Metabolic and Mitochondrial Alterations Following Brain Death and Heart Transplantation

L. E.See Hoe, M. A. Wells, M. Bouquet, K. Hyslop, M. R. Passmore, N. Bartnikowski, N. G. Obonyo, J. Reid, H. O'Neill, T. Shuker, C. McDonald, S. Engkilde-Pedersen, K. Wildi, C. Ainola, K. Skeggs, J. Jung, S. Colombo, K. Sato, L. James, P. HeE. S. Wood, S. Heinser, X. Wang, G. Abbate, S. Livingstone, A. Haymet, K. Walweel, D. Mullins, S. Marasco, S. Diab, J. Tung, P. Molenaar, G. Li Bassi, J. Y. Suen, D. C. McGiffin, J. F. Fraser

Research output: Contribution to journalMeeting AbstractOtherpeer-review

Abstract

PURPOSE: Brain death (BD) causes metabolic and energetic imbalances leading to cardiac dysfunction, and predisposes the donor heart to further injury following heart transplantation (HTx). The metabolic mechanisms required for myocardial energy production during BD and subsequent HTx are poorly understood. Our aim was to determine the myocardial metabolic profile and mitochondrial function following donor BD and HTx. METHODS: Donor BD in sheep was induced by inflation of a catheter placed through the skull (catheter placement, but no inflation for SHAM), followed by 24 hrs monitoring, and heart procurement (n=6/group, BD vs. SHAM). Additional donor hearts exposed to BD/SHAM were flushed with cold St Thomas cardioplegia, and stored via cold static storage (CSS) for ∼2 hrs. Following standard orthotopic HTx, recipients were weaned off bypass and monitored for ≤6 hrs prior to heart procurement (n=4/group, BD-Tx vs. Sh-Tx). Cardiac mitochondrial function was assessed using high resolution respirometry. Metabolic profiles were determined in hearts using metabolomics. Cardiac mitochondrial function was also determined in two sheep that underwent HTx following BD and 8 hr hypothermic ex vivo perfusion (HEVP) preservation. RESULTS: BD caused significant right ventricular (RV) mitochondrial uncoupling (vs. SHAM). HTx following CSS also impaired RV mitochondrial function, with these effects more pronounced in hearts exposed to both donor BD and HTx. Early findings show that HEVP improved cardiac mitochondrial function post-HTx (vs. CSS). Metabolically, BD increased myocardial amino-acid utilisation and accumulation of glucose metabolites. Post-HTx, particularly in those exposed to donor BD, there was a significant decrease in metabolites involved in mitochondrial respiration (eg. NAD, Acetyl-CoA) and accumulation of fatty acids and xanthine (purine breakdown). CONCLUSION: BD appears to trigger cardiac mitochondrial uncoupling. This may be a protective mechanism against higher amino-acid utilisation and glucose accumulation, in order to maintain adequate mitochondrial function for cell survival. HTx following CSS, particularly from BD donors, induces significant mitochondrial dysfunction, which occurs in response to upstream metabolic impairments. Strategies that improve cardiac mitochondrial function or metabolism (eg. HEVP) may assist to improve HTx outcomes.

Original languageEnglish
Pages (from-to)S355
Number of pages1
JournalJournal of Heart and Lung Transplantation
Volume39
Issue number4
DOIs
Publication statusPublished - 1 Apr 2020
Externally publishedYes
EventAnnual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation 2020 - Montreal, Canada
Duration: 22 Apr 202025 Apr 2020
Conference number: 40th

Cite this

Hoe, L. E. S., Wells, M. A., Bouquet, M., Hyslop, K., Passmore, M. R., Bartnikowski, N., Obonyo, N. G., Reid, J., O'Neill, H., Shuker, T., McDonald, C., Engkilde-Pedersen, S., Wildi, K., Ainola, C., Skeggs, K., Jung, J., Colombo, S., Sato, K., James, L., ... Fraser, J. F. (2020). Metabolic and Mitochondrial Alterations Following Brain Death and Heart Transplantation. Journal of Heart and Lung Transplantation, 39(4), S355. https://doi.org/10.1016/j.healun.2020.01.419