Sex-Specific Molecular Patterns Reveal Distinct Age-Associated Arterial Wall Remodeling

BACKGROUND: Coronary artery disease is highly prevalent among elderly patients and often requires revascularization through coronary artery bypass grafting. Women typically undergo coronary artery bypass grafting at older ages than men and experience worse outcomes, disparities that persist even after adjustment for age and clinical variables, suggesting that elderly women face unique biological vulnerabilities not captured by traditional risk factors. This study investigated sex-specific molecular patterns associated with distinct age-associated arterial wall remodeling in patients with coronary artery disease. METHODS: In this cross-sectional study, internal thoracic artery specimens were obtained between July 2022 and August 2023 from 135 patients undergoing coronary artery bypass grafting (88 males and 47 females; mean age, 66.3 years). Patients were stratified by age (<65 versus ≥65 years) and sex. Structural remodeling was assessed histologically, and transcriptomic profiles were characterized using whole transcriptome sequencing, followed by pathway-level bioinformatic analyses and targeted quantitative real-time polymerase chain reaction validation. RESULTS: Elderly patients exhibited distinct patterns of intimal hyperplasia: internal thoracic arteries from elderly males showed thicker intimal layers, whereas those from elderly females demonstrated medial thinning, with a significant age-by-sex interaction for medial thickness ( P =0.017). Transcriptomic profiling revealed age-associated enrichment of lipid metabolism–related pathways, with upregulation of ADIPOQ , LPL , and FABP4 in elderly patients of both sexes. Divergent molecular patterns were identified beyond this shared age-associated profile. Males showed a proliferative pattern associated with immune suppression and lower EGR1 expression, whereas females exhibited a pattern consistent with impaired structural integrity, accompanied by upregulation of stress-response genes ( JUN and JUNB ) and reduced expression of the extracellular matrix gene FN1 . CONCLUSIONS: Internal thoracic arteries from elderly patients with coronary artery disease exhibit distinct sex-specific arterial wall remodeling patterns, with immune-suppressed proliferative remodeling in males and stress-associated extracellular matrix vulnerability in females. These findings provide a biological framework for understanding sex differences in age-associated arterial remodeling and may provide context for sex disparities in cardiovascular outcomes.