Ionic determinants of functional reentry in a 2-D model of human atrial cells during simulated chronic atrial fibrillation.
Recent studies suggest that atrial fibrillation (AF) is maintained by fibrillatory conduction emanating from a small number of high-frequency reentrant sources (rotors). Our goal was to study the ionic correlates of a rotor during simulated chronic AF conditions. We utilized a two-dimensional (2-D), homogeneous, isotropic sheet (5 x 5 cm(2)) of human atrial cells to create a chronic AF substrate, which was able to sustain a stable rotor (dominant frequency approximately 5.7 Hz, rosette-like tip meander approximately 2.6 cm). Doubling the magnitude of the inward rectifier K(+) current (I(K1)) increased rotor frequency ( approximately 8.4 Hz), and reduced tip meander (approximately 1.7 cm). This rotor stabilization was due to a shortening of the action potential duration and an enhanced cardiac excitability. The latter was caused by a hyperpolarization of the diastolic membrane potential, which increased the availability of the Na(+) current (I(Na)). The rotor was terminated by reducing the maximum conductance (by 90%) of the atrial-specific ultrarapid delayed rectifier K(+) current (I(Kur)), or the transient outward K(+) current (I(to)), but not the fast or slow delayed rectifier K(+) currents (I(Kr)/I(Ks)). Importantly, blockade of I(Kur)/I(to) prolonged the atrial action potential at the plateau, but not at the terminal phase of repolarization, which led to random tip meander and wavebreak, resulting in rotor termination. Altering the rectification profile of I(K1) also slowed down or abolished reentrant activity. In combination, these simulation results provide novel insights into the ionic bases of a sustained rotor in a 2-D chronic AF substrate.
Pandit
Sandeep V
SV
Institute for Cardiovascular Research and Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
Berenfeld
Omer
O
Anumonwo
Justus M B
JM
Zaritski
Roman M
RM
Kneller
James
J
Nattel
Stanley
S
Jalife
José
J
D000200:Action Potentials; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000503:physiopathology*; D055592:Biophysical Phenomena; D001703:Biophysics; D020746:Calcium Channels, L-Type / Q000502:physiology; D002908:Chronic Disease; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000502:physiology*; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D015222:Sodium Channels / Q000502:physiology
D000889:Anti-Arrhythmia Agents; D020746:Calcium Channels, L-Type; D007473:Ion Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D015222:Sodium Channels