A systematic review and meta-analysis have demonstrated “convincing evidence” that sex differences exist in carotid atherosclerosis, with all types of plaque features—including those relating to size, composition, and morphology—found to be either larger or more common in men than in women.
“Our results highlight that sex is an important variable to include in both study design and clinical decision-making,” the authors, led by Dianne van Dam-Nolen (Erasmus University Medical Center, Rotterdam, The Netherlands), write in the journal Stroke. “Further investigation of sex-specific stroke risks with regard to plaque composition is warranted.”
Over the past few decades, several individual studies on sex differences in carotid atherosclerosis have been performed, covering a wide range of plaque characteristics and including different populations, van Dam-Nolen et al state.
In addition to summarising previously reported results on sex differences in this space, the researchers also sought to “present a roadmap explaining next steps needed for implementing this knowledge in clinical practice”.
They began by systematically searching PubMed, Embase, Web of Science, Cochrane Central and Google Scholar for eligible studies, including both male and female participants, and reporting the prevalence of imaging characteristics of carotid atherosclerosis. The eligible studies were then meta-analysed. Van Dam-Nolen et al prespecified which imaging modalities had to be used per plaque characteristic and excluded ultrasonography.
After initially identifying more than 1,000 unique citations, screening of the articles based on the inclusion criteria whittled this number down to a total of 60 articles, with 42 being included in the final meta-analyses.
Six of these studies were included in a meta-analysis on the relationship between sex and atherosclerotic plaque size. All three of the characteristics used to measure plaque size—maximum wall thickness (1D size), wall area (2D size), and wall volume (3D size)—were more likely to be larger in men than in women, van Dam-Nolen et al report. However, conversely, the normalised wall index, which accounts for the total vessel size, did not statistically significantly differ between male and female participants, which the researchers describe as “surprising”, and possibly indicative of sex differences in plaque size being driven by contrasting vessel sizes.
In addition, analysing three of the studies further regarding the degree of stenosis, the authors found no statistically significant sex difference for stenosis of 50–69%, although high-grade stenosis of 70–99% was more often seen in men than in women.
Meta-analyses relating to plaque composition examined the presence of calcifications, lipid-rich necrotic core (LRNC), and intraplaque haemorrhage (IPH), and found a higher prevalence in men versus women across all three components. Expounding briefly on their calcification findings, van Dam-Nolen et al report statistically significant differences between men and women for the presence and amount of carotid calcifications, but not in terms of calcification percentage i.e. the amount of calcification relative to the total plaque volume.
“Furthermore, we found more pronounced sex differences for LRNC in symptomatic as opposed to asymptomatic participants,” they add.
Five studies were also included in the meta-analysis of the relationship between sex and plaque morphology, with the presence of ulceration and the presence of a thin-or-ruptured fibrous cap both being higher in men.
In their report, the authors highlight multiple limitations of their analysis that “deserve comment”, including moderate-to-high heterogeneity among the included studies—especially with regard to plaque size and carotid calcifications—as well as the fact it was not possible to adjust for potential confounders on the relationship between sex and carotid atherosclerosis.
“The found sex differences in carotid atherosclerosis are of clinically significant importance, since the composition of plaque affects the risk of (recurrent) stroke,” van Dam-Nolen et al conclude. “Previous studies have shown that especially IPH contributes to a higher stroke risk. Carotid LRNC, calcifications, total plaque size, and plaque ulceration, have also been reported as important risk factors. With regard to sex-specific risk prediction and treatment, it is essential to investigate the effect of these plaque characteristics per sex separately. We hypothesise that the stroke risk as a result of specific plaque compositions varies among men and women.”
The authors further stress the importance of including an adequate number of men and women in clinical trials, as studies on sex-specific risks for (recurrent) stroke risk related to carotid plaque composition are “still lacking”. Men tend to have more “vulnerable” plaques than women, which has implications during stroke workup, for instance, and the role of IPH in carotid atherosclerosis underlines the relevance of using magnetic resonance imaging (MRI)—a modality that can identify IPH more reliably than ultrasonography or computed tomography angiography (CTA).
“It is important to realise that, although the exact mechanisms of sex differences in carotid atherosclerosis are still unclear, we are already able to act on these differences,” the authors add. “We can use this knowledge in clinical practice, being aware of differences in likelihood of having a vulnerable carotid plaque which affects patients’ stroke risk. Hence, the next step is to investigate the effect of plaque characteristics on stroke per sex separately. This will also allow us to make sex-specific risk scores in order to improve clinical decision-making.”
