Eplerenone Reduces Atrial Fibrillation Burden Without Preventing Atrial Electrical Remodeling

J Am Coll Cardiol. 2017 Dec 12;70(23):2893-2905. doi: 10.1016/j.jacc.2017.10.014.


Background: The aldosterone inhibitor eplerenone (EPL) has been shown to reduce the incidence of atrial fibrillation (AF) in patients with systolic heart failure, but the mechanism is unknown.

Objectives: This study hypothesized that by reducing atrial dilation and fibrosis in the absence of heart failure, EPL also reduces AF burden and prevents AF perpetuation.

Methods: The authors conducted a randomized controlled study in 34 sheep that were atrially tachypaced (13 ± 1 week). They compared daily oral EPL (n = 19) versus sugar pill (SP) treatment (n = 15) from the start of tachypacing. The endpoint was a continuous 7-day stretch of persistent AF (n = 29) or completion of 23 weeks tachypacing (n = 5).

Results: EPL significantly reduced the rate of left atrial dilation increase during AF progression. Atria from EPL-treated sheep had less smooth muscle actin protein, collagen-III expression, interstitial atrial fibrosis, and cell hypertrophy than SP-treated sheep atria did. However, EPL did not modify the AF-induced increase in the rate of dominant frequency and ion channel densities seen under SP treatment, but rather prolonged the time to persistent AF in 26% of animals. It also reduced the degree of fibrillatory conduction, AF inducibility, and AF burden.

Conclusions: In the sheep model, EPL mitigates fibrosis and atrial dilation, modifies AF inducibility and AF complexity, and prolongs the transition to persistent AF in 26% of animals, but it does not prevent AF-induced electrical remodeling or AF persistence. The results highlight structural remodeling as a central upstream target to reduce AF burden, and the need to prevent electrical remodeling to avert AF perpetuation.

Keywords: aldosterone; atrial dilation; atrial fibrillation progression; fibrosis; upstream therapy.

MeSH terms

  • Animals
  • Atrial Fibrillation / pathology
  • Atrial Fibrillation / prevention & control*
  • Atrial Remodeling / drug effects*
  • Cardiac Pacing, Artificial
  • Eplerenone
  • Fibrosis
  • Male
  • Mineralocorticoid Receptor Antagonists / therapeutic use*
  • Sheep
  • Spironolactone / analogs & derivatives*
  • Spironolactone / therapeutic use


  • Mineralocorticoid Receptor Antagonists
  • Spironolactone
  • Eplerenone