{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T04:43:55Z","timestamp":1774154635846,"version":"3.50.1"},"reference-count":42,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,7,7]],"date-time":"2023-07-07T00:00:00Z","timestamp":1688688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"publisher","award":["2013T091"],"award-info":[{"award-number":["2013T091"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCDD"],"abstract":"<jats:p>Fontan patients undergo multiple cardiothoracic surgeries in childhood. Following these procedures, ventricular function is temporarily decreased, and recovers over months. This is presumably related to cardiopulmonary bypass, but this is incompletely understood. Throughout the Fontan palliation, cardiac function is also affected by volume unloading. We aimed to gain insight into the biological processes related to impaired ventricular function and recovery following Fontan palliations using a panel of biomarkers. Furthermore, we described changes in ventricular function across the Fontan palliation due to volume unloading. We performed a prospective multicenter observational study in patients undergoing partial (PCPC) or total cavo-pulmonary connection (TCPC). Patients underwent assessment\u2014including echocardiography and blood sampling\u2014before surgery (T1), at first follow-up (T2), and 1 year after their procedures (T3). Blood samples were analyzed using a biomarker panel (OLINK CVD-III). Ninety-two biomarkers were expressed as principal components (PC) to limit multiple statistical testing. We included 32 PCPC patients aged 7.2 [5.3\u201310.3] months, and 28 TCPC patients aged 2.7 [2.2\u20133.8] years. The single ventricular longitudinal strain (SV GLS) temporarily decreased for PCPC patients at T2 (\u221215.1 \u00b1 5.6 (T1) to \u221213.5 \u00b1 5.2 (T2) to \u221217.3 \u00b1 4.5 (T3), p &lt; 0.047 for all differences), but not following TCPC. The serum biomarkers were expressed as 4 PCs. PC1, including biomarkers of cell\u2013cell adhesion, was not related to any patient characteristic. PC2, including biomarkers of superoxide anion regulation, increased at T2. PC3, including biomarkers of cardiovascular development, related to the stage of Fontan palliation. PC4 was of uncertain biological or clinical significance. No PC was found that related to ventricular performance. The SV GLS was temporarily diminished following PCPC, but not following TCPC. Several biomarkers were related to post-operative stress and adaptation to the PCPC or TCPC circulation, but none were related to the outcome.<\/jats:p>","DOI":"10.3390\/jcdd10070289","type":"journal-article","created":{"date-parts":[[2023,7,7]],"date-time":"2023-07-07T01:57:09Z","timestamp":1688695029000},"page":"289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cardiac Function and Serum Biomarkers throughout Staged Fontan Palliation: A Prospective Observational Study"],"prefix":"10.3390","volume":"10","author":[{"given":"J. P. G.","family":"van der Ven","sequence":"first","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatrics, Erasmus MC Sophia Children\u2019s Hospital, 3015 CN Rotterdam, The Netherlands"},{"name":"Netherlands Heart Institute, 3501 DG Utrecht, The Netherlands"},{"name":"Department of Cardiothoracic Surgery, Erasmus MC, 3015 CN Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V P.","family":"Kamphuis","sequence":"additional","affiliation":[{"name":"Netherlands Heart Institute, 3501 DG Utrecht, The Netherlands"},{"name":"Division of Pediatric Cardiology, Department of Pediatrics, Leiden University Medical Center, 2300 RA Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E","family":"van den Bosch","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatrics, Erasmus MC Sophia Children\u2019s Hospital, 3015 CN Rotterdam, The Netherlands"},{"name":"Netherlands Heart Institute, 3501 DG Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D","family":"Gnanam","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatrics, Erasmus MC Sophia Children\u2019s Hospital, 3015 CN Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Terol","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatrics, Leiden University Medical Center, 2300 RA Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A J. J. C.","family":"Bogers","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Erasmus MC, 3015 CN Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. M. P. J.","family":"Breur","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatrics, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4385-5784","authenticated-orcid":false,"given":"R. M. F.","family":"Berger","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatrics, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N. A.","family":"Blom","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatrics, Leiden University Medical Center, 2300 RA Leiden, The Netherlands"},{"name":"Division of Pediatric Cardiology, Department of Pediatrics, Amsterdam University Medical Center, 1007 MB Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3016-1086","authenticated-orcid":false,"given":"A. D. J.","family":"ten Harkel","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatrics, Leiden University Medical Center, 2300 RA Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L.","family":"Koopman","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatrics, Erasmus MC Sophia Children\u2019s Hospital, 3015 CN Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. A.","family":"Helbing","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatrics, Erasmus MC Sophia Children\u2019s Hospital, 3015 CN Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"935","DOI":"10.12688\/f1000research.13792.1","article-title":"State of the art of the Fontan strategy for treatment of univentricular heart disease","volume":"7","author":"Bosch","year":"2018","journal-title":"F1000Research"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.jtcvs.2013.09.074","article-title":"Trends in Fontan surgery and risk factors for early adverse outcomes after Fontan surgery: The Australia and New Zealand Fontan Registry experience","volume":"148","author":"Iyengar","year":"2014","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1016\/j.jacc.2006.07.053","article-title":"Early and late results of the modified fontan operation for heterotaxy syndrome 30 years of experience in 142 patients","volume":"48","author":"Bartz","year":"2006","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1097\/SLA.0b013e3181858286","article-title":"Fontan operation in the current era: A 15-year single institution experience","volume":"248","author":"Hirsch","year":"2008","journal-title":"Ann. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.acvd.2016.03.005","article-title":"Postoperative assessment of left ventricular function by two-dimensional strain (speckle tracking) after paediatric cardiac surgery","volume":"109","author":"Perdreau","year":"2016","journal-title":"Arch. Cardiovasc. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1111\/echo.13456","article-title":"Decreased biventricular longitudinal strain shortly after congenital heart defect surgery","volume":"34","author":"Kuipers","year":"2017","journal-title":"Echocardiography"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1093\/ejcts\/ezt003","article-title":"Disparity in right vs left ventricular recovery during follow-up after ventricular septal defect correction in children","volume":"44","author":"Klitsie","year":"2013","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"555","DOI":"10.4103\/0971-9784.166465","article-title":"Mechanisms of oxidative stress and myocardial protection during open-heart surgery","volume":"18","author":"Baikoussis","year":"2015","journal-title":"Ann. Card. Anaesth."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.bpa.2015.03.002","article-title":"Myocardial injury and protection related to cardiopulmonary bypass","volume":"29","author":"Moerman","year":"2015","journal-title":"Best. Pract. Res. Clin. Anaesthesiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/j.echo.2006.09.001","article-title":"Guidelines and standards for performance of a pediatric echocardiogram: A report from the Task Force of the Pediatric Council of the American Society of Echocardiography","volume":"19","author":"Lai","year":"2006","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Assarsson, E., Lundberg, M., Holmquist, G., Bjorkesten, J., Thorsen, S.B., Ekman, D., Eriksson, A., Rennel Dickens, E., Ohlsson, S., and Edfeldt, G. (2014). Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0095192"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.cca.2005.11.005","article-title":"Pediatric brain natriuretic peptide and N-terminal pro-brain natriuretic peptide reference intervals","volume":"366","author":"Soldin","year":"2006","journal-title":"Clin. Chim. Acta"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/nbt0308-303","article-title":"What is principal component analysis?","volume":"26","author":"Ringner","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1016\/j.echo.2018.01.006","article-title":"Normative Data for Left and Right Ventricular Systolic Strain in Healthy Caucasian Italian Children by Two-Dimensional Speckle-Tracking Echocardiography","volume":"31","author":"Cantinotti","year":"2018","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00246-013-0802-5","article-title":"Ventricular performance after surgery for a congenital heart defect as assessed using advanced echocardiography: From doppler flow to 3D echocardiography and speckle-tracking strain imaging","volume":"35","author":"Klitsie","year":"2014","journal-title":"Pediatr. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1007\/s00246-020-02433-9","article-title":"Loss of Ventricular Function After Bidirectional Cavopulmonary Connection: Who Is at Risk?","volume":"41","author":"Vincenti","year":"2020","journal-title":"Pediatr. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.echo.2013.11.012","article-title":"Insights into the evolution of myocardial dysfunction in the functionally single right ventricle between staged palliations using speckle-tracking echocardiography","volume":"27","author":"Tham","year":"2014","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1007\/s10554-020-01870-0","article-title":"Decreased right ventricular longitudinal strain in children with hypoplastic left heart syndrome during staged repair and follow-up: Does it have implications in clinically stable patients?","volume":"36","author":"Wang","year":"2020","journal-title":"Int. J. Cardiovasc. Imaging"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s12519-008-0021-y","article-title":"Doppler myocardial performance index in assessment of ventricular function in children with single ventricles","volume":"4","author":"Zhang","year":"2008","journal-title":"World J. Pediatr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1136\/hrt.2004.051789","article-title":"The Fontan circulation","volume":"91","author":"Gewillig","year":"2005","journal-title":"Heart"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/0735-1097(96)00111-8","article-title":"Late ventricular geometry and performance changes of functional single ventricle throughout staged Fontan reconstruction assessed by magnetic resonance imaging","volume":"28","author":"Fogel","year":"1996","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.ejcts.2010.03.056","article-title":"During treatment protocol for univentricular heart serum levels of natriuretic peptides decrease","volume":"38","author":"Eerola","year":"2010","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1007\/s00246-008-9201-8","article-title":"Increased natriuretic peptide type B level after the second palliative step in children with univentricular hearts with right ventricular morphology but not left ventricular morphology","volume":"29","author":"Holmgren","year":"2008","journal-title":"Pediatr. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.athoracsur.2020.06.059","article-title":"Cardiac Biomarkers Associated With Hospital Length of Stay After Pediatric Congenital Heart Surgery","volume":"112","author":"Green","year":"2021","journal-title":"Ann. Thorac. Surg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1111\/jocs.14038","article-title":"Biomarkers associated with 30-day readmission and mortality after pediatric congenital heart surgery","volume":"34","author":"Parker","year":"2019","journal-title":"J. Card. Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"594137","DOI":"10.3389\/fmed.2020.594137","article-title":"Role of Growth Differentiation Factor 15 in Lung Disease and Senescence: Potential Role Across the Lifespan","volume":"7","author":"Reddick","year":"2020","journal-title":"Front. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"690496","DOI":"10.3389\/fphys.2021.690496","article-title":"Mild Hypoxia Enhances the Expression of HIF and VEGF and Triggers the Response to Injury in Rat Kidneys","volume":"12","author":"Xu","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.freeradbiomed.2011.05.007","article-title":"beta1-Integrin is up-regulated via Rac1-dependent reactive oxygen species as part of the hypertrophic cardiomyocyte response","volume":"51","author":"Hauselmann","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"951","DOI":"10.3389\/fimmu.2020.00951","article-title":"Growth\/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint","volume":"11","author":"Wischhusen","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1080\/10715762.2019.1584399","article-title":"Epidermal growth factor protects against myocardial ischaemia reperfusion injury through activating Nrf2 signalling pathway","volume":"53","author":"Ma","year":"2019","journal-title":"Free Radic. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e015521","DOI":"10.1161\/JAHA.119.015521","article-title":"GDF-15 (Growth Differentiation Factor 15) Is Associated With Hospitalization and Mortality in Patients With a Fontan Circulation","volume":"9","author":"Meyer","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e015022","DOI":"10.1161\/JAHA.119.015022","article-title":"Associations Between Blood Biomarkers, Cardiac Function, and Adverse Outcome in a Young Fontan Cohort","volume":"10","author":"Bossers","year":"2021","journal-title":"J. Am. Heart Assoc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e015639","DOI":"10.1161\/JAHA.119.015639","article-title":"Body Composition in Young Adults Living With a Fontan Circulation: The Myopenic Profile","volume":"9","author":"Tran","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S2347","DOI":"10.1016\/j.athoracsur.2006.02.073","article-title":"Characterizing the inflammatory response to cardiopulmonary bypass in children","volume":"81","author":"Kozik","year":"2006","journal-title":"Ann. Thorac. Surg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/S1010-7940(97)00261-3","article-title":"Effects of cardiopulmonary bypass on neonatal and paediatric inflammatory profiles","volume":"12","author":"Ashraf","year":"1997","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.trsl.2020.10.001","article-title":"Proteomic profiling identifies key differences between inter-stage infants with single ventricle heart disease and healthy controls","volume":"229","author":"Frank","year":"2021","journal-title":"Transl. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s11306-021-01846-8","article-title":"Metabolic profiles identify circulating biomarkers associated with heart failure in young single ventricle patients","volume":"17","author":"Logsdon","year":"2021","journal-title":"Metabolomics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/j.immuni.2018.10.007","article-title":"Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues","volume":"49","author":"He","year":"2018","journal-title":"Immunity"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1093\/intimm\/10.9.1393","article-title":"Circadian rhythm of the soluble p75 tumor necrosis factor (sTNF-R75) receptor in humans\u2014A possible explanation for the circadian kinetics of TNR-alpha effects","volume":"10","author":"Liebmann","year":"1998","journal-title":"Int. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3389\/fphys.2020.00129","article-title":"The Role of Clock Genes in Fibrinolysis Regulation: Circadian Disturbance and Its Effect on Fibrinolytic Activity","volume":"11","author":"Carmona","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Dencker, M., G\u00e5rdinger, Y., Bj\u00f6rgell, O., and Hlebowicz, J. (2017). Effect of food intake on 92 biomarkers for cardiovascular disease. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178656"}],"container-title":["Journal of Cardiovascular Development and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2308-3425\/10\/7\/289\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:07:49Z","timestamp":1760126869000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2308-3425\/10\/7\/289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,7]]},"references-count":42,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["jcdd10070289"],"URL":"https:\/\/doi.org\/10.3390\/jcdd10070289","relation":{},"ISSN":["2308-3425"],"issn-type":[{"value":"2308-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,7]]}}}