771-2 Isoproterenol Amplification of Flecainide-induced Conduction Slowing in Depolarized Canine Purkinje Fibers: Elucidation of Flecainide Proarrhythmia in CAST

To elucidate the potential mechanism for the flecainide (FLEC) proarrhythmia observed in CAST, the voltage-dependence of β-adrenergic modulation of impulse propagation in 10 FLEC-superfused canine Purkinje fibers was examined using a dual microelectrode technique. At physiologic membrane potentials (Vm) ([K+]&z.omicr;=5.4mM), 1μM FLEC decreased Vmax from 677±72 to 576±97 V/sec (p=0.04) and squared conduction velocity (θ2) from 1.28±0.5 to 1.04±0.4 (M/s)2. With K+ depolarization to Vm=-70 mV, FLEC further reduced Vmax from 324±100 to 241±64 V/s and θ2 from 0.90±0.3 to 0.83±0.5 (M/s)2 and produced a 1.9 mV hyperpolarizing shift of apparent Na+ channel availability curves derived from θ2. The addition of 1 μM isoproterenol (ISO) to FLEC-superfused fibers at physiologic Vm increased θ2 by 10% to 1.14±0.5 (M/s)2 (p=0.009) without altering Vmax. At -70 mV, the addition of ISO magnified the FLEC-induced reduction of Vmax an additional 26% to 177±49 V/s (p=0.001) and θ2 by 20% to 0.67±0.4 (M/s)2 (p=0.008), producing an additional 1.8 mV (p=0.001) and 1.9 mV (p=0.001) hyperpolarizing shift in the apparent Na+channel inactivation curves generated from Vmax and θ2, respectively. At physiologic Vm, the action potential duration (APD95) was reduced from 308±32 to 266±25 (p<0.001) by FLEC and subsequently to 217±4 (p<0.001) with ISO addition. With 12mM K+, APD95 decreased from 193±24 to 179±20 ms (p=0.001) with FLEC and to 162±14 ms (p=0.001) with ISO. Thus. at depolarized Vm, ISO amplified the FLEC-induced reduction of Vmax and θ2, suggesting a further adrenergic-mediated reduction of Na+ current. Consequently, the synergy between catecholamines and FLEC at depolarized Vm and the shortened APD95 could facilitate double-wave reentrant arrhythmias in the presence of FLEC and superimposed ischemia