{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T12:39:54Z","timestamp":1773837594074,"version":"3.50.1"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":30,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"European Research Council","award":["Grant \u2018EU-Rhythmy\u2019 ERC-ADG-2014. ID 669387"],"award-info":[{"award-number":["Grant \u2018EU-Rhythmy\u2019 ERC-ADG-2014. ID 669387"]}]},{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"crossref","award":["Grant PID2020-113484RB-I00"],"award-info":[{"award-number":["Grant PID2020-113484RB-I00"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Italian Ministry of University and Research","award":["Grant PRIN PNRR 2022 (P2002B38NR)"],"award-info":[{"award-number":["Grant PRIN PNRR 2022 (P2002B38NR)"]}]},{"name":"European High-Performance Computing Joint Undertaking (JU) EuroHPC","award":["955495"],"award-info":[{"award-number":["955495"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-026-37707-4","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T16:46:45Z","timestamp":1771260405000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel computational model of human iPSC-derived ventricular myocytes with improved L-type calcium current for application to Timothy syndrome"],"prefix":"10.1038","volume":"16","author":[{"given":"Francesca","family":"Simone","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Trancuccio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaroslaw Karol","family":"Sochacki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celia Mart\u00ednez","family":"Prieto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia G.","family":"Priori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca F.","family":"Pavarino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Demetrio J.","family":"Santiago","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,16]]},"reference":[{"key":"37707_CR1","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1161\/CIRCRESAHA.117.305365","volume":"117","author":"I Karakikes","year":"2015","unstructured":"Karakikes, I., Ameen, M., Termglinchan, V. & Wu, J. C. Human induced pluripotent stem cell-derived cardiomyocytes: Insights into molecular, cellular, and functional phenotypes. Circ. Res. 117, 80\u201388 (2015).","journal-title":"Circ. Res."},{"key":"37707_CR2","unstructured":"Wu, X. et al. Clinical trials in-a-dish for cardiovascular medicine. Eur. Heart J.  ehae519 (2024)."},{"key":"37707_CR3","doi-asserted-by":"publisher","first-page":"H2006","DOI":"10.1152\/ajpheart.00694.2011","volume":"301","author":"J Ma","year":"2011","unstructured":"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\u2013H2017 (2011).","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"37707_CR4","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1172\/JCI62838","volume":"123","author":"SG Priori","year":"2013","unstructured":"Priori, S. G. et al. Induced pluripotent stem cell-derived cardiomyocytes in studies of inherited arrhythmias. J. Clin. Investig. 123, 84\u201391 (2013).","journal-title":"J. Clin. Investig."},{"key":"37707_CR5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1008109","volume":"16","author":"DC Kernik","year":"2020","unstructured":"Kernik, D. C., Yang, P.-C., Kurokawa, J., Wu, J. C. & Clancy, C. E. A computational model of induced pluripotent stem-cell derived cardiomyocytes for high throughput risk stratification of KCNQ1 genetic variants. PLoS Comput. Biol. 16, e1008109 (2020).","journal-title":"PLoS Comput. Biol."},{"key":"37707_CR6","doi-asserted-by":"publisher","first-page":"2334","DOI":"10.1007\/s10439-013-0833-3","volume":"41","author":"M Paci","year":"2013","unstructured":"Paci, M., Hyttinen, J., Aalto-Set\u00e4l\u00e4, K. & Severi, S. Computational models of ventricular-and atrial-like human induced pluripotent stem cell derived cardiomyocytes. Ann. Biomed. Eng. 41, 2334\u20132348 (2013).","journal-title":"Ann. Biomed. Eng."},{"key":"37707_CR7","doi-asserted-by":"publisher","first-page":"2596","DOI":"10.1016\/j.bpj.2020.03.018","volume":"118","author":"M Paci","year":"2020","unstructured":"Paci, M. et al. All-optical electrophysiology refines populations of in silico human iPSC-CMs for drug evaluation. Biophys. J . 118, 2596\u20132611 (2020).","journal-title":"Biophys. J ."},{"key":"37707_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.compbiomed.2024.108899","volume":"180","author":"S Botti","year":"2024","unstructured":"Botti, S. et al. A novel ionic model for matured and paced atrial-like human iPSC-CMs integrating IKur and IKca currents. Comput. Biol. Med. 180, 108899 (2024).","journal-title":"Comput. Biol. Med."},{"key":"37707_CR9","doi-asserted-by":"publisher","first-page":"80","DOI":"10.3389\/fphys.2018.00080","volume":"9","author":"JT Koivum\u00e4ki","year":"2018","unstructured":"Koivum\u00e4ki, J. T. et al. Structural immaturity of human iPSC-derived cardiomyocytes: In silico investigation of effects on function and disease modeling. Front. Physiol. 9, 80 (2018).","journal-title":"Front. Physiol."},{"key":"37707_CR10","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.cell.2004.09.011","volume":"119","author":"I Splawski","year":"2004","unstructured":"Splawski, I. et al. CaV1. 2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19\u201331 (2004).","journal-title":"Cell"},{"key":"37707_CR11","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1038\/s44161-023-00393-w","volume":"2","author":"A Porta-S\u00e1nchez","year":"2023","unstructured":"Porta-S\u00e1nchez, A. et al. Unexpected impairment of INa underpins reentrant arrhythmias in a knock-in swine model of Timothy syndrome. Nat. Cardiovasc. Res. 2, 1291\u20131309 (2023).","journal-title":"Nat. Cardiovasc. Res."},{"key":"37707_CR12","doi-asserted-by":"publisher","first-page":"29792","DOI":"10.1038\/s41598-024-80726-2","volume":"14","author":"A Trancuccio","year":"2024","unstructured":"Trancuccio, A., Tarifa, C., Bongianino, R., Priori, S. G. & Santiago, D. J. A novel computational model of swine ventricular myocyte reveals new insights into disease mechanisms and therapeutic approaches in Timothy syndrome. Sci. Rep. 14, 29792 (2024).","journal-title":"Sci. Rep."},{"key":"37707_CR13","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1038\/nm.2576","volume":"17","author":"SP Pa\u015fca","year":"2011","unstructured":"Pa\u015fca, S. P. et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat. Med. 17, 1657\u20131662 (2011).","journal-title":"Nat. Med."},{"key":"37707_CR14","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1038\/mp.2016.95","volume":"22","author":"MC Marchetto","year":"2017","unstructured":"Marchetto, M. C. et al. Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol. Psychiatry 22, 820\u2013835 (2017).","journal-title":"Mol. Psychiatry"},{"key":"37707_CR15","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.51037","volume":"8","author":"G Panagiotakos","year":"2019","unstructured":"Panagiotakos, G. et al. Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome. Elife 8, e51037 (2019).","journal-title":"Elife"},{"key":"37707_CR16","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1038\/nature09855","volume":"471","author":"M Yazawa","year":"2011","unstructured":"Yazawa, M. et al. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471, 230\u2013234 (2011).","journal-title":"Nature"},{"key":"37707_CR17","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.stemcr.2017.05.028","volume":"9","author":"L Song","year":"2017","unstructured":"Song, L., Seon-hye, E. P., Isseroff, Y., Morikawa, K. & Yazawa, M. Inhibition of CDK5 alleviates the cardiac phenotypes in Timothy syndrome. Stem Cell Rep. 9, 50\u201357 (2017).","journal-title":"Stem Cell Rep."},{"key":"37707_CR18","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1038\/s44161-021-00016-2","volume":"1","author":"L Song","year":"2022","unstructured":"Song, L. et al. Sigma non-opioid receptor 1 is a potential therapeutic target for long QT syndrome. Nat. Cardiovasc. Res. 1, 142\u2013156 (2022).","journal-title":"Nat. Cardiovasc. Res."},{"key":"37707_CR19","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.stem.2009.09.008","volume":"5","author":"A Giorgetti","year":"2009","unstructured":"Giorgetti, A. et al. Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell 5, 353\u2013357 (2009).","journal-title":"Cell Stem Cell"},{"key":"37707_CR20","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1038\/nprot.2012.150","volume":"8","author":"X Lian","year":"2013","unstructured":"Lian, X. et al. Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt\/$$\\beta$$-catenin signaling under fully defined conditions. Nat. Protoc. 8, 162\u2013175 (2013).","journal-title":"Nat. Protoc."},{"key":"37707_CR21","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.stem.2012.09.013","volume":"12","author":"S Tohyama","year":"2013","unstructured":"Tohyama, S. et al. Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell 12, 127\u2013137 (2013).","journal-title":"Cell Stem Cell"},{"key":"37707_CR22","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1161\/CIRCRESAHA.115.307580","volume":"117","author":"TK Feaster","year":"2015","unstructured":"Feaster, T. K. et al. Matrigel mattress: a method for the generation of single contracting human-induced pluripotent stem cell-derived cardiomyocytes. Circ. Res. 117, 995\u20131000 (2015).","journal-title":"Circ. Res."},{"key":"37707_CR23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0305248","volume":"19","author":"S Scacchi","year":"2024","unstructured":"Scacchi, S. et al. Transmural APD heterogeneity determines ventricular arrhythmogenesis in LQT8 syndrome: Insights from Bidomain computational modeling. PLoS ONE 19, e0305248 (2024).","journal-title":"PLoS ONE"},{"key":"37707_CR24","doi-asserted-by":"publisher","first-page":"314","DOI":"10.3389\/fphys.2020.00314","volume":"11","author":"C Bartolucci","year":"2020","unstructured":"Bartolucci, C., Passini, E., Hyttinen, J., Paci, M. & Severi, S. Simulation of the effects of extracellular calcium changes leads to a novel computational model of human ventricular action potential with a revised calcium handling. Front. Physiol. 11, 314 (2020).","journal-title":"Front. Physiol."},{"key":"37707_CR25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002061","volume":"7","author":"T O\u2019Hara","year":"2011","unstructured":"O\u2019Hara, T., Vir\u00e1g, L., Varr\u00f3, A. & Rudy, Y. Simulation of the undiseased human cardiac ventricular action potential: Model formulation and experimental validation. PLoS Comput. Biol. 7, e1002061 (2011).","journal-title":"PLoS Comput. Biol."},{"key":"37707_CR26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1009233","volume":"17","author":"KH J\u00e6ger","year":"2021","unstructured":"J\u00e6ger, K. H., Edwards, A. G., Giles, W. R. & Tveito, A. A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes. PLoS Comput. Biol. 17, e1009233 (2021).","journal-title":"PLoS Comput. Biol."},{"key":"37707_CR27","doi-asserted-by":"publisher","first-page":"5147","DOI":"10.1111\/bph.13282","volume":"172","author":"M Paci","year":"2015","unstructured":"Paci, M., Hyttinen, J., Rodriguez, B. & Severi, S. Human induced pluripotent stem cell-derived versus adult cardiomyocytes: An in silico electrophysiological study on effects of ionic current block. Br. J. Pharmacol. 172, 5147\u20135160 (2015).","journal-title":"Br. J. Pharmacol."},{"key":"37707_CR28","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1016\/j.bpj.2008.10.056","volume":"96","author":"EA Sobie","year":"2009","unstructured":"Sobie, E. A. Parameter sensitivity analysis in electrophysiological models using multivariable regression. Biophys. J . 96, 1264\u20131274 (2009).","journal-title":"Biophys. J ."},{"key":"37707_CR29","doi-asserted-by":"publisher","first-page":"2365","DOI":"10.1113\/JP273259","volume":"595","author":"A Fabbri","year":"2017","unstructured":"Fabbri, A., Fantini, M., Wilders, R. & Severi, S. Computational analysis of the human sinus node action potential: Model development and effects of mutations. J. Physiol. 595, 2365\u20132396 (2017).","journal-title":"J. Physiol."},{"key":"37707_CR30","doi-asserted-by":"crossref","unstructured":"Morotti, S. et al. Quantitative cross-species translators of cardiac myocyte electrophysiology: Model training, experimental validation, and applications. Science Advances7, eabg0927 (2021).","DOI":"10.1126\/sciadv.abg0927"},{"key":"37707_CR31","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.yjmcc.2013.10.021","volume":"66","author":"BM Drum","year":"2014","unstructured":"Drum, B. M., Dixon, R. E., Yuan, C., Cheng, E. P. & Santana, L. F. Cellular mechanisms of ventricular arrhythmias in a mouse model of Timothy syndrome (long QT syndrome 8). J. Mol. Cell. Cardiol. 66, 63\u201371 (2014).","journal-title":"J. Mol. Cell. Cardiol."},{"key":"37707_CR32","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1007\/s00395-021-00900-9","volume":"116","author":"B Hegyi","year":"2021","unstructured":"Hegyi, B. et al. Cardiomyocyte na+ and ca2+ mishandling drives vicious cycle involving CaMKII, ROS, and ryanodine receptors. Basic Res. Cardiol. 116, 58 (2021).","journal-title":"Basic Res. Cardiol."},{"key":"37707_CR33","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.yjmcc.2013.03.004","volume":"59","author":"VA Maltsev","year":"2013","unstructured":"Maltsev, V. A. & Lakatta, E. G. Numerical models based on a minimal set of sarcolemmal electrogenic proteins and an intracellular Ca2+ clock generate robust, flexible, and energy-efficient cardiac pacemaking. J. Mol. Cell. Cardiol. 59, 181\u2013195 (2013).","journal-title":"J. Mol. Cell. Cardiol."},{"key":"37707_CR34","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.yjmcc.2015.01.013","volume":"81","author":"JJ Kim","year":"2015","unstructured":"Kim, J. J. et al. Mechanism of automaticity in cardiomyocytes derived from human induced pluripotent stem cells. J. Mol. Cell. Cardiol. 81, 81\u201393 (2015).","journal-title":"J. Mol. Cell. Cardiol."},{"key":"37707_CR35","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1093\/cvr\/cvad163","volume":"120","author":"Y Xia","year":"2024","unstructured":"Xia, Y., Zhang, X.-H., Yamaguchi, N. & Morad, M. Point mutations in ryr2 ca2+-binding residues of human cardiomyocytes cause cellular remodelling of cardiac excitation contraction-coupling. Cardiovasc. Res. 120, 44\u201355 (2024).","journal-title":"Cardiovasc. Res."},{"key":"37707_CR36","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.vascn.2016.08.002","volume":"82","author":"G Rast","year":"2016","unstructured":"Rast, G., Kraushaar, U., Buckenmaier, S., Ittrich, C. & Guth, B. D. Influence of field potential duration on spontaneous beating rate of human induced pluripotent stem cell-derived cardiomyocytes: Implications for data analysis and test system selection. J. Pharmacol. Toxicol. Methods 82, 74\u201382 (2016).","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"37707_CR37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1011806","volume":"20","author":"J Yang","year":"2024","unstructured":"Yang, J., Daily, N. J., Pullinger, T. K., Wakatsuki, T. & Sobie, E. A. Creating cell-specific computational models of stem cell-derived cardiomyocytes using optical experiments. PLoS Comput. Biol. 20, e1011806 (2024).","journal-title":"PLoS Comput. Biol."},{"key":"37707_CR38","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/j.stem.2023.03.010","volume":"30","author":"S Marchiano","year":"2023","unstructured":"Marchiano, S. et al. Gene editing to prevent ventricular arrhythmias associated with cardiomyocyte cell therapy. Cell Stem Cell 30, 396-414.e9 (2023).","journal-title":"Cell Stem Cell"},{"key":"37707_CR39","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1159\/000329966","volume":"27","author":"L Guo","year":"2011","unstructured":"Guo, L. et al. The electrophysiological effects of cardiac glycosides in human iPSC-derived cardiomyocytes and in guinea pig isolated hearts. Cell. Physiol. Biochem. 27, 453\u2013462 (2011).","journal-title":"Cell. Physiol. Biochem."},{"key":"37707_CR40","doi-asserted-by":"publisher","first-page":"709","DOI":"10.3389\/fphys.2018.00709","volume":"9","author":"M Paci","year":"2018","unstructured":"Paci, M. et al. Automatic optimization of an in silico model of human iPSC derived cardiomyocytes recapitulating calcium handling abnormalities. Front. Physiol. 9, 709. https:\/\/doi.org\/10.3389\/fphys.2018.00709 (2018).","journal-title":"Front. Physiol."},{"key":"37707_CR41","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1161\/CIRCRESAHA.112.300567","volume":"112","author":"BC Knollmann","year":"2013","unstructured":"Knollmann, B. C. Induced pluripotent stem cell-derived cardiomyocytes: Boutique science or valuable arrhythmia model?. Circ. Res. 112, 969\u2013976 (2013).","journal-title":"Circ. Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-37707-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-37707-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-37707-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T09:17:39Z","timestamp":1773825459000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-37707-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,16]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["37707"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-37707-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,16]]},"assertion":[{"value":"10 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9260"}}