Key result
The axis of arrhythmia metric predicted the clinical arrhythmogenic risk labels of 109 drugs with an accuracy of 88.1% to 90.8% across various dosages.
Why the study?
Standard drug safety protocols focus primarily on IKr blockade, but pro-arrhythmic risk is better assessed using four key ion currents (IKr, ICaL, INaL, IKs).
Does the axis of arrhythmia metric accurately predict the pro-arrhythmic risk of drugs in simulated cardiomyocytes compared to conventional hERG assays?
Does the axis of arrhythmia metric accurately predict the pro-arrhythmic risk of drugs in simulated cardiomyocytes compared to conventional hERG assays?
A novel computational metric based on the axis of arrhythmia accurately predicts the pro-arrhythmic risk of drugs using multi-channel block profiles without requiring complex drug-specific simulations.
Multi-current cardiomyocyte simulations may refine pro-arrhythmic risk assessment beyond IKr; leaves open regulatory adoption pending validation.
Many classes of drugs can induce fatal cardiac arrhythmias by disrupting the electrophysiology of cardiomyocytes. Safety guidelines thus require all new drugs to be assessed for pro-arrhythmic risk prior to conducting human trials. The standard safety protocols primarily focus on drug blockade of the delayed-rectifier potassium current (IKr). Yet the risk is better assessed using four key ion currents (IKr, ICaL, INaL, IKs). We simulated 100,000 phenotypically diverse cardiomyocytes to identify the underlying relationship between the blockade of those currents and the emergence of ectopic beats in the action potential. We call that relationship the axis of arrhythmia. It serves as a yardstick for quantifying the arrhythmogenic risk of any drug from its profile of multi-channel block alone. We tested it on 109 drugs and found that it predicted the clinical risk labels to an accuracy of 88.1% to 90.8%. Pharmacologists can use our method to assess the safety of novel drugs without resort to animal testing nor unwieldy computer simulations.
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Heitmann et al. (2023) studied Drug-induced cardiac arrhythmias (Torsades des Pointes) (n=109). Axis of arrhythmia risk metric vs. Clinical risk labels (Credible Meds) was evaluated on Prediction accuracy of clinical risk labels (UNSAFE vs SAFE). The axis of arrhythmia metric predicted the clinical arrhythmogenic risk labels of 109 drugs with an accuracy of 88.1% to 90.8% across various dosages.
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