Key result
Molecular classifiers based on gene expression in endomyocardial biopsies predicted 3-year survival, with >95% survival for the highest probability quintile versus 50% for the lowest.
Why the study?
The study was conducted to explore changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies.
What gene expression changes in endomyocardial biopsies correlate with dysfunction and graft failure in heart transplant patients?
Observational (n=779)
What gene expression changes in endomyocardial biopsies correlate with dysfunction and graft failure in heart transplant patients?
Gene expression profiling of endomyocardial biopsies can identify molecular signatures of dedifferentiation, injury, and microcirculation abnormalities that predict heart transplant dysfunction and 3-year graft loss.
May refine post-transplant risk stratification; leaves open whether molecular classifiers improve outcomes over standard care.
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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Halloran et al. (2023) conducted an observational in Heart transplant (n=779). Molecular states (gene expression profiles) was evaluated on Dysfunction (LVEF ≤ 55) and postbiopsy 3-year survival. Molecular classifiers based on gene expression in endomyocardial biopsies predicted 3-year survival, with >95% survival for the highest probability quintile versus 50% for the lowest.
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