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(Circulation. 1995;91:1363-1367.)
© 1995 American Heart Association, Inc.
Articles |
Coronary Calcium, as Determined by Electron Beam Computed Tomography, and Coronary Disease on Arteriogram
Effect of Patient's Sex on Diagnosis
From the Departments of Cardiovascular Diseases, Internal Medicine (J.A.R., R.S.S.), and Diagnostic Radiology (P.F.S. III, J.F.B.), Mayo Clinic and Foundation, Rochester, Minn.
Correspondence to John A. Rumberger, PhD, MD, Department of Cardiovascular Diseases, Mayo Clinic and Foundation, 200 First St SW, Rochester, MN 55905.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Coronary artery calcium identified by electron beam computed tomography (EBCT) has potential for noninvasive localization of coronary atherosclerotic disease. However, the effect of a patient's sex on its diagnostic capability has not been examined in a clinical population.
Methods and Results Fifty women and 89 men had EBCT scans done an
average of 1 day after coronary arteriography. Maximum arteriographic
percent luminal diameter stenosis of any artery was paired with the
total EBCT coronary calcium score for each subject. The women (age,
56±11 years [mean±SD]) were older than the men (age,
47±7 years),
but the subjects were matched for indications for arteriography and
extent of disease as assessed by arteriography. Sensitivity,
specificity, and positive and negative predictive values for coronary
calcium were nearly identical for men and women, regardless of the
degree of arteriographic disease. EBCT was highly sensitive to the
presence of arteriographic disease (range, 94% to 100%), but had only
moderate specificity (57% to 66%) for significant disease (
50%
stenosis) and low specificity (35% to 38%) for any arteriographic
disease (>0% stenosis). Negative predictive values in men and women
ranged from 79% to 91% for any arteriographic disease and from 95%
to 100% for significant disease, respectively. Numerical calcium
scores were significantly different between subjects with normal
arteriograms and those with significant disease; however, calcium score
had limited power to separate trivial, moderate, and significant
disease. Receiver operating characteristic curve areas, determined as
an extension of the analyses of sensitivity and specificity, were high
for EBCT-defined calcium scores for both any arteriographic disease and
significant arteriographic disease, and were not different between the
sexes.
Conclusions In a middle-aged population, noninvasive definition of coronary calcium by EBCT has similar predictive value for arteriographic coronary artery disease in men and women.
Key Words: tomography • coronary disease • patients • angiography • diagnosis • imaging • calcium
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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In situ coronary artery calcium is a specific anatomic marker for coronary atheromata.1 2 3 4 Recent studies have suggested that coronary calcification is an active5 6 7 as opposed to a degenerative process. Electron beam computed tomography (EBCT) provides rapid, multilevel, ECG-triggered, stop-action images of the heart and has been shown to be an accurate noninvasive tool in the detection of coronary artery calcium.8 The potential for using EBCT and identification of coronary calcium as a direct method of detecting coronary atherosclerotic disease has been suggested by studies from our laboratory and elsewhere.8 9 10 11 12 However, the majority of previous investigations either have been conducted almost exclusively in men or have been presented with no consideration of the role of a patient's sex in the prediction of coronary disease by EBCT.
Clinical diagnosis of coronary disease in women with chest pain and no prior history of heart disease can be problematic. Chest pain history is less specific in women than in men,13 and the lower prevalence of atherosclerotic disease in women compared with men in some age groups limits the predictive accuracy of conventional stress testing. Definitive diagnosis of coronary disease in women is frequently delayed years beyond diagnosis in men. When the diagnosis is confirmed, the women are older; frequently have advanced and severe obstructive disease; are more likely to have unstable angina, reduced exercise capacity, or both; and may fare worse with coronary bypass grafting or coronary angioplasty than their male counterparts. The basic reasons for these consequences are many, but they are due in part to gender differences in perception and tolerance to warning signals, such as angina, as well as known differences in the predictive accuracy of traditional noninvasive tests in women compared with that in men.
A prior study from our laboratory that evaluated atherosclerotic luminal narrowing versus detection of coronary calcium in histopathological specimens suggested that the diagnostic potential of EBCT may be similar in men and women.14 If this is so, EBCT may be a valuable and easily performed means of identifying the absence or presence, and possibly the severity, of coronary artery disease in patients with chest pain syndromes, regardless of their sex. The purpose of the current investigation was to assess the effect of patients' sex on the results of EBCT coronary calcium scanning for the diagnosis of coronary disease in a population of men and women undergoing elective coronary arteriography.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Study Population
The sample consisted of 139 subjects (89 men and 50 women, enrolled consecutively) who underwent diagnostic coronary arteriography for clinical indications at the Mayo Clinic, Rochester, campus. Patients were invited to participate in the research if they had no previous arteriographic documentation of coronary artery disease or previous cardiac transplant surgery. No patient had unstable angina or underwent coronary angioplasty at the time of arteriographic examination. The research protocol was approved by the Mayo Clinic Institutional Review Committee. After signing informed consent, all subjects underwent EBCT scanning an average of 1 day after arteriography.
The most common indication for arteriography in men was chest pain (typical or atypical angina) (65 men, or 73%). Twelve (13%) had abnormal conventional stress tests, 4 (4%) had a history of myocardial infarction, 3 (3%) had arteriography as part of a workup for congestive heart failure or prior to cardiac transplantation, 1 (1%) had syncope, 1 had constrictive pericarditis, and 1 had unexplained dyspnea with effort. The most common indication for arteriography in women was also chest pain (39 women, or 78%). Four other women (8%) had abnormal stress tests, 4 had congestive heart failure, 2 (4%) had unexplained dyspnea with exertion, and 1 (2%) had a history of myocardial infarction.
Coronary Arteriography
Selective coronary arteriography was
performed by the Judkins
technique with a minimum of five views of the left system and two views
of the right system. The absence or presence of discrete coronary
artery stenoses was visually assessed by two angiographers, and the
maximum percent diameter stenosis in any epicardial coronary artery was
defined as 0% (normal coronary arteriogram), >0% but 
20% (trivial
coronary disease), >20% but <50% (moderate coronary disease), and
50% (significant disease). In case of a disagreement in the
interpretation of a given coronary arteriogram, it was read by a third
cardiologist to determine the correct category.
EBCT
High-resolution, non–contrast-enhanced EBCT
examinations
(Imatron C-100, Imatron Inc) were performed in a manner described
previously.9 12 In all subjects, 40 contiguous,
3-mm–thick, transaxial images were made commencing at the root of the
aorta and proceeding caudad through the apex of the heart. There were
two separate scanning sequences of 20 images per set, each done during
suspended respiration. Care was taken to instruct the subject to not
move between scanning intervals and to use the same breath-holding
technique throughout the examination. The patient's ECG provided
triggering for the imaging, so consecutive scans at each tomographic
level were obtained at the same phase of the cardiac cycle (80% of the
RR interval). Scans were taken using either a 26-cm or a 30-cm field of
view and a 512x512 reconstruction circle (0.25
mm2/pixel or 0.34 mm2/pixel,
respectively).
Each tomographic image was examined by a trained
observer, and regions
of the major epicardial coronary arteries were identified using
anatomic landmarks. An operator-defined region of interest was placed
around each focus of coronary artery calcium, which was defined as any
region within a coronary artery of two or more pixels with a computed
tomographic (CT) density above the threshold of 130 Hounsfield Units.
This threshold was selected because it is more than 2 SD above the
average CT density of blood and because it has been used in previous
studies in which EBCT was
used.9 10 11 12 14 15 16
Peak CT
brightness of each calcium focus and its area (in mm2) were
used to determine a calcium score for each scan by the use of a method
developed by Agatston et al.9 The area of any individual
calcium focus of 2 or more pixels was multiplied by a weighing factor
based on the brightest pixel in that region (1 if 130<peak CT
brightness200, 2 if 201<peak CT brightness 300, 3 if 301<peak CT
brightness 400, and 4 if peak CT brightness >400). Calcium scores
for each epicardial focus were then summed to define the total coronary
calcium score for each patient.
Statistics
Data for calcium scores are presented as
mean±SD.
Comparisons of proportions or unpaired t tests were used to
compare data from men with those from women when appropriate.
Sensitivity, specificity, and positive and negative predictive values
for EBCT compared with arteriography were determined in the
conventional manner from data entered into a 2x2 contingency table.
Standard errors for these variables were calculated using methods
described elsewhere.17 Each contingency table was analyzed
using a 
2 statistic. When the number of
observations in any section of the table contained less than 5
patients, Fisher's exact test was used to calculate the level of
significance. Receiver operating characteristic (ROC) curve
analysis was used as an extension of traditional sensitivity and
specificity analyses18 19 20 to establish
relationships
between total coronary calcium score by EBCT and maximal coronary
artery narrowing on arteriography for men and women. For the ROC
analysis, a curve was constructed plotting the "true positive
rate" (ie, sensitivity) as the dependent y variable and a
function of the "false positive rate" (ie, 1-specificity) as
the
x variable at a given definition of "disease."
Individual x,y pairs were determined for the ROC
analysis using increasing values for calcium score and different
definitions of coronary disease severity. Data are presented for
women and men separately. Each definition of "disease" yielded a
unique ROC curve and data set. ROC curve areas are presented as
mean±SEM. A test with equal numbers of true positive and false
positive examinations has an ROC curve area of 0.5. Curve areas of more
than 0.5 represent tests with increasingly greater diagnostic
accuracy; the "perfect" test (100% sensitive, 100% specific)
has a curve area of 1.0. Examination of the differences between
individual ROC curve areas in men versus women was done according to
methods for a generic model as presented by Hanley and
McNeil18 and as reported previously by our laboratory in
comparisons of histologically assessed coronary disease with coronary
calcium detected by EBCT.14 A value of P.05
for a two-tailed test was considered significant for all statistical
evaluations.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Patient Demographics
All subjects were Caucasian. The men were 47±7 (mean±SD) years old and the women were 56±11 years old (P<.001). There were 23 men (26%) and 16 women (32%) with normal coronary arteriograms (NS, P=.339 between proportions). Six of the men (7%) and 6 of the women (12%) had trivial coronary disease (NS, P=.492); 13 men (15%) and 10 women (20%) had moderate disease (NS, P=.603), and 47 men (53%) and 18 women (36%) had significant disease as determined by arteriography (NS, P=.08).
Absence or Presence of Coronary Calcium and Arteriographic Disease
Severity
Data are shown in Table 1
indicating the
distribution of arteriographic disease severities and the absolute
number and percentages of men and women in each arteriographic class
with and without coronary artery calcium identified by EBCT. In
general, the proportions of men and women with positive and negative
EBCT examinations were equal in each of the four arteriographic disease
categories. In patients without detectable coronary calcium, a majority
of women (10 of 11 [91%]) and a majority of men (15 of 19
[79%])
had normal coronary arteriograms. In patients with detectable coronary
calcium, the converse was true; 33 of 39 women (84%) and 62 of 70 men
(88%) had evidence of at least trivial coronary artery disease.
|
The
sensitivity, specificity, and positive and negative predictive
values for the absence or presence of EBCT-defined coronary artery
calcium in men and women with any arteriographic coronary disease
(>0% stenosis; ie, trivial or worse) or with at least one stenosis of
50% (significant disease) are shown in Table 2.
Results of 2 analysis of contingency tables
for EBCT and any arteriographic disease in men and women were
2=32.1 (P<.001) and
2=19.1 (P<.001), respectively.
Results of 2 analyses for EBCT and significant
arteriographic disease in men and women were
2=19.55 (P<.001) and
2=6.06 (P=.014), respectively. These
data suggest no differences between men and women for the detection of
coronary calcium by EBCT. In general, the sensitivity of EBCT for
trivial or significant coronary disease was on the order of 94% to
100% in this population. On the other hand, the specificity of EBCT
was low for significant arteriographic disease (57±8% to 66±8%)
and
even lower for arteriographic disease assessed as being trivial or
worse (35±10% to 38±12%). However, in this regard, the negative
predictive values for EBCT were excellent, ranging from a low of
79±9% for any disease in men to as high as 100% in men and women for
the absence of significant coronary disease.
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Coronary Calcium Score and Arteriographic Disease Severity
Fig 1 shows mean calcium scores in men versus women
for each of the four arteriographic disease categories. In general, in
both sexes the coronary calcium score by EBCT increased as the severity
of arteriographic coronary disease increased. Scores ranged from 4±10
in men and 6±19 in women with normal coronary arteriograms to
480±556
in men and 610±812 in women with significant disease. However, in both
men and women, scores were only statistically different (one-way ANOVA)
when patients with normal coronary arteriograms were compared with
patients with evidence of significant disease. Thus, in our subjects,
EBCT calcium score could be used to separate normal from significant
arteriographic disease but not to quantify percent luminal diameter
stenoses in patients with abnormal coronary arteriograms.
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ROC Curve Analyses
ROC curve analyses were performed on the
calcium score data from
men and women for two different arteriographic disease categories: any
disease (trivial or worse) and at least significant disease (50%
diameter stenosis). Curves demonstrating the true positive rate versus
the false positive rate in men versus women for these two categories
are shown in Figs 2 and 3. For detection
of any arteriographically defined coronary disease by EBCT, the curve
areas were 0.92±0.02 in women and 0.92±0.02 in men. In Fig
2 the
curves are superimposed on one another, and there was no statistical
difference between curve area in women versus men. For the detection of
significant coronary disease (Fig 3) using calcium score and
EBCT, the
curve areas were 0.88±0.03 in men and 0.83±0.06 in women.
Although
these data did not fall precisely along the same line, there was no
statistical difference between curve areas (P=.46). These
continuous data, along with the discrete data in Table 2
,
confirm a
high degree of similarity in the application of the EBCT coronary
calcium score to the diagnosis of arteriographic coronary disease in
men and women.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Four conclusions can be made on the basis of data presented here. First, confirming previous reports from our laboratory and others, coronary artery calcium identified noninvasively with high-resolution EBCT scanning is a highly sensitive indicator of the presence of coronary atherosclerotic disease as defined in patients undergoing clinically indicated coronary arteriography. However, the specificity for significant coronary narrowing was only moderate and, in fact, was low for predicting whether luminal narrowing of any degree was present. Although these specificities for arteriographically defined disease are disappointing, it must be kept in mind that coronary calcium is a specific marker for coronary plaque, and that luminal narrowing, because of atherosclerotic coronary remodeling, may be only poorly related to actual plaque volume.21 Thus, the false positive coronary calcium studies, compared with arteriography, are still true positives for coronary atheromatous plaque. Second, there were no clear statistical differences in the application of EBCT to diagnosis of coronary disease with respect to sex. Thus EBCT, unlike traditional stress testing, which has clearly limited applications in women compared with men in the age group of subjects in this study, has the potential to define arteriographic coronary disease with the same accuracy in both sexes. Third, as noted in previous investigations, the negative predictive value for EBCT-defined coronary calcium is highly consistent with the absence of arteriographically significant coronary luminal narrowing. In fact, nearly two thirds of men and women with a negative EBCT scan had normal coronary arteries at the time of catheterization. Performing EBCT scans in patients presenting with atypical chest pain as an initial screening examination may have important implications for cost containment and health care reform by limiting the need for further workup, especially coronary arteriography, in patients who have a low likelihood of obstructive disease (ie, a negative scan). The cost of an EBCT scan at our institution is one third that of a 201Th, approximately the same for an ECG stress test, and on the order of one fifth that of diagnostic coronary arteriography. Fourth, the amount of coronary calcium as defined by the Agatston calcium score increases with arteriographic disease severity in both men and women, there being minimal calcification in normal patients and extensive calcification in patients with advanced disease. The diagnostic potential for use of a calcium score or equivalent is emphasized by the high ROC curve areas in men and women (Figs 2
and 3). However, the
absolute magnitude of the
calcium score, because of significant intersubject variability, must be
used with caution in attempts to classify patients as having trivial,
moderate, or significant degrees of arteriographically defined coronary
obstruction.
Limitations of the Study
There are several limitations of the
present study that bear
upon its interpretation. Although the threshold of 130 HU for
definition of calcium is somewhat empirical, it has withstood testing
by a number of studies and is a well-accepted criterion for most
investigations. More importantly, however, it is the size or area of
calcium, as seen on each tomogram, that is considered to indicate the
absence or presence of calcification that is a source of current
debate. In a previous study from our laboratory, a value of at least 2
contiguous pixels above the threshold was considered indicative of
calcification,12 but Fallavollita et al22
have noted that when the minimal calcium area criteria for a positive
scan are increased, the sensitivity of coronary calcium for
arteriographic disease decreases but the specificity increases. Similar
data examining the variable effect of minimal calcium area on
sensitivity and sensitivity have been reported by Bielak et
al.23 However, one of the most powerful applications for
detection of coronary calcium by EBCT, as noted in the present
study, is in using a negative examination to identify individuals with
a low likelihood of anatomically significant coronary luminal
narrowing. The question of which minimal EBCT-defined calcium area
should be used to determine the presence of coronary atheromatous
disease remains moot and may depend on the clinical situation. It was
not the objective of the present study to precisely define the
threshold calcium area most appropriate for diagnosis of coronary
disease but to determine, using identical criteria, the potential
pitfalls to this unique application for EBCT with regard to a
patient's sex.
There were several other limitations of the current investigation. First, only one EBCT scan was done per session; therefore, reproducibility was not assessed. Studies from our laboratory24 have shown excellent interobserver reproducibility for calcium scores. However, other studies have shown interscan reproducibility to range from excellent (r=.98)25 to poor enough that there are differences (albeit small in magnitude) in 50 of 75 patients even when the patient scanning protocols are done in a careful and consistent fashion.26 Second, these data are predicated on use of the widely used Agatston scoring system. This system is used by most investigators but is not necessarily optimal in all situations. Third, the number of subjects in the study was small, most were middle-aged, and the population was biased towards individuals referred for arteriography by their cardiologist. The high percentage of men and women in this study who had significant coronary disease is reflective of this bias. Finally, all patients were Caucasian. Although there are no data suggesting differences in the results of EBCT between races, Tang et al27 have noted a lower prevalence of coronary calcium as assessed by fluoroscopy in African American men compared with Caucasian men with similar risk factor profiles. Therefore, extension of these data to the general population or to all races and age groups of men and women who undergo arteriography should be done with caution. A larger series in both men and women with significant ethnic diversity should be conducted to confirm these observations.
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Acknowledgments |
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This work was supported in part by the Mayo Clinic and Foundation, National Institutes of Health grant HL 46292, and an Established Investigator Award to Dr Rumberger.
Received July 12, 1994; revision received September 29, 1994; accepted October 9, 1994.
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L. F. Bielak, J. A. Rumberger, P. F. Sheedy II, R. S. Schwartz, and P. A. Peyser Probabilistic Model for Prediction of Angiographically Defined Obstructive Coronary Artery Disease Using Electron Beam Computed Tomography Calcium Score Strata Circulation, July 25, 2000; 102(4): 380 - 385. [Abstract] [Full Text] [PDF]
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R. A. O'Rourke, B. H. Brundage, V. F. Froelicher, P. Greenland, S. M. Grundy, R. Hachamovitch, G. M. Pohost, L. J. Shaw, W. S. Weintraub, W. L. Winters Jr, et al. American College of Cardiology/American Heart Association Expert Consensus Document on Electron-Beam Computed Tomography for the Diagnosis and Prognosis of Coronary Artery Disease : Committee Members Circulation, July 4, 2000; 102(1): 126 - 140. [Full Text] [PDF]
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D. M. Shavelle, M. J. Budoff, D. H. LaMont, R. M. Shavelle, J. M. Kennedy, and B. H. Brundage Exercise testing and electron beam computed tomography in the evaluation of coronary artery disease J. Am. Coll. Cardiol., July 1, 2000; 36(1): 32 - 38. [Abstract] [Full Text] [PDF]
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R. A. O'Rourke, B. H. Brundage, V. F. Froelicher, P. Greenland, S. M. Grundy, R. Hachamovitch, G. M. Pohost, L. J. Shaw, W. S. Weintraub, W. L. Winters Jr, et al. American College of Cardiology/American Heart Association expert consensus document on electron-beam computed tomography for the diagnosis and prognosis of coronary artery disease J. Am. Coll. Cardiol., July 1, 2000; 36(1): 326 - 340. [Full Text] [PDF]
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W. G. Goodman, J. Goldin, B. D. Kuizon, C. Yoon, B. Gales, D. Sider, Y. Wang, J. Chung, A. Emerick, L. Greaser, et al. Coronary-Artery Calcification in Young Adults with End-Stage Renal Disease Who Are Undergoing Dialysis N. Engl. J. Med., May 18, 2000; 342(20): 1478 - 1483. [Abstract] [Full Text] [PDF]
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R Erbel, A Schmermund, S Mohlenkamp, S Sack, and D Baumgart Electron-beam computed tomography for detection of early signs of coronary arteriosclerosis Eur. Heart J., May 1, 2000; 21(9): 720 - 732. [PDF]
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M. Nishino, M. J. Malloy, J. Naya-Vigne, J. Russell, J. P. Kane, and R. F. Redberg Lack of association of lipoprotein(a) levels with coronary calcium deposits in asymptomatic postmenopausal women J. Am. Coll. Cardiol., February 1, 2000; 35(2): 314 - 320. [Abstract] [Full Text] [PDF]
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A. Schmermund, A. E. Denktas, J. A. Rumberger, T. F. Christian, P. F. Sheedy II, K. R. Bailey, and R. S. Schwartz Independent and incremental value of coronary artery calcium for predicting the extent of angiographic coronary artery disease: Comparison with cardiac risk factors and radionuclide perfusion imaging J. Am. Coll. Cardiol., September 1, 1999; 34(3): 777 - 786. [Abstract] [Full Text] [PDF]
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A. Schmermund, K. R. Bailey, J. A. Rumberger, J. E. Reed, P. F. Sheedy II, and R. S. Schwartz An algorithm for noninvasive identification of angiographic three-vessel and/or left main coronary artery disease in symptomatic patients on the basis of cardiac risk and electron-beam computed tomographic calcium scores J. Am. Coll. Cardiol., February 1, 1999; 33(2): 444 - 452. [Abstract] [Full Text] [PDF]
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J. A. Rumberger, T. Behrenbeck, J. F. Breen, and P. F. Sheedy II Coronary calcification by electron beam computed tomography and obstructive coronary artery disease: a model for costs and effectiveness of diagnosis as compared with conventional cardiac testing methods J. Am. Coll. Cardiol., February 1, 1999; 33(2): 453 - 462. [Abstract] [Full Text] [PDF]
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S. S. Gidding, L. C. Bookstein, and E. V. Chomka Usefulness of Electron Beam Tomography in Adolescents and Young Adults With Heterozygous Familial Hypercholesterolemia Circulation, December 8, 1998; 98(23): 2580 - 2583. [Abstract] [Full Text] [PDF]
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A. D. Guerci, L. A. Spadaro, K. J. Goodman, A. Lledo-Perez, D. Newstein, G. Lerner, and Y. Arad Comparison of electron beam computed tomography scanning and conventional risk factor assessment for the prediction of angiographic coronary artery disease J. Am. Coll. Cardiol., September 1, 1998; 32(3): 673 - 679. [Abstract] [Full Text] [PDF]
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K. E. Watson, M. L. Abrolat, L. L. Malone, J. M. Hoeg, T. Doherty, R. Detrano, and L. L. Demer Active Serum Vitamin D Levels Are Inversely Correlated With Coronary Calcification Circulation, September 16, 1997; 96(6): 1755 - 1760. [Abstract] [Full Text]
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J. A. Rumberger, D. B. Simons, L. A. Fitzpatrick, P. F. Sheedy, and R. S. Schwartz Coronary Artery Calcium Area by Electron-Beam Computed Tomography and Coronary Atherosclerotic Plaque Area : A Histopathologic Correlative Study Circulation, October 15, 1995; 92(8): 2157 - 2162. [Abstract] [Full Text]
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