Heitmann, Stewart and Vandenberg, Jamie I. and Hill, Adam P. (2025) Independent derivations of the axis of arrhythmia for predicting drug‐induced torsades de pointes. British Journal of Pharmacology, 182 (18). pp.4299-4313. ISSN 0007-1188
Full text not available from this repository.Abstract
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 and 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 and . 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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 03 Nov 2025 02:44 |
| Last Modified: | 03 Nov 2025 02:44 |
| URI: | http://eprints.victorchang.edu.au/id/eprint/1744 |
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