Tachycardia-Induced Changes in Na + Current in a Chronic Dog Model of Atrial Fibrillation

Abstract

Abstract We have previously shown that chronic rapid atrial activation (400 bpm) reduces atrial conduction velocity in dogs, contributing to the development of a substrate supporting sustained atrial fibrillation (AF). However, the cellular and ionic mechanisms underlying these functional changes have not been defined. We applied whole-cell patch-clamp techniques to atrial myocytes from dogs subjected to atrial pacing at 400 bpm for 7 days (P7, n=6) and 42 days (P42, n=5) and compared the results with those from sham-operated dogs similarly instrumented but without pacemaker activation (P0, n=6). Rapid atrial pacing allowed for the induction of sustained AF in 67% and 100% of dogs paced for 7 and 42 days, respectively, and significantly decreased conduction velocity under P7 and P42 conditions. In dogs paced for 7 days, Na + current ( I Na ) density was reduced by 28% at −40 mV ( P <.0001, n=59 cells). I Na changes were even more decreased under P42 conditions, by ≈52% at −40 mV ( P <.0001): from −78.7±4.6 pA/pF (P0, n=28 cells) to −37.7±3.0 pA/pF (P42, n=43 cells). I Na was significantly reduced at all voltages ranging from −65 to −10 mV. Voltage-dependent activation and inactivation properties, activation kinetics, and recovery from inactivation were not altered by rapid atrial pacing; however, inactivation kinetics were slowed. AF duration was related to mean I Na in each dog ( r 2 =.573, P <.001). We conclude that rapid atrial activation significantly reduces both conduction velocity and I Na density. Since I Na is a major determinant of conduction velocity, our data point to I Na reduction as a potentially important mechanism contributing to the substrate for AF in this model.