TACHYCARDIA-INDUCED CHANGES IN NA-MODEL OF ATRIAL-FIBRILLATION( CURRENT IN A CHRONIC DOG)

We have previously shown that chronic rapid atrial activation (400 bpm ) reduces atrial conduction velocity in dogs, contributing to the deve lopment 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 tech niques 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 resul ts with those from sham-operated dogs similarly instrumented but witho ut 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 un der 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 cha nges were even more decreased under P42 conditions, by approximate to 52% at -40 mV (P<.0001): from -78.7+/-4.6 pA/pF (P0, n=28 cells) to -3 7.7+/-3.0 pA/pF (P42, n=43 cells). I-Na was significantly reduced at a ll voltages ranging from -65 to -10 mV. Voltage-dependent activation a nd inactivation properties, activation kinetics, and recovery from ina ctivation were not altered by rapid atrial pacing; however, inactivati on 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 sign ificantly reduces both conduction velocity and I-Na density. Since I-N a is a major determinant of conduction velocity, our data point to I-N a reduction as a potentially important mechanism contributing to the s ubstrate for AF in this model.