Assessing drug safety by identifying the axis of arrhythmia in cardiomyocyte electrophysiology

Heitmann, Stewart and Vandenberg, Jamie I and Hill, Adam P (2023) Assessing drug safety by identifying the axis of arrhythmia in cardiomyocyte electrophysiology. eLife, 12. ISSN 2050-084X

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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 (I(Kr)). Yet the risk is better assessed using four key ion currents (I(Kr), I(CaL), I(NaL), I(Ks)). 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 with an accuracy of 88.1-90.8%. Pharmacologists can use our method to assess the safety of novel drugs without resorting to animal testing or unwieldy computer simulations.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 02 May 2024 06:26
Last Modified: 02 May 2024 06:26

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