Key result
Prolonged administration of isoproterenol induced a similar degree of cardiac dysfunction, hypertrophy, and myocardial fibrosis in both male and female C57Bl/6NCrl mice, demonstrating a lack of sexual dimorphism.
Why the study?
Sex-related differences in cardiovascular diseases are complex in humans and model-dependent in animals, prompting an investigation into sex differences during acute and prolonged adrenergic stimulation in C57Bl/6NCrl mice.
Does female sex protect against isoproterenol-induced cardiac dysfunction and remodeling in a mouse model compared to male sex?
Does female sex protect against isoproterenol-induced cardiac dysfunction and remodeling in a mouse model compared to male sex?
This study demonstrates a lack of sexual dimorphism in isoproterenol-induced cardiac dysfunction in mice, highlighting that sex differences in cardiovascular models are highly model-dependent.
Supports mixed-sex cohorts in isoproterenol mouse models; leaves open whether sex differences exist in human HF.
Sex-related differences in cardiovascular diseases are highly complex in humans and model-dependent in experimental laboratory animals. The objective of this work was to comprehensively investigate key sex differences in the response to acute and prolonged adrenergic stimulation in C57Bl/6NCrl mice. Cardiac function was assessed by trans-thoracic echocardiography before and after acute adrenergic stimulation (a single sub-cutaneous dose of isoproterenol 10 mg/kg) in 15 weeks old male and female C57Bl/6NCrl mice. Thereafter, prolonged adrenergic stimulation was achieved by sub-cutaneous injections of isoproterenol 10 mg/kg/day for 14 days in male and female mice. Cardiac function and morphometry were assessed by trans-thoracic echocardiography on the 15th day. Thereafter, the mice were euthanized, and the hearts were collected. Histopathological analysis of myocardial tissue was performed after staining with hematoxylin & eosin, Masson's trichrome and MAC-2 antibody. Gene expression of remodeling and fibrotic markers was assessed by real-time PCR. Cardiac function and morphometry were also measured before and after isoproterenol 10 mg/kg/day for 14 days in groups of gonadectomized male and female mice and sham-operated controls. In the current work, there were no statistically significant differences in the positive inotropic and chronotropic effects of isoproterenol between male and female C57Bl/6NCrl. After prolonged adrenergic stimulation, there was similar degree of cardiac dysfunction, cardiac hypertrophy, and myocardial fibrosis in male and female mice. Similarly, prolonged isoproterenol administration induced hypertrophic and fibrotic genes in hearts of male and female mice to the same extent. Intriguingly, gonadectomy of male and female mice did not have a significant impact on isoproterenol-induced cardiac dysfunction as compared to sham-operated animals. The current work demonstrated lack of significant sex-related differences in isoproterenol-induced cardiac hypertrophy, dysfunction, and fibrosis in C57Bl/6NCrl mice. This study suggests that female sex may not be sufficient to protect the heart in this model of isoproterenol-induced cardiac dysfunction and underscores the notion that sexual dimorphism in cardiovascular diseases is highly model-dependent.
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Grant et al. (2020) studied Isoproterenol-induced cardiac dysfunction (n=54). Isoproterenol vs. Sterile saline was evaluated on Cardiac dysfunction (ejection fraction and fractional shortening). Prolonged administration of isoproterenol induced a similar degree of cardiac dysfunction, hypertrophy, and myocardial fibrosis in both male and female C57Bl/6NCrl mice, demonstrating a lack of sexual dimorphism.
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