{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T21:28:35Z","timestamp":1782941315995,"version":"3.54.5"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2015,4,22]]},"abstract":"\n Background<\/jats:title>\n \n Congenital long\n QT<\/jats:styled-content>\n syndrome type 2 (abnormal\n hERG<\/jats:styled-content>\n potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of\n hERG<\/jats:styled-content>\n \u2010blocking drugs. However, it is not known how additional calcium or late sodium block, that can decrease torsade risk, affects T wave morphology.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n Twenty\u2010two healthy subjects received a single dose of a pure\n hERG<\/jats:styled-content>\n blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5\u2010period, placebo\u2010controlled cross\u2010over trial. At pre\u2010dose and 15 time\u2010points post\u2010dose,\n ECG<\/jats:styled-content>\n s and plasma drug concentration were assessed. Patch clamp experiments were performed to assess block of\n hERG<\/jats:styled-content>\n , calcium (L\u2010type) and late sodium currents for each drug. Pure\n hERG<\/jats:styled-content>\n block (dofetilide) and strong\n hERG<\/jats:styled-content>\n block with lesser calcium and late sodium block (quinidine) caused substantial T wave morphology changes (\n P<\/jats:italic>\n <0.001). Strong late sodium current and\n hERG<\/jats:styled-content>\n block (ranolazine) still caused T wave morphology changes (\n P<\/jats:italic>\n <0.01). Strong calcium and\n hERG<\/jats:styled-content>\n block (verapamil) did not cause T wave morphology changes. At equivalent\n QT<\/jats:styled-content>\n c prolongation, multichannel blockers (quinidine and ranolazine) caused equal or greater T wave morphology changes compared with pure\n hERG<\/jats:styled-content>\n block (dofetilide).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n T wave morphology changes are directly related to amount of\n hERG<\/jats:styled-content>\n block; however, with quinidine and ranolazine, multichannel block did not prevent T wave morphology changes. A combined approach of assessing multiple ion channels, along with\n ECG<\/jats:styled-content>\n intervals and T wave morphology may provide the greatest insight into drug\u2010ion channel interactions and torsade de pointes risk.\n <\/jats:p>\n <\/jats:sec>\n \n Clinical Trial Registration<\/jats:title>\n \n URL:\n http:\/\/clinicaltrials.gov\/<\/jats:ext-link>\n Unique identifier:\n NCT<\/jats:styled-content>\n 01873950.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.114.001615","type":"journal-article","created":{"date-parts":[[2015,4,14]],"date-time":"2015-04-14T01:32:14Z","timestamp":1428975134000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":109,"title":["Comprehensive T wave Morphology Assessment in a Randomized Clinical Study of Dofetilide, Quinidine, Ranolazine, and Verapamil"],"prefix":"10.1161","volume":"4","author":[{"given":"Jose","family":"Vicente","sequence":"first","affiliation":[{"name":"Office of Science and Engineering Laboratories, CDRH, US FDA, Silver Spring, MD"},{"name":"Division of Cardiovascular and Renal Products, Office of New Drugs, CDER, US FDA, Silver Spring, MD"},{"name":"BSICoS Group, Arag\u00f3n Institute for Engineering Research (I3A), IIS Arag\u00f3n, University of Zaragoza, Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Johannesen","sequence":"additional","affiliation":[{"name":"Office of Science and Engineering Laboratories, CDRH, US FDA, Silver Spring, MD"},{"name":"Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay W.","family":"Mason","sequence":"additional","affiliation":[{"name":"Spaulding Clinical Research, West Bend, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Crumb","sequence":"additional","affiliation":[{"name":"Zenas Technologies, New Orleans, Louisiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Pueyo","sequence":"additional","affiliation":[{"name":"Office of Science and Engineering Laboratories, CDRH, US FDA, Silver Spring, MD"},{"name":"BSICoS Group, Arag\u00f3n Institute for Engineering Research (I3A), IIS Arag\u00f3n, University of Zaragoza, Zaragoza, Spain"},{"name":"Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER\u2010BBN), Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman","family":"Stockbridge","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular and Renal Products, Office of New Drugs, CDER, US FDA, Silver Spring, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Strauss","sequence":"additional","affiliation":[{"name":"Office of Science and Engineering Laboratories, CDRH, US FDA, Silver Spring, MD"},{"name":"Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001573-200201000-00007"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.080887"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.92.10.2929"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-013-0016-z"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00846-5"},{"key":"e_1_3_5_7_2","unstructured":"US Food and Drug Administration . 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