Atherosclerotic Plaque Development

Coronary atherosclerotic plaque development begins early in life and is characterized by the accumulation of lipid-laden macrophages within the intima of arterial walls.² With increasing accumulations, the lesions often progress to Stary type IV and type V atheroma, which are well-developed plaques characterized by intramural collections of cholesterol and phospholipids. These lipid collections are often covered by a thin, fibrous cap (fibroatheroma). Because of remodeling, the lesions initially have little significant luminal narrowing and are often undetected by angiography. Two thirds of individuals with acute myocardial infarctions or unstable angina have only minimal angiographic narrowing at the culprit site of occlusion. Myocardial perfusion studies that attempt to identify the hemodynamic effects of coronary stenoses may be normal and often underestimate an individual’s risk for a cardiac event.

Because these plaques are predisposed to spontaneous rupture, the lesions are often referred to as “vulnerable plaques.” Why plaques rupture is unclear, but the process is likely multifactorial and related to biomechanical stresses and localized plaque inflammation. The histologic composition of these plaques may predict eventual outcomes from CAD; screening examinations that can identify plaque morphology may provide the best assessment of risk for coronary heart disease.

When a fibrous cap ruptures, the lipid core is exposed to circulating blood, and an acute thrombogenic reaction may ensue. Advanced lesions that produce stenoses have a greater prevalence in patients with chronic or stable angina, and they are more frequently detected by traditional diagnostic techniques that either identify the stenosis or screen for their hemodynamic effects.

A strong correlation has been found between the quantitative measurements of coronary artery calcium and pathologic measurements of plaque area and volume. Rumberger and colleagues³ showed that calcium is identifiable by CT when plaque area measures 5 to 10 mm² per 3-mm-thick voxel. It has been established that as calcium increases, so does the likelihood of hemodynamically significant stenoses. Heavy concentrations of calcium suggest a greater atherosclerotic burden and a greater likelihood of hemodynamically significant stenoses. Supporting this concept is an article by Kragel and associates,⁴ who reported that atherosclerotic plaques associated with significant stenosis often contain more calcium than nonobstructive plaques.

Autopsy studies have shown that large CAC burdens correlate with greater likelihoods of significant arterial luminal narrowing, especially when distributed over multiple vessels. One such study was by Mautner and coworkers,⁵ who examined 1298 segments from 50 heart specimens and observed that 93% of arteries with stenoses greater than 75% had CAC. Conversely, only 14% of arteries with stenoses less than 25% were associated with calcification. Many other studies have shown that heavier CAC burdens were strongly associated with significant stenoses on angiography and with overall poorer patient outcomes. Calcium measurements derived from CT cannot predict site-specific stenoses. CAC measurements cannot be used to predict the site or the severity of the stenoses.⁶

Coronary calcium is a frequent constituent of vulnerable and hard plaques, and the presence and quantity of CAC correlate well with the overall severity of the atherosclerotic process, and make these lesions potentially identifiable by traditional noninvasive methods, such as fluoroscopy and CT. There are no diagnostic tests that can identify a priori vulnerable plaques that are susceptible to rupture. Postmortem analysis of coronary arteries of adults with sudden cardiac death have shown that histologically determined calcium scores for stable and ruptured plaques were similar (4.5 vs. 5.2).⁷ Despite this, plaque calcification is frequently present in most patients who have acute plaque disruption and sudden death. In addition, intravascular ultrasound examinations performed on patients with acute cardiac events (infarct or unstable angina) have shown that vulnerable plaques tend to be associated with less calcification than plaques found in patients with stable angina, and that moderate levels of coronary calcium portend a greater number of vulnerable plaques and a subsequent higher risk for sudden death. Complicating this issue further is evidence suggesting that small to moderate amounts of calcium within plaque may be associated with a more unstable plaque configuration, which may facilitate their eventual rupture, and may make plaques less tolerable to shear stresses and promote endothelial lining disruption.

Electron-Beam Computed Tomography

The electron-beam CT scanner was introduced in 1980. It generated images by having electrons sweep tungsten target rings located beneath the patient to produce x-rays that traversed the patient to be collected by solid-state detectors in the gantry above the patient. This technology, with its absence of moving parts, allowed temporal resolutions of 50 to 100 ms, which for the first time could essentially “freeze” cardiac motion.

Older electron-beam CT scanners operated at 130 kV, 625 mA to produce 50-ms to 100-ms 1.5-mm, 3-mm, and 6-mm slice thickness images at resolutions of 9.5 1 p/cm. Later model electron-beam CT scanners operated at 140 kV, 1000 mA, and were able to generate dual 1.5-mm, 3-mm, and 8-mm slices at 50-ms temporal resolution. The spatial resolution was 10 1 p/cm. This updated version provided a 100-ms mode for higher spatial resolution and a 33-ms mode for higher temporal resolution.

Multidetector Computed Tomography

Electron-beam CT scanners have now been replaced by multidetector CT scanners, which have detectors capable of generating 256 detector images of varying thicknesses with each gantry rotation. Gantry rotation times have been reduced from 1000 ms to 330 ms, and with segmented reconstruction and dual source imaging, times approximating 83 ms are possible. An added advantage with most scanners is that the information generated is as a volumetric data set, and this permits reformations at different slice thicknesses. Multidetector CT images are commonly ECG gated, and this further decreases motion unsharpness by allowing image acquisitions during the quieter phase of the cardiac cycle. The latter is particularly important in coronary calcification and CT angiography imaging.

Current multidetector CT scanners can generate images by prospective gating, wherein the scanner is activated only during the time needed to acquire an image; this is roughly at one half the gantry rotation time. The time of data collection is initiated from the R wave of the ECG, and the operator can select the desired delay. This mode is frequently used in CAC imaging because patient radiation dose can be kept to a minimum. Rapid or irregular heartbeats can affect image quality and reproducibility, however. Previous 4-detector ring scanners rotating at 0.5 seconds and programmed to provide 2.5-mm slice thicknesses could acquire data in about a 20-second breath-hold; however, current 64-detector scanners are able to reduce scanning times to 8 to 12 seconds.

Retrospective gating is the more commonly used operating mode. In this sequence, there is helical scanning of the entire heart while recording the patient’s ECG. On completion of the scan, the images are reconstructed at a preselected phase of the cardiac cycle. To avoid anatomic gaps in the data set, the pitch is set very low; the patient radiation exposure is higher. Nevertheless, the ability to reconstruct images during multiple phases of the cardiac cycle from the same high-resolution data set provides important information. Submillimeter slices 0.6 mm thick can be obtained to achieve high spatial resolution. The patient’s heart rate can be a major factor influencing image quality, however, and if the heart rate exceeds 65 to 70 beats/min, β blockers are commonly administered to allow data collection during a single heartbeat.

Calcium Score Reporting

Calcium scores are reported using the Agatston score, volume score, and mass score.⁸ The Agatston score was the initial reporting score and is used in much of the older literature. It used electron-beam CT technology to identify lesions with a threshold of +130 Hounsfield units (HU) and 2 to 3 contiguous pixels located over the course of the coronary artery. To calculate the score, a region of interest is placed around each lesion, and the area of the lesion is multiplied by a weighted factor of 1 to 4 based on the peak signal anywhere in the lesion. A weighted factor of 1 is used for a peak calcification of 130 to 199 HU; 2, for a peak calcification of 200 to 299 HU; 3, for a peak calcification of 300 to 399 HU; and 4, for a peak calcification of greater than 400 HU.

The volume score linearly interpolates the data for isotropic volumes and represents the volume (in mm³) of each lesion above the 130 HU threshold. Lesions with similar area but differing amounts of calcium may have different volume scores.⁸

The mass score uses a calibration factor derived from scanning a phantom containing a known amount of calcium. The phantom is placed in the scanning field, and a calibration factor is determined. From it, the calibration factor times the number of voxels containing threshold calcium times the volume of one voxel times the mean CT number for each lesion equates to the mass score (in mg). The total score is the sum of all individual scores.

Rumberger and Kaufman⁸ reviewed the Agatston, volume, and mass scores, and found equivalence of the three CAC scoring methods for stratification of their cohort of 11,490 individuals who had undergone electron-beam CT. Likewise, comparable agreement was found among the three CAC scoring methods over successive electron-beam CT scans. Based on phantom experiments, however, these investigators reported nonlinearity of the Agatston and volume scores with the volume score overestimating lesion volume. Using the same phantoms, mass scores were found to be linear with a few exceptions.

Standardization of Computed Tomography Scanners

To ensure that calcium scores are meaningful, it is important that CT scanners and protocols are standardized so that scores from one scanner can be compared with another. Toward that end, the Physics Task Group of the International Consortium on Standardization in Cardiac CT was formed.⁹ Using a phantom with inserts of calcium and water density material embedded in an epoxy anthropomorphic body torso, scanning algorithms for all five commercially available scanners were developed (Fig. 32-2). The manufacturers included were Toshiba, Imatron, General Electric, Phillips, and Siemens.

FIGURE 32-2 A semi-anthropomorphic thoracic phantom and three additional attenuation layers were used to represent small, medium, large, and extra-large adults. Two syringes were placed in the water-filled cardiac regions of the phantoms. The dotted circle on each phantom represents the ROI where the background noise level was measured.

(From Yu L, Primak AN, Liu X, McCollough CH: Image quality optimization and evaluation of linearly-mixed images in dual-source, dual-energy CT. Med Phys 2009; 36:1019-1024.)

Multidetector CT scanners were calibrated against the phantom for temporal and spatial resolution and noise. Minimum requirements included not less than 4 slices per rotation, rotation times less than 0.5 second, and an ability to reference an ECG signal. The target noise baseline was set at ± 20 HU for the water insert of the phantom. To accommodate different patent sizes, external circumferential rings can be added. Using consortium-developed scanner algorithms, variations of 4% for Agatston scores, 7.9% for volume scores, and 4.9% for mass scores were achieved. The calculated calcium score was within ± 5 mg of the actual calcium mass of the phantom. For the calibrations, a fixed density of 100 mg/mL of calcium hydroxyapatite was used. Subsequently, all manufacturers have now implemented these recommendations into their clinical protocols. To determine the approximate phantom size, the lateral skin-to-skin measurement width at mid-liver measured from an anteroposterior radiograph is used. A multidetector CT database registry is currently under development.

Comparison of Multidetector Computed Tomography and Electron-Beam Computed Tomography in Coronary Artery Calcium Score Determinations

Numerous articles have compared multidetector CT and electron-beam CT in CAC score determinations. Knez and colleagues¹¹ scanned 99 symptomatic men (mean age 60 years) with 4-detector multidetector CT and electron-beam CT (prospective triggering at 80% R–R interval) and found a correlation coefficient of r = 0.99 for volume and r = 0.98 for mass scoring. These investigators found a mean overall variability of 17%, but no significant differences for scores 1 to 100, 101 to 400, 401 to 1000, and greater than 1000. Knez and colleagues¹¹ concluded that multidetector CT was equivalent to electron-beam CT for CAC scoring.

Becker and associates¹² also compared 4-detector multidetector CT with electron-beam CT (prospective triggering) in 100 patients. They calculated Agatston, volume, and mass scores, and concluded that the variability was highest for the Agatston score (32%), and that the correlation between multidetector CT and electron-beam CT was excellent for volume and mass scores.

Horiguchi and colleagues¹³ compared electron-beam CT and 16-multidetector CT with retrospective gating in 100 patients and reported a high correlation between these scanners for the Agatston score (r² = 0.95), volume score (r² = 0.95), and mass score (r² = 0.97). Last, Daniell and coworkers¹⁴ compared the results of electron-beam CT and 4-detector multidetector CT in 68 patients. Electron-beam CT and multidetector CT scores correlated well (r = 0.98-0.99). The variability between electron-beam CT and multidetector CT Agatston score was 25%, and for the volume score the variability was 16%. The electron-beam CT scores were higher than multidetector CT scores in approximately 50% of the cases. Numerous investigators have documented high correlation coefficients for multidetector CT versus electron-beam CT in coronary calcium scoring.

Interscan Reproducibility

A major consideration in the use of calcium scores is the variability of changes in CAC between serial CT scans on repeat imaging. Although interscan variability is predominantly affected by motion and table position, it is influenced further by the extent of CAC burden, scanner type, scan protocol starting position, and image artifacts. With optimal ECG triggering, variability can be reduced to less than 15% for electron-beam CT. The correlation coefficients of Agatston score, volume score, and mass score are excellent (r = 0.96).¹⁵ The conclusion was that the electron-beam CT and multidetector CT scanners have equivalent reproducibility.

Differences between scanner types have been reported in many studies. In the Multi-Ethnic Study of Atherosclerosis (MESA) trial of 6814 multiethnic individuals scanned on three electron-beam CT and three multidetector CT scanners, the differences were 20.1% for the Agatston score, and 18.3% for the interpolated volume score (P < .01).¹⁶ Other authors¹⁷ reported a multidetector CT variation of 12% for Agatston scores, 7.5% for volume scores, and 7.5% for mass scores. Overall, reported variabilities on 16-detector to 64-detector multidetector CT scanners seem to be in the range of 8% to 18% for the Agatston, volume, and mass scores.

Coronary Artery Calcification as an Indicator of Coronary Stenosis

Many electron-beam CT studies have addressed the issue of CAC as an indicator of coronary stenosis. Haberl and coworkers¹⁸ looked at electron-beam CT calcium scores as an indicator of coronary luminal stenoses. They studied 1764 patients undergoing conventional coronary angiography and found that electron-beam CT CAC scores were a highly sensitive but only moderately specific determinant of stenosis. Knez and colleagues¹⁹ reviewed 16 electron-beam CT trials (N = 2115 patients) comparing electron-beam CT–derived Agatston scores with volume scores. The reference standard was conventional coronary angiography. Knez and colleagues¹⁹ found that electron-beam CT–derived CAC scores were an accurate predictor of the presence of greater than 50% luminal stenosis. Their results are shown in Table 32-1.

In another study, Budoff and colleagues²⁰ analyzed electron-beam CT volume scores as a predictor of luminal stenoses in 1851 patients undergoing conventional coronary angiography. Their results are shown in Table 32-2. From these studies, the investigators concluded that electron-beam CT volume scores provided incremental value in predicting the severity and extent of angiographically significant coronary artery stenosis. Last, the American College of Cardiology/American Heart Association Expert Consensus Document on Electron-Beam CT for the Diagnosis and Prognosis of Coronary Artery Disease²¹ evaluated these and many additional studies, and reported a pooled sensitivity of 91.8% and specificity of 55% for detection of greater than 50% coronary artery stenoses.

TABLE 32-2 Results from Budoff et al: Presence of Significant Stenosis (>50% Stenosis)

Value of Zero Calcium Score

More important than the total score may be the implications of a 0 calcium score. Several investigators have addressed this issue. Becker and associates²² studied 1347 symptomatic subjects with suspected CAD, and found an overall sensitivity of any calcium score to predict stenosis was 99%, with a specificity of 32%. An absolute score greater than or equal to 100 and an age-specific and gender-specific score greater than the 75th percentile were identified as the cutoff levels that provide the highest sensitivities (86% to 89%) and lowest false-positive rates (20% to 22%). Becker and associates²² also concluded that absence of coronary calcium was highly accurate for exclusion of CAD.

Several other studies have addressed this issue. Cheng and coworkers²³ assessed the presence and severity of noncalcified coronary plaques on 64-detector multidetector CT versus coronary angiography in 554 symptomatic patients with low to intermediate pretest likelihood for CAD, and concluded that the absence of CAC is associated with a very low presence of significantly occlusive CAD.

Coronary Artery Calcium as a Predictor of Cardiac Events

In an American College of Cardiology/American Heart Association Consensus Document on Coronary Artery Calcium Scoring, it was concluded that CAC scores added incremental prognostic value in the evaluation of patients at intermediate risk for a coronary event. A study by Raggi and coworkers²⁴ supported this conclusion. These investigators screened 632 patients with electron-beam CT for hard cardiac events (myocardial infarction and death), and found in 32-month follow-up that most events occurred in individuals with high calcium scores (>75th percentile) compared with age-matched and gender-matched controls. Arad and colleagues²⁵ used electron-beam CT to screen 1172 asymptomatic patients. They followed patients for a mean of 3.6 years to determine the incidence of cardiovascular end points (myocardial infarction, death, and need for revascularization) and concluded that in asymptomatic adults electron-beam CT calcium scores were highly predictive of events.

Pletcher and associates²⁶ reported a meta-analysis of studies between 1980 to 2003. In an analysis of 13,000 asymptomatic patients screened with electron-beam CT and followed for 3.6 years, they found the odds ratios for Agatston CAC scores less than 100, 100 to 400, and greater than 400 were 2.1, 4.2, and 7.2, and concluded that the electron-beam CT–derived Agatston calcium scores were independent predictors for hard coronary events in asymptomatic subjects. Several additional studies were reported in the American College of Cardiology Foundation/American Heart Association consensus document on CAC scoring, and all reported similar or better odds ratios for electron-beam CT as a predictor of a cardiac event.²⁷

In patients experiencing acute hard cardiac events, coronary calcium is almost always present in amounts exceeding those found in asymptomatic individuals. Although acute cardiac events do occur in individuals who have little or no demonstrable calcium, the absence of detectable CAC does portend a low likelihood of a major cardiac event within the next 2 to 5 years (5% to 10% overall risk).²¹

Risk Assessment in Asymptomatic Individuals

Traditional risk assessment algorithms such as the Framingham Risk Score have been the standard used in assessing an individual’s 10-year risk. Current definitions of risk are as follows:

Present recommendations are that individuals at high risk are more likely to benefit from intensive risk modification and that individuals at low risk should adhere to a healthy lifestyle. In individuals at intermediate risk, the situation is uncertain, and further tests are often indicated. Calcium scoring has been advocated in the assessment of risk over measured conventional risk factors^28,29 in intermediate-risk patients. Many authors believe it is reasonable to use CAC measurement as a treatment modifier in this group of patients.

Patients Presenting to Emergency Departments with Chest Pain

In patients presenting to emergency departments with chest pain, functional tests such as treadmill, nuclear stress tests, or stress-echocardiography are frequently used, especially when cardiac enzymes and the admitting ECG do not show evidence of acute coronary syndrome. In these patients, the absence of calcium has a high correlation with the absence of a coronary etiology for the pain.

Laudon and colleagues³⁰ performed CAC scoring in the emergency department in 104 patients, and reported a negative predictive value of 100% for a CAC score of 0. In another study, McLaughlin and associates³¹ reported a negative predictive value of 98% in 134 patients in a similar emergency department setting.³¹ Additionally, Georgiou and coworkers³² followed 198 patients presenting to the emergency department with chest pain and normal ECG and cardiac enzymes. They found that patients without CAC may safely be discharged from the emergency department because of the extremely low rate of future events (approximately 0.1%/yr). Numerous studies indicated the high negative predictive value of a 0 CAC score (r > 90%). The positive predictive value is lower, however, which results in CAC screening being a highly sensitive, but poorly specific modality for assessing patients with acute coronary syndrome.

More recently, Rubinshtein and coworkers³³ assessed the severity of CAD using 64-multidetector CT in patients undergoing investigation for acute coronary syndrome. In 668 consecutive patients, 231 had a low (<100) or 0 CAC score, and of these patients, obstructive CAD was present in 9 of 125 (7%) with a 0 score, and in 18 of 106 (17%) with a low score (1 to 100). Rubinshtein and coworkers³³ concluded a 0 CAC score seemed to be a good predictor for the exclusion of significant CAD in patients with intermediate to high pretest likelihood of obstructive CAD. Low CAC scores remain controversial, however, because many studies have shown that the presence of noncalcified and potentially obstructive lesions is higher in patients with low calcium scores compared with patients with a score of 0.

Relationship Between Race and Calcium Score

Many studies have shown differences in scores between men and women and between subjects of different ethnicities. Bild and colleagues,³⁴ evaluating data from the MESA study, found that the prevalence of CAC (score >0) was highest in whites followed by Chinese, Hispanics, and blacks. Also from the MESA study of 6722 multiethnic individuals, Detrano and coworkers³⁵ reported that CAC is a strong predictor of cardiovascular death, nonfatal myocardial infarction, angina, and need for revascularization. They concluded that CAC adds incremental prognostic value beyond traditional risk factors for the prediction of events. It seems appropriate to consider CAC as an indicator of increased risk in all races.

Elderly Populations

The assessment of CAC in elderly individuals is of interest because a small reduction in risk results in a significant reduction in event rates. Because the Framingham Risk Score has age thresholds that limit its applicability, one may miscalculate the true risk of CAD, and this may lead to inaccurate selection, especially in elderly patients for aggressive risk factor modification.

Currently, only a few studies have focused on the predictive value of CAC in elderly individuals. One of these was the Rotterdam Coronary Calcification Study, which evaluated older individuals with a mean age of 71 years. This study found that during a mean follow-up period of 3.3 years, 50 of the 1795 initially asymptomatic subjects had a coronary event.²⁹ From these data, the researchers reported that increasing calcium scores showed relative risks for CAD up to 8.2 for a calcium score greater than 1000 compared with absent or low calcium score (0 to 100). Increasing calcium scores seem to be strongly associated with an increasing incidence of events, and low calcium scores seem to be important even in elderly individuals. Supporting these findings is a study by LaMonte and associates,³⁶ in which CAD event rates were adjusted for gender. These investigators showed that in subjects older than 65 years there was a graded increase in event rates for calcium scores of 100 and 400 (7.1 and 8.2 per 1000 person-years). Conversely, the absence of coronary calcium was associated with a very low event rate (0.9 per 1000 person-years). There is support that CAC screening is valuable in all age groups.

Diabetes Mellitus and Coronary Artery Calcium Screening

It is well known that diabetes mellitus is associated with a high prevalence of CAD. Limited outcome data exist for diabetic patients, however. Anand and colleagues³⁷ performed sequential CAC and myocardial perfusion imaging in 180 patients with type 2 diabetes. The incidence of myocardial ischemia was found to be proportional to the CAC score. For patients with type 2 diabetes with a CAC score of 0, 11 to 100, 101 to 400, 401 to 1000, and greater than 1000, the incidence of myocardial ischemia on stress perfusion imaging was 0%, 18%, 23%, 48%, and 71%. Anand and colleagues³⁷ concluded that patients with a CAC score greater than 100 have an increased frequency of ischemia on myocardial perfusion imaging.

Raggi and coworkers³⁸ evaluated 903 diabetic patients from a database of 10,377 asymptomatic individuals followed for an average of 5 years after CAC screening. The end point of the study was all-cause mortality. The authors showed that all-cause mortality was higher in diabetic patients than nondiabetic patients for any degree of CAC, and the risk increased as the score increased. They also found the absence of CAC predicted a low short-term risk of death (approximately 1% at 5 years) for diabetic patients and nondiabetic subjects. It seems that the presence and the absence of CAC are important modifiers of risk even in the presence of established risk factors.

Renal Failure and Coronary Artery Calcium

It is also well known that the prevalence of CAC increases with declining renal function. Russo and colleagues³⁹ reported the prevalence of CAC to be 40% in 85 predialysis patients compared with 13% with normal renal function. In this prospective study of 313 high-risk hypertensive patients, a reduced glomerular filtration rate was shown to be the major determinant of the rate of progression of CAC. Consistent with these findings, Sigrist and associates⁴⁰ reported prevalence of CAC to be 46% in 46 predialysis patients compared with 70% and 73% in 60 hemodialysis patients and 28 peritoneal dialysis patients (P = .02).

In another study of patients undergoing hemodialysis followed for almost 5 years, Block and colleagues⁴¹ reported a low mortality rate for patients with a negative calcium score (3.9%/yr). This is a remarkable finding in view of the extremely high mortality and cardiovascular event rate in these patients (approximately 25%/yr to 30%/yr). CAC seems to be predictive of an adverse outcome in renal dialysis patients; however, its absence is associated with a low event rate.

Comparison of Coronary Calcium Screening with Treadmill and Nuclear Stress Imaging

Exercise stress testing is frequently used in patients with suspected CAD. There are often numerous false-negative results, however. Lamont and colleagues⁴² studied 153 patients who underwent electron-beam CT and coronary angiography because of a positive treadmill stress test. In patients with a CAC score of 0, the negative predictive value was 93%. The authors concluded that the absence of CAC reliably identified patients with a false-positive treadmill stress test result. Raggi and coworkers⁴³ also evaluated treadmill stress test and showed that in patients with low to intermediate pretest probabilities of disease, CAC scoring as the initial test provided a substantial cost benefit over exercise stress testing, and that a CAC score of 0 can reliably exclude CAD.

Berman and associates⁴⁴ also reported a positive relationship between stress-induced myocardial ischemia as seen on single-photon emission computed tomography (SPECT) myocardial perfusion studies and electron-beam CT CAC. They studied 1195 patients without known coronary disease and found the frequency for ischemic SPECT was less than 2% with CAC scores less than 100 and increased progressively with CAC greater than 100 (P ≤ .0001). Symptomatic patients with CAC scores equal to or greater than 400 had a higher likelihood of myocardial ischemic changes versus asymptomatic patients (P < .025). Berman and associates⁴⁴ concluded that ischemic SPECT was associated with a high likelihood of subclinical atherosclerosis, but is rarely seen in CAC scores less than 100, and that most low CAC scores would obviate the need for subsequent noninvasive testing.