{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T20:01:24Z","timestamp":1781553684194,"version":"3.54.5"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,2,10]],"date-time":"2020-02-10T00:00:00Z","timestamp":1581292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"FDA Center for Drug Evaluation and Research"},{"name":"CDER"},{"name":"National Center for Toxicological Research"},{"name":"NCTR"},{"name":"Department of Energy and FDA\/Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great potential for personalized cardiac safety prediction, particularly for that of drug-induced proarrhythmia. However, hiPSC-CMs fire spontaneously and the variable beat rates of cardiomyocytes can be a confounding factor that interferes with data interpretation. Controlling beat rates with pacing may reduce batch and assay variations, enable evaluation of rate-dependent drug effects, and facilitate the comparison of results obtained from hiPSC-CMs with those from adult human cardiomyocytes. As electrical stimulation (E-pacing) of hiPSC-CMs has not been validated with high-throughput assays, herein, we compared the responses of hiPSC-CMs exposed with classic cardiac ion channel blockers under spontaneous beating and E-pacing conditions utilizing microelectrode array technology. We found that compared with spontaneously beating hiPSC-CMs, E-pacing: (1) reduced overall assay variabilities, (2) showed limited changes of field potential duration to pacemaker channel block, (3) revealed reverse rate dependence of multiple ion channel blockers on field potential duration, and (4) eliminated the effects of sodium channel block on depolarization spike amplitude and spike slope due to a software error in acquiring depolarization spike at cardiac pacing mode. Microelectrode array optogenetic pacing and current clamp recordings at various stimulation frequencies demonstrated rate-dependent block of sodium channels in hiPSC-CMs as reported in adult cardiomyocytes. In conclusion, pacing enabled more accurate rate- and concentration-dependent drug effect evaluations. Analyzing responses of hiPSC-CMs under both spontaneously beating and rate-controlled conditions may help better assess the effects of test compounds on cardiac electrophysiology and evaluate the value of the hiPSC-CM model.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa010","type":"journal-article","created":{"date-parts":[[2020,1,29]],"date-time":"2020-01-29T04:24:20Z","timestamp":1580271860000},"page":"254-265","source":"Crossref","is-referenced-by-count":19,"title":["Effects of Electrical Stimulation on hiPSC-CM Responses to Classic Ion Channel Blockers"],"prefix":"10.1093","volume":"174","author":[{"given":"Feng","family":"Wei","sequence":"first","affiliation":[{"name":"Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas"},{"name":"Department of Structural Heart Disease, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Pourrier","sequence":"first","affiliation":[{"name":"IonsGate Preclinical Services Inc, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G","family":"Strauss","sequence":"first","affiliation":[{"name":"Division of Applied and Regulatory Science, Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman","family":"Stockbridge","sequence":"first","affiliation":[{"name":"Division of Cardiovascular and Renal Products, Office of New Drugs I, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Pang","sequence":"first","affiliation":[{"name":"Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,2,10]]},"reference":[{"key":"2020032609575518700_kfaa010-B304","first-page":"2019","volume":"6","year":"2019"},{"key":"2020032609575518700_kfaa010-B302","doi-asserted-by":"crossref","first-page":"3597","DOI":"10.2174\/092986711796642355","article-title":"Mechanism of reverse rate-dependent action of cardioactive agents","volume":"18","author":"B\u00e1ny\u00e1sz","year":"2011","journal-title":"Curr. 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