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1
Department of Radiology, Wake Forest University School of Medicine, Medical
Center Blvd., Winston-Salem, NC 27157-1088.
2
Department of Public Health Science, Wake Forest University School of
Medicine, Winston-Salem, NC 27157-1088.
3
Department of Internal Medicine, Wake Forest University School of Medicine,
Winston-Salem, NC 27157-1088.
4
Department of Radiology, Mission Saint Joseph Hospitals 509 Biltmore Ave.,
Asheville, NC 28801.
Received September 17, 1999;
accepted after revision February 2, 2000.
Presented at the annual meeting of the Conference on Cardiovascular
Disease, Epidemiology, and Prevention, Orlando, FL, March 1999.
Abstract
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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MATERIALS AND METHODS. We compared total calcium scores obtained using a general purpose, unmodified helical CT scanner with scores obtained using electron beam CT in 36 individuals who were 68 ± 11 years old (age range, 41-85 years).
RESULTS. Correlation coefficients ranged from 0.97 to 0.98 (Pearson's product moment) and from 0.95 to 0.96 (Spearman's rank order), depending on the coronary calcium scoring method used. Agreement in the classification of participants as "healthy" or "diseased" at threshold total calcium scores of 10, 100, 160, 200, 400, and 680 was, respectively, 94%, 97%, 89%, 92%, 94%, and 100% using the conventional electron beam CT scoring method and an equivalent method with helical CT.
CONCLUSION. A general purpose, current generation helical CT scanner equipped for retrospective cardiac gating can accurately quantify coronary calcium, and the results are highly correlated to scores obtained with electron beam CT. As an alternative method for measuring coronary calcium, gated subsecond cardiac helical CT offers greater availability and lower cost, thereby making population-based screening for coronary artery calcium more feasible.
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The standard method for quantification of coronary artery calcium is electron beam CT. This method has undergone rigorous testing for reliability [3, 4] and validity [5] and has proven useful in identifying individuals with coronary artery disease [6,7,8,9] and those with an increased likelihood of experiencing clinical coronary events [10, 11]. Access to the technology is limited because only approximately 50 electron beam CT sites are available in the United States.
Previously, conventional CT has been limited in its ability to quantify coronary calcium because of its image capture time (temporal resolution) of greater than 1 sec and its lack of synchronization with the cardiac cycle (ECG gating). Maximum cardiac motion occurs during the ejection phase of systole. To obtain coronary artery images that minimize motion and misregistration artifacts both in each slice and between slices, sufficient temporal resolution and ECG gating are needed. The temporal resolution of the helical CT technique has improved to the subsecond range, and cardiac gating methods have been described [12,13,14]. The purpose of this study was to compare calcium scores obtained with retrospectively gated helical CT and the current standard, electron beam CT.
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Sixty-one percent of all participants were women, 8% were African-American, and 6% were Hispanic. The average age of study participants was 69.4 years (range, 42-86 years). Participants' blood pressures ranged from normotensive to mildly hypertensive, with a mean blood pressure of 133 over 73 mm Hg and maximum blood pressures of 173 mm Hg systolic and 102 mm Hg diastolic. In addition, the group was normocholesterolemic to mildly hypercholesterolemic, with a mean total cholesterol of 178 mg/dl and a maximum cholesterol level of 227 mg/dl. The heart rate of these participants averaged 71.7 beats per minute, with a maximum heart rate of 96 beats per minute. Eight participants had heart rates greater than or equal to 80 beats per minute, and five had heart rates greater than or equal to 90 beats per minute at the time of helical CT. The following conditions were reported by a percentage of participants as follows: a diagnosis of hypertension, 53%; a prior heart attack, 24%; a prior stroke, 6%; diabetes, 19%; and a history of ever having smoked cigarettes, 19%.
Study Design
The study was a blinded, paired comparison of total calcium scores as
determined on ECG-gated helical CT and electron beam CT in the population of
36 individuals. Our institutional review board approved the study protocol,
and we obtained informed consent from all participants. Each participant
completed a short medical history and risk behavior questionnaire. We measured
blood pressure, height, and weight, using the Cardiovascular Health Study
protocol for these measures as previously reported
[15]. Participants' cardiac CT
studies were performed at two different medical centers. The CT scanners were
unmodified, clinically operational systems. The systems were calibrated to
manufacturer's operating specifications and no additional modifications or
calibrations were performed. The cardiac electron beam and helical CT studies
were conducted in a manner designed to replicate a clinical screening
program.
Electron Beam CT Protocol
All patients underwent imaging with an Evolution XP (C150) electron beam CT
scanner (Imatron, South San Francisco, CA, and Siemens Medical Systems,
Iselin, NJ). Imaging parameters included 100-msec scanning time and 3-mm
single slice thickness, with a total of 40 slices obtained during a single
breath-hold. The single-section mode of imaging was used, with imaging
electrocardiographically triggered to 80% of the R-R interval. Images were
reconstructed into a 512 x 512 matrix with a 26-cm field of view. The
pixel area was 0.26 mm2. Examinations were scored on the auxiliary
console of the C150 system using the Imatron-provided hardware and software
and the scoring system previously described by Agatston et al.
[1]. All calcification related
to a coronary artery equal to or greater than the minimum density of 130 H was
considered potential coronary calcium. In addition, a filter used in the
standard scoring algorithm required a minimum of three adjacent pixels with
density equal to or greater than 130 H to qualify coronary artery calcium as a
lesion that could be scored. Lesions were determined by drawing a region of
interest around each coronary calcification that equaled or exceeded the
threshold and filter requirements. The computer software calculated the plaque
area and the maximum attenuation in each region of interest. A score was then
calculated by multiplying the measured area by an attenuation coefficient
based on the peak attenuation. The sum of the individual scores measured
within the borders of each coronary artery was used to compute the total
calcium score. Scans were obtained, scored, and reviewed for quality at the
electron beam CT site. Electron beam CT site personnel had no knowledge of the
results of the helical CT study. Scores were reported as total calcium score
and by vessel.
Gated Helical CT Protocol
Cardiac helical CT was performed on a general purpose, clinically
operational 0.8-sec helical CT scanner (HiSpeed LX; General Electric Medical
Systems, Milwaukee, WI) with a high heat unit X-ray tube. Scanning parameters
included 0.8-sec helical acquisition, 3-mm beam collimation, 120-150 mm of
z-axis coverage (40-50 slices at 3 mm per slice), and a single
breath-hold at end inspiration. Images were reconstructed using a segmented
reconstruction algorithm, resulting in a temporal resolution of 500 msec per
image, 512 x 512 matrix, and 26-cm field of view. The pixel area was
0.26 mm2.
Participant Preparation
The participant preparation for the two methods of cardiac CT scanning
(electron beam CT and helical CT) were identical. Participants were instructed
to remove any jewelry or clothing with the potential to create artifacts
during the studies. They were placed in the supine position on the CT couch
with their arms above their heads. ECG leads were applied to the lower thorax,
after which the waveform was checked and the electrodes were repositioned as
required to obtain an acceptable tracing. Participants were instructed before
scanning about the breath-hold technique. CT scans were obtained at end
inspiration. For electron beam CT, breathing instructions were provided by the
technologist over an intercom; and for helical CT, a standardized recorded
voice was used for the scout and helical acquisitions to ensure consistency.
The entire heart was imaged in one breath-hold, starting 1.5 cm below the
carina and extending through the inferior aspect of the heart with electron
beam CT and helical CT. In a subset of 15 participants, electron beam CT and
helical CT studies were performed with a calibration phantom (Image Analysis,
Columbia, KY). The phantom was placed on the CT couch under participants as
previously described [16].
Gated helical CT requires a digital ECG to be recorded and synchronized with the acquisition of the image data. A Horizon 2000 ECG and vital signs monitor (Mennen Medical, Clarence, NY) was used for analog output of the ECG waveform. The analog ECG output was connected to a laptop computer (ThinkPad 600; International Business Machines, Armonk, NY) with an analog-to-digital conversion card and associated software (DAQCard-1200 and Lab View 5.0; National Instruments, Austin, TX) and was digitized at a rate of 250 samples per second. A second data channel was used to record start and stop of the image acquisition on the basis of the activation of the X-ray tube, as described by Woodhouse et al. [14]. For cardiac helical CT, the pitch, or relative motion of the CT couch to tube rotation, is adjusted on the basis of heart rate immediately before scanning (Table 1). This adjustment for heart rate is made so that the table moves in 3-mm increments for each cardiac cycle. The helical acquisition requires a breath-hold for the participant ranging from 22 to 42 sec, depending on the combination of heart rate and heart length. Individuals with slower heart rates and more elongated cardiac anatomy require longer breath-hold times for complete coverage of the heart. After the helical acquisition, the ECG leads are removed, and the participant leaves the scanning suite. The total scanning time, including localizer images, is less than 60 sec, and the total room time is less than 15 min, depending in large part on participant mobility for both methods of scanning.
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Postprocessing with Cardiac Helical CT
To minimize cardiac motion, a segmented or partial scan reconstruction
algorithm is used to produce images with a 500-msec temporal resolution from
the projection data stored in radon space (raw scan data)
[12]. A series of images 3-mm
thick at 0.3-mm increments along the z-axis (90% overlap) is created.
The overlap of the image data along the z-axis creates a volumetric
CT cine of the heart. The image and ECG data are transferred to an Ultral
workstation (Sun Microsystems, Palo Alto, CA) configured with the Advantage
Windows Workstation 3.1 software (SmartScore; General Electric Medical
Systems), which included a developmental version of a coronary artery
calcification scoring package for retrospectively gated helical CT. One
observer, unaware of the electron beam CT calcium score and other participant
information, scored the helical CT examination. For each examination, the
observer had access to the entire data set of approximately 400 images
(approximately 10 frames per cardiac cycle) synchronized with the digital ECG
tracing of the heart during image acquisition. An automated selection of the
reduced set of diastolic images was provided. The observer optimized the
diastolic image set by minimizing motion artifacts as determined by direct
visualization of the images. Particular attention was directed at minimizing
artifacts of the right coronary artery and the ventricular free wall (Fig.
1A,1B,1C,1D).
The diastolic image set was then scored for the presence or absence of
coronary calcium. Thresholds for identifying calcification in the coronary
arteries were 90 H, as suggested by previous investigators of helical CT
[17], and 130 H, along with
the requirement for two contiguous pixels. Calcifications were identified
according to vessel (left main, left anterior descending, circumflex, right
coronary, and posterior descending arteries).
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Scoring Methods
The helical CT scans were scored with five different algorithms:
conventional Agatston with a 130-H threshold, modified Agatston with a 90-H
threshold, a linear weighting method, calcium volume, and calcium mass. The
conventional method described by Agatston et al.
[1] uses categoric weighting
based on the maximum pixel intensity of each lesion greater than the 130-H
threshold multiplied by the area to determine the coronary artery calcium
score (Table 2). This scoring
method was used with both electron beam and helical CT in this study. Four
additional scoring methods were calculated for the helical CT technique. A
modified Agatston score using a lower threshold of 90 H, which has been used
previously with helical CT
[18], was calculated to take
advantage of the greater signal-to-noise ratio of helical CT. Regions of
interest were defined by vessel and slice, and the appropriate weighting
factor was applied to determine total scores and scores by vessel. For helical
CT, calcifications were not enumerated by lesion as with the original Agatston
method because of the bias introduced by vessels that course both within and
through the cross-sectional slice of the heart, as has been previously noted
[19]. Coronary calcium volume
and mass were determined [1,
4,
20,21,22],
as well as a linear weighting algorithm similar to that described by Broderick
et al. [17]. Detailed score
reports generated for each participant included a region-of-interest histogram
and calcium scores by image, vessel, and scoring method. These data were
exported to the SAS Statistical Program (SAS Institute, Cary, NC) for
analysis.
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Data Analysis
Descriptive statistics were used to characterize participants in this
study. Total calcium scores produced with the cardiac helical CT and electron
beam CT methods were compared using both product moment (Pearson's) and rank
order (Spearman's) correlation coefficients. In the subset of participants
scanned with the calibration phantom, mean CT attenuation for each of the four
reference concentrations of calcium phosphate (0, 50, 100, and 200 mg/ml) in
the phantom was determined. Linear regression equations were used to evaluate
for systematic bias in the measurement of calcium by the two scanners.
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The calibration phantom allows measurement of CT attenuation for known calcium concentrations with helical CT and electron beam CT during each participant's scan. At each of the four concentrations in the phantom, the measurement with electron beam CT averaged 25-30 H greater than the measurement with helical CT (Fig. 2). For electron beam CT, the standard threshold of 130 H corresponded to a calcium concentration of 105.6 mg/ml. For helical CT, 103 H corresponded to the calcium concentration of 105.6 mg/ml. For comparison of helical and electron beam CT scores using the same 105.6 mg/ml calcium threshold, an additional modified Agatston helical CT score, correcting for the systematic bias in measurement of density between the two CT scanners, was calculated. The helical CT scores using the thresholds of 90 and 120 H were interpolated to determine a total calcium score with a common threshold for calcium of 105.6 mg/ml (103 H on helical CT).
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The distribution of total calcium scores as measured on electron beam CT was as follows: 25% (n = 9) had a total calcium score of less than 10, 44% (n = 16) had a score of less than 100, and 72% (n = 26) had a score of less than 400. The means, medians, ranges, and correlations using electron beam CT and helical CT are presented in Table 3. Note that half of all participants had electron beam CT—measured total calcium scores of less than 161. Product moment and rank order correlations were strong among the various helical CT calcium scoring methods and the total calcium score determined by electron beam CT. A scatterplot of total calcium scores with electron beam CT and helical CT for conventional Agatston scoring with the 130-H threshold shows a high degree of concordance between helical CT and electron beam CT (Pearson's correlation coefficient, 0.98; Spearman's rank order correlation coefficient, 0.96) (Fig. 3). To further evaluate the performance of helical CT in respect to electron beam CT in the most variable subset of individuals with low total calcium scores, the correlation analysis was performed with only those participants with electron beam CT scores of less than the median score of 161 using electron beam CT. There remains a high correlation of total calcium scores between electron beam CT and helical CT (103 H), with Pearson's and Spearman's correlation coefficients being 0.91 and 0.84, respectively.
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Coronary calcium scores have been used to predict the risk of future cardiovascular disease events or likelihood of angiographic stenosis [11]. Various cut points for calcium scores using the Agatston method have been suggested as threshold points for clinical action or for maximizing parameters of diagnostic accuracy. We compared electron beam CT and helical CT scores at previously published cut points: 10, 100, 200, 400 and 100, 160, 680 [2, 11] for each of the helical CT calcium thresholds (90, 103, and 130 H). Agreement with electron beam CT scores was 94%, 94%, 94%, 92%, 92%, and 100%, respectively, with the 90-H threshold; the others are presented in Table 4. Discordant scores were present in both directions but were consistent with known variation in coronary calcium scores occurring across the respective cut point.
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Few attempts have been made to relate coronary calcification as identified on conventional or helical CT to clinical conditions. Broderick et al. [17] and Shemesh et al. [22] have refined algorithms for defining coronary calcium using double helical CT without cardiac gating. In particular, they found that using continuous instead of categoric algorithms for weighting calcification density, setting threshold at 90 H instead of 130 H, and considering overlapping slices for quantification led to greater reliability and predictive power for coronary artery disease. These researchers have shown greater coronary calcium in men than in women [24]; in older individuals than in younger ones [25]; and, among women, in nonusers of hormones than in users [26]. More important, they have identified associations with angina pectoris and myocardial infarction [27] or coronary artery disease defined on coronary angiography [17, 18, 25, 28]. Their data on prevalence of coronary calcium as identified by helical CT are similar to those identified on electron beam CT in published data from Agatston et al. [1], Janowitz et al. [29], and Wong et al. [30]. Two other reports have presented direct comparisons of helical CT with electron beam CT for coronary calcium. Baskin et al. [31] studied 10 subjects with known coronary calcium on electron beam CT and helical CT. Scanning time for helical CT was 0.6 sec per scan without cardiac gating. These researchers compared volumetric measures for the left main, left anterior descending, circumflex, and right coronary arteries for both techniques and found significantly more variability with helical CT-derived coronary calcium scores than electron beam CT—derived scores; they concluded that electron beam CT was more reliable than nongated helical CT. A 1998 abstract by Knez et al. [32] describes a high correlation between prospectively ECG-triggered helical CT and electron beam CT. In that study, 50 participants were examined with both helical CT and electron beam CT, and the correlation was very high. A limitation of that study is that two breath-holds were required to image the entire heart with helical CT.
Our experience comparing retrospectively gated helical CT with electron beam CT was favorable. In our study, two different CT technologies (electron beam and helical) were used, independent observers at each site scored examinations unaware of the results from the other technology, and participants had examinations at separate times and locations. These factors increased the expected variability among coronary calcium scores with the two methods, but provided a result that can be generalized to clinical practice. Previous studies comparing calcium score reproducibility with electron beam CT performed replicate scans on the same electron beam CT system and during the same examination (factors that would reduce variability). In this study, the correlation between total calcium scores with gated helical CT and those with electron beam CT was excellent even when evaluating only those participants with total calcium scores under the median value of 161. Perhaps more important, strong agreement exists for calcium scores with gated helical CT and electron beam CT in grouping participants into risk strata on the basis of the total calcium score (or Agatston score). We believe that the improved temporal resolution of 500 msec and the addition of retrospective cardiac gating are responsible for the enhanced validity of the helical CT method compared with nongated helical CT. Because of the wider availability and lower cost of CT systems compatible with the helical CT technique, we believe this development has great potential for coronary calcium screening.
We believe the use of a standard phantom to calibrate CT attenuation values will become increasingly important. The use of a calibration phantom reduces variability between electron beam CT scanners by 25%, as McCollough et al. [16] showed. In that study, the 130-H threshold for "scoreable coronary calcium" could vary from 77.1 to 136.4 mg/cm3 and was "dependent on patient girth, sex, smoking history, and image level." The observed variation between electron beam CT and helical CT in our study falls within the reported variation between electron beam CT scanners. This finding supports the need for quality control measures and use of a calibration phantom for coronary calcium studies of the heart to standardize measurements, both between and within individuals. A standard based on the concentration of calcium will be critical for the evaluation of progression and regression of coronary calcium over relatively short intervals of time (1-2 years). We propose that a standard concentration of calcium, rather than CT attenuation, which varies between and within CT scanners and individuals, be used as the definition of scoreable coronary calcium.
This initial comparison of gated helical CT with electron beam CT was performed with a modest number of participants; however, even with this limited sample size, an extremely high strength of association (0.98) was seen between calcium scores obtained with the two CT technologies. Corroboration of these results at other centers and evaluation of the reproducibility of the technique is needed. Initial results by our team and others show a similar reproducibility for helical and electron beam CT for measuring coronary calcium (Goldin JG et al. and Carr JJ et al., presented at the Radiological Society of North America meeting, December 1999). An additional concern is that helical CT might not perform as well as electron beam CT in individuals with limited coronary calcium (i.e., low total calcium scores). We address this concern in the analysis in three ways. First, the correlation between helical CT and electron beam CT remained high (0.91) even when subsetting the data for those participants with low total calcium scores (i.e., below the median score of 161 as measured with electron beam CT). Second, we calculated Pearson's and Spearman's correlation coefficients. The Spearman's correlation is a nonparametric test comparing the rank ordering of calcium scores with the two CT techniques. With this analysis, each participant's calcium score has equal weight in determining the correlation or strength of association. Thus, very high or very low scores will not artificially inflate the correlation between the two measures. Finally, to address how helical CT and electron beam CT would agree in clinical application, we compared agreement with previously recommended or published cut points. This analysis shows high agreement in grouping participants into risk strata but also shows how the relatively high variability with both methods in the measurement of coronary calcium can result in misclassification.
The variability of total calcium scores with electron beam CT is known to increase with smaller lesions and lower total scores. As Wang et al. [33] stated, "electron beam CT is not sufficiently reproducible to allow serial quantitation of coronary calcium in individual patients over relatively short periods (<2 years)." Likewise, Callister et al. [19] stated, "The results of previous analyses of the reproducibility of the TCS [total calcium score] have confirmed the large interscan variability of this measure." To improve reproducibility with electron beam CT, recommendations have included increasing the minimum scoreable calcification size to 2 mm [34], increasing slice thickness to 6 mm [33], and performing replicated examinations using the average of the two scores [35]. Callister et al. found improved reproducibility of calcium scores through an interpolation between slices to create a volumetric score. The volumetric scoring improved median percentage of change to 9% from the 15% seen using the traditional Agatston total calcium score. When evaluating the results of this initial study of retrospectively gated helical CT for coronary calcium, the intrinsic variability in the electron beam CT scores remains. The observed variability in total calcium scores in this report between electron beam CT and helical CT is consistent with the reported variability seen between patients scanned sequentially on the same electron beam CT system. Furthermore, if one assumes electron beam CT to be the current standard for coronary calcium quantification, the reproducibility of total calcium scores with helical CT compared with electron beam CT cannot exceed the inherent reproducibility of electron beam CT. Partial volume effects and beat-to-beat variation in coronary artery location are likely large components of the observed variation in calcium scores. Single- and multislice helical CT systems may be able to further improve reproducibility through coupling volumetric image acquisition and scoring, and are the subject of research in progress.
In summary, this comparability study shows that coronary calcium scores nearly identical to those produced by the current standard, electron beam CT, can be generated with a new technique, subsecond gated helical CT. The calcium scores measured on helical CT have an extremely high correlation with scores on electron beam CT. Equally important, high agreement is seen between electron beam CT and helical CT in grouping total calcium scores for clinical management. These findings suggest that current-generation "fast" or subsecond helical CT scanners can be used to measure coronary calcium. Furthermore, the wide availability of helical CT scanners and reduced capital cost to add ECG gating and analysis software makes deployment of helical CT for coronary calcium a potentially feasible option for population screening.
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