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  1. 1. Cardiac Imaging • Original Research Kelly et al. CTA in Patients Without Coronary Calcification Cardiac Imaging Original Research Coronary CT Angiography Findings in Patients Without Coronary Calcification Jason L. Kelly 1 David Thickman2 Simeon D. Abramson1 Pei R. Chen1 Stanley F. Smazal1 Matthew J. Fleishman1 Sharmila C. Lingam1 Kelly JL, Thickman D, Abramson SD, et al. Keywords: Agatston method, atherosclerosis, calcium scoring, coronary artery disease, coronary calcifications, coronary CT angiography DOI:10.2214/AJR.07.2954 Received July 29, 2007; accepted after revision January 28, 2008. 1 Thoracoabdominal Imaging, Radiology Imaging Associates, 10700 E Geddes Ave., Ste. 200, Englewood, CO 80210. Address correspondence to J. L. Kelly (jason.kelly@riaco.com). 2 Nighthawk Radiology Services, Coeur d’Alene, ID. AJR 2008; 191:50–55 0361–803X/08/1911–50 © American Roentgen Ray Society 50 objective. Coronary calcification detected by CT is a marker for atherosclerotic disease with prognostic significance. However, potentially unstable plaque is characterized by a high lipid content rather than calcification, which may make detection using the calcium score difficult. To assess the prevalence and severity of atherosclerotic disease in patients without coronary calcification, we evaluated findings in patients with a normal calcium score undergoing coronary CT angiography (CTA). materials and METHODS. Data from 794 consecutive coronary CTA examinations performed between February 2005 and May 2007 were reviewed. The calcium scores were determined as part of coronary CTA examinations, and calcium was quantified according to the Agatston method. Patients underwent coronary CTA because of high risk for coronary artery disease (53%) or atypical symptoms or abnormal stress test results (47%). On coronary CTA, plaque was characterized as mild disease without hemodynamically significant stenosis, moderate disease without hemodynamically significant stenosis, moderate stenosis (50–70% luminal narrowing), or severe stenosis (> 70% luminal narrowing). RESULTS. Of the 729 patients included in the study, 325 (45%) had a normal calcium score. Of these, 167 (51%) had noncalcified plaque on coronary CTA. Twelve (3.7%) of those with a normal calcium score had at least moderate stenosis, five (1.5%) of whom had severe stenosis. Eight of the 12 patients with significant stenosis underwent invasive angiography and coronary stenting. CONCLUSION. A considerable atheroma burden including significant stenoses may be present in patients with no coronary calcification. Although the calcium score does add prognostic value to standard risk factors and serum markers, imaging the vessel wall directly may be helpful to identify noncalcified plaque and guide therapy. T he presence of calcium in the coronary arteries has been shown to be a marker for atherosclerotic disease [1, 2]. This calcium is detectable on CT and is quantifiable using the Agatston method [3, 4], which adds prognostic information to available demographic and serologic risk stratification [5, 6]. However, CT performed for calcium scoring is not able to show noncalcified atheroma or stenosis. These findings are inferred from the presence of calcified plaque using probabilistic models [7]. Invasive angiographic studies have been performed to evaluate the significance of disease in patients with normal calcium scores. Those studies have shown a high negative predictive value for calcium scoring: 80% for any disease and up to 100% for significant stenosis [8, 9]. However, angiography alone has also been shown to significantly underestimate plaque in anatomic studies [10], particularly in vessels with compensatory positive remodeling. Coronary CT angiography (CTA) is an emerging noninvasive technique that can evaluate both calcified plaque and noncalcified plaque. Coronary CTA is able to show the lumen of the coronary arteries as well as the vessel wall, analogous to intravascular sonography [11–13]. Multiple studies have shown coronary CTA to have a high negative predictive value for the detection of coronary atherosclerosis: greater than 95% for significant stenosis [14, 15] and approximately 90% for any plaque [11, 12]. Because coronary CTA uses IV contrast material, it is able to detect lowvolume, noncalcified plaque that is not visible on CT performed for calcium scoring (Fig. 1). Identification of small-volume soft plaque is the crux of coronary artery disease management. Investigators have repeatedly shown AJR:191, July 2008
  2. 2. CTA in Patients Without Coronary Calcification A B Fig. 1—52-year-old man with increased fatique on long-distance runs. A, Coronary CT angiography image shows large soft plaque (between arrows) that is causing severe stenosis in the left main coronary artery. B, Corresponding coronary angiogram shows severe stenosis of the left main artery (arrow). The patient went on to have a stent placed. that acute coronary syndromes most frequently result from the rupture of these small plaques, which are generally not flow-limiting, do not cause stenosis, and may not be calcified [16]. Calcification is generally a marker of plaque stability, whereas unstable plaque is characterized by a large lipid core, thin fibrous cap, and inflammation. This unstable plaque has been termed the “vulnerable plaque” and is the target of current treatment algorithms. Although CT performed for calcium scoring is able to detect calcified atheromatous disease, patients with only noncalcified plaque are a potential diagnostic weakness. The detection of noncalcified plaques and stenoses has potential importance because it encourages therapeutic management to be initiated in the earliest stages of plaque formation and identifies previously occult disease in a group of patients at high risk for plaque rupture. To assess the presence of atherosclerosis in patients with normal calcium scores, we reviewed our findings in patients undergoing CT for calcium scoring as part of a coronary CTA examination. Materials and Methods A total of 794 consecutive coronary CTA examinations in 794 patients were performed from February 2005 to May 2007 at three sites. Calcium scores were not obtained in patients with coronary stents or bypass grafts, and those patients were excluded. In the remaining 729 examinations, a CT scan was obtained for calcium scoring immediately before CTA. The mean age of the patients in our study was 56 years (range, 17–77 years), and 32% were female. AJR:191, July 2008 TABLE 1:  Inclusion Criteria for Coronary CT Angiography Criteria Atypical chest pain Abnormal or indeterminant exercise stress test No. (%) of Patients (n = 729) 204 (28) 36 (5) Abnormal or indeterminant nuclear stress test 102 (14) Age ≥ 45 y 649 (89) Family history of heart disease 370 (51) Hyperlipidemia 191 (26) Hypertension 187 (26) Diabetes 48 (7) Smoking (current smoker or history of smoking) 61 (8) Patient ethnicity was not recorded, although most patients were white. For each study, the calcium score, presence and type of plaque, and study quality were recorded. Follow-up data, including invasive angiography, intravascular sono­ raphy, and stress g test results, were collected as well. This retrospective study met the standards of our hospital’s review board and was exempted from review. Patients were referred for atypical symptoms (28%), abnormal or indeterminant findings on exercise stress test (5%), abnormal or in­ eter­ d minant findings on nuclear stress test (14%), or coronary artery disease assessment in asympto­ matic patients with risk factors (53%) (Table 1). The scanning criteria for asymptomatic patients included the following: age of 45 years or more; family history of heart disease, hyperlipidemia, hypertension, or diabetes; or smoking (current or previous). Any patient with abnormal or indeter­ minant findings on a stress test, either exercise or nuclear, was considered to be symptomatic. For all patients less than 45 years old, coronary CTA was performed as part of the evaluation for atypical chest pain or abnormal findings on a stress test. Coronary CTA was not performed for evaluation of suspected acute coronary syndrome. When a patient arrived at the radiology department, a set of vital signs was taken and oral metoprolol or verapamil was administered according to the patient’s resting heart rate with a goal of less than 60 beats per minute (bpm) during scanning. Blood pressure, heart rate, and pulse oximetry were monitored. After 1 hour, a second dose of oral metoprolol was given if necessary and tolerated. A maximum of 200 mg of metoprolol was administered. In the case of contraindication to β-blockade, 240 mg of oral verapamil was given. Oxygen (2 L/min) was administered via nasal cannula. In the absence of a contraindic­ ation, 0.4 mg of sublingual nitro­ lycerin spray g (Nitrolingual Pumpspray, Sciele Pharma) was administered before the timing bolus. Imaging was performed on a 64-MDCT scan­ ner (Somatom Sensation 64, Siemens Medical 51
  3. 3. Kelly et al. Solutions; or LightSpeed VCT, GE Healthcare). Before coronary CTA was per­ ormed, patients f underwent an unenhanced prospectively gated study for measurement of coronary artery calci­ fication. All coronary CTA studies were perform­ ed with a total of 100 mL of IV contrast material, either iopamidol (Isovue 370, Bracco) or iohexol (Omnipaque 350, GE Healthcare), ad­ inistered m through an ante­ ubital vein at 5–6 mL/s. Scanning c was performed with retrospective gating and a slice thickness of 0.6 mm. Dose modulation techniques were used when the breath-hold heart rate during the test bolus showed variability of less than 5 bpm. Images were interpreted by at least one of seven radiologists on a 3D workstation (Vitrea, Vital Images; or CardIQ Pro, GE Healthcare) using axial and multiplanar reformatted data. Inter­ observer variability was not evaluated, although most cases were double-read to promote con­ sistency of interpretations. Three readers were involved in the interpretation of 98% (778 of 794) of the studies. Calcium scoring was performed according to the Agatston method [3] before evaluation of coronary CTA. All vessels with a luminal diam­ eter of greater than 2 mm were evaluated on coronary CTA, including the left main (LM) artery, left anterior descending (LAD) artery, diagonal branches, circumflex artery (Cx), obtuse marginal branches, right coronary artery (RCA), acute marginal branches, posterior descending artery, and post­ rior lateral segmental branches. e Plaque was characterized in one of four cate­ gories: mild disease without hemodynamically significant stenosis, moderate disease without hemo­ d ­ ynamically significant stenosis, moderate sten­ sis o (50–70% diameter reduction), or severe stenosis (> 70% diameter reduction). Hemo­ ynam­cally d i significant stenosis was defined as ≥ 50% diameter reduction. Mild disease was de­ ned as plaques fi resulting in a diameter reduction of less than 20% and involving only short segments (< 2 cm) of one or two coronary arteries. Moderate disease without stenosis included lesions causing diameter reduc­ tion of 20–50%, involved segments of at least moderate length (≥ 2 cm), or involved three vessels (or a combination of these findings). The degree of stenosis was measured using the narrowest dim­ ension of the lumen at the level of stenosis compared with a more normal lumen diameter distally. In patients with a technically limited coronary CTA examination and a normal calcium score, vessel segments that could not be evaluated were assumed to be normal. The p values were calculated using the twotailed Fisher’s exact test or unpaired Student’s t test. 52 TABLE 2: Demographic Data in Patients with a Normal Calcium Score Coronary CT Angiography Finding (No. [%] of Patients) Characteristic Normal Patients Female Mean age (y) Symptoms present Noncalcified Plaque 158 (49) 82 (52) 66 (40) 49 53 65 (41) p 167 (51) 78 (47) 0.008 < 0.001 0.32 TABLE 3:  Plaque Distribution in Patients with a Normal Calcium Score Coronary CT Angiography Finding No. of Patients Normal 158 Mild disease 147 Moderate disease, no hemodynamically significant stenosis 8 Moderate stenosis (50–70% luminal narrowing) 7 Severe stenosis (> 70% luminal narrowing) 5 Results A total of 325 patients (45%) had a normal calcium score. All 404 patients with an abnormal calcium score had detectable plaque on coronary CTA. Overall, 21.7% (158 of 729) had normal findings, 22.9% (167 of 729) had only noncalcified plaque, and 55.4% (404 of 729) had calcified plaque. Hemodynamically significant stenosis was seen in 149 of 729 patients (20%). Patients with both a normal calcium score and negative coronary CTA findings (Table 2) had a mean age of 49 years, significantly less than the mean age of 53 years for those with positive coronary CTA findings (p < 0.001). Plaque was seen in 66 of 148 women (45%) with a normal calcium score, which is significantly less (p = 0.026) than the 101 of 177 men (57%) with a normal calcium score. In 167 patients with only soft plaque, mild disease was present in 147 (88%), and moderate disease without stenosis was present in eight (4.8%). Twelve (7.2%) had at least moderate (≥ 50%) stenosis, and five (3%) had severe stenosis (> 70%) (Table 3). The average age of patients with a normal calcium score and significant stenosis was 54 years. Six of 148 women (4.1%) showed a significant stenosis without coronary calcium, as did six of 177 men (3.4%); this difference was not significant (p = 0.78). Eight of the 12 had no chest pain, although three of the asymptomatic patients had abnormal findings on either a nuclear stress test or a treadmill stress test. Eight of the 12 patients with significant stenosis underwent catheterization, including five of six patients with an abnormal stress test and all patients with severe stenosis. One patient with abnormal findings on a stress test in the vascular distribution of a moderate stenosis refused to undergo angiography. Catheter angiography images and reports were reviewed, and coronary CTA findings were confirmed in all patients with significant stenosis. Stenosis measurements on coronary CTA were within 5% of the angiographic measurements, and there was complete agreement between coronary CTA and catheter angiography as to categorization of stenoses as moderate or severe. The physician performing catheter angiography was aware of the coronary CTA results. In all eight patients who underwent catheterization, a stent was placed. No patient with a normal calcium score and a < 50% lesion on coronary CTA underwent catheter angiography to our knowledge. Symptoms did not correlate with the presence of disease or significant stenosis. Coronary CTA showed plaque in 571 patients, 278 (49%) of whom were symptomatic. Of 158 patients with a normal calcium score and normal coronary CTA, 65 (41%) presented with symptoms. This difference was not statistically significant (p = 0.11). Symptoms were present in 78 of 167 patients (47%) with plaque on coronary CTA in the absence of coronary calcium. This difference was also not statistically significant (p = 0.32) when compared with patients with a normal calcium score and normal coronary CTA. Seven of 12 patients (58%) with significant stenosis and a calcium score of 0 had symptoms, which was not significant (p = 0.36) either. AJR:191, July 2008
  4. 4. CTA in Patients Without Coronary Calcification Patient motion, heart rate variability, and poor contrast bolus were causes of limited studies. Visualization of each vessel (LM, LAD, RCA, and Cx) including major branches (> 2 mm luminal diameter) was categorized as excellent, adequate, limited, or poor. Adequate visualization denotes very minimal artifact, but diagnostic-quality images. Limited evaluation denotes vessels in which mild plaque might be missed because of artifact. Poor-quality visualization denotes vessels in which a hemodynamically significant stenosis might be missed. In 325 patients with a normal calcium score, 27 (8.3%) had at least one vessel for which visualization was considered either limited or poor. In these 27 patients, visualization of 45 vessel segments was categorized as limited and visualization of 14 segments was characterized as poor. The RCA was the vessel most commonly characterized as showing limited or poor visualization. Discussion We found a high prevalence of noncalcified plaque in patients with a calcium score of 0, with fewer than half of the patients in our study group being disease-free. Considering all 729 calcium score studies, this yields a false-negative rate of 29% for any plaque in our patient population and underscores the limitations of calcium scoring. Although most of these patients had mild disease, 4% showed a significant stenosis and eight went on to coronary stenting. The high prevalence of nonocclusive plaque (< 50%) found in our study is likely due to the high sensitivity of coronary CTA for plaque detection. The true prevalence of subclinical coronary artery disease in the general population is probably unknown, but it is certainly high. Autopsy studies have confirmed a high incidence of noncalcified plaque beginning in young adults. Strong et al. [17], for example, found that 47.4% of 30- to 34-year-old adults autopsied had raised RCA plaques, but only 2.9% had calcified plaques. Clinical heart disease prevalence increases with age and has been estimated to be present in 35% of persons ranging in age from 65 to 74 years [18]. Given that coronary CTA has been shown to underestimate plaque burden compared with intravascular sonography [12], we suspect that the noncalcified plaque burden in our study group may have been even greater than our results showed. To our knowledge, only one other study in the literature has evaluated the presence and severity of noncalcified plaque on coronary CTA [19]. In that study, the investigators found a 2.7% incidence of plaque in patients without coronary calcification and a 0.5% incidence of significant stenosis in those patients. Interestingly, normal coronary CTA findings were seen in 38.5% of the patients, and calcified plaque was seen in 58.8%. These findings suggest an almost bimodal distribution of atherosclerotic disease, progressing from undetectable plaque to calcified plaque with little intervening isolated soft plaque. Given the known natural history of plaque, beginning as fatty streaks in teenagers and slowly progressing over the course of decades, a low prevalence of isolated soft plaque is surprising to us. These results differ from those in our study in which CTA showed 21.7% of the patients had normal findings, 22.9% had only noncalcified plaque, and 55.4% had calcified plaque. Although the results of the Cheng et al. study [19] could be due to selection bias or a large number of low-risk patients, in our experience, detection of small amounts of soft plaque, particularly in vessels with positive remodeling, requires close inspection and a high index of suspicion. The results of other studies have suggested a high prevalence of noncalcified plaque, par- ticularly in high-risk patients. The St. Francis Heart Study is one clinical trial that helped validate the prognostic value of calcium scoring [20]. One of the interesting findings noted by Arad et al. [20] was the incidence of cardiovascular events in high-risk patients with the lowest calcium scores. Whereas low- and intermediate-risk patients with low calcium scores experienced an event rate below that predicted by Framingham criteria alone, high-risk patients with low calcium scores had the same risk predicted by Framingham criteria. This group presumably includes a high prevalence of noncalcified plaque. Because this plaque is not visible on unenhanced CT but is vulnerable to rupture, these patients remained at high risk for an acute coronary event despite their low calcium scores. Calcium scoring has been compared with catheter angiography in several studies, which have reported a very high negative predictive value for significant stenosis [9, 21, 22]. Haberl et al. [22] suggested that the absence of coronary calcium is highly predictive of the absence of stenosis, with significant stenosis in < 1% of patients with a normal calcium score. Rumberger et al. [8] also found only one significant stenosis on angiography in 65 patients (1.5%) with a normal calcium score. The 4% incidence of significant stenosis in our study is significantly higher than those in previous reports. Although correlation with catheter angiography was available in only eight of these 12 cases, we found excellent agreement between the two techniques. Angiographic studies have also documented that acute coronary events are associated with nonstenotic lesions in most cases [16, 23]. Positive remodeling, the phenomenon of vessel expansion to accommodate intramural plaque, has been associated with unstable plaques [24, 25]. Remodeling may A B Fig. 2—56-year-old woman who presented for coronary CT angiography because of a strong family history of heart disease. A, Curved reformatted image from coronary CT angiography shows a large soft plaque in mid left anterior descending artery (arrow). B, Corresponding catheter angiogram (arrow points to region of plaque seen on coronary CT angiography) did not identify this plaque. In retrospect, there may be mild narrowing in region of plaque on angiography. AJR:191, July 2008 53
  5. 5. Kelly et al. mask the size of a lesion on catheter angiography because of the relatively preserved luminal diameter and is a common cause of plaque underestimation (Fig. 2). Remodeling also may result in increased surface tension over a plaque and may alter flow dynamics in a manner that makes the overlying endothelium more atherogenic. These vulnerable plaques are most frequently lipid-rich and infiltrated with inflammatory cells. Currently, intravascular sonography and coronary CTA are the only imaging techniques available to evaluate the intramural plaque component and positive remodeling. Ideally, future advances in plaque characterization with coronary CTA and other techniques, such as molecular imaging and MRI, will allow identification of specific plaques at risk for imminent rupture. Because vulnerable plaque generally is not flow-limiting before undergoing acute rupture, plaque significance is not related to the degree of stenosis. Thus, stenosis does not appear to be useful in identifying patients at risk for acute myocardial infarction [23]. Medical treatment should focus on patients with early but detectable disease with a goal of early plaque stabilization, if not regression. We have found that the calcium score alone will not detect many patients who might benefit from medical therapy. Patients with a normal calcium score (and their physicians) may gain a false sense of security about the state of their coronary arteries and may not be as compliant with treatment as they might otherwise be. This phenomenon appears to be more common in men, who were statistically more likely than the women in our study group to have noncalcified plaque and a normal calcium score. The real significance of identifying soft plaque is probably unknown. Presumably, early identification of this potentially dangerous plaque should be the cornerstone of atherosclerosis management. Initiation of med­cal therapy—for the rest of a patient’s i lifetime—is a decision that is currently based on secondary markers, such as low-density lipoprotein cholesterol (LDL-C) levels. However, just as every child with a sore throat should not be treated with antibiotics, every patient with an LDL-C level of > 100 mg/dL may not need a multidrug treatment regimen. Conversely, someone with a “normal” lipid profile may have significant disease and should receive treatment. Because we now have a noninvasive means of identifying culprit plaques, we should directly interrogate 54 the coronary arteries rather than rely on secondary markers for determining disease risk. This is particularly true when the treatment regimen may involve multiple drugs—statin, niacin, aspirin, antihypertensives, cholesterol absorption blockers, fibrates, or omega-3 fatty acids—that are not without risk of side effects and significant expense to the patient. Calcium scoring does add useful information for patient risk stratification, as has been shown in multiple studies [5, 6]. However, in our patient population, the clinical utility of a normal calcium score was diminished because of the high false-negative rate. Coronary CTA provides significantly more diagnostic information than the calcium score. In patients with a 0 calcium score, coronary CTA was able to identify the large percentage of patients with subclinical disease not detected by unenhanced CT. In patients with a positive calcium score, coronary CTA was able to delineate the presence or absence of stenosis with a high degree of accuracy. Essentially, coronary CTA adds certainty to the evaluation of the coronary arteries, whereas the calcium score generates probabilities. Perhaps the greatest concerns regarding coronary CTA are cost and radiation exposure. Considering that the cost of statin therapy alone is at least $1,000 per year in the United States [26], patients with a negative coronary CTA examination would recoup the cost of the examination in 1 year. If imaging were performed at 10-year intervals, the cost savings could be considerable when applied to the number of patients eligible for lipid-lowering therapy. Radiation exposure is a significant concern with all x-ray-based imaging. In our patient population, using single-source 64-MDCT scanners, dose modulation, and retrospective gating, the median patient dose was 12 mSv. This dose includes the topogram, unenhanced CT for calcium scoring, timing bolus, and coronary CTA. With the advent of prospectively gated scanning and dual-source scanners, the radiation dose of coronary CTA has the potential to be equivalent to, or less than, that of a calcium score examination [27]. As the technology evolves, radiation doses will continue to decline, and CTA may play a larger role in the detection of coronary artery disease. Our study has some limitations. First, our study group is not a true screening population. There was a high prevalence of disease in our population, with almost as many patients having a significant stenosis (n = 149) as those having normal findings (n = 158). Many of our patients were referred because either they or their physician had a high suspicion of coronary disease. Forty-seven percent of referrals were for evaluation of atypical symptoms, an abnormal stress test, or both. All asymptomatic patients had at least intermediate risk for coronary artery disease based on Framingham criteria. However, symptoms did not significantly correlate with the presence of disease, so our study was not biased by the number of symptomatic patients. In clinical practice, workup of many of the patients in our study would not have included calcium scoring. The calcium score was determined as part of our routine coronary CTA, and a number of symptomatic patients would have undergone invasive angiography if coronary CTA had not been available. A normal calcium score would not have precluded further workup in these patients. However, if all symptomatic patients with a normal calcium score (n = 143) had undergone invasive angiography, 67 normal angiograms would have been performed. Another 65 patients with mild disease on coronary CTA would likely have had normal findings on angiography because low-volume plaque is often not detectable angiographically. Thus, 92% of angiograms in symptomatic patients with a normal calcium score would have been unlikely to show disease. Also, five of 12 (42%) significant stenoses—those without symptoms and without coronary calcification—would have been undiagnosed. These findings reinforce the diagnostic utility of coronary CTA in the evaluation of coronary artery disease. A third limitation is that coronary CTA was our gold standard for plaque detection. We do not have corollary imaging for patients who did not undergo angiography. We also did not evaluate interobserver variability in the interpretation of stenosis. This would be most significant in patients with very minimal plaque and in patients with stenosis approaching 50% diameter reduction because these patients would be the most likely to be miscategorized. Possibly, some patients with examinations interpreted as positive for mild plaque on coronary CTA did not actually have atherosclerosis. However, in comparing coronary CTA performed using 64-MDCT with intravascular sonography, Leber et al. [12] noted a significant trend of CT to underestimate plaque burden and overestimate luminal diameter. Given these findings, coronary CTA probably under­ stimated the amount e AJR:191, July 2008
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