A robust method for quantification of IKr-related T-wave morphology abnormalities

Abstract

The QTc interval plays an important role in premarket testing of new drugs, but the intrinsic variability of the measurement is critical. Most arrhythmogenic drugs inhibit the I <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Kr</sub> current and cause both QTc prolongation and changes in T-wave morphology. Quantification of T-wave morphology may be useful in drug testing, but no robust method exists for this purpose. We present a method for quantification of I <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Kr</sub> -related T-wave morphology changes: T-wave asymmetry, flatness and the presence of notches on the T-wave combined to an overall morphology combination score (MCS). In a population of 30 LQT2-subjects (congenital I <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Kr</sub> inhibition) and 1096 healthy subjects, both QTcF and MCS yield clear separation between the groups (p<0.001), sensitivity 90%, specificity 95%.