Human Atrial Action Potential and Ca 2+ Model

Abstract

Rationale: Understanding atrial fibrillation (AF) requires integrated understanding of ionic currents and Ca 2+ 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 (≈7 mV). We used higher I to,fast density in atrium, removed I to,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 Ca 2+ 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, [Ca 2+ ] 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 Ca 2+ and Na + in this effect. This also explained blunted Ca 2+ transient and rate-adaptation of [Ca 2+ ] 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 [Ca 2+ ] 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 Ca 2+ homeostases critically mediate abnormal repolarization in AF.

Rationale: Understanding atrial fibrillation (AF) requires integrated understanding of ionic currents and Ca 2+ 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 (≈7 mV). We used higher I to,fast density in atrium, removed I to,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 Ca 2+ 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, [Ca 2+ ] 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 Ca 2+ and Na + in this effect. This also explained blunted Ca 2+ transient and rate-adaptation of [Ca 2+ ] 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 [Ca 2+ ] 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 Ca 2+ homeostases critically mediate abnormal repolarization in AF.