{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T22:43:26Z","timestamp":1794005006966,"version":"4.8.0"},"reference-count":50,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2019,9,4]],"date-time":"2019-09-04T00:00:00Z","timestamp":1567555200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["RE\/08\/004\/23915"],"award-info":[{"award-number":["RE\/08\/004\/23915"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["RE\/13\/1\/30181"],"award-info":[{"award-number":["RE\/13\/1\/30181"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["EP\/K503769\/1"],"award-info":[{"award-number":["EP\/K503769\/1"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000849","name":"National Centre for the Replacement, Refinement and Reduction of Animals in Research","doi-asserted-by":"publisher","award":["116030"],"award-info":[{"award-number":["116030"]}],"id":[{"id":"10.13039\/501100000849","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["675451"],"award-info":[{"award-number":["675451"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010757","name":"National Centre for the Replacement Refinement and Reduction of Animals in Research","doi-asserted-by":"publisher","award":["NC\/P001076\/1"],"award-info":[{"award-number":["NC\/P001076\/1"]}],"id":[{"id":"10.13039\/501100010757","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005617","name":"BHF Centre of Research Excellence, Oxford","doi-asserted-by":"publisher","award":["214290\/Z\/18\/Z"],"award-info":[{"award-number":["214290\/Z\/18\/Z"]}],"id":[{"id":"10.13039\/501100005617","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005617","name":"BHF Centre of Research Excellence, Oxford","doi-asserted-by":"publisher","award":["100246\/Z\/12\/Z"],"award-info":[{"award-number":["100246\/Z\/12\/Z"]}],"id":[{"id":"10.13039\/501100005617","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Early identification of drug\u2010induced cardiac adverse events is key in drug development. Human\u2010based computer models are emerging as an effective approach, complementary to in vitro and animal models. Drug\u2010induced shortening of the electromechanical window has been associated with increased risk of arrhythmias. This study investigates the potential of a cellular surrogate for the electromechanical window (EMw) for prediction of pro\u2010arrhythmic cardiotoxicity, and its underlying ionic mechanisms, using human\u2010based computer models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>In silico drug trials for 40 reference compounds were performed, testing up to 100\u2010fold the therapeutic concentrations (EFTPC<jats:sub>max<\/jats:sub>) and using a control population of human ventricular action potential (AP) models, optimised to capture pro\u2010arrhythmic ionic profiles. EMw was calculated for each model in the population as the difference between AP and Ca<jats:sup>2+<\/jats:sup> transient durations at 90%. Drug\u2010induced changes in the EMw and occurrence of repolarisation abnormalities (RA) were quantified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Drugs with clinical risk of Torsade de Pointes arrhythmias induced a concentration\u2010dependent EMw shortening, while safe drugs lead to increase or small change in EMw. Risk predictions based on EMw shortening achieved 90% accuracy at 10\u00d7 EFTPC<jats:sub>max<\/jats:sub>, whereas RA\u2010based predictions required 100\u00d7 EFTPC<jats:sub>max<\/jats:sub> to reach the same accuracy. As it is dependent on Ca<jats:sup>2+<\/jats:sup> transient, the EMw was also more sensitive than AP prolongation in distinguishing between pure hERG blockers and multichannel compounds also blocking the calcium current.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>The EMw is an effective biomarker for in silico predictions of drug\u2010induced clinical pro\u2010arrhythmic risk, particularly for compounds with multichannel blocking action.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14786","type":"journal-article","created":{"date-parts":[[2019,7,4]],"date-time":"2019-07-04T17:46:32Z","timestamp":1562262392000},"page":"3819-3833","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Drug\u2010induced shortening of the electromechanical window is an effective biomarker for in silico prediction of clinical risk of arrhythmias"],"prefix":"10.1111","volume":"176","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0116-6347","authenticated-orcid":false,"given":"Elisa","family":"Passini","sequence":"first","affiliation":[{"name":"Department of Computer Science University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian","family":"Trovato","sequence":"additional","affiliation":[{"name":"Department of Computer Science University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Morissette","sequence":"additional","affiliation":[{"name":"SALAR, Safety and Exploratory Pharmacology Department, Merck Research Laboratories Merck &amp; Co., Inc.  West Point PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick","family":"Sannajust","sequence":"additional","affiliation":[{"name":"SALAR, Safety and Exploratory Pharmacology Department, Merck Research Laboratories Merck &amp; Co., Inc.  West Point PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Bueno\u2010Orovio","sequence":"additional","affiliation":[{"name":"Department of Computer Science University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Computer Science University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13883"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13884"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/15376516.2016.1256460"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2012.09.007"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.113.000322"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2008.09.013"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00597"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1304382110"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00278"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706070"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00917"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.134932"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2016.03.009"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.254367"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00616"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.160"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01795.x"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2012.03.007"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1121"},{"key":"e_1_2_11_21_1","unstructured":"ICH(2005a).Harmonised Tripartite Guideline E14. Clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non\u2010antiarrhythmic drugs."},{"key":"e_1_2_11_22_1","unstructured":"ICH(2005b).Harmonised Tripartite Guideline S7B. Non\u2010clinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals."},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.2307\/2986305"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.01059"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.367"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2017.03.008"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01255.x"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706894"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.116.004628"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1184"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00934.x"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr044"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2016.06.003"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2015.12.002"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2008.04.012"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002061"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2008.03.006"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2017.09.236"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00668"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.09.003"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000062469.83985.9B"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/euv320"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2013.11.004"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.102.17.2137"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12483"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2008.11.009"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2009.05.011"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.118.006558"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9592.1997.d01-73.x"},{"key":"e_1_2_11_50_1","unstructured":"Woosley R. &Romer K.(1999).www.Crediblemeds.org QTdrugs List[Accessed 2018\u201011\u201030]."},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.132456"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.14786","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bph.14786","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.14786","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T17:42:46Z","timestamp":1694194966000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.14786"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,4]]},"references-count":50,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2019,10]]}},"alternative-id":["10.1111\/bph.14786"],"URL":"https:\/\/doi.org\/10.1111\/bph.14786","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,4]]},"assertion":[{"value":"2018-12-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-06-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}