{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T04:04:35Z","timestamp":1792123475722,"version":"4.4.0"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2016,10]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              The basic defect in long-QT syndrome type III (LQT3) is an excessive inflow of sodium current during phase 3 of the action potential caused by mutations in the\n              <jats:italic>SCN5A<\/jats:italic>\n              gene. Most sodium channel blockers reduce the early (peak) and late components of the sodium current (\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>Na<\/jats:sub>\n              and\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>NaL<\/jats:sub>\n              ), but ranolazine preferentially reduces\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>NaL<\/jats:sub>\n              . We, therefore, evaluated the effects of ranolazine in LQT3 caused by the\n              <jats:italic>D1790G<\/jats:italic>\n              mutation in\n              <jats:italic>SCN5A<\/jats:italic>\n              .\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              We performed an experimental study of ranolazine in TSA201 cells expressing the\n              <jats:italic>D1790G<\/jats:italic>\n              mutation. We then performed a long-term clinical evaluation of ranolazine in LQT3 patients carrying the\n              <jats:italic>D1790G<\/jats:italic>\n              mutation. In the experimental study,\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>NaL<\/jats:sub>\n              was significantly higher in\n              <jats:italic>D1790G<\/jats:italic>\n              than in wild-type channels expressed in the TSA201 cells. Ranolazine exerted a concentration-dependent block of\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>NaL<\/jats:sub>\n              of the\n              <jats:italic>SCN5A-D1790G<\/jats:italic>\n              channel without reducing peak\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>Na<\/jats:sub>\n              significantly. In the clinical study, among 8 patients with LQT3 and confirmed\n              <jats:italic>D1790G<\/jats:italic>\n              mutation, ranolazine had no effects on the sinus rate or QRS width but shortened the QTc from 509\u00b141 to 451\u00b126 ms, a mean decrease of 56\u00b152 ms (10.6%;\n              <jats:italic>P<\/jats:italic>\n              =0.012). The QT-shortening effect of ranolazine remained effective throughout the entire study period of 22.8\u00b112.8 months. Ranolazine reduced the QTc at all heart rates but less so during extreme nocturnal bradycardia. A type I Brugada ECG was never noticed.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              Ranolazine blocks\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>NaL<\/jats:sub>\n              in experimental models of LQT3 harboring the\n              <jats:italic>SCN5A-D1790G<\/jats:italic>\n              mutation and shortened the QT interval of LQT3 patients.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Clinical Trial Registration\u2014<\/jats:title>\n            <jats:p>\n              URL:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\">https:\/\/clinicaltrials.gov<\/jats:ext-link>\n              ; Unique identifier: NCT01728025.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.116.004370","type":"journal-article","created":{"date-parts":[[2016,10,13]],"date-time":"2016-10-13T02:59:51Z","timestamp":1476327591000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":69,"title":["Ranolazine for Congenital Long-QT Syndrome Type III"],"prefix":"10.1161","volume":"9","author":[{"given":"Ehud","family":"Chorin","sequence":"first","affiliation":[{"name":"From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Hu","sequence":"additional","affiliation":[{"name":"From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Antzelevitch","sequence":"additional","affiliation":[{"name":"From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aviram","family":"Hochstadt","sequence":"additional","affiliation":[{"name":"From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz","family":"Belardinelli","sequence":"additional","affiliation":[{"name":"From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Zeltser","sequence":"additional","affiliation":[{"name":"From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hector","family":"Barajas-Martinez","sequence":"additional","affiliation":[{"name":"From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uri","family":"Rozovski","sequence":"additional","affiliation":[{"name":"From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Rosso","sequence":"additional","affiliation":[{"name":"From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnon","family":"Adler","sequence":"additional","affiliation":[{"name":"From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesaia","family":"Benhorin","sequence":"additional","affiliation":[{"name":"From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami","family":"Viskin","sequence":"additional","affiliation":[{"name":"From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90359-3"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2008.02.068"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.1.89"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.98.21.2314"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq029"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2008.10.017"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.950147"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.79.1.103"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.78.6.1009"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.92.12.3381"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.12.033"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.101.14.1698"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1542-474X.2005.00077.x"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(1998)12:1<72::AID-HUMU19>3.0.CO;2-T"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8159.2009.02190.x"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1159\/000437089"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000139333.83620.5D"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2011.03.045"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2011.06.007"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1177\/107424840400900106"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.104.066100"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2009.01.003"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.704890"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncpcardio1153"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.2008.01246.x"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.04.003"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.108.829192"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2013.12.084"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.12.015"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2015.06.040"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2012.01.026"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2011.10.032"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.062182"},{"key":"e_1_3_3_35_2","first-page":"353","article-title":"An analysis of the time-relations of electrocardiograms.","volume":"7","author":"Bazett HC","year":"1920","unstructured":"Bazett HC. 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