期刊
JOURNAL OF HEART AND LUNG TRANSPLANTATION
卷 41, 期 3, 页码 334-344出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.healun.2021.08.004
关键词
gene expression; biopsy; heart; transplantation; rejection
资金
- Genome Canada
- Canada Foundation for Innovation
- University of Alberta Hospital Foundation
- Alberta Ministry of Advanced Education and Technology
- Mendez National Institute of Transplantation Foundation
- Industrial Research Assistance Program
- One Lambda division of Thermo Fisher
This study extended the MMDx system to classify heart transplant endomyocardial biopsies into a new Minor category characterized by low-level inflammation and ABMR-related gene expression. The results suggest that low-level ABMR-related molecular stress may be operating in more hearts than previously estimated.
BACKGROUND: The Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new Minor category characterized by low-level inflammation in non-rejecting biopsies. METHODS: Using MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR Normal (N = 462) and NR-Minor (N = 359). RESULTS: Compared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss. CONCLUSIONS: Many heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (C) 2021 International Society for Heart and Lung Transplantation. All rights reserved.
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