Abstract: Coronary artery calcification (CAC) has long been known to occur as a part of the atherosclerotic process; recently it has been shown to be an active process resembling bone formation within the vessel wall. There is good evidence that the extent of CAC reflects the total coronary atherosclerotic burden and this has generated interest in using CAC as a marker of risk. The current consensus is that large amounts of CAC identify a patient highly vulnerable to future events. The advent of CT angiography added the ability to non-invasively detect critical luminal stenoses that are associated with a more immediate risk of events, and to visualize the non-calcified component of the atherosclerotic plaque.

Pathophysiology and Assessment of Coronary Artery Calcium

Calcification is a natural phenomenon occurring in most atherosclerotic plaques and it is typically limited to the subintimal space. Calcification involving the muscular media can be seen in patients with poorly controlled diabetes mellitus and patients suffering from end-stage renal disease (Qiao et al., 2005). With these exceptions, it is widely accepted that coronary artery calcium (CAC) is synonymous of coronary atherosclerosis. A large number of in vitro studies have highlighted the involvement, in the process of CAC, of osteoblast-like cells, cytokines, transcription factors, and bone morphogenic proteins found in normal bone. The goal, if any, of plaque calcification is unknown; some researchers suggested it represents a reparative process of the plaque since calcified plaques appear more stable (Beckman et al., 2001), while others noted a greater fragility of calcified vessels (Schmermund et al., 2001). It would appear, however, that calcified patients are more vulnerable to events than non-calcified patients; hence the current preventive trend is to focus on the identification of the “vulnerable, high-risk patient,” rather than the vulnerable plaque.

Figure 1. Cross sectional computed tomography image of heart showing calcification of the left anterior descending coronary artery (long arrow) and of the ascending and descending thoracic aorta (arrow heads).

A large body of experience has been accumulated with computed tomography imaging of CAC (Figure 1), first with electron beam computed tomography (EBCT), and more recently using multidetector computed tomography (MDCT). CAC can be visualized within a few seconds with a relatively low radiation exposure (effective dose 0.6-2.0 mSv) and can be quantified by means of well-standardized scores. The most widely used method for CAC quantification is the Agatston score (Agatston et al., 1990), although more recently the volume score (Callister et al., 1998) and the mass score (Rumberger et al., 2003) have also been proposed.

Coronary Artery Calcium and Prognosis

The total CAC score is directly proportional to the total plaque area, although CAC makes up only about 15%-20% of the total plaque burden (Rumberger et al., 1995). In asymptomatic patients the absence of CAC can rule out the presence of obstructive coronary artery disease with great confidence; only ~0.5% of the asymptomatic patients have obstructive disease on invasive angiography (Cheng et al., 2007). However, acute coronary events may occur in patients with no detectable CAC, especially among young smokers (Schmermund et al., 1997; Raggi et al., 2000). The prognostic impact of CAC screening has been examined in several studies. In the South Bay Heart Study, after a follow-up of 6.4 years, CAC was found to be an independent predictor of cardiovascular events in non-diabetic patients, and was superior to C-reactive protein (Park et al., 2002). Raggi et al. demonstrated that CAC provides incremental prognostic information for the occurrence of acute myocardial infarction or cardiac death in 632 individuals screened by EBCT followed for 32 months (Raggi et al., 2000). Arad et al. followed 1,172 asymptomatic subjects for 3.6 years after CAC screening and showed that a patient with a CAC score of >160 carries a 23.3-fold higher risk for nonfatal myocardial infarction or cardiovascular death than a patient without CAC, independent of other cardiovascular risk factors (Arad et al., 2000). In the St. Francis Heart Study, 4,613 middle aged asymptomatic subjects were followed for an average of 4.3 years; a CAC score of >100 was a strong independent predictor of cardiovascular events, better than the traditional Framingham Risk Score and C-reactive protein (Arad et al., 2005). The Multi-Ethnic Study of Atherosclerosis (MESA) showed that CAC is a better predictor of cardiovascular events than traditional risk factors in 6,722 asymptomatic subjects followed for a median of 3.9 years from the initial screening (Detrano et al., 2008). In comparison with subjects without CAC, the adjusted relative risk of a coronary event was 7.7 for CAC scores between 101 and 300 and 9.7 for CAC scores above 300 (p<0.001 for each). The independent predictive value of CAC was the same in all races examined (White, Black, Hispanic, and Chinese). Finally, the European Heinz Nixdorf Recall study showed that the implementation of CAC screening allows a frequent reclassification of risk (either higher or lower) in patients at intermediate pre-test probability of disease (Erbel et al., 2009)

Who Should Be Screened?

Cardiovascular risk in asymptomatic patients is currently estimated using methods such as the Framingham risk score, the PROCAM score, or the European Score, which take into account traditional risk factors. The Bayesian theorem states that a test’s post-test probability of an outcome (event) partly depends on the patient’s pre-test probability. Therefore, most patients with low-risk will remain at low [absolute] risk even with a high CAC score, because very few events are expected in these patients; similarly, most high-risk patients will remain high-risk even with a relatively low CAC score. Hence, several statements from international health organizations noted that CAC screening is best suited for screening of patients at intermediate risk of hard events (6%-20% 10 year risk) to improve risk prediction (De Backer et al., 2003; Budoff et al., 2006). In intermediate risk subjects, a low CAC score may reclassify them as low-risk, whereas a high CAC score would reclassify them as high-risk (Erbel et al., 2009). The CAC score cut-off value used to discriminate high- from intermediate-risk patients is >100, as suggested by the St. Francis Heart Study (Arad et al., 2005). However, a CAC score of >400 denotes even higher annual risk of cardiovascular events (4.8 and 6.5%, respectively).

In asymptomatic subjects CAC typically progresses 20% to 25% per year although a baseline score of zero is usually associated with a very slow and delayed increase (Gopal et al., 2007). Factors that increase progression include the baseline CAC score, gender, age, family history of premature CAD, ethnicity, diabetes mellitus, body mass index, hypertension, and renal insufficiency. Several reports have noted that a rapid change in CAC score is associated with worse clinical outcomes (Raggi et al., 2003; Raggi et al., 2004). It would appear that patients exhibiting significant CAC progression from their index scan (>15%/year) have a shorter lag time to the development of acute events. Nonetheless, in view of the radiation dose and the lack of prospective studies in this field, sequential CAC screening is currently discouraged.

Coronary CT Angiography

Coronary CT Angiography (CCTA) permits the visualization of the coronary artery lumen and assessment of coronary artery stenosis severity. In addition, excellent image quality allows the visualization and characterization of non-calcified atherosclerotic plaques. However, image acquisition for CCTA is substantially more elaborate than CAC imaging. Intravenous injection of contrast agent is required (approximately 60 to 100 ml), and both data acquisition protocols as well as hardware must provide for extremely high spatial and temporal resolution. Usually, CT systems with at least 64 slices are considered necessary for good to excellent quality CCTA (Abbara et al., 2009). In addition, image quality is strongly dependent on heart rate and it is usually required to lower the patient´s heart rate to less than 65 beats/minute, preferably even less than 60 beats/minute (Abbara et al., 2009).

Figure 2A. Visualization of non-obstructive coronary atherosclerotic plaque by contrast-enhanced computed tomography. Partly calcified and partly non-calcified plaque in the proximal left anterior descending coronary artery (arrow).

CCTA offers higher accuracy for the exclusion of coronary artery stenoses rather than the diagnosis of severe obstruction. In two recent multi-center trials (Budoff et al., 2008; Meijboom et al., 2008), CCTA was reported to have a sensitivity of 95% - 99%, a specificity of 64%-83%, and a negative predictive value of 97%-99% for identifying patients with at least one coronary artery stenosis among individuals at low to intermediate risk for coronary artery disease. Due to the somewhat limited specificity and a tendency to overestimate stenosis severity in CCTA, the positive predictive value is typically lower (64% and 86% in the trials). Defining the presence of coronary artery stenoses by CCTA has prognostic value. Several observation studies have demonstrated extremely low event rates in patients without critical luminal stenoses on CCTA in the setting of stable angina pectoris or acute chest pain (Danciu et al., 2007; Gilard et al., 2007; Hadamitzky et al., 2009; Hollander et al., 2009; Rubinshtein et al., 2007).

Besides the detection of coronary artery stenoses, CCTA also allows the visualization of non-obstructive coronary atherosclerotic plaque (Figure 2A and Figure 2B). In datasets of unimpaired quality, CCTA has a sensitivity of approximately 80% to 90% for the detection of segments which carry non-stenotic coronary atherosclerotic plaque (Springer et al., 2009). Also, various studies have shown that plaque areas and volumes as well as the extent of remodeling in coronary atherosclerotic lesions can be estimated by CCTA (Achenbach et al., 2004; Moselewski et al., 2004; Sun et al., 2008; Otsuka et al., 2008; Schepis et al., 2009). However, measurements of plaque dimensions remain difficult, depend on sufficient image quality, and are fraught with high inter-observer variability (up to 37%).

Figure 2B. Visualization of non-obstructive coronary atherosclerotic plaque by contrast-enhanced computed tomography. Non-calcified plaque in the proximal left anterior descending coronary artery. The atherosclerotic plaque demonstrates substantial positive (i.e., outward) remodeling (arrows).

Does the detection of coronary atherosclerotic plaque by contrast-enhanced CCTA have prognostic value? Indeed, several studies have shown a relationship between plaque detected on CCTA and future cardiovascular events. Typically, however, these trials were performed in symptomatic patients and not in asymptomatic “screening” populations. In a study that involved more than 2000 participants who were followed for a mean period of 6 years, Ostrom et al. demonstrated that the presence of detectable non-obstructive plaques in all three coronary arteries was associated with increased mortality (risk ratio 1.77 as compared to individuals without any detectable plaque), while the presence of non-obstructive plaque in only one or two vessels was not (Ostrom et al., 2008). Similarly, Min et al. could show that the presence of coronary atherosclerotic plaque in at least 5 coronary artery segments in symptomatic patients studied by 16-slice CT was associated with increased mortality as compared to patients with less than 5 segments affected by plaque (Min et al., 2007). It has even been demonstrated that additional information may be gained by analyzing specific plaque characteristics on CCTA. Motoyama et al., again in a group of symptomatic individuals, were able to demonstrate that plaques with positive remodeling and low CT attenuation are at particularly high risk for causing future cardiovascular events (Motoyama et al., 2009). Thus, the detection and further characterization of non-calcified plaque on CCTA may contribute to refine risk prediction. However, this has so far only been demonstrated for symptomatic patients. Also, the value of CCTA relative to other risk prediction methods is poorly understood. Only one recent trial demonstrated - again in symptomatic patients - that CCTA was superior to mere coronary calcium scoring for the identification of individuals at increased risk for future cardiovascular events (van Werkhoven et al., 2009).

Conclusions

Several years of research and a large number of publications have demonstrated the value of CAC as a marker of risk for atherosclerosis and coronary artery disease. There are, however, a few unanswered questions. While CAC is a useful tool to refine risk prediction in several segments of the population, it has not been demonstrated that therapy initiated after having detected sub-clinical atherosclerosis changes a patient’s outcome. CCTA appears to have overshadowed CAC as far as the enthusiasm demonstrated by its users and the public for its ability to non-invasively show luminal stenoses and the non-calcified portion of atherosclerotic plaques. Nonetheless, there is currently little prognostic information regarding non-calcified atherosclerotic plaques. Additionally, a potential prognostic benefit of CCTA over CAC scoring has to be weighed against the increased cost and radiation exposure as well as the necessity to inject intravenous contrast agent. As a consequence, currently CCTA is not recommended for risk stratification purposes (Hendel et al., 2006).

(Corresponding author: Paolo Raggi, M.D., 1365 Clifton Road NE, AT-504, Atlanta, GA, 30322, USA.)

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