Abstract 14981: Transcriptome Analysis Identifies Cardiomyopathy-Specific Mechanisms in Explanted Human Hearts
The genetic and phenotypic architecture of cardiomyopathy is diverse but has been proposed to progress via a “final common pathway” towards heart failure. The goal of this study was to determine if there are differentially regulated pathways of heart failure in cardiomyopathy patients. We used RNA-sequencing (RNA-seq) and pathway analysis in 42 samples of explanted left ventricular tissue. We investigated differential expression between ischemic cardiomyopathy (ICM, n=14) and dilated cardiomyopathy (DCM, n=28) as well as between DCM sub-phenotypes, arrhythmogenic DCM (aDCM, n=13) and non-arrhythmogenic DCM (naDCM, n=15). Pathway analysis was performed using Ingenuity Pathway Analysis (IPA). Between ICM and DCM, 878 genes were differentially expressed (p < 0.05, q < 0.05). Pathway analysis showed enrichment for mTOR signaling (p = 4x10-13), epithelial adherens junction remodeling (p = 3x10-10), and Rho signaling (p = 1x10-7) with functional enrichment in immune response (p = 7x10-7). These results support previous models of chronic myocardial infarction. Increased mTOR signaling is known to aid in myocardial remodeling, and the inflammatory response at the site of myocardial injury requires both immune cell motility via Rho signaling as well as immune cell infiltration via cell-cell junction remodeling. The DCM samples were sub-phenotyped based on history of ventricular tachycardia, which revealed 280 genes differentially expressed between aDCM and naDCM (p < 0.05, q < 0.20). Pathway analysis demonstrated downregulation in aDCM compared to naDCM of oxidative phosphorylation (p = 1x10-13) and genes involved in muscle contraction (p = 3x10-5). These results suggest that reduced ATP production and contractibility in aDCM compared to naDCM may contribute to arrhythmogenesis. More broadly, these results suggest that a ‘final common pathway’ model may need to be amended based on biological differences among DCM sub-phenotypes in advanced heart failure.
Author Disclosures: M.E. Sweet: None. A. Cocciolo: None. D. Slavov: None. S.L. Graw: None. K. Jones: None. L. Mestroni: None. M.R. Taylor: None.
- © 2016 by American Heart Association, Inc.