{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T18:42:33Z","timestamp":1780512153456,"version":"3.54.1"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T00:00:00Z","timestamp":1608163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["DPI2015-69125-R"],"award-info":[{"award-number":["DPI2015-69125-R"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["DPI2015-69125-R"],"award-info":[{"award-number":["DPI2015-69125-R"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010198","name":"Ministerio de Econom\u00eda, Industria y Competitividad, Gobierno de Espa\u00f1a","doi-asserted-by":"publisher","award":["PT17\/0015\/0043"],"award-info":[{"award-number":["PT17\/0015\/0043"]}],"id":[{"id":"10.13039\/501100010198","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PROMETEU2016\/088"],"award-info":[{"award-number":["PROMETEU2016\/088"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The prolongation of the QT interval represents the main feature of the long QT syndrome (LQTS), a life-threatening genetic disease. The heterozygous SCN5A V411M mutation of the human sodium channel leads to a LQTS type 3 with severe proarrhythmic effects due to an increase in the late component of the sodium current (INaL). The two sodium blockers flecainide and ranolazine are equally recommended by the current 2015 ESC guidelines to treat patients with LQTS type 3 and persistently prolonged QT intervals. However, awareness of pro-arrhythmic effects of flecainide in LQTS type 3 patients arose upon the study of the SCN5A E1784K mutation. Regarding SCN5A V411M individuals, flecainide showed good results albeit in a reduced number of patients and no evidence supporting the use of ranolazine has ever been released. Therefore, we ought to compare the effect of ranolazine and flecainide in a SCN5A V411M model using an in-silico modeling and simulation approach. We collected clinical data of four patients. Then, we fitted four Markovian models of the human sodium current (INa) to experimental and clinical data. Two of them correspond to the wild type and the heterozygous SCN5A V411M scenarios, and the other two mimic the effects of flecainide and ranolazine on INa. Next, we inserted them into three isolated cell action potential (AP) models for endocardial, midmyocardial and epicardial cells and in a one-dimensional tissue model. The SCN5A V411M mutation produced a 15.9% APD90 prolongation in the isolated endocardial cell model, which corresponded to a 14.3% of the QT interval prolongation in a one-dimensional strand model, in keeping with clinical observations. Although with different underlying mechanisms, flecainide and ranolazine partially countered this prolongation at the isolated endocardial model by reducing the APD90 by 8.7 and 4.3%, and the QT interval by 7.2 and 3.2%, respectively. While flecainide specifically targeted the mutation-induced increase in peak INaL, ranolazine reduced it during the entire AP. Our simulations also suggest that ranolazine could prevent early afterdepolarizations triggered by the SCN5A V411M mutation during bradycardia, as flecainide. We conclude that ranolazine could be used to treat SCN5A V411M patients, specifically when flecainide is contraindicated.<\/jats:p>","DOI":"10.3389\/fphar.2020.580481","type":"journal-article","created":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T20:30:20Z","timestamp":1610051420000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Ranolazine as an Alternative Therapy to Flecainide for SCN5A V411M Long QT Syndrome Type 3 Patients"],"prefix":"10.3389","volume":"11","author":[{"given":"Jordi","family":"Cano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Zorio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Mazzanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel \u00c1ngel","family":"Arnau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Trenor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia G.","family":"Priori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Saiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4201","DOI":"10.1113\/JP270139","article-title":"Differential thermosensitivity in mixed syndrome cardiac sodium channel mutants","volume":"593","author":"Abdelsayed","year":"2015","journal-title":"J. Physiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1016\/j.hrthm.2011.05.020","article-title":"HRS\/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies","volume":"8","author":"Ackerman","year":"2011","journal-title":"Hear. Rhythm"},{"key":"B3","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1093\/europace\/euq382","article-title":"Twenty-five years in the making: flecainide is safe and effective for the management of atrial fibrillation","volume":"13","author":"Aliot","year":"2011","journal-title":"Europace"},{"key":"B4","doi-asserted-by":"publisher","first-page":"76","DOI":"10.4330\/wjc.v7.i2.76","article-title":"Flecainide: current status and perspectives in arrhythmia management","volume":"7","author":"Andrikopoulos","year":"2015","journal-title":"World J. Cardiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1124\/jpet.112.198887","article-title":"A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias","volume":"344","author":"Belardinelli","year":"2013","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B6","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1007\/s11897-017-0333-0","article-title":"Inhibition of late sodium current as an innovative antiarrhythmic strategy","volume":"14","author":"Bengel","year":"2017","journal-title":"Curr. Heart Fail. Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1536\/ihj.18-705","article-title":"Specific therapy based on the genotype in a malignant form of long QT3, carrying the V411M mutation","volume":"60","author":"Blich","year":"2019","journal-title":"Int. Heart J."},{"key":"B8","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1152\/physrev.00008.2016","article-title":"Molecular pathophysiology of congenital long QT syndrome","volume":"97","author":"Bohnen","year":"2017","journal-title":"Physiological Reviews"},{"key":"B9","doi-asserted-by":"publisher","first-page":"E2098","DOI":"10.1073\/pnas.1304382110","article-title":"Experimentally calibrated population of models predicts and explains intersubject variability in cardiac cellular electrophysiology","volume":"110","author":"Britton","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B10","doi-asserted-by":"publisher","first-page":"15631","DOI":"10.1073\/pnas.1004021107","article-title":"Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification","volume":"107","author":"Caballero","year":"2010","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1016\/j.rec.2012.03.013","article-title":"Flecainide, a therapeutic option in a patient with long QT syndrome type 3 caused by the heterozygous V411M mutation in the SCN5A gene","volume":"65","author":"Carrasco","year":"2012","journal-title":"Rev. Espa\u00f1ola Cardiol. (English Ed."},{"key":"B12","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1007\/s00424-017-1959-1","article-title":"Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes","volume":"469","author":"Chadda","year":"2017","journal-title":"Pflugers Arch."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphys.2017.00917","article-title":"Uncertainty quantification reveals the importance of data variability and experimental design considerations for in silico proarrhythmia risk assessment","volume":"8","author":"Chang","year":"2017","journal-title":"Front. Physiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1161\/CIRCEP.116.004370","article-title":"Ranolazine for congenital long-QT syndrome type III: experimental and long-term clinical data","volume":"9","author":"Chorin","year":"2016","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1172\/JCI15928","article-title":"Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome","volume":"110","author":"Clancy","year":"2002","journal-title":"J. Clin. Invest."},{"key":"B16","doi-asserted-by":"publisher","first-page":"3510","DOI":"10.1529\/biophysj.103.038679","article-title":"How to impose microscopic reversibility in complex reaction mechanisms","volume":"86","author":"Colquhoun","year":"2004","journal-title":"Biophys. J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.vascn.2016.03.009","article-title":"An evaluation of 30 clinical drugs against the comprehensive in vitro proarrhythmia assay (CiPA) proposed ion channel panel","volume":"81","author":"Crumb","year":"2016","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"B18","doi-asserted-by":"publisher","first-page":"616","DOI":"10.3389\/fphys.2017.00616","article-title":"Optimization of an in silico cardiac cell model for proarrhythmia risk assessment","volume":"8","author":"Dutta","year":"2017","journal-title":"Front. Physiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.vascn.2013.04.007","article-title":"Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment","volume":"68","author":"Elkins","year":"2013","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"B20","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1161\/01.RES.82.3.386","article-title":"Molecular determinants of dofetilide block of HERG K+ channels","volume":"82","author":"Ficker","year":"1998","journal-title":"Circ. Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.yjmcc.2009.09.019","article-title":"A novel computational model of the human ventricular action potential and Ca transient","volume":"48","author":"Grandi","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"106575","DOI":"10.1016\/j.vascn.2019.04.001","article-title":"Simultaneous assessment of compound activity on cardiac Nav1.5 peak and late currents in an automated patch clamp platform","volume":"99","author":"Guo","year":"2019","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"B23","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.yjmcc.2018.09.006","article-title":"\u03b2-adrenergic regulation of late Na+ current during cardiac action potential is mediated by both PKA and CaMKII","volume":"123","author":"Hegyi","year":"2018","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1016\/j.hrthm.2010.12.041","article-title":"A novel mechanism for LQT3 with 2:1 block: a pore-lining mutation in Nav1.5 significantly affects voltage-dependence of activation","volume":"8","author":"Horne","year":"2011","journal-title":"Hear. Rhythm"},{"key":"B25","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.yjmcc.2013.08.010","article-title":"Dynamics of the late Na(+) current during cardiac action potential and its contribution to afterdepolarizations","volume":"64","author":"Horvath","year":"2013","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.yjmcc.2019.12.015","article-title":"Late sodium current in human, canine and Guinea pig ventricular myocardium","volume":"139","author":"Horv\u00e1th","year":"2020","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1111\/j.1540-8167.2008.01255.x","article-title":"Use of ranolazine in long-QT syndrome type 3","volume":"19","author":"Kaufman","year":"2008","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1002\/cpt.367","article-title":"Improved prediction of drug-induced torsades de Pointes through simulations of dynamics and machine learning algorithms","volume":"100","author":"Lancaster","year":"2016","journal-title":"Clin. Pharmacol. Ther."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e004628","DOI":"10.1161\/CIRCEP.116.004628","article-title":"Improving the In Silico Assessment of Proarrhythmia Risk by Combining hERG (Human Ether-\u00e0-go-go-Related Gene) Channel-Drug Binding Kinetics and Multichannel Pharmacology","volume":"10","author":"Li","year":"2017","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1085\/jgp.20028723","article-title":"Common molecular determinants of flecainide and lidocaine block of heart Na+ channels","volume":"121","author":"Liu","year":"2003","journal-title":"J. Gen. Physiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1085\/jgp.20028558","article-title":"Channel openings are necessary but not sufficient for use-dependent block of cardiac Na(+) channels by flecainide: evidence from the analysis of disease-linked mutations","volume":"120","author":"Liu","year":"2002","journal-title":"J. Gen. Physiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.vascn.2007.06.005","article-title":"Choice of cardiac tissue in vitro plays an important role in assessing the risk of drug-induced cardiac arrhythmias in human: beyond QT prolongation","volume":"57","author":"Lu","year":"2008","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"B33","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.tcm.2015.05.006","article-title":"Late sodium current: a mechanism for angina, heart failure, and arrhythmia","volume":"26","author":"Makielski","year":"2016","journal-title":"Trends Cardiovasc. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"2219","DOI":"10.1172\/JCI34057","article-title":"The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome","volume":"118","author":"Makita","year":"2008","journal-title":"J. Clin. Invest."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2545","DOI":"10.1161\/01.CIR.98.23.2545","article-title":"Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes","volume":"98","author":"Maltsev","year":"1998","journal-title":"Circulation"},{"key":"B36","article-title":"Safety pharmacology assessment of cardiac ion channels by manual patch clamp with CiPA protocols","author":"Matsukawa","year":"2019"},{"key":"B37","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1016\/j.yjmcc.2011.12.003","article-title":"Pathophysiology of the cardiac late Na current and its potential as a drug target","volume":"52","author":"Moreno","year":"2012","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e0150761","DOI":"10.1371\/journal.pone.0150761","article-title":"Parameterization for in-silico modeling of ion channel interactions with drugs","volume":"11","author":"Moreno","year":"2016","journal-title":"PLoS One"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e50","DOI":"10.1161\/CIRCRESAHA.113.301971","article-title":"Ranolazine for congenital and acquired late INa-linked arrhythmias: in silico pharmacological screening","volume":"113","author":"Moreno","year":"2013","journal-title":"Circ. Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"98ra83","DOI":"10.1126\/scitranslmed.3002588","article-title":"A computational model to predict the effects of class I anti-arrhythmic drugs on ventricular rhythms","volume":"3","author":"Moreno","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/j.1542-474X.2005.00077.x","article-title":"Safety and efficacy of flecainide in subjects with long QT-3 syndrome (\u0394KPQ mutation): a randomized, double-blind, placebo-controlled clinical trial","volume":"10","author":"Moss","year":"2005","journal-title":"Annals. of Noninvasive Electrocardiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1111\/j.1540-8167.2008.01246.x","article-title":"Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome","volume":"19","author":"Moss","year":"2008","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"B43","first-page":"101","article-title":"Preferential block of late sodium current in the LQT3 DeltaKPQ mutant by the class I(C) antiarrhythmic flecainide","volume":"57","author":"Nagatomo","year":"2000","journal-title":"Mol. Pharmacol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"e1002061","DOI":"10.1371\/journal.pcbi.1002061","article-title":"Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation","volume":"7","author":"O\u2019Hara","year":"2011","journal-title":"PLoS Comput. Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1038\/sj.bjp.0704784","article-title":"Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine","volume":"136","author":"Paul","year":"2002","journal-title":"Br. J. Pharmacol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.vascn.2010.06.007","article-title":"Assessing use-dependent inhibition of the cardiac Na\u00b1 current (INa) in the PatchXpress automated patch clamp","volume":"62","author":"Penniman","year":"2010","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1016\/j.hrthm.2008.03.037","article-title":"Accurate electrocardiographic assessment of the QT interval: teach the tangent","volume":"5","author":"Postema","year":"2008","journal-title":"Hear. Rhythm"},{"key":"B48","doi-asserted-by":"publisher","first-page":"2793","DOI":"10.1093\/eurheartj\/ehv316","article-title":"2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death","volume":"36","author":"Priori","year":"2015","journal-title":"Eur. Heart J."},{"key":"B49","doi-asserted-by":"publisher","first-page":"30623","DOI":"10.1074\/jbc.M104471200","article-title":"Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes","volume":"276","author":"Rivolta","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B50","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1021\/acs.jcim.7b00440","article-title":"In Silico QT and APD prolongation assay for early screening of drug-induced proarrhythmic risk","volume":"58","author":"Romero","year":"2018","journal-title":"J. Chem. Inf. Model."},{"key":"B51","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.yjmcc.2015.08.015","article-title":"In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome","volume":"87","author":"Romero","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1017\/S0033583506004227","article-title":"Computational biology in the study of cardiac ion channels and cell electrophysiology","volume":"39","author":"Rudy","year":"2006","journal-title":"Q. Rev. Biophys."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1038\/sj.bjp.0707492","article-title":"The cardiac persistent sodium current: an appealing therapeutic target","volume":"153","author":"Saint","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1007\/BF00168654","article-title":"Electrophysiological effects of flecainide enantiomers in canine Purkinje fibres","volume":"339","author":"Smallwood","year":"1989","journal-title":"Naunyn. Schmiedebergs. Arch. Pharmacol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1016\/j.bpj.2008.10.056","article-title":"Parameter sensitivity analysis in electrophysiological models using multivariable regression","volume":"96","author":"Sobie","year":"2009","journal-title":"Biophys. J."},{"key":"B56","doi-asserted-by":"publisher","first-page":"2038","DOI":"10.1016\/j.bpj.2010.08.016","article-title":"Synergy between CaMKII substrates and \u03b2-adrenergic signaling in regulation of cardiac myocyte Ca2 handling","volume":"99","author":"Soltis","year":"2010","journal-title":"Biophys. J."},{"key":"B57","doi-asserted-by":"publisher","first-page":"e32659","DOI":"10.1371\/journal.pone.0032659","article-title":"Simulation and mechanistic investigation of the arrhythmogenic role of the late sodium current in human heart failure","volume":"7","author":"Trenor","year":"2012","journal-title":"PLoS One"},{"key":"B58","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1161\/CIRCRESAHA.119.316404","article-title":"A computational pipeline to predict cardiotoxicity:from the atom to the rhythm","volume":"126","author":"Yang","year":"2020","journal-title":"Circ. Res."},{"key":"B59","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.yjmcc.2016.08.011","article-title":"A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current","volume":"99","author":"Yang","year":"","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1113\/JP271282","article-title":"In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia","volume":"594","author":"Yang","year":"","journal-title":"J. Physiol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1161\/CIRCRESAHA.118.314050","article-title":"Predicting patient response to the antiarrhythmic mexiletine based on genetic variation: personalized medicine for long QT syndrome","volume":"124","author":"Zhu","year":"2019","journal-title":"Circ. Res."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2020.580481\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T15:31:59Z","timestamp":1610724719000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2020.580481\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,17]]},"references-count":61,"alternative-id":["10.3389\/fphar.2020.580481"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2020.580481","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,17]]},"article-number":"580481"}}