editorial
Calcific Aortic Stenosis — Time to Look More Closely at the Valve

Catherine M. Otto, M.D.

Calcific aortic stenosis is a progressive disease that results in stiff valve leaflets with eventual obstruction to left ventricular outflow. Once symptoms occur, valve replacement is the only effective treatment, and there are no known therapies to prevent disease progression. However, several lines of evidence suggest that calcific valve disease is not simply due to age-related degeneration but, rather, is an active disease process with identifiable initiating factors, clinical and genetic risk factors, and cellular and molecular pathways that mediate disease progression.
The key initiating factor in the development of calcific aortic stenosis appears to be mechanical
stress. Specifically, a congenitally bicuspid valve, which is present in about 0.5 to 0.8% of
the population, is the underlying anatomy in the majority of valve replacements for aortic stenosis. [1] Blood-flow dynamics may also play a role, since early lesions are located on the aortic side of the valve in regions with low shear stress.
Clinical factors that are associated with the presence of calcific valve disease include older
age, male sex, elevated serum levels of low-density lipoprotein and lipoprotein(a), smoking, hypertension, diabetes, and the metabolic syndrome.[2]
The presence of mild valve changes, even in the absence of obstruction to blood flow, is associated with an increase of 50% in the risk of myocardial infarction and death from cardiovascular causes during the next 5 years. Genetic factors are difficult to study in a disease that often is not evident until the sixth or seventh decade of life. However, in a subgroup of families, a bicuspid valve appears to be inherited in an autosomal dominant pattern. In one study in France, familial clustering of calcific disease in trileaflet valves also was shown. Mutations in the signaling and transcriptional regulator NOTCH1 gene have been
identified in families with bicuspid aortic valves and leaflet calcification.[3] Case–control studies
have suggested an association between calcific aortic stenosis and genetic polymorphisms in
the vitamin D receptor, estrogen receptor, apolipoprotein E4, and interleukin-10 alleles.
Our understanding of disease progression at the tissue level is based on human valve studies
of either early lesions or end-stage disease, with the assumption that these processes represent
the ends of a disease spectrum .[4,5] Experimental models support this assumption, with
the demonstration that valve lesions occur in the presence of hypercholesterolemia, resulting in
leaflet calcification and valve obstruction.[6] Taken together, the association of calcific aortic stenosis with elevated serum lipid levels, the presence of lipid accumulation in the leaflets, and the increased risk of atherosclerotic clinical end points all lead to the hypothesis that lipid lowering therapy might slow or prevent disease progression. This hypothesis was supported by several retrospective clinical studies indicating slower hemodynamic progression or leaflet calcification in patients who were receiving lipid-lowering medications than in control subjects and by experimental models showing that lipid-lowering therapy blocks the development of valve lesions.[7]
Thus, the results of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study (ClinicalTrials. gov number, NCT00092677) that are reported in this issue of the Journal8 are disappointing. In this large, randomized, prospective clinical trial, Rossebø et al. convincingly show that aggressive lipid lowering does not affect either hemodynamic progression or the time to valve replacement in adults with aortic stenosis.[8] Although it is possible that treatment even earlier in the disease process might have some benefit, the study patients
had only mild-to-moderate disease. Other than those with a bicuspid valve or specific genetic
markers, earlier identification of patients at risk would be problematic. The reduction in
atherosclerotic clinical end points in this study is encouraging. However, the clinical effect was
small, given that benefit was primarily due to a reduced rate of coronary bypass grafting at the
time of valve replacement.
If intensive lipid-lowering therapy is not the answer to the prevention of aortic stenosis progression, where do we go from here? Many adults with calcific valve disease meet current indications for lipid-lowering therapy, and the SEAS study certainly supports the evaluation and reduction of risk factors in patients with aortic stenosis, as recommended for all adults by established guidelines. However, we can no longer reassure ourselves that either the lipid-lowering or pleiotropic effects of potent agents such as statins and ezetimibe might change the disease process in the valve leaflets. We need to explore other potential therapeutic targets, especially the pathways that lead to tissue calcification. Calcific aortic stenosis is not atherosclerosis. Although there is overlap in clinical risk factors, in tissue characteristics, and in the association between the presence of calcific valve disease and atherosclerotic clinical events, there also are major differences. In aortic valve stenosis, tissue calcification is more severe; the mechanism of clinical events is increased leaflet stiffness, not plaque rupture; and the severity of coronary and valve disease in an individual patient often is discordant.
Demonstrating clinical benefit of potential therapies for calcific aortic stenosis will be challenging.
The evaluation of clinical end points requires a large study group, and enrollment in prospective, randomized trials is slow, given the relatively low prevalence of valve disease. Calcific valve disease progresses slowly over decades, whereas clinical trials usually follow patients for
only a few years. Clinical end points often are difficult to assess because indications for valve
replacement remain somewhat subjective and because therapy may affect other cardiovascular
end points, which limits our understanding of the mechanism of benefit. Doppler echocardiography allows assessment of the effect of therapy on the degree of stenosis, but it is not perfect, because hemodynamic obstruction occurs only with a substantial amount of leaflet thickening. The ideal end point for measuring the effect of therapy would be direct evaluation of tissue changes in the valve leaflets. Such analysis is possible in experimental models but in humans is limited to the examination of leaflets removed at the time of valve surgery.[9] Computed tomographic imaging allows measurement of leaflet calcification but not of other tissue components. In the future, molecular imaging approaches may provide sensitive measures of tissue changes sequentially over time, allowing detection of significant differences between small study groups.[10]
It is time to integrate and expand our understanding of the interactions between initiating
factors, genetic and clinical cofactors, and the mechanisms of progression from an early inflammatory lesion to phenotypic transformation of valve myofibroblasts and then to the end stage of severe valve calcification. Discovery of an effective medical therapy for calcific aortic stenosis will require innovative approaches to disease prevention and ingenuity in proving the mechanism of benefit.
From the Division of Cardiology, Department of Medicine, University
of Washington, Seattle.
1. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid,
and tricuspid aortic valves in adults having isolated aortic
valve replacement for aortic stenosis, with or without associated
aortic regurgitation. Circulation 2005;111:920-5.
2. Katz R, Wong ND, Kronmal R, et al. Features of the metabolic
syndrome and diabetes mellitus as predictors of aortic
valve calcification in the Multi-Ethnic Study of Atherosclerosis.
Circulation 2006;113:2113-9.
3. Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1
cause aortic valve disease. Nature 2005;437:270-4.
4. Helske S, Oksjoki R, Lindstedt KA, et al. Complement system
is activated in stenotic aortic valves. Atherosclerosis 2008;
196:190-200.
5. Akat K, Borggrefe M, Kaden JJ. Aortic valve calcification —
basic science to clinical practice. Heart 2008 July 16 (Epub ahead
of print).
6. Weiss RM, Ohashi M, Miller JD, Young SG, Heistad DD. Calcific
aortic valve stenosis in old hypercholesterolemic mice. Circulation
2006;114:2065-9.
7. Rajamannan NM, Subramaniam M, Caira F, Stock SR, Spelsberg
TC. Atorvastatin inhibits hypercholesterolemia-induced
calcification in the aortic valves via the Lrp5 receptor pathway.
Circulation 2005;112:Suppl:I229-I234.
8. Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid
lowering with simvastatin and ezetimibe in aortic stenosis.
N Engl J Med 2008;359:1343-56.
9. Anger T, Pohle FK, Kandler L, et al. VAP-1, Eotaxin3 and
MIG as potential atherosclerotic triggers of severe calcified and
stenotic human aortic valves: effects of statins. Exp Mol Pathol
2007;83:435-42.
10. Aikawa E, Nahrendorf M, Sosnovik D, et al. Multimodality
molecular imaging identifies proteolytic and osteogenic activities
in early aortic valve disease. Circulation 2007;115:377- 86.