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Extent, prevalence and progression of coronary calcium in four ethnic groups
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Extent, prevalence and progression of coronary calcium in four ethnic groups
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Content
EXTENT, PREVALENCE AND PROGRESSION OF CORONARY CALCIUM
IN FOUR ETHNIC GROUPS
by
Miwa Kawakubo
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(APPLIED BIOSTATISTICS AND EPIDEMIOLOGY)
May 2003
Copyright 2003 Miwa Kawakubo
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UMI Number: 1416560
Copyright 2003 by
Kawakubo, Miwa
All rights reserved.
®
UMI
UMI Microform 1416560
Copyright 2003 by ProQuest Information and Learning Company.
All rights reserved. This microform edition is protected against
unauthorized copying under Title 17, United States Code.
ProQuest Information and Learning Company
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UNIVERSITY OF SOUTHERN CALIFORNIA
THE GRADUATE SCHOOL
UNIVERSITY PARK
LOS ANGELES, CALIFORNIA 90089-1695
This thesis, written by
r W A £ >
under the direction o f h *>r thesis committee, and
approved by all its members, has been presented to and
accepted by the Director o f Graduate and Professional
Programs, in partial fulfillm ent o f the requirements fo r the
degree o f
Director
Date May 1 6 , 2 0 0 3
Thesis Committee f j -
Chair
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ACKNOWLEDGEMENTS
First, I would like to express my gratitude to my graduate advisor Dr. Stanly
P. Azen and Dr. Robert Detrano (primal investigator) for their extensive guidance
and insight throughout the course o f this study to cultivate my foundation of
knowledge in this field. I can not thank them enough for their tremendous amount of
time and hard work. I would also like to thank my immediate colleagues Laurie
LaBree and Min Xiang for helping to improve this study with their constant advice
and problem solving. Finally, I would like to thank Dr. Nathan D. Wong, and
Terence M. Doherty, and Dr. Howard N. Hodis for their meaningful comments and
knowledge specific to coronary heart disease and coronary calcium.
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TABLE OF CONTENTS
ACKNOWLEDGEMENTS...............................................................................................ii
LIST OF TABLES............................................................................................................. iv
ABSTRACT......................................................................................................................... v
INTRODUCTION...............................................................................................................1
M ETHODS.......................................................................................................................... 2
Study Design....................................................................................................................2
Coronary Calcium Scanning..........................................................................................3
Coronary Calcium Scoring............................................................................................. 3
Risk Factor Determinations............................................................................................4
Statistical Analysis: Comparison of Ethnic G roup.....................................................4
Statistical Analysis: Evaluation of Follow-Up Bias....................................................5
RESULTS.............................................................................................................................6
Calcium Score at Baseline and Progression................................................................. 8
Evaluation o f Follow-Up B ias.....................................................................................10
Multi-variable Analysis of Risk Factors and Progression of Calcium
Score................................................................................................................................ 12
Coronary Events.............................................................................................................13
DISCUSSION.................................................................................................................... 15
REFERENCES................................................................................................................... 18
BIBLIOGRAPHY............................................................................................................. 21
iii
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LIST OF TABLES
Table 1: Baseline Comparisons between Caucasians and African-
Americans, Asians and Hispanics.................................................................... 7
Table 2: Coronary Calcium Prevalence and Score in the Four Ethnic
Groups..................................................................................................................9
Table 3. Analysis of Follow-up Bias between Complete and Partial
Participants....................................................................................................... 11
Table 4: Covariate-Adjusted Multiple Regression Analyses of Calcium
Score................................................................................................................... 12
Table 5: Comparison of the Incidence of Coronary Events between
Caucasians and African-Americans, Asians and Hispanics........................14
iv
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ABSTRACT
Between December 1990 and December 1992 in Los Angeles, California,
1289 participants without coronary heart disease underwent baseline risk factor
screening and computed tomography for coronary calcification. This is a report of
the relationship of ethnicity and coronary calcium prevalence, extent and
progression.
Compared to Caucasians, the prevalence rates of coronary calcium at baseline
and follow-up were lower in African-Americans (p<0.01). In addition, African-
Americans had lower calcium scores at baseline and follow-up (p<0.001), and
smaller increases in calcium scores (p=0.003). Compared to Caucasians at follow-
up, Hispanics had a lower prevalence rate of coronary calcium, smaller calcium
scores, and smaller increases in calcium scores (p<0.05). In contrast, there were no
differences in the incidence of coronary events between Caucasians and the other
ethnic groups.
The present results lend further credence to the notion that there are ethnic
differences in the prevalence and rate of progression o f coronary calcification.
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INTRODUCTION
Several studies have suggested that coronary artery calcification, as measured
by coronary calcium— a marker of the presence and quantity of coronary
atherosclerosis, is greater in Caucasians when compared to African-Americans. 1' 7
One study reported lower prevalence and extent of coronary calcium in African-
Americans, despite poorer coronary heart disease outcomes. 1 Another study
suggested that the difference in prevalence and extent o f coronary calcium is
Q
partially explained by differences in vitamin D metabolism. Finally, autopsy and
other studies of sub-clinical cardiovascular disease and mortality and incidence
statistics reveal other ethnic differences in atherosclerotic disease, but the results are
not consistent. 9 ' 1 6 Past research has not addressed the question as to whether ethnic
differences in the extent and prevalence o f calcification, and indeed of
atherosclerosis itself, are wholly due to later onset of these phenomena or due also to
differences in rates of progression.
The South Bay Heart Watch is a prospective cohort study designed to
appraise the value of coronary calcium and both traditional and non-traditional risk
factors for predicting cardiovascular outcomes and calcium progression in
asymptomatic adults. The objective of this report is to compare the prevalence and
amount of coronary calcium and the change in the extent of coronary calcium over a
seven-year period in four ethnic groups.
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METHODS
Study Design. The study design of the SOUTH BAY HEART WATCH has
1 7
been previously described. In brief, the cohort is comprised o f respondents to a
community-based mailing campaign of letters o f invitation to participate in a
research project. The cohort consists of 1461 asymptomatic participants >45 years
old with multiple cardiac risk factors (> 1 0 % 8 -year risk of developing coronary heart
disease by Framingham risk equation) without evidence of coronary heart disease at
the time of enrollment. Participants were initially screened and enrolled between
December 1990 and December 1992. Participants with ECG evidence of infarction
or a clinical history of infarction, revascularization or typical angina were excluded.
At the time of recruitment, participants were asked to classify their ethnicity as
Caucasian, African American, Asian American, or Hispanic.
Thirty months after enrollment, 1289 participants (cohort 1), who had not
suffered an intervening myocardial infarction or underwent revascularization
procedures, underwent a second medical and risk-factor evaluation including fasting
phlebotomy concurrent with baseline computed tomographic (CT) examinations for
coronary calcification. Approximately 8 years after the baseline examination for
coronary calcification, 828 of the Cohort 1 participants (Cohort 2) underwent a third
medical and risk-factor evaluation and follow-up CT examination for coronary
calcification. All participants gave informed consent at the time of recruitment and
again at the time of repeat risk factor assessment and CT scanning. The Harbor
2
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UCLA Research and Education Institute Human Participants Committee approved
this study.
Coronary Calcium Scanning. CT scans were performed within 2±2 days
after risk-factor evaluation using an Imatron C-100 scanner. The acquisition protocol
consisted o f 6 -mm image slices18 obtained at 80% of the electro-cardiographic RR
interval during breath-hold. In a subgroup of 286 participants who underwent both 6
mm and 3 mm scanning, we have demonstrated that the 6 mm protocol has increased
re-scan reliability and has similar predictive value. The Spearman rank correlation
coefficient between the calcium scores from the two methods was 0.94. All
participants were scanned over a bone mineral density phantom (Image Analysis,
Columbia Kentucky). During follow-up, an identical scanning protocol was used but
with a C-150 Imatron scanner.
Coronary Calcium Scoring. A single cardiologist blinded to all clinical
outcome and serologic data interpreted all scans, both baseline and follow-up. The
scoring software used was the same as that used for the Multi-Ethnic Study of
Atherosclerosis (MESA ) . 1 9 This includes a pixel adjustment which uses the formula:
new pixel value = (old pixel value - intercept)/slope, where slope and intercept refer
to the results o f a least-squares linear fit relating standard radiographic densities to
the measured mean CT numbers in the calibration phantom scanned under the
participants. The minimal calcific focus size was 4.1mm3 chosen to be equivalent to
that used in the ongoing MESA study. 1 9 The coronary calcium score was calculated
according to the method of Agatston. 2 0
3
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Risk Factor Determinations. Smoking, blood pressure measurements,
fasting lipoprotein measurements and ECGs to evaluate left ventricular hypertrophy
were obtained within two days of CT scanning both at baseline and follow-up.
91
Analysis for lipoproteins was done as previously described.
Statistical Analysis: Comparison of Ethnic Groups. Baseline
demographic and clinical characteristics for Cohort 1 were compared between
Caucasians (reference group) and each of the three ethnic groups using two-sample t-
tests or Wilcoxon rank sum tests for continuous measures and chi-square or Fisher’s
exact tests for discrete measures. Similar procedures were utilized to compare the
prevalence of coronary calcium and the coronary calcium score at baseline and
follow-up, and the change in coronary calcium (follow-up - baseline coronary
calcium score) between Caucasians and each of the three ethnic groups for
both Cohorts 1 and 2. For these analyses, calcium scores and change in calcium were
loglO transformed to induce normality. Because of the multiple pairwise
comparisons between Caucasians and three ethnic groups, the significance level was
set at 0.016 using a Bonferroni correction (two-sided).
In addition, multiple linear regression was utilized to evaluate the
independent effect of ethnicity on change in calcium score (log 1 0 transformed),
adjusting for covariates, defined to be a) standard risk factors for cardiac events, and
b) factors found to be related to change in calcium score. Preliminary analyses
demonstrated that covariates were: baseline calcium score, age, gender, current
smoker, diabetes, hypertension, body mass index, systolic blood pressure, diastolic
4
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blood pressure, and HDL-C. Because multiple pairwise comparisons were not
conducted for these analyses, the significance level was set at 0.05.
Finally, we evaluated ethnic differences in the incidence of coronary
endpoints using logistic regression analyses, adjusted for the above covariates. For
these analyses, the significance level was set at 0.016 to accommodate multiple
comparisons.
Statistical Analysis: Evaluation of Follow-up Bias. In order to evaluate
potential bias for those participants who did not return for a follow-up evaluation
(“partial participants”) with those that did (“complete participants”), we imputed the
follow-up calcium score and magnitude and direction of the change in calcium
scores for the “partial participants.” To this end, we used a standard imputation
procedure for estimating the follow-up coronary calcium score for the “partial
participants.” Namely, we developed a multiple regression model for the “complete
participants” which related the follow-up coronary calcium score (dependent
variable) to a) those demographic and clinical factors that were significantly different
between the two subgroups (found to be age, gender, HDL-C, hypertension, diabetes,
systolic blood pressure), b) the baseline calcium score, and c) ethnicity. From this
regression model, we estimated the follow-up coronary calcium score and the change
in coronary calcium (= estimated follow-up - observed baseline calcium scores) for
the “partial participants.” We then compared both the imputed coronary calcium
score and the imputed change scores in the “partial participants” with the actual
coronary calcium score and the change score (log transformed) in the “complete
5
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participants” using two sample Student t-tests. Finally, we reran the multiple linear
regression analyses for the full cohort of complete and partial participants to evaluate
the independent effect of ethnicity on change in calcium score (log transformed),
adjusting for the covariates identified above.
RESULTS
O f the 1289 subjects who underwent the baseline evaluation (Cohort 1), 1067
(83%) were Caucasian, 72 (6 %) were African-American, 76 (6 %) were Asian, and
74 (6 %) were Hispanic. Table 1 presents the distribution of demographic and risk
factors for each o f the ethnic groups. Compared to Caucasians (the reference group),
African Americans and Hispanics were younger (p<0.0002), African Americans had
a higher prevalence of hypertension (p=0.03) and elevated LDL-C (p=0.012), and
Asians and Hispanics had a higher prevalence of diabetes (p<0.01). No other
differences were found.
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Table 1: Baseline Comparisons between Caucasians and African-Americans, Asians and Hispanics (Cohort 1, n = 1289)
Risk Factor*
Caucasians
(n=1067)
African-
Americans
(n=72)
P1 ^
Asians
(n=76)
Pf
Hispanics
(n=74)
Pf
Age (yrs) 63.9 (7.6) 59.3 (8.0) <0.0001 62.3 (7.2) 0.08 60.5 (7.3) 0.0002
Gender: male 936 (88) 62 (86) 0.69 71 (93) 0.14 66 (89) 0.71
Hypertension 329(31) 31 (43) 0.03 23 (30) 0.92 30 (41) 0.07
Diabetes 194(18) 16 (22) 0.39 23 (30) 0.01 28 (39) 0.0001
Current Smoker 187(18) 10(14) 0.43 11(14) 0.49 10(14) 0.37
HDL-C (mg/dl) 45.1 (15.7) 47.0 (16.3) 0.34 45.0(15.2) 0.94 44.5(16.5) 0.73
LDL-C (mg/dl) 150.1 (36.6) 161.7(42.5) 0.012 146.4 (42.8) 0.41 144.2 (31.9) 0.19
* M ean (SD) for continuous variables; frequency (% ) for discrete variables.
f Independent Student t test or W ilcoxon rank sum test (for continuous variables); chi-square test or Fisher’s exact test (for discrete variables).
Significance level was set to 0.016 to accom m odate m ultiple pairw ise com parisons.
Calcium Score at Baseline and Progression. Table 2 presents the
distribution o f coronary calcium scores and changes in scores in the four ethnic
groups for Cohorts 1 and 2. The calcium score significantly increased over the
follow-up period within each of the four ethnic groups (p<0.0001). Compared to
Caucasians, the prevalence rates of coronary calcium (calcium score>0) were
significantly lower in African-Americans (pO.OOOl for Cohort 1 and p=0.012 for
Cohort 2 at baseline, and p=0.005 for Cohort 2 at follow-up). In addition, African-
Americans had a) lower calcium scores (p<0.0001 for Cohort 1 and p=0.005 for
Cohort 2 at baseline, and p=0.0004 for Cohort 2 at follow-up), and b) smaller
increases in calcium scores (p-0.001). The prevalence rate of coronary calcium and
calcium scores for Hispanics was lower compared to Caucasians at follow-up
(p<0.04); however, this was of marginal significance (using the Bonferroni adjusted
significance level). In addition, Hispanics had lower calcium score at follow-up
(p=0.011) and smaller increases in calcium scores (p=0.009). No differences were
found between Caucasians and Asians in prevalence, extent or progression of
coronary calcium.
8
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Table 2: Coronary Calcium Prevalence and Score in the Four Ethnic Groups^
Calcium * Caucasians
(n=1067)
African-
Americans
(n=72) Pf
Asians
(n=76) Pf
Hispanics
(n=74) Pf
Prevalence Rate
Cohort 1: Baseline (n=1289) 774/1067 (73%) 37/72 (51%) <0.001 57/76 (75%) 0.64 49/74 (66%) 0.24
Cohort 2: Baseline (n=828) 487/697 (70%) 18/36 (50%) 0.012 37/54 (69%) 0.83 24/41 (59%) 0.13
Cohort 2: Follow-up (n=828) 623/697 (89%) 26/36 (72%) 0.005 48/54 (89%) 0.91 32/41 (78%) 0.04
Cohort 2: Converter 140/210 (67%) 8/18(44%) 0.06 11/17(65%) 0.87 8/17 (47%) 0.10
Calcium Score
Cohort 1: Baseline (n=1289) 249 (459) 97 (204) <0.0001 248 (617) 0.75 238 (524) 0.19
Cohort 2: Baseline (n=828) 226 (443) 68 (150) 0.005 263(719) 0.99 115(213) 0.08
Cohort 2: Follow-up (n=828) 681 (969) 278 (438) 0.0004 787 (1462) 0.93 477 (782) 0.011
Cohort 2: Change in Calcium 455 (643)
(p<0.0001)f
210(323)
(p<0.0001)
0.001 524(817)
(p<0.0001)
0.97 362 (647)
(p<0.0001)
0.009
* Prevalence rate = number participants with calcium scores greater than 0 divided by the number of participants evaluated for calcium.
Cohort 1 is the group of participants who had calcium scores at baseline; Cohort 2 is the group of participants with calcium scores at baseline and at follow-up.
Converter = number of participants with calcium scores greater than 0 at follow-up / number of participants with calcium scores = 0 at baseline;
Calcium scores are reported as mean (SD).
t Two sample or paired Student t-tests (for continuous variables); chi-square test or Fisher’s exact test (for discrete variables).
Calcium scores and change in calcium were loglO transformed in order to induce normality. Significance level was set to 0.016 to accommodate multiple pairwise
comparisons.
Evaluation of Follow-Up Bias. From Table 2, it is apparent that the
retention rates in African-Americans and Hispanics are lower than in Caucasians and
Asians, thereby motivating the follow-up bias analysis summarized in Table 3. The
mean ± SD predicted follow-up calcium score for the 461 “partial participants” was
797±930 compared to the observed score o f 660±987 for the “complete participants”
(pO.OOOl). The predicted progression in coronary calcium for the “partial
participants” was 514±456 compared to the observed progression in coronary
calcium for the “complete participants” of 444±647 (pO.OOOl). The predicted
follow-up and progression scores were significantly higher than the observed scores
within each of the ethnic groups (p<0.002) except for Asians whose predicted
follow-up and progression scores were lower than the observed scores (pO.OOl for
both comparisons).
10
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Table 3. Analysis of Follow-up Bias between Complete and Partial Participants*
Complete
(n=828)
Partial
(n=461) Pf
Complete
(n=828)
Partial
(n=461) Pf
Follow-Up Calcium Score Change in Calcium Score
Observed Score* Predicted Score* Observed Score* Predicted Score*
Overall 660 (987) 797 (930) <0.0001 444 (647) 514(456) <0.0001
Caucasians 681 (969) 814(924) <0.0001 455 (643) 521 (450) <0.0001
African-Americans 278 (438) 419 (520) 0.002 210(323) 292 (291) 0.0002
Asians 787 (1462) 729 (449) 0.001 524 (817) 516(238) 0.0003
Hispanics 477 (782) 1075 (1391) <0.0001 362 (647) 680 (663) <0.0001
* “Complete participants” were those that returned for a follow-up CT scan (Cohort 2, n = 828);
“Partial participants” were those with only a baseline CT scan (Cohort 1 - Cohort 2, n = 461).
“Observed scores” = actual follow-up and progression scores for “complete participants”.
“Predicted follow-up scores” for “partial participants” estimated from the multiple regression equation generated for “Complete participants”, based on a) age +
gender + HDL-C + hypertension + diabetes + systolic blood pressure + b) baseline calcium score + c) ethnicity.
“Predicted progression score” for “partial participants” = predicted follow-up score - observed baseline score.
1 Two sample Student t-tests. Calcium scores and change in calcium were loglO transformed in order to induce normality. Significance level was set at 0.05.
Multi-variable Analysis of risk factors and Progression of Calcium
Scores. Table 4 summarizes the results of the multiple linear regression analysis
evaluating the relationship of ethnicity to change in calcium after adjusting for
significant inter-ethnicity risk-factor covariates. For Cohort 2, significant covariates
were found to be age, diabetes, body mass index, and baseline calcium score (all
p<0.03, data not shown in table). For the “full” cohort (i.e., Cohort 2 + the imputed
values for the “partial” participants), HDL-C was found to be an additional
independent covariate (p=0.01). As seen in Table 4, for both Cohort 2 and the full
cohort, African-Americans and Hispanics had significantly less calcium score
progression compared to Caucasians, after risk-factor adjustment (p<0.04 for Cohort
2, p<0.0003 for the full cohort).
Table 4: Covariate-Adjusted Multiple Regression Analyses of Calcium Score
Increase in African-Americans, Asians and Hispanics Compared to Caucasians
Ethnicity
Cohort 2 (n = 828)f
Parameter Estimate/p value*
Full Cohort (n=1289)f
Parameter Estimate/p value*
African-American -0.23/p=0.04 -0.23/p=0.0003
Asian -0.01/p=0.95 -0.02/p=0.73
Hispanics -0.22/p=0.03 -0.23/p=0.0003
* Dependent variable was log 10 of change in Ca score. Analyses for each covariate utilized univariate
regression analyses. Analyses by ethnicity relative to Caucasians (reference group) utilized multiple
regression analysis, adjusting for covariates: baseline calcium scores, age, diabetes, HDL-C, hypertension,
current smoking status, systolic BP, diastolic BP, gender (male), and body mass index. Significance level
was set at 0.05.
+ Cohort 2 is the group of participants with calcium scores at baseline and at follow- up.
Full cohort = Cohort 2 plus imputed calcium scores for Cohort 1 participants who did not return for follow-
up (see text).
12
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Coronary Event. Table 5 presents the incidence of coronary events during
85+4.5 months o f follow-up. Though the relative risk of revascularization was
marginally higher in African-Americans and Hispanics (p<0.10), no significant
differences in the incidence of coronary events was found among the four ethnic
groups.
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Table 5: Comparison of the Incidence of Coronary Events between Caucasians and African-Americans, Asians and
Hispanics
Event
Caucasians
(n=1067)
African-
Americans
(n=72)
RR*
(95% Cl)
Asians
(n=76)
RR*
(95% Cl)
Hispanics
(n=74)
RR*
(95% Cl)
New-onset angina 214(20.1) 21 (29.2) 0.67
(0.40-1.19)
16(21.1) 0.97
(0.54-1.77)
15(20.3) 0.10
(0.60-2.02)
MI (fatal or nonfatal) 67 ( 6.3) 7 ( 9.7) 0.54
(0.23-1.27)
5 ( 6.6) 1.01
(0.39-2.65)
4 ( 5.4) 1.70
(0.51-5.70)
CHD death 26 ( 2.4) 1 ( 1.4) 1.83
(0.23-14.67)
2 ( 2.6) 1.08
(0.23-5.01)
3 ( 4.1) 0.78
(0.21-2.96)
Revascularization 103 (9.7) 3 ( 4.2) 2.82*
(0.86-9.26)
5 ( 6.6) 1.49
(0.58-3.83)
4 ( 5.4) 2.96*
(0.90-9.78)
Total deaths 92 (8.6) 5 ( 6.9) 1.06
(0.40-2.79)
5 ( 6.6) 1.37
(0.52-3.59)
7 ( 9.5) 1.07
(0.43-2.64)
CHD death or MI 85 (8.0) 7 ( 9.7) 0.73
(0.31-1.69)
6 ( 7.9) 1.12
(0.46-2.74)
7 ( 9.5) 1.14
(0.46-2.82)
CHD death, MI, or
angina
274 (25.7) 24 (33.3) 0.72
(0.43-1.22)
21 (27.6) 0.98
(0.57-1.68)
20 (27.0) 1.15
(0.65-2.01)
CHD death, MI, angina
or Revascularization
298 (27.9) 24 (33.3) 0.84
(0.50-1.42)
21 (27.6) 1.09
(0.64-1.88)
21 (28.4) 1.22
(0.70-2.12)
* Relative risks and 95% confidence intervals from logistic regression evaluating event risk for each ethnic group relative to Caucasians, adjusting for covariates
(baseline calcium scores, age, diabetes, HDL-C, hypertension, current smoking status, systolic BP, diastolic BP, gender (male), and body mass index (see Table 4).
* P-value were marginally significant for African-Americans (p=0.09) and for Hispanics (p=0.07) when compared to Caucasians.
4 ^
DISCUSSION
Autopsy studies, done mostly in white populations, have shown that coronary
calcium and atherosclerosis are strongly correlated. 2 2 Clinical studies have
demonstrated less prevalent and less extensive coronary calcium in African-
Americans compared to Caucasians. 1 ' 6 In addition to further substantiating these
data, here we report that African-Americans have less progression of coronary
calcium during the 85 ± 4.5 months o f follow-up compared to Caucasians, although
many epidemiological study have shown that African-Americans are more likely to
suffer from CHD events. In this study, we evaluated ethnic differences in incidence
of coronary events. As reported in Tables 5, we did not find elevated coronary heart
disease incidence in African-Americans. Our data thus clearly demonstrate that
African-Americans have both a lesser prevalence and a slower rate o f progression of
coronary calcium, but nevertheless suffer similar numbers of subsequent coronary
events. We also similar but less pronounced findings regarding calcium progression
in Hispanics when compared to Caucasians.
Our study is limited in that there were few women in our cohort, so that these
findings may not apply to the female population. Also, since a large percentage of
our cohort did not return for follow-up scans, we were concerned that follow-up bias
might have affected our results. Therefore, we assessed the extent of follow-up bias
in our analysis o f ethnic differences in calcium progression. Participants who did not
return tended to be older, hypertensive, diabetic and to have higher systolic blood
pressure and HDL-C, implying that participants who did not return for a follow-up
15
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evaluation tended to have higher risk factors than those participants that did return.
To examine the impact of follow-up bias, we estimated calcium progression for those
who did not return, taking into account demographic and risk factors that distinguish
between returnee and non-returnee. We found a stronger inverse effect of
progression in African-American and Hispanics when compared to Caucasians
(p<0.0003), but not in Asians. This would support the robustness of our regression
analysis with “partial participants” (Table 4, cohort 2). While it is possible that
individuals not returning for follow-up in certain ethnic groups (e.g., African-
Americans) might be different (e.g., worse risk factor profile) than those not
returning among other ethnic groups, the comparability of the magnitude of the
regression coefficients observed between the partial model and the full imputed
model suggests that there was little impact o f follow-up bias on the relation of
ethnicity and risk factors to progression of coronary calcium. Therefore, the
relationships found relating ethnicity to progression of atherosclerosis in those who
did return for the follow-up examination were what would have been expected had
there been full participation at the follow-up examination.
The present results agree with and extend those of our previous reports1 ,2 ,8
and lend further credence to the notion that there are ethnic differences in the
prevalence and rate o f progression of coronary calcification, and that these
differences have clinical implications regarding the application o f coronary calcium
scanning as a risk predictor. From a pathobiologic perspective, the reasons for our
findings are not immediately apparent. Atherosclerosis is a chronic, fibroproliferative
16
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arterial inflammation that begins quite early, progresses nonlinearly and sporadically,
and may have long dormant periods. 2 3 ,2 4 Although the validity of indirect risk factor
correlates to both progression of atherosclerosis and its eventual clinical
manifestations is established, ’ the direct molecular and genetic mechanisms
governing how, where, and at what rate plaque development occurs are not well
understood. Furthermore, it is not clear how structural components o f plaque such as
calcium deposits are determined, how they are altered, and why these processes
might differ among individual plaques and among diverse ethnic groups. Our results
appear consistent with the suggestion that there might be ethnic differences in one or
more of these mechanisms. O f potential relevance, we previously reported that serum
levels of l a ,25 dihidroxyvitamin D 3 were independently and inversely related to the
prevalence o f coronary calcium 8 ,2 7 and that African-Americans had significantly
higher serum levels of this steroid. 8 However, the ethnic differences observed could
not fully account for the variability in coronary calcium quantity. It is conceivable
that ethnic variability in endocrine and/or other mechanisms involved in calcium
homeostasis and bone metabolism might have influenced our results, but evaluation
of these possibilities will require further investigation.
17
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REFERENCES
1. Doherty T, Tang W, Detrano R. Racial differences in the significance of coronary
calcium in asymptomatic black and white subjects with coronary risk factors.
JACC 1999; 34: 258-262.
2. Tang W, Detrano R, Brezden O, Georgiou D, French W, Wong N, et al. Racial
differences in coronary calcium prevalence among high-risk adults. Am J Cardiol
1995;75:1088-1091.
3. Budoff MJ, Yang TP, Shavelle RM, Lamong DH, Brundage BH. Ethnic
differences in coronary atherosclerosis. JACC 2002; 39:408-12.
4. Newman AB, Naydeck BL, Whittle J, Sutton-Tyrrell K, Edmundowicz D, Kuller
LH. Racial differences in coronary artery calcification in older adults.
Arterioscler Thromb Vase Biol 2002;22:242-430.
5. Loria CM, Detrano R, Liu K, Lewis C, Sidney S, Schreiner P, Williams D,
Hulley S, Bild D. Sex and Race Differences in Prevalence and Predictors of
Early Coronary Calcification: the CARDIA Study. Circulation 2003 (in press)
6 . Lee TC, O'Malley PG, FeuersteinI, Taylor AJ. he Prevalence and Severity of
Coronary Artery Calcification on Coronary Artery Computed Tomography in
Black and White Subjects (in press)
7. Khurana, C, Rosenbaum CG, Howard BV, Adams-Campbell LL, Detrano RC,
K louj,A, H siaJ. Coronary Artery Calcification in African-American and White
Women Am Heart J (in press)
8 . Doherty T, Tang W, Dascalos S, Watson KE, Demer LL, Shavelle RM, et al.
Ethnic origin and serum levels of la ,25-hydroxymvitamin D 3 are independent
predictors of coronary calcium mass measured by electron-beam computed
tomography. Circulation 1997; 96:1477-1481.
9. National Heart L, and Blood Institute. Morbidity and Mortality: 2000 Chartbook
on Cardiovascular, Lung, and Blood Diseases. U.S. Department o f Health and
Human Services, Public Health Service, 2000.
10. Gillum RF, Mussolino ME, Madans JH. Coronary heart disease incidence and
survival in African-American women and men. Ann Intern Med 1997;
127:111-118.
18
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
11. Strong JP, Malcom GT, McMahan CA, Tracy RE, Newman WP, 3d, Herderick
EE, et al. Prevalence and extent of atherosclerosis in adolescents and young
adults: implications for prevention from the Pathobiological Determinants of
Atherosclerosis in Youth Study. JAMA 1999; 281:727-735.
12. Freedman DS, Newman WP, 3d, Tracy RE, Voors AE, Srinivasan SR, Webber
LS, et al. Black-white differences in aortic fatty streaks in adolescence and early
adulthood: the Bogalusa Heart Study. Circulation 1988; 77:856-864.
13. Howard G, Sharrett AR, Heiss G, Evans GW, Chambless LE, Riley WA, et al.
Carotid artery intimal-medial thickness distribution in general populations as
evaluated by B-mode ultrasound. Stroke 1993; 24:1297-1304.
14. Manolio TA, Burke G.L. Black-white differences in subclinical cardiovascular
disease among older adults: the Cardiovascular Health Study. CHS Collaborative
Research Group. J Clin Epidemiol 1995; 48:1141-1152.
15. Sacco RL, Roberts JK, Boden-Albala B, Gu Q, Lin IF, Kargman DE, et al.
Race-ethnicity and determinants of carotid atherosclerosis in a multiethnic
population. The Northern Manhattan Stroke Study. Stroke 1997; 28:929-935.
16. Tintut Y, Demer LL. Recent advances in multifactorial regulation of vascular
calcification. Curr Opinion Lipidology 2001;12:555-560.
17. Detrano R, Wong ND, Doherty T, Shavelle R, Tang W, Ginzton L, Budoff M,
Narahara K. Coronary calcium does not accurately predict near-term future
coronary events in high risk adults. Circ 99: 2633-8.(1999).
18. Wang S, Detrano RC, Secci A, et al. Detection coronary calcification with
electron beam computed tomography: evaluation of inter-examination
reproducibility and comparison of three image acquisition protocols. Am Heart J.
1996;132:550-558.)
19. Multi-ethnic Study of Atherosclerosis. NHLBI http://140.142.220.3/mesa/
20. Agatston AS, Janowitz WR, Hildner FJ, Zusmer N, Viamonte M, Detrano RC.
Quantification of coronary artery calcium using ultrafast computed tomography.
JAm Coll Cardiol. 1990;15:827-832.
21. Secci A, Wong N, Tang W, Wang S, Doherty T, Detrano R. Electron Beam
Computed Tomography (EBCT) Coronary Calcium as a Predictor o f Coronary
Events(Comparison o f Two Protocols). Circulation. 1997; 96 (4) 1122-1129)
19
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
22. Sangiorgi G, Rumberger JA, Severson A, Edwards WD, Gregoire J, Fitzpatrick
LA, Schwartz RS. Arterial calcification and not lumen stenosis is highly
correlated with atherosclerotic plaque burden in humans: A histologic study of
723 coronary artery segments using nondecalcifying methodology. J Am Coll
Cardiol. 1998;31:126-133.
23. Lusis AJ. Atherosclerosis. Nature. 2000;407:233-41.
24. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868-74.
25. Kannel WB. Epidemiologic contributions to preventive cardiology and
challenges for the twenty-first century. In: Wong ND, Black HR, and Gardin JM
(eds.), Preventive Cardiology. McGraw-Hill, New York, NY;2000:pp. 3-20.
26. Gordon T, Kannel WB. Premature mortality from coronary heart disease: the
Framingham Study. JAMA. 1971;215:1617-1625.
27. Watson KE, Abrolat ML, Malone LL, Hoeg JM, Doherty TM, Detrano RC,
Demer, LL. Active serum vitamin D levels are inversely correlated with
coronary calcification. Circulation. 1997;96:1755-1760
20
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
BIBLIOGRAPHY
Agatston AS, Janowitz WR, Hildner FJ, Zusmer N, Viamonte M, Detrano RC.
Quantification of coronary artery calcium using ultrafast computed tomography.
JAm Coll Cardiol. 1990;15:827-832.
Budoff MJ, Yang TP, Shavelle RM, Lamong DH, Brundage BH. Ethnic differences
in coronary atherosclerosis. JACC 2002; 39:408-12.
Detrano R, Wong ND, Doherty T, Shavelle R, Tang W, Ginzton L, Budoff M,
Narahara K. Coronary calcium does not accurately predict near-term future
coronary events in high risk adults. Circ 99: 2633-8. (1999).
Doherty T, Tang W, Dascalos S, Watson KE, Demer LL, Shavelle RM, et al. Ethnic
origin and serum levels of la,25-hydroxymvitamin D 3 are independent predictors of
coronary calcium mass measured by electron-beam computed tomography.
Circulation 1997; 96:1477-1481.
Doherty T, Tang W, Detrano R. Racial differences in the significance o f coronary
calcium in asymptomatic black and white subjects with coronary risk factors.
JACC 1999; 34: 258-262.
Freedman DS, Newman WP, 3d, Tracy RE, Voors AE, Srinivasan SR, Webber LS,
et al. Black-white differences in aortic fatty streaks in adolescence and early
adulthood: the Bogalusa Heart Study. Circulation 1988; 77:856-864.
Gillum RF, Mussolino ME, Madans JH. Coronary heart disease incidence and
survival in African-American women and men. Ann Intern Med 1997; 127:111-118.
Gordon T, Kannel WB. Premature mortality from coronary heart disease: the
Framingham Study. JAMA. 1971;215:1617-1625.
Howard G, Sharrett AR, Heiss G, Evans GW, Chambless LE, Riley WA, et al.
Carotid artery intimal-medial thickness distribution in general populations as
evaluated by B-mode ultrasound. Stroke 1993; 24:1297-1304.
Kannel WB. Epidemiologic contributions to preventive cardiology and
challenges for the twenty-first century. In: Wong ND, Black HR, and Gardin JM
(eds.), Preventive Cardiology. McGraw-Hill, New York, NY;2000:pp. 3-20.
Khurana, C, Rosenbaum CG, Howard BV, Adams-Campbell LL, Detrano RC,
Klouj, A, Hsia J. Coronary Artery Calcification in African-American and White
Women Am Heart J (in press)
21
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Lee TC, O'Malley PG, Feuerstein I, Taylor AJ. he Prevalence and Severity of
Coronary Artery Calcification on Coronary Artery Computed Tomography in
Black and White Subjects (in press)
Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868-74.
Loria CM, Detrano R, Liu K, Lewis C, Sidney S, Schreiner P, Williams D, Hulley S,
Bild D. Sex and Race Differences in Prevalence and Predictors of Early Coronary
Calcification: the CARDIA Study. Circulation 2003 (in press)
Lusis AJ. Atherosclerosis. Nature. 2000;407:233-41.
National Heart L, and Blood Institute. Morbidity and Mortality: 2000 Chartbook on
Cardiovascular, Lung, and Blood Diseases. U.S. Department o f Health and
Human Services, Public Health Service, 2000.
Newman AB, Naydeck BL, Whittle J, Sutton-Tyrrell K, Edmundowicz D, Kuller
LH. Racial differences in coronary artery calcification in older adults. Arterioscler
Thromb Vase Biol 2002;22:242-430.
Manolio TA, Burke G.L. Black-white differences in subclinical cardiovascular
disease among older adults: the Cardiovascular Health Study. CHS Collaborative
Research Group. J Clin Epidemiol 1995; 48:1141-1152.
Multi-ethnic Study of Atherosclerosis. NHLBI httn://140.142.220.3/mesa/
Sacco RL, Roberts JK, Boden-Albala B, Gu Q, Lin IF, Kargman DE, et al.
Race-ethnicity and determinants of carotid atherosclerosis in a multiethnic
population. The Northern Manhattan Stroke Study. Stroke 1997; 28:929-935.
Sangiorgi G, Rumberger JA, Severson A, Edwards WD, Gregoire J, Fitzpatrick LA,
Schwartz RS. Arterial calcification and not lumen stenosis is highly correlated with
atherosclerotic plaque burden in humans: A histologic study of 723 coronary artery
segments using nondecalcifying methodology. JA m Coll Cardiol. 1998;31:126-133.
Secci A, Wong N, Tang W, Wang S, Doherty T, Detrano R. Electron Beam
Computed Tomography (EBCT) Coronary Calcium as a Predictor o f Coronary
Events(Comparison o f Two Protocols). Circulation. 1997; 96 (4) 1122-1129)
Strong JP, Malcom GT, McMahan CA, Tracy RE, Newman WP, 3d, Herderick EE,
et al. Prevalence and extent o f atherosclerosis in adolescents and young adults:
implications for prevention from the Pathobiological Determinants of
Atherosclerosis in Youth Study. JAMA 1999; 281:727-735.
22
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Tang W, Detrano R, Brezden O, Georgiou D, French W, Wong N, et al. Racial
differences in coronary calcium prevalence among high-risk adults. Am J Cardiol
1995; 75:1088-1091.
Tintut Y, Demer LL. Recent advances in multifactorial regulation o f vascular
calcification. Curr Opinion Lipidology 2001;12:555-560.
Wang S, Detrano RC, Secci A, et al. Detection coronary calcification with electron
beam computed tomography: evaluation of inter-examination reproducibility and
comparison o f three image acquisition protocols. Am Heart J. 1996;132:550-558.)
Watson KE, Abrolat ML, Malone LL, Hoeg JM, Doherty TM, Detrano RC,
Demer, LL. Active serum vitamin D levels are inversely correlated with
coronary calcification. Circulation. 1997;96:1755-1760
23
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
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Creator
Kawakubo, Miwa
(author)
Core Title
Extent, prevalence and progression of coronary calcium in four ethnic groups
School
Graduate School
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Master of Science
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Applied Biostatistics and Epidemiology
Publisher
University of Southern California
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biology, biostatistics,health sciences, medicine and surgery,OAI-PMH Harvest
Language
English
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Azen, Stanley (
committee chair
), [illegible] (
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