Human atrial action potential and Ca2+ model: sinus rhythm and chronic atrial fibrillation

Grandi, E., Pandit, S.V., Voigt, N., Workman, A.J. , Dobrev, D., Jalife, J. and Bers, D.M. (2011) Human atrial action potential and Ca2+ model: sinus rhythm and chronic atrial fibrillation. Circulation Research, 109(9), pp. 1055-1066. (doi: 10.1161/CIRCRESAHA.111.253955)

Abstract

<b>Rationale:</b> Understanding atrial fibrillation (AF) requires integrated understanding of ionic currents and Ca2+ transport in remodeled human atrium, but appropriate models are limited. <br></br> <b>Objective:</b> To study AF, we developed a new human atrial action potential (AP) model, derived from atrial experimental results and our human ventricular myocyte model. <br></br> <b>Methods and Results:</b> 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 Kv 1.5 loss-of-function increased [Ca2+]i and caused early afterdepolarizations under adrenergic stress, as observed experimentally. <br></br> <b>Conclusions:</b> Our study provides a novel tool and insights into ionic bases of atrioventricular AP differences, and shows how Na+ and Ca2+ homeostasis critically mediate abnormal repolarization in AF.

• Item Type: Articles
• Additional Information: Due to publisher policy the full text of this paper will not be available until 6 months after publication.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Workman, Dr Antony
• Authors: Grandi, E., Pandit, S.V., Voigt, N., Workman, A.J., Dobrev, D., Jalife, J., and Bers, D.M.
• Subjects: Q Science > QP Physiology
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Circulation Research
• ISSN: 0009-7330