Reliability of CAC measurements is a critically important requisite for EBCT if it is to serve as a screening examination for CAD. To perform effectively, EBCT CAC measurements must be accurate and reproducible. This is particularly important with regard to performing disease progression assessments on longitudinal studies. Although the interobserver and intraobserver variability of CAC measurements are excellent (17,42,43), interstudy variability has been problematic, particularly in consistently identifying smaller foci of calcium (44). This variability largely stems from slice misregistration and has been addressed by increasing the minimum threshold area, slice thickness (45), or by averaging computed tomography (CT) density measurements of lesions (rather than the peak) to calculate calcium scores (46). Callister et al. (47) have also implemented postprocessing data manipulation to improve interstudy reproducibility, with good results. Similarly, averaging scores from duplicate scans has improved reproducibility, and this is now becoming common practice at many sites. Shields et al. (48) reported a reliability of 0.99 in 50 subjects who underwent dual scanning (49). Hernigou et al. (43) reported an interexamination error rate of 7.2% (49).
Because CAC is an indisputable marker for CAD, it would appear logical that the identification of coronary calcification would be clinically valuable in measuring the relative severity of CAD. This has been the basis of a host of investigations that have attempted to establish the reliability, accuracy, and prognostic value of CAC measurements (1,2,5–7,15,17,18,20–22,30–33, 36,38,50–55). Studies have reported strong correlations between CAC EBCT measurements and both histologic examination and intravascular sonographic plaque assessments (32,34,38,40,56,57). Rumberger et al. (34) (and others) have showed a strong correlation between EBCT total heart CAC and actual histologic calcium measurements (r = 0.93, p < 0.001) (34). Similarly, there also was a strong correlation between individual artery CAC area measurements and plaque assessments by histology (r = 0.90, p < 0.001) (34). CAC measurements, however, underestimate total atherosclerotic plaque area by 80%, reflecting limited calcium deposition in plaques despite potentially significant or diffuse atherosclerosis. Rumberger et al. (34) showed that calcium was present in plaques only when lesion threshold areas measured 5 to 10 mm2 per 3-mm segment (34). Correspondingly, increases in atherosclerotic plaque area invariably were associated with greater amounts of CAC (34). These results are similar to that found by others (32,33,58). Kajinami et al. (38) identified specific morphologic features of foci of CAC that were more likely predictive of associated coronary stenoses. They reported that large and diffuse deposits of calcium were more likely associated with significant areas of narrowing on angiography on a site-by-site basis (38).
Numerous studies have shown repeatedly that heavy CAC burdens, particularly when distributed over multiple vessels, are associated with higher associations of significant coronary narrowing, and a corresponding, relationship between CAC measurements and angiography results, and patient outcomes. (1,3,15,31,32,36,37,40, 41,50,59–64) Mautner et al. (32) examined 1,298 segments from 50 heart specimens and observed that 93% of arteries with greater than 75% stenosis were associated with CAC. Conversely, only l4% of arteries with stenosis less than 25% were associated with calcium (2). Numerous studies have attempted to correlate EBCT coronary calcium measurements with angiographic findings and found consistently high sensitivities for identifying coronary arteriosclerosis, ranging from 80% to 100% (17,18, 20–22,30,36,38,40,44,53,57,66). Additionally, compared with exercise testing, CAC measurement, compared with angiography, was as predictive to the presence of luminal narrowing as was ECG and thallium scintigraphy (sensitivities: 73% vs. 74% vs. 78%, respectively; specificities: 83% vs. 72% vs. 83%, respectively) (5).
The specificity of EBCT CAC measurements for CAD, which depend largely on the calcium threshold, patient age, and angiographic disease severity criteria used to determine significance, are generally lower than the reported sensitivities. Review of the literature shows specificities ranging from 31% to 100%, with no gender differences noted between men and women (15,17,18, 20–22,30,36,38,40,44,53,57,65,66).
Although CAC reflects atherosclerosis, and increases in calcium quantity are related to a higher likelihood of significant luminal narrowing, the presence of coronary calcium regardless of extent cannot predict the actual severity or location of stenoses (67). Conversely, there is strong and convincing evidence that the absence of CAC, although not excluding the presence of coronary atherosclerotic disease, virtually excludes the likelihood of significant coronary arterial stenosis. This observation has been substantiated by numerous investigations in which negative predictive values of zero CAC measurements (compared with angiography and autopsy) are consistently very high (84% to 100%) (15,17,18,30,35,39, 52,62,68–70). These data have great potential clinical value in evaluating patients with a low likelihood for CAD, or those with atypical chest pain (71). Similarly, negative results may preclude the need for further diagnostic tests in patients with no identifiable risk factors.
There is growing consensus that the risk for developing CHD can be stratified according to CAC volume, with those individuals with extensive CAC and multivessel disease at higher risk. For instance, both Detrano et al. (72) and Margolis et al. (61), in separate studies, showed that high-risk patients with fluoroscopically detected CAC had a significantly higher likelihood for future cardiac events (61,72). This observation has been similarly made by several EBCT studies that have shown that as CAC quantity increases, so does coronary heart disease (17). Detrano and colleagues (36) showed that patients with EBCT calcium scores above the median (>75) were six times more likely to experience a cardiac event (myocardial infarction and sudden cardiac death), and that CAC determinations were equal to exercise electrocardiography in its ability to predict CAD in symptomatic patients (36). Arad et al. (62) showed that individuals with calcium scores greater than 160 were 35 times more likely to experience a cardiovascular event and that CAC assessments were more predictive of such events than other more traditional risk factors (62). Patients with coronary calcification experienced more cardiac events (5.4%) compared with those without (2.1%) (2). For coronary artery calcium score thresholds of 100, 160, and 680, the sensitivities of EBCT for cardiac events were 89%, 89%, and 50%; the specificities were 77%, 82%, and 95%, respectively. The odds ratios ranged from 20.0 to 35.4 (p < 0.00001) (2). These results were similar to those of studies that have shown that CAC measurements correlate as well as established risk factors in predicting angiographic disease (73); Detrano and colleagues (36) reported that, in logistic regression that included calcium score, age, gender, and coronary angiographic findings as independent variables, only log calcium score predicted events (2,36). Guerci and colleagues (60) showed that there is a “significant and independent association” between EBCT calcium scores (CS) and angiographic occlusive CAD, and that CS is a “powerful predictor” of CAD (60). They found that calcium scores greater than 80 were found to be associated with an increased risk of CAD regardless of the presence of additional risk factors. Similar results are have been reported by others (63,69,73,74,75).
Although angiography remains the gold standard to document coronary artery disease, and intravascular ultrasound is best at identifying both soft and hard atherosclerotic plaque, EBCT is the only noninvasive imaging modality that can both identity and quantify coronary calcium with high sensitivity. EBCT CAC examinations can be done quickly (usually in 10 minutes or less) without significant physician involvement. Radiation doses are well below that for fluoroscopy and radioisotope examinations. The examination cost (≅ $400) is much less than angiography, thallium scans, and exercise ECG stress tests. Newly developed software has made quantitation and scoring of CAC easy and straightforward.
There is no doubt that CAC measurements correlate well with angiographic results, showing a high likelihood of significant stenoses with increasing calcium burden. Similarly, event data that are now forthcoming are beginning to suggest that prognosis and risk can be predicted and proportionally linked to CAC extent. The most significant problems that are limiting the general applicability (and acceptability) of EBCT from serving as a screening tool relate to its suboptimal reproducibility and lack of standardization of threshold criteria for significance predicated upon both age and gender. Recent studies have attempted to identify “cut-off” points that would optimize both sensitivity and specificities of CAC measurements for different thresholds of angiographic severity (3,15,37), which would help address the need to establish screening criteria needed if EBCT is to serve as an effective screening tool.
Although the quantitation of CAC appears to have great potential to assist clinicians in identifying individuals considered “at risk” for CAD and CHD, the utility of EBCT screening is as guiding clinical decisions about therapy and risk factor modification. Recommendations and diagnostic algorithms have been established that attempt to provide direction for therapies based on calcium scores (1,3,5,76). EBCT also may serve well as an initial investigative tool for patients with atypical chest pain and may have value in investigating complaints of chest pain in individuals at low risk for CHD.
Although preliminary data look promising, more event data are needed to establish the prognostic power of EBCT calcium measurements. Although the application of EBCT as screening tool may be less clear and possibly unwarranted in younger and asymptomatic patients, it does appear to offer real value as a cost-effective initial diagnostic test to screen a subset of patients with a low/moderate disease prevalence (77). Evidence suggests that EBCT has great potential to help stratify risk among groups of patients, thereby identifying those who might benefit from timely risk factor modification (8,51).
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Editor: Jeffrey S. Klein
Associate Editors: Ann Leung, MD
David Lynch, MD, Jung-Gi Im, MD
Michio Kono, MD, Charles White, MD
Guest Editor: William Stanford, M.D.