In this study, we establish normal values and distributions of CAC in a community-based sample of healthy white men and women free of CLINCVD and any CHD risk factors. We further establish the absolute and relative distribution of CAC in a larger cohort of subjects free of CLINCVD and in subjects at intermediate risk for cardiovascular events.
We found similar age and sex associations of CAC that in all three cohorts. There was a remarkable consistency in the data in that the prevalence of CAC, the mean Agatston Score, the fraction of subjects with an Agatston Score >100 or >400, and the nominal percentiles were always lowest in the healthy reference group and highest in subjects at intermediate FRS.
We further demonstrate that using the 90th percentile of the healthy reference sample as a relative cutpoint, we determined that 15.2% of men, 13.7% of women, and 14.4% of total subjects within a community-based white sample free of CLINCVD have substantially elevated CAC. Thus, by applying the relative cutpoints from the healthy reference sample, we identified almost 50% more an additional 52%, 37%, and 44% of subjects with elevated CAC as compared to using cutpoints from the overall cohort at risk.
In addition, we formally compared the agreement between absolute and relative cutpoints for participants having moderately (Agatston Score >100 vs. 75th percentile) or severely (Agatston Score >400 vs. 90th percentile) elevated CAC. We determined that the disagreement is modest for the overall cohort, 12.6% and 17.6% of participants for Agatston Score >400 vs. 90th percentile and Agatston Score >100 vs. 75th percentile; respectively, but is driven by the fact that 57% of subjects have no CAC. However, in the 43% of subjects with evidence of any CAC, the population of greatest interest, the disagreement among subjects with any CAC was substantial and occurred in 29.3% and 40.9% of participants for Agatston Score >400 vs. 90th percentile and Agatston Score >100 vs. 75th percentile, respectively.
Similar findings were observed in the subset of subjects at intermediate CHD risk, a subset in which CAC has been recommended to improve risk stratification9
. The discrepancy between relative and absolute cutpoints was attenuated in women at intermediate CHD risk by the FRS (13.2 vs. 2%; respectively). It appears that among participants at intermediate CHD risk, fewer individuals are further identified at risk when using absolute CAC values rather than percentiles. Thus, the assessment of the distribution of CAC using percentiles may yield additional information compared with absolute values, with the potential to further improve prediction of CHD events in individuals at intermediate FHS risk.
In contrast to previous publications, we defined “normal CAC” by assessing the distribution of CAC in a cohort free of CLINCVD and risk factors. The distributions of CAC using both relative and absolute cutpoints as they relate to age- and sex-based differences in our community-based sample of white men and women free of CLINCVD were very similar to those described for the white subset of the Multiethnic Study of Atherosclerosis8
and similar to data from a self-referred cohort published earlier by Hoff10
. However, the Agatston Score for age- and sex-specific percentiles is often different, i.e. the 90th
percentile for men age 45-54 in these three studies varies, with the Agatston Score cutpoint being 166, 110, and 154, respectively. These cutpoint differences may be related in part to differences in sample size and CT technology used (Electron Beam Tomography by Hoff vs. both Electron Beam Tomography and MDCT in the Multiethnic Study of Atherosclerosis vs. MDCT in the FHS, respectively).
Age and sex are the dominant predictors for the prevalence and extent of CAC. However, the totality of evidence from prior studies has assumed that normality is based upon pre- specified absolute thresholds (i.e. 0>, >100, >400 Agatston Score). Indeed, because data are extremely limited regarding relative thresholds, these absolute thresholds are assumed in the most recent American Heart Association guidelines.9,11
The concept of relative cutpoints derived from a healthy reference sample, defined similarly to our criteria, was introduced in a recent report from Multiethnic Study of Atherosclerosis 8
. We have extended this concept and applied these cutpoints to our overall community- based cohort free of CLINCVD. Initial data suggest that while percentile ranks may enable improved risk stratification, absolute CAC scores are superior in predicting the probability of obstructive coronary artery disease12
Our findings regarding substantial differences between absolute and relative cutpoints and findings from Multiethnic Study of Atherosclerosis suggest that normal values of CAC should be more appropriately defined using age- and sex-specific strata and should be derived from a subset free of any CHD risk factors. Using such values as the reference for normal cutpoints may maximize the diagnostic yield from CAC beyond and above traditional risk factors. While our data suggest that relative CAC cutpoints may be more appropriately describe risk in women and younger individuals, confirmation through prospective outcome studies is needed.
The derivation of normal values for CAC based upon hard cardiovascular endpoints requires prospective trials of tens of thousands of men and women, so we are currently limited to use of cross-sectional community-based data to define normal values for CAC. Such definitions are prerequisites for defining any preventive or therapeutic measures to improve primary prevention of CHD related mortality based on CAC.
While some have advocated use of MDCT testing for CAC screening in all
middle-aged men and women 13
, the most recent consensus statements recommend that CAC screening be considered in men and women with intermediate FRS9
. However, because relatively few individuals, particularly women, are in this group, further research is warranted to define the intermediate risk populations to be considered for screening. Overall, a definitive answer as to which method should be applied in clinical practice cannot be provided based upon the available data.
Our study was conducted in men and women who were white and the distributions may not be extrapolated to other racial or ethnic groups. In addition, the healthy reference subset was relatively small and especially the data in elderly women and women at high FRS may be variable. Also, longitudinal follow-up data on the incidence of cardiovascular events in subjects with MDCT scans are not available at this time. The CT scanning was performed on an eight-slice MDCT scanner and thus, the exact percentiles may vary with those obtained using other CT scanners.