Digital twin for sex-specific identification of class III antiarrhythmic drugs based on in vitro measurements,...

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.