Abstract P1137: Novel Transcriptomic Interactions In Human Cardiomyopathic Heart Failure

Abstract

Noncoding regions span ~98% of the human genome and are emerging as key players in cardiovascular pathologies. However, the role of human noncoding RNAs and their interactions with other RNAs and protein-coding genes in ischemic (ICM) and nonischemic cardiomyopathic (NICM) heart failure is not clear. Twenty-eight patients (53±11 years; mix of gender and race) were studied using Tukey’s analysis of variance and post-hoc analyses. Significantly increased left ventricular (LV) internal diameter (diastole and systole; p<0.01) and decreased ejection fraction (EF:p<1E-10) were observed in both ICM (EF:17.5%±3.5) and NICM (EF:20.6%±3.2) compared to organ donor controls (EF:56.6%±6). End-systolic volume was increased in ICM, and QTc and QRS duration were prolonged in NICM (p<0.05). Following blinded quality control validation of both LV RNA and data, blinded whole transcriptomics (n=4/group) revealed differential expression of numerous long noncoding (lnc)RNAs, micro(mi)RNAs, and mRNAs (p-corrected/adjusted; padj<0.05). We uncovered 251 novel lncRNAs, 137 novel mature miRNAs, and 286 novel mRNAs (padj<0.05). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome and Disease Ontology enrichment analyses revealed several significant (padj<0.05) pathways in cancer, neuro/macular degeneration, neuroembryological development, endocrine, inflammation, bone remodeling, vein disease, etc. Seven lncRNA-associated protein-protein interaction networks were identified in ICM (>700 confidence score). Co-expression analysis revealed highly significant lncRNA-mRNA interactions with Pearson Correlation Coefficient of <0.95 and >0.95 with p<0.00001. GO/KEGG also revealed miRNA-mRNA interactions related to bacterial/viral, parathyroid, cancer, mTOR, etc. (padj<0.05). Importantly, several genes and interactions in all the above RNA species and multiple enrichment pathways distinguished ICM versus NICM (padj<0.05). We also observed several lncRNA alternative splicing events (padj<0.0004; false discovery rate<0.05), numerous missense and silent mutations, and minimal nonsense mutations. Together, this study offers novel transcriptomic and interactomic understanding in human ICM and NICM heart failure.