Models of Human Atrial Action Potential for Sinus Rhythm and Chronic Atrial Fibrillation

Abstract

The ionic mechanisms underlying remodeled atrial action potentials (AP) in chronic atrial fibrillation (cAF), particularly the role of intracellular Ca2+ dynamics, remain unclear. Our objectives were: 1) to develop a new human atrial cell model by implementing structural and ionic differences in atrial vs. ventricular cells from our recently published model of human ventricular myocytes with detailed Ca2+ handling; 2) to simulate APs in cAF by accounting for structural and electrical remodeling, and using recent data on altered Ca2+ homeostasis. Ionic currents in the ventricular model were modified based on experimental data in atrial vs. ventricular myocytes. Decreasing IK1 amplitude produced a ∼10 mV depolarization shift in the atrial (vs. ventricular) resting membrane potential. Ito,fast density was increased in the atrium, Ito,slow was removed, and a formulation for the atrial-specific IKur was included. INaCa and INaK densities were reduced to account for lower protein expression in atrial vs. ventricular myocytes. The INaK diminution also caused [Na]i to rise. SERCA function was increased to reproduce faster [Ca2+]i decline and relaxation in atrial cells. To simulate recent measured changes in cAF, we reduced ICaL, Ito and IKur and SERCA, and increased IK1 and INCX. The baseline alterations to our ventricular model resulted in a typical type-3 human atrial AP morphology. Consistent with experimental findings, our sinus rhythm model showed reduced AP rate adaptation (i.e., shortening at increasing pacing frequencies) when partially blocking ICaL, and suggested a crucial role of Ca2+ and Na+ homeostasis in mediating this effect. This also explained impaired AP adaptation in cAF, with shorter APs. Our atrial model with detailed Ca2+ handling description provides a useful framework to study human cAF, as growing experimental evidence point to abnormal Ca2+ homeostasis as a key mediator in AF-pathophysiology.