Female Sex Is Protective in a Preclinical Model of Heart Failure With Preserved Ejection Fraction
Why the study?
Does female sex protect against the development of cardiac remodeling and diastolic dysfunction in a murine model of heart failure with preserved ejection fraction (HFpEF)?
Key Points
- To determine whether sexual dimorphism affects the development and progression of heart failure with preserved ejection fraction (HFpEF) in a preclinical mouse model.
- Exposed 8-week-old male and female C57BL/6N wild-type mice to normal chow or a combination of high-fat diet and L-NAME (0.5 g/L in drinking water) for 5 or 15 weeks.
- Performed ovariectomy versus sham surgery in 8-week-old female mice prior to 15 weeks of HFpEF treatment to test the role of female sex hormones.
- Assessed cardiac hypertrophy, diastolic function, exercise performance, pulmonary congestion, fibrosis, and inflammatory markers.
- After 5 weeks, female and male mice had similar obesity (26.0% female vs 27.5% male, weight gain, p=NS), hypertension, and glucose intolerance, but females showed an attenuated increase in E/e' and no pulmonary congestion.
- After 15 weeks, males exhibited worsening left ventricular hypertrophy and remodeling index, whereas females maintained persistently normal heart mass and remodeling index even after ovariectomy.
- Cardiac hypertrophy markers (BNP, RCAN1.4) and inflammatory markers (IL-6, IL-1β, iNOS) increased only in males, leaving the protective Xbp1s pathway intact in females.
Structured PICO
Does female sex protect against the development of cardiac remodeling and diastolic dysfunction in a murine model of heart failure with preserved ejection fraction (HFpEF)?
P
Population
C57BL/6N wild-type mice (8-week old), male and female.
I
Intervention
High fat diet (HFD) plus N(w)-nitro-L-arginine methyl ester (L-NAME) 0.5 g/L in drinking water for 5 to 15 weeks; a subgroup of females underwent ovariectomy (OVX).
C
Comparator
Normal chow fed controls of the same sex; sham surgery for the OVX group.
O
Outcome
Development of HFpEF phenotype including left ventricular remodeling index (LVRI), diastolic dysfunction (E/e'), and lung water (pulmonary congestion).surrogate
Limitations
- Only studied young animals
- OVX is an imperfect proxy to physiological menopause
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“This study reveals different drug targets in males and females and will be a stepping-stone for future trials with sex-specific targeted drugs in HFpEF.”
DMDonald M. BersChair of Pharmacology, UC Davis School of Medicine
“If these same molecular male-female distinctions occur in obese diabetic patients with HFpEF, it may mean that the best therapeutic strategies for HFpEF in women may differ from those for men.”
Implication
In a murine model of HFpEF, female sex intrinsically protects against cardiac remodeling and diastolic dysfunction independently of sex hormones, challenging the traditional belief of higher female susceptibility.
Abstract
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Cite This Study
Tong et al. (2019) studied this question.