{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T03:15:48Z","timestamp":1787800548497,"version":"build-2784847793"},"reference-count":43,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T00:00:00Z","timestamp":1738195200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T00:00:00Z","timestamp":1738195200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL155378"],"award-info":[{"award-number":["R01HL155378"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS121234"],"award-info":[{"award-number":["R01NS121234"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>In 2021, the US Food and Drug Administration issued a safety warning concerning lamotrigine use in patients with underlying cardiac disorders. This warning was based on in\u00a0vitro data that predicted class Ib antiarrhythmic activity for lamotrigine. Therefore, we investigated the proarrhythmic potential of lamotrigine in the murine heart and compared its effect with flecainide.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Murine hearts were perfused with clinically relevant concentrations of lamotrigine 3.8\u2009\u03bcg\/mL (15\u2009\u03bcmol\u00b7L\n                      <jats:sup>\u22121<\/jats:sup>\n                      ) or flecainide .4\u2009\u03bcg\/mL (1\u2009\u03bcmol\u00b7L\n                      <jats:sup>\u22121<\/jats:sup>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Ex vivo electrocardiography revealed a high prevalence of ventricular tachycardia (VT) in lamotrigine\u2010perfused hearts (7\/9 hearts), whereas only two hearts exposed to flecainide evidenced VT. Optical voltage mapping showed that lamotrigine preferentially decreased ventricular conduction velocity (CV) in the longitudinal direction at all pacing frequencies tested (\u221222%\u2009\u00b1\u20098.6%, \u221230%\u2009\u00b1\u200915.4%, and \u221233%\u2009\u00b1\u200913.3% for pacing frequency of 200\u2010ms, 180\u2010ms, and 150\u2010ms\u2009cycle length, respectively,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009\u2264 .05) compared to the transverse direction, which only slowed CV at the fastest pacing frequency (\u221215%\u2009\u00b1\u200916% for pacing frequency of 150\u2010ms\u2009cycle length,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009\u2264 .01). Notably, the preferential CV slowing in the longitudinal direction altered the anisotropic ratio, giving rise to a functional substrate for reentrant VT. In contrast, flecainide slowed CV uniformly in both longitudinal and transverse directions (\u221230%\u2009\u00b1\u20098.5% vs. \u221227%\u2009\u00b1\u20095.3%, \u221232%\u2009\u00b1\u20099.4% vs. \u221229%\u2009\u00b1\u20096.9%, and\u2009\u2212\u200929%\u2009\u00b1\u20098.3% vs. \u221227%\u2009\u00b1\u200910% for pacing frequency of 200\u2010ms, 180\u2010ms, and 150\u2010ms\u2009cycle length, respectively,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009\u2264 .05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Our findings provide mechanistic insight into the proarrhythmic impact of lamotrigine.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.18295","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T08:30:36Z","timestamp":1738225836000},"page":"1691-1702","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Lamotrigine promotes reentrant ventricular tachycardia in murine hearts"],"prefix":"10.1111","volume":"66","author":[{"given":"Patr\u00edcia","family":"Dias","sequence":"first","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine Ohio State University Wexner Medical Center  Columbus Ohio USA"},{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Meng","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine Ohio State University Wexner Medical Center  Columbus Ohio USA"},{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoja","family":"Selimi","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine Ohio State University Wexner Medical Center  Columbus Ohio USA"},{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1758-0780","authenticated-orcid":false,"given":"Heather","family":"Struckman","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine Ohio State University Wexner Medical Center  Columbus Ohio USA"},{"name":"Department of Biomedical Engineering, College of Engineering Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rengasayee","family":"Veeraraghavan","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine Ohio State University Wexner Medical Center  Columbus Ohio USA"},{"name":"Department of Biomedical Engineering, College of Engineering Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0750-2308","authenticated-orcid":false,"given":"Przemys\u0142aw B.","family":"Radwa\u0144ski","sequence":"additional","affiliation":[{"name":"Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine Ohio State University Wexner Medical Center  Columbus Ohio USA"},{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,30]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000200189"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.84.3.1364"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(97)82543-0"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12012-014-9300-0"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajem.2018.04.008"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0196-0644(97)70093-3"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacep.2023.05.042"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2010.03.044"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr180"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000138424.33979.0C"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1211\/0022357055128"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs299"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201711909"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI152071"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacep.2024.01.003"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1431927619015289"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.37610"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2016.04.004"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.261705699"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.301055"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-014-1675-z"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/5.suppl_B.19"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2012.10.005"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.56.5.696"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13311"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2015.03.026"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s003950170068"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.62.4.811"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.102.21.2650"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.48.1.39"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.15420\/aer.2020.04"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.114.002693"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph15101208"},{"issue":"5","key":"e_1_2_10_35_1","first-page":"v3","article-title":"Microscopic variations in interstitial and intracellular structure modulate the distribution of conduction delays and block in cardiac tissue with source\u2010load mismatch","volume":"5","author":"Hubbard ML","year":"2012","journal-title":"Eur Eur Pacing Arrhythm Card Electrophysiol J Work Groups Card Pacing Arrhythm Card Cell Electrophysiol Eur Soc Cardiol"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12554"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000200164"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17339"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12693"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2023.109496"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17696"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.116.004662"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1101\/2024.09.10.24313446"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.118745"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.18295","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/epi.18295","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.18295","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T14:34:34Z","timestamp":1773930874000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.18295"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,30]]},"references-count":43,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1111\/epi.18295"],"URL":"https:\/\/doi.org\/10.1111\/epi.18295","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,30]]},"assertion":[{"value":"2024-09-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}