{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:23:13Z","timestamp":1790734993727,"version":"4.1.0"},"reference-count":69,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T00:00:00Z","timestamp":1682467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"European Joint Research Program on Rare Diseases","award":["31ER30_194836"],"award-info":[{"award-number":["31ER30_194836"]}]},{"name":"Biomedical Research","award":["2019-1691"],"award-info":[{"award-number":["2019-1691"]}]},{"name":"Leducq Foundation for Cardiovascular Research","award":["18CVD05"],"award-info":[{"award-number":["18CVD05"]}]},{"name":"European Research Council","award":["ERC-2017-COG-773181-iPS-ChOp-AF"],"award-info":[{"award-number":["ERC-2017-COG-773181-iPS-ChOp-AF"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum\/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum\/glucocorticoid-regulated kinase 1 inhibition effects (300\u2005nM\u201310\u2005\u00b5M) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3\u2005\u00b5M) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V\/p.A614V\/p.G628S\/IVS9-28A\/G), SGK1-Inh dose-dependently shortened FPD\/APD at 0.3\u201310\u2005\u00b5M (by 20\u201332%\/25\u201330%\/44\u201345%). Importantly, in LQT2 rabbit CMs, 3\u2005\u00b5M SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1\/3\/10\u2005\u00b5M (by 19\/26\/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10\u2005\u00b5M (by 29%). No SGK1-Inh-induced FPD\/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3\u20133\u2005\u00b5M.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/europace\/euad094","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T17:57:11Z","timestamp":1682531831000},"source":"Crossref","is-referenced-by-count":17,"title":["Gene- and variant-specific efficacy of serum\/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2"],"prefix":"10.1093","volume":"25","author":[{"given":"Federica","family":"Giannetti","sequence":"first","affiliation":[{"name":"Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics , Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Barbieri","sequence":"additional","affiliation":[{"name":"Translational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern , B\u00fchlplatz 5, 3012 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Assad","family":"Shiti","sequence":"additional","affiliation":[{"name":"Rappaport Faculty of Medicine and Research Institute, Technion\u2013Israel Institute of Technology , Haifa , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Casini","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Location AMC Department of Clinical and Experimental Cardiology, Heart Centre , Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip T","family":"Sager","sequence":"additional","affiliation":[{"name":"Thryv Therapeutics Inc. , Montreal , Canada"},{"name":"Cardiovascular Research Institute, Stanford University , Palo Alto, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saumya","family":"Das","sequence":"additional","affiliation":[{"name":"Thryv Therapeutics Inc. , Montreal , Canada"},{"name":"Massachusetts General Hospital, Harvard Medical School , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabindra","family":"Pradhananga","sequence":"additional","affiliation":[{"name":"Thryv Therapeutics Inc. , Montreal , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Thryv Therapeutics Inc. , Montreal , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saranda","family":"Nimani","sequence":"additional","affiliation":[{"name":"Translational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern , B\u00fchlplatz 5, 3012 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicol\u00f2","family":"Alerni","sequence":"additional","affiliation":[{"name":"Translational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern , B\u00fchlplatz 5, 3012 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Louradour","sequence":"additional","affiliation":[{"name":"Translational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern , B\u00fchlplatz 5, 3012 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Mura","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic and Vascular Sciences\u2013Translational Cardiology Center, Fondazione IRCCS Policlinico San Matteo , Pavia , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Gnecchi","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic and Vascular Sciences\u2013Translational Cardiology Center, Fondazione IRCCS Policlinico San Matteo , Pavia , Italy"},{"name":"Department of Molecular Medicine, Unit of Cardiology, University of Pavia , Pavia , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Brink","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Stellenbosch , Tygerberg , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Zehender","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology I, University Heart Center Freiburg, University Medical Center Freiburg , Freiburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gideon","family":"Koren","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Brown University , Providence, RI , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Zaza","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences, University of Milano-Bicocca , Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lia","family":"Crotti","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics , Milan , Italy"},{"name":"Department of Medicine and Surgery, University of Milano-Bicocca , Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur A M","family":"Wilde","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Location AMC Department of Clinical and Experimental Cardiology, Heart Centre , Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics , Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol Ann","family":"Remme","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Location AMC Department of Clinical and Experimental Cardiology, Heart Centre , Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lior","family":"Gepstein","sequence":"additional","affiliation":[{"name":"Rappaport Faculty of Medicine and Research Institute, Technion\u2013Israel Institute of Technology , Haifa , Israel"},{"name":"Cardiology Department, Rambam Health Care Campus , Haifa , 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