Eplerenone Reduces Atrial Fibrillation Burden Without Preventing Atrial Electrical Remodeling

• Published in: Journal of the American College of Cardiology 2017-12, Vol.70 (23), p.2893-2905
• Main Authors: Takemoto, Yoshio, Ramirez, Rafael J., Kaur, Kuljeet, Salvador-Montañés, Oscar, Ponce-Balbuena, Daniela, Ramos-Mondragón, Roberto, Ennis, Steven R., Guerrero-Serna, Guadalupe, Berenfeld, Omer, Jalife, José
• Format: Article
• Language: English
• Subjects: Actin; Aldosterone; Animals; Atria; atrial dilation; Atrial Fibrillation - pathology; Atrial Fibrillation - prevention & control; atrial fibrillation progression; Atrial Remodeling - drug effects; Cardiac arrhythmia; Cardiac Pacing, Artificial; Cardiology; Collagen; Conduction; Dilation; Electrocardiography; Eplerenone; Fibrillation; Fibrosis; Heart; Heart attacks; Heart diseases; Heart failure; Hypertrophy; Ion channels; Male; Mineralocorticoid Receptor Antagonists - therapeutic use; Muscles; Ovis aries; Prevention; Sheep; Smooth muscle; Spironolactone - analogs & derivatives; Spironolactone - therapeutic use; Sugar; upstream therapy
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2017.10.014

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. 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. 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). 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. 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. [Display omitted]