The prevalence of cardiometabolic disorders in both women and men has increased worldwide and is linked to a rise in obesity and obesity-associated associated clustering of other cardiometabolic risk factors such as hypertension, impaired glucose regulation and dyslipidemia. However, the predominance of common types of cardiometabolic disorders such as heart failure, atrial fibrillation and ischemic heart disease is sex specific, and our identification of these and the underlying mechanisms is only just emerging. New evidence suggests that sex hormones, sex-specific molecular mechanisms and gender influence glucose and lipid metabolisms, as well as cardiac energy metabolism, and function. Here we review sex differences in cardiometabolic risk factors, associated preclinical and clinical cardiac disorders and potential therapeutic avenues.

Sex differences in cardiometabolic disorders.

Background Obesity and the metabolic syndrome are increasingly prevalent in society and their complications and response to treatment exhibit sexual dimorphism. Mouse models of high fat diet-induced obesity are commonly used for both mechanistic and therapeutic studies of metabolic disease and diabetes. However, the inclusion of female mammals in obesity research has not been a common practice, and has resulted in a paucity of data regarding the effect of sex on metabolic parameters and its applicability to humans. Methods Here we analyzed male and female C57BL/6 J mice beginning at 4 weeks of age that were placed on a low-fat diet (LFD, 10% calories from fat), a Western Diet (WD, 45% calories from fat), or a high fat diet (HFD, 60% calories from fat). Assessments of body composition, glucose homeostasis, insulin production, and energy metabolism, as well as histological analyses of pancreata were performed. Results Both male and female C57BL/6 J mice had similar increases in total percent body weight gain with both WD and HFD compared to LFD, however, male mice gained weight earlier upon HFD or WD feeding compared to female mice. Male mice maintained their caloric food intake while reducing their locomotor activity with either WD or HFD compared to LFD, whereas female mice increased their caloric food intake with WD feeding. Locomotor activity of female mice did not significantly change upon WD or HFD feeding, yet female mice exhibited increased energy expenditure compared to WD or HFD fed male mice. Glucose tolerance tests performed at 4, 12 and 20 weeks of dietary intervention revealed impaired glucose tolerance that was worse in male mice compared to females. Furthermore, male mice exhibited an increase in pancreatic β cell area as well as reduced insulin sensitivity after HFD feeding compared to WD or LFD, whereas female mice did not. Conclusions Male and female C57BL/6 J mice exhibited strikingly different responses in weight, food consumption, locomotor activity, energy expenditure and β cell adaptation upon dietary manipulation, with the latter exhibiting less striking phenotypic changes. We conclude that the nature of these responses emphasizes the need to contextualize studies of obesity pathophysiology and treatment with respect to sex.

https://www.researchsquare.com/article/rs-36103/v1.pdf?c=1631858133000

Phenotypic Sexual Dimorphism in Response to Dietary Fat Manipulation in C57BL/6J Mice

Diabetes as a Risk Factor for Stroke in Women Compared With Men: A Systematic Review and Meta-Analysis of 64 Cohorts, Including 775,385 Individuals and 12,539 Strokes

As the prevalence of obesity continues to grow worldwide, the health and financial burden of obesity-related comorbidities grows too. Cardiovascular disease (CVD) is clearly associated with increased adiposity. Importantly, women are at higher risk of CVD when obese and insulin resistant, in particular at higher risk of developing heart failure with preserved ejection fraction and ischemic heart disease. Increased aldosterone and mineralocorticoid receptor activation, aberrant estrogenic signaling and elevated levels of androgens are among some of the proposed mechanisms explaining the heightened CVD risk. In addition to traditional cardiovascular risk factors, understanding nontraditional risk factors specific to women, like excess weight gain during pregnancy, preeclampsia, gestational diabetes, and menopause are central to designing personalized interventions aimed to curb the epidemic of CVD. In the present review, we examine the available evidence supporting a differential cardiovascular impact of increased adiposity in women compared with men and the proposed pathophysiological mechanisms behind these differences. We also discuss women-specific cardiovascular risk factors associated with obesity and insulin resistance.

Obesity and cardiovascular disease in women

Type 2 diabetes mellitus is a major risk factor for cardiovascular disease. However, compiled data suggest that type 2 diabetes affects the risk of cardiovascular disease differentially according to sex. In recent years, large meta-analyses have confirmed that women with type 2 diabetes have a higher relative risk of incident coronary heart disease, fatal coronary heart disease, and stroke compared with their male counterparts. The reasons for these disparities are not completely elucidated. A greater burden of cardiometabolic risk in women was proposed as a partial explanation. Indeed, several studies suggest that women experience a larger deterioration in major cardiovascular risk factors and put on more weight than do men during their transition from normoglycemia to overt type 2 diabetes. This excess weight is associated with higher levels of biomarkers of endothelial dysfunction, inflammation, and procoagulant state. Moreover, sex differences in the prescription and use of some cardiovascular drugs may compound an "existing" disparity. We searched PubMed for articles published in English and French, by using the following terms: ("cardiovascular diseases") AND ("diabetes mellitus") AND ("sex disparity" OR "sex differences" OR "sex related differences" OR "sex-related differences" OR "sex disparities"). In this article, we review the available literature on the sex aspects of primary and secondary prevention of cardiovascular disease in people with type 2 diabetes, in the predisposition to cardiovascular disease in those people, and in the control of diabetes and associated cardiovascular risk factors.

Cardiovascular Disease in Type 2 Diabetes: A Review of Sex-Related Differences in Predisposition and Prevention.

Reports from recent studies suggest that diabetes confers a higher risk of cardiovascular disease in women compared to men. Larger studies, including meta-analyses, report that women with diabetes have a 44 % greater risk of incident coronary heart disease and a 27 % greater risk of incident stroke compared to men with diabetes. In this article, we summarize results from longitudinal studies that examine sex differences in risk factors for and rates of macrovascular complications from diabetes. We also discuss possible mechanisms for increased cardiovascular risk associated with diabetes in women compared to men, including the clustering of hypertension, obesity, and elevated triglycerides, the possible contribution of hormonal differences, and sex differences in the prescription of and adherence to pharmacologic treatment. In conclusion, diabetes is associated with a slightly higher risk of cardiovascular disease in women compared to men. Future studies should further explore the reasons underlying imperfect use of medications that lower cardiovascular risk in both women and men with diabetes.

Sex-Specific Differential in Risk of Diabetes-Related Macrovascular Outcomes

Abstract No. 594 Single Session Mechanical Thrombectomy of Ileofemoral Deep Vein Thrombosis with ClotTriever: Exploring its Possibilities in an Outpatient Setting

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Sex-Specific Differential in Risk of Diabetes-Related Macrovascular Outcomes

Abstract No. 594 Single Session Mechanical Thrombectomy of Ileofemoral Deep Vein Thrombosis with ClotTriever: Exploring its Possibilities in an Outpatient Setting