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Enhanced heart failure, mortality and renin activation in female mice with experimental dilated cardiomyopathy
Ranjana Tripathi1, Ryan Sullivan2, Tai-Hwang M Fan1
1Departments of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
Insights
Female mice with experimental dilated cardiomyopathy (DCM) show accelerated heart failure progression, with worse cardiac dysfunction and lung edema compared to males. These changes were linked to hormonal and natriuretic peptide system alterations.
Area of Science:
- Cardiovascular Biology
- Translational Medicine
- Sex Differences in Disease
Background:
- Dilated cardiomyopathy (DCM) is a leading cause of heart failure (HF) in both sexes.
- Existing clinical data on sex-related differences in DCM progression and HF outcomes are conflicting.
- Understanding sex-specific disease mechanisms is crucial for targeted therapies.
Purpose of the Study:
- To investigate sex-related differences in the progression of DCM and heart failure development.
- To compare cardiomyopathy progression and HF outcomes between male and female mice in a transgenic DCM model.
- To explore the hormonal and molecular underpinnings of observed sex differences.
Main Methods:
- Utilized a well-established transgenic mouse model of DCM that mimics human disease progression.
- Assessed cardiac function, ventricular remodeling, and HF markers at multiple time points (4, 7, 13 weeks).
- Measured plasma levels of renin, angiotensin II, aldosterone, and analyzed natriuretic peptide system components (corin, ANP, BNP, cGMP).
- Evaluated the effect of early ovariectomy on disease progression in female mice.
Main Results:
- Female mice with DCM exhibited significantly more severe left ventricular systolic dysfunction, dilation, and wall thinning by 13 weeks compared to males.
- Female mice showed increased lung edema, cardiac fibrosis, and pleural effusions, independent of ovariectomy.
- Accelerated DCM in females was associated with elevated plasma active renin, angiotensin II, and aldosterone levels.
- DCM females displayed altered natriuretic peptide system expression, with lower corin and higher ANP, BNP, and cGMP levels.
Conclusions:
- Female mice with experimental DCM experience accelerated cardiomyopathy and HF progression compared to males.
- These sex-specific differences are associated with early renin-angiotensin-aldosterone system activation and dysregulation of the natriuretic peptide system.
- Early ovariectomy did not ameliorate the accelerated progression of DCM and HF in female mice, suggesting non-estrogen-dependent mechanisms.
Abstract:
Dilated cardiomyopathy (DCM) is the major cause of heart failure affecting both women and men. Limited clinical studies show conflicting data in sex-related differences in the progression of dilated cardiomyopathy and heart failure (HF) outcomes. We examined the comparative sex-related progression of cardiomyopathy and the development of HF (at 4, 7, 13 weeks of age) in a well-established, transgenic mouse model of DCM that recapitulates the progressive stages of human HF. By 13 weeks of age, female mice with DCM had more severe left ventricular systolic dysfunction, left ventricular dilation and wall thinning (P<0.001 for all) than age-matched male mice with DCM. Female mice also had greater lung edema (P<0.001), cardiac fibrosis (P<0.01) and pleural effusions, which were not rescued by ovariectomy. By comparison to DCM male mice at 13 weeks, these pathological changes in female mice with DCM, were associated with significant increases in plasma active renin (P<0.01), angiotensin II (P<0.01) and aldosterone levels (P<0.001). In comparison to DCM male mice, DCM female mice also showed differential expression of the natriuretic peptide system with lower corin and higher ANP, BNP and cGMP levels at 13 weeks of age. We conclude, that female mice with experimental DCM have an accelerated progression of cardiomyopathy and HF, which was not corrected by early ovariectomy. These alterations are associated with early renin activation with increased angiotensin II and aldosterone levels, and altered expression of the natriuretic peptide system.
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