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Published on: April 17, 2021
New insights into sexual dimorphism during progression of heart failure and rhythm disorders
Jérôme Thireau1, Franck Aimond, Denise Poisson
1Centre National de la Recherche Scientifique FRE3092, Université François-Rabelais, F-37041 Tours, France.
Insights
Female mice with heart failure (HF) show better protection against cardiac remodeling and rhythm disorders than males. This study highlights the role of sex hormones in HF progression and mortality, linking fibrosis and conduction time to outcomes.
Area of Science:
- Cardiovascular Biology
- Neuroendocrinology
- Cardiac Electrophysiology
Background:
- Neurohormonal imbalance significantly contributes to heart failure (HF) progression and mortality.
- HF incidence and prevalence are notably lower in women compared to men.
- Understanding sexual dimorphism in HF mechanisms is crucial for developing effective treatment strategies.
Purpose of the Study:
- To investigate sexual dimorphism in the progression of neurohormonal-dependent heart failure using a mouse model.
- To elucidate the role of sex hormones in cardiac remodeling, electrophysiological changes, and mortality in HF.
- To explore the relationship between fibrosis, conduction abnormalities, and arrhythmias in male and female HF mice.
Main Methods:
- Utilized a mouse model (TG4 strain) overexpressing the human beta2-adrenergic receptor to induce HF.
- Assessed cardiac function via echocardiography and electrocardiography.
- Performed histological studies, intracardiac electrophysiological exploration, and patch-clamp analysis.
- Investigated hormonal influence through surgical gonadectomy.
Main Results:
- TG4 mice exhibited high mortality, with a significant difference between males and females.
- Male TG4 mice displayed intraventricular conduction abnormalities (prolonged infrahisian interval and QRS duration), increasing arrhythmia susceptibility.
- HF severity correlated with fibrosis, which was modulated by gonadal hormones.
- While cellular action potentials were similar, both sexes showed delayed repolarization compared to controls.
Conclusions:
- Female TG4 mice demonstrated enhanced protection against cardiac remodeling and rhythm disorders compared to males.
- A significant link was established between fibrosis, conduction time, and mortality, influenced by sex hormones.
- These findings underscore the importance of sex-specific mechanisms in HF pathogenesis and suggest potential therapeutic targets.
Abstract:
Neurohormonal imbalance is a key determinant of the progression of heart failure (HF), which results in an elevated risk of mortality. A better understanding of mechanisms involved may influence treatment strategies. The incidence and prevalence of HF are lower in women. We explored sexual dimorphism in the progression of HF using a mice model of neurohormonal-dependent HF. Male and female mice overexpressing the human beta2-adrenergic receptor (TG4 strain) develop HF. We compared TG4 animals with age-matched wild-type controls. Cardiac function was studied in vivo by echocardiography and electrocardiography. Histological studies were performed. Conduction parameters were assessed by intracardiac electrophysiological exploration, as was the occurrence of spontaneous and inducible arrhythmias. The patch-clamp technique was used to determine the cellular electrophysiological profile. The role of hormonal status in HF progression was investigated by surgical gonadectomy. High mortality rate was observed in TG4 mice with a dramatic difference between males and females. Male TG4 mice exhibited intraventricular conduction abnormalities, as measured by infrahisian interval and QRS durations potentially determining reentrant circuits and increasing susceptibility to arrhythmia. The severity of HF was correlated with the degree of fibrosis, which was modulated by the gonadal hormones. Action potentials recorded from male and female left ventricular cardiomyocytes were indistinguishable, although both sexes exhibited delayed repolarization when compared with their wild-type counterparts. In conclusion, female TG4 mice were better protected than males against cardiac remodeling and rhythm disorders. A link between fibrosis, conduction time, and mortality was established in relation with sex hormones.
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