title: A new ECG biomarker for drug toxicity: a combined signal processing and computational modeling study.
abstract: QT prolongation is the only clinically proven, yet insufficient, electrocardiogram (ECG) biomarker for drug-induced cardiac toxicity. The goal of this study is to evaluate whether JT area, i.e., total area of the T-wave, can serve as an ECG biomarker for drug-induced cardiac toxicity using both signal processing and computational modeling approaches. An ECG dataset that contained recordings from patients under control and sotalol condition was analyzed. In order to relate sotalol-induced ECG changes to its effect on ion channel level, i.e., blockade of the rapid component of the delayed rectifier potassium channel (I(Kr)), varied degrees of I(Kr) blockade were simulated in a slab of ventricular tissue. The mean JT area increased by 36.5% following the administration of sotalol in patients. Simulations in the slab tissue showed that sotalol increased action potential duration preferentially in the midmyocardium, which led to increased transmural dispersion of repolarization and JT area. In conclusion, JT area reflects the transmural dispersion of repolarization and may be a potentially useful surrogate/supplemental ECG biomarker to assess drug safety.
authors.affiliation: Computing Laboratory, Oxford University, OX1 3QD, UK. xiao.jie@comlab.ox.ac.uk
authors.forename: Xiao
authors.initials: X
authors.lastname: Jie
authors.forename: Blanca
authors.initials: B
authors.lastname: Rodriguez
authors.forename: Esther
authors.initials: E
authors.lastname: Pueyo
mesh_terms: D000200:Action Potentials; D000465:Algorithms; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000633:toxicity*; D015415:Biomarkers; D003198:Computer Simulation; D004562:Electrocardiography / Q000379:methods*; D006801:Humans; D007473:Ion Channels / Q000737:chemistry; D007477:Ions; D015233:Models, Statistical; D012815:Signal Processing, Computer-Assisted; D012984:Software; D013015:Sotalol / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D007473:Ion Channels; D007477:Ions; D013015:Sotalol