Aortic valve stenosis (AS) and its precursor, aortic valve sclerosis (ASc), occur frequently in Western populations. Investigations to retard the progression of AS using statins have been unsuccessful. Development of ASc in humans is associated with increased aortic valve backscatter (AVBS) and poor tissue nitric oxide (NO) responsiveness. In an animal model, ramipril retarded AS/ASc development. We have now set out to identify factors associated with the progression of ASc in humans. METHODS AND RESULTS: At baseline and after 4 years, 204 randomly selected subjects (age 63 ? 6 years at study entry) underwent echocardiography with the determination of AVBS values, measurements of platelet NO responsiveness, plasma asymmetric dimethylarginine concentrations, lipid profile, high-sensitivity-C-reactive protein, routine biochemistry, and 25-hydroxy-vitamin D levels. During the study period, 68 of subjects had detectable AVBS progression. On multivariate analysis, higher calcium concentrations (? = 0.22; P = 0.004), poor platelet NO responsiveness (? = 0.18; P = 0.018), and increased arterial stiffness (? = 0.15; P = 0.044) were independent predictors of disease progression. The use of angiotensin-converting enzyme-inhibitors/angiotensin II receptor blockers (ACE-I/ARB) predicted the lack of disease progression (assessed categorically) in the overall cohort and in those without ASc at baseline (n = 159) (? = 0.8; P = 0.025 and ? = 1.3; P = 0.001, respectively). No conventional coronary risk factors were associated with disease progression. CONCLUSION: This study of early aortic valve disease (i) demonstrates that disease progression occurs in the majority of the normal ageing population over a 4-year period; (ii) provides evidence of the importance of the NO signalling cascade in disease development and progression; and (iii) provides additional data linking ACE-I/ARB use with the retardation of ASc.