Molecular states associated with dysfunction and graft loss in heart transplants
Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:43 |
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| Enthalten in: |
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation - 43(2024), 3 vom: 26. Feb., Seite 508-518 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Halloran, Philip F [VerfasserIn] |
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| Links: |
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| Themen: |
Endomyocardial biopsy |
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| Anmerkungen: |
Date Completed 26.02.2024 Date Revised 26.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.healun.2023.11.013 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM365334294 |
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| 100 | 1 | |a Halloran, Philip F |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Molecular states associated with dysfunction and graft loss in heart transplants |
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| 500 | |a Date Revised 26.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a BACKGROUND: We explored the changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a endomyocardial biopsy | |
| 650 | 4 | |a gene expression | |
| 650 | 4 | |a heart transplant | |
| 650 | 4 | |a heart transplant survival | |
| 650 | 4 | |a left ventricular ejection fraction | |
| 700 | 1 | |a Madill-Thomsen, Katelynn |e verfasserin |4 aut | |
| 700 | 1 | |a Mackova, Martina |e verfasserin |4 aut | |
| 700 | 1 | |a Aliabadi-Zuckermann, Arezu Z |e verfasserin |4 aut | |
| 700 | 1 | |a Cadeiras, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Crespo-Leiro, Marisa G |e verfasserin |4 aut | |
| 700 | 1 | |a Depasquale, Eugene C |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Mario |e verfasserin |4 aut | |
| 700 | 1 | |a Gökler, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Hall, Shelley A |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Daniel H |e verfasserin |4 aut | |
| 700 | 1 | |a Kobashigawa, Jon |e verfasserin |4 aut | |
| 700 | 1 | |a Macdonald, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Potena, Luciano |e verfasserin |4 aut | |
| 700 | 1 | |a Shah, Keyur |e verfasserin |4 aut | |
| 700 | 1 | |a Stehlik, Josef |e verfasserin |4 aut | |
| 700 | 1 | |a Zuckermann, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Reeve, Jeff |e verfasserin |4 aut | |
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