title: Profiling and validation of circulating microRNAs for cardiovascular events in patients presenting with ST-segment elevation myocardial infarction.
abstract: OBJECTIVE
  MicroRNAs (miRNA) are important non-coding modulators controlling patterns of gene expression. However, profiling and validation of circulating miRNA levels related to adverse cardiovascular outcome has not been performed in patients with an acute coronary syndrome (ACS).
  
  
  RESULTS
  In a multicentre, prospective ACS cohort, 1002 out of 2168 patients presented with ST-segment elevation myocardial infarction (STEMI). Sixty-three STEMI patients experienced an adjudicated major cardiovascular event (MACE, defined as cardiac death or recurrent myocardial infarction) within 1 year of follow-up. From a miRNA profiling in a matched derivation case-control cohort, 14 miRNAs were selected for validation. Comparing 63 cases vs. 126 controls, 3 miRNAs were significantly differentially abundant. In patients with MACE, miR-26b-5p levels (P = 0.038) were decreased, whereas miR-320a (P = 0.047) and miR-660-5p (P = 0.01) levels were increased. MiR-26b-5p has been suggested to prevent adverse cardiomyocyte hypertrophy, whereas miR-320a promotes cardiomyocyte death and apoptosis, and miR-660-5p has been related to active platelet production. This suggests that miR-26b-5p, miR-320a, and miR-660-5p may reflect alterations of different pathophysiological pathways involved in clinical outcome after ACS. Consistently, these three miRNAs reliably discriminated cases from controls [area under the receiver-operating characteristic curve (AUC) in age- and sex-adjusted Cox regression for miR-26b-5p = 0.707, miR-660-5p = 0.683, and miR-320a =0.672]. Combination of the three miRNAs further increased AUC to 0.718. Importantly, addition of the three miRNAs to both, the Global Registry of Acute Coronary Events (GRACE) score and a clinical model increased AUC from 0.679 to 0.720 and 0.722 to 0.732, respectively, with a net reclassification improvement of 0.20 in both cases.
  
  
  CONCLUSIONS
  This is the first study performing profiling and validation of miRNAs that are associated with adverse cardiovascular outcome in patients with STEMI. MiR-26b-5p, miR-320a, and miR-660-5p discriminated for MACE and increased risk prediction when added to the GRACE score and a clinical model. These findings suggest that the release of specific miRNAs into circulation may reflect the activation of molecular pathways that impact on clinical outcome after STEMI.
authors.affiliation: Department of Cardiology, Charité Berlin - University Medicine, Campus Benjamin Franklin and Berlin Institute of Health (BIH), Hindenburgdamm 30, 12203 Berlin, Germany.|Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland.|Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.|DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Jakob
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Kacprowski
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Briand-Schumacher
authors.affiliation: Institute of Social and Preventive Medicine (ISPM), and Clinical Trials Unit, Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Dik
authors.initials: D
authors.lastname: Heg
authors.affiliation: Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Klingenberg
authors.affiliation: Department of Cardiology, Charité Berlin - University Medicine, Campus Benjamin Franklin and Berlin Institute of Health (BIH), Hindenburgdamm 30, 12203 Berlin, Germany.|Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland.|DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Stähli
authors.affiliation: Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Milosz
authors.initials: M
authors.lastname: Jaguszewski
authors.affiliation: Department of General Internal Medicine, University Hospital Bern, Bern, Switzerland.|Institute of Primary Health Care (BIHAM), University of Bern, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Rodondi
authors.affiliation: Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Nanchen
authors.affiliation: Department of Cardiology, Bern University Hospital, Bern, Switzerland.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Räber
authors.affiliation: Department of Cardiology, Cardiovascular Center, University Hospital Lausanne, Lausanne, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vogt
authors.affiliation: Department of Cardiology, Cardiovascular Center, University Hospital Geneva, Geneva, Switzerland.
authors.forename: Francois
authors.initials: F
authors.lastname: Mach
authors.affiliation: Department of Cardiology, Bern University Hospital, Bern, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Windecker
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.affiliation: Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland.|Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
authors.affiliation: Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland.|Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.affiliation: Department of Cardiology, Charité Berlin - University Medicine, Campus Benjamin Franklin and Berlin Institute of Health (BIH), Hindenburgdamm 30, 12203 Berlin, Germany.|Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland.|Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.|DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D000074166:Circulating MicroRNA / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D011446:Prospective Studies; D012008:Recurrence; D000072657:ST Elevation Myocardial Infarction / Q000401:mortality / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D000074166:Circulating MicroRNA