In silico risk assessment for drug-induction of cardiac arrhythmia

The main components of repolarization reserve for the ventricular action potential (AP) are the rapid (I-Kr) and slow (I-Kr) delayed outward K+ currents. While many drugs block I-Kr and cause life-threatening arrhythmias including torsades de pointes, the frequency of arrhythmias varies between different I-Kr-blockers. Different types of block of I-Kr cause distinct phenotypes of prolongation of action potential duration (APD), increase in transmural dispersion of repolarization (TDR) and, accordingly, Occurrence of torsades de pointes. Therefore the assessment of a drug's proarrhythmic risk requires a method that provides quantitative and comprehensive comparison of the effects of different forms of I-Kr-blockade upon APDs and TDR. However, most currently available methods are not adapted to such an extensive comparison. Here, we introduce I-Kr-I-Ks two-dimensional maps of APD and TDR as a novel risk-assessment method. Taking the kinetics of I-Kr-blockade into account, APDs can be calculated upon a ventricular AP model which systematically alters the magnitudes of I-Kr and I-Ks. The calculated APDs are then plotted on a map where the x axis represents the conductance of I-Kr while the y axis represents that of I-Ks. TDR is simulated with models corresponding to APs in epicardial, midcardial and endocardial myocardium. These two-dimensional maps of APD and TDR Successfully account for differences in the risk resulting from three distinct types of I-Kr-blockade which correspond to the effects of dofetilide, quinidine and vesnarinone. This method may be of use to assess the arrhythmogenic risk of various I-Kr -blockers. (c) 2008 Elsevier Ltd. All rights reserved.