000060438 001__ 60438
000060438 005__ 20200221144327.0
000060438 0247_ $$2doi$$a10.1371/journal.pone.0163619
000060438 0248_ $$2sideral$$a97923
000060438 037__ $$aART-2016-97923
000060438 041__ $$aeng
000060438 100__ $$0(orcid)0000-0001-9963-1205$$aVicente, J.
000060438 245__ $$aElectrocardiographic biomarkers for detection of drug-induced late sodium current block
000060438 260__ $$c2016
000060438 5060_ $$aAccess copy available to the general public$$fUnrestricted
000060438 5203_ $$aBackground Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the ''CiPA'' initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans. Methods and Results In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected JTpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001). Conclusions Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block.
000060438 536__ $$9info:eu-repo/grantAgreement/ES/DGA/T96$$9info:eu-repo/grantAgreement/ES/MINECO/TIN2013-41998-R
000060438 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000060438 590__ $$a2.806$$b2016
000060438 591__ $$aMULTIDISCIPLINARY SCIENCES$$b15 / 63 = 0.238$$c2016$$dQ1$$eT1
000060438 592__ $$a1.236$$b2016
000060438 593__ $$aAgricultural and Biological Sciences (miscellaneous)$$c2016$$dQ1
000060438 593__ $$aMedicine (miscellaneous)$$c2016$$dQ1
000060438 593__ $$aBiochemistry, Genetics and Molecular Biology (miscellaneous)$$c2016$$dQ1
000060438 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000060438 700__ $$aJohannesen, L.
000060438 700__ $$aHosseini, M.
000060438 700__ $$aMason, J.W.
000060438 700__ $$aSager, P.T.
000060438 700__ $$0(orcid)0000-0002-1960-407X$$aPueyo, E.$$uUniversidad de Zaragoza
000060438 700__ $$aStrauss, D.G.
000060438 7102_ $$15008$$2800$$aUniversidad de Zaragoza$$bDpto. Ingeniería Electrón.Com.$$cÁrea Teoría Señal y Comunicac.
000060438 773__ $$g11, 12 (2016), 0163619 [16p]$$pPLoS One$$tPloS one$$x1932-6203
000060438 8564_ $$s4186857$$uhttps://zaguan.unizar.es/record/60438/files/texto_completo.pdf$$yVersión publicada
000060438 8564_ $$s100790$$uhttps://zaguan.unizar.es/record/60438/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000060438 909CO $$ooai:zaguan.unizar.es:60438$$particulos$$pdriver
000060438 951__ $$a2020-02-21-13:44:49
000060438 980__ $$aARTICLE