Plasma Proteome of Brain-Dead Organ Donors as a Predictor of Graft-Related Outcomes After Heart Transplantation

Abstract

<h3>Purpose</h3> Most solid organ transplantations are performed using organs from brain-dead donors. The inflammatory, cardiovascular, hormonal, and metabolic changes related to brain death may affect the quality of the transplanted organs and expose the recipients to pathological changes. We aimed to systemically characterize the plasma proteome of brain-dead heart transplant donors and to search for donor plasma proteins that would be related to graft-related outcome. <h3>Methods</h3> Plasma samples from 53 human brain-dead donors were analyzed by label-free protein quantification using high-definition mass spectrometry. Uni-and multivariate analyses were applied to determine potential proteome differences between brain-dead donors and healthy controls (n=24), and the enriched biological pathways were analyzed. Individual donor protein levels were correlated with clinical transplant outcomes, and predictive donor scores using the significant proteins were constructed. <h3>Results</h3> Uni-and multivariate analyses revealed that brain-dead donors have a distinct plasma proteome, with the levels of 237 of 463 proteins being changed compared to healthy controls. Significant pathways included upregulated coagulation, gluconeogenesis and glycolysis, and downregulated complement, LXR/RXR and production of nitric oxide and reactive oxygen species in macrophages. Lysine-specific demethylase 3A was moderately correlated with any grade and severe PGD in point-biserial correlation. Myosin Va and proteasome activator complex subunit 2 were significantly associated with acute rejections with hemodynamic compromise within 30 days in univariate and multivariate Cox regression analyses. Furthermore, lysine-specific demethylase 3A and moesin were associated with worse graft-related 1-year survival in univariate analysis. <h3>Conclusion</h3> Our detailed analysis revealed that brain death significantly altered plasma proteome. We further discovered altered donor protein signatures that are related to pathological changes such as cardiomyocyte and endothelial dysfunction, inflammation, and vascular growth and arteriogenesis, and correlate with clinical post-transplant outcomes. The current study can be leveraged to discover predictive donor protein signatures in future cohorts, which may lead to biomarker discovery for better donor organ evaluation.