Ionic Remodeling Underlying Action Potential Changes in a Canine Model of Atrial Fibrillation

Abstract Rapid electrical activation, as occurs during atrial fibrillation (AF), is known to cause reductions in atrial refractoriness and in adaptation to heart rate of the atrial refractory period, which promote the maintenance of AF, but the underlying ionic mechanisms are unknown. In order to determine the cellular and ionic changes caused by chronic atrial tachycardia, we studied right atrial myocytes from dogs subjected to 1, 7, or 42 days of atrial pacing at 400/min and compared them with myocytes from sham-operated dogs (pacemaker inserted but not activated). Rapid pacing led to progressive increases in the duration of AF induced by bursts of 10-Hz stimuli (from 3±2 seconds in sham-operated dogs to 3060±707 seconds in dogs after 42 days of pacing, P <.001) and reduced atrial refractoriness and adaptation to rate of the atrial refractory period. Voltage-clamp studies showed that chronic rapid pacing did not alter inward rectifier K + current, rapid or slow components of the delayed rectifier current, the ultrarapid delayed rectifier current, T-type Ca 2+ current, or Ca 2+ -dependent Cl − current. In contrast, the densities of transient outward current ( I to ) and L-type Ca 2+ current ( I Ca ) were progressively reduced as the duration of rapid pacing increased, without concomitant changes in kinetics or voltage dependence. In keeping with in vivo changes in refractoriness, action potential duration (APD) and APD adaptation to rate were decreased by rapid pacing. The response of the action potential and ionic currents flowing during the action potential (as exposed by action-potential voltage clamp) to nifedipine in normal canine cells and in cells from rapidly paced dogs suggested that the APD changes in paced dogs were largely due to reductions in I Ca . We conclude that sustained atrial tachycardia reduces I to and I Ca , that the reduced I Ca decreases APD and APD adaptation to rate, and that these cellular changes likely account for the alterations in atrial refractoriness associated with enhanced ability to maintain AF in the model.