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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2020 Apr 12

PMID 32276429

Citations 20

Authors

Suzan J G Knottnerus

Isabella Mengarelli

Rob C I Wust

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

Affiliations

Soon will be listed here.

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 Ca concentration ([Ca]) than control CMs. The mitochondrial booster resveratrol mitigated the biochemical, electrophysiological and [Ca] 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 [Ca] 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.

Citing Articles

Transcriptome analysis of effects of deficiency on cardiometabolic and calcium regulation in cardiac tissue.

Lin S, Chen S, Lin Q, Xiao T, Hou C, Xie L Open Med (Wars). 2024; 19(1):20230880.

PMID: 38283583 PMC: 10811529. DOI: 10.1515/med-2023-0880.

Metabolic Flexibility of the Heart: The Role of Fatty Acid Metabolism in Health, Heart Failure, and Cardiometabolic Diseases.

Actis Dato V, Lange S, Cho Y Int J Mol Sci. 2024; 25(2).

PMID: 38279217 PMC: 10816475. DOI: 10.3390/ijms25021211.

Injection of I through dynamic clamp can make all the difference in patch-clamp studies on hiPSC-derived cardiomyocytes.

Verkerk A, Wilders R Front Physiol. 2023; 14:1326160.

PMID: 38152247 PMC: 10751953. DOI: 10.3389/fphys.2023.1326160.

Urolithin A protects severe acute pancreatitis-associated acute cardiac injury by regulating mitochondrial fatty acid oxidative metabolism in cardiomyocytes.

Yang Y, Hu Q, Kang H, Li J, Zhao X, Zhu L MedComm (2020). 2023; 4(6):e459.

PMID: 38116065 PMC: 10728757. DOI: 10.1002/mco2.459.

Effects of High-Fat Diet on Cardiovascular Protein Expression in Mice Based on Proteomics.

Pan X, Zhang X, Ban J, Yue L, Ren L, Chen S Diabetes Metab Syndr Obes. 2023; 16:873-882.

PMID: 37012931 PMC: 10066704. DOI: 10.2147/DMSO.S405327.

References

Dudek J, Cheng I, Balleininger M, Vaz F, Streckfuss-Bomeke K, Hubscher D . Cardiolipin deficiency affects respiratory chain function and organization in an induced pluripotent stem cell model of Barth syndrome. Stem Cell Res. 2013; 11(2):806-19. DOI: 10.1016/j.scr.2013.05.005. View

Tohyama S, Hattori F, Sano M, Hishiki T, Nagahata Y, Matsuura T . Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell. 2012; 12(1):127-37. DOI: 10.1016/j.stem.2012.09.013. View

Janse M, dAlnoncourt C . Reflections on reentry and focal activity. Am J Cardiol. 1987; 60(11):21F-26F. DOI: 10.1016/0002-9149(87)90716-8. View

Hoffman B, Rosen M . Cellular mechanisms for cardiac arrhythmias. Circ Res. 1981; 49(1):1-15. DOI: 10.1161/01.res.49.1.1. View

Zhang L, Yin J, Liu Z, Zhang Y, Wang Q, Zhao J . Effect of resveratrol on L-type calcium current in rat ventricular myocytes. Acta Pharmacol Sin. 2006; 27(2):179-83. DOI: 10.1111/j.1745-7254.2006.00250.x. View

Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K . Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; 131(5):861-72. DOI: 10.1016/j.cell.2007.11.019. View

Wu J, Corr P . Palmitoylcarnitine increases [Na+]i and initiates transient inward current in adult ventricular myocytes. Am J Physiol. 1995; 268(6 Pt 2):H2405-17. DOI: 10.1152/ajpheart.1995.268.6.H2405. View

Meijer van Putten R, Mengarelli I, Guan K, Zegers J, van Ginneken A, Verkerk A . Ion channelopathies in human induced pluripotent stem cell derived cardiomyocytes: a dynamic clamp study with virtual IK1. Front Physiol. 2015; 6:7. PMC: 4315032. DOI: 10.3389/fphys.2015.00007. View

Pena L, van Calcar S, Hansen J, Edick M, Walsh Vockley C, Leslie N . Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016; 118(4):272-81. PMC: 4970910. DOI: 10.1016/j.ymgme.2016.05.007. View

10.

Wanders R, Ruiter J, Ijlst L, Waterham H, Houten S . The enzymology of mitochondrial fatty acid beta-oxidation and its application to follow-up analysis of positive neonatal screening results. J Inherit Metab Dis. 2010; 33(5):479-94. PMC: 2946543. DOI: 10.1007/s10545-010-9104-8. View

11.

Yamamoto A, Nakamura K, Matsumoto S, Iwai M, Shigematsu Y, Tajima G . VLCAD deficiency in a patient who recovered from ventricular fibrillation, but died suddenly of a respiratory syncytial virus infection. Pediatr Int. 2013; 55(6):775-8. DOI: 10.1111/ped.12111. View

12.

Diekman E, Ferdinandusse S, van der Pol L, Waterham H, Ruiter J, Ijlst L . Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency. Genet Med. 2015; 17(12):989-94. DOI: 10.1038/gim.2015.22. View

13.

Tucci S, Behringer S, Spiekerkoetter U . De novo fatty acid biosynthesis and elongation in very long-chain acyl-CoA dehydrogenase-deficient mice supplemented with odd or even medium-chain fatty acids. FEBS J. 2015; 282(21):4242-53. DOI: 10.1111/febs.13418. View

14.

Gillingham M, Scott B, Elliott D, Harding C . Metabolic control during exercise with and without medium-chain triglycerides (MCT) in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Mol Genet Metab. 2006; 89(1-2):58-63. PMC: 2706834. DOI: 10.1016/j.ymgme.2006.06.004. View

15.

Bastin J, Lopes-Costa A, Djouadi F . Exposure to resveratrol triggers pharmacological correction of fatty acid utilization in human fatty acid oxidation-deficient fibroblasts. Hum Mol Genet. 2011; 20(10):2048-57. DOI: 10.1093/hmg/ddr089. View

16.

Mathur A, Sims H, Gopalakrishnan D, Gibson B, Rinaldo P, Vockley J . Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation. 1999; 99(10):1337-43. DOI: 10.1161/01.cir.99.10.1337. View

17.

Knottnerus S, Bleeker J, Wust R, Ferdinandusse S, Ijlst L, Wijburg F . Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle. Rev Endocr Metab Disord. 2018; 19(1):93-106. PMC: 6208583. DOI: 10.1007/s11154-018-9448-1. View

18.

Wit A . Afterdepolarizations and triggered activity as a mechanism for clinical arrhythmias. Pacing Clin Electrophysiol. 2018; . DOI: 10.1111/pace.13419. View

19.

Olpin S, Manning N, Pollitt R, Clarke S . Improved detection of long-chain fatty acid oxidation defects in intact cells using [9,10-3H]oleic acid. J Inherit Metab Dis. 1997; 20(3):415-9. DOI: 10.1023/a:1005358802096. View

20.

Knabb M, Saffitz J, Corr P, Sobel B . The dependence of electrophysiological derangements on accumulation of endogenous long-chain acyl carnitine in hypoxic neonatal rat myocytes. Circ Res. 1986; 58(2):230-40. DOI: 10.1161/01.res.58.2.230. View