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

Abstract

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 APD90, 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 ICaL, INCX, and IKr, and decreases in IK1, Ib,Cl, IKur, ISERCA, and Ito are correlated with higher Smax values. The LIME algorithm determined that INaK plays a significant role in determining Smax as well as Ito and IKur. 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 INaK 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 INaK in heterogeneous behaviors of Smax in the atrial cardiomyocyte population.

Effects of hydroxychloroquine on atrial electrophysiology in in silico wild-type and PITX2+/- atrial cardiomyocytes

“…The copyright holder for this preprint this version posted December 11, 2022. ; https://doi.org/10.1101/2022.12.07.519115 doi: bioRxiv preprint would provide more statistically robust results by considering the biological uncertainty/variability in ion channel parameters [17,25,31,32]. Since atrial cell models have pacing protocol-dependent memory effects [56], various pacing protocol-related sensitivity analyses should be considered to obtain more robust and reliable results [57].…”

“…For each PCL, the cell was stimulated for 16 beats. The APD (or ΔCaT) alternans were evaluated by determining the maximum and minimum APD (or ΔCaT) values in the last three beats that differed by more than 2% [32]. We considered the beat-to-beat APD variation>10% as prominent APD alternans.…”

“…The copyright holder for this preprint this version posted December 11, 2022. ; https://doi.org/10.1101/2022.12.07.519115 doi: bioRxiv preprint At a pacing cycling length (PCL) of 1000 ms (=1 Hz), we measured the APD at 90% of repolarization (APD90), APD at 50% of repolarization (APD50), resting membrane potential (RMP), maximum upstroke velocity (Vmax), and calcium transient amplitude (ΔCaT) [31,32]. A steady state was achieved by stimulating the cells for 60 s. The ΔCaT was defined as the difference between the maximum and minimum intracellular Ca 2+ concentrations [31][32][33].…”

“…The copyright holder for this preprint this version posted December 11, 2022. ; https://doi.org/10.1101/2022.12.07.519115 doi: bioRxiv preprint At a pacing cycling length (PCL) of 1000 ms (=1 Hz), we measured the APD at 90% of repolarization (APD90), APD at 50% of repolarization (APD50), resting membrane potential (RMP), maximum upstroke velocity (Vmax), and calcium transient amplitude (ΔCaT) [31,32]. A steady state was achieved by stimulating the cells for 60 s. The ΔCaT was defined as the difference between the maximum and minimum intracellular Ca 2+ concentrations [31][32][33]. We also estimated the refractory period and APD (or ΔCaT) alternans threshold cycle lengths using a dynamic ramp pacing protocol as previously described [32]: PCLs of 1000, 600, and 500 ms were used, and the PCL was decreased to 300 ms in steps of 50 ms and further decreased in steps of 10 ms until failure of 1:1 capture.…”

“…A steady state was achieved by stimulating the cells for 60 s. The ΔCaT was defined as the difference between the maximum and minimum intracellular Ca 2+ concentrations [31][32][33]. We also estimated the refractory period and APD (or ΔCaT) alternans threshold cycle lengths using a dynamic ramp pacing protocol as previously described [32]: PCLs of 1000, 600, and 500 ms were used, and the PCL was decreased to 300 ms in steps of 50 ms and further decreased in steps of 10 ms until failure of 1:1 capture. For each PCL, the cell was stimulated for 16 beats.…”