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European Journal of Heart Failure 2008 10(1):60-62; doi:10.1016/j.ejheart.2007.11.001
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© 2008 European Society of Cardiology

B-type natriuretic peptide levels in patients with functionally univentricular hearts after total cavopulmonary connection

Andreas M.E. Koch*, Stefan Zink, Helmut Singer and Sven Dittrich

Department of Paediatric Cardiology, University of Erlangen-Nürnberg Germany

* Corresponding author. Kinder- und Jugendklinik der Universität, Pädiatrische Kardiologie, Loschgestr. 15, 91054 Erlangen, Germany. Tel.: +49 9131 853 3118; fax: +49 9131 853 5987. E-mail address: Andreas.Koch{at}kinder.imed.uni-erlangen.de (A.M.E. Koch).


   Abstract
Top
 Abstract
1. Background
 2. Aims
 3. Materials and methods
 4. Results
 5. Conclusion
 References
 
Aims: To assess plasma B-type natriuretic peptide (BNP) levels in patients with univentricular hearts late after volume unloading by total cavopulmonary connection (TCPC).

Methods: Plasma BNP was measured by sandwich immunoassay in 67 patients after a modified Fontan procedure. BNP levels were compared with age and sex-specific normal values, clinical and echocardiographic data, and results of exercise testing.

Results: BNP had a wide range of 5–290 pg/ml, but was normal in 81% of patients, and median BNP was only 13pg/ml. There was no difference between males and females, between patients with left or right ventricular morphology, and no correlation was found between BNP and age, post-operative follow-up period, maximum exercise capability, peak oxygen uptake, or blood oxygen saturation. New York Heart Association class I patients had lower BNP than class II patients (p=0.04). Plasma BNP concentration was positively correlated to the number of specific sequelae (r=0.59, p<0.001), and to severity of atrioventricular regurgitation (r=0.38, p=0.002). 5/13 patients with elevated BNP died during follow-up.

Conclusion: BNP plasma concentration was normal in the majority of patients up to 15 years after TCPC. Elevated and increasing BNP levels were associated with increased morbidity and late mortality.

Key Words: BNP • Fontan • Sequelae • Total cavopulmonary anastomosis • Univentricular heart

Received September 12, 2007; Revised October 30, 2007; Accepted November 5, 2007


   1. Background
Top
 Abstract
 1. Background
2. Aims
 3. Materials and methods
 4. Results
 5. Conclusion
 References
 
Children with a wide range of congenital heart defects unsuitable for biventricular repair can undergo modifications of the Fontan operation as their definitive palliation. One variant of the standard Fontan procedure, total cavopulmonary connection (TCPC), results in separation of systemic and pulmonary venous return, eliminates or reduces cyanosis, and relieves the heart of its volume overload. However, specific sequelae after modified Fontan operations mandate careful follow-up.

B-type natriuretic peptide (BNP) and the N-terminal fragment of its prohormone (NT-proBNP) are established markers of heart failure [1-3]. Both peptides have been shown to be useful in a variety of wide-ranging conditions including congenital heart disease [4-10].


   2. Aims
Top
 Abstract
 1. Background
 2. Aims
3. Materials and methods
 4. Results
 5. Conclusion
 References
 
The purpose of this study was to evaluate plasma levels of BNP in patients with TCPC and to assess the diagnostic validity of BNP measurements in the long-term follow-up of patients with this non-physiologic condition.


   3. Materials and methods
Top
 Abstract
 1. Background
 2. Aims
 3. Materials and methods
4. Results
 5. Conclusion
 References
 
From 2002 to 2007, plasma BNP was measured in all patients with TCPC who came to our outpatient clinic for follow-up or diagnostic work-up, including a venous puncture.

67 patients (37 females; aged 4.1 to 34.0 years, mean 13.8 ± standard deviation 5.8 years, median 14.1 years) were analysed retrospectively 0.9 to 22.2 years after surgery (8.6±4.9 years, median 8.8 years).

Underlying cardiac malformation was double inlet left ventricle (n=20), double outlet right ventricle (n=17), tricuspid atresia (n=15), atrioventricular septal defects (n=6), pulmonary atresia with intact ventricular septum (n=4), complex forms of transposition of the great arteries (n=3), and hypoplastic left heart syndrome [n=2].

The patients were asymptomatic or minimally symptomatic (New York Heart Association classification I [n=55] or II [n=12].

All patients were graded according to the number of identified haemodynamic restrictions and specific sequelae after TCPC, i.e. decreased systolic function of the ventricle, moderate or severe dysfunction of the atrioventricular (n=20) or aortic valve (n=2), tachyarrhythmias (n=1), permanent pacemaker (n=6), protein-losing enteropathy (n=3), or decreased liver function (n=1).

All patients underwent physical examination, transthoracic echocardiography, and standard 12-lead electrocardiogram. Exercise testing on an upright bicycle ergometer was performed in 48/67 patients.

BNP was measured by a sandwich immunoassay (Triage BNP assay, Biosite®, measurable range <5.0 to 5000 pg/ml) [11,12].

Plasma BNP levels of the patients were compared to clinical, spiroergometric, echocardiographic, and electrocardiographic data.

Statistical differences were evaluated using Wilcoxon rank-sum test to unpaired data. Correlations were assessed by Spearman's correlation coefficient or univariate regression analysis.


   4. Results
Top
 Abstract
 1. Background
 2. Aims
 3. Materials and methods
 4. Results
5. Conclusion
 References
 
Plasma BNP concentration was between 5 and 290 pg/ml in all patients (median BNP 13 pg/ml, interquartile range [IQR] 7-26 pg/ml). According to age- and sex-specific reference values [11,12], BNP was increased in only 13/67 patients.

There was no difference in BNP between male and female patients (14 [IQR 6-33] vs. 13 [IQR 7-25] pg/ml), nor between patients with left or right ventricular morphology (13 [IQR 6-24] vs. 14 [IQR 7-41] pg/ml).

There was no significant correlation between BNP and age, time interval between follow-up and surgery, body weight, body height, body mass index, maximum exercise capability, peak oxygen uptake, maximal or minimal blood oxygen saturation during exercise testing.

NYHA class I patients had significantly lower plasma BNP levels than NYHA class II patients (13 [IQR 7-22] vs. 44 [IQR 7-151] pg/ml; p=0.035).

Patients with specific sequelae or haemodynamic restrictions (n=26) had significantly higher BNP levels than patients without (n=41) (18 [IQR 12-69] vs. 12 [IQR 6-21] pg/ml; p=0.003).

Analyzing the most frequent factor separately, there was a positive correlation between BNP and severity of atrioventricular valve regurgitation (r=0.38; p=0.002) (Fig. 1).


Figure 01
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  		Fig. 1 BNP plasma concentration according to severity of atrioventricular valve regurgitation (AVR).

 
Excluding atrioventricular regurgitation, BNP was positively correlated to the number of sequelae (r=0.59, p<0.001).

During the follow-up period, 5/67 patients died within 3 years of the BNP measurement. These patients had significant higher BNP levels than survivors (170 [IQR 50-238] vs. 13 [IQR 6-22] pg/ml; p<0.001). BNP was elevated according to normal values in all deceased patients, and no patient with a BNP level of <40 pg/ml died. Additionally, one patient with a BNP level of 56 pg/ml was listed for transplant.


   5. Conclusion
Top
 Abstract
 1. Background
 2. Aims
 3. Materials and methods
 4. Results
 5. Conclusion
References
 
The majority of patients with cavopulmonary connection had normal BNP levels more than 15 years after surgery. In fact, the highest BNP level was less than 300 pg/ml. Comparable BNP levels have been reported in smaller groups composed of both Glenn and Fontan patients [13,14].

BNP is secreted mainly by the ventricles in response to volume expansion and pressure load [1,2]. Therefore, one possible explanation for the surprisingly low BNP levels is the reduced ventricular preload in patients with Fontan circulation together with a limited preload reserve [15,16].

Unfortunately, we were not able to correlate BNP levels with systolic function in our patients, because the broad spectrum of underlying cardiac malformation made it impossible to obtain reliable ejection fraction data by standard echocardiographic procedures. Nevertheless, typical complications in the long-term follow-up after the Fontan procedure were associated with higher BNP levels. A strong positive correlation was found between the severity of atrioventricular valve regurgitation and BNP. Moderate to severe atrioventricular valve regurgitation is a well known major risk factor influencing late mortality after total cavopulmonary connection [17]. In clinical practice, however, the predictive value of a single BNP level is limited due to the considerable overlap between the groups. The wide age span of our patients may contribute to this overlap, although we could not find any correlation between BNP and age or follow-up period.

Additionally, our data indicate a prognostic value of BNP for survival. In a similar way, BNP has been shown to provide prognostic information in adults with chronic heart failure or after acute myocardial infarction [18,19].

Our data suggest that determination of plasma BNP is useful in the long-term management of patients with univentricular hearts. Elevated or increasing plasma BNP levels indicate functional disorders of Fontan circulation. However, a low BNP level does not rule out haemodynamic restrictions or specific sequelae after TCPC.


   References
Top
 Abstract
 1. Background
 2. Aims
 3. Materials and methods
 4. Results
 5. Conclusion
 References
 

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