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Original Investigation |

Interaction of Age With Lipoproteins as Predictors of Aortic Valve Calcification in the Multi-Ethnic Study of Atherosclerosis FREE

David S. Owens, MD; Ronit Katz, DPhil; Eric Johnson, BA; David M. Shavelle, MD; Jeffrey L. Probstfield, MD; Junichiro Takasu, MD, PhD; John R. Crouse, MD; J. Jeffrey Carr, MD, MSCE; Richard Kronmal, PhD; Matthew J. Budoff, MD; Kevin D. O’Brien, MD
[+] Author Affiliations

Author Affiliations: Division of Cardiology, Department of Internal Medicine (Drs Owens, Probstfield, and O’Brien), and Department of Biostatistics (Drs Katz and Kronmal and Mr Johnson), University of Washington, Seattle; Division of Cardiology, Department of Medicine, Los Angeles Biomedical Research Institute at Harbor–University of California at Los Angeles Medical Center (Drs Shavelle, Takasu, and Budoff); and Division of Endocrinology and Metabolism, Department of Medicine (Dr Crouse), Department of Public Health Sciences (Dr Crouse), and Department of Radiology (Dr Carr), Wake Forest University School of Medicine, Winston-Salem, North Carolina.


Arch Intern Med. 2008;168(11):1200-1207. doi:10.1001/archinte.168.11.1200.
Text Size: A A A
Published online

Background  Previous epidemiologic studies have shown that low-density lipoprotein is an independent risk factor for prevalent aortic valve calcification (AVC); however, to our knowledge, the interactions between plasma lipoprotein concentrations and age on the relative risks (RRs) for AVC prevalence and severity have not been examined in a large, racially and ethnically diverse cohort.

Methods  Using stepwise RR regression, the relationships of baseline fasting lipid levels and lipoprotein levels to baseline prevalence and severity of AVC were determined in 5801 non–statin-using participants in the Multi-Ethnic Study of Atherosclerosis (MESA).

Results  In age-stratified, adjusted analyses, the low-density lipoprotein–associated RRs (95% confidence intervals) for prevalent AVC were higher for younger compared with older participants (age 45-54 years, 1.69 [1.19-2.39]; age 55-64 years, 1.48 [1.24-1.76]; age 65-74 years, 1.09 [0.95-1.25]; and age 75-84 years, 1.16 [0.99-1.36]; P interaction = .04]. There was a similar, significant interaction of age with total cholesterol–associated RR for prevalent AVC (P interaction = .04). In contrast, total- to high-density lipoprotein cholesterol ratio RRs were similar across all age strata (P interaction = .68). At multivariate analyses, no lipoprotein parameter was associated with AVC severity.

Conclusions  In this racially and ethnically diverse, preclinical cohort, low-density lipoprotein was a risk factor for AVC only in participants younger than 65 years, whereas the total cholesterol/high-density lipoprotein cholesterol ratio was associated with a modest increased risk of AVC across all ages. These findings may have important implications for the efficacy of and targets for dyslipidemia therapies in calcific aortic valve disease.

Trial Registration  clinicaltrials.gov Identifier: NCT00005487

Figures in this Article

Calcific degeneration of the aortic valve, in the form of either aortic sclerosis or stenosis, is a common feature of aging and is associated with substantial morbidity and mortality.1,2 The presence of aortic sclerosis (ie, valvular calcification without hemodynamic obstruction) is associated with a 50% increase in the risk of cardiovascular events,2 and the severity of calcification predicts worsened clinical outcome.3 However, while pathologic calcification is the defining feature of advanced degeneration, early-stage valvular lesions share many histologic similarities with vascular atherosclerosis, including lipid accumulation,4,5 inflammatory infiltrates,68 and the presence of renin-angiotensin system components.9 Epidemiologic studies also have suggested associations between aortic valve disease and traditional cardiovascular risk factors, including male sex, smoking, hypertension, hyperlipidemia,10,11 and diabetes mellitus.10,12,13 Recently, metabolic syndrome also has been associated with increased prevalence13 and rate of progression14 of calcific aortic valve disease.

These findings, bolstered by retrospective analyses that infer a beneficial effect of statin use,1519 have led to the hypothesis that statin therapy may reduce the morbidity and mortality associated with advanced aortic valve degeneration, akin to the benefits noted for coronary and peripheral vascular disease. However, the only randomized, placebo-controlled test of this hypothesis to date, the 155-participant SALTIRE (Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression) study, demonstrated no benefit of statin therapy in curbing the progressive natural history of the disease.20 It is unclear whether these null results were because of patient selection, small sample size, suboptimal timing or duration of therapy, or repudiation of the hypothesis.

One possibility is that statin therapy may be of little benefit in aortic valve disease if low-density lipoprotein cholesterol (LDL-C) is a weak risk factor in elderly patients such as those studied in SALTIRE.20 The relationship between LDL-C and aortic valve calcification (AVC) was relatively weak in the Cardiovascular Health Study,11 in which all participants were aged 65 years or older. Moreover, previous studies of coronary artery disease have consistently demonstrated an attenuation in LDL-C–associated risk with advancing age.2123

We reexamined the strengths of the relationship between total cholesterol (TC) level, lipoprotein levels, and AVC, with particular attention to the influence of age on AVC relative risk (RR). To test this association, we examined cross-sectional data from the Multi-Ethnic Study of Atherosclerosis (MESA), including baseline fasting lipoprotein levels and AVC scores, as determined using cardiac computed tomography (CT).

STUDY POPULATION

The MESA trial was initiated by the National Heart, Lung, and Blood Institute to characterize subclinical cardiovascular disease and its progression. A full description of the design and recruitment process has been reported previously.24 A total of 6814 free-living individuals without clinically apparent cardiovascular disease, aged 45 to 84 years, were recruited from 6 US communities, including Baltimore, Maryland (city and county); Chicago, Illinois; Forsyth County, North Carolina; Los Angeles County, California; New York, New York; and St Paul, Minnesota, between July 2000 and August 2002. Recruitment targeted 4 racial/ethnic groups: white, black, Hispanic, and Chinese. Participants were excluded if they had self-reported cardiovascular disease, including angina, or had undergone cardiovascular procedures such as percutaneous coronary interventions, coronary bypass or valvular surgery, or pacemaker or defibrillator implantation. The institutional review boards at each participating institution approved MESA, and each participant provided informed written consent before enrollment in the study.

Of the 6814 participants in MESA, 26 did not have cholesterol profiles and were, therefore, excluded from the study. To limit potential effect modification, the 987 subjects taking statins were also excluded. Thus, there were 5801 participants for these analyses. Baseline testing for and definitions of cardiovascular risk factors, including diabetes, hypertension, and impaired fasting glucose concentration, have been described previously.13

MEASUREMENTS
Lipoproteins

After a 12-hour fast, all participants had plasma samples drawn, prepared, and stored. Concentrations of TC, high-density lipoprotein cholesterol (HDL-C), and triglycerides were measured in a central lipid laboratory at Fairview–University Medical Center, Minneapolis, Minnesota, using the cholesterol oxidase method and a centrifugal analyzer (COBAS FARA; Roche Diagnostics, Indianapolis, Indiana). Full details of lipid quantification have been reported previously.25 Low-density lipoprotein cholesterol concentrations were estimated using the Friedewald equation.26 Non–HDL-C and TC/HDL-C ratios were calculated from these primary data.

Aortic Valve Calcification

All participants underwent cardiac CT as part of MESA. Three institutions performed electron beam tomography (Imatron C150 scanner; GE Medical Systems, Milwaukee, Wisconsin), and 3 institutions used multidetector CT scanners (4-slice). Spatial resolution was 1.38 mm3 for electron-beam tomography (0.68 × 0.68 × 3.00 mm) and 1.15 mm3 for the multidetector CT (0.68 × 0.68 × 2.50 mm). Full details about the equipment, scanning methods, and quality control in MESA, including image calibration and interscanner reproducibility between the 2 scanning methods, have been reported previously.27,28

All studies were sent to a central MESA CT scan reading center (Harbor-UCLA Research and Education Institute, Los Angeles, California), where they were retrospectively analyzed for AVC by a single blinded reader (J.T.) using the same method for all studies. Calcium strongly attenuates radiographs, appears bright on CT scans, and is easily differentiated from surrounding tissue. Aortic valve calcification was defined as any calcified lesion within the aortic valve leaflets, consistent with the definition of AVC used in other studies by our group.2931 Lesions involving the aortic annulus, sinuses, wall of the ascending aorta, or coronary arteries were not classified as AVC.2931 For each individual lesion, AVC was quantified using the method of Agatston et al,32 which factors in both lesion area and Hounsfield unit brightness, a reflection of calcium density. Single-lesion measurements were then summed to give an overall Agatston score. If aortic valve calcium was absent, the Agatston score was recorded as zero.

Demographic Information

Participant demographic data and medical history including medication use were obtained by questionnaire. While participants reporting cardiovascular disease were excluded from the study, screening for subclinical aortic stenosis was not specifically performed. Race/ethnicity was self-reported and those who identified themselves as white, black, Hispanic, or Chinese were eligible for inclusion.

Data Analyses

Participants were categorized by the presence or absence of AVC, and differences between the baseline characteristics of these groups were determined using t tests for continuous variables and χ2 analysis for categorical variables. Severity of AVC was determined using the log transformation of Agatston scores.

Because the prevalence of calcification was more than 10% in the cohort, odds ratios overestimate RR. Therefore, RR estimates are presented from the regression model y = exp(X). The exponentiated parameters are interpreted as RRs. We assumed gaussian error and used robust standard error estimates. Because AVC scores required log transformation based on the nature of the underlying data structure, the percent change in AVC score was calculated per unit increase in normalized risk factors. Risk factors were normalized by dividing their values by their standard deviations.

Statistical analyses were performed with commercially available software (SPSS for Windows, version 13.0.1; SPSS Inc, Chicago, Illinois; or STATA for Windows, version 8.0; StataCorp, College Station, Texas). Statistical significance was defined as P < .05, and RRs are reported with 95% confidence intervals.

PARTICIPANT CHARACTERISTICS

The MESA cohort included in these analyses comprised 5801 subjects with a mean age of 62 years (age range, 45-84 years). Of this cohort, 3061 participants (53%) were women, while 2186 participants (38%) were white, 1603 (28%) were black, 1312 (23%) were Hispanic, and 700 (12%) were Chinese. Seven hundred thirty participants (13%) had diabetes, with impaired fasting glucose levels in 1570 (27%), hypertension in 2416 (42%), current smoking for 789 (14%), and former smoking for 2073 (36%). At baseline, of these participants not receiving statin therapy, few (586 [10%]) were taking angiotensin-converting enzyme inhibitors or β-blockers (455 [8%]). The mean (SD) lipoprotein levels were as follows: TC, 196 (36) mg/dL; LDL-C, 120 (31) mg/dL; HDL-C, 51 (15) mg/dL; triglycerides, 130 (89) mg/dL; non–HDL-C, 145 (36) mg/dL; and TC/HDL-C ratio, 4.1 (1.3). (To convert all cholesterol values to millimoles per liter, multiply by 0.0259; to convert triglycerides to millimoles per liter, multiply by 0.0113.) Aortic valve calcification, that is, an Agatston score higher than zero, was present in 700 participants (12%). This group had a median Agatston score of 57 (interquartile range, 18-148).

The baseline characteristics of the study population, stratified by the presence (Agatston score >0) or absence (Agatston score 0) of AVC, are given in Table 1. Participants with AVC were older, were more likely to be white men, had higher prevalences of diabetes and hypertension, and were more likely to be taking cardiovascular medications than were those without AVC. While differences in TC levels were not statistically significant, there were significant between-group differences in all lipoprotein subclasses, including LDL-C, HDL-C, triglycerides, and non–HDL-C levels, and the TC/HDL-C ratio.

Table Graphic Jump LocationTable 1. Baseline Characteristics Stratified by Aortic Valve Calcification AGS
PREVALENCE OF AVC AND LIPOPROTEINS
Univariate Analyses

The associations between lipoprotein quartiles and the presence of AVC are given in Table 2, and the corresponding quartile cutoff values are given in Table 3. Univariate predictors of the presence of AVC include LDL-C, HDL-C, and triglyceride levels, and the TC/HDL-C ratio. The TC level was not a univariate predictor of the presence of AVC.

Table Graphic Jump LocationTable 2. Prevalence of Aortic Valve Calcification (AGS>0) Stratified by Lipoprotein Quartiles
Multivariate Analyses

Because age interacted with LDL-C–associated RR for prevalent AVC (P interaction = .04), all lipoprotein analyses were age-stratified in stepwise multivariate regressions (Figure), with adjustments for sex, race/ethnicity, site of enrollment, body mass index, smoking status, diabetes, hypertension, and medication use. There were no significant interactions between age and any of the other lipoprotein-associated RRs examined. No significant interactions were found for sex (P interaction = .39) or race/ethnicity (P interaction = .45).

Place holder to copy figure label and caption
Figure.

Lipoprotein-associated relative risk (RR) of prevalent aortic valve calcification (AVC). Shown are point estimates (squares) and 95% confidence intervals (CIs) for adjusted RR per 1-SD increase in lipoprotein levels (A-D) and total cholesterol to high-density lipoprotein cholesterol ratio (TC/HDL-C) (E), stratified by decade of age. LDL-C indicates low-density lipoprotein cholesterol.

Graphic Jump Location
Total Cholesterol

The fully adjusted TC-associated RR for prevalent AVC was higher in younger participants compared with older participants (P interaction = .04; Figure, A).

Low-Density Lipoprotein

The fully adjusted LDL-C–associated RR for prevalent AVC was also higher in younger compared with older participants (P interaction = .04; Figure, B).

High-Density Lipoprotein

In contrast, HDL-C was not associated with RR for prevalent AVC in participants younger than 65 years (Figure, C). Rather, HDL-C was associated with decreased RR for AVC in participants aged 65 to 74 years and 75 to 84 years, though the RR did not reach significance in the latter group.

Triglycerides

In addition, triglyceride levels were not associated with RR for prevalent AVC in participants younger than 65 years (Figure, D). However, triglyceride levels were associated with increased RR for AVC in participants aged 65 to 74 years and 75 to 84 years, although, again, the RR did not reach significance in the latter group.

Total Cholesterol to HDL-C Ratio

Overall, the most consistent relationship of a lipoprotein variable with AVC risk was the TC/HDL-C ratio (Figure, E). The TC/HDL-C ratio RRs were similar across all age strata (P interaction = .68), though the RR did not reach significance in the youngest group.

AVC SEVERITY AND LIPOPROTEIN LEVELS
Univariate Analyses

To examine the relationship between individual lipoprotein factors and AVC severity, the log(Agatston score) for each of the lipoprotein quartiles was examined (Table 4). Only TC showed a linear trend in AVC severity with increasing lipoprotein levels.

Table Graphic Jump LocationTable 4. Disease Severity (Log[AGS]) Stratified by Lipoprotein Quartiles in 700 Participants With AVC (AGS>0)
Multivariate Analyses

To exclude the possibility of masked interactions, the relative change in log(Agatston score) per unit increase in normalized risk factors was examined (Table 5). Despite the apparent association of TC with AVC severity at univariate analysis, no significant associations with AVC severity were identified at multivariate analysis.

Table Graphic Jump LocationTable 5. Relative Change in Disease Severitya in Persons With Aortic Valve Calcification (AGS > 0)

To our knowledge, this study is the largest to date to examine potential associations of plasma lipoproteins with the prevalence and severity of calcific aortic valve disease. The MESA cohort is notable for its diversity in age and race/ethnicity and for the absence of clinical cardiovascular disease at baseline. Our findings show that, even within this relatively young, healthy, and racially and ethnically diverse population, AVC is common, with a prevalence of 12% among subjects not taking statins. Our findings are consistent with those of previous studies that demonstrated associations of AVC with advanced age, male sex, and hypertension.10,11 Furthermore, they extend the results of studies that demonstrated a relationship between lipoprotein levels and aortic valve disease10,11 by emphasizing that, similar to coronary artery disease,21,23,33 the overall association of LDL-C with AVC prevalence is particularly weak in persons older than 65 years. They suggest that the TC/HDL-C ratio, a composite measure of dyslipidemia, may be a better marker of lipid-attributable risk for prevalent AVC across the full age range of MESA participants.

INTERACTION OF AGE AND LIPOPROTEIN-ASSOCIATED RELATIVE RISK

Two of the most striking findings of this study are the interactions of age with both TC-associated and LDL-C–associated risk for prevalent AVC. For every 31-mg/dL (ie, 1-SD) increase in the level of LDL-C, the youngest cohort (age 45-54 years) had a 69% (95% CI, 19-139) increase in adjusted RR for prevalent AVC. In contrast, the LDL-C–associated risk was a nonsignificant 12% increase for those 65 years or older. This magnitude of LDL-C–associated risk for AVC is similar to that seen for aortic valve disease in the Cardiovascular Health Study, in which all participants were 65 years or older.11 In that study, the odds ratio (25th vs 75th percentile) for LDL-C was 1.12 (95% CI, 1.03-1.23).11 A similar age attenuation in the lipoprotein-associated risk for coronary artery disease was seen in the Whitehall Study,21 Cardiovascular Health Study,22 and Honolulu Heart Study23 cohorts.

In participants 65 years or older, the level of HDL-C was associated with a modest decrease in RR for prevalent AVC, and the levels of triglyceride were associated with a modest increase in RR for prevalent AVC. Why increased age is associated with a shift in the associations of particular lipoprotein classes with AVC risk is unclear, but one possible explanation may be the age-related increase in prevalence of central obesity and metabolic syndrome.34 Development of metabolic syndrome is characterized, in part, by an increase in levels of triglyceride-rich very-low-density lipoprotein and a decrease in levels of HDL-C.35,36 We recently reported an association between metabolic syndrome and AVC prevalence in the MESA cohort.13

While there are many age-related differences in lipoprotein-associated RRs for prevalent AVC, the RR for AVC associated with the TC/HDL-C ratio remains largely age-independent. The TC/HDL-C ratio serves as an estimate of the degree of atherogenic dyslipidemia and has been found to be superior to either TC or LDL-C in predicting cardiovascular risk in both the Framingham Offspring Study37 and the Lipid Research Clinics Coronary Primary Prevention Trial.38 Some studies have suggested that the apolipoprotein B/apolipoprotein A-I ratio may be a superior predictor of lipoprotein-associated cardiovascular risk than the TC/HDL-C ratio,39,40 but an updated evaluation from the Framingham cohort recently has reported that the apolipoprotein B/apolipoprotein A-I and TC/HDL-C ratios have nearly identical predictive values for coronary heart disease.41

SEVERITY OF AVC AND LIPOPROTEIN LEVELS

While our results identified significant associations between specific lipoprotein classes and prevalent AVC in specific age groups, we found no association between any lipoprotein class and AVC severity in fully adjusted analyses. Thus, while dyslipidemia may contribute to the presence of AVC, the primary determinants of calcification progression may be independent of the lipoprotein classes we examined. Further conclusions are limited by the cross-sectional nature of these analyses.

BIOLOGY OF VALVULAR CALCIFICATION

The past decade has brought a growing understanding of the pathologic mechanisms underlying aortic valve sclerosis and subsequent calcification. It is now seen as an active process characterized by cellular infiltration68; deposition of atherogenic lipoproteins, primarily LDL-C and lipoprotein A4,5; extracellular proteoglycan accumulation42; and renin-angiotensin system components.9 Calcific nodules form in areas of previous lipoprotein deposition,4 particularly in those with oxidized lipids,5 and elegant studies in hypercholesterolemic rabbit models have implicated specific signaling pathways in this process.4345 In addition, studies have shown that statins inhibit the calcification process both in valve fibroblasts in vitro46 and in hypercholesterolemic rabbits in vivo.4345 These studies suggest a plausible role for lipoproteins in the pathogenesis of aortic valve calcification. However, despite these findings, clinical trials of statin therapy in aortic stenosis have shown mixed results,20,47 perhaps a testimony to our incomplete understanding of the disease process.

ASSESSMENT OF AVC

While MESA centers used either electron beam tomography or multidetector CT to assess the severity of AVC, the equivalency of these techniques within the MESA population has been established.48 These methods have been shown in both echocardiographic29,31 and ex vivo pathologic49,50 validation studies to provide reliable quantification of calcification severity and have demonstrated good correlation with the presence of echocardiographically determined aortic stenosis.30,51,52 However, results for the correlation between CT-determined AVC severity and the hemodynamic severity of aortic stenosis are mixed,30,52,53 likely because the location of calcification and its effects on restricting leaflet mobility influence valvular hemodynamics above and beyond severity of calcification. Despite this limitation, data suggest that CT-determined AVC scores are useful in their extremes, with threshold values (eg, Agatston scores >1100) above which clinically significant aortic stenosis is likely.30,52 Moreover, worsening calcification, measured by either echocardiography or CT, has been associated with worsened clinical outcomes in patients with asymptomatic aortic stenosis.3,54

STUDY LIMITATIONS

This study has several limitations. First, this is a cross-sectional study of the MESA cohort that was not prespecified during trial design, thus limiting conclusions about causality and potentially affecting analytic power. Second, the exclusion from MESA of individuals with baseline cardiovascular disease may both subject the study to survival bias and diminish strengths of association when compared with studies that included individuals with established cardiovascular disease. Thus, our data need to be corroborated in other populations. Third, other lipoprotein variables that have been associated with atherosclerotic risk such as lipoprotein(a), LDL particle size, apolipoprotein B or apolipoprotein A-I levels, and oxidation status were not measured in MESA. Third, MESA participants who were receiving statin therapy were excluded from these analyses. However, reanalysis of the data including MESA participants receiving statin therapy did not substantially alter our findings, and we were unable to detect an effect modification by statin therapy.

This cross-sectional analysis demonstrates an age-dependent decrement in the LDL-C–associated RR for AVC among otherwise healthy subjects without known cardiovascular disease. In contrast, there was a statistically significant, though modest, association between a composite measure of dyslipidemia, the TC/HDL-C ratio, and the presence but not severity of AVC. These findings may have important implications about pharmacologic lipid-lowering therapy in calcific aortic valve disease. To date, trials examining the benefits of statin therapy have shown mixed results.20,47 Our results suggest that alternative treatment strategies may include targeting dyslipidemia therapies to earlier-stage disease (eg, aortic sclerosis), especially in younger individuals, or testing dyslipidemia therapies that substantially raise HDL-C levels and lower triglyceride levels, thereby improving the TC/HDL-C ratio.

Correspondence: Kevin D. O’Brien, MD, Division of Cardiology, Box 356422, University of Washington, 1959 NE Pacific St, Seattle, WA 98195-6422 (cardiac@u.washington.edu).

Accepted for Publication: October 11, 2007.

Author Contributions: Dr Owens had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Carr, Kronmal, Budoff, and O’Brien. Acquisition of data: Katz, Takasu, Carr, Kronmal, and Budoff. Analysis and interpretation of data: Owens, Katz, Johnson, Shavelle, Probstfield, Crouse, Carr, Kronmal, and O’Brien. Drafting of the manuscript: Owens, Johnson, Budoff, and O’Brien. Critical revision of the manuscript for important intellectual content: Owens, Katz, Shavelle, Probstfield, Takasu, Crouse, Carr, Kronmal, Budoff, and O’Brien. Statistical analysis: Owens, Katz, Johnson, Kronmal, and Budoff. Obtained funding: Budoff and O’Brien. Administrative, technical, and material support: Shavelle, Takasu, Crouse, Carr, Kronmal, and O’Brien. Study supervision:Kronmal and O’Brien.

MESA Group Members: A full list of investigators and participating institutions for MESA is available at http://www.mesa-nhlbi.org.

Financial Disclosure: Dr Budoff has received honoraria from and is on the speakers' bureau of General Electric. Dr O’Brien has received honoraria from and is on the speakers' bureaus of AstraZeneca and Merck.

Funding/Support: This study was supported by grant R01-HL-63963-01A1 and by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute (NHLBI).

Role of the Sponsor: The NHLBI participated in the design and conduct of MESA, and the NHLBI Project Office reviewed and approved the manuscript before submission.

Previous Presentations: This study was presented in part as an abstract at the American Federation for Medical Research Eastern Section meeting; April 9, 2008; Washington, DC; and at the American Society for Clinical Investigation/Association of American Physicians (ASCI/AAP) Joint Meeting; April 26, 2008; Chicago, Illinois.

Additional Information: Dr Owens received the Henry Christian Award for the abstract at the joint meeting of the ASCI/AAP.

Additional Contributions: Karen Fowler, BS, assisted in manuscript preparation, and the investigators, staff, and participants of MESA provided valuable contributions.

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Holvoet  PJenny  NSSchreiner  PJTracy  RPJacobs  DR The relationship between oxidized LDL and other cardiovascular risk factors and subclinical CVD in different ethnic groups: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2007;194 (1) 245- 252
PubMed Link to Article
Friedewald  WTLevy  RIFredrickson  DS Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18 (6) 499- 502
PubMed
Carr  JJNelson  JCWong  ND  et al.  Calcified coronary artery plaque measurement with cardiac CT in population-based studies: standardized protocol of Multi-Ethnic Study of Atherosclerosis (MESA) and Coronary Artery Risk Development in Young Adults (CARDIA) study. Radiology 2005;234 (1) 35- 43
PubMed Link to Article
Detrano  RCAnderson  MNelson  J  et al.  Coronary calcium measurements: effect of CT scanner type and calcium measure on rescan reproducibility: MESA study. Radiology 2005;236 (2) 477- 484
PubMed Link to Article
Budoff  MJMao  STakasu  JShavelle  DMZhao  XQO'Brien  KD Reproducibility of electron-beam CT measures of aortic valve calcification. Acad Radiol 2002;9 (10) 1122- 1127
PubMed Link to Article
Shavelle  DMBudoff  MJBuljubasic  N  et al.  Usefulness of aortic valve calcium scores by electron beam computed tomography as a marker for aortic stenosis. Am J Cardiol 2003;92 (3) 349- 353
PubMed Link to Article
Budoff  MJTakasu  JKatz  R  et al.  Reproducibility of CT measurements of aortic valve calcification, mitral annulus calcification, and aortic wall calcification in the Multi-Ethnic Study of Atherosclerosis. Acad Radiol 2006;13 (2) 166- 172
PubMed Link to Article
Agatston  ASJanowitz  WRHildner  FJZusmer  NRViamonte  M  JrDetrano  R Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15 (4) 827- 832
PubMed Link to Article
Weverling-Rijnsburger  AWBlauw  GJLagaay  AMKnook  DLMeinders  AEWestendorp  RG Total cholesterol and risk of mortality in the oldest old [published correction appears in Lancet. 1998;351(9095):70]. Lancet 1997;350 (9085) 1119- 1123
PubMed Link to Article
Ford  ESGiles  WHDietz  WH Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287 (3) 356- 359
PubMed Link to Article
Grundy  SMCleeman  JIDaniels  SR  et al.  Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement [published corrections appear in Circulation. 2005;112(17):e297 and e298]. Circulation 2005;112 (17) 2735- 2752
PubMed Link to Article
Eckel  RHGrundy  SMZimmet  PZ The metabolic syndrome. Lancet 2005;365 (9468) 1415- 1428
PubMed Link to Article
Wilson  PWGarrison  RJCastelli  WPFeinleib  MMcNamara  PMKannel  WB Prevalence of coronary heart disease in the Framingham Offspring Study: role of lipoprotein cholesterols. Am J Cardiol 1980;46 (4) 649- 654
PubMed Link to Article
Kinosian  BGlick  HGarland  G Cholesterol and coronary heart disease: predicting risks by levels and ratios. Ann Intern Med 1994;121 (9) 641- 647
PubMed Link to Article
Walldius  GJungner  IAastveit  AHHolme  IFurberg  CDSniderman  AD The apoB/apoA-I ratio is better than the cholesterol ratios to estimate the balance between plasma proatherogenic and antiatherogenic lipoproteins and to predict coronary risk. Clin Chem Lab Med 2004;42 (12) 1355- 1363
PubMed Link to Article
Sniderman  ADJungner  IHolme  IAastveit  AWalldius  G Errors that result from using the TC/HDL C ratio rather than the apoB/apoA-I ratio to identify the lipoprotein-related risk of vascular disease [published correction appears in J Intern Med. 2006;260(2):186]. J Intern Med 2006;259 (5) 455- 461
PubMed Link to Article
Ingelsson  ESchaefer  EJContois  JH  et al.  Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 2007;298 (7) 776- 785
PubMed Link to Article
O’Brien  KDOtto  CMReichenbach  DDAlpers  CEWight  TN Regional accumulation of proteoglycans in lesions of “degenerative” valvular aortic stenosis and their relationship to apolipoproteins [abstract]. Circulation 1995;92 ((suppl 1)) I-612
Rajamannan  NMSubramaniam  MSpringett  M  et al.  Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation 2002;105 (22) 2660- 2665
PubMed Link to Article
Rajamannan  NMSubramaniam  MStock  SR  et al.  Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve. Heart 2005;91 (6) 806- 810
PubMed Link to Article
Rajamannan  NMSubramaniam  MCaira  FStock  SRSpelsberg  TC Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway. Circulation 2005;112 (9) ((suppl)) I229- I234
PubMed
Wu  BElmariah  SKaplan  FSCheng  GMohler  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 (3) 592- 597
PubMed Link to Article
Moura  LMRamos  SFZamorano  JL  et al.  Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis. J Am Coll Cardiol 2007;49 (5) 554- 561
PubMed Link to Article
Budoff  MJKatz  RWong  ND  et al.  Effect of scanner type on the reproducibility of extracoronary measures of calcification: the Multi-Ethnic Study of Atherosclerosis. Acad Radiol 2007;14 (9) 1043- 1049
PubMed Link to Article
Pohle  KDimmler  AFeyerer  R  et al.  Quantification of aortic valve calcification with electron beam tomography: a histomorphometric validation study. Invest Radiol 2004;39 (4) 230- 234
PubMed Link to Article
Koos  RMahnken  AHKühl  HP  et al.  Quantification of aortic valve calcification using multislice spiral computed tomography: comparison with atomic absorption spectroscopy. Invest Radiol 2006;41 (5) 485- 489
PubMed Link to Article
Cowell  SJNewby  DEBurton  J  et al.  Aortic valve calcification on computed tomography predicts the severity of aortic stenosis. Clin Radiol 2003;58 (9) 712- 716
PubMed Link to Article
Messika-Zeitoun  DAubry  MCDetaint  D  et al.  Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography. Circulation 2004;110 (3) 356- 362
PubMed Link to Article
Mohler  ER  IIIMedenilla  EWang  HScott  C Aortic valve calcium content does not predict aortic valve area. J Heart Valve Dis 2006;15 (3) 322- 328
PubMed
Feuchtner  GMMüller  SGrander  W  et al.  Aortic valve calcification as quantified with multislice computed tomography predicts short-term clinical outcome in patients with asymptomatic aortic stenosis. J Heart Valve Dis 2006;15 (4) 494- 498
PubMed

Figures

Place holder to copy figure label and caption
Figure.

Lipoprotein-associated relative risk (RR) of prevalent aortic valve calcification (AVC). Shown are point estimates (squares) and 95% confidence intervals (CIs) for adjusted RR per 1-SD increase in lipoprotein levels (A-D) and total cholesterol to high-density lipoprotein cholesterol ratio (TC/HDL-C) (E), stratified by decade of age. LDL-C indicates low-density lipoprotein cholesterol.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics Stratified by Aortic Valve Calcification AGS
Table Graphic Jump LocationTable 2. Prevalence of Aortic Valve Calcification (AGS>0) Stratified by Lipoprotein Quartiles
Table Graphic Jump LocationTable 4. Disease Severity (Log[AGS]) Stratified by Lipoprotein Quartiles in 700 Participants With AVC (AGS>0)
Table Graphic Jump LocationTable 5. Relative Change in Disease Severitya in Persons With Aortic Valve Calcification (AGS > 0)

References

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PubMed Link to Article
Bellamy  MFPellikka  PAKlarich  KWTajik  AJEnriquez-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 (10) 1723- 1730
PubMed Link to Article
Rosenhek  RRader  FLoho  N  et al.  Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation 2004;110 (10) 1291- 1295
PubMed Link to Article
Cowell  SJNewby  DEPrescott  RJ  et al.  A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352 (23) 2389- 2397
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Shipley  MJPocock  SJMarmot  MG Does plasma cholesterol concentration predict mortality from coronary heart disease in elderly people? 18-year follow-up in Whitehall Study. BMJ 1991;303 (6794) 89- 92
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Ettinger  WHWahl  PWKuller  LH  et al. CHS Collaborative Research Group, Lipoprotein lipids in older people: results from the Cardiovascular Health Study. Circulation 1992;86 (3) 858- 869
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Schatz  IJMasaki  KYano  KChen  RRodriguez  BLCurb  JD Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet 2001;358 (9279) 351- 355
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Bild  DEBluemke  DABurke  GL  et al.  Multi-Ethnic Study of Atherosclerosis: objectives and design. Am J Epidemiol 2002;156 (9) 871- 881
PubMed Link to Article
Holvoet  PJenny  NSSchreiner  PJTracy  RPJacobs  DR The relationship between oxidized LDL and other cardiovascular risk factors and subclinical CVD in different ethnic groups: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2007;194 (1) 245- 252
PubMed Link to Article
Friedewald  WTLevy  RIFredrickson  DS Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18 (6) 499- 502
PubMed
Carr  JJNelson  JCWong  ND  et al.  Calcified coronary artery plaque measurement with cardiac CT in population-based studies: standardized protocol of Multi-Ethnic Study of Atherosclerosis (MESA) and Coronary Artery Risk Development in Young Adults (CARDIA) study. Radiology 2005;234 (1) 35- 43
PubMed Link to Article
Detrano  RCAnderson  MNelson  J  et al.  Coronary calcium measurements: effect of CT scanner type and calcium measure on rescan reproducibility: MESA study. Radiology 2005;236 (2) 477- 484
PubMed Link to Article
Budoff  MJMao  STakasu  JShavelle  DMZhao  XQO'Brien  KD Reproducibility of electron-beam CT measures of aortic valve calcification. Acad Radiol 2002;9 (10) 1122- 1127
PubMed Link to Article
Shavelle  DMBudoff  MJBuljubasic  N  et al.  Usefulness of aortic valve calcium scores by electron beam computed tomography as a marker for aortic stenosis. Am J Cardiol 2003;92 (3) 349- 353
PubMed Link to Article
Budoff  MJTakasu  JKatz  R  et al.  Reproducibility of CT measurements of aortic valve calcification, mitral annulus calcification, and aortic wall calcification in the Multi-Ethnic Study of Atherosclerosis. Acad Radiol 2006;13 (2) 166- 172
PubMed Link to Article
Agatston  ASJanowitz  WRHildner  FJZusmer  NRViamonte  M  JrDetrano  R Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15 (4) 827- 832
PubMed Link to Article
Weverling-Rijnsburger  AWBlauw  GJLagaay  AMKnook  DLMeinders  AEWestendorp  RG Total cholesterol and risk of mortality in the oldest old [published correction appears in Lancet. 1998;351(9095):70]. Lancet 1997;350 (9085) 1119- 1123
PubMed Link to Article
Ford  ESGiles  WHDietz  WH Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287 (3) 356- 359
PubMed Link to Article
Grundy  SMCleeman  JIDaniels  SR  et al.  Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement [published corrections appear in Circulation. 2005;112(17):e297 and e298]. Circulation 2005;112 (17) 2735- 2752
PubMed Link to Article
Eckel  RHGrundy  SMZimmet  PZ The metabolic syndrome. Lancet 2005;365 (9468) 1415- 1428
PubMed Link to Article
Wilson  PWGarrison  RJCastelli  WPFeinleib  MMcNamara  PMKannel  WB Prevalence of coronary heart disease in the Framingham Offspring Study: role of lipoprotein cholesterols. Am J Cardiol 1980;46 (4) 649- 654
PubMed Link to Article
Kinosian  BGlick  HGarland  G Cholesterol and coronary heart disease: predicting risks by levels and ratios. Ann Intern Med 1994;121 (9) 641- 647
PubMed Link to Article
Walldius  GJungner  IAastveit  AHHolme  IFurberg  CDSniderman  AD The apoB/apoA-I ratio is better than the cholesterol ratios to estimate the balance between plasma proatherogenic and antiatherogenic lipoproteins and to predict coronary risk. Clin Chem Lab Med 2004;42 (12) 1355- 1363
PubMed Link to Article
Sniderman  ADJungner  IHolme  IAastveit  AWalldius  G Errors that result from using the TC/HDL C ratio rather than the apoB/apoA-I ratio to identify the lipoprotein-related risk of vascular disease [published correction appears in J Intern Med. 2006;260(2):186]. J Intern Med 2006;259 (5) 455- 461
PubMed Link to Article
Ingelsson  ESchaefer  EJContois  JH  et al.  Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 2007;298 (7) 776- 785
PubMed Link to Article
O’Brien  KDOtto  CMReichenbach  DDAlpers  CEWight  TN Regional accumulation of proteoglycans in lesions of “degenerative” valvular aortic stenosis and their relationship to apolipoproteins [abstract]. Circulation 1995;92 ((suppl 1)) I-612
Rajamannan  NMSubramaniam  MSpringett  M  et al.  Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation 2002;105 (22) 2660- 2665
PubMed Link to Article
Rajamannan  NMSubramaniam  MStock  SR  et al.  Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve. Heart 2005;91 (6) 806- 810
PubMed Link to Article
Rajamannan  NMSubramaniam  MCaira  FStock  SRSpelsberg  TC Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway. Circulation 2005;112 (9) ((suppl)) I229- I234
PubMed
Wu  BElmariah  SKaplan  FSCheng  GMohler  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 (3) 592- 597
PubMed Link to Article
Moura  LMRamos  SFZamorano  JL  et al.  Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis. J Am Coll Cardiol 2007;49 (5) 554- 561
PubMed Link to Article
Budoff  MJKatz  RWong  ND  et al.  Effect of scanner type on the reproducibility of extracoronary measures of calcification: the Multi-Ethnic Study of Atherosclerosis. Acad Radiol 2007;14 (9) 1043- 1049
PubMed Link to Article
Pohle  KDimmler  AFeyerer  R  et al.  Quantification of aortic valve calcification with electron beam tomography: a histomorphometric validation study. Invest Radiol 2004;39 (4) 230- 234
PubMed Link to Article
Koos  RMahnken  AHKühl  HP  et al.  Quantification of aortic valve calcification using multislice spiral computed tomography: comparison with atomic absorption spectroscopy. Invest Radiol 2006;41 (5) 485- 489
PubMed Link to Article
Cowell  SJNewby  DEBurton  J  et al.  Aortic valve calcification on computed tomography predicts the severity of aortic stenosis. Clin Radiol 2003;58 (9) 712- 716
PubMed Link to Article
Messika-Zeitoun  DAubry  MCDetaint  D  et al.  Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography. Circulation 2004;110 (3) 356- 362
PubMed Link to Article
Mohler  ER  IIIMedenilla  EWang  HScott  C Aortic valve calcium content does not predict aortic valve area. J Heart Valve Dis 2006;15 (3) 322- 328
PubMed
Feuchtner  GMMüller  SGrander  W  et al.  Aortic valve calcification as quantified with multislice computed tomography predicts short-term clinical outcome in patients with asymptomatic aortic stenosis. J Heart Valve Dis 2006;15 (4) 494- 498
PubMed

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