. There was no significant relationship between paired in obese patients. These findings indicated that the
age, sex, the presence of hypertension, echocardiographic BNP-guided diagnostic strategy for cardiovascular disparameters, the parameters of ventilation function tests eases was also affected by BMI (15). The mechanism un(tidal volume, FEV1.0%, %vital capacity), renal function, derlying this phenomenon has not been described, aland pulmonary clearance of ANP. Interestingly, the rethough there are two hypotheses for the low ANP levels in
gional pulmonary ANP clearance rate was also negatively
obese individuals, including increased systemic ANP
correlated with the BMI value in the inferior lung regions,
clearance and diminished myocardial hormone release.
but not in superior lung regions (Fig. 3). In the blood gas
The present study demonstrated, for the first time, that
analysis, the PO2 was significantly higher in the superior
systemic ANP clearance is positively correlated with the
PV than in the inferior PV (mean value, 88.7 ⫾ 2.7, 66.4 ⫾
BMI. Investigations of the effects of BMI on NP produc3.3, 91.8 ⫾ 2.0, and 77.0 ⫾ 2.8 mm Hg in the left superior,
tion or release are also of interest. A recent experimental
left inferior, right superior, and right inferior PV, respectively; P ⬍ 0.01). In addition, PO2 values of less than 60 study demonstrated that lipid accumulation in obese mice
mm Hg were observed in 12 PV in 11 cases, all of which was associated with decreased NP production (16). Nevwere identified in the inferior PV. As we reported previ- ertheless, because both paroxysmal and persistent AF paously (12), there is an inverse relationship between the tients were included in this study and ongoing AF rhythm
BMI and PO2 in the inferior PV (P ⫽ 0.004; R ⫽ ⫺0.420). is a powerful factor for stimulating ANP release, it was not
The regional pulmonary clearance of ANP in the inferior possible to analyze the relationship between myocardial
lung regions was strongly correlated to PO2 in each PV NP release and BMI in this study.
Several studies, including ours, have reported that immu(Fig. 4; P ⬍ 0.001). In contrast, no significant relationship
noreactive
ANP concentrations decreased across the lung,
was noted between the regional ANP clearance and oxygenation levels in the superior PV. Finally, a multiple lin- suggesting the metabolic clearance of ANP in the pulmonary
ear regression analysis demonstrated that the PO2 in the circulation (17–20). On the other hand, the BNP concentrainferior PV (coefficient, 0.008; P ⫽ 0.007; 95% confi- tion was not significantly changed across the pulmonary
dence interval, 0.003 to 0.014) but not the BMI (coeffi- circulation in this study, although there was a tendency for
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FIG. 3. Relation between the pulmonary regional ANP clearance rate and the BMI. Correlation between the pulmonary regional ANP clearance
rate and the BMI (kg/m2) in right superior lung (A), left superior lung (B), right and left superior lungs (C), right inferior lung (D), left inferior lung
(E), and right and left inferior lungs (F) (n ⫽ 30). A significant relationship between these factors was observed in the inferior, but not in the
superior, lung regions.
there to be a similar decrease as occurred for ANP. This
may be explained by the lower affinity of the NP receptor
(NPR)-C and neutral endopeptidase for BNP compared
with ANP (21), although a similar clearance system for
ANP, BNP, and C-type NP exists in the human circulation
(22). The binding affinity of BNP for the NPR-C is about
1 order of magnitude lower than those of ANP in the lung,
and BNP clearance from the circulation is slower than that
of ANP (23).
NP are cleared from the circulation by neutral endopeptidase and NPR-C-mediated internalization and degradation (23, 24). NPR-C is widely distributed in many
tissues and cell types, including vascular endothelial cells,
smooth muscle cells, and glomeruli. The main function of
NPR-C has been considered to be clearance of bound ligand by internalization and degradation (25). The NPR-C
expression or activity is regulated by various pathophysiological conditions (18, 26 –28). In particular, hypoxia
has been shown to reduce the pulmonary NPR-C expression level (29). Experimental studies have also demonstrated that neutral endopeptidase is down-regulated by
hypoxia in the lung (30). In this study, our observations
that the oxygenation levels in the inferior PV were lower
compared with superior PV were consistent with a previous report (12). The present study demonstrated that only
the BMI was significantly associated with the decreased
PO2 value in the inferior PV. We also showed that the
oxygenation level was significantly correlated with the
pulmonary clearance of ANP in inferior PV. In addition,
the pulmonary ANP clearance rate was negatively correlated with the BMI. A multiple linear regression analysis
clearly demonstrated that the inclusion of oxygen pressure
in the PVs canceled the correlation between the regional
ANP clearance in the inferior lobes and the BMI. These
results suggested that the pulmonary ANP clearance was
negatively correlated with obesity-associated regional hypoxic pulmonary circulation. Although the precise mechanism remains to be determined, these associations might
be partly due to the down-regulation of pulmonary neutral
endopeptidase by hypoxia. The down-regulation of
NPR-C by hypoxia in the inferior lungs of obese subjects
might be another possible cause of the low ANP clearance.
It was reported that the pulmonary sympathetic nervous
system activity was markedly increased by hypoxia, which
was greater than the hypoxia-induced renal sympathetic
nerve activation (31). Moreover, human obesity itself is
associated with marked sympathetic activation (32). The
NPR-C gene is transcriptionally down-regulated by stimulation of ␤2-adrenergic receptors (33), which are abundantly present throughout the lung. Taken together, these
lines of evidence might explain the differences in the reg-
J Clin Endocrinol Metab, January 2012, 97(1):E14 –E21
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FIG. 4. Relation between the pulmonary regional ANP clearance rate and gas analysis. Correlation between the pulmonary regional ANP clearance
rate and gas analysis (PO2) in right superior lung (A), left superior lung (B), right and left superior lungs (C), right inferior lung (D), left inferior lung
(E), and right and left inferior lungs (F) (n ⫽ 23). A significant relationship between the ANP and PO2 was observed in the inferior, but not in the
superior, lung regions.
ulation of ANP clearance under obese circumstances between the pulmonary and systemic circulation.
We demonstrated that the pulmonary ANP clearance
rate was significantly higher in superior PV than that in
inferior PV. We have not yet determined the reason for
this. Little is known about the distribution of NPR-C or
neutral endopeptidase in each region of the lungs. As we
previously reported (12), the inferior PV show lower PO2
values compared with superior PV. Therefore, one of the
postulated explanations for the differences in clearance of
ANP is that the relative hypoxia in the inferior portion of
the lungs elicits the down-regulation of NPR-C and neutral endopeptidase, which results in lower pulmonary
ANP clearance by the inferior lungs in comparison with
the superior lungs.
We have also shown that a significant amount of ANP
was removed from the systemic circulation and that this
elimination was dependent on the BMI value. NPR-C is
abundant in adipose tissues, indicating that adipocytes
play an important role in the removal of ANP from the
systemic circulation. Although the precise mechanism underlying the accelerated ANP clearance from the lower
limb circulation has not yet been determined, it is possible
that the excess of adipose tissues in obese subjects participates in the increased NP clearance. Low levels of circu-
lating ANP are associated with obesity and may contribute
to perpetuating the obese state through reducing the lipolytic and thermogenic effects of NP in adipose tissues (34,
35). This effect might also be related to the development
of heart failure (36) because an experimental study also
demonstrated that ANP plays an important role in improvement of pulmonary gas exchange by reducing extravascular lung water and pulmonary arterial pressure
(37). In this study, we found a reciprocal relationship between the pulmonary and systemic ANP clearance. Taken
together, these findings indicate that decreased pulmonary
clearance served to maintain ANP levels in the obese, and
without that mechanism the NP levels might be reduced
even further.
Study limitations
One of the major limitations of this study is that we
investigated patients with AF. It is well known that AF
patients have higher levels of NP in their venous blood
compared with those without AF (13, 38). There is a possibility that the plasma NP level in the venous blood of AF
patients may have a different clearance rate than for patients without AF. In addition, the increased ANP secreted
from the heart might lead to relatively smaller clearance of
BNP from the pulmonary circulation. Further studies in
E20
Date et al.
Natriuretic Peptide and Lungs
subjects without AF would be useful, although conducting
such studies in humans would be difficult for ethical reasons. Second, all of the study measurements were performed with the patients in a supine position. Posture affects the lung volumes and respiratory resistance, possibly
leading to changes in the regional oxygenation status in
the lungs (39). Therefore, the body position might also
have influenced the data about the pulmonary ANP clearance. Third, it has been reported that obese subjects have
increased circulatory congestion, with consequent alveolar capillary leak (40). The influences of these pathophysiological differences related to the obese state on pulmonary ANP clearance cannot be ruled out. Fourth, it is well
recognized that there are sex differences in body fat distribution. Men tend to accumulate adipose tissue in the
abdomen, whereas women tend to accumulate the glutealfemoral fat, which might affect systemic ANP clearance.
Because this study included only three women, our observations may not be generalizable to women.
Conclusions
Pulmonary ANP clearance was reciprocally correlated
with the systemic ANP clearance. Obese or overweight
subjects demonstrated higher systemic and lower pulmonary ANP clearance. The obesity-related hypoxia of the
inferior lung regions is associated with lower ANP pulmonary clearance. Taken together, these data indicate that
there may be a unique mechanism for maintaining NP
levels in the hypoxic lungs of overweight and obese
populations.
Acknowledgments
We are grateful to Dr. Brian Quinn (Department of Linguistic
Environment, Kyushu University) for helping us to improve the
English used in the manuscript.
Address all correspondence and requests for reprints to:
Taro Date, M.D., Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine,
3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
E-mail: [email protected].
Disclosure Summary: No competing interest exists for any of
the authors with regard to this article.
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