Sex-specific differences in age-related aortic valve calcium load: A systematic review and meta-analysis

Aging of the aortic valve, characterized by leaflet thickening and loss of extensibility, leads to progressive changes in valve function. These age-related mechanisms have not been evaluated yet in sex-specific calcific aortic valve stenosis (CAVS) onset and progression. Recent studies reported the association between high aortic valve calcification (AVC) load and male gender in patients with CAVS while women present faster progression than men. To evaluate these age- and sex-specific differences, we performed a systematic review and meta-analysis with meta-regression. A systematic search related to AVC measured by computed tomography and gender-specific differences was conducted according to PRISMA guidelines. Seven studies, enrolling 1859 men and 1055 women, were included in the quantitative synthesis. We found a significant difference between men and women both in AVC load and density. AVC load mean difference (MD), between men and women, was 1131 ± 243 AU (p < 0.0001; I²: 96.5 %, p < 0.001), while AVC density MD was 159 ± 20 AU/cm² (p < 0.0001) without heterogeneity among the studies (I²: 23.5, p = 0.3). Meta-regression analyses showed that AVC load MD positively correlated with age and other cardiovascular risk factors such as diabetes, hypertension, and coronary artery disease presence. Our meta-analysis shows a significant association of incremental AVC load with male gender, regardless of the individual anatomical characteristics and the cardiovascular risk factors. Further studies are needed: i) to clarify if there are different sex-related pathophysiological processes driving the development and the progression of age-related CAVS, and ii) to determine if a sex-specific therapeutic strategy should be applied for CAVS treatment and/or prevention.