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In silico risk assessment for drug-induction of cardiac arrhythmia

Shingo Suzuki1, Shingo Murakami, Kenji Tsujimae

  • 1Department of Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

Progress in Biophysics and Molecular Biology
|July 19, 2008
PubMed

Insights

New 2D maps assess drug risk by analyzing I(Kr) and I(Ks) currents. This method quantifies effects on action potential duration (APD) and transmural dispersion of repolarization (TDR), predicting torsades de pointes arrhythmia risk.

Area of Science:

  • Cardiovascular Pharmacology
  • Computational Biology
  • Electrophysiology

Background:

  • The ventricular action potential (AP) relies on rapid (I(Kr)) and slow (I(Ks)) outward K+ currents for repolarization.
  • Blockade of I(Kr) by drugs can lead to dangerous arrhythmias like torsades de pointes, with varying frequency depending on the drug.
  • Different I(Kr) block types produce distinct effects on AP duration (APD) and transmural dispersion of repolarization (TDR), influencing arrhythmia risk.

Purpose of the Study:

  • To introduce a novel method for quantitatively assessing the proarrhythmic risk of I(Kr)-blocking drugs.
  • To enable comprehensive comparison of how different I(Kr) blockade types affect APD and TDR.
  • To provide a tool for predicting drug-induced torsades de pointes risk.

Main Methods:

  • Development of I(Kr)-I(Ks) two-dimensional maps to visualize APD and TDR.
  • Calculation of APDs using a ventricular AP model with systematic alterations in I(Kr) and I(Ks) magnitudes.
  • Simulation of TDR using models for epicardial, midcardial, and endocardial myocardium.

Main Results:

  • The 2D maps successfully differentiate the arrhythmogenic risk associated with three distinct I(Kr)-blockade types (dofetilide, quinidine, vesnarinone).
  • The method accounts for variations in APD prolongation and TDR caused by different I(Kr) blockers.
  • Demonstrated correlation between map predictions and known clinical arrhythmia frequencies.

Conclusions:

  • I(Kr)-I(Ks) 2D maps offer a powerful new approach for assessing the proarrhythmic potential of drugs.
  • This method provides a quantitative and comprehensive comparison of drug effects on cardiac repolarization.
  • The tool can aid in predicting and mitigating the risk of drug-induced arrhythmias like torsades de pointes.

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