Independent derivations of the axis of arrhythmia for predicting drug-induced torsades de pointes

Abstract

Background and purpose: Torsades de pointes is a potentially lethal ventricular arrhythmia that can be induced by many classes of drugs. The risk for a given drug depends upon the combination of cardiac ion channels that it targets. The axis of arrhythmia quantifies that risk. It is a conceptual line in the electrophysiology that describes the most potent combination of ion channel blocks that is theoretically possible. The axis thus serves as a convenient yardstick for quantifying the pro-arrhythmic risk of real drugs. Until now, the axis of arrhythmia has only been derived from biophysical computer simulations.

Experimental approach: Here, we derive the axis directly from the response profiles of four key cardiac ion currents $(I_{\text{CaL}},I_{\text{Kr}},I_{\text{NaL}}$ and $I_{\text{Ks}})$ using publicly available drug datasets. The new method provides an independent line of evidence for the axis of arrhythmia.

Key results: Following a process of step-wise reduction, the two methods were found to converge to identical estimates of the axis in two ion currents $(I_{\text{CaL}}$ and $I_{\text{Kr}})$ . The final estimate of the axis predicted the pro-arrhythmic risk of the drugs (n=109) with 89.9% to 91.7% accuracy.

Conclusion and implications: The axis of arrhythmia offers a practical method for predicting the pro-arrhythmic risk of novel drugs prior to clinical trials, without the need for drug-specific computer simulations. It is the only metric of pro-arrhythmic risk that has been derived from both a biophysical model and a statistical model. It thus combines the benefits of biophysical interpretation and computational efficiency when assessing torsadogenic risk.

Keywords: axis of arrhythmia; pro‐arrhythmic risk; safety pharmacology; torsades de pointes.