American Journal of Epidemiology Advance Access originally published online on August 2, 2005
American Journal of Epidemiology 2005 162(5):421-429; doi:10.1093/aje/kwi228
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ORIGINAL CONTRIBUTIONS |
Coronary Artery Calcium Score and Coronary Heart Disease Events in a Large Cohort of Asymptomatic Men and Women
1 Centers for Integrated Health Research, The Cooper Institute, Dallas, TX
2 The Cooper Clinic, Dallas, TX
3 Institute for Exercise and Environmental Medicine, Presbyterian Hospital, Dallas, TX
4 University of Texas Southwestern Medical Center, Dallas, TX
Correspondence to Dr. Michael J. LaMonte, The Cooper Institute, 12330 Preston Road, Dallas, TX 75230 (e-mail: mlamonte{at}cooperinst.org).
Received for publication July 5, 2004. Accepted for publication April 8, 2005.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Coronary artery calcium (CAC), a measure of subclinical coronary heart disease (CHD), may be useful in identifying asymptomatic persons at risk of CHD events. The current study included 10,746 adults who were 22–96 years of age, were free of known CHD, and had their CAC quantified by electron-beam tomography at baseline as part of a preventive medical examination at the Cooper Clinic (Dallas, Texas) during 1995–2000. During a mean follow-up of 3.5 years, 81 hard events (CHD death, nonfatal myocardial infarction) and 287 total events (hard events plus coronary revascularization) occurred. Age-adjusted rates (per 1,000 person-years) of hard events were computed according to four CAC categories: no detectable CAC and incremental sex-specific thirds of detectable CAC; these rates were, respectively, 0.4, 1.5, 4.8, and 8.7 (trend p < 0.0001) for men and 0.7, 2.3, 3.1, and 6.3 (trend p = 0.02) for women. CAC levels also were positively associated with rates of total CHD events for women and men (trend p < 0.0001 each). The association between CAC and CHD events remained significant after adjustment for CHD risk factors. CAC was associated with CHD events in persons with no baseline CHD risk factors and in younger (aged <40 years) and older (aged >65 years) study participants. These findings show that CAC is associated with an increased risk of CHD events in asymptomatic women and men.
arteries; calcium; cohort studies; coronary disease; primary prevention
Abbreviations: CAC, coronary artery calcium; CHD, coronary heart disease; EBT, electron-beam tomography
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Atherosclerotic coronary heart disease (CHD) continues to exact a large economic and public health toll as the leading cause of death in men and women (1
). CHD has a lengthy incubation period, during which biologic risk factors interact with genetic and environmental influences to initiate and promote the development of atherosclerotic plaque (2, 3). Once established, CHD can exist in a subclinical state characterized by an absence of clinical signs and symptoms. Sudden death or myocardial infarction is often the initial manifestation of CHD (4). A substantial number of first myocardial infarctions occur among individuals with normal or only slightly elevated CHD risk factors (5, 6). Therefore, additional methods are needed to identify asymptomatic individuals with subclinical disease who would benefit from intensive primary prevention therapy (7, 8).
Coronary artery calcium (CAC) is present in only atherosclerotic arteries (9–12) and is a measure of subclinical CHD (8, 9). Electron-beam tomography (EBT) is sensitive enough to detect and quantify small amounts of CAC (9). EBT-derived CAC scores are directly associated with the number and severity of diseased vessels defined by quantitative coronary angiography (13–17). Although the amount of CAC is related to the burden of atherosclerotic plaque, the association between CAC and incident CHD among asymptomatic individuals is less well understood. A positive association between CAC and CHD-related events has been reported (18–26). However, studies of CAC as a predictor of CHD events have been conducted mostly among men, older individuals, or high-risk populations. Experts have concluded that a limited understanding exists regarding the utility of CAC to identify asymptomatic individuals who have an elevated CHD risk and that data are needed from large prospective studies of asymptomatic men and women across a broad age range to more fully assess the clinical usefulness of CAC evaluations (27). To address this paucity of data, we examined the association between CAC and incident CHD in a large cohort of asymptomatic adults free of known CHD at baseline. We also determined whether the association between CAC and incident CHD was independent of prevalent CHD risk factors.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Between June 1995 and May 2000, 16,097 men and women aged 22–96 years underwent EBT scanning at the Cooper Clinic in Dallas, Texas, as part of a preventive health examination (
45 percent) or because of physician or self-referral (55 percent). The cohort and clinic examination have been described in detail elsewhere (28). Demographic information and history of smoking, diabetes, hypertension, and hypercholesterolemia were obtained by using a standardized medical questionnaire. We examined the relation between self-reported and measured risk factors in 3,619 participants for whom such data were available (data not shown). On average, levels of CHD risk factors (e.g., blood pressure values, lipid values, glucose values) were significantly higher (p < 0.0001) and met clinical thresholds for individuals who reported having the related condition than for those who reported absence of the condition. The distribution of prevalent hypercholesterolemia, hypertension, and diabetes in our population was similar to that observed in other large, population-based studies of CHD (29) and in studies on CAC and CHD (21, 25, 30). We have previously shown a sensitivity of 98 percent and a specificity of 99 percent for self-reported hypertension (31). There is no reason to believe that other CHD risk factors would not be reported with a similar level of precision in this well-educated study population. These self-reported data are valid indicators of the overall coronary risk factor status in our study population. Participants provided written informed consent, and the Cooper Institute Institutional Review Board approved the study protocol annually.
CAC measurement
An EBT scanner (GE Imatron, San Francisco, California) was used to obtain 3-mm-thick slices with 2-mm table (3 x 2) increments during a breath-holding protocol (28). CAC scores were calculated according to the Agatston method (32).
Endpoint ascertainment
The primary endpoint was hard CHD events (nonfatal myocardial infarction or death from coronary causes). A secondary endpoint was all CHD events defined as hard events plus coronary revascularization (coronary artery bypass graft, percutaneous coronary intervention). Deaths were identified by using the National Death Index. CHD mortality was defined according to International Classification of Disease, Ninth Revision, codes 410.0–414.0. Nonfatal myocardial infarction and revascularization history were obtained from a mail-back questionnaire in which respondents were asked whether they had had a myocardial infarction or revascularization procedure since their EBT scan and the date on which the event occurred. Of the 16,097 individuals who were sent a questionnaire, 11,201 returned them, 450 were excluded because of a history of prior CHD events or stroke, and five were excluded because of missing data, resulting in a final analytic cohort of 10,746 individuals who were free of known CHD.
Statistical analyses
Because the distribution of CAC was skewed, log (Ln)-transformed scores were used for analysis, and median values with interquartile ranges were used for reporting. Student's t tests and the Wilcoxon test were used to compare continuous variables. Categorical variables were compared by using chi-square tests. Person-time for each participant was calculated from the date of the EBT scanning to either the date of death, the date of a reported event, or December 30, 2001. Incidence rates were computed as the number of cases divided by person-time follow-up in the following CAC categories: no detectable CAC and sex-specific CAC thirds (men: 1–38, 39–249, 
250; women: 1–16, 17–112, 113). Hazard ratios and 95 percent confidence intervals were computed with Cox regression (33) to quantify the strength of association between CAC and incident CHD. The proportional hazards assumption was confirmed with log-cumulative survival plots. Multivariable regression models included CAC, age (years), current smoker (yes/no), diabetes (yes/no), hypercholesterolemia (yes/no), and hypertension (yes/no). Tests of linear trends in CHD event rates across categories of CAC were conducted by ordinal scoring. Stratified analyses were conducted for sex-specific associations between CAC and CHD events according to age (<40, 40–60, >60 years) and number of baseline CHD risk factors (0, 1, or 2). A priori hypotheses related to sex differences in the association between CAC and CHD events were not tested. Two-tailed p values of <0.05 were considered statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The overall response rate to the follow-up questionnaire was 70 percent. Baseline variables were not substantially different between nonrespondents and the group of respondents and decedents, respectively: percentage of men (65 percent vs. 64 percent), age (52 years vs. 54 years), median CAC (0 vs. 1), current smoker (26 percent vs. 28 percent), high cholesterol (19 percent vs. 19 percent), high blood pressure (13 percent vs. 12 percent), and diabetes (4 percent vs. 3 percent). We therefore believe that the responders and decedents were representative of the total population who underwent EBT scanning.
The majority of study participants were men (64 percent) and were White (>97 percent); mean age was 53.8 (standard deviation, 9.9) years. Men and women who had had an event were older and had higher (p < 0.05) CAC scores and conventional risk factor values than same-sex, event-free individuals (table 1). The proportion of coronary events classified as CHD death or nonfatal myocardial infarction was higher (p = 0.08) among women (39 percent) than among men (26 percent). The prevalence of zero CAC was, respectively, 2.1 percent and 40.7 percent among men with and without coronary events (p < 0.01) and 20.4 percent and 71.7 percent among women with and without such events (p < 0.01). With the exception of smoking, all CHD risk factors were directly associated (p < 0.0001) with CAC scores for men and women (table 2).
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During a mean follow-up of 3.5 (standard deviation, 1.4) years and 37,326 person-years of exposure, 287 CHD events occurred (19 CHD deaths, 62 nonfatal myocardial infarctions, 206 revascularizations). We were able to adjudicate 99 of the CHD events using medical record review by investigators blinded to the EBT results. A total of 95 percent of events were verified as reported. Of the events reported incorrectly, three were cardiac catheterizations without revascularization and two were peripheral revascularization procedures. Of the adjudicated events, all of the CHD deaths or myocardial infarctions were confirmed.
We examined the association between CAC and coronary events across the continuous distribution of log-transformed calcium scores. Separate age-adjusted models were constructed for men and women with and without zero calcium scores included in the distribution. CAC was directly associated (p < 0.001) with CHD events in each model for men and women. In the model that included zero scores, the hazard ratios associated with a one-unit change in log CAC for all events and hard events were, respectively, 1.89 (95 percent confidence interval: 1.74, 2.1) and 1.59 (95 percent confidence interval: 1.39, 1.83) for men and 1.51 (95 percent confidence interval: 1.33, 1.72) and 1.32 (95 percent confidence interval: 1.08, 1.59) for women. Similar results were seen for men and women when those with no detectable CAC were excluded from the CAC distribution (data not shown).
CHD event rates according to CAC levels are shown in figure 1. A calcium score of zero is the first category shown on both graphs. The sex-specific CAC tertiles that comprise the second through fourth categories shown on the graphs were considerably different between men (1–38, 39–249, 250) and women (1–16, 17–112, 113). Nevertheless, we noted a steep, direct gradient in the age-adjusted rates of hard CHD events across CAC levels for men (trend p < 0.0001) and women (trend p = 0.02). The association between CAC and rates of all CHD events also was significant for men and women (trend p < 0.0001 each).
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The hazard ratio for CHD events according to CAC levels are shown for men and women in table 3. More women (70 percent) than men (40 percent) had CAC scores of zero (p < 0.0001). A total of 238 CHD events (62 hard events) occurred in men over 23,290 person-years of exposure and 49 events (19 hard events) occurred in women over 14,036 person-years of exposure. The age-adjusted hazard ratio for CHD events rose significantly (trend p < 0.0001) with incremental levels of CAC in men and women. Adjustment for conventional CHD risk factors had little effect on the pattern or strength of association between CAC and incident CHD events in either sex.
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We also examined the association between CAC and CHD events stratified by categories of age and number of prevalent CHD risk factors at baseline. The number of events was insufficient to allow cross-tabulation of the modifying variables with sex-specific CAC categories. Therefore, we examined the age- and sex-adjusted association between CAC and CHD events according to CAC cutpoints that have been reported as clinically relevant: 0, >0,
100, and 400 (27, 28, 34). These cutpoints were applied to the entire cohort distribution of CAC for this analysis. The prevalence of 0, 1, and 2 risk factors, respectively, was 54.4 percent, 32.9 percent, and 12.7 percent in men and 55.7 percent, 32.9 percent, and 11.4 percent in women.
The association between CAC and coronary events according to the number of baseline CHD risk factors is shown in table 4. The referent group is individuals with no risk factors and a calcium score of zero (n = 3,263). Significant increases in the age- and sex-adjusted risk of CHD events were observed among individuals whose CAC score was >0, 100, and 400 in all risk factor categories. Except among those with multiple coexisting risk factors, the risk of incident coronary events was not significantly elevated among individuals whose CAC was zero.
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The association between CAC and CHD stratified on age is shown in table 5. Sex-adjusted event rates increased with age among individuals whose CAC score was zero, but CHD rates were considerably higher among individuals with any calcium (CAC >0) and with CAC scores of
100 and 400 within each stratum of age. Even individuals aged <40 years whose CAC scores were >0 and 100 had a higher rate of CHD events compared with their counterparts whose CAC score was zero.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The results reported here show a strong, graded association between CAC scores and incident CHD events among asymptomatic individuals free of known CHD at the time of EBT scanning. The findings were consistent for men and women and held after adjustment for age and conventional CHD risk factors. CAC was associated with CHD events in individuals with and without baseline CHD risk factors and in young and older study participants. Strengths of this study are the use of CAC scores based on standardized EBT methodology, a large sample of participants free of known CHD at baseline and with extensive follow-up, a relatively large number of hard CHD events (n = 81), and a large enough sample of women to permit meaningful analyses.
EBT-derived CAC scores provide a sensitive, noninvasive method for quantifying the presence and amount of subclinical CHD, and it has been suggested as a means of identifying asymptomatic but high-risk individuals who could benefit from aggressive primary prevention. Because of differences in the distribution of CAC by age and sex (9, 28, 35), sex- and age-specific data are required to adequately examine the clinical usefulness of EBT scanning in identifying individuals with a high risk of future CHD events. Experts have concluded that there was insufficient evidence of a prospective association between CAC and coronary events to fully understand the prognostic application of EBT scanning, particularly for women, asymptomatic persons, and younger individuals (7, 27). Our findings of a direct association between CAC and incident CHD extends previous observations made in intermediate- and high-risk populations comprised mostly of older men (19, 22–24, 26) to low-risk, CHD-free men and women across a broad age range.
Our study design and primary findings are similar to those of two other prospective investigations that reported sex-specific data (21, 25) and one that reported sex-adjusted data (30) on CAC and CHD events in asymptomatic individuals. Length of follow-up (
3.5 years), CHD endpoints, EBT methods of quantifying CAC, proportion of men (70 percent) and women (30 percent), average age at baseline (53 years), and distribution of self-reported CHD risk factors reported in these studies were comparable to those in our study. Because the sample-specific categories of CAC and the associated number of events differed among studies, a precise comparison of the strength of association between CAC and CHD events between studies is not possible. In our study, as well as in the studies of Arad et al. (21) and Kondos et al. (25), a significantly higher risk of incident coronary events with higher CAC scores was observed for men and women, even after adjustment for age and other CHD risk factors. Because more hard events (coronary death and nonfatal myocardial infarction) occurred in our study (62 men, 19 women) compared with those reported by Wong et al. (n = 6), Arad et al. (n = 18), and Kondos et al. (52 men, six women) (21, 25, 30), our data provide a more stable estimate of the association between CAC and hard CHD events, particularly for women.
In this regard, our findings are similar to those in a recent study by Greenland et al. (26), who reported a direct association between EBT-derived CAC and hard CHD events (n = 84) in 1,461 asymptomatic individuals (90 percent men) with an intermediate CHD risk status at baseline who were followed for a median of 7 years. However, interpretation of these data is limited because the investigators did not address the influence of age and sex on associations between CAC and coronary events. Our observations of increased CHD risk across the distribution of CAC is consistent with reported data showing increases in CHD events in asymptomatic individuals with relatively small amounts of CAC (CAC score: 0–4) (20) as well as in asymptomatic individuals with extreme CAC elevations (>1,000) (24). Taken together, previously reported data (21, 25, 30) and the data reported here indicate that CAC is a significant predictor of fatal and nonfatal CHD events among men and women who were asymptomatic and at generally low risk at the time of EBT scanning. Whether therapeutic intervention guided by CAC scores will influence clinical event rates remains an important focus of research.
The majority of studies on CAC and incident CHD have reported age-adjusted rather than age-specific data to account for the variation in CAC distributions and CHD event rates due to age (18–25). Furthermore, the age ranges in these studies have not included a large proportion of young individuals, among whom the prognostic value of EBT-derived CAC is debated (27). Our study included a broad age range—about 20 percent of participants were less than 40 years of age and approximately the same proportion were older than 65 years of age—which allowed us to examine the association between CAC and CHD events in younger and older individuals. The presence of CAC was associated with higher event rates within each age stratum, and a graded increase in event rates was observed between CAC scores of 100 and 400 for participants aged 40–65 years and >65 years. Even among younger asymptomatic individuals, CHD rates were higher for those whose CAC scores were >0 or 100 compared with zero (table 5). The absence of hard events among young individuals with a CAC score of 100 and of any events among young individuals with a CAC score of 400 reflects the relative infrequency of CAC scores of >100 (n = 10) or >400 (n = 2) in younger individuals. Our data suggest that EBT scanning may identify relevant CAC levels for predicting CHD risk in younger populations; however, because the number of events was small in this subgroup, the data must be interpreted cautiously. Additional data are needed from younger populations with diverse demographic and clinical characteristics to understand the usefulness of CAC for coronary risk assessment in younger individuals.
Other studies (21, 25, 30, 36) on the association between EBT-derived CAC and incident CHD events have been criticized for use of mass media and self-referral methods of participant recruitment, inclusion of coronary revascularization as a study endpoint, short follow-up periods, and use of self-reported CHD risk factors (26, 27, 37–39). Therefore, it has been suggested that definitive conclusions as to the prognostic value of EBT-derived CAC cannot be drawn from extant data (27). Media advertisements were not a primary method of recruitment in our study. We accept that physician-referred participants would likely receive preventive therapy based on their EBT results. However, this would bias associations between CAC and incident events toward the null and may explain the lower risk of events among individuals with multiple risk factors and CAC scores of 400 shown in table 4. Self-referred participants may reflect a more health-conscious subgroup, but this too would weaken rather than strengthen the prospective association between CAC and CHD events seen in this study.
The association between CAC and coronary death or nonfatal myocardial infarction is important and indicates that coronary calcium identifies those at risk of significant clinical manifestations of CHD. A strength of our study is the large number of hard endpoints that were not driven by diagnostic cardiac catheterization. The association between CAC and coronary revascularization is rightly criticized because the presence of CAC may increase referral for diagnostic catheterizations and revascularization procedures. However, the association between CAC and coronary revascularization strengthens rather than weakens the clinical relevance of EBT-derived CAC scores. Use of this noninvasive method for identifying asymptomatic individuals with advanced subclinical coronary atherosclerosis may enhance selection of additional testing and initiation of aggressive primary prevention therapy to arrest and stabilize disease progression, thereby obviating the need for invasive intervention through percutaneous coronary intervention or coronary artery bypass graft.
Although the use of self-reported risk factors is not ideal in research settings, they have been shown to provide a valid assessment of study participants' overall risk profiles (40), particularly in well-educated populations (41). With the exception of a slightly lower prevalence of smoking, the distribution of self-reported risk factors in our population was similar to that reported in other epidemiologic studies of cardiovascular disease (29) and in previous studies of CAC and CHD events (21, 25, 30). Therefore, we believe that the self-reported data provide a reasonable indication of the overall coronary risk profile of our sample population. Statistical adjustment for these risk factors did not materially alter the strength or pattern of association between CAC and CHD events in our population. It is possible that adjustment for CHD risk factors did not greatly attenuate the CAC association with CHD because of residual confounding by self-reported risk factor data that were only moderately valid. However, we have previously reported a reasonably high level of sensitivity and specificity for self-reported chronic disease status in the overall population from which the current cohort was drawn (31), which reduces the likelihood of residual confounding as the principal explanation.
Another possibility is that, while conventional risk factors clearly initiate and promote atherosclerotic plaque development (3, 42), the presence of subclinical disease (e.g., detectable CAC) may account for a greater variation in event occurrence than the disease antecedents (e.g., CHD risk factors). Our observations that higher levels of detectable CAC were associated with increased risk of CHD-related events within strata of 0, 1, and 2 self-reported prevalent CHD risk factors is suggestive of additional benefit from CAC for risk assessment beyond conventional methods (table 4). However, we agree with others (26, 39) that it is necessary to use measured risk factor data when comparing the prognostic value of CAC scores with established clinical methods of individual risk assessment, such as the Framingham risk score (26). Because doing so was not the intention of our study, the use of self-reported risk factor data does not substantially weaken the internal validity of our results. The consistency in the pattern of association between CAC and CHD events seen in our study and others (20, 21, 25, 30, 36) cannot be dismissed on the basis of the aforementioned arguments.
Length of follow-up affects duration of exposure to disease antecedents and to precipitators of clinically manifest disease. Because the time course from subclinical disease to clinical events is highly variable (2, 3), it is important to have information on the association between CAC and incident CHD from studies with both short and long follow-up periods. The length of follow-up in our study is comparable to that of most studies of CAC and CHD events. We agree that studies with precise measures of CHD risk factors, longer follow-up periods, more diverse populations, and additional methods of quantifying subclinical coronary disease are required to fully examine the prognostic utility of EBT-derived CAC for use in global risk assessment. The Multi-Ethnic Study of Atherosclerosis (MESA) study (43) will address many of these issues but will not be completed until about 2008. Until then, continued analysis and reporting of data from large prospective epidemiologic studies such as ours and others (20, 21, 25, 26, 30, 36) will enhance current understanding of CAC as a predictor of CHD events and will provide the necessary background to interpret the findings of studies such as MESA.
Limitations to this study should be considered. Because of the widespread geographic distribution of patients evaluated at the Cooper Clinic, we were unable to verify all reported CHD events. However, of the 99 CHD events adjudicated, 95 percent were confirmed as reported, including 100 percent of the CHD deaths and myocardial infarctions. It is unlikely that adjudication of the remaining events would have materially changed our results. The study population is primarily non-Hispanic Whites of middle-to-upper socioeconomic status, and our observations require confirmation in more diverse populations. Quantification of CAC scores was not blinded to participant clinical information. However, computer-based CAC calculation was confirmed by a radiologist, which reduces our concern over scoring bias.
In conclusion, a direct association between CAC and incident CHD events was observed in an asymptomatic population of men and women with a broad age range. CAC was a significant predictor of both hard and all CHD events, and adjustment for conventional CHD risk factors did not change the strength or pattern of the observed association. The presence of CAC was associated with increased CHD event rates among study participants who were less than 40 years of age and older than age 65 years, and in participants with no baseline CHD risk factors. EBT-derived CAC may be a robust, noninvasive method of identifying asymptomatic individuals with an elevated risk of coronary events for whom intensive primary prevention therapy may be indicated.
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ACKNOWLEDGMENTS |
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This work was supported by National Institutes of Health grants AG06945 and HL62508.
The authors thank Dr. Kenneth H. Cooper for establishing the Aerobics Center Longitudinal Study, the Cooper Clinic physicians and technicians for collecting the baseline data, Dr. James Kampert for his statistical advice, Drs. Darren McGuire and Thomas Kimball for their consultation about the study, and Melba Morrow for editorial assistance.
Conflict of interest: none declared.
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