Ionic modulators of electrophysiology and re-entry properties in human atria

Current drugs used to treat atrial fibrillation (AF) often target tissue excitability (sodium channels) and refractoriness (hERG channels), but their efficacy is still modest. This study focuses on investigating new approaches to manage AF by conducting a systematic computer simulation study. The Maleckar action potential (AP) model was used to simulate human atrial cellular and tissue electrophysiology in control and AF-related electrically remodeled (AFER) conditions. Steady-state cellular AP duration (APD) and resting potential (V_rest), as well as tissue properties, such as refractory period (ERP), conduction velocity (CV) and reentrant dominant frequency (DF) were quantified for default conditions and following changes in model parameters. Results are compared to experimental data from the literature for validation. Results show the fundamental role of the Na⁺/K⁺ pump in electrophysiology and rotor dynamics in human atria through modulation of APD and ERP. I_K1 controls re-entrant DF through modulation of AP, ERP and CV. Furthermore, the fast Na⁺ current (I_Na) is key in determining DF through modulation of CV. The mechanisms underlying human atrial electrophysiological properties were qualitatively similar in control and AFER, although changes in ionic currents generally had smaller effects in AFER.