Abstract 11513: Eplerenone Treatment Mitigates Atrial Structural Remodeling but Does Not Modify the Transition From Paroxysmal to Persistent Atrial Fibrillation in an Ovine Model
Introduction: Recently we demonstrated that inhibition of the pro-fibrotic protein Galectin-3 reduces atrial dilatation, fibrosis and electrical remodeling as well as atrial fibrillation (AF) burden in a clinically relevant sheep model of lone persistent AF (Takemoto Y, et al. Heart Rhythm 12:S4; 2015). The mineralocorticoid blocker eplerenone (EPL) has been shown to reduce fibrosis and the incidence of AF in patients with systolic heart failure and mild symptoms, but the mechanism is poorly understood. We tested the hypothesis that by reducing atrial dilatation and fibrosis alone in the absence of heart failure EPL treatment also reduces atrial fibrosis and prevents AF perpetuation.
Methods: We conducted a placebo-controlled drug study in 17 atrially tachypaced sheep for 14±2 weeks (maximum 23 weeks). We compared effects of EPL treatment (100 mg/day, N=10) with sugar pill (SP, N=7) orally administered daily from the start of tachypacing. The terminal point of the study was a continuous 7-day stretch of persistent AF (N=14) or the completion of 23-weeks tachypacing (N=3).
Results: In vivo, EPL significantly reduced the rate of left atrial (LA) dilatation, mitral regurgitation, cellular hypertrophy, interstitial fibrosis (picrosirius red staining), and serum procollagen III N-terminal peptide (P3NP) levels during AF progression. However EPL did not affect the rate of dominant frequency (DF) increase or the maximum DF (DFmax). Ex-vivo optical mapping of the explanted hearts showed that EPL did not affect action potential duration or conduction velocity during pacing, or the DFmax during AF compared with hearts from SP-treated animals. However, EPL treatment significantly reduced the number of rotors and the trajectory areas of wavebreaks in LA during AF. Most important, unlike Gal-3 inhibition, EPL treatment did not change AF inducibility or AF burden at any time of weekly evaluation during AF progression.
Conclusions: Mineralocorticoid inhibition during AF progression mitigates fibrosis and structural remodeling, which reduces complexity of AF and possibly contributes to delay the AF substrate somewhat. However, while reduction of fibrosis might be necessary, it is not sufficient to prevent AF perpetuation when electrical remodeling endures.
Author Disclosures: Y. Takemoto: None. R.J. Ramirez: None. K. Kaur: None. D. Ponce-Balbuena: None. R. Ramos-Mondragon: None. B.C. Willis: None. S.R. Ennis: None. G. Guerrero-Serna: None. S.V. Pandit: None. O. Berenfeld: None. J. Jalife: None.
- © 2015 by American Heart Association, Inc.