{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T21:32:41Z","timestamp":1790371961624,"version":"4.1.0"},"reference-count":56,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2019,1,23]],"date-time":"2019-01-23T00:00:00Z","timestamp":1548201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"part","award":["P50 GM115305"],"award-info":[{"award-number":["P50 GM115305"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The QT interval, a global index of ventricular repolarization, varies among individuals and is influenced by diverse physiologic and pathophysiologic stimuli such as gender, age, heart rate, electrolyte concentrations, concomitant cardiac disease, and other diseases such as diabetes. Many drugs produce a small but reproducible effect on QT interval but in rare instances this is exaggerated and marked QT prolongation can provoke the polymorphic ventricular tachycardia \u2018torsades de pointes\u2019, which can cause syncope or sudden cardiac death. The generally accepted common mechanism whereby drugs prolong QT is block of a key repolarizing potassium current in heart, IKr, generated by expression of KCNH2, also known as HERG. Thus, evaluation of the potential that a new drug entity may cause torsades de pointes has relied on exposure of normal volunteers or patients to drug at usual and high concentrations, and on assessment of IKr block in vitro. More recent work, focusing on anticancer drugs with QT prolonging liability, is defining new pathways whereby drugs can prolong QT. Notably, the in vitro effects of some tyrosine kinase inhibitors to prolong cardiac action potentials (the cellular correlate of QT) can be rescued by intracellular phosphatidylinositol 3,4,5-trisphosphate, the downstream effector of phosphoinositide 3-kinase. This finding supports a role for inhibition of this enzyme, either directly or by inhibition of upstream kinases, to prolong QT through mechanisms that are being worked out, but include enhanced inward \u2018late\u2019 sodium current during the plateau of the action potential. The definition of non-IKr-dependent pathways to QT prolongation will be important for assessing risk, not only with anticancer therapies but also with other QT prolonging drugs and for generating a refined understanding how variable activity of intracellular signalling systems can modulate QT and associated arrhythmia risk.<\/jats:p>","DOI":"10.1093\/cvr\/cvz013","type":"journal-article","created":{"date-parts":[[2019,1,16]],"date-time":"2019-01-16T15:13:42Z","timestamp":1547651622000},"page":"895-903","source":"Crossref","is-referenced-by-count":63,"title":["A current understanding of drug-induced QT prolongation and its implications for anticancer therapy"],"prefix":"10.1093","volume":"115","author":[{"given":"Dan M","family":"Roden","sequence":"first","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Avenue, Room 1285B, Nashville, TN, USA"},{"name":"Department of Pharmacology, Vanderbilt University Medical Center, 2215B Garland Avenue, Room 1285B, Nashville, TN, USA"},{"name":"Department of Biomedical Informatics, Vanderbilt University Medical Center, 2215B Garland Avenue, Room 1285B, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,1,23]]},"reference":[{"key":"2021031603394836700_cvz013-B1","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.jacc.2013.04.044","article-title":"Impact of genetics on the clinical management of channelopathies","volume":"62","author":"Schwartz","year":"2013","journal-title":"J Am Coll Cardiol"},{"key":"2021031603394836700_cvz013-B2","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1056\/NEJMra032426","article-title":"Drug-induced prolongation of the QT Interval","volume":"350","author":"Roden","year":"2004","journal-title":"N Engl J Med"},{"key":"2021031603394836700_cvz013-B3","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/S0735-1097(99)00226-0","article-title":"Exaggerated QT prolongation after cardioversion of atrial fibrillation","volume":"34","author":"Choy","year":"1999","journal-title":"J Am Coll Cardiol"},{"key":"2021031603394836700_cvz013-B4","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1002\/pds.1607","article-title":"Drug-induced torsades de pointes: a review of the Swedish pharmacovigilance database","volume":"17","author":"Astrom-Lilja","year":"2008","journal-title":"Pharmacoepidemiol drug safety"},{"key":"2021031603394836700_cvz013-B5","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1136\/heartjnl-2016-311079","article-title":"Systemic inflammation as a novel QT-prolonging risk factor in patients with torsades de pointes","volume":"103","author":"Lazzerini","year":"2017","journal-title":"Heart"},{"key":"2021031603394836700_cvz013-B6","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1161\/CIRCULATIONAHA.115.009800","article-title":"Pathogenesis of the novel autoimmune-associated long QT syndrome","volume":"132","author":"Yue","year":"2015","journal-title":"Circulation"},{"key":"2021031603394836700_cvz013-B7","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1161\/CIRCULATIONAHA.118.034282","article-title":"Hypogonadism as a reversible cause of torsades de pointes in men","volume":"138","author":"Salem","year":"2018","journal-title":"Circulation"},{"key":"2021031603394836700_cvz013-B8","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.jacc.2010.01.001","article-title":"Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation","volume":"55","author":"Drew","year":"2010","journal-title":"J Am Coll Cardiol"},{"key":"2021031603394836700_cvz013-B9","doi-asserted-by":"crossref","first-page":"2788","DOI":"10.1001\/jama.1990.03450210088038","article-title":"Torsades de pointes occurring in association with terfenadine use","volume":"264","author":"Monahan","year":"1990","journal-title":"J Am Med Assoc"},{"key":"2021031603394836700_cvz013-B10","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1001\/jama.1993.03500120070028","article-title":"Mechanism of the cardiotoxic actions of terfenadine","volume":"269","author":"Woosley","year":"1993","journal-title":"J Am Med Assoc"},{"key":"2021031603394836700_cvz013-B11","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.2165\/00002018-200528110-00003","article-title":"Drugs, QTc interval prolongation and final ICH E14 guideline","volume":"28","author":"Shah","year":"2005","journal-title":"Drug Saf"},{"key":"2021031603394836700_cvz013-B12","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.vascn.2016.06.002","article-title":"The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative\u2014update on progress","volume":"81","author":"Colatsky","year":"2016","journal-title":"J Pharmacol Toxicol Methods"},{"key":"2021031603394836700_cvz013-B13","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1161\/01.RES.56.6.857","article-title":"Action potential prolongation and induction of abnormal automaticity by low quinidine concentrations in canine Purkinje fibers. Relationship to potassium and cycle length","volume":"56","author":"Roden","year":"1985","journal-title":"Circ Res"},{"key":"2021031603394836700_cvz013-B14","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1161\/01.RES.26.6.661","article-title":"Electrophysiological and beta-receptor blocking effects of MJ 1999 on dog and rabbit cardiac tissue","volume":"26","author":"Strauss","year":"1970","journal-title":"Circ Res"},{"key":"2021031603394836700_cvz013-B15","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1161\/01.RES.69.6.1427","article-title":"Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial, and M cells","volume":"69","author":"Antzelevitch","year":"1991","journal-title":"Circ Res"},{"key":"2021031603394836700_cvz013-B16","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1085\/jgp.96.1.195","article-title":"Two components of cardiac delayed rectifier K + current: differential sensitivity to block by class III antiarrhythmic agents","volume":"96","author":"Sanguinetti","year":"1990","journal-title":"J Gen Physiol"},{"key":"2021031603394836700_cvz013-B17","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/376683a0","article-title":"Molecular mechanism for an inherited cardiac arrhythmia","volume":"376","author":"Bennett","year":"1995","journal-title":"Nature"},{"key":"2021031603394836700_cvz013-B18","doi-asserted-by":"crossref","DOI":"10.1111\/pace.13419","article-title":"Afterdepolarizations and triggered activity as a mechanism for clinical arrhythmias","author":"Wit","year":"2018","journal-title":"Pacing Clin Electrophysiol"},{"key":"2021031603394836700_cvz013-B19","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/379833a0","article-title":"The inward rectification mechanism of the HERG cardiac potassium channel","volume":"379","author":"Smith","year":"1996","journal-title":"Nature"},{"key":"2021031603394836700_cvz013-B20","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1161\/CIRCULATIONAHA.105.550111","article-title":"Restricting excessive cardiac action potential and QT prolongation: a vital role for IKs in human ventricular muscle","volume":"112","author":"Jost","year":"2005","journal-title":"Circulation"},{"key":"2021031603394836700_cvz013-B21","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.yjmcc.2013.02.009","article-title":"beta-adrenergic stimulation activates early afterdepolarizations transiently via kinetic mismatch of PKA targets","volume":"58","author":"Xie","year":"2013","journal-title":"J Mol Cell Cardiol"},{"key":"2021031603394836700_cvz013-B22","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1161\/CIRCULATIONAHA.105.543306","article-title":"Subunit interaction determines IKs participation in cardiac repolarization and repolarization reserve","volume":"112","author":"Silva","year":"2005","journal-title":"Circulation"},{"key":"2021031603394836700_cvz013-B23","doi-asserted-by":"crossref","first-page":"12329","DOI":"10.1073\/pnas.210244497","article-title":"A structural basis for drug-induced long QT syndrome","volume":"97","author":"Mitcheson","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021031603394836700_cvz013-B24","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.tips.2017.06.004","article-title":"Towards a structural view of drug binding to hERG K(+) channels","volume":"38","author":"Vandenberg","year":"2017","journal-title":"Trends Pharmacol Sci"},{"key":"2021031603394836700_cvz013-B25","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2017.03.048","article-title":"Cryo-EM structure of the open human ether-a-go-go-related K(+) channel hERG","volume":"169","author":"Wang","year":"2017","journal-title":"Cell"},{"key":"2021031603394836700_cvz013-B26","first-page":"619","article-title":"The prolonged QT interval: role of pro-inflammatory cytokines, reactive oxygen species and the ceramide and sphingosine-1 phosphate pathways","volume":"29","author":"Sordillo","year":"2015","journal-title":"In Vivo"},{"key":"2021031603394836700_cvz013-B27","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1124\/mol.66.1.33","article-title":"Mechanisms of arsenic-induced prolongation of cardiac repolarization","volume":"66","author":"Ficker","year":"2004","journal-title":"Mol Pharmacol"},{"key":"2021031603394836700_cvz013-B28","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1161\/01.CIR.99.4.529","article-title":"Low penetrance in the long-QT syndrome: clinical impact","volume":"99","author":"Priori","year":"1999","journal-title":"Circulation"},{"key":"2021031603394836700_cvz013-B29","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/0092-8674(95)90359-3","article-title":"SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome","volume":"80","author":"Wang","year":"1995","journal-title":"Cell"},{"key":"2021031603394836700_cvz013-B30","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1007\/s00109-003-0522-z","article-title":"Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients","volume":"82","author":"Paulussen","year":"2004","journal-title":"J Mol Med"},{"key":"2021031603394836700_cvz013-B31","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1161\/01.CIR.0000014448.19052.4C","article-title":"Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes","volume":"105","author":"Yang","year":"2002","journal-title":"Circulation"},{"key":"2021031603394836700_cvz013-B32","doi-asserted-by":"crossref","first-page":"10613","DOI":"10.1073\/pnas.180223197","article-title":"A common polymorphism associated with antibiotic-induced cardiac arrhythmia","volume":"97","author":"Sesti","year":"2000","journal-title":"Proc Natl. Acad Sci USA"},{"key":"2021031603394836700_cvz013-B33","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1016\/j.jacc.2014.01.031","article-title":"Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome","volume":"63","author":"Weeke","year":"2014","journal-title":"J Am Coll Cardiol"},{"key":"2021031603394836700_cvz013-B34","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1111\/j.1540-8159.1998.tb00148.x","article-title":"Taking the idio out of idiosyncratic - predicting torsades de pointes","volume":"21","author":"Roden","year":"1998","journal-title":"Pacing Clin Electrophysiol"},{"key":"2021031603394836700_cvz013-B35","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1161\/CIRCGENETICS.111.960930","article-title":"A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes","volume":"5","author":"Kaab","year":"2012","journal-title":"Circ Cardiovasc Genet"},{"key":"2021031603394836700_cvz013-B36","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/j.hrthm.2018.04.031","article-title":"Arrhythmia genetics: not dark and lite, but 50 shades of gray","volume":"15","author":"Roden","year":"2018","journal-title":"Heart Rhythm"},{"key":"2021031603394836700_cvz013-B37","doi-asserted-by":"crossref","first-page":"e78511.","DOI":"10.1371\/journal.pone.0078511","article-title":"Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes","volume":"8","author":"Behr","year":"2013","journal-title":"PloS One"},{"key":"2021031603394836700_cvz013-B38","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1161\/CIRCULATIONAHA.116.023980","article-title":"Common genetic variant risk score is associated with drug-induced QT prolongation and torsade de pointes risk: a pilot study","volume":"135","author":"Strauss","year":"2017","journal-title":"Circulation"},{"key":"2021031603394836700_cvz013-B39","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/S0002-8703(96)90525-6","article-title":"Dose-response relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram: distinguishing a drug effect from spontaneous variability","volume":"131","author":"Pratt","year":"1996","journal-title":"Am Heart J"},{"key":"2021031603394836700_cvz013-B40","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1001\/jama.1993.03500120051025","article-title":"Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences","volume":"269","author":"Honig","year":"1993","journal-title":"J Am Med Assoc"},{"key":"2021031603394836700_cvz013-B41","doi-asserted-by":"crossref","first-page":"1035.","DOI":"10.3389\/fphar.2018.01035","article-title":"Experimentally validated pharmacoinformatics approach to predict hERG inhibition potential of new chemical entities","volume":"9","author":"Munawar","year":"2018","journal-title":"Front Pharmacol"},{"key":"2021031603394836700_cvz013-B42","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1161\/CIRCEP.114.002339","article-title":"Safety of oral dofetilide for rhythm control of atrial fibrillation and atrial flutter","volume":"8","author":"Abraham","year":"2015","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"2021031603394836700_cvz013-B43","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.tcm.2017.07.010","article-title":"CredibleMeds.org: what does it offer?","volume":"28","author":"Woosley","year":"2018","journal-title":"Trends Cardiovasc Med"},{"key":"2021031603394836700_cvz013-B44","doi-asserted-by":"crossref","first-page":"131ra150","DOI":"10.1126\/scitranslmed.3003623","article-title":"Suppression of phosphoinositide 3-kinase signaling and alteration of multiple ion currents in drug-induced long QT syndrome","volume":"4","author":"Lu","year":"2012","journal-title":"Sci Transl Med"},{"key":"2021031603394836700_cvz013-B45","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1124\/jpet.117.246157","article-title":"Inhibition of the alpha-subunit of phosphoinositide 3-kinase in heart increases late sodium current and is arrhythmogenic","volume":"365","author":"Yang","year":"2018","journal-title":"J Pharmacol Exp Ther"},{"key":"2021031603394836700_cvz013-B46","doi-asserted-by":"crossref","first-page":"4257","DOI":"10.2337\/db13-0420","article-title":"Increased persistent sodium current due to decreased PI3K signaling contributes to QT prolongation in the diabetic heart","volume":"62","author":"Lu","year":"2013","journal-title":"Diabetes"},{"key":"2021031603394836700_cvz013-B47","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1161\/CIRCULATIONAHA.113.007765","article-title":"Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current","volume":"130","author":"Yang","year":"2014","journal-title":"Circulation"},{"key":"2021031603394836700_cvz013-B48","doi-asserted-by":"crossref","first-page":"e003655.","DOI":"10.1161\/CIRCEP.115.003655","article-title":"Increased late sodium current contributes to the electrophysiological effects of chronic, but not acute, dofetilide administration","volume":"9","author":"Qiu","year":"2016","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"2021031603394836700_cvz013-B49","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s40264-013-0047-5","article-title":"Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval)","volume":"36","author":"Shah","year":"2013","journal-title":"Drug Saf"},{"key":"2021031603394836700_cvz013-B50","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1111\/j.1742-7843.2010.00556.x","article-title":"Electrophysiological effects of the anti-cancer drug lapatinib on cardiac repolarization","volume":"107","author":"Lee","year":"2010","journal-title":"Basic Clin Pharmacol Toxicol"},{"key":"2021031603394836700_cvz013-B51","doi-asserted-by":"crossref","first-page":"434","DOI":"10.5603\/CJ.2012.0078","article-title":"QT interval prolongation and torsades de pointes in a patient undergoing treatment with vorinostat: a case report and review of the literature","volume":"19","author":"Lynch","year":"2012","journal-title":"Cardiol J"},{"key":"2021031603394836700_cvz013-B52","doi-asserted-by":"crossref","first-page":"H1139","DOI":"10.1152\/ajpheart.00156.2016","article-title":"Changes in cardiac Nav1.5 expression, function, and acetylation by pan-histone deacetylase inhibitors","volume":"311","author":"Xu","year":"2016","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2021031603394836700_cvz013-B53","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1093\/toxsci\/kfw104","article-title":"Histone deacetylase inhibitors prolong cardiac repolarization through transcriptional mechanisms","volume":"153","author":"Spence","year":"2016","journal-title":"Toxicol Sci"},{"key":"2021031603394836700_cvz013-B54","first-page":"A14477","article-title":"Abstract 14477: Integrating patient-specific cardiomyocyte function with population multi-omics identifies a novel arrhythmia pathway (**Katz Prize finalist**)","volume":"136","author":"Bersell","year":"2017","journal-title":"Circulation"},{"key":"2021031603394836700_cvz013-B55","doi-asserted-by":"crossref","first-page":"5696","DOI":"10.1158\/1078-0432.CCR-16-1248","article-title":"A phase I study of the cyclin-dependent kinase 4\/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas","volume":"22","author":"Infante","year":"2016","journal-title":"Clin Cancer Res"},{"key":"2021031603394836700_cvz013-B56","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1161\/CIRCRESAHA.110.221911","article-title":"Reactive oxygen species-activated Ca\/calmodulin kinase II\u03b4 is required for late INa augmentation leading to cellular Na and Ca overload","volume":"108","author":"Wagner","year":"2011","journal-title":"Circ Res"}],"container-title":["Cardiovascular Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cardiovascres\/article-pdf\/115\/5\/895\/36605125\/cvz013.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cardiovascres\/article-pdf\/115\/5\/895\/36605125\/cvz013.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T23:40:43Z","timestamp":1615851643000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article\/115\/5\/895\/5299452"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,23]]},"references-count":56,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,1,23]]},"published-print":{"date-parts":[[2019,4,15]]}},"URL":"https:\/\/doi.org\/10.1093\/cvr\/cvz013","relation":{},"ISSN":["0008-6363","1755-3245"],"issn-type":[{"value":"0008-6363","type":"print"},{"value":"1755-3245","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,4,15]]},"published":{"date-parts":[[2019,1,23]]}}}