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

doi:10.3390/ijms21072589

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 Journal › Article › Academic › peer-review

Abstract

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 language	English
Article number	2589
Journal	International Journal of Molecular Sciences
Volume	21
Issue number	7
DOIs	https://doi.org/10.3390/ijms21072589
Publication status	Published - 8 Apr 2020
Externally published	Yes

Funding

Funding: This work was supported by an Innovation Impulse Grant 2016 from the Academic Medical Center, Amsterdam. Work in the Houtkooper group is financially supported by a VIDI grant from ZonMw (no. 91715305) and a grant from the Velux Stiftung (no. 1063). Work in the Bezzina group is supported by the Dutch Heart Foundation (CVON PREDICT2 project), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq. Work in the Guan group is financially supported by the Free State of Saxony and the European Union EFRE (SAB project “PhänoKard”) and by the DFG (GU595/3-1, IRTG2251). RC was supported by the Leducq Foundation (RHYTHM 16CVD 02).

Funders	Funder number
CVON
Dutch Heart Foundation
European Union EFRE
Free State of Saxony
Netherlands Organization for Scientific Research	016.150.610
Velux Stiftung	1063
Deutsche Forschungsgemeinschaft	IRTG2251, GU595/3-1
Fondation Leducq	RHYTHM 16CVD 02
ZonMw	91715305

Keywords

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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Knottnerus, S. J. G., Mengarelli, I., Wüst, R. C. I., Baartscheer, A., Bleeker, J. C., Coronel, R., Ferdinandusse, S., Guan, K., IJlst, L., Li, W., Luo, X., Portero, V. M., Ulbricht, Y., Visser, G., Wanders, R. J. A., Wijburg, F. A., Verkerk, A. O., Houtkooper, R. H., & Bezzina, C. R. (2020). Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Can Be Improved by Lowering Accumulation of Fatty Acid Oxidation Intermediates. International Journal of Molecular Sciences, 21(7), Article 2589. https://doi.org/10.3390/ijms21072589

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

abstract = "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.",

keywords = "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",

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

year = "2020",

month = apr,

day = "8",

doi = "10.3390/ijms21072589",

language = "English",

volume = "21",

journal = "International Journal of Molecular Sciences",

issn = "1422-0067",

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Knottnerus, SJG, Mengarelli, I, Wüst, RCI, Baartscheer, A, Bleeker, JC, Coronel, R, Ferdinandusse, S, Guan, K, IJlst, L, Li, W, Luo, X, Portero, VM, Ulbricht, Y, Visser, G, Wanders, RJA, Wijburg, FA, Verkerk, AO, Houtkooper, RH & Bezzina, CR 2020, 'Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Can Be Improved by Lowering Accumulation of Fatty Acid Oxidation Intermediates', International Journal of Molecular Sciences, vol. 21, no. 7, 2589. https://doi.org/10.3390/ijms21072589

Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Can Be Improved by Lowering Accumulation of Fatty Acid Oxidation Intermediates. / Knottnerus, Suzan J G; Mengarelli, Isabella; Wüst, Rob C I et al.
In: International Journal of Molecular Sciences, Vol. 21, No. 7, 2589, 08.04.2020.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Can Be Improved by Lowering Accumulation of Fatty Acid Oxidation Intermediates

AU - Knottnerus, Suzan J G

AU - Mengarelli, Isabella

AU - Wüst, Rob C I

AU - Baartscheer, Antonius

AU - Bleeker, Jeannette C

AU - Coronel, Ruben

AU - Ferdinandusse, Sacha

AU - Guan, Kaomei

AU - IJlst, Lodewijk

AU - Li, Wener

AU - Luo, Xiaojing

AU - Portero, Vincent M

AU - Ulbricht, Ying

AU - Visser, Gepke

AU - Wanders, Ronald J A

AU - Wijburg, Frits A

AU - Verkerk, Arie O

AU - Houtkooper, Riekelt H

AU - Bezzina, Connie R

PY - 2020/4/8

Y1 - 2020/4/8

N2 - 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.

AB - 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.

KW - Action Potentials

KW - Acyl-CoA Dehydrogenase, Long-Chain/deficiency

KW - Arrhythmias, Cardiac/etiology

KW - Cardiac Electrophysiology

KW - Congenital Bone Marrow Failure Syndromes/complications

KW - Epoxy Compounds/pharmacology

KW - Fatty Acids/chemistry

KW - Humans

KW - Induced Pluripotent Stem Cells

KW - Lipid Metabolism, Inborn Errors/complications

KW - Mitochondria/physiology

KW - Mitochondrial Diseases/complications

KW - Muscular Diseases/complications

KW - Myocytes, Cardiac/drug effects

KW - Oxidation-Reduction

KW - Resveratrol/pharmacology

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UR - http://www.scopus.com/inward/citedby.url?scp=85083211103&partnerID=8YFLogxK

U2 - 10.3390/ijms21072589

DO - 10.3390/ijms21072589

M3 - Article

C2 - 32276429

SN - 1422-0067

VL - 21

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 7

M1 - 2589

ER -

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

Abstract

Funding

Keywords

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