Coronary artery disease (CAD) remains the

Role of Cardiac CT in Atherosclerosis Imaging and Risk Stratification Firoz Gani, MBBS, MRCP, Cardiology Research Registrar, Cardiac Imaging & Research Centre, Wellington Hospital (South), London, UK. David Lipkin, BSc,MD, FRCP, Consultant Cardiologist, Cardiac Imaging & Research Centre, London, and Royal Free Hospital, London, UK. Vijay Anand, MBBS, MRCP, Cardiology Specialist Registrar, Lincoln County Hospital, Lincoln, UK. Avijit Lahiri, MBBS, MSc, MRCP, FESC, FACC, Consultant Cardiologist, Cardiac Imaging & Research Centre, London, UK. Correspondence: Firoz Gani, MBBS, MRCP, Cardiology Research Registrar, Cardiac Imaging & Research Centre, Wellington Place, London, NW8 9LE,UK. Email: dfgani@hotmail.com Coronary artery disease (CAD) remains the leading cause of death in Western countries. The intermediate-risk population accounts for the majority of patients seen in general and speciality practices and constitutes approximately 40% of all asymptomatic patients. 1 Approximately 50% of men and 64% of women who experience non-fatal myocardial infarction (MI) and sudden death are asymptomatic prior to such events. 2 A large number of coronary events in asymptomatic subjects occur with non-obstructive disease. The majority of acute MIs are triggered by lesions that cause < 50% stenosis of vessel lumen as shown by both pathologic and clinical studies (Figure 1). 3-6 Though the treadmill exercise electrocardiogram (ECG) was considered as the first-line diagnostic test in the 1970s and 1980s, the change in pre-test probability of CAD presenting to hospitals has significantly reduced its sensitivity and specificity. Furthermore, many patients are unable to achieve an adequate exercise workload. Thus, the use of initial functional tests such as myocardial perfusion scan (MPS) and stress echocardiogram have been proposed. However these tests depend on the premise that a flow-limiting coronary stenosis is present, and are therefore termed functional imaging whereas coronary artery calcium (CAC) measured by electron beam computerised tomography (EBCT) or multi-detector row computerised tomography (MDCT) provides anatomic information regarding coronary atherosclerotic burden which can be used as an important marker of risk in patients with risk factors for CAD. Coronary artery calcium and atherosclerosis The association between calcified coronary arteries and the development of symptomatic coronary artery disease was first recognised nearly 200 years ago. 7 In 1959 Blakenhorn defined the close relationship between coronary artery calcium and coronary atherosclerosis. 8 Initial studies based on the fluoroscopic detection of coronary calcium were limited by marginal sensitivity and the inability to quantify the amount of coronary calcium. In 1984, the electron-beam CT was introduced as the first system to enable ECG-synchronised CT imaging of the cardiac anatomy. 9 To date, the majority of outcome data published regarding the prognostic value of CAC has been generated by EBCT. The development of the atherosclerotic plaque is accompanied by deposition of crystals of hydroxyapatite (calcium phosphate) from its inception, 10 and CAC measured by CT correlates well with the size of the atherosclerotic plaque. 11,12 Coronary artery calcium is intimately associated with atherosclerotic plaque and is pathognomonic of atherosclerosis. 13-15 The total area and volume of coronary artery calcification, determined by EBCT, correlates in a linear fashion with the total area of coronary artery plaque on a segmental basis. 16 The EBCT CAC score may not always predict the existence of significant stenosis since the plaque could be intramural or spread into the lumen, but the sensitivity of EBCT to detect obstructive CAD increases with higher plaque burden (especially with an Agatston score of 400 units or more). 17-19 Therefore, the strong correlation of CAC with atherosclerotic plaque burden but only modest correlation with coronary luminal stenosis may be explained by the Glagov phenomenon that is, the common phenomenon of outward remodelling of the coronary arteries in the earlier stages of atherosclerosis. 20,21 The progression of coronary artery plaque is a slow and insidious process. Although advanced and obstructive CAD pose a high risk for cardiac events, nonstenotic lesions can also be dangerous because the rupture of the inflamed and lipid-rich plaque could cause a sudden luminal obstruction. EBCT and MDCT can detect CAC early in the atherosclerotic process, often long before the lesions become haemodynamically significant. Since CAC is an easily obtained surrogate for plaque burden, it is a potential tool for predicting cardiovascular risk in asymptomatic persons in whom atherosclerosis is developing and thus ideal for assessment of risk and also progression of disease. EBCT and MDCT the technology EBCT scanners use a rapidly rotating electron beam, which is reflected onto a stationary tungsten target rather than a standard X-ray tube to generate X-rays, permitting very rapid scanning times. EBCT is well suited for the imaging of coronary arteries with its unique combination of three dimensional capabilities (3D), its high spatial (nine line pairs/cm) and temporal resolution (50msec), and its ability to trigger image acquisition to the electrocardiogram (exposure gated to 80% of the R-R interval), which virtually eliminates motion artefacts related to cardiac contraction. For the purposes of detecting coronary calcium, 30 to 40 serial transaxial images are obtained in 50-100msec (the acquisition time for a single image), with a slice thickness of 3mm during a single breath hold; the recorded data is transformed through a filtered back-projection reconstruction 8 AUGUST/SEPTEMBER 2006

Figure 1: Percent stenosis of lesions resulting in myocardial infarction. (Reprinted from American Journal of Cardiology, Vol 96, Raggi P, Electron-beam computed tomography and nuclear stress testing in cardiovascular risk assessment, Pages 20-27, Copyright (2005), with kind permission from Excerpta Medica, Inc.) Figure 2: Prognostic value of coronary artery calcium scoring with EBCT. (Reprinted from Shaw LJ, Raggi P, et al. Prognostic value of cardiac risk factors and coronary artery calcium screening for all-cause mortality. Radiology 2003;228(3):826-33 with kind permission from the authors and the Radiological Society of North America.) technique into 2D images. The coronary arteries are easily identified by EBCT because the lower CT density of peripheral fat produces a marked contrast to blood in the coronary arteries, while the mural calcium is evident because of its high CT density relative to blood. The scanner software also allows quantification of coronary calcium area and density. Agatston and colleagues developed a calcium scoring algorithm based on x-ray attenuation coefficient or CT numbers measured in Hounsfield units by selecting the maximum calcium density within the area. 22 The area of calcium was calculated from the field of view and the image matrix that, on the standardised protocol, relate to three pixels or 1mm 2 with a density of 130 Hounsfield units. CAC scores are classified into five categories, based on cut-offs that have been widely used in the literature: < 10 (minimal or insignificant CAC), 11-100 (mild CAC), 101-400 (moderate CAC), 401-1,000 (severe CAC) and > 1,000 AU (extensive CAC). Callister et al improved the reproducibility of the calcium score, especially in the lower ranges, by introducing the volume score (isotropic interpolation) method. 23 Though initially developed for EBCT, methods for approximating the density weighted Agatston score using MDCT have also been developed. The reproducibility and variability of the EBCT calcium score have been extensively studied. Previously, the limitations on slice number, suboptimal gating and table motion led to higher interscan variability. Hardware for EBCT has improved significantly over the years, and there has been marked improvement in the reproducibility of the calcium score. The inherent issue of cardiac motion will continue to be a problem, especially for the right coronary and left circumflex arteries. 24,25 MDCT scanners can image a section of the heart simultaneously with ECG gating in either the prospective (ECG triggering) or retrospective mode for segmental reconstruction. Prospective gating usually produces 3-mm thick slices with a temporal resolution of 200 or 250ms. Temporal resolution of 100 to 125ms can be achieved with the retrospective mode with overlapping slices but with a marked increase in radiation dose. Both 32- and 64-MDCT have rotational speeds of 330ms, which will allow temporal resolutions of 175 or 87ms to improve resolution and reduce cardiac motion. 26 Comparison of CAC score with myocardial perfusion scan Though functional tests such as MPS or stress echocardiograms are often used in those patients with symptoms, these methods have also been employed for screening higher risk patient categories to exclude obstructive CAD. Although the presence and extent of left ventricular ischaemia can accurately identify individuals at high risk for cardiac events, the low prevalence of a positive test result among asymptomatic subjects with cardiac risk factors mitigates against this approach. 27,28 However, MPS has proved useful in risk stratification and in identifying patients who require coronary angiography for purposes of possible coronary revascularisation. Several reports have shown that CAC is also useful in risk stratification, but ischaemia determined by MPS provides unique information regarding the likelihood of benefit from a revascularisation procedure. 29 There are several studies which correlated the extent of CAC with the presence of ischaemia on MPS. These observations led to widespread interest in using CT screening for CAC detection to identify patients at risk of coronary events on the basis of the presence of atherosclerosis. He et al 30 studied 3,895 generally asymptomatic subjects prospectively over a period of 2.5 years with EBCT, 411 of whom had stress MPS within a close (median, 17 days) time period. They compared the MPS results with the CAC score assessed by EBCT. They noted a threshold phenomenon with a very low frequency of abnormal MPS studies in patients with a CAC score lower than 100 (2.6%) and a clear increase in the frequency of abnormal MPS studies in patients with high CAC scores. They reported abnormal MPS in 11.3% with a CAC score of 101 to 399 and in 46% with a CAC score of 400 or greater (P < 0.0001). They concluded that CAC score predicted an abnormal SPECT regardless of age or sex and CAC score identifies a high-risk group of asymptomatic subjects who have clinically important silent myocardial ischaemia. Berman et al 31 showed a correlation between increasing CAC score and ischemic changes with MPS; frequency of perfusion abnormalities also increased as the score rose above 400 Agatston units. The frequency of abnormal MPS results was < 2% in patients with CAC score < 100 and increased progressively with a CAC score 100 (p < 0.0001). Interestingly, 56% of patients who had normal MPS results had a CAC score 100, suggesting that EBCT is an appropriate method for detecting significant atherosclerosis in patients who have normal MPS results. Moser et al 32 conducted a retrospective study utilising MDCT on 794 aymptomatic patients who underwent CAC screening. On the basis of CAC score, 102 patients underwent MPS imaging, of whom 41% of patients with severe CAC score (> 400 AU) had an abnormal MPS and no patient with a CAC score lower than 100 AU had an abnormal MPS. This study demonstrated that CAC score of 400 Agatston units is a logical threshold to initiate follow-up stress MPS testing. Anand et al 33 prospectively recruited 220 patients with a CAC score of 100 or greater from a group of 864 patients with risk factors for CAD who were referred for CAC testing to undergo MPS by use of a two-day sestamibi stress-rest protocol. They noted There is a current growth in interest in cardiac CT as the new-generation scanners allow visualisation of the coronary artery lumen by coronary CT angiography 10 AUGUST/SEPTEMBER 2006

Figure 3: Event-free survival during an average follow-up of 2.2 years by Cox proportional Hazards model. Survival curves according to the extent of coronary calcification (A) and myocardial perfusion abnormalities (B) are shown. Relative risk ratios (RR), confidence intervals, and P-values are provided for each CAC/MPS category. (Reprinted from Anand DV, Lim E, et al. Risk stratification in uncomplicated type 2 diabetes: prospective evaluation of the combined use of coronary artery calcium imaging and selective myocardial perfusion scintigraphy. European Heart Journal 2006;27(6):713-21 with kind permission of the authors and Oxford University Press.) Figure 4: Comparison of studies between EBCT and MPS in asymptomatic non-diabetic and diabetic patients. 119 patients with moderate atherosclerosis (CAC score of 100-399) and 101 patients with severe atherosclerosis (CAC score 400). Abnormal MPS results were present in 18% of the moderate and 45% of the severe CAC groups. Anand et al suggested the following regarding the need for MPS in asymptomatic patients who have had CAC testing: MPS is generally not required when the CAC score is lower than 100. When the CAC score is greater than 400, MPS would appear to be beneficial, because the frequency of inducible ischemia is substantial within this CAC range. Some patients with CAC scores in the range of 100-400 may require stress test referral after CAC imaging, and the study suggests that the need for further testing in this CAC category may depend on the degree of clinical risk. 34 However, in diabetic subjects there appears to be a significantly greater chance of detecting silent ischaemia with lower CAC scores. Therefore, there is a rationale for combining MPS and CAC imaging in those with higher degrees of risk or those with higher calcium scores. Though negative MPS is predictive of a good outcome, this negative predictive value is lower in certain high-risk groups such as diabetic patients. Thus, in patients with nonischemic MPS studies, concern can persist that significant underlying CAD is nevertheless present in those who have a high clinical risk for developing CAD. In these patients, a normal CAC score, given the strong negative predictive value, should provide strong confirmatory information, and those who do have significant CAC can be identified for close surveillance and aggressive medical therapy. Risk stratification The extent of CAC predicts the risk of future cardiac events in patients with known coronary atherosclerosis. This is particularly important with asymptomatic patients in whom consideration of revascularisation may not be appropriate unless there is substantial risk of cardiac death. In making this prediction, the techniques of MPS and EBCT are likely to be complementary. A large body of data has been accumulated for risk stratification using EBCT derived CAC imaging. Prognostic information can be derived from the total coronary calcium burden as the presence of calcium in the coronary arteries is indicative of the presence of atherosclerosis. Shaw et al reported the results from five-year follow-up study of 10,377 asymptomatic individuals after CAC scoring with EBCT. 35 Patients with minimal or no calcium had an excellent survival, with a mortality of 1%, whereas mortality increased to 12.3% for patients with a score > 1,000 Agatson units as depicted in Figure 2. In a risk-adjusted model of mortality, it was demonstrated that the CAC score was indeed a strong and independent predictor of all-cause mortality. In fact, the authors showed that for various Framingham risk subsets, CAC score could provide superior prediction of death, with five-year mortality rates increasing from 1.1% for scores < 10 AU to 9.0% for scores > 1,000 AU in patients at an intermediate risk. Even in low-risk patients, CAC score could provide refinement of risk stratification, with mortality rates increasing from 0.9% to 3.9% for scores of < 10 to > 1,000. Anand et al 36 prospectively measured CAC scores and established risk factors in 510 asymptomatic type 2 diabetic patients with no previous cardiovascular disease. MPS was performed in all patients with CAC > 100 AU (n = 127) and a random sample of the remaining patients with CAC 100 AU (n = 53). They found significant CAC (> 10 AU) in 46.3%. During a median follow-up of 2.2 years, 20 events occurred and interestingly there were no cardiac events or perfusion abnormalities in patients with CAC score 10 AU. Anand et al showed a significant relationship between increasing CAC score and silent Table 1: Interaction between CAC scores and the extent of myocardial perfusion abnormality for prediction of 24-month event-free survival (P = 0.003). Interaction P = 0.003 (unadjusted) and < 0.0001 (adjusted for UKPDS risk score). Event-free survival estimates are from a stratified Cox model. (Adapted from Anand DV, Lim E, Hopkins D, Corder R, Shaw LJ, Sharp P, Lipkin D, Lahiri A. Risk stratification in uncomplicated type 2 diabetes: prospective evaluation of the combined use of coronary artery calcium imaging and selective myocardial perfusion scintigraphy. European Heart Journal 2006;27(6):713-21.) % Myocardium CAC 0 100 CAC 101 400 CAC 401 1000 CAC > 1000 0% 100% 98% 96% 90% 1 5% 100% 92% 83% 77% RR = 9.20 (1.48, 57.19) P = 0.017 > 5% 100% 80% 64% 48% RR = 8.30 RR = 12.64 RR = 24.43 (1.35, 50.99) (2.97, 53.84) (5.59, > 100) P = 0.022 P = 0.001 P < 0.0001 AUGUST/SEPTEMBER 2006 11

EBCT/MDCT is appealing as a relatively low-cost, primary screening technique through which coronary atherosclerosis can be detected and potentially treated before the development of critical coronary artery stenosis and/or stress induced myocardial ischemia ischaemia detected by MPS. Both CAC score and total ischaemic burden by MPS independently predicted adverse cardiovascular events (Figure 3). Furthermore, there was also a synergistic effect for the prediction of short-term cardiovascular events by combining CAC score and MPS results (Table 1). They concluded that subclinical atherosclerosis, measured by EBCT, is superior to the established cardiovascular risk factors for predicting silent myocardial ischaemia short-term outcome in high-risk diabetic patients. Clearly, diabetic patients with lower calcium scores have a higher probability of silent myocardial ischaemia than those without diabetes (Figure 4). Future perspectives There is a current growth in interest in cardiac CT as the new-generation scanners allow visualisation of the coronary artery lumen by coronary CT angiography (CTA). CTA is more technically demanding and visualisation of the small, tortuous and rapidly moving coronary arteries stretches the temporal and spatial resolution of CT to its very limits. However, all techniques are advancing at a rapid pace and consequently, image quality and diagnostic accuracy are improving continuously. Preselection and preparation of patients (target heart rate < 60 beats/minute, nitrates to dilate the coronary arteries) and very careful image acquisition are necessary to achieve optimum results. The image quality of CT does not equal that of invasive coronary angiography. However, in experienced hands, it is possible to achieve a high sensitivity and specificity for the detection of haemodynamically relevant coronary artery stenosis. Several studies using the latest generations of 16- and 64-slice CTA reported high sensitivities (82%-95%) and specificities (95%-96%) and more importantly a very high negative predictive value (96%-99%) which is shown in table 2. 37 Although these are on a small scale the initial results are encouraging and it may be possible to rule out the presence of significant coronary artery stenosis with modern scanners in future. Moreover stenoses of bypass grafts with CTA can be detected with very high accuracy as bypass vessels are somewhat larger and move less rapidly than the native coronary arteries. However, CTA has a number of limitations and cannot be expected to widely replace invasive cardiac catheterisation in the future. Presence of severe calcification (> 400 Agatston units), arrhythmias and movement artifacts are some of the limitations. Multi-detector row CTA can detect coronary segments with positive arterial remodelling that contains substantial amounts of noncalcified plaque without significant luminal stenosis. To define the role of multi-detector row CTA for the identification of atherosclerotic plaque and characterisation of plaque morphology and remodelling, future studies will need to compare multi-detector CT with established invasive modalities that include intravascular ultrasound. 47 Conclusion Both exercise ECG and MPS remain the cornerstones for evaluating risk in symptomatic patients with known or suspected CAD, whereas CAC by EBCT/MDCT can identify a high-risk group with silent myocardial ischemia among an otherwise low-risk heterogenous population with cardiac risk factors. Many asymptomatic individuals with subclinical CAD die suddenly and would not have been identified with ETT or MPS. In this regard, EBCT/MDCT is appealing as a relatively low-cost, primary screening technique through which coronary atherosclerosis can be detected and potentially treated before the development of critical coronary artery stenosis and/or stress induced myocardial ischemia. The absence of coronary calcium is Table 2: Sensitivity, specificity, and negative predictive value of recent studies comparing 16- and 64-slice MDCT with invasive coronary angiography for detection of coronary artery stenoses. Studies are not immediately comparable because prevalence of disease varied, because in some cases all coronary segments were evaluated, whereas in others only segments above a certain diameter were included in the analysis, and because technology for scanning and interpretation varied. (Adapted from Achenbach S. Current and future status on cardiac computed tomography imaging for diagnosis and risk stratification. J Nucl Cardiol 2005;12(6):703-13.) Author N Sensitivity Specificity Negative predictive Not Comment value evaluable Martuscelli et al 38 64 89% 98% 98% 16% 16-slice CT (500-ms rotation) Morgan-Hughes et al 39 58 83% 97% 97% 2% 16-slice CT (500-ms rotation) Hoffmann et al 40 103 95% 98% 99% 6% 16-slice CT (420-ms rotation) Mollet et al 41 51 95% 98% 99% 0% 16-slice CT (375-ms rotation) Kuettner et al 42 72 82% 98% 96% 7% 16-slice CT (375-ms rotation) Achenbach et al 43 50 93% 95% 99% 5% 16-slice CT (375-ms rotation) Leschka et al 44 57 94% 97% 99% 0% 64-slice CT (375-ms rotation) Leber et al 45 59 80% 97% 99% 0% 64-slice CT (330-ms rotation) Raff et al 46 70 86% 95% 98% 12% 64-slice CT (330-ms rotation) 12 AUGUST/SEPTEMBER 2006

associated with a very low rate of future cardiac events (0.1% per year) 48 and has 99% negative predictive value for the presence of obstructive CAD. An important potential area for the complementary use of both MPS and CAC is the use of EBCT/MDCT for calcium screening among patients being evaluated for CAD whose MPS result is normal. 49 CAC imaging may be helpful in association with MPS in appropriately selected populations. In fact, these two modalities used in concert may allow a more precise assessment of the likelihood of CAD than either test alone. Declaration of Conflicting Interests Firoz Gani: Supported by research grants from the Harrow Cardiovascular Research Trust, Michael Tabor Foundation and the Derrick Smith Research Grant. David Lipkin: None Declared. Vijay Anand: None Declared. Avijit Lahiri: Has been sponsored to present papers and invited lectures at medical meetings, and national and international conferences. 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