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Plasma

Atrial

Natriuretic

Peptide

in Patients

With Congenital

Heart

Diseases

Suguru

Matsuoka,

MD, Yoshihide

Kurahashi,

MD, Yohko

Miki,

MD,

Masuhide

Miyao,

MD, Yasuhiro

Yamazaki,

MD, Takeshi

Nishiuchi,

MD

and

Shiro

Saito,

MD

From the Departments of Pediatrics and Internal Medicine, University Hospital of

Tokushlma, Tokushima City, Japan

ABSTRACT.

The

plasma level of human a-atrial natri-uretic peptide was measured in healthy children and patients, 1 month to 15 years of age, with congenital heart diseases. Significant increases were found in

pa-tients with a ventricular septal defect, tricuspid valve atresia, patent ductus arteriosus, and atrial septal defect but not in those with pulmonary valve stenosis or tetral-ogy of Fallot.

The levels were significantly higher in children with

ventricular septal defects (221 ± 123 pg/mL) or patent

ductus arteriosus (124 ± 38 pg/mL) than in those with

atrial septa! defects (65 ± 42 pg/mL) (P < .01). The

increased levels appeared to be correlated with enlarge-ment of the left atrium (r = .85, P < .01) but not with

the right atrial size or the mean right atrial pressure. They were higher in younger than in older healthy in-fants, but this age difference did not affect the results.

These findings indicate that human a-atrial natriuretic peptide is released into the circulation in response to

chronic atrial expansion in patients with congenital heart disease and may have an important role in volume ho-meostasis. Pediatrics 1988;82:639-643; a-atrial natri-uretic peptide, congenital heart disease.

Recently, human a-atrial natriuretic peptide was shown to have many biologic effects, including na-triuretic, diuretic, and smooth muscle relaxant ac-tivities. The plasma level was shown to be high in patients with congestive heart fai!ure,7 renal failure,8 and paroxysmal atrial techycardia,9’1#{176} but it is unknown whether human a-atrial natriuretic peptide is released into the circulation as a

conse-Received for publication April 27, 1987; accepted July 29, 1987. Reprint requests to (S.M.) Department of Pediatrics, University

Hospital of Tokushima, Kurainoto-cho, Tokushima City, To-kyshima, 770 Japan.

PEDIATRICS (ISSN 0031 4005). Copyright © 1988 by the

American Academy of Pediatrics.

quence of chronic atrial expansion in patients with congenital heart diseases.

Children with congenital heart disease have var-ious degrees of pressure and volume loads in the right and left atria. We studied the relation between the human a-atrial natriuretic peptide level and the hemodynamic status in children with congenital heart disease.

SUBJECTS AND METhODS

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60 80 0 0 0 0 0 0 E 00 . 0 0 40 . 0 .! 0 l0 E . 00 . 0 0 20 0 0 0 0 0 0 0 0 L_________

0 4 8 12(M) 3 5 7 9 11 13 15(Y)

(Months) Age (Years)

Fig 1. Distribution ofplasma a-human atrial natriuretic peptide (hANP) levels in healthy

children (n = 53).

00 0 0 0 0 0 0 0

8

0 000 0

08

0

§

8

aprotinin (500 kallikrein inactivator units per nil!-liliter).

Plasma was separated by centrifugation and ap-plied to Sep-Pak C18 cartridges for extraction of human a-atrial natriuretic peptide as reported pre-viously.7 Briefly, samples were evaporated and ly-ophilized, and the residues were dissolved in radio-immunoassay buffer for determination of human a-atrial natriuretic peptide. The level was measured by radioimmunoassay with antibody raised in New Zealand White rabbits immunized with synthetic human a-atrial natriuretic peptide coupled to bo-vine thyroglobulin.7

Real-time two-dimensional echocardiographic studies were performed with a phase-array sector scanner (Toshiba SSH 65-A). Right atrial and left atrial areas were measured from selected freeze frames from videotypes using a Digisonics VRS 2000 video-review system. The area of both atria were obtained at end-ventricular systole in apical four-chamber view, defmed as the frame in which the simultaneous ECG reached the end of the T wave as previously described.”2 The areas were compared with age-matched control values.

The plasma sodium and chloride concentrations were also measured in the same blood samples as the human a-atrial natriuretic peptide levels.

Values are expressed as means ± SD. The signif-icance of differences was calculated by Student’s t

test, and P values of less than .05 were considered significant.

RESULTS

The human a-atrial natriuretic peptide levels in healthy children were all less than 80 pg/mL, and there was no significant difference in the levels between boys and girls, but younger infants tended to have higher levels (Fig 1). Most of the patients with congenital heart disease had higher human

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. PS :7

0 A :TOF :7

0 0 :TA :5

‘$00 )( :ASD :7

0 : VSD :18

0 L :PDA :6

p300 0

200 0 O0

;

E

i 0 X

0 0

A A

100 f 00

. 0 A

0 12(M)3579fli35(Y)

(months) Age (Years)

Fig 2. Plasma a-human atrial natriuretic peptide (hANP) levels in children with

congen-ital heart diseases. Dotted line represents control range. Abbreviations: PS, pulmonic

valve stenosis; TOF, tetrology of Fallot; TA, tricuspid atresia ASD, atrial septal defect; VSD, ventricular septal defect; PAD, patent ductus arteriosus.

500

atrium (65 ± 42 pg/mL, range 23 to 157) or no pressure load of left atrium (31 ± 17 pg/mL, range 7 to 84). The patients with congenital heart disease who had levels within the normal range of age-matched healthy children were those with tetralogy of Fallot and pulmonic stenosis.

The right and left atrial areas are shown as percentages of control values in the Table, as are the pressures that were determined by cardiac cath-eterization. The time between blood sampling and catheterization or echocardiography was less than 1 week in all patients.

The human a-atrial natriuretic peptide levels in patients with congenital heart disease correlated with their left atrial areas as percentages of control values (r =

.85;

P

< .01, Fig 3) but not with their right atrial areas or mean right and left atrial pressures.

All

children had normal levels of serum sodium (134 to 145 mEqJL) and chloride (96 to 104 mEqj L).

DISCUSSION

Plasma human a-atrial natriuretic peptide levels have mainly been studied in adults and there are only a few reports concerning children.”3 In this study we found that in healthy children the plasma levels were higher in young infants than in older

children. The reason for this is unknown but could be explained by the higher water to body weight ratio and faster heart rate in infants.

Tikkanen et a!6 examined the physiologic effect of a bolus injection of human a-atrial natriuretic peptide and found that plasma human a-atrial na-triuretic peptide levels of more than 100 pg/mL were followed by natriuresis and diuresis in healthy subjects. In the present work we observed several-fold higher levels than normal of endogenous im-munoreactive human a-atrial natriuretic peptide in the plasma ofpatients with congenital heart disease and chronic atrial loading. This magnitude of in-crease would have a defmitive impact on the regu-lation of volume homeostesis. This probability is supported by our previous fmdings of a correlation between the plasma human a-atrial natriuretic pep-tide level and pulmonary to systemic flow ratio in patients with ventricular septel defect.’3 Others have also reported that the plasma level is increased during volume loadine”4 and paroxysmal atrial techycardia,9”#{176} followed by an increase in natri-uresis and diuresis.

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0 S.. I0 35#{149} 205 15 I I I a a

right atrial size or the mean right atrial pressure.

0 This might be because no patients with congestive

heart failure were included and those with all types of congenital heart disease were included in this study. Moreover, pressure date may have changed because of sedation, patient position, and fluid state in preparation for catheterization.

These results suggest that measurement of the plasma human a-atrial natriuretic peptide level is useful for monitoring the severity of not only acute overload but also chronic overload of the atrium.

REFERENCES A 0 0 . A 0 0 0 Y::lOO#{149}$1#{149}X#{149}O.7 -0.15 P<0. 01

. :PS

a :TOP a : TA

x ASD

0 :VSD

A

___________2 150

LA as. (Co..t.o1100 5)

Fig 3. Relation between left atrial area as a percentage of normal and plasma a-human natriuretic peptide (hANP) level in children with congenital heart diseases. Abbreviations: PS, pulmonary valve stenosis; TOF, te-tralogy of Fallot; TA, tricuspid atresia; ASD, atrial septal defect; VSD, ventricular septal defect; PDA, patent

duc-tus

arteriosus.

through the atrial septel defect and greater buffer system of the right atrium, such as the liver and

When the right atrial pressure is higher than the left, causing a right-to-left atrial shunt, the plasma human a-atrial natriuretic peptide level could be increased much more, as in patients with tricuspid atresia. In this study right-to-left atrial shunt did not develop in any patient with pulmonic stenosis or tetralogy of Fallot; we did although observe sig-nificantly increased plasma levels in a patient with pulmonic stenosis who had a right-to-left atrial shunt during exercise.

The plasma human a-atrial natriuretic peptide levels correlated with the left atrial size but not the vena cava.

TABLE. Measurements in Patients With Congenital Heart Diseases*

Classification of Congenital Heart . Disease No. of . Patients Human . . a-Natriuretic .

AtrialA rea(%) Mean Atrial

Pressure (mm Hg)

Right Left Right Left

Type!

Ventricularseptaldefect 18 221±123 117±28 188±32 5±2 7±3(10)

Patent ductus arteriosus 6 124 ± 38 98 ± 14 158 ± 13 2 ± 2 6 ± 3 (4)

TypeII:Atrialseptaldefect 7 65±42 174±27 125±19 4±2 4±2(7)

Type

III: Tricuspid atresia lb 5 211 ± 90 120 ± 56 186 ± 55 7 ± 2 6 ± 2 (5)

Type

IV

Pulmonic stenosis 7 36 ± 21 105 ± 12 101 ± 14 3 ± 2 4 ± 2 (4)

Tetralogy of Fallot 7 25 ± 11 91 ± 15 54 ± 14 5 ± 3 3 ± 2 (4)

* Results are means ± SD. Numbers of patients in whom left atrial pressure was measured are given in parentheses.

0

1. Flynn TG, de Bold ML, de Bold AJ: The amino acid

se-quence of an atrial peptide with potent diuretic and

natri-uretic properties. Biochem Biophys Res Commun

1983;117:859-865

________

2. Sugawara A, Nakao K, Mon N, et al: a-Human atrial

200 220 natriuretic polypeptide is released from the heart and

cir-culates in the body. Biochem Biophys Res Commun

1985;129:439-446

3. de Bold AJ, Borenstein HE, Veress AT, et al: A rapid and

potent natriuretic response to intravenous injection of atrial

myocardial extract in rats. Life Sci 1981;28:89-94

4. Currie MG, Geller DM, Cole BR, et al: Bioactive cardiac substances: Potent vasore!axant activity in mammalian

atria. Science 1983;221:71-73

5. Hartter E, Weissel M, Stummvoll HK: Atrial natriuretic

peptide concentrations in blood from right atrium in patient with severe right failure. Lancet 1985;2:93

6. Tikkanen I,Fyhrquist F, Metsarinne K, et al: Plasma atrial natriuretic peptide in cardiac disease and during infusion in healthy volunteers. Lancet 1985;13:66-69

7. Nishiuchi T, Saito H, Yamasaki Y, et al: Radioimmunoassay for atrial natriuretic peptide: Method and results in normal

subjects and patients with various diseases. Clin Chim Acta

1986;1:1-3

8. Rascher W, Tulassay T, Lang RE: Atrial natriuretic peptide in plasma of volume-overloaded children with chronic renal

failure. Lancet 1985;10:303-305

9. Schiffrin EL, Gutkowska J, Kuchel 0, et al: Plasma concen-tration of atria! natriuretic factor in a patient with parox-ysmal atrial tachycardia. N EnglJ Med 1985;312:1196-1197

10. Yamaji T, Ishibashi M, Nakaoka H, et al: Possible role for

atrial natriuretic peptide in polyuria associated with

parox-ysmal atrial arrythniia. Lancet 1985;1:1211

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12. De Pace NL, Ren JF, Kotler MN, et al: Two-dimensional atrial natriuretic peptide levels in patients with a ventricular

echocardiographic volume: A noninvasive index in quanti- septal defect. Pediatr 1987;110:578-579

fying the degree of tricuspid regurgitation. Am J Cardiol 14. Richards AM, Nicholis MG, Ikram H, et al: Renal,

haemo-1983;52:523-529 dynamic, and hormonal effects of human alpha atrial

natri-13. Matsuoka S, Kurahashi Y, Tomimatsu H, et al: Plasma uretic peptides in healthy volunteers. Lancet 1985;1:545-549

ANNOUNCEMENT OF 1989 PEDIATRIC PULMONARY EXAMINATION

The Sub-Board of Pediatric Pulmonology ofthe American Board of Pediatrics will administer its next certifying examination on Friday, July 14, 1989.

The following criteria must be met to be eligible to sit for the examination: 1. Certification by the American Board of Pediatrics.

2. Subspecialty training or experience.

Three years of full-time subspecialty residency training in pediatric puLmonol-ogy is required of those physicians entering training on or after Jan 1, 1986. Physicians who entered training prior to Jan 1, 1986, may apply for admission

on the basis of their completion of two years of training in pediatric puhnonol-ogy. No foreign training will be accepted.

OR

Five years of broadly based pediatric pulmonology. A minimum of 50% of full-time professional activities must be spent in pediatric pulmonology to receive credit. It is assumed that night and weekend time would be distributed in the same manner as regular time. These 5 years should be of such type and quality

that they substitute for the clinical exposure one might have encountered during

subspecialty training.

All

pediatric pulmonology experience must be accrued before Dec 31, 1990.

OR

a) Those applicants who completed less than 12 months of subspecialty resi-dency training in pediatric pulmonology may receive credit on a month-for-month basis.

b) Those applicants completing 12 to 23 months of subspecialty residency training in pediatric pulmonology may receive credit on a two-for-one basis. (c) Those applicants completing 24 months of subspecialty residency training

in pediatric pulmonology beginning after Jan 1, 1986, will receive credit on a two-for-one basis. Such applicants would be credited with 48 months of pediatric pulmonology; this, supplemented by 12 months of pediatric pulmonology expe-rience, would total 60 months or 5 years.

3. Verification of training and recommendation by Program Director.

Each application will be considered individually and must be acceptable to the Sub-Board of Pediatric Pulmonology.

Registration for this examination will extend from Sept 1, 1988, to Dec 30, 1988. Requests for applications received prior to the opening of registration will be held on file until that date, at which time application materials will be

sent to those who have requested them.

The application fee for the examination is $800. Applications postmarked after Dec 30, 1988, must include an additional $200 late fee. New applica-tions postmarked after Feb 15, 1989, cannot be accepted for the 1989 examination.

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1988;82;639

Pediatrics

Yamazaki, Takeshi Nishiuchi and Shiro Saito

Suguru Matsuoka, Yoshihide Kurahashi, Yohko Miki, Masuhide Miyao, Yasuhiro

Plasma Atrial Natriuretic Peptide in Patients With Congenital Heart Diseases

Services

Updated Information &

http://pediatrics.aappublications.org/content/82/4/639

including high resolution figures, can be found at:

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtml

entirety can be found online at:

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(7)

1988;82;639

Pediatrics

Yamazaki, Takeshi Nishiuchi and Shiro Saito

Suguru Matsuoka, Yoshihide Kurahashi, Yohko Miki, Masuhide Miyao, Yasuhiro

Plasma Atrial Natriuretic Peptide in Patients With Congenital Heart Diseases

http://pediatrics.aappublications.org/content/82/4/639

the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Figure

TABLE.MeasurementsinPatientsWithCongenitalHeartDiseases*

References

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