Sex differences in innate immune phenotype and valvular remodelling in aortic stenosis

Aortic stenosis (AS) involves fibrocalcific aortic valve remodelling, leading to left ventricular outflow obstruction. Innate immune responses can contribute to AS by promoting inflammation, fibrotic, and calcific remodelling. AS presents differently between sexes: males typically show a calcific phenotype, whereas females display more fibrosis. The mechanisms underlying these differences remain unclear. Therefore, this study aimed to investigate sex differences in innate immune phenotype and function in AS.

This cross-sectional study included 119 patients with tricuspid AS (70% male) and 65 healthy controls (52% male). Aortic valves from 23 surgical aortic valve replacement (SAVR) patients (61% male) were examined histologically to assess fibrocalcific remodelling patterns. Blood cell composition, circulating inflammatory markers, and monocyte phenotypes were analysed, with cytokine production evaluated after peripheral blood mononuclear cell (PBMC) stimulation. Males with AS exhibited greater valve calcification, while females demonstrated higher proteoglycan deposition and fibrosis. Males had higher circulating monocyte numbers and percentages, while females had higher lymphocyte percentages. PBMC stimulation induced higher cytokine responses (IL-1β, IL-1Ra) in males, predominantly TLR-3-driven, compared to females. Both sexes displayed higher systemic inflammation versus controls, but with distinct patterns: females had lower platelet counts, higher monocyte CD41 and lower HLA-DR membrane expression, whereas males showed higher cytokine production capacity.

This study suggests sex-dependent inflammatory mechanisms in AS. Males exhibited a calcific valve phenotype, while females had more fibrosis. Males had higher monocyte numbers and a more pronounced innate immune response, whereas females showed higher lymphocyte percentages and, compared to controls, an altered monocyte phenotype.

ClinicalTrials.gov ID: NCT04717219