{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:30:54Z","timestamp":1787729454306,"version":"build-2784847793"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2013,6]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Timothy syndrome (TS) is a rare long-QT syndrome caused by\n              <jats:italic>CACNA1C<\/jats:italic>\n              mutations G406R in exon 8A (TS1) and G402S\/G406R in exon 8 (TS2). Management of TS is a challenge and prognosis is poor. This study aimed to explore the inheritance pattern and mechanism of an I\n              <jats:sub>Na<\/jats:sub>\n              blocker, mexiletine, to improve clinical manifestations in TS.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              A 2-year-old Chinese girl with a typical TS1 phenotype underwent candidate gene screening. Qualitative and quantitative cloning sequence and analyses for mosaicism were performed on family members. Therapeutic effects of mexiletine were evaluated using ECG and Holter monitoring. The electrophysiological effect of mexiletine was evaluated in a TS model using rabbit ventricular wedges. The proband with severe syndactyly and delayed language skills was identified harboring a G406R mutation in\n              <jats:italic>CACNA1C<\/jats:italic>\n              . Her baseline ECG showed markedly prolonged QTc, 2:1 AV block and macro-T wave alternans. G406R was absent in her mother but expressed in her father\u2019s oral mucosa, sperm, and white blood cells, indicating a mosaic carrier. Although asymptomatic, he exhibited mild QTc prolongation (470\u2013490 ms) and syndactyly. Mexiletine shortened QTc from 584 to 515 ms, blunted QT\u2013RR relationship, and abolished 2:1 AV block and T wave alternans in the girl. In in vitro studies, mexiletine inhibited late I\n              <jats:sub>Na<\/jats:sub>\n              with IC\n              <jats:sub>50<\/jats:sub>\n              of 17.6\u00b11.9 \u00b5mol\/L and attenuated brady-dependent QT prolongation and reduced QT\u2013RR slope in the TS model using BayK 8644.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              Mexiletine shortened QTc, attenuated QT\u2013RR slope, abolished 2:1 AV block and T wave alternans in a TS1 patient and TS model via inhibition of late I\n              <jats:sub>Na<\/jats:sub>\n              .\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.113.000092","type":"journal-article","created":{"date-parts":[[2013,4,12]],"date-time":"2013-04-12T04:29:35Z","timestamp":1365740975000},"page":"614-622","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":83,"title":["Inhibition of Late Sodium Current by Mexiletine"],"prefix":"10.1161","volume":"6","author":[{"given":"Yuanfeng","family":"Gao","sequence":"first","affiliation":[{"name":"Heart Center, Peking University People\u2019s Hospital, Beijing, People\u2019s Republic of China (Y.G., D.H., W.L., L.L., C.L.); First Affiliated Hospital of Medical College of Xi\u2019an Jiaotong University, Xi\u2019an, People\u2019s Republic of China (X.X., H.S., G.-X.Y.); Beijing Children\u2019s Hospital, Capital University of Medical Sciences, Beijing, People\u2019s Republic of China (Y.Y.); and Lankenau Medical Center, Lankenau Institute for Medical Research, Jefferson Medical College, Philadelphia, PA (K.W.T., L.Z., G.-X.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Xue","sequence":"additional","affiliation":[{"name":"Heart Center, Peking University People\u2019s Hospital, Beijing, People\u2019s Republic of China (Y.G., D.H., W.L., L.L., C.L.); First Affiliated Hospital of Medical College of Xi\u2019an Jiaotong University, Xi\u2019an, People\u2019s Republic of China (X.X., H.S., G.-X.Y.); Beijing Children\u2019s Hospital, Capital University of Medical Sciences, Beijing, People\u2019s Republic of China (Y.Y.); and Lankenau Medical Center, Lankenau Institute for Medical Research, Jefferson Medical College, Philadelphia, PA (K.W.T., L.Z., G.-X.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dayi","family":"Hu","sequence":"additional","affiliation":[{"name":"Heart Center, Peking University People\u2019s Hospital, Beijing, People\u2019s Republic of China (Y.G., D.H., W.L., L.L., C.L.); First Affiliated Hospital of Medical College of Xi\u2019an Jiaotong University, Xi\u2019an, People\u2019s Republic of China (X.X., H.S., G.-X.Y.); Beijing Children\u2019s Hospital, Capital University of Medical Sciences, Beijing, People\u2019s Republic of China (Y.Y.); and Lankenau Medical Center, Lankenau Institute for Medical Research, Jefferson Medical College, Philadelphia, PA (K.W.T., L.Z., G.-X.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenling","family":"Liu","sequence":"additional","affiliation":[{"name":"Heart Center, Peking University People\u2019s Hospital, Beijing, People\u2019s Republic of China (Y.G., D.H., W.L., L.L., C.L.); First Affiliated Hospital of Medical College of Xi\u2019an Jiaotong University, Xi\u2019an, People\u2019s Republic of China (X.X., H.S., G.-X.Y.); Beijing Children\u2019s Hospital, Capital University of Medical Sciences, Beijing, People\u2019s Republic of China (Y.Y.); and Lankenau Medical Center, Lankenau Institute for Medical Research, Jefferson Medical College, Philadelphia, PA (K.W.T., L.Z., G.-X.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yuan","sequence":"additional","affiliation":[{"name":"Heart Center, Peking University People\u2019s Hospital, Beijing, People\u2019s Republic of China (Y.G., D.H., W.L., L.L., C.L.); First Affiliated Hospital of Medical College of Xi\u2019an Jiaotong University, Xi\u2019an, People\u2019s Republic of China (X.X., H.S., G.-X.Y.); Beijing Children\u2019s Hospital, Capital University of Medical Sciences, Beijing, People\u2019s Republic of China (Y.Y.); and Lankenau Medical Center, Lankenau Institute for Medical Research, Jefferson Medical College, Philadelphia, PA (K.W.T., L.Z., G.-X.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Sun","sequence":"additional","affiliation":[{"name":"Heart Center, Peking University People\u2019s Hospital, Beijing, People\u2019s Republic of China (Y.G., D.H., W.L., L.L., C.L.); First Affiliated Hospital of Medical College of Xi\u2019an Jiaotong University, Xi\u2019an, People\u2019s Republic of China (X.X., H.S., G.-X.Y.); Beijing Children\u2019s Hospital, Capital University of Medical Sciences, Beijing, People\u2019s Republic of China (Y.Y.); and Lankenau Medical Center, Lankenau Institute for Medical Research, Jefferson Medical College, Philadelphia, PA (K.W.T., L.Z., G.-X.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Li","sequence":"additional","affiliation":[{"name":"Heart Center, Peking University People\u2019s Hospital, Beijing, People\u2019s Republic of China (Y.G., D.H., W.L., L.L., C.L.); First Affiliated Hospital of Medical College of Xi\u2019an Jiaotong University, Xi\u2019an, People\u2019s Republic of China (X.X., H.S., G.-X.Y.); Beijing Children\u2019s Hospital, Capital University of Medical Sciences, Beijing, People\u2019s Republic of China (Y.Y.); and Lankenau Medical Center, Lankenau Institute for Medical Research, Jefferson Medical College, Philadelphia, PA (K.W.T., L.Z., G.-X.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine W.","family":"Timothy","sequence":"additional","affiliation":[{"name":"Heart Center, Peking University People\u2019s Hospital, Beijing, People\u2019s Republic of China (Y.G., D.H., W.L., L.L., C.L.); First Affiliated Hospital of Medical College of Xi\u2019an Jiaotong University, Xi\u2019an, People\u2019s Republic of China (X.X., H.S., G.-X.Y.); Beijing Children\u2019s Hospital, Capital University of Medical Sciences, Beijing, People\u2019s Republic of China (Y.Y.); and Lankenau Medical Center, Lankenau Institute for Medical Research, Jefferson Medical College, Philadelphia, PA (K.W.T., L.Z., G.-X.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Heart Center, Peking University People\u2019s Hospital, Beijing, People\u2019s Republic of China (Y.G., D.H., W.L., L.L., C.L.); First Affiliated Hospital of Medical College of Xi\u2019an Jiaotong University, Xi\u2019an, People\u2019s Republic of China (X.X., H.S., G.-X.Y.); Beijing Children\u2019s Hospital, Capital University of Medical Sciences, Beijing, People\u2019s Republic of China (Y.Y.); and Lankenau Medical Center, Lankenau Institute for Medical Research, Jefferson Medical College, Philadelphia, PA (K.W.T., L.Z., G.-X.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuilan","family":"Li","sequence":"additional","affiliation":[{"name":"Heart Center, Peking University People\u2019s Hospital, Beijing, People\u2019s Republic of China (Y.G., D.H., W.L., L.L., C.L.); First Affiliated Hospital of Medical College of Xi\u2019an Jiaotong University, Xi\u2019an, People\u2019s Republic of China (X.X., H.S., G.-X.Y.); Beijing Children\u2019s Hospital, Capital University of Medical Sciences, Beijing, People\u2019s Republic of China (Y.Y.); and Lankenau Medical Center, Lankenau Institute for Medical Research, Jefferson Medical College, Philadelphia, PA (K.W.T., L.Z., G.-X.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gan-Xin","family":"Yan","sequence":"additional","affiliation":[{"name":"Heart Center, Peking University People\u2019s Hospital, Beijing, People\u2019s Republic of China (Y.G., D.H., W.L., L.L., C.L.); First Affiliated Hospital of Medical College of Xi\u2019an Jiaotong University, Xi\u2019an, People\u2019s Republic of China (X.X., H.S., G.-X.Y.); Beijing Children\u2019s Hospital, Capital University of Medical Sciences, Beijing, People\u2019s Republic of China (Y.Y.); and Lankenau Medical Center, Lankenau Institute for Medical Research, Jefferson Medical College, Philadelphia, PA (K.W.T., L.Z., G.-X.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.09.011"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502506102"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2008.161737"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2006.12.046"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8159.2010.02913.x"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2006.04.024"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2010.12.026"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2006.04.021"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2008.09.008"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2007.09.025"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.4065\/78.12.1479"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09855"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.34223"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00392-011-0358-4"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.34355"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg906"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/circep.109.921056"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2010.11.017"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2012.07.046"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.05.012"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.52.5.886"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1982.225"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1053\/euhj.2001.3079"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e31826e73b1"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.01181.x"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1540-8167.2001.00428.x"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01032.2007"}],"container-title":["Circulation: Arrhythmia and Electrophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCEP.113.000092","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T00:17:46Z","timestamp":1715559466000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCEP.113.000092"}},"subtitle":["A Novel Pharmotherapeutical Approach in Timothy Syndrome"],"short-title":[],"issued":{"date-parts":[[2013,6]]},"references-count":27,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2013,6]]}},"alternative-id":["10.1161\/CIRCEP.113.000092"],"URL":"https:\/\/doi.org\/10.1161\/circep.113.000092","relation":{},"ISSN":["1941-3149","1941-3084"],"issn-type":[{"value":"1941-3149","type":"print"},{"value":"1941-3084","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,6]]},"assertion":[{"value":"2012-10-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-03-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-04-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}