Left ventricular transcriptome and extracellular vesicle-derived miRNAs in porcine donation after circulatory death (DCD) hearts undergoing prolonged working mode ex situ perfusion

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Abstract

Donation after circulatory death (DCD) hearts suffer from warm ischemia-reperfusion injury, which compromises graft quality. We have previously demonstrated that a postconditioning-based cardioprotective treatment (1% Intralipid, 2% (v/v) sevoflurane, 3 nM remifentanil) improved the function and viability of porcine DCD hearts undergoing ex situ heart perfusion (ESHP). However, transcriptional changes in DCD hearts subjected to prolonged working mode ESHP as compared with healthy hearts, and more so transcriptional changes in the presence or absence of cardioprotection, as well as the early reperfusion profile of extracellular vesicle (EV)-derived miRNAs, critical regulators of the transcriptional control, have not been investigated. A total of 5,483 differentially expressed transcripts were identified in left ventricular tissue samples of DCD hearts (N=10) collected after 6 hours of ESHP when compared with healthy hearts not subjected to ESHP (N=8), irrespective of cardioprotection. Downregulation of protein synthesis, metabolic, and DNA repair gene sets was most prominent, while inflammatory and remodeling gene sets were upregulated. Between DCD hearts that were treated with (pDCD_ESHP, N=5) or without (uDCD_ESHP, N=5) cardioprotection, only 43 transcripts were differentially regulated. Specifically, lipid breakdown, beta-oxidation, and DNA repair gene sets were upregulated in pDCD_ESHP, whereas lipid accumulation, inflammation, oxidative stress, and maladaptive remodeling gene sets were upregulated in uDCD_ESHP. Predominantly cardioprotective EV-derived miRNAs were released into the perfusate in pDCD_ESHP, while predominantly cardiac injury-associated miRNAs were released into the perfusate in uDCD_ESHP. Cardioprotection promoted adaptive rather than maladaptive transcriptional changes and enabled the release of potentially beneficial miRNAs.

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