CLINICAL RESEARCH: VALVULAR HEART DISEASE
Clinical Factors, But Not C-Reactive Protein, Predict Progression of Calcific Aortic-Valve DiseaseThe Cardiovascular Health Study
Gian M. Novaro, MD*,*,
Ronit Katz, PhD ,
Ronnier J. Aviles, MD ,
John S. Gottdiener, MD ,
Mary Cushman, MD, MSc||,
Bruce M. Psaty, MD, PhD¶,
Catherine M. Otto, MD# and
Brian P. Griffin, MD**
* Department of Cardiology, Cleveland Clinic Florida, Weston, Florida
Department of Biostatistics, University of Washington, Seattle, Washington
Overlake Hospital Medical Center, Bellevue, Washington
Division of Cardiology, University of Maryland School of Medicine, Baltimore, Maryland
|| Department of Medicine, University of Vermont and Fletcher Allen Health Care, Colchester, Vermont
¶ Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, Washington
# Department of Cardiology, University of Washington, Seattle, Washington
** Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.
Manuscript received May 25, 2007;
revised manuscript received July 30, 2007,
accepted July 30, 2007.
* Reprint requests and correspondence: Dr. Gian M. Novaro, Department of Cardiology, Desk A23, Cleveland Clinic Florida, 2950 Cleveland Clinic Boulevard, Weston, Florida 33331. (Email: novarog{at}ccf.org).
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Abstract
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Objectives: The purpose of this study was to examine the relationship between C-reactive protein (CRP) and calcific aortic valve disease in a large, randomly selected, population-based cohort.
Background: The pathobiology of calcific aortic stenosis involves an active inflammatory, atheromatous, osteogenic process. Elevations in CRP, a measure of systemic inflammation, have been associated with aortic stenosis.
Methods: Two-dimensional and Doppler echocardiography and CRP measurement were performed at baseline in 5,621 participants in the Cardiovascular Health Study. Multivariable analysis was used to identify CRP as a predictor of baseline and incident aortic stenosis.
Results: At a mean echocardiographic follow-up of 5 years, 9% of subjects with aortic sclerosis progressed to some degree of aortic stenosis. Increasing age (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.09 to 1.16; p < 0.001) and male gender (OR 3.05, 95% CI 1.76 to 5.27; p < 0.001) were related to risk of incident aortic stenosis, whereas increasing height (OR 0.96, 95% CI 0.94 to 0.99; p = 0.013) and African-American ethnicity conveyed a lower risk (OR 0.49, 95% CI 0.25 to 0.95; p = 0.035). C-reactive protein, treated as a continuous variable, was not associated with baseline aortic stenosis, progression to aortic sclerosis (adjusted OR 0.93, 95% CI 0.85 to 1.02; p = 0.107), or progression to aortic stenosis (adjusted OR 0.85, 95% CI 0.70 to 1.03; p = 0.092).
Conclusions: In this large population-based cohort, approximately 9% of subjects with aortic sclerosis progressed to aortic stenosis over a 5-year follow-up period. There was no association between CRP levels and the presence of calcific aortic-valve disease or incident aortic stenosis. C-reactive protein appears to be a poor predictor of subclinical calcific aortic-valve disease.
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Abbreviations and Acronyms
| | CI = confidence interval | | CRP = C-reactive protein | | OR = odds ratio |
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Calcific aortic-valve disease refers to progressive aortic leaflet thickening and calcification, beginning with the early lesion of aortic-valve sclerosis leading to advanced leaflet disease of aortic-valve stenosis, characterized by restricted leaflet motion and outflow obstruction. The pathobiology of the aortic-valve lesion involves an atheromatous, osteogenic, inflammatory process sharing histologic similarities with coronary atherosclerosis (1–3). Clinical risk factors for calcific aortic-valve disease share considerable overlap with those of coronary artery disease, including hyperlipidemia, hypertension, smoking, and diabetes mellitus (4–9).
Current evidence suggests that inflammation contributes to the development and progression of atherosclerosis (10). C-reactive protein (CRP), a sensitive marker of systemic inflammation, has been associated with an increased risk of cardiovascular events (11–13) but is more weakly related to subclinical coronary atherosclerosis (14–16).
Given the role of inflammation in calcific aortic-valve disease, it is hypothesized that CRP might be a risk marker for aortic-valve stenosis. Studies suggesting a positive association have been limited to surgical populations of mainly symptomatic patients (17) and to cases of advanced aortic-valve stenosis (18). More recently, CRP has been localized in valve tissue of calcific aortic-valve stenosis (19), with a positive correlation between serum CRP levels and valvular CRP expression. Further, in an experimental hypercholesterolemic rabbit model of aortic-valve stenosis, highly sensitive CRP serum levels were increased compared with control rabbits (20). Despite the evidence from surgical series and animal models, the relation between CRP and calcific aortic-valve disease in the general population is not known.
Using the large cohort of community-dwelling older adults from the Cardiovascular Health Study (CHS), we tested the hypothesis that CRP is associated with calcific aortic-valve disease. Combining the baseline echocardiographic data from the CHS cohort with 5-year follow-up studies allowed us to study the usefulness of CRP in predicting incident calcific aortic-valve disease and progression from aortic-valve sclerosis to stenosis.
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Methods
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Study population.
The CHS is a multicenter, population-based observational study of cardiovascular disease in the elderly sponsored by the National Heart, Lung, and Blood Institute (Bethesda, Maryland). The CHS is a prospective study of 5,888 men and women 65 years of age or older who were randomly selected and recruited from Medicare-eligibility lists in four communities in the U.S.: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania. From 1989 to 1990, 5,201 subjects were recruited and examined; an additional 687 predominantly African-American participants were recruited and examined from 1992 to 1993. Ethnicity was assessed by subject self-report from the following list: white, African-American, American Indian/Alaskan Native, Asian/Pacific Islander, and other. The present report includes only participants with available baseline CRP measurements (n = 5,806) and adequate echocardiograms (n = 5,653). Of these subjects, 32 with endocarditis, rheumatic valve disease, a prosthetic valve, or hypertrophic cardiomyopathy were excluded, leaving a total of 5,621 subjects. The institutional review board at each participating center approved the study, and informed consent was obtained from the patients.
Details of the study design and rationale have been published previously (21). In brief, the enrollment interview and examination, conducted in 1989 and 1990, consisted of an extensive history, physical examination, 12-lead electrocardiography, spirometry, and M-mode, 2-dimensional, and Doppler echocardiography. Laboratory examination included serum-chemistry tests, an oral glucose-tolerance test, assessment of plasma lipid levels after fasting, lipoprotein (a), and CRP. The supplemental cohort of African-American subjects underwent a similar baseline examination in 1992 and 1993, and echocardiography was performed in 1994 and 1995. Prevalent coronary heart disease consisted of a clinical history of myocardial infarction, angina, coronary artery bypass grafting, or angioplasty.
Follow-up consisted of annual clinic visits through 1998 and 1999, followed by a telephone call 6 months later. Subjects were queried regarding any hospitalizations at each contact. The mean length of follow-up was 5.0 years overall; follow-up was complete for 95% of the cohort.
Echocardiographic protocol.
Two-dimensional echocardiographic studies were recorded on videotape with use of a cardiac ultrasound machine (model SSH-160A, Toshiba, Tustin, California) as previously described (22). Two-dimensional assessment of the aortic valve was performed on the basis of the parasternal long-axis and short-axis views. Baseline videotapes were sent to the echocardiography reading center (located at the University of California, Irvine, for the original cohort and at Georgetown University, Washington, DC, for the supplemental cohort), where abnormalities of the aortic valve were coded as representing aortic stenosis, a bicuspid aortic valve, aortic sclerosis, or aortic-valve vegetation, or the valve was coded as prosthetic.
Sclerosis was defined by focal areas of increased echogenicity and thickening of the aortic-valve leaflets without restriction of leaflet motion. Aortic stenosis was defined as thickened leaflets with reduced systolic opening on two-dimensional imaging and an increased velocity across the aortic valve ( 2.5 m/s in the original cohort and >2.0 m/s in the supplemental cohort). The results of 96% of the imaging studies were adequate and were classified as normal, indicative of sclerosis, or indicative of stenosis. As previously reported (4), aortic-valve morphology was reanalyzed in detail in a subgroup of 201 baseline studies from the original cohort, including all coded as indicating aortic stenosis as well as 109 randomly selected studies. Given the acceptable level of agreement between the results from the reading center and the results of the reanalysis (kappa = 0.62), the reading-center results were used for all subsequent analyses.
CRP analysis.
Baseline blood samples were obtained early in the day after an overnight fast. Plasma and serum samples were collected in aliquots, frozen at –70° C, and shipped to the CHS Core Laboratory, where they were analyzed. Personnel blinded to clinical data performed CRP measurements. An ultra-sensitive enzyme-linked immunosorbent assay developed at the CHS Core Laboratory was used to measure CRP using baseline samples in 1997 (23). The interassay coefficient of variation was 5.5% (24).
Statistical analysis.
We categorized participants according to the echocardiographic findings (normal, aortic sclerosis, or aortic stenosis) and compared the distributions of demographic characteristics, cardiovascular risk factors, and CRP using analysis of variance for continuous variables and chi-square test for categorical variables. Mantel-Haenszel tests were used to assess linear trends. Histograms and q-q plots revealed that serum levels of CRP and lipoprotein (a) were skewed; therefore, data are presented as median and interquartile range. We also categorized participants into ascending quartiles of CRP and used ANOVA for comparison of continuous variables and chi-square test for categorical variables.
We performed 2 separate analyses to evaluate the relationship between CRP and calcific aortic-valve disease. The first study consisted of a cross-sectional analysis to determine the association between CRP and baseline aortic sclerosis and stenosis. The second study consisted of a longitudinal analysis to evaluate the relationship between baseline CRP and incident calcific aortic-valve disease.
Logistic regression models were used to determine whether CRP was independently associated with aortic sclerosis or stenosis at baseline compared to those with normal valves. C-reactive protein was log-transformed, as it was found to be skewed. We also used logistic regression to further explore whether participants who had normal valves and aortic sclerosis at baseline but developed aortic stenosis by their follow-up echocardiogram were associated with levels of CRP. Incident aortic stenosis was defined as thickened leaflets with reduced systolic opening on 2-dimensional imaging and an increased velocity across the aortic valve of 2.5 m/s (aortic valve gradient of 25 mm Hg) during the follow-up echocardiographic study. Multivariable regression models were adjusted for demographic and laboratory covariates to evaluate whether the association of CRP with calcific aortic-valve disease was independent. The following covariates were selected for multivariable adjustment: age, gender, ethnicity, diabetes mellitus, hypertension, current smoking, height, renal insufficiency, and prevalent coronary heart disease. Subjects were also categorized into CRP quartile groups, and analyses were repeated, adjusting for the same covariates.
A p value of <0.05 was considered statistically significant. Statistical analyses were performed using S-Plus (release 6.1, Insightful Inc., Seattle, Washington) and SPSS statistical software (release 14.0.2, SPSS Inc., Chicago, Illinois).
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Results
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Baseline characteristics.
The baseline characteristics of the 3,917 subjects with normal aortic valves (70%), the 1,610 subjects with aortic sclerosis (29%), and the 94 with aortic stenosis (2%) at baseline are shown in Table 1. There was a progressive increase in age, proportion of male subjects, and prevalence of hypertension, coronary heart disease, and chronic renal disease (p for trend, <0.001), but not CRP, with increasing calcific aortic-valve abnormality. Other variables associated with aortic-valve abnormalities included African-American ethnicity and high- and low-density lipoprotein cholesterol levels.
Risk factors for incident calcific aortic-valve disease.
Of the baseline 3,917 subjects with normal aortic valves, 44% (n = 1,716) developed aortic sclerosis and 1% (n = 40) developed aortic stenosis at a mean 5-year follow-up. Multivariable analysis was performed to identify predictors of incident calcific aortic-valve disease, defined as subjects with normal aortic valves at baseline progressing to aortic sclerosis alone (Table 2) and those progressing to aortic sclerosis or aortic stenosis (Table 3). The odds ratios (ORs) associated with increasing age and increases in low-density lipoprotein cholesterol levels were significant. Male gender was associated with a 32% excess risk, whereas African-American ethnicity imparted a 69% lower risk. Neither a history of diabetes, hypertension, or tobacco use, nor the presence of coronary heart disease or renal insufficiency were independent predictors of progression.
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Table 2 Multivariate-Adjusted ORs for Incident Aortic Sclerosis in Subjects Who Have Normal Aortic Valves at Baseline
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Table 3 Multivariate-Adjusted ORs for Incident Calcific Aortic-Valve Disease (Aortic Sclerosis or Stenosis) in Subjects Who Have Normal Aortic Valves at Baseline
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Progression to incident aortic stenosis.
Of the baseline 1,610 subjects with aortic sclerosis, there were 1,091 subjects with available echocardiographic studies at follow-up. Of these, 9% (n = 96) developed aortic stenosis at a mean 5-year follow-up. Multivariable analysis was performed to identify predictors of progression to aortic stenosis, defined as subjects with normal valves or aortic sclerosis at baseline progressing to aortic stenosis (Table 4). Again, the odds ratio associated with increasing age was significant. Male gender was associated with a 3-fold excess risk. Height was weakly inversely related, and African-American ethnicity was associated with a strong protective effect, with a 51% lower risk.
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Table 4 Multivariate-Adjusted ORs for Incident Aortic Stenosis in Subjects Who Have Normal Aortic Valves or Aortic Sclerosis at Baseline
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Calcific aortic-valve disease progression and CRP.
Tables 5 and 6
 show unadjusted and adjusted risk of incident aortic sclerosis and aortic stenosis, respectively, according to quartiles of CRP. Both in univariate and multivariable analysis, CRP, treated as a continuous variable, was not associated with either progression to aortic sclerosis (adjusted OR 0.93, 95% confidence interval 0.85 to 1.02, p = 0.107) or progression to aortic stenosis (adjusted OR 0.85, 95% confidence interval 0.70 to 1.03, p = 0.092). Although use of aspirin (<4%) and statin drugs (<3%) was low at time of study enrollment, analyses excluding subjects on either agent at study entry yielded similar results.
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Table 5 Association of Quartiles of CRP With Incident Aortic Sclerosis in Subjects Who Have Normal Aortic Valves at Baseline
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Table 6 Association of Quartiles of CRP With Incident Aortic Stenosis in Subjects Who Have Normal Aortic Valves or Aortic Sclerosis at Baseline
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Discussion
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In this large cohort of asymptomatic elderly adults in the community, CRP was not associated with either the presence or progression of calcific aortic-valve disease. The rate of progression from aortic sclerosis to aortic stenosis was 9% over a mean 5-year follow-up period. Increasing age, male gender, white ethnicity, and shorter height were independent predictors of incident aortic stenosis in those with normal valves or aortic sclerosis. Our findings suggest that elevated CRP levels do not precede the development of incident calcific aortic stenosis.
Only a few studies have examined the relationship between CRP and aortic stenosis. Galante et al. (17) published the initial study demonstrating elevated CRP levels in association with calcific aortic stenosis. In 62 patients with severe symptomatic aortic stenosis awaiting valve surgery, CRP levels were higher than in 79 healthy control subjects after adjustment for covariates in multiple logistic regression analysis. Expanding these observations, several studies have attempted to confirm these results. In a surgical series, CRP levels were higher in severe aortic stenosis patients compared to patients with pure aortic regurgitation (18). In those who underwent aortic valve replacement for aortic stenosis, CRP levels decreased from before to 6 months after valve replacement. C-reactive protein has also been studied in a nonsurgical population of aortic stenosis; in 60 patients with varying degrees of aortic stenosis, CRP levels did not correlate with stenosis severity (25). Recently, CRP has been localized in valve tissue of both calcific aortic-valve stenosis and degenerative aortic-valve bioprostheses (19), with a positive correlation between serum CRP levels and valvular CRP expression. Thus, from the available human studies, it is apparent that CRP levels are elevated in aortic stenosis patients with severe disease awaiting surgery, do not correlate with stenosis severity, and decrease after valve replacement, supporting the histologic evidence that the aortic valve is a site of active inflammation.
Although aortic sclerosis and aortic stenosis are considered different stages in the continuum of calcific aortic-valve disease, the rate of disease progression beyond aortic sclerosis has not been widely studied. Two single-center retrospective studies have addressed the rate of progression of aortic sclerosis to aortic stenosis (26,27). During follow-up periods of 6 and 4 years, 16% (26) and 33% (27) of patients, respectively, with aortic sclerosis progressed to some degree of aortic stenosis. In the former study, a multivariate analysis that included age, mitral annular calcification, and left ventricular hypertrophy showed that only mitral annular calcification predicted progression to aortic stenosis. Other clinical information, including cardiovascular risk factors, was not available for analysis. Our findings, the first to be conducted prospectively in a large nonreferral population, demonstrate a lower rate of progression to aortic stenosis,  9% over a mean follow-up of 5 years.
Although several studies (26) have examined the clinical and biochemical risk factors related to the progression of established aortic stenosis, few have looked at the variables related to progression of calcific aortic-valve disease, namely aortic sclerosis to stenosis. Whereas cardiovascular risk factors and CRP levels failed to predict incident aortic stenosis, only 4 demographic variables (increasing age, male gender, white ethnicity, and shorter height) were associated with an increased risk of incident aortic stenosis. Increasing age is a well-recognized risk factor related to aortic stenosis (4). Gender appears to have an impact on the risk of both aortic stenosis (4) and the degree of aortic valve calcification (28), with men showing a greater predilection of both. An inverse relationship between height and the presence of calcific aortic-valve disease has been suggested in prior studies (4,29). Although speculative and still unclear, the mechanisms of disease might relate to osteoporosis or to tensile forces related to the length of the arterial vasculature. The influence of ethnicity has not been adequately examined in patients with calcific aortic-valve disease. Extrapolating from studies on coronary atherosclerosis and aortic sclerosis, African Americans appear to exhibit less coronary artery (30) and aortic valve calcification (31), a lower incidence of osteoporosis (32), and are possibly less apt to develop calcium overgrowth in sites of dystrophic calcification. The relationship of bone formation and aortic valve disease is increasingly relevant, as the mechanisms of valvular heart disease involving an endochondral bone process (33) and heterotopic ossification (34) are now recognized. From epidemiological studies, it is acknowledged that osteoporosis and vascular/valvular calcification frequently coexist (35). Therefore, the racial disparity in the rates of these 2 conditions may provide a link to the noted protective effect of African-American ethnicity on the development of aortic stenosis as evidenced in our findings.
The lack of association between CRP and calcific aortic-valve disease in our study, in contrast to the findings of previous studies, may be related to several factors. By using a population-based sample that is considerably larger than prior studies, we avoided referral bias. Importantly, prior studies included subjects with mainly advanced aortic stenosis and failed to study patients with milder asymptomatic aortic-valve disease. Accordingly, it is likely that advanced disease is pro-inflammatory or that inflammation is associated with other conditions like atherosclerosis that accompany advanced disease, whereas inflammation does not precede its development. Finally, analogous to the relationship between CRP and coronary atherosclerotic burden (16), CRP appears to be a poor predictor of subclinical calcific aortic-valve disease.
Despite the large sample size and randomly selected nature of this study population, there are several limitations to mention. C-reactive protein was determined once in this analysis, and thus, a longitudinal biochemical assessment is not available. However, it is known (36) that there is decade-to-decade consistency in CRP values, making CRP a stable marker for use in long-term prediction studies. No longitudinal information was analyzed on the use of aspirin and statin drugs during or at the 5-year follow-up period. However, only 2% to 4% of the participants were receiving these agents at baseline.
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Conclusions
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In this large population-based sample of asymptomatic elderly adults, approximately 9% of subjects with aortic sclerosis progressed to aortic stenosis over 5 years of follow-up. There was no relationship between elevated CRP levels and the presence of calcific aortic-valve disease or of incident aortic stenosis. C-reactive protein appears to be a poor predictor of subclinical calcific aortic-valve disease. Our findings provide information on clinical risk factors related to progression to aortic stenosis from sclerosis and offer preliminary insight into the influence of ethnicity on the development of calcific aortic-valve disease.
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J. Am. Coll. Cardiol.,
November 13, 2007;
50(20):
1999 - 2001.
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Abstract
Methods