Sex as a Biological Variable in Atherosclerosis

Abstract

Atherosclerosis is a chronic inflammatory vascular disease and the predominant cause of heart attack and ischemic stroke. Despite the well-known sexual dimorphism in the incidence and complications of atherosclerosis, there are relatively limited data in the clinical and preclinical literature to rigorously address mechanisms underlying sex as a biological variable in atherosclerosis. In multiple histological and imaging studies, overall plaque burden and markers of inflammation appear to be greater in men than women and are predictive of cardiovascular events. However, while younger women are relatively protected from cardiovascular disease, by the seventh decade, the incidence of myocardial infarction in women ultimately surpasses that of men, suggesting an interaction between sex and age. Most preclinical studies in animal atherosclerosis models do not examine both sexes, and even in those that do, well-powered direct statistical comparisons for sex as an independent variable remain rare. This article reviews the available data. Overall, male animals appear to have more inflamed yet smaller plaques compared to female animals. Plaque inflammation is often used as a surrogate end point for plaque vulnerability in animals. The available data support the notion that rather than plaque size, plaque inflammation may be more relevant in assessing sex-specific mechanisms since the findings correlate with the sex difference in ischemic events and mortality and thus may be more reflective of the human condition. Overall, the number of preclinical studies directly comparing plaque inflammation between the sexes is extremely limited relative to the vast literature exploring atherosclerosis mechanisms. Failure to include both sexes and to address age in mechanistic atherosclerosis studies are missed opportunities to uncover underlying sex-specific mechanisms. Understanding the mechanisms driving sex as a biological variable in atherosclerotic disease is critical to future precision medicine strategies to mitigate what is still the leading cause of death of men and women worldwide.

Arterial Thrombosis in Coronavirus Disease 2019 Patients: A Rapid Systematic Review

“…Arterial thromboembolism in the general population commonly affects more males compared with females. 46 , 47 This observation was similarly reflected in our analysis and has been explained by the differences in hormonal and genetic profiles of the 2 sexes 46 , 47 with female sex hormones producing a favorable immune modulation. 48 Furthermore, the prevalence and severity of COVID-19 has since been established to be higher in males than in females.…”

Moderate Alcohol Consumption Targets S100β+ Vascular Stem Cells and Attenuates Injury‐Induced Neointimal Hyperplasia

“…with other studies in mice, albeit using different models (ApoE -/-) (Zhang et al, 2018), and with clinical findings in humans supporting sex differences in the manifestation of cardiovascular disease (Man et al, 2020;Zhang et al, 2020). The precise mechanisms underlying these sex differences are likely complex and not yet fully understood.…”

Cohort profile: BIOVASC-late, a prospective multicentred study of imaging and blood biomarkers of carotid plaque inflammation and risk of late vascular recurrence after non-severe stroke in Ireland

“…Finally, age-specific and sex-specific variations in FDG-uptake, atherosclerotic plaque development and clinical endpoints are increasingly recognised. 37 The majority of the patients in this study are older men (mean age 69.8 years, 68.4% male) and therefore this may limit the generalisability of our findings. However, any association between FDG-uptake and outcome will adjust for age and gender to mitigate against potential confounding.…”