In silico risk assessment for drug-induction of cardiac arrhythmia

• Published in: Progress in biophysics and molecular biology Vol. 98; no. 1; pp. 52 - 60
• Main Authors: Suzuki, Shingo, Murakami, Shingo, Tsujimae, Kenji, Findlay, Ian, Kurachi, Yoshihisa
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2008
• Subjects: Action Potentials - drug effects; Animals; Anti-Arrhythmia Agents - pharmacology; Arrhythmias, Cardiac - chemically induced; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - pathology; Biophysics - methods; Cardiac action potential; Cardiac arrhythmia; Computational Biology - methods; Heart Ventricles - drug effects; Humans; IKr blocker; Mapping; Phenotype; Potassium Channel Blockers - pharmacology; Risk; Risk Assessment; Software; Torsades de Pointes - chemically induced; Torsades de Pointes - etiology; Cardiac arrhythmia; Cardiac action potential; I Kr blocker; Mapping
• ISSN: 0079-6107; 1873-1732
• DOI: 10.1016/j.pbiomolbio.2008.05.003

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.