CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Seth H. Goldbarg, MD*,
Sammy Elmariah, MD,
Marc A. Miller, MD and
Valentin Fuster, MD, PhD
* Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1030, New York, New York 10029 (Email: goldbash{at}post.harvard.edu).
We appreciate the insights that Dr. Merryman offers regarding degenerative aortic valve disease (DAVD) and our recent article (1). He emphasizes the point that the aortic valve interstitium plays a paramount role in the process of valve degeneration. The authors agree that the interstitium, along with the endothelium, generates an inflammatory milieu that promotes DAVD, and that structural changes in the interstitium and endothelium are inherent to the disease process. We attempted to discuss this in our review but perhaps should have further emphasized the importance of the interstitium to this process.
We agree with Dr. Merryman that matrix remodeling and degradation may result from direct effects on the interstitium (2,3). The effects of cytokines within the interstitium include the upregulation of matrix metalloproteinase (MMP), which causes valvular remodeling by degrading the extracellular matrix (4). As we state in our article, MMP seems to regulate valve plasticity, but its overexpression in DAVD leads to elastin degradation in the interstitium, which may contribute to adverse remodeling (5,6). We highlight the transformation of myofibroblasts into an osteogenic phenotype under the influence of cytokines, which alter expression of MMP and bone morphogenic protein (BMP) (7,8). Aortic valve remodeling is strongly linked to altered expression and cytokine production in the myofibroblasts of the interstitium.
In our review we discuss the hemodynamic and mechanical forces that affect the aortic side of the valve and the structural remodeling of the endothelium on that surface. The cascade of downstream effects initiated by endothelial disruption leads to the changes described above. As Dr. Merryman postulates, there may be further effects caused by altered stress transfer from variably oriented collagen fibers in the interstitium of aging valves. We agree that this process may contribute to the pathological changes described in DAVD. However, Dr. Merryman’s statement that nearly all DAVD pathology originates in the fibrosa may exclude other important processes contributing to this pathology. In addition, although Dr. Merryman has shown that transforming growth factor β1 alters smooth muscle alpha-actin and type I collagen C-terminal propeptide in an in vitro model, the notion that DAVD in vivo is largely predicated on transforming growth factor β1 activation may be a generalization (9).
In conclusion, we agree that the interstitium and the myofibroblasts therein play a critical role in the pathogenesis of DAVD. Stress transfer within the interstitium likely contributes to matrix remodeling and cytokine activation, but further studies are needed to confirm current studies and determine the relative importance of this pathway.
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References
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- Goldbarg SH, Elmariah S, Miller MA, et al. Insights into degenerative valve disease J Am Coll Cardiol 2007;50:1205-1213.[Abstract/Free Full Text]
- Schoen F. Aortic valve structure-function correlations: role of elastic fibers no longer a stretch of the imagination J Heart Valve Dis 1997;6:1-6.[ISI][Medline]
- Vesely I. The role of elastin in aortic valve mechanics J Biomech 1998;31:115-123.[ISI][Medline]
- Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly Circ Res 2002;90:251-262.[Abstract/Free Full Text]
- Basalyga DM, Simionescu DT, Xiong W, et al. Elastin degradation and calcification in an abdominal aorta injury model: role of matrix metalloproteinases Circulation 2004;110:3480-3487.[Abstract/Free Full Text]
- Mohler 3rd ER. Mechanisms of aortic valve calcification Am J Cardiol 2004;94:1396-1402.[CrossRef][ISI][Medline]
- Shetty R, Pepin A, Charest A, et al. Expression of bone-regulatory proteins in human valve allografts Heart 2006;92:1303-1308.[Abstract/Free Full Text]
- O’Brien KD. Pathogenesis of calcific aortic valve disease: a disease process comes of age (and a good deal more) Arterioscler Thromb Vasc Biol 2006;26:1721-1728.[Abstract/Free Full Text]
- Merryman WD, Lukoff HD, Long RA, et al. Synergistic effects of cyclic tension and transforming growth factor-beta1 on the aortic valve myofibroblast Cardiovasc Pathol 2007;16:268-276.[CrossRef][ISI][Medline]
Related Article
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Insights Into (the Interstitium of) Degenerative Aortic Valve Disease
- W. David Merryman
J. Am. Coll. Cardiol. 2008 51: 1415.
[Full Text]
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