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         headline:A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway
         description:A proteolytically derived fragment of the epigenetic regulator HDAC4 protects the heart through transcriptional repression of the hexosamine biosynthetic pathway, thereby inhibiting protein O-GlcNAcylation and maintaining normal calcium handling and contractility of cardiomyocytes. The stress-responsive epigenetic repressor histone deacetylase 4 (HDAC4) regulates cardiac gene expression. Here we show that the levels of an N-terminal proteolytically derived fragment of HDAC4, termed HDAC4-NT, are lower in failing mouse hearts than in healthy control hearts. Virus-mediated transfer of the portion of the Hdac4 gene encoding HDAC4-NT into the mouse myocardium protected the heart from remodeling and failure; this was associated with decreased expression of Nr4a1, which encodes a nuclear orphan receptor, and decreased NR4A1-dependent activation of the hexosamine biosynthetic pathway (HBP). Conversely, exercise enhanced HDAC4-NT levels, and mice with a cardiomyocyte-specific deletion of Hdac4 show reduced exercise capacity, which was characterized by cardiac fatigue and increased expression of Nr4a1. Mechanistically, we found that NR4A1 negatively regulated contractile function in a manner that depended on the HBP and the calcium sensor STIM1. Our work describes a new regulatory axis in which epigenetic regulation of a metabolic pathway affects calcium handling. Activation of this axis during intermittent physiological stress promotes cardiac function, whereas its impairment in sustained pathological cardiac stress leads to heart failure.
         datePublished:2017-12-11T00:00:00Z
         dateModified:2017-12-11T00:00:00Z
         pageStart:62
         pageEnd:72
         sameAs:https://doi.org/10.1038/nm.4452
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            Cardiomyopathies
            Epigenetics
            Heart failure
            Metabolism
            Biomedicine
            general
            Cancer Research
            Metabolic Diseases
            Infectious Diseases
            Molecular Medicine
            Neurosciences
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                     name:Heidelberg University
                     address:
                        name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
                        type:PostalAddress
                     type:Organization
               type:Person
               name:Johannes Backs
               url:http://orcid.org/0000-0002-2322-2699
               affiliation:
                     name:Heidelberg University
                     address:
                        name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
                        type:PostalAddress
                     type:Organization
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                     address:
                        name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                        type:PostalAddress
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               email:[email protected]
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ScholarlyArticle:
      headline:A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway
      description:A proteolytically derived fragment of the epigenetic regulator HDAC4 protects the heart through transcriptional repression of the hexosamine biosynthetic pathway, thereby inhibiting protein O-GlcNAcylation and maintaining normal calcium handling and contractility of cardiomyocytes. The stress-responsive epigenetic repressor histone deacetylase 4 (HDAC4) regulates cardiac gene expression. Here we show that the levels of an N-terminal proteolytically derived fragment of HDAC4, termed HDAC4-NT, are lower in failing mouse hearts than in healthy control hearts. Virus-mediated transfer of the portion of the Hdac4 gene encoding HDAC4-NT into the mouse myocardium protected the heart from remodeling and failure; this was associated with decreased expression of Nr4a1, which encodes a nuclear orphan receptor, and decreased NR4A1-dependent activation of the hexosamine biosynthetic pathway (HBP). Conversely, exercise enhanced HDAC4-NT levels, and mice with a cardiomyocyte-specific deletion of Hdac4 show reduced exercise capacity, which was characterized by cardiac fatigue and increased expression of Nr4a1. Mechanistically, we found that NR4A1 negatively regulated contractile function in a manner that depended on the HBP and the calcium sensor STIM1. Our work describes a new regulatory axis in which epigenetic regulation of a metabolic pathway affects calcium handling. Activation of this axis during intermittent physiological stress promotes cardiac function, whereas its impairment in sustained pathological cardiac stress leads to heart failure.
      datePublished:2017-12-11T00:00:00Z
      dateModified:2017-12-11T00:00:00Z
      pageStart:62
      pageEnd:72
      sameAs:https://doi.org/10.1038/nm.4452
      keywords:
         Cardiomyopathies
         Epigenetics
         Heart failure
         Metabolism
         Biomedicine
         general
         Cancer Research
         Metabolic Diseases
         Infectious Diseases
         Molecular Medicine
         Neurosciences
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         name:Nature Medicine
         issn:
            1546-170X
            1078-8956
         volumeNumber:24
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            Periodical
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         name:Springer New York
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      author:
            name:Lorenz H Lehmann
            affiliation:
                  name:Heidelberg University
                  address:
                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:Heidelberg University
                  address:
                     name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
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            type:Person
            name:Zegeye H Jebessa
            affiliation:
                  name:Heidelberg University
                  address:
                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
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                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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            type:Person
            name:Michael M Kreusser
            affiliation:
                  name:Heidelberg University
                  address:
                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:Heidelberg University
                  address:
                     name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Axel Horsch
            affiliation:
                  name:Heidelberg University
                  address:
                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
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                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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            type:Person
            name:Tao He
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                  name:Heidelberg University
                  address:
                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
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                  type:Organization
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
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                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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            type:Person
            name:Mariya Kronlage
            affiliation:
                  name:Heidelberg University
                  address:
                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
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                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
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                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:Heidelberg University
                  address:
                     name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
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            type:Person
            name:Matthias Dewenter
            affiliation:
                  name:Heidelberg University
                  address:
                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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            type:Person
            name:Viviana Sramek
            affiliation:
                  name:Heidelberg University
                  address:
                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
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                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
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                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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            name:Ulrike Oehl
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                  name:Heidelberg University
                  address:
                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
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                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
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                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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            name:Jutta Krebs-Haupenthal
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                  name:Heidelberg University
                  address:
                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
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                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
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            name:Albert H von der Lieth
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                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
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            name:Andrea Schmidt
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                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
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                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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            type:Person
            name:Qiang Sun
            affiliation:
                  name:Heidelberg University
                  address:
                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
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                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
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                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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            name:Julia Ritterhoff
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                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:Heidelberg University
                  address:
                     name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
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            type:Person
            name:Daniel Finke
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                  name:Heidelberg University
                  address:
                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
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                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
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                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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                  name:Heidelberg University
                  address:
                     name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
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            type:Person
            name:Mirko Völkers
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                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:Heidelberg University
                  address:
                     name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
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            type:Person
            name:Andreas Jungmann
            affiliation:
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
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                  name:Heidelberg University
                  address:
                     name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
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            type:Person
            name:Sven W Sauer
            affiliation:
                  name:Center for Child and Adolescent Medicine, Heidelberg University
                  address:
                     name:Department I, Center for Child and Adolescent Medicine, Heidelberg University, Heidelberg, Germany
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            type:Person
            name:Christian Thiel
            affiliation:
                  name:Center for Child and Adolescent Medicine, Heidelberg University
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                     name:Department I, Center for Child and Adolescent Medicine, Heidelberg University, Heidelberg, Germany
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            name:Alexander Nickel
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                  name:Saarland University Hospital
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                     name:Department of Internal Medicine, Saarland University Hospital, Homburg Saar, Germany
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                  name:University Hospital Würzburg
                  address:
                     name:Department of Translational Science, Comprehensive Heart Failure Center (DZHI), University Hospital Würzburg, Würzburg, Germany
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            name:Michael Kohlhaas
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                     name:Department of Translational Science, Comprehensive Heart Failure Center (DZHI), University Hospital Würzburg, Würzburg, Germany
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            name:Michaela Schäfer
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                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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                  name:Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich and Joint Heidelberg–IDC Translational Diabetes Program, Heidelberg University
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                     name:Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich and Joint Heidelberg–IDC Translational Diabetes Program, Heidelberg University, Neuherberg, Germany
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            name:Carsten Sticht
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                     name:Medical Research Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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            name:Christoph Maack
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                  name:Saarland University Hospital
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                     name:Department of Internal Medicine, Saarland University Hospital, Homburg Saar, Germany
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                  name:University Hospital Würzburg
                  address:
                     name:Department of Translational Science, Comprehensive Heart Failure Center (DZHI), University Hospital Würzburg, Würzburg, Germany
                     type:PostalAddress
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            name:Norbert Gretz
            affiliation:
                  name:Medical Research Center, Medical Faculty Mannheim, Heidelberg University
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                     name:Medical Research Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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            name:Michael Wagner
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                  name:Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden
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                     name:Department of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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            name:Ali El-Armouche
            affiliation:
                  name:Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden
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                     name:Department of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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            name:Lars S Maier
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                  name:University Hospital Regensburg
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                     name:Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
                     type:PostalAddress
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            type:Person
            name:Juan E Camacho Londoño
            affiliation:
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:Institute of Pharmacology, Heidelberg University
                  address:
                     name:Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Benjamin Meder
            affiliation:
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:Heidelberg University
                  address:
                     name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Marc Freichel
            affiliation:
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
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                  name:Institute of Pharmacology, Heidelberg University
                  address:
                     name:Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
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            type:Person
            name:Hermann-Josef Gröne
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                  name:German Cancer Research Center
                  address:
                     name:Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Patrick Most
            affiliation:
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:Heidelberg University
                  address:
                     name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Oliver J Müller
            url:http://orcid.org/0000-0001-8223-2638
            affiliation:
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:Heidelberg University
                  address:
                     name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:University Hospital Würzburg
                  address:
                     name:Department of Translational Science, Comprehensive Heart Failure Center (DZHI), University Hospital Würzburg, Würzburg, Germany
                     type:PostalAddress
                  type:Organization
                  name:University of Kiel
                  address:
                     name:Department of Internal Medicine III, University of Kiel, Kiel, Germany
                     type:PostalAddress
                  type:Organization
                  name:partner site Hamburg/Kiel/Lübeck
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Kiel, Germany
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Stephan Herzig
            affiliation:
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich and Joint Heidelberg–IDC Translational Diabetes Program, Heidelberg University
                  address:
                     name:Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich and Joint Heidelberg–IDC Translational Diabetes Program, Heidelberg University, Neuherberg, Germany
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Eileen E M Furlong
            url:http://orcid.org/0000-0002-9544-8339
            affiliation:
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:European Molecular Biology Laboratory, Genome Biology Unit
                  address:
                     name:European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Hugo A Katus
            affiliation:
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:Heidelberg University
                  address:
                     name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Johannes Backs
            url:http://orcid.org/0000-0002-2322-2699
            affiliation:
                  name:Heidelberg University
                  address:
                     name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
                     type:PostalAddress
                  type:Organization
                  name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
                  address:
                     name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
                     type:PostalAddress
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         1546-170X
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            name:University Hospital Würzburg
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               name:Department of Translational Science, Comprehensive Heart Failure Center (DZHI), University Hospital Würzburg, Würzburg, Germany
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            name:Medical Research Center, Medical Faculty Mannheim, Heidelberg University
            address:
               name:Medical Research Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
               type:PostalAddress
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      name:Michael Wagner
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            name:Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden
            address:
               name:Department of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
               type:PostalAddress
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      name:Ali El-Armouche
      affiliation:
            name:Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden
            address:
               name:Department of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
               type:PostalAddress
            type:Organization
      name:Lars S Maier
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            address:
               name:Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
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      name:Juan E Camacho Londoño
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               name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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            address:
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               type:PostalAddress
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               name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
               type:PostalAddress
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               name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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               type:PostalAddress
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            address:
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            address:
               name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
               type:PostalAddress
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            name:Heidelberg University
            address:
               name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
               type:PostalAddress
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            name:University Hospital Würzburg
            address:
               name:Department of Translational Science, Comprehensive Heart Failure Center (DZHI), University Hospital Würzburg, Würzburg, Germany
               type:PostalAddress
            type:Organization
            name:University of Kiel
            address:
               name:Department of Internal Medicine III, University of Kiel, Kiel, Germany
               type:PostalAddress
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            name:partner site Hamburg/Kiel/Lübeck
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               name:German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Kiel, Germany
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            address:
               name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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            name:Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich and Joint Heidelberg–IDC Translational Diabetes Program, Heidelberg University
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            address:
               name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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            name:European Molecular Biology Laboratory, Genome Biology Unit
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               name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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            name:Heidelberg University
            address:
               name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
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      url:http://orcid.org/0000-0002-2322-2699
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            address:
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               type:PostalAddress
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            name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim
            address:
               name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
               type:PostalAddress
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      email:[email protected]
PostalAddress:
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
      name:Department I, Center for Child and Adolescent Medicine, Heidelberg University, Heidelberg, Germany
      name:Department I, Center for Child and Adolescent Medicine, Heidelberg University, Heidelberg, Germany
      name:Department of Internal Medicine, Saarland University Hospital, Homburg Saar, Germany
      name:Department of Translational Science, Comprehensive Heart Failure Center (DZHI), University Hospital Würzburg, Würzburg, Germany
      name:Department of Internal Medicine, Saarland University Hospital, Homburg Saar, Germany
      name:Department of Translational Science, Comprehensive Heart Failure Center (DZHI), University Hospital Würzburg, Würzburg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich and Joint Heidelberg–IDC Translational Diabetes Program, Heidelberg University, Neuherberg, Germany
      name:Medical Research Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
      name:Department of Internal Medicine, Saarland University Hospital, Homburg Saar, Germany
      name:Department of Translational Science, Comprehensive Heart Failure Center (DZHI), University Hospital Würzburg, Würzburg, Germany
      name:Medical Research Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
      name:Department of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
      name:Department of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
      name:Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
      name:Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
      name:Department of Translational Science, Comprehensive Heart Failure Center (DZHI), University Hospital Würzburg, Würzburg, Germany
      name:Department of Internal Medicine III, University of Kiel, Kiel, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Kiel, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich and Joint Heidelberg–IDC Translational Diabetes Program, Heidelberg University, Neuherberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
      name:Department of Cardiology, Heidelberg University, Heidelberg, Germany
      name:Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany
      name:German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany
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