title: Antiarrhythmic effects of simvastatin in canine pulmonary vein sleeve preparations.
abstract: OBJECTIVE
  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.
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York 13501-1787, USA. sicouris@mmrl.edu
authors.forename: Serge
authors.initials: S
authors.lastname: Sicouri
authors.forename: Brittany
authors.initials: B
authors.lastname: Gianetti
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Zygmunt
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Cordeiro
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D022062:Electrophysiologic Techniques, Cardiac; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D023421:Models, Animal; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology; D011667:Pulmonary Veins / Q000187:drug effects* / Q000502:physiology; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D019821:Simvastatin; D007545:Isoproterenol; D000109:Acetylcholine