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Cardiac Imaging |
1 From the Department of Diagnostic Imaging, Kaiser Moanalua Medical Center, 3288 Moanalua Rd, Honolulu, HI 96819 (H.C.Y.); and Departments of Radiological Sciences (A.M.E., J.A.H., J.G.G.) and Biomathematics (D.W.G.), UCLA School of Medicine, Los Angeles, Calif. From the 2000 RSNA scientific assembly. Received July 12, 2001; revision requested September 10; revision received November 15; accepted December 20. Address correspondence to H.C.Y. (e-mail: Hyo-Chun.Yoon@kp.org).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSION REFERENCES |
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MATERIALS AND METHODS: This was a retrospective study of the progression of coronary artery calcium in 217 consecutive asymptomatic subjects who underwent at least two electron-beam computed tomographic studies of the heart. Calcium in the distribution of the epicardial arteries was quantified by using both the conventional coronary artery calcium score (CCS) and the calcium volume score (CVS). Linear regression models were used to judge the joint influence of various risk factors, including sex and age, on rates of coronary artery calcium progression.
RESULTS: This study included 103 women and 114 men. The mean interval between the subjects’ first and last studies was 25 months ± 11 (SD). Regression analyses clearly demonstrated that the amount of coronary artery calcium present at the initial study was the most important determinant of calcium progression. This was true when coronary artery calcium was quantified by using the conventional CCS (P < .001) or CVS (P < .001). Neither sex nor age was a significant predictor of coronary artery calcium progression. Among traditional risk factors, only hypertension (P = .02) and diabetes (P = .01) were significant independent factors for calcium progression.
CONCLUSION: In asymptomatic subjects, the initial CCS and CVS were the most important factors that affected rate of coronary artery calcium progression. Neither age nor sex was as important as these factors in determination of coronary artery calcium progression.
© RSNA, 2002
Index terms: Arteriosclerosis, 54.76 • Computed tomography (CT), electron beam, 54.1211 • Coronary vessels, calcification, 54.812
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSION REFERENCES |
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Findings in previous studies (6–8) suggested that sex and age of the patient influence the amount and progression of coronary artery calcium. However, findings in a recent study (5) demonstrated that sex and age did not significantly affect progression in the CCS, although the preponderance of subjects in that study were men (75%). There are few other published data regarding the possible differences in the rate of progression of coronary artery calcium between asymptomatic men and women.
This study was designed to test the hypothesis that the rate of coronary artery calcium progression is sex specific, namely, that it is greater in men, and that it is age related, particularly in women.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSION REFERENCES |
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Definitions
For the purpose of this study, asymptomatic was defined as having no history of documented ischemic heart disease, including no abnormal results of electrocardiography, a stress test, or coronary angiography, and no history of myocardial infarction or coronary bypass surgery. All subjects completed a detailed risk factor and coronary artery disease event questionnaire administered at the time of each scanning. This questionnaire included the following information: sex; age; excessive weight; and history of hypercholesterolemia, hypertension, diabetes, smoking within 3 years of the first CT scanning, and premature coronary artery disease in a first-degree relative. Hypercholesterolemia was defined as a total cholesterol level of greater than >200 mg/dL (5.17 mmol/L) or a level requiring the use of a cholesterol-lowering agent. Hypertension was defined as a blood pressure level requiring the current use of an antihypertensive medication or known and untreated diastolic blood pressure greater than 90 mm Hg or systolic blood pressure greater than 140 mm Hg. Excessive weight was defined as a body mass index greater than 25. Subjects who reported the use of insulin or oral hypoglycemic agents were classified as diabetic.
CT Scanning and Calcium Scoring Protocols
The standard electron-beam CT acquisition protocol was followed, and it included 3-mm beam collimation, 3-mm table incrementation, and electrocardiogram-gated single-section mode (100-msec acquisition) with acquisition triggered on 80% of the R-R interval. Thirty to 40 contiguous transverse images that included the entire heart were obtained with a single breath hold. Image reconstruction was performed with a 512 x 512-pixel matrix by using the sharp reconstruction algorithm. A display field of view of 26 cm was chosen for image reconstruction, which yielded a nominal pixel area of 0.25 mm2.
All electron-beam CT images were transferred to a workstation (Octane; Silicon Graphics, Mountain View, Calif) equipped with software (Vitrea version 2; Vital Images, Plymouth, Minn). Calcium volume was evaluated because findings in recent studies (9,10) suggested that there is less interscan variability with calcium volume than with the conventional Agatston scoring algorithm. Each image was scored for coronary artery calcium volume by using the software proprietary algorithm. We defined a calcified lesion as three or more contiguous pixels with attenuation of 130 HU or greater in the expected location of an epicardial artery. The volume of each lesion was the product of the pixel area and the section thickness. The sum of all lesion volumes yields the total calcium volume score (CVS) in cubic millimeters.
The same lesions were also scored for coronary artery calcium by using the Agatston algorithm (9) with the same software. With the Agatston algorithm, lesions are assigned a value between 1 and 4 that is determined according to the peak pixel attenuation of the lesion. Lesions with a peak attenuation of 130–200 HU are assigned a value of 1; those with a peak attenuation of 201–300 HU are assigned a value of 2; those with a peak attenuation of 301–400 HU are assigned a value of 3; and those with a peak attenuation value greater than 400 HU are assigned a value of 4. The integer value of each lesion is multiplied by the area of that lesion to yield a lesion-specific calcium score. The sum of all lesion scores calculated by using the Agatston algorithm yields the total coronary artery calcium score (CCS).
Since the same lesions are used to generate the CVS and the CCS, each sequence need only be evaluated once to generate both scores by using the software. All images were scored by one of two observers (A.M.E., J.A.H.), both of whom had extensive clinical experience in calcium scoring.
Statistical Analysis
Subjects within each sex category were then stratified according to age. Since findings in previous studies (6,8) showed that the CCS for women generally tends to be similar to that in men who are approximately 10 years younger, we used an age cutoff of 50 years or younger for men and 60 years or younger for women.
To compare differences in mean values in stratified univariate analyses between men and women, t tests were used. A separate-variance t procedure was substituted whenever SDs were more than two times different from one another. Nominal variables were evaluated by using the 
2 test.
For subjects with scores that were not 0, an annualized relative rate of change was determined by using the following equation:
Therefore, monthly rates of change in CVS and CCS were determined for each subject by subtracting first and last scores and dividing the difference by the number of elapsed months. Individual plots of CVS and CCS over time suggested that a linear progression rate was feasible when subjects were subclassified according to their initial scores, which were grouped as 0, 1–10, 11–100, 101–400, 401–1,000, and greater than 1,000 units. These values were used in multifactorial analyses to judge the joint influence of various risk factors on calcium progression. In addition to initial calcium levels, other risk factors included a subject’s initial age (in years); indicator variables for sex; family history of coronary artery disease; and history of hypertension, elevated cholesterol level, diabetes, obesity, and smoking.
A preliminary multiple linear regression model with the monthly rate of change of CVS as the dependent variable was used to determine that a subject’s initial score accounted for most (88%) of the explainable variation (R2 = 0.33) in calcium progression. However, visual inspection of diagnostic residual plots indicated mild data heteroskedasticity, and this outcome, as well as R2, suggested use of an alternative model. Since the study was longitudinal and repeated observations within randomly selected subjects were not independent, a random-effects repeated-measures model (with all calcium measurements including 451 first, last, and intermediate scores in 217 subjects) was chosen to estimate the main effects of risk factors on calcium progression (11). Here, diagnostic plots following estimation did not indicate serious violations in assumptions, and R2 is 0.97. Separate random-effects models were used to generate standard progression curves and CIs for asymptomatic subjects stratified according to their initial score.
The previously mentioned analysis was also performed by using CCS values in place of their corresponding CVS values. All P values were two sided and all estimates (including model parameters just described) were calculated with statistical software (STATA version 6.0; Stata, College Station, Tex). P values less than .05 were considered to indicate a significant difference.
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RESULTS |
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The mean number of cardiovascular risk factors was 1.4 ± 0.9 for all subjects. The mean number of risk factors for men was 1.5 ± 0.9, whereas that for women was 1.3 ± 0.9 (P = .05). Among all 217 subjects, 127 (58.5%) had hypercholesterolemia, 68 (31.3%) were overweight, 44 (20.3%) were hypertensive, 39 (18.0%) had a family history of early heart disease, 18 (8.3%) were current or recent smokers, and 10 (4.4%) were diabetic. No significant differences in risk profile were seen between the sexes.
Table 1 demonstrates the correlation between the CVS and CCS in all 217 subjects when they were grouped according to their initial study values. There was excellent correlation between the two studies; 
value was 0.86 and Pearson R was 0.98. In 12 subjects, the initial CCS category exceeded the CVS category, whereas in another 11 subjects, the initial CCS category underestimated the CVS category. All differences were of only one score category. A similar degree of correlation was noted between CVS and CCS on the basis of the scores from the follow-up scans; value was 0.89 and Pearson R was 0.98. In 11 subjects, the follow-up CCS category exceeded the corresponding CVS category, whereas in another seven subjects, the follow-up CCS category underestimated the CVS category. Again, all differences were of only one category.
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Among men, there were 23 subjects who had a baseline CVS of 0. At the time of follow-up, only two of these subjects had identifiable coronary artery calcium, with the largest increase being 7. There were two men who had a CVS that was not 0 and who had identifiable calcium at the time of follow-up. The highest initial score in these two men was 16.
For the 134 subjects with a CCS that was not 0, the mean annualized relative rate of change was 38% ± 87. The mean annualized relative rate of change in CVS was 29% ± 53. For the 45 women with a CCS that was not 0, the mean annualized relative rate of change was 60% ± 129. The mean annualized relative rate of change in CVS was 45% ± 78. For 89 men with a CCS that was not 0, the mean annualized relative rate of change was 27% ± 53. The mean annualized relative rate of change in CVS was 20% ± 32. Although there was no significant difference in the annualized rate of change in CCS between men and women (P = .10), there was a significant difference in the rate of change in CVS (P = .04).
When women younger than 60 years of age were compared with women 60 years of age or older, there was a significant difference in the initial CVS, the change in CVS, and the monthly rate of change in CVS (Table 3). A significant difference in all three parameters was also noted when men younger than 50 years of age were compared with men 50 years of age or older. Similar significant differences were noted when CCS was used to compare younger versus older adults of both sexes. When we compared the annualized rates of change for women with coronary artery calcium, there was no significant difference between the 13 women younger than 60 years old (CVS, 60% ± 115; CCS, 103% ± 213) and the 32 women 60 years and older (CVS, 39% ± 59; CCS, 42% ± 70). This was true for both CVS (P = .54) and CCS (P = .33). When we compared the annualized rates of change for men with coronary artery calcium, there was also no significant difference between the 23 men who were younger than 50 years old (CVS, 20% ± 32; CCS, 28% ± 50) and the 66 who were men 50 years and older (CVS, 20% ± 32; CCS, 26% ± 54). This was true for both CVS (P = .96) and CCS (P = .90).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSION REFERENCES |
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By using a generalized mixed linear model, the authors estimated that the annualized relative increase in CCS was 24% (95% CI: 6%, 45%). Among the 15 subjects with a baseline CCS that was not 0 and a follow-up CCS greater than 20 in this pilot study, the mean annualized relative increase in CCS, as determined by using the equation that was mentioned earlier, was 30% ± 30. This is not significantly different from that in the 114 subjects in our study with a baseline score that was not 0 and a follow-up CCS less than 20 who had a mean annualized relative increase in CCS of 35% ± 86 (P = .67). The study by Maher et al (1) was limited by the fact that only 35 subjects had calcium identified on at least one scan, and these researchers were unable to assess progression in women because only five women had calcium identified on their baseline scans.
Budoff et al (5) evaluated 299 asymptomatic subjects (227 men, 72 women) who underwent two electron-beam CT studies with a mean interscan period of 2.2 years ± 1.1. They observed a mean annualized rate of change in CCS of 33% ± 9, although the authors did not describe a method for calculating this rate of change. Assuming that the annualized rate of change was determined in a manner similar to that used in our study, these values are in accord with the 38% annualized rate of change seen in our subjects. In the study of Budoff et al (5), no significant difference in the rate of change with respect to sex or any other standard cardiac risk factors was established. Findings in our study showed that while age, sex, and most standard cardiac risk factors did not significantly affect the monthly rate of coronary artery calcium progression, hypertension and diabetes were significant covariates. However, given the relatively small numbers of subjects in both studies, the true importance of any of these risk factors cannot be determined until further studies are performed.
Most recently, Sutton-Tyrell et al (2) reported findings in a group of 80 postmenopausal women with a mean age of 63 years who underwent two electron-beam CT studies with a mean interscan period of 18 months. Only 28 (35%) subjects had identifiable coronary artery calcium on their baseline scan, and the mean interval increase in CCS was 11 for all subjects. In comparison, there were 57 women older than 60 years of age in our study, and 35 (61%) of them had coronary artery calcium at the time of their baseline study. The greater percentage of subjects with initial calcium and the longer mean study interval (25 months) likely explain why we observed a mean CCS increase of 47.
In asymptomatic or screening populations, the most important determinants of the rate of calcium progression appear to be the initial CCS and CVS rather than a specific risk factor, including sex and age. The results from these progression studies suggest that subjects without coronary artery calcium at baseline do not rapidly develop new calcium deposits. The lower rates of CVS and CCS progression observed in women as compared with those observed in men reflect the lower initial amounts of calcium present in the distribution of the epicardial arteries. Similarly, younger subjects have significantly lower rates of calcium progression than do older subjects because younger subjects initially have smaller amounts of coronary artery calcium. This study demonstrates that calcium begets calcium.
Study Limitations
Our relatively small sample size limits the evaluation of the influence of individual risk factors on calcium progression. While hypertension and diabetes were significant factors that influenced the rate of calcium progression, the lack of effect of the other risk factors may be due to the limited number of subjects. As an example, findings in a recent study (3) showed that patients with chronic renal failure have an unusually high prevalence of coronary artery calcium as well as rapid progression regardless of conventional coronary risk factors.
In conclusion, in this population of asymptomatic subjects, the initial CCS and CVS were the most important factors that affected the rate of coronary artery calcium progression. Neither age nor sex proved to be as important as these factors in the determination of coronary artery calcium progression.
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FOOTNOTES |
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Abbreviations: CCS = coronary artery calcium score, CVS = calcium volume score
Author contributions: Guarantor of integrity of entire study, H.C.Y.; study concepts and design, H.C.Y., A.M.E., J.G.G.; literature research, H.C.Y., A.M.E.; clinical studies, H.C.Y., A.M.E., J.A.H.; data acquisition, H.C.Y., A.M.E., J.A.H.; data analysis/interpretation, H.C.Y., A.M.E., D.W.G.; statistical analysis, D.W.G.; manuscript preparation, H.C.Y., A.M.E.; manuscript definition of intellectual content, H.C.Y., J.G.G.; manuscript editing, H.C.Y., A.M.E., J.G.G.; manuscript revision/review, H.C.Y., J.G.G., D.W.G.; manuscript final version approval, H.C.Y., J.G.G.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSION REFERENCES |
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