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

Halloran, PF; Madill-Thomsen, K; Aliabadi-Zuckermann, AZ; Cadeiras, M; Crespo-Leiro, MG; Depasquale, EC; Deng, M; Gökler, J; Kim, DH; Kobashigawa, J; Macdonald, P; Potena, L; Shah, K; Stehlik, J; Zuckermann, A

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

Halloran, PF Madill-Thomsen, K Aliabadi-Zuckermann, AZ Cadeiras, M Crespo-Leiro, MG Depasquale, EC Deng, M Gökler, J Kim, DH Kobashigawa, J Macdonald, P

Potena, L Shah, K Stehlik, J Zuckermann, A

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Journal of Heart and Lung Transplantation, 2022, 41, (3), pp. 334-344
Issue Date:: 2022-01-01

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Field	Value	Language
dc.contributor.author	Halloran, PF
dc.contributor.author	Madill-Thomsen, K
dc.contributor.author	Aliabadi-Zuckermann, AZ
dc.contributor.author	Cadeiras, M
dc.contributor.author	Crespo-Leiro, MG
dc.contributor.author	Depasquale, EC
dc.contributor.author	Deng, M
dc.contributor.author	Gökler, J
dc.contributor.author	Kim, DH
dc.contributor.author	Kobashigawa, J
dc.contributor.author	Macdonald, P https://orcid.org/0000-0001-5378-2825
dc.contributor.author	Potena, L
dc.contributor.author	Shah, K
dc.contributor.author	Stehlik, J
dc.contributor.author	Zuckermann, A
dc.date.accessioned	2022-11-16T23:45:30Z
dc.date.available	2021-08-18
dc.date.available	2022-11-16T23:45:30Z
dc.date.issued	2022-01-01
dc.identifier.citation	Journal of Heart and Lung Transplantation, 2022, 41, (3), pp. 334-344
dc.identifier.issn	0887-2570
dc.identifier.issn	1557-3117
dc.identifier.uri	http://hdl.handle.net/10453/163525
dc.description.abstract	<h4>Background</h4>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.<h4>Methods</h4>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).<h4>Results</h4>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.<h4>Conclusions</h4>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).
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	Journal of Heart and Lung Transplantation
dc.relation.isbasedon	10.1016/j.healun.2021.08.004
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1102 Cardiorespiratory Medicine and Haematology
dc.subject.classification	Surgery
dc.subject.mesh	Antibodies
dc.subject.mesh	Biopsy
dc.subject.mesh	Cross-Sectional Studies
dc.subject.mesh	Graft Rejection
dc.subject.mesh	Heart Transplantation
dc.subject.mesh	Humans
dc.subject.mesh	Microscopy
dc.subject.mesh	Molecular Diagnostic Techniques
dc.subject.mesh	Myocardium
dc.subject.mesh	Prospective Studies
dc.subject.mesh	Myocardium
dc.subject.mesh	Humans
dc.subject.mesh	Antibodies
dc.subject.mesh	Microscopy
dc.subject.mesh	Biopsy
dc.subject.mesh	Heart Transplantation
dc.subject.mesh	Molecular Diagnostic Techniques
dc.subject.mesh	Prospective Studies
dc.subject.mesh	Cross-Sectional Studies
dc.subject.mesh	Graft Rejection
dc.title	Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes.
dc.type	Journal Article
utslib.citation.volume	41
utslib.location.activity	United States
utslib.for	1102 Cardiorespiratory Medicine and Haematology
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-11-16T23:45:28Z
pubs.issue	3
pubs.publication-status	Published
pubs.volume	41
utslib.citation.issue	3

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).

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http://hdl.handle.net/10453/163525