Abstract
BACKGROUND: A later age at menopause (≥55 years) is associated with lower cardiovascular disease risk compared with a normal age at menopause (45-54 years) in postmenopausal women (PMW). Aortic stiffening increases cardiovascular disease risk, but the impact of late-onset menopause on aortic stiffness is unknown. METHODS: Total aortic stiffness (carotid-femoral pulse wave velocity [PWV(CF)]) was measured in 40 late-onset and 86 normal-onset PMW. Structural- and load/blood pressure-dependent PWV(CF) were calculated with exponential models; the percent of total PWV(CF) attributable to each was determined. Elastic modulus was assessed in aortic rings from female C57BL/6 N mice (3-6 months) exposed to 5% PMW serum. Lipidomics and triglyceride-related metabolite exposure of aortas with/without the mitochondrial antioxidant MitoQ identified lipid drivers of mitochondrial reactive oxygen species-related stiffness. RESULTS: PWV(CF) was 128 cm/s lower in late-onset (835±24 cm/s) versus normal-onset (963±24 cm/s) PMW. The difference in PWV(CF) remained >100 cm/s in multivariable models adjusted for age and education, cardiovascular disease risk factors, and medication use. Systolic and diastolic blood pressure were 10 and 6 mmHg lower in late-onset PMW. Some (<20%) of the attenuated PWV(CF) in late-onset PMW was related to lower load-dependent PWV(CF). However, the majority (≈85%) was attributable to lower structural-dependent PWV(CF). Elastic modulus was 35% lower in aortas exposed to serum from late- versus normal-onset PMW because of less mitochondrial reactive oxygen species-dependent stiffness. Triglyceride (16:0) was a driver of the effects of serum. CONCLUSIONS: Our findings suggest attenuated aortic stiffening via lower structural-dependent factors may be one mechanism by which late-onset menopause lowers cardiovascular disease risk.