Circulating ACE2 levels and ACE I/D polymorphism in severe aortic stenosis

The renin–angiotensin system (RAS) contributes to the fibro-calcific remodeling characteristic of aortic stenosis (AS). Although increased circulating ACE2 enzymatic activity has been reported in severe AS, data on circulating ACE2 protein concentration, ACE levels, and their relationship with ACE genetic variation remain limited. In this cross-sectional case–control study, 80 participants (40 severe AS, 40 matched controls) underwent measurement of circulating ACE and ACE2 concentrations by ELISA and genotyping for the ACE insertion/deletion (I/D) polymorphism (rs4340). Multivariable logistic regression assessed the independent association between ACE2 and severe AS after adjustment for age, serum creatinine, ACEi/ARB therapy, and genotype. Firth penalized regression was performed as sensitivity analysis. Circulating ACE2 concentrations were higher in severe AS compared with controls (median 1.9 vs. 0.8 ng/mL, p = 0.005), whereas ACE levels were similar between groups. ACE2 remained independently associated with severe AS (odds ratio per doubling 1.48, 95% CI 1.05–2.08; p = 0.025), with consistent estimates in penalized models. ACE I/D genotype distribution differed between groups (p = 0.012), with the II genotype independently associated with severe AS compared with ID. Neither circulating ACE2 nor ACE I/D genotype correlated with echocardiographic indices of stenosis severity or CT-derived valvular calcification. Severe AS was associated with higher circulating ACE2 concentrations despite comparable ACE levels and a differential distribution of the ACE I/D polymorphism, consistent with altered systemic RAS balance in advanced valvular disease. These findings are hypothesis-generating and require validation in larger prospective cohorts.