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

Vicente, J. ; Johannesen, L. ; Mason, J. W. ; Crumb, W.J. ; Pueyo, E. (Universidad de Zaragoza) ; Stockbridge, N. ; Strauss, D.G.

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: Artículo (Versión definitiva)

Área (Departamento): Área Teoría Señal y Comunicac. (Dpto. Ingeniería Electrón.Com.)