title: Myocardial microRNAs associated with reverse remodeling in human heart failure.
abstract: In dilated cardiomyopathies (DCMs) changes in expression of protein-coding genes are associated with reverse remodeling, and these changes can be regulated by microRNAs (miRs). We tested the general hypothesis that dynamic changes in myocardial miR expression are predictive of β-blocker-associated reverse remodeling.
  
  
  
  Forty-three idiopathic DCM patients (mean left ventricular ejection fraction 0.24 ± 0.09) were treated with β-blockers. Serial ventriculography and endomyocardial biopsies were performed at baseline, and after 3 and 12 months of treatment. Changes in RT-PCR (candidate miRs) or array-measured miRs were compared based on the presence (R) or absence (NR) of a reverse-remodeling response, and a miR-mRNA-function pathway analysis (PA) was performed.
  
  
  
  At 3 months, 2 candidate miRs were selectively changed in Rs, decreases in miR-208a-3p and miR-591. PA revealed changes in miR-mRNA interactions predictive of decreased apoptosis and myocardial cell death. At 12 months, 5 miRs exhibited selective changes in Rs (decreases in miR-208a-3p, -208b-3p, 21-5p, and 199a-5p; increase in miR-1-3p). PA predicted decreases in apoptosis, cardiac myocyte cell death, hypertrophy, and heart failure, with increases in contractile and overall cardiac functions.
  
  
  
  In DCMs, myocardial miRs predict the time-dependent reverse-remodeling response to β-blocker treatment, and likely regulate the expression of remodeling-associated miRs.
  
  
  
  ClinicalTrials.gov NCT01798992.
  
  
  
  NIH 2R01 HL48013, 1R01 HL71118 (Bristow, PI); sponsored research agreements from Glaxo-SmithKline and AstraZeneca (Bristow, PI); NIH P20 HL101435 (Lowes, Port multi-PD/PI); sponsored research agreement from Miragen Therapeutics (Port, PI).
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Sucharov
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: David P
authors.initials: DP
authors.lastname: Kao
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: J David
authors.initials: JD
authors.lastname: Port
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Anis
authors.initials: A
authors.lastname: Karimpour-Fard
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Quaife
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Wayne
authors.initials: W
authors.lastname: Minobe
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Karin
authors.initials: K
authors.lastname: Nunley
authors.affiliation: Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lowes
authors.affiliation: Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Gilbert
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bristow
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D017209:Apoptosis; D001706:Biopsy; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D013318:Stroke Volume; D015899:Tomography, Emission-Computed, Single-Photon; D020257:Ventricular Remodeling
chemical_list: D000319:Adrenergic beta-Antagonists; C544547:MIRN1 microRNA, human; C550906:MIRN208 microRNA, human; C524940:MIRN21 microRNA, human; C583766:MIRN591 microRNA, human; D035683:MicroRNAs; C531408:mirn199 microRNA, human