Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes

JOURNAL OF HEART AND LUNG TRANSPLANTATION

卷:41

Article

Halloran, Philip F.¹  Madill-Thomsen, Katelynn¹  Aliabadi-Zuckermann, Arezu Z.²  Cadeiras, Martin³  Crespo-Leiro, Marisa G.⁴  Depasquale, Eugene C.³  Deng, Mario³  Gokler, Johannes²  Kim, Daniel H.¹  Kobashigawa, Jon⁵  Macdonald, Peter⁶  Potena, Luciano⁷  Shah, Keyur⁸  Stehlik, Josef⁹  Zuckermann, Andreas² 

[1] Univ Alberta, Edmonton, AB, Canada

[2] Med Univ Vienna, Vienna, Austria

[3] UCLA, Med Ctr, Ronald Reagan, Los Angeles, CA 90024 USA

[4] Complexo Hosp Univ A Coruna, La Coruna, Spain

[5] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA

[6] Victor Chang Cardiac Res Inst, Sydney, NSW, Australia

[7] Univ Bologna, Bologna, Italy

[8] Virginia Commonwealth Univ, Richmond, VA USA

[9] Univ Utah, Salt Lake City, UT USA

关键词: gene expression;    biopsy;    heart;    transplantation;    rejection;   

DOI  :  10.1016/j.healun.2021.08.004

来源: Elsevier

【 摘 要 】

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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