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 I-K1, resulting in more depolarized resting membrane potential (approximate to 7 mV). We used higher I-to,I-fast density in atrium, removed I-to,I-slow, and included an atrial-specific I-Kur. I-NCX and I-NaK 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 I-CaL, I-to, I-Kur and SERCA, and increased I-K1,I-Ks and I-NCX. 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 I-CaL 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 I-NaK and I-NCX causes rate-dependent atrial AP shortening. Blocking I-Kur to mimic Kv1.5 loss-of-function increased [Ca2+](i) and caused early afterdepolarizations under adrenergic stress, as observed experimentally. Conclusions: Our study provides a novel tool and insights into ionic bases of atrioventricular AP differences, and shows how Na+ and Ca2+ homeostases critically mediate abnormal repolarization in AF. (Circ Res. 2011;109:1055-1066.)