Search
Close this search box.

Stem cell models of inherited arrhythmias – Nature Cardiovascular Research

  • 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
     

  • 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
     

  • 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
     

  • 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 
    ADS 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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 
    ADS 

    Google Scholar
     

  • 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
     

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

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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 
    ADS 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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 
    ADS 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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 
    ADS 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

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

    Article 
    PubMed 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

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

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • Latest Intelligence