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Cardiac Imaging |
1 From the Department of Clinical Radiology, Klinikum Grosshadern, University of Munich, Marchioninistrasse 15, 81377 Munich, Germany (C.H., C.R.B., R.B., M.F.R.); Department of Radiology, Huazhong University of Science and Technology, Wuhan, People’s Republic of China (C.H.); and Siemens Medical Systems, Forchheim, Germany (B.O.). Received May 14, 2001; revision requested June 13; revision received August 27; accepted September 20. Address correspondence to C.R.B. (e-mail: christoph.becker@ikra.med.uni-muenchen.de).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: A heart phantom containing calcified cylinders was scanned to determine calibration factors and absolute calcium mass. In 50 patients, the variability (value 1 - value 2/mean value 1 - value 2), limit of agreement (±2SD value 1 - value 2), and systematic error (mean value 1 - value 2) of the total amount of coronary calcium calculated at traditional 3-mm section width CT and at 1.25-mm section width CT angiography were determined.
RESULTS: The correlation coefficient between the 3-mm section width, nonenhanced protocol and the 1.25-mm section width CT angiography protocol was very high (r = 0.977) and the mean variability was low (19.7%) for the absolute mass. There was a systematic error of -6.7 mg and a limit of agreement between 45.0 mg and -58.5 mg.
CONCLUSION: Use of the mass quantification algorithm in combination with a calibration phantom allows accurate quantification of coronary calcium. Measurements of calcium mass obtained at 1.25-mm section width CT angiography have the best agreement with those obtained at the traditional 3-mm section width imaging protocol.
© RSNA, 2002
Index terms: Coronary vessels, calcification, 54.812 • Coronary vessels, CT, 54.12111, 54.12116 • Phantoms
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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A method for semiquantitative assessment of the amount of coronary calcium based on findings at electron-beam CT has been introduced by Agatston et al (1). The calcium score derived with this method appears to correlate closely with the overall atherosclerotic coronary plaque burden (7). However, some analyses (8,9) have revealed that this traditional scoring method is not suited for accurate and reproducible determination of the amount of coronary calcium for clinical purposes, mainly because this method involves the multiplication of the area of a calcified plaque by an arbitrary coefficient that is based on peak plaque attenuation values. For this reason, a volumetric method, based on the principle of isotropic interpolation, that allows more precise and reproducible measurements of calcified plaque volume was developed by Callister et al (10).
Spiral CT acquisition of the entire cardiac volume allows image reconstruction with a small section increment and thus improves the reproducibility of the calcium measurement (11,12). A comparison of score values obtained with electron-beam and single-detector CT scanners shows high correlation (13). Furthermore, semiautomatic workstations can help increase interobserver agreement, and calibration phantoms may help determine absolute values for calcium mass, enabling accurate quantification.
New-generation multi–detector row spiral CT scanners have become available that are capable of short exposure times (up to 125 msec) and simultaneous acquisition of four sections with one electrocardiogram (ECG)-synchronized scan (14,15). In a recent study (16), results obtained at multi–detector row CT were shown to have very good agreement with those obtained at electron-beam CT for every quantification algorithm of coronary calcium that was tested. However, mass and volume indexes were superior to the traditional calcium score, density measurements, and lesion count. The purposes of this study were (a) to determine the accuracy of multi–detector row CT in the measurement of calcium concentration in a cardiac CT calibration phantom with 3-mm section width, 1.25-mm section width, and 0.6-mm section width imaging protocols, and (b) to assess the correlation between a traditional 3-mm section width CT imaging protocol and a 1.25-mm section width CT angiography imaging protocol in quantifying the absolute mass of coronary calcium in patients who underwent both a traditional coronary screening CT examination and CT angiography performed with a multi–detector row CT scanner.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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The calibration insert contained three series of calcified cylinders. Each series contained three cylinders that were 1, 3, and 5 mm in both diameter and height. The calcium hydroxyapatite (CaHA) densities of each series of cylinders equaled 200, 400, and 800 mg/cm3 (Fig 1). In addition, the phantom contained two large inserts equivalent in attenuation to water (0 HU ± 3 [SD]) and spongy bone (CaHA density, 200 mg/cm3). Table 1 gives an overview of the CaHA densities and the sizes of the cylindrical calcifications and the values for the volume of the cylinders and the mass of the CaHA inside the calcifications.
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All three sets of images were transferred to a dedicated workstation (InSight; NeoImagery Technologies, City of Industry, Calif). With this workstation, the means and standard deviations of the CT numbers in circular (2 cm2) regions of interest were measured (C.H.) within the three regions of each calibration insert for each imaging protocol used. CaHA mass (calculated as 1/250 x area x section increment x mean attenuation value) of the calcified cylinders was determined by using a range of different Hounsfield unit thresholds (130–490 HU) with an interval of 20 HU.
To obtain an absolute value for each CaHA mass, a calibration measurement of a calcified cylinder with known CaHA density (
CaHA) was performed and a calibration factor (c) was determined according to the following equation: c = CaHA/(CTcylinder - CTwater), where CaHA is measured in milligrams per cubic centimeters, CTcylinder is the attenuation value of the cylinder, and CTwater is the attenuation value of water (17) at each threshold for each of the three protocols. The calibration factor c is therefore given by the CaHA density CaHA of the known calcification divided by the mean difference in CT numbers (CTcylinder minus CTwater) in the calibration measurement. The measured CaHA mass at each threshold and at each section width multiplied by the respective calibration factor corresponds to the absolute value of the CaHA mass.
Patient Population
The study was approved by the local board of ethics of our institution. Fifty consecutive patients suspected of having coronary artery disease with atypical chest pain and equivocal stress test results who were referred to our department for quantification of coronary artery calcifications and CT angiography were included. All patients gave informed consent after the procedure had been explained to them in detail. Exclusion criteria included renal insufficiency with creatinine levels greater than 1.5 mg/dL (133 µmol/L), previous coronary artery bypass surgery or stent placement, and unstable clinical condition. There were 38 men and 12 women; the mean age of the patients was 60.2 years ± 11.7. The mean heart rate was 60.1 beats per minute ± 12.5 during the investigation.
Image Acquisition
With the same multi–detector row CT scanner, 40 consecutive nonoverlapped 3-mm-thick sections were acquired for coronary screening, with 120 kV, 100 mA, and retrospective ECG gating at 450 msec prior to the next R-wave. The range of the entire heart (120 mm) was covered within a single breath hold (15–20 seconds).
After the calcium scan, which was not enhanced with contrast material, coronary CT angiography was performed. First, the scan delay was determined as the interval from the start of the injection of a small bolus of contrast medium (20 mL) to the time of peak enhancement in the ascending aorta. Coronary vascular enhancement was achieved with 140 mL of nonionic contrast material (iomeprol 300, Imeron; Bracco-Byk Gulden, Konstanz, Germany) injected at a flow rate of 2.5 mL/sec.
After the predetermined delay, helical scanning (at 120 kV and 300 mA) was begun, with simultaneous acquisition of four 1.25-mm-collimated sections at a 3.6-mm/sec table speed and a 500-msec rotation time. During the scan, the ECG signal was digitally recorded. The volume of the entire heart (120 mm) was covered within a single breath hold in 30–34 seconds (mean, 32 seconds).
The raw data and digital ECG tracings were used to retrospectively reconstruct transverse images with a constant temporal resolution of 250 msec per section for lower heart rates (<65 beats per minute) or a heart rate–dependent temporal resolution of up to 125 msec per section for higher heart rates (
65 beats per minute). The effective section thickness and reconstruction increment were 1.25 mm and 0.6 mm, respectively.
Measurements of Coronary Calcium
All images from the traditional coronary screening CT examinations and CT angiography were transferred to the InSight workstation. The InSight workstation automatically provides the Agatston score, mass equivalent, and number of lesions of calcified plaques in the coronary arteries. The calcium score, which was calculated according to the algorithm suggested by Agatston et al (1)—area x cofactor; 1 = 130–199 HU, 2 = 200–299 HU, 3 = 300–399 HU, 4 = 400 HU—and the absolute calcium mass (ie, the measured mass equivalent multiplied by the calibration factor calculated in the phantom study) were determined by one radiologist (C.H.). The commonly used threshold of 130 HU was chosen for images obtained at traditional coronary screening CT examinations; a threshold of 350 HU was chosen for CT angiography images. The reason for choosing a threshold of 350 HU for CT angiography was to ensure that the attenuation threshold used for calcium quantification was higher than the attenuation levels in the enhanced coronary vessels. In addition, 350 HU was the lowest threshold at which actual CaHA masses greater than 10 mg could reliably be detected in the phantom study (see the Statistical Analysis section).
Statistical Analysis
For comparison of the score and the absolute calcium mass, statistical analysis was performed with the nonparametric Wilcoxon signed rank test for paired data, with linear regression, and by determining the correlation coefficient between traditional coronary screening CT and CT angiography. The percentage variability (v) between the two protocols was calculated as the mean of the following: (Abs [value 1 - value 2])/(0.5 x [value 1 + value 2]), where Abs is the absolute value of the measurement of interest (ie, either score or mass). The systematic error (bias = d) and the limit of agreement (d ± 2s, where s is the standard deviation) of the two measurements were determined according to the method described by Bland and Altman (18) with MedCalc 5 (MedCalc Software, Mariakerke, Belgium).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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.05). When a threshold of 130 HU was set, nine, eight, and six calcified cylinders were detected on the 0.6-mm section width images, the 1.25-mm section width images, and the 3-mm section width images, respectively (Fig 1). Five calcified cylinders with an actual CaHA mass less than 10 mg (8.5 mg, 4.2 mg, 0.6 mg, 0.3 mg, and 0.2 mg) could not be detected on 0.6-mm section width images at a threshold above 490 HU. With thresholds of 350 HU and 290 HU, the same inserts could not be detected on 1.25-mm section width images and 3-mm section width images, respectively. On the basis of the known absolute CaHA mass and the measured CaHA mass, the calibration factor c for all three imaging protocols at each threshold was calculated; the calibration factors for the 3-mm section width protocol at 130 HU and the 1.25-mm section width protocol at 350 HU were used for calculation of the absolute calcium mass in patient studies. The relationships between attenuation thresholds and the calculated calibration factors in the three imaging protocols are shown in Figure 2. The calibration factor increased with increasing attenuation thresholds in the three imaging protocols, especially in the 3-mm protocol.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Previous studies have demonstrated that coronary calcium quantification at electron-beam CT has relatively poor reproducibility (8,9,20). The large variation in calcium scores suggests that a more accurate approach is needed. Some investigators (9) used a 6-mm section width protocol with electron-beam CT screening in an attempt to create a more reproducible and reliable scoring method by means of shorter study acquisition times that allow for reduction of motion artifacts and greater volume averaging. However, Callister et al (21) found that the greater volume averaging associated with a 6-mm section width protocol compared with that associated with a 3-mm section width protocol resulted in a loss of vital information. Accordingly, they speculated that an investigation protocol that incorporated the use of thinner sections may be even more accurate in the quantification of coronary calcium.
The use of a volume score that is based on isotropic interpolation has become more widespread because some studies (10) have indicated its robustness with respect to reproducibility. This score measures the volume of calcification and is calculated as the number of voxels in the volume data set that are contingent with the calcification multiplied by the volume of 1 voxel. This measurement may be less susceptible to partial volume effects than the Agatston score or other noninterpolated measurements of calcified volume (9,22). However, when one uses this score in the evaluation of a relatively large section thickness for small calcifications with high density, one has to be aware that it can lead to large deviations from the true diameters of the calcification because objects much smaller than 1 voxel but with high density nevertheless contribute to the score with their complete voxel volume.
Measurement of coronary artery calcium is more complex than calculating a calcium score or a calcified plaque volume. The inherently quantitative nature of CT allows several different parameters to be measured on a pixel-by-pixel basis, including calcified plaque area, plaque volume, mean and peak attenuation of individual lesions, and attenuation distribution. The best and more accurate quantification method possibly consists of measuring the calcium mass to determine the absolute amount of calcium. The equation used for its calculation (see Materials and Methods section) automatically corrects for linear partial volume effects in that objects smaller than the section thickness are displayed with adjusted mean CT numbers. From a clinical perspective, the calcium mass value is at least as accurate as the traditional Agatston score (16) and appears to be more descriptive of the coronary calcium load than an abstract score.
A comparison of the Agatston score to the real calcium burden is very difficult due to the unconventional definition of this score, which does not correspond to the physical measurements of the calcification. The CaHA mass can be compared with the true values of the phantoms that are given by the manufacturer of the phantom. Scanning a calibration phantom (in addition to the patient) allows normalization of the measured attenuation values into biologically equivalent units of CaHA concentration on a scan-by-scan basis (19). This may provide greater consistency in the identification of the presence of coronary artery calcifications and may reduce the effects of scanner and patient variations on any final measurement of calcium burden. Analysis of image data with a definition of coronary artery calcification that is based on CaHA concentration may result in a change in both the classification of disease in an individual patient and the prevalence of coronary artery calcification in a population.
In the quantification of coronary calcium, our findings showed nearly identical calcium mass for each patient, whether the findings were obtained with the 1.25-mm section width CT angiography protocol or with the traditional 3-mm section width protocol. In repeated scanning with electron-beam CT, Yoon et al (22) found a percentage variability of 28.4% for the mass algorithm, which is comparable to our result (19.7%) concerning agreement between the 3-mm section width protocol and the 1.25-mm section width protocol. In contrast to the mass algorithm, the percentage variability for the traditional scoring method was significantly higher (81.7%) in our study—even higher than the reported range of variability for repeated measurements obtained with electron-beam CT (29%–49%) (8,9,22). Some factors in our study contributed to this higher variability, such as small sample size and small multifocal calcifications, which have the same score as large calcifications if the total amount of calcification is similar. However, misregistration due to 3-mm section-by-section acquisition and the arbitrary attenuation scaling factor of the traditional scoring system likely play the greatest roles. Yoon et al (22) concluded that the variability of the score may be decreased by adopting a continuous weighting function rather than the step function inherent in the current quantification technique. Such an approach is also supported by Shemesh et al (23) for use with the dual-section CT scanner.
To avoid loss of vital diagnostic and prognostic information and decrease partial volume effects, the section thickness used in coronary screening should be as thin as possible. The newer multi–detector row CT technology that routinely supports retrospective ECG gating helps reduce the partial volume effect by enabling a reduction in the section thickness; it can also help eliminate intersection gaps because it acquires a true volume of contiguous data. Additionally, by using a spiral CT technique, some factors known to affect score reproducibility such as motion and arrhythmia artifacts could be reduced with retrospective cardiac gating. In future studies, the reproducibility of measurements of calcium mass derived from the retrospective combination of data must be investigated in a clinical setting.
In measuring CaHA particles, Tang et al (24) noted that the calcium mass measurement is less dependent on the section thickness used than is the calcium score. Detrano et al (25) concluded that an estimate of the relative calcium mass in human heart specimens at electron-beam CT is as accurate as the currently employed calcium scores and reflects the actual mass of precipitated calcium phosphate in diseased coronary arteries. When one considers our results, these statements seem to be true, given the agreement between the calcium mass measurements obtained with the 3-mm section width imaging protocol and those obtained with the 1.25-mm section width angiography protocol at multi–detector row CT. It is likely that, given its better reproducibility, measurement of the mass of the total plaque burden will replace the traditional Agatston score in the future (22).
Our initial results in using thin sections (such as 1.25 mm and 0.6 mm) in phantoms, combined with the mass quantification algorithm to measure calcium, vouch for the feasibility of this approach for in vivo scanning of humans. Further development and testing of this approach are required prior to large-scale clinical application. Use of the 1.25-mm section width coronary CT angiography protocol in combination with mass calcium measurement may allow both detection of coronary artery luminal changes and quantification of coronary calcium in one scan. This should also reduce patient radiation dose. Higher attenuation threshold values may increase specificity but probably would result in reduced sensitivity and necessarily lead to a systematic error, as shown in our study (-6.7 mg). Some small calcium mass could be missed with use of the higher thresholds; however, such small calcified nodules are weak predictors of stenotic lesions in a calcified area (26). Furthermore, the presence of a severe stenosis does not necessarily predict the site or likelihood of a coronary event (27).
In conclusion, this study demonstrates that despite the use of high CT number thresholds, mass scores of coronary calcifications obtained by using a 1.25-mm section width, multi–detector row CT angiography protocol in conjunction with a quantitative CT calibration phantom strongly correlate with those obtained by using a traditional scoring system and a 3-mm section width CT imaging protocol. Currently, the best way to assess coronary artery disease by the presence or absence of coronary calcium at both multi–detector row CT and electron-beam CT is to measure an absolute index of calcium plaque burden, such as calcium mass. Further research is needed to determine the accuracy of thin-section CT angiography in calcium measurement. If the results are as favorable, it would be feasible that both luminal change and calcification of coronary arteries could be comprehensively detected and measured with the same study.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, C.R.B., M.F.R.; study concepts, C.H., C.R.B., B.O., M.F.R.; study design, C.H., C.R.B., U.J.S.; literature research, C.H., R.B.; clinical studies, C.H., C.R.B., R.B., U.J.S.; experimental studies, C.H., C.R.B., B.O.; data acquisition, C.H., U.J.S.; data analysis/interpretation, C.H., C.R.B., U.J.S.; statistical analysis, C.H., C.R.B.; manuscript preparation, C.H., C.R.B., U.J.S.; manuscript definition of intellectual content, C.R.B.; manuscript editing, C.H., C.R.B.; manuscript revision/review, U.J.S., M.F.R.; manuscript final version approval, M.F.R.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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, long-dashed line), 1.25-mm section width (
, solid line), and 0.6-mm section width (
, short-dashed line) imaging protocols. The attenuation threshold increases between 130 HU and 490 HU, especially in the 3-mm protocol. (Absolute mass = c/250 x area x section increment x mean attenuation value.)
