Coronary Artery Calcification: Clinical Significance and Current Methods of Detection

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1 Review Coronary Artery Calcification: Clinical Significance and Current Methods of Detection William Stanford,1 Brad H. Thompson,1 and Robert M. Weiss2 Coronary artery disease affects 1,500,000 Americans each year; 500,000 of these will die. The earliest detectable lesion of coronary atherosclerosis is the fatty streak. Later, crescentshaped lipid plaques occur, which may rupture and produce either progressive stenosis or sudden occlusion with myocardial infarction. Calcium is deposited early in the formation of the atherosclerotic plaque, and calcification can be used as a marker of the atherosclerotic process. Many imaging techniques can be used to detect calcification of coronary arteries. The most promising are fluoroscopy, ultrafast CT, and intravascular sonography. Detection of calcification is most valuable in persons less than 40 years old in whom modification of risk factors may be important. In addition, the progression and possible regression of calcification can be used as an indicator of the atherosclerotic process. The absence of calcification in coronary arteries may diminish the need for further testing. Coronary artery disease is a major cause of mortality and morbidity in the United States. In 1989, heart and blood yessel disease affected more than 69 million Americans and claimed 944,688 lives; one fifth of these persons were less than 65 years old. Coronary artery disease was responsible for 497,850 of these deaths. This year more than 1,500,000 Americans will have a heart attack and about 500,000 will die [1]. It is not rare for coronary artery disease to remain silent until a major catastrophic event occurs. Therefore, markers that can indicate which persons are prone to the development of coronary atherosclerosis are becoming increasingly important. Calcification of coronary arteries is one of these markers. This review emphasizes the significance and pathophysiology Article of coronary artery calcification and discusses the current imaging methods available for its detection. Pathophysiology The presence of atheromata within the intima of coronary arteries has been well documented [2, 3] and, as these atheromas often become calcified, the presence of calcium is widely recognized as a marker of coronary atherosclerosis [4-9]. Blankenhorn [2] examined 3500 coronary arterial segments from 89 patients and found that in each instance coronary calcification was associated with intimal atheromata. Although calcification is recognized as a reliable marker of atherosclerosis, its presence does not necessarily signify significant stenosis. Plaques that tend to rupture and produce stenosis or thrombotic occlusion of the coronary artery may only minimally or moderately narrow the coronary arterialtree [10, 11]. The earliest detectable lesion of atherosclerosis is the fatty streak, which is composed of layers of macrophage foam cells, lipid-laden smooth muscle cells, and scattered extracellular lipid particles. These fatty streaks may occur in the first decade of life [12] and are increasingly found by the second decade [13, 14]. Later, atherosclerotic plaques are seen as crescentshaped masses of lipid separated from the vessel lumen by a fibrous cap that can be disrupted. These plaques tend to be relativelysoft and have high concentrations of cholesterol and cholesterol esters. As the disease progresses, the fibrous cap can thin and rupture. The most common site of Received May 6, 1993; accepted after revision August 6, of Radiology, The University of Iowa College of Medicine, 200 Hawkins Dr., Iowa City, IA Address correspondence to W. Stanford. 2Department of Intemal Medicine, The University of Iowa College of Medicine, Iowa City, IA AJR 1993;161 : X/93/ American Roentgen Ray Society

2 1140 STANFORD ET AL. AJR:161, December 1993 rupture is the junction of the fibrous cap with the normal yessel. Plaques in which the lipid pool is eccentric and plaques located at sites exposed to increased shear forces appear to be more prone to rupture [3]. Initially, monocytes attach to the endothelium, then migrate helow the subendothelium, accumulate lipid, and are transformed into macrophage foam cells. These cells enhance the transport and oxidation of low-density lipoproteins and secrete a factor that can lead to the proliferation of smooth muscle cells and to plaque neovascularization. These macrophages may also release proteases (elastase and collagenase) and thereby generate toxic products that facilitate rupture of plaques and necrosis of vessel walls. High-density lipoproteins appear to have an inverse effect on this process and may not only prevent the development of atherosclerosis but also reverse the process by initiating transport of cholesterol into the circulation and to the liver [15]. Calcification usually indicates formation of complex plaques [16]. As yet, no clinical studies have examined the interval between the formation of plaque and the deposition of calcium in the coronary arteries [16]. Once a plaque ruptures, it exposes the blood to collagen, lipids, and smooth muscle cells in the vessel wall. These events lead to deposition of platelets and activation of the coagulation cascade system, with resultant formation of thrombus. The thrombi can become anchored and acutely narrow the vessel, causing infarction, or can be incorporated into the vessel wall, causing the more gradual narrowing associated with progressive atherosclerosis [1 5]. The extent of an infarction is determined by the size of the vessel, the location and duration of the occlusion, and the extent of collateralization that may be present. Once formed, the thrombus continues to be exposed to circulating blood, and this can promote additional episodes of thrombosis and reocclusion [3, 1 7]. As up to two thirds of patients who have acute myocardial infarction or unstable angina may have only mmimal narrowing at the site of the occlusion, exercise tests, which detect abnormalities in flow through stenotic arteries, often shown no abnormalities [15]. The severity of the stenoses and the number of vessels involved do not appear to correlate with future morbidity and mortality [6, 18, 19]. Although severely stenotic lesions often progress to occlusion [17], the occlusion may not always produce infarcts because the process may be slow enough to allow the development of collateral vessels. In addition, atherosclerotic coronary arteries often enlarge eccentrically, and, consequently, the luminal cross-sectional area may be preserved despite extensive atherosclerotic involvement within the vessel wall. Therefore, although angiographic findings may be helpful in the diagnosis of stenotic disease, they may not be helpful for accurately predicting the sites of future occlusion. Also, with angiography, only the luminal diameter is visualized, and the extent and severity of the atherosclerotic process may be underestimated. As a general rule, unstable angina occurs when the thrombogenic stimulus is limited and the resulting occlusion causes recurrent lysis and rethrombosis. This appears to be different from the injury caused by rupture of plaques, which leads to relatively persistent occlusion and often myocardial infarction [17]. However, infarction may be silent and hence unrecognized [20]. Deposition of calcium usually is greatest in the proximal portions of the coronary artery. Calcification in distal parts without involvement of proximal parts is rare [4, 1 0, 16, 21, 22]. However, recent studies of asymptomatic young men indicate this may not always be the case (unpublished data). Nevertheless, the prevalence of calcification increases with age [1 6, 22], and the extent of calcification has a direct correlation with the extent of the atherosclerotic process. Some recent data (unpublished) show a 26% prevalence of coronary calcification in asymptomatic young men less than 37 years old. Factors contributing to this development are genetic predisposition, hematologic alterations, diabetes, smoking, and abnormalities in lipid metabolism. Because the prevalence of coronary calcification increases with age, it has been argued that this is merely a sign of aging. However, quantitative pathologic studies [5-7] have consistently shown a direct relationship between the extent of coronary calcification and the severity of coronary atherosclerosis independent of age. It has also been shown that atherosclerosis is associated with elevated serum levels of triglycerides. Currently, the only reliable indicator for the development of early onset coronary artery disease is thought to be an elevated serum triglyceride level [23-25], an association that appears to be independent of high-density lipoproteins [23, 26]. It has also been shown that there is a reduction of plaque stenosis and a reduction of cardiac events when levels of lipids are lowered by a variety of regimens [27]. Association of Calcification with Extent of Coronary Artery Disease Margolis et al. [28] evaluated calcification of coronary arteries in 800 consecutive patients. Cine cardiac fluoroscopy and selective coronary angiography were performed within 5 days of each other in all the patients. Calcification was detected in 250 patients, and 236 (94%) of these had stenosis of more than 75% in one or more major coronary arteries. Forty percent of patients who had marked coronary artery disease seen on angiograms had calcification. Of additional importance, the survival rate at 6 months to 5 years was poorer in patients with calcification than in those without (5-year survival rate, 58% vs 87%). In all age groups studied, the prevalence of calcium increased as the extent of disease seen on angiograms increased. Additionally, the predictive value of the presence of calcium for future coronary events was independent of age, sex, number of diseased vessels detected on angiograms, results of exercise tests, and left ventricular function. Kragel et al. [29] found that more obstructive plaques contamed more calcium than less obstructive ones did. This amount of calcium was zero or minimal in 0-25% of luminal obstructive plaques but increased exponentially with increasing amounts of obstruction. In this study, the authors examined pathologic material from 1 5 patients who died after sudden myocardial infarction. Inasmuch as the pathologic specimens were decalcified at the time of the study, the prevalence of calcium may have been even higher. In a cadavenc study, Strong et al. [30] found the area of plaques projecting into the vessel lumen was greater in persons who died of coronary artery disease than those who died

3 AJR:161, December 1993 CORONARY ARTERY CALCIFICATION 1141 of accidents or had natural deaths. In an expanded group at the same institution, the area of calcification in plaques projecting into the lumen in those who died of coronary artery disease vs those who died of other causes was even higher than the equivalent ratios of atherosclerotic areas. The latter group consisted of 349 specimens from consecutive necropsies. In another cadavenc study, McCarthy and Palmer [7] found calcium in 16 of 19 total coronary obstructions. The three cadavers without coronary calcium had evidence of recent infarcts, and it was thought that time was probably insufficient for the development of calcification. Agatston et al. [22] used ultrafast CT to examine 584 consecutive subjects years old with and without histories of coronary artery disease. The prevalence of coronary calcification in the 30- to 39-year-old group was 25% in individuals without a history of coronary artery disease vs 100% in individuals with a history of coronary artery disease. This prevalence of calcification in individuals without coronary artery disease increased to 39% at age 40-59, 73% at age 50-59, and 74% at age Comparable figures for individuals with coronary artery disease were 88% (age 40-49), 96% (age 50-59), 100% (age 60-69) (p <.0001 between all groups). The authors concluded that the total calcium score and the number of lesions increased with age, and calcification was significantly greater in those patients with a history of coronary artery disease than in those without. In this study, coronary artery disease was defined as a proven history of myocardial infarction (22 patients) or angiographic evidence of coronary atherosclerosis (87 patients). Overall, it is generally thought that calcium in the coronary artery is associated with atherosclerosis and that its quantity reflects the overall extent of the atherosclerotic process [2, 4-6, 21, 31]. Likewise, some investigators think that a coronary artery calcification study that shows no calcium significantly diminishes the need for further testing [22]. Detection of Coronary Artery Calcification Several imaging techniques are useful in detecting calcification of coronary arteries. These include plain radiography of the chest, fluoroscopy, sonography, conventional CT, ultrafast CT, and MR imaging. Plain Chest Radiographs Coronary calcification is not easily detected on chest radiographs. Accuracy is only 42% [32] compared with fluoroscopy, which also is not extremely accurate. The chest film appears to be useful only when extensive coronary calcification is present [33]. In another study, where digital radiography was compared with angiography in 77 patients, the detection appeared better with digitalradiography (71% vs 32% for calcifications in the left anterior descending artery and 27% vs 0% for calcifications in the right coronary artery) [34]. Fluoroscopy Fluoroscopy has been widely used to detect calcification of coronary arteries. The sensitivity of fluoroscopy in the detection of calcium as a marker of a coronary artery stenosis of 50% diameter or greater is40-79% with a specificity of 52-95% [35, 36]. The comparative test was angiography. The sensitivity of digital subtraction fluoroscopy is somewhat better (92% vs 63%) [35]. Loecker et al. [37] compared fluoroscopic detection of calcium with angiography in 61 3 asymptomatic young men (mean age, 40 ± 5 years). The authors found a sensitivity of 66%, specificity of 78%, positive predictive value of 38%, and negative predictive value of 92% for significant disease. In any stenosis, the sensitivity was 60%, specificity was 85%, positive predictive value was 68%, and negative predictive value was 80%. These authors concluded that a study that showed no calcium indicated a low risk of significant coronary artery disease, whereas a study showing calcium indicated a substantially increased risk. In this study and those following, a significant angiographic lesion was defined as 50% or greater diameter stenosis on coronary angiograms or a luminal narrowing of greater than 70% area on quantitative coronary angiograms. Uretsky et al. [31] also compared fluoroscopy with coronary angiography for detecting calcification. They studied 600 patients and found a sensitivity for detecting calcium in angiographically significant stenosis of 65% and a specificity exceeding 90% in patients less than 45 years old; the specificity was 85% in patients less than 55 years old. In patients less than 45 years old, a single minimal area of calcification markedly increased the chances of stenosis, whereas calcif i- cation of two or more vessels in individuals between 45 and 64 years substantially increased the chances of detecting significant stenosis. These authors thought that the patient s age and the number of vessels calcified were important predictors of significant stenosis. However, they concluded that the fluoroscopic detection of calcium was not helpful in diagnosing significant stenosis in patients more than 65 years old. In another study, Bobbio et al. [38] showed that the fluoroscopic detection of calcium had a 72% diagnostic and a 67% prognostic accuracy in diagnosing significant coronary artery disease and in predicting a future cardiac event. Neither, however, is extremely high. Kelley and Newell [33] reviewed the value of fluoroscopy for detecting coronary artery calcification. Fluoroscopic detection of coronary calcification is more sensitive than ST depression on a stress ECG; however, the combined predictive value of fluoroscopy and stress ECG was better than for each technique alone. Fluoroscopic detection of calcification is useful in distinguishing ischemic from nonischemic cardiomyopathy. The prognosis for patients with significant coronary artery disease who do not have calcification is better than the prognosis for those who do. The convenience, low cost, and low risk of fluoroscopic screening of coronary artery disease are advantages. However, in older patients, the importance of calcification is decreased. In a study that compared fluoroscopy with high-resolution ultrafast CT, Agatston and Janowitz [16] found that only 52% of calcific deposits (p =.001) could be detected fluoroscopically. The mean calcium density for lesions detected by ultrafast CT was +99 H, whereas that for lesions detected by fluoroscopy was +546 H, signifying that only larger, more calcified plaques are detected with fluoroscopy. Fluoroscopy appeared to be less sensitive for detection of proximal lesions than for detection of distal lesions.

4 1142 STANFORD ET AL. AJA:161, December 1993 Fluoroscopy has several disadvantages. In addition to its only moderate sensitivity, the fluoroscopic detection of catcium depends on the skill and experience of the operator as well as on the duration of the study and the number of views obtained. Other important factors include equipment differences, the patient s body habitus, overlying anatomic structures, and overlying calcifications in structures such as vertebrae and valve annuli. With fluoroscopy, quantification of calcium is not possible, and film documentation is usually not obtained. Intraobserver and interobserver variabilities have not been determined [16]. Sonography On sonograms, atherosclerotic plaques and areas of calcification have increased echogenicity relative to soft tissue. If an association could be established between plaque in the carotid and femoral arteries or abdominal aorta and coronary calcification, imaging of the carotid or femoral arteries might provide an easier method for detecting significant coronary lesions. Megnien et al. [26] found that these techniques could help in detecting coronary atherosclerosis. However, sonography is not widely used clinically for detection of calcification. A new and exciting application is intravascular sonography [40]. By using transducers with rotating reflectors mounted on the tips of catheters, it is possible to obtain cross-sectional images of the coronary arteries. The sonograms provide information not only about the thickness of the artery but also about the tissue characteristics of the arterial wall. Calcification is seen as a hyperechoic area with shadowing; fibrotic noncalcified plaques are seen as hyperechoic areas without shadowing [41]. This technique requires a transducer to be placed directly within the lumen of the coronary artery. Although invasive, the technique is important because it can show atherosclerotic involvement in patients with normal findings on coronary arteriograms [42-44]. Conventional CT Because calcium causes attenuation of the X-ray beam, CT is extremely sensitive in detecting calcification. The limitations of conventional CT are slow scan times, motion artifacts, volume averaging, breathing misregistrations, and inability to quantify the extent of the plaque. Representative CT images of coronary calcification are shown in Figure 1. Timins et al. [45] found sensitivities of 16-78%, specificities of %, and positive predictive values of % for CT detection of coronary calcification as a marker of significant angiographic stenosis. CT findings in the right coronary artery had the poorest correlation with angiographic findings. They concluded that significant coronary artery disease is likely to be present when coronary calcification is seen on CT scans of the chest. Conventional CT is useful for detection of coronary artery calcification. Moore et al. [46] devised a scoring system for coronary calcification and compared the detection of calcification on conventional CT scans with the detection of 70% or greater diameter stenosis on angiograms. Extensive calcification had a high positive predictive value for significant disease. Angiograms showed some stenosis in 88% of calcified vessels and 57% of noncalcified vessels detected on CT scans. Among those vessels without luminal stenosis, 33% still showed some evidence of calcification. Among vessels with stenosis of any degree, 69% showed some calcification. In this study, 10-mm thick sections were scanned and the scan times were not stated, so smaller calcifications might have been missed. Reinm#{252}ller and Lipton [47] used CT, fluoroscopy, and angiography in a study of 47 patients whose mean age was 57 years. CT scans showed calcification in 62% of vessels with significant lesions on angiography, whereas fluoroscopy showed it in only 35%. In the asymptomatic group, coronary calcification was found in only 4%. In this study, CT showed calcification in all patients in whom fluoroscopy showed calcification and in all patients in whom angiography showed Fig. 1.-A-C, Picker (A), Siemens DRH (B), and Imatron C-i 00 ultrafast (C) CT scans of coronary arteries in a 63-year-old patient. Scans were taken within 1 day of each other. Picker scan was a 2-mm, 2-sec scan at 95 ma and processed with a sharp (bone) algorithm. Siemens scan was a 2- mm, 2-sec scan at 125 kv and processed with a bone algorithm. Ultrafast ci scan was a 3-mm 100-msec scan at 630 ma and processed with a sharp algorithm. Scans were at identical levels. On each scan, an arrow points to same calcification in left anterior descending coronary artery.

5 AJA:161, December 1993 CORONARY ARTERY CALCIFICATION 1143 stenosis. Overall, CT showed calcification in 50% more yessels than fluoroscopy did. Calcification in aortic and mitral valves and within the myocardium at sites of infarction interfered with the imaging. The CT slices were 8-mm thick. Generally, conventional CT is superior to fluoroscopy for detecting calcification in coronary arteries [47] and to angiography in detecting calcification in significant coronary artery disease [47, 48]. Ultrafast CT Ultrafast CT has significant advantages in detecting calcification of coronary arteries. Images with pixel sizes of mm2 can be obtained in 100 msec. Because ofthis rapid imaging and high spatial resolution and because 3-mm-thick sections can be scanned, small amounts of calcium can be detected with considerable accuracy [16] (Fig. 2). With ultrafast CT, the dose of radiation is less than 1.1 cgy, and no contrast material is required. No specific Hounsfield value indicates that a lesion is calcified. Therefore, an arbitrary level of +130 H has been chosen by some investigators. This level is based on the premise that the attenuation of soft tissues is about +50 H, and #{247}1 30 H is enough of an increase that any structure with an attenuation of #{247}130H probably contains calcium. The results of a study by Simons et al. [49] support this premise. Although +130 H has been generally accepted as an indication of calcification, disagreement exists as to the density area needed to define a lesion as calcific. Probably a +130 H density area of 2 mm2 or greater indicates a calcific lesion, whereas areas of less than 2 mm2 should be considered noise. The 100-msec speed minimizes cardiac motion, and the proximal coronary arteries can be imaged during one breath-hold; this allows detection of pixels of more than +130 H. Also, software available on the ultrafast CT scanner enables the operator to quantify the area of calcification, which is important in monitoring the progression and/or possible regression of disease. In addition, because contiguous sections can be scanned, three-dimensional reconstruction is possible. When the scanner s software was used to determine interobserver and intraobserver variabilities, the corre- Fig. 2.-A, Ultrafast CT scan shows extensive calcification of left anterior descending (arrow) and circumflex coronary artery (arrowhead). B, Peak density and area of calcification within a specific region of Interest are calculated by scanner software. Peak density for A = 861 H, B = 527 H, C = 831H,D=366H,E=612H,F=303H,G=958 H. Area for A = 46.9 mm2, B = 39.4 mm2, C = 25.0 mm2, D = 6.7 mm2, E = 19.6 mm2, F = 3.3 mm2, G = 24.5 mm2. lation factor was 0.99 [16]. An additional advantage of ultrafast CT is that precursors of calcification formation can be detected because they are thought by some investigators to have densities between +115 and +130 H. Tanenbaum et al. [50] and Janowitz et al. [51] were the first to report on the use of ultrafast CT for detecting calcific deposits in the coronary arteries. Tanenbaum et al. used ultrafast CT and coronary angiography to examine 54 patients. The examinations were done within 36 days (mean) of each other. Stenosis of the coronary artery was considered significant when luminal narrowing was more than 70%, except in instances of calcification of the left main coronary artery. In these, stenosis more than 50% was considered significant. Angiograms showed significant coronary artery disease in 43 patients, and 88% of these had detectable calcium in at least one coronary artery. The specificity in this study was 100%. They used 50-msec scans with 1.5 mm2 of spatial resolution, and the scans covered the proximal 76 mm of the coronary arteries. In 1990, Agatston et al. [22] reported the results of the first large series in which ultrafast CT was used to detect calcification of the coronary arteries. These investigators used 100-msec scans and 3-mm-thick slices. They studied 584 consecutive patients, 50 of whom also had fluoroscopy. In this group, 109 patients had a history of coronary artery disease, and 475 did not. (Coronary artery disease was established by a history of myocardial infarction [22 patients] or angiographic evidence of more than 50% diameter narrowing of coronary arteries [87 patients]). The mean age was 48 years. Significant differences (p =.0001) were found in the group with coronary artery disease vs the group without coronary artery disease. The sensitivities were 71-74% and the specificities were %. The negative predictive value of a zero calcification score was %. Ultrafast CT showed calcium in 90% and fluoroscopy showed it in 52%. The authors concluded that ultrafast CT appears to be an excellent technique for detecting and quantifying calcification of coronary arteries. The study showed that the mean totalcalcium score increased with age. Agatston et al. [19] also evaluated 313 patients in a collaborative study with a Japanese hospital: 161 patients had

6 1144 STANFORD ET AL. AJA:161, December 1993 angiographic evidence of coronary obstructive disease; 152 had no coronary disease or had nonobstructive disease. The mean calcium score increased significantly (p = <. 0001) from no disease through disease involving three vessels. The overall sensitivity for detecting calcification in association with obstructive disease was 95%, and the specificity was 76%. For nonobstructive disease, the sensitivity was 90%, and the specificity was 62%. The mean age of the patients was 61 ± 1 2 years. Breen et al. [52] studied 100 patients years old who had ultrafast CT and angiography. Significant obstruction was defined as more than 50% narrowing of the vessel diameter on the angiogram. The sensitivity of finding calcium in significant angiographic stenosis was 100%, and the specificity was 47%. In cases in which angiograms showed stenosis of more than 10%, the sensitivity was 94%, and the specificity was 72%. They concluded that ultrafast CT screening was an important technique in patients less than 60 years old. In this series, eight patients with calcification had no angiographic evidence of coronary artery disease, and 28 patients with calcification had mild or moderate coronary artery disease. Therefore, ultrafast CT shows promise as a noninvasive method for detecting calcification and thus providing evidence of coronary atherosclerosis when the disease is in its nonobstructive preclinical stage. Additionally, ultrafast CT is superior to conventional risk-factor analysis in the detection of nonobstructive disease for predicting future cardiac events [16]. Pathologic studies have supported the importance of these calcification observations. Simons et al. [53] sectioned postmortem coronary arteries from 1 3 cadavers and evaluated 3-mm slices both microscopically and with ultrafast CT (mean age of patient, 43 years). These investigators measured the luminal cross-sectional area of the coronary artery and divided the subjects into three categories: no disease, 1-49% stenosis, and % stenosis. On ultrafast CT scans, the area of voxels with calcium increased from a mean of 0.1 mm2 in those without disease, to 1.8 mm2 in those with 1-49% narrowing, to 6.6 mm2 in those with % narrowing (p =.005 between each group). The authors concluded that calcification as detected on ultrafast CT scans correlated well with severity of stenosis and that ultrafast CT could be used as a screening technique to detect coronary artery disease in humans. They found that in detecting some form of atheromatous disease, the ultrafast CT detection of calcification had a sensitivity of 77% and a specificity of 81% as compared with pathologic findings. The ultrafast CT study was more sensitive for proximal than for distal coronary artery disease [49]. Bormann et al. [54] used the ultrafast CT calcium score as a method of predicting significant stenosis of the coronary artery. They examined the proximal 2 cm of each coronary artery and found that, although the presence of calcification increased with age, calcium scores were not predictive of stenotic lesions at the specific sites of calcification and that sums of calcium scores either within a single vessel or within allvessels could not be used to predict significant stenoses within the coronary artery circulation. No receiver-operatingcharacteristic curve could be found that would suggest a clinically useful calcium score as an indicator of more than 70% stenosis. Although the calcium score could not be used to predict significant site-specific stenosis, Stanford et al. [55] determined that absence of calcium on ultrafast CT scans appeared to be a significant indicator of the absence of coronary artery disease. In a group of 150 patients from two institutions, only one patient had significant stenosis in the absence of calcification. The angiographic and ultrafast CT studies were done within 18 days (mean, 1.7 days) of each other. Ultrafast CT is useful in following the progression and regression of coronary artery disease. Janowitz et al. [56] evaluated coronary calcification in 25 subjects who had ultrafast CT twice, 406 days apart. Twenty subjects who had evidence of calcium in the first study had statistically significant increases in the total calcium score in the second study. Subjects with angiographically proved coronary artery disease showed a 48% increase in calcified plaque volume; asymptomatic subjects had a 22% increase. Smaller calcific deposits often coalesced into larger calcific deposits. Ninetyeight percent of the deposits seen in the first study were accounted for in the second study. Also, patients with obstructive coronary artery disease had significantly more new calcific deposits than did the asymptomatic group (55 vs 1 8). From these data, the authors concluded that ultrafast CT was useful for studying the natural history of coronary artery disease and changes that occur after modification of risk factors. Breen et al. [52] also found that ultrafast CT showed calcification in all patients with angiographic evidence of significant coronary artery disease, whereas some of those with no angiographic evidence of coronary artery disease had calcifications detected on ultrafast CT scans and others did not. As mentioned previously, however, another study has shown that coronary calcium, per se, is not a reliable indicator of significant stenosis [55]. Megnien et al. [26] compared ultrafast CT assessment of coronary artery calcification with sonographic assessment of extracoronary plaques in asymptomatic patients with type Ill hypercholesterolemia. They found that 65% had coronary calcification and 72% had extracoronary artery plaques in the abdominal aorta, carotid arteries, and femoral arteries. The authors thought that this close correlation between coronary artery calcification and extracoronary plaques suggests that sonographic screening of extracoronary vessels could be helpful in detecting coronary calcification in high-risk asymptomatic persons. Calcification of coronary arteries was also associated with increased age and elevated serum levels of triglycerides. This association was independent of the levels of high-density lipoproteins. MR Imaging Fibrous tissue, scar tissue and calcium have little signal on MR images, all appear as signal voids. As these lesions cannot be differentiated, and because MR imaging has poorer resolution than CT, this technique is generally not useful for detecting coronary calcification.

7 AJA:161, December 1993 CORONARY ARTERY CALCIFICATION 1145 Summary It is generally accepted that coronary artery calcification is a marker of atherosclerosis. It is also important to understand that calcification indicates atheromata within the intima and that calcification may occur before the atheromata narrows the lumen sufficiently to be recognized on stress ECGs or stress thallium tests. Coronary artery calcification increases with age and with multiple vessel involvement; however, the amount of calcification does not equate with a site-specific stenosis. Although it has been reported otherwise, coronary artery calcification probably does not predict future cardiac events because it has repeatedly been shown that thrombotic occlusions resulting in myocardial infarctions can occur in areas of noncalcified plaque. However, the majority of patients having coronary artery events will have detectable calcification somewhere within their coronary arterial tree. Significant stenoses, as defined by a 50% diameter narrowing on coronary angiograms or a 70% area luminal occlusion on quantitative coronary angiography, will probably be absent in patients who have no calcification within their coronary arterial tree. Although several imaging techniques can show coronary artery calcification, fluoroscopy and CT appear to be the most useful. Because conventional CT has slower scan times, the 100-msec scan time of the electron beam scanners coupled with mm resolution and ability to image 3-mm slice thicknesses appear to give ultrafast CT advantages over these other imaging techniques. If spiral CT scanners allow accurate detection of calcification, another imaging technique would be available. At the present time, the detection of coronary calcification has its primary utility in three areas: the early detection of calcification in persons less than 40 years old in whom riskfactor modification may be indicated in spite of the absence of symptoms; the evaluation of progression or possible regression of calcification by quantifying the extent of calcification present and then monitoring any changes in the calcification as an indication of the activity of the atherosclerotic process; and the verification of the absence of calcification at any age, because in all except 5-6% of persons, this would appear to rule out significant stenosis. With the advent of newer imaging devices, radiologists will play an increasing role in the detection and follow-up of coronary atherosclerosis, and it behooves the radiologic cornmunity to understand the atherosclerotic process and the significance of coronary artery calcification. The jury is still out on the importance of calcification, especially in the older patient, and what should be its impact in the overall management of patients with atherosclerosis. REFERENCES 1. Heart and stroke facts. Dallas: American Heart Association, 1992: Blankenhorn DH. Coronary arterial calcification: a review. Am J Med Sci : Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation 1988;77: Beadenkopf WG, Daoud AS, Love BM. Calcification in the coronary arteries and its relationship to arteriosclerosis and myocardial infarction: a review of the problem and a description of a patient with involvement of peripheral, visceral, and coronary arteries. AJR 1964;92: Warburton AK, Tampas JP, Soule AB, Taylor HC Ill. Coronary artery calcification: its relationship to coronary artery stenosis and myocardial infarction. Radiologyl968;91 : Frink Ri, Achor RWP, Brown AL Jr, Kincaid OW, Brandenburg RO. Significance ofcalcification ofthe coronary arteries. Am J Caniioll97O;26: McCarthy JH, Palmer FJ. Incidence and significance of coronary artery calcification. Br Heart J 1974:36: Eggen DA, Strong JP, McGill HC Jr. Coronary calcification: relationship to clinically significant coronary lesions and race, sex and topographic distribution. Circulation 1965;32: Blankenhom DH, Stern D. Calcification of the coronary arteries. AJR 1 959;81 : Ambrose JA, Tannebaum MA, Alexopoulos D, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. JAm CoIl Cardiollg88;12: Little WC, Constantinescu M, Applegate AJ, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation 1988;78: Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis 1989;9[suppl l]:l-19-l Enos WF, Holmes RH, Beyer J. Coronary disease among United States soldiers killed in action in Korea. JAMA 1953;152: McNamara JJ, Molot MA, Stremple JF, Cutting AT. Coronary artery disease in combat casualties in Vietnam. JAMA 1971;216: Fuster V, Stein B, Ambrose JA, Badimon L, Badimon JJ, Chesebro JH. Atherosclerotic plaque rupture and thrombosis: evolving concepts. Circulation 1990;82[suppl li]:ll-47-ll Agatston AS, Janowitz WA. Coronary calcification: detection by ultrafast computed tomography. In: Stanford W, Aumberger JA, eds. Ultrafast cornputed tomography in cardiac imaging: principles andpractice. Mt Kisco, NY: Futura, 1992: Aoberts WC, Buja LM. The frequency and significance of coronary arterial thrombi and other observations in fatal acute myocardial infarction: a study of 107 necropsy patients. Am J Med 1972;52: Moise A, Lesperance J, Theroux P, Taeymans Y, Goulet C, Bourassa MG. Clinical and angiographic predictors of new total coronary occlusion in coronary artery disease: analysis of 31 3 nonoperated patients. Am J Cardiol 1984;54: Agatston AS, Janowitz WA, Aizawa N, et al. Quantification of coronary calcium reflects the angiographic extent of coronary artery disease (abstr). Circulation 1991;84[suppl Il]:Il Kannel WB, Abbott AD. Incidence and prognosis of unrecognized myocardial infarction: an update on the Framingham Study. N EngI J Med 1984;311: Aifkin AD, Parisi AF, Folland E. Coronary calcification in the diagnosis of coronary artery disease. Am J Cardioll97g;44: Agatston AS, Janowitz WA, Hildner FJ, Zusmer NA, Viamonte M Jr, Detrano A. Quantification of coronary artery calcium using ultrafast computed tomography. JAm Coil Cardiol 1990;15: Austin MA. Plasma triglyceride and coronary heart disease. Arterioscler Thromb 1991;11: Glynn AJ, Aosner B, Silbert JE. Changes in cholesterol and triglyceride as predictors of ischemic heart disease in men. Circulation 1982;66: Kannel WB, Castelli WP, Gordon T, McNamara PM. Serum cholesterol, lipoproteins, and the risk of coronary heart disease: the Framingham Study. Ann Intern Med : Megnien JL, Sene V, Jeannin 5, et al. Coronary calcification and its relation to extra coronary atherosclerosis in asymptomatic hypercholesterolemic men. Circulation 1992;85: Brown BG, Xue-Qiao Z, Sacco DE, Albers JJ. Lipid lowering and plaque regression: new insights into prevention of plaque disruption and clinical events in coronary disease. Circulation 1993;87: Margolis JA, Chen JTT, Kong Y, Peter AH, Behar VS, Kissio JA. The diagnostic and prognostic significance of coronary artery calcification: a report of 800 cases. Radiology 1980;137: Kragel AH, Reddy SG, Wittes JT, Roberts WC. Morphometric analysis of the composition of atherosclerotic plaques in the four major epicardial coronary arteries in acute myocardial infarction and in sudden coronary death. Circulation 1 989;80:

8 1146 STANFORD ET AL. AJR:161, December Strong JP, Solberg LA, Restrepo C. Atherosclerosis in persons with coronary heart disease. Lab Invest 1 968;18: Uretsky BF, Aifkin AD, Sharma SC, Reddy PS. Value offluoroscopy in the detection of coronary stenosis: influence of age, sex, and number of yessels calcified on diagnostic efficacy. Am Heart J 1988;115: Souza AS Jr, Bream PA, Elliott LP. Chestfilm detection of coronary artery calcification: the value of the CAC triangle. Radiology 1 978; 129: Kelley MJ, Newell JD. Chest radiography and cardiac fluoroscopy in coronary artery disease. Cardiol Ciln 1983;1 : Sakuma H, Takeda K, Hirano T, et al. Plain chest radiograph with computed radiography: improved sensitivity for the detection of coronary artery calcification. AiR 1988;151: Detrano A, Froelicher V. A logical approach to screening for coronary artery disease. Ann Intern Med 1987;106: Carboni GP, Celli P, D Ermo M, Santoboni A, Zanchi E. Combined cardiac cinefluoroscopy, exercise testing and ambulatory ST-segment monitoring in the diagnosis of coronary artery disease: a report of 1 04 symptomatic patients. IntJ CardioIl985;9: Loecker TH, Schwartz AS, Cotta CW, Hickman JR Jr. Fluoroscopic coronary artery calcification and associated coronary disease in asymptomatic young men. JAm Coil Cardiol 1992;19: Bobbio M, Pollock BH, Cohen I, Diamond GA. Comparative accuracy of clinical tests for diagnosis and prognosis of coronary artery disease. Am J Cardiol 1988;62: Detrano A, Markovic D, Simpfendorfer C, et al. Digital subtraction fluoroscopy: a new method of detecting coronary calcifications with improved sensitivityforthe prediction of coronary disease. Circulation 1985;71: WaIler BF, Pinkerton CA, Slack JD. Intravascular ultrasound: a histological study of vessels during life. The new gold standard for vascular imaging. Circulation 1992;85: Honye J, Mahon DJ, Tobis JM. Intravascular ultrasound imaging. Trends Cardiovasc Med : Tobias JM, Mallory J, Mahon D, et al. Intravascular ultrasound imaging of human coronary arteries in vivo: analysis of tissue characterizations with comparison to in vitro histological specimens. Circulation : Nissen SE, Gurley JC, Grimes CL, et al. Intravascular ultrasound assessment of lumen size and wall morphology in normal subjects and patients with coronary artery disease. Circulation : Mintz GS, Douek P, Pichard AD, et al. Target lesion calcification in coronary artery disease: an intravascular ultrasound study. J Am Coil Cardiol 1992;20: Timins ME, Pinsk A, Sider L, Bear G. The functional significance of calcification of coronary arteries as detected on CT. J Thorac Imaging 19917: Moore EH, Greenberg AW, Merrick SH, Miller SW, McLoud TC, Shepard JO. Coronary artery calcifications: significance of incidental detection on CT scans. Radiologyl989;172: AeinmOller A, Lipton MJ. Detection of coronary artery calcification by computed tomography. Dyn Cardiovasc Imaging 1987;1 : Masuda Y, Naito 5, Aoyagi Y, et al. Coronary artery calcification detected by CT: clinical significance and angiographic correlates. Angiology 1990;12: Simons DB, Schwartz AS, Sheedy PF, Breen JF, Rumberger JA. Noninvasive detection of anatomic coronary artery disease by ultrafast CT: a quantitative pathologic study. JAm Coil CardioIl99l;17:104A 50. Tanenbaum SR, Kondos GT, Veselik KE, Prendergast MA, Brundage BH, Chomka EV. Detection of calcific deposits in coronary arteries by ultrafast computed tomography and correlation with angiography. Am J Cardiol 1989;63: Janowitz WA, Agatston AS, King D, Smoak WM, Samet P, Viamonte M. High resolution ultrafast CT of the coronary arteries: new technique for visualizing coronary artery anatomy (abstr). Radiology 1988;169(P): Breen JB, Sheedy PF, Schwartz AS, et al. Coronary artery calcification detected with ultrafast CT as an indication of coronary artery disease. Radiology 1992;185: Simons DB, Schwartz AS, Sheedy PF, et al. Coronary artery calcification by ultrafast CT predicts size: a necropsy study. Circulation 1990;82[suppl III]:III Bormann JL, Stanford W, Stenberg AG, et al. Ultrafast computed tomographic detection of coronary artery calcification as an indicator of stenosis. Am J Cardiac Imaging 1992;6: Stanford W, Breen J, Thompson B, et al. Can the absence of coronary calcification on ultrafast CT be used to rule out of (sic) nonsignificant coronary artery stenosis? JAm Coil Cardioll992;19:189A 56. Janowitz WA, Agatston AS, Viamonte M Jr. Comparison of serial quantitative evaluation of calcified coronary artery plaque by ultrafast computed tomography in persons with and without obstructive coronary artery disease. Am J CardioIl99l;68:1-6