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Failing Fontan Following Total Cavopulmonary Connection: Extracardiac Biomarkers Reveal 2 Distinct Phenotypes With Divergent Clinical Courses.

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Τίτλος: Failing Fontan Following Total Cavopulmonary Connection: Extracardiac Biomarkers Reveal 2 Distinct Phenotypes With Divergent Clinical Courses.
Συγγραφείς: Matsubara M; Department of Congenital and Pediatric Heart Surgery, TUM University Hospital, German Heart Center, Munich, Germany; Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig- Maximilians-Universität München, Munich, Germany; Europäisches Kinderherzzentrum München, Munich 80636, Germany.; Department of Cardiovascular Surgery, Tokyo Metropolitan Children's Medical Center, Tokyo 183-8561, Japan., Aldogan H; Department of Congenital and Pediatric Heart Surgery, TUM University Hospital, German Heart Center, Munich, Germany; Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig- Maximilians-Universität München, Munich, Germany; Europäisches Kinderherzzentrum München, Munich 80636, Germany., Schaeffer T; Department of Congenital and Pediatric Heart Surgery, TUM University Hospital, German Heart Center, Munich, Germany; Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig- Maximilians-Universität München, Munich, Germany; Europäisches Kinderherzzentrum München, Munich 80636, Germany., Ruda C; Department of Congenital and Pediatric Heart Surgery, TUM University Hospital, German Heart Center, Munich, Germany; Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig- Maximilians-Universität München, Munich, Germany; Europäisches Kinderherzzentrum München, Munich 80636, Germany., Röhlig C; Department of Congenital Heart Disease and Pediatric Cardiology, TUM University Hospital, German Heart Center, Munich 80636, Germany., Palm J; Department of Congenital Heart Disease and Pediatric Cardiology, TUM University Hospital, German Heart Center, Munich 80636, Germany., Piber N; Department of Cardiovascular Surgery, TUM University Hospital, German Heart Center, Munich 80636, Germany., Hager A; Department of Congenital Heart Disease and Pediatric Cardiology, TUM University Hospital, German Heart Center, Munich 80636, Germany., Ewert P; Department of Congenital Heart Disease and Pediatric Cardiology, TUM University Hospital, German Heart Center, Munich 80636, Germany., Hörer J; Department of Congenital and Pediatric Heart Surgery, TUM University Hospital, German Heart Center, Munich, Germany; Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig- Maximilians-Universität München, Munich, Germany; Europäisches Kinderherzzentrum München, Munich 80636, Germany., Ono M; Department of Congenital and Pediatric Heart Surgery, TUM University Hospital, German Heart Center, Munich, Germany; Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig- Maximilians-Universität München, Munich, Germany; Europäisches Kinderherzzentrum München, Munich 80636, Germany.
Πηγή: Interdisciplinary cardiovascular and thoracic surgery [Interdiscip Cardiovasc Thorac Surg] 2026 Aug 03; Vol. 41 (8).
Τύπος έκδοσης: Journal Article; Research Support, Non-U.S. Gov't
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Oxford University Press Country of Publication: England NLM ID: 9918540787006676 Publication Model: Print Cited Medium: Internet ISSN: 2753-670X (Electronic) Linking ISSN: 2753670X NLM ISO Abbreviation: Interdiscip Cardiovasc Thorac Surg Subsets: MEDLINE
Imprint Name(s): Original Publication: [Oxford, England] : Oxford University Press, [2023]-
Ιατρικοί όροι (MeSH): Fontan Procedure*/adverse effects , Heart Defects, Congenital*/surgery , Heart Defects, Congenital*/blood , Protein-Losing Enteropathies*/blood , Protein-Losing Enteropathies*/etiology , Protein-Losing Enteropathies*/diagnosis , Heart Failure*/blood , Heart Failure*/etiology , Heart Failure*/diagnosis , Peptide Fragments*/blood , Natriuretic Peptide, Brain*/blood , Heart Bypass, Right*/adverse effects, Biomarkers/blood ; Humans ; Female ; Male ; Phenotype ; Treatment Failure ; Retrospective Studies ; Child ; Lymphocyte Count ; Risk Factors ; Child, Preschool ; Time Factors
Περίληψη: Objectives: Failing Fontan is an increasingly recognized complication after total cavopulmonary connection (TCPC), yet longitudinal biomarker data remain scarce. We aimed to characterize the incidence, biomarker trajectories, and prognostic determinants of failing Fontan.
Methods: All patients who underwent primary TCPC (n = 650) or conversion to TCPC (n = 19) at our centre between 1994 and 2022 were reviewed. Lymphocyte count, N-terminal pro-brain natriuretic peptide (NT-proBNP) and its zlog value, and Fibrosis-4 index were assessed at 1 year before, 6 months before, at onset, and at last follow-up. Patients were classified into protein-losing enteropathy (PLE)/plastic bronchitis (PB) and heart failure phenotypes.
Results: Failing Fontan developed in 78 primary TCPC patients (12.0%) and 12 conversion patients (63.2%). Conversion patients developed failing Fontan earlier (P < .001), but survival after onset was comparable. Lymphocyte counts declined before onset (2.49 to 0.89 × 10³/µL, P < .001) and the Fibrosis-4 index increased (0.060 to 0.330, P < .001). Phenotypes showed divergent profiles: zlog-NT-proBNP at onset was 0.71 in PLE/PB versus 5.34 in heart failure (P < .001). Lymphocytopenia (LP) predicted mortality early (hazard ratio 6.77, P = .013) but appeared protective at last follow-up (hazard ratio 0.18, P = .049), reflecting a phenotypic shift. On multivariable analysis, lower lymphocyte count independently predicted mortality (hazard ratio 2.44, P = .041), while stent implantation was independently associated with lower mortality (hazard ratio 0.32, P = .040).
Conclusions: Lymphocyte counts and the Fibrosis-4 index change progressively before clinical onset and may serve as early warning biomarkers. The prognostic interpretation of LP depends on the underlying phenotype, underscoring the need for phenotype-aware monitoring.
(© The Author(s) 2026. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)
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Grant Information: Förderverein des Deutschen Herzzentrums München
Contributed Indexing: Keywords: Fib 4; NT-proBNP; failing Fontan; lymphocytopenia; total cavopulmonary connection
Substance Nomenclature: 0 (Biomarkers)
0 (pro-brain natriuretic peptide (1-76))
0 (Peptide Fragments)
114471-18-0 (Natriuretic Peptide, Brain)
Entry Date(s): Date Created: 20260730 Date Completed: 20260821 Latest Revision: 20261009
Update Code: 20261009
PubMed Central ID: PMC13496394
DOI: 10.1093/icvts/ivag213
PMID: 42530872
Βάση Δεδομένων: MEDLINE
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  Data: Failing Fontan Following Total Cavopulmonary Connection: Extracardiac Biomarkers Reveal 2 Distinct Phenotypes With Divergent Clinical Courses.
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  Data: &lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Matsubara+M%22&quot;&gt;Matsubara M&lt;/searchLink&gt;; Department of Congenital and Pediatric Heart Surgery, TUM University Hospital, German Heart Center, Munich, Germany; Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig- Maximilians-Universit&#228;t M&#252;nchen, Munich, Germany; Europ&#228;isches Kinderherzzentrum M&#252;nchen, Munich 80636, Germany.; Department of Cardiovascular Surgery, Tokyo Metropolitan Children&#39;s Medical Center, Tokyo 183-8561, Japan.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Aldogan+H%22&quot;&gt;Aldogan H&lt;/searchLink&gt;; Department of Congenital and Pediatric Heart Surgery, TUM University Hospital, German Heart Center, Munich, Germany; Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig- Maximilians-Universit&#228;t M&#252;nchen, Munich, Germany; Europ&#228;isches Kinderherzzentrum M&#252;nchen, Munich 80636, Germany.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Schaeffer+T%22&quot;&gt;Schaeffer T&lt;/searchLink&gt;; Department of Congenital and Pediatric Heart Surgery, TUM University Hospital, German Heart Center, Munich, Germany; Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig- Maximilians-Universit&#228;t M&#252;nchen, Munich, Germany; Europ&#228;isches Kinderherzzentrum M&#252;nchen, Munich 80636, Germany.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Ruda+C%22&quot;&gt;Ruda C&lt;/searchLink&gt;; Department of Congenital and Pediatric Heart Surgery, TUM University Hospital, German Heart Center, Munich, Germany; Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig- Maximilians-Universit&#228;t M&#252;nchen, Munich, Germany; Europ&#228;isches Kinderherzzentrum M&#252;nchen, Munich 80636, Germany.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22R&#246;hlig+C%22&quot;&gt;R&#246;hlig C&lt;/searchLink&gt;; Department of Congenital Heart Disease and Pediatric Cardiology, TUM University Hospital, German Heart Center, Munich 80636, Germany.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Palm+J%22&quot;&gt;Palm J&lt;/searchLink&gt;; Department of Congenital Heart Disease and Pediatric Cardiology, TUM University Hospital, German Heart Center, Munich 80636, Germany.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Piber+N%22&quot;&gt;Piber N&lt;/searchLink&gt;; Department of Cardiovascular Surgery, TUM University Hospital, German Heart Center, Munich 80636, Germany.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Hager+A%22&quot;&gt;Hager A&lt;/searchLink&gt;; Department of Congenital Heart Disease and Pediatric Cardiology, TUM University Hospital, German Heart Center, Munich 80636, Germany.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Ewert+P%22&quot;&gt;Ewert P&lt;/searchLink&gt;; Department of Congenital Heart Disease and Pediatric Cardiology, TUM University Hospital, German Heart Center, Munich 80636, Germany.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22H&#246;rer+J%22&quot;&gt;H&#246;rer J&lt;/searchLink&gt;; Department of Congenital and Pediatric Heart Surgery, TUM University Hospital, German Heart Center, Munich, Germany; Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig- Maximilians-Universit&#228;t M&#252;nchen, Munich, Germany; Europ&#228;isches Kinderherzzentrum M&#252;nchen, Munich 80636, Germany.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Ono+M%22&quot;&gt;Ono M&lt;/searchLink&gt;; Department of Congenital and Pediatric Heart Surgery, TUM University Hospital, German Heart Center, Munich, Germany; Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig- Maximilians-Universit&#228;t M&#252;nchen, Munich, Germany; Europ&#228;isches Kinderherzzentrum M&#252;nchen, Munich 80636, Germany.
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– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Objectives: Failing Fontan is an increasingly recognized complication after total cavopulmonary connection (TCPC), yet longitudinal biomarker data remain scarce. We aimed to characterize the incidence, biomarker trajectories, and prognostic determinants of failing Fontan.&lt;br /&gt;Methods: All patients who underwent primary TCPC (n = 650) or conversion to TCPC (n = 19) at our centre between 1994 and 2022 were reviewed. Lymphocyte count, N-terminal pro-brain natriuretic peptide (NT-proBNP) and its zlog value, and Fibrosis-4 index were assessed at 1 year before, 6 months before, at onset, and at last follow-up. Patients were classified into protein-losing enteropathy (PLE)/plastic bronchitis (PB) and heart failure phenotypes.&lt;br /&gt;Results: Failing Fontan developed in 78 primary TCPC patients (12.0%) and 12 conversion patients (63.2%). Conversion patients developed failing Fontan earlier (P &amp;lt; .001), but survival after onset was comparable. Lymphocyte counts declined before onset (2.49 to 0.89 &#215; 10&#179;/&#181;L, P &amp;lt; .001) and the Fibrosis-4 index increased (0.060 to 0.330, P &amp;lt; .001). Phenotypes showed divergent profiles: zlog-NT-proBNP at onset was 0.71 in PLE/PB versus 5.34 in heart failure (P &amp;lt; .001). Lymphocytopenia (LP) predicted mortality early (hazard ratio 6.77, P = .013) but appeared protective at last follow-up (hazard ratio 0.18, P = .049), reflecting a phenotypic shift. On multivariable analysis, lower lymphocyte count independently predicted mortality (hazard ratio 2.44, P = .041), while stent implantation was independently associated with lower mortality (hazard ratio 0.32, P = .040).&lt;br /&gt;Conclusions: Lymphocyte counts and the Fibrosis-4 index change progressively before clinical onset and may serve as early warning biomarkers. The prognostic interpretation of LP depends on the underlying phenotype, underscoring the need for phenotype-aware monitoring.&lt;br /&gt; (&#169; The Author(s) 2026. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)
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  Label: References
  Group: RefInfo
  Data: Circulation. 2019 Aug 6;140(6):e234-e284. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2231256636%22&quot;&gt;31256636)&lt;/searchLink&gt;&lt;br /&gt;Cardiol Young. 2020 May;30(5):641-648. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2232248856%22&quot;&gt;32248856)&lt;/searchLink&gt;&lt;br /&gt;J Cardiovasc Dev Dis. 2025 Sep 16;12(9):. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2241002637%22&quot;&gt;41002637)&lt;/searchLink&gt;&lt;br /&gt;JHEP Rep. 2021 Sep 14;3(6):100362. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2234693238%22&quot;&gt;34693238)&lt;/searchLink&gt;&lt;br /&gt;Front Cardiovasc Med. 2022 Mar 10;9:767503. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2235360016%22&quot;&gt;35360016)&lt;/searchLink&gt;&lt;br /&gt;Circulation. 1998 Jan 6-13;97(1):19-22. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%229443426%22&quot;&gt;9443426)&lt;/searchLink&gt;&lt;br /&gt;Eur J Cardiothorac Surg. 2016 Oct;50(4):632-641. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2227009106%22&quot;&gt;27009106)&lt;/searchLink&gt;&lt;br /&gt;Int J Cardiol. 2013 Oct 9;168(4):3764-9. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2223849105%22&quot;&gt;23849105)&lt;/searchLink&gt;&lt;br /&gt;Thorac Cardiovasc Surg. 2015 Aug;63(5):380-7. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2225803119%22&quot;&gt;25803119)&lt;/searchLink&gt;&lt;br /&gt;Ann Thorac Surg. 2007 Sep;84(3):894-9. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2217720396%22&quot;&gt;17720396)&lt;/searchLink&gt;&lt;br /&gt;J Allergy Clin Immunol Pract. 2016 May-Jun;4(3):491-6. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2226897303%22&quot;&gt;26897303)&lt;/searchLink&gt;&lt;br /&gt;Eur Heart J. 2019 Apr 1;40(13):1057-1068. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2230346512%22&quot;&gt;30346512)&lt;/searchLink&gt;&lt;br /&gt;CJC Open. 2024 Feb 06;6(6):773-780. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2239022165%22&quot;&gt;39022165)&lt;/searchLink&gt;&lt;br /&gt;J Am Coll Cardiol. 2018 Mar 6;71(9):1009-1017. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2229495980%22&quot;&gt;29495980)&lt;/searchLink&gt;&lt;br /&gt;Circ Heart Fail. 2025 Dec;18(12):e012990. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2241082342%22&quot;&gt;41082342)&lt;/searchLink&gt;&lt;br /&gt;J Am Coll Cardiol. 2021 Nov 9;78(19):1890-1900. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2234736565%22&quot;&gt;34736565)&lt;/searchLink&gt;&lt;br /&gt;Hepatology. 2006 Jun;43(6):1317-25. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2216729309%22&quot;&gt;16729309)&lt;/searchLink&gt;&lt;br /&gt;Congenit Heart Dis. 2016 Jul;11(4):296-308. (PMID: &lt;searchLink fieldCode=&quot;PM&quot; term=&quot;%2227226033%22&quot;&gt;27226033)&lt;/searchLink&gt;
– Name: GrantInfo
  Label: Grant Information
  Group: Grant
  Data: F&#246;rderverein des Deutschen Herzzentrums M&#252;nchen
– Name: SubjectMinor
  Label: Contributed Indexing
  Group:
  Data: &lt;i&gt;Keywords: &lt;/i&gt;Fib 4; NT-proBNP; failing Fontan; lymphocytopenia; total cavopulmonary connection
– Name: NumberCAS
  Label: Substance Nomenclature
  Group: ID
  Data: 0 (Biomarkers)&lt;br /&gt;0 (pro-brain natriuretic peptide (1-76))&lt;br /&gt;0 (Peptide Fragments)&lt;br /&gt;114471-18-0 (Natriuretic Peptide, Brain)
– Name: DateEntry
  Label: Entry Date(s)
  Group: Date
  Data: &lt;i&gt;Date Created: &lt;/i&gt;20260730 &lt;i&gt;Date Completed: &lt;/i&gt;20260821 &lt;i&gt;Latest Revision: &lt;/i&gt;20261009
– Name: DateUpdate
  Label: Update Code
  Group: Date
  Data: 20261009
– Name: PubmedCentralID
  Label: PubMed Central ID
  Group: ID
  Data: PMC13496394
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1093/icvts/ivag213
– Name: AN
  Label: PMID
  Group: ID
  Data: 42530872
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=cmedm&AN=42530872
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1093/icvts/ivag213
    Languages:
      – Code: eng
        Text: English
    Subjects:
      – SubjectFull: Biomarkers blood
        Type: general
      – SubjectFull: Humans
        Type: general
      – SubjectFull: Female
        Type: general
      – SubjectFull: Male
        Type: general
      – SubjectFull: Phenotype
        Type: general
      – SubjectFull: Treatment Failure
        Type: general
      – SubjectFull: Retrospective Studies
        Type: general
      – SubjectFull: Child
        Type: general
      – SubjectFull: Lymphocyte Count
        Type: general
      – SubjectFull: Risk Factors
        Type: general
      – SubjectFull: Child, Preschool
        Type: general
      – SubjectFull: Time Factors
        Type: general
      – SubjectFull: Fontan Procedure adverse effects
        Type: general
      – SubjectFull: Heart Defects, Congenital surgery
        Type: general
      – SubjectFull: Heart Defects, Congenital blood
        Type: general
      – SubjectFull: Protein-Losing Enteropathies blood
        Type: general
      – SubjectFull: Protein-Losing Enteropathies etiology
        Type: general
      – SubjectFull: Protein-Losing Enteropathies diagnosis
        Type: general
      – SubjectFull: Heart Failure blood
        Type: general
      – SubjectFull: Heart Failure etiology
        Type: general
      – SubjectFull: Heart Failure diagnosis
        Type: general
      – SubjectFull: Peptide Fragments blood
        Type: general
      – SubjectFull: Natriuretic Peptide, Brain blood
        Type: general
      – SubjectFull: Heart Bypass, Right adverse effects
        Type: general
    Titles:
      – TitleFull: Failing Fontan Following Total Cavopulmonary Connection: Extracardiac Biomarkers Reveal 2 Distinct Phenotypes With Divergent Clinical Courses.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Matsubara M
      – PersonEntity:
          Name:
            NameFull: Aldogan H
      – PersonEntity:
          Name:
            NameFull: Schaeffer T
      – PersonEntity:
          Name:
            NameFull: Ruda C
      – PersonEntity:
          Name:
            NameFull: Röhlig C
      – PersonEntity:
          Name:
            NameFull: Palm J
      – PersonEntity:
          Name:
            NameFull: Piber N
      – PersonEntity:
          Name:
            NameFull: Hager A
      – PersonEntity:
          Name:
            NameFull: Ewert P
      – PersonEntity:
          Name:
            NameFull: Hörer J
      – PersonEntity:
          Name:
            NameFull: Ono M
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 03
              M: 08
              Text: 2026 Aug 03
              Type: published
              Y: 2026
          Identifiers:
            – Type: issn-electronic
              Value: 2753-670X
          Numbering:
            – Type: volume
              Value: 41
            – Type: issue
              Value: 8
          Titles:
            – TitleFull: Interdisciplinary cardiovascular and thoracic surgery
              Type: main
ResultId 1