Prediction of arrhythmia susceptibility through mathematical modeling and machine learning

At present, the QT interval on the electrocardiographic (ECG) waveform is the most common metric for assessing an individual's susceptibility to ventricular arrhythmias, with a long QT, or, at the cellular level, a long action potential duration (APD) considered high risk. However, the limitations of this simple approach have long been recognized. Here, we sought to improve prediction of arrhythmia susceptibility by combining mechanistic mathematical modeling with machine learning (ML). Simulations with a model of the ventricular myocyte were performed to develop a large heterogenous population of cardiomyocytes (n = 10,586), and we tested each variant's ability to withstand three arrhythmogenic triggers: 1) block of the rapid delayed rectifier potassium current (I_Kr Block), 2) augmentation of the L-type calcium current (I_CaL Increase), and 3) injection of inward current (Current Injection). Eight ML algorithms were trained to predict, based on simulated AP features in preperturbed cells, whether each cell would develop arrhythmic dynamics in response to each trigger. We found that APD can accurately predict how cells respond to the simple Current Injection trigger but cannot effectively predict the response to I_Kr Block or I_CaL Increase. ML predictive performance could be improved by incorporating additional AP features and simulations of additional experimental protocols. Importantly, we discovered that the most relevant features and experimental protocols were trigger specific, which shed light on the mechanisms that promoted arrhythmia formation in response to the triggers. Overall, our quantitative approach provides a means to understand and predict differences between individuals in arrhythmia susceptibility.