Molecular states associated with dysfunction and graft loss in heart transplants.

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

Molecular states associated with dysfunction and graft loss in heart transplants.

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

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

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: J Heart Lung Transplant, 2023, pp. S1053-2498(23)02132-0
Issue Date:: 2023-11-30

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Field	Value	Language
dc.contributor.author	Halloran, PF
dc.contributor.author	Madill-Thomsen, K
dc.contributor.author	Mackova, M
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, SA
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.contributor.author	Reeve, J
dc.date.accessioned	2024-01-10T01:30:48Z
dc.date.available	2023-11-21
dc.date.available	2024-01-10T01:30:48Z
dc.date.issued	2023-11-30
dc.identifier.citation	J Heart Lung Transplant, 2023, pp. S1053-2498(23)02132-0
dc.identifier.issn	1053-2498
dc.identifier.issn	1557-3117
dc.identifier.uri	http://hdl.handle.net/10453/174183
dc.description.abstract	BACKGROUND: We explored the changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies. METHODS: Genome-wide microarrays (19,462 genes) were used to define mRNA changes correlating with dysfunction (left ventricular ejection fraction [LVEF] ≤ 55) and risk of graft loss within 3 years postbiopsy. LVEF data was available for 1,013 biopsies and survival data for 779 patients (74 losses). Molecular classifiers were built for predicting dysfunction (LVEF ≤ 55) and postbiopsy 3-year survival. RESULTS: Dysfunction is correlated with dedifferentiation-decreased expression of normal heart transcripts, for example, solute carriers, along with increased expression of inflammation genes. Many genes with reduced expression in dysfunction were matrix genes such as fibulin 1 and decorin. Gene ontology (GO) categories suggested matrix remodeling and inflammation, not rejection. Genes associated with the risk of failure postbiopsy overlapped dysfunction genes but also included genes affecting microcirculation, for example, arginase 2, which reduces NO production, and endothelin 1. GO terms also reflected increased glycolysis and response to hypoxia, but decreased VEGF and angiogenesis pathways. T cell-mediated rejection was associated with reduced survival and antibody-mediated rejection with relatively good survival, but the main determinants of survival were features of parenchymal injury. Both dysfunction and graft loss were correlated with increased biopsy expression of BNP (gene NPPB). Survival probability classifiers divided hearts into risk quintiles, with actuarial 3-year postbiopsy survival >95% for the highest versus 50% for the lowest. CONCLUSIONS: Dysfunction in transplanted hearts reflects dedifferentiation, decreased matrix genes, injury, and inflammation. The risk of short-term loss includes these changes but is also associated with microcirculation abnormalities, glycolysis, and response to hypoxia.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	J Heart Lung Transplant
dc.relation.isbasedon	10.1016/j.healun.2023.11.013
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1102 Cardiorespiratory Medicine and Haematology
dc.subject.classification	Surgery
dc.subject.classification	3201 Cardiovascular medicine and haematology
dc.subject.classification	3202 Clinical sciences
dc.title	Molecular states associated with dysfunction and graft loss in heart transplants.
dc.type	Journal Article
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	open_access	*
dc.date.updated	2024-01-10T01:30:47Z
pubs.publication-status	Published online

Abstract:

BACKGROUND: We explored the changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies. METHODS: Genome-wide microarrays (19,462 genes) were used to define mRNA changes correlating with dysfunction (left ventricular ejection fraction [LVEF] ≤ 55) and risk of graft loss within 3 years postbiopsy. LVEF data was available for 1,013 biopsies and survival data for 779 patients (74 losses). Molecular classifiers were built for predicting dysfunction (LVEF ≤ 55) and postbiopsy 3-year survival. RESULTS: Dysfunction is correlated with dedifferentiation-decreased expression of normal heart transcripts, for example, solute carriers, along with increased expression of inflammation genes. Many genes with reduced expression in dysfunction were matrix genes such as fibulin 1 and decorin. Gene ontology (GO) categories suggested matrix remodeling and inflammation, not rejection. Genes associated with the risk of failure postbiopsy overlapped dysfunction genes but also included genes affecting microcirculation, for example, arginase 2, which reduces NO production, and endothelin 1. GO terms also reflected increased glycolysis and response to hypoxia, but decreased VEGF and angiogenesis pathways. T cell-mediated rejection was associated with reduced survival and antibody-mediated rejection with relatively good survival, but the main determinants of survival were features of parenchymal injury. Both dysfunction and graft loss were correlated with increased biopsy expression of BNP (gene NPPB). Survival probability classifiers divided hearts into risk quintiles, with actuarial 3-year postbiopsy survival >95% for the highest versus 50% for the lowest. CONCLUSIONS: Dysfunction in transplanted hearts reflects dedifferentiation, decreased matrix genes, injury, and inflammation. The risk of short-term loss includes these changes but is also associated with microcirculation abnormalities, glycolysis, and response to hypoxia.

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http://hdl.handle.net/10453/174183