© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Presence of Oxidized Low Density Lipoprotein in Nonrheumatic Stenotic Aortic Valves
From the Department of Cardiology (M.O.), Karolinska Hospital, and the Department of Cell and Molecular Biology (J.T.), Karolinska Institute, Stockholm, and the Department of Medicine (J.N.), Malmö University Hospital, University of Lund, Sweden.
Correspondence to Margareta Olsson, MD, Department of Cardiology, Thoracic Clinics, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail margareta.olsson{at}medks.ki.se
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Abstract |
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Abstract—The aim of the present study was to analyze if LDL particles trapped in stenotic aortic valve tissue undergo oxidative modification. Degenerative aortic stenosis affects >3% of the population >75 years of age in the Western world. Recent studies have revealed the presence of a chronic inflammatory process similar to what has been described in other degenerative diseases such as atherosclerosis. However, the underlying disease mechanisms of degenerative aortic stenosis still remain largely unknown. Six tricuspid stenotic valves, obtained at valve replacement, were compared with 3 control valves collected from hearts taken out during transplantation. The stenotic valves and the control valves were examined by immunohistochemistry, using antibodies against apoB, 4-hydroxynonenal-modified LDL, leukocytes, and HLA-DR. All valves were also stained with oil red O for neutral lipids. Extracellular neutral lipids were found in all stenotic valves, extending from the bases along the fibrosa layer. This lipid colocalized with apoB- and 4-hydroxynonenal–modified LDL immunoreactivity. 4-Hydroxynonenal–modified LDLs were present around calcium deposits, subendothelially, and in the deeper layer of the fibrosa. There was also a colocalization with macrophages, T lymphocytes, and HLA-DR expression. Control valves had a thin area of neutral lipid accumulation, a small amount of apoB, but no signs of inflammation. A distinct colocalization between oxidized LDLs, T-lymphocyte accumulation, and calcium deposits suggests that oxidized lipids may play a role in the disease process.
Key Words: degenerative aortic stenosis • low density lipoprotein • lipid oxidation • T-lymphocyte accumulation
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Introduction |
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With the decline in the incidence of rheumatic fever, degenerative valvular aortic stenosis has become the most common valvular disorder in the Western world.1 It affects >3% of the population >75 years of age and is a major cause of disability and death in this age group.2 The cause as well as the underlying disease mechanisms remain largely unknown. Epidemiological studies have revealed no major risk factors for the disease, with the exception of the presence of bicuspid valves.3 4 The latter observation has been taken as an indication of an involvement of mechanical stress in the disease process. This notion is also supported by the finding that valvular fibrosis and calcification initially occurs at the base of the cusps.5 6 7 By using immunohistochemical techniques, we and others have recently characterized the cellular composition of degenerative aortic stenotic valves.8 9 The increase in valve thickness is caused by the combined effect of increased cellularity, increased extracellular matrix deposition, and focal accumulation of calcium deposits. Most cells in aortic stenotic valves are fibroblast-like mesenchymal cells expressing HLA-DR antigen as well as the smooth muscle cell markers, such as
-actin and desmin, in a manner closely resembling
that observed in other chronic fibrotic disorders.10
Aortic stenotic valves also contain numerous
macrophages and activated T lymphocytes, suggesting
involvement of local immune reactions.8 Lipids are known to accumulate in aortic valves with increasing age.11 12 More recently, O'Brien et al13 demonstrated the presence of a large amount of apoB in aortic stenotic valves, indicating that lipid accumulation occurs as a result of retention of LDLs in valve tissue. The aim of the present study was to analyze if LDL particles trapped in aortic stenotic valve tissue undergo oxidative modification. Previous studies have shown that oxidized LDLs are cytotoxic, stimulate inflammatory activity, and promote connective tissue cell proliferation.14 15 If present in aortic valve tissue, oxidized LDLs may thus play a role in the changes leading to the development of valvular aortic stenosis.
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Methods |
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Six tricuspid stenotic aortic valves, obtained at valve replacement, were examined. The ages of the patients ranged from 72 to 79 years. The valves were fixed in 4% formaldehyde:0.02 mol/L butylated hydroxytoluene immediately after removal to avoid oxidation. Three control valves were collected from hearts obtained at transplantation and fixed in 4% formaldehyde. All 3 cusps from each control valve were examined. The ages of the control patients ranged from 25 to 58 years.
The study was approved by the Ethics Committee of the Karolinska Hospital and the patients were included after informed consent.
Histological Analysis
All valves were stained for neutral lipids with oil red O
(Sigma).
Immunohistochemical Analysis
To optimize antigen preservation, the specimens were not
decalcified before sectioning. Suitable tissue samples, not including
the commissures, were cryosectioned in 10-µm-thick sections. Indirect
immunohistochemistry was performed by using the
Avidin-Biotin-Complex method with peroxidase.
Endogenous peroxidase was blocked by incubation with 0.3%
hydrogen peroxide in methanol for 30 minutes. This step was preceded by
incubation with 0.2% Triton X-100 in PBS when staining for apoB was
performed. The slides were then rinsed in PBS, incubated with 5% horse
serum for 30 minutes, and incubated with primary antibodies for 60
minutes (Table
). As evidenced by using
this protocol, there might be an oxidation of lipids during the
procedure. However, incubation with antibodies against oxidized LDLs
before pretreatment with hydrogen peroxide showed the same results.
Negative controls were incubated with irrelevant mouse sera. To
demonstrate the specificity of the staining against
4-hydroxynonenal–modified LDLs, a blocking procedure with NA59
antibodies and oxidized LDLs was performed (100 µg/mL of oxidized
LDLs in F10 medium+1:400 anti-NA59).
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After rinsing in PBS the specimens were incubated with a biotin-labeled horse anti-mouse antibody for 30 minutes followed by an avidin-biotin complex conjugated with peroxidase for 30 minutes. The sections were rinsed in PBS and exposed to diaminobenzidine solution for 5 minutes followed by rinsing in PBS. They were counterstained with Gill's hematoxylin, dehydrated in ethanol and xylene, and mounted in Eukitt (O. Kindler Gimbtt Co).
Double staining was performed to test for possible colocalization between apoB and oxidized LDLs. The specimens were first incubated with a sheep antibody against human apoB (Boehringer-Mannheim) in 1% BSA/PBS overnight, rinsed, and incubated with a biotin-labeled rabbit anti-sheep IgG (Vector) for 30 minutes followed by an alkaline phosphatase–conjugated avidin-biotin complex for another 30 minutes and finally stained by using fast red substrate (Vector). After blocking in 5% horse serum for 30 minutes, the sections were then incubated with the NA59 antibody against oxidized LDLs for 30 minutes, rinsed, and exposed to hydrogen peroxide for 30 minutes. After rinsing they were subsequently incubated with a biotin-labeled horse anti-mouse IgG antibody for 30 minutes followed by an avidin-biotin complex conjugated with peroxidase for 30 minutes. The sections were rinsed in PBS and exposed to diaminobenzidine solution for 5 minutes followed by rinsing in PBS.
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Results |
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Macroscopic Evaluation
All aortic valves examined were tricuspid. One of the control valves showed signs of tissue hypertrophy at the base of 1 cusp but was without visible calcification, whereas the remaining 2 control valves were thin and transparent. All valves obtained from patients undergoing valve replacement were markedly hypertrophic and contained multiple calcium nodules. There was no commissural fusion present in any of the stenotic valves.
Oil Red O and Immunohistochemical Staining
In the control valves, oil red O staining demonstrated presence of
lipids in all cusps. In the youngest control valve, lipids were
present only as a thin border between the fibrosa and the spongiosa
(Figure 1). The staining was most clearly
seen close to the base of the cusps, whereas essentially no staining
could be observed in the tip region. The valvular lipid content
appeared to increase with age, and in the oldest control valve 1 cusp
showed an early lesion, with lipids present in the entire fibrosa
part of the valve. Immunohistochemical analyses demonstrated
presence of apoB, small amounts in the thin and transparent cusps and
more markedly in the cusp with the early lesion. This immunoreactivity
appeared in the same areas that were stained by oil red O.
4-Hydroxynonenal–modified LDL immunoreactivity was present and
colocalized with apoB and oil red O staining in the cusp with the early
lesion.
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All stenotic valves were intensively stained by oil red O.
Staining was most prominent in the endothelial region
of the fibrosa, but it was also present in the deeper layers of the
valve and, in particular, close to the lamina elastica. Staining was
also strong in the vicinity of calcified areas and no calcium deposits
could be detected in areas devoid of lipids (Figure 2a). Stenotic valves contained
markedly more apoB immunoreactivity than control valves (Figure 2b). As in the control valves, there was a distinct
colocalization between apoB immunoreactivity and oil red O
staining.
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Antibodies raised against 4-hydroxynonenal–modified LDLs and
malondialdehyde-modified LDL were used to detect presence of oxidized
LDLs in the valves. These antibodies have previously been used to
identify oxidized LDLs in human atherosclerotic plaques.21
4-Hydroxynonenal–modified LDL immunoreactivity was present in all
of the stenotic valves. The 4-hydroxynonenal–modified LDL
immunoreactivity was present predominantly in the
endothelial region of the fibrosa and around calcium
deposits (Figure 2c
), thus demonstrating a clear colocalization
with apoB immunoreactivity and oil red O staining. The colocalization
between apoB and 4-hydroxynonenal–modified LDL could also be
demonstrated by using double staining (Figure 3). Preincubation of the
4-hydroxynonenal–modified LDL antibodies with 100 µg/mL of
copper-oxidized LDL resulted in a complete removal of the
immunostaining, further supporting the specificity of
the immune reaction (Figure 4).
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Relation Between Markers of Inflammatory Activity and Oxidized
LDLs
In the control valves unaffected by tissue
hypertrophy, only occasional T lymphocytes and
macrophages could be detected. These were uniformly distributed
in the valve tissue and did not colocalize with lipid deposition. In
the control valve with 1 cusp demonstrating an early lesion, T
lymphocytes and macrophages were found at the base of the valve
and in the endothelial region of the fibrosa. A few
foam cells were present in these areas. Expression of HLA-DR was
also observed on some cells colocalized with lipid depositions.
All stenotic valves contained T-cell and macrophage
immunoreactivity in the subendothelial layer of the
fibrosa, in the vicinity of calcium deposits, and along the lamina
elastica. Thus, these cells were clearly localized to regions also
staining for neutral and oxidized lipids (Figure 2d). No T
lymphocytes were present in lipid-poor areas, whereas some
macrophages could be detected in these regions.
HLA-DR–expressing cells were most prominent in regions with lipid
accumulation but could also be found in lipid-poor areas of the
valves.
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Discussion |
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Lipids have been shown to accumulate in aortic valves with increasing age.11 12 The present findings demonstrate that aortic valves affected by degenerative stenosis contain markedly higher amounts of lipids than healthy valves. Our findings also confirm previous studies by O'Brien et al13 showing a colocalization between lipid staining and apoB immunorectivity in stenotic valves. This colocalization is a strong indication that the lipid deposits encountered in stenotic valves are derived from LDLs, the major carriers of apoB in the circulation. In accordance with observations of O'Brien et al,13 we found that most lipids and apoB immunoreactivity were present in the subendothelial area of the fibrosa. This part of the valve faces the aortic lumen and is exposed to much lower shear stress than the opposite, ventricular side of the valve. It is noteworthy that areas exposed to low shear stress also show an enhanced uptake of LDLs in blood vessels and are predisposed to develop atherosclerosis in response to hyperlipidemia.16 17 The mechanism responsible for the increased accumulation of LDLs at low shear stress areas remains to be fully clarified, but it may involve an enhanced endothelial permeability and/or retention of LDLs by extracellular matrix.18
The present findings also demonstrate that LDLs that have become trapped in stenotic valves undergo oxidative modification. The role of LDL oxidation in atherosclerosis has attracted considerable interest, and the chemical characteristics and pathophysiological properties of oxidized LDLs have therefore been studied intensely.19 20 21 22 The oxidative modification of LDLs in extracellular tissues is initiated by reactive oxygen intermediates or radicals generated by cellular enzymes. Oxidized LDL particles are taken up by macrophage scavenger receptors, resulting in the formation of foam cells.23 In the core region of advanced atherosclerotic plaques, lipid deposition is associated with massive accumulation of macrophage foam cells and necrosis.24 This is clearly in contrast to the situation in stenotic valves, where lipid deposition is more pronounced in the subendothelial than in the deeper layers. Macrophages are uniformly present in lipid-rich areas but are markedly fewer than the surrounding connective tissue cells. Moreover, stenotic valves do not contain areas with extensive lipid-associated necrosis. This difference in response to lipid accumulation and oxidation between the atherosclerotic plaque and the stenotic valve may be of considerable pathophysiological relevance. The clinical manifestations of atherosclerosis are closely linked to the necrotic degeneration and rupture of the plaque.25 In contrast, the clinical manifestations of aortic stenosis are due to tissue hypertropy and calcium deposition. One may speculate that differences in the rate of accumulation and/or clearance of oxidized LDLs between atherosclerotic plaques and stenotic valves may account for some of these differences in the tissue response.
Oxidized LDLs are highly cytotoxic for most cells.26 In atherosclerotic plaques, accumulation of toxic concentrations of oxidized lipids is believed to result in extensive cell death eventually causing plaque rupture. A similar process clearly does not take place in stenotic valves. However, it is reasonable to believe that oxidized LDLs, to some extent, are also toxic for valve fibroblasts. An interesting possibility is that the combination of extracellular lipid deposits and matrix vesicles released from valve fibroblasts exposed to oxidized toxic components of these lipid deposits may serve as nuclei for calcium deposition and nodules formation. The ability of extracellular phospholipid deposits to polymerize calcium crystals has been shown in atherosclerotic plaques.27 Mineralization of bone is activated by small, membrane-surrounded matrix vesicles released from osteoblasts.28 Vesicles of similar structure are also found as cells undergo necrotic degeneration. The possible role of oxidized lipids in valve fibroblast cytotoxicity and calcium deposition clearly requires further study and may even represent a possible mechanism for therapeutic intervention and/or prevention of the development of vulvular aortic stenosis.
Components of oxidized LDLs have also shown proinflammatory and growth-stimulatory properties.29 It is thus possible that products generated by lipid oxidation are involved in the inflammatory process present in the stenotic valves.
Are, then, atherosclerosis and degenerative aortic stenosis essentially the same disease? This is probably not the case, because aortic stenosis and coronary artery disease show little covariation and because the major risk factors for coronary artery disease do not appear to predispose for development of aortic stenosis. However, both disease processes are likely to involve a combination of toxic and mechanical injuries resulting in inflammation and fibrosis, subsequently leading to tissue necrosis in 1 disease and massive calcium deposition in the other.
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Acknowledgments |
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This study was supported by grants from the Swedish Heart and Lung Foundation, the King Gustav V and Queen Victoria Foundation, the Swedish Medical Research Council, and the Swedish Society of Medicine. For excellent technical assistance we thank Inger Brodin.
Received June 5, 1998; accepted July 17, 1998.
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D. Messika-Zeitoun, L. F. Bielak, P. A. Peyser, P. F. Sheedy, S. T. Turner, V. T. Nkomo, J. F. Breen, J. Maalouf, C. Scott, A. J. Tajik, et al. Aortic Valve Calcification: Determinants and Progression in the Population Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 642 - 648. [Abstract] [Full Text] [PDF]
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E. Aikawa, M. Nahrendorf, D. Sosnovik, V. M. Lok, F. A. Jaffer, M. Aikawa, and R. Weissleder Multimodality Molecular Imaging Identifies Proteolytic and Osteogenic Activities in Early Aortic Valve Disease Circulation, January 23, 2007; 115(3): 377 - 386. [Abstract] [Full Text] [PDF]
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N. M. Rajamannan Calcific Aortic Stenosis: A Disease Ready for Prime Time Circulation, November 7, 2006; 114(19): 2007 - 2009. [Full Text] [PDF]
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J R Ortlepp, M Pillich, V Mevissen, C Krantz, M Kimmel, R Autschbach, G Langebartels, J Erdmann, R Hoffmann, and K Zerres APOE alleles are not associated with calcific aortic stenosis Heart, October 1, 2006; 92(10): 1463 - 1466. [Abstract] [Full Text] [PDF]
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R. O. Bonow, B. A. Carabello, K. Chatterjee, A. C. de Leon Jr, D. P. Faxon, M. D. Freed, W. H. Gaasch, B. W. Lytle, R. A. Nishimura, P. T. O'Gara, et al. ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease) Developed in Collaboration With the Society of Cardiovascular Anesthesiologists Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons J. Am. Coll. Cardiol., August 1, 2006; 48(3): e1 - e148. [Full Text] [PDF]
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K. D. O'Brien Pathogenesis of Calcific Aortic Valve Disease: A Disease Process Comes of Age (and a Good Deal More) Arterioscler Thromb Vasc Biol, August 1, 2006; 26(8): 1721 - 1728. [Abstract] [Full Text] [PDF]
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S. Helske, S. Syvaranta, K. A. Lindstedt, J. Lappalainen, K. Oorni, M. I. Mayranpaa, J. Lommi, H. Turto, K. Werkkala, M. Kupari, et al. Increased Expression of Elastolytic Cathepsins S, K, and V and Their Inhibitor Cystatin C in Stenotic Aortic Valves Arterioscler Thromb Vasc Biol, August 1, 2006; 26(8): 1791 - 1798. [Abstract] [Full Text] [PDF]
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D E Newby, S J Cowell, and N A Boon Emerging medical treatments for aortic stenosis: statins, angiotensin converting enzyme inhibitors, or both? Heart, June 1, 2006; 92(6): 729 - 734. [Abstract] [Full Text] [PDF]
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R. Katz, N. D. Wong, R. Kronmal, J. Takasu, D. M. Shavelle, J. L. Probstfield, A. G. Bertoni, M. J. Budoff, and K. D. O'Brien Features of the Metabolic Syndrome and Diabetes Mellitus as Predictors of Aortic Valve Calcification in the Multi-Ethnic Study of Atherosclerosis Circulation, May 2, 2006; 113(17): 2113 - 2119. [Abstract] [Full Text] [PDF]
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M. A. Allison, P. Cheung, M. H. Criqui, R. D. Langer, and C. M. Wright Mitral and Aortic Annular Calcification Are Highly Associated With Systemic Calcified Atherosclerosis Circulation, February 14, 2006; 113(6): 861 - 866. [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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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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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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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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K. Pohle, M. Otte, R. Maffert, D. Ropers, M. Schmid, W. G. Daniel, and S. Achenbach Association of Cardiovascular Risk Factors to Aortic Valve Calcification as Quantified by Electron Beam Computed Tomography Mayo Clin. Proc., October 1, 2004; 79(10): 1242 - 1246. [Abstract] [PDF]
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A. Mazzone, M. C. Epistolato, R. De Caterina, S. Storti, S. Vittorini, S. Sbrana, J. Gianetti, S. Bevilacqua, M. Glauber, A. Biagini, et al. Neoangiogenesis, T-lymphocyte infiltration, and heat shock protein-60 are biological hallmarks of an immunomediated inflammatory process in end-stage calcified aortic valve stenosis J. Am. Coll. Cardiol., May 5, 2004; 43(9): 1670 - 1676. [Abstract] [Full Text] [PDF]
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C. M. Otto Why is aortic sclerosis associated with adverse clinical outcomes? J. Am. Coll. Cardiol., January 21, 2004; 43(2): 176 - 178. [Full Text] [PDF]
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G. M. Novaro, R. Sachar, G. L. Pearce, D. L. Sprecher, and B. P. Griffin Association Between Apolipoprotein E Alleles and Calcific Valvular Heart Disease Circulation, October 14, 2003; 108(15): 1804 - 1808. [Abstract] [Full Text] [PDF]
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R. S. Farivar and L. H. Cohn Hypercholesterolemia is a risk factor for bioprosthetic valve calcification and explantation J. Thorac. Cardiovasc. Surg., October 1, 2003; 126(4): 969 - 975. [Abstract] [Full Text] [PDF]
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J R Ortlepp, F Schmitz, T Bozoglu, P Hanrath, and R Hoffmann Cardiovascular risk factors in patients with aortic stenosis predict prevalence of coronary artery disease but not of aortic stenosis: an angiographic pair matched case-control study Heart, September 1, 2003; 89(9): 1019 - 1022. [Abstract] [Full Text] [PDF]
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K.-L. Chan Is aortic stenosis a preventable disease? J. Am. Coll. Cardiol., August 20, 2003; 42(4): 593 - 599. [Abstract] [Full Text] [PDF]
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N. M Rajamannan, B. Gersh, and R. O Bonow CALCIFIC AORTIC STENOSIS: FROM BENCH TO THE BEDSIDE--EMERGING CLINICAL AND CELLULAR CONCEPTS Heart, July 1, 2003; 89(7): 801 - 805. [Full Text] [PDF]
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M. F. Bellamy, P. A. Pellikka, K. W. Klarich, A. J. Tajik, and M. Enriquez-Sarano Association of cholesterol levels, hydroxymethylglutaryl coenzyme-a reductase inhibitor treatment, and progression of aortic stenosis in the community J. Am. Coll. Cardiol., November 20, 2002; 40(10): 1723 - 1730. [Abstract] [Full Text] [PDF]
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K. D. O'Brien, D. M. Shavelle, M. T. Caulfield, T. O. McDonald, K. Olin-Lewis, C. M. Otto, and J. L. Probstfield Association of Angiotensin-Converting Enzyme With Low-Density Lipoprotein in Aortic Valvular Lesions and in Human Plasma Circulation, October 22, 2002; 106(17): 2224 - 2230. [Abstract] [Full Text] [PDF]
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C M Otto Calcification of bicuspid aortic valves Heart, October 1, 2002; 88(4): 321 - 322. [Full Text] [PDF]
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L Wallby, B Janerot-Sjoberg, T Steffensen, and M Broqvist T lymphocyte infiltration in non-rheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspid aortic valves Heart, October 1, 2002; 88(4): 348 - 351. [Abstract] [Full Text] [PDF]
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B. Iung, C. Gohlke-Barwolf, P. Tornos, C. Tribouilloy, R. Hall, E. Butchart, and A. Vahanian Recommendations on the management of the asymptomatic patient with valvular heart disease Eur. Heart J., August 2, 2002; 23(16): 1253 - 1266. [PDF]
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K. Pohle, R. Maffert, D. Ropers, W. Moshage, N. Stilianakis, W. G. Daniel, and S. Achenbach Progression of Aortic Valve Calcification: Association With Coronary Atherosclerosis and Cardiovascular Risk Factors Circulation, October 16, 2001; 104(16): 1927 - 1932. [Abstract] [Full Text] [PDF]
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C. M OTTO and K. D O'BRIEN Why is there discordance between calcific aortic stenosis and coronary artery disease? Heart, June 1, 2001; 85(6): 601 - 602. [Full Text]
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C. M. Otto Aortic Stenosis -- Listen to the Patient, Look at the Valve N. Engl. J. Med., August 31, 2000; 343(9): 652 - 654. [Full Text]
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