Evidence of Osteogenic Regulation in Calcific Porcine Aortic Valves
Background: Chemically cross-linked animal tissues, such as porcine aortic valves (PAVs) have many documented advantages over mechanical valves. However, calcification is the major underlying pathologic process that results in bioprosthetic valve failure. Recently, several reports described the expression of noncollagenous bone matrix proteins in bioprosthetic valves and suggested an actively regulated process of tissue repair.
Methods: Thirty-one explanted PAVs with evidence of calcification were collected and examined for the protein expression implicated in myofibroblast activation, osteoblast differentiation, and bone matrix deposition by using immunohistochemistry.
Results: The mean duration that PAVs were implanted was 11.5 ± 5.6 years, ranging from 12 months to 28 years. Pearson correlation analysis showed a significant relationship between the duration and valvular calcification (r = 0.3818,
P = .034). The number of vimentin-positive mesenchymal cells in explanted PAVs was significantly lower than that of unused PAVs (P < .01). However, increased expression of α-smooth muscle actin (α-SMA) (P < .01), proliferating cell nuclear antigen (PCNA, P < .01), Cbfa1/Runx2 (P < .01), osterix (P = .0126), bone sialoprotein (BSP, P < .01), osteocalcin (P < .01), and osteopontin (P < .01) was found in explanted PAVs. Immunohistochemical staining of alkaline phosphatase (ALP) and osteocalcin was negative in the unused PAVs. In explanted PAVs, the expression level of these 2 proteins was also significantly increased.
Conclusions: Our results support the view that PAV calcification is an actively regulated process with osteogenic signaling activation.
Alsoufi B, Manlhiot C, McCrindle BW, et al. 2009. Aortic and mitral valve replacement in children: is there any role for biologic and bioprosthetic substitutes? Eur J Cardiothorac Surg 36:84-90; discussion 90.
Birkmeyer NJ, Birkmeyer JD, Tosteson AN, Grunkemeier GL, Marrin CA, O’Connor GT. 2000. Prosthetic valve type for patients undergoing aortic valve replacement: a decision analysis. Ann Thorac Surg 70:1946-52.
Brandenburg VM, Reinartz S, Kaesler N, et al. 2017. Slower progress of aortic valve calcification with vitamin K supplementation: results from a prospective interventional proof-of-concept study. Circulation 135:2081-3.
Butany J, Nair V, Leong SW, Soor GS, Feindel C. 2007. Carpentier-Edwards Perimount valves--morphological findings in surgical explants. J Card Surg 22:7-12.
Calero JA, Muñoz MT, Argente J, et al. 1999. A variation in Bone Alkaline Phosphatase levels that correlates positively with bone loss and normal levels of aminoterminal propeptide of collagen I in girls with anorexia nervosa. Clin Chim Acta 285:121-9.
Cheng SL, Shin CS, Towler DA, Civitelli R. 2000. A dominant negative cadherin inhibits osteoblast differentiation. J Bone Miner Res 15:2362-70.
Cho HJ, Cho HJ, Kim HS. 2009. Osteopontin: a multifunctional protein at the crossroads of inflammation, atherosclerosis, and vascular calcification. Curr Atheroscler Rep 11:206-13.
Ciavarella C, Gallitto E, Ricci F, Buzzi M, Stella A, Pasquinelli G. 2017. The crosstalk between vascular MSCs and inflammatory mediators determines the pro-calcific remodelling of human atherosclerotic aneurysm. Stem Cell Res Ther 8:99.
Detre S, Saclani Jotti G, Dowsett M. 1995. A “quickscore” method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas. J Clin Pathol 48:876-8.
Hammermeister K, Sethi GK, Henderson WG, Grover FL, Oprian C, Rahimtoola SH. 2000. Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs randomized trial. J Am Coll Cardiol 36:1152-8.
Jono S, Peinado C, Giachelli CM. 2000. Phosphorylation of osteopontin is required for inhibition of vascular smooth muscle cell calcification. J Biol Chem 275:20197-203.
Khan SS, Trento A, DeRobertis M, et al. 2001. Twenty-year comparison of tissue and mechanical valve replacement. J Thorac Cardiovasc Surg 122:257-69.
Komori T. 2005. Regulation of skeletal development by the Runx family of transcription factors. J Cell Biochem 95:445-53.
Levy RJ. 1983. Biologic determinants of dystrophic calcification and osteocalcin deposition in glutaraldehyde-preserved porcine aortic valve leaflets implanted subcutaneously in rats. Am J Pathol 113:143-55.
Levy RJ, Gundberg C, Scheinman R. 1983. The identification of the vitamin K-dependent bone protein osteocalcin as one of the gamma-carboxyglutamic acid containing proteins present in calcified atherosclerotic plaque and mineralized heart valves. Atherosclerosis 46:49-56.
Lian JB, Gundberg CM. 1988. Osteocalcin. Biochemical considerations and clinical applications. Clin Orthop Relat Res 226:267-91.
Lomashvili KA, Cobbs S, Hennigar RA, Hardcastle KI, O’Neill WC. 2004. Phosphate-induced vascular calcification: role of pyrophosphate and osteopontin. J Am Soc Nephrol 15:1392-401.
Miller JD, Weiss RM, Serrano KM, et al. 2010. Evidence for active regulation of pro-osteogenic signaling in advanced aortic valve disease. Arterioscler Thromb Vasc Biol 30:2482-6.
Minakata K, Tanaka S, Okawa Y, et al. 2015. Twenty-year outcome of aortic valve replacement with St. Jude Medical mechanical valves in Japanese patients. Circ J 79:2380-8.
Nakashima K, Zhou X, Kunkel G, et al. 2002. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108:17-29.
Nimni ME, Bernick S, Cheung DT, et al. 1988. Biochemical differences between dystrophic calcification of cross-linked collagen implants and mineralization during bone induction. Calcif Tissue Int 42:313-20.
Nishio Y, Dong Y, Paris M, O’Keefe RJ, Schwarz EM, Drissi H. 2006. Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene. Gene 372:62-70.
Pillai ICL, Li S, Romay M, et al. 2017. Cardiac fibroblasts adopt osteogenic fates and can be targeted to attenuate pathological heart calcification. Cell Stem Cell 20:218-232.e5.
Saleeb SF, Newburger JW, Geva T, et al. 2014. Accelerated degeneration of a bovine pericardial bioprosthetic aortic valve in children and young adults. Circulation 130:51-60.
Schoen FJ, Levy RJ. 2005. Calcification of tissue heart valve substitutes: progress toward understanding and prevention. Ann Thorac Surg 79:1072-80.
Shao JS, Cai J, Towler DA. 2006. Molecular mechanisms of vascular calcification: lessons learned from the aorta. Arterioscler Thromb Vasc Biol 26:1423-30.
Shen M, Marie P, Farge D, et al. 1997. Osteopontin is associated with bioprosthetic heart valve calcification in humans. C R Acad Sci III 320:49-57.
Shetty R, Pepin A, Charest A, et al. 2006. Expression of bone-regulatory proteins in human valve allografts. Heart 92:1303-8.
Singh M, Dalal S, Singh K. 2014. Osteopontin: at the cross-roads of myocyte survival and myocardial function. Life Sci 118:1-6.
Skowasch D, Steinmetz M, Nickenig G, Bauriedel G. 2006. Is the degeneration of aortic valve bioprostheses similar to that of native aortic valves? Insights into valvular pathology. Expert Rev Med Devices 3:453-62.
Srivatsa SS, Harrity PJ, Maercklein PB, et al. 1997. Increased cellular expression of matrix proteins that regulate mineralization is associated with calcification of native human and porcine xenograft bioprosthetic heart valves. J Clin Invest 99:996-1009.
van Straalen JP, Sanders E, Prummel MF, Sanders GT. 1991. Bone-alkaline phosphatase as indicator of bone formation. Clin Chim Acta 201:27-33.
Yu PJ, Skolnick A, Ferrari G, et al. 2009. Correlation between plasma osteopontin levels and aortic valve calcification: potential insights into the pathogenesis of aortic valve calcification and stenosis. J Thorac Cardiovasc Surg 138:196-9.
Zhou HY, Takita H, Fujisawa R, Mizuno M, Kuboki Y. 1995. Stimulation by bone sialoprotein of calcification in osteoblast-like MC3T3-E1 cells. Calcif Tissue Int 56:403-7.