Preoperative N-terminal pro-brain natriuretic peptide is associated with Fontan outcomes

Published:December 09, 2021DOI:



      The role of preoperative N-terminal pro-brain natriuretic peptide level in patient outcomes after the Fontan operation remains unclear.


      The medical records of all patients who underwent their first Fontan operation from June 2011 to October 2019 in our tertiary referral pediatric cardiac center were retrospectively reviewed. Preoperative hemodynamic factors and N-terminal pro-brain natriuretic peptide were analyzed to test the association of mortality and morbidity.


      We enrolled 110 patients (men/women 62/48; median age, 4.1 [3.4, 5.8] years; median follow-up period, 4.28 [2.31, 6.71] years). Almost all operations were extracardiac conduits (98.2%). Primary outcomes of death, Fontan takedown, and heart transplantation were observed in 9 patients (8.2%). Abnormal ventricular contractility, elevated preoperative pulmonary artery pressure, high pulmonary vascular resistance index, and high log10 N-terminal pro-brain natriuretic peptide level were associated with poor outcomes. Secondary outcomes: atrioventricular valve regurgitation moderate or greater, elevated pulmonary artery pressure, high pulmonary vascular resistance index, and high log10 N-terminal pro-brain natriuretic peptide level were associated with rehospitalization due to heart failure. Multivariable Cox regression analysis revealed that log10 N-terminal pro-brain natriuretic peptide was the only significant predictor of all primary and secondary outcomes. A scoring system including factors of pulmonary artery pressure, pulmonary vascular resistance index, and N-terminal pro-brain natriuretic peptide was established, and the risk stratification is associated with outcomes after the Fontan operation.


      High preoperative N-terminal pro-brain natriuretic peptide was associated with poor outcomes after the Fontan operation.

      Graphical abstract

      Key Words

      Abbreviations and Acronyms:

      AVVR (atrioventricular valve regurgitation), BNP (brain natriuretic peptide), CI (confidence interval), HR (hazard ratio), NT-proBNP (N-terminal pro-brain natriuretic peptide), PAP (pulmonary artery pressure), PVRI (pulmonary vascular resistance index)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Thoracic and Cardiovascular Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Lin H.C.
        • Wu M.H.
        • Wang J.K.
        • Lin M.T.
        • Chen C.A.
        • Lu C.W.
        • et al.
        Perioperative outcomes of Fontan operation: impact of heterotaxy syndrome.
        J Formos Med Assoc. 2022; 121: 89-97
        • Downing T.E.
        • Allen K.Y.
        • Glatz A.C.
        • Rogers L.S.
        • Ravishankar C.
        • Rychik J.
        • et al.
        Long-term survival after the Fontan operation: twenty years of experience at a single center.
        J Thorac Cardiovasc Surg. 2017; 154: 243-253.e242
        • Hosein R.B.
        • Clarke A.J.
        • McGuirk S.P.
        • Griselli M.
        • Stumper O.
        • De Giovanni J.V.
        • et al.
        Factors influencing early and late outcome following the Fontan procedure in the current era. The ‘Two Commandments’?.
        Eur J Cardiothorac Surg. 2007; 31: 344-353
        • Hall C.
        NT-ProBNP: the mechanism behind the marker.
        J Card Fail. 2005; 11: S81-S83
        • Sawada Y.
        • Suda M.
        • Yokoyama H.
        • Kanda T.
        • Sakamaki T.
        • Tanaka S.
        • et al.
        Stretch-induced hypertrophic growth of cardiocytes and processing of brain-type natriuretic peptide are controlled by proprotein-processing endoprotease furin.
        J Biol Chem. 1997; 272: 20545-20554
        • Palazzuoli A.
        • Gallotta M.
        • Quatrini I.
        • Nuti R.
        Natriuretic peptides (BNP and NT-proBNP): measurement and relevance in heart failure.
        Vasc Health Risk Manag. 2010; 6: 411-418
        • Fijalkowska A.
        • Kurzyna M.
        • Torbicki A.
        • Szewczyk G.
        • Florczyk M.
        • Pruszczyk P.
        • et al.
        Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension.
        Chest. 2006; 129: 1313-1321
        • Nir A.
        • Nasser N.
        Clinical value of NT-ProBNP and BNP in pediatric cardiology.
        J Card Fail. 2005; 11: S76-S80
        • LaFarge C.G.
        • Miettinen O.S.
        The estimation of oxygen consumption.
        Cardiovasc Res. 1970; 4: 23-30
        • Choussat A.
        • Fontan F.
        • Besse P.
        Selection criteria for the Fontan procedure.
        in: Anderson R.H. Shinebourne E.A. Paediatric Cardiology. Churchill Livingstone, Edinburgh, Scotland1977: 559-566
        • Stern H.J.
        Fontan “Ten Commandments” revisited and revised.
        Pediatr Cardiol. 2010; 31: 1131-1134
        • Hsu D.T.
        The Fontan operation: the long-term outlook.
        Curr Opin Pediatr. 2015; 27: 569-575
        • Rogers L.S.
        • Glatz A.C.
        • Ravishankar C.
        • Spray T.L.
        • Nicolson S.C.
        • Rychik J.
        • et al.
        18 years of the Fontan operation at a single institution: results from 771 consecutive patients.
        J Am Coll Cardiol. 2012; 60: 1018-1025
        • Egbe A.C.
        • Connolly H.M.
        • Miranda W.R.
        • Ammash N.M.
        • Hagler D.J.
        • Veldtman G.R.
        • et al.
        Hemodynamics of Fontan failure: the role of pulmonary vascular disease.
        Circ Heart Fail. 2017; 10: e004515
        • Malhotra S.P.
        • Ivy D.D.
        • Mitchell M.B.
        • Campbell D.N.
        • Dines M.L.
        • Miyamoto S.
        • et al.
        Performance of cavopulmonary palliation at elevated altitude: midterm outcomes and risk factors for failure.
        Circulation. 2008; 118: S177-S181
        • Yoshimura N.
        • Yamaguchi M.
        • Oshima Y.
        • Oka S.
        • Ootaki Y.
        • Tei T.
        • et al.
        Risk factors influencing early and late mortality after total cavopulmonary connection.
        Eur J Cardiothorac Surg. 2001; 20: 598-602
        • Stephens E.H.
        • Dearani J.A.
        • Niaz T.
        • Arghami A.
        • Phillips S.D.
        • Cetta F.
        Effect of earlier atrioventricular valve intervention on survival after the Fontan operation.
        Am J Cardiol. 2020; 137: 103-110
        • Kim S.J.
        • Kim W.H.
        • Lim H.G.
        • Lee C.H.
        • Lee J.Y.
        Improving results of the Fontan procedure in patients with heterotaxy syndrome.
        Ann Thorac Surg. 2006; 82: 1245-1251
        • Marathe S.P.
        • Cao J.Y.
        • Celermajer D.
        • Ayer J.
        • Sholler G.F.
        • d’Udekem Y.
        • et al.
        Outcomes of the Fontan operation for patients with heterotaxy: a meta-analysis of 848 patients.
        Ann Thorac Surg. 2020; 110: 307-315
        • Marathe S.P.
        • Zannino D.
        • Cao J.Y.
        • du Plessis K.
        • Marathe S.S.
        • Ayer J.
        • et al.
        Heterotaxy is not a risk factor for adverse long-term outcomes after Fontan completion.
        Ann Thorac Surg. 2020; 110: 646-653
        • Shao P.L.
        • Chen M.Y.
        • Wu M.H.
        • Wang J.K.
        • Huang L.M.
        • Chiu S.N.
        Nosocomial severe bacterial infection after cardiac surgery for complex congenital heart disease in heterotaxy syndrome.
        Pediatr Infect Dis J. 2020; 39: e163-e168
        • Chiu S.N.
        • Shao P.L.
        • Wang J.K.
        • Chen H.C.
        • Lin M.T.
        • Chang L.Y.
        • et al.
        Severe bacterial infection in patients with heterotaxy syndrome.
        J Pediatr. 2014; 164: 99-104.e101
        • Julsrud P.R.
        • Weigel T.J.
        • Van Son J.A.
        • Edwards W.D.
        • Mair D.D.
        • Driscoll D.J.
        • et al.
        Influence of ventricular morphology on outcome after the Fontan procedure.
        Am J Cardiol. 2000; 86: 319-323
        • Tweddell J.S.
        • Nersesian M.
        • Mussatto K.A.
        • Nugent M.
        • Simpson P.
        • Mitchell M.E.
        • et al.
        Fontan palliation in the modern era: factors impacting mortality and morbidity.
        Ann Thorac Surg. 2009; 88: 1291-1299
        • Lechner E.
        • Schreier-Lechner E.M.
        • Hofer A.
        • Hofer A.
        • Gitter R.
        • Mair R.
        • et al.
        Aminoterminal brain-type natriuretic peptide levels correlate with heart failure in patients with bidirectional Glenn anastomosis and with morbidity after the Fontan operation.
        J Thorac Cardiovasc Surg. 2009; 138: 560-564
        • Qu J.
        • Liang H.
        • Zhou N.
        • Li L.
        • Wang Y.
        • Li J.
        • et al.
        Perioperative NT-proBNP level: potential prognostic markers in children undergoing congenital heart disease surgery.
        J Thorac Cardiovasc Surg. 2017; 154: 631-640
        • Choi J.H.
        • Cho D.K.
        • Song Y.B.
        • Hahn J.Y.
        • Choi S.
        • Gwon H.C.
        • et al.
        Preoperative NT-proBNP and CRP predict perioperative major cardiovascular events in non-cardiac surgery.
        Heart. 2010; 96: 56-62
        • Souza R.
        • Jardim C.
        • Julio Cesar Fernandes C.
        • Silveira Lapa M.
        • Rabelo R.
        • Humbert M.
        NT-proBNP as a tool to stratify disease severity in pulmonary arterial hypertension.
        Respir Med. 2007; 101: 69-75
        • Chiu S.N.
        • Weng K.P.
        • Lin M.C.
        • Wang J.N.
        • Hwang B.T.
        • Dai Z.K.
        • et al.
        Congenital heart disease with pulmonary artery hypertension in an Asian cohort-initial report from TACHYON (TAiwan congenital heart disease associated with pulmonarY arterial hypertension) registry.
        Int J Cardiol. 2020; 317: 49-55
        • Lechner E.
        • Gitter R.
        • Mair R.
        • Pinter M.
        • Schreier-Lechner E.
        • Vondrys D.
        • et al.
        Aminoterminal brain natriuretic peptide levels in children and adolescents after Fontan operation correlate with congestive heart failure.
        Pediatr Cardiol. 2008; 29: 901-905
        • Lowenthal A.
        • Camacho B.V.
        • Lowenthal S.
        • Natal-Hernandez L.
        • Liszewski W.
        • Hills N.K.
        • et al.
        Usefulness of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide as biomarkers for heart failure in young children with single ventricle congenital heart disease.
        Am J Cardiol. 2012; 109: 866-872
        • Eindhoven J.A.
        • van den Bosch A.E.
        • Ruys T.P.
        • Opić P.
        • Cuypers J.A.A.E.
        • McGhie J.S.
        • et al.
        N-terminal pro-B-type natriuretic peptide and its relationship with cardiac function in adults with congenital heart disease.
        J Am Coll Cardiol. 2013; 62: 1203-1212
        • Salazar J.D.
        • Zafar F.
        • Siddiqui K.
        • Coleman R.D.
        • Morales D.L.S.
        • Heinle J.S.
        • et al.
        Fenestration during Fontan palliation: now the exception instead of the rule.
        J Thorac Cardiovasc Surg. 2010; 140: 129-136
        • Fan F.
        • Liu Z.
        • Li S.
        • Yi T.
        • Yan J.
        • Yan F.
        • et al.
        Effect of fenestration on early postoperative outcome in extracardiac Fontan patients with different risk levels.
        Pediatr Cardiol. 2017; 38: 643-649

      Linked Article

      • Commentary: A new Fontan commandment
        The Journal of Thoracic and Cardiovascular SurgeryVol. 164Issue 3
        • Preview
          Choussat's Ten Commandments1 delineating the appropriate selection criteria for Fontan palliation are well known and carefully regarded among practicing congenital heart surgeons. While many of the criteria have evolved, ventricular performance and the hemodynamic health of the pulmonary vascular bed remain cornerstones of candidacy. Lin and colleagues2 share important insights in their study, “Preoperative N-terminal pro-brain natriuretic peptide is associated with Fontan outcomes,” and provide compelling data that would suggest adding an 11th commandment to the list.
        • Full-Text
        • PDF
      • Commentary: A new Fontan commandment?
        The Journal of Thoracic and Cardiovascular SurgeryVol. 164Issue 3
        • Preview
          Since its inception in 1971, the Fontan procedure has become the mainstay of surgical palliation of single-ventricle anomalies.1 Over the years, several surgical modifications have been adopted with the aim to address some of the shortcomings associated with the original descriptions of the procedure.2 The Fontan “10 commandments” were first defined by Choussat and colleagues3 in 1978 as the basic criteria that the patient should meet to predict successful Fontan palliation. These commandments served for many years as guidelines for physicians to select patients who will be advanced toward the last stage of palliation: the Fontan procedure.
        • Full-Text
        • PDF