Research output: Contribution to journal › Article › Academic › peer-review
Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Do not Improve with Carnitine Supplementation. / Verkerk, Arie O.; Knottnerus, Suzan J. G.; Portero, Vincent et al.
In: Frontiers in pharmacology, Vol. 11, 616834, 12.01.2021.Research output: Contribution to journal › Article › Academic › peer-review
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TY - JOUR
T1 - Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Do not Improve with Carnitine Supplementation
AU - Verkerk, Arie O.
AU - Knottnerus, Suzan J. G.
AU - Portero, Vincent
AU - Bleeker, Jeannette C.
AU - Ferdinandusse, Sacha
AU - Guan, Kaomei
AU - IJlst, Lodewijk
AU - Visser, Gepke
AU - Wanders, Ronald J. A.
AU - Wijburg, Frits A.
AU - Bezzina, Connie R.
AU - Mengarelli, Isabella
AU - Houtkooper, Riekelt H.
N1 - Funding Information: KG was supported by the Free State of Saxony and the European Union EFRE (SAB project “PhänoKard”) and by the DFG (GU595/3-1, IRTG2251). CB was supported by the Dutch Heart Foundation (CVON PREDICT2 project), Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq. RH was supported by a VIDI grant from ZonMw (no. 91715305) and a grant from the Velux Stiftung (no. 1063). Publisher Copyright: © Copyright © 2021 Verkerk, Knottnerus, Portero, Bleeker, Ferdinandusse, Guan, IJlst, Visser, Wanders, Wijburg, Bezzina, Mengarelli and Houtkooper.
PY - 2021/1/12
Y1 - 2021/1/12
N2 - Patients with a deficiency in very long-chain acyl-CoA dehydrogenase (VLCAD), an enzyme that is involved in the mitochondrial beta-oxidation of long-chain fatty acids, are at risk for developing cardiac arrhythmias. In human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), VLCAD deficiency (VLCADD) results in a series of abnormalities, including: 1) accumulation of long-chain acylcarnitines, 2) action potential shortening, 3) higher systolic and diastolic intracellular Ca2+ concentrations, and 4) development of delayed afterdepolarizations. In the fatty acid oxidation process, carnitine is required for bidirectional transport of acyl groups across the mitochondrial membrane. Supplementation has been suggested as potential therapeutic approach in VLCADD, but its benefits are debated. Here, we studied the effects of carnitine supplementation on the long-chain acylcarnitine levels and performed electrophysiological analyses in VLCADD patient-derived hiPSC-CMs with a ACADVL gene mutation (p.Val283Ala/p.Glu381del). Under standard culture conditions, VLCADD hiPSC-CMs showed high concentrations of long-chain acylcarnitines, short action potentials, and high delayed afterdepolarizations occurrence. Incubation of the hiPSC-CMs with 400 µM L-carnitine for 48 h led to increased long-chain acylcarnitine levels both in medium and cells. In addition, carnitine supplementation neither restored abnormal action potential parameters nor the increased occurrence of delayed afterdepolarizations in VLCADD hiPSC-CMs. We conclude that long-chain acylcarnitine accumulation and electrophysiological abnormalities in VLCADD hiPSC-CMs are not normalized by carnitine supplementation, indicating that this treatment is unlikely to be beneficial against cardiac arrhythmias in VLCADD patients.
AB - Patients with a deficiency in very long-chain acyl-CoA dehydrogenase (VLCAD), an enzyme that is involved in the mitochondrial beta-oxidation of long-chain fatty acids, are at risk for developing cardiac arrhythmias. In human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), VLCAD deficiency (VLCADD) results in a series of abnormalities, including: 1) accumulation of long-chain acylcarnitines, 2) action potential shortening, 3) higher systolic and diastolic intracellular Ca2+ concentrations, and 4) development of delayed afterdepolarizations. In the fatty acid oxidation process, carnitine is required for bidirectional transport of acyl groups across the mitochondrial membrane. Supplementation has been suggested as potential therapeutic approach in VLCADD, but its benefits are debated. Here, we studied the effects of carnitine supplementation on the long-chain acylcarnitine levels and performed electrophysiological analyses in VLCADD patient-derived hiPSC-CMs with a ACADVL gene mutation (p.Val283Ala/p.Glu381del). Under standard culture conditions, VLCADD hiPSC-CMs showed high concentrations of long-chain acylcarnitines, short action potentials, and high delayed afterdepolarizations occurrence. Incubation of the hiPSC-CMs with 400 µM L-carnitine for 48 h led to increased long-chain acylcarnitine levels both in medium and cells. In addition, carnitine supplementation neither restored abnormal action potential parameters nor the increased occurrence of delayed afterdepolarizations in VLCADD hiPSC-CMs. We conclude that long-chain acylcarnitine accumulation and electrophysiological abnormalities in VLCADD hiPSC-CMs are not normalized by carnitine supplementation, indicating that this treatment is unlikely to be beneficial against cardiac arrhythmias in VLCADD patients.
KW - action potential
KW - acylcarnitines
KW - arrhythmia < cardiovascular
KW - carnitine
KW - human induced pluripotent stem cell derived cardiomyocytes
KW - patients
KW - treatment
KW - very long-chain acyl-CoA dehydrogenase
UR - http://www.scopus.com/inward/record.url?scp=85100067223&partnerID=8YFLogxK
U2 - 10.3389/fphar.2020.616834
DO - 10.3389/fphar.2020.616834
M3 - Article
C2 - 33597881
VL - 11
JO - Frontiers in pharmacology
JF - Frontiers in pharmacology
SN - 1663-9812
M1 - 616834
ER -
ID: 15596358