In Silico Modeling and Validation of the Effect of Calcium-Activated Potassium Current on Ventricular Repolarization in Failing Myocytes.

Abstract

The pathophysiological role of the small conductance calcium-activated potassium (SK) channels in human ventricular myocytes remains unclear. Experimental studies have reported upregulation of SK channels in pathological states, potentially contributing to ventricular repolarization. In heart failure (HF) patients, this upregulation could be an adaptive physiological response to shorten the action potential duration (APD) under conditions of reduced repolarization reserve. This work aimed to uncover the contribution of SK channels to ventricular repolarization in failing myocytes. We extended an in silico electrophysiological model of human ventricular failing myocytes by including SK channel activity. To calibrate the maximal SK current conductance (G$_{{SK}}$), we simulated action potentials (APs) at different pacing frequencies and matched the AP duration changes induced by SK channel inhibition or activation to different available experimental data from human failing ventricles for adjustment. The optimal value obtained for G$_{{SK}}$ was 4.288 $\mu$S/$\mu$F in mid-myocardial cells, and 6.4 $\mu$S/$\mu$F for endocardial and epicardial cells. The output of the models was compared with independent experimental data for validation. 1-D simulations of a transmural ventricular fiber indicated that SK channel block may prolong the QT interval and increase the transmural dispersion of repolarization, potentially increasing the risk of arrhythmia in HF. Our results highlight the importance of considering the SK channels to improve the characterization of HF-induced ventricular remodeling. Simulations across various single-cell and 1-D scenarios suggest that pharmacological SK channel inhibition could lead to adverse effects in failing ventricles.