Dynamic Regulation Of Myocardial Long Noncoding Rnas In Human Heart Failure And Reverse Remodeling With Left Ventricular Assist Device Support

Introduction: Long noncoding RNAs (lncRNAs) have emerged as critical regulators of gene expression and have been implicated in various biological processes. Modulating lncRNA levels could be a plausible strategy for the treatment of heart failure (HF), however the specific lncRNAs responsible for cardiac reverse remodeling remain largely unknown. Hypothesis: Myocardial lncRNAs mediate reverse remodeling through cis -regulation of the neighboring mRNAs Methods: RNA sequencing was performed using total RNA isolated from failing human myocardium before (n=21) and after (n=12) left ventricular assist device (LVAD) implantation as well as from non-failing controls (n=5). Mapped reads for all GENCODE v26 lncRNAs were calculated. Differentially regulated mRNAs and lncRNAs were identified using a fold-change cut-off of 2 and a false discovery rate of 5%. Pearson correlation coefficient was used to determine the relationship between lncRNA and neighboring mRNAs. Results: 81 incident HF and 47 reverse remodeling lncRNAs were identified (Figure 1A). 46 HF lncRNAs (56.8%) were normalized following LVAD support and showed reciprocal regulation in the pre- vs. post-LVAD myocardium (Figure 1B). Recovery lncRNAs included recently described Myheart (originating in the MYH7 locus) as well as novel lncRNAs (NPPA-AS1, RORB-AS1, lnc-TECRL). Majority of the antisense, intergenic, and intronic myocardial lncRNAs demonstrated a positive correlation with neighboring genes suggesting cis -regulation by lncRNAs during cardiac reverse remodeling (Figure 1C). Conclusions: Myocardial lncRNAs are dynamically regulated during myocardial remodeling (HF) and reverse remodeling with LVAD support. Mechanical unloading is accompanied by partial normalization of the pathological lncRNA signature. Further studies will determine mechanisms by which neighboring protein coding genes are regulated by lncRNAs in the failing human heart.