title: Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support.
abstract: 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 noncoding RNA (lncRNA) expression in failing human heart before and after mechanical support with a left ventricular (LV) assist device (LVAD).
  
  
  RESULTS
  Deep sequencing of RNA isolated from paired nonischemic (NICM; n=8) and ischemic (ICM; n=8) human failing LV samples collected before and after LVAD and from nonfailing 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 nonfailing LV. Among these, only 2 (ICM) and 5 (NICM) miRNAs are normalized with LVAD. RNASeq detected 18 480, 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 ICM from NICM. 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 after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies 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.
authors.affiliation: Department of Developmental Biology (K.-C.Y., J.M.N.) and Center for Cardiovascular Research, Division of Cardiology, Department of Internal Medicine (K.A.Y., A.Y.P., V.K.T., G.A.E., D.L.M.), Washington University Medical School, St. Louis, MO; Division of Cardiothoracic Surgery, New York Presbyterian Hospital, Columbia University College of Physicians and Surgeons, New York, NY (I.G.); and Department of Surgery, University of Maryland School of Medicine, Baltimore (F.H.C.). Dr Yang's current affiliation is the Department of Pharmacology, National Taiwan University School of Medicine, Taipei, Taiwan.
authors.forename: Kai-Chien
authors.initials: KC
authors.lastname: Yang
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Yamada
authors.forename: Akshar Y
authors.initials: AY
authors.lastname: Patel
authors.forename: Veli K
authors.initials: VK
authors.lastname: Topkara
authors.forename: Isaac
authors.initials: I
authors.lastname: George
authors.forename: Faisal H
authors.initials: FH
authors.lastname: Cheema
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Ewald
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Nerbonne
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000378:metabolism* / Q000628:therapy; D006353:Heart-Assist Devices; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000077278:RNA, Mitochondrial; D022661:RNA, Untranslated / Q000378:metabolism*; D017423:Sequence Analysis, RNA / Q000379:methods*
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; D022661:RNA, Untranslated; D012313:RNA
keywords: RNA, long noncoding; deep sequencing; heart failure; ventricular assist device