Key result
Cold ischemic storage of human donor hearts for 8 hours elicited distinct responses, with the left ventricle showing inflammation and the right ventricle showing increased cell death.
Why the study?
Ischemic tolerance of donor hearts impacts utilization and outcomes, and molecular events during storage may influence ischemic injury severity.
Human donor hearts exhibit distinct, time-dependent transcriptomic and cellular responses to cold ischemic storage in the left versus right ventricles, particularly after 8 hours.
Distinct LV/RV transcriptomic responses to cold storage, most pronounced at 8 hours; leaves open whether targeting these pathways improves donor heart utilization.
BACKGROUND: Ischemic tolerance of donor hearts has a major impact on the efficiency in utilization and clinical outcomes. Molecular events during storage may influence the severity of ischemic injury. METHODS: RNA sequencing was used to study the transcriptional profile of the human left ventricle (LV, n=4) and right ventricle (RV, n=4) after 0, 4, and 8 hours of cold storage in histidine-tryptophan-ketoglutarate preservation solution. Gene set enrichment analysis and gene ontology analysis was used to examine transcriptomic changes with cold storage. Terminal deoxynucleotidyl transferase 2´-Deoxyuridine, 5´-Triphosphate nick end labeling and p65 staining was used to examine for cell death and NFκB activation, respectively. RESULTS: The LV showed activation of genes related to inflammation and allograft rejection but downregulation of oxidative phosphorylation and fatty acid metabolism pathway genes. In contrast, inflammation-related genes were down-regulated in the RV and while oxidative phosphorylation genes were activated. These transcriptomic changes were most significant at the 8 hours with much lower differences observed between 0 and 4 hours. RNA velocity estimates corroborated the finding that immune-related genes were activated in the LV but not in the RV during storage. With increasing preservation duration, the LV showed an increase in nuclear translocation of NFκB (p65), whereas the RV showed increased cell death close to the endocardium especially at 8 hours. CONCLUSIONS: Our results demonstrated that the LV and RV of human donor hearts have distinct responses to cold ischemic storage. Transcriptomic changes related to inflammation, oxidative phosphorylation, and fatty acid metabolism pathways as well as cell death and NFκB activation were most pronounced after 8 hours of storage.
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Lei et al. (2020) studied Human donor hearts (n=8). Cold storage in histidine-tryptophan-ketoglutarate preservation solution vs. 0 hours of storage (baseline) was evaluated on Transcriptomic changes, cell death, and NFκB activation. Cold ischemic storage of human donor hearts for 8 hours elicited distinct responses, with the left ventricle showing inflammation and the right ventricle showing increased cell death.
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