{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:22:40Z","timestamp":1792023760678,"version":"4.4.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function mutations in KCNQ1, is triggered by early afterdepolarizations (EADs) that initiate polymorphic ventricular tachycardia (pVT). We investigated ionic mechanisms that underlie pVT in LQT1 using a transgenic rabbit model of LQT1.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Optical mapping, cellular patch clamping, and computer modeling were used to elucidate the mechanisms of EADs in transgenic LQT1 rabbits.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              The results showed that shorter action potential duration in the right ventricle (RV) was associated with focal activity during pVT initiation. RV cardiomyocytes demonstrated higher incidence of EADs under 50 nmol\/L isoproterenol. Voltage-clamp studies revealed that the transient outward potassium current (I\n              <jats:sub>to<\/jats:sub>\n              ) magnitude was 28% greater in RV associated with KChiP2 but with no differences in terms of calcium-cycling kinetics and other sarcolemmal currents. Perfusing with the I\n              <jats:sub>to<\/jats:sub>\n              blocker 4-aminopyridine changed the initial focal sites of pVT from the RV to the left ventricle, corroborating the role of I\n              <jats:sub>to<\/jats:sub>\n              in pVT initiation. Computer modeling showed that EADs occur preferentially in the RV because of the larger conductance of the slow-inactivating component of I\n              <jats:sub>to<\/jats:sub>\n              , which repolarizes the membrane potential sufficiently rapidly to allow reactivation of I\n              <jats:sub>Ca,L<\/jats:sub>\n              before I\n              <jats:sub>Kr<\/jats:sub>\n              has had sufficient time to activate.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              I\n              <jats:sub>to<\/jats:sub>\n              heterogeneity creates both triggers and an arrhythmogenic substrate in LQT1. In the absence of I\n              <jats:sub>Ks<\/jats:sub>\n              , I\n              <jats:sub>to<\/jats:sub>\n              interactions with I\n              <jats:sub>Ca,L<\/jats:sub>\n              and I\n              <jats:sub>Kr<\/jats:sub>\n              promote EADs in the RV while prolonging action potential duration in the left ventricle. This heterogeneity of action potential enhances dispersion of refractoriness and facilitates conduction blocks that initiate pVTs.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.117.005414","type":"journal-article","created":{"date-parts":[[2018,5,16]],"date-time":"2018-05-16T09:15:08Z","timestamp":1526462108000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["Transient Outward K\n            <sup>+<\/sup>\n            Current (I\n            <sub>to<\/sub>\n            ) Underlies the Right Ventricular Initiation of Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long-QT Syndrome Type 1"],"prefix":"10.1161","volume":"11","author":[{"given":"Bum-Rak","family":"Choi","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence (B.-R.C., W.L., D.T., A.Y.K., R.T., T.Y.K., G.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyan","family":"Li","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence (B.-R.C., W.L., D.T., A.Y.K., R.T., T.Y.K., G.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Terentyev","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence (B.-R.C., W.L., D.T., A.Y.K., R.T., T.Y.K., G.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anatoli Y.","family":"Kabakov","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence (B.-R.C., W.L., D.T., A.Y.K., R.T., T.Y.K., G.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingwang","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Physics, Northeastern University, Boston MA (M.Z., C.M.R., A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin M.","family":"Rees","sequence":"additional","affiliation":[{"name":"Department of Physics, Northeastern University, Boston MA (M.Z., C.M.R., A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radmila","family":"Terentyeva","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence (B.-R.C., W.L., D.T., A.Y.K., R.T., T.Y.K., G.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Yun","family":"Kim","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence (B.-R.C., W.L., D.T., A.Y.K., R.T., T.Y.K., G.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhilin","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Medicine (Cardiology), University of California, Los Angeles (Z.Q.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuwen","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Karma","sequence":"additional","affiliation":[{"name":"Department of Physics, Northeastern University, Boston MA (M.Z., C.M.R., A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gideon","family":"Koren","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence (B.-R.C., W.L., D.T., A.Y.K., R.T., T.Y.K., G.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0196-17"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.102.10.1178"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(99)00458-0"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-0736(99)90077-8"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000068344.54010.B3"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000048142.85076.A2"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.2000.tb00342.x"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01331.x"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI33578"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2014.10.003"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2011.218164"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.086223"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.113.4.581"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.305146"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.106.98160"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/hh1301.093633"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2015.11.003"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.77.1.140"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.665406"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt104"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.64.5.977"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.02.009"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs183"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.114.002451"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2001.281.3.H1201"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1053\/pcad.2000.0420345"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1996.271.2.H548"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.2.206"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.93.1.168"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.87.1.73"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2002.033704"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.058172"},{"key":"e_1_3_3_34_2","first-page":"PO3","volume-title":"Heart Rhythm","author":"Gravelin L","year":"2012","unstructured":"Gravelin L, Ziv O, Liu G, Hartmann K, Patel D, Schofield L, Chaves L, Shearer M, Koren G, Choi BR. Transgenic LQT1 animal model reveals shifiting focus of EADs as mechanism for polymorphic ventricular tachycardia. Heart Rhythm. Poster presented at the 33rd Annual Scientific Sessions of the Heart Rhythm Society; Denver, Colorado, May 9\u201312, 2012, 2012:PO3\u2013104."},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2012.07.053"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2011.09.066"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/s003950170002"},{"key":"e_1_3_3_38_2","first-page":"137","article-title":"Two components of delayed rectifier K+ current in heart: molecular basis, functional diversity, and contribution to repolarization.","volume":"25","author":"Cheng JH","year":"2004","unstructured":"Cheng JH, Kodama I. Two components of delayed rectifier K+ current in heart: molecular basis, functional diversity, and contribution to repolarization. Acta Pharmacol Sin. 2004;25:137\u2013145.","journal-title":"Acta Pharmacol Sin"}],"container-title":["Circulation: Arrhythmia and Electrophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCEP.117.005414","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T00:05:06Z","timestamp":1715558706000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCEP.117.005414"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6]]},"references-count":37,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2018,6]]}},"alternative-id":["10.1161\/CIRCEP.117.005414"],"URL":"https:\/\/doi.org\/10.1161\/circep.117.005414","relation":{},"ISSN":["1941-3149","1941-3084"],"issn-type":[{"value":"1941-3149","type":"print"},{"value":"1941-3084","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6]]},"assertion":[{"value":"2017-05-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-03-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-07-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e005414"}}