Comprehensive T wave Morphology Assessment in a Randomized Clinical Study of Dofetilide, Quinidine, Ranolazine, and Verapamil
Resumen: Background
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.

Idioma: Inglés
DOI: 10.1161/JAHA.114.001615
Año: 2015
Publicado en: Journal of the American Heart Association. Cardiovascular and cerebrovascular disease 4 (2015), e001615 [13 pp]
ISSN: 2047-9980

Factor impacto JCR: 5.117 (2015)
Categ. JCR: CARDIAC & CARDIOVASCULAR SYSTEMS rank: 18 / 124 = 0.145 (2015) - Q1 - T1
Factor impacto SCIMAGO: 2.787 - Cardiology and Cardiovascular Medicine (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MINECO/TIN2013-41998-R
Tipo y forma: Article (Published version)
Área (Departamento): Área Teoría Señal y Comunicac. (Dpto. Ingeniería Electrón.Com.)

Creative Commons You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.


Exportado de SIDERAL (2021-01-21-11:19:55)

Este artículo se encuentra en las siguientes colecciones:
Articles



 Record created 2016-05-12, last modified 2021-01-21


Versión publicada:
 PDF
Rate this document:

Rate this document:
1
2
3
 
(Not yet reviewed)