{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T09:13:39Z","timestamp":1792919619497,"version":"4.5.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2024,8,13]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium channel blocker, with proven efficacy in patients with sodium channel\u2013mediated long QT syndrome type 3. Our aim was to evaluate the efficacy of mexiletine in long QT syndrome type 2 (LQT2) using cardiomyocytes derived from patient-specific human induced pluripotent stem cells, a transgenic LQT2 rabbit model, and patients with LQT2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Heart rate\u2013corrected field potential duration, a surrogate for QTc, was measured in human induced pluripotent stem cells from 2 patients with LQT2 (KCNH2-p.A561V, KCNH2-p.R366X) before and after mexiletine using a multiwell multi-electrode array system. Action potential duration at 90% repolarization (APD\n                      <jats:sub>90<\/jats:sub>\n                      ) was evaluated in cardiomyocytes isolated from transgenic LQT2 rabbits (KCNH2-p.G628S) at baseline and after mexiletine application. Mexiletine was given to 96 patients with LQT2. Patients were defined as responders in the presence of a QTc shortening \u226540 ms. Antiarrhythmic efficacy of mexiletine was evaluated by a Poisson regression model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      After acute treatment with mexiletine, human induced pluripotent stem cells from both patients with LQT2 showed a significant shortening of heart rate\u2013corrected field potential duration compared with dimethyl sulfoxide control. In cardiomyocytes isolated from LQT2 rabbits, acute mexiletine significantly shortened APD\n                      <jats:sub>90<\/jats:sub>\n                      by 113 ms, indicating a strong mexiletine-mediated shortening across different LQT2 model systems. Mexiletine was given to 96 patients with LQT2 either chronically (n=60) or after the acute oral drug test (n=36): 65% of the patients taking mexiletine only chronically and 75% of the patients who performed the acute oral test were responders. There was a significant correlation between basal QTc and \u2206QTc during the test (\n                      <jats:italic toggle=\"yes\">r<\/jats:italic>\n                      = \u22120.8;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001). The oral drug test correctly predicted long-term effect in 93% of the patients. Mexiletine reduced the mean yearly event rate from 0.10 (95% CI, 0.07\u20130.14) to 0.04 (95% CI, 0.02\u20130.08), with an incidence rate ratio of 0.40 (95% CI, 0.16\u20130.84), reflecting a 60% reduction in the event rate (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.01).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Mexiletine significantly shortens cardiac repolarization in LQT2 human induced pluripotent stem cells, in the LQT2 rabbit model, and in the majority of patients with LQT2. Furthermore, mexiletine showed antiarrhythmic efficacy. Mexiletine should therefore be considered a valid therapeutic option to be added to conventional therapies in higher-risk patients with LQT2.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.124.068959","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T05:00:57Z","timestamp":1719550857000},"page":"531-543","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":42,"title":["Therapeutic Efficacy of Mexiletine for Long QT Syndrome Type 2: Evidence From Human Induced Pluripotent Stem Cell\u2013Derived Cardiomyocytes, Transgenic Rabbits, and Patients"],"prefix":"10.1161","volume":"150","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8739-6527","authenticated-orcid":true,"given":"Lia","family":"Crotti","sequence":"first","affiliation":[{"name":"Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano, IRCCS, Milan, Italy (L.C., F.D., G.M., F.G., P.C., F.L.F.G., M.T., L.S., P.J.S.)."},{"name":"Departments of Medicine and Surgery (L.C.), University of Milano-Bicocca, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2619-0036","authenticated-orcid":true,"given":"Raquel","family":"Neves","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (R.N., J.M.B., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1090-3292","authenticated-orcid":true,"given":"Federica","family":"Dagradi","sequence":"additional","affiliation":[{"name":"Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano, IRCCS, Milan, Italy (L.C., F.D., G.M., F.G., P.C., F.L.F.G., M.T., L.S., P.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5596-1349","authenticated-orcid":true,"given":"Giulia","family":"Musu","sequence":"additional","affiliation":[{"name":"Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano, IRCCS, Milan, Italy (L.C., F.D., G.M., F.G., P.C., F.L.F.G., M.T., L.S., P.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1785-5529","authenticated-orcid":true,"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, Italy (L.C., F.D., G.M., F.G., P.C., F.L.F.G., M.T., L.S., P.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3635-2003","authenticated-orcid":true,"given":"J. 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