Human Atrial Action Potential and Ca 2+ Model
Open Access
- 14 October 2011
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 109 (9), 1055-1066
- https://doi.org/10.1161/circresaha.111.253955
Abstract
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, 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.Keywords
This publication has 65 references indexed in Scilit:
- Local control of β-adrenergic stimulation: Effects on ventricular myocyte electrophysiology and Ca2+-transientJournal of Molecular and Cellular Cardiology, 2011
- Deja vu in the theories of atrial fibrillation dynamicsCardiovascular Research, 2010
- Targeting atrioventricular differences in ion channel properties for terminating acute atrial fibrillation in pigsCardiovascular Research, 2010
- The ryanodine receptor channel as a molecular motif in atrial fibrillation: pathophysiological and therapeutic implicationsCardiovascular Research, 2010
- Synergy between CaMKII Substrates and β-Adrenergic Signaling in Regulation of Cardiac Myocyte Ca2+ HandlingBiophysical Journal, 2010
- A novel computational model of the human ventricular action potential and Ca transientJournal of Molecular and Cellular Cardiology, 2010
- Repolarization and Activation Restitution Near Human Pulmonary Veins and Atrial Fibrillation Initiation: A Mechanism for the Initiation of Atrial Fibrillation by Premature BeatsJournal of the American College of Cardiology, 2008
- Dynamics of human atrial cell models: Restitution, memory, and intracellular calcium dynamics in single cellsProgress in Biophysics and Molecular Biology, 2008
- Cellular bases for human atrial fibrillationHeart Rhythm, 2008
- Regional and tissue specific transcript signatures of ion channel genes in the non‐diseased human heartJournal Of Physiology-London, 2007