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Stem cell models of inherited arrhythmias

Nature Cardiovascular Research volume 3, pages 420–430 (2024)Cite this article

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Abstract

Inherited arrhythmias are a heterogeneous group of conditions that confer risk of sudden death. Many inherited arrhythmias have been linked to pathogenic genetic variants that result in ion channel dysfunction, although current genetic testing panels fail to identify variants in many patients, potentially secondary to their underlying substrates being oligogenic or polygenic. Here we review the current state of knowledge surrounding the cellular mechanisms of inherited arrhythmias generated from stem cell models with a focus on integrating genetic and mechanistic data. The utility and limitations of human induced pluripotent stem cell models in disease modeling and drug development are also explored with a particular focus on examples of pharmacogenetics and precision medicine. We submit that progress in understanding inherited arrhythmias is likely to be made by using human induced pluripotent stem cells to model probable polygenic cases as well as to interrogate the diverse and potentially complex molecular networks implicated by genome-wide association studies.

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Fig. 1: Molecular mechanisms of LQTS.
Fig. 2: Molecular mechanisms of BrS.
Fig. 3: Molecular mechanisms of CPVT A.

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References

  1. Mazzanti, A., Maragna, R. & Priori, S. G. Genetic causes of sudden cardiac death in the young. Curr. Opin. Cardiol. 32, 253–261 (2017).

    Article  PubMed  Google Scholar 

  2. Moretti, A. et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N. Engl. J. Med. 363, 1397–1409 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Bellin, M. et al. Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome. EMBO J. 32, 3161–3175 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mesquita, F. C. P. et al. R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome. Sci. Rep. 9, 19203 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Feng, L. et al. Long QT syndrome KCNH2 variant induces hERG1a/1b subunit imbalance in patient-specific induced pluripotent stem cell-derived cardiomyocytes. Circ. Arrhythm. Electrophysiol. 14, e009343 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mehta, A. et al. Re-trafficking of hERG reverses long QT syndrome 2 phenotype in human iPS-derived cardiomyocytes. Cardiovasc. Res. 102, 497–506 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Lee, Y. K. et al. MTMR4 SNVs modulate ion channel degradation and clinical severity in congenital long QT syndrome: insights in the mechanism of action of protective modifier genes. Cardiovasc. Res. 117, 767–779 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Arking, D. E. et al. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat. Genet. 46, 826–836 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lahrouchi, N. et al. Transethnic genome-wide association study provides insights in the genetic architecture and heritability of long QT syndrome. Circulation 142, 324–338 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Arking, D. E. et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat. Genet. 38, 644–651 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Ronchi, C. et al. NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis. Cardiovasc. Res. 117, 472–483 (2021).

    Article  CAS  PubMed  Google Scholar 

  12. Nishio, Y. et al. D85N, a KCNE1 polymorphism, is a disease-causing gene variant in long QT syndrome. J. Am. Coll. Cardiol. 54, 812–819 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Kolder, I. et al. Analysis for genetic modifiers of disease severity in patients with long-QT syndrome type 2. Circ Cardiovasc. Genet. 8, 447–456 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Roberts, J. D. et al. An international multicenter evaluation of type 5 long QT syndrome: a low penetrant primary arrhythmic condition. Circulation 141, 429–439 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Adler, A. et al. An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome. Circulation 141, 418–428 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kim, M. et al. Development of a patient-specific p.D85N-potassium voltage-gated channel subfamily E member 1-induced pluripotent stem cell-derived cardiomyocyte model for drug-induced long QT syndrome. Circ. Genom. Precis. Med. 14, e003234 (2021).

    Article  CAS  PubMed  Google Scholar 

  17. Wada, Y. et al. Common ancestry-specific ion channel variants predispose to drug-induced arrhythmias. Circulation 145, 299–308 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sala, L. et al. A new hERG allosteric modulator rescues genetic and drug-induced long-QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells. EMBO Mol. Med. 8, 1065–1081 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mehta, A. et al. Identification of a targeted and testable antiarrhythmic therapy for long-QT syndrome type 2 using a patient-specific cellular model. Eur. Heart J. 39, 1446–1455 (2018).

    Article  CAS  PubMed  Google Scholar 

  20. Priori, S. G. et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 10, 1932–1963 (2013).

    Article  PubMed  Google Scholar 

  21. O’Hare, B. J. et al. Promise and potential peril with lumacaftor for the trafficking defective type 2 long-QT syndrome-causative variants, p.G604S, p.N633S, and p.R685P, using patient-specific re-engineered cardiomyocytes. Circ. Genom. Precis. Med. 13, 466–475 (2020). This study showed that rescuing trafficking defects in long QT syndrome can worsen the arrhythmic phenotype depending on the variant.

    Article  PubMed  Google Scholar 

  22. Garg, P. et al. Genome editing of induced pluripotent stem cells to decipher cardiac channelopathy variant. J. Am. Coll. Cardiol. 72, 62–75 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Perry, M. D. et al. Pharmacological activation of IKr in models of long QT type 2 risks overcorrection of repolarization. Cardiovasc Res 116, 1434–1445 (2020). This study showed that a small-molecule activator of Kv11.1 could overcorrect prolonged repolarization in an hiPS cell model of long QT, resulting in a pro-arrhythmic effect.

    Article  CAS  PubMed  Google Scholar 

  24. McKeithan, W. L. et al. Reengineering an antiarrhythmic drug using patient hiPSC cardiomyocytes to improve therapeutic potential and reduce toxicity. Cell Stem Cell 27, 813–821 (2020). McKeithan et al. use hiPS cell-derived cardiomyocytes to re-engineer mexiletine generating a molecule with improved efficacy and reduced toxicity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Colatsky, T. et al. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative - update on progress. J. Pharmacol. Toxicol. Methods 81, 15–20 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Strauss, D. G. et al. Comprehensive In vitro Proarrhythmia Assay (CiPA) Update from a Cardiac Safety Research Consortium / Health and Environmental Sciences Institute / FDA meeting. Ther. Innov. Regul. Sci. 53, 519–525 (2019).

    Article  PubMed  Google Scholar 

  27. Ando, H. et al. A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes. J. Pharmacol. Toxicol. Methods 84, 111–127 (2017).

    Article  CAS  PubMed  Google Scholar 

  28. Goversen, B., van der Heyden, M. A. G., van Veen, T. A. B. & de Boer, T. P. The immature electrophysiological phenotype of iPSC-CMs still hampers in vitro drug screening: special focus on IK1. Pharmacol. Ther. 183, 127–136 (2018).

    Article  CAS  PubMed  Google Scholar 

  29. Li, M. et al. Overexpression of KCNJ2 in induced pluripotent stem cell-derived cardiomyocytes for the assessment of QT-prolonging drugs. J. Pharmacol. Sci. 134, 75–85 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. Goversen, B. et al. A hybrid model for safety pharmacology on an automated patch clamp platform: using dynamic clamp to join iPSC-derived cardiomyocytes and simulations of Ik1 ion channels in real-time. Front. Physiol. 8, 1094 (2017).

    Article  PubMed  Google Scholar 

  31. Vaidyanathan, R. et al. IK1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes. Am. J. Physiol. Heart Circ. Physiol. 310, H1611–H1621 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hosseini, S. M. et al. Reappraisal of reported genes for sudden arrhythmic death: evidence-based evaluation of gene validity for brugada syndrome. Circulation 138, 1195–1205 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Barc, J. et al. Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility. Nat. Genet. 54, 232–239 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liang, P. et al. Patient-specific and genome-edited induced pluripotent stem cell-derived cardiomyocytes elucidate single-cell phenotype of Brugada syndrome. J. Am. Coll. Cardiol. 68, 2086–2096 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Perez-Hernandez, M. et al. Brugada syndrome trafficking-defective Nav1.5 channels can trap cardiac Kir2.1/2.2 channels. JCI Insight 3, e96291 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lu, A. et al. Inhibition of Wnt/β-catenin signaling upregulates Nav1.5 channels in Brugada syndrome iPSC-derived cardiomyocytes. Physiol Rep. 11, e15696 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cai, D. et al. Patient-specific iPSC-derived cardiomyocytes reveal aberrant activation of Wnt/beta-catenin signaling in SCN5A-related Brugada syndrome. Stem Cell Res. Ther. 14, 241 (2023). Refs. 36 and 37 show that Wnt signaling is probably involved in the pathophysiology of BrS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sun, Y. et al. Patient-specific iPSC-derived cardiomyocytes reveal variable phenotypic severity of Brugada syndrome. EBioMedicine 95, 104741 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Glatter, K. A. et al. Effectiveness of sotalol treatment in symptomatic Brugada syndrome. Am. J. Cardiol. 93, 1320–1322 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Bezzina, C. R. et al. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat. Genet. 45, 1044–1049 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. El-Battrawy, I. et al. A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes. Europace 21, 1410–1421 (2019).

    Article  PubMed  Google Scholar 

  42. Man, J. C. K. et al. Variant intronic enhancer controls SCN10A-short expression and heart conduction. Circulation 144, 229–242 (2021).

    Article  CAS  PubMed  Google Scholar 

  43. van den Boogaard, M. et al. A common genetic variant within SCN10A modulates cardiac SCN5A expression. J. Clin. Invest. 124, 1844–1852 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Arnolds, D. E. et al. TBX5 drives Scn5a expression to regulate cardiac conduction system function. J. Clin. Invest. 122, 2509–2518 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nieto-Marin, P. et al. Tbx5 variants disrupt Nav1.5 function differently in patients diagnosed with Brugada or long QT syndrome. Cardiovasc. Res. https://doi.org/10.1093/cvr/cvab045 (2021).

    Article  Google Scholar 

  46. Bersell, K. R. et al. Transcriptional dysregulation underlies both monogenic arrhythmia syndrome and common modifiers of cardiac repolarization. Circulation https://doi.org/10.1161/CIRCULATIONAHA.122.062193 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Li, Y. et al. Novel insights in the pathomechanism of Brugada syndrome and fever-related type 1 ECG changes in a preclinical study using human-induced pluripotent stem cell-derived cardiomyocytes. Clin. Transl. Med. 13, e1130 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. McCormick, J. J., Dokladny, K., Moseley, P. L. & Kenny, G. P. Autophagy and heat: a potential role for heat therapy to improve autophagic function in health and disease. J. Appl. Physiol. 130, 1–9 (2021).

    Article  CAS  PubMed  Google Scholar 

  49. Stamenkovic, M. et al. Comparative analysis of cell death mechanisms induced by lysosomal autophagy inhibitors. Eur. J. Pharmacol. 859, 172540 (2019).

    Article  CAS  PubMed  Google Scholar 

  50. Cerrone, M. et al. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype. Circulation 129, 1092–1103 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Veerman, C. C. et al. hiPSC-derived cardiomyocytes from Brugada syndrome patients without identified mutations do not exhibit clear cellular electrophysiological abnormalities. Sci. Rep. 6, 30967 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Catalano, O. et al. Magnetic resonance investigations in Brugada syndrome reveal unexpectedly high rate of structural abnormalities. Eur. Heart J. 30, 2241–2248 (2009).

    Article  PubMed  Google Scholar 

  53. Gussak, I. et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology 94, 99–102 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Walsh, R. et al. Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. Eur. Heart J. 43, 1500–1510 (2022).

    Article  CAS  PubMed  Google Scholar 

  55. McPate, M. J., Duncan, R. S., Hancox, J. C. & Witchel, H. J. Pharmacology of the short QT syndrome N588K-hERG K+ channel mutation: differential impact on selected class I and class III antiarrhythmic drugs. Br. J. Pharmacol. 155, 957–966 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. El-Battrawy, I. et al. Modeling short QT syndrome using human-induced pluripotent stem cell-derived cardiomyocytes. J. Am. Heart Assoc. 7, e007394 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Shinnawi, R. et al. Modeling reentry in the short QT syndrome with human-induced pluripotent stem cell-derived cardiac cell sheets. J. Am. Coll. Cardiol. 73, 2310–2324 (2019).

    Article  PubMed  Google Scholar 

  58. Guo, F. et al. Patient-specific and gene-corrected induced pluripotent stem cell-derived cardiomyocytes elucidate single-cell phenotype of short QT syndrome. Circ. Res. 124, 66–78 (2019).

    Article  CAS  PubMed  Google Scholar 

  59. van der Werf, C. et al. Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest. Eur. Heart J. 40, 2953–2961 (2019).

    Article  PubMed  Google Scholar 

  60. Itzhaki, I. et al. Modeling of catecholaminergic polymorphic ventricular tachycardia with patient-specific human-induced pluripotent stem cells. J. Am. Coll. Cardiol. 60, 990–1000 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Jung, C. B. et al. Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia. EMBO Mol. Med. 4, 180–191 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kujala, K. et al. Cell model of catecholaminergic polymorphic ventricular tachycardia reveals early and delayed afterdepolarizations. PLoS ONE 7, e44660 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lodola, F. et al. Adeno-associated virus-mediated CASQ2 delivery rescues phenotypic alterations in a patient-specific model of recessive catecholaminergic polymorphic ventricular tachycardia. Cell Death Dis. 7, e2393 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Dobrev, D. & Wehrens, X. H. Role of RyR2 phosphorylation in heart failure and arrhythmias: controversies around ryanodine receptor phosphorylation in cardiac disease. Circ. Res. 114, 1311–1319 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Park, S. J. et al. Insights into the pathogenesis of catecholaminergic polymorphic ventricular tachycardia from engineered human heart tissue. Circulation 140, 390–404 (2019). Park et al. explored the molecular mechanism of CPVT and showed that whereas individual cardiomyocytes did exhibit abnormal calcium handling at baseline, a tissue model only displayed reentry in response to high-frequency pacing or adrenergic stimulus, in keeping with the clinical phenotype.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bezzerides, V. J. et al. Gene therapy for catecholaminergic polymorphic ventricular tachycardia by inhibition of Ca2+/calmodulin-dependent kinase II. Circulation 140, 405–419 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Uchinoumi, H. et al. Catecholaminergic polymorphic ventricular tachycardia is caused by mutation-linked defective conformational regulation of the ryanodine receptor. Circ. Res. 106, 1413–1424 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Penttinen, K. et al. Antiarrhythmic effects of dantrolene in patients with catecholaminergic polymorphic ventricular tachycardia and replication of the responses using iPSC models. PLoS ONE 10, e0125366 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Word, T. A. et al. Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell-derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia. J. Cell. Mol. Med. 25, 6115–6124 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Di Pasquale, E. et al. CaMKII inhibition rectifies arrhythmic phenotype in a patient-specific model of catecholaminergic polymorphic ventricular tachycardia. Cell Death Dis. 4, e843 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Schweitzer, M. K. et al. Suppression of arrhythmia by enhancing mitochondrial Ca2+ uptake in catecholaminergic ventricular tachycardia models. JACC Basic Transl. Sci. 2, 737–747 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Sander, P. et al. Approved drugs ezetimibe and disulfiram enhance mitochondrial Ca2+ uptake and suppress cardiac arrhythmogenesis. Br. J. Pharmacol. 178, 4518–4532 (2021).

    Article  CAS  PubMed  Google Scholar 

  73. Blackwell, D. J. et al. The Purkinje-myocardial junction is the anatomic origin of ventricular arrhythmia in CPVT. JCI Insight 7, e151893 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Roselli, C. et al. Multi-ethnic genome-wide association study for atrial fibrillation. Nat. Genet. 50, 1225–1233 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Benaglio, P. et al. Allele-specific NKX2-5 binding underlies multiple genetic associations with human electrocardiographic traits. Nat. Genet. 51, 1506–1517 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ellinor, P. T. et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat. Genet. 44, 670–675 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gudbjartsson, D. F. et al. Large-scale whole-genome sequencing of the Icelandic population. Nat. Genet. 47, 435–444 (2015).

    Article  CAS  PubMed  Google Scholar 

  78. Orr, N. et al. A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation. Nat. Commun. 7, 11303 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ghazizadeh, Z. et al. Metastable atrial state underlies the primary genetic substrate for MYL4 mutation-associated atrial fibrillation. Circulation 141, 301–312 (2020).

    Article  CAS  PubMed  Google Scholar 

  80. Hong, L. et al. Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation. Stem Cell Reports 16, 1542–1554 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Benzoni, P. et al. Human iPSC modelling of a familial form of atrial fibrillation reveals a gain of function of If and ICaL in patient-derived cardiomyocytes. Cardiovasc. Res. 116, 1147–1160 (2020).

    Article  CAS  PubMed  Google Scholar 

  82. Garg, P. et al. Human induced pluripotent stem cell-derived cardiomyocytes as models for cardiac channelopathies: a primer for non-electrophysiologists. Circ. Res. 123, 224–243 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ma, J. et al. High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. Am. J. Physiol. Heart Circ. Physiol. 301, H2006–H2017 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Veerman, C. C. et al. Switch from fetal to adult SCN5A isoform in human induced pluripotent stem cell-derived cardiomyocytes unmasks the cellular phenotype of a conduction disease-causing mutation. J. Am. Heart Assoc. 6, e005135 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Kim, J. J. et al. Mechanism of automaticity in cardiomyocytes derived from human induced pluripotent stem cells. J. Mol. Cell. Cardiol. 81, 81–93 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Satin, J. et al. Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes. J. Physiol. 559, 479–496 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hong, T. & Shaw, R. M. Cardiac T-tubule microanatomy and function. Physiol. Rev. 97, 227–252 (2017).

    Article  PubMed  Google Scholar 

  88. Vuckovic, S. et al. Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling. Stem Cell Res. Ther. 13, 332 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Mason, F. E., Pronto, J. R. D., Alhussini, K., Maack, C. & Voigt, N. Cellular and mitochondrial mechanisms of atrial fibrillation. Basic Res. Cardiol. 115, 72 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Tanaka, M. et al. Elevated oxidative stress is associated with ventricular fibrillation episodes in patients with Brugada-type electrocardiogram without SCN5A mutation. Cardiovasc. Pathol. 20, e37–e42 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Karbassi, E. et al. Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine. Nat. Rev. Cardiol. 17, 341–359 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Campostrini, G. et al. Maturation of hiPSC-derived cardiomyocytes promotes adult alternative splicing of SCN5A and reveals changes in sodium current associated with cardiac arrhythmia. Cardiovasc. Res. 119, 167–182 (2023).

    Article  CAS  PubMed  Google Scholar 

  93. Morrissey, J., Mesquita, F. C. P., Hochman-Mendez, C. & Taylor, D. A. Whole heart engineering: advances and challenges. Cells Tissues Organs 211, 395–405 (2022).

    CAS  PubMed  Google Scholar 

  94. Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Itzhaki, I. et al. Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471, 225–229 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Nakajima, T. et al. Novel mechanism of HERG current suppression in LQT2: shift in voltage dependence of HERG inactivation. Circ. Res. 83, 415–422 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Salvage, S. C. et al. Ion channel gating in cardiac ryanodine receptors from the arrhythmic RyR2-P2328S mouse. J. Cell Sci. 132, jcs229039 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Giustetto, C. et al. Long-term follow-up of patients with short QT syndrome. J. Am. Coll. Cardiol. 58, 587–595 (2011).

    Article  PubMed  Google Scholar 

  99. Zeppenfeld, K. et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur. Heart J. 43, 3997–4126 (2022).

    Article  PubMed  Google Scholar 

  100. Hindricks, G. et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur. Heart J. 42, 373–498 (2021).

    Article  PubMed  Google Scholar 

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  1. McMaster University, Hamilton, Ontario, Canada

    Tammy Ryan & Jason D. Roberts

  2. Population Health Research Institute and Hamilton Health Sciences, Hamilton, Ontario, Canada

    Jason D. Roberts

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Ryan, T., Roberts, J.D. Stem cell models of inherited arrhythmias. Nat Cardiovasc Res 3, 420–430 (2024). https://doi.org/10.1038/s44161-024-00451-x

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