The risk of life-threatening ventricular tachyarrhythmia such as Torsades de Pointes (TdP) is
assessed in drug trials by measurement of QT prolongation on the ECG. However, the QT interval
is not a strong biomarker for TdP risk. Especially, the sensitivity and specificity of the measurement
is limited. Investigation of alternative biomarkers to assess the risk of drug-induced arrhythmia is
therefore an active area of research. Much of the current research is based on the drug-induced
changes in the morphology of the T-wave.
Drug-induced inhibition of the delayed rectifier potassium current (IKr) can cause delayed cardiac
repolarization and lead to development of TdP. Inhibition of the potassium current appears as QT
interval prolongation and changes in the morphology of the T-wave on the ECG. IKr inhibiting
drugs and their effect on ECG markers of abnormal repolarization therefore play a central role in
In our first study, we used common classification methods to separate congenital and drug-induced
IKr inhibition from healthy controls who were not taking any medication during the trial period. We
investigated separation of data by two electrocardiographic repolarization parameters: The heart
rate-corrected QT interval (QTc) and the MCS, a composite score of T-wave morphology which
measures flatness, asymmetry and the presence of notches on the ECG. Changes in the T-wave
morphology were better at separating normal from abnormal repolarization compared to QTc. Also,
nonlinear boundaries can provide better classifiers than linear boundaries.
In our second study we investigated the electrocardiographic T-wave peak-to-end interval (Tpe), a
commonly used measurement, thought to represent transmural repolarization heterogeneity.
Repolarization heterogeneities induced by torsadogenic drugs are thought to be responsible for
inscription of electrocardiographic T-wave and the QT interval. However, there is no widely
accepted approach which can be used to assess repolarization heterogeneity. The Tpe interval was
proposed to quantify transmural dispersion of repolarization (Tdr) in previous vitro experiments.
However, there have been an increasing number of reports of inconsistencies about whether the Tpe
interval can be used to predict arrhythmia. It also remains controversial what the Tpe measurements
actually represents. However, it is important to quantify how the Tpe interval is correlated with the
whole heart repolarization time, represented by the QT interval. We therefore investigated whether
the Tpe interval is correlated with QT prolongation induced by two torsadogenic drugs. Despite
significant QT prolongation with both IKr-inhibiting drugs, the Tpe interval remained almost
unchanged. Thus, at least, this study raises a doubt about usefulness of Tpe as a biomarker for
repolarization changes and torsadogenic potential in drug safety studies.
In our third study we propose a new method for assessing abnormal repolarization characteristics on
the ECG. The T-wave is down-sampled to a minimal number of samples in such a way that
reconstruction of the original T-wave is possible. Using a combination of 8 samples extracted from
the down-sampled T-wave as features it was possible to separate normal from abnormal
repolarization significantly better compared to QTc. In addition, this approach has the advantage,
unlike the QT interval, of being robust to the T-wave end determination. In the down-sampled ECG
representation of the T-wave, it is further indicated that Tpe interval may shorten following IKr
inhibition and that the most prominent drug-induced repolarization changes occur on the ascending
segment of the minimal T-wave representation.
Collectively, this work may lead to improved prediction and interpretation of ECG-related