Reviewer #2 (Public Review): Assessing drug safety by identifying the axis of arrhythmia in cardiomyocyte electrophysiology

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.Many classes of drugs interfere with the electrical signaling of the heart, leading to arrhythmias and cardiac arrest. Newly developed drugs must therefore undergo mandatory safety testing in animals prior to human trials. Computational models of cardiac electrophysiology offer an ethical alternative but the current methods are difficult to apply beyond specialist computing laboratories. This study uses such models to identify the underlying relationship between drugs and cardiac arrhythmias. Those findings are then translated into a compact metric that can be applied using simple pen and paper calculations. The new metric allows pharmacology laboratories to assess the safety of novel drugs without using animals nor unwieldy computer simulations.