CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Frank C. Caira, BSc,
Stuart R. Stock, PhD,
Thomas G. Gleason, MD,
Edwin C. McGee, MD,
Jie Huang, ScD,
Robert O. Bonow, MD, FACC,
Thomas C. Spelsberg, PhD,
Patrick M. McCarthy, MD, FACC,
Shahbudin H. Rahimtoola, MB, FRCP, DSc, MACC, MACP and
Nalini M. Rajamannan, MD, FACC*
* Northwestern University Feinberg School of Medicine, 300 East Chicago Avenue, Tarry 12-717, Chicago, Illinois 60611 (Email: n-rajamannan{at}northwestern.edu).
We appreciate the thoughtful comments of Dr. Pai regarding our recent publication in JACC on the up-regulation of low-density lipoprotein receptor-related protein 5 receptor mediated bone formation in patients with degenerative valve disease (1). We agree that there are probably other molecular and cellular targets that play an important role in the pathogenesis of valvular heart disease including mechanical factors that mediate shear stress and blood pressure, cellular targets such as matrix metalloproteinases (2), and cytokines such as transforming growth factor-beta (3). Our group has published experimental animal evidence implicating endothelial nitric oxide (4), early inflammatory markers such as foam cell formation, high sensitivity C-reactive protein, and cellular proliferation (5) as additional important modifiable cellular targets in the early valvular lesion. Our studies have shown a link between lipids and bone formation in the cellular mechanisms of valvular heart disease (6–8), which may provide an early target for future therapies.
We would like to respond to Dr. Pai’s question regarding the predominant cellular process associated with the degree of valvular heart disease. We and others have found differences in the cellular processes across the valve leaflets depending on the degree of disease within the valve (9). We observed phenotypic regional bone differences in the myxomatous mitral valve leaflets and the calcified stenotic aortic valves. We found that the myxomatous mitral valve leaflets had more chondrocytic cells at the leaflet edges where the leaflet repair was excised. In the calcific aortic valves there was increased bone formation at the attachment site of the leaflet to the aorta. We have discovered similar changes in our experimental models of valvular heart disease (10). We did not test for specific biochemical changes across the different areas of the valve leaflet for this study, but we agree that this would be of interest in future studies. We did test the entire leaflet for the biochemical and cellular markers that we reported in the recent JACC study. We hope that ongoing prospective clinical trials testing the effects of statins in valvular heart disease will shed light on the question of whether early treatment slows the degenerative process in valves with more inflammatory and less calcified pathology that may be more amenable to medical therapy.
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1. Caira FC, Stock SR, Gleason TG, et al. Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation J Am Coll Cardiol 2006;47:1707-1712.[Abstract/Free Full Text]2. Jian B, Jones PL, Li Q, Mohler ER3rd, Schoen FJ, Levy RJ. Matrix metalloproteinase-2 is associated with tenascin-C in calcific aortic stenosis Am J Pathol 2001;159:321-327.[Abstract/Free Full Text] 3. Osman L, Yacoub MH, Latif N, Amrani M, Chester AH. Role of human valve interstitial cells in valve calcification and their response to atorvastatin Circulation 2006;114(Suppl):1547-1552. 4. Rajamannan NM, Subramaniam M, Stock SR, et al. Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve Heart 2005;91:806-810.[Abstract/Free Full Text] 5. Rajamannan NM, Subramaniam M, Caira F, Stock SR, Spelsberg TC. Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve Circulation 2002;105:2260-2265. 6. Rajamannan NM, Edwards WD, Spelsberg TC. Hypercholesterolemic aortic-valve disease N Engl J Med 2003;349:717-718.[Free Full Text] 7. Rajamannan NM, Nealis TB, Subramaniam M, et al. Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation Circulation 2005;111:3296-3301. 8. Rajamannan NM, Sangiorgi G, Springett M, et al. Experimental hypercholesterolemia induces apoptosis in the aortic valve Heart Valve Dis 2001;10:371-374. 9. O’Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of ‘degenerative’ valvular aortic stenosis Arterioscler Thromb Vasc Biol 1996;16:523-532.[Abstract/Free Full Text] 10. Rajamannan NM, Subramaniam M, Springett M, et al. Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway Circulation 2005;112(Suppl 9):1229-1234.
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