Antiarrhythmic effects of simvastatin in canine pulmonary vein sleeve preparations

J Am Coll Cardiol. 2011 Feb 22;57(8):986-93. doi: 10.1016/j.jacc.2010.08.649.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Action Potentials / drug effects*
  • Action Potentials / physiology
  • Animals
  • Anti-Arrhythmia Agents / pharmacology
  • Cells, Cultured
  • Dogs
  • Dose-Response Relationship, Drug
  • Electrophysiologic Techniques, Cardiac
  • Isoproterenol / pharmacology
  • Membrane Potentials / drug effects
  • Models, Animal
  • Muscle Cells / drug effects
  • Muscle Cells / physiology
  • Pulmonary Veins / drug effects*
  • Pulmonary Veins / physiology
  • Random Allocation
  • Reference Values
  • Sensitivity and Specificity
  • Simvastatin / pharmacology*

Substances

  • Anti-Arrhythmia Agents
  • Simvastatin
  • Isoproterenol
  • Acetylcholine