Karina Gasbarrino, Doctorate Degree: Sonaro: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing)
Background: Sex differences exist in plaque morphology and composition; men are more prone to develop unstable plaques, while women develop more stable plaques. However, despite these differences, there is lack of sex-specific guidelines for carotid disease management; this leads to suboptimal prevention and/or treatment of strokes particularly in women. Thus, circulating markers that reflect sex-specific features in the plaque should be explored for better prediction of stroke risk in women and in men. Herein we investigated 1) sex differences in the adipokine, lipid, and immune circulating profiles of men and women with stable versus unstable plaques, and 2) sex-specific differences in circulating sex hormone levels.
METHODS AND RESULTS: Plaque specimens and pre-operative blood samples were collected from men and women undergoing a carotid endarterectomy (n=460) at McGill University-affiliated hospitals. Blood samples were used to perform adipokine, lipid, immune and sex hormone profiling. Specifically, sex hormones were analyzed via in-house liquid chromatography-tandem mass spectrometry methods. 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. Several circulating immune parameters served as independent sex-specific markers of plaque instability; low total white blood cell (WBC) counts, a high monocyte to WBC ratio, and a 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. In men, multivariate regression models also identified higher circulating testosterone and lower 17ß-estradiol [E2] levels, as well as a higher testosterone to E2 ratio to be independently associated with greater plaque instability (1.005 [1.001-1.009], 0.987 [0.976-0.997], 1.029 [1.005-1.054], respectively) and unstable plaque composition (i.e., greater presence of inflammation and neovascularization). However, among women, no consistent associations were observed between sex hormones and plaque instability.
Conclusion: Our novel findings demonstrated sex-specific differences between older men and postmenopausal women with severe carotid atherosclerosis at the level of the circulation and plaque. We revealed several immune parameters to serve as independent sex-specific markers of plaque instability. Following future validation, these markers could be implemented into clinical practice to monitor when the plaque becomes unstable and help better select men and women for plaque management. Finally, our findings also suggest that high testosterone and low estradiol levels may play a critical role in the development of plaque instability in men with carotid atherosclerotic disease but not in women.
