000048689 001__ 48689
000048689 005__ 20210121114547.0
000048689 0247_ $$2doi$$a10.1161/JAHA.114.001615
000048689 0248_ $$2sideral$$a94775
000048689 037__ $$aART-2015-94775
000048689 041__ $$aeng
000048689 100__ $$aVicente, J.
000048689 245__ $$aComprehensive T wave Morphology Assessment in a Randomized Clinical Study of Dofetilide, Quinidine, Ranolazine, and Verapamil
000048689 260__ $$c2015
000048689 5060_ $$aAccess copy available to the general public$$fUnrestricted
000048689 5203_ $$aBackground
Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of hERG-blocking drugs. However, it is not known how additional calcium or late sodium block, that can decrease torsade risk, affects T wave morphology.
Methods and Results
Twenty-two healthy subjects received a single dose of a pure hERG blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5-period, placebo-controlled cross-over trial. At pre-dose and 15 time-points post-dose, ECGs and plasma drug concentration were assessed. Patch clamp experiments were performed to assess block of hERG, calcium (L-type) and late sodium currents for each drug. Pure hERG block (dofetilide) and strong hERG block with lesser calcium and late sodium block (quinidine) caused substantial T wave morphology changes (P<0.001). Strong late sodium current and hERG block (ranolazine) still caused T wave morphology changes (P<0.01). Strong calcium and hERG block (verapamil) did not cause T wave morphology changes. At equivalent QTc prolongation, multichannel blockers (quinidine and ranolazine) caused equal or greater T wave morphology changes compared with pure hERG block (dofetilide).
Conclusions
T wave morphology changes are directly related to amount of hERG 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 ECG intervals and T wave morphology may provide the greatest insight into drug-ion channel interactions and torsade de pointes risk.
000048689 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/TIN2013-41998-R
000048689 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000048689 590__ $$a5.117$$b2015
000048689 591__ $$aCARDIAC & CARDIOVASCULAR SYSTEMS$$b18 / 124 = 0.145$$c2015$$dQ1$$eT1
000048689 592__ $$a2.787$$b2015
000048689 593__ $$aCardiology and Cardiovascular Medicine$$c2015$$dQ1
000048689 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000048689 700__ $$aJohannesen, L.
000048689 700__ $$aMason, J. W.
000048689 700__ $$aCrumb, W.J.
000048689 700__ $$0(orcid)0000-0002-1960-407X$$aPueyo, E.$$uUniversidad de Zaragoza
000048689 700__ $$aStockbridge, N.
000048689 700__ $$aStrauss, D.G.
000048689 7102_ $$15008$$2800$$aUniversidad de Zaragoza$$bDpto. Ingeniería Electrón.Com.$$cÁrea Teoría Señal y Comunicac.
000048689 773__ $$g4 (2015), e001615 [13 pp]$$tJournal of the American Heart Association. Cardiovascular and cerebrovascular disease$$x2047-9980
000048689 8564_ $$s4441179$$uhttps://zaguan.unizar.es/record/48689/files/texto_completo.pdf$$yVersión publicada
000048689 8564_ $$s127900$$uhttps://zaguan.unizar.es/record/48689/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000048689 909CO $$ooai:zaguan.unizar.es:48689$$particulos$$pdriver
000048689 951__ $$a2021-01-21-11:19:55
000048689 980__ $$aARTICLE