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 (IKr) and slow (IKs) delayed outward K+ currents. While many drugs block IKr and cause life-threatening arrhythmias including torsades de pointes, the frequency of arrhythmias varies between different IKr-blockers. Different types of block of IKr 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 IKr-blockade upon APDs and TDR. However, most currently available methods are not adapted to such an extensive comparison. Here, we introduce IKr–IKs two-dimensional maps of APD and TDR as a novel risk-assessment method. Taking the kinetics of IKr-blockade into account, APDs can be calculated upon a ventricular AP model which systematically alters the magnitudes of IKr and IKs. The calculated APDs are then plotted on a map where the x axis represents the conductance of IKr while the y axis represents that of IKs. 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 IKr-blockade which correspond to the effects of dofetilide, quinidine and vesnarinone. This method may be of use to assess the arrhythmogenic risk of various IKr-blockers.