Digital twin for sex-specific identification of class III antiarrhythmic drugs based on in vitro measurements, computer models, and machine learning tools

Atrial fibrillation (AF) significantly affects morbidity and mortality rates. Class III antiarrhythmic drugs (AADs) play a crucial role in managing AF but often exhibit gender-specific complications. Our study aims to identify gender-specific Class III AADs by integrating in vitro measurements, in silico models, and machine learning (ML). By simulating drug effects on a diverse cardiomyocyte model population (5,663 males and 6,184 females), we classified drugs based on changes in action potentials and calcium transients. Using sex-dependent Support Vector Machine (SVM) algorithms, we achieved high prediction accuracy (>89%) and F1 score (>87%). Key features included changes in resting membrane potential and action potential amplitude, duration and area. Gender differences in drug responses were attributed to lower IK1, INa, and Ito in females.