Risk of aortic stenosis

Anatomical, genetic, and clinical factors all contribute to the pathogenesis of aortic stenosis. Calcification occurs in many patients with a normal trileaflet aortic valve, but the presence of a congenital bicuspid valve accounts for 60% of the patients younger than 70 years of age who undergo valve replacement for severe aortic stenosis and for 40% of those 70 years of age or older. Bicuspid aortic-valve disease is present in 1 to 2% of the U.S. population, and nearly all affected persons require aortic-valve replacement during their lifetimes. Although rheumatic heart disease, which can cause aortic stenosis in association with rheumatic mitral-valve disease, is now rare in the United States and Europe, the condition remains prevalent in underdeveloped countries, where improvement in primary prevention (treatment of streptococcal throat infections) is needed.

A genetic component in calcific aortic stenosis is suggested by familial clustering of patients with bicuspid aortic valves in a pattern suggesting autosomal dominant inheritance with variable penetrance. A specific gene abnormality has not been identified, and only about one third of families have more than one affected family member. Familial clustering has also been reported for calcific trileaflet aortic stenosis, with several generations of patients descended from a single ancestor. In a few families with congenital aortic-valve abnormalities and valve calcification, a mutation in NOTCH1 has been documented. In a genomewide linkage meta-analysis of three large population-based studies, a specific lipoprotein(a) polymorphism was shown to be associated with elevated serum levels of lipoprotein(a), aortic-valve calcification, and incident aortic stenosis.

Clinical factors associated with calcific valve disease mirror those associated with coronary atherosclerosis, and coronary artery disease is common among adults with aortic stenosis. Population-based studies have shown associations between calcific valve disease and older age, male sex, elevated serum levels of low-density lipoprotein (LDL) cholesterol and lipoprotein(a), hypertension, smoking, diabetes, and the metabolic syndrome.

Specific populations at increased risk for aortic stenosis include patients with a history of mediastinal irradiation, renal failure, familial hypercholesterolemia, or disorders of calcium metabolism. The role of subtle differences in calcium metabolism has received increased attention, with one study showing a close relationship between serum phosphate levels and calcific aortic-valve disease.