title: Comparative RNA-sequencing analysis of myocardial and circulating small RNAs in human heart failure and their utility as biomarkers.
abstract: Heart failure (HF) is associated with high morbidity and mortality and its incidence is increasing worldwide. MicroRNAs (miRNAs) are potential markers and targets for diagnostic and therapeutic applications, respectively. We determined myocardial and circulating miRNA abundance and its changes in patients with stable and end-stage HF before and at different time points after mechanical unloading by a left ventricular assist device (LVAD) by small RNA sequencing. miRNA changes in failing heart tissues partially resembled that of fetal myocardium. Consistent with prototypical miRNA-target-mRNA interactions, target mRNA levels were negatively correlated with changes in abundance for highly expressed miRNAs in HF and fetal hearts. The circulating small RNA profile was dominated by miRNAs, and fragments of tRNAs and small cytoplasmic RNAs. Heart- and muscle-specific circulating miRNAs (myomirs) increased up to 140-fold in advanced HF, which coincided with a similar increase in cardiac troponin I (cTnI) protein, the established marker for heart injury. These extracellular changes nearly completely reversed 3 mo following initiation of LVAD support. In stable HF, circulating miRNAs showed less than fivefold differences compared with normal, and myomir and cTnI levels were only captured near the detection limit. These findings provide the underpinning for miRNA-based therapies and emphasize the usefulness of circulating miRNAs as biomarkers for heart injury performing similar to established diagnostic protein biomarkers.
authors.affiliation: Laboratory of RNA Molecular Biology,Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065;
authors.forename: Kemal Marc
authors.initials: KM
authors.lastname: Akat
authors.affiliation: Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY 10032;
authors.forename: D'Vesharronne
authors.initials: D
authors.lastname: Moore-McGriff
authors.affiliation: Laboratory of RNA Molecular Biology,Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065;
authors.forename: Pavel
authors.initials: P
authors.lastname: Morozov
authors.affiliation: Laboratory of RNA Molecular Biology,Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065;
authors.forename: Miguel
authors.initials: M
authors.lastname: Brown
authors.affiliation: Laboratory of RNA Molecular Biology,Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065;
authors.forename: Tasos
authors.initials: T
authors.lastname: Gogakos
authors.affiliation: the Center for Clinical and Translational Science, and.
authors.forename: Joel
authors.initials: J
authors.lastname: Correa Da Rosa
authors.affiliation: Laboratory of RNA Molecular Biology,Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065;
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Mihailovic
authors.affiliation: Laboratory of RNA Molecular Biology,Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065;
authors.forename: Markus
authors.initials: M
authors.lastname: Sauer
authors.affiliation: Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY 10032;
authors.forename: Ruiping
authors.initials: R
authors.lastname: Ji
authors.affiliation: Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY 10032;
authors.forename: Aarthi
authors.initials: A
authors.lastname: Ramarathnam
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612; and.
authors.forename: Hana
authors.initials: H
authors.lastname: Totary-Jain
authors.affiliation: Laboratory of RNA Molecular Biology,Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065;Program for Early and Recurrent Pregnancy Loss, Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY 10461.
authors.forename: Zev
authors.initials: Z
authors.lastname: Williams
authors.affiliation: Laboratory of RNA Molecular Biology,Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065; ttuschl@rockefeller.edu pcs2121@cumc.columbia.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
authors.affiliation: Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY 10032; ttuschl@rockefeller.edu pcs2121@cumc.columbia.edu.
authors.forename: P Christian
authors.initials: PC
authors.lastname: Schulze
mesh_terms: D015415:Biomarkers / Q000097:blood; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000473:pathology / Q000628:therapy; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012343:RNA, Transfer / Q000097:blood*; D019210:Troponin I / Q000097:blood
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D019210:Troponin I; D012343:RNA, Transfer
keywords: body fluids; cardiovascular disease; development; exRNA; miRNA-mRNA regulation