The main components of repolarization reserve for the ventricular action potential (AP) are the rapid (
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Kr) and slow (
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Ks) delayed outward K
+ currents. While many drugs block
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Kr and cause ...life-threatening arrhythmias including
torsades de pointes, the frequency of arrhythmias varies between different
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Kr-blockers. Different types of block of
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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
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Kr-blockade upon APDs and TDR. However, most currently available methods are not adapted to such an extensive comparison. Here, we introduce
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Kr–
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Ks two-dimensional maps of APD and TDR as a novel risk-assessment method. Taking the kinetics of
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Kr-blockade into account, APDs can be calculated upon a ventricular AP model which systematically alters the magnitudes of
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Kr and
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Ks. The calculated APDs are then plotted on a map where the
x axis represents the conductance of
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Kr while the
y axis represents that of
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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
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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
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Kr-blockers.
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