Sex-specific cardiac ageing and sympathetic compensation: a translational study

Abstract Background and Aims Recent evidence suggests that individuals with smaller left ventricular (LV) volumes and high LV ejection fraction face an increased risk of cardiovascular morbidity and mortality. Age-related cardiac changes may particularly predispose women to these risk conditions. Methods LV morphometry was analysed by cardiac magnetic resonance imaging in 39 616 individuals (aged 45–85 years, 52.2% women) from the UK Biobank using an observational cross-sectional study design. Additional analyses were conducted in a mouse model of hormone withdrawal and ageing (118 mice aged 4–6 [young cohort] or 18–20 [aged cohort] months, 50% females) as well as in a 3D human microtissue (hMT) model assessing the cellular effects of sex hormones. Results Both women and men exhibited age-related reduction of LV volumes, with women showing a significantly stronger decline than men (indexed LV end-diastolic volume [LVEDVI]: r = −0.272, P = .037 vs men). A compensatory increase in baseline heart rate (HR) was more pronounced in women (r = 0.121, P < .001 vs men) resulting in a lesser age-related decline in cardiac indices in women than in men (r = −0.169 in women vs r = −0.211 in men, P = .045 vs men). In mice, sex differences in cardiac ageing were more pronounced than in humans, with age-related reductions in LV volumes alongside an increase in collagen I production (0.743 ± 0.364 vs 1.611 ± 0.372 arbitrary units [AU], P = .002 and 1.925 ± 0.27 vs 1.838 ± 0.329 AU, P = .0972 for young vs old in males), being significant only in females (LVEDVI: P < .001 for young vs old females). Withdrawal of sex hormones in mice eliminated age-related changes in LV volumes. Compensatory mechanisms accounting for smaller LV volumes, including an age-related increase in HR (377 ± 45 vs 438 ± 40 bpm, P = .012 for young vs old females) and cardiac sympathetic activity (0.206 ± 0.02 vs 0.148 ± 0.03% injected dose per mL, P = .008 for young vs old females), were significant only in female mice. In a 3D hMT model, both female and male sex hormones exerted anti-fibrotic and anti-apoptotic effects on cardiomyocytes and fibroblasts. A decline in female sex hormone production with age was observed in both species, while testosterone levels remained essentially unchanged over the lifespan. Conclusions Age-related cardiac changes affect both women and men in similar ways, but are more pronounced in women—likely reflecting a greater decline in sex hormones. This is associated with more prominent compensatory mechanisms to offset their disadvantage of having a smaller heart. Animal and tissue models support these findings by revealing hormone- and sex-specific effects on cardiac structure and sympathetic regulation.