Thompson, Brad H. M.D; Stanford, William M.D
Coronary heart disease (CHD) affects 1.6 million Americans annually, with many of the cardiac events coming unexpectedly, and often with fatal results (1,2). CHD accounts for approximately 500,000 deaths each year (1,2). Of the patients who experience myocardial infarction, only approximately 50% have a history of coronary artery disease (CAD) (3). Although epidemiologic studies have clearly identified cardiac risk factors that are assessed routinely in an effort to identify those individuals predisposed for CHD/myocardial infarction, risk factors predict only two thirds of patients who eventually die of heart disease (3). For good reason, significant efforts are put forth by physicians each year in an attempt to identify those individuals at risk for CHD so that appropriate risk factor modification can be initiated in the hope of reducing the high mortality and morbidity rates characteristic of cardiovascular disease. In fact, results of therapies targeting risk factors such as hypertension and hypercholesterolemia have been shown to significantly reduce the mortality rates from heart disease (1,4).
Unfortunately, global screening programs that attempt to identify those at risk are not generally thought to be cost-effective; health screening initiatives and subsequent efforts at risk factor modification are expensive. Although the pathogenesis of cardiovascular heart disease is complex, poorly understood, and related to a multitude of predisposing factors, all of which increase the aggregate risk for CHD, many individuals with CAD do not experience a “cardiac event.” Despite the fact that the 8-year risk of CHD for the average middle-aged person is only 1% to 5% depending on risk factors, the enormous costs of this disease (in both lives lost and health care expenditures) make the development of an effective screening program of paramount importance (5). Thus, there is a critical need to develop a simple and reliable screening test that could provide accurate documentation of the presence and severity of CAD, as well as prognosticate the likelihood or individual risk for developing CHD.
In the last 10 years, there has been an explosion of interest and associated scrutiny examining the potential of electron beam computed tomography (EBCT) to serve as an effective screening tool for CAD. Because coronary arterial calcification (CAC) has been unequivocally shown to be a marker of atherosclerosis, much research interest (and debate) has been generated revolving around the quantification of CAC by EBCT and how such measurements can be used to identify and predict those at greatest risk for CHD. The purpose of this article represents an objective attempt to provide a synopsis of the literature illustrating consensus opinions (where they exist) regarding the potential role EBCT may have to serve to establish itself as an accurate and cost-effective screening tool for CAD/CHD, especially as it compares with alternative diagnostic examinations and conventional risk factor analyses.
CORONARY CALCIFICATION AND ITS SIGNIFICANCE
A thorough review of coronary calcification and its significance is provided elsewhere in this issue. Briefly, coronary arteriosclerosis is a complex and relatively poorly understood process, related to a host of genetic, biochemical, and environmental factors (2). Traditional risk factors such as smoking, age, gender, obesity, elevated blood lipids, and diabetes mellitus, among others, all have been linked to an increased risk for the development of coronary arteriosclerosis. Unfortunately, the progression of CAD is a highly variable and unpredictable process.
Beginning early in life, the lesions of arteriosclerosis go through a series of six stages that correspond to the morphologic and histologic composition of the plaque (6). Severe lesions that are associated most commonly with significant luminal narrowing are plaques that are in the latter stages of development and generally composed of lipids with areas of fibrosis (6). Occlusive coronary disease appears to arise from the rupture of lipid-rich plaques that occur independent of plaque size or severity of luminal narrowing (2,5). In fact, up to two thirds of patients who have acute myocardial infarction or unstable angina may have only minimal narrowing at the site of the occlusion (2). Unfortunately, this may result in falsely negative results from traditional screening tests (electrocardiogram [ECG], stress tests, thallium scans) that attempt to measure the physiologic results of coronary narrowing.
Post mortem studies have shown a definite correlation between coronary calcium and the frequency of myocardial infarction (7–10), and clinical outcomes data after coronary angiography have established a correlation between stenosis severity and the likelihood of future cardiac events (11). Although the causes of acute coronary occlusion attributable to atherosclerosis are likely multifactorial, “unstable” plaque configurations in conjunction with localized inflammation probably act as precipitating factors (2,5,6). Histologically, those plaques with lipid cores and fibrous caps are believed to be at greatest risk for rupture and subsequent luminal thrombosis (6). What is not clear is whether calcium acts a plaque destabilizer, facilitating rupture, or whether the presence of calcification signifies plaque maturity and stability. In reality, the stabilizing effect of CAC is proportional to the calcium quantity present within each individual plaque. It is postulated that “soft plaques” are more likely unstable and prone to rupture, leading to “acute cardiac syndromes” (5), but that such plaques are not necessarily associated with significant luminal narrowing (5,6). Although calcium deposits are found in both unstable and stable plaques (3,12), there is, unfortunately, no diagnostic test that can identify which plaques are most susceptible for rupture. Because calcified and uncalcified plaques are believed to coexist in similar proportions (12–14), quantifying CAC has been postulated as a surrogate measure of the number of soft plaques, thereby providing some insight into the likelihood of eventual occlusive coronary disease, albeit in an indirect manner (3). The presence of extensive CAC by default suggests a greater number of unstable atherosclerotic plaques and, therefore, can be clinically useful in establishing relative risk for CHD.
Coronary atherosclerotic calcification is an inevitable part of the aging process. It is well documented that the prevalence of CAC for both sexes increases with age. Despite the fact that women show an approximate 10-year delay in CAC development compared with men, this difference disappears at the age of 70 years (15,16). At age 75 years, there is an approximate 90% prevalence of CAC for both men and women (16–22). Correspondingly as calcium burdens increase, there is concern that the clinical significance of CAC and clinical value of screening examinations that merely document its presence may diminish in older cohorts of patients. Specifically, the specificity of CAC for predicting aggregate risk for occlusive coronary artery disease, particularly in the elderly, should decrease with age. For this reason, and despite the wide consensus that CAC serves as a marker for CAD, the clinical utility of CAC screening has been considered somewhat uncertain, particularly in older and asymptomatic individuals.
ELECTRON BEAM COMPUTED TOMOGRAPHY
Although the presence of CAC as measured by calcium volumes and scores is reflective of CAD burdens, can such quantification be predictive of future cardiac events? Assessment of coronary calcification initially performed by conventional and digital fluoroscopy showed a correlation between the amount of CAC and CAD (5,23) as well as to actual calcium mass from pathologic specimens (24). Computed tomography is uniformly recognized as a more sensitive noninvasive radiologic method to perform CAC assessments (25–27). Studies have substantiated the superiority of CT by showing an approximately 50% greater detection rate of CAC compared with fluoroscopy (28,29). This improvement in sensitivity is attributable to greatly enhanced contrast and image resolution.
Building on the inherent advantages of conventional CT, the unique technical characteristics of EBCT have further facilitated and greatly enhanced the role of CT in cardiac imaging. By virtue of millisecond acquisition times and ECG gating, EBCT has resolved many problems of conventional CT such as slice misregistration, motion artifacts, and volume averaging (5) (Fig. 1). As a reflection of the superior image quality of EBCT provided of the coronary arteries, investigators soon realized its clinical potential in performing quantitative measurements of CAC (17,20,28). Pioneering work by Agatston and colleagues (17) showed that EBCT was superior in sensitivity to fluoroscopy in identifying CAC (90% versus 52%), proclaiming EBCT an “excellent tool” for the detection and measurement of CAC (17). These investigators were instrumental in developing the imaging and standardized scoring protocols that have become universally accepted (albeit with some minor modifications) by investigators worldwide. (15–19,31–41).
In an attempt to provide a quantitative assessment of CAC, Agatston et al. (17) formulated the “calcium score,” which represents an attempt to quantify CAC burden. The calcium score is calculated by multiplying calcium area (in square millimeters) by a modifier that adjusts for peak calcium density for each lesion (17). This scoring protocol has been incorporated in several commercial software packages that have greatly facilitated quantitative CAC measurements (Fig. 2).
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).
CALCIUM PLAQUE MEASUREMENTS BY EBCT
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).
THE CORRELATION BETWEEN CAC MEASUREMENTS AND ANGIOGRAPHIC DATA
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.
CLINICAL UTILITY OF EBCT AS A PREDICTOR OF CORONARY HEART DISEASE
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).
CLINICAL UTILITY OF EBCT AS A SCREENING EXAMINATION
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.
© 2001 Lippincott Williams & Wilkins, Inc.