Donor Metabolic Risk Score Predicts Graft-Related Outcome After Heart Transplantation

Abstract

<h3>Purpose</h3> Brain death may trigger profound metabolic and molecular changes that significantly affect the function of the heart transplant. We investigated the effect of brain death on the metabolomics of heart transplant donors, addressed the impact of the donor metabolomics to transplant outcome, and designed and validated a heart donor metabolomic risk score to predict the risk of allograft failure. <h3>Methods</h3> We analyzed plasma samples from 84 brain-dead heart transplant donors, and from 20 healthy blood donors. We profiled over 100 metabolites using targeted UPLC mass spectrometry. We carried out bioinformatic and statistical analysis on the identified altered metabolites, biological pathways, and their impact on graft-related outcome after transplantation. <h3>Results</h3> Brain death significantly altered the donor plasma metabolome profiles of 30 metabolites, of which 12 were upregulated and 18 were downregulated compared to the healthy controls. Major changes in mitochondrial energy metabolism occurred during brain death with significant alteration in nucleotide metabolism suggesting probable effect of mitochondrial dysfunction. Assessment of donor plasma metabolites revealed that mitochondrial pathways related metabolites such as serine, 4-pyridoxic acid, cytidine, inosine, aspartate, glutamine, niacinamide, taurine and tryptophan metabolites could serve as key biomarkers for transplant outcomes. Interestingly, the donor metabolic high-risk scores generated using these 9 metabolites were associated with a higher incidence of acute rejection and increased graft-related mortality after heart transplantation (Figure 1). <h3>Conclusion</h3> In this study, we demonstrate that brain-dead heart transplant donors had unique but heterogenous plasma metabolome. Furthermore, our result show that brain-death induces mitochondria-related metabolic alterations that may affect the recipient outcome suggesting new therapeutic strategies for donor treatment.