期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 21, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/ijms21072589
关键词
VLCADD; arrhythmias; hiPSC; acylcarnitines
资金
- Innovation Impulse Grant 2016 from the Academic Medical Center, Amsterdam
- VIDI grant from ZonMw [91715305]
- Velux Stiftung [1063]
- Dutch Heart Foundation (CVON PREDICT2 project)
- Netherlands Organization for Scientific Research (VICI fellowship) [016.150.610]
- Fondation Leducq
- Free State of Saxony
- European Union EFRE (SAB project PhanoKard)
- DFG [GU595/3-1, IRTG2251]
- Leducq Foundation [RHYTHM 16CVD 02]
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.
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