Abstract 15540: Deep RNA Sequencing Reveals Dynamic Regulation of Myocardial Noncoding RNA in Failing Human Heart and Remodeling with Mechanical Circulatory Support
Background: Left ventricular assist device (LVAD) support in advanced heart failure (HF) leads to favorable changes in LV shape and size (reverse remodeling). Previous mRNA expression profiling studies in LVAD patients have not been informative with respect to the molecular mechanisms of HF nor reverse remodeling. Here, we used deep sequencing to quantify the impact of LVAD support on the expression of LV noncoding RNA (ncRNA), including miRNA and long noncoding RNA (lncRNA).
Methods and Results: Deep RNA sequencing was conducted using total RNA isolated from paired dilated non-ischemic (DCM, n=8) and ischemic (ICM, n=6) human failing LV, pre- and post-LVAD (11±7 mo), as well as from non-failing LV (n=8). A total of 624697446 read pairs (RNASeq) and 563771372 reads (miRNASeq) were obtained. miRNASeq data showed that 103 and 157 miRNAs are differentially expressed in NICM and ICM, respectively. Among them, 9 (miR-548, 2114, 103a, 373, 210, 542, 130b, 760, 425) and 6 (miR-144-3p, 144, 182, 183, 378, 378f) miRNAs are normalized by LVAD in NICM and ICM, respectively. RNASeq data showed that 1690 lncRNAs (intra- and intergenic) express at significant levels (≥1 copy/cell) in human LV; among these, 272 (DCM) and 247 (ICM) are differentially expressed; LVAD support led to normalization of 41 (DCM) and 43 (ICM) of these lncRNAs. Principal component analyses (Figure) revealed that expression profiles of lncRNA, but not miRNA, distinguish the etiology of heart failure (DCM vs ICM). The expression profile of lncRNA was normalized to a greater degree in DCM than in ICM patients.
Conclusion: ncRNA expression is dynamically regulated in advanced heart failure following LVAD support. In addition, lncRNA expression profiles discriminate failing hearts of different etiologies and are markedly altered in response to LVAD support. Taken together, these results suggest that lncRNA may play an important role in the pathogenesis of HF and in reverse remodeling observed with mechanical support.
- © 2012 by American Heart Association, Inc.