Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Can Be Improved by Lowering Accumulation of Fatty Acid Oxidation Intermediates

Suzan J G Knottnerus, Isabella Mengarelli, Rob C I Wüst, Antonius Baartscheer, Jeannette C Bleeker, Ruben Coronel, Sacha Ferdinandusse, Kaomei Guan, Lodewijk IJlst, Wener Li, Xiaojing Luo, Vincent M Portero, Ying Ulbricht, Gepke Visser, Ronald J A Wanders, Frits A Wijburg, Arie O Verkerk, Riekelt H Houtkooper, Connie R Bezzina

Research output: Contribution to JournalArticleAcademicpeer-review


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.

Original languageEnglish
Article number2589
JournalInternational Journal of Molecular Sciences
Issue number7
Publication statusPublished - 8 Apr 2020
Externally publishedYes


  • Action Potentials
  • Acyl-CoA Dehydrogenase, Long-Chain/deficiency
  • Arrhythmias, Cardiac/etiology
  • Cardiac Electrophysiology
  • Congenital Bone Marrow Failure Syndromes/complications
  • Epoxy Compounds/pharmacology
  • Fatty Acids/chemistry
  • Humans
  • Induced Pluripotent Stem Cells
  • Lipid Metabolism, Inborn Errors/complications
  • Mitochondria/physiology
  • Mitochondrial Diseases/complications
  • Muscular Diseases/complications
  • Myocytes, Cardiac/drug effects
  • Oxidation-Reduction
  • Resveratrol/pharmacology


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