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

Wiriya Maisat; Lifei Hou; Sumiti Sandhu; Yi-Cheng Sin; Samuel Kim; Hanna Van Pelt; Yue Chen; Sirisha Emani; Sek Won Kong; Sitram Emani; Juan Ibla; Koichi Yuki

doi:10.1038/s41390-024-03717-z

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

Pediatr Res. 2024 Nov 11. doi: 10.1038/s41390-024-03717-z. Online ahead of print.

Authors

Wiriya Maisat^{1

2

3

4}, Lifei Hou^{1

2

3}, Sumiti Sandhu⁵, Yi-Cheng Sin⁶, Samuel Kim¹, Hanna Van Pelt¹, Yue Chen⁶, Sirisha Emani⁷, Sek Won Kong^{5

8}, Sitram Emani⁷, Juan Ibla^{1

2}, Koichi Yuki^{9

10

11

12}

Affiliations

¹ Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA.
² Department of Anaesthesia, Harvard Medical School, Boston, MA, USA.
³ Department of Immunology, Harvard Medical School, Boston, MA, USA.
⁴ Department of Anesthesiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
⁵ Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.
⁶ Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
⁷ Department of Cardiac Surgery, Boston Children's Hospital, Boston, MA, USA.
⁸ Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁹ Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA. [email protected].
¹⁰ Department of Anaesthesia, Harvard Medical School, Boston, MA, USA. [email protected].
¹¹ Department of Immunology, Harvard Medical School, Boston, MA, USA. [email protected].
¹² Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].

PMID: 39528743
DOI: 10.1038/s41390-024-03717-z

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.