Abstract
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.
Highlights
Cardiovascular diseases remain the leading cause of mortality in both men and women globally [1], despite the conventional dogma that women are more protected against cardiovascular diseases than men
Since most of the previous work has focused on determining sex-related differences in isoproterenol-induced cardiac hypertrophy and fibrosis [17,18,19,20], in the current work, we comprehensively investigated key echocardiographic, molecular, and histopathologic sex differences in a model of cardiac dysfunction produced by prolonged administration of moderate doses of isoproterenol (10 mg/kg/day for 14 days) in male and female C57Bl/ 6NCrl mice
The current study demonstrates lack of significant sex-related differences in cardiac hypertrophy, dysfunction, and fibrosis in response to moderate-dose isoproterenol (10 mg/kg/day for 14 days) in C57Bl/6NCrl mice
Summary
Cardiovascular diseases remain the leading cause of mortality in both men and women globally [1], despite the conventional dogma that women are more protected against cardiovascular diseases than men. There are a number of cardiovascular diseases that are more prevalent in women than in men, including Takotsubo cardiomyopathy [3, 4] and microvascular angina [5]. Despite similar overall risk of heart failure between men and women, heart failure with reduced ejection fraction (HFrEF) is more prevalent in men, while heart failure with preserved ejection fraction (HFpEF) is more prevalent in women [6, 7]. The rationale for the higher prevalence of these specific conditions in women is still not fully understood, coronary microvascular dysfunction and endothelial inflammation have been suggested to play key roles [6]
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