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(Ks)) 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.
Suzuki
Shingo
S
Department of Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Murakami
Shingo
S
Tsujimae
Kenji
K
Findlay
Ian
I
Kurachi
Yoshihisa
Y
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D001703:Biophysics / Q000379:methods; D019295:Computational Biology / Q000379:methods*; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012306:Risk; D018570:Risk Assessment; D012984:Software; D016171:Torsades de Pointes / Q000139:chemically induced / Q000209:etiology
D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers