Integrative Physiology Human Atrial Action Potential and Ca2 Model Sinus Rhythm and Chronic Atrial Fibrillation

Rationale: Understanding atrial fibrillation (AF) requires integrated understanding of ionic currents and Ca2 transport in remodeled human atrium, but appropriate models are limited. Objective: To study AF, we developed a new human atrial action potential (AP) model, derived from atrial experimental results and our human ventricular myocyte model. Methods and Results: Atria versus ventricles have lower IK1, resulting in more depolarized resting membrane potential (7 mV). We used higher Ito,fast density in atrium, removed Ito,slow, and included an atrial-specific IKur. INCX and INaK densities were reduced in atrial versus ventricular myocytes according to experimental results. SERCA function was altered to reproduce human atrial myocyte Ca2 transients. To simulate chronic AF, we reduced ICaL, Ito, IKur and SERCA, and increased IK1,IKs and INCX. We also investigated the link between Kv1.5 channelopathy, [Ca2]i, and AF. The sinus rhythm model showed a typical human atrial AP morphology. Consistent with experiments, the model showed shorter APs and reduced AP duration shortening at increasing pacing frequencies in AF or when ICaL was partially blocked, suggesting a crucial role of Ca2 and Na in this effect. This also explained blunted Ca2 transient and rate-adaptation of [Ca2]i and [Na]i in chronic AF. Moreover, increasing [Na]i and altered INaK and INCX causes rate-dependent atrial AP shortening. Blocking IKur to mimic Kv1.5 loss-of-function increased [Ca2]i and caused early afterdepolarizations under adrenergic stress