Abstract 16779: Mitochondrial Related Intragraft Gene Expression During Acute Rejection After Heart Transplantation

Abstract

Introduction: Endomyocardial biopsies (EMB) for the surveillance of acute cellular rejection (ACR) after heart transplant (HT) is inconsistent and provides limited information. Mitochondrial dysfunction is associated with poor allograft prognosis and can overstimulate the inflammatory response. Mitochondrial related gene expression (GE) in EMB may be useful as a functional surrogate for EMB. Hypothesis: We hypothesize that down-regulated mitochondrial associated GE in EMB correlates with ACR. Methods: We collected 64 EMB from 47 post HT patients (mean age 50 ± 14.7 years). Purified mRNA was subjected to whole-genome next-generation sequencing. Weighted gene co-expression network analysis was applied to construct functional gene modules. Module derived eigengenes were correlated with ISHLT EMB criteria or using an unsupervised classification method we previously developed and B-type natriuretic peptide (BNP) levels. Biological significance and function of each module were assessed by gene ontology (GO) and pathway analyses. Highly relevant genes were identified by Hub gene analysis. Results: The reconstructed network resulted in 16 modules including two mitochondria-related modules (MRM) and one immune response module (IRM). Compared to 0R (n= 30/46.9%) samples, 2R (n= 11/17.2%) EMB showed enrichment of IRM and decreased expression of MRM. ISHLT 1R (n= 23/35.9%) samples did not show a significant correlation with IRM or MRM. Following the unsupervised classification method, findings were concordant, with higher phenotype-module eigengene correlation and significance level. MRM Hub genes included ATP5B, ATP5O, ACO2, COX14, COX4I1 , FH, NDUFV1, PDK2, SDHA and UQCR11 among others. GO categories enriched by these genes included oxidative phosphorylation, beta-oxidation, tricarboxylic acid cycle, glycolysis and gluconeogenesis. There was an inverse correlation between MRM and BNP level and positive correlation between IRM and BNP (Figure). Conclusions: EMB of patients with ISHLT 2R ACR show decrease activity of MRM, increased activity of IRM and elevated BNP suggesting an inverse functional relationship between immune activation, mitochondrial activity and cardiac allograft function.