Abstract 14051: T wave Morphology Assessment in a Randomized Double-blind Crossover Study of Four hERG Potassium Channel Blocking Drugs
Introduction: Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients have flat, asymmetric and notched T waves and are at risk for torsade de pointes. Similar observations have been made with a limited number of hERG blocking drugs. However, it is not known how additional calcium and sodium channel block affect T wave morphology.
Objective: To assess T wave morphology changes induced by a pure hERG blocker (dofetilide) and three drugs that also block calcium or sodium (quinidine, ranolazine and verapamil).
Methods: 22 subjects received a single dose of each drug along with placebo in a double-blind 5-period crossover study. At 15 time points post-dose, plasma drug concentration and ECGs were assessed. T wave flatness, asymmetry and notching were automatically measured using QT-Guard+ (GE Healthcare). Regression models were used to assess the relationship between plasma drug concentration and T wave.
Results: See Figure. Pure hERG block (dofetilide) caused concentration-dependent T wave flatness, asymmetry and notching (p<0.001 for all). Strong hERG block with lesser calcium and sodium block (quinidine) also caused substantial T wave flatness, asymmetry and notching (p<0.001 for all). Strong late sodium current block with additional hERG block (ranolazine) still caused T wave flatness and asymmetry (p<0.001), but not notching (p=0.32). Strong calcium block with additional hERG block (verapamil) did not cause T wave flatness (p=0.68), asymmetry (p=0.15) or notching (p=0.89).
Conclusions: Strong hERG block caused substantial concentration-dependent T wave morphology changes. Ranolazine (late sodium > hERG block) still caused T wave flatness and asymmetry, but not notching. Verapamil did not cause T wave morphology changes, likely because of a combination of strong calcium and weaker hERG block. Additional outcomes research is needed to determine the potential value of T wave morphology for torsade de pointes risk assessment.
Author Disclosures: J. Vicente: None. L. Johannesen: None. R.K. Afoakwa: None. E. Pueyo: None. N. Stockbridge: None. J.W. Mason: None. D.G. Strauss: None.
- © 2014 by American Heart Association, Inc.