Correspondence

Calcific Aortic Stenosis

N Engl J Med 2009; 360:85-86January 1, 2009

Article

To the Editor:

In their article on intensive lipid lowering, Rossebø et al. (Sept. 25 issue)1 report that therapy with simvastatin and ezetimibe did not reduce aortic-valve disease and calcifications in patients with mild-to-moderate asymptomatic aortic stenosis. In an accompanying editorial, Otto2 accurately states that “calcific aortic stenosis is not atherosclerosis.” However, she does not take advantage of this opportunity to develop the conclusion further. Indeed, in a variety of murine models, vascular calcification develops in the absence of overt atherosclerosis.3 Furthermore, osteoprotegerin has been reported to inhibit vascular calcification without affecting atherosclerosis,3 and therapy with bone morphogenetic protein 7 (BMP-7) has also shown similar results.4 Therefore, it might be the right time to look more closely at the calcific aortic valve in other models and conditions, including chronic renal disease, in which the incidence of calcification is increased5 and the cellular basis of calcification has been clarified.

Michael Pazianas, M.D.
Oxford University Institute of Musculoskeletal Sciences, Oxford OX3 7LD, United Kingdom
michael.pazianas@ndos.ox.ac.uk

5 References

1. 1

   Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-1356
   Full Text | Web of Science | Medline

2. 2

   Otto CM. Calcific aortic stenosis -- time to look more closely at the valve. N Engl J Med 2008;359:1395-1398
   Full Text | Web of Science | Medline

3. 3

   Hsu JJ, Tintut Y, Demer LL. Murine models of atherosclerotic calcification. Curr Drug Targets 2008;9:224-228
   CrossRef | Web of Science | Medline

4. 4

   Davies MR, Lund RJ, Mathew S, Hruska KA. Low turnover osteodystrophy and vascular calcification are amenable to skeletal anabolism in an animal model of chronic kidney disease and the metabolic syndrome. J Am Soc Nephrol 2005;16:917-928
   CrossRef | Web of Science | Medline

5. 5

   Maher ER, Pazianas M, Curtis JR. Calcific aortic stenosis: a complication of chronic uraemia. Nephron 1987;47:119-122
   CrossRef | Medline

Author/Editor Response

In our study, we reported that clinical end points and echocardiographic hemodynamic measures of the progression of aortic stenosis were not influenced by combined lipid-lowering therapy. For clinical purposes, our findings resolved the role of lipid lowering in patients with mild-to-moderate aortic stenosis. The influence on the degree of calcification of the valve is the subject of an ongoing substudy. We agree with Pazianas that future research should focus on basic cellular pathophysiology. Since renal insufficiency was an exclusion criterion in our study, we were unable to study its effect on the progression of valve disease. In addition to the mechanisms mentioned by Pazianas, the factors that activate and regulate the alpha–smooth-muscle actin–positive valve interstitial cells (myofibroblasts), which also induce biomineralization, are strong candidates.1 Other mechanisms include possible up-regulation of osteogenic genes and numerous regulatory processes, possibly resembling vascular processes.2 The role of Ca-phosphate product, calcification of matrix vesicles, fetuin-A,3 the osteoprotegerin–RANKL–RANK axis,4 BMP-7, and the renin–angiotensin system5 must be clarified in valvular tissue and in human aortic valves in vivo.

Anne B. Rossebø, M.D.
Aker University Hospital, N-0514 Oslo, Norway
anne@rossebo.net

Terje R. Pedersen, M.D., Ph.D.
Ullevål University Hospital, N-0407 Oslo, Norway

Y. Antero Kesäniemi, M.D., Ph.D.
University of Oulu, SF-90029 Oulu, Finland

5 References

1. 1

   Akat K, Borggrefe M, Kaden JJ. Aortic valve calcification — basic science to clinical practice. Heart 2008 July 16 (Epub ahead of print).
   

2. 2

   Giachelli CM. Vascular calcification mechanisms. J Am Soc Nephrol 2004;15:2959-2964
   CrossRef | Web of Science | Medline

3. 3

   Ix JH, Chertow GM, Shlipak MG, Brandenburg VM, Ketteler M, Whooley MA. Association of fetuin-A with mitral annular calcification and aortic stenosis among persons with coronary heart disease: data from the Heart and Soul Study. Circulation 2007;115:2533-2539
   CrossRef | Web of Science | Medline

4. 4

   Bennett BJ, Scatena M, Kirk EA, et al. Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE−/− mice. Arterioscler Thromb Vasc Biol 2006;26:2117-2124
   CrossRef | Web of Science | Medline

5. 5

   Helske S, Lindstedt KA, Laine M, et al. Induction of local angiotensin II-producing systems in stenotic aortic valves. J Am Coll Cardiol 2004;44:1859-1866
   CrossRef | Web of Science | Medline

Author/Editor Response

As Pazianas notes, recent studies highlight the differences between calcific aortic stenosis and atherosclerosis. Unlike atherosclerosis, increased oxidative stress in calcific aortic valves is associated with increased levels of superoxide and hydrogen peroxide, possibly mediated by the uncoupling of nitric oxide synthase activity.1 The association between increased oxidative stress and leaflet calcification suggests a possible causal relationship, perhaps potentiated by genetic and clinical factors.2 Decreased activity of normal tissue inhibitors appears to be a factor in both pathologic angiogenesis and in dystrophic calcification of valve leaflets.3 For example, reduced expression of chondromodulin-I, an antiangiogenic factor, has been shown in aged mice with calcific valve disease.4 In addition, studies of human valves with a range of disease from normal to severe stenosis showed progressive increases in gene expression of osteopontin, osteoprotegerin, and bone sialoprotein II, along with decreased expression of other noncollagenous matrix proteins. The complexity of this active disease process is a challenge for researchers but also suggests there are many potential targets for intervention to prevent disease progression.

Catherine M. Otto, M.D.
University of Washington, Seattle, WA 98195-6422
cmotto@u.washington.edu

4 References

1. 1

   Miller JD, Chu Y, Brooks RM, Richenbacher WE, Pena-Silva R, Heistad DD. Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. J Am Coll Cardiol 2008;52:843-850
   CrossRef | Web of Science | Medline

2. 2

   Bosse Y, Mathieu P, Pibarot P. Genomics: the next step to elucidate the etiology of calcific aortic valve stenosis. J Am Coll Cardiol 2008;51:1327-1336
   CrossRef | Web of Science | Medline

3. 3

   Hakuno D, Kimura N, Yoshioka M, Fukuda K. Molecular mechanisms underlying the onset of degenerative aortic valve disease. J Mol Med 2008 September 3 (Epub ahead of print).
   

4. 4

   Pohjolainen V, Taskinen P, Soini Y, et al. Noncollagenous bone matrix proteins as a part of calcific aortic valve disease regulation. Hum Pathol 2008 August 11 (Epub ahead of print).