Document Detail


Sex-specific impact of aldosterone receptor antagonism on ventricular remodeling and gene expression after myocardial infarction.
MedLine Citation:
PMID:  20072663     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Rosemeire M Kanashiro-Takeuchi; Bettina Heidecker; Guillaume Lamirault; Jennifer W Dharamsi; Joshua M Hare
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Clinical and translational science     Volume:  2     ISSN:  1752-8062     ISO Abbreviation:  Clin Transl Sci     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2010-05-06     Completed Date:  2010-09-14     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  101474067     Medline TA:  Clin Transl Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  134-42     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cluster Analysis
Female
Fibrosis
Gene Expression Profiling
Gene Expression Regulation / drug effects*
Male
Mineralocorticoid Receptor Antagonists*
Myocardial Infarction / complications,  genetics*,  pathology,  physiopathology*
Placebos
Rats
Rats, Wistar
Sex Characteristics*
Spironolactone / analogs & derivatives*,  pharmacology
Ventricular Remodeling / drug effects*
Grant Support
ID/Acronym/Agency:
R01 HL-65455/HL/NHLBI NIH HHS; R01 HL065455/HL/NHLBI NIH HHS; R01 HL065455-01/HL/NHLBI NIH HHS; R01 HL107110/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Mineralocorticoid Receptor Antagonists; 0/Placebos; 27O7W4T232/Spironolactone; 6995V82D0B/eplerenone
Comments/Corrections

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