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 w...