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Whole transcriptome profiling of prospective endomyocardial biopsies reveals prognostic and diagnostic signatures of cardiac allograft rejection.

Piening, Brian D and Dowdell, Alexa K and Zhang, Mengqi and Loza, Bao-Li and Walls, David and Gao, Hui and Mohebnasab, Maede and Li, Yun Rose and Elftmann, Eric and Wei, Eric and Gandla, Divya and Lad, Hetal and Chaib, Hassan and Sweitzer, Nancy K and Deng, Mario and Pereira, Alexandre C and Cadeiras, Martin and Shaked, Abraham and Snyder, Michael P and Keating, Brendan J (2022) Whole transcriptome profiling of prospective endomyocardial biopsies reveals prognostic and diagnostic signatures of cardiac allograft rejection. J Heart Lung Transplant, 41 (6). 840 - 848.

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BACKGROUND: Heart transplantation provides a significant improvement in survival and quality of life for patients with end-stage heart disease, however many recipients experience different levels of graft rejection that can be associated with significant morbidities and mortality. Current clinical standard-of-care for the evaluation of heart transplant acute rejection (AR) consists of routine endomyocardial biopsy (EMB) followed by visual assessment by histopathology for immune infiltration and cardiomyocyte damage. We assessed whether the sensitivity and/or specificity of this process could be improved upon by adding RNA sequencing (RNA-seq) of EMBs coupled with histopathological interpretation. METHODS: Up to 6 standard-of-care, or for-cause EMBs, were collected from 26 heart transplant recipients from the prospective observational Clinical Trials of Transplantation (CTOT)-03 study, during the first 12-months post-transplant and subjected to RNA-seq (n = 125 EMBs total). Differential expression and random-forest-based machine learning were applied to develop signatures for classification and prognostication. RESULTS: Leveraging the unique longitudinal nature of this study, we show that transcriptional hallmarks for significant rejection events occur months before the actual event and are not visible using traditional histopathology. Using this information, we identified a prognostic signature for 0R/1R biopsies that with 90% accuracy can predict whether the next biopsy will be 2R/3R. CONCLUSIONS: RNA-seq-based molecular characterization of EMBs shows significant promise for the early detection of cardiac allograft rejection.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Piening, Brian D
Dowdell, Alexa K
Zhang, Mengqi
Loza, Bao-Li
Walls, David
Gao, Hui
Mohebnasab, MaedeMAM1236@pitt.eduMAM12360000-0001-6623-9514
Li, Yun Rose
Elftmann, Eric
Wei, Eric
Gandla, Divya
Lad, Hetal
Chaib, Hassan
Sweitzer, Nancy K
Deng, Mario
Pereira, Alexandre C
Cadeiras, Martin
Shaked, Abraham
Snyder, Michael P
Keating, Brendan J
Date: 25 January 2022
Date Type: Acceptance
Journal or Publication Title: J Heart Lung Transplant
Volume: 41
Number: 6
Page Range: 840 - 848
DOI or Unique Handle: 10.1016/j.healun.2022.01.1377
Schools and Programs: School of Medicine > Pathology
Refereed: Yes
Uncontrolled Keywords: acute rejection, cardiac allograft, transcriptomics, Allografts, Biopsy, Gene Expression Profiling, Graft Rejection, Heart Transplantation, Humans, Myocardium, Postoperative Complications, Prognosis, Prospective Studies, Quality of Life
Related URLs:
Funders: NIAID NIH HHS (U01 AI152960), NIDDK NIH HHS (F32 DK100072), NIAID NIH HHS (U01 AI063589), NIAID NIH HHS (R01 AI144522), NHLBI NIH HHS (T32 HL098049), NIH HHS (S10 OD020141)
PubMed Central ID: PMC9133065
PubMed ID: 35317953
Date Deposited: 25 Oct 2022 17:51
Last Modified: 28 Jun 2023 08:55


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