{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T19:09:38Z","timestamp":1768417778788,"version":"3.49.0"},"reference-count":54,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,4,8]],"date-time":"2020-04-08T00:00:00Z","timestamp":1586304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["91715305"],"award-info":[{"award-number":["91715305"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001827","name":"Universiteit van Amsterdam","doi-asserted-by":"publisher","award":["Impulse grant 2016"],"award-info":[{"award-number":["Impulse grant 2016"]}],"id":[{"id":"10.13039\/501100001827","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007214","name":"Velux Stiftung","doi-asserted-by":"publisher","award":["1063"],"award-info":[{"award-number":["1063"]}],"id":[{"id":"10.13039\/100007214","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","award":["CVON, PREDICT2"],"award-info":[{"award-number":["CVON, PREDICT2"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["VICI, 0.16.150.610"],"award-info":[{"award-number":["VICI, 0.16.150.610"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["RHYTHM 16CVD 02"],"award-info":[{"award-number":["RHYTHM 16CVD 02"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with life-threatening cardiac arrhythmias. The pathophysiological mechanism is unknown. We reprogrammed fibroblasts from one mildly and one severely affected VLCADD patient, into human induced pluripotent stem cells (hiPSCs) and differentiated these into cardiomyocytes (VLCADD-CMs). VLCADD-CMs displayed shorter action potentials (APs), more delayed afterdepolarizations (DADs) and higher systolic and diastolic intracellular Ca2+ concentration ([Ca2+]i) than control CMs. The mitochondrial booster resveratrol mitigated the biochemical, electrophysiological and [Ca2+]i changes in the mild but not in the severe VLCADD-CMs. Accumulation of potentially toxic intermediates of fatty acid oxidation was blocked by substrate reduction with etomoxir. Incubation with etomoxir led to marked prolongation of AP duration and reduced DADs and [Ca2+]i in both VLCADD-CMs. These results provide compelling evidence that reduced accumulation of fatty acid oxidation intermediates, either by enhanced fatty acid oxidation flux through increased mitochondria biogenesis (resveratrol) or by inhibition of fatty acid transport into the mitochondria (etomoxir), rescues pro-arrhythmia defects in VLCADD-CMs and open doors for new treatments.<\/jats:p>","DOI":"10.3390\/ijms21072589","type":"journal-article","created":{"date-parts":[[2020,4,9]],"date-time":"2020-04-09T03:40:19Z","timestamp":1586403619000},"page":"2589","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Can Be Improved by Lowering Accumulation of Fatty Acid Oxidation Intermediates"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4961-6968","authenticated-orcid":false,"given":"Suzan J. G.","family":"Knottnerus","sequence":"first","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Paediatric Metabolic Diseases, Wilhelmina Children\u2019s Hospital, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabella","family":"Mengarelli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rob C. I.","family":"W\u00fcst","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonius","family":"Baartscheer","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9092-575X","authenticated-orcid":false,"given":"Jeannette C.","family":"Bleeker","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Paediatric Metabolic Diseases, Wilhelmina Children\u2019s Hospital, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruben","family":"Coronel","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sacha","family":"Ferdinandusse","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0753-3083","authenticated-orcid":false,"given":"Kaomei","family":"Guan","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, Technische Universit\u00e4t Dresden, 01069 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lodewijk","family":"IJlst","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wener","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, Technische Universit\u00e4t Dresden, 01069 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaojing","family":"Luo","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, Technische Universit\u00e4t Dresden, 01069 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7221-859X","authenticated-orcid":false,"given":"Vincent M.","family":"Portero","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Ulbricht","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, Technische Universit\u00e4t Dresden, 01069 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gepke","family":"Visser","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Paediatric Metabolic Diseases, Wilhelmina Children\u2019s Hospital, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald J. A.","family":"Wanders","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frits A.","family":"Wijburg","sequence":"additional","affiliation":[{"name":"Department of Paediatric Metabolic Diseases, Emma Children\u2019s Hospital, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2140-834X","authenticated-orcid":false,"given":"Arie O.","family":"Verkerk","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9961-0842","authenticated-orcid":false,"given":"Riekelt H.","family":"Houtkooper","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Connie R.","family":"Bezzina","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1161\/01.CIR.99.10.1337","article-title":"Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death","volume":"99","author":"Mathur","year":"1999","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s11154-018-9448-1","article-title":"Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle","volume":"19","author":"Knottnerus","year":"2018","journal-title":"Rev. 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