CORRESPONDENCE: LETTER TO THE EDITOR
Insights Into (the Interstitium of) Degenerative Aortic Valve Disease
W. David Merryman, PhD*
* Department of Biomedical Engineering, University of Alabama at Birmingham, 811 Shelby Biomedical Research Building, 1825 University Boulevard, Birmingham, Alabama 35294-2182 (Email: merryman{at}uab.edu).
I read with great interest the recent State-of-the-Art paper by Goldbarg et al. (1) concerning degenerative aortic valve disease (DAVD). This paper succinctly covers the pathophysiological insights into DAVD from endothelial cell function to genetic factors. However, I believe one significant contributor to DAVD was not given proper consideration in their review. Namely, the interstitial cells, or myofibroblasts, within the interstitium of the valve are likely a great source of etiology and/or perpetuation of DAVD. These cells are both highly contractile and biosynthetic in the aortic valve (AV) compared with the cells from the other valves (2–4), likely because of stresses and strains imposed during valve closure. Moreover, the cyclic loading they undergo during the cardiac cycle, in the presence of bioactive transforming growth factor β1 (TGFβ1), leads to significantly altered cell phenotype, biosynthesis, and drastic changes in the leaflet matrix within 2 weeks in vitro (5).
Because of these known characteristics of the interstitial cells, I propose that there is an age-dependent mechanism that may initiate DAVD from within the interstitium. Christie and Barrett-Boyes (6) first showed how biaxial tissue compliance is lost in the AV with increasing age. It is well established that the biaxial tissue compliance of the AV is largely dictated by the type I collagen found in the fibrosa (aorta side) layer of the AV (7–9). This circumferentially oriented fibrillar collagen provides the leaflets with structural integrity to withstand transvalvular pressure while permitting large strains for apposition in the radial direction. Additionally, Robicsek et al. (10) presented a theory of stress overload in the AV with increasing age; however, to date, little work has been done to explore this theory further. Primarily, they theorized that a likely culprit for DAVD is increased stress on the AV leaflets because of a loss of compliance in the aortic wall. As compliance decreases in the aortic wall, vessel dilation decreases, which inhibits stress transfer from the collagen fibers in the circumferential direction to the highly extensible elastic fibers oriented radially (11,12). This transfer inhibition results in larger circumferential stresses and strains on the collagen fibers, to which the circumferentially orientated interstitial cells are tightly anchored. To further support this theory of stress overload in the circumferential direction, nearly all DAVD pathologies originate and perpetuate in fibrosa layer of the leaflet, where the circumferentially oriented collagen resides (13).
Although it is undoubtedly a complex cell-matrix interaction, I believe that loss of tissue compliance, via collagen damage or fatigue with age or stress transfer inhibition in the radial direction, serves to directly increase interstitial cellular deformation. The natural progression of DAVD may therefore be predicated largely on a particular series of events in aging individuals in which TGFβ1 becomes bioactive from its latent state by interstitial cellular stretch. The interstitial cell population then undergoes phenotypic and biosynthetic changes caused by TGFβ1 activation, leading to further loss of tissue compliance, directly contributing to DAVD. Although work is underway to address the many potential etiologies of DAVD, I believe that insights should be made into the interstitium of the tissue and not merely at the endothelium.
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References
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1. Goldbarg SH, Elmariah S, Miller MA, Fuster V. Insights into degenerative aortic valve disease J Am Coll Cardiol 2007;50:1205-1213.[Abstract/Free Full Text]2. Merryman WD, Huang HY, Schoen FJ, Sacks MS. The effects of cellular contraction on aortic valve leaflet flexural stiffness J Biomech 2006;39:88-96.[CrossRef][Web of Science][Medline] 3. Merryman WD, Liao J, Parekh A, Candiello JE, Lin H, Sacks MS. Differences in tissue-remodeling potential of aortic and pulmonary heart valve interstitial cells Tissue Eng 2007;13:2281-2289.[CrossRef][Web of Science][Medline] 4. Merryman WD, Youn I, Lukoff HD, et al. Correlation between heart valve interstitial cell stiffness and transvalvular pressure: implications for collagen biosynthesis Am J Physiol Heart Circ Physiol 2006;290:H224-H231.[Abstract/Free Full Text] 5. Merryman WD, Lukoff H, Long RA, Engelmayr Jr. GC, Hopkins RA, Sacks MS. Synergistic effects of cyclic tension and transforming growth factor beta1 on the aortic valve myofibroblast Cardiovasc Pathol 2007;16:268-276.[CrossRef][Web of Science][Medline] 6. Christie GW, Barratt-Boyes BG. Age-dependent changes in the radial stretch of human aortic valve leaflets determined by biaxial stretching Ann Thorac Surg 1995;60:S156-S159.[CrossRef][Web of Science][Medline] 7. Billiar KL, Sacks MS. Biaxial mechanical properties of the natural and glutaraldehyde treated aortic valve cusp—part I: experimental results J Biomech Eng 2000;122:23-30.[CrossRef][Web of Science][Medline] 8. Billiar KL, Sacks MS. Biaxial mechanical properties of the native and glutaraldehyde-treated aortic valve cusp: part II—a structural constitutive model J Biomech Eng 2000;122:327-335.[CrossRef][Web of Science][Medline] 9. Merryman WD, Engelmayr Jr GC, Liao J, Sacks MS. Defining biomechanical endpoints for tissue engineered heart valve leaflets from native leaflet properties Progr Pediatr Cardiol 2006;21:153-160.[CrossRef] 10. Robicsek F, Thubrikar MJ, Fokin AA. Cause of degenerative disease of the trileaflet aortic valve: review of subject and presentation of a new theory Ann Thorac Surg 2002;73:1346-1354.[Abstract/Free Full Text] 11. 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.[Web of Science][Medline] 12. Vesely I. The role of elastin in aortic valve mechanics J Biomech 1998;31:115-123.[Web of Science][Medline] 13. Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O’Brien KD. Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis. Histological and immunohistochemical studies. Circulation 1994;90:844-853.[Abstract/Free Full Text]
Related Article
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- Seth H. Goldbarg, Sammy Elmariah, Marc A. Miller, and Valentin Fuster
J. Am. Coll. Cardiol. 2008 51: 1416.
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