{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:21:37Z","timestamp":1792524097622,"version":"4.5.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"20","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,10,15]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Long\u2010QT syndrome is a primary cardiac ion channelopathy predisposing a patient to ventricular arrhythmia through delayed repolarization on the resting ECG. We aimed to establish a patient\u2010specific, human induced pluripotent stem cell (hiPSC)\u2010derived cardiomyocytes model of long\u2010QT syndrome type 3 (LQT3) using clustered regularly interspaced palindromic repeats (CRISPR\/Cas9), for disease modeling and drug challenge.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              HiPSCs\u00a0were generated from a patient with LQT3 harboring an\n              <jats:italic>SCN5A<\/jats:italic>\n              pathogenic variant (c.1231G&gt;A; p.Val411Met), and an unrelated healthy control. The same\n              <jats:italic>SCN5A<\/jats:italic>\n              pathogenic variant was engineered into the background healthy control hiPSCs via CRISPR\/Cas9\u00a0gene editing to generate a second disease model of LQT3 for comparison with an isogenic control. All 3 hiPSC lines were differentiated into cardiomyocytes. Both the patient\u2010derived LQT3 (\n              <jats:italic>SCN5A<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              ) and genetically engineered LQT3 (\n              <jats:italic>SCN5A<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              ) hiPSC\u2010derived cardiomyocytes\u00a0showed significantly prolonged cardiomyocyte repolarization compared with the healthy control. Mexiletine, a cardiac voltage\u2010gated sodium channel (Na\n              <jats:sub>V<\/jats:sub>\n              1.5) blocker, shortened repolarization in both patient\u2010derived LQT3 and genetically\u00a0engineered LQT3 hiPSC\u2010derived cardiomyocytes, but had no effect in the control. Notably, calcium channel blockers nifedipine and verapamil showed a dose\u2010dependent shortening of repolarization, rescuing the phenotype. Additionally, therapeutic drugs known to prolong the corrected QT in humans (ondansetron, clarithromycin, and sotalol) demonstrated this effect in\u00a0vitro, but the LQT3 clones were not more disproportionately affected compared with the control.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">We demonstrated that patient\u2010derived and genetically engineered LQT3 hiPSC\u2010derived cardiomyocytes\u00a0faithfully recapitulate pathologic characteristics of LQT3. The clinical significance of such an in\u00a0vitro model is in the exploration of novel therapeutic strategies, stratifying drug adverse reaction risk and potentially facilitating a more targeted, patient\u2010specific approach in high\u2010risk patients with LQT3.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.124.034690","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T16:09:31Z","timestamp":1728403771000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Defining Cardiomyocyte Repolarization Response to Pharmacotherapy in Long\u2010QT Syndrome Type 3"],"prefix":"10.1161","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8407-2439","authenticated-orcid":false,"given":"Ning","family":"Ge","sequence":"first","affiliation":[{"name":"Regenerative Medicine Institute, School of Medicine University of Galway Galway Ireland"},{"name":"Department of Pharmacology 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