Abstract
The aim of this study was to identify metabolite biomarkers associated with acute rejection after heart transplantation in rats using a LC-MS-based metabolomics approach. A model of heterotopic cardiac xenotransplantation was established in rats, with Wistar rats as donors and SD rats as recipients. Blood and cardiac samples were collected from blank control rats (Group A), rats 5 (Group B) and 7 days (Group C) after heart transplantation, and pretreated rats 5 (Group D) and 7 days (Group E) post-transplantation for pathological and metabolomics analyses. We assessed International Society for Heart and Lung Transplantation (ISHLT) grades 0, 3B, 4, 1 and 1 rejection in groups A to E. There were 15 differential metabolites between groups A and B, 14 differential metabolites between groups A and C, and 10 differential metabolites between groups B and C. In addition, four common differential metabolites, including D-tagatose, choline, C16 sphinganine and D-glutamine, were identified between on days 5 and 7 post-transplantation. Our findings demonstrate that the panel of D-tagatose, choline, C16 sphinganine and D-glutamine exhibits a high sensitivity and specificity for the early diagnosis of acute rejection after heart transplantation, and LC-MS-based metabolomics approach has a potential value for screening post-transplantation biomarkers.
Highlights
Heart transplantation has increasingly become the primary treatment for end-stage heart diseases[1,2,3]
Quality control (QC) and quality assurance (QA) are required in order to obtain reliable and high-quality data from liquid-chromatography-tandem-mass-spectrometry (LC-MS)-based metabolomics analysis, and the QA samples cluster is considered reliable if the error in QC is within two standard deviations (SDs)
All QC samples were found to cluster in the principal component analysis (PCA) plot and within the 95% confidential intervals (CIs), and the error in QC was within two SDs (Fig. 2)
Summary
Heart transplantation has increasingly become the primary treatment for end-stage heart diseases[1,2,3]. Diagnosis and treatment of rejection may cause irreversible damages to transplanted organs and even be life-threatening[5]. Immunosuppressant treatment has been proved to greatly reduce the incidence of acute rejection; acute rejection remains a major cause that affects the early survival of the transplanted organs post-transplantation[7,8,9]. Diagnosis of acute rejection and the subsequent adjustment of immunosuppressive protocols is of great importance to improve the survival in patients undergoing transplantation. The transplanted organs often undergo irreversible damages upon on diagnosis of acute rejection by pathological examinations[15]. The aim of this study was to identify metabolite biomarkers associated with acute rejection after heart transplantation in rats using non-targeted metabolomics, so as to provide potential candidates for the early diagnosis of post-transplantation acute rejection
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