Circulating Sex-specific Markers of Plaque Instability in Women and Men with Severe Carotid Atherosclerosis

Background Differences in plaque composition and instability exist among men and women. Circulating markers that reflect sex-specific features in the plaque should be explored for better prediction of high-risk plaques in women and in men. This study aims to 1) investigate differences in the lipid, immune, and adipokine circulating profiles of men and women with stable versus unstable plaques, and 2) identify circulating markers that can better classify men and women according to plaque instability. Methods Pre-operative blood samples as well as plaque specimens were collected from men and women undergoing a carotid endarterectomy (n=460). Blood samples were used for adipokine, lipid, and immune profiling. Plaque stability was determined by gold-standard histological classifications. Results Men had more unstable plaques than women (P<0.001), exhibiting greater plaque hemorrhage, a larger lipid core, and more inflammation (P<0.001), as well as less favourable circulating profiles. Significant antagonistic interactions were observed between sex and white blood cell (WBC) counts, sex and basophil to WBC ratio, and sex and platelet counts on impacting plaque instability. Several circulating immune parameters served as independent sex-specific markers of plaque instability; low total white blood cell (WBC) counts, high monocyte to WBC ratio, and low basophil to WBC ratio were associated with greater plaque instability in men, while a higher basophil to WBC ratio was observed in women with unstable plaques. Conclusions Our findings demonstrated sex-specific differences between older men and postmenopausal women with severe carotid atherosclerosis, with women displaying more stable plaque phenotypes, and favourable circulating profiles compared to men. We identified several potential circulating markers that relate to sex-specific plaque phenotypes for better prediction of high-risk plaques in women and in men. Following future validation, these markers could be implemented into clinical practice to monitor when the plaque becomes unstable and better select men and women for intervention.