N-Terminal Pro-Brain Natriuretic Peptide: Defining a Role in Adult Congenital Heart Disease

Editor's Note: This article is based on Eindhoven JA, van den Bosch AE, Ruys TPE, et al. N-terminal proBrain Natriuretic Peptide and its Relation with Cardiac Function in Adult Patients with Congenital Heart Disease. J Am Coll Cardiol 2013. [Epub ahead of print].


Improved diagnosis and management has led to a surge in the population of adult patients with chronic congenital heart disease (ACHD). There is a growing interest in modalities that can help improve risk stratification in ACHD. N-terminal pro-brain natriuretic peptide (NT-proBNP) is secreted by cardiac myocytes in response to ventricular wall stress and overload and has been used widely as a biomarker in acquired heart disease.1

In this study, Eindhoven and colleagues2 have aimed to evaluate NT-proBNP levels in different forms of ACHD and its relation to cardiac function and exercise capacity. The authors recruited 475 consecutive ACHD patients with a wide range of anomalies from outpatient clinics of Erasmus Medical Center in Rotterdam, Netherlands between May 2010 and October 2012. All subjects underwent a 2D- transthoracic echocardiography (TTE), 12-lead electrocardiogram (ECG), and laboratory studies including NT-proBNP levels. In addition, 198 patients also underwent bicycle ergometry to determine their exercise tolerance.

Even among asymptomatic patients with ACHD, 50% had NT-proBNP levels above the upper limit of normal (14 pmol/L). NT-proBNP levels were similarly associated with patient characteristics among ACHD patients as they are among patients with acquired heart disease, correlating with increasing age, women, QRS duration, atrial arrhythmia, and higher NYHA functional class (NYHA I 13.3, NYHA II 42.7, NYHA III 172.5 pmol/L, p<0.001) . The levels of NT-proBNP significantly varied with the complexity of repaired congenital anomaly, with the highest levels in patients with systemic RV (TGA-Mustard and ccTGA) or Fontan. NT-proBNP levels were correlated with reduced systemic RV function only among patients with a systemic RV. In patients post Fontan, NT-proBNP values were significantly higher in those with severely impaired ventricular function in comparison to those with only mild impairment (p=0.023). In patients with AoS, CoA and ToF, the E/E' ratio showed a significant positive correlation with NT-proBNP. Of the 198 (42%) patients that underwent exercise bicycle ergometry, an independent association was found between logNT-proBNP and lower workloadmax (β= -0.08, p=0.02) and a lower VO2max (β= -0.012, p=0.01) on multivariable regression analysis.

The authors concluded that NT-proBNP levels in ACHD patients differ with underlying diagnosis and its severity and are related to echocardiographic parameters and exercise capacity. Their disease-specific correlations could contribute to the understanding of hemodynamic problems in the underlying anomaly and further follow-up data is needed to determine additional prognostic value of NT-proBNP in ACHD.


This interesting study evaluates the role of NT-proBNP as a biomarker in patients with ACHD.2 NT-proBNP has been a long established biomarker for acquired heart failure and is used in monitoring therapy as well as for risk estimation.1 With a growing number of ACHD patients with chronic disease, the findings of this study will facilitate future studies on the role of biomarkers in assessing disease severity and risk of morbidity and death.

The results from the study confirm several established associations between natriuretic peptides and cardiac structure and function within the ACHD population, including correlations with worsening NHYA functional class, presence of atrial arrhythmias, and poor exercise capacity.3 The study, however, brings forth some interesting results with regards to ACHD. The levels of NT-proBNP differed significantly among the types of ACHD. Furthermore, a disease-specific correlation was seen between NT-proBNP and ECG / echocardiographic parameters. NT-proBNP was correlated with impaired diastolic dysfunction only among ACHD patients with left-sided pathology and with impaired RV systolic function only among ACHD patients with a systemic RV. Exercise capacity has been found to be strong risk predictor in the ACHD patients.4 The correlation of worsening exercise capacity with increasing NT-proBNP in this study may indicate the possible use of this cardiac biomarker for risk estimation in ACHD. The onset of RV failure is considered a poor prognostic sign in repaired ACHD. The positive correlations of NT-proBNP with RV overload and failure in systemic RV support the potential future use of this marker for monitoring RV function in ACHD and may help decide the timing of an intervention in patients with severe tricuspid regurgitation.

The most significant limitation of the study is its cross sectional design. A prospective longitudinal study may further elucidate the role of NT-proBNP as a prognostic biomarker in ACHD patients

To summarize, the study is the most comprehensive biomarker study in ACHD to date supporting the potential for NT-proBNP to become a clinically relevant biomarker in ACHD patients. However, whether this biomarker adds incremental prognostic value to clinical symptoms, echocardiography and exercise testing in these patients remains to be seen.


  1. Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998;339:321-8.
  2. Eindhoven JA, van den Bosch AE, Ruys TPE, et al. N-terminal proBrain Natriuretic Peptide and its Relation with Cardiac Function in Adult Patients with Congenital Heart Disease. J Am Coll Cardiol 2013. [Epub ahead of print].
  3. Luchner A, Behrens G, Stritzke J, Markus M, Stark K, Peters A, et al. Long-term pattern of brain natriuretic peptide and N-terminal pro brain natriuretic peptide and its determinants in the general population: contribution of age, gender, and cardiac and extra-cardiac factors. Eur J Heart Fail 2013;15:859-67.
  4. Inuzuka R, Diller GP, Borgia F, Benson L, Tay EL, Alonso-Gonzalez R, et al. Comprehensive use of cardiopulmonary exercise testing identifies adults with congenital heart disease at increased mortality risk in the medium term. Circulation 2012;125:250-9.

Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Congenital Heart Disease

Keywords: Biological Markers, Heart Defects, Congenital, Heart Diseases, Myocytes, Cardiac, Natriuretic Peptide, Brain

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