Jan Lukac1, Kishor Dhaygude2, Mayank Saraswat3, Sakari Joenväärä4, Simo O Syrjälä5, Emil J Holmström2, Rainer Krebs2, Risto Renkonen4, Antti I Nykänen5, Karl B Lemström2. 1. Translational Immunology Research Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland; Department of Cardiothoracic Surgery, University Hospital Cologne and University of Cologne, Germany. Electronic address: jan.lukac@helsinki.fi. 2. Translational Immunology Research Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland. 3. Translational Immunology Research Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. 4. Translational Immunology Research Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland; HUSLAB, Helsinki University Hospital, Helsinki, Finland. 5. Translational Immunology Research Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland; Department of Cardiothoracic Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Abstract
BACKGROUND: The pathophysiological changes related to brain death may affect the quality of the transplanted organs and expose the recipients to risks. We probed systemic changes reflected in donor plasma proteome and investigated their relationship to heart transplant outcomes. METHODS: Plasma samples from brain-dead multi-organ donors were analyzed by label-free protein quantification using high-definition mass spectrometry. Unsupervised and supervised statistical models were used to determine proteome differences between brain-dead donors and healthy controls. Proteome variation and the corresponding biological pathways were analyzed and correlated with transplant outcomes. RESULTS: Statistical models revealed that donors had a unique but heterogeneous plasma proteome with 237 of 463 proteins being changed compared to controls. Pathway analysis showed that coagulation, gluconeogenesis, and glycolysis pathways were upregulated in donors, while complement, LXR/RXR activation, and production of nitric oxide and reactive oxygen species in macrophages pathways were downregulated. In point-biserial correlation analysis, lysine-specific demethylase 3A was moderately correlated with any grade and severe PGD. In univariate and multivariate Cox regression analyses myosin Va and proteasome activator complex subunit 2 were significantly associated with the development of acute rejections with hemodynamic compromise within 30 days. Finally, we found that elevated levels of lysine-specific demethylase 3A and moesin were identified as predictors for graft-related 1-year mortality in univariate analysis. CONCLUSIONS: We show that brain death significantly changed plasma proteome signature Donor plasma protein changes related to endothelial cell and cardiomyocyte function, inflammation, and vascular growth and arteriogenesis could predict transplant outcome suggesting a role in donor evaluation.
BACKGROUND: The pathophysiological changes related to brain death may affect the quality of the transplanted organs and expose the recipients to risks. We probed systemic changes reflected in donor plasma proteome and investigated their relationship to heart transplant outcomes. METHODS: Plasma samples from brain-dead multi-organ donors were analyzed by label-free protein quantification using high-definition mass spectrometry. Unsupervised and supervised statistical models were used to determine proteome differences between brain-dead donors and healthy controls. Proteome variation and the corresponding biological pathways were analyzed and correlated with transplant outcomes. RESULTS: Statistical models revealed that donors had a unique but heterogeneous plasma proteome with 237 of 463 proteins being changed compared to controls. Pathway analysis showed that coagulation, gluconeogenesis, and glycolysis pathways were upregulated in donors, while complement, LXR/RXR activation, and production of nitric oxide and reactive oxygen species in macrophages pathways were downregulated. In point-biserial correlation analysis, lysine-specific demethylase 3A was moderately correlated with any grade and severe PGD. In univariate and multivariate Cox regression analyses myosin Va and proteasome activator complex subunit 2 were significantly associated with the development of acute rejections with hemodynamic compromise within 30 days. Finally, we found that elevated levels of lysine-specific demethylase 3A and moesin were identified as predictors for graft-related 1-year mortality in univariate analysis. CONCLUSIONS: We show that brain death significantly changed plasma proteome signature Donor plasma protein changes related to endothelial cell and cardiomyocyte function, inflammation, and vascular growth and arteriogenesis could predict transplant outcome suggesting a role in donor evaluation.
Authors: Dongmei Wei; Jesus D Melgarejo; Lutgarde Thijs; Xander Temmerman; Thomas Vanassche; Lucas Van Aelst; Stefan Janssens; Jan A Staessen; Peter Verhamme; Zhen-Yu Zhang Journal: J Am Heart Assoc Date: 2022-04-12 Impact factor: 6.106