{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T22:43:25Z","timestamp":1794005005305,"version":"4.8.0"},"reference-count":83,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018693","name":"Horizon Europe EU","doi-asserted-by":"publisher","award":["HORIZON-MSCA-2022-PF-01"],"award-info":[{"award-number":["HORIZON-MSCA-2022-PF-01"]}],"id":[{"id":"10.13039\/100018693","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018693","name":"Horizon Europe EU","doi-asserted-by":"publisher","award":["101105561"],"award-info":[{"award-number":["101105561"]}],"id":[{"id":"10.13039\/100018693","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","award":["H2020-MSCA-IF-2017"],"award-info":[{"award-number":["H2020-MSCA-IF-2017"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","award":["795209"],"award-info":[{"award-number":["795209"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002803","name":"Fondazione CARIPLO","doi-asserted-by":"publisher","award":["2019-1691"],"award-info":[{"award-number":["2019-1691"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Leducq Foundation","doi-asserted-by":"publisher","award":["18CVD05"],"award-info":[{"award-number":["18CVD05"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Italian Ministry of University and Research within Mission 4","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Education and Research"},{"DOI":"10.13039\/100001818","name":"From Research to Business","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]},{"name":"young researchers"},{"name":"National Recovery and Resilience Plan","award":["2022-NAZ-0485"],"award-info":[{"award-number":["2022-NAZ-0485"]}]},{"name":"National Recovery and Resilience Plan","award":["H45E22001210006"],"award-info":[{"award-number":["H45E22001210006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Long QT syndrome (LQTS) is a life-threatening genetic disorder characterized by prolonged QT intervals on electrocardiograms. Congenital forms are mostly associated with variants in the KCNQ1 and KCNH2 genes. Among pathogenic or likely pathogenic (P\/LP) variants, some are associated with a significantly higher incidence of cardiac events compared to others. While therapies have significantly reduced mortality, some patients are unresponsive or intolerant to therapy, perpetuating their arrhythmic risk, including sudden cardiac death. Current approaches for risk stratification are insufficient, highlighting the critical need for more accurate identification and management of patients carrying high-risk genetic variants. Here, we aimed to develop a refined risk stratification model for P\/LP variants by applying machine learning classification to electrophysiological data measured in patient-specific human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Ten patient-specific hiPSC lines, each carrying one of six pathogenic or likely pathogenic (P\/LP) variants in the KCNQ1 or KCNH2 genes, along with two healthy control hiPSC lines, were differentiated into hiPSC-CMs. Electrophysiological responses from multielectrode array recordings at baseline and after application of selective ion channel blockers or pro-arrhythmic compounds were used to train a machine learning model to classify variant-specific risk levels based on in vitro electrophysiological readouts. An independent validation cohort of two additional KCNH2 hiPSC lines was used to test the model\u2019s performance in predicting single-variant risk. Our findings revealed a correlation between variant risk level, hiPSC-CM electrophysiological profiles, and drug responses. The machine learning classifier, trained on multielectrode array recordings, achieved 89% accuracy in the classification of P\/LP genetic variants according to the associated risk levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study demonstrates that integrating hiPSC-CM electrophysiological profiling with machine learning provides a robust method for granular variant-specific risk stratification of LQTS patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag105","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T12:01:31Z","timestamp":1778760091000},"page":"1374-1390","source":"Crossref","is-referenced-by-count":2,"title":["Machine learning-guided risk stratification for long QT syndrome genetic variants with hiPSC-derived cardiomyocytes"],"prefix":"10.1093","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9214-0868","authenticated-orcid":false,"given":"Aleksandr","family":"Khudiakov","sequence":"first","affiliation":[{"name":"Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Mura","sequence":"additional","affiliation":[{"name":"Translational Cardiology Unit, Fondazione IRCCS Policlinico San Matteo , Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1785-5529","authenticated-orcid":false,"given":"Federica","family":"Giannetti","sequence":"additional","affiliation":[{"name":"Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladislav","family":"Leonov","sequence":"additional","affiliation":[{"name":"Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS , Milan ,","place":["Italy"]},{"name":"Department of Surgery, Dentistry, Pediatrics and Gynecology, Cardiovascular Science, The University of Verona, Policlinico G.B. Rossi , Verona ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4727-0994","authenticated-orcid":false,"given":"Chiara","family":"Alberio","sequence":"additional","affiliation":[{"name":"Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marem","family":"Eskandr","sequence":"additional","affiliation":[{"name":"Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS , Milan ,","place":["Italy"]},{"name":"Department of Biotechnology and Biosciences, University of Milano-Bicocca , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola Adele","family":"Lonati","sequence":"additional","affiliation":[{"name":"Laboratory of ImmunoRheumatologic Researches, Istituto Auxologico Italiano IRCCS , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Orietta","family":"Borghi","sequence":"additional","affiliation":[{"name":"Laboratory of ImmunoRheumatologic Researches, Istituto Auxologico Italiano IRCCS , Milan ,","place":["Italy"]},{"name":"Dipartimento di Scienze Cliniche e di Comunit\u00e0, Dipartimento di Eccellenza 2023-2027, University of Milan , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A","family":"Brink","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Stellenbosch , Tygerberg ,","place":["South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lia","family":"Crotti","sequence":"additional","affiliation":[{"name":"Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS , Milan ,","place":["Italy"]},{"name":"Department of Medicine and Surgery, University of Milano-Bicocca , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Gnecchi","sequence":"additional","affiliation":[{"name":"Translational Cardiology Unit, Fondazione IRCCS Policlinico San Matteo , Pavia ,","place":["Italy"]},{"name":"Department of Molecular Medicine, Unit of Cardiology, University of Pavia , Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4129-6632","authenticated-orcid":false,"given":"Luca","family":"Sala","sequence":"additional","affiliation":[{"name":"Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS , Milan ,","place":["Italy"]},{"name":"Department of Biotechnology and Biosciences, University of Milano-Bicocca , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"2026071113023237600_cvag105-B1","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/0002-8703(75)90089-7","article-title":"The long Q-T syndrome","volume":"89","author":"Schwartz","year":"1975","journal-title":"Am Heart J"},{"key":"2026071113023237600_cvag105-B2","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1161\/01.CIR.103.1.89","article-title":"Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening 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