Redefining the molecular rejection states in 3230 heart transplant biopsies: Relationships to parenchymal injury and graft survival.

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

Redefining the molecular rejection states in 3230 heart transplant biopsies: Relationships to parenchymal injury and graft survival.

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

Melenovsky, V Patel, J Potena, L Shah, K Stehlik, J Zuckermann, A

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Am J Transplant, 2024, 24, (8), pp. 1414-1426
Issue Date:: 2024-08

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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	Hall, S
dc.contributor.author	Jamil, A
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	Melenovsky, V
dc.contributor.author	Patel, J
dc.contributor.author	Potena, L
dc.contributor.author	Shah, K
dc.contributor.author	Stehlik, J
dc.contributor.author	Zuckermann, A
dc.date.accessioned	2025-01-14T02:13:20Z
dc.date.available	2024-03-20
dc.date.available	2025-01-14T02:13:20Z
dc.date.issued	2024-08
dc.identifier.citation	Am J Transplant, 2024, 24, (8), pp. 1414-1426
dc.identifier.issn	1600-6135
dc.identifier.issn	1600-6143
dc.identifier.uri	http://hdl.handle.net/10453/183429
dc.description.abstract	The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) but also acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.gov NCT02670408), plus 1589 service biopsies added to improve the power of the machine learning algorithms. The new system used 6 rejection classifiers instead of RATs and generated 7 rejection archetypes: No rejection, 48%; Minor, 24%; TCMR1, 2.3%; TCMR2, 2.7%; TCMR/mixed, 2.7%; early-stage ABMR, 3.9%; and fully developed ABMR, 16%. Using rejection classifiers eliminated cross-reactions with acute injury, permitting separate assessment of rejection and injury. TCMR was associated with severe-recent injury and late atrophy-fibrosis and rarely had normal parenchyma. ABMR was better tolerated, seldom producing severe injury, but in later biopsies was often associated with atrophy-fibrosis, indicating long-term risk. Graft survival and left ventricular ejection fraction were reduced not only in hearts with TCMR but also in hearts with severe-recent injury and atrophy-fibrosis, even without rejection.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	Am J Transplant
dc.relation.isbasedon	10.1016/j.ajt.2024.03.031
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	11 Medical and Health Sciences
dc.subject.classification	Surgery
dc.subject.classification	3202 Clinical sciences
dc.subject.classification	3204 Immunology
dc.subject.mesh	Heart Transplantation
dc.subject.mesh	Graft Rejection
dc.subject.mesh	Humans
dc.subject.mesh	Graft Survival
dc.subject.mesh	Male
dc.subject.mesh	Biopsy
dc.subject.mesh	Female
dc.subject.mesh	Middle Aged
dc.subject.mesh	Follow-Up Studies
dc.subject.mesh	Prognosis
dc.subject.mesh	Myocardium
dc.subject.mesh	Adult
dc.subject.mesh	Risk Factors
dc.subject.mesh	Myocardium
dc.subject.mesh	Humans
dc.subject.mesh	Biopsy
dc.subject.mesh	Prognosis
dc.subject.mesh	Heart Transplantation
dc.subject.mesh	Risk Factors
dc.subject.mesh	Follow-Up Studies
dc.subject.mesh	Graft Rejection
dc.subject.mesh	Graft Survival
dc.subject.mesh	Adult
dc.subject.mesh	Middle Aged
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Heart Transplantation
dc.subject.mesh	Graft Rejection
dc.subject.mesh	Humans
dc.subject.mesh	Graft Survival
dc.subject.mesh	Male
dc.subject.mesh	Biopsy
dc.subject.mesh	Female
dc.subject.mesh	Middle Aged
dc.subject.mesh	Follow-Up Studies
dc.subject.mesh	Prognosis
dc.subject.mesh	Myocardium
dc.subject.mesh	Adult
dc.subject.mesh	Risk Factors
dc.title	Redefining the molecular rejection states in 3230 heart transplant biopsies: Relationships to parenchymal injury and graft survival.
dc.type	Journal Article
utslib.citation.volume	24
utslib.location.activity	United States
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Health
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated	2025-01-14T02:13:18Z
pubs.issue	8
pubs.publication-status	Published
pubs.volume	24
utslib.citation.issue	8

Abstract:

The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) but also acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.gov NCT02670408), plus 1589 service biopsies added to improve the power of the machine learning algorithms. The new system used 6 rejection classifiers instead of RATs and generated 7 rejection archetypes: No rejection, 48%; Minor, 24%; TCMR1, 2.3%; TCMR2, 2.7%; TCMR/mixed, 2.7%; early-stage ABMR, 3.9%; and fully developed ABMR, 16%. Using rejection classifiers eliminated cross-reactions with acute injury, permitting separate assessment of rejection and injury. TCMR was associated with severe-recent injury and late atrophy-fibrosis and rarely had normal parenchyma. ABMR was better tolerated, seldom producing severe injury, but in later biopsies was often associated with atrophy-fibrosis, indicating long-term risk. Graft survival and left ventricular ejection fraction were reduced not only in hearts with TCMR but also in hearts with severe-recent injury and atrophy-fibrosis, even without rejection.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/183429