{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T21:09:39Z","timestamp":1789160979594,"version":"build-2803163510"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"7","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R00 HG010904"],"award-info":[{"award-number":["R00 HG010904"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35 GM150465"],"award-info":[{"award-number":["R35 GM150465"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005859","name":"Heart Rhythm Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005859","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["23CDA1048873"],"award-info":[{"award-number":["23CDA1048873"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>While variants in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small IKs in cardiomyocytes from human-induced pluripotent stem cells (iPSC-CMs) or human ventricular myocytes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>We studied population control iPSC-CMs and iPSC-CMs from a patient with Jervell and Lange-Nielsen (JLN) syndrome due to compound heterozygous loss-of-function (LOF) KCNQ1 variants. We compared the effects of pharmacologic IKs block to those of genetic KCNQ1 ablation, using JLN cells, cells homozygous for the KCNQ1 LOF allele G643S, or siRNAs reducing KCNQ1 expression. We also studied the effects of two blockers of IKr, the other major cardiac repolarizing current, in the setting of pharmacologic or genetic ablation of KCNQ1: moxifloxacin, associated with a very low risk of drug-induced long QT, and dofetilide, a high-risk drug. In control cells, a small IKs was readily recorded but the pharmacologic IKs block produced no change in action potential duration at 90% repolarization (APD90). In contrast, in cells with genetic ablation of KCNQ1 (JLN), baseline APD90 was markedly prolonged compared with control cells (469 \u00b1 20 vs. 310 \u00b1 16\u2005ms). JLN cells displayed increased sensitivity to acute IKr block: the concentration (\u03bcM) of moxifloxacin required to prolong APD90 100 msec was 237.4 [median, interquartile range (IQR) 100.6\u2013391.6, n = 7] in population cells vs. 23.7 (17.3\u201328.7, n = 11) in JLN cells. In control cells, chronic moxifloxacin exposure (300\u2005\u03bcM) mildly prolonged APD90 (10%) and increased IKs, while chronic exposure to dofetilide (5\u2005nM) produced greater prolongation (67%) and no increase in IKs. However, in the siRNA-treated cells, moxifloxacin did not increase IKs and markedly prolonged APD90.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our data strongly suggest that KCNQ1 expression modulates baseline cardiac repolarization, and the response to IKr block, through mechanisms beyond simply generating IKs.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvae042","type":"journal-article","created":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T06:45:37Z","timestamp":1709621137000},"page":"735-744","source":"Crossref","is-referenced-by-count":10,"title":["The electrophysiologic effects of <i>KCNQ1<\/i> extend beyond expression of <i>I<\/i>Ks: evidence from genetic and pharmacologic block"],"prefix":"10.1093","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8533-8040","authenticated-orcid":false,"given":"Yuko","family":"Wada","sequence":"first","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn D","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura L","family":"Short","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph F","family":"Solus","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M","family":"Glazer","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6302-0389","authenticated-orcid":false,"given":"Dan M","family":"Roden","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232 , USA"},{"name":"Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center , 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,3,5]]},"reference":[{"key":"2024052916231387200_cvae042-B1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0008-6363(01)00349-2","article-title":"Divergent expression of delayed rectifier K+ channel subunits during mouse heart development","volume":"52","author":"Franco","year":"2001","journal-title":"Cardiovasc 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