Interpretable machine learning of action potential duration restitution kinetics in single-cell models of atrial cardiomyocytes

Action potential duration (APD) restitution curve and its maximal slope (Smax) reflect single cell-level dynamic instability for inducing chaotic heart rhythms. However, conventional parameter sensitivity analysis often fails to describe nonlinear relationships between ion channel parameters and electrophysiological phenotypes, such as Smax. We explored the parameter–phenotype mapping in a population of 5,000 single-cell atrial cell models through interpretable machine learning (ML) approaches. Parameter sensitivity analyses could explain the linear relationships between parameters and electrophysiological phenotypes, including APD 90 , resting membrane potential, Vmax, refractory period, and APD/calcium alternans threshold, but not for Smax. However, neural network models had better prediction performance for Smax. To interpret the ML model, we evaluated the parameter importance at the global and local levels by computing the permutation feature importance and the local interpretable model-agnostic explanations (LIME) values, respectively. Increases in I CaL , I NCX , and I Kr , and decreases in I K1 , I b,Cl , I Kur , I SERCA , and I to are correlated with higher Smax values. The LIME algorithm determined that INaK plays a significant role in determining Smax as well as Ito and I Kur . The atrial cardiomyocyte population was hierarchically clustered into three distinct groups based on the LIME values and the single-cell simulation confirmed that perturbations in I NaK resulted in different behaviors of APD restitution curves in three clusters. Our combined top-down interpretable ML and bottom-up mechanistic simulation approaches uncovered the role of I NaK in heterogeneous behaviors of Smax in the atrial cardiomyocyte population.