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

Philip F. Halloran, Katelynn Madill-Thomsen, Arezu Z. Aliabadi-Zuckermann, Martin Cadeiras, Marisa G. Crespo-Leiro, Eugene C. Depasquale, Mario Deng, Johannes Gökler, Daniel H. Kim, Jon Kobashigawa, Peter Macdonald, Luciano Potena, Keyur Shah, Josef Stehlik, Andreas Zuckermann

Research output: Contribution to journalArticlepeer-review

Abstract

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. (ClinicalTrials.gov #NCT02670408).

Original languageEnglish (US)
JournalJournal of Heart and Lung Transplantation
DOIs
StateAccepted/In press - 2021
Externally publishedYes

Keywords

  • biopsy
  • gene expression
  • heart
  • rejection
  • transplantation

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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