Modeling Polymorphic Ventricular Tachycardia at Rest Using Patient-specific Induced Pluripotent Stem Cell-derived Cardiomyocytes

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2020 Sep 27

PMID 32980690

Citations 14

Authors

Yvonne Sleiman

Monia Souidi

Ritu Kumar

Ellen Yang

Fabrice Jaffre

Ting Zhou

Albin Bernardin

Steve Reiken

Olivier Cazorla

Andrey V Kajava

Adrien Moreau

Jean-Luc Pasquie

Andrew R Marks

Bruce B Lerman

Shuibing Chen

Jim W Cheung

Todd Evans

Alain Lacampagne

Albano C Meli

Affiliations

Soon will be listed here.

Abstract

Background: While mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to exercise-induced or catecholaminergic polymorphic ventricular tachycardia (CPVT), its association with polymorphic ventricular tachycardia (PMVT) occurring at rest is unclear. We aimed at constructing a patient-specific human-induced pluripotent stem cell (hiPSC) model of PMVT occurring at rest linked to a single point mutation in RyR2.

Methods: Blood samples were obtained from a patient with PMVT at rest due to a heterozygous RyR2-H29D mutation. Patient-specific hiPSCs were generated from the blood samples, and the hiPSC-derived cardiomyocytes (CMs) were generated via directed differentiation. Using CRIPSR/Cas9 technology, isogenic controls were generated by correcting the RyR2-H29D mutation. Using patch-clamp, fluorescent confocal microscopy and video-image-based analysis, the molecular and functional properties of RyR2-H29D hiPSCCMs and control hiPSCCMs were compared.

Findings: RyR2-H29D hiPSCCMs exhibit intracellular sarcoplasmic reticulum (SR) Ca leak through RyR2 under physiological pacing. RyR2-H29D enhances the contribution of inositol 1,4,5-trisphosphate receptors to excitation-contraction coupling (ECC) that exacerbates abnormal Ca release in RyR2-H29D hiPSCCMs. RyR2-H29D hiPSCCMs exhibit shorter action potentials, delayed afterdepolarizations, arrhythmias and aberrant contractile properties compared to isogenic controls. The RyR2-H29D mutation causes post-translational remodeling that is fully reversed with isogenic controls.

Interpretation: To conclude, in a model based on a RyR2 point mutation that is associated with short-coupled PMVT at rest, RyR2-H29D hiPSCCMs exhibited aberrant intracellular Ca homeostasis, shortened action potentials, arrhythmias and abnormal contractile properties.

Funding: French Muscular Dystrophy Association (AFM; project 16,073, MNM2 2012 and 20,225), "Fondation de la Recherche Médicale" (FRM; SPF20130526710), "Institut National pour la Santé et la Recherche Médicale" (INSERM), National Institutes of Health (ARM; R01 HL145473) and New York State Department of Health (NYSTEM C029156).

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PMID: 37740238 PMC: 10517551. DOI: 10.1186/s13287-023-03502-5.

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References

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

Tiso N, Salamon M, Bagattin A, Danieli G, Argenton F, Bortolussi M . The binding of the RyR2 calcium channel to its gating protein FKBP12.6 is oppositely affected by ARVD2 and VTSIP mutations. Biochem Biophys Res Commun. 2002; 299(4):594-8. DOI: 10.1016/s0006-291x(02)02689-x. View

Hsu P, Scott D, Weinstein J, Ran F, Konermann S, Agarwala V . DNA targeting specificity of RNA-guided Cas9 nucleases. Nat Biotechnol. 2013; 31(9):827-32. PMC: 3969858. DOI: 10.1038/nbt.2647. View

Labun K, Montague T, Gagnon J, Thyme S, Valen E . CHOPCHOP v2: a web tool for the next generation of CRISPR genome engineering. Nucleic Acids Res. 2016; 44(W1):W272-6. PMC: 4987937. DOI: 10.1093/nar/gkw398. View

Lian X, Zhang J, Azarin S, Zhu K, Hazeltine L, Bao X . Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions. Nat Protoc. 2012; 8(1):162-75. PMC: 3612968. DOI: 10.1038/nprot.2012.150. View

Park S, Zhang D, Qi Y, Li Y, Lee K, Bezzerides V . Insights Into the Pathogenesis of Catecholaminergic Polymorphic Ventricular Tachycardia From Engineered Human Heart Tissue. Circulation. 2019; 140(5):390-404. PMC: 6750809. DOI: 10.1161/CIRCULATIONAHA.119.039711. View

Leenhardt A, Glaser E, Burguera M, Nurnberg M, Maison-Blanche P, COUMEL P . Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias. Circulation. 1994; 89(1):206-15. DOI: 10.1161/01.cir.89.1.206. View

Meli A, Refaat M, Dura M, Reiken S, Wronska A, Wojciak J . A novel ryanodine receptor mutation linked to sudden death increases sensitivity to cytosolic calcium. Circ Res. 2011; 109(3):281-90. PMC: 3690513. DOI: 10.1161/CIRCRESAHA.111.244970. View

Tiso N, Stephan D, Nava A, Bagattin A, Devaney J, Stanchi F . Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet. 2001; 10(3):189-94. DOI: 10.1093/hmg/10.3.189. View

10.

Acimovic I, Vilotic A, Pesl M, Lacampagne A, Dvorak P, Rotrekl V . Human pluripotent stem cell-derived cardiomyocytes as research and therapeutic tools. Biomed Res Int. 2014; 2014:512831. PMC: 3996932. DOI: 10.1155/2014/512831. View

11.

Yamazaki M, Osaka T, Yokoyama E, Kodama I . A case of short-coupled variant of torsade de pointes characterized by spatial heterogeneity of action potential duration and its restitution kinetics. J Interv Card Electrophysiol. 2007; 17(1):35-40. DOI: 10.1007/s10840-006-9048-y. View

12.

Santulli G, Nakashima R, Yuan Q, Marks A . Intracellular calcium release channels: an update. J Physiol. 2017; 595(10):3041-3051. PMC: 5430224. DOI: 10.1113/JP272781. View

13.

Ribeiro M, Tertoolen L, Guadix J, Bellin M, Kosmidis G, DAniello C . Functional maturation of human pluripotent stem cell derived cardiomyocytes in vitro--correlation between contraction force and electrophysiology. Biomaterials. 2015; 51:138-150. DOI: 10.1016/j.biomaterials.2015.01.067. View

14.

Jung C, Moretti A, Mederos Y Schnitzler M, Iop L, Storch U, Bellin M . Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia. EMBO Mol Med. 2011; 4(3):180-91. PMC: 3376852. DOI: 10.1002/emmm.201100194. View

15.

Dunnink A, Stams T, Bossu A, Meijborg V, Beekman J, Wijers S . Torsade de pointes arrhythmias arise at the site of maximal heterogeneity of repolarization in the chronic complete atrioventricular block dog. Europace. 2017; 19(5):858-865. DOI: 10.1093/europace/euw087. View

16.

Grais I, Sowers J . Thyroid and the heart. Am J Med. 2014; 127(8):691-8. PMC: 4318631. DOI: 10.1016/j.amjmed.2014.03.009. View

17.

Watanabe H, Chopra N, Laver D, Hwang H, Davies S, Roach D . Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med. 2009; 15(4):380-3. PMC: 2904954. DOI: 10.1038/nm.1942. View

18.

Fleming S, Thompson M, Stevens R, Heneghan C, Pluddemann A, Maconochie I . Normal ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic review of observational studies. Lancet. 2011; 377(9770):1011-8. PMC: 3789232. DOI: 10.1016/S0140-6736(10)62226-X. View

19.

Beach L, Goldschlager N, Moss J, Scheinman M . Idiopathic Ventricular Fibrillation in a 29-Year-Old Man. Circulation. 2017; 136(1):112-114. DOI: 10.1161/CIRCULATIONAHA.117.029120. View

20.

Zalk R, Clarke O, des Georges A, Grassucci R, Reiken S, Mancia F . Structure of a mammalian ryanodine receptor. Nature. 2014; 517(7532):44-9. PMC: 4300236. DOI: 10.1038/nature13950. View