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Neutrophil extracellular traps formation is associated with postoperative complications in congenital cardiac surgery

Pediatric Research (2024)Cite this article

Abstract

Backgrounds

Pediatric patients with congenital heart disease (CHD) often require surgical repair using cardiopulmonary bypass. Despite advancements, mortality and complication rates remain significant.

Methods & Results

We prospectively examined 101 patients undergoing congenital cardiac surgery, identifying a mortality rate of 4.0% and a complication rate of 31.6%. Neonates and infants exhibited multiple complications more frequently. Prolonged bypass time was significantly associated with complications, with each additional 30 min increasing the odds by 1.46 times (95% CI 1.01–2.10, p = 0.042). We further investigated the involvement of damage-associated molecular pattern (DAMP) molecules by proteomics and ELISA. Plasma levels of DAMPs, including histones and high mobility group box 1 (HMGB1), were significantly elevated in the complication group. As these molecules target Toll-like receptor (TLR)2 and TLR4, mRNA expression of TLR2 and TLR4 in neutrophils was upregulated in the complication group. In vitro and in vivo analyses demonstrated that histones and HMGB1 induced the formation of neutrophil extracellular traps (NETs). This finding aligned with greater NETs formation observed at the end of CPB and during the postoperative period in neonates and infants who developed postoperative complications.

Conclusion

Targeting NETs and associated DAMPs may provide a novel therapeutic approach to mitigate complications in this patient population.

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Fig. 1: Temporal changes in neutrophil, monocyte, and platelet counts and TEG parameters following congenital cardiac surgery with CPB.
Fig. 2: RNA sequencing analysis of neutrophils in neonates and infants at T0 and T2.
Fig. 3: RNA sequencing analysis of neutrophils in neonates and infants at T0 and T2 compared to age 1–6 and ≥ 7 years.
Fig. 4: Proteomics-based expression profiles of DAMP molecules in neonates and infants following congenital cardiac surgery with CPB and neutrophil DAMP-related gene expression.
Fig. 5: Plasma proteomic analysis of neonates and infants following congenital cardiac surgery with CPB.
Fig. 6: DAMPs induced organ injury, thrombosis, and NETs formation in neonates and infants.
Fig. 7: Proposed mechanism of tissue/organ injury and transfusion requirement in patients with complications.

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Data availability

All the data are presented in this manuscript.

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Funding

This is supported by NICHD R21HD109119 (K.Y.).

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA, USA

    Wiriya Maisat, Lifei Hou, Samuel Kim, Hanna Van Pelt, Juan Ibla & Koichi Yuki

  2. Department of Anaesthesia, Harvard Medical School, Boston, MA, USA

    Wiriya Maisat, Lifei Hou, Juan Ibla & Koichi Yuki

  3. Department of Immunology, Harvard Medical School, Boston, MA, USA

    Wiriya Maisat, Lifei Hou & Koichi Yuki

  4. Department of Anesthesiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Wiriya Maisat

  5. Computational Health Informatics Program, Boston Children’s Hospital, Boston, MA, USA

    Sumiti Sandhu & Sek Won Kong

  6. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA

    Yi-Cheng Sin & Yue Chen

  7. Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA, USA

    Sirisha Emani & Sitram Emani

  8. Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Sek Won Kong

  9. Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Koichi Yuki

Authors
  1. Wiriya Maisat
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  2. Lifei Hou
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  11. Juan Ibla
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Contributions

Idea and Experiment design- W.M., L.H., Y.C., S.E., S.W.K., J.C, and K.Y. Experiment execution- W.M., L.H., S.S., Y.S., S.E. Manuscript draft- W.M., K.Y. Manuscript editing- S.K., H.V.P., S.E., Grant acquisition- K.Y.

Corresponding author

Correspondence to Koichi Yuki.

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Competing interests

The authors declare no competing interests.

Patient consent

For clinical samples, the protocol was approved by the Boston Children’s Hospital IRB committee, and we obtained consent from patients’ parents and/or guardians.

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Posted history: This manuscript was previously posted to bioRxiv preprint https://doi.org/10.1101/2023.12.21.572768.

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Maisat, W., Hou, L., Sandhu, S. et al. Neutrophil extracellular traps formation is associated with postoperative complications in congenital cardiac surgery. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03717-z

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