Philipp Jakob1,2,3,4, Tim Kacprowski5,6, Sylvie Briand-Schumacher3, Dik Heg7, Roland Klingenberg2, Barbara E Stähli1,2,4, Milosz Jaguszewski2, Nicolas Rodondi8,9, David Nanchen10, Lorenz Räber11, Pierre Vogt12, Francois Mach13, Stephan Windecker11, Uwe Völker5,6, Christian M Matter2,3, Thomas F Lüscher2,3, Ulf Landmesser1,2,3,4. 1. Department of Cardiology, Charité Berlin - University Medicine, Campus Benjamin Franklin and Berlin Institute of Health (BIH), Hindenburgdamm 30, 12203 Berlin, Germany. 2. Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland. 3. Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland. 4. DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany. 5. Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany. 6. DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. 7. Institute of Social and Preventive Medicine (ISPM), and Clinical Trials Unit, Department of Clinical Research, University of Bern, Bern, Switzerland. 8. Department of General Internal Medicine, University Hospital Bern, Bern, Switzerland. 9. Institute of Primary Health Care (BIHAM), University of Bern, Switzerland. 10. Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland. 11. Department of Cardiology, Bern University Hospital, Bern, Switzerland. 12. Department of Cardiology, Cardiovascular Center, University Hospital Lausanne, Lausanne, Switzerland. 13. Department of Cardiology, Cardiovascular Center, University Hospital Geneva, Geneva, Switzerland.
Abstract
AIMS: 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). METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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). METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Wolfgang Poller; Stefanie Dimmeler; Stephane Heymans; Tanja Zeller; Jan Haas; Mahir Karakas; David-Manuel Leistner; Philipp Jakob; Shinichi Nakagawa; Stefan Blankenberg; Stefan Engelhardt; Thomas Thum; Christian Weber; Benjamin Meder; Roger Hajjar; Ulf Landmesser Journal: Eur Heart J Date: 2018-08-01 Impact factor: 29.983
Authors: Sri H Kanuri; Joseph Ipe; Kameel Kassab; Hongyu Gao; Yunlong Liu; Todd C Skaar; Rolf P Kreutz Journal: Atherosclerosis Date: 2018-10-03 Impact factor: 5.162