Published online before print January 12, 2009, doi: 10.1161/CIRCULATIONAHA.108.800235
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(Circulation. 2009;119:382-389.)
© 2009 American Heart Association, Inc.
Epidemiology |
Prevalence and Progression of Subclinical Atherosclerosis in Younger Adults With Low Short-Term but High Lifetime Estimated Risk For Cardiovascular Disease
The Coronary Artery Risk Development in Young Adults Study and Multi-Ethnic Study of Atherosclerosis
From the UT Southwestern Medical Center, Department of Medicine (J.D.B.), Dallas, Tex; Northwestern University, Departments of Preventive Medicine (K.L., D.M.L.-J., C.C.) and Medicine (K.L., D.M.L.-J.), Chicago, Ill; University of Minnesota, Division of Epidemiology and Community Health, Minneapolis (A.R.F.); University of Alabama at Birmingham, Department of Preventive Medicine (C.E.L.); Wake Forest University School of Medicine, Division of Public Health Sciences and Department of Internal Medicine, Section of Cardiology, Winston-Salem, NC (J.J.C.); Tufts University School of Medicine, Department of Radiology, Boston, Mass (J.F.P., D.H.O.); Departments of Medicine and Epidemiology, Columbia University, New York, NY (S. Shea); and Kaiser Permanente Northern California, Oakland (S. Sidney).
Correspondence to Jarett Berry, 5323 Harry Hines Blvd, Dallas, TX 75390–9047. E-mail jarett.berry{at}utsouthwestern.edu
Received June 17, 2008; accepted October 14, 2008.
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Abstract |
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Background— We hypothesized that individuals with low 10-year but high lifetime cardiovascular disease risk would have a greater burden of subclinical atherosclerosis than those with low 10-year but low lifetime risk.
Methods and Results— We included 2988 individuals 
50 years of age at examination year 15 from the Coronary Artery Risk Development in Young Adults (CARDIA) study and 1076 individuals 50 of age at study entry from the Multi-Ethnic Study of Atherosclerosis (MESA). The 10-year risk and lifetime risk for cardiovascular disease were estimated for each participant, permitting stratification into 3 groups: low 10-year (<10%)/low lifetime (<39%) risk, low 10-year (<10%)/high lifetime risk (
39%), and high 10-year risk (10%) or diagnosed diabetes mellitus. Baseline levels and change in levels of subclinical atherosclerosis (coronary artery calcium or carotid intima-media thickness) were compared across risk strata. Among participants with low 10-year risk (91% of all participants) in CARDIA, those with a high lifetime risk compared with low lifetime risk had significantly greater common (0.83 versus 0.80 mm in men; 0.79 versus 0.75 mm in women) and internal (0.85 versus 0.80 mm in men; 0.80 versus 0.76 mm in women) carotid intima-media thickness, higher coronary artery calcium prevalence (16.6% versus 9.8% in men; 7.1% versus 2.3% in women), and significantly greater incidence of coronary artery calcium progression (22.3% versus 15.4% in men; 8.7% versus 5.3% in women). Similar results were observed in MESA.
Conclusions— Individuals with low 10-year but high lifetime risk have a greater subclinical disease burden and greater incidence of atherosclerotic progression compared with individuals with low 10-year and low lifetime risk, even at younger ages.
Key Words: epidemiology • prevention • risk estimation • risk factors
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Introduction |
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Although the Framingham Risk Score represents an important advance in the primary prevention of cardiovascular disease (CVD),1,2 it has well-recognized limitations. For example, it classifies most younger individuals3 and virtually all women4,5 as low risk despite significant differences in risk factor burden, reflecting the importance of age in the 10-year risk equation. Recently, we have found that adults 50 years of age with
1 elevated traditional risk factors have observed lifetime risks for CVD of 39% to 70% despite 10-year predicted risks of <10%.6 In response to these and other data, practice guidelines7–9 suggest that physicians consider current risk factor burden within the context of long-term or lifetime risk for CVD.
Editorial p 362
Clinical Perspective p 389
Long-term risk estimates provide novel information for risk prediction that is not obtained through modifications of the 10-year risk window. For example, adjusting the threshold of "low risk" to <5% will do little to improve stratification of risk across the remaining lifespan.10 Because of the intuitive nature and distinct features of lifetime risk estimates,11,12 we sought to combine the 10-year and the lifetime risk windows into a single, clinically relevant method of risk stratification.13
We hypothesized that among individuals 50 years with low predicted 10-year risk, there would be 2 distinct groups: 1 with low predicted lifetime risk and 1 with high predicted lifetime risk. We further hypothesized that individuals with low 10-year but high lifetime predicted risk would have a greater burden and progression of established measures of subclinical atherosclerosis such as coronary artery calcium (CAC)14 and carotid intima-media thickness (IMT)15 compared with those with low 10-year and low predicted lifetime risk.
Differences in subclinical atherosclerotic burden between these 2 groups would provide a mechanistic explanation for the differences in observed event rates seen in prior studies of lifetime risk in younger adults and potentially identify novel groups of individuals for more intensive lifestyle or pharmacological preventive interventions.
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Methods |
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Study Populations
The Coronary Artery Risk Development in Young Adults (CARDIA) study is a National Heart, Lung and Blood Institute (NHLBI)-sponsored longitudinal study of the development of cardiovascular risk in young adults. Details of the study have been reported previously.16 Of the 3652 CARDIA participants 32 to 47 years of age at the year 15 examination, the exclusion criteria were missing CAC score data (n=615), missing total cholesterol data (n=36), and other missing critical covariates (n=13), leaving a total of 2988 individuals for analyses. Carotid IMT was measured in 3164 participants 38 to 50 years of age at the year 20 CARDIA examination. For these analyses, we excluded those with missing total cholesterol data (n=34) and other missing critical covariates (n=33), leaving a total of 3097 individuals for analyses.
The Multi-Ethnic Study of Atherosclerosis (MESA) is an NHLBI-sponsored community-based study of 6814 men and women 45 to 84 years of age who were free of clinical CVD at study entry. Participants from 4 ethnic backgrounds were recruited from 6 US communities. Details of the study have been reported previously.17 Carotid IMT and CAC were measured at study entry; CAC was then measured once in each participant at examination 2 or 3. Of the 1085 MESA participants 44 to 50 years of age, we excluded individuals with missing risk factor data (n=9), leaving a total of 1076 for analyses. Both CARDIA and MESA have been approved by the Institutional Review Board at each contributing institution, and all participants have given informed consent for their participation at each examination. For both CARDIA and MESA, baseline characteristics were obtained in accordance with standard protocols.16,17 For CARDIA participants, risk factors measured at year 15 when participants were 33 to 45 years of age were included for CAC analyses (year 20 risk factors for carotid IMT analyses).
Risk Classification Definitions
Low predicted short-term risk was defined as an estimated 10-year risk of <10% using the Adult Treatment Panel III risk assessment tool, which incorporates age, gender, total and high-density lipoprotein cholesterol levels, smoking, blood pressure, and treatment for hypertension into a multivariable equation to estimate 10-year risk for hard coronary heart disease (coronary death or nonfatal myocardial infarction).7 For the present study, high 10-year (short-term) risk was defined as 10-year risk 10% or the presence of diabetes mellitus. Individuals with diabetes mellitus were treated as having a high 10-year risk as suggested by current Adult Treatment Panel III guidelines. Lifetime risk was estimated for 5 mutually exclusive strata of risk factor burden using our previously published algorithm6 in which risk factors were classified as all optimal risk factors, 1 nonoptimal risk factors, 1 elevated risk factors, 1 major risk factor, or 2 major risk factors (Table 1).
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Differences in baseline risk factors result in marked differences in remaining lifetime risk for CVD.6 For example, a 50-year-old man with all optimal risk factors has a lifetime risk for CVD of 5%. In contrast, a different 50-year-old man with 2 major risk factors (ie, untreated systolic blood pressure of 160 mm Hg and total cholesterol of 250 mg/dL) has a lifetime risk for CVD of 69% despite a low 10-year risk. From these findings, we observed an apparent natural separation in lifetime risks based on these differences in risk factors and defined a priori high predicted lifetime risk as 39% and low predicted lifetime risk as <39%. This threshold also was chosen a priori because of clinical relevance; individuals with a calculated lifetime risk 39% have at least 1 elevated risk factor that could be treated.
Using the above definitions, we first stratified the study samples into 2 groups: those with low predicted short-term risk (10-year risk <10%) and those with high predicted short-term risk (10-year risk 10% or diabetes mellitus). The low predicted short-term risk group was then further stratified into 2 groups: low predicted lifetime risk and high predicted lifetime risk. This method of classification resulted in the formation of 3 mutually exclusive risk groups: low short-term/low lifetime predicted risk, low short-term/high lifetime predicted risk, and high predicted short-term risk.
Subclinical Disease Measures
In both CARDIA and MESA, CAC was measured with an electron-beam computed tomography scanner18 or a multidetector computed tomography system19 in accordance with standard protocols. Details of these techniques have been reported previously.20 In CARDIA, CAC was measured at year 15 and at year 20, with an average of 60 months between examinations. The prevalence of coronary calcium was treated as a categorical variable (CAC=0 or CAC >0) and as a continuous variable using the Agatston score for participants with CAC >0.21 Prior analyses in the CARDIA and MESA studies have demonstrated the presence or absence of CAC to be a reliable measure, with observed agreement of 96% in both studies.20 Because of the challenges posed by the large number of zeros and skewed distribution for CAC change data and because no consensus exists in the literature, we defined CAC progression a priori as follows. For those with CAC=0 at baseline, progression was defined as CAC score >0 at follow-up. For participants with 0<CAC<100 at baseline, progression was defined as annualized change of 10 Agatston units at follow-up. For participants with CAC >100 at baseline, progression was defined as annualized percent change (annualized change in CAC score divided by the baseline CAC score) 10% at follow-up. This method allowed a categorical definition of CAC progression (progression versus no progression). In MESA, CAC was measured at study entry. Follow-up examinations were performed in 50% of individuals at examination 2 and the remaining 50% at examination 3, with an average of 22 and 40 months between examinations, respectively. Similar methods were used to define CAC prevalence and progression. For both CARDIA and MESA, annualized refers to the difference between CAC score at baseline and follow-up divided by the number of years between examinations. Carotid IMT was measured at the year 20 examination in CARDIA and at the baseline examination in MESA with high-resolution B-mode ultrasound in accordance with standard procedures.22 Although the techniques were similar in CARDIA and MESA, minor differences in technique could be identified as reported previously.23,24
Statistical Methods
In all analyses, the risk group functioned as the independent variable, and the measure of atherosclerosis (ie, CAC or IMT) functioned as the dependent or outcome variable. Because of potentially large differences in associations of CAC and carotid IMT with the risk groups by gender, all analyses were conducted separately for women and men. Baseline characteristics were computed for the 3 risk groups with general linear models for continuous variables and cross-tabulations (proportions) for categorical variables. The age-adjusted prevalence (percentage) rates of CAC >0 (or CAC progression) across the 3 risk groups were computed using general linear models with the binary variable of CAC >0 (or CAC progression) as the outcome in which the least-square means of the binary outcome provided the percentages of CAC >0 (or CAC progression) for each risk group, adjusting for the age distribution within each risk group. Logistic regression was used to calculate age-adjusted odds ratios and 95% confidence intervals (CIs) for each binary outcome across risk groups. Age-adjusted logistic regression also was used to test differences between the reference group (low short-term and low lifetime risk) and other risk groups (represented by the coefficient for the dummy variable of that group). Means for common and internal carotid IMT were computed by use of general linear models with adjustment for age. Linear regression was used to test associations between each IMT outcome variable and the 3 risk groups (2 dummy variables, with low short-term and low lifetime risk category as the omitted reference group) with adjustment for age. All analyses were conducted with SAS statistical software (version 9.1; SAS Institute, Inc, Cary, NC).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Baseline Characteristics
Baseline characteristics are shown for the 3 strata of classification for CARDIA (Table 2) and MESA (Table 3) participants separately for men and women. The low predicted short-term risk group made up a substantial proportion of the study sample (91% of the CARDIA cohort, 75% of the MESA cohort). Lifetime risk stratification further divided the low predicted short-term risk group into 2 approximately equal-sized groups: 1 with low and 1 with high predicted lifetime risk. For CARDIA, the low short-term/low lifetime predicted risk represented 48% of the total low predicted short-term risk group, and a similar pattern was observed in MESA. Some racial differences were noted in both the CARDIA and MESA cohorts across the classification scheme.
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Overall, the patterns of risk factor differences across the 3 groups were similar between the 2 cohorts, with higher risk factor burden in individuals with low predicted short-term but high predicted lifetime risk. Although the mean 10-year risk was significantly higher (P<0.001) for individuals classified as low short-term/high lifetime predicted risk compared with individuals classified as low short-term/low-lifetime predicted risk, the levels were far below treatment thresholds of 10% or 20% 10-year risk.7
Baseline Subclinical Disease: Carotid IMT and CAC
For CARDIA participants with low short-term/high lifetime predicted risk, both the common carotid and internal carotid IMTs were greater compared with the low short-term/low lifetime predicted risk group. The point estimates for MESA participants were similar but nonsignificant with wider CIs (Table 4). Similarly, in both CARDIA and MESA, CAC prevalence was higher in the low short-term/high lifetime predicted risk group compared with the low short-term/low lifetime predicted risk group (Table 5). When CAC was analyzed as a continuous variable (Agatston score in those with CAC >0), the findings were less consistent, particularly in women (see Table 5).
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Progression of CAC
We noted a similar pattern of results for CAC progression. In CARDIA, CAC progression was higher in the low short-term/high lifetime predicted risk group compared with the low short-term/low lifetime predicted risk group. The point estimates for MESA participants were similar but nonsignificant with wider CIs (Table 6). Of interest, we also observed a similar pattern of results for CAC progression using a variety of different measures, including CAC incidence and annualized CAC change scores (data not shown). When we compared the regression coefficients in both studies for baseline subclinical atherosclerosis (carotid IMT and CAC prevalence) and progression of atherosclerosis (CAC change), we noted a similar effect size across the risk strata (Table 7).
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Secondary Analyses
Because we classified all individuals with at least 1 major risk factor (current smoking, stage 2 or treated hypertension, or total cholesterol 240 mg/dL or treated) as having high predicted lifetime risk, we performed secondary analyses to determine whether our findings were due largely to any single major risk factor. For example, we excluded all smokers from the analysis and compared atherosclerotic burden and progression between the 3 risk strata. Similar analyses were performed after the exclusion of those with stage 2 hypertension or total cholesterol 240 mg/dL. In all cases, the pattern of results was nearly identical in both CARDIA and MESA men and women, suggesting that no individual risk factor alone determined our findings. In secondary analyses designed to examine whether our findings were consistent across race/ethnic groups, we performed the regressions in white and nonwhite participants in both the CARDIA and MESA samples separately. Likewise, we also examined the association of the present risk stratification method with CAC >100 as an outcome. Although our power was limited for these analyses, we observed an overall similar pattern of results for whites and nonwhites and for the end point of CAC >100 (data not shown).
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Discussion |
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Our study resulted in several important findings. First, among the relatively large group with low short-term risk (10-year risk
10%), 2 distinct, similarly sized groups could be identified using our previously published algorithm6 for lifetime risk stratification: 1 with high lifetime risk and 1 with low lifetime risk. Second, the low short-term/high lifetime risk group had a baseline burden of subclinical atherosclerosis that was significantly greater than the low short-term/low lifetime risk group. Third, the low short-term/high lifetime risk group had a rate of CAC progression that also was significantly higher than the low short-term/low lifetime risk group. Finally, in 2 distinct cohorts with different racial characteristics, we found a very similar pattern of results.
Clinical Implications
Although >90% of individuals <50 years of age have a low 10-year risk,4 prior data suggest that differences in risk factor burden translate into marked differences in CVD events across the remaining lifespan. Clinical practice guidelines7–9 recognize the discordance between short-term and long-term risk, encouraging long-term risk estimation as a supplement to the 10-year risk window.
Consider a hypothetical case of a 50-year-old woman with the following risk factors: total cholesterol of 220 mg/dL, systolic blood pressure of 130 mm Hg, nonsmoker, and nondiabetic. Prior data suggest that despite a 10-year risk of 1%, her expected lifetime risk for CVD is 39%.25 But what about now? Without any additional testing, we would predict that she would have a greater burden and progression of subclinical atherosclerosis compared with a woman with an optimal cholesterol and blood pressure. These results suggest a potential benefit of aggressive prevention efforts for individuals <50 years of age with low short-term but high lifetime predicted risk.
Throughout the lifespan, exposure to high risk factor levels promotes the accumulation of subclinical atherosclerosis.26 In older adults, this accumulated atherosclerotic burden confers an increased risk for clinical CVD events.14,15 In younger adults, these risk factors will translate into CVD events, but typically not until much later in life.27,28 Thus, multiple risk factors in young adulthood (<40 years of age) appear to promote greater subclinical atherosclerotic burden in middle age (40 to 50 years), but the majority of clinical CVD events do not occur until older age (>65 years).
The converse is also true. Clinical CVD in individuals with low risk factor burden is rare.6,29 We have shown previously that an optimal risk factor profile at 50 years of age is associated with a remaining lifetime risk for atherosclerotic CVD of 
5%,6 even in the face of a dramatically longer median survival. The lower prevalence and progression of subclinical disease that we found in the present study are consistent with the virtual absence of clinical CVD events in these low-risk individuals.
Clinical Significance of Subclinical Atherosclerosis
The significant differences in subclinical atherosclerosis noted in the present study may provide a mechanistic explanation for the substantial differences in lifetime risk for CVD among individuals with differences in baseline risk factor burden.6,30 For example, among individuals 65 years of age in the Cardiovascular Health Study, a difference of 0.20 mm for common carotid IMT was associated with an 40% increase in risk for incident myocardial infarction and stroke.15 In the present study of adults <50 years of age, individuals with a low short-term/high lifetime predicted risk had a common carotid IMT that was 0.05 mm greater than individuals with a low short-term/low lifetime predicted risk. Such a difference in baseline subclinical atherosclerosis in younger adults would likely translate into substantial differences in cumulative risk across the lifespan.
Study Limitations
Several limitations should be acknowledged. We applied a risk prediction algorithm derived from the Framingham Heart Study (exclusively white) to 2 separate, multiethnic samples. Although this might have influenced our results, prior literature suggests that risk factors in isolation31 and in aggregate32 provide reliable estimates of CVD burden across ethnicities. For example, we recently demonstrated the similarity of lifetime risk estimates for CVD in blacks and whites,33 providing further justification for using a similar stratification method for whites and nonwhites.
Second, the group with low short-term but high lifetime predicted risk had slightly higher risk factor burden and 10-year risk. Nevertheless, these levels are far below current treatment thresholds, underscoring the importance of long-term risk estimation emphasized by current clinical guidelines.7–9 Finally, mild differences in techniques used to measure IMT were found in the 2 cohorts.23,24 Despite these differences, we observed patterns of results that were remarkably similar.
Conclusions
In the present study, we found that individuals with low short-term but high lifetime predicted risk had a subclinical disease burden that was intermediate between individuals with low short-term/low lifetime predicted risk and those individuals with high short-term predicted risk. In addition, we found that the rate of progression of subclinical disease was greater in this group, although the clinical significance of this measure of CAC progression remains unknown. Nevertheless, these findings, taken together, provide a mechanistic explanation for the marked differences in lifetime risk across different strata of risk factors and may have potential clinical and public health implications.
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Acknowledgments |
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Sources of Funding
Dr Berry has received support from an National Research Service Award/NHLBI fellowship at Northwestern University (T32HL069771). Dr Lloyd-Jones is supported by grant R21HL085375 from the NHLBI. The CARDIA study was supported by NHLBI contracts NO1-HC-48047, NO1-HC-48048, NO1-HC-48049, NO1-HC-48050, NO1-HC95095, and NO1-HC-45134. The MESA Study was supported by contracts NO1-HC-95159 through NO1-HC-95165 and NO1-HC-95169 from the NHLBI. A full list of MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.
Disclosures
Dr O'Leary has ownership interest in Medpace and has served as a consultant or on the advisory board for Sonafi Aventis. The other authors report no conflicts.
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CLINICAL PERSPECTIVE
Although the Framingham Risk Score represents a significant advance in the primary prevention of cardiovascular disease, it has well-established limitations. For example, it classifies virtually all younger adults as low risk regardless of risk factor burden. One proposed solution is to extend the time horizon to include the remaining lifespan so that differences in risk factor burden translate into substantial differences in risk for cardiovascular disease across the remaining lifespan. Thus, we hypothesized that among individuals <50 years of age with low 10-year risk, 2 distinct groups can be identified: those we would predict to have a high lifetime risk and those we would predict to have a low lifetime risk. In 2 unique cohorts, the Coronary Artery Risk Development in Young Adults study and the Multi-Ethnic Study of Atherosclerosis, we found that those with low short-term but high lifetime risk had a greater burden and progression of subclinical atherosclerosis as measured by coronary artery calcium and carotid intima-media thickness compared with those with low short-term and low lifetime risk, even at <50 years of age. Thus, prior data would suggest that individuals with these differences in risk factor burden would have marked differences in event rates across their lifespan. But what about now? The present findings suggest that these risk factor differences translate into significant differences in the prevalence and progression of subclinical atherosclerosis even at younger ages. We believe that these findings suggest a potential benefit of more aggressive prevention efforts for individuals <50 years of age with low short-term but high lifetime risk.
Circulation 2009 119: 359-361.
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  R. S. Vasan and W. B. Kannel Strategies for Cardiovascular Risk Assessment and Prevention Over the Life Course: Progress Amid Imperfections Circulation, August 4, 2009; 120(5): 360 - 363. [Full Text] [PDF]
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