The time course of new T-wave ECG descriptors following single- and double-dose administration of sotalol in healthy subjects.

INTRODUCTION

The aim of the study was to assess the time course effect of IKr blockade on ECG biomarkers of ventricular repolarization and to evaluate the accuracy of a fully automatic approach for QT duration evaluation.

METHODS

Twelve-lead digital ECG Holter was recorded in 38 healthy subjects (27 males, mean age = 27.4 + or - 8.0 years) on baseline conditions (day 0) and after administration of 160 mg (day 1) and 320 mg (day 2) of d-l sotalol. For each 24-hour period and each subject, ECGs were extracted every 10 minutes during the 4-hour period following drug dosage. Ventricular repolarization was characterized using three biomarker categories: conventional ECG time intervals, principal component analysis (PCA) analysis on the T wave, and fully automatic biomarkers computed from a mathematical model of the T wave.

RESULTS

QT interval was significantly prolonged starting 1 hour 20 minutes after drug dosing with 160 mg and 1 hour 10 minutes after drug dosing with 320 mg. PCA ventricular repolarization parameters sotalol-induced changes were delayed (>3 hours). After sotalol dosing, the early phase of the T wave changed earlier than the late phase prolongation. Globally, the modeled surrogate QT paralleled manual QT changes. The duration of manual QT and automatic surrogate QT were strongly correlated (R(2) = 0.92, P < 0.001). The Bland and Altman plot revealed a nonstationary systematic bias (bias = 26.5 ms + or - 1.96*SD = 16 ms).

CONCLUSIONS

Changes in different ECG biomarkers of ventricular repolarization display different kinetics after administration of a potent potassium channel blocker. These differences need to be taken into account when designing ventricular repolarization ECG studies.