Circulation, Vol 90, 844-853, Copyright © 1994 by American Heart Association
CM Otto, J Kuusisto, DD Reichenbach, AM Gown and KD O'Brien
BACKGROUND: Nonrheumatic stenosis of trileaflet aortic valves, often termed
senile or calcific valvular aortic stenosis, is considered a "degenerative"
process, but little is known about the cellular or molecular factors that
mediate its development. METHODS AND RESULTS: To characterize the
developing aortic valvular lesion, we performed histological and
immunohistochemical studies on Formalin-fixed and methanol-Carnoy's-fixed
paraffin-embedded aortic valve leaflets or on frozen sections obtained at
autopsy from 27 adults (age, 46 to 82 years) with normal leaflets (n = 6),
mild macroscopic leaflet thickening (n = 15), or clinical aortic stenosis
(n = 6). Focal areas of thickening ("early lesions") were characterized by
(1) subendothelial thickening on the aortic side of the leaflet, between
the basement membrane (PAS-positive) and elastic lamina (Verhoeff-van
Gieson), (2) the presence of large amounts of intracellular and
extracellular neutral lipids (oil red O) and fine, stippled mineralization
(von Kossa), and (3) disruption of the basement membrane overlying the
lesion. Regions of the fibrosa adjacent to these lesions were characterized
by thickening and by protein, lipid, and calcium accumulation. Control
valves showed none of these abnormalities. Immunohistochemical studies were
performed using monoclonal antibodies directed against macrophages
(anti-CD68 or HAM-56), and contractile proteins of smooth muscle cells or
myofibroblasts (anti-alpha-actin and HHF-35) or rabbit polyclonal antiserum
against T lymphocytes (anti- CD3). In normal valves, scattered macrophages
were present in the fibrosa and ventricularis, and occasional muscle
actin-positive cells were detected in the proximal portion of the
ventricularis near the leaflet base, but no T lymphocytes were found. In
contrast, early lesions were characterized by the presence of an
inflammatory infiltrate composed of non-foam cell and foam cell
macrophages, occasional T cells, and rare alpha-actin-positive cells. In
stenotic aortic valves, a similar but more advanced lesion was seen.
CONCLUSIONS: The early lesion of "degenerative" aortic stenosis is an
active inflammatory process with some similarities (lipid deposition,
macrophage and T-cell infiltration, and basement membrane disruption) and
some dissimilarities (presence of prominent mineralization and small
numbers of smooth muscle cells) to atherosclerosis.
ARTICLES
Characterization of the early lesion of 'degenerative' valvular aortic stenosis. Histological and immunohistochemical studies
Department of Medicine, University of Washington, Seattle 98195.
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J. T. Butcher, S. Tressel, T. Johnson, D. Turner, G. Sorescu, H. Jo, and R. M. Nerem Transcriptional Profiles of Valvular and Vascular Endothelial Cells Reveal Phenotypic Differences: Influence of Shear Stress Arterioscler Thromb Vasc Biol, January 1, 2006; 26(1): 69 - 77. [Abstract] [Full Text] [PDF]
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D. Skowasch, S. Schrempf, N. Wernert, M. Steinmetz, A. Jabs, I. Tuleta, U. Welsch, C. J. Preusse, J. A. Likungu, A. Welz, et al. Cells of primarily extravalvular origin in degenerative aortic valves and bioprostheses Eur. Heart J., December 1, 2005; 26(23): 2576 - 2580. [Abstract] [Full Text] [PDF]
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A K Nightingale and J D Horowitz Aortic sclerosis: not an innocent murmur but a marker of increased cardiovascular risk Heart, November 1, 2005; 91(11): 1389 - 1393. [Abstract] [Full Text] [PDF]
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D M Shavelle Are angiotensin converting enzyme inhibitors beneficial in patients with aortic stenosis? Heart, October 1, 2005; 91(10): 1257 - 1259. [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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D. Weisenberg, Y. Sahar, G. Sahar, Y. Shapira, Z. Iakobishvili, B. A. Vidne, and A. Sagie Atherosclerosis of the aorta is common in patients with severe aortic stenosis: An intraoperative transesophageal echocardiographic study J. Thorac. Cardiovasc. Surg., July 1, 2005; 130(1): 29 - 32. [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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S. J. Cowell, D. E. Newby, R. J. Prescott, P. Bloomfield, J. Reid, D. B. Northridge, N. A. Boon, and the Scottish Aortic Stenosis and Lipid Lowering Tr A Randomized Trial of Intensive Lipid-Lowering Therapy in Calcific Aortic Stenosis N. Engl. J. Med., June 9, 2005; 352(23): 2389 - 2397. [Abstract] [Full Text] [PDF]
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J Kuusisto, K Rasanen, T Sarkioja, E Alarakkola, and V-M Kosma Atherosclerosis-like lesions of the aortic valve are common in adults of all ages: a necropsy study Heart, May 1, 2005; 91(5): 576 - 582. [Abstract] [Full Text] [PDF]
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K. D. O'Brien, J. L. Probstfield, M. T. Caulfield, K. Nasir, J. Takasu, D. M. Shavelle, A. H. Wu, X.-Q. Zhao, and M. J. Budoff Angiotensin-Converting Enzyme Inhibitors and Change in Aortic Valve Calcium Arch Intern Med, April 25, 2005; 165(8): 858 - 862. [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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 A. Kablak-Ziembicka, T. Przewlocki, W. Tracz, P. Podolec, I. Stopa, M. Kostkiewicz, J. Sadowski, A. Mura, and G. Kopec Prognostic Value of Carotid Intima-Media Thickness in Detection of Coronary Atherosclerosis in Patients With Calcified Aortic Valve Stenosis J. Ultrasound Med., April 1, 2005; 24(4): 461 - 467. [Abstract] [Full Text] [PDF]
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D. A. Towler Inorganic Pyrophosphate: A Paracrine Regulator of Vascular Calcification and Smooth Muscle Phenotype Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 651 - 654. [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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A. Y.-M. Wang, S. S.-Y. Ho, M. Wang, E. K.-H. Liu, S. Ho, P. K.-T. Li, S.-F. Lui, and J. E. Sanderson Cardiac Valvular Calcification as a Marker of Atherosclerosis and Arterial Calcification in End-stage Renal Disease Arch Intern Med, February 14, 2005; 165(3): 327 - 332. [Abstract] [Full Text] [PDF]
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G Le Gal, V Bertault, E Bezon, J-C Cornily, J-A Barra, and J-J Blanc Heterogeneous geographic distribution of patients with aortic valve stenosis: arguments for new aetiological hypothesis Heart, February 1, 2005; 91(2): 247 - 249. [Full Text] [PDF]
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Systolic murmur in an asymptomatic 70 year old man Heart, January 1, 2005; 91(1): 125 - 125. [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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 R. Atak, M. Ileri, O. Yetkin, E. Yetkin, H. Turhan, K. Senen, O. Sahin, C. Ozbakir, and D. Demikan The Role of Valvular and Thoracic Aortic Calcifications in Distinction Between Ischemic and Nonischemic Cardiomyopathy Angiology, November 1, 2004; 55(6): 661 - 667. [Abstract] [PDF]
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G. M. Novaro Electron Beam Computed Tomography: The Latest "Stethoscope" for Calcific Aortic Valve Disease Mayo Clin. Proc., October 1, 2004; 79(10): 1239 - 1241. [PDF]
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G. A. Walker, K. S. Masters, D. N. Shah, K. S. Anseth, and L. A. Leinwand Valvular Myofibroblast Activation by Transforming Growth Factor-{beta}: Implications for Pathological Extracellular Matrix Remodeling in Heart Valve Disease Circ. Res., August 6, 2004; 95(3): 253 - 260. [Abstract] [Full Text] [PDF]
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P. F. Davies, A. G. Passerini, and C. A. Simmons Aortic Valve: Turning Over a New Leaf(let) in Endothelial Phenotypic Heterogeneity Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1331 - 1333. [Full Text] [PDF]
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