title: Pathogenesis of aortic stenosis: not just a matter of wear and tear.
abstract: Aortic valve stenosis (AS) is the commonest form of valvular heart disease in the Western world. Its prevalence increases exponentially with age and it is present in 2-7% of all patients over 65 years of age. In view of the considerable cardiovascular morbidity and mortality associated not only with AS, but even its earlier stage, aortic sclerosis, many investigations have been directed towards better understanding of its pathogenesis, with the ultimate objective of developing strategies to retard its progression. Although risk factors and downstream mediators appear similar for AS and atherosclerosis (older age, male sex, hypertension, smoking, hypercholesterolemia, and diabetes, as many as 50% of patients with AS do not have clinically significant atherosclerosis. On the basis both of recent experimental evidence and clinical trials, it appears that atherogenesis is not pivotal to the pathogenesis of AS. On the other hand, there is increasing evidence of active involvement of aortic valve fibroblasts with resultant increased production of reactive oxygen species, active pro-inflammatory and pro-fibrotic processes culminating in calcification. We also discuss the evidence of involvement of the nitric oxide system in the pathogenesis of AS. The renin-angiotensin system has also emerged as a major player in the pathogenesis of AS. Histologically, there is increased ACE expression and elevated angiotensin II levels in stenotic valves, while we have just demonstrated amelioration of AS with the use of ACE inhibitors in an animal model. We further discuss intervention studies aimed at retarding AS progression, including recent failures of statins to retard progression of AS in large randomized clinical studies. Finally, we discuss the special case of bicuspid aortic valve, including its genetics and unique associated features.
authors.affiliation: The Queen Elizabeth Hospital, University of Adelaide South Australia, Australia.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sverdlov
authors.forename: Doan Tm
authors.initials: DT
authors.lastname: Ngo
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Chapman
authors.forename: Onn Akbar
authors.initials: OA
authors.lastname: Ali
authors.forename: Yuliy Y
authors.initials: YY
authors.lastname: Chirkov
authors.forename: John D
authors.initials: JD
authors.lastname: Horowitz