CLINICAL RESEARCH: CORONARY ARTERY DISEASE
Early Adult Risk Factor Levels and Subsequent Coronary Artery CalcificationThe CARDIA Study
Catherine M. Loria, PhD*,*,
Kiang Liu, PhD ,
Cora E. Lewis, MD, MPSPH ,
Stephen B. Hulley, MD ,
Stephen Sidney, MD, MPH¶,
Pamela J. Schreiner, PhD||,
O. Dale Williams, PhD,
Diane E. Bild, MD, MPH* and
Robert Detrano, MD, PhD**
* Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland
Department of Preventive Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
Division of Preventive Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
Department of Epidemiology and Biostatistics, University of California, San Francisco, California
¶ Division of Research, Kaiser Permanente, Oakland, California
|| Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota
** Harbor-University of California Los Angeles Research and Education Institute, Torrance, California.
Manuscript received September 25, 2006;
revised manuscript received January 19, 2007,
accepted January 22, 2007.
* Reprint requests and correspondence: Dr. Catherine M. Loria, National Heart, Lung, and Blood Institute, Division of Prevention and Population Sciences, 6701 Rockledge Drive, Room 10116, Bethesda, Maryland 20892-7936. (Email: loriac{at}mail.nih.gov).
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Abstract
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Objectives: We sought to determine whether early adult levels of cardiovascular risk factors predict subsequent coronary artery calcium (CAC) better than concurrent or average 15-year levels and independent of a 15-year change in levels.
Background: Few studies have used multiple measures over the course of time to predict subclinical atherosclerosis.
Methods: African American and white adults, ages 18 to 30 years, in 4 U.S. cities were enrolled in the prospective CARDIA (Coronary Artery Risk Development in Young Adults) study from 1985 to 1986. Risk factors were measured at years 0, 2, 5, 7, 10, and 15, and CAC was assessed at year 15 (n = 3,043).
Results: Overall, 9.6% adults had any CAC, with a greater prevalence among men than women (15.0% vs. 5.1%), white than African American men (17.6% vs. 11.3%), and ages 40 to 45 years than 33 to 39 years (13.3% vs. 5.5%). Baseline levels predicted CAC presence (C = 0.79) equally as well as average 15-year levels (C = 0.79; p = 0.8262) and better than concurrent levels (C = 0.77; p = 0.019), despite a 15-year change in risk factor levels. Multivariate-adjusted odds ratios of having CAC by ages 33 to 45 years were 1.5 (95% confidence interval [CI] 1.3 to 1.7) per 10 cigarettes, 1.5 (95% CI 1.3 to 1.8) per 30 mg/dl low-density lipoprotein cholesterol, 1.3 (95% CI 1.1 to 1.5) per 10 mm Hg systolic blood pressure, and 1.2 (95% CI 1.1 to 1.4) per 15 mg/dl glucose at baseline. Young adults with above optimal risk factor levels at baseline were 2 to 3 times as likely to have CAC.
Conclusions: Early adult levels of modifiable risk factors, albeit low, were equally or more informative about odds of CAC in middle age than subsequent levels. Earlier risk assessment and efforts to achieve and maintain optimal risk factor levels may be needed.
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Abbreviations and Acronyms
| | BMI = body mass index | | BP = blood pressure | | CAC = coronary artery calcium | | CI = confidence interval | | CT = computed tomography | | CVD = cardiovascular disease | | HDL-C = high-density lipoprotein cholesterol | | LDL-C = low-density lipoprotein cholesterol | | OR = odds ratio |
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Fewer young adults report being screened for serum cholesterol than older adults (1), possibly because cardiovascular disease (CVD) risk factor levels are generally low at this age. A common approach is to wait until risk factors develop to prescribe lifestyle changes or pharmacological treatment, rather than prevent or delay the onset of risk factors. Yet, young adults from a large autopsy study already had atherosclerotic lesions, and the extent of lesions was associated with risk factor levels (2). Thus, higher risk factor levels, despite being relatively low, may identify young adults more likely to develop early atherosclerosis. If early adult levels predict CVD risk as well as levels measured in middle age, augmented efforts to encourage young adults to achieve and maintain optimal risk factor levels might lead to more adults reaching middle age at low risk for CVD. A low-risk status in middle age has been linked to lower CVD morbidity and mortality, lower health care costs, increased life expectancy, and higher self-reported quality of life (3–7).
Few studies have followed younger adults to assess later morbidity and mortality, but all of the studies concur that established risk factors early in adulthood, such as serum total cholesterol (8,9), blood pressure (10,11), and cigarette smoking (12), predict subsequent CVD. However, none of these studies examined multiple measures throughout young adulthood to assess whether subsequent risk was predicted better by earlier compared with later levels. Further, none of these cohorts assessed the relation of risk factors to subclinical disease. Only a few studies with recently established cohorts have examined whether early adult risk factor levels are as informative of later subclinical disease risk as risk factors measured later in life, when levels generally are higher (13,14). These studies tend to be small or have little or no ethnic diversity, which limits their generalizability.
We used data from the CARDIA (Coronary Artery Risk Development in Young Adults) study, a large, biracial, prospective cohort study, to determine whether established, modifiable CVD risk factors measured in adults ages 18 to 30 years predicted the presence of coronary artery calcium (CAC) at ages 33 to 45 years as well as levels of these same risk factors measured concurrently with CAC. We also assessed how well long-term exposure, using average levels measured several times over 15 years, predicted CAC. Coronary artery calcium is correlated with histological plaque area (15), and the extent of CAC predicts coronary heart disease events in asymptomatic adults (16–21). Previous studies found that CAC is greater among whites than African Americans and greater among men than women and that prevalence increases with age (13,22–29). Accordingly, we report CAC prevalence among 33- to 45-year-old African American and white adults and test differences by race, gender, and age.
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Methods
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CARDIA is a multicenter study of the development and determinants of CVD risk factors in young adults initially ages 18 to 30 years. The study design has been published elsewhere in detail (30). In brief, 5,115 African American and white participants were recruited at baseline from 1985 to 1986 in 4 U.S. cities (Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California) with population-based samples approximately balanced within center by gender, age, race, and education. Follow-up examinations were completed at years 2, 5, 7, 10, and 15 with 90%, 86%, 81%, 79%, and 74%, respectively, of the surviving cohort returning. Each examination protocol was approved by institutional review boards at each site, and informed consent was obtained at every examination.
Assessment of risk factors.
A common protocol and quality control procedures were used at all examinations. Participants were asked to fast for 12 h and to avoid smoking and heavy physical activity for 2 h before their examination. Age, gender, and smoking habits were ascertained through questionnaires. Three seated blood pressure (BP) measurements were obtained with a random-zero sphygmomanometer; the mean of the second and third readings was used for this report. Plasma total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides were determined using an enzymatic assay by Northwest Lipids Research Laboratory (Seattle, Washington) at all time periods; reanalysis at each examination of stored samples from the previous examination indicates that measures over the course of time were comparable. Low-density lipoprotein cholesterol (LDL-C) was derived by the Friedewald equation (31). Serum glucose was measured at year 0 using the hexokinase ultraviolet method by American Bio-Science Laboratories (Van Nuys, California), and at years 7, 10, and 15 using hexokinase coupled to glucose-6-phosphate dehydrogenase by Linco Research (St. Louis, Missouri). Body weight was measured with light clothing to the nearest 0.2 lb, body height without shoes was measured to the nearest 0.5 cm, and body mass index (BMI) was calculated from these measures (kg/m2).
Assessment of CAC.
Two computed tomography (CT) scans were obtained at year 15 for each participant using electron beam CT (Imatron C-150, GE Medical Systems, Milwaukee, Wisconsin [Chicago and Oakland centers]) or multidetector CT scanners (GE Lightspeed, GE Medical Systems [Birmingham center] or Volume Zoom, Siemans, Erlangen, Germany [Minneapolis center]) (32). For each scan, 40 consecutive images from the root of the aorta to the apex of the heart were obtained. Participants remained supine between scans taken 1 to 2 min apart.
Scans were read centrally by a trained reader who examined each participant’s scan independently of the other. The reader identified a region of interest for each potential focus of CAC, defined as 4 or more adjacent pixels (1.87 mm2) with a CT number >130 HU (field of view = 35 cm). Agatston scores (33) were adjusted for between-center differences using a standard calcium phantom scanned underneath each participant (32), and summed across the 4 major coronary arteries to compute a total calcium score. The presence of CAC was defined as having a positive, non-zero Agatston score, using the average of 2 scans. Given the young age of the subjects, each scan set with at least one non-zero score (n = 350, 11.5%) was reviewed by an expert investigator (R.D.), who was blinded to the scan scores to verify CAC presence. The agreement between scans was reasonable (kappa = 0.79, 95% confidence interval [CI] 0.75 to 0.83), with only 3.6% discordant.
Exclusions.
Participants who completed the year 15 examination (n = 3,672) were excluded from analyses if they were missing data on CAC (n = 629) or additionally risk factors at year 0 (n = 287) or year 15 (n = 322). Complete risk factor and CAC data were available for 2,433 participants from both examinations and 2,756 from the baseline examination. Participants who returned compared with those who did not return to the year 15 examination were older and at baseline smoked fewer cigarettes and had greater total and LDL cholesterol (data not shown). Participants were ineligible for CT scanning if pregnant (n = 18 tested positive in clinic) or if weight was above scanner limits (n = 44). Participants who had a CT scan (n = 3,043; 83% of year 15 participants) were older, had greater LDL-C levels but smoked fewer cigarettes, and had lower BMI values than those not scanned (data not shown). Compared with other race-gender groups, more white men who returned at year 15 had a CT scan (88.6% vs. 78.3% to 83.4%).
Statistical analyses.
Baseline characteristics by CAC presence were computed as means or percents and differences tested using t tests or chi-square statistics, respectively. Spearman correlation coefficients were used to assess associations between baseline and year 15 risk factor levels. Using logistic regression, odds ratios (ORs) and 95% CIs of CAC were estimated for continuous risk factor levels at: 1) baseline (year 0); 2) year 15; and 3) averaged during the 15-year period. Average risk factor levels were calculated using all nonmissing data from years 0, 2, 5, 7, 10, and 15 for cigarettes smoked, systolic BP, and BMI; from years 0, 5, 7, 10, and 15 for LDL-C and HDL-C; and from years 0, 7, 10, and 15 for glucose. Each of the 3 risk factor sets was examined using minimally adjusted models, which included age, race, gender, and field site, and multivariate-adjusted models, which additionally included all risk factors within the set. For each risk factor, ORs were calculated per approximate SD units at baseline to facilitate comparisons. All baseline and 15-year change (year 15 – year 0) in risk factor levels were entered simultaneously into a model adjusted also for age, race, gender, and site. Models were compared using a nonparametric test of correlated C-statistics, which are summary measures of each model’s sensitivity and specificity (34). A fifth model used variables indicating whether each continuous, baseline risk factor was greater than (or less than for HDL-C) optimal levels (LDL-C <130 mg/dl, HDL-C >40 mg/dl, systolic/diastolic BP <120/80 mm Hg, glucose <110 mg/dl) (35,36). Variables indicating field site were not statistically significant (at p < 0.05) in any model and are not presented in the tables. Finally, to assess effects of nonresponse bias, we used a response propensity approach, which used the probability of having a CT examination based on all 5,115 participants as weights to compute point estimates, and bootstrap methods to calculate 95% CI. All analyses were conducted with SAS versions 8.02 and 9.1 (SAS Institute Inc., Cary, North Carolina).
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Results
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Of the 3,043 participants with a CT scan, 258 or 9.6% had detectable CAC at year 15 (Table 1). CAC was more prevalent among men than women (15.0% vs. 5.1%) and white than African-American men (17.6% vs. 11.3%) but similar among African-American and white women (5%). CAC was twice as prevalent among adults ages 40 to 45 years than 33 to 39 years (13.3% vs. 5.5%). Approximately one-half of non-zero Agatston scores were <20, with one-half >20 (Table 1).
Very few participants at baseline had high levels of total cholesterol (4%,  200 mg/dl), LDL-C (6%, 130 mg/dl), BP (2%, 120/80 mm Hg), or serum glucose (<1%, 110 mg/dl) according to clinical guidelines, although 11% had a HDL-C level <40 mg/dl. In contrast, more than 20% had above optimal levels of LDL-C or BP, 34% were overweight or obese, and 25% smoked cigarettes (Fig. 1). By year 15, more participants had above-optimal levels of LDL-C (30%) and BP (35%), whereas 67% were overweight or obese, but fewer smoked cigarettes (19%) (Fig. 1). Participants with versus without CAC were older and at both years 0 and 15 smoked more cigarettes, had lower HDL-C, and had greater total cholesterol, LDL-C, triglycerides, systolic and diastolic BP, and glucose levels (Table 2). Participants with CAC had greater BMI values at year 0 but not at year 15. Few, if any, participants reported taking medications for hypertension or diabetes at baseline (<0.05%); lipid-lowering drug use was not collected but is presumed low too. Medication use at year 15 was still infrequent for lipids (2%), diabetes (2%), and BP (8%). Baseline and year 15 levels were correlated for most risk factors (r = 0.8 for BMI; r = 0.6 for LDL-C, HDL-C, smoking; r = 0.5 for systolic BP; p < 0.001), although less so for systolic BP among men and for glucose (r = 0.3, p < 0.001).
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Table 2 Baseline and Year 15 Characteristics (Mean or Percent) by CAC Status at Ages 33 to 45 Years in the CARDIA Study
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At baseline, more cigarettes smoked per day in addition to greater levels of LDL-C, systolic BP, and glucose were associated with having CAC 15 years later, after adjustment for each other, BMI, HDL-C, race, gender, and age (Table 3). In separate models adjusted for race, gender, and age, BMI (OR 1.28; 95% CI 1.10 to 1.49 per 5 kg/m2) and HDL-C (OR 0.80; 95% CI 0.70 to 0.90 per 10 mg/dl) were associated with CAC, even though they were not associated independently of other risk factors. Year 15 levels of LDL-C, systolic BP, and smoking were correlates of CAC in multivariate-adjusted models, with OR of similar magnitude, direction, and significance to baseline models (Table 3). Body mass index, HDL-C, and glucose level were not cross-sectional correlates independently of other risk factors, although glucose was associated with CAC in minimally adjusted models (OR 1.11; 95% CI 1.02 to 1.22 per 15 mg/dl). Using average 15-year levels in multivariate-adjusted models, the same risk factors as in baseline models were associated with CAC at year 15, although the OR was lower for number of cigarettes and higher for systolic BP (Table 3). The C-statistic was larger for models containing baseline versus year 15 risk factor levels (0.79 vs. 0.77; p = 0.019) but the same for models containing risk factors at baseline versus 15-year averages (0.79 vs. 0.79; p = 0.8262). In sensitivity analyses with CAC presence defined as an Agatston score >15, nearly identical ORs remained statistically significant, except for race and 15-year average glucose level (data not shown). C-statistics were greater than models using an Agatston score >0 for year 0 (C = 0.82; 95% CI 0.79 to 0.85) and 15-year average levels (C = 0.81; 95% CI 0.77 to 0.84), but comparisons among C-statistics remained the same. Analyses to assess the effects of nonresponse bias yielded similar results to those presented based on only the 2,433 participants who returned and had a CT scan at year 15 (data not shown).
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Table 3 ORs for Having CAC at Year 15 by Cardiovascular Risk Factors in 3 Multivariate Models*
Using Levels at Year 0, Year 15, and the Average Over 15 Years From the CARDIA Study (n = 2,433)
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In a model including baseline and 15-year changes in levels, ORs for baseline levels were of similar magnitude and significance as in models with baseline levels alone, although systolic BP was only borderline significant (Table 4, Model 1). In contrast, systolic BP was the only risk factor for which 15-year change was a significant CAC predictor. The C-statistic for this model (C = 0.80; 95% CI 0.77 to 0.83) was greater than for models containing year 0 (p = 0.03) or year 15 (p = 0.0004) risk factors alone but the same as the average 15-year model (p = 0.12). Results were similar when adjusted for self-reported use of BP, lipids, or diabetes medications at year 15 (Table 4, Model 2), although baseline systolic BP was no longer borderline significant. In sensitivity analyses redefining CAC presence as an Agatston score >15, baseline systolic BP was significant but 15-year change in systolic BP and race were no longer significant while other results did not change (data not shown). The C-statistic for this model (C = 0.83; 95% CI 0.80 to 0.86) was no longer significantly different from the year 0 model.
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Table 4 ORs for Having CAC at Year 15 by Cardiovascular Risk Factors in Multivariate Models*
Including Baseline and 15-Year Change in Levels (Model 1) and Adjusting for Medication Use at Year 15 (Model 2) in the CARDIA Study (n = 2,433)
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The OR for having CAC was significant for each aforementioned risk factor compared with below-optimal levels at baseline in minimally adjusted models (Table 5). In the multivariate-adjusted model, ORs of having CAC were 2-fold greater for smokers and participants with above-optimal LDL-C, and 3 times greater for above-optimal glucose levels. A BMI 25 kg/m2 and elevated BP ( 120/80 mm Hg) were associated with a 1.5 to 2 times greater risk.
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Table 5 ORs for Having CAC at Year 15 by Age, Race, Gender, and Presence of Above*
Optimal Levels of Cardiovascular Disease Risk Factors at Baseline in the CARDIA Study (n = 2,756)
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Discussion
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As expected, few young adults in the CARDIA study had high levels of established CVD risk factors at baseline using thresholds set for older adults. Yet, the relatively low levels at ages 18 to 30 years predicted CAC presence by ages 33 to 45 years as well as average levels during the 15-year period, and better than more adverse risk factor levels measured at ages 33 to 45 years. Baseline levels predicted CAC regardless of 15-year change in levels, but 15-year changes in levels were not related to CAC independently of baseline levels. The only exception was 15-year change in systolic BP, suggesting it provides additional information to baseline systolic BP about the odds of having CAC. Nevertheless, our data strongly indicate that early adult levels of modifiable risk factors predicted subsequent CAC. Moreover, young adults with above- versus below-optimal levels at baseline were 2 to 3 times as likely to have CAC. Coronary artery calcium was more prevalent in older versus younger participants, suggesting that plaque calcification may begin to accelerate by ages 40 to 45 years. Thus, greater efforts aimed at achieving and maintaining optimal risk factor levels as early as possible may be warranted to prevent or delay calcification of arterial plaque.
The prevalence of CAC in adults in the CARDIA study was similar among 39- to 45-year-old Army personnel (22,23) but lower than in 3 studies with comparable ages (13,37,38). Discrepancies with the latter studies may be explained by their small sample size (13,38), little ethnic diversity (13,38), and nonrepresentative samples of self-referred or physician-referred volunteers (37,38). Also, researchers in the CARDIA study used a larger minimum area threshold to identify calcified lesions (1.87 mm2 vs. 0.51 to 1.03 mm2) and 2 CT scans to reduce variability, which could explain differences with the latter 3 studies, especially in young populations (39,40). Year 15 CAC prevalence was lower than previously published estimates from a CARDIA pilot of 427 participants at year 10 (14), using a different CT reading center, protocol, and software than at year 15. When the year 10 scans were reread using identical methods by the year 15 reading center, CAC prevalence was greater at year 15 than at year 10 (11.7% and 5.5% in white and African-American men, 2.3% and 2.4% in white and African-American women).
The higher prevalence in men versus women was consistent with previous studies of widely varying ages (13,22–26). As in most other studies, we found that CAC was more prevalent in white versus African-American men (22,24,26–28,41), despite general findings of higher CVD morbidity and mortality among African Americans (42). Only 2 studies found equal or higher CAC prevalence in African Americans versus whites (43,44); both included older participants and had smaller samples with less geographic variation than in the CARDIA study. Importantly, our findings provide new evidence that, at least in men, differential trends by race in CAC prevalence begin early in adulthood. The lack of a significant race difference among women was probably the result of their lower CAC prevalence at this age, which is not surprising given that CVD develops later in women. Our findings in young men support the contention that race differences in CAC are not due to survival bias as has been suggested based on studies of older adults (24).
Only 2 other young adult studies reported cross-sectional relationships between CAC and established risk factors, and just 1 study examined them prospectively. Greater levels of LDL-C, triglycerides, systolic BP, and BMI were associated with CAC in 630 39- to 45-year-old male and female, multiethnic Army personnel, but LDL-C was the only independent CAC correlate (23). Greater systolic BP, BMI, and LDL-C, and lower HDL-C in 384 white men and women ages 20 to 34 years were associated with subsequent CAC at ages 29 to 37 years, but only diastolic BP, BMI, and the ratio of total cholesterol to HDL cholesterol predicted CAC independently of other risk factors (13). More risk factors may have been associated independently with CAC in the CARDIA study than in other studies because of the larger sample and greater power. The longer follow-up in the CARDIA study also may explain differences, particularly for smoking, given the long incubation period for CVD. Unlike previous studies, BMI was not independently associated with CAC in the CARDIA study. High BMI values are associated with greater noise in CT scans that may be mistakenly read as CAC (39). The CARDIA study scanning and reading protocols were designed to reduce noise effects, but other studies may have failed to do so. We observed an association with baseline BMI before adjusting for other risk factors, suggesting that BMI may influence subsequent CAC through its effect on other risk factors.
Our finding that 15-year change in risk factor levels did not predict CAC independently of baseline levels may be explained by several factors. Secular declines in risk factors, particularly smoking and LDL-C, may have diminished CAC and year 15 risk factor associations even though levels in the CARDIA study worsened in part because of aging. Alternatively, baseline levels may have captured long-term exposure, including the years before baseline, better than year 15 levels, as suggested by the lack of difference in C-statistics for baseline versus average 15-year levels but a higher C-statistic for average 15-year versus year 15 levels. Systolic BP did not track as well as other risk factors among men and may explain why both baseline and 15-year change in systolic BP levels were predictive of CAC. In addition, exposure duration to the higher year 15 level may have been insufficient to affect CAC levels. Treatment of risk factors during follow-up may have masked an association with year 15 levels, but we found similar results after adjustment for medication use at year 15.
Study limitations.
The CARDIA study, with comparable measures over a relatively long follow-up, has many strengths. Its large, ethnically and socioeconomically diverse sample increases the generalizability of our findings. However, those participants who had versus those who did not have a CT scan were at baseline older, had a higher LDL-C but a lower BMI, and were less likely to smoke cigarettes. Thus, CAC prevalence estimates could have been biased both upward and downward because of attrition, but the effects of nonresponse bias on risk factor associations appeared to be minimal. This study used a conservative CT reading protocol, which may have underestimated CAC. Additionally, participants with very high body weight (>300 to 330 lbs) were ineligible for CT; this BMI truncation is also conservative and may explain why year 15 BMI was not a correlate of CAC. Finally, the low prevalence of CAC, especially among women, decreased statistical power to detect associations, and risk factors may be more strongly related to CAC with longer follow-up.
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Conclusions
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Risk factor levels in 18- to 30-year-old young adults predicted calcification of plaque in coronary arteries at ages 33 to 45 years better than concurrent levels, equally well as average 15-year levels, and regardless of 15-year change in levels. Thus, early adult levels of modifiable CVD risk factors, albeit relatively low, may be more informative than generally recognized by young adults and their clinicians. Young adults with above-optimal risk factor levels at baseline, who were 2 to 3 times as likely to have CAC, and those with family history of CVD, which predicted CAC independently of established risk factors in the CARDIA study (45), could be targeted for preventive efforts. Waiting until modifiable risk factor levels reach clinical guideline thresholds to prevent CVD may not be desirable because plaque calcification is already underway and appears to be accelerating by ages 40 to 45 years. Earlier risk assessment and efforts to encourage young adults to achieve and maintain optimal levels may be needed to prevent or delay coronary calcification, which has been shown to predict subsequent coronary heart disease (16–21).
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Footnotes
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The CARDIA study is supported by the National Heart, Lung, and Blood Institute (N01-HC-95095, N01-HC-48047-48050, and N01-HC-05187).
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Abstract
Methods
40 mg/dl; systolic/diastolic blood pressure