The contribution of ionic currents to rate-dependent action potential duration and pattern of reentry in a mathematical model of human atrial fibrillation

Persistent atrial fibrillation (PeAF) in humans is characterized by shortening of action potential duration (APD) and attenuation of APD rate-adaptation. However, the quantitative influences of particular ionic current alterations on rate-dependent APD changes, and effects on patterns of reentry in atrial tissue, have not been systematically investigated. Using mathematical models of human atrial cells and tissue and performing parameter sensitivity analysis, we evaluated the quantitative contributions to action potential (AP) shortening and APD rate-adaptation of ionic current remodeling seen with PeAF. Ionic remodeling in PeAF was simulated by reducing L-type Ca²⁺ channel current (I_CaL), increasing inward rectifier K+ current (I_K1) and modulating five other ionic currents. Parameter sensitivity analysis, which quantified how each ionic current influenced APD in control and PeAF conditions, identified interesting results, including a negative effect of Na⁺/Ca²⁺ exchange on APD only in the PeAF condition. At high pacing rate (2 Hz), electrical remodeling in I_K1 alone accounts for the APD reduction of PeAF, but at slow pacing rate (0.5 Hz) both electrical remodeling in I_CaL alone (-70%) and I_K1 alone (+100%) contribute equally to the APD reduction. Furthermore, AP rate-adaptation was affected by I_Kur in control and by I_NaCa in the PeAF condition. In a 2D tissue model, a large reduction (-70%) of I_CaL becomes a dominant factor leading to a stable spiral wave in PeAF. Our study provides a quantitative and unifying understanding of the roles of ionic current remodeling in determining rate-dependent APD changes at the cellular level and spatial reentry patterns in tissue.