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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,11,26]]},"abstract":"<jats:p>\n                    Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. The major AF susceptibility locus 4q25 establishes long-range interactions with the promoter of\n                    <jats:italic>PITX2<\/jats:italic>\n                    , a transcription factor gene with critical functions during cardiac development. While many AF-linked loci have been identified in genome-wide association studies, mechanistic understanding into how genetic variants, including those at the 4q25 locus, increase vulnerability to AF is mostly lacking. Here, we show that loss of\n                    <jats:italic>pitx2c<\/jats:italic>\n                    in zebrafish leads to adult cardiac phenotypes with substantial similarities to pathologies observed in AF patients, including arrhythmia, atrial conduction defects, sarcomere disassembly, and altered cardiac metabolism. These phenotypes are also observed in a subset of\n                    <jats:italic>pitx2c<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    fish, mimicking the situation in humans. Most notably, the onset of these phenotypes occurs at an early developmental stage. Detailed analyses of\n                    <jats:italic>pitx2c<\/jats:italic>\n                    loss- and gain-of-function embryonic hearts reveal changes in sarcomeric and metabolic gene expression and function that precede the onset of cardiac arrhythmia first observed at larval stages. We further find that antioxidant treatment of\n                    <jats:italic>pitx2c<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    larvae significantly reduces the incidence and severity of cardiac arrhythmia, suggesting that metabolic dysfunction is an important driver of conduction defects. We propose that these early sarcomere and metabolic defects alter cardiac function and contribute to the electrical instability and structural remodeling observed in adult fish. Overall, these data provide insight into the mechanisms underlying the development and pathophysiology of some cardiac arrhythmias and importantly, increase our understanding of how developmental perturbations can predispose to functional defects in the adult heart.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1913905116","type":"journal-article","created":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T20:59:20Z","timestamp":1573246760000},"page":"24115-24121","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":49,"title":["Early sarcomere and metabolic defects in a zebrafish\n                    <i>pitx2c<\/i>\n                    cardiac arrhythmia model"],"prefix":"10.1073","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8439-5278","authenticated-orcid":false,"given":"Michelle M.","family":"Collins","sequence":"first","affiliation":[{"name":"Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany;"},{"name":"DZHK German Centre for Cardiovascular Research, Partner Site Rhine-Main, D-61231 Bad Nauheim, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustav","family":"Ahlberg","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Cardiology, Department of Cardiology, Vascular, Pulmonary and Infectious Diseases, University Hospital of Copenhagen, 2100 Copenhagen, Denmark;"},{"name":"Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla Vestergaard","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Exercise and Sport, University of Copenhagen, 2200 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Guenther","sequence":"additional","affiliation":[{"name":"Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rub\u00e9n","family":"Mar\u00edn-Juez","sequence":"additional","affiliation":[{"name":"Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany;"},{"name":"DZHK German Centre for Cardiovascular Research, Partner Site Rhine-Main, D-61231 Bad Nauheim, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"Sokol","sequence":"additional","affiliation":[{"name":"Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany;"},{"name":"DZHK German Centre for Cardiovascular Research, Partner Site Rhine-Main, D-61231 Bad Nauheim, Germany;"},{"name":"Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadil","family":"El-Sammak","sequence":"additional","affiliation":[{"name":"Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janett","family":"Piesker","sequence":"additional","affiliation":[{"name":"Microscopy Service Group, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ylva","family":"Hellsten","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Exercise and Sport, University of Copenhagen, 2200 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten S.","family":"Olesen","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Cardiology, Department of Cardiology, Vascular, Pulmonary and Infectious Diseases, University Hospital of Copenhagen, 2100 Copenhagen, Denmark;"},{"name":"Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier Y. 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