Calcific aortic valve disease: outflow obstruction is the end stage of a systemic disease process.

Over the past decade, a body of evidence has accumulated demonstrating that calcific aortic valve disease (CAVD) is prevalent in older adults and that the presence of calcific valve disease is associated with adverse clinical outcomes, even in the absence of left ventricular (LV) outflow tract obstruction. Stritzke et al. report for the KORA/MONICA study that degenerative (or calcific) aortic valve disease was present in 28% of a population-based sample of .900 adults with a mean age of 50 years. This finding parallels previous population-based studies such as the Helsinki Aging Study with a prevalence of aortic sclerosis of 21% in adults aged 55–71 years and the Cardiovascular Health Study (CHS) with aortic sclerosis in 26% of adults age 65 years or older. Further, in the KORA/MONICA study, the presence of calcific valve disease was associated with age, active smoking, and elevated total cholesterol on a baseline evaluation carried out 10 years before the echocardiographic study. These findings support the concept that patients ‘at risk’ of CAVD can be identified based on these associated clinical factors. In addition to age, smoking, and hypercholesterolaemia, previous studies have convincingly shown that the presence of calcific valve disease is associated with hypertension, diabetes, and the metabolic syndrome. Recent data from the Multi-Ethnic Study of Atherosclerosis (MESA) study indicated that the total cholesterol to HDL ratio is associated with an increased risk of CAVD across the entire age range (45–84 years), whereas LDL is associated with increased risk only in those ,65 years of age. ‘At risk’ patients also include those with a congenitally bicuspid aortic valve, which accounts for .50% of aortic valve replacements, and may explain the male predominance of CAVD. Genetic factors may modulate the risk of calcific valve disease, with clustering of cases suggesting a familial component and case–control studies suggesting association with polymorphisms in the vitamin D receptor, oestrogen receptor, interleukin-10, and apolipoprotein E4 allele, among others. We also know that the presence of CAVD without obstruction to LV outflow, e.g. aortic sclerosis, is associated with adverse clinical outcomes. In the CHS study, aortic sclerosis was associated with an 50% increased risk of cardiovascular death and myocardial infarction, even after correction for known coronary disease and associated clinical factors. In the LIFE hypertension study, the presence of aortic sclerosis was associated with a doubling of cardiovascular events, both in those with and without known coronary artery disease. In the ARIC study of 2279 African-American adults, the strongest multivariate predictor of myocardial infarction and cardiovascular death was aortic sclerosis, with less strong predictors including blood pressure, smoking, and markers of systemic inflammation. The consistent findings of these diverse studies suggest that CAVD is a marker of systemic disease and that these patients are at increased risk of adverse clinical events long before there is mechanical obstruction to ventricular ejection. In that light, it is intriguing that the KORA/MONICA study found differences in LV geometry and diastolic function between subjects with and without calcific valve disease, even though these patients did not have significant outflow obstruction. Compared with subjects with a normal aortic valve, those with calcific valve disease had a higher relative wall thickness and LV mass index, as well as a higher ratio of early diastolic transmitral to tissue Doppler velocity, suggesting elevated LV filling pressures. Further, over the 10 year interval, relative wall thickness increased more in those with calcific valve disease than in those with a normal valve. The possibility of subtle changes in LV afterload related to early valve disease cannot be ignored, although the reported haemodynamics are consistent with aortic sclerosis, not valve obstruction. If these findings are confirmed in future studies, they suggest that adverse changes in LV geometry accompany CAVD, rather than simply reflecting the ventricular response to chronic pressure overload.