Published online before print May 18, 2006, doi: 10.1161/01.ATV.0000227513.13697.ac
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© 2006 American Heart Association, Inc.
Brief Reviews |
Pathogenesis of Calcific Aortic Valve Disease
A Disease Process Comes of Age (and a Good Deal More)
From the Division of Cardiology, University of Washington, Seattle.
Correspondence to Kevin D. O’Brien, MD, Division of Cardiology, Box 356422, University of Washington, Seattle, WA 98195-6422. E-mail cardiac{at}u.washington.edu
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Abstract |
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Background— Over the past 10 to 15 years, calcific aortic valve disease, which includes aortic sclerosis and aortic stenosis, has come to be recognized as an active process, based on: (1) epidemiologic studies demonstrating associations of specific risk factors with increased prevalence or rate of progression of aortic valve disease; (2) identification, in valve lesions, of histopathologic features of chronic inflammation, lipoprotein deposition, renin-angiotensin system components, and molecular mediators of calcification; and (3) identification of cell-signaling pathways and genetic factors that may participate in valve disease pathogenesis. These studies will be reviewed and organized into a proposed global hypothesis for the pathogenesis of calcific aortic valve disease.
Over the past 10 to 15 years, calcific aortic valve disease, which includes aortic sclerosis and aortic stenosis, has come to be recognized as an active process, based on numerous studies. These studies will be reviewed and organized into a proposed, global hypothesis for the pathogenesis of calcific aortic valve disease.
Key Words: aortic valve disease • calcification • lipoproteins • matrix • angiotensin II
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Introduction |
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Calcific aortic valve disease is identified by thickening and calcification of the aortic valve leaflets in the absence of rheumatic heart disease. It is divided, on a functional basis, into aortic sclerosis, in which the leaflets do not obstruct left ventricular outflow, and aortic stenosis, in which obstruction to left ventricular outflow is present. Aortic sclerosis is present in more than 25% of patients over age 651 and is associated with a 50% increase risk of cardiovascular events.2 Aortic stenosis is present in 2% to 5% of very elderly patients,1,3 is the second most common indication for cardiac surgery,4 and carries an 80% 5-year risk of progression to heart failure, valve replacement, or death.5 Though the disease is associated with substantial clinical consequences, there currently is no effective therapy for the disease other than surgical aortic valve replacement.
The lack of medical therapies for calcific aortic valve disease can be traced to at least two important issues, one intellectual, the other practical. The first was the long-held notion that calcific aortic valve disease was a "degenerative," and therefore unmodifiable, condition.6 However, more recent studies have demonstrated convincingly that calcific aortic valve lesions have many features characteristic of an active pathobiological process, including chronic inflammation,7–9 lipoprotein deposition,10–12 active calcification,13–18 and renin-angiotensin system activation.19,20 These features are present in both trileaflet and bileaflet aortic valve lesions.21 Also, an emerging body of literature is investigating how genetic factors might influence disease development.22–25
The second issue is that, for many years, there were no animal models that faithfully replicated the key histological features of the disease. Recently, rabbit models been developed,16,26,27 with that of Rajamannan and colleagues already providing a number of novel insights.16–18,28,29 In particular, these models have implicated the Wnt18 and Runx2/Cbfa116,17,27 signaling pathways in disease pathogenesis. Only very recently has a purported mouse model of calcific aortic valve disease been described.30
Nonetheless, through a combination of epidemiological studies, histopathologic evaluation of human lesions, and genetic epidemiology, the past several years have seen rapid advances in our understanding of calcific aortic valve disease pathogenesis. Some potential therapies have been evaluated in retrospective studies using echocardiography31–33 or computed tomography.34–36 Moreover, the era of randomized clinical trials in aortic valve disease has finally begun.37 This review will summarize our current understanding of the pathogenesis of calcific aortic valve disease, attempt to place what currently is known in the context of on-going or recently-completed clinical trials, and identify some areas for future investigation.
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Epidemiology |
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Over the past several years, a number of risk factors for calcific aortic valve disease have been identified. One early study identified male gender, triglycerides, and smoking as independent risk factors for early aortic valve replacement in AS patients.38 In the Cardiovascular Health Study cohort, age, male gender, hypertension, and current smoking were correlated with the presence of echocardiographically-detected aortic sclerosis.1 Correlations also were found between elevated levels of lipoprotein(a) [Lp(a)] and low-density lipoprotein cholesterol (LDL) and increased risk of aortic sclerosis,1 though the relative risks appeared to be lower than those typically reported for atherosclerosis. Other studies have identified high LDL, smoking, and hypertension, as well as diabetes and elevated body mass index, as risk factors for echocardiographic progression of aortic stenosis.39 However, a more recent study found no correlation between LDL or total cholesterol levels and risk of aortic stenosis progression.32 In addition, end-stage renal disease has long been known to be a risk factor for the presence and progression of aortic stenosis,40,41 though mild to moderate renal disease does not appear to be significantly associated with aortic valve calcification.42 One study recently has identified metabolic syndrome as an additional risk factor for valve calcification.43 The similarities between risk factors for atherosclerosis and calcific aortic valve disease have led to the hypothesis that calcific aortic valve disease is primarily a manifestation of atherosclerosis.38,44 However, there also are dissimilarities in these disease processes that may suggest a more complicated picture.
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Biological Processes Implicated In Aortic Valve Lesion Pathogenesis |
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Chronic Inflammation
In 1994, a series of 3 studies reported that aortic valve lesions contained the cell types characteristic of chronic inflammation: macrophages8,9 and T lymphocytes.7–9 One also found expression of important chronic inflammation effector molecules, including interleukin (IL)-2 and the Class II human leukocyte antigen, HLA-DR.9 More recently, mast cells20 and the proinflammatory cytokines, IL-1ß45 and tumor necrosis factor (TNF)-
,46 also have been identified in stenotic aortic valves. In addition, aortic valve lesions contain a number of matrix-metalloproteinases (MMPs),45–48 which degrade various components of the extracellular matrix. Results differ as to whether levels of the natural inhibitors of MMPs, tissue inhibitors of matrix metalloproteinases (TIMPs), are increased48 or unchanged46 in valve lesions. These molecules typically are expressed in inflammatory and fibrosing illnesses. In the case of atherosclerosis, MMPs appear to play important roles in the regulation of vascular calcification, but also are thought to play a key role in the extracellular matrix degradation and subsequent plaque instability that leads to plaque rupture and clinical cardiovascular events.49–51 It is not clear why MMPs and TIMPs may contribute to the extracellular matrix degradation and plaque instability that lead to clinical cardiovascular events in some individuals but participate in the progressive fibrosis and leaflet rigidity that result in aortic stenosis in others.
Lipoprotein Deposition
Another hallmark of atherosclerosis is deposition of plasma lipoproteins in plaques. Similarly, the "atherogenic" lipoproteins, LDL10–12 and Lp(a),11 are deposited in human aortic valve lesions, and aortic valve cholesterol content is increased in a hypercholesterolemic rabbit model of aortic valve disease.16 Similar to atherosclerosis,52 aortic lesion lipoprotein deposition likely is mediated, at least in part, by accumulated extracellular matrix proteoglycans, including biglycan and decorin.53 Proteoglycans consist of a core protein to which is attached one or more glycosaminoglycan (GAG) side chains.54 In general, lipoproteins bind to proteoglycans via charge-charge interactions between positively-charged basic amino acids on apolipoproteins and negatively-charged glycosaminoglycan side chains of proteoglycans.55 Interestingly, a mutation of the single basic amino acid in apoB that mediates LDL binding to proteolgycans markedly decreases atherosclerosis in a murine model.56 Therefore, lipoprotein-proteoglycan interactions may not only link elevated plasma LDL and Lp(a) levels with increased aortic valve disease risk,1 but also may represent a therapeutic target.
Oxidized lipids also have been detected in human aortic valve lesions,12 particularly in areas of developing calcification. In vitro studies have shown that oxidized cholesterol stimulates calcified nodule formation by valve fibroblasts,57 and that calcified nodule formation by these cells is inhibited by simvastatin.58 Together, these observations provide a potential link between accumulated lesion lipoproteins and calcification and also suggest that statins might have therapeutic benefit. Other potential mechanisms mediating lesion calcification will be discussed subsequently.
Consistent with a role for lipoproteins in valve calcification, retrospective studies have demonstrated strong associations between statin use and decreased risk of progression of aortic valve calcification34,35 and stenosis.31–33 However, a recent small prospective randomized trial showed no benefit of high-dose statin therapy over an average of 3 years.37 This highlights the concern that more advanced AS may be less amenable to statin therapy.32 It also it is possible that effective statin therapy may require longer treatment periods and/or targeting of earlier disease stages.
Renin-Angiotensin System Activation
Recent studies also have implicated the renin-angiotensin system, particularly angiotensin converting enzyme (ACE), angiotensin II (Ang II), and the angiotensin II Type 1 (AT1) receptor in aortic valve lesion pathogenesis.19,20 Ang II, which is generated from angiotensin I by ACE, has a number of potential, AT-1 receptor-mediated, lesion-promoting effects. These include stimulating inflammation and macrophage cholesterol accumulation, impairing fibrinolysis, increasing oxidant stress (summarized in reference 19), and stimulating fibroblast expression of the lipoprotein-retaining proteoglycan, biglycan.59,60
A subset of aortic valve lesion macrophages express ACE.19,20 Surprisingly, a large proportion of valve lesion ACE colocalizes with LDL in the extracellular matrix.19 Ang II also is localized to these regions, suggesting that the LDL-associated ACE is enzymatically active.19 In addition, AT1 receptor is expressed by fibroblasts only in lesions.19,20 Degranulated mast cells also are present in lesions.20 This latter observation is important, because mast cell granules contain chymase, a non-ACE enzyme that also can generate Ang II.20
Thus, aortic valve lesions contain a number of potential sources of Ang II: (1) LDL-associated ACE, (2) macrophage-associated ACE, and (3) mast cell chymase. Moreover, the major pathogenic receptor for Ang II is present in valve lesion fibroblasts. However, whereas smooth muscle cells constitutively express AT-1 receptor, this receptor is only expressed by valve fibroblasts of lesions. Thus, unlike atherosclerosis, where Ang II may affect normal non-plaque smooth muscle cells, valve fibroblasts may be protected from the adverse effects of Ang II until they begin to express AT-1 receptor in early-stage lesions, thereby blunting any potential effects of Ang II on valve lesion pathogenesis. This also may account for the mixed results of retrospective studies, with one showing a strong association between ACE inhibitor use and decreased rate of valve calcification36 and another finding no effect on progression of AS.33 However, in the latter study, AS was severe in nearly half of all subjects and mean follow-up was only 24 months.33 It therefore may be that, if ACE inhibitors or angiotensin receptor antagonists are to have any benefit, treatment will need to be extended over longer periods of time and/or targeted to either aortic sclerosis36 or earlier-stage AS.
A proposed scheme for the roles of lipoprotein retention and oxidative modification and renin-angiotensin system activation in disease pathogenesis is shown in Figure 1.
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Calcification
In addition to fibrosis, calcification is a defining feature of aortic valve lesions. Calcification may contribute to lesion rigidity, thereby worsening obstruction to left ventricular outflow. Moreover, the extent of lesion calcification correlates both with more rapid disease progression and worse clinical outcomes.61,62
Aortic valve calcification now has been shown unequivocally to be an active, rather than a passive, process. Valvular calcium deposits contain both calcium and phosphate11,57,63,63 as hydroxyapatite,57,63 the form of calcium-phosphate mineral present in both calcified arterial tissue64 and bone. Proteins involved in regulation of tissue calcification have been detected in calcified valvular tissue, including osteopontin,13,14 bone morphogenic proteins (BMPs) 2 and 4,15 and receptor activator of nuclear factor NF-
B ligand (RANKL).65 Osteoprotegrin (OPG), which prevents mineral resorption in bone tissue, is a soluble decoy receptor that resembles RANK and acts as a competitive inhibitor of RANK binding to RANKL. RANK is expressed in normal valve leaflets, but is downregulated in aortic valve lesions.65 The osteoblast-specific transcription factor, Runx2/Cbfa1, has been detected in rabbit models of experimental aortic valve disease,16,17,27 and osteoblast-like cells have been identified both in a rabbit model17 and in calcified human valves.15 Finally, a subset of end-stage human aortic valve lesions contain heterotopic bone,15 further confirming the dysregulated nature of aortic valvular calcification.
In aortic valve lesions, calcified nodules appear to first form in regions of lipid deposition,11,12 particularly those with oxidized lipids.12 They also contain tenascin C,66 an extracellular matrix glycoprotein found in developing bones.66 Recently, groups have isolated a subset of valvular fibroblasts that express osteoblast markers57,65 and spontaneously form hydroxyapatite-containing calcified nodules in vitro.57,65 In response to oxidized cholesterol,57 transforming growth factor (TGF) ß1,57 BMP2,57 and RANKL,65 these cells increase their expression of osteoblast markers and increase their rate of calcified nodule formation. In addition, tenascin C upregulates matrix metalloproteinase (MMP)-2 expression in these cells.66 Importantly, it recently has been shown that statins inhibit calcified nodule formation in these cells, at least in part through inhibition of protein prenylation.58 Finally, hyperphosphatemia has been shown to induce calcified vesicle formation in myofibroblasts,67 thereby suggesting a potential mechanism linking chronic kidney disease to valvular calcification.41 Osteopontin may be an important inhibitor of valvular calcification. In one recent study, calcification was dramatically increased in glutaraldehyde-fixed aortic valve leaflets after subcutaneous implantation into osteopontin-deficient as compared with wild-type mice.68 These authors also demonstrated that, by inducing macrophage carbonic anhydrase expression (thereby creating an acidic extracellular environment), osteopontin actively promoted the dissolution of hydroxyapatite.68 Carbonic anhydrase has also been demonstrated to play an inhibitory role in a rat model of aortic medial elastocalcinosis.69 Interestingly, osteopontin is expressed by infiltrating macrophages in both atherosclerotic70 and aortic valve13 lesions. However, whereas atherosclerotic plaque smooth muscle cells also express osteopontin,70 valve lesion fibroblasts do not.13 Thus, as a result of differences in osteopontin expression by the dominant mesenchymal cell type, the relative efficacy of osteopontin as a calcification inhibitor may differ in atherosclerosis and aortic valve disease.
Together, these findings implicate oxidized lipids and macrophage- and T-lymphocyte-produced cytokines in valvular calcification. They also suggest that specific signaling mechanisms are involved in valvular calcification. For example, the presence of chronic inflammation, inflammatory cytokines, oxidized lipids, and RANKL in lesions suggests that NF-B activation is a crucial step in the vascular calcification process. NF-B is upregulated by inflammatory cytokines, oxidant stress, and Ang II, and it signals through the mitogen-activated protein (MAP) kinase pathway.
Atherogenic factors, including oxidized lipids,12,57 TNF-,46 and hyperglycemia,39,43,71 all might mediate valvular calcification, at least in part, through pathways activated by BMP2. BMP2 is present in human aortic valve lesions72 and stimulates calcified nodule formation by valvular fibroblasts in vitro.57 BMP2 can upregulate both an "osteogenic" pathway involving the transcription factor Msx2 (which activates Wnt signaling), and a chondro-osteogenic pathway involving the transcription factor Runx2/Cbfa1.73 Shao and colleagues have demonstrated that Msx2-overexpressing mice have increased vascular calcification.74 That this effect was mediated through Wnt activation was supported by additional evidence by Msx2 overexpression experiments in TOPGAL+ (Wnt reporter) mice.74 Rajamannan and colleagues have directly implicated the Wnt/LDL receptor-related protein 5 (Lrp5)/ß-catenin pathway in valvular calcification18 by demonstrating upregulation of Lrp5 and ß-catenin in hypercholesterolemic rabbit aortic valve lesions. In addition, they have shown that atorvastatin decreases aortic valve lesion levels of Lrp5 and ß-catenin and that LDL exposure upregulates Lrp5 and ß-catenin expression in valve myofibroblasts in vitro.18 More recently, that group has published immunohistochemical results suggesting that the canonical osteogenic Wnt ligand, Wnt3, is detectable in calcified human aortic valves, though this observation was not confirmed by Western blot analysis or by reverse transcriptase-polymerase chain reaction (PCR) analyses of Wnt3 mRNA levels.75
However, atherogenic factor-mediated upregulation of valve lesion BMP2 could also activate a chondro-osteogenic pathway involving Runx2/Cbfa1. Indeed, a recent in vitro study has demonstrated that BMP signaling is required for activation of the Runx2/Cbfa1 pathway in both a mesenchymal cell line as well as in primary cultures of marrow stromal cells.76 The Runx/Cbfa1 transcription factor is increased in aortic valves of 2 hypercholesterolemic rabbit models.16,17,27 Interestingly, treatment with an angiotensin receptor antagonist, olmesartan, inhibited aortic valve leaflet Runx2/Cbfa1 upregulation and macrophage accumulation in the latter study.27 As noted previously, phosphate induces vesicle formation in myofibroblasts.67 In vascular smooth muscle cells, this effect of phosphate is mediated by its binding to the sodium-dependent phosphate cotransporter Pit1, which upregulates Runx2/Cbfa1.77 It is possible that phosphate binding to Pit1 has a similar effect on valve fibroblasts. In addition, a recent article25 (discussed below) has implicated mutations in NOTCH1, a transcription factor that normally represses Runx2/Cbfa1, in valvular calcification in two families. Thus, the chondro-osteogenic Runx2/Cbfa1 pathway may be activated not only by BMP2, but also both by chronic kidney disease-associated hyperphosphatemia and by specific genetic abnormalities.
Together, these studies have demonstrated that calcific aortic valve disease is an actively-regulated process and have identified several potential therapeutic targets, including lipid-lowering, lipoprotein/proteoglycan retention, inflammatory and fibrosing cytokines, the renin-angiotensin system, and specific cell-signaling pathways regulating vascular calcification. Recent studies also have begun to investigate how genetic factors may influence valve disease pathogenesis.
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Genetic Factors |
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Studies now have begun to emerge that have correlated specific genetic polymorphisms with increased risk of aortic valve disease.22–24 A specific Vitamin D receptor allele has been found with increased frequency in AS patients as compared with controls.22 Also, the apolipoprotein E4 allele, which has been associated with increased risks for atherosclerosis and Alzheimer disease, is significantly increased in frequency in AS patients, an association that persists after adjustment for age, gender, and coronary artery disease.23 More recently, combinations of specific estrogen receptor and TGF-ß1 polymorphisms have been associated with increased risk of AS in postmenopausal women.24 Although intriguing, particularly because each of these polymorphisms has potential functional consequences that lend biological plausibility to their apparent associations with AS, these are all small single center reports. Therefore, these apparent associations must also be tested prospectively in larger and more ethnically-diverse cohorts.
Importantly, recent studies have emphasized not only the importance of bicuspid aortic valves as a risk factor for aortic stenosis4,78 but also demonstrated one specific genetic defect that can contribute to bicuspid valve morphogenesis.25 A recent, single center, consecutive series of 932 surgically-excised nonrheumatic AS valves found 49% of these valves to be congenitally bicuspid.4 This would represent a substantial enrichment of the proportion of congenitally abnormal valves in nonrheumatic AS as compared with the overall population4 and suggests that the bicuspid valve has a much more powerful and widespread influence on progression to severe disease than recognized previously. Interestingly, a small, earlier study found a similar 42% prevalence of bicuspid valves in 43 consecutive patients referred for aortic valve replacement surgery.78
Another recent study has identified that mutations in a specific transcription factor can link congenital valve abnormalities and valvular calcification.25 Mutations in the gene for the NOTCH1 transcriptional factor were identified in two families with an autosomal dominant pattern of inheritance of cardiac valvular and aortic wall abnormalities.25 The murine homolog Notch1 is highly expressed in developing aortic valves and acts through the hairy-related family of transcriptional proteins (Hrt) to represses Runx2/Cbfa1. Runx2/Cbfa1 appears to play central roles both in early valve development and in a chondro-osteogenic differentiation pathway. Thus, functional mutations in the NOTCH1 gene derepress Hrt and Runx2/Cbfa1, thereby leading to increased osteoblast differentiation. This latter effect could, in part, mediate an increased propensity to valvular calcification in patients with bicuspid aortic valves. However, what then explains the structural abnormalities, ie, the failure of normal leaflet formation and increased risk of aortic dissection seen in patients with bicuspid aortic valves? This may be in part attributable to an adverse effect of NOTCH1 mutations on valve morphogenesis. However, it also is possible that the Runx2/Cbfa1 activation resulting from mutations in NOTCH1 (or other proteins involved in this transcriptional pathway, including hrt or Runx2/Cbfa1 itself) may direct adult valve cells along an osteoblast differentiation pathway. Thus, valve cells could be directed away from the normal differentiation pathway that results in mature, collagen- and elastin-expressing adult valve fibroblasts. In this way, genetic defects in this key cell-signaling pathway could help to explain both the structural abnormalities that manifest in bicuspid aortic valves as well as the increased propensity to valve calcification. It also calls into question the common assumption that abnormal valve flow dynamics alone account for the increased risk of calcification in patients with congenital bicuspid valves. One important caveat is that, to date, NOTCH1 mutations have been associated with the bicuspid aortic valve phenotype in only 2 families.25 It is unlikely that NOTCH1 mutations account for a majority, or even a significant minority, of cases of congenitally bicuspid aortic valves. Moreover, a potential role for NOTCH1, or other downstream proteins involved in this transcriptional pathway, needs to be replicated by others. Nonetheless, the study by Garg et al25 does serve as an important proof-of-principle that specific genetic defects might both mediate morphological defects and promote a calcifying cell phenotype in aortic valves.
Together, these sets of observations may have significant implications for relative benefit and timing of potential pharmacological therapies for calcific aortic valve disease. Aortic sclerosis and stenosis have been considered to be a continuum of the same disease process, as supported by a recent study demonstrating a rate of progression of echocardiographically-identified aortic sclerosis to AS in an elderly cohort of 
15% over 7 years.79 However, although tricuspid and bicuspid aortic valve lesions share many common epidemiologic risk factors and histopathologic lesion characteristics,21 it may be that genetic factors, as typified by NOTCH1 mutations,25 are more potent and more prevalent in the subset of patients who progress from aortic sclerosis to AS.4 Thus, it might be that currently-proposed pharmacological therapies directed against atherogenic risk factors31–36,62 are relatively less effective in the subset of AS patients with a genetic defect affecting valve morphology and/or may need to be started at an earlier time point to achieve a therapeutic benefit.33,37
Summary
The past 10 to 15 years have been marked by significant advances in our understanding of the pathogenesis of calcific aortic valve disease. A proposed scheme integrating lipids, the renin-angiotensin system, inflammation, signaling pathways, and genetic predisposition in the pathogenesis of valve calcification is shown in Figure 2. A number of risk factors for this disease have been identified, and the histological features of valve lesions have been better delineated. More recent studies have led to an emerging understanding of the roles of separate cell-signaling pathways involving Wnt and Runx2/Cbfa1 in disease pathogenesis. Both of these pathways appear to be activated by atherogenic factors, whereas a recent study has linked a specific genetic defect with activation of the Runx2/Cbfa1 pathway. As a result, we have moved well beyond the old paradigm that considered aortic valve disease development to be a fait accompli to understanding that it is actively mediated, with many mechanisms similar to those operative in atherogenesis.8,11,38,44 Recent data should now guide us toward a more nuanced view, which considers the interplay in valve disease pathogenesis between lipid/inflammatory mediators as well as anatomic and genetic mechanisms unique to aortic valves.
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Acknowledgments |
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I thank Jane E.B. Reusch for helpful comments and Karen Fowler for assistance with manuscript preparation.
Sources of Funding
Supported in part by grants DK02456 and HL30086 from the National Institutes of Health, Bethesda, Md.
Disclosure(s)
Dr O’Brien has received honoraria from Merck and Co, Pfizer, Takeda and AstraZeneca, has served as a consultant to Sanofi-Aventis and has received grant support from Merck and Co. He is listed as a coinventor on a patent application relating to renin-angiotensin system inhibition in aortic valve disease, filed by the University of Washington, but has indicated to the University, in writing, that he will divest himself of all personal financial interest in any patents that may issue from the application, including any right to share in royalties arising from any such patents.
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Footnotes |
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Original received October 28, 2005; final version accepted May 8, 2006.
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References |
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TopAbstractIntroductionEpidemiologyBiological Processes Implicated...Genetic FactorsReferences |
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1. Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol. 1997; 29: 630–634.[Abstract]
2. Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly [see comments]. N Engl J Med. 1999; 341: 142–147.
3. Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol. 1993; 21: 1220–1225.[Abstract]
4. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation. 2005; 111: 920–925.
5. Otto CM, Burwash IG, Legget ME, Munt BI, Fujioka M, Healy NL, Kraft CD, Miyake-Hull CY, Schwaegler RG. Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise predictors of outcome. Circulation. 1997; 95: 2262–2270.
6. Sell S, Scully RE. Aging changes in the aortic and mitral valves: histologic and histochemical studies, with observations on the pathogenesis of calcific aortic stenosis and calcification of the mitral annulus. Am J Pathol. 1965; 46: 345–365.[Medline] [Order article via Infotrieve]
7. Olsson M, Dalsgaard CJ, Haegerstrand A, Rosenqvist M, Ryden L, Nilsson J. Accumulation of T lymphocytes and expression of interleukin-2 receptors in nonrheumatic stenotic aortic valves. J Am Coll Cardiol. 1994; 23: 1162–1170.[Abstract]
8. 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.
9. Olsson M, Rosenqvist M, Nilsson J. Expression of HLA-DR antigen and smooth muscle cell differentiation markers by valvular fibroblasts in degenerative aortic stenosis. J Am Coll Cardiol. 1994; 24: 1664–1671.[Abstract]
10. Walton KW, Williamson N, Johnson AG. The pathogenesis of atherosclerosis of the mitral and aortic valves. J Pathol. 1970; 101: 205–220.[CrossRef][Medline] [Order article via Infotrieve]
11. O’Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of ‘degenerative’ valvular aortic stenosis. Arterioscler Thromb Vasc Biol. 1996; 16: 523–532.
12. Olsson M, Thyberg J, Nilsson J. Presence of oxidized low density lipoprotein in nonrheumatic stenotic aortic valves. Arterioscler Thromb Vasc Biol. 1999; 19: 1218–1222.
13. O’Brien KD, Kuusisto J, Reichenbach DD, Ferguson M, Giachelli C, Alpers CE, Otto CM. Osteopontin is expressed in human aortic valvular lesions [see comments]. Circulation. 1995; 92: 2163–2168.
14. Mohler ER, III, Adam LP, McClelland P, Graham L, Hathaway DR. Detection of osteopontin in calcified human aortic valves. Arterioscler Thromb Vasc Biol. 1997; 17: 547–552.
15. Mohler ER III, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS. Bone formation and inflammation in cardiac valves. Circulation. 2001; 103: 1522–1528.
16. Rajamannan NM, Subramaniam M, Springett M, Sebo TC, Niekrasz M, McConnell JP, Singh RJ, Stone NJ, Bonow RO, Spelsberg TC. Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation. 2002; 105: 2660–2665.
17. Rajamannan NM, Subramaniam M, Rickard D, Stock SR, Donovan J, Springett M, Orszulak T, Fullerton DA, Tajik AJ, Bonow RO, Spelsberg T. Human aortic valve calcification is associated with an osteoblast phenotype. Circulation. 2003; 107: 2181–2184.
18. Rajamannan NM, Subramaniam M, Caira F, Stock SR, Spelsberg TC. Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway. Circulation. 2005; 112: I229–I234.
19. O’Brien KD, Shavelle DM, Caulfield MT, McDonald TO, Olin-Lewis K, Otto CM, Probstfield JL. Association of Angiotensin-converting enzyme with low-density lipoprotein in aortic valvular lesions and in human plasma. Circulation. 2002; 106: 2224–2230.
20. Helske S, Lindstedt KA, Laine M, Mayranpaa M, Werkkala K, Lommi J, Turto H, Kupari M, Kovanen PT. Induction of local angiotensin II-producing systems in stenotic aortic valves. J Am Coll Cardiol. 2004; 44: 1859–1866.
21. Wallby L, Janerot-Sjoberg B, Steffensen T, Broqvist M. T lymphocyte infiltration in non-rheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspid aortic valves. Heart. 2002; 88: 348–351.
22. Ortlepp JR, Hoffmann R, Ohme F, Lauscher J, Bleckmann F, Hanrath P. The vitamin D receptor genotype predisposes to the development of calcific aortic valve stenosis. Heart. 2001; 85: 635–638.
23. Novaro GM, Sachar R, Pearce GL, Sprecher DL, Griffin BP. Association between apolipoprotein E alleles and calcific valvular heart disease. Circulation. 2003; 108: 1804–1808.
24. Nordstrom P, Glader CA, Dahlen G, Birgander LS, Lorentzon R, Waldenstrom A, Lorentzon M. Oestrogen receptor alpha gene polymorphism is related to aortic valve sclerosis in postmenopausal women. J Intern Med. 2003; 254: 140–146.[CrossRef][Medline] [Order article via Infotrieve]
25. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005; 437: 270–274.[CrossRef][Medline] [Order article via Infotrieve]
26. Drolet MC, Arsenault M, Couet J. Experimental aortic valve stenosis in rabbits. J Am Coll Cardiol. 2003; 41: 1211–1217.
27. Arishiro K, Hoshiga M, Negoro N, Okabe T, Ishihara T, Hanafusa T Angiotensin Receptor 1 Blocker Reduces Atherosclerotic Changes of Aortic Valve in Hypercholesterolemic Rabbit Model. J Am Coll Cardiol. 2006; 47: 284A–285A.
28. Rajamannan NM, Subramaniam M, Stock SR, Stone NJ, Springett M, Ignatiev KI, McConnell JP, Singh RJ, Bonow RO, Spelsberg TC. Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve. Heart. 2005; 91: 806–810.
29. Rajamannan NM, Nealis TB, Subramaniam M, Pandya S, Stock SR, Ignatiev CI, Sebo TJ, Rosengart TK, Edwards WD, McCarthy PM, Bonow RO, Spelsberg TC. Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation. Circulation. 2005; 111: 3296–3301.
30. Drolet MC, Roussel E, Deshaies Y, Couet J, Arsenault M. A high fat/high carbohydrate diet induces aortic valve disease in C57BL/6J mice. J Am Coll Cardiol. 2006; 47: 850–855.
31. Novaro GM, Tiong IY, Pearce GL, Lauer MS, Sprecher DL, Griffin BP. Effect of hydroxymethylglutaryl coenzyme a reductase inhibitors on the progression of calcific aortic stenosis. Circulation. 2001; 104: 2205–2209.
32. Bellamy MF, Pellikka PA, Klarich KW, Tajik AJ, Enriquez-Sarano M. Association of cholesterol levels, hydroxymethylglutaryl coenzyme-A reductase inhibitor treatment, and progression of aortic stenosis in the community. J Am Coll Cardiol. 2002; 40: 1723–1730.
33. Rosenhek R, Rader F, Loho N, Gabriel H, Heger M, Klaar U, Schemper M, Binder T, Maurer G, Baumgartner H. Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation. 2004; 110: 1291–1295.
34. Pohle K, Maffert R, Ropers D, Moshage W, Stilianakis N, Daniel WG, Achenbach S. Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. Circulation. 2001; 104: 1927–1932.
35. Shavelle DM, Takasu J, Budoff MJ, Mao S, O’Brien KD. HMG CoA reductase inhibitor (statin) and aortic valve calcium. Lancet. 2002; 359: 1125–1126.[CrossRef][Medline] [Order article via Infotrieve]
36. O’Brien KD, Probstfield JL, Caulfield MT, Nasir K, Takasu J, Shavelle DM, Wu AH, Zhao XQ, Budoff MJ. Angiotensin-converting enzyme inhibitors and change in aortic valve calcium. Arch Intern Med. 2005; 165: 858–862.
37. Cowell SJ, Newby DE, Prescott RJ, Bloomfield P, Reid J, Northridge DB, Boon NA. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med. 2005; 352: 2389–2397.
38. Mohler ER, Sheridan MJ, Nichols R, Harvey WP, Waller BF. Development and progression of aortic valve stenosis: atherosclerosis risk factors-a causal relationship? A clinical morphologic study. Clin Cardiol. 1991; 14: 995–999.[Medline] [Order article via Infotrieve]
39. Aronow WS, Ahn C, Kronzon I, Goldman ME. Association of coronary risk factors and use of statins with progression of mild valvular aortic stenosis in older persons. Am J Cardiol. 2001; 88: 693–695.[CrossRef][Medline] [Order article via Infotrieve]
40. Maher ER, Pazianas M, Curtis JR. Calcific aortic stenosis: a complication of chronic uraemia. Nephron. 1987; 47: 119–122.[Medline] [Order article via Infotrieve]
41. Raggi P, Bommer J, Chertow GM. Valvular calcification in hemodialysis patients randomized to calcium-based phosphorus binders or sevelamer. J Heart Valve Dis. 2004; 13: 134–141.[Medline] [Order article via Infotrieve]
42. Fox CS, Larson MG, Vasan RS, Guo CY, Parise H, Levy D, Leip EP, O’donnell CJ, D’Agostino RB Sr, Benjamin EJ. Cross-sectional association of kidney function with valvular and annular calcification: the framingham heart study. J Am Soc Nephrol. 2006; 17: 521–527.
43. Katz R, Wong ND, Kronmal R, Takasu J, Shavelle DM, Probstfield JL, Bertoni AG, Budoff MJ, O’Brien KD. Circulation. 2006; 113: 2113–2119.
44. Mohler ER III. Are atherosclerotic processes involved in aortic-valve calcification? Lancet. 2000; 356: 524–525.[CrossRef][Medline] [Order article via Infotrieve]
45. Kaden JJ, Dempfle CE, Grobholz R, Tran HT, Kilic R, Sarikoc A, Brueckmann M, Vahl C, Hagl S, Haase KK, Borggrefe M. Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. Atherosclerosis. 2003; 170: 205–211.[CrossRef][Medline] [Order article via Infotrieve]
46. Kaden JJ, Dempfle CE, Grobholz R, Fischer CS, Vocke DC, Kilic R, Sarikoc A, Pinol R, Hagl S, Lang S, Brueckmann M, Borggrefe M. Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis. Cardiovasc Pathol. 2005; 14: 80–87.[CrossRef][Medline] [Order article via Infotrieve]
47. Edep ME, Shirani J, Wolf P, Brown DL. Matrix metalloproteinase expression in nonrheumatic aortic stenosis. Cardiovasc Pathol. 2000; 9: 281–286.[CrossRef][Medline] [Order article via Infotrieve]
48. Soini Y, Satta J, Maatta M, Autio-Harmainen H. Expression of MMP2, MMP9, MT1-MMP, TIMP1, and TIMP2 mRNA in valvular lesions of the heart. J Pathol. 2001; 194: 225–231.[CrossRef][Medline] [Order article via Infotrieve]
49. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994; 94: 2493–2503.[Medline] [Order article via Infotrieve]
50. Nikkari ST, O’Brien KD, Ferguson M, Hatsukami T, Welgus HG, Alpers CE, Clowes AW. Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis. Circulation. 1995; 92: 1393–1398.
51. Galis ZS, Sukhova GK, Kranzhofer R, Clark S, Libby P. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc Natl Acad Sci U S A. 1995; 92: 402–406.
52. O’Brien KD, Olin KL, Alpers CE, Chiu W, Ferguson M, Hudkins K, Wight TN, Chait A. Comparison of apolipoprotein and proteoglycan deposits in human coronary atherosclerotic plaques: colocalization of biglycan with apolipoproteins. Circulation. 1998; 98: 519–527.
53. O’Brien KD, Otto CM, Reichenbach DD, Alpers CE, Wight TN. Regional accumulation of proteoglycans in lesions of "degenerative" valvular aortic stenosis and their relationship to apolipoproteins. Circulation. 1995; 92 (suppl I): I-612.
54. Wight TN. Cell biology of arterial proteoglycans. Arteriosclerosis. 1989; 9: 1–20.
55. Olsson U, Camejo G, Hurt-Camejo E, Elfsber K, Wiklund O, Bondjers G. Possible functional interactions of apolipoprotein B-100 segments that associate with cell proteoglycans and the ApoB/E receptor. Arterioscler Thromb Vasc Biol. 1997; 17: 149–155.
56. Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature. 2002; 417: 750–754.[CrossRef][Medline] [Order article via Infotrieve]
57. Mohler ER, III, Chawla MK, Chang AW, Vyavahare N, Levy RJ, Graham L, Gannon FH. Identification and characterization of calcifying valve cells from human and canine aortic valves. J Heart Valve Dis. 1999; 8: 254–260.[Medline] [Order article via Infotrieve]
58. Wu B, Elmariah S, Kaplan FS, Cheng G, Mohler ER III. Paradoxical effects of statins on aortic valve myofibroblasts and osteoblasts: implications for end-stage valvular heart disease. Arterioscler Thromb Vasc Biol. 2005; 25: 592–597.
59. Tiede K, Stoter K, Petrik C, Chen WB, Ungefroren H, Kruse ML, Stoll M, Unger T, Fischer JW. Angiotensin II AT(1)-receptor induces biglycan in neonatal cardiac fibroblasts via autocrine release of TGFß in vitro. Cardiovasc Res. 2003; 60: 538–546.
60. Ahmed MS, Oie E, Vinge LE, Yndestad A, Andersen GG, Andersson Y, Attramadal T, Attramadal H. Induction of myocardial biglycan in heart failure in rats-an extracellular matrix component targeted by AT(1) receptor antagonism. Cardiovasc Res. 2003; 60: 557–568.
61. Bahler RC, Desser DR, Finkelhor RS, Brener SJ, Youssefi M. Factors leading to progression of valvular aortic stenosis. Am J Cardiol. 1999; 84: 1044–1048.[CrossRef][Medline] [Order article via Infotrieve]
62. Rosenhek R, Binder T, Porenta G, Lang I, Christ G, Schemper M, Maurer G, Baumgartner H. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med. 2000; 343: 611–617.
63. Anderson HC. Calcific diseases. A concept. Arch Pathol Lab Med. 1983; 107: 341–348.[Medline] [Order article via Infotrieve]
64. Bostrom K, Watson KE, Horn S, Wortham C, Herman IM, Demer LL. Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest. 1993; 91: 1800–1809.[Medline] [Order article via Infotrieve]
65. Kaden JJ, Bickelhaupt S, Grobholz R, Haase KK, Sarikoc A, Kilic R, Brueckmann M, Lang S, Zahn I, Vahl C, Hagl S, Dempfle CE, Borggrefe M. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulate aortic valve calcification. J Mol Cell Cardiol. 2004; 36: 57–66.[CrossRef][Medline] [Order article via Infotrieve]
66. Jian B, Jones PL, Li Q, Mohler ER III, Schoen FJ, Levy RJ. Matrix metalloproteinase-2 is associated with tenascin-C in calcific aortic stenosis. Am J Pathol. 2001; 159: 321–327.
67. Reynolds JL, Joannides AJ, Skepper JN, McNair R, Schurgers LJ, Proudfoot D, Jahnen-Dechent W, Weissberg PL, Shanahan CM. Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol. 2004; 15: 2857–2867.
68. Steitz SA, Speer MY, McKee MD, Liaw L, Almeida M, Yang H, Giachelli CM. Osteopontin inhibits mineral deposition and promotes regression of ectopic calcification. Am J Pathol. 2002; 161: 2035–2046.
69. Essalihi R, Dao HH, Gilbert LA, Bouvet C, Semerjian Y, McKee MD, Moreau P. Regression of medial elastocalcinosis in rat aorta: a new vascular function for carbonic anhydrase. Circulation. 2005; 112: 1628–1635.
70. Giachelli CM, Bae N, Almeida M, Denhardt DT, Alpers CE, Schwartz SM. Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques. J Clin Invest. 1993; 92: 1686–1696.[Medline] [Order article via Infotrieve]
71. Aronow WS, Schwartz KS, Koenigsberg M. Correlation of serum lipids, calcium, and phosphorus, diabetes mellitus and history of systemic hypertension with presence or absence of calcified or thickened aortic cusps or root in elderly patients. Am J Cardiol. 1987; 59: 998–999.[CrossRef][Medline] [Order article via Infotrieve]
72. Kaden JJ, Bickelhaupt S, Grobholz R, Vahl CF, Hagl S, Brueckmann M, Haase KK, Dempfle CE, Borggrefe M. Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis. J Heart Valve Dis. 2004; 13: 560–566.[Medline] [Order article via Infotrieve]
73. Wozney JM, Rosen V. Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair. Clin Orthop Relat Res. 1998; 26–37.
74. Shao JS, Cheng SL, Pingsterhaus JM, Charlton-Kachigian N, Loewy AP, Towler DA. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest. 2005; 115: 1210–1220.[CrossRef][Medline] [Order article via Infotrieve]
75. Caira FC, Stock SR, Gleason TG, McGee EC, Huang J, Bonow RO, Spelsberg TC, McCarthy PM, Rahimtoola SH, Rajamannan NM. Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. J Am Coll Cardiol. 2006; 47: 1707–1712.
76. Phimphilai M, Zhao Z, Boules H, Roca H, Franceschi RT. BMP signaling is required for RUNX2-dependent induction of the osteoblast phenotype. J Bone Miner Res. 2006; 21: 637–646.[CrossRef][Medline] [Order article via Infotrieve]
77. Li X, Yang HY, Giachelli CM. Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification. Circ Res. 2006; 98: 905–912.
78. Chui MC, Newby DE, Panarelli M, Bloomfield P, Boon NA. Association between calcific aortic stenosis and hypercholesterolemia: is there a need for a randomized controlled trial of cholesterol-lowering therapy? Clin Cardiol. 2001; 24: 52–55.[Medline] [Order article via Infotrieve]
79. Cosmi JE, Kort S, Tunick PA, Rosenzweig BP, Freedberg RS, Katz ES, Applebaum RM, Kronzon I. The risk of the development of aortic stenosis in patients with "benign" aortic valve thickening. Arch Intern Med. 2002; 162: 2345–2347.
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