Session S44.2

Measurements of the T-Loop Morphology to Describe the Effect of Sotalol on the Ventricular Repolarization in Healthy Subjects

JP Couderc*

University of Rochester Medical Center
Rochester, NY, USA

Background: The dissociation between a drug-induced increased of the QT interval prolongation and an increased risk for ventricular arrhythmias has been suggested by academic investigators and regulatory agencies. And because the QT/QTc prolongation is recognized as an imperfect surrogate marker of drug cardiotoxicity, regulators are in need of improved technologies for assessing cardiotoxicity of novel compounds. In this study, we investigated the drug-induced changes of parameters measuring both repolarization delay (QTc, QTc apex and TpTe intervals) and T-loop morphology and compare them in ECGs from healthy individuals exposed to a drug with torsadogenic properties.
Methods: In this study we describe a set of parameters describing the morphology of the T-loop in its preferential plan. These parameters measure the time interval needed for the heart vector to change from its maximum value (identified at the apex of the T-wave) to a time when its amplitude has been reduced by 30, 50 and 70%. When these measurements are located prior to the apex, they are called early repolarization duration (ERD), and late repolarization durations (LRD) when measured after the apex. These measurements depend on both the speed of the repolarization process and the morphology of the T-loop. We compared these parameters to QTc, QTc apex and TpTe interval when applied to first eigenvector computed from 12-lead ECGs. Thirty nine healthy individuals exposed to sotalol which is a torsadogenic drug known to prolong the QTc interval and profoundly change the kinetics of myocardial ion currents involved in the ventricular recovery phase. Following a cross-over design, sixteen ECGs were recorded per day during three days. The first day (Day 0) was baseline, a single dose of sotalol (160mg) was given during day 1 and a double dose during day 2 (320mg). The plasma concentration of the drug was measured just prior to the ECG recordings.
Results: All parameters reveal a dose-dependent effect of sotalol on their values. Our investigations describe rather profound and statistically significant changes in the morphology of the vectorial T-loop. When investigating the timing of peak drug concentration and peak effect of the drug on the various repolarization parameters, we found asynchrony between ERDs/LRDs and QTc/QTc apex profiles suggesting that the time of maximum delay on the repolarization process was not synchronized with the time of maximum drug-induced heterogeneity of repolarization.
Conclusion: This study describes the sotalol-induced changes of the T-loop morphology in healthy individuals based on novel Vectrocardiographic parameters. These observations might help improving the next generation of ECG markers for the evaluation of drug cardiotoxicity.

(Abstract Control Number: 6)