(Circulation. 2001;103:1522.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Bone Formation and Inflammation in Cardiac Valves
From the Department of Medicine, Cardiovascular Division (E.R.M., M.G.K., F.S.K.), Department of Pathology and Laboratory Medicine (F.G., C.R., R.Z.), and Department of Orthopedic Surgery (F.S.K.), University of Pennsylvania, School of Medicine, Philadelphia, Pa. Dr Gannon is currently affiliated with the Armed Forces Institute of Pathology, Washington, DC.
Correspondence to Emile R. Mohler III, MD, 432 PHI Bldg, 51 North 39th St, Philadelphia, PA 19104. E-mail emmd{at}mail.med.upenn.edu
Background—For nearly a century, the mechanical failure of calcified heart valves was attributed to a passive degenerative process. Recently, several case reports described bone formation in surgically excised heart valves and suggested an unexpected process of tissue repair.
Methods and Results—We studied the prevalence and pathology of heterotopic ossification in 347 surgically excised heart valves (256 aortic, 91 mitral) in 324 consecutive patients (182 men, 142 women; mean age 68 years) who underwent cardiac valve replacement surgery between 1994 and 1998. The valves were examined microscopically to determine the prevalence and features of bone formation and remodeling. Two hundred eighty-eight valves (83%) had dystrophic calcification. Mature lamellar bone with hematopoietic elements and active bone remodeling were present in 36 valves (13%) with dystrophic calcification. Endochondral bone formation, similar to that seen in normal fracture repair, was identified in 4 valves. Microfractures were present in 92% of all valves with ossification. Neoangiogenesis was found in all valves with ossification. Bone morphogenetic proteins 2 and 4 (BMP 2/4), potent osteogenic morphogens, were expressed by myofibroblasts and preosteoblasts in areas adjacent to B- and T-lymphocyte infiltration in valves where ossification was identified. Mast cells were present in calcified and ossified valves and were especially prominent in atheromatous regions.
Conclusions—Heterotopic ossification consisting of mature lamellar bone formation and active bone remodeling is a relatively common and unexpected finding in end-stage valvular heart disease and may be associated with repair of pathological microfractures in calcified cardiac valves.
Key Words: pathology • valves • inflammation • risk factors • stenosis
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V. Liebe, M. Brueckmann, M. Borggrefe, and J. J. Kaden Statin therapy of calcific aortic stenosis: hype or hope? Eur. Heart J., April 1, 2006; 27(7): 773 - 778. [Abstract] [Full Text] [PDF]
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R. J. Levy Serotonin Transporter Mechanisms and Cardiac Disease Circulation, January 3, 2006; 113(1): 2 - 4. [Full Text] [PDF]
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A. Armulik, A. Abramsson, and C. Betsholtz Endothelial/Pericyte Interactions Circ. Res., September 16, 2005; 97(6): 512 - 523. [Abstract] [Full Text] [PDF]
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N. M. Rajamannan, M. Subramaniam, F. Caira, S. R. Stock, and T. C. Spelsberg Atorvastatin Inhibits Hypercholesterolemia-Induced Calcification in the Aortic Valves via the Lrp5 Receptor Pathway Circulation, August 30, 2005; 112(9_suppl): I-229 - I-234. [Abstract] [Full Text] [PDF]
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K. Tanaka, M. Sata, D. Fukuda, Y. Suematsu, N. Motomura, S. Takamoto, Y. Hirata, and R. Nagai Age-Associated Aortic Stenosis in Apolipoprotein E-Deficient Mice J. Am. Coll. Cardiol., July 5, 2005; 46(1): 134 - 141. [Abstract] [Full Text] [PDF]
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R. V. Freeman and C. M. Otto Spectrum of Calcific Aortic Valve Disease: Pathogenesis, Disease Progression, and Treatment Strategies Circulation, June 21, 2005; 111(24): 3316 - 3326. [Full Text] [PDF]
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N. M. Rajamannan, T. B. Nealis, M. Subramaniam, S. Pandya, S. R. Stock, C. I. Ignatiev, T. J. Sebo, T. K. Rosengart, W. D. Edwards, P. M. McCarthy, et al. Calcified Rheumatic Valve Neoangiogenesis Is Associated With Vascular Endothelial Growth Factor Expression and Osteoblast-Like Bone Formation Circulation, June 21, 2005; 111(24): 3296 - 3301. [Abstract] [Full Text] [PDF]
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G.D.M. Collett and A.E. Canfield Angiogenesis and Pericytes in the Initiation of Ectopic Calcification Circ. Res., May 13, 2005; 96(9): 930 - 938. [Abstract] [Full Text] [PDF]
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C. A. Simmons, G. R. Grant, E. Manduchi, and P. F. Davies Spatial Heterogeneity of Endothelial Phenotypes Correlates With Side-Specific Vulnerability to Calcification in Normal Porcine Aortic Valves Circ. Res., April 15, 2005; 96(7): 792 - 799. [Abstract] [Full Text] [PDF]
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J. S. Borer Aortic Stenosis and Statins: More Evidence of "Pleotropy"? Arterioscler. Thromb. Vasc. Biol., March 1, 2005; 25(3): 476 - 477. [Full Text] [PDF]
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B. Wu, S. Elmariah, F. S. Kaplan, G. Cheng, and E. R. Mohler III Paradoxical Effects of Statins on Aortic Valve Myofibroblasts and Osteoblasts: Implications for End-Stage Valvular Heart Disease Arterioscler. Thromb. Vasc. Biol., March 1, 2005; 25(3): 592 - 597. [Abstract] [Full Text] [PDF]
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C. M. Giachelli Vascular Calcification Mechanisms J. Am. Soc. Nephrol., December 1, 2004; 15(12): 2959 - 2964. [Abstract] [Full Text] [PDF]
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P. Collin-Osdoby Regulation of Vascular Calcification by Osteoclast Regulatory Factors RANKL and Osteoprotegerin Circ. Res., November 26, 2004; 95(11): 1046 - 1057. [Abstract] [Full Text] [PDF]
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S. Helske, K. A. Lindstedt, M. Laine, M. Mayranpaa, K. Werkkala, J. Lommi, H. Turto, M. Kupari, and P. T. Kovanen Induction of local angiotensin II-producing systems in stenotic aortic valves J. Am. Coll. Cardiol., November 2, 2004; 44(9): 1859 - 1866. [Abstract] [Full Text] [PDF]
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