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European Journal of Heart Failure 2000 2(2):161-165; doi:10.1016/S1388-9842(00)00076-3
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© 2000 European Society of Cardiology

Serum N-terminal atrial natriuretic peptide in adult patients late after surgical repair of atrial septal defect

Tiina E. Iivainena,*, Kaj W.E. Groundstroemb, Jorma T. Lahtelab, Taisto J. Talvensaarib, Amos Pasternackb and Arto Uusitaloa

a Department of Clinical Physiology, Tampere University Hospital P.O. Box 2000, FIN-33520 Tampere, Finland
b Department of Internal Medicine, Tampere University Hospital Tampere, Finland

* Corresponding author. Tel.: +358-3-2475111; fax: +358-3-2475511. E-mail address: kljola{at}uta.fi (T.E. Iivainen).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The purpose of surgical closure of atrial septal defect (ASD) is to relieve the cardiovascular system from a haemodynamic burden. Excessive amounts of atrial peptides are released in congestive heart failure, valvular diseases and congenital heart diseases.

Aims: To examine whether patients after surgical repair of ASD have higher concentrations of N-terminal atrial natriuretic peptide (ANP-N) than age-, sex- and body mass index (BMI)-matched control subjects.

Methods: Medical history, physical examination, standard 12-lead electrocardiogram, and ANP-N concentrations were obtained in 65 adult patients operated for ASD at the age of 21 ± 13 years (mean ± standard deviation), 21 ± 6 years after surgical closure of ASD. Sixty-seven healthy subjects matched for age, sex and BMI served as controls.

Results: In the patients serum ANP-N was higher than in the control subjects 0.41 ± 0.32 nmol/l, median 0.31 nmol/l, interquartile range (IQR) 0.21–0.49 nmol/l vs. 0.24 ± 0.12 nmol/l, median 0.23 nmol/l, IQR 0.17–0.29 nmol/l, (P = 0.0003). Patients with concomitant diseases had higher ANP-N concentrations (0.51 ± 0.39 nmol/l, median 0.34, IQR 0.26–0.73 nmol/l) than ASD patients without any history or signs of disease (0.28 ± 0.16 nmol/l, median 0.27, IQR 0.17–0.40 nmol/l, P = 0.01). The ‘healthy’ ASD patients had higher hormone concentrations than age-, sex- and BMI-matched control subjects (0.28 ± 0.16 median 0.27 nmol/l, IQR 0.17–0.40 nmol/l and 0.21 ± 0.07 nmol/l, median 0.20 nmol/l, IQR 0.15–0.27 nmol/l, P = 0.01). Multiple stepwise linear regression analysis showed that age at operation was strongly associated with the post-operative ANP-N concentration (r2 = 0.25, P = 0.0002).

Conclusion: ASD patients have higher ANP-N concentrations late after surgical repair. Hormone levels correlate with age at operation. Our finding supports the clinical praxis of operating on these patients in their childhood and adolescence.

Key Words: Atrial septal defect • Heart • Surgery • Congenital heart defect • Haemodynamics • Natriuretic peptide

Received February 12, 1999; Revised February 23, 2000; Accepted March 6, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Atrial septal defect (ASD) is one of the most common congenital heart diseases [1]. In newborns its incidence is 0.7/1000 [1], and often it is not recognized until adulthood [2]. Shunting of blood causes volume overload on the right side of the heart, cardiomegaly, insufficiency of the atrioventricular valves, pulmonary hypertension, cardiac arrhythmias, congestive heart failure, embolism [3] and excess mortality with advancing age [4]. Surgical closure of the defect aims at relieving the heart and pulmonary circulation from the haemodynamic burden. Although patients benefit from surgical repair [5] of ASD, they still suffer from cardiovascular morbidity after the operation [4,5]. Patients operated in childhood have a better survival rate [4] and fewer complications than patients operated in adulthood [4–7].

Atrial natriuretic peptides, N-terminal atrial natriuretic peptide (ANP-N) and the biologically active C-terminal atrial natriuretic peptide (ANP-C), are synthesized, stored and secreted in equimolar amounts by the myocytes of the cardiac atria due to atrial wall stretch, but also by the ventricles in cardiac failure [8,9]. ANP-N can be measured more reliably because of its better stability and longer half-life than ANP-C [8,9]. The peptides are cleared by the natriuretic peptide-C receptor and are degraded by the ectoenzyme neutral endopeptidase 24.11, both of which are widely expressed in the kidneys, lungs and the vascular wall [8,9]. ANP-C has a diuretic, natriuretic and vasodilatory effect and it inhibits the renin–angiotensin–aldosterone system [8,9]. Excessive amounts of the peptides are released into the circulation in congestive heart failure [8,9], congenital heart diseases [10–13] and valvular diseases [14].

We measured serum ANP-N in 65 ASD patients to examine whether patients after surgical repair of ASD have higher concentrations of this haemodynamic marker than 67 age-, sex- and body mass index (BMI)-matched control subjects.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
Two groups of patients operated for isolated ASD were included in the study. The first group consisted of 88 operated patients [54 females (f)/34 males (m)] found in a computer search of our hospital records from 1 January 1966 to 31 December 1978. Patients with ostium primum defects were excluded. Six patients had died (4 f/2 m). Of the remaining 82 ASD patients (50 f/32 m), 47 lived in our area and were contacted by mail. Two female and four male patients aged 36±7 years refused to participate in the study, leaving 41 patients (26 f/15 m). The second group consisted of 24 patients (19 f/5 m), who in 1993–1994 came for check-ups to our hospital’s cardiac outpatient clinic. The clinical characteristics of the 65 patients (45 f/20 m) are shown in Table 1 and Table 2. Sixty-one patients had ASD of the secundum type and three of the sinus venosus type, two of whom had an anomalous pulmonary venous connection. One patient had both secundum and sinus venosus type ASD with an anomalous pulmonary venous connection. The method of ASD repair was direct suture in 61 patients and patch repair in four patients.


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  		Table 1 Clinical characteristics of 67 control subjects and 65 patients operated for ASDa

 


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  		Table 2 Clinical characteristics of 65 patients operated for ASD divided into two groups according to origin of patientsa

 
Medical history was obtained from interviews and patient records. There were 34 patients with concomitant diseases (arterial hypertension, 17; medicated cardiac arrhythmias, eight; medicated congestive heart failure, five; angina pectoris, two; diabetes mellitus, two; hypothyroidism, three). There were no patients with renal failure in our study. Eighteen patients used medication; digitalis (five), β-blockers (four), Ca2+-blockers (two), chinidine sulfate (one), nitrates (two), diuretics (three), ACE inhibitors (three), insulin or oral antidiabetic medication (two), thyroxin (three), carbamazepine for trigeminal neuralgy (one), topical pilocarpin and timolol for glaucoma (one), Warfarin or acetosalisylic acid (four), antidepressant alpratsolam (two) and potassium substitution (one).

A standard 12-lead electrocardiogram was obtained on the day of clinical examination. Arterial blood pressure (mean of three auscultatory sphygmomanometric measurements) and heart rate were measured in sitting position after the patient had rested for at least 5 min. Systolic blood pressure ≥140 and/or diastolic blood pressure ≥90 mmHg were defined as hypertension [15]. Blood samples for ANP-N measurement were drawn from an antecubital vein in the sitting position before noon. After centrifugation the samples were stored at –70°C. Serum ANP-N concentrations were measured with the commercial IRMA method using two monoclonal antibodies (Medix, Kauniainen, Finland). The interassay coefficients of variation at the levels of 0.30 and 0.70 nmol/l were 6.5 and 5.1%, respectively [16].

2.2. Control subjects
The 67 control subjects were recruited among 98 employees in companies from the Tampere region. After history and clinical examination, electrocardiogram and trans-thoracic echocardiography, 28 subjects were excluded. In 14 the reason was history of cardiovascular disease or sphygmomanometric blood pressure ≥140/90, in three abnormal electrocardiogram, in two non-cardiovascular disorders, in one regular medication and in eight poor quality echocardiogram. During matching of control subjects and patients for sex, age and BMI another three subjects were excluded, leaving 67 healthy individuals. Their clinical characteristics are shown in Table 1.

The Ethics Committee of Tampere University Hospital approved the study protocol. The investigation conforms to the principles outlined in the Declaration of Helsinki [17].

2.3. Statistics
The Kolmogorov–Smirnov test was used to assess the normality of data distribution. In the case of normal distribution (P≥0.05) differences between means were tested using the Student’s t-test, otherwise the Mann–Whitney U-test was used. The results are expressed as mean±standard deviation (S.D.), and as median and interquartile range (IQR) when the distribution was skewed. Differences between categorical variables among the groups were tested by using the {chi}2-test or Fischer’s exact test if the assumptions of the {chi}2-test were not met.

The multiple linear stepwise regression analysis was used to evaluate the associations between independent variables. The statistical analyses were done using SPSS statistical software (V 5.0.1, Chicago, IL, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Patients
In the patients serum ANP-N level was significantly higher than in the control subjects [0.41±0.32 nmol/l (S.D.), median 0.31 nmol/l (IQR 0.21–0.49nmol/l), P=0.0003 (Fig. 1]. The distribution of ANP-N concentrations was skewed. Multiple linear stepwise regression analysis including current age, age at operation, sex, cardiac rhythm, heart rate, systolic and diastolic blood pressure, BMI, pre-operative pulmonary to systemic blood flow ratio and mean pulmonary artery pressure showed that the combination of current age and diastolic blood pressure were significantly associated with serum ANP-N concentrations (r2=0.30, P=0.0001). Exclusion of one patient with aortic insufficiency from the analysis made age at operation the only significant parameter correlating with ANP-N concentration (r2=0.25, P=0.0002). Systolic blood pressure and heart rate were higher in the patients than in the control subjects (Table 1).


Figure 1
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  		Fig. 1 Serum ANP-N values in 67 control subjects and 65 operated ASD patients. The solid lines represent the median and interquartiles. The difference is significant, P=0.0003 with the Mann–Whitney test.

 
3.2. Control subjects
In the control subjects ANP-N concentration was 0.24±0.12 nmol/l, median 0.23 nmol/l (IQR 0.17–0.29 nmol/l) (Fig. 1). The distribution of ANP-N concentrations in the control subjects was normal. Multiple linear stepwise regression analysis using age, sex, systolic and diastolic blood pressure, BMI and heart rate showed the combination of male sex and systolic blood pressure to correlate with ANP-N levels (r2=0.13, P=0.02 and P=0.03, respectively).

3.3. Patient subgroups
The clinical characteristics of the patients collected from the hospital records (group 1) did not differ from those in the outpatient clinic (group 2) except that the patients in group 1 had higher blood pressure (Table 2). Serum ANP-N levels were similar in the two groups (0.36±0.24 nmol/l in group 1 and 0.48±0.41 nmol/l in group 2, P=0.46) and higher than in the control subjects (P=0.008 for group 1 and P=0.0007 for group 2, respectively).

The 34 patients with concomitant diseases had an ANP-N level 0.51±0.39 nmol/l, median 0.34 nmol/l, IQR 0.26–0.73 nmol/l, that was significantly higher than in the ‘healthy’ ASD patients (P=0.011). Sixty-one patients were in sinus rhythm. The ANP-N concentrations in two patients in atrial fibrillation were 0.40 nmol/l and 0.71 nmol/l, respectively, in one with a VVI pacemaker 0.61 nmol/l and in one with ectopic atrial rhythm 0.28 nmol/l. The 31 ASD patients (23 f/8 m) who were in sinus rhythm, normotensive and without concomitant diseases (‘healthy’ ASD patients) had higher serum ANP-N levels than control subjects matched for age, sex and BMI (0.29±0.16 nmol/l median 0.27, IQR 0.17–0.40nmol/l and 0.21±0.07 nmol/l, median 0.20nmol/l, IQR 0.15–0.27nmol/l, respectively, P=0.01). Among the 33 patients with ANP-N>0.31 nmol/l, 23 individuals and among the 32 with ANP-N≤0.31 nmol/l, nine individuals had a concomitant disease, respectively (P=0.049). Among the 33 symptomatic (palpitations, dyspnoea, chest pain, dizziness, syncope or fatigue) patients, were 11 with ANP-N concentration >0.31 nmol/l and among the 32 asymptomatic patients 22 (not significant).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Serum atrial peptide levels reflect both the severity of congestive heart failure [18] and the efficacy of its medical treatment [8], the severity of valvular disease [19] and mortality [20,21]. High atrial peptide concentrations have been reported in children with congenital heart diseases with pressure and/or volume overload, especially when heart failure is present [21]. In children the plasma concentrations of atrial peptide may diminish [22,23] or remain elevated [23] 24–48 h after an operation for congenital heart disease. These studies, however, were done with children under the age of 15 years and several types of congenital heart diseases were included. No post-operative data are available for atrial peptides in adult ASD patients.

In our ASD patients serum ANP-N levels were elevated late after surgical closure. The follow-up period was as long as 35 years. The clinical practice of treating ASD during this time was essentially unchanged. Pre-Operative shunt magnitude and pulmonary artery pressure did not correlate with ANP-N concentration. This may be explained by the fact that a cut-off value was used whereby patients with minor shunts were not operated. Also, depending on their age, patients with similar pre-operative shunt sizes and pulmonary artery pressures may be in different stages of cardiac and pulmonary artery structural changes, some of which are reversible and some not.

Symptomatic patients did not have higher ANP-N concentrations than asymptomatic patients. However, most patients felt well and reported symptoms only upon specific questioning. Patients with concomitant diseases had higher ANP-N concentrations than the ‘healthy’ ASD patients. This is not unexpected since most had cardiovascular disorders that are known to stimulate ANP-N secretion [8] Elevated atrial peptide levels have been reported in hypertensive patients [24] with left ventricular hypertrophy. However, in our patients we did not find any association between blood pressure and ANP-N levels. In the control subjects there was an association between systolic blood pressure and ANP-N concentrations but all were normotensive.

ASD patients without concomitant diseases or any physical or electrocardiography signs of heart disease had higher ANP-N levels than the control subjects. Age at operation correlated significantly with serum ANP-N concentration. Our finding supports the clinical praxis of operating these patients in their childhood and adolescence.


   Acknowledgements
 
This study was supported by the Medical Research Fund of Tampere University Hospital, Tampere, Finland, Finska Läkaresällskapet, Helsingfors, Finland and the Aarne Koskelo Foundation, Helsinki, Finland.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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