Antiarrhythmic effects of simvastatin in canine pulmonary vein sleeve preparations.

OBJECTIVES: The purpose of this study was to determine the electrophysiologic effects of simvastatin in canine pulmonary vein (PV) sleeve preparations. BACKGROUND: Ectopic activity arising from the PV plays a prominent role in the development of atrial fibrillation. METHODS: Transmembrane action potentials were recorded from canine superfused left superior or inferior PV sleeves using standard microelectrode techniques. Acetylcholine (1 μM), isoproterenol (1 μM), high calcium ([Ca(2+)](o) = 5.4 mM), or a combination was used to induce early afterdepolarizations or delayed afterdepolarizations and triggered activity. Voltage clamp experiments were performed in the left atrium measuring fast and late sodium currents. RESULTS: Under steady-state conditions, simvastatin (10 nM, n = 9) induced a small increase in action potential duration measured at 85% repolarization and a significant decrease in action potential amplitude, take-off potential, and maximum rate of rise of action potential upstroke at the fastest rates. The V(max) decreased from 175.1 ± 34 V/s to 151.7 ± 28 V/s and from 142 ± 47 V/s to 97.4 ± 39 V/s at basic cycle lengths of 300 and 200 ms, respectively. Simvastatin (10 to 20 nM) eliminated delayed afterdepolarizations and delayed afterdepolarization-induced triggered activity in 7 of 7 PV sleeve preparations and eliminated or reduced late-phase 3 early afterdepolarizations in 6 of 6 PV sleeve preparations. Simvastatin (20 nM) did not affect late or fast sodium currents measured using voltage clamp techniques. CONCLUSIONS: Our data suggest that in addition to its upstream actions to reduce atrial structural remodeling, simvastatin exerts a direct antiarrhythmic effect by suppressing triggers responsible for the genesis of atrial fibrillation.