To the Editor: In their article on intensive lipid lowering,Rossebø et al. (Sept. 25 issue)1 report that therapywith simvastatin and ezetimibe did not reduce aortic-valve diseaseand calcifications in patients with mild-to-moderate asymptomaticaortic stenosis. In an accompanying editorial, Otto2 accuratelystates that "calcific aortic stenosis is not atherosclerosis."However, she does not take advantage of this opportunity todevelop the conclusion further. Indeed, in a variety of murinemodels, vascular calcification develops in the absence of overtatherosclerosis.3 Furthermore, osteoprotegerin has been reportedto inhibit vascular calcification without affecting atherosclerosis,3 and therapy with bone morphogenetic protein 7 (BMP-7) hasalso shown similar results.4 Therefore, it might be the righttime to look more closely at the calcific aortic valve in othermodels and conditions, including chronic renal disease, in whichthe incidence of calcification is increased5 and the cellularbasis of calcification has been clarified.
Michael Pazianas, M.D. Oxford University Institute of Musculoskeletal Sciences Oxford OX3 7LD, United Kingdom michael.pazianas{at}ndos.ox.ac.uk
References
Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-1356. [Free Full Text]
Otto CM. Calcific aortic stenosis -- time to look more closely at the valve. N Engl J Med 2008;359:1395-1398. [Free Full Text]
Hsu JJ, Tintut Y, Demer LL. Murine models of atherosclerotic calcification. Curr Drug Targets 2008;9:224-228. [CrossRef][Web of Science][Medline]
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. [Free Full Text]
Maher ER, Pazianas M, Curtis JR. Calcific aortic stenosis: a complication of chronic uraemia. Nephron 1987;47:119-122. [Web of Science][Medline]
The authors reply: In our study, we reported that clinical endpoints and echocardiographic hemodynamic measures of the progressionof aortic stenosis were not influenced by combined lipid-loweringtherapy. For clinical purposes, our findings resolved the roleof lipid lowering in patients with mild-to-moderate aortic stenosis.The influence on the degree of calcification of the valve isthe subject of an ongoing substudy. We agree with Pazianas thatfuture research should focus on basic cellular pathophysiology.Since renal insufficiency was an exclusion criterion in ourstudy, we were unable to study its effect on the progressionof valve disease. In addition to the mechanisms mentioned byPazianas, the factors that activate and regulate the alpha–smooth-muscleactin–positive valve interstitial cells (myofibroblasts),which also induce biomineralization, are strong candidates.1Other mechanisms include possible up-regulation of osteogenicgenes and numerous regulatory processes, possibly resemblingvascular processes.2 The role of Ca-phosphate product, calcificationof matrix vesicles, fetuin-A,3 the osteoprotegerin–RANKL–RANKaxis,4 BMP-7, and the renin–angiotensin system5 must beclarified in valvular tissue and in human aortic valves in vivo.
Anne B. Rossebø, M.D. Aker University Hospital N-0514 Oslo, Norway anne{at}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
References
Akat K, Borggrefe M, Kaden JJ. Aortic valve calcification — basic science to clinical practice. Heart 2008 July 16 (Epub ahead of print).
Giachelli CM. Vascular calcification mechanisms. J Am Soc Nephrol 2004;15:2959-2964. [Free Full Text]
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. [Free Full Text]
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. [Free Full Text]
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. [Free Full Text]
The editorialist replies: As Pazianas notes, recent studieshighlight the differences between calcific aortic stenosis andatherosclerosis. Unlike atherosclerosis, increased oxidativestress in calcific aortic valves is associated with increasedlevels of superoxide and hydrogen peroxide, possibly mediatedby the uncoupling of nitric oxide synthase activity.1 The associationbetween increased oxidative stress and leaflet calcificationsuggests a possible causal relationship, perhaps potentiatedby genetic and clinical factors.2 Decreased activity of normaltissue inhibitors appears to be a factor in both pathologicangiogenesis and in dystrophic calcification of valve leaflets.3 For example, reduced expression of chondromodulin-I, an antiangiogenicfactor, has been shown in aged mice with calcific valve disease.4 In addition, studies of human valves with a range of diseasefrom normal to severe stenosis showed progressive increasesin gene expression of osteopontin, osteoprotegerin, and bonesialoprotein II, along with decreased expression of other noncollagenousmatrix proteins. The complexity of this active disease processis a challenge for researchers but also suggests there are manypotential targets for intervention to prevent disease progression.
Catherine M. Otto, M.D. University of Washington Seattle, WA 98195-6422 cmotto{at}u.washington.edu
References
Miller JD, Chu Y, Brooks RM, Richenbacher WE, Peña-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. [Free Full Text]
Bossé 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. [Free Full Text]
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).
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).
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