Various studies have shown that CAC has a prognostic significance in symptomatic individuals. Margolis and associates [49] assessed the significance of CAC found on fluoroscopy in 800 patients undergoing coronary angiography. The 5-year survival rate for the patients with CAC was 58 %, compared with 87 % for the patients without CAC. In a study of 192 patients who were observed for an average of 50 ± 10 months after undergoing a CAC study while in the emergency department for chest discomfort, Georgiou and colleagues [50] found that the presence of CAC (calcium score >0) and increasing absolute calcium score values were strongly related to the occurrence of hard cardiovascular events (P <0.001) and all cardiovascular events (P <0.001). Compared to patients with lower scores, the patients with absolute calcium scores in the top two quartiles had a relative risk of 13.1 (95 % CI, 5.6–36; P < 0.001) for new cardiovascular events. The annualized cardiovascular event rate was 0.6 % for subjects with a CAC score of 0 versus 13.9 % for patients with a CAC score of >400 (P < 0.001).

A multicenter study of 491 patients undergoing coronary angiography and CT scanning showed that higher calcium scores were associated with a markedly increased risk of coronary events over the next 30 months [51]. On multivariate analysis, the only predictor of a hard cardiac event was the log calcium score, even with coronary risk factors and angiographic disease included in the model. In another study of symptomatic patients, CAC was a stronger independent predictor of disease and future events than were all the traditional risk factors combined [52]. In following up 288 symptomatic persons who underwent angiography and calcium scanning for a mean of 6.9 years, Keelan and coauthors [53] found that age and CAC score were the only independent predictors of future hard coronary events.

Coronary artery calcium is also a useful predictor of cardiovascular events in asymptomatic individuals. Unfortunately, at least half of all first coronary events occur in asymptomatic individuals who are unaware that they have CAD, and far too often these events involve sudden death or acute MI [48]. Several lipid-lowering trials have shown that substantial risk reduction can be attained with both secondary and primary prevention measures [54].

Multiple prospective trials have shown the prognostic ability of CAC to identify asymptomatic patients at high risk of cardiac events. Arad and colleagues [55] reported a 3.6-year follow-up study of 1,173 patients. Asymptomatic individuals were evaluated with CT, as well as measures of traditional risk factors, and were followed up prospectively for cardiac events. This study showed CAC to be the strongest predictor of future cardiac events, patients in the highest score category being over 20 times more likely to have a cardiac event (odds ratio, 22.3; CI, 5.1–97.4).

Wong and associates [56] followed up 926 asymptomatic patients (mean age, 54 years) for an average of 3.3 years. The presence of CAC and increasing score quartiles were related to the occurrence of new MI (P < 0.05), revascularization (P < 0.001), and total cardiovascular events (P < 0.001). The risk ratio for events in patients whose absolute calcium score was in the upper quartile (>271) compared with individuals whose absolute calcium score was in the lowest quartile (<15) was 12 (relative risk, 8.8 vs. 0.72, respectively; P < 0.001).

In a long-term follow-up evaluation of the South Bay Heart Watch study, Greenland and colleagues [57] demonstrated that CAC was predictive of risk in patients with a Framingham Risk Score of >10 % and that a high CAC score was able to predict risk beyond the Framingham Risk Score alone. Compared to a CAC score of 0, a CAC score of >300 was highly predictive of cardiac events (HR, 3.9; P < 0.001).

In a series reported by Raggi and coauthors [58], 632 asymptomatic individuals with risk factors for CAD were followed up for an average of 32 ± 7 months. The event rate was 0.11 %/year for patients with a CAC score of 0 versus 4.8 %/year for patients with a CAC score of >400. The event rate in patients with calcium scores in the highest quartile was 22 times the event rate in patients with calcium scores in the lowest quartile; therefore, the CAC score significantly outperformed risk-factors in cardiac-event prediction. Multiple logistic regression analyses showed that the calcium-score percentile was the only significant predictor of events and that it provided an incremental prognostic value when added to traditional risk factors for CAD.

Larger trials have revealed an approximately 10-fold increased risk with the presence of CAC. Kondos and associates [59] reported 37-month follow-up results for 5,635 initially asymptomatic low-to-intermediate–risk adults. In men, events (n = 192) were associated with the presence of CAC (relative risk [RR], 10.5; P < 0.001), diabetes mellitus (RR, 1.98; P = 0.008), and smoking (RR, 1.4; P = 0.025), whereas in women, events (n = 32) were linked to the presence of CAC (RR, 2.6; P = 0.037) and not to risk factors.

In a prospective study of 5,585 subjects aged 59 ± 5 years, Arad and coauthors [60] found that a calcium score of ≥100 predicted all atherosclerotic cardiovascular disease events, all coronary events, and the sum of nonfatal MI and coronary death events with an RR of 9.5–10.7 at 4.3 years. The calcium score also predicted events independently of, and more accurately than, measured risk factors. The area under the receiver operating characteristic curve for event prediction with risk factors alone in this study was 0.71, increasing to 0.81 with CAC testing (P < 0.01). In this prospective study, the investigators strongly demonstrated the ability of this test to identify patients who do not require therapy. Only 19 % of patients had calcium scores above the diagnostic threshold (≥100), yet relying on this threshold had a negative predictive power of 99.2 %. Thus, clinicians can focus on a smaller, yet higher–risk population (in this group, risk was increased 10.7–fold in patients with scores of >100) for risk–reduction therapy.

Shaw and colleagues [61] demonstrated the power of CAC to predict all-cause mortality over the next 5 years. A cohort of 10,377 asymptomatic individuals undergoing cardiac risk-factor evaluation and CAC measurement was followed up for a mean period of 5.0 years. In a risk-adjusted model, CAC was an independent predictor of mortality (P < .001). Coronary calcium was a better predictor than traditional cardiovascular risk factors, and very high scores (>1,000) were associated with a 13-fold increased risk of death as compared to lower scores.

More recently, large population-based studies, such as MESA, the Rotterdam Study, and others, all have shown that CAC is a strong independent predictor of future cardiovascular events and adds incremental prognostic value to traditional cardiovascular risk factors.

In the Heinz Nixdorff Recall (HNR) Study [62], a large population-based study with nearly 5,000 participants, 5-year follow-up evaluation has shown that CAC testing resulted in a high net reclassification rate (30.6 %) in participants at intermediate risk and that the adjusted RR increases with increasing CAC scores. Also, a CAC score of 0 indicates an excellent prognosis, with an event rate of only 0.16 %/year. These results compare favourably with those of MESA, in which the net reclassification improvement was 25 % (CI: 16–34 %).

The Rotterdam Study [63] started 10 years earlier than HNR and MESA and included a prospective population based on a subject age range of 62–85 years. After exclusion of subjects with CAD, 1,795 (49 %) of 3,370 asymptomatic subjects remained in the study. During a mean follow-up period of 3.3 years, 40 (2.2 %) of 1,795 asymptomatic participants had a hard coronary event, including MI and cardiac death. The relative risk of events was calculated by using a CAC score of 0–100 as a referent, yielding a value of 2.7 (1.0–7.7) for those with a CAC score of 101–400; a value of 4.1 (1.4–11.6) for those with a CAC score of 401–1,000; and a value of 8.1 (2.9–22.3) for those with a CAC score of >1,000. The Rotterdam Calcification Study [64] showed that the upper percentile range reflects a 12-fold increased risk of MI—independent of the classical risk factors—even in elderly people.

In the MESA study [65], major coronary events (MI or cardiac death) were observed in 89 (1.3 %) of 6,712 participants within 3.8 years. Those with a CAC score of >100 had a 7-fold increase in the odds for developing events, and those with a CAC score of >400 had a 10.3-fold increase in events. In the MESA and Rotterdam trials, CAC was shown to be a much more robust predictor of events than C-reactive protein (CRP) levels, carotid intima-media thickness (IMT), and the ankle-brachial index—three other tests advocated for screening in an asymptomatic population.

In MDCT, scanners produce images by rotating an X-ray tube around a circular gantry through which the patient advances on a moving table. The pitch is the speed of the table relative to the speed of the gantry rotation, which allows each cross-sectional level of the heart to be imaged during more than one cardiac cycle. The number of image slices acquired during each gantry rotation (4–320 slices) determines the overall duration of the MDCT scan. Developments in MDCT technology led to rapid advancement from the 4-slice machines available in 1998 to the 64-multislice scanners available for clinical use by 2004. The current 64-slice MDCT systems are capable of simultaneously acquiring 64 sections of the heart at the fastest gantry speed of 330 ms per rotation. The increased numbers of detectors provide greater cranio-caudal coverage per rotation, resulting in faster scan times and allowing the entire cardiac anatomy to be imaged in less than 10 s.

Like EBT, which originated decades earlier, cardiac CT is performed with ECG gating in a prospective or retrospective mode. Electrocardiography gating synchronizes image acquisition with the cardiac cycle. The optimal phase or interval for image analysis is the period during which the heart is least mobile (usually mid-diastole, focused around 70–75 % of the R-R interval) and least degraded by motion artifacts. In prospective ECG gating, scanning is initiated at a defined interval after the R wave, continues for a prespecified duration, and then stops until the same optimal period is reached in the subsequent cardiac cycle, at which time scanning resumes.

In retrospective ECG gating, images are continuously acquired throughout the cardiac cycle. The images from multiple consecutive heartbeats are then reconstructed at various percentages of the R-R interval (e.g., from 0 to 90 % of an R-R cycle at 10 % intervals). With retrospective gating, several thousand images can be acquired during a single cardiac study, allowing the interpreting physician to select the images that have the least amount of motion-related distortion before final image reconstruction is performed. Gating has the most advantages at slow heart rates (<60 beats/min), when the R-R interval is >1,000 ms and the fastest imaging protocols are used.

Cardiac motion is minimized with the use of oral and/or intravenous beta blockers before scanning, thereby reducing the heart rate and prolonging the time during the cardiac cycle at which coronary artery velocity is low. For individuals without a contraindication to beta blockade, these drugs are the medication of choice: they not only decrease the heart rate by reducing sympathetic tone but may also reduce the number of premature atrial or ventricular beats, which adversely affect the overall quality of the images. For individuals with high heart rates and contraindications to beta blockers (i.e., allergy or bronchial asthma), calcium-channel blockers with chronotropic effects are used (diltiazem or verapamil). Another crucial element for obtaining high-quality coronary images is to maximally dilate coronary vessels by administering nitroglycerin (sublingual tablets or spray). Respiratory motion is excluded by performing the scan during a breath-hold.

Coronary CTA requires the intravenous administration of an iodinated contrast medium (which is contraindicated in persons with renal impairment). Approximately 50–100 mL of contrast medium is necessary for adequate coronary artery enhancement. The accurate timing of image acquisition relative to the contrast injection is a major determinant of overall image quality. A test bolus or bolus-tracking technique is used to optimize this timing by determining the amount of time necessary to achieve peak enhancement in the aorta.

Advancements in MDCT technology have led to shorter scan times, a reduced breath-hold duration, smaller intravenous contrast injections, and decreased motion-related artifacts, resulting in lower radiation exposure and improved diagnostic accuracy.

With cardiac CTA, the coronary vasculature is evaluated through axial images, multiplanar (coronal, sagittal, or oblique) reformations, and 3D datasets constructed from information obtained at specific phases during the cardiac cycle. Maximum-intensity-projection images allow evaluation of longer segments of the coronary vessels, but these images can be limited by overlapping structures adjacent to the artery of interest. Curved multiplanar reformations are reconstructed on a plane to fit a curve and allow the entire vessel to be displayed in a single image. Three-dimensional volume rendering is useful for selecting images with the least motion artifact and for assessing the relationships among different anatomic structures. Most assessments of plaque, however, have been qualitative; there is not yet any reliable software that can reproducibly quantitate the soft or mixed plaque burden and that is easy to use.

Recently, three large multicenter studies comparing 64-channel coronary CTA with conventional angiography have been completed. In the first study, Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography (ACCURACY), the investigators prospectively enrolled 245 patients with typical or atypical chest pain who were referred for invasive coronary angiography at 16 (predominantly nonacademic) sites in the United States [92]. On a per-patient basis, the sensitivity of coronary CTA was 94–95 %, depending on the cutpoint chosen to represent a positive invasive coronary angiographic result, and the specificity was 82 %. The post-test probability after a negative test (negative predictive value) was 99 % for both disease definitions, but the post-test probability after a positive test ranged from 48 % (with a disease prevalence of 14 %) to 64 % (with a disease prevalence of 25 %). The Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography (CORE 64) study was conducted at nine international centers and involved 316 symptomatic patients, age 40 years or more, with suspected or known coronary disease. Patients with calcium scores of <600 were referred for invasive coronary angiography; 291 (92 %) of them completed coronary CTA before undergoing invasive coronary angiography [93]. The prevalence of obstructive CAD as assessed by quantitative coronary angiography was 56 %. More than 99 % of 3,782 coronary segments were suitable for quantitative evaluation by CT. On a per-patient– based analysis, the sensitivity of quantitative coronary CTA for detecting a ≥50 % diameter stenosis was 0.85, and the specificity was 0.90. The post-test probability of significant CAD after a positive test was 0.91, while the post-test probability that disease was truly absent after a negative test was 0.83. This method was similar to invasive coronary angiography in its ability to identify, based on the presence of ≥50 % obstructive stenosis, patients who were subsequently referred for revascularization.

Three university hospitals in the Netherlands prospectively enrolled 433 symptomatic patients age 50–70 years who were referred for invasive coronary angiography [94]. The prevalence of significant coronary obstructive disease was 68 %; sensitivity for CTA was 99 % with a specificity of 64 %. Only two patients with single-vessel disease were missed.

Overall, core-laboratory and multicenter studies, even those involving blinded investigators and multiple vendors, continue to confirm that CTA has a 99 % negative predictive power for ruling out obstructive CAD in symptomatic persons. Therefore, CTA is the most sensitive noninvasive test available for this purpose.