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

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Publisher
I E E E Computer Society
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Disciplines
  • Communication
  • Pharmacology

Abstract

Title A Robust Method for Quantification of IKr-Related T-Wave Morphology Abnormalities MP Andersen 1 , JQ Xue 2 , C Graff 1 , TB Hardahl 1 , E Toft 1,3 , JK Kanters 3,4 , M Christiansen 5 , HK Jensen 6 , JJ Struijk 1 1 Department of Health Science and Technology, Aalborg University, Aalborg, Denmark 2 GE Healthcare, Milwaukee, WI, USA 3 Gentofte and Aalborg University Hospital, Denmark 4 Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), University of Copenhagen, Copenhagen, Denmark 5 Statens Seruminstitut 6 Aarhus University Hospital Skejby, Aarhus, Denmark Abstract The QTc interval plays an important role in pre- market testing of new drugs, but the intrinsic variability of the measurement is critical. Most arrhythmogenic drugs inhibit the IKr 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 IKr-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 IKr inhibition) and 1096 healthy subjects, both QTcF and MCS yield clear separation between the groups (p<0.001), sensitivity 90%, specificity 95%. 1. Introduction The QTc interval is the most commonly used measure to quantify repolarization abnormalities. It is a well- known requirement to measure QTc interval prolongation in “Thorough QT Studies” during the pre-marketing phase of drug evaluation. Still it is widely recognized by the scientific environment, the pharmaceutical industry and the relevant authorities that QTc is associated with limited sensitivity and extensive variability.[1] Most of the drugs deemed arrhythmogenic and withdrawn from the market have b

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