Improved Prediction of Drug-Induced Torsades de Pointes Through Simulations of Dynamics and Machine Learning Algorithms.

ABSTRACT: The ventricular arrhythmia Torsades de Pointes (TdP) is a common form of drug-induced cardiotoxicity, but prediction of this arrhythmia remains an unresolved issue in drug development. Current assays to evaluate arrhythmia risk are limited by poor specificity and a lack of mechanistic insight. We addressed this important unresolved issue through a novel computational approach that combined simulations of drug effects on dynamics with statistical analysis and machine-learning. Drugs that blocked multiple ion channels were simulated in ventricular myocyte models, and metrics computed from the action potential and intracellular (Ca(2+) ) waveform were used to construct classifiers that distinguished between arrhythmogenic and nonarrhythmogenic drugs. We found that: (1) these classifiers provi

SUBMITTER: Lancaster MC 

PROVIDER: S-EPMC6375298 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature