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Journal of Investigative Medicine:
doi: 10.2310/6650.2007.00010
EB Symposium

Epidemiology and Genetics of Calcific Aortic Valve Disease

O'Brien, Kevin D.

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From the Division of Cardiology, University of Washington, Seattle, WA.

Address correspondence to: Dr. Kevin D. O'Brien, Division of Cardiology, Box 356422, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195‐6422; e‐mail: cardiac@u.washington.edu.

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Abstract

Calcific aortic valve disease is a common condition in the elderly and is associated with significant morbidity and mortality. Although biologically plausible roles in disease pathogenesis have been proposed for both lipoproteins and the renin‐angiotensin system, no properly controlled, randomized trials have demonstrated that any pharmacologic therapy slows development of the disease. This review defines the stages of calcific aortic valve disease; discusses the role of nonechocardiographic techniques, such as cardiac computed tomography, that may allow identification and study of earlier‐stage disease; reviews associated epidemiologic factors; and summarizes recent studies of “novel” risk factors, such as metabolic syndrome and inflammatory biomarkers. Finally, the role of genetics in this disease is receiving greater attention, and recent studies are reviewed that examine genetic polymorphisms and identify single‐gene defects associated with this disease. Together these latter sets of studies emphasize that unique “nonatherosclerotic” factors can influence calcific aortic valve disease development, suggesting the possibility of novel therapeutic strategies for this condition.

Calcific aortic valve disease is a common condition affecting 25% of individuals over age 65 years and > 50% of those over age 85 years.1 This disease is characterized pathologically by thickening, fibrosis, and calcification of the aortic valve leaflets in the absence of the significant neovascularization that characterizes rheumatic aortic valve disease.2 These distinctive pathologic changes typically involve the fibrosa, the valve layer adjacent to the aortic surface of the valve.3 Functionally, calcific aortic valve disease is divided into two stages. The first is aortic sclerosis, in which valve leaflet thickening and calcification are present, but leaflet mobility is not so impaired as to substantially limit the flow of blood from the left ventricular chamber into the proximal ascending aorta (ie, “left ventricular outflow”).4 In contrast, aortic stenosis, the end stage of the disease, is defined as present if leaflet mobility has become sufficiently restricted to impede left ventricular outflow. In response to the higher resistance to transvalvular blood flow imposed by aortic stenosis, the rate of blood flow across the valve increases in an attempt to maintain cardiac output, and a systolic pressure gradient develops between the left ventricle and the proximal aorta.5

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Aortic Sclerosis and Aortic Stenosis Both Confer Increased Risk

Both aortic sclerosis and aortic stenosis are associated with increased morbidity and mortality. Aortic sclerosis is associated with an approximately 50% increase in the risk for cardiovascular death.6 In one study, aortic stenosis was associated with an 80% risk for progression to congestive heart failure, aortic valve replacement surgery, or death over 5 years.4 In addition, aortic stenosis is the most common indication for valve replacement surgery in the United States.7 Unfortunately, there currently are no nonsurgical therapies that have been shown definitively, in randomized, properly controlled clinical trials, to decrease the risk for progression of calcific aortic valve disease.

What data exist to demonstrate that aortic sclerosis and aortic stenosis represent a continuum of disease? One retrospective study reported that among 2,131 subjects with an average age of 69 years and aortic valve thickening (sclerosis) on a baseline echocardiogram, there was a prevalence of progression to aortic stenosis of 15.8% over an average follow‐up of 7.3 years.8

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Methods for Quantifying and Monitoring Calcific Aortic Valve Disease

Classically, the severity of aortic stenosis was quantified in the cardiac catheterization laboratory by measuring the magnitude of the transvalvular pressure gradient. However, a major advance in the field was the recognition that the magnitude of the systolic transvalvular pressure gradient is proportional to the velocity of flow across the valve (ie, the “aortic jet velocity”), as measured by Doppler echocardiography.9‐11 A typical definition of aortic jet velocity that distinguishes aortic sclerosis from aortic stenosis is an aortic jet velocity of ≥ 2.5 m/s.4,12 The distinction between aortic sclerosis and aortic stenosis is summarized in Table 1.

Table 1
Table 1
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However, one major impediment to the study of progression of aortic sclerosis to aortic stenosis has been the relative limitation of echocardiography in detecting and precisely quantifying calcific aortic valve disease. Specifically, echocardiography can quantify the hemodynamic severity of aortic stenosis, as measured by Doppler jet velocity, with relatively good precision. However, aortic sclerosis progression is characterized as progression of anatomic abnormalities of the valve without significant changes in valvular hemodynamics. Specifically, echocardiography is not well suited to quantify anatomic progression of aortic sclerosis for the following reasons: (1) the relatively low spatial resolution of echocardiography makes it difficult to quantify subtle changes in valve thickness and (2) the borders of calcium deposits are not well defined owing to the reflection of the ultrasound beam by the leading edge of calcium deposits. Thus, it is not possible to precisely quantify leaflet calcium content by echocardiography.

As a result, cardiac computed tomography (CT) has been developed as a method for quantifying the calcium component of aortic sclerosis.13‐15 Median interscan variabilities for CT‐measured aortic valve calcium (AVC) scores have been shown to be as low as 6 to 10%.14,15 Thus, CT has emerged as a viable method for identifying the presence and quantifying the severity of AVC, as well as for following its progression. CT also has been used to quantify the severity of calcium deposition in aortic stenosis.13,16 However, there is a relatively poor correlation of absolute calcium score with Doppler echocardiographically assessed hemodynamic measures of aortic stenosis severity.17,18 Thus, an “anatomic” method, such as CT‐assessed valve calcium scores, may be the preferred method for quantifying severity and following the progression of aortic sclerosis, whereas “hemodynamic” methods, such as Doppler echocardiography, remain the gold standard for quantifying severity and following the progression of aortic stenosis (Figure 1).

Figure 1
Figure 1
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Epidemiology of Calcific Aortic Valve Disease

“Traditional” Atherosclerosis Risk Factors and Aortic Valve Disease

Over the years, a number of small studies have reported associations between increased prevalence of aortic valve disease, especially aortic stenosis, and a number of standard risk factors, including hypercholesterolemia19 or hypertriglyceridemia,20 diabetes,19 hypertension,19 male gender,20 and smoking.20 Diabetes, hypertension, smoking, and increased body mass index also have been associated with increased rates of aortic stenosis progression.21

One of the largest studies to date examining the relationship of “atherosclerotic” risk factors to the prevalence of aortic sclerosis or stenosis is that of Stewart and colleagues using data from the Cardiovascular Health Study.1 In that study of 5,201 participants age ≥ 65 years, increased prevalence of echocardiographically identified aortic sclerosis or stenosis was associated with age, male gender, hypertension, smoking, and elevated plasma levels of low‐density lipoprotein (LDL) cholesterol and lipoprotein (a) (Table 2).1

Table 2
Table 2
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“Nontraditional” Atherosclerosis Risk Factors and Aortic Valve Disease

Recent reports have carefully examined the relationships of additional risk factors to the risk for aortic valve disease, especially aortic sclerosis.

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Metabolic Syndrome and Aortic Valve Disease

In 2006, three studies reported associations of increased risk for aortic valve disease with the presence of metabolic syndrome (MetS),22‐24 a constellation of cardiometabolic risk factors, including central adiposity, high triglycerides, low high‐density lipoprotein cholesterol, modest hypertension, and impaired fasting glucose that has been associated with increased risk for cardiovascular disease.25,26 In the first study, MetS was associated with increases in adjusted relative risk for aortic valve calcium of 45% in women and 70% in men; there also was an association of an increased number of MetS features with increased AVC prevalence in both genders.22 In the second study, MetS was associated with a doubling in the rate of progression of aortic stenosis, and the 3‐year event‐free survival was 3.85‐fold lower in MetS subjects.23 Finally, in those with bioprosthetic aortic valves, MetS was associated with a higher rate of progression of bioprosthetic valve stenosis and a doubling in the prevalence of hemodynamically significant bioprosthetic valve regurgitation.24 Together these studies (summarized in Table 3) extend the known relationship of glucose metabolism abnormalities with aortic valve disease beyond diabetes and raise the possibility that insulin resistance may represent a novel pharmacologic target in all “stages”27 of calcific aortic valve disease.

Table 3
Table 3
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Renal Dysfunction and Aortic Valve Disease

A number of reports have documented associations of end‐stage renal disease with increased prevalence and/or progression of aortic stenosis.28‐30 Whether more moderate renal dysfunction also confers increased aortic valve disease risk was examined more recently.31,32 In an echocardiography‐based report from the Framingham Offspring Study, Fox and colleagues reported a nonsignificant, 10% increase in relative risk for prevalent aortic valve calcium for those with estimated glomerular filtration rate (eGFR) < 60 mL/min/m2 (by the modified diet in renal disease equation).31 In a similar CT‐based study of the Multi‐Ethnic Study of Atherosclerosis (MESA) cohort, in which AVC prevalence was approximately twofold higher, Ix and colleagues reported a 24% increase in prevalent AVC for those with an eGFR < 60 mL/min/m2, although this difference just failed to reach statistical significance.32 Thus, more moderate degrees of renal dysfunction appear to be associated with an increase in calcific aortic valve disease risk that is, at best, modest.

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Inflammatory Biomarkers and Aortic Valve Disease

There has been substantial interest recently in whether specific inflammatory biomarkers might add additional prognostic information to that provided by “traditional” cardiovascular risk factors. One small, 42‐subject study reported an association of elevated levels of C‐reactive protein (CRP) with an increased rate of aortic stenosis progression.33 However, another recent report from the much larger Framingham Offspring Study found no relationship of CRP levels with increased prevalence of AVC after adjustment for standard cardiovascular risk factors.34 Thus, the situation for aortic valve disease may be similar to atherosclerosis, in which there appears to be little, if any, residual risk prediction for CRP after full adjustment for traditional cardiovascular risk factors.35,36

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Genetics of Aortic Valve Disease

Genetic Polymorphisms and Aortic Valve Disease

Over the past 6 years or so, a limited number of studies have examined the relationship of various genetic polymorphisms to aortic valve disease, and the results have been, to some extent, contradictory. The first of these, a 200‐subject case‐control study, reported an association of the B allele of the vitamin D receptor with an increased risk of aortic stenosis.37 Another small, 124‐subject case‐control study reported that a polymorphism identified by a Xba1 restriction endonuclease site on the apolipoprotein B gene also was associated with increased prevalence of aortic stenosis.38 Finally, another 82‐subject case‐control study found an apparent interaction between an estrogen receptor α PvuII polymorphism and the risk for aortic stenosis in postmenopausal women, with an apparent interaction of this polymorphism with an AcoI polymorphism in the transforming growth factor β1 gene.39

However, the limitations of these small, single‐center studies are highlighted by the divergent findings of three separate studies examining associations of apolipoprotein E (apo E) alleles with aortic stenosis. The previously mentioned study examining apolipoprotein B alleles also reported that the apo E e2 was associated with increased aortic stenosis prevalence.38 In contrast, another 804 participants found that the apo E e4 allele was associated with aortic stenosis.40 Finally, a 1,074‐subject case‐control study found no association of either the e2 or e4 alleles with aortic stenosis.41 Thus, we can have little confidence that this type of genetic study, particularly studies with small numbers of participants, will identify true relationships of genetic polymorphisms with increased risk for calcific aortic valve disease. A summary of these small studies is shown in Table 4.

Table 4
Table 4
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Single‐Gene Defects and Aortic Valve Disease
Bicuspid Aortic Valve: High Prevalence in Surgically Resected, Stenotic Aortic Valves

Recently, two pathologic studies raised the possibility that single‐gene defects might be stronger contributors to progression to aortic stenosis than many had recognized previously.

The first of these was a small series from Scotland in which the primary goal of the study was to investigate the relative prevalence of hypercholesterolemia in aortic versus mitral stenosis of sufficient severity to require surgical valve replacement.42 However, an intriguing, ancillary finding of this study was that, when examined pathologically, 18 of 43 (42%) aortic valves resected from consecutive aortic valve replacement cases were anatomically bicuspid. This was a surprising finding since this high prevalence of bicuspid valves had not been appreciated from preoperative echocardiograms. The best estimate of the population prevalence of bicuspid aortic valves is approximately 1.4%.43,44 Therefore, the 42% prevalence in aortic valve replacement cases represents a substantial overrepresentation of bicuspid valves relative to their prevalence in the general population.

A much larger, single‐center, consecutive series evaluated 932 aortic valves resected for isolated aortic stenosis (with or without aortic insufficiency) between January 1993 and June 2004.45 Tricuspid aortic valves represented a slight minority (46%) of total valves in this series, whereas 49% of the valves were bicuspid and another 5% were unicuspid.45

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Single‐Gene Defects and Bicuspid Aortic Valve Disease

Along with studies suggesting an autosomal dominant pattern of inheritance for bicuspid aortic valves,46,47 the studies of Chui and colleagues and Roberts and Ko have contributed to a reexamination of whether specific single‐gene defects might be causal for bicuspid aortic valves.42,45 At least two studies have identified specific, molecular defects associated with increased risk for bicuspid aortic valves.48,49

The first of these studies identified a number of mutations in the type II TGF‐β receptor gene (TGFBR2) that were associated with a number of cardiovascular, craniofacial, neural, and/or skeletal abnormalities48; two of these mutations were associated with a bicuspid aortic valve. These researchers also went on to show that some of these receptor abnormalities were associated with increased aortic expression of connective tissue growth factor, which can upregulate collagen synthesis48 and which would, therefore, be expected to be associated with increased aortic stiffness (or decreased aortic elasticity). Indeed, a number of studies have demonstrated that bicuspid aortic valves are associated with decreased aortic elasticity.50,51 Thus, mutations in the TGFBR2 gene can be associated with two abnormal phenotypes that have been recognized to occur concurrently, bicuspid aortic valve and decreased aortic elasticity.

The second study identified two families in which genetic mutations in the transcriptional regulator NOTCH1 were associated with autosomal dominant transmission of a number of cardiovascular abnormalities, including aortic valve calcification with or without bicuspid aortic valve.49 NOTCH1 signaling activates hairy‐related transcriptional repressors, which downregulate expression of Runx2/Cbfa1, a key mediator of osteoblastic differentiation.52 Therefore, defects in the NOTCH1 gene would be expected to increase osteoblastic differentiation by the Runx2/Cbfa1 pathway, thereby increasing vascular and/or valvular calcification. Indeed, activation of Runx2/Cbfa1 has been documented in rabbit models of calcific aortic valve disease.53‐55 In addition, Garg and colleagues demonstrated that NOTCH1 messenger ribonucleic acid is highly expressed during aortic valve development in mice.49 This observation suggests an important role for the NOTCH1 protein in normal valve development and is consistent with the association of defects in the NOTCH1 gene with abnormal aortic valve morphology. Together these findings demonstrate that mutations in the NOTCH1 gene can be associated with two concurrent abnormal phenotypes, increased valvular calcification and bicuspid aortic valve. Table 5 summarizes some key points of the Loeys and colleagues and Garg and colleagues studies.48,49

Table 5
Table 5
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Genetics versus Genomics in Calcific Aortic Valve Disease

It is important to note that mutations in TGFBR2 and NOTCH1 likely are present in a very small minority of patients with bicuspid valves. In particular, mutations in TGFBR2 are associated with other profound phenotypic features. In addition, not all individuals with TGFBR2 and NOTCH1 mutations exhibited the bicuspid aortic valve phenotype,48,49 calling into question the utility of echocardiography as a tool for screening families for these genetic defects. Nonetheless, these mutations represent a “proof of principle” that factors unique from traditional “atherosclerotic” risk factors may predispose patients to the development of calcific aortic valve disease.

The relative importance of single‐gene defects (ie, “genetics”) versus genetic polymorphisms (ie, “genomics”) is emphasized in Figure 2. Severe single‐gene defects, as typified by mutations in the TGFBR2 and NOTCH1 genes, may result in profound phenotypes (ie, large effects) but are typically rare. In contrast, genetic polymorphisms typically have a relatively small, individual effect on phenotype; however, they may be more common and so, on a population basis, have a greater effect on expression of the abnormal phenotype. Therefore, future studies of genetic influences on the calcific aortic valve disease phenotype must be focused on identifying and confirming associations of specific genetic polymorphisms with the disease in large cohorts.

Figure 2
Figure 2
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Summary

Calcific aortic valve disease is a common condition in the elderly and is associated with significant morbidity and mortality. Biologically plausible roles in pathogenesis have been proposed for both lipoproteins and the renin‐angiotensin system. Unfortunately, to date, no properly controlled, randomized trials have demonstrated that a pharmacologic therapy slows development of the disease. However, validation of associations of “novel” risk factors, such as metabolic syndrome and specific inflammatory biomarkers, with increased disease risk may lead to the development of novel therapies for this disease. In addition, use of nonechocardiographic techniques, such as cardiac CT, may allow identification of the disease at an earlier stage, when pharmacologic interventions might be more effective.

Moreover, the role of genetics in this disease is receiving greater appreciation. Recently identified genetic defects that are associated with a severe valve disease phenotype both emphasize that unique “nonatherosclerotic” factors can influence disease development and may lead to the development of additional novel therapies. Finally, the results of small studies attempting to identify genetic polymorphisms associated with calcific aortic valve disease have been inconclusive and even contradictory. However, identification and validation of associations of genetic polymorphisms with the disease in large, phenotypically well‐defined cohorts likely represent the best opportunity for revealing potential therapeutic targets applicable to a broader range of individuals with calcific aortic valve disease.

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Acknowledgments

I thank David M. Shavelle, MD, and Emile R. Mohler III, MD, for their helpful comments about the manuscript and Orion Gudgell for expert assistance in manuscript preparation.

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Key words:: aortic valve disease; risk factors; computed tomography; echocardiography; genetics; genomics

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