Sex-specific impact of aldosterone receptor antagonism on ventricular remodeling and gene expression after myocardial infarction

Abstract

Aldosterone receptor antagonism reduces mortality and improves post-myocardial infarction (MI) remodeling. Because aldosterone and estrogen signaling pathways interact, we hypothesized that aldosterone blockade is sex-specific. Therefore, we investigated the impact of eplerenone on left ventricular (LV) remodeling and gene expression of male infarcted rats versus female infarcted rats. MI and Sham animals were randomized to receive eplerenone (100 mg/kg/day) or placebo 3 days post-surgery for 4 weeks and assessed by echocardiography. In the MI placebo group, left ventricular end-diastolic dimension (LVEDD) increased from 7.3 +/- 0.4 mm to 10.2 +/- 1.0 mm (p < 0.05) and ejection fraction (EF) decreased from 82.3 +/- 4% to 45.5 +/- 11% (p < 0.05) in both sexes (p = NS between groups). Eplerenone attenuated LVEDD enlargement more effectively in females (8.8 +/- 0.2 mm, p < 0.05 vs. placebo) than in males (9.7 +/- 0.2 mm, p = NS vs. placebo) and improved EF in females (56.7 +/- 3%, p < 0.05 vs. placebo) but not in males (50.6 +/- 3%, p = NS vs. placebo). Transcriptomic analysis using Rat_230-2.0 microarrays (Affymetrix) revealed that in females 19% of downregulated genes and 44% of upregulated genes post-MI were restored to normal by eplerenone. In contrast, eplerenone only restored 4% of overexpressed genes in males. Together, these data suggest that aldosterone blockade reduces MI-induced cardiac remodeling and phenotypic alterations of gene expression preferentially in females than in males. The use of transcriptomic signatures to detect greater benefit of eplerenone in females has potential implications for personalized medicine.

Keywords: aldosterone antagonism; gene expression; heart failure; myocardial infarction; sex.

Figure 1

(A) Bar graphs showing percentage of cardiac fibrosis in male and female infarcted rats; *p < 0.05 versus placebo, same sex. Values are means ± SEM. (B) Trichrome‐stained histological cross‐sections of myocardial tissue from male placebo (top left) versus male treated (top right) and female placebo (bottom left) versus female treated (bottom right). Scale bar corresponds to 5 mm.

Figure 2

Line graphs showing changes in LVEDD (A), LVESD (B), EF (C), and FS (D) over time in male and female rats after Ml or Sham surgery. *p < 0.05 versus BSN, same sex; fp < 0.05 versus placebo, same sex, same time point. Bar graphs showing percentage of changes in male and female infarcted rats at week 4. *p < 0.05 versus nlacebo. same sex. Values are means + SFM.

Figure 3

Left: Hierarchical clustering of the genes differentially expressed after Ml. Expression data are centered on genes so that the mean value for each Sham group is zero. For each gender, red and green colors represent up‐ and downregulation relative to Sham, respectively. Right: Cluster‐specific analysis of the mean expression profile in male and female rats. Blue and red bars correspond to male and female animals, respectively. Gene expression level is expressed as the fold‐change versus same‐gender Sham group.

Figure 4

Volcano plot graphs showing the significance and magnitude of change in expression in the male (A, B) and female (C, D) groups. Expression profile of the Sham nontreated group is compared with expression profile of the Ml nontreated group (A, C) and the Ml treated group (B, D), respectively. Differentially expressed genes are selected based on their statistical significance (p < 0.05, f‐test) and variation in amplitude (fold‐change <‐l .4 or >1.4) are shown in red. X‐axis: Fold‐change of gene expression levels between the two compared groups. Y‐axis: p is the p‐value obtained from the comparison (f‐test) of gene expression levels in the two groups.

Figure 5

Pie charts showing distribution of genes differentially expressed after eplerenone therapy in male (A) and female (B) infarcted rats on the basis of their involvement in different biological processes (>1.4 fold, p < 0.05). Data in pie charts are expressed as a percentage of total genes.

Figure 6

Representative heat map of the impact of eplerenone after Ml or Sham surgery on genes related to RAA system (A), gonadal hormones (B), and fibrosis (C) in male and female rats. Expression data are centered on genes so that the mean value for each Sham group is zero. For each gender, red and green colors represent up‐ and downregulation relative to Sham, respectively. Genes are indicated using their official symbol (gene name is provided in Table S10, supporting information).