Abstract
Abstract 4359514: Inhaled Nitric Oxide Impairs Mitochondrial Complex I Respiration Capacity and Increases Microglial Inflammation in Subcortical White Matter Following Deep Hypothermic Circulatory Arrest in Neonatal Swine
Circulation (New York, N.Y.), Vol.152(Suppl_3), pp.A4359514-A4359514
11/04/2025
DOI: 10.1161/circ.152.suppl_3.4359514
Abstract
Background: Nitric oxide signaling can mediate ischemia-reperfusion injury by altering vascular resistance and inflammatory responses, including the production and degradation of reactive oxygen species (ROS). Excess ROS contributes to oxidative stress and can impair mitochondrial energy synthesis via oxidative phosphorylation (OxPhos). We previously demonstrated that ROS and mitochondrial respiration in the neonatal brain can be adversely affected following deep hypothermic circulatory arrest (DHCA). It is unknown if inhaled nitric oxide (iNO) alters cerebral ROS and OxPhos capacity post-DHCA.
Research Question: Does intraoperative iNO therapy affect cerebral ROS, OxPhos capacity, and neurologic injury or recovery after DHCA?
Methods: Ten neonatal swine underwent DHCA (90min, 18oC) prior to reperfusion and rewarming, of which half were randomized and blinded to receive iNO (40ppm) intraoperatively (DHCA90min+iNO, N=5) and half did not (DHCA90min, N=5). Five additional piglets underwent sham procedures without bypass, DHCA, or iNO. Upon study completion, brain tissue was analyzed using high-resolution mitochondrial respirometry. Immunohistochemistry assessed microglia- and neuron-specific inflammation using antibodies for ionized calcium-binding adaptor molecule 1 (IBA-1) and beta-amyloid precursor protein (β-APP), respectively.
Results: Following DHCA90min+iNO, cerebral ROS production did not decline compared to DHCA90min animals (P=0.210, Figure), and OxPhos capacity via mitochondrial complex I was reduced compared to both sham (P=0.041) and DHCA90min animals (P=0.078, Figure). Rare and frequent β-APP staining was more common after DHCA90min and DHCA90min+iNO compared to sham animals (P=0.055), and IBA-1 staining in subcortical white matter increased following DHCA90min+iNO compared to both sham (P=0.001) and DHCA90min animals (P=0.013, Figure).
Conclusions iNO does not attenuate cerebral ROS following DHCA, and may even increase microglial inflammation and post-operative white matter injury by impairing energy synthesis via mitochondrial complex I. Further studies are warranted to elucidate how regional changes in the cerebral microcirculation may affect the delivery, efficacy, and toxicity of targeted therapeutics following DHCA. Improved insights into how microglial inflammation and mitochondrial energy synthesis mediate neurologic injury and recovery post-DHCA might ultimately help improve neurocognitive outcomes in congenital cardiac surgery.
Details
- Title: Subtitle
- Abstract 4359514: Inhaled Nitric Oxide Impairs Mitochondrial Complex I Respiration Capacity and Increases Microglial Inflammation in Subcortical White Matter Following Deep Hypothermic Circulatory Arrest in Neonatal Swine
- Creators
- Benjamin Smood - University of PennsylvaniaKatsunari Terakawa - Children's Hospital of PhiladelphiaJonathan Starr - Children's Hospital of PhiladelphiaTiffany Ko - Children's Hospital of PhiladelphiaNicolina Ranieri - Children's Hospital of PhiladelphiaMcKenna Mason - Children's Hospital of PhiladelphiaRinat Degani - Children's Hospital of PhiladelphiaMarco Hefti - University of IowaNatalie Napolitano - Children's Hospital of PhiladelphiaMadison Gratsy - University of PennsylvaniaMichael Catalano - University of PennsylvaniaRichard Melchior - Children's Hospital of PhiladelphiaJonathan Chen - Children's Hospital of PhiladelphiaJames Gaynor - Children's Hospital of PhiladelphiaTodd Kilbaugh - Children's Hospital of PhiladelphiaConstantine Mavroudis - The University of Texas at Austin
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.152(Suppl_3), pp.A4359514-A4359514
- DOI
- 10.1161/circ.152.suppl_3.4359514
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Publisher
- Lippincott Williams & Wilkins
- Language
- English
- Date published
- 11/04/2025
- Academic Unit
- Pathology; Iowa Neuroscience Institute
- Record Identifier
- 9985024249402771
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