Molecular states associated with dysfunction and graft loss in heart transplants

Abstract

PurposeWe explored the changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies (EMBs). MethodsGenome-wide microarrays (19462 genes) were used to define mRNA changes correlating with dysfunction (LVEF≤55) and risk of graft loss within 3 years post biopsy. LVEF data was available for 1013 biopsies, and survival data for 779 patients (74 losses). Molecular classifiers were built for predicting dysfunction (LVEF≤55) and post-biopsy 3-year survival. ResultsDysfunction correlated with dedifferentiation - decreased expression of normal heart transcripts e.g., solute carriers, along with increased expression of inflammation genes. Many genes with reduced expression in dysfunction were matrix genes e.g., fibulin1 and decorin. Gene ontology (GO) categories suggested matrix remodeling and inflammation, not rejection.Genes associated with risk of failure post-biopsy overlapped dysfunction genes, but also included genes affecting microcirculation e.g., arginase 2 (ARG2), which reduces NO production, and endothelin 1 (EDN1). GO terms also reflected increased glycolysis and response to hypoxia, but decreased VEGF and angiogenesis pathways. TCMR was associated with reduced survival and ABMR with relatively good survival, but the main determinants of survival were features of parenchymal injury.Both dysfunction and graft loss correlated with increased biopsy expression of BNP (gene NPPB).Survival probability classifiers divided hearts into risk quintiles, with actuarial 3-year post-biopsy survival >95% for the highest vs. 50% for the lowest. ConclusionsDysfunction in transplanted hearts reflects dedifferentiation, decreased matrix genes, injury and inflammation. Risk of short-term loss includes these changes but is also associated with microcirculation abnormalities, glycolysis, and response-to-hypoxia.