Piel 2023 MiP2023

Piel 2023 MiP2023

Effect of dimethyl fumarate on cerebral mitochondrial metabolism in a porcine model of pediatric in-hospital cardiac arrest.

Link: MiP2023 Obergurgl AT

Piel Sarah (2023)

Event: MiP2023 Obergurgl AT

Authors: Piel Sarah, cManus Meagan J, Heye K, Beaulieu F, Fazeliniae H, Janowska Joanna I, McTurk B, Starr Jonathan, Gaudio H, Patel N, Hefti MM, Smalley M, Hook JF, Kohli NV, Bruton J, Hallowell T, Delso N, Roberts A, Lin Y, Ehinger Johannes K, Karlsson Michael, Berg RA, Morgan RW, Kilbaugh Todd J

Introduction: Despite advancements in cardiopulmonary resuscitation (CPR), secondary neurological injury remains the key determinant of successful recovery from cardiac arrest (CA) [1-3]. Currently, there are no established clinical therapies that preserve neurological function [4]. We previously found that acute decline in mitochondrial health up to 24 hours post-CA correlated with poor neurological outcome [5-6]. Here, we tested the potential of dimethyl fumarate (DMF), a derivative of the TCA-cycle intermediate fumaric acid shown to enhance mitochondrial bioenergetics [7], to improve mitochondrial injury in brain and heart following successful resuscitation after CA.
Methods: Female piglets representing toddler age underwent asphyxia, followed by ventricular fibrillation, cardiopulmonary resuscitation and defibrillation until return of spontaneous circulation. Subsequently, animals received daily treatment with DMF or vehicle. Sham animals underwent identical anesthesia protocols and instrumentation without CA. After 4 days, animals (n=5 of each group) were euthanized, tissues were harvested and their mitochondrial function, quantity and proteomic profile was analyzed.
Results and discussion: Mitochondrial content and function, as measured by citrate synthase activity and high-resolution respirometry, was reduced at 4 days following CA. In contrast, myocardial mitochondria demonstrated a complete restoration of mitochondrial content and function despite persistent changes in mitochondrial ultrastructure. DMF treatment prevented 25 % of the long-term proteomic changes in the brain, including proteins related to mitochondrial bioenergetics and oxidative stress. In addition, myocardial mitochondrial morphology was normalized by DMF. In this model of CA, mitochondria sustained persistent damage in an organ-specific manner. DMF partially prevents these long-term mitochondrial changes in myocardium and brain.

1. Berg RA et al: Incidence and Outcomes of Cardiopulmonary Resuscitation in PICUs. Crit Care Med 2016; 44(4):798-808
2. Slomine BS, Silverstein FS, Christensen JR, et al: Neurobehavioural outcomes in children after In-Hospital cardiac arrest. Resuscitation 2018; 124:80-89
3. Laver S, Farrow C, Turner D, et al: Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med 2004; 30(11):2126-2128
4. Neumar RW et al: Post-Cardiac Arrest Syndrome. Circulation 2008; 118(23):2452-2483
5. Lautz AJ, Morgan RW, Karlsson M, et al: Hemodynamic-Directed Cardiopulmonary Resuscitation Improves Neurologic Outcomes and Mitochondrial Function in the Heart and Brain. Critical care medicine 2019; 47(3):e241-e249
6. Kilbaugh TJ, Sutton RM, Karlsson M, et al: Persistently Altered Brain Mitochondrial Bioenergetics After Apparently Successful Resuscitation From Cardiac Arrest. Journal of the American Heart Association 2015; 4(9):e002232
7. Hayashi G, Jasoliya M, Sahdeo S, et al: Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans. Human molecular genetics 2017; 26(15):2864-2873

• Keywords: cardiac arrest, mitochondria, dimethyl fumarate, emergency medicine, metabolism

• O2k-Network Lab: DE Duesseldorf Westenfeld R, US PA Philadelphia Kilbaugh T

Figures

Figure 1. (a) Piglets underwent asphyxia by clamping of the endotracheal tube (ETT), followed by ventricular fibrillation (VF), cardiopulmonary resuscitation (CPR) and defibrillation until return of spontaneous circulation (ROSC). Next, animals received either DMF (30 mg/kg) or vehicle (Placebo) daily for four days. Sham animals underwent identical anesthesia protocols and instrumentation without CA. Tissues were collected for analysis of molecular markers. (b) Protein expression was measured in cortex and proteins with p < 0.05 were subjected to pathway-enrichment analysis (KEGG) and identification of mitochondrial proteins.

Affiliations

Piel S^1,2,3, McManus MJ^1,2, Heye K⁴, Beaulieu F⁵, Fazeliniae H⁶, Janowska JI^1,2, McTurk B^1,2, Starr JP^1,2, Gaudio H^1,2, Patel N^1,2, Hefti MM⁶, Smalley ME⁶, Hook JF⁷, Kohli NV^1,2, Bruton J^1,2, Hallowell T^1,2, Delso N^1,2, Roberts A^1,2, Lin Y^1,2, Ehinger JK^8,9,10, Karlsson M¹¹, Berg RA^1,2, Morgan RW^1,2, Kilbaugh TJ^1,2,

1. Resuscitation Science Cent of Emphasis, The Children’s Hospital of Philadelphia, Philadelphia, USA
2. Dept of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Philadelphia, USA
3. CARID, Cardiovascular Research Inst Düsseldorf, University Hospital Düsseldorf, Heinrich-Heine-Univ Düsseldorf, DEU
4. Div of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, USA
5. Dept of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, USA
6. Proteomics Core Facility, The Children’s Hospital of Philadelphia, Philadelphia, USA
7. Dept of Pathology, Univ of Iowa, Iowa City, USA
8. Mitochondrial Medicine, Dept of Clinical Sciences Lund, Lund Univ, Lund, SWE
9. Otorhinolaryngology, Dept of Clinical Sciences Lund, Lund University, Lund, SWE
10. Otorhinolaryngology, Head and Neck Surgery, Skåne University Hospital, Lund, SWE
11. Neurosurgery, Rigshospitalet, CPH, DNK

Labels: Pathology: Cardiovascular 

Organism: Pig  Tissue;cell: Heart, Nervous system 

Event: Poster