The time course of new T-wave ECG descriptors following single- and double-dose administration of sotalol in healthy subjects.
BACKGROUND
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.
Lariboisière Hospital, APHP, Paris 7 University, INSERM U942, Paris, France. fabrice.extramiana@lrb.aphp.fr
Fabrice
F
Extramiana
Rémi
R
Dubois
Martino
M
Vaglio
Pierre
P
Roussel
Gerard
G
Dreyfus
Fabio
F
Badilini
Antoine
A
Leenhardt
Pierre
P
Maison-Blanche
D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000097:blood; D015415:Biomarkers / Q000097:blood; D004305:Dose-Response Relationship, Drug; D019560:Echocardiography, Three-Dimensional / Q000379:methods / Q000706:statistics & numerical data; D015716:Electrocardiography, Ambulatory / Q000187:drug effects* / Q000379:methods / Q000706:statistics & numerical data*; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D016011:Normal Distribution; D025341:Principal Component Analysis / Q000379:methods; D012016:Reference Values; D015203:Reproducibility of Results; D012815:Signal Processing, Computer-Assisted; D013015:Sotalol / Q000008:administration & dosage* / Q000097:blood; D013997:Time Factors; D014672:Vectorcardiography / Q000379:methods / Q000706:statistics & numerical data
D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D013015:Sotalol