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

Abstract

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.

Figure 1

(A) Study design and time points for ECG extraction. (B) Biomarker categories: (1) manual cursors are set for both conventional ECG time intervals and markers derived from a PCA analysis on the T wave, (2) fully automatic biomarkers computation from the bi‐Gaussian function (BGF) model. (C) Left part: standard eight‐lead ECG change to PCA eight‐lead transformation. Right part: Bi‐Gaussian function model of the T wave.

Figure 2

Upper panel: time course of sotalol concentration after single‐dose administration (160 mg). Lower panels: sotalol effects on ventricular repolarization biomarkers expressed as a percentage change relative to the baseline period. H0 to H4: time after sotalol administration in hours (H).

Figure 3

Panel A: relationship between manual QT interval (x‐axis) and the automatic QT interval (y‐axis). Panel B: Bland and Altman plot of manually and automatically measured QT interval duration.

Figure 4

Upper panel: relationship between RR interval (x‐axis) and T‐wave amplitude (y‐axis). Lower panel: Drug's effects expressed as a percentage change relative to the baseline period on RR interval and T‐wave amplitude after sotalol 160 mg and 320 mg administration. H0 to H4: time after sotalol administration in hours (H).