{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T03:19:43Z","timestamp":1776914383388,"version":"3.51.2"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2020,8]]},"abstract":"\n Background:<\/jats:title>\n \n Long QT syndrome has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs). Suppressing the late sodium current (I\n NaL<\/jats:sub>\n ) may counterbalance the reduced repolarization reserve in long QT syndrome and prevent EADs and PVTs.\n <\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n We tested the effects of the selective I\n NaL<\/jats:sub>\n blocker GS967 on PVT induction in a transgenic rabbit model of long QT syndrome type 2 using intact heart optical mapping, cellular electrophysiology and confocal Ca\n 2+<\/jats:sup>\n imaging, and computer modeling.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n GS967 reduced ventricular fibrillation induction under a rapid pacing protocol (n=7\/14 hearts in control versus 1\/14 hearts at 100 nmol\/L) without altering action potential duration or restitution and dispersion. GS967 suppressed PVT incidences by reducing Ca\n 2+<\/jats:sup>\n -mediated EADs and focal activity during isoproterenol perfusion (at 30 nmol\/L, n=7\/12 and 100 nmol\/L n=8\/12 hearts without EADs and PVTs). Confocal Ca\n 2+<\/jats:sup>\n imaging of long QT syndrome type 2 myocytes revealed that GS967 shortened Ca\n 2+<\/jats:sup>\n transient duration via accelerating Na\n +<\/jats:sup>\n \/Ca\n 2+<\/jats:sup>\n exchanger (I\n NCX<\/jats:sub>\n )-mediated Ca\n 2+<\/jats:sup>\n efflux from cytosol, thereby reducing EADs. Computer modeling revealed that I\n NaL<\/jats:sub>\n potentiates EADs in the long QT syndrome type 2 setting through (1) providing additional depolarizing currents during action potential plateau phase, (2) increasing intracellular Na\n +<\/jats:sup>\n (Na\n i<\/jats:sub>\n ) that decreases the depolarizing I\n NCX<\/jats:sub>\n thereby suppressing the action potential plateau and delaying the activation of slowly activating delayed rectifier K\n +<\/jats:sup>\n channels (I\n Ks<\/jats:sub>\n ), suggesting important roles of I\n NaL<\/jats:sub>\n in regulating Na\n i<\/jats:sub>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n \n Selective I\n NaL<\/jats:sub>\n blockade by GS967 prevents EADs and abolishes PVT in long QT syndrome type 2 rabbits by counterbalancing the reduced repolarization reserve and normalizing Na\n i<\/jats:sub>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Graphic Abstract:<\/jats:title>\n \n A\n graphic abstract<\/jats:ext-link>\n is available for this article.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circep.118.006875","type":"journal-article","created":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T16:55:17Z","timestamp":1594054517000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Late I\n Na<\/sub>\n Blocker GS967 Supresses Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long QT Type 2"],"prefix":"10.1161","volume":"13","author":[{"given":"Jungmin","family":"Hwang","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (J.H., T.Y.K., D.T., A.Y.K., P.B., K.A., Y.K., Z.P., Y.L., G.K., B.-R.C.)."},{"name":"Department of Experiential Education, College of Pharmacy, University of Rhode Island, Kingstown (J.H.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0605-9575","authenticated-orcid":true,"given":"Tae Yun","family":"Kim","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (J.H., T.Y.K., D.T., A.Y.K., P.B., K.A., Y.K., Z.P., Y.L., G.K., B.-R.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9530-7384","authenticated-orcid":true,"given":"Dmitry","family":"Terentyev","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (J.H., T.Y.K., D.T., A.Y.K., P.B., K.A., Y.K., Z.P., Y.L., G.K., B.-R.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingwang","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Physics, Northeastern University, Boston, MA (M.Z., A.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anatoli Y.","family":"Kabakov","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (J.H., T.Y.K., D.T., A.Y.K., P.B., K.A., Y.K., Z.P., Y.L., G.K., B.-R.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Bronk","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (J.H., T.Y.K., D.T., A.Y.K., P.B., K.A., Y.K., Z.P., Y.L., G.K., B.-R.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karuppiah","family":"Arunachalam","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (J.H., T.Y.K., D.T., A.Y.K., P.B., K.A., Y.K., Z.P., Y.L., G.K., B.-R.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luiz","family":"Belardinelli","sequence":"additional","affiliation":[{"name":"Department of Biology, Gilead Science, Foster City, CA (L.B., S.R.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sridharan","family":"Rajamani","sequence":"additional","affiliation":[{"name":"Department of Biology, Gilead Science, Foster City, CA (L.B., S.R.)."},{"name":"Amgen Inc, South San Francisco, CA (S.R.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukiko","family":"Kunitomo","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (J.H., T.Y.K., D.T., A.Y.K., P.B., K.A., Y.K., Z.P., Y.L., G.K., B.-R.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zachary","family":"Pfeiffer","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (J.H., T.Y.K., D.T., A.Y.K., P.B., K.A., Y.K., Z.P., Y.L., G.K., B.-R.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yichun","family":"Lu","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Alpert 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