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

Eplerenone Reduces Atrial Fibrillation Burden Without Preventing Atrial Electrical Remodeling

Yoshio Takemoto  1 , Rafael J Ramirez  2 , Kuljeet Kaur  2 , Oscar Salvador-Montañés  2 , Daniela Ponce-Balbuena  2 , Roberto Ramos-Mondragón  2 , Steven R Ennis  2 , Guadalupe Guerrero-Serna  2 , Omer Berenfeld  2 , José Jalife  3
Affiliations

Eplerenone Reduces Atrial Fibrillation Burden Without Preventing Atrial Electrical Remodeling

Yoshio Takemoto et al. J Am Coll Cardiol. .

Abstract

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.

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Figures

Figure 1
Figure 1. EPL mitigates structural remodeling
(A) Echocardiographically measured atrial areas adjusted by body weight at 5 different time points from SP-treated (N=15), EPL-treated (N=19) and sham-operated (N=6) groups. *p < 0.05 versus sham; #p < 0.05 vs EPL-treated group. LA=left atrium; RA=right atrium. (B) Mitral regurgitation (MR) at 5 different time points. (C) Atrial tissue weight adjusted by body weight at the end of the experiment. (D) Atrial areas obtained by direct measurement of the tissue at the end of experiment. (E) Single isolated cell length and width in Sham (N/n=4/192), SP-treated (N/n=4/144) and EPL-treated groups (N/n=5/244). *P<0.05, **P<0.01, ****P<0.0001. N = number of animals, n = number of cells.
Figure 2
Figure 2. EPL reduces fibrosis development during AF progression
(A) Representative picrosirius red staining of PLA, LA and RA. (B) Interstitial fibrosis for sham operated (N=6), SP-treated (N=7) and EPL-treated groups (N=10). Ten pictures per slide were randomly selected and analyzed. *P<0.05, **P<0.01. (C) EPL mitigates the increase of serum Procollagen III N-Terminal Propeptide (P3NP) during AF progression. *P<0.05 vs. Baseline, #P<0.05 vs. EPL. (D, E) Western blots for smooth muscle actin (SMA) and collagen III (COLIII) in atrial homogenates relative to GAPDH from SP-treated (N=4) and EPL-treated groups (N=5). (F,G) Mineralocorticoid receptor (NR3C2) and 11b-HSD2 (HSD11B2) gene expression in the LA. (H) serum aldosterone in sham operated, AF sheep treated with SP and AF sheep treated with EPL. For F–H, Sham (N=7), SP-treated (N=8) and EPL-treated groups (N=5). N=number of animal. *P<0.05. (B, F–H) One-way ANOVA followed by post hoc Bonferroni’s test. (C) Two-way ANOVA followed by post hoc Bonferroni’s test.
Figure 3
Figure 3. EPL does not change electrical remodeling
(A) Dominant frequency (DF) measured in-vivo in LA and RA at 4 different time points during AF progression in SP-treated (N=15) and EPL-treated groups (N=19). (B–E) Data from optical mapping experiments: DF (B), rotor frequency (C), number of rotors (D), action potential duration (APD90) (E) and conduction velocity (CV) (F) recorded on the LA and RA from SP-treated (N=3) and EPL-treated sheep hearts (N=5). N=number of animals.
Figure 4
Figure 4. EPL does not reduce ion channel remodeling during AF progression
(A) Left, Inward rectifier potassium (IK1) current-voltage relationships for LA cells from SP treated (N/n=3/7) and EPL-treated (N/n=5/14) animals. Right, IK1 current-voltage relationships for RA cells from for SP-treated (N/n=2/7) and EPL-treated (N/n=5/13) animals. (B) Left, current-ICaL voltage relationships for LA from SP treated (N/n=4/11) and EPL-treated (N/n=5/24) animals. Right, current-voltage relationships for RA from SP treated (N/n=4/17) and EPL-treated ICaL (N/n=5/26) animals. Two-way ANOVA with post hoc Bonferroni’s test. (C) Western blots for Kir2.3 (left) and Cav1.2 (right) in LA tissue lysate. Protein expression of both ion channel types was similar for SP-treated (N=4) and EPL-treated groups (N=5).
Figure 5
Figure 5. EPL reduces AF wave propagation complexity
(A) Representative 3-dimensional plots of spatial trajectories of rotors at consecutive movie frame numbers (500 μm2 pixels, 600 frames/s) for SP-treated (left) and EPL-treated (right) hearts. Note the reduced complexity in the trajectories of two rotors recorded from persistent AF hearts in the EPL treated compared with the SP treated hearts. (B and C) Quantification of lifespan (B) and trajectory length per rotation (C) of rotors recorded in optical mapping experiments from the PLA, LA and RA of SP-treated and EPL-treated hearts. Rotor lifespans were similar, but rotor trajectories were significantly shorter and less complex for EPL-treated than SP-treated hearts.
Figure 6
Figure 6. EPL prolonged the time to 12h-AF, and reduced AF inducibility and AF burden
Kaplan–Meier plot for freedom from 12h-AF (A) and 7d-PeAF (B) in SP-treated (N=15) and EPL-treated groups (N=19). Log-rank test (P=0.04 in 12hr-AF and P=0.15 in 7d-PeAF). (C) Percentage of sheep with 7d-PeAF within 23 weeks in SP-treated (N=15/15) and EPL-treated groups (N=14/19). Fisher’s exact test (P=0.04). Time course of AF burden (D) and AF inducibility index (F) in-vivo fitted with Hill equation for SP-treated (N=15) and EPL-treated (N=19 groups throughout AF progression. Time to 50% AF burden (E) and AF inducibility index (G), calculated individually fitted with Hill equation, for SP-treated (N=15) and EPL-treated (N=19) groups. Double sided t-test. *P<0.05. N=number of animals.
Central Illustration
Central Illustration. High frequency atrial excitation leads to persistent AF by inducing electrical and structural remodeling
Left, increased aldosterone during high frequency stimulation contributes to structural remodeling via atrial cardiomyocyte hypertrophy, atrial dilatation, myofibroblast proliferation, increased collagen synthesis and extracellular matrix (ECM) remodeling. Right, by blocking aldosterone, eplerenone (EPL), minimizes structural but not electrical remodeling.
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