{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:46:01Z","timestamp":1787013961746,"version":"build-2736575974"},"reference-count":45,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2022,7,24]],"date-time":"2022-07-24T00:00:00Z","timestamp":1658620800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["U01HL136297"],"award-info":[{"award-number":["U01HL136297"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["F31HL154655"],"award-info":[{"award-number":["F31HL154655"]}],"id":[{"id":"10.13039\/100000050","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":[[2022,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>Before advancing to clinical trials, new drugs are screened for their pro\u2010arrhythmic potential using a method that is overly conservative and provides limited mechanistic insight. The shortcomings of this approach can lead to the mis\u2010classification of beneficial drugs as pro\u2010arrhythmic.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      An in silico\n                      <jats:italic>\u2013<\/jats:italic>\n                      in vitro pipeline was developed to circumvent these shortcomings. A computational human induced pluripotent stem cell\u2010derived cardiomyocyte (iPSC\u2010CM) model was used as part of a genetic algorithm to design experiments, specifically electrophysiological voltage clamp (VC) protocols, to identify which of several cardiac ion channels were blocked during in vitro drug studies. Such VC data, along with dynamically clamped action potentials (AP), were acquired from iPSC\u2010CMs before and after treatment with a control solution or a low\u2010 (verapamil), intermediate\u2010 (cisapride or quinine) or high\u2010risk (quinidine) drug.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Significant AP prolongation (a pro\u2010arrhythmia marker) was seen in response to quinidine and quinine. The VC protocol identified block of I\n                      <jats:sub>Kr<\/jats:sub>\n                      (a source of arrhythmias) by all strong I\n                      <jats:sub>Kr<\/jats:sub>\n                      blockers, including cisapride, quinidine and quinine. The protocol also detected block of I\n                      <jats:sub>CaL<\/jats:sub>\n                      by verapamil and I\n                      <jats:sub>to<\/jats:sub>\n                      by quinidine. Further demonstrating the power of the approach, the VC data uncovered a previously unidentified I\n                      <jats:sub>f<\/jats:sub>\n                      block by quinine, which was confirmed with experiments using a HEK\u2010293 expression system and automated patch\u2010clamp.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>\n                      We developed an in silico\n                      <jats:italic>\u2013<\/jats:italic>\n                      in vitro pipeline that simultaneously identifies pro\u2010arrhythmia risk and mechanism of ion channel\u2010blocking drugs. The approach offers a new tool for evaluating cardiotoxicity during preclinical drug screening.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.15915","type":"journal-article","created":{"date-parts":[[2022,7,4]],"date-time":"2022-07-04T13:43:20Z","timestamp":1656942200000},"page":"4829-4843","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["An in silico\u2013in vitro pipeline for drug cardiotoxicity screening identifies ionic pro\u2010arrhythmia mechanisms"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5200-6573","authenticated-orcid":false,"given":"Alexander P.","family":"Clark","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Cornell University  Ithaca New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology SUNY Downstate Medical Center  Brooklyn New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darshan","family":"Kalola","sequence":"additional","affiliation":[{"name":"Computational Biology Summer Program Weill Cornell Medicine &amp; Memorial Sloan Kettering Cancer Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trine","family":"Krogh\u2010Madsen","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Biophysics Weill Cornell Medicine  New York New York USA"},{"name":"Institute for Computational Biomedicine Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Christini","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Cornell University  Ithaca New York USA"},{"name":"Department of Physiology and Pharmacology SUNY Downstate Medical Center  Brooklyn New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7,24]]},"reference":[{"key":"e_1_2_12_2_1","first-page":"S157","article-title":"The concise guide to PHARMACOLOGY 2021\/22: Ion channels","volume":"178","author":"Alexander S. 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