Importance of sex and gender in ischaemic stroke and carotid atherosclerotic disease

Abstract Stroke is a leading cause of death and disability worldwide. Women are disproportionately affected by stroke, exhibiting higher mortality and disability rates post-stroke than men. Clinical stroke research has historically included mostly men and studies were not properly designed to perform sex- and gender-based analyses, leading to under-appreciation of differences between men and women in stroke presentation, outcomes, and response to treatment. Reasons for these differences are likely multifactorial; some are due to gender-related factors (i.e. decreased social support, lack of stroke awareness), yet others result from biological differences between sexes. Unlike men, women often present with ‘atypical’ stroke symptoms. Lack of awareness of ‘atypical’ presentation has led to delays in hospital arrival, diagnosis, and treatment of women. Differences also extend to carotid atherosclerotic disease, a cause of stroke, where plaques isolated from women are undeniably different in morphology/composition compared to men. As a result, women may require different treatment than men, as evidenced by the fact that they derive less benefit from carotid revascularization than men but more benefit from medical management. Despite this, women are less likely than men to receive medical therapy for cardiovascular risk factor management. This review focuses on the importance of sex and gender in ischaemic stroke and carotid atherosclerotic disease, summarizing the current evidence with respect to (i) stroke incidence, mortality, awareness, and outcomes, (ii) carotid plaque prevalence, morphology and composition, and gene connectivity, (iii) the role of sex hormones and sex chromosomes in atherosclerosis and ischaemic stroke risk, and (iv) carotid disease management. Graphical Abstract Graphical Abstract Summary of differences between women and men at the pre-stroke, stroke management, and outcome level. All differences listed are described as observed in women. Blue text indicates where gender may play a role. CEA, carotid endarterectomy; tPA, tissue plasminogen activator. Created with BioRender.com.