Deep RNA Sequencing Reveals Dynamic Regulation of Myocardial Noncoding RNA in Failing Human Heart and Remodeling with Mechanical Circulatory Support
Background—Microarrays have been used extensively to profile transcriptome remodeling in failing human heart, although the genomic coverage provided is limited and fails to provide a detailed picture of the myocardial transcriptome landscape. Here, we describe sequencing-based transcriptome profiling, providing comprehensive analysis of myocardial mRNA, microRNA (miRNA) and long non-coding RNA (lncRNA) expression in failing human heart, before and after mechanical support with a left ventricular assisted device (LVAD)
Methods and Results—Deep sequencing of RNA isolated from paired non-ischemic (NICM,n=8) and ischemic (ICM,n=8) human failing LV samples collected pre- and post-LVAD, as well as from non-failing human LV (n=8), was conducted. These analyses revealed high abundance of mRNA (37%) and lncRNA (71%) of mitochondrial origin. miRNASeq revealed 160 and 147 differentially expressed miRNAs in ICM and NICM, respectively, compared with non-failing LV. Among these only 2 (ICM) and 5 (NICM) miRNAs are normalized with LVAD. RNASeq detected 18480, including 113 novel, lncRNAs in human LV. Among the 679 (ICM) and 570 (NICM) lncRNAs differentially expressed with heart failure, ~10% are improved or normalized with LVAD. In addition, the expression signature of lncRNAs, but not miRNAs or mRNAs, distinguishes cardiomyopathy of ischemic and non-ischemic origins. Further analysis suggests that cis-gene regulation represents a major mechanism of action of human cardiac lncRNAs.
Conclusions—The myocardial transcriptome is dynamically regulated in advanced heart failure and following LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different etiologies and are markedly altered in response to LVAD support. These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.
- Received May 16, 2013.
- Revision received November 11, 2013.
- Accepted November 15, 2013.