Abstract 18693: Myocardial RNA Sequencing Reveals Critical miRNA-mRNA Interactions That Mediate Heart Failure

Introduction: Understanding the genomic signatures that mediate HF may help reveal potential pathways that may be targeted to halt HF progression or reverse disease. MicroRNAs (miR) are key regulators of messenger RNA (mRNA) expression. Hypothesis: We hypothesized that genomic networks that include miR-mRNA exist that mediate the pathophysiologic processes of HF. Methods: Myocardial tissue was collected from 39 patients with end-stage HF undergoing left ventricular assist device implantation and 25 healthy hearts (median age 52y) that were not accepted for transplantation. Myocardial tissue was preserved in RNAlater and RNA extraction was performed using a miRNeasy Mini Kit. After ribosomal RNA removal, RNA-and miR-sequencing was performed on the Illumina platform. Sequence data on 21,625 mRNA transcripts and 2,256 miR transcripts were normalized and then analyzed with the mRNA v8.0 pipeline, DAVID functional annotation, DIANA miRpath and KEGG pathway analysis. Results: Thirty-seven 37 miRs and 64 mRNAs differentially regulated in the myocardium between HF patients and controls with a corrected p +/- 4 were identified. Pathway analysis revealed that many of these differentially regulated genes were involved in key HF pathways (TGF-β signaling, Akt signaling, apoptosis, MAPK signaling, RNA transport). Certain miR were up-regulated (miR-766-3p, 1.55 FC, miR-942, 1.9 FC) and led to downregulation of MYH6 (10.4-FC). MiR-133, a cardiac myomir, was down-regulated (1.6-FC) in the HF patients and led to up-regulation of CXCR4 (4.5-FC). Conclusion: Next-generation sequencing of the miR and mRNA myocardial transcriptome in patients with HF and healthy controls revealed miR-mRNA networks that may mediate HF. Two examples from this study include: 1) MYH6 is a gene involved in the production of the heavy chain of cardiac myosin; and 2) CXCR4 encodes a chemokine receptor which is associated with abnormal calcium handling and negative inotropy in the myocardium. Additional research needs to be done to fully understand the role of these and other miRs in the regulation of mRNA genes implicated in HF.